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Alzheimer’s Facts and Figures Report | Alzheimer’s Association

Posted: July 19, 2021 at 1:54 am

Quick Facts










The number of Americans living with Alzheimer's is growing and growing fast. More than 6 million Americans of all ages have Alzheimer's.

An estimated 6.2 million Americans age 65 and older are living with Alzheimer's dementia in 2021. Seventy-two percent are age 75 or older.

As the number of older Americans grows rapidly, so too will the number of new and existing cases of Alzheimer's. By 2050, the number of people age 65 and older with Alzheimers dementia may grow to a projected 12.7 million, barring the development of medical breakthroughs to prevent, slow or cure Alzheimers disease.

Alzheimers is not just memory loss. Alzheimers kills.

People age 65 and older survive an average of four to eight years after a diagnosis of Alzheimers dementia, yet some live as long as 20 years with Alzheimers. This reflects the slow, uncertain progression of the disease.

Eighty-three percent of the help provided to older adults in the United States comes from family members, friends or other unpaid caregivers. Nearly half of all caregivers who provide help to older adults do so for someone living with Alzheimer's or another dementia.

Who are the caregivers?

Of the total lifetime cost of caring for someone with dementia, 70% is borne by families either through out-of-pocket health and long-term care expenses or from the value of unpaid care.

The costs of health care and long-term care for individuals living with Alzheimers or other dementias are substantial, and dementia is one of the costliest conditions to society.

In 2021, Alzheimer's and other dementias will cost the nation $355 billion, including $239 billion in Medicare and Medicaid payments combined. Unless a treatment to slow, stop or prevent the disease is developed, in 2050, Alzheimer's is projected to cost more than $1.1 trillion (in 2021 dollars). This dramatic rise includes more than three-fold increases both in government spending under Medicare and Medicaid and in out-of-pocket spending.

Despite decades of research and calls to action to ensure that health care is accessible and equal for all regardless of gender, race, ethnicity, geography and socioeconomic status, that aim is still far from reality for too many Americans, as the Alzheimers Association Race, Ethnicity and Alzheimers in America special report shows:

These findings suggest there is a lot of work ahead to achieve better health equity. Paths forward include:

The 2021 Alzheimer's Disease Facts and Figures report contains data on the impact of this disease in every state across the nation. Click below to see the effect that Alzheimer's is having in your state.

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Alzheimer's Facts and Figures Report | Alzheimer's Association

Alzheimer’s Disease Symptoms – Psych Central

Posted: at 1:54 am

Alzheimers disease is a neurocognitive disorder (either major or minor, depending upon its severity) that has a subtle onset and is characterized by a gradual progression in cognitive impairment.

The specific symptoms of Alzheimers disease are:

1. The criteria are met for either major neurocognitive disorder or minor neurocognitive disorder.

2. There is subtle onset and gradual progression of impairment in one or more cognitive domains (for major neurocognitive disorder, at least two domains must be impaired).

3. The following criteria are also met.

For major neurocognitive disorder

For minor neurocognitive disorder

The cognitive deficits each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning. The course is characterized by gradual onset and continuing cognitive decline. The deficits do not occur exclusively during the course of a delirium.

The cognitive deficits above are not due to any of the following:

Updated for the DSM-5.

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Alzheimer's Disease Symptoms - Psych Central

Alzheimer’s Disease Research Center (ADRC), University of …

Posted: at 1:54 am

The UW Alzheimers Disease Research Center (ADRC) is one of a nationwide network of 30 research resource centers funded by the National Institute on Aging. ADRCs are major sources of discovery into the nature of Alzheimers disease and related dementias and into the development of more effective approaches to prevention, diagnosis, care, and therapy. The UW ADRC contributes to the development of shared resources that support dementia-relevant research, and coordinates research efforts with other NIH-funded programs and investigators. UW ADRC resources are designed to facilitate and empower related research efforts at UW.

The UW ADRC is closely affiliated with the UW Memory and Brain Wellness Center clinic and links the Seattle community with information and opportunities to participate in studies of Alzheimers disease and related disorders (Lewy Body dementia, and frontotemporal degeneration, and vascular dementia). Our busy outreach team is influential in promoting strengths-based reframing of Alzheimers disease and dementia-friendly communities, and they organize and promote educational public talks and events and research seminars. We support outreach and culturally adapted Alzheimers disease programs for Indigenous communities and clinics. Join us!

Director: Dr. Thomas J. Grabowski, MDProgram Manager: Annika Noreen, PhD, PMP

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Alzheimer's Disease Research Center (ADRC), University of ...

CMS to Conduct NCD Analysis on Treatment for Alzheimer’s Disease – RCPA

Posted: at 1:54 am

Today, the Centers for Medicare and Medicaid Services (CMS) announced they will be opening a National Coverage Determination (NCD) analysis on the treatment for Alzheimers disease. This NCD process will allow CMS to carefully review and determine whether Medicare will establish a national Medicare coverage policy for monoclonal antibodies targeting amyloid for the treatment of Alzheimers disease. NCDs are program instructions developed by CMS to describe the nationwide conditions for Medicare coverage for a specific item or service. This NCD analysis will be applicable to national coverage considerations for aducanumab, which was recently approved by the Food and Drug Administration (FDA), as well as any future monoclonal antibodies that target amyloid for the treatment of Alzheimers disease.

Currently, coverage determinations for aducanumab are being made at the local level by Medicare Administrative Contractors (MACs) who represent 12 jurisdictions across the country. CMSs coverage decisions are based on careful analysis of the evidence and benefits a given therapy provides to Medicare beneficiaries. To determine whether a national policy is appropriate, CMS will follow a standard process that includes multiple opportunities for the public to participate and present comments through both listening sessions and the CMS Coverage website. The analysis will determine whether the evidence meets the Medicare laws requirements that items or services be reasonable and necessary for the diagnosis or treatment of illness or injury. To make this determination, CMS uses a formal process established by statute. The process includes an assessment of the clinical evidence such as published clinical studies, professional society guidelines, and public comments to determine coverage.

Following this analysis, CMS will post a proposed NCD, which will be open to a second 30-day public comment period. After reviewing all comments received on a proposed determination, CMS will announce its final decision for a national policy which could range from Medicare coverage of this product type, coverage with evidence development, non-coverage, or deference to the Medicare Administrative Contractors. A proposed decision is expected to be posted within 6 months and a final within 9 months.

As part of the NCD process, a 30-day public comment period will begin today. CMS will also host two public listening sessions in July to provide an opportunity for public input.

To register for the listening sessions:July 22, 2021 from 9:00 am11:00 am (EDT) orJuly 27, 2021 from 2:00 pm4:00 pm (EDT)

NCDs are posted on the CMS Medicare Coverage Center website and provide stakeholders with the Medicare coverage criteria, a summary of the evidence considered, and CMSs rationale for the decision. Comments can be submitted and viewed here.

Excerpt from:
CMS to Conduct NCD Analysis on Treatment for Alzheimer's Disease - RCPA

New book offers valuable insight for caregivers of those with Alzheimer’s disease – Albany Times Union

Posted: at 1:54 am

Fifteen years ago, when the doctor informed Maryanne Scott that her father, Sam Valenti, was suffering from the early stages of Alzheimers disease, she was unclear what that meant.

Today theres a lot of news about Alzheimers, but it wasnt like that 15 years ago, said Scott from her home in Doylestown, Pa. After the doctor said that, I asked what this meant. I wanted to know how we could cure it, but he informed me there was no cure and that it was a progressive degenerative disease.

Alzheimers would ultimately take her and her younger brother Sam on an eight-year journey of caring for their beloved dad. It also led to her first book, An Eight Year Goodbye: A Memoir.

As she writes in her book, There are over five million Americans living with Alzheimers disease today and over sixteen million caregivers riding this emotional roller coaster. These caregivers are also saying goodbye to their loved ones, a long, painful goodbye. Ive been in those shoes.

Scott, who lived in Clifton Park 2o years ago before moving to Doylestown, wrote the book as a form of therapy. She never intended to publish it.

"After my dad died I began seeing a counselor who told me to write down all my feelings of guilt. I wondered if I had done enough for him, she said.

Her counselor said Scott was suffering post-traumatic stress disorder. She said for eight years I had been focusing on a battle with Alzheimers. I had never had any time to focus on much of anything else, and after it was over everything came crashing down. So I wrote down all my feelings, the anger and the guilt. It felt good to get that all out of me.

The more Scottwrote, the more she began to think her words might be helpful for someone else going through the trauma she and her brother had experienced.

I had nowhere to turn 15 years ago when my dad was first diagnosed. There were books about the symptoms of the disease, but I needed someone to tell me it was normal to feel impatience, despair and loneliness when caring for someone like my dad. Its a lonely battle to be a caregiver, and I hope this book can help others going through this.

She wrote the book in sections, rather than in chronological order. It took me a long time to write this book because I was reliving these painful events. I would often start crying and have to put the writing away only to return to it a month or so later. Sometimes Id write about some lighter moments that happened, just so the book wouldnt be as depressing like the time near the end when dad was not very responsive and I wanted to play a beautiful song that he used to play for me when I was 12 years old. It was the song he played when he taught me how to dance, but inadvertently the song Im on the Highway to Hell by AC/DC came out of the speaker. As my brother would often say, If we dont laugh, well cry.

Scott wrote the book to help other caregivers going through this, and to pay tribute to her dad.

He was such an honorable man, she said. He served his country in World War II, loved his family with all his heart, worked hard to support his family, and even at the end he never lost his sense of humor, his dignity or his kindhearted nature.

Her book contains valuable information for caregivers on navigating ones way through Alzheimers from its early stages to the final stages when those with the disease are often incontinent, unable to talk or even swallow.

Early on, families need to get some sort of in-home care. You cannot possibly do this on your own. There may also be days when you need to take a break and regroup. My brother and I were so lucky to have each other.

Scott's advice for a family considering an assisted-care facility is to be a squeaky wheel. When dad could no longer stay in his home we found a place for him, and Im not so sure they liked me because I visited almost every day and expected a certain level of care for my dad. Some families drop off the aging parent and never visit. My brother and I made sure he had the best care possible, received his newspaper every day, had clean sheets in his bed and was treated with respect.

Being with her dad in the last days of his life enriched Scott's spiritual faith. There was a certain peace that came over him in his last days. He was mostly unresponsive, but we could hear him talking to his brother Joe, who had died years ago. He was asking Joe what it was like up there. Once he wanted to know what was on my shoulder. It was like there was an angel there, and when I told him it was OK for him to go, that he could see Mom again, he smiled, and I felt like somebody was there taking him. The room itself just felt so calm.

One of the many things she learned from writing this book is that she is much stronger than she ever thought. There were times when I didnt know how much longer I could sustain this. During that eight-year period, my husband had a spinal cord injury, I had two teenagers at home, my son was going off to college, and I didnt know where to turn for support. My brother and I look back now and dont know how we did it, but we got the strength from somewhere. I guess when a loved one is suffering, you somehow rise to the challenge to care for them.

"An Eight Year Goodbye: A Memoir" (Page Publishing, $16.95) can be found online and at The Book House in Stuyvesant Plaza, I Love Books in Delmar, Northshire Bookstore in Saratoga Springs and Barnes & Noble in Colonie.

See more here:
New book offers valuable insight for caregivers of those with Alzheimer's disease - Albany Times Union

Therapy and prevention of Alzheimer’s disease | NDT – Dove Medical Press

Posted: at 1:54 am


Amyloid- (A) in the brain is a causative protein of Alzheimers disease (AD). Harmful proteins primarily include 40 amino-acid A140, 42 amino-acid A142, and abnormally phosphorylated tau.1 Impaired A clearance from the brain might increase brain A, particularly in sporadic AD cases. A clearance from the brains of patients with sporadic AD was 30% lower than the clearance in normal subjects, although A production was similar.2 The peripheral administration of anti-A antibodies to increase the clearance of As from the brain has been investigated. Unfortunately, most clinical trials using anti-A antibodies did not meet the endpoint criteria, although brain As were reduced. However, a recent re-analysis of the clinical results for Aducanumab, an anti-A antibody, revealed reduced cognitive decline at the high dose,3 resulting in the accelerated approval of an Alzheimers drug by the FDA on June 7, 2021. Furthermore, Gantenerumab, an anti-A antibody used in the dominantly inherited Alzheimers network trial unit (DIAN-TU), reduced As and tau in the brain.4,5 Therefore, A may be the primary causative protein for AD.4

We proposed extracorporeal blood A removal systems (E-BARS) as another method for enhancing A clearance from the brain (Figure 1).6 There are several rationales for blood A removal systems. First, there is an A concentration gradient between the brain and blood. A concentration in the cerebrospinal fluid (CSF) of patients with AD is approximately 100 times higher than in the plasma.7,8 Second, A moves from the brain into the blood via transporters, including low-density lipoprotein receptor-related protein 1 (LRP-1), ApoJ, ApoE, and receptor for advanced glycation end products (RAGE).911 Pharmaceuticals targeting RAGE and LRP-1 are being developed to increase A transportation.12

Figure 1 Schematic diagram of the extracorporeal blood A removal systems (E-BARS) using HexDC or the PSf dialyzer. Postulated mechanisms for the E-BARS include: 1) HexDC and/or PSf hemodialyzer remove blood As in an extracorporeal circulation system, 2) rapid decrease in plasma As, and 3) it triggers increased A influx from the brain into the blood, resulting in retention or improvements of Alzheimers disease.

We have reported the following evidence to support the efficacy of blood A removal for AD therapy and prevention. First, we found several medical materials of high efficacy for A removal from the blood, including hexadecyl alkylated cellulose beads (HexDC)6,13 and hollow fibers in hemodialyzers, such as polysulfone (PSf), polymethylmethacrylate, and polyethersulfone.14 The A removal efficiency of PSf dialyzers was as high as 50% for both A140 and A142 during a 4 h hemodialysis session.15,16 The mechanism of blood A removal by these hemodialyzers is mainly by adsorption.14,17 Second, the removal of blood A evoked a large influx of A into the blood from certain tissues during hemodialysis.15,16,18,19 Third, we showed that A accumulation in the brains of patients undergoing hemodialysis was significantly lower than A accumulation in age-matched controls not undergoing hemodialysis.20 Furthermore, we reported more direct evidence showing that hemodialysis decreased A accumulation in the brain by positron emission tomography (PET)-imaging with Pittsburgh compound B (PiB) as a probe (PiB/PET).21 The brain A accumulation in a chronic renal failure patient suffering from mild cognitive impairment was decreased by 0.19 standard uptake value ratio (SUVR) after hemodialysis for 6 months (4 h/session, three sessions/week). The data suggest that the brain is an origin of A influx into the blood during hemodialysis. Fourth, A concentration in the CSF was decreased in rat studies using HexDC columns. Plasma A concentrations increased during blood A removal, despite the 90% efficiency of A removal using HexDC columns.22 Finally, the mini-mental state examination scores of hemodialysis patients were maintained or slightly improved in a prospective study.18 We also reported that longer hemodialysis duration correlated with lower dementia risk in an analysis of more than 200,000 Japanese hemodialysis patients.23 Furthermore, we recently reported that A oligomers were effectively removed by size-separation methods with hollow fiber devices of appropriately large pore sizes in vitro and in humans.24

Several other groups also reported that removing blood As may be a helpful AD therapy. Peritoneal dialysis, in which peritoneal membranes are used as dialysis membranes instead of hemodialyzers, reduced plasma A in humans and brain A in mouse AD models.25 The authors reported that peritoneal dialysis only removed 131.33 ng of As,25 whereas hemodialysis removed 7219 ng of A140 and 664 ng of A142, totaling 7883 ng of As as we reported previously.19 Furthermore, plasma exchange therapy, which removes plasma A by discarding the plasma with albumin replacement as A binding protein, effectively improves cognitive functions in patients with AD.26 This therapeutic plasma exchange discarded all plasma proteins, including coagulation factors and immunoglobulins. Therefore, intravenous immunoglobulin was injected every 4 months.

Thus, the removal of blood A has attracted attention as a therapeutic strategy for AD.27

Furthermore, regarding A influx into the blood, we reported that the total amount of A influx during one hemodialysis session (4 h) was calculated as 7219 ng for A140 and 664 ng for A142 for 30 patients undergoing hemodialysis.19 These amounts of A influx during one hemodialysis session of 4 h are comparable with the reported total A content of 7760 ng in the brain.28

We found several effective materials suitable for blood A removal, including HexDC and PSf-HFs. This study aimed to determine which materials are more efficient at removing As from the blood (Figure 1). Another and primary objective in this study was what systems are more effective to evoke a larger A influx into the blood. We compared two systems: one was a system of enhanced A removal activity by using doubled A removal devices (concomitant use of HexDC and PSf hemodialyzer) for 4 h, the other was a longer treatment system by using PSf hemodialyzer alone for 8 h.

This study conformed to the Declaration of Helsinkis Good Clinical Practice. This research was comprehensively reviewed and approved by the institutional review board at Fujita Health University (the latest approval number is HM16-266). Patients undergoing blood purification provided written informed consent for collecting blood samples.

Human plasma remaining in used bags of fresh frozen plasma and discarded plasma from patients was obtained after plasma exchange therapy. The plasma was refrozen at 80C with additional heparin. Before use, the plasma was thawed and shook in a water bath at 37C and centrifuged to remove precipitates. Detailed procedures were previously described.24

HexDC was chosen for this study because it is one of the most efficient adsorbents for blood A removal, as described in the Introduction.6,13 HexDC beads, shown in Figure 2A, came from a commercially available HexDC device (LIXELLE S-35 containing 350 mL HexDC, Kaneka, Osaka, Japan), which is used to remove 2-microglobulin from the blood of hemodialysis patients having carpal tunnel syndrome in the clinical circuit with tandem connection to hemodialyzers. Hexadecyl alkyl chains are appropriately hydrophobic, interacting with hydrophobic proteins, such as 2-microglobulin and As. HexDC beads (1.75 mL, 1/200 of LIXELLE S-35) were put into a 2.5 mL polypropylene syringe to form the mini-HexDC column.

Figure 2 Materials for A removal: hexadecyl alkylated cellulose beads (HexDC) and polysulfone hollow fibers (PSf-HF) fragments were used for A removal in this study. (A) HexDC: bottom, the chemical structure of HexDC; top left, a photo of HexDC beads; top right, enlarged HexDC photo. (B) Fragments of PSf-HF: bottom, the chemical structure of polysulfone; lower middle, PSf hemodialyzer; upper middle, PSf hollow-fiber bundles as main components of the PSf hemodialyzer; top left, a photo of PSf-HF fragments of 25 mm length which were cut from PSf-HF bundles; top right, enlarged photo of PSf-HF fragments.

PSf-HFs were also used in this study as one of the most efficient adsorbents for blood A removal.1417 Among various materials of hollow fibers in hemodialyzers, PSf is hydrophobic enough to adsorb hydrophobic proteins, such as albumin and As. PSf-HF was obtained from hemodialyzers (APS-13EA, Asahi Kasei Medical, Tokyo, Japan) and cut into 25 mm fragments (Figure 2B) to eliminate the filtration effect. The membrane surface area of the fragments in the mini-column of PSf-HF was 0.01 m2, which was 1/200 of 2.0 m2 (a representative membrane area used in clinical hemodialysis). The fragments were put into a 2.5 mL syringe to form a mini-column of PSf-HF fragments.

Eighteen milliliters of pooled human plasma was applied continuously to mini-columns of HexDC or PSf-HF fragments and returned to the plasma pool at a flow rate of 240 L/min using a Perista pump (ATTO, Tokyo, Japan), as shown in Figure 3A. This plasma flow rate was set to 1/200 of the flow rate in a clinical setting with 50 mL plasma/min (77 mL blood/min when the hematocrit is 35%), determined in our previous study.14

Figure 3 Experimental and clinical circuits of A removal systems. (A) In vitro experimental circuit for A removal with mini columns of HexDC or PSf-HF fragments. Plasma flow rate and the quantities of HexDC or PSf HF were set to 1/200 of the human clinical setting. A removal efficiencies of the columns and reduction rates in the plasma pool are defined in Eqs (1) and (2), respectively. (B) The basic concept of adsorptive filtration system for A removal to enhance adsorption to the inner surface of hollow-fiber walls in hemodialyzers. (C) One-pump adsorptive filtration circuit with a Venturi tube and PSf hemodialyzer. (D) The clinical setting for treatment of renal failure patients suffering from carpal tunnel syndrome as a complication. The PSf hemodialyzer was tandemly connected just after the HexDC column (pale green background). (E) The clinical setting for treatment of renal failure patients with a PSf hemodialyzer (light orange background).

The A removal efficiency of the column was calculated as follows:

The A reduction rate for the experimental pool solution was defined as follows:

The primary mechanism of A removal using hemodialyzers is adsorption, not filtration.14 To enhance adsorption to the surface of micropores in the hollow fiber walls of hemodialyzers (Figure 3B), we developed adsorptive filtration systems with two pumps.17 One pump is for blood circulation and the other for filtration. In this study, to make adsorptive filtration systems with two pumps easier to use in clinical settings, one-pump adsorptive filtration systems were created with Venturi tubes instead of filtration pumps (Figure 3C). The Venturi tube has a narrow pass in the middle part, which increases fluid pressure before the narrow pass and decreases the pressure after the narrow pass. The increased fluid (blood) pressure enhances filtration through the wall of hollow fiber membranes in adsorptive filtration systems.

The Venturi tubes were designed with three-dimensional computer-aided design software, DesignSpark Mechanical (RS Components, Yokohama, Japan). Using the designed standard triangulated language (STL) data, Venturi tubes were produced with 1.75 mm filaments of polylactic acid using a fused deposition modeling 3D printer (Replicator 2; MakerBot, NY, USA). In the experimental circuit (Figure 3C), a Venturi tube was added after the polysulfone dialyzer outlet (APS-13EA, Asahi Kasei Medical, Tokyo, Japan) to control the filtration rate. A flowmeter (Coriolis Flow Meter FD-SS02A, Keyence, Osaka, Japan) was placed between the filtrate outlet (one of the dialysate ports) and the junction with the return tube to the pool of 250 mL of human plasma. Human plasma was circulated at a 50 mL/min flow rate using peristaltic pumps (Masterflex Variable-Speed Drive; Cole-Parmer, IL, USA). This flow rate was determined based on our previous studies of adsorptive filtration.14,17

Table 1 summarizes the demographics of the blood treatment subjects. All subjects were nondiabetic, as diabetes mellitus is an AD risk factor. Three hemodialysis patients having carpal tunnel syndrome underwent treatment using PSf hemodialyzers (APS-21SA, Asahi Kasei Medical, Tokyo, Japan) and tandemly connected HexDC (LIXELLE S-15, Kaneka, Osaka, Japan). Figure 3D shows the clinical circuit for these treatments. Treatment time was 4 h, and patients were treated during the day. Dialysate flowed outside PSf-HF in the PSf hemodialyzer at a flow rate of 500 mL/min.

Table 1 Demographics of the Subjects Undergoing Blood Purification

This treatment system can be regarded as a kind of E-BARS with double A-removal devices (concomitant use of HexDC and PSf hemodialyzer). Furthermore, PSf hemodialyzer in this system worked as an adsorptive filtration system14,17 because of water removal by filtration. Hemodialysis patients can pass little or no urine because of renal failure; excess water by drinking and eating should be removed from the blood during hemodialysis. The filtration rate for the removal of excess water from the blood was approximately 10 mL/min (Figure 3D).

Three additional patients were treated using only PSf hemodialyzers (APS-21SA) for 8 h overnight because they had daytime jobs. Figure 3E shows the clinical circuit. Dialysate flowed outside PSf-HF in the PSf hemodialyzer at a flow rate of 400 mL/min. This treatment system can be regarded as longer time treatment of E-BARS. The first 4 h of hemodialysis in these patients was regarded as the hemodialyzer-only (without HexDC) control group compared with concomitant treatments with HexDC and hemodialyzer. Filtration rates of the hemodialyzers were 69 mL/min for removal of excess blood water (Figure 3E).

Blood samples were obtained at 0, 1, and 4 h (for all patients) and 8 h (for ON13 patients in Table 1). The dialysate flow rate was 400 mL/min (24 L/h) for ON13 patients (Table 1). Part of the mixture of filtrate and discarded dialysate were collected at the rate of 1 L/h for the periods of 04 h and 48 h for ON13 patients. The accumulated filtrate/dialysate was mixed well before sampling.

A influx into the plasma during blood treatment was estimated as the sum of As changed in the plasma during blood treatments and As removed by dialyzers, HexDC, or both, according to the following equation.

where A removed by a device during the period=(concentration of A at the inlet of a device) X (removal efficiency of the device) X (plasma flow rate during the period) X (minutes of the period)

Decreased plasma concentration is denoted with a minus sign. The period is divided into 01, 14, and 48 h of a treatment session. A concentration at the devices inlet was set as the average of each period: 0 and 1 h for the 01 h period, 1 and 4 h for the 14 h period, and 4 and 8 h for the 48 h period. The removal efficiency of the devices for the 01 h was the removal efficiency at 1 h. The removal efficiency for the 14 h period was the average of those at 1 and 4 h, and the removal efficiency for the 48 h period was the average of those at 4 and 8 h. The whole blood volume was calculated as 1/13 of the patients body weight. The plasma volume was calculated as (whole blood volume) (1 hematocrit/100).

A1-40 and A1-42 concentrations in the plasma were measured using the High-Sensitive Human Amyloid (140) and (142) ELISA Kit Wako II (WAKO Pure Chemical, Osaka, Japan), respectively. ApoE4 was measured by the ApoE4/Pan-ApoE ELISA kit (MBL, Nagoya, Japan).

All data are expressed as the mean standard deviation unless otherwise specified. Differences were determined using a Wilcoxon rank-sum test for nonparametric variables and the Students t-test for parametric variables, unless otherwise specified, using the statistical package JMP14 (SAS Institute Inc., Cary, USA). Values of p < 0.05 were considered statistically significant.

The in vitro A removal efficiencies and reduction rates for HexDC were compared with PSf-HFs using mini-columns. Figure 3A shows the experimental circuit; quantities of HexDC and PSf-HF and the plasma flow rates were set at about 1/200 of the parameters used in clinical patient treatment. PSf-HF fragments of 25 nm length were packed in the column to eliminate the filtration effect and detect adsorption effects only.

A140 and A142 in the plasma pool were significantly decreased to about half of the initial concentrations by HexDC and PSf-HF fragment columns (solid lines in Figure 4AD). The A140 and A142 concentrations at the HexDC columns outlet (Post) were almost zero during the treatment period, indicating that almost all As flowing into the column were removed by the HexDC columns (dotted lines in Figure 4A and C). By contrast, A concentrations at the outlet (Post) of PSf-HF fragment columns gradually increased after 30 min of treatment, especially the A140 (dotted lines in Figure 4B and D). The A140 concentrations at the outlet (Post) were similar to those in the plasma pool (Pool) at 60 min (Figure 4B), indicating that PSf-HF fragments removed almost no A1-40 at the end of the treatment.

Figure 4 A concentration changes in the plasma pool and post-filtration for the mini columns in vitro. (A and B) A1-40 (blue) concentration changes with mini columns of HexDC (A) and PSf-HF fragments (B). (C and D) A1-42 (red) concentration changes with HexDC (C) and PSf-HF Fragments (D). Solid lines with circle symbols, in the plasma pool; Dotted lines with square symbols, post-filtration (at the outlet of mini columns). ns, not significant, *p < 0.05; **p < 0.01; and ***p < 0.001 indicate significant changes compared with 0 min for the plasma pool and with 15 min for the post-filtration measurements).

Figure 5A and B for A140 and Figure 5C and D for A142 show the removal efficiencies for the mini-columns and reduction rates in the plasma pool. Using HexDC, the removal efficiencies for both As were approximately 100% during the entire treatment period (dashed line in Figure 5A and C). However, the removal efficiencies and reduction rates decreased after 30 min treatment using the PSf-HF fragments. The A140 removal efficiency was significantly lower using the PSf-HF fragments than the removal efficiency using HexDC (Figure 5A, p < 0.01). The A140 removal efficiency at 60 min using PSf-HF fragments was below zero, indicating that some adsorbed A140 was desorbed at the end of the treatment. In contrast to the removal efficiencies, the reduction rates increased for both materials and reached more than 50% after 60 min of treatment (Figure 5B and D). Thus, more than half of the existing As in the plasma pool were removed after 60 min of treatment. The A140 reduction rates after 60 min of HexDC treatment were significantly higher than the reduction rates when using PSf-HF fragments because of the higher removal efficiency (Figure 5B, p < 0.05).

Figure 5 A removal efficiencies and reduction rates for the in vitro systems using HexDC or PSf-HF fragments. (A and B) A1-40 (blue) removal efficiency (A) and reduction rate (B). (C and D) A1-42 (red) removal efficiency (C) and reduction rate (D). Dashed line with rhombus symbols represent HexDC; dotted line with square cross marks represent PSf-HF fragments. (*p < 0.05; **p < 0.01; and ***p < 0.001 indicate significant changes compared with 0 min). Removal efficiencies of HexDC were significantly higher than those of PSf-HF fragments for A1-40 at 60 min (p < 0.01) (A). Reduction rates of HexDC were significantly higher than those of PSf-HF fragments for A1-40 at 60 min (p < 0.05) (B).

Adsorption on the surface of the small inner pores in the walls of hollow fibers was enhanced by filtration to increase the A removal activity of PSf-HF (adsorptive filtration, Figure 3B). The previous adsorptive filtration was conducted using two pumps, a main blood circulation pump and a filtration pump through the hollow fiber walls.17 The representative clinical setting of the two-pump adsorptive filtration system is similar to that in Figure 3E, but no dialysate. A one-pump system was created to make this adsorptive filtration easy to use. The basic concept of this system was that the pressure changes in the Venturi tubes at the outlet of the dialyzer increase filtration through the hollow fibers membrane walls. Venturi tubes with various minimum internal diameters were produced using a 3D printer (Figure 6A and B). When melted PLA filaments were piled in the long axis direction (Figure 6C), the cross sections were not circular in parts, resulting in frequent leakage at the circuit tube connections. Melted PLA filaments were then piled circumferentially (Figure 6D), resulting in less leakage.

Figure 6 Preparation of Venturi tubes for the one-pump adsorptive filtration system. (A and B) Design and dimensions of the Venturi tubes. Melted PLA filaments were piled in the long axis direction (C) or circumferentially (D). The latter resulted in less leakage.

Abbreviations: o.d., outer diameter; i.d., internal diameter; Min, minimum; Max, maximum.

Circulation analysis using these Venturi tubes was first conducted using water (Figure 7A). As expected, the filtration rate (QF) depended on the tubes narrowest inner diameter and the flow rate (QB) of water. This one-pump adsorptive filtration system was then applied to A removal from human plasma with PSf hemodialyzers for 60 min (Figure 3C). The pressures before and after the hemodialyzer and at the filtrate outlet were mostly stable throughout the 60 min sessions at 50 mL/min QB (Figure 7B, an example using the Venturi tube 14j-2, whose minimum internal diameter was 1.4 mm). The A reduction rates in the plasma pool were high, as shown in Figure 7C and D for A140 and A142, respectively. Thus, the one-pump system functioned as designed.

Figure 7 Performance of the one-pump adsorptive filtration system with Venturi tubes. (A) Correlation between the narrowest internal diameter (i.d.) and flow rate (QB) measured with water. At 50 mL/min QB, suitable filtration rate (QF) (around 610 mL/min) was obtained with an i.d. of 1.42.5 mm. (B) Representative data for stable QF (mL/min) and pressures (kPa) at Pre (the inlet of hemodialyzers), Post (the outlet of Venturi tubes connected to hemodialyzers), and Filtrate of PSf hemodialyzer during A reduction from human plasma with the 14j-2 Venturi tube of 1.4 mm i.d. (C and D) Reduction rates of plasma A1-40 (C) and A1-42 (D) in the human plasma pool for three Venturi tubes. **p < 0.01.

To enhance A influx into the blood, an E-BARS with double A removal devices seemed effective. We hypothesized that concomitant use of a HexDC column and a PSf hemodialyzer (double efficient A removal devices13,14) would enhance blood A removal and increase A influx from the brain into the blood. Therefore, blood A changes and A removal efficiency were investigated in three hemodialysis patients undergoing blood purification with HexDC columns and PSf hemodialyzers (Hex-0103 in Table 1) as an observational study. These patients underwent blood purification with HexDC columns to remove blood 2 microglobulin for carpal tunnel syndrome and hemodialysis for renal failure. Figure 3D shows the clinical circuit. During hemodialysis, excess blood water was filtered out at approximately 10 mL/min. This filtration can be considered adsorptive filtration for A removal.

Figure 8A shows the plasma concentration changes for A140 and A142 in whole-body circulation. Both A140 and A142 decreased similarly. Figure 8B and C show the A removal efficiencies of the HexDC column and PSf hemodialyzer, respectively. A140 and A142 removal efficiencies for both devices were maintained during the 4 h treatment. The removal efficiencies were lower in this clinical setting than the removal efficiencies in the in vitro experiments (Figures 3A, 5A and C). The plasma flow rates were higher in human treatment (200 mL blood/min, approximately 130 mL plasma/min) than the flow rates in in vitro experiments (equivalent to 50 mL plasma/min in humans). Lower blood flow rates resulted in higher A removal efficiencies, as previously reported.14,17

Figure 8 A removal during hemodialysis with concomitant use of HexDC and PSf hemodialyzers for 4 h. (A) Changes in plasma A1-40 (left blue vertical axis) and A1-42 (right red vertical axis) concentrations in whole-body circulation. (B and C) A removal efficiencies of HexDC (B) or PSf hemodialyzers (C). (A1-40, blue solid line; A1-42, red dotted line).

Another method of enhancing A influx into the blood, an E-BARS with long-time treatment, was also believed to be effective. Blood A changes in hemodialysis patients using hemodialyzers alone for 4 h were already investigated in the previous study.15,16,18,19 We then hypothesized that longer hemodialysis times, such as 8 h (doubled compared with ordinal 4 h treatment), would enhance A influx into the blood. Three patients suffering from end-stage renal failure underwent overnight hemodialysis for 8 h using a PSf hemodialyzer alone (ON-13 in Table 1). Overnight hemodialysis during sleep for 8 h was provided because these patients worked during the day. This was also an observational study. Figure 3E shows the clinical circuit. The blood was partially filtered at a 69 mL/min rate during hemodialysis to remove excess water, resulting in enhanced A adsorption on the surface of small pores in the membrane wall (Figure 3B, adsorptive filtration).

Figure 9A shows the plasma concentration changes for A140 and A142 in whole-body circulation. Both A140 and A142 similarly decreased. The A removal efficiencies using the PSf hemodialyzer were maintained at over 60% during the 8 h treatment (Figure 9B). A concentrations in the filtrate of the dialyzers were also measured. The flow rate of the mixture of filtrate and waste dialysate was approximately 400 mL/min. The total volume was up to 192 L, and part of the fluid was collected at a rate of 1000 mL/h for the periods of 04 h and 48 h. Figure 9C shows the A concentrations in the filtrate and waste dialysate, indicating that almost all As were adsorbed (trapped) on the inner surface of the PSf-HFs.

Figure 9 A removal during hemodialysis with PSf hemodialyzer alone for 8 h. (A) Changes in plasma A1-40 (left blue vertical axis) and A1-42 (right red vertical axis) concentrations in whole-body circulation. (B) A removal efficiencies of the PSf hemodialyzer. (C) As concentrations in the filtrate from the PSf hemodialyzer. (A1-40, left blue vertical axis; A1-42, right red vertical axis; A1-40, blue solid line; A1-42, red dotted line).

Removing blood A evokes a large A influx into the blood,15,16,18,19,22 probably from the brain.20,22 A influx into the blood was estimated according to the equation shown in Figure 10 for studies of renal failure patients using the concomitant HexDC and PSf hemodialyzer for 4 h and using the hemodialyzer alone for 8 h (Figure 3D and E, respectively).

Figure 10 A influx into the blood was calculated by subtracting the A amounts decreased in the plasma from the A amounts removed by the devices.

Figure 11 shows A140 (Figure 11A) and A142 (Figure 11B) amounts removed by each device, and As decreased in the plasma compared with the starting amounts. The A amounts are shown separately for the 01, 14, and 04 h periods for both systems and 48 and 08 h for the dialyzer alone. A140 removed by HexDC increased time-dependently (blue diagonal cross lattice in Figure 11A). A140 removed by HexDC during the 14 h period (3 h) was nearly three times larger than the removal during the 01 h period. However, the A142 removed by HexDC and both A140 and A142 removed by PSf dialyzers showed no clear trend over time and were suppressed in later treatment periods.

Figure 11 A amounts removed by HexDC (blue diagonal cross lattice), by PSf hemodialyzer (orange solid bar), and A amounts decreased in the plasma (green vertical stripe) for each period. (A) A1-40, (B) A1-42.

Figure 12 shows the A influx evoked by the A removal systems, calculated based on the data shown in Figure 11. A140 influxes (blue diagonal striped bars in Figure 12) during concomitant use of the HexDC and PSf dialyzer were significantly (p < 0.05) higher than the influxes during use of the PSf dialyzer alone in the 14 h period. By contrast, A142 influxes (red solid bars in Figure 12) during concomitant use of HexDC and the PSf dialyzer were significantly (p < 0.05) lower than influxes during the use of the PSf dialyzer alone in the 01, 14, and 04 h periods. Consequently, the sums of A140 and A142 influxes (black horizontal striped bars in Figure 12) were not significantly different between the two systems.

Figure 12 A influx into the plasma evoked by concomitant use of HexDC and the PSf hemodialyzer (HexDC+Dialyzer) and by the PSf hemodialyzer alone (Dialyzer Only). A1-40, blue diagonal line (left black vertical axis); A1-42, red solid bar (right red vertical axis); summation of A1-40 and A1-42, black lateral stripe (left black vertical axis). (*p < 0.05).

The average A140 influx for both systems in the 14 h (3 h) period was nearly three times higher than the influx in the 01 h (1 h) period (11,549 ng vs 4042 ng for the concomitant use of HexDC and the PSf dialyzer and 8132 ng vs 3478 ng for PSf dialyzer alone). On the other hand, A142 influxes in both systems during the 14 h period were larger than those in the 01 h period, but not proportional to the treatment time (425 ng vs 256 ng for the concomitant use of HexDC and PSf dialyzer, and 892 ng vs 410 ng for PSf dialyzer-alone system).

A influxes for the PSf dialyzer alone during the 08 h period were not doubled compared with those in the 04 h period, as shown on the right of Figure 12. Thus, the influxes of both A140 and A142 may decrease over time during the treatment.

The absolute amounts of As removed, those decreased in systemic plasma, and A influxes are dependent on the beginning plasma A concentrations of each patient. Therefore, relative values for these A amounts were calculated relative to the plasma A amounts at the beginning of the treatment (Figure 13). Interestingly, standard deviations for each relative A value were far smaller than expected. Thus, the A amounts similarly changed for each patient during blood treatments.

Figure 13 Relative A amounts normalized to the A amounts existing in the plasma at the beginning of blood purification.(A and B) A1-40 (blue lines), (C and D) A1-42 (red lines). Relative A amount changes during treatment with concomitant use of HexDC and the PSf hemodialyzer (HexDC+Dialyzer) (A and C, pale green background). Relative A amount changes during treatment with PSf hemodialyzer alone (Dialyzer only) (B and D, light orange background). Solid lines with triangle symbols, relative A amounts removed by HexDC; dotted lines with cross square marks, relative A amounts removed by PSf hemodialyzer; dashed lines with circle symbols, relative A amounts decreased in the plasma.

Relative A amounts removed by HexDC and PSf dialyzers (solid lines and dotted lines in Figure 13, respectively) increased time-dependently. This suggests that HexDC and PSf dialyzers had adequate A adsorption capacity during the 4 and 8 h treatments. However, the changes were smaller in the latter half of the treatment than in the first half. The relative decreases in plasma A (dashed lines under 0% in Figure 13) seemed to plateau after 1 h of treatment. This indicates that blood A140 and A142 reached homeostasis, even though large amounts of A were removed from the blood because of A influx.

Figure 14 shows the comparison of relative A influx for the two A removal systems. As shown in Figure 14A, relative A140 influx after 4 h using the combined HexDC and PSf dialyzer was significantly higher than influx using the PSf dialyzer alone (p < 0.05). The total relative A140 influx for the PSf dialyzer alone at 8 h was similar to that of HexDC and PSf dialyzer at 4 h. In contrast to A140, relative A142 influx after 4 h using the HexDC and PSf dialyzer was slightly, but significantly, lower than that of the PSf dialyzer alone (Figure 14B). A total relative A1-42 influx during 8 h of treatment using the PSf dialyzer alone was almost double the A1-42 influx of the combined HexDC and PSf dialyzer during 4 h.

Figure 14 Relative A influxes normalized to the A amounts existing in the plasma at the beginning of blood purification. (A) Relative A1-40 influx into the plasma, (B) relative A1-42 influx into the plasma. Solid green lines with rhombus symbols, relative A influxes evoked by concomitant use of HexDC and the PSf hemodialyzer (HexDC+Dialyzer); dotted lines with square symbols, relative A influxes evoked by the PSf hemodialyzer alone (Dialyzer Only). *, p < 0.05.

Regarding A influx into the blood, we have reported that ordinal hemodialysis with hemodialyzers alone for 4 h evoked an influx of 7219 ng A140 and 664 ng A142 based on analysis of 30 hemodialysis patients.19 In this study, as shown in Figure 12, A140, A142, A140 + A142 influx evoked by the concomitant use of HexDC and the PSf hemodialyzer for 04 h were 15,591 5407 ng, 690 166 ng, and 16,281 5565 ng, respectively. Those by PSf hemodialyzer alone were 11,610 1335 ng, 1302 211 ng, and 12,912 1224 ng for 04 h, and 19,198 1556 ng, 1673 928 ng, and 20,871 1699 ng for 08 h, respectively. Thus, compared with E-BARS with hemodialyzers alone for 4 h, E-BARS with double devices of A removal (HexDC and PSf hemodialyzer) for 4 h evoked nearly doubled As (A140 + A142) influx: 7219 ng vs 16,281 ng, and E-BARS of longer treatment with PSf hemodialyzer alone for 8 h also evoked more than doubled or nearly tripled As (A140 + A142) influx: 7219 ng vs 20,871 ng. A influx in this study was two to three times larger than the estimated total As (7760 ng) in the normal human brain28 and far larger than As removed by peritoneal dialysis: 131.33 ng, which was approximately 2% of the total A in the normal brain.25 Therefore, efficient A removal systems, such as a combination of HexDC and PSf hemodialyzer or longer treatment time, may be more effective in removing brain As than ordinal hemodialysis (hemodialyzers alone) for 4 h.

One aim of our blood A removal systems was to enhance A influx (migration) from the brain into the blood, especially A142, which readily forms neurotoxic A142 oligomers. Both A removal systems in this study showed very similar time dependency (Figure 14B) for relative A142 influxes. However, PSf dialyzer alone evoked slightly higher (p < 0.05) relative A142 influx than the combined system of HexDC and PSf dialyzer. Furthermore, the 8 h treatment with the PSf hemodialyzer alone evoked significantly larger, almost doubled, A142 influx than the concomitant use of HexDC and the PSf hemodialyzer for 4 h (Figure 14B). Focused on A142 removal, PSf hemodialyzer alone may have enough ability to evoke A142 influx into the blood.

In contrast to the A142 influx, concomitant use of HexDC and the PSf hemodialyzer evoked a larger A140 influx (significantly for only 14 h) than the PSf hemodialyzer alone (Figures 12 and 14A).

Overall, A removal systems with concomitant use of HexDC and PSf hemodialyzer evoked similar or less A142 influxes and larger A140 influx compared with A influx using the PSf hemodialyzer alone. Although the reason for this difference is unclear at present, it provides information to establish appropriate systems of E-BARS.

Regarding discrepancy between this and previous studies, A influx with PSf hemodialyzer in 04 h period at night in this study was larger than those we reported previously for ordinal hemodialysis patients for 4 h during the day:19 12,912 ng vs 16,281 ng. One possible reason is the variations in hemodialyzer materials used. Hemodialyzer material in this study was only PSf, one of the efficient A adsorbents. By contrast, some hemodialyzers used in the previous study included less efficient A removal devices, such as cellulose triacetate. Another reason may be that blood purification was conducted overnight or daytime. In this study, the blood purification with the PSf hemodialyzer alone for 8 h was provided overnight, including when patients were sleeping, whereas 4 h blood purification was provided during the day in the previous study.19 It was reported that A concentrations in CSF are higher in the evening (about 18:0022:00) than during the awake daytime hours and decrease while a patient is sleeping (about 22:007:00).29,30 Therefore, the differences in As concentrations in CSF depending on the time of day might affect this studys results. Thus, blood A removal during sleeping might be an effective method for brain A removal.

The amounts of A140 and A142 removed by the PSf hemodialyzers in concomitant use with HexDC were smaller than the A amounts removed by PSf hemodialyzers alone in each period of 01, 14, and 04 h, as shown in Figure 11A and B (the solid orange bars of HexDC + Dialyzer and Dialyzer only). One explanation is that the A concentrations at the PSf hemodialyzer inlet (Figure 3D) were lower than the A concentrations for the PSf hemodialyzer directly connected with the blood vessels of patients (Figure 3E) because approximately 5060% of the As in the blood were already removed by the HexDC column (Figure 3D) before PSf hemodialyzer in the system of concomitant use of tandemly connected HexDC and PSf hemodialyzer. To use the total A removal activity capacity of PSf hemodialyzer, blood should be introduced in parallel to the HexDC and PSf hemodialyzer systems. However, such parallel systems require doubled blood flow rates, which are unsuitable for Japanese hemodialysis patients because of blood outflow limitations.

Figure 15 summarizes the factors that may affect blood A removal. The key factors are not only A removal efficacy of the device but also the treatment period, blood flow rates into the devices, A concentrations in the blood, A concentrations in CSF that change depending on the time of day and A production/degradation rates in the brain, the activity of A transporters (for example, LRP-1 and RAGE), and frequency of treatment (for example, three times a week, or once a month?) of A removal. When comparing dual A removal devices with a single A removal device, the relative A142 influx was similar (Figure 14B). Therefore, the rate of A influx to the blood from the brain, especially A142, might be the rate-limiting step for brain A142 removal, even if more effective devices are used for A removal.

Figure 15 A transportation pathway from the brain to A removal devices. Key factors affecting A influxes and removal are also shown.

As blood A removal devices, PSf hemodialyzer in adsorptive filtration methods and HexDC showed comparable adsorption capacity for plasma As. Doubled A removal devices consisting of tandemly connected HexDC and PSf hemodialyzer for 4 h evoked a larger A140 influx into the blood than PSf hemodialyzer alone for the same period. However, both systems evoked similar A142 influx for 4 h. These systems evoked As (A140 + A142) influx nearly two times larger than As existing in the normal brain. Furthermore, longer A removal evoked more influxes of A140 and A142. These findings of blood A removal systems may lead to an optimal clinical setting for therapy and prevention of AD.

The authors thank Hiroshi Tomizawa of Mizuno Clinic, and, Yuri Sakakibara, Kota Watanabe, Miki Kamiya, and Tatsuya Hama of Fujita Health University for their technical assistance. The authors also thank Yoshiyuki Hiki for fruitful discussion, and Fumiyasu Hirai and Ai Yonezawa of Kaneka for providing HexDC for in vitro experiments. This work was partly supported by KAKENHI (20509008, 23500531, 26282126) and the Smoking Research Foundation.

Nobuya Kitaguchi has stock ownership in Asahi Kasei Corporation Co., Ltd and reports grants from Japanese Government, grants from Smoking Research Foundation, grants from Asahi Kasei Medical Co. LTD, grants, non-financial support from Kaneka Corporation, during the conduct of the study.

The other authors declare that they have no conflict of interest.

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2. Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS -amyloid in Alzheimers disease. Science. 2010;330:1774. doi:10.1126/science.1197623

3. Aisen PS, Cummings J, Doody R, et al. The future of anti-amyloid trials. J Prev Alzheimers Dis. 2020;7:146151. doi:10.14283/jpad.2020.24

4. Selkoe DJ. A is for amyloid. J Prev Alz Dis. 2020;3:140141. doi:10.14283/jpad.2020.27

5. In DIAN-TU, gantenerumab brings down tau. By a Lot. Open Extension Planned. Alzforum; 2020. Available from: https://www.alzforum.org/news/conference-coverage/dian-tu-gantenerumab-brings-down-tau-lot-open-extension-planned. Accessed July 2, 2021.

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7. Schoonenboom NS, Mulder C, Van Kamp GJ, et al. Amyloid beta 38, 40, and 42 species in cerebrospinal fluid: more of the same? Ann Neurol. 2005;58:139142. doi:10.1002/ana.20508

8. Lopez OL, Kuller LH, Mehta PD, et al. Plasma amyloid levels and the risk of AD in normal subjects in the cardiovascular health study. Neurology. 2008;70:16641671. doi:10.1212/01.wnl.0000306696.82017.66

9. Bell RD, Sagare AP, Friedman AE, et al. Transport pathways for clearance of human Alzheimers amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab. 2007;27:909918. doi:10.1038/sj.jcbfm.9600419

10. Donahue JE, Flaherty SL, Johanson CE, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimers disease. Acta Neuropathol. 2006;112:405415. doi:10.1007/s00401-006-0115-3

11. Silverberg GD, Miller MC, Messier AA, et al. Amyloid deposition and influx transporter expression at the bloodbrain barrier increase in normal aging. J Neuropathol Exp Neurol. 2010;69:98108. doi:10.1097/NEN.0b013e3181c8ad2f

12. Lao K, Zhang R, Luan J, et al. Therapeutic strategies targeting amyloid- receptors and transporters in Alzheimers disease. J Alzheimers Dis. 2021;79:14291442. doi:10.3233/JAD-200851

13. Kawaguchi K, Takeuchi M, Yamagawa H, et al. A potential therapeutic system for Alzheimers disease using adsorbents with alkyl ligands for removal of blood Amyloid . J Artif Organs. 2013;16:211217. doi:10.1007/s10047-012-0675-z

14. Kawaguchi K, Saigusa A, Yamada S, et al. Toward the treatment for Alzheimers disease: adsorption is primary mechanism of removing amyloid protein with hollow-fiber dialyzers of the suitable materials, polysulfone and polymethyl methacrylate. J Artif Organs. 2016;19:149158. doi:10.1007/s10047-015-0878-1

15. Kitaguchi N, Kawaguchi K, Nakai S, et al. Reduction of Alzheimers disease Amyloid- in plasma by hemodialysis and its relation to cognitive functions. Blood Purif. 2011;32:5762. doi:10.1159/000322624

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High cost of Biogen’s Alzheimer’s drug blocks getting reimbursement in US – Korea Biomedical Review

Posted: at 1:54 am

Experts from the Institute for Clinical and Economic Review (ICER), a U.S. non-profit organization, say Biogen's Alzheimer's disease treatment, Aduhelm (ingredient: aducanumab), is not cost-effective, putting a brake on its advance to the U.S. market.

At a meeting last Thursday, the ICER experts reviewed the cost and clinical trial results of Aduhelm set by Biogen. All 15 participants unanimously voted that Aduhelm does not provide more benefits to patients, doctors, and society than the current standard treatment.

The experts pointed out that while one of the later clinical trials submitted for approval showed that Aduhelm had some benefit in slowing disease progression, a different study contradicted such results. The expert group also took issue with the frequent reports of adverse events concerning amyloid-related imaging abnormalities (ARIA).

Biogen recently set the annual treatment cost of Aduhelm at $56,000 after the U.S. Food and Drug Administration (FDA) approved the treatment. However, the treatment cost does not include the price of a positron emission tomography (PET) scan or magnetic resonance imaging (MRI) for diagnosing Alzheimer's disease. Including these collateral costs, the figure soars up to about $100,000 a year.

"The price of Aduhelm set by Biogen does not reasonably match the clinical benefit," the ICER said in late June, pointing out that Biogen needs to lower the drug price by 85-95 percent from the current list price to meet a reasonable price tag.

At that time, ICER's estimated that the cost-effectiveness of Aduhelm ranges from a minimum of $3,000 to a maximum of $8,400, which is far lower than the price set by Biogen.

In response, Biogen's Chief Medical Officer Maha Radhakrishnan criticized the ICER, saying that evaluating drugs requires innovative thinking and a new framework for assessing potential value.

"We regret that ICER assessment missed this point," Radhakrishnan said.

However, ICER reconvened the experts meeting and presented opinions that the price set by Biogen for Aduhelm does not provide any benefits compared to existing treatments, which will likely have negative effects on the discussion of Medicare application to the drug that starts next week, industry insiders predicted.

Medicare is a health insurance system for the elderly in the United States. The federal government subsidizes 50 percent of medical expenses for seniors 65 years of age or older and people with disabilities who have paid social security tax for 20 years or more.

Currently, some major hospitals are refusing to prescribe Aduhelm until the drug receives coverage by Medicare, and private insurance companies are also delaying coverage plans.

Meanwhile, the FDA significantly reduced the number of treatment targets by inserting and updating the label for Aduhelm and restricted the drug use for "patients with mild cognitive impairment or mild dementia stage of the disease" on July 8.

In the updated label, the FDA added that Aduhelm treatment should only treat patients with mild cognitive impairment or mild dementia, as Biogen's trial only used the therapy in such patients, and that there are no safety or efficacy data for use at earlier or later stages than those studied.

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High cost of Biogen's Alzheimer's drug blocks getting reimbursement in US - Korea Biomedical Review

Alzheimer’s Association Welcomes CMS Announcement of National Coverage Determination Analysis on Treatment for Alzheimer’s Disease – Newswise

Posted: at 1:54 am

Newswise CHICAGO, July 12, 2021 /PRNewswire/ -- On behalf of all those living with Alzheimer's disease, their caregivers, and their families, we appreciate the Centers for Medicare & Medicaid Services (CMS) thoughtful consideration on coverage considerations for monoclonal antibodies targeting amyloid for the treatment of Alzheimer's disease, including aducanumab, which was recently approved by the Food and Drug Administration (FDA).

We welcome today's announcement of a National Coverage Determination (NCD) analysis, consistent with the Alzheimer's Associationposition. An NCD would help prevent regional and community level disparities due to barriers that would be difficult to overcome, particularly by those who have greater challenges accessing health care services.

As the leading voluntary health organization in Alzheimer's care, support and research, the Alzheimer's Association looks forward to providing comment as part of the NCD process. In addition, the Alzheimer's Association supports an NCD outcome that includes Coverage with Evidence Development (CED) to ensure confirmatory data is collected in a timeframe and manner that meaningfully informs important near term decision making by policymakers, payers, health care providers, and patients and their families.

As the only patient advocacy group with experience in leading neurology CED programs, the Association believes a well constructed CED study would create rapid, open access to crucial information regarding efficacy, safety and equity to help ensure that everyone who might benefit has access.

We're committed to working with CMS and with the private payer community to ensure coverage for those who would benefit from this treatment. Additionally, we call on CMS to provide immediate guidance to help our community navigate access to coverage as the NCD process moves forward over the next several months. Patients and their families are understandably eager for treatment to begin now; providers need to understand what will be covered as we wait for an eventual NCD.

The Alzheimer's Association position remains, coverage should include the appropriate population as represented by those studied in the clinical trials people with mild cognitive impairment (MCI) due to Alzheimer's or early stage Alzheimer's dementia.

If you or a loved one is experiencing memory changes, the Alzheimer's Association strongly encourages speaking with a health care provider for a thorough evaluation, diagnosis and to discuss treatment options. For more information on diagnosis or to find a local health care provider, visit the Alzheimer's Association atalz.org, or the Helpline 24/7 at 800.272.3900.

Alzheimer's AssociationThe Alzheimer's Association leads the way to end Alzheimer's and all other dementia by accelerating global research, driving risk reduction and early detection, and maximizing quality care and support. Our vision is a world without Alzheimer's and all other dementia. Visitalz.orgor call the 24/7 Helpline at 800.272.3900.

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Alzheimer's Association Welcomes CMS Announcement of National Coverage Determination Analysis on Treatment for Alzheimer's Disease - Newswise

Lilly and Banner Alzheimer’s Institute collaborate on planned Phase 3 prevention trial of donanemab – PRNewswire

Posted: at 1:54 am

INDIANAPOLIS and PHOENIX, July 15, 2021 /PRNewswire/ --Eli Lilly and Company (NYSE: LLY) and Banner Alzheimer's Institute today announced a strategic research collaboration as part of the planned Phase 3, randomized, placebo-controlled study evaluating donanemab in participants at risk for cognitive and functional decline related to Alzheimer's disease (TRAILBLAZER-ALZ 3). TRAILBLAZER-ALZ 3 will evaluate whether treatment with donanemab can slow the clinical progression of Alzheimer'sdisease in trial participants.

As part of the collaboration, Banner will leverage its expertise and proven leadership in Alzheimer's prevention trials, and support enrollment of trial participants with and without the e4 type of the apolipoprotein E (APOE4) gene through the Alzheimer's Prevention Registry's GeneMatchprogram. The collaboration will introduce a more virtual approach to the evaluation of Alzheimer's prevention therapies. Lilly and Banner are committed to using the screening and treatment data as a shared scientific resource. Lilly remains the sole sponsor of the clinical trial and plans to begin enrollment later this year.

"This collaboration combines Lilly's more than 30 years of dedication to Alzheimer's research with Banner's unique expertise and showcases our collective commitment to partner within the health care community to find potential treatments to end this devastating disease," said Mark Mintun, M.D., vice president of pain and neurodegeneration, Lilly. "Our TRAILBLAZER-ALZ 3 trial will evaluate whether donanemab can prevent clinical progression in patients who have evidence of Alzheimer's pathology, but don't yet demonstrate clinical symptoms. While these types of trials are challenging to enroll and conduct, Lilly, together with Banner, is proud to undertake the opportunity to bring about this new study in an area of high unmet medical need."

"We are excited about the chance to work with Lilly in the effort to find an effective Alzheimer's prevention therapy as soon as possible, introduce novel ways to increase the size, speed, and ease of participating in Alzheimer's prevention trials, and do so in ways that might benefit the entire field," said Eric M. Reiman, MD, Banner Alzheimer's Institute executive director and one of the study's lead principal investigators. "We must do everything we can to find and support the availability of effective prevention therapies for this devastating disease, and this trial includes several potentially transformational elements to help in this endeavor."

Donanemab is an investigational antibody that targets a modified form of beta amyloid called N3pG. Results from a Phase 2 study of donanemab were announced earlier this year. VisitLillyMemoryTrials.comfor additional information onenrolling in Alzheimer's disease trials.Donanemab is also being studied in the ongoing Phase 3 TRAILBLAZER-ALZ 2 study in early, symptomatic Alzheimer's disease patients. To learn more about the TRAILBLAZER-ALZ 2 study or to see prequalifications, visit http://www.trailblazer2study.com.

About Alzheimer's DiseaseAlzheimer's disease is a fatal illness that causes progressive decline in memory and other aspects of cognition. Dementia due to Alzheimer's disease is the most common form of dementia, accounting for 60 to 80 percent of all cases1. There are currently over 50 million people living with dementia around the world, with numbers expected to increase to nearly 152 million by 20502. Almost 10 million new cases of dementia are diagnosed each year worldwide, implying one new case every 3 seconds, and a significant increase in the caregiving burden placed on society and families.In the US alone, there was an increase of 8 million new caregivers from 2015 to 20203. The current annual societal and economic cost of dementia is estimated at $1 trillion, an amount that is expected to double by 2030 unless we find a way to slow the disease2.

In an addition to age and family history of AD, the greatest risk factor for developing AD is the presence of the apolipoprotein E 4 (APOE4) allele.1 Having one APOE4 allele increases the risk of developing Alzheimer's disease by approximately three times compared with those with two copies of the APOE3 form. Those who inherit two copies of the APOE4 allele have an 8 - 12-fold risk. In addition, those with the APOE4 allele are more likely to have beta-amyloid accumulation and Alzheimer's dementia at a younger age than those with the APOE2 or APOE3 forms of the APOE gene.

About Banner Alzheimer's InstituteSince its inception in 2006, Banner Alzheimer's Institute (BAI) has sought to find effective Alzheimer's disease prevention therapies without losing another generation, establish a new model of dementia care for patients and family caregivers, and forge new models of collaboration in biomedical research. It has made groundbreaking contributions to the unusually early detection, tracking, diagnosis and study of Alzheimer's, and aims to find an effective prevention therapy by 2025. It includes the pioneering Alzheimer's Prevention Initiative (API), an extensive profile of research studies and clinical trials, comprehensive clinical, family and community service programs, a leading brain imaging research program, and strategic partnerships with numerous public and private research organizations around the world. Learn more at http://www.BannerAlz.org.

About Alzheimer's Prevention InitiativeThe Alzheimer's Prevention Initiative (API) is an international collaborative formed to launch a new era of Alzheimer's prevention research. Led by the Banner Alzheimer's Institute, the API conducts prevention trials in cognitively healthy people at increased genetic risk for Alzheimer's disease. It will continue to establish the brain imaging, biological and cognitive measurements needed to rapidly test promising prevention therapies and provide registries to support enrollment into Alzheimer's-focused studies. API is intended to provide the scientific means, accelerated approval pathway and enrollment resources needed to evaluate the range of promising Alzheimer's prevention therapies and find ones that work without losing another generation. For more information, visit http://www.alzheimerspreventioninitiative.com.

AboutEli Lilly and CompanyLilly is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by a man committed to creating high-quality medicines that meet real needs, and today we remain true to that mission in all our work. Across the globe, Lilly employees work to discover and bring life-changing medicines to those who need them, improve the understanding and management of disease, and give back to communities through philanthropy and volunteerism. To learn more about Lilly, please visit us at lilly.comand lilly.com/newsroom. P-LLY

Lilly Cautionary Statement Regarding Forward-Looking Statements

This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about donanemab as a potential treatment for people with Alzheimer's disease, the timing for Lilly's trials, and the benefits of a collaboration with Banner Alzheimer's Institute and reflects Lilly's current beliefs and expectations. However, as with any such undertaking, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that future study results will be consistent with study results to date, that donanemab will prove to be a safe and effective treatment for Alzheimer's disease, that donanemab will receive regulatory approval, that Lilly will realize the expected benefits of the collaboration, or that Lilly will execute its strategy as expected. For further discussion of these and other risks and uncertainties, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

SOURCE Eli Lilly and Company


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Lilly and Banner Alzheimer's Institute collaborate on planned Phase 3 prevention trial of donanemab - PRNewswire

Early signs of Alzheimer’s can show up in your driving – New Haven Register

Posted: at 1:54 am

According to a study, there are certain qualities that make it possible to distinguish the early stages of the disease.

Entrepreneur en Espaol,Entrepreneur.com

July 16, 2021Updated: July 16, 2021 2:07p.m.

A study led by researcher Sayed Bayat suggests that certain forms of driving may be related to the early stages of Alzheimer's disease. To test this theory, an experiment was conducted involving 139 people over 65 years of age in Washington, United States.

As the BBC reports, with medical tests (analysis of the cerebrospinal fluid and positron emission tomography) it was diagnosed that half of the participants were in an early phase of progressive disease and the other half were not. With this in mind, the driving analysis was started for one year, each car was fitted with a locating device based on the Global Positioning System to record the movements and times in detail.

The differences they identified were that preclinical Alzheimer's patients tended to log fewer miles, drive slower, travel less at night, limit routes, visit fewer destinations, and make abrupt changes. "The way people move in their everyday environment, from the places they visit to the way they drive, can tell us a lot about their health," said Sayed Bayat.

Thanks to the data collection, it was possible to design a first model that predicts the probability of having preclinical Alzheimer's only using age and driving data, it was 86% accurate. But adding the results of an apolipoprotein E (APOE) genotype genetic test resulted in a 90% accuracy. It must always be remembered that only a small percentage of people end up developing Alzheimer's when it is due to genetic inheritance.

It must always be remembered that only a small percentage of people end up developing Alzheimer's when it is due to genetic inheritance / Image: Depositphotos.com

This new model could avoid expensive and invasive medical procedures to diagnose preclinical Alzheimer's, even though it takes longer than normal. The National Institute on Aging of the United States mentions that family members may notice that their loved one takes longer to complete an easy trip, that he or she drives more erratically or gets confused on the pedal.

This article originally appeared on entrepreneur.com

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Early signs of Alzheimer's can show up in your driving - New Haven Register

Bone Therapeutics provides update on the progress of clinical studies – Yahoo Finance

Posted: at 1:53 am


JTA-004 Phase III top-line results planned first half September

ALLOB Phase IIb currently on track but recruitment slow due to COVID-19 pandemic

Gosselies, Belgium, 19 July 2021, 7am CEST BONE THERAPEUTICS (Euronext Brussels and Paris: BOTHE), the cell therapy company addressing unmet medical needs in orthopedics and other diseases, today provides an update on its two leading ongoing clinical studies.

These studies are the pivotal Phase III clinical trial with Bone Therapeutics enhanced viscosupplement, JTA-004, targeting osteoarthritic knee pain, and the Phase IIb study with its allogeneic cell therapy product, ALLOB, in patients with difficult-to-heal tibial fractures.

The JTA-004 Phase III clinical study, having achieved target patient recruitment in December 2020, has now completed the six-month follow-up in all patients. Bone Therapeutics expects to report topline results for the 3-month primary endpoint and 6-month follow-up data in the first half of September 2021.

The Phase IIb ALLOB clinical study in high-risk tibial fractures is currently experiencing a delay in patient recruitment due to the COVID-19 pandemic and the associated containment measures. This delay is as a result of fewer accidents and reduced availability of health care facilities in the first half of 2021. Bone Therapeutics has instituted corrective measures to mitigate the impact of the pandemic on recruitment for the trial, in collaboration with its clinical research organization. At this point, Bone Therapeutics does not expect the pandemic delay in recruitment rate to have a material effect on the anticipated completion of recruitment in H1 2022. As a result, Bone Therapeutics still currently expects to deliver top line results in H2 2022 as planned. Should the pandemic continue, Bone Therapeutics may have to re-evaluate these timelines and, in that eventuality, will communicate again to the markets.

The JTA-004 Phase III study is a controlled, randomized, double-blind trial. It is evaluating the potential of a single, intra-articular injection of JTA-004 to reduce osteoarthritic pain in the knee up to 12 months, compared to placebo or Hylan G-F 20, the leading osteoarthritis treatment on the market. The study is being conducted in 22 centers across six European countries as well as Hong Kong. More than 700 patients have been treated. These patients fulfill all the strict protocol criteria including mild to moderate symptomatic knee osteoarthritis.

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ALLOB is currently being evaluated in a randomized, double-blind, placebo-controlled Phase IIb study in patients with high-risk tibial fractures. This study will assess and compare against placebo, in association with standard of care stabilization surgery, the potential for ALLOB to accelerate fracture healing after 3-months follow-up and prevent late-stage complications in these patients, after a follow-up period of 6 months. ALLOB will be applied by a single percutaneous injection 24-96 hours post-definitive reduction surgery in patients with fresh tibial fractures at risk of delayed or non-union. Following the approval in seven European countries, the study is now in the process of enrolling 178 patients in over 40 sites.

About JTA-004

JTA-004 is Bone Therapeutics next generation of intra-articular injectable for the treatment of osteoarthritic pain in the knee, a highly prevalent joint condition affecting an estimated 250 million patients worldwide. It consists of a unique mix of hyaluronic acid - a natural component of knee synovial fluid, plasma proteins, and a fast-acting analgesic. JTA-004 intends to provide added lubrication and protection to the cartilage of the arthritic joint and to alleviate osteoarthritic pain. In a previous randomized, double-blind Phase II study involving 164 patients, JTA-004 showed superior clinical benefit with an improved pain relief at 3 and 6 months compared to Hylan G-F 20, the global market leader in osteoarthritis treatment.


ALLOB is Bone Therapeutics off-the-shelf allogeneic cell therapy platform consisting of human allogeneic bone-forming cells derived from cultured bone marrow mesenchymal stromal cells (MSC) from healthy adult donors. To address critical factors for the development and commercialization of cell therapy products, Bone Therapeutics has established a proprietary, optimized production process that improves consistency, scalability, cost effectiveness and ease of use of ALLOB. This optimized production process significantly increases the production yield, generating thousands of doses per bone marrow donation. Additionally, the final ALLOB product is cryopreserved, enabling easy shipment and the capability to be stored at the point of care for easy clinical use. The process will therefore substantially improve product quality, reduce overall production costs, simplify supply chain logistics, increase patient accessibility and facilitate global commercialization. The Company has implemented the optimized production process to produce clinical batches for the ongoing Phase IIb clinical trial in patients with difficult-to-heal tibial fractures.

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and other diseases. The Company has a, diversified portfolio of cell and biologic therapies at different stages ranging from pre-clinical programs in immunomodulation to mid-to-late stage clinical development for orthopedic conditions, targeting markets with large unmet medical needs and limited innovation.

Bone Therapeutics is developing an off-the-shelf next-generation improved viscosupplement, JTA-004, which is currently in Phase III development for the treatment of pain in knee osteoarthritis. Consisting of a unique combination of plasma proteins, hyaluronic acid - a natural component of knee synovial fluid, and a fast-acting analgesic, JTA-004 intends to provide added lubrication and protection to the cartilage of the arthritic joint and to alleviate osteoarthritic pain and inflammation. Positive Phase IIb efficacy results in patients with knee osteoarthritis showed a statistically significant improvement in pain relief compared to a leading viscosupplement.

Bone Therapeutics core technology is based on its cutting-edge allogeneic cell therapy platform with differentiated bone marrow sourced Mesenchymal Stromal Cells (MSCs) which can be stored at the point of use in the hospital. Currently in pre-clinical development, BT-20, the most recent product candidate from this technology, targets inflammatory conditions, while the leading investigational medicinal product, ALLOB, represents a unique, proprietary approach to bone regeneration, which turns undifferentiated stromal cells from healthy donors into bone-forming cells. These cells are produced via the Bone Therapeutics scalable manufacturing process. Following the CTA approval by regulatory authorities in Europe, the Company has initiated patient recruitment for the Phase IIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process. ALLOB continues to be evaluated for other orthopedic indications including spinal fusion, osteotomy, maxillofacial and dental.

Bone Therapeutics cell therapy products are manufactured to the highest GMP (Good Manufacturing Practices) standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available at http://www.bonetherapeutics.com.

For further information, please contact:

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerJean-Luc Vandebroek, Chief Financial OfficerTel: +32 (0)71 12 10 00investorrelations@bonetherapeutics.com

For Belgian Media and Investor Enquiries:BepublicCatherine HaquenneTel: +32 (0)497 75 63 56catherine@bepublic.be

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: +44 (0)20 8943 4685neil.hunter@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: +33 (0)1 44 71 94 94bone@newcap.eu

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such persons officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

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Bone Therapeutics provides update on the progress of clinical studies - Yahoo Finance

YishengBio Announces PIKA recombinant COVID-19 vaccine received Phase I clinical trial IND clearance from the UAE – Markets Insider

Posted: at 1:53 am

BEIJING, July 19, 2021 /PRNewswire/ -- YishengBio Co., Ltd("YishengBio") today announced that it has received IND clearance for PIKA recombinant COVID-19 vaccine to conduct Phase I clinical trial from United Arab Emirates Ministry of Health & Prevention. PIKA recombinant COVID-19 vaccine is a PIKA adjuvanted recombinant trimeric SARS-Cov-2 spike (S) protein subunit vaccine (CHO cells). YishengBio is a biopharmaceutical company focusing on discovery, development, manufacturing and commercialization of new generations of vaccines and therapeutic biologics in the field of infectious diseases and cancer.

Preclinical studies have demonstrated that PIKA recombinant COVID-19 vaccine is capable of inducing rapid and efficient production of neutralizing antibody and cellular immunity against the currently prevalent virus variants of SARS-CoV-2, including the variants from the United Kingdom, South Africa, Brazil and India. ThePIKA recombinant COVID-19 vaccine has achieved effective long-term protection broadlyagainst those prevalent variants even at day 406 post vaccination based on animal serum studies. In addition, PIKA recombinant COVID-19 vaccine exhibits promising therapeutic benefit in non-human primates challenge study.

Considering the evolvement of the COVID-19 pandemic around the world, YishengBio is going to initiate clinical studies and intends to seek approval to market YS-SC2-010 in multiple countries. With its universal profile against existing and emerging variants, PIKA recombinant COVID-19 vaccine has the potential to become both prophylactic and therapeutic vaccine. A state-of-art manufacturing facility is currently under construction with annual production capacity of up to one billion doses to meet the future need for mass immunization.

Mr. Yi Zhang, YishengBio's chairman and the project leader, expressed his enthusiasm saying "we are very pleased with this important milestone for PIKA recombinant COVID-19 vaccine. Since the outbreak of COVID-19, our research team has designed and optimized several recombinant protein antigen candidates and ultimately selected YS-SC2-010 antigen to move forward after rigorous screening and optimization efforts. PIKA adjuvant plays a critical role in the vaccine complex by enhancing both antibody and cellular immunity and ultimately providing broad and sustainable protective effect."

"Our proprietary PIKA adjuvant technology is based on TLR-3 agonist technology independently developed by our researchteam and has been granted over 60 patents among more than 30 countries with additional40 patents in application or review stage. PIKA technology has been used in developing a variety of new generation of vaccine candidates, such as PIKA rabies vaccine, PIKA immuno-oncology product, PIKA HBV vaccine and PIKA influenza vaccine. In addition, PIKA adjuvant technology can significantly reduce the dose of antigens used hence significantly increases vaccine production and provide vaccines to more countries and regions around the world, benefiting more people" commented by Mr. Yi Zhang.

Dr. Zhongkai Shi, chief medical officer of YishengBio shared his view saying"considering emergence of prevalent variants of concerns around the globe we would like to accelerate the clinical development plan of PIKA recombinant COVID-19 vaccine by conducting a series of clinical trials in China, Southeast Asia, the Middle East, the United States and Europe. We look forward to the desired clinical benefits and advantages of YS-SC2-010 to be demonstrated in human subjects, and the next clinical milestone of PIKA recombinant COVID-19 vaccine in the global fight against the COVID-19 pandemic."

About YishengBio

YishengBio is a fully integrated biopharmaceutical company with a global footprint that is discovering, developing and commercializing innovative biotherapeutics for infectious disease and cancer. The PIKA immunomodulating technology platform is developed in-house through which it empowered and nurtured a diverse pipeline of vaccines and therapeutic biologics with better efficacy and safety potential to address the unmet medical needs in infectious disease and cancer fields. In addition, YishengBio has a revenue generating marketed product, YSJA () rabies vaccine, which is the first aluminum-free lyophilized rabies vaccine launched in China. YishengBio's other product candidates also include PIKA rabies vaccine, PIKA recombinant COVID-19 vaccine, PIKA YS-ON-001, and PIKA YS-HBV-001, PIKA YS-HBV-002, PIKA YS-ON-002 and PIKA influenza vaccine. YishengBio is headquartered in Beijing with more than 600 employees in China, U.S., Singapore. For more information on Yisheng, please visit http://www.yishengbio.com.

About PIKA recombinant COVID-19 vaccine

PIKA recombinant COVID-19 vaccine is an innovative prophylactic and therapeutic vaccine candidate against multiple SARS-COV-2 variants.It isa PIKA adjuvanted recombinant trimeric SARS-Cov-2 spike (S) protein subunit vaccine (CHO cells). Preclinical studies have demonstrated that PIKA recombinant COVID-19 vaccine is capable of inducing rapid and efficient production of neutralizing antibody and cellular immunity against the currently prevalent virus variants of SARS-CoV-2, including the variants from the United Kingdom, South Africa, Brazil and India. ThePIKA recombinant COVID-19 vaccine has achieved effective long-term protection broadlyagainst those prevalent variants even at day 406 post vaccination based on animal serum studies, indicating good durability of the immune response. In addition, PIKA recombinant COVID-19 vaccine exhibits promising therapeutic benefit in non-human primates challenge study.

SOURCE Yisheng Biopharma Co., Ltd.

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YishengBio Announces PIKA recombinant COVID-19 vaccine received Phase I clinical trial IND clearance from the UAE - Markets Insider

Biological functions and clinical studies of FGF21 | DMSO – Dove Medical Press

Posted: at 1:53 am


Fibroblast growth factors (FGFs) are widely expressed in the human body and have numerous and complicated physiological functions. FGFs regulate cell growth, proliferation, differentiation, and metabolic modulation, tissue repair, and inflammatory response.1,2 FGFs can be divided into three types (classic, intracellular and hormone-like types) based on their action modes.3 Classic and intracellular FGFs mostly act in an autocrine or paracrine way,4 while hormone-like FGFs mainly act in the endocrine way.5 Most autocrine and paracrine FGFs have a high affinity for the heparin glucosamine sulfate (HSGAG), which promotes the binding of the FGFs to the tyrosine kinase FGF receptor (FGFR1-4) on the cell surface, inducing FGFR activation, dimerization, and activation of downstream signaling pathways.69 HSGAGs can also stabilize FGFs, prevent FGFs degradation, and limit the diffusion range of FGFs.10

FGF21 is a member of the FGF19 subfamily in the FGFs family and belongs to the hormone-like FGFs. Compared to other FGFs members, FGF21 has three special features: 1. It has no obvious mitogenic or tumor-promoting function;11 2. The spatial configuration variation of the region that binds to HSGAGs makes it have a weaker affinity for HSGAG, thus not easily bound in the extracellular matrix. However, it enters the circulation in the form of endocrine hormones to regulate metabolism and cross the blood-brain barrier through simple diffusion;12 3. It does not directly bind to cell receptors, and it needs -Klotho protein to form a stable combination to play its physiological role. Herein, the latest research progress on FGF21 is summarized.

Unlike the classical FGFs, FGF21 binds to FGF receptors (FGFRs) and the co-receptor protein -Klotho (a single transmembrane protein expressed during the differentiation of adipose precursor cells into adipocytes). Besides, FGF21 activates the signal transduction downstream only when FGFRs and -Klotho are dimerized and autophosphorylated.13,14 Neither -Klotho nor FGFRs can be activated by FGF21 alone.15 In the FGF21-FGFRs--Klotho complex, -Klotho, a zip code-like receptor, is the main high-affinity receptor of FGF21, providing the targeted signals for FGF21. At the same time, FGFR acts as a catalytic subunit that mediates receptor dimerization and intracellular signal transduction.16 Studies have also shown that the C-terminus and N-terminus are involved in activating FGF21 receptors, and any deletion of the terminus greatly reduces FGF21 activity. The C-terminus of FGF21 has a sugar-mimicking Ser-pro-Ser motif, which can be recognized and bound by -Klotho. Besides, the C-terminus mutation of FGF21 is associated with an affinity decrease of -Klotho, indicating that the C-terminal also mediates the binding of FGF21 and -Klotho. Although the N-terminal mutation of FGF21 is also associated with decreased activity, it can still bind to -Klotho, suggesting that the N-terminal only participates in the receptor activation process.1619 Therefore, complete C-terminal and N-terminal structure and simultaneous binding to -Klotho and FGFRs promote the physiological functions of FGF21.

Studies have shown that FGF21 is highly expressed in the liver, skeletal muscle, kidney, heart, fat, and blood vessels.20 FGF21 (mainly produced by liver cells) is also expressed in the blood circulation due to its hormone-like characteristics,21 targeting the heart, bones, kidneys, small intestine, and brain because of its strong diffusion and distribution ability.13 However, FGF21 produced in adipose tissue most acts in an autocrine or paracrine manner on the metabolic regulation of itself and adjacent tissues.22 Moreover, the expression level of FGF21 varies greatly in different tissues and under different conditions. FGF21 expression level can be regulated in the following ways;

Numerous transcription regulators can also regulate the FGF21 expression level. For instance, peroxisome proliferator-activated receptor (PPAR) can regulate FGF21 expression by binding to the transcriptional regulatory element at the beginning of the FGF21 promoter region, and FGF21 and PPAR can regulate each other. PPAR contains three subtypes: PPAR, PPAR/, and PPAR. PPAR and PPAR can induce FGF21 expression. PPAR can induce FGF21 expression in the liver,23 and FGF21 level in the liver of mice was significantly increased after the administration of PPAR agonist fenofibrate, indicating the effect of PPAR on promoting FGF21 expression. Similarly, PPAR can regulate the expression and function of FGF21 in adipose tissue. Muise et al24 found that the PPAR agonist rosiglitazone can activate PPAR, promoting fat cells to produce FGF21 and synergistically regulating FGF21 to accelerate glucose uptake and utilization. Conversely, FGF21 in the tissue can also activate PPAR and PPAR . Dutchak et al25 indicated that FGF21 induced by PPAR in adipose tissue can increase its transcription by inhibiting PPAR ubiquitination. These processes form a cyclic loop of PPAR, PPAR, and FGF21 and feed-forward to regulate FGF21 expression.

Recent studies have indicated that microRNAs (miRNAs) are associated with the regulation of metabolism and metabolic disorders.26 MiRNAs primarily bind to the 3-untranslated region (3UTR) of mRNAs, inhibiting mRNAs translation and regulating the expression of related genes. The activity of the 3UTR of FGF21 mRNA in the liver can be inhibited by circulating exosomal miRNAs, in which miR-99b is the identified regulatory factor.27 Furthermore, anti-miR-577 therapy can protect and restore the insulin regulation of FGF21 and improve the survival and function of diabetic pancreatic -cells.28,29 MiR-212 can inhibit FGF21 expression in HepG2 cells in non-alcoholic fatty liver disease (NAFLD), while miR-212 inhibitors can increase FGF21 protein level and reduce lipid synthesis. Si-FGF-21 silences the expression of FGF21, significantly increasing the lipid content in HepG2 cells, thus hindering the anti-lipid effect of miR-212 inhibitors in these cells.30 Collectively, these suggest that miR-212 targets FGF21, thus regulating FGF21 expression.

Fasting, ketogenic diet, high-sugar diet, and high-fat diet are all important transcription inducers for FGF21 expression. Fasting can strongly induce FGF21 expression.31 A ketogenic diet or fasting can significantly increase FGF21 expression by recruiting PPAR in the region near the FGF21 transcriptional promoter.23,32 Notably, neither the ketogenic diet (up to 3 months) nor short-term fasting (up to 48 hours) can increase serum FGF21 levels in humans.23 However, prolonged fasting (710 days) can increase serum FGF21 levels in humans, possibly due to the different metabolic rates and fasting tolerances among different species.33 A high-fat diet induces excessive unsaturated fatty acids and bile acids, increasing the transcription and secretion of FGF21 in the liver by activating the farnesoid X receptor (FXR) and PPAR.34 Lundsgaard et al35 found that a high-carbohydrate diet can also induce FGF21 gene expression in the liver.

FGF21 can also be highly expressed under oxidative stress, energy stress, endoplasmic reticulum stress, cold stress, and mitochondrial dysfunction, and its expression is also regulated by sodium butyrate, metformin, glucocorticoids, etc.3638 Animal studies have shown that one-time acute exercise (60 minutes on a treadmill or until repeated electrical stimulation rendered normal running impossible) promotes gene expression in the liver of mice and increases serum levels of FGF21. Clinical trials have also shown that 30 minutes of acute aerobic exercise can also increase circulating FGF21 levels.39 FGF21 expression level in skeletal muscle is very low in healthy conditions, and circulating FGF21 mainly comes from the liver. However, the expression of myogenic FGF21 significantly increases in some stress states, such as hunger, endoplasmic reticulum stress, mitochondrial dysfunction, etc.40,41 Kim et al42 found that the FGF21 content significantly increased in the soleus muscle of Zucker diabetic obese rats after 12 weeks of resistance exercise. However, the phenomenon was not observed in the gastrocnemius muscle.

Earlier research on FGF21 function mainly focused on reducing blood sugar and lipids, lowering body weight, improving insulin resistance (IR), and cardiovascular diseases related to abnormal glucose and lipid metabolism, such as coronary heart disease, heart remodeling.12,43 In recent years, the functions of FGF21 in inhibiting inflammation, reducing oxidative stress levels,44,45 and inhibiting apoptosis of endothelial cells46 and cardiomyocytes47 have been studied. The regulatory effects of FGF21 on metabolic diseases, such as obesity, hyperlipidemia, and hyperglycemia, the damage repair effects on inflammation and apoptosis, and the blocking effects on some cancers indicate that FGF21 has a broad prospect for development. Studies have shown that FGF21 mainly participates in the processes of material metabolism, heart and brain damage by activating Adenosine 5-monophosphate (AMP)-activated protein kinase (AMPK), serine/threonine protein kinase (Akt), and extracellular-regulated protein kinases (ERK) and other downstream factors. FGF21 plays metabolic regulation functions, such as promoting glucose uptake, gluconeogenesis, increasing the oxidation of free fatty acids, promoting ketogenesis, increasing energy production and utilization.48,49 FGF21 also has the effect of apoptosis protection and neurocognitive function recovery.

Insulin, as one of the most important humoral factors regulating glucose metabolism, enhances glucose absorption by activating the Phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and promoting the expression of glucose transporter 4 (GLUT4).50 FGF21 can also activate the PI3K signaling pathway and regulate Akt activation. However, FGF21 mainly inhibits the expression of related gluconeogenesis and glucose production by inducing phosphorylation of atypical protein kinase C (PKC) I/L and exerts insulin-like hypoglycemic effect to control blood glucose balance.51 Ge et al52 found that glucose transporter-1 (GLUT1) promoter is highly conserved in serum response element (SRE) and E-26 (ETS) binding motifs. FGF21 binds to the receptor to activate the downstream factor extracellular signal-regulated kinases (ERK1/2)), and then activate ETS-like protein-1 (ELK-1) and serum response factor (SRF, the downstream target of ERK1/2), enhancing glucose uptake and reducing blood glucose concentration by combining the promoter sequence of GLUT1 gene, trans-activating GLUT1 gene and inducing GLUT1 expression. Furthermore, there can be a synergistic effect between insulin and FGF21. Insulin can activate PKC, enhancing the FGF21 regulation effect on the GLUT1 expression through the ERK1/2-SRF/Elk-1 pathway.53 FGF21 can also improve insulin sensitivity and enhance the hypoglycemic effect of insulin. The mammalian target of rapamycin complex 1 (mTORC1) and its downstream effector, ribosomal protein S6 kinase 1 (S6K1), are the key regulators of nutritional overload-induced insulin resistance and the pathogenesis of type 2 diabetes mellitus (T2DM).54 S6K1 phosphorylates insulin receptor substrate 1 (IRS-1), thereby destroying PI3K, a key molecular basis for inducing IR. FGF21 binds to the receptor complex, downregulating mTORC1 in a tuberous sclerosis complex (TSC)-dependent manner, thus activating downstream pathways to improve insulin resistance and increase insulin sensitivity.55 Notably, FGF21 has a two-way regulatory role in lowering and raising blood sugar levels. Besides, animal experiments and clinical trials have shown different functions of FGF21 and the body regulation mechanism of normal and abnormal metabolism.

Rat experiments showed FGF21 improves IR, increases insulin sensitivity, and reduces blood insulin concentration.12 FGF21 analogues also improve IR, reduces blood glucose and insulin levels, and improve glucose tolerance in primates.56 Moreover, scholars have discovered that adipose tissue is a key target of FGF21 for glucose metabolism regulation, and a certain amount of adipose tissue in mice is the guarantee for FGF21 to regulate blood sugar.57 Clinical trials have shown that FGF21 analogues (LY2405319, PF-05231023, BMS-986036, etc.) also lower blood glucose. However, their effect on lowering blood glucose was not significant.17,58,59 Further studies have shown that FGF21 also promotes gluconeogenesis and maintains blood glucose balance, preventing hypoglycemia occurrence.12

FGF21 reduces blood glucose by promoting the phosphorylation of Akt via insulin, thereby upregulating the number of insulin receptors, increasing insulin sensitivity, and alleviating chronic inflammatory response, thus improving IR, thus regulating glucose metabolism.6062 Second, FGF21 can upregulate adiponectin expression in adipocytes by activating the PPAR signaling pathway to promote GLUT4 migration from cytoplasm to cell membrane, or directly promoting GLUT1 expression, increasing glucose transport and lowering blood glucose.22,63,64 FGF21 can also act on pancreatic islets and indirectly induce a hypoglycemic effect. FGF21 can inhibit islet cells to reduce glucagon secretion,12 inhibiting the synergistic toxicity of glycolipid and cytokine-induced cell apoptosis, reducing the damage of islet cells and enhancing the function of islet cells, thereby improving blood sugar level.65

In terms of gluconeogenesis, studies have shown that FGF21 can increase and maintain blood sugar under fasting or starvation.66 FGF21 secreted by tissue cells can cross the blood-brain barrier and directly act on the hypothalamus through the hypothalamic-pituitary-adrenal axis, stimulating the synthesis and release of adrenal corticosterone increasing blood glucose via liver gluconeogenesis.67 Furthermore, FGF21 can bind to FGFRs in the liver to activate the downstream RAS-RAF-MAPK signaling pathway via the -Klotho, resulting in a cascade reaction. FGF21 then induces the expression of early liver genes, such as PPAR coactivator-activated receptor- coactivator 1 (PGC1) gene, which increases the transcriptional activity of PPAR. It upregulates the expression of gluconeogenesis-related genes, thereby regulating gluconeogenesis.68,69

FGF21 is an adipokine, which regulates blood lipid. It can significantly reduce the plasma levels of total cholesterol (TC), low-density lipoprotein (LDL), and triglyceride (TG) and increase the plasma levels of high-density lipoprotein (HDL) and adiponectin in normal subjects.70 A study indicated that diet-induced obese mice and hereditary db/db obese mice have weight loss, reversal of liver steatosis, and reduction in plasma TG levels changes after several weeks of continuous FGF21 administration. Plasma TC and LDL levels decrease, while HDL level increases in a dose-dependent manner in mice administered with different FGF21 doses.71,72 Similar findings were found in diabetic monkeys. Besides the decrease in blood glucose to the normal level, the decrease of blood insulin level, and the enhancement of the bodys sensitivity to insulin, blood lipid also decreased, especially the selective decrease of TG and LDL. At the same time, HDL showed an upward trend after long-term injection of FGF21 in diabetic monkeys.73

FGF21 also plays an important role in liver fat metabolism. Liu et al74 indicated that long-term alcohol exposure induces liver damage and steatosis, inducing the body to upregulate FGF21 as compensation. Knockout of the FGF21 gene inhibits -oxidation of liver fatty acids, aggravating alcoholic steatohepatitis (ASH). However, recombinant FGF21 alleviates liver steatosis and inflammation induced by ASH. Furthermore, the treatment of rodent and non-human primate model animals of NAFLD, FGF21 analog, and B1344 showed an inhibited liver inflammation and natural immune cell infiltration, reduced liver injury and hepatocyte death, significantly improved liver lipid accumulation, liver fibrosis, and prevented further development of non-alcoholic steatohepatitis (NASH).75 However, B1344 has greater potency, higher maximum response, and lower immunogenicity than FGF21.

Humans and animals have white adipose tissue (WAT) and brown adipose tissue (BAT). The WAT mainly stores metabolic surplus energy in the form of TG, which causes weight gain.76 Unlike WAT, BAT is rich in multi-crystal mitochondria, which is the main source of non-shivering thermogenesis. BAT maintains the body temperature and energy balance by increasing the uptake of glycolipids and using uncoupling protein 1 (UCP1) to decouple biological oxidation from ATP synthesis, thus converting energy released via biological oxidation into heat, reducing ATP synthesis.77,78 FGF21 can upregulate the expression of UCP1 and other thermogenesis genes, promoting the Browning of WAT, thus regulating the balance between body temperature and energy.79 However, scholars have also found that FGF21 regulates energy metabolism only in mice with abnormal metabolism.79,80 Furthermore, Liver kinase B1 (LKB1) phosphorylation activates AMPK, thereby increasing the content of NAD+ in cells, activating Sirtuin 1 (SIRT1), thus promoting mitochondrial energy transformation in skeletal muscles.8183 FGF21 in skeletal muscle is also transported to adipose tissue through blood circulation, increasing the level of FGF21 in WAT and further inducing the expression of silent mating type information regulation 2 homolog 1 (SIRT1), PGC1 , UCP1 and other factors, thus promoting the Browning of WAT and increasing energy consumption.84 Collectively, the above studies indicate that FGF21 maintains the energy balance of the body with abnormal metabolism through the regulation of glucose and lipid metabolism, which does not affect the normal metabolism in the body.

Recent studies have shown that FGF21 has an important protective effect on the heart, reflected by reducing myocardial cell apoptosis, antagonism against ischemia-reperfusion injury (IRI), and oxidative stress reaction. Roberts et al85 and Cong et al86 showed that FGF21 could inhibit the activity of the apoptotic factor C-caspase 3 through the PI3K /Akt signaling pathway, increase cardiac energy supply through the AMPK pathway, thus inhibiting the apoptosis of cardiomyocytes. Moreover, FGF21 interferes with the PER K-eIF2-ATF4-CHOP signaling axis during endoplasmic reticulum stress, activating the ATF4 signaling pathway and promoting the phosphorylation of c-Jun N-terminal kinase (JNK), thus reducing the accumulation of abnormally folded proteins and inhibiting myocardial cell apoptosis.87 FGF21 can also effectively prevent palmitate-induced cardiac apoptosis by upregulating the ERK1/2-dependent p38 mitogen-activated protein kinase (MAPK)-AMPK signaling pathway88 and reduce cardiomyocyte IRI and apoptosis after oxidative stress through PI3K/AKT-dependent pathways. 1. FGF21, as an antioxidant factor, induces the expression of antioxidant genes, such as Ucp3, Ucp2, and Sod2 in the heart, thereby preventing the production of reactive oxygen species (ROS).89 2. FGF21 can also activate MAPK to produce a cascade reaction by binding FGFR1c/-klotho. Therefore, FGF21 can promote the activation of AMPK, the target gene of Liver kinase B1 (LKB1), and reduce the accumulation of ROS, inhibiting apoptosis.89 3. FGF21 promotes transcriptional activation of PPAR by regulating PPAR coactivator 1, thus controlling energy metabolism and oxidative stress in multiple tissues,90 inducing a protective role on cardiac hypertrophy.

Although it is unknown whether the brain can directly generate FGF21, it has been proved that FGF21 can move to the brain through the blood-brain barrier via simple diffusion,91,92 playing a key role in metabolic regulation, neuroprotection, and the potential role of cognition.

FGF21 can bind to FGFRs and -klotho expressed in the hypothalamus, the suprachiasmatic nucleus (SCN), paraventricular nucleus of the hypothalamus (PVN), and other regions of the brain, and act on the Hypothalamus-pituitary-adrenal axis (HPA) and hypothalamic-pituitary-gonad axis (HPG) to regulate the levels of corticotropin-releasing hormone (CRH) and vasopressin (AVP). The increased release of CRH can promote the substantial release of adrenal cortex hormones, which combine with the liver to induce PGC1 expression. Therefore, FGF21 can upregulate the expression of gluconeogenesis genes, such as glucose 6 phosphatase and phosphoenolpyruvate carboxykinase via PGC1, increasing liver gluconeogenesis and preventing hypoglycemia.67 Moreover, increased CRH in the circulation can increase sympathetic nerve activity in BAT, upregulate UCP1 expression and increase lipolysis in BAT, leading to an increase in energy use and a decrease in weight gain in diet-induced obese mouse models.93 The inhibited release of AVP decreases kisspeptin in the hypothalamus, causing a decrease in the release of luteinizing hormone, affecting ovulation and fertility.94

Several studies have shown that FGF21 has an important protective effect on nerve injury and cognitive impairment. Shahror et al95 showed that FGF21 can significantly improve the spatial memory deficits, hippocampal nerve damage, and dendritic morphology abnormalities induced by traumatic brain injuries (TBI). Therefore, FGF21 alleviates TBI-induced defects in neurogenesis and maturation of immature hippocampal neurons, thereby restoring the hippocampal independent learning and memory impairment caused by TBI. Sa-Nguanmoo et al96 also confirmed that FGF21 enhances hippocampal synaptic plasticity, increases the density of dendritic spines, restoring the function of brain mitochondria. FGF21 can prevent defective neuroprotective molecules in astrocytes, alleviating memory dysfunction and neurodegeneration, such as amyloid plaque pathology and pathological Tau hyperphosphorylation, thus acting as a neuroprotective agent in Alzheimers disease (AD).97,98 FGF21 can also protect the blood-brain barrier after ischemic stroke by activating PPAR in cerebral blood vessels,99 antagonize the M1 polarization of microglia and the accumulation of pro-inflammatory cytokines by inhibiting NF-B and upregulating PPAR, and reduce cerebral edema and inflammation after TBI and stroke.100,101

The level of FGF21 in normal human circulation is low, while it is significantly increased in patients with atherosclerosis, hypertension, and liver disease.102104 Some scholars have also indicated that FGF21 levels in obese or hyperlipidemia patients are 1.52 times higher than in normal people. Patients with renal insufficiency may also accumulate FGF21, while FGF21 levels in patients with long-term malnutrition (such as patients with anorexia nervosa) are low.105107 FGF21 expression is decreased in patients with type 1 diabetes mellitus (T1DM) and increased in patients with T2DM in individuals with abnormal glucose metabolism, indicating that FGF21 resistance or compensatory increase may exist in patients with T2DM.108 Similarly, FGF21 up-regulation occurs in patients with metabolic syndrome,109 possibly because FGF21 plays a compensatory role in the early stage of the disease, promoting the occurrence and development of the disease. Li et al110 found that the plasma FGF21 content and liver FGF21 levels are significantly higher in NAFLD patients than in healthy people. Therefore, FGF21 may be a new biomarker for NAFLD diagnosis. Taken together, these findings indicate that FGF21 has broad prospects as a serum marker in the prevention, diagnosis, treatment, and efficacy evaluation of metabolic abnormalities. Presently, FGF21 has been partially used in clinical practice.

The routine auxiliary examination items, such as serum lactic acid, alanine, creatine kinase have low specificity and sensitivity during the diagnosis of mitochondrial diseases. Recent studies have shown that serum levels of FGF21 are elevated when mitochondrial DNA mutations occur in skeletal muscle but not when similar mutations occur in other organs. Therefore, serum FGF21 is a relatively good biomarker for muscle mitochondrial diseases than other indicators.111

Serum FG21 can also be used for early disease detection. For instance, the incidence rate of myocardial ischemia, cardiac hypertrophy, and diabetic cardiomyopathy is positively correlated with serum FGF21 levels.112114 Some studies have also indicated that higher serum FGF21 levels are associated with a higher risk of coronary heart disease, NAFLD, and T2DM.89,115117 Besides, higher circulating FGF21 levels are associated with higher mortality in patients with end-stage renal disease.110 However, animal experiments and clinical trials have shown different results. Therefore, further studies are necessary to determine whether FGF21 can be used as a molecular marker for the early diagnosis and evaluation of related diseases.

FGF21 also has important clinical significance for disease treatment. Animal experiments have shown that the metabolic phenotypes, such as decreased blood glucose, serum TC and TG levels, increased insulin sensitivity and glucose uptake of two groups of mice overexpressing human and mouse FGF21 are highly similar. However, there are also some differences. For instance, the weight and body fat rate of mice overexpressing human FGF21 decreased, while those overexpressing mouse FGF21 were obese and unresponsive despite having normal metabolism.17 This study provides a basis for the clinical treatment of FGF21. Clinically, FGF21 levels are elevated in patients with various metabolic abnormalities. In contrast, the findings have shown that FGF21 effectively treats various metabolic abnormalities in animal models. However, it is speculated that the phenomenon is similar to hyperinsulinemia. The increase of FGF21 may be due to FGF21 resistance produced by the activation of its compensatory mechanism,118 indicating that the elevated FGF21 is the bodys self-protection mechanism. Therefore, FGF21 can treat metabolic disorders, such as diabetes and lipid metabolism disorders, because it does not possess the classic mitogenic activity of the FGFs.119

This article reviews the metabolic regulation, injury protection, and other physiological and pathological functions of FGF21 in various tissues and organs in the body, such as the liver, heart, brain, and adipose tissue, and related regulatory mechanisms. To date, the relevant signal pathways of FGF21 have not been fully elucidated. Therefore, an in-depth study on the systemic biological functions and regulatory pathways of FGF21 can promote the prevention and treatment of metabolic disorders, such as diabetes and obesity, and cardiac and brain diseases, such as myocardial IRI and AD, TBI, and stroke.

The authors report no conflicts of interest in this work.

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73. Kharitonenkov A, Wroblewski VJ, Koester A, et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology. 2007;148(2):774781. doi:10.1210/en.2006-1168

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Biological functions and clinical studies of FGF21 | DMSO - Dove Medical Press

Dying patients with rare diseases struggle to get experimental therapies – The Detroit News

Posted: at 1:53 am

Christina Bennett| Kaiser Health News

At 15, Autumn Fuernisen is dying. She was diagnosed at age 11 with a rare degenerative brain disorder that has no known cure or way to slow it down: juvenile-onset Huntingtons disease.

Theres lots of things that she used to be able to do just fine, said her mom, Londen Tabor, who lives with her daughter in Gillette, Wyoming. Autumns speech has become slurred and her cognitive skills slower. She needs help with many tasks, such as writing, showering and dressing, and while she can walk, her balance is off.

Autumn has been turned down for clinical trials because she is too young.

It is so frustrating to me, Tabor said. I would sell my soul to try to get any type [of treatment] to help my daughter.

For patients like Autumn with serious or immediately life-threatening conditions who do not qualify for clinical trials and have exhausted all treatment options, there may be another option: seeking approval from the Food and Drug Administration for expanded access, or compassionate use, of experimental therapies.

Definitive numbers are hard to find, but studies from researchers, actions by drugmakers and insights from experts suggest that getting expanded access to unproven therapies for rare diseases is more difficult than for more common illnesses, such as cancer.

Even with experimental treatments on the rise, patients with rare diseases frequently face an unwillingness by drug companies to provide them before clinical studies are completed. Developing drugs for these diseases is an especially fragile process because the patient populations are small and often diverse, having different genetics, symptoms and other characteristics, which makes studying the drugs effects difficult.

Drugmakers believe offering a drug before studies are finished could impair its development and jeopardize FDA approval.

Companies working on therapies for rare diseases, especially smaller ones, could feel those repercussions acutely, said Lisa Kearns, a researcher in the ethics division of New York Universitys medical school and member of the divisions working group on compassionate use and preapproval access. Theres not as much investment in rare diseases, so an [adverse] event could frighten the already limited number of potential investors.

Drugs that were not made available for compassionate use last year until studies were completed include Evrysdi, for spinal muscular atrophy; Enspryng, for an autoimmune disease of the optic nerve and spinal cord called neuromyelitis optica spectrum disorder; and Viltepso, for certain patients with Duchenne muscular dystrophy.

A spokesperson for Roche, which makes Evrysdi and Enspryng and is working on a treatment for Huntingtons disease, said the decision was tied not to the type of disease but to company policy: Roche does not set up expanded access programs for any drugs until results are available from a phase 3 clinical trial. (Those phase 3 studies are typically the last testing done before the company seeks drug approval.)

Another companys experimental drug for myasthenia gravis, an autoimmune disease that leads to skeletal muscle weakness, similarly was not available through an expanded access program until research was completed last year, and no programs have started for a therapy being studied in a phase 3 clinical trial for Huntingtons disease and for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease often referred to as Lou Gehrigs disease.

One slight, but notable, deviation: Drugmaker Biogen agreed this year to allow certain ALS patients to receive an experimental drug as early as July 15, after the testing was to be completed but before the results are known.

Dr. Merit Cudkowicz, a neurologist at Massachusetts General Hospital in Boston, has helped patients get therapies through expanded access. Since September 2018, she and colleagues launched 10 programs that seek to match people with ALS therapies being developed by drug companies, but only about 120 patients have received therapies this way. More than 16,000 people in the United States were estimated in 2015 to have ALS and most do not qualify for clinical trials because of the progression of their disease or very strict eligibility requirements.

These examples contrast with some drugs for more common problems. Gleevec, for leukemia, was offered to thousands of patients through expanded access programs before the manufacturer completed the clinical studies that led to FDA approval. Videx, for HIV/AIDS, and Iressa, for the most common type of lung cancer, were similarly offered to large numbers of patients even as clinical trials were ongoing.

Last year, Novartis gave more than 7,000 patients worldwide early access to cancer drugs.

Doctors also report that getting experimental drugs for cancer patients is relatively simple. More than 200 physicians around the country were surveyed, and among those who applied for access, nearly 90% said they had secured drugs still being investigated for patients who were not responding to approved therapies.

California researchers found similar trends in a review of 23 social media campaigns launched by patients between 2005 and 2015 seeking a variety of experimental treatments. While seven of the 19 patients with cancer received early access to requested drugs, no access was allowed for three patients with rare diseases, although one of those patients was allowed to enroll in a clinical trial.

Companies base their decisions on whether to provide a therapy through expanded access on a number of factors, said Jess Rabourn, CEO of WideTrial, which helps pharmaceutical companies run compassionate use programs. In general, there should be evidence that patients can tolerate the treatment and an expectation that any benefit outweighs the risk, he said.

This idea that you have to wait until the research is done is baloney, he said. Were talking about patients who are going to die if theyre told to wait.

But drugmakers often view it differently, even though evidence suggests that granting early access very rarely disrupts drug approval.

Kearns explained that companies often wait until phase 3, or after, because they can be relatively confident of a drugs safety and effectiveness. They dont want to harm patients, of course, but they also do not want to threaten the drugs eventual regulatory approval with an adverse event in [a] very sick patient population.

Melissa Hogan, who consults on clinical trials for rare diseases and is an FDA patient representative, attributes the lack of access to the high cost of therapies and the tightknit nature of the rare disease community, where patients and their families often set up social media groups and exchange ideas and treatment plans. Companies know that if one patient gains access, other patients will know and ask for access, said Hogan, who has a son with mucopolysaccharidosis type II. That could overwhelm small drugmakers with little manufacturing capacity.

These concerns cause many companies [to] just throw up their hands and take a hard line of no [expanded access] until they reach approval stage, said Hogan.

The 2018 Right to Try law offers another option for some patients. Unlike expanded access, the law applies only to requests for medicines not medical devices and does not require approval from the FDA or an institutional review board, a committee that reviews and monitors people participating in research for their protection. The legislation, however, doesnt oblige companies to grant a request.

For Cali Orsulak, expanded access may be her husbands only option. He was diagnosed with ALS in 2019 at age 43.

We did our best with the skill level we had to search clinical trials all over Canada and the U.S., and then covid hit and it became increasingly difficult, said Orsulak, explaining that they live in Canada but seek medical care in the United States. Now that my husband has progressed, its even harder to get into clinical trials.

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Dying patients with rare diseases struggle to get experimental therapies - The Detroit News

Tezepelumab as an Emerging Biologic to Treat Asthma – MD Magazine

Posted: at 1:53 am

Reynold Panettieri Jr, MD: Lets transition. The alarmin cytokines was a perfect setup. TSLP, IL-33, IL-25: these are cytokines, liberated by the epithelium after injuryvirus, toxic, allergicthat then rain down into the effector cells. I imagine that epithelial muscle interaction really doesnt need other players, because many of these receptors are found on the muscle. You could have an uncoupling of airway inflammation from asthma, or airway hyperresponsiveness or bronchoconstriction, which wasnt really recognized before. Everything was felt to be but IL-33 or TSLP can directly affect the muscle and excitation-contraction coupling [actin and myosin binding]. I dont need another immunocyte to transmit that signal. Nic, do you want to discuss tezepelumab? This is really exciting. This is a new biologic. Its not out. Its still in development, but the phase 3 trials are going on and theyre encouraging. What excites you, Nic?

Nicola Hanania, MD, MS: Everything you said excites me. This light at the end of the tunnel for these patients that we see every day keeps us going and keeps the hopes up. We talked about smooth muscles, which also is something that is of interest to me. But another very important structural set of cells in the airway that has been focused on is the airway epithelium. The airway epithelium is like the scene of the crime. The exposuresallergen, microbes, smoke, pollutantsare the first hit to the airway, so the airway epithelium has been the focus of potentially new drugs. Because of this, alarminsthese are the cytokines you mentioned, Reyincluding the thymic stromal lymphopoietin, which is TSLP, interleukin 33, and interleukin 25. These are the alarmins, which are important epithelial cytokines that drive inflammatory cascade down to the different pathways that we talked about: not only the T2 pathway but the non-T2 pathway. In fact, emerging data suggest that TSLP can play a key role in not only allergic inflammation but eosinophilic inflammation and, potentially, neutrophilic inflammation.

Which really makes you think, Why do we even need to phenotype? We give this blanket type of block, this type of cytokine. Tezepelumab is 1 of these more advanced monoclonal antibodies that blocks TSLP. There are several others: antiIL-33, inhaled TSLP. Tezepelumab is an injectable subcutaneous monoclonal antibody thats given for patients with severe asthma, in the hope that it blocks T2 inflammation. Were going to talk more about clinical trials. Some of these clinical trials show that it blocks non-T2 signals as well. Its certainly something that has been a long time in the making, and Im hoping well see the clinical outcomes, at least in our clinic. We know there are clinical studies that suggest that tezepelumab is good in its efficacy and safety.

Reynold Panettieri Jr, MD: Sid, any comments on Nics observations?

Sidney Braman, MD: Yeah. One other thing that we know about asthma is that if theres a virus around, and they catch that rhinovirus, or respiratory syncytial virus, or even severe influenza, theyre going to have an exacerbation. Its really well known that the virus stays around in the nose and throat longer. The viral shedding lasts much longer. We know that not only are the viral symptoms worse, but this causes more severe exacerbations. We also know that these viruses attack the epithelium. This is really 1 of the exciting aspects of the alarming storythe antialarming, like the anti-TSLP. Will they begin to show some effect on the other viral-induced respiratory exacerbation of asthma? Theres probably some reason to think so.

Reynold Panettieri Jr, MD: Yeah. The concept of the viral-mediated or toxic-mediated airway inflammation, which then extends exacerbations, is relatively straight insensitive too. We use steroids, of course, with an exacerbation. Dont get me wrong, but these are not the ones that are weakly resolved; not like a typical allergic exposure exacerbation. Those people really respond to steroids quickly. We see the viral, or the toxicant, patients languish a bit as we eventually get bored treating them with steroids and we taper them off. So you raised some really important points.

Thank you for watching this HCPLive Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. It comes to you wherever youre at: on your phone, in your office, or in your home. I want to thank everyone and our sponsors for this wonderful opportunity. Have a wonderful day, and be safe. Thank you.

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Tezepelumab as an Emerging Biologic to Treat Asthma - MD Magazine

Inotrem Receives Approval to Expand Nangibotide Clinical Trial in Critically Ill COVID-19 Patients and Receives Additional Public Funding of 45…

Posted: at 1:53 am

PARIS--(BUSINESS WIRE)--Inotrem S.A., a biotechnology company specializing in the development of immunotherapies targeting the TREM-1 pathway, announces that it has obtained authorization to pursue the clinical development of nangibotide up to registration in COVID-19 patients from both the French and Belgian competent authorities.

As part of this program, Inotrem receives additional 45 million euros in public funding under the "Capacity Building" Call for Expression of Interest, operated on behalf of the French government by Bpifrance, the French national investment bank, as part of the Programme dinvestissements davenir (PIA) and the France Recovery Plan, bringing French state support for the project to a total of 52,5 million euros. This public funding will support Inotrems clinical program including the phase 2/3 study ESSENTIAL which aims to demonstrate the efficacy and safety of nangibotide in treating patients in respiratory distress with severe forms of COVID-19.

The primary endpoint is evaluation of the impact of nangibotide on the progression of disease in patients receiving ventilatory support due to COVID-19 as well as on the severity of the respiratory failure, duration of mechanical ventilation, length of stay in intensive care and mortality. In ESSENTIAL, a Phase 2/3 clinical program, up to 730 patients will be enrolled initially in France and Belgium and, possibly in other European countries. Pre-defined interim analyses will be conducted by an independent Data Monitoring Board to test futility and to allow for the study design to be adapted as necessary. ESSNTIAL is the continuation of a 60 patients phase 2a evaluating the safety and efficacy of nangibotide in patients suffering from severe COVID-19. In July 2020, the CoviTREM-1 consortium, which includes the Nancy and Limoges university hospitals and Inotrem, obtained public funding of 7,5 million euros under the PSPC-COVID call for projects, operated on behalf of the French government by Bpifrance

New pre-clinical studies with nangibotide have demonstrated that the administration of nangibotide in murine models infected with SARS-CoV-2 was associated with a decrease in inflammatory mediators and an improvement of clinical signs, in particular respiratory function, and survival. Inotrem also confirmed in 3 different and independent cohorts that sTREM-1, a marker of the activation of the TREM-1 biological pathway, is associated with both severity and mortality in critically ill COVID-19 patients.

Leveraging the results of these preclinical studies and the implications for the role of the TREM-1 pathway in COVID-19, Inotrem has filed additional patents to cover nangibotide use in severe forms of COVID-19 as well as the use of sTREM-1 as a biomarker and companion diagnostic. This significantly strengthens Inotrems already broad patent estate.

Jean-Jacques Garaud, Executive Vice-President, Head of Scientific and Medical Affairs and Inotrems co-founder said :We are eager to pursue the development of nangibotide in these severe forms of COVID-19. Nangibotide is a TREM-1 inhibitor which has already demonstrated a trend towards efficacy in septic shock patients and has the potential to modulate the dysregulated immune response in critically ill COVID-19 patients. With this large clinical study, we can demonstrate efficacy for nangibotide in a further indication with the goals of reducing the duration of hospitalization and mortality.

Sven Zimmerman, CEO of Inotrem, also declared: The size of the financial support awarded to us as part of the French governments initiative against COVID-19 is a testimony to the relevance of targeting the TREM-1 pathway with nangibotide in these severely ill patients. We are delighted by the confidence placed in our technology and our team. Everyone at Inotrem is fully committed to deliver on this ambitious program alongside nangibotides ongoing Phase 2b trial in septic shock patients.

About InotremInotrem S.A. is a biotechnology company specialized in immunotherapy for acute and chronic inflammatory syndromes. The company has developed a new concept of immunomodulation that targets the TREM-1 pathway to control unbalanced inflammatory responses. Through its proprietary technology platform, Inotrem has developed the first-in-class TREM-1 inhibitor, LR12 (nangibotide), with potential applications in a number of therapeutic indications such as septic shock and myocardial infarction. In parallel, Inotrem has also launched another program to develop a new therapeutic modality targeting chronic inflammatory diseases. The company was founded in 2013 by Dr. Jean-Jacques Garaud, a former head of research and early development at the Roche Group, Prof. Sbastien Gibot and Dr. Marc Derive. Inotrem is supported by leading European and North American investors.


About TREM-1 pathwayTREM-1 pathway is an amplification loop of the immune response that triggers an exuberant and hyperactivated immune state which is known to play a crucial role in the pathophysiology of septic shock and acute myocardial infarction.

About NangibotideNangibotide is the formulation of the active ingredient LR12, which is a 12 amino-acid peptide prepared by chemical synthesis. LR12 is a specific TREM-1 inhibitor, acting as a decoy receptor and interfering in the binding of TREM-1 and its ligand. In preclinical septic shock models, nangibotide was able to restore appropriate inflammatory response, vascular function, and improved animals survival post septic shock.

About ESSENTIAL study:The Efficacy and Safety Study Exploring Nangibotide Treatment in COVID-19 pAtients with ventiLatory support, is a randomized, double-blind, placebo-controlled confirmatory study with adaptive features that will be performed in Europe. This is a pivotal study and it is expected that based on its results, nangibotide could be registered in this indication. The first part of the study (i.e.: 60 patients) has been already finalized and assessed by an independent data monitoring committee with excellent safety results. The study will recruit up to 730 patients in up to 40 sites. Several interim and futility analyses are foreseen as part of the adaptive design of the study.

About BpifranceBpifrance is the French national investment bank: it finances businesses at every stage of their development through loans, guarantees, equity investments and export insurances. Bpifrance also provides extra-financial services (training, consultancy.). to help entrepreneurs meet their challenges (innovation, export).For more information, please visit: http://www.bpifrance.fr and presse.bpifrance.frFollow us on Twitter: @Bpifrance - @BpifrancePresse

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Inotrem Receives Approval to Expand Nangibotide Clinical Trial in Critically Ill COVID-19 Patients and Receives Additional Public Funding of 45...

Wugen Raises $172 Million to Advance Clinical Stage Memory NK Cell Platform, Progress Best-In-Class AML Program, and Initiate Multiple Solid Tumor…

Posted: at 1:53 am

ST. LOUIS & SAN DIEGO--(BUSINESS WIRE)--Wugen, Inc., a clinical stage biotechnology company developing a pipeline of off-the-shelf cell therapies, today announced the completion of an oversubscribed $172 million Series B financing led by Abingworth and Tybourne Capital Management, and joined by new investors Fidelity Management & Research Company, Intermediate Capital Group (ICG), Sands Capital, Aisling Capital Management, Alexandria Venture Investments, Velosity Capital and Falcon Edge Capital. Existing investors, including RiverVest Venture Partners, LYZZ Capital, and Lightchain Capital, also participated. In connection with the financing, Bali Muralidhar, M.D., Ph.D., Managing Partner at Abingworth, Bosun Hau, Managing Director at Tybourne Capital Management, and Peter Kiener, Ph.D., Venture Partner at ICG, will join Wugens Board of Directors. The proceeds of the financing will support further clinical development of Wugens best-in-class memory natural killer (NK) cell platform and advance ongoing trials for patients with severe acute myelogenous leukemia (AML) and other oncology indications, including solid tumors. Wugen also plans to apply these proceeds to advance its broader pipeline of next-generation products into the clinic, including its allogeneic CD7-targeted CAR-T cell therapy to treat T-cell leukemia and lymphoma.

Dan Kemp, Ph.D., President and Chief Executive Officer of Wugen, said, We have tremendous confidence that our off-the-shelf memory NK cell platform will give rise to a significant pipeline of highly effective and safe anti-cancer therapies. In an ongoing Phase 1/2 clinical trial, our lead product WU-NK-101 has demonstrated an impressive complete response rate in relapsed/refractory AML and we look forward to advancing into a global multi-center study later this year. In parallel, were also pursuing solid tumor indications both as monotherapy and in combination with antibody drugs. The rapid growth of the company could not have happened without the commitment of RiverVest Venture Partners, and in particular the vision and leadership of John McKearn as our founding CEO.

Were delighted to welcome these premier investors as Wugen stakeholders as we build on the significant potential for the companys unique memory NK cell platform, said John McKearn, Ph.D., Managing Director at RiverVest Venture Partners and Chairman of the Board of Directors of Wugen. This significant capital raise will enable Wugen to advance its off-the-shelf cell therapies to develop a broad and differentiated oncology pipeline.

Wugens memory NK cell platform, with enhanced tumor-killing functionality and in vivo persistence, is designed to overcome the limitations of conventional NK cell therapies. In clinical studies, WU-NK-101 was shown to be highly effective against AML, including in patients with a high burden of disease, and without causing cytokine release syndrome (CRS) or neurotoxicity.

Wugen utilizes its proprietary GMP-grade fusion molecules to manufacture and scale its memory NK cell products using cells from healthy donors. In addition, Wugens feeder cell-free expansion and cryopreservation method enables an off-the-shelf treatment approach, with the opportunity for streamlined global distribution and convenient outpatient dosing for cancer patients.

Were excited to participate in this financing round with Wugen and are confident this exceptional team will deliver on the promise of memory NK cells, added Bali Muralidhar, M.D., Ph.D., Managing Director at Abingworth. We believe that Wugens strong collaborative partnership with Washington University is also a key strength, especially at the translational level, where co-founders and world-class investigators Todd Fehniger, M.D., Ph.D., John DiPersio, M.D., Ph.D., Melissa Berrien-Elliott, Ph.D., and Matt Cooper, Ph.D., who is also Wugens Chief Scientific Officer, provide critical support.

About Wugen

Wugen, Inc., is a clinical-stage biotechnology company developing a pipeline of off-the-shelf memory natural killer (NK) cell therapies to treat a broad range of hematological and solid tumor malignancies. Memory NK cells are hyper-functional, long-lasting immune cells that have evolved to attack cancer and respond to infection. Wugen is harnessing the power of this rare cell population by using its proprietary technologies to create WU-NK-101, currently in clinical development for acute myelogenous leukemia (AML). In addition, Wugen is developing a pipeline of programs targeting solid tumor indications. For more information, please visit http://www.wugen.com.

About Abingworth

Abingworth is a leading transatlantic life sciences investment firm. Abingworth helps transform cutting-edge science into novel medicines by providing capital and expertise to top calibre management teams building world-class companies. Since 1973, Abingworth has invested in over 170 life science companies, leading to 44 M&As and 71 IPOs. Abingworths therapeutic focused investments fall into three categories: seed and early-stage, development stage, and clinical co-development. Abingworth supports its portfolio companies with a team of experienced professionals at offices in London, Menlo Park (California), and Boston. For more information, please visit http://www.abingworth.com.

About Tybourne

Tybourne Capital Management is a global growth investor in public and private equity markets, focusing on investments in the Healthcare, Consumer, Financials and TMT sectors. The firm was founded in 2012 and is headquartered in Hong Kong with an office in San Francisco. Tybourne manages long duration capital on behalf of prominent non-profits, university endowments, sovereigns, corporate pensions and family offices. For more information, please visit http://www.tybournecapital.com.

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Wugen Raises $172 Million to Advance Clinical Stage Memory NK Cell Platform, Progress Best-In-Class AML Program, and Initiate Multiple Solid Tumor...

Dopavision Closes 12 Million Series A Round to Advance Digital Childhood Myopia Therapeutic Through Clinical Trials – Yahoo Finance

Posted: at 1:52 am

- Seventure Partners and Novartis Pharmaceuticals join as new investors- Transformative treatment for millions of children with myopia

Berlin, Germany, July 14, 2021 --- Dopavision, a company pioneering the development of digital therapeutics, today announced the closing of a 12 million Series A financing round. Seventure Partners led the round and was joined by Novartis Pharmaceuticals and the Companys existing shareholders such as Boehringer Ingelheim Venture Fund and Ababax Health, significantly broadening the Companys shareholder base of leading international life science investors.

Myopia is recognized as a public health concern and is the leading cause of correctable visual impairment, expected to reach a global prevalence of 50% by 2050. The condition manifests as blurring of distant objects due to image focusing in front of the retina instead of falling on the retina, most often caused by excessive elongation of the eyeball during growth. Severe cases are associated with sight-threatening conditions, including glaucoma, cataract, retinal detachment, and myopic maculopathy.

Halting disease progression in children and young adults at present is regarded as the most promising intervention approach to prevent severe impairments at a later age. Dopavisions mission is to support this myopia control strategy by providing transformative treatments and addressing the disease at an early stage, providing medical benefits for later years of life.

The proceeds will be used to fund the clinical development of MyopiaX, the Companys lead product in childhood myopia, with the goal to demonstrate its safety and efficacy in clinical studies and advance this innovative treatment to market to improve the lives of millions of myopic children. The breakthrough technology targets children and young adolescents, leveraging a patented, light-based technology that stimulates specific photosensitive cells of the retina, which in turn modulate retinal dopamine, a key neurotransmitter involved in eye growth. The Company has demonstrated proof-of-mechanism in preclinical models and exploratory human studies. MyopiaX has the potential to become the first digital therapy to control childhood myopia. It is designed to achieve a medical effect while children play exciting games or use educational digital content and can be conveniently integrated into their daily routine. It runs on standard digital devices and is easy to use for children under minimal supervision of their parents.

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Moreover, the funding will be dedicated to additional product development activities in order to provide innovative digital treatments for children leveraging games, educational or cognitive training applications, and potentially broaden the Companys pipeline to new indications. The Company also intends to continue to recruit and build a team of people passionate about using digital innovation to improve the lives of children and adults.

"We are excited that Seventure Partners and Novartis Pharmaceuticals have decided to support Dopavision as new investors in the Series A round," said Dr. Hamed Bahmani, co-founder and managing director of Dopavision. "The extensive use of smartphones is suspected to worsen childhood myopia but stopping children from using them is unrealistic. Therefore, we have decided to transform the use of digital devices into a beneficial therapeutic activity. Our first-of-its-kind MyopiaX combines ease of use with an exciting user experience that promotes adherence to the therapy with the goal of addressing this serious medical condition already at a young age."

"Novartis is committed to advancing transformational treatments - including digital therapeutics - to people of all ages living with visual impairment," said Jill Hopkins, Global Development Head, Ophthalmology, Novartis Pharmaceuticals.

"Dopavision is pursuing a unique digital therapeutic approach to achieve a significant clinical benefit," said Isabelle de Cremoux, CEO and Managing Partner of Seventure Partners. "This is the first real digital therapeutic for childhood myopia - a non-invasive, patient-friendly approach that will not only transform the global ophthalmology market, but also provide a breakthrough for affected children by improving their sight and quality of life from an early age onwards. Moreover, the technology has great potential for other disease indications as dopamine plays a key role in many physiological processes. Dopavision therefore excellently fits into our strategic commitment to develop groundbreaking digital health solutions."

To reflect the new shareholder structure, Dr. Annegret de Baey-Diepolder of Seventure Partners will join Dopavisions Advisory Board.


About Dopavision Dopavision is pioneering the development of digital therapeutics. As its lead product, the Company is developing a game-changing therapeutic for childhood myopia which can be seamlessly and invisibly integrated into the use of a smartphone. Myopia, or shortsightedness, is a visual condition that affects on average every third person globally, a share that has increased rapidly during the last two decades. It has grown to alarming proportions in Asia where prevalence rates, e.g. in Singapore, have reached 80% among young adults. High childhood myopia imposes a significant risk to cause visual impairment and even blindness later in life. Dopavisions goal is to develop a clinically validated therapy to halt myopia progression in children and adolescents. Founded in 2017 by Hamed Bahmani, Dopavision has so far raised 14.7 million in private equity and public grants and is backed by top-tier international investors such as Seventure Partners, Novartis Pharma and Boehringer Ingelheim Venture Fund. Dopavision is supported by the German government via the Industrie-in-Klinik program of the German Federal Ministry of Education and Research BMBF (Aktionsfeld Gesundheitswirtschaft im Rahmenprogramm Gesundheitsforschung, Forderkennzeichen/contract number 13GW0256). http://www.dopavision.com

About Seventure PartnersWith 850m net commitments under management as of the end of 2020, Seventure Partners is a leading venture capital firm in Europe. Since 1997, Seventure has been investing in innovative businesses with high growth potential in two fields: Life sciences across Europe, Israel, Asia and North America, and Digital technologies in France and Northern Europe.In life sciences, the main areas of focus include classic approaches such as biotechnology and pharmaceuticals, diagnostic and medtech, industrial biotechnology, as well as beyond the pill approaches such as microbiome-linked innovations, nutrition, foodtech, digital/connected health, wellbeing and personalized medicine & personalized nutrition. Investments can range between 500k and 10m per round, or up to 20m per company, from early to late stage, growth & pre-IPO. Seventure successfully launched Health for Life Capital which invests in life sciences (health, nutrition, digital/connected health) with a core focus on the microbiome revolution and its applications in human health, nutrition and food.In March 2018, Seventure launched AVF, a new fund dedicated to animal nutrition, feed and health with Adisseo as a strategic partner. In July 2019, it launched Sport & Performance Capital, dedicated to innovations in sport & wellness. The 160m first Health For Life Capital fund launched in 2014 has invested in 20 companies at the forefront of their fields, such as Enterome, Vedanta Biosciences, MaaT Pharma, Eligo Bioscience, Ysopia Bioscience, TargEDys, A-Mansia Biotech, BiomX, Microbiotica, LiMM Therapeutics, Siolta Therapeutics, DayTwo, Zipongo (renamed Foodsmart), Cambrooke, Mdoloris Medical Systems, MycoTechnology, etc. In January 2019 it launched the second fund Health for Life Capital II, now over 250m, which invested in Axial Therapeutics, BCD Biosciences, Citryll, Cytoki, Ervaccine, Federation Bio, Galecto etc. Both the first fund and second Health For Life Capital fund attracted strategic investments from prestigious organizations including Danone, Novartis, two US-based global food ingredient providers (to be disclosed), Lesaffre, Tornier, Tereos, Unigrains and Bel, as well as financial institutions, family offices and entrepreneurs. For more details: http://www.seventure.fr/en Twitter: @seventurep

About Boehringer Ingelheim Venture FundOperating as a separate legal entity, the Boehringer Ingelheim Venture Fund (BIVF) drives innovation through its strategic investments in early-stage science and technology. With an investment volume of 300 million Euro, the Venture Fund invests in biotech and start-up companies with innovative concepts and technologies that have the potential to provide ground-breaking platforms. BIVF currently holds a portfolio of more than 30 companies and creates companies when it identifies promising research projects in university and academia. BIVFs interest in young, mainly technology-oriented companies demonstrates its commitment to investigate new ideas and new science to create options for Boehringer Ingelheim to expand into new approaches and businesses in the field of Oncology, Regenerative Medicine, Infectious Diseases and Digital Health.


About Ababax HealthAbabax Health is a Digital Health technology company dedicated to developing Digital Drugs that enable tailored, non-invasive digital interventions to unlock and advance mental and physical health. Ababax pools Software-as-a-Drug competencies by uniting multidisciplinary scientists and technology experts to shape the future of medicine. The Ababax founders, Dr. Markus Mschenich and Christian Lautner, have been Founding Investors at Dopavision since 2017.


For further information please contact: Dopavision GmbH Stefan Zundel Managing Director info@dopavision.com

Media InquiriesakampionDr. Ludger Wess / Ines-Regina Buth Managing Partnersinfo@akampion.comTel. +49 40 88 16 59 64 /Tel. +49 30 23 63 27 68

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Dopavision Closes 12 Million Series A Round to Advance Digital Childhood Myopia Therapeutic Through Clinical Trials - Yahoo Finance

Heart Healthy Foods: 25 Foods That Are Good for Your Heart – Parade Magazine

Posted: at 1:51 am

Every year, 647,000 Americans die from heart disease and heart-related conditions, according to the Centers for Disease Control and Prevention (CDC). In fact, its the leading cause of death in the United States.

In terms of prevention, living a healthy lifestyle is the best thing you can do. Some activities that can increase risk of developing heart disease include smoking, a lack of exercise, heavily drinking alcohol, and eating a diet high in cholesterol, fat, salt, and sugar. To stay as heart-healthy as possible, its best to avoid this activities and try to eat a diet that consists of heart healthy foods.

Wondering which foods are good for your heart? Weve got you covered.

Known as the fruit with the healthy fats, avocados are super nutritious thanks to their high concentration in dietary fiber, antioxidants, and other minerals. All of these things work together to keep your heart healthy, but a study from Penn State University also suggests that an avocado a day can lower LDL cholesterol levels.

Avocados contain heart healthy monounsaturated fatty acids, which can help lower LDL cholesterol (the bad kind), Laura Yautz, RDN, LDN, NBC-HWC, registered dietician and owner of Being Nutritious, tells Parade. In addition, avocados contain potassium and fiber, two essential components of heart health, which can work to lower blood pressure and cholesterol, respectively!

Sure, all fruits are relatively high in sugar, but the heart-healthy benefits of berriesstrawberries, blueberries, blackberries, cranberries, aa berries, bilberries, goji berries, raspberries, and even grapes!certainly outweigh the negatives of their natural sugar content.

Berries are a good source of polyphenols, especially anthocyanins, micronutrients, and fiber, explains Harland Adkins, a registered dietitian nutritionist and founder of Fast Food Menu Prices. In epidemiological and clinical studies, these constituents have been associated with improved cardiovascular risk profiles.

Adkins adds, Black raspberries and strawberries have been shown to help lower cholesterol in people who are obese or have metabolic syndrome.

Spinach is good for you in just about every way possiblenot solely for your heart. But besides the benefits it has for your eyes, reduced blood pressure, and even cancer prevention, spinachs high levels of omega-3 fatty acids, antioxidants, B vitamins, fiber, folate, calcium, and iron work wonders for your heart.

Spinach is most known for its folate content, but its also a great addition to heart healthy diets, Yautz explains. Spinach contains a healthy dose of vitamin K (ask your doctor if youre on a blood thinner!), vitamin A, iron, and fiber, all while being low in calories, so you can fill your plate up!

All dark leafy greens are heart-healthy foods, but kale in particular is a superfood. According to the American Heart Association (AHA), kale is high in potassium, which can reduce your risk of blood pressure and also heart disease.

Kale, like spinach, is very high in vitamin K, which is important to help your blood clot properly, Yautz says. Its also high in vitamins A and C. But unlike spinach, its a cruciferous vegetable (like broccoli and cauliflower), so it contains special compounds that may be particularly helpful in preventing clogged arteries.

Related: 125 Quotes About Heart Disease

Collard greens are another dark leafy green, cruciferous vegetable that works hard to keep your heart feeling strong. This superfood also can prevent cancer, features anti-inflammatory properties, and because theyre high in potassium, magnesium, and vitamin C, theyve been known to lower hypertension and support the heart.

Collard greens are an excellent source of vitamin A, vitamin C, and calcium, a rich source of vitamin K, and a good source of iron, vitamin B-6, and magnesium, Adkins explains. They also contain thiamin, niacin, pantothenic acid, and choline. Thanks to their many nutrients, collard greens have been associated with cancer prevention, detox support, anti-inflammatory properties, heart health, and digestive support.

Definitely dont underestimate the power of nuts when it comes to supporting your heart. As Yautz explains, Walnuts contain the highest amount of ALA (a plant-based form of Omega-3) of any of the tree nuts, making it an excellent heart healthy staple. They are also high in magnesium, which can help your heart maintain a normal rhythm.

Another nut thats great for your heart is the almond. Yautz explains, Almonds are a great source of vitamin E, a type of antioxidant that helps prevent cell damage. It can be particularly helpful for those who do or have smoked, and/or are exposed to air pollution, to help mitigate the effect.

Plus, they can be roasted, thrown into a salad, or eaten raw, and are known as a health, unsaturated fat that increases the bodys good cholesterol and decreases its bad cholesterol.

You know how that old adage goesbeans, beans, theyre good for your heart! We wont finish the rhyme here for the sake of being appropriate, but this kid-friendly diddy is true.

Beans are incredibly healthy, especially for your heart, high in both protein and fiber, and theyre amazingly versatile, Yautz says. Many studies have been conducted on their health benefits. They are known to help decrease blood cholesterol levels, and consuming 1/2 cup a day is associated with a lower risk of having a heart attack and heart disease in general.

Black beans are not only high in fiber, but they keep your blood sugar levels in check, control your cholesterol, and can even lower blood pressure.

Related: Can a Broken Heart Cause Actual Heart Damage? Heres What Doctors Say

Fatty fish is one of the best heart-healthy foods there is thanks to its high levels of Omega-3 fatty acids. In fact, the American Heart Association recommends eating salmon as much as twice a week.

Yautz adds, Salmon is well known for its healthy fat profile. The main type of fat is a polyunsaturated fat, known as omega-3. Eating fish high in Omega-3s has been linked to decreased coronary heart disease (CHD), including fatal CHD, myocardial infarction, and sudden cardiac death. Wild caught salmon is a better source than farmed.

High in lycopene, which can lower LDL levels and also blood pressure, eating tomatoes semi-frequently can reduce your risk of heart disease.

Tomatoes claim to fame is their lycopene content, which is widely known for its benefit to prostate health. But lycopene can also protect your heart! Studies have shown lycopene may lower your risk of stroke, and of having additional cardiac events, Yautz explains.

Chia seeds are also a superfood and theyre unique in that they contain the antioxidant quercetin. Quercetin reduces risk of heart disease, as well as other heart-related conditions as well.

Chia seeds are full of heart protecting antioxidants, as well as ALA Omega-3 fats, Yautz says. This tiny seed is also showing promise as being able to potentially lower triglycerides, inflammation, and blood pressure, as well as raising HDL (the good cholesterol).

Its the one youve been waiting foryes, its true! Dark chocolate is, in fact, good for your heart.

Dark chocolate is rich in flavanols, and a heart healthy addition with a caveat: all the added sugar, cream or milk, and cocoa butter tend to negate its effects, Yautz says. Choose the darkest chocolate you can to reap the benefits, such as lower total cholesterol, LDL cholesterol, and triglycerides.

Just like nuts, many seeds are considered to be heart-healthy food as well. Flax seeds are high in the Omega-3 fatty acids that hearts love and are even known to reduce the risk of stroke.

Flax, like chia, is high in Omega-3, and is particularly helpful in managing blood pressure and cholesterol, Yautz says.

Its a win-win!

Another heart-healthy seed is the hemp seed. These little-seeds-that-could regulate your heart beat, reduce bad cholesterol levels, and fight hard against coronary heart disease.

Hemp seeds are lower in both omega-3s and fiber then either chia or flax seeds, but they are high in protein a complete protein at that. They do have a high ratio of Omega-6 to Omega 3, which isnt problematic in the context of an otherwise healthy diet, but something to be aware of. They also contain iron and zinc, two minerals important for cardiac function, Yautz adds.

Cooking with oilespecially if its in place of butteris a meaningful decision for your heart. As Yautz explains, When it comes to oils for heart health, olive oil takes the cake. Studies have shown olive oil can help reduce cardiovascular disease and coronary artery disease. The benefit seems to cap out at about 1/2 tablespoon per day, though. Oils of all kinds are high in calories, so its preferable to replace fats like butter and margarine with olive oil instead of simply adding olive oil to the diet, to avoid unintentional weight gain.

As oranges are high in both fiber and potassium, this citrus fruit makes a great addition to any heart-healthy diet. After all, the more you eat of both, the less likely you are to develop a fatal heart disease.

Oranges are an excellent source of potassium, making them a good food for heart health. Potassium can help control blood pressure, because it acts opposite to sodium, Yautz says. While sodium attracts water and promotes retention, potassium helps the body release water, thereby reducing blood pressure.

Aside from their high levels of potassium, another heart-healthy benefit of oranges is their pectin.

Oranges have the cholesterol-fighting fiber pectin, Adkins says. In one study, two cups of OJ a day boosted blood vessel health. It also lowered blood pressure in men.

Just as fatty fish is good for the heart, fish oil is one of the best foods for the heart as well.

Fish oil is high in Omega-3s, and often recommended for its heart promoting benefits. While the omega-3s in flax, chia, and hemp are mostly in the form of ALA (alpha linolenic acid), the Omega-3s in fish oil are in the form of DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid), which are more usable by the body, Yautz explains. ALA must first be made into DHA and EPA.

Tuna is another fatty fish that has benefits for the heart because of its high levels of Omega-3 fatty acids. But, you should be wary of the tuna you choose.

Tuna is another great source of Omega-3 fats, Yautz says. Look for bluefin tuna, which is a better source of Omega-3s, and has a lower chance of being contaminated with heavy metals.

When you think heart-healthy food, you may not immediately envision garlic, but in reality, garlic has long been used as a medicinal herb, thanks to its health benefits.

Garlic and garlic supplements may have positive effects on heart health by preventing cell damage, regulating cholesterol, and lowering blood pressure, Adkins explains. Other research shows that garlic supplements may also reduce plaque build-up in the arteries. This is due to the presence of a compound called allicin, which is believed to have a multitude of therapeutic effects.

In addition to all those heart-healthy benefits, garlic may improve memory as well.

Fish and almonds arent the only significant source of heart-healthy proteins. As Yautz points out, Edamame is the most unprocessed form of soybeans, and incredibly nutritious. Its high in protein a complete proteinand also boasts tons of fiber and antioxidants. Studies show edamame may improve cholesterol and triglycerides, as well as reduce blood pressure. Other studies are being conducted on its ability to improve arterial stiffness, and improve markers of inflammation.

Sardines are jam-packed with Omega-3 fatty acids as well as fish oils that can regulate heart rhythms. Yautz adds, Unlike salmon and tuna, however, sardines are very low on the food chain. That means the likelihood of heavy metal contamination is very low. Just make sure to look for sardines without too much sodium.

Related: The Best and Worst Cooking Oils for Your Heart

Thank goodness! Of course, red wine has to be drank in moderation in order to reap its heart-healthy benefits, but some research shows that the antioxidants in red wines can prevent coronary artery disease and ultimately, decrease your risk of a heart attack.

If you drink alcohol, a little red wine maybe a heart-healthy choice, Adkins explains. Resveratrol and catechinstwo antioxidants in red winemay protect artery walls. Alcohol can also boost HDL, the good cholesterol [but] too much alcohol hurts the heart.

Yautz adds, Alcohol in excess can damage the heart, and contribute to high blood pressure. So, if you dont drink, dont start, but if you do, do so in moderation only (one or less 5-ounce glass of wine per day for women and two for men).

Another fatty fish rich in Omega-3 fatty acids, its recommended to eat mackerel at least once weekly in order to reduce your risk of a heart attack.

Mackerel are similar to sardines in their lower likelihood of heavy metal contamination, Yautz says. Eat it, and the other fatty fish on this list, at least once a week to help prevent heart attacks and other serious heart problems.

According to the Cleveland Heart Lab, herbs like cinnamon, cardamom, ginger, turmeric, and berberine can be used to prepare other foods for an added heart-healthy benefit.

Yautz adds, Herbs and spices are incredibly concentrated sources of antioxidants. Including a variety in liberal amounts on your food daily can contribute to lower inflammation, lower blood pressure, and lower cholesterol.

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Drinking tea could reduce risk of heart disease and stroke, but it should be done frequently in order to reap the benefits. In fact, the European Journal of Preventative Cardiology published research that found drinking green tea three or more times per week is ideal for improving the health of the heart.

Drinking green tea daily can also contribute to heart health! Studies show green tea may lower both LDL cholesterol and triglycerides, Yautz says. As long as youre careful about what you put in itadding sugar, creamer, etc. may offset those benefits!

Next up, important lifestyle changes to make for a healthy heart.

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Heart Healthy Foods: 25 Foods That Are Good for Your Heart - Parade Magazine

Food that can help ease stress – Jacaranda FM

Posted: at 1:51 am

Stress is defined as a stateof mental or emotional strain or tension resulting from adverse or demandingcircumstances.

It is caused by a variety of things including; anything that puts high demands on you, major life changes, financial problems, and relationship difficulties. The current state of events in South Africa is also leading to a lot of uncertainty.

Stress can lead to otherhealth complications including; depression,weight problems,anxiety, sleep problems, and thinking and memory problems.

All of us will deal with stressat some point in our lives and it is important that you seek help from a professionalwhen you feel overwhelmed and are struggling to cope.

READ:Three foods that can help you fight stress

Dietitian Sylven Masoga saysthere is no specific food that can reduce stress, but it's the ingredients containedin the food item that can help reduce stress.

You need food that containsVitamin C, such as grapes and oranges. That Vitamin C can destroy the freeradicals which are usually released when a person is suffering from stress related oxidation," says Masoga.

The dietitian recommendseating one orange a day or a bunch of grapes.

He also recommends eatingfoods that contain Vitamin A and Vitamin E.

READ: Expert tips on how to better manage stress

An example of these foods areyellow vegetables (pumpkin, carrots, gem squash etc.).

Vitamin A and Vitamin Econtaining foods will minimise the oxidation that will occur as a result ofstress in your blood, says the dietitian.

He adds: The intake ofVitamin A and Vitamin E protects the lining of the cells inside your body sothat they cannot be damaged by release of the free radicals.

The dietitian recommendseating foods that contain lycopene, phytochemical, and resveratrol.

Examples of such foods aretomatoes, guava, green vegetables, watermelon, papaya, pink grapefruit, and theskin of the grapes, peanuts, blueberries, cranberries, broccoli, pears, celery, and spinach.

The dietitian says such foods preventthe development of the free radicals.

He warns against eating foodsthat contain saturated fat and trans-fat.

READ: DrD on how to plan for a year-end holidays that bring more joy that stress

Image courtesy of iStock/ @Chinnapong

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Food that can help ease stress - Jacaranda FM

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