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Friday, April 30, 2021

Werewolf Therapeutics (HOWL) IPO Opens 14% Higher

 Today's IPO for Werewolf Therapeutics, Inc. (NASDAQ: HOWL) opened for trading at $18.21 after pricing 7,500,000 shares of common stock at a public offering price of $16.00 per share.

Jefferies, SVB Leerink and Evercore ISI are acting as joint book-running managers for the offering. H.C. Wainwright & Co. is acting as lead manager for the offering.

Werewolf Therapeutics, Inc. is an innovative biopharmaceutical company pioneering the development of therapeutics engineered to stimulate the body’s immune system for the treatment of cancer. We are leveraging our proprietary PREDATOR™ platform to design conditionally activated molecules that stimulate both adaptive and innate immunity with the goal of addressing the limitations of conventional proinflammatory immune therapies. Our INDUKINE™ molecules are intended to remain inactive in peripheral tissue yet activate selectively in the tumor microenvironment. Our most advanced product candidates, WTX-124 and WTX-330, are systemically delivered, conditionally activated Interleukin-2 (IL-2), and Interleukin-12 (IL-12) INDUKINE molecules for the treatment of solid tumors. We are continuing preclinical studies for both WTX-124 and WTX-330 and expect to advance each candidate in multiple tumor types as a single agent and in combination with an immune checkpoint inhibitor.

SARS-CoV-2 sculpts immune system to induce sustained virus-specific naïve-like and memory B cell responses

 Leire de Campos-Mata, Sonia Tejedor Vaquero, Roser Tachó-Piñot, Janet Piñero, Emilie K. Grasset, Itziar Arrieta Aldea, Natalia Rodrigo Melero, Carlo Carolis, Juan P. Horcajada, Andrea Cerutti, Judit Villar-García, 

Giuliana Magri

Prior SARS-CoV-2 infection rescues B, T cell responses to variants after 1st vaccine dose

 Catherine J. Reynolds1,, 

  1. Corinna Pade2,
  2. Joseph M. Gibbons2,
  3. David K. Butler1
  4. Ashley D. Otter3
  5. Katia Men
    1. DOI: 10.1126/science.abh1282
      1. PDF: 


        SARS-CoV-2 vaccine rollout has coincided with the spread of variants of concern. We investigated if single dose vaccination, with or without prior infection, confers cross protective immunity to variants. We analyzed T and B cell responses after first dose vaccination with the Pfizer/BioNTech mRNA vaccine BNT162b2 in healthcare workers (HCW) followed longitudinally, with or without prior Wuhan-Hu-1 SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 and B.1.351. By comparison, HCW receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351 spike mutations resulted in increased, abrogated or unchanged T cell responses depending on human leukocyte antigen (HLA) polymorphisms. Single dose vaccination with BNT162b2 in the context of prior infection with a heterologous variant substantially enhances neutralizing antibody responses against variants.

1/3 of kids develop a mental health problem after concussion

 A third of children and adolescents develop a mental health problem after a concussion, which could persist for several years post-injury, according to a new literature review.

The research, led by the Murdoch Children's Research Institute (MCRI) and published in the British Journal of Sports Medicine, found mental health should be evaluated as part of standard pediatric concussion assessment and management.

MCRI researcher and Monash University PhD candidate Alice Gornall said despite many post-concussion and mental health symptoms overlapping, the relationship between delayed recovery and mental health had remained poorly understood until this literature review.

The review of 69 articles published between 1980 to June 2020, involved almost 90,000 children, aged 0-18 years, from nine countries including Australia, US, Canada and New Zealand, who had a concussion. Falls (42.3 per cent) and sporting injuries (29.5 per cent) were the most common cause of injury, followed by car accidents (15.5 per cent).

It found up to 36.7 per cent experienced significantly high levels of internalising problems such as withdrawing, anxiety, depression and post-traumatic stress and 20 per cent externalising problems such as aggression, attention problems and hyperactivity after concussion compared with healthy children or children who sustained other injuries such as an arm fracture.

Pre-existing mental health problems were a strong predictor of post-concussion mental health issues. The review stated 29 per cent of children with a pre-injury mental health diagnoses received a new mental health diagnosis post-concussion. Up to 26 per cent without prior mental health problems went onto develop symptoms.

Ms Gornall said while significant improvements in mental health emerged between three and six months post-injury, a minority of children experienced persisting symptoms for several years afterwards.

The findings come after a recent study, led by MCRI and published in The Journal of Head Trauma Rehabilitation, found having a traumatic brain injury in early childhood was associated with lower IQ scores that persist up to seven years post-injury.

Ms Gornall said concussion was a growing public health concern with a third of children experiencing a head injury before 13 years of age.

"Despite the high incidence of concussion among children and adolescents, identifying those at risk of ongoing difficulties after concussion remains a prominent challenge for clinicians," she said.

"On top of this, children take twice as long to recover from concussion than adults, with one in four children experiencing symptoms beyond one-month post-injury."

Melbourne resident Emma, 17, has been seeking mental health support after suffering two concussions, a year apart.

In 2019 while playing netball she knocked her head on a goal post and last March she was hit with a ball in the back of the head.

Emma said after the second concussion she developed anxiety, headaches, a sense of hopelessness and had trouble concentrating.

"After my last concussion I found it very hard to be motivated for school and everyday life. Doing the simplest of tasks such as a walk was difficult for me, not being able to complete these tasks got me quite disheartened which impacted on my mental health," she said.

Emma's dad Bruce Henry said he welcomed the push for mental health to be part of paediatric concussion assessment and management as many cases would be going untreated.

"When a child has a concussion they might look fine but you can't see the underlying impact," he said. It's so important for mental health to form part of concussion management, which has been essential to Emma's recovery process."

MCRI researchers are also trialling an intervention, Concussion Essentials, to prevent children suffering long term post-concussion symptoms.

The eight session intervention combines physiotherapy and psychology treatments that target presenting symptoms with education around common concerns such as headache, fatigue and return to exercise, school and sports. Early data shows that the intervention is effective in accelerating recovery.

MCRI Professor Vicki Anderson said assessment, prevention and intervention of mental health difficulties after concussion should be integrated into standard concussion management.

"Mental health is central to concussion recovery. Concussion may both precipitate and exacerbate mental health difficulties, impacting delayed recovery and psychosocial outcomes," she said.

"Incorporating mental health risk into post-injury management represents an opportunity to engage children and adolescents with mental health services to either prevent unnecessary problems emerging or to treat already existing issues."

Developed by world-leading concussion experts at MCRI and The Royal Children's Hospital and in collaboration with the AFL, the HeadCheck app also helps parents, coaches and first aiders to recognise the signs of concussion and manage the child's safe return to school, play and organised sport.

Story Source:

Materials provided by Murdoch Childrens Research InstituteNote: Content may be edited for style and length.

Journal Reference:

  1. Alice Gornall, Michael Takagi, Thilanka Morawakage, Xiaomin Liu, Vicki Anderson. Mental health after paediatric concussion: a systematic review and meta-analysisBritish Journal of Sports Medicine, 2021; bjsports-2020-103548 DOI: 10.1136/bjsports-2020-103548

How diet controls RNA maturation

 Particularly sensitive to chemical modifications, messenger RNAs (mRNAs) are molecules responsible for transmitting the information encoded in our genome, allowing for the synthesis of proteins, which are necessary for the functioning of our cells. Two teams from the University of Geneva (UNIGE), Switzerland, in collaboration with the Norwegian University of Science and Technology (NTNU), have focused on a specific type of chemical modification -- called methylation -- of mRNA molecules in the small worm Caenorhabditis elegans. They found that methylation on a particular sequence of an mRNA leads to its degradation and that this control mechanism depends on the worm's diet. These findings are to be read in the journal Cell.

Several steps take place before a DNA-encoded gene produces the corresponding protein. One of the two strands of DNA is first transcribed into RNA, which then undergoes several processes, including splicing, before being translated into a protein. This process removes unnecessary non-coding sequences (introns) from the gene, leaving only the protein-coding sequences (exons). This mature form of RNA is called messenger RNA (mRNA).

A "post-it" to block protein synthesis

In addition to these processes, RNA -- but also DNA molecules -- can undergo a chemical modification: methylation. This consists in adding a methyl group (CH3) which allows to modify the fate of these molecules without altering their sequence. Deposited on the RNA or DNA in very specific places like "post-its," methyl groups indicate to the cell that a particular fate must be given to these molecules. Methylation of RNA is essential: mice without RNA methylation die at an early embryonic stage.

Two neighboring teams at the UNIGE, one working on RNA regulation and the other specializing in DNA organisation in the worm C. elegans, have studied the role of methylation in controlling gene expression. The laboratories of Ramesh Pillai and Florian Steiner, professors in the Department of Molecular Biology at the UNIGE Faculty of Science, have shown for the first time that methylation at the end of the intron of a particular gene blocks the splicing machinery. The intron cannot be removed and the protein is not produced.

Fine regulation to ensure a fair balance

This gene, whose mRNA is modified by methylation, encodes for the enzyme that produces the methyl donor. "It is therefore a self-regulating mechanism since the gene involved in producing a key factor required for methylation is itself regulated by methylation!," explains Mateusz Mendel, a researcher in the Department of Molecular Biology at the UNIGE Faculty of Science, and the first author of this study.

Moreover, this modification is dependent on the quantity of nutrients received by the worms. "When nutrients are abundant, the mRNA is methylated, gene splicing is blocked, and the level of methyl donors decreases, which limits the number of possible methylation reactions. On the other hand, when there are few nutrients, there is no methylation of the particular RNA of this gene, so splicing is not blocked and the synthesis of methyl donors increases," reports Kamila Delaney, a researcher in the Department of Molecular Biology at the UNIGE Faculty of Science. Elements present in the food provide the raw materials required for producing the methyl donor, so methylation-dependent splicing inhibition puts a brake on its production under conditions of a rich diet. "Aberrant methylation reactions -- too much or too little -- are the cause of many diseases. The cell has set up this very sophisticated regulatory system to ensure a fair balance of methylations in the cell," summarizes Mateusz Mendel.

Methylation of mRNAs at these specific sequences was discovered in the 1970s by scientists, including Ueli Schibler, a former professor at the UNIGE, before being forgotten. It took 40 years before researchers rediscovered its importance in gene regulation in 2012. With this study, scientists from the Department of Molecular Biology highlight the crucial role of methylation in the control of splicing and in the response to environmental changes.

Story Source:

Materials provided by Université de GenèveNote: Content may be edited for style and length.

Journal Reference:

  1. Mateusz Mendel, Kamila Delaney, Radha Raman Pandey, Kuan-Ming Chen, Joanna M. Wenda, Cathrine Broberg Vågbø, Florian A. Steiner, David Homolka, Ramesh S. Pillai. Splice site m6A methylation prevents binding of U2AF35 to inhibit RNA splicingCell, 2021; DOI: 10.1016/j.cell.2021.03.062

Engineering T cells to attack cancer broadly

 Through T cell engineering, researchers at Virginia Commonwealth University Massey Cancer Center show that it's possible to arrest tumor growth for a variety of cancers and squash the spread of cancer to other tissues. This research will be published in tomorrow's print edition of Cancer Research.

The paper builds on decades of research by study co-senior author Paul B. Fisher, M.Ph., Ph.D., a member of Massey's Cancer Biology research program, who discovered a protein called IL-24 that attacks a variety of cancers in several different ways.

In this latest study, Fisher teamed up with his colleague Xiang-Yang (Shawn) Wang, Ph.D., who co-leads the Developmental Therapeutics research program at Massey, to deliver the gene coding for IL-24, which is called MDA-7, to solid tumors using T cells.

"I think the beauty of what we've been involved in is that it expands the scope of immunotherapy," said Fisher, professor and chair of the Department of Human and Molecular Genetics at the VCU School of Medicine, director of the VCU Institute of Molecular Medicine (VIMM) and Thelma Newmeyer Corman Endowed Chair in Oncology Research. "Our approach is less dependent on cancer cells expressing something specific to target."

After all, this isn't the first time T cells have been engineered for cancer immunotherapy. FDA-approved chimeric antigen receptor T (CAR-T) cell therapy -- which is designed to destroy cancer cells expressing specific surface molecules -- has shown tremendous success for treating advanced cancers of the blood and lymphatic systems.

But CAR-T has made limited progress on solid tumors, such as prostate cancer or melanoma, because the cells that make up those tumors aren't all the same, which blocks the engineered T cells from recognizing and attacking.

Wang and Fisher armed T cells with MDA-7/IL-24 to target cancer more broadly.

"Engineering T cells to produce MDA-7/IL-24 allows killing of cancer cells regardless of their expression of target molecules. This will help prevent cancer cells from escaping immune attack," said Wang, who is also a professor of human and molecular genetics at VCU, associate director of immunology in the VIMM and holds the Harry and Judy Wason Distinguished Professorship at Massey.

At the sub-cellular level, MDA-7/IL-24 binds to receptors on the surface of cells and instructs them to make and release more copies of the MDA-7/IL-24 protein. If the cell is normal, the protein is simply secreted and no damage occurs. But if the cell is cancerous, MDA-7/IL-24 causes oxidative stress damage and ultimately cell death, not only within the primary tumor but also among its distant metastases -- the cause of death in 90% of patients.

As a result of this process, the immune system generates memory T cells that can theoretically kill the tumor if it ever comes back. At the whole tumor level, IL-24 also blocks blood vessel formation, starving tumors of the nutrients so badly needed to sustain their unchecked growth.

In mice with prostate cancer, melanoma or other cancer metastases, MDA-7/IL-24-expressing T cells slowed or stopped cancer progression better than unmodified T cells.

The researchers also discovered that arming T cells with MDA-7/IL-24 allowed them to survive better and multiply in the tumor microenvironment -- the space right around the cancerous mass.

"The tumor site is often very hostile to immune cells," Wang said. "We discovered that MDA-7/IL-24 can help T cells to proliferate and outnumber cancer cells."

In the clinic, this approach would involve extracting the patient's own T cells from tumor samples, genetically engineering them to express MDA-7/IL-24, growing millions of copies of the cells in the lab and finally transplanting them back into the patient. With federally-mandated manufacturing standards, the procedure is generally safe and minimally invasive. CAR-T cells could also be engineered to express MDA-7/IL-24.

To be most effective, MDA-7/IL-24 T cells would likely be used in conjunction with other therapies.

Although it's never easy bringing a technology from the bench to the bedside, Fisher is optimistic that much of the groundwork has already been laid.

Clinical trials using different methods of delivering IL-24 are already underway for several cancers. A phase 1 trial using an adenovirus -- similar to the common cold -- to deliver MDA-7/IL24 to the tumor demonstrated about 44% efficacy against multiple forms of cancer and generally proved non-toxic.

"I think we have a head start and a running ramp that could be really accelerated," Fisher said.

Together, Wang and Fisher recently secured a grant from the National Cancer Institute to optimize their technology for the treatment of solid tumors and cancer metastases, in anticipation of future human trials.

Story Source:

Materials provided by Virginia Commonwealth UniversityNote: Content may be edited for style and length.

Journal Reference:

  1. Zheng Liu, Chunqing Guo, Swadesh K. Das, Xiaofei Yu, Anjan K. Pradhan, Xia Li, Yanxia Ning, Shixian Chen, Wenjie Liu, Jolene J. Windle, Harry D. Bear, Masoud H. Manjili, Paul B. Fisher, Xiang-Yang Wang. Engineering T cells to express tumoricidal MDA-7/IL-24 enhances cancer immunotherapyCancer Research, 2021; canres.2604.2020 DOI: 10.1158/0008-5472.CAN-20-2604

FDA Approves AstraZeneca's Farxiga to Treat Chronic Kidney Disease

 The U.S. Food and Drug Administration on Friday said it approved AstraZeneca PLC's Farxiga as a treatment for chronic kidney disease.

The FDA said Farxiga, or dapagliflozin, oral tablets were approved "to reduce the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression."

The FDA also said, "Farxiga was originally approved in 2014 to improve glycemic control in adults with type 2 diabetes in addition to diet and exercise."

India variant of COVID-19 confirmed in Michigan

 A new variant of the coronavirus has been confirmed in Michigan.

The India variant of the virus, also known as B.1.617 has been confirmed in Clinton County, according to the Michigan Department of Health and Human Services.

As of April 29, there have been more than 6,000 confirmed cases of different variants in Michigan.

Brazil pharma flags 'retaliation' risk over bill to drop vaccine patents

 Brazilian pharmaceutical associations on Friday called for lawmakers to reject a bill that seeks to suspend COVID-19 vaccine patents, saying it could spark international retaliation and reduce medical supplies in Latin America's biggest country.

Brazil's Senate passed the proposal on Thursday night, sending it to the lower house for consideration.

The bill's backers say the emergency measure is needed due to a shortage of shots and a grave outbreak in Brazil, where over 400,000 people have died from the virus.

The government of President Jair Bolsonaro has publicly opposed calls to suspend patent protections, arguing they could endanger talks with vaccine producers.

In a joint statement, five of Brazil's leading pharmaceutical associations sided with his administration.

"The approval of a bill that allows for the weakening of intellectual property could lead to international retaliation and reduce the supply of pharmaceutical inputs," it said. "We cannot support measures that could generate more instability and scenarios that may have irreversible consequences, in the short, medium and long term for Brazil."

Brazil has signed vaccine supply deals with AstraZeneca , China's Sinovac Biotech Ltd, Pfizer Inc and Johnson & Johnson. AstraZeneca and Pfizer declined to comment, while Johnson & Johnson directed Reuters to the associations' statement. Sinovac did not immediately respond.

A senior pharmaceutical executive in Brazil, who was involved in COVID-19 vaccine talks, said the bill was "very poorly thought through" and "sends a poor message."

The executive, who asked to speak anonymously due to ongoing relationships with the government, said the legislation could especially hurt U.S. firms, which hampering Brasilia's efforts to improve relations with Washington.

In a Friday statement on the bill, Brazil's Health Ministry said the priority is to strengthen the country's infrastructure to produce more vaccines domestically.

The presidential press office did not respond to a request for comment.

The legislation passed by the Senate would oblige patent holders to provide authorities with all the information needed to produce COVID-19 vaccines and medicines. Then, if the government were to call a state of emergency, they could be produced locally under a government-mandated arrangement.

It remains to be seen whether lower house lawmakers will pass the bill.

CVS No-Cost Health Screening Program Expanding to 14 New Metro Markets

 CVS Health Corp. on Friday said it would be expanding its no-cost, community-based screening program to 14 new metropolitan areas this year.

Project Health is expected to begin offering service in Phoenix, Baton Rouge and New Orleans, Jackson, Miss., Cleveland and several other metro areas, CVS Health said.

The company also said it would launch four mobile units this year "to increase program's reach to areas of significant need."

Project Health offers free biometric screenings at CVS Pharmacy locations, which include blood pressure, cholesterol, glucose level and body mass index, the company said. Participants are given the opportunity to meet with a nurse-practitioner who can give referrals for treatment and advice on follow-up care, the company said.

Kyu Rhee, CVS Health's SVP and chief medical officer, said, "Over the last 15 years, Project Health has been extremely successful in connecting people to the health information and follow-up care they need to address the chronic conditions in many health disparity populations. As we expand the program this year, we will be able to dramatically increase our impact, ability to reduce health disparities and promote health equity."

U.S. extends transit face mask requirements through Sept. 13

 The Biden administration said ON Friday it is extending face mask requirements across all U.S. transportation networks through Sept. 13 to address the spread of COVID-19.

The U.S. Transportation Security Administration requirements that took effect Feb. 1 were to set to expire May 11. They cover workers and travelers at airports, on board commercial aircraft, on over-the-road buses, and on commuter bus and rail systems through Sept. 13.

Astrazeneca denies problems with US Covid-19 vaccine filing

 Astrazeneca today confirmed a substantial delay for the US filing of its Covid-19 vaccine, saying this would be made "within weeks". The first half of April had been the initial target. Astra's chief executive, Pascal Soriot, denied that there were problems, saying it was simply taking time to gather the huge package, which will encompass ex-US trials and real-world data. Speaking on a media call, executives said AZD1222 would be travelling down an emergency use authorisation route, although they will submit a full BLA if required. Given that the US has few vaccine supply problems, this longer path cannot be ruled out. This questions the logic of pursuing US approval in the first place, but the importance of the FDA’s validation can probably not be overstated in the wake of concerns over lack of safety and controversial data disclosures. In a robust defence of Astra’s vaccine programme, Mr Soriot said “we don’t regret anything”, and denied over-promising on the quantities that could be delivered. The vaccine is still in high demand, he told reporters. “Everywhere, countries have told us they still want the totality of what they ordered, and they want it delivered even faster.”