Fungal infections an unintended consequence of advanced immunotherapy

 Major fungal infections have become more common across the globe, and one unexpected phenomenon among the rise of fungi is life-threatening infections as a result of a complication of certain immunotherapies and small molecule kinase inhibitors.

A scientist at the Hackensack Meridian Center for Discovery and Innovation (CDI) has identified the specific mechanistic cause of one such phenomenon, which will likely save lives into the future, via a new publication.

The paper "C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection" appeared in the journal Cell on May 22.

"Our findings will assist clinicians in their understanding of how these life-threatening infections are emerging," said Jigar Desai, Ph.D., assistant member of the CDI, assistant professor of medical sciences at the Hackensack Meridian School of Medicine, and first author of the paper. "These findings may help doctors and scientists alike better understand how some of these cases arise—and how to avoid them."

The team of scientists established that the C5a protein, the penultimate effector constituent of the complement pathway, is key to the body's innate ability to fight systemic fungal infections. Additionally, the team also identified enhanced complement pathway signature acts as a predictive biomarker for systemic candidiasis. With the use of animal models, patient data and sera, the team showed how C5a and its downstream effects are crucial for the body's immune cells, specifically neutrophils and macrophages, to clear the fungus Candida albicans, when it has overtaken the body's natural defenses.

Desai and the team—which includes colleagues from the National Institutes of Health, Duke University, and Mount Sinai, among others—showed this in stages, both in animal models and in patient serum, by isolating what roles the C5 plays.

In addition to uncovering induced complement signature as a potential biomarker for systemic candidiasis, this work will be highly impactful in the clinical setting, where complement C5-targeted therapeutics, such as the anti-C5 monoclonal antibodies eculizumab/ravulizumab (as well as the C5a receptor inhibitor, avacopan) are the treatment of choice. In these settings, findings from this work emphasizes the importance of vigilant surveillance for opportunistic fungal infections, where early diagnosis can improve patient outcomes.

"Our findings establish a new paradigm in immunobiology, demonstrating for the first time the direct critical role of cell-intrinsic complement generation for effective host defense against Candida," write the authors. "The multifaceted translation of our work shows promise for the development of individualized risk stratification and prognostication strategies in patients at-risk for invasive fungal disease."

Desai, a fungal expert who joined the CDI last year, has had other recent publications.

In two papers in 2022 he and colleagues showed a particular genetic deficiency may weaken certain people to the onslaught of a certain plant pathogenic fungus, and also explore how systemic candidiasis may actually carry enhanced mortality following the use of broad-spectrum antibiotics. Those papers were published in The Journal of Clinical Investigation, and Cell Host and Microbe.

"Jigar Desai is uncovering novel insights into life-threatening fungal diseases," said David Perlin, Ph.D., chief scientific officer and executive vice president of the CDI, who is also an expert in fungal infections. "As we know, this is an emerging health problem, and it's key to have his work drive our understanding forward."

More information: Jigar V. Desai et al, C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection, Cell (2023). DOI: 10.1016/j.cell.2023.04.031

https://medicalxpress.com/news/2023-06-fungal-infections-unintended-consequence-advanced.html

T cells could fight many coronaviruses at once

 Scientists at La Jolla Institute for Immunology (LJI) are investigating how the immune system's T cells react to a wide variety of coronaviruses, ranging from SARS to common cold coronaviruses. Their goal is to guide the development of vaccines that could halt future pandemic by combatting many types of coronaviruses at once.

"While it was recognized that coronaviruses were potentially dangerous viruses, because of SARS-CoV and MERS viruses causing very severe disease in humans, nobody knew that the next pandemic was going to be caused by SARS-CoV-2," says LJI Professor Alessandro Sette, Dr.Biol.Sci. "So the issue now is how can we develop strategies that are broadly applicable to different viral families of concern?"

In their latest collaboration, published in Cell Reports Medicine, Sette and LJI Research Assistant Professor Alba Grifoni, Ph.D., show that T cells can recognize several different viral targets, called "antigens," shared between most coronaviruses, including common cold coronaviruses and SARS-CoV-2. They also looked more in-depth at what fragments of these antigens, called "epitopes," are recognized and how conserved they are across different coronaviruses.

"This study suggests a way to enhance vaccines so that they have broader activity against many different coronaviruses and variants," says Grifoni.

What coronaviruses have in common

Sette and Grifoni are experts in studying which of the antigens that make up a virus's structure are recognized by T cells down to the epitope level. While viruses with similar protein sequences tend to be closely related, even more distant viruses can have some smaller sequences in common. If sequences are recognized by T cells, this immune response can recognize multiple viruses from the same family, even if the viruses themselves are not as similar.

The body's memory CD4+ "helper" T cells patrol the body for protein sequences belonging to past viral invaders. These T cells help launch the immune system attack against a repeat offender—or any closely related pathogens—they come across. This kind of "cross reactivity" is exactly what scientists want to harness to train immune cells to fight many types of coronaviruses at once.

No one had been exposed to SARS-CoV-2 before 2019. Still, humanity was no stranger to coronaviruses. Some coronaviruses cause common colds, others have been shown to cause severe respiratory disease. Of the two groups of coronaviruses, alpha and beta, scientists have so far found beta coronaviruses to be most likely to have pandemic potential and cause severe disease based on three different outbreaks.

The 2002–2003 SARS outbreak, the 2012 MERS outbreak, and more recently SARS-CoV-2, were all caused by beta coronaviruses. Alpha and beta coronaviruses also share similarities in some of the epitopes recognized, and previous research from Sette and Grifoni has demonstrated that T cells against common cold coronaviruses can "cross-react" with SARS-CoV-2.

Taking aim at four viral targets

For the new study, the goal was to see exactly which viral protein sequences or epitopes prompted the strongest reactions from T cells cross reactive across different coronavirus types.

The researchers first comprehensively analyzed T cells collected from 88 patients before the COVID-19 pandemic. These patients had never been exposed to SARS-CoV-2, of course, but they had been exposed to other types of common cold coronaviruses belonging to either the alpha or beta groups. Researchers used these samples to define which viral antigens and which specific epitopes were recognized by T cells.

Then the LJI team, in collaboration with Professor Richard Scheuerman, Ph.D., of the J. Craig Venter Institute, applied a computational approach to predict which epitopes might be the same between different coronaviruses including SARS-CoV-2. This work, led by LJI Postdoctoral Fellow Alison Tarke, Ph.D., revealed 18 coronavirus epitopes highly conserved across multiple coronaviruses, suggesting these epitopes could induce cross-reactive T cells.

The LJI researchers showed that T cells against alpha or beta common cold coronaviruses tend to be cross-reactive across the two different groups. These coronaviruses had a lot of similarities in their epitope sequences, and T cells showed cross-reactivity in 89% of tests.

Cross-reactivity declined to 50% when the T cells encountered SARS-CoV-2. This means that although SARS-CoV-2 resembles a distant relative of common cold coronaviruses, it still shares protein sequences with members of its family.

Future coronavirus vaccines could leverage a combined approach using antibody target and T cell responses against epitope sequences conserved across the many types of coronaviruses. "The key finding here is that we could potentially develop vaccines that would focus immune responses on these shared sequences, allowing recognition of many different viruses at once," says Grifoni. "While the SARS-CoV-2 Spike protein is the major target for antibodies, T cells can recognize additional antigens that are conserved across different coronaviruses. The combination of the two could be optimal in the design of a panCorona vaccine."

"This work is also exciting because it suggests this is a viable strategy to induce other families of viruses of concern in light of potential future pandemics, such as for example the family of viruses causing influenza, or the ones causing hemorrhagic fevers, or the family of viruses which includes dengue and Zika virus," adds Sette.

Additional authors of the study were Yun Zhang, Nils Methot, Tara M. Narowski, Elizabeth Phillips, Simon Mallal, April Frazier, Gilberto Filaci, Daniela Weiskopf, Jennifer M. Dan, Lakshmanane Premkumar and Richard H. Scheuermann.

More information: Alison Tarke et al, Targets and cross-reactivity of human T cell recognition of Common Cold Coronaviruses, Cell Reports Medicine (2023). DOI: 10.1016/j.xcrm.2023.101088

https://medicalxpress.com/news/2023-06-family-resemblance-cells-coronaviruses.html

Money stored in payment apps such as Venmo may be more vulnerable than bank deposits: CFPB

 Money held in nonbank, peer-to-peer payment apps is not guaranteed for federal deposit insurance protection, which makes the funds more vulnerable, the Consumer Financial Protection Bureau warned Thursday.

The watchdog said the 85% of adults ages 18 to 29 in the U.S. who have used PayPal, Cash App, Zelle and other peer-to-peer apps would be in danger of losing their money if it was stored on one of those platforms and the companies failed. None of those platforms appear to be at risk of collapsing, but the CFPB highlighted the protection offered by deposit insurance after three regional banks collapsed since March.

The risks to user funds increase as the applications grow in popularity. More than three-quarters of U.S. adults have used a payment app, according to the Pew Research Center. Millennials made up the bulk of users in 2022 at 94%.

“Popular digital payment apps are increasingly used as substitutes for a traditional bank or credit union account but lack the same protections to ensure that funds are safe,” CFPB Director Rohit Chopra said.

CFPB is also monitoring whether tech companies adhere to fiscal safeguards as they expand into banking and payments, according to Chopra. Tesla mogul Elon Musk began exploring payment functions on Twitter soon after he took over the social media company last fall.

Peer-to-peer applications have proven lucrative. PayPal, the parent company of Venmo, reported $27.5 billion in revenue last year. Block, which owns Cash App, posted $17.5 billion in revenue last year.

The standards for storing consumer funds differ from company to company. Some invest the money in interest-earning loans and bonds instead of depositing into a traditional bank or credit union. This runs the risk of investment losses, interest rate changes, currency exchange rate fluctuations and liquidity issues, the CFPB said.

Other peer-to-peer companies, meanwhile, do not say where consumer money is held or invested.

Others claim to offer “pass-through” insurance that protects funds against the failure of the banking institution where the deposit is held, according to the CFPB. But the insurance is only provided under certain conditions and does not protect users’ money if the parent app collapses.

CFPB said Thursday it will continue coordinating with state and federal regulators to monitor progress on automated funds sweeping into insured banking accounts. Until then, app users must be proactive in moving money into an insured financial facility until a method is adopted, the agency said.

PayPal, Cash App and Zelle did not immediately respond to requests for comment.

https://www.cnbc.com/2023/06/01/cfpb-says-money-stored-in-payment-apps-is-not-federally-insured.html

EQT to take UK's Dechra Pharma private for $5.6 bln

 Swedish investment firm EQT will take Dechra Pharmaceuticals DPH.L private in a deal with an equity value of 4.46 billion pounds ($5.62 billion), the British veterinary drugmaker said on Friday.

Under the terms of the deal, each Dechra shareholder will receive 3,875 pence in cash, which represents a premium of about 44% to the last closing price before the offer period commenced.

The firms had been in talks for a deal since April.

The enterprise value of the deal is 4.88 billion pounds.

https://www.nasdaq.com/articles/eqt-to-take-uks-dechra-pharma-private-for-$5.6-bln

Axsome: New Sunosi® Data at SLEEP 2023

 Axsome Therapeutics, Inc. (NASDAQ: AXSM), a biopharmaceutical company developing and delivering novel therapies for the management of central nervous system (CNS) disorders, today announced presentations on Sunosi^® (solriamfetol) at SLEEP 2023, the annual meeting of the American Academy of Sleep Medicine and the Sleep Research Society, being held in Indianapolis, Ind., from June 3-7, 2023. The presentations include new data from the SHARP (Solriamfetol’s Effect on Cognitive Health in Apnea Participants During a Randomized Placebo-controlled) study in patients with excessive daytime sleepiness (EDS) associated with obstructive sleep apnea (OSA), demonstrating sustained improvement with Sunosi on measures of cognition across 8-hours with once daily dosing. Additional new data and analyses include real-world data from OSA patients taking Sunosi as part of the SURWEY study in Germany, healthcare resource use in OSA patients with residual EDS, and effect sizes and numbers needed to treat analyses.

https://www.biospace.com/article/releases/axsome-therapeutics-to-present-new-sunosi-data-at-sleep-2023/

Hochul announces all graduating seniors to be offered spots at SUNY and CUNY

 Gov. Kathy Hochul announced on Thursday that New York will be offering spots at SUNY and CUNY colleges for all of the state’s graduating high school seniors.

According to the governor’s office, SUNY will soon be sending out letters to roughly 125,000 senior students informing them that they have been automatically accepted to their local community colleges this fall. 

“Access to quality higher education is an engine for social mobility and we are taking comprehensive steps to ensure that college is affordable and accessible for students from all backgrounds,” Hochul said in a statement.

“My administration remains committed to removing barriers and easing the pathway to higher education for all high school seniors – lifting up students to build a brighter future for themselves and New York.”

Sending a personalized letter to students is expected to spark their decision to enroll, the governor’s office said.

Gov. Kathy Hochul said 125,000 senior students in New York will receive letters offering enrollment at SUNY universities.

William Farrington

Earlier this year, financially struggling CUNY announced a partnership with New York City Public Schools to send 65,000 graduating seniors personalized letters also confirming their acceptance at the city’s university system, according to the governor’s office. 

The letters will reveal students’ college options at CUNY, and invite them to send in a CUNY application.

“CUNY is sending seniors and their families the tools they need to find the right program at the right price,” CUNY Chancellor Félix V. Matos Rodríguez said. “This partnership will increase the number of seniors going to college, enhance New York’s workforce and help end systemic inequities.”

Both SUNY and CUNY are ready to assist all students with questions about applying for financial aid, the governor’s office said.

The measure was first proposed by Hochul as part of her 2023 State of the State agenda “to eliminate barriers to higher education.”

https://nypost.com/2023/06/01/hochul-announces-all-graduating-seniors-to-be-offered-spots-at-suny-and-cuny/

Virginia, West Virginia Governors Sending National Guard Troops To Texas Border

 by Ryan Morgan via The Epoch Times (emphasis ours)

The governors of Virginia and West Virginia are the latest Republican state leaders to announce deployments of National Guard troops to assist Texas Gov. Greg Abbott’s border security efforts

On Wednesday morning, Virginia Gov. Glenn Youngkin announced he would deploy 100 of his state’s National Guard troops to Texas.

“The ongoing border crisis facing our nation has turned every state into a border state,” Youngkin said. “As leadership solutions at the federal level fall short, states are answering the call to secure our southern border, reduce the flow of fentanyl, combat human trafficking and address the humanitarian crisis. Following a briefing from Governor Abbott last week, Virginia is joining other states to deliver on his request for additional assistance.”

In a Wednesday morning press conference, West Virginia Gov. Jim Justice also announced he would deploy 50 of his state’s National Guard troops to Texas.

“I know our National Guard will do incredible work, and we’ll wish them Godspeed to get home safe and sound,” Justice said. “I thank them all for their incredible bravery and for stepping up yet again to answer the call.”

Abbott has been using Texas state resources in recent months in a mission to stem the flow of illegal border crossings into the country. In recent weeks, Texas National Guard troops and Department of Public Safety officers have been seen setting up razor fences and turning back people attempting to cross from Mexico into Texas illegally.

Abbott has stepped up this border security effort after President Joe Biden’s administration ended the federal Title 42 immigration policy on May 11. Following the outbreak of COVID-19, U.S. officials had used Title 42 authorities to rapidly turn away and expel illegal immigrants under public health justifications.

On May 16, 24 Republican governors signed a letter pledging to support Abbott’s border security effort, including Youngkin and Justice. Since then, several Republican governors have deployed their state National Guard troops and state police resources to assist border control efforts.

Other States Sending Troops

Florida Gov. Ron DeSantis was among the first Republican governors to pledge specific resources to Abbott’s border security mission. On May 16, DeSantis announced his state would send 800 Florida National Guard soldiers, 200 Florida Department of Law Enforcement officers, 20 Florida Fish and Wildlife Conservation Commission officers, and 20 Emergency Management personnel to Texas. DeSantis also pledged five fixed-wing aircraft, two mobile command vehicles, 17 unmanned aerial vehicles (drones), and 10 watercraft.

On May 17, Mississippi Gov. Tate Reeves announced an unspecified number of troops from the Mississippi National Guard’s 112th Military Police Battalion would deploy to assist U.S. Customs and Border Protection (CBP) officers and agents along the southwest border.

On May 24, Tennessee Gov. Bill Lee announced he had authorized the deployment of 100 Tennessee National Guard troops to the border. Lee said these troops would patrol and provide an added security presence at the border, help staff outposts, and assist in road and route clearance, barrier placement, and debris removal.

“America continues to face an unprecedented border crisis that threatens our nation’s security and the safety of Tennesseans,” Lee said of the deployment.

“The federal government owes Americans a plan to secure our country, and in the meantime, states continue to answer this important call to service,” Lee added. “I am again authorizing the Tennessee National Guard to help secure the Southern border, and I commend these troops for providing critical support.”

On May 24, Nebraska Gov. Jim Pillen also announced he would send 10 Nebraska state troopers to Texas to assist Abbott’s border security mission.

https://www.zerohedge.com/political/virginia-west-virginia-governors-sending-national-guard-troops-texas-border