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Friday, December 9, 2022

Roughly 60% Of Students Fear Expressing Their Views In Higher Education; New Poll Finds

 by Jonathan Turley,

There is a new poll out and it is strikingly similar to the polls previously featured on this blog on free speech and intellectual diversity in higher education.  The Buckley annual survey found that almost 60 percent of college students fear sharing an opinion in classrooms or on campuses. That tracks other polls by different groups.  Yet, colleges and universities continue to exclude Republican and conservative faculty members and maintain environments of speech intolerance.The poll shows a sharp increase from just last year with 63% reporting feeling intimidated in sharing opinions different than their peers. That is almost identical to the 65 percent found in other polls.

The poll of over 800 students included many liberal students, as reflected in the 67 percent who would require all professors and administrators to make statements in favor of diversity, equity, and inclusion. Half of students believe “America is inextricably linked to white supremacy” and another 33 percent would prefer to live in a socialist system.

The poll tracks earlier polls showing a rising view of viewpoint intolerance that now characterizes higher education in America. That intolerance is reflected in the overwhelmingly Democratic and liberal makeup of faculties.

new survey of 65 departments in various states found that 33 do not have a single registered Republican. For these departments, the systemic elimination of Republican faculty has finally reached zero, but there is still little recognition of the crushing bias reflected in these numbers. Others, as discussed below, have defended the elimination of conservative or Republican faculty as entirely justified and commendable. Overall, registered Democrats outnumbered registered Republicans by a margin of over 10-1.

The survey found 61 Republican professors across 65 departments at seven universities while it also found 667 professors identified as Democrats based on their political party registration or voting history.

While there may be a couple professors missed on either side of this ideological divide, most faculty will privately admit that it is rare to find self-identified Republicans or conservatives on many faculties. Most faculties are overwhelmingly Democratic and liberal. Diversity generally runs from the left to the far left.

Another survey found that only nine percent of law professors identified as conservative. The virtual absence of Republican or conservative members on many faculties are just shrugged off by many academics.   It is the subject of my recent publication in the Harvard Journal of Law and Public Policy. The article entitled “Harm and Hegemony: The Decline of Free Speech in the United States.

Notably, a 2017 study found 15 percent of faculties were conservative. This is the result of years of faculty replicating their own ideological preferences and eradicating the diversity that once existed on faculties. When I began teaching in the 1980s, faculties were undeniably liberal but contained a significant number of conservative and libertarian professors. It made for a healthy and balanced intellectual environment. Today such voices are relatively rare and faculties have become political echo chambers, leaving conservatives and Republican students increasingly afraid to speak openly in class.

The trend is the result of hiring systems where conservative or libertarian scholars are often rejected as simply “insufficiently intellectually rigorous” or “not interesting” in their scholarship. This can clearly be true with individual candidates but the wholesale reduction of such scholars shows a more systemic problem. Faculty insist that there is no bias against conservatives, but the obviously falling number of conservative faculty speaks for itself.

As discussed earlier, the editors of the legal site Above the Law have repeatedly swatted down objections to the loss of free speech and viewpoint diversity in the media and academia. In a recent column, they mocked those of us who objected to the virtual absence of conservative or libertarian faculty members at law schools.

Senior editor Joe Patrice defended “predominantly liberal faculties” based on the fact that liberal views reflect real law as opposed to junk law.  (Patrice regularly calls those with opposing views “racists,” including Chief Justice John Roberts because of his objection to race-based criteria in admissions as racial discrimination). He explained that hiring a conservative academic was akin to allowing a believer in geocentrism (or that the sun orbits the earth) to teach at a university.

It is that easy. You simply declare that conservative views shared by a majority of the Supreme Court and roughly half of the population are not acceptable to be taught.

We have previously discussed the worrisome signs of a rising generation of censors in the country as leaders and writers embrace censorship and blacklisting. The latest chilling poll was released by 2021 College Free Speech Rankings after questioning a huge body of 37,000 students at 159 top-ranked U.S. colleges and universities. It found that sixty-six percent of college students think shouting down a speaker to stop them from speaking is a legitimate form of free speech.  Another 23 percent believe violence can be used to cancel a speech. That is roughly one out of four supporting violence.

This has been an issue of contention with some academics who believe that free speech includes the right to silence others.  Berkeley has been the focus of much concern over the use of a heckler’s veto on our campuses as violent protesters have succeeded in silencing speakers, including a speaker from the ACLU discussing free speech.  Both students and some faculty have maintained the position that they have a right to silence those with whom they disagree and even student newspapers have declared opposing speech to be outside of the protections of free speech.  At another University of California campus, professors actually rallied around a professor who physically assaulted pro-life advocates and tore down their display.

In the meantime, academics and deans have said that there is no free speech protection for offensive or “disingenuous” speech.  CUNY Law Dean Mary Lu Bilek showed how far this trend has gone. When conservative law professor Josh Blackman was stopped from speaking about “the importance of free speech,”  Bilek insisted that disrupting the speech on free speech was free speech. (Bilek later cancelled herself and resigned after she made a single analogy to acting like a “slaveholder” as a self-criticism for failing to achieve equity and reparations for black faculty and students).

There are now a wide array of polls and surveys showing a rising sense of viewpoint intolerance and a lack of ideological diversity on faculties. When confronted, faculty often shrug and say that the students are simply wrong about speech intolerance. They also dismiss the importance of labels (even self-reported party affiliations). Few, however, seriously deny that faculties are now overwhelmingly, if not exclusive, Democratic or liberal. Intellectual diversity today on faculties often runs from the left to the far left.

I frankly do not understand why professors want to maintain this one-sided environment in hiring. I was drawn to academia by the diversity of viewpoints and intellectual challenges on campuses.  However, the lack of diversity works to the advantage of those on the “correct” side of this new orthodoxy. Conversely, those with dissenting views are often targeted or isolated on faculties. They risk the loss of everything that gives an intellectual life meaning from publishing to speaking opportunities. For faculty, the viewpoint intolerance seen by students is magnified a hundred times over for those seeking to enter or to advance in teaching.

https://www.zerohedge.com/political/roughly-60-students-fear-expressing-their-views-higher-education-new-poll-finds

Setting the Stage for ASH 2022

 When the 64th American Society of Hematology (ASH) annual meeting kicks off Saturday in New Orleans, established hematology leaders like AstraZeneca, Janssen and Merck will showcase new data, and new players like Vega Therapeutics will launch new programs.  

Janssen 

J&J’s Janssen will take a leading role at this year’s conference with more than 70 presentations on the schedule.  

Janssen will provide efficacy and safety data for Tecvayli (teclistamab) in addition to Darzelx Faspro and lenalidomide in patients who have received one to three prior lines of therapy. The FDA approved Tecvayli in this indication in October.  

The company will also reveal longer follow-up data from the MajesTEC-1 trial – which formed the basis of the approval - for Tecvayli as a monotherapy. 

In mantle cell lymphoma (MCL), Janssen will present data from the Phase III TRIANGE study of Imbruvica (ibrutinib) combination therapy in transplant-eligible younger adults with untreated disease. These results will be reported during the Sunday plenary session. 

In a real-world study, eight years of observational analysis showed Janssen’s oral Factor Xa inhibitor Xareleto was equally effective in treating cancer-associated thromboembolism (CAT) as Factor Xa inhibitor apixaban, an anticoagulant medication.  

This held true across a broad range of patients with varying cancers. Patients with CAT are at greater risk of venous thromboembolism. It is the second leading cause of death for people with cancer. Janssen and development partner Bayer will present the results on Dec. 11.  

Affimed 

Germany-based Affimed comes to ASH ready to provide a review of data and development update for its lead candidate AFM13, a CD30/CD16A bispecific Innate Cell Engager (ICE).  

In a Phase I study, the therapy showed an 88% overall response rate and 46% complete response rate when combined with Merck’s Keytruda in relapsed/refractory Hodgkin lymphoma. AFM13 is also being evaluated as a monotherapy in a registration-directed trial for peripheral T cell lymphoma.  

In a Phase I/II trial, a combination of AFM13 with allogeneic cord blood-derived NK cells yielded an ORR of 100% and a CR of 71% in 24 patients with CD30+ R/R Hodgkin and non-Hodgkin lymphomas treated at the highest dose level.  

Affimed is developing innate cell engagers that link natural killer cells to tumor cells. Other programs include AFM24 and AFM24 + adoptive NK cells. These therapies, both in Phase I, target EGFR-positive solid tumors. At the developmental stage, AFM28 targets CD123-positive acute myeloid leukemia (AML). 

The company plans to update investors on its development plans for AFM13 in hematologic malignancies on Saturday at 4 pm CT at the conference and via webcast. BioSpace will update this story accordingly. 

Merck 

With the industry’s largest immuno-oncology clinical research program, it’s no surprise that Merck’s drugs and therapies currently involved in clinical studies will be featured in nearly 40 abstracts.  

One of the most anticipated presentations includes new and updated data for Keytruda, the company’s IO centerpiece.

Keytruda is an anti-programmed death receptor-1 (PD-1) therapy that helps the immune system fight tumor cells. It keeps PD-1 and its ligands from interacting, which then activates T lymphocytes, which affect both healthy cells and tumor cells.  

Keytruda is prolific as part of various combination treatments. It is currently being studied in over 1600 trials in myriad cancer varieties. 

Merck will also present data for several of its investigational therapies, including favezelimab, an anti-LAG-3 antibody, zilovertamab vedotin, an antibody-drug conjugate targeting receptor tyrosine kinase-like orphan receptor 1 [ROR1] and nemtabrutinib, a reversible, non-covalent Bruton’s tyrosine kinase [BTK] inhibitor. 

Indications include melanoma, non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma and many more. 

AstraZeneca 

AstraZeneca will present 47 abstracts showcasing new data from trials in its hematology portfolio.

Ahead of the annual meeting, the company stated it will feature eight approved and potential new medicines in over 10 rare diseases and blood cancers. These include chronic lymphocytic leukemia (CLL), follicular lymphoma, diffuse large B-cell lymphoma, MCL, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and amyloid light chain amyloidosis. 

One of the most anticipated presentations will include updated results from the Phase II study of acalabrutinib, venetoclax and obinutuzumab (AVO) as a treatment for patients with CLL enriched for high-risk disease. All patients in the trial have been previously untreated.  

AstraZeneca also plans to spotlight breaking data from its next-generation BTK-inhibitor Calquence (acalabrutinib). Among these updates, the drugmaker will discuss a post-hoc safety analysis from the ELEVATE-RR Phase III trial comparing Calquence versus ibrutinib in relapsed or refractory CLL, as well as final long-term follow-up results of Phase I/II trials involving the therapy. 

Elixirgen Therapeutics 

On Monday, Elixirgen Therapeutics and its research collaborators will present data from the company's lead candidate, EXG-34217, a first-in-human cell therapy that aims to extend telomere length in patients with telomere biology disorders. 

EXG-34217 is a therapeutic dose of autologous CD34+ hematopoietic stem cells (HSCs) that have been treated ex vivo with EXG-001, a non-integrating, temperature-sensitive and non-transmissible Sendai virus vector encoding for human zinc finger and SCAN Domain containing 4 (ZSCAN4).

Diseases like the rare skin and bone marrow disorder, dyskeratosis congenita, are characterized by short telomeres, which are believed to cause premature cellular senescence and put patients at higher risk of bone marrow failure. 

Elixirgen CEO Akihiro Ko explained that there are currently limited treatment options for TBDs including androgen therapy. Ultimately, many patients will need to undergo hematopoietic stem cell transplant, which comes with a preconditioning regiment that can cause toxicities.

"EXG-34217 is an autologous therapy...and it is infused into a patient without preconditioning or systemic immunosuppression," Ko told BioSpace

In a first-in-human clinical trial, the cell therapy increased telomere length of autologous CD34+ hematopoietic stem cells ex vivo from adult patients with dyskeratosis congenita, bringing them into a healthy normal control range. 

The company's work is based on a 2010 paper by CSO Minoru Ko, M.D., Ph.D., which showed how ZSCAN4 is involved in telomere maintenance and long-term-genomic stability in ES cells.

Aside from its work in TBDs, Ko said Elixirgen is "actively exploring" how the technologies can be used to design cancer immunotherapies including CAR-T cell therapies as well as potential solutions for aging-related disorders.

Vega Therapeutics  

Exploding into the constellation of Star Therapeutics this week, Vega will debut its first-in-class monoclonal antibody therapy, VGA039, being developed for von Willebrand disease (VWD), a common and chronic blood disorder. 

In a podium presentation given Dec. 12 by Chief Scientific Officer Sandip Panicker, Ph.D., Vega will unveil preclinical data demonstrating the potential of VGA039 as a universal hemostatic therapy for bleeding disorders. In particular, the antibody will address a fundamental mechanism of clot formation in VWD, according to the Tuesday press release.  

VGA039 reportedly works by modulating Protein S, which it describes as a key cofactor involved in thrombin generation during both the initiation and propagation of coagulation.

The new company has secured Austrian Competent Authority approval of a clinical trial application for a Phase I study in VWD.  

Vega CEO and Co-founder Adam Rosenthal, Ph.D. said drug innovation for VWD has lagged. “At Vega, we see a future where we can better meet the needs of patients by advancing VGA039 as the first purpose-built antibody therapy for VWD,” he said in a statement Tuesday.  

Vega is supported by $40 million in financing from Star and several other investors including Westlake Village BioPartners, OrbiMed and Redmile

https://www.biospace.com/article/setting-the-stage-for-ash-2022-/

Roche: FDA OKs Tecentriq for alveolar sarcoma

 The FDA has approved atezolizumab (Tecentriq) for adult and pediatric patients aged 2 years and older with unresectable or metastatic alveolar soft part sarcoma (ASPS).

The safety and efficacy of the agent was examined in the open-label, single-arm study, referred to as Study ML39345 (NCT03141684). To be eligible for enrollment, patients were required to have histologically or cytologically confirmed ASPS that was not curable by surgery, and an ECOG performance status of up to 2.

If patients had known primary central nervous system (CNS) malignancy or symptomatic CNS metastases, known clinically significant liver disease, or a history of idiopathic pulmonary fibrosis, they were excluded. Other exclusion criteria also included having pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography scan.

Adult and pediatric patients enrolled to trial were given 1200 mg or 15 mg/kg, respectively, of atezolizumab intravenously once every 21 days until progressive disease or intolerable toxicity.

Independent review committee–assessed overall response rate (ORR) and duration of response (DOR) by RECIST v1.1 criteria served as the main efficacy outcome measures of the trial.

Among the 49 patients enrolled, the median age was 31 years (range, 12-70); 2% (n = 47) of patients were at least 65 years of age, and the 2 pediatric patients were at least 12 years of age. Moreover, 51% of patients were female and 55% were White. Regarding ECOG performance status, 53% had a status of 0 and 45% had a status of 1.

All patients previously underwent surgery for their disease and more than half (55%) received at least 1 previous line of therapy. Fifty-five percent of patients received prior radiotherapy and 53% had prior chemotherapy. All patients who reported their disease stage at the time of their initial diagnosis had stage IV disease.

Data showed that atezolizumab elicited an ORR of 24% (95% CI, 13%-39%), which included a partial response rate of 24%. The median DOR was not evaluable (NE; 95% CI, 17.0-NE), with 67% of patients experiencing a response that persisted for at least 6 months and 42% experiencing a response that lasted for 12 months or longer.

The safety of atezolizumab was examined in a total of 47 adult patients and 2 pediatric patients. The median duration of exposure to the drug was 8.9 months (range, 1-40).

The most common adverse reactions to occur in 15% or more of patients were musculoskeletal pain (67%), fatigue (55%), rash (47%), cough (45%), nausea (43%), headache (43%), hypertension (43%), vomiting (37%), constipation (33%), dyspnea (33%), dizziness (29%), hemorrhage (29%), insomnia (27%), diarrhea (27%), pyrexia (25%), anxiety (25%), abdominal pain (25%), hypothyroidism (25%), decreased appetite (22%), arrhythmia (22%), influenza-like illness (18%), decreased weight (18%), allergic rhinitis (16%), and increased weight (16%).

Forty-one percent of patients experienced serious adverse reactions to the treatment, and 35% required dose interruptions due to toxicity.

The recommended dosage of the agent for adult patients is 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks until progressive disease or intolerable toxicity. For pediatric patients ag ed 2 years and older, the recommended dosage is 15 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

https://www.onclive.com/view/fda-approves-atezolizumab-for-alveolar-soft-part-sarcoma

Missing piece of the asthma puzzle found

 An inflammatory molecule called LIGHT, appears to be the cause of life-threatening airway damage in patients with severe asthma. According to the new research from scientists at La Jolla Institute for Immunology (LJI), therapeutics to stop LIGHT (which is related to tumor necrosis factor) could reverse airway and lung damage in patients—and potentially offer a long-term treatment for asthma.

"This is a very, very significant finding," says LJI Professor Michael Croft, Ph.D., senior author of the new study and member of the LJI Center for Autoimmunity and Inflammation. "This research gives us a better understanding of the potential of therapeutic targeting of LIGHT and what we might do to relieve some of the symptoms and some of the inflammatory features seen in patients who have severe ."

This research was published recently in the Journal of Allergy and Clinical Immunology. The study included experiments with both mouse and  and was spearheaded by LJI Instructor Haruka Miki, M.D., Ph.D.

Croft's team has studied LIGHT for more than a decade. The LIGHT protein is a type of inflammatory "cytokine" produced by the immune system's T cells. T cells normally fight disease, but in asthma, T cells overreact to environmental triggers and flood the airways with LIGHT and other . Researchers have developed therapies to block the activity of some of the other harmful cytokines made by T cells, but these therapies aren't effective for many with severe asthma.

LIGHT can be found elevated in the sputum of asthmatic patients with severe disease, and Croft's previous work showed that LIGHT is essential in a process called tissue "remodeling," where the lungs and airways grow thicker following an . These thicker airways can leave a person with long-term breathing problems.

"Current treatments for asthma are mainly to suppress symptoms and subdue allergic inflammation. No treatment has been developed to fundamentally cure asthma," says Miki. "Even when inflammation is suppressed by current treatments, underlying  hyperresponsiveness and airway tissue changes (airway remodeling) often remain, especially in severe asthma."

Even though they knew LIGHT was involved in this remodeling, the researchers did not know whether LIGHT directly affects the smooth muscle tissue that lines the major airways of the lungs. These cells increase in number and size in moderate and severe asthmatics, which is thought to be a primary cause of loss of lung function.

Their investigation showed that one of the two receptors for LIGHT, named LTβR, was strongly expressed on airway . By then "knocking out" the genes for one receptor or the other in mice, Miki was able to show that LIGHT's binding with LTβR is what triggers tissue remodeling in the airway smooth muscles. The researchers further confirmed this finding using bronchial smooth muscle tissue from human samples.

"When those cells in the lungs cannot express LTβR, then essentially all of the hallmarks of the smooth muscle response associated with  are either gone or they're highly limited," says Croft.

Of course, LIGHT isn't the only cytokine in the mix during an asthma attack, but the new study suggests that LIGHT packs the biggest punch. By acting directly on airway smooth muscle cells, LIGHT coordinates the remodeling process. Without LIGHT and LTβR activity, the other cytokines can't pick up the slack. In fact, the new study is the first to show that the deletion of a single receptor or absence of a single cytokine can limit airway smooth muscle tissue remodeling.

"Unlike other inflammatory cytokines, LIGHT induces a delayed and persistent signal via its receptor, LTβR, which may be responsible for the sustained increase in contractility and mass in airway smooth muscle," says Miki.

"This is a very striking and significant result that essentially separates LIGHT from any of the other inflammatory cytokines that have been implicated in the process in severe asthmatics," adds Croft.

Right now, pharmaceutical company and LJI research partner Kiowa Kirin is advancing a potential therapeutic based on Croft's finding. For Croft, the study is the long-awaited conclusion to years of research. "I think it completes the circle that we started many years ago in first linking LIGHT to lung inflammation," he says.

More information: Haruka Miki et al, LTβR Signaling Directly Controls Airway Smooth Muscle Deregulation and Asthmatic Lung Dysfunction, Journal of Allergy and Clinical Immunology (2022). DOI: 10.1016/j.jaci.2022.11.016
https://medicalxpress.com/news/2022-12-piece-asthma-puzzle.html

How a viral toxin may exacerbate severe COVID-19

 A new study in the journal Nature Communications reveals how a viral toxin produced by the SARS-CoV-2 virus may contribute to severe COVID-19 infections.

The study shows how a portion of the SARS-CoV-2 ""  can damage cell barriers that line the inside of blood vessels within organs of the body such as the lungs, contributing to what is known as vascular . Blocking the activity of this protein may help prevent some of COVID-19's deadliest symptoms, including pulmonary edema, which contributes to acute respiratory distress syndrome (ARDS).

"In theory, by specifically targeting this pathway, we could block pathogenesis that leads to vascular disorder and acute respiratory distress syndrome without needing to target the  itself," said study lead author Scott Biering, a postdoctoral scholar at the University of California, Berkeley. "In light of all the different variants that are emerging and the difficulty in preventing infection from each one individually, it might be beneficial to focus on these triggers of pathogenesis in addition to blocking infection altogether."

While many vaccine skeptics have stoked fears about potential dangers of the SARS-CoV-2 —which is the target of COVID-19 mRNA vaccines—the researchers say that their work provides no evidence that the spike protein can cause symptoms in the absence of viral infection. Instead, their study suggests that the spike protein may work in tandem with the virus and the body's own immune response to trigger life-threatening symptoms.

In addition, the amount of spike protein circulating in the body after vaccination is far less concentrated than the amounts that have been observed in patients with severe COVID-19 and that were used in the study.

"The amount of spike protein that you would have in a vaccine would never be able to cause leak," said study senior author Eva Harris, a professor of infectious diseases and vaccinology at UC Berkeley. "In addition, there's no evidence that [the spike protein] is pathogenic by itself. The idea is that it's able to aid and abet an ongoing infection."

By examining the impact of the SARS-CoV-2 spike protein on human lung and , and on the lungs of mice, the research team was able to uncover the molecular pathways that allow the spike protein to disrupt critical internal barriers in the body. In addition to opening new avenues for the treatment of severe COVID-19, understanding how the spike protein contributes to vascular leak could shed light on the pathology behind other emerging infectious diseases.

"We think that a lot of viruses that cause severe disease may encode a viral toxin," Biering said. "These proteins, independent of viral infection, interact with barrier cells and cause these barriers to malfunction. This allows the virus to disseminate, and that amplification of virus and vascular leak is what triggers severe disease. I'm hoping that we can use the principles that we've learned from the SARS-CoV-2 virus to find ways to block this pathogenesis so that we are more prepared when the next pandemic happens."

How spike protein triggers vascular leak

Vascular leak occurs when the cells that line blood vessels and capillaries are disrupted, allowing plasma and other fluids to leak out of the bloodstream. In addition to causing the lung and heart damage observed in severe COVID-19, vascular leak can also lead to hypovolemic shock, the primary cause of death from dengue.

Before the COVID-19 pandemic, Biering and other members of the Harris Research Program were studying the role of dengue virus protein NS1 in triggering vascular leak and contributing to hypovolemic shock. When the pandemic hit, the team wondered if a similar viral toxin in SARS-CoV-2 could also be contributing to the  that was killing COVID-19 patients.

"People are aware of the role of bacterial toxins, but the concept of a viral toxin is still a really new idea," Harris said. "We had identified this protein secreted from dengue virus-infected cells that, even in the absence of the virus, is able to cause endothelial permeability and disrupt internal barriers. So, we wondered if a SARS-CoV-2 protein, like spike, might be able to do similar things."

Spike proteins coat the outer surface of SARS-CoV-2, giving the virus its knobby appearance. They play a critical role in helping the virus infect its hosts: The spike protein binds to a receptor called ACE2 on human and other mammalian cells, which—like a key turning a lock—allows the virus to enter the cell and hijack cellular function. The SARS-CoV-2 virus sheds a large portion of the spike protein containing the receptor-binding domain (RBD) when it infects a cell.

"What's really interesting is that circulating spike protein correlates with severe COVID-19 cases in the clinic," Biering said. "We wanted to ask if this protein was also contributing to any vascular leak we saw in the context of SARS-CoV-2."

Currently, scientists attribute the heart and lung damage associated with severe COVID-19 to an overactive immune response called a cytokine storm. To test the theory that the spike protein might also play a role, Biering and other team members used thin layers of human endothelial and epithelial cells to mimic the linings of blood vessels in the body. They found that exposing these cellular layers to the spike protein increased their permeability, a hallmark of vascular leak.

Using CRISPR-Cas9 gene editing technology, the team showed that this increased permeability occurred even in cells that did not express the ACE2 receptor, indicating that it could occur independently of viral infection. In addition, they found that mice that were exposed to the spike protein also exhibited vascular leak, even though mice do not express the human ACE2 receptor and cannot be infected with SARS-CoV-2.

Finally, with the help of RNA sequencing, the researchers found that the spike protein triggers vascular leak through a molecular signaling pathway that involves glycans, integrins and transforming growth factor beta (TGF-beta). By blocking the activity of integrins, the team was able to reverse the vascular leak in mice.

"We identified a new pathogenic mechanism of SARS-CoV-2 in which the spike protein can break down the barriers lining our vasculature. The resulting increase in permeability can lead to vascular leak, as is commonly observed in severe COVID-19 cases, and we could recapitulate those disease manifestations in our mouse models," said study co-author Felix Pahmeier, a graduate student in the Harris lab at UC Berkeley's School of Public Health. "It was interesting to see the similarities and differences between spike and dengue virus protein NS1. Both are able to disrupt endothelial barriers, but the timelines and host pathways involved seem to differ between the two."

While blocking the activity of integrins may be a promising target for treating severe COVID-19, Harris said more work needs to be done to understand the exact role of this pathway in disease progression. While increased vascular permeability can accelerate infection and lead to internal bleeding, it can also help the body fight off the virus by giving immune machinery better access to infected cells.

"SARS-CoV-2 evolved to have a spike surface protein with increased capacity of interacting with host cell membrane factors, such as integrins, by acquiring an RGD motif. This motif is a common integrin-binding factor exploited by many pathogens, including bacteria and other viruses, to infect host cells," said Francielle Tramontini Gomes de Sousa, former assistant project scientist in Harris's lab and co-first author of the study. "Our study shows how spike RGD interacts with integrins, resulting in TGF-beta release and activation of TGF-beta signaling. Using in vitro and in vivo models of epithelial, endothelial and vascular permeability, we were able to improve understanding of the cellular mechanisms of increased levels of TGF-beta in COVID-19 patients and how spike-host cell interactions could contribute to disease."

The team is continuing to study the molecular mechanisms that lead to vascular leak and is also investigating possible viral toxins in other viruses that cause severe disease in humans.

"COVID-19 is not gone. We have better vaccines now, but we don't know how the virus is going to mutate in the future," Biering said. "Studying this process may be able to help us develop a new arsenal of drugs so that if someone is experiencing vascular leak, we can just target that. Maybe it doesn't stop the virus from replicating, but it could stop that person from dying."

More information: Scott B. Biering et al, SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling, Nature Communications (2022). DOI: 10.1038/s41467-022-34910-5
https://medicalxpress.com/news/2022-12-viral-toxin-exacerbate-severe-covid-.html

New customizable, strontium-filled scaffold could improve dental implant healing

 A team of University at Buffalo researchers has developed a new strontium-loaded scaffold that can be personalized to fit any size dental implant and could help improve healing and tissue attachment in patients.

The success of dental implants is dependent on the growth and adhesion of soft tissues to the implant surface. Previous research by UB investigators found that strontium, a bone-seeking element that improves bone density and strength, also supports soft tissue function. Strontium, they discovered, can promote the function of fibroblasts—a type of cell that forms connective tissues and plays a critical role in .

The new study, published earlier this year in the Journal of Biomedical Materials Research, found that scaffolds loaded with strontium—even at —promoted wound healing by stimulating gingival fibroblast activity.

"Scaffold materials have been explored to promote bone and skin wound healing, but adaptations for the  are limited," says lead investigator, Michelle Visser, Ph.D., associate professor of oral biology in the UB School of Dental Medicine. "These novel scaffolds represent a system for effective strontium release in the oral cavity."

To produce the scaffolds—which are porous structures that promote and guide cell growth—the researchers developed reusable, ring-shaped templates and molds. The flexible hydrogel scaffolds are infused with a range of strontium concentrations that are released in an initial burst over 24 hours, followed by a sustained dosage over four days with minimal toxicity.

Tested in the laboratory, the -loaded scaffolds increased the cellular activity of isolated gingival fibroblasts cells, while the hydrogel  alone had little effect on the cells.

More information: Shahad Bakheet Alsharif et al, Strontium‐loaded hydrogel scaffolds to promote gingival fibroblast function, Journal of Biomedical Materials Research Part A (2022). DOI: 10.1002/jbm.a.37439
https://medicalxpress.com/news/2022-12-customizable-strontium-filled-scaffold-dental-implant.html

Marijuana Industry's Buzz Wears Off As Pandemic Party Over

 The party is over, and the buzz is wearing off. Mature legal cannabis markets are experiencing a slowdown in sales since the pandemic boom. 

A new report from cannabis data firm Headset said the industry in established marijuana markets, such as Oregon and Washington, has slowed down from a year ago. For example, Colorado's market recorded sales that dropped 11.4% in June from a year ago. 

"What we saw in 2020 was a massive spike in sales tied to the pandemic as people stayed home, had government stimulus money, and not a lot to do," Chris Wash, CEO of Marijuana Business Daily, told CNBC

Headset noted marijuana sales spiked between March 2020-21, with monthly average year-over-year sales of around 25.8% in Colorado. But sales began sliding last year as people returned to work and stimulus checks ran out. The report found the number of purchases and amount of money people spent declined. 

In July, customers spent an average of $55.21 per visit at Colorado stores -- four dollars less than the average of $59.73 in July 2021, according to the data. 

"Right now, the Colorado marijuana industry is going through the largest downturn that we've ever seen," Truman Bradley, executive director of the Wheat Ridge-based Marijuana Industry Group, told the local media outlet 9News Denver. 

Even though marijuana sales are normalizing in mature markets after a pandemic-fueled party, the industry nationwide is expected to grow as new markets come online. Marijuana Business Daily expects US medical and recreational cannabis sales could exceed $33 billion this year, up from $27 billion last year. Forecasts for 2026 are around $52.6 billion. 

So why are sales slowing in mature markets? Well, these states were the only ones open for business during the pandemic, and when tens of millions of Americans were out of work or forced to stay home because of the government shutdown, there was nothing better to do than sit on the couch, consume marijuana, and watch Netflix. Now that people aren't stuck at home, they aren't purchasing as much cannabis, and producers have to readjust production levels lower due to declining demand. 

One exchange-traded fund tied to the cannabis sector, called ETFMG Alternative Harvest ETF (MJ), has plunged more than 84% since the February 2021 peak of $33. 

The buzz is over. 

https://www.zerohedge.com/markets/marijuana-industry-buzz-wears-pandemic-party-over