Categories
Cardiology COVID-19

American Heart Association Quells Vaccine Myocarditis Fears Amid Growing Public Concern

As concerns regarding mRNA vaccine-caused myocarditis skyrocket on social media and news outlets, researchers have published a study in the American Heart Association’s Circulation journal with statistics regarding the potential side effect.

Google Search interest in “COVID vaccine myocarditis” from December 6, 2020 to December 6, 2021. / trends.google.com

Myocarditis is a condition that causes inflammation in the heart, which can weaken its ability to regularly pump blood throughout the body. It can lead to heart failure, abnormal heartbeat, and sudden death. Most cases of myocarditis are caused by viruses, but the rare heart condition has been noticed as a potential side effect of mRNA vaccines for COVID-19.

The study published in Circulation statistically analyzed cases in patients younger than 21 years old who had received an mRNA vaccine within 30 days of showing symptoms of myocarditis. Researchers found that, in general, young people who experience myocarditis as a side effect of the COVID-19 vaccine recover quickly and completely.

The Circulation study found that 90.6% of adolescent and young adult patients who experienced myocarditis after vaccination were male. In most cases, symptoms presented 2 days after vaccination. The most common symptom was chest pain, which presented in 99.3% of the patients. 18.7% of the patients had low left ventricular ejection fraction (LVEF), meaning that not enough blood was pumping out of their hearts. However, all patients with low LVEF who followed up had fully recovered with normalized function.

Another study published in the New England Journal of Medicine reported that only 2.13 in 100,000 people who received the mRNA vaccine experienced myocarditis. This is much lower than the 150 in 100,000 rate of myocarditis in unvaccinated patients infected with COVID-19 as reported by the Morbidity and Mortality Weekly Report. This means that unvaccinated people infected with COVID-19 had about 70 times greater incidence of myocarditis than any person receiving the mRNA vaccine.

The Circulation study’s first author, Dr. Dongngan T. Truong, told the American Heart Association Newsroom that the data showed that “most cases of suspected COVID-19 vaccine-related myocarditis in people younger than 21 are mild and resolve quickly.”

As the data shows that myocarditis as a side effect of COVID-19 vaccination is extremely rare (2.13 in 100,000) and that almost all of those patients recovered quickly and completely, the American Heart Association continues holding its position that COVID-19 vaccines are safe and highly effective (preventing hospitalization and death in 91% of severe infections). Dr. Donald M. Lloyd-Jones, president of the AHA, said that COVID-19 vaccines were “fundamental to saving lives, protecting our families and communities against COVID-19, and ending the pandemic,” then urging parents to vaccinate their children as soon as possible.

References

Note from the Editors

This article does not offer medical advice. It is a review of statements and data offered by the American Heart Association. Consult with a doctor regarding concerns related to health effects from the COVID-19 vaccine.

Categories
COVID-19

Mutation of Nucleocapsid, Not Spike Protein, Responsible for Delta Variant’s Increased Transmissibility

Since the emergence of the Delta variant as the world’s predominant variant of SARS-CoV-2, little has been discovered regarding its mechanism for increased transmissibility. Researchers from the Gladstone Institute of Data Science and Biotechnology (San Francisco, CA) and the Innovative Genomics Institute at UC Berkeley (Berkeley, CA) believe they have found a key site of genetic mutations in the nucleocapsid that could be responsible for the Delta variant’s increased transmissibility.

One author of the study, Abdullah Syed, described in a press release that the life cycle of a virus can be divided into three parts:

  • Entry: the virus is enters a cell
  • Replication: the virus hijacks the cell, causing it to create more copies of proteins and genetic material that comprise the virus
  • Assembly: the copied proteins and genetic material are packaged into new virus particles

The nucleocapsid, a multifunctional structural protein, is critical to the efficiency of the assembly stage in the coronavirus. Though it was previously hypothesized that mutations in the spike protein were causing increased efficiency during the entry stage, the researchers found that mutations in the nucleocapsid were the most significant contributor to Delta’s higher infectivity.

Typically, researching the nucleocapsid would require real viruses, because unlike the spike protein, it is located inside of the virus. This has caused nucleocapsid research to be overlooked, as working with real viruses is inherently dangerous due to the possibility of infecting researchers.

Taha Taha of the Gladstone Institute of Virology described the method that enabled the researchers to study virus replication without using live SARS-CoV-2 virions. They used virus-like particles (VLPs), which have the same structure as the virus, but lack any genetic material for replication. This means that researchers do not risk infection, as the VLPs are unable to replicate. VLPs are also easier to mutate than live viruses.

The researchers genetically engineered the VLPs to express luciferase (the enzyme that causes fireflies to glow), as the light it gives off can be used to gauge activity of a protein-expressing gene. By mutating the nucleocapsid with the mutations found in the Delta variant, an increase in luciferase expression (measured by light) would signal that the mutations increase the functionality of the nucleocapsid.

This was confirmed as one single amino acid mutation (the most basic mutation possible) in the nucleocapsid was found to cause a tenfold increase of luciferase expression, meaning that the mutated virus-assembly protein was ten times as active. Syed noted that this matched the tenfold increase in viral load observed in patients infected with the Delta variant.

The researchers further proved that the mutations increased the activity of the nucleocapsid by infecting cells with real SARS-CoV-2 virions in a highly controlled lab setting, finding that the real mutated virus also demonstrated faster reproduction.

This research has the potential to completely redirect the focus of scientists searching for culprit mutations in new variants of SARS-CoV-2, as research has largely focused on the spike protein until now. An improved understanding of the mechanisms of improved infectivity is important to researchers developing new therapies.

The novel virus-like particle method used could also prove to change virus research forever, as Taha states that this faster and safer alternative to using real viruses could also be used to test existing therapeutics (like vaccines) on new variants. Syed mentioned that the VLP method could even be used to find out if certain animal coronaviruses are capable of infecting humans, to develop new methods of therapy for COVID-19, or to do research on newly emerging viruses that are potentially too dangerous to work with.

This article is based on the following sources

– A. M. Syed et al., Science. (2021, November 4). Rapid assessment of SARS-Cov-2 evolved variants using virus-like particleshttps://doi.org/10.1126/science.abl6184
– Henderson, H. (2021, November 4). New method sheds light on why some SARS-Cov-2 variants are more infectious. Innovative Genomics Institute (IGI). https://innovativegenomics.org/news/sars-cov-2-variants-infection/
– Peters Kostman, M. (2021, May 17). Free COVID-19 (SARS-Cov-2) illustrations. Innovative Genomics Institute (IGI). https://innovativegenomics.org/free-covid-19-illustrations

Categories
Immunotherapy Oncology

Mass-Producible Specialized T Cells Exhibit High Cancer-Killing Efficacy, Minimized Complications

UCLA researchers have shown in preclinical studies that their mass-producible engineered invariant natural killer T (iNKT) cells demonstrate promising antitumor efficacy and low immunogenicity (unwanted immune response) compared to current cell-based immunotherapy for cancer treatment.

Invariant natural killer T (iNKT) cells are specialized T cells that are notable for their speedy response to danger signals and activation of macrophages (white blood cells that destroy cancer cells, microbes, cellular debris, and foreign substances).

Dr. Lili Yang’s UCLA lab generated iNKT cells by engineering hematopoietic stem cells (HSCs, precursors to all types of blood cells). These cells are allogeneic—they are not genetically specific to patients. Normally, in the realm of cell-based immunotherapy, this would be expected to cause an immune response in the form of graft-versus-host disease (GvHD), a condition in which donor stem cells attack the recipient. The study mentioned that such immunogenicity can also decrease efficacy of therapeutic cells. Therefore, allogeneic cells have not been widely used for T-cell-based therapies, with most therapies using autologous (from the patient) cells instead.

Generally, autologous T-cell therapy requires a patient’s T cells to be extracted from blood, sent to a lab, engineered to find and kill cancer cells, then returned intravenously to the patient—all costing hundreds of thousands of dollars.

Unexpectedly, when tested on mice, the Yang Engineering Immunity Lab’s allogeneic HSC-iNKT cells did not cause the negative effects associated with allogeneic cells. The researchers found that while other types of allogeneic T cells killed mice by GvHD after 2 months of cell transfer, the mice that received HSC-iNKT cells sustained long-term survival.

Figures showing (G) experimental design, (H) mouse tumor imaging, (I) quantification of tumor size based on imaging, (J) survival curves of mice over 4 months following tumor challenge.

Following irradiation of mice, those without cell therapy (labeled as vehicle) died of tumors within 45 days. Those treated with allogeneic BCAR-T cells were tumor-free but died of GvHD. Only those treated with allogeneic HSC-iNKT were tumor-free and survived long term.

This important development means that cell-based cancer therapies would no longer have to rely only on autologous cells extracted from each individual patient. Instead, with the advent of the Yang lab’s one-size-fits-all allogeneic solution, therapeutic cells could be mass-produced and given to any patient, significantly bringing down treatment costs.

The reason why allogeneic HSC-iNKT cells do not cause GvHD is currently unknown to researchers.

Graphs showing tumor load of irradiated mice over time. The Yang lab’s HSC-iNKT cells are shown to have decreased tumor load to near-zero levels (p < 0.001), a more significant decrease than was shown by the other tested therapy (PBMC-NK).
Frozen and fresh allogeneic HSC-iNKT cells were shown to kill more live lung cancer cells (H292-FG) than PBMC-NK cell therapy.

The study also showed that both frozen and fresh allogeneic HSC-iNKT cells killed live leukemia, melanoma, lung cancer, prostate cancer, and multiple myeloma cells in vitro. Compared to PBMC-NK cells, the Yang lab’s cells displayed greater tumor-killing efficacy. Importantly, allogeneic HSC-iNKT cells were also found to remain functional following freezing and thawing, which is crucial for their viability as a widespread, mass-produced treatment.

Factors that support allogeneic HSC-iNKT cells’ prospects as a future widespread cancer therapy include remaining functional following freezing and thawing, high tumor-killing efficacy, and mass-producible by virtue of low immunogenicity.

Dr. Yang told the UCLA Newsroom that one peripheral blood donation could yield 300,000 doses. The researchers are now focused on streamlining manufacturing processes, hoping to better enable mass-production, potentially bringing it to clinical and commercial development more quickly. The Newsroom noted that clinical trials have not yet occurred—this therapy has yet to be tested in humans or evaluated by the FDA. The UCLA Technology Development Group has filed a patent application for this method.

This article is based on the following sources

UCLA scientists make strides toward an ‘off-the-shelf’ immune cell therapy for cancer. (2021, November 16). UCLA Newsroom. https://newsroom.ucla.edu/releases/off-the-shelf-immune-cell-therapy-for-cancer
– Yang, L., et al. (2021, November 16). Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy. Cell Reports Medicine. https://doi.org/10.1016/j.xcrm.2021.100449

Categories
Public Health

Study Shows Reddit’s Potential as an Early Warning System for New Designer Drugs

In a new study, researchers demonstrated the use of data mining of social networks like Reddit to predict increased use of novel psychoactive substances (NPS).

Reddit is a social network and media aggregator divided into subreddits pertaining to certain topics, like college football, art, movies, and world news. Niche subreddits exist for many topics, including specific drugs.

Users on subreddits like r/ResearchChemicals discuss designer drugs (including analogs) and other newly discovered substances. Analogs are two drug compounds that have similar molecular structures and/or effects. Sometimes, an analog of an illegal drug has similar effects and properties to its illegal counterpart but has yet to be made illegal.

Under the Federal Analogue Act, compounds “substantially similar” to controlled substances are meant to be treated as if they were the controlled substances themselves. However, designer drugs are often overlooked or may take years for federal authorities to address.

Reddit post on “research chemicals” subreddit discussing novel psychoactive substances.

Researchers from Florida Atlantic University, the University of Florida, and New York University gathered and analyzed data on mentions of newly discovered NPS on Reddit. They found that users mentioned certain NPS months to years before the substances became prevalent in toxicology reports. Such reports are conducted to identify a culprit substance when a patient has overdosed or is subjected to a toxic exposure.

The study mentioned that NPS mentioned on Reddit before any exposures were recorded include:

  • Carfentanil
  • U-47700
  • Eutylone
  • Flualprazolam
  • N-ethylpentylone
  • Isotonitazene
  • Brorphine

Carfentanil, for example, was first mentioned on Reddit in February 2013–almost 4 years before its first reported exposure in October 2016.

Reddit mentions of N-ethylpentylone peaked 5 months before the number of reported cases. (Barenholtz et al, 2021)

The study found that seven of the eight analyzed NPS were mentioned on Reddit before there were any reported cases of the substances in toxicology reports.

Five of the eight analyzed NPS peaked in Reddit mentions months before the substances peaked in reported exposures.

The researchers posit that these data mining methods could prove to be a useful tool for early detection of NPS trends by public health authorities and legislatures.

This article is based on the following works:

– Barenholtz et al. (2021, August 5). Online surveillance of novel psychoactive substances (NPS): Monitoring Reddit discussions as a predictor of increased NPS-related exposures. https://doi.org/10.1016/j.drugpo.2021.103393

Categories
Cardiology

Surgeons at Duke University First to Implant New Total Artificial Heart Into Patient

A team of surgeons at Duke University led by Dr. Carmelo Milano and Dr. Jacob Schroder were the first to implant a new generation of Total Artificial Heart (TAH) in a 39-year-old male patient with heart failure after receiving FDA approval for human trials.

Home - Carmat :Carmat
The total artificial heart made by French company CARMAT acts to replace that of an organic diseased heart of patients with heart failure, hoping to one day replace the need for living donor heart transplantation. (carmatsa.com)

CARMAT’s Total Artifical Heart product, called Aeson, is a new TAH that solves many of the issues with current treatment options associated with biventricular heart failure. Current options include human organ transplantation, which carries high risk of rejection. Such rejection can lead to the need for repeat cardiac transplant or even death. Other treatment options such as biventricular assist devices (BiVADs) carry high risk of neurological complication incidence such as stroke caused by accumulation of clots or seizures that can lead to life debilitating changes.

CARMAT’s Aeson is only the second TAH on the market. Aeson has made notable improvements over competitor SynCardia’s total artificial heart. CARMAT’s TAH is quieter and has a variable heart rate that adjusts based on patient activity, while SynCardia is notably louder and has a fixed heart rate.

Aeson replaces the patient’s heart by pumping blood to the pulmonary tract and systemic system. It does this through the use of battery-powered electrohydraulic rotary pumps with attached sensors that respond to changes in pressure and cardiac demands.

The French company’s device can be used as an intermediate heart prior to transplantation, or even as a complete replacement for living donor hearts. This development has radical implications to heart failure treatment, as American patients can expect to wait more than six months for a transplant.

Dr. Jacob Schroder (Assistant Professor of Surgery) and Dr. Carmelo (Professor of Surgery) installing the CARMAT TAH. (CBS17)

The surgery at Duke University was the first of its kind in the United States. It consisted of an 8-hour surgery in which Dr. Jacob Schroder and Dr. Carmelo Milano worked to remove Matthew Moore’s (a 39-year-old patient with biventricular heart failure on the transplant waiting list) left and right ventricles of his heart. They then installed the device successfully replacing the structures removed.

Each device costs around $190,000, not including the costs of critical care staff and other medications. However, this price point is significantly lower than the average cost for a human heart transplant, which is about $1.4 million.

CARMAT hopes to solve long wait lists and high costs with its TAH, Aeson, potentially offering a permanent solution in which a heart will always be available for any patient in need.

This article is based on the following sources

– Bailey, S. (2021, March 25). This new artificial heart responds to the patient. CNN Business. https://www.cnn.com/2021/03/25/business/carmat-artificial-heart-spc-intl/index.html
– Duke University School of Medicine. (2021, July 16). New generation artificial heart implanted in patient at Duke – First in U.Shttps://medschool.duke.edu/blog/new-generation-artificial-heart-implanted-patient-duke-first-us
– Rapp, N., & Vandermey, A. (2017, September 14). Here’s what every organ in the body would cost to transplant. Fortune. https://fortune.com/2017/09/14/organ-transplant-cost/
– Tan, K. (2021, July 29). Duke surgical team successfully implants new generation artificial heart in patient, first in U.S. Duke Chronicle. https://www.dukechronicle.com/article/2021/07/duke-university-hospital-health-artificial-heart-transplant-research-study-carmat
– University of California, San Francisco Health. (n.d.). FAQ: Heart transplanthttps://www.ucsfhealth.org/education/faq-heart-transplant

Categories
Oncology

Researchers Create Synthetic Microenvironment for Pancreatic Ductal Adenocarcinoma Organoids

When PDA (pancreatic ductal adenocarcinoma) cancer cells form in the body, the extracellular matrix is remodeled to create an immunosuppressive environment which is rigid and poorly perfused. Through the normalization of these matrices, therapeutic treatments can be administered more effectively which makes the replication and synthesis of such models instrumental to the development of the efficacies of remedial treatments. 

As a result, a team from the Cancer Research UK Manchester Institute has developed a synthetic hydrogel-based model for pancreatic organoids that aims to replicate the extracellular microenvironments of both normal and pancreatic cancer cells in vitro.  

To formulate a working prototype, they analyzed 10 normal and 12 tumorous pancreatic samples using liquid chromatography with tandem mass spectrometry and identified 83 proteins that were relevant to the structural function of the matrix. Through the comparison of the matricellular proteins involved in cellular adhesion, they found that the proteins fibronectin (FN), versican, and laminin-332 were upregulated in cancerous cells. Additionally, they found that the proteins laminin 521 and types 1 & 4 collagen were abundant in both normal and cancerous cells, highlighting the potential importance of matrisomal components in PDA development. 

To form the gel, researchers used an eight-arm PEG-based hydrogel system through a network of peptides to help mimic the environment in which PDA organelles could develop. They found that contrary to traditional assays that were supported through FN-mimicking peptides, the use of collagen-mimicking peptides helped to increase the variety of murine pancreatic cancer organoids (mPCOs) that were supported by the hydrogel system. This change has allowed for the increased the growth efficiency of the organoids and supports the efficacy of their microenvironment.

Researchers also found that their models were able to support stromal co-cultures as they were able to replicate phenotypes of elongated, mesenchymal-structured fibroblasts that were similar to what they would find in vivo. The morphology data of tested species were consistent with  myCAF, iCAF and apCAF (cancer-associated fibroblasts) subsets and illustrated that the environments they developed were able to successfully mirror those of live specimens. These results support the idea that stromal cells in the synthetic setting are able to display relevant phenotypes that are consistent with in vivo models.

The University of Manchester-led study found that their new scaffold models were not only able to replicate the stiffness range of both cancerous and normal tissue but were also able to facilitate the growth of associated organoids and induced stromal samples. The researchers hope that their research will help other scientists replicate essential cell-ECM interactions as well as grow cultures of epithelial and stromal cells to help facilitate growth of organoids to better understand the mechanisms behind PDA and its development.

This article is based on the following sources and clinical studies.

– Below, C.R., Kelly, J., Brown, A. et al. (2021, September 13). A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids. https://doi.org/10.1038/s41563-021-01085-1
– Tayao, M. (2016, March 16). Loss of BAP1 Expression Is Very Rare in Pancreatic Ductal Adenocarcinoma. https://dx.doi.org/10.1371%2Fjournal.pone.0150338

Categories
Pharmacology

How “Docking Software” Helped Discover Compounds That Could Boost Stroke, TBI Recovery

Using the University of Florida’s HiPerGator supercomputer with the University of California San Francisco’s DOCK software, researchers have identified two dipeptides as small molecule activators of the peptidase neurolysin enzyme.

Render of peptidase neurolysin enzyme.

Peptidase neurolysin is an enzyme that has been found to be “one of the brain’s potent, self-protective mechanisms promoting preservation and recovery of the brain after acute injury” (Karamyan). Karamyan’s research posited that in the case of these injuries, neurolysin is responsible for:

  • reducing fluid buildup around the brain (cerebral edema)
  • reducing neural cell death caused by excess neurotransmitters (excitotoxicity)
  • reducing inflammatory response in the brain (neuroinflammation)

Searching for ways to make neurolysin more effective, lead researcher Vardan Karamyan, PhD (Texas Tech University Health Sciences Center Department of Pharmaceutical Sciences) enlisted the help of David Ostrov, PhD (University of Florida College of Medicine Department of Pathology, Immunology and Laboratory Medicine).

Neurolysin is similar in structure to a molecule called ACE2 (angiotensin converting enzyme-2), the main receptor for the virus that causes COVID. Dr. Ostrov previously identified drugs that bind ACE2, and he used the same strategy to identify drug candidates that bind neurolysin.

Superposition of neurolysin (copper) on ACE2 (teal).

Ostrov used UF’s HiPerGator supercomputer to screen 139,725 compounds from a repository at the National Cancer Institute Developmental Therapeutics Program to identify candidates that could fit a site on neurolysin that would facilitate an increase in the enzyme’s function. This was achieved using the DOCK program package, developed by UCSF.

DOCK’s molecular docking simulations were used to identify if and how a ligand (drug-like small molecule) can bind to the active site of a macromolecule (in this case, neurolysin). This is usually done to find ways to promote or inhibit a macromolecule’s function, making molecular docking software a key component in the ever-expanding world of computational drug discovery.

According to the UFHealth Newsroom, UF’s HiPerGator supercomputer completed the query in 15 hours–only 1.4% of the time it would take a desktop computer to complete the same task.

In the lab, the researchers tested the function of DOCK’s best matches on rat neurolysin. They found that the dipeptides L-histidlyl-L-tyrosine and L-histidlyl-L-histidine enhanced the activity of neurolysin.

According to Ostrov, human clinical trials with the mentioned drug candidates could begin within 2 years if FDA approved drugs are found to enhance neurolysin activity. An approved drug could assist or facilitate recovery in stroke and traumatic brain injury (TBI) patients.

This article is based on the following sources

– Bennett, D. (2021, September 7). UF health researcher, collaborators discover compounds that might boost stroke recovery. University of Florida Health. https://ufhealth.org/news/2021/uf-health-researcher-collaborators-discover-compounds-might-boost-stroke-recovery
– Karamyan, V. T. (2019, October). Peptidase neurolysin is an endogenous cerebroprotective mechanism in acute neurodegenerative disorders. https://doi.org/10.1016/j.mehy.2019.109309
– Statements from David A. Ostrov, PhD (University of Florida College of Medicine, Department of Pathology, Immunology and Laboratory Medicine)