Monthly Archives: July 2021

Immunology

Ireland getting "very close to the end of the pandemic", says Immunology Professor – JOE.ie

Immunology Professor Paul Moynagh has said that Ireland is getting "very close to the end of the pandemic" and closer to moving to an "endemic phase".

Moynagh, who is Professor of Immunology at Maynooth University, said that while the virus will still be "circulating in the background", most people will be "protected" via vaccination or natural immunity.

Moynaghtold Newstalk Breakfast that things could be taking a positive turn in spite of increasing case numbers over the last number of weeks.

A number of weeks ago, the projections were not very good, we were hearing very large numbers," he said.

Now what we seem to be seeing is a decrease in the day-to-day increase we had been seeing. The percentage of those cases ending up in hospital is going down the duration of hospital stays is going down.

He added that Ireland and other countries in the UK and Europe could be getting close to the "end of the pandemic phase".

I think were getting to the stage where a number of countries like ourselves, the UK and most countries in Europe - are getting very close to the end of the pandemic phase, and will probably move more into an endemic phase," he added.

The virus will be circulating in the background, but thankfully most of us will be protected by either vaccination or natural immunity through infection.

Moynagh's comments come as 1,408 cases of Covid-19 were reported across Ireland on Wednesday, just 2% of which were hospitalised cases.

Chief Medical Officer (CMO) Dr Tony Holohan said on Wednesday that Ireland might be in a position "in the coming weeks" to move away from some economic and social Covid-19 restrictions.

During a Department of Health press briefing he said: "If we keep pushing on with the kinds of uptake rates we've seen in some of the older age groups, which by international standards are some of the best in the world, that gives us a lot of reason for optimism that the conditions that we think will need to be satisfied to allow us to move away from some of the restrictions that still remain in place could be met."

Read more from the original source:
Ireland getting "very close to the end of the pandemic", says Immunology Professor - JOE.ie

Immunology

Study Shows Improved Tolerance with Second COVID-19 Vaccine – MD Magazine

Ever since the COVID-19 vaccines were approved for the public population, conversations have persisted regarding their efficacy, especially regarding people who had immediate allergic reactions with the first dose.

Despite this, a multicenter, retrospective study confirmed that most patients with immediate and potentially allergic reactions to the COVID-19 vaccines tolerated the 2nd dose.

In an interview with HCPLive, 2 of the leading authors of the study, Kimberly Blumenthal, MD, MSc, Quality and Safety Officer for Allergy, Massachusetts General Hospital, Co-Director, Clinical Epidemiology Program, Division of Rheumatology Allergy and Immunology and Matthew Krantz, MD, Clinical Fellow, Allergy/Immunology, Vanderbilt University Medical Center spoke of the genesis of the study as well as the data gathered on reactions from participants.

Prior to the study, the team targeted healthcare workers who had received some of the first doses of the Pfizer-BioNTech and Moderna vaccines.

One of the unexpected observations early on after emergency use authorization in December of 2020 where we primarily targeted vaccinating healthcare workers was we did observe a higher rate of immediate potentially allergic reactions and anaphylaxis than with traditional vaccines, Krantz said.

Krantz, Blumenthal and colleagues set out to find if participants in the study were truly allergic to the COVID-19 vaccines.

If you're allergic to something, you have an IgE antibody, [so] you have to avoid it, Blumenthal said. Thats really important for mRNA vaccines: were people forming true, classic allergy to these vaccines?

From January 1, 2021-March 31, 2021, the investigators enrolled 189 patients from participating centers, all of whom recorded an immediate reaction to their first Pfizer-BioNTech or Moderna vaccine.

Patient population demographics showed that the mean age of all patients was 43 years, and that most of the total population (86%) were women. Of the vaccine first-dose reactions, 130 (69%) were Moderna and 59 (31%) were Pfizer-BioNTech.

Allergic reactions were defined as symptom onset within 4 hours of dose 1, at least 1 allergic symptom, and referral for an allergy/immunology consultation with in-clinic or tele-heath assessment.

Anaphylaxis was scored using the Brighton and the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network Criteria.

Blumenthal, Krantz and colleagues defined second dose tolerance as 1 of the following:

1. No immediate symptoms after second dose administration

2. Symptoms that were mild, self-limited and/or resolved with antihistamines

Phone calls regarding clinical details were made for individuals who did not have their second dose observed by allergy/immunology departments.

The investigators noted that the most frequently reported first-dose reactions in patients were flushing or erythema (28%), dizziness or lightheadedness (26%), tingling (24%), throat tightness (22%), and hives (21%), and 32 participants (21%) met the anaphylaxis criteria.

Encouragingly, 159 patients as well as 19 individuals who experienced first-dose anaphylaxis tolerated the second dose of the COVID-19 vaccine. Only 20% of participants reported immediate and potentially allergic symptoms associated with the second dose, which were either self-limited, mild, or resolved with antihistamines alone.

Additionally, most of the participants in the study (89%) received the second dose, and 47 patients (30%) were given an antihistamine premedication before the second dose.

It's important to note that in terms of classic IgE allergy, we do not expect premedications to abort a reaction, Krantz said. But, in the case of a non-IgE mediated reaction, antihistamines can also blunt or make these reactions (milder).

The effectiveness of the drugs on some patients supported the hypothesis that the participants did not have to avoid the COVID-19 vaccines, as they did not have whats considered a classic allergy response.

Blumenthal also noted the effectiveness of the premedication and clarified that the study was not intended to recommend a specific medication, as each patient was treated with individual methods depending on what their allergist felt was appropriate.

Everybody had a different [recommendation], Blumenthal said. This study wasn't designed to test how best to get from a dose 1 immediate reaction to safe dose 2 completion. But it gives us a hint that it's largely possible.

Blumenthal noted that further research might explore the possibilities of a specific premedication or treatment methods for patients who had a reaction to the COVID-19 vaccines, especially considering the possibilities of COVID-19 vaccine boosters in the coming fall season.

What we really need is a prospective study when it comes to the booster doses, Blumenthal said. So, prospective, meaning that we enroll people who had reactions before (and) who didn't have reactions, and we have them diary their medication so that we can piece out what premedication regimen might work.

Blumenthal and Krantz both noted the potential for improvement in identifying allergic reactions in patients regarding the COVID-19 vaccines and general vaccines.

The study, Safety Evaluation of the Second Dose of Messenger RNA COVID-19 Vaccines in Patients With Immediate Reactions to the First Dose, was published online in JAMA Internal Medicine.

Continued here:
Study Shows Improved Tolerance with Second COVID-19 Vaccine - MD Magazine

Immunology

iShares – iShares Genomics Immunology and Healthcare ETF (IDNA) gains 0.04% in Active Trading on July 29 – Equities.com

Last Price$ Last TradeChange$ Change Percent %Open$ Prev Close$ High$ low$ 52 Week High$ 52 Week Low$ Market CapPE RatioVolumeExchange

IDNA - Market Data & News

iShares Trust - iShares Genomics Immunology and Healthcare ETF (NYSE: IDNA) gained to close at $50.03 Thursday after gaining $0.02 (0.04%) on volume of 107,527 shares. The stock ranged from a high of $50.52 to a low of $49.80 while iShares - iShares Genomics Immunology and Healthcare ETFs market cap now stands at $327,696,500.

Visit iShares Trust - iShares Genomics Immunology and Healthcare ETFs profile for more information.

The New York Stock Exchange is the worlds largest stock exchange by market value at over $26 trillion. It is also the leader for initial public offerings, with $82 billion raised in 2020, including six of the seven largest technology deals. 63% of SPAC proceeds in 2020 were raised on the NYSE, including the six largest transactions.

To get more information on iShares Trust - iShares Genomics Immunology and Healthcare ETF and to follow the companys latest updates, you can visit the companys profile page here: iShares Trust - iShares Genomics Immunology and Healthcare ETFs Profile. For more news on the financial markets be sure to visit Equities News. Also, dont forget to sign-up for the Daily Fix to receive the best stories to your inbox 5 days a week.

Sources: Chart is provided by TradingView based on 15-minute-delayed prices. All other data is provided by IEX Cloud as of 8:05 pm ET on the day of publication.

DISCLOSURE:The views and opinions expressed in this article are those of the authors, and do not represent the views of equities.com. Readers should not consider statements made by the author as formal recommendations and should consult their financial advisor before making any investment decisions. To read our full disclosure, please go to: http://www.equities.com/disclaimer

See the original post here:
iShares - iShares Genomics Immunology and Healthcare ETF (IDNA) gains 0.04% in Active Trading on July 29 - Equities.com

Immunology

New Approach for Cell Therapy Shows Potential Against Solid Tumors with KRAS Mutations – pennmedicine.org

Adham Bear, MD, PhD, Mark O'Hara, MD, Gerald P. Linette, MD, PhD, Beatriz M. Carreno, PhD, and Robert H. Vonderheide, MD, DPhil.

PHILADELPHIAA new technology for cellular immunotherapy developed by Abramson Cancer Center researchers at Penn Medicine showed promising anti-tumor activity in the lab against hard-to-treat cancers driven by the once-considered undruggable KRAS mutation, including lung, colorectal, and pancreatic.

The study, published online in Nature Communications, successfully demonstrated using human cells that a T-cell receptor, or TCR, therapy could be designed to mobilize an immune system attack on mutated KRAS solid tumors and shrink them. The preclinical work has laid the groundwork for the first-in-human clinical trial now in the planning stages for the treatment of advanced pancreatic cancer in patients whose tumors harbor specific KRAS mutations and express a specific type of human leukocyte antigen, or HLA, the therapy is built to recognize.

Weve shown that targeting mutant KRAS immunologically is feasible and potentially generalizable for a group of patients with lung, colorectal and pancreatic tumors, said senior author Beatriz M. Carreno, PhD, an associate professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania and a member of the Center for Cellular Immunotherapies, the Abramson Cancer Center, and Parker Institute for Cancer Immunotherapy at Penn. We look forward to taking this research to the next level and closer to clinical study.

KRAS mutations are among the most prevalent mutations observed in cancers and have been shown to drive tumor development and growth. Only recently have targeted therapies been shown to successfully treat a specific KRAS mutation found most commonly in lung cancer; however, no treatments currently exist for the majority of other KRAS mutations more prevalent in other tumor types. Immunological targeting of mutant KRAS represents an alternative treatment approach but has been less studied and understood.

Using a multiomics approach, the Penn team identified specific neoantigens associated with mutations at the G12 site on the KRAS gene. Neoantigens are protein fragments that form on the cancer cell surface when certain mutations occur in tumor DNA. More than 75 percent of the alterations in the KRAS protein occur at G12, making it an ideal site to target with therapies.

Armed with this knowledge, the researchers tested a TCR therapy directed toward specific KRAS G12 mutations present in conjunction with particular HLA types highly prevalent among patients. They showed in a mouse tumor model that it was effective at attacking and eliminating tumor cells. HLAs are an important part of the immune system because they encode cell surface molecules that present specific neoantigens to the T-cell receptors on T cells.

In other words, HLAs are key genetic codes needed for these engineered T cells to find and attack tumors.

The research further supports the use of neoantigens for targeting tumor cells, for both cellular therapy and cancer vaccines, which have been underway at Penn Medicine and elsewhere.

Importantly, the neoantigen and HLA information from this latest study is being used to develop TCR therapies to treat solid tumors, as well as new cancer vaccines. Based off these latest findings, the team initiated a vaccine clinical trial led by Mark OHara, MD, an assistant professor of Hematology-Oncology at Penn and co-author on the study, in pancreatic cancer targeting mutated KRAS.

The first clinical trial for the TCR therapy is projected to launch as soon as 2022, depending on regulatory approval, at Penns Abramson Cancer Center for patients with advanced pancreatic cancer who have both the KRAS mutation and specific HLA types identified in this latest studywhich could represent up to 10 percent of patients with pancreatic cancer. The study opens the door, however, to expand the patient population as researchers continue to discover more about the neoantigens derived from regions of the KRAS gene and other mutated oncogenes implicated in driving cancer.

We provide evidence that this oncogenic protein is a very promising clinical target of immune-based therapies, said lead author Adham Bear, MD, PhD, an instructor in the division of Hematology-Oncology at Penn and member of the Parker Institute for Cancer Immunotherapy at Penn. The goal, now that we have identified these neoantigens and T cell receptors, is to translate these findings and apply them to develop new therapies at Penn.

Robert H. Vonderheide, MD, DPhil, director of the Abramson Cancer Center, and Gerald P. Linette, MD, PhD, a professor of Medicine in the Perelman School of Medicine, served as co-authors.

The study was supported by the National Institutes of Health (R01 CA204261, P30 CA016520, CA196539 and CA232568), The Stand Up to Cancer/Lustgarten Foundation Pancreatic Cancer Collective, the Penn Institute for Immunology, and the Parker Institute for Cancer Immunotherapy.

Penn Medicineis one of the worlds leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of theRaymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nations first medical school) and theUniversity of Pennsylvania Health System, which together form a $8.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according toU.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $496 million awarded in the 2020 fiscal year.

The University of Pennsylvania Health Systems patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Centerwhich are recognized as one of the nations top Honor Roll hospitals byU.S. News & World ReportChester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nations first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 44,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2020, Penn Medicine provided more than $563 million to benefit our community.

Originally posted here:
New Approach for Cell Therapy Shows Potential Against Solid Tumors with KRAS Mutations - pennmedicine.org

Immunology

Fighting off food poisoning depends on the time of day – UT Southwestern

Scanning electron micrograph shows segmented filamentous bacteria attaching to the intestinal surface of a mouse. More bacteria attach during the night than during the day. Credit: John F. Brooks II

DALLAS July 28, 2021 The bodys ability to prevent food poisoning by producing a natural antimicrobial compound increases during the day, when exposure to noxious bacteria is most likely, a new study by UT Southwestern scientists suggests. The findings, published online in Cell, could eventually lead to timed therapies and vaccination regimens designed to maximize this immune response.

John F. Brooks II, Ph.D.

This study shows that our immune systems are not turned on all the time, which is an unexpected result, says study leader John F. Brooks II, Ph.D., a postdoctoral fellow in the laboratory of Lora Hooper, Ph.D., study co-leader and professor of immunology and microbiology at UTSW. Our findings suggest that there are peak times in which the body is more primed to fight infections.

Researchers have long known that virtually all animals follow circadian cycles that are tied to sunrise and sunset. These cycles allow animals to anticipate and prepare for changes in their environment. Disrupting circadian rhythms can have serious health consequences; for example, chronic sleep disruption is related to increased intestinal infection in humans. However, why this occurs has been unclear.

Lora Hooper, Ph.D.

Brooks, Hooper, and their colleagues suspected that antibacterial immunity might change in the intestines on a circadian cycle. To investigate this idea, the researchers looked for rhythms in the expression of natural antimicrobial agents produced in the gut of mice to fight foodborne illness. The researchers saw that in normal lab mice, one of these antimicrobial molecules known as regenerating islet-derived protein 3g (REG3G) was more abundant at night, when these nocturnal animals are active, and less so during the day, when mice sleep. However, in mice raised to have no gut bacteria, REG3G was essentially absent throughout both the day and the night.

Searching for the microbial components driving the rhythmic pattern, the researchers found that mice with cycling amounts of REG3G had large resident populations of segmented filamentous bacteria in their guts microbes typically present in rodents, nonhuman primates, and humans that have a unique ability to attach to the intestinal lining and change their hosts gene activity. Further experiments showed that these bacteria attached to the animals intestinal lining during feeding, probably to siphon off nutrients. When they attached, REG3G production ramped up in the intestines.

This cycling had significant consequences for the ability of mice to fight off infection. When the researchers infected normal mice with bacteria, the animals had higher bacterial burdens and rates of death if they were exposed at sunset than at sunrise. Mice that cant make antimicrobial proteins, including REG3G, had similarly high rates of bacterial burden and death regardless of when they were infected.

If further research shows this phenomenon also occurs in humans, scientists may eventually be able to capitalize on it by timing the administration of synthetic antibiotics for intestinal infections and oral vaccines or finding new ways to avoid intestinal infections altogether.

These results make me think twice about waking up in the middle of the night and raiding the refrigerator, Hooper says. It may be more dangerous to eat bacteria-laden potato salad when your gut defenses are lowest.

Other UTSW researchers who contributed to this study include Cassie L. Behrendt, Kelly A. Ruhn, Syann Lee, Prithvi Raj, and Joseph S. Takahashi.

This work was supported by grants from the National Institutes of Health (R01 DK070855), The Welch Foundation (I-1874), and the Walter M. and Helen D. Bader Center for Research on Arthritis and Autoimmune Diseases.

Hooper holds the Jonathan W. Uhr, M.D. Distinguished Chair in Immunology, the Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in Honor of Dr. Bill S. Vowell, and is an investigator of the Howard Hughes Medical Institute.

Takahashi holds the Loyd B. Sands Distinguished Chair in Neuroscience and is an investigator of the Howard Hughes Medical Institute.

Brooks is a recipient of the highly competitive Howard Hughes Medical Institute Hanna Gray Fellowship.

About UTSouthwestern Medical Center

UT Southwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

More here:
Fighting off food poisoning depends on the time of day - UT Southwestern

Immunology

iShares Trust – iShares Genomics Immunology and Healthcare ETF (IDNA) falls 0.91% for July 27 – Equities.com

Last Price$ Last TradeChange$ Change Percent %Open$ Prev Close$ High$ low$ 52 Week High$ 52 Week Low$ Market CapPE RatioVolumeExchange

IDNA - Market Data & News

Today, iShares Trust - iShares Genomics Immunology and Healthcare ETF Incs (NYSE: IDNA) stock fell $0.4424, accounting for a 0.91% decrease. iShares - iShares Genomics Immunology and Healthcare ETF opened at $48.92 before trading between $48.92 and $47.38 throughout Tuesdays session. The activity saw iShares - iShares Genomics Immunology and Healthcare ETFs market cap fall to $317,085,500 on 93,591 shares -above their 30-day average of 89,687.

Visit iShares Trust - iShares Genomics Immunology and Healthcare ETF's profile for more information.

The New York Stock Exchange is the worlds largest stock exchange by market value at over $26 trillion. It is also the leader for initial public offerings, with $82 billion raised in 2020, including six of the seven largest technology deals. 63% of SPAC proceeds in 2020 were raised on the NYSE, including the six largest transactions.

To get more information on iShares Trust - iShares Genomics Immunology and Healthcare ETF and to follow the company's latest updates, you can visit the company's profile page here: iShares Trust - iShares Genomics Immunology and Healthcare ETF's Profile. For more news on the financial markets be sure to visit Equities News. Also, don't forget to sign-up for the Daily Fix to receive the best stories to your inbox 5 days a week.

Sources: Chart is provided by TradingView based on 15-minute-delayed prices. All other data is provided by IEX Cloud as of 8:05 pm ET on the day of publication.

DISCLOSURE:The views and opinions expressed in this article are those of the authors, and do not represent the views of equities.com. Readers should not consider statements made by the author as formal recommendations and should consult their financial advisor before making any investment decisions. To read our full disclosure, please go to: http://www.equities.com/disclaimer

Read the rest here:
iShares Trust - iShares Genomics Immunology and Healthcare ETF (IDNA) falls 0.91% for July 27 - Equities.com

Immunology

Call in the T-Cell Cavalry to Fight COVID in the Immunocompromised – MedPage Today

Last year was one of collective confinement. The majority of us shuttered our doors to visitors, worked from home, and ventured out sparingly in hopes of evading the grasp of COVID-19. Now in 2021, thanks to vaccination rollout, those who have been vaccinated are hopefully on the path to normalcy. But not everyone is so fortunate. For some, 2021 will bring more isolation and loneliness than ever before, which is hard to imagine. I'm talking about immunocompromised adults and children. While much of the rest of the populace clinks glasses, hugs loved ones, and joins parties, immunocompromised individuals do not have the security of an effective vaccine, and for their health and safety will maintain their distance and watch the social revelry from the sidelines.

The normal vaccine response that elicits antibodies and immune cells to fight infection are absent in these immunocompromised individuals, who fall into two categories: those living with congenital or acquired diseases that weaken their immune system, or those with pre-existing conditions whose treatment requires dampening of the immune system (e.g., patients with blood cancers or transplant recipients). This vulnerable population represents a sizable proportion of the U.S. population. A 2018-2019 analysis in JAMA Network Open estimated that 2.8% of adults in America were on a treatment regimen that dampened their immune system. That percentage may seem small but extrapolate it to the entire U.S. population and you hit 9 million vulnerable people. This doesn't even include immunocompromised individuals who are not taking immune-suppressing medication.

The plight of immune-compromised individuals has large-scale implications. This inability to combat the virus not only can be potentially life-threatening but can also lead to the continued evolution of mutant strains that infiltrate healthy populations. The so-called New York variant (B.1.526) was identified in a patient with advanced AIDS. Similarly, the highly transmissible and more deadly Alpha strain (B.1.1.7) emerged in a patient receiving immune suppressive treatment for a blood cancer.

So, while COVID-19 vaccines administered in the U.S. have been highly effective for mounting an antibody immune response in people with functional immune systems, it's not enough to vanquish the contagion. In our fight against virus infection, another critical arm of the immune system is required: The T-cell immune response. While antibodies may prevent infection, these warriors destroy already infected cells. And initial research suggests they may be active even in absence of antibodies.

Just recently, researchers (including myself) published a study in the Journal of Clinical Immunology that showed that pediatric patients with primary immune deficiencies, who often fail to make protective immune responses to infections and vaccinations, show robust T-cell activity and immunity against SARS-CoV-2. These findings are important because if T-cell responses to COVID-19 are protective in this highly vulnerable population, this could suggest that a COVID-19-directed T-cell immunotherapy might benefit other profoundly immunocompromised patients. However, we still don't know if such responses will persist to provide protective long-term immunity, especially against mutant strains of the virus.

Indeed, earlier findings published by me and my team in Blood, show T cells can be taken from the blood of recovered COVID-19 patients and multiplied in a lab, which could then be infused into bone marrow transplant patients whose immune systems can't fight the virus on their own. In effect, this creates an army of trained coronavirus fighters to potentially provide protective T-cell immunity long-term to these highly immunosuppressed patients. My team and I submitted this coronavirus-killing T-cell therapy (CST) clinical trial proposal to the FDA and have recently received approval to start this first-in-human clinical research protocol to treat these vulnerable patients who are currently falling through the cracks in the vaccine fight against COVID-19.

Ongoing research in the race to outpace the pandemic has helped us to increasingly unravel the prominent role of T cells in long-term immunity. A study published in Nature showed patients who recovered from the 2003 SARS epidemic, whose antibodies faded within 2 to 3 years, had a robust T-cell response to SARS 17 years later. These T cells also recognize the SARS-CoV-2 nucleocapsid protein.

For immunocompromised patients, adoptive immunotherapy using T cells from recovered COVID-19 patients may be the answer when vaccines only offer partial protection. T cells could vanquish infected cells to limit the severity of disease or avoid hospitalization, and they remember a contagion for decades.

With the number of COVID-19 variants multiplying, this is an arms race. As a society, we need to deploy every weapon in our arsenal to ensure no one is left behind in the return to normalcy, especially not the most vulnerable. If antibodies were the infantry in our fight against the pandemic, then T cells are the cavalry. It's time we call them in.

Catherine Bollard, MD, MBChB, is the director of the Center for Cancer and Immunology Research at the Children's National Research Institute, director of the Program for Cell Enhancement and Technologies for Immunotherapy, and a member of the Division of the Blood and Marrow Transplantation at Children's National Hospital in Washington, D.C.

Disclosures

Bollard is co-founder and on the scientific advisory boards for Catamaran Bio and Mana Therapeutics with stock and/or ownership; is on the Board of Directors for Cabaletta Bio with stock options; has stock in NexImmune and Repertoire Immune Medicines; and has submitted patent applications on SARS-CoV-2 T cells.

The rest is here:
Call in the T-Cell Cavalry to Fight COVID in the Immunocompromised - MedPage Today

Physiology

Defining Physiologys Upper Limits and Again Winning the Tour de France – CU Anschutz Today

First of all, congratulations on an incredible accomplishment your top cyclist winning his second Tour de France.

It was a great victory. This year we were not the underdog anymore. Its too bad (Primoz) Roglic (last years second-place General Classification finisher) had a bad crash and had to quit the race. It was unfortunate because otherwise it would have been better (duel-wise between the two top-rated Slovenians). He crashed in the first week.

We did all the homework for the Tour de France in Sestriere, which is in the Italian Alps. I told the team the first day of pre-training camp, Guys, lets take this seriously. Lets focus, because we have never been in this situation. We have never had to defend a Tour de France, and since the very last day of last years Tour, everybody has tried to figure out how to beat Tadej. Everybodys guns are loaded to shoot at us this year. Be ready for that.

Our strategy was to try to control the race as best as we could, and that was the most stressful part to put together that block of riders. Out of 29 riders we have on the team, to select that block of seven who could help Tadej do the job. Ineos Grenadiers would be the team to bring the race. They have a very strong roster, and they are signing from other teams their leaders, so its difficult to compete as a block against Ineos. But we were able to put a good block together, and yeah, it worked out.

Yeah, it was a coincidence (laughs). It was the last time trial, and that was when we kind of said, OK, boom, now we won the Tour, and we celebrated. Also, that is an area of the world with some of the best wines some are $3,000 a bottle. Im crazy about wine, so that area was very special because of Tadej, because of the wine and because of my last name (laughs).

He has an amazing recovery capacity. Each stage of the Tour is like (playing) about three soccer games, or five American football games. So, imagine playing five games for 21 days in a row. By day 10, many players would be gone, right? Only the best, the fittest ones, will make it to day seven, 10 and so on. This is how fit these cyclists are. Their (physiologic) machinery is some of the best you will ever find in humans. These athletes and marathon runners, but probably more so cyclists, because they have to recover between stages.

And while everybody might start (a stage) at 100%, some people finish at 60% because they go lower and lower and lower. And maybe Tadej finishes at 80%, so that 20% extra at the end is what makes one of his parameters. Contenders at the Tour all recover well. But at the same time, you also have other physiological capabilities which are the ability to clear lactate, to have very good mitochondrial function. You need to have a very economical and efficient engine, but its both the recovery capacity and the ability to go at a very hard pace without utilizing a lot of energy.

No, we didnt do that this year at the Tour because the logistics have been difficult. We (Angelo DAlessandro, PhD, Travis Nemkov, PhD, and San Milln) are developing the first metabolomics platform in the world of sports. Were very close to the finish line. We learned a lot from last year, but from this year also. We did a training camp and at another race, so we looked at more parameters, and all of it keeps telling us the same story: Tadejs recovery capacity and mitochondrial function are spectacular, at a whole different level. He has an ability to burn fat and use fuels very efficiently.

Its like the 23andMe or the DNA test kits you can buy in the supermarket and do yourself and send through the mail to a laboratory. In a few days you get the whole report. This (platform) would be for metabolomics, which is more precise than genetics. Genetics is the science of probability, and metabolomics is the science of reality.

Genetics is the science of probability, and metabolomics is the science of reality. Inigo San Millan

In genetic testing, especially for sports, the accuracy might be less than 20%. A few years ago, athletes would get these genetic tests and they showed, Oh, youre not a good sprinter or Youre not a good climber or You dont have much strength or power. Thats only because a few genes showed that, but you can improve the signal, the expression, of those genes through training, through nutrition, through recovery, through the right psychology. This is where you can transform a normal athlete into a very good athlete. And this is what we capture through metabolomics.

Genes are transcribed into proteins, and proteins into multiple biological actions. So, the genes are the very first step of the journey, but by no means do they mean an athlete is going to become something. Thats why the accuracy is less than 20%, whereas in metabolomics its, Hey, this is who you are right now, and now we know how you can improve.

This is what were developing. Its a platform where someone can send a blood sample put on a small card before and after exercise, and we can then give them those metabolomic parameters.

Yes, exactly, so we know the upper levels of human physiology and metabolic health.

It was really bad. And 10 or 15 kilometers later, there was another bad crash, and I forget in which of them Tadej received a minor cut. It didnt affect him much.

We have patterns or signatures at the research level we call them signatures and this is what we see as who you are now. With this, we can help athletes to improve. At the same time and this is our ultimate goal we want to take this into the fitness, wellness and even the clinical space. Because with the lessons we have learned from these athletes, we can understand the many pathologies people are having at the metabolic level, as athletes are the absolute gold standard of metabolic health.

For example, people with Type 2 diabetes are at the opposite metabolic pole of someone like Pogaar. They dont burn fat very well at all, they dont burn glucose. They have very poor mitochondrial function, and they have inflammation, whereas Pogaar is completely the opposite. This is something Ive been pushing at the university for years, since I arrived, using elite athletes as the gold standard.

I think some people are finally understanding this concept that, yes, you cannot understand imperfection if you dont first understand perfection. In my modest opinion, the best way to understand a faulty metabolism, like people with Type 2 diabetes, is to in the first place understand how does a perfect metabolism work? And who do you go to to understand that? You dont go to the sedentary people who, until recently, have been the gold standard. Thats not the best population to go to (for study). You need to go to the elite athletes.

To our advantage we have access to these populations which most scientists dont have access to. So, we are very lucky to have this unique population to be able to understand what perfection is. And now we know better how to get there and how bad imperfection is. So, we can use all of these technologies for diagnoses and also therapeutics down the road for people with chronic diseases.

Absolutely. For someone his age, hes amazing. It seems like youre dealing with a 30-plus-year-old professional athlete who has been a professional for 10 or 15 years. Its unbelievable. And also, how calm he is. He doesnt feel so much the stress of the competition as others. Some great athletes have amazing physiological capabilities, but they cant sleep well the day before an event, or they have anxiety and are nervous the day of the competition, and they cant give their 100%. Its not uncommon at all and its too bad, because some of them could have been incredible athletes. But I guess thats what it takes to be a big, big champion to have all these qualities together.

So far, nobody in (cycling) history has done what Tadej has done at this age. The best rider ever is Eddy Merckx and Tadej has done more than what Merckx had done at his age. So this is the unusual and special thing about Tadej.

From the Tour he went to Tokyo for the Summer Olympics where took the bronze medal in the road race, and he was the one who broke the entire race. Also, we have an American from the UAE team at the Olympics, too, Brandon McNulty, who I also personally coach. He was in the Tour with Tadej. Brandon can be one of the best time trialists in the world. He placed sixth in the road race in Tokyo and was the best finish of an American cyclist since 2012.

Regarding Tadej, absolutely, a third Tour win in a row is the goal. You always want to win and keep breaking records. We are already thinking about next year, how we can keep improving. We still have some margin for improvement, but the other (teams) do, too. As were speaking, theyre trying to figure out how to do things better for next year. This is why next year it will be harder than this year for sure. We better be prepared and not sleep on our laurels.

Link:
Defining Physiologys Upper Limits and Again Winning the Tour de France - CU Anschutz Today

Physiology

A blood test for your body clock? It’s on the horizon – CU Boulder Today

What time is your body clock set on?

The answer, mounting research suggests, can influence everything from your predisposition to diabetes, heart disease and depression to the optimal time for you to take medication. But unlike routine blood tests for cholesterol and hormone levels, theres no easy way to precisely measure a persons individual circadian rhythm.

At least not yet.

New CU Boulder research, published in the Journal of Biological Rhythms, suggests that day could come in the not-too-distant future. The study found its possible to determine the timing of a persons internal circadian or biological clock by analyzing a combination of molecules in a single blood draw.

If we can understand each individual persons circadian clock, we can potentially prescribe the optimal time of day for them to be eating or exercising or taking medication, said senior author Christopher Depner, who conducted the study while an assistant professor of integrative physiology at CU Boulder. From a personalized medicine perspective, it could be groundbreaking.

For decades, researchers have known that a central master clock in a region of the brain called the hypothalamus helps to regulate the bodys 24-hour cycle, including when we naturally feel sleepy at night and have the urge to wake up in the morning.

More recently, studies reveal that nearly every tissue or organ in the body also has an internal timing device, synced with that master clock, dictating when we secrete certain hormones, how our heart and lungs function throughout the day, the cadence of our metabolism of fats and sugars, and more.

As many as 82% of protein-coding genes that are drug targets show 24-hour time-of-day patterns, suggesting many medications could work better and yield fewer side effects if administration was timed appropriately.

And when our internal rhythm is at odds with our sleep-wake cycle, that can boost risk of an array of diseases, said study co-author Ken Wright, a professor of integrative physiology and director of the Sleep and Chronobiology Laboratory at CU Boulder.

If we want to be able to fix the timing of a persons circadian rhythm, we need to know what that timing is, he said. Right now, we do not have an easy way to do that.

Even among healthy people, sleep-wake cycles can vary by four to six hours.

Simply asking someone, are you a morning lark, a night owl or somewhere in-between? can provide hints to what a persons circadian cycle is.

But the only way to precisely gauge the timing of an individuals circadian clock (including where the peaks and troughs of their daily rhythm) is to perform a dim-light melatonin assessment. This involves keeping the person in dim light and drawing blood or saliva hourly for up to 24 hours to measure melatoninthe hormone that naturally increases in the body to signal bedtime and wanes to help wake us up.

In pursuit of a more precise and practical test, Wright and Depner brought 16 volunteers to live in a sleep lab on the CU Anschutz Medical campus in Aurora for 14 days under tightly controlled conditions.

In addition to testing their blood for melatonin hourly, they also used a method called metabolomicsassessing levels of about 4,000 different metabolites (things like amino acids, vitamins and fatty acids that are byproducts of metabolism) in the blood.

They used a machine learning algorithm to determine which collection of metabolites were associated with the circadian clockcreating a sort of molecular fingerprint for individual circadian phases.

When they tried to predict circadian phase based on this fingerprint from a single blood draw, their findings were surprisingly similar to those using the more arduous melatonin test.

It was within about one hour of the gold standard of taking blood every hour around the clock, said Depner, now an assistant professor of kinesiology at the University of Utah.

He noted the test was significantly more accurate when people were well rested and hadnt eaten recentlya requirement that could make the test challenging outside of a laboratory setting. And to be feasible and affordable, a commercial test would likely have to narrow down the number of metabolites its looking for (their test narrowed it down to 65).

But the study is a critical first step, said Wright.

We are at the very beginning stages of developing these biomarkers for circadian rhythm, but this promising study shows it can be done.

Other research, including some from Wrights lab, is exploring proteomics (looking for proteins in blood) or transcriptomics (measuring the presence of ribonucleic acid, or RNA) to assess circadian phase.

Ultimately, the researchers imagine a day when people can, during a routine physical, get a blood test to precisely determine their circadian phaseso doctors can prescribe not only what to do, but when.

This is an important step forward in paving the way for circadian medicinefor providing the right treatment to the right individual at the right time of day, said Depner.

Excerpt from:
A blood test for your body clock? It's on the horizon - CU Boulder Today

Physiology

Microphysiological Systems: Approaches, Applications and Opportunities – Technology Networks

Microphysiological systems (MPS), also commonly referred to as organ-on-a-chip or body-on-a-chip technologies, have gained considerable attention in recent years. They provide a more physiologically relevant setting compared to static two-dimensional cell culture assays or animal models, as they more closely recapitulate human physiology and the downstream effects of drugs on multiple tissues. The development of MPS technologies has been driven by advances in several areas 3D cell culture techniques, microfluidics, tissue engineering and bioprinting enabling the creation of various key components. In this article, we highlight advances in the field that have been instrumental to the development of MPS, as well as key applications and future opportunities.

However, building a device that encompasses several tissue constructs to produce an interconnected multi-organ environment is no easy feat, as Dokmeci explains, Finding a universal media that satisfies the needs of multiple cells or organs is one of the main challenges.

Also, being able to control the fluid flow between different systems sometimes requires microvalves, which enables automation but complicates the design and manufacturing of the system. Overall, adding more components complicates the design, he adds.

In recent years, there have been efforts to improve the in vitro models used in preclinical drug development and disease research. In particular the use of microphysiological systems (MPS), also sometimes referred to as organ-on-a-chip (OOC) technologies, has become more widespread. Download this app note to discover a gut MPS that has physiologically relevant morphology, reduced barrier integrity and mucus expression. It can also be used to predict drug permeability across an intestinal barrier.

To prevent loss of the drug compounds, the team chose to assemble their MPS using polymethyl methacrylate (PMMA) rather than polydimethylsiloxane (PDMS). While PDMS has been widely used to build microfluidic chips until now, it can cause small molecules to be absorbed into the walls of the chip, reducing the free concentration of drug within the circulated medium, affecting drug bioavailability.

Atala explains that to create the MPS they employed strategies like those used to implant engineered tissues in patients. We first determine the major cell types present in the specific organ, and we use normal cells in the same proportions as present in humans. We also use the tissue-specific glue that holds cells together, the extracellular matrix, he says. The team then combined the different organoids of interest into a single system by immobilizing them in hydrogels within individual chambers.

Atala elaborates, We can therefore test many parameters, such as the effects of one drug on a specific organ, and how the drug gets metabolized and processed, or its bystander effects on other organs. The system, depending on how many tissues it uses, can be designed to fit an area about the size of a matchbox.

This is one of the main promises of the organ-on-a-chip field being able to borrow cells from patients and test the drugs on individual patients beforehand, explains Dokmeci.

The invention of induced pluripotent stem cells (iPSCs) has helped to expedite research in this field, he adds. Personalized MPS can be created using blood samples, primary human tissue and cells derived from iPSCs, as Dokmeci emphasized above.

There are efforts by different groups in this area, explains Prof. Nureddin Ashammakhi, ex-associate director of the Center for Minimally Invasive Therapeutics, UCLA. Ashammakhis research is focused on 3D bioprinting and the development of organ-on-a-chip models for regenerative and personalized medicine.

In a recent study, published in Bio-Design and Manufacturing, Ashammakhi and colleagues reviewed the development of lung MPS to model the pathology of COVID-19. According to Ashammakhi, when designing a lung MPS it is important to mirror the organs unique organization and function.

This is achieved by designing a chip with one chamber for air, representing alveolus and one chamber lined with endothelial cells, representing the blood vessel. The two chambers are separated by a porous membrane that allows the movement of molecules between the two sides, says Ashammakhi.

It is even possible to emulate the motion of in vivo breathing by applying a vacuum to chambers surrounding the epithelialcapillary membrane, causing it to stretch. This is an important element as stress has been shown to influence permeability of the membrane and the release of reactive oxygen species, as well as other molecules.

COVID-19 pathology can be organized into the following stages: SARS-CoV-2 viral entry by the ACE2 receptor; inflammation or malfunction of the innate immune response; coagulopathy or clotting dysregulation; edema or swelling and fluid accumulation; and fibrosis or scarring through the buildup of fibrotic connective tissue, explains Ashammakhi.

While there are surely benefits to assessing COVID-19 using a single lung-on-a-chip device, as Ashammakhi eludes above, the systemic nature of the disease means that a multi-organ MPS would be needed to reflect secondary and systemic effects of the drugs being tested. The inclusion of other cell types such as immune cells is also of utmost importance in developing relevant models especially for infection-related studies, he stresses.

AI is very important in this sense, it can make the big data obtained from multiple MPS chips, for a multitude of variables comprehendible relations [can be] identified and conclusions can be drawn, says Ashammakhi.

See more here:
Microphysiological Systems: Approaches, Applications and Opportunities - Technology Networks