Category Archives: Molecular Medicine

image:E. Sally Ward, Ph.D., at UT Southwestern in 2004 view more

Credit: UT Southwestern Medical Center

A first-in-kind immune-modulating drug that arose from decades of basic research at UTSouthwestern Medical Center has received approval from the U.S. Food and Drug Administration as a new treatment for adults with a form of myasthenia gravis. This rare and chronic autoimmune disease is characterized by debilitating and potentially life-threatening muscle weakness.

The new drug, efgartigimod alfa-fcab, is an engineered fragment of a human antibody that binds to a cell surface receptor known as the neonatal Fc receptor, or FcRn. Between 1990 and 2015, former UTSW Professor ofImmunologyE. Sally Ward, Ph.D., led work that characterized this receptors role in regulating the levels and persistence of immunoglobulin G (IgG) antibodies. In 2005, her laboratory described an approach to lower antibody levels by blocking FcRn activity, and subsequently demonstrated preclinical proof-of-concept to treat antibody-mediated autoimmune disease. The global immunology company argenx has licensed exclusive patent rights related to this drug from UTSW.

The development of this FcRn inhibitor came out of the fundamental work on FcRn biology that my group had worked on during the decades that I was on the UTSW faculty, said Dr. Ward, now a Professor of Molecular Immunology and Director of Translational Immunology at the University of Southampton in England. Working out the molecular and cell biological processes involved in FcRn biology and its regulation and transport of antibody molecules was a major focus of our work at UTSW over more than two decades, starting when I was an assistant professor there.

Clinical trials that led to the recent FDA approval found that 68% percent of patients with anti-acetylcholine receptor antibody positive myasthenia gravis responded to efgartigimod, compared to 30% of those taking a placebo. The company is exploring possible uses for the agent in other conditions mediated by IgG.

Efgartigimod represents Dr. Wards second commercial success based on fundamental research conducted at UTSW. That work also led to technology that can extend the half-life of therapeutic antibodies and currently is used in the FDA-approved drug ravulizumab and two antibody therapies against COVID-19, as well as another antibody in development to treat respiratory syncytial virus (RSV).

It is also the second first-in-kind drug developed from basic research at UTSW to be approved by the FDA in the past year. Less than six months ago, belzutifan, aHIF-2 inhibitor, received approval as a treatment for familial kidney cancer.

Considered together, these approvals mark UTSW as one of the major sources of breakthrough medicines for previously untreatable diseases. We are indeed a center for biotechnology, saidMichael Brown, M.D., Professor of Molecular Genetics and Internal Medicine and joint recipient of the 1985 Nobel Prize in Physiology or Medicine with research partner UTSW colleagueJoseph Goldstein, M.D.Dr. Brown helped recruit Dr. Ward to UTSW in 1990.

UTSouthwestern receives financial compensation from argenx for the newly approved drugs foundational intellectual property. Dr. Ward also receives compensation related to the licensing of the technology and research funding from the company.

Both Drs. Goldstein and Brown are Regental Professors.

Dr. Brown holds The W. A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research and the Paul J. Thomas Chair in Medicine.

Dr. Goldstein holds the Julie and Louis A. Beecherl, Jr. Distinguished Chair in Biomedical Research and the Paul J. Thomas Chair in Medicine.

About UTSouthwestern Medical Center

UTSouthwestern, 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 14 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.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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More than two decades of UTSW research paves way for first-in-kind drug - EurekAlert

Responses among those treated with Brutons tyrosine kinase (BTK) inhibitors differ across subtypes of diffuse large B-cell lymphoma (DLBCL), according to Mark Roschewski, MD.

Although the combination of ibrutinib (Imbruvica) and rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) does improve survival in patients, the benefit is limited by the toxicity of the regimen. Similarly, acalabrutinib (Calquence) has activity in DLBCL, according to research.

However, what remains unknown is how patients with DLBCL who have varying molecular profiles will respond to the therapy. Investigators sought to provide a better understanding of acalabrutinib treatment for DLBCL by administering the agent 14 days before frontline therapy.

In a recent study, a total of 34 patients were enrolled, and complete responses (CRs) to acalabrutinib were observed in 27. Two patients relapsed after the achievement of a CR. The estimated progression-free survival rate observed after a median follow-up of 9.2 months was 84.9% (95% CI, 58-95). Fifty percent and 35% of patients, respectively, experienced grade 3 or 4 neutropenia. Grade 3 thrombocytopenia occurred in 22%, and the events were grade 4 for 12% of patients. There were no increases in infections, atrial fibrillation, or bleeding in the patients treated with acalabrutinib in the study.

In an interview with Targeted Oncology, Roschewski, senior clinician, Lymphoid Malignancies Branch, Center of Cancer Research, National Cancer Institute, discussed precision medicine in DLBCL and using acalabrutinib in a pre-chemotherapy window to better understand its potential benefit.

TARGETED ONCOLOGY: Can you explain the differences between the DLBCL subtypes?

Roschewski: During ASH 2021, we talked a little bit about precision medicine and large B-cell lymphoma. What we know is that our preclinical models suggest that there are certain subtypes of large cell lymphoma that will preferentially respond to targeted agents. We've seen that in clinical studies, most of those clinical studies have been in the relapse setting. And so those are slightly different patient populations. In the untreated patient population. We do have randomized studies that don't show much difference with the use of targeted agents. But recently, our group did show that there were specific genetic subtypes of diffuse large B cell lymphoma that seem and in younger patients that seemed to have a benefit when a Bruton it was added to our job. So, we don't know yet enough about the individual response to targeted agents within subtypes of lymphoma.

What efficacy and safety findings have been reported so far with the combination of ibrutinib and R-CHOP in DLBCL?

In untreated large B-cell lymphoma, the most important study has been a randomized study known as the PHOENIX trial. The primary end point of that study was negative, meaning we could not see a benefit of ibrutinib with our R-CHOP across diffuse large B-cell lymphoma. But what was very interesting is that younger patients under 16 did seem to have a benefit, according to a subgroup analysis. More recently, our group published that there were 2 genetic subtypes of large B-cell lymphoma in that younger patient population, these are known as N1 and MCD that did seem to have a benefit. So, 1 of the problems we have is the heterogeneity of large cell lymphoma. But at this point, it's unclear who should get those medicines just because the data isn't sufficient.

What makes acalabrutinib a good treatment candidate for certain DLBCL subgroups?

The BTK inhibitors do seem like they have a role and they work very quickly. There are many patients that benefit from them, which we can see in the relapse setting. Acalabrutinib is very similar to ibrutinib, but it has more specificity. So, it binds to te similar epitope of the receptor. But it gets higher concentrations because it's given twice a day. So, the BTK occupancy is higher. Because of that selectivity, there is this theoretical benefit that it will have fewer off-target effects. So that will limit potentially some of the toxicity that is seen, and there is some evidence that that's true.

What were the key goals of your phase 2 study of acalabrutinib prior to frontline therapy in untreated patients with aggressive b-cell lymphoma?

It is important understand that we have a very unique study design. So, since we're interested in understanding, primarily, the role of the calibrated what we did was we implemented a window design. What happens is we first give the acalabrutinib by itself to all comers for up to 14 days. Because the medicine works very quickly, when patients benefit from it, we can see reductions in tumors very fast. The main focus in research is what are the types of patients that benefit from this acalabrutinib and we're going to be doing molecular profiling of these tumors, and we're going to be comparing tumors that respond to acalabrutinib of compared to those that don't. So, that's the primary goal.

Now, from a clinical perspective, what happens is, if we see a response, and we define that as only a 25% reduction, so that's less than we might think about in conventional response criteria. But if there's only a 20%, at least a 25% reduction, then we take that to mean the tumor is at least somewhat responsive to acalabrutinib, and then they get that acalabrutinib with their chemotherapy. But if there is no response in the window, then they get treated with chemotherapy alone. So, it also has a response adaptive design, and in that way, we can justify giving acalabrutinib to patients because we know they have a benefit, and we don't have to take the risk of the toxicity in patients that we don't see any benefit in the window.

Can you discuss the results you recently presented during the ASH Annual Meeting?

This was an interim analysis, and overall, we're going to enroll up to 100 patients. So far, we've enrolled 40. What we've seen so far is that in the 39 patients that have completed the window, 18 of them have responded to acalabrutinib, while 21 have not. So, it's about half and half. Then, we will look very closely at the genetic profile of these tumors both by cell of origin, as well as Han's criteria, and genetic subtypes. Now, we take all subtypes of large cell lymphoma on this study, except for primary mediastinal B-cell lymphoma. So, we took an agnostic approach. In other words, a preceding hypothesis would be that the patients with ABC large cell lymphoma or non-GCB lymphoma would be the ones that are most likely to respond. But that's not what we've observed. So far, what we've seen is that our responders have been enriched for patients with GCB. And this has been confirmed by cell of origin testing by RNA sequencing.

Then we've also looked closely at the genetic subtype. As I mentioned, 1 of our preceding hypotheses would be that patients with MCD or N1 genetic subtypes would respond. But none of our responders have had those genetic subtypes. So, we do see that the responses to acalabrutinib are broader than we may have thought before this study.

Another important aspect of this study is we're interested in developing and understanding the role of circulating tumor DNA [ctDNA]. So, this is an analyte that may help us predict responses much quicker than imaging. In this 14-day window, we're actually sampling ctDNA every 7 days to see if early changes in ctDNA, we can predict response that we see on CT scan. So far, on the first patients that we've looked at, that's been very true, there's been a very tight correlation with how quickly the ctDNA goes down and CT scan response. What's really interesting is that we saw that we could predict CT response after 14 days, as early as only 7 days by ctDNA. So, it does suggest that changes or decreases are actually a sign that the patient is responding to the tumor. It's a pretty good correlation between that and kind of overall tumor burden. So, those are the main findings. And of course, our patients have done very well. The safety has been good on this study. We've only had a few events, and our survival right now is over 90%. So, I think it looks in a randomized way and uncontrolled way that our patients are benefiting.

In your opinion, what would a randomized phase 3 study for this strategy look like?

I think we have a little bit more to learn. One of the focuses, of course, is to try to home in very tightly on which patients benefit from acalabrutinib. If we can identify a group of patients that do not benefit from acalabrutinib, we could design a study where we just don't enroll those patients, so we don't take the risk of acalabrutinib in those patients. So, both of those are key objectives. And so, I think what we're focused on here is who's the right patient population.

So, if we had the ideal patient population if we knew how to identify them, and then we would only enroll those patients and then do a randomized study, probably acalabrutinib or not with conventional chemotherapy that would be one way to go. Now the ctDNA adds in a whole other aspect. The question then becomes, can we do a different type of randomized study where we're looking at responses early on with ctDNA to be the reason to randomize from there? So that's another potential study. I think we're already discussing these types of options, but it's a little early to know for sure, just because our data aren't quite mature enough. But we're starting to get a signal for the right way to move forward.

How would you explain the importance of doing gene expression profiling for these patients?

It's important to recognize that gene expression profiling is distinguishing that these are truly different tumors. So, we have to have an understanding of the underlying molecular biology of these tumors. Now, does that currently help us in the clinic select which treatment to use? No, not yet. Part of the reason it doesn't is that the story is much more complex than just gene expression profiling. So, we've been interested in this question for a long time. And the most recent papers we've done show us that these genetic subtypes sort of cross over with the gene expression profiling subgroups. There are also some tight correlations, and there are some that aren't. So, I do think it's really important with therapy, particularly new therapies to know which groups of patients benefit the most, so they can be prioritized. We have all these targeted agents and immunotherapy agents. The disease is so heterogeneous, that if we don't have a nuanced understanding of which patients benefit, then we're going to be guessing in the clinic, or we're going to be relegated to only answering important questions with randomized studies. Now, randomized studies are important. But we also have to have a better understanding of how we approach individual patients. It takes a long time to get there. But I think every study that tests new agents should be also reporting how it responds within these subgroups of patients and genetic subtypes. I think that's the future.

Reference:

Roschewski M, Phelan JD, Pittaluga S, et al.Phase 2 study of acalabrutinib window prior to frontline therapy in untreated aggressive b-cell lymphoma: preliminary results and correlatives of response to acalabrutinib. Presented 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 524.

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Determining the Molecular Profile of BTK Inhibitor Responsive DLBCL Tumors - Targeted Oncology

A global proteomics approach to study the influence of COVID-19 on host signaling pathways. One resource to bring all the structural databases together. A new way to automate and optimize proteinprotein studies. Read about papers on these topics recently published in the journal Molecular & Cellular Proteomics.

NIAID-RML

This scanning electron microscope image shows SARS-CoV-2 (round blue objects)emerging from the surface of cells cultured in the lab. SARS-CoV-2 is the virus thatcauses COVID-19.

COVID-19 has taken over the world as the largest global pandemic of our time. While the inflammatory implications of SARS-CoV-2 have been well studied, researchers do not yet understand the effect of the virus on signaling pathways. This is crucial, since COVID-19 manifests in severities ranging from asymptomatic infection to multiorgan failure. Immune response to a viral antigen is wide-ranging, from an interferon-mediated antiviral response to downstream events that activate transcription factors. This eventually leads to an inhibition of replication, transcription and translation of the viral genome, followed by its degradation and recruitment of immune cells.

In a recent study in the journal Molecular & Cellular Proteomics, Patrick M.Vanderboom and colleagues at the Mayo Clinic compared SARS-CoV-2 negative and positive patient samples to analyze molecular features of the host response. A global proteomics approach was used to characterize the influence of this infection, and samples were obtained from the nasopharynx due to the proximity to the lungs, where this COVID-19 most often progresses to severity.

When they subjected these samples to mass spectrometry, the researchers found 7,582 proteins, of which 143 were upregulated and 80 were downregulated in patients who had COVID-19. The upregulated proteins were involved mostly in interferon signaling. In particular, the authors monitored two specific molecules, RIG-1 and STAT1, involved in interferon signaling and found that the levels of these proteins correlate with viral loads.

The authors state that while these studies provide definitive information about the signaling pathways that are affected by SARS-CoV-2 infections, they will need to do more research to understand completely the pathogenesis of the virus and its potential outcomes in individual patients.

A popular technique used to validate direct interactions in protein complexes is cross-linking mass spectrometry, or XL-MS, which typically will detect linked residues while integrating these networks with structural techniques to generate accurate models of high-level molecular processes. XL-MS can overcome ambiguity in modest-resolution cryo-EM density maps and add more information to extrapolate X-ray maps into more accurate models.

In a recent paper in the journal Molecular & Cellular Proteomics, Daniel S. Ziemianowicz and colleagues at the University of California, San Francisco, and the University of Calgary, Canada, describe a new tool known as IMProv that can integrate cryo-EM densities, existing structures and cross-linking data. This addresses the effect of underlying protein dynamics on cross-linking. To use this resource, a user provides the sequence information for each protein building block and available partial or homologous structures. IMProv generates models using four steps: building a Python modeling interface, creating corresponding directories, using a SLURM bash script to model on a high-performance cluster and combining all of the above to generate the final model.

The authors show how IMProv could fill some gaps in the current model of the polycomb repressive complex 2. Overall, this resource will serve as an effective tool to develop existing data repositories and enable the use of cross-linking data to interpret and model structural data with greater precision.

When protein interactions occur in intrinsically disordered regions, its often through short linear motifs, known as SLiMs, which are both tedious and challenging to study. Researchers must incubate individual peptide spots with the protein extract on a cellulose membrane and then retrieve them for further analysis. This time-consuming procedure limits the number of samples that can be analyzed at a time.

To overcome these shortcomings, Evelyn Ramberger, Lorena SuarezArtiles, Daniel PerezHernandez and colleagues at Max Delbrck Center for Molecular Medicine in the Helmholtz Association, Germany, have developed an optimized method for using protein interaction screen on a peptide matrix, or PRISMA, in combination with quantitative mass spectrometry.

PRISMA is a new way to study point mutations and post-translational modifications within protein interaction motifs and to map these motifs.

In a recent paper in the journal Molecular & Cellular Proteomics, the authors write that PRISMA can be automated and allow the detection of phosphorylation-dependent interactors of certain proteins or mutation-dependent interactions of certain peptides. The authors propose that the transfer of this method from manual low-throughput procedures to an automated, microwell format with a high-throughput output retrieval will enable researchers to use PRISMA to explore disordered protein functions more efficiently. This method could contribute to deciphering the protein networks dependent on these short motifs that are involved in signaling processes and diseases.

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From the journals: MCP - American Society for Biochemistry and Molecular Biology

SILICON VALLEY, Calif., Jan. 4, 2022 /PRNewswire/ -- Predicine, a global molecular insights company, announced today that it has appointed Dennis Merkle, PhD, MBA, as its new Chief Executive Officer (CEO) for Predicine Europe as well as its Global Head of Biopharma Business. Dr. Merkle moves into the role after leading the oncology development strategy, alliance management and biorepository teams at Invitae, which he joined as part of the acquisition of ArcherDx, where he was Senior Vice President of corporate development.

Dr. Dennis Merkle

Known for his strategic leadership across commercial and R&D organizations, Dr. Merkle has extensive experience building high performing teams and novel functions in both the biopharma and in vitro diagnostic (IVD) industries. Based in Germany, Dr. Merkle's primary role will be to build, scale and manage Predicine's European business strategy, operations, and organization, while growing, synergizing and strengthening its partnerships with biopharma clients globally.

Dr. Merkle has over 20 years' experience in cancer biology, molecular and companion diagnostics and drug development. Prior to joining ArcherDx and Invitae, Dr. Merkle built and lead the global companion diagnostics group at Merck KGaA, leading to that organization's first ever drug-companion diagnostic co-approvals. Dr. Merkle has also held senior positions in marketing and R&D at Merck KGaA, Abbott Laboratories and Philips building extensive experience in the development and launch of novel drug and diagnostic products, as well as the lifecycle management and marketing of mature products.

"Predicine Europe is one step closer to our grand mission - to empower the global healthcare ecosystem through innovation. Dr. Merkle is an accomplished industrial leader with a proven track record of product development and launch in the diagnostics and biopharma space. In the last six years, Predicine has made significant progress in precision medicine in both the biopharma and patient testing businesses. We welcome strong leaders, such as Dr. Merkle, to drive our next-phase business growth in global oncology and infectious diseases." said Dr. Shidong Jia, Predicine's Founder and Global CEO.

Story continues

Dennis Merkle, new CEO of Predicine Europe, said:

"Predicine offers a best-in-class genomic platform that enables minimally-invasive diagnostics and molecular analysis for patients, healthcare providers and the biopharmaceutical industry. Through its unique portfolio of blood-, urine- and tissue-based diagnostic solutions, I am confident Predicine will be a market leader in precision medicine for years to come.

I am excited to be joining Predicine's world-class global team and establishing its European business operations, while also continuing to strengthen collaborations with our very important pharmaceutical partners. Complementing our presence in Silicon Valley, Tustin, Shanghai, Singapore, Houston and Boston, the European affiliate will make Predicine a truly global player in personalized healthcare. So, stay tuned for more announcements from this very important region!"

About Predicine

Predicine is a global molecular insights company that is committed to advancing precision medicine in oncology and infectious diseases. Predicine has developed a breakthrough cell-free DNA- and cell-free RNA-based liquid biopsy technology enabling minimally invasive molecular diagnosis for treatment selection, therapy monitoring, and minimal residual disease and early cancer detection. The company has launched a portfolio of blood-, urine- and tissue-based diagnostic assays for oncology and infectious diseases, including COVID-19. Through its business operations in Silicon Valley, Tustin, Houston, Shanghai, Singapore, Berlin and Boston, Predicine partners with leading biopharma companies, institutions and governments to support personalized healthcare on a global scale. Further information is available on the company's website, http://www.predicine.com. Stay in touch on LinkedIn or @Predicine on Twitter.

Contact Information:

Sushmasri TakkilapatiPredicine Inc.(857) 756-3469 326820@email4pr.com

Cision

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Predicine Appoints Dr. Dennis Merkle as Chief Executive Officer of Predicine Europe and Global Head of Biopharma Business - Yahoo Finance

Goodbye, 2021. We wont focus on the way you left us dealing with a new COVID-19 variant anduncertain about the future. No, we at Washington University in St. Louis will focus on the good bold new discoveries, hopeful new students and a promising new direction for the university.

Here, the Source shares some of the years most-read stories that highlight the great strides of the WashU community.

Supporting students; expanding opportunities

With an unprecedented endowment return of 65%, Washington University made a bold $1 billion investment in student success. The initiative, which the university is calling Gateway to Success, includes a $800 million in endowed funding to support need-blind undergraduate admissions long a top goal for the university. As a need-blind institution, the university will not consider an applicants financial situation when making admissions decisions while still meeting 100% of demonstrated financial need for admitted undergraduates. An additional $200 million will be designated for financial aid for graduate and professional students in the Brown School, the School of Law and the School of Medicine, as well as in business, engineering, art and architecture, and Arts & Sciences.

Since I became chancellor nearly two years ago, becoming need-blind has been a top priority. Building on the momentum that began with our previous administration, were finally making it happen, Chancellor Andrew D. Martin said upon announcing Gateway to Success in October. This is a proud moment for us as an institution and Im grateful to all who have contributed along the way, including generous donors who have provided scholarships and other financial support for our students.

The university also announced other major gifts to support students. Alumnus and emeritus trustee Arnold B. Zetcher and his wife, Ellen, made a commitment of at least $8 million in outright and estate gifts to establish an endowed scholarship for undergraduate students. Alumnus and emeritus trustee John Dains donated $8 million to support an undergraduate student success fund to help cover emergency and educational enrichment expenses. And P. Roy Vagelos, MD, founder of the Division of Biology & Biomedical Sciences (DBBS), and his wife, Diana Vagelos, made a $15 million gift to undergraduate programs and graduate student fellowships in the life sciences.

Studying COVID-19; seeking solutions

Washington University scientists committed 2021 to studying the deadly COVID-19 pandemic. Readers were especially intrigued by the following stories:

Research from Ziyad Al-Aly, MD, assistant professor of medicine, found that COVID-19 survivors including those not sick enough to be hospitalized have an increased risk of death in the six months following diagnosis with the virus.

Research published in August co-led by Ali Ellebedy, associate professor of pathology and immunology, of medicine and of molecular microbiology, found that the delta variant of the virus that causes COVID-19 is largely unable to evade antibodies elicited by vaccination.

Research from the lab of Ryan Bogdan, associate professor of psychological and brain sciences in Arts & Sciences, suggests cannabis use disorder (CUD) should be added to the list of COVID-19 risk factors because the genetic predisposition to CUD is overrepresented in people with poor COVID-19 outcomes.

And research from Jeannie Kelly, MD, assistant professor of obstetrics and gynecology, suggests nursing mothers who receive a COVID-19 vaccine may pass protective antibodies to their babies through breast milk for at least 80 days following vaccination.

Saying hello, bidding farewell to amazing students

During an exceptional admissions cycle, Undergraduate Admissions reviewed 33,634 applications a 20% increase from 2020. In August, 1,994 of those students moved onto the South 40, made new friends at the Bear Beginnings tailgate party and celebrated Convocation in Brookings Quadrangle. The Class of 2025 is the largest and most diverse in university history 17% are Pell Grant-eligible, 12% are the first in their families to attend college, 5% are international and 49% identify as students of color.

Washington University celebrated the Commencement of the Class of 2021 in its new home, Francis Olympic Field. Basketball legend and activist Kareem Abdul-Jabbar served as speaker. The Class of 2020 also was welcomed home for an in-person ceremony featuring Julie L. Gerberding, MD, the first woman to serve as director of the Centers for Disease Control and Prevention.

Among those who left their mark at Washington University are the School of Medicines graduating physicians; a Maryland man who graduated 67 years after he started his education at Washington University; and baseball Bears Caleb Durbin and Ryan Loutos, who signed deals with Major League Baseball teams Durbin as a 14th-round draft pick to the Atlanta Braves and Loutos as an undrafted free agent to the St. Louis Cardinals.

Digging for clues; overcoming obstacles

Despite the pandemic, Washington University researchers persisted in their research, making groundbreaking discoveries in archeology, medicine, engineering and other disciplines.

Two archeological studies especially fascinated readers. In one, Tristram T.R. Kidder, the Edward S. and Tedi Macias Professor of Anthropology in Arts & Sciences, found evidence that suggests Americas first civilization was made up of sophisticated engineers capable of building massive earthen structures in a matter of months possibly even weeks that withstood the test of time. In the other, Caitlin Rankin, who conducted her graduate studies at Washington University, found there is little evidence to support the prevailing theory that wood overuse led to the collapse of Cahokia, the pre-Columbian Native American city in present-day Illinois.

Other top stories include:

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2021 in review: New direction, new discoveries - The Source - Washington University in St. Louis - Washington University in St. Louis Newsroom

Its no secret that going hard on the steaks and burgers isnt going to do your heart any good. This effect is typically put down to the high amounts of fats and cholesterol found in red meats, but a new study suggests another culprit might be responsible: bacteria in your gut.

As reported in the journal Nature Microbiology, a new study builds on evidence that gut bacteria and a compound produced by some of them trimethylamine-N-oxide (TMAO) have an intriguing link to the increased risk of heart attacks and strokes seen in people with a diet heavy in red meat.

Our intestines are home to trillions and trillions of microorganisms. Most are perfectly harmless and, in fact, play a diverse range of important functions such as breaking down food, manufacturing vitamins, guiding metabolism, and bolstering our immune system. Some of this work is carried out through the compounds the bacteria produce and secrete. One of these compounds is TMAO, which is produced by certain bacteria from choline, lecithin, and carnitine, three nutrients that are in many animal products but are especially abundant in red meat and liver.

In this latest study, a team of researchers from the Cleveland Clinic found that high levels of circulating TMAO in the body have been shown to be a strong indicator that a person is at risk of heart attacks, stroke, and even death.Furthermore, they discovered a two- to three-fold increase in TMAO levels in people who ate red meat as their primary source of protein for one month, compared to participants who relied on white meat or plant-based foods as their prime protein source.

There is some good news, however: some of the impacts of red meat on gut bacteria and TMAO appear to be relatively reversible. Their research indicated that TMAO levels dropped to healthier levels within three to four weeks after cutting red meat from their diet.

We know lifestyle factors are critical for cardiovascular health, and these findings build upon our previous research on TMAOs link with heart disease, Dr Stanley Hazen, study author and Chairman of the Department of Cellular and Molecular Medicine at Cleveland Clinics Lerner Research Institute, said in a statement. They provide further evidence for how dietary interventions may be an effective treatment strategy to reduce TMAO levels and lower subsequent risk of heart disease.

Through working with isolated bacteria, the team investigated how microorganisms in the gut create TMAO from choline, carnitine, and lecithin. This knowledge, they believe, could help pave the way towards medical and nutritional interventions that reduce a persons risk for cardiovascular disease.

We can use a TMAO level to help personalize dietary choices in an individual to help identify, for a given person, how much red meat is too much, and how to try to chase after lowering the level, much in the same way we do with cholesterol levels or triglyceride levels or glucose levels, Dr Hazen explains.

Excerpt from:
Gut Bacteria Helps Explain Why Too Much Red Meat Is Bad For Your Heart - IFLScience

Our Phase 1a trial has been open 12 months and Im pleased with both the pace of development and the early responses seen. Its particularly gratifying to have followed a patient in the trial for over 12 months where their tumour burden has been reduced to zero.

Imugene Ltd (ASX:IMU, OTC:IUGNF)has successfully completed Phase 1a monotherapy dose escalation of PD1-Vaxx and will now proceed to combination dose escalation.

The clinical-stage immuno-oncology company is developing a range of new and novel immunotherapies that seek to activate the immune system of cancer patients to treat and eradicate tumours.

Finalisation of the dose escalation of PD1-Vaxx was confirmed by the Cohort Review Committee (CRC), following the Phase 1a monotherapy dose escalation performed with 10, 50 and 100g of PD1-Vaxx in non-small cell lung cancer (NSCLC) patients who progressed on one or more immune checkpoint inhibitors (ICIs).

The primary objective of the phase 1 trial is to determine safety and optimal biological dose as monotherapy and in combination with ICIs. Plans are now being finalised to combine PD1-Vaxx with Roche/Genentechs PD-L1 targeting blockbuster ICI atezolizumab (Tecentriq) as first-line in ICI treatment nave NSCLC patients.

CRC reviewed monotherapy safety, tolerability and biomarker data. It then advised IMU to proceed to the combination phase of clinical development of PD1-Vaxx.

Phase 1 trials are generally designed to look for safety, tolerability and early response signals to determine the optimal dose for further development, Imugene MD & CEO Leslie Chong said.

I am encouraged that we are seeing positive signals at such an early stage of our PD1-Vaxx Phase I trial and we are now progressing to the Phase 1b combination studies in treatment nave patients.

Our Phase 1a trial has been open 12 months and Im pleased with both the pace of development and the early responses seen. Its particularly gratifying to have followed a patient in the trial for over 12 months where their tumour burden has been reduced to zero.

Dual targeting of the PD-1/PD-L1 axis is an area of considerable interest with ongoing clinical results creating strong interest inside the pharma industry.

Combination with PD1-Vaxx may overcome treatment resistance to ICIs with dual inhibition of the PD-1/PD-L1 axis extending the treatment benefit of atezolizumab.

In contrast to combination of two monoclonal antibodies, PD1-Vaxx has the advantage that it induces a unique polyclonal immune response which may increase response rates for the combination therapy.

Imugenes PD1-Vaxx is a B-cell activating immunotherapy designed to treat tumours such as lung cancer by interfering with PD-1/PD-L1 binding and interaction and produce an anti-cancer effect similar to Tecentiq, Keytruda, Opdivo and the other immune checkpoint inhibitor monoclonal antibodies that are transforming the treatment of a range of cancers.

Full study details can also be found on clinical trials.gov under study ID: NCT04432207.

While it has been conducting these promising trials, IMU has also been strengthening its management team.

Today, it not only announced the successful completion of Phase 1a monotherapy dose escalation of PD1-Vaxx, IMU also informed the market that it has appointed industry leaders Ursula McCurry and Dr Nimali Withana to its senior management team.

The former Roche/Genentech employees and experts in oncology clinical development started with IMU at the beginning of January 2022, with McCurry appointed as the senior vice president of Clinical Operations and Dr Nimali Withana appointed senior director of Clinical Science.

Ursula and Nimali add critical and considerable clinical development capability to our senior management team, and I am delighted to welcome them to Imugene, Chong said.

About Ursula McCurry

McCurry is a well-regarded clinical operations leader with more than 20 years of global clinical development experience across a number of established and emerging biotech and pharmaceutical companies including Genentech, Exelixis (NASDAQ:EXEL), Astex, QLT Inc and Amunix.

She has led global clinical operations programs spanning a variety of therapeutic areas and all phases of clinical development, contributing to in excess of20 programs and subsequent multiple regulatory approvals at both small and large biotech companies.

McCurrys significant partnership and alliance management experience are expected to be invaluable to IMU as it progresses its therapies.

Prior to joining Imugene, Ursula served as the VP of Clinical Operations at Amunix Pharmaceuticals and was a Clinical Program director at Genentech, leading multiple programs from entry into the clinic to phase three development, including taselisib and GDC-9545.

She has also led the Drug Safety teams, ensuring quality, compliance, pharmacovigilanceand safety reporting.

About Dr Nimali Withana

Dr Withana has more than18 years of drug development experience spanning both academia and industry and most recently was the Lead Country medical manager for the Breast Cancer and Cancer Immunotherapy portfolios including bevacizumab, trastuzumab emtansine, ipatasertib and atezolizumab at Hoffman-La Roche New Zealand.

Prior to that, Dr Withana was the clinical scientist lead across Phase I III global oncology trials at Genentech.

Dr Withana received her academic training at Stanford University and The Peter MacCallum Cancer Centre, majoring in Immunology and Molecular Medicine.

Continued here:
Imugene completes Phase 1a monotherapy dose escalation of PD1-Vaxx and adds industry leaders to management team - Proactive Investors USA

Researchers at the University of Oxford uncover the importance of iron for the development of complex life on Earth which also may hint at the likelihood of complex life on other planets.

Iron is an essential nutrient that almost all life requires to grow and thrive. Irons importance goes all the way back to the formation of the planet Earth, where the amount of iron in the Earths rocky mantle was set by the conditions under which the planet formed and went on to have major ramifications for how life developed. Now, scientists at the University of Oxford have uncovered the likely mechanisms by which iron influenced the development of complex life forms, which can also be used to understand how likely (or unlikely) advanced life forms might be on other planets. The work was published recently in PNAS.

The initial amount of iron in Earths rocks is set by the conditions of planetary accretion, during which the Earths metallic core segregated from its rocky mantle, says co-author Jon Wade, Associate Professor of Planetary Materials at the Department of Earth Sciences, University of Oxford. Too little iron in the rocky portion of the planet, like the planet Mercury, and life is unlikely. Too much, like Mars, and water may be difficult to keep on the surface for times relevant to the evolution of complex life.

Initially, iron conditions on Earth would have been optimal to ensure surface retention of water. Iron would have also been soluble in sea water, making it easily available to give simple life forms a jumpstart in development. However, oxygen levels on Earth began to rise approximately 2.4 billion years ago (referred to as the Great Oxygenation Event). An increase in oxygen created a reaction with iron, which led to it becoming insoluble. Gigatons of iron dropped out of sea water, where it was much less available to developing life forms.

Life had to find new ways to obtain the iron it needs, says co-author Hal Drakesmith, Professor of Iron Biology at the MRC Weatherall Institute of Molecular Medicine, University of Oxford. For example, infection, symbiosis and multicellularity are behaviors that enable life to more efficiently capture and utilise this scarce but vital nutrient. Adopting such characteristics would have propelled early life forms to become ever more complex, on the way to evolving into what we see around us today.

The need for iron as a driver for evolution, and consequent development of a complex organism capable of acquiring poorly available iron, may be rare or random occurrences. This has implications for how likely complex life forms might be on other planets.

It is not known how common intelligent life is in the Universe, says Prof Drakesmith. Our concepts imply that the conditions to support the initiation of simple life-forms are not enough to also ensure subsequent evolution of complex life-forms. Further selection by severe environmental changes may be needed for example, how life on Earth needed to find a new way to access iron. Such temporal changes at planetary scale may be rare, or random, meaning that the likelihood of intelligent life may also be low.

However, knowing now about how important iron is in the development of life may aid in the search for suitable planets that could develop life forms. By assessing the amount of iron in the mantle of exo-planets, it may now be possible to narrow the search for exo-planets capable of supporting life.

Reference: Temporal variation of planetary iron as a driver of evolution by Jon Wade, David J. Byrne, Chris J. Ballentine and Hal Drakesmith, 6 December 2021, Proceedings of the National Academy of Sciences.DOI: 10.1073/pnas.2109865118

Link:
Iron Integral to the Development of Complex Life on Earth And the Possibility of Life on Other Planets - SciTechDaily

When it's that time of the month, we almost always know. Not only because we're likely keeping track of our menstrual cycles, but also because many of us experience symptoms and changes in our bodies, including bloating, cramping, fatigue, and more.

Most womenaround 90%experience minor symptoms leading up to their periods, according to the U.S. Department of Health & Human Services, and this is normal. However, premenstrual symptoms can feel uncomfortable. One of the biggest culprits to discomfort is menstrual cramping, which occur when the uterus contracts while shedding the uterine lining.

The causes of menstrual cramping are not completely understood, but typically it's the inflammatory reaction from the uterine lining expulsion, says Mazen Abbas, D.O., M.P.H., Pediatric and Young Adult Gastroenterologist in Kailua, Hawaii. Other considerations include endometriosis, age, hormone levels, uterine fibroids, ovarian cysts, and more.

The good news is that there's a ton of ways to alleviate minor menstrual cramps at home. In addition to the classic heating pad, Abbas says that over-the-counter such as non-steroidal anti-inflammatory medication should help you find relief. You can also sip on some warm teas, which have been found to reduce menstrual cramps.

Ginger, green tea, chamomile, fennel, cinnamon, and French maritime pine bark extract have been studied and found helpful to alleviating menstrual cramps, Abbas says. Avoiding certain foods like processed foods, sugar, and caffeine may help, too. If you're looking for some natural relief, read on for the teas you can count on to help reduce painful period cramps, according to doctors and research.

Ginger tea seems to be the best option for reducing menstrual cramps, Abbas says, because it's rich in anti-inflammatory and pain-relieving properties like gingerols and shogaols. A review published in Phytotherapy Research examined the use of ginger for pain relief in randomized controlled trials and found that ginger significantly reduced pain and inflammation when taken orally.

Around menstruation specifically, a review published in Pain Medications examined the pain levels in women who consumed 7502,000 mg of ginger powder during the first 34 days of their period and found that ginger helped relieve their pain. So, sipping on some ginger tea may help you find relief from painful cramping.

Not only can chamomile help soothe you to sleep, but it also has anti-inflammatory and anti-spasmodic properties that can help alleviate painful cramps associated with menstrual cramps, a review published in the Journal of Pharmacupuncture shows. Specifically, a study published in the Internal Journal of Molecular Medicine found that chamomile inhibits the production of nitric oxide, which is a signaling molecule that plays a key role in the pathophysiology of inflammation. As Abbas previously mentioned, inflammation has been associated with menstrual cramps.

Another study published in the Iranian Journal of Obstetrics, Gynecology and Infertility had women drink two cups of chamomile a day one week leading up to menstruation and during the first five days of their cycle for three months, which resulted in a reduction in their pain from cramps.

According to Abbas, fennel tea is another great option for alleviating pain from menstrual cramps. Fennel is full of powerful antioxidants such as vitamin C and quercetin, which can help reduce inflammation. A small study published in Ayu examined pain levels in 60 girls who experienced dysmenorrhoea, or painful periods, after they took 30 mg of fennel extract four times a day for three days at the start of their menstrual cycles compared to a placebo. Results showed that those who consumed the fennel saw a significant reduction in their pain.

Not only is cinnamon a delicious way to spice up your favorite winter dishes, but it has also been used for centuries as a natural healing agent. Cinnamon has antioxidant, anti-inflammatory, and anti-fungal properties that help aid in digestion, improve blood sugar levels, and reduce menstrual pain in the body.

A review published in Complementary Therapies in Medicine found that cinnamon may help reduce inflammation and bloating associated with menstruation. Another small study published in the Iranian Journal of Obstetrics, Gynecology and Infertility had 76 girls with dysmenorrhea take three capsules of 420 mg of cinnamon a day and found that menstrual pain and bleeding was significantly reduced.

As energy levels begin to drop during menstruation thanks to reduced oestrogen levels, you may be wanting to reach for some caffeine. Go for green tea, which will not only give you energy, but it may also help alleviate your cramps. A study published in BMJ found that girls who drank green tea regularly had way less cramping and bloating than in those who did not drink the tea. This may be because green tea is full of flavonoid, antioxidant, and anti-inflammatory compounds. Green tea also has a ton of L-theanine, an amino acid that boosts dopamine and reduces anxiety, which can be helpful for those period-induced mood swings.

Fennel Seed Tea

$6.99

Green Tea

$7.40

Chamomile Herbal Tea

$13.10

Many species of pine trees have been used for their healing properties, and one that may help with painful period cramping is French maritime pink bark extract tea. French maritime pink bark extract contains many plant compounds like vitamins, polyphenols, and other phytonutrients, which may be beneficial to our health.

The tea may also soothe menstrual pain in women with dysmenorrhea, a small study published in the Journal of Reproductive Medicine found. In the study, 116 women were given either a French maritime pink bark extract pill or a placebo throughout two full menstrual cycles, and results showed that the women who tool the pine bark experienced less pain.

Overall, research shows you can rely on tea for natural remedies to reducing period cramps. However, if your cramps persist for more than two days and the pain begins to interfere with your daily life, then Abbas suggests consulting with your doctor.

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Link:
6 Teas That Reduce Menstrual Cramps and Pain, According to Experts - Tea for Period Pain and Bloating - Prevention.com

About the position

A position as PhD candidate is open at the Cardiac Exercise Research Group, Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU (Trondheim, Norway). The group is headed by Professor Ulrik Wislff.

The position has fixed-term duration of three years (100%). At CERG we investigate the effects of exercise in chronic diseases, such as heart diseases, diabetes, and Alzheimers disease using a wide range of tools spanning from animal experiments to clinical trials and epidemiological studies. For more information about the Department and the research group, see the following pages:www.ntnu.edu/isbandwww.ntnu.edu/cerg.

This project consists of three complementary studies that aim to (1) explore the effect of increased cardiorespiratory fitness in exercise-trained older adults on their future risk of Alzheimers disease, (2) identify biomarkers in blood that might underlie the expected effect of increased fitness on the risk of Alzheimers disease and that could identify the future Alzheimers disease patients up to 8 years before clinical manifestation of the disease, and (3) detect changes in these biomarkers in early Alzheimers disease patients following treatment with blood plasma from exercise-trained donors. We seek a talented and diligent candidate with a high motivation and commitment to research.

Duties of the position

The successful candidate will be responsible for daily management of the projects, hereunder data collection, analysis and interpretation and communication of results.

Required selection criteria

Medical degree or Master`s degree in Molecular Medicine, Neuroscience, Biology, Biotechnology, Exercise Physiology, or equivalent program:

Preferred selection criteria

Emphasis will also be placed on:

Personal characteristics

NTNU is an equal opportunity employer and welcomes applicants from anywhere in the world. The university is strongly committed to diversity and welcomes applications from members of ethnic minorities. The appointment will be made in accordance with current regulations for employment at universities and university colleges in Norway.

We offer

Salary and conditions

Appointment to a PhD position requires that you are admitted to the PhD programme in within three months of employment, and that you participate in an organized PhD programme during the employment period.

It is a prerequisite you can be present at and accessible to the institution daily.

About the application

Applicants are asked to apply via this page, and to attach all relevant documents, see list below:

Candidates from universities outside Norway are kindly requested to send a Diploma Supplement or a similar document, which describes in detail the study and grade system and the rights for further studies associated with the obtained degree:http://ec.europa.eu/education/tools/diploma-supplement_en.htm

For inquiries regarding the position, please contact:

PhD Atefe R. Tari, Department of Circulation and Medical Imaging, NTNU, email: atefe.r.tari@ntnu.no

Professor Ulrik Wislff, Department of Circulation and Medical Imaging, NTNU, email: ulrik.wisloff@ntnu.no

For inquiries regarding the application procedures, please contact:HR Advisor Julie Hoff, email: julie.hoff@ntnu.no

General information

Working at NTNU

A good work environment is characterized by diversity. We encourage qualified candidates to apply, regardless of their gender, functional capacity or cultural background.

The city of Trondheimis a modern European city with a rich cultural scene. Trondheim is the innovation capital of Norway with a population of 200,000. The Norwegian welfare state, including healthcare, schools, kindergartens and overall equality, is probably the best of its kind in the world. Professional subsidized day-care for children is easily available. Furthermore, Trondheim offers great opportunities for education (including international schools) and possibilities to enjoy nature, culture and family life and has low crime rates and clean air quality.

As an employeeatNTNU, you must at all times adhere to the changes that the development in the subject entails and the organizational changes that are adopted.

In accordance with The Public Information Act (Offentleglova), your name, age, position and municipality may be made public even if you have requested not to have your name entered on the list of applicants.

Please submit your application electronically via jobbnorge.no with your CV, diplomas and certificates. Applications submitted elsewhere will not be considered.

If you are invited for interview you must include certified copies of transcripts and reference letters.

Application deadline: 10.01.2022

NTNU - knowledge for a better world

The Norwegian University of Science and Technology (NTNU) creates knowledge for a better world and solutions that can change everyday life.

The Department of Circulation and Imaging(ISB) has 260 employees, and its research units are at the Cardiothoracic Centre at St. Olavs Hospital, integrated with collaborating clinical divisions. The Department of Circulation and Medical Imaging (ISB) includes anaesthesiology, radiology, radiography, ultrasound, magnetic resonance imaging, exercise physiology, cardiovascular physiology, pulmonary physiology, pulmonary medicine, cardiology, vascular surgery, thoracic surgery and biomedical engineering.

The department is also responsible for the Centre for Innovative Ultrasound Solutions (CIUS), the Medical Simulation Centre and the MR Centre. More information about the department is available at http://www.ntnu.edu/isb

Deadline10th January 2022EmployerNTNU - Norwegian University of Science and TechnologyMunicipalityTrondheimScopeFulltimeDurationTemporaryPlace of serviceya cmapus

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