The human body uses many tactics to fight invaders. Scientists just found another weapon in its arsenal: tiny fat blobs packed with toxic proteins that are fired at the enemy.

Complex organisms including fungi, plants and animals are made up of eukaryotic cells that contain subcellular structures called organelles. These organelles all work together to keep the cells functioning; the nucleus, for example, is the brain of the cell and lipid droplets (LDs) are teeny blobs of fat that store and provide fuel for the cell when needed.

Lipid droplets are usually attached to the mitochondria an organelle that generates most of the cell's energy and serve as a source of fuel when needed. Previous research has found that certain parasites, viruses and bacteria steal these droplets and also use them to fuel growth. So until now, scientists thought that these lipid droplets supported infection, the authors wrote in a new study published Oct. 15 in the journal Science.

Related: 5 ways gut bacteria affect your health

"It was previously thought that bacteria were merely using the lipid droplets to feed on, but we have discovered these fatty droplets are involved in the battle between the pathogens and our cells," co-author Robert Parton, head of the cell biology and molecular medicine division of the University of Queensland's Institute for Molecular Bioscience in Australia, said in a statement. Previously, scientists found that exposing fruit flies to a microbe induced formation of lipid droplets with antimicrobial activity, according to an accompanying commentary in the journal Science.

Parton and his team wanted to see whether this strange battle technique also existed in mammalian cells. They injected mice with lipopolysaccharide, a toxin that's produced by bacteria. The toxin spurred threatened cells in the mice's liver to produce more lipid droplets and increase the size of existing ones, according to the study.

In cells infected with the toxin, threatened cells packed lipid droplets with hundreds of antiviral and antibacterial proteins.The scientists also found that the droplets detached from the mitochondria and moved toward the bacterial toxin.

"Fat is part of the cell's arsenal cells manufacture toxic proteins, package them into the lipid droplets, then fire them at the intruders," Parton said. "This is a new way that cells are protecting themselves, using fats as a covert weapon, and giving us new insights into ways of fighting infection."

The researchers also saw a similar response when they exposed human macrophages a type of white blood cell that helps detect and destroy pathogens and problem cells to the bacterial toxin in the lab. Now, Parton and his team hope to figure out how the lipid droplets actually target the bacteria, he said in the statement. "By understanding the body's natural defenses, we can develop new therapies that don't rely on antibiotics to fight drug-resistant infections."

Though scientists are just discovering this defense strategy now, these droplets were first discovered more than 130 years ago, and they are present in all types of eukaryotic cells, according to the commentary.

"There is great and justifiable excitement regarding the functions of LDs and other membraneless organelles," and how they change in many cellular processes, Douglas Green, the chair of the immunology department at St. Jude Children's Research Hospital in Tennessee, wrote in the accompanying commentary. "We have much to learn about these drops of oil in cells."

Originally published on Live Science.

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The body fires 'blobs of fat' packed with toxic proteins to fight bacteria - Live Science

A microscope photograph of a heart muscle cell. The regular green patterns show stained actin filaments.

By Tina Hilding, Voiland College of Engineering and Architecture

It might look like a little game at the molecular scale.

Filament-like proteins in heart muscle cells have to be exactly the same length so that they can coordinate perfectly to make the heart beat.

Another protein decides when the filament is the right size and puts a wee little cap on it. But, if that protein makes a mistake and puts the cap on too early, another protein, leiomodin, comes along and knocks the cap out of the way.

This little dance at the molecular scale might sound insignificant, but it plays a critical role in the development of healthy heart and other muscles. Reporting in the journal, Plos Biology,a WSU research team has proven for the first time how the mechanism works.

The finding could someday lead to improved diagnostics and medical treatments for serious and sometimes devastating hereditary heart conditions that come about from genetic mutations in the proteins. One of these conditions, cardiomyopathy, affects as many as one in 500 people around the world and can often be fatal or have lifetime health consequences. A similar condition called nemaline myopathy affects skeletal muscles throughout the body with often devastating consequences.

Mutations in these proteins are found in patients with myopathy, saidAlla Kostyukova, associate professor in the Gene and LindaVoiland School of Chemical Engineering and Bioengineeringand leader of the project. Our work is to prove that these mutations cause these problems and to propose strategies for treatment.

Heart muscle is made of tiny thick and thin filaments of proteins. With the help of electrical signals, the rope-like filaments bind and unbind in an intricate and precise architecture, allowing heart muscle to contract and beat.

The thin filaments are made of actin, the most abundant protein in the human body. Tropomysin, another protein, wraps itself around the actin filaments. Tropomyosin together with two other proteins, tropomodulin and leiomodin, at the end of the actin filaments act as a sort of cap and determine the filament length.

Its beautifully designed, said Kostyukova, whose research is focused on understanding protein structures.

And, tightly regulated.

To keep heart muscle healthy, the actin filaments, which are about a micron long, all have to be the exact same length. In families with cardiomyopathy, genetic mutations result in formation of filaments that are either too short or too long. Those affected can have significant heart problems that cause disability, illness and death.

In a project that spanned seven years, the researchers proved that leiomodin attaches to the end of the actin filament and kicks out the other protein, tropomodulin, to assure the actin filaments proper length.

This is the first time that this has been shown with the atomic-level precision, said Dmitri Tolkatchev, research assistant professor in the Voiland School and lead author on the paper. Previously, several laboratories attempted to solve this problem with very little success. With our data we finally have a direct proof.

The researchers used state-of-the-art approaches to make the key proteins and study them at the molecular and cellular level. The work entailed designing the molecules, constructing them at the gene level in a plasmid, and then producing them into bacterial or cardiac cells. The researchers used nuclear magnetic resonance, which works on the same physical principle as Magnetic Resonance Imaging (MRIs), to understand the proteins binding at the atomic level. They also used molecular dynamic simulation to model them.

The probability of being able to show this mechanism was not high, but the impact of the discovery is, said Tolkatchev, an expert in nuclear magnetic resonance. This was a very important problem to study and could have a significant impact in the field of muscle mechanics.

The researchers hope to continue the work, identifying additional components and molecular mechanisms that regulate thin filament architecture, whether diseased or healthy.

The multidisciplinary group included researchers from the University of Arizona led by Carol Gregorio, director of the Cellular and Molecular Medicine Department. WSUs group has expertise in protein structure, structural biochemistry, and properties of actin filaments and regulatory proteins, and UAs group has expertise in molecular, cellular and developmental biology of muscle assembly. The collaborative work was funded by the National Institutes of Health.

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Study shows a molecular dance that keeps your heart beating - WSU News

Evgenia Shishkova, assistant staff scientist from the Coon Lab. Credit: Morgridge Institute for Research

While most COVID-19 cases are asymptomatic or mild, severe complications associated with acute respiratory distress have led to more than one million deaths worldwide in just several months.

Researchers from the Morgridge Institute for Research, the University of Wisconsin-Madison, and Albany Medical College sought to better understand the molecular factors that drive the severity of COVID-19, and offer insight into treatment options for those with advanced disease.

The collaborative study published online in Cell Systems identified more than 200 molecular features that strongly correlate with COVID-19 severity.

To my knowledge, this the largest outcome study, says Dr. Ariel Jaitovich, a pulmonary and critical care physician at Albany Medical Center. I know that there are some large studies focused on the diagnostics (infected versus non-infected). We have a large group of just COVID patients, but with a very granular difference in terms of severitythat is something that I hadnt seen.

The team analyzed 102 blood samples from patients diagnosed with COVID-19, and 26 samples from patients with acute respiratory distress syndrome (ARDS) but negative for COVID-19 as controls.

I felt like we had a unique opportunity with Ariels cohort that he had recruited. It was very early in the COVID epidemic here in the United States, so he was really out on the forefront of getting these types of samples from the clinic, says Josh Coon, Morgridge metabolism investigator and professor of biomolecular chemistry at the UW-Madison School of Medicine and Public Health.

Using methods in mass spectrometry, RNA sequencing, and machine learning, the researchers explored a database of more than 17,000 different proteins, metabolites, lipids, and RNA transcripts associated with clinical outcomes.

They identified 219 molecules and genes that influence blood coagulation, vessel damage, inflammation, and other biological process reported to play a role in severe disease.

We had to think hard about how to actually compare it to the existing data, says Ron Stewart, Morgridge investigator and associate director of bioinformatics whose team was tasked with analyzing the transcriptome data. What weve largely found is we recapitulated prior work, which is good.

One particularly unique aspect to the study, which contributed to the robust dataset, was the teams use of plasma samples.

Most of the research done in proteomics, the blood samples use the serum fraction that doesnt have the clotting factors, says Jaitovich. This is very important because patients with COVID-19 have accelerated clotting activity.

A metabolite called citrate is used as a therapeutic anticoagulant to decrease the likelihood of developing clotting. Yet the study revealed that the presence of metabolic citrate decreased as patients presented with more severe illness.

The fact that citrate is reduced in these patients will potentially indicate that the reduction facilitates the hypercoagulation phenotype that we found in these patients, says Jaitovich.

Another molecule possibly contributing to hypercoagulation in severe COVID-19 is a protein called gelsolin, which is normally released as a response to inflammation due to cellular injury or infection. Gelsolin was also reduced in the plasma samples from people with severe disease.

In addition to biomarkers associated with hypercoagulation, the team also identified a cluster of proteins involved with blood vessel damage, with higher abundance in severe COVID-19 samples.

There are all these factors upstream of the process that are actually being changed, that you need to address as much as just the process of clotting in order to manage this phenotype, says Evgenia Shishkova, assistant staff scientist in the Coon Lab.

The analysis also revealed increased levels of proteins and upregulated genes involved in neutrophil degranulation, which has been associated inflammation, thrombosis, and the development of ARDS.

So it seems like theres this really strong interplay between the inflammatory response and probably these thrombotic events, which are also being seen in the COVID patients, saysKatie Overmyer, associate director of theLaboratory for Biomolecular Mass Spectrometry at UW-Madison.

Finally, the multi-omic analysis revealed a network of high-density lipoproteinsthe proteins APOA1 and APOA2, and a group of lipids known as plasmalogens which act as antioxidants were all lower in the severe COVID-19 cases.

These aspects were not on our radar, says Jaitovich. The ability to merge these dimensions in one single unifying narrative allowed us to make sense of stuff that was completely obscured to us.

And by identifying these various molecules, it opens up the potential for developing targeted therapeutics that may help alleviate disease.

We can offer hard data for people who are specialists in all these different areas to go and maybe learn about the prospects that what theyre thinking might have an impact on COVID, says Coon.

The researchers made the data publicly available through an interactive web tool, covid-omics.app, where the scientific community has been comparing and analyzing the data along with their own workflows.

Coon adds, I think weve tried to do our best to highlight vignettes that we think are important, but the bigger impact is probably going to come from the community being able to dig into this.

Reference: Large-scale Multi-omic Analysis of COVID-19 Severity by Katherine A Overmyer, Evgenia Shishkova, Ian Miller, Joseph Balnis, Matthew N. Bernstein, Trenton M. Peters-Clarke, Jesse G. Meyer, Qiuwen Quan, Laura K. Muehlbauer, Edna A. Trujillo, Yuchen He, Amit Chopra, Hau Chieng, Anupama Tiwari, Marc A. Judson, Brett Paulson, Dain R. Brademan, Yunyun Zhu, Lia R. Serrano, Vanessa Linke, Lisa A. Drake, Alejandro P. Adam, Bradford S. Schwartz, Harold A. Singer, Scott Swanson, Deane F. Mosher, Ron Stewart, Joshua J. Coon and Ariel Jaitovich, Accepted 5 October 2020, Cell Systems.DOI: 10.1016/j.cels.2020.10.003

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Researchers Unravel the Network of Molecules That Influence COVID-19 Severity - SciTechDaily

In May, PhD students who are funded by the Medical Research Council (MRC) were invited to enter the Max Perutz science writing award 2020 and to tell the general public why your research matters. From the many entries received, the 10 that made the shortlist covered diverse topics, including motor neurone disease, self-harm, babies experiences of pain, and bone loss resulting from space travel.

The essays were judged by the Observers Ian Tucker, the Science Museums Roger Highfield, Prof Fiona Watt from the MRC, Bristol Universitys Andy Ridgeway and the journalist and broadcaster Samira Ahmed.

At a virtual ceremony last Tuesday, the 1,500 prize was presented to the winner, Sarah Taylor from the MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh for her article about her research into the influence of proteins on the effectiveness of chemotherapy.

Here we publish the winning article, described by Samira Ahmed as a terrifically told and intriguing story.

She sits in the small consulting room once again, waiting to hear the news of her latest scan. It has been a difficult journey since the last time she sat in this chair, before her most recent round of treatment began. Over a month of exhaustion, vomiting, soreness, sleepless nights and the inevitable hair loss. But this time, the chemotherapy has not been successful. After all the side effects, all the pain that she has endured, her tumour is still growing, a dark mass on her ovary. Where does she go from here? What can she do when the treatment shes pinned all her hopes on just stops working?

This situation is all too common for women with high grade serous ovarian cancer (HGSOC), a devastating form of ovarian cancer. Only 35% survive longer than five years following their diagnosis. While chemotherapy and surgery are highly effective at initially shrinking tumours, the cancer continues to fight back. Over time the tumour changes, with cells that survive treatment prevailing and replicating, passing on the protective traits that give them that survival edge. The tumour becomes completely resistant to chemotherapy, and no barrier remains to stop it from growing out of control and overwhelming the body.

However, there are groups of patients whose cancers are much more sensitive to chemotherapy treatment than others, who can be completely cured by chemotherapy. One key to this is DNA repair proteins, the tools that all cells use to protect their DNA from damage. Think of this DNA as the instruction manual for a cell, detailing how to build all the proteins the cell requires to live and carry out different functions. Cancer cells often have defective DNA repair proteins, as this allows them to adapt and grow rapidly. Strange as it may sound, this can be a good thing from our perspective! Chemotherapy kills cancer cells by attacking their DNA, and those which lack DNA repair proteins essentially forgot to bring a first aid kit they cannot fix themselves up and keep going. This means that the chemotherapy can completely kill off the cancer, so the patient will survive. This reveals gaps in the armour of this cancer, which we can exploit to help the women who need it most.

No two cancers are quite the same, even within a specific type like HGSOC. Some have completely functional DNA repair proteins. Some have defective proteins initially but can adapt and fix these. Others can make excessive amounts of the proteins to combat the effects of chemotherapy and survive. I hope that by learning what happens to these proteins as a cancer cell becomes resistant to chemotherapy, I can make new drugs to prevent the crucial DNA repair proteins from functioning, which will enable the chemotherapy to kill cancer cells more effectively.

The first question that I asked was which, if any, of these proteins are actually important for the way HGSOC reacts to chemotherapy. I used cells taken from HGSOC patient tumours and adapted to grow easily in the lab, called cell lines, which have similar properties to an actual tumour in a patient. By using cell lines taken from a selection of patient tumours, scientists can build up a picture of the similarities and differences between patient tumours. I started by assessing the growth of various cell lines when treated with a drug called carboplatin, the standard chemotherapy used to treat HGSOC. The slower the cells grow, the more effective it is as a treatment. I found that there was a lot of variation in sensitivity to carboplatin between the different cell lines unsurprising really since one of the main challenges in cancer research is how many differences there are between individuals tumours, and even between different parts of the same tumour.

Next, I set out to find the reason for these differences, looking for changes in the DNA repair proteins. I studied a database of ovarian cancer patients looking for clues on what could be going on, and found that it is common for the tumour cells to produce either abnormally high or low amounts of certain DNA repair proteins. So, I decided to measure the amount of repair proteins produced by my cell lines. I found that in the cell line that was most sensitive to chemotherapy, one of these repair proteins was almost entirely missing! This is a really good indicator that this protein could be an important factor behind repairing the damage caused by chemotherapy.

So, I had identified a protein potentially involved in chemotherapy effectiveness. What next? I wanted to confirm that this protein acts in the way I suspected within the cancer cells. I blocked the cell lines from producing the protein I was interested in, and again looked to see how sensitive to chemotherapy the cancer cells were. This confirmed my initial suspicions removing the protein made the cancer cells much more susceptible to chemotherapy!

As I am only in my first year of working on this project, there is still much to be done, but this is an exciting starting point. I certainly find it very exciting! I plan to study the mechanism used by these cancer cells to alter the amount of this repair protein, and see how smart the cancer cells are are they cheating the chemotherapy by producing more of this protein to prevent the cells from being killed? Does this result in a chemotherapy-resistant tumour? Most importantly, I would like to identify patients whose cancers have high levels of this repair protein, for whom conventional chemotherapy might be less effective, and focus on how I can help them. To tackle this problem, I would like to test drugs that block this protein from carrying out DNA damage repair, leaving the cancer powerless, unable to repair the damage inflicted by chemotherapy. My dream is that one day this will help more women to leave that consulting room feeling victorious, having beaten the odds, and able to shut the door for good on their way out.

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Curing the incurable: teaching an old drug new tricks to fight ovarian cancer - The Guardian

Invitae CEO Sean George joins Yahoo Finances on the move to talk about how Invitae is bringing genetic testing and information into mainstream discussions.

JULIE HYMAN: Im watching shares of Invitae, which have just about tripled this year. We are joined now by the CEO, Sean George, from San Francisco. Sean, thanks for joining us. You guys do diagnostic testing and you dont do it for COVID specifically, but you do it for a host of other diseases. And weve obviously seen COVID-19 testing really expand. You can drive up and get it in places. There are now going to be at-home tests that are going to be introduced. Do you think that this then gets people more comfortable with testing for a range of different diseases? Or are you hoping that it does?

SEAN GEORGE: Well, I think it does. And I think in general, trend of the last decade or so is people are starting to understand that this diagnostic information is very useful in advance of when theres an actual problem. Obviously, people are now getting very familiar with COVID testing, what it could have done prior to, and certainly during an outbreak and to manage it.

And when you think about how fundamental in an individuals genomic information is for their health, the idea is starting to catch hold with more and more people, especially generalists, and the idea that genetic information used at the right time, ahead of time, at every stage in life, has profound implications on an individuals health.

ADAM SHAPIRO: So these kinds of tests, we keep hearing in relation to COVID, the issue of false positives. But putting that to the side, in the traditional diagnostic models, whats an accepted, if there is, metric, for when youre going to get a false positive or false negative? How does the industry deal with that issue?

SEAN GEORGE: Right, and especially in medical genetics, that threshold is very, very, very, very tight. Its exacting on 99 and a few nines of how the percentage of sensitivity and specificity these tests need to have because of the profound implications of genetics. Whether its dealing with cancer, cardiovascular disorders, pediatric disorders, battling cancer as 45 million people are per year in the markets we serve, and to answer those fundamental questions and then take concrete medical next steps. The sensitivity specificity, the precision of the tests need to be extraordinarily high.

Story continues

BRIAN CHEUNG: Hey, Sean, Brian Cheung here. So for those that maybe arent that well versed in this type of science, explain to us exactly where you fit in the business world of things that might be tangentially related to genetic testing. I mean, do you guys work with say CRISPR firms or types of, I guess, diagnostic or treatment relative to businesses in that space? Where does your business fit in that universe?

SEAN GEORGE: I think the way to think about it, the people who, certainly anybody who has had an introduction or a brush with genetics and the health care, their clinician, were the number one brand in medical genetics around the globe. Their clinician certainly knows us and has been working with us for many years. And again, whether thats to diagnose any number of 1,000 rare disorders, to help an individual understand their prognosis and next best steps for cancer treatment.

Certainly around reproductive health. You may have heard carrier screening or non-invasive prenatal screening. Those are the kind of tests that we do. And we primarily do it with your clinician. Certainly up until now, mostly the specialists of the world, the medical genetics, the various conditions. Like I said, there are thousands. Ever increasingly, as we have dramatically driven down the price of the, weve driven down the cost of this testing by almost two orders of magnitude over the last 10 years.

And ever increasingly, generalists are starting to use this information. Theyre becoming more comfortable with it. We have tools and front end capabilities to allow clinicians to use the information without the deepest of knowledge around each individual gene, around each individual condition. And have tools online to follow the patients, follow up on their results, make sure they understand what the next best step is, and really support the clinician, the patient with the use of genetics in mainstream medical care.

JULIE HYMAN: And Sean, when were talking about genetics testing, is it mostly probability testing, particularly for cancers when you talk about carrier testing that youre at X percent risk for developing a certain disorder? Or is genetics testing also increasingly being used for actual diagnosis?

SEAN GEORGE: The kind of testing we specialize, the kind of testing put into play by most clinicians, medical geneticists, is a little more precise than just a very slight probability increase over average risk. These are, carrier screens, you mentioned, this will tell you whether you and your partner are carrying different conditions. It will tell you what are the odds specifically of having a child who might be affected by the condition. Or if you were to have a child, what would the odds be.

Ill take, for example, some of the cardiovascular diseases or cancer genetic diseases. If you have some of these genes that are affected, your risk is 30 to 80 times the population average risk of these conditions. So its quite prognostic. Now like I said, when you do get an answer, it really helps to diagnose the condition far earlier than you would otherwise be able to without the use of genetics.

And then depending on the disease, there are a variety of next steps, all the way from preventive approaches to therapies. And we work with over 100 biopharmaceutical partners too, who have therapies that are specifically targeted against genetic conditions that we can introduce our patients to as early as possible.

JULIA LA ROCHE: Sean, this is such a fascinating discussion, what youve been bringing up, and youre talking about the next best action. And its such an interesting way to look at health care, especially looking at it from preventative as well, or even just having a better understanding of your genetics and what it could mean or what the outcomes can be. I guess for you, if we could just kind of step back, what is the moonshot for you when it comes to your business and the broader health care system?

SEAN GEORGE: And in fact, were kind of, Im not sure at what inning we are in of that moonshot, I think its probably early, first or second. But the real idea, and when we founded the company, it was a simple idea. Genetics is so impactful for health care on an individual basis, yet is sparingly used at all in modern health care around the globe. The moonshot is really to have an individuals genome available, managed on their behalf, so that information can be put into play at the right point, at the right time, with all of the people around them that can help put that information to use for their health.

So for example, upon birth. 3% of live births end up in the NICU or the PICU because of genetic conditions. Having that information instantaneously would dramatically improve the outcome of the children in that situation. Some 20% to 30% of populations primary health care complaint over their lives will be genetic in nature.

Knowing that ahead of time instead of after years and years and years of symptoms kind of popping up and then getting worse over time and finally getting diagnosed, knowing ahead of time can greatly improve the preventive measures taken. I think we will in five to 10 years, we will look back in horror thinking that women had children, started families without accessing the fundamental genetic information that can introduce so much risk along the way, either for the women themselves during carrying to term, and then certainly upon delivery.

And I think cancer is another example. Its one of the more advanced conditions when considering molecular medicine. I think again, in 10 years well look back, and the idea that we didnt access the fundamental information about a persons genetic background and the genomics of the cancer itself to precision tailor treatment to them, I think well look back and wonder why we didnt do it faster.

But again, a big problem with that has been cost in the past, and weve taken care of that and are continuing to work on it. So I think across all stages in life, were about to see here in the next decade this genetic information to be used almost as a medical utility. Again, and our aim is, the moonshot is to across all stages of life, all the way from birth until youre dealing with aging and senescence.

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Invitae CEO on how COVID-19 testing could have a positive impact on the future of genetics testing - Report Door

(UroToday.com) While cisplatin-based chemotherapy is a mainstay for neoadjuvant and adjuvant treatment of patients with muscle-invasive bladder cancer (MIBC), and none of the reported biomarkers for predicting response have been implemented in the clinic thus far.

Dr. Ann Taber presented data from researchers at the Aarhus University Hospital, Denmark, where they performed comprehensive genomic, transcriptomic, epigenomic, and proteomic analysis of 300 MIBC patients treated with cisplatin-based chemotherapy to identify molecular changes associated with treatment response. Based on mutational signatures, they identified two patient groups: those characterized by mutations in a tri-nucleotide signature 5 context (SBS5) that are related to ERCC2 mutations, and those related to APOBEC mutations.

Expression data identified the basal/squamous gene expression subtype to be associated with poor cisplatin-based treatment response. Immune cell infiltration and high PD-1 protein expression was also significantly associated with treatment response; they identified a unique subset that corresponds to an immune desert, which was associated with poor treatment response (Figure 1).

Figure 1: Association of immune cell infiltration and cisplatin-based treatment response.

The authors then assigned patients to high and low genomic instability groups based on SBS5 mutations, indels, allelic imbalance and BRCA2 mutation status. Patients with high genomic instability had a response rate of 71% versus 49% for patients with low genomic instability (p = 0.007). Through further integration, they identified a group of patients with a very high response rate (80%) characterized by high genomic instability and non-basal/squamous gene expression subtype and a group of patients with a very low response rate (25%) characterized by low genomic instability and basal/squamous gene expression subtype (p<0.001, Figure 2).

Figure 2: Patient subclassification based on genomic instability and basal/squamous gene expression subtype.

The results highlight several molecular correlates of chemotherapy response. These findings are now the basis of a new clinical trial for the treatment of metastatic bladder cancer following radical cystectomy.1

Presented by: Ann Taber, Ph.D., Department of Molecular Medicine (MOMA), Aarhus University Hospital, Denmark.

Written by:Anirban P. Mitra, MD, Ph.D., Urologic Oncology Fellow, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter: @APMitra, with Ashish M. Kamat, MD, MBBS, President of IBCN and IBCG, Endowed Professor, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter:@UroDocAsh,at the International Bladder Cancer Network (IBCN) Annual Meeting, #IBCN2020, October 17, 2020.

References:1. Treatment Of Metastatic Bladder Cancer at the Time Of Biochemical reLApse Following Radical Cystectomy (TOMBOLA). ClinicalTrials.gov identifier NCT04138628.

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IBCN 2020: IBCN 2020: Molecular Correlates of Cisplatin-Based Chemotherapy Response In Muscle-Invasive Blad... - UroToday

NEW YORK--(BUSINESS WIRE)-- The Canadian Cancer Trials Group (CCTG) today announced the commencement of a new sub-study evaluating CFI-400945, an oral, first-in-class inhibitor of Polo-like Kinase 4 (PLK4), in patients with metastatic castrate-resistant prostate cancer (mCRPC).

We are very excited to see the initiation of this trial, that builds on preclinical work demonstrating an association between loss of the tumor suppressor PTEN, a common alteration in this disease setting, and response to CFI-400945, says Dr. Mark Bray, Treadwell Chief Scientific Officer and Co-Founder.

This is the first trial that evaluates a precision medicine approach for patients with advanced prostate cancer using liquid biopsies for genomic testing. This innovative trial design, which incorporates liquid biopsy-based biomarker evaluation, helps meet the urgent need to identify more effective therapies for men with advanced prostate cancer, said Dr. Lesley Seymour, CCTGs Director, Investigational New Drug Program and a Medical Oncologist in the Department of Oncology at Queens University.

The study is supported by the Canadian Cancer Society, Prostate Cancer Canada and the Movember Foundation through a Translation Acceleration Grant to Tak Mak (The Princess Margaret Cancer Centre), the Canadian Clinical Trials Group and a team of co-investigators from across Canada.

Our understanding of the molecular drivers of prostate cancer is increasing, and for some of these molecular variations we have few therapeutic options, says the trail study chair Dr. Aaron R. Hansen, GU Medical Oncology Site Lead Division of Medical Oncology at Princess Margaret Cancer Center. The innovative trial design of IND234 will match men with metastatic castration resistant prostate cancer with agents designed to target their specific molecular abnormalities, in order to improve their outcomes.

This sub-study is part of the IND.234 - Prostate Cancer Biomarker Enrichment and Treatment Selection (PC-BETS) Study. The primary endpoint is clinical benefit rate defined as proportion of patients who had PSA decline 50%, complete or partial objective response, or stable disease for 12 weeks.

The CCTG IND234 trial will be open at sites across Canada, for a full list of participating centers and for additional information about the study, please visit http://www.clinicaltrials.gov.

About CFI-400945

CFI-400945 is a first-in-class, oral selective and potent inhibitor of Polo-like Kinase 4 (PLK4), which regulates centriole duplication and thus mitotic progression. PLK4 is overexpressed in a variety of solid tumors and elevated expression is associated with poor clinical outcomes. Depletion of PLK4 expression in cancer cells by RNA interference leads to mitotic defects and cell death. PLK4 was identified as a drug target based on functional screening to identify vulnerabilities of genomically unstable breast cancers.

Anti-tumor activity of CFI-400945 has been shown in mice bearing human cancer xenografts, including robust tumor growth inhibition and durable tumor regression in primary tumor xenografts from breast cancer.

About Treadwell Therapeutics

Treadwell Therapeutics is a clinical-stage oncology company exploiting cancer cells vulnerabilities to develop first-in-class and best-in-class small molecules to address unmet needs in patients with cancer.

The Companys robust, internally developed pipeline includes a first-in-class PLK4 kinase inhibitor, CFI-400945 and a potentially best in class TTK inhibitor, CFI-402257 in Phase 2 studies, and CFI-402411, an oral immunomodulatory kinase inhibitor with activity toward HPK1, in Phase 1/2 studies. For more information, please visit http://www.treadwelltx.com.

About Canadian Cancer Trials Group (CCTG)

Celebrating its 40th year, the Canadian Cancer Trials Group (CCTG) is a cancer clinical trials research cooperative that runs phase I-III trials to test anti-cancer and supportive therapies in over 80 institutions across Canada and internationally. From its operations centre at Queens University, CCTG has led and participated in over 500 trials in over 40 countries aimed at improving survival and quality of life for all people with cancer. CCTG is a national program of the Canadian Cancer Society that provides core funding for the Group. To learn more about the CCTG, go to http://www.cctg.ca

View source version on businesswire.com: https://www.businesswire.com/news/home/20201019005662/en/

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Treadwell Announces Initiation of New Clinical Trial of CFI-400945 in Patients with Metastatic Castrate-Resistant Prostate Cancer (mCRPC) - BioSpace

In summary

Proposition 14 asks voters to spend nearly $8 billion to continue the stem cell research program at a time when the coronavirus pandemic has decimated the state budget.

For the second time in 16 years, California voters will decide the fate of the states multi-billion dollar stem cell research program that established the state as a worldwide leader.

How the times have changed.

In November, as the pandemic drags on, Proposition 14 asks voters to spend nearly $8 billion to continue the program during a period when the research environment has significantly evolved and coronavirus has battered the states budget.

The bond measure would approve $5.5 billion in bonds to keep the states stem cell research agency running and grants flowing to California universities and companies.

At least $1.5 billion would be earmarked for brain and central nervous system diseases like Alzheimers and Parkinsons. The overall cost of the bonds and their interest totals about $7.8 billion, according to the state legislative analyst. The state would pay about $260 million annually for 30 years, or about 1 percent of Californias annual budget.

Proposition 14 is essentially a repeat with a bigger price tag and a few tweaks of Proposition 71, which California voters approved in 2004 after then-President George W. Bush prohibited, on religious grounds, all federal funding of any stem cell research using human embryos.

The bond measure would approve $5.5 billion in bonds to keep the states stem cell research agency running and grants flowing to California universities and companies.

That groundbreaking measure authorized $3 billion in state bonds to create the states stem cell research agency, the California Institute for Regenerative Medicine, and fund grants for research into treatments for Alzheimers disease, cancer, spinal cord injuries and other diseases.

The institute has nearly used up its original funding, so Prop. 71s author, real estate investor and attorney Robert N. Klein II, led a new effort to get Prop. 14 on the November ballot.

This time, embryonic stem cell research is in a much different place, with federal funding no longer blocked and more funding from the biotech industry.

Voters will want to consider what Californias previous investment in stem cell research has accomplished. Its a nuanced track record.

While many scientific experts agree that Prop 71 was a bold social innovation that successfully bolstered emerging stem cell research, some critics argue that the institutes grantmaking was plagued by conflicts of interest and did not live up to the promises of miracle cures that Prop. 71s supporters made years ago. Although the agency is funded with state money, its overseen by its own board and not by the California governor or lawmakers.

The agency had done a very good job of setting priorities for stem cell research, including research using human embryos, and doling out $300 million annually to build up California as a regenerative medicine powerhouse, according to a 2013 evaluation by the National Academies of Science, Engineering and Medicine.

But the report also found that because the institutes board is made up of scientists from universities and biotech firms likely to apply for grants, board members had almost unavoidable conflicts of interest.

Because human stem cells can develop into many types of cells, including blood, brain, nerve and muscle cells, scientists have long looked to them for potential treatments for currently incurable diseases and injuries. Researchers use two types of stem cells: embryonic stem cells, derived from unused human embryos created through in vitro fertilization, and adult stem cells, which are harder to work with but in some cases can be coaxed in a lab into behaving more like embryonic stem cells.

From the start, stem cell research has been ethically charged and politically controversial because human embryos are destroyed in some types of studies. Federal restrictions on the research have waxed and waned, depending on which political party holds power. While former President Bush restricted federal money for embryonic stem cell research, former President Obama removed those restrictions.

The Trump administration has restricted government research involving fetal tissue but not embryonic stem cells. However, anti-abortion lawmakers have called on the President to once again end federal funding for embryonic stem cell research.

California-funded research has led to one stem cell treatment for a form of Severe Combined Immunodeficiency known as the bubble baby disease. Children with the rare disease dont make enough of a key enzyme needed for a normal immune system. Without treatment, they can die from the disease if not kept in a protective environment. The U.S. Food and Drug Administration is now reviewing the treatment but has not yet approved it for widespread use.

Although many of the agencys early grants were for basic science, the institute also has supported 64 clinical trials of treatments for many types of cancer, sickle cell disease, spinal cord injuries, diabetes, kidney disease and amyotrophic lateral sclerosis, commonlyknown as Lou Gehrigs disease.

A June 2020 analysis by University of Southern California health policy researchers estimated that taxpayers initial $3 billion investment in the research institute helped create more than 50,000 jobs and generated $10 billion for the states economy.

Gov. Gavin Newsom has endorsed Proposition 14, and other supporters include the Regents of the University of California, the California Democratic Party, the Juvenile Diabetes Research Foundation, patient advocacy groups like the March of Dimes, and some local politicians and chambers of commerce.

Supporters have raised more than $8.5 million, including about $2 million from billionaire Dagmar Dolby, to pass the measure, according to California Secretary of State campaign finance reports.

The passage of Proposition 71 helped save my life, Sandra Dillon, a blood cancer patient, wrote in a San Diego Union-Tribune commentary supporting Proposition 14. She wrote that she had benefited from a drug developed with Institute-funded research that has been designated by the FDA as a breakthrough therapy.

It is unimaginable to think that Californians would vote to discontinue this amazing effort I dont know where I would be or what condition I would be in if it wasnt for the investment Californians made nearly two decades ago.

I think the agencys done good work, but this was never planned to be funded forever with debt.

Lawrence Goldstein, a UC San Diego professor of cellular and molecular medicine and stem cell researcher, said the grants were instrumental in furthering his research on treatments for Alzheimers disease and that Prop. 14 will help create new jobs. The agency has funded a great deal of very important stem cell medical research thats already produced terrific results and has the prospect of saving many more lives in the decade to come, he said.

Opponents include one member of the institutes board and a nonprofit that advocates for privacy in genetic research. They contend that the proposition seeks too much money and does not sufficiently address the conflicts of interest that cropped up after Prop. 71 was passed. They also note that private funding, including venture capital, for stem cell research has grown in recent years. Opponents had raised only $250 by late September, from a single contribution by the California Pro Life Council.

The editorial boards of some of Californias biggest newspapers also have opposed the measure, including the Los Angeles Times, the Orange County Register, the San Francisco Chronicle and the San Jose Mercury News/East Bay Times. The Fresno Bee, Modesto Bee, and San Luis Obispo Tribune newspaper editorial boards support Prop 14.

Jeff Sheehy, the only institute board member not to support Proposition 14, told CalMatters that the research environment has changed since voters initially approved state funding for stem cell research in 2004 and that California should prioritize other needs like education, health care, and housing.

I think the agencys done good work, but this was never planned to be funded forever with debt, Sheehy said. At this point the state cant afford it; were looking at a huge deficit.

Read more here:

Prop. 14: In the COVID age, can California still afford its stem cell research program? - CALmatters

Cancer immune plays a critical role in cancer progression. Tumour immunology and immunotherapy are one of the exciting areas in bladder cancer research. In this study, we aimed to develop an immune-related gene signature to improve the prognostic prediction of bladder cancer. Firstly, we identified 392 differentially expressed immune-related genes (IRGs) based on TCGA and ImmPort databases. Functional enrichment analysis revealed that these genes were enriched in inflammatory and immune-related pathways, including in 'regulation of signaling receptor activity', 'cytokine-cytokine receptor interaction' and 'GPCR ligand binding'. Then, we separated all samples in TCGA data set into the training cohort and the testing cohort in a ratio of 3:1 randomly. Data set GSE13507 was set as the validation cohort. We constructed a prognostic six-IRG signature with LASSO Cox regression in the training cohort, including AHNAK, OAS1, APOBEC3H, SCG2, CTSE and KIR2DS4. Six IRGs reflected the microenvironment of bladder cancer, especially immune cell infiltration. The prognostic value of six-IRG signature was further validated in the testing cohort and the validation cohort. The results of multivariable Cox regression and subgroup analysis revealed that six-IRG signature was a clinically independent prognostic factor for bladder cancer patients. Further, we constructed a nomogram based on six-IRG signature and other clinicopathological risk factors, and it performed well in predict patients' survival. Finally, we found six-IRG signature showed significant difference in different molecular subtypes of bladder cancer. In conclusions, our research provided a novel immune-related gene signature to estimate prognosis for patients' survival with bladder cancer.

Journal of cellular and molecular medicine. 2020 Oct 13 [Epub ahead of print]

Yongwen Luo, Liang Chen, Qiang Zhou, Yaoyi Xiong, Gang Wang, Xuefeng Liu, Yu Xiao, Lingao Ju, Xinghua Wang

Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China., Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China., Department of Pathology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Washington, DC, USA.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/33048468

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Identification of a prognostic gene signature based on an immunogenomic landscape analysis of bladder cancer. - UroToday

Dr. Paul Offit, a professor at the University of Pennsylvania and a member of the F.D.A.s vaccine advisory panel, said that pausing a trial is a huge logistical challenge especially for one like Johnson & Johnsons, with plans for 60,000 volunteers in 10 countries.

Its this big warship that you just stop moving, Dr. Offit said.

Once a trial is paused, a safety board may ask for a volunteer who experienced an adverse event to be unblinded in other words, to find out if the volunteer got the placebo or the treatment. If the volunteer received a placebo, then the treatment cant be the cause of the event and the trial can continue.

If it turns out that the volunteer got the treatment, the board does a flurry of detective work. The members look over the medical records. They may ask for more information about volunteers health or even order new tests not just for the people who experienced adverse events, but for everyone in the trial.

The board uses this evidence to come to a conclusion about whether the treatment most likely had anything to do with the event. On very rare occasions, for example, some vaccines can cause a nerve disorder called Guillain-Barr syndrome. But the condition takes weeks to develop. If a volunteer shows signs of Guillain-Barr syndrome on the day of a vaccine injection, it cant be the cause.

Regulators then review the decision of these boards and may accept it or ask for more information. For trials that are running in several countries at once, this review can make pausing a trial even more of a challenge. After AstraZeneca paused its global trials on Sept. 6 for a review, regulators in Brazil, India, Japan, South Africa and the United Kingdom all gave the green light for the trial to resume. But American regulators are still keeping the U.S. trial on pause as they continue to look over the evidence.

If a safety board rules that an adverse event most likely was not a result of the vaccine or treatment, it may allow the trial to start up again. If, on the other hand, theres some urgent problem a contaminated batch of drugs, for example the trial may have to stop. When the evidence isnt so clear, the board may let the trial resume with extra tests or exams. A second case of the same event might be more common than you would expect from chance, forcing the trial to end.

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3 Covid-19 Trials Have Been Paused for Safety. Thats a Good Thing. - The New York Times

Meseret Derbew Molla,1 Yonas Akalu,2 Zeleke Geto,3 Baye Dagnew,2 Birhanu Ayelign,4 Tewodros Shibabaw1

1Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 2Department of Human Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia; 3Department of Biomedical Sciences, School of Medicine, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia; 4Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia

Correspondence: Meseret Derbew MollaDepartment of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, PO Box 196, Gondar, Ethiopia, Tel +251918331617Email messidrm19@gmail.com

Abstract: Caspase-1 is the first and extensively studied inflammatory caspase that is activated through inflammasome assembly. Inflammasome is a cytosolic formation of multiprotein complex that aimed to start inflammatory response against infections or cellular damages. The process leads to an auto-activation of caspase-1 and consequent maturation of caspase-1 target molecules such as interleukin (IL)-1 and IL-18. Recently, the role of caspase-1 and inflammasome in inflammatory-induced noncommunicable diseases (NCDs) like obesity, diabetes mellitus (DM), cardiovascular diseases (CVDs), cancers and chronic respiratory diseases have widely studied. However, their reports are distinct and even they have reported contrasting role of caspase-1 in the development and progression of NCDs. A few studies have reported that caspase-1/inflammasome assembley has a protective role in the initiation and progression of these diseases through the activation of the noncanonical caspase-1 target substrates like gasdermin-D and regulation of immune cells. Conversely, others have revealed that caspase-1 has a direct/indirect effect in the development and progression of several NCDs. Therefore, in this review, we systematically summarized the role of caspase-1 in the development and progression of NCDs, especially in obesity, DM, CVDs and cancers.

Keywords: caspase-1, inflammasome, IL-1, IL-18, noncommunicable diseases

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Role of Caspase-1 in the Pathogenesis of Inflammatory-Associated Chron | JIR - Dove Medical Press