Posted: December 7, 2020 at 4:58 pm
BASKING RIDGE, N.J., Dec. 07, 2020 (GLOBE NEWSWIRE) -- electroCore, Inc. (Nasdaq: ECOR), a commercial-stage bioelectronic medicine company, announced today that management is scheduled to present at the 13th Annual LD Micro Main Event Conference.
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electroCore to Present at the 13th Annual LD Micro Main Event Conference
Posted: December 7, 2020 at 4:56 pm
Blood vessels are supposed to act like trees, pumping in oxygen tissues need to grow and immune cells required to clear out pathogens. But in tumors, the forest can go a bit haywire. Vessels grow prodigiously and bulge and twist at abrupt points, making it difficult to even tell whats a vein and whats an artery. It starts to look less like a forest and more like a gnarled root floor. A disorganized labyrinth, one oncologist has called it.
For cancer, chaos is a virtue. That gnarled root floor insulates solid tumors from immune cells and, in recent years, has flustered drug developers best attempts at developing therapies meant to rev up the immune system and direct it toward the tumors.
Researchers at the University of Pennsylvania, however, think they may have stumbled onto a solution, a way of whipping the blood vessels back into proper shape. If it works, experts say, it could pave the way for CAR-T treatments that attack solid tumors and potentially improve the effectiveness for more traditional approaches, such as radiation and chemotherapy.
Its a really novel and potentially important approach, Patrick Wen, a neuro-oncologist at Dana-Farber who was not involved in the work, told Endpoints News. They really did good work. This is a very different way of improving immunotherapy.
Yi Fan, a radiation oncologist at Penns School of Medicine, has been working for the last few years to understand why the labyrinth appears in the first place. Researchers had previously circled in on the so-called growth factors that stimulate blood vessel formation. Attempts to block these factors, though, disappointed; Avastin, an antibody against the factor VEGF, became a blockbuster but has continually failed to improve survival on a range of malignancies.
Scientists would have to go more fundamental. In a pair of 2018 papers, Fan showed that part of the problem is a process called endothelial cell transformation. Cells lining the blood vessels around the tumor acquire stem cell-like properties that allow them to reproduce and expand rapidly, as stem cells do.
Theres a genetic reprogramming, Fan told Endpoints. Theyll become really aggressive.
But how did that reprogramming happen? If Fan could pin down the pathway, he figured he could then devise a way to block it. He started knocking out kinases the cellular engines that can drive epigenetic change, or reprogramming one by one in endothelial cells isolated from patients with an aggressive brain cancer called glioblastoma. Out of 518, 35 prevented transformation and one did so particularly well: PAK4.
Then they injected tumors into mice, some who had PAK4 and some who had the kinase genetically removed: Eighty percent of the mice who had PAK4 removed lived for 60 days, while all of the wild-type mice died within 40. Fans team also showed that T cells infiltrated the tumors more easily in the PAK4-less mice.
It was a fortuitous finding: Drug companies had developed several PAK inhibitors a decade ago, when kinase inhibitors were the flashiest thing in pharma. Many had been abandoned, but Karyopharm had recently brought a PAK4 blocker into Phase I.
To see whether drug developers could exploit this finding, Fan and his team removed T cells from mice and developed a CAR-T therapy to attack the tumors.
They gave mice three different regimens. The CAR-T therapy on its own failed to reduce tumor size, apparently unable to reach through the vessels. The Karyopharm drug also had little effect on its own. But combined, they managed to reduce tumor size by 80% after five days. They published the results in Nature Cancer this week.
It is a really eye-opening result, Fan said. I think we see something really dramatic.
That, of course, is just in mice, but Fan already has strong supporting evidence for PAK4s role in cancer. Last December, while Fan was still completing his experiment, Nature Cancer published a paper from Antoni Ribas UCLA lab suggesting that PAK4 inhibitors can help T cells infiltrate around various solid tumors. They showed that the same Karyopharm inhibitor could boost the effects of PD-1 inhibitors in mice, allowing activated T cells to better reach tumors.
That work has already translated into the clinic; weeks after it came out, Karyopharm added an arm to their Phase I study of the drug that will look at the PAK4 inhibitor in combination with the PD-1 blocker Opdivo.
Ribas said that Fans work is compelling and helps confirm the role of PAK4, but he said a CAR-T therapy would face a much longer path to the clinic. Its simply much easier to combine an approved drug with an experimental one than to devise a new CAR-T therapy, mix it with the unapproved inhibitor (and all the other things, such as bone marrow-clearing chemotherapy, CAR-T recipients receive) and then deduce what effect each is having.
It will a take a while, Ribas told Endpoints. But I hope this is right and its developed clinically.
There are also other unresolved obstacles for CAR-T in solid tumors, Wen said. Developers still struggle to find targets that wont also send the super-charged T cells after healthy tissue. And tangled blood vessels are just one of several mechanisms tumors have of defending themselves. They can, for example, turn tumor-eating immune cells into tumor-defending ones.
Still, Wen said, in the short term, the approach offered a path toward boosting the efficacy of radiation, chemotherapy and other small molecule drugs. Although Fan focused on glioblastoma, researchers agreed PAK4 likely plays the same vessel-warping role in many other solid tumors.
Theres a lot of things you could look at, he said.
In a January review, Jessica Fessler and Thomas Gajewski at the University of Chicago said Ribas paper pointed towards a path for improving PD-1 and overcoming resistance in some tumors. But they also raised questions about the Karyopharm drug, noting that it hits other proteins besides PAK4. That could mean other mechanisms are also at play and that the drug could affect other tissues in humans.
Ribas agreed that Karyopharms drug might not be the perfect molecule but said others could be on their way. He serves as a scientific advisor to Arcus, the Terry Rosen startup that is now working on developing its own PAK4 inhibitor.
If they can develop a very selective PAK4 inhibitor, he said, it may be a more direct way of testing the role of PAK4.
Tests with that drug, in turn, could help clear up a biological mystery that emerged out of Fans and Ribas papers. Although both investigators zeroed in on PAK4, each of them suggested very different mechanisms by which PAK4 kept immune cells out of the tumor. Ribas suggested it directly suppresses T cells, while Fan found it led to those transformations inside the blood vessels near the tumor.
Kinases are versatile proteins and both researchers said its possible that PAK4 is doing both. Its also possible, they said, that one is more important than the other, or simply that one of them is just wrong.
When you start with completely new biology, its hard to get it right the first time, Ribas said.
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Penn researchers find a way through the labyrinth keeping CAR-T from solid tumors - Endpoints News
Posted: December 7, 2020 at 4:56 pm
A world-first light bulb moment discovery by a modest Queensland scientist could deliver the ultimate gift in modern science - a way to reverse the ageing process.
On a lab bench at the University of Queensland, Professor Justin Cooper-White, a chemical engineer, is working on an incredible project that will one day help peel back the years and allow older people to live a more youthful, active life and ultimately look younger.
This Benjamin Button-effect is just one of the areas of regenerative science that will change the world of healthcare.
"It's fantastical to think that a 70 year old will suddenly have the youth of a 20 year old that's not going to happen but there is very real evidence that it will be possible to slow ageing and revert cells in the body that are "frustrated" due to age into more calm cells that will allow easier movement, better breathing and faster healing," Prof Cooper-White said.
Professor Justin Cooper-White at UQs Robotic Stem Cell Engineering Facility.
"I can't say that people will look younger but it's possible. When a person is active and living life to the full they generally look better. The focus is not necessarily about prolonging life span, it's more about prolonging health span. Our work is not a silver bullet, exercise and nutrition will all play a part," he said.
Prof Cooper-White made the discovery that body tissues are not just elastic and solid but also work a bit like a liquid and now his team is investigating how the viscoelasticity of bodies change over time and ways to reverse the process.
"Viscoelasticity describes the way materials, like our skin, muscles, bones or even our organs, respond to being 'stressed', through pushing, pulling or shearing, the forces that our tissues experience in everyday life," he said.
"All tissues in the body are viscoelastic - it is an intrinsic property of them. We age because our body gets less viscoelastic. This is something we are focusing on now. Maybe it's just because I am getting older. As we age, daily ailments cause inflammation. Inflammation in one area is carried around the whole body by our blood vessels, causing the extracellular matrix of all our tissues to become stiff and corrupted, or 'fibrotic'. This corrupts the stem cell 'niches', the homes of stem cells that live next to our blood vessels," he said.
"We're investigating what happens when those tissues become less viscoelastic and how we might reverse that," Professor Cooper-White said.
Professor Cooper-White says allowing people to live full lives into old age would be a good investment.
Since the scientist and his team from UQ's Australian Institute for Bioengineering and Nanotechnology (AIBN) unit first flagged the importance of viscoelasticity on stem cell behaviours in 2011, researchers around the world have been working to confirm those findings and probe other related mechanical properties of cells, building an in-depth body of knowledge that can be used to inform biological, medical and engineering research.
"We have been working on the ageing area for the last four or five years and making progress," the professor said.
Late this year Prof Cooper-White joined the world's top tissue engineering experts from Stanford University, Harvard University and University of Pennsylvania to review the works investigating viscoelasticity.
The latest research in their field was published in the prestigious scientific journal Nature.
"There is a lot of work to be done and I would estimate we are talking at least a couple of decades before therapeutics would even be available. We would have to look at trials in small animals, larger animals and then human trials. But this is very important science. We are looking at a future where Australia will have a very high percentage of older people. It would make sense for more investment to be put into allowing older people to live life to the full and have a long health span. Doesn't that make more sense that putting all the money into programs to look after people after they end up decrepit?" the chemical engineer said.
"This has not come to the public eye as much as I would have expected it to, given how important it is," the professor said.
Brad Pitt in a scene from The Curious Case of Benjamin Button. Picture: AP Photo
It is predicted that almost one quarter of Australians will be over 65 by June 2050 and other countries will have an even bigger aged population.
"We are not talking about offering the fountain of life but regenerative science is a key area of research for the future. It's exciting what we have found so far," Prof Cooper-White said. Leading them into work in engineering of healthy ageing with stem cells, the team at UQ works on artificially creating new tissue like recreating breast tissue for women who have had a mastectomy. It was this work into body tissues that lead to the professor's world stopping discovery in regenerative medicine.
Originally published as 'Benjamin Button' discovery could reverse ageing process
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'Benjamin Button' discovery could reverse ageing process - Queensland Times
Posted: December 6, 2020 at 2:57 am
Detailed look: Some mutations in the autism gene NCKAP1 interfere with a cells ability to transport NCKAP1 protein into and out of its nucleus.
Many people with mutations that disrupt a gene called NCKAP1 have autism or autism traits along with speech and language problems, motor delays and learning difficulties according to a new study. The results, from a large international team of researchers and clinicians, clarify how mutations in NCKAP1 affect people and solidify its position as a top autism gene.
Sequencing studies over the past decade have turned up three autistic people with de novo, or non-inherited, variants that likely disrupt NCKAP1, putting it on a list of genes strongly tied to autism. Other work has shown that mice that do not express the gene have atypical brain development.
But those reports contain little information about the outward characteristics of people with NCKAP1 mutations which are challenging to study because variants in the gene are rare, says Hui Guo, associate professor of life sciences at Central South University in Changsha, China.
In the new work, Guo teamed up with scientists and clinicians across the globe to identify and characterize 18 additional people with NCKAP1 mutations.
This study demonstrates that international cooperation among many institutions is becoming fundamental to advancing our understanding of rare variants, says Abha Gupta, assistant professor of pediatrics at Yale University, who was not involved in the study.
Painting a detailed picture of traits associated with NCKAP1 mutations can also improve a persons chance of being diagnosed and provide guidance about expected outcomes, she says.
Guo asked colleagues who collect genetic data for other research to sift through their records for people with NCKAP1 variants. He also used GeneMatcher, a site that connects researchers to clinicians interested in the same genetic variants.
For each person Guo and his colleagues identified, they followed up to assess that individuals clinical traits; they either contacted the person directly or asked medical professionals to review the persons records.
The researchers also collected genetic and clinical information about family members of the people with NCKAP1 mutations to determine if the variants had been inherited.
In all, the team identified and characterized the traits of 21 affected people across seven countries.
Thats a lot of work, considering how rare an NCKAP1 variant is, says Megan Dennis, assistant professor of biochemistry and molecular medicine at the University of California, Davis MIND Institute, who was not involved in the study.
The people in Guos cohort ranged in age from 7 to 23 years at the time they were assessed.
The researchers diagnosed autism in 10 out of 15 participants who had been previously assessed for the condition; 2 others have autism traits but no formal diagnosis; the remaining 3 have no reported autism traits. Another 12 participants have difficulties with speech and language, 11 have delayed motor function, and 11 have intellectual or learning disabilities.
According to the clinical assessments, nine of the participants have had sleep problems and seven have experienced seizures, both of which are also associated with autism. The results were published in The American Journal of Human Genetics in November.
Guo and his colleagues further investigated the variants effects on NCKAP1 function by introducing mutations from five participants into cultured human embryonic kidney cells. They tagged NCKAP1 protein with a fluorescent marker to trace its location in the cells.
NCKAP1 protein is typically present throughout the cell. Two variants, though, cause it to appear mainly in the cytoplasm, suggesting that these mutations create problems with transporting the protein into and out of the nucleus.
The team also evaluated how NCKAP1 expression varies throughout development by using the BrainSpan atlas, which catalogs gene-expression data from human brain tissue from 8 weeks after conception to 40 years of age. NCKAP1 is highly expressed during the second and third month of prenatal development, and at multiple points throughout a persons life, they found.
They also found that the spatial distribution of NCKAP1 expression across the brain most closely resembles the spatial distribution of gene clusters associated with excitatory neurons and radial glia, and not with inhibitory neurons. This pattern suggests the NCKAP1 gene has a function that is specific for these cell types perhaps by regulating their structure or ensuring that they differentiate properly, the researchers say.
The team further compared the brains of typically developing mice with those of mice that were treated to express less NCKAP1 protein. They injected the embryonic mice with a fluorescent protein that tags nascent cortical neurons, and then assessed where those cells ended up after two or four days. In mice that express less NCKAP1, many of the neurons did not arrive at the correct final location, the team found, suggesting that the gene may play a role in the migration of these cells. That finding, though preliminary, fits with prior work tying premature NCKAP1 expression to delayed neuronal migration.
The functional studies shed some light on the mechanisms that may underlie a genetically based form of autism, Dennis says. But in terms of being able to have any kind of actionable clinical information, theres still more to be done.
Guo and his colleagues plan to characterize the traits tied to rare mutations in other top autism genes, with the goal of defining specific genetic or molecular subtypes of the condition.
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Rare variants tied to neuronal migration, autism traits - Spectrum
Posted: December 6, 2020 at 2:57 am
In 2020, we celebrate 90% of the human proteome being mapped by the Human Proteome Project (HPP). In this article, we reflect on the history of this endeavor and the future of the proteomics field.
Throughout the history of medicine, we have sought to characterize and analyze the molecular self, in a bid to understand the underpinnings of human physiology and, in turn, pathophysiology. This knowledge holds many applications that transcend biology and circle around the question of what it means to be a human. In the context of human disease, it aids our ability to prevent it, or even cure it.
Almost 17 years after the completion of The Human Genome Project (HGP), the insights garnered by DNA sequencing studies have filtered into modern medicine in several ways. Next-generation sequencing (NGS) of tumors has facilitated the discovery of biomarkers unique to specific cancers. Pharmacogenomics has taught us that certain drug compounds will elicit different therapeutic effects in different people. Arguably more niche fields of research have benefitted too; transgenerational epigenetics, for example, is teaching us how biological memories could be passed on to future generations.
The HGP has undisputedly progressed our knowledge of human biology in ways that scientists of the past could only dream of.
But still, gaps remain.
DNA is only part of the story; there are many steps required to transcribe and translate the DNA code into proteins, the functional workhorses of the cell. As Professor Chris Overall, Canada research chair in proteinase proteomics and systems biology at the University of British Columbia, Centre for Blood Research, described, "The HGP was a massive achievement it really was brilliant. But it's only the blueprint for us."
The term "proteome" was first used in 1994 by Marc Wilkins, and refers to the complete set of proteins that are expressed in a cell, tissue, organism or system, at a given time.
Proteomics, the large-scale study of proteomes, sits within an area of science known as "omics", which also comprises genomics, transcriptomics and metabolomics.
Historically, proteomics has been somewhat overshadowed by the field of genomics. Stephen Curry, a professor of structural biology at Imperial College London, wrote about an apparent "lack of interest in our "inner molecules": "[As soon as] someone mentions gene products, the myriad of protein molecules encoded by genes, suddenly theres a switch off." Critics of Curry's writing expressed that it wasn't a lack of interest, but rather a lack of understanding; studying the proteome is far more complex than the genome.
Why? The proteome is exceptionally diverse. "A surprise revealed by the success of the HGP was the lower-than-anticipated number of genes identified: ~20,300, rather than the ~100,000 estimated," wrote Lloyd Smith and Neil Kelleher.1 This finding of the HGP ultimately led to the acknowledgement that the complexity of human biology is attributed to protein variation, resulting from processes such as alternative splicing of RNA transcripts and the formation of post-translational modifications.
It cast a spotlight on proteomics.
Professor Emanuel Petricoin, co-leader of the Applied Proteomics and Molecular Medicine team at George Mason University, was one of the co-founders of HUPO. In an interview with Technology Networks he described how, "In proteomics you have so many different technologies and methodologies []. All of these specialties and subspecialties have different cohorts of scientists that in themselves are in their own little subgroups."
The aim of HUPO, in Petricoin's words, was to represent the efforts of these cohorts across the globe, and develop what he referred to as "campfire" projects that researchers could "congregate" around and participate in together to advance the field.
The Human Proteome Project (HPP) is an example of such a venture; however, as an endeavor that involves scientists, clinicians and industry members from many countries across the world, it's a little larger than a campfire circle. The project first launched on September 23, 2010 is a collaborative endeavor designed to map the entire human proteome using current and novel analytical technologies.
The HPP is divided into two subcategories, the Chromosome-Centric HPP (C-HPP) and the Biology/Disease-Driven HPP (B/D)-HPP. Lane, the co-chair of the C-HPP, explains why, "One of the very first tasks of the HPP was to get convincing experimental evidence for the existence of each of the ~20,000 proteins predicted by the analysis of the human genome. Since the genes encoding these ~20,000 proteins are distributed on the 24 human chromosomes, it was natural to divide the work chromosome per chromosome." Because the HPP is an international project, it was logical for each participating country to be allocated one of the 24 chromosomes. They are then responsible for monitoring the validation status of all the predicted proteins on this chromosome.
"However, once the proteins are produced, the function they perform in the body is independent from the chromosome that originally encoded them. In order to study their role or their involvement in disease it is important to study proteins in their global context," Lane added. "The B/D HPP project tackles this challenge by focusing on broad biological or medical questions and applying more systemic approaches."
The C-HPP and B/D HPP are complementary projects. The first ensures that all proteins are covered, and the second puts the all the pieces together.Milestone: 90% of the human proteome is mapped
There are five levels of supporting data for protein existence (PE) as part of the HPP's data system:
A table outlining the five levels of supporting data for protein existence.
On the HPP's 10th anniversary this year, the project celebrated a major milestone: mapping 90.4% of the human proteome at the PE1 level, as reported in Nature Communications.2 In 2011, just 70% of the human proteome had been mapped to this level.
How is the data collected in the last decade of the HPP being utilized, particularly in a clinical context? This, according to Petricoin whose research focus lies in oncology is the "elephant in the room": "Patients stood at the [HGP] announcement and said, 'so what?'. 'How does this information and list of genes help me today, or tomorrow, with my cancer?' The same can rightfully be said here how does a simple list of proteins help a cancer patient today?"
In the publication, A high-stringency blueprint of the human proteome, Adhikari and colleagues highlight how the HPP data has assisted research groups across the globe in the study of different diseases thus far. The National Cancer Institutes Office of Cancer Clinical Proteomics Research, for example, is working to improve the prevention, early detection, diagnosis and treatment of cancer via programs such as the Clinical Proteomic Tumor Analysis Consortium. Cardiovascular disease (CVD) proteomics has advanced from simply identifying proteins, to mapping proteoforms that enable subclassification of CVD.3 Most recently, proteomics-based analysis of the SARS-CoV-2 virus has identified potential therapeutic targets for treating COVID-19 and highlighted the potential utility of existing drugs.4
"Deciphering this new 'proteome code' is the challenge that lies ahead for the proteomics and HPP communities and for addressing the broken hyperbole springing from the euphoria of the publication of the human genome papers 20 years ago, when the media and pundits predicted the curing of some, if not all, human diseases within a few years," Overall added.
An appreciation for the sheer complexity of the proteome, the growing capabilities of analytical technologies and the pressures faced by an arguably under-funded research field particularly when compared to genomics is pertinent to understand why 90% is a huge triumph, and a cause for celebration. And so, the HPP chooses to "mind the gap", respecting this achievement whilst acknowledging the intention to complete the coverage with "high fidelity" in due course.
Credit: Suad Kamardeen on Unsplash.The "missing" proteins of the human proteome may be hiding out of sight in rare cells or tissues, expressed at specific fetal or childhood developmental stages or perhaps in quantities that are too low to be detected by current mass spectrometry approaches. Others may be hiding in plain sight, but their amino acid sequence and chemical composition may render such proteins not amenable to current mass spectrometry instrumentation and methodology. When asked whether it is possible that some proteins may never be mapped, Petricoin says that it would be dogmatic to say never: "Science is always improving and getting better. Right now, it is a product of these 10% being extremely low abundance, having extremely short half-lives and mass spectrometry still not being analytically sensitive enough to 'see' these markers," he explained.
The ability to analyze and integrate large omics data sets will be critical for the implementation of proteomic data in the clinical space. This is a core focus for Lane's group. She says, "We will continue to improve the interoperability of neXtProt with resources focusing on clinical and pharmacological data in order to better answer the needs of the medical community."
Funding is also a pertinent issue for the field. The instrumentation adopted in high-throughput proteomics primarily mass spectrometry is both expensive and complex, requiring large budgets to fund the equipment and to train specialists to use it.
"One of the biggest challenges is that there is no dedicated funding for the HPP project, in contrast to the former HGP. Nearly all the teams (including ours) participate in the global HPP effort on a voluntary basis, which undoubtedly slows down the whole project," said Lane.
Her thoughts are echoed by Overall, who emphasizes that, whilst he feels privileged to be involved in what he deems a "worthwhile endeavor" that drives him and his lab members, their work would progress much faster and more accurately if more funding was available for essential infrastructure.
"The post SARS-CoV-2 pandemic world will be different. It is likely that new paradigms to accelerate precision medicine will emerge. These will undoubtedly involve global collaboration (even between competing entities) using multi-disciplinary approaches that enable the fast-tracking of novel diagnostic tests and precision therapeutics. Almost certainly these outcomes will require knowledge involving the human proteome celebrated here in the inaugural HPP High-Stringency Blueprint," Adhikari and colleagues concluded.
Professor Chris Overall, Professor Emanuel Petricoin and Dr Lydie Lane were speaking to Molly Campbell, Science Writer, Technology Networks.References:
1.Smith LM, Kelleher NL; Consortium for Top Down Proteomics. Proteoform: a single term describing protein complexity. Nat Methods. 2013;10(3):186-187. doi:10.1038/nmeth.2369.
2.Adhikari S, Nice EC, Deutsch EW, et al. A high-stringency blueprint of the human proteome. Nature Communications. 2020;11(1):5301. doi:10.1038/s41467-020-19045-9.
3.Cai Wenxuan, Zhang Jianhua, de Lange Willem J., et al. An Unbiased Proteomics Method to Assess the Maturation of Human Pluripotent Stem CellDerived Cardiomyocytes. Circulation Research. 2019;125(11):936-953. doi:10.1161/CIRCRESAHA.119.315305.
4.Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature. 2020;583(7816):459-468. doi:10.1038/s41586-020-2286-9.
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Mapping the Human Proteome: A Journey - Technology Networks
Posted: December 6, 2020 at 2:57 am
This year, science celebrates mapping 90% of the human proteome, an endeavor that has been achieved by the Human Proteome Project (HPP). Technology Networks explored the journey to this successful feat by speaking with Professor Emanuel Petricoin.Petricoin is a professor and co-director of the Center for Applied Proteomics and Molecular Medicine at George Mason University. Petricoin's research focus is on the development of cutting-edge microproteomic technologies, identifying and discovering biomarkers for early stage disease detection, developing novel bioinformatic approaches for protein-protein interaction analysis and creating nanotechnology tools for increased analytical detection, drug delivery and monitoring. He is one of the founding members of the Human Proteome Organization (HUPO).Molly Campbell (MC): As one of the co-founders of HUPO, how do you feel about the news that ~90% of the human proteome has now been mapped?Emanuel Petricoin (EP): Its a great achievement! One of the major objectives when we first launched HUIPO was to simply understand the nature and existence of the human proteome. But the development of the catalogue is really only the beginning, and of course those last 10% may be exceedingly difficult to categorize and uncover; they are the lowest abundance analytes which may contain the most important biochemical information as far as human disease and the biomarkers that everyone is after are concerned.
We need to couple new advances in sample preparation to concentrate and be able to bring them into the sensitivity range of mass spectrometry. Moreover, and critically, there are a massive number of post-translational modifications (PTMs) of the proteome and it is really these PTMs that make all of the difference in biology and disease. We really dont have a clue as to that proteome! This is what is difficult about proteomics, it's not simply a list of proteins but it is their expression level, location, activation state and who is talking to who, as the proteome is a dynamic, physically interconnected network of interacting molecules with fine-tuned orchestration of location and amounts. Even with this great achievement, it is simply a list and like a list of parts for a 747 aircraft, it doesnt tell you anything about how the aircraft is put together, how it operates and most importantly how to fly it. But, before you can do anything, you have to know the parts list. This is what the field has achieved, and it is fantastic but just a start we need to take the parts list and construct the instruction manual, and that is going to take a huge amount of continued effort.
MC: The blueprint of the human proteome comes almost twenty years after the completion of the Human Genome Project. During this time, do you think attitudes towards the proteomics field have changed? If so, how?EP: Absolutely. I think there is a real and important shift to proteomics now a beyond genomics orientation. I think some of this is the limitations that are being seen in the narrow actionability landscape of genomics in many diseases, notably cancer, as well as recognition that genomics-stratified patients do not effectively capture many of the responders and non-responders in many targeted therapy efforts. We still need a massive injection of new discoveries of highly sensitive and specific biomarkers for disease detection. HUPOs efforts here provide that catalyst and I think you are seeing more and more examples of biomarker signatures comprised of both genomic and proteomic markers for more accurate and sensitive disease detection. Moreover, I think that there is a re-focused interest by the field of molecular diagnostics and precision medicine on the potential for true synergy between proteomics and genomic based profiling for better clinical outcomes and better biomarker signatures for detection and treatment of human diseases.
MC: The HPP is divided into the C-HPP and the B/D-HPP. What are each of these subcategories, and why is the project divided in this way?EP: These efforts underscore the unbelievable complexity of the human proteome- in fact it illustrates the fact that a simple parts list, while important, is not even close to being enough; as they say, while the DNA is the information archive, its the proteins that do all of the work and it's all about what proteins are expressed, how much is expressed, where they are expressed, at what time they are expressed, in what isoform they are expressed and to what levels (phosphorylated, myristolated, glycolsylated etc.) and in what cell type are they expressed. You may actually argue that there should be a further subdivision of other sub-categories within each of the disease subgroups in the B/D -HPP and C-HPP categories!
MC: Confident detection of the human proteome has risen from 69.8% in 2011 to 90.4% in 2020. How has this been achieved?EP: Massive improvements in mass spectrometry instrumentation and mass accuracy and the computational informatics side together have led to this along with better enrichment and fractionation methods for better sample input integrity.
MC: Are there some proteins that we may never be able to map? If so, why is this?
EP: Perhaps it will take quite a while, but I can't imagine that we can be so dogmatic to say NEVER- science is always improving and getting better and better. Right now, it is a product of these 10% being extremely low abundance and having extremely short half-lives and mass spectrometry still not being analytically sensitive enough to see these markers.
MC: How can the data from the HPP be used in a clinical context? What barriers exist to translating the research from lab to the clinic?EP: Well, that is the elephant in the room, isnt it? The same was said after the human genome was mapped. Patients stood at the announcement and said so what? How does this information and list of genes help me today or tomorrow with my cancer? The same can rightfully be said here how does a simple list of proteins help a cancer patient today? The field needs to be very transparent and thoughtful about how it conveys the impact of the achievement to everyday impact on humans and society. It will take years and decades more effort to take the aggregate of this proteomic data to translate into well performing clinical grade diagnostics/therapeutics that impact patients at the bedside and it is not like we didnt already have most of the 90% already much of this has been had for years and we still havent taken a vast majority of it to new biomarkers/treatments/drug targets that physicians use to manage care.
Emanuel Petricoin was speaking to Molly Campbell, Science Writer, Technology Networks.
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Mapping the Human Proteome: A Conversation With Professor Emanuel Petricoin - Technology Networks
Posted: December 6, 2020 at 2:57 am
By Conlan Doherty, Fourth Year, Cellular and Molecular Medicine
Bristol plays a key role in a new FDA-funded collaboration of international research centres to enhance our understanding of severe coronavirus infections and how COVID-19 progresses.
A new international project funded by the FDA has been approved and will collaborate with the University of Bristols School of Cellular and Molecular Medicine, as well as The Universities of Liverpool and Oxford, Public Health England, A*STAR in Singapore and King Fahd Medical City in Saudi Arabia.
The aim of the project is to increase our understanding of severe coronavirus infections in humans, which will help to discern novel therapeutics to combat COVID-19. Currently, there are no licensed therapies to treat or prevent the infection and the virus remains a burden to healthcare systems and global economies.
In recent years, emerging infectious diseases have become an increasing threat to normality, with SARS-CoV, MERS-CoV and the culprit of the current pandemic, SARS-CoV-2, all being members of the same virus family: coronavirus. The patterns of disease are somewhat similar among the three family members, especially when regarding the hosts enhanced inflammatory response.
This new study will investigate viral evolution, host-pathogen interactions, any elicited immune responses, and diagnostic biomarkers throughout the infection in all three viruses within the family, to elucidate any common mechanisms of virulence. Identifying shared pathways and disease-associated biomarkers will help inform the development of new therapies, and how the infection progresses.
Professor Julian Hiscox of the University of Liverpool said: The development of licensed drugs to treat severe coronavirus infection, and especially SARS-CoV-2, is a huge priority for the international community. There is a time-sensitive need to assess the efficacy of novel COVID-19 interventions, address the continuing challenge of MERS and prepare for potential future coronavirus pandemics.
The Bristol team will be headed by Dr David Matthews and Dr Andrew Davidson and will focus on how SARS-CoV-2 and MERS-CoV infect living cells and cause disease, as well as exploring how antiviral drugs may be implicated to perturb the pathogens virulence.
Viral evolution will be assessed via identification of any diagnostic target sites that are no longer present in the virus, suggesting diagnostic and therapeutic intervention has acted as a selection pressure, compelling the virus to mutate, become evasive and remain successfully infectious.
Additionally, the study is assessing a newly developed technology, Organs-on-Chips, which can mimic organ systems and will highlight characteristics of the virus and the ensuing infection.
The international team is led by Dr Julian Hiscox at the University of Liverpool and will unite a multi-disciplinary team of scientists in understanding several characteristics of the virus.
Chief Scientist at the FDA, RADM Denise Hinton elaborated: FDAs work with our international regulatory counterparts and key partners in academia and industry has paved the way for numerous critical collaborations on many scientific and regulatory fronts as part of our COVID-19 response.
This work will undeniably impart crucial findings in the molecular mechanisms underlying COVID-19 infections, and allude to any therapies that might successfully prevent or counter any progressive decline in health engineered by SARS-CoV-2.
The FDA will continue to collaborate on important regulatory science projects like this one, as we seek to bring safe and effective COVID-19 vaccines and treatments to our citizens as quickly as possible.
Featured image: Kendal/Unsplash
Are you hopeful we will learn more about the virus with well funded studies like this?
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Bristol partners with FDA on new 4 million study to understand severe coronavirus infections - Epigram
Posted: December 6, 2020 at 2:57 am
Then the league rescheduled the game again, this time for Wednesday afternoon.
Why not play at night, giving players who have barely practiced in recent days more time to prepare, decreasing their risk of injury? The scheduling decision hinged on television, the leagues cash cow. NBC, which will broadcast the game, wanted to stick with its plans to air the tree-lighting ceremony at Rockefeller Center during a two-hour prime-time special.
On the West Coast, the league didnt look any better. The San Francisco 49ers will play their next two home games at the Arizona Cardinals Stadium, near Phoenix. That last-minute, jury-rigged plan came about after officials in Santa Clara County, Calif., where the 49ers stadium is, wisely decided to ban contact sports through late December in a bid to stem the virus surge wreaking havoc in large parts of the state.
But there is a problem: State Farm Stadium is in Maricopa County, Ariz., which has had an average daily rate of 42.7 cases per 100,000 residents in the past week well above the alarming rate of 29.5 cases per 100,000 residents in Santa Clara County.
The change of venues only makes sense for a league trying to keep a troubled season going, not from the standpoint of public health.
The league was making things up on the fly, the same as it has done all season. It seems like they didnt have a plan for what to do once people started testing positive, said Angela Rasmussen, a virologist at the Georgetown Center for Global Health and Security, when we spoke this week. Theyre sort of flying by the seat of their pants, trying to figure out how to actually finish the season.
Remaining on the current path is a fools errand, added Eric Topol, a coronavirus expert and professor of molecular medicine at Scripps Research. Trying to play without the benefit of an N.B.A.-style restricted environment, he said, is an exercise not just in futility, but in danger.
Agreed.
It would be better to pause the season now, retool the health protocols and wait out the coming storm. If the virus recedes to controllable levels by the early part of 2021, resume with a shortened playoff and a Super Bowl ditching the current plan to allow fans in the stands at that game.
See more here:
Do We Need Football in America This Badly? - The New York Times
Posted: December 6, 2020 at 2:57 am
To perform a Covid 19 test, the laboratory must be validated.In public laboratories the test has no cost, but it does generate an expense.Know the average cost of the Covid 19 test in private laboratories.
One of the main factors to avoid the spread of the coronavirus is the timely taking of a Covid 19 test to reduce the number of infections.According to the Ministry of Health, Mexico adds 105 thousand 655 deaths from Covid 19 and one million 107 thousand 71 accumulated confirmed cases.In the last few hours alone, 6,388 new confirmed cases of Covid 19 were registered in Mexico.Given this, the WHO assured that Mexico is in a bad situation in the face of the Covid 19 epidemic, which saw the number of cases and deaths double between mid and late November, warned Tedros Adhanom Ghebreyesus.
Related Notes:This is what a hospitalization for Covid 19 costs in MexicoCoronavirus: Medicines and healing materials cost 60% more in Mexico due to pandemicThe debts of Covid 19 patients and their families increase in Mexico
In addition to social isolation, another measure to contain the pandemic is to carry out the Covid 19 test in a timely manner and in Mexico there are 168 validated public and private laboratories.According to the Ministry of Health, the places authorized to test for Covid 19 have been growing, as it is necessary to have the recognition of the Institute for Epidemiological Diagnosis and Reference (InDRE).
There is the IMSS Division of Epidemiological Surveillance Laboratories that made three laboratories available in the entities.Support Laboratory for Epidemiological Surveillance of the Western Research Center (CIBO), Guadalajara, Jalisco.Laboratory of Support for Epidemiological Surveillance of the Center for Biomedical Research of the Northwest (CIBIN), Monterrey, Nuevo Len.Support Laboratory for Epidemiological Surveillance of the High Specialty Medical Unit in Yucatn (UIMY).The Laboratories to Support Epidemiological Surveillance (LAVES) are also available:National Institute of Respiratory Diseases.National Institute of Medical Sciences and Nutrition Salvador Zubirn.General Hospital of Mexico.November 20 Hospital (ISSSTE).37 Central Laboratory of Epidemiology, CMN La Raza (IMSS).Also in the public sector are:Childrens Hospital of Mexico, Federico Gmez.Hospital Central Sur Alta Especialidad PEMEX.New Civil Hospital of Guadalajara, Dr. Juan I. Menchaca .Molecular Biology and Biosafety Laboratory of the Naval Medical Center.Laboratory of Microbiology and Molecular Diagnosis of the Department of Immunobiochemistry, National Institute of Perinatology.Regional Hospital of High Specialty of Ixtapaluca.Virology Laboratory of the National Institute of Pediatrics.Infectology Laboratory of the National Rehabilitation Institute, Luis Guillermo Ibarra Ibarra.Central Military Hospital, dependent on the General Directorate of Military Health and the Secretariat of National Defense.Hospital Jurez de Mxico.
ABC Medical Center, Observatory Campus.Angeles Interlomas HospitalOlartey Akle, Bacteriologists.Lister Laboratories.Biomedical Laboratories of Mrida.LABIOMOLA.Spanish Hospital of Mexico City.South Medical.Aries Diagnostic Group.CARPERMOR Laboratory.ORTHIN Specialized Reference.Puebla Clinical Laboratories.Worthy Health.Jurez Laboratory.BIOQUIMIA Corporate Group, Siglo XXI.LSG Clnicos Mexicali.LANS, Reference Laboratories.Molecular Diagnostic Laboratory AL Gens.Diagnostic Molecular Biology (BIMODI).Molecular Genetic Pathology (PGM Laboratory).Central DNA.Clinical Diagnostic Advisors.Vitagenesis.Genodiagnostics.Laboratory of Surgical Pathology and Cytology of Puebla.GENOLIFE.Certus Laboratory.Specialized Developments in Biotechnology and Molecular Diagnosis, (Denatbio).Laboratory of Specialized Genetic Analysis Mexico, (LAGEM).Alfonso Ramos Laboratory.DIAGNOMOL Laboratories.Analytical and Diagnostic Unit,San jose hospital.LSD Clinical Analysis Diagnosis.La Hoz clinical diagnoses.Mrida Clinical Laboratories.SERVACARE.Immunological Specialties Laboratories.Christus Muguerza Laboratory.Hospital San ngel Inn University.Clinical Laboratory of the Campestre.Chontalpa Laboratories.Micro-Tec.Santa Maria Group.CENEBA,Diagnostic Image.LACLICSA Laboratories.CEDIMI Laboratories.Diagnostic and Associated Laboratories.PrimeLab Molecular Diagnostics.SIMNSA Molecular Biology Laboratory.GD Technologies.Huella Gnica, SA de CV
Also in some public universities they take the Covid 19 test sample.Center for Research in Health Sciences and Biomedicine (CICSaB), Autonomous University of San Luis Potos.Department of Genetics and Molecular Physiology of the Institute of Biotechnology (IBT) of the Autonomous University of Mexico (UNAM).Bioprocess Development and Research Unit of the National School of Biological Sciences (UDIBI-ENCB) of the National Polytechnic Institute (IPN).
Biosafety Laboratory for the Diagnosis and Research of Emerging Diseases, Cinvestav.Department of Cellular and Developmental Biology, of the Institute of Cellular Physiology, of the UNAM.Virology Laboratory, Institute of Biomedical Research, UNAM. Laboratory of Microbial Molecular Immunology of the Faculty of Medicine, UNAM.Infectious Diseases Research Laboratory, UNAM.Institute of Immunodeficiencies and HIV Research of the University Center for Health Sciences, University of Guadalajara (Ude-G).Laboratory for the Diagnosis of Emerging and Reemerging Diseases of the UdeG.CIR-Biomedical Virology Laboratory of the Autonomous University of Yucatn.Molecular Medicine Laboratory, of the Autonomous University of Zacatecas Francisco Garca Salinas.Molecular Microbiology Laboratory, of the Autonomous University of Quertaro.PABIOM Laboratory, of the Autonomous University of Chihuahua.Genomic Services Laboratory (Labsergen) of Cinvestavs Advanced Genomics Unit.Diagnostic and Research Laboratory of the Autonomous University of Guerrero.National Laboratory of Agricultural, Medical and Environmental Biotechnology of the Potosino Institute of Scientific and Technological Research.Food and Development Research Center, in Hermosillo, Sonora.Food and Development Research Center, in Mazatln, Sinaloa.Food and Development Research Center, in Culiacn, Sinaloa.National Institute of Genomic Medicine.National Laboratory of the Autonomous University of Nayarit.Biosafety Laboratory, Center for Nanosciences and Nanotechnology, UNAM.Molecular Diagnostic Laboratory of the University of Colima.Preclinical Research Unit of the UNAM.Biosafety Laboratory of the Ensenada Center for Scientific Research and Higher Education.Bioseguro Laboratory of the Center for Biological Research of the Northwest.Clinical Services Unit of the Autonomous University of Quertaro.Infectology Laboratory, Autonomous University of Nuevo Len.Molecular Biology Laboratory of the University Center of the Coast University of Guadalajara.Reference Laboratory Analysis and Diagnosis in Aquaculture Health, Hermosillo Unit.Center for Molecular Diagnosis and Personalized Medicine, University of Monterrey.Proteogenic Unit, Institute of Neurobiology, UNAM.Virology Laboratory of the Center for Research and Assistance in Technology and Design of the State of Jalisco.Research Unit Faculty of Veterinary Medicine and Zootechnics, UNAM.Laboratory of the Transdisciplinary Institute for Research and Services of the UdeG.Campus CUSUR Laboratory, of the UdeG.Molecular Virology Laboratory of the Cell Dynamics Research Center of the Autonomous University of the State of Morelos.Yucatan Scientific Research Center.Center for Genomic Biotechnology, National Polytechnic Institute, Reynosa, Tamaulipas.
The Covid 19 tests have no cost in public hospitals and state laboratories, although they generate an expense of approximately 1,492 pesos, according to the Director of Diagnosis and Reference of the InDRE, Irma Lpez Martnez, while in the private laboratories of the City of Mexico offer the test for a price between 3,300 and 3,400 pesos.Irma Lpez Martnez explained that it is necessary to first evaluate the type of test, because although they are all polymerase chain reaction (PCR), they have different methodologies. Remember that only a doctor can evaluate if you need to take a Covid 19 test according to the symptoms you present.
Continued here:
Tech : Public and private laboratories validated to perform the Covid 19 test - Explica
Posted: December 6, 2020 at 2:57 am
When in need of a beverage to warm them up, billions of people across the globe routinely look to tea. That choice has been made since ancient times, as various historians trace the habitual consumption of tea to ancient China.
Anything that has survived since ancient times no doubt has some good qualities, and tea is no exception. According to Penn Medicine, various types of tea each provide their own unique health benefits, some of which may surprise even the most devoted tea drinkers.
1. White tea: A 2010 study published in the Journal of Food Science found that antioxidant-rich white tea boasts anti-carcinogenic properties. Penn Medicine also notes that white tea is a significant source of fluoride, catechins and tannins, ingredients that can strengthen teeth, improve their resistance to acid and sugar and fight plaque.
2. Chamomile tea: Many people like drinking this herbal tea before bedtime because they feel it helps them fall asleep, and one study published in Molecular Medicine Reports in 2010 notes that chamomile tea is widely regarded as a mild tranquilizer and sleep-inducer. Chamomile tea also has been shown to improve heart health. A 2015 study of 64 patients with diabetes published in the Journal of Endocrinological Investigation found that those who consumed chamomile tea with meals had improved triglyceride and bad cholesterol levels compared to patients who drank water.
3. Peppermint tea: The Mount Sinai Health System notes that peppermint calms the muscles of the stomach and improves the flow of bile. Made from dried leaves of the peppermint plant, peppermint tea can help to soothe an upset stomach and help people overcome conditions like constipation, irritable bowel syndrome and motion sickness.
4. Green tea: Green tea is loaded with flavonoids, which Penn Medicine notes improve heart health by lowering bad cholesterol and reducing blood clotting. In addition, the National Cancer Institute notes that the polyphenols in green tea may protect people against the damage caused by exposure to ultraviolet B radiation. One study published in Stroke: Journal of the American Heart Association also associated green tea consumption with a reduced risk of stroke.
Tea has been consumed for millenia. Though many people drink tea simply for its taste, those same people may drink even more after learning about the effects this beloved beverage can have on their overall health.
Original post:
The health benefits of 4 popular teas | Food and Drink | frontiersman.com - Mat-Su Valley Frontiersman
