Category Archives: Molecular Medicine

VIENNA & OXFORD, England--(BUSINESS WIRE)--Exscientia (Nasdaq: EXAI), ETH Zurich, the Medical University of Vienna, and the Center for Molecular Medicine (CeMM) today announced a new publication in Blood Cancer Discovery, a journal of the American Association for Cancer Research, titled Deep Morphology Learning Enhances Precision Medicine by Image-Based Ex Vivo Drug Testing from the laboratory of Prof. Berend Snijder. This post-hoc analysis builds on the transformative work of the EXALT-1 trial, published in Cancer Discovery, by using deep learning algorithms to classify complex cell morphologies in patient cancer tissue samples into disease morphotypes.

EXALT-1 was the first prospective trial to demonstrate significantly improved outcomes for late-stage haematological cancer patients using an AI-supported precision medicine platform to guide personalised treatment recommendations as compared to physicians choice of treatment. In EXALT-1, 40% of patients experienced exceptional responses lasting at least three times longer than expected for their respective disease. The post-hoc analysis published today in Blood Cancer Discovery shows that combining the technology as used in EXALT-1 with new deep learning advancements that take advantage of cell-specific features in high-content images revealed a potential to further increase these patient outcomes.

Following results of the EXALT-1 study, these findings continue to validate that our AI-guided precision medicine platform has the ability to identify highly actionable clinical treatment recommendations for blood cancers, deepening our insights and enhancing the clinical predictive power of the platform to help patients, said Gregory Vladimer, Ph.D., VP Translational Research at Exscientia and co-inventor of the platform technology. Cell morphology, or assessing the characteristics of cells, is fundamental to the diagnosis of cancer. Within this research, we were able to utilise deep learning within the platform to improve our ability to identify personalised cancer treatments, leading to improved clinical outcomes for patients. At Exscientia, we are excited to expand the platforms applications in order to bring personalised medicine to broader populations.

We believe performing drug screens directly in tumour tissues of cancer patients is a great step forward in understanding tumour complexity compared to traditional cell model systems. The fact that we can now harness the power of deep learning to turn these terabytes of images into actionable insights is very exciting indeed, added Prof. Berend Snijder, Principal Investigator at the Institute of Molecular Systems Biology of the ETH Zurich in Switzerland.

The impact of deep learning on the clinical predictive power of ex vivo drug screening was assessed in a post-hoc analysis of 66 patients over a period of three years in a combined data set of 1.3 billion patient cells across 136 ex vivo tested drugs across haematological diagnoses including acute myeloid leukaemia, T-cell lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukaemia and multiple myeloma. Patients receiving treatments that were recommended by the platforms immunofluorescence analysis or deep learning on cell morphologies showed an increased rate of achievement of exceptional clinical response, defined as a progression free survival period that lasted three times longer than expected for each patients respective disease. Post-hoc analyses confirmed that the clinical predictions became more accurate when also considering the drug toxicity on the healthy cells within the tested patient sample.

Exscientias precision medicine platform uses custom deep learning and computer vision techniques to extract meaningful single-cell data from high content images of individual patient tissue samples. This analysis generates clinically-relevant insights into which treatments will deliver the most benefit to an individual patient. Further evaluation of individual patient results through Exscientias genomics and transcriptomics capabilities may help Exscientia further understand which other patients may benefit from similar treatments. The underlying technology was developed by Dr. Gregory Vladimer and Prof. Berend Snijder while working in the laboratory of Giulio Superti-Furga at the CeMM Research Center for Molecular Medicine in Austria.

About Exscientia

Exscientia is an AI-driven pharmatech company committed to discovering, designing and developing the best possible drugs in the fastest and most effective manner. Exscientia developed the first-ever functional precision oncology platform to successfully guide treatment selection and improve patient outcomes in a prospective interventional clinical study, as well as to progress AI-designed small molecules into the clinical setting. Our internal pipeline is focused on leveraging our precision medicine platform in oncology, while our partnered pipeline broadens our approach to other therapeutic areas. By pioneering a new approach to medicine creation, we believe the best ideas of science can rapidly become the best medicines for patients.

Exscientia is headquartered in Oxford (England, U.K.), with offices in Vienna (Austria), Dundee (Scotland, U.K.), Boston (Mass., U.S.), Miami (Fla., U.S.), Cambridge (England, U.K.), and Osaka (Japan).

Visit us at https://www.exscientia.ai or follow us on Twitter @exscientiaAI.

Forward-Looking Statements

This press release contains certain forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including statements with regard to Exscientias expectations with respect to the progress of development of candidate molecules, timing and progress of, and data reported from, preclinical studies and clinical trials of Exscientias product candidates, and Exscientias expectations regarding its precision medicine platform and AI-driven drug discovery platform. Words such as anticipates, "believes," expects, "intends," "projects," "anticipates," and "future" or similar expressions are intended to identify forward-looking statements. These forward-looking statements are subject to the uncertainties inherent in predicting future results and conditions, including the scope, progress and expansion of Exscientias product development efforts; the initiation, scope and progress of Exscientias and its partners clinical trials and ramifications for the cost thereof; clinical, scientific, regulatory and technical developments; and those inherent in the process of discovering, developing and commercialising product candidates that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such product candidates. Exscientia undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

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Blood Cancer Discovery Publication Further Validates Exscientia's AI Precision Medicine Platform for Improving Patient Outcomes - Business Wire

During the 2021-22 fiscal year, 13 startup companies executed agreements to access foundational intellectual property and commercialize new technologies developed at the University of California, Davis.

The bold pursuit of novel solutions through research at UC Davis often results in new technologies and services aligned with a commercial pathway for impact, said Prasant Mohapatra, vice chancellor for research at UC Davis. In most cases those innovations are licensed to existing companies, but many also become the foundation for emerging startups. We are thrilled to see the success of this pathway continue at UC Davis.

The process for connecting innovations from the university to commercial impact is managed by the Innovation and Technology Commercialization division, which is part of the Office of Research. During the 2021-2022 fiscal year, the division processed 132 new records of invention and executed 48 license agreements.

The divisions Venture Catalyst unit focuses on advancing potential technologies with proof-of-concept funding and facilitating startup formation.

The University of California system of campuses ranks first in the world for the number of U.S. utility patents according to a recent report from the National Academy of Inventors and the Intellectual Property Owners Association.

Venture Catalyst, which was launched in 2013, provides resources to help campus innovators advance technologies and launch new companies, said Janine Elliott, interim director Venture Catalyst. It is exciting to see the results of these efforts and the broad range of solutions being advanced.

In the last 10 years Venture Catalyst assisted 130 startups with foundational intellectual property. The 13 emerging startups over the past year are focused on developing technology to meet needs in food, health and agriculture.

One of the startups,Eunicera is developing novel therapeutics to treat and cure advanced drug-resistant prostate cancer. Co-founded by Allen Gao, a professor in the Department of Urology, the companys proprietary, orally bioavailable small molecules targeting both AKR1C3 and androgen receptor variants either work alone or in combination with current therapies to overcome and prevent treatment resistance.

Another company, Optimized Foods is propelled by innovations in the food technology and cultivated meat sectors. By using a novel approach in mycelium technology, the team is creating nutritious, sustainable foods, starting with cultured caviar. Minami Ogawa, a graduate student in the Department of Food Science, discovered how the innovation could be harnessed as an ideal proprietary scaffold for cell cultivation. In parallel, Ruihong Zhang, a professor in the Department of Biological and Agricultural Engineering, and her lab had been developing foundational elements of the platform for food applications. The companys platform is focused on making the dream of cultivated meat a reality, and improving human, animal and planetary health.

Peak B is commercializing natural alternatives to synthetic food colorants with superior color qualities, stability and potency. The UC Davis-led startup hasdiscovered a cyan blue color, solving one of the biggest challenges in the food industrys search to source natural food colorants. The researchers examinedanthocyanin, a water-soluble pigment thats found in many familiar fruits and vegetables, giving them their vibrant red, purple, pink and blue hues. A specific anthocyanin was discovered in red cabbage thatdisplayed the desired blue properties. Since the amount of anthocyanin is small in red cabbage, they used an enzyme-based process to turn its other anthocyanins into blue.Co-founded byJustin Siegel,an associate professor in chemistry, biochemistry and molecular medicine, the companys patented enzyme-based process now turns extracts from natural sources into blue and green colorants that can be used in a variety of food applications.

Additional companies that executed agreements to access the foundational intellectual property from UC Davis during the 2021-22 fiscal year are highlighted below. Three companies have chosen to remain in stealth mode for competitive reasons and are not listed.

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New Startups Built From UC Davis Innovations Drive Solutions in Food, Health and Agriculture - University of California, Davis

University of Gothenburg Researchers have identified a procedure that was not known to scientists in the past which can be used to control cancer growth. The new research has hinted at the direction of possible new drugs with lesser side effects in near future.

The study was published in the journal Nature Communications. The study focuses on the protein that binds the genetic material and controls the conditions that lead to tumor development. The properties that promote tumor growth are neutralized, paving the way for the development of drugs, says Chandrasekhar Kanduri, one of the research leaders behind the study. Drugs can be manufactured in the future to neutralize the effect of protein that promotes tumor growth.

Drugs come with their own side effects. But a recent study shows that controlling the protein responsible for tumors can be done without posing any danger. The mechanism has the potential to become a more attractive cancer treatment option, with fewer side effects, says Meena Kanduri, Associate Professor of Molecular Medicine.

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Scientists Discover New Cancer Treatment - The Morning News

Precision medicine places the patient at the center of healthcare, using a variety of tools to develop tailored and targeted therapeutics and diagnostics.

Promised to revolutionize the landscape of modern medicine, precision medicine requires an in-depth knowledge of the molecular underpinnings of healthy and diseased states. Advances in molecular biology techniques and bioinformatic platforms are helping to provide such knowledge, equipping researchers and physicians with the tools to implement precision medicine approaches across different disease areas.

Thus far, oncology the field of cancer research and treatment has arguably seen the most benefit from precision medicine. However, the pharmaceutical and biotechnology company AstraZeneca believes that precision medicine will rewrite the textbook for the diagnosis and treatment of chronic diseases. Technology Networks recently had the pleasure of speaking with Mark Fidock, vice president for Diagnostic Development, Precision Medicine at AstraZeneca, to find out how the company is rising to the challenge of delivering precision medicines for chronic diseases.

Molly Campbell (MC): Can you talk about some of the ways in which AstraZeneca is actively pursuing precision medicine?

Mark Fidock (MF): I think an interesting metric is that, when we look at our portfolio, over 90% of it has a precision medicine strategy. Precision medicine as a strategy and as a discipline really does encompass the full spectrum of drug research and development. That includes finding new targets which requires the use of cutting-edge methods that are available advancing and pioneering new technologies and of course, driving for better patient outcomes and a more sustainable healthcare system.

One of the areas in which we've made major advances is oncology. AstraZeneca has already achieved over 50 regulatory-approved companion diagnostics across a variety of indications and across a variety of different sample types. This has enabled innovative targeted therapies to be developed and benefit millions of cancer patients worldwide.

The work and success we have achieved in oncology has almost produced a framework for which we can develop precision medicine approaches for chronic diseases. However, we need to recognize that chronic disease is biologically complex and very heterogenous in origin, so a key priority in this space is to investigate the ways in which precision medicine can be deployed and used that increases our disease understanding and leads to better patient outcomes.

The opportunity in the precision medicine space is huge, especially for chronic diseases. Were now in an era where, through precision medicine, we are rewriting the textbook for many indications, and changing the way in which we ultimately treat patients.

MC: Lets talk more about the tools and technologies used. What are the key technological developments that are helping us to understand the biology behind diseases, and harness that information to tailor treatments?

MF: One of the key technology areas (in which AstraZeneca is a leader) is genomics research. Our in-house Centre for Genomics Research intends to sequence 2 million genomes by 2026 which of course, isnt all that far away now. Using very innovative bioinformatics analysis methods, the groups behind this project are looking for rare variants associated with diseases. Through doing so, they are uncovering new biological insights into disease, discovering new therapeutic targets and describing the diseases at a much more granular almost molecular or genetic, way.This creates opportunities for the development of targeted therapies for different segments of a particular disease.

Key examples include the discovery of novel targets in respiratory and immunology diseases, cardiovascular research and renal and metabolic diseases. One of AstraZenecas areas of interest is pulmonary fibrosis, and the group has previously published the discovery of a gene called SPDL1 identified in idiopathic pulmonary fibrosis.

The SPDL1 gene encodes a protein known as Spindly which is responsible for signaling during cell division. Previously, this gene had not been described in relation to idiopathic pulmonary fibrosis. The identification of a novel mechanism underpinning the disease opens the door for novel therapeutic discoveries.

In cardiomyopathy, the group also published a finding relating to the TTN gene. Both examples are key illustrations of how genomic techniques can be used to inform our understanding of a disease. These publications have been shared widely amongst the scientific community.

The TTN gene encodes a protein called titin. Truncated variants of the gene contribute to approximately 1525% cases of nonischemic dilated cardiomyopathy, a condition where the left ventricle becomes enlarged.

MC: Can you talk about the importance of biomarkers in precision medicine? How are they used to identify patients and develop targeted therapies?

MF: I think the opportunity space for precision medicine across all disease indications that AstraZeneca is exploring is huge. It will enhance our ability to rewrite the medical textbooks that physicians are using to understand, diagnose and treat disease.

How do we do this? A core aspect of precision medicine is identifying predictive biomarkers, which is achieved through the insights gathered using genomic studies and other means. Predictive biomarkers provide the opportunity to include the right patients in our clinical trials and to develop targeted companion diagnostics and treatment approaches most appropriately.

In those disease areas where we already have multiple targeted treatment options available, we also have identified biomarkers for selecting patients. One example is in non-alcoholic steatohepatitis (NASH) where A second example is IL33 a cytokine that is seen and raised in many different indications, from asthma to diabetic kidney disease and even in COVID-19.

These are areas whereby the biomarker and the scientific research surrounding the biomarker is helping us to identify the right patients, which allows us to direct where our targeted therapeutics will have the most beneficial clinical outcomes.

MC: Can you talk about the importance of collaboration in the precision medicine space? How is AstraZeneca pursuing collaborative projects?

MF: AstraZeneca works in a very collaborative way, with many collaborations established across each of the different research spaces in which we choose to operate.

We must develop companion diagnostics that are scalable and have global reach, so they're aligned not only to our targeted treatments, but they're also analytically and clinically validated and demonstrate patient benefit. We've built global partnerships to deliver these tests that can be commercialized, which really does enable maximal access to patients. It also ensures these diagnostics are used consistently within the regulatory requirements across whichever part of the world that they will be used.

Through one of our collaborations with Almac, we are developing and validating companion diagnostic tests for patient selection across a variety of different clinical trials for a range of therapeutic areas, such as chronic kidney disease, NASH and respiratory diseases. This is a robust framework that we can adapt for use with other ongoing collaborations, such as our work with Roche diagnostics, among others.

In terms of challenges, when you're innovative, leading in a space and you are creating information that is rewriting rulebooks and rewriting the ways in which treatments are being derived, of course there are going to be some challenges. I think we can all agree that health is a fundamental right that we should all have access to, and that it should be inclusive and tailored to the individual. We think that precision medicine will be a vital part of this offering, it will improve health and it will improve health equality. We need to have discussions to ensure that all healthcare systems can fully adopt this approach into clinical practice, which is achieved through interactions, partnerships and engaging in symposiums and summits. We recently spoke at the World Health Summit, and AstraZeneca aims to bring together panels of external leaders across different diagnostic organizations, to talk through policy and to look at ways in which we can help to bring novel approaches to the clinical community and healthcare structures.

MC: Looking to the future of precision medicine, what are the key priorities in precision medicine for AstraZeneca? What do you envision that this space is going to look like in, say, 1015 years?

MF: The more that we use precision medicine within the chronic disease space, and the more that science really begins to uncover how these complex chronic diseases are derived and their etiology, the more we can look to develop new therapeutic modalities. We can identify the right patient populations for diagnostics to target treatments and ultimately, this will deliver much better outcomes for patients in the long term.

What will it look like in the future? I think that a key focus is asking: how do we bring in novel diagnostics into clinical practice? How do we bring precision medicine to the patient? The future is about patient convenience. One day, it would be fantastic to be able to introduce molecular diagnostic devices to the home, so that patients can monitor their diseases as they are happening. This will involve bringing digital advancements such as progress in artificial intelligence (AI) into the different areas of precision medicine. How do we do this? How do we use digital mediums to derive actionable diagnostic data, where patients can take a diagnostic test in their own environment, that data is then shared with their treating physician enabling decisions and discussions to be held for the patients benefit? These will be important considerations.

A big part of the future is looking to further develop the scientific understanding of chronic disease and bringing together all the learnings that we've had in precision medicine and maximizing the outcome for patients. The future of precision medicine is about having a deep understanding of chronic disease at a molecular, genetic or metabolic level, in such a way that we're able to really make sure that the patient is at the heart of everything, and that they can have the benefit and the convenience of precision medicine in the future.

Mark Fidock, VP for Diagnostic Development, Precision Medicine at AstraZeneca was speaking to Molly Campbell, Senior Science Writer for Technology Networks.

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Rewriting the Textbook for Precision Medicine - Technology Networks

In an interview with '60 Minutes', the president said the pandemic is over, but much work remains. Physicians rejected the assessment and noted hundreds are dying each day.

In a wide-ranging interview on the season premiere of 60 Minutes Sunday night, President Biden surprised many health experts by saying, The pandemic is over.

Responding to a question from CBS journalist Scott Pelley, Biden also said, We still have a problem with COVID. We're still doing a lotta work on it. It's-- but the pandemic is over. if you notice, no one's wearing masks. Everybody seems to be in pretty good shape. And so I think it's changing. (Heres the transcript of the interview.)

Many healthcare experts cringed at the presidents assessment.

Esther Choo, an emergency physician and researcher, wrote on Twitter, The pandemic is not over, and acting like it is harming its ability to *ever* be over. Just last week, she wrote in a piece for MSNBC, The pandemic is marching along quite robustly.

While COVID-19 deaths and hospitalizations are well below the peaks of last winter, the virus continues to take a toll.

After Bidens interview aired, Eric Topol, a physician, author and professor of molecular medicine at Scripps Research, said on Twitter, Wish this was true. What's over is @POTUS's and our government's will to get ahead of it, with magical thinking on the new bivalent boosters.

Topol added Bidens statement ignores the reality of long Covid, the likelihood of new variants, and our current incapability for blocking infections and transmission.

Gavin Yamey, director of global health and public policy at Duke University, disagreed with the president in a piece for Time magazine. The headline: Biden is wrong, the COVID-19 pandemic isnt over. Yamey said the pandemic will end, but were not at the finish line.

The major problem with the President saying the pandemic is over is that it could impede our efforts to reach low endemic levels, Yamey wrote. For example, Congress is less likely to renew funding for COVID-19 measures if the pandemic has ended.

Hospitals have been urging Biden and Congress to approve more federal aid. While acknowledging federal aid helped sustain hospitals in the pandemic, they also say they havent received aid for the influx of COVID-19 patients infected with the Delta and Omicron variants.

Rick Pollack, president of the American Hospital Association, has urged the president and lawmakers to support American hospitals. More than half of U.S. hospitals could end 2022 in negative margins as hospitals are losing billions, the AHA said in a report last week. Hospitals and health systems are also anxious to continue waivers for key services, including telehealth, that are tied to the COVID-19 public health emergency.

In a media call last week, Pollack also pointed out the fight against COVID-19 hasnt ended. Hospitals continue to treat COVID-19 patients, along with a host of patients who deferred care in the pandemic and are now requiring longer hospital stays.

Hundreds are dying each day due to COVID-19 (the 7-day average is 410, The Washington Post reports). The 7-day average of COVID-19 hospitalizations is just over 24,000, according to the U.S. Centers for Disease Control and Prevention.

Jorge Caballero, who co-founded Coders Against COVID, a collaborative to address data gaps in the pandemic, said on Twitter that he feared saying the 'pandemic is over' will directly lead to preventable illness and death.

The Biden administration sought to clarify the messaging on the pandemic.

Sarah Lovenheim, a spokeswoman for the U.S. Department of Health and Human Services, reiterated Monday that the COVID-19 public health emergency remains in effect.

HHS will provide a 60-day notice to states before any possible termination or expiration, Lovenheim posted on Twitter. As weve done previously, well continue to lean on the science to determine the length of the PHE.

Health officials are also urging the continuation of the public health emergency so millions won't lose health coverage. When the emergency declaration expires and Medicaid's continuous enrollment provision ends, the health department projects as many as 15 million Americans could lose coverage.

Anthony S. Fauci, the federal governments chief expert on infectious diseases, told The Washington Post, We still have a lot of work to do to get it down to a low enough level that we would feel comfortable with it.

Im not comfortable with 400 deaths per day, Fauci said in the interview.

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Biden says 'The pandemic is over,' but health experts disagree - Chief Healthcare Executive

Aggregates of the protein alpha-synuclein spread in the brains of people with Parkinsons disease through a cellular waste-ejection process, suggests a new study led by Weill Cornell Medicine researchers.

During the process, called lysosomal exocytosis, neurons eject protein waste they cannot break down and recycle. The discovery, published Aug. 22 in Nature Communications, could resolve one of the mysteries of Parkinsons disease and lead to new strategies for treating or preventing the neurological disorder.

Our results also suggest that lysosomal exocytosis could be a general mechanism for the disposal of aggregated and degradation-resistant proteins from neuronsin normal, healthy circumstances and in neurodegenerative diseases, said study senior author Dr. Manu Sharma, an assistant professor of neuroscience in the Feil Family Brain and Mind Research Institute and Appel Alzheimers Disease Research Institute at Weill Cornell Medicine.

Parkinsons is a disorder that features the deaths of neurons in a characteristic pattern of spread through the brain, normally unfolding over decades. The disease is best known for causing hand tremors, muscle rigidity, slowed gait and other impairments of normal movement. But it affects a broad set of brain regions, resulting in many different symptoms, including dementia in late stages. Approximately 1 million people in the United States have Parkinsons. Available treatments can alleviate some movement abnormalities but do not stop disease progressionessentially because researchers dont yet have a full understanding of that process.

One important finding that has emerged from the past few decades of Parkinsons research is that the deaths of neurons in the disease follow the spread, within the brain, of abnormal aggregates of alpha synuclein, a neuronal protein. This spread is an infection-like, chain-reaction process in which aggregates induce normal alpha synuclein to join them, andas they grow largerbreak into smaller aggregates that continue to propagate. Experiments in mice and non-human primates have shown that injecting these aggregates into the brain can initiate this spread as well as some Parkinsons-like neurodegeneration. But the details of how neurons transmit them to other neurons, have never been well understood.

In the study, Dr. Sharma and his team, including co-first author Ying Xue Xie, a doctoral candidate in the Weill Cornell Graduate School of Medical Sciences, showed with detailed studies of Parkinsons mouse models that alpha synuclein aggregatescapable of spreading and causing neurodegenerationoriginated within neurons. These aggregates, they found, then accumulate within capsule-like waste bins in cells called lysosomes.

Lysosomes contain enzymes that can break down, or lyse, proteins and other molecular waste into their building blocks, essentially digesting and recycling them. But the researchers found evidence that alpha synuclein aggregates, which are knit together with tight bonds in a close-fitting/snugly layered structure called amyloid, are not broken down well within lysosomes; instead, they were often found to be simply dumped from their originating neurons. In this process, called exocytosis, the lysosome moves to the cell membrane and merges with it, so that the lysosome contents are dischargedas-is, without any encapsulationinto the fluid surrounding the cell. The finding helps resolve a hotly debated question in the field.

The researchers also showed in further experiments that by reducing the rate of lysosomal exocytosis, they could reduce the apparent concentration of spread-capable aggregates. That, Dr. Sharma said, suggests a future approach to treating Parkinsons.

We dont know yet, but neurons might be better off, even in the long term, if they keep these aggregates inside their lysosomes, he said. We see a similar impairment of lysosomal function in some genetic disorders, but these dont necessarily lead to a Parkinsons level of disease.

Dr. Sharma emphasized that prior studies, including genetic studies, have linked lysosomal abnormalities not only to Parkinsons but to also many other neurodegenerative disorders. This hints that lysosomal exocytosis may be a general mechanism of protein-aggregate spread in these diseasesand potentially a general target for treatments and preventives.

He and his team are currently following up with studies of lysosomes roles in Alzheimers disease.

Link:
Discovery Illuminates How Parkinson's Disease Spreads in The Brain - Weill Cornell Medicine Newsroom

Novel artificial intelligence methods have revealed unexpected microscopic abnormalities that can predict cognitive impairment, according to a study led by researchers at Mount Sinai. These findings were published in the journalActa Neuropathologica Communicationsthis week.

AI represents an entirely new paradigm for studying dementia and will have a transformative effect on research into complex brain diseases, especially Alzheimers disease, said co-corresponding author John Crary, MD, PhD, Professor of Pathology, Molecular and Cell-Based Medicine, Neuroscience, and Artificial Intelligence and Human Health, at the Icahn School of Medicine at Mount Sinai.

He added that, The deep learning approach was applied to the prediction of cognitive impairment, a challenging problem for which no current human-performed histopathologic diagnostic tool exists.

The Mount Sinai team identified and analyzed the underlying architecture and cellular features of two regions in the brain, the medial temporal lobe and frontal cortex. In an effort to improve the standard of postmortem brain assessment to identify signs of diseases, the researchers used a weakly supervised deep learning algorithm to examine slide images of human brain autopsy tissues from a group of more than 700 elderly donors to predict the presence or absence of cognitive impairment.

The weakly supervised deep learning approach, they report, is able to handle noisy, limited, or imprecise sources to provide signals for labeling large amounts of training data in a supervised learning setting. This model was used to pinpoint a reduction in Luxol fast blue staining, which is used to quantify the amount of myelin, the protective layer around brain nerves.

The researchers identified a signal for cognitive impairment that was associated with decreasing amounts of myelin staining; scattered in a non-uniform pattern across the tissue; and focused in the white matter, which affects learning and brain functions. The two sets of models trained and used by the researchers were able to predict the presence of cognitive impairment with an accuracy that was better than random guessing.

The team believe the diminished staining intensity in particular areas of the brain identified by AI may serve as a scalable platform to evaluate the presence of brain impairment in other associated diseases. The methodology lays the groundwork for future studies, which could include deploying larger scale artificial intelligence models as well as further dissection of the algorithms to increase their predictive accuracy and reliability. The team said, ultimately, the goal of this neuropathologic research program is to develop better tools for diagnosis and treatment of people suffering from Alzheimers disease and related disorders.

Leveraging AI allows us to look at exponentially more disease relevant features, a powerful approach when applied to a complex system like the human brain, said co-corresponding author Kurt W. Farrell, PhD, Assistant Professor of Pathology, Molecular and Cell-Based Medicine, Neuroscience, and Artificial Intelligence and Human Health, at Icahn Mount Sinai. It is critical to perform further interpretability research in the areas of neuropathology and artificial intelligence, so that advances in deep learning can be translated to improve diagnostic and treatment approaches for Alzheimers disease and related disorders in a safe and effective manner.

Lead author Andrew McKenzie, MD, PhD, Co-Chief Resident for Research in the Department of Psychiatry at Icahn Mount Sinai, added: Interpretation analysis was able to identify some, but not all, of the signals that the artificial intelligence models used to make predictions about cognitive impairment. As a result, additional challenges remain for deploying and interpreting these powerful deep learning models in the neuropathology domain.

Researchers from the University of Texas Health Science Center in San Antonio, Texas, Newcastle University in Tyne, United Kingdom, Boston University School of Medicine in Boston, and UT Southwestern Medical Center in Dallas also contributed to this research.

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AI Used to Determine Cause of Alzheimer's and Related Disorders - Inside Precision Medicine

William J. Gradishar, MD, professor of medicine of hematology and oncology, Betsy Bramsen Professor of Breast Oncology, and chief of hematology and oncology in the Department of Medicine at the Feinberg School of Medicine at Northwestern University, discusses the questions ongoing studies are looking to answer in the breast cancer space.

New data has led to an increase of treatment options for patients with breast cancer with guidelines constantly changing to reflect what is newly available. However, Gradishar notes that even with more treatment options, experts are unable to perfectly predict which patients will recur.

In order to gain more insight on this space, the next steps for investigators will include continuing to develop molecular tools, defining the patients who need chemotherapy, and learning who may need extended durations of endocrine therapy.

Transcription:

0:08 | With respect to early-stage breast cancer and how we approach things, our prediction of who is going to recur is still not perfect. We've made an effort over time to develop molecular tools, whether you're talking about MammaPrint or the oncotype test, to define patients who may need chemotherapy, and those that can be treated effectively and safely with anti-hormone therapy alone. They're not absolutely perfect.

0:40 | Similarly, trying to determine who needs extended durations of endocrine therapy. We've had potential tools, the breast cancer index, other things, and that is met with some discordance in the results, so it's not entirely clear. We can always use those tools confidently to determine who can stop therapy or who needs to continue it with respect to endocrine therapy. I think as we go forward, we'll probably be developing better molecular tools to identify a minimal residual disease trying to identify those patients who have subclinical microscopic disease. That may be based on circulating tumor DNA or specific signatures from the primary tumor that we can still identify in the blood. Then we'll have to validate whether or not finding those things and treating them results in a better outcome.

1:43 | The next phase is probably trying to employ some of those molecular tools in a way that helps us further refine what therapies we would give to patients at high risk, but also the same thing, to de-escalate where patients don't need it. Hopefully, we can do that without having to do these 5000 or 7000 patient trials to figure it out.

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Looking Ahead in the Treatment of Breast Cancer - Targeted Oncology

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Credit: Allyn DiVito

It may soon be possible to identify Group 4 medulloblastomasthe most common malignant brain tumor in children--from more aggressive Group 3 tumors. Research based on a little-explored part of RNA, which creates proteins, could lead to the development of better-targeted cancer treating drugs, according to investigators at the Johns Hopkins Kimmel Cancer Center.

Four groups of medulloblastomas have been identified, with Group 3 being the most aggressive survival at 5 years is a 45% to 60% rate. Group 4 is the most common form of medulloblastoma, accounting for 35-40% of all cases.

The findings were published in Aug. 22 in the journal Neuro-Oncology Advances.

To date, it is difficult to distinguish Group 3 tumors which have a better prognosis (five-year survival is 75%-80%) from Group 4 tumors. Treatment for Group 3 is more aggressive than Group 4, often including radiation therapy. Distinguishing between Group 3 and Group 4 medulloblastomas relies on immunohistochemistry of tissue samples--specialized testing used to distinguish typesand imaging.

Group 3 and group 4 medulloblastomas are very similar to each other and, it's hard to differentiate them under the microscope. So, we started looking at the molecular markers, said senior study author Ranjan Perera, Ph.D., director of the Center for RNA Biology at Johns Hopkins All Childrens Hospital (JHACH) in St. Petersburg, Florida. Perera is also a senior scientist at the JHACH Cancer & Blood Disorders Institute and an associate professor of oncology at the Johns Hopkins University School of Medicine. He has a secondary affiliation with the JHACH Institute for Fundamental Biomedical Research.

In particular, the investigators looked at long non-coding RNA (lncRNA), which experts thought did not play a role in building proteins. New evidence, however, finds that they play a role in regulating gene expression that impacts cancer growth and behavior.

Perera and coinvestigators found that a lncRNA gene, called SPRIGHTLY, is highly expressed in Group 4 medulloblastomas, but not Group 3. We found that this long noncoding RNA (SPRIGHTLY) interacts with one gene called SMYD3, he said. SMYD3 regulates endothelial growth factor receptor (EGFR), which helps the cancer develop new blood vessels that nourish the tumor.

Clearly, SPRIGHTLY could serve as a biomarker for Group 4 because we have not seen this in Group 3 or the other two groups, he says.

The researchers studied SPRIGHTLY in mouse and human models of medulloblastoma and observed that developing tumors were smaller than cells without SPRIGHTLY. Tumor growth was also slower in models where SPRIGHTLY deactivated, supporting the role of SPRIGHTLY in tumor growth and proliferation.

The investigators also conducted laboratory tests that showed that SPRIGHTLY interacts with another protein called PTPB1, which regulates SMYD3 protein production. This pathway enhances the expression of EGFR in Group 4 medulloblastomas and potentially provides a treatment target. There are several existing drugs that inhibit EGFR. Of course, much work is needed to better understand the molecular mechanisms of the SPRIGHTLY pathway in Group 4 medulloblastomas before investigation of treatments.

In addition to Perera, study co-authors were Bongyong Lee, Keisuke Katsushima, Rudramani Pokhrel, Menglang Yuan, Stacie Stapleton, George Jallo and Charles Eberhart of Johns Hopkins; Robert J. Wechsler-Reya of Sanford Burnham Prebys Medical Discovery Institute in La Jolla, California; and Animesh Ray of Keck Graduate Institute in Claremont, California, and California Institute of Technology in Pasadena, California.

The work was supported in part by the Schamroth Project funded by Ians Friends Foundation, Hough Family Foundation, and Susan and Robb Hough to Ranjan J. Perera and George Jallo, and NCI grant to Ranjan J. Perera and Charles Eberhart (1R37CA230400).

Neuro-Oncology Advances

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Researchers identify potential biomarker to distinguish two aggressive types of brain tumors in children - EurekAlert

Health care systems encourage everyone eligible to get a COVID-19 vaccination and booster. (Getty Images)

Vaccine boosters and breakthrough infections following vaccination both provide a substantial and potentially pandemic-breaking immunity against COVID-19, according to new laboratory research from Oregon Health & Science University.

The study, published Wednesday in the journal Med, is the latest in a series of OHSU discoveries using blood samples to characterize immune response to the SARS-CoV-2 virus.

As the number of omicron subvariant cases rise and as global vaccination and booster campaigns continue, an increasing proportion of the worlds population will acquire potent immune responses that may be protective against future SARS-CoV-2 variants, the researchers conclude.

The research measured a powerful immune response among samples from 99 OHSU employees who had blood drawn for the research. Notably, researchers measured an equally potent immune response to the virus with dramatic increases in magnitude, potency and breadth among people whose blood was drawn three months after a third vaccine booster dose and another group one month after a breakthrough infection.

In addition, the study found the immune response was just as powerful among people 65 and older.

Marcel Curlin, M.D. (OHSU)

Early in the pandemic, we had very high mortality in certain vulnerable groups, such as older adults in nursing homes, but that reality is slowly changing, said co-senior author Marcel Curlin, M.D., associate professor of medicine (infectious diseases) in the OHSU School of Medicine and medical director of OHSU Occupational Health. Our study bolsters the idea that vaccination is a pathway to a milder illness. Even if youre older, your chances of having a severe illness if youre re-infected down the line appears to be much lower than it was at the start of the pandemic.

Fikadu Tafesse, Ph.D. (OHSU)

Co-senior author Fikadu Tafesse, Ph.D., associate professor of molecular microbiology and immunology in the OHSU School of Medicine, said he would expect an even more robust immune response among people receiving the new bivalent vaccine booster targeting the BA.4 and BA.5 variants.

We anticipate that updated vaccine strategies with variant-specific regimens will significantly improve the breadth of the immune response and provide better protections against the SARS-CoV-2 variants, he said.

In contrast to the onset of the pandemic, the SARS-CoV-2 virus is no longer novel to the human immune system. Most people in the world have now been vaccinated, infected or both meaning the virus is running up against a much more effective immune response with each new infection.

Curlin said the new study most likely reflects the fact that the virus is evolving to become more transmissible but less harmful.

Evolutionary pressure is driving the virus to find more ways to infect people at the cost of pathogenicity, most likely, he said. Pathogenicity refers to the capacity to cause symptoms associated with the disease.

Funding for this study was supported by the M.J. Murdock Charitable Trust; the OHSU Foundation; the National Institutes of Health training grant T32HL083808; and a grant from the OHSU Innovates IDEA fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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New study reveals breakthrough infections increase immunity to COVID-19 - OHSU News