Sergio Vaccari Ph.D., HCLD

Mutations in an orphan receptor protects aginst obesity and steatotic liver Orphan G protein-coupled receptor 75 (GPR75) is involved in liver lipid accumulation, The authors show that Gpr75 gene is co-expressed with hunger-promoting hypothalamic neurons. CRISPR deleted Gpr75 mice fed a palatable western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. The authors identify that mutations in orphan receptor GPR75 are protective against the development of non-alcoholic fatty liver disease. These findings provide a much-needed novel treatment target for a prevalent disease in the global population. #sciencenewshighlights #ScienceMission https://lnkd.in/grHQ4Smi https://lnkd.in/gaPRab_a

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13% of #patients w/ #gastriccancer (GC) had pathogenic #germline variants (PGVs) w/ #germline #genetictesting (GGT) including BRCA1, BRCA2, PALB2, ATM, CDH1, CTNNA1, MLH1, MSH2, MSH6, PMS2,EPCAM These data support consideration of universal GGT in all GC #patients 'Prevalence of pathogenic #genetic variants in #patients with GC ascertained through multi-gene panel GGT' #DrOphirGilad University of Chicago Medicine Comprehensive Cancer Center Invitae #ASCO24 American Society of Clinical Oncology (ASCO) c/w https://lnkd.in/gBhpWi3k Pedro Uson et al. #DigestiveDiseasesSciences @ Springer Nature Group #access #universal #germlinetesting #reducedisparities #precisionmedicine #precisiontherapy #clinicaltrials #precisionprevention CGA IGC

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One of the major challenges in treating lung cancer, particularly EGFR mutant types, is overcoming drug resistance that often leads to treatment failure and disease relapse. Traditional strategies primarily focus on genetic alterations, but non-genetic mechanisms also play a critical role in resistance. A recent study published in Communications Biology by Matthias Pfeifer and colleagues brings new insights into this issue. Through genome-wide CRISPR screens, the research identifies the YAP/TEAD axis within the Hippo pathway as a key player in the survival of drug-resistant persister cells in EGFR mutant lung cancer. The Hippo pathway, which regulates organ size by controlling cell growth and death, when disrupted, can lead to uncontrolled cell proliferation commonly seen in cancers. This discovery suggests that targeting the Hippo pathway, along with EGFR, could significantly improve treatment outcomes by not only attacking cancer cells but also preventing the emergence of resistance. The study's findings pave the way for developing dual-target therapies, which might be more effective in managing and potentially overcoming drug resistance. Looking ahead, a crucial challenge will be to develop combination therapies that effectively target both genetic and non-genetic mechanisms of resistance to enhance treatment outcomes. Enjoy reading this great research here: https://lnkd.in/dYsFT8_B #LungCancerResearch #Genomics #CRISPR #CancerTreatment #MedicalResearch #Oncology

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CDK4/6 Inhibitors in Triple Negative Breast Cancer: A New Biomarker for Palbociclib Resistance Published on 2024 Jun Triple negative breast cancer (TNBC) is an aggressive subtype with limited treatment options. While CDK4/6 inhibitors like palbociclib have shown promise, predicting their efficacy in TNBC remains a challenge. Key Findings: In vivo CRISPR Screen: A genome-wide CRISPR screen in TNBC identified TGFβ3 as a key gene influencing palbociclib sensitivity. TGFβ3 as a Biomarker: Low TGFβ3 levels correlate with palbociclib resistance in TNBC, offering a potential biomarker for patient selection. Synergistic Effect: Combining TGFβ3 with palbociclib enhances its anti-tumor effects, even in palbociclib-resistant cells. Mechanism of Action: TGFβ3 increases p21 expression, a cell cycle inhibitor, which enhances palbociclib's ability to induce cell cycle arrest. Clinical Implications: This discovery may lead to improved treatment strategies for TNBC, personalizing therapy based on TGFβ3 levels. Many thanks to: Sophie Poule, Meiou Dai, Ni Wan, Gang Yan, Julien Boudreault, Girija Daliah, Alan Guillevin, Huong Nguyen, Soaad Galal, Suhad Ali, Jean-Jacques Lebrun. Read the full research article here: https://lnkd.in/dAV8wmkd #TNBC #BreastCancer #CancerResearch #PersonalizedMedicine #DrugResistance #Biomarkers #CRISPR #TGFbeta #Palbociclib #CDK4/6inhibitors

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Molecular cellular mechanism linked to microcephaly Nonsense-mediated RNA decay, or NMD, is an evolutionarily conserved molecular mechanism in which potentially defective messenger RNAs, or mRNAs (genetic material that instructs the body on how to make proteins), are degraded. Disruption of the NMD pathway can lead to neurological disorders, immune diseases, cancers, and other pathologies. Mutations in human NMD regulators are seen in neurodevelopmental disorders, including autism and intellectual disability. Why NMD mutations are enriched in neurodevelopmental disorders remains a mystery. The senior author said " We generated various NMD deficiency animal models by knocking out a key NMD factor, Upf2, in different cell types and determined their phenotypic differences. We found NMD deficiency causes more impacts on the proliferative neural progenitors, which is consistent with the notion that NMD function is essential for early brain development and its mutations are enriched in neurodevelopmental disorders. Importantly, we showed NMD deficiency in progenitor cells cause microcephaly, a novel finding that links an NMD decay pathway to brain size control." The author continued " Once we found the microcephaly phenotype, we used primary cell culture models to define the growth defects of Upf2 knockout, or Upf2KO, in neural progenitors. Next, we applied CRISPRi screening to identify genes whose perturbation can interfere with Upf2KO NPCs’ growth defect. Among hundreds of genes we screened, we identified a few candidates and followed on the top candidate, p53, which is well known to be a tumor suppressor gene that controls cell growth. Subsequently, we used various single cell approaches and transcriptomics technologies to determine precisely how NMD and p53 intersect in controlling cell growth." hashtag #ScienceMission #sciencenewshighlights https://lnkd.in/gUswB4Y2

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Alterations in nucleus size, shape, and color are ubiquitous in cancer, but comprehensive quantification of nuclear morphology across a whole-slide histologic image remains challenging. A new open-access publication by John Abel and larger team at PathAI details the development of a pan-tissue, deep learning-based digital pathology pipeline for exhaustive nucleus detection, segmentation, and classification. I included the link to the full paper and a summary below for anyone interested. AI powered quantification of nuclear morphology in cancers enables prediction of genome instability and prognosis. https://lnkd.in/esNTTDjs Methods overview: The authors collected over 29,000 manual annotations of cell nuclei from H&E images of 21 tumor types and other diseases to train and validate an object detection and segmentation model. Their model for nucleus analysis is a Mask-RCNN-style architecture with a ResNet50 backbone pretrained on ImageNet. It was deployed on whole-slide H&E images from breast cancer (TCGA BRCA), lung adenocarcinoma (TCGA LUAD), and prostate adenocarcinoma (TCGA PRAD) cohorts. Following nuclear segmentation, the cell class of each nucleus was assigned using PathExplore models specific to each cancer type. Interpretable features describing the size, shape, stain intensity, and texture were computed for each individual nucleus. The mean and standard deviation of each feature for each cell class on each slide were used to summarize the nuclear morphology. Statistical analyses were performed to assess relationships between nuclear morphology and cancer type, genomic instability, breast cancer molecular subtype, survival, and gene expression. Results overview: The nuclear segmentation and classification model performed comparably to previously reported models. It revealed differences in nuclear morphology sufficient to distinguish between BRCA, LUAD, and PRAD. Cancer cell nuclear area was associated with increased aneuploidy score and homologous recombination deficiency across cancer types. It was also predictive of whole genome doubling. In the breast BRCA cohort, cell-type-specific nuclear morphology enabled classification of luminal A, basal-like, and HER2 molecular subtypes. Increased fibroblast nuclear area in BRCA was indicative of poor progression-free and overall survival and was associated with gene expression signatures related to extracellular matrix remodeling and anti-tumor immunity. In summary, this work highlights the power of machine learning-driven quantitative nuclear morphometry in multiple cancer types at scale. The models and resulting features have the potential to aid pathologists in discerning novel biomarkers and provide meaningful prognostic information for cancer patients.

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Scientists at the University of California, Riverside have developed a new, RNA-based vaccine strategy that could be effective against just about any strain of a virus, and can be used safely even for babies or the immunocompromised. Targeting a common part of the viral genome could provide broader protection against various strains, potentially streamlining the vaccination process. It could be a significant advancement in combating viral diseases like influenza and SARS-CoV-2. Traditional vaccines work by introducing a weakened or inactivated form of the virus to trigger the immune system's response. This process involves the production of T-cells and memory B-cells to fight off the virus and remember it for future encounters. However, the time it takes for these responses to develop can leave individuals vulnerable for a period. The new strategy you mentioned seems to offer a potential solution to this delay by targeting a common part of the viral genome, possibly providing faster and more comprehensive protection. Source: Genetic Engineering & Biotechnology News #vaccine #geneticengineering #immunology

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Fluorescence and Flow Cytometry Principles

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>15,000 unselected #patients w/ #cancer provided #universal #germline #genetictesting (GGT), 20% PGV rate in cancer-risk genes Scalable model to increase GGT in unselected #cancer #patients across >20 sites was highly feasible. A significant proportion of #patients had actionable findings in #cancer & non-cancer genes. #Universal GGT for #cancer susceptibility and actionable noncancer disorders among 19,842 patients: Initial findings from the City of Hope #INSPIRE study #DrStephenGruber @ City of Hope #ASCO24 American Society of Clinical Oncology (ASCO) c/w https://lnkd.in/g9MKNYv7 Vivek Subbiah, MD Razelle Kurzrock #JCO American Society of Clinical Oncology (ASCO) https://lnkd.in/gcEBSzQJ #access #reducedisparities #universal #germlinetesting #precisionmedicine #precisiontherapy #clinicaltrials #precisionprevention CGA IGC

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Remarkable work cataloguing the diversity and complexity of tumor associated macrophages. This will be a valuable tool in cancer immunotherapy. https://lnkd.in/gNVxZiX2

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CanCellVar: A database for single-cell variants map in human cancer. They established a database which aims to provide and visualize the comprehensive atlas of single-cell variants in tumor microenvironment. The current CanCellVar identified ∼3 million variants (∼1.4 million SNVs and ∼1.4 million A>G RNA edits) involved in 2,754,531 cells of 5 major cell types across 37 cancer types. CanCellVar provides the basic annotation information as well as cellular and molecular function properties of variants. In addition, the clinical relevance of variants can be obtained including tumor grade, treatment, metastasis, and others. https://lnkd.in/d_i7bbb8

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New kinase-deficient PAK2 variants associated with Knobloch syndrome type 2. #RareDisease #Genetics In this report, they describe the impairment of PAK2 kinase activity for two other de novo PAK2 missense variants associated with Knobloch syndrome phenotype. These results provide additional evidence that Knobloch syndrome is genetically heterogeneous and that PAK2 is a second causative gene. https://lnkd.in/dNzcUEaT

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Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function. #RareDisease #Genetics They studied a primary lymphoedema cohort with 770 index patients and identified ten variants in the HGF gene predicted to cause loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of their cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). https://lnkd.in/da-uqYbb

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In >14,000 #patients w/ #lungcancer w/ #germline #genetictesting (GGT), >12% had a pathogenic #germline variant (PGV), the majority in DDR genes. PGV rate did not differ btw smokers (12.6%) & non-smokers (12.7%) These data support that clinicians now consider GGT for all #patients w/ #lungcancer, independent of age, personal cancer history, family history or smoking history. Smoking and pathogenic #germline variants in #patients w/ #lungcancer Ed Esplin @ Invitae w/ #DrAlecWatson #DrDaraAisner University of Colorado Anschutz Medical Campus #ASCO24 American Society of Clinical Oncology (ASCO) c/w https://lnkd.in/gC27KzF3 Steven Sorscher et al. #JCOPrecisionOncology @ American Society of Clinical Oncology (ASCO) #access #reducedisparities #germlinetesting #precisionmedicine #precisiontherapy #clinicaltrials #precisionprevention

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Mendel first described his laws of genetic inheritance in 1865. They were promptly ignored for 35 years. Because, let's be honest, who gives a husk about peas?!?! It probably also didn't help that his paper was titled, 'Versuche über Pflanzenhybriden.' Which in English translates to, 'Experiments in plant hybridization.' While this sounds exhilarating, it belies the foundational concepts described in its pages and Mendel's work breeding peas wasn't revisited until 1900 when his results were independently rediscovered and confirmed by E. Tschermak (peas), W. Spillman (wheat) and C. Correns (peas). H. de Vries (flowers) also independently characterized plant genetics in 1900 but had to be told that Mendel scooped him 35 years earlier. Oof. So, what was it that Mendel discovered while studying peas? He observed the physical traits of peas and how these traits were passed to their offspring after breeding. Mendel established 3 genetic principles from these observations: Segregation - Traits come in two forms but only one from each parent is passed to offspring. Independent Assortment - The segregation of the forms of each trait occurs independently of any other trait. Dominance - Dominant forms of each trait mask the recessive forms and they occur in a 3:1 ratio. Mendel initially described these as laws, but we know now that there are numerous exceptions, so in genetics we often refer to Mendelian and non-Mendelian inheritance. But in the early 1900's, the race was on to see if Mendel's phenomenon wasn't just some weird plant thing. One of the biggest proponents of Mendel at the time was William Bateson. Bateson is a forgotten figure nowadays, but he popularized the works of Mendel and also did some of the earliest work on genetic linkage. He also became fast friends with a clinician scientist, Archibald Garrod. Garrod was most interested in the biology of the diseases in his patients and had a particular fondness for chemistry. This could be why he was so enamored with the color of his patients’ urine. This curiosity paid off in 1899 when he first noticed a chemical aberration in the urine of patients with Alkaptonuria. This is an ancient disease with symptoms being described as far back as 1500 BC, but one of its tell-tale signs is darkly pigmented pee. Garrod noted to his friend Bateson that this disease was found most often as the result of marriages between first cousins, and at Bateson’s urging, Garrod documented the incidence of Alkaptonuria in these families. Today’s #FigureFriday is the first evidence of a recessive Mendelian disease in Humans. In the table you can see that in these families the dominant form of the trait is observed in 36 offspring, and the Alkaptonuria form in 12. This perfectly aligns with the 3:1 ratio Mendel first observed in his peas! ### Garrod AE. 1902. The incidence of alkaptonuria: a study in chemical individuality. The Lancet. DOI: 10.1016/S0140-6736(01)41972-6

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Enhanced affinity T cell receptors (TCRs) are a type of engineered TCR designed to have high antigen binding affinity, allowing T cells to efficiently target tumor-associated antigens. Despite their therapeutic potential, clinical trials evaluating affinity enhanced TCR-engineered T-cells have resulted in patient deaths due to off-target binding caused by TCR cross-reactivity with epitopes on healthy tissue. I have been learning how to use a tool called GROMACS for molecular dynamics (MD) simulations, so I thought it would be a good exercise to create a MD simulation of a TCR engineered for cancer immunotherapy applications. The MD simulation below was created from a crystal structure of MAGE-A3 reactive TCR in complex with MAGE-A3 in HLA-A1 https://lnkd.in/eRedU5d7. MAGE (melanoma associated antigen)- A3 is a tumor associated antigen that is normally expressed by reproductive tissues. MAGE-A3 is also expressed by solid tumors like melanoma, making it an attractive target for new cancer therapies. MAGE-A3 reactive TCR was developed by Immunocore for cancer immunotherapy, but it was eventually shown the engineered TCR led to patient deaths due to off-target binding with an epitope from the Titin protein on cardiac tissue. Here is a paper with additional information: Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy https://lnkd.in/eVnwDRgM. Additional details on the GROMACS protocol and code I used to create the simulation can be found in this Github repository: https://lnkd.in/eqW5FxkT To create the simulation, I used a NVIDIA A100 GPU on Google Colab since running MD simulations on a laptop is computationally intensive. I then used Pymol from Schrödinger to visualize the simulation and create the video for export. I also used a python library called MDAnalysis to analyze the simulation results and create the Radius of Gyration and Root Mean Squared Fluctuation graphs in the video. I also used Adobe Premier Pro and Illustrator to make final edits and graphics for the video. I am new to using all of these tools, so any feedback from experts in Molecular Dynamics is always appreciated!

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16% of #lungcancer #patients, w/no prior #cancer or #familyhistory of #cancer, had PGVs on #germlinetesting https://lnkd.in/gzdHQTQC "...it may be of interest to routinely examine all #patients w/ #lungcancer for...PGVs [pathogenic germline variants] in #cancer-risk genes, benefiting #patients & their relatives." Steven Sorscher et al. https://lnkd.in/gCCfHGZG #JCOPrecisionOncology American Society of Clinical Oncology (ASCO) Invitae #access #reducedisparities #universal #genetictesting #precisionmedicine #precisiontherapy #clinicaltrials #precisionprevention

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Crazy new study showing durable treatment of asthma from a single dose of CAR-T cells... The T-cells were designed to present IL-5, which binds to a surface receptor primarily present on eosinophils. These immune cells are overabundant in asthma. The cells also spit out mutated IL-4 molecules that block both IL-4 and IL-13, in an attempt "dampen type 2 inflammation" that's going haywire in asthma patients. Multi-pronged immune engineering. Study: https://lnkd.in/gdNW9H_9

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