tbuckley/cabot-search huggingface dataset:
Loss of FBXW7 Correlates with Increased IDH1 Expression in Glioma and Enhances IDH1-Mutant Cancer Cell Sensitivity to Radiation
Authors: Zhuo Yang, Nan Hu, Weiwei Wang, Weihua Hu, Shaolong Zhou, Jianxiang Shi, Minghe Li, Zhou Jing, Chao Chen, Xuyang Zhang, Ruyi Yang, Xudong Fu, Xinjun Wang
Journal: Cancer Research (2021)

F-box and WD repeat domain containing 7 (FBXW7) is a substrate receptor of the ubiquitin ligase SKP1-Cullin1-F-box complex and a potent tumor suppressor that prevents unregulated cell growth and tumorigenesis. However, little is known about FBXW7-mediated control of cell metabolism and related functions in cancer therapy. Here, we report that FBXW7 expression inversely correlates with the expression levels of the key metabolic enzyme isocitrate dehydrogenase 1 (IDH1) in patients with glioma and public glioma datasets. Deletion of FBXW7 significantly increased both wild-type (WT) and mutant IDH1 expression, which was mediated by blocking degradation of sterol regulatory element binding protein 1 (SREBP1). The upregulation of neomorphic mutant IDH1 by FBXW7 deletion stimulated production of the oncometabolite 2-hydroxyglutarate at the expense of increasing pentose phosphate pathway activity and NADPH consumption, limiting the buffering ability against radiation-induced oxidative stress. In addition, FBXW7 knockout and IDH1 mutations induced nonhomologous end joining and homologous recombination defects, respectively.
The genome-editing decade
Authors: Paula M. Cannon, Hans-Peter Kiem
Journal: Molecular Therapy (2021)

Although still in its early days, this decade is shaping up to be a golden age for genome editing. In 2020, the Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer Doudna for their 2012 demonstration that the bacterial clustered regularly interspaced short palindromic repeats (CRISPR)-Cas defense system could be turned into a genome-editing tool based on RNA-programmable DNA nucleases. 1 Jinek M. Chylinski K. Fonfara I. Hauer M. Doudna J.A. Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012; 337: 816-821 Crossref PubMed Scopus (8553) Google Scholar The ability to re-direct CRISPR-Cas to a specific DNA target simply by designing a guide RNA catalyzed an explosion of research that has covered the spectrum from fundamental discoveries in biology to the first-in-human clinical trials.
No causal effect of school closures in Japan on the spread of COVID-19 in spring 2020
Authors: Kentaro Fukumoto, Charles T. McClean, Kuninori Nakagawa
Journal: Nature Medicine (2021)

Among tool kits to combat the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, school closures are one of the most frequent non-pharmaceutical interventions. However, school closures bring about substantial costs, such as learning loss. To date, studies have not reached a consensus about the effectiveness of these policies at mitigating community transmission, partly because they lack rigorous causal inference. Here we assess the causal effect of school closures in Japan on reducing the spread of COVID-19 in spring 2020. By matching each municipality with open schools to a municipality with closed schools that is the most similar in terms of potential confounders, we can estimate how many cases the municipality with open schools would have had if it had closed its schools. We do not find any evidence that school closures in Japan reduced the spread of COVID-19. Our null results suggest that policies on school closures should be reexamined given the potential negative consequences for children and parents.
Impact of intracellular innate immune receptors on immunometabolism
Authors: Wei-Chun Chou, Elena Rampanelli, Xin Li, Jenny P.-Y. Ting
Journal: Cellular and Molecular Immunology (2021)

Abstract Immunometabolism, which is the metabolic reprogramming of anaerobic glycolysis, oxidative phosphorylation, and metabolite synthesis upon immune cell activation, has gained importance as a regulator of the homeostasis, activation, proliferation, and differentiation of innate and adaptive immune cell subsets that function as key factors in immunity. Metabolic changes in epithelial and other stromal cells in response to different stimulatory signals are also crucial in infection, inflammation, cancer, autoimmune diseases, and metabolic disorders. The crosstalk between the PI3K–AKT–mTOR and LKB1–AMPK signaling pathways is critical for modulating both immune and nonimmune cell metabolism. The bidirectional interaction between immune cells and metabolism is a topic of intense study. Toll-like receptors (TLRs), cytokine receptors, and T and B cell receptors have been shown to activate multiple downstream metabolic pathways. However, how intracellular innate immune sensors/receptors intersect with metabolic pathways is less well understood. The goal of this review is to examine the link between immunometabolism and the functions of several intracellular innate immune sensors or receptors, such as nucleotide-binding and leucine-rich repeat-containing receptors (NLRs, or NOD-like receptors), absent in melanoma 2 (AIM2)-like receptors (ALRs), and the cyclic dinucleotide receptor stimulator of interferon genes (STING). We will focus on recent advances and describe the impact of these intracellular innate immune receptors on multiple metabolic pathways. Whenever appropriate, this review will provide a brief contextual connection to pathogenic infections, autoimmune diseases, cancers, metabolic disorders, and/or inflammatory bowel diseases.
TCT-246 Hemodynamic Performance and Patient Prosthesis Mismatch in Small Aortic Annuli: A Comparison of Different Transcatheter Heart Valves
Authors: Gregory Fontana, Raj Makkar, Mark Groh, Federico Asch, Lars Sondergaard, Stephen G. Worthley, Bassem Chehab, Ron Waksman, Francesco Bedogni, James Hermiller
Journal: Journal of the American College of Cardiology (2021)
TCT-37 Impact of Bleeding During Dual Antiplatelet Treatment on Long-Term Prognosis in Patients Undergoing Percutaneous Coronary Intervention
Authors: Kevin Kris Warnakula Olesen, Morten Würtz, Pernille Thrane, Troels Thim, Steen Dalby Kristensen, Michael Maeng
Journal: Journal of the American College of Cardiology (2021)
Deletion of <i>BCG_2432c</i> from the Bacillus Calmette‐Guérin vaccine enhances autophagy‐mediated immunity against tuberculosis
Authors: Yaqi Wu, Maopeng Tian, Yandi Zhang, Huiming Peng, Qing Lei, Xuefeng Yuan, Shijie Liu, Yulong Xiong, Xiaosong Lin, Banga Ndzouboukou Jo‐Lewis, Zongjie Yao, Hui Fu, Xionglin Fan
Journal: Allergy (2021)

Mycobacterium bovis bacillus Calmette-Guérin (BCG) is an attenuated live vaccine that provides insufficient protection against tuberculosis (TB), the underlying mechanisms for which remain unknown. Assuming that the BCG vaccine inherits immune evasive strategies from virulent parent M. bovis strains, we aimed to identify the associated genes and assess their effects on the vaccine efficacy.Three genes, BCG_3174, BCG_1782, and BCG_2432c, associated with immune evasion were first identified via bioinformatics analysis and then confirmed in the genome of M. bovis and 12 commercial BCG vaccine substrains using Polymerase Chain Reaction (PCR) and DNA sequencing. These genes were disrupted to develop mutant strains, and their effects on autophagy and their protective efficacy were further compared with the BCG vaccine in vitro and in vivo.Of the three identified genes, only the disruption of BCG_2432c, namely ΔBCG_2432c, conferred stronger protection against intranasal TB in vaccinated mice, when compared with the BCG vaccine. ΔBCG_2432c showed a stronger ability to trigger intracellular ROS-mediated complete autophagic flux in infected THP-1 cells that resulted in higher antigen presentation. The improved protection could be attributed to early and increased IFN-γ+ CD4+ TEM and IL-2+ CD4+ TCM cells in the spleens and lungs of ΔBCG_2432c-vaccinated mice.The insufficient efficacy of the BCG vaccine is attributable to the important autophagy-inhibition gene BCG_2432c that blocks the autophagosome-lysosome pathway of antigen presentation. ΔBCG_2432c provides a promising platform to either replace the current BCG vaccine or develop vaccines that are more effective against TB.
Home Oxygen Therapy for Adults With Chronic Obstructive Pulmonary Disease or Interstitial Lung Disease
Authors: Hannah C. Wenger, Adam S. Cifu, Cathryn T. Lee
Journal: JAMA (2021)

This JAMA Clinical Guidelines Synopsis summarizes the clinical practice guideline from the American Thoracic Society (ATS) regarding the home use of oxygen for adults with COPD and interstitial lung disease.
Similarity-Based Analysis of Allele Frequency Distribution among Multiple Populations Identifies Adaptive Genomic Structural Variants
Authors: Marie Saitou, Naoki Masuda, Omer Gokcumen
Journal: Molecular Biology and Evolution (2021)

Structural variants have a considerable impact on human genomic diversity. However, their evolutionary history remains mostly unexplored. Here, we developed a new method to identify potentially adaptive structural variants based on a similarity-based analysis that incorporates genotype frequency data from 26 populations simultaneously. Using this method, we analyzed 57,629 structural variants and identified 576 structural variants that show unusual population differentiation. Of these putatively adaptive structural variants, we further showed that 24 variants are multiallelic and overlap with coding sequences, and 20 variants are significantly associated with GWAS traits. Closer inspection of the haplotypic variation associated with these putatively adaptive and functional structural variants reveals deviations from neutral expectations due to: 1) population differentiation of rapidly evolving multiallelic variants, 2) incomplete sweeps, and 3) recent population-specific negative selection. Overall, our study provides new methodological insights, documents hundreds of putatively adaptive variants, and introduces evolutionary models that may better explain the complex evolution of structural variants.
Access to personal health records—why is progress so slow?
Authors: Emma Doble, Henry Scowcroft
Journal: BMJ (2021)

As part of its Patient and Public Partnership Strategy, <i>The BMJ</i> is shining a spotlight on the barriers and challenges to enabling better access to personal health records. <i>The BMJ</i>’s patient editors start to unpick why progress has been so slow, and how to speed it up.
Abstract 10952: Novel Insights Into Cardiac Developmental Regulation by Epigenetic Histone Modifying Factors in Multiple Species
Authors: Rwik Sen, Elizabeth A Geiger, Tamim H Shaikh, Kristin B Artinger
Journal: Circulation (2019)

Introduction: Cardiac neural crest cells (NCC) undergo cellular growth, patterning, and differentiation in branchial arches to form great arteries, cardiac ganglia, and outflow tract myocardium of ...
THU0502 The Longitudinal Relationship Between Changes in Body Weight and Changes in Knee Cartilage and Pain Among Community-Based Adults with and without Meniscal Tears
Authors: A. Wluka, A. Teichtahl, Y. Wang, B. Strauss, J. Dixon, J. Proietto, G. Jones, A. Forbes, S. Kouloyan-Ilic, J. Martel-Pelletier, J. P. Pelletier, F. Cicuttini
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Meniscal tears are commonly found on magnetic resonance imaging (MRI) and increase the risk for incident radiographic knee osteoarthritis (OA). While meniscectomy is recommended when there is severe knee pain or associated knee locking, it is unclear how to best treat meniscal tears in the absence of these symptoms. <h3>Objectives</h3> The aim of this longitudinal study was to examine the effect of weight change on knee cartilage and pain in a cohort of community-based adults with and without meniscal tears detected by MRI. <h3>Methods</h3> 250 adults (78% completing follow-up) with no history of knee OA or knee injury were recruited from the general community and weight loss clinics. MRI of the knee, Western Ontario and McMaster University Osteoarthritis Index (WOMAC), weight and height were measured at baseline and again at follow-up approximately 2 years later. <h3>Results</h3> Medial meniscal tears were present in 36 (18%) of the cohort. In those with medial meniscal tears, after adjustment for age, gender, body mass index, the presence of medial tibiofemoral osteophytes and time between MRI scans, percentage weight change was significantly associated with percentage change in medial tibial cartilage volume [0.2% (95% CI 0.08% – 0.30%), p = 0.002] and knee pain [11.6% (95% CI 2.1% – 21.1%), p = 0.02]. In those with no medial meniscal tear, neither change in knee cartilage volume [0.02% (95% CI -0.005% – 0.10%), p = 0.53] or pain [1.9% (95% CI -2.2% – 6.1%), p = 0.36] was significantly associated with change in weight. <h3>Conclusions</h3> This study demonstrated that among adults with medial meniscal tears, weight gain is associated with increased cartilage loss and pain, while weight loss is associated with the converse. This suggests attention to weight is particularly important in the management of people with medial meniscal tears. <h3>Disclosure of Interest</h3> None Declared
Remission, relapse, and risk of major cardiovascular events after metabolic surgery in persons with hypertension: A Swedish nationwide registry-based cohort study
Authors: Erik Stenberg, Richard Marsk, Magnus Sundbom, Johan Ottosson, Tomas Jernberg, Ingmar Näslund, Erik Näslund
Journal: PLoS Medicine (2021)

Background Several studies have shown that metabolic surgery is associated with remission of diabetes and hypertension. In terms of diabetes, factors such as duration, insulin use, weight loss, and age have been shown to contribute to the likelihood of remission. Such factors have not been determined for hypertension. The aim of this study was to evaluate factors associated with the remission and relapse of hypertension after metabolic surgery, as well as the risk for major adverse cardiovascular event (MACE) and mortality in patients with and without remission. Methods and findings All adults who underwent metabolic surgery between January 2007 and June 2016 were identified in the nationwide Scandinavian Obesity Surgery Registry (SOReg). Through cross-linkage with the Swedish Prescribed Drug Register, Patient Register, and Statistics Sweden, individual data on prescriptions, inpatient and outpatient diagnoses, and mortality were retrieved. Of the 15,984 patients with pharmacologically treated hypertension, 6,286 (39.3%) were in remission at 2 years. High weight loss and male sex were associated with higher chance of remission, while duration, number of antihypertensive drugs, age, body mass index (BMI), cardiovascular disease, and dyslipidemia were associated with lower chance. After adjustment for age, sex, BMI, comorbidities, and education, the cumulative probabilities of MACEs (2.8% versus 5.7%, adjusted odds ratio (OR) 0.60, 95% confidence interval (CI) 0.47 to 0.77, p &lt; 0.001) and all-cause mortality (4.0% versus 8.0%, adjusted OR 0.71, 95% CI 0.57 to 0.88, p = 0.002) were lower for patients being in remission at 2 years compared with patients not in remission, despite relapse of hypertension in 2,089 patients (cumulative probability 56.3%) during 10-year follow-up. The main limitations of the study were missing information on nonpharmacological treatment for hypertension and the observational study design. Conclusions In this study, we observed an association between high postoperative weight loss and male sex with better chance of remission, while we observed a lower chance of remission depending on disease severity and presence of other metabolic comorbidities. Patients who achieved remission had a halved risk of MACE and death compared with those who did not. The results suggest that in patients with severe obesity and hypertension, metabolic surgery should not be delayed.
Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy
Authors: Yongrong Yao, Huachao Chen, Ninghua Tan
Journal: Acta Pharmaceutica Sinica B (2021)

Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments, but its clinical implementation has been restricted by the low host antitumor response rate. Recently, chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication. The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism. Herein, a synergistic antitumor platform (designated as BMS/RA@CC-Liposome) was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug (RA-V) and PD-1/PD-L1 blockade inhibitor (BMS-202) to remarkably enhance antitumor immunity. In this study, the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem. To achieve the cell-specific targeting drug delivery, the combination therapy nanosystem was functionalized with cancer cell membrane camouflage. The biomimetic drug delivery system perfectly disguised as endogenous substances, and realized elongated blood circulation due to anti-phagocytosis capability. Moreover, the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells. The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response, RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells. Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically, demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.
Immunotherapy Adverse Effects
Authors: Timothy J. Brown, Ronac Mamtani, Erin M. Bange
Journal: JAMA Oncology (2021)

Immunotherapy Adverse Effects ImmunotherapyImmunotherapies treat many types of cancer.These drugs are not chemotherapy; instead, they use the body's immune system to target the cancer.Most people do not have serious adverse effects from these medicines.When adverse effects happen, it is because the immune system mistakenly targets a person's healthy cells.This is called an immune-related adverse event, or irAE.
The systemic inflammatory landscape of COVID-19 in pregnancy: Extensive serum proteomic profiling of mother-infant dyads with in utero SARS-CoV-2
Authors: Suan-Sin Foo, Mary Catherine Cambou, Thalia Mok, Viviana M. Fajardo, Kyle L. Jung, Trevon Fuller, Weiqiang Chen, Tara Kerin, Jenny Mei, Debika Bhattacharya, Younho Choi, Xin Wu, Tian Xia, Woo-Jin Shin, Jessica Cranston, Grace Aldrovandi, Nicole Tobin, Deisy Contreras, Francisco J. Ibarrondo, Otto Yang, Shangxin Yang, Omai Garner, Ruth Cortado, Yvonne Bryson, Carla Janzen, Shubhamoy Ghosh, Sherin Devaskar, Brenda Asilnejad, Maria Elisabeth Moreira, Zilton Vasconcelos, Priya R. Soni, L. Caroline Gibson, Patricia Brasil, Suzy A.A. Comhair, Vaithilingaraja Arumugaswami, Serpil C. Erzurum, Rashmi Rao, Jae U. Jung, Karin Nielsen-Saines
Journal: Cell Reports Medicine (2021)
Sex without crossing over in the yeast Saccharomycodes ludwigii
Authors: Ioannis A. Papaioannou, Fabien Dutreux, France A. Peltier, Hiromi Maekawa, Nicolas Delhomme, Amit Bardhan, Anne Friedrich, Joseph Schacherer, Michael Knop
Journal: Genome biology (2021)

Abstract Background Intermixing of genomes through meiotic reassortment and recombination of homologous chromosomes is a unifying theme of sexual reproduction in eukaryotic organisms and is considered crucial for their adaptive evolution. Previous studies of the budding yeast species Saccharomycodes ludwigii suggested that meiotic crossing over might be absent from its sexual life cycle, which is predominated by fertilization within the meiotic tetrad. Results We demonstrate that recombination is extremely suppressed during meiosis in Sd. ludwigii . DNA double-strand break formation by the conserved transesterase Spo11, processing and repair involving interhomolog interactions are required for normal meiosis but do not lead to crossing over. Although the species has retained an intact meiotic gene repertoire, genetic and population analyses suggest the exceptionally rare occurrence of meiotic crossovers in its genome. A strong AT bias of spontaneous mutations and the absence of recombination are likely responsible for its unusually low genomic GC level. Conclusions Sd. ludwigii has followed a unique evolutionary trajectory that possibly derives fitness benefits from the combination of frequent mating between products of the same meiotic event with the extreme suppression of meiotic recombination. This life style ensures preservation of heterozygosity throughout its genome and may enable the species to adapt to its environment and survive with only minimal levels of rare meiotic recombination. We propose Sd. ludwigii as an excellent natural forum for the study of genome evolution and recombination rates.
TCT-362 Comparison of Radial Versus Femoral Arterial Access for Complex Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis
Authors: Muhammad Sabih Saleem, Najam Saqib, Sana Shahzad Memon, Ayesha Khan, Abdul Mannan Khan Minhas, Hamza Hanif, Muhammad Affan, Arpit Sothwal, Muhammad Siddique Pir
Journal: Journal of the American College of Cardiology (2021)
Differential dynamics of peripheral immune responses to acute SARS-CoV-2 infection in older adults
Authors: Sloan A. Lewis, Suhas Sureshchandra, Michael Z. Zulu, Brianna Doratt, Allen Jankeel, Izabela Coimbra Ibraim, Amanda N. Pinski, Nicholas S. Rhoades, Micaila Curtis, Xiwen Jiang, Delia Tifrea, Frank Zaldivar, Weining Shen, Robert A. Edwards, Daniel Chow, Dan Cooper, Alpesh Amin, Ilhem Messaoudi
Journal: Nature Aging (2021)
Osteogenic and anti-tumor Cu and Mn-doped borosilicate nanoparticles for syncretic bone repair and chemodynamic therapy in bone tumor treatment
Authors: Libin Pang, Renliang Zhao, Jing Chen, Jingxin Ding, Xiaochen Chen, Wenwen Chai, Xu Cui, Xiaolin Li, Deping Wang, Haobo Pan
Journal: Bioactive Materials (2021)

Critical bone defects caused by extensive excision of malignant bone tumor and the probability of tumor recurrence due to residual tumor cells make malignant bone tumor treatment a major clinical challenge. The present therapeutic strategy concentrates on implanting bone substitutes for defect filling but suffers from failures in both enhancing bone regeneration and inhibiting the growth of tumor cells. Herein, Cu and Mn-doped borosilicate nanoparticles (BSNs) were developed for syncretic bone repairing and anti-tumor treatment, which can enhance bone regeneration through the osteogenic effects of Cu2+ and Mn3+ ions and meanwhile induce tumor cells apoptosis through the hydroxyl radicals produced by the Fenton-like reactions of Cu2+ and Mn3+ ions. In vitro study showed that both osteogenic differentiation of BMSCs and angiogenesis of endothelial cells were promoted by BSNs, and consistently the critical bone defects of rats were efficiently repaired by BSNs through in vivo evaluation. Meanwhile, BSNs could generate hydroxyl radicals through Fenton-like reactions in the simulated tumor microenvironment, promote the generation of intracellular reactive oxygen species, and eventually induce tumor cell apoptosis. Besides, subcutaneous tumors of mice were effectively inhibited by BSNs without causing toxic side effects to normal tissues and organs. Altogether, Cu and Mn-doped BSNs developed in this work performed dual functions of enhancing osteogenesis and angiogenesis for bone regeneration, and inhibiting tumor growth for chemodynamic therapy, thus holding a great potential for syncretic bone repairing and anti-tumor therapy.