tbuckley/cabot-search huggingface dataset:
Increased risk of infection with SARS-CoV-2 Omicron BA.1 compared with Delta in vaccinated and previously infected individuals, the Netherlands, 22 November 2021 to 19 January 2022
Authors: Dirk Eggink, Stijn P Andeweg, Harry Vennema, Noortje van Maarseveen, Klaas Vermaas, Boris Vlaemynck, Raf Schepers, Arianne B van Gageldonk-Lafeber, Susan van den Hof, Chantal BEM Reusken, Mirjam J Knol
Journal: Eurosurveillance (2022)

Infections with the Omicron SARS-CoV-2 variant are rapidly increasing worldwide. Among 174,349 SARS-CoV-2-infected individuals (≥ 12 years), we observed an increased risk of S gene target failure, predictive of the Omicron variant, in vaccinated (odds ratio (OR): 3.6; 95% confidence interval (CI): 3.4-3.7) and previously infected individuals (OR: 4.2; 95% CI: 3.8-4.7) compared with infected naïve individuals. This suggests vaccine- or infection-induced immunity against SARS-CoV-2 infections is less effective against the Omicron than the Delta variant.
Abstract 10591: Epigenetic BET Reader Inhibitor Apabetalone (RVX-208) Counters Proinflammatory Aortic Gene Expression in a Diet Induced Obesity Mouse Model
Authors: Sylwia Wasiak, Emily Daze, Laura M Tsujikawa, Dean Gilham, Christopher Sarsons, Stephanie Stotz, Brooke Rakai, Salman Azhar, Ravi Jahagirdar, Michael Sweeney, Jan Johansson, Norman Wong, Ewelina Kulikowski
Journal: Circulation (2021)

Introduction: Obesity increases the risk of type 2 diabetes (DM2) and cardiovascular disease (CVD), due to associated insulin resistance, dyslipidemia, high blood pressure and chronic inflammation. Bromodomain and extraterminal (BET) proteins such as BRD4 enhance the expression of proinflammatory genes by recruiting transcription factors to promoters and enhancers. Inhibition of BET binding to chromatin leads to anti-inflammatory and anti-atherogenic effects in models of DM2 and CVD. Hypothesis: BET inhibition with apabetalone, a clinical-stage small molecule, reduces vascular inflammation in a mouse model of diet-induced obesity. Methods: From 8 to 30 weeks of age, C57 BL/6J mice were fed a high-fat (HFD) or low-fat diet (LFD). Mice received apabetalone at 150 mg/kg b.i.d between 14 and 30 weeks. Gene expression was analyzed post necropsy in the aorta by PCR, nCounter® Inflammation Panel and Ingenuity® Pathway Analysis. Human aortic endothelial cells (HAECs) treated with TNFα and apabetalone were analyzed by BRD4 ChIP-seq and RNA-seq to assess BRD4 chromatin occupancy and transcriptional changes. Results: Profiling of 254 genes in the aorta showed an upregulation of 27 inflammatory genes in HFD-fed mice as compared to LFD (p&lt;0.05), including transcription factors Rela (22%), Hif1a (25%) and Tcf4 (44%), involved in inflammation, hypoxia and cell growth, respectively. Other upregulated genes mapped to cytokine, cytoskeleton, coagulation and complement pathways. Apabetalone reduced aortic mRNA expression of transcription factors Rela (12%), Nfkb1 (22%) and Tcf4 (15%), chemokines Ccl2 (47%), Ccl7 (49%) and Ccl8 (69%), leukocyte receptors Ccr2 (64%) and Itgam (29%) and endothelial receptors Sele (64%) and Icam1 (36%). Bioinformatics predicted enhanced signaling by TNFα in the HFD vs. LFD aorta, which was countered by apabetalone. In HAECs, apabetalone lowered gene expression and BRD4 binding to Rela , Hif1a and Tcf4 genes and prevented TNFα-mediated BRD4 accumulation in proximity of Ccl2 , Sele and Icam1 genes. Conclusions: HFD induces vascular inflammation in mice. Apabetalone treatment diminishes this proinflammatory phenotype, providing mechanistic insight into how BET inhibitors may reduce CVD risk in DM2 patients.
Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer
Authors: Vicky Makker, Nicoletta Colombo, Antonio Casado Herráez, Alessandro D. Santin, Emeline Colomba, David S. Miller, Keiichi Fujiwara, Sandro Pignata, Sally Baron-Hay, Isabelle Ray-Coquard, Ronnie Shapira-Frommer, Kimio Ushijima, Jun Sakata, Kan Yonemori, Yong Man Kim, Eva M. Guerra, Ulus A. Sanli, Mary M. McCormack, Alan D. Smith, Stephen Keefe, Steven Bird, Lea Dutta, Robert J. Orlowski, Domenica Lorusso
Journal: New England Journal of Medicine (2022)

Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear.
Heterogeneity of Circulating Tumor Cell–Associated Genomic Gains in Breast Cancer and Its Association with the Host Immune Response
Authors: Nisha Kanwar, Zaldy Balde, Ranju Nair, Melanie Dawe, Shiyi Chen, Manjula Maganti, Eshetu G. Atenafu, Sabrina Manolescu, Carrie Wei, Amanda Mao, Fred Fu, Dan Wang, Alison Cheung, Yulia Yerofeyeva, Rachel Peters, Kela Liu, Christine Desmedt, Christos Sotiriou, Borbala Szekely, Janina Kulka, Trevor D. McKee, Naoto Hirano, John M.S. Bartlett, Martin J. Yaffe, Philippe L. Bedard, David McCready, Susan J. Done
Journal: Cancer Research (2021)

Abstract Tumor cells that preferentially enter circulation include the precursors of metastatic cancer. Previously, we characterized circulating tumor cells (CTC) from patients with breast cancer and identified a signature of genomic regions with recurrent copy-number gains. Through FISH, we now show that these CTC-associated regions are detected within the matched untreated primary tumors of these patients (21% to 69%, median 55.5%, n = 19). Furthermore, they are more prevalent in the metastases of patients who died from breast cancer after multiple rounds of treatment (70% to 100%, median 93%, samples n = 41). Diversity indices revealed that higher spatial heterogeneity for these regions within primary tumors is associated with increased dissemination and metastasis. An identified subclone with multiple regions gained (MRG clone) was enriched in a posttreatment primary breast carcinoma as well as multiple metastatic tumors and local breast recurrences obtained at autopsy, indicative of a distinct early subclone with the capability to resist multiple lines of treatment and eventually cause death. In addition, multiplex immunofluorescence revealed that tumor heterogeneity is significantly associated with the degree of infiltration of B lymphocytes in triple-negative breast cancer, a subtype with a large immune component. Collectively, these data reveal the functional potential of genetic subclones that comprise heterogeneous primary breast carcinomas and are selected for in CTCs and posttreatment breast cancer metastases. In addition, they uncover a relationship between tumor heterogeneity and host immune response in the tumor microenvironment. Significance: As breast cancers progress, they become more heterogeneous for multiple regions amplified in circulating tumor cells, and intratumoral spatial heterogeneity is associated with the immune landscape.
Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies
Authors: George Robinson, Ines Pineda-Torra, Coziana Ciurtin, Elizabeth C. Jury
Journal: Journal of Clinical Investigation (2022)

Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.
Re: Dual-Time-Point 18F-Fluorocholine PET/CT Improves Characterization of Thyroid Nodules in Patients Referred for Primary Hyperparathyroidism: A Proof-of-Concept Study
Authors: María Alejandra Rueda, Patricia Bernal, Gonzalo Ucros
Journal: Clinical Nuclear Medicine (2022)

Fundación Santa Fe de Bogotá [email protected] Conflicts of interest and sources of funding: none declared.
Childhood Risk Factors and Prediction of Adult Cardiovascular End Points
Authors: Julie R. Ingelfinger
Journal: New England Journal of Medicine (2022)

Children almost never have myocardial infarctions or other adverse cardiovascular (CV) events, yet there has long been evidence that atherosclerosis may be found on postmortem examination of youths who have died accidently.1-3 Indeed, cohort studies such as the Cardiovascular Risk in Young Finns Study, the Bogalusa Heart Study, and the Muscatine Study have shown increased coronary-artery calcification4,5 and increased carotid-artery intima–media thickness among adolescents.6-8 But direct evidence that CV risk factors in childhood are linked to hard CV disease (CVD) outcomes in adulthood has been elusive. And no wonder! Given the length of each human generation, studies that aim to . . .
Decreased Renal Gluconeogenesis Is a Hallmark of Chronic Kidney Disease
Authors: Thomas Verissimo, Anna Faivre, Anna Rinaldi, Maja Lindenmeyer, Vasiliki Delitsikou, Christelle Veyrat-Durebex, Carolyn Heckenmeyer, Marylise Fernandez, Lena Berchtold, Delal Dalga, Clemens Cohen, Maarten Naesens, Sven-Erik Ricksten, Pierre-Yves Martin, Jérôme Pugin, Franck Merlier, Karsten Haupt, Joseph M. Rutkowski, Solange Moll, Pietro E. Cippà, David Legouis, Sophie de Seigneux
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement The ability to produce glucose from nonhexose precursors is a main metabolic function of renal proximal tubule (PT) cells. PT cells adapt metabolically during CKD, but little is known about gluconeogenesis in chronically injured PT cells. Our study demonstrates the progressive loss of gluconeogenesis enzymes in animal models and in CKD patients in parallel to global change in metabolic pathway expression and activation of injury pathways. This alteration is not only due to loss of PT cells but has systemic repercussions on glucose and lactate levels in experimental and human CKD. In retrospective human studies, gluconeogenesis downregulation predicted CKD progression. This work provides new evidence for metabolic regulation during CKD and the functional effect. Introduction CKD is associated with alterations of tubular function. Renal gluconeogenesis is responsible for 40% of systemic gluconeogenesis during fasting, but how and why CKD affects this process and the repercussions of such regulation are unknown. Methods We used data on the renal gluconeogenic pathway from more than 200 renal biopsies performed on CKD patients and from 43 kidney allograft patients, and studied three mouse models, of proteinuric CKD (POD-ATTAC), of ischemic CKD, and of unilateral urinary tract obstruction. We analyzed a cohort of patients who benefitted from renal catheterization and a retrospective cohort of patients hospitalized in the intensive care unit. Results Renal biopsies of CKD and kidney allograft patients revealed a stage-dependent decrease in the renal gluconeogenic pathway. Two animal models of CKD and one model of kidney fibrosis confirm gluconeogenic downregulation in injured proximal tubule cells. This shift resulted in an alteration of renal glucose production and lactate clearance during an exogenous lactate load. The isolated perfused kidney technique in animal models and renal venous catheterization in CKD patients confirmed decreased renal glucose production and lactate clearance. In CKD patients hospitalized in the intensive care unit, systemic alterations of glucose and lactate levels were more prevalent and associated with increased mortality and a worse renal prognosis at follow-up. Decreased expression of the gluconeogenesis pathway and its regulators predicted faster histologic progression of kidney disease in kidney allograft biopsies. Conclusion Renal gluconeogenic function is impaired in CKD. Altered renal gluconeogenesis leads to systemic metabolic changes with a decrease in glucose and increase in lactate level, and is associated with a worse renal prognosis.
A Combinatorial CRISPR–Cas9 Screen Identifies Ifenprodil as an Adjunct to Sorafenib for Liver Cancer Treatment
Authors: Feng Xu, Man Tong, Cindy S.W. Tong, Becky K.C. Chan, Hoi Yee Chu, Tin Lok Wong, John H.C. Fong, Maggie S.H. Cheung, Kylie Hin-Man Mak, Lakhansing Pardeshi, Yuanhua Huang, Koon Ho Wong, Gigi C.G. Choi, Stephanie Ma, Alan S.L. Wong
Journal: Cancer Research (2021)

Abstract Systematic testing of existing drugs and their combinations is an attractive strategy to exploit approved drugs for repurposing and identifying the best actionable treatment options. To expedite the search among many possible drug combinations, we designed a combinatorial CRISPR–Cas9 screen to inhibit druggable targets. Coblockade of the N-methyl-d-aspartate receptor (NMDAR) with targets of first-line kinase inhibitors reduced hepatocellular carcinoma (HCC) cell growth. Clinically, HCC patients with low NMDAR1 expression showed better survival. The clinically approved NMDAR antagonist ifenprodil synergized with sorafenib to induce the unfolded protein response, trigger cell-cycle arrest, downregulate genes associated with WNT signaling and stemness, and reduce self-renewal ability of HCC cells. In multiple HCC patient-derived organoids and human tumor xenograft models, the drug combination, but neither single drug alone, markedly reduced tumor-initiating cancer cell frequency. Because ifenprodil has an established safety history for its use as a vasodilator in humans, our findings support the repurposing of this drug as an adjunct for HCC treatment to improve clinical outcome and reduce tumor recurrence. These results also validate an approach for readily discovering actionable combinations for cancer therapy. Significance: Combinatorial CRISPR–Cas9 screening identifies actionable targets for HCC therapy, uncovering the potential of combining the clinically approved drugs ifenprodil and sorafenib as a new effective treatment regimen.
Cabozantinib Enhances Anti-PD1 Activity and Elicits a Neutrophil-Based Immune Response in Hepatocellular Carcinoma
Authors: Roger Esteban-Fabró, Catherine E. Willoughby, Marta Piqué-Gili, Carla Montironi, Jordi Abril-Fornaguera, Judit Peix, Laura Torrens, Agavni Mesropian, Ugne Balaseviciute, Francesc Miró-Mur, Vincenzo Mazzaferro, Roser Pinyol, Josep M. Llovet
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Immune checkpoint inhibitors combined with antiangiogenic agents produce benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination. Experimental Design: C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumors received cabozantinib, anti-PD1, their combination, or placebo. Tumor and blood samples were analyzed by flow cytometry, IHC, transcriptome, and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer patient-derived xenograft model. Transcriptomic data from three human HCC cohorts (cohort 1: n = 167, cohort 2: n = 57, The Cancer Genome Atlas: n = 319) were used to cluster patients according to neutrophil features, and assess their impact on survival. Results: The combination of cabozantinib and anti-PD1 showed increased antitumor efficacy compared with monotherapy and placebo (P &amp;lt; 0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced intratumor CD8+PD1+ T-cell proportions, while the combination with anti-PD1 further stimulated both effects and significantly decreased regulatory T cell (Treg) infiltration (all P &amp;lt; 0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P &amp;lt; 0.01) and memory/effector T cells (P &amp;lt; 0.05), while lowering the neutrophil-to-lymphocyte ratio (P &amp;lt; 0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumor enrichment in neutrophil features observed with the treatment combination was linked to less aggressive tumors with more differentiated and less proliferative phenotypes. Conclusions: Cabozantinib in combination with anti-PD1 enhanced antitumor immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favors this approach for HCC treatment.
MicroRNA loaded edible nanoparticles: an emerging personalized therapeutic approach for the treatment of obesity and metabolic disorders
Authors: F. Campolo, G. Catanzaro, M.A. Venneri, E. Ferretti, Z.M. Besharat
Journal: Theranostics (2022)

Obesity is a metabolic chronic disease whose prevalence is strongly growing in the last years, reaching pandemic proportions.Nowadays weight loss, achieved through lifestyle changes, is the first line therapeutic objective, although great inter-individual variabilities influence response to treatment, suggesting the involvement of epigenetic factors.In this contest, there is increasing recognition of the role of small RNA molecules, particularly microRNAs in the epigenetic regulation of genes involved in adipose tissue and glucose metabolism and several microRNAs have been found to be dysregulated in obesity and metabolic diseases.The development of novel personalized therapeutic strategies using microRNAs bears promise.However, the application of naked microRNAs has been hampered by their low specificity and sensitivity.In a recent issue of Theranostics, Kumar et al. explored the possibility of microRNA delivery through ginger-derived nanoparticles (GDNPs) as an alternative therapeutic approach for obesity treatment.The results reported by Kumar et al., addressing non-coding RNAs and edible plant derived nanoparticles, open new perspectives for the application of this innovative and safe delivery system in the clinical practice for the treatment of obesity and other metabolic disorders.
124P Comparison of survival among multimodality treatment regimens in malignant pleural mesothelioma patients in an integrated health system
Authors: K. Banks, S. Ossowski, Y-Y. Hung, D.S. Hsu, S.K. Ashiku, A.R. Patel, J.B. Velotta, J.M. Suga
Journal: Annals of Oncology (2022)
Association of Bleeding Severity With Mortality in Extended Thromboprophylaxis of Medically Ill Patients in the MAGELLAN and MARINER Trials
Authors: Alex C. Spyropoulos, Gary E. Raskob, Alexander T. Cohen, Walter Ageno, Jeffrey I. Weitz, Theodore E. Spiro, Wentao Lu, Concetta Lipardi, Gregory W. Albers, C. Gregory Elliott, Jonathan L. Halperin, William R. Hiatt, Gregory Maynard, P. Gabriel Steg, Chiara Sugarmann, Elliot S. Barnathan
Journal: Circulation (2022)

Extended thromboprophylaxis has not been widely implemented in acutely ill medical patients because of bleeding concerns. The MAGELLAN (Multicenter, Randomized, Parallel Group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) and MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) trials evaluated whether rivaroxaban compared with enoxaparin or placebo could prevent venous thromboembolism without increased bleeding. We hypothesized that patients with major bleeding but not those with nonmajor clinically relevant bleeding would be at an increased risk of all-cause mortality (ACM).We evaluated all bleeding events in patients taking at least 1 dose of study drug and their association with ACM in 4 mutually exclusive groups: (1) no bleeding, or first event was (2) nonmajor clinically relevant bleeding, (3) major bleeding, or (4) trivial bleeding. Using a Cox proportional hazards model adjusted for differences in baseline characteristics associated with ACM, we assessed the risk of ACM after such events.Compared with patients with no bleeding, the risk of ACM for patients with nonmajor clinically relevant bleeding was not increased in MARINER (hazard ratio, 0.43; P=0.235) but was increased in MAGELLAN (hazard ratio, 1.74; P=0.021). Major bleeding was associated with a higher incidence of ACM in both studies, whereas trivial bleeding was not associated with ACM in either study.Patients with major bleeding had an increased risk of ACM, whereas nonmajor clinically relevant bleeding was not consistently associated with an increased risk of death. These results inform the risk-benefit calculus of extended thromboprophylaxis in medically ill patients.URL: https://www.gov; Unique identifier: MAGELLAN, NCT00571649. URL: https://www.gov; Unique identifier: MARINER, NCT02111564.
Multi-regional module-based signal transmission in mouse visual cortex
Authors: Xiaoxuan Jia, Joshua H. Siegle, Séverine Durand, Greggory Heller, Tamina K. Ramirez, Christof Koch, Shawn R. Olsen
Journal: Neuron (2022)

The visual cortex is hierarchically organized, yet the presence of extensive recurrent and parallel pathways make it challenging to decipher how signals flow between neuronal populations. Here, we tracked the flow of spiking activity recorded from six interconnected levels of the mouse visual hierarchy. By analyzing leading and lagging spike-timing relationships among pairs of simultaneously recorded neurons, we created a cellular-scale directed network graph. Using a module-detection algorithm to cluster neurons based on shared connectivity patterns, we uncovered two multi-regional communication modules distributed across the hierarchy. The direction of signal flow both between and within these modules, differences in layer and area distributions, and distinct temporal dynamics suggest that one module transmits feedforward sensory signals, whereas the other integrates inputs for recurrent processing. These results suggest that multi-regional functional modules may be a fundamental feature of organization beyond cortical areas that supports signal propagation across hierarchical recurrent networks.
In suspected or provisionally diagnosed ACS, early CTCA did not reduce mortality or nonfatal MI at 1 y
Authors: Thomas Lardaro, Benton R. Hunter
Journal: Annals of Internal Medicine (2022)

Gray AJ, Roobottom C, Smith JE, et al. Early computed tomography coronary angiography in patients with suspected acute coronary syndrome: randomised controlled trial. BMJ. 2021;374:n2106. 34588162.
Vitamin D, Skin Filaggrin, Allergic Sensitization, and Race: a Complex Interplay
Authors: Elisabet Johansson, Jocelyn Biagini, Lisa Martin, Hua He, John Kroner, Stanley DeVore, Daniel Spagna, Brittany Grashel, Gurjit Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2022)
Efficacy of once-weekly tirzepatide versus once-daily insulin degludec on glycaemic control measured by continuous glucose monitoring in adults with type 2 diabetes (SURPASS-3 CGM): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial
Authors: Tadej Battelino, Richard M Bergenstal, Angel Rodríguez, Laura Fernández Landó, Ross Bray, Zhentao Tong, Katelyn Brown
Journal: The Lancet Diabetes & Endocrinology (2022)
112P Patient-reported outcomes (PROs) with first-line (1L) cemiplimab in patients with locally advanced non-small cell lung cancer (laNSCLC): EMPOWER-Lung 1 subpopulation
Authors: I. Bondarenko, A. Sezer, S. Kilickap, M. Gümüş, M. Özgüroğlu, M. Gogishvili, X. He, G. Gullo, P. Rietschel, R.G. Quek
Journal: Annals of Oncology (2022)