tbuckley/cabot-search huggingface dataset:
EXERCISE TRAINING INCREASES TOXIC PROTEIN OLIGOMERS UPTAKE FUNCTION OF PERIPHERAL BLOOD MONONUCLEAR CELLS IN PATIENTS WITH HEART FAILURE
Authors: Marisol Gouveia, Manuel Teixeira, Cristine Schmidt, Sandra Magalhães, Alexandra Nunes, Mário Santos, Sandra Vieira, Fernando Ribeiro
Journal: Journal of the American College of Cardiology (2022)
Genome-wide association studies identify novel genetic loci for epigenetic age acceleration among survivors of childhood cancer
Authors: Qian Dong, Nan Song, Na Qin, Cheng Chen, Zhenghong Li, Xiaojun Sun, John Easton, Heather Mulder, Emily Plyler, Geoffrey Neale, Emily Walker, Qian Li, Xiaotu Ma, Xiang Chen, I-Chan Huang, Yutaka Yasui, Kirsten K. Ness, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang
Journal: Genome Medicine (2022)

Abstract Background Increased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA. Methods Genome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability. Results For EAA-Horvath, a genome-wide significant association was mapped to the SELP gene with the strongest SNP rs732314 (meta-GWAS: β =0.57, P =3.30×10 -11 ). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS: β =0.97 vs. 0.51, I 2 =73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure ( β =0.64 vs. 0.31, I 2 =66.3%). For EAA-Hannum, an association was mapped to the HLA locus with the strongest SNP rs28366133 (meta-GWAS: β =0.78, P =3.78×10 -11 ). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath ( β =1.09, P =5.43×10 -5 ), whereas rs28366133 was not associated with EAA-Hannum ( β =0.21, P =0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge. Conclusions We identified novel genetic variants in the SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.
Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial
Authors: Song-Yang Wu, Ying Xu, Li Chen, Lei Fan, Xiao-Yan Ma, Shen Zhao, Xiao-Qing Song, Xin Hu, Wen-Tao Yang, Wen-Jun Chai, Xiao-Mao Guo, Xi-Zi Chen, Yan-Hui Xu, Xiao-Yu Zhu, Jian-Jun Zou, Zhong-Hua Wang, Yi-Zhou Jiang, Zhi-Ming Shao
Journal: Molecular Cancer (2022)

Abstract Background Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients. Methods We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes. Results CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2–92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4–18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen. PKD1 somatic mutation indicates worse progression-free and overall survival. Conclusion This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments. Trial registration ClinicalTrials.gov: NCT04129996 . Registered 11 October 2019.
Genetic Diversity, Heteroplasmy, and Recombination in Mitochondrial Genomes of<i>Daphnia pulex</i>,<i>Daphnia pulicaria</i>, and<i>Daphnia obtusa</i>
Authors: Zhiqiang Ye, Chaoxian Zhao, R. Taylor Raborn, Man Lin, Wen Wei, Yue Hao, Michael Lynch
Journal: Molecular Biology and Evolution (2022)

Genetic variants of mitochondrial DNA at the individual (heteroplasmy) and population (polymorphism) levels provide insight into their roles in multiple cellular and evolutionary processes. However, owing to the paucity of genome-wide data at the within-individual and population levels, the broad patterns of these two forms of variation remain poorly understood. Here, we analyze 1,804 complete mitochondrial genome sequences from Daphnia pulex, Daphnia pulicaria, and Daphnia obtusa. Extensive heteroplasmy is observed in D. obtusa, where the high level of intraclonal divergence must have resulted from a biparental-inheritance event, and recombination in the mitochondrial genome is apparent, although perhaps not widespread. Global samples of D. pulex reveal remarkably low mitochondrial effective population sizes, <3% of those for the nuclear genome. In addition, levels of population diversity in mitochondrial and nuclear genomes are uncorrelated across populations, suggesting an idiosyncratic evolutionary history of mitochondria in D. pulex. These population-genetic features appear to be a consequence of background selection associated with highly deleterious mutations arising in the strongly linked mitochondrial genome, which is consistent with polymorphism and divergence data suggesting a predominance of strong purifying selection. Nonetheless, the fixation of mildly deleterious mutations in the mitochondrial genome also appears to be driving positive selection on genes encoded in the nuclear genome whose products are deployed in the mitochondrion.
Omicron variant Spike-specific antibody binding and Fc activity are preserved in recipients of mRNA or inactivated COVID-19 vaccines
Authors: Yannic C. Bartsch, Xin Tong, Jaewon Kang, María José Avendaño, Eileen F. Serrano, Tamara García-Salum, Catalina Pardo-Roa, Arnoldo Riquelme, Yongfei Cai, Isabella Renzi, Guillaume Stewart-Jones, Bing Chen, Rafael A. Medina, Galit Alter
Journal: Science Translational Medicine (2022)

The Omicron variant of SARS-CoV-2 has been shown to evade neutralizing antibodies elicited by vaccination or infection. Despite the global spread of the Omicron variant, even among highly vaccinated populations, death rates have not increased concomitantly. These data suggest that immune mechanisms beyond antibody-mediated virus neutralization may protect against severe disease. In addition to neutralizing pathogens, antibodies contribute to control and clearance of infections through Fc effector mechanisms. Here, we probed the ability of vaccine-induced antibodies to drive Fc effector activity against the Omicron variant using samples from individuals receiving one of three SARS-CoV-2 vaccines. Despite a substantial loss of IgM, IgA, and IgG binding to the Omicron variant receptor binding domain (RBD) in samples from individuals receiving BNT162b2, mRNA-1273, and CoronaVac vaccines, stable binding was maintained against the full-length Omicron Spike protein. Compromised RBD binding IgG was accompanied by a loss of RBD-specific antibody Fcγ receptor (FcγR) binding in samples from individuals who received the CoronaVac vaccine, but RBD-specific FcγR2a and FcγR3a binding was preserved in recipients of mRNA vaccines. Conversely, Spike protein-specific antibodies exhibited persistent but reduced binding to FcγRs across all three vaccines, although higher binding was observed in samples from recipients of mRNA vaccines. This was associated with preservation of FcγR2a and FcγR3a binding antibodies and maintenance of Spike protein-specific antibody-dependent natural killer cell activation. Thus, despite the loss of Omicron neutralization, vaccine-induced Spike protein-specific antibodies continue to drive Fc effector functions, suggesting a capacity for extraneutralizing antibodies to contribute to disease control.
CHILDREN WHO DEVELOPED ACUTE KIDNEY INJURY AFTER PEDIATRIC CARDIAC SURGERY HAVE PERSISTENT MARKERS OF RENAL INJURY AT MID- AND LONG-TERM FOLLOW-UP
Authors: Jef Van den Eynde, Thomas Salaets, Jacoba J. Louw, Jean Herman, Luc Breysem, Dirk Vlasselaers, Lars Desmet, Bart Meyns, Werner Budts, Marc H. Gewillig, Djalila Mekahli
Journal: Journal of the American College of Cardiology (2022)
MODE OF PRESENTATION, PROGNOSIS AND PREDICTORS OF OUTCOME IN A CONTEMPORARY CARDIAC SARCOIDOSIS POPULATION
Authors: Vasileios Kouranos, Rajdeep Singh Khattar, Raheel Ahmed, Alessia Azzu, Joseph Okafor, Rui Shi, Arun John Baksi, Kshama Wechalekar, Martin R. Cowie, Dudley J. Pennell, Athol Umfrey Wells, Rakesh Sharma
Journal: Journal of the American College of Cardiology (2022)
Neoadjuvant clinical trials provide a window of opportunity for cancer drug discovery
Authors: Thomas U. Marron, Matthew D. Galsky, Bachir Taouli, Maria Isabel Fiel, Stephen Ward, Edward Kim, David Yankelevitz, Deborah Doroshow, Emma Guttman-Yassky, Benjamin Ungar, Saurabh Mehandru, Benjamin J. Golas, Daniel Labow, John Sfakianos, Sujit S. Nair, Dimple Chakravarty, Michael Buckstein, Xiaoyu Song, Effi Kenigsberg, Sacha Gnjatic, Brian D. Brown, Joseph Sparano, Ashutosh Tewari, Myron Schwartz, Nina Bhardwaj, Miriam Merad
Journal: Nature Medicine (2022)
Cost-Effectiveness of a Household Salt Substitution Intervention: Findings From 20 995 Participants of the Salt Substitute and Stroke Study
Authors: Ka-Chun Li, Liping Huang, Maoyi Tian, Gian Luca Di Tanna, Jie Yu, Xinyi Zhang, Xuejun Yin, Yishu Liu, Zhixin Hao, Bo Zhou, Xiangxian Feng, Zhifang Li, Jianxin Zhang, Jixin Sun, Yuhong Zhang, Yi Zhao, Ruijuan Zhang, Yan Yu, Nicole Li, Lijing L. Yan, Darwin R. Labarthe, Paul Elliott, Yangfeng Wu, Bruce Neal, Thomas Lung, Lei Si
Journal: Circulation (2022)

Background: SSaSS (Salt Substitute and Stroke Study), a 5-year cluster randomized controlled trial, demonstrated that replacing regular salt with a reduced-sodium, added-potassium salt substitute reduced the risks of stroke, major adverse cardiovascular events, and premature death among individuals with previous stroke or uncontrolled high blood pressure living in rural China. This study assessed the cost-effectiveness profile of the intervention. Methods: A within-trial economic evaluation of SSaSS was conducted from the perspective of the health care system and consumers. The primary health outcome assessed was stroke. We also quantified the effect on quality-adjusted life-years (QALYs). Health care costs were identified from participant health insurance records and the literature. All costs (in Chinese yuan [¥]) and QALYs were discounted at 5% per annum. Incremental costs, stroke events averted, and QALYs gained were estimated using bivariate multilevel models. Results: Mean follow-up of the 20 995 participants was 4.7 years. Over this period, replacing regular salt with salt substitute reduced the risk of stroke by 14% (rate ratio, 0.86 [95% CI, 0.77–0.96]; P =0.006), and the salt substitute group had on average 0.054 more QALYs per person. The average costs (¥1538 for the intervention group and ¥1649 for the control group) were lower in the salt substitute group (¥110 less). The intervention was dominant (better outcomes at lower cost) for prevention of stroke as well as for QALYs gained. Sensitivity analyses showed that these conclusions were robust, except when the price of salt substitute was increased to the median and highest market prices identified in China. The salt substitute intervention had a 95.0% probability of being cost-saving and a &gt;99.9% probability of being cost-effective. Conclusions: Replacing regular salt with salt substitute was a cost-saving intervention for the prevention of stroke and improvement of quality of life among SSaSS participants.
Abstract PD3-04: Multi-omics characterization of triple-negative breast cancer identifies therapeutic vulnerabilities and epigenetic immune suppression in the mesenchymal subtype
Authors: Brian D Lehmann, Antonio Colaprico, Tiago C Silva, Jianjiao Chen, Hanbing An, Yuguang Ban, Lily Wang, Jamaal L James, Justin Balko, Paula I Gonzalez-Ericsson, Melinda E Sanders, Bing Zhang, Jennifer A Pietenpol, Xi S Chen
Journal: Cancer Research (2022)

Abstract Triple-negative breast cancer (TNBC) is a collection of biologically diverse cancers characterized by distinct transcriptional patterns, biology and immune composition. TNBCs display transcriptional diversity with at least four tumor-intrinsic subtypes that include two basal-like (BL1, BL2), a mesenchymal (M) and a luminal androgen receptor (LAR) subtype. Using integrative analyses of transcriptomic, epigenetic, proteomic and phospho-proteomic patterns we have identified subtype-specific vulnerabilities, which advanced our understanding of the cellular origins of TNBC subtypes. In mesenchymal subtype tumors we observed high mutation load and genomic instability, absence of immune cells, low PD-L1 expression, loss of global DNA methylation and transcriptional repression of antigen presentation genes through the polycomb repressor complex 2 (PRC2). Using cell line models, we demonstrate that MHC-I expression is epigenetically silenced by the PRC2 in mesenchymal TNBC cell lines and inhibition of EZH2 restores expression. Pharmacological inhibition of EZH2 enhances chemotherapy efficacy in syngeneic murine tumor models providing a rationale for using PRC2 inhibitors in PD-L1 negative mesenchymal tumors. Citation Format: Brian D Lehmann, Antonio Colaprico, Tiago C Silva, Jianjiao Chen, Hanbing An, Yuguang Ban, Lily Wang, Jamaal L James, Justin Balko, Paula I Gonzalez-Ericsson, Melinda E Sanders, Bing Zhang, Jennifer A Pietenpol, Xi S Chen. Multi-omics characterization of triple-negative breast cancer identifies therapeutic vulnerabilities and epigenetic immune suppression in the mesenchymal subtype [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-04.
DEEP LEARNING POWERED SOLUTION FOR DETECTING CORONARY ARTERY DISEASE AND STENOSIS QUANTIFICATION FROM ECG GATED CT CORONARY ANGIOGRAM (CTCA)
Authors: AliAsghar Mortazi, Ashish Gautam, Prashant Raghav, Samir Rathore, Aradhna Singh, Sudhir Rathore
Journal: Journal of the American College of Cardiology (2022)
Prior upregulation of interferon pathways in the nasopharynx impacts viral shedding following live attenuated influenza vaccine challenge in children
Authors: André G. Costa-Martins, Karim Mane, Benjamin B. Lindsey, Rodrigo L.T. Ogava, I′caro Castro, Ya Jankey Jagne, Hadijatou J. Sallah, Edwin P. Armitage, Sheikh Jarju, Bankole Ahadzie, Rebecca Ellis-Watson, John S. Tregoning, Colin D. Bingle, Debby Bogaert, Ed Clarke, Jose Ordovas-Montanes, David Jeffries, Beate Kampmann, Helder I. Nakaya, Thushan I. de Silva
Journal: Cell Reports Medicine (2022)

[This corrects the article DOI: 10.1016/j.xcrm.2021.100465.].
Effectiveness and safety of pneumocystis pneumonia prophylaxis for patients receiving temozolomide chemoradiotherapy
Authors: Seth A Climans, Eva Grunfeld, Warren P Mason, Kelvin K W Chan
Journal: Neuro-Oncology (2022)

Abstract Background Malignant gliomas are treated with temozolomide chemoradiotherapy. Because pneumocystis pneumonia (PCP) can occur in patients receiving temozolomide, the product monograph recommends PCP prophylaxis during temozolomide chemoradiotherapy. Not all neuro-oncologists follow these recommendations, though. Methods We performed a population-based retrospective cohort study of glioma patients undergoing temozolomide chemoradiotherapy 2005 to 2019 in Ontario, Canada. A propensity score model was used to predict the use of PCP prophylaxis. We compared the risk of PCP within 90 days of starting radiotherapy with versus without PCP prophylaxis using inverse probability of treatment weighting (IPTW). We also examined overall survival, hospitalizations, and myelosuppression. Results There were 3,225 patients included in the cohort (648 received antibiotics and 2,434 did not). Only 18 patients developed PCP within 90 days of therapy. The IPTW-adjusted absolute risk reduction in PCP with antibiotics was 0.0035 (95% CI, −0.0013 to 0.0083), number needed to treat: 288. Neither overall survival nor hospitalization count differed between the groups. The number needed to harm by causing grade 3/4 neutropenia was 39. Conclusions In regions (like Ontario) where PCP is rare, routine PCP prophylaxis with trimethoprim-sulfamethoxazole should not be offered, since the harms may outweigh the benefits.
Surgical Management of Gastric Cancer
Authors: George Z. Li, Gerard M. Doherty, Jiping Wang
Journal: JAMA Surgery (2022)

<h3>Importance</h3> Surgery plays a critical role in the management of all stages of gastric cancer. <h3>Observations</h3> For patients with early gastric cancer and low risk of lymph node metastasis, endoscopic therapy or surgery alone is potentially curative. Novel techniques, such as sentinel lymph node biopsy, may allow for greater use of stomach-sparing procedures that could improve quality of life without compromising oncologic outcomes; however, experience with these techniques is rare outside of East Asia, and studies of long-term outcomes are still ongoing. Patients with later-stage localized gastric cancer benefit from more extensive lymphadenectomy and multimodality therapy, as they are at risk for nodal and distant metastases. There have been recent advances in chemotherapy that have led to improved survival, but the optimal sequencing of multimodality therapy is still being investigated. Better systemic therapy may also increase the role of surgery for patients with oligometastatic disease. There are ongoing studies examining the efficacy of peritoneal-directed therapies in both patients with low-volume peritoneal disease and patients at high risk of peritoneal recurrence. <h3>Conclusions and Relevance</h3> The management of gastric cancer continues to evolve. Surgeons should be aware of novel surgical approaches currently under investigation as well as how surgery fits into the contemporary multidisciplinary approach to this disease.
35P NSCLC: Real-world data analysis from a chain of oncology centres in Western India
Authors: A.A. Shivchhand, A. Joshi, U. Maheshwari, V. Maniar, K. Joshi, P. Kalaskar, S. Sheth, P. Kendre, R. Korgavkar, D. Morzaria, C. Pethe, S. Dhande, M. Mekha, D. Rane, S. Jagiasi
Journal: Annals of Oncology (2022)
Diagnostic Strategy Using an Elevated Age-Adjusted D-Dimer Threshold and Thromboembolic Events in the Emergency Department
Authors: Daniël A. Korevaar, Josien van Es, Jérémie F. Cohen
Journal: JAMA (2022)

To the Editor A recent randomized clinical trial1 compared the YEARS rule combined with age-adjusted D-dimer vs age-adjusted D-dimer only on the primary outcome of proportion of missed venous thromboembolism (VTE) events.
Arginine deprivation alters microglial polarity and synergizes with radiation to eradicate non-arginine-auxotrophic glioblastoma tumors
Authors: Nabil Hajji, Juan Garcia-Revilla, Manuel Sarmiento Soto, Richard Perryman, Jake Symington, Chad C. Quarles, Deborah R. Healey, Yijie Guo, Manuel Luis Orta-Vázquez, Santiago Mateos-Cordero, Khalid Shah, John Bomalaski, Giulio Anichini, Andreas G. Tzakos, Timothy Crook, Kevin O’Neill, Adrienne C. Scheck, Jose Luis Venero, Nelofer Syed
Journal: Journal of Clinical Investigation (2022)

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1-positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.
The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming
Authors: Sophia M. Hochrein, Hao Wu, Miriam Eckstein, Laura Arrigoni, Josip S. Herman, Fabian Schumacher, Christian Gerecke, Mathias Rosenfeldt, Dominic Grün, Burkhard Kleuser, Georg Gasteiger, Wolfgang Kastenmüller, Bart Ghesquière, Jan Van den Bossche, E. Dale Abel, Martin Vaeth
Journal: Cell Metabolism (2022)
COMPARISON OF ELECTROCAUTERY PLATFORMS FOR PULSE GENERATOR REPLACEMENTS PROCEDURES
Authors: Caleb Chiang, Muhammad Talha Ayub, Kousik Krishnan, Richard G. Trohman, Timothy R. Larsen, Henry Darchon Huang, Parikshit S. Sharma, Janet M. Haw, Jeremiah Wasserlauf
Journal: Journal of the American College of Cardiology (2022)
HSR22-184: The Association of the Social Vulnerability Index to Timely Treatment of Metastatic Cancers Among Insured Adult Patients in the US
Authors: Teresa Zyczynski, Ying Tabak, Xiaowu Sun, Henriette Coetzer, Ying Zhang, Cardinale Smith
Journal: Journal of the National Comprehensive Cancer Network (2022)

"HSR22-184: The Association of the Social Vulnerability Index to Timely Treatment of Metastatic Cancers Among Insured Adult Patients in the US" published on 31 Mar 2022 by National Comprehensive Cancer Network.