tbuckley/cabot-search huggingface dataset:
Single-Cell Atlas of Lineage States, Tumor Microenvironment, and Subtype-Specific Expression Programs in Gastric Cancer
Authors: Vikrant Kumar, Kalpana Ramnarayanan, Raghav Sundar, Nisha Padmanabhan, Supriya Srivastava, Mayu Koiwa, Tadahito Yasuda, Vivien Koh, Kie Kyon Huang, Su Ting Tay, Shamaine Wei Ting Ho, Angie Lay Keng Tan, Takatsugu Ishimoto, Guowei Kim, Asim Shabbir, Qingfeng Chen, Biyan Zhang, Shengli Xu, Kong-Peng Lam, Huey Yew Jeffrey Lum, Ming Teh, Wei Peng Yong, Jimmy Bok Yan So, Patrick Tan
Journal: Cancer Discovery (2021)

Gastric cancer heterogeneity represents a barrier to disease management. We generated a comprehensive single-cell atlas of gastric cancer (>200,000 cells) comprising 48 samples from 31 patients across clinical stages and histologic subtypes. We identified 34 distinct cell-lineage states including novel rare cell populations. Many lineage states exhibited distinct cancer-associated expression profiles, individually contributing to a combined tumor-wide molecular collage. We observed increased plasma cell proportions in diffuse-type tumors associated with epithelial-resident KLF2 and stage-wise accrual of cancer-associated fibroblast subpopulations marked by high INHBA and FAP coexpression. Single-cell comparisons between patient-derived organoids (PDO) and primary tumors highlighted inter- and intralineage similarities and differences, demarcating molecular boundaries of PDOs as experimental models. We complemented these findings by spatial transcriptomics, orthogonal validation in independent bulk RNA-sequencing cohorts, and functional demonstration using in vitro and in vivo models. Our results provide a high-resolution molecular resource of intra- and interpatient lineage states across distinct gastric cancer subtypes. We profiled gastric malignancies at single-cell resolution and identified increased plasma cell proportions as a novel feature of diffuse-type tumors. We also uncovered distinct cancer-associated fibroblast subtypes with INHBA-FAP-high cell populations as predictors of poor clinical prognosis. Our findings highlight potential origins of deregulated cell states in the gastric tumor ecosystem. This article is highlighted in the In This Issue feature, p. 587.
P40.14 Efficacy and Safety of Endostar Combined With Camrelizumab and Chemotherapy in Treatment of Advanced NSCLC: A Multi-Center Retrospective Study
Authors: L. Wu, X. Pu, B. Chen, Q. Wang, L. Liu, K. Li, Y. Kong, F. Xu, J. Li, L. Xu, Y. Tang, Y. Xu, M. Xiao, P. Liu
Journal: Journal of Thoracic Oncology (2021)
P63.02 Exposure-Response Analysis of Lurbinectedin Alone or With Doxorubicin in Overall Survival in Small Cell Lung Cancer
Authors: S. Fudio, L. Pérez-Ramos, Q. Wang, J.A. Lopez-Vilariño, C. Kahatt, A. Zeaiter, R. Lubomirov
Journal: Journal of Thoracic Oncology (2021)
Voices from the abyss
Authors: Marco De Ambrogi
Journal: The Lancet Infectious Diseases (2021)

With COVID-19, everyone has sadly experienced directly the havoc, confusion, and fear that a new disease may generate. We have witnessed how opinions on the cause, origin, and way of transmission of the disease differ and how politicians faced the pandemic with very different approaches, some of them rejecting the evidence provided by science. The same sense of uncertainty and panic characterised the emergence of new diseases, such as AIDS, in the past but this aspect can be easily forgotten because now we look at them from the distance as neatly reported historical events benefitting from current scientific evidence.
Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis of Individual Participant Data from Randomised Controlled Trials
Authors: Sarah Burdett, David J. Fisher, Claire L. Vale, Cora N. Sternberg, Noel W. Clarke, Mahesh K.B. Parmar, Aldo V. Bono, Francesco Cognetti, Laurence Collette, Richard J. Cote, Peter J. Goebell, Susan Groshen, Jan Lehmann, Alexander I. Rolevich, Roland W. Sonntag, Michael Stockle, Urs E. Studer, Frank M. Torti, Alexander G. Zhegalik, Jayne F. Tierney
Journal: European Urology (2021)

Our prior systematic review and meta-analysis of individual participant data (IPD) suggesting a benefit of adjuvant chemotherapy for muscle-invasive bladder cancer was limited by the number and size of included randomised trials. We have updated results to include additional trials, providing the most up-to-date and reliable evidence of the effects of this treatment. To investigate the role of adjuvant cisplatin-based chemotherapy in the treatment of muscle-invasive bladder cancer. Published and unpublished trials were sought via searches of bibliographic databases, trials registers, conference proceedings, and hand searching. Updated IPD were centrally collected, checked, and analysed. Results from individual randomised controlled trials (RCTs) were combined using a two-stage fixed-effect model. Prespecified analyses explored any variation in effect by trial and participant characteristics. Analyses of ten RCTs (1183 participants) demonstrated a benefit of cisplatin-based adjuvant chemotherapy on overall survival (hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70–0.96, p = 0.02). This represents an absolute improvement in survival of 6% at 5 yr, from 50% to 56%, and a 9% absolute benefit when adjusted for age, sex, pT stage, and pN category (HR = 0.77, 95% CI = 0.65–0.92, p = 0.004). There was no clear evidence that the effect varied by trial or participant characteristics. Adjuvant chemotherapy was also shown to improve recurrence-free survival (HR = 0.71, 95% CI = 0.60–0.83, p < 0.001), locoregional recurrence-free survival (HR = 0.68, 95% CI = 0.55–0.85, p < 0.001), and metastasis-free survival (HR = 0.79, 95% CI = 0.65–0.95, p = 0.01), with absolute benefits of 11%, 11%, and 8%, respectively. This systematic review and meta-analysis demonstrates that cisplatin-based adjuvant chemotherapy is a valid option for improving outcomes for muscle-invasive bladder cancer. We looked at the effect of cisplatin-based chemotherapy on outcomes in participants with muscle-invasive bladder cancer. We gathered this information from eligible randomised controlled trials. We demonstrated that cisplatin-based chemotherapy is a valid option for improving outcomes of muscle-invasive bladder cancer.
Maternal Levels of Perfluoroalkyl Substances (PFAS) during Early Pregnancy in Relation to Preeclampsia Subtypes and Biomarkers of Preeclampsia Risk
Authors: Paige A. Bommarito, Kelly K. Ferguson, John D. Meeker, Thomas F. McElrath, David E. Cantonwine
Journal: Environmental Health Perspectives (2021)

Background: Prenatal exposure to perfluoroalkyl substances (PFAS) has been previously associated with preeclampsia, although findings are mixed with respect to the direction and magnitude of effect. To our knowledge, no studies have examined associations between PFAS and preeclampsia subtypes, which may have distinct etiologies. Objective: We examined associations between PFAS, any preeclampsia diagnosis, and early- and late-onset preeclampsia. In addition, we estimated associations between PFAS and the angiogenic biomarkers soluble fms-like tyrosine kinase-1 (sFLT-1) and placental growth factor (PlGF), which provide an estimate of pro- and anti-angiogenic activity within the placenta. Methods: This case–control study (n=75 cases, n=75 controls) was sampled from the LIFECODES birth cohort. Nine legacy PFAS were quantified in maternal plasma from early pregnancy (median= 10 wk) and angiogenic biomarkers were quantified in maternal plasma from four study visits (median= 10, 18, 26, and 35 wk). Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the association between an interquartile range (IQR)-increase in PFAS and preeclampsia outcomes. Linear regression was used to estimate associations between an IQR-increase in PFAS and concentrations of angiogenic biomarkers. Results: Both perfluorodecanoic acid (OR= 1.64, 95% CI: 1.08, 2.47) and perfluorooctanesulfonic acid (OR= 1.60, 95% CI: 1.06, 2.43) were associated with higher odds of late-onset preeclampsia. Associations tended to be below the null for early-onset preeclampsia, although findings were imprecise. Few associations were noted between PFAS and angiogenic biomarkers. Discussion: Maternal PFAS concentrations were associated with higher odds of late-onset preeclampsia. Heterogeneity of preeclampsia should be considered in future studies because populations may have different distributions of disease subtypes. https://doi.org/10.1289/EHP9091
Brown adipose tissue transplantation ameliorates diabetic nephropathy through the miR-30b pathway by targeting Runx1
Authors: Yudan Zhang, Yingying Cai, Hongbin Zhang, Jiajun Zhang, Yanmei Zeng, Cunxia Fan, Shaozhou Zou, Chunyan Wu, Shu Fang, Ping Li, Xiaochun Lin, Ling Wang, Meiping Guan
Journal: Metabolism (2021)

ObjectiveAdipose tissue is a major source of circulating microRNAs (miRNAs) that can regulate target genes in distant organs. However, the role of brown adipose tissue (BAT) in diabetic kidney disease (DKD) is still unknown. We studied the original BAT miR-30b targeting two key fibrotic regulators, Runt-related transcription factor 1 (Runx1) and snail family zinc finger 1 (Snail1), to combat DKD.MethodsFirst, we transplanted healthy BAT from normal mouse donors into diabetic mice (induced by a high-fat diet and streptozotocin injection). In vitro, we observed extracellular vesicles (EVs) secreted from brown adipocytes. AgomiR-30b was directly administered to the BAT of diabetic mice twice weekly for 4 consecutive weeks. Next, the role of Runx1 in DKD was determined by using siRUNX1 or pCMV-RUNX1 in HK-2 cells and in diabetic mice treated with AAV9-U6-shRunx1 or AAV9-EF1a-Runx1.ResultsBAT transplantation reactivated endogenous BAT activity in diabetic mice, increased circulating miR-30b levels and significantly ameliorated DKD. In TGFβ1-treated HK-2 cells, miR-30b expression was significantly suppressed. miR-30b overexpression markedly decreased fibronectin and downregulated Runx1 and Snail1 expression, while silencing of miR-30b had the opposite effects. Next, Runx1 knockdown and overexpression mimicked the above phenotype of miR-30b mimics and inhibitors, respectively, both in vitro and in vivo. Moreover, Runx1 promoted TGFβ1-induced fibrosis by upregulating the PI3K pathway.ConclusionBAT-derived miRNAs might be a promising target for kidney protection in diabetes mellitus.
Inherited Mutations in Chinese Men With Prostate Cancer
Authors: Yao Zhu, Yu Wei, Hao Zeng, Yonghong Li, Chi-Fai Ng, Fangjian Zhou, Caiyun He, Guangxi Sun, Yuchao Ni, Peter K.F. Chiu, Jeremy Y.C. Teoh, Beihe Wang, Jian Pan, Fangning Wan, Bo Dai, Xiaojian Qin, Guowen Lin, Hualei Gan, Junlong Wu, Dingwei Ye
Journal: Journal of the National Comprehensive Cancer Network (2021)

Although China accounts for 7.8% of worldwide new prostate cancer (PCa) cases and 14.5% of new deaths according to GLOBOCAN 2020, the risk of PCa associated with germline mutations is poorly defined, hampered in part by lack of nationwide evidence. Here, we sequenced 19 PCa predisposition genes in 1,836 Chinese patients with PCa and estimated disease risk associated with inherited mutations.Patients were recruited from 4 tertiary cancer centers (n=1,160) and a commercial laboratory (n=676). Germline DNA was sequenced using a multigene panel, and pathogenic/likely pathogenic (P/LP) mutation frequencies in patients with PCa were compared with populations from the gnomAD (Genome Aggregation Database) and ChinaMAP (China Metabolic Analytics Project) databases. Clinical characteristics and progression-free survival were assessed by mutation status.Of 1,160 patients from hospitals, 89.7% had Gleason scores ≥8, and 65.6% had metastases. P/LP mutations were identified in 8.49% of Chinese patients with PCa. Association with PCa risk was significant for mutations in ATM (odds ratio [OR], 5.9; 95% CI, 3.1-11.1), BRCA2 (OR, 15.3; 95% CI, 10.0-23.2), MSH2 (OR, 15.8; 95% CI, 4.2-59.6), and PALB2 (OR, 5.9; 95% CI, 2.7-13.2). Compared with those without mutations, patients with mutations in ATM, BRCA2, MSH2, or PALB2 showed a poor outcome with treatment using androgen deprivation therapy and abiraterone (hazard ratio, 2.19 [95% CI, 1.34-3.58] and 2.47 [95% CI, 1.23-4.96], respectively) but similar benefit from docetaxel.The present multicenter study confirmed that a significant proportion of Chinese patients with PCa had inherited mutations and identified predisposition genes in this underreported ethnicity. These data provide empirical evidence for precision prevention and prognostic estimation in Chinese patients with PCa.
FP02.01 Utilization and Refusal of Adjuvant Chemotherapy for Non-Small Cell Lung Cancer: A National Cancer Database Study
Authors: R. Pathak, R. Nelson, H. West, A. Amini, E. Massarelli, M. Koczywas, M. Villalona-Calero, V. Villaflor, A. Katel, R. Salgia, V. Sun
Journal: Journal of Thoracic Oncology (2021)
P05.07 Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer Without Pretreatment Pathologic Results in a Chinese Population
Authors: R. Zhang, Y. Guo, Y. Yan, Y. Liu, Y. Zhu, J. Kang, F. Li, X. Sun, L. Xing, Y. Xu
Journal: Journal of Thoracic Oncology (2021)
OA06.02 High-Grade Patterns Cause the Upstaging of Lung Adenocarcinomas From T1 to T2a: A Multicentric Analysis
Authors: P. Bertoglio, V. Aprile, L. Ventura, M. Cattoni, D. Nachira, F. Lococo, M. Rodriguez-Perez, F. Guerrera, F. Minervini, G. Querzoli, G. Bocchialini, D. Bacchin, F. Franzi, G. Rindi, S. Bellafiore, F. Femia, G. Bogina, P. Solli, P. Kestenholz, E. Ruffini, M. Paci, S. Margaritora, A. Imperatori, M. Lucchi, L. Gnetti, A. Terzi
Journal: Journal of Thoracic Oncology (2021)
Review of Jean-Pierre Changeux and Paul Ricoeur. 2000.<i>What Makes Us Think? A Neuroscientist and Philosopher Argue about Ethics, Human Nature, and the Brain</i>
Authors: Robert H. Blank
Journal: The American Journal of Bioethics (2002)

(2002). Review of Jean-Pierre Changeux and Paul Ricoeur. 2000. What Makes Us Think? A Neuroscientist and Philosopher Argue about Ethics, Human Nature, and the Brain. The American Journal of Bioethics: Vol. 2, No. 4, pp. 69-70.
Infection-Related Myelopathies
Authors: E. Ann Yeh, Carmen Yea, Ari Bitnun
Journal: Annual Review of Pathology Mechanisms of Disease (2021)

Recent years have seen growing attention to inflammatory and infectious disorders of the spinal cord, not only due to the discovery of autoantibody-mediated disorders of the spinal cord [e.g., aquaporin-4 immunoglobulin G (IgG) antibodies and myelin oligodendrocyte glycoprotein IgG antibodies], but also due to the emergence of clusters of infection-related myelopathy, now known as acute flaccid myelitis. We review the spectrum of infection-related myelopathies and outline a nosological classification system based on association with infection. We describe the epidemiology and definitions of myelopathies, with a discussion of clinical presentation and neuroimaging features, and then turn to specific discussion of myelopathies due to direct pathogen invasion and those considered to be post- or parainfectious.
Assessing the association between lifetime exposure to greenspace and early childhood development and the mediation effects of air pollution and noise in Canada: a population-based birth cohort study
Authors: Ingrid Jarvis, Zoë Davis, Hind Sbihi, Michael Brauer, Agatha Czekajlo, Hugh W Davies, Sarah E Gergel, Martin Guhn, Michael Jerrett, Mieke Koehoorn, Tim F Oberlander, Jason Su, Matilda van den Bosch
Journal: The Lancet Planetary Health (2021)

Exposure to greenspace is associated with improved childhood development, but the pathways behind this relationship are insufficiently understood. Therefore, we aimed to investigate the association between lifetime residential exposure to greenspace and early childhood development and evaluate the extent to which this association is mediated by reductions in traffic-related air pollution and noise.This population-based birth cohort study comprised singleton births in Metro Vancouver, BC, Canada, between April 1, 2000, and Dec 31, 2005. Children and mothers had to be registered with the mandatory provincial health insurance programme, Medical Services Plan, and have lived within the study area from the child's birth to the time of outcome assessment. Early childhood development was assessed via teacher ratings on the Early Development Instrument (EDI), and we used the total EDI score as the primary outcome variable. We estimated greenspace using percentage vegetation derived from spectral unmixing of annual Landsat satellite image composites. Lifetime residential exposure to greenspace was estimated as the mean of annual percentage vegetation values within 250 m of participants' residential postal codes. Multilevel modelling, adjusted for eight covariates, was used to investigate associations between greenspace exposure and EDI scores. We estimated the mediation effects of nitrogen dioxide (NO2), fine particulate matter (PM2·5), and noise levels using causal mediation analyses.Of the 37 745 children born in Metro Vancouver between April 1, 2000, and Dec 31, 2005, 27 372 were included in our final study sample. In the adjusted model, 1 IQR increase in percentage vegetation was associated with a 0·16 (95% CI 0·04-0·28; p=0·0073) increase in total EDI score, indicating small improvements in early childhood development. We estimated that 97·1% (95% CI 43·0-396·0), 29·5% (12·0-117·0), and 35·2% (17·9-139·0) of the association was mediated through reductions in NO2, PM2·5, and noise, respectively.Increased exposure to residential greenspace might improve childhood development by reducing the adverse developmental effects of traffic-related exposures, especially NO2 air pollution. Our study supports the implementation of healthy urban planning and green infrastructure interventions.Canadian Institutes of Health Research.
Valuing Alzheimer Disease Therapies—Considering Costs and Benefits Beyond the Patient
Authors: Pei-Jung Lin, Peter J. Neumann
Journal: JAMA Network Open (2021)

Kouta Ito, MD, MS; Rick Chapman, PhD; Steven D. Pearson, MD, MSc; Ali Tafazzoli, PhD; Kristine Yaffe, MD; Jerry H. Gurwitz, MD
83TiP Clinical implications of clonal hematopoiesis mutations in patients with solid tumors
Authors: V.M. Croitoru, I.M. Cazacu, D. Paul, A. Colita, C.V. Lungulescu, V. Herlea, N.I. Luca, D. Bogdan, I. Sandra, I-M. Gramaticu, F. Buica, M.I. Dinu, A. Sorop, S. Dima, I. Popescu, A.E. Croitoru, T. Alina
Journal: Annals of Oncology (2021)
Ischemic Preconditioning for Prevention of Contrast Medium–Induced Nephropathy
Authors: Fikret Er, Amir M. Nia, Henning Dopp, Martin Hellmich, Kristina M. Dahlem, Evren Caglayan, Torsten Kubacki, Thomas Benzing, Erland Erdmann, Volker Burst, Natig Gassanov
Journal: Circulation (2012)

Contrast medium-induced acute kidney injury is associated with substantial morbidity and mortality. The underlying mechanism has been attributed in part to ischemic kidney injury. The aim of this randomized, double-blind, sham-controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium-induced acute kidney injury.Patients with impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate <60 mL · min(-1) · 1.73 m(-2)) undergoing elective coronary angiography were randomized in a 1:1 ratio to standard care with (n=50) or without ischemic preconditioning (n=50; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff). Overall, both study groups were at high risk of developing contrast medium-induced acute kidney injury according to the Mehran risk score. The primary end point was the incidence of contrast medium-induced kidney injury, defined as an increase in serum creatinine ≥25% or ≥0.5 mg/dL above baseline at 48 hours after contrast medium exposure. Contrast medium-induced acute kidney injury occurred in 26 patients (26%), 20 (40%) in the control group and 6 (12%) in the remote ischemic preconditioning group (odds ratio, 0.21; 95% confidence interval, 0.07-0.57; P=0.002). No major adverse events were related to remote ischemic preconditioning.Remote ischemic preconditioning before contrast medium use prevents contrast medium-induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes.URL: http://www.germanctr.de. Unique identifier: U1111-1118-8098.
P45.05 Sequencing of PD-1 Inhibitors and TKIs in Metastatic NSCLC with MET Exon 14 Skipping Mutation May Influence Survival
Authors: S. Lau, K. Perdrizet, D. Giffoni M.M. Mata, A. Fung, G. Liu, P. Bradbury, F.A. Shepherd, A. Sacher, B. Sheffield, D. Hwang, M. Tsao, S. Cheng, P. Cheema, N. Leighl
Journal: Journal of Thoracic Oncology (2021)
Effect of Metformin in Patients with ALL Who Express High Levels of the ABCB1 Gene and Its Impact on Survival
Authors: Christian Omar Ramos Penafiel, Irma Olarte Carrillo, Rafael Cerón Maldonado, Humberto Baldemar Castellanos Sinco, Etta Rozen Fuller, Efreen Montaño Figueroa, Juan Collazo Jaloma, Adolfo Martinez Tovar
Journal: Blood (2017)
Abstract MP020: Sleep as a Mediator of Racial Disparities in Cardiometabolic Disease Risk: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: David S Curtis, Thomas E Fuller-Rowell, Mona El-Sheikh, Kristen L Knutson, Kiarria N Kershaw, April P Carson, Mercedes R Carnethon
Journal: Circulation (2017)

Introduction: Approximately half of the disparity in premature mortality between African American (AA) and European American (EA) adults is due to greater hypertension, diabetes, and stroke risk. The current study tests sleep as a mediator of racial disparities in cardiometabolic (CMB) disease risk in adulthood. Methods: A total of 618 CARDIA Study members took part in a sleep sub-study (2003-2005) and had measured CMB risk (2000-2011; mean age at baseline=40.1; 43.5% AA; 56.5% EA; 42.1% male). Sleep efficiency (% of time in bed asleep) and total sleep time were assessed via actigraphy for six total nights in years 17 and 18 of the CARDIA Study. CMB risk was assessed in years 15 and 25 from borderline high (coded as 1) and high (coded as 2) levels in seven markers using recommended cutpoints from NCEP ATP III and AHA: blood pressure, glucose, insulin resistance, waist circumference, triglycerides, HDL-C, and C-reactive protein. Scores were averaged across markers, ranging from 0 to 2 (a score of 1 indicates a borderline high average in the seven markers). Using linear path models, sleep variables were tested as mediators of racial disparities in ten-year changes in CMB risk. Results: AAs obtained less efficient sleep and less total sleep than EAs (76.5% vs 84.3%; 5.63 hrs vs. 6.43 hrs), and AAs had higher CMB risk at both periods (Mean at Y15: .75 vs. .55; Y25: .94 vs. .67) ( p ’s &lt; .001). Mediation tests are shown in the Table. Race was indirectly associated with increasing CMB risk over the ten-year period via sleep efficiency, explaining 25% of the racial disparity. Racial disparities in CMB risk were attenuated by 24.5% when adjusting for sleep time, although the mediation test was not significant. After adjusting for education and household income, 18.1% of the race disparity in diverging CMB risk was explained by sleep efficiency and 20.8% by sleep time. Conclusions: Differences in sleep likely contribute to greater CMB risk among AAs as compared to EAs in adulthood. Sleep may be an important intervention point to reduce racial health disparities.