tbuckley/cabot-search huggingface dataset:
Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study
Authors: Kathleen N. Moore, Setsuko K. Chambers, Erika P. Hamilton, Lee-may Chen, Amit M. Oza, Sharad A. Ghamande, Gottfried E. Konecny, Steven C. Plaxe, Daniel L. Spitz, Jill J.J. Geenen, Tiffany A. Troso-Sandoval, Janiel M. Cragun, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh M. Mugundu, Zhongwu Lai, Juliann Chmielecki, Suzanne F. Jones, David R. Spigel, Karen A. Cadoo
Journal: Clinical Cancer Research (2021)

Abstract Purpose: This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer. Patients and Methods: Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate. Results: Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progression-free survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade ≥3 adverse events across all cohorts were neutropenia [45/94 (47.9%) patients], anemia [31/94 (33.0%)], thrombocytopenia [30/94 (31.9%)], and diarrhea and vomiting [10/94 (10.6%) each]. Conclusions: Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1–3, 8–10, and 15–17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.
Unilateral Breast Uptake of 99mTc-MIBI in a Lactating Woman During Myocardial Perfusion Imaging
Authors: Gaurav Malhotra, Milind S. Phadke, Sutapa Rakshit, Swati D. Bagul, Priyanka Verma, Ramesh V. Asopa
Journal: Clinical Nuclear Medicine (2021)

Abstract A 34-year-old woman, who was 11 months postpartum, underwent 99m Tc-MIBI myocardial perfusion SPECT imaging for atypical symptomatology with normal baseline electrocardiogram and 2-dimensional echocardiography. She was lactating on and off, preferentially from the right breast. Analysis of the raw images revealed unilateral intense tracer uptake in the right breast region that persisted in the delayed spot views (24-hour postinjection). Although bilateral breast uptake of 99m Tc-MIBI may be seen in postpartum scenario, unilateral breast uptake can also occur in patients with preferential lactation from 1 breast as seen in this case and should not be mistaken for pathology.
Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation
Authors: Minghui Li, Xing Lyu, James Liao, Victoria P. Werth, Ming-Lin Liu
Journal: Theranostics (2022)

Objective: Ultraviolet B (UVB) is an important trigger of skin inflammation and lupus with leukocyte recruitment to inflamed skin. We recently reported the involvement of neutrophil NETosis in UVB-induced skin inflammation, and that NETotic nuclear envelope rupture is driven by PKCα-mediated nuclear lamin B disassembly. To address the role of Actin cytoskeleton in NETosis, we investigated the effects of Rho kinase (ROCK) and its downstream actomyosin cytoskeletal networks on PKCα nuclear translocation and NET formation, as well as their involvement in UVB-induced skin inflammation. Methods: We studied the dynamic changes of ROCK and actomyosin cytoskeletal networks during NETosis induction and their involvement in PKCα nuclear translocation. Using mice with hematopoietic-specific ROCK1 deficiency, we investigated the effects of ROCK1 deficiency on NETosis, and its involvement in UVB-induced skin inflammation. Results: Our time course studies demonstrated the dynamic changes of actin polymerization and ROCK activation, support the role of actin cytoskeleton in nuclear translocation of cytosolic PKCα in early stage of NETosis induction. Inhibition of actin polymerization or key molecules of the ROCK/MLCK/myosin pathway decreased PKCα nuclear translocation and NET formation. Genetic deficiency of ROCK1, inhibited NETosis ex vivo and in vivo, decreased extracellular display of NET-associated IL-17A, TNFα, IFNγ, and IFNα in inflamed skin, which were correlated with the ameliorated skin inflammation in UVB-irradiated mice with hematopoietic-specific ROCK1 deficiency. Conclusions: ROCK regulated NETosis through modulation of PKCα nuclear translocation via actomyosin cytoskeletal networks in neutrophils. ROCK1 deficiency ameliorated UVB-induced skin inflammation by attenuation of NETosis and NET-associated cytokines.
Abstract MP35: Circulating MicroRNA-21 And Cardiovascular Risk Reduction In Response To Weight-loss Diets: The Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) Trial
Authors: Qiaochu Xue, Yoriko Heianza, Xiang Li, Hong-Wen Deng, Jennifer Rood, George Bray, Frank Sacks, Lu Qi
Journal: Circulation (2022)

Introduction: MicroRNA-21 (MiR-21) is one of the most highly expressed microRNAs in the cardiovascular system and plays a pivotal role in the pathogenesis of cardiovascular diseases (CVD). Hypothesis: We assessed the hypothesis that circulating miR-21 is associated with the change in overall CVD risk and individual cardiovascular risk factors in response to weight-loss diet interventions. Methods: Circulating miR-21 was measured at baseline and 6 months in 511 participants with overweight or obesity from the 2-year weight-loss diet intervention study, the POUNDS LOST trial. MiR-21-5p is a mature sequence derived from the 5' end of the miR-21 stem-loop precursor and another mature sequence, miR-21-3p, is derived from the 3' end of miR-21. The primary outcome was the change in the global Framingham Risk Score (FRS), which estimates the 10-year probability of a CVD event. Secondary outcomes were the change in the FRS components including systolic blood pressure, diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, insulin, homeostatic model assessment of insulin resistance, gut microbiota metabolites, and adiposity measures. Results: Circulating miR-21-3p levels were positively associated with fasting insulin ( P =0.011), insulin resistance ( P =0.008), and triglycerides ( P =0.003) at baseline. We found that lower pre-intervention expression levels of miR-21-3p and miR-21-5p were related to a greater reduction in FRS (β[SE]=11.020 [5.025], P =0.029 and β[SE]=0.023 [0.008], P =0.005, respectively) over 6 months. The trajectory of the FRS across the 2-year intervention period differed between the patterns of pre-intervention miR-21 ( P time*miR-21-3p =0.002 and P time*miR-21-5p =0.033). Compared to those with a higher level of miR-21, participants with a lower level of miR-21 had a greater decrease in FRS from baseline to 6 months and then increased substantially from 6 months to 2 years. We also found significant interactions between baseline miR-21-5p and dietary fat on change in FRS ( P fat diets* miR-21-5p =0.04). Participants with a lower level of baseline miR-21-5p on the low-fat diet group showed a greater reduction of FRS than those on the high-fat diet at 6 months. In addition, a greater decrease in miR-21-3p rather than miR-21-5p was significantly associated with a greater reduction in body weight (P&lt;0.0001), waist circumference ( P =0.002), and improvement in trimethylamine N-oxide ( P =0.011) at 6 months. These associations were attenuated at 2 years of the intervention. Conclusions: In conclusion, decreased circulating miR-21 levels were related to a significant reduction in overall CVD risk and improvement in individual cardiovascular risk factors in response to dietary weight-loss interventions.
Intratumor Heterogeneity and Antitumor Immunity Shape One Another Bidirectionally
Authors: Yochai Wolf, Yardena Samuels
Journal: Clinical Cancer Research (2022)

Abstract Over the last decade, it has become clear that the genomic landscapes of tumors profoundly impact their immunogenicity and how tumor cells interact with immune cells. Whereas past discoveries mainly focused on the interplay between tumor immunogenicity and tumor mutational burden (TMB), under the assumption that a higher mutation load would give rise to a better patient response to immune checkpoint blockade therapies, we and others have underlined intratumor heterogeneity (ITH) as an important determinant of the magnitude of the antitumor response and the nature of the tumor microenvironment. In this review, we define TMB versus ITH and how the two factors are being inferred from data, examine key findings in the cancer immunogenomics literature deciphering the complex cross-talk between TMB, ITH, and antitumor immunity in human cancers and in vivo models, and discuss the mutual influence of ITH and immunity—how the antitumor response can give rise to tumors with higher ITH, and how higher ITH can put shackles on the antitumor response.
A three-step support strategy for relatives of patients dying in the intensive care unit: a cluster randomised trial
Authors: Nancy Kentish-Barnes, Sylvie Chevret, Sandrine Valade, Samir Jaber, Lionel Kerhuel, Olivier Guisset, Maëlle Martin, Amélie Mazaud, Laurent Papazian, Laurent Argaud, Alexandre Demoule, David Schnell, Eddy Lebas, Frédéric Ethuin, Emmanuelle Hammad, Sybille Merceron, Juliette Audibert, Clarisse Blayau, Pierre-Yves Delannoy, Alexandre Lautrette, Olivier Lesieur, Anne Renault, Danielle Reuter, Nicolas Terzi, Bénédicte Philippon-Jouve, Maud Fiancette, Michel Ramakers, Jean-Philippe Rigaud, Virginie Souppart, Karim Asehnoune, Benoît Champigneulle, Dany Goldgran-Toledano, Jean-Louis Dubost, Pierre-Edouard Bollaert, Renaud Chouquer, Frédéric Pochard, Alain Cariou, Elie Azoulay
Journal: The Lancet (2022)
Disarming the Old Foe. Restoring T-Cell Immune Function with mTor-Inhibitors to Tackle Cytomegalovirus Infection
Authors: Oriol Bestard, Elena Crespo
Journal: Journal of the American Society of Nephrology (2021)

Cytomegalovirus (CMV) infection remains a main opportunistic infection after solid organ transplantation (SOT), challenging both patient and graft outcomes.[1][1] Yet, despite important advances in the field in the last decades with more precise molecular tools to detect viral replication and
Prognostic Value of Time in Blood Pressure Target Range Among Patients With Heart Failure
Authors: Kangyu Chen, Chao Li, Victoria Cornelius, Dahai Yu, Qi Wang, Rui Shi, Zhenqiang Wu, Hao Su, Ji Yan, Tao Chen, Zhixin Jiang
Journal: JACC Heart Failure (2022)

Blood pressure (BP) is a continuous and dynamic measure. However, standard BP control metrics may not reflect the variability in BP over time.This study assessed the prognostic value of time in BP target range among hypertensive patients with heart failure (HF).The authors performed a post hoc analysis of data from the TOPCAT (Treatment of Preserved Cardiac Function HF with an Aldosterone Antagonist) trial and the BEST (Beta-Blocker Evaluation of Survival Trial). Time in target range (TTR) for each patient was calculated using linear interpolation across the study period with the target range of systolic BP between 120 and 130 mm Hg.A total of 4,789 hypertensive patients (n = 1,654 from BEST and n = 3,135 from TOPCAT) were included. The cumulative incidences of primary endpoint (ie, cardiovascular death or HF hospitalization) were highest among the top quartile of TTR with a dose-dependent manner across quartiles (Ptrend <0.005). The top quartile of TTR was significantly associated with a lower risk of primary outcome using adjusted Cox regression model (HR: 0.71; 95% CI: 0.60-0.82), cardiovascular mortality (HR: 0.68; 95% CI: 0.55-0.84), HF hospitalization (HR: 0.70; 95% CI: 0.58-0.85), all-cause mortality (HR: 0.69; 95% CI: 0.58-0.83), and any hospitalization (HR: 0.76; 95% CI: 0.67-0.85). Further analyses using restricted cubic spline indicated a linear relationship between TTR and primary outcome. Similar patterns were observed in the individual trial. Sensitivity analyses generated consistent results while redefining target range as 110 to 130 mm Hg for systolic BP or 70 to 80 mm Hg for diastolic BP.TTR could independently predict major adverse cardiovascular events in hypertensive patients with HF.
Perioperative ctDNA-Based Molecular Residual Disease Detection for Non–Small Cell Lung Cancer: A Prospective Multicenter Cohort Study (LUNGCA-1)
Authors: Liang Xia, Jiandong Mei, Ran Kang, Senyi Deng, Yaohui Chen, Ying Yang, Gang Feng, Yulan Deng, Fanyi Gan, Yidan Lin, Qiang Pu, Lin Ma, Feng Lin, Yong Yuan, Yang Hu, Chenglin Guo, Hu Liao, Chengwu Liu, Yunke Zhu, Wenping Wang, Zheng Liu, Yuyang Xu, Kaidi Li, Chuan Li, Qingyun Li, Ji He, Weizhi Chen, Xiaolong Zhang, Yingli Kou, Yun Wang, Zhu Wu, Guowei Che, Longqi Chen, Lunxu Liu
Journal: Clinical Cancer Research (2021)

Abstract Purpose: We assessed whether perioperative circulating tumor DNA (ctDNA) could be a biomarker for early detection of molecular residual disease (MRD) and prediction of postoperative relapse in resected non–small cell lung cancer (NSCLC). Experimental Design: Based on our prospective, multicenter cohort on dynamic monitoring of ctDNA in lung cancer surgery patients (LUNGCA), we enrolled 950 plasma samples obtained at three perioperative time points (before surgery, 3 days and 1 month after surgery) of 330 stage I–III NSCLC patients (LUNGCA-1), as a part of the LUNGCA cohort. Using a customized 769-gene panel, somatic mutations in tumor tissues and plasma samples were identified with next-generation sequencing and utilized for ctDNA-based MRD analysis. Results: Preoperative ctDNA positivity was associated with lower recurrence-free survival (RFS; HR = 4.2; P &amp;lt; 0.001). The presence of MRD (ctDNA positivity at postoperative 3 days and/or 1 month) was a strong predictor for disease relapse (HR = 11.1; P &amp;lt; 0.001). ctDNA-based MRD had a higher relative contribution to RFS prediction than all clinicopathologic variables such as the TNM stage. Furthermore, MRD-positive patients who received adjuvant therapies had improved RFS over those not receiving adjuvant therapy (HR = 0.3; P = 0.008), whereas MRD-negative patients receiving adjuvant therapies had lower RFS than their counterparts without adjuvant therapy (HR = 3.1; P &amp;lt; 0.001). After adjusting for clinicopathologic variables, whether receiving adjuvant therapies remained an independent factor for RFS in the MRD-positive population (P = 0.002) but not in the MRD-negative population (P = 0.283). Conclusions: Perioperative ctDNA analysis is effective in early detection of MRD and relapse risk stratification of NSCLC, and hence could benefit NSCLC patient management.
Abstract 003: Contextual- And Personal-level Social Determinants Of Health And Real-world Adoption Of Novel Treatments For Improving Cardiovascular Outcomes In Type 2 Diabetes
Authors: Jingchuan Guo, Hui Hu, Yi Zheng, Yi Guo, Aokun Chen, Jared W Magnani, Inmaculada Hernandez, LaToya O'Neal, Elizabeth Shenkman, Jiang Bian
Journal: Circulation (2022)

Background: The two novel antidiabetic drugs ( ADD ), sodium-glucose cotransporter-2 inhibitors ( SGLT2i ) and glucagon-like peptide-1 receptor agonists ( GLP1a ), have shown distinctive cardiovascular benefits. However, prior studies have found racial disparities in the initiation of SGLT2i/GLP1a, suggesting that, despite their potential, the real-world utilization of these therapies may exacerbate health inequities. Our study was aimed to understand how contextual and personal-level social determinants of health ( SDoH ) interact and drive inequities in access to these novel agents. Methods: Using electronic health records ( EHR ) from the University of Florida Health system, we assembled a cohort of type 2 diabetes ( T2D ) who initiated a second line ADD in 2015-2020. The T2D cohort was spatiotemporally linked to a set of 79 contextual SDoH documenting social and built environment at census tract level. Normalization transformation was conducted for these variables, as needed. We applied an exposome-wide association study ( ExWAS ) approach to identify key contextual SDoH associated with SGTL2i/GLP1a initiation vs. other second line ADD. We identified patients’ marital status, as proxy of social support, among other personal-level SDoH from clinical notes via a natural language processing pipeline. We applied logistic regression and adjusted for clinical factors to determine the effect of contextual SDoH on SGLT2i/GLP1a initiation across racial groups and by personal-level SDoH. Results: Of 2,563 study patients, 57% were females, 42% were Blacks, and the mean age was 59 (13) years. We identified three contextual SDoH factors that were statistically significantly associated with lower likelihood of SGLT2i/GLP1a initiation: neighborhoods with limited food access, with more long-term vacant houses, and with less group quarters (e.g., living in nursing facilities and group homes). In the subgroup analysis by race, neighborhoods with limited food access ( p =.025) and having less group quarter ( p =.028) are barriers to initiate newer ADD only in White patients, while living in neighborhoods having more vacant houses was a risk factor of the newer drug initiation only in Black patients ( p &lt;.001). When subgrouped by marital status, living in a place with less group quarters was a risk factor of non-initiation of SGLT2i/GLP1a only in those being unmarried ( p =.027), while living in a place having more vacant addresses was a risk factor of non-initiation only in those being married ( p &lt;.001). Conclusion: We identified novel contextual SDoH associated with lower initiation of novel cardioprotective drugs in patients with T2D. The effect of contextual SDOH in such treatment initiation varies across racial groups and by marital status.
Global and regional sepsis and infectious syndrome mortality in 2019: a systematic analysis
Authors: Authia Gray, Fablina Sharara
Journal: The Lancet Global Health (2022)

Infections can lead to sepsis, a life-threatening reaction in which a dysregulated host response to the infection leads to organ dysfunction. Infectious syndromes can be either infectious underlying causes of death, or intermediate causes of death leading to sepsis. Therefore, infections participate in the cause-of-death chain of communicable, maternal, neonatal, and nutritional diseases, non-communicable diseases, and injuries. Infectious syndromes contribute substantially to global mortality, but data are scarce and neither sepsis nor infectious syndromes are included in standard Global Burden of Disease, Injuries, and Risk Factors Study estimates. Therefore, accurate estimates of infectious syndromes burden are needed to improve health-care policies.We used 126 million individual death records from multiple causes of death, hospital, linkage, and mortality surveillance data covering 16 countries. Our analysis captures infectious syndromes in the blood, bone, heart, CNS, peritoneum, abdomen, respiratory system, skin, urogenital system, and other locations, as well as specific diseases such as tuberculosis, gonorrhoea, chlamydia, and salmonella infections. We assigned each record an infectious syndrome on the basis of the causes-of-death chain. Through a mixed-effects binomial logistic regression, we calculated infectious syndrome mortality fractions in 2019 by underlying Global Burden of Disease cause, age group, sex, and location, and multiplied on the sepsis mortality envelope in 2019 to obtain attributable deaths.In 2019, 13·7 million people worldwide died from infectious syndromes, 5·2 million of which co-occurred with non-communicable diseases. 3 million of these deaths occurred in children under the age of 5 years. Globally, respiratory infections and bloodstream infections are the deadliest. Regional disparities are stark, with a death rate of 52·6 per 100 000 for bloodstream infections in sub-Saharan Africa, compared with 37·7 per 100 000 in high-income countries. The burden varies across age groups: adults aged 50-69 years face the highest burden from bloodstream infections, whereas children under the age of 5 years are most burdened by respiratory infections.In 2019, infectious syndromes contributed substantially to mortality, especially in non-communicable disease. Infectious syndrome mortality rivalled ischemic heart disease (9 million deaths) and neoplasms (10 million deaths), suggesting that infections, both as underlying and intermediate causes, are an immense source of mortality and must be recorded, analysed, and treated.Bill & Melinda Gates Foundation, Wellcome Trust, and Fleming Fund.
Abstract P007: Liver Biomarkers And Brain Health: The Atherosclerosis Risk In Communities (aric) Study
Authors: Yifei Lu, Yifei Lu, James R Pike, Timothy M Hughes, Ron C Hoogeveen, Gerardo M Heiss, Priya Palta
Journal: Circulation (2022)

Introduction: Animal studies and emerging population data link liver function and integrity to brain health, although mostly based on cross-sectional estimates. We reported that low liver transaminases are associated with risk of dementia, but prospective studies on liver biomarkers and altered brain morphology are lacking. Methods: We studied 1,596 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort examined in 1996-98 (mean age: 62 years, 59% female, 27% Black) free of chronic liver disease, cirrhosis, and stroke, and with alanine aminotransferase (ALT) to aspartate aminotransferase (AST) ratio ≤2. Brain magnetic resonance imaging (MRI) scans were performed in 2011-13, at the time of re-examination. Serum transaminases (ALT, AST) and gamma-glutamyl transferase (GGT) at baseline were analyzed as sex-specific quintiles, with the first quintile further subdivided into a &lt;10 th and 10 th -20 th percentiles to allow for nonlinear associations at low biomarker levels. Brain MRI markers were measured with 3 Tesla MRI. Multinomial logistic and linear regressions were used, adjusted for demographics and APOE-ε4. Results: Monotonic associations were observed between higher GGT levels and smaller cortical volume and temporal lobe volume meta regions of interest (Figure) . The lowest GGT levels were associated with smaller volumes of white matter hyperintensities. In contrast, associations of transaminases with brain morphological measures were inconclusive. Conclusions: GGT levels measured in late mid-life are associated vascular sequelae on brain MRI among older adults. As a potent regulator of antioxidant capacity and a predictor of atherosclerosis, GGT may point to vascular pathways that influence brain health. The lack of association between low transaminases and brain MRI findings suggests non-vascular pathways for their association with incident dementia. A deeper understanding of the links between hepatic metabolic dysregulation and brain health is warranted.