tbuckley/cabot-search huggingface dataset:
Cystic Fibrosis–related Diabetes Is Associated with Worse Lung Function Trajectory despite Ivacaftor Use
Authors: Charles D. Bengtson, Jianghua He, Michael D. Kim, Matthias A. Salathe
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Cystic Fibrosis–related Diabetes Is Associated with Worse Lung Function Trajectory despite Ivacaftor Use." American Journal of Respiratory and Critical Care Medicine, 204(11), pp. 1343–1345
Functional Genomic Analysis of<i>CDK4</i>and<i>CDK6</i>Gene Dependency across Human Cancer Cell Lines
Authors: Zhouwei Zhang, Lior Golomb, Matthew Meyerson
Journal: Cancer Research (2022)

Abstract Cyclin-dependent kinase 4 (CDK4) and CDK6 are key cell-cycle regulators that are frequently dysregulated in human malignancies. CDK4/6 inhibitors are clinically approved for the treatment of hormone receptor–positive, HER2–negative (HR+/HER2−) breast cancer, but improved specificity and reduced toxicity might expand their use to other indications. Through analysis of publicly available genome-wide loss-of-function data combined with single and dual-targeting CRISPR assays, we found differential cell proliferation vulnerability of cell lines to either CDK4 deletion alone, CDK6 deletion alone, combined CDK4/CDK6 deletion, or neither. CDK6 expression was the best single predictor of CDK4 (negatively correlated) and CDK6 (positively correlated) dependencies in the cancer cell lines, with adenocarcinoma cell lines being more sensitive to CDK4 deletion and hematologic and squamous cancer cell lines being more sensitive to CDK6 deletion. RB–E2F signaling was confirmed as a main downstream node of CDK4/6 in these experiments as shown by the survival effects of RB1 deletion. Finally, we show in a subset of cancer cell lines not dependent on CDK4/6 that CDK2–CCNE1 is an important alternative dependency for cell proliferation. Together, our comprehensive data exploration and functional experiments delineate the landscape of pan-cancer CDK4/6 gene dependencies and define unique cancer cell populations that might be sensitive to CDK4-selective or CDK6-selective inhibitors. Significance: This study provides functional genomic insight toward understanding the scenarios in which cancer cells are differentially sensitive to CDK4 or CDK6 inhibition and their implications in current treatment strategies.
Abstract P210: Acculturation And Associations With Ultra-processed Food Consumption Among Asian Americans: NHANES, 2011-2018
Authors: Krithi Pachipala, Vishal Shankar, Zachary Rezler, Ranjana Vittal, Shahmir Ali, Malathi Srinivasan, Latha Palaniappan, Eugene Yang, Filippa Juul, Tali Elfassy
Journal: Circulation (2022)

Introduction: Ultra-processed food (UPF) consumption is linked to adverse health outcomes, including cardiovascular disease and all-cause mortality. Asian Americans (AAs) are the fastest growing ethnic group in the United States (US), yet their dietary patterns have seldom been described. Objectives: To characterize UPF consumption among AAs and determine whether acculturation is associated with increased UPF consumption. Methods: The National Health and Nutrition Examination Survey (NHANES) is an annual, cross-sectional survey representative of the US population. We examined NHANES dietary data, combining years in which AAs were over-sampled (2011-2018). We included 2,404 AAs ≥ 18 years old with valid 24-hour dietary recall data. Using day 1 dietary recalls, we characterized UPF consumption as the percentage of caloric intake from UPFs, using the NOVA classification system. This framework classifies foods from any culture based on degree of industrial processing. Acculturation was characterized by nativity, nativity/years in the US, home language, and an acculturation index (based on a sum of levels related to nativity/years in the US and home language). We assessed the relationship between each acculturation measure and UPF consumption using linear regression analyses adjusted for age, sex, marital status, education, income, self-reported health, and self-reported diet quality. All analyses accounted for the complex survey design. Results: Among all AAs, the percentage of caloric intake attributable to UPFs was 39.3% (95% CI: 38.1-40.5). In adjusted regression analyses, UPF consumption was 14% (95% CI: 9.5-17.5; p&lt;0.05) greater among those with the highest vs. lowest acculturation index score, 12% (95% CI: 8.5-14.7: p&lt;0.05) greater among those who speak English only vs. non-English only in the home, 12% (95% CI: 8.6-14.7: p&lt;0.05) greater among US-born vs. foreign-born AAs, and 15% (95% CI: 10.7-18.3: p&lt;0.05) greater among US-born vs. foreign-born AAs with less than ten years in the US. Conclusions: Among AAs, UPF consumption was common, and acculturation was strongly associated with greater proportional UPF intake. As the US-born AA population continues to grow, UPF consumption in this group is likely to increase. Further research is necessary to characterize trends in dietary patterns across disaggregated AA subgroups to better inform culturally tailored dietary interventions.
RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11
Authors: Wenjing Zhang, Yu Sun, Lu Bai, Lili Zhi, Yun Yang, Qingzhi Zhao, Chaoqun Chen, Yangfan Qi, Wenting Gao, Wenxia He, Luning Wang, Dan Chen, Shujun Fan, Huan Chen, Hai-Long Piao, Qinglong Qiao, Zhaochao Xu, Jinrui Zhang, Jinyao Zhao, Sirui Zhang, Yue Yin, Chao Peng, Xiaoling Li, Quentin Liu, Han Liu, Yang Wang
Journal: Journal of Clinical Investigation (2021)

Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3′- and 5′-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.
TGFBI Production by Macrophages Contributes to an Immunosuppressive Microenvironment in Ovarian Cancer
Authors: Laura S.M. Lecker, Chiara Berlato, Eleni Maniati, Robin Delaine-Smith, Oliver M.T. Pearce, Owen Heath, Samuel J. Nichols, Caterina Trevisan, Marian Novak, Jacqueline McDermott, James D. Brenton, Pedro R. Cutillas, Vinothini Rajeeve, Ana Hennino, Ronny Drapkin, Daniela Loessner, Frances R. Balkwill
Journal: Cancer Research (2021)

Abstract The tumor microenvironment evolves during malignant progression, with major changes in nonmalignant cells, cytokine networks, and the extracellular matrix (ECM). In this study, we aimed to understand how the ECM changes during neoplastic transformation of serous tubal intraepithelial carcinoma lesions (STIC) into high-grade serous ovarian cancers (HGSOC). Analysis of the mechanical properties of human fallopian tubes (FT) and ovaries revealed that normal FT and fimbria had a lower tissue modulus, a measure of stiffness, than normal or diseased ovaries. Proteomic analysis of the matrisome fraction between FT, fimbria, and ovaries showed significant differences in the ECM protein TGF beta induced (TGFBI, also known as βig-h3). STIC lesions in the fimbria expressed high levels of TGFBI, which was predominantly produced by CD163-positive macrophages proximal to STIC epithelial cells. In vitro stimulation of macrophages with TGFβ and IL4 induced secretion of TGFBI, whereas IFNγ/LPS downregulated macrophage TGFBI expression. Immortalized FT secretory epithelial cells carrying clinically relevant TP53 mutations stimulated macrophages to secrete TGFBI and upregulated integrin αvβ3, a putative TGFBI receptor. Transcriptomic HGSOC datasets showed a significant correlation between TGFBI expression and alternatively activated macrophage signatures. Fibroblasts in HGSOC metastases expressed TGFBI and stimulated macrophage TGFBI production in vitro. Treatment of orthotopic mouse HGSOC tumors with an anti-TGFBI antibody reduced peritoneal tumor size, increased tumor monocytes, and activated β3-expressing unconventional T cells. In conclusion, TGFBI may favor an immunosuppressive microenvironment in STICs that persists in advanced HGSOC. Furthermore, TGFBI may be an effector of the tumor-promoting actions of TGFβ and a potential therapeutic target. Significance: Analysis of ECM changes during neoplastic transformation reveals a role for TGFBI secreted by macrophages in immunosuppression in early ovarian cancer.
Abstract MP78: Heart Failure And The Subsequent Risk Of Lymphedema In The Community
Authors: Yejin Mok, Corinne Joshu, Elizabeth Platz, Patricia Chang, Christie M Ballantyne, Lena Mathews, Kuni Matsushita
Journal: Circulation (2022)

Background: Lymphedema, abnormal lymphatic fluid accumulation in tissues, results in serious complications such as ulceration and reduces quality of life. Cancer treatment, through damage to lymph nodes and lymphatic vessels, is recognized as the main risk factor of lymphedema. However, understanding other risk factors is crucial for the prevention of lymphedema since there is no established curative treatment. Heart failure (HF) is considered an emerging risk factor for lymphedema through increased central and peripheral venous pressure, but the association of HF with incident lymphedema has not been systematically studied. Methods: In the Atherosclerosis Risk in Communities study, we included 9,895 individuals without prevalent lymphedema and cancer at visit 4 (1996-98) (n=9362 with no HF and n=533 with HF). Lymphedema was defined as two outpatient encounters (at least a week apart) or inpatient diagnoses through 2015 (ICD-9: 457.1 and ICD-10: I89.0). Participants without prevalent HF were categorized into two groups according to NT-proBNP, a marker of cardiac volume overload (&gt;125 vs. ≤125 pg/mL [reference]), to acknowledge potential contribution of subclinical cardiac overload. Results: During a median follow-up of 17.7 (IQI 14.1-18.7) years, 149 participants developed lymphedema. 15-y cumulative incidence was higher in participants with HF and no HF with elevated NT-proBNP than those with no HF and non-elevated NT-proBNP (5.2% vs. 2.0% vs. 0.7%, respectively) ( Figure ). After accounting for potential confounders (e.g., body mass index, blood pressure, diabetes), the associations remained consistent (hazard ratios: 3.07 [95% CI 1.86, 5.08] for HF and 1.95 [1.33, 2.87] for no HF with elevated NT-proBNP). Results were consistent when using HF as a time-varying variable and censoring incident cancer. Conclusions: HF and subclinical elevation of NT-proBNP were associated with incident lymphedema, supporting the contribution of HF to the development of lymphedema.
Chronic Generalized Pruritus
Authors: Tomoaki Yokoyama
Journal: New England Journal of Medicine (2022)

A 57-year-old man presented with itching of the whole body. Examination showed hyperpigmentation and excoriations, with sparing of a butterfly-shaped area on his back. Laboratory studies showed evidence of advanced kidney disease, and chronic generalized pruritus due to chronic kidney disease was diagnosed. Hemodialysis was initiated, and his symptoms abated.
Diabetes Suppresses Glucose Uptake and Glycolysis in Macrophages
Authors: Yunosuke Matsuura, Masami Shimizu-Albergine, Shelley Barnhart, Farah Kramer, Cheng-Chieh Hsu, Vishal Kothari, Jingjing Tang, Sina A. Gharib, Jenny E. Kanter, E. Dale Abel, Rong Tian, Baohai Shao, Karin E. Bornfeldt
Journal: Circulation Research (2022)
Abstract P127: Differences By Gender In Autopsy-determined Myocardial Characteristics Following Myocardial Infarction
Authors: Janelle O'Neal, Juan McCook, Ashwin Sunderraj, Jon W Lomasney, Matthew J Feinstein
Journal: Circulation (2022)

Introduction: Women are at higher risk for heart failure and mortality after myocardial infarction (MI) than men. Differences in tissue-level response to ischemia and MI for women vs. men are incompletely understood and have the potential to contribute to differences in post-MI sequelae such as heart failure and sudden death. Methods: We analyzed clinical data and paired autopsy reports from decedent patients who underwent autopsy at a large urban medical center from 4/6/2002 to 4/1/2021. Using clinical autopsy reports completed by a trained pathologist, we then determined the presence or absence of five specific autopsy-based myocardial characteristics: fibrosis, pathologic evidence of a remote vs. acute myocardial infarction, myocardial inflammation, and/or myocardial infiltrates. Linked clinical data were used to determine demographics, anthropometrics, and presence/absence of clinical diagnoses (the latter of which were based on administrative codes). Our primary analyses compared the presence of autopsy-based diagnoses for men vs. women, stratified by prior clinical diagnoses of MI; we used Chi-square analyses with a p-value of &lt;0.05 to indicate statistical significance. Results: Ages at death of men (N=152) and women (N=103) who had clinical diagnoses of MI preceding death and autopsy were similar (Table), but men with MI diagnoses were more commonly White non-Hispanic (75/152, 49%) whereas women were more commonly Black non-Hispanic (51/103, 50%). Women with clinical diagnoses of MI were significantly less likely to have myocardial fibrosis at autopsy compared with men (68% vs 79%; p=0.048). Conclusions: Among individuals with clinical diagnoses of MI prior to death, we observed that men were more likely to have autopsy-determined myocardial fibrosis compared with women. These data do not suggest increased post-MI myocardial scar among women as a likely cause of higher rates of heart failure following MI; however, our data require validation in other cohorts with linked clinical and pathology data.
Decreased risk of treatment failure with vedolizumab and thiopurines combined compared with vedolizumab monotherapy in Crohn’s disease
Authors: Julien Kirchgesner, Rishi J Desai, Maria C Schneeweiss, Laurent Beaugerie, Sebastian Schneeweiss, Seoyoung C Kim
Journal: Gut (2022)

Objective While infliximab combined to thiopurines is more effective than infliximab monotherapy in patients with Crohn’s disease (CD) and UC, the impact of adding thiopurines to vedolizumab remains controversial. We emulated two target trials comparing the effectiveness of combination therapy versus vedolizumab monotherapy in CD and UC. Design Based on two US and the French nationwide healthcare databases, patients with CD and UC who initiated vedolizumab were identified. The study methodology, including confounding adjustment and outcome definitions, were previously validated in successful emulations of the SONIC and SUCCESS trials. Risk ratios for treatment failure based on hospitalisation or surgery related to disease activity, treatment switch, or prolonged corticosteroids use, were estimated after 1:1 propensity score (PS) matching. Results Among a total of 10 299 vedolizumab users, 804 CD and 1088 UC pairs of combination therapy versus vedolizumab monotherapy users were PS matched. Treatment failure occurred at week 26 in 236 (29.3%) and 376 (34.3%) patients with CD and at week 16 in 236 (21.7%) and 263 (24.2%) patients with UC initiating combination therapy and vedolizumab monotherapy, respectively. The risk of treatment failure was decreased with combination therapy compared with vedolizumab monotherapy in CD (RR 0.85, 95% CI: 0.74 to 0.98) and to a lesser extent in UC (RR 0.90, 95% CI: 0.77 to 1.05). Findings were consistent across databases. Conclusion Using validated methodologies, combination therapy with vedolizumab and thiopurines was associated with lower treatment failure compared with vedolizumab monotherapy in CD but not UC across the USA and France.
Abstract P186: Healthcare Access Disparities Among Asian, African, And Latino Immigrants With Hypertension Or Diabetes In The 2010-2018 National Health Interview Survey
Authors: Chinenye C Azoba, Ruth-Alma N Turkson-Ocran, Oluwabunmi B Ogungbe, Binu Koirala, Yvonne Commodore-Mensah
Journal: Circulation (2022)

Background: Morbidity and mortality due to cardiovascular disease (CVD) disproportionately affects racial and ethnic minorities and can be mitigated by access to preventative services. However, research describing health access in immigrants with CVD risk in the US is lacking. Hypothesis: Immigrants with hypertension or diabetes will have less healthcare access (HCA) than US-born non-Hispanic (NH) White persons. Methods: We analyzed cross-sectional data from the 2010-2018 National Health Interview Survey on 75,631 Asian (N=3,120), African (N=393), and Latino (N=7,315) immigrants and US-born NH White (N=64,803) people with hypertension or diabetes. HCA was defined as insurance coverage, usual place for sick care, and delay in care due to cost. We used multivariable logistic regression to examine disparities in HCA between immigrants and NH Whites and compared HCA among immigrants stratified by length of US residence. Results: Participants had a mean (±SE) age of 60.4 (±0.1) years (52% female). After adjusting for sociodemographic factors, health status, and region, Asian immigrants were 13% more likely to be insured than NH Whites, but this pattern was not statistically significant (95% CI: 0.93-1.39, Table ). Compared to NH Whites, African [adjusted odds ratio (AOR): 0.56; 95% CI: 0.39-0.80] and Latino (AOR: 0.65; 95% CI: 0.57-0.74) immigrants were less likely to be insured, and Asian (AOR: 0.50; 95% CI: 0.41-0.60) and Latino (AOR: 0.70; 95% CI: 0.63-0.79) immigrants were less likely to delay care due to cost. All immigrant groups were less likely to have a usual place for sick care. Compared to those with &lt;10 years of US residence, HCA did not improve in African immigrants with ≥10 years of residence (data not shown). Conclusion: Immigrants with CVD risk are less likely to establish a usual place for sick care, yet Asian immigrants may be less likely to experience gaps in HCA compared to NH White people. CVD health policies must account for heterogeneity among and within immigrant groups to improve HCA and prevent CVD complications.
Congenital Diaphragmatic Hernia in an Adult
Authors: Hao-Hsun Liu, Yu-Chang Liu
Journal: New England Journal of Medicine (2022)

An asymptomatic 25-year-old man presented to the emergency department with abnormal results on a preemployment chest radiograph. Computed tomography of the chest revealed herniation of the right kidney, omentum, and intestines into the right thoracic cavity.
Prospective Surveillance for Breast Cancer–Related Arm Lymphedema: A Systematic Review and Meta-Analysis
Authors: Bolette S. Rafn, Jan Christensen, Anders Larsen, Kira Bloomquist
Journal: Journal of Clinical Oncology (2022)

The call to integrate prospective surveillance for lymphedema into cancer care pathways is building momentum to enable early intervention and prevent the progression of the condition. We offer a critical evaluation of the literature on prospective surveillance and early management for cancer-related lymphedema and evaluate the effect of such programs in preventing chronic lymphedema (CRD42019137965).Five databases and two registries were searched for randomized controlled trials or observational studies that assessed the incidence or prevalence of lymphedema associated with participation in a prospective surveillance program, published until February 26, 2021. Numbers triggered for early lymphedema management, resolved, and chronic lymphedema were extracted. Pooled relative risk (trials) and pooled rate (cumulative incidence; observational studies) of chronic lymphedema was calculated. Subgroup analyses assessed the effect of study design, length of follow-up, and extent of axillary surgery.Twenty-three studies were included, of which 21 studies evaluated breast cancer-related arm lymphedema (BCRaL). Participation in prospective surveillance with early management reduced the risk of chronic BCRaL versus usual care (relative risk 0.31; 95% CI, 0.10 to 0.95; two randomized controlled trials; N = 106). The pooled rate of chronic BCRaL was 4% (95% CI, 3 to 6; 15 observational studies; N = 3,545), and 6% (95% CI, 4 to 9) when restricted to participants with axillary lymph node dissection (12 studies; N = 1,527).The findings suggest that participation in prospective surveillance with early management reduces the risk of chronic BCRaL. Only a minority of patients at high risk of lymphedema because of axillary surgery developed chronic lymphedema. More robust research is needed to determine whether prospective surveillance with early management can reduce the risk of chronic lymphedema, particularly among cancer survivors other than breast cancer.
Abstract P008: Atherogenic Cholesterol Across The Lifespan And The Relationship With Midlife Global Cognitive Function: The Bogalusa Heart Study
Authors: Ileana De Anda-Duran, David Libon, Vijaya B Kolachalama, Rhoda Au, Lydia A Bazzano
Journal: Circulation (2022)

Background: Higher levels of non-atherogenic cholesterol (HDL) may be protective against vascular risk and inflammation, mechanisms accompanying cognitive impairment in late life. However, the role of atherogenic lipoproteins remains controversial. Evidence suggests that CV risk burden in middle age may be more closely associated with late-life brain health. Therefore, we aimed to explore the relationship between atherogenic cholesterol (non-HDL) in a community-based cohort of midlife adults. Methods: A total of 1,266 adult participants (58.9% Woman, 34.5% African American) from the Bogalusa Heart Study, with cognitive function assessment at age 48 ± 5 years and at least 3 observations of lipoproteins since childhood. A standardized global cognitive score (GCS) was obtained from a battery of tests covering major neuropsychological domains. Non-HDL trajectories were created using latent class trajectory modeling. Linear regression models were used to determine the association between non-HDL trajectories and GCS in midlife. Results: The mean follow-up for non-HDL and other traditional cardiovascular (CV) risk factors was 41.8 ± 3.4 years. Four distinct trajectory classes were identified: class 1 (n= 451 [ 36%]), class 2(n=168 [13.2%]), class 3 (n=530 [41.8%]), and class 4 (n=117 [9 %] (Figure 1). With class 1 as reference, and after adjustment for sex, race, education, cholesterol medication, hypertension, and diabetes comorbidities. Class 2 and class 4 trajectories were associated with lower GCS (Beta= -0.65 [SE 0.28]; p =0.022, and Beta = -0.06 [0.31]; p=0.057, respectively). (Table 1) Conclusions: These findings suggest that highly-increasing atherogenic cholesterol trajectories over time, particularly from early adulthood to middle age, may adversely affect cognitive performance in midlife, independent of other dementia risk factors. This underscores the importance of addressing CV risk factors earlier in the life course, as their cumulative burden could have a detrimental impact on brain health.