tbuckley/cabot-search huggingface dataset:
Abstract P153: Racial/ethnic- And Education-level Differences In Poor, Intermediate, And Ideal Cardiovascular Health Among Women Of Reproductive Age: Behavioral Risk Factor Surveillance System, 2019
Authors: Donald K Hayes, Fatima Coronado, Nicole Ford, Jing Fang, Cheryl L Robbins, Jean Ko, Fleetwood V Loustalot
Journal: Circulation (2022)

Introduction: The American Heart Association (AHA) promotes ideal cardiovascular health (CVH) to reduce the risk of heart disease and stroke by achieving seven metrics (normal weight, not smoking, ≥5 fruits and vegetables daily, physical activity ≥150 minutes per week, no diabetes, no high blood pressure, and no high cholesterol). Overall, about 5% of the adult population report ideal CVH. Characterizing CVH among women of reproductive age (WRA; 18-44 years of age) offers opportunities to promote overall cardiovascular and preventive health along the life course. Methods: Data from the 2019 Behavioral Risk Factor Surveillance System was used to estimate define CVH categories (poor, intermediate, ideal) among 38,012 WRA from 49 states (New Jersey didn’t meet standards for weighting), District of Columbia, Guam, and Puerto Rico. Per commonly used standards, having &gt; 6 metrics defined ideal CVH, 3-5 metrics defined intermediate, and 0-2 metrics defined poor CVH. A generalized logit model was used to estimate the associations between race/ethnicity and education with CVH (poor vs intermediate CVH, and ideal vs. intermediate CVH), accounting for age and insurance status. Results: Overall, 8.6% (95%CI:8.2-9.1%) of WRA reported poor CVH, 85.4% (95%CI: 84.8-86.1) reported intermediate CVH, and 6.0% (95%CI:5.5-6.5) reported ideal CVH. Non-Hispanic Black (NHB) WRA had higher odds of reporting poor vs. intermediate CVH (AOR=1.34; 95%CI:1.14-1.58) and lower odds of reporting ideal vs. intermediate CVH (AOR=0.47; 95%CI:0.33-0.68) compared to non-Hispanic White WRA. College graduates also had lower odd of reporting poor vs. intermediate CVH (AOR=0.21; 95%CI:0.17-0.27) and higher odds of reporting ideal vs. intermediate CVH (AOR=2.59; 95%CI:1.52-4.43) compared to those with less than a high school education. Conclusion: Most WRA have intermediate CVH, nearly 1 in 10 have poor CVH, and only about 1 in 16 have ideal CVH. The CVH metric used in this study provides evidence of the disproportionate burden of poor CVH among NHB WRA and women with less than a college degree. Understanding the barriers to ideal CVH for WRA, particularly social and structural determinants, may improve cardiovascular health and reduce disparities across the life course.
Abstract MP27: Associations Of Accelerometer-measured Physical Activity And Sedentary Behavior With Incident Ischemic Stroke: The Women’s Health Study (WHS)
Authors: Kennedy M Peter, Kelly R Evenson, Carmen Cuthbertson, Annie Green G Howard, I-min M Lee
Journal: Circulation (2022)

Introduction: Higher self-reported physical activity and lower sedentary behavior (SB) are associated with lower incidence of ischemic stroke (IS). Objective measurement by accelerometer allows for novel, in-depth examination of these relationships with IS. Objective: Assess the association of accelerometer-measured physical activity and SB with IS. Methods: We included 16,031 women adherent with accelerometer wear (≥ 10 hours/day for 4 days) from the WHS cohort (2011-2015) with no prior cardiovascular disease [age 71.4 (SD 5.6) years, BMI 26.2 (SD 5.0), and 67% hypertensive]. ActiGraph GT3X+ accelerometers measured total volume of physical activity (average vector magnitude [VM]/min), mins spent in light-high (LHPA) and moderate-to-vigorous (MVPA) intensity physical activity, and SB. We categorized all metrics as quartiles and residualized to account for accelerometer wear time. We produced adjusted hazard ratios (HR) and 95% confidence intervals (CI) that independently relate physical activity and SB with IS using Cox proportional hazards models. Sensitivity analyses excluded events in the first year and those with poor self rated health to assess reverse causality. Results: Over a mean of 7.1 (SD 1.6) years of follow-up, 181 IS were observed (30 in first year). Greater total volume of physical activity and more minutes spent in MPVA were associated with lower hazards of ischemic stroke (quartile 4 vs. ref: VM/min HR=0.51, 95% CI: 0.32, 0.82, MVPA HR=0.42, 95% CI: 0.26, 0.67). Minutes spent in LHPA were not associated with IS. Less time spent in SB was associated with lower hazards of IS, but was not statistically significant (Table). Results were robust when adjusted for clinical covariates. Exclusions for reverse causality did not alter inferences made and decreased precision. Conclusion: Greater total volume of physical activity and more minutes spent in MVPA were associated with lower occurrence of IS in this cohort. Less time spent in SB appeared to be protective against IS, but requires further investigation.
Oxidized Phospholipids Promote NETosis and Arterial Thrombosis in LNK(SH2B3) Deficiency
Authors: Huijuan Dou, Andriana Kotini, Wenli Liu, Trevor Fidler, Kaori Endo-Umeda, Xiaoli Sun, Malgorzata Olszewska, Tong Xiao, Sandra Abramowicz, Mustafa Yalcinkaya, Brian Hardaway, Sotirios Tsimikas, Xuchu Que, Alexander Bick, Conor Emdin, Pradeep Natarajan, Eirini P. Papapetrou, Joseph L. Witztum, Nan Wang, Alan R. Tall
Journal: Circulation (2021)

Background: LNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association studies have shown association of a common single nucleotide polymorphism in LNK (R262W, T allele) with neutrophilia, thrombocytosis, and coronary artery disease. We have shown that LNK(TT ) reduces LNK function and that LNK-deficient mice display prominent platelet–neutrophil aggregates, accelerated atherosclerosis, and thrombosis. Platelet–neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of NETs in atherosclerosis and thrombosis in mice with hematopoietic Lnk deficiency. Methods: We bred mice with combined deficiency of Lnk and the NETosis-essential enzyme PAD4 (peptidyl arginine deiminase 4) and transplanted their bone marrow into Ldlr –/– mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2 V617F ). Results: Lnk -deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated Lnk –/– platelets promoted increased NETosis when incubated with Lnk –/– neutrophils compared with wild-type platelets or wild-type neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from Lnk –/– platelets, as well as increased priming and response of Lnk –/– neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis, and thrombosis in Lnk –/– mice. We also showed increased NETosis when human induced pluripotent stem cell–derived LNK(TT ) neutrophils were incubated with LNK(TT ) platelet/megakaryocytes, but not in isogenic LNK(CC ) controls, confirming human relevance. Using data from the UK Biobank, we found that individuals with the JAK2 VF mutation only showed increased risk of coronary artery disease when also carrying the LNK R262W allele. Mice with hematopoietic Lnk +/– and Jak2 VF clonal hematopoiesis showed accelerated arterial thrombosis but not atherosclerosis compared with Jak2 VF Lnk +/+ controls. Conclusions: Hematopoietic Lnk deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils, promoting NETosis, and increases coronary artery disease risk in humans carrying Jak2 VF mutations. Therapies targeting OxPL may be beneficial for coronary artery disease in genetically defined human populations.
RE-MIND: Comparing Tafasitamab + Lenalidomide (L-MIND) with a Real-world Lenalidomide Monotherapy Cohort in Relapsed or Refractory Diffuse Large B-cell Lymphoma
Authors: Pier Luigi Zinzani, Thomas Rodgers, Dario Marino, Maurizio Frezzato, Anna Maria Barbui, Claudia Castellino, Erika Meli, Nathan H. Fowler, Gilles Salles, Bruce Feinberg, Nuwan C. Kurukulasuriya, Sascha Tillmanns, Stephan Parche, Debarshi Dey, Günter Fingerle-Rowson, Sumeet Ambarkhane, Mark Winderlich, Grzegorz S. Nowakowski
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Tafasitamab, an Fc-modified, humanized, anti-CD19 monoclonal antibody, in combination with lenalidomide, demonstrated efficacy in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), in the single-arm, phase II L-MIND study (NCT02399085). RE-MIND, a retrospective observational study, generated a historic control for L-MIND to delineate the contribution of tafasitamab to the efficacy of the combination. Patients and Methods: Data were retrospectively collected from patients with R/R DLBCL treated with lenalidomide monotherapy for comparison with tafasitamab + lenalidomide–treated patients (L-MIND). Key eligibility criteria were aligned with L-MIND. Estimated propensity score–based Nearest Neighbor 1:1 Matching methodology balanced the cohorts for nine prespecified prognostic baseline covariates. The primary endpoint was investigator-assessed best overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). Results: Data from 490 patients going through lenalidomide monotherapy were collected; 140 qualified for matching with the L-MIND cohort. The primary analysis included 76 patients from each cohort who received a lenalidomide starting dose of 25 mg/day. Cohort baseline covariates were comparable. A significantly better ORR of 67.1% (95% confidence interval, 55.4–77.5) was observed for the combination therapy versus 34.2% (23.7–46.0) for lenalidomide monotherapy [odds ratio, 3.89 (1.90–8.14); P &amp;lt; 0.0001]. Higher CR rates were achieved with combination therapy compared with lenalidomide monotherapy [39.5% (28.4–51.4) vs. 13.2% (6.5–22.9)]. Survival endpoints favored combination therapy. Lenalidomide monotherapy outcomes were similar to previously published data. Conclusions: RE-MIND enabled the estimation of the additional treatment effect achieved by combining tafasitamab with lenalidomide in patients with R/R DLBCL.
Tumor Thrombus on 18F-FDG PET/CT in Stage IV Plasmablastic Lymphoma
Authors: Thibaut Jacquet, Virginie Huchet, Manel Bedoui, Nina Jehanno
Journal: Clinical Nuclear Medicine (2021)

Abstract A 71-year-old woman with a history of back pain and recent weight loss presented to the emergency department with hematuria. A CT scan was performed and showed left retroperitoneal mass with left renal vein thrombus extended to the vena cava. Tumor biopsy revealed plasmablastic lymphoma. Staging with 18 F-FDG PET/CT scan was performed and revealed pulmonary, hepatic, and left supraclavicular lymph node extension. The left retroperitoneal mass showed intense FDG uptake and was associated with widespread tumor thrombus in the peripheral abdominal veins. Differentiating tumor thrombus from bland thrombosis has a significant impact on patient’s management.
Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study
Authors: Cristina Menni, Ana M Valdes, Lorenzo Polidori, Michela Antonelli, Satya Penamakuri, Ana Nogal, Panayiotis Louca, Anna May, Jane C Figueiredo, Christina Hu, Erika Molteni, Liane Canas, Marc F Österdahl, Marc Modat, Carole H Sudre, Ben Fox, Alexander Hammers, Jonathan Wolf, Joan Capdevila, Andrew T Chan, Sean P David, Claire J Steves, Sebastien Ourselin, Tim D Spector
Journal: The Lancet (2022)

The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population.
Abstract P041: Increases In Low-density Lipoprotein Subclasses During The Menopause Transition Are Associated With Greater Risk Of Coronary Calcification And Carotid Atherosclerosis: The SWAN HDL Study
Authors: Samar R El Khoudary, Xirun Chen, Maria M Brooks, Trevor Orchard, Sybil Crawford, Imke Janssen, Susan A Everson-rose, Dan McConnell, Karen A Matthews
Journal: Circulation (2022)

Objectives: Increase in LDL-C occurs within 1 year of the final menstrual period (FMP), and this increase has been linked to a greater plaque risk. LDL subclasses have been linked to CAD beyond LDL-C, promising a better risk stratification. We aim to characterize changes in LDL subclasses over the menopause transition (MT) and assess associations of these changes with presence of coronary artery calcification (CAC Agatston score ≥10) and carotid intima-media thickness (cIMT), and test the effect modification of time relative to FMP on these associations. Design: Midlife women with nuclear magnetic resonance spectroscopy LDL subclasses measured over the MT for a maximum of 5 timepoints were included (n=471; baseline age 50.19 ± 2.7 years; 81.0% Pre-/Early perimenopausal). A subset of women had CAC and cIMT measured for a maximum of 2 timepoints (n=221). LOESS plots were used to characterize changes in LDL subclasses over the MT in the full sample. Inflection points identified from the LOESS plots suggested timing of changes in slope (Figure). Linear mixed effect models or generalized estimating equation was used for analysis. Effect modification by time relative to FMP was tested. Results: All LDL metrics increased around the FMP except for Intermediate LDL Particles (IDL-P), which declined (Figure). Higher total LDL particles (LDL-P) and greater ApoB independently associated with higher CAC prevalence and greater cIMT. Although none of the associations of LDL metrics with cIMT or CAC were modified by time relative to FMP, higher LDL-C, ApoB and total LDL-P were associated with higher cIMT during peri- or postmenopausal stages (Table), while higher LDL-C, small LDL-P and large LDL-P were associated with greater CAC prevalence, mainly during perimenopause stage in adjusted models (Table). Conclusions: During the MT women experience significant increases in LDL subclasses found to be related to greater cIMT levels and CAC prevalence. Monitoring LDL subclasses over the MT may help in identifying women at greater risk for future CAD.
A Phase I Study of Autologous Dendritic Cell Vaccine Pulsed with Allogeneic Stem-like Cell Line Lysate in Patients with Newly Diagnosed or Recurrent Glioblastoma
Authors: Jethro L. Hu, Oluwaseun A. Omofoye, Jeremy D. Rudnick, Sungjin Kim, Mourad Tighiouart, Surasak Phuphanich, Hongqiang Wang, Mia Mazer, Toni Ganaway, Ray M. Chu, Chirag G. Patil, Keith L. Black, Stephen L. Shiao, Rongfu Wang, John S. Yu
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Glioblastoma (GBM) is a heterogeneous malignancy with multiple subpopulations of cancer cells present within any tumor. We present the results of a phase I clinical trial using an autologous dendritic cell (DC) vaccine pulsed with lysate derived from a GBM stem-like cell line. Patients and Methods: Patients with newly diagnosed and recurrent GBM were enrolled as separate cohorts. Eligibility criteria included a qualifying surgical resection or minimal tumor size, ≤ 4-mg dexamethasone daily dose, and Karnofsky score ≥70. Vaccine treatment consisted of two phases: an induction phase with vaccine given weekly for 4 weeks, and a maintenance phase with vaccines administered every 8 weeks until depletion of supply or disease progression. Patients with newly diagnosed GBM also received standard-of-care radiation and temozolomide. The primary objective for this open-label, single-institution trial was to assess the safety and tolerability of the autologous DC vaccine. Results: For the 11 patients with newly diagnosed GBM, median progression-free survival (PFS) was 8.75 months, and median overall survival was 20.36 months. For the 25 patients with recurrent GBM, median PFS was 3.23 months, 6-month PFS was 24%, and median survival was 11.97 months. A subset of patients developed a cytotoxic T-cell response as determined by an IFNγ ELISpot assay. Conclusions: In this trial, treatment of newly diagnosed and recurrent GBM with autologous DC vaccine pulsed with lysate derived from an allogeneic stem-like cell line was safe and well tolerated. Clinical outcomes add to the body of evidence suggesting that immunotherapy plays a role in the treatment of GBM.
Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy
Authors: Hsin-Chieh Wu, Domitille Rérolle, Caroline Berthier, Rita Hleihel, Takashi Sakamoto, Samuel Quentin, Shirine Benhenda, Claudia Morganti, Chengchen Wu, Lidio Conte, Sylvie Rimsky, Marie Sebert, Emmanuelle Clappier, Sylvie Souquere, Stéphanie Gachet, Jean Soulier, Sylvère Durand, Jennifer J. Trowbridge, Paule Bénit, Pierre Rustin, Hiba El Hajj, Emmanuel Raffoux, Lionel Ades, Raphael Itzykson, Hervé Dombret, Pierre Fenaux, Olivier Espeli, Guido Kroemer, Lorenzo Brunetti, Tak W. Mak, Valérie Lallemand-Breitenbach, Ali Bazarbachi, Brunangelo Falini, Keisuke Ito, Maria Paola Martelli, Hugues de Thé
Journal: Cancer Discovery (2021)

Abstract Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of promyelocytic leukemia (PML) nuclear bodies (NB), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mitochondrial DNA, activating cyclic GMP-AMP synthase signaling, and boosting reactive oxygen species (ROS) production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies. Significance: ActD induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML NBs. ActD targets mitochondria, yielding ROS which enforce PML NB biogenesis and restore senescence. Dual targeting of mitochondria with ActD and venetoclax sharply potentiates their anti-AML activities in vivo. This article is highlighted in the In This Issue feature, p. 2945
Abstract MP32: Healthy Dietary Patterns Are Associated With The Gut Microbiome In The Hispanic Community Health Study/Study Of Latinos (HCHS/SOL)
Authors: Brandilyn A Peters, Jiaqian Xing, Guo-Chong Chen, Mykhaylo Usyk, Zheng Wang, Amanda McClain, Bharat Thyagarajan, Martha L Daviglus, Daniela Sotres-Alvarez, Frank B Hu, Rob Knight, Robert D Burk, Robert C Kaplan, Qibin Qi
Journal: Circulation (2022)

Introduction: Dietary patterns high in healthy plant foods play an important role in modulating the gut microbiome and promoting cardiometabolic health. Little is known on the diet-gut microbiome relationship in U.S. Hispanics/Latinos, who have a high burden of obesity and diabetes. Hypothesis: Three healthy dietary patterns - the alternate Mediterranean diet (aMED), the Healthy Eating Index (HEI)-2015, and the healthful Plant-based Diet Index (hPDI), will be associated with gut microbiome composition in U.S. Hispanic/Latino adults, and healthy-diet-related species will be related to favorable cardiometabolic traits. Methods: HCHS/SOL is a multi-site community-based cohort. At baseline (2008-11), diet was assessed via two 24-hr recalls. Shotgun sequencing was performed on stool samples collected in 2014-17 (n=2,985). Analysis of Compositions of Microbiomes 2 (ANCOM2) was used to identify associations of dietary pattern scores with gut microbiome species and functions, adjusting for sociodemographic, behavioral, and clinical covariates. Results: Better diet quality according to multiple healthy dietary patterns was associated with higher abundance of species from class Clostridia, including [Eubacterium] eligens , Butyrivibrio crossotus , and Lachnospiraceae bacterium TF01-11 , as well as functions related to fiber fermentation (e.g. pyruvate:ferredoxin oxidoreductase). Poorer diet quality was associated with higher abundance of Acidaminococcus intestini , as well as functions of manganese/iron transport, adhesin protein transport, and nitrate reduction. Healthy diet pattern-enriched Clostridia species were related to more favorable cardiometabolic traits such as lower triglycerides ( Figure 1 ). Conclusions: Healthy dietary patterns in this population are associated with a fiber-fermenting gut microbiome, consistent with previous studies in other racial/ethnic groups. Gut microbiota may be involved in the beneficial effect of higher diet quality on cardiometabolic disease risk.
Global tuberculosis progress reversed by COVID-19 pandemic
Authors: Tony Kirby
Journal: The Lancet Respiratory Medicine (2021)

For the first time in more than a decade, global deaths from tuberculosis have increased (from 1·4 million to 1·5 million), not because of any direct resurgence of this ancient disease—the cause has been the COVID-19 pandemic, which has fractured and strained health systems in all nations from the wealthiest to the poorest. While countries have struggled with implementing, lifting, and reimplementing restrictions, access to all other medical services—from complex cancer treatment in high-income countries to provision of tuberculosis diagnosis and treatment in high-burden countries—has suffered.
Intense 68Ga-DOTA-FAPI-04 Uptake in Diffuse Sclerotic Skeletal Metastases of Gastric Cancer
Authors: Özge Erol Fenercioğlu, Ediz Beyhan, Esra Arslan, Tevfik Fikret Çermik, Nurhan Ergül
Journal: Clinical Nuclear Medicine (2022)

Abstract Diffuse sclerotic metastases of the bone as initial presentation at gastric carcinoma are very rare. We present a 48-year-old man who was examined for pancytopenia and diagnosed with gastric cancer. 18 F-FDG PET/CT showed moderate uptake in the primary gastric tumor and mild uptake in diffuse sclerotic metastatic lesions in the bone matrix, whereas 68 Ga-DOTA-FAPI-04 showed mild uptake in the gastric lesion and intense uptake at the whole skeleton.