tbuckley/cabot-search huggingface dataset:
Abstract P022: MS #279 - Use Of Dietary Supplements And Risk Of Chronic Kidney Disease In The Hispanic Community Health Study/Study Of Latinos (HCHS/SOL)
Authors: Carmen E Mendoza, Keturah R Faurot, James Lash, Daniela Sotres-Alvarez, Martha L Daviglus, Gerardo M Heiss
Journal: Circulation (2022)

Background: Dietary supplements (DS) are often used for their perceived health-promoting and therapeutic properties. Certain supplements can be nephrotoxic, especially among individuals at risk for chronic kidney disease (CKD). Hispanic/Latino populations are users of DS (30-70%) and have a high prevalence of conditions predisposing CKD. The potential contribution of DS use to risk of CKD in this population has not been studied. Objective: To assess whether DS use is associated with higher prevalence and incidence of CKD in Hispanic/Latinos. Methods: DS use was assessed in 16,279 of 16,415 Hispanic/Latinos enrolled in HCHS/SOL in 24-hour recall and 30-day medications inventory. Users of any DS were compared to those reporting no DS use. Prevalent CKD was defined with estimated glomerular filtration rate (eGFR) using the serum creatinine-cystatin C equation or urine albumin-to-creatinine ratio (ACR) ≥ 30 mg/g at baseline. Incident low eGFR and incident albuminuria at follow-up were defined as &lt;60 mL/min/1.73 m 2 and ACR ≥ 30 mg/g, respectively. Incident CKD was defined as no prevalent CKD and incident low eGFR with eGFR decline ≥1ml/min/1.73 m 2 /year or incident albuminuria. We used multivariable logistic regression to estimate odds ratios (OR) for prevalence and Poisson regression for incidence rate ratios (IRR). Analyses accounted for HCHS/SOL complex sampling design. Results: DS users were older (median age 45 vs 35 years) and more likely to be female (57 vs 48%), have health insurance (54 vs 48%) and be born in the United States (26 vs 19%). Of DS users, 13% had prevalent CKD while 12% of non-DS users had prevalent CKD (adjusted OR 0.77 (95% CI 0.66, 0.91)). IRRs for incident CKD, low eGFR and albuminuria between users and non-users of DS were 1.0 (95% CI 0.84, 1.3), 0.87 (95% CI 0.61, 1.3), and 1.2 (95% CI 0.88, 1.6), respectively. Conclusions: DS use was associated with lower prevalent CKD at visit 1 and not associated with incident CKD, low eGFR or albuminuria at visit 2. DS use may be a proxy for health-seeking behavior in this population.
Hypothetical generalized framework for a new imaging endpoint of therapeutic activity in early phase clinical trials in brain tumors
Authors: Benjamin M Ellingson, Elizabeth R Gerstner, Andrew B Lassman, Caroline Chung, Howard Colman, Patricia E Cole, David Leung, Joshua E Allen, Manmeet S Ahluwalia, Jerrold Boxerman, Matthew Brown, Jonathan Goldin, Edjah Nduom, Islam Hassan, Mark R Gilbert, Ingo K Mellinghoff, Michael Weller, Susan Chang, David Arons, Clair Meehan, Wendy Selig, Kirk Tanner, W K Alfred Yung, Martin van den Bent, Patrick Y Wen, Timothy F Cloughesy
Journal: Neuro-Oncology (2022)

Abstract Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for “response” and ultimately lead to identification of effective treatments.
COMPARISON BETWEEN SAME-DAY DISCHARGE AND OVERNIGHT STAY AFTER ATRIAL FIBRILLATION ABLATION: SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Narut Prasitlumkum, Wisit Cheungpasitporn, Ronpichai Chokesuwattanaskul, Jakrin Kewcharoen, Nithi Tokavanich, Leenhapong Navaravong, Krit Jongnarangsin
Journal: Journal of the American College of Cardiology (2022)
Abstract P089: N-terminal Pro-B-type Natriuretic Peptide And Incident Metabolic Syndrome And Its Components In REGARDS
Authors: Charles D Nicoli, Tim B Plante, Leann Long, Leslie A McClure, Suzanne E Judd, April P Carson, Mary Cushman
Journal: Circulation (2022)

Introduction: Natriuretic peptides are released in response to cardiomyocyte stretch and are markers of atriopathy and heart failure. Lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been associated with greater risk for diabetes mellitus (DM) in prospective studies, but associations of B-type natriuretic peptides with incident metabolic syndrome (MetS) have not been evaluated. Hypothesis: Higher baseline NT-proBNP is associated with lower risk for incident metabolic syndrome and its components. Methods: We included 2,144 Black and white participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study without MetS at baseline (2003-2007). These participants had baseline plasma NT-proBNP measured by immunoassay and underwent follow-up in 2013-2016. Those with NT-proBNP &gt;100 pg/mL were excluded. Incident MetS was defined as ≥3 harmonized criteria at follow-up: high systolic blood pressure, increased waist circumference, dysglycemia, high triglycerides, and low high-density lipoprotein. Three sequential logistic regression models estimated odds ratios of incident MetS and for individual MetS criteria, incorporating demographic factors, metabolic risk factors, and laboratory markers related to insulin resistance. Results &amp; Conclusions: Over mean 9.4 (SD 1.0) years follow up, 426 participants (mean [SD] age 60.7 [0.4] years, 193 (45%) Black race, 228 (54%) women) developed MetS. Median [IQR] plasma NT-proBNP was 34 [16-58] pg/mL. No significant association of NT-proBNP with incident MetS was observed (Table). There were no observed interactions of this association by race (P=0.22), age (P=0.15), or sex (P=0.60). Each 1-SD higher log NT-proBNP was associated with lower risk of incident dysglycemia, but not other MetS components. The metabolic implications of B-type natriuretic peptides may be limited to glycemic homeostasis.
A multitope SARS-CoV-2 vaccine provides long-lasting B cell and T cell immunity against Delta and Omicron variants
Authors: Chang Yi Wang, Kao-Pin Hwang, Hui-Kai Kuo, Wen-Jiun Peng, Yea-Huei Shen, Be-Sheng Kuo, Juin-Hua Huang, Hope Liu, Yu-Hsin Ho, Feng Lin, Shuang Ding, Zhi Liu, Huan-Ting Wu, Ching-Tai Huang, Yuarn-Jang Lee, Ming-Che Liu, Yi-Ching Yang, Po-Liang Lu, Hung-Chin Tsai, Chen-Hsiang Lee, Zhi-Yuan Shi, Chun-Eng Liu, Chun-Hsing Liao, Feng-Yee Chang, Hsiang-Cheng Chen, Fu-Der Wang, Kuo-Liang Hou, Jennifer Cheng, Min-Sheng Wang, Ya-Ting Yang, Han-Chen Chiu, Ming-Han Jiang, Hao-Yu Shih, Hsuan-Yu Shen, Po-Yen Chang, Yu-Rou Lan, Chi-Tian Chen, Yi-Ling Lin, Jian-Jong Liang, Chun-Che Liao, Yu-Chi Chou, Mary Kate Morris, Carl V. Hanson, Farshad Guirakhoo, Michael Hellerstein, Hui-Jing Yu, Chwan-Chuen King, Tracy Kemp, D. Gray Heppner, Thomas P. Monath
Journal: Journal of Clinical Investigation (2022)

BackgroundThe Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.MethodWe conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 μg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 μg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 μg of UB-612 (n = 3,875, 18-85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.ResultsNo vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.ConclusionUB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial RegistrationClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.FundingUBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.
NOTCH3 as a modulator of vascular disease: a target in elastin deficiency and arterial pathologies
Authors: Kimberly Malka, Lucy Liaw
Journal: Journal of Clinical Investigation (2022)

During blood vessel disease, vascular smooth muscle cell (VSMC) expansion and interaction with the matrix trigger changes in gene expression and phenotype. In this issue of the JCI, Dave et al. discover a signaling network that drives VSMC expansion and vascular obstruction caused by elastin insufficiency. Using a combination of gene-targeted mice, tissues and cells from patients with Williams-Beuren syndrome, and targeting of elastin in human VSMCs, the authors identified VSMC-derived NOTCH3 signaling as a critical mediator of aortic hypermuscularization and loss of vascular patency. NOTCH3-specific therapies or therapies that target downstream molecular pathways may provide opportunities to minimize VSMC growth and treat cardiovascular disease with minimal side effects.
Targeting macrophagic 17β-HSD7 by fenretinide for the treatment of nonalcoholic fatty liver disease
Authors: Xiaoyu Dong, Yiting Feng, Dongqin Xu, Mengya Zhang, Xiao Wen, Wenhao Zhao, Qintong Hu, Qinyong Zhang, Hui Fu, Jie Ping
Journal: Acta Pharmaceutica Sinica B (2022)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and macrophage polarization plays an important role in its pathogenesis. However, which molecule regulates macrophage polarization in NAFLD remains unclear. Herein, we showed NAFLD mice exhibited increased 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7) expression in hepatic macrophages concomitantly with elevated M1 polarization. Single-cell RNA sequencing on hepatic non-parenchymal cells isolated from wild-type littermates and macrophage-17β-HSD7 knockout mice fed with high fat diet (HFD) for 6 weeks revealed that lipid metabolism pathways were notably changed. Furthermore, 17β-HSD7 deficiency in macrophages attenuated HFD-induced hepatic steatosis, insulin resistance and liver injury. Mechanistically, 17β-HSD7 triggered NLRP3 inflammasome activation by increasing free cholesterol content, thereby promoting M1 polarization of macrophages and the secretion of pro-inflammatory cytokines. In addition, to help demonstrate that 17β-HSD7 is a potential drug target for NAFLD, fenretinide was screened out from an FDA-approved drug library based on its 17β-HSD7 dehydrogenase inhibitory activity. Fenretinide dose-dependently abrogated macrophage polarization and pro-inflammatory cytokines production, and subsequently inhibited fat deposition in hepatocytes co-cultured with macrophages. In conclusion, our findings suggest that blockade of 17β-HSD7 signaling by fenretinide would be a drug repurposing strategy for NAFLD treatment.
Abstract MP18: A Multi-ethnic Polygenic Risk Score Is Associated With Hypertension Prevalence And Progression Throughout Adulthood
Authors: Tamar Sofer, Nuzulul Kurniansyah, Matthew Goodman, Joshua Bis, Xiuqing Guo, Jeffrey Haessler, Yan Gao, Jennifer A Smith, Elena Feofanova, Don M Lloyd-jones, Ruth Loos, Robert Kaplan, Daniel Levy
Journal: Circulation (2022)

Background: We used summary statistics from previously-published GWAS of systolic and diastolic BP and of hypertension (HTN) to construct Polygenic Risk Scores (PRS) to predict hypertension across diverse populations. Methods: We used 10,314 participants of diverse ancestry from BioMe to train trait-specific PRS. We implemented a novel approach to select one of multiple potential PRS based on the same GWAS, by optimizing the coefficient of variation across estimated PRS effect sizes in independent subsets of the training dataset. We combined the 3 selected trait-specific PRS as their unweighted sum, called “PRSsum”. We evaluated PRS associations in an independent dataset of 39,035 individuals from eight cohort studies, to select the final, multi-ethnic, HTN-PRS. We estimated its association with prevalent and incident hypertension 4-6 years later. We studied hypertension development within HTN-PRS strata in a longitudinal, six-visit, longitudinal dataset of 3,087 self-identified Black and White participants from the CARDIA study. Finally, we evaluated the HTN-PRS association with clinical outcomes in 40,201 individuals from the MGB Biobank. Results: Compared to other race/ethnic backgrounds, African-Americans had higher average values of the HTN-PRS. The HTN-PRS was associated with prevalent hypertension (OR=1.76, 95% CI [1.70, 1.83], per one standard deviation (SD) of the PRS) across all participants, and in each race/ethnic background, with heterogeneity by background (p-value=1.87x10 -4 ). The lowest estimated effect size was in African Americans (OR=1.49, 95% CI [1.36, 1.61]). The HTN-PRS was associated with new onset hypertension among individuals with normal (respectively, elevated) BP at baseline: OR=1.54, 95% CI [1.43, 1.66] (OR=1.39, 95% CI [1.23, 1.55]). Association was further observed in age-stratified analysis. In CARDIA, Black participants with high HTN-PRS percentiles developed hypertension earlier than White participants with high HTN-PRS percentiles. The HTN-PRS was significantly associated with increased risk of coronary artery disease (OR=1.11), ischemic stroke (OR=1.12), type 2 diabetes (OR=1.16), and chronic kidney disease (OR=1.12), in the MGB Biobank. Conclusions: The multi-ethnic HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up across adulthood and is associated with clinical outcomes.
115P Concurrent versus sequential immune checkpoint inhibition in stage III NSCLC patients treated with chemoradiation
Authors: L. Käsmann, J. Taugner, C. Eze, J. Guggenberger, B. Flörsch, S. Kenndoff, A. Tufman, N. Reinmuth, C. Belka, F. Manapov
Journal: Annals of Oncology (2022)
Inevitable Progress—Relying on the Immune System, Not Chance
Authors: Assuntina G. Sacco, Ezra E.W. Cohen
Journal: Clinical Cancer Research (2021)

Locoregional recurrence of head and neck cancer after curative therapy portends a poor prognosis even when resectable. Immunotherapy has opened the door to novel strategic approaches in the curative treatment paradigm. Potentially improving outcomes for patients with recurrent, resectable disease through combination immune modulators highlights a new frontier.See related article by Hanna et al., p. 468.
Excellent Response to Adapted Low-Dose 177Lu-PSMA-617 PSMA Therapy in Renal Compromise Patient
Authors: Sharjeel Usmani, Fareeda Al Kandari, Ibrahim Alrekhais, Shatha N. Khalaf, Najeeb Ahmed
Journal: Clinical Nuclear Medicine (2021)

Abstract Prostate-specific membrane antigen (PSMA)–targeted radioligand therapy with 177 Lu-PSMA-617 has shown promising results in patients with metastasized castration-resistant prostate cancer. We report a case of a 74-year-old man with metastatic prostate cancer with comorbidities of diabetes mellitus, hypertension, and chronic kidney disease. In order to minimize radiation burden to kidneys, a lower dose of 4 GBq of 177 Lu-PSMA-617 was prescribed instead of the usual 6 to 7 GBq. There was significant decrease in prostate-specific antigen levels and symptoms. Renal profile remained stable. This case highlights that compromised renal function is not a definite contraindication to radionuclide therapy, and doses can be modified based on risk versus benefits.
Role of Dynamic Parameters of 18F-DOPA PET/CT in Pediatric Gliomas
Authors: Francesco Fiz, Fabiano Bini, Edoardo Gabriele, Gianluca Bottoni, Maria Luisa Garrè, Franco Marinozzi, Claudia Milanaccio, Antonio Verrico, Michela Massollo, Victoria Bosio, Marco Lattuada, Andrea Rossi, Antonia Ramaglia, Matteo Puntoni, Giovanni Morana, Arnoldo Piccardo
Journal: Clinical Nuclear Medicine (2022)

Purpose of the Report PET with 18 F-DOPA can be used to evaluate grading and aggressiveness of pediatric cerebral gliomas. However, standard uptake parameters may underperform in circumscribed lesions and in diffuse pontine gliomas. In this study, we tested whether dynamic 18 F-DOPA PET could overcome these limitations. Patients and Methods Patients with available dynamic 18 F-DOPA PET were included retrospectively. Static parameters (tumor/striatum ratio [T/S] and tumor/cortex ratio [T/N]) and dynamic ones, calculated on the tumor time activity curve (TAC), including time-to-peak (TTP), slope steepness, the ratio between tumor and striatum TAC steepness (dynamic slope ratio [DSR]), and TAC shape (accumulation vs plateau), were evaluated as predictors of high/low grading (HG and LG) and of progression-free survival and overall survival. Results Fifteen patients were included; T/S, T/N, TTP, TAC slope steepness, and DSR were not significantly different between HG and LG. The accumulation TAC shape was more prevalent in the LG than in the HG group (75% vs 27%). On progression-free survival univariate analysis, TAC accumulation shape predicted longer survival ( P &lt; 0.001), whereas T/N and DSR showed borderline significance; on multivariate analyses, only TAC shape was retained ( P &lt; 0.01, Harrell C index, 0.93–0.95). On overall survival univariate analysis, T/N ( P &lt; 0.05), DSR ( P &lt; 0.05), and TAC “accumulating” shape predicted survival ( P &lt; 0.001); once more, only this last parameter was retained in the multivariate models ( P &lt; 0.05, Harrell C index, 0.86–0.89). Conclusions Dynamic 18 F-DOPA PET analysis outperforms the static parameter evaluation in grading assessment and survival prediction. Evaluation of the curve shape is a simple-to-use parameter with strong predictive power.
Incidental [18F]PSMA-1007 Appendiceal Uptake Mimicking Nodal Disease
Authors: Ayah Adel Nawwar, Julie Searle, Iain Douglas Lyburn
Journal: Clinical Nuclear Medicine (2021)

Abstract When interpreting an [ 18 F]prostate specific membrane antigen (PSMA)–1007 PET/CT, it is important to understand the normal biodistribution of the tracer. A 73-year-old man with prostate cancer underwent [ 18 F]PSMA-1007 PET/CT for biochemical recurrence. There was no abnormal uptake in the prostatectomy bed, but PSMA-avid pelvic nodal disease was found. Incidental intense focal uptake was also noted corresponding to the tip of the appendix, which was concluded to be physiological. This is an example of an uncommon site of physiological uptake of [ 18 F]PSMA-1007 in the appendix.
Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone
Authors: Peter J. Siska, Sonja-Maria Decking, Nathalie Babl, Carina Matos, Christina Bruss, Katrin Singer, Jana Klitzke, Marian Schön, Jakob Simeth, Josef Köstler, Heiko Siegmund, Ines Ugele, Michael Paulus, Alexander Dietl, Kristina Kolodova, Louisa Steines, Katharina Freitag, Alice Peuker, Gabriele Schönhammer, Johanna Raithel, Bernhard Graf, Florian Geismann, Matthias Lubnow, Matthias Mack, Peter Hau, Christopher Bohr, Ralph Burkhardt, Andre Gessner, Bernd Salzberger, Ralf Wagner, Frank Hanses, Florian Hitzenbichler, Daniel Heudobler, Florian Lüke, Tobias Pukrop, Wolfgang Herr, Daniel Wolff, Rainer Spang, Hendrik Poeck, Petra Hoffmann, Jonathan Jantsch, Christoph Brochhausen, Dirk Lunz, Michael Rehli, Marina Kreutz, Kathrin Renner
Journal: Journal of Clinical Investigation (2021)

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non–COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.
Prognostic Impact of Mildly Impaired Renal Function in Patients Undergoing Multivessel Coronary Revascularization
Authors: Tae Oh Kim, Do-Yoon Kang, Jung-Min Ahn, Seon Ok Kim, Pil Hyung Lee, Junghoon Lee, Ju Hyeon Kim, Ho Jin Kim, Joon Bum Kim, Suk Jung Choo, Cheol-Hyun Chung, Jae-Won Lee, Seung-Jung Park, Duk-Woo Park
Journal: Journal of the American College of Cardiology (2022)