tbuckley/cabot-search huggingface dataset:
Randomized phase II trial of avelumab alone or in combination with cetuximab for patients with previously treated, locally advanced, or metastatic squamous cell anal carcinoma: the CARACAS study
Authors: Sara Lonardi, Alessandra Anna Prete, Federica Morano, Marco Messina, Vincenzo Formica, Domenico Cristiano Corsi, Corrado Orciuolo, Giovanni Luca Frassineti, Maria Giulia Zampino, Mariaelena Casagrande, Gianluca Masi, Monica Ronzoni, Mario Scartozzi, Angela Buonadonna, Stefania Mosconi, Margherita Ratti, Andrea Sartore-Bianchi, Emiliano Tamburini, Michele Prisciandaro, Francesca Bergamo, Massimiliano Spada, Salvatore Corallo, Valentina Vettore, Fotios Loupakis, Matteo Fassan, Paola Del Bianco, Vittorina Zagonel, Filippo Pietrantonio
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background No standard therapies beyond first line are established for advanced squamous cell anal carcinoma (aSCAC). Earlier preliminary data suggest activity of epidermal growth factor receptor (EGFR) inhibition and programmed cell death ligand (PD-(L))1 blockade in patients with previously treated disease. Aim of this study was to explore activity and safety of avelumab with/without cetuximab in patients with aSCAC. Methods In this open-label, non-comparative, ‘pick the winner’, multicenter randomized phase II trial ( NCT03944252 ), patients with aSCAC progressing after one or more lines of treatment were randomized 1:1 to the anti-PD-L1 agent avelumab alone (arm A) or combined with cetuximab (arm B). Overall response rate (ORR) was the primary endpoint. With one-sided α error set at 0.05 and power of 80%, at least 4 responses out of 27 patients per arm had to be observed to declare the study positive. Secondary endpoints were progression free survival (PFS), overall survival (OS), and safety. Results Thirty patients per arm were enrolled. Three patients in arm A and five in arm B achieved partial response: primary endpoint was reached in combination arm. ORR was 10% (95% CI 2.1 to 26.5) and 17% (95% CI 5.6 to 34.7) in arms A and B; disease control rate was 50% (95% CI 31.3 to 68.7) in arm A and 57 (95% CI 37.4–74.5) in arm B. At a median follow-up of 26.7 months (IQR 26.5–26.9), median PFS was 2.0 months (95% CI 1.8 to 4.0) in arm A and 3.9 (95% CI 2.1 to 5.6) in arm B. Median OS was 13.9 months (95% CI 7.7 to 19.4) in arm A and 7.8 (95% CI 6.2 to 11.2) in arm B. Acceptable safety profile was observed in both arms. Conclusions CARACAS study met its primary endpoint in arm B, documenting promising activity of dual EGFR and PD-L1 blockade in aSCAC.
Dynamic PET-facilitated modeling and high-dose rifampin regimens for <i>Staphylococcus aureus</i> orthopedic implant–associated infections
Authors: Oren Gordon, Donald E. Lee, Bessie Liu, Brooke Langevin, Alvaro A. Ordonez, Dustin A. Dikeman, Babar Shafiq, John M. Thompson, Paul D. Sponseller, Kelly Flavahan, Martin A. Lodge, Steven P. Rowe, Robert F. Dannals, Camilo A. Ruiz-Bedoya, Timothy D. Read, Charles A. Peloquin, Nathan K. Archer, Lloyd S. Miller, Kimberly M. Davis, Jogarao V. S. Gobburu, Sanjay K. Jain
Journal: Science Translational Medicine (2021)

Staphylococcus aureus is a major human pathogen causing serious implant–associated infections. Combination treatment with rifampin (10 to 15 mg/kg per day), which has dose-dependent activity, is recommended to treat S. aureus orthopedic implant–associated infections. Rifampin, however, has limited bone penetration. Here, dynamic 11C-rifampin positron emission tomography (PET) performed in prospectively enrolled patients with confirmed S. aureus bone infection (n = 3) or without orthopedic infection (n = 12) demonstrated bone/plasma area under the concentration-time curve ratio of 0.14 (interquartile range, 0.09 to 0.19), exposures lower than previously thought. PET-based pharmacokinetic modeling predicted rifampin concentration-time profiles in bone and facilitated studies in a mouse model of S. aureus orthopedic implant infection. Administration of high-dose rifampin (human equipotent to 35 mg/kg per day) substantially increased bone concentrations (2 mg/liter versus <0.2 mg/liter with standard dosing) in mice and achieved higher bacterial killing and biofilm disruption. Treatment for 4 weeks with high-dose rifampin and vancomycin was noninferior to the recommended 6-week treatment of standard-dose rifampin with vancomycin in mice (risk difference, −6.7% favoring high-dose rifampin regimen). High-dose rifampin treatment ameliorated antimicrobial resistance (0% versus 38%; P = 0.04) and mitigated adverse bone remodeling (P < 0.01). Last, whole-genome sequencing demonstrated that administration of high-dose rifampin in mice reduced selection of bacterial mutations conferring rifampin resistance (rpoB) and mutations in genes potentially linked to persistence. These data suggest that administration of high-dose rifampin is necessary to achieve optimal bone concentrations, which could shorten and improve treatments for S. aureus orthopedic implant infections.
Covid-19: Omicron may be more transmissible than other variants and partly resistant to existing vaccines, scientists fear
Authors: Ingrid Torjesen
Journal: BMJ (2021)

By abruptly changing the size and composition of a population, bottlenecks can dramatically alter evolutionary trajectories. In the traditional picture, the faster a population recovers from a bottleneck, the more rapidly finite-size intrinsic fluctuations are suppressed and therefore the greater the likelihood of fixation to the attractor within whose basin the bottleneck constrained the population, initially. We now argue that this intuition is misleading; demonstrating that precisely the opposite behaviour is also possible. Depending critically on the rate of mutation, increased population growth can drive fixation to attractors that are <i>different</i> to that from whose basin it started. These findings are explained in terms of statistically distinct regimes of demographic behaviour, drawing parallels with the notion of non-equilibrium phase transitions. Such dynamical demographic phases are delimited by sharp transitions in time, as a population grows, and ultimately result from a time-dependent antagonism between mutation and the stochastically-induced effects of frequency-dependent birth.
Abstract 10765: Plasma Cell-Free DNA Predicts Survival and Maps Tissue-Specific Sources of Injury in Pulmonary Arterial Hypertension
Authors: Samuel B Brusca, Jason M Elinoff, Yvette Zou, Moon K Jang, Hyesik Kong, Cumhur Y Demirkale, Junfeng Sun, Fayaz Seifuddin, Mehdi Pirooznia, Hannah A Valantine, Carl Tanba, Abhishek Chaturvedi, Manreet Kanwar, Raymond L Benza, Ioana R Preston, sean agborenoh, Michael A Solomon
Journal: Circulation (2021)

Background: Cell-free DNA (cfDNA) is a non-invasive marker of tissue injury. Although being incrementally used as a clinical biomarker, its significance in pulmonary arterial hypertension (PAH) is unknown. Methods: Plasma cfDNA was isolated in two independent PAH cohorts (A, n=48; B, n=161) and healthy controls (n=48). Clinical variables and survival status were collected for Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL 2.0) scores and outcome determinations. Total cfDNA levels were compared amongst controls and PAH patients and also used to predict transplant-free survival. A subset of samples from cohort B (n=96) and controls (n=16) were subjected to bisulfite sequencing and methylation analysis to quantify tissue-specific sources of cfDNA. Results: Median (IQR) cfDNA concentrations were higher in cohort A PAH patients (exploratory cohort) compared to controls and increased according to REVEAL 2.0 risk group: controls 13.7 (10.8-18.8) vs low risk 14.4 (10.0-19.9) vs medium risk 14.6 (11.3-28.2) vs high risk 31.5 (17.2-45.6) ng/ml (P&lt;0.01). cfDNA analysis in cohort B (validation cohort) demonstrated a similar cfDNA pattern: controls 13.7 (10.8-18.8) vs low risk 24.3 (16.0-57.9) vs medium risk 50.4 (29.4-70.9) vs high risk 51.5 (34.0-110.5) ng/ml (P&lt;0.0001). cfDNA tertiles (Log-Rank; P=0.0001) and REVEAL 2.0 risk group (Log-Rank; P&lt;0.0001) similarly predicted transplant-free survival, and the addition of cfDNA to REVEAL 2.0 improved model performance (AUC 0.64 to 0.70; P&lt;0.05). Tissue-specific methylation analysis revealed increased cfDNA originating from vascular endothelium, cardiac myocytes, monocytes, erythrocyte progenitors, neutrophils, natural killer cells, and adipocytes (all P&lt;0.005), but not colon, head/neck, liver, bladder, or kidney. With the exception of natural killer cells, cfDNA from enriched tissues also differentiated PAH patients of varying REVEAL 2.0 risk. Conclusions: cfDNA is elevated in PAH patients, correlates with disease severity and predicts worse survival. Methylation analysis of cfDNA in PAH patients is consistent with prevailing paradigms of disease pathogenesis. Thus, cfDNA may add prognostic power to PAH risk assessment and provide insight into disease progression.
Abstract 14320: High Density Lipoprotein Affinity and Transport of Small RNAs in Atherosclerosis
Authors: Danielle L Michell, Ryan M Allen, Elizabeth Semler, Ashley Cavnar, Chase Raby, Mark Castleberry, Marisol Ramirez, SHilin Zhao, Quanhu Sheng, Macrae F Linton, Kasey C Vickers
Journal: Circulation (2021)

HDL have many alternative functions outside of cholesterol efflux likely due to its diverse cargo of proteins, lipids, and small non-coding RNAs (sRNA). We have reported that HDL transports microRNAs (miRNA) and other sRNA classes, including tRNA-derived sRNAs (tDR), which are produced during cell stress. We hypothesize that HDL-tDR transport is conferred by apolipoprotein A-I (apoA-I) RNA binding capacity. HDL-miRNAs have previously been shown to be altered in many diseases; however, changes to HDL-tDRs in diseases such as cardiovascular disease, have not been reported. Based on sRNA sequencing, tDR-GlyGCC was identified as one of the most abundant sRNAs on HDL and HDL-tDR-GlyGCC levels were found to be significantly increased in humans with advanced atherosclerosis, as determined by coronary artery calcium scores. Moreover, we found that macrophages readily export tDR-GlyGCC to HDL. To determine the binding properties of HDL-tDR-GlyGCC, microscale thermophoresis (MST) and electromobility shift assays were completed. HDL were determined to have the strongest binding affinity to tDR-GlyGCC (K d =48nM) compared to other sRNAs, including miR-223-3p (K d =372nM), suggesting that HDL has preferences for distinct sRNAs. As sRNAs can be post-transcriptionally modified, we investigated if RNA modifications inhibit HDL binding. Both 2- O -methylation and locked-nucleic acid modifications diminished HDL binding while other chemical forms of tDR-GlyGCC, namely dsRNA and ssDNA, were found to completely block binding. To determine if apoA-I confers RNA binding capacity of HDL, MST studies were completed on lipid-free apoA-I and single unilamellar lipid vesicles (SUV), and while apoA-I was found to bind moderately, SUVs failed to bind tDR-GlyGCC. Interestingly, reconstitution of SUVs with apoA-I rescued tDR-GlyGCC binding. Moreover, chemical cross-linking of 4-thiouridine-containing tDR-GlyGCC to apoA-I caused both protein size shift and dimerization as determined by western blotting. Crosslinked proteins were also used to uncover potential apoA-I RNA binding domains, as determined by LC-MS/MS. These results support that apoA-I RNA binding capacity confers HDL-tDR-GlyGCC acceptance from macrophages and transport in atherosclerosis.
Evidence That Hypothalamic Gliosis Is Related to Impaired Glucose Homeostasis in Adults With Obesity
Authors: Jennifer L. Rosenbaum, Susan J. Melhorn, Stefan Schoen, Mary F. Webb, Mary Rosalynn B. De Leon, Madelaine Humphreys, Kristina M. Utzschneider, Ellen A. Schur
Journal: Diabetes Care (2021)

OBJECTIVE Preclinical research implicates hypothalamic glial cell responses in the pathogenesis of obesity and type 2 diabetes (T2D). In the current study we sought to translate such findings to humans by testing whether radiologic markers of gliosis in the mediobasal hypothalamus (MBH) were greater in individuals with obesity and impaired glucose homeostasis or T2D. RESEARCH DESIGN AND METHODS Using cross-sectional and prospective cohort study designs, we applied a validated quantitative MRI approach to assess gliosis in 67 adults with obesity and normal glucose tolerance, impaired glucose tolerance (IGT), or T2D. Assessments of glucose homeostasis were conducted via oral glucose tolerance tests (OGTT) and β-cell modeling. RESULTS We found significantly greater T2 relaxation times (a marker of gliosis by MRI), that were independent of adiposity, in the groups with IGT and T2D as compared with the group with normal glucose tolerance. Findings were present in the MBH, but not control regions. Moreover, positive linear associations were present in the MBH but not control regions between T2 relaxation time and glucose area under the curve during an OGTT, fasting glucose concentrations, hemoglobin A1c, and visceral adipose tissue mass, whereas negative linear relationships were present in the MBH for markers of insulin sensitivity and β-cell function. In a prospective cohort study, greater MBH T2 relaxation times predicted declining insulin sensitivity over 1 year. CONCLUSIONS Findings support a role for hypothalamic gliosis in the progression of insulin resistance in obesity and thus T2D pathogenesis in humans.
Abstract 14344: The Competing Roles of Glucose and Lipoprotein Lipase on Regulatory Macrophage Function
Authors: Ashita Bhatnagar, Francis J Alenghat
Journal: Circulation (2021)

Background: Atherosclerosis causes more death than any other pathophysiologic process. It has a well-established inflammatory, macrophage(MФ)-mediated component which can be stoked by uncontrolled diabetes. However, there are also protective, regulatory MФ processes that can help quell atherosclerosis. Lipoprotein Lipase (LPL) on the MФ surface can hydrolyze circulating triglyceride-rich lipoproteins into glycerol and free fatty acids to provide a non-glucose energy source. We hypothesized that regulatory MФs have high LPL activity, which would promote fatty acid metabolism to drive inflammation-resolving functions, and that this LPL activity is inversely related to ambient glucose. Results: MФs were cultured and differentiated from bone marrow harvested from wild-type mice aged 9-16 weeks. Two weeks after harvest, these MФs were polarized with (1) interferon-γ and lipopolysaccharide to stimulate classically-activated, inflammatory MФs or (2) interleukin-4 to stimulate alternatively-activated, regulatory MФs. The resulting phenotypes were validated by canonical transcript markers ( Tnfa / Nos2 for inflammatory MФs and Ym1 / Arg1 for regulatory MФs) and cell surface markers (CD86 and CD206, respectively). Using a triglyceride analog that fluoresces when cleaved by LPL, we found that regulatory MФs have far greater LPL activity than inflammatory macrophages at baseline (33 ± 2 vs 1 ± 0.2 a.u., p &lt; 0.001, n=8). By varying glucose concentration during the polarization, this effect was most pronounced at normal, physiological concentrations of glucose (5 mM, ~90 mg/dL) and blunted at a high-glucose concentration that can be found in uncontrolled diabetes (25 mM). Each experiment was repeated across multiple batches of MФs (n≥4) and from multiple mice (n=15), male and female. Conclusions: Taken together, our findings support a model in which regulatory MФs are programmed to utilize LPL to drive the inflammation-resolving phenotype and that this process works best at low, physiologic glucose concentrations. Future translational work will investigate whether a lack of LPL-mediated regulatory MФ function is a reason why patients with uncontrolled diabetes have higher atherosclerotic burden and plaque instability.
Abstract 12092: IMB-1018792, an Investigational Agent Designed to Augment Cardiac Glucose Utlization and Energetics Reduces Cardiac Remodelling and Preserves Cardiac Function in a Model of Pressure Overload-Induced Heart Failure
Authors: Matthew Harding, Jaikrishna Patel, Paul Chamberlin, Claudia Calcagno, Andrew Levin
Journal: Circulation (2021)

Introduction: Energetic impairments play a key role in heart failure (HF). Contributors include reduced pyruvate dehydrogenase activity partially uncoupling glycolysis from glucose oxidation, increased dependence on fatty acid (FA) metabolism yielding less ATP than glucose per O 2 molecule consumed, a lower phosphate-to-O 2 ratio, mitochondrial uncoupling and futile cycling of FA intermediates. IMB-1018972 (IMB-101) is a novel investigational agent designed to increase cardiac glucose uptake to promote glucose oxidation (Randle effect) through partial inhibition of FA oxidation enhancing cardiac energetics and mechanical efficiency. Hypotheses: Administration of IMB-101 will: 1) increase cardiac glucose uptake and 2) attenuate LV hypertrophic remodelling and progression of HF resulting from chronic pressure overload. Methods: 1) Cardiac glucose metabolism was evaluated using dynamic 18 F-FDG PET/CT imaging in vivo in fasted normal rats following a subcutaneous dose of IMB-101 or saline. Each animal had 2 randomized sequenced scan sessions (n=16). 2) Male C57BL/6 mice aged 12 weeks underwent transverse aortic constriction (TAC) or sham surgery (n=15) and were treated with IMB-101 (10 mg/kg/day, n=15) or saline (n=15) from day 1 (D1) for 6 weeks by osmotic minipump. Cardiac function was assessed by conscious echocardiography (D1, week 3 and 6). Cardiac fibrosis was measured by Masson’s Trichrome staining. Results: IMB-101 robustly increased in vivo cardiac 18 F-FDG uptake vs saline in rats. In mice subjected to TAC, compared to saline controls, IMB-101 treatment: preserved LV systolic function (fractional shortening 46%±3% vs 34%±3%, at week 6, p&lt;0.05); improved LV relaxation with less prolonged isovolumic relaxation time (32±1 ms vs 36±1 ms, p&lt;0.05); reduced cardiac hypertrophy (LV mass 156±10 mg vs 195±12 mg, p&lt;0.05; and heart:body weight ratio 7.4±0.3 mg/g vs. 9.1±0.5 mg/g, p&lt;0.05); and attenuated cardiac fibrosis (6.6±0.6% vs 10.7±1%, p&lt;0.01). Conclusions: IMB-101 increases cardiac glucose uptake and protects against LV dysfunction, hypertrophic remodelling and interstitial fibrosis after chronic pressure overload.
Blood stem cell PU.1 upregulation is a consequence of differentiation without fast autoregulation
Authors: Nouraiz Ahmed, Martin Etzrodt, Philip Dettinger, Tobias Kull, Dirk Loeffler, Philipp S. Hoppe, James S. Chavez, Yang Zhang, Germán Camargo Ortega, Oliver Hilsenbeck, Hideaki Nakajima, Eric M. Pietras, Timm Schroeder
Journal: The Journal of Experimental Medicine (2021)

Transcription factors (TFs) regulate cell fates, and their expression must be tightly regulated. Autoregulation is assumed to regulate many TFs’ own expression to control cell fates. Here, we manipulate and quantify the (auto)regulation of PU.1, a TF controlling hematopoietic stem and progenitor cells (HSPCs), and correlate it to their future fates. We generate transgenic mice allowing both inducible activation of PU.1 and noninvasive quantification of endogenous PU.1 protein expression. The quantified HSPC PU.1 dynamics show that PU.1 up-regulation occurs as a consequence of hematopoietic differentiation independently of direct fast autoregulation. In contrast, inflammatory signaling induces fast PU.1 up-regulation, which does not require PU.1 expression or its binding to its own autoregulatory enhancer. However, the increased PU.1 levels induced by inflammatory signaling cannot be sustained via autoregulation after removal of the signaling stimulus. We conclude that PU.1 overexpression induces HSC differentiation before PU.1 up-regulation, only later generating cell types with intrinsically higher PU.1.
Abstract 10271: Correlates and Prognostic Significance of B-Type Natriuretic Peptide in Patients with Sickle Cell Hemoglobinopathies
Authors: Ashwin Gupta, Eric Farber-Eger, Deepak K Gupta
Journal: Circulation (2021)

Introduction: Natriuretic peptides (NP) are hormones released from the heart in response to cardiac stress. Sickle cell hemoglobinopathies are conditions with increased cardiovascular stress, yet few studies have examined determinants of and the relative prognostic significance of NP levels in these patients. Hypothesis: We assessed the hypothesis that plasma B-type NP (BNP) level is one of the strongest independent predictors of death among patients with sickle cell hemoglobinopathies. Methods: From the Vanderbilt University Medical Center electronic health record, we retrospectively studied adult patients with sickle cell disease (SCD, n = 278; median age 30 years, 50% female) and sickle trait (ST, n = 196; median age 45 years, 73% female) in whom BNP was clinically measured from 2003-2020. The association between BNP and risk of death was assessed with multivariable Cox regression. Correlates of BNP levels were examined in multivariable ordinal logistic regression. Results: Over 1846 person-years of follow-up, 43 (9%) patients died. BNP, age, and lactate dehydrogenase levels were the three strongest predictors of death, accounting for 29%, 18%, and 13% of the explained variance in the risk of death, respectively. Each 110 pg/ml greater BNP was associated with a 5% (95% CI: 4-6%) increased risk of death. SCD was associated with a 19% (95% CI: 5 to 36%) increased risk of death compared to ST. Among patients with SCD, significant correlates of BNP ranked by strength of association were hemoglobin, white blood cell count, age, pulmonary artery systolic pressure (PASP), hypertension, left ventricular ejection fraction (LVEF), and neutrophil count (Figure). For patients with ST, the strongest correlates of BNP were PASP, hemoglobin, stroke, age, diabetes, and LVEF. Conclusions: In conclusion, BNP is the strongest predictor of death independent of anemia severity and other features of cardiac structure and function among patients with sickle cell hemoglobinopathies.
Potential Role of <i>STAG1</i> Mutations in Genetic Predisposition to Childhood Hemato-Oncological Diseases
Authors: Claudia Saitta, Stefano Rebellato, Laura Rachele Bettini, Giovanni Giudici, Nicolò Panini, Eugenio Erba, Simona Songia, Valentina Massa, Andrea Biondi, Grazia Fazio, Giovanni Cazzaniga
Journal: Blood (2021)
Impact of Vitamin D Deficiency on Survival for Patients Received Haploidentical Hematopoietic Stem Cell Transplantation (haplo-HSCT)
Authors: Nicholas Cox, Supawee Saengboon, Amanda L. Olson, Muzaffar H. Qazilbash, Elizabeth J. Shpall, Richard E. Champlin, Samer A. Srour
Journal: Blood (2021)