tbuckley/cabot-search huggingface dataset:
LDH-stabilized ultrasmall iron oxide nanoparticles as a platform for hyaluronidase-promoted MR imaging and chemotherapy of tumors
Authors: Ni Zhang, Yue Wang, Changchang Zhang, Yu Fan, Du Li, Xueyan Cao, Jindong Xia, Xiangyang Shi, Rui Guo
Journal: Theranostics (2020)

Development of unique theranostic nanoplatforms for tumor imaging and therapy remains an active topic in current nanomedicine.Here, we designed a novel targeted theranostic nanoplatform for enhanced T 1 -weighted magnetic resonance (MR) imaging-guided chemotherapy by constructing layered double hydroxide (LDH)-stabilized ultrasmall iron oxide (Fe 3 O 4 ) nanoparticles with hyaluronic acid (HA) modified as targeting agents, and anticancer drug doxorubicin (DOX) loaded with a high loading efficiency.Methods: The structure and release property of LDH-Fe 3 O 4 -HA/DOX nanoplatforms were characterized systematically.B16 melanoma cells with CD44 receptors overexpressed were used as model cells to determine the biocompatibility, targeting capability, and therapeutic efficiency of nanoplatforms.For in vivo experiment, hyaluronidase (HAase) pretreatment was combined with nanoplatform administration to investigate the MR imaging and chemotherapeutic effect.Results: The LDH-Fe 3 O 4 -HA nanohybrids possess good colloidal stability and cytocompatibility, display an r 1 relaxivity 10-fold higher than the pristine ultrasmall Fe 3 O 4 (4.38 mM -1 s -1 vs 0.42 mM -1 s -1 ), and could release drug in a pH-responsive manner.In vitro experiments demonstrate that LDH-Fe 3 O 4 -HA/DOX nanohybrids are able to specifically target B16 cells overexpressing CD44 receptors and effectively release DOX to nucleus.In vivo results show that with the pretreatment of tumor tissue by HAase to degrade the overexpressed HA in extra-cellular matrix, the designed nanoplatforms have a better tumor penetration for significantly enhanced MR imaging of tumors and tumor chemotherapy with low side effects. Conclusion:The designed LDH-Fe 3 O 4 -HA/DOX nanohybrids may be developed as a novel targeted theranostic nanoplatform for enhanced T 1 -weighted MR imaging-guided chemotherapy of CD44 receptor-overexpressing tumors.
Case 5-2020: A 32-Day-Old Male Infant with a Fall
Authors: Alice W. Newton, Paul A. Caruso, David H. Ebb, Grace Linder
Journal: New England Journal of Medicine (2020)

A 32-day-old male infant was evaluated for suspected abusive head trauma. The patient's mother called emergency medical services and reported that the patient had fallen off a bed; the baby had not lost consciousness and was behaving normally. Imaging studies of the head showed several areas of hemorrhage. Management decisions were made.
Prevalence and Prevention of Contact Dermatitis Caused by FreeStyle Libre: A Monocentric Experience
Authors: Jeroen Pyl, Ella Dendooven, Ine Van Eekelen, Marieke den Brinker, Hilde Dotremont, Annick France, Kenn Foubert, Luc Pieters, Julien Lambert, Christophe De Block, Olivier Aerts
Journal: Diabetes Care (2020)

OBJECTIVE Cutaneous adverse events (CAE) from FreeStyle Libre include allergic contact dermatitis (ACD) caused by the allergen isobornyl acrylate (IBOA). We aim to report CAE from this glucose sensor, ACD to IBOA in particular, and the outcome of using barrier films as a prevention. RESEARCH DESIGN AND METHODS A monocentric, retrospective review of medical files from adult and pediatric patients with diabetes using Freestyle Libre, in the period between December 2016 and April 2019, was performed with a focus on CAE. RESULTS Fifty-seven of 1,036 patients with diabetes (5.5%) were referred to our dermatology department because of CAE from FreeStyle Libre. Thirty-nine of 1,036 (3.8%) had ACD due to IBOA. Only two patients, of whom one sensitized to IBOA, had a benefit from using barrier films. CONCLUSIONS CAE occurred in 5.5% of FreeStyle Libre users, and 3.8% suffered from ACD due to IBOA. Barrier films had limited value in the prevention.
CT derived radiomic score for predicting the added benefit of adjuvant chemotherapy following surgery in stage I, II resectable non-small cell lung cancer: a retrospective multicohort study for outcome prediction
Authors: Pranjal Vaidya, Kaustav Bera, Amit Gupta, Xiangxue Wang, Germán Corredor, Pingfu Fu, Niha Beig, Prateek Prasanna, Pradnya D Patil, Priya D Velu, Prabhakar Rajiah, Robert Gilkeson, Michael D Feldman, Humberto Choi, Vamsidhar Velcheti, Anant Madabhushi
Journal: The Lancet Digital Health (2020)

Development and validation of a quantitative radiomic risk score (QuRiS) and associated nomogram (QuRNom) for early-stage non-small cell lung cancer (ES-NSCLC) that is prognostic of disease-free survival (DFS) and predictive of the added benefit of adjuvant chemotherapy (ACT) following surgery.QuRiS was developed using radiomic texture features derived from within and outside the primary lung nodule on chest CT scans using a cohort D1 of 329 patients from the Cleveland Clinic. A LASSO-Cox regularization model was used for data dimension reduction, feature selection, and QuRiS construction. QuRiS was independently validated on D2(N=114; University of Pennsylvania) and D3(N=82; TCIA). QuRNom was constructed by integrating QuRiS with T-, N-Descriptors, and LVI. The added benefit of ACT using QuRiS and QuRNom was validated by comparing patients who received ACT against patients who underwent surgery alone in D1-D3. To explore the underlying morphologic basis of the QuRiS, we explored associations with corresponding whole-slide tissue scans (WSIs) and mRNA sequencing data using subsets of D1 and D3.QuRiS consisted three intra- and ten peri-tumoral CT-radiomic features and was found to be significantly associated with DFS (D1: HR=1.60 [1.10-2.20];p<·05; D2:HR=2.70 [1.40-5.10]; p<·01; D3:HR=2.70 [1.20-5.70];p<·01). Patients were partitioned into three risk groups (QH, QI, QL) based off their corresponding QuRiS score. High QuRiS group, QH, patients were observed to have significantly prolonged survival with ACT when compared to surgery alone (D1: HR=0·27[0.07-0.95],p<0.05; D2+D3: HR=0·08[0.01-0.42],p<0.01). For developed QuRNom, the actual efficacy of ACT was predictive of nomogram-estimated survival benefit (D1: HR= D1:0·25 [0·12-0·55], D3: HR=0·13 [0·004-0·99]). QuRiS features were found to be associated with the spatial arrangement of TILs and cancer nuclei on corresponding WSIs (D1: Rho=0·23,p<0·05, N=70). They were also observed to have an association with biological pathways implicated in chemotaxis (D3,p<0·05, N=86) and other immune specific biological pathways.QuRiS and QuRNom were validated as being prognostic of DFS and predictive of the added benefit of ACT.
Targeting microtubule sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors
Authors: Tan-Min Chin, Gandhi T. K. Boopathy, Ellen P.S. Man, John G. Clohessy, Eva Csizmadia, Margaret P Quinlan, Thomas Putti, Seow-Ching Wan, Chen Xie, Azhar Ali, Fhu Chee Wai, Yan Shan Ong, Boon-Cher Goh, Jeff Settleman, Wanjin Hong, Elena Levantini, Daniel G. Tenen
Journal: Theranostics (2020)

Oncogene-addicted cancers are predominantly driven by specific oncogenic pathways and display initial exquisite sensitivity to designer therapies, but eventually become refractory to treatments. Clear understanding of lung tumorigenic mechanisms is essential for improved therapies. Methods: Lysosomes were analyzed in EGFR-WT and mutant cells and corresponding patient samples using immunofluorescence or immunohistochemistry and immunoblotting. Microtubule organization and dynamics were studied using immunofluorescence analyses. Also, we have validated our findings in a transgenic mouse model that contain EGFR-TKI resistant mutations. Results: We herein describe a novel mechanism that a mutated kinase disrupts the microtubule organization and results in a defective endosomal/lysosomal pathway. This prevents the efficient degradation of phosphorylated proteins that become trapped within the endosomes and continue to signal, therefore amplifying downstream proliferative and survival pathways. Phenotypically, a distinctive subcellular appearance of LAMP1 secondary to microtubule dysfunction in cells expressing EGFR kinase mutants is seen, and this may have potential diagnostic applications for the detection of such mutants. We demonstrate that lysosomal-inhibitors re-sensitize resistant cells to EGFR tyrosine-kinase inhibitors (TKIs). Identifying the endosome-lysosome pathway and microtubule dysfunction as a mechanism of resistance allows to pharmacologically intervene on this pathway. Conclusions: We find that the combination of microtubule stabilizing agent and lysosome inhibitor could reduce the tumor progression in EGFR TKI resistant mouse models of lung cancer.
Pharmacodynamic Analysis of BTK Inhibition in Patients with Chronic Lymphocytic Leukemia Treated with Acalabrutinib
Authors: Anfal Alsadhan, Jean Cheung, Michael Gulrajani, Erika M. Gaglione, Pia Nierman, Ahmed Hamdy, Raquel Izumi, Elena Bibikova, Priti Patel, Clare Sun, Todd Covey, Sarah E.M. Herman, Adrian Wiestner
Journal: Clinical Cancer Research (2020)

Abstract Purpose: To determine the pharmacodynamic relationship between target occupancy of Bruton tyrosine kinase (BTK) and inhibition of downstream signaling. Patients and Methods: Patients with chronic lymphocytic leukemia (CLL) enrolled in a phase II clinical trial (NCT02337829) with the covalent, selective BTK inhibitor acalabrutinib donated blood samples for pharmacodynamic analyses. Study design included randomization to acalabrutinib 100 mg twice daily or 200 mg once daily and dose interruptions on day 4 and 5 of the first week. BTK occupancy and readouts of intracellular signaling were assessed sequentially between 4 and 48 hours from last dose. Results: Four hours from last dose, BTK occupancy exceeded 96% and at trough, was higher with twice daily, median 95.3%, than with once daily dosing, median 87.6% (P &amp;lt; 0.0001). By 48 hours from last dose, median free BTK increased to 25.6%. Due to covalent binding of acalabrutinib, free BTK is generated by de novo synthesis. The estimated rate of BTK synthesis varied widely between patients ranging from 3.6% to 31.4% per day. Acalabrutinib reduced phosphorylation of BTK and inhibited downstream B-cell receptor (BCR) and NFκB signaling. During dosing interruptions up to 48 hours, expression of BCR target genes rebounded, while phosphorylation of signaling molecules remained repressed. In vitro cross-linking of IgM on CLL cells obtained 36 to 48 hours from last dose upregulated CD69, with high correlation between cellular free BTK and response (R = 0.7, P ≤ 0.0001). Conclusions: Higher BTK occupancy was achieved with twice daily over once daily dosing, resulting in deeper and more sustained inhibition of BCR signaling.
Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity
Authors: Nina Dumauthioz, Benjamin Tschumi, Mathias Wenes, Bastien Marti, Haiping Wang, Fabien Franco, Wenhui Li, Isabel C. Lopez-Mejia, Lluis Fajas, Ping-Chih Ho, Alena Donda, Pedro Romero, Lianjun Zhang
Journal: Cellular and Molecular Immunology (2020)

Abstract Memory CD8 T cells can provide long-term protection against tumors, which depends on their enhanced proliferative capacity, self-renewal and unique metabolic rewiring to sustain cellular fitness. Specifically, memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands. In contrast, tumor-infiltrating lymphocytes (TILs) display severe metabolic defects, which may underlie their functional decline. Here, we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1α expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1α maintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host. Altogether, our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation, metabolic fitness, and antitumor immunity in vivo.
ANCA-Associated Vasculitis — Refining Therapy with Plasma Exchange and Glucocorticoids
Authors: Vimal K. Derebail, Ronald J. Falk
Journal: New England Journal of Medicine (2020)

Plasma exchange has been a mainstay of induction therapy for patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis who have rapidly progressive glomerulonephritis or diffuse alveolar hemorrhage.1-3 Clinical data, in vitro data, and data from studies in animals have shown that ANCAs are pathogenic.4 Plasma exchange rapidly depletes pathogenic ANCAs and theoretically should diminish vascular injury and end-organ damage and hasten resolution of disease. In this issue of the Journal, Walsh et al. report the results of the PEXIVAS trial, a very large randomized clinical trial involving patients with ANCA-associated vasculitis (704 patients with a median follow-up of 2.9 years).5 The . . .
Smart Sorting of Tumor Phenotype with Versatile Fluorescent Ag Nanoclusters by Sensing Specific Reactive Oxygen Species
Authors: Xin Chen, Tiegong Wang, Wenjun Le, Xin Huang, Minghui Gao, Qian Chen, Shuogui Xu, Detao Yin, Qingge Fu, Chengwei Shao, Bingdi Chen, Donglu Shi
Journal: Theranostics (2020)

Reactive oxygen species (ROS) play a crucial role in cancer formation and development, especially cancer metastasis. However, lack of a precise tool, which could accurately distinguish specific types of ROS, restricts an in-depth study of ROS in cancer development and progression. Herein, we designed smart and versatile fluorescent Ag nanoclusters (AgNCs) for sensitive and selective detection of different species of ROS in cells and tissues. Methods: Firstly, dual-emission fluorescent AgNCs was synthesized by using bovine serum albumin (BSA) to sense different types of ROS (H2O2, O2•-, •OH). The responsiveness of the AgNCs to different species of ROS was explored by fluorescence spectrum, hydrodynamic diameter, and so on. Furthermore, dual-emission fluorescent AgNCs was used to sense ROS in tumor with different degrees of differentiation. Finally, the relationship between specific types of ROS and tumor cell invasion was explored by cell migration ability and the expression of cell adhesion and EMT markers. Results: This dual-emission fluorescent AgNCs possessed an excellent ability to sensitively and selectively distinguish highly reactive oxygen species (hROS, including O2•-and •OH) from moderate reactive oxygen species (the form of H2O2), and exhibited no fluoresence and green fluorescence, respectively. The emission of AgNCs is effective in detecting cellular and tissular ROS. When cultured with AgNCs, malignant tumor cells exhibit non-fluorescence, while the benign tumor emits green and reduced red light and the normal cells appear in weak green and bright red fluorescence. We further verified that not just H2O2 but specific species of ROS (O2•-and •OH) were involved in cell invasion and malignant transformation. Our study warrants further research on the role of ROS in physiological and pathophysiological processes. Conclusion: Taken together, AgNCs would be a promising approach for sensing ROS, and offer an intelligent tool to detect different kinds of ROS in tumors.
Comparison of Cardiovascular and Safety Outcomes of Chlorthalidone vs Hydrochlorothiazide to Treat Hypertension
Authors: George Hripcsak, Marc A. Suchard, Steven Shea, RuiJun Chen, Seng Chan You, Nicole Pratt, David Madigan, Harlan M. Krumholz, Patrick B. Ryan, Martijn J. Schuemie
Journal: JAMA Internal Medicine (2020)

Chlorthalidone is currently recommended as the preferred thiazide diuretic to treat hypertension, but no trials have directly compared risks and benefits.To compare the effectiveness and safety of chlorthalidone and hydrochlorothiazide as first-line therapies for hypertension in real-world practice.This is a Large-Scale Evidence Generation and Evaluation in a Network of Databases (LEGEND) observational comparative cohort study with large-scale propensity score stratification and negative-control and synthetic positive-control calibration on databases spanning January 2001 through December 2018. Outpatient and inpatient care episodes of first-time users of antihypertensive monotherapy in the United States based on 2 administrative claims databases and 1 collection of electronic health records were analyzed. Analysis began June 2018.Chlorthalidone and hydrochlorothiazide.The primary outcomes were acute myocardial infarction, hospitalization for heart failure, ischemic or hemorrhagic stroke, and a composite cardiovascular disease outcome including the first 3 outcomes and sudden cardiac death. Fifty-one safety outcomes were measured.Of 730 225 individuals (mean [SD] age, 51.5 [13.3] years; 450 100 women [61.6%]), 36 918 were dispensed or prescribed chlorthalidone and had 149 composite outcome events, and 693 337 were dispensed or prescribed hydrochlorothiazide and had 3089 composite outcome events. No significant difference was found in the associated risk of myocardial infarction, hospitalized heart failure, or stroke, with a calibrated hazard ratio for the composite cardiovascular outcome of 1.00 for chlorthalidone compared with hydrochlorothiazide (95% CI, 0.85-1.17). Chlorthalidone was associated with a significantly higher risk of hypokalemia (hazard ratio [HR], 2.72; 95% CI, 2.38-3.12), hyponatremia (HR, 1.31; 95% CI, 1.16-1.47), acute renal failure (HR, 1.37; 95% CI, 1.15-1.63), chronic kidney disease (HR, 1.24; 95% CI, 1.09-1.42), and type 2 diabetes mellitus (HR, 1.21; 95% CI, 1.12-1.30). Chlorthalidone was associated with a significantly lower risk of diagnosed abnormal weight gain (HR, 0.73; 95% CI, 0.61-0.86).This study found that chlorthalidone use was not associated with significant cardiovascular benefits when compared with hydrochlorothiazide, while its use was associated with greater risk of renal and electrolyte abnormalities. These findings do not support current recommendations to prefer chlorthalidone vs hydrochlorothiazide for hypertension treatment in first-time users was found. We used advanced methods, sensitivity analyses, and diagnostics, but given the possibility of residual confounding and the limited length of observation periods, further study is warranted.
How Does Aldosterone Work in the β-Intercalated Cell?
Authors: Jens Leipziger, Helle Praetorius
Journal: Journal of the American Society of Nephrology (2020)

Aldosterone is a steroid hormone produced by the cells of the zona glomerulosa in the adrenal glands serving both K+ and volume homeostasis. One key physiologic function is to guard our potassium homeostasis, and aldosterone is liberated in response to increased plasma levels of potassium.
Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney
Authors: Petra Simic, Wondong Kim, Wen Zhou, Kerry A. Pierce, Wenhan Chang, David B. Sykes, Najihah B. Aziz, Sammy Elmariah, Debby Ngo, Paola Divieti Pajevic, Nicolas Govea, Bryan R. Kestenbaum, Ian H. de Boer, Zhiqiang Cheng, Marta Christov, Jerold Chun, David E. Leaf, Sushrut S. Waikar, Andrew M. Tager, Robert E. Gerszten, Ravi I. Thadhani, Clary B. Clish, Harald Jüppner, Marc N. Wein, Eugene P. Rhee
Journal: Journal of Clinical Investigation (2020)

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography-mass spectrometry-based (LC-MS-based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase-mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.
In type 2 diabetes, early metformin plus vildagliptin reduced treatment failure vs a stepwise approach
Authors: Krysta Brown, Anthony A. Donato
Journal: Annals of Internal Medicine (2020)

Source Citation Matthews DR, Paldánius PM, Proot P, et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet. 2019;394:1519-29. 31542292