tbuckley/cabot-search huggingface dataset:
Personalized predictions of patient outcomes during and after hospitalization using artificial intelligence
Authors: C. Beau Hilton, Alex Milinovich, Christina Felix, Nirav Vakharia, Timothy Crone, Chris Donovan, Andrew Proctor, Aziz Nazha
Journal: npj Digital Medicine (2020)

Hospital systems, payers, and regulators have focused on reducing length of stay (LOS) and early readmission, with uncertain benefit. Interpretable machine learning (ML) may assist in transparently identifying the risk of important outcomes. We conducted a retrospective cohort study of hospitalizations at a tertiary academic medical center and its branches from January 2011 to May 2018. A consecutive sample of all hospitalizations in the study period were included. Algorithms were trained on medical, sociodemographic, and institutional variables to predict readmission, length of stay (LOS), and death within 48-72 h. Prediction performance was measured by area under the receiver operator characteristic curve (AUC), Brier score loss (BSL), which measures how well predicted probability matches observed probability, and other metrics. Interpretations were generated using multiple feature extraction algorithms. The study cohort included 1,485,880 hospitalizations for 708,089 unique patients (median age of 59 years, first and third quartiles (QI) [39, 73]; 55.6% female; 71% white). There were 211,022 30-day readmissions for an overall readmission rate of 14% (for patients ≥65 years: 16%). Median LOS, including observation and labor and delivery patients, was 2.94 days (QI [1.67, 5.34]), or, if these patients are excluded, 3.71 days (QI [2.15, 6.51]). Predictive performance was as follows: 30-day readmission (AUC 0.76/BSL 0.11); LOS > 5 days (AUC 0.84/BSL 0.15); death within 48-72 h (AUC 0.91/BSL 0.001). Explanatory diagrams showed factors that impacted each prediction.
Pedigree analysis of a POLD1 germline mutation in urothelial carcinoma shows a close association between different mutation burdens and overall survival
Authors: Yejinpeng Wang, Lingao Ju, Zicheng Guo, Kaiyu Qian, Hongbo Chen, Yi Zhang, Yu Xiao, Xinghuan Wang
Journal: Cellular and Molecular Immunology (2020)
The financial implications of a conversion from enoxaparin to dalteparin as the LMWH of choice at a comprehensive cancer center
Authors: S. G. Patterson, P. Johnson, B. Bradbury, J. Tata, R. Quilitz, R. Carlton, T. Bramley, G. Wetzstein
Journal: Journal of Clinical Oncology (2009)

e17566 Background: To assess the financial implications of a conversion from enoxaparin to dalteparin as the low molecular weight heparin (LMWH) of choice at a large, comprehensive cancer center. Methods: A full class review of LMWH's was conducted in September of 2007 resulting in dalteparin replacing enoxaparin as the LMWH of choice. The Pharmacy and Therapeutics Committee approved automatic substitution with notification of the prescribing physician. The one exception to the policy was conversion if the patient was on enoxaparin at home, the policy would allow for continuation of therapy. Once the policy was approved, laminated dosing conversion cards and pre-printed order sets were developed. Multiple in-services were held prior to the official conversion date of October 15, 2007, to address any issues and to facilitate the conversion. Cost comparisons were made within individual settings adjusting for utilization levels. Results: In the fiscal year prior to the conversion from enoxaparin to dalteparin the cancer center purchased nearly $360,000 of enoxaparin for the inpatient and infusion center settings. In the year following the LMWH change, the total projected cost for LMWHs is $244,000, resulting in a 32% cost savings of $115,000. Conclusions: The change from enoxaparin to dalteparin resulted in significant cost savings for the cancer center. Additional studies are underway to examine the clinical outcomes of the LMWH change. No significant financial relationships to disclose.
Toll‐Like Receptor 8 Agonist GS‐9688 Induces Sustained Efficacy in the Woodchuck Model of Chronic Hepatitis B
Authors: Stephane Daffis, Scott Balsitis, Jason Chamberlain, Jim Zheng, Rex Santos, William Rowe, Dhivya Ramakrishnan, Divya Pattabiraman, Sandra Spurlock, Ruth Chu, Don Kang, Michael Mish, Ricardo Ramirez, Li Li, Bei Li, Sarina Ma, Magdeleine Hung, Christian Voitenleitner, Changsuek Yon, Manasa Suresh, Stephan Menne, Paul Cote, William E. Delaney, Richard Mackman, Simon P. Fletcher
Journal: Hepatology (2020)

Background and Aims GS‐9688 (selgantolimod) is an oral selective small molecule agonist of toll‐like receptor 8 in clinical development for the treatment of chronic hepatitis B. In this study, we evaluated the antiviral efficacy of GS‐9688 in woodchucks chronically infected with woodchuck hepatitis virus (WHV), a hepadnavirus closely related to hepatitis B virus. Approach and Results WHV‐infected woodchucks received eight weekly oral doses of vehicle, 1 mg/kg GS‐9688, or 3 mg/kg GS‐9688. Vehicle and 1 mg/kg GS‐9688 had no antiviral effect, whereas 3 mg/kg GS‐9688 induced a &gt;5 log 10 reduction in serum viral load and reduced WHV surface antigen (WHsAg) levels to below the limit of detection in half of the treated woodchucks. In these animals, the antiviral response was maintained until the end of the study (&gt;5 months after the end of treatment). GS‐9688 treatment reduced intrahepatic WHV RNA and DNA levels by &gt;95% in animals in which the antiviral response was sustained after treatment cessation, and these woodchucks also developed detectable anti‐WHsAg antibodies. The antiviral efficacy of weekly oral dosing with 3 mg/kg GS‐9688 was confirmed in a second woodchuck study. The antiviral response to GS‐9688 did not correlate with systemic GS‐9688 or cytokine levels but was associated with transient elevation of liver injury biomarkers and enhanced proliferative response of peripheral blood mononuclear cells to WHV peptides. Transcriptomic analysis of liver biopsies taken prior to treatment suggested that T follicular helper cells and various other immune cell subsets may play a role in the antiviral response to GS‐9688. Conclusions Finite, short‐duration treatment with a clinically relevant dose of GS‐9688 is well tolerated and can induce a sustained antiviral response in WHV‐infected woodchucks; the identification of a baseline intrahepatic transcriptional signature associated with response to GS‐9688 treatment provides insights into the immune mechanisms that mediate this antiviral effect.
Peptides as surface coatings of nanoparticles that penetrate human cystic fibrosis sputum and uniformly distribute in vivo following pulmonary delivery
Authors: Jasmim Leal, Xiujuan Peng, Xinquan Liu, Dhivya Arasappan, Dennis C. Wylie, Sarah H. Schwartz, Jason J. Fullmer, Bennie C. McWilliams, Hugh D.C. Smyth, Debadyuti Ghosh
Journal: Journal of Controlled Release (2020)
Salivary gland macrophages and tissue-resident CD8 <sup>+</sup> T cells cooperate for homeostatic organ surveillance
Authors: Bettina Stolp, Flavian Thelen, Xenia Ficht, Lukas M. Altenburger, Nora Ruef, V. V. G. Krishna Inavalli, Philipp Germann, Nicolas Page, Federica Moalli, Andrea Raimondi, Kirsten A. Keyser, S. Morteza Seyed Jafari, Francesca Barone, Matthias S. Dettmer, Doron Merkler, Matteo Iannacone, James Sharpe, Christoph Schlapbach, Oliver T. Fackler, U. Valentin Nägerl, Jens V. Stein
Journal: Science Immunology (2020)

Salivary gland memory CD8 + T cells use distinct motility modes and cooperate with tissue macrophages for organ surveillance.
Physical Therapy before the Needle for Osteoarthritis of the Knee
Authors: Kim L. Bennell, David J. Hunter
Journal: New England Journal of Medicine (2020)

Clinical guidelines for the treatment of osteoarthritis of the knee emphasize education, exercise, and (if appropriate) weight loss, rather than the use of drugs or surgery.1,2 However, a survey conducted in four European countries showed that these treatments were recommended to fewer than half the patients; stronger painkillers were recommended in 52% of patients, and 36% were referred for surgery.3 Intraarticular glucocorticoid injections are commonly used to treat osteoarthritis of the knee, partly because they are easy to administer, they involve fewer visits than other treatments, and patient adherence is not an issue. But benefits may be short-lived, and adverse . . .
Endothelial Palmitoylation Cycling Coordinates Vessel Remodeling in Peripheral Artery Disease
Authors: Xiaochao Wei, Sangeeta Adak, Mohamed Zayed, Li Yin, Chu Feng, Sarah L. Speck, Rahul S. Kathayat, Qiang Zhang, Bryan C. Dickinson, Clay F. Semenkovich
Journal: Circulation Research (2020)

Rationale: Peripheral artery disease, common in metabolic syndrome and diabetes mellitus, responds poorly to medical interventions and is characterized by chronic vessel immaturity leading to lower extremity amputations. Objective: To define the role of reversible palmitoylation at the endothelium in the maintenance of vascular maturity. Methods and Results: Endothelial knockout of the depalmitoylation enzyme APT-1 (acyl-protein thioesterase 1) in mice impaired recovery from chronic hindlimb ischemia, a model of peripheral artery disease. Endothelial APT-1 deficiency decreased fibronectin processing, disrupted adherens junctions, and inhibited in vitro lumen formation. In an unbiased palmitoylation proteomic screen of endothelial cells from genetically modified mice, R-Ras, known to promote vessel maturation, was preferentially affected by APT-1 deficiency. R-Ras was validated as an APT-1 substrate, and click chemistry analyses demonstrated increased R-Ras palmitoylation in cells with APT-1 deficiency. APT-1 enzyme activity was decreased in endothelial cells from db/db mice. Hyperglycemia decreased APT-1 activity in human umbilical vein endothelial cells, due, in part, to altered acetylation of the APT-1 protein. Click chemistry analyses demonstrated increased R-Ras palmitoylation in the setting of hyperglycemia. Altered R-Ras trafficking, increased R-Ras palmitoylation, and fibronectin retention were found in diabetes mellitus models. Loss of R-Ras depalmitoylation caused by APT-1 deficiency constrained R-Ras membrane trafficking, as shown by total internal reflection fluorescence imaging. To rescue cellular phenotypes, we generated an R-Ras molecule with an inserted hydrophilic domain to circumvent membrane rigidity caused by defective palmitoylation turnover. This modification corrected R-Ras membrane trafficking, restored fibronectin processing, increased adherens junctions, and rescued defective lumen formation induced by APT-1 deficiency. Conclusions: These results suggest that endothelial depalmitoylation is regulated by the metabolic milieu and controls plasma membrane partitioning to maintain vascular homeostasis.
Targeted Inhibition of the E3 Ligase SCFSkp2/Cks1 Has Antitumor Activity in <i>RB1</i>-Deficient Human and Mouse Small-Cell Lung Cancer
Authors: Hongling Zhao, Niloy J. Iqbal, Vineeth Sukrithan, Cari Nicholas, Yingjiao Xue, Cindy Yu, Joseph Locker, Juntao Zou, Edward L. Schwartz, Liang Zhu
Journal: Cancer Research (2020)

Abstract The RB1 tumor suppressor gene is mutated in highly aggressive tumors including small-cell lung cancer (SCLC), where its loss, along with TP53, is required and sufficient for tumorigenesis. While RB1-mutant cells fail to arrest at G1–S in response to cell-cycle restriction point signals, this information has not led to effective strategies to treat RB1-deficient tumors, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/Trp53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, which was confirmed as the mechanism of protection by using knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind/inhibit Skp2 have in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using genetic and pharmacologic approaches, antitumor activity was seen with Skp2 loss or inhibition in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. Our data highlight a downstream actionable target in RB1-deficient cancers, for which there are currently no targeted therapies available. Significance: There are no effective therapies for SCLC. The identification of an actionable target downstream of RB1, inactivated in SCLC and other advanced tumors, could have a broad impact on its treatment.
Clinical course of COVID-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies
Authors: Sara Monti, Silvia Balduzzi, Paolo Delvino, Elisa Bellis, Verdiana Serena Quadrelli, Carlomaurizio Montecucco
Journal: Annals of the Rheumatic Diseases (2020)

Table 1 Clinical characteristics of the patients with confirmed or suspected COVID-19 Confirmed COVID-19 Clinical picture highly suggestive of COVID-19 Contact with a known COVID-19 patient Number of patients 4 4 5 Age (years) (mean±SD) 58±5 56±8 54±12 Female, n (%) 4 (100) 3 (75) 4 (80) Comorbidities, n (%) Hypertension 1 (25) 2 (50) 1 (20) Diabetes 0 0 0 Cardiovascular disease 0 0 1 (20) Other 4 (100) 4 (100) 3 (60) Smoking, n (%)
Quality of Surgery and Outcome in Localized Gastrointestinal Stromal Tumors Treated Within an International Intergroup Randomized Clinical Trial of Adjuvant Imatinib
Authors: Alessandro Gronchi, Sylvie Bonvalot, Andres Poveda Velasco, Dusan Kotasek, Piotr Rutkowski, Peter Hohenberger, Elena Fumagalli, Ian R. Judson, Antoine Italiano, Hans J. Gelderblom, Frits van Coevorden, Nicolas Penel, Hans-Georg Kopp, Florence Duffaud, David Goldstein, Javier Martin Broto, Eva Wardelmann, Sandrine Marréaud, Mark Smithers, Axel Le Cesne, Facundo Zaffaroni, Saskia Litière, Jean-Yves Blay, Paolo G. Casali
Journal: JAMA Surgery (2020)

The association between quality of surgery and overall survival in patients affected by localized gastrointestinal stromal tumors (GIST) is not completely understood.To assess the risk of death with and without imatinib according to microscopic margins status (R0/R1) using data from a randomized study on adjuvant imatinib.This is a post hoc observational study on patients included in the randomized, open-label, phase III trial, performed between December 2004 and October 2008. Median follow-up was 9.1 years (IQR, 8-10 years). The study was performed at 112 hospitals in 12 countries. Inclusion criteria were diagnosis of primary GIST, with intermediate or high risk of relapse; no evidence of residual disease after surgery; older than 18 years; and no prior malignancies or concurrent severe/uncontrolled medical conditions. Data were analyzed between July 17, 2017, and March 1, 2020.Patients were randomized after surgery to either receive imatinib (400 mg/d) for 2 years or no adjuvant treatment. Randomization was stratified by center, risk category (high vs intermediate), tumor site (gastric vs other), and quality of surgery (R0 vs R1). Tumor rupture was included in the R1 category but also analyzed separately.Primary end point of this substudy was overall survival (OS), estimated using Kaplan-Meier method and compared between R0/R1 using Cox models adjusted for treatment and stratification factors.A total of 908 patients were included; 51.4% were men (465) and 48.6% were women (440), and the median age was 59 years (range, 18-89 years). One hundred sixty-two (17.8%) had an R1 resection, and 97 of 162 (59.9%) had tumor rupture. There was a significant difference in OS for patients undergoing an R1 vs R0 resection, overall (hazard ratio [HR], 2.05; 95% CI, 1.45-2.89) and by treatment arm (HR, 2.65; 95% CI, 1.37-3.75 with adjuvant imatinib and HR, 1.86; 95% CI, 1.16-2.99 without adjuvant imatinib). When tumor rupture was excluded, this difference in OS between R1 and R0 resections disappeared (HR, 1.05; 95% CI, 0.54-2.01).The difference in OS by quality of surgery with or without imatinib was associated with the presence of tumor rupture. When the latter was excluded, the presence of R1 margins was not associated with worse OS.ClinicalTrials.gov Identifier: NCT00103168.
Cooperation as an alternative to nationalisation of the pharmaceutical industry
Authors: Jonathan R Denfhy
Journal: BMJ (2020)

Head to Head, 7 March

Serial title in print: Drug industry debate

Mazzucato and Li, and Darzi provide compelling arguments for and against the nationalisation of the pharmaceutical industry.1 Mazzucato and Li’s argument regarding the “short termism and misalignment of public interest” are justified criticisms of big pharma, and Darzi’s counter on the singular financial power that these companies wield is an effective response. This argument is not, however, the …
Improved melanoma suppression with target-delivered TRAIL and Paclitaxel by a multifunctional nanocarrier
Authors: Shiqi Huang, Yicong Zhang, Luyao Wang, Wei Liu, Linyu Xiao, Qing Lin, Tao Gong, Xun Sun, Qin He, Zhirong Zhang, Ling Zhang
Journal: Journal of Controlled Release (2020)
Coreceptor blockade targeting CD4 and CD8 allows acceptance of allogeneic human pluripotent stem cell grafts in humanized mice
Authors: Jiatao Li, Xisheng Li, Cai Liang, Lijun Ling, Zhiwei Chen, Chun Kwok Wong, Herman Waldmann, Kathy O. Lui
Journal: Biomaterials (2020)

We have previously demonstrated that short-term coreceptor blockade with non-lytic monoclonal antibodies enables the long-term survival of fully allogeneic embryonic stem cell (ESC) transplants in mice. Here, we describe the use of Hu-PBL humanized mice to determine whether short-term coreceptor blockade with humanized anti-human CD4 and CD8 antibodies can achieve the same outcome towards human ESC derivatives. While control Hu-PBL mice rejected allogeneic hESC-derived transplants within weeks, mice treated with coreceptor blocking antibodies held their grafts for 7 weeks, the duration of the study. Rejection in the control mice was associated with demonstrable infiltrates of human CD45 white blood cells, predominantly of CD8 T-cells, whereas anti-CD4, but not anti-CD8 antibody treated mice showed remarkably reduced lymphocyte infiltration and prolonged allograft survival, indicating that the CD4+ T-cells were crucial to the rejection process. Our results give support to the principle that short-term blockade of T-cell co-receptors can achieve long-term acceptance of regenerative cell transplants in humans.
A different vision of translational research in biomarker discovery: a pilot study on circulatory mitochondrial proteins as Parkinson’s disease potential biomarkers
Authors: Sandra I. Anjo, Patrícia Valério dos Santos, Luiza Rosado, Graça Baltazar, Inês Baldeiras, Diana Pires, Andreia Gomes, Cristina Januário, Miguel Castelo-Branco, Mário Grãos, Bruno Manadas
Journal: Translational Neurodegeneration (2020)

Abstract Background The identification of circulating biomarkers that closely correlate with Parkinson’s Disease (PD) has failed several times in the past. Nevertheless, in this pilot study, a translational approach was conducted, allowing the evaluation of the plasma levels of two mitochondrial-related proteins, whose combination leads to a robust model with potential diagnostic value to discriminate the PD patients from matched controls. Methods The proposed translational approach was initiated by the analysis of secretomes from cells cultured under control or well-defined oxidative stress conditions, followed by the identification of proteins related to PD pathologic mechanisms that were altered between the two states. This pipeline was further translated into the analysis of undepleted plasma samples from 28 control and 31 PD patients. Results From the secretome analysis, several mitochondria-related proteins were found to be differentially released between control and stress conditions and to be able to distinguish the two secretomes. Similarly, two mitochondrial-related proteins were found to be significantly changed in a PD cohort compared to matched controls. Moreover, a linear discriminant model with potential diagnostic value to discriminate PD patients was obtained using the combination of these two proteins. Both proteins are associated with apoptotic mitochondrial changes, which may correspond to potential indicators of cell death. Moreover, one of these proteins, the VPS35 protein, was reported in plasma for the first time, and its quantification was only possible due to its previous identification in the secretome analysis. Conclusions In this work, an adaptation of a translational pipeline for biomarker selection was presented and transposed to neurological diseases, in the present case Parkinson’s Disease. The novelty and success of this pilot study may arise from the combination of: i) a translational research pipeline, where plasma samples are interrogated using knowledge previously obtained from the evaluation of cells’ secretome under oxidative stress; ii) the combined used of statistical analysis and an informed selection of candidates based on their link with relevant disease mechanisms, and iii) the use of SWATH-MS, an untargeted MS method that allows a complete record of the analyzed samples and a targeted data extraction of the quantitative values of proteins previously identified.
Trends in Marijuana Vaping and Edible Consumption From 2015 to 2018 Among Adolescents in the US
Authors: Megan E. Patrick, Richard A. Miech, Deborah D. Kloska, Anna C. Wagner, Lloyd D. Johnston
Journal: JAMA Pediatrics (2020)

also associated with several psychological symptoms among students in China. 6findings suggest that serious infectious diseases may influence the mental health of children as other traumatic experiences do.A limitation is that our current study could not evaluate whether these outcomes will be long-lasting after the COVID-19 outbreak.We will continue to follow up with these participants to improve our understanding about how long those outcomes will last.A better understanding of how the epidemic affects students' mental health can help guide future interventions.
Honing in on PARPi Response in Prostate Cancer: from HR Pathway to Gene-by-Gene Granularity
Authors: Alexandra O. Sokolova, Evan Y. Yu, Heather H. Cheng
Journal: Clinical Cancer Research (2020)

PARP inhibitors (PARPi) are promising in BRCA2-altered prostate cancer. Data were presented on PARPi efficacy in prostate cancers with alterations in other DNA damage repair genes which suggest low response rates in ATM-, CHEK2-, CDK12-altered tumors and promising results in PALB2-, RAD51B-, FANCA-, and BRIP1-altered tumors.See related article by Abida et al., p. 2487.