tbuckley/cabot-search huggingface dataset:
Aurora A Kinase Inhibition Destabilizes PAX3-FOXO1 and MYCN and Synergizes with Navitoclax to Induce Rhabdomyosarcoma Cell Death
Authors: Johannes Ommer, Joanna L. Selfe, Marco Wachtel, Eleanor M. O'Brien, Dominik Laubscher, Michaela Roemmele, Stephanie Kasper, Olivier Delattre, Didier Surdez, Gemma Petts, Anna Kelsey, Janet Shipley, Beat W. Schäfer
Journal: Cancer Research (2019)

Abstract The clinically aggressive alveolar rhabdomyosarcoma (RMS) subtype is characterized by expression of the oncogenic fusion protein PAX3-FOXO1, which is critical for tumorigenesis and cell survival. Here, we studied the mechanism of cell death induced by loss of PAX3-FOXO1 expression and identified a novel pharmacologic combination therapy that interferes with PAX3-FOXO1 biology at different levels. Depletion of PAX3-FOXO1 in fusion-positive (FP)-RMS cells induced intrinsic apoptosis in a NOXA-dependent manner. This was pharmacologically mimicked by the BH3 mimetic navitoclax, identified as top compound in a screen from 208 targeted compounds. In a parallel approach, and to identify drugs that alter the stability of PAX3-FOXO1 protein, the same drug library was screened and fusion protein levels were directly measured as a read-out. This revealed that inhibition of Aurora kinase A most efficiently negatively affected PAX3-FOXO1 protein levels. Interestingly, this occurred through a novel specific phosphorylation event in and binding to the fusion protein. Aurora kinase A inhibition also destabilized MYCN, which is both a functionally important oncogene and transcriptional target of PAX3-FOXO1. Combined treatment with an Aurora kinase A inhibitor and navitoclax in FP-RMS cell lines and patient-derived xenografts synergistically induced cell death and significantly slowed tumor growth. These studies identify a novel functional interaction of Aurora kinase A with both PAX3-FOXO1 and its effector MYCN, and reveal new opportunities for targeted combination treatment of FP-RMS. Significance: These findings show that Aurora kinase A and Bcl-2 family proteins are potential targets for FP-RMS.
Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study
Authors: Andrea Necchi, Marco Bandini, Giuseppina Calareso, Daniele Raggi, Filippo Pederzoli, Elena Farè, Maurizio Colecchia, Laura Marandino, Marco Bianchi, Andrea Gallina, Renzo Colombo, Nicola Fossati, Giorgio Gandaglia, Umberto Capitanio, Federico Dehò, Patrizia Giannatempo, Roberta Lucianò, Andrea Salonia, Russell Madison, Siraj M. Ali, Jon H. Chung, Jeffrey S. Ross, Alberto Briganti, Francesco Montorsi, Francesco De Cobelli, Antonella Messina
Journal: European Urology (2019)
Hispanic and Black Patients with Adult B-Cell Acute Lymphoblastic Leukemia Have a Significantly Worse Survival in the Modern Era - a SEER 2010-2016 Analysis
Authors: Nishi Shah, Mohammad Kazemi, Stephen Zachary Peeke, Lizamarie Bachier-rodriguez, R.Alejandro Sica, Noah Kornblum, Ira Braunschweig, Aditi Shastri, Amit Verma, Ioannis Mantzaris
Journal: Blood (2019)
Value of cell cycle progression (CCP) score to predict biochemical recurrence and definitive post-surgical pathology.
Authors: Thorsten Schlomm, Zaina Sangale, Jerry S. Lanchbury, Alexander Gutin, Julia E. Reid, Markus Graefen, Alexander Haese, Pierre Tennstedt, Stefan Steurer, Guido Sauter, Steven Stone
Journal: Journal of Clinical Oncology (2013)

5043 Background: Prostate cancer (PCA) has a highly variable natural history and better tools are needed to more appropriately match treatment to a patient’s risk of progression. A prognostic mRNA expression signature composed of genes involved in cell cycle progression (CCP) has been previously developed. Here, we tested the utility of this signature to predict biochemical recurrence (BCR) and definitive post-surgical pathological stage. Methods: The eligible patient population was treated for PCA by radical prostatectomy at a single high volume center (2005-2006). We randomly selected 390 patients for the study. From each patient we prepared a ‘simulated biopsy’ by removing a tissue cylinder (0.6mm) from the post-surgical FFPE block containing the largest tumor foci. 249 patients remained eligible for analysis after excluding patients for either insufficient tumor in the biopsy, poor quality molecular data, or receiving neoadjuvant therapy. The median follow-up time for patients who did not recur was 60.8 months. 46 patients experienced BCR. CCP scores were generated as in previous studies. Cox PH models and logistic regression were used to evaluate CCP associations with outcome. Results: The CCP signature was a highly significant univariate predictor of BCR (HR=2.03; 95%CI: 1.48-2.79; p=3.1x10 -5 ). After adjusting for clinical parameters including biopsy Gleason and PSA, the hazard ratio for CCP score remained significant (HR=1.6; 95%CI: 1.15-2.24; p=0.0068). In a multivariate model including PSA, biopsy Gleason, and clinical stage, CCP score was also an independent predictor of pathological stage (pT2 vs. pT3, p=0.029). In this analysis, PSA was the most predictive variable, but CCP score and clinical stage also provided important and non-redundant information. Conclusions: The CCP score has predicted PCA outcomes in multiple patient cohorts and different clinical settings. In this study, we have extended the demonstrated clinical utility to a modern patient cohort from Europe, and for the first time, provided evidence that the score can be used to predict definitive post-surgical tumor stage. The CCP expression score is an emerging and important component in evaluating PCA prognosis.
Deep Residual Neural Networks Resolve Quartet Molecular Phylogenies
Authors: Zhengting Zou, Hongjiu Zhang, Yuanfang Guan, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2019)

Phylogenetic inference is of fundamental importance to evolutionary as well as other fields of biology, and molecular sequences have emerged as the primary data for this task. Although many phylogenetic methods have been developed to explicitly take into account substitution models of sequence evolution, such methods could fail due to model misspecification or insufficiency, especially in the face of heterogeneities in substitution processes across sites and among lineages. In this study, we propose to infer topologies of four-taxon trees using deep residual neural networks, a machine learning approach needing no explicit modeling of the subject system and having a record of success in solving complex nonlinear inference problems. We train residual networks on simulated protein sequence data with extensive amino acid substitution heterogeneities. We show that the well-trained residual network predictors can outperform existing state-of-the-art inference methods such as the maximum likelihood method on diverse simulated test data, especially under extensive substitution heterogeneities. Reassuringly, residual network predictors generally agree with existing methods in the trees inferred from real phylogenetic data with known or widely believed topologies. Furthermore, when combined with the quartet puzzling algorithm, residual network predictors can be used to reconstruct trees with more than four taxa. We conclude that deep learning represents a powerful new approach to phylogenetic reconstruction, especially when sequences evolve via heterogeneous substitution processes. We present our best trained predictor in a freely available program named Phylogenetics by Deep Learning (PhyDL, https://gitlab.com/ztzou/phydl; last accessed January 3, 2020).
Use of Telehealth Expedites Evaluation and Listing of Patients Referred for Liver Transplantation
Authors: Binu V. John, Eleanor Love, Bassam Dahman, Nargiza Kurbanova, Venkata Rajesh Konjeti, Latha Thankam Sundaram, Yangyang Deng, Sean Aubuchon, Douglas Heuman, Jasmohan S. Bajaj, Hochong Gilles, Michael Chang, Rehan Qayyum, Mohammad S. Siddiqui
Journal: Clinical Gastroenterology and Hepatology (2019)
Efficacy and safety of balugrastim in chemotherapy-induced neutropenia: Integrated analysis of two randomized phase III studies.
Authors: Oleg Gladkov, Constantin D. Volovat, Steven Barash, Anton Buchner, Noa Avisar, Peter Bias, Udo W. Mueller
Journal: Journal of Clinical Oncology (2013)

e17572 Background: Balugrastim is a recombinant fusion protein composed of human serum albumin and human granulocyte colony-stimulating factor, which allows for once-per-chemotherapy cycle administration. We present a combined analysis of two double-blind, randomized Phase III studies comparing efficacy and safety of balugrastim vs pegfilgrastim in breast cancer patients receiving myelosuppressive chemotherapy (CTx). Methods: All patients were treated with doxorubicin 60 mg/m 2 followed by docetaxel 75 mg/m 2 administered by i.v. infusion on Day 1 of a 21-day cycle for up to 4 cycles. For each cycle, patients received a single s.c. injection of balugrastim approximately 24 hours after administration of CTx. The primary endpoint for both studies was duration of severe neutropenia (DSN) in Cycle 1. Safety of balugrastim was assessed by evaluating the type, frequency, and severity of adverse events (AEs); changes in laboratory parameters and vital signs, and immunogenicity over time. Analyses were performed in the per-protocol population. Results: A total of 469 patients were randomized to receive balugrastim 40 mg (N=235) or pegfilgrastim 6 mg (N=234). Mean DSN in Cycle 1 was 1.1±1.11 days in patients receiving balugrastim (n=236) and 1.0±1.14 days in patients receiving pegfilgrastim (n=234). Non-inferiority was demonstrated by statistical analysis for balugrastim vs pegfilgrastim for reduction in DSN across studies. Patients treated with balugrastim had a significantly shorter time to ANC recovery in Cycle 1 vs pegfilgrastim (2.0 vs 2.3 days; P=0.015). No other significant differences were seen between treatment groups in either study for any other secondary endpoints in Cycles 1–4. The safety profile was similar for both drugs, with the incidence of AEs consistent with the underlying medical condition and administration of myelosuppressive CTx. Conclusions: In both Phase III studies, non-inferiority was clearly demonstrated for balugrastim 40 mg vs pegfilgrastim 6 mg. Balugrastim is a safe and effective alternative to long-acting pegfilgrastim for reducing DSN in breast cancer patients receiving myelosuppressive chemotherapy. Clinical trial information: 2010-019001-42.
Anti‐Infective Application of Graphene‐Like Silicon Nanosheets via Membrane Destruction
Authors: Yao Luo, Min Ge, Han Lin, Renke He, Xiangwei Yuan, Chao Yang, Wei Wang, Xianlong Zhang
Journal: Advanced Healthcare Materials (2020)

Abstract The increasing problem of bacterial resistance to the currently effective antibiotics has resulted in the need for increasingly potent therapeutics to eradicate pathogenic microorganisms. 2D nanomaterials (2D NMs) have unique physical and chemical properties that make them attractive candidates for biomedical applications. Recently, the application of 2D NMs as antibacterial agents has attracted significant attention. Herein, a novel 2D graphene‐like silicon nanosheet (GS NS) antimicrobial agent is fabricated from pristine silicon crystals by ultrasonication, which results in a highly exfoliated planar morphology and a significantly larger surface area as compared with bulk silicon. The GS NSs exhibit remarkable in vitro broad‐spectrum bactericidal activity against Gram (−) Escherichia coli and Gram (+) Staphylococcus aureus because of a close interaction with the bacteria, which leads to highly efficient membrane destruction. The in vivo studies demonstrate that the local administration of GS NSs effectively mitigates implant‐related infection by reducing the bacterial burden of the extracted samples and accelerating the remission of local inflammation. Based on these encouraging results, GS NSs are expected to be a useful new member of the 2D NMs family, with the potential of effectively killing pathogenic bacteria in clinical applications.
Case 40-2019: A 26-Year-Old Returning Traveler with Headache
Authors: Geren S. Stone, McKinley Glover, Nikolaus Jilg, Maroun M. Sfeir
Journal: New England Journal of Medicine (2019)

A 26-year-old woman presented to the hospital because of headache that developed during a winter vacation in Europe. Analysis of cerebrospinal fluid revealed 1422 total nucleated cells per microliter (of which 85% were lymphocytes), a glucose level of 28 mg per deciliter, and a total protein level of 680 mg per deciliter. A diagnostic test result was received.
CBMT-37. OSMR CONTROLS CELLULAR RESPIRATION AND RESISTANCE TO THERAPY
Authors: Ahmad Sharanek, Audrey Burban, Arezu Jahani-Asl
Journal: Neuro-Oncology (2019)

Abstract Cytokines and their receptors play important roles in the regulation of cell fate, inflammation and immunity. The cytokine receptor for Oncostatin M (OSMR) drives brain tumor stem cell (BTSC) proliferation and tumorigenesis. Here, we report a novel role for OSMR in regulation of cellular respiration. Genetic knockdown of OSMR in BTSCs impairs mitochondrial biogenesis and oxidative phosphorylation. Importantly, blockade of OSMR signalling in BTSCs sensitizes them to ionizing radiation and Temozolomide in vitro and in vivo. This mechanism whereby OSMR regulates mitochondrial respiration and metabolism is conserved in post-mitotic neutrons. Thus, while OSMR is required for BTSC proliferation, OSMR confers resistance to therapy via enhancing mitochondrial respiration, independent of its role in proliferation. Our data suggest that therapeutic targeting of OSMR may be beneficial to eradicate quiescent tumour stem cells and tumour relapse.
A prospective study of costs associated to the evaluation of non‐steroidal anti‐inflammatory hypersensitivity reactions
Authors: Miriam Sobrino‐García, Francisco J. Muñoz‐Bellido, Esther Moreno, Eva Macías, María‐Teresa Gracia‐Bara, Elena Laffond, Milagros Lázaro‐Sastre, Cristina Martín‐García, Sonia de Arriba‐Méndez, María‐Valle Campanón‐Toro, Alicia Gallardo‐Higueras, Ignacio Dávila
Journal: Allergy (2019)

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TMTP1-modified Indocyanine Green-loaded Polymeric Micelles for Targeted Imaging of Cervical Cancer and Metastasis Sentinel Lymph Node<i> in vivo</i>
Authors: Rui Wei, Guiying Jiang, MengQin Lv, Songwei Tan, Xueqian Wang, Ying Zhou, Teng Cheng, Xueqin Gao, Xi Chen, Wei Wang, Chenming Zou, Fei Li, Xiangyi Ma, Junbo Hu, Ding Ma, Danfeng Luo, Ling Xi
Journal: Theranostics (2019)

Metastasis is one of the most threatening aspects of cervical cancer. We developed a method to intraoperatively map the primary tumor, metastasis and metastatic sentinel lymph nodes (SLNs), providing real-time intraoperative guidance in cervical cancer. Methods: TMTP1, a tumor metastasis targeting peptide, was employed to modify the indocyanine green (ICG)-loaded poly (ethylene glycol)- poly (lactic-co-glycolic acid) (PEG-PLGA) micelles. The cervical cancer subcutaneous tumor model and lung metastasis model were established to determine the active targeting of ICG-loaded TMTP1-PEG-PLGA micelles (ITM) for the primary tumor and occult metastasis of cervical cancer. Human cervical cancer HeLa cells engineered by firefly luciferase were injected into the right hocks of BALB/c nude mice to develop the SLN metastasis model. The ITM and control ICG-loaded PEG-PLGA micelles (IM) were injected into the right hind footpads in the SLN metastasis model, and the migration and retention of micelles were recorded under near-infrared fluorescence. K14-HPV16 transgenic mice were also used to detect the image capability of ITM to target cancerous lesions. Results: ITM could actively target imaging of the primary tumor and cervical cancer metastasis. ITM quickly diffused from the injection site to SLNs along lymphatic capillaries and remained in the SLNs for 12 h. Moreover, ITM specifically accumulated in the tumor metastatic SLNs (T-SLNs), which could be successfully distinguished from normal SLNs (N-SLNs). Conclusion: ITM could achieve active targeting of the primary tumor, metastasis and T-SLNs, providing precise and real-time intraoperative guidance for cervical cancer.
A Sober Reality? Alcohol, Abstinence, and Atrial Fibrillation
Authors: Anne M. Gillis
Journal: New England Journal of Medicine (2020)

Atrial fibrillation is the most common sustained arrhythmia and is associated with significant morbidity, including an increased risk of stroke and death. The prevalence of atrial fibrillation is predicted to at least double over the next 4 decades. This emerging atrial fibrillation epidemic is fueled by the aging of the population, as well as lifestyle factors including more sedentary activity and a substantial increase in obesity worldwide.1 These factors are associated with an increase in hypertension, type 2 diabetes mellitus, and obstructive sleep apnea, all of which are important risk factors for atrial fibrillation. The treatment of atrial fibrillation has . . .
Primary Care Practitioners’ Perspectives on Burnout and What to Do About It
Authors: Richard W. Grant, Lara Goitein
Journal: JAMA Internal Medicine (2020)

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Social disconnectedness, perceived isolation, and symptoms of depression and anxiety among older Americans (NSHAP): a longitudinal mediation analysis
Authors: Ziggi Ivan Santini, Paul E Jose, Erin York Cornwell, Ai Koyanagi, Line Nielsen, Carsten Hinrichsen, Charlotte Meilstrup, Katrine R Madsen, Vibeke Koushede
Journal: The Lancet Public Health (2020)

Research indicates that social isolation and loneliness increase the risk of mental disorders, but less is known about the distinct contributions of different aspects of isolation. We aimed to distinguish the pathways through which social disconnectedness (eg, small social network, infrequent social interaction) and perceptions of social isolation (eg, loneliness, perceived lack of support) contribute to anxiety and depression symptom severity in community-residing older adults aged 57-85 years at baseline.We did a longitudinal mediation analysis with data from the National Social Life, Health, and Aging Project (NSHAP). The study included individuals from the USA born between 1920 and 1947. Validated measures on social disconnectedness, perceived isolation, and depression and anxiety symptoms were used. Structural equation modelling was used to construct complete longitudinal path models.Using data from 3005 adults aged 57-85 years, we identified two significant longitudinal mediation patterns with symptoms of depression, and two with anxiety symptoms. Overall, social disconnectedness predicted higher subsequent perceived isolation (β=0·09; p<0·0001), which in turn predicted higher depression symptoms (β=0·12; p<0·0001) and anxiety symptoms (β=0·12; p<0·0001). The reverse pathways were statistically supported as well, suggesting bi-directional influences.Social network structure and function are strongly intertwined with anxiety and depression symptoms in the general population of older adults. Public health initiatives could reduce perceived isolation by facilitating social network integration and participation in community activities, thereby protecting against the development of affective disorders.Nordea-fonden.
Abstract 17: Cognitive, Psychological, and Functional Limitations After Sudden Cardiac Arrest Among a Racially and Ethnically Diverse United States Population
Authors: Sachin Agarwal, Evie Sobczak, Alex Presciutti, David Roh, Soojin Park, Jan Claassen, Mitchell S Elkind, Donald Edmondson
Journal: Circulation (2019)

Background: To estimate the frequency of post-sudden cardiac arrest survivorship (PSCAS) problems (i.e., cognitive impairment, disability in activities of daily living, depression and posttraumatic stress disorder (PTSD)). Methods: We prospectively enrolled adults with return of spontaneous circulation after in-hospital or out-of-hospital CA between 9/2015-8/2018 at a high-volume, major academic center. A consecutive sample of survivors at hospital discharge and at one-year follow-up able to engage in the Repeatable Battery for Neuropsychological Status (RBANS) or Telephone Interview for Cognitive Status (TICS), Barthel Index (BI) as a measure of disability, Center for Epidemiological Studies Depression Scale (CES-D), and PTSD Checklist - Specific (PCL-S) were included. Results: Of 159 patients included, average age was 54±15 years, 41% were women, 30% identified themselves as Latinos and 18% as African-American. There were 14 deaths and 13 lost to follow-up at one-year. As shown in table 1, 1 out of 2 patients at discharge, and 1 out of 4 at one-year had global cognition scores similar to scores for patients with moderate traumatic brain injury and patients with mild Alzheimer’s disease, respectively. The majority had physical disability at hospital discharge, which showed improvement within one-year. A significant proportion of patients experienced depressive and PTSD symptoms at hospital discharge and the symptoms persisted at one-year. Conclusions: In a racial and ethnically diverse cohort in a major academic center in the US, one or more PSCAS problems were present and persisted in the majority of CA survivors, and co-occurring problems were present in one out of four at one-year. Future studies are needed to understand better the heterogeneous subtypes of PCAS and to identify modifiable risk factors and potential ameliorating factors. Table 1. Estimates of post-sudden cardiac arrest survivorship problems at discharge and one-year
Ceramides: A Cause of Insulin Resistance in Nonalcoholic Fatty Liver Disease in Both Murine Models and Humans
Authors: Hannele Yki‐Järvinen
Journal: Hepatology (2020)

Yki‐Järvinen, Hannele M.D., F.R.C.P.Editor(s): Corey, Kathleen E.3; Malhi, Harmeet4 Author Information