tbuckley/cabot-search huggingface dataset:
Precision Oncology: Between Vaguely Right and Precisely Wrong
Authors: Amy Brock, Sui Huang
Journal: Cancer Research (2017)

Abstract Precision Oncology seeks to identify and target the mutation that drives a tumor. Despite its straightforward rationale, concerns about its effectiveness are mounting. What is the biological explanation for the "imprecision?" First, Precision Oncology relies on indiscriminate sequencing of genomes in biopsies that barely represent the heterogeneous mix of tumor cells. Second, findings that defy the orthodoxy of oncogenic "driver mutations" are now accumulating: the ubiquitous presence of oncogenic mutations in silent premalignancies or the dynamic switching without mutations between various cell phenotypes that promote progression. Most troublesome is the observation that cancer cells that survive treatment still will have suffered cytotoxic stress and thereby enter a stem cell–like state, the seeds for recurrence. The benefit of “precision targeting” of mutations is inherently limited by this counterproductive effect. These findings confirm that there is no precise linear causal relationship between tumor genotype and phenotype, a reminder of logician Carveth Read's caution that being vaguely right may be preferable to being precisely wrong. An open-minded embrace of the latest inconvenient findings indicating nongenetic and "imprecise" phenotype dynamics of tumors as summarized in this review will be paramount if Precision Oncology is ultimately to lead to clinical benefits. Cancer Res; 77(23); 6473–9. ©2017 AACR.
High Costs of FDA Approval for Formerly Unapproved Marketed Drugs
Authors: Aaron Hakim, Ravi Gupta, Joseph S. Ross
Journal: JAMA (2017)

This Viewpoint describes how the US Food and Drug Administration's 2006 Unapproved Drugs Initiative may have unintentionally made generic drugs more expensive and inaccessible and proposes policy reforms to address the harms of those price increases.
Abstract 19102: Cell Injection Site Influences the Human Mesenchymal Stem Cell Therapy Effectiveness for Left Ventricular Dysfunction in Ischemic Cardiomyopathy
Authors: Angela M Castellanos, Wayne Balkan, Darcy L DiFede, Joshua M Hare
Journal: Circulation (2016)

Introduction: Clinical trials have shown that trans-endocardial stem cell injection (TESI) of mesenchymal stem cells (MSC) both reduced myocardial infarct scars and normalizes cardiac sphericity, 2...
Lactadherin promotes microvesicle clearance to prevent coagulopathy and improves survival of severe TBI mice
Authors: Yuan Zhou, Wei Cai, Zilong Zhao, Tristan Hilton, Min Wang, Jason Yeon, Wei Liu, Fangyi Zhang, Fu-Dong Shi, Xiaoping Wu, Perumal Thiagarajan, Min Li, Jianning Zhang, Jing-fei Dong
Journal: Blood (2017)
Physicians and Advanced Practitioners Specializing in Nursing Home Care, 2012-2015
Authors: Kira L. Ryskina, Daniel Polsky, Rachel M. Werner
Journal: JAMA (2017)

This study characterizes trends in the use by nursing homes of nursing home specialists (defined as generalist physicians, nurse practitioners, and physician assistants) who billed at least 90% of their clinical episodes from nursing home settings between 2012 ans 2015.
P1.07-037 Clinicopathological Significance of Cancer Stem-Like Cell Markers in High-Grade Neuroendocrine Carcinoma of the Lung
Authors: Masahiro Morise, Tomoyuki Hishida, Akiko Takahashi, Junji Yoshida, Yuichiro Ohe, Kanji Nagai, Genichiro Ishii
Journal: Journal of Thoracic Oncology (2017)
External validation of the ITA.LI.CA prognostic system for patients with hepatocellular carcinoma: A multicenter cohort study
Authors: Mauro Borzio, Elena Dionigi, Angelo Rossini, Massimo Marignani, Rodolfo Sacco, Ilario De Sio, Emanuela Bertolini, Giampiero Francica, Anna Giacomin, Giancarlo Parisi, Susanna Vicari, Anna Toldi, Andrea Salmi, Sergio Boccia, Mario Mitra, Fabio Fornari
Journal: Hepatology (2017)

Several staging systems for hepatocellular carcinoma (HCC) have been developed. The Barcelona Clinic Liver Cancer staging system is considered the best in predicting survival, although limitations have emerged. Recently, the Italian Liver Cancer (ITA.LI.CA) prognostic system, integrating ITA.LI.CA tumor staging (stages 0, A, B1‐3, C) with the Child‐Turcotte‐Pugh score, Eastern Cooperative Oncology Group performance status, and alpha‐fetoprotein with a strong ability to predict survival, was proposed. The aim of our study was to provide an external validation of the ITA.LI.CA system in an independent real‐life occidental cohort of HCCs. From September 2008 to April 2016, 1,508 patients with cirrhosis and incident HCC were consecutively enrolled in 27 Italian institutions. Clinical, tumor, and treatment‐related variables were collected, and patients were stratified according to scores of the Barcelona Clinic Liver Cancer system, ITA.LI.CA prognostic system, Hong Kong Liver Cancer system, Cancer of the Liver Italian Program, Japanese Integrated System, and model to estimate survival in ambulatory patients with hepatocellular carcinoma. Harrell's C‐index, Akaike information criterion, and likelihood‐ratio test were used to compare the predictive ability of the different systems. A subgroup analysis for treatment category (curative versus palliative) was performed. Median follow‐up was 44 months (interquartile range, 23‐63 months), and median overall survival was 34 months (interquartile range, 13‐82 months). Median age was 71 years, and patients were mainly male individuals and hepatitis C virus carriers. According to ITA.LI.CA tumor staging, 246 patients were in stage 0, 472 were in stage A, 657 were in stages B1/3, and 133 were in stage C. The ITA.LI.CA prognostic system showed the best discriminatory ability (C‐index = 0.77) and monotonicity of gradients compared to other systems, and its superiority was also confirmed after stratification for treatment strategy. Conclusion : This is the first study that independently validated the ITA.LI.CA prognostic system in a large cohort of Western patients with incident HCCs. The ITA.LI.CA system performed better than other multidimensional prognostic systems, even after stratification by curative or palliative treatment. This new system appears to be particularly useful for predicting individual HCC prognosis in clinical practice. (H epatology 2018;67:2215‐2225)
A cell-penetrating whole molecule antibody targeting intracellular HBx suppresses hepatitis B virus via TRIM21-dependent pathway
Authors: Jun-Fang Zhang, Hua-Long Xiong, Jia-Li Cao, Shao-Juan Wang, Xue-Ran Guo, Bi-Yun Lin, Ying Zhang, Jing-Hua Zhao, Ying-Bin Wang, Tian-Ying Zhang, Quan Yuan, Jun Zhang, Ning-Shao Xia
Journal: Theranostics (2017)

Rationale: Monoclonal antibodies (mAbs) mostly targeting extracellular or cell surface molecules have been widely used in the treatment of various diseases. However, mAbs cannot pass through the cell membrane as efficiently as small compounds, thus limiting their use against intracellular targets. Methods to shuttle antibodies into living cells may largely expand research and application in areas based on mAbs. Hepatitis B virus X protein (HBx) is an important intracellular multi-functional viral protein in the life cycle of hepatitis B virus (HBV). HBx plays essential roles in virus infection and replication and is strongly associated with HBV-related carcinogenesis. Methods: In this study, we developed a cell-penetrating whole molecule antibody targeting HBx (9D11-Tat) by the fusion of a cell penetrating peptide (CPP) on the C-terminus of the heavy chain of a potent mAb specific to HBx (9D11). The anti-HBV effect and mechanism of 9D11-Tat were investigated in cell and mouse models mimicking chronic HBV infection. Results: Our results demonstrated that the recombinant 9D11-Tat antibody could efficiently internalize into living cells and significantly suppress viral transcription, replication, and protein production both in vitro and in vivo. Further analyses suggested the internalized 9D11-Tat antibody could greatly reduce intracellular HBx via Fc binding receptor TRIM21-mediated protein degradation. This process simultaneously stimulated the activations of NF-κB, AP-1, and IFN-β, which promoted an antiviral state of the host cell. Conclusion: In summary, our study offers a new approach to target intracellular pathogenesis-related protein by engineered cell-penetrating mAb expanding their potential for therapeutic applications. Moreover, the 9D11-Tat antibody may provide a novel therapeutic agent against human chronic HBV infection.
Abstract 19455: A Novel Caveolin-1 Frameshift Mutation Shows Critical Regulation of Mitochondrial Structure, Function and Extracellular Transport
Authors: Jamila H Siamwala, Ross Corridien, Uyen Nguyen, Angela Meier, Isabelle Schrauwen, Keri Ramsey, Vinodh Narayanan, David M Roth, Hemal H Patel
Journal: Circulation (2016)

Introduction: Caveolins act as molecular scaffolds for signal transduction. A number of caveolin-1 (Cav-1) mutations are associated with pulmonary hypertension with one recent frameshift mutation in exon 3 (c.478_479delTT) resulting in progeroid-like phenotype, lipodystrophy, and pulmonary hypertension. The cellular etiology of these diverse phenotypes is unknown. We have recently shown a critical relationship between caveolins in regulation of mitochondrial function. Hypothesis: As mitochondria are a key to cellular homeostasis, we hypothesize that a Cav-1 mutation (CM) can alter mitochondrial structure and function. Methods and Results: We obtained fibroblasts from a patient containing the CM as well as controls and utilized a variety of microscopy, cell biology, and biochemical techniques to study the role of Cav-1 in mitochondrial regulation. Transmission electron microscopy revealed dysmorphic nuclei, enlarged and increased number of endoplasmic reticulum, and increased number of smaller, swollen, and rounded mitochondria compared to normal cells. Mitochondrial DNA content was increased in CM cells with immunoblots showing decreased mitochondrial fission protein DRP1. Mitotracker staining showed large pools of aggregated mitochondria and DCFDA assay showed 3-fold increase in production of reactive oxygen species in CM cells compared to normal cells (p&lt;0.0001, n=8). Seahorse metabolic flux assay showed lower maximal respiration rates in CM cells compared to normal cells (p=0.0035, n=24). Mitochondrial complex II activity was impaired as addition of succinate failed to evoke any response to ADP in CM cells compared to normal cells. Live 3D microscopy with mitotracker staining showed extracellular mitochondria being transported along structured nanotubes between normal cell; however, impaired extracellular mitochondrial cargo arrangement and movement was observed in cells with the CM. Rescue experiments with Cav-1 overexpression resulted in improved mitochondrial respiration in CM cells. Conclusion: Together the results indicate that Cav-1 may be a critical regulator of mitochondrial structure, function, and transport and mutations in Cav-1 may explain the mitochondrial etiology of a variety of diseases.
Long-term outcome and quality of life after initial and repeat resection of colorectal liver metastasis: A retrospective analysis
Authors: D. Heise, W. Bayings, A. Tuinhof, R. Eickhoff, A. Kroh, F. Ulmer, C.H.C. Dejong, U. Neumann, M. Binnebösel
Journal: International Journal of Surgery (2017)
Impact of pharmacy interventions on pain management in an oncology palliative medicine (PM) outpatient clinic.
Authors: Jai Narendra Patel, Issam Hamadeh, James Thomas Symanowski, Rebecca Edwards, Beth Susi, Connie Edelen
Journal: Journal of Clinical Oncology (2017)

119 Background: PM can improve the quality of life and survival for cancer patients (pts); however, the demand for PM challenges providers with delayed follow ups resulting in less than one-third of pts achieving significant pain improvement between clinic visits. Engaging pharmacists in the provision of PM may help improve pain management in cancer pts. Methods: Adult cancer pts starting a new pain regimen or requiring changes to an existing regimen at baseline were referred for pharmacy follow up in 3-7 days (assessment #1). The pharmacist evaluated each pt using the Edmonton Symptom Assessment Scale and recommended changes to the referring PM provider, prompting a 2 nd follow up in 3-7 days (assessment #2). If no changes were required, pts continued therapy and returned for the final clinic visit (day 28 +/- 7). The primary endpoint was the proportion of pts achieving significant pain improvement (≥ 2-point decrease in pain score on a scale of 0-10) from baseline to final visit, which was compared to historical controls using Fisher’s Exact test. Changes in pain severity from baseline to final visit were compared using Generalized McNemar’s test, and descriptive statistics were used to describe characteristics at assessment #1. Results: Of 102 pts evaluable for the primary endpoint, 76% had stage IV disease, 58% were female, and median age was 57 yrs. Significantly more pts achieved pain improvement from baseline to final visit compared to historical controls (49% v 30%; P &lt; 0.001). Changes in pain severity from baseline to final visit are described in the table. At assessment #1, 70% of pts required an intervention, primarily due to uncontrolled pain (72%), side effects (26%), and/or lack of response to non-pain medications (22%). The most common types of interventions were dose adjustments (62%), education (36%), and/or adding a new medication (30%). Over 90% of recommendations were accepted by the referring PM provider. The median time of assessment was 15 mins. Conclusions: Routine inclusion of pharmacists in the outpatient PM interdisciplinary team improves the effectiveness of pain management. [Table: see text]
Pentraxin-3 as a marker of sepsis severity and predictor of mortality outcomes: A systematic review and meta-analysis
Authors: Yee Ting Lee, Mengqi Gong, Alex Chau, Wing Tak Wong, George Bazoukis, Sunny Hei Wong, Konstantinos Lampropoulos, Yunlong Xia, Guangping Li, Martin C.S. Wong, Tong Liu, William K.K. Wu, Gary Tse
Journal: Journal of Infection (2017)
The link between deprivation and its behavioural constellation is confounded by genetic factors
Authors: James M. Sherlock, Brendan P. Zietsch
Journal: Behavioral and Brain Sciences (2017)

Abstract Most research cited throughout Pepper &amp; Nettle's (P&amp;N's) target article is correlational and suffers from a serious genetic confound that renders it of little evidentiary value. Of correlational findings that are not confounded, P&amp;N ignore examples that contradict their model. Further, P&amp;N's claim that evolutionary models explaining between-species differences in behaviour can be used to understand that corresponding individual differences lack any evidence.
A Phase I Clinical Trial of the Poly(ADP-ribose) Polymerase Inhibitor Veliparib and Weekly Topotecan in Patients with Solid Tumors
Authors: Andrea E. Wahner Hendrickson, Michael E. Menefee, Lynn C. Hartmann, Harry J. Long, Donald W. Northfelt, Joel M. Reid, Felix Boakye-Agyeman, Olumide Kayode, Karen S. Flatten, Maria I. Harrell, Elizabeth M. Swisher, Guy G. Poirier, Daniel Satele, Jake Allred, Janet L. Lensing, Alice Chen, Jiuping Ji, Yiping Zang, Charles Erlichman, Paul Haluska, Scott H. Kaufmann
Journal: Clinical Cancer Research (2017)

Abstract Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting &amp;gt;5 days. The median number of cycles was 2 (1–26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.
Type I IFN–related NETosis in ataxia telangiectasia and Artemis deficiency
Authors: Ersin Gul, Esra Hazar Sayar, Bilgi Gungor, Fehime Kara Eroglu, Naz Surucu, Sevgi Keles, Sukru Nail Guner, Siddika Findik, Esin Alpdundar, Ihsan Cihan Ayanoglu, Basak Kayaoglu, Busra Nur Geckin, Hatice Asena Sanli, Tamer Kahraman, Cengiz Yakicier, Meltem Muftuoglu, Berna Oguz, Deniz Nazire Cagdas Ayvaz, Ihsan Gursel, Seza Ozen, Ismail Reisli, Mayda Gursel
Journal: Journal of Allergy and Clinical Immunology (2017)
P1.01-017 The Dramatic Shift of Lung Cancer toward Young in Prisons
Authors: Luc Renault, Eric Pradat, Emmanuel Perrot, Christophe Bartoli, Laurent Greillier, Anne Remacle-Bonnet, Norbert Telmon, Laurent Molinier, Julien Mazières, Sébastien Couraud
Journal: Journal of Thoracic Oncology (2017)
Predictive value of the improvement in tumor microenvironment for progression in breast cancer patients treated with neoadjuvant chemotherapy
Authors: W. Goto, S. Kashiwagi, Y. Asano, K. Takada, K. Takahashi, S. Noda, T. Takashima, N. Onoda, S. Tomita, K. Hirakawa, M. Ohira
Journal: Annals of Oncology (2017)
Igβ ubiquitination activates PI3K signals required for endosomal sorting
Authors: Margaret Veselits, Azusa Tanaka, Yaoqing Chen, Keith Hamel, Malay Mandal, Matheswaran Kandasamy, Balaji Manicassamy, Shannon K. O’Neill, Patrick Wilson, Roger Sciammas, Marcus R. Clark
Journal: The Journal of Experimental Medicine (2017)

A wealth of in vitro data has demonstrated a central role for receptor ubiquitination in endocytic sorting. However, how receptor ubiquitination functions in vivo is poorly understood. Herein, we report that ablation of B cell antigen receptor ubiquitination in vivo uncouples the receptor from CD19 phosphorylation and phosphatidylinositol 3-kinase (PI3K) signals. These signals are necessary and sufficient for accumulating phosphatidylinositol (3,4,5)-trisphosphate (PIP3) on B cell receptor–containing early endosomes and proper sorting into the MHC class II antigen-presenting compartment (MIIC). Surprisingly, MIIC targeting is dispensable for T cell–dependent immunity. Rather, it is critical for activating endosomal toll-like receptors and antiviral humoral immunity. These findings demonstrate a novel mechanism of receptor endosomal signaling required for specific peripheral immune responses.
177lu-Satetraxetan-Lilotomab in the Treatment of Patients with Indolent Non-Hodgkin B-Cell Lymphoma (NHL), Phase 1/2 Safety and Efficacy Data from Four Different Pre-Dosing Regimens
Authors: Arne Kolstad, Ulf Madsbu, Matthew Beasley, Michael Bayne, Tim Illidge, Noelle O'Rourke, Caroline Stokke, Tore Bach-Gansmo, Ayca Muftuler Løndalen, Jon Erik Holtedahl, Mona Elisabeth Revheim, Øyvind Bruland, Jostein Dahle, Laurie Baylor Curtis, Åse Østengen, Simon Turner, Nils Bolstad, Roy Hartvig Larsen, Signe Spetalen, Martin Erlanson, Stine Nygaard Rudå, Harald Holte
Journal: Blood (2016)
The physiological constellation of deprivation: Immunological strategies and health outcomes
Authors: Angela R Garcia, Aaron D Blackwell
Journal: Behavioral and Brain Sciences (2017)

Abstract Physiology and behavior are best thought of as two aspects of the same biological process, shaped simultaneously by natural selection. Like behavioral strategies, ecological conditions may affect physiological strategies, leading to changes in immunity and hormonal regulation. These alternate strategies help explain the health correlations of deprivation and provide additional pathways for feedback from early-life experiences.
Abstract #5525: Survival factor Nrf2 and its role in chemoresistance of ovarian cancer cells
Authors: Gi-Seong Shim, Sarala Manandhar, Dongha Shin, Aram You, Mi-kyoung Kwak
Journal: Cancer Research (2009)

The NF-E2 family transcription factor Nrf2 plays a critical role in the up-regulation of a battery of genes encoding detoxifying enzymes, antioxidant-modulating enzymes and the 26S proteasome. Now, it is widely accepted that Nrf2 is an essential element for the mammalian defense system against oxidative damage. However, there have been several lines of evidence supporting that Nrf2 may participate in the resistance of cancer cells by facilitating detoxication of anticancer agents. In our current study, it has been found that human ovarian cancer cell A2780, which is highly sensitive to doxorubicin and cisplatin, shows low levels of the ARE binding activity and the ARE-derived luciferase activity, as well as the repressed expression of Nrf2-target genes compared with resistant ovarian cancer cells. Acquisition of the resistance following a prolonged exposure of A2780 cells to doxorubicin was accompanied with the elevation of the ARE-Nrf2 pathway and resulted increase in total GSH contents. While, the chemoresistance of SK-OV3 ovarian cancer cells was in part, associated with high level of the Nrf2 pathway and functional inhibition of Nrf2 by using siRNA could sensitize SK-OV3 to anticancer agents. These results indicate that effective modulation of Nrf2, which plays a protective role in normal cells, might be a promising strategy to control the chemoresistance of ovarian cancer cells.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5525.
Abstract 18377: The Relationship Between Heart Failure Readmission and Mortality in Patients Receiving Transcatheter Aortic Valve Implantation
Authors: Hamed Nazzari, Nathaniel Hawkins, Sandra Lauck, Lillian Ding, Jopie Polderman, Maggie Yu, Omid Gerami, Justin Ezekowitz, Robert Boone, Anson Cheung, Jian Ye, David Wood, John Webb, Mustafa Toma
Journal: Circulation (2016)

Introduction:  Symptomatic severe aortic stenosis (AS) is associated with significant morbidity and mortality. Transcatheter aortic valve implantation (TAVI) is an option for select high-risk patients with AS. We examined the 30-day and 1-year heart failure (HF) and non-HF hospitalization rates and their associated mortality rates.   Hypothesis:  HF hospitalization post-TAVI is associated with higher mortality rates at 30-day and 1-year when compared to non-HF hospitalization.   Methods:  We conducted a retrospective analysis of 535 TAVI patients between August 6 th , 2010 and March 31 st , 2014 at St. Paul’s Hospital, in Vancouver, BC. We used data from the CSBC TAVI registry, and linked this to the CIHI DAD and Vital Statistics for hospitalization and mortality.   Results:  Within 1-year, 279 (52%) patients were hospitalized, of which 108 (20%) had a HF hospitalization (HFH), 171 (32%) had a non-HFH, and 256 (47%) were not hospitalized. There were no differences in age, sex, presence of severe COPD, and history of PCI, CABG and AVR. The pre-TAVI mean LVEF, AVA and gradients were not different between groups. The HFH cohort had more patients with baseline eGFR    Conclusions:  Readmission rates post-TAVI is high, with 52% of patients requiring hospitalization within one year; with over one-third of these readmissions due to HF. Mortality rates were higher in patients with HFH at 30-days and 1-year when compared with patients with non-HFH.