tbuckley/cabot-search huggingface dataset:
Abstract 13881: Novel Candidate Markers for Evaluating Safety in iPSC-derived Cardiomyocytes Contaminated With Tumorigenic Cells
Authors: Shigeo Masuda, Shigeru Miyagawa, Terumi Nakamura, Mao Nakatani, Kohei Kawaguchi, Tsuyoshi Ishikawa, Atsuhiro Saito, Yoshiki Sawa
Journal: Circulation (2017)

Background: Regenerative medicine using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be promising for next generation therapy for heart failure. It would be essentia...
Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency
Authors: Min Zhang, Julio Gallego-Delgado, Cristina Fernandez-Arias, Norman C. Waters, Ana Rodriguez, Moriya Tsuji, Ronald C. Wek, Victor Nussenzweig, William J. Sullivan
Journal: Cell Host & Microbe (2017)
Early Changes in Circulating T-Cell Immune Profiles in Patients with Relapsed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Data from the Phase 3, Double-Blind HELIOS Trial
Authors: Rajendra Damle, Michael Schaffer, Shalini Chaturvedi, Charles Phelps, Regina Aquino, Michelle Mahler, Mariya Salman, Angela Howes, Javier Loscertales, Marek Trneny, Dina Ben Yehuda, Alexander Pristupa, Asher A. Chanan-Khan, Sriram Balasubramanian
Journal: Blood (2016)
High-Resolution CBV-fMRI Allows Mapping of Laminar Activity and Connectivity of Cortical Input and Output in Human M1
Authors: Laurentius Huber, Daniel A. Handwerker, David C. Jangraw, Gang Chen, Andrew Hall, Carsten Stüber, Javier Gonzalez-Castillo, Dimo Ivanov, Sean Marrett, Maria Guidi, Jozien Goense, Benedikt A. Poser, Peter A. Bandettini
Journal: Neuron (2017)
Circulating Thyroxine
Authors: Jeffrey L. Anderson
Journal: Circulation Research (2017)

Background: Thyroid Function and Atherosclerotic Cardiovascular Disease RiskThyroid dysfunction has long been known to affect certain cardiovascular conditions.Measuring thyroid function to discover occult hyperthyroidism is recommended to evaluate causal factors for new-onset atrial fibrillation. 1Similarly, thyroid function testing is advocated to exclude hypothyroidism as a secondary cause of dyslipidemia before initiating lipidlowering therapy. 2 However, the effect of thyroid hormone on atherothrombosis, the major cause of cardiovascular morbidity and mortality, remains controversial, with various studies showing no effect on cardiovascular risk, 3,4 increased risk associated with low thyroid function, 5,6 and greater risk associated with high thyroid function, [7][8][9] in some cases within the reference range.Thus, whether variations in thyroid function both without and within the normal reference range can impact atherosclerotic cardiovascular disease (ASCVD) risk is unresolved.
Basic Surveillance Network, una base de datos para la vigilancia de las enfermedades transmisibles
Authors: A Ternhag, A Tegnell, B Lesko, K Skaerlund, P Penttinen
Journal: Eurosurveillance (2004)

La Red Basica de Vigilancia (Basic Surveillance Network) comenzo a funcionar en el ano 2000 y es una de las redes sobre enfermedades transmisibles financiadas por la Comision Europea. En ella se recogen datos de la vigilancia de las enfermedades transmisibles de todos los estados miembros de la antigua Union Europea (anterior a 2004) y su objetivo es proporcionar una facil acceso a los datos descriptivos ya disponibles en las bases de datos nacionales, facilitando la vigilancia y la comparacion de tendencias de las distintas enfermedades transmisibles en los Estados miembros de la UE. 
La lista de enfermedades cubiertas por la red, inicialmente limitada a 10 a modo de prueba, comprende actualmente mas de 40 enfermedades sujetas a vigilancia en el conjunto del territorio europeo. En un futuro proximo, los nuevos estados miembros seran invitados a participar en la Red.
Los datos disponibles de los casos notificados incluyen la fecha de inicio de sintomas de la enfermedad, la edad y el sexo. Solo se recogen unas pocas variables especificas de ciertas enfermedades, tales como el pais de infeccion y el estado vacunal. La clasificacion de los casos (posible, probable, confirmado) corresponde a las definiciones de caso establecidas por la UE. 
Los participantes tienen acceso a un sitio web interno donde todos los datos se presentan en tablas y graficos. Ademas existe un sitio abierto para el publico ( https://www.eubsn.org./BSN/).
Rosai–Dorfman Disease with Activating <i>KRAS</i> Mutation — Response to Cobimetinib
Authors: Eric Jacobsen, Vignesh Shanmugam, Jyothi Jagannathan
Journal: New England Journal of Medicine (2017)

A 60-year-old man with fatigue and a perinephric mass was found to have Rosai–Dorfman disease expressing an activating mutation in KRAS. A course of therapy with oral cobimetinib produced a respons...
Validation of a post-hypomethylating agent failure prognostic model in myelodysplastic syndromes patients treated in a randomized controlled phase III trial of rigosertib vs. best supportive care
Authors: Aziz Nazha, Mikkael A. Sekeres, Rami Komrokji, David P. Steensma, Hagop Kantarjian, Gail Roboz, Pierre Fenaux, Thomas Prebet, Nozar Azarnia, Patrick S. Zbyszewski, Steven M. Fruchtman, Valeria Santini, Lewis R. Silverman, Uwe Platzbecker, Guillermo Garcia-Manero
Journal: Blood Cancer Journal (2017)
Analysis of Drug Development Paradigms for Immune Checkpoint Inhibitors
Authors: Denis L. Jardim, Débora de Melo Gagliato, Francis J. Giles, Razelle Kurzrock
Journal: Clinical Cancer Research (2017)

Abstract Immune checkpoint inhibitors have unique toxicities and response kinetics compared with cytotoxic and gene-targeted anticancer agents. We investigated the impact of innovative/accelerated immunotherapy drug development/approval models on the accuracy of safety and efficacy assessments by searching the FDA website. Initial phase I trials for each agent were reviewed and safety and efficacy data compared with that found in later trials leading to regulatory approvals of the same agents. As of June 2017, the FDA approved six checkpoint inhibitors for a variety of cancer types. All checkpoint inhibitors received a priority review status and access to at least two additional FDA special access programs, more often breakthrough therapy designation and accelerated approval. Median clinical development time (investigational new drug application to approval) was 60.77 months [avelumab had the shortest timeline (52.33 months)]. Response rates during early phase I trials (median = 16%) are higher than for phase I trials of other agents (with the exception of gene-targeted agents tested with a biomarker). Doses approved were usually not identical to doses recommended on phase I trials. Approximately 50% of types of immune-related and 43% of types of clinically relevant toxicities from later trials were identified in early-phase trials. Even so, treatment-related mortality remains exceedingly low in later studies (0.33% of patients). In conclusion, efficacy and safety of immune checkpoint inhibitors appear to be reasonably predicted from the dose-finding portion of phase I trials, indicating that the fast-track development of these agents is safe and justified. Clin Cancer Res; 24(8); 1785–94. ©2017 AACR.
Small molecule antagonists for CXCR1 and CXCR2 inhibit human colon cancer metastasis by decreasing angiogenesis and enhancing apoptosis
Authors: Michelle Varney, Aihua Li, Seema Singh, Rosemary Mayer-Ezell, Richard Bond, Rakesh Singh
Journal: Cancer Research (2007)

5632  Our previous reports suggest the important role of the CXCR1 and CXCR2 ligands, interleukin-8 and growth regulated oncogene (gro)-α in colon cancer growth and metastasis. The objective of this study was to determine whether inhibition of CXCR1 and CXCR2 activity by using a small molecule antagonist(s) inhibits colon cancer growth and metastasis. KM12L4, a highly metastatic colon carcinoma cell line was implanted intrasplenically into nude mice and SCH527123 (which blocks both CXCR1 and CXCR2) or SCH479833 (which preferentially blocks CXCR2) were given orally at 0, 25, 50 or 100 MPK twice daily for three weeks. Primary splenic tumors and liver metastases were examined in treated and control groups. SCH57213 and SCH479833 were well tolerated with no toxicity. We did not observe significant differences in the primary spleen tumor weight. We observed significant inhibition of liver metastases in CXCR antagonist treated groups as compared to the control group; however, the effect was not dose-dependent. The levels of neovascularization in SCH57213 and SCH479833 treated groups were lower in primary tumors and liver metastases. The number of apoptotic tumor cells in SCH57213, SCH479833 and control treated splenic tumors were similar. However, we observed significantly higher levels of apoptotic tumor cells in liver metastases from SCH57213 and SCH479833 treated groups as compared to control. We did not observe any significant differences between SCH57213 and SCH479833 treated groups. Together, these studies demonstrate the important role of CXCR1 and CXCR2 in colon cancer growth and metastasis. In addition, inhibition of CXCR1 and CXCR2 using a small molecule antagonist provides a novel therapeutic strategy for metastatic colon cancer.
Pre-existing antitumor CD4 Th1 immunity in blood and PD-1/TIM-3+ CD4 T cells predict distinct outcome in lung cancer
Authors: M. Dosset, C. Laheurte, D. Vernerey, E. Lauret Marie Joseph, L. Rangan, E. Fabre, F. Le Pimpec-Barthes, E. Tartour, G. Eberst, V. Kaulek, M. Jacquin, V. Westeel, C. Borg, Y. Godet, O. Adotevi
Journal: Annals of Oncology (2017)
A phase 1 dose-escalation study of the folic acid-tubulysin small molecule drug conjugate (SMDC) folate-tubulysin EC1456 in advanced cancer patients.
Authors: Jasgit C. Sachdev, Daniela Matei, Wael A. Harb, Romnee Clark, Martin J. Edelman, Alexander Starodub
Journal: Journal of Clinical Oncology (2016)

2585 Background: The folate receptor (FR) is highly expressed in several epithelial cancers (e.g. ovarian, NSCLC) but is expressed at low levels in most normal tissues. EC1456 is a novel, next generation SMDC of folic acid and the potent cytotoxic agent tubulysin B hydrazide (TubBH). EC1456 targets folate receptor positive (FR+) tumors to deliver TubBH intracellularly, leading to mitotic inhibition. Etarfolatide is a folate-containing tracer that chelates technetium-99m for SPECT imaging. 99mTc-etarfolatide non-invasively identifies FR+ malignant lesions to select pts for FR-targeted treatment. Phase 2 studies with the first generation therapeutic folate SMDC vintafolide have shown its utility in patient selection for FR-targeted therapy. Methods: The primary objective is to determine the MTD of EC1456 administered on 2 schedules BIW: days 1, 4, 8, 11 q 21 or 28 days (dosages: 0.5-4.5 mg/m2), or QW: days 1, 8 q 21 days (dosages: 1.5-10.0 mg/m2). Key inclusion criteria include: age ≥ 18 years, ECOG PS 0–1, and adequate end-organ function. 99mTc-etarfolatide scan to evaluate FR status is obtained on enrolled pts. Dose escalation follows the "3+3" protocol. Cycle 1 DLT evaluation must be completed for each dose level prior to dosing a new cohort. Results: 46 pts have been treated and are evaluable for cycle 1 toxicity. Median age is 66.5 years (range: 39-86); 27 pts are female. 23 pts have received 93 cycles of EC1456 BIW (median: 2; range: 1-22), and 23 pts have received 87 cycles of EC1456 QW (median: 2; range: 1-18). There have been no treatment-related deaths. One pt experienced uncomplicated G4 neutropenia. Two DLT's have been observed, both on the QW schedule: G3 infusion reaction (4.5 mg/m2), and G3 headache (10.0 mg/m2). Stable disease (SD) > 4 months has been observed in 3 FR+ pts (mesothelioma, GEJ CA, SCLC) on the BIW schedule, and in 1 FR+ NSCLC pt and 1 FR non-evaluable pt with leiomyosarcoma on the QW schedule. Conclusions: Overall, both schedules of EC1456 appear to be well tolerated. Dose escalation is ongoing on both schedules. Anti-tumor activity of EC1456 is suggested by durable SD in pts with FR+ disease. Pharmacokinetic analyses are ongoing. Clinical trial information: NCT01999738.
New drugs that block brain peptide reduce migraine attacks, trials show
Authors: Susan Mayor
Journal: BMJ (2017)

A new monoclonal antibody that inhibits the calcitonin gene related peptide (CGRP) receptor, which plays a central role in the pathophysiology of migraine, significantly reduced the frequency of migraine episodes in the first phase 3 randomised trial to investigate erenumab in preventing episodic migraine.1 Another new agent blocking the same peptide, fremanezumab, also reduced the frequency of headache in patients with chronic migraine in a second trial.2

“Erenumab administered subcutaneously significantly reduced migraine frequency, the effects of migraines on daily activities, and the use of acute migraine specific drugs over a period of six months,” said the authors of the episodic migraine trial, led by Peter Goadsby from King’s College Hospital, London, UK. They added, “The treatment response achieved with erenumab was apparent from the first efficacy time point at one month, which suggests that patients had an early benefit.” They said that further trials are needed …
HIF-1α promotes autophagic proteolysis of Dicer and enhances tumor metastasis
Authors: Hui-Huang Lai, Jie-Ning Li, Ming-Yang Wang, Hsin-Yi Huang, Carlo M Croce, Hui-Lung Sun, Yu-Jhen Lyu, Jui-Wen Kang, Ching-Feng Chiu, Mien-Chie Hung, Hiroshi I Suzuki, Pai-Sheng Chen
Journal: Journal of Clinical Investigation (2017)

HIF-1α, one of the most extensively studied oncogenes, is activated by a variety of microenvironmental factors. The resulting biological effects are thought to depend on its transcriptional activity. The RNAse enzyme Dicer is frequently downregulated in human cancers, which has been functionally linked to enhanced metastatic properties; however, current knowledge of the upstream mechanisms regulating Dicer is limited. In the present study, we identified Dicer as a HIF-1α–interacting protein in multiple types of cancer cell lines and different human tumors. HIF-1α downregulated Dicer expression by facilitating its ubiquitination by the E3 ligase Parkin, thereby enhancing autophagy-mediated degradation of Dicer, which further suppressed the maturation of known tumor suppressors, such as the microRNA let-7 and microRNA-200b. Consequently, expression of HIF-1α facilitated epithelial-mesenchymal transition (EMT) and metastasis in tumor-bearing mice. Thus, this study uncovered a connection between oncogenic HIF-1α and the tumor-suppressive Dicer. This function of HIF-1α is transcription independent and occurs through previously unrecognized protein interaction–mediated ubiquitination and autophagic proteolysis.
Screening in the community to reduce fractures in older women (SCOOP): a randomised controlled trial
Authors: Lee Shepstone, Elizabeth Lenaghan, Cyrus Cooper, Shane Clarke, Rebekah Fong-Soe-Khioe, Richard Fordham, Neil Gittoes, Ian Harvey, Nick Harvey, Alison Heawood, Richard Holland, Amanda Howe, John Kanis, Tarnya Marshall, Terence O'Neill, Tim Peters, Niamh Redmond, David Torgerson, David Turner, Eugene McCloskey, Lee Shepstone, Elizabeth Lenaghan, Cyrus Cooper, Shane Clarke, Rebekah Fong-Soe-Khioe, Ric Fordham, Neil Gittoes, Ian Harvey, Nick Harvey, Alison Heawood, Richard Holland, Amanda Howe, John Kanis, Tarnya Marshall, Terence O'Neill, Tim Peters, Niamh Redmond, David Torgerson, David Turner, Eugene McCloskey, Nicola Crabtree, Helen Duffy, Jim Parle, Farzana Rashid, Katie Stant, Kate Taylor, Clare Thomas, Emma Knox, Cherry Tenneson, Helen Williams, David Adams, Veronica Bion, Jeanette Blacklock, Tony Dyer, Selina Bratherton, Matt Fidler, Katharine Knight, Carol McGurk, Katie Smith, Stacey Young, Karen Collins, Janet Cushnaghan, Catherine Arundel, Kerry Bell, Laura Clark, Sue Collins, Sarah Gardner, Natasha Mitchell
Journal: The Lancet (2017)
Association of Household Opioid Availability and Prescription Opioid Initiation Among Household Members
Authors: Marissa J. Seamans, Timothy S. Carey, Daniel J. Westreich, Stephen R. Cole, Stephanie B. Wheeler, G. Caleb Alexander, Virginia Pate, M. Alan Brookhart
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> Increases in prescription opioid use in the United States have been attributed to changing prescribing guidelines and attitudes toward pain relief; however, the spread of opioid use within households through drug diversion may also be a contributing factor. <h3>Objective</h3> To investigate whether individuals living in a household with a prescription opioid user are more likely to initiate prescription opioids themselves, compared with individuals in households with a prescription nonsteroidal anti-inflammatory drug (NSAID) user. <h3>Design, Setting, and Participants</h3> This was a retrospective cohort study using administrative health care claims data from 2000 to 2014 of commercial insurance beneficiaries sharing a health plan with continuous prescription drug coverage, without opioid or NSAID use in the prior year. Enrollees were followed from the date of the first prescription filled by a household member for an eligible opioid or NSAID until initiation of prescription opioids, disenrollment, or administrative censoring after 1 year or the end of follow-up on December 31, 2014. Risk of opioid initiation was derived from inverse probability-weighted (IPW) Kaplan-Meier estimators that adjusted for potential confounders, prognostic factors, and predictors of censoring. <h3>Exposure</h3> Outpatient pharmacy dispensing of a prescription opioid or prescription NSAID. <h3>Main Outcomes and Measures</h3> Incident outpatient pharmacy fill for a prescription opioid by a household member. <h3>Results</h3> From 2000 to 2014, 12 695 280 individuals were exposed to prescription opioids and 6 359 639 to prescription NSAIDS through an index prescription to a household member. The IPW estimated risk of opioid initiation in the subsequent year was 11.83% (95% CI, 11.81%-11.85%) among individuals exposed to prescription opioids in the household, compared with 11.11% (95% CI, 11.09%-11.14%) among individuals exposed to prescription NSAIDs, resulting in a risk difference of 0.71% (95% CI, 0.68%-0.74%). An unmeasured confounder that is modestly associated with the exposure (eg, prevalence difference = 0.9%) and the outcome (eg, risk difference = 0.9) after adjustment for all measured variables could explain our observed estimate of the overall risk difference (0.71%). <h3>Conclusions and Relevance</h3> Living in a household with a prescription opioid user may increase risk of prescription opioid use, which may reflect both increased access to these products as well as shared risk factors, such as prescriber preference and prescription drug monitoring.
Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice
Authors: Stuart Bunting, Lening Zhang, Lin Xie, Sherry Bullens, Rajeev Mahimkar, Sylvia Fong, Krystal Sandza, Danielle Harmon, Bridget Yates, Britta Handyside, Choong-Ryoul Sihn, Nicole Galicia, Laurie Tsuruda, Charles A. O’Neill, Anil Bagri, Peter Colosi, Shinong Long, Gordon Vehar, Barrie Carter
Journal: Molecular Therapy (2017)

Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding the factor VIII (FVIII) coagulation protein. Bleeding episodes in patients are reduced by prophylactic therapy or treated acutely using recombinant or plasma-derived FVIII. We have made an adeno-associated virus 5 vector containing a B domain-deleted (BDD) FVIII gene (BMN 270) with a liver-specific promoter. BMN 270 injected into hemophilic mice resulted in a dose-dependent expression of BDD FVIII protein and a corresponding correction of bleeding time and blood loss. At the highest dose tested, complete correction was achieved. Similar corrections in bleeding were observed at approximately the same plasma levels of FVIII protein produced either endogenously by BMN 270 or following exogenous administration of recombinant BDD FVIII. No evidence of liver dysfunction or hepatocyte endoplasmic reticulum stress was observed. Comparable doses in primates produced similar levels of circulating FVIII. These preclinical data support evaluation of BMN 270 in hemophilia A patients. Hemophilia A is an X-linked bleeding disorder caused by mutations in the gene encoding the factor VIII (FVIII) coagulation protein. Bleeding episodes in patients are reduced by prophylactic therapy or treated acutely using recombinant or plasma-derived FVIII. We have made an adeno-associated virus 5 vector containing a B domain-deleted (BDD) FVIII gene (BMN 270) with a liver-specific promoter. BMN 270 injected into hemophilic mice resulted in a dose-dependent expression of BDD FVIII protein and a corresponding correction of bleeding time and blood loss. At the highest dose tested, complete correction was achieved. Similar corrections in bleeding were observed at approximately the same plasma levels of FVIII protein produced either endogenously by BMN 270 or following exogenous administration of recombinant BDD FVIII. No evidence of liver dysfunction or hepatocyte endoplasmic reticulum stress was observed. Comparable doses in primates produced similar levels of circulating FVIII. These preclinical data support evaluation of BMN 270 in hemophilia A patients.
Fractional-Dose Inactivated Poliovirus Vaccine Campaign — Sindh Province, Pakistan, 2016
Authors: Aslam Pervaiz, Chukwuma Mbaeyi, Mirza Amir Baig, Ashley Burman, Jamal A. Ahmed, Sharifa Akter, Fayaz A. Jatoi, Abdirahman Mahamud, Rana Jawad Asghar, Naila Azam, Muhammad Nadeem Shah, Mumtaz Ali Laghari, Kamaluddin Soomro, Mufti Zubair Wadood, Derek Ehrhardt, Rana M. Safdar, Noha Farag
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Following the declaration of eradication of wild poliovirus (WPV) type 2 in September 2015, trivalent oral poliovirus vaccine (tOPV) was withdrawn globally to reduce the risk for type 2 vaccine-derived poliovirus (VDPV2) transmission; all countries implemented a synchronized switch to bivalent OPV (type 1 and 3) in April 2016 (1,2). Any isolation of VDPV2 after the switch is to be treated as a potential public health emergency and might indicate the need for supplementary immunization activities (3,4). On August 9, 2016, VDPV2 was isolated from a sewage sample taken from an environmental surveillance site in Hyderabad, Sindh province, Pakistan. Possible vaccination activities in response to VDPV2 isolation include the use of injectable inactivated polio vaccine (IPV), which poses no risk for vaccine-derived poliovirus transmission. Fractional-dose, intradermal IPV (fIPV), one fifth of the standard intramuscular dose, has been developed to more efficiently manage limited IPV supplies. fIPV has been shown in some studies to be noninferior to full-dose IPV (5,6) and was used successfully in response to a similar detection of a single VDPV2 isolate from sewage in India (7). Injectable fIPV was used for response activities in Hyderabad and three neighboring districts. This report describes the findings of an assessment of preparatory activities and subsequent implementation of the fIPV campaign. Despite achieving high coverage (>80%), several operational challenges were noted. The lessons learned from this campaign could help to guide the planning and implementation of future fIPV vaccination activities.
Sixteen Years of Overregulation: Time to Unburden Mifeprex
Authors: Elizabeth G Raymond, Kelly Blanchard, Paul D Blumenthal, Kelly Cleland, Angel M Foster, Marji Gold, Daniel Grossman, Mary K Pendergast, Carolyn L Westhoff, Beverly Winikoff
Journal: New England Journal of Medicine (2017)

This Sounding Board article argues against the need for the currently required Risk Evaluation and Mitigation Strategy (REMS) for the drug Mifeprex for abortion, given the very low rate of adverse events associated with its use.