tbuckley/cabot-search huggingface dataset:
Outbreaks of Enterovirus 71 Infection
Authors: AbuBakar S, Chan Yf, Lam Sk
Journal: New England Journal of Medicine (2000)

The Sounding Board articles by Freeman et al. 1 and Macklin 2 (Sept.23 issue) provided an excellent discussion of sham surgery for patients with Parkinson's disease.However, Freeman et al. seem overenthusiastic about downplaying the risks of sham surgery.Their statement that these procedures are easier to perform, standardize, and reproduce than traditional surgical procedures does not do justice to the neurosurgical skills involved in performing stereotactic brain surgery.It is probable that the wide range of outcomes regarding the effectiveness of and morbidity associated with pallidotomy is related to the varying skills of the operating neurosurgeon.Freeman et al. present the cogent argument that sham surgery is the only solution for proving the validity of the neurosurgical procedures discussed in relation to Parkinson's disease.Not only are there important clinical questions that need to be answered, but society also needs to know whether any surgical therapy for Parkinson's disease provides substantial enduring benefit.Macklin is no doubt correct that the informed-consent process is less than perfect.Rather than turn our backs on objectively evaluating surgical procedures, however, we should be more diligent in obtaining consent.In the end, the patients with Parkinson's disease who give informed and valid consent to participate in trials in which sham surgery is used are truly brave pioneers who are helping to advance the frontier of research.We should not prevent such trials from taking place.
Impact of ROS1, ALK, and/or MET expression level on the therapeutic efficacy of GEMOX with and without cetuximab in ABTC: A post hoc analysis of a randomized phase II trial.
Authors: Nai-Jung Chiang, Chiun Hsu, Jen-Shi Chen, Hiso-Hui Tsou, Yee Chao, Yang-Shen Shan, Shiu-Feng Huang, Chang-Fang Chiu, Kuan-Der Lee, Li-Tzong Chen
Journal: Journal of Clinical Oncology (2014)

267 Background: Our randomized phase II trial showed adding cetuximab to GEMOX marginally improved the ORR and median PFS in ABTC patients regardless their KRAS mutation status. Recently, MET overexpression was noted in 11.7% to 16.2% of BTC, and associated with poor OS. ROS1 kinase fusion has also been detected in 8.6% of IHCC.The aim of the study is to evaluate the impact of ROS1, ALK and/or MET (RAM) overexpression on the clinical outcomes of ABTC patients. Methods: FFPE tissue sections that were prospectively collected for biomarker study from all 122 patients were subjected for determining the expression of ROS1, ALK and MET by IHC in a central laboratory. Results: Of 110 patients with enough tissue section for IHC of all three markers, 18 tumors were found to over-express ROS1 (in 9), ALK (in 5) and/or MET (in 6). One tumor over-expressed all three biomarkers. As compared with RAM low tumors, the 18 RAM high tumors were significantly more of IHCC and without prior surgery, and with more frequent concurrent KRAS mutation. RAM high tumors was associated with significant inferior median OS than RAM low tumors, 5.7 vs 11.8 months (p=0.04). Of the latter 92 patients, adding cetuximab improved the therapeutic efficacy of GEMOX in ABTC, with ORR of 31.8% vs 10.4% (p=0.02), DCR of 61.4% vs 37.5% (p=0.04) and median PFS of 7.0 vs 4.5 months (p=0.02). OS was only marginally affected, with median OS of 12.5 vs 10.4 months (p=0.36). The ORR in KRAS wt and KRAS mut patients receiving C-GEMOX and GEMOX was 34.5% vs 11.8% (p=0.04) and 26.7% vs 7.1% (p=0.33), respectively; whiles the DCR was 65.5% vs 50.0% (p=0.31) and 53.3% vs 7.1% (p=0.01), respectively, and the median PFS was 7.1 vs 5.8 months (p=0.07) and 7.0 vs 1.9 months (p=0.05), respectively. The results suggest that, the presence of KRAS mutation did not preclude the benefit of adding cetuximab to GEMOX in RAM low subpopulation. Conclusions: ROS1/ALK/MET high ABTC had poor survival after C-GEMOX/GEMOX; while C-GEMOX significantly improved the ORR, DCR and PFS as compared to GEMOX alone in patients with ROS1/ALK/MET low tumors regardless their KRAS mutation status. Biomarker-driven design is warranted for future ABTC trials.
FOLFIRINOX for advanced pancreatic cancer: The Princess Margaret experience.
Authors: Muralidharan Chllamma, Natalie Cook, Kazim Giby, Anna Dodd, Lisa Wang, Neesha C. Dhani, David W. Hedley, Malcolm J. Moore
Journal: Journal of Clinical Oncology (2015)

417 Background: The FOLFIRINOX regimen has been shown to significantly increase both overall (OS) and progression free (PFS) survival in metastatic pancreas cancer (MPC), albeit with an increase in adverse events (AEs). It is not known whether initial dose reductions compromise FOLFIRINOX efficacy and there are limited data regarding treatment of locally advanced pancreatic cancer (LAPC). Methods: We conducted a retrospective review of patients (pts) treated with FOLFIRINOX for MPC or LAPC at Princess Margaret Cancer Centre, and began treatment between Dec 2011 and April 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. Results: 102 pts were identified; 66 MPC and 36 LAPC. Median age was 65 years. 72% of pts had pancreatic head tumors. At baseline 95% of pts had an ECOG performance status of 0 or 1; 95% had bilirubin &lt; 1.5 ULN and 45% had a biliary stent. 68% of pts initiated treatment with a dose reduction (93% reduction or omission of bolus 5FU, 88% reduction in Irinotecan, 68% reduction in Oxaliplatin and 66% reduction in infusional 5FU). Median number of cycles was 6 (1-31); 25% of pts received &lt;4 cycles. Median OS in metastatic pts was 12.9 months (mo) and 23 mo in LAPC; Median PFS was 8.7 mo (metastatic) and 11.1 mo in LAPC. There was no significant difference in PFS (10.9 vs. 10.3 mo; p=0.60) or OS (11.1 vs. 14.0 mo; p=0.19) between the full starting dose and reduced starting dose groups respectively. Partial response or stable disease was achieved in 57% of pts; 11% of the LAPC pts had a surgical resection. Grade 3/4 hematologic AEs were observed in 43% of pts (febrile neutropenia in 6%). Only 13% of pts received G-CSF support. Grade 3/4 non-hematologic AEs were observed in 28% of pts, including vomiting (19%), nausea (16%) and diarrhea (16%). 18% of pts had a treatment related hospitalization (5% neutropenic sepsis, 13% GI toxicity/dehydration.) There was one treatment related death. Pt wellbeing (scored on a validated questionnaire) significantly improved from baseline to cycle 4 (p=0.002). Conclusions: Modest dose reductions do not appear to compromise efficacy of FOLFIRINOX. Our median PFS, OS and AEs are comparable to other studies using FOLFIRINOX in both LAPC and metastatic disease.
2009 Thomas W. Smith Memorial Lecture—GRK2 Inhibition as a Novel Therapeutic Target in Heart Failure
Authors: Walter Koch
Journal: Circulation (2009)

For more than 15 years, our laboratory has been researching the role of the G protein–coupled receptor kinases (GRKs) in myocardial function. This includes how GRKs are involved in the cardiovascular pathological processes of hypertension, ventricular hypertrophy, and heart failure. Studies with GRK2 (also known as β ARK1) have shown, from cell studies to whole-animal studies, that the increased activity of this kinase is pathological to the cardiomyocyte. Importantly, lowering its expression or activity has led to beneficial effects in several animal models of heart failure. Most recently, studies in myocyte-specific GRK2-knockout mice have revealed that the loss of GRK2 in heart cells prevents the development of heart failure after a myocardial infarction. In separate animal studies, gene therapy with a GRK2 inhibitor peptide has shown that lowering the activity of this kinase can reverse ventricular contractile failure and also adverse remodeling. Large animal preclinical studies are being done with gene therapy; however, development of small-molecule inhibitors of GRK2 is warranted. This lecture will focus on the translational continuum of research for the past 15+ years in the development of GRK2 as a definitive target for heart failure therapy. The lecture will also include new data supporting unique roles for GRK2 in myocardial signaling and function.
Risk factors associated with fluoroquinolones-resistance of M.tuberculosis in Novosibirsk Oblast, Russian Federation: Results of retrospective cohort study
Authors: Yana Batyrshina, Tatyana Petrenko
Journal: European Respiratory Journal (2013)

Background:Fluoroquinolones(FQ) are most effective of second-line antituberculosis drugs in treatment of multidrug-resistant tuberculosis(MDR-TB). Increased resistance of M.tuberculosis(MTB) to FQ may reduce the clinical benefit of them.  Aims:To define risk factors(RF) of the FQ-resistance development during treatment of patients with MDR-TB. To estimate proportion of secondary drug resistance(SDR) of MTB to FQ in Novosibirsk Oblast(NO).  Methods:Retrospective analysis of drug susceptibility testing results and socio-demographic and clinical data of patients with newly diagnosed MDR-TB registered in NO in 2003-2010 was performed. The sample is - 338 patients(69,5% male, 30,5% female) receiving FQ-containing treatment regimens. Two groups of patients: with acquired FQ-resistance of MTB (94 of 338) and without one (244 of 338) were compared.  Results:RF associated with FQ-resistance of MTB were treatment interruptions(OR =9,6, 95%CI:5,5-16,8, p  Conclusions:The risk of SDR of MTB to FQ is increased among socially maladjusted patients. These findings should be considered in the MDR-TB clinical management.
Effect of roflumilast on hospitalizations in COPD patients
Authors: Eric Bateman, José Jardim, Udo-Michael Goehring, Manja Brose, Peter Calverley
Journal: European Respiratory Journal (2012)

Background: Severe exacerbations of COPD require hospitalization and have serious long-term consequences for patients. Roflumilast (ROF) is a PDE4 inhibitor that significantly reduced moderate-to-severe exacerbations in clinical studies. Its effects on severe exacerbations and any adverse events leading to hospitalization have not been described previously. Aim: To investigate the effects of ROF on the rate of hospitalizations resulting from severe exacerbations or any other adverse events in two 1-year studies (M2-124 and M2 125). Methods: In a post-hoc pooled analysis of the pivotal studies of ROF 500µg (n=1537) vs placebo (n=1554), statistical analyses were performed on the overall population and in patient subgroups with: A) severe/very severe COPD; B) frequent COPD exacerbations; and C) severe/very severe COPD and frequent COPD exacerbations. Negative binomial regression analyses were used to investigate the rate reduction for hospitalizations. Results: In the overall population, ROF decreased the rate of hospitalizations resulting from severe exacerbations vs placebo by 21.6% (rate ratio 0.784, [95% CI 0.619, 0.993, p=0.0439), and overall there were trends towards extended times-to-onset of severe exacerbations leading to hospitalization. Although not statistically significant, ROF reduced hospitalizations resulting from any adverse event compared with placebo. In all subgroups analyzed, ROF had a positive numerical but not statistically significant effect on rate reduction of all-cause hospitalizations, time to hospitalization and risk of hospitalizations. Conclusions: Roflumilast significantly reduces the rate of severe exacerbations leading to hospitalization vs placebo.
Association of short-term ozone and temperature with sleep disordered breathing
Authors: Gerhard Weinreich, Thomas E. Wessendorf, Noreen Pundt, Gudrun Weinmayr, Frauke Hennig, Susanne Moebus, Stefan Möhlenkamp, Raimund Erbel, Karl-Heinz Jöckel, Helmut Teschler, Barbara Hoffmann
Journal: European Respiratory Journal (2015)

Scarce evidence suggests that ambient air pollution and temperature might play a role in incidence and severity of sleep disordered breathing (SDB). We investigated the association of short-term exposure to fine particulate matter (particles with a 50% cut-off aerodynamic diameter of 10 μm (PM 10 )), ozone and temperature with SDB in the general population. Between 2006 and 2008, 1773 participants (aged 50–80 years) of the Heinz Nixdorf Recall study underwent screening for SDB, as defined by the apnoea–hypopnoea index (AHI). We assessed daily exposure to PM 10 , ozone, temperature and humidity. We used multiple linear regression to estimate associations of daily PM 10 , ozone levels and temperature on the day of screening, adjusting for relative humidity, season, age, sex, body mass index, education, smoking habits, alcohol consumption and physical activity. In the study population, the mean± sd AHI was 11.2±11.4 events·h −1 . Over all seasons, an interquartile range increase in temperature (8.6°C) and ozone (39.5 µg·m −3 ) was associated with a 10.2% (95% CI 1.2–20.0%) and 10.1% (95% CI 2.0–18.9%) increase in AHI, respectively. Associations for temperature were stronger in summer, yielding a 32.4% (95% CI 0.0–75.3%) increase in AHI per 8.6°C (p-value for season–temperature interaction 0.08). We observed that AHI was not associated with PM 10 . This study suggests that short-term variations in ozone concentration and temperature are associated with SDB.
Antigen‐specific blocking of CD4‐Specific immunological synapse formation using BPI and current therapies for autoimmune diseases
Authors: Prakash Manikwar, Paul Kiptoo, Ahmed H. Badawi, Barlas Büyüktimkin, Teruna J. Siahaan
Journal: Medicinal Research Reviews (2011)

Abstract In this review, we discuss T‐cell activation, etiology, and the current therapies of autoimmune diseases (i.e., MS, T1D, and RA). T‐cells are activated upon interaction with antigen‐presenting cells (APC) followed by a “bull's eye”‐like formation of the immunological synapse (IS) at the T‐cell–APC interface. Although the various disease‐modifying therapies developed so far have been shown to modulate the IS and thus help in the management of these diseases, they are also known to present some undesirable side effects. In this study, we describe a novel and selective way to suppress autoimmunity by using a bifunctional peptide inhibitor (BPI). BPI uses an intercellular adhesion molecule‐1 (ICAM‐1)‐binding peptide to target antigenic peptides (e.g., proteolipid peptide, glutamic acid decarboxylase, and type II collagen) to the APC and therefore modulate the immune response. The central hypothesis is that BPI blocks the IS formation by simultaneously binding to major histocompatibility complex‐II and ICAM‐1 on the APC and selectively alters the activation of T cells from T H 1 to T reg and/or T H 2 phenotypes, leading to tolerance. © 2011 Wiley Periodicals, Inc. Med Res Rev., 32, No. 4, 727‐764, 2012
Abstract 4187: Culprit Lesions Located in the Proximal Segments of the Coronary Arteries Have Thinner Fibrous Cap and Greater Incidence of Plaque Rupture: An Optical Coherence Tomography Study
Authors: Maria Drakopoulou, Konstantinos Toutouzas, Maria Riga, Andreas Synetos, Antonis Karanasos, Chrysoula Patsa, Eleftherios Tsiamis, Dimitrios Tousoulis, Elli Stefanadi, Christodoulos Stefanadis
Journal: Circulation (2009)
Patients will be told cost of missed appointments and may be charged:
Authors: Ingrid Torjesen
Journal: BMJ (2015)

Patients who miss an appointment will be told how much it cost the NHS and could potentially be billed for it, the health secretary has announced.

Appearing on Question Time on BBC1 on 2 July, Jeremy Hunt said that the government had taken a first step towards introducing greater patient responsibility for the use of resources by introducing measures to ensure that patients who miss appointments are told how much NHS money they have wasted.

Hunt said that the NHS was “very stretched for resources” and that he had not ruled out charging people who do not attend their appointment.

“If we are going to square the …
Reduction in Platelet Reactivity With Prasugrel 5 mg in Low-Body-Weight Patients Is Noninferior to Prasugrel 10 mg in Higher-Body-Weight Patients
Authors: David Erlinge, Jurrien ten Berg, David Foley, Dominick J. Angiolillo, Henrik Wagner, Patricia B. Brown, Chunmei Zhou, Junxiang Luo, Joseph A. Jakubowski, Brian Moser, David S. Small, Thomas Bergmeijer, Stefan James, Kenneth J. Winters
Journal: Journal of the American College of Cardiology (2012)
Viral expression of ALS-linked ubiquilin-2 mutants causes inclusion pathology and behavioral deficits in mice
Authors: Carolina Ceballos-Diaz, Awilda M. Rosario, Hyo-Jin Park, Paramita Chakrabarty, Amanda Sacino, Pedro E. Cruz, Zoe Siemienski, Nicolas Lara, Corey Moran, Natalia Ravelo, Todd E. Golde, Nikolaus R. McFarland
Journal: Molecular Neurodegeneration (2015)

UBQLN2 mutations have recently been associated with familial forms of amyotrophic lateral sclerosis (ALS) and ALS-dementia. UBQLN2 encodes for ubiquilin-2, a member of the ubiquitin-like protein family which facilitates delivery of ubiquitinated proteins to the proteasome for degradation. To study the potential role of ubiquilin-2 in ALS, we used recombinant adeno-associated viral (rAAV) vectors to express UBQLN2 and three of the identified ALS-linked mutants (P497H, P497S, and P506T) in primary neuroglial cultures and in developing neonatal mouse brains.In primary cultures rAAV2/8-mediated expression of UBQLN2 mutants resulted in inclusion bodies and insoluble aggregates. Intracerebroventricular injection of FVB mice at post-natal day 0 with rAAV2/8 expressing wild type or mutant UBQLN2 resulted in widespread, sustained expression of ubiquilin-2 in brain. In contrast to wild type, mutant UBQLN2 expression induced significant pathology with large neuronal, cytoplasmic inclusions and ubiquilin-2-positive aggregates in surrounding neuropil. Ubiquilin-2 inclusions co-localized with ubiquitin, p62/SQSTM, optineurin, and occasionally TDP-43, but were negative for α-synuclein, neurofilament, tau, and FUS. Mutant UBLQN2 expression also resulted in Thioflavin-S-positive inclusions/aggregates. Mice expressing mutant forms of UBQLN2 variably developed a motor phenotype at 3-4 months, including nonspecific clasping and rotarod deficits.These findings demonstrate that UBQLN2 mutants (P497H, P497S, and P506T) induce proteinopathy and cause behavioral deficits, supporting a "toxic" gain-of-function, which may contribute to ALS pathology. These data establish also that our rAAV model can be used to rapidly assess the pathological consequences of various UBQLN2 mutations and provides an agile system to further interrogate the molecular mechanisms of ubiquilins in neurodegeneration.
Abstract A05: Identification of RASA1 as a novel melanoma tumor suppressor gene
Authors: Hyeran Sung, Krishna L. Kanchi, Jane Messina, Ji-Hyun Lee, Li Ding, Richard K. Wilson, Jeffrey S. Weber, Minjung Kim
Journal: Cancer Research (2015)

Abstract Hyperactivation of the Ras-Raf-Mitogen-activated protein kinase (MAPK) pathway via frequent activating mutations in NRAS and BRAF has been commonly observed in melanoma. Novel mutations in other components of this pathway such as MEK1, MEK2, MAP3K5, and MAP3K9 have been reported recently by high-throughput sequencing efforts. In addition, NF1 (neurofibromatosis type 1), one of the Ras GTPase activating proteins (RasGAPs), has been shown to be mutated or suppressed in melanoma. However, importance of other RasGAPs has not been addressed in melanoma. To obtain a comprehensive view of melanoma genomes, we conducted whole genome sequencing (WGS) of 15 metastatic melanomas and matched normal PBMC genomes from 13 melanoma patients. All melanoma genomes from these 13 patients contained at least one mutation in genes of Ras-Raf-MAPK pathway (MAPK1, MAP3K1, MAP4K2, MAP3K14, NRAS, and BRAF). In addition, we identified two novel, clustered somatic missense mutations (p.Tyr472His and p.Leu481Phe) in RASA1 (RAS p21 protein activator 1, p120RasGAP) that negatively regulates Ras by catalyzing the hydrolysis of active Ras-GTP to inactive Ras-GDP. In this study, we addressed functional roles of RASA1 in melanoma tumorigenesis. Ectopic expression of wild-type RASA1 in human melanoma cell lines SKMEL28 and WM983C (with BRAF V600E) decreased, while RASA1 Y472H mutant enhanced soft agar colony formation, tumor growth, and Ras activity. The RASA1 L481F mutant lost its tumor suppressive activity. The siRNA- or shRNA-mediated knockdown of RASA1 promoted soft agar colony formation, tumor growth, and RAS activation in human melanoma cell lines IGR1 and KML1 (with BRAFV600E). Mechanistically, RASA1 required RasGAP activity to suppress colony formation and showed higher activity toward R-Ras isoform among Ras superfamily of small GTPases. To determine RASA1 level in melanocytic lesions, immunohistochemical analysis of RASA1 on human melanoma tissue microarray (TMA) was performed. RASA1 expression was frequently down-regulated in metastatic melanoma samples (11.4% (4/35) of lymph node metastasis and 3.4% (1/29) of distal metastases) compared to primary melanomas (33.3% (21/63)) and dysplastic nevi (44.1% (15/34)). Thus, these data support that RASA1 is a novel melanoma tumor suppressor that is inactivated by loss of expression or by mutation. Citation Format: Hyeran Sung, Krishna L. Kanchi, Jane Messina, Ji-Hyun Lee, Li Ding, Richard K. Wilson, Jeffrey S. Weber, Minjung Kim. Identification of RASA1 as a novel melanoma tumor suppressor gene. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A05.
Abstract 139: A Short Pause in Chest Compressions Before Defibrillation Increases the Chance for Successful Return of Spontaneous Circulation During CPR
Authors: Young Kwon, Timothy Matsuura, Scott McKnite, Keith Lurie, Demetris Yannopoulos
Journal: Circulation (2012)

Background: Minimizing chest compression interruptions during CPR has been associated with improved outcomes in patients with cardiac arrest. Delivering defibrillation shocks while performing chest compressions may offer an advantage. We hypothesized that delivering shocks with on going chest compressions would be superior to a pre-shock compressions pause of ten seconds in achieving ROSC following the shock. Methods: 39 pigs had 15 minutes of untreated ventricular fibrillation. Animals received standard CPR for 4 minutes before the first biphasic 150 J DC defibrillation attempt. If animals did not achieve return of spontaneous circulation (ROSC), shocks were attempted every 30 seconds for a total of 3 times at which time another 2-min cycle of CPR was performed until the next shock. All animals received one dose of 0.5 mg of epinephrine one minute before the first shock. Animals were randomized to receive the first shock either during on going compressions or after a 10 second pause in compressions. The ...