tbuckley/cabot-search huggingface dataset:
Definition and Implications of the Preventable Stroke
Authors: Mark Fisher, Lisa Moores, Mohamad N. Alsharif, Annlia Paganini-Hill
Journal: JAMA Neurology (2015)

<h3>Importance</h3> Although patients with acute stroke are routinely evaluated for potential treatment (ie, treatability of the stroke), preventability of the presenting stroke is generally not seriously considered. <h3>Objective</h3> To systematically analyze stroke preventability. <h3>Design, Setting, and Participants</h3> We evaluated medical records of 274 consecutive patients discharged with a diagnosis of ischemic stroke between December 2, 2010, and June 11, 2012, at the University of California Irvine Medical Center. Mean (SE) patient age was 67.2 (0.8) years. Data analysis was conducted from July 3, 2014, to August 4, 2015. <h3>Exposures</h3> Medical records were systematically examined for demographic information, stroke risk factors, stroke severity, and acute stroke treatment. <h3>Main Outcomes and Measures</h3> We defined stroke preventability as the degree to which the patient's presenting stroke was preventable. Using variables easily determined at onset of stroke, we developed a 10-point scale (0, not preventable; 10, most preventable) to classify the degree of stroke preventability. Our focus was effectiveness of treatment of hypertension (0-2 points), hyperlipidemia (0-2 points), and atrial fibrillation (0-4 points), as well as use of antithrombotic treatment for known prior cerebrovascular and cardiovascular disease (0-2 points). <h3>Results</h3> Total risk scores ranged from 0 to 8 (mean [SE], 2.2 [0.1]), with 207 patients (75.5%) exhibiting some degree of preventability (score of 1 or higher). Seventy-one patients (25.9%) had scores of 4 or higher, indicating that the stroke was highly preventable. Severity of stroke as determined by the National Institutes of Health Stroke Scale score was not related to preventability of stroke. However, 21 of 71 patients (29.6%) whose stroke was highly preventable were treated with intravenous or intra-arterial acute stroke therapy while these treatments were provided for only 13 of 67 patients (19.4%) with scores of 0 (no preventability) and 19 of 136 patients (14.0%) with scores of 1 to 3 (low preventability) (<i>P</i> = .03). <h3>Conclusions and Relevance</h3> Most patients with acute stroke exhibited some degree of preventability. Preventability and treatment of stroke were significantly associated, indicating that the most preventable strokes paradoxically were more likely to receive acute treatment.
Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients
Authors: Antonio Marchetti, John F. Palma, Lara Felicioni, Tommaso M. De Pas, Rita Chiari, Maela Del Grammastro, Giampaolo Filice, Vienna Ludovini, AlbaA. Brandes, Antonio Chella, Francesco Malorgio, Flavio Guglielmi, Michele De Tursi, Armando Santoro, Lucio Crinò, Fiamma Buttitta
Journal: Journal of Thoracic Oncology (2015)

IntroductionThe potential to accurately quantify epidermal growth factor receptor (EGFR) mutations in plasma from non–small-cell lung cancer patients would enable more rapid and more frequent analyses to assess disease status; however, the utility of such analyses for clinical purposes has only recently started to explore.MethodsPlasma samples were obtained from 69 patients with EGFR-mutated tumors and 21 negative control cases. EGFR mutations in plasma were analyzed by a standardized allele-specific polymerase chain reaction (PCR) test and ultra-deep next-generation sequencing (NGS). A semiquantitative index (SQI) was derived from dilutions of known EGFR mutation copy numbers. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors 1.1 criteria and expressed as percent tumor shrinkage.ResultsThe sensitivity and specificity of the PCR test and NGS assay in plasma versus tissue were 72% versus 100% and 74% versus 100%, respectively. Quantitative indices by the PCR test and NGS were significantly correlated (p < 0.001). EGFR testing at baseline and serially at 4 to 60 days during tyrosine kinase inhibitor therapy revealed a progressive decrease in SQI, starting from day 4, in 95% of cases. The rate of SQI decrease correlated with percent tumor shrinkage at 2 months (p < 0.0001); at 14 days, it was more than 50% in 70% of patients (rapid responders). In two patients with slow response, an early increase in the circulating levels of the T790M mutation was observed. No early T790M mutations were seen in plasma samples of rapid responders.ConclusionsQuantification of EGFR mutations from plasma with a standardized PCR test is feasible. To our knowledge, this is the first study showing a strong correlation between the EGFR SQI in the first days of treatment and clinical response with relevant implications for patient management.
α-synuclein interacts with SOD1 and promotes its oligomerization
Authors: Anika M. Helferich, Wolfgang P. Ruf, Veselin Grozdanov, Axel Freischmidt, Marisa S. Feiler, Lisa Zondler, Albert C. Ludolph, Pamela J. McLean, Jochen H. Weishaupt, Karin M. Danzer
Journal: Molecular Neurodegeneration (2015)

Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are both neurodegenerative diseases leading to impaired execution of movement. α-Synuclein plays a central role in the pathogenesis of PD whereas Cu, Zn superoxide dismutase (SOD1) is a key player in a subset of familial ALS cases. Under pathological conditions both α-synuclein and SOD1 form oligomers and fibrils. In this study we investigated the possible molecular interaction of α-synuclein and SOD1 and its functional and pathological relevance. Using a protein-fragment complementation approach and co-IP, we found that α-synuclein and SOD1 physically interact in living cells, human erythrocytes and mouse brain tissue. Additionally, our data show that disease related mutations in α-synuclein (A30P, A53T) and SOD1 (G85R, G93A) modify the binding of α-synuclein to SOD1. Notably, α-synuclein accelerates SOD1 oligomerization independent of SOD1 activity. This study provides evidence for a novel interaction of α-synuclein and SOD1 that might be relevant for neurodegenerative diseases.
Further Progress in Understanding Fibrosing Mediastinitis
Authors: Stephen B. Strock, Wendi Mason, James E. Loyd
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

A potential concern is the effect of exogenous flow on endogenous cardiac output.Assessment of this relationship is complex (12); however, it is unlikely that native cardiac output would perfectly adjust (increasing or decreasing) to match the induced ECMO flow variations.Thus, if _ VO 2 was dependent on _ DO 2 , we would expect to see some correlating fluctuation.This conclusion is reinforced by the fact that the pattern of _ DO 2 versus _ VO 2 in the full cohort was identical to that in two patients without endogenous cardiac output (Figure 1).Finally, although O 2 supply dependency has traditionally been proposed in patients with sepsis (1), careful delineation of _ DO 2 -_ VO 2 relationships in individual patients reveals no differences between patients with proven sepsis versus those without sepsis (6); patients in the current had elevated inflammatory markers (e.g., CRP .50 mg/L in most), suggesting important systemic inflammation (see Table E6).In summary, we studied the _ DO 2 -_ VO 2 relationships in hemodynamically resuscitated critically ill patients with evidence of systemic inflammation receiving VA ECMO and found _ VO 2 to be independent of _ DO 2 in the ranges studied.Clinical trial registered with www.clinicaltrials.
Perfusion Pressure Is a Critical Determinant of the Intratumoral Extravasation of Oncolytic Viruses
Authors: Amber Miller, Rebecca Nace, Camilo Ayala-Breton C, Michael Steele, Kent Bailey, Kah Whye Peng, Stephen J Russell
Journal: Molecular Therapy (2015)

Antitumor efficacy of oncolytic virotherapy is determined by the density and distribution of infectious centers within the tumor, which may be heavily influenced by the permeability and blood flow in tumor microvessels. Here, we investigated whether systemic perfusion pressure, a key driver of tumor blood flow, could influence the intratumoral extravasation of systemically administered oncolytic vesicular stomatitis virus (VSV) in myeloma tumor-bearing mice. Exercise was used to increase mean arterial pressure, and general anesthesia to decrease it. A recombinant VSV expressing the sodium iodide symporter (NIS), which concentrates radiotracers at sites of infection, was administered intravenously to exercising or anesthetized mice, and nuclear NIS reporter gene imaging was used to noninvasively track the density and spatial distribution of intratumoral infectious centers. Anesthesia resulted in decreased intratumoral infection density, while exercise increased the density and uniformity of infectious centers. Perfusion state also had a significant impact on the antitumor efficacy of the VSV therapy. In conclusion, quantitative dynamic radiohistologic imaging was used to noninvasively interrogate delivery of oncolytic virotherapy, highlighting the critical importance of perfusion pressure as a driver of intratumoral delivery and efficacy of oncolytic viruses.
Characterization of the First PCSK9 Gain of Function Homozygote
Authors: Ana Catarina Alves, Aitor Etxebarria, Ana Margarida Medeiros, Asier Benito-Vicente, Aurélie Thedrez, Maxime Passard, Mikaël Croyal, Cesar Martin, Gilles Lambert, Mafalda Bourbon
Journal: Journal of the American College of Cardiology (2015)
Eradication of Helicobacter pylori in management of peptic ulceration
Authors: J P Miller, S G W Jones
Journal: BMJ (1995)

agents in minimal change nephropathy is contro- versial.This implies that the benefits are unproved, whereas a definite, sustained effect has been shown in controlled trials.3There are, however, side effects associated with these agents, and the authors are correct in stating that their use should be carefully considered.The consensus statement lists two clear indications for second line treatment.(1) Relapse while taking prednisolone > 0 5 mg/kg on alternate days plus one or more of (a) unaccept- able side effects of corticosteroid treatment; (b) high risk of steroid toxicity-for example, in boys approaching puberty or in diabetes; (c) unusually severe relapses (hypovolaemia or thrombosis); and (ad) inadequate facilities for follow up or concern about compliance.(2) Relapse while taking prednisolone > 1 mg/kg on alternate days.The recommended dose of cyclophos- phamide is 3 mg/kg/day for eight weeks.The report describing fewer relapses in children treated with cyclophosphamide for 12 weeks was limited to patients with steroid dependent disease.4
ADHD diagnosis in US schoolchildren rose 43% in past decade, study shows
Authors: Susan Mayor
Journal: BMJ (2015)

One in eight US children and teenagers had a diagnosis of attention deficit hyperactivity disorder (ADHD) in 2011, representing a 43% increase since 2003, shows an analysis of national surveys based on parental reports that their child had the diagnosis.

The study, published in the Journal of Clinical Psychiatry ,1 analysed data on the parent reported prevalence of ADHD in three waves (2003, 2007, and 2011) of the US National Survey of Children’s Health, a nationally representative cross sectional survey carried out by the National …
CRISPR/dCas9-mediated Transcriptional Inhibition Ameliorates the Epigenetic Dysregulation at D4Z4 and Represses DUX4-fl in FSH Muscular Dystrophy
Authors: Charis L Himeda, Takako I Jones, Peter L Jones
Journal: Molecular Therapy (2015)

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent myopathies, affecting males and females of all ages. Both forms of the disease are linked by epigenetic derepression of the D4Z4 macrosatellite repeat array at chromosome 4q35, leading to aberrant expression of D4Z4-encoded RNAs in skeletal muscle. Production of full-length DUX4 (DUX4-fl) mRNA from the derepressed D4Z4 array results in misexpression of DUX4-FL protein and its transcriptional targets, and apoptosis, ultimately leading to accumulated muscle pathology. Returning the chromatin at the FSHD locus to its nonpathogenic, epigenetically repressed state would simultaneously affect all D4Z4 RNAs, inhibiting downstream pathogenic pathways, and is thus an attractive therapeutic strategy. Advances in CRISPR/Cas9-based genome editing make it possible to target epigenetic modifiers to an endogenous disease locus, although reports to date have focused on more typical genomic regions. Here, we demonstrate that a CRISPR/dCas9 transcriptional inhibitor can be specifically targeted to the highly repetitive FSHD macrosatellite array and alter the chromatin to repress expression of DUX4-fl in primary FSHD myocytes. These results implicate the promoter and exon 1 of DUX4 as potential therapeutic targets and demonstrate the utility of CRISPR technology for correction of the epigenetic dysregulation in FSHD. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent myopathies, affecting males and females of all ages. Both forms of the disease are linked by epigenetic derepression of the D4Z4 macrosatellite repeat array at chromosome 4q35, leading to aberrant expression of D4Z4-encoded RNAs in skeletal muscle. Production of full-length DUX4 (DUX4-fl) mRNA from the derepressed D4Z4 array results in misexpression of DUX4-FL protein and its transcriptional targets, and apoptosis, ultimately leading to accumulated muscle pathology. Returning the chromatin at the FSHD locus to its nonpathogenic, epigenetically repressed state would simultaneously affect all D4Z4 RNAs, inhibiting downstream pathogenic pathways, and is thus an attractive therapeutic strategy. Advances in CRISPR/Cas9-based genome editing make it possible to target epigenetic modifiers to an endogenous disease locus, although reports to date have focused on more typical genomic regions. Here, we demonstrate that a CRISPR/dCas9 transcriptional inhibitor can be specifically targeted to the highly repetitive FSHD macrosatellite array and alter the chromatin to repress expression of DUX4-fl in primary FSHD myocytes. These results implicate the promoter and exon 1 of DUX4 as potential therapeutic targets and demonstrate the utility of CRISPR technology for correction of the epigenetic dysregulation in FSHD.
The cytotoxic T cell proteome and its shaping by the kinase mTOR
Authors: Jens L Hukelmann, Karen E Anderson, Linda V Sinclair, Katarzyna M Grzes, Alejandro Brenes Murillo, Phillip T Hawkins, Len R Stephens, Angus I Lamond, Doreen A Cantrell
Journal: Nature Immunology (2015)
Rational design of multifunctional magnetic mesoporous silica nanoparticle for tumor-targeted magnetic resonance imaging and precise therapy
Authors: Wei-Hai Chen, Guo-Feng Luo, Qi Lei, Feng-Yi Cao, Jin-Xuan Fan, Wen-Xiu Qiu, Hui-Zhen Jia, Sheng Hong, Fang Fang, Xuan Zeng, Ren-Xi Zhuo, Xian-Zheng Zhang
Journal: Biomaterials (2015)
Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10-Color flow cytometry diagnosis and HyperCVAD therapy
Authors: Uday Deotare, Karen W.L. Yee, Lisa W. Le, Anna Porwit, Anne Tierens, Rumina Musani, David Barth, Emina Torlakovic, Aaron Schimmer, Andre C. Schuh, Matthew Seftel, Mark D. Minden, Vikas Gupta, Elizabeth Hyjek
Journal: American Journal of Hematology (2015)

Few studies describe the comprehensive immunophenotypic pattern of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in the bone marrow and its treatment. This retrospective analysis evaluates the diagnostic flow cytometry (FCM) pattern and outcome of nine patients diagnosed with BPDCN. A four-tube 10-color FCM panel used for diagnosis of acute leukemia (AL), showed cells in the blast gate (CD45dim/low SSC) and were positive for CD4(bright), CD33(dim), CD56(heterogenous), CD123(bright), CD36, CD38, HLA-DR, CD71. Seven patients received front-line induction therapy with HyperCVAD with an overall response rate of 86%. Five of six responders underwent planned allogeneic hematopoietic cell transplantation (allo-HCT). For a median follow up of 13.3 months, the 1-year disease free survival and overall survival were 56 and 67%, respectively. An accurate diagnosis of BPDCN can be made by 10-color FCM using a four-tube AL panel demonstrating a characteristic pattern of antigen expression. Front-line induction chemotherapy with HyperCVAD can yield high remission rates, but allo-HCT is required for long-term durable remissions.
Screening for early breast cancer reduces invasive cancer, study finds
Authors: Susan Mayor
Journal: BMJ (2015)

The postinjury regenerative capacity of neurons is known to be mediated by a complex interaction of intrinsic regenerative pathways and external cues. In <i>Caenorhabditis elegans</i>, the initiation of axon regeneration is regulated by the nonmuscle myosin light chain-4 (MLC-4) phosphorylation signaling pathway. In this study, we have identified <i>svh-16</i>/<i>cdk-14</i>, a mammalian CDK14 homolog, as a positive regulator of axon regeneration in motor neurons. We then isolated the CDK-14-binding protein MIG-5/Disheveled (Dsh) and found that EGL-20/Wnt and the MIG-1/Frizzled receptor (Fz) are required for efficient axon regeneration. Further, we demonstrate that CDK-14 activates EPHX-1, the <i>C. elegans</i> homolog of the mammalian ephexin Rho-type GTPase guanine nucleotide exchange factor (GEF), in a kinase-independent manner. EPHX-1 functions as a GEF for the CDC-42 GTPase, inhibiting myosin phosphatase, which maintains MLC-4 phosphorylation. These results suggest that CDK14 activates the RhoGEF–CDC42–MLC phosphorylation axis in a noncanonical Wnt signaling pathway that promotes axon regeneration. <b>SIGNIFICANCE STATEMENT</b> Noncanonical Wnt signaling is mediated by Frizzled receptor (Fz), Disheveled (Dsh), Rho-type GTPase, and nonmuscle myosin light chain (MLC) phosphorylation. This study identified <i>svh-16</i>/<i>cdk-14</i>, which encodes a mammalian CDK14 homolog, as a regulator of axon regeneration in <i>Caenorhabditis elegans</i> motor neurons. We show that CDK-14 binds to MIG-5/Dsh, and that EGL-20/Wnt, MIG-1/Fz, and EPHX-1/RhoGEF are required for axon regeneration. The phosphorylation-mimetic MLC-4 suppressed axon regeneration defects in <i>mig-1</i>, <i>cdk-14</i>, and <i>ephx-1</i> mutants. CDK-14 mediates kinase-independent activation of EPHX-1, which functions as a guanine nucleotide exchange factor for CDC-42 GTPase. Activated CDC-42 inactivates myosin phosphatase and thereby maintains MLC phosphorylation. Thus, the noncanonical Wnt signaling pathway controls axon regeneration via the CDK-14–EPHX-1–CDC-42–MLC phosphorylation axis.
Attitudes of 47 mothers of pediatric oncology patients toward genetic testing for cancer predisposition.
Authors: A F Patenaude, L Basili, D L Fairclough, F P Li
Journal: Journal of Clinical Oncology (1996)

PURPOSE To assess attitudes toward testing for cancer susceptibility genes, we interviewed mothers of pediatric oncology patients about their cancer causation theories, interest in hypothetical predisposition testing for themselves and their healthy children, and anticipated impact of testing. PATIENTS AND METHODS The subjects were 47 mothers of two or more living children, one of whom was 6 to 24 months postdiagnosis of cancer. Potential risks and benefits of hypothetical genetic predisposition testing for cancer susceptibility were described. A semistructured interview assessed the following: (1) recall of discussions with the pediatric oncologist about the possible role of heredity in causing the child's cancer; (2) mothers' personal theories of the etiology of their child's cancer; (3) family cancer history; (4) interest in genetic predisposition testing for themselves and unaffected (cancer-free) children; and (5) expected sequelae of testing. RESULTS If genetic cancer predisposition tests were available, 51% of mothers would test themselves and 42% would test healthy children, even with no medical benefit. With established medical benefit, an additional 36% of mothers would seek testing for themselves and another 49% would test their healthy children. Interest in cancer predisposition testing among mothers extended far beyond those with significant family histories of cancer. Most mothers would consider minor children's wishes in the decision about testing and would tell children under age 18 their test results. CONCLUSION As increasing numbers of cancer susceptibility genes are identified, parents of pediatric oncology patients may be receptive to opportunities to test themselves and their healthy children. Counseling will be important to aid in decisions about testing. Research is essential to evaluate the long-term impact of predisposition testing.
Novel drug targets for personalized precision medicine in relapsed/refractory diffuse large B-cell lymphoma: a comprehensive review
Authors: Rosalba Camicia, Hans C. Winkler, Paul O. Hassa
Journal: Molecular Cancer (2015)

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy and the most common subtype of non-Hodgkin's lymphoma in adults, with one of the highest mortality rates in most developed areas of the world. More than half of DLBLC patients can be cured with standard R-CHOP regimens, however approximately 30 to 40 % of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality due to the limited therapeutic options. Recent advances in gene expression profiling have led to the identification of at least three distinct molecular subtypes of DLBCL: a germinal center B cell-like subtype, an activated B cell-like subtype, and a primary mediastinal B-cell lymphoma subtype. Moreover, recent findings have not only increased our understanding of the molecular basis of chemotherapy resistance but have also helped identify molecular subsets of DLBCL and rational targets for drug interventions that may allow for subtype/subset-specific molecularly targeted precision medicine and personalized combinations to both prevent and treat relapsed/refractory DLBCL. Novel agents such as lenalidomide, ibrutinib, bortezomib, CC-122, epratuzumab or pidilizumab used as single-agent or in combination with (rituximab-based) chemotherapy have already demonstrated promising activity in patients with relapsed/refractory DLBCL. Several novel potential drug targets have been recently identified such as the BET bromodomain protein (BRD)-4, phosphoribosyl-pyrophosphate synthetase (PRPS)-2, macrodomain-containing mono-ADP-ribosyltransferase (ARTD)-9 (also known as PARP9), deltex-3-like E3 ubiquitin ligase (DTX3L) (also known as BBAP), NF-kappaB inducing kinase (NIK) and transforming growth factor beta receptor (TGFβR). This review highlights the new insights into the molecular basis of relapsed/refractory DLBCL and summarizes the most promising drug targets and experimental treatments for relapsed/refractory DLBCL, including the use of novel agents such as lenalidomide, ibrutinib, bortezomib, pidilizumab, epratuzumab, brentuximab-vedotin or CAR T cells, dual inhibitors, as well as mechanism-based combinatorial experimental therapies. We also provide a comprehensive and updated list of current drugs, drug targets and preclinical and clinical experimental studies in DLBCL. A special focus is given on STAT1, ARTD9, DTX3L and ARTD8 (also known as PARP14) as novel potential drug targets in distinct molecular subsets of DLBCL.