bluuebunny/crossref_metadata_2025_split huggingface dataset:
Applications of Recombinant Dna Technology in Gastrointestinal Medicine and Hepatology: Basic Paradigms of Molecular Cell Biology. Part B: Eukaryotic Gene Transcription and Post-Transcripional Rna Processing
Authors: Wild Gary E , Papalia Patrizia , Ropeleski Mark J , Faria Julio , Thomson Alan BR 
Published: April 2016

The transcription of DNA into RNA is the primary level at which gene expression is controlled in eukaryotic cells. Eukaryotic gene transcription involves several different RNA polymerases that interact with a host of transcription factors to initiate transcription. Genes that encode proteins are transcribed into messenger RNA (mRNA) by RNA polymerase II. Ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs) are transcribed by RNA polymerase I and III, respectively. The production of each mRNA in human cells involves complex interactions of proteins (ie, trans-acting factors) with specific sequences on the DNA (ie, cis-acting elements). Cis-acting elements are short base sequences adjacent to or within a particular gene. While the regulation of transcription is a pivotal step in the control of gene expression, a variety of molecular events, collectively known as ’RNA processing’ add an additional level of control of gene expression in eukaryotic cells.
Consensus Guidelines: Agreement and Debate Surrounding the Optimal Management ofHelicobacter pyloriInfection
Authors: McNamara D , O’Morain C 
Published: April 2016

Helicobacter pyloriis a recognized cause of a variety of gastroduodenal pathology. The high prevalence of bothH pyloriinfection and related diseases within the community warrants its consideration as a public health care issue. The availability of reliable and safe noninvasive diagnostic techniques coupled with the development of effective and tolerable treatments has enabled primary health care personnel to manage this infection actively. The role of the primary care physician in the future management ofH pyloriinfection is thus of central importance. The wealth of evidence produced by over 15 years of research intoH pylorihas expanded the list of disease associations and treatment benefits as well as elucidated the pathophysiological mechanisms involved. As a result, there has been a growing need to harmonize this information with clinical practice and to provide direction for the appropriate management by both specialists and general practitioners. Several national guidelines have been produced. The areas relating toH pyloriinfection that they considered and their recommendations vary. In 1994, the National Institutes of Health produced globally accepted recommendations for the management ofH pylori-related peptic ulceration. The broader role ofH pylorias a gastroduodenal pathogen and a public health care issue was not addressed. Recently, European and Canadian consensus guidelines have been published that identified overall management issues, including the role of primary and specialist care, and considered the appropriateness of employing eradication therapy for the spectrum of conditions in whichH pylorihas a direct or indirect association based on the available information. These guidelines, while in agreement regarding many issues, differ considerably in their recommendations for primary health care and regarding central issues such as the management of dyspepsia and gastric cancer. Some variations may reflect differing health care structures as well as the prevalence of both infection and associated diseases. However, the interpretation of evidence produced by recent research contributes to their conflicting statements.
Bismuth-Based Triple Therapy with Bismuth Subcitrate, Metronidazole and Tetracycline in the Eradication ofHelicobacter pylori: A Randomised, Placebo Controlled, Double-Blind Study
Authors: van Zanten Sander Veldhuyzen , Farley Alain , Marcon Norman , Lahaie Raymond , Archambault André , Hunt Richard , Bailey Robert , Owen David , Spénard Jean , Stiglick Alan , Aimola Nick , Colin Patrick 
Published: April 2016

OBJECTIVE: To determine the rate ofHelicobacter pylorieradication following bismuth-based triple therapy with colloidal bismuth subcitrate, tetracycline hydrochloride and metronidazole.PATIENTS AND METHODS: One hundred and eleven patients were randomly assigned, in a two to one ratio, to colloidal bismuth subcitrate 120 mg qid plus metronidazole 250 mg qid plus tetracycline 500 mg qid (Gastrostat), or matching placebo tablets and capsules for 14 days. Presence or absence ofH pyloriwas documented by histology at entry and at least 28 days after treatment. Patients had dyspeptic symptoms with or without a history of peptic ulcer. Patients with any previous attempt(s) at eradication ofH pylori, who used bismuth, antibiotics, H2 receptor antagonists or proton pump inhibitors in the previous four weeks were excluded.RESULTS: Fifty-three of 59 (90%) patients on bismuth-based treatment and only one of 35 (3%) on placebo achieved eradication by per protocol analysis. Fifty-three of 65 (82%) patients on bismuth-based treatment achieved eradication, while only two of 34 (5%) achieved eradication on placebo by intention to treat analysis. Eradication rates for bismuth-based treatment across sites ranged from 83% to 100%. Only two patients in the bismuth-based treatment group (4%) and one in the placebo group (3%) discontinued treatment because of adverse events.CONCLUSIONS: Colloidal bismuth subcitrate plus metronidazole plus tetracycline, given in the doses studied for 14 days, is safe and highly effective againstH pyloriinfection and would be appropriate as a first-line therapy for eradication.
Examination of Gastroesophageal Reflux by Transabdominal Ultrasound: Can a Slow, Trickling form of Reflux be Responsible for Reflux Esophagitis?
Authors: Madi-Szabo László , Kocsis György 
Published: April 2016

BACKGROUND: Ultrasound can visualize significant portions of the upper and lower esophagus; it is without any instrumental interference in real conditions and displays events in motion.PURPOSE: To study the events that occur during swallowing and gastroesophageal reflux.PATIENTS AND METHODS: Group 1 comprised 25 patients with retrosternal complaints, selected for esophageal surface ultrasonography for endoscopic signs of esophagitis. Group 2 comprised 25 patients who underwent initial transabdominal ultrasonography. For 3 to 6 h before ultrasonography, nothing was given by mouth to the 50 patients labelled as having gastroesophageal reflux disease (GERD). Ultrasonography was then performed for 15 to 20 mins after drinking one mouthful of water or tea, or swallowing some saliva to provoke reflux. The events were recorded on videotape rolls. Endoscopy was carried out in all 50 cases; in 46 cases (21 and 25 from groups 1 and 2, respectively), gastric acidity and bacteriology were subsequently examined (test meal). Manometry and pH were not measured to avoid provocation of reflux by the instruments. Thirty patients without any esophageal complaints or signs of esophagitis (though suffering from gastric and duodenal diseases) were designated as the control group (group 3). The available results were compared.RESULTS: In 32 of 46 patients diagnosed with GERD (69.5% in groups 1 and 2), a special kind of reflux was observed by ultrasonography: a slow, trickling reflux of the gastric content was seen, mostly after swallowing. A fast clearance followed four to six episodes of the trickling reflux, only after an interval of 0.5 to 2 mins. Only fast refluxes and immediate clearance were observed in the control group.CONCLUSIONS: The observations above may indicate a special form of gastroesophageal reflux, namely, a slow, trickling form of it. It can be responsible for the development of GERD. Fast reflux and immediate clearance are common; however, this special trickling form was observed only in GERD patients. This may explain a number of often contradictory measurements and can make the effect of cisapride more understandable. A test meal is always necessary to distinguish a bilious reflux from an acidic one, because only the latter may require aggresive antacidic treatment.
Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway
Authors: Crowther Andrew J. , Ocasio Jennifer K. , Fang Fang , Meidinger Jessica , Wu Jaclyn , Deal Allison M. , Chang Sha X. , Yuan Hong , Schmid Ralf , Davis Ian , Gershon Timothy R. 
Published: April 2016

Abstract
While treatments that induce DNA damage are commonly used as anticancer therapies, the mechanisms through which DNA damage produces a therapeutic response are incompletely understood. Here we have tested whether medulloblastomas must be competent for apoptosis to be sensitive to radiotherapy. Whether apoptosis is required for radiation sensitivity has been controversial. Medulloblastoma, the most common malignant brain tumor in children, is a biologically heterogeneous set of tumors typically sensitive to radiation and chemotherapy; 80% of medulloblastoma patients survive long-term after treatment. We used functional genetic studies to determine whether the intrinsic apoptotic pathway is required for radiation to produce a therapeutic response in mice with primary, Shh-driven medulloblastoma. We found that cranial radiation extended the survival of medulloblastoma-bearing mice and induced widespread apoptosis. Expression analysis and conditional deletion studies showed that Trp53 (p53) was the predominant transcriptional regulator activated by radiation and was strictly required for treatment response. Deletion of Bax, which blocked apoptosis downstream of p53, was sufficient to render tumors radiation resistant. In apoptosis-incompetent, Bax-deleted tumors, radiation activated p53-dependent transcription without provoking cell death and caused two discrete populations to emerge. Most radiated tumor cells underwent terminal differentiation. Perivascular cells, however, quickly resumed proliferation despite p53 activation, behaved as stem cells, and rapidly drove recurrence. These data show that radiation must induce apoptosis in tumor stem cells to be effective. Mutations that disable the intrinsic apoptotic pathways are sufficient to impart radiation resistance. We suggest that medulloblastomas are typically sensitive to DNA-damaging therapies, because they retain apoptosis competence. Cancer Res; 76(11); 3211–23. ©2016 AACR.
MYC-Driven Neuroblastomas Are Addicted to a Telomerase-Independent Function of Dyskerin
Authors: O'Brien Rosemary , Tran Sieu L. , Maritz Michelle F. , Liu Bing , Kong Cheng Fei , Purgato Stefania , Yang Chen , Murray Jayne , Russell Amanda J. , Flemming Claudia L. , von Jonquieres Georg , Pickett Hilda A. , London Wendy B. , Haber Michelle , Gunaratne Preethi H. , Norris Murray D. , Perini Giovanni , Fletcher Jamie I. , MacKenzie Karen L. 
Published: April 2016

Abstract
The RNA-binding protein dyskerin, encoded by the DKC1 gene, functions as a core component of the telomerase holoenzyme as well as ribonuclear protein complexes involved in RNA processing and ribosome biogenesis. The diverse roles of dyskerin across many facets of RNA biology implicate its potential contribution to malignancy. In this study, we examined the expression and function of dyskerin in neuroblastoma. We show that DKC1 mRNA levels were elevated relative to normal cells across a panel of 15 neuroblastoma cell lines, where both N-Myc and c-Myc directly targeted the DKC1 promoter. Upregulation of MYCN was shown to dramatically increase DKC1 expression. In two independent neuroblastoma patient cohorts, high DKC1 expression correlated strongly with poor event-free and overall survival (P &lt; 0.0001), independently of established prognostic factors. RNAi-mediated depletion of dyskerin inhibited neuroblastoma cell proliferation, including cells immortalized via the telomerase-independent ALT mechanism. Furthermore, dyskerin attenuation impaired anchorage-independent proliferation and tumor growth. Overexpression of the telomerase RNA component, hTR, demonstrated that this proliferative impairment was not a consequence of telomerase suppression. Instead, ribosomal stress, evidenced by depletion of small nucleolar RNAs and nuclear dispersal of ribosomal proteins, was the likely cause of the proliferative impairment in dyskerin-depleted cells. Accordingly, dyskerin suppression caused p53-dependent G1 cell-cycle arrest in p53 wild-type cells, and a p53-independent pathway impaired proliferation in cells with p53 dysfunction. Together, our findings highlight dyskerin as a new therapeutic target in neuroblastoma with crucial telomerase-independent functions and broader implications for the spectrum of malignancies driven by MYC family oncogenes. Cancer Res; 76(12); 3604–17. ©2016 AACR.
Inhibition of PAI-1 Limits Tumor Angiogenesis Regardless of Angiogenic Stimuli in Malignant Pleural Mesothelioma
Authors: Takayama Yusuke , Hattori Noboru , Hamada Hironobu , Masuda Takeshi , Omori Keitaro , Akita Shin , Iwamoto Hiroshi , Fujitaka Kazunori , Kohno Nobuoki 
Published: April 2016

Abstract
Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor that secretes various angiogenic factors. The main inhibitor of plasminogen activators, PAI-1 (SERPINE1), has been implicated in tumor progression and angiogenesis, and high PAI-1 expression has been associated with poor prognosis in MPM patients. In this study, we examined the antiangiogenic effects of PAI-1 inhibition in MPM. We administered the PAI-1 inhibitor, SK-216, to orthotopic mouse models in which MPM cells expressing high levels of VEGF (VEGFA) or bFGF (FGF2) were intrapleurally transplanted. SK-216 administration reduced tumor weights and the degree of angiogenesis in intrapleural tumors, irrespective of their angiogenic expression profiles. In addition, a combination of SK-216 and the chemotherapeutic agent cisplatin significantly reduced tumor weights compared with monotherapy, prolonging the survival of animals compared with cisplatin treatment alone. Furthermore, SK-216 inhibited migration and tube formation of cultured human umbilical vein endothelial cells induced by various angiogenic factors known to be secreted by MPM. These findings suggest that PAI-1 inactivation by SK-216 may represent a general strategy for inhibiting angiogenesis, including for the treatment of MPM. Cancer Res; 76(11); 3285–94. ©2016 AACR.
A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors
Authors: Dowlati Afshin , Vlahovic Gordana , Natale Ronald B. , Rasmussen Erik , Singh Indrajeet , Hwang Yuying C. , Rossi John , Bass Michael B. , Friberg Gregory , Pickett Cheryl A. 
Published: April 2016

Abstract
Purpose: To assess the toxicity, pharmacokinetics, tumor vascular response, tumor response, and pharmacodynamics of AMG 780, a mAb designed to inhibit the interaction between angiopoietin-1 and -2 and the Tie2 receptor.
Experimental Design: This was a phase I dose-escalation study of patients with advanced solid tumors refractory to standard treatment without previous antiangiogenic treatment. AMG 780 was administered by intravenous infusion every 2 weeks in doses from 0.1 to 30 mg/kg. The primary endpoints were incidences of dose-limiting toxicity (DLT) and adverse events (AE), and pharmacokinetics. Secondary endpoints included tumor response, changes in tumor volume and vascularity, and anti-AMG 780 antibody formation.
Results: Forty-five patients were enrolled across nine dose cohorts. Three patients had DLTs (0.6, 10, and 30 mg/kg), none of which prevented dose escalation. At 30 mg/kg, no MTD was reached. Pharmacokinetics of AMG 780 were dose proportional; median terminal elimination half-life was 8 to 13 days. No anti-AMG 780 antibodies were detected. At week 5, 6 of 16 evaluable patients had a &gt;20% decrease in volume transfer constant (Ktrans), suggesting reduced capillary blood flow/permeability. The most frequent AEs were hypoalbuminemia (33%), peripheral edema (29%), decreased appetite (27%), and fatigue (27%). Among 35 evaluable patients, none had an objective response; 8 achieved stable disease.
Conclusions: AMG 780 could be administered at doses up to 30 mg/kg every 2 weeks in patients with advanced solid tumors. AMG 780 treatment resulted in tumor vascular effects in some patients. AEs were in line with toxicity associated with antiangiopoietin treatment. Clin Cancer Res; 22(18); 4574–84. ©2016 AACR.
Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia
Authors: Teachey David T. , Lacey Simon F. , Shaw Pamela A. , Melenhorst J. Joseph , Maude Shannon L. , Frey Noelle , Pequignot Edward , Gonzalez Vanessa E. , Chen Fang , Finklestein Jeffrey , Barrett David M. , Weiss Scott L. , Fitzgerald Julie C. , Berg Robert A. , Aplenc Richard , Callahan Colleen , Rheingold Susan R. , Zheng Zhaohui , Rose-John Stefan , White Jason C. , Nazimuddin Farzana , Wertheim Gerald , Levine Bruce L. , June Carl H. , Porter David L. , Grupp Stephan A. 
Published: April 2016

Abstract
Chimeric antigen receptor (CAR)–modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFNγ, IL6, sgp130, and sIL6R, in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results were validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology and, importantly, represent the first data that can accurately predict which patients have a high probability of becoming critically ill.
Significance: CRS is the most common severe toxicity seen after CAR T-cell treatment. We developed models that can accurately predict which patients are likely to develop severe CRS before they become critically ill, which improves understanding of CRS biology and may guide future cytokine-directed therapy. Cancer Discov; 6(6); 664–79. ©2016 AACR.
See related commentary by Rouce and Heslop, p. 579.
This article is highlighted in the In This Issue feature, p. 561
Protein S testing in patients with protein S deficiency, factor V Leiden, and rivaroxaban by North American Specialized Coagulation Laboratories
Authors: Smock Kristi , Plumhoff Elizabeth , Meijer Piet , Hsu Peihong , Zantek Nicole , Heikal Nahla , Van Cott Elizabeth 
Published: April 2016

SummaryIn 2010–2012, the North American Specialized Coagulation Laboratory Association (NASCOLA) distributed 12 proficiency testing challenges to evaluate laboratory testing for protein S (PS). Results were analysed to assess the performance of PS activity, PS free antigen, and PS total antigen testing. Statistical analysis was performed on the numeric results and qualitative classification submitted for each method. There were 2,106 total results: 716 results from PS activity assays, 833 results from PS free antigen assays, and 557 results from PS total antigen assays. The three assay types performed well in the classification of five normal samples and nine abnormal samples, although certain PS activity methods were more likely to classify normal samples as abnormal and one PS total antigen assay was more likely to classify abnormal samples as normal. PS activity methods were affected by interfering substances such as heterozygous or homozygous factor V Leiden mutation (underestimation) and the anticoagulant drug rivaroxaban (overestimation). In conclusion, NASCOLA laboratories using a variety of PS assays performed well in the classification of clearly normal and abnormal samples. Laboratories performing PS activity assays should be aware of potential interferences in samples positive for FV Leiden or containing certain anticoagulant medications.
Ischemic Stroke or Systemic Embolism After Transseptal Ablation of Arrhythmias in Patients With Cardiac Implantable Electronic Devices
Authors: Madhavan Malini , Yao Xiaoxi , Sangaralingham Lindsey R. , Asirvatham Samuel J. , Friedman Paul A. , McLeod Christopher J. , Sugrue Alan M. , DeSimone Christopher V. , Noseworthy Peter A. 
Published: April 2016

Background

Incidental mobile thrombi are commonly found on endovascular leads of cardiac implantable electronic devices (
CIED
s). Transseptal puncture for catheter ablation of arrhythmia poses a risk for paradoxical embolism. We examined risk of ischemic stroke, transient ischemic attack (
TIA
), or systemic embolism after transseptal ablation in patients with and without
CIED
s.

Methods and Results

Using a national administrative claims database, 31 720 patients who underwent a transseptal catheter ablation between January 2004 and September 2014 were identified. Two propensity‐matched cohorts were created by matching demographic variables, administrative variables, Charlson Comorbidity Index,
CHA
2
DS
2
‐Vasc score, and year and indication for ablation (5533 and 11 300 patients with and without
CIED
s). Incidence rates and Cox proportional hazards models were used to estimate risk of ischemic stroke,
TIA
, or systemic embolism for patients with and without
CIED
s. Impact of oral anticoagulation (
OAC
) use on the endpoint was examined. Over a mean follow‐up of 2.1 years, the incidence of the combined endpoint was 1.9 per 100 person‐years in patients with
CIED
s and 1.5 per 100 person‐years in patients without
CIED
s (
P
=0.03). Among patients not on
OAC
, presence of a cardiac device was associated with an increased risk (hazard ratio [
HR
], 1.71 [1.24–2.35];
P
<0.01), whereas there was no association noted among patients treated with
OAC
(
HR
, 0.98 [0.75–1.28]).

Conclusion

CIED
s are associated with an increased risk of stroke,
TIA
, or systemic embolism after transseptal ablation, but this risk is attenuated with postablation
OAC
use. Role of anticoagulation post‐transseptal ablation in patients with
CIED
warrants further investigation.