bluuebunny/crossref_metadata_2025_split huggingface dataset:
GPs’ perspectives on the management of patients with multimorbidity: systematic review and synthesis of qualitative research
Authors: Sinnott Carol , Mc Hugh Sheena , Browne John , Bradley Colin 
Published: September 2013

ObjectiveTo synthesise the existing published literature on the perceptions of general practitioners (GPs) or their equivalent on the clinical management of multimorbidity and determine targets for future research that aims to improve clinical care in multimorbidity.DesignSystematic review and metaethnographic synthesis of primary studies that used qualitative methods to explore GPs’ experiences of clinical management of multimorbidity or multiple chronic diseases.Data sourcesEMBASE, MEDLINE, CINAHL, PsycInfo, Academic Search Complete, SocIndex, Social Science Full Text and digital theses/online libraries (database inception to September 2012) to identify literature using qualitative methods (focus groups or interviews).Review methodsThe 7-step metaethnographic approach described by Noblit and Hare, which involves cross-interpretation between studies while preserving the context of the primary data.ResultsOf 1805 articles identified, 37 were reviewed in detail and 10 were included, using a total of 275 GPs in 7 different countries. Four areas of difficulty specific to the management of multimorbidity emerged from these papers: disorganisation and fragmentation of healthcare; the inadequacy of guidelines and evidence-based medicine; challenges in delivering patient-centred care; and barriers to shared decision-making. A ‘line of argument’ was drawn which described GPs’ sense of isolation in decision-making for multimorbid patients.ConclusionsThis systematic review shows that the problem areas for GPs in the management of multimorbidity may be classified into four domains. There will be no ‘one size fits all’ intervention for multimorbidity but these domains may be useful targets to guide the development of interventions that will assist and improve the provision of care to multimorbid patients.
Antimicrobial resistance monitoring inNeisseria gonorrhoeaeand strategic use of funds from the Global Fund to set up a systematic Moroccan gonococcal antimicrobial surveillance programme
Authors: Hançali Amina , Ndowa Francis , Bellaji Bahija , Bennani Aziza , Kettani Amina , Charof Reda , Aouad Rajae El 
Published: September 2013

ObjectivesThe aims of this study were to assess antimicrobial resistance inNeisseria gonorrhoeaeinfections and update the treatment in the national guidelines for the syndromic management of sexually transmitted infections in Morocco.Methods171 men complaining of urethral discharge were recruited from basic health services during 2009. Urethral swab samples were collected andN gonorrhoeaeidentification was performed by culture. Antimicrobial susceptibility testing was performed using the Etest method and the antimicrobial agents tested were ciprofloxacin, penicillin, spectinomycin, tetracycline, ceftriaxone and cefixime.ResultsA total of 72 isolates were examined. Significant resistance to tetracycline (92.8%) and ciprofloxacin (86.8%), which was used as first-line treatment in gonococcal infections, was noted. No resistance to spectinomycin, ceftriaxone or cefixime was detected in all the isolates.ConclusionsFollowing these results the Ministry of Health of Morocco replaced ciprofloxacin and introduced ceftriaxone 250 mg as a single dose in the treatment of gonococcal infections. Using funds from the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund), a surveillance programme was set up for antimicrobial resistance testing inN gonorrhoeae.
Antitumor Efficacy of a Monoclonal Antibody That Inhibits the Activity of Cancer-Associated Carbonic Anhydrase XII
Authors: Gondi Gabor , Mysliwietz Josef , Hulikova Alzbeta , Jen Jian Ping , Swietach Pawel , Kremmer Elisabeth , Zeidler Reinhard 
Published: September 2013

Abstract
Carbonic anhydrase XII (CA XII) is a membrane-tethered cell surface enzyme that is highly expressed on many human tumor cells. Carbonic anhydrase members in this class of exofacial molecules facilitate tumor metabolism by facilitating CO2 venting and intracellular pH regulation. Accordingly, inhibition of exofacial CAs has been proposed as a general therapeutic strategy to target cancer. The recent characterization of 6A10, the first CA XII-specific inhibitory monoclonal antibody, offered an opportunity to evaluate this strategy with regard to CA XII-mediated catalysis. Using functional assays, we showed that 6A10 inhibited exofacial CA activity in CA XII-expressing cancer cells. 6A10 reduced spheroid growth in vitro under culture conditions where CA XII was active (i.e., alkaline pH) and where its catalytic activity was likely rate-limiting (i.e., restricted extracellular HCO3− supply). These in vitro results argued that the antibody exerted its growth-retarding effect by acting on the catalytic process, rather than on antigen binding per se. Notably, when administered in a mouse xenograft model of human cancer, 6A10 exerted a significant delay on tumor outgrowth. These results corroborate the notion that exofacial CA is critical for cancer cell physiology and they establish the immunotherapeutic efficacy of targeting CA XII using an inhibitory antibody. Cancer Res; 73(21); 6494–503. ©2013 AACR.
Targeting Protein Kinase CK2 Suppresses Prosurvival Signaling Pathways and Growth of Glioblastoma
Authors: Zheng Ying , McFarland Braden C. , Drygin Denis , Yu Hao , Bellis Susan L. , Kim Hyunsoo , Bredel Markus , Benveniste Etty N. 
Published: September 2013

AbstractPurpose: Gliomas are the most frequently occurring primary malignancies in the brain, and glioblastoma is the most aggressive of these tumors. Protein kinase CK2 is composed of two catalytic subunits (α and/or α′) and two β regulatory subunits. CK2 suppresses apoptosis, promotes neoangiogenesis, and enhances activation of the JAK/STAT, NF-κB, PI3K/AKT, Hsp90, Wnt, and Hedgehog pathways. Aberrant activation of the NF-κB, PI3K/AKT, and JAK/STAT-3 pathways is implicated in glioblastoma progression. As CK2 is involved in their activation, the expression and function of CK2 in glioblastoma was evaluated.Experimental Design and Results: Analysis of 537 glioblastomas from The Cancer Genome Atlas Project demonstrates the CSNK2A1 gene, encoding CK2α, has gene dosage gains in glioblastoma (33.7%), and is significantly associated with the classical glioblastoma subtype. Inhibition of CK2 activity by CX-4945, a selective CK2 inhibitor, or CK2 knockdown by siRNA suppresses activation of the JAK/STAT, NF-κB, and AKT pathways and downstream gene expression in human glioblastoma xenografts. On a functional level, CX-4945 treatment decreases the adhesion and migration of glioblastoma cells, in part through inhibition of integrin β1 and α4 expression. In vivo, CX-4945 inhibits activation of STAT-3, NF-κB p65, and AKT, and promotes survival of mice with intracranial human glioblastoma xenografts.Conclusions: CK2 inhibitors may be considered for treatment of patients with glioblastoma. Clin Cancer Res; 19(23); 6484–94. ©2013 AACR.
Variation within 3′-UTRs of Base Excision Repair Genes and Response to Therapy in Colorectal Cancer Patients: A Potential Modulation of microRNAs Binding
Authors: Pardini Barbara , Rosa Fabio , Barone Elisa , Di Gaetano Cornelia , Slyskova Jana , Novotny Jan , Levy Miroslav , Garritano Sonia , Vodickova Ludmila , Buchler Tomas , Gemignani Federica , Landi Stefano , Vodicka Pavel , Naccarati Alessio 
Published: September 2013

Abstract
Purpose: Colorectal cancer is routinely treated with a 5-fluorouracil (5-FU)–based chemotherapy. 5-FU incorporates into DNA, and the base excision repair (BER) pathway specifically recognizes such damage. We investigated the association of single-nucleotide polymorphisms (SNP) in the 3′-untranslated regions (UTR) of BER genes, and potentially affecting the microRNA (miRNA) binding, on the risk of colorectal cancer, its progression, and prognosis. SNPs in miRNA-binding sites may modulate the posttranscriptional regulation of gene expression operated by miRNAs and explain interindividual variability in BER capacity and response to 5-FU.
Experimental Design: We tested 12 SNPs in the 3′-UTRs of five BER genes for colorectal cancer susceptibility in a case–control study (1,098 cases and 1,459 healthy controls). Subsequently, we analyzed the role of these SNPs on clinical outcomes of patients (866 in the Training set and 232 in the Replication set).
Results: SNPs in the SMUG1 and NEIL2 genes were associated with overall survival. In particular, SMUG1 rs2233921 TT carriers showed increased survival compared with those with GT/GG genotypes [HR, 0.54; 95% confidence interval (CI), 0.36–0.81; P = 0.003] in the Training set and after pooling results from the Replication set. The association was more significant following stratification for 5-FU–based chemotherapy (P = 5.6 × 10−5). A reduced expression of the reporter gene for the T allele of rs2233921 was observed when compared with the common G allele by in vitro assay. None of the genotyped BER polymorphisms were associated with colorectal cancer risk.
Conclusions: We provide the first evidence that variations in miRNA-binding sites in BER genes 3′-UTR may modulate colorectal cancer prognosis and therapy response. Clin Cancer Res; 19(21); 6044–56. ©2013 AACR.
The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas
Authors: Gini Beatrice , Zanca Ciro , Guo Deliang , Matsutani Tomoo , Masui Kenta , Ikegami Shiro , Yang Huijun , Nathanson David , Villa Genaro R. , Shackelford David , Zhu Shaojun , Tanaka Kazuhiro , Babic Ivan , Akhavan David , Lin Kelly , Assuncao Alvaro , Gu Yuchao , Bonetti Bruno , Mortensen Deborah S. , Xu Shuichan , Raymon Heather K. , Cavenee Webster K. , Furnari Frank B. , James C. David , Kroemer Guido , Heath James R. , Hege Kristen , Chopra Rajesh , Cloughesy Timothy F. , Mischel Paul S. 
Published: September 2013

Abstract
Purpose: mTOR pathway hyperactivation occurs in approximately 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here, we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacologic strategy to overcome it.
Experimental Design: We conducted in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin-resistant signaling and blocking glioblastoma growth and a novel single-cell technology—DNA Encoded Antibody Libraries—was used to identify mechanisms of resistance.
Results: Here, we show that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling, block mTORC2 signaling, and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes glioblastoma cells and orthotopic xenografts to CC214-1- and CC214-2–induced cell death.
Conclusions: These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in glioblastoma, and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. In addition, this study also shows a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacologic strategy for overcoming it. Clin Cancer Res; 19(20); 5722–32. ©2013 AACR.
Identification of Preferred Chemotherapeutics for Combining with a CHK1 Inhibitor
Authors: Xiao Yang , Ramiscal Judi , Kowanetz Kaska , Del Nagro Christopher , Malek Shiva , Evangelista Marie , Blackwood Elizabeth , Jackson Peter K. , O'Brien Thomas 
Published: September 2013

Abstract
Here we report that GNE-783, a novel checkpoint kinase-1 (CHK1) inhibitor, enhances the activity of gemcitabine by disabling the S- and G2 cell-cycle checkpoints following DNA damage. Using a focused library of 51 DNA-damaging agents, we undertook a systematic screen using three different cell lines to determine which chemotherapeutics have their activity enhanced when combined with GNE-783. We found that GNE-783 was most effective at enhancing activity of antimetabolite-based DNA-damaging agents; however, there was a surprisingly wide range of activity within each class of agents. We, next, selected six different therapeutic agents and screened these in combination with GNE-783 across a panel of cell lines. This revealed a preference for enhanced chemopotentiation of select agents within tumor types, as, for instance, GNE-783 preferentially enhanced the activity of temozolomide only in melanoma cell lines. Additionally, although p53 mutant status was important for the overall response to combinations with some agents; our data indicate that this alone was insufficient to predict synergy. We finally compared the ability of a structurally related CHK1 inhibitor, GNE-900, to enhance the in vivo activity of gemcitabine, CPT-11, and temozolomide in xenograft models. GNE-900 significantly enhanced activity of only gemcitabine in vivo, suggesting that strong chemopotentiation in vitro can translate into chemopotentiation in vivo. In conclusion, our results show that selection of an appropriate agent to combine with a CHK1 inhibitor needs to be carefully evaluated in the context of the genetic background and tumor type in which it will be used. Mol Cancer Ther; 12(11); 2285–95. ©2013 AACR.
Advances in Understanding the Expression and Function of Dipeptidyl Peptidase 8 and 9
Authors: Zhang Hui , Chen Yiqian , Keane Fiona M. , Gorrell Mark D. 
Published: September 2013

AbstractDPP8 and DPP9 are recently identified members of the dipeptidyl peptidase IV (DPPIV) enzyme family, which is characterized by the rare ability to cleave a post-proline bond two residues from the N-terminus of a substrate. DPP8 and DPP9 have unique cellular localization patterns, are ubiquitously expressed in tissues and cell lines, and evidence suggests important contributions to various biological processes including: cell behavior, cancer biology, disease pathogenesis, and immune responses. Importantly, functional differences between these two proteins have emerged, such as DPP8 may be more associated with gut inflammation whereas DPP9 is involved in antigen presentation and intracellular signaling. Similarly, the DPP9 connections with H-Ras and SUMO1, and its role in AKT1 pathway downregulation provide essential insights into the molecular mechanisms of DPP9 action. The recent discovery of novel natural substrates of DPP8 and DPP9 highlights the potential role of these proteases in energy metabolism and homeostasis. This review focuses on the recent progress made with these post-proline dipeptidyl peptidases and underscores their emerging importance. Mol Cancer Res; 11(12); 1487–96. ©2013 AACR.
Carotid Atherosclerosis and Incident Atrial Fibrillation
Authors: Willeit Karin , Pechlaner Raimund , Egger Georg , Weger Siegfried , Oberhollenzer Martin , Willeit Johann , Kiechl Stefan 
Published: September 2013

Objective—
Atrial fibrillation (AF) and atherosclerotic vascular disease are closely entangled disorders and often coexist. Whether atherosclerosis predisposes to the development of AF has not been fully elucidated.

Approach and Results—

This study was performed within the framework of the Bruneck Study, a population-based survey with near-complete participation (932 of 1000), long-term follow-up (1990–2010), and thorough assessment of AF. The carotid arteries served as a window to systemic atherosclerosis and were scanned every 5 years. Pooled logistic regression and multistate proportional hazards models were used to identify risk predictors of incident AF and effects of AF on mortality. During follow-up, 118 new cases of AF were detected (incidence per 1000 person-years of 8.1; 95% confidence interval, 6.8–9.6). Individuals with atherosclerosis were more likely to develop AF than individuals without (odds ratio, 1.8; 95% confidence interval, 1.1–3.1;
P
=0.021). This finding applied to women and men and to both baseline and incident atherosclerosis during follow-up. Subjects with atherosclerosis and AF were significantly more likely to die than those with either condition alone (
P
=0.0034), and mortality in this group was ≈4-fold compared with individuals free of atherosclerosis and AF (hazard ratio, 4.2; 95% confidence interval, 2.6–6.8;
P
<0.0001).

Conclusions—
We found that subjects with carotid atherosclerosis are at high risk of developing AF.
Evolution of Ventricular Tachycardia and Its Electrophysiological Substrate Early After Myocardial Infarction
Authors: Hsieh Calvin H.C. , Chia Ee-May , Huang Kaimin , Lu Juntang , Barry Michael , Pouliopoulos Jim , Ross David L. , Thomas Stuart P. , Kovoor Pramesh 
Published: September 2013

Background—
Sudden arrhythmic death after myocardial infarction (MI) is most frequent in the first month. Early programmed ventricular stimulation (within 1 week) post-MI has been able to identify long-term ventricular tachycardia (VT) occurrence. We aimed to determine the timing of development and stabilization of VT circuits after MI and how the evolution of the underlying substrate differs with VT inducibility.

Methods and Results—

MIs were induced in 36 sheep. The 21 survivors underwent serial electroanatomic mapping and programmed ventricular stimulation. Animals were classified as VT
pos
(inducible VT) or VT
neg
(noninducible VT) at day 8. Forty-three percent of MI survivors were VT
pos
on day 8 (9/21), and all remained inducible on day 100 with 1.5 (1.0–2.0) and 1.0 (1.0–2.0) morphologies per animal on days 8 and 100, respectively. Twelve-lead electrocardiogram matched in 15 of 19 VTs between days 8 and 100. The earliest presystolic ventricular activations during VT circuits were in similar locations at the 2 time points. The 12 VT
neg
animals remained noninducible on day 100. There was no difference in voltage or velocity substrate with time or inducibility. The area with fractionated signals increased with time and VT inducibility. VT
pos
animals had more linear regions of slowed conduction forming conducting channels.

Conclusions—
The inducibility and earliest presystolic endocardial activation sites of VT as well as voltage and velocity substrate on day 8 predicted those on day 100 postinfarct, indicating early formation and stabilization of the arrhythmogenic substrate. VT inducibility was influenced by the distribution of conducting channels and increased complex fractionated signals.
Contrast-Enhanced MRI–Derived Scar Patterns and Associated Ventricular Tachycardias in Nonischemic Cardiomyopathy
Authors: Piers Sebastiaan R.D. , Tao Qian , van Huls van Taxis Carine F.B. , Schalij Martin J. , van der Geest Rob J. , Zeppenfeld Katja 
Published: September 2013

Background—
There are limited data on typical arrhythmogenic substrates and associated ventricular tachycardias (VT) in patients with nonischemic cardiomyopathy. The substrate location may have implications for the ablation strategy.

Methods and Results—
Nineteen consecutive patients with nonischemic cardiomyopathy (age 58±14 years, 79% men, left ventricular ejection fraction 41±11%) who underwent contrast-enhanced MRI and VT ablation were included. On the basis of 3-dimensional contrast-enhanced MRI–derived scar reconstructions, 8 patients (42%) had predominant basal anteroseptal scar, 9 patients (47%) had predominant inferolateral scar, and 2 patients (11%) had other scar types. Three distinct VT morphologies (≥1 of 3 inducible in 16/19 patients) were associated with underlying scar type. In 9 patients with anteroseptal scar–related VT (8/9 predominant scar, 1/9 nonpredominant), ablation target sites (defined as sites with ≥11/12 pacemap, concealed entrainment or VT termination during ablation) were located in the aortic root and/or anteroseptal left ventricular endocardium in 8 patients (89%) and in the anterior cardiac vein in 1 patient (11%), with additional target sites at the right ventricular septum in 2 patients (22%) and at the epicardium in 1 patient (11%). In contrast, in 8 patients with predominant inferolateral scar–related VT, target sites were located at the epicardium in 5 patients (63%) and in the endocardial inferolateral left ventricle in 3 patients (37%).

Conclusions—
Two typical scar patterns (anteroseptal and inferolateral) account for 89% of arrhythmogenic substrates in patients with nonischemic cardiomyopathy. Three distinct VT morphologies are highly suggestive of the presence of these scars. Anteroseptal scars were, in general, most effectively approached from the aortic root or anteroseptal left ventricular endocardium, whereas inferolateral scars frequently required an epicardial approach.
Electrocardiographic Screening of 1-Month-Old Infants for Identifying Prolonged QT Intervals
Authors: Yoshinaga Masao , Ushinohama Hiroya , Sato Seiichi , Tauchi Nobuo , Horigome Hitoshi , Takahashi Hideto , Sumitomo Naokata , Kucho Yuu , Shiraishi Hirohiko , Nomura Yuichi , Shimizu Wataru , Nagashima Masami 
Published: September 2013

Background—
Neonatal electrocardiographic screening is used to screen infants with prolonged QT intervals, as previously shown in whites. However, this procedure needs to be confirmed in other ethnic groups.

Methods and Results—

In 8 areas in Japan, an ECG was recorded in 4285 infants at 1-month medical checkup. A prospective study showed that a provisional criterion of QTc ≥470 ms was appropriate for infants. To assess the validity of the criterion, all infants with a QTc between 460 and 470 ms were followed up. Five infants had a QTc ≥470 ms. Four infants were diagnosed with prolonged QT intervals from follow-up ECGs. Four infants showed no symptoms and did not have a family history of long-QT syndrome. Two infants showed progressive prolongation of QT intervals, and medication was started. Genetic testing was performed in 3 of 4 infants with prolonged QT intervals, and it revealed a
KCNH2
mutation (3065 delT, L1021fs+34X) in 1 infant. One infant with a QTc ≥470 ms and 2 infants with a QTc between 460 and 470 ms showed a decline in their QTc values during follow-up. The study screened another infant with Wolff–Parkinson–White syndrome who was diagnosed with noncompaction before symptoms appeared.

Conclusions—
Neonatal electrocardiographic screening can identify infants likely to be affected by long-QT syndrome in the Japanese population, as already shown in whites. This screening may also be useful in identifying other important cardiac diseases.