bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinician-scientist MB/PhD training in the UK: a nationwide survey of medical school policy
Authors: Barnett-Vanes Ashton , Ho Guiyi , Cox Timothy M 
Published: December 2015

ObjectiveThis study surveyed all UK medical schools regarding their Bachelor of Medicine (MB), Doctor of Philosophy (PhD) (MB/PhD) training policy in order to map the current training landscape and to provide evidence for further research and policy development.SettingDeans of all UK medical schools registered with the Medical Schools Council were invited to participate in this survey electronically.PrimaryThe number of medical schools that operate institutional MB/PhD programmes or permit self-directed student PhD intercalation.SecondaryMedical school recruitment procedures and attitudes to policy guidance.Findings27 of 33 (81%) registered UK medical schools responded. Four (14%) offer an institutional MB/PhD programme. However, of those without institutional programmes, 17 (73%) permit study interruption and PhD intercalation: two do not (one of whom had discontinued their programme in 2013), three were unsure and one failed to answer the question. Regarding student eligibility, respondents cited high academic achievement in medical studies and a bachelor's or master's degree. Of the Medical schools without institutional MB/PhD programmes, 5 (21%) have intentions to establish a programme, 8 (34%) do not and 3 were unsure, seven did not answer. 19 medical schools (70%) considered national guidelines are needed for future MB/PhD programme development.ConclusionsWe report the first national survey of MB/PhD training in the UK. Four medical schools have operational institutional MB/PhD programmes, with a further five intending to establish one. Most medical schools permit study interruption and PhD intercalation. The total number MB/PhD students yet to graduate from medical school could exceed 150, with 30 graduating per year. A majority of medical school respondents to this survey believe national guidelines are required for MB/PhD programme development and implementation. Further research should focus on the MB/PhD student experience. Discussion regarding local and national MB/PhD policies between medical schools and academic stakeholders are needed.
Influenza newspaper reports and the influenza epidemic: an observational study in Fukuoka City, Japan
Authors: Hagihara Akihito , Onozuka Daisuke , Miyazaki Shougo , Abe Takeru 
Published: December 2015

ObjectivesWe examined whether the weekly number of newspaper articles reporting on influenza was related to the incidence of influenza in a large city.DesignProspective, non-randomised, observational study.SettingRegistry data of influenza cases in Fukuoka City, Japan.ParticipantsA total of 83 613 cases of influenza cases that occurred between October 1999 and March 2007 in Fukuoka City, Japan.Main outcome measureA linear model with autoregressive time series errors was fitted to time series data on the incidence of influenza and the accumulated number of influenza-related newspaper articles with different time lags in Fukuoka City, Japan. In order to obtain further evidence that the number of newspaper articles a week with specific time lags is related to the incidence of influenza, Granger causality was also tested.ResultsOf the 16 models including ‘number of newspaper articles’ with different time lags between 2 and 17 weeks (xt-2 to t-17), the β coefficients of ‘number of newspaper articles’ at time lags between t-5 and t-13 were significant. However, the β coefficients of ‘number of newspaper articles’ that are significant with respect to the Granger causality tests (p<0.05) were the weekly number of newspaper articles at time lags between t-6 and t-10 (time shift of 10 weeks, β=−0.301, p<0.01; time shift of 9 weeks, β=−0.200, p<0.01; time shift of 8 weeks, β=−0.156, p<0.01; time shift of 7 weeks, β=−0.122, p<0.05; time shift of 6 weeks, β=−0.113, p<0.05).ConclusionsWe found that the number of newspaper articles reporting on influenza in a week was related to the incidence of influenza 6–10 weeks after media coverage in a large city in Japan.
Can transcutaneous carbon dioxide pressure be a surrogate of blood gas samples for spontaneously breathing emergency patients? The ERNESTO experience
Authors: Peschanski Nicolas , Garcia Léa , Delasalle Emilie , Mzabi Lynda , Rouff Edwin , Dautheville Sandrine , Renai Fayrouz , Kieffer Yann , Lefevre Guillaume , Freund Yonathan , Ray Patrick 
Published: December 2015

BackgroundIt is known that the arterial carbon dioxide pressure (PaCO2) is useful for emergency physicians to assess the severity of dyspnoeic spontaneously breathing patients. Transcutaneous carbon dioxide pressure (PtcCO2) measurements could be a non-invasive alternative to PaCO2measurements obtained by blood gas samples, as suggested in previous studies. This study evaluates the reliability of a new device in the emergency department (ED).MethodsWe prospectively included patients presenting to the ED with respiratory distress who were breathing spontaneously or under non-invasive ventilation. We simultaneously performed arterial blood gas measurements and measurement of PtcCO2using a sensor placed either on the forearm or the side of the chest and connected to the TCM4 CombiM device. The agreement between PaCO2and PtcCO2was assessed using the Bland–Altman method.ResultsSixty-seven spontaneously breathing patients were prospectively included (mean age 70 years, 52% men) and 64 first measurements of PtcCO2(out of 67) were analysed out of the 97 performed. Nineteen patients (28%) had pneumonia, 19 (28%) had acute heart failure and 19 (28%) had an exacerbation of chronic obstructive pulmonary disease. Mean PaCO2was 49 mm Hg (range 22–103). The mean difference between PaCO2and PtcCO2was 9 mm Hg (range −47 to +54) with 95% limits of agreement of −21.8 mm Hg and 39.7 mm Hg. Only 36.3% of the measurement differences were within 5 mm Hg.ConclusionsOur results show that PtcCO2measured by the TCM4 device could not replace PaCO2obtained by arterial blood gas analysis.
Effects of state-level policy changes on homicide and nonfatal shootings of law enforcement officers
Authors: Crifasi Cassandra K , Pollack Keshia M , Webster Daniel W 
Published: December 2015

ObjectiveTo evaluate the impact of state-level policy changes on assaults on law enforcement officers (LEOs) in the USA.MethodsPooled time series and cross-sections with negative binomial regression were used to estimate the impact of state-level changes of right-to-carry (RTC), three-strikes and permit-to-purchase (PTP) handgun laws on fatal and non-fatal assaults of LEOs. LEO assaults were stratified by weapon type (all methods, handgun and non-handgun) and whether or not the assault was fatal. Data were collected from the Federal Bureau of Investigation's Law Enforcement Officers Killed and Assaulted database and analysed for the period 1984–2013 for fatal assaults and 1998–2013 for non-fatal assaults.ResultsRTC laws showed no association with fatal (p>0.4) or non-fatal (p>0.15) assaults on LEOs. Three-strikes laws were associated with a 33% increase in the risk of fatal assaults on LEOs. Connecticut's PTP law was not associated with fatal (p>0.16) or non-fatal (p>0.13) assaults. Missouri's repeal of its PTP legislation was marginally associated with a twofold increased risk of non-fatal handgun assaults (p=0.089).ConclusionsThis research indicates that three-strikes laws increase the risk of fatal assaults. RTC laws are not associated with increased risk of assault. Missouri's PTP repeal may increase the risk of non-fatal handgun assaults.
Comparative effectiveness of biologic monotherapy versus combination therapy for patients with psoriatic arthritis: results from the Corrona registry
Authors: Mease Philip J , Collier David H , Saunders Katherine C , Li Guo , Kremer Joel M , Greenberg Jeffrey D 
Published: December 2015

ObjectivesTo characterise the comparative effectiveness of combination therapy (a tumour necrosis factor inhibitor (TNFi) and a conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate) and monotherapy (TNFi only) for psoriatic arthritis (PsA) from a large US registry.MethodsThe analysis included adult patients with PsA who were enrolled in the Corrona database (ClinicalTrials.gov,NCT01402661), had initiated a TNFi, were biologic naïve, and had a follow-up visit ≥90 days after drug initiation. The endpoints of the analysis were TNFi persistence (drug survival) and time to Clinical Disease Activity Index (CDAI) remission. All analyses were performed using propensity scoring, which were estimated using CDAI and patient sex, to control for channelling bias.ResultsOf 519 patients meeting the inclusion criteria (318 with combination therapy and 201 with monotherapy), the analysis population was 497 for TNFi persistence and 380 for time to remission. The difference between combination therapy (TNFi+methotrexate, 91% of patients; TNFi+other csDMARD, 9%) and monotherapy was not statistically significant for TNFi persistence (32 and 31 months, p=0.73) and time to remission (21 and 25 months, p=0.56). Predictors of TNFi persistence included Hispanic ethnicity (longer persistence), PsA duration (longer persistence), history of methotrexate use (shorter persistence), body mass index (shorter persistence) and disease activity (shorter persistence).ConclusionsPatients with PsA from a large US registry experienced similar TNFi persistence on combination therapy and monotherapy. Prospective, randomised clinical trials evaluating the efficacy of combination therapy versus monotherapy would provide much-needed clarity on treatment options for patients with PsA.Trial registration numberNCT01402661.
Angiotensin-(1-7) Decreases Cell Growth and Angiogenesis of Human Nasopharyngeal Carcinoma Xenografts
Authors: Pei Nana , Wan Renqiang , Chen Xinglu , Li Andrew , Zhang Yanling , Li Jinlong , Du Hongyan , Chen Baihong , Wei Wenjin , Qi Yanfei , Zhang Yi , Katovich Michael J. , Sumners Colin , Zheng Haifa , Li Hongwei 
Published: December 2015

Abstract
Angiotensin-(1-7) [Ang-(1-7)] is an endogenous, heptapeptide hormone acting through the Mas receptor (MasR), with antiproliferative and antiangiogenic properties. Recent studies have shown that Ang-(1-7) has an antiproliferative action on lung adenocarcinoma cells and prostate cancer cells. In this study, we report that MasR levels were significantly upregulated in nasopharyngeal carcinoma (NPC) specimens and NPC cell lines. Viral vector–mediated expression of Ang-(1-7) dramatically suppressed NPC cell proliferation and migration in vitro. These effects were completely blocked by the specific Ang-(1-7) receptor antagonist A-779, suggesting that they are mediated by the Ang-(1-7) receptor Mas. In this study, Ang-(1-7) not only caused a significant reduction in the growth of human nasopharyngeal xenografts, but also markedly decreased vessel density, suggesting that the heptapeptide inhibits angiogenesis to reduce tumor size. Mechanistic investigations revealed that Ang-(1-7) inhibited the expression of the proangiogenic factors VEGF and PlGF. Taken together, the data suggest that upregulation of MasR could be used as a diagnostic marker of NPC and Ang-(1-7) may be a novel therapeutic agent for nasopharyngeal cancer therapy because it exerts significant antiangiogenic activity. Mol Cancer Ther; 15(1); 37–47. ©2015 AACR.
The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis
Authors: Herath Nirmitha I. , Devun Flavien , Lienafa Marie-Christine , Herbette Aurélie , Denys Alban , Sun Jian-Sheng , Dutreix Marie 
Published: December 2015

Abstract
Metastatic liver disease from colorectal cancer is a significant clinical problem. This is mainly attributed to nonresectable metastases that frequently display low sensitivities to available chemotherapies and develop drug resistance partly via hyperactivation of some DNA repair functions. Combined therapies have shown some disease control; however, there is still a need for more efficient chemotherapies to achieve eradication of colorectal cancer liver metastasis. We investigated the tolerance and efficacy of a novel class of DNA repair inhibitors, Dbait, in association with conventional chemotherapy. Dbait mimics double-strand breaks and activates damage signaling, consequently inhibiting single- and double-stranded DNA repair enzyme recruitment. In vitro, Dbait treatment increases sensitivity of HT29 and HCT116 colorectal cancer cell lines. In vivo, the pharmacokinetics, biodistribution and the efficacy of the cholesterol-conjugated clinical form of Dbait, DT01, were assessed. The chemosensitizing abilities of DT01 were evaluated in association with oxaliplatin and 5-fluorouracil in intrahepatic HT29 xenografted mice used as a model for colorectal cancer liver metastasis. The high uptake of DT01 indicates that the liver is a specific target. We demonstrate significant antitumor efficacy in a liver metastasis model with DT01 treatment in combination with oxaliplatin and 5-fluorouracil (mean: 501 vs. 872 mm2, P = 0.02) compared to chemotherapy alone. The decrease in tumor volume is further associated with significant histologic changes in necrosis, proliferation, angiogenesis and apoptosis. Repeated cycles of DT01 do not increase chemotherapy toxicity. Combining DT01 with conventional chemotherapy may prove to be a safe and effective therapeutic strategy in the treatment of metastatic liver cancer. Mol Cancer Ther; 15(1); 15–22. ©2015 AACR.
AKT Inhibition Promotes Nonautonomous Cancer Cell Survival
Authors: Salony  , Solé Xavier , Alves Cleidson P. , Dey-Guha Ipsita , Ritsma Laila , Boukhali Myriam , Lee Ju H. , Chowdhury Joeeta , Ross Kenneth N. , Haas Wilhelm , Vasudevan Shobha , Ramaswamy Sridhar 
Published: December 2015

Abstract
Small molecule inhibitors of AKT (v-akt murine thymoma viral oncogene homolog) signaling are being evaluated in patients with various cancer types, but have so far proven therapeutically disappointing for reasons that remain unclear. Here, we treat cancer cells with subtherapeutic doses of Akti-1/2, an allosteric small molecule AKT inhibitor, in order to experimentally model pharmacologic inhibition of AKT signaling in vitro. We then apply a combined RNA, protein, and metabolite profiling approach to develop an integrated, multiscale, molecular snapshot of this “AKTlow” cancer cell state. We find that AKT-inhibited cancer cells suppress thousands of mRNA transcripts, and proteins related to the cell cycle, ribosome, and protein translation. Surprisingly, however, these AKT-inhibited cells simultaneously upregulate a host of other proteins and metabolites posttranscriptionally, reflecting activation of their endo-vesiculo-membrane system, secretion of inflammatory proteins, and elaboration of extracellular microvesicles. Importantly, these microvesicles enable rapidly proliferating cancer cells of various types to better withstand different stress conditions, including serum deprivation, hypoxia, or cytotoxic chemotherapy in vitro and xenografting in vivo. These findings suggest a model whereby cancer cells experiencing a partial inhibition of AKT signaling may actually promote the survival of neighbors through non-cell autonomous communication. Mol Cancer Ther; 15(1); 142–53. ©2015 AACR.
Developing Antagonists for the Met-HGF/SF Protein–Protein Interaction Using a Fragment-Based Approach
Authors: Winter Anja , Sigurdardottir Anna G. , DiCara Danielle , Valenti Giovanni , Blundell Tom L. , Gherardi Ermanno 
Published: December 2015

Abstract
In many cancers, aberrant activation of the Met receptor tyrosine kinase leads to dissociation of cells from the primary tumor, causing metastasis. Accordingly, Met is a high-profile target for the development of cancer therapies, and progress has been made through development of small molecule kinase inhibitors and antibodies. However, both approaches pose significant challenges with respect to either target specificity (kinase inhibitors) or the cost involved in treating large patient cohorts (antibodies). Here, we use a fragment-based approach in order to target the protein–protein interaction (PPI) between the α-chain of hepatocyte growth factor/scatter factor (HGF/SF; the NK1 fragment) and its high-affinity binding site located on the Met Sema domain. Surface plasmon resonance was used for initial fragment library screening and hits were developed into larger compounds using substructure (similarity) searches. We identified compounds able to interfere with NK1 binding to Met, disrupt Met signaling, and inhibit tumorsphere generation and cell migration. Using molecular docking, we concluded that some of these compounds inhibit the PPI directly, whereas others act indirectly. Our results indicate that chemical fragments can efficiently target the HGF/SF-Met interface and may be used as building blocks for generating biologically active lead compounds. This strategy may have broad application for the development of a new class of Met inhibitors, namely receptor antagonists, and in general for the development of small molecule PPI inhibitors of key therapeutic targets when structural information is not available. Mol Cancer Ther; 15(1); 3–14. ©2015 AACR.
High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer
Authors: Schouten Philip C. , Vollebergh Marieke A. , Opdam Mark , Jonkers Martijn , Loden Martin , Wesseling Jelle , Hauptmann Michael , Linn Sabine C. 
Published: December 2015

Abstract
In previous studies, high expression of XIST and low expression of 53BP1 were respectively associated with poor systemic therapy outcome in patients and therapy resistance in BRCA1-deficient mouse tumor models, but have not been evaluated in BRCA1-deficient patients. Previously, we demonstrated that classifying breast cancer copy number profiles as BRCA1-like or non–BRCA1-like identified patients enriched for defects in BRCA1 that benefit from high-dose (HD) alkylating chemotherapy compared with a conventional standard regimen. We investigated whether XIST and 53BP1 expression predicted poor outcome of HD chemotherapy within 28 BRCA1-like patients from a trial randomizing between HD [4 cycles 5-fluorouracil, epirubicin, cyclophosphamide (FEC) followed by 1 cycle HD carboplatin, thiotepa, cyclophosphamide] or conventional chemotherapy (5 cycles FEC), for which both XIST and 53BP1 statuses were available. High RNA expression of XIST (n = 5) and low protein expression of 53BP1 (n = 3) expression did not coincide. Patients with either one had poor outcome after treatment with HD chemotherapy, whereas patients with low expression of XIST and high expression of 53BP1 derived substantial benefit of this regimen on recurrence-free survival, disease-free survival, and overall survival, corroborating preclinical findings. XIST and 53BP1 may be predictive biomarkers in BRCA1-like breast cancer. Mol Cancer Ther; 15(1); 190–8. ©2015 AACR.
The Role of HMGB1 in Radioresistance of Bladder Cancer
Authors: Shrivastava Sanhita , Mansure Jose Joao , Almajed Wael , Cury Fabio , Ferbeyre Gerardo , Popovic Marija , Seuntjens Jan , Kassouf Wassim 
Published: December 2015

Abstract
Although radical cystectomy surgery is the standard-of-care for muscle-invasive bladder cancer, it entails complete removal of the bladder and surrounding organs which leads to substantial loss in the quality-of-life of patients. Radiotherapy, which spares the bladder, would be a more appropriate treatment modality if we can utilize molecular markers to select patients with better response to radiation. In this study, we investigate a protein called high mobility group box protein 1 (HMGB1) as a predictive marker for radiotherapy response in bladder cancer. Our in vitro results indicate a positive correlation between higher levels of HMGB1 protein and resistance to radiation in various cell lines. Upon HMGB1 protein knockdown, highly significant (&gt;1.5-fold) sensitization to radiotherapy was achieved. We saw that loss of HMGB1 was associated with at least two times higher (P &lt; 0.001) DNA damage in cell lines postradiation. Our results also depicted that autophagy was inhibited more than 3-fold (P &lt; 0.001) upon HMGB1 knockdown, implicating its role in autophagy as another cause of bladder cancer radioresistance. Further validation was done in vivo by conducting mouse tumor xenograft experiments, where HMGB1 knockdown tumors showed a significantly better (P &lt; 0.001) response to radiotherapy and decreased autophagy (shown by P62 staining) as compared with controls. The cumulative findings of our in vitro and in vivo studies highlight the significance of HMGB1 as a radiation response marker as well as its utility in radiosensitization of bladder cancer. Mol Cancer Ther; 15(3); 471–9. ©2015 AACR.
ML264, A Novel Small-Molecule Compound That Potently Inhibits Growth of Colorectal Cancer
Authors: Ruiz de Sabando Ainara , Wang Chao , He Yuanjun , García-Barros Mónica , Kim Julie , Shroyer Kenneth R. , Bannister Thomas D. , Yang Vincent W. , Bialkowska Agnieszka B. 
Published: December 2015

AbstractColorectal cancer is one of the leading causes of cancer mortality in Western civilization. Studies have shown that colorectal cancer arises as a consequence of the modification of genes that regulate important cellular functions. Deregulation of the WNT and RAS/MAPK/PI3K signaling pathways has been shown to be important in the early stages of colorectal cancer development and progression. Krüppel-like factor 5 (KLF5) is a transcription factor that is highly expressed in the proliferating intestinal crypt epithelial cells. Previously, we showed that KLF5 is a mediator of RAS/MAPK and WNT signaling pathways under homeostatic conditions and that it promotes their tumorigenic functions during the development and progression of intestinal adenomas. Recently, using an ultrahigh-throughput screening approach we identified a number of novel small molecules that have the potential to provide therapeutic benefits for colorectal cancer by targeting KLF5 expression. In the current study, we show that an improved analogue of one of these screening hits, ML264, potently inhibits proliferation of colorectal cancer cells in vitro through modifications of the cell-cycle profile. Moreover, in an established xenograft mouse model of colon cancer, we demonstrate that ML264 efficiently inhibits growth of the tumor within 5 days of treatment. We show that this effect is caused by a significant reduction in proliferation and that ML264 potently inhibits the expression of KLF5 and EGR1, a transcriptional activator of KLF5. These findings demonstrate that ML264, or an analogue, may hold a promise as a novel therapeutic agent to curb the development and progression of colorectal cancer. Mol Cancer Ther; 15(1); 72–83. ©2015 AACR.