bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-
N
-Oxide
Authors: Romano Kymberleigh A. , Vivas Eugenio I. , Amador-Noguez Daniel , Rey Federico E. 
Published: March 2015

ABSTRACT

Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine-
N
-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice and positively correlates with the severity of this disease in humans. However, which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., genotype) and diet affect TMA production and colonization of these microbes, and the effects TMA-producing microbes have on the bioavailability of dietary choline remain largely unknown. We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline
in vitro
. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline
in vitro
. Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest that the TMA-producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans.

IMPORTANCE
Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and increased trimethylamine
N
-oxide (TMAO) levels have been causally linked with CVD development. This work identifies members of the human gut microbiota responsible for both the accumulation of trimethylamine (TMA), the precursor of the proatherogenic compound TMAO, and subsequent decreased choline bioavailability to the host. Understanding how to manipulate the representation and function of choline-consuming, TMA-producing species in the intestinal microbiota could potentially lead to novel means for preventing or treating atherosclerosis and choline deficiency-associated diseases.
Efficacy and safety of diosmectite in acute childhood diarrhoea: a meta-analysis
Authors: Das Rashmi Ranjan , Sankar Jhuma , Naik Sushree Samiksha 
Published: March 2015

ObjectiveWe evaluated the role of diosmectite as an add-on treatment to the ‘recommended treatment’ of acute diarrhoea in children.MethodsWe searched all published literature through the major databases: Medline via Ovid, PubMed, CENTRAL, Embase and Google Scholar till May 2014. Randomised clinical trials comparing diosmectite versus placebo were included (PROSPERO registration: CRD42014013783).Main outcome measuresThe primary outcome measures were duration of acute diarrhoea (h), and day-to-day cure rates (%). The secondary outcome measures were stool output (volume), stool output (frequency) and adverse events.ResultsOf 384 citations retrieved, a total of 13 randomised clinical trials (2164 children, 1–60 months old) were included in the meta-analysis. A dose of 3–6 grams per day of diosmectite was given for a duration from 3 days until recovery. Compared with placebo, diosmectite significantly decreased the duration of acute diarrhoea (mean difference, −23.39; 95% CI −28.77 to −18.01), and increased the cure rate (%) at day 5 (OR, 4.44; 95% CI 1.66 to 11.84), without any increases in the risk of adverse events. Diosmectite was effective in all types of acute childhood diarrhoea except dysentery. Because, most of the trials were open-label, and there was a high possibility of publication bias, the GRADE evidence generated was of ‘low quality’.ConclusionsDiosmectite may be a useful additive in the treatment of acute childhood diarrhoea. As the evidence generated was of ‘low quality’, future research is needed with higher quality designs before any firm recommendations can be made.Trial registration numberPROSPERO registration: CRD42014013783.
Doctors’ approaches to PSA testing and overdiagnosis in primary healthcare: a qualitative study
Authors: Pickles Kristen , Carter Stacy M , Rychetnik Lucie 
Published: March 2015

Objectives(1) To explain general practitioners’ (GPs’) approaches to prostate-specific antigen (PSA) testing and overdiagnosis; (2) to explain how GPs reason about their PSA testing routines and (3) to explain how these routines influence GPs’ personal experience as clinicians.SettingPrimary care practices in Australia including men's health clinics and rural practices with variable access to urology services.Participants32 urban and rural GPs within Australia. We included GPs of varying ages, gender (11 female), clinical experience and patient populations. All GPs interested in participating in the study were included.Primary and secondary outcome measure(s)Data were analysed using grounded theory methods to determine how and why GPs provide (or do not provide) PSA testing to their asymptomatic male patients.ResultsWe observed patterned variation in GP practice, and identified four heuristics to describe GP preference for, and approaches to, PSA testing and overdiagnosis: (1) GPs who prioritised avoiding underdiagnosis, (2) GPs who weighed underdiagnosis and overdiagnosis case by case, (3) GPs who prioritised avoiding overdiagnosis and (4) GPs who did not engage with overdiagnosis at all. The heuristics guided GPs’Routine Practice(usual testing, communication and responses to patient request). The heuristics also reflected GPs’ differentPractice Rationales(drawing on experience, medicolegal obligations, guidelines and evidence) and produced differentPractice Outcomes(GPs’ experiences of the consequences of their PSA testing decisions). Some of these heuristics were more responsive to patient preferences than others.ConclusionsVariation in GPs’ PSA testing practices is strongly related to their approach to overdiagnosis and underdiagnosis of prostate cancer. Men receive very different care depending on their GP's reasoning and practice preferences. Future policy to address overdiagnosis will be more likely to succeed if it responds to these patterned variations.
The pathway to diagnosis of type 1 diabetes in children: a questionnaire study
Authors: Usher-Smith Juliet A , Thompson Matthew J , Zhu Hannah , Sharp Stephen J , Walter Fiona M 
Published: March 2015

ObjectiveTo explore the pathway to diagnosis of type 1 diabetes (T1D) in children.DesignQuestionnaire completed by parents.ParticipantsParents of children aged 1 month to 16 years diagnosed with T1D within the previous 3 months.SettingChildren and parents from 11 hospitals within the East of England.Results88/164 (54%) invited families returned the questionnaire. Children had mean±SD age of 9.41±4.5 years. 35 (39.8%) presented with diabetic ketoacidosis at diagnosis. The most common symptoms were polydipsia (97.7%), polyuria (83.9%), tiredness (75.9%), nocturia (73.6%) and weight loss (64.4%) and all children presented with at least one of those symptoms. The time from symptom onset to diagnosis ranged from 2 to 315 days (median 25 days). Most of this was the appraisal interval from symptom onset until perceiving the need to seek medical advice. Access to healthcare was good but one in five children presenting to primary care were not diagnosed at first encounter, most commonly due to waiting for fasting blood tests or alternative diagnoses. Children diagnosed at first consultation had a shorter duration of symptoms (p=0.022) and children whose parents suspected the diagnosis were 1.3 times more likely (relative risk (RR) 1.3, 95% CI 1.02 to 1.67) to be diagnosed at first consultation.ConclusionsChildren present with the known symptoms of T1D but there is considerable scope to improve the diagnostic pathway. Future interventions targeted at parents need to address the tendency of parents to find alternative explanations for symptoms and the perceived barriers to access, in addition to symptom awareness.
Small-for-gestational age and large-for-gestational age thresholds to predict infants at risk of adverse delivery and neonatal outcomes: are current charts adequate? An observational study from the Born in Bradford cohort
Authors: Norris T , Johnson W , Farrar D , Tuffnell D , Wright J , Cameron N 
Published: March 2015

ObjectivesConstruct an ethnic-specific chart and compare the prediction of adverse outcomes using this chart with the clinically recommended UK-WHO and customised birth weight charts using cut-offs for small-for-gestational age (SGA: birth weight <10th centile) and large-for-gestational age (LGA: birth weight >90th centile).DesignProspective cohort study.SettingBorn in Bradford (BiB) study, UK.Participants3980 White British and 4448 Pakistani infants with complete data for gestational age, birth weight, ethnicity, maternal height, weight and parity.Main outcome measuresPrevalence of SGA and LGA, using the three charts and indicators of diagnostic utility (sensitivity, specificity and area under the receiver operating characteristic (AUROC)) of these chart-specific cut-offs to predict delivery and neonatal outcomes and a composite outcome.ResultsIn White British and Pakistani infants, the prevalence of SGA and LGA differed depending on the chart used. Increased risk of SGA was observed when using the UK-WHO and customised charts as opposed to the ethnic-specific chart, while the opposite was apparent when classifying LGA infants. However, the predictive utility of all three charts to identify adverse clinical outcomes was poor, with only the prediction of shoulder dystocia achieving an AUROC>0.62 on all three charts.ConclusionsDespite being recommended in national clinical guidelines, the UK-WHO and customised birth weight charts perform poorly at identifying infants at risk of adverse neonatal outcomes. Being small or large may increase the risk of an adverse outcome; however, size alone is not sensitive or specific enough with current detection to be useful. However, a significant amount of missing data for some of the outcomes may have limited the power needed to determine true associations.
Development and validation of risk prediction algorithms to estimate future risk of common cancers in men and women: prospective cohort study
Authors: Hippisley-Cox Julia , Coupland Carol 
Published: March 2015

ObjectiveTo derive and validate a set of clinical risk prediction algorithm to estimate the 10-year risk of 11 common cancers.DesignProspective open cohort study using routinely collected data from 753 QResearch general practices in England. We used 565 practices to develop the scores and 188 for validation.Subjects4.96 million patients aged 25–84 years in the derivation cohort; 1.64 million in the validation cohort. Patients were free of the relevant cancer at baseline.MethodsCox proportional hazards models in the derivation cohort to derive 10-year risk algorithms. Risk factors considered included age, ethnicity, deprivation, body mass index, smoking, alcohol, previous cancer diagnoses, family history of cancer, relevant comorbidities and medication. Measures of calibration and discrimination in the validation cohort.OutcomesIncident cases of blood, breast, bowel, gastro-oesophageal, lung, oral, ovarian, pancreas, prostate, renal tract and uterine cancers. Cancers were recorded on any one of four linked data sources (general practitioner (GP), mortality, hospital or cancer records).ResultsWe identified 228 241 incident cases during follow-up of the 11 types of cancer. Of these 25 444 were blood; 41 315 breast; 32 626 bowel, 12 808 gastro-oesophageal; 32 187 lung; 4811 oral; 6635 ovarian; 7119 pancreatic; 35 256 prostate; 23 091 renal tract; 6949 uterine cancers. The lung cancer algorithm had the best performance with an R2of 64.2%; D statistic of 2.74; receiver operating characteristic curve statistic of 0.91 in women. The sensitivity for the top 10% of women at highest risk of lung cancer was 67%. Performance of the algorithms in men was very similar to that for women.ConclusionsWe have developed and validated a prediction models to quantify absolute risk of 11 common cancers. They can be used to identify patients at high risk of cancers for prevention or further assessment. The algorithms could be integrated into clinical computer systems and used to identify high-risk patients.Web calculator:There is a simple web calculator to implement the Qcancer 10 year risk algorithm together with the open source software for download (available athttp://qcancer.org/10yr/).
CHCHD2 Is Coamplified with EGFR in NSCLC and Regulates Mitochondrial Function and Cell Migration
Authors: Wei Yuhong , Vellanki Ravi N. , Coyaud Étienne , Ignatchenko Vladimir , Li Lei , Krieger Jonathan R. , Taylor Paul , Tong Jiefei , Pham Nhu-An , Liu Geoffrey , Raught Brian , Wouters Bradly G. , Kislinger Thomas , Tsao Ming Sound , Moran Michael F. 
Published: March 2015

Abstract
Coiled-coil-helix-coiled-coil-helix domain-containing 2, a mitochondrial protein, encoded by CHCHD2 is located at chromosome 7p11.2 and proximal to the EGFR gene. Here, bioinformatic analyses revealed that CHCHD2 is consistently coamplified with EGFR in non–small cell lung carcinoma (NSCLC). In addition, CHCHD2 and EGFR protein expression levels were positively correlated and upregulated relative to normal lung in NSCLC tumor-derived xenografts. Knockdown of CHCHD2 expression in NSCLC cells attenuated cell proliferation, migration, and mitochondrial respiration. CHCHD2 protein–protein interactions were assessed by the complementary approaches of affinity purification mass spectrometry and in vivo proximity ligation. The CHCHD2 interactome includes the apparent hub proteins C1QBP (a mitochondrial protein) and YBX1 (an oncogenic transcription factor), and an overlapping set of hub-associated proteins implicated in cell regulation.
Implications: CHCHD2 influences mitochondrial and nuclear functions and contributes to the cancer phenotype associated with 7p11.2 amplification in NSCLC. Mol Cancer Res; 13(7); 1119–29. ©2015 AACR.
Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis
Authors: Baldassarre Tomas , Watt Kathleen , Truesdell Peter , Meens Jalna , Schneider Mark M. , Sengupta Sandip K. , Craig Andrew W. 
Published: March 2015

AbstractTriple-negative breast cancers (TNBCs) are highly aggressive cancers that lack targeted therapies. However, EGFR is frequently activated in a subset of TNBCs and represents a viable clinical target. Because the endocytic adaptor protein Endophilin A2 (SH3GL1/Endo II) has been implicated in EGFR internalization, we investigated Endo II expression and function in human TNBCs. Endo II expression was high in several TNBC cells compared with normal breast epithelial cells. Stable knockdown (KD) of Endo II was achieved in two TNBC cell lines, and although cell viability was unaffected, defects in receptor-mediated endocytosis were observed. EGFR signaling to Erk and Akt kinases was impaired in Endo II KD cells, and this correlated with reduced rates of EGFR internalization and cell motility. Endo II KD cells also displayed defects in three dimensional (3D) cell invasion, and this correlated with impaired extracellular matrix degradation and internalization of MT1-MMP. Endo II silencing also caused a significant reduction in TNBC tumor growth and lung metastasis in mammary orthotopic tumor xenograft assays. In human breast tumor specimens, Endo II expression was highest in TNBC tumors compared with other subtypes, and at the level of gene expression, high Endo II was associated with reduced relapse-free survival in patients with basal-like breast cancers. Together, these results identify a positive role for Endo II in TNBC tumor metastasis and a potential link with poor prognosis.Implications: Endophilin A2 and related adaptor proteins represent important signaling hubs to target in metastatic cancers. Mol Cancer Res; 13(6); 1044–55. ©2015 AACR.
UCP2 Knockout Suppresses Mouse Skin Carcinogenesis
Authors: Li Wenjuan , Zhang Chunjing , Jackson Kasey , Shen Xingui , Jin Rong , Li Guohong , Kevil Christopher G. , Gu Xin , Shi Runhua , Zhao Yunfeng 
Published: March 2015

Abstract
Mitochondrial uncoupling (uncouples electron transport from ATP production) has recently been proposed as a novel survival mechanism for cancer cells, and reduction in free radical generation is the accepted mechanism of action. However, there is no direct evidence supporting that uncoupling proteins promote carcinogenesis. Herein, we examined whether mitochondrial uncoupling affects mouse skin carcinogenesis using uncoupling protein 2 (UCP2) homozygous knockout and wild-type mice. The results indicate that knockout of Ucp2 significantly reduced the formation of both benign (papilloma) and malignant (squamous cell carcinoma) tumors. UCP2 knockout did not cause increases in apoptosis during skin carcinogenesis. The rates of oxygen consumption were decreased only in the carcinogen-treated UCP2 knockout mice, whereas glycolysis was increased only in the carcinogen-treated wild-type mice. Finally, the levels of metabolites pyruvate, malate, and succinate showed different trends after carcinogen treatments between the wild-type and UCP2 knockout mice. Our study is the first to demonstrate that Ucp2 knockout suppresses carcinogenesis in vivo. Together with early studies showing that UCP2 is overexpressed in a number of human cancers, UCP2 could be a potential target for cancer prevention and/or therapy. Cancer Prev Res; 8(6); 487–91. ©2015 AACR.
3,6-Dihydroxyflavone Suppresses Breast Carcinogenesis by Epigenetically Regulating miR-34a and miR-21
Authors: Peng Xiaoli , Chang Hui , Gu Yeyun , Chen Junli , Yi Long , Xie Qi , Zhu Jundong , Zhang Qianyong , Mi Mantian 
Published: March 2015

Abstract
Our previous study selected a promising chemopreventive agent 3,6-dihydroxyflavone (3,6-DHF) and found that 3,6-DHF significantly upregulates miR-34a and downregulates miR-21 in breast carcinogenesis, yet the upstream and downstream events of the anticancer mechanism remain unclear. The present study showed that 3,6-DHF cotreatment effectively inhibits carcinogens-induced breast carcinogenic transformation in human breast epithelial MCF10A cells. The data revealed the significant downregulation of miR-34a and upregulation of miR-21 in breast carcinogenesis, which could be mitigated by 3,6-DHF treatment. Methylation-specific PCR detections showed that 3,6-DHF inhibits the hypermethylation of the miR-34a promoter. Further studies indicated that 3,6-DHF is an effective methyltransferase (DNMT)1 inhibitor, docking to the putative cytosine pocket of the protein, and thus decreases the DNMT activity in a dose-dependent manner. Moreover, the ChIP-qPCR analysis for histone modifications showed that 3,6-DHF treatment significantly lowers the H3K9-14ac on the miR-21 promoter. In addition, our study revealed that 3,6-DHF represses the PI3K/Akt/mTOR signaling pathway in breast carcinogenesis in vitro and in vivo. Inhibition of miR-34a or overexpression of miR-21 significantly reduced the effects of 3,6-DHF on Notch-1 and PTEN, and consequently weakened the suppression of 3,6-DHF on PI3K/Akt/mTOR. We concluded that 3,6-DHF upregulates miR-34a via inhibiting DNMT1 and hypermethylation, whereas downregulates miR-21 by modulating histone modification, and consequently suppresses the PI3K/Akt/mTOR signaling pathway in breast carcinogenesis. Cancer Prev Res; 8(6); 509–17. ©2015 AACR.
Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage
Authors: Yang Fan , Wang Zhe , Zhang John H. , Tang Jiping , Liu Xin , Tan Liang , Huang Qing-Yuan , Feng Hua 
Published: March 2015

Background and Purpose—
To determine whether the receptor for advanced glycation end-products (RAGE) plays a role in early brain injury from intracerebral hemorrhage (ICH), RAGE expression and activation after injury were examined in a rat model of ICH with or without administration of a RAGE-specific antagonist (FPS-ZM1).

Methods—
Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. The motor function of the rats was examined, and water content was detected after euthanization. Blood–brain barrier permeability was determined by Evans blue staining and colloidal gold nanoparticle tracers. Nerve fiber injury in white matter was determined by diffusion tensor imaging analysis, and the expression of target genes was analyzed by Western blotting and quantitative reverse transcription polymerase chain reaction. FPS-ZM1 was administered by intraperitoneal injection.

Results—

Expression of RAGE and its ligand high-mobility group protein B1 were increased at 12 hours after ICH, along with blood–brain barrier permeability and perihematomal nerve fiber injury. RAGE and nuclear factor-κB p65 upregulation were also observed when FeCl
2
was infused into the basal ganglia at 24 hours. FPS-ZM1 administration resulted in significant improvements of blood–brain barrier damage, brain edema, motor dysfunction, and nerve fiber injury, and the expression of RAGE, nuclear factor-κB p65, proinflammatory mediators interleukin 1β, interleukin-6, interleukin-8R, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metallopeptidase-9 was attenuated. Moreover, decreases in claudin-5 and occludin expression were partially recovered. FPS-ZM1 also reversed FeCl
2
-induced RAGE and nuclear factor-κB p65 upregulation.

Conclusions—
RAGE signaling is involved in blood–brain barrier and white matter fiber damage after ICH, the initiation of which is associated with iron. RAGE antagonists represent a novel therapeutic intervention to prevent early brain injury after ICH.
A method for establishing taxonomic research priorities in a megadiverse country
Authors: Victor Janine , Smith Gideon F. , VAN WYK ABRAHAM E. 
Published: March 2015

A coordinated strategy for biosystematics research that addresses the needs of end-users can improve the relevance and impact of research products. The basic types of information that taxonomists provide, common to all organisms, are the names, descriptions, and a mechanism for identifying components of biodiversity, and associated data such as distribution information. This information is provided through taxonomic research. A biosystematics research strategy has been developed in South Africa to focus on the main gaps in taxonomic knowledge. A prioritisation process has been developed and applied to plants, but can potentially be used for all organisms. The methodology for development of the taxonomic priorities to formulate a research strategy is described. Determining priorities for taxonomic research and development of the strategy will facilitate bridging the gaps among compilers, users and implementers of taxonomic information, and streamline the taxonomy-conservation impediment.