bluuebunny/crossref_metadata_2025_split huggingface dataset:
Actinobacterial Acyl Coenzyme A Synthetases Involved in Steroid Side-Chain Catabolism
Authors: Casabon Israël , Swain Kendra , Crowe Adam M. , Eltis Lindsay D. , Mohn William W. 
Published: November 2013

ABSTRACT

Bacterial steroid catabolism is an important component of the global carbon cycle and has applications in drug synthesis. Pathways for this catabolism involve multiple acyl coenzyme A (CoA) synthetases, which activate alkanoate substituents for β-oxidation. The functions of these synthetases are poorly understood. We enzymatically characterized four distinct acyl-CoA synthetases from the cholate catabolic pathway of
Rhodococcus jostii
RHA1 and the cholesterol catabolic pathway of
Mycobacterium tuberculosis
. Phylogenetic analysis of 70 acyl-CoA synthetases predicted to be involved in steroid metabolism revealed that the characterized synthetases each represent an orthologous class with a distinct function in steroid side-chain degradation. The synthetases were specific for the length of alkanoate substituent. FadD19 from
M. tuberculosis
H37Rv (FadD19

Mtb

) transformed 3-oxo-4-cholesten-26-oate (
k
cat
/

K
m

= 0.33 × 10
5
± 0.03 × 10
5
M
−1
s
−1
) and represents orthologs that activate the C
8
side chain of cholesterol. Both CasG
RHA1
and FadD17

Mtb

are steroid-24-oyl-CoA synthetases. CasG and its orthologs activate the C
5
side chain of cholate, while FadD17 and its orthologs appear to activate the C
5
side chain of one or more cholesterol metabolites. CasI
RHA1
is a steroid-22-oyl-CoA synthetase, representing orthologs that activate metabolites with a C
3
side chain, which accumulate during cholate catabolism. CasI had similar apparent specificities for substrates with intact or extensively degraded steroid nuclei, exemplified by 3-oxo-23,24-bisnorchol-4-en-22-oate and 1β(2′-propanoate)-3aα-
H
-4α(3″-propanoate)-7aβ-methylhexahydro-5-indanone (
k
cat

/K
m

= 2.4 × 10
5
± 0.1 × 10
5
M
−1
s
−1
and 3.2 × 10
5
± 0.3 × 10
5
M
−1
s
−1
, respectively). Acyl-CoA synthetase classes involved in cholate catabolism were found in both
Actinobacteria
and
Proteobacteria
. Overall, this study provides insight into the physiological roles of acyl-CoA synthetases in steroid catabolism and a phylogenetic classification enabling prediction of specific functions of related enzymes.
Interaction of Apurinic/Apyrimidinic Endonucleases Nfo and ExoA with the DNA Integrity Scanning Protein DisA in the Processing of Oxidative DNA Damage during Bacillus subtilis Spore Outgrowth
Authors: Campos Silvia S. , Ibarra-Rodriguez Juan R. , Barajas-Ornelas Rocío C. , Ramírez-Guadiana Fernando H. , Obregón-Herrera Armando , Setlow Peter , Pedraza-Reyes Mario 
Published: November 2013

ABSTRACT

Oxidative stress-induced damage, including 8-oxo-guanine and apurinic/apyrimidinic (AP) DNA lesions, were detected in dormant and outgrowing
Bacillus subtilis
spores lacking the AP endonucleases Nfo and ExoA. Spores of the Δ
nfo exoA
strain exhibited slightly slowed germination and greatly slowed outgrowth that drastically slowed the spores' return to vegetative growth. A null mutation in the
disA
gene, encoding a DNA integrity scanning protein (DisA), suppressed this phenotype, as spores lacking Nfo, ExoA, and DisA exhibited germination and outgrowth kinetics very similar to those of wild-type spores. Overexpression of DisA also restored the slow germination and outgrowth phenotype to
nfo exoA disA
spores. A
disA-lacZ
fusion was expressed during sporulation but not in the forespore compartment. However,
disA-lacZ
was expressed during spore germination/outgrowth, as was a DisA-green fluorescent protein (GFP) fusion protein. Fluorescence microscopy revealed that, as previously shown in sporulating cells, DisA-GFP formed discrete globular foci that colocalized with the nucleoid of germinating and outgrowing spores and remained located primarily in a single cell during early vegetative growth. Finally, the slow-outgrowth phenotype of
nfo exoA
spores was accompanied by a delay in DNA synthesis to repair AP and 8-oxo-guanine lesions, and these effects were suppressed following
disA
disruption. We postulate that a DisA-dependent checkpoint arrests DNA replication during
B. subtilis
spore outgrowth until the germinating spore's genome is free of damage.
Diagnosis of cystic fibrosis in London and South East England before and after the introduction of newborn screening
Authors: Lim MTC , Wallis C , Price J F , Carr S B , Chavasse R J , Shankar A , Seddon P , Balfour-Lynn I M 
Published: November 2013

IntroductionNewborn screening (NBS) for cystic fibrosis (CF) was introduced to London and South East England in 2007. We wished to assess the details of missed cases, and to compare the age at diagnosis and other clinical parameters, prescreening and postscreening.MethodsRetrospective and prospective case notes and database review of all newly diagnosed CF patients in our 7 CF centres, for 18 months before and 4 years after NBS started.Results347 patients were diagnosed with CF. 126 patients were not screened (born before or abroad), and had a median age at diagnosis of 2.4 years, excluding those with meconium ileus (MI). Their median time to diagnosis from initial symptoms was 1 year, and in 10% it was >6 years. After NBS started, 170 were diagnosed by NBS (48% were already symptomatic); 7 moved into the region after NBS elsewhere; 34 presented with MI (6 were negative on NBS); and 10 screened children were missed (false negative cases). Median age of diagnosis was 3 weeks. Prevalence was 1 in 3991 live births. By 2 years of age (with data on 104 patients), 49 children (47%) had their first isolation of Pseudomonas aeruginosa, while 37 (36%) had their first growth of Staphylococcus aureus from respiratory cultures.ConclusionsNBS has significantly reduced the age of diagnosis, although many were symptomatic even at 3 weeks of age. A small number of patients with CF can still be missed by the screening programme, and the diagnosis should be considered even with a negative screen result.
A reliability study of colour-Doppler sonography for the diagnosis of chronic cerebrospinal venous insufficiency shows low inter-rater agreement
Authors: Leone Maurizio A , Raymkulova Olga , Lucenti Ausiliatrice , Stecco Alessandro , Bolamperti Laura , Coppo Lorenzo , Liboni William , Rivadossi Gianandrea , Zaccala Giuseppe , Maggio Maurizio , Melis Fabio , Giaccone Claudia , Carriero Alessandro , Lochner Piergiorgio 
Published: November 2013

ObjectiveChronic cerebrospinal venous insufficiency (CCSVI) has been extremely variable, associated with multiple sclerosis in colour-Doppler sonographic studies. We aimed to evaluate inter-rater agreement in a colour-Doppler sonography venous examination.DesignInter-rater agreement study.SettingFirst-referral multiple sclerosis centre.Participants38 patients with multiple sclerosis and 55 age-matched (±5 years) controls.InterventionSonography was carried out in accordance with Zamboni’s five criteria by eight sonographers with different expertise, blinded to the status of cases and controls. Each participant was evaluated by two operators.Primary and secondary outcome measuresInter-rater agreement was measured through the κ statistics and the intraclass correlation coefficient.ResultsThe agreement was no higher than chance for criterion 2—reflux in the deep cerebral veins (κ=−0.02) and criterion 4—flow not Doppler detectable in one or both the internal jugular veins (IJVs) or vertebral veins (VVs; −0.09). It was substantially low for criterion 1—reflux in the IJVs and/or VVs (0.29), criterion 3—IJV stenosis or malformations (0.23) and criterion 5—absence of IJV diameter increase when passing from the sitting to the supine position (0.22). The κ value for CCSVI as a whole was 0.20 (95% confidence limit −0.01 to 0.42). Intraclass correlation coefficients for the measure of cross-sectional area ranged from 0.05 to 0.25. Inter-rater agreement was low for CCSVI experts (κ=0.24; −0.11 to 0.59) and non-experts (0.20; −0.33 to 0.73); neurologists (0.21; −0.06 to 0.47) and non-neurologists (0.18; −0.20 to 0.56); cases (0.19; −0.14 to 0.52) and controls (0.21; −0.08 to 0.49). Zamboni-trained neurosonographers ascertained CCSVI more frequently than the non-trained neurosonographers.ConclusionsAgreement was unsatisfactory for the diagnosis of CCSVI as a whole, for each of its five criteria and according to the different subgroups. Standardisation of the method is urgently needed prior to its further application in studies of patients with multiple sclerosis or other neurological diseases.
Epidemiology of time-loss injuries in English community-level rugby union
Authors: Roberts Simon P , Trewartha Grant , England Mike , Shaddick Gavin , Stokes Keith A 
Published: November 2013

ObjectivesUsing a prospective cohort study design, to establish the incidence and nature of time-loss injuries in English community rugby and to assess the differences between different playing levels.SettingEnglish community rugby clubs.ParticipantsInjury information for 4635 matches was collected during seasons 2009/2010 (46 clubs), 2010/2011(67 clubs) and 2011/2012 (76 clubs). Clubs were subdivided into groups A (semiprofessional), B (amateur) and C (recreational) for analysis.Primary and secondary outcome measuresAny injury resulting in 8 days or greater absence from match play was reported by injury management staff at the clubs. The primary outcome measure was injury incidence (per 1000 player match-hours) and the secondary outcome measure was severity (ie, days absence).ResultsOverall match injury incidence was 16.9 injuries per 1000 player match-hours. Incidence was higher for group A (21.7; 95% CI 19.8 to 23.6) compared with group B (16.6; 95% CI 15.2 to 17.9) and C (14.2; 95% CI 13.0 to 15.5, both p<0.001). The mean time-loss was 7.6 weeks absence, with knee and shoulder injuries the most severe with mean absences of 11.6 and 9.3 weeks, respectively. Half of all injuries occurred to the lower limb, with knee and ankle joint/ligament injuries the most common diagnoses. Shoulder joint/ligament injuries were the most common and severe upper limb injuries. Contact events accounted for 80% of all injuries and tackles accounted for 50%. Running was the most common non-contact injury event, of which 56% were hamstring injuries.ConclusionsMore time-loss injuries occur at higher levels of community rugby. Injury prevention strategies should focus on good technique in the tackle and conditioning exercises for the knee, ankle, hamstrings and shoulder.
MicroRNAs and liver disease: viral hepatitis, liver fibrosis and hepatocellular carcinoma
Authors: Li Gang , Cai Guohong , Li Demin , Yin Wen 
Published: November 2013

Abstract
MicroRNAs (miRNAs), a type of highly conserved small non-coding RNAs with an average length of 22 nucleotides, may serve as major regulators of gene expression and indispensable components of cellular gene expression networks. They have critical roles in normal biological processes and have been linked to many tumours, including hepatocellular carcinoma (HCC). HCC is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Viral hepatitis, caused by infection with hepatitis B or C viruses (HBV or HCV), can increase the risk of HCC and contributes to a significant disease burden around the world. Because of the variety of molecular alterations that may arise during the development and progression of HCC, standard of care and treatment for patients with HCC remains unsatisfactory. MiRNAs have been shown to participate in the pathogenesis of both HBV and HCV. In addition to a role in pathogenesis, miRNAs have significant clinical value in the early diagnosis of HCC since they are present in the blood and can be used as diagnostic markers and potential targets for specific systemic treatment.
Interns and their smartphones: use for clinical practice
Authors: O’Connor P , Byrne D , Butt M , Offiah G , Lydon S , Mc Inerney K , Stewart Brian , Kerin M J 
Published: November 2013

Abstract

Purpose of the study
Smartphone use among healthcare professionals has become widespread and will continue to grow in the coming years.

Study design
In October 2012, a survey was distributed to 230 interns at two of the national intern training networks in the Republic of Ireland, asking how they used smartphones to carry out their clinical work.

Results
It was found that out of 108 interns (47.0% response rate, 108/230), 94.4% (102/108) owned a smartphone. Of those respondents who owned a smartphone, on at least a daily basis for the purposes of work, 83.3% (85/102) made or received phone calls, 87.2% (89/102) sent or received texts, and 41.2% (42/102) sent or received emails on their smartphone. A total of 52.9% (54/102) had used their smartphone to take a work related picture. The most commonly used app was the British National Formulary. It was used daily by 30.4% (31/102) of respondents with a smartphone. The most commonly used website was Wikipedia. It was accessed at least weekly by 38.2% (39/102) of respondents with a smartphone.

Conclusions
Smartphones are used by the majority of interns on a daily basis in order to perform their job. As such, there is a need for guidance on how patient information can be safely secured and transmitted using smartphones, their appropriate use, and any restrictions on the use of these devices in certain clinical settings. For interns in particular, advice is needed on the credibility of medical apps and websites.
Genome-wide Profiling of Genetic Synthetic Lethality Identifies CDK12 as a Novel Determinant of PARP1/2 Inhibitor Sensitivity
Authors: Bajrami Ilirjana , Frankum Jessica R. , Konde Asha , Miller Rowan E. , Rehman Farah L. , Brough Rachel , Campbell James , Sims David , Rafiq Rumana , Hooper Sean , Chen Lina , Kozarewa Iwanka , Assiotis Ioannis , Fenwick Kerry , Natrajan Rachael , Lord Christopher J. , Ashworth Alan 
Published: November 2013

Abstract
Small-molecule inhibitors of PARP1/2, such as olaparib, have been proposed to serve as a synthetic lethal therapy for cancers that harbor BRCA1 or BRCA2 mutations. Indeed, in clinical trials, PARP1/2 inhibitors elicit sustained antitumor responses in patients with germline BRCA gene mutations. In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes. In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51, and Fanconi's anemia susceptibility genes. In addition, the set included genes implicated in established networks of DNA repair, DNA cohesion, and chromatin remodeling, none of which were known previously to confer sensitivity to PARP1/2 inhibition. Notably, integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity. In models of high-grade serous ovarian cancer (HGS-OVCa), CDK12 attenuation was sufficient to confer sensitivity to PARP1/2 inhibition, suppression of DNA repair via homologous recombination, and reduced expression of BRCA1. As one of only nine genes known to be significantly mutated in HGS-OVCa, CDK12 has properties that should confirm interest in its use as a biomarker, particularly in ongoing clinical trials of PARP1/2 inhibitors and other agents that trigger replication fork arrest. Cancer Res; 74(1); 287–97. ©2013 AACR.
SIRT1 and AMPK Mediate Hypoxia-Induced Resistance of Non–Small Cell Lung Cancers to Cisplatin and Doxorubicin
Authors: Shin Dong Hoon , Choi Yong-Joon , Park Jong-Wan 
Published: November 2013

Abstract
SIRT1 is an NAD+-dependent protein deacetylase induced by metabolic stresses, such as nutrition or oxygen deprivation. Although SIRT1 contributes to aging and metabolic disorders, its role in cancer progression and therapeutic responses remains controversial. Because hypoxia occurs widely in solid tumors, where it provokes drug resistance, we investigated the involvement of SIRT1 in hypoxia-induced chemoresistance. SIRT1 was downregulated in a panel of non–small cell lung carcinoma (NSCLC) cells exposed to hypoxia for 48 hours. The master metabolic kinase AMP-activated protein kinase (AMPK) was inactivated under the same conditions, likely due to attenuation of the SIRT1/LKB1-mediated AMPK activation process. Notably, hypoxic inactivation of this SIRT1–AMPK pathway led to cisplatin and doxorubicin resistance. Mechanistic investigations suggested that this pathway supported the cytotoxic response to cisplatin and doxorubicin by licensing an apoptotic process controlled by mitochondria. We confirmed the involvement of this pathway in a mouse xenograft model of human NSCLC. Furthermore, we demonstrated that a SIRT1 activator SRT1720 augmented the antitumor effects of cisplatin, and these effects could be blocked by administration of an AMPK inhibitor compound C. Taken together, our results offer preclinical proof-of-concept to target the SIRT1–AMPK pathway as a strategy to overcome hypoxia-induced chemoresistance in NSCLC. Cancer Res; 74(1); 298–308. ©2013 AACR.
Iron and Cancer Risk—A Systematic Review and Meta-analysis of the Epidemiological Evidence
Authors: Fonseca-Nunes Ana , Jakszyn Paula , Agudo Antonio 
Published: November 2013

Abstract
Iron has been suggested as a risk factor for different types of cancers mainly due to its prooxidant activity, which can lead to oxidative DNA damage. Furthermore, subjects with hemochromatosis or iron overload have been shown to have a higher risk of developing liver cancer. We have systematically reviewed 59 epidemiologic studies, published between 1995 and 2012, reporting information on total iron, dietary iron, heme iron, and biomarkers of iron status and cancer risk. Furthermore we conducted meta-analysis for colorectal [relative risk (RR), 1.08; 95% confidence interval (CI), 1.00–1.17], colon (RR = 1.12; 95% CI, 1.03–1.22), breast (RR = 1.03; 95% CI, 0.97–1.09), and lung cancer (RR = 1.12; 95% CI, 0.98–1.29), for an increase of 1 mg/day of heme iron intake. Globally, on the basis of the systematic review and the meta-analysis results, a higher intake of heme iron has shown a tendency toward a positive association with cancer risk. Evidence regarding high levels of biomarkers of iron stores (mostly with serum ferritin) suggests a negative effect toward cancer risk. More prospective studies combining research on dietary iron intake, iron biomarkers, genetic susceptibility, and other relevant factors need to be conducted to clarify these findings and better understand the role of iron in cancer development. Cancer Epidemiol Biomarkers Prev; 23(1); 12–31. ©2013 AACR.
HDM2 Regulation by AURKA Promotes Cell Survival in Gastric Cancer
Authors: Sehdev Vikas , Katsha Ahmed , Arras Janet , Peng Dunfa , Soutto Mohammed , Ecsedy Jeffrey , Zaika Alexander , Belkhiri Abbes , El-Rifai Wael 
Published: November 2013

Abstract
Purpose: Suppression of P53 (tumor protein 53) transcriptional function mediates poor therapeutic response in patients with cancer. Aurora kinase A (AURKA) and human double minute 2 (HDM2) are negative regulators of P53. Herein, we examined the role of AURKA in regulating HDM2 and its subsequent effects on P53 apoptotic function in gastric cancer.
Experimental Design: Primary tumors and in vitro gastric cancer cell models with overexpression or knockdown of AURKA were used. The role of AURKA in regulating HDM2 and cell survival coupled with P53 expression and activity were investigated.
Results: Overexpression of AURKA enhanced the HDM2 protein level; conversely, knockdown of endogenous AURKA decreased expression of HDM2 in AGS and SNU-1 cells. Dual co-immunoprecipitation assay data indicated that AURKA was associated with HDM2 in a protein complex. The in vitro kinase assay using recombinant AURKA and HDM2 proteins followed by co-immunoprecipitation revealed that AURKA directly interacts and phosphorylates HDM2 protein in vitro. The activation of HDM2 by AURKA led to induction of P53 ubiquitination and attenuation of cisplatin-induced activation of P53 in gastric cancer cells. Inhibition of AURKA using an investigational small-molecule specific inhibitor, alisertib, decreased the HDM2 protein level and induced P53 transcriptional activity. These effects markedly decreased cell survival in vitro and xenograft tumor growth in vivo. Notably, analysis of immunohistochemistry on tissue microarrays revealed significant overexpression of AURKA and HDM2 in human gastric cancer samples (P &lt; 0.05).
Conclusion: Collectively, our novel findings indicate that AURKA promotes tumor growth and cell survival through regulation of HDM2-induced ubiquitination and inhibition of P53. Clin Cancer Res; 20(1); 76–86. ©2013 AACR.
Neutrophils Promote the Malignant Glioma Phenotype through S100A4
Authors: Liang Ji , Piao Yuji , Holmes Lindsay , Fuller Gregory N. , Henry Verlene , Tiao Ningyi , de Groot John F. 
Published: November 2013

Abstract
Purpose: Antiangiogenic therapy is effective in blocking vascular permeability, inhibiting vascular proliferation, and slowing tumor growth, but studies in multiple cancer types have shown that tumors eventually acquire resistance to blockade of blood vessel growth. Currently, the mechanisms by which this resistance occurs are not well understood.
Experimental Design: In this study, we evaluated the effects of neutrophils on glioma biology both in vitro and in vivo and determined target genes by which neutrophils promote the malignant glioma phenotype during anti-VEGF therapy.
Results: We found that an increase in neutrophil infiltration into tumors is significantly correlated with glioma grade and in glioblastoma with acquired resistance to anti-VEGF therapy. Our data demonstrate that neutrophils and their condition media increased the proliferation rate of glioblastoma-initiating cells (GIC). In addition, neutrophils significantly increased GICs Transwell migration compared with controls. Consistent with this behavior, coculture with neutrophils promoted GICs to adopt morphologic and gene expression changes consistent with a mesenchymal signature. Neutrophil-promoting tumor progression could be blocked by S100A4 downregulation in vitro and in vivo. Furthermore, S100A4 depletion increased the effectiveness of anti-VEGF therapy in glioma.
Conclusions: Collectively, these data suggest that increased recruitment of neutrophils during anti-VEGF therapy promotes glioma progression and may promote treatment resistance. Tumor progression with mesenchymal characteristics is partly mediated by S100A4, the expression of which is increased by neutrophil infiltration. Targeting granulocytes and S100A4 may be effective approaches to inhibit the glioma malignant phenotype and diminish antiangiogenic therapy resistance. Clin Cancer Res; 20(1); 187–98. ©2013 AACR.