bluuebunny/crossref_metadata_2025 huggingface dataset:
Are Jordanian primary healthcare practitioners fulfilling their potential in cancer prevention and community health? Findings from a cross-sectional survey
Authors: Obeidat N A , Habashneh M A , Shihab R A , Hawari F I
Published: April 2017

Introduction

Primary healthcare practitioners (PHCPs) can contribute to the control of cancer by promoting healthy lifestyles to patients. Given the scarcity of data in the Middle East on this subject, we sought to determine, through a cross-sectional survey, the status of healthy lifestyle promotion by PHCPs (physicians, nurses, midwives, nurse aids) in Jordan.

Methods

Building on published studies, an Arabic questionnaire was developed to measure knowledge, perceptions and practices of Jordanian PHCPs with regard to healthy lifestyle counselling. A purposive sample of 20 clinics covering the main regions of Jordan was selected and all PHCPs were asked to complete the questionnaire.

Results

322 practitioners (32.3% physicians) responded (a 75.1% response rate). 24.4% of PHCPs were current cigarette smokers (physicians 44.2%). Roughly 58% of physicians and 50% of non-physicians reported advising the majority of patients to quit tobacco, but proportions were lower for providing other services (eg, asking about frequency of tobacco use, inquiring about diet and exercise, providing evidence-based guidance on quitting tobacco or improving diet and activity). Only 8% of the sample reported collectively asking the majority of patients about smoking status, exercise and diet; and providing evidence-based tips to improve these. Among physicians and non-physicians, 14.2% and 40.4% were able to identify the lifestyle-related risk factors associated with breast, colorectal and lung cancer. In multivariable analyses, confidence was the only significant variable associated with provision of counselling on healthy lifestyles.

Conclusions

Among Jordanian PHCPs, primary prevention services are underprovided, and data suggest ample room to improve PHCPs' skills and practices.
The interaction of socioeconomic position and type 2 diabetes mellitus family history: a cross-sectional analysis of the Lifelines Cohort and Biobank Study
Authors: van Zon Sander K.R. , Snieder Harold , Bültmann Ute , Reijneveld Sijmen A.
Published: April 2017

Background

Low socioeconomic position (SEP) and family history of type 2 diabetes mellitus (T2DM) contribute to increased T2DM risk, but it is unclear whether they exacerbate each other’s effect. This study examined whether SEP reinforces the association of T2DM family history with T2DM, and whether behavioural and clinical risk factors can explain this reinforcement.

Methods

We used cross-sectional data on 51 725 participants from Lifelines. SEP was measured as educational level and was self-reported, just as family history of T2DM. T2DM was diagnosed based on measured fasting plasma glucose and glycated haemoglobin, combined with self-reported disease and recorded medication use. We assessed interaction on the additive scale by calculating the relative excess risk due to interaction (RERI).

Results

ORs of T2DM were highest for males (4.37; 95% CI 3.47 to 5.51) and females (7.77; 5.71 to 10.56) with the combination of low SEP and a family history of T2DM. The RERIs of low SEP and a family history of T2DM were 0.64 (−0.33 to 1.62) for males and 3.07 (1.53 to 4.60) for females. Adjustment for behavioural and clinical risk factors attenuated associations and interactions, but risks remained increased.

Conclusion

Low SEP and family history of T2DM are associated with T2DM, but they also exacerbate each other’s impact in females but not in males. Behavioural and clinical risk factors partly explain these gender differences, as well as the associations underlying the interaction in females. The exacerbation by low SEP of T2DM risks in T2DM families deserves attention in prevention and community care.
The impact of rifaximin-α on the hospital resource use associated with the management of patients with hepatic encephalopathy: a retrospective observational study (IMPRESS)
Authors: Hudson Mark , Radwan Amr , Di Maggio Paola , Cipelli Riccardo , Ryder Stephen D , Dillon John F , Cash William Jonathan , Przemioslo Robert T , Wright Mark , Shawcross Debbie L , Jalan Rajiv , Saksena Sushma , Allison Michael , Richardson Paul , Farrington Elizabeth , Aspinall Richard J
Published: April 2017

Objective

To compare all-cause and liver-related hospital resource use in the 6 and 12 months pre-rifaximin-α and post-rifaximin-α initiation in UK patients with hepatic encephalopathy (HE).

Design

A UK multicentre, retrospective, observational study. Patients' medical records were reviewed for demographics, clinical outcomes and adverse events (AEs) to rifaximin-α. Details of hospital admissions/attendances in the 6 and 12 months pre-rifaximin-α and post-rifaximin-α initiation were extracted from hospital electronic databases.

Setting

13 National Health Service centres.

Patients

207 patients with HE who initiated rifaximin-α between July 2008 and May 2014. Hospital resource use data were available for 145/207 patients.

Main outcome measure

Change in mean number of liver-related hospital bed days/patient (total and critical care) between the 6 months pre-rifaximin-α and post-rifaximin-α initiation.

Results

Comparing the 6 months pre-rifaximin-α and post-rifaximin-α initiation in alive patients at the end of the observation period (N=114): there were significant reductions in the mean number of hospitalisations/patient (liver-related 1.3 to 0.5, p<0.001; all-cause 1.9 to 0.9, p<0.001), hospital bed days/patient (liver-related 17.8 to 6.8, p<0.001; all-cause 25.4 to 10.6, p<0.001), 30-day hospital readmissions/patient (liver-related 0.5 to 0.2, p=0.039; all-cause 0.8 to 0.4, p=0.024) and emergency department (ED) attendances/patient (all-cause, 1.0 to 0.5, p<0.001). The mean critical care bed days/patient reduced significantly for all-cause admissions (1.3 to 0.3, p=0.049); non-significant reduction for liver-related admissions. 4% of patients (9/207) developed AEs.

Conclusions

In UK clinical practice, treatment with rifaximin-α for HE is well-tolerated and associated with significant reductions in hospitalisations, bed days (including critical care), ED attendances and 30-day readmissions.
CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells
Authors: Manic Gwenola , Signore Michele , Sistigu Antonella , Russo Giorgio , Corradi Francesca , Siteni Silvia , Musella Martina , Vitale Sara , De Angelis Maria Laura , Pallocca Matteo , Amoreo Carla Azzurra , Sperati Francesca , Di Franco Simone , Barresi Sabina , Policicchio Eleonora , De Luca Gabriele , De Nicola Francesca , Mottolese Marcella , Zeuner Ann , Fanciulli Maurizio , Stassi Giorgio , Maugeri-Saccà Marcello , Baiocchi Marta , Tartaglia Marco , Vitale Ilio , De Maria Ruggero
Published: April 2017

Objective

Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies.

Design

To discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents.

Results

The drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (∼36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in TP53 and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368.

Conclusions

LY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of RAS mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC.
Haematological cancers: improving outcomes. A summary of updated NICE service guidance in relation to Specialist Integrated Haematological Malignancy Diagnostic Services (SIHMDS)
Authors: Snowden John A , O'Connell Susan , Hawkins James , Dalley Chris , Jack Andrew , Mannari Deepak , McNamara Chris , Scott Mike , Shenton Geoff , Soilleux Elizabeth , Macbeth Fergus
Published: April 2017

Haematological malignancies are a diverse group of cancers that affect the blood, bone marrow and lymphatic systems. Laboratory diagnosis of haematological malignancies is dependent on combining several technologies, including morphology, immunophenotyping, cytogenetics and molecular genetics correlated clinical details and classification according to the current WHO guidelines. The concept of the Specialised Integrated Haematological Malignancy Diagnostic Services (SIHMDS) has evolved since the UK National Institute for Health and Care Excellence (NICE) Improving Outcomes Guidance (IOG) in 2003 and subsequently various models of delivery have been established. As part of the 2016 update to the NICE IOG, these models were systematically evaluated and recommendations produced to form the basis for quality standards for future development of SIHMDS. We provide a summary of the systematic review and recommendations. Although the recommendations pertain to the UK National Health Service (NHS), they have relevance to the modern delivery of diagnostic services internationally.
Diagnostic accuracy of endometrial biopsy in relation to the amount of tissue
Authors: Reijnen Casper , Visser Nicole C M , Bulten Johan , Massuger Leon F A G , van der Putten Louis J M , Pijnenborg Johanna M A
Published: April 2017

Aims

For the diagnostic workup of postmenopausal bleeding, histological examination of the endometrium is frequently performed. Failure of endometrial sampling due to insufficient material is often reported but objective criteria for quality assessment of endometrial biopsies are lacking. The aim of the present study is to evaluate the association between the amount of tissue obtained by endometrial sampling and the diagnostic accuracy, and to establish a cut-off level for a minimal amount of tissue required for a conclusive diagnosis.

Methods

For this retrospective cohort study, clinicopathological data and Pipelle endometrial sampling slides of 139 patients who were treated with hysterectomy were collected. The surface of evaluable endometrial tissue was measured by means of structured digital assessment. The correlation between the predictive values in relation to the endometrial tissue surface was calculated for different cut-off values.

Results

The median endometrial tissue surface was 4.7 mm2(range 0.4–156.4) for benign endometrium, 27.8 mm2(range 0.0–208.4) for premalignant endometrium and 43.8 mm2(range 0.0–223.6) for malignant endometrium. There was a significant association between the endometrial tissue surface and the correctness of diagnosis. A minimal endometrial tissue surface of 35 mm2could be defined, for positive and negative predictive values of 92.6% and 85.7%, respectively.

Conclusions

The diagnostic accuracy of Pipelle endometrial sampling is associated with the amount of endometrial tissue surface, with a minimal cut-off value of 35 mm2required to classify an endometrial sample as conclusive. Quantification of endometrial tissue can contribute to standardisation of quality assessment of endometrial samplings.
Paediatric hypoglycaemia; are we investigating appropriately and adequately?
Authors: Ramsden Louise , Wright Katherine , Natarajan Anuja
Published: April 2017

Introduction

Paediatric hypoglycaemia is a relatively common medical emergency. To allow identification of the underlying cause, investigations need to be performed urgently prior to treatment being given. Careful consideration is needed to ensure correct patient selection, as inadequate investigations have further cost and patient safety implications.

Methods

49 cases of proven or suspected hypoglycaemia (glucose ≤2.6 mmol/L) were identified via the laboratory. Clinical notes, laboratory investigations and results were reviewed.

Results

Only 41% of patients (15 neonates, 5 children) required investigation with a ‘Hyposcreen’. Of these 20 patients, 3 had no investigations performed. In the remaining patients the cause for hypoglycaemia was identifiable, but 6 had investigations regardless. In total 23 patients had ‘Hyposcreen’ but only 2 were complete. Intermediary metabolites (96%), lactate (100%), cortisol (100%), insulin (83%) and growth hormone (87%) were taken most commonly with urine samples (52%) and ammonia (30%) taken least often. 40% cortisol, 29% insulin and 56% intermediary metabolite results were abnormal affecting 10 patients, but only 5 had follow-up. A total of £6977 was spent on investigations, of which £1630 has subsequently been found to be unnecessary. If investigations in the 23 children had been complete, this would have totalled £2700 of unnecessary expenditure.

Conclusions

Investigations for hypoglycaemia are generally incomplete (91%) or inappropriate (21%). This has major cost implications for both the National Health Service and the individual who is investigated inadequately or incorrectly. We need national evidence-based guidance for investigation thresholds and normal ranges to help avoid inappropriate investigations and delay in diagnosis.
Evaluation of multiple referral strategies for axial spondyloarthritis in the SPondyloArthritis Caught Early (SPACE) cohort
Authors: Abawi Ozair , van den Berg Rosaline , van der Heijde Désirée , van Gaalen Floris A
Published: April 2017

Background

Several models have been proposed to refer patients with possible axial spondyloarthritis (axSpA) to a rheumatologist. Our aim was to evaluate performance of these models in a single cohort.

Methods

13 referral models found in the literature were evaluated in the Leiden SPondyloArthritis Caught Early (SPACE) cohort, which includes patients with back pain (≥3 months, ≤2 years, onset <45 years; n=261) referred to a rheumatology outpatient clinic. Imaging was not considered as a referral parameter. Performance of the strategies was evaluated (sensitivity, specificity, positive likelihood ratio (LR+)) using diagnosis by a rheumatologist as an external standard. For secondary analyses, fulfilment of the Assessment in SpondyloArthritis international Society (ASAS) axSpA criteria was used as an external standard.

Results

In total, 107/261 patients were diagnosed with axSpA. Most models performed well regarding sensitivity and specificity. The MASTER strategy showed a balanced sensitivity/specificity with the highest LR+. The ASAS and Brandt I strategies are the most sensitive strategies. Using classification by ASAS axSpA criteria as the external standard gave comparable results. Most patients missed by the strategies fulfilled the imaging arm of the ASAS axSpA criteria.

Conclusions

Most referral models performed well, although patients in SPACE have already been referred, which may have led to overestimation of performance. If no patient is to be missed, the ASAS strategy would be most preferable. If the number of referrals needs to be limited, the MASTER strategy seems to perform best. The ‘ideal’ referral strategy may be different from country to country, due to differences in healthcare structure and prevalence of referral parameters such as human leucocyte antigen-B27.
Effects of acidic pH on wild, farmed, and F1 hybrid Atlantic salmon (Salmo salar) parr
Authors: Lush Lynn , Costa Isabel , Marshall Kimberly , Pérez-Casanova Juan Carlos , Belley Rénald , Hamoutene Dounia
Published: April 2017

Farmed escapees have the potential to introduce novel genes to wild salmon and alter locally adapted populations. We tested whether the acidic conditions found in rivers on Newfoundland’s south coast might differentially impact offspring of farmed Atlantic salmon (Salmo salar) in comparison to wild populations. We performed crosses with wild and farmed parents to obtain wild (W♂ × W♀), farmed (F♂ × F♀), and F1 hybrid (W♂ × F♀, F♂ × W♀) parr and conducted a common garden experiment at neutral or acidic pH. No differences were observed between pure wild crosses and F1 hybrids, suggesting that acidic waters do not differentially affect survival, growth, condition factor, and Na+/K+-ATPase activity of F1 hybrids. Trends in mortality show that pure farmed parr had lower survival than pure wild and F1 hybrids in low pH. Considering that production of F1 hybrids rather than pure farmed offspring is the most likely outcome in the wild, pure farmed parr survival may have little bearing on the prediction of genetic risks of farmed–wild interactions. There is no evidence to indicate that the survival of the F1 generation in acidic waters acts as a potential barrier against introgression.
Rapid evolution meets invasive species control: the potential for pesticide resistance in sea lamprey
Authors: Dunlop Erin S. , McLaughlin Rob , Adams Jean V. , Jones Michael , Birceanu Oana , Christie Mark R. , Criger Lori A. , Hinderer Julia L.M. , Hollingworth Robert M. , Johnson Nicholas S. , Lantz Stephen R. , Li Weiming , Miller James , Morrison Bruce J. , Mota-Sanchez David , Muir Andrew , Sepúlveda Maria S. , Steeves Todd , Walter Lisa , Westman Erin , Wirgin Isaac , Wilkie Michael P.
Published: April 2017

Rapid evolution of pest, pathogen, and wildlife populations can have undesirable effects, for example, when insects evolve resistance to pesticides or fishes evolve smaller body size in response to harvest. A destructive invasive species in the Laurentian Great Lakes, the sea lamprey (Petromyzon marinus) has been controlled with the pesticide 3-trifluoromethyl-4-nitrophenol (TFM) since the 1950s. We evaluated the likelihood of sea lamprey evolving resistance to TFM by (i) reviewing sea lamprey life history and control; (ii) identifying physiological and behavioural resistance strategies; (iii) estimating the strength of selection from TFM; (iv) assessing the timeline for evolution; and (v) analyzing historical toxicity data for evidence of resistance. The number of sea lamprey generations exposed to TFM was within the range observed for fish populations where rapid evolution has occurred. Mortality from TFM was estimated as 82%–90%, suggesting significant selective pressure. However, 57 years of toxicity data revealed no increase in lethal concentrations of TFM. Vigilance and the development of alternative controls are required to prevent this aquatic invasive species from evolving strategies to evade control.
Coyote (Canis latrans) diet in an urban environment: variation relative to pet conflicts, housing density, and season
Authors: Poessel S.A. , Mock E.C. , Breck S.W.
Published: April 2017

Coyotes (Canis latrans Say, 1823) are highly successful in urbanized environments, but as they populate cities, conflict can occur and often manifests in the form of incidents with pets. To better understand whether coyotes view pets as prey or, alternatively, as competitors or a threat, we conducted a diet analysis of coyotes in the Denver metropolitan area (DMA) by analyzing scats. We also examined differences in diet between high- and low-density housing and among seasons. We found only small percentages of trash and domestic pets in the coyote diet. The presence of pets in the diet did not coincide with the increase of pet conflicts in the DMA in December and January, supporting the hypothesis that coyote conflict with pets is primarily driven by competition or a threat response. Coyotes relied mostly on native plant and animal species, and rodents and lagomorphs were the most prevalent diet items. Coyotes consumed rodents and non-native plants more often in high-density housing and deer, corn, and native plants more often in low-density housing. Coyotes also consumed more fruits and invertebrates during summer and autumn and more mammals and birds in winter and spring. As human–coyote conflicts increase in urban areas, understanding how coyotes and other urban-adapted carnivores use anthropogenic resources may provide insight that can be used to promote coexistence between humans and wildlife.
Geology and seepage in the NE Atlantic region
Authors: Vis Geert-Jan
Published: April 2017

Exploration for hydrocarbons in the NE Atlantic mainly focuses on the central eastern margin. The western margin has remained virtually unexplored, with no exploration wells drilled so far. A cost-efficient way to infer the presence of natural hydrocarbons in the poorly explored regions of the NE Atlantic is the application of synthetic aperture radar (SAR). This study presents four areas, the Western Barents Sea Margin, the Irish Atlantic Margin, East Greenland and Jan Mayen, where clustered oil-slick data indicate possible active oil seepage. The eastern margin of the NE Atlantic contains numerous oil-slick observations, but along the western margin the number of observations is limited, partly due to a persistent sea-ice coverage. Based on the tectonostratigraphic setting, it is suggested that Triassic and Jurassic source rocks are the most likely candidates for the generation of seeps in the areas studied. Near Jan Mayen and East Greenland, Cenozoic source rocks could also be present. SAR data are a useful tool in an early stage of exploration, but further work is needed to improve the understanding of the subsurface below the observed oil slicks in the NE Atlantic to determine the origin of the seepage.
Shear-mediated dilation of the internal carotid artery occurs independent of hypercapnia
Authors: Hoiland Ryan L. , Smith Kurt J. , Carter Howard H. , Lewis Nia C.S. , Tymko Michael M. , Wildfong Kevin W. , Bain Anthony R. , Green Daniel J. , Ainslie Philip N.
Published: April 2017

Evidence for shear stress as a regulator of carotid artery dilation in response to increased arterial CO2was recently demonstrated in humans during sustained elevations in CO2(hypercapnia); however, the relative contributions of CO2and shear stress to this response remains unclear. We examined the hypothesis that, after a 30-s transient increase in arterial CO2tension and consequent increase in internal carotid artery shear stress, internal carotid artery diameter would increase, indicating shear-mediated dilation, in the absence of concurrent hypercapnia. In 27 healthy participants, partial pressures of end-tidal O2and CO2, ventilation (pneumotachography), blood pressure (finger photoplethysmography), heart rate (electrocardiogram), internal carotid artery flow, diameter, and shear stress (high-resolution duplex ultrasound), and middle cerebral artery blood velocity (transcranial Doppler) were measured during 4-min steady-state and transient 30-s hypercapnic tests (both +9 mmHg CO2). Internal carotid artery dilation was lower in the transient compared with steady-state hypercapnia (3.3 ± 1.9 vs. 5.3 ± 2.9%, respectively, P < 0.03). Increases in internal carotid artery shear stress preceded increases in diameter in both transient (time: 16.8 ± 13.2 vs. 59.4 ± 60.3 s, P < 0.01) and steady-state (time: 18.2 ± 14.2 vs. 110.3 ± 79.6 s, P < 0.01) tests. Internal carotid artery dilation was positively correlated with shear rate area under the curve in the transient ( r2= 0.44, P < 0.01) but not steady-state ( r2= 0.02, P = 0.53) trial. Collectively, these results suggest that hypercapnia induces shear-mediated dilation of the internal carotid artery in humans. This study further promotes the application and development of hypercapnia as a clinical strategy for the assessment of cerebrovascular vasodilatory function and health in humans.

NEW & NOTEWORTHY Shear stress dilates the internal carotid artery in humans. This vasodilatory response occurs independent of other physiological factors, as demonstrated by our transient CO2test, and is strongly correlated to shear area under the curve. Assessing carotid shear-mediated dilation may provide a future avenue for assessing cerebrovascular health and the risk of cerebrovascular events.
Impact of RyR2 potentiation on myocardial function
Authors: Lascano E. , Negroni J. , Vila Petroff M. , Mattiazzi A.
Published: April 2017

This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca2+transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca2+release, shifting the intracellular Ca2+transient versus sarcoplasmic reticulum (SR) Ca2+content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca2+content, to enhance contractility if SR Ca2+content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention.

NEW & NOTEWORTHY Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca2+transient-sarcoplasmic reticulum (SR) Ca2+content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca2+content, or successfully counteract the effects of a negative inotropic action.
De novo RNA sequence assembly during in vivo inflammatory stress reveals hundreds of unannotated lincRNAs in human blood CD14+monocytes and in adipose tissue
Authors: Xue Chenyi , Zhang Xuan , Zhang Hanrui , Ferguson Jane F. , Wang Ying , Hinkle Christine C. , Li Mingyao , Reilly Muredach P.
Published: April 2017

Long intergenic noncoding RNAs (lincRNAs) have emerged as key regulators of cellular functions and physiology. Yet functional lincRNAs often have low, context-specific and tissue-specific expression. We hypothesized that many human monocyte and adipose lincRNAs would be absent in current public annotations due to lincRNA tissue specificity, modest sequencing depth in public data, limitations of transcriptome assembly algorithms, and lack of dynamic physiological contexts. Deep RNA sequencing (RNA-Seq) was performed in peripheral blood CD14+monocytes (monocytes; average ~247 million reads per sample) and adipose tissue (average ~378 million reads per sample) collected before and after human experimental endotoxemia, an in vivo inflammatory stress, to identify tissue-specific and clinically relevant lincRNAs. Using a stringent filtering pipeline, we identified 109 unannotated lincRNAs in monocytes and 270 unannotated lincRNAs in adipose. Most unannotated lincRNAs are not conserved in rodents and are tissue specific, while many have features of regulated expression and are enriched in transposable elements. Specific subsets have enhancer RNA characteristics or are expressed only during inflammatory stress. A subset of unannotated lincRNAs was validated and replicated for their presence and inflammatory induction in independent human samples and for their monocyte and adipocyte origins. Through interrogation of public genome-wide association data, we also found evidence of specific disease association for selective unannotated lincRNAs. Our findings highlight the critical need to perform deep RNA-Seq in a cell-, tissue-, and context-specific manner to annotate the full repertoire of human lincRNAs for a complete understanding of lincRNA roles in dynamic cell functions and in human disease.
Role of renal transporters and novel regulatory interactions in the TAL that control blood pressure
Authors: Graham Lesley A. , Dominiczak Anna F. , Ferreri Nicholas R.
Published: April 2017

Hypertension (HTN), a major public health issue is currently the leading factor in the global burden of disease, where associated complications account for 9.4 million deaths worldwide every year. Excessive dietary salt intake is among the environmental factors that contribute to HTN, known as salt sensitivity. The heterogeneity of salt sensitivity and the multiple mechanisms that link high salt intake to increases in blood pressure are of upmost importance for therapeutic application. A continual increase in the kidney’s reabsorption of sodium (Na+) relies on sequential actions at various segments along the nephron. When the distal segments of the nephron fail to regulate Na+, the effects on Na+homeostasis are unfavorable. We propose that the specific nephron region where increased active uptake occurs as a result of variations in Na+reabsorption is at the thick ascending limb of the loop of Henle (TAL). The purpose of this review is to urge the consideration of the TAL as contributing to the pathophysiology of salt-sensitive HTN. Further research in this area will enable development of a therapeutic application for targeted treatment.
Association of Tissue Abiraterone Levels and SLCO Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer
Authors: Mostaghel Elahe A. , Cho Eunpi , Zhang Ailin , Alyamani Mohammad , Kaipainen Arja , Green Sean , Marck Brett T. , Sharifi Nima , Wright Jonathan L. , Gulati Roman , True Lawrence D. , Loda Massimo , Matsumoto Alvin M. , Tamae Daniel , Penning Trevor N. , Balk Steven P. , Kantoff Phillip W. , Nelson Peter S. , Taplin Mary-Ellen , Montgomery R. Bruce
Published: April 2017

Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes.

Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes.

Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, P = 0.09, respectively). SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, P = 0.0008; rs12422149, P = 0.03) and higher rates of minimal residual disease (tumor volume < 0.5 cc; rs1789693, 67% vs. 27%, P = 0.009; rs1077858, 46% vs. 0%, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P < 0.05).

Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment. Clin Cancer Res; 23(16); 4592–601. ©2017 AACR.
Epigenetic Regulation of KPC1 Ubiquitin Ligase Affects the NF-κB Pathway in Melanoma
Authors: Iida Yuuki , Ciechanover Aaron , Marzese Diego M. , Hata Keisuke , Bustos Matias , Ono Shigeshi , Wang Jinhua , Salomon Matthew P. , Tran Kevin , Lam Stella , Hsu Sandy , Nelson Nellie , Kravtsova-Ivantsiv Yelena , Mills Gordon B. , Davies Michael A. , Hoon Dave S.B.
Published: April 2017

Purpose: Abnormal activation of the NF-κB pathway induces a more aggressive phenotype of cutaneous melanoma. Understanding the mechanisms involved in melanoma NF-κB activation may identify novel targets for this pathway. KPC1, an E3 ubiquitin ligase, is a regulator of the NF-κB pathway. The objective of this study was to investigate the mechanisms regulating KPC1 expression and its clinical impact in melanoma.

Experimental Design: The clinical impact of KPC1 expression and its epigenetic regulation were assessed in large cohorts of clinically well-annotated melanoma tissues (tissue microarrays; n = 137, JWCI cohort; n = 40) and The Cancer Genome Atlas database (TCGA cohort, n = 370). Using melanoma cell lines, we investigated the functional interactions between KPC1 and NF-κB, and the epigenetic regulations of KPC1, including DNA methylation and miRNA expression.

Results: We verified that KPC1 suppresses melanoma proliferation by processing NF-κB1 p105 into p50, thereby modulating NF-κB target gene expression. Concordantly, KPC1 expression was downregulated in American Joint Committee on Cancer stage IV melanoma compared with early stages (stage I/II P = 0.013, stage III P = 0.004), and low KPC1 expression was significantly associated with poor overall survival in stage IV melanoma (n = 137; HR 1.810; P = 0.006). Furthermore, our data showed that high miR-155-5p expression, which is controlled by DNA methylation at its promoter region (TCGA; Pearson's r −0.455; P < 0.001), is significantly associated with KPC1 downregulation (JWCI; P = 0.028, TCGA; P = 0.003).

Conclusions: This study revealed novel epigenetic regulation of KPC1 associated with NF-κB pathway activation, promoting metastatic melanoma progression. These findings suggest the potential utility of KPC1 and its epigenetic regulation as theranostic targets. Clin Cancer Res; 23(16); 4831–42. ©2017 AACR.
Differential Expression of OATP1B3 Mediates Unconjugated Testosterone Influx
Authors: Sissung Tristan M. , Ley Ariel M. , Strope Jonathan D. , McCrea Edel M. , Beedie Shaunna , Peer Cody J. , Shukla Suneet , van Velkinburgh Jennifer , Reece Kelie , Troutman Sarah , Campbell Tessa , Fernandez Elena , Huang Phoebe , Smith Jordan , Thakkar Nilay , Venzon David J. , Brenner Stefan , Lee Wooin , Merino Maria , Luo Ji , Jager Walter , Price Douglas K. , Chau Cindy H. , Figg William D.
Published: April 2017

Castration-resistant prostate cancer (CRPC) has greater intratumoral testosterone concentrations than similar tumors from eugonadal men; simple diffusion does not account for this observation. This study was undertaken to ascertain the androgen uptake kinetics, functional, and clinical relevance of de novo expression of the steroid hormone transporter OATP1B3 (SLCO1B3). Experiments testing the cellular uptake of androgens suggest that testosterone is an excellent substrate of OATP1B3 (Km = 23.2 μmol/L; Vmax = 321.6 pmol/mg/minute), and cells expressing a doxycycline-inducible SLCO1B3 construct had greater uptake of a clinically relevant concentration of 3H-testosterone (50 nmol/L; 1.6-fold, P = 0.0027). When compared with Slco1b2 (−/−) mice, Slco1b2 (−/−)/hSLCO1B3 knockins had greater hepatic uptake (15% greater AUC, P = 0.0040) and lower plasma exposure to 3H-testosterone (17% lower AUC, P = 0.0030). Of 82 transporters genes, SLCO1B3 is the second-most differentially expressed transporter in CRPC cell lines (116-fold vs. androgen-sensitive cells), with a differentially spliced cancer-type ct-SLCO1B3 making up the majority of SLCO1B3 expression. Overexpression of SLCO1B3 in androgen-responsive cells results in 1.5- to 2-fold greater testosterone uptake, whereas siRNA knockdown of SLCO1B3 in CRPC cells did not change intracellular testosterone concentration. Primary human prostate tumors express SLCO1B3 to a greater extent than ct-SLCO1B3 (26% of total SLCO1B3 expression vs. 0.08%), suggesting that androgen uptake in these tumor cells also is greater. Non-liver tumors do not differentially express SLCO1B3.

Implications: This study suggests that de novo OATP1B3 expression in prostate cancer drives greater androgen uptake and is consistent with previous observations that greater OATP1B3 activity results in the development of androgen deprivation therapy resistance and shorter overall survival. Mol Cancer Res; 15(8); 1096–105. ©2017 AACR.
Dynamic Computed Tomography Myocardial Perfusion Imaging
Authors: Rossi Alexia , Wragg Andrew , Klotz Ernst , Pirro Federica , Moon James C. , Nieman Koen , Pugliese Francesca
Published: April 2017

Background—

The clinical analysis of myocardial dynamic computed tomography myocardial perfusion imaging lacks standardization. The objective of this prospective study was to compare different analysis approaches to diagnose ischemia in patients with stable angina referred for invasive coronary angiography.

Methods and Results—

Patients referred for evaluation of stable angina symptoms underwent adenosine-stress dynamic computed tomography myocardial perfusion imaging with a second-generation dual-source scanner. Quantitative perfusion parameters, such as blood flow, were calculated by parametric deconvolution for each myocardial voxel. Initially, perfusion parameters were extracted according to standard 17-segment model of the left ventricle (fully automatic analysis). These were then manually sampled by an operator (semiautomatic analysis). Areas under the receiver-operating characteristic curves of the 2 different approaches were compared. Invasive fractional flow reserve ≤0.80 or diameter stenosis ≥80% on quantitative coronary angiography was used as reference standard to define ischemia. We enrolled 115 patients (88 men; age 57±9 years). There were 72 of 286 (25%) vessels causing ischemia in 52 of 115 (45%) patients. The semiautomatic analysis method was better than the fully automatic method at predicting ischemia (areas under the receiver-operating characteristic curves, 0.87 versus 0.69;
P
<0.001) with readings obtained in the endocardial myocardium performing better than those in the epicardial myocardium (areas under the receiver-operating characteristic curves, 0.87 versus 0.72;
P
<0.001). The difference in performance between blood flow, expressed as relative to remote myocardium, and absolute blood flow was not statistically significant (areas under the receiver-operating characteristic curves, 0.90 versus 0.87;
P
=ns).

Conclusions—

Endocardial perfusion parameters obtained by semiautomatic analysis of dynamic computed tomography myocardial perfusion imaging may permit robust discrimination between coronary vessels causing ischemia versus not causing ischemia.
Coronary Computed Tomography Angiography Predicts Guidewire Crossing and Success of Percutaneous Intervention for Chronic Total Occlusion
Authors: Yu Cheol-Woong , Lee Hyun-Jong , Suh Jon , Lee Nae-Hee , Park Sang-Min , Park Taek Kyu , Yang Jeong Hoon , Song Young Bin , Hahn Joo-Yong , Choi Seung Hyuk , Gwon Hyeon-Cheol , Lee Sang-Hoon , Choe Yeon Hyeon , Kim Sung Mok , Choi Jin-Ho
Published: April 2017

Background—

We developed a model that predicts difficulty of percutaneous coronary intervention for coronary chronic total occlusion (CTO) using coronary computed tomographic angiography.

Methods and Results—

A total of 684 CTO lesions with preprocedural computed tomographic angiography were enrolled from 4 centers. Data were randomly divided into derivation and validation datasets at 2:1 ratio. The end point was successful guidewire crossing ≤30 minutes, which was met in 50%. The KCCT (Korean Multicenter CTO CT Registry) score was developed based on independent predictors identified by multivariable analysis, which were proximal blunt entry, proximal side branch, bending, occlusion length ≥15 mm, severe calcification, whole luminal calcification, reattempt, and ≥12 months or unknown duration of occlusion. The KCCT score was compared with the other prediction scores, including angiography-based J-CTO, PROGRESS-CTO, CL-score, and CT-based CT-RECTOR. The probability of guidewire crossing ≤30 minutes declined consistently from 100% to 0% according to the KCCT score (
P
<0.01, all). The KCCT score showed higher discriminative performance compared with the other scoring systems (c-statistics=0.78 versus 0.65–0.72,
P
<0.001, all). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of a KCCT score of <4 for guidewire crossing ≤30 minutes was 70%, 68%, 72%, 73%, and 70%, respectively. The KCCT score also showed consistent results with procedural success (
P
<0.05, all). These results could be reproduced in validation data set (
P
<0.05, all).

Conclusions—

KCCT scoring could predict successful guidewire crossing ≤30 minutes and also procedural success. KCCT scoring may enable noninvasive grading difficulty of CTO percutaneous coronary intervention.
Prognostic Value of Noninvasive Cardiovascular Testing in Patients With Stable Chest Pain
Authors: Hoffmann Udo , Ferencik Maros , Udelson James E. , Picard Michael H. , Truong Quynh A. , Patel Manesh R. , Huang Megan , Pencina Michael , Mark Daniel B. , Heitner John F. , Fordyce Christopher B. , Pellikka Patricia A. , Tardif Jean-Claude , Budoff Matthew , Nahhas George , Chow Benjamin , Kosinski Andrzej S. , Lee Kerry L. , Douglas Pamela S.
Published: April 2017

Background:

Optimal management of patients with stable chest pain relies on the prognostic information provided by noninvasive cardiovascular testing, but there are limited data from randomized trials comparing anatomic with functional testing.

Methods:

In the PROMISE trial (Prospective Multicenter Imaging Study for Evaluation of Chest Pain), patients with stable chest pain and intermediate pretest probability for obstructive coronary artery disease (CAD) were randomly assigned to functional testing (exercise electrocardiography, nuclear stress, or stress echocardiography) or coronary computed tomography angiography (CTA). Site-based diagnostic test reports were classified as normal or mildly, moderately, or severely abnormal. The primary end point was death, myocardial infarction, or unstable angina hospitalizations over a median follow-up of 26.1 months.

Results:

Both the prevalence of normal test results and incidence rate of events in these patients were significantly lower among 4500 patients randomly assigned to CTA in comparison with 4602 patients randomly assigned to functional testing (33.4% versus 78.0%, and 0.9% versus 2.1%, respectively; both
P
<0.001). In CTA, 54.0% of events (n=74/137) occurred in patients with nonobstructive CAD (1%–69% stenosis). Prevalence of obstructive CAD and myocardial ischemia was low (11.9% versus 12.7%, respectively), with both findings having similar prognostic value (hazard ratio, 3.74; 95% confidence interval [CI], 2.60–5.39; and 3.47; 95% CI, 2.42–4.99). When test findings were stratified as mildly, moderately, or severely abnormal, hazard ratios for events in comparison with normal tests increased proportionally for CTA (2.94, 7.67, 10.13; all
P
<0.001) but not for corresponding functional testing categories (0.94 [
P
=0.87], 2.65 [
P
=0.001], 3.88 [
P
<0.001]). The discriminatory ability of CTA in predicting events was significantly better than functional testing (c-index, 0.72; 95% CI, 0.68–0.76 versus 0.64; 95% CI, 0.59–0.69;
P
=0.04). If 2714 patients with at least an intermediate Framingham Risk Score (>10%) who had a normal functional test were reclassified as being mildly abnormal, the discriminatory capacity improved to 0.69 (95% CI, 0.64–0.74).

Conclusions:

Coronary CTA, by identifying patients at risk because of nonobstructive CAD, provides better prognostic information than functional testing in contemporary patients who have stable chest pain with a low burden of obstructive CAD, myocardial ischemia, and events.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01174550.
Benefits of Emergency Departments’ Contribution to Stroke Prophylaxis in Atrial Fibrillation
Authors: Coll-Vinent Blanca , Martín Alfonso , Sánchez Juan , Tamargo Juan , Suero Coral , Malagón Francisco , Varona Mercedes , Cancio Manuel , Sánchez Susana , Carbajosa José , Ríos José , Casanovas Georgina , Ràfols Carles , del Arco Carmen , Agud María , Aguilar José , Aguirre Alfons , de Simón Almela Amparo , Almirall Mercè , Álvarez Oscar , Amador Luis , Andueza Juan Antonio , Aramburu Francisco José , Ayala Ignacio , Bajo Ángel , Bilbaíno Carlos , Calvo Ricardo , Díaz María Elena , Estévez Maria Jesús , Flaño Cristina , Fuenzalida Carolina , Garcés Cristina , García María Teresa , García Pedro , García-Castrillo Luis , Gargallo Carmen , Garrido José Manuel , González Juan , Herrero Pablo , Jiménez Eduardo , Jiménez Gregorio , Lázaro José , Lopetegui Pedro , López Ignacio , Lubillo José Maria , Marchena María José , Moya Francisco , Mozota Julián , Navarro Francisco José , Palom Xavier , Ochoa Javier , Peiró Ana María , Parra Juan Manuel , Perea Álvaro , Piñera Pascual , Riambau Pere , Richard Fernando , Rodríguez Belén , Rodríguez Roberto , Ruiz Eva , Ruiz Francisco , Segarra Ana Maria , Seijas Carmen , Sesma Javier , Soler Wilfredo , Sousa María del Mar , Torres José Manuel , Trejo Olga Maria , Vicente José
Published: April 2017

Background and Purpose—

Long-term benefits of initiating stroke prophylaxis in the emergency department (ED) are unknown. We analyzed the long-term safety and benefits of ED prescription of anticoagulation in atrial fibrillation patients.

Methods—

Prospective, multicenter, observational cohort of consecutive atrial fibrillation patients was performed in 62 Spanish EDs. Clinical variables and thromboprophylaxis prescribed at discharge were collected at inclusion. Follow-up at 1 year post-discharge included data about thromboprophylaxis and its complications, major bleeding, and death; risk was assessed with univariate and bivariate logistic regression models.

Results—

We enrolled 1162 patients, 1024 (88.1%) at high risk according to CHA
2
DS
2
-VASc score. At ED discharge, 935 patients (80.5%) were receiving anticoagulant therapy, de novo in 237 patients (55.2% of 429 not previously treated). At 1 year, 48 (4.1%) patients presented major bleeding events, and 151 (12.9%) had died. Anticoagulation first prescribed in the ED was not related to major bleeding (hazard ratio, 0.976; 95% confidence interval, 0.294–3.236) and was associated with a decrease in mortality (hazard ratio, 0.398; 95% confidence interval, 0.231–0.686). Adjusting by the main clinical and sociodemographic characteristics, concomitant antiplatelet treatment, or destination (discharge or admission) did not affect the results.

Conclusions—

Prescription of anticoagulation in the ED does not increase bleeding risk in atrial fibrillation patients at high risk of stroke and contributes to decreased mortality.