bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparable mRNA expression of inflammatory markers but lower claudin-1 mRNA levels in foreskin tissue of HSV-2 seropositive versus seronegative asymptomatic Kenyan young men
Authors: Röhl Maria , Tjernlund Annelie , Mehta Supriya D , Pettersson Pernilla , Bailey Robert C , Broliden Kristina 
Published: February 2015

ObjectivesSkin biopsies from local sites of herpes simplex virus 2 (HSV-2)-induced ulcers can show infiltrates of inflammatory cells several months after macroscopic healing. We hypothesise that foreskin tissue samples of asymptomatic HSV-2 seropositive men had remaining signs of inflammation at the molecular level. Even in the absence of clinical lesions, genital inflammation may contribute to increased HIV susceptibility on sexual exposure to the virus.SettingForeskin tissue samples were collected from men undergoing elective circumcision in Kisumu, Kenya.ParticipantsThe foreskin tissue samples (n=86) were stratified into study groups based on HSV-2 serology and assessed for mRNA expression of inflammatory markers. Markers of interest were further assessed by immunohistochemical staining within the tissue samples.ResultsThe two study groups had comparable levels of all molecular markers (CD3, CD4, CD8, CD69, CCR5, HLA-DR, Langerin, DC-SIGN, Mannose Receptor 1, IL-1, IL-6, TNF-α, β7, IgA, IFN-α, CCL5, E-cadherin, ZO-1 and occludin), except for lower mRNA levels of the epithelial junction protein claudin-1 in the HSV-2 seropositive group (p=0.008). Although mRNA levels of claudin-1 were lower in HSV-2 seropositive individuals, the corresponding protein could be visualised in the foreskin epithelium of all samples tested.ConclusionsWhereas no general inflammation was demonstrated in the foreskin of asymptomatic HSV-2 seropositive individuals, a decreased expression of claudin-1 indicates a less robust genital epithelial barrier. An intact epithelial barrier is essential for blocking mucosal entry of genital infections, including HIV.
A tool for prediction of risk of rehospitalisation and mortality in the hospitalised elderly: secondary analysis of clinical trial data
Authors: Alassaad Anna , Melhus Håkan , Hammarlund-Udenaes Margareta , Bertilsson Maria , Gillespie Ulrika , Sundström Johan 
Published: February 2015

ObjectivesTo construct and internally validate a risk score, the ‘80+ score’, for revisits to hospital and mortality for older patients, incorporating aspects of pharmacotherapy. Our secondary aim was to compare the discriminatory ability of the score with that of three validated tools for measuring inappropriate prescribing: Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert doctors to Right Treatment (START) and Medication Appropriateness Index (MAI).SettingTwo acute internal medicine wards at Uppsala University hospital. Patient data were used from a randomised controlled trial investigating the effects of a comprehensive clinical pharmacist intervention.ParticipantsData from 368 patients, aged 80 years and older, admitted to one of the study wards.Primary outcome measureTime to rehospitalisation or death during the year after discharge from hospital. Candidate variables were selected among a large number of clinical and drug-specific variables. After a selection process, a score for risk estimation was constructed. The 80+ score was internally validated, and the discriminatory ability of the score and of STOPP, START and MAI was assessed using C-statistics.ResultsSeven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid or being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked to a lower risk of the outcome. These variables made up the components of the 80+ score. The C-statistics were 0.71 (80+), 0.57 (STOPP), 0.54 (START) and 0.63 (MAI).ConclusionsWe developed and internally validated a score for prediction of risk of rehospitalisation and mortality in hospitalised older people. The score discriminated risk better than available tools for inappropriate prescribing. Pending external validation, this score can aid in clinical identification of high-risk patients and targeting of interventions.
Implementation of a ward round pro-forma to improve adherence to best practice guidelines
Authors: Boland Xavier 
Published: February 2015

AbstractOur aim was firstly to assess adherence to best practice guidelines for the prevention of healthcare associated causes of inpatient mortality and morbidity by junior doctors. Secondly, we wanted to measure the impact of a ward round checklist on rates of adherence.The rates of correct prescribing of antibiotics, venous thrombo-embolism prophylaxis, and oxygen (pro re nata) as well as correctly completed paperwork for peripheral venous cannulas were measured in a spot audit of all medical notes of patients on a medical assessment unit. This was repeated two weeks and two months after the introduction of a specifically designed ward round checklist for junior doctors.Initial audit of 40 patient notes confirmed generally poor compliance with best practice guidelines in the prescription of antibiotics (58% correctly prescribed) and oxygen (42%), and in the use cannula care plans (39%). Venous thrombo-embolism prophylaxis prescribing on the other hand was widespread (82%). The introduction and extensive use of the ward round checklist did not have a significant impact on these figures as shown in the two following stop audits (30 and 36 notes respectively).Checklists are helpful in providing a structured and systematic approach to complex tasks and have been shown to have a measurable impact in improving patient care. Their effectiveness is however limited by their uptake and regular correct use. Obstructing issues include poor understanding of the need for change in practice, lack of individual accountability and variable involvement of clinical leaders. These issues must be addressed together in order to effect a successful change in clinical practice.
Predictors of response to TNF antagonists in patients with ankylosing spondylitis and psoriatic arthritis: systematic review and meta-analysis
Authors: Maneiro Jose Ramon , Souto Alejandro , Salgado Eva , Mera Antonio , Gomez-Reino Juan J 
Published: February 2015

ObjectiveTo identify predictors of response to tumor necrosis factor (TNF) antagonists in ankylosing spondylitis (AS) and psoriatic arthritis (PsA).MethodsSystematic review and meta-analysis of clinical trials and observational studies based on a systematic search. Meta-analyses of similar observations were performed using random effects computing summary OR. Heterogeneity was tested using I2, and risks of bias using funnel plots and the Egger test. Meta-regression was used to explore causes of heterogeneity.ResultsThe electronic search captured 1340 references and 217 abstracts. 17 additional articles were identified after searching by hand. A total of 59 articles meet the purpose of the study and were reviewed. 37 articles (33 studies) included 6736 patients with AS and 23 articles (22 studies) included 4034 patients with PsA. 1 article included data on AS and PsA. Age (OR (95% CI) 0.91 (0.84 to 0.99), I2=84.1%), gender (1.57 (1.10 to 2.25), I2=0.0%), baseline BASDAI (1.31 (1.09 to 1.57), I2=0.0%), baseline BASFI (0.86 (0.79 to 0.93), I2=24.9%), baseline dichotomous C reactive protein (CRP) (2.14 (1.71 to 2.68), I2=22.3%) and human leucocyte antigen B27 (HLA-B27) (1.81 (1.35 to 2.42), I2=0.0%) predict BASDAI50 response in AS. No factor was identified as a source of heterogeneity. Only meta-analysis of baseline BASFI showed risk of publication bias (Egger test, p=0.004). Similar results were found for ASAS criteria response. No predictors of response were identified in PsA.ConclusionsYoung age, male sex, high baseline BASDAI, low baseline BASFI, high baseline CRP and HLA-B27 predict better response to TNF antagonists in AS but not in PsA.
Desmoplasia in Primary Tumors and Metastatic Lesions of Pancreatic Cancer
Authors: Whatcott Clifford J. , Diep Caroline H. , Jiang Ping , Watanabe Aprill , LoBello Janine , Sima Chao , Hostetter Galen , Shepard H. Michael , Von Hoff Daniel D. , Han Haiyong 
Published: February 2015

Abstract
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is characterized by high levels of fibrosis, termed desmoplasia, which is thought to hamper the efficacy of therapeutics treating PDAC. Our primary focus was to evaluate differences in the extent of desmoplasia in primary tumors and metastatic lesions. As metastatic burden is a primary cause for mortality in PDAC, the extent of desmoplasia in metastases may help to determine whether desmoplasia targeting therapeutics will benefit patients with late-stage, metastatic disease.
Experimental Design: We sought to assess desmoplasia in metastatic lesions of PDAC and compare it with that of primary tumors. Fifty-three patients' primaries and 57 patients' metastases were stained using IHC staining techniques.
Results: We observed a significant negative correlation between patient survival and extracellular matrix deposition in primary tumors. Kaplan–Meier curves for collagen I showed median survival of 14.6 months in low collagen patients, and 6.4 months in high-level patients (log rank, P &lt; 0.05). Low-level hyaluronan patients displayed median survival times of 24.3 months as compared with 9.3 months in high-level patients (log rank, P &lt; 0.05). Our analysis also indicated that extracellular matrix components, such as collagen and hyaluronan, are found in high levels in both primary tumors and metastatic lesions. The difference in the level of desmoplasia between primary tumors and metastatic lesions was not statistically significant.
Conclusions: Our results suggest that both primary tumors and metastases of PDAC have highly fibrotic stroma. Thus, stromal targeting agents have the potential to benefit PDAC patients, even those with metastatic disease. Clin Cancer Res; 21(15); 3561–8. ©2015 AACR.
See related commentary by Olive, p. 3366
Hotspot Mutation Panel Testing Reveals Clonal Evolution in a Study of 265 Paired Primary and Metastatic Tumors
Authors: Goswami Rashmi S. , Patel Keyur P. , Singh Rajesh R. , Meric-Bernstam Funda , Kopetz E. Scott , Subbiah Vivek , Alvarez Ricardo H. , Davies Michael A. , Jabbar Kausar J. , Roy-Chowdhuri Sinchita , Lazar Alexander J. , Medeiros L. Jeffrey , Broaddus Russell R. , Luthra Rajyalakshmi , Routbort Mark J. 
Published: February 2015

Abstract
Purpose: We used a clinical next-generation sequencing (NGS) hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors.
Experimental Design: A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single-nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interval between onset of primary tumor and metastasis, and neoadjuvant therapy status.
Results: Of note, 227 of 265 (85.7%) tumor metastasis pairs showed identical mutation calls. Of the tumor pairs with identical mutation calls, 160 (60.4%) possessed defining somatic mutation signatures and 67 (25.3%) did not exhibit any somatic mutations. There were 38 (14.3%) cases that showed at least one novel mutation call between the primary and metastasis. Metastases were almost two times more likely to show novel mutations (n = 20, 7.5%) than primary tumors (n = 12, 4.5%). TP53 was the most common additionally mutated gene in metastatic lesions, followed by PIK3CA and SMAD4. PIK3CA mutations were more often associated with metastasis in colon carcinoma samples.
Conclusions: Clinical NGS hotspot panels can be useful in analyzing clonal evolution within tumors as well as in determining subclonal mutations that can expand in future metastases. PIK3CA, SMAD4, and TP53 are most often involved in clonal divergence, providing potential targets that may help guide the clinical management of tumor progression or metastases. Clin Cancer Res; 21(11); 2644–51. ©2015 AACR.
Preclinical Pharmacological Evaluation of Letrozole as a Novel Treatment for Gliomas
Authors: Dave Nimita , Chow Lionel M.L. , Gudelsky Gary A. , LaSance Kathleen , Qi Xiaoyang , Desai Pankaj B. 
Published: February 2015

Abstract
We present data that letrozole, an extensively used aromatase inhibitor in the treatment of estrogen receptor–positive breast tumors in postmenopausal women, may be potentially used in the treatment of glioblastomas. First, we measured the in vitro cytotoxicity of letrozole and aromatase (CYP19A1) expression and activity in human LN229, T98G, U373MG, U251MG, and U87MG, and rat C6 glioma cell lines. Estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells served as controls. Cytotoxicity was determined employing the MTT assay, and aromatase activity using an immunoassay that measures the conversion of testosterone to estrogen. Second, in vivo activity of letrozole was assessed in Sprague–Dawley rats orthotopically implanted with C6 gliomas. The changes in tumor volume with letrozole treatment (4 mg/kg/day) were assessed employing μPET/CT imaging, employing [18F]-fluorodeoxyglucose (F18-FDG) as the radiotracer. Brain tissues were collected for histologic evaluations. All glioma cell lines included here expressed CYP19A1 and letrozole exerted considerable cytotoxicity and decrease in aromatase activity against these cells (IC50, 0.1–3.5 μmol/L). Imaging analysis employing F18-FDG μPET/CT demonstrated a marked reduction of active tumor volume (&gt;75%) after 8 days of letrozole treatment. Immunohistochemical analysis revealed marked reduction in aromatase expression in tumoral regions of the brain after letrozole treatment. Thus, employing multifaceted tools, we demonstrate that aromatase may be a novel target for the treatment of gliomas and that letrozole, an FDA-approved drug with an outstanding record of safety may be repurposed for the treatment of such primary brain tumors, which currently have few therapeutic options. Mol Cancer Ther; 14(4); 857–64. ©2015 AACR.
PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy
Authors: Patel Sandip Pravin , Kurzrock Razelle 
Published: February 2015

AbstractThe resurgence of cancer immunotherapy stems from an improved understanding of the tumor microenvironment. The PD-1/PD-L1 axis is of particular interest, in light of promising data demonstrating a restoration of host immunity against tumors, with the prospect of durable remissions. Indeed, remarkable clinical responses have been seen in several different malignancies including, but not limited to, melanoma, lung, kidney, and bladder cancers. Even so, determining which patients derive benefit from PD-1/PD-L1–directed immunotherapy remains an important clinical question, particularly in light of the autoimmune toxicity of these agents. The use of PD-L1 (B7-H1) immunohistochemistry (IHC) as a predictive biomarker is confounded by multiple unresolved issues: variable detection antibodies, differing IHC cutoffs, tissue preparation, processing variability, primary versus metastatic biopsies, oncogenic versus induced PD-L1 expression, and staining of tumor versus immune cells. Emerging data suggest that patients whose tumors overexpress PD-L1 by IHC have improved clinical outcomes with anti-PD-1–directed therapy, but the presence of robust responses in some patients with low levels of expression of these markers complicates the issue of PD-L1 as an exclusionary predictive biomarker. An improved understanding of the host immune system and tumor microenvironment will better elucidate which patients derive benefit from these promising agents. Mol Cancer Ther; 14(4); 847–56. ©2015 AACR.
Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women
Authors: Knapen Marjo H. J. , Braam Lavienja A. J. L. M. , Drummen Nadja E. , Bekers Otto , Hoeks Arnold P. G. , Vermeer Cees 
Published: February 2015

SummaryObservational data suggest a link between menaquinone (MK, vitamin K2) intake and cardiovascular (CV) health. However, MK intervention trials with vascular endpoints are lacking. We investigated long-term effects of MK-7 (180 μg MenaQ7/day) supplementation on arterial stiffness in a double-blind, placebo-controlled trial. Healthy postmenopausal women (n=244) received either placebo (n=124) or MK-7 (n=120) for three years. Indices of local carotid stiffness (intimamedia thickness IMT, Diameter end-diastole and Distension) were measured by echotracking. Regional aortic stiffness (carotid-femoral and carotid-radial Pulse Wave Velocity, cfPWV and crPWV, respectively) was measured using mechanotransducers. Circulating desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP) as well as acute phase markers Interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α) and markers for endothelial dysfunction Vascular Cell Adhesion Molecule (VCAM), E-selectin, and Advanced Glycation Endproducts (AGEs) were measured. At baseline dp-ucMGP was associated with IMT, Diameter, cfPWV and with the mean z-scores of acute phase markers (APMscore) and of markers for endothelial dysfunction (EDFscore). After three year MK-7 supplementation cfPWV and the Stiffness Index β significantly decreased in the total group, whereas distension, compliance, distensibility, Young’s Modulus, and the local carotid PWV (cPWV) improved in women having a baseline Stiffness Index β above the median of 10.8. MK-7 decreased dp-ucMGP by 50 % compared to placebo, but did not influence the markers for acute phase and endothelial dysfunction. In conclusion, long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness.
Association of Objectively Measured Physical Activity With Cardiovascular Risk in Mobility‐limited Older Adults
Authors: Fitzgerald Jodi D. , Johnson Lindsey , Hire Don G. , Ambrosius Walter T. , Anton Stephen D. , Dodson John A. , Marsh Anthony P. , McDermott Mary M. , Nocera Joe R. , Tudor‐Locke Catrine , White Daniel K. , Yank Veronica , Pahor Marco , Manini Todd M. , Buford Thomas W. ,   the LIFE Study Research Group
Published: February 2015

Background
Data are sparse regarding the impacts of habitual physical activity (PA) and sedentary behavior on cardiovascular (CV) risk in older adults with mobility limitations.

Methods and Results

This study examined the baseline, cross‐sectional association between CV risk and objectively measured PA among participants in the Lifestyle Interventions and Independence for Elders (LIFE) study. The relationship between accelerometry measures and predicted 10‐year Hard Coronary Heart Disease (HCHD) risk was modeled by using linear regression, stratified according to CVD history. Participants (n=1170, 79±5 years) spent 642±111 min/day in sedentary behavior (ie, <100 accelerometry counts/min). They also spent 138±43 min/day engaging in PA registering 100 to 499 accelerometry counts/min and 54±37 min/day engaging in PA ≥500 counts/min. Each minute per day spent being sedentary was associated with increased HCHD risk among both those with (0.04%, 95% CI 0.02% to 0.05%) and those without (0.03%, 95% CI 0.02% to 0.03%) CVD. The time spent engaging in activities 100 to 499 as well as ≥500 counts/min was associated with decreased risk among both those with and without CVD (
P
<0.05). The mean number of counts per minute of daily PA was not significantly associated with HCHD risk in any model (
P
>0.05). However, a significant interaction was observed between sex and count frequency (
P
=0.036) for those without CVD, as counts per minute was related to HCHD risk in women (β=−0.94, −1.48 to −0.41;
P
<0.001) but not in men (β=−0.14, −0.59 to 0.88;
P
=0.704).

Conclusions
Daily time spent being sedentary is positively associated with predicted 10‐year HCHD risk among mobility‐limited older adults. Duration, but not intensity (ie, mean counts/min), of daily PA is inversely associated with HCHD risk score in this population—although the association for intensity may be sex specific among persons without CVD.

Clinical Trial Registration

URL:
www.clinicaltrials.gov
Unique identifier: NCT01072500
Soil nematode assemblages in an acid soil as affected by lime application
Authors: Zhao Jie , Zhao Cancan , Wan Songze , Wang Xiaoli , Zhou Lixia , Fu Shenglei 
Published: February 2015

Liming can affect soil biota through alterations in soil pH and soil structure. Many earlier studies monitored the responses of soil nematode communities to lime application but they did not come to a consensus and did not use indices of soil nematode community and multivariate statistical approaches developed over the past two decades. The present research explored the short-term effects of lime application on soil nematode communities in an acrisol in threeEucalyptusplantations in southern China. Nematodes were sampled from control and lime-treated plots at three periods from October 2011 to February 2012 at 0-10 cm and 10-20 cm soil depths. Repeated measures ANOVA showed that lime application significantly reduced the abundance of herbivores at 10-20 cm depth during the study. Lime application tended to increase the bacterivore index at 0-10 cm depth over time. Principal response curves of soil nematode community structure, in terms of nematode trophic group composition, revealed that the differences between control and lime application treatments increased over time, primarily because of the decline of fungivores in plots treated with lime. The decline in fungivores resulted mainly from declines ofFilenchusandDitylenchus. The results suggest that the fungal-mediated decomposition channel in the soil food web was suppressed by lime application. Our study also demonstrated that the sensitivity of different nematode genera to lime application varied widely, even for genera within the same trophic group. In particular, the abundance of several bacterivorous genera (Prismatolaimus,Plectus,Wilsonema,Protorhabditis,DiploscapterandHeterocephalobus) gradually declined and that ofRhabditonemaat 0-10 cm depth gradually increased following lime application during the study; two herbivorous genera,TrophotylenchulusandHelicotylenchus, had opposite responses to lime application at 0-10 cm depth. Integrating univariate statistical approaches with multivariate approaches facilitated the analysis of soil nematode responses to lime application.