bluuebunny/crossref_metadata_2025_split huggingface dataset:
Broadly Reactive Anti-Respiratory Syncytial Virus G Antibodies from Exposed Individuals Effectively Inhibit Infection of Primary Airway Epithelial Cells
Authors: Cortjens B. , Yasuda E. , Yu X. , Wagner K. , Claassen Y. B. , Bakker A. Q. , van Woensel J. B. M. , Beaumont T. 
Published: March 2017

ABSTRACT

Respiratory syncytial virus (RSV) causes severe respiratory disease in young children. Antibodies specific for the RSV prefusion F protein have guided RSV vaccine research, and in human serum, these antibodies contribute to >90% of the neutralization response; however, detailed insight into the composition of the human B cell repertoire against RSV is still largely unknown. In order to study the B cell repertoire of three healthy donors for specificity against RSV, CD27
+
memory B cells were isolated and immortalized using BCL6 and Bcl-xL. Of the circulating memory B cells, 0.35% recognized RSV-A2-infected cells, of which 59% were IgA-expressing cells and 41% were IgG-expressing cells. When we generated monoclonal B cells selected for high binding to RSV-infected cells, 44.5% of IgG-expressing B cells and 56% of IgA-expressing B cells reacted to the F protein, while, unexpectedly, 41.5% of IgG-expressing B cells and 44% of IgA expressing B cells reacted to the G protein. Analysis of the G-specific antibodies revealed that 4 different domains on the G protein were recognized. These epitopes predicted cross-reactivity between RSV strain A (RSV-A) and RSV-B and matched the potency of antibodies to neutralize RSV in HEp-2 cells and in primary epithelial cell cultures. G-specific antibodies were also able to induce antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis of RSV-A2-infected cells. However, these processes did not seem to depend on a specific epitope. In conclusion, healthy adults harbor a diverse repertoire of RSV glycoprotein-specific antibodies with a broad range of effector functions that likely play an important role in antiviral immunity.

IMPORTANCE
Human RSV remains the most common cause of severe lower respiratory tract disease in premature babies, young infants, the elderly, and immunocompromised patients and plays an important role in asthma exacerbations. In developing countries, RSV lower respiratory tract disease has a high mortality. Without an effective vaccine, only passive immunization with palivizumab is approved for prophylactic treatment. However, highly potent RSV-specific monoclonal antibodies could potentially serve as a therapeutic treatment and contribute to disease control and mortality reduction. In addition, these antibodies could guide further vaccine development. In this study, we isolated and characterized several novel antibodies directed at the RSV G protein. This information can add to our understanding and treatment of RSV disease.
Internal Disequilibria and Phenotypic Diversification during Replication of Hepatitis C Virus in a Noncoevolving Cellular Environment
Authors: Moreno Elena , Gallego Isabel , Gregori Josep , Lucía-Sanz Adriana , Soria María Eugenia , Castro Victoria , Beach Nathan M. , Manrubia Susanna , Quer Josep , Esteban Juan Ignacio , Rice Charles M. , Gómez Jordi , Gastaminza Pablo , Domingo Esteban , Perales Celia 
Published: March 2017

ABSTRACT
Viral quasispecies evolution upon long-term virus replication in a noncoevolving cellular environment raises relevant general issues, such as the attainment of population equilibrium, compliance with the molecular-clock hypothesis, or stability of the phenotypic profile. Here, we evaluate the adaptation, mutant spectrum dynamics, and phenotypic diversification of hepatitis C virus (HCV) in the course of 200 passages in human hepatoma cells in an experimental design that precluded coevolution of the cells with the virus. Adaptation to the cells was evidenced by increase in progeny production. The rate of accumulation of mutations in the genomic consensus sequence deviated slightly from linearity, and mutant spectrum analyses revealed a complex dynamic of mutational waves, which was sustained beyond passage 100. The virus underwent several phenotypic changes, some of which impacted the virus-host relationship, such as enhanced cell killing, a shift toward higher virion density, and increased shutoff of host cell protein synthesis. Fluctuations in progeny production and failure to reach population equilibrium at the genomic level suggest internal instabilities that anticipate an unpredictable HCV evolution in the complex liver environment.

IMPORTANCE
Long-term virus evolution in an unperturbed cellular environment can reveal features of virus evolution that cannot be explained by comparing natural viral isolates. In the present study, we investigate genetic and phenotypic changes that occur upon prolonged passage of hepatitis C virus (HCV) in human hepatoma cells in an experimental design in which host cell evolutionary change is prevented. Despite replication in a noncoevolving cellular environment, the virus exhibited internal population disequilibria that did not decline with increased adaptation to the host cells. The diversification of phenotypic traits suggests that disequilibria inherent to viral populations may provide a selective advantage to viruses that can be fully exploited in changing environments.
ACE and response to pulmonary rehabilitation in COPD: two observational studies
Authors: Kon Samantha S C , Jolley Caroline J , Shrikrishna Dinesh , Montgomery Hugh E , Skipworth James R A , Puthucheary Zudin , Moxham John , Polkey Michael I , Man William D-C , Hopkinson Nicholas S 
Published: March 2017

IntroductionSkeletal muscle impairment is an important feature of chronic obstructive pulmonary disease (COPD). Renin–angiotensin system activity influences muscle phenotype, so we wished to investigate whether it affects the response to pulmonary rehabilitation.MethodsTwo studies are described; in the first, the response of 168 COPD patients (mean forced expiratory volume in one second 51.9% predicted) to pulmonary rehabilitation was compared between different ACE insertion/deletion polymorphism genotypes. In a second, independent COPD cohort (n=373), baseline characteristics and response to pulmonary rehabilitation were compared between COPD patients who were or were not taking ACE inhibitors or angiotensin receptor antagonists (ARB).ResultsIn study 1, the incremental shuttle walk distance improved to a similar extent in all three genotypes; DD/ID/II (n=48/91/29) 69(67)m, 61 (76)m and 78 (78)m, respectively, (p>0.05). In study 2, fat free mass index was higher in those on ACE-I/ARB (n=130) than those who were not (n=243), 17.8 (16.0, 19.8) kg m−2vs 16.5 (14.9, 18.4) kg/m2(p<0.001). However change in fat free mass, walking distance or quality of life in response to pulmonary rehabilitation did not differ between groups.ConclusionsWhile these data support a positive association of ACE-I/ARB treatment and body composition in COPD, neither treatment to reduce ACE activity nor ACE (I/D) genotype influence response to pulmonary rehabilitation.
Variation in haemoglobin measurement across different HemoCue devices and device operators in rural Cambodia
Authors: Rappaport Aviva I , Barr Susan I , Green Timothy J , Karakochuk Crystal D 
Published: March 2017

Point-of-use haemoglobinometers, such as the HemoCue, are a common method to measure haemoglobin (Hb) concentration in field settings as the device is portable, requires only a small finger-prick capillary blood sample and computes an immediate Hb reading. The aim of this study was to compare Hb measurements across different HemoCue devices and across device operators using capillary blood samples collected from women during a trial in rural Cambodia. We compared mean±SD capillary Hb concentration (g/L) across n=12 different HemoCue Hb 301 devices and across n=9 device operators among 2846 Cambodian women. Significant variability in mean Hb concentration was observed across HemoCue devices (means ranged from 117 to 124 g/L) and across device operators (means ranged from 118 to 124 g/L). This variability is of particular concern when a single HemoCue device or device operator is used at different time points in surveys or research trials.Trial registration numberNCT02481375
MicroRNA-29a mediates the impairment of intestinal epithelial integrity induced by intrauterine growth restriction in pig
Authors: Zhu Yuhua , Wang Wei , Yuan Taolin , Fu Liangliang , Zhou Lian , Lin Gang , Zhao Shuhong , Zhou Huaijun , Wu Guoyao , Wang Junjun 
Published: March 2017

An important characteristic of intrauterine growth restricted (IUGR) neonate is the impaired intestinal barrier function. With the use of a pig model, this study was conducted to identify the responsible microRNA (miRNA) for the intestinal damage in IUGR neonates through comparing the miRNA profile of IUGR and normal porcine neonates and to investigate the regulation mechanism. Compared with the normal ones, we identified 83 upregulated and 76 downregulated miRNAs in the jejunum of IUGR pigs. Notably, IUGR is associated with profoundly increasesd miR-29 family and decreased expression of extracellular matrix (ECM) and tight junction (TJ) proteins in the jejunum. Furthermore, in vitro study using theporcine intestinal epithelial cell line (IPEC-1) showed that inhibition of miR-29a expression could improve the monolayer integrity by increasing cell proliferation and transepithelial resistance. Also, overexpression/inhibition of miR-29a in IPEC-1 cells can suppress/increase the expression of integrin-β1, collagen I, collagen IV, fibronectin, and claudin 1, both at transcriptional and translational levels. Subsequent luciferase reporter assay confirmed a direct interaction between miR-29a and the 3′-untranslated regions of these genes. In conclusion, this study reveals that IUGR-impaired intestinal barrier function is associated with downregulated ECM and TJ protein expression mediated by the upregulation of miR-29a. NEW & NOTEWORTHY Intrauterine growth restricted (IUGR) remains a major problem for both human health and animal production due to its association with high rates of preweaning morbidity and mortality. We have identified the abnormal expression of microRNA-29a (miR-29a) in the small intestine of IUGR neonates, as well as its targets and mechanisms. These results provide new information about biological characteristics of IUGR-affected intestinal dysfunction and can lead to the development of potentially solution for preventing and treating IUGR in the future.
Hydrogen sulfide improves intestinal recovery following ischemia by endothelial nitric oxide-dependent mechanisms
Authors: Jensen Amanda R. , Drucker Natalie A. , Khaneki Sina , Ferkowicz Michael J. , Markel Troy A. 
Published: March 2017

Hydrogen sulfide (H2S) is an endogenous gasotransmitter that has vasodilatory properties. It may be a novel therapy for intestinal ischemia-reperfusion (I/R) injury. We hypothesized that 1) H2S would improve postischemic survival, mesenteric perfusion, mucosal injury, and inflammation compared with vehicle and 2) the benefits of H2S would be mediated through endothelial nitric oxide. C57BL/6J wild-type and endothelial nitric oxide synthase knockout (eNOS KO) mice were anesthetized, and a midline laparotomy was performed. Intestines were eviscerated, the small bowel mesenteric root identified, and baseline intestinal perfusion was determined using laser Doppler. Intestinal ischemia was established by temporarily occluding the superior mesenteric artery. Following ischemia, the clamp was removed, and the intestines were allowed to recover. Either sodium hydrosulfide (2 nmol/kg or 2 µmol/kg NaHS) in PBS vehicle or vehicle only was injected into the peritoneum. Animals were allowed to recover and were assessed for mesenteric perfusion, mucosal injury, and intestinal cytokines. P values < 0.05 were significant. H2S improved mesenteric perfusion and mucosal injury scores following I/R injury. However, in the setting of eNOS ablation, there was no improvement in these parameters with H2S therapy. Application of H2S also resulted in lower levels of intestinal cytokine production following I/R. Intraperitoneal H2S therapy can improve mesenteric perfusion, intestinal mucosal injury, and intestinal inflammation following I/R. The benefits of H2S appear to be mediated through endothelial nitric oxide-dependent pathways. NEW & NOTEWORTHY H2S is a gaseous mediator that acts as an anti-inflammatory agent contributing to gastrointestinal mucosal defense. It promotes vascular dilation, mucosal repair, and resolution of inflammation following intestinal ischemia and may be exploited as a novel therapeutic agent. It is unclear whether H2S works through nitric oxide-dependent pathways in the intestine. We appreciate that H2S was able to improve postischemic recovery of mesenteric perfusion, mucosal integrity, and inflammation. The beneficial effects of H2S appear to be mediated through endothelial nitric oxide-dependent pathways.
Clinical Trial Characteristics and Barriers to Participant Accrual: The MD Anderson Cancer Center Experience over 30 years, a Historical Foundation for Trial Improvement
Authors: Tang Chad , Sherman Steven I. , Price Mellanie , Weng Jun , Davis Suzanne E. , Hong David S. , Yao James C. , Buzdar Aman , Wilding George , Lee J. Jack 
Published: March 2017

Abstract
Purpose: Slow-accruing clinical trials delay the translation of basic biomedical research, contribute to increasing health care costs, and may prohibit trials from reaching their original goals.
Experimental Design: We analyzed a prospectively maintained institutional database that tracks all clinical studies at the MD Anderson Cancer Center (Houston, TX). Inclusion criteria were activated phase I–III trials, maximum projected accrual ≥10 participants, and activation prior to March 25, 2011. The primary outcome was slow accrual, defined as &lt;2 participants per year. Correlations of trial characteristics with slow accrual were assessed with logistic regression.
Results: A total of 4,269 clinical trials met inclusion criteria. Trials were activated between January 5, 1981, and March 25, 2011, with a total of 145,214 participants enrolled. Median total enrolment was 16 [interquartile range (IQR), 5–34], with an average enrolment rate of 8.7 participants per year (IQR, 3.3–17.7). There were 755 (18%) trials classified as slow accruing. On multivariable analysis, slow accrual exhibited robust associations with national cooperative group trials (OR = 4.16, P &lt; 0.0001 vs. industry sponsored), time from trial activation to first enrolment (OR = 1.13 per month, P &lt; 0.0001), and maximum targeted accrual (OR = 0.16 per log10 increase, P &lt; 0.0001). Recursive partitioning analysis identified trials requiring more than 70 days (2.3 months) between activation and first participant enrolment as having higher odds of slow accrual (23% vs. 5%, OR = 5.56, P &lt; 0.0001).
Conclusions: We identified factors associated with slow trial accrual. Given the lack of data on clinical trials at the institutional level, these data will help build a foundation from which targeted initiatives may be developed to improve the clinical trial enterprise. Clin Cancer Res; 23(6); 1414–21. ©2017 AACR.
Calcium Sensor, NCS-1, Promotes Tumor Aggressiveness and Predicts Patient Survival
Authors: Moore Lauren M. , England Allison , Ehrlich Barbara E. , Rimm David L. 
Published: March 2017

Abstract
Neuronal Calcium Sensor 1 (NCS-1) is a multi-functional Ca2+-binding protein that affects a range of cellular processes beyond those related to neurons. Functional characterization of NCS-1 in neuronal model systems suggests that NCS-1 may influence oncogenic processes. To this end, the biological role of NCS-1 was investigated by altering its endogenous expression in MCF-7 and MB-231 breast cancer cells. Overexpression of NCS-1 resulted in a more aggressive tumor phenotype demonstrated by a marked increase in invasion and motility, and a decrease in cell-matrix adhesion to collagen IV. Overexpression of NCS-1 was also shown to increase the efficacy of paclitaxel-induced cell death in a manner that was independent of cellular proliferation. To determine the association between NCS-1 and clinical outcome, NCS-1 expression was measured in two independent breast cancer cohorts by the Automated Quantitative Analysis method of quantitative immunofluorescence. Elevated levels of NCS-1 were significantly correlated with shorter survival rates. Furthermore, multivariate analysis demonstrated that NCS-1 status was prognostic, independent of estrogen receptor, progesterone receptor, HER2, and lymph node status. These findings indicate that NCS-1 plays a role in the aggressive behavior of a subset of breast cancers and has therapeutic or biomarker potential.
Implications: NCS-1, a calcium-binding protein, is associated with clinicopathologic features of aggressiveness in breast cancer cells and worse outcome in two breast cancer patient cohorts. Mol Cancer Res; 15(7); 942–52. ©2017 AACR.
Crown-like Structures in Breast Adipose Tissue from Normal Weight Women: Important Impact
Authors: Berger Nathan A. 
Published: March 2017

Abstract
Crown-like structures (CLS), composed of macrophages surrounding dead or dying adipocytes, are a histologic hallmark of the proinflammatory process by which adipose tissue contributes to the increased risk and worse prognosis of breast cancer in obese, postmenopausal patients. In this issue of Cancer Prevention Research, Iyengar and colleagues report the intriguing finding that CLS can be identified in a significant proportion of normal-BMI women undergoing mastectomy for breast cancer risk reduction or therapy. This surprising observation suggests that some normal weight women may have similar mechanisms driving initiation and/or progression of breast cancer as those contributing to the increased incidence and worse prognosis of breast cancer in obese postmenopausal women. The possibility of a common mechanism in both lean and obese women provides added impetus to more fully define this process and evaluate its important implications for prevention and screening strategies as well as therapeutic interventions. Cancer Prev Res; 10(4); 223–5. ©2017 AACR.
See related article by Iyengar et al., p. 235–43.
Patient values and preferences for antithrombotic therapy in atrial fibrillation
Authors: Loewen Peter S. , Ji Angela Tianshu , Kapanen Anita , McClean Alison 
Published: March 2017

SummaryGuidelines recommend that patients’ values and preferences should be considered when selecting stroke prevention therapy for atrial fibrillation (SPAF). However, doing so is difficult, and tools to assist clinicians are sparse. We performed a narrative systematic review to provide clinicians with insights into the values and preferences of AF patients for SPAF antithrombotic therapy. Narrative systematic review of published literature from database inception. Research questions: 1) What are patients’ AF and SPAF therapy values and preferences? 2) How are SPAF therapy values and preferences affected by patient factors? 3) How does conveying risk information affect SPAF therapy preferences? and 4) What is known about patient values and preferences regarding novel oral anticoagulants (NOACs) for SPAF? Twenty-five studies were included. Overall study quality was moderate. Severe stroke was associated with the greatest disutility among AF outcomes and most patients value the stroke prevention efficacy of therapy more than other attributes. Utilities, values, and preferences about other outcomes and attributes of therapy are heterogeneous and unpredictable. Patients’ therapy preferences usually align with their values when individualised risk information is presented, although divergence from this is common. Patients value the attributes of NOACs but frequently do not prefer NOACs over warfarin when all therapy-related attributes are considered. In conclusion, patients’ values and preferences for SPAF antithrombotic therapy are heterogeneous and there is no substitute for directly clarifying patients’ individual values and preferences. Research using choice modelling and tools to help clinicians and patients clarify their SPAF therapy values and preferences are needed.Supplementary Material to this article is available online at www.thrombosis-online.com.
External validation of the VTE-BLEED score for predicting major bleeding in stable anticoagulated patients with venous thromboembolism
Authors: Klok Frederikus A. , Barco Stefano , Konstantinides Stavros V. 
Published: March 2017

SummaryOne of the main determinants of establishing the optimal treatment duration of patients with venous thromboembolism (VTE) is the risk of major bleeding during long-term anticoagulant therapy. The 6-variable VTE-BLEED score was recently developed to enable estimation of this bleeding risk. This study aimed at externally validating VTE-BLEED. This was a post-hoc study of the randomised, double-blind, double-dummy, Hokusai-VTE study that compared edoxaban versus warfarin for treatment of VTE. VTE-BLEED was calculated in all 8,240 study patients. The numbers of adjudicated major bleeding events during ‘stable anticoagulation’, i. e. occurring after day 30, in patients with low (total score <2 points) and high risk of bleeding (total score ≥2 points) were compared for the overall study population, patients randomised to edoxaban or warfarin, and for important patient subcategories. During ‘stable’ anticoagulation, major bleeding occurred in 1.02% (40/3,903) and 0.82% (32/3,899) of patients treated with warfarin and edoxaban, respectively. For the overall study population, the risks of bleeding in the low and high risk groups were 0.51% and 2.03%, respectively, for an odds ratio (OR) of 4.04 (95% confidence interval [CI]: 2.51–6.48). ORs were 5.04 (95%CI: 2.62–9.69) and 3.09 (95%CI: 1.54–6.22) for warfarin and edoxaban, respectively. VTE-BLEED was consistently able to identify patients at a 2.5- to 11-fold higher bleeding risk across all the predefined subcategories, as well as for the treatment period between day 30 to day 180, and beyond day 180. In conclusion, patients identified as high risk by VTE-BLEED had a four-fold increased risk of bleeding during the chronic phase of treatment.Supplementary Material to this article is available online at www.thrombosis-online.com.
Predictors of active cancer thromboembolic outcomes
Authors: Tafur Alfonso J. , Caprini Joseph A. , Cote Lauren , Trujillo-Santos Javier , Del Toro Jorge , Garcia-Bragado Fernando , Tolosa Carles , Barillari Giovanni , Visona Adriana , Monreal Manuel ,   the RIETE Investigators
Published: March 2017

SummaryEven though the Khorana risk score (KRS) has been validated to predict against the development of VTE among patients with cancer, it has a low positive predictive value. It is also unknown whether the score predicts outcomes in patients with cancer with established VTE. We selected a cohort of patients with active cancer from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry to assess the prognostic value of the KRS at inception in predicting the likelihood of VTE recurrences, major bleeding and mortality during the course of anticoagulant therapy. We analysed 7948 consecutive patients with cancer-associated VTE. Of these, 2253 (28 %) scored 0 points, 4550 (57 %) 1–2 points and 1145 (14 %) scored ≥3 points. During the course of anticoagulation, amongst patient with low, moderate and high risk KRS, the rate of VTE recurrences was of 6.21 (95 %CI: 4.99–7.63), 11.2 (95 %CI: 9.91–12.7) and 19.4 (95 %CI: 15.4–24.1) events per 100 patient-years; the rate of major bleeding of 5.24 (95 %CI: 4.13–6.56), 10.3 (95 %CI: 9.02–11.7) and 19.4 (95 %CI: 15.4–24.1) bleeds per 100 patient-years and the mortality rate of 25.3 (95 %CI: 22.8–28.0), 58.5 (95 %CI: 55.5–61.7) and 120 (95 %CI: 110–131) deaths per 100 patient-years, respectively. The C-statistic was 0.53 (0.50–0.56) for recurrent VTE, 0.56 (95 %CI: 0.54–0.59) for major bleeding and 0.54 (95 %CI: 0.52–0.56) for death. In conclusion, most VTEs occur in patients with low or moderate risk scores. The KRS did not accurately predict VTE recurrence, major bleeding, or mortality among patients with cancer-associated thrombosis.