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Background: Beak morphology exhibits considerable adaptive plasticity in birds, which results in highly varied or specialized forms in response to variations in ecology and life history. As the only parid species endemic to the Qinghai-Tibet Plateau, the Ground Tit (Parus humilis) has evolved a distinctly long and curved beak from other parids. An integration of morphometrics, phylogenetics, transcriptomics and embryology allows us to address the evolutionary and developmental mechanisms of the adaptive beak structure observed in the Ground Tit. Results: A morphometric approach quantified that the Ground Tit has a comparatively longer and more decurved upper beaks than other parids. We estimated that the ancestor of the Ground Tit likely had a short straight upper beak similar to most current recognized parid species using an ancestral state reconstruction. This morphological specialization is considered an adaptation to its ground-oriented behavior on the high plateau. To identify genetic mechanisms behind this adaptive change, a comparative transcriptomic analysis was applied between the Ground Tit and its closely related species, the Great Tit (Parus major). We detected that 623 genes were significantly differentially expressed in embryonic upper beaks between the two species, 17 of which were functionally annotated to correlate with bone development and morphogenesis, although genes related to bone development were not found to undergo accelerated evolution in the Ground Tit. RT-qPCR validation confirmed differential expression of five out of eight genes that were selected from the 17 genes. Subsequent functional assays in chicken embryos demonstrated that two of these genes, FGF13 and ITGB3, may affect beak morphology by modulating levels of osteoblasts and osteoclasts. Conclusions: Our results provide preliminary evidence that development of the long decurved beak of the Ground Tit is likely regulated by transcriptional activities of multiple genes coordinating osteoblasts and osteoclasts. The integration of multiple approaches employed here sheds light on ecological and genetic mechanisms in the evolution of avian morphology. [ABSTRACT FROM AUTHOR]

Background: Mathematical models of human mobility have demonstrated a great potential for infectious disease epidemiology in contexts of data scarcity. While the commonly used gravity model involves parameter tuning and is thus difficult to implement without reference data, the more recent radiation model based on population densities is parameter-free, but biased. In this study we introduce the new impedance model, by analogy with electricity. Previous research has compared models on the basis of a few specific available spatial patterns. In this study, we use a systematic simulation-based approach to assess the performances. Methods: Five hundred spatial patterns were generated using various area sizes and location coordinates. Model performances were evaluated based on these patterns. For simulated data, comparison measures were average root mean square error (aRMSE) and bias criteria. Modeling of the 2010 Haiti cholera epidemic with a basic susceptible-infected-recovered (SIR) framework allowed an empirical evaluation through assessing the goodness-of-fit of the observed epidemic curve. Results: The new, parameter-free impedance model outperformed previous models on simulated data according to average aRMSE and bias criteria. The impedance model achieved better performances with heterogeneous population densities and small destination populations. As a proof of concept, the basic compartmental SIR framework was used to confirm the results obtained with the impedance model in predicting the spread of cholera in Haiti in 2010. Conclusions: The proposed new impedance model provides accurate estimations of human mobility, especially when the population distribution is highly heterogeneous. This model can therefore help to achieve more accurate predictions of disease spread in the context of an epidemic. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory failure (ARF) is still one of the most severe complications in immunocompromised patients. Our previous systematic review showed noninvasive mechanical ventilation (NIV) reduced mortality, length of hospitalization and ICU stay in AIDS/hematological malignancy patients with relatively less severe ARF, compared to invasive mechanical ventilation (IMV). However, this systematic review was based on 13 observational studies and the quality of evidence was low to moderate. The efficacy of NIV in more severe ARF and in patients with other causes of immunodeficiency is still unclear. We aim to determine the efficacy of the initial ventilation strategy in managing ARF in immunocompromised patients stratified by different disease severity and causes of immunodeficiency, and explore predictors for failure of NIV.Methods and Analysis: The VENIM is a multicentre randomized controlled trial (RCT) comparing the effects of NIV compared with IMV in adult immunocompromised patients with severe hypoxemic ARF. Patients who meet the indications for both forms of ventilatory support will be included. Primary outcome will be 30-day all-cause mortality. Secondary outcomes will include in-hospital mortality, length of stay in hospital, improvement of oxygenation, nosocomial infections, seven-day organ failure, adverse events of intervention, et al. Subgroups with different disease severity and causes of immunodeficiency will also be analyzed.Discussion: VENIM is the first randomized controlled trial aiming at assessing the efficacy of initial ventilation strategy in treating moderate and severe acute respiratory failure in immunocompromised patients. The result of this RCT may help doctors with their ventilation decisions.Trial Registration: ClinicalTrials.gov NCT02983851 . Registered 2 September 2016. [ABSTRACT FROM AUTHOR]

Background: Choriocarcinoma of the ovary is rare. This tumor can arise from gestational tissue or pure germ cells of the ovary, the former results in gestational choriocarcinoma. The clinical characteristics and histology of both tumor types are identical, differentiation of these tumors is necessary for effective treatment. One strategy for the differentiation of these tumors types is to identify the presence of paternal DNA by DNA polymorphic analysis. Case presentation: In the present case, a 27-year-old patient with a history of amenorrhea, lower abdominal pain and vaginal bleeding received a laparoscopic dissection of cystic mass of the right ovary according to an initial diagnosis of ectopic pregnancy. Primary choriocarcinoma of the ovary was diagnosed by pathology, but its origin was uncertain. DNA polymorphic analysis was then performed and a gestational origin was confirmed. The patient subsequently exhibited an excellent response to chemotherapy, achieved complete remission and gave birth to a healthy baby. Conclusion: Differentiation between two etiologies of primary choriocarcinoma can be achieved with DNA polymorphic analysis and it is necessary to distinguish between them to approach to an appropriate treatment of a patient. [ABSTRACT FROM AUTHOR]

Background: Long non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor progression. However, the role and molecular mechanism of lncRNA XIST in gastric cancer is still unknown. Methods: Real-time PCR analysis was performed to measure the expression levels of lncRNA XIST in gastric cancer tissues and cell lines, the correlation between lncRNA XIST expression and clinicopathological characteristics and prognosis was analyzed in gastric cancer patients. The biological function of lncRNA XIST on gastric cancer cells were determined both in vitro and in vivo. The regulating relationship between lncRNA XIST and miR-101 was investigated in gastric cancer cells. Results: lncRNA XIST was significantly up-regulated in gastric cancer tissues and cell lines. Overexpression of lncRNA XIST was markedly associated with larger tumor size, lymph node invasion, distant metastasis and TNM stage in gastric cancer patients. Functionally, knockdown of lncRNA XIST exerted tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Furthermore, an inverse relationship between lncRNA XIST and miR-101 was found. Polycomb group protein enhancer of zeste homolog 2 (EZH2), a direct target of miR-101, could mediated the biological effects that lncRNA XIST exerted. Conclusions: lncRNA XIST is up-regulated and is associated with aggressive tumor phenotypes and patient survival in gastric cancer, and the newly identified lncRNA XIST/miR-101/EZH2 axis could be a potential biomarkers or therapeutic targets for gastric cancer patients. [ABSTRACT FROM AUTHOR]

Background: Recent upsurge of new HIV infections among men who have sex with men (MSM) is a major concern in China. Paucity of national-level information regarding the burden and predictors of this progressive epidemic of new infections called for a multi-centric, timely and comprehensive investigation. Methods: Mixed methods were used to recruit MSM from seven cities in China between 2012 and 2013. Recent and established HIV infections were estimated by Western Blot and BED HIV-1 capture enzyme immunoassay. Syphilis and herpes simplex virus-2 (HSV-2) were also tested. Results: A total of 4496 eligible MSM were recruited. The majority was aged =35 years (77.5%), migrants (60.3%), never married (69.8%), and played receptive role in anal sex (70.5%). The HIV prevalence was 9.9%, and 41.9% were recently infected, with sensitivity/specificity adjusted HIV incidence of 8.9 (95% CI: 7.6-10.2)/ 100 Person-Years. The prevalence of history HSV-2 and syphilis were 12.5% and 8.5%, respectively. Recent HIV infection was associated with having multiple male partners (aOR = 1.4, 95% CI 1.1-1.9), recreational drug use (aOR = 2.2, 95% CI 1.6-3.0), anal bleeding (aOR = 2.1, 95% CI 1.4-3.0), syphilis infection (aOR = 2.8, 95% CI 1.9-4.3) and history HSV-2 infection (aOR = 2.3, 95% CI 1.5-3.3). Conclusion: High rate of recent HIV infection is potentially resulting in progressive deterioration of the overall HIV epidemic among MSM in China. Targeted interventions to address high-risk MSM including those having multiple partners, history of recreational drug use and syphilis or HSV-2 infection seemed to be the need of the hour. [ABSTRACT FROM AUTHOR]

Background: This study was aimed to explore the role of long noncoding RNA C17orf91 and its potential mechanisms in ovarian cancer development. Results: To assess its role in ovarian cancer, microarray datasets (GSE14407, GSE30587, and GSE17260) in Gene Expression Omnibus (GEO) were utilized to assess the expression and clinical significance of C17orf91 in ovarian cancer. Next, loss-of-function studies were performed to establish the role of C17orf91 and the underlying mechanisms in ovarian cancer development. It was found that elevated expression of C17orf91 was observed in omental metastases when compared with matched primary ovarian tumors(GSE30587, P = 0.016). Moreover, Log Rank analysis revealed that increased expression of C17orf91 was associated with shorter progression free survival(PFS)(HR = 1.90(1.19-3.03), P = 0.008). Overall survival(OS) also showed a similar trend, but did not reach statistical significance(HR = 1.75(0.97-3.13), P = 0.061). Loss-of-function studies further demonstrated that C17orf91 repression impaired migration, invasion and viability of ovarian cancer cells, and downregulated the pro-metastatic gene, MYC, at both mRNA and protein level. Conclusion: Collectively, our findings revealed that C17orf91 was a potential prognostic marker and functioned as an oncogene in ovarian cancer. It remains to be seen whether modulation of C17orf91 expression will cause phenotypic changes in vivo. [ABSTRACT FROM AUTHOR]

Backgroud: As magicians of the DNA world, topoisomerases resolve all of the topological problems in relation to DNA during a variety of genetic processes. While the prognostic value of topoisomerase isoenzymes in epithelial ovarian carcinoma (EOC) is still elusive. In current study, we investigated the prognostic value of topoisomerase isoenzymes in the EOC patients. Kaplan Meier plotter (KM plotter) database were used to assess the relevance of individual topoisomerase isoenzyme mRNA expression to EOC patients overall survival (OS), in which updated survival information and gene expression data were from a total of 1,648 EOC patients. Results: High expression of TOP1 and TOP2A were found to be correlated to worse OS in all patients and serous patients, but not in endometrioid patients. Contrary to TOP1 and TOP2A, TOP3A and TOP3B expression were associated with better OS in all patients and serous patients, but not in endometrioid patients. While TOP2B were not found any significant prognostic value for EOC patients. From the Oncomine database, we also found widespread upregulation in the expression of TOP1 and TOP2A genes in primary tumor tissues. Albeit limited in number, all datasets exhibiting differential expression showed TOP3A and TOP3B under-regulated. Conclusion: These results strongly supported that TOP1 and TOP2A were potential biomarkers for predicting poor survival of EOC patients, while TOP3A and TOP3B were expected to be further exploited as tumor suppressors. Comprehensive understanding of the topoisomerase isoforms may have guiding significance for the diagnosis treatment and prognosis in EOC patients. [ABSTRACT FROM AUTHOR]

Background: Numerous countries around the world are approaching malaria elimination. Until global eradication is achieved, countries that successfully eliminate the disease will contend with parasite reintroduction through international movement of infected people. Human-mediated parasite mobility is also important within countries near elimination, as it drives parasite flows that affect disease transmission on a subnational scale. Methods: Movement patterns exhibited in census-based migration data are compared with patterns exhibited in a mobile phone data set from Haiti to quantify how well migration data predict short-term movement patterns. Because short-term movement data were unavailable for Mesoamerica, a logistic regression model fit to migration data from three countries in Mesoamerica is used to predict flows of infected people between subnational administrative units throughout the region. Results: Population flows predicted using census-based migration data correlated strongly with mobile phone-derived movements when used as a measure of relative connectivity. Relative population flows are therefore predicted using census data across Mesoamerica, informing the areas that are likely exporters and importers of infected people. Relative population flows are used to identify community structure, useful for coordinating interventions and elimination efforts to minimize importation risk. Finally, the ability of census microdata inform future intervention planning is discussed in a country-specific setting using Costa Rica as an example. Conclusions: These results show long-term migration data can effectively predict the relative flows of infected people to direct malaria elimination policy, a particularly relevant result because migration data are generally easier to obtain than short-term movement data such as mobile phone records. Further, predicted relative flows highlight policy-relevant population dynamics, such as major exporters across the region, and Nicaragua and Costa Rica's strong connection by movement of infected people, suggesting close coordination of their elimination efforts. Country-specific applications are discussed as well, such as predicting areas at relatively high risk of importation, which could inform surveillance and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Fertility-sparing surgery for patients with borderline ovarian tumors (BOTs) is still controversial. This study aimed to evaluate the oncological safety and fertility benefits in conservative surgery,as well as efficiency of surgical procedures and approaches. Results: In total 122 patients with BOTs, four types of fertility-sparing surgery were performed: unilateral adnexectomy (UA, n = 47), unilateral cystectomy (UC, n = 59), unilateral adnexectomy + contralateral cystectomy (UA + CC, n = 7) and bilateral cystectomy (BC, n = 9). Fifty-two (42.6 %) patients had undergone laparoscopy, while 70 (57.4 %) had undergone laparotomy. After a median follow-up of 58.0 months, eight patients (6.6 %) relapsed in average of 25.9 months. Only one patient progressed to invasive cancer. None died within our observational period. Univariate analysis showed that patients with elevated CA125, bilateral tumors, extra-ovary tumor or mucinous type tended to replase in shorter time (p < 0.05). Among all cases, 45 patients attempted to conceive and 34 (75.6 %) patients had successful pregnancy. The recurrence rates were successively increased (2.1 %, 6.8 %, 14.3 %, and 22.2 %), the recurrence interval were shortened (48.0, 25.3, 26.0 and 21.2 months) and the subsequent fertility rates were 76.9 %, 77.3 %, 66.7 % and 71.4 % in UA, UC, UA + CC, and BC groups, respectively. As for surgical approaches, three patients (5.8 %) relapsed in 26.3 months in the laparoscopy group and five (7.1 %) in 25.5 months in the laparotomy group. The subsequent fertility rate was higher in laparoscopy group (88.9 %) than in laparotomy group (66.7 %). In our study, 38 patients underwent staging surgery. Two patients (5.3 %) recurrent in average of 21.0 months, and the subsequent pregnancy rate of staging surgery group was 61.5 %. Twelve patients received adjuvant chemotherapy but they didn't get any benefit from it, both in term of recurrence (8.3 %, 26.0 months) and subsequent pregnancy rate (75.5 %). Conclusion: Fertility-sparing surgery is safe and beneficial for most young BOTs. UA through laparoscopy should be recommended as the first choice. To the patients with bilateral tumors, elevated CA125, extra-ovary tumor or mucinous type, conservative surgery should be carefully chosen and subsequent pregnancy should be attempted in short term. In addition, the benefit of comprehensive surgical staging is to be further investigated and adjuvant chemotherapy is not recommended. [ABSTRACT FROM AUTHOR]

Introduction: Adult stem cell-derived hepatocytes transplantation holds considerable promise for future clinical individualized therapy of liver failure or dysfunction. However, the low engraftment of the available hepatocytes in the liver disease microenvironment has been a major obstacle. Methods: Acellular human amniotic membrane was developed as a three-dimensional scaffold and combined with hepatocyte-like cells derived from human adipose stem cells to engineer a hepatic tissue graft that would allow hepatocyte engraftment in the liver effectively. Results: The hepatic tissue grafts maintained hepatocyte-specific gene expression and functionality in vitro. When transplanted into the surgical incision in livers for engraftment, the engineered hepatic grafts significantly decreased the degree of liver injury caused by a carbon tetrachloride treatment and generated cords that were similar to the ductal plates in the liver between the acellular human amniotic membrane and the liver of receipts at day 3 post-transplantation. The hepatic tissue grafts maintained the expression of human hepatocyte-specific markers albumin, hepatocyte nuclear factor 4α, and cytochrome P450 2B6 in the liver of receipts, and acquired human-specific drug metabolism ability at eight weeks post-transplantation. Conclusions: The acellular human amniotic membrane has the ability to maintain the functional phenotype of the hepatocyte-like cells derived from human adipose stem cells. Functional acellular human amniotic membrane-hepatocytes grafts integrated with the liver decreases the acute liver injury of mice. These engineered tissue constructs may support stem cell-based individualized therapy for liver disease and for bioartificial liver establishment. [ABSTRACT FROM AUTHOR]

Objective: The prognostic value of anti-angiogenesis therapy in ovarian cancer patients is currently under debate. In this study, we assessed the effects of anti-angiogenesis therapy on the progression free survival (PFS) and overall survival (OS) of ovarian cancer patients. Materials and methods: PubMed was searched to identify relevant studies that evaluated the therapeutic value of anti-angiogenic agents in ovarian cancer (the final search was current to Dec. 13th 2014). Reviews of each study were conducted, and the data were extracted. The primary outcomes that were analysed were progression free survival (PFS) and overall survival (OS). The pooled hazard ratio (HR) and 95 % confidence intervals (CIs) were calculated using the random and fixed-effects models, and subgroup and sensitivity analyses were subsequently performed. Results: A total of 12 studies were included in the meta-analysis. The overall analysis revealed that the incorporation of anti-angiogenesis therapy was significantly associated with a longer PFS (HR, 0.66; 95 % CI, 0.58-0.75; P < 0.01) and a longer OS (HR, 0.89; 95 % CI, 0.82-0.97; P = 0.01) in the total population, and these findings were confirmed by one-way sensitivity analyses. Further subgroup analyses demonstrated that the administrations of each of the agents were associated with improved PFSs. The prognostic value of anti-angiogenesis therapy for the OS was significant in the trebananib subgroup (HR, 0.81; 95 % CI, 0.67-0.99; P = 0.04). The bevacizumab subgroup exhibited a similar trend that did not reach statistical significance (HR, 0.90; 95 % CI, 0.80-1.01; P = 0.08). Conclusions: The present meta-analysis indicated that anti-angiogenesis therapy in ovarian cancer patients was associated with a better clinical outcome. Further studies are warranted to identify the specific subgroup of patients who are most likely to benefit from anti-angiogenesis therapy. [ABSTRACT FROM AUTHOR]

Background: Intracorporeal Roux-en-Y esophagojejunostomy during laparoscopic total gastrectomy for gastric cancer remains a challenging manipulation due to the uncontrolled direction of the jejunal side or unintended embedded tissues, although several methods have been introduced. In this study, we simplified the procedure based on a surgical string fixing technique using a transorally inserted anvil (OrVil™; Covidien Ltd., Mansfield, MA, USA). Methods: From March 2012 to September 2013, 14 consecutive patients underwent simplified intracorporeal Roux-en-Y esophagojejunostomy using OrVil™ during laparoscopic total gastrectomy for gastric cancer at our hospital. Clinicopathologic characteristics and surgical outcomes of these patients were retrospectively analyzed. Results: All of the procedures were successful completed with no complication or conversion to open surgery. Themean overall operative time was 193.8 ± 41.8 min, whereas the mean reconstruction time was 32.6 ± 4.6 min. The mean estimated blood loss was 105.7 ± 65.4 ml. The mean diameter of anastomosis measured by upper gastrointestinal contrast X-ray test at 1 month after operation was 2.3 cm. During a median follow-up period of 12 months, neither local recurrence nor anastomosis-related morbidity was observed. Conclusions: Our preliminary results suggested that this automatically contamination-avoiding technique based on a surgical-string-fixing strategy using OrVil™ during laparoscopic total gastrectomy for gastric cancer might be feasible and safe and provide a simple solution for intracorporeal Roux-en-Y esophagojejunostomy. [ABSTRACT FROM AUTHOR]

Background: Interleukin-27 (IL-27) is a multifunctional cytokine with both pro-inflammatory and immunoregulatory functions. At present, the role of IL-27 in pulmonary fibrosis remains unknown. Methods: In this study, we observed the expression of IL-27/IL-27R in a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. We verified the role of IL-27 using hematoxylin and eosin as well as Masson's staining methods and measuring the content of hydroxyproline as well as collagen I and III. We assessed the differentiation of T lymphocytes in the spleen and measured the concentration of cytokines in bronchoalveolar lavage fluid (BALF) and the expression level of relevant proteins in the JAK/STAT and TGF-ß/Smad signaling pathways in lung tissue. Results: Increased IL-27 expression in BLM-induced pulmonary fibrosis was noted. IL-27 treatment may alleviate pulmonary fibrosis and increase the survival of mice. IL-27 inhibited the development of CD4+ IL-17+, CD4+ IL-4+ T, and CD4+ Foxp3+ cells and the secretion of IL-17, IL-4, IL-6, and TGF-ß. IL-27 induced the production of CD4+ IL-10+ and CD4+ INF-γ+ T cells. IL-27 decreased the levels of phosphorylated STAT1, STAT3, STAT5, Smad1, and Smad3 but increased the level of SOCS3. Conclusions: This study demonstrates that IL-27 potentially attenuates BLM-induced pulmonary fibrosis by regulating Th17 differentiation and cytokine secretion. [ABSTRACT FROM AUTHOR]

Background: To determine patients’ preferences for, and understanding of, FRAX® fracture risk conveyed through illustrations. Methods: Drawing on examples from published studies, four illustrations of fracture risk were designed and tested for patient preference, ease of understanding, and perceived risk. We enrolled a convenience sample of adults aged 50 and older at two medical clinics located in the Midwestern and Southern United States. In-person structured interviews were conducted to elicit patient ranking of preference, ease of understanding, and perceived risk for each illustration. Results: Most subjects (n = 142) were female (64%), Caucasian (76%) and college educated (78%). Of the four risk depictions, a plurality of participants (37%) listed a bar graph as most preferred. Subjects felt this illustration used the stoplight color system to display risk levels well and was the most “clear,” “clean,” and “easy to read”. The majority of subjects (52%) rated the pictogram as the most difficult to understand as this format does not allow people to quickly ascertain their individual risk category. Conclusions: Communicating risk to patients with illustrations can be done effectively with clearly designed illustrations responsive to patient preference. [ABSTRACT FROM AUTHOR]

Background It is unknown whether previously reported disparities for acute myocardial infarction (AMI) by race and sex have declined over time. Methods We used Medicare Part A administrative data files for 1992 to 2010 to evaluate changes in per-capita hospitalization rates for AMI, rates of revascularization (percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG)), and 30-day mortality for four distinct patient subcohorts: black women; black men; white women; and white men, adjusted for age, comorbidities and year using logistic regression. Results The study sample consisted of 4,045,267 AMI admissions between the years 1992 and 2010 (166,660 black women; 116,201 black men; 1,870,816 white women; 1,891,590 white men). AMI hospitalization rates differed significantly in 1992 to 1993 among black women (61.6 hospitalizations per 10,000 Medicare enrollees), black men (73.2 hospitalizations), white women (72.0 hospitalizations) and white men (113.2 hospitalizations) (P <0.0001). By 2009 to 2010 AMI hospitalization rates had declined substantially in all cohorts but disparities remained with significantly lower hospitalization rates among women and blacks compared to men and whites, respectively (P <0.0001). In multivariable-adjusted analyses, despite narrowing of the differences between cohorts over time, disparities in AMI hospitalization rates by race and sex remained statistically significant in 2009 to 2010 (P <0.001). In 1992 to 1993 and 2009 to 2010, rates of PCI within 30-days of AMI differed significantly among black women (8.6% in 1992 to 1993; 24.2% in 2009 to 2010), black men (10.4% and 32.6%), white women (12.8% and 30.5%), and white men (16.1% and 40.7%) (P <0.0001). In multivariable-adjusted analyses, racial disparities in procedure utilization appeared somewhat larger and sex-based disparities remained significant. Unadjusted 30-day mortality after AMI in 1992 to 1993 for black women, black men, white women and white men was 20.4%, 17.9%, 23.1% and 19.5%, respectively (P <0.0001); in 2009 to 2010 mortality was 17.1%, 15.3%, 18.2% and 16.2%, respectively (P <0.0001). In adjusted analyses, racial differences in mortality declined over time but differences by sex (higher mortality for women) persisted. Conclusions Disparities in AMI have declined modestly, but remain a problem, particularly with respect to patient sex. [ABSTRACT FROM AUTHOR]

Background To comparatively evaluate the cardioprotective activity of placental growth factor (PGF) delivered through direct injection and a nanoparticle-based system respectively and to study the underlying mechanisms in a rat model of acute myocardial infarction (AMI). Methods Poly lactic-co-glycolic acid (PLGA)-based PGF-carrying nanoparticles (PGF-PLGANPs) were created. The mean size and morphology of particles were analyzed with particle size analyzer and transmission electronic microscopy (TEM). Encapsulation efficiency and sustained-release dose curve were analyzed by ELISA. Sprague-Dawley rats were randomized into four groups (n = 10). While animals in the first group were left untreated as controls, those in the other 3 groups underwent surgical induction of AMI, followed by treatment with physiological saline, PGF, and PGF-PLGANPs, respectively. Cardiac function was evaluated by transthoracic echocardiography at 4 weeks after treatment. At 6 weeks, rats were sacrificed, infarction size was analyzed with Masson trichrome staining, and protein contents of TIMP-2, MT1-MMP and MMP-2 at the infarction border were determined by immunohistochemistry and western blotting analysis. Results PGF was released for at least 15 days, showing successful preparation of PGF-PLGANPs. Coronary artery ligation successfully induced AMI. Compared to physiological saline control, PGF, injected to the myocardium either as a nude molecule or in a form of nanoparticles, significantly reduced infarction size, improved cardiac function, and elevated myocardial expression of TIMP-2, MT1-MMP, and MMP-2 (P < 0.05). The effect of PGFPLGANPs was more pronounced than that of non-encapsulated PGF (P < 0.05). Conclusion Target PGF delivery to myocardium may improve cardiac function after AMI in rats. PLGA-based nanoparticles appear to be a better approach to delivery PGF. PGF exerts its cardioprotective effect at least partially through regulating metalloproteinase-mediated myocardial tissue remodeling. [ABSTRACT FROM AUTHOR]

Background: Lymphocytes act as a major component of the adaptive immune system, taking very crucialresponsibility for immunity. Differences in proportions of T-cell subpopulations in peripheral blood among individuals under same conditions provide evidence of genetic control on these traits, but little is known about the genetic mechanism of them, especially in swine. Identification of the genetic control on these variants may help the genetic improvement of immune capacity through selection. Results: To identify genomic regions responsible for these immune traits in swine, a genome-wide association study was conducted. A total of 675 pigs of three breeds were involved in the study. At 21 days of age, all individuals were vaccinated with modified live classical swine fever vaccine. Blood samples were collected when the piglets were 20 and 35 days of age, respectively. Seven traits, including the proportions of CD4+, CD8+, CD4+CD8+, CD4+CD8-, CD4-CD8+, CD4-CD8- and the ratio of CD4+ to CD8+ T cells were measured at the two ages. All the samples were genotyped for 62,163 single nucleotide polymorphisms (SNP) using the Illumina porcineSNP60k BeadChip. 40833 SNPs were selected after quality control for association tests between SNPs and each immune trait considered based on a single-locus regression model. To tackle the issue of multiple testing in GWAS, 10,000 permutations were performed to determine the chromosome-wise and genome-wise significance levels of association tests. In total, 61 SNPs with chromosome-wise significance level and 3 SNPs with genome-wise significance level were identified. 27 significant SNPs were located within the immune-related QTL regions reported in previous studies. Furthermore, several significant SNPs fell into the regions harboring known immunity-related genes, 14 of them fell into the regions which harbor some known T cell-related genes. Conclusions: Our study demonstrated that genome-wide association studies would be a feasible way for revealing the potential genetics variants affecting T-cell subpopulations. Results herein lay a preliminary foundation for further identifying the causal mutations underlying swine immune capacity in follow-up studies. [ABSTRACT FROM AUTHOR]

Background: Aptamer-based tumor targeted drug delivery system is a promising approach that may increase the efficacy of chemotherapy and reduce the related toxicity. HER2 protein is an attractive target for tumor-specific drug delivery because of its overexpression in multiple malignancies, including breast, gastric, ovarian, and lung cancers. Methods: In this paper, we developed a new HER2 aptamer (HB5) by using systematic evolution of ligands by exponential enrichment technology (SELEX) and exploited its role as a targeting ligand for delivering doxorubicin (Dox) to breast cancer cells in vitro. Results: The selected aptamer was an 86-nucleotide DNA molecule that bound to an epitope peptide of HER2 with a K&d of 18.9 nM. The aptamer also bound to the extracellular domain (ECD) of HER2 protein with a K&d of 316 nM, and had minimal cross reactivity to albumin or trypsin. In addition, the aptamer was found to preferentially bind to HER2-positive but not HER2-negative breast cancer cells. An aptamer-doxorubicin complex (Apt-Dox) was formulated by intercalating Dox into the DNA structure of HB5. The Apt-Dox complex could selectively deliver Dox to HER2-positive breast cancer cells while reducing the drug intake by HER2-negative cells in vitro. Moreover, Apt-Dox retained the cytotoxicity of Dox against HER2-positive breast cancer cells, but reduced the cytotoxicity to HER2-negative cells. Conclusions: The results suggest that the selected HER2 aptamer may have application potentials in targeted therapy against HER2-positive breast cancer cells. [ABSTRACT FROM AUTHOR]

Background: There is overwhelming evidence that dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs), mainly EPA (C20:5n-3) and DHA (C22:6n-3), has cardiovascular protective effects on patients with type 2 diabetes mellitus (T2DM) but not on healthy people. Because the T2DM heart increases fatty acid oxidation (FAO) to compensate for the diminished utilization of glucose, we hypothesize that T2DM hearts consume more n-3 PUFAs and, therefore, need more n-3 PUFAs. In the present study, we investigated the changes in cardiac n-3 PUFAs and peroxisomal beta-oxidation, which are responsible for the degradation of PUFAs in a high-fat diet (HFD) and low-dose streptozotocin- (STZ) induced type 2 diabetic rat model. Methods and results: The capillary gas chromatography results showed that all the n-3 (or omega-3) PUFAs, especially DHA (~50%) and EPA (~100%), were significantly decreased, and the n-6/n-3 ratio (~115%) was significantly increased in the hearts of diabetic rats. The activity of peroxisomal beta-oxidation, which is crucial to very-long-chain and unsaturated FA metabolism (including DHA), was significantly elevated in DM hearts. Additionally, the real-time PCR results showed that the mRNA expression of most peroxisomal beta-oxidation key enzymes were up-regulated in T2DM rat hearts, which might contribute to the reduction of n-3 (or omega-3) PUFAs. Conclusion: In conclusion, our results indicate that T2DM hearts consume more n-3 PUFAs, especially DHA and EPA, due to exaggerated peroxisomal beta-oxidation. [ABSTRACT FROM AUTHOR]

Background: Cancer is a heterogeneous disease caused by genomic aberrations and characterized by significant variability in clinical outcomes and response to therapies. Several subtypes of common cancers have been identified based on alterations of individual cancer genes, such as HER2, EGFR, and others. However, cancer is a complex disease driven by the interaction of multiple genes, so the copy number status of individual genes is not sufficient to define cancer subtypes and predict responses to treatments. A classification based on genome-wide copy number patterns would be better suited for this purpose. Method: To develop a more comprehensive cancer taxonomy based on genome-wide patterns of copy number abnormalities, we designed an unsupervised classification algorithm that identifies genomic subgroups of tumors. This algorithm is based on a modified genomic Non-negative Matrix Factorization (gNMF) algorithm and includes several additional components, namely a pilot hierarchical clustering procedure to determine the number of clusters, a multiple random initiation scheme, a new stop criterion for the core gNMF, as well as a 10-fold cross-validation stability test for quality assessment. Result: We applied our algorithm to identify genomic subgroups of three major cancer types: non-small cell lung carcinoma (NSCLC), colorectal cancer (CRC), and malignant melanoma. High-density SNP array datasets for patient tumors and established cell lines were used to define genomic subclasses of the diseases and identify cell lines representative of each genomic subtype. The algorithm was compared with several traditional clustering methods and showed improved performance. To validate our genomic taxonomy of NSCLC, we correlated the genomic classification with disease outcomes. Overall survival time and time to recurrence were shown to differ significantly between the genomic subtypes. Conclusions: We developed an algorithm for cancer classification based on genome-wide patterns of copy number aberrations and demonstrated its superiority to existing clustering methods. The algorithm was applied to define genomic subgroups of three cancer types and identify cell lines representative of these subgroups. Our data enabled the assembly of representative cell line panels for testing drug candidates. [ABSTRACT FROM AUTHOR]

Background: The filamentous fungus Aspergillus niger is well-known as a producer of primary metabolites and extracellular proteins. For example, glucoamylase is the most efficiently secreted protein of Aspergillus niger, thus the homologous glucoamylase (glaA) promoter as well as the glaA signal sequence are widely used for heterologous protein production. Xylose is known to strongly repress glaA expression while maltose is a potent inducer of glaA promoter controlled genes. For a more profound understanding of A. niger physiology, a comprehensive analysis of the intra- and extracellular proteome of Aspergillus niger AB1.13 growing on defined medium with xylose or maltose as carbon substrate was carried out using 2-D gel electrophoresis/Maldi-ToF and nano-HPLC MS/MS. Results: The intracellular proteome of A. niger growing either on xylose or maltose in well-aerated controlled bioreactor cultures revealed striking similarities. In both cultures the most abundant intracellular protein was the TCA cycle enzyme malate-dehydrogenase. Moreover, the glycolytic enzymes fructose-bis-phosphate aldolase and glyceraldehyde-3-phosphate-dehydrogenase and the flavohemoglobin FhbA were identified as major proteins in both cultures. On the other hand, enzymes involved in the removal of reactive oxygen species, such as superoxide dismutase and peroxiredoxin, were present at elevated levels in the culture growing on maltose but only in minor amounts in the xylose culture. The composition of the extracellular proteome differed considerably depending on the carbon substrate. In the secretome of the xylose-grown culture, a variety of plant cell wall degrading enzymes were identified, mostly under the control of the xylanolytic transcriptional activator XlnR, with xylanase B and ferulic acid esterase as the most abundant ones. The secretome of the maltose-grown culture did not contain xylanolytic enzymes, instead high levels of catalases were found and glucoamylase (multiple spots) was identified as the most abundant extracellular protein. Surprisingly, the intracellular proteome of A. niger growing on xylose in bioreactor cultures differed more from a culture growing in shake flasks using the same medium than from the bioreactor culture growing on maltose. For example, in shake flask cultures with xylose as carbon source the most abundant intracellular proteins were not the glycolytic and the TCA cycle enzymes and the flavohemoglobin, but CipC, a protein of yet unknown function, superoxide dismutase and an NADPH dependent aldehyde reductase. Moreover, vacuolar proteases accumulated to higher and ER-resident chaperones and foldases to lower levels in shake flask compared to the bioreactor cultures. Conclusions: The utilization of xylose or maltose was strongly affecting the composition of the secretome but of minor influence on the composition of the intracellular proteome. On the other hand, differences in culture conditions (pH control versus no pH control, aeration versus no aeration and stirring versus shaking) have a profound effect on the intracellular proteome. For example, lower levels of ER-resident chaperones and foldases and higher levels of vacuolar proteases render shake flask conditions less favorable for protein production compared to controlled bioreactor cultures. [ABSTRACT FROM AUTHOR]

Background: Haematological traits, which consist of mainly three components: leukocyte traits, erythrocyte traits and platelet traits, play extremely important role in animal immune function and disease resistance. But knowledge of the genetic background controlling variability of these traits is very limited, especially in swine. Results: In the present study, 18 haematological traits (7 leukocyte traits, 7 erythrocyte traits and 4 platelet traits) were measured in a pig resource population consisting of 368 purebred piglets of three breeds (Landrace, Large White and Songliao Black Pig), after inoculation with the swine fever vaccine when the pigs were 21 days old. A whole-genome scan of QTL for these traits was performed using 206 microsatellite markers covering all 18 autosomes and the X chromosome. Using variance component analysis based on a linear mixed model and the false discovery rate (FDR) test, 35 QTL with FDR < 0.10 were identified: 3 for the leukocyte traits, 28 for the erythrocyte traits, and 4 for the platelet traits. Of the 35 QTL, 25 were significant at FDR < 0.05 level, including 9 significant at FDR < 0.01 level. Conclusions: Very few QTL were previously identified for hematological traits of pigs and never in purebred populations. Most of the QTL detected here, in particular the QTL for the platelet traits, have not been reported before. Our results lay important foundation for identifying the causal genes underlying the hematological trait variations in pigs. [ABSTRACT FROM AUTHOR]

Racemic albuterol is an equimolar mixture of two isomers, (R) and (S). Whether (R) and (S) isomers and the combination of both exert different effects in immune activation is not well defined. We analyzed the effects of (R+S)-albuterol, (R)-albuterol and (S)-albuterol in a murine model of allergic pulmonary inflammation and in activated T cells. Mice (C57BL/6) sensitized and aerosol challenged with the allergen ovalbumin (OVA) or phosphate buffered saline (PBS) were treated with (R)-albuterol, (S)-albuterol or (R+S)-albuterol. Following administration of (R)- albuterol, allergen induced bronchoalveolar lavage eosinophils and IgE showed a decrease, albeit not significantly by ANOVA. As T cells are important in allergic inflammation, we asked whether (R+S), (R) or (S)-albuterol might differ in effects on T cells and on the activity of the inflammatory transcription factor NF-κB. In activated T cells, (R)-albuterol administration decreased levels of inflammatory cytokines and NF-κB activity. These studies suggest that (R)-albuterol decreases cytokine secretion and NF-κB activity in T cells. [ABSTRACT FROM AUTHOR]

Background: High throughput screens with RNA interference technology enable loss-of-function analyses of gene activities in mammalian cells. While the construction of genome-scale shRNA libraries has been successful, results of large-scale screening of those libraries can be difficult to analyze because of the relatively high noise levels and the fact that not all shRNAs in a library are equally effective in silencing gene expression. Results: We have screened a library consisting of 43,828 shRNAs directed against 8,500 human genes for functions that are necessary in cell detachment induced by a constitutively activated c-Abl tyrosine kinase. To deal with the issues of noise and uncertainty of knockdown efficiencies, we employed an analytical strategy that combines quantitative data analysis with biological knowledge, i.e. Gene Ontology and pathway information, to increase the power of the RNAi screening technique. Using this strategy we found 16 candidate genes to be involved in Abl-induced disruption of cell adhesion, and verified that the knockdown of IL6ST is associated with enhanced cell attachment. Conclusion: Our results suggest that the power of genome-wide quantitative shRNA screens can be significantly increased when analyzed using a systems biology-based approach to identify functional gene networks. [ABSTRACT FROM AUTHOR]

Background: Like microarray-based investigations, high-throughput proteomics techniques require machine learning algorithms to identify biomarkers that are informative for biological classification problems. Feature selection and classification algorithms need to be robust to noise and outliers in the data. Results: We developed a recursive support vector machine (R-SVM) algorithm to select important genes/biomarkers for the classification of noisy data. We compared its performance to a similar, state-of-the-art method (SVM recursive feature elimination or SVM-RFE), paying special attention to the ability of recovering the true informative genes/biomarkers and the robustness to outliers in the data. Simulation experiments show that a 5 %-~20 % improvement over SVM-RFE can be achieved regard to these properties. The SVM-based methods are also compared with a conventional univariate method and their respective strengths and weaknesses are discussed. RSVM was applied to two sets of SELDI-TOF-MS proteomics data, one from a human breast cancer study and the other from a study on rat liver cirrhosis. Important biomarkers found by the algorithm were validated by follow-up biological experiments. Conclusion: The proposed R-SVM method is suitable for analyzing noisy high-throughput proteomics and microarray data and it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features. The multivariate SVM-based method outperforms the univariate method in the classification performance, but univariate methods can reveal more of the differentially expressed features especially when there are correlations between the features. [ABSTRACT FROM AUTHOR]

A correction to the article "Cardioprotective activity of placental growth factor in a rat model of acute myocardial infarction: Nanoparticle-based delivery versus direct myocardial injection," by Zhe-xin Lu and colleagues published in an issue of the journal.