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In this population-based propensity score matched (PSM) cohort study, we aimed to investigate the risk of developing dementia with the use of acid suppressants, including proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2 antagonists). Cohorts of PPI users (n = 2,778), H2 antagonist users (n = 6,165), and non-users (n = 86,238) were selected from a dataset covering the years 2000 to 2010 in Taiwan's National Health Insurance Research Database. Patients in the three groups were PSM at a ratio of 1:1 within each comparison cohort (CC). Three CCs were created: (1) PPI users compared to non-users (CC1, n = 2,583 pairs); (2) H2 antagonist users compared to non-users (CC2, n = 5,955 pairs); and (3) PPI users compared to H2 antagonist users (CC3, n = 2,765 pairs). A multivariable robust Cox proportional hazard model was used to estimate the adjusted hazard ratio (aHR) and the 95% confidence interval (CI) for the risk of developing dementia. The multivariable analysis results show that the aHR of developing dementia during the follow-up period was 0.72 (CC1: 95% CI = 0.51–1.03, P = 0.07) for PPI users and 0.95 (CC2: 95% CI = 0.74–1.22, P = 0.69) for H2 antagonist users, when compared to non-users. Between the patients using acid suppressants, there was no difference between PPI and H2 antagonist users in the risk of developing dementia (CC3: aHR = 0.82, 95% CI = 0.58–1.17, P = 0.28). In conclusion, no association was observed between the use of acid suppressants and the risk of developing dementia in any of the three CCs. Further, randomized controlled trials are warranted to confirm this relationship. [ABSTRACT FROM AUTHOR]

We aimed to profile the metabolism of soybean roots that were infected with soybean cyst nematodes and treated with Bacillus simplex to identify metabolic differences that may explain nematode resistance. Compared with control soybean roots, B. simplex-treated soybean roots contained lower levels of glucose, fructose, sucrose, and trehalose, which reduced the nematodes' food source. Furthermore, treatment with B. simplex led to higher levels of melibiose, gluconic acid, lactic acid, phytosphingosine, and noradrenaline in soybean roots, which promoted nematocidal activity. The levels of oxoproline, maltose, and galactose were lowered after B. simplex treatment, which improved disease resistance. Collectively, this study provides insight into the metabolic alterations induced by B. simplex treatment, which affects the interactions with soybean cyst nematodes. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid progenitor cells that are expanded in cancer and act as potent suppressors of the anti-tumor immune response. MDSCs consist of two major subsets, namely monocytic (M-) MDSCs and granulocytic (G-) MDSCs that differ with respect to their phenotype, morphology and mechanisms of suppression. Here, we cultured bone marrow cells with IL-6 and GM-CSF in vitro to generate a population of bone marrow MDSCs (BM-MDSCs) similar to G-MDSCs from tumor-bearing mice in regards to phenotype, morphology and suppressive-function. Through fluorescent labeling of these BM-MDSCs and optical imaging, we could visualize the recruitment and localization of BM-MDSCs in breast tumor-bearing mice in vivo. Furthermore, we were able to demonstrate that BM-MDSCs home to primary and metastatic breast tumors, but have no significant effect on tumor growth or progression. Ex vivo flow cytometry characterization of BM-MDSCs after adoptive transfer demonstrated both organ-and tumor-specific effects on their phenotype and differentiation, demonstrating the importance of the local microenvironment on MDSC fate and function. In this study, we have developed a method to generate, visualize and detect BM-MDSCs in vivo and ex vivo through optical imaging and flow cytometry, in order to understand the organ-specific changes rendered to MDSCs in breast cancer. [ABSTRACT FROM AUTHOR]

Objective: Gastroesophageal reflux disease (GERD) is a common disease which can cause troublesome symptoms and affect quality of life. In addition to esophageal complications, GERD may also be a risk factor for extra-esophageal complications. Both GERD and coronary artery disease (CAD) can cause chest pain and frequently co-exist. However, the association between GERD and acute myocardial infarction (AMI) remain unclear. The purpose of the study was to compare the incidence of acute myocardial infarction in GERD patients with an age-, gender-, and comorbidity matched population free of GERD. We also examine the association of the risk of AMI and the use of acid suppressing agents in GERD patients. Methods: We identified patients with GERD from the Taiwan National Health Insurance Research Database. The study cohort comprised 54,422 newly diagnosed GERD patients; 269,572 randomly selected age-, gender-, comorbidity-matched subjects comprised the comparison cohort. Patients with any prior CAD, AMI or peripheral arterial disease were excluded. Incidence of new AMI was studied in both groups. Results: A total 1,236 (0.5%) of the patients from the control group and 371 (0.7%) patients from the GERD group experienced AMI during a mean follow-up period of 3.3 years. Based on Cox proportional-hazard model analysis, GERD was independently associated with increased risk of developing AMI (hazard ratio (HR) = 1.48; 95% confidence interval (CI): 1.31–1.66, P < 0.001). Within the GERD group, patients who were prescribed proton pump inhibitors (PPIs) for more than one year had slightly decreased the risk of developing AMI, compared with those without taking PPIs (HR = 0.57; 95% CI: 0.31–1.04, P = 0.066). Conclusions: This large population-based study demonstrates an association between GERD and future development of AMI, however, PPIs use only achieved marginal significance in reducing the occurrence of AMI in GERD patients. Further prospective studies are needed to evaluate whether anti-reflux medication may reduce the occurrence of acute ischemic event in GERD patients. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy in women of reproductive age. It is difficult to treat PCOS because of its complex etiology and pathogenesis. Here, we characterized the roles of gut microbiota on the pathogenesis and treatments in letrozole (a nonsteroidal aromatase inhibitor) induced PCOS rat model. Changes in estrous cycles, hormonal levels, ovarian morphology and gut microbiota by PCR-DGGE and real-time PCR were determined. The results showed that PCOS rats displayed abnormal estrous cycles with increasing androgen biosynthesis and exhibited multiple large cysts with diminished granulosa layers in ovarian tissues. Meanwhile, the composition of gut microbiota in letrozole-treated rats was different from that in the controls. Lactobacillus, Ruminococcus and Clostridium were lower while Prevotella was higher in PCOS rats when compared with control rats. After treating PCOS rats with Lactobacillus and fecal microbiota transplantation (FMT) from healthy rats, it was found that the estrous cycles were improved in all 8 rats in FMT group, and in 6 of the 8 rats in Lactobacillus transplantation group with decreasing androgen biosynthesis. Their ovarian morphologies normalized. The composition of gut microbiota restored in both FMT and Lactobacillus treated groups with increasing of Lactobacillus and Clostridium, and decreasing of Prevotella. These results indicated that dysbiosis of gut microbiota was associated with the pathogenesis of PCOS. Microbiota interventions through FMT and Lactobacillus transplantation were beneficial for the treatments of PCOS rats. [ABSTRACT FROM AUTHOR]

Objective: The axillary reverse mapping (ARM) technique has recently been developed to prevent lymphedema by preserving the arm lymphatic drainage during sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) procedures. The objective of this systematic review and meta-analysis was to evaluate the feasibility and oncological safety of ARM. Methods: We searched Medline, Embase, Web of science, Scopus, and the Cochrane Library for relevant prospective studies. The identification rate of ARM nodes, the crossover rate of SLN-ARM nodes, the proportion of metastatic ARM nodes, and the incidence of complications were pooled into meta-analyses by the random-effects model. Results: A total of 24 prospective studies were included into meta-analyses, of which 11 studies reported ARM during SLNB, and 18 studies reported ARM during SLNB. The overall identification rate of ARM nodes was 38.2% (95% CI 32.9%-43.8%) during SLNB and 82.8% (78.0%-86.6%) during ALND, respectively. The crossover rate of SLN-ARM nodes was 19.6% (95% CI 14.4%-26.1%). The metastatic rate of ARM nodes was 16.9% (95% CI 14.2%-20.1%). The pooled incidence of lymphedema was 4.1% (95% CI 2.9–5.9%) for patients undergoing ARM procedure. Conclusions: The ARM procedure was feasible during ALND. Nevertheless, it was restricted by low identification rate of ARM nodes during SLNB. ARM was beneficial for preventing lymphedema. However, this technique should be performed with caution given the possibility of crossover SLN-ARM nodes and metastatic ARM nodes. ARM appeared to be unsuitable for patients with clinically positive breast cancer due to oncological safety concern. [ABSTRACT FROM AUTHOR]

There is renewed interest in the immune regulatory role of the spleen in oncology. To date, very few studies have examined macroscopic variations of splenic volume in the setting of cancer, prior to or during therapy, especially in humans. Changes in splenic volume may be associated with changes in splenic function. The purpose of this study was to investigate variations in spleen volume in NSCLC patients during chemo-radiotherapy. Sixty patients with stage I-IIIB NSCLC underwent radiotherapy (60Gy/30 fractions) for six weeks with concomitant carboplatin/paclitaxel (Ca/P; n = 32) or cisplatin/etoposide (Ci/E; n = 28). A baseline PET/CT scan was performed within 2 weeks prior to treatment and during Weeks 2 and 4 of chemo-radiotherapy. Spleen volume was measured by contouring all CT slices. Significant macroscopic changes in splenic volume occurred early after the commencement of treatment. A significant decrease in spleen volume was observed for 66% of Ca/P and 79% of Ci/E patients between baseline and Week 2. Spleen volume was decreased by 14.2% for Ca/P (p<0.001) and 19.3% for Ci/E (p<0.001) patients. By Week 4, spleen volume was still significantly decreased for Ca/P patients compared to baseline, while for Ci/E patients, spleen volume returned to above baseline levels. This is the first report demonstrating macroscopic changes in the spleen in NSCLC patients undergoing radical chemo-radiotherapy that can be visualized by non-invasive imaging. [ABSTRACT FROM AUTHOR]

We previously demonstrated that vancomycin treatment increased acquisition of eDNA and enhanced biofilm formation of drug-resistant Staphylococcus aureus through a cidA-mediated autolysis mechanism. Recently we found that such enhancement became more significant under a higher glucose concentration in vitro. We propose that besides improper antibiotic treatment, increased glucose concentration environment in diabetic animals may further enhance biofilm formation of drug-resistant S. aureus. To address this question, the diabetic mouse model infected by vancomycin-resistant S. aureus (VRSA) was used under vancomycin treatment. The capacity to form biofilms was evaluated through a catheter-associated biofilm assay. A 10- and 1000-fold increase in biofilm-bound bacterial colony forming units was observed in samples from diabetic mice without and with vancomycin treatment, respectively, compared to healthy mice. By contrast, in the absence of glucose vancomycin reduced propensity to form biofilms in vitro through the increased production of proteases and DNases from VRSA. Our study highlights the potentially important role of increased glucose concentration in enhancing biofilm formation in vancomycin-treated diabetic mice infected by drug-resistant S. aureus. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) has been shown to play an important role in the plant response to biotic and abiotic stresses in Arabidopsis mutants with lower or higher levels of endogenous NO. The exogenous application of NO donors or scavengers has also suggested an important role for NO in plant defense against environmental stress. In this study, rice plants under drought and high salinity conditions showed increased nitric oxide synthase (NOS) activity and NO levels. Overexpression of rat neuronal NO synthase (nNOS) in rice increased both NOS activity and NO accumulation, resulting in improved tolerance of the transgenic plants to both drought and salt stresses. nNOS-overexpressing plants exhibited stronger water-holding capability, higher proline accumulation, less lipid peroxidation and reduced electrolyte leakage under drought and salt conditions than wild rice. Moreover, nNOS-overexpressing plants accumulated less H2O2, due to the observed up-regulation of OsCATA, OsCATB and OsPOX1. In agreement, the activities of CAT and POX were higher in transgenic rice than wild type. Additionally, the expression of six tested stress-responsive genes including OsDREB2A, OsDREB2B, OsSNAC1, OsSNAC2, OsLEA3 and OsRD29A, in nNOS-overexpressing plants was higher than that in the wild type under drought and high salinity conditions. Taken together, our results suggest that nNOS overexpression suppresses the stress-enhanced electrolyte leakage, lipid peroxidation and H2O2 accumulation, and promotes proline accumulation and the expression of stress-responsive genes under stress conditions, thereby promoting increased tolerance to drought and salt stresses. [ABSTRACT FROM AUTHOR]

Autophagy is the mechanism by which cytoplasmic components and organelles are degraded by the lysosomal machinery in response to diverse stimuli including nutrient deprivation, intracellular pathogens, and multiple forms of cellular stress. Here, we show that the membrane-associated E3 ligase RNF5 regulates basal levels of autophagy by controlling the stability of a select pool of the cysteine protease ATG4B. RNF5 controls the membranal fraction of ATG4B and limits LC3 (ATG8) processing, which is required for phagophore and autophagosome formation. The association of ATG4B with--and regulation of its ubiquitination and stability by--RNF5 is seen primarily under normal growth conditions. Processing of LC3 forms, appearance of LC3-positive puncta, and p62 expression are higher in RNF5-/- MEF. RNF5 mutant, which retains its E3 ligase activity but does not associate with ATG4B, no longer affects LC3 puncta. Further, increased puncta seen in RNF5-/- using WT but not LC3 mutant, which bypasses ATG4B processing, substantiates the role of RNF5 in early phases of LC3 processing and autophagy. Similarly, RNF-5 inactivation in Caenorhabditis elegans increases the level of LGG-1/LC3::GFP puncta. RNF5-/- mice are more resistant to group A Streptococcus infection, associated with increased autophagosomes and more efficient bacterial clearance by RNF5-/- macrophages. Collectively, the RNF5-mediated control of membranalATG4B reveals a novel layer in the regulation of LC3 processing and autophagy. [ABSTRACT FROM AUTHOR]

Direct reprogramming of human somatic cells into induced pluripotent stem (iPS) cells by defined transcription factors (TFs) provides great potential for regenerative medicine and biomedical research. This procedure has many challenges, including low reprogramming efficiency, many partially reprogrammed colonies, somatic coding mutations in the genome, etc. Here, we describe a simple approach for generating fully reprogrammed human iPS cells by using a single polycistronic retroviral vector expressing four human TFs in a single open reading frame (ORF), combined with a cocktail containing three small molecules (Sodium butyrate, SB431542, and PD0325901). Our results demonstrate that human iPS cells generated by this approach express human ES cells markers and exhibit pluripotency demonstrated by their abilities to differentiate into the three germ layers in vitro and in vivo. Notably, this approach not only provides a much faster reprogramming process but also significantly diminishes partially reprogrammed iPS cell colonies, thus facilitating efficient isolation of desired fully reprogrammed iPS cell colonies. [ABSTRACT FROM AUTHOR]

The level of total adiponectin, a mixture of different adiponectin forms, has been reported associated with breast cancer risk with inconsistent results. Whether the different forms play different roles in breast cancer risk prediction is unclear. To examine this, we measured total and high molecular weight (HMW) adiponectin in a case-control study (1167 sets). Higher circulating HMW adiponectin was negatively associated with breast cancer risk after adjusting for menopausal status and family history of breast cancer (P=0.024). We analyzed the relationship between adiponectin and breast cancer risk in 6 subgroups. Higher circulating HMW adiponectin was also negatively associated with breast cancer risk (P=0.020, 0.014, 0.035) in the subgroups of postmenopausal women, negative family history of breast cancer, BMI>=24.0. Total adiponectin was positively associated with breast cancer (P=0.028) in the subgroup of BMI<=24.0. Higher HMW/total adiponectin ratio was negatively associated with breast cancer (P=0.019) in the subgroup of postmenopausal women. Interestingly, in the subgroup of women with family history of breast cancer, higher circulating total and HMW adiponectin were positively associated with breast cancer risk (P=0.034, 0.0116). This study showed different forms of circulating adiponectin levels might play different roles in breast cancer risk. A higher circulating HMW adiponectin is associated with a decreased breast cancer risk, especially in postmenopausal, without family history of breast cancer or BMI>=24.0 subgroups, whereas higher circulating HMW adiponectin levels is a risk factor in women with a family history of breast cancer. Further investigation of different forms of adiponectin on breast cancer risk is needed.

Background: Focal Dermal Hypoplasia (FDH) is a genetic disorder characterized by developmental defects in skin, skeleton and ectodermal appendages. FDH is caused by dominant loss-of-function mutations in X-linked PORCN. PORCN orthologues in Drosophila and mice encode endoplasmic reticulum proteins required for secretion and function of Wnt proteins. Wnt proteins play important roles in embryo development, tissue homeostasis and stem cell maintenance. Since features of FDH overlap with those seen in mouse Wnt pathway mutants, FDH likely results from defective Wnt signaling but molecular mechanisms by which inactivation of PORCN affects Wnt signaling and manifestations of FDH remain to be elucidated., Results: We introduced intronic loxP sites and a neomycin gene in the mouse Porcn locus for conditional inactivation. Porcn-ex3-7flox mice have no apparent developmental defects, but chimeric mice retaining the neomycin gene (Porcn-ex3-7Neo-flox) have limb, skin, and urogenital abnormalities. Conditional Porcn inactivation by EIIa-driven or Hprt-driven Cre recombinase results in increased early embryonic lethality. Mesenchyme-specific Prx-Cre-driven inactivation of Porcn produces FDH-like limb defects, while ectodermal Krt14-Cre-driven inactivation produces thin skin, alopecia, and abnormal dentition. Furthermore, cell-based assays confirm that human PORCN mutations reduce WNT3A secretion., Conclusions: These data indicate that Porcn inactivation in the mouse produces a model for human FDH and that phenotypic features result from defective WNT signaling in ectodermal- and mesenchymal-derived structures.

Direct reprogramming of human somatic cells into induced pluripotent stem (iPS) cells by defined transcription factors (TFs) provides great potential for regenerative medicine and biomedical research. This procedure has many challenges, including low reprogramming efficiency, many partially reprogrammed colonies, somatic coding mutations in the genome, etc. Here, we describe a simple approach for generating fully reprogrammed human iPS cells by using a single polycistronic retroviral vector expressing four human TFs in a single open reading frame (ORF), combined with a cocktail containing three small molecules (Sodium butyrate, SB431542, and PD0325901). Our results demonstrate that human iPS cells generated by this approach express human ES cells markers and exhibit pluripotency demonstrated by their abilities to differentiate into the three germ layers in vitro and in vivo. Notably, this approach not only provides a much faster reprogramming process but also significantly diminishes partially reprogrammed iPS cell colonies, thus facilitating efficient isolation of desired fully reprogrammed iPS cell colonies.