Bromodomain containing 7 (BRD7) was identified as a nuclear transcriptional regulatory factor. BRD7 functions as a tumor suppressor in multiple cancers, including nasopharyngeal carcinoma (NPC). In this study, we reported a novel mechanism of BRD7 in NPC progression. We demonstrated that the expression of miR-141 was remarkably increased in NPC tissues and was negatively correlated with the expression of BRD7 and the survival rate of NPC patients. Decreased expression levels of miR-141, including the primary, the precursor and the mature forms of miR-141, were found in BRD7-overexpressing HEK293, 5-8F and HNE1 cells compared the control cells, while there was no obvious effect on the expression levels of the two critical enzymes Drosha and Dicer. BRD7 can negatively regulate the promoter activity of miR-141, while no obvious binding site of BRD7 was found in the potential promoter region of miR-141. Moreover, ectopic expression of miR-141 can significantly promote cell proliferation and inhibit apoptosis in NPC, and rescuing the expression of miR-141 in BRD7-overexpressing NPC cells could partially reverse the tumor suppressive effect of BRD7 on cell proliferation and tumor growth in vitro and in vivo. Furthermore, the activation of the PTEN/AKT pathway mediated by the overexpression of BRD7 could be inhibited by rescuing the expression of miR-141, which accordingly results in the partial restoration of cell proliferation and tumor growth. Our findings demonstrate that the BRD7/miR-141/PTEN/AKT axis has critical roles in the progression of NPC and provide some promising targets for the diagnosis and treatment of NPC.

In the socially monogamous prairie voles (Microtus ochrogaster), the development of a social bonding is indicated by the formation of partner preference, which involves a variety of environmental and neurochemical factors and brain structures. In a most recent study in female prairie voles, we found that treatment with the histone deacetylase inhibitor trichostatin A (TSA) facilitates the formation of partner preference through up-regulation of oxytocin receptor (OTR) and vasopressin V1a receptor (V1aR) genes expression in the nucleus accumbens (NAcc). In the present study, we tested the hypothesis that TSA treatment also facilitates partner preference formation and alters OTR and V1aR genes expression in the NAcc in male prairie voles. We thus observed that central injection of TSA dose-dependently promoted the formation of partner preference in the absence of mating in male prairie voles. Interestingly, TSA treatment up-regulated OTR, but not V1aR, gene expression in the NAcc similarly as they were affected by mating - an essential process for naturally occurring partner preference. These data, together with others, not only indicate the involvement of epigenetic events but also the potential role of NAcc oxytocin in the regulation of partner preference in both male and female prairie voles.

We have previously reported that presynaptic dysfunction and cognitive decline have been found in lipoprotein lipase (LPL) deficient mice, but the mechanism remains to be elucidated. Accumulating evidence supported that α-synuclein (α-syn) and ubiquitin C-terminal hydrolase L1 (UCHL1) are required for normal synaptic and cognitive function. In this study, we found that α-syn aggregated and the expression of UCHL1 decreased in the brain of LPL deficient mice. Reduction of UCHL1 was resulted from nuclear retention of DNA cytosine-5-methyltransferase 1 in LPL knockout mice. Reverse changes were found in cultured cells overexpressing LPL. Furthermore, deficiency of LPL increased ubiquitination of α-syn. These results indicated that aggregation of α-syn and reduction of UCHL1 expression in LPL-deficient mice may affect synaptic function.

The paper presents studies of Bose-Einstein Correlations (BEC) for pairs of like-sign charged particles measured in the kinematic range [Formula: see text] 100 MeV and [Formula: see text] 2.5 in proton collisions at centre-of-mass energies of 0.9 and 7 TeV with the ATLAS detector at the CERN Large Hadron Collider. The integrated luminosities are approximately 7 [Formula: see text]b[Formula: see text], 190 [Formula: see text]b[Formula: see text] and 12.4 nb[Formula: see text] for 0.9 TeV, 7 TeV minimum-bias and 7 TeV high-multiplicity data samples, respectively. The multiplicity dependence of the BEC parameters characterizing the correlation strength and the correlation source size are investigated for charged-particle multiplicities of up to 240. A saturation effect in the multiplicity dependence of the correlation source size parameter is observed using the high-multiplicity 7 TeV data sample. The dependence of the BEC parameters on the average transverse momentum of the particle pair is also investigated.

To develop effective therapies for advanced high grade serous ovarian cancer (HGSOC), understanding mechanisms of recurrence and metastasis is necessary. In this study, we define the epithelial/mesenchymal status of cell lines that accurately model HGSOC, and evaluate the therapeutic potential of targeting Snai1 (Snail), a master regulator of the epithelial/mesenchymal transition (EMT) in vitro and in vivo. The ratio of Snail to E-cadherin (S/E index) at RNA and protein levels was correlated with mesenchymal morphology in four cell lines. The cell lines with high S/E index (OVCAR8 and COV318) showed more CSC-like, motile, and chemoresistant phenotypes than those with low S/E index (OVSAHO and Kuramochi). We tested the role of Snail in regulation of malignant phenotypes including stemness, cell motility, and chemotherapy resistance: shRNA-mediated knockdown of Snail reversed these malignant phenotypes. Interestingly, the expression of let-7 tumour suppressor miRNA was upregulated in Snail knockdown cells. Furthermore, knockdown of Snail decreased tumour burden in an orthotopic xenograft mouse model. We conclude that Snail is important in controlling HGSOC malignant phenotypes and suggest that the Snail/Let-7 axis may be an attractive target for HGSOC treatment.

Participants in deep space missions face protracted exposure to galactic cosmic radiation (GCR). In this setting, lung cancer is a significant component of the overall risk of radiation-exposure induced death. Here we investigate persistent effects of GCR exposure on DNA repair capacity in lung-derived epithelial cells, using an enzyme-stimulated chromosomal rearrangement as an endpoint. Replicate cell cultures were irradiated with energetic 48Ti ions (a GCR component) or reference γ-rays. After a six-day recovery, they were challenged by expression of a Cas9/sgRNA pair that creates double-strand breaks simultaneously in the EML4 and ALK loci, misjoining of which creates an EML4-ALK fusion oncogene. Misjoining was significantly elevated in 48Ti-irradiated populations, relative to the baseline rate in mock-irradiated controls. The effect was not seen in γ-ray irradiated populations exposed to equal or higher radiation doses. Sequence analysis of the EML4-ALK joints from 48Ti-irradiated cultures showed that they were far more likely to contain deletions, sometimes flanked by short microhomologies, than equivalent samples from mock-irradiated cultures, consistent with a shift toward error-prone alternative nonhomologous end joining repair. Results suggest a potential mechanism by which a persistent physiological effect of GCR exposure may increase lung cancer risk.

RanBP9 is a multi-domain scaffolding protein known to integrate extracellular signaling with intracellular targets. We previously demonstrated that RanBP9 enhances Aβ generation and amyloid plaque burden which results in loss of specific pre- and postsynaptic proteins in vivo in a transgenic mouse model. Additionally, we showed that the levels of spinophilin, a marker of dendritic spines were inversely proportional to the RanBP9 protein levels within the synaptosomes isolated from AD brains. In the present study, we found reduced dendritic intersections within the layer 6 pyramidal neurons of the cortex as well as the hippocampus of RanBP9 transgenic mice compared to age-matched wild-type (WT) controls at 12 months of age but not at 6months. Similarly, the dendritic spine numbers were reduced in the cortex at only 12 months of age by 30% (p<0.01), but not at 6months. In the hippocampus also the spine densities were reduced at 12 months of age (38%, p<0.01) in the RanBP9 transgenic mice. Interestingly, the levels of phosphorylated form of cofilin, an actin binding protein that plays crucial role in the regulation of spine numbers were significantly decreased in the cortical synaptosomes at only 12months of age by 26% (p<0.01). In the hippocampal synaptosomes, the decrease in cofilin levels were 36% (p<0.01) at 12 months of age. Thus dendritic arbor and spine density were directly correlated to the levels of phosphorylated form of cofilin in the RanBP9 transgenic mice. Similarly, cortical synaptosomes showed a 20% (p<0.01) reduction in the levels of spinophilin in the RanBP9 transgenic mice. These results provided the physical basis for the loss of synaptic proteins by RanBP9 and most importantly it also explains the impaired spatial learning and memory skills previously observed in the RanBP9 transgenic mice.

Background. Randomized controlled trials (RCTs) have been conducted comparing the efficacy of rabeprazole 20 mg or omeprazole 20 mg once daily for patients with erosive gastroesophageal reflux disease (GERD). Until now, no study has synthesized all available data examining this issue. Method. Medline, Embase, and the Cochrane central register of controlled trials were searched (through December 2012). Eligible RCTs recruited adults with erosive GERD and reported endoscopic and symptomatic relief rates at the last point of follow-up. The effect of rabeprazole versus omeprazole was reported as relative risk (RR) of relief with a 95% confidence interval (CI). Results. The search identified 605 citations, and six RCTs containing 1,895 patients were eligible. Endoscopic relief rates were not significantly different between rabeprazole 20 mg and omeprazole 20 mg in treatment trials of up to 8 weeks. Heartburn relief rates were significantly different between the two groups for 8-week treatment trials. Adverse events were not significantly different between the two groups for 8-week treatment trials. Conclusion. These data suggest that rabeprazole demonstrates a clinical advantage over omeprazole in symptomatic relief but no significant difference in endoscopic relief of erosive GERD for up to 8 weeks of treatment. Rabeprazole and omeprazole were both tolerated by GERD patients.

The p63 gene regulates thymic epithelial cell (TEC) proliferation, whereas FoxN1 regulates their differentiation. However, their collaborative role in the regulation of TEC homeostasis during thymic aging is largely unknown. In murine models, the proportion of TAp63(+), but not ΔNp63(+), TECs was increased with age, which was associated with an age-related increase in senescent cell clusters, characterized by SA-β-Gal(+) and p21(+) cells. Intrathymic infusion of exogenous TAp63 cDNA into young wild-type (WT) mice led to an increase in senescent cell clusters. Blockade of TEC differentiation via conditional FoxN1 gene knockout accelerated the appearance of this phenotype to early middle age, whereas intrathymic infusion of exogenous FoxN1 cDNA into aged WT mice brought only a modest reduction in the proportion of TAp63(+) TECs, but an increase in ΔNp63(+) TECs in the partially rejuvenated thymus. Meanwhile, we found that the increased TAp63(+) population contained a high proportion of phosphorylated-p53 TECs, which may be involved in the induction of cellular senescence. Thus, TAp63 levels are positively correlated with TEC senescence but inversely correlated with expression of FoxN1 and FoxN1-regulated TEC differentiation. Thereby, the p63-FoxN1 regulatory axis in regulation of postnatal TEC homeostasis has been revealed.

Mortalin (mot-2) induces inactivation of the tumor suppressor p53's transcriptional and apoptotic functions by cytoplasmic sequestration of p53 in select cancers. The mot-2-dependent cytoprotective function enables cancer cells to support malignant transformation. Abrogating the p53-mot-2 interaction can control or slow down the growth of cancer cells. In this study, we report the discovery of a ubiquitin-like (UBX)-domain-containing protein, UBXN2A, which binds to mot-2 and consequently inhibits the binding between mot-2 and p53. Genetic analysis showed that UBXN2A binds to mot-2's substrate binding domain, and it partly overlaps p53's binding site indicating UBXN2A and p53 likely bind to mot-2 competitively. By binding to mot-2, UBXN2A releases p53 from cytosolic sequestration, rescuing the tumor suppressor functions of p53. Biochemical analysis and functional assays showed that the overexpression of UBXN2A and the functional consequences of unsequestered p53 trigger p53-dependent apoptosis. Cells expressing shRNA against UBXN2A showed the opposite effect of that seen with UBXN2A overexpression. The expression of UBXN2A and its apoptotic effects were not observed in normal colonic epithelial cells and p53-/- colon cancer cells. Finally, significant reduction in tumor volume in a xenograft mouse model in response to UBXN2A expression was verified in vivo. Our results introduce UBXN2A as a home defense response protein, which can reconstitute inactive p53-dependent apoptotic pathways. Inhibition of mot-2-p53 interaction by UBXN2A is an attractive therapeutic strategy in mot-2-elevated tumors.

Metastasis is the leading cause of death in patients with hepatocellular carcinoma (HCC) after curative resection. Therefore, it is critical to understand the mechanisms underlying tumor metastasis in HCC. We have previously shown that elevated expression of myeloid differentiation factor 88 (MyD88) may promote tumor growth and metastasis in HCC. In this study, we reported that enhanced expression of MyD88 promoted epithelial-mesenchymal transition (EMT) properties and tumor-initiating capabilities in HCC cells. MyD88 was found to be able to interact with p85, a regulatory subunit of phosphoinositide 3-kinase (PI3-K), independent of TLR/IL-1R-mediated response and caused PI3-K/v-akt murine thymoma viral oncogene homolog (Akt) activation, which resulted in subsequent phosphorylation of glycogen synthase kinase-3β and stabilization of Snail, a critical EMT mediator. Consistently, we observed a significant correlation between MyD88 expression and p-Akt levels in a cohort of HCC patients, and found that the combination of these two parameters have better prognostic value for HCC patients. Taken together, these results suggest that elevated MyD88 may facilitate HCC metastasis by promoting EMT properties and tumor-initiating capabilities via PI3-K/Akt pathway.

Mesenchymal stromal cells (MSCs) are heterogeneous cells with immunoregulatory and wound-healing properties. In cancer, they are known to be an essential part of the tumour microenvironment. However, their role in tumour growth and rejection remains unclear. To investigate this, we co-cultured human MSCs, tumour infiltrating lymphocytes (TIL), and melanoma cells to investigate the role of MSCs in the tumour environment.

Non-apoptotic functions of Fas-associated protein with death domain (FADD) have been implicated in T lineage lymphocytes, but the nature of FADD-dependent non-apoptotic mechanism in early T-cell development has not been completely elucidated. In this study, we show that tissue-specific deletion of FADD in immature (CD44(-)CD25(+)) thymocytes results in severe perturbation of αβ lineage development. Meanwhile, loss of FADD signaling at a later (CD44(-)CD25(-)) developmental stage does not affect subsequent T-cell development. Collectively, our work presents that FADD deficiency induces failed survival in double-negative 4 (DN4) cells, while pre-T-cell receptor (TCR) signal remains intact. In addition, Notch signaling is positive regulated on DN4 and double-positive thymocytes in T-cell-specific FADD-knockout mice, which express higher levels of a subset of Notch-target genes, including Hes1, Deltex1 and CD25. Moreover, a transcriptional repressor of Notch1, NKAP is downregulated coupled with the loss of FADD in thymocytes and is found to associate with FADD. These data suggest that as a death receptor, FADD is also required for cell survival in β-selection as a regulator of Notch1 expression.

Obesity and eating disorders are prevailing health concerns worldwide. It is important to understand the regulation of food intake and energy metabolism. Thiamine (vitamin B1) is an essential nutrient. Thiamine deficiency (TD) can cause a number of disorders in humans, such as Beriberi and Wernicke-Korsakoff syndrome. We demonstrated here that TD caused anorexia in C57BL/6 mice. After feeding a TD diet for 16days, the mice displayed a significant decrease in food intake and an increase in resting energy expenditure (REE), which resulted in a severe weight loss. At the 22nd day, the food intake was reduced by 69% and 74% for male and female mice, respectively in TD group. The REE increased by ninefolds in TD group. The loss of body weight (17-24%) was similar between male and female animals and mainly resulted from the reduction of fat mass (49% decrease). Re-supplementation of thiamine (benfotiamine) restored animal's appetite, leading to a total recovery of body weight. The hypothalamic adenosine monophosphate-activated protein kinase (AMPK) is a critical regulator of food intake. TD inhibited the phosphorylation of AMPK in the arcuate nucleus (ARN) and paraventricular nucleus (PVN) of the hypothalamus without affecting its expression. TD-induced inhibition of AMPK phosphorylation was reversed once thiamine was re-supplemented. In contrast, TD increased AMPK phosphorylation in the skeletal muscle and upregulated the uncoupling protein (UCP)-1 in brown adipose tissues which was consistent with increased basal energy expenditure. Re-administration of thiamine stabilized AMPK phosphorylation in the skeletal muscle as well as energy expenditure. Taken together, TD may induce anorexia by inhibiting hypothalamic AMPK activity. With a simultaneous increase in energy expenditure, TD caused an overall body weight loss. The results suggest that the status of thiamine levels in the body may affect food intake and body weight.

It is largely recognized that fibroblast activation protein (FAP) is expressed in cancer-associated fibroblasts (CAFs) of many human carcinomas. Furthermore, FAP was recently also reported to be expressed in carcinoma cells of the breast, stomach, pancreatic ductal adenocarcinoma, colorectum, and uterine cervix. The carcinoma cell expression pattern of FAP has been described in several types of cancers, but the role of FAP in oral squamous cell carcinoma (OSCC) is unknown. The role of endogenous FAP in epithelium-derived tumors and molecular mechanisms has also not been reported. In this study, FAP was found to be expressed in carcinoma cells of OSCC and was upregulated in OSCC tissue samples compared with benign tissue samples using immunohistochemistry. In addition, its expression level was closely correlated with overall survival of patients with OSCC. Silencing FAP inhibited the growth and metastasis of OSCC cells in vitro and in vivo. Mechanistically, knockdown of FAP inactivated PTEN/PI3K/AKT and Ras-ERK and its downstream signaling regulating proliferation, migration, and invasion in OSCC cells, as the inhibitory effects of FAP on the proliferation and metastasis could be rescued by PTEN silencing. Our study suggests that FAP acts as an oncogene and may be a potential therapeutic target for patients with OSCC.

Signal transducer and activator of transcription 3(STAT3) is an emerging target for cancer therapy. In this study, we identify Toosendanin (TSN) is an effective inhibitor of STAT3, leading to the impediment of various oncogenic processes in osteosarcoma. TSN selectively inactivates phospho-STAT3 (Tyr-705); subsequent molecular docking and in vitro SPR analysis uncover TSN directly binds to the SH2 domain of STAT3. Consequently, TSN blocks STAT3 dimerization and impairs the complex formation of STAT3 and epidermal growth factor receptor (EGFR). In an animal tumor model study, TSN is well tolerated, inhibits osteosarcoma growth and metastasis. In another osteosarcoma patient-derived xenografts (PDX) model, we find TSN triggers strong inhibitory effects on patient-derived tumors. Further studies show that TSN also displays activity against other solid tumors. Our preclinical work therefore supports that TSN acts as a novel inhibitor of STAT3 that blocks tumorigenesis in ostoesarcoma.

This meta-analysis compared the efficacy and safety of the contact force (CF)-sensing catheter and second-generation cryoballoon (CB) ablation for treating atrial fibrillation (AF). Six controlled clinical trials comparing ablation for AF using a CF-sensing catheter or second-generation CB were identified from PubMed, EMBASE, Cochrane Library, Wanfang Data, and China National Knowledge Infrastructure. The procedure duration was significantly lower in the CB group compared with that in the CF group [mean difference (MD)=29.4; 95%CI=17.84-40.96; P=0.01], whereas there was no difference between the groups for fluoroscopy duration (MD=0.59; 95%CI=-4.48-5.66; P=0.82). Moreover, there was no difference in the incidence of non-lethal complications (embolic event, tamponade, femoral/subclavian hematoma, arteriovenous fistula, pulmonary vein stenosis, phrenic nerve palsy, and esophageal injury) between the CB and the CF groups (8.38 vs 5.35%; RR=0.66; 95%CI=0.37-1.17; P=0.15). Transient phrenic nerve palsy occurred in 17 of 326 patients (5.2%) of the CB group vs none in the CF group (RR=0.12; 95%CI=0.03-0.43; P=0.001). A comparable proportion of patients in CF and CB groups suffered from AF recurrence during the 12-month follow-up after a single ablation procedure [risk ratio (RR)=1.03; 95%CI=0.78-1.35; P=0.84]. AF ablation using CF-sensing catheters and second-generation CB showed comparable fluoroscopy duration and efficacy (during a 12-month follow-up), with shorter procedure duration and different complications in the CB group.

Connective tissue growth factor (CTGF) has different roles in different types of cancer. However, the involvement and molecular basis of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC) have almost never been reported. In this study, we observed that downregulated CTGF expression was significantly associated with NPC progression and poor prognosis. Knockdown of CTGF markedly elevated the ability of cell proliferation in vivo and in vitro. Subsequently, we discovered that the reduction of CTGF increased the expression of miR-18b, an oncomir-promoting cell proliferation. Further, we discovered that attenuated CTGF-mediated upregulation of miR-18b was dependent on the increased binding of transcription factors Jun proto-oncogene (C-Jun) and v-Myc myelocytomatosis viral oncogene homolog (C-Myc) to miR-18b promoter region via phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we further found that miR-18b directly suppressed the expression of CTGF in NPC. In clinical fresh specimens, miR-18b was widely overexpressed and inversely correlated with CTGF expression in NPC. Our studies are the first to demonstrate that reduced CTGF as an unfavorable prognosis factor mediates the activation of miR-18b, an oncomir directly suppresses CTGF expression, by PI3K/AKT/C-Jun and C-Myc and promotes cell growth of NPC.

rhuMAb Beta7 is a humanized anti-human β7 monoclonal antibody currently in phase I in inflammatory bowel disease. rhuMAb Beta7 binds the β7 subunit of the integrins α4β7 and αEβ7, blocking interaction with their ligands. These integrins play key roles in immune cell homing to and retention in mucosal sites, and are associated with chronic inflammatory diseases of the gastrointestinal tract. The goal of this study was to evaluate the mucosal specificity of rhuMAb Beta7.

No abstract available