Proper wound healing is dynamic in order to maintain the corneal integrity and transparency. Impaired or delayed corneal epithelial wound healing is one of the most frequently observed ocular defect and difficult to treat. Cyclin dependen kinase (cdk), a known cell cycle regulator, required for proper proliferating and migration of cell. We therefore investigated the role of cell cycle regulator cdk10, member of cdk family and its functional association with transcriptional factor (ETS2) at active phase of corneal epithelial cell migration. Our data showed that cdk10 was associated with ETS2, while its expression was upregulated at the active phase (18 hours) of cell migration and gradually decrease as the wound was completely closed. Topical treatment with anti-cdk10 and ETS2 antibodies delayed the wound closure time at higest concentration (10 µg/ml) compared to control. Further, our results also showed increased mRNA expression of cdk10 and ETS2 at active phase of migration at approximately 2 fold. Collectively, our data reveals that cdk10 and ETS2 efficiently involved during corneal wound healing. Further studies are warranted to better understand the mechanism and safety of topical cdk10 and ETS2 proteins in corneal epithelial wound-healing and its potential role for human disease treatment.

Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations1. One example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs)2. A relatively overlooked potential source of this loss of function is the stem cell 'niche'-a set of cell-extrinsic cues that include chemical and mechanical signals3,4. Here we show that the OPC microenvironment stiffens with age, and that this mechanical change is sufficient to cause age-related loss of function of OPCs. Using biological and synthetic scaffolds to mimic the stiffness of young brains, we find that isolated aged OPCs cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, the proliferation and differentiation rates of OPCs are increased. We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPC mechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS. We also show that PIEZO1 is important in regulating cell number during CNS development. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how the function of adult stem and progenitor cells changes with age. Our findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself.

Cholangiocarcinoma or biliary tract cancer has a high mortality rate resulting from late presentation and ineffective treatment strategy. Since immunotherapy by dendritic cells (DC) may be beneficial for cholangiocarcinoma treatment but their efficacy against cholangiocarcinoma was low. We suggest how such anti-tumor activity can be increased using cell lysates derived from an honokiol-treated cholangiocarcinoma cell line (KKU-213L5).

Post endoscopic retrograde cholangiopancreatography (ERCP) is comparatively complex application. Researchers has been investigated prevention of post-ERCP pancreatitis (PEP), since it has been considered to be the most common complication of ERCP. Although ERCP can lead various complications, it can also be avoided.AIMSTo study the published evidence and systematically review the literature on the prevention and treatment for PEP.

Abdominal aortic aneurysm (AAA) demonstrates many features of autoimmune diseases. Y chromosome, sex-determining region of the Y chromosome (SRY) gene, androgen receptor (AR) gene, and androgen appear as potential candidates for influence of the male immune function. This study investigated Y chromosome numbers, SRY gene, AR gene, and androgen levels in male AAAs. We also investigated the correlation between Y chromosome loss (LOY) ratio, SRY expression, androgen levels, and age.

Background: Vinpocetine (VPN) is a synthetic derivative of the Vinca minor alkaloids. The drug is characterized by a short half-life, limited water solubility and high hepatic first-pass effect. The objective was to develop different lipid-based nanocarriers (NCs) loaded into a thermosensitive in situ gelling (ISG) system to improve VPN bioavailability and brain targeting via intranasal (IN) delivery. Methods:  Different lipid-based NCs were developed and characterized for vesicle size, zeta potential, VPN entrapment efficiency (EE) and morphological characterization using transmission electron microscope (TEM). The prepared NCs were loaded into ISG formulations and characterized for their mucoadhesive properties. Ex-vivo permeation and histological study of the nasal mucosa were conducted. Pharmacokinetic and brain tissue distribution were investigated and compared to a marketed VPN product following administration of a single dose to rats. Results: VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. VPN-D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) micelles nano-formulation showed the smallest particle size, highest EE among the studied NCs. TEM images revealed an almost spherical shape for all the prepared NCs. Among the NCs studied, VPN-loaded TPGS micelles demonstrated the highest percent cumulative VPN ex vivo permeation. All the prepared ISG formulations revealed the presence of mucoadhesive properties and showed no signs of inflammation or necrosis upon histological examination. Rats administered IN VPN-loaded TPGS-micelles ISG showed superior VPN concentration in the brain tissue and significant high relative bioavailability when compared to that received raw VPN-loaded ISG and marketed drug oral tablets. Conclusion: VPN-loaded TPGS-micelles ISG formulation is a successful brain drug delivery system with enhanced bioavailability for drugs with poor bioavailability and those that are frequently administered.

Exosomes are natural nanovesicles with unique characteristics, such as long circulating half-life, the intrinsic ability to target tissues, biocompatibility, and minimal or no inherent systemic toxicity. Mesenchymal stem cells produce large amounts of exosomes with regenerative properties and more stability in human plasma. TUBO breast cancer cell lines overexpress rat HER2/neu protein.

Background: AEG-1 has been proven to be tumor enhancer in gastric cancer. However, its mechanism has not yet been fully clarified. Methods: Gain-of-function and loss-of-function experiments were conducted to determine the role of eIF4E in AEG-1-induced growth of gastric cancer cells and xenografts of a nude mouse model. Western blot analysis and SRB assay were used to determine the protein expression levels and survival cell numbers. Results: Silencing the expression of AEG-1 inhibited the growth of gastric cancer cells in parallel with a decreased eIF4E and cyclin D1 expression; however, the overexpression of AEG-1 promoted cell growth and increased eIF4E and cyclin D1 expression. Moreover, the overexpression of eIF4E partially reversed the AEG-1 silencing-induced reduction of cyclin D1 and the inhibition of cell growth. An eIF4E knockdown also partially reversed the AEG-1 overexpression-induced upregulation of cyclin D1 and cell growth. Notably, manipulating the expression of eIF4E did not affect the expression of AEG-1. Finally, the silencing of AEG-1 expression inhibited the growth of SGC-7901 xenografts in parallel with the downregulation of eIF4E and cyclin D1 expression in the nude mouse model. Conclusion: AEG-1 promoted the growth of gastric cancer through upregulation of eIF4E/cyclin D1 signaling pathway.

Background: We previously demonstrated that liver resection triggers estradiol production, which, in turn, induces the proliferation of hepatocytes to promote liver regeneration in mice. In this study, we demonstrated estradiol-induced estrogen receptor alpha (ERα) expression. Methods: To further explore the role of ERα in estradiol-mediated liver regeneration, in the present study, we confirmed impaired liver regeneration ability in ERα knockout mice. Results: Further analysis during liver regeneration revealed a role for ERα in hepatic steatosis, tumor necrosis factor-alpha and interleukin 6 expression, and nuclear factor-κB and signal transducer and activator of transcription 3 DNA-binding activities. Conclusion: Moreover, estradiol administration accelerated liver regeneration through ERα, indicating the feasibility of the estrogen-ERα axis as a target for accelerating the rate of liver regeneration.

Background: The primary objective of this systematic review was to identify the characteristics of physicians who prescribe opioids to adults with chronic pain. This review was limited to studies examining fully-trained physicians, as relevant characteristics of resident physicians and non-physician clinicians may differ. Methods: A comprehensive search of databases from January 1, 1980 to December 5, 2017 was conducted. Eligible study designs included (1) randomized trials; (2) nonrandomized prospective and retrospective studies; and (3) cross-sectional observational studies. The risk of bias in the included studies was assessed using an adapted version of the Newcastle-Ottawa Scale for cross-sectional studies. A total of 2508 records were screened and 22 studies met inclusion criteria. The majority of studies were cross-sectional (n=20) and the total number of participants was 8433. Results: The risk of bias was high overall. The majority of physicians were confident managing and prescribing opioids for chronic pain but had high levels of dissatisfaction. Physicians reported high awareness of the potential for opioid misuse and were concerned about inadequate prior training in pain management. The majority of physicians were less likely to prescribe for patients with a history of substance abuse and reported major concerns about regulatory scrutiny. Conclusion: This systematic review provides the foundation for the development of prospective studies aimed at further elucidating the constellation of mechanisms that influence physicians who manage pain and prescribe opioids.

Quadratus lumborum block (QLB) is shown to be effective on analgesia following cesarean section. This study aimed to compare the effects of three practical QLB approaches and classic epidural analgesia (EA) for cesarean section under spinal anesthesia.

Thymic epithelial tumors (TETs) belong to orphan oncology. The incidence of TETs is about 1.3-3.2 cases per million worldwide. Following pathology, evolution and prognosis are variable. The World Health Organization classification distinguishes thymomas and thymic carcinomas. TETs are composed of thymic epithelial tumoral cells and normal lymphocytes. The mean age at diagnosis is 50-60 years-old. There are no identified risk factors. TETs are frequently associated with paraneoplastic syndromes as myasthenia gravis. The complete R0 surgical resection is the most significant prognosis factor on survival. In 2010, the French National Institute of Cancer labeled the RYTHMIC network as a specific tumor board including thoracic surgeons, oncologist, and radiation therapist to define standard of care for the management of TETs. The aim of the review was to update knowledge to optimize the standard of care.

The intergenerational transmission of posttraumatic stress disorder (PTSD) from parent to offspring has been suggested in the literature, but this is highly controversial. We aimed to study the association between veterans' war exposure and lifetime PTSD and the psychological characteristics of their respective offspring, 40 years after war-related trauma.

Globally, 10-20% of children and adolescents suffer from mental disorders, with half of all them starting by the age of 14 and three-quarters before the age of 25. In Nepal, 40% of the population is younger than 18 years of age, and as such there is a large proportion of the population that is at risk of developing a mental disorder. There has been a recent recognition of child and adolescent mental health problems in Nepal, although prior to this it had remained almost invisible on the health agenda. In response to growing concern, there is a need to conduct a review on children and adolescent mental health problems in Nepal.

Using RNA-seq, RT-qPCR, and bioinformatics we have studied the influence of a wide spectrum of chemotherapeutic drugs on transcription of AKR1B10, AKR1C1, ALDH1A1, and ALDH1A3 genes, which encode the major aldehyde-metabolizing enzymes. The strongest alterations were detected in case of AKR1B10 mRNA that was significantly upregulated in wild type p53 cancer cells, but downregulated in mutant p53 cancer cells. Subsequent experiments demonstrated the significant and consistent decrease in the AKR1B10 mRNA content in sera of colon cancer patients, as compared to sera of healthy donors (p<0.0001, SPE=92.9%, SNE=79.3%, AUC=0.889), which implies that this RNA is a valuable marker for serological diagnosis of colorectal cancer. Moreover, we have found that ALDH1A3 protein is a key inactivator of ROS-generated aldehydes, which is a perspective target for the development of new chemotherapeutic drugs.

Nuclear receptor binding protein 1 (NRBP1) is an evolutionarily highly conserved adaptor protein with multiple domains. Recently, its role in cancers has received increasing attention. To investigate whether NRBP1 is involved in the development of bladder cancer, we used tissue microarray and analyzed the association between the expression levels of NRBP1 and clinico-pathological features of 56 patients diagnosed with bladder cancer. Subsequently, NRBP1 was silenced using siRNA in bladder cancer cell lines T24 and 5637, and cell phenotype such as proliferation and apoptosis were observed. Further, in vivo tumor formation assay was performed. The expression of apoptosis markers was detected by Western blot. A significant positive correlation between increased NRBP1 expression and tumor stage, and lymph node metastasis was observed in 56 patients. High expression of NRBP1 was associated with poor prognosis and NRBP1 knockdown significantly inhibited cell proliferation and induced intrinsic apoptosis in vitro. Moreover, we also found that NRBP1 knockdown significantly suppress tumor growth in xenograft mouse model. Taken together, these data suggest that NRBP1 plays a critical role in the development of bladder cancer and may represent a potential target for bladder cancer treatment.

Objective: Growing evidence has proved that MRE11, a protein underpinned to be involved in DNA double-strand break (DSB) repair process, is correlated with cancer outcomes. However, its role in prostate cancer (PCa) remains unclear. This study aimed to investigate the expression of MRE11 in tumor tissue and defining its value in predicting prognosis of PCa patients. Methods: A total of 578 patients from two cohorts were enrolled in this study. Distribution of categorical clinical-pathological data together with levels of MRE11 expression was compared with χ2-test in a contingency table. Immunohistochemical (IHC) staining and evaluation was detected from 78 paired PCa and adjacent normal tissues. Partial likelihood test from univariate and multivariate Cox regression analysis was developed to address the influence of independent factors on disease-free survival (DFS) and overall survival (OS) in two cohorts. The Kaplan-Meier method and log-rank test were performed to assess the survival benefits between discrete levels. Set Enrichment Analysis (GSEA) was performed to select related genes and pathways from The Cancer Genome Atlas (TCGA) database. Results: In the current study, we demonstrated that MRE11 was highly expressed in PCa compared with normal tissues (P=0.011). In addition, in the TCGA cohort, the median DFS in patients with IHC positive and negative MRE11 expression levels was 24.5 and 30.6 months, and median OS was 28.7 and 33.0 months, respectively. In FUSCC cohort, median DFS in patients with IHC positive and negative MRE11 expression was 28.0 and 35.6 months. Furthermore, survival curves suggested that PCa patients with elevated MRE11 expression levels showed poorer OS (P=0.019) in TCGA cohort and poor DFS (P=0.047) in FUSCC cohort. Conclusion: In conclusion, our study reveals that elevated MRE11 expression is significantly correlated with cancer progression and poor survival in PCa patients. These data suggest that MRE11 may act as an oncoprotein and a promising prognostic marker for PCa patients.

S-Adenosylmethionine (SAMe) is a kind of common liver-protection medicine. Recent studies have shown that SAMe has the inhibitory effects on hepatocellular carcinoma (HCC). But the specific mechanism has not been elucidated. Here, we examine the effects and relevant mechanisms of SAMe on human hepatocellular carcinoma cell HepG2 and mouse hepatocyte AML12. We applied the technique of RNA sequencing (RNA-Seq) to identify the differentially expressed genes between HepG2 cells which were treated with SAMe or not. And western blot and Quantitative RT-PCR was used to confirm some of these genes. To investigate the response to SAMe treatment, cell proliferation assay (MTS) and flow cytometry-based assays were carried out. A total of 472 SAMe-related genes were identified by RNA-Seq. We found that differentially expressed genes were enriched in cell cycle related signaling pathway significantly by the KEGG and GO Pathway enrichment analysis. Through the construction of protein-protein interaction network, we observed the module associated with cell cycle is in the core of the whole network. All these results implied that cell cycle pathway may be very important in the regulation of SAMe effected on HepG2 cells. Then the RNA-Seq-characterized genes involved in cell cycle (MCM3, MCM4, and E2F1) were confirmed by Western blot and Quantitative RT-PCR in HepG2 and AML12 cells. MTS analysis showed that SAMe could diminish cell proliferation. And flow cytometry-based assays indicated that treatment with SAMe altered cell cycle kinetic S phase cell cycle arrest. Altogether, our data uncovered the evidence of the antiproliferative action of SAMe in liver cells, and SAMe could lead to cell cycle inhibition by up-regulating MCM3, MCM4 and E2F1 expression. It provided an important theoretical basis for the clinical chemoprevention and treatment in HCC of SAMe.

Objective: Whether age affects lymph node metastasis (LNM) in patients with gastric cancer (GC) is currently inconclusive. This study investigates the effect of age on LNM in patients with GC. Methods: From January 1988 to December 2013, 22,808 GC patients underwent gastrectomy at the Surveillance, Epidemiology, and End Results database were included. The relationship between age and LNM was analyzed. Results: The median number of examined lymph nodes (ELNs) was 12 (interquartile range [IQR], 7-20) among the 22,808 patients with GC, and the median numbers of ELNs were 10 (IQR, 5-18), 12 (IQR, 6-19), 13 (IQR, 7-21) and 13 (IQR, 7-21) in patients with T1 to T4 disease, respectively. A total of 13,780 (60.4%) patients presented with LNM. The LNM rates were 69.6%, 66.1%, 64.7%, 61.8%, 57.8% and 55.6% for patients in the 20-39, 40-49, 50-59, 60-69, 70-79 and ≥ 80 age groups, respectively (P < 0.001). The LNM rates and the number of positive lymph nodes were correlated with age among patients whose diseases were of the same T stage (all P < 0.01). Multivariate analysis showed that age was an independent predictor for LNM in patients with early gastric cancer (EGC) (P < 0.05), and linear regression analysis showed that the LNM rate was higher in young patients with EGC (P < 0.05). Conclusions: Age is an independent predictor for LNM in EGC. Moreover, LNM is more common in young patients with EGC than in other age groups, which indicates that limited lymph node dissection may not be appropriate for young patients with EGC.

Chronic obstructive pulmonary disease (COPD) is a common and preventable illness that carries significant economic and social burden. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) provides a comprehensive review of the available literature for the diagnosis and management of COPD. Despite being considered the standard of care, adherence to the GOLD guidelines varies among practitioners. In addition, there is yet to be a clear correlation between misalignment with GOLD practicing guidelines and patient outcomes. We studied the outpatient management of COPD, with special attention paid to whether or not adherence to the 2017 GOLD guidelines affected patient outcomes.