Transmembrane protein 176B regulates amino acid metabolism through the PI3K-Akt-mTOR signaling pathway and promotes gastric cancer progression.

BACKGROUND: The present study aimed to investigate the expression level, biological function, and underlying mechanism of transmembrane protein 176B (TMEM176B) in gastric cancer (GC). METHODS: TMEM176B expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). The function of TMEM176B was determined by various in vitro assays including colony formation, 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and flow cytometry. Bioinformatics techniques were then used to elucidate the signaling pathways associated with TMEM176B activity. Tumor formation experiments were conducted on nude mice for in vivo validation of the preceding findings. TMEM176B expression was cross-referenced to clinicopathological parameters and survival outcomes. RESULTS: It was observed that TMEM176B was overexpressed in GC cells and tissues. Targeted TMEM176B abrogation inhibited colony formation, proliferation, migration, and invasion but promoted apoptosis in GC cell lines while TMEM176B overexpression had the opposite effects. Subsequent experimental validation disclosed an association between TMEM176B and the phosphatidylinositol 3-carboxykinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling axis. Moreover, TMEM176B affects GC cancer progression by regulating asparagine synthetase (ASNS). The in vivo assays confirmed that TMEM176B is oncogenic and the clinical data revealed a connection between TMEM176B expression and the clinicopathological determinants of GC. CONCLUSION: The foregoing results suggest that TMEM176B significantly promotes the development of gastric cancer and is an independent prognostic factor of it.

The correlation between NEDD4L and HIF-1α levels as a gastric cancer prognostic marker.

NEDD4L (neural precursor cell expressed developmentally down-regulated 4-like) protein is a member of ubiquitin ligases Nedd4 family. Although studies have shown that Nedd4L may act as a tumor suppressor in various cancers, including gastric cancer (GC), its clinical significance and the diagnostic value in GC is not well defined. HIF-1α (hypoxia inducible factor family of transcription factors) is actively involved in the metabolism of many tumors, although the relationship between its expression levels and clinical significance in GC still need to be established. In this study, the level of HIF-1α and NEDD4L mRNA and protein in 25 freshly frozen GC- and matched normal-tissues were determined by western blot and quantitative PCR (qPCR). Additionally, immunohistochemistry assay was performed to measure the protein level of NEDD4L and HIF-1α in 124 GC and 25 normal control tissues. We observed that the NEDD4L mRNA and protein levels decreased significantly (P < 0.001) in GC tissues, while that of HIF-1α increased (P < 0.001), and they both were associated with a poor prognosis, as was the case in patients with lower NEDD4L and higher HIF-1α expression (P < 0.001). On correlation analysis, a significantly negative relationship (r = 0.288, P < 0.01) was revealed between NEDD4L and HIF-1α expressions. Multivariate analysis revealed that co-expression of NEDD4L (P < 0.05) and HIF-1α (P < 0.001) were independent predictors of GC prognosis. Thus, the correlation of NEDD4L and HIF-1α levels may act as a prognostic marker of GC.

Robotic total gastrectomy with π-shaped esophagojejunostomy using a linear stapler as a novel technique.

OBJECTIVE: To evaluate the intraoperative and short-term postoperative outcomes of a novel robotic intracorporeal π-shaped esophagojejunostomy (EJS) after D2 total gastrectomy (TG) using the Da Vinci robotic surgical system for intracorporeal anastomosis after TG. BACKGROUND: Intracorporeal π-shaped EJS, using a linear stapler, was recently reported for laparoscopic total gastrectomy in patients with gastric cancer. However, robotic intracorporeal π-shaped EJS using a linear stapler has not been reported. This report aimed to describe the use of a novel technique for π-shaped EJS using the Da Vinci robotic system. METHODS: Robotic intracorporeal π-shaped esophagojejunostomy after total gastrectomy was performed in 11 consecutive patients diagnosed with early gastric cancer, and their perioperative outcomes were analyzed. RESULTS: All the operations were successful without conversion to open or laparoscopic surgery and postoperative complications. The total number of patients was 11 (7 males and 4 females). The mean age of the patients was 63.36 ± 10.56 years old. Seven patients were diagnosed with cardia cancer, 3 patients were diagnosed with gastric body cancer, and 1 patient was diagnosed with gastric antrum cancer. The patients' mean proximal resection margin was 3.18 ± 1.17 cm, the distal resection margin was 6.18 ± 1.40 cm, the mean length of the incision was 4.55 ± 0.69 cm, the mean operative time was 287.27 ± 30.69 min, the mean day of first flatus was 3.27 ± 0.79 days, the mean day of the start of diet was 2.91 ± 0.94 days, the mean postoperative hospital stay was 11.45 ± 5.13 days, and the mean operative blood loss was 47.27 ± 31.33 ml. No complications were observed during anastomosis, and the median anastomosis time was 19.5 min. The mean number of lymph node dissections was 17.91 ± 4.59, the mean number of positive lymph nodes was 0.45 ± 0.69, all patients were diagnosed with stage I-II gastric cancer, and the mean maximum diameter of the tumor was 2.67 ± 1.30 cm. All the patients had a smooth hospital discharge. CONCLUSION: A novel robotic gastrectomy with intracorporeal π-shaped EJS for esophagojejunal anastomosis described and shows acceptable resulted. This technique has the potential to offer better short-term surgical outcomes and overcomes the drawbacks of laparoscopy with a decreased risk of complications during and after surgery.

miR-140-5p suppresses the proliferation, migration and invasion of gastric cancer by regulating YES1.

BACKGROUND: The aberrant expression of microRNA-140-5p (miR-140-5p) has been described in gastric cancer (GC). However, the role of miR-140-5p in GC remains unclear. In this study, the prognostic relevance of miR-140-5p in GC was investigated and YES1 was identified as a novel target of miR-140-5p in regulating tumor progression. METHODS: miR-140-5p level was determined in 20 paired frozen specimens through quantitative real-time PCR, and analyzed in tissue microarrays through in situ hybridization. The target of miR-140-5p was verified through a dual luciferase reporter assay, and the effects of miR-140-5p on phenotypic changes in GC cells were investigated in vitro and in vivo. RESULTS: Compared with that in adjacent normal tissues, miR-140-5p expression decreased in cancerous tissues. The downregulated miR-140-5p in 144 patients with GC was significantly correlated with the reduced overall survival of these patients. miR-140-5p could inhibit GC cell proliferation, migration and invasion by directly targeting 3'-untranlated region of YES1. miR-140-5p could also remarkably reduce the tumor size in GC xenograft mice. CONCLUSIONS: miR-140-5p serves as a potential prognostic factor in patients with GC, and miR-140-5p mediated YES1 inhibition is a novel mechanism behind the suppressive effects of miR-140-5p in GC.

Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating lncRNA AK022798 expression.

Gastric cancer is now the fourth most common malignancy and the second leading cause of death because of cancer. The resistance to anticancer drugs is the main cause of chemotherapy failure. In this study, we explored the role of Notch 1 and long noncoding RNA (lncRNA) in drug-resistant gastric cancer formation. First, we found that Notch 1 was highly expressed in the cisplatin-resistant gastric cancer cell lines SGC7901/DDP and BGC823/DDP cells. Then, we constructed a Notch 1 overexpression vector plasmid; after successful transfection, the SGC7901 and BGC823 cells highly expressed Notch 1. Moreover, the expression of multidrug resistance-associated protein 1 (MRP1), P-glycoprotein, increased significantly and the apoptosis of SGC7901 and BGC823 cells obviously reduced. We further screened out the lncRNA AK022798 involved in this process. Furthermore, we used siRNA to interfere with lncRNA AK022798 expression, and found that the expression of MRP1 and P-glycoprotein decreased significantly in SGC7901/DDP and BGC823/DDP cells, and their apoptosis as well as the expressions of caspase 3 and caspase 8 obviously increased. These results suggest that Notch 1 can promote the lncRNA AK022798 expression and result in the formation of SGC7901/DDP and BGC823/DDP cells. It may provide a new, useful method for gastric cancer chemotherapy.

Down regulation of Thrombospondin2 predicts poor prognosis in patients with gastric cancer.

BACKGROUND: Thrombospondins (THBSs) are a family of multidomain and secreted matricellular Ca(2+)-binding glycoproteins which has at least five members encoded by independent genes. As a THBSs family member, Thrombospondin2 (THBS2) has been reported to regulate angiogenesis. Nevertheless, the functions and clinical significance of THBS2 still remains unclear in gastric cancer. METHODS: The mRNA and protein expression levels of THBS2 were assessed in 14 paired of gastric cancer specimens and corresponding normal mucosas using quantitative real-time PCR and western blot analysis. Immunohistochemistry of THBS2 and CD34 on population-based tissue microarrays consisting of 129 gastric cancer cases were used to evaluate the prognostic significance of THBS2 and microvessel density (MVD) of each sample. Survival analyses were performed by Kaplan-Meier method and Cox's proportional hazards model. Colony formation assay, endothelial cell tube formation assay, cell migration assay and apoptosis analysis in MKN-45 and SGC-7901 cell lines were carried out to evaluate the effects of THBS2 on gastric cancer in vitro. RESULTS: 85.71% (12 of 14) gastric cancer tissues expressed remarkably lower THBS2 in both mRNA and protein levels than the corresponding normal controls. Consistently, tissue microarray (TMA) results showed THBS2 levels were also inhibited in gastric cancer tissues compared with the normal controls. Moreover, we observed that patients with higher levels of THBS2 were significantly correlated with more favourable prognosis while decreased THBS2 expression were associated with poorer histological grades of gastric cancer. Additionally, our in vitro experiments further demonstrated that overexpression of THBS2 could impede both the proliferation rate and the tube formation of Human umbilical vein endothelial cells (HUVECs) in MKN-45 and SGC-7901 cell lines. CONCLUSION: Our study suggests THBS2 is aberrantly expressed in gastric cancer and plays a critical role in cancer progression, which can be a potential prognosis predictor of gastric cancer.

Tousled-like kinase 1 promotes gastric cancer progression by regulating the tumor growth factor-beta signaling pathway.

BACKGROUND: The role of Tousled-like kinase 1 (TLK1) in in gastric cancer (GC) remains unclear. AIM: To investigate the expression, biological function, and underlying mechanisms of TLK1 in GC. METHODS: We measured TLK1 protein expression levels and localized TLK1 in GC cells and tissues by western blot and immunofluorescence, respectively. We transfected various GC cells with lentiviruses to create TLK1 overexpression and knockdown lines and established the functional roles of TLK1 through in vitro colony formation, 5-ethynyl-2`-deoxyuridine, and Transwell assays as well as flow cytometry. We applied bioinformatics to elucidate the signaling pathways associated with TLK1. We performed in vivo validation of TLK1 functions by inducing subcutaneous xenograft tumors in nude mice. RESULTS: TLK1 was significantly upregulated in GC cells and tissues compared to their normal counterparts and was localized mainly to the nucleus. TLK1 knockdown significantly decreased colony formation, proliferation, invasion, and migration but increased apoptosis in GC cells. TLK1 overexpression had the opposite effects. Bioinformatics revealed, and subsequent experiments verified, that the tumor growth factor-beta signaling pathway was implicated in TLK1-mediated GC progression. The in vivo assays confirmed that TLK1 promotes tumorigenesis in GC. CONCLUSION: The findings of the present study indicated that TLK1 plays a crucial role in GC progression and is, therefore, promising as a therapeutic target against this disease.

Targeting TLK2 inhibits the progression of gastric cancer by reprogramming amino acid metabolism through the mTOR/ASNS axis.

Several recent studies have suggested that TLKs are related to tumor progression. However, the function and mechanism of action of TLK2 in gastric cancer (GC) remain elusive. In this study, TLK2 was found to be significantly upregulated in patients with GC and was identified as an independent prognostic factor for GC. Consistently, TLK2 knockdown markedly reduced the aggressiveness of GC, whereas its overexpression had the opposite effect. IP-MS revealed that the effects of TLK2 on GC were mainly associated with metabolism reprogramming. TLK2 knockdown suppressed amino acid synthesis by downregulating the mTORC1 pathway and ASNS expression in GC cells. Mechanistically, mTORC1 directly interacts with the ASNS protein and inhibits its degradation. Further experiments validated that the ASNS protein was degraded via ubiquitination instead of autophagy. Inhibiting and activating the mTORC1 pathway can upregulate and downregulate ASNS ubiquitination, respectively, and the mTORC1 pathway can reverse the regulatory effects of TLK2 on ASNS. Furthermore, TLK2 was found to regulate the mRNA expression of ASNS. TLK2 directly interacted with ATF4, a transcription factor of ASNS, and promoted its expression. The kinase inhibitor fostamatinib significantly inhibited the proliferative, invasive, and migratory capabilities of GC cells by inhibiting TLK2 activity. Altogether, this study reveals a novel functional relationship between TLK2 and the mTORC1/ASNS axis in GC. Therefore, TLK2 may serve as a potential therapeutic target for GC.

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and tumor microenvironment, overcoming multiple obstacles of CAR T therapy for solid tumors.

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumor is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach massively reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquired early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogrammed and reversed immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells (PBMC) of healthy or metastatic breast cancer patients, induced robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a novel therapy for solid tumor.

Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment.

The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.

Hypoxia Inducible Factor-1alpha (HIF-1A) plays different roles in Gallbladder Cancer and Normal Gallbladder Tissues.

Purpose: Hypoxia-inducible factor-1alpha (HIF-1A) is a transcription factor that plays an "angiogenic switch" role especially under hypoxia microenvironment in solid tumor. However, the functions and clinical significance of HIF-1A in gallbladder cancer (GBC) are still controversial, and it has not been studied in normal gallbladder tissues. In this study, we sought to clarify the role of sub-cellular localization of HIF-1A expression in GBC and normal gallbladder tissues. Methods: The expressions of HIF-1A and CD34 in 127 GBC and 47 normal gallbladder tissues were evaluated by immunohistochemistry. Cox's proportional hazards model analysis and Kaplan-Meier method analysis were used to assess the correlations between these factors and clinicopathological features and prognosis. Results: HIF-1A was expressed in both cytoplasm and nucleus of GBC and normal control tissues, and was significantly correlated with microvessel density (MVD). GBC tissues with positive nuclear HIF-1A expression had higher MVD compared to that with positive cytoplasmic HIF-1A expression; however, in normal gallbladder tissues, samples with positive cytoplasmic HIF-1A had higher MVD compared to that with positive nuclear HIF-1A expression. Moreover, GBC with nuclear HIF-1A expression tended to be more poorly differentiated and had larger tumor size compared to that with cytoplasm HIF-1A expression. Furthermore, GBC patients with nuclear HIF-1A positive were significantly correlated with worse overall survival (OS) compared with cytoplasmic HIF-1A positive. Multivariate Cox regression analysis identified lymph node metastasis and nuclear HIF-1A expression to be independent prognostic parameter in GBC. Conclusions: Our findings provide evidence for the first time that HIF-1A is expressed in normal gallbladder tissues. Nuclear HIF-1A and cytoplasm HIF-1A plays different roles in GBC and normal gallbladder tissues.

A novel method for π-shaped esophagojejunostomy and double-tract reconstruction (DTR) as an alternative in totally laparoscopic or robotic proximal gastrectomy for treating upper third proximal early gastric cancer.

This study evaluated the impact of a new intracorporeal π-shaped esophagojejunostomy (EJS) and double-tract reconstruction (DTR) in totally laparoscopic and totally robotic proximal gastrectomy (TLPG or TRPG) for treating upper third early gastric cancer (U-EGC) in terms of intraoperative and short-term postoperative outcomes. Early proximal gastric cancer patients were identified based on a prospectively established database. From January 2017 to December 2018, these patients underwent intracorporeal π-shaped EJS and DTR after totally laparoscopic (n = 8) or robotic (n = 4) proximal gastrectomy (PG). We recorded and analyzed the baseline characteristics and surgical outcomes, including postoperative complications for these patients. No severe postoperative complications were observed following the operational procedures. Twelve patients (seven male and five female) diagnosed with cardia cancer (Siewert II and III) were enrolled, of which eight underwent the totally laparoscopic proximal gastrectomy (TLPG), and four underwent the totally robotic proximal gastrectomy (TRPG). The mean operative time, blood loss, day of the start of the diet, and postoperative hospital stay was 235.54 ± 20.79 min, 50.65 ± 35.44 mL, 3.85 ± 0.65 days, and 12.45 ± 3.24 days, respectively. All patients presented with a diagnosis of stage I gastric cancer. The mean number of lymph node dissections and the maximum tumor diameter was 13.91 ± 4.63 and 2.18 ± 0.73 cm, respectively. After the operational procedure, using the iodoethylene contrast reagent, we observed that a large proportion of iodoethylene contrast agents entered the jejunum directly, and a small proportion entered the jejunum through the duodenum. Surgeons followed up with ten patients for more than 12 months and the remaining two patients for more than 24 months. None of the patients showed any signs of anastomotic stenosis or reflux esophagitis or anemia symptoms. This study presents a novel method for π-shaped EJS and DTR as an alternative in TLPG or TRPG for treating proximal early gastric cancer, and it offers better short-term postoperative and intraoperative surgical outcomes.

Targeting Radiation-Resistant Prostate Cancer Stem Cells by B7-H3 CAR T Cells.

Radiotherapy (RT) is a key treatment for prostate cancer. However, RT resistance can contribute to treatment failure. Prostate cancer stem cells (PCSCs) are radioresistant. We recently found that fractionated irradiation (FIR) upregulates expression of the immune checkpoint B7-H3 (CD276) on PCSCs and bulk cells in each prostate cancer cell line tested. These findings prompted us to investigate whether B7-H3 targeting chimeric antigen receptor (CAR) T cells, which may abrogate function of an immune checkpoint and mediate lysis of targeted cells, can target RT-resistant PCSCs in vitro and in vivo. B7-H3 expression is naturally higher on PCSCs than bulk prostate cancer cells and cytotoxicity of B7-H3 CAR T cells to PCSCs is more potent than to bulk prostate cancer cells. Furthermore, FIR significantly upregulates B7-H3 expression on PCSCs and bulk prostate cancer cells. The duration of FIR or single-dose irradiation-induced further upregulation of B7-H3 on bulk prostate cancer cells and PCSCs lasts for up to 3 days. B7-H3 CAR T-cell cytotoxicity against FIR-resistant PCSCs at a low effector to target ratio of 1:1 was assessed by flow cytometry and sphere formation assays. Further upregulation of B7-H3 expression by FIR made PCSCs even more sensitive to B7-H3 CAR T-cell-mediated killing. Consequently, the FIR and B7-H3 CAR T-cell therapy combination is much more effective than FIR or CAR T cells alone in growth inhibition of hormone-insensitive prostate cancer xenografts in immunodeficient mice. Our work provides a sound basis for further development of this unique combinatorial model of RT and B7-H3 CAR T-cell therapy for prostate cancer. SIGNIFICANCE: We demonstrate that FIR significantly upregulates B7-H3 expression by RT-resistant PCSCs and bulk cells; cytotoxicity of B7-H3 CAR T cells to FIR-treated PCSCs is potent and results in significantly improved antitumor efficacy in mice.

Increased expression of RBMS3 predicts a favorable prognosis in human gallbladder carcinoma.

Multiple regions in the short arm of chromosome 3 are frequently deleted in a variety of solid tumors including gallbladder carcinoma (GBC). RNA binding motif, single­stranded interacting protein 3 (RBMS3), a tumor suppressor gene (TSG), is located in this region. However, the role of RBMS3 in GBC remains unclear. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and western blotting were performed to evaluate the mRNA and protein expression levels of RBMS3 in 41 fresh frozen GBC tissues and paired normal tissues. An immunohistochemical assay was performed on a tissue microarray (TMA, consisting of 125 cases GBC and 47 normal controls). Microvessel density (MVD) counts were determined using CD34 immunohistochemical staining. Moreover, univariate and multivariate analyses were performed to determine the correlations between RBMS3 expression, MVD and patient prognosis. Cellular functions including proliferation, clonogenicity and apoptosis, were assessed to further identify in vitro roles of RBMS3. It was revealed that both mRNA and protein expression levels of RBMS3 were significantly lower in GBC tissues than in normal controls. Multivariate Cox regression analyses demonstrated cytoplasmic RBMS3 expression as an independent prognostic factor correlated with GBC angiogenesis, histopathological differentiation and TNM stage. Kaplan­Meier curves revealed that patients with lower cytoplasmic RBMS3 levels had a significantly worse OS than patients with higher cytoplasmic RBMS3 expression. Additionally, ectopic expression of RBMS3 markedly suppressed GBC cell proliferation and clonogenicity and promoted apoptosis in vitro. These findings indicated the potential of cytoplasmic RBMS3 as a tumor prognostic biomarker and a promising therapeutic target for GBC.

The relationship between psychological health and social support: Evidence from physicians in China.

BACKGROUND: The psychological health (PH) of doctors affects the quality of medical service and is related to the safety of patients. The serious problems with the doctor-patient relationship in China can lead to long-term imbalances in doctor PH, and the poor PH status of doctors has raised scholars' concern. Current research mainly focuses on how factors such as social support and the impact of the residential environment correlate with individual PH. We continue this direction of research to see how the mechanism of social support impacts physician PH, also investigating the moderating effect of demographic indicators on physician PH. METHODS: Based on a survey of 399 physicians, a descriptive analysis of measured data was done using SPSS 19.0. Pearson correlation coefficient analysis was used to examine the correlations between PH and the social support rating scale (SSRS) and the demographic variables. KMO and Bartlett methods were used to examine the correlations between PH and SDS (a scale to measure depression) and between PH and SAS (a scale to measure anxiety). The method of factor analysis was used for multicollinearity tests, and multiple stepwise regression analysis was used to explore the demographic factors correlated with PH and SSRS. Two-way interactions in moderated multiple regression were used to test the moderating effect of education level and title on SSRS, SDS, and SAS. RESULTS: Our results indicate that the level of PH is influenced by the age, education, and title of a doctor. A physician's title is significantly and positively correlated with PH, but age and education are significantly negatively related. Age, education, and title also affect the level of SSRS in physicians. SSRS is positively correlated with age, education, and title, and SSRS positively influences PH. Education and title had significant effects on the moderating influences of SSRS, SDS, SAS, and PH. CONCLUSION: The factors directly affecting PH include SSRS, age, and title, while education was found to be an indirect influencing factor. To meet goals expressed in Chinese government policy related to these issues, we suggest strengthening the guidance of the media, introducing laws and regulations on doctor-patient risk management and control, reforming the review mechanism of hospital job titles, improving the education level of doctors, building a comprehensive evaluation system of "practice performance + doctor-patient satisfaction", and strengthening doctor-patient empathy. Through such measures, the level of PH in physicians will improve.

NDRG3 facilitates colorectal cancer metastasis through activating Src phosphorylation.

BACKGROUND: NDRG3 is an N-myc downregulated gene (NDRG). The aim of this article was to identify the role of NDRG3 in colorectal cancer (CRC) and to determine the mechanism underlying its function. METHODS: Using immunohistochemical staining, expression and clinicopathological variables of NDRG3 were analyzed in 170 CRC samples. Overexpression of NDRG3 was employed in SW1116 cells, downregulation of NDRG3 was achieved in RKO cells, then migration and invasion assays were performed in vitro, and a mouse model was constructed in vivo. RESULTS: Increased expression of NDRG3 was observed in primary CRC tissues, and this expression was correlated with distant metastasis. Consistently, ectopic expression of NDRG3 in SW1116 cells enhanced cell migration and invasion, while knockdown of NDRG3 in RKO cells significantly suppressed CRC cell metastasis. The portal vein injection models suggested that NDRG3 overexpression facilitates liver metastasis. These events were associated with the phosphorylation of Src (c-Src) at Tyr 419 site. CONCLUSION: Our results showed that NDRG3 facilitates CRC migration and invasion by activating Src phosphorylation, suggesting the role of NDRG3 as a candidate oncogene.

Exploring the influence of resiliency on physician trust in patients: An empirical study of Chinese incidents.

BACKGROUND: The tension in doctor-patient relationships is becoming progressively greater due to the high expectations of patients and the physicians' work pressure. Recent studies have addressed factors which affect the tension of doctor-patient relationships, and our study continues this trend by looking at the influence of resiliency and physician trust in the patient (PTP), that is, how much the doctor trusts the patient. METHODS: Based on a survey of 329 physicians, a descriptive analysis of measured data was done using SPSS 19.0. Pearson correlation coefficient analysis was used to examine the correlation between PTP and resilience and the demographic variables. KMO and Bartlett methods were used to examine the correlation between PTPS and resilience. The method of factor analysis was used for multicollinearity tests, and multiple stepwise regression analysis was used to explore the demographic factors correlated with PTP and resilience. RESULT: Our results indicate that the level of PTP is influenced by the age, education, and income of the doctors. Physician age and income are significantly and positively correlated with PTP, but education is significantly and negatively related. Age, education, and income also affect the level of psychological resilience of physicians. Resilience is positively correlated with age and education but is negatively related to income. Resilience positively influences PTP. CONCLUSION: The direct factors of PTP include resilience, age, education, and income, while gender, title, and hospital department were found to be indirect influencing factors. To meet goals expressed in Chinese government policy related to these issues, we suggest improving the level of education of the doctors, providing reasonable annual salary increases for doctors, easing the tensions involved in medical treatment, reducing the physicians' work pressure, improving the physicians' work environment, and enhancing the physicians' professional sympathy. Through such measures, the level of PTP will be enhanced.

Upregulation of KIF20A correlates with poor prognosis in gastric cancer.

BACKGROUND: KIF20A is well known as one of the key proteins in mitosis. Recently, a number of studies illustrated that KIF20A might function as an oncogene in some carcinomas. However, its expression levels and clinical value remained unclear in gastric cancer (GC). PATIENTS AND METHODS: In this study, we investigated the expression of KIF20A in samples from GC patients and cell lines by quantitative real-time PCR and Western blot. The function of KIF20A in cell proliferation of GC cell lines was examined via cell viability and colony formation assays. Immunohistochemistry assay based on a tissue microarray consisting of 146 cases was performed to evaluate the prognostic value of KIF20A. The overall survival rate of 122 GC patients based on KIF20A expression was analyzed as well. Finally, using KIF20A inhibitor, genistein, and combining it with cisplatin or fluorouracil, the antitumor effects were studied. RESULTS: Most GC samples (56.76%) showed higher KIF20A expression level compared to their corresponding normal specimens, which demonstrated the potential oncogenic role of KIF20A in GC. The functional studies elucidated the essential role of KIF20A in GC cell proliferation. Besides, tissue microarray result showed that the expression level of KIF20A was significantly related to the histological grades (P=0.036). Furthermore, we found the expression of KIF20A was related to poor overall survival rate, which is coincident with the results from Kaplan-Meier plotter database. In addition, we found that a KIF20A inhibitor, genistein, could enhance the antitumor activity of cisplatin and fluorouracil, which might be considered as a chemosensitive agent in GC. CONCLUSION: KIF20A can promote cell proliferation in GC, which might be used as an independent prognostic factor and a potential therapeutic target.

Down regulation of RNA binding motif, single-stranded interacting protein 3, along with up regulation of nuclear HIF1A correlates with poor prognosis in patients with gastric cancer.

Frequent loss of multiple regions in short arm of chromosome 3 is found in various tumors including gastric cancer (GC). RNA binding motif, single-stranded interacting protein 3 (RBMS3) is a tumor suppressor gene located in this region and mediates cancer angiogenesis. However, the role of RBMS3 in GC remains unclear.To evaluate whether RBMS3, together with HIF1A, another key regulator of angiogenesis, predicts GC prognosis, the levels of RBMS3 and HIF1A were first examined by quantitative PCR (qPCR) and western blot from 27 fresh frozen GC and paired normal gastric tissues and then tested by immunohistochemistry (IHC) from 191 GC and 46 normal controls. Moreover, uni- and multivariate analysis were employed to assess the correlations between their levels and microvessel density (MVD) and clinical prognosis. To further identify RBMS3 function in vitro, cell proliferation assay, clonogenic assay, flow cytometry analysis and endothelial cell tube formation assay were employed.We found that RBMS3 level was decreased, whereas HIF1A was elevated in GC. Furthermore, we demonstrated that RBMS3 was an independent prognostic factor and the levels of RBMS3 and HIF1A were associated with GC angiogenesis and histopathological differentiation: patients with lower RBMS3 level and higher nuclear HIF1A expression had poorer prognosis. Besides, gain- and loss-of-function study revealed RBMS3 regulation on G1/S progression, cell proliferation and the tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. These findings implicated that RBMS3 and nuclear HIF1A could act as prognostic biomarkers and therapeutic targets for GC.

[Expression of KIF18A in gastric cancer and its association with prognosis].

OBJECTIVE: To explore the expression of KIF18A gene protein in gastric cancer tissues and its association with the prognosis of patients. METHODS: Twenty fresh paired gastric cancer specimens and adjacent normal mucosa(at least 5 cm from the edge of tumor) from 20 gastric cancer patients undergoing operation in Department of General Surgery at the First Affiliated Hosptial of Anhui Medical University between March 2015 and July 2015 were collected. Real-time PCR was used to examine KIF18A mRNA expression in above specimens. Meanwhile, paraffin embedded cancer tissue samples from 129 gastric cancer patients undergoing operation and 23 samples of randomly selected normal gastric tissue(adjacent non-cancer tissue) were collected to establish the microarray. Immunohistochemistry method was applied to detect the KIF18A protein expression in the microarray after confirmation by pathologists. Association of KIF18A expression with clinicopathological features in gastric cancer patients was evaluated. Cox proportional hazard model was used to identify prognostic risk factors. RESULTS: Among 20 fresh paired gastric cancer specimens, mRNA expression of KIF18A in 16 specimens was obviously lower than that in adjacent normal tissues. The positive rate of KIF18A protein expression in gastric cancer tissues was significantly lower than that in normal gastric tissues in microarray[45.0%(58/129) vs. 69.6%(16/23), P=0.041]. KIF18A protein expression was significantly associated with invasion depth (P=0.008) and TNM staging (P=0.032). The median overall survival of all the 129 patients was 44.0(95% CI: 39.78-49.24) months. The three-year survival rates of patients with high and low KIF18A expression were 67.2% and 36.6% respectively(P=0.020). Cox regression analysis showed that KIF18A expression was an independent protective factor of the prognosis of gastric cancer patients (HR=0.570, 95% CI:0.335 to 0.970). CONCLUSIONS: KIF18A expression is down-regulated in gastric cancer tissue, which may play a critical role in gastric cancer carcinogenesis. Lower expression of KIF18A is associated with poor prognosis of gastric cancer patients. KIF18A may be a potential prognostic marker of gastric cancer.