Propofol inhibited gastric cancer proliferation via the hsa-miR-328-3p/STAT3 pathway.

PURPOSE: The aim of the present study was to elucidate the functional role of hsa-miR-328-3p/STAT3 pathway in the effects of propofol on gastric cancer proliferation. METHODS: Bioinformatics was used to analyze the molecular expression differences of hsa-miR-328-3p/STAT3 axis in stomach adenocarcinoma (n = 435) and normal samples (n = 41) from TCGA database. The expression of the above molecules in gastric cancer cells SGC-7901 and normal gastric mucosal cells GES-1 was verified via qPCR. The dual-luciferase assay was carried out to confirm the interaction between hsa-miR-328-3p and STAT3. Subsequently, the cell proliferation and the expression of the above molecules in SGC-7901 and GES-1 cells were evaluated after 10 µM propofol treatment. Finally, we analyzed whether propofol still inhibited the proliferation of gastric cancer by suppressing STAT3 pathway after hsa-miR-328-3p down-regulation. RESULTS: Compared with normal samples, the expression of hsa-miR-328-3p was significantly down-regulated in stomach adenocarcinoma samples, while the expression of STAT3 and downstream target genes (MMP2, CCND1 and COX2) was up-regulated. The results were consistent with those in GES-1 and SGC-7901 cell lines. Meanwhile, we found that hsa-miR-328-3p can bind to the 3'-UTR of the potential target gene STAT3. Furthermore, propofol significantly inhibited the proliferation of gastric cancer cell line SGC-7901, where hsa-miR-328-3p was up-regulated and the expression of STAT3 and downstream proliferation-related target genes were down-regulated. However, the growth inhibition of propofol on SGC-7901 cell was significantly reversed after the inhibition of hsa-miR-328-3p. CONCLUSIONS: To sum up, propofol suppressed the STAT3 pathway via up-regulating hsa-miR-328-3p to inhibit gastric cancer proliferation.

Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy.

Background: Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups. Patients and methods: A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation. Results: Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-γ signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-ß signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01). Conclusions: This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.

The clinical observation of verapamil in combination with interventional chemotherapy in advanced gastric cancer.

OBJECTIVE: We analyzed the clinical observations of target arterial infusion of verapamil combined with chemotherapy as therapy for advanced gastric cancer. PATIENTS AND METHODS: From March 2012 to December 2015, a total of 63 patients with advanced gastric cancer were admitted to our department. The target artery in the control group was perfused with chemotherapy drugs only, and the target artery in the therapy group was injected with verapamil combined with chemotherapy drugs. RESULTS: The therapeutic effect of the therapy group was significantly better than that of the control group in the primary foci of gastric cancer. Liver metastatic lesions: 11 patients in the control group had liver metastases and 25 patients in the therapy group had liver metastases. The effective rate (CR+PR) of the therapy group was significantly better than the control group. Clinical benefit evaluation: in the therapy group of 43 cases, 40 cases presented positive clinical benefit and 38 cases positive clinical weight in KFS scoring system; the clinical benefit of the therapy group was significantly better than control group. Survival analysis: the disease progression-free rate and survival rate of the therapy group were 12 months and 24 months, which were higher than those in the control group. The median PFS and median OS were also significantly longer than those in the control group (p<0.01). In the therapy group, adverse effects of chemotherapy in 43 patients were relieved in a short time. CONCLUSIONS: Target arterial infusion of verapamil combined with chemotherapy drugs for advanced gastric cancer can significantly improve the efficacy of chemotherapy drugs and prolong the survival of patients.

Plasma soluble cluster of differentiation 147 levels are increased in breast cancer patients and associated with lymph node metastasis and chemoresistance.

INTRODUCTION: Cluster of differentiation 147 (CD147) contributes to breast cancer invasion, metastasis, and multidrug resistance. Recent studies have shown that peripheral soluble CD147 (sCD147) is increased in hepatocellular tumour and multiple myeloma patients and correlated with disease severity. The primary aim of our study was to assess the level, as well as the biological and clinical significance of sCD147 in breast cancer. METHODS: We tested plasma sCD147 levels in 308 breast cancer patients by enzyme-linked immunosorbent assay between February 2014 and February 2017. A subset of 165 cases of benign breast diseases was included as a control group at the same period. We analysed the clinical significance of plasma sCD147 with relevance to clinicopathological factors of breast cancer patients. RESULTS: Plasma sCD147 levels were significantly higher in patients with primary breast cancer than those with benign breast diseases (P=0.001), in patients with locally advanced breast cancer (T3-T4 tumour) than those in early breast cancer (T1-T2 tumour; P=0.001), in patients with lymph node metastasis than in those without (P<0.001), and in patients with high recurrence risk than those with medium recurrence risk (P<0.001). Plasma sCD147 levels were also significantly higher in the chemotherapy-resistant group than in the chemotherapy-sensitive group (P=0.040). Plasma sCD147 was an independent predictor for lymph node metastasis in breast cancer patients (P=0.001). CONCLUSION: This is the first study to demonstrate that plasma sCD147 levels are elevated in breast cancer patients. Soluble CD147 is also associated with tumour size, lymph node metastasis, high recurrent risk, and chemoresistance. Our findings support that plasma sCD147 is an independent predictive factor for lymph node metastasis.

[A multicenter, randomized, controlled, phase â £ clinical study of PEG-rhG-CSF for preventing chemotherapy induced neutropenia in patients with breast cancer].

Objective: To explore the efficacy and safety of polyethylene glycal recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in preventing chemotherapy-induced neutropenia in patiens with breast cancer. Methods: There were two parts in the present phase Ⅳ clinical study. One was a randomized, controlled clinical study. Patients in this study received PEG-rhG-CSF or rhG-CSF in the first cycle and followed with both PEG-rhG-CSF in the rest of 3 cycles. The other one was a single arm study. Patients who developed Ⅲ/Ⅳ grade neutropenia in the screening cycle received PEG-rhG-CSF in the rest of 3 cycles chemotherapy. Results: In the first cycle of randomized, controlled study, the incidence of Ⅳ grade neutropenia are 31.48% and 35.58% respectively in PEG-rhG-CSF and rhG-CSF group, with no statistically significant differences (P=0.527 6). The duration of Ⅳ grade neutropenia respectively are 2.22±1.58 and 3.00±1.59 days, with a statistically significant difference (P=0.016 6). In the single arm study, the incidence of Ⅳ grade neutropenia was 57.76% in screening cycle. And the incidence decreased to 16.35%, 10%, and 8.57% in the followed 3 cycle after the use of PEG-rhG-CSF. The incidence of adverse effects was 5.06%, and the major adverse effect was bone pain which with an incidence of 2.8%. Conclusion: The fixed 6mg dose of PEG-rhG-CSF can effectively prevent neutropenia in patients with breast cancer in multicycle chemotherapy and it has a low incidence of adverse events and mild adverse reaction.

A Bayesian network meta-analysis comparing concurrent chemoradiotherapy followed by adjuvant chemotherapy, concurrent chemoradiotherapy alone and radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND: Given the lack of studies, whether the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. The main objective of this Bayesian network meta-analysis was to determine the efficacy of CCRT + AC when compared with CCRT alone. PATIENTS AND METHODS: We systematically searched databases and extracted data from randomized, controlled trials involving NPC patients randomly assigned to receive CCRT + AC, CCRT, or radiotherapy (RT). Overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) with hazard ratios (HRs) were investigated. A Bayesian network for different outcomes was established to incorporate all evidence. Multiple treatment comparisons based on the network integrated the efficacy of CCRT + AC, CCRT, and RT. RESULTS: Eight studies involving 2144 patients were analyzed. In the network meta-analysis, CCRT + AC and CCRT were both significantly better than RT alone for all outcomes, except that no significant difference was found between CCRT and RT for LRFS. Though ranking probabilities showed that CCRT + AC was ranked superior to CCRT for OS, LRFS, and DMFS, no significant differences were found between CCRT+AC and CCRT for all outcomes [OS: HR = 0.86, 95% credible interval (CrI) 0.60-1.16; LRFS: HR = 0.72, 95% CrI 0.43-1.15; DMFS: HR = 0.86, 95% CrI 0.62-1.16]. CONCLUSIONS: No significant improvement was found following CCRT + AC compared with CCRT alone. Whether the omission of additional AC can reduce toxic effects without adversely affecting survival in patients with locoregionally advanced NPC should be further explored, in addition to the precise patient status that would benefit from AC following CCRT.

Environmental risk factors for women with polycystic ovary syndrome in china: a population-based case-control study.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrinology disease with heterogeneous phenotype. Environmental factors are thought to be involved in the development of PCOS. The present study aimed to explore the potential environmental risk factors of PCOS. A cross-sectional study and stratified population-based case-control study were carried out. Pre-designed questionnaires were prepared, including questions about medication history, contact history of endocrine disruptors (EDs), environment and habituation. Fasting blood was collected for measurement of sex hormone, glucose and insulin. Matched logistic regression analysis was used to find the potential independent risk factor of PCOS. One thousand eight hundred fifty-four participants (aged 12-44 years) were analyzed in the cross-sectional investigation. One hundred sixty-nine PCOS patients and 338 matched controls were compared. PCOS patients were more frequent than controls in eating plastic-packaged food (p=0.001), contacting pesticide (p=0.021), eating fruit with pericarp (p=0.001), living beside a garbage heap (p=0.001), working at an acid plant (p=0.028), taking Chinese patent drugs (p=0.001), smoking (p=0.028) and drinking alcohol (p=0.001). However, PCOS patients were less likely to use kitchen ventilators (p=0.002), eat canned food (p=0.049), contact decorated materials, use skin care products (p=0.01) and cosmetics (p=0.027). No difference was found in taking antiepileptic drugs (p=0.93). Eating plastic-packaged food (p=0.001, OR=44.449), eating fruit with pericarp (p=0.03, OR=5.7) and drinking alcohol (p=0.001, OR=29.632) were found to be the independent risk factors for PCOS. The existence of an association between EDs and PCOS was proved. Plastic-packaged food, fruit with pericarp and drinking alcohol should be avoided as possible as we can. However, the causal relationships among these factors and PCOS should be proved by further research.

Prognostic value of magnetic resonance imaging-detected cranial nerve invasion in nasopharyngeal carcinoma.

BACKGROUND: We previously reported that magnetic resonance imaging evidence of cranial nerve invasion was an unfavourable prognostic factor in nasopharyngeal carcinoma. However, the prognostic value of this evidence in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy remains unknown. METHODS: We retrospectively analysed 749 nasopharyngeal carcinoma patients who underwent intensity-modulated radiotherapy. RESULTS: Cranial nerve invasion was observed in 299 (39.9%) patients with T3-4 disease. In T3-4 nasopharyngeal carcinoma, magnetic resonance imaging-detected cranial nerve invasion was associated with inferior 5-year overall survival, distant metastasis-free survival, and locoregional relapse-free survival (P=0.002, 0.003, and 0.012, respectively). Multivariate analyses confirmed that cranial nerve invasion was an independent prognostic factor for distant metastasis-free survival (hazard ratio, 1.927; P=0.019) and locoregional relapse-free survival (hazard ratio, 2.605; P=0.032). Furthermore, the receiver-operating characteristic curves verified that the predictive validity of T classifications was significantly improved when combined with magnetic resonance imaging-detected cranial nerve invasion in terms of death, distant metastasis, and locoregional recurrence (P=0.015, 0.021 and 0.008, respectively). CONCLUSIONS: Magnetic resonance imaging-detected cranial nerve invasion is an independent adverse prognostic factor in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy.

Polyelectrolyte capsules packaging BSA gels for pH-controlled drug loading and release and their antitumor activity.

Polyelectrolyte multilayer capsules, promising candidates for multifunctional drug delivery systems, have recently received increased interest. However, the low encapsulation efficiency of drugs and the lack of reports about animal experiments have greatly slowed down their development for drug delivery. Here, a polyelectrolyte multilayer capsule filled with bovine serum albumin gel (BSA-gel-capsule) was constructed by a layer-by-layer assembly technique and thermally induced gelation of BSA. Owing to the charge variability of BSA with change in pH, BSA-gel-capsules not only showed a pronounced accumulation effect of drugs into capsules, but also displayed excellent pH-controlled loading and release properties. Moreover, a remarkable targeting action to the lung was discovered after intravenous injection of fluorescein isothiocyanate (FITC)-labeled BSA-gel-capsules into mice. After treatment with doxorubicin-loaded BSA-gel-capsules, effective cytotoxicity against B16-F10 cells and inhibition of the pulmonary melanoma growth were revealed. This paper introduces a new type of smart microstructure with notable pH-responsive ability. This material renders feasible the intravenous administration of polyelectrolyte microcapsules, which will be a big step towards their application as drug delivery vehicles.

Thymidine kinase 1 is a potential marker for prognosis and monitoring the response to treatment of patients with breast, lung, and esophageal cancer and non-Hodgkin's lymphoma.

Thymidine kinase 1 (TK1) is converting thymidine to thymidine monophosphate, and is related to DNA replication and cell proliferation. The use of the TK1 protein levels as a proliferation marker in malignancies is here summarized. TK1 protein in serum (STK1p) and TK1 expression in tissues were determined by a chemoluminescent dot blot assay and by immunohistochemistry staining, respectively. The expression of TK1 in tumor tissues correlated to pathological stages and clinical grades of carcinomas (ca) of esophagus, lung and in premalignancy of breast ductal ca. STK1p could monitor the out-come of tumor therapy by being correlated to remission [breast ca, non-Hodgkin's lymphoma], relapse [breast ca] and to survival [non-Hodgkin's lymphoma] of patients. In a health screening study of 12,641 persons, STK1p seemed to predict the risk of development of neoplasia related diseases at early stage.

Insulin receptor substrate 2 plays important roles in 17beta-estradiol-induced bone formation.

BACKGROUND: Discovering the mechanisms of the estrogen effects on the osteoblasts is very important for the development of new agents which have the clear-cut beneficial effects of estrogen while free of adverse effect. AIM: The aim of this study was to investigate the differential gene expression of 17beta-estradiol (E2)-treated osteoblast-like cells, and the effect of E2 on the insulin receptor substrate 2 (IRS- 2) expression in human cultured osteoblast-like cells and the osteoblasts of ovariectomized (OVX) rats. MATERIAL AND METHODS: The differential gene expression of E2-treated osteoblast- like cells was analyzed by cytokine expression array and validated by RT-PCR and Western blot analysis. The protein expression and phosphorylation of one of the differentially expressed gene, IRS-2, treated at different times with E2 were analyzed. The Sprague-Dawley rats were ovariectomized and then treated with E2, the IRS-2 expression was analyzed by immunohistochemistry analysis. RESULTS: E2 upregulated the mRNA expression of IRS-2, bone morphogenetic protein 9, and connective tissue growth factor expression, down-regulated the mRNA expression of matrix metalloproteinase 15 and some tumor suppressor genes. Peak expression of IRS-2 was observed at 12-24 h of treatment by 10-8M E2. E2 can also increase the phosphorylation of IRS-2. The IRS-2 expression was down-regulated in the osteoblasts and bone marrow cells of the OVX rats, which had lower bone mineral density (BMD) than the normal rats. However, both BMD and IRS-2 expression can be rescued by 10-8M E2 in the OVX rats. CONCLUSION: IRS-2 in osteoblast is up-regulated by E2 and plays important roles in the estrogen- induced bone formation.

Systemic use of argatroban reduces tumor mass, attenuates neurological deficits and prolongs survival time in rat glioma models.

Our previous studies showed that intracerebral infusion of argatroban, a specific thrombin inhibitor, reduces brain edema and neurological deficits in a C6 glioma model. The present study investigated whether systemic argatroban administration can reduce glioma mass and neurological deficits and extend survival time in C6 and F98 gliomas. Rat C6 or F98 glioma cells were infused into the right caudate of adult male Fischer 344 rats. Osmotic minipump loaded with argatroban (0.3 mg/hour) or vehicle was implanted into abdomen immediately after glioma implantation. Tumor mass was determined at day 9. Over the period of the experiment, the animals underwent behavioral testing (forelimb placing and forelimb use asymmetry). In addition, survival time was tested in the F98 glioma model. In C6 glioma, argatroban reduced glioma mass (p < 0.05) and neurological deficits (p < 0.05) at day 9. In F98 glioma, agratroban prolonged the survival time (p < 0.05) and reduced the body weight loss (84 +/- 15 gram vs. 99 +/- 2 gram in the vehicle group, P < 0.05). In conclusion, systemic use of argatroban reduced tumor mass and neurological deficits, and prolonged survival time. These results suggest that thrombin plays a key role in glioma growth and thrombin inhibition with argatroban may be a novel treatment for gliomas.

IFN-gamma regulation of class II transactivator promoter IV in macrophages and microglia: involvement of the suppressors of cytokine signaling-1 protein.

The discovery of the class II transactivator (CIITA) transcription factor, and its IFN-gamma-activated promoter (promoter IV), have provided new opportunities to understand the molecular mechanisms of IFN-gamma-induced class II MHC expression. Here, we investigated the molecular regulation of IFN-gamma-induced murine CIITA promoter IV activity in microglia/macrophages. In the macrophage cell line RAW264.7, IFN-gamma inducibility of CIITA promoter IV is dependent on an IFN-gamma activation sequence (GAS) element and adjacent E-Box, and an IFN response factor (IRF) element, all within 196 bp of the transcription start site. In both RAW cells and the microglia cell line EOC20, two IFN-gamma-activated transcription factors, STAT-1alpha and IRF-1, bind the GAS and IRF elements, respectively. The E-Box binds upstream stimulating factor-1 (USF-1), a constitutively expressed transcription factor. Functionally, the GAS, E-Box, and IRF elements are each essential for IFN-gamma-induced CIITA promoter IV activity. The effects of the suppressors of cytokine signaling-1 (SOCS-1) protein on IFN-gamma-induced CIITA and class II MHC expression were examined. Ectopic expression of SOCS-1 inhibits IFN-gamma-induced activation of CIITA promoter IV and subsequent class II MHC protein expression. Interestingly, SOCS-1 inhibits the constitutive expression of STAT-1alpha and its IFN-gamma-induced tyrosine phosphorylation and binding to the GAS element in CIITA promoter IV. As well, IFN-gamma-induced expression of IRF-1 and its binding to the IRF element is inhibited. These results indicate that SOCS-1 may be responsible for attenuating IFN-gamma-induced CIITA and class II MHC expression in macrophages.

[Repair of bone defect with benign tumor by embryonic bone transplantation].

OBJECTIVE: To evaluate the clinical results of repair of bone defect by embryonic bone transplantation. METHODS: From January 1994 to June 1999, 148 cases of bone defect were repaired by embryonic bone transplantation following alcohol treatment, there were 63 cases with bone cyst, 42 cases with fibrous dysplasia of bone, 26 cases with giant cell tumor of bone, and 17 cases with enchondroma among them. The maximal bone defect was 3.5 cm x 10.0 cm, while the minimal defect was 0.5 cm x 1.0 cm. RESULTS: All of those bone defect with benign tumor were bone union used by embryonic bone transplantation after 3 months to 1 year of operation, the average healing course was 6.2 months, followed up 1 to 6 years, averaged 14 months, no tumor recurrence and no obvious local or system response were observed. CONCLUSION: Embryonic bone can be used as a good repairing material of postoperative bone defect of benign tumors, the clinical results are satisfactory.

[High efficiency gene transfer into breast cancer cells by pseudotyped retroviral vector].

OBJECTIVE: To investigate the efficiency of gene transfer mediated by pseudotyped retroviral vector in breast cancer, and to provide an useful vector for breast cancer gene therapy. METHODS: We used a MuLV vector pseudotyped with the vesicular stomatitis virus glycoprotein(VSV-G) envelope to transduce breast cancer cells MDA-MB-435, To compare the transfer efficiency with MuLV. RESULTS: The transfer efficiency is (92 +/- 12)% by using MuLV/VSV-G vector, (24 +/- 5)% by MuLV vector. The transfer efficiency of MuLV/VSV-G is 3.8 times that of MuLV vector. CONCLUSION: Our results suggest that pseudotyped retroviral vector MuLV/VSV-G is a kind of high efficiency gene transfer vector in breast cancer cells.

[Clinical observation of phenytoin in promoting fracture healing].

OBJECTIVE: To observe the promoting effect of phenytoin on fracture healing. METHODS: Fourty cases with close fractures of tibia and fibula were included and divided into two groups randomly: the experimental group was administrated with phenytoin and Chinese traditional drug-Jiegudan orally, while the control group was given Jiegudan only. Longitudinal percussion pain, clinical healing time of fracture, growth of calus in X-ray film were detected to evaluate the clinical result. RESULTS: All the fractures were healed in 3 months. But the experimental group was superior to the control group in all indexes. CONCLUSION: Administration of phenytoin orally can markedly promote fracture healing.

Biochemical studies on McLeod phenotype erythrocytes.

Red cells of the McLeod phenotype in the Kell blood group system have an acanthocytic morphology. The membrane protein composition analyzed on sodium dodecyl-sulfate-polyacrylamide gel electrophoresis, the ATP level and the activities of a large number of intracellular enzymes appear to be normal. Membranes prepared from McLeod red cells incubated with gamma AT[32P] and MgCl2 incorporated twice as much radioactivity into spectrin and also showed a slight elevation of phosphorylation in band 3 protein when compared to membranes from normal cells. Intact normal red cells incubated with carrier-free [32P] incorporated radioactivity into several proteins, with most incorporation in spectrin and band 3 protein. In comparison, McLeod cells incorporated three times more radioactivity into spectrin and band 3 protein but increased phosphorylation also occurred in other, but not all, membrane proteins. Intact McLeod red cells also showed increased phosphorylation of membrane phospholipids, but they incorporated [32P] into intracellular nucleotide phosphates in a normal manner.