Overexpression of MiR-633 Suppresses the Tumorigenicity of Gastric Cancer Cells and Induces Apoptosis by Targeting MAPK1.

OBJECTIVE: MicroRNA (miRNA/miR)-633 is dysregulated in several types of cancers and is involved in tumorigenesis. However, the function and role of this miRNA in gastric cancer (GC) are not fully understood. The aim of the present study was to evaluate miR-633 expression in GC cell lines and in GC tissue vs. adjacent normal tissue, and to determine its association with clinicopathological data. This work was extended to investigate the effects of miR-633 overexpression on tumor cells in vitro. METHODS: Reverse transcription-quantitative PCR (RT-qPCR) was used to detect and compare the expression level of miR-633 in GC cells, as well as in GC and normal adjacent tissue samples. The clinical significance of miR-633 was also analyzed. MiR-633 lentivirus (LV-miR-633) and negative control lentivirus (LV-NC) were generated and used to transduce SGC-7901 and HGC-27 GC cells in order to analyze the effect of miR-633 on their phenotype. The effects of miR-633 overexpression on GC cell proliferation, apoptosis, migration and invasion were investigated. The target gene of miR-633 was predicted, then confirmed using a dual luciferase reporter gene assay, RT-qPCR and Western blotting. RESULTS: MiR-633 was significantly downregulated in GC cell lines, as well as in GC tissue compared with adjacent normal tissue. Moreover, miR-633 expression was associated with the tumor/node/metastasis (TNM) stage, invasion depth, Borrmann classification and lymph node metastasis (P<0.05). Compared with the LV-NC group, transduction with LV-miR-633 reduced the proliferation, the number of clones, the wound healing rate, the number of invading cells and the number of cells in the G1 phase of the cell cycle (P<0.01). LV-miR-633 also increased the apoptosis rate (P<0.01). The expression level of mitogen-activated protein kinase (MAPK) 1, high-mobility group box 3 (HMGB3), claudin 1 (CLDN1) and MAPK13 were downregulated in LV-miR-633-transduced cells (P<0.01). The dual luciferase reporter assay confirmed that the 3'-untranslated region of MAPK1 was the target site of miR-633 (P<0.01). CONCLUSION: MiR-633 acts as a tumor suppressor in GC, and its expression level is associated with TNM stage, invasion depth, Borrmann type and lymph node metastasis. Overexpression of miR-633 inhibits the proliferation and migration of GC cells and induces apoptosis and cell cycle arrest at the in G1 phase. In addition, miR-633 negatively regulates the expression of MAPK1, HMGB3, CLDN1 and MAPK13 and directly targets MAPK1.

Atractylenolide-I Sensitizes Triple-Negative Breast Cancer Cells to Paclitaxel by Blocking CTGF Expression and Fibroblast Activation.

This investigation was conducted to elucidate whether atractylenolide-I (ATL-1), which is the main component of Atractylodes macrocephala Koidz, can sensitize triple-negative breast cancer (TNBC) cells to paclitaxel and investigate the possible mechanism involved. We discovered that ATL-1 could inhibit tumor cell migration and increase the sensitivity of tumor cells to paclitaxel. ATL-1 downregulated the expression and secretion of CTGF in TNBC cells. Apart from inhibiting TNBC cell migration via CTGF, ATL-1 downregulated the expression of CTGF in fibroblasts and decreased the ability of breast cancer cells to transform fibroblasts into cancer-associated fibroblasts (CAFs), which in turn increased the sensitivity of TNBC cells to paclitaxel. In a mouse model, we found that ATL-1 treatments could enhance the chemotherapeutic effect of paclitaxel on tumors and reduce tumor metastasis to the lungs and liver. Primary cultured fibroblasts derived from inoculated tumors in mice treated with ATL-1 combined with paclitaxel expressed relatively low levels of CAF markers. Collectively, our data indicate that ATL-1 can sensitize TNBC cells to paclitaxel by blocking CTGF expression and fibroblast activation and could be helpful in future research to determine the value of ATL-1 in the clinical setting.

Transdermal granisetron for the prevention of nausea and vomiting following moderately or highly emetogenic chemotherapy in Chinese patients: a randomized, double-blind, phase III study.

BACKGROUND: The granisetron transdermal delivery system (GTDS) has been demonstrated effectiveness in the control of chemotherapy-induced nausea and vomiting (CINV) in previous studies. This is the first phase III study to evaluate the efficacy and tolerability of GTDS in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in China. METHODS: A total of 313 patients were randomized into the GTDS group (one transdermal granisetron patch, 7 days) or the oral granisetron group (granisetron oral 2 mg/day, ≥2 days). The primary endpoint was the percentage of patients achieving complete control (CC) from chemotherapy initiation until 24 h after final administration (PEEP). Chi-square test and Fisher's exact test were used for statistical analysis. RESULTS: Two hundred eighty-one patients were included in the per protocol analysis. During PEEP, CC was achieved by 67 (47.52%) patients in the GTDS group and 83 (59.29%) patients in the oral granisetron group. There was no statistical significance between the groups (P=0.0559). However, the difference of the CC percentage mainly occurred on the first day of chemotherapy between the groups. The CC was 70.13% on day 1 in the GTDS group, which was significantly lower than that of 91.03% in the oral granisetron group in the full analysis set. In the following days of chemotherapy, the CC was similar between the groups. In terms of cisplatin-contained regimen and female, there was statistical significance between the groups. Both treatments were well tolerated and safe. The most common adverse event was constipation. CONCLUSIONS: GTDS provided effective and well-tolerated control of CINV in Chinese patients, especially to non-cisplatin-contained regimen.

Raltitrexed induces mitochondrial­mediated apoptosis in SGC7901 human gastric cancer cells.

Raltitrexed is a specific inhibitor of thymidylate synthase (TS), which has been considered as a potential chemotherapeutic agent for the treatment of advanced gastric cancer. In the present study, the apoptosis mechanisms of raltitrexed in SGC7901 human gastric cancer cells were investigated. The cytotoxic activity of raltitrexed on SGC7901 cells was determined by cell counting kit-8 (CCK-8) assay. The CCK­8 assay indicated that raltitrexed inhibits SGC7901 cell growth in a dose- and time-dependent manner. The morphological changes were observed by fluorescent microscopy, and characteristic morphological changes, including nuclear shrinkage and apoptotic bodies, were observed following Hoechst 33258 staining. The effects on apoptosis, cell cycle, mitochondrial transmembrane potential and reactive oxygen species (ROS) were measured by flow cytometry. The analysis revealed that raltitrexed exerted a growth inhibitory effect by inducing time-dependent apoptosis and cell-cycle arrest at the G0/G1 phase. In addition, a compromised mitochondrial membrane potential and overproduction of ROS demonstrated the involvement of the mitochondrial signaling pathway. Raltitrexed­induced caspase­3­dependent apoptosis was identified using a caspase-3 activity assay and pretreatment with the caspase-3 inhibitor, Ac­DEVD­CHO (sequence, Ac-Asp-Glu-Val-Asp-CHO). The activity of caspase-3 was analyzed with a spectrometer. The protein expression levels of Bax, Bcl-2, cytochrome c, cleaved caspase-3 and TS were examined by western blot and the mRNA expression level of TS was detected by quantitative polymerase chain reaction. The analysis revealed that the protein levels of Bax, cytochrome c and cleaved caspase­3 were significantly increased by raltitrexed, while Bcl-2 expression levels were reduced. Furthermore, raltitrexed increased the expression of the TS protein and mRNA in a time­dependent manner. These results indicate that raltitrexed induces the apoptosis of SGC7901 cells through the caspase­3­dependent mitochondrial signaling pathway and upregulates the expression of the TS protein and mRNA.

Electronic clinical decision support for management of depression in primary care: a prospective cohort study.

OBJECTIVE: To assess the utility of an electronic clinical decision support tool for management of depression in primary care. METHOD: This prospective study was conducted in a national network of ambulatory practices over a 1-year period (October 2007-October 2008). A clinical decision support tool was embedded into the electronic health record of 19 primary care practices with 119 providers. The main components included (1) the 9-item Patient Health Questionnaire (PHQ-9), with 9 questions paralleling the 9 DSM-IV criteria for the diagnosis of major depressive disorder; (2) a suicide assessment form; and (3) brief patient and provider education. Use of each component was tracked in the electronic health record. Providers completed baseline and postintervention surveys regarding their depression management practices and their perceptions of the clinical decision support tool. RESULTS: According to electronic health record tracking, the PHQ-9 form was used in 45.6% of the 16,052 adult patients with depression and in 73.7% of the 1,422 patients with new depression. The suicide assessment form was used in 62.0% of patients with possible suicidality. Education modules were rarely used. From before to after the study, providers reported increased use of standardized tools for depression diagnosis (47% to 80%, P < .001) and monitoring (27% to 85%, P < .001). The majority of providers reported often using the PHQ-9 and suicide forms and felt them to be very helpful in patient care, with 85% planning to continue their use after the study. CONCLUSIONS: The electronic health record-based clinical decision support tool was extensively used and perceived as very helpful for assessment of patients' symptoms but not for provider education. These findings can help guide national efforts incorporating clinical decision support for quality improvement.

Using electronic health record-based tools to screen for bipolar disorder in primary care patients with depression.

PURPOSE: National guidelines recommend screening all persons with depression for bipolar disorder (BPD); one way to facilitate screening is through the use of electronic health records (EHRs). This study examined the impact of an EHR-based screening and decision support tool on diagnosis and treatment of BPD among patients diagnosed with depression in primary care offices. METHODS: This nonrandomized, controlled trial was conducted in a national network of offices using EHRs. The intervention included a screening instrument and other tools for diagnosis and management of BPD, which were embedded into the EHR. This instrument automatically activated when a patient with a diagnosis of depression but no diagnosis of BPD was seen in the office. The primary outcomes were the rates of new diagnoses of BPD and prescription of new BPD medications during the 6-month study period (April to October 2009). RESULTS: Twenty-one offices with 75 clinicians and 8355 adult patients with depression composed the intervention group, whereas 17 offices with 81 clinicians and 8799 adult patients with depression served as the comparison group. The screening tool was used with 47.5% of intervention patients, of whom 2.5% scored at high or very high risk for BPD. Intervention patients were more likely than comparison patients to be newly diagnosed with BPD (1.11% vs. 0.36%; P < .01) and be prescribed new BPD medications (1.85% vs. 1.19%; P < .01). CONCLUSIONS: The study suggests that EHR-based tools can be useful for screening and management of BPD for patients with depression in primary care offices.

Impact of EHR-based clinical decision support on adherence to guidelines for patients on NSAIDs: a randomized controlled trial.

PURPOSE: Electronic health records (EHRs) with clinical decision support hold promise for improving quality of care, but their impact on management of chronic conditions has been mixed. This study examined the impact of EHR-based clinical decision support on adherence to guidelines for reducing gastrointestinal complications in primary care patients on nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: This randomized controlled trial was conducted in a national network of primary care offices using an EHR and focused on patients taking traditional NSAIDs who had factors associated with a high risk for gastrointestinal complications (a history of peptic ulcer disease; concomitant use of anticoagulants, anti-platelet medications [including aspirin], or corticosteroids; or an age of 75 years or older). The offices were randomized to receive EHR-based guidelines and alerts for high-risk patients on NSAIDs, or usual care. The primary outcome was the proportion of patients who received guideline-concordant care during the 1-year study period (June 2007-June 2008), defined as having their traditional NSAID discontinued (including a switch to a lower-risk medication), having a gastroprotective medication coprescribed, or both. RESULTS: Participants included 27 offices with 119 clinicians and 5,234 high-risk patients. Intervention patients were more likely than usual care patients to receive guideline-concordant care (25.4% vs 22.4%, adjusted odds ratio = 1.19; 95% confidence interval, 1.01-1.42). For individual high-risk groups, patients on low-dose aspirin were more likely to receive guideline-concordant care with the intervention vs usual care (25.0% vs 20.8%, adjusted odds ratio = 1.30; 95% confidence interval, 1.04-1.62), but there was no significant difference for patients in other high-risk groups. CONCLUSIONS: This study showed only a small impact of EHR-based clinical decision support for high-risk patients on NSAIDs in primary care offices. These results add to the growing literature about the complexity of EHR-based clinical decision support for improving quality of care.

An electronic medical record-based intervention to improve quality of care for gastro-esophageal reflux disease (GERD) and atypical presentations of GERD.

BACKGROUND: Gastro-esophageal reflux disease (GERD) is common in primary care but is often underdiagnosed and untreated. GERD can also present with atypical symptoms like chronic cough and asthma, and physicians may be unaware of this presentation. We aimed to implement and evaluate an intervention to improve diagnosis and treatment for GERD and atypical GERD in primary care. METHOD: This was a randomised controlled trial in primary care office practice using a national network of US practices (the Medical Quality Improvement Consortium - MQIC) that share the same electronic medical record (EMR). Thirteen offices with 53 providers were randomised to the intervention of EMR-based prompts and education, and 14 offices with 66 providers were randomised to the control group totalling over 67 000 patients and examining outcomes of GERD diagnosis and appropriate treatment. RESULTS: Among patients who did not have GERD at baseline, new diagnoses of GERD increased significantly in the intervention group (3.1%) versus the control group (2.3%) (P<0.01). This remained significant after controlling for clustering with an odds of diagnosis of 1.33 (95% CI 1.13-1.56) for the intervention group. For patients with atypical symptoms, those in the intervention group had both higher odds of being diagnosed with GERD (OR 2.02, 95% CI 1.41-2.88) and of being treated for GERD (OR 1.40, 95% CI 1.08-1.83) than those in the control group. CONCLUSIONS: GERD diagnosis and treatment in primary care, particularly among patients with atypical symptoms, can be improved through the use of an EMR-based tool incorporating decision support and education. However, significant room for improvement exists in use of appropriate treatment.

Antidepressant medication use for primary care patients with and without medical comorbidities: a national electronic health record (EHR) network study.

BACKGROUND: Because comorbid depression can complicate medical conditions (eg, diabetes), physicians may treat depression more aggressively in patients who have these conditions. This study examined whether primary care physicians prescribe antidepressant medications more often and in higher doses for persons with medical comorbidities. METHODS: This secondary data analysis of electronic health record data was conducted in the Centricity Health Care User Research Network (CHURN), a national network of ambulatory practices that use a common outpatient electronic health record. Participants included 209 family medicine and general internal medicine providers in 40 primary care CHURN offices in 17 US states. Patients included adults with a new episode of depression that had been diagnosed during the period October 2006 through July 2007 (n = 1513). Prescription of antidepressant medication and doses of antidepressant medication were compared for patients with and without 6 comorbid conditions: diabetes, coronary heart disease, congestive heart failure, cerebrovascular disease, chronic obstructive pulmonary disease, and cancer. RESULTS: 20.7% of patients had at least one medical comorbidity whereas 5.8% had multiple comorbidities. Overall, 77% of depressed patients were prescribed antidepressant medication. After controlling for age and sex, patients with multiple comorbidities were less likely to be prescribed medication (adjusted odds ratio, 0.58; 95% CI, 0.35-0.96), but there was no significant difference by individual comorbidities. Patients with cerebrovascular disease were less likely to be prescribed a full dose of medication (adjusted odds ratio, 0.26; 95% CI, 0.08-0.88), but there were no differences for other comorbidities or for multiple comorbidities, and there was no difference for any comorbidities in the prescription of minimally effective doses. CONCLUSIONS: Patients with new episodes of depression who present to a primary care practice are not treated more aggressively if they have medical comorbidities. In fact, patients with multiple comorbidities are treated somewhat less aggressively.

Impact of decision support in electronic medical records on lipid management in primary care.

Electronic decision-support tools may help to improve management of hyperlipidemia and other chronic diseases. This study examined the impact of lipid management tools integrated into an electronic medical record (EMR) in primary care practices. This randomized controlled trial was conducted in a national network of physicians who use an outpatient EMR. Adult primary care physicians were randomized by office to receive an electronic form that was embedded in the EMR. The form contained prompts regarding suboptimal care based on Adult Treatment Panel-III (ATP-III) guidelines, as well as reporting tools to identify patients outside of office visits whose lipid management was suboptimal. All active patients, ages 20-79 years, whose physicians participated in the study, were categorized as high, moderate, or low cardiovascular risk, and the proportion who were tested for hyperlipidemia, at lipid goal, and on lipid-lowering medications if not at goal were measured according to ATP-III guidelines. A total of 105 physicians from 25 offices and 64,150 patients were included in the study. Outcomes improved for most measures from before to 1 year after the intervention (November 1, 2005 to October 31, 2006). However, after controlling for confounding variables and for clustering in multilevel modeling, only up-to-date lipid testing for high-risk patients was statistically better in the intervention group as compared to the control group (adjusted odds ratio 15.0, P < 0.05). This study showed few differences in quality of lipid management after implementing an EMR-based disease management intervention in primary care settings. Future studies may need to examine more comprehensive interventions that include office staff in a team approach to care.

Management of depression in ambulatory care for patients with medical co-morbidities: a study from a national Electronic Health Record (EHR) network.

OBJECTIVE: Since co-morbid depression can complicate medical conditions such as cardiovascular disease and cancer, physicians may treat depression more aggressively in patients with these conditions. This study compared antidepressant medication use in persons with and without medical co-morbidities. METHODS: This cross-sectional study was conducted in a national network of outpatient electronic medical record users. Participants included active adult patients with an active diagnosis of depression as of 11/30/05 (the "prevalent" population, 185,029 patients) or a new episode of depression during the one-year period 12/1/03-11/30/04 (the "incident" population, 29,768 patients). For each population, four co-morbid conditions were defined--diabetes, coronary heart disease (CHD), stroke, and cancer. Prescription of antidepressant medication was compared for persons with and without each medical condition. RESULTS: The most common medical condition was diabetes, with cancer being the least common (7.6% and 2.4% of the prevalent population). Overall, 69.6% of the prevalent population and 76.1% of the incident population were treated with antidepressant medications. For the prevalent population, treatment was significantly more likely for patients with diabetes (OR 1.07, 95% CI 1.03-1.11) but significantly less likely for patients with CHD (OR 0.94 95% CI 0.90-0.99), after controlling for differences in age and gender. For the incident population, treatment was significantly more likely for persons with diabetes (OR 1.14, 95% CI 1.04-1.26), CHD (OR 1.23 95% CI 1.08-1.39), and stroke (OR 1.21, 95% CI 1.04-1.42). CONCLUSIONS: Antidepressant medication use was somewhat higher in persons with medical co-morbidities, although these differences were small and inconsistent.

[Oxaliplatin plus capecitabine as a second line chemotherapy for patients with advanced gastric cancer].

OBJECTIVE: To evaluate the effect and toxicity of oxaliplatin combined with capecitabine (Xeloda) as a second-line chemotherapy regimen for patients with advanced gastric cancer. METHODS: Twenty-four patients with advanced gastric cancer who had been treated by multiple chemotherapy regimens presenting poor responses were allotted. LX regimen (oxaliplatin 85 mg/m(2) in 2-hour infusion on D1 and D15, capecitabine 1250 mg/m(2)/d divided in two daily doses given from D1 to D14) was adopted. The cycles were repeated every 28 days. All patients received two or more cycles. RESULTS: All 24 patients were evaluated after having received 2 to 6 cycles of chemotherapy, totally 92 cycles. The overall response rate was 29.2% (including 2 CR, 5 PR, 10 NC and 7 PD). The time to tumor progression (TTP) was 2 to 18 months (median 5 months), and duration of remission was 4 to 14 months (median 8 months). The major toxicities were bone marrow suppression and nausea/vomiting. CONCLUSION: Oxaliplatin combined with capitabine is effective as a secondary line regimen for patients with advanced gastric cancer. This protocol is active and well tolerated. Further clinical studies are warranted.