Abstract 5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 ( PCDH17 ) gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between PCDH17 and 5-FU resistance in CRC remains unclear. Here, we revealed that PCDH17 was more highly expressed in 5-FU-sensitive CRC tissues than in 5-FU-resistant CRC tissues, and high expression of PCDH17 was correlated with high BECN1 expression. Moreover, this expression profile contributed to superior prognosis and increased survival in CRC patients. Restoring PCDH17 expression augmented the 5-FU sensitivity of CRC in vitro and in vivo by promoting apoptosis and autophagic cell death. Furthermore, autophagy played a dominant role in PCDH17 -induced cell death, as an autophagy inhibitor blocked cell death to a greater extent than the pancaspase inhibitor Z-VAD-FMK. PCDH17 inhibition by siRNA decreased the autophagy response and 5-FU sensitivity. Mechanistically, we showed that c-Jun NH2-terminal kinase (JNK) activation was a key determinant in PCDH17 -induced autophagy. The compound SP600125, an inhibitor of JNK, suppressed autophagy and 5-FU-induced cell death in PCDH17 -reexpressing CRC cells. Taken together, our findings suggest for the first time that PCDH17 increases the sensitivity of CRC to 5-FU treatment by inducing apoptosis and JNK-dependent autophagic cell death. PCDH17 may be a potential prognostic marker for predicting 5-FU sensitivity in CRC patients.
To explore the risk factors for nosocomial infection caused by extended-spectrum beta-lactamases (ESBLs)-producing bacteria in hospitals of Zhejiang province.One hundred and eighty-five cases with nosocomial infection (108 men and 77 women, with an average age of 55 +/- 17 years) caused by positive-ESBLs bacteria, including 59 cases of respiratory infection, 71 with urinary infection, ten with blood infection, 30 with wound infection and 59 with other infection, and 77 controls with nosocomial infection (54 men and 23 women, with an average age of 54 +/- 20 years) caused by negative-ESBLs bacteria, including 38 cases of respiratory infection, 20 with urinary infection, six with blood infection, eight with wound infection and five with other infection, from six hospitals in Zhejiang Province were studied during May 1999 to May 2000. Data were analyzed with unconditional logistic regression and principal component analysis (PCA).Multivariate unconditional logistic regression analysis showed that the independent risk factors for nosocomial infection were use of the third generation cephalosporins for more than three days (odds ratio, OR 4.52, 95% confidence interval of OR 2.30 - 8.89), combined use of antibiotics (OR 2.86, 95% CI 1.51 - 5.43), use of quinolones for more than three days (OR 2.44, 95% CI 1.18 - 5.04), use of adrenal cortical hormone (OR 2.16, 95% CI 1.08 - 4.31) and oxygen inhalation (OR 2.56, 95% CI 1.14 - 5.72). Five principal components were extracted from the 14 risk factors for nosocomial infection with ESBLs-producing bacteria by principal component analysis, with a contribution of cumulative variance of 60.2%, and arranged in an order as follows, use of ventilator, tracheal intubation or tracheotomy, oxygen inhalation, retaining needle in vein, indwelling urethral catheter, use of the third generation cephalosporins over three days, hospitalization over ten days, use of quinolones over three days, combined use of antibiotics, use of aminoglycosides antibiotic over a week, use of adrenal cortical hormone, catheterized examination and prophylactic use of antibiotics.Nosocomial infection with ESBLs-producing bacteria could attribute to multiple factors, mainly to invasive manipulation and use of antibiotics.
Objective: To observe the difference of brain activity in patients with diarrhea-type irritable bowel syndrome (IBS-D) treated with pinaverium bromide (PB) combined with flupentixol-melitracen (FM), and to explore the mechanism of efficacy of combined with anxiolytic/antidepressant drugs in IBS-D patients at the central level, using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Forty-eight patients with IBS-D, including 28 males, 20 females, mean age 22-48 (33±7) years, were selected from the Affiliated Hospital of Hangzhou Normal University from October 2015 to October 2018.All patients with IBS-D underwent rs-fMRI scans before and after receiving either PB (basic treatment group, n=16), PB combined with FM (combination therapy group, n=16), or no medication (no treatment group, n=16). Rs-fMRI regional homogeneity (ReHo) parameter among the three groups of patients were compared using One-way ANOVA analysis and post analysis.Partial correlation and mediation analyses were performed on ReHo values and the improvement of symptoms scores (gastrointestinal symptom rating scale(GSRS) and hospital anxiety/depression scale (HAD)) in the two medicated groups. Results: No significant differences in ReHo values were observed among the three groups before treatment. Compared with patients on no-medication, patients receiving either PB or PB-FM showed decreased ReHo in the striatum, insular lobe, medial prefrontal cortex (MPFC) and subcallosal gyrus, and increased ReHo in the occipital cortex. In particular, the combined treatment group showed more extensive decreased ReHo in the left thalamus and left temporal pole, and increased in the left precuneus. Compared with the basic treatment group, the combined treatment group showed decreased ReHo in the right putamen, right insula, right MPFC and subcallosal gyrus, and increased ReHo in the left precuneus. In addition, the combined treatment group demonstrated a positive correlation between ReHo values in the left thalamus and the improvement of HAD score (r=0.653, P=0.011) , and a negative correlation between ReHo values in left precuneus and the improvement of GSRS and HAD score (r=-0.771, P=0.001; r=-0.716, P=0.004). ReHo values in the left precuneus were observed to mediate between gastrointestinal symptoms and anxiety-depressive symptoms in the combined treatment group. Conclusions: The efficacy of PB combined with FM is superior to PB alone in the treatment of IBS. In addition to more extensive changes in pain-related brain areas, IBS-D patients treated with anxiolytic/antidepressant also show changes in default network and brain areas related to emotional regulation, and are associated with improvement in gastrointestinal symptoms, anxiety and depression.目的： 采用静息态功能磁共振成像（rs-fMRI）观察腹泻型肠易激综合征（IBS-D）患者在胃肠解痉药（匹维溴铵，PB）和其联合抗焦虑抑郁药（氟哌噻吨美利曲辛，FM）两种治疗方法后大脑活动的区域差异，从中枢层面上探讨联合抗焦虑抑郁药治疗IBS-D患者有效性的机制。 方法： 选取2015年10月至2018年10月杭州师范大学附属医院消化内科诊断的IBS-D患者48例（男28例/女20例），年龄22~48（33±7）岁，在接受匹维溴铵（基础治疗组，16例）、联合FM（联合治疗组，16例）和不服药（未接受治疗组，16例）后接受rs-fMRI扫描。采用单因素ANOVA分析和事后分析比较三组患者的rs-fMRI区域局部一致性（ReHo）差异，并与患者胃肠道症状评分（GSRS）和医院焦虑抑郁量表评分（HAD）治疗前后差值进行相关分析和中介效应分析。 结果： 治疗前，三组患者未显示存在ReHo值显著差异的脑区。治疗后，两组服药患者均显示纹状体、岛叶、内侧前额叶皮质（MPFC）、胼胝体下回ReHo值减低，左侧枕中回ReHo值高于未接受治疗组。此外，联合治疗组还存在左侧丘脑、左侧颞极ReHo值减低及左侧楔前叶ReHo值增高。联合治疗组显示右侧壳核、右侧岛叶、右侧MPFC及胼胝体下回ReHo值低于基础治疗组，左侧楔前叶ReHo值高于基础治疗组。联合治疗组左侧丘脑ReHo值与HAD差值呈显著正相关（r=0.653，P=0.011），左侧楔前叶ReHo值与GSRS差值、HAD差值均呈显著负相关（r=-0.771，P=0.001；r=-0.716，P=0.004）。联合治疗组患者显示左楔前叶的ReHo值介导胃肠道症状和焦虑-抑郁症状。 结论： 匹维溴铵联合FM治疗IBS的疗效优于单纯匹维溴铵治疗。联合抗抑郁药治疗的IBS-D患者除了表现出更广泛的疼痛相关脑区的变化外，还存在默认网络及情绪调节相关脑区的改变，并与胃肠道症状及焦虑抑郁的改善相关。.
AIM:To establish an accurate and rapid stem-loop reverse transcriptional real-time PCR (RT-PCR) method to quantify human let-7a miRNA in gastric cancer. METHODS:According to the sequence of let-7a miRNA, the stem-loop reverse transcriptional primer, the primers and quantitative MGB probes of real-time PCR were designed and synthesized.The dynamic range and the sensitivity of quantitative reverse transcriptional real-time PCR were determined.The levels of let-7a miRNA were examined in 32 gastric carcinoma samples by stem-loop RT-PCR method. RESULTS:The dynamic range and sensitivity of the let-7a miRNA quantification scheme were evaluated, the result showed the assay could precisely detect 10 copies of mature let-7a miRNA in as few as 0.05 ng of total RNA of gastric mucosa.The results of specificity analysis showed no fluorescence signal occurred even though 50 ng of human genomic DNA was added to the reverse transcription (RT) reaction.The expression level of let-7a miRNA in gastric tumor tissues was significantly lower compared to normal tissues in 14 samples from 32 patients. CONCLUSION:The stem-loop RT-PCR is a reliable method to detect let-7a miRNA which may play an important role in the development of gastric carcinoma.
Depressive symptom is one of the most common symptoms in patients with irritable bowel syndrome (IBS), but its pathogenetic mechanisms remain unclear. As a voxel-level graph theory analysis method, degree centrality (DC) can provide a new perspective for exploring the abnormalities of whole-brain functional network of IBS with depressive symptoms (DEP-IBS).DC, voxel-wise image and clinical symptoms correlation and seed-based functional connectivity (FC) analyses were performed in 28 DEP-IBS patients, 21 IBS without depressive symptoms (nDEP-IBS) patients and 36 matched healthy controls (HC) to reveal the abnormalities of whole brain FC in DEP-IBS.Compared to nDEP-IBS patients and HC, DEP-IBS patients showed significant decrease of DC in the left insula and increase of DC in the left precentral gyrus. The DC's z-scores of the left insula negatively correlated with depression severity in DEP-IBS patients. Compared to nDEP-IBS patients, DEP-IBS patients showed increased left insula-related FC in the left inferior parietal lobule and right inferior occipital gyrus, and decreased left insula-related FC in the left precentral gyrus, right supplementary motor area (SMA), and postcentral gyrus. In DEP-IBS patients, abstracted clusters' mean FC in the right SMA negatively correlated with depressive symptoms.DEP-IBS patients have abnormal FC in brain regions associated with the fronto-limbic and sensorimotor networks, especially insula and SMA, which explains the vicious circle between negative emotion and gastrointestinal symptoms in IBS. Identification of such alterations may facilitate earlier and more accurate diagnosis of depression in IBS, and development of effective treatment strategies.
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