TMEM97/Sigma 2 Receptor Increases Estrogen Receptor α Activity in Promoting Breast Cancer Cell Growth.

Aberrant estrogen receptor (ER) signaling is a major driver of breast tumor growth and progression. Sigma 2 receptor has long been implicated in breast carcinogenesis based on pharmacological studies, but its molecular identity had been elusive until TMEM97 was identified as the receptor. Herein, we report that the TMEM97/sigma 2 receptor is highly expressed in ER-positive breast tumors and its expression is strongly correlated with ERs and progesterone receptors (PRs) but not with HER2 status. High expression levels of TMEM97 are associated with reduced overall survival of patients. Breast cancer cells with increased expression of TMEM97 had a growth advantage over the control cells under both nutrition-limiting and sufficient conditions, while the knockdown of TMEM97 expression reduced tumor cell proliferations. When compared to their vector control cells, MCF7 and T47D cells with increased TMEM97 expression presented increased resistance to tamoxifen treatment and also grew better under estrogen-depleted conditions. The TMEM97/sigma 2 receptor enhanced the ERα transcriptional activities and increased the expression of genes responsive to estrogen treatment. Increased TMEM97 also stimulated the mTOR/S6K1 signaling pathways in the MCF7 and T47D cells. The increased level of active, phosphorylated ERα, and the enhanced resistance to tamoxifen treatment with increased TMEM97, could be blocked by an mTOR inhibitor. The knockdown of TMEM97 expression reduced the ERα and mTOR/S6K1 signaling activities, rendering the cells with an increased sensitivity to tamoxifen. The observations suggest that the TMEM97/sigma 2 receptor is a novel regulator of ERα activities in breast tumor cell growth.

Interaction of pregnane X receptor with hypoxia-inducible factor-1 regulates chemoresistance of prostate cancer cells.

Aim: The nuclear pregnane X receptor (PXR) is a pivotal regulator of steroid and xenobiotics metabolism and plays an important role in shaping tumor cell responses to chemotherapy. Hypoxia within tumor tissue has multifaceted effects, including multiple drug resistance. The goal of this study was to determine whether PXR contributes to hypoxia-induced drug resistance. Methods: Metastatic prostate cancer cells were used to study the interaction of PXR and hypoxia-inducible factor-1 (HIF-1 in drug resistance associated with hypoxia. The activities of PXR and HIF-1 were determined by assays for its reporter gene or target gene expression. Co-immunoprecipitation (Co-IP) was used to determine the interaction of PXR and HIF-1. Ablation or inhibition of PXR or HIF-1 was used to determine their roles in hypoxia-induced chemoresistance. Results: PXR was activated by hypoxia, leading to increased expression of multidrug resistance protein 1 (MDR1). Inhibition of PXR by pharmacological compounds or depletion by shRNAs reduced the hypoxic induction of MDR1 and sensitized prostate cancer cells to chemotherapy under hypoxia. HIF-1 was required for PXR activation under hypoxia. Co-immunoprecipitation results showed that HIF-1 and PXR could physically interact with each other, leading to crosstalk between these two transcription factors. Conclusion: PXR contributes to hypoxia-induced drug resistance in prostate cancer cells through its interaction with HIF-1.

Risk factors and potential predictors of pulmonary embolism in cancer patients undergoing thoracic and abdominopelvic surgery: a case control study.

BACKGROUND: Postoperative pulmonary embolism (PE) is a severe complication leading to death and poor prognosis. The present study investigated the risk factors and potential predictors of PE in cancer patients undergoing thoracic and abdominopelvic surgery. METHODS: A retrospective study was conducted on the patients with cancer who underwent thoracic and abdominopelvic surgery in Sichuan Cancer Hospital from December 2016 to January 2022. A total of 189 patients were included, in which 63 patients diagnosed PE after operation were collected as PE group, and 126 patients matched by age, type of cancer and cancer location were enrolled as control group. Conditional logistic regression was conducted to analyze the association between PE and risk factors. Predictive values of key factors were compared by the area under the curve (AUC) in receiver operating characteristic curve (ROC) curve. RESULTS: Conditional multivariate logistic regression showed that BMI (odds ratio [OR] 4.065, 95% confidence interval [CI] 1.138-14.527; p = 0.031), intraoperative hypotension time (OR 4.095, 95% CI 1.367-12.266; p = 0.009), same day fluid balance (OR 0.245, 95% CI 0.061-0.684; p = 0.048), and postoperative D-Dimer (OR 1.693, 95% CI 1.098-2.611; p = 0.017) were significantly related to the occurrence of postoperative PE. Postoperative D-Dimer had the maximal AUC value 0.8014 (95% CI: 0.7260-0.8770) for predicting PE, with a cutoff value of 1.505 µg/ml. CONCLUSIONS: BMI, intraoperative hypotension time, lower same day fluid balance and postoperative D-dimer are independent risk factors associated with PE in cancer patients undergoing thoracic and abdominopelvic surgery. Postoperative D-Dimer seems to be a good indicator to predict postoperative PE for cancer patients.

Impact on Short-Term Complications of Early Oral Feeding in Patients with Esophageal Cancer After Esophagectomy.

To evaluate early oral feeding (EOF) in short-term outcomes of patients with esophageal cancer after esophagectomy. 179 patients with esophageal cancer who underwent esophagectomy between January 2016 and February 2018 were enrolled for this study. 87 patients with EOF without nasogastric tube or nasogastric tube was removed within 24 h, were selected as the experimental group, whereas 92 patients who received nasojejunal tube feeding were set as the control group. All laboratory testing, clinical features, and hospitalization expenses were compared between the two groups. No statistical significance was observed between the two groups in hemoglobin, albumin, and prealbumin levels after esophagectomy. Notably, there was no significant difference in the incidence of severe pneumonia and anastomotic leakage between the two groups. Admittance period, postoperative defecation time, and medical expenses were significantly decreased among patients with EOF (P < 0.001). Multivariate Cox multiple-factor regression analysis revealed that there was no correlation between EOF and the risk of anastomotic leakage. EOF might not be a risk factor for increasing the incidence of severe pneumonia and anastomotic leakage in patients with esophageal cancer after esophagectomy, and it could reduce the hospitalization period as well as control medical expenses.

Tumor suppressor function of miR-129-5p in lung cancer.

Lung cancer causes severe health problems worldwide and, in China, besides being the principal cause of mortality among urbanites, it is the second leading cause of mortality in the rural population, preceded by hepatocellular carcinoma. Between 80 and 85% of lung cancer is classified as non-small cell lung cancer (NSCLC). The high mobility group box 1 (HMGB1) protein serves an important function in the tumor microenvironment and antitumor response, and may be targeted by microRNA (miR). In the present study, miR-129-5p was identified to target HMGB1 and miR-129-5p exhibited low expression levels in NSCLC tissues. Overexpression of miR-129-5p inhibited cell proliferation and promoted cell apoptosis. In conclusion, the results of the present study suggested the inhibitory function of miR-129-5p and revealed a novel therapeutic target for further investigation.

State variable technique islanding detection using time-frequency energy analysis for DFIG wind turbine in microgrid system.

This paper introduces a new combined technique for wind turbine islanding detection using the trajectory of state variables and wavelet transform in microgrid system. The proposed relay is utilized of energy variation state of time-frequency transform coefficients of local signals in two-dimensional space. In order to improve of the proposed relay performance, a signal selection method based on the correlation concept between islanding and non-islanding signals. From of all patterns, the best of them with high correlation in islanding status is selected for the proposed relay learning. A neuro-fuzzy machine is used as learning of selected patterns to avoid threshold selection. The proposed technique is utilized to wind turbine islanding detection in a microgrid system contains various types of distributed generation including wind turbine, Combined Heat and Power (CHP) and photovoltaic system. Many islanding and non-islanding situation including motor starting, various load and capacitor switching in various operation conditions in the studied microgrid are simulated. Millstone characteristics of the proposed technique are included passive-based technique, negligible None Detection Zone (NDZ), suitable for microgrid application, performance increment in detection and fast detection time. Operation results of the proposed relay in various conditions confirm the performance of the proposed detection relay.

Does cervical lymph node recurrence after oesophagectomy or definitive chemoradiotherapy for thoracic oesophageal squamous cell carcinoma benefit from salvage treatment?

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'Does cervical lymph node recurrence after oesophagectomy or definitive chemoradiotherapy for thoracic oesophageal squamous cell carcinoma benefit from salvage treatment?' Altogether, 659 articles were found using the reported search, of which 8 represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results of these articles were tabulated. All were retrospective or institutional reports. Seven of the 8 articles suggested that cervical lymphadenectomy (LD) or multimodal treatment with LD and radiotherapy (RT)/chemoradiotherapy (CRT) was associated with good outcomes in patients with cervical lymph node (LN) recurrence after curative oesophagectomy for thoracic oesophageal squamous cell carcinoma (ESCC). Salvage cervical LD was the main treatment and could achieve locoregional disease control and prolonged survival. It was safe with no postoperative mortality, although minor LD complications such as recurrent laryngeal nerve palsy were observed. Most reports highlighted that a solitary cervical LN relapse after curative oesophagectomy could be considered a good prognostic indicator for salvage cervical LD or multimodal treatment. Patients with microscopic residual tumour after salvage cervical LD or suspected extensive metastasis might benefit from a combination of LD and CRT. One article described salvage RT alone, again with a positive effect on survival. Conversely, data suggested that salvage LD in patients after definitive CRT for thoracic ESCC was not likely to control locoregional disease.

Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters.

Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing enzymes (DMEs) and efflux transporters promote the metabolism, elimination, and detoxification of chemotherapeutic agents. Consequently, elevated levels of DMEs and efflux transporters reduce the therapeutic effectiveness of chemotherapeutics and, often, lead to treatment failure. Nuclear receptors, especially pregnane X receptor (PXR, NR1I2) and constitutive androstane activated receptor (CAR, NR1I3), are increasingly recognized for their role in xenobiotic metabolism and clearance as well as their role in the development of multidrug resistance (MDR) during chemotherapy. Promiscuous xenobiotic receptors, including PXR and CAR, govern the inducible expressions of a broad spectrum of target genes that encode phase I DMEs, phase II DMEs, and efflux transporters. Recent studies conducted by a number of groups, including ours, have revealed that PXR and CAR play pivotal roles in the development of MDR in various human carcinomas, including prostate, colon, ovarian, and esophageal squamous cell carcinomas. Accordingly, PXR/CAR expression levels and/or activation statuses may predict prognosis and identify the risk of drug resistance in patients subjected to chemotherapy. Further, PXR/CAR antagonists, when used in combination with existing chemotherapeutics that activate PXR/CAR, are feasible and promising options that could be utilized to overcome or, at least, attenuate MDR in cancer cells.

Cyp2c19 genotype and omeprazole hydroxylation phenotype in Chinese Li population.

1. CYP2C19 is a polymorphism of cytochrome P450, which is responsible for the metabolism of many drugs. The genetic polymorphism shows interethnic variation and it has been demonstrated that the frequency of poor metabolizers (PM) and the distribution of alleles of CYP2C19 vary among Chinese ethnic nationalities. The aim of the present study was to investigate the incidence of CYP2C19 polymorphism in the Chinese Li population. 2. One hundred and sixty-five unrelated healthy Li subjects were identified with respect to CYP2C19 by genotype and phenotype analysis. A polymerase chain reaction-restriction fragment length polymorphism method was performed for genotyping. The plasma concentrations of omeprazole and 5-hydroxyomeprazole were assayed by reversed-phase high-performance liquid chromatography and the omeprazole hydroxylation index (HI) was determined. 3. The frequency distribution of omeprazole HI is bimodal and the antimode for HI was estimated to be 5.6. The prevalence of phenotypic PM in the Li population was 16.6% (13.7-19.5; 95% CI). Genotype analysis revealed that the frequencies of the CYP2C19*1, *2 and *3 alleles in the Li population were 0.617 (0.590-0.644; 95% CI), 0.353 (0.327-0.379; 95% CI) and 0.031 (0.021-0.041; 95% CI), respectively. The frequency of genotypic PM was 14.7% (11.9-17.5; 95% CI), which almost agreed with the frequency of phenotypic PM. Omeprazole HI was significantly different among the different genotype groups (P < 0.05). 4. The present study revealed that the incidence of the CYP2C19*1, *2 and *3 alleles in Chinese Li population is different to that in other ethnic populations of China. There was an obvious relationship between CYP2C19 genotype and omeprazole hydroxylation phenotype, and about 90% of phenotypic PM can be explained by the CYP2C19*2 and *3 alleles.