Discovery of a novel Coumarin-Dihydroquinoxalone derivative MY-673 as a tubulin polymerization inhibitor capable of inhibiting the ERK pathway with potent anti-gastric cancer activities.

As a class of microtubule targeting agents, colchicine binding site inhibitors (CBSIs) are considered as promising drug candidates for cancer therapy. However, due to adverse reactions, there are currently no CBSIs approved by FDA for cancer treatment. Therefore, extensive efforts are still encouraged to find novel CBSIs with different chemical structures and better anticancer efficacies. In this work, we designed and synthesized a new coumarin-dihydroquinoxalone derivative, MY-673, and evaluated its anticancer potency in vitro and in vivo. We confirmed that MY-673 was a potent CBSI that it not only inhibited tubulin polymerization, but also exhibited significant inhibitory potency on the growth of 13 cancer cells with IC50 values from 11.7 nM to 395.9 nM. Based on the results of kinase panel screening, MY-673 could inhibit ERK (extracellular regulated protein kinases) pathways-related kinases. We further confirmed that MY-673 could inhibit ERK signaling pathway in MGC-803 and HGC-27 cells, and then affected the expression level of SMAD4 protein in TGF-ß (transforming growth factor ß) /SMAD (small mother against decapentaplegic) signaling pathway using the western blotting assay. In addition, compound MY-673 could effectively inhibit cell proliferation, migration and induce cell apoptosis. We also further confirmed the in vivo efficacy of MY-673 in inhibiting tumor growth using the MGC-803 xenograft tumor model. At 20 mg/kg, the TGI rate was 85.9%, and it did not cause obvious toxicity to the main organs of mice. Together, the results we report here indicated that MY-673 was a promising CBSI for cancer treatment, which was capable of inhibiting the ERK pathway with potent antiproliferative activities in vitro and in vivo.

Anion-Controlled Assembly of a Silver-Responsive Bifunctional Coordination Polymer with Detection and Large Adsorption Capacity.

The recognition and adsorption of silver ions (Ag+) from industrial wastewater are necessary but still challenging. Herein, we constructed four Zn(II)-based coordination polymers (CPs), namely, [Zn(btap)2(NO3)2]n (1), [Zn(btap)(SO4)(H2O)3]n (2), {[Zn(btap)2(H2O)2]·(ClO4)2}n (3), and [Zn(btap)Cl2]n (4), by using 3,5-bis(triazol-1-yl)pyridine (btap) with different anionic Zn(II) salts. The crystal structures of 1-4, varying from one-dimensional beaded (1) and zigzag chain (2) to two-dimensional sql (3) and bex (4) typologies, were regulated by the coordination modes of btap and the counter-anions. The water stability, pH stability, thermostability, and luminescent properties of the CPs were investigated. The luminescence performances in a series of cations and anions were also explored. Considering the high density of chloride groups in the structure, 4 showed luminescence sensing for Ag+ [KSV = 9188.45 M-1 and a limit of detection (LOD) of 4.9 µM], as well as an excellent ability for Ag+ adsorption in aqueous solution (maximum adsorption capacity, 653.3 mg/g). Additionally, anti-interference experiments revealed that 4 had excellent recognition and adsorption capacities for Ag+ even when multiple ions coexisted. Moreover, XRD, EDS, and XPS analyses confirmed that the coordination of Ag+ with chloride groups in 4 resulted in excellent adsorption capacity and prevented ligand-to-ligand electron transfer, showing excellent detection ability. Suitable coordination sites were introduced to interact strongly with Ag+, along with detection and large adsorption capacity. Our strategy can effectively design and develop multifunctional CP-based materials, which are applicable in removal processes and environmental protection, by regulating anions in the self-assembly and introducing CP functional groups.

Progress of tubulin polymerization activity detection methods.

Tubulin, an important target in tumor therapy, is one of the hotspots in the field of antineoplastic drugs in recent years, and it is of great significance to design and screen new inhibitors for this target. Natural products and chemical synthetic drugs are the main sources of tubulin inhibitors. However, due to the variety of compound structure types, it has always been difficult for researchers to screen out polymerization inhibitors with simple operation, high efficiency and low cost. A large number of articles have reported the screening methods of tubulin inhibitors and their biological activity. In this article, the biological activity detection methods of tubulin polymerization inhibitors are reviewed. Thus, it provides a theoretical basis for the further study of tubulin polymerization inhibitors and the selection of methods for tubulin inhibitors.

WITHDRAWN: Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization.

Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84 µM (MGC-803 cells), 6.82 µM (A549 cells), 1.61 µM (Kyse30 cells), 1.49 µM (Kyse450 cells), 2.08 µM (Kyse510 cells) and 2.24 µM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of ß-tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in time and dose-dependent manners. All the results suggest that the indoline derivatives might be a class of novel tubulin inhibitors with potential anticancer activity and is worthy of further study.

Discovery of indoline derivatives as anticancer agents via inhibition of tubulin polymerization.

Human esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers in human digestive system. It is necessary to discover novel antitumor agents for the treatment of esophageal cancers because of its poor prognosis. Indoline has been reported as an efficient anticancer fragment to design novel anticancer agents. In this work, indoline derivatives were designed, synthesized and explored their anticancer activity. Compound 9d, which exhibited potent antiproliferative activity with IC50 values of 1.84 µM (MGC-803 cells), 6.82 µM (A549 cells), 1.61 µM (Kyse30 cells), 1.49 µM (Kyse450 cells), 2.08 µM (Kyse510 cells) and 2.24 µM (EC-109 cells), respectively. The most active compound 9d was identified as a tubulin inhibitor targeting colchicine binding site with an IC50 value of 3.4 µM. Compound 9d could strongly suppress the tubulin polymerization in Kyse450 cells. The results of molecular docking also suggested compound 9d could tightly bind into the colchicine binding site of tubulin. Besides, compound 9d inhibited the growth of KYSE450 cells in a time and dose-dependent manner. All the results suggest that the indoline derivatives may be a class of novel tubulin inhibitors with potential anticancer activity, and which is worthy of further study.

Transcriptome analysis of differentially expressed genes in the red swamp crayfish Procambarus clarkii challenged with Aeromonas hydrophila.

As an important economic species in China, aquaculture of the crayfish Procambarus clarkii has suffered huge losses due to infection by pathogenic bacteria, mainly by Aeromonas hydrophila, which leads to high mortality and huge economic loss. To better understand the immune response of crayfish against bacterial infection, we compared and analyzed transcriptome data of hepatopancreatic tissue from P. clarkii that were either challenged with A. hydrophila or treated with PBS. After assembly and annotation of the data, 32,041 unigenes with an average length of 1512 base pairs were identified. Compared to control group, Differential gene expression (DEG) analysis revealed 608 DEGs were obtained, of which 274 unigenes were upregulated and 334 were downregulated in the A. hydrophila group. Furthermore, the expression levels of eight selected immune-related DEGs were validated by qRT-PCR, substantiating the reliability of RNA-seq results. This study not only provides effective data support for immune defense strategies of P. clarkii in response to bacterial infections, but also provides new information about the P. clarkii immune system and defense mechanisms, and a valuable basis for further studies to elucidate the molecular immune mechanisms of this species.

Review of NEDDylation inhibition activity detection methods.

NEDDylation is a post-translational modification of a protein, which transfers Ubiquitin like protein NEDD8 (Neuronal Precursor Cell-expressed Developmentally Down-regulated Protein 8) to the lysine residue of the product through a three-stage enzymatic reaction, and widely regulates many biological processes, such as cell cycle signal transduction and immune recognition. In the past ten years, we have witnessed tremendous progress in the study of protein ubiquitination modification, from modification mechanisms to drug development. Which suggests that inhibition of NEDDylation is an effective way to inhibit tumor. A variety of biological detection methods have been developed during the development of the inhibitor. In this review, we briefly introduced the modification process and substrates of NEDDylation, and discussed detection methods of NEDDylation activity in detail. This review will provide an up-to-date and comprehensive review of the methods for detecting NEDDylation activity that will contribute to NEDDylation inhibitor development.

Wild-type p53-induced phosphatase 1 down-regulation promotes apoptosis by activating the DNA damage-response pathway in amyotrophic lateral sclerosis.

Accumulation of DNA damage has been detected in the spinal cord of patients as well as in the G93A mouse model of amyotrophic lateral sclerosis (ALS). Wild-type p53-induced phosphatase 1 (Wip1) is a p53-inducible serine/threonine phosphatase that terminates DNA-damage responses via dephosphorylation of DNA-damage response proteins, namely ataxia-telangiectasia mutated (ATM) kinase, checkpoint kinase 2, and p53, thus enhancing cell proliferation. However, the role of Wip1, DNA-damage responses, and their interaction in ALS development remains to be elucidated. Here, we showed that Wip1 expression levels were substantially decreased in ALS motor neurons compared with wild-type controls both in vivo and in vitro. The DNA-damage response was activated in superoxide dismutase 1 (SOD1) G93A-transfected cells. However, increased expression of Wip1 improved cell viability and inhibited the DNA-damage response in mutated SOD1G93A cells. Further studies demonstrated that decreased Wip1 expression reduced cell viability and further activated the DNA-damage response in chronic H2O2-treated NSC34 cells. In contrast, Wip1 promoted cell survival and suppressed DNA damage-induced apoptosis during persistent DNA damage conditions. Over-expression of Wip1 in the central nervous system (CNS) can delay the onset of disease symptoms, extended the survival, decreased MN loss improved motor function and inhibit the DNA-damage response in SOD1 G93A mice. Furthermore, homeodomain-interacting protein kinase 2 (HIPK2) promoted the degradation of Wip1 via the ubiquitin-proteasome system during chronic stress. These findings indicate that persistent accumulation of DNA damage and subsequent chronic activation of the downstream DNA damage-response ATM and p53 pro-apoptotic signaling pathways may trigger neuronal dysfunction and neuronal death in ALS. Wip1 may play a protective role by targeting the DNA-damage response in ALS motor neurons. Importantly, these findings provide a novel direction for therapeutic options for patients with ALS.

Recent advances in nanomaterial-based electrochemical and optical sensing platforms for microRNA assays.

MicroRNA (MiRNA) plays a crucial role in biological cells to enable assessment of a cancer's development stage. Increasing evidence has shown that the accurate and sensitive detection of miRNA holds the key toward correct disease diagnosis. However, some characteristics of miRNAs, such as their short chains, low concentration, and similar sequences, make it difficult to detect miRNA in biological samples. Nanomaterials usually have good optical, electronic, and mechanical properties and therefore provide new possibilities for improving the performance of miRNA assays. Many different sorts of nanomaterials, including metal nanomaterials, carbon nanomaterials, quantum dots, and transition-metal dichalcogenides, have been used to construct optical and electrochemical assays for miRNA and have shown attractive results. This review describes recent efforts in the application of nanomaterials as sensing elements in electrochemical and optical miRNA assays. The analytical figures of merit of various methods for the detection of miRNA are compared in the present article. The current capabilities, limitations, and future challenges in miRNA detection and analysis based on nanomaterials are also addressed.

Transient risk factors for acute occupational hand injuries among metal manufacturing workers: A case-crossover study in southern China.

BACKGROUND: Acute occupational hand injuries are a common occurrence in China's metal manufacturing industries. This study aimed to explore the transient risk factors for acute occupational hand injuries among metal manufacturing workers. METHODS: A case-crossover study was conducted from October 2013 through December 2013 in Zhongshan city, southern China. Face-to-face interviews were used to collect information on the occurrence of 12 transient risk factors during the "hazard" period (a 60-min period prior to occupational hand injury) and a "control" period (the week before the injury). RESULTS: One hundred ninety-four qualified acute occupational hand injury cases (139 male, 55 female) were enrolled in this study, with a mean age of 35.5 (standard deviation [SD] 10.4) years. The most common (64.9%) type of work was punching, and the most common injures were crushes and fractures (28.8 and 23.7%, respectively). Of these cases, 62.9% were regarded as severe or major. Among the 12 transient risk factors, 11 ones were significantly associated with acute occupational hand injuries occurring during the hazard period: "replacing sharp knives" (IRR = 14.38, 95%CI 11.43-18.08), "using malfunctioning machinery" (IRR = 30.59, 95%CI 17.84-52.48), "using different tools" (IRR = 10.96, 95%CI 4.77-25.17), "using different machines" (IRR = 5.20, 95%CI 2.25-12.00), "performing unusual work tasks" (IRR = 24.38, 95%CI 14.11-42.15), "working overtime" (IRR = 13.40, 95%CI 7.70-23.29), "performing a task with a different method" (IRR = 56.41, 95%CI 23.61-134.81), "being in a bad mood" (IRR = 108.11, 95%CI 55.10-211.11), "feeling ill" (RR = 12.27, 95%CI 4.95-30.43), "rushing" (IRR = 5.16, 95%CI 2.49-10.70), and "not wearing gloves" (IRR = 1.63, 95%CI 1.23-2.15). CONCLUSIONS: Our study suggested that multiple transient risk factors were responsible for the acute occupational hand injuries in China's metal manufacturing industries. Am. J. Ind. Med. 59:832-840, 2016. © 2016 Wiley Periodicals, Inc.

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid.

BACKGROUND: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). However, the molecular mechanisms have not been elucidated yet. Homer family protein Homer1b/c is expressed widely in the central nervous system and plays important roles in neurological diseases. In this study, we explored whether Homer1b/c was involved in SOD1 mutation-linked ALS. RESULTS: In vitro studies showed that the SOD1 G93A mutation induced an increase of Homer1b/c expression at both the mRNA and protein levels in NSC34 cells. Knockdown of Homer1b/c expression using its short interfering RNA (siRNA) (si-Homer1) protected SOD1 G93A NSC34 cells from apoptosis. The expressions of Homer1b/c and apoptosis-related protein Bax were also suppressed, while Bcl-2 was increased by lithium and valproic acid (VPA) in SOD1 G93A NSC34 cells. In vivo, both the mRNA and protein levels of Homer1b/c were increased significantly in the lumbar spinal cord in SOD1 G93A transgenic mice compared with wild type (WT) mice. Moreover, lithium and VPA treatment suppressed the expression of Homer1b/c in SOD1 G93A mice. CONCLUSION: The suppression of SOD1 G93A mutation-induced Homer1b/c upregulation protected ALS against neuronal apoptosis, which is a novel mechanism of the neuroprotective effect of lithium and VPA. This study provides new insights into pathogenesis and treatment of ALS.

Simultaneous type III congenital esophageal atresia and patent ductus arteriosus in a low-weight patient: A case report.

BACKGROUND: We report a low-birth-weight child (1.8 kg) with neonatal type III congenital esophageal atresia (CEA) combined with symptomatic patent ductus arteriosus (PDA). After comprehensive evaluation, esophageal anastomosis was performed on postnatal day 11 after excluding surgical contraindications, and arterial catheter ligation was performed at the same time. Concurrent surgery for CEA combined with PDA has not been clearly reported in the literature. CASE SUMMARY: We report a 6-day-old female child with type III CEA and PDA. The patient presented with foam at the mouth after birth, cough and shortness of breath after feeding. At another hospital, she was considered to have neonatal pneumonia, neonatal jaundice and congenital heart disease and transferred to our hospital. After iodine oil radiography of the esophagus and echocardiography we confirmed diagnosis of CEA and PDA. The diameter of the PDA was 8 mm, with obvious left to right shunting. We performed right rear extrapleural orificium fistula ligation and esophageal anastomosis, and ligation of PDA via left axilla straight incision after 5 d of hospitalization. The operations were successful, and the incision healed after 12 d, and the patient was discharged. We re-examined the patient 1 mo after surgery. She did not vomit when she ate rice flour. Esophageal angiography showed no stricture of the anastomotic stoma. The patient weighed 3.2 kg. CONCLUSION: For CEA patients with multiple risk factors, comprehensive, timely and accurate diagnosis and evaluation, and early treatment may improve prognosis.

Obesity, malnutrition, and the prevalence and outcome of hypertension: Evidence from the National Health and Nutrition Examination Survey.

Background: Nutritionally unhealthy obesity is a newly introduced phenotype characterized by a combined condition of malnutrition and obesity. This study aims to explore the combined influence of obesity and nutritional status on the prevalence and outcome of hypertension. Methods: Participants collected from the National Health and Nutrition Examination Survey (NHANES) database were divided into four subgroups according to their obesity and nutritional conditions, as defined by waist circumference and serum albumin concentration. The lean-well-nourished was set as the reference group. Logistic regression models were applied to evaluate the hypertension risk. Kaplan-Meier analysis and Cox proportional hazard regression models were used to assess the survival curve and outcome risk of participants with hypertension. Results: A total of 28,554 participants with 10,625 hypertension patients were included in the analysis. The lean-malnourished group showed a lower hypertension risk (odds ratio [OR] 0.85, 95% confidence interval [CI]: 0.77-0.94), while the obese-well-nourished condition elevated the risk (OR 1.47, 95% CI: 1.3-1.67). Two malnourished groups had higher mortality risks (HR 1.42, 95% CI: 1.12-1.80 and HR 1.31, 95% CI: 1.03-1.69 for the lean and obese, respectively) than the reference group. The outcome risk of the obese-well-nourished group (HR 1.02, 95% CI: 0.76-1.36) was similar to the lean-well-nourished. Conclusion: Malnutrition was associated with a lower risk of developing hypertension in both lean and obese participants, but it was associated with a worse outcome once the hypertension is present. The lean-malnourished hypertension patients had the highest all-cause mortality risk followed by the obese-malnourished. The obese-well-nourished hypertension patients showed a similar mortality risk to the lean-well-nourished hypertension patients.

Albuminuria independently predicts cardiovascular and all-cause mortality in a middle-aged and elderly Chinese population.

AIM: To investigate the relationship between albuminuria and mortality in a middle-aged-to-elderly Chinese population. METHODS: A total of 2,344 individuals aged over 40 in the same district were interviewed and followed up for 4 years. Information on survival or cause of death was recorded. A total of 2,181 participants with detailed information were finally recruited. Baseline overnight urine samples were obtained to measure urinary albumin and creatinine. The urinary albumin excretion rate was expressed as albumin-to-creatinine ratio (ACR). Participants were divided into three groups, according to their ACR: normoalbuminuria (ACR < 30 mg/g), microalbuminuria (≥ 30 - < 300 mg/g ACR) and macroalbuminuria (ACR ≥ 300 mg/g). The Cox proportional hazard model was used to analyze the relationships between albuminuria and cardiovascular and all-cause mortalities. RESULTS: Seventy-seven deaths with known causes were registered. The prevalences of microalbuminuria and macroalbuminuria at baseline were 8.3% and 1.6%, respectively. Cardiovascular mortalities in the normoalbuminuria, microalbuminuria and macroalbuminuria groups were 2.4, 11.0, and 36.8/1,000 person years (pyrs) respectively, and all-cause mortalities were 6.9, 20.6, and 58.8/1,000 pyrs. After adjusting for confounding factors, the relative risks (RR) of cardiovascular mortality were 2.72 (95% CI, 1.06-4.20) in the microalbuminuria group, and 4.87 (95% CI, 2.46-9.45) in the macroalbuminuria group. Adjusted RRs for all-cause mortality were 2.01 (95% CI, 0.96-4.77) and 3.76 (95% CI, 1.52-7.15) in the two groups, respectively. CONCLUSION: Albuminuria is a useful predictor of cardiovascular mortality and all-cause mortality in the general population.

[Association between left ventricular twist/untwist and diastolic dysfunction of high cardiovascular risk population in the community].

OBJECTIVE: To assess the association between left ventricular (LV) twist and untwist with the severity of diastolic dysfunction of high cardiovascular risk population in the community. METHODS: This cross-sectional survey was performed in high cardiovascular risk people with normal left ventricular (LV) ejection fraction in an urban community of Beijing (n = 620). Normal LV diastolic function was defined in 305 subjects, mild diastolic dysfunction in 266 subjects and moderate/severe diastolic dysfunction in 49 subjects. Peak LV twist, peak twist velocity, peak untwist velocity and untwist rate were measured in apical and basal short-axis images using speckle tracking echocardiography. RESULTS: Peak LV twist was similar among subjects with normal diastolic function, mild diastolic dysfunction and moderate/severe diastolic dysfunction. Peak twist velocity [(129.3 ± 45.3)°/s vs. (118.0 ± 36.2)°/s] and untwist velocity [(-132.9 ± 50.4) °/s vs. (-121.2 ± 41.4)°/s] were significantly higher in mild diastolic dysfunction group than in normal diastolic function group (all P < 0.01) and similar between normal diastolic function and moderate/severe diastolic dysfunction group (P > 0.05). Untwist rate of moderate/severe diastolic dysfunction decreased significantly than that of normal diastolic function [(41.9 ± 32.9)°/s vs. (57.7 ± 36.2) °/s, P < 0.01] and mild diastolic dysfunction group [(41.9 ± 32.9)°/s vs. (60.9 ± 39.9) °/s, P < 0.01]. CONCLUSIONS: Twist and untwist parameters are increased/preserved in population with normal systolic function and mild diastolic dysfunction and "normalized" or reduced in those with advanced diastolic dysfunction. The maintaining (if not increasing) of LV twist in early diastolic dysfunction might serve as a compensatory mechanism in case of reduced myocardial relaxation in these subjects.

[Association between serum uric acid and brachial ankle pulse wave velocity in Beijing community residents].

OBJECTIVE: To observe the relationship between serum uric acid and brachial ankle pulse wave velocity (ba-PWV) in Beijing community individuals. METHODS: This epidemiological survey was performed in residents of two communities from Shijingshan District in Beijing from 2007 to 2008. Cardiovascular risk factors and ba-PWV were measured. Two thousand five hundred and forty three individuals with both ba-PWV and serum uric acid measurements were included. Ba-PWV ≥ 1400 cm/s was defined as abnormal. The individuals were divided into four groups (Q1, Q2, Q3 and Q4 group) according to the gender-specific quartiles of serum uric acid. Univariate logistic regression was used to evaluate the relation between various cardiovascular risk factors and ba-PWV abnormality. Multivariate logistic regression was used to evaluate the relation between serum uric acid and ba-PWV abnormality after adjusting for other cardiovascular risk factors. RESULTS: Body mass index, triglyeride and prevalence of hypertension increased with increasing levels of serum uric acid (all P < 0.01). Univariate logistic regression analysis showed that age, gender, smoking, hypertension, systolic blood pressure, diastolic blood pressure, diabetes, body mass index, total cholesterol, triglyeride and estimated glomerular filtration rate were related with ba-PWV abnormality (all P < 0.01). Compared with Q1 group, ba-PWV abnormality OR value of Q4 group was 1.73 (95%CI: 1.34 - 2.22, P < 0.01). Multivariate logistic regression revealed that ba-PWV abnormality OR value of Q4 group was 1.66 (95%CI: 1.16 - 2.37, P < 0.01 ) after adjusting for age, gender, smoking, hypertension, systolic blood pressure, diastolic blood pressure, diabetes, body mass index, total cholesterol, triglyeride and estimated glomerular filtration rate when compared with Q1 group and OR values were 1.55 (95%CI: 0.88 - 2.74, P > 0.05) and 1.65 (95%CI: 1.04 - 2.64, P < 0.05) in male and female respectively. CONCLUSION: Increased serum uric acid was independently associated with ba-PWV abnormality in Beijing community residents.

Effects of Transcutaneous Electrical Acupoint Stimulation on Ovarian Responses and Pregnancy Outcomes in Patients Undergoing IVF-ET: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the influence of different transcutaneous electrical acupoint stimulation (TEAS) modes on ovarian responses and pregnancy outcomes in patients with infertility undergoing in vitro fertilization and embryo transfer (IVF-ET). METHODS: Two hundred infertility patients undergoing IVF-ET were divided randomly into experimental groups (TEAS groups: E-I, E-II, E-III, and E-IV, 40 cases each group) and a control group (mock TEAS group, 40 patients) using the random number method. The patients in the experimental groups received TEAS treatment of 20, 30, 40 and 50 mA for the E-I, E-II, E-III and E-IV groups, respectively. The control group received a treatment of 5 mA. TEAS was applied at acupoints of Guanyuan (RN 4), Zhongji (RN 3), Sanyinjiao (SP 6), Zigong (EX-CA 1), and Taixi (KI 13), once a day for 30 min each time for a treatment period of 10-13 d. Treatment effect was assessed using the following indicators: endometrial thickness on the 6th day of gonadotropin treatment (GN6 day), endometrial thickness on the day on chorionic gonadotropin administration (HCG day), number of ovarian follicles on HCG day, number of ova captured, amount of estrogen required for each harvested ova, number of mature ova divided by the total number of ova, percentage of high-quality embryos, and clinical pregnancy. RESULTS: Endometrial thickness in the experimental groups on the HCG day was significantly better than that of the control group after TEAS stimulation (P=0.01). TEAS exhibited a greater impact on the number of ova captured (P=0.003). However, the effect of TEAS stimulation on the high-quality embryo rate and clinical pregnancy in patients was not statistically significant (P>0.05). CONCLUSIONS: TEAS is an effective method in improving the ovarian state. When the stimulus intensity was at 40 mA and above, it could be helpful to improve the patient's endometrial condition and endometrial receptivity and to retrieve more oocytes. (Trial registration No. ChiCTR-TRC-11001780).

Identification of key genes and pathway related to chemoresistance of small cell lung cancer through an integrative bioinformatics analysis.

Background: Small cell lung cancer (SCLC), the most malignant of all the lung cancer subtypes, is characterized by drug resistance. This study sought to explore the key genes and pathways associated with the chemoresistance of SCLC. Methods: The drug sensitivity of chemosensitive and chemoresistance SCLC cell lines was measured by Cell Counting Kit-8 assays. The total RNA from chemosensitive cell line H69 and chemoresistance cell line H69AR cells was extracted and subjected to messenger RNA (mRNA) and long non-coding RNA (lncRNA) microarray analyses. The differentially expressed genes (DEGs) and the differentially expressed lncRNAs (DELs) were screened out with a threshold of a |log fold change | ≥1 and an adjusted P value <0.05. A protein-protein interaction network was constructed, and hub genes were screened out. A lncRNA-mRNA co-expression network was also constructed. Gene Ontology and Kyoto Encyclopedia of Genes, Genomes enrichment analyses and Cis-regulatory element analyses were conducted on the DEGs and the top 10 upregulated DEL-co-expressed DEGs. The expression of the key genes was further analyzed in the GSE149507 data set and validated in H69/H69AR and H446/H446DDP cells by quantitative polymerase chain reaction assays. Results: The microarray results showed that a total of 609 mRNAs and 394 lncRNAs were differentially expressed in the chemoresistant SCLC cells. The mammalian target of rapamycin (mTOR) signaling pathway was enriched among the DEGs, the top 10 upregulated DEL-co-expressed DEGs, and the NCRNA00173-co-expressed DEGs, which included IGF1, INS, WNT6, WNT11, WNT2B, and SESN2. IGF1, WNT2B, and SESN2 were downregulated, and WNT11 was upregulated in the SCLC tumor tissues in the GSE149507 data set. Further, IGF1, WNT6, WNT11, and WNT2B were lowlier expressed and SESN2 and NCRNA00173 were more highly expressed in the chemoresistant cells than sensitive cells. Conclusions: The top 10 upregulated DELs containing NCRNA00173 may be involved in the regulation of drug resistance in SCLC. These DELs may regulate the genes related to the mTOR signaling pathway. These genes may also be biomarkers and potential targets for the treatment of SCLC.

[Relationship between the Akt-regulated direct p53 mitochondrial translocation and the resistance to cisplatin of ovarian cancer cells].

OBJECTIVE: To explore Akt-regulated direct p53 mitochondrial translocation in cisplatin-induced apoptosis in ovarian cancer cells and the relationship between this and chemoresistance in ovarian cancer. METHODS: Chemosensitive ovarian cancer cell lines (OV2008 and A2780s) and chemoresistant cells (C13(*) and A2780cp) were treated with cisplatin and whole cell and mitochondrial p53 contents were determined by Western blot. The p53 accumulation in mitochondria was determined in purified mitochondrial fractions in cisplatin-sensitive and -resistant ovarian cancer cells. Akt1/2 siRNA were transfected into C13(*) cells. Cisplatin-induced apoptosis was measured by Hoechst staining and p53 translocation was determined by Western blot. RESULTS: Cisplatin induced mitochondrial p53 accumulation and apoptosis in chemosensitive cells (P < 0.05), but not in resistant cells (P > 0.05). Over-expression of active Akt2 inhibited p53 directly translocate to mitochondria, and downregulation of Akt by Akt1/2 siRNA increased p53 mitochondrial accumulation and sensitize C13(*) cells to cisplatin treatment. CONCLUSIONS: Cisplatin induces direct p53 mitochondrial accumulation in chemosensitive cells, and Akt confers resistance in ovarian cancer cells, in part, by regulating the direct action of p53 in mitochondrial death pathway.

[Relation between aortic root dimension and cardiovascular disease].

OBJECTIVE: To analyze the relation among aortic root dimension (ARD) measured by echocardiography, cardiovascular disease risk factors and cardiovascular disease in adult Beijing community population. METHODS: Echocardiography was performed in 1041 individuals in a suburban community of Beijing from 2004 to 2005. ARD and other echocardiographic parameters including left atria dimension, left ventricular mass, septal and posterior wall thickness and dimension were analyzed. Histories of cardiovascular disease as well as risk factors were obtained. Spearman correlation was used to determine the relation between ARD and other cardiovascular risk factors. Multifactorial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of ARD and cardiovascular disease. RESULTS: Ascending aortic dimension (AAD) and mean root dimension (MRD) were positively associated with age, weight, BMI, systolic and diastolic blood pressure, left atria dimension, left ventricular mass, left ventricular septal and posterior wall thickness, and left ventricular dimension. With the lowest quintile of AAD and MRD as the reference, ORs for the highest quintile of AAD for specific cardiovascular diseases in female were as follows: stroke (OR = 2.20, 95%CI: 1.03 - 4.72, P = 0.04), chronic heart failure (OR = 2.62, 95%CI: 1.49 - 4.61, P = 0.001), total cardiovascular disease (OR = 2.52, 95%CI: 1.51 - 4.21, P < 0.001). ORs of MRD were as follows: chronic heart failure (OR = 2.19, 95%CI: 1.26 - 3.80, P = 0.01), total cardiovascular disease (OR = 2.20, 95%CI: 1.32 - 3.68, P = 0.002). After adjustment for age, BMI, smoking status, TC, hypertension, diabetes mellitus, the ORs were not statistically significant (P > 0.05). CONCLUSION: ARD was positively associated with several CHD risk factors, but was not independent risk factor for cardiovascular disease. ARD may act as an intermediate risk factor for cardiovascular disease. Combined ARD and traditional cardiovascular disease risk factors might enhance the predict power for cardiovascular disease.