Ubiquitin-specific protease-7 promotes expression of airway mucin MUC5AC via the NF-κB signaling pathway.

Chronic obstructive pulmonary disease (COPD) and other respiratory diseases frequently present with airway mucus hypersecretion, which not only affects the patient's quality of life but also poses a constant threat to their life expectancy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, affects cell differentiation, tissue growth, and disease development. However, its role in airway mucus hypersecretion induced by COPD remains elusive. In this study, USP7 expression was significantly upregulated in airway epithelial samples from patients with COPD, and USP7 was also overexpressed in mouse lung and human airway epithelial cells in models of airway mucus hypersecretion. Inhibition of USP7 reduced the expression of nuclear factor kappa B (NF-κB), phosphorylated-NF-κB (p-NF-κB), and phosphonated inhibitor of nuclear factor kappa B (p-IκBα), and alleviated the airway mucus hypersecretion in vivo and in vitro. Further research revealed that USP7 stimulated airway mucus hypersecretion through the activation of NF-κB nuclear translocation. In addition, the expression of mucin 5AC (MUC5AC) was suppressed by the NF-κB inhibitor erdosteine. These findings suggest that USP7 stimulates the NF-κB signaling pathway, which promotes airway mucus hypersecretion. This study identifies one of the mechanisms regulating airway mucus secretion and provides a new potential target for its prevention and treatment.

eIF3a sustains non-small cell lung cancer stem cell-like properties by promoting YY1-mediated transcriptional activation of ß-catenin.

Cancer stem cells (CSCs) are the leading cause of recurrence and poor prognosis in non-small cell lung cancer (NSCLC). Eukaryotic translation initiation factor 3a (eIF3a) participates in many tumor development processes, such as metastasis, therapy resistance, and glycolysis, all of which are closely associated with the presence of CSCs. However, whether eIF3a maintains NSCLC-CSC-like properties remains to be elucidated. In this study, eIF3a was highly expressed in lung cancer tissues and was linked to poor prognosis. eIF3a was also highly expressed in CSC-enriched spheres compared with adherent monolayer cells. Moreover, eIF3a is required for NSCLC stem cell-like traits maintenance in vitro and in vivo. Mechanistically, eIF3a activates the Wnt/ß-catenin signaling pathway, promoting the transcription of cancer stem cell markers. Specifically, eIF3a promotes the transcriptional activation of ß-catenin and mediates its nuclear accumulation to form a complex with T cell factor 4 (TCF4). However, eIF3a has no significant effect on protein stability and translation. Proteomics analysis revealed that the candidate transcription factor, Yin Yang 1 (YY1), mediates the activated effect of eIF3a on ß-catenin. Overall, the findings of this study implied that eIF3a contributes to the maintenance of NSCLC stem cell-like characteristics through the Wnt/ß-catenin pathway. eIF3a is a potential target for the treatment and prognosis of NSCLC.

Pharmacogenetics of P450 oxidoreductase: implications in drug metabolism and therapy.

The redox reaction of cytochrome P450 enzymes (CYP) is an important physiological and biochemical reaction in the human body, as it is involved in the oxidative metabolism of both endogenous and exogenous substrates. Cytochrome P450 oxidoreductase (POR) is the only obligate electron donor for all of the hepatic microsomal CYP enzymes. It plays a crucial role in drug metabolism and treatment by not only acting as an electron donor involved in drug metabolism mediated by CYP enzymes but also by directly inducing the transformation of some antitumor precursors. Studies have found that the gene encoding human POR is highly polymorphic, which is of considerable clinical significance as it affects the metabolism and curative effects of clinically used drugs. This review aims to discuss the effect of POR and its genetic polymorphisms on drug metabolism and therapy, as well as the potential mechanisms of POR pharmacogenetics.

Assessing the utility of whole genome amplified DNA as a template for DMET Plus array.

BACKGROUND: Large amounts of high quality DNA are typically required for high-throughput genotyping arrays but sometimes study participant DNA is in limited supply. Multiple displacement amplification (MDA)-based whole genome amplification is an in vitro technique that permits the genetic analysis of limited amounts of high molecular weight genomic DNA (gDNA). METHODS: The performance of MDA-whole genome amplified DNA (wgaDNA) as a template for DMET Plus (Affymetrix) was assessed. wgaDNA was generated from gDNA from three HapMap CEU cell lines and 11 breast cancer patients. One HapMap sample and three patient samples were randomly selected for replication to assess reproducibility. Accuracy was assessed by comparing the wgaDNA genotypes with gDNA genotypes. The kappa (κ) statistic was used to measure genotype concordance between paired gDNA-wgaDNA and wgaDNA-wgaDNA samples. Copy number variants (CNV) were not included in concordance analysis in this study. RESULTS: A good genotype call rate of 98.8%±1.06% (mean±standard deviation, 1931 markers) was observed for all 18 wgaDNA samples with three samples having call rates lower than 98%. High genotype concordance rates were observed between four HapMap wgaDNA-gDNA pairs (98.5%, κ=0.9817, p<0.0001, 1931 markers) and 14 patient wgaDNA-gDNA pairs (100%, κ=1.00, p<0.0001, 19 markers among CYP2D6 and CYP2C19). Excellent genotype concordance was also observed between four independently amplified duplicate samples (98.0%, κ=0.9745; p<0.0001, 1931 markers). CONCLUSIONS: MDA-produced wgaDNA provides accurate and reproducible genotypes with the DMET Plus array and is therefore a suitable template for this targeted pharmacogenetic genotyping array.

MANF Inhibits α-Synuclein Accumulation through Activation of Autophagic Pathways.

Progressive accumulation of misfolded SNCA/α-synuclein is key to the pathology of Parkinson's disease (PD). Drugs aiming at degrading SNCA may be an efficient therapeutic strategy for PD. Our previous study showed that mesencephalic astrocyte-derived neurotrophic factor (MANF) facilitated the removal of misfolded SNCA and rescued dopaminergic (DA) neurons, but the underlying mechanisms remain unknown. In this study, we showed that AAV8-MANF relieved Parkinsonian behavior in rotenone-induced PD model and reduced SNCA accumulation in the substantia nigra. By establishing wildtype (WT) SNCA overexpression cellular model, we found that chaperone-mediated-autophagy (CMA) and macroautophagy were both participated in MANF-mediated degradation of SNCAWT. Nuclear factor erythroid 2-related factor (Nrf2) was activated to stimulating macroautophagy activity when CMA pathway was impaired. Using A53T mutant SNCA overexpression cellular model to mimic CMA dysfunction situation, we concluded that macroautophagy rather than CMA was responsible to the degradation of SNCAA53T, and this degradation was mediated by Nrf2 activation. Hence, our findings suggested that MANF has potential therapeutic value for PD. Nrf2 and its role in MANF-mediated degradation may provide new sights that target degradation pathways to counteract SNCA pathology in PD.

Genistein alters caffeine exposure in healthy female volunteers.

PURPOSE: This study investigated the effect of 1 g genistein daily for 14 days on caffeine-based metrics of cytochrome P4501A2 (CYP1A2), cytochrome P4502A6 (CYP2A6), N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO). METHODS: A single dose of 100 mg caffeine was administered once before and once on the last day of a 14-day treatment regime with 1 g genistein once daily to 18 healthy female volunteers. Urine and blood samples were collected up to 12 and 24 h, respectively, after each caffeine dose. Using high-performance liquid chromatography (HPLC), caffeine and 1,7-dimethylxanthine (17X) were quantified in plasma, whereas 17X, 1,7-dimethylurate (17U), 1-methylxanthine (1X), 1-methylurate (1U), and 5-acetylamino-6-formylamine-3-methyluracil (AFMU) were quantified in urine. Urinary metabolite ratios were calculated to assess enzyme activities and compared between administrations using analysis of variance (ANOVA). RESULTS: Genistein decreased the urinary caffeine metabolite ratio used to assess CYP1A2 activity by 41% [90% confidence interval (CI) 28-51%). The urinary ratio indicating XO activity decreased by 29% (90% CI 24-32%), whereas urinary ratio for CYP2A6 activity increased by 47% (90% CI 29-66%) after 2 weeks of genistein. The NAT2 urinary caffeine metabolite ratio did not change significantly. CONCLUSIONS: Two weeks of intake of 1 g genistein daily led to decreases in CYP1A2 and XO activity and an increase in CYP2A6 activity, whereas NAT2 activity did not change in healthy Chinese female volunteers. Pharmacokinetics of other substrates of the enzymes investigated here may be influenced in a similar manner.

Effect of glycyrrhizin on the activity of CYP3A enzyme in humans.

BACKGROUND: Glycyrrhizin is a major ingredient of licorice which is widely used in the treatment of various diseases such as chronic hepatitis. Licorice or glycyrrhizin has been shown to alter the activity of CYP3A in rodents. The influence of glycyrrhizin on CYP3A has not been elucidated in humans. OBJECTIVE: To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of midazolam, a probe drug for CYP3A activity in humans. METHODS: Sixteen healthy adult male subjects were enrolled in a two-phase randomized crossover design. In each phase the volunteers received placebo or glycyrrhizin for 14 days. On the 15th day, midazolam was administered and blood samples were obtained to determine midazolam plasma concentrations. Bioequivalence was assessed by determining geometric mean ratios (GMRs) and 90% confidence intervals (90% CI). RESULTS: The geometric mean (geometric coefficient of variation) for the AUC(0-infinity) of midazolam in the placebo group was 196.4 ng x h/ml (30.3%) and after glycyrrhizin treatment, 151.3 ng x h/ml (34.7%). The GMRs and 90% CI for AUC(0-infinity) and Cmax of midazolam in the presence/ absence of glycyrrhizin were 0.77 (0.70, 0.89) and 0.83 (0.74, 1.01), respectively. The 90% CI for AUC(0-infinity) and Cmax for the GMR of glycyrrhizin over placebo were both out of the no-effect boundaries of 0.80-1.25. CONCLUSIONS: Administration of glycyrrhizin resulted in a modest induction of CYP3A that was clinically relevant according to the bioequivalence analysis.

The evaluation of online course of Traditional Chinese Medicine for MBBS international students during the COVID-19 epidemic period.

BACKGROUND: During the COVID-19 epidemic period, Traditional Chinese Medicine (TCM) course for international students of Medical Bachelor, Bachelor of Surgery (MBBS) program in Zhejiang University has shifted from traditional classroom to online environment. This study aimed to investigate MBBS international students' perception on online TCM course, and to assess the online learning efficacy. METHODS: A total of 84 MBBS international students attending course of "Basic Traditional Chinese Medicine" during 2020 academic years at Zhejiang University were enrolled in this study. A quantitative questionnaire was respectively completed before and after the TCM course using a pretest-post-test design. By means of two online learning platforms, Learning in ZJU and DingTalk, TCM course was broadcast in both live and archived format to students. RESULTS: A total of 48 participants completed both baseline and follow-up questionnaires. The majority of participants preferred face-to-face classroom learning (26, 54.17% of total) when compared with online learning. Students felt that the course had brought in much benefits (mean 3.88, SD 0.87), and they were satisfied with the course content (mean 3.83, SD 0.95). Students' TCM related knowledge and their behaviors of discussion and consulting were significantly improved by online TCM course (all P < 0.001). Students' awareness of the necessity of TCM education and their feeling of difficulty in learning TCM were significantly strengthened (P = 0.042, 0.025, respectively). CONCLUSION: Online learning is a good alternative for TCM course of MBBS international students when classroom learning is suspended, whereas it cannot replace the need for onsite and face-to-face learning.

Lack of effect of Ginkgo biloba on voriconazole pharmacokinetics in Chinese volunteers identified as CYP2C19 poor and extensive metabolizers.

BACKGROUND: Ginkgo biloba is one of the most popular herbal supplements in the world. The supplement has been shown to induce the enzymatic activity of CYP2C19, the main cytochrome P450 isozyme involved in voriconazole metabolism. Because this enzyme exhibits genetic polymorphism, the inductive effect was expected to be modulated by the CYP2C19 metabolizer status. OBJECTIVE: To examine the possible effects of Ginkgo biloba as an inducer of CYP2C19 on single-dose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CYP2C19 extensive or poor metabolizers. METHODS: Fourteen healthy, nonsmoking volunteers-7 CYP2C19 extensive metabolizers (2C19(*)1/2C19(*)1) and 7 poor metabolizers (2C19(*)2/2C19(*)2)-were selected to participate in this study. Pharmacokinetics of oral voriconazole 200 mg after administration of Ginkgo biloba 120 mg twice daily for 12 days were determined for up to 24 hours by liquid chromatography-electrospray tandem mass spectrometry in a 2-phase randomized crossover study with 4-week washout between phases. RESULTS: For extensive metabolizers, the median value for voriconazole area under the plasma concentration-time curve from zero to infinity (AUC(0-)(infinity)) was 5.17 microg.h/mL after administration of voriconazole alone and 4.28 microg.h/mL after voriconazole with Ginkgo biloba (p > 0.05). The other pharmacokinetic parameters of voriconazole such as AUC(0-24), time to reach maximum concentration, half-life, and apparent clearance also did not change significantly for extensive metabolizers in the presence of Ginkgo biloba. Pharmacokinetic parameters followed a similar pattern for poor metabolizers. CONCLUSIONS: The results suggest that 12 days of treatment with Ginkgo biloba did not significantly alter the single-dose pharmacokinetics of voriconazole in either CYP2C19 extensive or poor metabolizers. Therefore, the pharmacokinetic interactions between voriconazole and Ginkgo biloba may have limited clinical significance.

Effects of Ginkgo biloba extract ingestion on the pharmacokinetics of talinolol in healthy Chinese volunteers.

BACKGROUND: Ginkgo biloba extract (GBE), the best selling herbal medicine in the world, has been reported to inhibit P-glycoprotein in vitro. However, the effects of GBE on P-glycoprotein activity in humans have not been clarified. OBJECTIVE: To investigate the effects of single and repeated GBE ingestion on the oral pharmacokinetics of talinolol, a substrate drug for P-glycoprotein in humans. METHODS: Ten unrelated healthy male volunteers were selected to participate in a 3-stage sequential study. Plasma concentrations of talinolol from 0 to 24 hours were measured by high-performance liquid chromatography after talinolol 100 mg was administrated alone, with a single oral dose of GBE (120 mg), and after 14 days of repeated GBE ingestion (360 mg/day). RESULTS: A single oral dose of GBE did not affect the pharmacokinetics of talinolol. Repeated ingestion of GBE increased the talinolol maximum plasma concentration (C(max)) by 36% (90% CI 10 to 68; p = 0.025), the area under the concentration-time curve (AUC)(0-24) by 26% (90% CI 11 to 43; p = 0.008) and AUC(0-infinity) by 22% (90% CI 8 to 37; p = 0.014), respectively, without significant changes in elimination half-life and the time to C(max). CONCLUSIONS: Our results suggest that long-term use of GBE significantly influenced talinolol disposition in humans, likely by affecting the activity of P-glycoprotein and/or other drug transporters.

Effect of bifendate on the pharmacokinetics of cyclosporine in relation to the CYP3A4*18B genotype in healthy subjects.

AIM: To evaluate the potential drug-drug interactions between bifendate and cyclosporine, a substrate of CYP3A4, in relation to different CYP3A4*18B genotype groups. METHODS: Eighteen unrelated healthy subjects (six CYP3A4*1*1, six CYP3A4*1/*18B, and six CYP3A4*18/*18B) were selected for this study. After repeated oral administration of a placebo or bifendate (three times daily for 14 d), the whole-blood level of cyclosporine was measured using high performance liquid chromatography-electrospray mass spectrometry (HPLC/ESI-MS). This study was carried out in a two-phase randomized crossover manner. RESULTS: After the treatment with bifendate, the areas under the curve (AUC(0-24) and AUC(0-infinity)) decreased significantly by 9.7%+/-3.7% (P=0.01) and 19.2%+/-16.8% (P=0.001) in CYP3A4*1/*1 subjects, 11.3%+/-9.4% (P=0.03) and 10.5%+/-9.6% (P=0.043) in CYP3A4*1/*18B subjects, and 40.2%+/-14.7% (P=0.02) and 37.5%+/-15.8% (P=0.003) in CYP3A4*18B/*18B subjects. Meanwhile, the decreases in the AUC(0-24) and AUC(0-infinity) values in the three groups were significantly different (using one-way analysis of variance, P=0.001 and P=0.001), and the change in the CYP3A4*18B/*18B group was greater than that in the other two groups. The oral clearance of cyclosporine was altered in all the subjects, with substantial increases by 10.2%+/-4.4% (P=0.004) in CYP3A4*1/*1 subjects, 14.0%+/-12.0% (P=0.048) in CYP3A4*1/*18B subjects, and 32.4%+/-21.7% (P=0.013) in CYP3A4*18B/*18B subjects. CONCLUSION: These results suggest that bifendate decreases the plasma concentration of cyclosporine in a CYP3A4 genotype-dependent manner.

ß­blockers inhibit the viability of breast cancer cells by regulating the ERK/COX­2 signaling pathway and the drug response is affected by ADRB2 single­nucleotide polymorphisms.

The ß2­adrenergic receptor (ß2­AR, encoded by the ADRB2 gene) is a member of the G­protein­coupled receptor superfamily that can be stimulated by catecholamines. Studies in vivo and in vitro have confirmed that ß­blockers (ß­AR antagonists) exert antitumor effects on various tumors. Furthermore, ADRB2 single­nucleotide polymorphisms (SNPs) have been identified to alter the expression and conformation of ß2­AR, which may alter the ß­blocker drug response. The aim of the present study was to investigate the effect of ß­blockers on triple­negative breast cancer cells and determine whether ADRB2 SNPs affect the response to ß­blocker drugs. Propranolol and ICI 118,551 significantly inhibited the viability of MDA­MB­231 cells, arrested cell cycle progression at G0/G1 and S phase and induced cell apoptosis. Western blot analysis indicated that the phosphorylation levels of extracellular­signal­regulated kinase (ERK)1/2 and the expression levels of cyclo­oxygenase 2 (COX­2) were significantly decreased following ß­blocker treatment. Four haplotypes, which comprised ADRB2 SNPs rs1042713 and rs1042714, were transfected into 293 cells. After 24 and 48 h of transfection, ADRB2 mRNA expression was significantly decreased in mutant groups compared with the wild­type group. The ADRB2 SNPs exerted no effect on cell viability, but did affect the drug response of ICI 118,551. Furthermore, ADRB2 SNPs also affected the regulatory function of ICI 118,551 on the ERK/COX­2 signaling pathway. Collectively, propranolol and ICI 118,551 inhibited the viability of MDA­MB­231 cells by downregulating the ERK/COX­2 signaling pathway and inducing apoptosis. The results of the present study indicated that SNPs rs1042713 and rs1042714 of ADRB2 affected the response to ICI 118,551, and the underlying molecular mechanism was elucidated.

Genetic polymorphism predicting Methotrexate efficacy in Chinese patients with psoriasis vulgaris.

BACKGROUND: Methotrexate is the first systemic therapeutics of psoriasis. It is reported that 40% of the patients achieved a PASI75 after 12 weeks with a small dose of methotrexate (15mg / w) treatment. So far there is not any large-scale exome sequencing been used to predict the efficacy of methotrexate in the treatment of psoriasis vulgaris. OBJECTIVE: To analyze the genetic polymorphism to predict methotrexate efficacy in Chinese patients with psoriasis vulgaris. METHODS: In this study, we used the whole exon high-throughput sequencing technology to detect the DNA sequence of 22 psoriasis vulgaris patients (11 responders, 11 non-responders) treated with methotrexate and captured approximately 236 variants with statistically significant in the whole exon sequencing, then in accordance with statistical differences and clinical relevance, we further selected 36 SNPs and 14 SNPs that have been reported in articles associated with the response of methotrexate. We used MassARRAY method to verify the 50 SNPs in 100 psoriatic patients treated with methotrexate. RESULTS: We found 3 SNPs, rs216195T>C in SMG6, rs1050301G>A in IMMT, rs2285421T>C in UPK1A which might associate with the drug response of methotrexate. CONCLUSION: We have searched 3 new SNPs that could predict the efficacy of methotrexate in psoriasis vulgaris to some extent, providing a theoretical basis for precision medicine of methotrexate in future.

Hepatic nuclear factor 1alpha inhibitor ursodeoxycholic acid influences pharmacokinetics of the organic anion transporting polypeptide 1B1 substrate rosuvastatin and bilirubin.

Expression of the organic anion transporting polypeptide 1B1 (OATP1B1) is regulated by transcription factor hepatic nuclear factor (HNF) 1alpha. The aim of this study was to investigate the effect of ursodeoxycholic acid (UDCA), an inhibitor of transcription factor HNF1alpha, on rosuvastatin and bilirubin kinetics in human healthy volunteers. Both substances are substrates of OATP1B1. Twelve subjects with OATP1B1(*)1b/(*)1b genotype predicting high transport activity were recruited for this randomized, crossover study. Each subject received a single p.o. dose of 20 mg of rosuvastatin after 14 days of p.o. intake of either 500 mg of UDCA or placebo. Plasma concentrations of rosuvastatin were determined on days 15 to 18 of each study period. Subjects were randomly assigned to UDCA or placebo group. Intake of UDCA led to a significant increase in rosuvastatin area under the curve (AUC)(0-72) from 128.5 ng/ml.h to 182.1 ng/ml.h(P = 0.008) compared with the control group. The oral clearance decreased from 155.2 l/h with placebo to 109.8 l/h with UDCA. In addition, the mean values of total bilirubin, conjugated bilirubin, and unconjugated bilirubin significantly increased to 139 +/- 39% (P = 0.003), 127 +/- 29% (P = 0.005), and 151 +/- 52% (P = 0.004), respectively, after UDCA treatment. These results in healthy volunteers confirm the findings from in vitro studies that UDCA inhibits OATP1B1 activity by inhibition of the transcription factor HNF1alpha. They highlight a novel mechanism of OATP1B1-based interaction that is mediated by transcription factor HNF1alpha.

Inhibition of ADP-induced platelet aggregation by clopidogrel is related to CYP2C19 genetic polymorphisms.

1. Clopidogrel is one of the most important antithrombotic drugs but has different efficacies in different populations. The aim of the present study was to evaluate the contribution of CYP2C19 genetic polymorphisms to the inhibition of ADP-induced platelet aggregation by clopidogrel in healthy Chinese volunteers. 2. Eighteen healthy male volunteers (six CYP2C19*1/CYP2C19*1, six CYP2C19*1/CYP2C19*2and*3 and six CYP2C19*2/CYP2C19*2and*3) were enrolled in the study. Each subject took 300 mg clopidogrel on the first day and then 75 mg once daily for 2 consecutive days. Blood samples were taken to measure ADP-induced platelet aggregation at baseline and 4, 24 and 72 h after administration of the first dose of clopidogrel. 3. There were significant decrease in 2 and 5 micromol/L ADP-induced platelet aggregation at 4, 24 and 72 h after clopidogrel among the three CYP2C19 genotypes compared with baseline (P < 0.001). The change in 5 micromol/L ADP-induced platelet aggregation in subjects with the CYP2C19*1/CYP2C19*1 genotype was greater than that in subjects with the CYP2C19*2/CYP2C19*2and*3 genotype at 4 h (49.0 +/- 15.5 vs 29.7 +/- 17.4%, respectively; P = 0.029), 24 h (48.7 +/- 20.5 vs 25.0 +/- 17.6%, respectively; P = 0.035) and 72 h (45.5 +/- 15.2 vs 26.5 +/- 15.8%, respectively; P = 0.030) after clopidogrel administration. 4. In conclusion, CYP2C19*2 and CYP2C19*3 genetic polymorphisms reduced clopidogrel inhibition of ADP-induced platelet aggregation, with the degree of inhition dependent on the genetic polymorphism present.

Discordance of Somatic Mutations Between Asian and Caucasian Patient Populations with Gastric Cancer.

BACKGROUND: Differences in response to cancer treatments have been observed among racially and ethnically diverse gastric cancer (GC) patient populations. In the era of targeted therapy, mutation profiling of cancer is a crucial aspect of making therapeutic decisions. Mapping driver gene mutations for the GC patient population as a whole has significant potential to advance precision therapy. METHODS: GC patients with sequencing data (N = 473) were obtained from The Cancer Genome Atlas (TCGA; n = 295), Moffitt Cancer Center Total Cancer Care™ (TCC; n = 33), and three published studies (n = 145). In addition, relevant somatic mutation frequency data were obtained from cBioPortal, the TCC database, and an in-house analysis tool, as well as relevant publications. RESULTS: We found that the somatic mutation rates of several driver genes vary significantly between GC patients of Asian and Caucasian descent, with substantial variation across different geographic regions. Non-parametric statistical tests were performed to examine the significant differences in protein-altering somatic mutations between Asian and Caucasian GC patient groups. The frequencies of somatic mutations of five genes were: APC (Asian: Caucasian 6.06 vs. 14.40%, p = 0.0076), ARIDIA (20.7 vs. 32.1%, p = 0.01), KMT2A (4.04 vs. 12.35%, p = 0.003), PIK3CA (9.6 vs. 18.52%, p = 0.01), and PTEN (2.52 vs. 9.05%, p = 0.008), showing significant differences between Asian and Caucasian GC patients. CONCLUSIONS: Our study found significant differences in protein-altering somatic mutation frequencies in diverse geographic populations. In particular, we found that the somatic patterns may offer better insight and important opportunities for both targeted drug development and precision therapeutic strategies between Asian and Caucasian GC patients.

Transcutaneous Electrical Acupoint Stimulation Improves the Outcomes of In Vitro Fertilization: A Prospective, Randomized and Controlled Study.

OBJECTIVES: To explore whether transcutaneous electrical acupoint stimulation (TEAS) can improve the outcomes of in vitro fertilization (IVF). DESIGN: A prospective, randomized, and controlled study. SETTING: IVF center in a university hospital. PARTICIPANTS: Four hundred and eighty-one infertile patients with bilateral tubal blockage who were referred for IVF. Patients were randomized into four groups. INTERVENTION: TEAS was administered for 30min, respectively, at 24h before TVOR and two hours before ET. The acupoints included SP10 (Xuehai, bilateral), SP8 (Diji, bilateral), LR3 (Taichong, bilateral), ST36 (Zusanli, bilateral), EX-CA1 (Zigong, bilateral), RN4 (Guanyuan), PC6 (Neiguan, bilateral), and RN12 (Zhongwan). Based on different frequencies of TEAS, patients were grouped into a TEAS-2Hz group, a TEAS-100Hz group and a TEAS-2/100Hz group. Patients in the control group only received routine IVF treatment and no TEAS was applied on them. PRIMARY AND SECONDARY OUTCOME MEASURES: The number of mature oocytes, normally fertilized oocytes and good-quality embryos were used to evaluate oocyte developmental competence of the patients. Data of clinical pregnancy rate (CPR), implantation rate (IR), and live birth rate (LBR) were also obtained. The levels of neuropeptide Y (NPY), transforming growth factor alpha and granulocyte colony-stimulating factor in the follicular fluids were measured with enzyme-linked immunosorbent assay (ELISA). RESULTS: No significant differences were found between the control, TEAS-2Hz, TEAS-100Hz and TEAS-2/100Hz groups on the numbers of metaphase II oocytes, normally fertilized zygotes, early cleavage embryos or good quality embryos (P > .05). However, the CPR, IR and LBR of the TEAS-2/100Hz group were significantly higher than those of the other groups, respectively (P < .05). The NPY levels in the follicular fluids of TEAS-2/100Hz group were significantly higher than those of the other groups (P < .05). CONCLUSION: TEAS using a frequency of 2/100Hz could help to improve the IVF outcomes partly by increasing NPY levels in the follicular fluids.

Use of electroacupuncture and transcutaneous electrical acupoint stimulation in reproductive medicine: a group consensus.

With the rapid development of assisted reproductive technology, various reproductive disorders have been effectively addressed. Acupuncture-like therapies, including electroacupuncture (EA) and transcutaneous electrical acupoint stimulation (TEAS), become more popular world-wide. Increasing evidence has demonstrated that EA and TEAS are effective in treating gynecological disorders, especially infertility. This present paper describes how to select acupoints for the treatment of infertility from the view of theories of traditional Chinese medicine and how to determine critical parameters of electric pulses of EA/TEAS based on results from animal and clinical studies. It summarizes the principles of clinical application of EA/TEAS in treating various kinds of reproductive disorders, such as polycystic ovary syndrome (PCOS), pain induced by oocyte retrieval, diminished ovarian reserve, embryo transfer, and oligospermia/ asthenospermia. The possible underlying mechanisms mediating the therapeutic effects of EA/TEAS in reproductive medicine are also examined.