Role of EGFR expressed on the granulosa cells in the pathogenesis of polycystic ovarian syndrome.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrinological disorders affecting between 6 to 20% of reproductive aged women. However, the etiology of PCOS is still unclear. Epidermal growth factor receptor (EGFR) plays a critical role in the growth and development of ovarian follicles. In our previous study, we showed that the expression level of EGFR was significantly higher in the cumulus granulosa cells from women with PCOS than that of normal women, suggesting that EGFR may play a potential role in the pathogenesis of PCOS. The present study further evaluated the association between EGFR and PCOS through both in clinical observation and animal experiments. We firstly validated the differential expression of EGFR in cumulus granulosa cells between PCOS patients and normal subjects by qRT-PCR and immunofluorescence staining. Then we generated a mouse model (n=20) of PCOS by injecting dehydroepiandrosterone (DHEA). The PCOS mice were then injected with an E corpus GFR inhibitor (AG1478) (n=10), which significantly improved the sex hormone levels in the estrous cycle stage, and the serum levels of LH, FSH and testosterone were compared with the PCOS mice without EGFR inhibitor treatment (n=10). Decreasing the expression level of EGFR in the PCOS mice also improved the ovulatory function of their ovaries which was indicated by the multifarious follicle stage in these mice as compared with the PCOS mice without EGFR inhibitor treatment. Also, the number of corpopa lutea were higher in the control group and the EGFR inhibitor treated group than in the PCOS group. The sex hormone levels and reproductive function were not significantly different between the control mice and the PCOS mice treated with the EGFR inhibitor. Our results demonstrated that EGF/EGFR signaling affected the proliferation of cumulus granulosa cells, oocyte maturation and meiosis, and played a potential role in the pathogenesis of PCOS. Therefore, the selective inhibition of EGFR may serve as a novel strategy for the clinical management of PCOS.

N-linked glycoproteomic profiling in esophageal squamous cell carcinoma.

BACKGROUND: Mass spectrometry-based proteomics and glycomics reveal post-translational modifications providing significant biological insights beyond the scope of genomic sequencing. AIM: To characterize the N-linked glycoproteomic profile in esophageal squamous cell carcinoma (ESCC) via two complementary approaches. METHODS: Using tandem multilectin affinity chromatography for enrichment of N-linked glycoproteins, we performed N-linked glycoproteomic profiling in ESCC tissues by two-dimensional gel electrophoresis (2-DE)-based and isobaric tags for relative and absolute quantification (iTRAQ) labeling-based mass spectrometry quantitation in parallel, followed by validation of candidate glycoprotein biomarkers by Western blot. RESULTS: 2-DE-based and iTRAQ labeling-based quantitation identified 24 and 402 differentially expressed N-linked glycoproteins, respectively, with 15 in common, demonstrating the outperformance of iTRAQ labeling-based quantitation over 2-DE and complementarity of these two approaches. Proteomaps showed the distinct compositions of functional categories between proteins and glycoproteins with differential expression associated with ESCC. Western blot analysis validated the up-regulation of total procathepsin D and high-mannose procathepsin D, and the down-regulation of total haptoglobin, high-mannose clusterin, and GlcNAc/sialic acid-containing fraction of 14-3-3ζ in ESCC tissues. The serum levels of glycosylated fractions of clusterin, proline-arginine-rich end leucine-rich repeat protein, and haptoglobin in patients with ESCC were remarkably higher than those in healthy controls. CONCLUSION: Our study provides insights into the aberrant N-linked glycoproteome associated with ESCC, which will be a valuable resource for future investigations.

Effects of penehyclidine hydrochloride on myocardial ischaemia-reperfusion injury in rats by inhibiting TLR4/MyD88/NF-κB pathway via miR-199a-3p.

This study was to probe the role of penehyclidine hydrochloride (PHC) mediating the impact of toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB) signalling pathway on myocardial ischaemia-reperfusion injury (MI/RI) in rats through miR-199a-3p. The rat MI/RI model was established through ligating left anterior descending (LAD) coronary artery. PHC was injected preoperatively into the model rats, and injected with miR-199a-3p lentiviral vector or TLR4 antagonist (TAK-242). Next, cardiac function of rats was examined by echocardiography, and rat serum indicators, oxidative stress levels and inflammatory factors were detected. HE staining was applied to detect pathological tissue structure, TUNEL staining to detect apoptosis rate, qRCR and western blot to detect miR-199a-3p and TLR4/MyD88/NF-κB expressions in rat myocardial tissues. Dual luciferase reporter experiment was conducted to confirm the relationship between miR-199a-3p and TLR4. In conclusion, PHC suppresses TLR4/MyD88/NF-κB signalling pathway through miR-199a-3p, thereby improving MI/RI in rats.

A Prognostic Model Based on mRNA Expression Analysis of Esophageal Squamous Cell Carcinoma.

Background: The aim of this study was to identify prognostic markers for esophageal squamous cell carcinoma (ESCC) and build an effective prognostic nomogram for ESCC. Methods: A total of 365 patients with ESCC from three medical centers were divided into four cohorts. In the discovery phase of the study, we analyzed transcriptional data from 179 cancer tissue samples and identified nine marker genes using edgeR and rbsurv packages. In the training phase, penalized Cox regression was used to select the best marker genes and clinical characteristics in the 179 samples. In the verification phase, these marker genes and clinical characteristics were verified by internal validation cohort (n = 58) and two external cohorts (n = 81, n = 105). Results: We constructed and verified a nomogram model based on multiple clinicopathologic characteristics and gene expression of a patient cohort undergoing esophagectomy and adjuvant radiochemotherapy. The predictive accuracy for 4-year overall survival (OS) indicated by the C-index was 0.75 (95% CI, 0.72-0.78), which was statistically significantly higher than that of the American Joint Committee on Cancer (AJCC) seventh edition (0.65). Furthermore, we found two marker genes (TM9SF1, PDZK1IP) directly related to the OS of esophageal cancer. Conclusion: The nomogram presented in this study can accurately and impersonally predict the prognosis of ESCC patients after partial resection of the esophagus. More research is required to determine whether it can be applied to other patient populations. Moreover, we found two marker genes directly related to the prognosis of ESCC, which will provide a basis for future research.

Dual-Functional Metal-Organic Framework for Luminescent Detection of Carcinoid Biomarkers and High Proton Conduction.

It remains a challenge to exploit dual-functional metal-organic frameworks (MOFs) for applications, including luminescence detection and proton conduction. With the deliberate selection of the bifunctional organic ligand 5-sulfoisophthalic acid monosodium salt (NaH2bts), and the phosphonic acid ligand N,N'-piperazine (bismethylenephosphonic acid; H4L), a robust three-dimensional (3D) noninterpenetrating dual-functional MOF, [Tb(H2L)(H2bts)(H2O)]·H2O (1), has been synthesized hydrothermally. On the basis of the excellent thermal and chemical as well as superior luminescence stabilities in water and solutions with different pHs, 1 can serve as the simple, rapid, and highly selective and sensitive luminescence detection of the carcinoid biomarkers 5-hydroxytryptamine (HT) and its metabolite 5-hydroxyindole-3-acetic acid (HIAA) with detection limits of nanomolar magnitude in water and in simulated blood plasma and urine systems. Due to the change in the signals that could be readily differentiated by the naked eye under a UV lamp, a portable test paper has been developed. The probable quenching mechanisms are discussed in detail. In addition, a great number of hydrogen-bonding networks are formed among the uncoordinated carboxylic oxygen atoms, sulfonate oxygen atoms, protonated nitrogen atoms, and water molecules, which provide potential proton-hopping sites for proton conduction, leading to a maximum proton conductivity of 2.3 × 10-4 S cm-1 at 368 K and 95% relative humidity. The above results suggest that rationally designed dual-functional MOFs can open an avenue for the development of occupational diagnostic tools and alternative energy technology.

Porphyromonas gingivalis promotes progression of esophageal squamous cell cancer via TGFß-dependent Smad/YAP/TAZ signaling.

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-ß (TGFß)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFß through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFß axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.

Out of Refugia: Population Genetic Structure and Evolutionary History of the Alpine Medicinal Plant Gentiana lawrencei var. farreri (Gentianaceae).

Understanding the genetic structure and evolutionary history of plants contributes to their conservation and utilization and helps to predict their response to environmental changes. The wildflower and traditional Chinese and Tibetan medicinal plant Gentiana lawrencei var. farreri is endemic to the Qinghai-Tibetan Plateau (QTP). To explore its genetic structure and evolutionary history, the genetic diversity, divergence, and demographics were analyzed in individuals from 31 locations across the QTP using 1 chloroplast marker and 10 nuclear microsatellite loci. High genetic diversity was detected in G. lawrencei var. farreri, and most of the genetic variance was found within populations. Values of F ST in G. lawrencei var. farreri from nuclear microsatellite and chloroplast data were 0.1757 and 0.739, respectively. The data indicated the presence of isolation by distance. The southeast edge of the QTP was the main refugium for G. lawrencei var. farreri, and one microrefugium was also detected in the plateau platform of the QTP. Both nuclear microsatellite and chloroplast data indicated that the populations were divided into two geographically structured groups, a southeast group and a northwest group. The current genetic pattern was mainly formed through recolonization from the two independent refugia. Significant melt was detected at the adjacent area of the two geographically structured groups. Approximate Bayesian computation showed that the northwest group had diverged from the southeast group, which then underwent population expansion. Our results suggest that the two-refugia pattern had a significant impact on the genetic structure and evolutionary history of G. lawrencei var. farreri.

The utility of high-sensitivity C-reactive protein levels in patients with moderate coronary lesions and gray-zone fractional flow reserve.

OBJECTIVE: It remains controversial whether patients with fractional flow reserve (FFR) values of 0.75-0.80 (gray-zone) should be treated with percutaneous coronary intervention (PCI). This study aimed to evaluate the prediction of high-sensitivity C-reactive protein (hs-CRP) levels to guide treatment selection in gray-zone patients. METHODS: This prospective interventional trial was conducted between January 2015 and March 2016. A total of 785 patients with stable angina and single-vessel stenosis with moderate coronary lesions were admitted to hospital in this period. After measurement of hs-CRP levels, coronary angiography, and FFR, gray-zone patients (n=308) were included in the study and were divided into four groups on the basis of a cutoff hs-CRP level of 3 mg/L and then on the basis of whether they underwent PCI or not. Patients in groups I (≥3 mg/L, n=70) and III (<3 mg/L, n=84) underwent PCI, whereas those in groups II (≥3 mg/L, n=70) and IV (<3 mg/L, n=84) were administered only drugs. Major adverse clinical events (MACEs) included cardiac death, nonfatal myocardial infarction (MI), target vessel revascularization (TVR), and PCI or coronary artery bypass grafting (CABG). These parameters were also evaluated during follow-up. RESULTS: The total Kaplan-Meier curves showed macrodistribution differences among the four groups (p<0.05). There was a significantly increased MACE incidence in group II compared with group I or IV (p=0.039 or 0.006, respectively), and an increased incidence in group I compared with group III (p=0.028). However, there were no differences in MACE incidence between groups III and IV (p=0.095) despite the fact that these patients received different treatments. CONCLUSION: Among FFR gray-zone patients, hs-CRP level was a predictor of MACE and risk stratification could guide treatment selection. Increased hs-CRP levels (≥3 mg/L) are an indication for urgent PCI whereas normal levels (<3 mg/L) are an indication for delayed PCI treatment. Patients with identical FFR values could require different treatment.

A systematic review on efficacy and safety of gasless laparoscopy in the management of uterine leiomyoma.

Uterine leiomyoma causes considerable morbidity in women. This study systematically reviewed the efficacy and safety of gasless laparoscopic myomectomy (GLM) in the management of uterine leiomyoma by comparing GLM with other minimally invasive procedures. Cochrane Library, Pub- Med, EMBASE, Web of Science, WANFANG database and China National Knowledge Infrastructure (CNKI) were searched for studies published in English or Chinese between January 1995 and May 2015, and related references were traced. Study outcomes from randomized controlled trials and retrospective cohort studies were presented as mean difference (MD) or odds ratio (OR) with a 95% confidence interval (CI). Seventeen studies (including 1862 patients) meeting the inclusion criteria, including 934 treated with GLM and 928 treated with other minimally invasive procedures were reviewed. The results of meta-analysis revealed that GLM resulted in significantly shorter operating time [MD=-10.34, 95% CI (-18.12,-2.56), P<0.00001], shorter hospital stay [MD=-0.47, 95% CI (-0.88,-0.06)], less time to flatus [MD=-2.04, 95% CI (-2.59,-1.48)], less postoperative complications [OR=0.20, 95% CI (0.06, 0.62)] and less blood loss [MD =-30.74, 95% CI (-47.50,-13.98)]. On the other hand, there were no significant differences in duration of post-operative fever [MD=-0.52, 95% CI (-1.46, 0.42)] between the two groups. Additionally, GLM was associated with lower febrile morbidity, lower postoperative abdominal pain, and higher postoperative hemoglobin than other minimally invasive procedures for the treatment of uterine leiomyoma. In conclusion, GLM and other minimally invasive procedures are feasible, safe, and reliable for uterine leiomyoma treatment. However, available studies show that GLM is more effective and safer than other minimally invasive approaches.

Long-term outcome of intravascular ultrasound application in patients with moderate coronary lesions and grey-zone fractional flow reserve.

OBJECTIVE: This study aimed to assess the long-term outcome of intravascular ultrasound (IVUS) application in patients with a fractional flow reserve (FFR) of 0.75-0.80. BACKGROUND: Scientifically evaluating anatomical structures is vital because structure influences both physiological function and decision-making in moderate coronary lesions, especially for those with an FFR of 0.75-0.80. MATERIALS AND METHODS: Patients (n=128) were divided into three groups based on treatment: the drug control group (n=40), the IVUS-percutaneous coronary intervention (PCI) group (n=40) and the IVUS-drug group (n=48). A PCI was performed when a patient had a minimum lumen area less than 4 mm(2) and a plaque burden of 70% or greater. Major adverse clinical events were defined as cardiac death, nonfatal myocardial infarction, target vessel revascularization, including PCI or coronary artery bypass grafting, and unstable angina, all of which were also evaluated during follow-up. RESULTS: Kaplan-Meier curves indicated that the incidence of major adverse clinical events did not differ between the IVUS-PCI and IVUS-drug groups (5 vs. 6.3%, P=0.810), but the levels in both of these groups significantly decreased compared with the drug control group (5 vs. 22.5%, P=0.024, and 6.5 vs. 22.5%, P=0.026, respectively). CONCLUSION: The long-term outcome of the application of IVUS in patients with a grey-zone FFR of 0.75-0.80 was superior to that of patients who were treated only with drugs without IVUS measurement. Patients with a grey-zone FFR should receive an individualized treatment strategy according to their IVUS parameters. Patients with the same FFR values may require different treatment strategies.