[Stratified application of gene expression in diagnosis of thyroid nodules].

Objective: To investigate the value of BRAF V600E and multigene detection and stratified application for the diagnosis of thyroid nodules. Methods: A total of 1 117 patients with thyroid nodules resection at Nanjing Gulou Hospital from December 2020 to July 2022 were enrolled in the study. Fine needle aspiration (FNA) and core biopsy samplings were performed for cytopathologic examination and genetic testings; the findings were combined with BSRTC classification. The diagnostic performance of BRAF V600E and multigene detection were compared. Results: Among the 1, 117 patients who underwent thyroid nodules resection, 285 were male and 832 were female, with a median age of 46 years (range: 24-76 years). Postoperative histopathologic examination confirmed 1 040 cases of thyroid cancer and 77 cases of benign nodules. The sensitivity (87.0% vs. 80.8%, P<0.01) and diagnostic accuracy (87.9% vs. 82.1%, P<0.01) of multigene detection were significantly higher than those of BRAF V600E detection. The result of multigene detection showed that BRAF V600E mutation was the most common finding, followed by CCDC6-RET (E1-E12) fusion, ETV6-NTRK3 fusion, and KRAS mutation. Multigene detection had a higher sensitivity (81.9% vs. 72.8%, P<0.01) and lower cancer risk in wild-type (47.6% vs. 57.7%, P=0.069) than BRAF V600E detection in BSRTCⅠ-Ⅴ lesions. Compared with BRAF V600E detection, multigene had no significant difference of sensitivity in BSRTC Ⅰ lesions, but significantly higher sensitivity (86.3% vs 74.0%, P<0.01) in BSRTC Ⅲ lesions. Conclusions: Genetic detection can be used as an effective tool for the diagnosis of thyroid nodules. A stratified application of molecular markers in the diagnosis of thyroid nodules is proposed. Combined with FNA, single gene or multigene detection both can effectively assist in the diagnosis of thyroid nodules. Moreover, multigene detection is superior to single gene detection. For BSRTC Ⅲ lesion with wild-type BRAF, multigene detection can be considered with a repeated FNA.

[Prostate cancer with BRCA2 pathogenic mutation: a clinicopathological analysis].

Objective: To analyze the clinicopathological features of prostate cancers with BRCA2 pathogenic mutations, and the association between BRCA2 pathogenic mutation and clinicopathological characteristics. Patient survivals were also examined. Methods: Clinicopathological data of 249 prostate cancer patients who underwent genetic testing in West China Hospital of Sichuan University, Chengdu, China from June 2014 to August 2021 were collected. A retrospective analysis of histopathological morphology, clinicopathological characteristics, and patient survivals was conducted. Results: The genetic testing in the 249 prostate cancer patients showed a pathogenic mutation of DNA damage repair gene (DRG) in 73 cases (73/249, 29.3%), including 22 cases (8.8%) with BRCA2 pathogenic mutation and 51 cases with pathogenic mutations of other DRG. Among the 22 patients with BRCA2 pathogenic mutation, 14 patients (5.6%) harbored germline mutations and 8 patients (3.2%) somatic mutations. Their ages ranged from 48 to 91 years, with a median of 67 years. Seventeen patients (77.3%) had distant metastasis, including 16 cases with bone metastasis and 1 case with multiple metastases. Thirteen patients (59.1%) were castration-resistant prostate cancer. The histological type was mainly classical prostatic acinar adenocarcinoma, including 16 cases (72.7%) with intraductal carcinoma of the prostate (IDC-P). Six cases (27.3%) showed focal neuroendocrine differentiation. Perineural/vascular invasion and extraprostatic extension were seen in 11 cases (50.0%) and 8 cases (36.4%), respectively. The Gleason scores of 19 patients (86.4%) were≥8. IDC-P was more commonly found in patients with BRCA2 germline pathogenic mutation than those with BRCA2 somatic pathogenic mutation, other DRG pathogenic mutation or no-DRG pathogenic mutation (P=0.002). With a total follow-up time of 189 months, the median overall survival (OS) was 132.3 months. Patients with DRG pathogenic mutation had shorter OS than those with no-DRG pathogenic mutation (P=0.040). The OS of patients with BRCA2 germline pathogenic mutation did not significantly differ from that of patients with BRCA2 somatic pathogenic mutation, other DRG pathogenic mutation or no-DRG pathogenic mutation (P=0.216). Conclusions: The presence of BRCA2 gene pathogenic mutation is common in the prostate cancers with high Gleason grade, advanced clinical stage, and castration resistance. IDC-P is more commonly noted in cases with BRCA2 germline pathogenic mutation than those without. Patients with DRG pathogenic mutation have shorter OS than those with no-DRG pathogenic mutation, but there is no significant association between BRCA2 pathogenic mutations and OS.

The association of serum testosterone with dyslipidemia is mediated by obesity: the Henan Rural Cohort Study.

BACKGROUND AND AIMS: This study aimed to evaluate the relationships of serum testosterone with dyslipidemia and blood lipid levels and test whether obesity mediated these associations by gender in Chinese rural population. METHODS AND RESULTS: A total of 6150 subjects were finally analyzed in this study. Serum testosterone for each subject was detected by liquid chromatography equipped with tandem mass spectrometry. Logistic regression and linear regression were employed to evaluate the associations of serum testosterone with the prevalence of dyslipidemia and blood lipid levels. Mediation analysis was conducted to identify the mediation effects of obesity on the relationship between serum testosterone and dyslipidemia. After adjusting for multiple confounders, per unit change in serum ln-testosterone levels was associated with a decreased prevalent dyslipidemia in men (odds ratio (OR): 0.785, 95% confidence interval (CI) (0.708, 0.871)). Males with the levels of serum testosterone in the third or fourth quartiles had a 49.4% (OR: 0.506, 95% CI 0.398, 0.644) or 67.1% (OR: 0.329, 95% CI 0.253, 0.428) significantly lower odds of prevalence of dyslipidemia. In addition, a onefold increase in ln-testosterone was related to a 0.043 mmol/L (95% CI 0.028, 0.059) increase in high-density lipoprotein cholesterol (HDL-C) in men. Results of the mediation analysis suggested that obesity played a partial role in the association of testosterone with dyslipidemia in men. CONCLUSIONS: These findings suggested that serum testosterone levels were negatively associated with lipid levels and prevalent dyslipidemia, and obesity mediated the effects of serum testosterone on dyslipidemia in men, implying that obesity prevention should be highlighted to decrease the prevalence of dyslipidemia related to changes in testosterone levels.

[Apatinib Suppressed Macrophage-Mediated Malignant Behavior of Hepatocellular Carcinoma Cells via Modulation of VEGFR2/STAT3/PD-L1 Signaling].

Hepatocellular carcinoma (HCC) is the most frequently diagnosed primary liver tumor worldwide. Tumor-associated macrophages (TAMs) usually have a similar phenotype to M2-like macrophages and can participate in tumor progression by secreting cytokines to suppress the immune response and activity of tumor-infiltrating lymphocytes. We investigated the role of M2 macrophages in HCC progression and explored the effects of vascular endothelial growth factor receptor 2 inhibitor-apatinib. As a cellular model of HCC, Hepb3 cell line was used. M2 macrophages were obtained by differentiation of THP-1 cells. The Transwell chamber was used to co-culture M2 macrophages and Hepb3 cells. CCK-8 and EdU assays were conducted to measure cell viability and proliferation capacity. Transwell migration assay was performed to estimate cellular metastatic potential. Cytokine expression levels were assessed by ELISA. Western blotting was used to characterize activation of the VEGFR2/STAT3/PD-L1 axis. It has been shown that co-culture with M2 macrophages increased viability, cytokine production, promoted proliferation, invasion, and migration of Hepb3 cells. The secretion of TGF-ß1, IL-6, MMP-9, and VEGF was significantly increased after co-culture. In contrast apatinib suppressed M2 macrophage-induced proliferation, cell viability, invasion, and migration of Hepb3 cells. Moreover, apatinib markedly decreased expression levels of p-VEGFR2, p-STAT3, and PD-L1 in Hepb3 cells under the co-culture conditions. In conclusion, apatinib treatment can suppress TAMs-mediated malignant behavior of HCC cells via modulation of the VEGFR2/STAT3/PD-L1 signaling pathway.

[Thoracic SMARCA4-deficient undifferentiated tumor-pathological diagnosis and combined immune checkpoint inhibitor treatment].

We explored clinicopathological features and treatment strategies for thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT). Thoracic SMARCA4-UT is a new entity recently acknowledged in the 2021 edition of World Health Organization Classification of Thoracic Tumors, and doctors are relatively unfamiliar with its diagnosis, treatment, and prognosis. Taking a case of SMARCA4-UT treated in Peking University First Hospital as an example, this multi-disciplinary discussion covered several hot issues on diagnosing and treating thoracic SMARCA4-UT, including histological features, immu- nohistochemical and molecular phenotype, immune checkpoint inhibitor (ICI) therapy, and pathological assessment of neoadjuvant therapy response. The patient was an older man with a long history of smoking and was admitted due to a rapidly progressing solid tumor in the lower lobe of the right lung. Histologically, tumor cells were epithelioid, undifferentiated, diffusely positive for CD34, and partially positive for SALL4.The expression of BRG1 protein encoded by SMARCA4 gene was lost in all of tumor cells, and next-generation sequencing(NGS)confirmed SMARCA4 gene mutation (c.2196T>G, p.Y732Ter). The pathological diagnosis reached as thoracic SMARCA4-UT, and the preoperative TNM stage was T1N2M0 (ⅢA). Tumor proportion score (TPS) detected by immunohistochemistry of programmed cell death 1-ligand 1 (PD-L1, clone SP263) was 2%. Tumor mutation burden (TMB) detected by NGS of 1 021 genes was 16. 3/Mb. Microsatellite detection showed the tumor was microsatellite stable (MSS). Neo-adjuvant therapy was implemented with the combined regimen of chemotherapy and ICI. Right lower lobectomy was performed through thoracoscopy after the two weeks' neoadjuvant. The pathologic assessment of lung tumor specimens after neoadjuvant therapy revealed a complete pathological response (CPR). The post-neoadjuvant tumor TNM stage was ypT0N0M0. Then, five cycles of adjuvant therapy were completed. Until October 2022, neither tumor recurrence nor metastasis was detected, and minimal residual disease (MRD) detection was negative. At present, it is believed that if BRG1 immunohistochemical staining is negative, regardless of whether SMARCA4 gene mutation is detected, it should be classified as SMARCA4-deficient tumors. SMARCA4-deficient tumors include a variety of carcinomas and sarcomas. The essential criteria for diagnosing SMARCA4-UT includes loss of BRG1 expression, speci-fic histological morphology, and exclude other common thoracic malignant tumors with SMARCA4-deficiency, such as squamous cell carcinoma, adenocarcinoma and large cell carcinoma. SMARCA4-UT is a very aggressive malignant tumor with a poor prognosis. It has almost no targeted therapy mutations, and little response to chemotherapy, but ICI is currently the only effective drug. The successful diagnosis and treatment for this case of SMARCA4-UT should enlighten significance for various kinds of SMARCA4-deficient tumors.

[Microfocal prostate cancer: a clinicopathological analysis of 206 cases].

Objective: To investigate the clinical and pathological features and prognosis of patients with microfocal prostate adenocarcinoma. Methods: Clinical and pathological data of the patients diagnosed with microfocal adenocarcinoma on prostate biopsy at the West China Hospital from 2013 to 2019 were collected. Microfocal adenocarcinoma was defined as follows: Gleason score of 3+3=6, total number of the cores ≥10, number of the positive cores ≤2, and proportion of the tumor in each positive core<50%. Clinicopathological parameters, treatment plans and follow-up data were collected. Pathological information of the biopsy and radical resection specimens was used to analyze the correlation between pathological parameters in the biopsy report and adverse pathological features of radical resection specimens, including increased Gleason score, capsule invasion, positive surgical margin and perineural invasion. Results: A total of 206 cases of microfocal adenocarcinoma were diagnosed on prostate biopsies from 2013 to 2019, accounting for 6.7% of all adenocarcinoma cases. There were 139 cases of 1 positive core and 67 cases of 2 positive cores. Patients with microfocal adenocarcinoma were younger than those with non-microfocal adenocarcinoma (69 years versus 71 years, P<0.001). Compared with patients with non-microfocal adenocarcinoma, the pre-biopsy total prostate specific antigen (tPSA) and free prostate specific antigen (fPSA) levels in patients with microfocal adenocarcinoma were both lower (11.2 µg/L2 versus 23.7 µg/L2; 1.4 µg/L2 versus 3.0 µg/L2, P<0.001), the fPSA/tPSA level was higher (12.9% versus 10.7%, P<0.05), the prostate volume was larger (38.9 mL versus 34.3 mL, P<0.05), and the PSA density was lower (0.3 µg/L2 versus 0.8 µg/L2, P<0.001). 130 patients underwent radical prostatectomy, 30 patients chose active monitoring, 31 patients chose endocrine or radiation therapy, and 15 patients were lost to follow-up. Three patients in the active surveillance group underwent radical prostatectomy for disease progression after 21-39 months observation. Biochemical relapses occurred in two patients in the radical prostatectomy group. The remaining patients have no disease progression or recurrence at present. Compared with radical prostatectomy specimens, Gleason score in the biopsy material was increased in 64/115 patients (55.7%). Among resection excision specimens, 14 cases (12.2%) had extraprostatic extension (EPE), 35 cases (30.4%) had perineural invasion, and 16 cases (13.9%) had a positive margin. Univariate and multivariate analyses showed that low fPSA/tPSA ratio and 2 positive cores were independent risk factors for Gleason score increase in the radical prostatectomy specimens. A low fPSA/tPSA ratio was an independent risk factor for perineural invasion. Low fPSA/tPSA ratio and low prostate volume were associated with a positive margin in radical prostatectomy specimens. Conclusions: In this study, patients diagnosed with microfocal adenocarcinoma on prostate biopsy account for a high proportion of the patients with increased Gleason score in the radical prostatectomy specimens, and there is a certain proportion of adverse pathological features in the radical specimens. Therefore, for the patients with only a small amount of low-grade adenocarcinoma found in biopsy, PSA levels and PSA density should be taken into consideration in treatment selection.

Intrinsic Spin Susceptibility and Pseudogaplike Behavior in Infinite-Layer LaNiO_{2}.

The recent discovery of superconductivity in doped infinite-layer nickelates has stimulated intensive interest, especially for similarities and differences compared to that in cuprate superconductors. In contrast to cuprates, although earlier magnetization measurement reveals a Curie-Weiss-like behavior in undoped infinite-layer nickelates, there is no magnetic ordering observed by elastic neutron scattering down to liquid helium temperature. Until now, the nature of the magnetic ground state in undoped infinite-layer nickelates was still elusive. Here, we perform a nuclear magnetic resonance (NMR) experiment through ^{139}La nuclei to study the intrinsic spin susceptibility of infinite-layer LaNiO_{2}. First, the signature for magnetic ordering or freezing is absent in the ^{139}La NMR spectrum down to 0.24 K, which unambiguously confirms a paramagnetic ground state in LaNiO_{2}. Second, a pseudogaplike behavior instead of Curie-Weiss-like behavior is observed in both the temperature-dependent Knight shift and nuclear spin-lattice relaxation rate (1/T_{1}), which is widely observed in both underdoped cuprates and iron-based superconductors. Furthermore, the scaling behavior between the Knight shift and 1/T_{1}T has also been discussed. Finally, the present results imply a considerable exchange interaction in infinite-layer nickelates, which sets a strong constraint for the proposed theoretical models.

Negative associations of morning serum cortisol levels with obesity: the Henan rural cohort study.

AIMS: To evaluate the associations of morning serum cortisol levels with obesity defined by different indices in Chinese rural populations. MATERIALS AND METHODS: A cross-sectional study was performed including 6198 participants (2566 males and 3632 females). Serum cortisol was collected in morning and quantified by liquid chromatography-tandem mass spectrometry. Obesity was defined by body mass index (BMI), body fat percentage (BFP), waist-to-height ratio (WHtR), waist circumference (WC), visceral fat index (VFI) and waist-to-hip ratio (WHR). Both multivariable liner regression, logistic regression and restrictive cubic splines models were used to estimate the gender-specific relationships between cortisol levels and obesity defined by different indices, respectively. RESULTS: After adjusting for potential confounders, serum cortisol was negatively associated with different obesity measures, except obese females defined by BFP (for instance, overall obesity defined by BMI, Quartile 4 vs. Quartile 1, odds ratio (OR) = 0.25, 95% confidence interval (CI):0.15, 0.41 in males, and OR = 0.58, 95% CI: 0.42,0.80 in females, central obesity defined by WC, OR = 0.52, 95% CI:0.39,0.69 in males and OR = 0.63, 95% CI:0.51,0.77 in females). Similarly, restrictive cubic splines showed the nonlinear relationship between high levels of cortisol and different obesity indices. Furthermore, ROC curve analysis indicated that cortisol could improve the discrimination of model with common biomarkers. CONCLUSION: Morning serum cortisol were negatively related to obesity defined by different indices in Chinese rural populations. In addition, cortisol could be as a biomarker for prediction of obesity in males.

[Construction of professional competency model of center for disease prevention and control].

Objective: Analyze and contruct the post competency model of professionals in centers for disease prevention and control in Beijing, so as to provide information for cultivation and construction of public health personnel, and the human Resource Management in relevant institutions. Methods: Cross-sectional research method was used, and based on literature research, functional analysis and referring to Hay Group Competency Dictionary and McClellan Competency Dictionary, the post competency dictionary was established after the unified discussion of the subject group. Hierarchical cluster sampling method was used to investigate an online survey on competency factors of professionals in centers for Disease prevention and Control in Beijing, and factor analysis was conducted on the survey data. Results: The competency model of professionals in centers for disease prevention and control in Beijing was composed of six factors, which are Public health practical operation skills and norms, public health emergency response thinking and deductive and inductive ability, professional quality and professional ethics, communication, coordination ability and team spirit, medicine humanities knowledge and health management and guidance. Conclusions: This competency model is basically in line with the job responsibilities of professionals in centers for disease prevention and control in Beijing. However, it can only reflect the post competence and ability of the middle and junior technical personnel for practice, so which should belongs to the category of basic competence.

Preformed Cooper Pairs in Layered FeSe-Based Superconductors.

Superconductivity arises from two distinct quantum phenomena: electron pairing and long-range phase coherence. In conventional superconductors, the two quantum phenomena generally take place simultaneously, while in the underdoped high- T_{c} cuprate superconductors, the electron pairing occurs at higher temperature than the long-range phase coherence. Recently, whether electron pairing is also prior to long-range phase coherence in single-layer FeSe film on SrTiO_{3} substrate is under debate. Here, by measuring Knight shift and nuclear spin-lattice relaxation rate, we unambiguously reveal a pseudogap behavior below T_{p}∼60 K in two kinds of layered FeSe-based superconductors with quasi2D nature. In the pseudogap regime, a weak diamagnetic signal and a remarkable Nernst effect are also observed, which indicates that the observed pseudogap behavior is related to superconducting fluctuations. These works confirm that strong phase fluctuation is an important character in the 2D iron-based superconductors as widely observed in high-T_{c} cuprate superconductors.

[Expression of PD-1, TIM-3, LAG-3 and BTLA in diffuse large B-cell lymphoma and its effect on prognosis].

Objective: To investigate the expression levels of programmed death protein 1 (PD-1)、T cell immunoglobulin domain and mucin domain 3(TIM-3)、lymphocyte activating gene 3 (LAG-3) and B and T lymphocyte attenuator (BTLA) in Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) and their effects on prognosis. Methods: The paraffin specimens of 30 patients with DLBCL, NOS newly diagnosed in People's Hospital of Zhengzhou University were stained with immunohistochemistry. The effects of single positive and co-expression of the above molecules on progression-free survival (PFS) phase and overall survival (OS) phase were analyzed. Results: There was no significant difference in prognosis between PD-1, TIM-3, LAG3, BTLA single positive group and single negative group. The median PFS phase of PD-1 and TIM-3 co-expression group and TIM3 and BTLA co-expression group were 26 and 24 months respectively, which were both lower than the 54 months (P=0.021) and 47 months (P=0.037) in non-co-expression group. The median PFS phase and OS phase of PD-1, TIM-3 and LAG-3 co-expression group were 17 and 25 months respectively, which were significantly lower than the 41 months (P=0.024) and 60 months (P=0.015) of non-co-expression group. The median PFS phase and OS phase of PD-1, TIM-3, LAG-3 and BTLA co-expression group were 18 and 26 months respectively, which were significantly lower than the 40 months (P=0.038) and 57 months (P=0.041) of non-co-expression group. Conclusions: In patients with DLBCL, NOS, those with PD-1 and TIM-3 co-expression as well as those with TIM-3 and BTLA co-expression have poor PFS phase. Patients with PD-1, TIM-3 and LAG-3 co-expression and patients with PD-1, TIM-3, LAG-3 and BTLA co-expression have poor PFS and OS phase.

Ideal charge-density-wave order in the high-field state of superconducting YBCO.

The existence of charge-density-wave (CDW) correlations in cuprate superconductors has now been established. However, the nature of the CDW ground state has remained uncertain because disorder and the presence of superconductivity typically limit the CDW correlation lengths to only a dozen unit cells or less. Here we explore the field-induced 3D CDW correlations in extremely pure detwinned crystals of YBa2Cu3O2 (YBCO) ortho-II and ortho-VIII at magnetic fields in excess of the resistive upper critical field ([Formula: see text]) where superconductivity is heavily suppressed. We observe that the 3D CDW is unidirectional and possesses a long in-plane correlation length as well as significant correlations between neighboring CuO2 planes. It is significant that we observe only a single sharply defined transition at a critical field proportional to [Formula: see text], given that the field range used in this investigation overlaps with other high-field experiments including quantum oscillation measurements. The correlation volume is at least two to three orders of magnitude larger than that of the zero-field CDW. This is by far the largest CDW correlation volume observed in any cuprate crystal and so is presumably representative of the high-field ground state of an "ideal" disorder-free cuprate.

[The subgroup analysis of the prognostic value of the intraductal carcinoma of the prostate in patients with metastatic prostate cancer].

Objective: To determine the prognostic value of the intraductal carcinoma of the prostate IDC-P in metastatic prostate cancer (mPCa) patients of different subgroups. Methods: Data of 582 de novo mPCa patients between January 2011 and December 2017 diagnosed at Departments of Urology, West China Hospital, Sichuan University were retrospectively analyzed. The age was (70±8) years (range: 45 to 89 years). IDC-P was identified from 12-core prostate biopsy. The prognostic role of IDC-P was assessed by Kaplan-Meier curves and Cox regression. Subgroup analysis was conducted by the forest plot. The endpoints were castration-resistant prostate cancer free survival (CFS) and overall survival (OS). Results: In total, 177/582 (30.4%) patients harbored IDC-P. Patients with IDC-P had poorer CFS and OS than those without IDC-P (mCFS: 12.1 months vs. 16.9 months, P=0.000; mOS: 39.7 months vs. not reached, P=0.000). Multivariate Cox regression analysis indicated that, the existence of IDC-P was an independent prognosticator of both CFS (HR=1.40, 95% CI: 1.10 to 1.79, P=0.006) and OS (HR=1.51, 95% CI: 1.02 to 2.25, P=0.041). Subanalysis indicated that, in most subgroups, IDC-P was an adverse prognosticator of both CFS and OS. Even in subgroups with adverse clinicopathological features, e.g. Gleason score 9 to 10 (CFS: HR=1.467, P=0.007; OS: HR=1.807, P=0.013), baseline prostate specific antigen≥50 µg/L (CFS: HR=1.616, P=0.000; OS: HR=1.749, P=0.006), anemia (CFS: HR=1.653, P=0.036; OS: HR=2.100, P=0.038), alkaline phosphatase≥160 U/L (CFS: HR=1.326, P=0.038; OS: HR=1.725, P=0.010) or abnormal lactate dehydrogenase level (CFS: HR=1.614, P=0.001; OS: HR=1.900, P=0.003), IDC-P was still closely associated with shorter CFS and OS. Conclusions: The presence of IDC-P was closely related to poor survival outcomes for patients with mPCa. IDC-P was an adverse prognosticator in most subgroup patients. The description of IDC-P in the pathological report of prostate biopsy would help clinicians to evaluate the prognosis of mPCa patients more accurately and make better treatment choices.

Composite urinary biomarkers to predict pathological tubulointerstitial lesions in lupus nephritis.

Objective This study aimed to evaluate the clinical value of urinary biomarkers including kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemoattractant protein-1 (MCP-1) in lupus nephritis. Methods A total of 109 biopsy-proven lupus nephritis patients were included and 50 healthy individuals were used as normal controls. Urinary KIM-1, NGAL, and MCP-1 levels were measured by ELISA and their correlations with clinical and histological features were assessed. Receiver operating characteristic curves were performed and the Cox regression model was applied to identify prognostic factors associated with renal outcomes. Results Active lupus nephritis patients exhibited elevated urinary levels of KIM-1, NGAL, and MCP-1 compared with lupus nephritis patients in remission ( P < 0.001) and normal controls ( P < 0.001). The urinary KIM-1 level was correlated with pathological tubular atrophy ( r = 0.208, P < 0.05) and increased significantly in the presence of interstitial inflammatory lesions ( P = 0.031). Urinary KIM-1, NGAL, and MCP-1 levels were higher in patients with active tubulointerstitial lesions than in those with only chronic lesions ( P = 0.015, P = 0.230, and P = 0.086, respectively). A combination of KIM-1, NGAL, and MCP-1 was a good indicator for diagnosing active tubulointerstitial lesions (area under the curve: 0.796). The combination of KIM-1 and NGAL was identified as an independent risk factor for renal outcomes (hazard ratio = 7.491, P < 0.05). Conclusion Urinary KIM-1, NGAL, and MCP-1 levels were associated with kidney injury indices in lupus nephritis. The combination of the three biomarkers showed increased power in predicting tubulointerstitial lesions and renal outcomes.

[Prognostic significance of combined TERT and IDH gene mutation analysis in diffusely infiltrating gliomas].

Objective: To investigate the status and prognostic significance of TERT and IDH1/2 genes mutations in diffusely infiltrating gliomas. Methods: Hot spot mutations of TERT and IDH1/2 genes were detected by DNA sequencing in 236 cases of gliomas at West China Hospital from 2012 to 2016, including pilocytic astrocytoma (WHO grade Ⅰ, 16 cases), diffuse astrocytoma and oligodendroglioma (WHO grade Ⅱ, 89 cases), anaplastic astrocytoma and oligodendroglioma (WHO grade Ⅲ, 72 cases) and glioblastoma (WHO grade Ⅳ, 59 cases). The prognostic significance of TERT and IDH1/2 hot spot mutations was evaluated. Results: No IDH or TERT mutations were detected in pilocytic gliomas. TERT promoter mutation frequency was higher in patients aged ≥40 years(60.8%, 93/153) than in patients aged <40 years (32.8%, 22/67; P<0.01). TERT promoter mutation rate was also significantly higher in oligodendroglioma (87.5% , 56/64) than that in astrocytoma(37.8%, 59/156; P<0.01). Young age (<40 years), oligodendroglioma and IDH1 mutation were favorable prognostic factors for diffusely infiltrating astrocytic and oligodendroglial tumors. TERT mutation alone was not of prognostic significance. Diffusely infiltrating astrocytic and oligodendroglial tumors were divided into four molecular subtypes according to TERT and IDH1 mutation status: IDH(+ )/TERT(+ ), IDH(+ )/TERT(-), IDH(-)/TERT(-) and IDH(-)/TERT(+ ). There was significant prognostic difference among the 4 subtypes. Conclusions: Combined IDH and TERT gene mutation analysis may be useful for prognostic subgrouping. Notably, IDH1 wild-type cases can be further subdivided into TERT(+ ) or (-) subgroups with significant prognostic difference.

Phylogenetic relationships and divergence dates of softshell turtles (Testudines: Trionychidae) inferred from complete mitochondrial genomes.

The softshell turtles (Trionychidae) are one of the most widely distributed reptile groups in the world, and fossils have been found on all continents except Antarctica. The phylogenetic relationships among members of this group have been previously studied; however, disagreements regarding its taxonomy, its phylogeography and divergence times are still poorly understood as well. Here, we present a comprehensive mitogenomic study of softshell turtles. We sequenced the complete mitochondrial genomes of 10 softshell turtles, in addition to the GenBank sequence of Dogania subplana, Lissemys punctata, Trionyx triunguis, which cover all extant genera within Trionychidae except for Cyclanorbis and Cycloderma. These data were combined with other mitogenomes of turtles for phylogenetic analyses. Divergence time calibration and ancestral reconstruction were calculated using BEAST and RASP software, respectively. Our phylogenetic analyses indicate that Trionychidae is the sister taxon of Carettochelyidae, and support the monophyly of Trionychinae and Cyclanorbinae, which is consistent with morphological data and molecular analysis. Our phylogenetic analyses have established a sister taxon relationship between the Asian Rafetus and the Asian Palea + Pelodiscus + Dogania + Nilssonia + Amyda, whereas a previous study grouped the Asian Rafetus with the American Apalone. The results of divergence time estimates and area ancestral reconstruction show that extant Trionychidae originated in Asia at around 108 million years ago (MA), and radiations mainly occurred during two warm periods, namely Late Cretaceous-Early Eocene and Oligocene. By combining the estimated divergence time and the reconstructed ancestral area of softshell turtles, we determined that the dispersal of softshell turtles out of Asia may have taken three routes. Furthermore, the times of dispersal seem to be in agreement with the time of the India-Asia collision and opening of the Bering Strait, which provide evidence for the accuracy of our estimation of divergence time. Overall, the mitogenomes of this group were used to explore the origin and dispersal route of Trionychidae and have provided new insights on the evolution of this group.

[Analysis of related factors for primary hepatic carcinoma caused by chronic hepatitis B and hepatitis C].

Objective: To explore the related factors for primary hepatic carcinoma (PHC) caused by chronic hepatitis B (CHB) and hepatitis C (CHC). Methods: According to the principle of cross-sectional study, a cluster random sample method was used, a total of 366 chronic hepatitis patients in hospitals were recruited from three provincial tertiary hospitals in Shanxi, Henan and Jilin between July 2016 and October 2016, respectively. Using a self-designed unified questionnaire, face-to-face interviews was conducted on subjects, including sex, age, alcohol consumption, coffee consumption, green tea consumption, fish consumption, smoking, HBV/HCV diagnosis and treatment, diabetes mellitus, family history of PHC (whether PHC in first-degree relatives), etc. Multivariate unconditional logistic regression were performed to identify the related factors for PHC with CHB and CHC. According to the clinical diagnosis the patients were divided into a chronic hepatitis group (not developing to PHC) and a PHC group. Results: Among 366 cases patients, 287 (78.4%) cases were male, 79 cases were female (21.6%), average age was (52.7±9.3) years. 202 cases were chronic hepatitis group, 164 cases were PHC group. Multivariate unconditional logistics regression analysis indicated that alcohol consumption (odds ratio (OR)=2.11, 95%CI: 1.18-3.75), family history of PHC (OR=5.12, 95%CI: 2.60-10.08) were positively correlated with the development of PHC in chronic b, green tea consumption (OR=0.45, 95%CI: 0.23-0.88), antiviral treatment (OR=0.19, 95%CI: 0.11-0.32) were negatively correlated. Alcohol consumption (OR=3.98, 95%CI: 1.14-13.85) was positively correlated with the development of PHC in chronic c, antiviral treatment (OR=0.14, 95%CI: 0.04-0.50) was negatively correlated. Conclusion: Alcohol consumption, family history of PHC, green tea consumption and antiviral treatment were the related factors for the development of PHC in chronic hepatitis b. Alcohol consumption and antiviral treatment were the related factors for the development of PHC in chronic hepatitis c.

RESISTIN INHIBITS GLUCOSE-STIMULATED INSULIN SECRETION THROUGH MIR-494 BY TARGET ON STXBP5.

AIMS: Resistin has been reported to impair the pancreatic beta cells and associated with insulin resistance. MicroRNAs (miRNAs) are short, endogenously produced non-coding ribonucleotides that bind mRNAs and function mainly as negative regulators in mammals. MiRNAs have been implicated in many diseases, including insulin resistance and diabetes. A considerable body of evidence has indicated an important function for miRNAs in insulin secretion. The current study was designed to investigate the effects of miR-494 in the reductions in insulin secretion attributable to resistin. METHODS: Insulin secretion was determined by ELISA, and expressions of genes were identified using quantitative RT-PCR (qRT-PCR) or Western blot analysis. RESULTS: Insulin secretion was significantly reduced by resistin. Overexpression of miR-494 inhibited insulin secretion both in diet culture and high glucose medium in MIN6 cell lines. MiR-494 down-regulated the protein level of STXBP5 by pairing with sites in the 3'UTR. CONCLUSION: miR-494 is involved in the insulin secretion regulated by resistin via its effects on STXBP5 in MIN6 cells.

Notch1 is associated with the multidrug resistance of hypoxic osteosarcoma by regulating MRP1 gene expression.

Hypoxia and Notch signaling pathway are closely related and both participate in cell proliferation and drug resistance of tumors. However, the molecular mechanisms of hypoxia and Notch signaling pathway in cell proliferation and drug resistance of osteosarcoma (OS) remain unclear. In this study, to further evaluate the role of hypoxia and Notch1 on drug resistance of OS, we investigated the influence of inhibiting Notch1 pathway by Notch1 small interference RNA (siRNA) on human MG-63 OS cells in hypoxia. Our data showed that hypoxia promoted OS cell proliferation, induced the G0/G1-S-G2/M phase transition, and increased multidrug resistance of human OS cells. Western blot analysis suggested that hypoxia increased the expression of HIF-1α, Notch1, and multidrug resistance protein-1 (MRP1) in human OS cells. Notch1 siRNA inhibits proliferation and increases apoptosis of hypoxic OS cells. Finally, these hypoxic OS cells can be sensitized to multidrug treatment through inhibition of the Notch protein expression by siRNA. Repression of the Notch protein expression resulted in down-regulation of MRP1 protein. These data support the conclusion that Notch signaling is up-regulated in human OS cells under hypoxia and Notch1 may represent a viable target to overcome chemoresistant OS cells in a hypoxic niche by regulating MRP1 gene expression.

Esophageal submucosal gland duct adenoma: a clinicopathological and immunohistochemical study with a review of the literature.

Esophageal submucosal gland duct adenoma (ESGDA) is a rare tumor. The clinicopathological features of the ESGDA and its precursor lesion have not been comprehensively evaluated. In this study, we aimed at delineating the clinicopathological features of the ESGDA and cyst formation of the esophageal submucosal gland duct (ESGD), as well as their correlations and clinical implications. We identified three cases of ESGDA and 16 cases of cyst formation of the ESGD among 786 endoscopic mucosal resection specimens over a 7-year period. The median patient age was 58 years with a male predominance. These lesions were small submucosal bulges locating at the lower esophagus with a size no more than 1 cm. The main microscopic changes of these lesions included content retention, multilayered epithelium or papillary folds of the ESGD and inflammatory cell infiltration, acidophilic degeneration, hyperplasia or atrophy of the acini. The included cases generally showed moderate to severe microscopic esophagitis. The ESGDA was mainly consisted by multiple glandular cysts covered by two layers of cells. Immunohistochemical results showed that the luminal duct lining cells and basal cells were positive for CK7 and p63, respectively. Both of the two layer cells were positive for HMWCK and negative for CK20, p53, CDX2, MUC5AC, MUC6, MUC2 and MUC1. The proliferation index was very low (1%). The diagnostic criteria of the ESGDA were proposed and, the differential diagnosis was discussed. Cyst formation of the ESGD is considered to be the precursor lesion of the ESGDA, because they have overlapping clinicopathological features with progressive relationship. In addition, the ESGDA have close connection with advance of the GERD and, probably, an increased risk of carcinoma.