Discovery of LAH-1 as potent c-Met inhibitor for the treatment of non-small cell lung cancer.

ABSTRCTDysregulated HGF/c-Met pathway has been implicated in multiple human cancers and has become an attractive target for cancer intervention. Herein, we report the discovery of N-(3-fluoro-4-((2-(3-hydroxyazetidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (LAH-1), which demonstrated nanomolar MET kinase activity as well as desirable antiproliferative activity, especially against EBC-1 cells. Mechanism studies confirmed the effects of LAH-1 on modulation of HGF/c-Met pathway, induction of cell apoptosis, inhibition on colony formation as well as cell migration and invasion. In addition, LAH-1 also showed desirable in vitro ADME properties as well as acceptable in vivo PK parameters. The design, synthesis, and characterisation of LAH-1 are described herein.

Design, synthesis and evaluation of 2, 6, 8-substituted Imidazopyridine derivatives as potent PI3Kα inhibitors.

Inhibition of PI3K pathway has become a desirable strategy for cancer treatment. In this work, a series of 2, 6, 8-substituted Imidazo[1,2-a]pyridine derivatives were designed and screened for their activities against PI3Kα and a panel of PI3Kα-addicted cancer cells. Among them, compound 35 was identified as a PI3Kα inhibitor with nanomolar potency as well as acceptable antiproliferative activity. Flow cytometry analysis confirmed 35 induced cell cycle arrest and apoptosis in T47D cells. In addition, it also showed desirable in vitro ADME properties. The design, synthesis, and SAR exploration of 35 are described within.

Effects of osmotic stress on Na+/K+-ATPase, caspase 3/7 activity, and the expression profiling of sirt1, hsf1, and hsp70 in the roughskin sculpin (Trachidermus fasciatus).

Osmoregulation mechanism underlying acclimation of migratory fish to different salinities has been a classical research topic for decades. In this study, the roughskin sculpin (Trachidermus fasciatus) were subjected to two different acute osmotic treatments (one extreme acute and one acute treatment, i.e., E-acute and acute group). Comparisons of branchial enzyme activity, as well as the time-course expression profiling of sirt1, hsf1, and hsp70 were performed to reveal changes at the physiological and molecular levels. As a result, the branchial Na+/K+-ATPase activity was significantly inhibited and the caspase 3/7 relating to apoptosis was significantly induced in the E-acute group; no significant difference of branchial enzyme activity was detected in the acute group. These results suggested that T. fasciatus could keep stable physiological levels when experiencing the acute salinity change but not under extreme osmotic stress. Significant variations of sirt1, hsf1, and hsp70 expression were determined in the four target tissues (gill, intestine, kidney, and liver). Similar profiling was detected between the time-course expression of sirt1 and hsf1, suggesting their association in the osmoregulation process. Tissue-specific gene expression patterns in all the three target genes showed that each tissue possesses its own gene expression pattern in response to salinity changes. The overall different expression profiling of sirt1, hsf1, and hsp70 under the extreme acute and acute osmotic treatments might respectively represent the molecular regulation of stress response and acclimation. The findings make it possible to provide more reliable data to decipher the mechanism of osmoregulation in migratory fish.

Influences of an Aluminum Covering Layer on the Performance of Cross-Like Hall Devices.

This work studies the effects of an aluminum covering on the performance of cross-like Hall devices. Four different Hall sensor structures of various sizes were designed and fabricated. The sensitivity and offset of the Hall sensors, two key points impacting their performance, were characterized using a self-built measurement system. The work analyzes the influences of the aluminum covering on those two aspects of the performance. The aluminum layer covering mainly leads to an eddy-current effect in an unstable magnetic field and an additional depletion region above the active region. Those two points have influences on the sensitivity and the offset voltage, respectively. The analysis guides the designer whether to choose covering with an aluminum layer the active region of the Hall sensor as a method to reduce the flicker noise and to improve the stability of the Hall sensor. Because Hall devices, as a reference element, always suffer from a large dispersion, improving their stability is a crucial issue.

Performance comparison of cross-like Hall plates with different covering layers.

This paper studies the effects of the covering layers on the performance of a cross-like Hall plate. Three different structures of a cross-like Hall plate in various sizes are designed and analyzed. The Hall plate sensitivity and offset are characterized using a self-built measurement system. The effect of the P-type region over the active area on the current-related sensitivity is studied for different Hall plate designs. In addition, the correlation between the P-type covering layer and offset is analyzed. The best structure out of three designs is determined. Besides, a modified eight-resistor circuit model for the Hall plate is presented with improved accuracy by taking the offset into account.

Biochemical composition and quality of turbot (Scophthalmus maximus) eggs throughout the reproductive season.

The present study investigated the biochemical composition and quality of turbot (Scophthalmus maximus) eggs throughout the reproductive season. Results showed that the fertilization, hatching and egg floating rates were variable throughout the reproductive season, with the highest values recorded during the mid-season. Meanwhile, positive correlations were found between fertilization, hatching rate and floating rate. The composition of turbot eggs, including total lipid, protein, carbohydrate, moisture and dry weight showed no significant differences during the reproductive season. Furthermore, no correlations were found between egg compositions and viability parameters (VPs), including fertilization and hatching rates as well as larval deformity rate. However, egg diameter varied and correlated with fertilization, hatching and egg floating rates. The fatty acid in eggs at mid-season had significantly higher levels of C14:0, C16:0, C16:1n-7, C18:0, C18:1, C20:4n-6, C20:5n-3 and C22:6n-3. Moreover, significant relationships were found between fatty acids and VPs. Eggs of the middle season had significantly higher concentration of isoleucine, leucine, lysine, methionine, valine, alanine, aspartate, glutamate and serine, whereas no significant relationships were found between amino acids and VPs. These observations suggest that the biochemical profile of eggs may be useful in evaluating egg quality and improving broodstock management for turbot.

[Evaluation of screening performance of HPV DNA test on specimens from different sites of the female genital tract].

OBJECTIVE: To evaluate the diagnostic performance of different specimens for detecting CIN2(+), and to find the solution of the problem that why the performance of self-collected specimen is worse than cervical specimen collected by physician. METHODS: The cervix, lower 1/3 vagina, upper 1/3 vagina and self-collected specimens from each of the 806 women who took part in this multi-center screening program from May 2006 to April 2007 were tested by hybrid capture 2 (HC2) technique. The diagnostic performance of HC2 on the four specimens for detecting CIN2(+) lesions was calculated. Linear array was performed on the four specimens from 489 out of the 806 women and the diagnostic performance of linear array on the four specimens for detecting CIN2(+) lesions was also calculated. Z test was used to compare the area under ROC and McNemar or χ(2) test was used to compare the sensitivity and specificity of different specimens. RESULTS: The area under ROC of the cervix, 1/3 upper vagina, 1/3 lower vagina and self-collected samples testing by HC2 for detecting CIN2(+) lesions were 0.902, 0.793, 0.769 and 0.773, respectively (P < 0.001). Using 1 RUL/CO as the cut-point of HC2, the sensitivity of the cervix, upper vagina, lower vagina and self-collected samples were 98.0%, 91.8%, 83.7% and 81.6%. Compared with the cervical specimen, the sensitivity of self-collected specimen for detecting CIN2(+) lesions was significantly lower (P = 0.008). Lowering the cutoff value for HC2 test could improve the sensitivity of self-collected specimen, but it significantly compromised the specificity. The sensitivity of self-collected specimen tested by linear array for detecting CIN2(+) lesions was 95.7% and it was not significantly different compared with the sensitivity of cervical specimen (97.9%) tested by HC2. CONCLUSIONS: The performance of self-collected specimen tested by HC2 for detecting CIN2(+) lesions is lower than that of physician-collected cervical specimen, and lowering the cutoff value can't improve its diagnostic performance. Using linear array as the HPV DNA test can significantly improve the screening diagnostic performance of self-collected specimens.

Apatinib successfully administered in malignant tumour patients with severe hypotension: a case series, literature review, and considerations for treatment.

The most notable side-effect of apatinib, a novel antiangiogenic agent for the treatment of cancer, is hypertension, but there are few published studies regarding the use of apatinib to treat patients with cancer and severe hypotension. Here, the cases of three patients with tumours and severe hypotension are described: case 1, a 73-year-old male patient with lung squamous cell carcinoma who initially received radiotherapy and chemotherapy, and developed pneumonia and severe hypotension after 6 months; case 2, a 56-year-old male patient with nasopharyngeal carcinoma who was treated with chemotherapy and presented with fever and persistent hypotension; and case 3, a 77-year-old male patient with oesophageal cancer who was admitted with deglutition difficulty and severe hypotension. Apatinib was added to the treatment regimen of all three patients for antitumor therapy. Pneumonia, tumour progression, and severe hypotension improved noticeably in all patients within 1 month after receiving apatinib. Apatinib was associated with a positive effect on blood pressure stability, in synergy with other means of therapy, and the patients achieved satisfactory short-term clinical results. The role of apatinib in treating patients with cancer and hypotension merits further investigation.

Comprehensive analysis of prognosis of patients with GBM based on 4 m6A-related lncRNAs and immune cell infiltration.

Objective: To investigate the immune cell infiltration status in glioblastoma multiforme (GBM) and construct a novel prognostic risk model that can predict patients' prognosis. Methods: The Cancer Genome Atlas (TCGA) database was used to obtain RNA-sequence information and relevant clinical data. We performed Pearson correlation, univariate Cox regression to screen m6A-related prognostic lncRNA. GMB patients' samples were separated into different clusters through the ConsensusClusterPlus package. The risk score model was established through LASSO regression analysis. Besides, KEGG pathway enrichment analysis was implemented. CIBERSORT algorithm was used to analyze the difference of 22 types of immune cell infiltration in different cluster of GBM patient. Cox regression analyses were used to verify the independence of the model and correlation analysis was performed to demonstrate the link between our model and clinical characteristics of GBM patients. Experiments were used to validate the differential expression of the model lncRNA in patients with different prognosis. Results: 17 lncRNA related to prognosis were screened from 1021 m6A-related lncRNAs. Further, four m6A-related lncRNAs that were significantly correlated with GBM prognosis were selected to establish our prognostic risk model, which had excellent accuracy and can independently predict the prognosis of GBM patients. The infiltration fractions of T regulatory cells, T cells CD4 memory activated and neutrophils were positively associated with risk score, which suggested a significant relationship between the model and tumor immune microenvironment. Conclusion: The m6A-related RNA risk model offered potential for identifying biomarkers of therapy and predicting prognosis of GBM patients.

[Prospective study of the association between fasting glucose concentrations and liver cirrhosis risk].

OBJECTIVE: To investigate the association between concentration levels of fasting serum glucose and liver cirrhosis. METHODS: A nested case-control study was carried out based on the sample cohort from the Nutrition Intervention Trials previously conducted in one country in Henan province. Using an automatic biochemical analysis system and enzyme-linked immunoassay, baseline serum samples from 310 liver cirrhosis patients and 620 healthy controls were tested for fasting glucose concentration, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis C virus antibody (anti-HCV). Baseline demographic information was collected by questionnaire. The serum glucose values were divided into quintiles and applied to a logistic regression model to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: The mean fasting blood glucose level was significantly higher in cases (4.5+/-1.8 mmol/L) than in controls (4.2+/-2.1 mmol/L) (t=-2.414, P=0.016). The individuals in the highest quintile had a significantly higher risk of disease than those in the lowest quintile [OR=1.672 (1.080, 2.588)]. Moreover, increase in glucose level was accompanied by increased risk, and the relation showed statistically significant linearity (P=0.002). The statistical significance of risk remained after adjustment for potential confounders, including sex, age, HBsAg, anti-HBc, and residence running water status [OR=1.96 (1.216, 3.157), P=0.001]. CONCLUSION: Elevated serum fasting glucose concentration was an independent risk factor of cirrhosis.

Elevated pretreatment neutrophil-to-lymphocyte ratio indicate low survival rate in apatinib-treated patients with non-small cell lung cancer: A STROBE-compliant article.

This study aimed to analyze the predictive value of the neutrophil-to-lymphocyte ratio (NLR) to better clarify which patients with advanced non-small cell lung cancer (NSCLC) would benefit most from apatinib after multiline treatment for drug resistance. This observational cohort study involved patients with advanced NSCLC who were treated with apatinib between May 2016 to May 2018. The participants in this study had previously been treated with at least two treatment regimens. Multivariate logistic regression and Cox proportional risk models were used to evaluate the overall survival (OS) and progression-free survival (PFS) of the pretreatment NLR. A total of 125 patients were reviewed. The median age was 64 years (range, 33-92); and 32.8% of the patients were female. Only 0.8% of the patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score ≥ 2. In multivariate analysis, pretreatment NLR ≥ 5 had an independent correlation with inferior OS (median 2.07 vs 3.40 months; HR 1.493, 95% CI 1.022-2.182; P = .038) and inferior PFS (median 1.83 vs 2.76 months; HR 1.478, 95% CI 1.015-2.153; P = .042). Elevated pretreatment NLR is associated with shorter OS and PFS in patients with advanced NSCLC treated with apatinib after multiline treatment for drug resistance.

Anti-inflammatory activity of the extracts and fractions from Erigeron multiradiatus through bioassay-guided procedures.

ETHNOPHARMACOLOGICAL RELEVANCE: Erigeron multiradiatus (Lindl.) Benth., an herb that grows in the alpine and subalpine meadow of Qinghai-Tibet plateau, has been widely used as a folk remedy by the native people for treatment of various inflammatory ailments. AIM OF THE STUDY: In order to isolate and identify the active components of Erigeron multiradiatus for anti-inflammatory activity, a preliminary phytochemical study and a bioassay-guided fractionation and purification process was performed. MATERIAL AND METHODS: The dry whole plant Erigeron multiradiatus was extracted with 50% ethanol and then separated into CHCl(3), n-BuOH, and aqueous fractions. The anti-inflammatory activities of each fraction were investigated using two in vivo inflammation models. RESULTS: These results exhibited varying degrees of anti-inflammatory activities and the n-BuOH fraction showed the strongest anti-inflammatory activities. The n-BuOH fraction was then subjected to separation and purification using macroporous resins column chromatography and Sephadex LH-20 leading to two flavonoids glucuronides identified as scutellarein-7-O-beta-glucuronide and apigenin-7-O-beta-glucuronide. Furthermore, LC-MS/MS identification and quantification of isolated compounds were also performed. CONCLUSION: Scutellarein-7-O-beta-glucuronide and apigenin-7-O-beta-glucuronide were considered as major components and principally responsible for the anti-inflammatory activity of Erigeron multiradiatus. Thus the results of our study provide a scientific basis for the utilization of Erigeron multiradiatus in traditional Tibetan medicine.

[Human papillomavirus genotype distribution in invasive squamous cell carcinoma of the uterine cervix in Mongolian women in inner Mongolia autonomy region].

OBJECTIVE: To investigate the prevalence of human papillomavirus (HPV) and the HPV genotype distribution in invasive squamous cell carcinoma of the uterine cervix in the Mongolian women in Inner Mongolia autonomy region. METHODS: The prevalence data of HPV in our department were retrospectively reviewed. INNO-LiPA genotyping technique was used to detect HPV genotypes in the reserved carcinoma tissue specimens. RESULTS: Totally 63 tissue specimens were collected and detected. The prevalence of HPV was 93.7%. The positive rates of HPV among different clinical staging and different pathological grading were not significantly different (P >0.05). The prevalence of HPV16 was not significantly different among different age groups (P>0.05). HPV16 (69.8%), HPV18 (4.8%), HPV31 (4.8%), HPV39 (4.8%), and HPV52 (3.2%) were the 5 dominating HPV genotypes in all cases. CONCLUSIONS: HPV infection is closely correlated with invasive squamous cell carcinoma of the uterine cervix in Mongolia women. HPV16 is the most important genotype in invasive squamous cell carcinoma of the uterine cervix, followed by HPV18, 31, and 39. HPV infection dose not affect the progression and differentiation of invasive squamous cell carcinoma of the uterine cervix.

Analyses of the molecular mechanisms associated with salinity adaption of Trachidermus fasciatus through combined iTRAQ-based proteomics and RNA sequencing-based transcriptomics.

Osmoregulation mechanism underlying acclimation and adaptation of migratory fish to different salinities has been studied for decades. Recently developed transcriptomic and proteomic techniques would make it possible to provide more reliable data to decipher the mechanism study at a molecular level. Here in this study, an integrative analysis of the kidney-specific transcriptome and proteome was performed to identify important regulators and pathways involved in salinity adaption of roughskin sculpin (Trachidermus fasciatus). Fish were subjected to seawater-to-freshwater transfer that was achieved in 24 h, samples were collected at 12, 24 and 48 h after the start of the experiment. Time course profiling of gene and protein expressions were examined using RNA-seq and iTRAQ methods. A total of 1504 differentially expressed genes (DEGs) and 378 differentially expressed proteins (DEPs) were identified at the three time points. 66 proteins were filtered by correlation of transcriptome and proteome results. When comparing the data obtained from the three time points, 12 h exhibited the largest number of DEGs and DEPs, suggesting the time course experiment is critical to clarify the framework of regulatory genes/proteins in response to salinity change. This study provides the first time-course, kidney-specific, combined transcriptomic and proteomic profiling associated with salinity adaption of Trachidermus fasciatus. The results revealed the possibility of T. fasciatus as an experimental animal for osmoregulation studies, showed the powerfulness of combining transcriptomic and proteomic approaches to provide molecular insights of osmoregulation mechanisms in migratory fish.

[Human papillomaviruses infections among village women in Henan province].

OBJECTIVE: To investigate the prevalence of Human papillomaviruses (HPVs) among village women in Henan and to determine its relevant risk factors. METHODS: A population based cross-sectional study on cervical cancer was conducted among village women in Xinmi, Henan. Women aged 20 - 54 who had sexual intercourse experiences were enrolled in this study. Self-sampling and direct-sampling were used in collecting women's vaginal discharge. 13 high-risk HPVs were tested with HC2 for all of the specimens. Then women with abnormal results did colposcopy and biopsy. The biopsy results were regarded as the golden standard. RESULTS: There were 881 women enrolled in this paper and 881 self-sampling and 880 direct-sampling specimens were collected. The HPVs prevalence rates for the self-sampling and direct-sampling were 13.05% and 12.27%, respectively. Age-specific prevalence rates were 10.57% (20-), 9.60% (25-), 12.00% (30-), 9.52% (35-), 17.60% (40-), 13.74% (45-) and 12.80% (50 - 54). HPV prevalence rates were increased with progression of cervical disease (chi(2) = 200.69, P = 0.00). And HPV prevalence rates were higher in women with more advanced education background (chi(2) = 11.05, P = 0.01). HPV infection rate in women whose husbands have more than one sexual partner was 18.02% and whose husbands have only one sexual partner was 10.88% (chi(2) = 6.37, P = 0.01). CONCLUSION: The infection rate of high-risk HPVs in this area is high. The relationship of HPV infection with age has not been observed in this study, but the the sexual activity is the major risk factor for cervical cancer.

[Present state of studies on anatomical anomalies in cryptorchidism].

Cryptorchidism is a clinically common congenital deformity of the genital organ, the etiological factors of which are still not clarified up to now. Undescended testis is frequently accompanied with the anomalies of the spermatic cord, gubernaculum testis, processus vaginalis, and epididymis. Because these anatomical anomalies act as terminal factors or the ending in the links of the cause of cryptorchidism, it is of important directive significance for the clinical treatment of the problem to seek evidence of anatomical anomalies at orchiopexy to demonstrate the etiological factors of cryptorchidism.

Life-style and genital human papillomavirus in a cross-sectional survey in Shanxi Province, China.

BACKGROUND: To determine the age-stratified HPV prevalence rate and the risk factors of life-style associated with HPV infection among women in rural China. METHODS: An age-stratified, cross-sectional survey of 941 women between 16-59 years old was conducted in rural China. Carcinogenic HPV infection was determined using Digene's Hybrid Capture II HPV DNA test and interviews of life-style were conducted. Odds ratios (OR) and 95% confidence interval (CI) from the logistic regression models were used to determine the risk factors associated with HPV. RESULTS: Among 941 women, 745 who had sexual intercourse underwent a cervical examination. The prevalence rate of 13 carcinogenic HPV infections among women 20-59 years old was 15.97%. the rate of HPV prevalence in the 25-34 age group was statistically lower than that in 20-24 and 35-59 age groups (X²=13.3, P=0.0013). The OR of bathing every 7-19 days, 20-180 days, less than once every 180 days vs. bathing at least once a week were 1.19, 1.83 and 2.29 respectively and they had a dose-response relationship (Trend Test: P=0.003). The OR of women aged 25-34 age group vs. 20-24 age group was 0.40 (0.16 - 0.97) and the OR of bathing once every 180 days or less vs. at least once weekly was 2.22 (1.14 - 4.33) adjusted for the other confounding factors,. CONCLUSIONS: The HPV prevalence rate was lowest among child bearing women aged 25-34 year. Also, personal hygiene is significantly associated with the HPV infection in this area, regardless of age.