Annulation Reaction of Quinoxalin-2(1H)-ones Initiated by Electrochemical Decarboxylation of N-Arylglycines.

A new methodology for the synthesis of tetrahydroimidazo[1,5-a]quinoxalin-4(5H)-ones has been accomplished through annulation of quinoxalin-2(1H)-ones initiated by electrochemical decarboxylation of N-arylglycines catalyzed by ferrocene. With a pair of oxidative and reductive processes occurring among the substrates and intermediates instead of on the electrodes, the electricity consumption was decreased.

Stability Study of Cervical Specimens Collected by Swab and Stored Dry Followed by Human Papillomavirus DNA Detection Using the cobas 4800 Test.

Safer, more convenient methods for cervical sample collection and storage are necessary to facilitate human papillomavirus (HPV) DNA testing in low-resource settings. Our study aimed to evaluate the stability of cervical specimens collected with dry swabs and stored dry, compared to liquid-based cytology (LBC) samples, as detected by HPV DNA testing. Women with abnormal cytological findings or HPV-positive results at colposcopy were recruited from the West China Second University Hospital, Sichuan University, between October 2013 and March 2014. From each woman, physicians collected cervical specimens with a swab placed into a Sarstedt tube and a CytoBrush placed into LBC medium. Samples were randomly assigned to be stored at uncontrolled ambient temperature for 2, 7, 14, or 28 days and then were tested for 14 high-risk HPV (HR-HPV) types using the cobas HPV test. The rates of agreement between dry swab and LBC samples for any HR-HPV type, HPV16, HPV18, and the 12 pooled HR-HPV types were 93.8%, 97.8%, 99.4%, and 93.2%, respectively, with kappa values of 0.87 (95% confidence interval [CI], 0.83 to 0.91), 0.94 (95% CI, 0.91 to 0.97), 0.94 (95% CI, 0.87 to 1.00), and 0.86 (95% CI, 0.82 to 0.90). The performance of swab samples for detection of cervical precancerous lesions by means of cobas HPV testing was equal to that of LBC samples, even with stratification by storage time. Dry storage of swab-collected cervical samples can last for 1 month without loss of test performance by cobas HPV testing, compared to LBC samples, which may offer a simple inexpensive approach for cervical cancer screening in low-resource settings.

Application of LA-ICP-AES to Distinguish the Different Turquoise Mines.

Currently, the technological development of non-destructive analysis and micro-damage analysis of turquoise is fast. LA-ICP-AES, an almost non-destructive analysis, has multiple advantages. This paper attempts to use this analysis method to examine sample turquoise from five places of origin on Mount East Qinling, including ancient turquoise ore in Laziya, in order to attain its major element and microelement data. Then the paper uses PCA to analyze and study its chemical elements in a comparative way. Three main elements are gained through analysis, and their cumulative variance contribution rate has reached 84.96%. The former two main elements' variance contribution rate is 72.289%. Therefore, the corresponding elements, including V2O5, NiO, B2O3, SrO, BaO, CaO, ZrO, MnO2, are the featured chemical elements of turquoise from different places of origin. Through comparative analysis and research on corresponding chemical elements, turquoise samples produced by different ores vary in terms of the content of some chemical element and chemical components. Two analysis methods combined together will basically realize the appreciation of turquoise in various places of origin. In addition, the research indicates that some chemical contents have positive or negative correlations. Such correlations can be regarded as features of producing area, and can also provide clues as to the cause of formation of turquoise ore. This study preliminarily indicates that LA-ICP-AES combined with PCA and comparative analysis of chemical composition and content has the function of distinguishing turquoise produced in different places of origin to a certain extent.

Prevalence of type-specific human papillomavirus and pap results in Chinese women: a multi-center, population-based cross-sectional study.

PURPOSE: To estimate the burden of human papillomavirus (HPV) infection among sexually active women in China. METHODS: We conducted a multi-center, population-based study between May 2006 and April 2007. A total of 4,215 women aged 17-54 years were surveyed from five geographical sites: Beijing, Shanghai, Shanxi, Henan, and Xinjiang. Direct endocervical exfoliated cells were collected from consenting participants for Sure Path liquid-based cytology (BD) and HPV testing. HPV testing was performed with Hybrid Capture II (Qiagen) with high-risk and low-risk probes, and Linear Array (Roche) was utilized for HPV genotyping. RESULTS: Approximately 11 % of the study population had a cytological abnormality (ASCUS or worse). HPV prevalence in the entire study population was 14.3 % (age-standardized to the world standard female population 14.5 %). The most prevalent types found were HPV16 (2.9 %), HPV52 (1.7 %), HPV58 (1.5 %), HPV33 (1 %), and HPV18 (0.8 %). Patterns of HPV prevalence differed by age, geographic region, and cytology findings. However, HPV16 was predominant among all grades of cytological abnormalities for all areas. CONCLUSIONS: Although HPV18 appeared to be less frequent among population-based samples of China, given the high prevalence of HPV 16 and 18 in high-grade squamous intraepithelial lesion (HSIL) or worse pap abnormalities, prophylactic HPV16/18 vaccines should substantially reduce the burden of cervical cancer in China.

[Prospective study on the relation between serum vitamin D levels and liver cirrhosis risk].

OBJECTIVE: To explore the relation between serum vitamin D (25(OH)D) concentrations and liver cirrhosis. METHODS: A nested case control study was designed based on the Nutrition Intervention Trial (NIT) cohort, from which non-degraded serum samples and complete baseline and follow-up data were available for 282 individuals diagnosed with liver cirrhosis and 564 healthy controls. The serum samples were tested by enzyme-linked immunosorbent assay to detect and quantify 25(OH)D, as well as hepatitis B virus surface antigen and core antibody and hepatitis C virus antibody. The study participants were divided into four groups according to quartile range of 25(OH)D concentration and logistic regression modeling was used to evaluate the relation with liver cirrhosis risk by estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The liver cirrhosis group had a significantly lower concentration of 25(OH)D than the control group (median and quartile range in nmol/L, cases: 15.3 and 13.8; controls: 20.2 and 16.6; t = 5.169, P = 0.002). When the first interval was set as the reference level, the ORs(95% CIs) of the second, third, and fourth intervals were: 0.495(0.333 - 0.736), 0.452(0.303 - 0.675), and 0.349(0.231- 0.527). After adjusting the analysis for the presence of pathogenic-related confounding factors, the ORs(95% CIs) of the second, third, and fourth intervals were: 0.499(0.328 - 0.759), 0.427(0.278 - 0.654), and 0.344(0.222-0.532). The 25(OH)D level was inversely correlated with risk of liver cirrhosis (Chi2 = 25.200, P < 0.001). CONCLUSION: Risk of liver cirrhosis increases as 25(OH)D serum concentration decreases. Vitamin D might function as a protective factor against development of cirrhosis.

[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.

[Characteristics of chemical composition of glass finds from the Qiemo tomb sites on the Silk Road].

Qiemo was an ancient country on the south branch of the Silk Road. The Zagunluke tomb site is located at the Qiemo County of the Xinjiang Uygur Autonomous Region. Glass beads and only colourless glass cup were excavated from the 3rd cultural layer of the tomb site M133 and M49, dated between the 1st AD-6th AD. LA-ICP-AES was applied to analyse chemical composition of these glass finds with the corning glass as reference. According to the result, characteristics of chemical composition are very similar to typical soda-lime glass, which indicates the glasses were imported productions from the west. These soda-lime glasses were divided into two groups in terms of flux source: natron glass and plant ash glass. This analytical research indicates the history of glass trade and communication between the East and the West on the Silk Road.

Association of elevated E6 oncoprotein with grade of cervical neoplasia using PDZ interaction-mediated precipitation of E6.

OBJECTIVE: To determine the expression of human papillomavirus (HPV) type 16 E6 oncoprotein in cervical specimens of women with and without cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: Cervical specimens from 2,530 unscreened women aged 30 to 54 years from Shanxi, China, were obtained. All women were assessed by liquid-based cytology, high-risk HPV DNA tests, and colposcopy with directed biopsy and endocervical curettage as necessary. Women with abnormal cytologic results or positive HPV DNA results were recalled for colposcopy, 4-quadrant cervical biopsies, and endocervical curettage. Women with biopsy-proven CIN and cancer and a convenience sample of HC2-positive, disease-negative women were tested for the presence of HPV-16 infection via HPV-16 E6 DNA-specific polymerase chain reaction. A PDZ interaction-mediated E6 oncoprotein precipitation method followed by E6-specific Western blot was performed on specimens from women with HPV-16 infections. Associations between elevated expression of E6 oncoprotein and CIN 2 and 3 were determined using logistic regression and a reference category of CIN 1 and disease-negative. RESULTS: A significant trend for the detection of HPV-16 E6 oncoprotein in specimen of women with proven HPV-16 infection was determined: 0% (0/12), 12.5% (1/8), 36.4% (4/11), and 42.9% (3/7) of those with negative findings, CIN 1, 2, and 3, respectively (p = .01). Compared with the category combining negative findings and CIN 1, detection of E6 oncoprotein was associated with CIN 2 (odds ratio = 10.9, p = .05) and CIN 3 (odds ratio = 14.3, p = .04). CONCLUSIONS: There is a significant association between elevated expression of E6 oncoprotein and grade of CIN. This finding seems consistent with the role played by E6 oncoprotein in carcinogenesis.

Iminyl-radicals by electrochemical decarboxylation of α-imino-oxy acids: construction of indole-fused polycyclics.

Iminyl radicals are reactive intermediates that can be used for the construction of various valuable heterocycles. Herein, the electrochemical decarboxylation of α-imino-oxy acids for the generation of iminyl radicals has been accomplished under exogenous-oxidant- and metal-free conditions through the use of nBu4NBr as a mediator. The resulting iminyl radicals undergo intramolecular cyclization smoothly with the adjacent (hetero)arenes to afford a series of indole-fused polycyclic compounds.

Posthepatectomy jaundice induced by paroxysmal nocturnal hemoglobinuria: A case report.

BACKGROUND: Jaundice is a major manifestation of posthepatectomy liver failure, a feared complication after hepatic resection. Herein, we report a case of posthepatectomy jaundice that was not caused by liver failure but by paroxysmal nocturnal hemoglobinuria (PNH)-induced hemolysis. CASE SUMMARY: A 56-year-old woman underwent right hepatectomy and biliary tract exploration surgery due to hepatic duct stones. Prior to surgery, the patient was mildly anemic. The direct antiglobulin test was negative. A bone marrow biopsy showed mild histiocyte hyperplasia. After surgery, the patient suffered a progressive increase in serum bilirubin. Meanwhile, the patient developed hemolytic symptoms after blood transfusion. She was ultimately diagnosed with PNH. PNH is a rare bone marrow failure disorder that manifests as complement-dependent intravascular hemolysis with varying severity. After steroid treatment, the patient's jaundice gradually decreased, and the patient was discharged on the 35th postoperative day. CONCLUSION: PNH-induced hemolysis is a rare cause of posthepatectomy jaundice. It should be suspected in patients having posthepatectomy hyperbilirubinemia without other signs of liver failure. Steroid therapy can be considered for the treatment of PNH in such cases.

Independent and Joint Associations between Serum Calcium, 25-Hydroxy Vitamin D, and the Risk of Primary Liver Cancer: A Prospective Nested Case-Control Study.

BACKGROUND: Accumulating evidence has shown that serum calcium and vitamin D may be associated with or influence various cancer risks. However, no prospective studies have evaluated the independent and joint associations between prediagnostic levels of serum calcium and vitamin D and future risk of incident primary liver cancer. METHODS: We used a nested case-control design to evaluate subjects over 22 years of follow-up. Serum calcium, 25-hydroxy vitamin D [25(OH)D], and three markers of hepatitis B virus and hepatitis C virus were measured in baseline serum from 226 incident primary liver cancer cases and 1,061 matched controls. We calculated ORs and 95% confidence intervals (CI) using logistic regression to estimate the associations between calcium, 25(OH)D, and primary liver cancer risk. RESULTS: Multivariable adjusted models showed that subjects with both low (ORLow/Medium = 1.48, 95% CI = 1.01-2.17) or high (ORHigh/Medium = 1.92, 95% CI = 1.34-2.76) calcium had an increased primary liver cancer risk, while those with high 25(OH)D had a decreased risk of primary liver cancer (ORHigh/Medium = 0.54, 95% CI = 0.35-0.82). In joint analyses, when compared with subjects with medium calcium and 25(OH)D, subjects with high calcium and medium 25(OH)D had elevated odds of developing primary liver cancer (OR = 1.89, 95% CI = 1.17-3.05); those with medium calcium and high 25(OH)D had reduced odds of developing primary liver cancer (OR = 0.34, 95% CI = 0.17-0.67); and subjects in other classifications of calcium and serum 25(OH)D levels had no change in the odds of developing primary liver cancer (all P > 0.05). CONCLUSIONS: In a nutrient-deficient population, we found that serum calcium and serum 25(OH)D could potentially be modifiable risk or protective factors. IMPACT: Our findings provide potential targets for primary liver cancer prevention and control.

[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.

[Hepatocellular glycogen alleviates hepatic ischemia reperfusion injury and its relationship to ICAM-1 gene expression].

OBJECTIVE: To investigate if higher hepatocellular glycogen contents can alleviate hepatic ischemia reperfusion injury and its relationship to ICAM-1 gene expression in hepatic sinusoidal cells (HSCs). METHODS: Twenty-one rabbits fed with a standard diet were randomly divided into three groups (n=7 in each). All the animals were subjected to hepatic ischemia reperfusion injury then sacrificed. Before the injury, group A rabbits fasted for 24 hours; group C rabbits had 6 intravenous glucose solution (25%, 20 ml) injections, 4 hours between two injections. Hepatic enzymological changes, hepatic ICAM-1 mRNA expressions and leukocytic counts in the sinusoids were observed. RESULTS: The liver glycogen contents of the three groups were significantly different. Livers of group A had higher contents of glycogen (9.85+/-0.91 mg/g. wet tissue); in group B they were 38.93+/-5.72; and in group C they were 48.31+/-6.58. Group C animals had the slightest liver function damage. There were no differences in the pre- and post-ischemic ICAM-1 mRNA contents in the three groups. However, livers with a higher content of glycogen showed less expression of ICAM-1 mRNA (group A: 1.398+/-0.365 ng/mg wet tissue; group B: 0.852+/-0.297; group C: 0.366+/-0.183) and lower leukocytic counts. The relationship analysis showed a negative relationship between hepatocellular glycogen and hepatic ICAM-1 mRNA contents (r= -0.965, P less than 0.01). CONCLUSIONS: Hepatocellular glycogen is important in protecting liver ischemic reperfusion injury. Also hepatocellular glycogen decreases the expression of ICAM-1 mRNA of HSCs.

Intra-Abdominal Pressure Reduction After Percutaneous Catheter Drainage Is a Protective Factor for Severe Pancreatitis Patients With Sterile Fluid Collections.

OBJECTIVES: Severe acute pancreatitis (SAP) is a fatal disease with natural course of early SAP (ESAP) and late SAP (LSAP) phases. Peripancreatic percutaneous catheter drainage (PCD) is effective in management of LSAP. Although our previous study indicates that intra-abdominal PCD ahead of peripancreatic PCD benefits ESAP patients with sterile fluid collections, the mechanism is still uncovered. METHODS: According to therapeutic results, 452 SAP patients who underwent PCD were divided into sterile group (248 cases), secondary infection group (145 cases), and primary infection group (59 cases). RESULTS: The mortality was 4.1%, 10.9%, and 18.6%, respectively. Logistic-regression analysis indicated that multiorgan dysfunction syndrome (odds ratio [OR], 1.717; 95% confidence interval [95% CI], 1.098-2.685; P = 0.018), catheters located intra-abdominally (OR, 0.511; 95% CI, 0.296-0.884; P = 0.016), and intra-abdominal hypertension (OR, 1.534; 95% CI, 1.016-2.316; P = 0.042) were predictors for infection after PCD. Receiver operating characteristics curve delineated that decrease of intra-abdominal pressure (IAP) of more than 6.5 mm Hg after PCD had the ability to predict infection with sensitivity of 84.0% and specificity of 79.5%. CONCLUSIONS: Intra-abdominal PCD for acute sterile fluid collections seems to be an effective option rather than peripancreatic PCD. Patients with a significant decrease of IAP had a lower incidence of infection and better alleviation of organ failure.

Human Papillomavirus Genotyping to Predict the Risk of Cervical Precancerous Lesions or Cancer in Women with Minor Abnormal Cytology in China.

OBJECTIVE: To evaluate the role of human papillomavirus (HPV) genotyping in predicting the risk of cervical precancerous lesions or cancer in women with minor abnormal cytology. METHODS AND MATERIALS: This study was conducted on 329 women with atypical squamous cells of undetermined significance (ASC-US) and 77 women with low-grade squamous intraepithelial lesions (LSIL) out of a total of 4,215 participants in a multicenter, cross-sectional study. Liquid-based cytology and the Hybrid Capture 2 test (HC2) were used to screen eligible women, and a Linear Array HPV genotyping test was performed on women with positive HC2 results. RESULTS: The sensitivity and specificity for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) based on HPV 16/18 were 82% [95% confidence interval (CI): 52-95%] and 91% (95% CI: 87-94%) in women with ASC-US and 67% (95% CI: 35-88%) and 84% (95% CI: 73-91%) in women with LSIL. The women infected with HPV 16/18 had a significantly higher risk of developing CIN2+ than those infected with other high-risk HPV types in both the ASC-US (OR 9.93, 95% CI: 2.02-48.88) and LSIL (OR 7.45, 95% CI: 1.60-34.68) arms. CONCLUSIONS: Genotyping for HPV 16/18 greatly improves specificity, but at the expense of potential sensitivity in the triage of minor cytology abnormalities. The role of genotyping for HPV 16/18 in order to triage women with minor abnormal cytology should be further evaluated in future studies.

Gastric bypass surgery in non-obese patients with type 2 diabetes mellitus: a 1-year follow-up of 58 cases in Chinese.

OBJECTIVE: To investigate the clinical efficacy of gastric bypass surgery in non-obese patients with type 2 diabetes. METHODS: Clinical data of 58 non-obese patients with type 2 diabetes (body mass index range from 22.1-25.8 kg/m(2)) were collected one year after gastric bypass surgery. Collected parameters included fasting plasma glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, fasting plasma glucagon-like peptide-1 and 2-hour postprandial plasma glucagon-like peptide-1. The insulin resistance index (HOMA-IR = fasting plasma glucose × fasting serum insulin/22.5) and the body mass index were calculated. RESULTS: Of the 58 patients, 48 had stopped taking all hypoglycemic drug treatments and had achieved complete remission (82.8%). Seven patients were unable to completely withdraw from hypoglycemic agents, although their intake of drugs was reduced at least 50% compared to pre-surgical values (12.0%). Three of the cases showed no significant change in blood glucose after surgery (5.2%). In addition, values for fasting plasma glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin and HOMA-IR significantly decreased after surgery. Values for fasting plasma glucagon-like peptide-1 and 2-hour postprandial plasma glucagon-like peptide-1 significantly increased after surgery, and the body mass index at the sixth post-operative month were significantly lower than pre-operative. CONCLUSION: For non-obese patients with type 2 diabetes, gastric bypass surgery has a significant clinical effect. Potential mechanisms include improvements in insulin resistance and/or increased endogenous intestinal glucagon-like peptide-1 secretion leading to improved insulin secretion.

Down-Regulation of Renal Gluconeogenesis in Type II Diabetic Rats Following Roux-en-Y Gastric Bypass Surgery: A Potential Mechanism in Hypoglycemic Effect.

OBJECTIVE: This study was initiated to evaluate the effects of Roux-en-Y gastric bypass surgery on renal gluconeogenesis in type 2 diabetic rats and its relationship with hormonal parameters. METHODS: Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ; 35 mg/kg) combined with a high-fat diet. They were then randomly divided into three groups: diabetes model group (DM group, n = 8), sham Roux-en-Y gastric bypass group (SRYGB group, n = 8), and Roux-en-Y gastric bypass group (RYGB group, n = 14). Another 8 normal rats comprised the normal control group (NC group, n = 8). Body weight, glucose, serum lipid, insulin, glucagon-like peptide-1 (GLP-1), leptin, and adiponectin were measured pre- and postoperatively. Glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), insulin receptor-α (IR-α), insulin receptor-ß (IR-ß), and glycogen synthase kinase 3 beta (Gsk3b) were measured in renal cortex by using RT-PCR and Western immune-blot analyses on the 4th week after operation. RESULTS: Following RYGB surgery, surgery-treated rats showed significantly improved oral glucose tolerance, dyslipidemia and insulin resistance as well as increased post-gavage insulin levels and serum circulating levels of GLP-1 and adiponectin. RT-PCR and Western immune-blot analyses showed PEPCK and G6Pase protein and mRNA to be significantly decreased in the renal cortex in the RYGB group (p < 0.05 vs. DM or SRYGB group); in addition, IR-α and Gsk3b phosphorylation levels increased in the RYGB group (p < 0.05 vs. DM or SRYGB group). CONCLUSION: Down-regulation of renal gluconeogenic enzymes might be a potential mechanism in hypoglycemia. An improved insulin signal pathway in the renal cortex and increased circulating adiponectin concentrations may contribute to the decline of renal gluconeogenesis following RYGB surgery.

The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent.

The colorectal cancer is the leading contributor of cancer-related mortality. Mammalian target of rapamycin (mTOR), existing in 2 complexes (mTORC1/2), is frequently dysregulated and constitutively activated in colorectal cancers. It represents an important drug target. Here we found that INK-128, the novel ATP-competitive kinase inhibitor of mTOR, blocked both mTORC1 and mTORC2 activation in colorectal cancer cells (both primary and transformed cells). The immunoprecipitation results showed that the assembly of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-Sin1 association) was also disrupted by INK-128. INK-128 inhibited colorectal cancer cell growth and survival, and induced both apoptotic and non-apoptotic cancer cell death. Further, INK-128 showed no effect on Erk/MAPK activation, while MEK/Erk inhibition by MEK-162 enhanced INK-128-induced cytotoxicity in colorectal cancer cells. Meanwhile, INK-128 downregulated Fascin1 (FSCN1)/E-Cadherin expressions and inhibited HT-29 cell in vitro migration. In vivo, daily INK-128 oral administration inhibited HT-29 xenograft growth in mice, which was further enhanced by MEK-162 administration. Finally, we found that INK-128 sensitized 5-fluorouracil-(5-FU)-mediated anti-HT-29 activity in vivo and in vitro. Thus, our preclinical studies strongly suggest that INK-128 might be investigated for colorectal cancer treatment in clinical trials.

Comparison of HPV genotypes and viral load between different sites of genital tract: the significance for cervical cancer screening.

OBJECTIVES: To compare the consistency of HPV genotype and viral loads among different sites within the female genital tract, and to correlate these with clinical outcomes. METHODS: 2646 previously unscreened rural women were enrolled in this population-based, cross-sectional study between May 2006 and April 2007. Physician-collected samples from lower vagina, upper vagina, cervix, and one self-collected sample were taken from each woman. Viral load was assessed by HC2 using the relative light unit/cutoff ratio (RLU/CO), and HPV genotyping was tested by Linear Array. RESULTS: The low risk HPV positive rate was highest in lower vagina samples and lowest in cervix samples. Overall kappa values of high risk HPV types between various anatomic sampling sites showed substantial or almost perfect agreement among women with normal pathology, CIN1, and CIN2+. In the CIN2+ population, high risk HPV viral load for cervix samples (557.25 RLU/CO) were much higher than upper vagina samples (96.43 RLU/CO, P<0.001), lower vagina samples (36.51 RLU/CO, P<0.001), and self-collected (206.83RLU/CO, P=0.003) samples. CONCLUSIONS: Although the distribution of high risk HPV genotypes was fairly equivalent across different genital sites, particularly for CIN2+ lesions, viral loads were largely variable. The findings may affect the cervical cancer screening methods using self-collected samples, particularly in resource-challenged areas.