A cross-sectional evaluation of opt-in testing for sexually transmitted and blood-borne infections in three Canadian provincial correctional facilities: a missed opportunity for public health?

PURPOSE: Incarceration provides an opportunity for screening and treatment of sexually transmitted and blood-borne infections (STBBIs) in high-risk groups. The purpose of this paper is to determine positivity rates of STBBI screening within correctional facilities using opt-in strategies and estimate the proportion of admissions tested. DESIGN/METHODOLOGY/APPROACH: A cross-sectional, retrospective review of testing data from January 2012 to August 2015 from three provincial correctional facilities located in Alberta, Canada was completed. Analysis variables included STBBI, gender, facility, collection year and age. STBBI-stratified analysis was performed to identify correlates for positivity using univariate and logistic regressions. FINDINGS: Overall prevalence of chlamydia was 11.2 percent and gonorrhea was 3.5 percent; correlates for both were younger age and facility type. The syphilis prevalence rate was 3.2 percent; correlates included being female, older age, adult facilities, with later years being protective. In total, 14 (0.3 percent) newly diagnosed HIV cases were found, prevalence increased with age. HBV prevalence was 1.7 percent with no significant correlations. Nearly one-tenth (n=422) of those screened for HCV antibody were positive; all variables were significantly correlated. Overall estimates of the proportion of admissions tested by STBBI were low and ranged from 4.8 to 16.1 percent. ORIGINALITY/VALUE: This study found high rates of STBBI in correctional facilities and showed that only a small proportion of the population was tested using an opt-in strategy. Shifting to an "opt-out" strategy may be warranted.

Secretion-mediated STAT3 activation promotes self-renewal of glioma stem-like cells during hypoxia.

High-grade gliomas (HGGs) include the most common and the most aggressive primary brain tumor of adults and children. Despite multimodality treatment, most high-grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven, at least partly, by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1α (HIF-1α) transcription factor and the JAK1/2-STAT3 (Janus Kinase 1/2 - Signal Transducer and Activator of Transcription 3) axis to enhance the self-renewal of glioma stem-like cells. Hypoxia is a commonly found pathologic feature of HGGs. Under hypoxic conditions, HIF-1α levels are greatly increased in glioma stem-like cells. Increased HIF-1α activates the JAK1/2-STAT3 axis and enhances tumor stem-like cell self-renewal. Our data further demonstrate the importance of Vascular Endothelial Growth Factor (VEGF) secretion for this pathway of hypoxia-mediated self-renewal. Brefeldin A and EHT-1864, agents that significantly inhibit VEGF secretion, decreased stem cell self-renewal, inhibited tumor growth, and increased the survival of mice allografted with S100ß-v-erbB/p53-/- glioma stem-like cells. These agents also inhibit the expression of a hypoxia gene expression signature that is associated with decreased survival of HGG patients. These findings suggest that targeting the secretion of extracellular, autocrine/paracrine mediators of glioma stem-like cell self-renewal could potentially contribute to the treatment of HGGs.

FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction.

This corrects the article DOI: 10.1038/onc.2014.184.

Inverse Association Between Serum Osteoprotegerin and Bone Mineral Density in Renal Transplant Recipients.

BACKGROUND: Osteoprotegerin (OPG) has pleiotropic effects on bone metabolism as well as endocrine function. Our aim was to evaluate the relationship between bone mineral density (BMD) and serum OPG concentration in renal transplant recipients. METHODS: Fasting blood samples were obtained from 69 renal transplant recipients. BMD was measured in lumbar vertebrae (L2-L4) by dual-energy X-ray absorptiometry. Eight patients (11.6%) had BMD values indicative of osteoporosis, 28 patients (40.6%) had BMD values indicative of osteopenia, and 33 patients had normal BMD values. Increased serum OPG levels (P < .001), decreased body mass index (BMI) (P = .033), and decreased body weight (P = .010) were significantly correlated with low lumbar T-score cut-off points between groups (normal, osteopenia, and osteoporosis). RESULTS: Women had significantly lower lumbar BMD values than men (P = .013). Menopause (P = .005), use of tacrolimus (P = .020), and use of cyclosporine (P = .046) were associated with lower lumbar BMD in renal transplant recipients. Univariate linear regression analysis revealed that lumbar BMD was positively correlated with height (P = .016), body weight (P = .001), and BMI (P = .015) and negatively correlated with age (P = .039) and log-OPG (P = .001). Multivariate linear regression analysis revealed that log-OPG (ß: -0.275, R(2) change = 0.154, P = .014), body weight (ß: 0.334, R(2) change = 0.073, P = .004), and age (ß: -0.285, R(2) change = 0.079, P = .008) were independent predictors of lumbar BMD values in renal transplant recipients. CONCLUSIONS: Serum OPG concentration correlated negatively with lumbar BMD values in renal transplant recipients.

Prospective evaluation of skin and nipple-areola sensation and patient satisfaction after nipple-sparing mastectomy.

BACKGROUND: Sensation and quality of life (QOL) before and after nipple sparing mastectomy (NSM) are poorly understood. METHODS: Women electing mastectomy with immediate reconstruction and eligible for NSM were prospectively enrolled in a sensation and satisfaction/QOL study. Women self-selected skin-sparing mastectomy (SSM) or NSM. Skin sensation testing using Semmes Weinstein monofilaments and patient satisfaction/QOL surveys were administered preoperatively and at 1 year postoperatively. RESULTS: 53 patients were enrolled (n = 38, 72% NSM and n = 15, 28% SSM). Both groups had significant reduction in postoperative skin sensation. For NSM, measurable NAC sensation was preserved in both NAC for 26% of patients and in one NAC for 68%. QOL and satisfaction was similar between groups. Neither group was satisfied with sexual arousal with breast or nipple stimulation after surgery. CONCLUSION: Patients undergoing SSM and NSM have considerable loss in skin and NAC sensation following surgery. Satisfaction and QOL did not differ between groups. J. Surg. Oncol. 2016;114:11-16. © 2016 Wiley Periodicals, Inc.

FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction.

Correction to: Oncogene (2015) 34, 2505­2515; doi:10.1038/onc. 2014.184; published online 7 July 2014. Since the publication of the above paper, the authors found a misplacing band in Figure 2e. The correct version of the figure is given below. The correction does not affect the validity of the data presented and does not limit the conclusions drawn in the paper. The authors apologize for this mistake.

Providing instrumental social support is more beneficial to reduce mortality risk among the elderly with low educational level in Taiwan: a 12-year follow-up national longitudinal study.

BACKGROUND: To evaluate whether the effects of providing or receiving social support are more beneficial to reduce mortality risk among the elderly with different educational levels. METHODS: In this long-term prospective cohort study, data were retrieved from the Taiwan Longitudinal Study on Aging. This study was initiated from 1996 until 2007. The complete data from 1492 males and 1177 females aged ≥67 years were retrieved. Participants received financial, instrumental, and emotional support, and they actively provided instrumental and emotional support to others and involved in social engagement. Education attainment was divided into two levels: high and low. The low education level included illiterate and elementary school. The high education level included junior high school to senior high school and above college. Cox regression analysis was used to examine the association between providing or receiving social support on mortality with different educational levels. RESULTS: The average age of the participants in 1996 was 73.0 (IQR=8.0) years, and the median survival following years (1996-2007) of participants was 10.3 (IQR=6.7) years. Most participants were low educational level including illiterate (39.3%) and elementary school (41.2%). Participants with high educational level tend to be younger and more male significantly. On the contrary, participants with low educational level tend to have significant more poor income, more depression, more cognition impairment, more with IADL and ADL disability than high educational level. Most participants received instrumental support from others (95.5%) and also provided emotional support to others (97.7%). Providing instrumental support can reduce 17% of mortality risk among the elderly with a low level of education after adjusting several covariates [Hazard ratio (HR) = 0.83; 95% confidence interval (CI) = 0.70-0.99; p = 0.036]. CONCLUSIONS: Providing instrumental social support to others confer benefits to the giver and prolong life expectancy among the elderly with low educational levels.

c-Myc suppresses microRNA-29b to promote tumor aggressiveness and poor outcomes in non-small cell lung cancer by targeting FHIT.

The dual role of the microRNA-29 (miR-29) family in tumor progression and metastasis in solid tumors has been reported. Evidence for the role of miR-29 in tumor malignancy and its prognostic value in overall survival (OS) and relapse-free survival (RFS) in non-small cell lung cancer (NSCLC) remains conflicting. Mechanistic studies presented herein demonstrated that c-Myc suppressed the expression of miR-29b, promoting soft agar growth and invasion capability in lung cancer cells. Interestingly, the decrease in the expression of miR-29b by c-Myc is responsible for soft agar growth and invasiveness mediated by FHIT loss due to promoter methylation. Among patients, low expression of miR-29b and FHIT was more common in tumors with high c-Myc expression than in tumors with low c-Myc expression. Kaplan-Meier and Cox regression analysis showed that tumors with high c-Myc, low miR-29b and low FHIT expression had shorter OS and RFS periods than their counterparts. In conclusion, the decrease in the expression of miR-29b by c-Myc may be responsible for FHIT loss-mediated tumor aggressiveness and for poor outcome in NSCLC. Therefore, we suggest that restoration of the miR-29b expression using the c-Myc inhibitor might be helpful in suppressing tumor aggressiveness mediated by FHIT loss and consequently improving outcomes in NSCLC patients with tumors with low expression of FHIT.

FHIT loss confers cisplatin resistance in lung cancer via the AKT/NF-κB/Slug-mediated PUMA reduction.

Fragile histidine triad (FHIT) loss by the two-hit mechanism of loss of heterozygosity and promoter hypermethylation commonly occurrs in non-small cell lung cancer (NSCLC) and may confer cisplatin resistance in NSCLC cells. However, the underlying mechanisms of FHIT loss in cisplatin resistance and the response to cisplatin-based chemotherapy in NSCLC patients have not yet been reported. In the present study, inhibition concentration of 50% cell viability induced by cisplatin (IC50) and soft agar growth and invasion capability were increased and decreased in FHIT-knockdown and -overexpressing cells, respectively. Mechanistically, Slug transcription is upregulated by AKT/NF-κB activation due to FHIT loss and, in turn, Slug suppresses PUMA expression; this decrease of PUMA by FHIT loss is responsible for cisplatin resistance. In addition, cisplatin resistance due to FHIT loss can be conquered by AKT inhibitor-perifosine in xenograft tumors. Among NSCLC patients, low FHIT, high p-AKT, high Slug and low PUMA were correlated with shorter overall survival, relapse-free survival and poorer response to cisplatin-based chemotherapy. Therefore, the AKT inhibitor perifosine might potentially overcome the resistance to cisplatin-based chemotherapy in NSCLC patients with low-FHIT tumors, and consequently improve the outcome.

Glycopeptide capture for cell surface proteomics.

Cell surface proteins, including extracellular matrix proteins, participate in all major cellular processes and functions, such as growth, differentiation, and proliferation. A comprehensive characterization of these proteins provides rich information for biomarker discovery, cell-type identification, and drug-target selection, as well as helping to advance our understanding of cellular biology and physiology. Surface proteins, however, pose significant analytical challenges, because of their inherently low abundance, high hydrophobicity, and heavy post-translational modifications. Taking advantage of the prevalent glycosylation on surface proteins, we introduce here a high-throughput glycopeptide-capture approach that integrates the advantages of several existing N-glycoproteomics means. Our method can enrich the glycopeptides derived from surface proteins and remove their glycans for facile proteomics using LC-MS. The resolved N-glycoproteome comprises the information of protein identity and quantity as well as their sites of glycosylation. This method has been applied to a series of studies in areas including cancer, stem cells, and drug toxicity. The limitation of the method lies in the low abundance of surface membrane proteins, such that a relatively large quantity of samples is required for this analysis compared to studies centered on cytosolic proteins.

Phosphorylation of paxillin confers cisplatin resistance in non-small cell lung cancer via activating ERK-mediated Bcl-2 expression.

Paxillin (PXN) is required for receptor tyrosine kinase-mediated ERK activation, and the activation of the Raf/MEK/ERK cascade has been linked with Bcl-2 expression. We hypothesized that phosphorylation of PXN by the EGFR/Src pathway might contribute to cisplatin resistance via increased Bcl-2 expression. We show that cisplatin resistance was dependent on PXN expression, as evidenced by PXN overexpression in TL-13 and TL-10 cells and PXN knockdown in H23 and CL1-5 cells. Specific inhibitors of signaling pathways indicated that the phosphorylation of PXN at Y118 and Y31 via the Src pathway was responsible for cisplatin resistance. We further demonstrated that ERK activation was also dependent on this PXN phosphorylation. Bcl-2 transcription was upregulated by phosphorylated PXN-mediated ERK activation via increased binding of phosphorylated CREB to the Bcl-2 promoter. A subsequent increase in Bcl-2 levels by a PXN/ERK axis was responsible for the resistance to cisplatin. Animal models further confirmed the findings of in vitro cells indicating that xenograft tumors induced by TL-13-overexpressing cells were successfully suppressed by cisplatin combined with Src or ERK inhibitor compared with treatment of cisplatin, Src inhibitor or ERK inhibitor alone. A positive correlation of phosphorylated PXN with phosphorylated ERK and Bcl-2 was observed in lung tumors from NSCLC patients. Patients with tumors positive for PXN, phosphorylated PXN, phosphorylated ERK and Bcl-2 more commonly showed a poorer response to cisplatin-based chemotherapy than did patients with negative tumors. Collectively, PXN phosphorylation might contribute to cisplatin resistance via activating ERK-mediated Bcl-2 transcription. Therefore, we suggest that Src or ERK inhibitor might be helpful to improve the sensitivity for cisplatin-based chemotherapy in NSCLC patients with PXN-positive tumors.

DDX3 loss by p53 inactivation promotes tumor malignancy via the MDM2/Slug/E-cadherin pathway and poor patient outcome in non-small-cell lung cancer.

P53 inactivation by p53 mutation and E6 oncoprotein has a crucial role in human carcinogenesis. DDX3 has been shown to be a target of p53. In this study, we hypothesized that DDX3 loss by p53 inactivation may promote tumor malignancy and poor patients' outcome. Mechanically, DDX3 loss by p53 knockdown and E6 overexpression was observed in A549 lung cancer cells. Conversely, DDX3 expression was markedly elevated by wild-type (WT) p53 ectopic expression in p53-null H1299 cells, E6-knockdown TL-1 lung cancer and SiHa cervical cancer cells. Interestingly, DDX3 loss promotes soft-agar growth and invasive capability; however, both capabilities were suppressed by DDX3 overexpression. We next expected that DDX3 loss might result in Slug-suppressed E-cadherin expression via decreased MDM2-mediated Slug degradation. As expected, MDM2 transcription is suppressed by DDX3 loss via decreased SP1 binding activity to the MDM2 promoter. Consequently, Slug expression was elevated by the reduction of MDM2 because of DDX3 loss, and E-cadherin expression was suppressed by Slug. Consistent observations in the correlation of DDX3 loss with MDM2, Slug and E-cadherin were seen in lung tumors from lung cancer patients. In addition, patients with low-DDX3 tumors had poorer survival and relapse than patients with high-DDX3 tumors. In conclusion, we suggest that DDX3 loss by p53 inactivation via MDM2/Slug/E-cadherin pathway promotes tumor malignancy and poor patient outcome.

Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia.

Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1, CEBPA, IDH2, RUNX1, WT1, ASXL1, DNMT3A and FLT3, that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (P<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.

Urinary tuberculosis is associated with the development of urothelial carcinoma but not renal cell carcinoma: a nationwide cohort study in Taiwan.

BACKGROUND: Obstructive uropathy and chronic urinary tract infection increase the risk of urinary tract cancer. Urinary tuberculosis (UTB) can cause chronic urinary tract inflammation, lead to obstructive uropathy, and potentially contribute to the development of urinary tract cancer. However, the association between UTB and urinary tract cancer has not been studied. METHODS: This study enrolled 135 142 tuberculosis (TB) cases (male, 69%) from a nationwide health insurance research database in Taiwan and investigated the risk factors for urinary tract cancer, with emphasis on a history of UTB. The incidence of urinary tract cancer in the general population without TB was also calculated for comparison. RESULTS: The TB patients had a mean age of 57.5 ± 19.5 years. Of the 1287 UTB and 133 855 non-UTB patients, 15 (1.2%) and 396 (0.3%) developed urothelial carcinoma, respectively (P<0.001); and 2 (0.2%) and 96 (0.1%) developed renal cell carcinoma, respectively (P=0.240). Cox regression analysis revealed that age, male sex, end-stage renal disease, obstructive uropathy, arsenic intoxication, organ transplantation, and UTB (hazard ratio: 3.38 (2.01-5.69)) were independent risk factors for urothelial carcinoma. The hazard ratio of UTB was higher among female patients (5.26 (2.12-13.06)) than that among male patients (2.96 (1.57-5.60)). CONCLUSION: Urinary tuberculosis had a strong association with urothelial carcinoma, but not with renal cell carcinoma. In TB endemic areas, the urinary tract of TB patients should be scrutinised. It is also imperative that these patients be followed-up carefully in the post-treatment period, and urinalysis, ultrasonography or endoscopy should be an integral part of the follow-up.

Prediction of nodal metastasis in head and neck cancer using a 3T MRI ADC map.

BACKGROUND AND PURPOSE: The detection of cervical nodal metastases is important for the prognosis and treatment of head and neck tumors. The purpose of this study was to assess the ability of ADC values at 3T to distinguish malignant from benign lymph nodes. MATERIALS AND METHODS: From July 2009 to June 2010, twenty-two patients (21 men and 1 woman; mean age, 49.8±9.5 years; age range, 28-66 years) scheduled for surgical treatment of biopsy-proved head and neck cancer were prospectively and consecutively enrolled in this study. All patients were scanned on a 3T imaging unit (Verio) by using a 12-channel head coil combined with a 4-channel neck coil. Histologic findings were the reference standard for the diagnosis of lymph node metastasis. RESULTS: The ADC values derived from the signal intensity averaged across images obtained with b-values of 0 and 800 s/mm2 were 1.086±0.222×10(-3) mm2/s for benign lymph nodes and 0.705±0.118×10(-3) mm2/s for malignant lymph nodes (P<.0001). When an ADC value of 0.851×10(-3) mm2/s was used as a threshold value for differentiating benign from malignant lymph nodes, the best results were obtained with an accuracy of 91.0%, sensitivity of 91.3%, and specificity of 91.1%. CONCLUSIONS: The ADC value is a sensitive and specific parameter that can help to differentiate malignant from benign lymph nodes.

Adolescent mothers and older mothers: who is at higher risk for adverse birth outcomes?

OBJECTIVES: To document the patterns of first-order fertility rates associated with extreme maternal ages in Taiwan; determine if there is a gap in adverse birth outcomes (specifically low birth weight and prematurity) between adolescent mothers and older mothers; and determine which factors are important in explaining the differences in adverse birth outcomes between adolescent mothers and older mothers. STUDY DESIGN: Government statistics and survey data [Taiwan Birth Cohort Survey (TBCS)]. METHODS: Descriptive statistics and logistic regression. RESULTS: Between 1989 and 2009, the first-order fertility rate for mothers aged 15-19 years decreased, whereas that for mothers aged 35-49 years increased. Analysis of TBCS data revealed that, in comparison with older mothers, adolescent mothers are not necessarily at higher risk for adverse birth outcomes. Birth complications, pregnancy-related risks, adequate number of prenatal care visits and weight gain are more important than socio-economic status and prevalence of smoking in determining birth outcomes among first-time mothers of extreme reproductive ages. Adolescent mothers are less likely to have birth complications and pregnancy-related risks, but are more likely to have an inadequate number of prenatal care visits and to gain an inadequate amount of weight compared with older mothers. CONCLUSIONS: The risks associated with adolescent mothers are easier to manage than the risks associated with older mothers. Their birth outcomes can be improved through good policy. Taiwan's health policy should target specific risks to reduce the number of adverse birth outcomes among adolescent mothers rather than try to prevent all childbearing during adolescence.

Deposition of beryllium-7 in Hsinchu, Taiwan.

In the present study, factors that influence the distribution and variation of (7)Be in Hsinchu, Taiwan were elucidated. The (7)Be activity including the deposition flux and air concentration was continuously monitored and recorded throughout a 15-year period (1996-2010). To explain the observed variability in the (7)Be activity over time, air concentration and deposition flux of (7)Be were correlated to rainfall and solar activity. The monthly average deposition flux and air concentration of (7)Be were inversely related to solar activity with the 11-year cycle and were not strongly correlated to rainfall. The highest seasonal deposition flux of (7)Be occurred in March, which is commonly referred to as the spring maximum, due to air-mass mixing processes in the troposphere. The air concentration of (7)Be was seasonally variable and was significantly affected by monsoons. The lowest deposition flux and air concentration of (7)Be were observed in July and August due to the occurrence of southwest monsoons from low latitudes, which carry air masses with low concentrations of (7)Be. The deposition flux was enhanced by precipitation, which increased the deposition velocity, transferring more (7)Be from the troposphere to the ground. The fraction of dry to total deposition varied seasonally and was equal to 9.86%, on average.

Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia.

BACKGROUND: Aberrant activation of Wnt signalling through hypermethylation of Wnt inhibitor genes is involved in several human malignancies, including acute myeloid leukaemia (AML). It remains unclear whether hypermethylation of Wnt inhibitors is associated with molecular gene mutations in the development of AML. METHODS: We investigated the association of the promoter hypermethylation of six Wnt inhibitors (Wif-1, SFRP1, SFRR2, SFRP4, SFRP5, and DKK1) with gene aberrations in the leukaemogenesis of 269 AML patients. RESULTS: In total, 166 patients (61.7%) had hypermethylation of at least one Wnt inhibitor. The majority (68.5%) of patients with Wnt inhibitor hypermethylation had concurrent Class II gene mutations that affect transcription factors or cofactors. There was a close association of Wif-1 hypermethylation with t(15;17) (P=0.0005) and CEBPA mutation (P<0.0001), DKK1 hypermethylation with t(8;21) (P<0.0001) and ASXL1 mutation (P=0.0078), SFRP-1 hypermethylation with t(8;21) (P<0.0001), SFRP-2 hypermethylation with AML1/RUNX1 mutation (P=0.0012), and SFRP-5 hypermethylation with MLL/PTD (P=0.0505). On the other side, hypermethylation of Wnt inhibitors was always negatively associated with NPM1 mutation and FLT3/ITD. CONCLUSION: There was distinct association between hypermethylation of individual Wnt inhibitors and specific gene aberrations, especially Class II mutations. The Wnt inhibitor hypermethylation might interact with genetic alterations in the leukaemogenesis.