Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world but is common in southern China. A recent report from the Hong Kong Cancer Registry, a high-risk area for NPC in southern China, showed that incidence rate decreased by 29% for males and by 30% for females from 1980–1999, while mortality rate decreased by 43% for males and 50% for females. Changing environmental risk factors and improvements in diagnosis and treatment were speculated to be the major factors contributing to the downward trend of the incidence and mortality rates of NPC. To investigate the secular trends in different Cantonese populations with different socio-economic backgrounds and lifestyles, we report the incidences and mortality rates from two population-based cancer registries in Sihui and Cangwu counties from 1978–2002.
Incidence and mortality rates were aggregated by 5-year age groups and 5 calendar years. To adjust for the effect of difference in age composition for different periods, the total and age-specific rates of NPC incidence and mortality rate were adjusted by direct standardization according to the World Standard Population (1960). The Estimated Annual Percentage Change (EAPC) was used as an estimate of the trend.
The incidence rate of NPC has remained stable during the recent two decades in Sihui and in females in Cangwu, with a slight increase observed in males in Cangwu from 17.81 to 19.76 per 100,000. The incidence rate in Sihui is 1.4–2.0 times higher during the corresponding years than in Cangwu, even though the residents of both areas are of Cantonese ethnicity. A progressive decline in mortality rate was observed in females only in Sihui, with an average reduction of 6.3% (p = 0.016) per five-year period.
To summarize, there is great potential to work in the area of NPC prevention and treatment in southern China to decrease NPC risk and improve survival risk rates in order to reduce M:I ratios. Future efforts on effective prevention, early detection and treatment strategies were also discussed in this paper. Furthermore, the data quality and completeness also need to be improved.
PTEN (phosphatase and tensin homolog), a tumor suppressor frequently mutated in human cancer, has various cytoplasmic and nuclear functions. PTEN translocates to the nucleus from the cytoplasm in response to oxidative stress. However, the mechanism and function of the translocation are not completely understood. In this study, topotecan (TPT), a topoisomerase I inhibitor, and cisplatin (CDDP) were employed to induce DNA damage. The results indicate that TPT or CDDP activates ATM (ATM serine/threonine kinase), which phosphorylates PTEN at serine 113 and further regulates PTEN nuclear translocation in A549 and HeLa cells. After nuclear translocation, PTEN induces autophagy, in association with the activation of the p-JUN-SESN2/AMPK pathway, in response to TPT. These results identify PTEN phosphorylation by ATM as essential for PTEN nuclear translocation and the subsequent induction of autophagy in response to DNA damage.
ATM; autophagy; DNA damage; PTEN; topotecan; AKT/PKB, v-akt murine thymoma viral oncogene homolog; AMPK, protein kinase, AMP-activated; ATG, autophagy-related; ATM, ATM serine/threonine kinase; Baf.A1, bafilomycin A1; CASP3, caspase 3, apoptosis-related cysteine peptidase; CCND1, cyclin D1; CDDP, cisplatin; CENPC/CENP-C, centromere protein C; CITED1/p300/CBP, Cbp/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 1; CSNK2/CK2, casein kinase 2; DSBs, DNA double-strand breaks; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; GLTSCR2/PICT-1, glioma tumor suppressor candidate region gene 2; GSK3B, glycogen synthase kinase 3 β; GST, glutathione S-transferase; H2AFX; H2A histone family; member X; JUN; jun proto-oncogene; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MTORC1, mechanistic target of rapamycin complex 1; MVP, major vault protein; NC, normal control; NEDD4, neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase; PAGE, polyacrylamide gel electrophoresis; PARP, poly (ADP-ribose) polymerase 1; PI3K, phosphoinositide 3-kinase; PMSF, phenylmethanesulfonyl fluoride; PPase, protein phosphatase; PtdIns(3, 4, 5)P3, phosphatidylinositol (3, 4, 5)-trisphosphate; PTEN, phosphatase and tensin homolog; RAD51, RAD51 recombinase; RPS6KB/p70S6K; ribosomal protein S6 kinase, 70kDa; SDS, sodium dodecyl sulfate; SESN2, sestrin 2; siRNA, small interfering RNA; SQSTM1/p62, sequestosome 1; TP53, tumor protein p53; TPT, topotecan; TUBA4A, tubulin, α, 4a; WT, wild type; YFP, yellow fluorescent protein
Enterovirus 71 (EV71) is the most common causative pathogens of hand, foot and mouth disease (HFMD) associated with severe neurological complications. There is a great need to develop prophylactic vaccine against EV71 infection.
EV71 virus-like particle (VLP) was produced in yeast expression system by the co-expression of four EV71 structural proteins VP1–VP4. Immunization with the recombinant VLPs elicited potent anti-EV71 antibody responses in adult mice and anti-VLP sera were able to neutralize EV71 virus in vitro. Neonatal mice model demonstrated VLP immunization conferred protection to suckling mice against the lethal viral challenge.
Co-expression of four EV71 structural proteins VP1–VP4 in yeast expression systems is an effective method to produce EV71 VLPs. VLP-based vaccine shows great potential to prevent EV71 infection.
Enterovirus 71; Vaccine; Yeast; Virus-like particle; Hand foot and mouth disease
Epidemiological studies show that cigarette smoking increase the risk of nasopharyngeal carcinoma (NPC), however, whether other common, potentially adverse household inhalants increase NPC risk remains uncertain.
We conducted a large case-control study to explore the effects of household inhalants, such as incense, mosquito coil, cooking fumes, and wood combustion, on NPC risk. We recruited 1,845 cases and 2,275 controls from Guangdong province, a high-risk area for NPC in China, to obtain the demographic data and relevant exposure information through face-to-face interviews.
We found that incense burning was associated with NPC risk by comparing frequent incense use with never using incense [OR and 95 % confidence interval (CI) = 1.73, (1.43, 2.09)]. Wood fuel use was also associated with NPC risk compared with non-wood fire use [OR and 95 % CI = 1.95, (1.65, 2.31)]. More intriguingly, we observed a significant addictive interaction between frequent incense burning and heavy cigarette smoking on NPC risk [synergistic index (SI) = 1.67; 95 % CI: 1.01, 2.76]. We also found a significant joint effect between wood fuel use and NPC family history for NPC risk (SI = 1.77; 95 % CI: 1.06, 2.96). However, neither mosquito oil nor cooking fumes were associated with NPC risk.
Our study shows that incense smoke is not only the potential independent risk factor but also co-contributes with cigarette smoking to NPC risk. Moreover, wood combustion is another potential environmental risk factor and exerts a joint effect with NPC family history on NPC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-2035-x) contains supplementary material, which is available to authorized users.
Incense burning; Mosquito coil; Cooking fumes; Wood fuel using; NPC risk
Objective: To conduct a systematic evaluation of the efficacy of lansoprazole and omeprazole for the treatment of Helicobacter pylori-associated duodenal ulcer. Methods: Online databases, including CHKD, VIP, China Info, the National Digital Library of China, Google Scholar, PubMed, Lippincott Williams & Wilkins, and Wiley Online Library were searched for related studies. The quality of the studies was evaluated in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, and relevant information was extracted from them. The studies were subjected to meta-analysis using RevMan5.3 software, and qualitative analysis was performed for studies, in which the data could not be merged. Results: A total of nine randomized controlled trials (RCTs) were included, all of which presented the possibility of bias. Meta-analysis showed no significant differences between patients treated with lansoprazole combinations and omeprazole combinations in terms of DU healing rate (RR = 1.04, 95% CI = 0.99~1.09, P = 0.93). There were significant differences between those treated by lansoprazole combination and omeprazole combination in terms of HP eradication rate (RR = 1.09, 95% CI = 1.01~1.18, P = 0.04), and there was no serious adverse reaction during the treatment process for both lansoprazole and omeprazole. Conclusion: Lansoprazole and omeprazole exhibit similar efficacy in the treatment of Helicobacter pylori associated duodenal ulcers.
Lansoprazole; omeprazole; duodenal ulcer; HP infection; meta-analysis
Perception of microbe-associated molecular patterns (MAMPs) elicits host transcriptional reprogramming as part of the immune response. Although pathogen perception is well studied, the signaling networks orchestrating immune gene expression remain less clear. In a genetic screen for components involved in the early immune gene transcription reprogramming, we identified Arabidopsis RNA polymerase II C-terminal domain (CTD) phosphatase-like 3 (CPL3) as a negative regulator of immune gene expression. MAMP perception induced rapid and transient cyclin-dependent kinase (CDKC)-mediated phosphorylation of Arabidopsis CTD. The CDKCs, which are in-turn phosphorylated and activated by a canonical MAP kinase (MAPK) cascade, represent a point of signaling convergence downstream of multiple immune receptors. CPL3 directly dephosphorylated CTD to counteract MAPK-mediated CDKC regulation. Thus, modulation of the phosphorylation dynamics of eukaryotic RNA polymerase II transcription machinery by MAPKs, CTD kinases and phosphatases constitutes an essential mechanism for rapid orchestration of host immune gene expression and defense upon pathogen attacks.
To evaluate the association between vitamin D status and cognitive impairment (CI) in elderly aged 60 years and above
Cross-sectional cohort study
Chinese Longitudinal Healthy Longevity Survey, a community-based cohort study in longevity areas in China
Individuals with mean age of 84.9 (± 12.7) (n=2004)
Participants’ cognitive state was evaluated using the Mini-Mental State Examination (MMSE). Vitamin D in plasma was measured using enzyme-linked immunoassay.
The cross-sectional association between quartiles of plasma vitamin D level and CI (MMSE score <18) was modeled using logistic regressions. Plasma vitamin D levels were lower in individuals with CI compared to those without (31.9 (±15.3) versus 45.6 (±19.6)nmol/L). There was a reverse association between plasma vitamin D and CI. After adjusting for age, gender, chronic conditions, smoking and drinking habits, outdoor activities, depression, and Activities of Daily Living limitations, the association remained significant. The multivariable adjusted odds ratio for lowest versus highest vitamin D levels was 2.15 (1.05–4.41) for CI, and the multivariable odds ratio associated with 1-SD decrement of plasma vitamin D was 1.32 (1.00–1.74) for CI.
In our sample population, low plasma vitamin D levels were associated with increased odds of CI. Further prospective studies in Asian populations are needed to examine the causal direction of this association.
Vitamin D; cognition; elderly; oldest old; China
The expansion of myeloid-derived suppressor cells (MDSCs) and its correlation with advanced disease stage have been shown in solid cancers. Here, we investigated the functional features and clinical significance of MDSCs in extranodal NK/T cell lymphoma (ENKL). A higher percentage of circulating HLA-DR−CD33+CD11b+ MDSCs was observed in ENKL patients than in healthy controls (P < 0.05, n = 32) by flow cytometry analysis. These MDSCs from ENKL patients (ENKL-MDSCs) consisted of CD14+ monocytic (Mo-MDSCs, >60 %) and CD15+ granulocytic (PMN-MDSCs, <20 %) MDSCs. Furthermore, these ENKL-MDSCs expressed higher levels of Arg-1, iNOS and IL-17 compared to the levels of MDSCs from healthy donors, and they expressed moderate levels of TGFβ and IL-10 but lower levels of CD66b. The ENKL-MDSCs strongly suppressed the anti-CD3-induced allogeneic and autologous CD4 T cell proliferation (P < 0.05), but they only slightly suppressed CD8 T cell proliferation (P > 0.05). Interestingly, ENKL-MDSCs inhibited the secretion of IFNγ but promoted IL-10, IL-17 and TGFβ secretion as well as Foxp3 expression in T cells. The administration of inhibitors of iNOS, Arg-1 and ROS significantly reversed the suppression of anti-CD3-induced T cell proliferation by MDSCs (P < 0.05). Importantly, based on multivariate Cox regression analysis, the HLA-DR−CD33+CD11b+ cells and CD14+ Mo-MDSCs were independent predictors for disease-free survival (DFS, P = 0.013 and 0.016) and overall survival (OS, P = 0.017 and 0.027). Overall, our results identified for the first time that ENKL-MDSCs (mainly Mo-MDSCs) have a prognostic value for patients and a suppressive function on T cell proliferation.
Electronic supplementary material
The online version of this article (doi:10.1007/s00262-015-1765-6) contains supplementary material, which is available to authorized users.
Prognosis; Immunosuppression; Hematopoietic malignancy; MDSCs; NK/T cell lymphoma
Mitochondrial diabetes is a kind of rare diabetes caused by monogenic mutation in mitochondia. The study aimed to summarize the clinical phenotype profiles in mitochondrial diabetes withm.3243A>G mitochondrial DNA mutation and to investigate the mechanism in this kind of diabetes by analyzing the relationship among clinical phenotypes and peripheral leukocyte DNA telomere length.
Fifteen patients with maternally inherited diabetes in five families were confirmed as carrying the m.3243A>G mitochondrial DNA mutation. One hundred patients with type 2 diabetes and one hundred healthy control subjects were recruited to participate in the study. Sanger sequencing was used to detect the m.3243A>G mitochondrial DNA mutation. The peak height G/A ratio in the sequence diagram was calculated. Real-time polymerase chain reaction (PCR) was used to measure telomere length.
The patients with mitochondrial diabetes all had definite maternally inherited history, normal BMI (19.5 ± 2.36 kg/m2), early onset of diabetes (35.0 ± 14.6 years) and deafness. The peak height G/A ratio correlated significantly and negatively with the age at onset of diabetes (≦25 years, 61.6 ± 20.17 %; 25–45 years, 16.59 ± 8.64 %; >45 years, 6.37 ± 0.59 %; p = 0.000). Telomere length was significantly shorter among patients with mitochondrial diabetes and type 2 diabetes than in the control group (1.28 ± 0.54 vs. 1.14 ± 0.43 vs. 1.63 ± 0.61; p = 0.000). However, there was no significant difference between patients with mitochondrial diabetes and those with type 2 diabetes. There was no correlation between telomere length and the peak height G/A ratio.
Deafness with definite maternal inheritance and normal BMI, associated with elevated blood lactic acid and encephalomyopathy, for the most part, suggest the diagnosis of mitochondrial diabetes . The peak height G/A ratio could reflect the spectrum of age at onset of the disease. Telomere length was shorter in patients with mitochondrial diabetes and those with type 2 diabetes, which suggests that the shorter telomere length is likely involved in the pathogenesis of diabetes but is not specific for this kind of diabetes.
Mitochondrial diabetes; m.3243A>G mitochondrial DNA mutation; Clinical features; Leukocyte telomere length
Understanding the mechanism by which cell growth, migration, polyploidy, and tumourigenesis are regulated may provide important therapeutic strategies for cancer therapy. Here we identify the Skp2-macroH2A1 (mH2A1)-CDK8 axis as a critical pathway for these processes, and deregulation of this pathway is associated with human breast cancer progression and patient survival outcome. We showed that mH2A1 is a new substrate of Skp2 SCF complex whose degradation by Skp2 promotes CDK8 gene and protein expression. Strikingly, breast tumour suppression upon Skp2 deficiency can be rescued by mH2A1 knockdown or CDK8 restoration using mouse tumour models. We further show that CDK8 regulates p27 protein expression by facilitating Skp2-mediated p27 ubiquitination and degradation. Our study establishes a critical role of Skp2-mH2A1-CDK8 axis in breast cancer development and targeting this pathway offers a promising strategy for breast cancer therapy.
Nasopharyngeal carcinoma (NPC) is a malignancy with high metastatic potential and loco-regional recurrence. The overall survival of NPC has been limited from further improvement partly due to the lack of effective biomarker for accurate prognosis prediction and precise treatments. Here, in light of the implication of CELF gene family in cancer prognosis, we selected 112 tagging single nucleotide polymorphisms (SNPs) located in six members of the family and tested their associations with the clinical outcomes in a discovery cohort of 717 NPC patients. Survival analyses under multivariate cox proportional hazards model and Kaplan–Meier curve revealed five promising SNPs, which were further validated in another independent sample of 1,520 cases. Combined analysis revealed that SNP rs3740194 in CELF2 was significantly associated with the decreased risk of death with a Hazard ratio (HR) of 0.69 (95% confidence interval [CI] = 0.58–0.82, codominant model). Moreover, rs3740194 also showed a significant association with superior metastasis-free survival (HR = 0.69, 95% CI = 0.57–0.83, codominant model). Taken together, our findings suggested that genetic variant of rs3740194 in CELF2 gene might be a valuable predictor for NPC prognosis, and potentially useful in the personalized treatment of NPC.
nasopharyngeal carcinoma; SNP; CELF2; prognosis
Familial adenomatous polyposis (FAP) is an autosomal dominant disease manifesting as colorectal cancer in middle-aged patients. Mutations of the adenomatous polyposis coli (APC) gene contribute to both FAP and sporadic or familial colorectal carcinogenesis. Here we describe the identification of the causative APC gene defects associated with FAP in a Chinese pedigree. All patients with FAP were diagnosed by their combination of clinical features, family history, colonoscopy, and pathology examinations. Blood samples were collected and genomic DNA was extracted. Mutation analysis of APC was conducted by targeted next-generation sequencing, long-range PCR and Sanger sequencing. A novel mutation in exon 14–15(c.1936-2148 del) and intron 14 of the APC gene was demonstrated in all FAP patients and was absent in unaffected family members. This novel deletion causing FAP in Chinese kindred expands the germline mutation spectrum of the APC gene in the Chinese population.
APC gene; familial adenomatous polyposis; exon deletion; targeted next-generation sequencing; chinese population
The interface effect is one of the most important factors that strongly affect the structural transformations and the properties of nano-/submicro-crystals under pressure. However, characterization of the granular boundary changes in materials is always challenging. Here, using tetrakaidecahedral Zn2SnO4 microcrystals as an example, we employed alternating current impedance, X-ray diffraction methods and transmission electron microscopy to elucidate the effect of the interface on the structure and electrical transport behavior of the Zn2SnO4 material under pressure. We clearly show that grain refinement of the initial microcrystals into nanocrystals (approximately 5 nm) occurs at above 12.5 GPa and is characterized by an anomalous resistance variation without a structural phase transition. A new phase transition pathway from the cubic to hexagonal structure occurs at approximately 29.8 GPa in Zn2SnO4. The unexpected grain refinement may explain the new structural transition in Zn2SnO4, which is different from the previous theoretical prediction. Our results provide new insights into the link between the structural transition, interface changes and electrical transport properties of Zn2SnO4.
To describe the distribution of plasma high sensitivity C-reactive protein (hsCRP) and explore the relationship between hsCRP and metabolic risk factors among residents living in longevity areas of China.
268 individuals aged between 40 and 59 years and 506 individuals aged over 90 years were selected from 5 longevity areas of China to participate in a cross section longitudinal cohort study. The participants were interviewed with general health related questionnaire to collect their demographic, behavioral and lifestyle data, as well as their chronic conditions, and meanwhile their physical and biomedical parameters including waist circumference (WC), blood pressure (BP), hsCRP, plasma lipids, and fasting blood glucose (FBG) were measured.
The median of hsCRP was 0.99 mg/L in the middle-aged group and 1.76 mg/L in the oldest old group. No significant gender difference was observed between the above two groups. Among the oldest old individuals, 36.56% had an hsCRP level >3.0 mg/L. The prevalence of high hsCRP was 16.79% in the middle-aged group. The results of stepwise multiple linear regression analyses showed that HDL-C was independently associated with ln (hsCRP) concentration in the middle-aged group, whereas ln (TG), HDL-C and FBG were correlated after adjustment for gender, study site, smoking, drinking, education and BMI in the oldest old group.
HDL-C is a stronger predictor of elevated hsCRP than other metabolic factors in the middle-aged population. For the oldest old persons, high TG, low HDL-C, and FBG predict elevated plasma hsCRP.
High-sensitivity C-reactive protein; Blood lipids; Fasting blood glucose; Middle-aged; Oldest old individuals; Longevity; China
NOP14, which is functionally conserved among eukaryotes, has been implicated in cancer development. Here, we show that NOP14 is poorly expressed in breast cancer cells and invasive breast cancer tissues. In vivo and in vitro studies indicated that NOP14 suppressed the tumorigenesis and metastasis of breast cancer cells. Further investigations revealed that NOP14 enhanced ERα expression and inhibited the Wnt/β-catenin pathway by up-regulating NRIP1 expression. Survival analysis indicated that low NOP14 expression was significantly associated with poor overall survival (P = 0.0006) and disease-free survival (P = 0.0007), suggesting that NOP14 is a potential prognostic factor in breast cancer. Taken together, our findings reveal that NOP14 may suppress breast cancer progression and provide new insights into the development of targeted therapeutic agents for breast cancer.
NOP14; breast cancer; NRIP1; Wnt/β-catenin pathway
To investigate the origin and evolutionary history of the spread of HIV-1 subtype B in China, a total of 409 sequences of pol gene sampled from 1994 to 2012 in 29 provinces across China was subjected to phylogenetic and Bayesian molecular clock analyses. The study reveals that subtype B strains in China are genetically diverse and can be classified into four distinct subgroups, namely B′ (Thai-B), BJ-B (Beijing-B), Pan-B (Pandemic-B), and TW-B (Taiwan-B), according to the origin of the sequences. The BJ-B and TW-B are reported for the first time. Phylogeographic analysis reveals that B′ exhibits a nationwide, transprovincial distribution, and is found in 21 provinces in China in this study, whereas the Pan-B, BJ-B, and TW-B lineages are restricted to particular regions. From the same common ancestor of B′, there arise two subclusters in which sequences from Yunnan occupy the basal position. The times of the most recent common ancestors (tMRCAs) of B′ and BJ-B are estimated to be 1983.6 (1975.9–1990.3) and 1995.3 (1989.6–2000.3), respectively. The skyline plot profile reveals an exponential decrease in median number of effective infections of subtype B in China from 1994 to 2009. The existence of four types of B clades also indicates distinct transmission networks of subtype B, originating from different introduction events at different time points. The data presented here offer a new perspective on the epidemic of HIV-1 subtype B in China.
Carbon nanoparticles have a strong affinity for the lymphatic system. The purpose of this study was to evaluate the feasibility of sentinel lymph node biopsy using carbon nanoparticles in early breast cancer and to optimize the application procedure.
Firstly, we performed a pilot study to demonstrate the optimized condition using carbon nanoparticles for sentinel lymph nodes (SLNs) detection by investigating 36 clinically node negative breast cancer patients. In subsequent prospective study, 83 patients with clinically node negative breast cancer were included to evaluate SLNs using carbon nanoparticles. Another 83 SLNs were detected by using blue dye. SLNs detection parameters were compared between the methods. All patients irrespective of the SLNs status underwent axillary lymph node dissection for verification of axillary node status after the SLN biopsy.
In pilot study, a 1 ml carbon nanoparticles suspension used 10–15min before surgery was associated with the best detection rate. In subsequent prospective study, with carbon nanoparticles, the identification rate, accuracy, false negative rate was 100%, 96.4%, 11.1%, respectively. The identification rate and accuracy were 88% and 95.5% with 15.8% of false negative rate using blue dye technique. The use of carbon nanoparticles suspension showed significantly superior results in identification rate (p = 0.001) and reduced false-negative results compared with blue dye technique.
Our study demonstrated feasibility and accuracy of using carbon nanoparticles for SLNs mapping in breast cancer patients. Carbon nanoparticles are useful in SLNs detection in institutions without access to radioisotope.
Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China and Southeast Asia, with the highest metastasis rate among head and neck cancers. The mechanisms underlying NPC progression remain poorly understood. Genome-wide expression profiling on 18 NPC vs. 18 noncancerous nasopharyngeal tissues together with GeneGo pathway analysis and expression verification in NPC cells and tissues revealed a potential role of urokinase-type plasminogen activator receptor (uPAR) in NPC progression, which has not been investigated in NPC. We then observed that uPAR expression is increased in poorly differentiated, highly metastatic NPC cells compared with lowly metastatic cells or differentiated NPC cells. In vitro studies demonstrated that uPAR regulates NPC cell growth, colony formation, migration, and invasion and promotes the epithelial–mesenchymal transition (EMT). Additional tumor xenograft and spontaneous metastasis experiments revealed that uPAR promotes NPC cell growth and metastasis in vivo. The JAK–STAT pathway is involved in uPAR-regulated signaling in NPC cells as determined by immunoblotting. Moreover, uPAR-mediated growth and motility is partially abolished upon treatment with the Jak1/Jak2 inhibitor INCB018424. We suppressed uPA expression in uPAR-overexpressing NPC cells and found that uPAR-mediated cellular growth and motility is not exclusively dependent on uPA. In summary, uPAR is a significant regulator of NPC progression and could serve as a promising therapeutic target.
uPAR; nasopharyngeal carcinoma; JAK; STAT; genome-wide expression profiling; tumor growth; metastasis
IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10−10), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10−9) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10−9), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10−19), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10−19; rs12716641, P=9.53 × 10−9; rs9314614, P=4.25 × 10−9, multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.
IgA nephropathy is a major cause of end-stage renal disease in China, occurring at a high frequency in Asian populations. Here Li and colleagues conduct a four-stage genome-wide association study in a Chinese population, identifying novel loci and variants associated with disease risk.
Low-density lipoprotein cholesterol (LDL-C) is a risk factor for survival in middle-aged individuals, but conflicting evidence exists on the relationship between LDL-C and all-cause mortality among the elderly. The goal of this study was to assess the relationship between LDL-C and all-cause mortality among Chinese oldest old (aged 80 and older) in a prospective cohort study.
LDL-C concentration was measured at baseline and all-cause mortality was calculated over a 3-year period. Multiple statistical models were used to adjust for demographic and biological covariates.
During three years of follow-up, 447 of 935 participants died, and the overall all-cause mortality was 49.8%. Each 1 mmol/L increase of LDL-C concentration corresponded to a 19% decrease in 3-year all-cause mortality (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.71–0.92). The crude HR for abnormally higher LDL-C concentration (≥3.37 mmol/L) was 0.65 (0.41–1.03); and the adjusted HR was statistically significant around 0.60 (0.37–0.95) when adjusted for different sets of confounding factors. Results of sensitivity analysis also showed a significant association between higher LDL-C and lower mortality risk.
Among the Chinese oldest old, higher LDL-C level was associated with lower risk of all-cause mortality. Our findings suggested the necessity of re-evaluating the optimal level of LDL-C among the oldest old.
LDL-C; mortality; oldest old; epidemiology; China
p21-activated kinase 2 (Pak2), a serine/threonine kinase, has been previously shown to be essential for hematopoietic stem cell (HSC) engraftment. However, Pak2 modulation of long-term hematopoiesis and lineage commitment remain unreported. Utilizing a conditional Pak2 knock out (KO) mouse model, we found that disruption of Pak2 in HSCs induced profound leukopenia and a mild macrocytic anemia. Although loss of Pak2 in HSCs leads to less efficient short- and long-term competitive hematopoiesis than wild type (WT) cells, it does not affect HSC self-renewal per se. Pak2 disruption decreased the survival and proliferation of multi-cytokine stimulated immature progenitors. Loss of Pak2 skewed lineage differentiation toward granulocytopoiesis and monocytopoiesis in mice as evidenced by 1) a three to six-fold increase in the percentage of peripheral blood granulocytes and a significant increase in the percentage of granulocyte-monocyte progenitors (GMPs) in mice transplanted with Pak2-disrupted BM; 2) Pak2-disrupted BM and c-kit+ cells yielded higher numbers of more mature subsets of granulocyte-monocyte colonies and polymophonuclear neutrophils (PMNs), respectively, when cultured in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF). Pak2 disruption resulted respectively in decreased and increased gene expression of transcription factors JunB and c-Myc, which may suggest underlying mechanisms by which Pak2 regulates granulocyte-monocyte lineage commitment. Furthermore, Pak2 disruption led to 1) higher percentage of CD4+CD8+ double positive T cells and lower percentages of CD4+CD8− or CD4−CD8+ single positive T cells in thymus and 2) decreased numbers of mature B cells and increased numbers of Pre-Pro B cells in BM, suggesting defects in lymphopoiesis.
Pak2; hematopoietic progenitor cell; myelopoiesis; lymphopoiesis
Nasopharyngeal carcinoma (NPC) has the highest metastasis rate among head and neck cancers with unclear mechanism. WNT5A belongs to the WNT family of cysteine-rich secreted glycoproteins. Our previous high-throughput gene expression profiling revealed that WNT5A was up-regulated in highly metastatic cells. In the present study, we first confirmed the elevated expression of WNT5A in metastatic NPC tissues at both the mRNA and protein levels. We then found that WNT5A promoted epithelial-mesenchymal transition (EMT) in NPC cells, induced the accumulation of CD24-CD44+ cells and side population, which are believed to be cancer stem cell characteristics. Moreover, WNT5A promoted the migration and invasion of NPC cells in vitro, while in vivo treatment with recombinant WNT5A promoted lung metastasis. Knocking down WNT5A diminished NPC tumorigenesis in vivo. When elevated expression of WNT5A coincided with the elevated expression of vimentin in the primary NPC, the patients had a poorer prognosis. Among major signaling pathways, protein kinase C (PKC) signaling was activated by WNT5A in NPC cells. A positive feedback loop between WNT5A and phospho-PKC to promote EMT was also revealed. Taken together, these data suggest that WNT5A is an important molecule in promoting stem cell characteristics in NPC, leading to tumorigenesis and metastasis.
nasopharyngeal carcinoma; WNT5A; metastasis; tumorigenesis; PKC
It has previously been observed that a loss of β-catenin expression occurs with melanoma progression and that nuclear β-catenin levels are inversely proportional to cellular proliferation, suggesting that activation of the Wnt/β-catenin pathway may provide benefit for melanoma patients. In order to further probe this concept we tested LY2090314, a potent and selective small-molecule inhibitor with activity against GSK3α and GSK3β isoforms. In a panel of melanoma cell lines, nM concentrations of LY2090314 stimulated TCF/LEF TOPFlash reporter activity, stabilized β-catenin and elevated the expression of Axin2, a Wnt responsive gene and marker of pathway activation. Cytotoxicity assays revealed that melanoma cell lines are very sensitive to LY2090314 in vitro (IC50 ~10nM after 72hr of treatment) in contrast to other solid tumor cell lines (IC50 >10uM) as evidenced by caspase activation and PARP cleavage. Cell lines harboring mutant B-RAF or N-RAS were equally sensitive to LY2090314 as were those with acquired resistance to the BRAF inhibitor Vemurafenib. shRNA studies demonstrated that β-catenin stabilization is required for apoptosis following treatment with the GSK3 inhibitor since the sensitivity of melanoma cell lines to LY290314 could be overcome by β-catenin knockdown. We further demonstrate that in vivo, LY2090314 elevates Axin2 gene expression after a single dose and produces tumor growth delay in A375 melanoma xenografts with repeat dosing. The activity of LY2090314 in preclinical models suggests that the role of Wnt activators for the treatment of melanoma should be further explored.
To understand the role of environmental and genetic influences on nasopharyngeal carcinoma (NPC) in populations at high risk of NPC, we have performed a case-control study in Guangxi Province of Southern China in 2004-2005. NPC cases (n=1049) were compared to 785 NPC-free matched controls who were seropositive for IgA antibodies (IgA) to Epstein-Barr virus (EBV) capsid antigen (VCA)—a predictive marker for NPC in Chinese populations. A questionnaire was used to capture exposure and NPC family history data. Risk factors associated with NPC in a multivariant analysis model were the following: 1) a first, second or third degree relative with NPC [Attributable risk (AR)= 6%, Odds ratio (OR) = 3.1, 95%CI = 2.0-4.9, p < 0.001]; 2) consumption of salted fish 3 or more than 3 times per month (AR=3%, OR = 1.9, 95%CI = 1.1-3.5, p = 0.035); 3) exposure to domestic wood cooking fires for more than 10 years (AR=69%, OR = 5.8, 95%CI = 2.5-13.6, p < 0.001); and 4) exposure to occupational solvents for 10 or less years (AR=4%, OR = 2.6, 95%CI = 1.4-4.8, p = 0.002). Consumption of preserved meats or a history of tobacco smoking were not associated with NPC (P>0.05). We also assessed the contribution of EBV/IgA/VCA antibody serostatus to NPC risk—32.2% of NPC can be explained by IgA+ status. However, family history and environmental risk factors cumulatively explained only 2.7% of NPC development in NPC high risk population. These findings should have important public health implications for NPC risk reduction in endemic regions.
Nasopharyngeal Carcinoma; Risk factor; Epidemiology; Southern China; Epstein Barr Virus