TMEM106B and APOE polymorphisms interact to confer risk for late-onset Alzheimer's disease in Han Chinese.

Recent large genome-wide association studies have found variants in TMEM106B (top SNP rs1990622) as a strong risk factor for frontotemporal lobar degeneration. Moreover, the TMEM106B risk variant is also implicated in the pathologic presentation of Alzheimer's disease (AD). Here, we evaluated the association between TMEM106B rs1990622 polymorphism and late-onset AD (LOAD) in a Northern Han Chinese population consists of 1,133 LOAD patients and 1,159 controls. Our data demonstrate that TMEM106B and APOE interact to increase AD risk.

Specific association of MTHFD1 expressions with small cell lung cancer development and chemoradiotherapy outcome.

OBJECTIVES: To identify biomarkers that can discriminated small cell lung cancer (SCLC) from non-SCLC (NSCLC), and explore their association with the prognosis of SCLC under chemoradiotherapy. METHODS: The GSE40275 dataset was used to identify potential targets in SCLC. There were 196 patients of lung cancer (LC) in cohort 1 of this study. MTHFD1 levels in tissues were determined by immunohistochemistry assay in cohort 1. Lung cancer patients who were all underwent local chemoradiotherapy (CRT) were included in cohort 2, and the association of MTHFD1 levels with CRT treatment outcome were determined in cohort 2. Cell experiments were used to determine the function of MTHFD1 on the radio-sensitivity of SCLC and NSCLC cells. RESULTS: The MTHFD1 levels in LC tissues were increased, and could discriminate SCLC from both lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). Small cell lung cancer patients with MTHFD1 high phenotype had a poorer prognosis after CRT treatment, whereas no significant correlation was found between MTHFD1 levels and prognosis in LUSC and LUAD group. Cell experiments demonstrated that overexpression of MTHFD1 increases radio-resistance in both SCLC and NSCLC in vitro. CONCLUSION: MTHFD1 expressions might be a novel specifically prognostic biomarker for SCLC and the CRT treatment outcome.

Identification of biomarkers associated with pathological tumor staging and their utility in the diagnosis and prognosis of prostate cancer.

OBJECTIVE: Pathological tumor (pT) staging plays a crucial role in prostate cancer (PCa) diagnosis. This study aimed to identify pT stage-associated biomarkers and explored their utility in PCa prognosis. METHODS: GSE69223 was used to identify potential targets differentially expressed between level 2 of pT staging (pT2) and level 3 of pT staging (pT3). Quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry were performed on tissues from patients with PCa to screen the pT stage-associated targets and to explore the prognostic value of these targets in PCa. RESULTS: CENPI and SLC38A11 were most significantly upregulated, whereas ANO6 and KANK2 were mostly decreased in pT3 tumors compared with pT2 staging. ANO6 levels were negatively associated with preoperative prostate-specific antigen (PSA) levels, lymph node staging (N staging), Gleason score, and overall survival (OS); CENPI was positively associated with preoperative PSA levels, N staging, and OS, but was not associated with the Gleason score; SLC38A11 and KANK2 were not associated with OS. ANO6 and KANK2 were correlated with neutrophil markers, whereas CENPI was correlated with macrophage M2 types. CONCLUSION: We identified 4 reliable PCa biomarkers associated with pT staging that would be valuable for diagnosing and determining PCa prognosis.

Gold nanoparticles enhances radiosensitivity in glioma cells by inhibiting TRAF6/NF-κB induced CCL2 expression.

Gliomas are inherently difficult to treat by radiotherapy because glioma cells become radioresistant over time. However, combining radiotherapy with a radiosensitizer could be an effective strategy to mitigate the radioresistance of glioma cells. Gold nanoparticles (AuNPs) have emerged as a promising nanomaterial for cancer therapy, but little is known about whether AuNPs and X-ray radiation have cytotoxic synergistic effects against tumors. In this study, we found that the combination of AuNPs and X-ray irradiation significantly reduced the viabilities, as well as the migration and invasion, of glioma cells. Mechanistically, we observed that the AuNPs inhibited radiation-induced CCL2 expression by inhibiting the TRAF6/NF-κB pathway, which likely manifested the synergistic therapeutic effect between the AuNPs and X-ray radiation. The AuNPs also re-sensitized radioresistant glioma cells by inhibiting CCL2 expression. These results were also observed in another tumor cell line with a different molecular pattern, indicating that the underlying mechanism may be ubiquitous through cancer cells. Lastly, using the glioma mouse model, we observed that AuNPs significantly reduced tumor growth in the presence of X-ray radiation compared to radiotherapy alone.

Association of HLA-DRB1 polymorphism with Alzheimer's disease: a replication and meta-analysis.

Genome-wide association studies (GWAS) have identified one single-nucleotide polymorphism (SNP) rs9271192 within HLA-DRB1 as a risk factor for Alzheimer's disease (AD) in Caucasians. The effect of rs9271192 on AD needed to be verified in other ethnic cohorts. In order to evaluate the association between HLA-DRB1 rs9271192 polymorphism and late-onset AD (LOAD) in the Northern Han Chinese population, we recruited 982 LOAD patients and 1344 sex- and age-matched healthy controls. The results showed that HLA-DRB1 rs9271192 was associated with LOAD (genotype P = 0.015, allele P = 0.04). The results of logistic regression revealed the C allele homozygosity strongly increased the risk of LOAD under a recessive model in the total sample (P = 0.004, OR =2.069, 95% CI = 1.262-3.434). When these data were stratified by apolipoprotein E (APOE) ε4 status, the observed association was confined to APOE ε4 non-carriers (additive model: P=0.048, OR =1.191, 95% CI =1.001-1.417; recessive model: P < 0.001, OR = 2.601, 95% CI =1.519-4.566). Furthermore, meta-analysis after sensitive analysis confirmed that rs9271192 within HLA-DRB1 increased the risk of LOAD (OR = 1.12, 95% CI = 1.08-1.15). To summarize, the C allele in HLA-DRB1 rs9271192 may be an independent risk factor for LOAD.

Interleukin-23 receptor polymorphisms are associated with Alzheimer's disease in Han Chinese.

Inhibition of interleukin-23 (IL-23) signaling was reported to reduce AD pathology, and IL-23 receptor gene (IL23R) which encodes IL-23 receptor may represent a candidate susceptibility gene for AD. Here, we conducted a case-control association study to assess the effect of IL23R genetic polymorphisms on the risk of AD in a Northern Han Chinese population. Two tag functional single polymorphisms (SNPs), rs10889677 and rs1884444 were selected, and their associations with AD risk factors were assessed in 1133 AD patients and 1156 matched controls. Our association analysis showed that C allele of rs10889677 was significantly associated with decreased AD risk even after adjusting for age, gender, and apolipoprotein E gene (APOE) ɛ4 status. The G allele of rs1884444 polymorphism is significantly associated with a higher risk of AD in APOE ɛ4 carriers. Our results demonstrate that IL23R genetic polymorphisms are associated with AD in a Northern Han Chinese population.

SIRT2 polymorphism rs10410544 is associated with Alzheimer's disease in a Han Chinese population.

Sirtuin 2 (SIRT2) is a strong protein deacetylase, which is highly expressed in central nervous system. Recently, an association between SIRT2 rs10410544 polymorphism and late-onset Alzheimer's disease (LOAD) was found in the APOEε4-negative Caucasian population. To investigate the potential association between the rs10410544 C/T polymorphism of SIRT2 and the risk of LOAD, we conducted an independent replication case-control study in a Northern Han Chinese population comprising 1133 cases and 1159 healthy controls being matched for age and gender. The results revealed that there were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P=0.008, allele P=0.009). When compared with the C allele, the T allele of rs10410544 demonstrated a 1.709-fold risk for developing LOAD. After stratification by apolipoprotein E (APOE) ε4-carrying status, only APOEε4 noncarriers (P=0.035, adjusted OR=1.656, 95% CI: 1.036-2.647) showed the relation between LOAD and SIRT2 rs10410544 T allele. This study provides the evidence that the rs10410544 C/T polymorphism of SIRT2 was associated with genetic susceptibility to LOAD in a Northern Han Chinese population.

Heat shock protein 70 in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease that caused dementia which has no effective treatment. Growing evidence has demonstrated that AD is a "protein misfolding disorder" that exhibits common features of misfolded, aggregation-prone proteins and selective cell loss in the mature nervous system. Heat shock protein 70 (HSP70) attracts extensive attention worldwide, because it plays a crucial role in preventing protein misfolding and inhibiting aggregation and represents a class of proteins potentially involved in AD pathogenesis. Numerous studies have indicated that HSP70 could suppress the progression of AD with in vitro and in vivo experiments. Thus, targeting HSP70 and the related compounds might represent a promising strategy for the treatment of AD.

Heat shock proteins at the crossroads between cancer and Alzheimer's disease.

Heat shock proteins 70 and heat shock proteins 90 (Hsp70/90) have been implicated in many crucial steps of carcinogenesis: stabilizing oncogenic proteins, inhibiting programmed cell death and replicative senescence, induction of tumor angiogenesis, and activation of the invasion and metastasis. Plenty of cancer related proteins have the ability of regulating the expression of Hsp70/90 through heat shock factor 1. Cancer and Alzheimer's disease (AD) have plenty of overlapping regions in molecular genetics and cell biology associated with Hsp70/90. The Hsp70, as a protein stabilizer, has a cellular protection against neurodegeneration of the central nervous system, while Hsp90 promote neurodegenerative disorders indirectly through regulating the expression of Hsp70 and other chaperones. All these make existing anticancer drugs target Hsp70/90 which might be used in AD therapy.

Association of DAPK1 genetic variations with Alzheimer's disease in Han Chinese.

Apoptosis and autophagy are common physiological and pathological processes in the human body. Death-associated kinase protein 1 (DAPK1), which participates in the process of cell death, has attracted people's attention for its potential risk with late-onset Alzheimer's disease (LOAD). A recent study identified two single nucleotide polymorphisms (SNPs) in DAPK1 that show significant association with LOAD in Caucasians. In order to clarify the role of these genetic variations in Chinese population, we examined the genetic variations of DAPK1/rs4877365 and DAPK1/rs4878104 in a group of 400 LOAD patients and 400 healthy controls. All samples were recruited from Northern Han Chinese population. Data collected from this study showed that there were significant differences in genotype (P=0.02) and allele (P=0.007) frequencies of DAPK1/rs4878104 but not in DAPK1/rs4877365 between LOAD patients and controls. The "C" allele of rs4878104 worked as a protective factor of LOAD (P=0.0026, odds ratio/OR=0.75) in Han Chinese. Logistic regression analysis revealed that homozygosity was strongly associated with LOAD under a recessive model (P=0.003, OR=0.23). No significant association was observed between rs4877365 and LOAD. Haplotype analysis identified the G/T haplotype as a risk factor for LOAD (P=0.007, OR=1.33, 95% CI=1.08-1.64). This study provides the evidence that variation in DAPK1 gene influences susceptibility to LOAD in the Northern Han Chinese population.

Tau-tubulin kinase-1 gene variants are associated with Alzheimer's disease in Han Chinese.

Tau-tubuline kinase 1 (TTBK1) is a recently discovered brain-specific protein kinase involved in tau phosphorylation at AD-related sites. A recent large study has identified significant association of two single nucleotide polymorphisms (SNPs) (rs2651206 and rs7764257) in the TTBK1 gene with late-onset Alzheimer's disease (LOAD) in Spanish. Here, we performed a case-control study to clarify whether the risk for LOAD might be influenced by these polymorphisms in a large Chinese cohort consisting of 400 patients and 388 healthy controls. The minor alleles of the rs2651206 polymorphism within TTBK1 was significantly associated with a reduced risk of LOAD (odds ratio/OR=0.69, P=0.011). Furthermore, rs2651206 polymorphism was still strongly associated with LOAD (OR=0.72, P=0.05) after adjusted for age, gender, and the apolipoprotein E (APOE) ɛ4 status. Haplotype analysis identified the TG haplotype, deriving from the two minor alleles, to decrease the risk of LOAD (OR=0.78, P=0.037). This study provides the evidence that variations in the TTBK1 gene may play an important role in the pathogenesis of sporadic LOAD in a Han Chinese population.

Interleukin-18 promoter polymorphisms and risk of ischemic stroke.

Ischemic stroke (IS) is a major cause of morbidity and mortality around the world. Interleukin-18 (IL-18) plays an important role in the pathogenesis of IS and IL-18 promoter polymorphisms have been shown to be associated with levels of expression of IL-18. We investigated the association of two functional polymorphisms in IL-18 promoter, -607C/A (rs1946518) and -137G/C (rs187238), with the risk of ischemic stroke in a Han Chinese population of 423 patients and 384 healthy controls matched for sex and age. The results revealed that the -607C allele was associated with an increased risk of IS with an odds ratios (OR) of 1.358 (P = 0.002, power = 100%) and the presence of the -137G allele was correlated with increased the risk of IS in the subtype of patients with large artery atherosclerosis (LAA) (OR = 1.583, P = 0.02, power = 94%). Patients with the -607C/-137G haplotype also had significantly increased risk of IS compared to controls (OR = 1.341, P = 0.005, power = 100%). Our findings suggest that these functional polymorphisms in the IL-18 promoter are involved in development of IS in the Han Chinese population.

Blocking beta2-adrenergic receptor attenuates acute stress-induced amyloid beta peptides production.

Environmental factors play an important role in the Alzheimer's disease (AD) development and stress may accelerate the progression of AD. Beta-adrenergic receptors are activated by stress and may influence different aspects of cognitive function. So, it was hypothesized that stress may accelerate the pathological progression of AD by the activation of beta(2)-adrenergic receptor (beta(2)-AR). We have investigated the role of acute stress and activation of beta(2)-AR in amyloid beta (Abeta) peptides production in a mouse model of acute restraint stress. Injections of the beta(2)-AR-selective agonist clenbuterol hydrochloride enhanced the production of acute stress-induced Abeta peptides production; the beta(2)-AR-selective antagonist ICI 118,551 reduced Abeta peptides production. It is suggested that acute stress induces abnormal activation of beta(2)-AR which subsequently enhances Abeta peptides (the main neuropathological hallmarks of AD) production possibly resulting in the onset of AD. The findings indicate that new therapeutic strategies designed to blocking beta(2)-AR might be valuable for the prevention and treatment of AD.