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Background: The dysregulation of lipid metabolism plays an important role in the pathogenesis of Alzheimer’s disease (AD). Liver-type fatty acid-binding protein (L-FABP, also known as FABP1) is critical for fatty acid transport and may be involved in AD. Objective: To investigate whether the FABP1 level is altered in patients with AD, and its associations with levels of amyloid-β (Aβ) and tau in the plasma and cerebrospinal fluid (CSF). Methods: A cross-sectional study was conducted in a Chinese cohort consisting of 39 cognitively normal controls and 47 patients with AD. The levels of FABP1 in plasma, and Aβ and tau in CSF, were measured by enzyme-linked immunosorbent assay (ELISA). A single-molecule array (SIMOA) was used to detect plasma Aβ levels. Results: The level of plasma FABP1 was significantly elevated in the AD group (p = 0.0109). Further analysis showed a positive correlation of FABP1 with CSF total tau (t-tau) and phosphorylated tau (p-tau) levels. Besides, plasma FABP1/Aβ42 (AUC = 0.6794, p = 0.0071) and FABP1/t-tau (AUC = 0.7168, p = 0.0011) showed fair diagnostic efficacy for AD. When combined with other common AD biomarkers including plasma Aβ42, Aβ40, and t-tau, both FABP1/Aβ42 and FABP1/t-tau showed better diagnostic efficacy than using these biomarkers alone. Among all AUC analyses, the combination of plasma FABP1/t-tau and Aβ42 had the highest diagnostic value (AUC = 0.8075, p

Background: The G protein-coupled receptor P2RY2 protein of the purinergic receptor family is involved in the pathogenesis of Alzheimer’s disease (AD). Naturally occurring antibodies against P2RY2 (NAbs-P2RY2) are present in human plasma, with their clinical relevance in AD unknown. Objective: To explore the alteration of NAbs-P2RY2 in AD patients and its associations with biomarkers and cognition of AD patients. Methods: The levels of naturally occurring antibodies against the four extracellular domains of P2RY2 (NAbs-P2RY2-1, NAbs-P2RY2-2, NAbs-P2RY2-3, and NAbs-P2RY2-4) were measured in the plasma of 55 AD patients, 28 non-AD dementia patients, and 70 cognitively normal participants. The correlations of autoantibody levels with cognitive scale scores, AD plasma biomarkers, and brain amyloid burden were examined. Results: NAbs-P2RY2-1, NAbs-P2RY2-3, and NAbs-P2RY2-4 were reduced in AD patients. Plasma levels of NAbs-P2RY2-2 and NAbs-P2RY2-3 levels were positively associated with cognitive and functional performances. Among these antibodies, plasma NAbs-P2RY2-2 levels were positively associated with plasma amyloid-β 42 levels. While plasma NAbs-P2RY2-3 levels were negatively associated with brain amyloid burden in AD patients. Conclusion: These findings indicate an alteration of humoral immunity against P2RY2 in AD patients. Further mechanistical investigations are needed to reveal the role of NAbs-P2RY2 in the pathogenesis of AD.

Angiostatin, an endogenous angiogenesis inhibitor generated by the proteolytic cleavage of plasminogen, was recently reported to contribute to the development of Alzheimer’s disease (AD). However, whether there are pathological changes in angiostatin levels in individuals with AD dementia is unclear, and whether plasma angiostatin has a relationship with major AD pathological processes and cognitive impairment remains unknown. To examine plasma angiostatin levels in patients with AD dementia and investigate the associations of angiostatin with blood and cerebrospinal fluid (CSF) AD biomarkers, we conducted a cross-sectional study including 35 cognitively normal control (CN) subjects and 59 PiB-PET-positive AD dementia patients. We found that plasma angiostatin levels were decreased in AD dementia patients compared to CN subjects. Plasma angiostatin levels were negatively correlated with plasma Aβ42 and Aβ40 levels in AD dementia patients and positively correlated with CSF total tau (t-tau) levels and t-tau/Aβ42 in AD dementia patients with APOE-ε4. In addition, plasma angiostatin levels had the potential to distinguish AD from CN. These findings suggest a link between angiostatin and AD pathogenesis and imply that angiostatin might be a potential diagnostic biomarker for AD.

Background:. Recent studies suggest that a healthy diet helps to prevent the development of Alzheimer disease (AD). This study aimed to investigate whether spicy food consumption is associated with cognition and cerebrospinal fluid (CSF) biomarkers of AD in the Chinese population. Methods:. We enrolled 55 AD patients and 55 age- and gender-matched cognitively normal (CN) subjects in a case-control study, as well as a cohort of 131 participants without subjective cognitive decline (non-AD) in a cross-sectional study. Spicy food consumption was assessed using the Food Frequency Questionnaire (FFQ). Associations of FFQ scores with cognition and CSF biomarkers of AD were analyzed. Results:. In the case-control study, spicy food consumption was lower in AD patients than that in CNs (4.0 [4.0–8.0] vs. 8.0 [4.5–10.0], P

Overactivation of N-methyl-D-aspartate receptor (NMDAR) in the spinal cord dorsal horn (SDH) in the setting of injury represents a key mechanism of neuropathic pain. However, directly blocking NMDAR or its downstream signaling, interaction between postsynaptic density-95 (PSD-95) and neuronal nitric oxide synthase (nNOS), causes analgesic tolerance, mainly due to GABAergic disinhibition. The aim of this study is to explore the possibility of preventing analgesic tolerance through co-targeting NMDAR downstream signaling and γ-aminobutyric acid type A receptors (GABAARs). Methods: Mechanical/thermal hyperalgesia were quantified to assess analgesic effects. Miniature postsynaptic currents were tested by patch-clamp recording to evaluate synaptic transmission in the SDH. GABA-evoked currents were tested on HEK293 cells expressing different subtypes of recombinant GABAARs to assess the selectivity of (+)-borneol and ZL006-05. The expression of α2 and α3 subunits of GABAARs and BDNF, and nNOS-PSD-95 complex levels were analyzed by western blotting and coimmunoprecipitation respectively. Open field test, rotarod test and Morris water maze task were conducted to evaluate the side-effect of ZL006-05. Results: (+)-Borneol selectively potentiated α2- and α3-containing GABAARs and prevented the disinhibition of laminae I excitatory neurons in the SDH and analgesic tolerance caused by chronic use of ZL006, a nNOS-PSD-95 blocker. A dual-target compound ZL006-05 produced by linking ZL006 and (+)-borneol through an ester bond blocked nNOS-PSD-95 interaction and potentiated α2-containing GABAAR selectively. Chronic use of ZL006-05 did not produce analgesic tolerance and unwanted side effects. Conclusion: By targeting nNOS-PSD-95 interaction and α2-containing GABAAR simultaneously, chronic use of ZL006-05 can avoid analgesic tolerance and unwanted side effects. Therefore, we offer a novel candidate drug without analgesic tolerance for treating neuropathic pain.

Deficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22–89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson’s disease patients (PD), and 15 age- and sex-matched CN subjects were recruited. The Aβ uptake by blood monocytes was measured and its alteration during ageing and in AD patients were investigated. Aβ1-42 uptake by monocytes decreased during ageing and further decreased in AD but not in PD patients. Aβ1-42 uptake by monocytes was associated with Aβ1-42 levels in the blood. Among the Aβ uptake-related receptors and enzymes, the expression of Toll-like receptor 2 (TLR2) was reduced in monocytes from AD patients. Our findings suggest that monocytes regulate the blood levels of Aβ and might be involved in the development of AD. The recovery of the Aβ uptake function by blood monocytes represents a potential therapeutic strategy for AD.

Numerous long noncoding RNAs (lncRNAs) are abnormally expressed in breast cancer (BC), but the underlying mechanisms remain large unknown. Here, we aimed to investigate the functions and mechanisms of lncRNA cancer susceptibility candidate 9 (CASC9) in BC. Western blotting and quantitative real-time PCR (qRT-PCR) were performed to assess gene and protein expression, respectively. The proliferative and metastatic abilities of BC cells were tested by cell counting kit-8 and transwell assays, respectively. The formation of lymphatic vessels was detected by tube formation assay. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter assays were performed to verify molecular interactions. CASC9 was found to be highly expressed in BC tissues and cell lines, and ectopic overexpression was positively associated with tumor volume, TNM stage, and lymph node metastasis. In addition, CASC9 silencing significantly inhibited the proliferation and invasion of BC cells, as well as BC-associated invasion and formation of lymphatic vessels of human dermal lymphatic endothelial cells. Mechanical studies demonstrated that CASC9 could be transcriptionally activated by STAT3 and elevate SOX4 expression by enhancing the acetylation of its promoter region. Our results illustrated that STAT3-activated CASC9 served as a tumor-promoting gene involved in promoting BC invasion and BC-associated formation of lymphatic vessels by upregulating SOX4 through altering H3K27ac level. This finding elucidated a new underlying network of CASC9 in the metastasis of BC.

CD22 has been suggested to contribute to Alzheimer’s disease (AD) pathogenesis by inhibiting microglial amyloid β (Aβ) phagocytosis. Soluble CD22 (sCD22) generated by cleavage from cell membranes may be a marker of inflammation and microglial dysfunction; but alterations of sCD22 levels in AD and their correlation with AD biomarkers remain unclear. Plasma sCD22 levels were measured in cognitively normal non-AD participants and patients with preclinical AD and AD dementia from a Chinese cohort and the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. Plasma sCD22 levels were elevated in patients with preclinical and dementia AD. Plasma sCD22 levels were negatively correlated with cerebrospinal fluid (CSF) Aβ42 levels and Aβ42/Aβ40, and positively correlated with CSF phosphorylated tau levels and brain Aβ burden, but negatively correlated with cognitive function. Moreover, higher plasma sCD22 levels were associated with faster cognitive decline during follow-up. These findings suggest that CD22 plays important roles in AD development, and that sCD22 is a potential biomarker for AD.

Background and purpose The chemokine monocyte chemoattractant protein-1 (MCP-1) is involved in the pathogenesis of Alzheimer's disease (AD). This study aimed to investigate whether urinary MCP-1 can distinguish patients with AD, patients with amnestic mild cognitive impairment (aMCI) and cognitively normal (CN) subjects. Methods A total of 754 participants, including 97 patients with AD, 50 patients with aMCI and 84 age- and sex-matched CN controls as well as a cohort of 523 CN subjects of different ages, were enrolled from five hospitals located in different areas of China. Urinary MCP-1 levels were determined using enzyme-linked immunosorbent assays. The correlations between urinary MCP-1 levels and cognition test scores or age were analysed. The optimal diagnostic sensitivity and specificity were determined using receiver operating characteristic curve analysis. Results In the cohort of CN subjects of different ages, urinary MCP-1 levels increased with ageing and were correlated with age. The urinary MCP-1 levels were higher in females than in males. In the cohort composed of patients with AD, aMCI and age- and sex-matched CN controls, urinary MCP-1 levels were significantly higher in patients with AD and aMCI than in CN controls. There were no differences in urine MCP-1 levels between the AD group and the aMCI group. The urinary MCP-1 levels were correlated with the Mini-Mental State Examination scores and age, and were able to differentiate patients with AD and aMCI from CN subjects. Conclusions Urinary MCP-1 is a potential biomarker for the diagnosis of AD and aMCI.

Cerebrospinal fluid (CSF) biomarkers are essential for the accurate diagnosis of Alzheimer’s disease (AD), yet their measurement levels vary widely across centers and regions, leaving no uniform cutoff values to date. Diagnostic cutoff values of CSF biomarkers for AD are lacking for the Chinese population. As a member of the Alzheimer’s Association Quality Control program for CSF biomarkers, we aimed to establish diagnostic models based on CSF biomarkers and risk factors for AD in a Chinese cohort. A total of 64 AD dementia patients and 105 age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study cohort were included. CSF Aβ42, P-tau181, and T-tau levels were measured by ELISA. Combined biomarker models and integrative models with demographic characteristics were established by logistic regression. The cutoff values to distinguish AD from CN were 933 pg/mL for Aβ42, 48.7 pg/mL for P-tau181 and 313 pg/mL for T-tau. The AN model, including Aβ42 and T-tau, had a higher diagnostic accuracy of 89.9%. Integrating age and APOE ε4 status to AN model (the ANA’E model) increased the diagnostic accuracy to 90.5% and improved the model performance. This study established cutoff values of CSF biomarkers and optimal combined models for AD diagnosis in a Chinese cohort.

Objective. To explore associations of serum neurofilament light chain (sNfL) at admission with clinical deficits and the long-term prognosis of acute ischaemic stroke (AIS). Methods. We recruited 110 AIS patients with serum sampled at hospital arrival. The concentrations of sNfL were detected by a Simoa HD-1 analyser. We first investigated the determinants of sNfL levels at admission within the study population. Associations of sNfL levels with National Institutes of Health Stroke Scale (NIHSS) scores and modified Rankin Scale (mRS) scores were then tested. We further divided the patients into revascularized and nonrevascularized groups, and the associations of sNfL levels with NIHSS and mRS scores were assessed in these subgroups. Results. Age, sex, stroke history, and the time between the onset of illness and arrival at the hospital were independent influencing factors of sNfL levels within the study population. The sNfL levels at admission were correlated with the NIHSS scores 7 days after stroke ( p = 0.004 ) across all subjects but showed no correlation with the NIHSS scores at admission ( p = 0.293 ) or the mRS scores 6 months after stroke ( p = 0.065 ). Further analysis revealed that in the nonrevascularized group of AIS patients, the sNfL levels at admission were positively correlated with NIHSS scores (NIHSS at admission, p = 0.005 ; NIHSS 7 days after stroke, p = 0.003 ) and negatively correlated with mRS scores ( p = 0.011 ). Conclusion. sNfL levels at admission could be a potential biomarker for predicting clinical deficits and prognosis in the natural course of AIS.

The neurotrophin receptor p75 (p75NTR) plays important roles in regulating amyloid-beta (Aβ) metabolism in the brain. The expression of p75NTR is altered in the brain of patients with Alzheimer's disease (AD). In this study, we aimed to evaluate whether p75NTR mRNA level in the peripheral blood cells is changed among AD patients and its potential to be a biomarker for AD. The study subjects included 26 patients with AD (PiB-PET positive) and 28 cognitively normal controls (PiB-PET negative). RNA was extracted from peripheral blood cells of fast blood. p75NTR mRNA was measured using quantitative real-time PCR assay. p75NTR mRNA levels in blood cells were comparable between AD patients and controls. p75NTR mRNA levels in blood cells were not correlated with MMSE scores, ApoE genotypes, gender, and age. p75NTR mRNA expression in blood cells is not changed in AD patients and is unlikely to be a biomarker for AD Refereed/Peer-reviewed

Objective Obstructive sleep apnea syndrome (OSAS) is characterized by nocturnal intermittent hypoxemia and can increase the risk of Parkinson's disease. This study aimed to investigate the association between plasma α‐synuclein levels and hypoxia in the patients with OSAS. Methods We recruited 42 OSAS patients and 46 controls with simple snoring matched for age and gender. OSAS was diagnosed on the basis of the clinical symptoms as well as the nighttime polysomnography. Plasma total α‐synuclein and phosphorylated α‐synuclein levels were measured by ELISA kits. Results The OSAS patients had significant higher levels of plasma total α‐synuclein and phosphorylated α‐synuclein levels. Both of the above indexes were positively correlated with the apnea–hypopnea index and the oxygen desaturation index, while they were negatively correlated with the mean and lowest oxyhemoglobin saturations. Interpretation This study suggests that chronic intermittent hypoxia can increase the α‐synuclein levels, which may contribute to the pathogenesis of Parkinson's disease.

Bones are the most common metastatic sites for prostate cancer (PCa). Receptor tyrosine kinase-like orphan receptor 2 (ROR2), a noncanonical Wnt receptor, plays crucial roles in skeletal morphogenesis, osteoblast differentiation, and bone formation. The role of ROR2 in PCa metastasis is unclear. We analyzed online datasets from Oncomine as well as using IHC staining on tissue array to determine the relationship between ROR2 expression level and disease outcome of PCa. To investigate how ROR2 regulates migration and invasion of PCa cells, we performed transwell assay and orthotopic xenograft model in nude mice. We then applied the Micro-Western Array (MWA), a high-throughput western blotting platform to analyze the downstream signaling pathways being regulated by ROR2. Compared with nonmalignant PZ-HPV-7 and RWPE-1 cells, PCa cell lines express lower level of ROR2 protein. Constitutive expression of ROR2 in PC-3, DU-145, or C4-2B PCa cells significantly suppressed the cell migration, invasion, and epithelial–mesenchymal transition (EMT) proteins. MWA, western blotting, and microRNA analysis showed that elevation of ROR2 suppressed the expression of miR-199a-5p, which in turn increased the expression of PIAS3. The upregulation of PIAS3 then decreased AKT2 and the phosphorylation of AKT, resulting in the inhibition of migration and invasion of PCa cells both in vitro and in orthotopic xenograft mice model. IHC staining of tissue array and Oncomine datasets analysis indicated that the gene and protein level of ROR2 is much lower in metastatic prostate tumors as compared with primary tumors or adjacent normal prostate tissues. Low level of ROR2 correlated to poor survival and high recurrent frequency in PCa patients. In conclusion, we discovered that ROR2 suppresses PCa metastasis via regulation of PIAS3–PI3K–AKT2 signaling axis.

To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer’s disease (sAD) and pathological biomarkers in cerebrospinal fluid (CSF), 462 sAD patients and 463 age-matched cognitively normal (CN) controls were genotyped for 35 single-nucleotide polymorphisms (SNPs) that are significantly associated with sAD. Then, the alleles found to be associated with sAD were used to build polygenic risk score (PRS) models to represent the genetic risk. Receiver operating characteristic (ROC) analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset. We measured the CSF levels of Aβ42, Aβ42/Aβ40, total tau (T-tau), and phosphorylated tau (P-tau) in a subgroup (60 sAD and 200 CN participants), and analyzed their relationships with the PRSs. We found that 14 SNPs, including SNPs in the APOE, BIN1, CD33, EPHA1, SORL1, and TOMM40 genes, were associated with sAD risk in our cohort. The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls, and were able to predict the incidence rate of sAD and age at onset. Furthermore, the PRSs were correlated with the CSF levels of Aβ42, Aβ42/Aβ40, T-tau, and P-tau. Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD. As genetic risk profiles vary among populations, large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-020-00469-8) contains supplementary material, which is available to authorized users.

To evaluate the regulation of VEGF-Notch signaling pathway on proliferation and apoptosis of mesenchymal stem cells (MSC) in the patients with aplastic anemia (AA).The bone marrow specimens of AA patients were collected for isolation and identification of BM MSC. Westen blot was used to detect the expression of VEGF-Notch signaling pathway-related proteins (VEGF, VEGFR, Notch 1, Jagged 1, Delta-like 1 and Hes1). The VEGF (100 ng/ml) and DAPT (γ-secretase inhibitor, 10 μmol/L) were respectively added into MSC culture system in oder to activate and inhibit the signaling transduction of VEGF-Notch in BM MSC. The proliferation, apoptosis and cell cycle of MSC in AA patients were detected by CCK8 assay and flow cyfometry. The adipogenic differentiation of BM MSC was detected by oil red O staining.The VEGF-Notch signaling pathway was significantly inhibited in AA BM tissues and AA MSC (P＜0.05) detected by Western blot. The intervention of VEGF and DAPT significantly activated and inhibited VEGF-Notch signaling in AA MSC, respectively. CCK8 assay showed that VEGF intervention significantly promoted the proliferation of MSC in AA patients (P＜0.05). Flow cytometry showed that VEGF significantly inhibited apoptosis of MSCs by blocking S phase cells (P＜0.05).The activation of VEGF-Notch can restore the proliferation function of MSC in AA patients.VEGF-Notch信号通路对再生障碍性贫血患者骨髓MSC增殖和凋亡的作用.评估VEGF-Notch信号通路对再生障碍性贫血（aplastic anemia，AA）患者骨髓间充质干细胞（mesenchymal stem cell, MSC）增殖和凋亡的调节作用.收集再生障碍性贫血患者骨髓标本，进行骨髓MSC分离及鉴定，应用Western blot检测AA患者骨髓（BM）中VEGF-Notch信号通路相关蛋白（VEGF，VEGFR，Notch-1，Jagged1，Delta-like1和hes1）的表达。在MSC培养体系中分别加入VEGF（100 ng/ml）和DAPT（γ-secretase inhibitor）（10μmol/L），以活化和抑制MSC中的VEGF-Notch信号传导。利用细胞计数试剂盒8和流式细胞术评估AA患者MSC的细胞增殖、凋亡和细胞周期；应用油红0染色法检测成脂分化.AA患者MSC中VEGF-Notch信号通路受到明显抑制（P＜0.05）。VEGF和DAPT的干预分别激活和抑制AA患者MSC中的VEGF-Notch信号传导。CCK8检测结果显示，VEGF的干预明显促进MSC的增殖（P＜0.05）。流式细胞仪检测显示，VEGF通过阻断S期细胞显著抑制MSC的凋亡（P＜0.05）.VEGF-Notch信号通路的激活有可能恢复AA患者MSC的增殖功能.

Brain amyloid-β (Aβ) deposition is a hallmark to define Alzheimer's disease (AD). We investigated the positive rate of brain amyloid deposition assessed with 11C-Pittsburgh compound (PiB)-PET and blood Aβ levels in a cohort of probable AD patients who were diagnosed according to the 1984 NINCDS-ADRDA criteria. Eighty-four subjects with a clinical diagnosis of probable AD dementia, amnestic mild cognitive impairment (MCI), and cognitively normal (CN) status were subjected to PiB-PET and 18F-fluorodeoxyglucose (FDG)-PET scans. Plasma biomarkers of Aβ42, Aβ40, and T-tau were measured using single molecule array technology. The positive rate of PiB-PET, the associations between PiB-PET status and FDG-PET, plasma biomarkers, and clinical manifestations were analyzed. PiB-PET was positive in 77.36% of probable AD patients, 31.80% of MCI patients, and 0 of NC. Plasma Aβ42/Aβ40 ratio was associated with PiB-PET, the ROC curve analysis revealing an AUC of 0.77 (95% CI: 0.66-0.87), with a sensitivity of 82% and specificity of 64%. Some clinical manifestations were associated with PiB-PET imaging. Our findings indicate that only three-fourths of patients diagnosed with probable AD fit the pathological criteria, suggesting that we should be cautious regarding the accuracy of AD diagnosis when no biomarker evidence is available in our clinical practice.

Parkinson’s disease (PD) is attributed to interactions among genes and environmental and lifestyle factors, but the genetic architecture of PD is complex and not completely understood. To evaluate whether the genetic profile modifies PD development and cerebrospinal fluid (CSF) pathological biomarkers, we enrolled 418 PD patients and 426 age- and sex-matched normal controls. Forty-six single nucleotide polymorphisms (SNPs) that were reported to be significantly associated with PD in large-scale genome-wide association studies (GWASs) were genotyped and analysed. The alleles associated with PD were used to build polygenic risk score (PRS) models to represent polygenic risk. The Cox proportional hazards model and receiver operating characteristic (ROC) analyses were used to evaluate the prediction value of the PRS for PD risk and age at onset. The CSF α-synuclein levels were measured in a subgroup of control subjects (n = 262), and its relationship with the PRS was analysed. We found that some SNPs identified from other populations had significant correlations with PD in our Chinese cohort. The PRS we built had prediction value for PD risk and age at onset. The CSF α-synuclein level had no correlation with the PRS in normal subjects.

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by neuronal loss in the substantia nigra. The p75 neurotrophin receptor (p75NTR, encoded by NGFR) was found to play an important role in the selective neuronal death of dopamine neurons in the substantia nigra, as well as the pathogenesis and development of PD. To assess the association between NGFR gene polymorphism and the susceptibility of PD, this case-control study consisting of 414 PD patients and 623 age- and sex-matched controls in a Chinese Han cohort was conducted. Twelve tag-single nucleotide polymorphisms (tag-SNPs) were selected from the NGFR gene through the construction of linkage disequilibrium blocks. One tag-SNP from the ADAM17 gene was also selected owing to its function of encoding tumor necrosis factor α-converting enzyme, which is responsible for the shedding of the extracellular domain of p75NTR. A multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) method was applied for genotyping. The associations between tag-SNPs and the risk of PD with the adjustment for age and sex were analyzed by unconditional logistic regression, and five genetic models including codominant, dominant, recessive, over-dominant, and additive models were applied. The results showed that among the 13 tag-SNPs, rs741073 was associated with a reduced risk of PD in the codominant (OR = 0.71, 95% CI = 0.54–0.93, P = 0.037), dominant (OR = 0.76, 95% CI = 0.58–0.98, P = 0.033), and over-dominant models (OR = 0.71, 95% CI = 0.54–0.92, P = 0.010), and rs1804011 was also associated with a reduced risk of PD in the codominant (OR = 0.69, 95% CI = 0.50–0.95, P = 0.049), dominant (OR = 0.69, 95% CI = 0.50–0.93, P = 0.014), over-dominant (OR = 0.70, 95% CI = 0.51–0.96, P = 0.025), and additive models (OR = 0.72, 95% CI = 0.54–0.94, P = 0.016). However, these associations did not retain after Bonferroni correction. Conclusively, our study failed to reveal the association between the selected tag-SNPs within NGFR, ADAM17, and the susceptibility of PD. The role of p75NTR and its gene polymorphisms in the pathogenesis of PD needs to be further studied.

Metastasis of the cervical lymph nodes frequently leads to poor survival of patients with oral squamous cell carcinoma (OSCC). The underlying mechanisms of lymph node metastasis are unclear. Wingless-type MMTV integration site family, member 5B (WNT5B), one component of the WNT signal pathway, was markedly up-regulated in OSCC sublines with high potential of lymphatic metastasis compared to that in OSCC cells with low nodal metastasis. Increased WNT5B mRNA was demonstrated in human OSCC tissues in comparison with adjacent non-tumorous tissues. Interestingly, the high level of WNT5B protein in serum was associated with lymph node metastasis in OSCC patients. Knockdown of WNT5B expression in OSCC sublines did not affect tumour growth but impaired lymph node metastasis and tumour lymphangiogenesis of orthotopic transplantation. Conditioned medium from WNT5B knockdown cells reduced the tube formation of lymphatic endothelial cells (LECs). In contrast, recombinant WNT5B enhanced the tube formation, permeability and migration of LECs. In LECs stained with phalloidin, the morphology of those treated with recombinant WNT5B changed from flat to spindle-like. Recombinant WNT5B also increased α-smooth muscle actin and inhibited the expression of vascular endothelial-cadherin but retained characteristics of endothelial cells. The results suggest that WNT5B functions in the partial endothelial-mesenchymal transition (EndoMT). Furthermore, WNT5B-induced tube formation was impaired in the LECs following the knockdown of EndoMT-related transcription factor, SNAIL or SLUG. The WNT5B-induced expression of Snail or Slug was abolished by IWR-1-endo and Rac1 inhibitors, which are involved in the WNT/β-catenin and planar cell polarity pathways, respectively. Collectively, the data suggest that WNT5B induces tube formation by regulating the expression of Snail and Slug proteins through activation of canonical and non-canonical WNT signalling pathways.

In an effort to understand the underlying mechanisms of lymph node metastasis in oral squamous cell carcinoma (OSCC), through in vivo selection, LN1-1 cells were previously established from OEC-M1 cells and showed enhanced lymphangiogenesis and lymphatic metastasis capabilities. In the current study, we use a stable isotope labeling with amino acids in cell culture (SILAC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic platform to compare LN1-1 to OEC-M1 cells. Interferon-stimulated gene 15 (ISG15) was found highly expressed in LN1-1 cells. Immunohistochemical analysis and meta-analysis of publicly available microarray datasets revealed that the ISG15 level was increased in human OSCC tissues and associated with poor disease outcome. Knockdown of ISG15 had minimal effects on tumor growth but did decrease tumor lymphangiogenesis and lymphatic metastasis of LN1-1 cells. Consistent with the in vivo assay, ISG15 knockdown did not impair cell growth but diminished cell migration, invasion, and transendothelial migration in vitro. ISG15-induced cell migration was independent of ISGylation and associated with membrane protrusion. Ectopic expression of ISG15 increased Rac1 activity and knockdown of Rac1 impaired ISG15-enhanced migration. Furthermore, Rac1 colocalized with ISG15 to a region of membrane protrusion and ISG15 coimmunoprecipitated with Rac1, especially with the Rac1-GDP form. Importantly, as shown by proximity ligation assays, ISG15 and Rac1 physically interacted with each other. Our results indicated that ISG15 affects cell migration by interacting with Rac1 and regulating Rac1 activity and contributes to lymphatic metastasis in OSCC.

To investigate the potential effects of pure total flavonoid compounds (PTFCs) from Citrus paradisi Macfadyen separately or combined with arsenic trioxide on the proliferation of human myeloid leukemia cells and the mechanisms underlying the action of PTFCs. The effects of PTFCs separately or combined with arsenic trioxide on the proliferation and apoptosis of leukemia cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), fluorescence microscopy, and flow cytometry. Their effects on the expression levels of apoptosis-related regulators were determined by Western blot assay. PTFCs combined with arsenic trioxide significantly inhibited the growth of Kasumi-1 cells, and apoptosis was confirmed by flow cytometry analysis. Hoechst 33258 staining showed more significant morphological changes and more apoptosis following the combined treatment. Western blots showed changes in the expression of genes for poly ADP-ribose polymerase (PARP), caspase 3/9, and P65. The results indicated that PTFCs separately or combined with arsenic trioxide inhibited proliferation of leukemia cells in vitro and induced their apoptosis by modulating the expression of apoptosis-related regulator genes.

CISD2 is a redox-sensitive gene critical for normal development and mitochondrial integrity. CISD2 was known to have aberrant expression in several types of human cancers. However, its relation with lung cancer is still not clear. In this study we found CISD2 mRNA was significantly upregulated in lung adenocarcinoma (ADC) samples, compared with their adjacent normal counterparts, and was correlated with tumor stage, grade, and prognosis based on analysis of clinical specimens-derived expression data in public domain and our validation assay. Cell based assay indicated that CISD2 expression regulated accumulation of reactive oxygen species (ROS), polarization of mitochondrial membrane potential, as well as cell viability, apoptosis, invasiveness, and tumorigenicity. In addition, CISD2 expression was found significantly correlated with stress response/redox signaling genes such as EGR1 and GPX3, while such correlations were also found valid in many public domain data. Taken together, upregulation of CISD2 is involved in an increased antioxidant capacity in response to elevated ROS levels during the formation and progression of lung ADC. The molecular mechanism underlying how CISD2 regulates ROS homeostasis and augments malignancy of lung cancer warrants further investigations.

Aberrant expression of ROS1, ALK or c-MET (RAM) is implicated in carcinogenesis and cancer drug resistance. We retrospectively evaluated the effect of RAM expression on outcomes for advanced biliary tract cancer patients, who were treated with gemcitabine plus oxaliplatin (GEMOX), with or without cetuximab, in a randomized phase II trial. RAM expression levels on archived tissue sections were scored using immunohistochemistry (IHC). Of 110 tumors with IHC staining for all three markers, 18 were RAMhigh (IHC intensity 3+ for any markers). Ninety-two tumors were RAMlow (IHC intensity high tumors were intra-hepatic cholangiocarcinomas (IHCC). Of the patients with IHCC (n = 80), median overall survival (OS) of RAMhigh group was inferior to that of the RAMlow group (5.7 vs. 11.7 months, p = 0.021). In multivariate analysis RAMhigh remained an independently adverse prognostic factor, with a hazard ratio of 2.01 (p = 0.039). In the RAMlow group, GEMOX treatment with cetuximab significantly improved the disease control rate (68% vs. 41%, p = 0.044), median progression-free survival (7.3 vs. 4.9 months, p = 0.026), and marginally prolonged median OS (14.1 vs 9.6 months, p = 0.056), compared to GEMOX treatment alone. Future trials of anti-EGFR inhibitors for IHCC may consider RAM expression as a patient stratification factor.

The risk factors for occupational eye injuries have never been published in Taiwan. We conducted a case-control study to analyze the differences among workers on their knowledge, attitude to and practice (KAP) of occupational accident prevention. In the study, a statistical model was also set up for predicting the occupational problem. Subjects, including 31 cases of work-related eye injuries and 62 controls, completed a structured questionnaire on KAP, which revealed that 80.6% and 62.7% of workers in the case and control groups, respectively, did not wear eye protection during work. Furthermore, we found that temporary employment (OR, 10.7; 95% CI, 3.03-36.16) and fewer than 10 years of education (OR, 4.44; 95% CI, 1.73-11.44) were the major risk factors for occupational eye injuries. In addition, we developed a logistic regression model with four predictors (temporary employment, education years less than 10, poor management of industrial health and safety in the workplace, and poor attitude towards accident prevention) for the occurrence of occupational eye injuries. In conclusion, in Taiwan, compulsory regulation of wearing eye protection during work, good education, management of work safety and hygiene and employee (especially temporary worker) commitment to safety and health are strongly recommended prevention strategies.

Background The epithelial-to-mesenchymal transition (EMT) process results in a loss of cell-cell adhesion, increased cell mobility, and is crucial for enabling the metastasis of cancer cells. Recently, the enzyme SIRT1 has been implicated in a variety of physiological processes; however, its role in regulating oral cancer metastasis and EMT is not fully elucidated. Here, we propose a mechanism by which the enzyme sirtuin1 (SIRT1) regulates the EMT process in oral cancer by deacetylating Smad4 and repressing the effect of TGF-β signaling on matrix metalloproteinase-7 (MMP7). Methods The roles of SIRT1 in tumor cell migration/invasion and metastasis to the lungs were investigated using the Boyden chamber assay and orthotopic injections, respectively. RNA interference was used to knockdown either SIRT1 or Smad4 expression in oral squamous cell carcinoma (OSCC) cell lines. Immunoblotting, zymographic assays, and co-immunoprecipitation were used to examine the effects of SIRT1 overexpression on MMP7 expression and activity, as well as on SIRT1/ Smad4 interaction. Results We found that compared with normal human oral keratinocytes (HOKs), SIRT1 was underexpressed in OSCC cells, and also in oral cancer tissues obtained from 14 of 21 OSCC patients compared with expression in their matched normal tissues. Overexpression of SIRT1 inhibited migration of OSCC cells in vitro, as well as their metastasis to the lung in vivo. Furthermore, up-regulation of SIRT1 in metastatic OSCCs significantly inhibited the migration and invasion abilities of OSCC cells, while concomitantly increasing the expression of E-cadherin, and decreasing the expressions of mesenchymal markers. We also identified Smad4, a TGF-β-activated transcription factor, as a direct target protein for SIRT1. Overexpression of SIRT1 in OSCC cells led to decreased levels of acetylated Smad4, and inhibition of TGF-β-induced signaling. By associating and deacetylating Smad4, SIRT1 enzyme can influence MMP7 expression, MMP enzyme activity, and consequently, cell migration, invasion, and tumor metastasis in OSCCs. Conclusions These findings provide a valuable insight into the potential role of the SIRT1 enzyme in regulating cell migration and invasion in oral squamous cell carcinoma. Our findings suggest the SIRT1/Smad4/MMP7 pathway as a target for oral cancer driven by EMT. Electronic supplementary material The online version of this article (doi:10.1186/1476-4598-13-254) contains supplementary material, which is available to authorized users.

The properties of an ideal photosensitizer are water solubility, low cytotoxicity in the dark, high ability to produce reactive oxygen species (ROS). The characteristics of water-soluble fullerene (C60) amino acid nanoparticles as a photosensitizer were evaluated. C60 modified with l-phenylalanine (C60-phe) or glycine (C60-gly) was very efficient to carry out photodynamic activity leading to cleavage of plasmid DNA in vitro. These C60 amino acid nanoparticles were the most active photosensitizer against human Liver cancer cells and induced cancer cells apoptosis after illumination. However, these derivatives exhibited no significant cytotoxicity in dark. It produced diffuse intracellular fluorescence when 2',7'-dichlorfluorescein-diacetate (DCFH-DA) was added as an ROS probe, suggesting phototoxicity of these derivatives related with the generation of intracellular ROS. These findings indicate that these fullerene derivatives may be excellent candidate PDT enhancing agents.

To study Chinese medicine (CM) syndrome types of chronic aplastic anemia (CAA) patients and the distribution laws of typical CM symptoms in different genders.From June 2002 to June 2012, 220 CAA outpatients/inpatients at Department of Hematology, Zhejiang Chinese Medical Hospital were recruited. Patients' symptoms and signs, as well as four diagnostic information at the first onset were collected. CM syndrome differentiation was performed. The syndrome types and typical symptoms were analyzed.(1) In the 220 CAA patients, there were 121 cases of Shen yang deficiency syndrome (55.0%), 18 of Shen yin deficiency syndrome type (8.18%), 81 cases of Shen yin-yang deficiency syndrome (36.82%). (2) The distribution of typical symptoms: fatigue and shortness of breath (77.12% males and 73.53% females), pale complexion (64.41% males and 57.84% females), low temperature of four limbs (12.71% males and 26.47% females), spontaneous perspiration and night sweating (32.20% males and 26.47% females), dry mouth and throat (6.78% males and 6.86% females), feverish feelings in palms and soles (14.41% males and 20.59% females), loose stool (6.78% males and 2.94% females), petechiae and ecchymosis (42.37% males and 43.14% females).Shen yang deficiency syndrome was most often seen in CAA patients at the initial diagnosis, followed by Shen yin-yang deficiency syndrome. Shen yin deficiency syndrome was the least seen. In CM symptoms, fatigue and shortness of breath were most common seen, followed by pale complexion, skin petechia and ecchymosis.

Background: Tumor invasion and metastasis represent a major unsolved problem in cancer pathogenesis. Recent studies have indicated the involvement of Src-homology 2 domain-containing tyrosine phosphatase 2 (SHP2) in multiple malignancies; however, the role of SHP2 in oral cancer progression has yet to be elucidated. We propose that SHP2 is involved in the progression of oral cancer toward metastasis. Methods: SHP2 expression was evaluated in paired oral cancer tissues by using immunohistochemical staining and real-time reverse transcription polymerase chain reaction. Isogenic highly invasive oral cancer cell lines from their respective low invasive parental lines were established using a Boyden chamber assay, and changes in the hallmarks of the epithelial-mesenchymal transition (EMT) were assessed to evaluate SHP2 function. SHP2 activity in oral cancer cells was reduced using si-RNA knockdown or enforced expression of a catalytically deficient mutant to analyze migratory and invasive ability in vitro and metastasis toward the lung in mice in vivo. Results: We observed the significant upregulation of SHP2 in oral cancer tissues and cell lines. Following SHP2 knockdown, the oral cancer cells markedly attenuated migratory and invasion ability. We observed similar results in phosphatase-dead SHP2 C459S mutant expressing cells. Enhanced invasiveness was associated with significant upregulation of E-cadherin, vimentin, Snail/Twist1, and matrix metalloproteinase-2 in the highly invasive clones. In addition, we determined that SHP2 activity is required for the downregulation of phosphorylated ERK1/2, which modulates the downstream effectors, Snail and Twist1 at a transcript level. In lung tissue sections of mice, we observed that HSC3 tumors with SHP2 deletion exhibited significantly reduced metastatic capacity, compared with tumors administered control si-RNA. Conclusions: Our data suggest that SHP2 promotes the invasion and metastasis of oral cancer cells. These results provide a rationale for further investigating the effects of small-molecule SHP2 inhibitors on the progression of oral cancer, and indicate a previously unrecognized SHP2-ERK1/2-Snail/Twist1 pathway that is likely to play a crucial role in oral cancer invasion and metastasis.

Frequent metastasis to the cervical lymph nodes leads to poor survival of patients with oral squamous cell carcinoma (OSCC). To understand the underlying mechanisms of lymph node metastasis, two sublines were successfully isolated from cervical lymph nodes of nude mice through in vivo selection, and identified as originating from poorly metastatic parental cells. These two sublines specifically metastasized to cervical lymph nodes in 83% of mice, whereas OEC-M1 cells did not metastasize after injection into the oral cavity. After gene expression analysis, we identified insulin-like growth factor binding protein 3 (IGFBP3) as one of the significantly up-regulated genes in the sublines in comparison with their parental cells. Consistently, meta-analysis of the public microarray datasets and IGFBP3 immunohistochemical analysis revealed increased both levels of IGFBP3 mRNA and protein in human OSCC tissues when compared to normal oral or adjacent nontumorous tissues. Interestingly, the up-regulated IGFBP3 mRNA expression was significantly associated with OSCC patients with lymph node metastasis. IGFBP3 knockdown in the sublines impaired and ectopic IGFBP3 expression in the parental cells promoted migration, transendothelial migration and lymph node metastasis of orthotopic transplantation. Additionally, ectopic expression of IGFBP3 with an IGF-binding defect sustained the IGFBP3-enhanced biological functions. Results indicated that IGFBP3 regulates metastasis-related functions of OSCC cells through an IGF-independent mechanism. Furthermore, exogenous IGFBP3 was sufficient to induce cell motility and extracellular signal-regulated kinase (ERK) activation. The silencing of integrin β1 was able to impair exogenous IGFBP3-mediated migration and ERK phosphorylation, suggesting a critical role of integrin β1 in IGFBP3-enchanced functions.

To compare short-term postoperative outcomes between antecolic and retrocolic laparoscopic Roux-en-Y gastric bypass(LRYGB).Forty obesity patients were admitted into The First Affiliated Hospital of Jinan University from March 2008 to July 2010. All patients were randomly assigned to undergo antecolic (group A, 20 cases) and retrocolic (group B, 20 cases) gastroenteric anastomosis. Short-term outcomes were compared.LRYGB procedures were successfully performed in all the 40 patients. There were no significant differences between the two groups in estimated blood loss during surgery, time to flatus passage, time to resumption of oral intake, or length of postoperative hospital stay. The operation time was longer in group B than that in group A [(163.4±28.1) min vs.(131.8±22.7) min, P0.05]. There were no patients developed internal hernia or anastomotic leakage in either group. Comparison of short-term gastrointestinal symptoms after surgery showed no statistical significance.Although retrocolic procedure may be closer to anatomical structure, antecolic and retrocolic anastomosis have comparable short-term outcomes after surgery. Further study is warranted to investigate long-term outcomes.

To investigate the efficacy of laparoscopic Roux-en-Y gastric bypass (LRYGB) in the treatment for obesity and type 2 diabetes mellitus (DM).Twenty-one cases of obesity and 9 cases of type 2 DM received the LRYGB. Weigh changes, excess body weight lose rate (EWL%) and blood glucose level were measured after surgery and occurrence of complications was observed postoperatively.LRYGB procedures in all the 30 cases were successfully performed with no conversion to open surgery. Average operation time was 168 minutes (110-270 mins), volume of blood loss during the surgery was 24.0 ml (10-75 ml). Twenty-one cases of simple obesity received follow-up from 2 months to 5 years. Body weight and BMI decreased significantly in one month [(85.1+/-10.1) kg vs (97.2+/-15.0) kg, 31.2+/-2.2 vs 35.3+/-3.5, both P0.01] and to a minimal level in 2 to 3 years [(66.8+/-9.2) kg, 24.3+/-1.1], and then maintained at this level. EWL% was correspondingly higher (all P0.05). Nine type 2 DM patients were followed up for 3 to 8 months, fasting blood glucose and blood glucose OGTT2 hours decreased significantly [(5.9+/-1.4) mmol/L vs (12.6+/-2.6) mmol/L, (7.8+/-1.4) mmol/L vs (17.8+/-4.1) mmol/L, both P0.05], of whom 4 patients with obesity decreased in BMI significantly (P0.05), and 5 patients without obesity had no significant changes in BMI (P0.05). Five cases (16.7%) had postoperative complications, including 1 case of death due to acute fulminant pancreatitis, 1 case of mesenteric hiatal hernia with obstruction in line for reoperation, and the other 3 cases of healing by conservative therapy.Treatment of obesity and type 2 DM by LRYGB surgery is feasible with significant short term result. Long term outcome needs further observation.

To investigate the surgical approach, feasibility and effectiveness of laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery for treating type 2 diabetes mellitus.Seven obese patients with type 2 diabetes and 5 type 2 diabetic patients without obesity received LRYGB surgery. The changes of the body mass, fasting blood glucose (FBG), 2-hour postprandial blood glucose (2 h PBG), C peptide (C-P) and HbA1c% were observed postoperatively.LRYGB procedures were successfully performed in all the 12 patients with no conversion to open surgery. The resolution rate was 85.7% in the obese group and 80% in the non-obese diabetic group.LRYGB surgery is feasible for treatment of type 2 diabetes with good short-term result, but the long-term outcome awaits further observation.

To describe the epidemiologic features of work-related eye injuries in Kaohsiung, a hospital-based study was performed. Four hundred and eighty-six patients who were treated at emergency service or were admitted to the ophthalmology ward over a 4-year period were reviewed. Among these, 38.9% of eye injuries in the study were work-related. Male workers had a 3.99 higher odds ratio (OR) than females to suffer from eye injuries (95% confidence interval [CI], 1.99-8.04). Most of the work-related eye injuries occurred in subjects who were 30-49 years old (OR, 3.02, and 95% CI, 1.56-5.82, when compared with those aged < or = 29 years). The most common type of eye injury in the occupational exposure group was foreign body injury (31.2%), followed by blunt injuries (20.6%), chemical burn (19.6%), UV light radiation (12.7%), and corneal abrasions (11.6%). On the other hand, in the non-occupational exposure group, the most common types of eye injury were blunt injuries (43.4%), corneal abrasions (28.3%), and foreign body injury (20.2%). Our study found that foreign body injury and blunt injuries were the two highest priority injuries for which prevention strategies should be developed in Kaohsiung city. Furthermore, after advanced examination of types of media that caused eye injuries, we found that being hit by wooden objects around the eye, by flying objects in the eye, and by welding flashes are important risk factors for workers to avoid. In conclusion, most of the occupational eye injuries occurred among male workers aged 30-49 years. Due to the lack of an occupational eye injury surveillance system to monitor the incidence of eye injuries and to undertake risk assessment, preventable occupational eye injuries have not been properly controlled. We hope to provide information for further development of preventive strategies.