Association between physical activity and health-related quality of life among adults in China: the moderating role of age.

Objective: The aim of the study was to examine the association between physical activity (PA) and health-related quality of life (HRQOL) among adults and explore the role of age in the association between PA and HRQOL in Shandong, China. Methods: We investigated the relationship between PA and HRQOL and examined the moderated role of age in this association among adults with different age groups and physical activity levels. Data were obtained from the sixth China National Health Services Survey conducted in Shandong province in 2018. The multi-stage-stratified cluster random sampling method was used to selected respondents, with individuals aged 18 and above included in the present study. The tool of assessing HRQOL was the three-level EuroQol Five Dimensions Questionnaire (EQ-5D-3L). Results: The study found PA was significantly related to HRQOL (P < 0.05). The interaction analysis indicated that the relationship between PA and HRQOL was significantly different across young, middle-aged, and older adults (P < 0.05). Older adults with the sufficient PA (coefficient = 0.090, 95%CI: [0.081, 0.100]) and active PA (coefficient = 0.057, 95%CI: [0.043, 0.072]) had significantly higher HRQOL compared with young and middle-aged groups. Conclusion: PA was positively associated with HRQOL among the adults. Age played a moderate role between the association between PA and HRQOL. Guidelines for PA should be specifically tailored to adults of different age groups in order to enhance their HRQoL.

CD22 blockade modulates microglia activity to suppress neuroinflammation following intracerebral hemorrhage.

Microglia are first responders to acute brain insults and initiate neuroinflammation to drive secondary tissue injury. Yet the key molecular switches in control of the inflammatory activity of microglia remain poorly understood. Intracerebral hemorrhage (ICH) is a devastating stroke subtype whereby a hematoma is formed within the brain parenchyma and associated with high mortality. Using a mouse model of ICH, we found upregulation of CD22 that predominantly occurred in microglia. Antibody blockade of CD22 led to a reduction in neurological deficits, brain lesion and hematoma volume. This was accompanied by reduced inflammatory activity, increased expression of alternative activation markers (CD206 and IL-10) and enhanced phagocytosis activity in microglia after ICH. CD22 blockade also led to an increase of phosphorylated SYK and AKT after ICH. Notably, the benefits of CD22 blockade were ablated in ICH mice subjected to microglial depletion with a colony-stimulating factor 1 receptor inhibitor PLX5622. Additionally, the protective effects of CD22 blockade was diminished in ICH mice receiving a SYK inhibitor R406. Together, our findings highlight CD22 as a key molecular switch to control the detrimental effects of microglia after acute brain injury, and provide a novel strategy to improve the outcome of ICH injury.

Abrocitinib Attenuates Microglia-Mediated Neuroinflammation after Traumatic Brain Injury via Inhibiting the JAK1/STAT1/NF-κB Pathway.

BACKGROUND AND PURPOSE: Neuroinflammation has been shown to play a critical role in secondary craniocerebral injury, leading to poor outcomes for TBI patients. Abrocitinib, a Janus kinase1 (JAK1) selective inhibitor approved to treat atopic dermatitis (AD) by the Food and Drug Administration (FDA), possesses a novel anti-inflammatory effect. In this study, we investigated whether abrocitinib could ameliorate neuroinflammation and exert a neuroprotective effect in traumatic brain injury (TBI) models. METHODS: First, next-generation sequencing (NGS) was used to select genes closely related to neuroinflammation after TBI. Then, magnetic resonance imaging (MRI) was used to dynamically observe the changes in traumatic focus on the 1st, 3rd, and 7th days after the induction of fluid percussion injury (FPI). Moreover, abrocitinib's effects on neurobehaviors were evaluated. A routine peripheral blood test was carried out and Evans blue dye extravasation, cerebral cortical blood flow, the levels of inflammatory cytokines, and changes in the numbers of inflammatory cells were evaluated to investigate the function of abrocitinib on the 1st day post-injury. Furthermore, the JAK1/signal transducer and activator of transcription1 (STAT1)/nuclear factor kappa (NF-κB) pathway was assessed. RESULTS: In vivo, abrocitinib treatment was found to shrink the trauma lesions. Compared to the TBI group, the abrocitinib treatment group showed better neurological function, less blood-brain barrier (BBB) leakage, improved intracranial blood flow, relieved inflammatory cell infiltration, and reduced levels of inflammatory cytokines. In vitro, abrocitinib treatment was shown to reduce the pro-inflammatory M1 microglia phenotype and shift microglial polarization toward the anti-inflammatory M2 phenotype. The WB and IHC results showed that abrocitinib played a neuroprotective role by restraining JAK1/STAT1/NF-κB levels after TBI. CONCLUSIONS: Collectively, abrocitinib treatment after TBI is accompanied by improvements in neurological function consistent with radiological, histopathological, and biochemical changes. Therefore, abrocitinib can indeed reduce excessive neuroinflammation by restraining the JAK1/STAT1/NF-κB pathway.

The vertebrate- and testis- specific transmembrane protein C11ORF94 plays a critical role in sperm-oocyte membrane binding.

Sperm-oocyte membrane fusion is necessary for mammalian fertilization. The factors that determine the fusion of sperm with oocytes are largely unknown. So far, spermatozoon factor IZUMO1 and the IZUMO1 counter-receptor JUNO on the oocyte membrane has been identified as a protein requiring fusion. Some sperm membrane proteins such as FIMP, SPACA6 and TEME95, have been proved not to directly regulate fusion, but their knockout will affect the fusion process of sperm and oocytes. Here, we identified a novel gene C11orf94 encoding a testicular-specific small transmembrane protein that emerges in vertebrates likely acquired via horizontal gene transfer from bacteria and plays an indispensable role in sperm-oocyte binding. We demonstrated that the deletion of C11orf94 dramatically decreased male fertility in mice. Sperm from C11orf94-deficient mice could pass through the zona pellucida, but failed to bind to the oocyte membrane, thus accumulating in the perivitelline space. In consistence, when the sperm of C11orf94-deficient mice were microinjected into the oocyte cytoplasm, fertilized oocytes were obtained and developed normally to blastocysts. Proteomics analysis revealed that C11orf94 influenced the expression of multiple gene products known to be indispensable for sperm-oocyte binding and fusion, including IZUMO1, EQTN and CRISP1. Thus, our study indicated that C11ORF94 is a vertebrate- and testis-specific small transmembrane protein that plays a critical role in sperm binding to the oolemma.

Selective Sphingosine 1-Phosphate Receptor 1 Modulation Augments Thrombolysis of Low-Dose Tissue Plasminogen Activator Following Cerebrovascular Thrombosis.

Background: Results from our recent study demonstrate that sphingosine-1-phosphate receptor 1 (S1PR1) modulation improves microvascular hemodynamics after cerebrovascular thrombosis. This study was to determine the microvascular hemodynamic effects of a sub-thrombolytic dose of tPA combined with a selective S1PR1 modulator ozanimod in a mouse model of cerebrovascular thrombosis. Methods: Microvascular circulation in mice was monitored in vivo by two-photon microscopy. Thrombosis was induced in cortical arterioles by laser irradiation. Arteriolar flow velocity was measured by line-scanning following plasma-labeling with fluorescein-dextran. Results: Laser-induced thrombosis led to a persistent reduction of flow velocity in cortical arterioles. Sub-thrombolytic dose of tPA along with vehicle control did not improve the flow velocity in cortical arterioles following thrombosis. In contrast, a sub-thrombolytic dose of tPA along with ozanimod dramatically restored flow velocity in cortical arterioles following thrombosis. Ozanimod did not affect coagulation and bleeding time. Notably, ozanimod reduced thrombus volume without altering microvascular lumen diameter. In addition, ozanimod reduced leukocyte components within the thrombus. Conclusions: These findings demonstrate that the thrombolytic effect of a sub-thrombolytic dose of tPA is markedly enhanced by S1PR1 modulation, implying that S1PR1 modulation may improve the therapeutic benefit of low-dose tPA in patients with acute ischemic stroke.

Productivity Losses Due to Diabetes in Urban Rural China.

BACKGROUND: Productivity losses due to diabetes are increasing in China, but research about the impact of diabetes on productivity in urban and rural areas requires further in-depth study. This article provides the first estimate of the cost of productivity losses attributed to diabetes in individuals 20-69 years old in urban and rural areas of China. METHODS: The human capital approach is employed to measure the productivity losses attributed to absenteeism, presenteeism, labor force dropout, and premature deaths due to diabetes of the 20-69-year-old population of males and females in urban and rural areas of China. Based on the life table modelling, we calculate the years of potential life lost and working years of life lost of people with diabetes. RESULTS: In 2017, we estimated that there were 100.46 million people with diabetes, with the total cost of productivity losses being USD 613.60 billion, comprising USD 326.40 billion from labor force dropout, USD 186.34 billion from premature death, USD 97.71 billion from absenteeism, and USD 27.04 billion from presenteeism. Productivity loss was greater in urban (USD 490.79 billion) than rural areas (USD 122.81 billion), with urban presenteeism (USD 2.54 billion) greater than rural presenteeism (USD 608.55 million); urban absenteeism (USD 79.10 billion) greater than rural absenteeism (USD 18.61 billion); urban labor force dropout (USD 261.24 billion) greater than rural labor force dropout (USD 65.15 billion); and urban premature death (USD 147.90 billion) greater than rural premature death (USD 38.44 billion). CONCLUSIONS: Diabetes has a large and significant negative impact on productivity in urban and rural China. Productivity loss is significantly higher in urban versus rural regions. Further investment is required in the prevention, diagnosis, and control of diabetes in under-resourced health services in rural locations as well as in urban areas, where most diabetes cases reside. Specifically, targeted and effective diabetes prevention and management actions are urgently required.

Chitosan-based composite film adsorbents reinforced with nanocellulose for removal of Cu(II) ion from wastewater: Preparation, characterization, and adsorption mechanism.

Utilizing natural and renewable natural polysaccharides as substrates to fabricate films or spinning with high metal ion adsorption and retain their mechanical properties is essential but challenging for the treatment of polluted water systems. In this study, the adsorption film was prepared with excellent mechanical properties and adsorption properties by blending chitosan (CS), poly (vinyl pyrrolidone) (PVP), ß-cyclodextrin (ß-CD), and nanocellulose (NCC). Fourier transform infrared spectroscopy, X-ray diffraction analysis, and scanning electron microscopy were used to investigate the microstructure of the film. The effects of the NCC content, contact time, temperature, initial concentration, and pH on the adsorption of Cu(II) ion were investigated. X-ray photoelectron spectroscopy (XPS) was used to explore the adsorption mechanism. The results showed that a suitable content of NCC enhanced the tensile strength of the CS/PVP/ß-CD/NCC composite film and improved its adsorption capacity under acidic conditions. The adsorption kinetics followed the pseudo-second-order kinetic model and the equilibrium data could be better described by the Langmuir isotherm. The thermodynamic parameters indicated that the adsorption of the Cu(II) ion onto the CS/PVP/ß-CD/NCC film exhibited physical adsorption and spontaneous process. XPS analysis showed that the nitrogen-containing functional groups play an important role during the adsorption process. Therefore, applying this adsorbent to remove metal ions during wastewater treatment is promising.

Exosome to Promote Cancer Progression via Its Bioactive Cargoes.

Exosomes are nanosized, organelle-like membranous vesicles secreted from various cell types, including normal cells and cancer cells. Exosomes contain abundant bioactive molecules, including nucleic acids, lipids, and proteins and dynamically participate in intercellular communications. By shuttling the functional molecules into the recipient cells, exosomes secreted by cancerous cells can alter the cellular environment to favor tumor growth and metastasis. In this review, we focus on exosomes to promote cancer progression via their various bioactive cargoes through different mechanisms/pathways. By recognizing these pathways, we can design efficient therapeutic strategies to control cancer progression.

Age-related transcriptome changes in melanoma patients with tumor-positive sentinel lymph nodes.

Age is an important factor for determining the outcome of melanoma patients. Sentinel lymph node (SLN) status is also a strong predictor of survival for melanoma. Paradoxically, older melanoma patients have a lower incidence of SLN metastasis but a higher mortality rate when compared with their younger counterparts. The mechanisms that underlie this phenomenon remain unknown. This study uses three independent datasets of RNA samples from patients with melanoma metastatic to the SLN to identify age-related transcriptome changes in SLNs and their association with outcome. Microarray was applied to the first dataset of 97 melanoma patients. NanoString was performed in the second dataset to identify the specific immune genes and pathways that are associated with recurrence in younger versus older patients. qRT-PCR analysis was used in the third dataset of 36 samples to validate the differentially expressed genes (DEGs) from microarray and NanoString. These analyses show that FOS, NR4A, and ITGB1 genes were significantly higher in older melanoma patients with positive SLNs. IRAK3- and Wnt10b-related genes are the major pathways associated with recurrent melanoma in younger and older patients with tumor-positive SLNs, respectively. This study aims to elucidate age-related differences in SLNs in the presence of nodal metastasis.

Comparative gene expression analysis in melanocytes driven by tumor cell-derived exosomes.

Abundant with organelle-like membranous structures, the tumor microenvironment is composed of cancer cells that secrete exosomes. Studies have shown that these secreted exosomes transport RNA and active molecules to other cells to reshape the tumor microenvironment and promote tumor growth. In fact, we found that exosomes derived from melanoma cells drive pre-malignant transition in primary melanocytes. However, there is little available in the scientific literature on how exosomes modulate melanocytes in the microenvironment to optimize conditions for tumor progression and metastasis. We therefore focused this current study on identifying these conditions genetically. Through RNA sequencing, we analyzed gene expression levels of melanocytes driven by exosomes derived from melanoma and lung cancer cells compared with those without exosome controls. Significant differences were found in gene expression patterns of melanocytes driven by exosomes derived from melanoma and lung cancer cells. In the melanocytes responding to exosomes derived from melanoma cells, genes of lipopolysaccharide and regulation of leukocyte chemotaxis were predominant. In the melanocytes responding to exosomes derived from lung cancer cells, genes of DNA replication and mitotic nuclear division played an important role. These results provide further mechanistic understanding of tumor progression promoted by tumor-derived exosomes. This will also help identify potential therapeutic targets for melanoma progression.

Seasonal and Monthly Patterns, Weekly Variations, and the Holiday Effect of Outpatient Visits for Type 2 Diabetes Mellitus Patients in China.

OBJECTIVE: To explore the seasonal and monthly patterns, weekly variations, and the holiday effect of outpatient visits for type 2 diabetes mellitus patients, as well as the influence of gender, age, and insurance type on variations. METHODS: Data were obtained from the Shandong medical insurance database, including all outpatients in 12 cities of Shandong province in China from 2015 to 2017. The seasonal index (St) was calculated in terms of seasons, months, and weeks by the moving average method. RESULTS: A total of 904,488 patients received outpatient services during the study period. The seasonal indices of outpatient visits by type 2 diabetes patients were higher in autumn (108.36%) and spring (102.67%), while lower in winter (89.92%) and summer (99.04%), exhibiting an obvious seasonality. Gender and age had no effect on seasonal patterns. The month impacted the seasons patterns: January to February were the lowest and December the highest months of outpatient visits, complicating the seasonal patterns. We also identified a weekly pattern of outpatient visits. In addition, the outpatient visits for type 2 diabetes mellitus patients was also strongly affected by the Spring Festival, Lantern Festival, and National Day holiday periods. The type of medical insurance had a significant impact on outpatient visits. CONCLUSIONS: The outpatient visits for type 2 diabetes mellitus patients displayed seasonal patterns that were contradictory to the variations in blood glucose fluctuations found in previous studies and was also strongly affected by the holiday effect. The type of medical insurance impacted the pattern of outpatient visits.

Differential expression of ABCB5 in BRAF inhibitor-resistant melanoma cell lines.

BACKGROUND: More than 50% of metastatic melanoma patients have a specific mutation in the serine/threonine kinase BRAF. This results in constitutive activation of the RAS-RAF-MEK-ERK-MAP kinase pathway, which causes uncontrolled cell growth. Vemurafenib (PLX4032) is an oral chemotherapeutic agent that targets the specific mutation V600E in the BRAF protein. Initial response rates are high in patients with BRAF mutant melanoma treated with a BRAF inhibitor such as vemurafenib, but resistance nearly always develops and disease progression ensues. There are several different mechanisms by which melanoma develops BRAF inhibitor resistance. One potential component of resistance is increased drug efflux. Overexpressed ABCB5 (ATP-binding cassette transporter, subfamily B, member 5) has been shown to efflux anti-cancer drugs from cancer cells. The purpose of this study is to determine whether ABCB5 is highly expressed in BRAF inhibitor-resistant melanoma cells and to evaluate whether ABCB5 is involved in the development of resistance to BRAF inhibitors in cutaneous melanoma. METHODS: We established three BRAF inhibitor-resistant melanoma cell lines with BRAF mutation. The expression level of ABCB5 in PLX-resistant cell lines was checked by real-time PCR and Western blot analysis. SK-MEL-2 melanoma cells with wild-type BRAF were used for comparison. The association of different levels of ABCB5 with the changes of ERK, p-ERK, Akt and p-Akt was also assessed by Western blotting. Re-sensitization of melanoma cells to PLX was tested by p-ERK inhibitor PD58059 and ABCB5 knockdown by ABCB5 siRNA, respectively. RESULTS: We showed that ABCB5 was overexpressed in SK-MEL-28PLXr and A2058PLXr cells but not in A375PLXr cells. ABCB5 overexpression is associated with activation of p-ERK status but not Akt. Inhibition of p-ERK re-sensitized SK-MEL-28PLXr and A2058PLXr cells to PLX treatment, but knockdown of ABCB5 did not re-sensitize A2058 PLXr and SK-MEL-28 PLXr cells to PLX treatment. CONCLUSION: These results confirm that, even though ABCB5 was overexpressed in SK-MEL-28 and A2058 melanoma cells that develop resistance to BRAF inhibitors, ABCB5 may not be a major targetable contributor to BRAF resistance. p-ERK inhibition may play important roles in BRAF resistance in these two melanoma cell lines.

Unique Genes in Tumor-Positive Sentinel Lymph Nodes Associated with Nonsentinel Lymph Node Metastases in Melanoma.

BACKGROUND: Current risk assessment tools to estimate the risk of nonsentinel lymph node metastases after completion lymphadenectomy for a positive sentinel lymph node (SLN) biopsy in cutaneous melanoma are based on clinical and pathologic factors. We identified a novel genetic signature that can predict non-SLN metastases in patients with cutaneous melanoma staged with a SLN biopsy. METHODS: RNA was collected for tumor-positive SLNs in patients staged by SLN biopsy for cutaneous melanoma. All patients with a tumor-positive SLN biopsy underwent completion lymphadenectomy. A 1:10 case:control series of positive and negative non-SLN patients was analyzed by microarray and quantitative RT-PCR. Candidate differentially expressed genes were validated in a 1:3 case:control separate cohort of positive and negative non-SLN patients. RESULTS: The 1:10 case:control discovery set consisted of 7 positive non-SLN cases matched to 70 negative non-SLN controls. The cases and controls were similar with regards to important clinicopathologic factors, such as gender, primary tumor site, age, ulceration, and thickness. Microarray and RT-PCR identified six potential differentially expressed genes for validation. In the 40-patient separate validation set, 10 positive non-SLN patients were matched to 30 negative non-SLN controls based on gender, ulceration, age, and thickness. Five of the six genes were differentially expressed. The five gene panel identified patients at low (7.1%) and high risk (66.7%) for non-SLN metastases. CONCLUSIONS: A novel, non-SLN gene score based on differential expressed genes in a tumor-positive SLN can identify patients at high and low risk for non-SLN metastases.

Sentinel Lymph Node Genes to Predict Prognosis in Node-Positive Melanoma Patients.

PURPOSE: Melanoma patients with a single microscopically-positive sentinel lymph node (SLN) are classified as stage III and are often advised to undergo expensive and substantially toxic adjuvant therapy. However, the 5-year survival rate for these patients, with or without adjuvant therapy, varies from 14 to 85 %, representing a heterogeneous biological population with a variable prognosis. We aimed to identify an SLN gene signature to aid in risk stratification of patients with tumor-positive SLNs. METHODS: Microarray experiments were performed to screen SLN genes in recurrence (N = 39) versus non-recurrence (N = 58) groups in the training dataset. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assay was applied to confirm the expression of selected SLN genes, which were further verified using an independent validation cohort (N = 30). Area under the receiver operating characteristic curve (AUC) was calculated to evaluate prognostic accuracy of the selected SLN gene panel, and the prognostic value of our SLN gene signature was also compared with the current American Joint Committee on Cancer (AJCC) staging system. RESULTS: We identified two SLN genes (PIGR and TFAP2A) that provided high prognostic accuracy in SLN-positive melanoma patients (AUC = 0.864). These two SLN genes, along with clinicopathological features, can differentiate the high- and low-risk groups in node-positive melanoma patients in this cohort. CONCLUSION: The two SLN genes, when combined with clinicopathological features, may offer a new tool for personalized patient risk assessment.

Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment.

The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma.

Hematite nanoplates: Controllable synthesis, gas sensing, photocatalytic and magnetic properties.

Uniform hematite (α-Fe2O3) nanoplates exposing {001} plane as basal planes have been prepared by a facile solvothermal method under the assistance of sodium acetate. The morphological evolution of the nanoplates was studied by adjusting the reaction parameters including the solvent and the amount of sodium acetate. The results indicated that both the adequate nucleation/growth rate and selective adsorption of alcohol molecules and acetate anions contribute to the formation of the plate-like morphology. In addition, the size of the nanoplates can be adjusted from ca. 180nm to 740nm by changing the reaction parameters. Three nanoplate samples with different size were selected to investigate the gas sensing performance, photocatalytic and magnetic properties. As gas sensing materials, all the α-Fe2O3 nanoplates exhibited high gas sensitivity and stability toward n-butanol. When applied as photocatalyst, the α-Fe2O3 nanoplates show high photodegradation efficiency towards RhB. Both the gas sensing performance and the photocatalytic property of the products exhibit obvious size-dependent effect. Magnetic measurements reveal that the plate-like α-Fe2O3 particles possess good room temperature magnetic properties.

[Polymorphisms of catechol-O-methyltransferase and monoamine oxidase B genes among Chinese patients with Parkinson's disease].

OBJECTIVE: To study polymorphisms of catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) genes among Chinese patients with Parkinson's disease. METHODS: Genotypes of the COMT and MAO-B genes of 1408 patients with Parkinson's disease was sequenced using Sanger method. And these patients were recruited by Chinese Parkinson Study Group from 29 research centers throughout the country. RESULTS: The genotypic frequencies of COMT rs4680 AA, AG, GG were 8.9%, 42.0% and 49.1%. Those of rs4818 CC, CG, GG were 42.5%, 45.6% and 11.9%, respectively. The genotype frequencies of MAO-B rs1799836 A/AA, AG, G/GG were 74.4%, 14.1% and 11.5%, respectively. The haplotype formed by COMT rs4680 (GG) and MAO-B rs1799836 (A/AA) genotype has a frequency of 36.86%. CONCLUSION: Polymorphisms of COMT and MAO-B genes has a unique characteristics among Chinese patients with Parkinson's disease. They may be related with differences in drug response in such patients.

Association of Catechol-O-Methyltransferase and monoamine oxidase B gene polymorphisms with motor complications in parkinson's disease in a Chinese population.

BACKGROUND: Catechol-O-Methyltransferase (COMT) and Monoamine oxidase B (MAO-B) are the main enzymes that metabolize dopamine in the brain. The polymorphisms of the COMT gene and MAO-B gene are associated with high, intermediate and low levels of activity. This may influence the prevalence of motor complications in Parkinson's Disease (PD). METHODS: The study enrolled 1087 Chinese PD patients throughout the country. Sanger dideoxynucleotide chain termination methods were used for COMT and MAO-B genotyping. The researchers compared the association between presence of motor complications and COMT and MAO-B gene polymorphisms, both separately and in combination. RESULTS: Comparison of the allele frequencies revealed that COMT (GG) was significantly more common among PD patients who exhibited wearing-off compared to PD patients without wearing-off (P < 0.05). A statistically higher frequency of the MAO-B (AG) genotype in PD patients with dyskinesias was found (P < 0.05). Although these differences were not significant after Bonferroni's correction. The combined haplotype of the MAO-B and COMT showed no increase (p < 0.05) in the risk of wearing-off and dyskinesias. CONCLUSIONS: Our findings suggest that polymorphisms in COMT and MAO-B may increase the risk of wearing-off and dyskinesias. COMT (GG) genotype may be the risk factor of wearing-off. While MAO-B (AG) genotype may be the risk factor of dyskinesias.

Identifying mRNA, microRNA and protein profiles of melanoma exosomes.

BACKGROUND: Exosomes are small membranous vesicles secreted into body fluids by multiple cell types, including tumor cells, and in various disease conditions. Tumor exosomes contain intact and functional mRNAs, small RNAs (including miRNAs), and proteins that can alter the cellular environment to favor tumor growth. Molecular profiling may increase our understanding of the role of exosomes in melanoma progression and may lead to discovery of useful biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we used mRNA array profiling to identify thousands of exosomal mRNAs associated with melanoma progression and metastasis. Similarly, miRNA array profiling identified specific miRNAs, such as hsa-miR-31, -185, and -34b, involved in melanoma invasion. We also used proteomic analysis and discovered differentially expressed melanoma exosomal proteins, including HAPLN1, GRP78, syntenin-1, annexin A1, and annexin A2. Importantly, normal melanocytes acquired invasion ability through molecules transported in melanoma cell-derived exosomes. CONCLUSIONS/SIGNIFICANCE: Our results indicate that melanoma-derived exosomes have unique gene expression signatures, miRNA and proteomics profiles compared to exosomes from normal melanocytes. To the best of our knowledge, this is the first in-depth screening of the whole transcriptome/miRNome/proteome expression in melanoma exosomes. These results provide a starting point for future more in-depth studies of tumor-derived melanoma exosomes, which will aid our understanding of melanoma biogenesis and new drug-targets that may be translated into clinical applications, or as non-invasive biomarkers for melanoma.

Adenovirus-mediated expression of mutated forkhead human transcription like-1 suppresses tumor growth in a mouse melanoma xenograft model.

Melanoma is generally resistant to chemotherapy, which may be related to defects in death receptor signaling and to defects in induction of apoptosis. Forkhead family transcription factors induce the expression of death receptor ligands such as Fas ligand (Fas-L) resulting in apoptosis. We therefore investigated whether a triple mutant form of forkhead transcription factor FKHRL1 (FKHRL1/TM) can enhance Fas-L mediated-apoptosis in melanoma cells. Two melanoma cells A2058 or DM6 were tested for their sensitivity to agonistic anti-Fas antibody (CH-11); adenovirus expressing FKHRL1/TM (Ad-FKHRL1/TM) was assessed for its capability to induce activation of the caspase pathway; the role of Fas-L in the Ad-FKHRL1/TM mediated-cell death was also assessed in vitro. Ad-FKHRL1/TM antitumor activity in vivo was also evaluated in a mouse melanoma xenograft model. We found that DM6 melanoma cells were more resistant to Fas/Fas-L-mediated apoptosis induced by agonistic anti-Fas antibody than A2058 melanoma cells. Ectopic expression of FKHRL1/TM in melanoma cells upregulated Fas-L expression, decreased procaspase-8 levels, and significantly increased Fas/FasL-mediated cell death in both cells lines; this induced cell death was partially blocked by a Fas/Fas-L antagonist. Importantly, Ad-FKHRL1/TM treatment of subcutaneous melanoma xenografts in mice resulted in approximately 70% decrease in tumor size compared with controls. These data indicate that overexpression of FKHRL1/TM can induce the Fas-L pathway in melanoma cells. Ad-FKHRL1/TM therefore might represent a promising vector for melanoma treatment.