Murine mesothelin: characterization, expression, and inhibition of tumor growth in a murine model of pancreatic cancer

Background Mesothelin has attracted much interest as a tumor specific antigen; it has been reported to promote tumor development and to be a good target for cancer treatment. Most studies to date have used human mesothelin in immunocompromised mice. Since these models do not allow for study of the natural immune response to mesothelin expressing tumors, we have undertaken the characterization of mouse mesothelin so the effects of this protein can be assessed in immunocompetent mouse strains. Methods We analyzed mouse mesothelin expression, tissue distribution, shedding and biochemistry. In addition we constructed stable mesothelin overexpressing lines of the pancreatic cancer line Panc02 by two methods and tested them for growth and tumorigencity in vitro and in vivo. Results We show here that mouse mesothelin is similar to human mesothelin in biochemical characteristics, tumor expression and tissue distribution, suggesting the mouse may be a suitable model for study of mesothelin. Stable overexpression of mesothelin in a pancreatic cancer cell line did not increase cell proliferation or anchorage-independent growth in vitro, suggesting that mesothelin is not necessarily a tumor progression factor. Surprisingly overexpression of mesothelin inhibited tumor formation in vivo in immunocompetent mice. Conclusion The mouse may be a good model for studying mesothelin in the context of an intact immune response. Mesothelin is not necessarily a tumor progression factor, and indeed mesothelin overexpression inhibited tumor growth in immunocompetent mice

Physical growth during the first year of life. A longitudinal study in rural and urban areas of Hanoi, Vietnam

<p>Abstract</p> <p>Background</p> <p>Good infant growth is important for future health. Assessing growth is common in pediatric care all over the world, both at the population and individual level. There are few studies of birth weight and growth studies comparing urban and rural communities in Vietnam. The first aim is to describe and compare the birth weight distributions and physical growth (weight and length) of children during their first year in one rural and one urban area of Hanoi Vietnam. The second aim is to study associations between the anthropometric outcomes and indicators of the economic and educational situations.</p> <p>Methods</p> <p>Totally 1,466 children, born from 1^stMarch, 2009 to June 2010, were followed monthly from birth to 12 months of age in two Health and Demographic Surveillance Sites; one rural and one urban. In all, 14,199 measurements each of weight and length were made. Birth weight was recorded separately. Information about demographic conditions, education, occupation and economic conditions of persons and households was obtained from household surveys. Fractional Polynomial models and standard statistical methods were used for description and analysis.</p> <p>Results</p> <p>Urban infants have higher birth weight and gain weight faster than rural infants. The mean birth weight for urban boys and girls were 3,298 grams and 3,203 grams as compared to 3,105 grams and 3,057 grams for rural children. At 90 days, the urban boys were estimated to be 4.1% heavier than rural boys. This difference increased to 7.2% at 360 days. The corresponding difference for girls was 3.4% and 10.5%. The differences for length were comparatively smaller. Both birth weight and growth were statistically significantly and positively associated with economic conditions and mother education.</p> <p>Conclusion</p> <p>Birth weight was lower and the growth, weight and length, considerably slower in the rural area, for boys as well as for girls. The results support the hypothesis that the rather drastic differences in maternal education and economic conditions lead to poor nutrition for mothers and children in turn causing inferior birth weight and growth.</p

HNF1A G319S variant, active cigarette smoking and incident type 2 diabetes in Aboriginal Canadians: a population-based epidemiological study

<p>Abstract</p> <p>Background</p> <p>In a recent report of large-scale association analysis, a type 2 diabetes susceptibility locus near <it>HNF1A </it>was identified in predominantly European descent populations. A population-specific G319S polymorphism in <it>HNF1A </it>was previously identified in Aboriginal Canadians who have a high prevalence of type 2 diabetes. We aimed to investigate the association of the <it>HNF1A </it>G319S polymorphism with incident type 2 diabetes and to assess whether clinical risk variables for type 2 diabetes influence the association in an Aboriginal population.</p> <p>Methods</p> <p>Of 606 participants who were free of diabetes at baseline in 1993-1995, 540 (89.1%) participated in 10-year follow-up assessments in 2003-2005. Fasting glucose and a 75-g oral glucose tolerance test were obtained to determine incident type 2 diabetes. Participants were genotyped for the <it>HNF1A </it>G319S polymorphism. Interviewers administered questionnaires on smoking behavior.</p> <p>Results</p> <p>The incidence rates of type 2 diabetes were 14.2% (55/388) in major allele homozygotes and 31.2% (29/93) in minor allele carriers (p < 0.001). The <it>HNF1A </it>G319S carrier status was associated with incident type 2 diabetes (odds ratio [OR] 3.78 [95% CI 2.13-6.69]) after adjustment for age, sex, hypertension, triglyceride, HDL cholesterol, and waist circumference. A statistical interaction was observed between <it>HNF1A </it>G319S and baseline active cigarette smoking on the development of type 2 diabetes with similar adjustment (p = 0.006). When participants were stratified by baseline smoking status, <it>HNF1A </it>G319S carriers who were active smokers had increased risk of developing diabetes (OR 6.91 [95% CI 3.38-14.12]), while the association was attenuated to non-significance among non-smokers (1.11 [0.40-3.08]).</p> <p>Conclusions</p> <p>The <it>HNF1A </it>G319S variant is associated with incident type 2 diabetes in Aboriginal Canadians. Furthermore, cigarette smoking appears to amplify incident diabetes risk in carriers of <it>HNF1A </it>G319S.</p

Central Role of SREBP-2 in the Pathogenesis of Osteoarthritis

Background: Recent studies have implied that osteoarthritis (OA) is a metabolic disease linked to deregulation of genes involved in lipid metabolism and cholesterol efflux. Sterol Regulatory Element Binding Proteins (SREBPs) are transcription factors regulating lipid metabolism with so far no association with OA. Our aim was to test the hypothesis that SREBP-2, a gene that plays a key role in cholesterol homeostasis, is crucially involved in OA pathogenesis and to identify possible mechanisms of action. Methodology/Principal Findings: We performed a genetic association analysis using a cohort of 1,410 Greek OA patients and healthy controls and found significant association between single nucleotide polymorphism (SNP) 1784G>C in SREBP-2 gene and OA development. Moreover, the above SNP was functionally active, as normal chondrocytes’ transfection with SREBP-2-G/C plasmid resulted in interleukin-1β and metalloproteinase-13 (MMP-13) upregulation. We also evaluated SREBP-2, its target gene 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR), phospho-phosphoinositide3-kinase (PI3K), phospho-Akt, integrin-alphaV (ITGAV) and transforming growth factor-$\beta$ (TGF-$\beta$) mRNA and protein expression levels in osteoarthritic and normal chondrocytes and found that they were all significantly elevated in OA chondrocytes. To test whether TGF-$\beta$ alone can induce SREBP-2, we treated normal chondrocytes with TGF-$\beta$ and found significant upregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13. We also showed that TGF-$\beta$ activated aggrecan (ACAN) in chondrocytes only through Smad3, which interacts with SREBP-2. Finally, we examined the effect of an integrin inhibitor, cyclo-RGDFV peptide, on osteoarthritic chondrocytes, and found that it resulted in significant upregulation of ACAN and downregulation of SREBP-2, HMGCR, phospho-PI3K and MMP-13 expression levels. Conclusions/Significance: We demonstrated, for the first time, the association of SREBP-2 with OA pathogenesis and provided evidence on the molecular mechanism involved. We suggest that TGF-$\beta$ induces SREBP-2 pathway activation through ITGAV and PI3K playing a key role in OA and that integrin blockage may be a potential molecular target for OA treatment

Sunitinib and other targeted therapies for renal cell carcinoma

Targeted therapy has radically altered the way metastatic renal cancer is treated. Six drugs are now licensed in this setting, with several other agents under evaluation. Sunitinib is currently the most widely used in the first line setting with impressive efficacy and an established toxicity profile. However, as further randomised studies report and as newer drugs become available this may change. In this review, we address our current understanding of targeted therapy in renal cancer. We also discuss areas in which our knowledge is incomplete, including the identification of correlative biomarkers and mechanisms of drug resistance. Finally, we will describe the major areas of clinical research that will report over the next few years

Loss of Arc renders the visual cortex impervious to the effects of sensory experience or deprivation

A myriad of mechanisms have been suggested to account for the full richness of visual cortical plasticity. We found that visual cortex lacking Arc is impervious to the effects of deprivation or experience. Using intrinsic signal imaging and chronic visually evoked potential recordings, we found that Arc−/− mice did not exhibit depression of deprived-eye responses or a shift in ocular dominance after brief monocular deprivation. Extended deprivation also failed to elicit a shift in ocular dominance or open-eye potentiation. Moreover, Arc−/− mice lacked stimulus-selective response potentiation. Although Arc−/− mice exhibited normal visual acuity, baseline ocular dominance was abnormal and resembled that observed after dark-rearing. These data suggest that Arc is required for the experience-dependent processes that normally establish and modify synaptic connections in visual cortex.Howard Hughes Medical InstituteNational Science Foundation (U.S.

Identification of QTLs for Arsenic Accumulation in Maize (Zea mays L.) Using a RIL Population

The Arsenic (As) concentration in different tissues of maize was analyzed using a set of RIL populations derived from an elite hybrid, Nongda108. The results showed that the trend of As concentration in the four measured tissues was leaves>stems>bracts>kernels. Eleven QTLs for As concentration were detected in the four tissues. Three QTLs for As concentration in leaves were mapped on chromosomes 1, 5, and 8, respectively. For As concentration in the bracts, two QTLs were identified, with 9.61% and 10.03% phenotypic variance. For As concentration in the stems, three QTLs were detected with 8.24%, 14.86%, and 15.23% phenotypic variance. Three QTLs were identified for kernels on chromosomes 3, 5, and 7, respectively, with 10.73%, 8.52%, and 9.10% phenotypic variance. Only one common chromosomal region between SSR marker bnlg1811 and umc1243 was detected for QTLs qLAV1 and qSAC1. The results implied that the As accumulation in different tissues in maize was controlled by different molecular mechanism. The study demonstrated that maize could be a useful plant for phytoremediation of As-contaminated paddy soil, and the QTLs will be useful for selecting inbred lines and hybrids with low As concentration in their kernels

Transmission of Vibrio cholerae Is Antagonized by Lytic Phage and Entry into the Aquatic Environment

Cholera outbreaks are proposed to propagate in explosive cycles powered by hyperinfectious Vibrio cholerae and quenched by lytic vibriophage. However, studies to elucidate how these factors affect transmission are lacking because the field experiments are almost intractable. One reason for this is that V. cholerae loses the ability to culture upon transfer to pond water. This phenotype is called the active but non-culturable state (ABNC; an alternative term is viable but non-culturable) because these cells maintain the capacity for metabolic activity. ABNC bacteria may serve as the environmental reservoir for outbreaks but rigorous animal studies to test this hypothesis have not been conducted. In this project, we wanted to determine the relevance of ABNC cells to transmission as well as the impact lytic phage have on V. cholerae as the bacteria enter the ABNC state. Rice-water stool that naturally harbored lytic phage or in vitro derived V. cholerae were incubated in a pond microcosm, and the culturability, infectious dose, and transcriptome were assayed over 24 h. The data show that the major contributors to infection are culturable V. cholerae and not ABNC cells. Phage did not affect colonization immediately after shedding from the patients because the phage titer was too low. However, V. cholerae failed to colonize the small intestine after 24 h of incubation in pond water—the point when the phage and ABNC cell titers were highest. The transcriptional analysis traced the transformation into the non-infectious ABNC state and supports models for the adaptation to nutrient poor aquatic environments. Phage had an undetectable impact on this adaptation. Taken together, the rise of ABNC cells and lytic phage blocked transmission. Thus, there is a fitness advantage if V. cholerae can make a rapid transfer to the next host before these negative selective pressures compound in the aquatic environment

Indigenous use and bio-efficacy of medicinal plants in the Rasuwa District, Central Nepal

<p>Abstract</p> <p>Background</p> <p>By revealing historical and present plant use, ethnobotany contributes to drug discovery and socioeconomic development. Nepal is a natural storehouse of medicinal plants. Although several ethnobotanical studies were conducted in the country, many areas remain unexplored. Furthermore, few studies have compared indigenous plant use with reported phytochemical and pharmacological properties.</p> <p>Methods</p> <p>Ethnopharmacological data was collected in the Rasuwa district of Central Nepal by conducting interviews and focus group discussions with local people. The informant consensus factor (F_IC) was calculated in order to estimate use variability of medicinal plants. Bio-efficacy was assessed by comparing indigenous plant use with phytochemical and pharmacological properties determined from a review of the available literature. Criteria were used to identify high priority medicinal plant species.</p> <p>Results</p> <p>A total of 60 medicinal formulations from 56 plant species were documented. Medicinal plants were used to treat various diseases and disorders, with the highest number of species being used for gastro-intestinal problems, followed by fever and headache. Herbs were the primary source of medicinal plants (57% of the species), followed by trees (23%). The average F_IC value for all ailment categories was 0.82, indicating a high level of informant agreement compared to similar studies conducted elsewhere. High F_ICvalues were obtained for ophthalmological problems, tooth ache, kidney problems, and menstrual disorders, indicating that the species traditionally used to treat these ailments are worth searching for bioactive compounds: <it>Astilbe rivularis</it>, <it>Berberis asiatica</it>, <it>Hippophae salicifolia, Juniperus recurva</it>, and <it>Swertia multicaulis</it>. A 90% correspondence was found between local plant use and reported plant chemical composition and pharmacological properties for the 30 species for which information was available. Sixteen medicinal plants were ranked as priority species, 13 of which having also been prioritized in a country-wide governmental classification.</p> <p>Conclusions</p> <p>The <it>Tamang </it>people possess rich ethnopharmacological knowledge. This study allowed to identify many high value and high priority medicinal plant species, indicating high potential for economic development through sustainable collection and trade.</p