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Downregulation of HLA class I (HLA-I) impairs immune recognition and surveillance in prostate cancer and may underlie the ineffectiveness of checkpoint blockade. However, the molecular mechanisms regulating HLA-I loss in prostate cancer have not been fully explored. Here, we conducted a comprehensive analysis of HLA-I genomic, epigenomic and gene expression alterations in primary and metastatic human prostate cancer. Loss of HLA-I gene expression was associated with repressive chromatin states including DNA methylation, histone H3 tri-methylation at lysine 27, and reduced chromatin accessibility. Pharmacological DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibition decreased DNA methylation and increased H3 lysine 27 acetylation and resulted in re-expression of HLA-I on the surface of tumor cells. Re-expression of HLA-I on LNCaP cells by DNMT and HDAC inhibition increased activation of co-cultured prostate specific membrane antigen (PSMA)27-38-specific CD8+ T-cells. HLA-I expression is epigenetically regulated by functionally reversible DNA methylation and chromatin modifications in human prostate cancer. Methylated HLA-I was detected in HLA-Ilow circulating tumor cells (CTCs), which may serve as a minimally invasive biomarker for identifying patients who would benefit from epigenetic targeted therapies. Loss of HLA-I gene expression in prostate cancer is associated with repressive chromatin states, which can be reversed by pharmacological DNMT and HDAC inhibition leading to increased activation of co-cultured tumor-specific CD8+ T-cells. [ABSTRACT FROM AUTHOR]

Future thinking is defined as the ability to withdraw from reality and mentally project oneself into the future. The primary aim of the present study was to examine whether functions of future thoughts differed depending on their mode of elicitation (spontaneous or voluntary) and an attribute of goal-relatedness (selected-goal-related or selected-goal-unrelated). After producing spontaneous and voluntary future thoughts in a laboratory paradigm, participants provided ratings on four proposed functions of future thinking (self, directive, social, and emotional regulation). Findings showed that spontaneous and voluntary future thoughts were rated similarly on all functions except the directive function, which was particularly relevant to spontaneous future thoughts. Future thoughts classed as goal-related (selected-goal-related) were rated higher across all functions, and there was largely no interaction between mode of elicitation and goal-relatedness. A higher proportion of spontaneous future thoughts were selected-goal-related compared with voluntary future thoughts. In general, these results indicate that future thinking has significant roles across affective, behavioural, self and social functions, and supports theoretical views that implicate spontaneous future thought in goal-directed cognition and behaviour. [ABSTRACT FROM AUTHOR]

Background: Impact experiments, routinely performed at the macroscale, have long been used to study mechanical properties of materials. Microscale high-velocity impact, relevant to applications such as ballistic drug delivery has remained largely unexplored at the level of a single impact event. Objective: In this work, we study the mechanical behavior of polymer gels subjected to high-velocity microparticle impact, with strain rates up to 107 s−1, through direct visualization of the impact dynamics. Methods: In an all-optical laser-induced particle impact test, 10–24 μm diameter steel microparticles are accelerated through a laser ablation process to velocities ranging from 50 to 1000 m/s. Impact events are monitored using a high-speed multi-frame camera with nanosecond time resolution. Results: We measure microparticle trajectories and extract both maximum and final penetration depths for a range of particle sizes, velocities, and gel concentrations. We propose a modified Clift-Gauvin model and demonstrate that it adequately describes both individual trajectories and penetration depths. The model parameters, namely, the apparent viscosity and impact resistance, are extracted for a range of polymer concentrations. Conclusions: Laser-induced microparticle impact test makes it possible to perform reproducible measurements of the single particle impact dynamics on gels and provides a quantitative basis for understanding these dynamics. We show that the modified Clift-Gauvin model, which accounts for the velocity dependence of the drag coefficient, offers a better agreement with the experimental data than the more commonly-used Poncelet model. Microscale ballistic impact imaging performed with high temporal and spatial resolution can serve as direct input for simulations of high-velocity impact responses and high strain rate deformation in gels and other soft materials. [ABSTRACT FROM AUTHOR]

Purpose: This study examines posttraumatic growth (PTG) among adolescents and young adults (AYAs) with cancer, as well as its correlates and trajectories over time. The study also explores the buffering role of PTG on the associations between posttraumatic stress (PTS), health-related quality of life (HRQoL), and psychological distress.Methods: A multicenter, longitudinal, prospective study was conducted among AYA cancer patients aged 14-39 years. One hundred sixty-nine patients completed a self-report measure of PTG (PTGI) and PTS (PDS) 6, 12, and 24 months after baseline (within the first 4 months of diagnosis). At 24-month follow-up, HRQoL (SF-36) and psychological distress (BSI-18) were also assessed.Results: Among participants, 14% showed increasing PTG, 45% remained at a stable high PTG level, 14% showed decreasing PTG, and 27% remained at a stable low PTG level. AYAs who remained high on PTG were more often younger, female, and received chemotherapy. PTG level at 6-month follow-up was predictive of mental HRQoL (β = 0.19; p = 0.026) and psychological distress (β = -0.14; p = 0.043) at 24-month follow-up when corrected for PTS and sociodemographic and clinical covariates. No relationship between PTG and physical HRQoL was found. The interactive effects of PTS and PTG on outcomes were not significant, indicating that buffering did not take place.Conclusion: This study indicates that PTG is dynamic and predicts mental well-being outcomes but does not buffer the effects of PTS. Psychosocial interventions should focus on promoting PTG and reducing PTS in order to promote the adjustment of AYAs diagnosed with cancer. [ABSTRACT FROM AUTHOR]

H69AR is a multidrug-resistant human small-cell lung carcinoma cell line that was selected in doxorubicin and has previously been shown to be cross-resistant to a variety of natural-product-type anticancer drugs. H69AR is unlike many other multidrug-resistant cell lines in that it does not overexpress P-glycoprotein. In the present study, the drug sensitivity and cross-resistance patterns of H69AR cells were further characterized. A total of 15 drugs belonging to a number of chemical classes were screened. These compounds included anthracyclines, DNA binders (anthrapyrazoles, benzothiopyranoindazoles, and pyrazoloacridines), and lipophilic antifolates. The alkylating agent melphalan and the antimetabolite cytosine arabinofuranoside (Ara-C) were also tested. In general, the drug sensitivity and cross-resistance profiles of H69AR cells were consistent with those reported by others using other drug-resistant cell lines. However, there were several unexpected instances of cross-resistance. Thus, the H69AR cell line was more resistant than its parent cell line to the potent 3'-deamino-3'-(3-cyano-4-morpholinyl) doxorubicin, bisantrene, the pyrazoloacridine PD 114541, Ara-C, and melphalan. In addition, no cross-resistance to the four lipophilic antifolates tested, including trimetrexate, was found. The absence of a consistent pattern among the various drug-resistant cell lines indicates that assumptions about the efficacy of anticancer drugs in multidrug resistance should be made with caution. [ABSTRACT FROM AUTHOR]

Numerous procedures have been described which test the chemosensitivity of tumor cell lines. A major disadvantage of most of these assays is that practical limitations prevent the testing of more than a few variables. We have adapted a rapid and efficient colorimetric assay for testing the chemosensitivity of human lung tumor cells. In this assay, a tetrazolium salt (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide, MTT) is converted to a colored formazan product by enzymes active only in living cells. The MTT assay may be carried out entirely in 96-well microtiter plates, so that large experiments examining a number of variables can be readily performed. Thus, drug concentration, time of exposure to drug, length of assay, and cell density can be varied and tested. Moreover, the simplicity of this assay allows simultaneous testing of multiple drugs on multiple cell lines. Finally, the MTT assay is useful for monitoring the development of multidrug-resistant cells in culture. [ABSTRACT FROM AUTHOR]

Background:Occult blood-based colorectal cancer (CRC) screening may result in adverse psychological outcomes for participants. The aims of this study were to measure the psychological consequences of participating in screening at key points along the screening and diagnostic pathway, and examine variation over time within or between test outcome groups.Methods:A total of 301 people (positives=165, negatives=136) aged 50-76 years were surveyed via validated psychological questionnaires after result notification, post colonoscopy (positives only) and 1 year following result notification.Results:Negatives scored significantly higher in quality of life domains and lower state anxiety, anger and depression in comparison to positives both after result notification and at 1 year follow-up. Positives had significantly decreased state anxiety and depression at 1 year and improvement in HLoC power and reduced screening decision doubtfulness post colonoscopy. Positives experienced heightened CRC risk perception both after result notification and at 1 year follow-up in comparison to negatives, but reported less difficulty participating in ongoing screening.Conclusions:In positives, increased anxiety and doubtfulness about the decision to screen declined over time. Lower CRC risk perception in negatives indicates the need for education to promote CRC screening participation. [ABSTRACT FROM AUTHOR]

Background:In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown.Objective:The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R.Methods:Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean±s.d.): age, 15.7±6.5 years; body mass index z-scores (BMI-Z), 1.63±1.03) and 69 subjects of Hispanic heritage (10.8±3.6 years; BMI-Z, 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped.Results:In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P=0.29) or 20 GOF subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction.Conclusions:Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Type 2 diabetes is a chronic, heterogeneous disease and a major risk factor for cardiovascular diseases. The underlying mechanisms leading to progression to type 2 diabetes are not fully understood and genetic tools may help to identify important pathways of glycaemic deterioration. Methods: Using prospective data on American Indians from the Strong Heart Family Study, we identified 373 individuals defined as progressors (diabetes incident cases), 566 individuals with transitory impaired fasting glucose (IFG) and 1,011 controls (normal fasting glycaemia at all visits). We estimated the heritability (h) of the traits and the evidence for association with 16 known variants identified in type 2 diabetes genome-wide association studies. Results: We noted high h for diabetes progression (h = 0.65 ± 0.16, p = 2.7 × 10) but little contribution of genetic factors to transitory IFG (h = 0.09 ± 0.10, p = 0.19) for models adjusted for multiple risk factors. At least three variants (in WFS1, TSPAN8 and THADA) were nominally associated with diabetes progression in age- and sex-adjusted analyses with estimates showing the same direction of effects as reported in the discovery European ancestry studies. Conclusions/interpretation: Our findings do not exclude these loci for diabetes susceptibility in American Indians and suggest phenotypic heterogeneity of the IFG trait, which may have implications for genetic studies when diagnosis is based on a single time-point measure. [ABSTRACT FROM AUTHOR]

Quantitative ultrasound (QUS) traits are correlated with bone mineral density (BMD), but predict risk for future fracture independent of BMD. Only a few studies, however, have sought to identify specific genes influencing calcaneal QUS measures. The aim of this study was to conduct a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing normal variation in QUS traits. QUS measures were collected from a total of 719 individuals (336 males and 383 females) from the Fels Longitudinal Study who have been genotyped and have at least one set of QUS measurements. Participants ranged in age from 18.0 to 96.6 years and were distributed across 110 nuclear and extended families. Using the Sahara ® bone sonometer, broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (QUI) were collected from the right heel. Variance components based linkage analysis was performed on the three traits using 400 polymorphic short tandem repeat (STR) markers spaced approximately 10 cM apart across the autosomes to identify QTL influencing the QUS traits. Age, sex, and other significant covariates were simultaneously adjusted. Heritability estimates (h2) for the QUS traits ranged from 0.42 to 0.57. Significant evidence for a QTL influencing BUA was found on chromosome 11p15 near marker D11S902 (LOD = 3.11). Our results provide additional evidence for a QTL on chromosome 11p that harbors a potential candidate gene(s) related to BUA and bone metabolism. [ABSTRACT FROM AUTHOR]

Although disrupted in schizophrenia 1 (DISC1) has been implicated in many psychiatric disorders, including schizophrenia, bipolar disorder, schizoaffective disorder and major depression, its biological role in these disorders is unclear. To better understand this gene and its role in psychiatric disease, we conducted transcriptional profiling and genome-wide association analysis in 1232 pedigreed Mexican-American individuals for whom we have neuroanatomic images, neurocognitive assessments and neuropsychiatric diagnoses. SOLAR was used to determine heritability, identify gene expression patterns and perform association analyses on 188 quantitative brain-related phenotypes. We found that the DISC1 transcript is highly heritable (h2=0.50; P=1.97 × 10−22), and that gene expression is strongly cis-regulated (cis-LOD=3.89) but is also influenced by trans-effects. We identified several DISC1 polymorphisms that were associated with cortical gray matter thickness within the parietal, temporal and frontal lobes. Associated regions affiliated with memory included the entorhinal cortex (rs821639, P=4.11 × 10−5; rs2356606, P=4.71 × 10−4), cingulate cortex (rs16856322, P=2.88 × 10−4) and parahippocampal gyrus (rs821639, P=4.95 × 10−4); those affiliated with executive and other cognitive processing included the transverse temporal gyrus (rs9661837, P=5.21 × 10−4; rs17773946, P=6.23 × 10−4), anterior cingulate cortex (rs2487453, P=4.79 × 10−4; rs3738401, P=5.43 × 10−4) and medial orbitofrontal cortex (rs9661837; P=7.40 × 10−4). Cognitive measures of working memory (rs2793094, P=3.38 × 10−4), as well as lifetime history of depression (rs4658966, P=4.33 × 10−4; rs12137417, P=4.93 × 10−4) and panic (rs12137417, P=7.41 × 10−4) were associated with DISC1 sequence variation. DISC1 has well-defined genetic regulation and clearly influences important phenotypes related to psychiatric disease. [ABSTRACT FROM AUTHOR]

Background: We investigated prostate involvement during sexually transmitted infections by measuring serum prostate-specific antigen (PSA) as a marker of prostate infection, inflammation, and/or cell damage in young, male US military members.Methods: We measured PSA before and during infection for 299 chlamydia, 112 gonorrhoea, and 59 non-chlamydial, non-gonococcal urethritis (NCNGU) cases, and 256 controls.Results: Chlamydia and gonorrhoea, but not NCNGU, cases were more likely to have a large rise (40%) in PSA than controls (33.6%, 19.1%, and 8.2% vs 8.8%, P<0.0001, 0.021, and 0.92, respectively).Conclusion: Chlamydia and gonorrhoea may infect the prostate of some infected men. [ABSTRACT FROM AUTHOR]

The notion that family support may buffer individuals under adversity from poor outcomes has been theorized to have important implications for mental and physical health, but little is known about the biological mechanisms that explain these links. We hypothesized that adults who grew up in low socioeconomic status (SES) households but who experienced high levels of maternal warmth would be protected from the pro-inflammatory states typically associated with low SES. A total of 53 healthy adults (aged 25-40 years) low in SES early in life were assessed on markers of immune activation and systemic inflammation. Genome-wide transcriptional profiling also was conducted. Low early-life SES individuals who had mothers, who expressed high warmth toward them, exhibited less Toll-like receptor-stimulated production of interleukin 6, and reduced bioinformatic indications of pro-inflammatory transcription factor activity (NF-κB) and immune activating transcription factor activity (AP-1) compared to those who were low in SES early in life but experienced low maternal warmth. To the extent that such effects are causal, they suggest the possibility that the detrimental immunologic effects of low early-life SES environments may be partly diminished through supportive family climates. [ABSTRACT FROM AUTHOR]

We present multi-parameter geophysical measurements of rainfall-induced lahars at Semeru Volcano, East Java, using two observation sites 510 m apart, 11.5 km from the summit. Our study site in the Curah Lengkong channel is composed of a 30-m wide box-valley, with a base of gravel and lava bedrock, representing an ideal geometry for high density measurements of active lahars. Instrumentation included pore-pressure sensors (stage), a broad-band seismograph (arrival times, vibrational energy, and turbulence), video footage, and direct bucket sampling. A total of 8 rainfall-induced lahars were recorded, with durations of 1-3 h, heights 0.5-2 m, and peak velocities 3-6 m/s. Flow types ranged from dilute to dense hyperconcentrated flows. These recorded flows were commonly composed of partly coalesced, discrete and unsteady gravity current packets, represented by multiple peaks within each lahar. These packets most likely originate from multiple lahar sources, and can be traced between instrument sites. Those with the highest concentrations and greatest wetted areas were often located mid-lahar at our measured reach, accelerating towards the flow front. As these lahars travel downstream, the individual packets thus coalesce and the flow develops a more organised structure. Observations of different degrees of coalescence between these discrete flow packets illustrate that a single mature debris flow may have formed from multiple dynamically independent lahars, each with different origins. [ABSTRACT FROM AUTHOR]

Paraoxonase-1 (PON1) is associated with high-density lipoprotein (HDL) particles and is believed to contribute to antiatherogenic properties of HDLs. We assessed the determinants of PON1 activity variation using different substrates of the enzyme. PON1 activity in serum samples from 922 participants in the San Antonio Family Heart Study was assayed using a reliable microplate format with three substrates: paraoxon, phenyl acetate and the lactone dihydrocoumarin. There were major differences among results from the three substrates in degree of effect by various environmental and genetic factors, suggesting that knowledge of one substrate activity alone may not provide a complete sense of PON1 metabolism. Three significant demographic covariates (age, smoking status and contraceptive usage) together explained 1–6% of phenotypic variance, whereas four metabolic covariates representing lipoprotein metabolism (apoAII, apoAI, triglycerides and non-HDL cholesterol) explained 4–19%. Genes explained 65–92% of phenotypic variance and the dominant genetic effect was exerted by a locus mapping at or near the protein structural locus (PON1) on chromosome 7. Additional genes influencing PON1 activity were localized to chromosomes 3 and 14. Our study identified environmental and genetic determinants of PON1 activity that accounted for 88–97% of total phenotypic variance, suggesting that few, if any, major biological determinants are unrepresented in the models.Heredity (2009) 102, 147–154; doi:10.1038/hdy.2008.110; published online 29 October 2008 [ABSTRACT FROM AUTHOR]

The genetic contribution to age-related bone loss is not well understood. We estimated that genes accounted for 25–45% of variation in 5-year change in bone mineral density in men and women. An autosome-wide linkage scan yielded no significant evidence for chromosomal regions implicated in bone loss. The contribution of genetics to acquisition of peak bone mass is well documented, but little is known about the influence of genes on subsequent bone loss with age. We therefore measured 5-year change in bone mineral density (BMD) in 300 Mexican Americans (>45 years of age) from the San Antonio Family Osteoporosis Study to identify genetic factors influencing bone loss. Annualized change in BMD was calculated from measurements taken 5.5 years apart. Heritability (h2) of BMD change was estimated using variance components methods and autosome-wide linkage analysis was carried out using 460 microsatellite markers at a mean 7.6 cM interval density. Rate of BMD change was heritable at the forearm (h2 = 0.31, p = 0.021), hip (h2 = 0.44, p = 0.017), spine (h2 = 0.42, p = 0.005), but not whole body (h2 = 0.18, p = 0.123). Covariates associated with rapid bone loss (advanced age, baseline BMD, female sex, low baseline weight, postmenopausal status, and interim weight loss) accounted for 10% to 28% of trait variation. No significant evidence of linkage was observed at any skeletal site. This is one of the first studies to report significant heritability of BMD change for weight-bearing and non-weight-bearing bones in an unselected population and the first linkage scan for change in BMD. [ABSTRACT FROM AUTHOR]

Resistin has been associated with inflammation and risk for cardiovascular disease. We previously reported evidence of a QTL on chromosome 19p13 affecting the abundance of resistin (RETN) mRNA in the omental adipose tissue of baboons (L0D score 3.8). In this study, whole genome transcription levels were assessed in human lymphocyte samples from 1240 adults participating in the San Antonio Family Heart Study, using the Sentrix Human-6 Expression Beadchip. Lymphocytes were surveyed, as it has been proposed that their expression levels may reflect those in harder to ascertain tissues, such as adipose tissue, that are thought to be more directly relevant to disease procesn was conducted to detect loci affecting RETN mRNA levels. We obtained significant evidence for a QTL influencing the RETN expression (LOD score 10.7) on chromosome 19p. This region is orthologous/homologous to the region previously localized on baboon chromosome 19. The strongest positional candidate gene in this region is the structural gene for resistin, itself. We also found evidence for a QTL influencing resistin protein levels (LOD score 5.3) on chromosome 14q. This differs from our previously reported QTL on chromosome 18 in baboons. The different QTLs for circulating protein suggests that post-translational processing and turnover may be influenced by different or multiple genes in baboons and humans. The parallel findings of a cis-eQTL for RETN mRNA in baboon omental tissue and human lymphocytes lends support to the strategy of using lymphocyte gene expression levels as a surrogate for gene expression levels in other tissues.Heredity (2008) 101, 60–66; doi:10.1038/hdy.2008.28; published online 30 April 2008 [ABSTRACT FROM AUTHOR]

Objective:Genome-wide scans were conducted in search for genetic locations linked to energy expenditure and substrate oxidation in children.Design:Pedigreed data of 1030 Hispanic children and adolescents were from the Viva La Familia Study which was designed to investigate genetic and environmental risk factors for the development of obesity in Hispanic families. A respiratory calorimeter was used to measure 24-h total energy expenditure (TEE), basal metabolic rate (BMR), sleep metabolic rate (SMR), 24-h respiratory quotient (24RQ), basal metabolic respiratory quotient (BMRQ) and sleep respiratory quotient (SRQ). Protein, fat and carbohydrate oxidation (PROOX, FATOX and CHOOX, respectively) were also estimated. All participants were genotyped for 384 single tandem repeat markers spaced an average of 10 cM apart. Computer program SOLAR was used to perform the genetic linkage analyses.Results:Significant linkage for TEE was detected on chromosome 1 near marker D1S2841, with a logarithm of the odds (LOD) score of 4.0. SMR, BMRQ and PROOX were associated with loci on chromosome 18, 17 and 9, respectively, with LOD scores of 4.88, 3.17 and 4.55, respectively. A genome-wide scan of SMR per kg fat-free mass (SpFFM) peaked in the same region as SMR on chromosome 18 (LOD, 5.24). Suggestive linkage was observed for CHOOX and FATOX. Several candidate genes were found in the above chromosomal regions including leptin receptor (LEPR).Conclusion:Regions on chromosomes 1, 9, 17 and 18 harbor genes affecting variation in energy expenditure and substrate oxidation in Hispanic children and adolescents.International Journal of Obesity (2008) 32, 579–585; doi:10.1038/ijo.2008.20; published online 4 March 2008 [ABSTRACT FROM AUTHOR]

To detect and localize the effects of genes influencing variation in adiponectin mRNA and protein levels, we conducted statistical genetic analyses of circulating concentrations of adiponectin and adiponectin (ADIPOQ) mRNA expression in omental adipose tissue in adult, pedigreed baboons (Papio anubis). An omental adipose tissue biopsy and blood sample were collected from 427 baboons from the colony at the Southwest Foundation for Biomedical Research, San Antonio, TX. Total RNA was isolated from adipose tissue and adiponectin mRNA levels were assayed by real-time, quantitative reverse transcriptase-PCR. Adiponectin, insulin, glucose, cholesterol, high-density lipoproteins and triglycerides were measured in fasting serum. Quantitative genetic analyses were conducted for adiponectin mRNA and serum protein using a maximum likelihood-based variance decomposition approach. A genome-wide linkage analysis was conducted using adiponectin mRNA and protein levels as phenotypes. Significant heritability was estimated for ADIPOQ mRNA levels (h2=0.19±0.07, P=0.01) and protein levels (h2=0.28±0.14, P=0.003). Genetic correlations were found between adiponectin protein and body weight (ρG=−0.51, P=0.03), cell volume (ρG=−0.73, P=0.04), serum triglycerides (ρG=−0.67, P=0.03), and between adiponectin mRNA and glucose (ρG=0.93, P<0.01). A logarithm of odds score of 2.9 was found for ADIPOQ mRNA levels on baboon chromosome 4p, which is orthologous to human 6p21. There is a significant genetic component affecting variation in the analyzed traits, and common genes may be influencing adiponectin expression, adipocyte volume, body weight and circulating triglycerides. The region on 6p21 has been linked to diabetes-related phenotypes in human studies.Heredity (2008) 100, 382–389; doi:10.1038/sj.hdy.6801089; published online 20 February 2008 [ABSTRACT FROM AUTHOR]

Introduction:Adiponectin, a hormone produced exclusively by adipose tissue, is inversely associated with insulin resistance and proinflammatory conditions. The aim of this study was to find quantitative trait loci (QTLs) that affect circulating levels of adiponectin in Hispanic children participating in the VIVA LA FAMILIA Study by use of a systematic genome scan.Methods:The present study included extended families with at least one overweight child between 4 and 19 years old. Overweight was defined as body mass index (BMI) 95th percentile. Fasting blood was collected from 466 children from 127 families. Adiponectin was assayed by radioimmunoassay (RIA) technique in fasting serum. A genome-wide scan on circulating levels of adiponectin as a quantitative phenotype was conducted using the variance decomposition approach.Results:The highest logarithm of odds (LOD) score (4.2) was found on chromosome 11q23.2–11q24.2, and a second significant signal (LOD score=3.0) was found on chromosome 8q12.1–8q21.3. In addition, a signal suggestive of linkage (LOD score=2.5) was found between 18q21.3 and 18q22.3. After adjustment for BMI-Z score, the LOD score on chromosome 11 remained unchanged, but the signals on chromosomes 8 and 18 dropped to 1.6 and 1.7, respectively. Two other signals suggestive of linkage were found on chromosome 3 (LOD score=2.1) and 10 (LOD score=2.5). Although the region on chromosome 11 has been associated with obesity and diabetes-related traits in adult populations, this is the first observation of linkage in this region for adiponectin levels. Our suggestive linkages on chromosomes 10 and 3 replicate results for adiponectin seen in other populations. The influence of loci on chromosomes 18 and 8 on circulating adiponectin seemed to be mediated by BMI in the present study.Conclusion:Our genome scan in children has identified a novel QTL and replicated QTLs in chromosomal regions previously shown to be linked with obesity and type 2 diabetes (T2D)-related phenotypes in adults. The genetic contribution of loci to adiponectin levels may vary across different populations and age groups. The strong linkage signal on chromosome 11 is most likely underlain by a gene(s) that may contribute to the high susceptibility of these Hispanic children to obesity and T2D.International Journal of Obesity (2007) 31, 535–542. doi:10.1038/sj.ijo.0803436; published online 8 August 2006 [ABSTRACT FROM AUTHOR]

Blood pressure (BP) reactivity to orthostatic tilt may be predictive of cardiovascular disease. However, the genetic and environmental influences on BP reactivity to tilt have not been well examined. Identifying different influences on BP at rest and BP during tilt is complicated by the intercorrelation among multiple measurements. In this study, we use principal components analysis (PCA) to reduce multivariate BP data into components that are orthogonal. The objective of this study is to characterize and examine the genetic architecture of BP at rest and during head-up tilt (HUT). Specifically, we estimate the heritability of individual BP measures and three principal components (PC) derived from multiple BP measurements during HUT. Additionally, we estimate covariate effects on these traits. The study sample consisted of 444 individuals, distributed across four large families. HUT consisted of 70° head-up table tilting while strapped to a tilt table. BP reactivity (ΔBP) was defined as BP during HUT minus BP while supine. Three PC extracted from the PCA were interpreted as ‘general BP’ (PC1), ‘pulse pressure’ (PC2) and ‘BP reactivity’ (PC3). Variance components methods were used to estimate the heritabilities of resting BP, HUT BP, ΔBP, as well as the three BP PC. Significant (P<0.05) heritabilities were found for all BP measurements, except for systolic ΔBP at 1 and 3 min, and diastolic ΔBP at 2 min. Significant genetic effects were also found for the three PC. Each of these orthogonal components is significantly influenced by somewhat different sets of covariates.Journal of Human Hypertension (2006) 20, 281–289. doi:10.1038/sj.jhh.1001975; published online 26 January 2006 [ABSTRACT FROM AUTHOR]

INTRODUCTION:: The hormone resistin was recently discovered in adipose tissue of mice. Functional tests suggest a role for resistin in the regulation of insulin sensitivity. However, human studies have reported controversial results on the metabolic function of this hormone. METHODS:: A 1?g omental adipose tissue biopsy was obtained from 404 adult baboons. Resistin mRNA expression was assayed by real-time, quantitative RT-PCR, and univariate and bivariate quantitative genetic analyses were performed, via the variance decomposition approach. A genome scan analysis was conducted using resistin mRNA abundance in omental adipose tissue as a quantitative phenotype. RESULTS:: A significant heritability of h2=0.23 (P=0.003) was found for resistin mRNA abundance in omental adipose tissue. A genome scan detected a quantitative trait locus for resistin expression with an LOD score of 3.8, in the region between markers D19S431 and D19S714, corresponding to human chromosome 19 p13. This chromosomal region contains genes related to insulin resistance phenotypes, such as resistin, insulin receptor, angiopoietin-like 4 protein and LDL receptor. CONCLUSIONS:: Individual variation in resistin mRNA expression has a significant genetic component, and a gene or genes on chromosome 19p13 may regulate resistin mRNA levels in baboon omental adipose tissue.International Journal of Obesity (2005) 29, 406-412. doi:10.1038/sj.ijo.0802699 Published online 24 August 2004 [ABSTRACT FROM AUTHOR]

OBJECTIVE:: To perform a meta-analysis of genome-wide linkage scans using body mass index (BMI) to identify genetic loci predisposing to obesity. DATA:: A total of 13 published genome scans on obesity have used BMI as their primary end point. Five of these 13 groups agreed to provide detailed results from their scans that were required for a meta-analysis. Collectively, these five studies included a total of 2814 individuals from 505 families. METHODS:: The results of the five studies were analysed using the GSMA (genome scans meta-analysis) method. RESULTS:: The analysis revealed significant evidence for linkage of the quantitative phenotype BMI to 8p (P<0.0005).International Journal of Obesity (2005) 29, 413-419. doi:10.1038/sj.ijo.0802817 Published online 1 February 2005 [ABSTRACT FROM AUTHOR]

OBJECTIVE: Leptin gene expression is higher in females than in males, and is regulated by many factors including energy intake and insulin, but little is known about the inheritance of leptin gene expression. We have investigated leptin (LEP) gene expression, to determine whether it is heritable, and whether the difference in LEP expression between males and females has a genetic component. STUDY POPULATION: A total of 319 baboons (Papio hamadryas) (220 females, 99 males) from a captive, pedigreed colony. MEASUREMENTS AND METHODS: We cloned a baboon LEP cDNA, and quantified LEP mRNA expression in baboon omental adipose tissue using a ribonuclease protection assay. In addition, we assayed circulating leptin levels, adipocyte cell volume, and weight. We used maximum likelihood-based variance decomposition methods to determine the genetic architecture of LEP levels, including testing for genotype-by-sex interaction. RESULTS: Omental LEP mRNA expression was significantly and positively correlated with weight and adipocyte cell volume in baboons. Both mRNA and plasma levels of leptin were higher in females than in males, and both measures were heritable. The results of our genetic analysis show that there was a genotype-by-sex interaction in the levels of plasma leptin, but not in omental LEP mRNA. CONCLUSIONS: As in humans, baboon leptin mRNA and protein levels are expressed at a higher level in females than in males. We detected evidence that the plasma levels were affected by genes that are differentially expressed in males and females, while the omental mRNA levels were not. This finding suggests that the genes that differentially regulate plasma leptin levels between males and females may exert their effects on post-transcriptional processes. [ABSTRACT FROM AUTHOR]

Somatostatin receptors (SSTRs) have been extensively mapped in human tumors by means of autoradiography, reverse-transcriptase polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry (IHC). We analyzed the SSTR type 1-5 expression by means of RT-PCR and/or IHC in a series of 81 functioning and non-functioning gastroenteropancreatic (GEP) endocrine tumors and related normal tissues. Moreover, we compared the results with clinical, pathological and hormonal features. Forty-six cases (13 intestinal and 33 pancreatic) were studied for SSTR 1-5 expression using RT-PCR, IHC with antibodies to SSTR types 2, 3, 5 and ISH for SSTR2 mRNA. The vast majority of tumors expressed SSTR types 1, 2, 3 and 5, while SSTR4 was detected in a small minority. Due to the good correlation between RT-PCR and IHC data on SSTR types 2, 3, and 5, thirty-five additional GEP endocrine tumors were studied with IHC alone. Pancreatic insulinomas had an heterogeneous SSTR expression, while 100% of somatostatinomas expressed SSTR5 and 100% gastrinomas and glucagonomas expressed SSTR2. Pre-operative biopsy material showed an overlapping immunoreactivity with that of surgical specimens, suggesting that the SSTR status can be detected in the diagnostic work-up. It is concluded that SSTRs 1-5 are heterogeneously expressed in GEP endocrine tumors and that IHC is a reliable tool to detect SSTR types 2, 3 and 5 in surgical and biopsy specimens. [ABSTRACT FROM AUTHOR]

The multidrug resistance protein 1 (MRP1) belonging to the ATP-binding cassette (ABC) superfamily of transport proteins can confer resistance to multiple natural product drugs and methotrexate in human tumor cells. In addition, MRP1 is expressed in normal tissues acting as an efflux pump for glutathione, glucuronate, and sulfate conjugates and may thus influence the pharmacokinetic properties of many drugs. Using polymerase chain reaction–single-strand conformation polymorphism analysis, we screened 36 Caucasian volunteers for mutations in the coding exons of the MRP1 gene, including the adjacent intron sequences. Among several mutations found, two are expected to cause amino acid substitutions. One of these mutations (G671V) was of special interest because it is located near the first nucleotide binding domain. To determine whether this mutation caused a change in the MRP1 phenotype, a mutant MRP1 expression vector was constructed and transfected into SV40-transformed human embryonic kidney cells (HEKSV293T) and the transport properties of the mutant protein were examined. Transport of the MRP1 substrates leukotriene C[sub 4] , 17β-estradiol 17β-(d)-glucuronide, and estrone sulfate by membrane vesicles prepared from transiently transfected HEKSV293T cells was comparable to that of wild-type MRP1. [ABSTRACT FROM AUTHOR]

Recently (Granato, Lacey, Silva et al., 2000, astro-ph/0001308) we have combined our spectrophotometric galaxy evolution code which includes dust reprocessing (GRASIL, Silva et al., 1998) with semi-analytical galaxy formation models (GALFORM, Cole et al., 1999). One of the most characteristic features of the former is that the dust is divided in two main phases: molecular cloud complexes, where stars are assumed to be born, and the diffuse interstellar medium. As a consequence, stellar populations of different ages have different geometrical relationships with the two phases, which is essential in understanding several observed properties of galaxies, in particular those undergoing major episodes of star formation at any redshift. Indeed, our merged GRASIL+GAL-FORM model reproduces fairly well the SEDs of normal spirals and starbursts from the far-UV to the sub-mm and their internal extinction properties. In particular in the model the observed starburst attenuation law (Calzetti,1999) is accounted for as an effect of geometry of stars and dust, and has nothing to do with the optical properties of dust grains. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate whether the region of chromosome 11 (11q13) containing the genes UCP2 and UCP3 could be excluded for linkage with a variety of obesity-related phenotypes in humans. DESIGN: Exclusion mapping using a variance component approach in extended pedigrees. SUBJECTS: Four-hundred and fifty eight individuals (195 females, 263 males) distributed in 10 Mexican American families of probands randomly ascertained with respect to any disease state and who are participating in the San Antonio Family Heart Study. Ages range from 18 to 87 (mean age 35 y). MEASUREMENTS: Serum leptin levels, fat mass (FM), body mass index (BMI), and waist circumference. RESULTS: We were able to exclude the chromosomal region containing UCP2/UCP3 as having an effect on this set of obesity-related phenotypes at relative effect sizes of 10% or greater (P-values<0.05). CONCLUSIONS: These results suggest that variation in these genes is unlikely to have a substantial effect on the expression of obesity-related phenotypes in the Mexican American population. International Journal of Obesity (2000) 24, 1065–1068 [ABSTRACT FROM AUTHOR]

AQ4 (1,4-Bis-[[2-(dimethylamino-N-oxide)ethyl]amino]5,8-dihydroxyanthrace ne-9, 10-dione) is a prodrug designed to be excluded from cell nuclei until bioreduced in hypoxic cells to AQ4, a DNA intercalator and topoisomerase II poison. Thus, AQ4N is a highly selective bioreductive drug that is activated in, and is preferentially toxic to, hypoxic cells in tumours. Five murine tumours (MAC16, MAC26, NT, SCCVII and RIF-1) have been used to investigate the anti-tumour effects of AQ4N. In only one tumour (MAC16) was AQ4N shown to be active as a single agent. However, when combined with methods to increase the hypoxic tumour fraction in RIF-1 (by physical clamping) and MAC26 tumours (using hydralazine) there was a substantial enhancement in anti-tumour effect. Notably, RIF-1 tumours treated with AQ4N (250 mg kg(-1)) followed 15 min later by physically occluding the blood supply to the tumour for 90 min, resulted in a 13-fold increase in growth delay. When combined with radiation or chemotherapy, AQ4N substantially increased the effectiveness of these modalities in a range of in vivo model systems. AQ4N potentiates the action of radiation in both a drug and radiation dose-dependent manner. Further the enhancement observed is schedule-independent with AQ4N giving similar effects when given at any time within 16 h before or after the radiation treatment. In combination with chemotherapy it is shown that AQ4N potentiates the activity of cyclophosphamide, cisplatin and thiotepa. Both the chemotherapeutic drugs and AQ4N are given at doses which individually are close to their estimated maximum tolerated dose (data not included) which provides indirect evidence that in the combination chemotherapy experiments there is some tumour selectivity in the enhanced action of the drugs. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. The short-term efficacy, safety and tolerability of rosiglitazone were compared with placebo in patients with Type II (non-insulin-dependent) diabetes mellitus in a dose-ranging study.¶Methods. After a 2-week placebo run-in phase, 303 patients were randomly assigned to 8 weeks of treatment with twice-daily placebo or 2, 4 or 6 mg of rosiglitazone.¶Results. All rosiglitazone doses significantly reduced fasting plasma glucose compared with baseline. All rosiglitazone treatment groups showed significantly reduced peak postprandial glucose concentrations compared with baseline (p < 0.001) and with placebo (p < 0.0001) and reduced postprandial glucose excursion, without an increase in the area under the postprandial insulin concentration-time curve. Rosiglitazone at 4 and 6 mg twice daily prevented the increase in HbA1 c observed in the placebo group. C peptide and serum insulin concentrations were significantly reduced from baseline in all rosiglitazone treatment groups. In all rosiglitazone treatment groups, non-esterified fatty acids decreased significantly (p < 0.0001) and triglycerides did not change. Although total LDL and HDL cholesterol increased significantly in the rosiglitazone treatment groups, total cholesterol/HDL ratios did not change significantly. The proportion of patients with one or more adverse event was similar in all four treatment groups. No patient showed evidence of hepatotoxicity.¶Conclusion/interpretation. Rosiglitazone given twice daily significantly reduced fasting and postprandial glucose concentrations, C peptide, insulin and non-esterified fatty acids in Type II diabetic patients. The glucose-lowering effect of the 4-mg twice-daily dose of rosiglitazone was similar to that of 6-mg twice daily, suggesting that 4 mg twice daily should be the maximum clinical dose. [Diabetologia (2000) 43: 278–284] [ABSTRACT FROM AUTHOR]

Presents research which completed the genome sequence for the Mycobacterium tuberculosis strain H37Rv. Number of base pairs and genes; Very high guanine and cytosine content; How M. tuberculosis differs from other bacteria; Implications for new prophylactic and therapeutic interventions.; Pull-out section with the complete genome sequence of Mycobacterium tuberculosis.

In bacterial and mammalian cells, N-(phosphonoacetyl)- l-aspartate (PALA) suppresses growth by strongly inhibiting aspartate transcarbamoylase (ATCase; EC 2.1.3.2), a key enzyme of the pyrimidine biosynthetic pathway. At a concentration that would suppress growth in mammalian or bacterial cells, and that is nearly a million-fold greater than the inhibition constant ( K) for ATCase in carrot ( Daucus carota) seedling extracts, PALA does not suppress growth of carrot cells in suspension culture. To study this anomaly an assay based on the inhibition of wheat ( Triticum vulgare) ATCase ( K=2 nM) was developed. Using this assay it was found that PALA is detoxified relatively rapidly by low inocula of carrot cells. The detoxification product accumulates in the extracellular fluid although the enzyme(s) responsible is intracellular or in the cell wall. The PALA-detoxifying activity can be detected at all stages of the growth cycle in culture, but reaches a maximum early in the exponential phase of growth. Cells that were repeatedly subcultured into media initially containing 1 mM PALA had the same low level of ATCase activity as control cells; there was no evidence of the amplification of the gene for this enzyme, such as occurs in mammalian cells upon repeated exposure to the drug. [ABSTRACT FROM AUTHOR]

Examines the genetic similarities and differences between sublines of certain inbred strains of mice within Australia. Use of twelve different blood proteins in genetic comparison along with the morphometric analysis of a series of lower jaws; Detection of genetic differentiation between sublines in two cases; Evidence for a strain contamination within another stock.

The use of cadmium telluride is limited by the occurrence of twins in the material. Mechanical deformation experiments and studies of the growth interface suggest that these arise through growth accidents occurring on the liquid-solid inter-face rather than by mechanical deformation of the solidified ingot. The incidence of twinning is found to be higher in Czochralski-grownmaterial than that grown by other techniques and there is a consequent reduction in grain-size due to the formation of incoherent boundaries at twin intersections. From comparisons with other II-VI and III-V compounds it is concluded that the twinning is an intrinsic feature of the CdTe chemical bond structure and can only be totally elimina-ted by changing the ionicity of the material. Nevertheless, the twin density can be reduced by the use of low growth rates and the avoidance of interface perturbations. [ABSTRACT FROM AUTHOR]

We have previously shown that the doxorubicin-selected multidrug-resistant small-cell lung-cancer cell line H69AR is resistant to VP-16-induced single-strand DNA breaks as compared with its parental H69 cell line. Levels of immunoreactive topoisomerase II alpha are also reduced in H69AR cells. In the present study, we found that cleaved complex formation in the presence of VP-16 was decreased in H69AR cells as compared with H69 cells. In addition, the resistant cells contained lower levels of both topoisomerase II alpha and topoisomerase II beta protein and mRNA. However, these changes were not accompanied by a decrease in the P4-unknotting (strand-passing) activity of 0.67 M NaCl nuclear extracts of H69AR cells, nor was there any difference in VP-16 inhibition of unknotting activity in the H69 and H69AR nuclear extracts. These data suggest that reduced levels of topoisomerase II alpha and II beta may contribute to the resistance of H69AR cells to VP-16 and other drugs that target these isoenzymes. [ABSTRACT FROM AUTHOR]

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