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There is strong evidence that chemotherapy can induce tumor necrosis which can be exploited for the targeted delivery of immuno-oncology agents into the tumor microenvironment (TME). We hypothesized that docetaxel, a chemotherapeutic agent that induces necrosis, in combination with the bifunctional molecule NHS-IL-12 (M9241), which delivers recombinant IL-12 through specific targeting of necrotic regions in the tumor, would provide a significant antitumor benefit in the poorly inflamed murine tumor model, EMT6 (breast), and in the moderately immune-infiltrated tumor model, MC38 (colorectal). Docetaxel, as monotherapy or in combination with NHS-IL-12, promoted tumor necrosis, leading to the improved accumulation and retention of NHS-IL-12 in the TME. Significant antitumor activity and prolonged survival were observed in cohorts receiving docetaxel and NHS-IL-12 combination therapy in both the MC38 and EMT6 murine models. The therapeutic effects were associated with increased tumor infiltrating lymphocytes and were dependent on CD8+ T cells. Transcriptomics of the TME of mice receiving the combination therapy revealed the upregulation of genes involving crosstalk between innate and adaptive immunity factors, as well as the downregulation of signatures of myeloid cells. In addition, docetaxel and NHS-IL-12 combination therapy effectively controlled tumor growth of PD-L1 wild-type and PD-L1 knockout MC38 in vivo, implying this combination could be applied in immune checkpoint refractory tumors, and/or tumors regardless of PD-L1 status. The data presented herein provide the rationale for the design of clinical studies employing this combination or similar combinations of agents. [ABSTRACT FROM AUTHOR]

Dermal exposure to metal allergens can lead to irritant and allergic contact dermatitis (ACD). In this paper we present a mathematical model of the absorption of metal ions, hexavalent chromium and nickel, into the viable epidermis and compare the localised irritant and T-lymphocyte (T-cell) mediated immune responses. The model accounts for the spatial-temporal variation of skin health, extra and intracellular allergen concentrations, innate immune cells, T-cells, cytokine signalling and lymph node activity up to about 6 days after contact with these metals; repair processes associated with withdrawal of exposure to both metals is not considered in the current model, being assumed secondary during the initial phases of exposure. Simulations of the resulting system of PDEs are studied in one-dimension, i.e. across skin depth, and three-dimensional scenarios with the aim of comparing the responses to the two ions in the cases of first contact (no T-cells initially present) and second contact (T-cells initially present). The results show that on continuous contact, chromium ions elicit stronger skin inflammation, but for nickel, subsequent re-exposure stimulates stronger responses due to an accumulation of cytotoxic T-cell mediated responses which characterise ACD. Furthermore, the surface area of contact to these metals has little effect on the speed of response, whilst sensitivity is predicted to increase with the thickness of skin. The modelling approach is generic and should be applicable to describe contact dermatitis from a wide range of allergens. [ABSTRACT FROM AUTHOR]

The effect of macadamia nut shell biochar on nitrogen, potassium, phosphorus, magnesium, calcium and sodium concentrations in potting mix used to grow Eucalyptus nitens seedlings was investigated in a glasshouse experiment. The treatments combined two fertiliser rates (50 and 100% rate of the commercial mix commonly used in forestry nurseries) with eight biochar rates (0, 2, 5, 10, 20, 50, 80 and 100 t ha−1) arranged in a randomised complete block with three replicates of four sample plants. Nutrients were quantified in the potting mix and seedling leaves at four destructive harvests 135, 177, 219 and 269 days after planting. Biochar significantly increased nitrate-N, Colwell P, Colwell K and exchangeable Na and reduced ammonium-N, Mg and Ca concentrations in the potting mix. Seedling leaf concentrations of P, K and Na were increased by biochar application, while N remained dependent on fertiliser rate only. Mg and Ca leaf concentrations decreased in response to increasing biochar rates. Elevated nitrate-N and decreased ammonium-N concentrations suggest that biochar might have increased nitrification in the potting mix. We presumed that biochar mediated processes that reduced uptake of P and K when high doses of biochar were combined with full fertilisation. Changes in potting mix K, Na, Mg and Ca were consistent with selective adsorption of ions to biochar surfaces. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: FTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS. Methods: A systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis. Results: A total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10). This translated into an approximately 3.3 kg/m increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations. Conclusions/interpretation: The effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS. [ABSTRACT FROM AUTHOR]

Molecular profiling has allowed a more precise classification of human cancers. With respect to breast cancer, this approach has been used to identify five subtypes; luminal A, luminal B, HER2-enriched, basal-like and claudin-low. In addition, this approach can be used to determine the type of tumor represented by particular cell lines or transgenic animal models. Therefore, this approach was utilized to classify the mammary tumors that develop in MTB-IGFIR transgenic mice. It was determined that the primary mammary tumors, which develop due to elevated expression of the type I insulin-like growth factor receptor (IGF-IR) in mammary epithelial cells, most closely resemble murine tumors with basal-like or mixed gene expression profiles and with human basal-like breast cancers. Downregulation of IGF-IR transgene in MTB-IGFIR tumor-bearing mice leads to the regression of most of the tumors, followed by tumor reappearance in some of the mice. These tumors that reappear following IGF-IR transgene downregulation do not express the IGF-IR transgene and cluster with murine mammary tumors that express a mesenchymal gene expression profile and with human claudin-low breast cancers. Therefore, IGF-IR overexpression in murine mammary epithelial cells induces mammary tumors with primarily basal-like characteristics, whereas tumors that develop following IGF-IR downregulation express a gene signature that most closely resembles human claudin-low breast tumors. [ABSTRACT FROM AUTHOR]

Objective: To evaluate and compare MRI-based ovarian morphology in groups of women with polycystic ovary syndrome (PCOS) and controls.Methods: All PCOS cases (n = 44) had oligo-amenorrhoea and hyperandrogenism irrespective of ovarian morphology, and fulfilled NIH/Rotterdam diagnostic criteria for PCOS. All control women (n = 40) had normal menses and normoandrogenaemia. All subjects were of white British/Irish origin and pre-menopausal. Group comparisons were based on independent-sample t tests. Polycystic ovarian morphology was defined by at least 12 follicles 2-9 mm in diameter and/or an ovarian volume greater than 10 cm(3).Results: Ovarian morphology differed significantly in PCOS cases and controls (follicle number geometric mean [SD range] 18.6 [9.9, 35.0] vs 6.6 [3.1, 14.2], unadjusted P = 1.3 x 10(-16); calculated ovarian volume 8.8 cm(3) [5.0, 15.5] vs 5.1 cm(3) [2.5, 10.3], unadjusted P = 3.0 x 10(-7); peripheral follicle location in 55% vs 18% of ovaries, P = 7.9 x 10(-6); visible central ovarian stroma in 61% vs 24% of ovaries, P = 2.3 x 10(-5)). Follicle number and calculated ovarian volume were not concordant with clinical/biochemical assignment of PCOS/control status in 36 (23%) and 52 (34%) of ovaries, respectively.Conclusion: Ovarian morphology overlaps in PCOS cases and controls, emphasising the importance of considering clinical/biochemical presentation together with imaging ovarian morphology in the diagnosis of PCOS. [ABSTRACT FROM AUTHOR]

Background:Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women and typically presents during adolescence. The clinical and biochemical presentation is heterogeneous, but elevated serum concentrations of androgens are the most consistent biochemical abnormality and may be considered to be the hallmark of the syndrome. Many women with PCOS also have insulin resistance and hyperinsulinaemia, which may contribute to the clinical and endocrine abnormalities. The aetiology of PCOS is not clear but studies in the Rhesus monkey suggest that exposure to excess androgen during intrauterine life results in many of the features of human PCOS, including ovarian dysfunction, abnormal LH secretion and insulin resistance.Objective:To review the studies from the literature, including those of the author, regarding aetiology, presentation and management of PCOS in adolescents.Results and conclusions:We have proposed that PCOS in adolescents arises as a result of a genetically determined disorder of ovarian function that results in hyper-secretion of androgens, possibly during fetal life and also during physiological activation of the hypothalamic–pituitary–ovarian in infancy and at the onset of puberty. There is plentiful evidence for a genetic basis for PCOS (it appears to be a complex endocrine disorder resulting from the effects of a several genes), but environmental factors, notably nutrition, influence the clinical and biochemical phenotype. Obesity unmasks or amplifies symptoms, endocrine and metabolic abnormalities. The increasing incidence of childhood obesity has resulted in an alarming Increase not only in distressing symptoms but also impaired glucose tolerance and even diabetes among adolescent girls with PCOS. The search for PCOS genes in this condition, that is not only heterogeneous but also presents only in women of reproductive age, is not straightforward and has produced few convincing candidates so far. In due course, however, identification of the major susceptibility loci is likely to provide key insight into the aetiology of the syndrome and improve diagnosis and management.International Journal of Obesity (2008) 32, 1035–1041; doi:10.1038/ijo.2008.61; published online 6 May 2008 [ABSTRACT FROM AUTHOR]

Variants in the fat-mass and obesity-associated gene ( FTO) influence susceptibility to type 2 diabetes via an effect on adiposity/obesity. Given the important role of obesity in the aetiology of both polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus, our aim was to establish whether FTO variants are also implicated in PCOS susceptibility. We performed a genetic association study of FTO variant rs9939609 using case–control analyses, conducted in 463 PCOS patients (geometric mean BMI 27.5 kg/m2) and 1,336 female controls (geometric mean BMI 25.3 kg/m2) of UK British/Irish origin. We also sought evidence for associations between FTO variation and circulating testosterone levels in 324 UK PCOS patients and 1,000 women from the Northern Finland Birth Cohort of 1966. Outcome measures included FTO rs9939609 genotype frequencies by participant group and androgen measures (testosterone, free androgen index) by genotype. There was a significant association between FTO genotype and PCOS status in the UK case–control analysis, which was attenuated by adjustment for BMI (Cochran–Armitage test, odds ratio [per minor allele copy] 1.30 [95% CI 1.12, 1.51], p = 7.2 × 10−4 [unadjusted], p = 2.9 × 10−3 [adjusted]). This association was most evident in obese PCOS patients (PCOS patients below median BMI vs UK controls, p = 0.11; above median BMI vs controls, p = 2.9 × 10−4). No relationship between FTO genotype and androgen levels was seen. We provide the first evidence that variants that predispose to common obesity also result in altered susceptibility to PCOS, confirming the mechanistic link between these conditions. The predominant effect of FTO variants on PCOS susceptibility is probably mediated through adiposity. [ABSTRACT FROM AUTHOR]

The P12A variant in the PPARG gene and the E23K polymorphism in KCNJ11 are both known to influence individual predisposition to type 2 diabetes. If the effect of these variants on insulin secretion and action were to extend to an influence on early growth (which is largely mediated by insulin), it would offer an explanation for observed associations between low birthweight and subsequent diabetes. Since previous studies of the effects of these variants on early growth have been limited and conflicting, we examined these associations in a large, well-characterised birth cohort. The P12A and E23K variants were genotyped in (respectively) 5,652 and 5,632 individuals from the Northern Finland Birth Cohort of 1966 and we sought associations with early growth phenotypes. Neither variant was associated with birthweight (P12A, p = 0.42; E23K, p = 0.44, additive models) or other measures of early growth. Although a previous report had suggested that the P12A effect on adult insulin sensitivity was restricted to small babies, we were unable to reproduce this finding ( p = 0.40), nor did we confirm a previous report of an association with gestational age ( p = 0.23). Despite a larger sample size than previous studies, we were unable to detect any effect of these variants on early growth. These findings do not support the notion that there are shared genetic determinants of low birthweight and adult diabetes. [ABSTRACT FROM AUTHOR]

Common variants of the gene encoding transcription factor 7-like 2 ( TCF7L2) have a powerful effect on individual risk of type 2 diabetes (per allele odds ratio ∼1.35). Polycystic ovary syndrome (PCOS) and type 2 diabetes are familial conditions sharing common features. Based on this, the aim of the present study was to establish whether variation in TCF7L2 also influences the development of PCOS. We conducted a genetic association study of variants of TCF7L2 (rs7903146 and rs12255372) using both case–control and quantitative trait approaches. Case–control analyses were conducted in (1) 369 PCOS cases and 2574 controls of UK British/Irish origin, and (2) 540 women with PCOS symptoms and 1083 controls from the Northern Finland Birth Cohort of 1966. Quantitative trait analyses (androgen levels) were also performed (1249 individuals). There was no association between rs7903146 and PCOS in the UK case–control study (Cochran–Armitage test, p = 0.51); nor with symptomatic status in the Finnish cohort ( p = 0.36). In addition, there were no relationships between the TCF7L2 single nucleotide polymorphism rs7903146 and androgen levels (UK cases, p = 0.99; Finnish controls, p = 0.57; Finnish symptomatic cases, p = 0.80). Results at rs12255372 were similar, reflecting strong linkage disequilibrium with rs7903146. Our study was powered to detect an effect on PCOS susceptibility similar to that previously reported for these variants on type 2 diabetes. Failure to detect any evident association with PCOS provides the strongest evidence yet that the genetic architecture of these related conditions is qualitatively distinct. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Although the variable number tandem repeat (VNTR) minisatellite 5' to the insulin gene is among the most studied polymorphisms in diabetes, the relationships between VNTR variation, diabetes-related traits and predisposition to type 2 diabetes remain unclear. Since inadequate sample size is likely to have been an obstacle to reliable inference, we examined the relationship between VNTR variation and a range of diabetes-related traits in a cohort of 5,753 Finnish adults. Materials and methods: VNTR genotypes were derived, by typing at the -23HphI variant site, for 5,646 individuals from the Northern Finland Birth Cohort 1966. Associations were sought between these genotypes and a range of anthropometric (BMI, WHR), physiological (blood pressure) and biochemical (fasting glucose, insulin, lipids, indices of insulin sensitivity and beta cell function) measures obtained at clinical examination at 31 years. Results: We found no evidence that VNTR genotype was significantly associated with measures of insulin secretion, insulin sensitivity, glycaemia, adiposity or blood pressure. Conclusions/interpretation: Despite evidence from several relatively small studies suggesting that INS-VNTR genotypes are associated with predisposition to type 2 diabetes, reduced beta cell function and measures of adiposity, the present study failed to detect any association with a range of diabetes-related traits. Taken with other recent studies in large population-based cohorts, these data suggest that previous studies have, at the very least, over- estimated the influence of the INS-VNTR on type 2 diabetes-related traits. The effects of INS-VNTR variation on insulin transcription observed in vitro appear not to translate into detectable differences in basal insulin secretion in humans. [ABSTRACT FROM AUTHOR]

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Numerical Weather Prediction (NWP)-models require accurate simulation of land surface fluxes. Land surface models increasingly use complex descriptions of the physical mechanisms governing land surface processes. Consequently, these models may require large numbers of soil and land surface parameters controlling the vertical fluxes. Uncertainty in land surface parameterisation and the heterogeneous nature of landscape hydrological controls may lead to considerable uncertainty in predicted land surface fluxes and state variables such as soil moisture. In this paper, the predictive uncertainty associated with possible model parameterisations, and the role of calibration data, are reviewed. It is noted that spatial variability may lead to significant uncertainty when represented by one-dimensional models. As heterogeneity is an essential property of the land surface, surface parameterisation needs to adequately describe this heterogeneity. This paper discusses the use of remotely sensed thermal imagery with surface energy budget models for prediction of land surface fluxes. Particular emphasis is given to the role of remote sensing in assessing spatial variability in land surface processes, obtaining landscape fluxes and predicting soil moisture status. Recent studies have shown that remote sensing in combination with land surface modelling has significant potential in improving the estimation of fluxes and derived variables such as surface wetness. Remotely derived fluxes and surface wetness information may be assimilated in NWP-models providing better land surface boundary conditions as well as contributing to improved land surface models. This paper concludes with a brief discussion of recent work on the assimilation of satellite derived heating rates in regional atmospheric mesoscale models. [ABSTRACT FROM AUTHOR]

Plasma growth hormone (GH) concentrations in Parkinsonian patients following 3 months optimum therapy with bromocriptine showed no significant change from pretreatment values, whilst plasma prolactin concentrations were uniformly suppressed. Pretreatment GH and prolactin levels were unrelated to clinical disability, and no correlation between hormonal changes and therapeutic response was found. These results suggest the presence of different dopaminergic receptor mechanisms for GH and prolactin release as well as between the extrapyramidal and neuroendocrine systems. [ABSTRACT FROM AUTHOR]

The control of ovulation in mammalian species appears to be a highly robust process. The primary mechanism is believed to be competition amongst a group of developing follicles, mediated by a hormonal feedback loop involving in the first instance the pituitary. Successful follicles reach maturity and ovulate, the remainder atrophy and die. A model of this control process has been derived by Lacker and his group. Based on simple qualitative assumptions about the hormonal feedback loop, this is able to reflect many of the basic physiological features of ovulation in mammals. However, a fundamental hypothesis of Lacker’s work is that all follicles are identical and respond to hormonal signals in precisely the same way. Not only is this improbable, but it also leads to several aspects of the model which are qualitatively unrealistic, most notable of these is its inability to accurately model the condition known as Polycystic Ovary Syndrome. This common malfunction of the ovulatory control mechanism accounts for up to three-quarters of cases of anovulatory infertility in humans and its understanding is therefore of considerable medical significance. In this paper we extend the analysis of Lacker’s model to the case of non-identical follicles; this allows us to obtain behaviour much closer to that observed in PCOS patients and to draw some tentative conclusions about the mechanisms underlying this condition. [ABSTRACT FROM AUTHOR]