ResearchPad - endocrine-physiology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation]]> https://www.researchpad.co/article/elastic_article_14711 Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to other frequently used cell lines such as HEK293, A549, Hela and DLD1. Ablation of EGFR by CRISPR/Cas9 significantly restrained tumor cell growth and activated the MAPK (pERK1/2) pathway. The VEGFR and PDGFR inhibitor, sunitinib, attenuated the expression of MAPK (pERK1/2) and pAKT induced by EGFR loss and further inhibited EGFR-/- cell proliferation. We showed that loss of EGFR eventually leads to resistance to SAHA and cisplatin. Furthermore, EGFR loss induced G2/M phase arrest and resulted in an increased resistance to TNF-related apoptosis-inducing ligand (TRAIL) in renal cell carcinoma. Thus, ablation of overexpressed EGFR by CRISPR/Cas9 alone or in combination with sunitinib may be a new treatment option for renal cell carcinoma.

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<![CDATA[Association between the rs1544410 polymorphism in the vitamin D receptor (VDR) gene and insulin secretion after gestational diabetes mellitus]]> https://www.researchpad.co/article/elastic_article_14643 Genetic variants involved in vitamin D metabolism have been associated with diabetes and related syndromes/diseases. We wanted to investigate possible associations of polymorphisms in genes involved in vitamin D metabolism with indices of insulin resistance and insulin secretion, and also with development of diabetes after gestational diabetes mellitus (GDM).Materials and methodsWe have studied 376 women with previous GDM. Eight single nucleotide polymorphisms (SNPs) in the genes for vitamin D receptor (VDR) [rs731236, rs7975232, rs10735810, and rs1544410], vitamin D binding protein (DBP) [rs7041 and rs4588], and cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [rs10877012 and rs4646536] were genotyped by TaqMan Allelic Discrimination Assay using the Quantstudio 7 Flex system. A 75-g oral glucose tolerance test (OGTT) was performed 1–2 years postpartum. The homeostasis model assessment of insulin resistance (HOMA-IR) and the disposition index [(insulinogenic index: I30/G30)/HOMA-IR] were used to calculate insulin resistance and insulin secretion, respectively. Serum samples for determination of 25(OH)D3 were collected at the time of the OGTT. Manifestation of diabetes was followed up to five years postpartum.ResultsAfter adjustment for BMI, age, and ethnicity, the A-allele of the VDR rs1544410 polymorphism was found to be associated with increased disposition index (difference per allele = 3.56, 95% CI: 0.4567–6.674; p = 0.03). The A-allele of the DBP rs7041 polymorphism was found to be associated with 25(OH)D3 levels (difference [in nmol/L] per allele = −5.478, 95% CI: -8.315 to −2.641; p = 0.0002), as was the T-allele of the DBP rs4588 polymorphism (OR = −6.319, 95% CI: −9.466 to −3.171; p = 0.0001). None of the SNPs were significantly associated with HOMA-IR or postpartum diabetes.ConclusionsThis study provides evidence that the rs1544410 polymorphism of the VDR gene may be associated with increased insulin secretion in women after pregnancy complicated by GDM. Further studies in other populations are needed to confirm the results. ]]> <![CDATA[When two are better than one: Modeling the mechanisms of antibody mixtures]]> https://www.researchpad.co/article/elastic_article_14641 With the rise of new antibody combinations in therapeutic regimens, it is important to understand how antibodies work together as well as individually. Here, we investigate the specific case of monoclonal antibodies targeting a cancer-causing receptor or the influenza virus and develop a statistical mechanical framework that predicts the effectiveness of a mixture of antibodies. The power of this model lies in its ability to make a large number of predictions based on a limited amount of data. For example, once 10 antibodies have been individually characterized and their epitopes have been mapped, our model can predict how any of the 210 = 1024 combinations will behave. This predictive power can aid therapeutic efforts by assessing which combinations of antibodies will elicit the most effective response.

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<![CDATA[Corticosterone and testosterone treatment influence expression of gene pathways linked to meiotic segregation in preovulatory follicles of the domestic hen]]> https://www.researchpad.co/article/elastic_article_14547 Decades of work indicate that female birds can control their offspring sex ratios in response to environmental and social cues. In laying hens, hormones administered immediately prior to sex chromosome segregation can exert sex ratio skews, indicating that these hormones may act directly on the germinal disc to influence which sex chromosome is retained in the oocyte and which is discarded into an unfertilizable polar body. We aimed to uncover the gene pathways involved in this process by testing whether treatments with testosterone or corticosterone that were previously shown to influence sex ratios elicit changes in the expression of genes and/or gene pathways involved in the process of meiotic segregation. We injected laying hens with testosterone, corticosterone, or control oil 5h prior to ovulation and collected germinal discs from the F1 preovulatory follicle in each hen 1.5h after injection. We used RNA-sequencing (RNA-seq) followed by DESeq2 and gene set enrichment analyses to identify genes and gene pathways that were differentially expressed between germinal discs of control and hormone-treated hens. Corticosterone treatment triggered downregulation of 13 individual genes, as well as enrichment of gene sets related to meiotic spindle organization and chromosome segregation, and additional gene sets that function in ion transport. Testosterone treatment triggered upregulation of one gene, and enrichment of one gene set that functions in nuclear chromosome segregation. This work indicates that corticosterone can be a potent regulator of meiotic processes and provides potential gene targets on which corticosterone and/or testosterone may act to influence offspring sex ratios in birds.

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<![CDATA[Prevalence of endosalpingiosis and other benign gynecologic lesions]]> https://www.researchpad.co/article/elastic_article_14492 Endosalpingiosis, traditionally regarded as an incidental pathological finding, was recently reported to have an association with gynecologic malignancies. To determine the prevalence of endosalpingiosis, we evaluated all benign appearing adnexal lesions using the Sectioning and Extensively Examining-Fimbria (SEE-Fim) protocol, and queried the pathology database for the presence of endosalpingiosis, gynecologic malignancy, endometriosis, Walthard nests, and paratubal cysts. Using the SEE-Fim protocol, the prevalence of endosalpingiosis, endometriosis, Walthard nests, and paratubal cysts were 22%, 45%, 33%, and 42% respectively, substantially higher than previously reported. All lesions were observed to increase with age except endometriosis which increased until menopause then decreased dramatically. Among specimens including ovarian tissue, the prevalence of implantation of at least one lesion type was ubiquitous in patients age 51 and older (93%). The clinical significance of endosalpingiosis should be a continued area of research with larger trials assessing prevalence, factors affecting incidence, and association with malignancy. Our findings contribute to elucidating the origin of ectopic lesions and gynecologic disease risk.

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<![CDATA[Effects of amotosalen treatment on human platelet lysate bioactivity: A proof-of-concept study]]> https://www.researchpad.co/article/Ne8e94533-b9bd-43e3-83be-324d5eb7ad87

Background

Clinical application of mesenchymal stromal cells (MSCs) usually requires an in vitro expansion step to reach clinically relevant numbers. In vitro cell expansion necessitates supplementation of basal mammalian cell culture medium with growth factors. To avoid using supplements containing animal substances, human platelet lysates (hPL) produced from expired and pathogen inactivated platelet concentrates can be used in place of fetal bovine serum. However, globally, most transfusion units are currently not pathogen inactivated. As blood banks are the sole source of platelet concentrates for hPL production, it is important to ensure product safety and standardized production methods. In this proof-of-concept study we assessed the feasibility of producing hPL from expired platelet concentrates with pathogen inactivation applied after platelet lysis by evaluating the retention of growth factors, cytokines, and the ability to support MSC proliferation and tri-lineage differentiation.

Methodology/Principal findings

Bone marrow-derived MSCs (BM-MSCs) were expanded and differentiated using hPL derived from pathogen inactivated platelet lysates (hPL-PIPL), with pathogen inactivation by amotosalen/ultraviolet A treatment applied after lysis of expired platelets. Results were compared to those using hPL produced from conventional expired pathogen inactivated platelet concentrates (hPL-PIPC), with pathogen inactivation applied after blood donation. hPL-PIPL treatment had lower concentrations of soluble growth factors and cytokines than hPL-PIPC treatment. When used as supplementation in cell culture, BM-MSCs proliferated at a reduced rate, but more consistently, in hPL-PIPL than in hPL-PIPC. The ability to support tri-lineage differentiation was comparable between lysates.

Conclusion/Significance

These results suggest that functional hPL can be produced from expired and untreated platelet lysates by applying pathogen inactivation after platelet lysis. When carried out post-expiration, pathogen inactivation may provide a valuable solution for further standardizing global hPL production methods, increasing the pool of starting material, and meeting future demand for animal-free supplements in human cell culturing.

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<![CDATA[Mystery or method? Evaluating claims of increased energy expenditure during a ketogenic diet]]> https://www.researchpad.co/article/N1fb27919-9738-4fc6-9f1b-08c7be150010 ]]> <![CDATA[Heterochrony of puberty in the European badger (Meles meles) can be explained by growth rate and group-size: Evidence for two endocrinological phenotypes]]> https://www.researchpad.co/article/5c897769d5eed0c4847d2c1b

Puberty is a key stage in mammalian ontogeny, involving endocrinological, physiological and behavioural changes, moderated by intrinsic and extrinsic factors. Thus, not all individuals within one population achieve sexual maturity simultaneously. Here, using the European badger (Meles meles) as a model, we describe male testosterone and female oestrone profiles (using Enzyme-immunoassays) from first capture (3 months, post-weaning) until 28 months (attaining sexual maturity and final body size), along with metrics of somatic growth, scent gland development and maturation of external reproductive organs as well as intra-specific competition. In both sexes, endocrinological puberty commenced at ca. 11 months. Thereafter, cub hormone levels followed adult seasonal hormone patterns but at lower levels, with the majority of cubs reaching sexual maturity during their second mating season (22–28 months). Interestingly, there was evidence for two endocrinological phenotypes among male cubs (less evident in females), with early developers reaching sexual maturity at 11 months (first mating season) and late developers reaching sexual maturity at 22–26 months (second mating season). Early developers also attained a greater proportion of their ultimate adult size by 11 months, exhibiting faster growth rates than late developers (despite having similar adult size). Male cubs born into larger social groups tended to follow the late developer phenotype. Our results support the hypothesis that a minimum body size is required to reach sexual maturity, which may be achieved at different ages, even within a single population, where early maturity can confer individual fitness advantages and enhance population growth rate.

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<![CDATA[Psychological factors and premenstrual syndrome: A Spanish case-control study]]> https://www.researchpad.co/article/5c89777bd5eed0c4847d2df4

Objective

To assess whether the psychological variables perceived stress, neuroticism and coping strategies, are associated with Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Syndrome (PMDD).

Design

Case-control study with incident cases using the Spanish public healthcare system.

Setting

3 major public hospitals and one family counseling and planning center.

Population

Women consulting for troubles related to menstruation and for other motives such as screening for uterine cancer, contraception counselling or desire for pregnancy.

Methods

Logistic regression.

Main outcome measures

Odds of PMS and PMDD.

Results

285 PMS and 285 age-matched controls, as well as 88 PMDD cases and 176 controls participated in the study. Medium and high levels of perceived stress were associated with an increase in the odds of PMS (Odds Ratio (OR) = 2.49; 95%CI: 1.41–4.39 and OR = 4.90; 95%CI: 2.70–8.89, respectively). For PMDD the results were: OR = 2.61; 95%CI: 1.35–5.05 and OR = 5.79; 95%CI: 2.63–12.76, respectively.

Subjects with medium and high levels of neuroticism were also at higher odds of suffering from PMS (OR = 2.53; 95%CI: 1.06–6.06 and OR = 8.05; 95%CI: 3.07–2.12, respectively). For PMDD, the results were OR = 3.70; 95%CI: 1.27–10.77 and 5.73: 95%CI: 1.96–16.77, respectively.

High levels in the large majority of coping strategies were also associated with increased odds of PMS and PMDD.

Conclusions

Psychological factors including perceived stress, neuroticism and coping strategies are strongly related to PMS/PMDD. This association is unlikely to be due to confounding or misclassification bias. A reverse causation process cannot be ruled out although its likelihood is remote.

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<![CDATA[Comparison of triglyceride glucose index, and related parameters to predict insulin resistance in Korean adults: An analysis of the 2007-2010 Korean National Health and Nutrition Examination Survey]]> https://www.researchpad.co/article/5c990272d5eed0c484b97e62

The triglyceride glucose (TyG) index, a product of triglyceride and fasting glucose, is a reliable marker for insulin resistance (IR). Obesity is also known to be closely related with IR. Recently, the efficiency of TyG-related markers that combine obesity markers with TyG index has been studied; however, earlier studies were limited in number and the results were inconsistent. Therefore, in this study, we investigated the efficiency of several combinations of TyG index and obesity indices, namely, body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR), in reflecting IR. Data were obtained from the Korean National Health and Nutrition Examination Survey from 2007–2010. A total of 11,149 subjects (4,777 men and 6,372 women) were included. IR was defined as the homeostasis model assessment for IR (HOMA-IR) of above the 75th percentile for each gender. Logistic regression analysis was performed after adjusting for confounding factors, to compare and identify the associations of the 4 parameters (TyG index, TyG-BMI, TyG-WC, and TyG-WHtR) with IR. For each parameter, odds ratios (OR) and 95% confidence intervals (CIs) of quartiles 2–4 were calculated and compared with quartile 1 as a reference. A receiver operating characteristic (ROC) curve analysis was conducted to evaluate the ability of each parameter to predict IR. The adjusted ORs of quartile 4 in comparison with quartile 1 (95% CIs) for IR were 7.60 (6.52–8.87) for TyG index, 12.82 (10.89–15.10) for TyG-BMI, 16.29 (13.70–19.38) for TyG-WC, and 14.86 (12.53–17.62) for TyG-WHtR. The areas under the ROC curve for each parameter were 0.690 for TyG index, 0.748 for TyG-BMI, 0.731 for TyG-WC, and 0.733 for TyG-WHtR. In conclusion, TyG-BMI was found to be superior to other parameters for IR prediction. We propose TyG-BMI as an alternative marker for assessing IR in clinical settings.

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<![CDATA[Genome-wide DNA methylation analysis of pituitaries during the initiation of puberty in gilts]]> https://www.researchpad.co/article/5c8accc9d5eed0c48498ffd8

It has been widely recognized that the early or delayed puberty appears to display harmful effects on adult health outcomes. During the timing of puberty, pituitaries responds to the hypothalamus and then introduce the following response of ovaries in hypothalamic-pituitary-gonadal axis. DNA methylation has been recently suggested to regulate the onset of puberty in female mammals. However, to date, the changes of DNA methylation in pituitaries have not been investigated during pubertal transition. In this study, using gilts as the pubertal model, the genome-scale DNA methylation of pituitaries was profiled and compared across Pre-, In- and Post-puberty by using the reduced representation bisulfite sequencing. We found that average methylation levels of each genomic feature in Post- were lower than Pre- and In-pubertal stage in CpG context, but they were higher in In- than that in Pre- and Post-pubertal stage in CpH (where H = A, T, or C) context. The methylation patterns of CpHs were more dynamic than that of CpGs at the location of high CpG content, low CpG content promoter genes, and differently genomic CGIs. Furthermore, the differently genomic CGIs were likely to show in a similar manner in CpG context but display in a stage-specific manner in the CpH context across the Pre-, In- and Post-pubertal stage. Among these pubertal stages, 5 kb upstream regions of the transcription start sites were protected from both CpG and CpH methylation changes. 12.65% of detected CpGs were identified as the differentially methylated CpGs, regarding 4301 genes which were involved in the fundamental functions of pituitaries. 0.35% of detected CpHs were identified as differentially methylated CpHs, regarding 3691 genes which were involved in the biological functions of releasing gonadotropin hormones. These observations and analyses would provide valuable insights into epigenetic mechanism of the initiation of puberty in pituitary level.

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<![CDATA[Indirect treatment comparisons including network meta-analysis: Lenvatinib plus everolimus for the second-line treatment of advanced/metastatic renal cell carcinoma]]> https://www.researchpad.co/article/5c8823dbd5eed0c484639163

Background

In the absence of clinical trials providing direct efficacy results, this study compares different methods of indirect treatment comparison (ITC), and their respective impacts on efficacy estimates for lenvatinib (LEN) plus everolimus (EVE) combination therapy compared to other second-line treatments for advanced/metastatic renal cell carcinoma (a/mRCC).

Methods

Using EVE alone as the common comparator, the Bucher method for ITC compared LEN + EVE with cabozantinib (CAB), nivolumab (NIV), placebo (PBO) and axitinib (AXI). Hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) estimated the impact of applying three versions of the LEN+EVE trial data in separate ITCs. Last, to overcome exchangeability bias and potential violations to the proportional hazards assumption, a network meta-analysis using fractional polynomials was performed.

Results

Bucher ITCs demonstrated LEN + EVE superiority over EVE for PFS, indirect superiority to NIV, AXI, and PBO, and no difference to CAB. For OS, LEN + EVE was superior to EVE and indirectly superior to PBO, applying original HOPE 205 data. Using European Medicines Agency data, LEN + EVE was directly superior to EVE for OS. Fractional polynomial HRs for PFS and OS substantially overlapped with Bucher estimates, demonstrating LEN+EVE superiority over EVE, alone, NIV, and CAB. However, there were no statistically significant results as the credible intervals for HR crossed 1.0.

Conclusions

Comparing three Bucher ITCs, LEN + EVE demonstrated superior PFS when indirectly compared to NIV, AXI, and PBO, and mixed results for OS. While fractional polynomial modelling for PFS and OS failed to find statistically significant differences in LEN + EVE efficacy, the overall HR trends were comparable.

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<![CDATA[Brief communication: β-cell function influences dopamine receptor availability]]> https://www.researchpad.co/article/5c8c1952d5eed0c484b4d3f2

We aim to identify physiologic regulators of dopamine (DA) signaling in obesity but previously did not find a compelling relationship with insulin sensitivity measured by oral-minimal model (OMM) and DA subtype 2 and 3 receptor (D2/3R) binding potential (BPND). Reduced disposition index (DI), a β-cell function metric that can also be calculated by OMM, was shown to predict a negative reward behavior that occurs in states of lower endogenous DA. We hypothesized that reduced DI would occur with higher D2/3R BPND, reflecting lower endogenous DA. Participants completed PET scanning, with a displaceable radioligand to measure D2/3R BPND, and a 5-hour oral glucose tolerance test to measure DI by OMM. We studied 26 age-similar females without (n = 8) and with obesity (n = 18) (22 vs 39 kg/m2). Reduced DI predicted increased striatal D2/3R BPND independent of BMI. By accounting for β-cell function, we were able to determine that the state of insulin and glucose metabolism is pertinent to striatal D2/3R BPND in obesity.

Clinical Trial Registration Number: NCT00802204

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<![CDATA[Retraction: A Functional Nuclear Epidermal Growth Factor Receptor, Src and Stat3 Heteromeric Complex in Pancreatic Cancer Cells]]> https://www.researchpad.co/article/5c76fe1cd5eed0c484e5b51c ]]> <![CDATA[Lens differentiation is controlled by the balance between PDGF and FGF signaling]]> https://www.researchpad.co/article/5c61e8e2d5eed0c48496f303

How multiple receptor tyrosine kinases coordinate cell fate determination is yet to be elucidated. We show here that the receptor for platelet-derived growth factor (PDGF) signaling recruits the p85 subunit of Phosphoinositide 3-kinase (PI3K) to regulate mammalian lens development. Activation of PI3K signaling not only prevents B-cell lymphoma 2 (BCL2)-Associated X (Bax)- and BCL2 Antagonist/Killer (Bak)-mediated apoptosis but also promotes Notch signaling to prevent premature cell differentiation. Reducing PI3K activity destabilizes the Notch intracellular domain, while the constitutive activation of Notch reverses the PI3K deficiency phenotype. In contrast, fibroblast growth factor receptors (FGFRs) recruit Fibroblast Growth Factor Receptor Substrate 2 (Frs2) and Rous sarcoma oncogene (Src) Homology Phosphatase 2 (Shp2) to activate Mitogen-Activated Protein Kinase (MAPK) signaling, which induces the Notch ligand Jagged 1 (Jag1) and promotes cell differentiation. Inactivation of Shp2 restored the proper timing of differentiation in the p85 mutant lens, demonstrating the antagonistic interaction between FGF-induced MAPK and PDGF-induced PI3K signaling. By selective activation of PI3K and MAPK, PDGF and FGF cooperate with and oppose each other to balance progenitor cell maintenance and differentiation.

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<![CDATA[Identifying developmental trajectories of worldwide road traffic accident death rates using a latent growth mixture modeling approach]]> https://www.researchpad.co/article/5c76fe61d5eed0c484e5b9a7

Road Traffic Accidents (RTA) are a major worldwide public health problem. The aim of this study was to use the growth mixture model for clustering countries on the basis of the mortality rate patterns of RTAs from 2007 to 2013. We obtained the data on RTA death rates from World Health Organization reports and Human Development Index (HDI) of United Nations Development Programme reports for the years 2007, 2010 and 2013. Simple Latent Growth Models (LGM) in 181 countries were applied to estimate overall RTA mortality rate growth trajectories and the latent growth mixture modeling utilized to cluster them. According to non-linear LGM, the overall mortality rate of RTAs showed a decrease from 2007 to 2010 followed by an increase from 2010 to 2013. The HDI covariate had a significant negative and positive effect on intercept and slope of the LGM, respectively. The extracted mixture model appeared to have seven classes with different trends in RTA mortality rates. The worldwide countries were clustered into seven classes. Further studies on each of the seven classes are suggested to provide recommendations for reducing the mortality rate of the RTAs. Additionally, increasing HDI in some countries could have a significant effect on reducing the RTA death rates.

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<![CDATA[Consistency of compact and extended models of glucose-insulin homeostasis: The role of variable pancreatic reserve]]> https://www.researchpad.co/article/5c7067acd5eed0c4847c74a3

Published compact and extended models of the glucose-insulin physiologic control system are compared, in order to understand why a specific functional form of the compact model proved to be necessary for a satisfactory representation of acute perturbation experiments such as the Intra Venous Glucose Tolerance Test (IVGTT). A spectrum of IVGTT’s of virtual subjects ranging from normal to IFG to IGT to frank T2DM were simulated using an extended model incorporating the population-of-controllers paradigm originally hypothesized by Grodsky, and proven to be able to capture a wide array of experimental results from heterogeneous perturbation procedures. The simulated IVGTT’s were then fitted with the Single-Delay Model (SDM), a compact model with only six free parameters, previously shown to be very effective in delivering precise estimates of insulin sensitivity and secretion during an IVGTT. Comparison of the generating, extended-model parameter values with the obtained compact model estimates shows that the functional form of the nonlinear insulin-secretion term, empirically found to be necessary for the compact model to satisfactorily fit clinical observations, captures the pancreatic reserve level of the simulated virtual patients. This result supports the validity of the compact model as a meaningful analysis tool for the clinical assessment of insulin sensitivity.

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<![CDATA[Reproductive characteristics modify the association between global DNA methylation and breast cancer risk in a population-based sample of women]]> https://www.researchpad.co/article/5c6f1484d5eed0c48467a21a

DNA methylation has been implicated in breast cancer aetiology, but little is known about whether reproductive history and DNA methylation interact to influence carcinogenesis. This study examined modification of the association between global DNA methylation and breast cancer risk by reproductive characteristics. A population-based case-control study assessed reproductive history in an interviewer-administered questionnaire. Global DNA methylation was measured from white blood cell DNA using luminometric methylation assay (LUMA) and pyrosequencing assay (long interspersed elements-1 (LINE-1). We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) among 1 070 breast cancer cases and 1 110 population-based controls. Effect modification was assessed on additive and multiplicative scales. LUMA methylation was associated with elevated breast cancer risk across all strata (comparing the highest to the lowest quartile), but estimates were higher among women with age at menarche ≤12 years (OR = 2.87, 95%CI = 1.96–4.21) compared to >12 years (OR = 1.66, 95%CI = 1.20–2.29). We observed a 2-fold increase in the LUMA methylation-breast cancer association among women with age at first birth >23 years (OR = 2.62, 95%CI = 1.90–3.62) versus ≤23 years (OR = 1.32, 95% CI = 0.84–2.05). No modification was evident for parity or lactation. Age at menarche and age at first birth may be modifiers of the association between global DNA methylation and breast cancer risk.

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<![CDATA[Subclinical atherosclerosis in psoriasis. Usefulness of femoral artery ultrasound for the diagnosis, and analysis of its relationship with insulin resistance]]> https://www.researchpad.co/article/5c6730cfd5eed0c484f38183

Background

Psoriasis is associated with an increased risk of cardiovascular disease (CVD) at younger ages that is not identifiable by traditional risk factors. Screening for subclinical atherosclerosis with ultrasound has only been investigated in carotid arteries. Femoral artery ultrasound has never been considered for this purpose. The link between psoriasis and accelerated atherosclerosis has not yet been established.

Objective

To study the usefulness of femoral artery ultrasound for the detection of subclinical atherosclerosis in psoriasis. We also investigated its possible relationship with changes in insulin resistance.

Methods

We conducted a cross-sectional study in 140 participants, 70 patients with moderate-to-severe psoriasis and 70 healthy controls, matched 1:1 for age, sex, and BMI. Femoral and carotid atherosclerotic plaques were evaluated by ultrasonography. Insulin resistance was assessed by the homeostasis model assessment method (HOMA-IR).

Results

Femoral atherosclerotic plaque prevalence was significantly higher in patients with psoriasis (44.64%) than in controls (19.07%) (p<0.005), but no significant difference was found in carotid plaque prevalence (p<0.3). Femoral plaques were significantly more prevalent than carotid plaques (21.42%) among patients with psoriasis (p<0.001). In the regression analysis, insulin resistance was the most influential determinant of atherosclerosis in psoriasis and C-reactive protein the most significant predictor of insulin resistance.

Conclusions

Ultrasound screening for femoral atherosclerotic plaques improves the detection of subclinical atherosclerosis in patients with psoriasis, whereas the study of carotid arteries is not sufficiently accurate. Insulin resistance appears to play a greater role in the development of atherosclerosis in these patients in comparison to other classical CVD risk factors.

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<![CDATA[Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling during chronic liver injury]]> https://www.researchpad.co/article/5c59feedd5eed0c4841357ce

Insulin provides important information to tissues about feeding behavior and energy status. Defective insulin signaling is associated with ageing, tissue dysfunction, and impaired wound healing. In the liver, insulin resistance leads to chronic damage and fibrosis, but it is unclear how tissue-repair mechanisms integrate insulin signals to coordinate an appropriate injury response or how they are affected by insulin resistance. In this study, we demonstrate that insulin resistance impairs local cellular crosstalk between the fibrotic stroma and bipotent adult liver progenitor cells (LPCs), whose paracrine interactions promote epithelial repair and tissue remodeling. Using insulin-resistant mice deficient for insulin receptor substrate 2 (Irs2), we highlight dramatic impairment of proregenerative fibroblast growth factor 7 (Fgf7) signaling between stromal niche cells and LPCs during chronic injury. We provide a detailed account of the role played by IRS2 in promoting Fgf7 ligand and receptor (Fgfr2-IIIb) expression by the two cell compartments, and we describe an insulin/IRS2-dependent feed-forward loop capable of sustaining hepatic re-epithelialization by driving FGFR2-IIIb expression. Finally, we shed light on the regulation of IRS2 and FGF7 within the fibrotic stroma and show—using a human coculture system—that IRS2 silencing shifts the equilibrium away from paracrine epithelial repair in favor of fibrogenesis. Hence, we offer a compelling insight into the contribution of insulin resistance to the pathogenesis of chronic liver disease and propose IRS2 as a positive regulator of communication between cell types and the transition between phases of stromal to epithelial repair.

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