ERK1/2, PI3K and p70S6K are important mediators for HGF-induced migration and invasion in human ovarian cancer cells

published_or_final_versio

Impact of \u3cem\u3eMYH6\u3c/em\u3e Variants in Hypoplastic Left Heart Syndrome

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P \u3c 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P \u3c 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P \u3c 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P \u3c 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications

Human gene copy number spectra analysis in congenital heart malformations

The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency “spectra” to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways

Lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of prostate carcinogenesis

This work aimed to understand how lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of PCa. Fifty-five male Wistar rats were divided into four groups: control sedentary, control exercised, induced PCa sedentary and induced PCa exercised. Exercised animals were trained in a treadmill for 53 weeks. Pca induction consisted on the sequential administration of flutamide, N-methyl-N-nitrosourea and testosterone propionate implants. Serum concentrations of C-reactive protein (CRP) and tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) were not different among groups. Peripheral levels of γδ T cells were higher in Pca exercised group than in the PCa sedentary group (p < 0.05). Exercise training also induced Oestrogen Receptor (ESR1) upregulation and Mitogen-activated Protein Kinase 13 (MAPK13) downregulation, changed the content of the phosphorylated (at Ser-104) form of this receptor (coded by the gene ESR1) and seemed to increase Erα phosphorylation and activity in exercised PCa rats when compared with sedentary PCa rats. Our data highlight the exercise-induced remodelling of peripheral lymphocyte subpopulations and lymphocyte infiltration in prostate tissue. Moreover, exercise training promotes the remodelling prostate signalome in this rat model of prostate carcinogenesis

Unveiling the role of moderate exercise training in immune system and prostate signalome: data from a rat model

Background: Prostate cancer (PCa) is among the most prevalent cancers worldwide. This work aimed to under- stand the effects of exercise training in a rat model of PCa chemically and hormonally-induced. Material and Methods: Fifty-five male Wistar rats were divided into: control sedentary (SED+CONT; n=10), control exercised (EX+CONT; n=10), induced seden- tary (SED+PCa; n = 15) and induced exercised (EX+PCa; n=20). Exercised animals were trained in a treadmill for 53weeks. PCa induction consisted in a multistep proto- col including flutaminde and N-methyl-N-nitrosourea administration, followed by testosterone propionate im- plants. At sacrifice, dorsolateral prostate lobe and periph- eral blood was collected. Data were analysed using SPSS 25 and values were statistically significant at p < 0.05. Results: CD4+/CD8+ ratio in dorsolateral prostate tis- sue was decreased in EX+PCa group when compared to SED+PCa group. Peripheral levels of γδ T cells were higher in exercised groups (p < 0.05). The most prominent changes in prostate proteome induce by exercise were Estrogen Receptor-alpha (ERalfa; ESR1) upregulation of stimulatory Ser-104 phosphorylation (+ 1976% change from SED+PCa rats) and Mitogen-activated Protein Kinase 13 (MAPK13; p38δ MAPK) downregulation of stimulatory Thr-180 and Tyr-182 phosphorylation (-80% change from SED+PCa rats). Conclusions: Our results reinforce the beneficial role of exercise in anti-tumour immune response, with modula- tion of ER-alpha and MAPK pathways and remodelling of peripheral lymphocyte subpopulations, and lymphocyte infiltration in prostate tissue during carcinogenesis

Moderate intensity treadmill exercise influences the immune system and prostate signalome in a rat model of prostate cancer

Material & Methods: Fifty-five male Wistar rats were divided into: control sedentary (SED+CONT; n=10), control exercised (EX+CONT; n=10), induced sedentary (SED+PCa; n=15), and induced exercised (EX+PCa; n=20). Exercised animals were trained in a treadmill, for 53 weeks. PCa induction consisted of flutamide and N-methyl-N-nitrosourea administration, followed by testosterone propionate implants. At sacrifice, prostate was collected for histopathological, immunohistochemical and antibody microarray analysis. Peripheral blood was collected for biochemical and immunophenotyping analysis. Data were analysed using SPSS 25 and values were statistically significant at p<0.05. Results: Body weight was lower in exercised groups than in sedentary ones, either in control and in PCa groups (p<0.05). C-reactive protein and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) levels were not different among groups. observed in prostate gland. Peripheral levels of γδ T cells (p<0.05). Exercise training also induced Oestrogen Receptor (ESR1) upregulation and Mitogen-activated Protein Kinase 13 (MAPK13) downregulation

Moderate intensity treadmill exercise influences the immune system and prostate signalome in a rat model of prostate cancer

MODERATE INTENSITY TREADMILL EXERCISE INFLUENCES THE IMMUNE SYSTEM AND PROSTATE SIGNALOME IN A RAT MODEL OF PROSTATE CANCE

An integrative paradigm to impart quality to correlative science

Correlative studies are a primary mechanism through which insights can be obtained about the bioactivity and potential efficacy of candidate therapeutics evaluated in early-stage clinical trials. Accordingly, well designed and performed early-stage correlative studies have the potential to strongly influence further clinical development of candidate therapeutic agents, and correlative data obtained from early stage trials has the potential to provide important guidance on the design and ultimate successful evaluation of products in later stage trials, particularly in the context of emerging clinical trial paradigms such as adaptive trial design

Overexpression of CD97 in Intestinal Epithelial Cells of Transgenic Mice Attenuates Colitis by Strengthening Adherens Junctions

The adhesion G-protein-coupled receptor CD97 is present in normal colonic enterocytes but overexpressed in colorectal carcinoma. To investigate the function of CD97 in colorectal carcinogenesis, transgenic Tg(villin-CD97) mice overexpressing CD97 in enterocytes were generated and subjected to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated tumorigenesis. Unexpectedly, we found a CD97 cDNA copy number-dependent reduction of DSS-induced colitis in Tg compared to wild-type (WT) mice that was confirmed by applying a simple DSS protocol. Ultrastructural analysis revealed that overexpression of CD97 strengthened lateral cell-cell contacts between enterocytes, which, in contrast, were weakened in CD97 knockout (Ko) mice. Transepithelial resistance was not altered in Tg and Ko mice, indicating that tight junctions were not affected. In Tg murine and normal human colonic enterocytes as well as in colorectal cell lines CD97 was localized preferentially in E-cadherin-based adherens junctions. CD97 overexpression upregulated membrane-bound but not cytoplasmic or nuclear β-catenin and reduced phospho-β-catenin, labeled for degradation. This was associated with inactivation of glycogen synthase kinase-3β (GSK-3β) and activation of Akt. In summary, CD97 increases the structural integrity of enterocytic adherens junctions by increasing and stabilizing junctional β-catenin, thereby regulating intestinal epithelial strength and attenuating experimental colitis