Role of ADAMTS16 metalloproteinase in pathogenesis of cryptorchidism

IntroductionThe etiology of cryptorchidism is still not fully elucidated, but several hypotheses have been proposed. One of the latest concerns is the involvement of metalloproteinase ADAMTS16 in testis descent. The aim of this study was to evaluate both expression and occurrence of selected polymorphisms of metalloproteinase ADAMTS16 in patients diagnosed with cryptorchidism.Material and methodsThe study group consisted of 158 boys (mean age: 4.1 ±2.04 years) who underwent surgery due to undescended testis. Tissue samples from patients with cryptorchidism were obtained from the cremaster muscle, gubernaculum and hernial sac. The reference group consisted of 123 age-related subjects (mean age: 4.1 ±2.41 years) who had no cryptorchidism and underwent surgery for other reasons. Tissue samples from controls were obtained from the cremaster muscle and hernial sac.ResultsThe obtained data indicate that patients with undescended testis have significantly lower expression of Adamts16, especially in the gubernaculum. We also demonstrated a tendency that Adamts16 expression depends on the age of patients; the older the patient was, the higher was the observed expression of Adamts16. These studies also established that polymorphisms rs16875319, rs16875122, and rs58353460 in the Adamts16 gene are not a major determinant to develop cryptorchidism while rs16875054 is associated with increased risk.ConclusionsThese studies highlight ADAMTS16 involvement in cryptorchidism and confirm data obtained in animal models.

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Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium

Genetics ◽

10.1534/genetics.119.302268 ◽

2019 ◽

Vol 212 (3) ◽

pp. 655-665 ◽

Cited By ~ 1

Author(s):

Joseph Christopher ◽

Ann-Sofie Thorsen ◽

Sam Abujudeh ◽

Filipe C. Lourenço ◽

Richard Kemp ◽

...

Keyword(s):

Stem Cell ◽

Fold Increase ◽

Mutation Rates ◽

Wild Type ◽

Cell Dynamics ◽

Tissue Samples ◽

Age Related ◽

Increased Risk ◽

Microsatellite Mutation ◽

Risk Of Cancer

Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus, and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (∼50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2-deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 × 10−2) compared to wild-type epithelium (6.2 × 10−5).

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Aging shapes the population-mean and ‐dispersion of gene expression in human brains

10.1101/039933 ◽

2016 ◽

Author(s):

Candice L. Brinkmeyer-Langford ◽

Jinting Guan ◽

Guoli Ji ◽

James J. Cai

Keyword(s):

Gene Expression ◽

Age Groups ◽

Tissue Expression ◽

Brain Regions ◽

Tissue Samples ◽

Protein Coding ◽

Age Related ◽

Increased Risk ◽

Neurotransmitter Transport ◽

Human Brains

AbstractHuman aging is associated with cognitive decline and an increased risk of neurodegenerative disease. Our objective for this study was to evaluate potential relationships between age and variation in gene expression across different regions of the brain. We analyzed the Genotype-Tissue Expression (GTEx) data from 54 and 101 tissue samples across 13 brain regions in post-mortem donors of European descent aged between 20 and 70 years at death. After accounting for the effects of covariates and hidden confounding factors, we identified 1,446 protein-coding genes whose expression in one or more brain regions is correlated with chronological age at a false discovery rate of 5%. These genes are involved in various biological processes including apoptosis, mRNA splicing, amino acid biosynthesis, and neurotransmitter transport. The distribution of these genes among brain regions is uneven, suggesting variable regional responses to aging. We also found that the aging response of many genes, e.g., TP37 and C1QA, depends on individuals’ genotypic backgrounds. Finally, using dispersion-specific analysis, we identified genes such as IL7R, MS4A4E, and TERF1/TERF2 whose expressions are differentially dispersed by aging, i.e., variances differ between age groups. Our results demonstrate that age-related gene expression is brain region-specific, genotype-dependent, and associated with both mean and dispersion changes. Our findings provide a foundation for more sophisticated gene expression modeling in the studies of age-related neurodegenerative diseases.

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Circadian PERformance in breast cancer: a germline and somatic genetic study of PER3VNTR polymorphisms and gene co-expression

npj Breast Cancer ◽

10.1038/s41523-021-00329-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Jaume Fores-Martos ◽

Raimundo Cervera-Vidal ◽

Julia Sierra-Roca ◽

Carlos Lozano-Asencio ◽

Vita Fedele ◽

...

Keyword(s):

Breast Cancer ◽

Variable Number ◽

Luminal A ◽

Tissue Samples ◽

Free Survival ◽

Expression Levels ◽

Cancer Subtypes ◽

Increased Risk ◽

Combined Data

AbstractPolymorphisms in the PER3 gene have been associated with several human disease phenotypes, including sleep disorders and cancer. In particular, the long allele of a variable number of tandem repeat (VNTR) polymorphism has been previously linked to an increased risk of breast cancer. Here we carried out a combined germline and somatic genetic analysis of the role of the PER3VNRT polymorphism in breast cancer. The combined data from 8284 individuals showed a non-significant trend towards increased breast cancer risk in the 5-repeat allele homozygous carriers (OR = 1.17, 95% CI: 0.97–1.42). We observed allelic imbalance at the PER3 locus in matched blood and tumor DNA samples, showing a significant retention of the long variant (risk) allele in tumor samples, and a preferential loss of the short repetition allele (p = 0.0005). Gene co-expression analysis in healthy and tumoral breast tissue samples uncovered significant associations between PER3 expression levels with those from genes which belong to several cancer-associated pathways. Finally, relapse-free survival (RFS) analysis showed that low expression levels of PER3 were linked to a significant lower RSF in luminal A (p = 3 × 10−12) but not in the rest of breast cancer subtypes.

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Expression of Proton-Sensitive GPR31, GPR151, TASK1 and TASK3 in Common Skin Tumors

Cells ◽

10.3390/cells11010027 ◽

2021 ◽

Vol 11 (1) ◽

pp. 27

Author(s):

Antonia Förch ◽

Susanne Wallner ◽

Florian Zeman ◽

Tobias Ettl ◽

Christoph Brochhausen ◽

...

Keyword(s):

Expression Profiles ◽

Expression Patterns ◽

Skin Tumors ◽

Tissue Samples ◽

Basal Cell Carcinomas ◽

Common Skin ◽

G Protein Coupled ◽

Nevus Cell ◽

Lower Expression

TWIK-related acid-sensitive potassium channels TASK1 and TASK3, as well as the G-protein-coupled receptors GPR31 and GPR151, are proton-sensitive membrane proteins. They can be activated or inhibited by low extracellular pH (pHe), which is a hallmark of the tumor microenvironment in solid tumors. However, the role of these channels in the development of skin tumors is still unclear. In this study, we investigated the expression profiles of TASK1, TASK3, GPR31 and GPR151 in squamous cell carcinomas (SCCs), basal cell carcinomas (BCCs), nevus cell nevi (NCN), and malignant melanomas (MMs). We performed immunohistochemistry using paraffin-embedded tissue samples from patients and found that most skin tumors express TASK1/3 and GPR31/151. The results show that BCCs are often negative for GPR31/151 as well as for TASK1/3, while nearly all SCCs express these markers. MMs and NCN show similar expression patterns. However, some tumors show a decreasing TASK1/3 expression in deeper dermal tumor tissue, while GPCRs were expressed more evenly. The lower frequency of GPR31/151 and TSAK1/3 expression in BCCs when compared to SCCs is a novel histological feature distinguishing these two entities. Moreover, BCCs also show lower expression of GPR31/151 and TASK1/3 as compared to NCN and MMs.

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Vitamin K, Vascular Calcification, and Chronic Kidney Disease: Current Evidence and Unanswered Questions

Current Developments in Nutrition ◽

10.1093/cdn/nzz077 ◽

2019 ◽

Vol 3 (9) ◽

Cited By ~ 5

Author(s):

M Kyla Shea ◽

Sarah L Booth

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Vitamin K ◽

Animal Studies ◽

Arterial Calcification ◽

Current Evidence ◽

Age Related ◽

Increased Risk ◽

The Us

ABSTRACTMore than 15% of the US population is currently >65 y old. As populations age there is a concomitant increase in age-related chronic diseases. One such disease is chronic kidney disease (CKD), which becomes more prevalent with age, especially over age 70 y. Individuals with CKD are at increased risk of cardiovascular disease, in part because arterial calcification increases as kidney function declines. Vitamin K is a shortfall nutrient among older adults that has been implicated in arterial calcification. Evidence suggests CKD patients have low vitamin K status, but data are equivocal because the biomarkers of vitamin K status can be influenced by CKD. Animal studies provide more compelling data on the underlying role of vitamin K in arterial calcification associated with CKD. The purpose of this review is to evaluate the strengths and limitations of the available evidence regarding the role of vitamin K in CKD.

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Hypertension and Risk of Post-Operative Cognitive Dysfunction (POCD): A Systematic Review and Meta-Analysis

Clinical Practice and Epidemiology in Mental Health ◽

10.2174/1745017901713010027 ◽

2017 ◽

Vol 13 (1) ◽

pp. 27-42 ◽

Cited By ~ 5

Author(s):

I. Feinkohl ◽

G. Winterer ◽

T. Pischon

Keyword(s):

Systematic Review ◽

Risk Factor ◽

Cognitive Dysfunction ◽

Fixed Effects ◽

Meta Analysis ◽

Major Surgery ◽

Relative Risks ◽

Age Related ◽

Increased Risk

Background:Post-operative cognitive dysfunction (POCD) occurs frequently after major surgery. Hypertension is well-established as a risk factor for age-related cognitive impairment, but it is unclear whether or not it also increases the risk of POCD.Objective:To evaluate the role of hypertension in POCD risk in a systematic review and meta-analysis.Method:PubMed, Ovid SP and the Cochrane Database of Systematic Reviews were searched for longitudinal studies of adults undergoing surgery with reporting of hypertension, blood pressure and/or anti-hypertensive treatment associations with POCD as relative risks or odds ratios. Fixed-effects meta-analyses were performed using Review Manager (version 5.3).Results:Twenty-four studies on 4317 patients (mean age 63 years) were included. None of the studies had set out to assess hypertension as a risk factor for POCD. Hypertension was used as a categorical predictor throughout and only 2 studies adjusted for potential confounders. Across all 24 studies, hypertension was not significantly associated with POCD risk (RR 1.01; 95% CI 0.93, 1.09;p=0.82), though among 8 studies with >75% males, we found hypertension associations with a 27% increased risk of POCD (RR 1.27, 95% CI 1.07, 1.49;p=0.005).Conclusion:Our findings do not support the hypothesis that hypertension is a risk factor for POCD. However, since none of the studies included in our analysis were hypothesis-driven and most did not adjust for potential confounders, further systematic investigations are needed to evaluate the role of hypertension in the epidemiology of POCD.

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Environmental Contaminants Acting as Endocrine Disruptors Modulate Atherogenic Processes: New Risk Factors for Cardiovascular Diseases in Women?

Biomolecules ◽

10.3390/biom12010044 ◽

2021 ◽

Vol 12 (1) ◽

pp. 44

Author(s):

Silvia Migliaccio ◽

Viviana M. Bimonte ◽

Zein Mersini Besharat ◽

Claudia Sabato ◽

Andrea Lenzi ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Endocrine Disruptors ◽

Successful Aging ◽

Molecular Mechanisms ◽

Potential Role ◽

Unhealthy Lifestyle ◽

Age Related ◽

Increased Risk ◽

Artery Disease

The number of aged individuals is increasing worldwide, rendering essential the comprehension of pathophysiological mechanisms of age-related alterations, which could facilitate the development of interventions contributing to “successful aging” and improving quality of life. Cardiovascular diseases (CVD) include pathologies affecting the heart or blood vessels, such as hypertension, peripheral artery disease and coronary heart disease. Indeed, age-associated modifications in body composition, hormonal, nutritional and metabolic factors, as well as a decline in physical activity are all involved in the increased risk of developing atherogenic alterations that raise the risk of CVD development. Several factors have been reported to play a role in the alterations observed in muscle and endothelial cells and that lead to increased CVD, such as genetic pattern, smoking and unhealthy lifestyle. Moreover, a difference in the risk of these diseases in women and men has been reported. Interestingly, in the past decades attention has been focused on a potential role of several pollutants that disrupt human health by interfering with hormonal pathways, and more specifically in non-communicable diseases such as obesity, diabetes and CVD. This review will focus on the potential alteration induced by Endocrine Disruptors (Eds) in the attempt to characterize a potential role in the cellular and molecular mechanisms involved in the atheromatous degeneration process and CVD progression.

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Sonneradon A Extends Lifespan of Caenorhabditis elegans by Modulating Mitochondrial and IIS Signaling Pathways

Marine Drugs ◽

10.3390/md20010059 ◽

2022 ◽

Vol 20 (1) ◽

pp. 59

Author(s):

Shu Jiang ◽

Cui-Ping Jiang ◽

Pei Cao ◽

Yong-Hong Liu ◽

Cheng-Hai Gao ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Innate Immune ◽

C Elegans ◽

Enhanced Resistance ◽

Age Related ◽

Increased Risk ◽

Pseudomonas Aeruginosa Infection ◽

New Evidence ◽

Overall Functioning

Aging is related to the lowered overall functioning and increased risk for various age-related diseases in humans. Sonneradon A (SDA), a new compound first extracted from the edible fruits of mangrove Sonneratia apetala, showed remarkable antiaging activity. However, the role of SDA in antiaging remains unclear. In this article, we studied the function of SDA in antiaging by using the animal model Caenorhabditis elegans. Results showed that SDA inhibited production of reactive oxygen species (ROS) by 53%, and reduced the accumulation of aging markers such as lipids and lipofuscins. Moreover, SDA also enhanced the innate immune response to Pseudomonas aeruginosa infection. Genetic analysis of a series of mutants showed that SDA extended the lifespan of the mutants of eat-2 and glp-1. Together, this effect may be related to the enhanced resistance to oxidative stress via mitochondrial and insulin/insulin-like growth factor-1 signaling (IIS) pathways. The results of this study provided new evidence for an antiaging effect of SDA in C. elegans, as well as insights into the implication of antiaging activity of SDA in higher organisms.

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Role of miR-182/PDCD4 axis in aggressive behavior of prostate cancer in the African Americans

BMC Cancer ◽

10.1186/s12885-021-08723-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Marisa Shiina ◽

Yutaka Hashimoto ◽

Priyanka Kulkarni ◽

Pritha Dasgupta ◽

Varahram Shahryari ◽

...

Keyword(s):

Prostate Cancer ◽

African Americans ◽

Cell Line ◽

Cell Lines ◽

Critical Role ◽

Gleason Grade ◽

Tissue Samples ◽

Free Survival ◽

Increased Risk

Abstract Background Prostate cancer is one of the most commonly diagnosed cancers among men. African Americans (AA) are at an increased risk of developing prostate cancer compared to European Americans (EA). miRNAs play a critical role in these tumors, leading to tumor progression. In this study, we investigated the role of miR-182 in racial disparity in prostate cancer. Results We found significantly increased levels of miR-182 in prostate cancer tissues compared to BPH. Also, miR-182 shows increased expression in AA prostate cancer cell line and tissue samples compared to EA. We performed biochemical recurrence (BCR) - free survival time in AA and EA patients and found that high miR-182 expression had significantly shorter BCR-free survival than patients with low miR-182 expression (P = 0.031). To elucidate the role of miR-182, we knocked down miR-182 in EA (DU-145 and LNCaP) and AA (MDA-PCa-2b) cell lines and found an increase in apoptosis, arrest of the cell cycle, and inhibition of colony formation in the AA cell line to a greater extent than EA cell lines. Conclusions Our results showed that PDCD4 is a direct miR-182 target and its inhibition is associated with aggressiveness and high Gleason grade in prostate cancer among AA. These findings show that miR-182 is highly expressed in AA patients and miR-182 may be a target for effective therapy in AA patients.

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Role of Secreted Frizzled-Related Protein 1 in Early Mammary Gland Tumorigenesis and Its Regulation in Breast Microenvironment

Cells ◽

10.3390/cells9010208 ◽

2020 ◽

Vol 9 (1) ◽

pp. 208 ◽

Cited By ~ 4

Author(s):

Alisson Clemenceau ◽

Caroline Diorio ◽

Francine Durocher

Keyword(s):

Mammary Gland ◽

Tumor Development ◽

Physiological Age ◽

Mammary Tissue ◽

Grey Zone ◽

Related Protein ◽

Mammary Gland Involution ◽

Age Related ◽

Increased Risk

In mice, the lack of secreted frizzled-related protein 1 (SFRP1) is responsible for mammogenesis and hyperplasia, while, in bovines, its overexpression is associated with post-lactational mammary gland involution. Interestingly, there are no reports dealing with the role of SFRP1 in female involution. However, SFRP1 dysregulation is largely associated with human tumorigenesis in the literature. Indeed, the lack of SFRP1 is associated with both tumor development and patient prognosis. Considering the increased risk of breast tumor development associated with incomplete mammary gland involution, it is crucial to demystify the “grey zone” between physiological age-related involution and tumorigenesis. In this review, we explore the functions of SFRP1 involved in the breast involution processes to understand the perturbations driven by the disappearance of SFRP1 in mammary tissue. Moreover, we question the presence of recurrent microcalcifications identified by mammography. In bone metastases from prostate primary tumor, overexpression of SFRP1 results in an osteolytic response of the tumor cells. Hence, we explore the hypothesis of an osteoblastic differentiation of mammary cells induced by the lack of SFRP1 during lobular involution, resulting in a new accumulation of hydroxyapatite crystals in the breast tissue.

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