scholarly journals Epistatic Interaction ofCYP1A1andCOMTPolymorphisms in Cervical Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Andreia Matos ◽  
Cindy Castelão ◽  
Alda Pereira da Silva ◽  
Irina Alho ◽  
Manuel Bicho ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Lower Risk ◽  
Alternative Pathway ◽  
Cumulative Exposure ◽  
Estrogen Metabolism ◽  
Protection Effect ◽  
Functional Polymorphisms ◽  
Metabolic Sequence ◽  
Hormone Sensitive ◽  
Estradiol Levels

There is a clear association between the excessive and cumulative exposure to estrogens and the development of cancer in hormone-sensitive tissues, such as the cervix. We studied the association ofCYP1A1 M1(rs4646903) andCOMT(rs4680) polymorphisms in 130 cervical cancer cases (c-cancer) and 179 controls. TheCYP1A1TT genotype was associated with a lower risk for c-cancer (OR = 0.39,p=0.002). The allele C ofCYP1A1was a risk for c-cancer (OR = 2.29,p=0.002). Women withCOMT LLgenotype had a higher risk of developing c-cancer (OR = 4.83,p<0.001). For the interaction of theCYP1A1&COMT, we observed that TC&HL genotypes had a greater risk for c-cancer (OR = 6.07,p=0.006) and TT&HL genotypes had a protection effect (OR = 0.24,p<0.001). TheCYP1A1 TTandCOMT LLgenotypes had higher estradiol levels in c-cancer (p<0.001andp=0.037, resp.). C-cancer is associated with less production of 2-methoxy-estradiol resultant of functional polymorphisms ofCYP1A1andCOMT, separately.CYP1A1andCOMTwork in a metabolic sequence and their interaction could lead to an alternative pathway of estrogen metabolism with production of 16-OH-estrone that is more proliferative.

Functional roles of female sex hormones and their nuclear receptors in cervical cancer

2021 ◽  
Author(s):  
Seoung-Ae Lee ◽  
Seunghan Baik ◽  
Sang-Hyuk Chung
Keyword(s):  
Cervical Cancer ◽  
Mouse Model ◽  
Estrogen Receptor Α ◽  
Functional Roles ◽  
Genetic Ablation ◽  
Cervical Cancers ◽  
Female Sex Hormones ◽  
Exogenous Estrogen ◽  
Valuable Treatment ◽  
Hormone Sensitive

Abstract There has been little progress for several decades in modalities to treat cervical cancer. While the cervix is a hormone-sensitive tissue, physiologic roles of estrogen receptor α (ERα), progesterone receptor (PR), and their ligands in this tissue are poorly understood. It has hampered critical assessments of data in early epidemiologic and clinical studies for cervical cancer. Experimental evidence obtained from studies using mouse models has provided new insights into the molecular mechanism of ERα and PR in cervical cancer. In a mouse model expressing human papillomavirus (HPV) oncogenes, exogenous estrogen promotes cervical cancer through stromal ERα. In the same mouse model, genetic ablation of PR promotes cervical carcinogenesis without exogenous estrogen. Medroxyprogesterone acetate, a PR-activating drug, regresses cervical cancer in the mouse model. These results support that ERα and PR play opposite roles in cervical cancer. They further support that ERα inhibition and PR activation may be translated into valuable treatment for a subset of cervical cancers.

scholarly journals Sex Differences in Peritraumatic Inflammatory Cytokines and Steroid Hormones Contribute to Prospective Risk for Nonremitting Posttraumatic Stress Disorder

2021 ◽  
Vol 5 ◽  
pp. 247054702110322
Author(s):  
Chloe S. Lalonde ◽  
Yara Mekawi ◽  
Kelly F. Ethun ◽  
Eleonore Beurel ◽  
Felicia Gould ◽  
...  
Keyword(s):  
Sex Differences ◽  
Inflammatory Cytokines ◽  
Lower Risk ◽  
Inflammatory Cytokine ◽  
Stress Disorder ◽  
Steroid Hormone ◽  
Trauma Exposure ◽  
Inflammatory Cytokine Response ◽  
Estradiol Levels ◽  
Pro Inflammatory Cytokines

Women are at higher risk for developing posttraumatic stress disorder (PTSD) compared to men, yet little is known about the biological contributors to this sex difference. One possible mechanism is differential immunological and neuroendocrine responses to traumatic stress exposure. In the current prospective study, we aimed to identify whether sex is indirectly associated with the probability of developing nonremitting PTSD through pro-inflammatory markers and whether steroid hormone concentrations influence this effect. Female ( n = 179) and male ( n = 197) trauma survivors were recruited from an emergency department and completed clinical assessment within 24 h and blood samples within ∼three hours of trauma exposure. Pro-inflammatory cytokines (IL-6, IL-1[Formula: see text], TNF, IFNγ), and steroid hormone (estradiol, testosterone, progesterone, cortisol) concentrations were quantified in plasma. Compared to men, women had a higher probability of developing nonremitting PTSD after trauma ( p = 0.04), had lower pro-inflammatory cytokines and testosterone ( p’ s<0.001), and had higher cortisol and progesterone ( p’ s<0.001) concentrations. Estradiol concentrations were not different between the sexes ( p = 0.24). Pro-inflammatory cytokines were a significant mediator in the relationship between sex and probability of developing nonremitting PTSD ( p < 0.05), such that men had higher concentrations of pro-inflammatory cytokines which were associated with lower risk of nonremitting PTSD development. This effect was significantly moderated by estradiol ( p < 0.05), as higher estradiol levels in men were associated with higher pro-inflammatory cytokine concentrations and lower risk for developing nonremitting PTSD. The current results suggest that sex differences in the pro-inflammatory cytokine response to trauma exposure partially mediate the probability of developing nonremitting PTSD, and that the protective ability to mount an pro-inflammatory cytokine response in men may depend on higher estradiol levels in the aftermath of trauma exposure.

scholarly journals Cumulative exposure to high estradiol levels during the follicular phase of IVF cycles negatively affects implantation

2007 ◽  
Vol 24 (4) ◽  
pp. 111-117 ◽  
Author(s):  
Murat Arslan ◽  
Silvina Bocca ◽  
Ebru Ozturk Arslan ◽  
Hakan E. Duran ◽  
Laurel Stadtmauer ◽  
...  
Keyword(s):  
Follicular Phase ◽  
Cumulative Exposure ◽  
Estradiol Levels

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Toward an Individualized Approach

Nephron ◽  
2021 ◽  
pp. 1-17
Author(s):  
Javier Villacorta ◽  
Laura Martinez-Valenzuela ◽  
Irene Martin-Capon ◽  
Juliana Bordignon-Draibe
Keyword(s):  
Alternative Pathway ◽  
Treatment Options ◽  
Immunosuppressive Treatment ◽  
Standard Of Care ◽  
Antineutrophil Cytoplasmic Antibody ◽  
Organ Damage ◽  
Cumulative Exposure ◽  
Clinical Approach ◽  
Clinical Syndromes ◽  
Individualized Approach

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), characterized by the presence of autoantibodies to neutrophil cytoplasmic antigens, proteinase 3 (PR3), and myeloperoxidase (MPO), typically involves small blood vessels of the respiratory tract and kidneys. It includes distinct clinical syndromes: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic GPA. GPA is commonly associated with PR3-ANCA, while MPA is associated with MPO-ANCA. AAVs have a complex pathogenesis, influenced by genetics and environmental factors. There is evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation and injury, with effector T cells and activation of the alternative pathway of the complement also involved. Advances in immunosuppressive treatment have drastically reduced mortality of AAV in the past decades, opting for a more individualized approach. Careful assessment of ANCA specificity, disease activity, organ damage, and quality of life allows for a tailored immunosuppressive therapy. Contemporary AAV treatment is characterized by regimens that minimize the cumulative exposure to glucocorticoids and cyclophosphamide, and novel approaches including complement blockage and immunosuppressant combinations might be the standard of care in the future. In this review, we examine the pathogenesis, clinical approach, and evidence-based treatment options for the management of AAV patients.

scholarly journals Differences in Bisphenol A and Estrogen Levels in the Plasma and Seminal Plasma of Men With Different Degrees of Infertility

2015 ◽  
pp. S303-S311 ◽  
Author(s):  
J. VITKU ◽  
L. SOSVOROVA ◽  
T. CHLUPACOVA ◽  
R. HAMPL ◽  
M. HILL ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Seminal Plasma ◽  
Seminal Fluid ◽  
Sperm Count ◽  
Sperm Concentration ◽  
Endocrine System ◽  
Estrogen Metabolism ◽  
Healthy Men ◽  
Infertile Men ◽  
Estradiol Levels

The general population is potentially exposed to many chemicals that can affect the endocrine system. These substances are called endocrine disruptors (EDs), and among them bisphenol A (BPA) is one of the most widely used and well studied. Nonetheless, there are still no data on simultaneous measurements of various EDs along with steroids directly in the seminal fluid, where deleterious effects of EDs on spermatogenesis and steroidogenesis are assumed. We determined levels of BPA and 3 estrogens using LC-MS/MS in the plasma and seminal plasma of 174 men with different degrees of infertility. These men were divided according their spermiogram values into 4 groups: (1) healthy men, and (2) slightly, (3) moderate, and (4) severely infertile men. Estradiol levels differed across the groups and body fluids. Slightly infertile men have significantly higher BPA plasma and seminal plasma levels in comparison with healthy men (p<0.05 and p<0.01, respectively). Furthermore, seminal BPA, but not plasma BPA, was negatively associated with sperm concentration and total sperm count (–0.27; p<0.001 and –0.24; p<0.01, respectively). These findings point to the importance of seminal plasma in BPA research. Overall, a disruption of estrogen metabolism was observed together with a weak but significant impact of BPA on sperm count and concentration.

scholarly journals T Cell Receptor Repertoires Acquired via Routine Pap Testing May Help Refine Cervical Cancer and Precancer Risk Estimates

2021 ◽  
Vol 12 ◽  
Author(s):  
Scott Christley ◽  
Jared Ostmeyer ◽  
Lisa Quirk ◽  
Wei Zhang ◽  
Bradley Sirak ◽  
...  
Keyword(s):  
Machine Learning ◽  
Cervical Cancer ◽  
T Cell ◽  
T Cell Receptor ◽  
Lower Risk ◽  
Pap Test ◽  
Cell Receptor ◽  
Precursor Lesions ◽  
Risk Of Cancer

Cervical cancer is the fourth most common cancer and fourth leading cause of cancer death among women worldwide. In low Human Development Index settings, it ranks second. Screening and surveillance involve the cytology-based Papanicolaou (Pap) test and testing for high-risk human papillomavirus (hrHPV). The Pap test has low sensitivity to detect precursor lesions, while a single hrHPV test cannot distinguish a persistent infection from one that the immune system will naturally clear. Furthermore, among women who are hrHPV-positive and progress to high-grade cervical lesions, testing cannot identify the ~20% who would progress to cancer if not treated. Thus, reliable detection and treatment of cancers and precancers requires routine screening followed by frequent surveillance among those with past abnormal or positive results. The consequence is overtreatment, with its associated risks and complications, in screened populations and an increased risk of cancer in under-screened populations. Methods to improve cervical cancer risk assessment, particularly assays to predict regression of precursor lesions or clearance of hrHPV infection, would benefit both populations. Here we show that women who have lower risk results on follow-up testing relative to index testing have evidence of enhanced T cell clonal expansion in the index cervical cytology sample compared to women who persist with higher risk results from index to follow-up. We further show that a machine learning classifier based on the index sample T cells predicts this transition to lower risk with 95% accuracy (19/20) by leave-one-out cross-validation. Using T cell receptor deep sequencing and machine learning, we identified a biophysicochemical motif in the complementarity-determining region 3 of T cell receptor β chains whose presence predicts this transition. While these results must still be tested on an independent cohort in a prospective study, they suggest that this approach could improve cervical cancer screening by helping distinguish women likely to spontaneously regress from those at elevated risk of progression to cancer. The advancement of such a strategy could reduce surveillance frequency and overtreatment in screened populations and improve the delivery of screening to under-screened populations.

scholarly journals The UGT1 locus is a determinant of prostate cancer recurrence after prostatectomy

2014 ◽  
Vol 22 (1) ◽  
pp. 77-85 ◽  
Author(s):  
Isabelle Laverdière ◽  
Christine Flageole ◽  
Étienne Audet-Walsh ◽  
Patrick Caron ◽  
Yves Fradet ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Proportional Hazards ◽  
Prognostic Significance ◽  
Cancer Recurrence ◽  
Cox Proportional Hazards ◽  
Estrogen Metabolism ◽  
Nucleotide Polymorphisms ◽  
Functional Polymorphisms ◽  
Risk Alleles ◽  
Caucasian Men

The prognostic significance of common deletions in uridine diphospho-glucuronosyltransferase 2B (UGT2B) genes encoding sex steroid metabolic enzymes has been recently recognized in localized prostate cancer (PCa) after radical prostatectomy (RP). However, the role of germline variations at theUGT1locus, encoding half of all human UGTs and primarily involved in estrogen metabolism, remains unexplored. We investigated whether variants ofUGT1are potential prognostic markers. We studied 526 Caucasian men who underwent RP for clinically localized PCa. Genotypes of patients for 34 haplotype-tagged single-nucleotide polymorphisms (htSNPs) and 11 additional SNPs across theUGT1locus previously reported to mark common variants including functional polymorphisms were determined. The risk of biochemical recurrence (BCR) was estimated using adjusted Cox proportional hazards regression and Kaplan–Meier analysis. We further investigated whether variants are associated with plasma hormone levels by mass spectrometry. In multivariable models, seven htSNPs were found to be significantly associated with BCR. A greater risk was revealed for fourUGT1intronic variants with hazard ratios (HRs) of 1.59–1.88 (P<0.002) for htSNPs inUGT1A10,UGT1A9, andUGT1A6. Conversely, decreased BCR was associated with three htSNPs in introns ofUGT1A10andUGT1A9(HR=0.56–058;P≤0.01). An unfavorableUGT1haplotype comprising all risk alleles, with a frequency of 14%, had a HR of 1.68 (95% CI=1.13–2.50;P=0.011). Significant alteration in circulating androsterone levels was associated with this haplotype, consistent with changes in hormonal exposure. This study provides the first evidence, to our knowledge, that germline polymorphisms ofUGT1are potential predictors of recurrence of PCa after prostatectomy.

scholarly journals Functional Polymorphisms and Gene Expression of TLR9 Gene as Protective Factors for Nasopharyngeal Carcinoma Severity and Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Macherki Yosra ◽  
Souissi Sameh ◽  
Ghedira Randa ◽  
Remadi Yassmine ◽  
Gabbouj Sallouha ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Protective Factors ◽  
Mrna Expression ◽  
Distant Metastasis ◽  
Tumor Size ◽  
Lower Risk ◽  
Clinical Stage ◽  
Risk Of Death ◽  
Functional Polymorphisms ◽  
Tlr9 Gene

Nasopharyngeal carcinoma (NPC) is a disease that is closely associated with EBV infection. Toll-like receptor 9 is an important factor mediating the interaction between EBV and the host immune response. Any genetic (single nucleotide polymorphisms, SNPs) or expression variation in TLR9 gene may modify the ability of the receptor to respond correctly to viral infection as in NPC. This study is aimed at evaluating the effect of TLR9 functional polymorphisms (TLR9-1486 T/C and TLR9-1237 T/C) and TLR9 mRNA expression in NPC severity and progression at diagnosis and after treatment. This study included 322 patients with NPC. RFLP-PCR and real-time PCR were used to assess, respectively, the genotypes and the mRNA expression of TLR9 gene. The genotyping analysis showed that the presence of mutated allele -1237C (TLR9-1237 TC+CC) was associated with large tumor size (p=0.017; OR CI 95%=1.888 (1.11-3.19)) at diagnosis. After treatment, the -1237C allele was associated with a better chance of complete remission (p=0.031, OR CI 95%=0.486 (0.25-0.95)), a lower risk of distant metastasis (p=0.028, OR CI 95%=0.435 (0.18-1.02)), and a lower risk of death by NPC (p=0.003, OR CI 95%=0.20 (0.06-0.67)). Kaplan-Meier analysis showed that patients with -1237CC and -1237TC genotypes had a better overall survival (OVS) (p<0.01) and distant metastasis-free survival (DMFS) (p<0.05). A multivariate analysis revealed that TLR9-1237 T/C polymorphism was an independent prognostic factor in OVS (p=0.02; HR=0.244) and DMFS (p=0.048; HR=0.388). The transcriptomic analysis showed that the mRNA expression was reduced in patients with larger tumor size (T4) (p=0.013) and advanced clinical stage (SIII-SIV) (p=0.037). The TLR9 mRNA expression was inversely correlated with tumor size (p=0.014; r=−0.314) at diagnosis. Our results indicated for the first time that the functional -1237 T/C polymorphism and mRNA expression of TLR9 gene may be considered as protective factors for NPC severity and progression.

scholarly journals FASL –844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer

2005 ◽  
Vol 202 (7) ◽  
pp. 967-974 ◽  
Author(s):  
Tong Sun ◽  
Yifeng Zhou ◽  
Hua Li ◽  
Xiaohong Han ◽  
Yuankai Shi ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
Cell Death ◽  
Fas Ligand ◽  
Immune Escape ◽  
Apoptotic Cell ◽  
Host Susceptibility ◽  
Tumor Immune Escape ◽  
Functional Polymorphisms ◽  
Increased Risk

The FAS receptor–ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis. We have recently demonstrated (Sun, T., X. Miao, X. Zhang, W. Tan, P. Xiong, and D. Lin. 2004. J. Natl. Cancer Inst. 96:1030–1036; Zhang, X., X. Miao, T. Sun, W. Tan, S. Qu, P. Xiong, Y. Zhou, and D. Lin. 2005. J. Med. Genet. 42:479–484) that functional polymorphisms in FAS and FAS ligand (FASL) are associated with susceptibility to lung cancer and esophageal cancer; however, the mechanisms underlying this association have not been elucidated. We show that the FAS –1377G, FAS –670A, and FASL –844T variants are expressed more highly on ex vivo–stimulated T cells than the FAS –1377A, FAS –670G, and FASL –844C variants. Moreover, activation-induced cell death (AICD) of T cells carrying the FASL –844C allele was increased. We also found a threefold increased risk of cervical cancer among subjects with the FASL –844CC genotype compared with those with the –844TT genotype in a case-control study in Chinese women. Together, these observations suggest that genetic polymorphisms in the FAS–FASL pathway confer host susceptibility to cervical cancers, which might be caused by immune escape of tumor cells because of enhanced AICD of tumor-specific T cells.

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