Downregulation of Serotonergic System Components in an Experimentally Induced Cryptorchidism in Rabbits.

Cryptorchidism (CO) or undescended testes is defined as the failure of one or both testes to be positioned inside the scrotum. Typically, cryptorchidism is detected at birth or shortly thereafter, and in humans, it is considered to be part of the testicular dysgenesis syndrome (TDS), a complex pathology regarding the male reproductive system that apparently involves the interaction of both genetic and environmental harmful factors, mainly during embryonic development. Serotonin (5-HT) is an ancient molecule that participates in a broad range of body functions, and in recent years, its importance in reproduction has started to be elucidated. In male pathologies such as infertility, varicocele, erectile dysfunction, and primary carcinoid tumors, an increase in 5-HT concentration or its metabolites in the blood, semen, and urine has been directly related; nevertheless, the role of 5-HT in CO remains unknown. In the present work, our goal was to answer two important questions: (1) whether some serotonergic system components are present in adult male Oryctolagus cuniculus (chinchilla rabbit) and (2) if there are changes in their expression in an experimental model of CO. Using histological, molecular, and biochemical approaches, we found the presence of some serotonergic system components in the adult chinchilla rabbit, and we demonstrated that its expression is downregulated after CO was pharmacologically induced. Although we did not test the role of 5-HT in the etiology of CO, our results suggest that this indoleamine could be important for the regulation of steroidogenesis and spermatogenesis processes in the chinchilla rabbit during adulthood. Finally, in parallel experimental series, we found downregulation of kynurenine concentration in COI rabbits when compared to control ones, suggesting that CO could be affecting the kynurenine pathway and probably testicular immune privilege which in turn could lead to infertility/sterility conditions in this disorder.

Deep DNA sequencing of MGMT, TP53 and AGT in Mexican astrocytoma patients identifies an excess of genetic variants in women and a predictive biomarker.

PURPOSE: Astrocytomas are a type of malignant brain tumor with an unfavorable clinical course. The impact of AGT and MGMT somatic variants in the prognosis of astrocytoma is unknown, and it is controversial for TP53. Moreover, there is a lack of knowledge regarding the molecular characteristics of astrocytomas in Mexican patients. METHODS: We studied 48 Mexican patients, men and women, with astrocytoma (discovery cohort). We performed DNA deep sequencing in tumor samples, targeting AGT, MGMT and TP53, and we studied MGMT gene promoter methylation status. Then we compared our findings to a cohort which included data from patients with astrocytoma from The Cancer Genome Atlas (validation cohort). RESULTS: In the discovery cohort, we found a higher number of somatic variants in AGT and MGMT than in the validation cohort (10.4% vs < 1%, p < 0.001), and, in both cohorts, we observed only women carried variants AGT variants. We also found that the presence of either MGMT variant or promoter methylation was associated to better survival and response to chemotherapy, and, in conjunction with TP53 variants, to progression-free survival. CONCLUSIONS: The occurrence of AGT variants only in women expands our knowledge about the molecular differences in astrocytoma between men and women. The increased prevalence of AGT and MGMT variants in the discovery cohort also points towards possible distinctions in the molecular landscape of astrocytoma among populations. Our findings warrant further study.

Breaking the Mold: Epigenetics and Genomics Approaches Addressing Novel Treatments and Chemoresponse in TGCT Patients.

Testicular germ-cell tumors (TGCT) have been widely recognized for their outstanding survival rates, commonly attributed to their high sensitivity to cisplatin-based therapies. Despite this, a subset of patients develops cisplatin resistance, for whom additional therapeutic options are unsuccessful, and ~20% of them will die from disease progression at an early age. Several efforts have been made trying to find the molecular bases of cisplatin resistance. However, this phenomenon is still not fully understood, which has limited the development of efficient biomarkers and precision medicine approaches as an alternative that could improve the clinical outcomes of these patients. With the aim of providing an integrative landscape, we review the most recent genomic and epigenomic features attributed to chemoresponse in TGCT patients, highlighting how we can seek to combat cisplatin resistance through the same mechanisms by which TGCTs are particularly hypersensitive to therapy. In this regard, we explore ongoing treatment directions for resistant TGCT and novel targets to guide future clinical trials. Through our exploration of recent findings, we conclude that epidrugs are promising treatments that could help to restore cisplatin sensitivity in resistant tumors, shedding light on potential avenues for better prognosis for the benefit of the patients.

Association of SLC12A1 and GLUR4 Ion Transporters with Neoadjuvant Chemoresistance in Luminal Locally Advanced Breast Cancer.

Chemoresistance to standard neoadjuvant treatment commonly occurs in locally advanced breast cancer, particularly in the luminal subtype, which is hormone receptor-positive and represents the most common subtype of breast cancer associated with the worst outcomes. Identifying the genes associated with chemoresistance is crucial for understanding the underlying mechanisms and discovering effective treatments. In this study, we aimed to identify genes linked to neoadjuvant chemotherapy resistance in 62 retrospectively included patients with luminal breast cancer. Whole RNA sequencing of 12 patient biopsies revealed 269 differentially expressed genes in chemoresistant patients. We further validated eight highly correlated genes associated with resistance. Among these, solute carrier family 12 member 1 (SLC12A1) and glutamate ionotropic AMPA type subunit 4 (GRIA4), both implicated in ion transport, showed the strongest association with chemoresistance. Notably, SLC12A1 expression was downregulated, while protein levels of glutamate receptor 4 (GLUR4), encoded by GRIA4, were elevated in patients with a worse prognosis. Our results suggest a potential link between SLC12A1 gene expression and GLUR4 protein levels with chemoresistance in luminal breast cancer. In particular, GLUR4 protein could serve as a potential target for drug intervention to overcome chemoresistance.

Mutational Landscape of Bladder Cancer in Mexican Patients: KMT2D Mutations and chr11q15.5 Amplifications Are Associated with Muscle Invasion.

Bladder cancer (BC) is the most common neoplasm of the urinary tract, which originates in the epithelium that covers the inner surface of the bladder. The molecular BC profile has led to the development of different classifications of non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). However, the genomic BC landscape profile of the Mexican population, including NMIBC and MIBC, is unknown. In this study, we aimed to identify somatic single nucleotide variants (SNVs) and copy number variations (CNVs) in Mexican patients with BC and their associations with clinical and pathological characteristics. We retrospectively evaluated 37 patients treated between 2012 and 2021 at the National Cancer Institute-Mexico (INCan). DNA samples were obtained from paraffin-embedded tumor tissues and exome sequenced. Strelka2 and Lancet packages were used to identify SNVs and insertions or deletions. FACETS was used to determine CNVs. We found a high frequency of mutations in TP53 and KMT2D, gains in 11q15.5 and 19p13.11-q12, and losses in 7q11.23. STAG2 mutations and 1q11.23 deletions were also associated with NMIBC and low histologic grade.

Large-scale topological disruption of chromosome territories 9 and 22 is associated with nonresponse to treatment in CML.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined by the presence of t(9;22) translocation whose origin has been associated with the tridimensional genome organization. This rearrangement leads to the fusion of BCR and ABL1 genes giving rise to a chimeric protein with constitutive kinase activity. Imatinib, a tyrosine kinase inhibitor (TKI), is used as a first-line treatment for CML, though ~40% of CML patients do not respond. Here, using structured illumination microscopy (SIM) and 3D reconstruction, we studied the 3D organization patterns of the ABL1 and BCR genes, and their chromosome territories (CTs) CT9 and CT22, in CD34+ cells from CML patients that responded or not to TKI. We found that TKI resistance in CML is associated with high levels of structural disruption of CT9 and CT22 in CD34+ cells, increased CT volumes (especially for CT22), intermingling between CT9 and CT22, and an open-chromatin epigenetic mark in CT22. Altogether our results suggest that large-scale disruption of CT9 and CT22 correlates with the clinical response of CML patients, which could be translated into a potential prognostic marker of response to treatment in this disease and provide novel insights into the mechanisms underlying resistance to TKI in CML.

DNA Methyltransferases: From Evolution to Clinical Applications.

DNA methylation is an epigenetic mark that living beings have used in different environments. The MTases family catalyzes DNA methylation. This process is conserved from archaea to eukaryotes, from fertilization to every stage of development, and from the early stages of cancer to metastasis. The family of DNMTs has been classified into DNMT1, DNMT2, and DNMT3. Each DNMT has been duplicated or deleted, having consequences on DNMT structure and cellular function, resulting in a conserved evolutionary reaction of DNA methylation. DNMTs are conserved in the five kingdoms of life: bacteria, protists, fungi, plants, and animals. The importance of DNMTs in whether methylate or not has a historical adaptation that in mammals has been discovered in complex regulatory mechanisms to develop another padlock to genomic insurance stability. The regulatory mechanisms that control DNMTs expression are involved in a diversity of cell phenotypes and are associated with pathologies transcription deregulation. This work focused on DNA methyltransferases, their biology, functions, and new inhibitory mechanisms reported. We also discuss different approaches to inhibit DNMTs, the use of non-coding RNAs and nucleoside chemical compounds in recent studies, and their importance in biological, clinical, and industry research.

The Roles of Histone Post-Translational Modifications in the Formation and Function of a Mitotic Chromosome.

During mitosis, many cellular structures are organized to segregate the replicated genome to the daughter cells. Chromatin is condensed to shape a mitotic chromosome. A multiprotein complex known as kinetochore is organized on a specific region of each chromosome, the centromere, which is defined by the presence of a histone H3 variant called CENP-A. The cytoskeleton is re-arranged to give rise to the mitotic spindle that binds to kinetochores and leads to the movement of chromosomes. How chromatin regulates different activities during mitosis is not well known. The role of histone post-translational modifications (HPTMs) in mitosis has been recently revealed. Specific HPTMs participate in local compaction during chromosome condensation. On the other hand, HPTMs are involved in CENP-A incorporation in the centromere region, an essential activity to maintain centromere identity. HPTMs also participate in the formation of regulatory protein complexes, such as the chromosomal passenger complex (CPC) and the spindle assembly checkpoint (SAC). Finally, we discuss how HPTMs can be modified by environmental factors and the possible consequences on chromosome segregation and genome stability.

Transcriptomics and RNA-Based Therapeutics as Potential Approaches to Manage SARS-CoV-2 Infection.

SARS-CoV-2 is a coronavirus family member that appeared in China in December 2019 and caused the disease called COVID-19, which was declared a pandemic in 2020 by the World Health Organization. In recent months, great efforts have been made in the field of basic and clinical research to understand the biology and infection processes of SARS-CoV-2. In particular, transcriptome analysis has contributed to generating new knowledge of the viral sequences and intracellular signaling pathways that regulate the infection and pathogenesis of SARS-CoV-2, generating new information about its biology. Furthermore, transcriptomics approaches including spatial transcriptomics, single-cell transcriptomics and direct RNA sequencing have been used for clinical applications in monitoring, detection, diagnosis, and treatment to generate new clinical predictive models for SARS-CoV-2. Consequently, RNA-based therapeutics and their relationship with SARS-CoV-2 have emerged as promising strategies to battle the SARS-CoV-2 pandemic with the assistance of novel approaches such as CRISPR-CAS, ASOs, and siRNA systems. Lastly, we discuss the importance of precision public health in the management of patients infected with SARS-CoV-2 and establish that the fusion of transcriptomics, RNA-based therapeutics, and precision public health will allow a linkage for developing health systems that facilitate the acquisition of relevant clinical strategies for rapid decision making to assist in the management and treatment of the SARS-CoV-2-infected population to combat this global public health problem.

Expression of DNA Methyltransferase 3B Isoforms Is Associated with DNA Satellite 2 Hypomethylation and Clinical Prognosis in Advanced High-Grade Serous Ovarian Carcinoma.

Alterations in DNA methylation are critical for the carcinogenesis of ovarian tumors, especially ovarian carcinoma (OC). DNMT3B, a de novo DNA methyltransferase (DNMT), encodes for fifteen spliced protein products or isoforms. DNMT3B isoforms lack exons for the catalytic domain, with functional consequences on catalytic activity. Abnormal expression of DNMT3B isoforms is frequently observed in several types of cancer, such as breast, lung, kidney, gastric, liver, skin, leukemia, and sarcoma. However, the expression patterns and consequences of DNMT3B isoforms in OC are unknown. In this study, we analyzed each DNMT and DNMT3B isoforms expression by qPCR in 63 OC samples and their association with disease-free survival (DFS), overall survival (OS), and tumor progression. We included OC patients with the main histological subtypes of EOC and patients in all the disease stages and found that DNMTs were overexpressed in advanced stages (p-value < 0.05) and high-grade OC (p-value < 0.05). Remarkably, we found DNMT3B1 overexpression in advanced stages (p-value = 0.0251) and high-grade serous ovarian carcinoma (HGSOC) (p-value = 0.0313), and DNMT3B3 was overexpressed in advanced stages (p-value = 0.0098) and high-grade (p-value = 0.0004) serous ovarian carcinoma (SOC). Finally, we observed that overexpression of DNMT3B isoforms was associated with poor prognosis in OC and SOC. DNMT3B3 was also associated with FDS (p-value = 0.017) and OS (p-value = 0.038) in SOC patients. In addition, the ovarian carcinoma cell lines OVCAR3 and SKOV3 also overexpress DNMT3B3. Interestingly, exogenous overexpression of DNMT3B3 in OVCAR3 causes demethylation of satellite 2 sequences in the pericentromeric region. In summary, our results suggest that DNMT3B3 expression is altered in OC.

Somatic Mutational Landscape in Mexican Patients: CDH1 Mutations and chr20q13.33 Amplifications Are Associated with Diffuse-Type Gastric Adenocarcinoma.

The Hispanic population, compared with other ethnic groups, presents a more aggressive gastric cancer phenotype with higher frequency of diffuse-type gastric adenocarcinoma (GA); this could be related to the mutational landscape of GA in these patients. Using whole-exome sequencing, we sought to present the mutational landscape of GA from 50 Mexican patients who were treated at The Instituto Nacional de Cancerología from 2019 to 2020. We performed a comprehensive statistical analysis to explore the relationship of the genomic variants and clinical data such as tumor histology and presence of signet-ring cell, H. pylori, and EBV. We describe a potentially different mutational landscape between diffuse and intestinal GA in Mexican patients. Patients with intestinal-type GA tended to present a higher frequency of NOTCH1 mutations, copy number gains in cytobands 13.14, 10q23.33, and 12q25.1, and copy number losses in cytobands 7p12, 14q24.2, and 11q13.1; whereas patients with diffuse-type GA tended to present a high frequency of CDH1 mutations and CNV gains in cytobands 20q13.33 and 22q11.21. This is the first description of a mutational landscape of GA in Mexican patients to better understand tumorigenesis in Hispanic patients and lay the groundwork for discovering potential biomarkers and therapeutic targets.

Methylation of Subtelomeric Chromatin Modifies the Expression of the lncRNA TERRA, Disturbing Telomere Homeostasis.

The long noncoding RNA (lncRNA) telomeric repeat-containing RNA (TERRA) has been associated with telomeric homeostasis, telomerase recruitment, and the process of chromosome healing; nevertheless, the impact of this association has not been investigated during the carcinogenic process. Determining whether changes in TERRA expression are a cause or a consequence of cell transformation is a complex task because studies are usually carried out using either cancerous cells or tumor samples. To determine the role of this lncRNA in cellular aging and chromosome healing, we evaluated telomeric integrity and TERRA expression during the establishment of a clone of untransformed myeloid cells. We found that reduced expression of TERRA disturbed the telomeric homeostasis of certain loci, but the expression of the lncRNA was affected only when the methylation of subtelomeric bivalent chromatin domains was compromised. We conclude that the disruption in TERRA homeostasis is a consequence of cellular transformation and that changes in its expression profile can lead to telomeric and genomic instability.

Sex-dependent pronociceptive role of spinal α5 -GABAA receptor and its epigenetic regulation in neuropathic rodents.

Extrasynaptic α5 -subunit containing GABAA (α5 -GABAA ) receptors participate in chronic pain. Previously, we reported a sex difference in the action of α5 -GABAA receptors in dysfunctional pain. However, the underlying mechanisms remain unknown. The aim of this study was to examine this sexual dimorphism in neuropathic rodents and the mechanisms involved. Female and male Wistar rats or ICR mice were subjected to nerve injury followed by α5 -GABAA receptor inverse agonist intrathecal administration, L-655,708. The drug produced an antiallodynic effect in nerve-injured female rats and mice, and a lower effect in males. We hypothesized that changes in α5 -GABAA receptor, probably influenced by hormonal and epigenetic status, might underlie this sex difference. Thus, we performed qPCR and western blot. Nerve injury increased α5 -GABAA mRNA and protein in female dorsal root ganglia (DRG) and decreased them in DRG and spinal cord of males. To investigate the hormonal influence over α5 -GABAA receptor actions, we performed nerve injury to ovariectomized rats and reconstituted them with 17ß-estradiol (E2). Ovariectomy abrogated L-655,708 antiallodynic effect and E2 restored it. Ovariectomy decreased α5 -GABAA receptor and estrogen receptor α protein in DRG of neuropathic female rats, while E2 enhanced them. Since DNA methylation might contribute to α5 -GABAA receptor down-regulation in males, we examined CpG island DNA methylation of α5 -GABAA receptor coding gene through pyrosequencing. Nerve injury increased methylation in male, but not female rats. Pharmacological inhibition of DNA methyltransferases increased α5 -GABAA receptor and enabled L-655,708 antinociceptive effect in male rats. These results suggest that α5 -GABAA receptor is a suitable target to treat chronic pain in females.

Long-term PM2.5 exposure before diagnosis is associated with worse outcome in breast cancer.

PURPOSE: Increasingly epidemiological evidence supports that environmental factors are associated with breast cancer (BC) outcomes after a BC diagnosis. Although evidence suggests that air pollution exposure is associated with higher mortality in women with BC, studies investigating potential mechanisms have been lacking. METHODS: We evaluated women with BC (N = 151) attended at the National Cancer Institute-Mexico from 2012 to 2015. We calculated 1-year average exposures to particulate matter < 2.5 µm (PM2.5) at home address before diagnosis. We used linear and logistic regression models to determine the associations between PM2.5 exposure and BC aggressiveness (tumor size, molecular phenotype). RESULTS: Average annual PM2.5 exposure of this population was 23.0 µg/m3 [standard deviation (SD)]: 1.90 µg/m3]. PM2.5 levels were positively correlated with tumor size at diagnosis (r = 0.22; p = 0.007). Multivariable linear models had a similar inference [risk ratio (RR): 1.32; 95% confidence interval (95% CI): 1.04, 1.674]. We did not observe differences in this association by age or menopause status. Further, women with triple-negative BC (TNBC) had significantly higher PM2.5 levels compared with other phenotypes (p = 0.015). Multivariable-adjusted logistic regression models assessing the association between PM2.5 and tumor size had a similar inference (RR 1.41; 95% CI 1.05, 1.89) overall for all ages and also for women who were ≤ 50 years old at diagnosis (RR 1.63; 95% CI 1.036, 2.57). CONCLUSIONS: Our findings suggest a significant association between long-term PM2.5 exposure and BC aggressiveness based on tumor size and phenotype, as well as a worse outcome.

Preoperative intragastric balloon in morbid obesity is unable to decrease early postoperative morbidity of bariatric surgery (sleeve gastrectomy and gastric bypass): a clinical assay.

INTRODUCTION: There are few studies that investigate the usefulness of the preoperative intragastric balloon (IGB). This study will evaluate if pre-surgical weight loss with IGB reduces morbidity and mortality after surgery. METHOD: Prospective randomised study of patients with morbid obesity treated with gastric bypass or vertical gastrectomy, with two arms: the balloon arm (B-arm), where an IGB was inserted within the 6 months before surgery, and the control arm (C-arm). RESULTS: The study included 66 patients: 65.6% women, 69.6% with bypass. Age: 43 years (SD 10.2) B-arm and 42.6 years (SD 9.2) in the C-arm. We found 34.4% therapeutic failures in IGB. The mean body weight loss, %EWL and BMI reduction before surgery was 16.2 kg (SD 9.84) B-arm versus 4.7 (SD 8.70) in the C-arm, 23.6% versus 4.7% (p < 0.001) and 6.04 versus 1 (p < 0.001), respectively. The hospital stay was 7 days (p25-75: 5-8) B-arm and 7 days (p25-75: 5-9) in the C-arm (p = 0.937). Post-surgical morbidity with IGB was 25% versus 29.5% in the C-arm, p = 0.689. The number needed to treat (NNT) to prevent of post-surgical morbidity was 23 patients. The B-arm presented 54.5% moderate-severe post-surgical adverse events (12.5%) versus 82.6% in the C-arm (23.5%), p = 0.111. The cost of placing a balloon was more than 4000 Euros each. CONCLUSIONS: The preoperative balloon does not achieve a reduction in the post-surgical morbidity, nor does it reduce the hospital stay or rate of re-operations. The balloon achieves a higher weight loss result when compared to a diet programme, its added cost must also be given due consideration. TRAIL REGISTRY: This study has been registered on ClinicalTrials.gov with the Identifier: NCT01998243 (November 28, 2013).

What is the impact of radical hysterectomy on endometrial cancer with cervical involvement?

BACKGROUND: When endometrial carcinoma invades the cervical stroma, overall survival and disease-free survival decrease. However, it is still controversial whether patients in suspected stage II should be treated with radical hysterectomy. The goal of this study is to describe the role of radical hysterectomy in patients with endometrial carcinoma and cervical involvement. METHODS: This was a retrospective cohort study were a total of 239 patients with endometrial carcinoma with cervical involvement from Mexico City's National Cancer Institute were divided according to the type of hysterectomy, and the outcomes were compared using statistical analysis. RESULTS: The 5-year overall survival was 75.76% for the simple hysterectomy group and 89.19% for the radical hysterectomy group, without achieving statistical significance. The 5-year disease-free survival was 72.95% for the simple hysterectomy group and 64.31% for the radical hysterectomy group, without achieving statistical significance. Radicality was associated with longer surgical times, intraoperative complications, and bleeding over 500 ml. CONCLUSIONS: In patients with endometrial carcinoma with cervical involvement, radical hysterectomy does not improve prognosis or alter adjuvant therapy.

Prognostic Significance of the MAD1L1 1673 G: A Polymorphism in Ovarian Adenocarcinomas.

BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer. Although most patients respond adequately to the first-line therapy, up to 85% experience a recurrence of disease, which carries a poor prognosis. Mitotic arrest deficiency 1 is a protein that helps in the assembly of the mitotic spindle assembly checkpoint by preventing anaphase until all chromatids are properly aligned. A single-nucleotide polymorphism in the MAD1L1 gene is prevalent in patients with advanced epithelial ovarian cancer and alters the way in which it responds to chemotherapy. OBJECTIVE: The objective of the study was to study the relationship between the rs1801368 polymorphism of MAD1L1 and prognosis of ovarian adenocarcinoma. METHODS: A total of 118 patients in whom the MAD1L1 gene was sequenced were analyzed using descriptive and comparative statistics. RESULTS: Patients carrying the wild-type genotype had a higher distribution of early-stage disease. Having a MAD1L1 polymorphic allele increased the risk of being non-sensitive to chemotherapy. The median disease-free survival for patients with the wild-type MAD1L1 was 46.93 months, compared to 10.4 months for patients with at least one polymorphic allele. CONCLUSIONS: The rs1801368 polymorphism of MAD1L1 gene worsens prognosis in patients with ovarian adenocarcinoma. Traditional therapy for ovarian cancer might not be optimal in patients carrying this polymorphism.

Prognostic Significance of the MAD1L1 1673 G: A Polymorphism in Ovarian Adenocarcinomas.

BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer. Although most patients respond adequately to the first-line therapy, up to 85% experience a recurrence of disease, which carries a poor prognosis. Mitotic arrest deficiency 1 is a protein that helps in the assembly of the mitotic spindle assembly checkpoint by preventing anaphase until all chromatids are properly aligned. A single-nucleotide polymorphism in the MAD1L1 gene is prevalent in patients with advanced epithelial ovarian cancer and alters the way in which it responds to chemotherapy. OBJECTIVE: The objective of the study was to study the relationship between the rs1801368 polymorphism of MAD1L1 and prognosis of ovarian adenocarcinoma. METHODS: A total of 118 patients in whom the MAD1L1 gene was sequenced were analyzed using descriptive and comparative statistics. RESULTS: Patients carrying the wild-type genotype had a higher distribution of early-stage disease. Having a MAD1L1 polymorphic allele increased the risk of being non-sensitive to chemotherapy. The median disease-free survival for patients with the wild-type MAD1L1 was 46.93 months, compared to 10.4 months for patients with at least one polymorphic allele. CONCLUSIONS: The rs1801368 polymorphism of MAD1L1 gene worsens prognosis in patients with ovarian adenocarcinoma. Traditional therapy for ovarian cancer might not be optimal in patients carrying this polymorphism.

Extracellular vesicle-enriched microRNAs interact in the association between long-term particulate matter and blood pressure in elderly men.

BACKGROUND: Several studies have shown that exposure to particulate matter (PM) may lead to increased systemic blood pressure, but the underlying biological mechanisms remain unknown. Emerging evidence shows that extracellular vesicle-enriched miRNAs (evmiRNAs) are associated with PM exposure and cardiovascular risk. In this study, we investigated the role of evmiRNAs in the association between PM and blood pressure, as well as their epigenetic regulation by DNA methylation. METHODS: Participants (n = 22, men) were randomly selected from the Veterans Affairs Normative Aging Study (NAS). Long-term (1-year and 6-month average) PM2.5 exposure was estimated at 1 × 1-km resolution using spatio-temporal prediction models and BC was estimated using validated time varying land use regression models. We analyzed 31 evmiRNAs detected in ≥ 90% of all individuals and for statistical analysis, we used mixed effects models with random intercept adjusted for age, body mass index, smoking, C-reactive protein, platelets, and white blood cells. RESULTS: We found that per each 2-standard deviations increase in 6-month PM2.5 ambient levels, there was an increase in 0.19 mm Hg (95% Confidence Interval [95%CI]: 0.11, 0.28 mmHg; p < 0.001) in systolic blood pressure (SBP). Per each 2-standard deviations increase in 1-year PM2.5 levels, there was an increase in 0.11 mm Hg (95% Confidence Interval [95% CI]: 0.03, 0.19 mmHg; p = 0.012) in SBP in older male individuals. We also found that both miR-199a/b (ß = 6.13 mmHg; 95% CI: 0.87, 11.39; pinteraction = 0.07) and miR-223-3p (ß = 30.17 mmHg; 95% CI: 11.96, 48.39 mmHg; pinteraction = 0.01) modified the association between 1-year PM2.5 and SBP. When exploring DNA methylation as a potential mechanism that could epigenetically regulate expression of evmiRNAs, we found that PM2.5 ambient levels were negatively associated with DNA methylation levels at CpG (cg23972892) near the enhancer region of miR-199a/b (ß = -13.11; 95% CI: -17.70, -8.52; pBonferroni< 0.01), but not miR-223-3p. CONCLUSIONS: Our findings suggest that expression of evmiRNAs may be regulated by DNA methylation in response to long-term PM2.5 ambient levels and modify the magnitude of association between PM2.5 and systolic blood pressure in older individuals.

Prognostic significance of promoter CpG island methylation of obesity-related genes in patients with nonmetastatic renal cell carcinoma.

BACKGROUND: Greater than 40% of renal cell carcinoma (RCC) cases in the United States are attributed to excessive body weight. Moreover, obesity also may be linked to RCC prognosis. However, the molecular mechanisms underlying these associations are unclear. In the current study, the authors evaluated the role of promoter methylation in obesity-related genes in RCC tumorigenesis and disease recurrence. METHODS: Paired tumors (TU) and normal adjacent (N-Adj) tissues from 240 newly diagnosed and previously untreated white patients with RCC were examined. For the discovery phase, 63 RCC pairs were analyzed. An additional 177 RCC pairs were evaluated for validation. Pyrosequencing was used to determine CpG methylation in 20 candidate obesity-related genes. An independent data set from The Cancer Genome Atlas also was analyzed for functional validation. The association between methylation and disease recurrence was analyzed using multivariate Cox proportional hazards models and Kaplan-Meier survival analysis. RESULTS: Methylation in neuropeptide Y (NPY), leptin (LEP), and leptin receptor (LEPR) was significantly higher in TU compared with N-Adj tissues (P<.0001) in both the discovery and validation groups. High methylation in LEPR was associated with an increased risk of disease recurrence (hazard ratio, 3.15; 95% confidence interval, 1.23-8.07 [P = .02]). Patients with high methylation in LEPR had a shorter recurrence-free survival compared with patients in the low-methylation group (log-rank P = 2.25 × 10-3 ). In addition, high LEPR methylation in TU was associated with more advanced features (P≤.05). Consistent with the findings of the current study, lower LEPR expression in TU compared with N-Adj tissues (P = 1.00 × 10-3 ) was found in data from The Cancer Genome Atlas. CONCLUSIONS: Somatic alterations of promoter methylation in the NPY, LEP, and LEPR genes are involved in RCC tumorigenesis. Furthermore, LEPR methylation appears to be associated with RCC recurrence. Future research to elucidate the biology underlying this association is warranted. Cancer 2017;123:3617-27. © 2017 American Cancer Society.