Transcriptome and microbiome-immune changes across preinvasive and invasive anal cancer lesions.

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy linked to high-risk Human papillomavirus (HPV) infection, which develops from precursor lesions like Low-Grade Squamous Intraepithelial Lesions (LGSIL) and High-Grade Squamous Intraepithelial Lesions (HGSIL). ASCC incidence varies across populations, posing increased risk for People Living with HIV (PLWH). Our investigation focused on transcriptomic and metatranscriptomic changes from Squamous Intraepithelial Lesions (SILs) to ASCC. Metatranscriptomic analysis highlighted specific bacterial species (e.g., Fusobacterium nucleatum, Bacteroides fragilis) more prevalent in ASCC than precancerous lesions. These species correlated with gene encoding enzymes (Acca, glyQ, eno, pgk, por) and oncoproteins (FadA, dnaK), presenting potential diagnostic or treatment markers. Unsupervised transcriptome analysis identified distinct sample clusters reflecting histological diagnosis, immune infiltrate, HIV/HPV status, and pathway activities, recapitulating anal cancer progression's natural history. Our study unveiled molecular mechanisms in anal cancer progression, aiding in stratifying HGSIL cases based on low- or high-risk progression to malignancy.

Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy.

Several studies have indicated that interrupted epigenetic reprogramming using Yamanaka transcription factors (OSKM) can rejuvenate cells from old laboratory animals and humans. However, the potential of OSKM-induced rejuvenation in brain tissue has been less explored. Here, we aimed to restore cognitive performance in 25.3-month-old female Sprague-Dawley rats using OSKM gene therapy for 39 days. Their progress was then compared with the cognitive performance of untreated 3.5-month-old rats as well as old control rats treated with a placebo adenovector. The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39 days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation. In summary, the administration of Yamanaka genes via viral vectors rejuvenates the functional capabilities and the epigenetic landscape of the rat hippocampus.

Unveiling the role of KSHV-infected human mesenchymal stem cells in Kaposi's sarcoma initiation.

Kaposi's sarcoma (KS) may derive from Kaposi's sarcoma herpesvirus (KSHV)-infected human mesenchymal stem cells (hMSCs) that migrate to sites characterized by inflammation and angiogenesis, promoting the initiation of KS. By analyzing the RNA sequences of KSHV-infected primary hMSCs, we have identified specific cell subpopulations, mechanisms, and conditions involved in the initial stages of KSHV-induced transformation and reprogramming of hMSCs into KS progenitor cells. Under proangiogenic environmental conditions, KSHV can reprogram hMSCs to exhibit gene expression profiles more similar to KS tumors, activating cell cycle progression, cytokine signaling pathways, endothelial differentiation, and upregulating KSHV oncogenes indicating the involvement of KSHV infection in inducing the mesenchymal-to-endothelial (MEndT) transition of hMSCs. This finding underscores the significance of this condition in facilitating KSHV-induced proliferation and reprogramming of hMSCs towards MEndT and closer to KS gene expression profiles, providing further evidence of these cell subpopulations as precursors of KS cells that thrive in a proangiogenic environment.

Surrogate indices of insulin resistance using the Matsuda index as reference in adult men-a computational approach.

Background: Overweight and obesity, high blood pressure, hyperglycemia, hyperlipidemia, and insulin resistance (IR) are strongly associated with non-communicable diseases (NCDs), including type 2 diabetes, cardiovascular disease, stroke, and cancer. Different surrogate indices of IR are derived and validated with the euglycemic-hyperinsulinemic clamp (EHC) test. Thus, using a computational approach to predict IR with Matsuda index as reference, this study aimed to determine the optimal cutoff value and diagnosis accuracy for surrogate indices in non-diabetic young adult men. Methods: A cross-sectional descriptive study was carried out with 93 young men (ages 18-31). Serum levels of glucose and insulin were analyzed in the fasting state and during an oral glucose tolerance test (OGTT). Additionally, clinical, biochemical, hormonal, and anthropometric characteristics and body composition (DEXA) were determined. The computational approach to evaluate the IR diagnostic accuracy and cutoff value using difference parameters was examined, as well as other statistical tools to make the output robust. Results: The highest sensitivity and specificity at the optimal cutoff value, respectively, were established for the Homeostasis model assessment of insulin resistance index (HOMA-IR) (0.91; 0.98; 3.40), the Quantitative insulin sensitivity check index (QUICKI) (0.98; 0.96; 0.33), the triglyceride-glucose (TyG)-waist circumference index (TyG-WC) (1.00; 1.00; 427.77), the TyG-body mass index (TyG-BMI) (1.00; 1.00; 132.44), TyG-waist-to-height ratio (TyG-WHtR) (0.98; 1.00; 2.48), waist-to-height ratio (WHtR) (1.00; 1.00; 0.53), waist circumference (WC) (1.00; 1.00; 92.63), body mass index (BMI) (1.00; 1.00; 28.69), total body fat percentage (TFM) (%) (1.00; 1.00; 31.07), android fat (AF) (%) (1.00; 0.98; 40.33), lipid accumulation product (LAP) (0.84; 1.00; 45.49), leptin (0.91; 1.00; 16.08), leptin/adiponectin ratio (LAR) (0.84; 1.00; 1.17), and fasting insulin (0.91; 0.98; 16.01). Conclusions: The computational approach was used to determine the diagnosis accuracy and the optimal cutoff value for IR to be used in preventive healthcare.

miR-877-5p as a Potential Link between Triple-Negative Breast Cancer Development and Metabolic Syndrome.

Metabolic syndrome (MS) is a risk factor for breast cancer (BC) that increases its aggressiveness and metastasis. The prevalence of MS is higher in triple-negative breast cancer (TNBC), which is the molecular subtype with the worst prognosis. The molecular mechanisms underlying this association have not been fully elucidated. MiRNAs are small, non-coding RNAs that regulate gene expression. Aberrant expression of miRNAs in both tissues and fluids are linked to several pathologies. The aim of this work was to identify circulating miRNAs in patients with alterations associated with MS (AAMS) that also impact on BC. Using microarray technology, we detected 23 miRNAs altered in the plasma of women with AAMS that modulate processes linked to cancer. We found that let-7b-5p and miR-28-3p were decreased in plasma from patients with AAMS and also in BC tumors, while miR-877-5p was increased. Interestingly, miR-877-5p expression was associated with lower patient survival, and its expression was higher in PAM50 basal-like BC tumors compared to the other molecular subtypes. Analyses from public databases revealed that miR-877-5p was also increased in plasma from BC patients compared to plasma from healthy donors. We identified IGF2 and TIMP3 as validated target genes of miR-877-5p whose expression was decreased in BC tissue and moreover, was negatively correlated with the levels of this miRNA in the tumors. Finally, a miRNA inhibitor against miR-877-5p diminished viability and tumor growth of the TNBC model 4T1. These results reveal that miR-877-5p inhibition could be a therapeutic option for the treatment of TNBC. Further studies are needed to investigate the role of this miRNA in TNBC progression.

Oral and anal microbiome from HIV-exposed individuals: role of host-associated factors in taxa composition and metabolic pathways.

Evidence indicates that the microbiome plays a significant role in HIV immunopathogenesis and associated complications. This study aimed to characterize the oral and anal microbiome of Men who have Sex with Men (MSM) and Transgender Women (TGW), with and without HIV. One hundred and thirty oral and anal DNA-derived samples were obtained from 78 participants and subjected to shotgun metagenomics sequencing for further microbiome analysis. Significant differences in the microbiome composition were found among subjects associated with HIV infection, gender, sex behavior, CD4+ T-cell counts, antiretroviral therapy (ART), and the presence of HPV-associated precancerous anal lesions. Results confirm the occurrence of oncogenic viromes in this high HIV-risk population. The oral microbiome in HIV-associated cases exhibited an enrichment of bacteria associated with periodontal disease pathogenesis. Conversely, anal bacteria showed a significant decrease in HIV-infected subjects (Coprococcus comes, Finegoldia magna, Blautia obeum, Catenibacterium mitsuokai). TGW showed enrichment in species related to sexual transmission, which concurs that most recruited TGW are or have been sex workers. Prevotella bivia and Fusobacterium gonidiaformans were positively associated with anal precancerous lesions among HIV-infected subjects. The enrichment of Holdemanella biformis and C. comes was associated with detectable viral load and ART-untreated patients. Metabolic pathways were distinctly affected by predominant factors linked to sexual behavior or HIV pathogenesis. Gene family analysis identified bacterial gene signatures as potential prognostic and predictive biomarkers for HIV/AIDS-associated malignancies. Conclusions: Identified microbial features at accessible sites are potential biomarkers for predicting precancerous anal lesions and therapeutic targets for HIV immunopathogenesis.

Hsa-miR-133a-3p, miR-1-3p, GOLPH3 and JUP combination results in a good biomarker to distinguish between prostate cancer and non-prostate cancer patients.

The incidence and mortality of Prostate Cancer (PCa) worldwide correlate with age and bad dietary habits. Previously, we investigated the mRNA/miRNA role on PCa development and progression using high fat diet (HFD) fed mice. Here our main goal was to investigate the effect of HFD on the expression of PCa-related miRNAs and their relevance in PCa patients. We identified 6 up- and 18 down-regulated miRNAs in TRAMP-C1 mice prostate tumors under HFD conditions using miRNA microarrays. Three down-regulated miRNAs: mmu-miR-133a-3p, -1a-3p and -29c-3p were validated in TRAMP-C1 mice prostate tumor by stem-loop RT-qPCR. Hsa-miR-133a-3p/1-3p expression levels were significantly decreased in PCa compared to normal tissues while hsa-miR-133a-3p was found to be further decreased in metastatic prostate cancer tumors compared to non-metastatic PCa. We examined the promoter region of hsa-miR-133a-3p/1-3p genes and compared methylation at these loci with mature miRNA expression. We found that hsa-miR-1-2/miR-133a-1 cluster promoter hypermethylation decreased hsa-miR-133a-3p/1-3p expression in PCa. GOLPH3 and JUP, two hsa-miR-133a-3p and miR-1-3p predicted target genes, were up-regulated in PCa. ROC analysis showed that the combination of hsa-miR-133a-3p, miR-1-3p, GOLPH3 and JUP is a promising panel biomarker to distinguish between PCa and normal adjacent tissue (NAT). These results link PCa aggressiveness to the attenuation of hsa-miR-133a-3p and miR-1-3p expression by promoter hypermethylation. Hsa-miR-133a-3p and miR-1-3p down-regulation may enhance PCa aggressiveness in part by targeting GOLPH3 and JUP.

MALINC1 an Immune-Related Long Non-Coding RNA Associated with Early-Stage Breast Cancer Progression.

Long non-coding RNAs are increasingly being recognized as cancer biomarkers in various malignancies, acting as either tumor suppressors or oncogenes. The long non-coding MALINC1 intergenic RNA was identified as significantly upregulated in breast ductal carcinoma in situ. The aim of this study was to characterize MALINC1 expression, localization, and phenotypic and molecular effects in non-invasive and invasive breast cancer cells. We determined that MALINC1 is an estrogen-estrogen receptor-modulated lncRNA enriched in the cytoplasmic fraction of luminal A/B breast cancer cells that is associated with worse overall survival in patients with primary invasive breast carcinomas. Transcriptomic studies in normal and DCIS cells identified the main signaling pathways modulated by MALINC1, which mainly involve bioprocesses related to innate and adaptive immune responses, extracellular matrix remodeling, cell adhesion, and activation of AP-1 signaling pathway. We determined that MALINC1 induces premalignant phenotypic changes by increasing cell migration in normal breast cells. Moreover, high MALINC1 expression in invasive carcinomas was associated with a pro-tumorigenic immune environment and a favorable predicted response to immunotherapy both in luminal and basal-like subtypes compared with low-MALINC1-expression tumors. We conclude that MALINC1 behaves as an oncogenic and immune-related lncRNA involved with early-stage breast cancer progression.

Fatty acid binding protein 5 regulates lipogenesis and tumor growth in lung adenocarcinoma.

AIMS: Lung cancer is the leading cause of cancer-related death. Unfortunately, targeted-therapies have been unsuccessful for most patients with lung adenocarcinoma (LUAD). Thus, new early biomarkers and treatment options are a pressing need. Fatty acid binding protein 5 (FABP5) has been associated with various types of cancers. Its contribution to LUAD onset, progression and metabolic reprogramming is, however, not fully understood. In this study we assessed the importance of FABP5 in LUAD and its role in cancer lipid metabolism. MAIN METHODS: By radioactive labeling and metabolite quantification, we studied the function of FABP5 in fatty acid metabolism using genetic/pharmacologic inhibition and overexpression models in LUAD cell lines. Flow cytometry, heterologous transplantation and bioinformatic analysis were used, in combination with other methodologies, to assess the importance of FABP5 for cellular proliferation in vitro and in vivo and in patient survival. KEY FINDINGS: We show that high expression of FABP5 is associated with poor prognosis in patients with LUAD. FABP5 regulates lipid metabolism, diverting fatty acids towards complex lipid synthesis, whereas it does not affect their catabolism in vitro. Moreover, FABP5 is required for de novo fatty acid synthesis and regulates the expression of enzymes involved in the pathway (including FASN and SCD1). Consistently with the changes in lipid metabolism, FABP5 is required for cell cycle progression, migration and in vivo tumor growth. SIGNIFICANCE: Our results suggest that FABP5 is a regulatory hub of lipid metabolism and tumor progression in LUAD, placing it as a new putative therapeutic target for this disease.

IGF-1 Gene Transfer Modifies Inflammatory Environment and Gene Expression in the Caudate-Putamen of Aged Female Rat Brain.

Brain aging is characterized by chronic neuroinflammation caused by activation of glial cells, mainly microglia, leading to alterations in homeostasis of the central nervous system. Microglial cells are constantly surveying their environment to detect and respond to diverse signals. During aging, microglia undergoes a process of senescence, characterized by loss of ramifications, spheroid formation, and fragmented processes, among other abnormalities. Therefore, the study of changes in microglia during is of great relevance to understand age-related declines in cognitive and motor function. We have targeted the deleterious effects of aging by implementing IGF-1 gene transfer, employing recombinant adenoviral vectors (RAds) as a delivery system. In this study, we performed intracerebroventricular (ICV) RAd-IGF-1 or control injection on aged female rats and evaluated its effect on caudate-putamen unit (CPu) gene expression and inflammatory state. Our results demonstrate that IGF-1 overexpression modified aged microglia of the CPu towards an anti-inflammatory condition increasing the proportion of double immuno-positive Iba1+Arg1+ cells. We also observed that phosphorylation of Akt was increased in animals treated with RAd-IGF-1. Moreover, IGF-1 gene transfer was able to regulate CPu pro-inflammatory environment in female aged rats by down-regulating the expression of genes typically overexpressed during aging. RNA-Seq data analysis identified 97 down-modulated DEG in the IGF-1 group as compared to the DsRed one. Interestingly, 12 of these DEG are commonly overexpressed during aging, and 9 out of 12 are expressed in microglia/macrophages and are involved in different processes that lead to neuroinflammation and/or neuronal loss. Finally, we observed that IGF-1 overexpression led to an improvement in motor functions. Although further studies are necessary, with the present results, we conclude that IGF-1 gene transfer is modifying both the pro-inflammatory environment and activation of microglia/macrophages in CPu. In this regard, IGF-1 gene transfer could counteract the neuroinflammatory effects associated with aging and improve motor functions in senile animals.

MiR-106b-5p: A Master Regulator of Potential Biomarkers for Breast Cancer Aggressiveness and Prognosis.

Breast cancer (BCa) is the leading cause of death by cancer in women worldwide. This disease is mainly stratified in four subtypes according to the presence of specific receptors, which is important for BCa aggressiveness, progression and prognosis. MicroRNAs (miRNAs) are small non-coding RNAs that have the capability to modulate several genes. Our aim was to identify a miRNA signature deregulated in preclinical and clinical BCa models for potential biomarker discovery that would be useful for BCa diagnosis and/or prognosis. We identified hsa-miR-21-5p and miR-106b-5p as up-regulated and hsa-miR-205-5p and miR-143-3p as down-regulated in BCa compared to normal breast or normal adjacent (NAT) tissues. We established 51 shared target genes between hsa-miR-21-5p and miR-106b-5p, which negatively correlated with the miRNA expression. Furthermore, we assessed the pathways in which these genes were involved and selected 12 that were associated with cancer and metabolism. Additionally, GAB1, GNG12, HBP1, MEF2A, PAFAH1B1, PPP1R3B, RPS6KA3 and SESN1 were downregulated in BCa compared to NAT. Interestingly, hsa-miR-106b-5p was up-regulated, while GAB1, GNG12, HBP1 and SESN1 were downregulated in aggressive subtypes. Finally, patients with high levels of hsa-miR-106b-5 and low levels of the abovementioned genes had worse relapse free survival and worse overall survival, except for GAB1.

A Non-Coding RNA Network Involved in KSHV Tumorigenesis.

Regulatory pathways involving non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNA), have gained great relevance due to their role in the control of gene expression modulation. Using RNA sequencing of KSHV Bac36 transfected mouse endothelial cells (mECK36) and tumors, we have analyzed the host and viral transcriptome to uncover the role lncRNA-miRNA-mRNA driven networks in KSHV tumorigenesis. The integration of the differentially expressed ncRNAs, with an exhaustive computational analysis of their experimentally supported targets, led us to dissect complex networks integrated by the cancer-related lncRNAs Malat1, Neat1, H19, Meg3, and their associated miRNA-target pairs. These networks would modulate pathways related to KSHV pathogenesis, such as viral carcinogenesis, p53 signaling, RNA surveillance, and cell cycle control. Finally, the ncRNA-mRNA analysis allowed us to develop signatures that can be used to an appropriate identification of druggable gene or networks defining relevant AIDS-KS therapeutic targets.

RHBDD2­WWOX protein interaction during proliferative and differentiated stages in normal and breast cancer cells.

Rhomboid pseudoproteases are catalytically inactive members of the rhomboid superfamily that modulate the traffic, turnover and activity of their target proteins. Rhomboid domain containing 2 (RHBDD2) is a rhomboid family member overexpressed during mammary gland development and advanced stages of breast cancer. Interactome profiling studies have identified RHBDD2 as a novel binding partner of WW domain­containing oxidoreductase (WWOX) protein. The present study characterized the RHBDD2­WWOX interaction in proliferating and differentiated stages of normal mammary and breast cancer cells by co­immunoprecipitation and confocal microscopy. Normal breast and proliferating cancer cells showed significantly increased RHBDD2 mRNA levels compared with their differentiated counterparts. WWOX mRNA was primarily expressed in differentiated cells. WWOX co­precipitated with RHBDD2, indicating that endogenous RHBDD2 and WWOX were physically associated in normal and breast cancer proliferating cells compared with the differentiated stage. Co­localization assays corroborated the co­immunoprecipitation results, demonstrating the RHBDD2­WWOX protein interaction in normal and proliferating breast cancer cells. RHBDD2 harbors a conserved LPPY motif at the C­terminus region that directly interacted with the WW domains of WWOX. Since WWOX serves as an inhibitor of the TGFß/SMAD3 signaling pathway in breast cells, modulation of SMAD3 target genes was analyzed in proliferating and differentiated mammary cells and in RHBDD2 silencing assays. Increased expression levels of SMAD3­regulated genes were detected in proliferating cells compared with their differentiated counterparts. Follistatin and angiopoietin­like 4 mRNA was significantly downregulated in RHBDD2 transiently silenced cells compared with scrambled control small interfering RNA. Based on these results, WWOX was suggested to be a novel RHBDD2 target protein involved in the modulation of breast epithelial cell proliferation and differentiation.

Nuclear Localization of Heme Oxygenase-1 in Pathophysiological Conditions: Does It Explain the Dual Role in Cancer?

Heme Oxygenase-1 (HO-1) is a type II detoxifying enzyme that catalyzes the rate-limiting step in heme degradation leading to the formation of equimolar quantities of carbon monoxide (CO), free iron and biliverdin. HO-1 was originally shown to localize at the smooth endoplasmic reticulum membrane (sER), although increasing evidence demonstrates that the protein translocates to other subcellular compartments including the nucleus. The nuclear translocation occurs after proteolytic cleavage by proteases including signal peptide peptidase and some cysteine proteases. In addition, nuclear translocation has been demonstrated to be involved in several cellular processes leading to cancer progression, including induction of resistance to therapy and enhanced metastatic activity. In this review, we focus on nuclear HO-1 implication in pathophysiological conditions with special emphasis on malignant processes. We provide a brief background on the current understanding of the mechanisms underlying how HO-1 leaves the sER membrane and migrates to the nucleus, the circumstances under which it does so and, maybe the most important and unknown aspect, what the function of HO-1 in the nucleus is.

Clinical factors affecting the determination of radiotherapy-induced skin toxicity in breast cancer.

PURPOSE: Radiotherapy is essential for the treatment of breast cancer (BC). However, adverse effects may occur in healthy tissue, during treatment and even after several months. Although it is known that this clinical radiosensitivity is multifactorial, the factors involved are unknown yet. In this study, we evaluated the effect of these factors on the development of radiodermatitis in patients undergoing radiotherapy. MATERIALS AND METHODS: Demographic and lifestyle data collected during face-to-face interviews of 122 BC patients and data from clinical records were investigated. Most patients underwent conventional three-dimensional radiotherapy treatment. A total dose of 50 Gy was administered (2 Gy/day), followed by a boost in a tumor bed with a total dose of 18 Gy (2 Gy/day). Radiotoxicity was evaluated weekly using the Radiation Therapy Oncology Group classification system (range, 0 to 4, according to the severity). RESULTS: In the present study, 75.4% of patients presented acute skin toxic effects with different degrees of severity. In 25% of cases, these effects manifested at the end of the fourth week at a cumulative dose of 40 Gy. The association of grade ≥2 acute skin reactions with body mass index (BMI) and breast size and between grade 3-4 and age was positive compared with controls. However, the role of the other factors could not be confirmed. CONCLUSION: Analysis of the factors related to individual radiosensitivity suggests that age, BMI and breast size play an important role in the development of acute skin toxicity during treatment. Particular attention to patients who present these characteristics would help to control treatment effectiveness and therefore optimize their quality of life.

LINC00885 a Novel Oncogenic Long Non-Coding RNA Associated with Early Stage Breast Cancer Progression.

Long intergenic non-protein coding RNA 885 (LINC00885) was identified as significantly upregulated in breast ductal carcinoma in situ (DCIS). The aim of this study was to characterize the phenotypic effects and signaling pathways modulated by LINC00885 in non-invasive and invasive breast cancer models. We determined that LINC00885 induces premalignant phenotypic changes by increasing cell proliferation, motility, migration and altering 3D growth in normal and DCIS breast cell lines. Transcriptomic studies (RNA-seq) identified the main signaling pathways modulated by LINC00885, which include bioprocesses related to TP53 signaling pathway and proliferative signatures such as activation of EREG, EGFR and FOXM1 pathways. LINC00885 silencing in breast cancer lines overexpressing this lncRNA leads to downregulation of proliferation related transcripts such as EREG, CMYC, CCND1 and to significant decrease in cell migration and motility. TCGA-BRCA data analyses show an association between high LINC00885 expression and worse overall survival in patients with primary invasive breast carcinomas (p = 0.024), suggesting that the pro-tumorigenic effects of LINC00885 overexpression persist post-invasion. We conclude that LINC00885 behaves as a positive regulator of cell growth both in normal and DCIS breast cells possibly operating as a ceRNA and representing a novel oncogenic lncRNA associated with early stage breast cancer progression.

Adipose tissue from metabolic syndrome mice induces an aberrant miRNA signature highly relevant in prostate cancer development.

Prostate cancer (PCa) remains an important public health concern in Western countries. Metabolic syndrome (MeS) is a cluster of pathophysiological disorders with increasing prevalence in the general population that is a risk factor for PCa. Several studies have determined that a crosstalk between white adipose tissue (WAT) and solid tumors favors cancer aggressiveness. In this work, our main goal was to investigate the interaction between WAT and PCa cells through microRNAs (miRNAs), in MeS mice. We developed a MeS-like disease model using C57BL/6J mice chronically fed with high-fat diet (HFD) that were inoculated with TRAMP-C1 PCa cells. A group of five miRNAs (mmu-miR-221-3p, 27a-3p, 34a-5p, 138-5p, and 146a-5p) were increased in gonadal WAT (gWAT), tumors, and plasma of MeS mice compared to control animals. Three of these five miRNAs were detected in the media from gWAT and TRAMP-C1 cell cocultures, and significantly increased in MeS context. More importantly, hsa-miR-221-3p, 146a-5p, and 27a-3p were increased in bloodstream of PCa patients compared to healthy donors. Using miRNA microarrays, we found that 121 miRNAs were differentially released to the coculture media between HFD-gWAT and tumor cells compared to control diet-gWAT and tumor cells. Target genes for the 66 most deregulated miRNAs were involved in common pathways, mainly related to fatty acid metabolism, ER protein processing, amino acid degradation, PI3K AKT signaling, and PCa. Our findings show for the first time a signature of five miRNAs as important players involved in the interaction between WAT and PCa in MeS mice. Further research will be necessary to track these miRNAs in the interaction between these tissues as well as their role in PCa patients with MeS.

Identification of early stage recurrence endometrial cancer biomarkers using bioinformatics tools.

Endometrial cancer (EC) is the sixth most common cancer in women worldwide. Early diagnosis is critical in recurrent EC management. The present study aimed to identify biomarkers of EC early recurrence using a workflow that combined text and data mining databases (DisGeNET, Gene Expression Omnibus), a prioritization algorithm to select a set of putative candidates (ToppGene), protein­protein interaction network analyses (Search Tool for the Retrieval of Interacting Genes, cytoHubba), association analysis of selected genes with clinicopathological parameters, and survival analysis (Kaplan­Meier and Cox proportional hazard ratio analyses) using a The Cancer Genome Atlas cohort. A total of 10 genes were identified, among which the targeting protein for Xklp2 (TPX2) was the most promising independent prognostic biomarker in stage I EC. TPX2 expression (mRNA and protein) was higher (P<0.0001 and P<0.001, respectively) in ETS variant transcription factor 5­overexpressing Hec1a and Ishikawa cells, a previously reported cell model of aggressive stage I EC. In EC biopsies, TPX2 mRNA expression levels were higher (P<0.05) in high grade tumors (grade 3) compared with grade 1­2 tumors (P<0.05), in tumors with deep myometrial invasion (>50% compared with <50%; P<0.01), and in intermediate­high recurrence risk tumors compared with low­risk tumors (P<0.05). Further validation studies in larger and independent EC cohorts will contribute to confirm the prognostic value of TPX2.

Genomics and bioinformatics as pillars of precision medicine in oncology.

The battle against cancer has advanced tremendously in the last thirty years and the survival rate has doubled. However, it is still difficult to achieve a generalized cure. The challenge is that cancer is not a unique disease; it is about dozens of different manifestations, even within the same tumor location. For systems biology, each solid tumor is a unique system characterized by its cellular heterogeneity, its interaction with the microenvironment in which it grows and develops, and its ability to adapt and modify it. Recent advances in understanding the molecular mechanisms that underlie cancer are transforming the diagnosis and treatment of the disease. In this sense, a growing set of treatments capable of attacking a specific tumor with higher efficiency has been developed, defining a new paradigm: the precision medicine in oncology. Genomics and bioinformatics are two fundamental pillars in this applied field. These technologies generate massive data (Big Data) that require analytical tools and trained personnel for the analysis, integration and transfer of the information to physicians. This presentation describes the concepts of personalized medicine, Big Data, the main advances in genomics and bioinformatics as well as their future perspectives and challenges.

La batalla contra el cáncer ha avanzado enormemente en los últimos treinta años y la tasa de supervivencia se ha duplicado, sin embargo aún es difícil alcanzar una cura generalizada. El desafío reside en que el cáncer no es una enfermedad única, se trata de decenas de manifestaciones diferentes incluso dentro de una misma localización tumoral. Para la biología de sistemas, cada tumor sólido es un sistema único caracterizado por su heterogeneidad celular, su interacción con el microambiente en el que crece y se desarrolla, y su capacidad de adaptarse y modificarlo. Los avances recientes en la comprensión de los mecanismos moleculares que subyacen al cáncer están transformando el diagnóstico y el tratamiento de la enfermedad. En este sentido, se ha desarrollado un conjunto creciente de tratamientos capaces de atacar con mayor eficiencia a un tumor específico dando paso a nuevo paradigma: el de la medicina de precisión. La genómica y la bioinformática son dos ejes fundamentales en el desarrollo y aplicación de la medicina personalizada. Estas tecnologías generan datos masivos (Big Data) que requieren de herramientas analíticas y personal capacitado para su análisis, integración y transferencia de la información hacia los médicos especialistas. En esta presentación se describen los principales avances en genómica y bioinformática aplicados a la medicina de precisión así como sus perspectivas futuras, desafíos y problemáticas.

Single nucleotide polymorphisms in ATM, TNF-α and IL6 genes and risk of radiotoxicity in breast cancer patients.

Although oncological therapies have improved in the last decades, breast cancer (BC) remains a serious health problem worldwide. Radiotherapy (RT) is one of the most frequently used treatments for cancer aimed at eliminating tumor cells. However, it can also alter the surrounding normal tissue, especially the skin, and patient reactions may vary as a result of extrinsic and intrinsic factors. We evaluated the association of gene polymorphisms ATM Asp1853Asn, IL-6 G-174C and TNF-α G-308A involved in central phenotype pathways and development of individual radiosensitivity in BC patients with an exacerbated response to RT. Although univariate analysis results did not show a significant association with this trait, the interaction analysis between polymorphisms showed an increased risk of patients presenting wild-type TNF-α G-308A genotype and mutant IL-6 G-174C genotype, and heterozygous TNF-α G-308A genotype and heterozygous IL-6G-174C genotype. On the other hand, our results showed that breast size and patient age influenced the determination of RT-associated effects. Considering that the trait is multifactorial, other significant elements for the determination of individual radiosensitivity should be considered, together with the establishment of specific polymorphic variants.