Prevalence and Risk Factors for High-Risk Human Papillomavirus Infection and Cervical Disorders: Baseline Findings From an Human Papillomavirus Cohort Study.

BACKGROUND: A persistent infection by high-risk human papillomavirus (HR-HPV) is a prerequisite for the development of cervical neoplasms; however, most studies have focused on risk factors associated with HPV-16 and HPV-18 only. OBJECTIVES: We assessed the association of risk factors with the prevalence of HPV-16, HPV-18, and non-16/18 HR-HPV infection and with the occurrence of cervical lesions in the baseline of a cohort study of HPV persistence in a Mexican population. METHODS: Cross-sectional study within the baseline of a 5-year dynamic cohort study of HR-HPV persistence in women with an abnormal cytology study result from 2015 to 2021. HPV DNA was detected using the Anyplex II HPV 28 kit. Data on lifestyle, sociodemographic, and reproductive factors were assessed using bivariate and multivariate analyses to determine the association of risk factors with HR-HPV infection status and histopathologic diagnosis. RESULTS: A total of 373 women were included in the study. The overall prevalence of HR-HPV infection was 69.97%. The most prevalent HR-HPV genotypes, including single and multiple infections, were HPV-53 (13.4%), HPV-16 (11.8%), HPV-58 (10.9%), HPV-31 (10.9%), and HPV-66 (10.7%). We found 90 multiple HR-HPV infection patterns, all of them with α-6 and -9 species. Significant associations of multiple HPV-16 and non-16/18 HR-HPV infections were found with marital status, number of lifetime sexual partners, and smoking history. The most prevalent genotype in CIN1 and CIN2 patients was HPV-16. No association was found between biological plausibility risk factors and cervical lesions. CONCLUSIONS: The risk factors for non-16/18 HR-HPV multiple infections are no different than those linked to HPV-16 multiple infections.

Cervical cancer prevention program in Mexico disrupted due to COVID-19 pandemic: Challenges and opportunities.

Introduction: The COVID-19 pandemic disrupted the preventive services for cervical cancer (CC) control programs in Mexico, which will result in increased mortality. This study aims to assess the impact of the pandemic on the interruption of three preventive actions in the CC prevention program in Mexico. Methods: This study is a retrospective time series analysis based on administrative records for the uninsured population served by the Mexican Ministry of Health. Patient data were retrieved from the outpatient service information system and the hospital discharge database for the period 2017-2021. Data were aggregated by month, distinguishing a pre-pandemic and a pandemic period, considering April 2020 as the start date of the pandemic. A Poisson time series analysis was used to model seasonal and secular trends. Five process indicators were selected to assess the disruption of the CC program, these were analyzed as monthly data (N=39 pre-pandemic, N=21 during the pandemic). HPV vaccination indicators (number of doses and coverage) and diagnostic characteristics of CC cases were analyzed descriptively. The time elapsed between diagnosis and treatment initiation in CC cases was modeled using restricted cubic splines from robust regression. Results: Annual HPV vaccination coverage declined dramatically after 2019 and was almost null in 2021. The number of positive Papanicolaou smears decreased by 67.8% (90%CI: -72.3, -61.7) in April-December 2020, compared to their expected values without the pandemic. The immediate pandemic shock (April 2020) in the number of first-time and recurrent colposcopies was -80.5% (95%CI:-83.5, -77.0) and -77.9% (95%CI: -81.0, -74.4), respectively. An increasing trend was observed in the proportion of advanced stage and metastatic CC cases. The fraction of CC cases that did not receive medical treatment or surgery increased, as well as CC cases that received late treatment after diagnosis. Conclusions: Our analyses show significant impact of the COVID-19 pandemic with declines at all levels of CC prevention and increasing inequalities. The restarting of the preventive programs against CC in Mexico offers an opportunity to put in place actions to reduce the disparities in the burden of disease between socioeconomic levels.

Critical Role of the Transcription Factor AKNA in T-Cell Activation: An Integrative Bioinformatics Approach.

The human akna gene encodes an AT-hook transcription factor, the expression of which is involved in various cellular processes. The goal of this study was to identify potential AKNA binding sites in genes that participate in T-cell activation and validate selected genes. Here we analyzed ChIP-seq and microarray assays to determine AKNA-binding motifs and the cellular process altered by AKNA in T-cell lymphocytes. In addition, we performed a validation analysis by RT-qPCR to assess AKNA's role in promoting IL-2 and CD80 expression. We found five AT-rich motifs that are potential candidates as AKNA response elements. We identified these AT-rich motifs in promoter regions of more than a thousand genes in activated T-cells, and demonstrated that AKNA induces the expression of genes involved in helper T-cell activation, such as IL-2. The genomic enrichment and prediction of AT-rich motif analyses demonstrated that AKNA is a transcription factor that can potentially modulate gene expression by recognizing AT-rich motifs in a plethora of genes that are involved in different molecular pathways and processes. Among the cellular processes activated by AT-rich genes, we found inflammatory pathways potentially regulated by AKNA, suggesting AKNA is acting as a master regulator during T-cell activation.

Lethality risk markers by sex and age-group for COVID-19 in Mexico: a cross-sectional study based on machine learning approach.

BACKGROUND: Mexico ranks fifth worldwide in the number of deaths due to COVID-19. Identifying risk markers through easily accessible clinical data could help in the initial triage of COVID-19 patients and anticipate a fatal outcome, especially in the most socioeconomically disadvantaged regions. This study aims to identify markers that increase lethality risk in patients diagnosed with COVID-19, based on machine learning (ML) methods. Markers were differentiated by sex and age-group. METHODS: A total of 11,564 cases of COVID-19 in Mexico were extracted from the Epidemiological Surveillance System for Viral Respiratory Disease. Four ML classification methods were trained to predict lethality, and an interpretability approach was used to identify those markers. RESULTS: Models based on Extreme Gradient Boosting (XGBoost) yielded the best performance in a test set. This model achieved a sensitivity of 0.91, a specificity of 0.69, a positive predictive value of 0.344, and a negative predictive value of 0.965. For female patients, the leading markers are diabetes and arthralgia. For males, the main markers are chronic kidney disease (CKD) and chest pain. Dyspnea, hypertension, and polypnea increased the risk of death in both sexes. CONCLUSIONS: ML-based models using an interpretability approach successfully identified risk markers for lethality by sex and age. Our results indicate that age is the strongest demographic factor for a fatal outcome, while all other markers were consistent with previous clinical trials conducted in a Mexican population. The markers identified here could be used as an initial triage, especially in geographic areas with limited resources.

RIPOR2 Expression Decreased by HPV-16 E6 and E7 Oncoproteins: An Opportunity in the Search for Prognostic Biomarkers in Cervical Cancer.

High-risk human papillomavirus (HPV) infection is the main risk factor for cervical cancer (CC) development, where the continuous expression of E6 and E7 oncoproteins maintain the malignant phenotype. In Mexico, around 70% of CC cases are diagnosed in advanced stages, impacting the survival of patients. The aim of this work was to identify biomarkers affected by HPV-16 E6 and E7 oncoproteins that impact the prognosis of CC patients. Expression profiles dependent on E6 and E7 oncoproteins, as well as their relationship with biological processes and cellular signaling pathways, were analyzed in CC cells. A comparison among expression profiles of E6- and E7-expressing cells and that from a CC cohort obtained from The Cancer Genome Atlas (TCGA) demonstrated that the expression of 13 genes impacts the overall survival (OS). A multivariate analysis revealed that the downregulated expression of RIPOR2 was strongly associated with a worse OS. RIPOR2, including its transcriptional variants, were overwhelmingly depleted in E6- and E7-expressing cells. Finally, in a Mexican cohort, it was found that in premalignant cervical lesions, RIPOR2 expression decreases as the lesions progress; meanwhile, decreased RIPOR2 expression was also associated with a worse OS in CC patients.

Alteration of the IFN-Pathway by Human Papillomavirus Proteins: Antiviral Immune Response Evasion Mechanism.

A persistent infection with the so-called high-risk Human Papillomaviruses (hr-HPVs) plays a fundamental role in the development of different neoplasms. The expression of the HPV proteins throughout the different steps of the viral life cycle produce a disruption of several cellular processes, including immune response, which can lead to cell transformation. The interferon-mediated response plays an important role in eliminating HPV-infected and -transformed cells. The ability of HPV to disrupt the proper function of the interferon response is based on a series of molecular mechanisms coordinated by HPV proteins intended to prevent clearance of infection, ultimately producing an immunotolerant environment that facilitates the establishment of persistence and cancer. In this review, we focus on the molecular actions performed by HPV E1, E2, E5, E6 and E7 proteins on IFN signaling elements and their contribution to the establishment of infection, viral persistence and the progression to cancer.

Fas and Fas ligand are highly expressed in lymphocytes from cervical intraepithelial neoplasia and cervical cancer patients: A possible role for immune escaping.

Objectives: Infection with high-risk human papillomavirus is required to develop cervical cancer. Some viruses modulate the Fas/FasL signaling to evade the immune response; the role of these molecules in cervical cancer is not clear. In this study, we measured the expression levels of Fas and FasL mRNA, soluble proteins, and cell surface proteins in peripheral blood mononuclear cells from patients with low- and high-grade squamous intraepithelial lesions and cervical cancer in relation to healthy women, to gain new insights into the role of Fas/FasL in cervical cancer development. Materials and Methods: Fas/FasL mRNA expression was measured in cervical tissues and peripheral blood mononuclear cells from patients and healthy subjects; serum soluble proteins Fas/FasL were measured by ELISA, and cell-surface protein expression was detected by flow cytometry. Results: Varying expression levels were found for both molecules. Cervical Fas and FasL mRNA expression was decreased in low- and high-grade lesions, but it was increased in cervical cancer cases. While, systemic Fas mRNA expression increased as malignity progressed; systemic FasL mRNA expression was increased in low- and high-grade lesions, but it was decreased in cancer patients. Soluble FasL levels decreased as lesions progressed, while soluble Fas levels increased. Finally, overexpression of Fas/FasL on the surface of peripheral blood mononuclear cells was found in patients with low-grade lesion with respect to healthy donors. Conclusion: Fas and FasL act as negative modulators of the immune response, probably by removing specific cytotoxic T lymphocytes against papillomavirus -infected cells and tumor cells.

Burden of disease and associated complications of hepatitis a in children and adults in Mexico: A retrospective database study.

BACKGROUND: Hepatitis A virus (HAV) infection is a leading cause of viral hepatitis in children, yet the HAV vaccine is not included in the national immunization program (NIP) in Mexico. This study addresses an identified evidence gap of the burden of hepatitis A disease, complications, and associated costs in Mexico by analyzing surveillance and healthcare data. Data review included disease morbidity (incidence and hospitalization), mortality, and healthcare resource utilization costs. METHODS: In this observational, retrospective database study, we conducted a systematic screening, extraction, and analysis of outcome data from the national surveillance system in Mexico from January 2000 to December 2019. RESULTS: During the analysis period (2000-2019), the average incidence rate/year of HAV cases was 14.7 (5.4-21.5) per 100,000 inhabitants. Children 1-9 years of age (YoA) had the highest average incidence rate/year with 47.8 (14.7-74.5). The average hospitalization rate/year due to HAV infection was 5.8% (2.9-9.6%). Although the highest burden of HAV continued to be in children (1-9 YoA), an increase in incidence and hospitalizations (with complications) in older age groups (≥ 10-64 YoA) was observed. The annual average fatality rate was estimated to be 0.44% (0.26-0.83%) of which 28.8% of deaths were concentrated in adults ≥ 65 YoA. The total direct costs of medical attention due to HAV and related complications were estimated at $382 million Mexican pesos. CONCLUSION: The overall results suggest an uptrend in HAV infections in adolescents/adults compared to children in Mexico. Therefore, as the overall incidence risk of HAV infection decreases, the mean age of infection increases. This consequently increases the risk of severity and complications in older age groups, thus increasing the demand for healthcare resources. Our findings provide evidence for including the inactivated HAV vaccine in the Mexican NIP.

The Autophagy Process in Cervical Carcinogenesis: Role of Non-Coding-RNAs, Molecular Mechanisms, and Therapeutic Targets.

Autophagy is a highly conserved multistep lysosomal degradation process in which cellular components are localized to autophagosomes, which subsequently fuse with lysosomes to degrade the sequestered contents. Autophagy serves to maintain cellular homeostasis. There is a close relationship between autophagy and tumor progression, which provides opportunities for the development of anticancer therapeutics that target the autophagy pathway. In this review, we analyze the effects of human papillomavirus (HPV) E5, E6, and E7 oncoproteins on autophagy processes in cervical cancer development. Inhibition of the expression or the activity of E5, E6, and E7 can induce autophagy in cells expressing HPV oncogenes. Thus, E5, E6, and E7 oncoproteins target autophagy during HPV-associated carcinogenesis. Furthermore, noncoding RNA (ncRNA) expression profiling in cervical cancer has allowed the identification of autophagy-related ncRNAs associated with HPV. Autophagy-related genes are essential drivers of autophagy and are regulated by ncRNAs. We review the existing evidence regarding the role of autophagy-related proteins, the function of HPV E5, E6, and E7 oncoproteins, and the effects of noncoding RNA on autophagy regulation in the setting of cervical carcinogenesis. By characterizing the mechanisms behind the dysregulation of these critical factors and their impact on host cell autophagy, we advance understanding of the relationship between autophagy and progression from HPV infection to cervical cancer, and highlight pathways that can be targeted in preventive and therapeutic strategies against cervical cancer.

Functional Role of AKNA: A Scoping Review.

Human akna encodes an AT-hook transcription factor whose expression participates in various cellular processes. We conducted a scoping review on the literature regarding the functional role of AKNA according to the evidence found in human and in vivo and in vitro models, stringently following the "PRISMA-ScR" statement recommendations. METHODS: We undertook an independent PubMed literature search using the following search terms, AKNA OR AKNA ADJ gene OR AKNA protein, human OR AKNA ADJ functions. Observational and experimental articles were considered. The selected studies were categorized using a pre-determined data extraction form. A narrative summary of the evidence was produced. RESULTS: AKNA modulates the expression of CD40 and CD40L genes in immune system cells. It is a negative regulator of inflammatory processes as evidenced by knockout mouse models and observational studies for several autoimmune and inflammatory diseases. Furthermore, AKNA contributes to the de-regulation of the immune system in cancer, and it has been proposed as a susceptibility genetic factor and biomarker in CC, GC, and HNSCC. Finally, AKNA regulates neurogenesis by destabilizing the microtubules dynamics. CONCLUSION: Our results provide evidence for the role of AKNA in various cellular processes, including immune response, inflammation, development, cancer, autoimmunity, and neurogenesis.

Health status and gerontological evaluation in Mexican older adults in the face of the COVID-19 pandemic.

INTRODUCTION: Older adults constitute the most vulnerable population group to the COVID-19 pandemic. In Mexico, their biopsychosocial conditions might intensify their vulnerability. METHOD: Affiliation to health systems, health conditions and gerontological evaluation of 3,218 older adults were analyzed following the methodology of the PAHO-Mexico Health, Well-being and Aging Survey. RESULTS: 88.6 % of older adults referred being affiliated to health systems; 30.2 %, 52.4 %, 10.3 %, 4.1 % and 5.6 % referred suffering from diabetes mellitus, high blood pressure, chronic obstructive pulmonary disease, heart disease and cerebrovascular disease, respectively; 15.6 % reported urinary incontinence, and 11.3%, fecal incontinence; 12.1 % of the women referred having suffered from breast cancer at some point, and 6.3 %, cervical cancer. The habit of smoking tobacco was observed in 11.1 %, risk of malnutrition in 32.8 %, established malnutrition in 4.1 %, functional dependence for basic and instrumental activities of daily life in 16.3 % and 17.6 %, respectively. CONCLUSION: Comprehensive gerontological evaluation is essential for efficient care of older adults who suffer from COVID-19, and for adequate care of the effects or health conditions at the conclusion of the confinement imposed by the pandemic.

INTRODUCCIÓN: Los adultos mayores constituyen el grupo más vulnerable ante la pandemia por COVID-19; en México, sus condiciones biopsicosociales podrían potenciar su vulnerabilidad. MÉTODO: Se analizó afiliación a sistemas de salud, condiciones de salud y evaluación gerontológica de 3218 adultos mayores conforme a la metodología de la Encuesta Salud, Bienestar y Envejecimiento OPS-México. RESULTADOS: 88.6 % de los adultos mayores refirió afiliación a un sistema de salud; 30.2, 52.4, 10.3, 4.1 y 5.6 % indicaron padecer diabetes mellitus, hipertensión arterial, enfermedad pulmonar obstructiva crónica, enfermedad cardiaca y evento vascular cerebral, respectivamente; 15.6 % reportó incontinencia urinaria y 11.3 %, fecal; 12.1 % de las mujeres indicó haber padecido en algún momento cáncer de mama y 6.3 %, cáncer cervicouterino. Se observó hábito de fumar tabaco en 11.1 %, riesgo de malnutrición en 32.8 %, malnutrición establecida en 4.1 %, dependencia funcional para las actividades básicas en 16.3 % e instrumentales de la vida diaria en 17.6 %. CONCLUSIÓN: La evaluación gerontológica integral es fundamental para la atención eficiente de los adultos mayores que padecen COVID-19 y para la adecuada atención por los efectos o condiciones de salud al terminar el confinamiento por la pandemia.

IMMUNOLOGY OF CERVICAL CANCER.

Optimal function of the immune system allows the recognition and elimination of infected and tumor cells. However, these cells can develop mechanisms to evade the cellular immune response. In human papillomavirus (HPV) infection, dysregulation of major histocompatibility complex Class I molecules and other components of the innate immune system promote the survival of infected cells by allowing the infection to persist which, in turn, favors the development of cancer. Further, tumor cells possess inherent mechanisms designed to block the recognition and activation of cytotoxic lymphocytes: particularly, HPV proteins such as E1 and E2 and oncoproteins E5, E6, and E7 that inhibit immune mechanisms and/or stimulate the expression of immunosuppressive cytokines. These mechanisms include a decrease in receptor activation and costimulating molecules on the surface of immune cells, as well as the constitutive expression of molecules that inhibit their function, which allow HPV persistence and tumor progression. Immunotherapy-based therapeutic options are positioned as excellent candidates for the treatment of cervical cancer.

Estado de salud y valoración gerontológica en adultos mayores mexicanos ante la pandemia por COVID-19 / Health status and gerontological evaluation in Mexican older adults in the face of the COVID-19 pandemic

Resumen Introducción: Los adultos mayores constituyen el grupo más vulnerable ante la pandemia por COVID-19; en México, sus condiciones biopsicosociales podrían potenciar su vulnerabilidad. Método: Se analizó afiliación a sistemas de salud, condiciones de salud y evaluación gerontológica de 3218 adultos mayores conforme a la metodología de la Encuesta Salud, Bienestar y Envejecimiento OPS-México. Resultados: 88.6 % de los adultos mayores refirió afiliación a un sistema de salud; 30.2, 52.4, 10.3, 4.1 y 5.6 % indicaron padecer diabetes mellitus, hipertensión arterial, enfermedad pulmonar obstructiva crónica, enfermedad cardiaca y evento vascular cerebral, respectivamente; 15.6 % reportó incontinencia urinaria y 11.3 %, fecal; 12.1 % de las mujeres indicó haber padecido en algún momento cáncer de mama y 6.3 %, cáncer cervicouterino. Se observó hábito de fumar tabaco en 11.1 %, riesgo de malnutrición en 32.8 %, malnutrición establecida en 4.1 %, dependencia funcional para las actividades básicas en 16.3 % e instrumentales de la vida diaria en 17.6 %. Conclusión: La evaluación gerontológica integral es fundamental para la atención eficiente de los adultos mayores que padecen COVID-19 y para la adecuada atención por los efectos o condiciones de salud al terminar el confinamiento por la pandemia.

Abstract Introduction: Older adults constitute the most vulnerable population group to the COVID-19 pandemic. In Mexico, their biopsychosocial conditions might intensify their vulnerability. Method: Affiliation to health systems, health conditions and gerontological evaluation of 3,218 older adults were analyzed following the methodology of the PAHO-Mexico Health, Well-being and Aging Survey. Results: 88.6 % of older adults referred being affiliated to health systems; 30.2 %, 52.4 %, 10.3 %, 4.1 % and 5.6 % referred suffering from diabetes mellitus, high blood pressure, chronic obstructive pulmonary disease, heart disease and cerebrovascular disease, respectively; 15.6 % reported urinary incontinence, and 11.3%, fecal incontinence; 12.1 % of the women referred having suffered from breast cancer at some point, and 6.3 %, cervical cancer. The habit of smoking tobacco was observed in 11.1 %, risk of malnutrition in 32.8 %, established malnutrition in 4.1 %, and functional dependence for basic and instrumental activities of daily life in 16.3 % and 17.6 %, respectively. Conclusion: Comprehensive gerontological evaluation is essential for efficient care of older adults who suffer from COVID-19, and for adequate care of the effects or health conditions at the conclusion of the confinement imposed by the pandemic.

Immunology of cervical cancer

ABSTRACT Optimal function of the immune system allows the recognition and elimination of infected and tumor cells. However, these cells can develop mechanisms to evade the cellular immune response. In human papillomavirus (HPV) infection, dysregulation of major histocompatibility complex Class I molecules and other components of the innate immune system promote the survival of infected cells by allowing the infection to persist which, in turn, favors the development of cancer. Further, tumor cells possess inherent mechanisms designed to block the recognition and activation of cytotoxic lymphocytes: particularly, HPV proteins such as E1 and E2 and oncoproteins E5, E6, and E7 that inhibit immune mechanisms and/or stimulate the expression of immunosuppressive cytokines. These mechanisms include a decrease in receptor activation and costimulating molecules on the surface of immune cells, as well as the constitutive expression of molecules that inhibit their function, which allow HPV persistence and tumor progression. Immunotherapy-based therapeutic options are positioned as excellent candidates for the treatment of cervical cancer.

Bovine Interferon-Tau Activates Type I interferon-Associated Janus-signal Transducer in HPV16-positive Tumor Cell.

The mechanisms of signal transduction by interferon-tau (IFN-τ) are widely known during the gestation of ruminants. In trophoblast cells, IFN-τ involves the activation of the JAK-STAT pathway, and it can have effects on other cell types, such as tumor cells. Here we report that the HPV16-positive BMK-16/myc cell treated with ovine IFN-τ, results in the activation of the canonical JAK-STAT and non-canonical JAK-STAT pathway. The MAPK signaling pathway was activated, we detected the proteins MEK1, MEK2, Raf1, STAT3, STA4, STAT5 and STAT6. Moreover, IFN-τ induced the expression of MHC Class I, MX and IP10 in the tumor cells and this response may be associated with the viral replication and with the anti-proliferative and the immunoregulatory effects of IFN-τ.

The Human Papillomavirus (HPV) E1 protein regulates the expression of cellular genes involved in immune response.

The Human Papillomavirus (HPV) E1 protein is the only viral protein with enzymatic activity. The main known function of this protein is the regulation of the viral DNA replication. Nevertheless, it has been demonstrated that the ablation of HPV18 E1 mRNA in HeLa cells promotes a deregulation of several genes, particularly those involved in host defense mechanisms against viral infections; however, the specific contribution of E1 protein in HPV-independent context has not been studied. The aim of this work was to determine the effect of the HPV E1 protein in the regulation of cellular gene expression profiles evaluated through RNA-seq. We found that E1 proteins from HPV16 and 18 induced an overexpression of different set of genes associated with proliferation and differentiation processes, as well as downregulation of immune response genes, including IFNß1 and IFNλ1 and Interferon-stimulated gene (ISG), which are important components involved in the antiviral immune response. Together, our results indicate that HR-(High-Risk) and LR-(Low-Risk) HPV E1 proteins play an important role in inhibiting the anti-viral immune response.

Transregulation of microRNA miR-21 promoter by AP-1 transcription factor in cervical cancer cells.

BACKGROUND: Gene expression profiles have demonstrated that miR-21 expression is altered in almost all types of cancers and it has been classified as an oncogenic microRNA. Persistent HPV infection is the main etiologic agent in cervical cancer and induces genetic instability, including disruption of microRNA gene expression. In the present study, we analyzed the underlying mechanism of how AP-1 transcription factor can active miR-21 gene expression in cervical cancer cells. METHODS: To identify that c-Fos and c-Jun regulate the expression of miR-21 we performed RT-qPCR and western blot assays. We analyzed the interaction of AP-1 with miR-21 promoter by EMSA and ChIP assays and determined the mechanism of its regulation by reporter construct plasmids. We identified the nuclear translocation of c-Fos and c-Jun by immunofluorescence microscopy assays. RESULTS: We demonstrated that c-Fos and c-Jun proteins are expressed and regulate the expression of miR-21 in cervical cancer cells. DNA sequence analysis revealed the presence of AP-1 DNA-binding sites in the human miR-21 promoter region. EMSA analyses confirmed the interactions of the miR-21 upstream transcription factor AP-1. ChIP assays further showed the binding of c-Fos to AP-1 sequences from the miR-21 core promoter in vivo. Functional analysis of AP-1 sequences of miR-21 in reporter plasmids demonstrated that these sequences increase the miR-21 promoter activation. CONCLUSIONS: Our findings suggest a physical interaction and functional cooperation between AP-1 transcription factor in the miR-21 promoter and may explain the effect of AP-1 on miR-21 gene expression in cervical cancer cells.

Polymorphisms in IL-10 and TGF-ß gene promoter are associated with lower risk to gastric cancer in a Mexican population.

BACKGROUND: Helicobacter pylori infection is recognized as the main risk factor for gastric cancer (GC), the fifth most common neoplasia worldwide. H. pylori interacts with the immune system, disrupting the cytokine network and inducing chronic inflammation. This work aimed to evaluate the association between single nucleotide polymorphisms (SNPs) in selected cytokine gene promoters and GC. METHODS: The study included 359 subjects, 125 GC patients, 109 intestinal metaplasia (IM) patients and 125 asymptomatic controls. DNA was extracted from white blood cells and nine SNPs in cytokine gene promoters were genotyped using predesigned 5'-endonulease assays. The association of the SNPs with IM and GC was evaluated using multinomial regression models. RESULTS: Both genotypes, TC (OR = 0.51, 95% CI = 0.27-0.98) and TT (OR = 0.42, 95% CI = 0.20-0.91) in the locus - 509 of the TGF-ß promoter were significantly associated with GC. The TT genotype in the locus - 819 of the IL-10 promoter was also significantly associated with GC (OR = 0.37, 95% CI = 0.17-0.81). No significant association was found with SNPs IL-4 -590 T/C (rs1800629), IL-6 -573G/C (rs1800796), IL-10 -592C/A (rs1800872), IL-10 -1082A/G (rs1800896), and, IFN-γ -1615C/T (rs2069705). CONCLUSIONS: SNPs in TGFß (- 509 C/T, rs1800469) and IL-10 (- 819 C/T, rs1800871) promoters were associated with a lower risk for GC in a Mexican population.

The Human Papillomavirus (HPV) E6 Oncoprotein Regulates CD40 Expression via the AT-Hook Transcription Factor AKNA.

Persistent infection with high-risk Human Papillomavirus (HR-HPV) is the main requisite for cervical cancer development. Normally, HPV is limited to the site of infection and regulates a plethora of cellular elements to avoid the immune surveillance by inducing an anti-inflammatory state, allowing the progress through the viral cycle and the carcinogenic process. Recent findings suggest that the AT-hook transcriptional factor AKNA could play a role in the development of cervical cancer. AKNA is strongly related to the expression of co-stimulatory molecules such CD40/CD40L to achieve an anti-tumoral immune response. To date, there is no evidence demonstrating the effect of the HPV E6 oncoprotein on the AT-hook factor AKNA. In this work, minimal expression of AKNA in cervical carcinoma compared to normal tissue was found. We show the ability of E6 from high-risk HPVs 16 and 18 to interact with and down-regulate AKNA as well as its co-stimulatory molecule CD40 in a proteasome dependent manner. We also found that p53 interacts with AKNA and promotes AKNA expression. Our results indicate that the de-regulation of CD40 and AKNA is induced by the HPV E6 oncoprotein, and this event involves the action of p53 suggesting that the axis E6/p53A/AKNA might play an important role in the de-regulation of the immune system during the carcinogenic process induced by HR-HPV.

High relative abundance of firmicutes and increased TNF-α levels correlate with obesity in children.

OBJECTIVE: To investigate the correlation among pro- or anti-inflammatory cytokines and the two main gut microbiota phyla in obese children. MATERIALS AND METHODS: Anthropometric data were obtained from 890 children under 14 years old to determine the degree of obesity. Serum cytokine concentration was measured by ELISA. Relative abundance of gut microbiota in feces was evaluated by quantitative RealTime PCR assays. RESULTS: Anthropometric and biochemical parameters were statistically higher in overweigth/ obese children (OW/O) than in lean (NW), Increased TNF-α levels were found in obese children that also have a high relative abundance of Firmicutes. CONCLUSIONS: Obese children have a high relative abundance of Firmicutes that correlates with increased levels of TNF-α. This is the first study that shows a relation between Firmicute abundance and TNF-α serum concentration in obese children.