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Glioblastoma multiforme (GBM) is one of the most aggressive astrocytic tumors; it is resistant to most chemotherapeutic agents currently available and is associated with a poor patient survival. Thus, the development of new anticancer compounds is urgently required. Herein, we studied the molecular mechanisms of cell death induced by the experimental drugs resveratrol and MG132 or the antineoplastic drugs cisplatin and etoposide on a human GBM cell line (D54) and on primary cultured mouse astrocytes (PCMAs). Caspases, Bcl-2, inhibitors of apoptosis proteins (IAP) family members, and p53 were identified as potential molecular targets for these drugs. All drugs had a cytotoxic effect on D54 cells and PCMAs, with a similar inhibitory concentration (IC50) after 24 h. However, MG132 and cisplatin were more effective to induce apoptosis and autophagy than resveratrol and etoposide. Cell death by apoptosis involved the activation of caspases-3/7, -8, and -9, increased lysosomal permeability, LC3 lipidation, poly-(ADP-ribose) polymerase (PARP)-1 fragmentation, and a differential expression of genes related with apoptosis and autophagy like Mcl-1, Survivin, Noxa, LC3, and Beclin. In addition, apoptosis activation was partially dependent on p53 activation. Since experimental and antineoplastic drugs yielded similar results, further work is required to justify their use in clinical protocols. [ABSTRACT FROM AUTHOR]

Objective. We aimed to explore the association between polymorphisms of IRS1 (rs1801278), TCF7L2 (rs7903146 and rs12255372), ADRB1 (rs1801253), PPARG (rs1801282), and HHEX (rs5015480) genes with atherogenic risk (AI = Total cholesterol/HDL) in MetS, T2D, and healthy populations from the Mexican Social Security Institute. Methodology and Results. Four hundred thirty-five MetS, 517 T2D, and 547 healthy individuals were selected. The association between the SNPs and the atherogenic index was evaluated by multiple linear regression and multinomial logistic regression mo dels. The ADRB1 gene showed a statistically significant association with high-risk atherogenic index, OR = 2.94 (IC 95% 1.64-5.24; P < 0.0001) for the Arg/Gly variant, under the dominant model an OR = 2.96 (IC 95% 1.67-5.25; P < 0.0001), and under the Log additive model an OR = 2.52 (IC 95% 1.54-4.15; P < 0.0001). Conclusions. The Arg389Gly polymorphism of the ADRB1 gene may be a worthy biological marker to predict the risk of developing cardiovascular diseases given a high-risk atherogenic index. [ABSTRACT FROM AUTHOR]

Background: Mexico reports low follow-up completion rates among women with abnormal cervical cancer screenings. This study aimed to identify barriers and facilitators to follow-up adherence among women with human papillomavirus (HPV) infection and premalignant cervical lesions in Mexico., Methods: A mixed-methods study was conducted from February to April 2019. Participants included women undergoing follow-up care for high-risk human papillomavirus (HR-HPV) and premalignant lesions, along with health personnel from the Women's Healthcare Center (CAPASAM) in Mexico. Quantitative data were obtained from the Women's Cancer Information System and through a questionnaire about factors affecting follow-up adherence. Additionally, the health personnel involved completed a compliance checklist regarding care regulations. Descriptive statistics were used for analysis. Qualitative data were collected via semi-structured interviews with both groups, followed by a content analysis based on identified categories. The Hazard Analysis and Critical Control Point System confirmed care process risks. Proposals to enhance the Early Detection Program for Prevention and Control of Cervical Cancer were collected from a CAPASAM health personnel nominal group., Results: Identified barriers to follow-up included low income among CAPASAM users, family provider roles limiting time for appointments, long waits for testing and results delivery, distant facilities, insufficient service hour communication, inadequate health personnel training, and a lack of systematic counseling. Hesitation toward follow-up was also linked to shame, apprehension, uncertainty, test aversion, fear of positive results, and limited cervical cancer and screening knowledge. Patriarchal attitudes of partners and limited access to the now-discontinued PROSPERA government program further discouraged follow-up. Facilitators comprised respectful treatment by CAPASAM staff, no-cost services, health campaigns, and positive user attitudes., Conclusions: The study found more barriers than facilitators to follow-up adherence, highlighting the need for strategies to bolster the Early Detection Program. Future strategies must address the comprehensive array of factors and incorporate stakeholder perspectives., (© 2024. The Author(s).)

Abstract: Routine use of human papillomavirus (HPV) vaccines is recommended in adolescents under 15 years of age worldwide. Still, effective programs remain suboptimal for several factors, making the WHO strategy to eradicate cervical cancer public health with an uncertain future., Objective: To review the literature on the effectiveness, long-term protection, and safety of HPV vaccination programs and vaccination as adjuvant management. This review aims to describe the current state of vaccination programs and demonstrate the long-term protection and safety of vaccines implemented worldwide targeting adolescent girls, with the most recent published evidence of the three prophylactic HPV vaccines - bivalent (bHPV), quadrivalent (qHPV), and nonavalent (nHPV)-. We mainly focus on publications evaluating efficacy, dosing schemes, and HPV vaccination, as well as studies contributing to the mounting evidence for the real-life effectiveness of prophylactic HPV vaccines from several countries., Findings: Human Papillomavirus vaccination programs have made remarkable strides in preventing HPV-related diseases; countries with robust vaccination efforts have witnessed substantial reductions in HPV-related diseases with a decline in high-grade cervical abnormalities and genital warts (54%-83%). However, global coverage remains uneven, with disparities between high-income (HICs) and low-income countries (LMICs). The long-term efficacy of the available human papillomavirus (HPV) goes up to 9.4 years and continues to be immunogenic and well tolerated with an excellent safety profile., Conclusions and Relevance: As these are crucial topics in HPV vaccination, it is essential to establish systems for continued monitoring of vaccine immunogenicity, efficacy, and safety over time., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 González-Rodríguez, Cruz-Valdez and Madrid-Marina.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cruz-Valdez, Palacio-Mejía, Quezada-Sánchez, Hernández-Ávila, Galicia-Carmona, Cetina-Pérez, Arango-Bravo, Isla-Ortiz, Aranda-Flores, Uscanga-Sánchez, Madrid-Marina and Torres-Poveda.)

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.

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., (© 2023. The Author(s).)

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.

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.

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.

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AG-H, MYC-A, AA, and GH-G are employed by the GSK group of companies. MYC-A, AA, and GH-G hold shares from the GSK group of companies. GL-C and GS-G are owners of Estimatio SC and report that this company received support from the GSK group of companies to conduct this study. GS-G is an investigator at the Instituto Nacional de Salud Pública (INSP, Mexico). AG-H, MYC-A, AA, GH-G, GL-C, and GS-G declare no other financial and non-financial relationships and activities. ABG and VM-M declare no financial and non-financial relationships and activities and no conflicts of interest.

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.

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 Fas L 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., Competing Interests: The authors declare that they have no conflicts of interest.

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.

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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)