Barriers and facilitators for adherence to follow-up by HR-HPV-positive women with premalignant cervical lesions: a mixed-design study in Mexico.

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.

Association between Gut Microbiota and Inflammation: Mediation Analysis Using Waist Circumference.

Chronic low-grade inflammation (CLI) is implicated in the development of multiple metabolic diseases. The gut microbiota (GM) activates different signaling pathways and induces phenotypic changes, offering an exciting opportunity to treat CLI. We evaluated the mediation of waist circumference on the association of GM with serum cytokines. In this cross-sectional study of 331 children, we measured 5 gut bacterial species, namely, Lactobacillus (L.) casei, L. paracasei, L. reuteri, Staphylococcus (S.) aureus, and Akkermansia (A.) muciniphila, as well as anthropometry, serum cytokines, and other covariates. We evaluated adjusted regression models, path analysis, and structural equation modeling to obtain path coefficients (PCs) for direct, indirect (waist circumference-mediated), and total effects. We found that L. paracasei was directly associated with lower interleukin-10 (IL-10) levels (PC = -173.5 pg/mL). We also observed indirect associations between S. aureus with lower adiponectin levels (PC = -0.1 µg/mL and -0.09 µg/mL). Finally, A. muciniphila was indirectly associated with higher adiponectin levels (PC = 0.1 µg/mL). Our findings suggest the importance of considering the GM composition and waist circumference when evaluating inflammatory-related factors, providing a basis for future research to identify potential strategies to intervene in inflammatory processes and prevent metabolic diseases in childhood. [Figure: see text].

Interaction between Akkermansia muciniphila and Diet Is Associated with Proinflammatory Index in School-Aged Children.

BACKGROUND: Imbalance in the intestinal microbiota can lead to chronic low-grade inflammation. Diet may influence this association. In this study, we aimed to evaluate the interaction between Akkermansia muciniphila (A. muciniphila) and dietary patterns using a proinflammatory index. METHODS: We conducted a cross-sectional study with school-aged children. We quantified the relative abundance (RA) of A. muciniphila in feces using a polymerase chain reaction. We collected dietary information through employing a food frequency questionnaire and generated dietary patterns using principal component analysis. We generated a proinflammatory index from serum levels of interleukin-6, interleukin-10, tumor necrosis factor alpha, and adiponectin validated by receptor operating characteristic curves. We evaluated the association between A. muciniphila and the proinflammatory index using logistic regression, including an interaction term with dietary patterns. RESULTS: We found that children with a low RA of A. muciniphila and a high intake of simple carbohydrates and saturated fats had increased odds of being high on the proinflammatory index. However, when the consumption of this dietary pattern is low, children with a low RA of A. muciniphila had decreased odds of being high on the proinflammatory index. CONCLUSIONS: Our results suggest that the simultaneous presence of A. muciniphila and diet have a more significant impact on the presence of being high on the proinflammatory index compared to both factors separately.

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.

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.

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.

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.

High Relative Abundance of Staphylococcus aureus and Serum Cytokines Are Associated with Cardiometabolic Abnormalities in Children.

Background: The alteration in the composition of the gut microbiota has been associated with an increased risk of developing cardiovascular and metabolic diseases. The present study evaluated the association between the relative abundance (RA) of intestinal Staphylococcus aureus and the inflammatory response with cardiometabolic alterations in children. Methods: This cross-sectional study included 1142 children (age 6-12 years), which were classified by degree of adiposity. Anthropometry, cardiometabolic markers, and RA of intestinal S. aureus were measured. Cytokine concentrations were available in 626 children. Path coefficients (PC) were estimated by path analysis. Results: RA of S. aureus was positively associated with cholesterol PC = 24.98 (95% CI 10.76 to 39.21) and negatively with triglycerides PC = -13.10 (95% CI -22.73 to -3.48). Body mass index (BMI) Z-scores had significant mediation effects on the association between RA of S. aureus with waist circumference PC = 2.87 (95% CI 0.58 to 5.16), triglycerides PC = 6.63 (95% CI 1.29 to 11.98), low-density lipoproteins (LDL) PC = 1.73 (95% CI 0.27 to 3.18), and high-density lipoproteins PC = -1.20 (95% CI -2.19 to -0.22). Interleukin 6 (IL-6) was negatively associated with glucose PC = -3.01 (95% CI -5.85 to -0.17) and LDL PC = -8.65 (95% CI -16.54 to -0.77), and interleukin 10 (IL-10) was positively associated with glucose PC = 3.37 (95% CI 0.47 to 6.26). Conclusions: It is suggested that the RA of S. aureus, IL-6, and IL-10 are associated with cardiometabolic alterations in children, where BMI Z-scores have an important mediating effect for the development of these.

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.

Lactobacillus paracasei as a protective factor of obesity induced by an unhealthy diet in children.

This study examined the association between intestinal lactobacilli and obesity dependent on dietary patterns in children. A cross-sectional study was conducted including 1111 children, 6-12 years old. Obesity was determined according to the WHO cut-off points. Diet information from a Food Frequency Questionnaire identified three dietary patterns. Lactobacillus sp. were determined by a real-time polymerase chain reaction (PCR). The consumption of complex carbohydrates and a high abundance of L. paracasei were associated with a lower risk of obesity (0.35, Confidence Interval 95% 0.19-0.65). The same happened with a medium consumption of fats and a medium abundance of L. paracasei (0.43, CI95% 0.24-0.78). In contrast, an increased risk of obesity is observed with a medium and high consumption of simple carbohydrates (2.37, CI95% 1.29-4.34 and 2.52, CI95% 1.36-4.66, respectively, p-trend<0.05), and low consumption of complex carbohydrates (2.49, CI95% 1.35-4.58), in the presence of a high relative abundance of L. reuteri. A high relative abundance of L. paracasei decreased the risk of obesity, even when high-fat and simple carbohydrate diets were consumed; while a high relative abundance of L. reuteri was associated with a greater possibility of obesity with these types of diets. Our results provide evidence of diet implication in metabolism regulators like lactobacilli. This is helpful in strategies development to promote healthy diets during early stages of life.

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.

High relative abundance of firmicutes and increased TNF-α levels correlate with obesity in children / Obesidad infantil y su correlación con la alta abundancia relativa de firmicutes y el aumento de los niveles de TNF-α

Abstract: 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 Real-Time PCR assays. Results: Anthropometric and biochemical parameters were statistically higher in overweight /obese children than in lean ones. 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.

Resumen: Objetivo: Investigar la correlación entre las citocinas proinflamatorias o antiinflamatorias y los dos principales filos de la microbiota intestinal en niños obesos. Material y métodos: Se obtuvieron mediciones antropométricas de 890 niños de 6 a 14 años; posteriormente se clasificaron en normopeso y sobrepeso/obeso. Las concentraciones séricas fueron medidas por el método de ELISA. La abundancia relativa de la microbiota intestinal en heces se evaluó por PCR tiempo real. Resultados: Los parámetros bioquímicos y antropométricos fueron estadísticamente más altos en niños con sobrepeso / obesidad que en niños delgados. Se encontraron niveles más altos de FNT-α en niños obesos que también tenían una abundancia relativa alta de Firmicutes. Conclusiones: Los niños obesos tienen una alta abundancia relativa de Firmicutes, la cual se correlaciona con un incremento de los niveles de FNT-α. Este es el primer estudio que evalúa la reacción entre la abundancia de Firmicutes y la concentración sérica de FNT-α en niños obesos.

TLR9 gene polymorphism -1486T/C (rs187084) is associated with uterine cervical neoplasm in Mexican female population.

PURPOSE: The aim of this work was to evaluate the association of single nucleotide polymorphisms in TLR9 (-1486 T/C [rs187084], -1237T/C [rs5743836] and G2848A [rs352140]) with HPV infection, squamous intraepithelial lesions, and uterine cervical neoplasm in a Mexican population. Additionally, the peripheral expression of TLR9 was evaluated to evaluate the differences in the TLR9 expression associated with every genotype in the locus -1486 of the TLR9 gene. The serum concentration of TLR9 was evaluated in a randomly selected subsample. METHODS: Genotyping was performed using predesigned 5' endonuc lease assays and the association of the polymorphisms with the diagnosis groups were assessed by performing multinomial regression models. The relative expression of TLR9 in peripheral blood mononuclear cells was evaluated by real-time polymerase chain reaction and the association of the level of TLR9 expression with the diagnosis was evaluated by performing multinomial regression models. The serum concentration of TLR9 was evaluated in a subsample of patients diagnosed with uterine cervical neoplasm by ELISA. RESULTS: The results showed that genotype TT in the -1486 locus of TLR9 was significantly associated with HPV infection (OR = 3.25, 95% CI 1.12-9.46), squamous intraepithelial cervical lesion (OR = 3.76, 95% CI 1.36-10.41), and uterine cervical neoplasm (OR = 5.30, 95% CI 1.81-15.55). Moreover, the highest level of TLR9 expression was significantly associated with a greater risk for developing squamous intraepithelial cervical lesion and uterine cervical neoplasm. The serum TLR9 concentration was higher in patients with uterine cervical cancer than in controls. CONCLUSION: Our findings indicate that genotype TT in the -1486 locus of the TLR9 gene could comprise a risk genotype for HPV infection, squamous intraepithelial cervical lesion, and uterine cervical neoplasm in Mexican female population. Further studies with larger samples are needed to evaluate if the peripheral expression of TLR9 could be used as a biomarker of uterine cervical neoplasm progression.

Cervical Microbiome and Cytokine Profile at Various Stages of Cervical Cancer: A Pilot Study.

Cervical cancer (CC) is caused by high-risk human papillomavirus persistence due to the immunosuppressive tumor microenvironment mediated by cytokines. Vaginal microbiota determines the presence of certain cytokines locally. We assessed the association between cervical microbiota diversity and the histopathological diagnosis of each stage of CC, and we evaluated mRNA cervical expression levels of IL-4, IL-6, IL-10, TGF-ß1, TNF-α and IFN-γ across the histopathological diagnosis and specific bacterial clusters. We determined the cervical microbiota by high throughput sequencing of 16S rDNA amplicons and classified it in community state types (CST). Mean difference analyses between alpha-diversity and histopathological diagnosis were carried out, as well as a ß-diversity analysis within the histological diagnosis. Cervical cytokine mRNA expression was analyzed across the CSTs and the histopathological diagnoses. We found a significant difference in microbiota's diversity in NCL-HPV negative women vs those with squamous intraepithelial lesions (SIL) and CC(p = 0.006, p = 0.036).When ß-diversity was evaluated, the CC samples showed the highest variation within groups (p<0.0006) and the largest distance compared to NCL-HPV negative ones (p<0.00001). The predominant bacteria in women with normal cytology were L. crispatus and L. iners, whereas for SIL, it was Sneathia spp. and for CC, Fusobacterium spp. We found higher median cervical levels of IL-4 and TGF-ß1 mRNA in the CST dominated by Fusobacterium spp. These results suggest that the cervical microbiota may be implicated in cervical cancer pathology. Further cohort studies are needed to validate these findings.

Role of IL-10 and TGF-ß1 in local immunosuppression in HPV-associated cervical neoplasia.

Cervical cancer is a worldwide disease that constitutes a significant public health problem, especially in developing countries, not only due to its high incidence but also because the most affected population comprises women who belong to marginalized socio-economic classes. Clinical and molecular research has identified immunological impairment in squamous intraepithelial cervical lesions and cervical cancer patients. Human Papillomavirus (HPV) has several mechanisms for avoiding the immune system: it down-regulates the expression of interferon and upregulates interleukin (IL)-10 and transforming growth factor (TGF)-ß1 to produce a local immunosuppressive environment, which, along with altered tumor surface antigens, forms an immunosuppressive network that inhibits the antitumor immune response. In this review we analyzed the available data on several deregulated cellular immune functions in patients with NIC I, NIC II and NIC III and cervical cancer. The effects of immunosuppressive cytokines on innate immune response, T-cell activation and cellular factors that promote tumor cell proliferation in cervical cancer patients are summarized. We discuss the functional consequences of HPV E2, E6, and E7 protein interactions with IL-10 and TGF-ß1 promoters in the induction of these cytokines and postulate its effect on the cellular immune response in squamous intraepithelial cervical lesions and cervical cancer patients. This review provides a comprehensive picture of the immunological functions of IL-10 and TGF-ß1 in response to HPV in humans.

Human papillomavirus genotypes among females in Mexico: a study from the Mexican institute for social security.

BACKGROUND: The aetiological relationship between human papillomavirus (HPV) infection and cervical cancer (CC) is widely accepted. Our goal was to determine the prevalence of HPV types in Mexican women attending at the Mexican Institute for Social Security from different areas of Mexico. MATERIALS AND METHODS: DNAs from 2,956 cervical samples were subjected to HPV genotyping: 1,020 samples with normal cytology, 931 with low-grade squamous intraepithelial lesions (LGSIL), 481 with high grade HGSIL and 524 CC. RESULTS: Overall HPV prevalence was 67.1%. A total of 40 HPV types were found; HPV16 was detected in 39.4% of the HPV-positive samples followed by HPV18 at 7.5%, HPV31 at 7.1%, HPV59 at 4.9%, and HPV58 at 3.2%. HPV16 presented the highest prevalence both in women with altered or normal cytology and HPV 18 presented a minor prevalence as reported worldwide. The prevalence ratio (PR) was calculated for the HPV types. The analysis of PR showed that HPV16 presents the highest association with CC, HPV 31, -33, -45, -52 and -58 also demonstrating a high association. CONCLUSIONS: The most prevalent HPV types in cervical cancer samples were -16, -18, -31, but it is important to note that we obtained a minor prevalence of HPV18 as reported worldwide, and that HPV58 and -52 also were genotypes with an important prevalence in CC samples. Determination of HPV genotypes is very important in order to evaluate the impact of vaccine introduction and future cervical cancer prevention strategies.

The SNP at -592 of human IL-10 gene is associated with serum IL-10 levels and increased risk for human papillomavirus cervical lesion development.

BACKGROUND: Women with Human Papilloma Virus (HPV) persistence are characterized by high levels of IL-10 at cervix. We have determined whether polymorphisms of IL-10 gene promoter might be associated with increased risk of squamous intraepithelial cervical lesions (SICL) and whether exist significative differences of IL-10 mRNA expression at cervix and systemic and serum IL-10 protein between SICL cases and non-Cervical Lesions (NCL). METHODS: Peripheral blood samples from SICL (n = 204) and NCL (n = 166) were used to detect IL-10 promoter polymorphisms at loci -592A/C (rs1800872), -819C/T (rs1800871), -1082A/G (rs1800896), -1352A/G (rs1800893), by allelic discrimination and to evaluate serum IL-10 protein. Cervical epithelial scrapings from NCL and biopsies from SICLs were used for HPV-typing and to evaluate IL-10 mRNA expression level. The systemic and local IL-10 mRNA expression levels were measured by real time-PCR. Genotypic and allelic frequencies of the selected polymorphisms were analyzed by logistic regression, adjusting by age and HPV-genotype, to determine the association with SICL. RESULTS: No significant differences were found between genotype frequencies at loci -819, -1082, and -1352. Individuals carrying at least one copy of risk allele A of polymorphism -592 had a two-fold increased risk of developing SICL [adjusted odds ratio (OR), 2.02 (95% CI, 1.26-3.25), p = 0.003], compared to NCL. The IL-10 mRNA expression and serum IL-10 protein, were significantly higher in SICL cases (p < 0.01), being higher in patients carrying the risk allele A. CONCLUSIONS: The -592 polymorphism is associated with increased risk of SICL and can serve as a marker of genetic susceptibility to SICL among Mexican women. According to IL-10 levels found in SICL, IL-10 can be relevant factor for viral persistence and progression disease.

A polymorphism in the AT-hook motif of the transcriptional regulator AKNA is a risk factor for cervical cancer.

The AKNA gene is part of the 9q32 susceptibility locus for cervical cancer. A single-nucleotide polymorphism at codon 1119 of AKNA, yields a biologically relevant amino acid change (R1119Q) at the DNA binding AT-hook motif. Genotype frequencies in 97 allele pairs were: R/R = 0.597, R/Q = 0.278, Q/Q = 0.123. Q/Q homozygosity was present in 8.33% of healthy controls, 16.67% of patients with cervical intraepithelial neoplasia and 75% of cervical cancer patients. These differences are highly significant for the presence of Q/Q in cervical cancer (p = 0.01, odds ratio 3.66, 95% confidence interval 1.35-9.94). Therefore, AKNA appears to be an important genetic factor associated with the risk cervical cancer.

Regulación del ciclo celular y desarrollo de cáncer: perspectivas terapéuticas / Relationship between cell cycle and cancer development: Therapeutical approaches

Durante el proceso de transformación de las células normales a células cancerosas, ocurren varias alteraciones genéticas. En este proceso se presenta la pérdida del control de los mecanismos de replicación y reparación del ADN, así como de la segregación del material genético. Aunque las células normales tienen estrategias de defensa contra el desarrollo del cáncer, las células tumorales activan diferentes vías de escape que permiten la progresión de la neoplasia. Avances recientes han permitido enfocar la investigación del cáncer hacia la identificación de algunos de sus factores etiológicos. El estudio del ciclo celular y su regulación han permitido conocer cómo la fidelidad y la integridad de la replicación del genoma son mantenidas por las funciones coordinadas de los puntos de control y de los sistemas de reparación del ADN. El funcionamiento adecuado de estos procesos puede ser alterado por mutaciones genéticas. Estos hallazgos sugieren que los mecanismos moleculares de regulación que participan en la transformación celular pueden ser empleados como sistemas potenciales para instrumentar nuevas terapias contra el desarrollo del cáncer

Several genetic alterations occur during the transformation process from normal to tumor cells, that involve the loss of fidelity of processes as replication, reparation, and segregation of the genomic material. Although normal cells ha ve defense mechanisms against cancer progression, in tumor cells different escape pathways are activated leading to tumor progression. Recent advances have permitted cancer research to focus on the identification of some of its etiological factors. The knowledge of cell cycle reveals a precise mechanism achieved by the coordinated interactions and functions of cyclin-dependent kinases, control checkpoint, and repair pathways. Furthermore, it has been demonstrated that this cordinated function can be abrog ated by specific genetic changes. These findings suggest that the molecular mechanisms responsible for cellular transformation may help to identify potential targets to improve cancer therapies.