Epidemiology of childhood acute leukemias in marginalized populations of the central-south region of Mexico: results from a population-based registry.

Introduction: Acute leukemias (AL) are the main types of cancer in children worldwide. In Mexico, they represent one of the main causes of death in children under 20 years of age. Most of the studies on the incidence of AL in Mexico have been developed in the urban context of Greater Mexico City and no previous studies have been conducted in the central-south of the country through a population-based study. The aim of the present work was to identify the general and specific incidence rates of pediatric AL in three states of the south-central region of Mexico considered as some of the marginalized populations of Mexico (Puebla, Tlaxcala, and Oaxaca). Methods: A population-based study was conducted. Children aged less than 20 years, resident in these states, and newly diagnosed with AL in public/private hospitals during the period 2021-2022 were identified. Crude incidence rates (cIR), standardized incidence rates (ASIRw), and incidence rates by state subregions (ASIRsr) were calculated. Rates were calculated using the direct and indirect method and reported per million children under 20 years of age. In addition, specific rates were calculated by age group, sex, leukemia subtype, and immunophenotype. Results: A total of 388 cases with AL were registered. In the three states, the ASIRw for AL was 51.5 cases per million (0-14 years); in Puebla, it was 53.2, Tlaxcala 54.7, and Oaxaca de 47.7. In the age group between 0-19 years, the ASIRw were 44.3, 46.4, 48.2, and 49.6, in Puebla, Tlaxcala, and Oaxaca, respectively. B-cell acute lymphoblastic leukemia was the most common subtype across the three states. Conclusion: The incidence of childhood AL in the central-south region of Mexico is within the range of rates reported in other populations of Latin American origin. Two incidence peaks were identified for lymphoblastic and myeloid leukemias. In addition, differences in the incidence of the disease were observed among state subregions which could be attributed to social factors linked to the ethnic origin of the inhabitants. Nonetheless, this hypothesis requires further investigation.

Evidence of spatial clustering of childhood acute lymphoblastic leukemia cases in Greater Mexico City: report from the Mexican Inter-Institutional Group for the identification of the causes of childhood leukemia.

Background: A heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC). Methods: A population-based case-control study was conducted. Children <18 years old, newly diagnosed with ALL and residents of GMC were included. Controls were patients without leukemia recruited from second-level public hospitals, frequency-matched by sex, age, and health institution with the cases. The residence address where the patients lived during the last year before diagnosis (cases) or the interview (controls) was used for geolocation. Kulldorff's spatial scan statistic was used to detect spatial clusters (SCs). Relative risks (RR), associated p-value and number of cases included for each cluster were obtained. Results: A total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (p<0.0001) was observed for the main cluster. Similar results were noted for the remaining seven ones. Additionally, a proximity between SCs, electrical installations and petrochemical facilities was observed. Conclusions: The identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL.

Distinct fecal microbial signatures are linked to sex and chronic immune activation in pediatric HIV infection.

Introduction: Our understanding of HIV-associated gut microbial dysbiosis in children perinatally-infected with HIV (CLWH) lags behind that of adults living with HIV. Childhood represents a critical window for the gut microbiota. Any disturbances, including prolonged exposure to HIV, antiretroviral drugs, and antibiotics are likely to have a significant impact on long-term health, resulting in a less resilient gut microbiome. The objective of our study was to characterize the gut microbiota in CLWH, and compare it with HIV-unexposed and -uninfected children. Methods: We enrolled 31 children aged 3 to 15 years; 15 were CLWH and 16 were HUU. We assessed dietary patterns and quality; quantified soluble and cellular markers of HIV disease progression by flow cytometry, enzyme-linked immunosorbent and multiplex-bead assays, and profiled the gut microbiota by 16S rRNA sequencing. We explored relationships between the gut microbiota, antibiotic exposure, dietary habits, soluble and cellular markers and host metadata. Results: Children had a Western-type diet, their median health eating index score was 67.06 (interquartile range 58.76-74.66). We found no discernable impact of HIV on the gut microbiota. Alpha diversity metrics did not differ between CLWH and HUU. Sex impacted the gut microbiota (R-squared= 0.052, PERMANOVA p=0.024). Male children had higher microbial richness compared with female children. Two taxa were found to discriminate female from male children independently from HIV status: Firmicutes for males, and Bacteroides for females. Markers of HIV disease progression were comparable between CLWH and HUU, except for the frequency of exhausted CD4+ T cells (PD-1+) which was increased in CLWH (p=0.0024 after adjusting for confounders). Both the frequency of exhausted CD4+ and activated CD4+ T cells (CD38+ HLADR+) correlated positively with the relative abundance of Proteobacteria (rho=0.568. false discovery rate (FDR)-adjusted p= 0.029, and rho=0.62, FDR-adjusted p=0.0126, respectively). Conclusion: The gut microbiota of CLWH appears similar to that of HUU, and most markers of HIV disease progression are normalized with long-term ART, suggesting a beneficial effect of the latter on the gut microbial ecology. The relationship between exhausted and activated CD4+ T cells and Proteobacteria suggests a connection between the gut microbiome, and premature aging in CLWH.

Maternal diet in pregnancy and acute leukemia in infants: a case-control study in Mexico City.

Introduction: Epidemiological studies around the world on acute leukemia (AL) and risk factors in infants are scarce. Infant AL has been proposed to originate in utero, which facilitates its study by establishing a short exposure time in pregnant women to environmental and dietary factors that could contribute to the risk of or protection against leukemia. We hypothesized that maternal diet during pregnancy may be an important factor involved in AL in offspring. Methods: We conducted a hospital-based case-control study from 2010 to 2019 on maternal diet during pregnancy in nine high-specialty public hospitals of different health institutions that diagnose and offer treatment to children with AL in Mexico City. Cases (n=109) were children ≤24 months of age with de novo diagnosis of AL, and controls (n=252) were children obtained in hospitals from second-level medical care matched for age, sex, and health institution. Maternal diet during pregnancy was obtained by a semiquantitative food frequency questionnaire. Unconditional logistic regression models were used to assess the association between food groups and infant AL. Potential confounders were assessed by constructing directed acyclic graphs (DAGs) with Dagitty software in which adjusted options were identified for the construction of unconditional logistic regression models. Results: Cases were slightly predominantly female (52.3%). The years of education of the mother in cases and controls was 0-9 on average, and those who reported smoking cigarettes and consuming alcohol during pregnancy did so at a low frequency. Regarding the mother's diet, the main findings were that the consumption of allium vegetables during pregnancy was inversely associated with AL for medium and high consumption (OR=0.26, 95% CI 0.14-0.46; P-trend< 0.001). In contrast, the high consumption of high-fat dairy products had a positive association with AL (OR=2.37, 95% CI 1.30-4.34; P-trend<0.001). No association was found between consumption of topoisomerase II inhibitor foods during pregnancy and AL. Conclusion: The results suggest that maternal intake during pregnancy of allium vegetables, specifically garlic, is inversely associated with the development of AL in children ≤24 months old. On the other hand, consumption of high-fat dairy products is positively associated with AL in children ≤24 months old.

Analytical study of RUNX1-RUNXT1, PML-RARA, CBFB-MYH11, BCR-ABL1p210 , and KMT2-MLLT3 in Mexican children with acute myeloid leukemia: A multicenter study of the Mexican interinstitutional group for the identification of the causes of childhood leukemia (MIGICCL).

Background: The distribution of RUNX1-RUNXT1, PML-RARA, CBFB-MYH11, BCR-ABL1p210 , and KMT2A-MLLT3 in the pediatric population with acute myeloid leukemia (AML) in many countries of Latin America is largely unknown. Therefore, we aimed to investigate the frequency of these fusion genes in children with de novo AML from Mexico City, which has one of the highest incidence rates of acute leukemia in the world. Additionally, we explored their impact in mortality during the first year of treatment. Methods: We retrospectively analyzed the presence of RUNX1-RUNXT1, PML-RARA, CBFB-MYH11, BCR-ABL1p210 , and KMT2A-MLLT3 by RT-PCR among 77 patients (<18 years) diagnosed with de novo AML between 2019 and 2021 in nine Mexico City hospitals. Results: The overall frequency of the fusion genes was 50.7%; RUNX1-RUNXT1 (22.1%) and PML-RARA (20.8%) were the most prevalent, followed by CBFB-MYH11 (5.2%) and BCR-ABL1p210 (2.4%). KMT2A-MLLT3 was not detected. Patients with PML-RARA showed the lowest survival with high early mortality events. However, more studies are required to evaluate the impact of analyzed fusion genes on the overall survival of the Mexican child population with AML. Conclusion: The pediatric population of Mexico City with AML had frequencies of AML1-ETO, PML-RARA, CBFB-MYH11, and BCR-ABL1p210 similar to those of other populations around the world. Patients with BCR-ABL1p210 and CBFB-MYH11 were few or did not die, while those with MLL-AF9 was not detected. Although patients with PML-RARA had a low survival and a high early mortality rate, further studies are needed to determine the long-term impacts of these fusion genes on this Latino population.

Persistently high incidence rates of childhood acute leukemias from 2010 to 2017 in Mexico City: A population study from the MIGICCL.

Introduction: Over the years, the Hispanic population living in the United States has consistently shown high incidence rates of childhood acute leukemias (AL). Similarly, high AL incidence was previously observed in Mexico City (MC). Here, we estimated the AL incidence rates among children under 15 years of age in MC during the period 2010-2017. Methods: The Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia conducted a study gathering clinical and epidemiological information regarding children newly diagnosed with AL at public health institutions of MC. Crude age incidence rates (cAIR) were obtained. Age-standardized incidence rates worldwide (ASIRw) and by municipalities (ASIRm) were calculated by the direct and indirect methods, respectively. These were reported per million population <15 years of age; stratified by age group, sex, AL subtypes, immunophenotype and gene rearrangements. Results: A total of 903 AL cases were registered. The ASIRw was 63.3 (cases per million) for AL, 53.1 for acute lymphoblastic leukemia (ALL), and 9.4 for acute myeloblastic leukemia. The highest cAIR for AL was observed in the age group between 1 and 4 years (male: 102.34 and female: 82.73). By immunophenotype, the ASIRw was 47.3 for B-cell and 3.7 for T-cell. The incidence did not show any significant trends during the study period. The ASIRm for ALL were 68.6, 66.6 and 62.8 at Iztacalco, Venustiano Carranza and Benito Juárez, respectively, whereas, other municipalities exhibited null values mainly for AML. Conclusion: The ASIRw for childhood AL in MC is among the highest reported worldwide. We observed spatial heterogeneity of rates by municipalities. The elevated AL incidence observed in Mexican children may be explained by a combination of genetic background and exposure to environmental risk factors.

Mutational Landscape of CEBPA in Mexican Pediatric Acute Myeloid Leukemia Patients: Prognostic Implications.

Background: In Mexico, the incidence of acute myeloid leukemia (AML) has increased in the last few years. Mortality is higher than in developed countries, even though the same chemotherapy protocols are used. CCAAT Enhancer Binding Protein Alpha (CEBPA) mutations are recurrent in AML, influence prognosis, and help to define treatment strategies. CEBPA mutational profiles and their clinical implications have not been evaluated in Mexican pediatric AML patients. Aim of the Study: To identify the mutational landscape of the CEBPA gene in pediatric patients with de novo AML and assess its influence on clinical features and overall survival (OS). Materials and Methods: DNA was extracted from bone marrow aspirates at diagnosis. Targeted massive parallel sequencing of CEBPA was performed in 80 patients. Results: CEBPA was mutated in 12.5% (10/80) of patients. Frameshifts at the N-terminal region were the most common mutations 57.14% (8/14). CEBPA biallelic (CEBPA BI) mutations were identified in five patients. M2 subtype was the most common in CEBPA positive patients (CEBPA POS) (p = 0.009); 50% of the CEBPA POS patients had a WBC count > 100,000 at diagnosis (p = 0.004). OS > 1 year was significantly better in CEBPA negative (CEBPA NEG) patients (p = 0.0001). CEBPA POS patients (either bi- or monoallelic) had a significantly lower OS (p = 0.002). Concurrent mutations in FLT3, CSF3R, and WT1 genes were found in CEBPA POS individuals. Their contribution to poor OS cannot be ruled out. Conclusion: CEBPA mutational profiles in Mexican pediatric AML patients and their clinical implications were evaluated for the first time. The frequency of CEBPA POS was in the range reported for pediatric AML (4.5-15%). CEBPA mutations showed a negative impact on OS as opposed to the results of other studies.

Underexpression of LINC00173 in TCF3/PBX1-Positive Cases Is Associated With Poor Prognosis in Children With B-Cell Precursor Acute Lymphoblastic Leukemia.

Background: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent pediatric cancer worldwide. Despite improvements in treatment regimens, approximately 20% of the cases cannot be cured, highlighting the necessity for identifying new biomarkers to improve the current clinical and molecular risk stratification schemes. We aimed to investigate whether LINC00173 is a biomarker in ALL and to explore its expression level in other human cancer types. Methods: A nested case-control study including Mexican children with BCP-ALL was conducted. LINC00173 expression was evaluated by qRT-PCR using hydrolysis probes. To validate our findings, RNA-seq expression data from BCP-ALL and normal tissues were retrieved from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Genotype-Tissue Expression (GTEx) repositories, respectively. LINC00173 expression was also evaluated in solid tumors by downloading available data from The Cancer Genome Atlas (TCGA). Results: A lower expression of LINC00173 in BCP-ALL cases compared to normal subjects was observed (p < 0.05). ALL patients who carry the TCF3/PBX1 fusion gene displayed lower expression of LINC00173 in contrast to other BCP-ALL molecular subtypes (p < 0.04). LINC00173 underexpression was associated with a high risk to relapse (HR = 1.946, 95% CI = 1.213-3.120) and die (HR = 2.073, 95% CI = 1.211-3.547). Patients with TCF3/PBX1 and underexpression of LINC00173 had the worst prognosis (DFS: HR = 12.24, 95% CI = 5.04-29.71; OS: HR = 11.19, 95% CI = 26-32). TCGA data analysis revealed that underexpression of LINC00173 is also associated with poor clinical outcomes in six new reported tumor types. Conclusion: Our findings suggest that LINC00173 is a biomarker of poor prognosis in BCP-ALL and other types of cancer. We observed an association between the expression of LINC00173 and TCF3/PBX1 and the risk to relapse and die in BCP-ALL, which is worse in TCF3/PBX1-positive cases displaying underexpression of LINC00173. Experimental studies are needed to provide insight into the LINC00173 and TCF3/PBX relationship.

Protease and gag diversity and drug resistance mutations among treatment-naive Mexican people living with HIV.

INTRODUCTION: In Mexico, HIV genotyping is performed in people living with HIV (PLWH) failing their first-line antiretroviral (ARV) regimen; it is not routinely done for all treatment-naive PLWH before ARV initiation. The first nationally representative survey published in 2016 reported that the prevalence of pretreatment drug mutations in treatment-naive Mexican PLWH was 15.5% to any antiretroviral drug and 10.6% to non-nucleoside reverse transcriptase inhibitors (NNRTIs) using conventional Sanger sequencing. Most reports in Mexico focus on HIV pol gene and nucleoside and non-nucleoside reverse transcriptase inhibitor (NRTI and NNRTI) drug resistance mutations (DRMs) prevalence, using Sanger sequencing, next-generation sequencing (NGS) or both. To our knowledge, NGS has not be used to detect pretreatment drug resistance mutations (DRMs) in the HIV protease (PR) gene and its substrate the Gag polyprotein. METHODS: Treatment-naive adult Mexican PLWH were recruited between 2016 and 2019. HIV Gag and protease sequences were obtained by NGS and DRMs were identified using the WHO surveillance drug resistance mutation (SDRM) list. RESULTS: One hundred PLWH attending a public national reference hospital were included. The median age was 28 years-old, and most were male. The median HIV viral load was 4.99 [4.39-5.40] log copies/mL and median CD4 cell count was 150 [68.0-355.78] cells/mm3. As expected, most sequences clustered with HIV-1 subtype B (97.9%). Major PI resistance mutations were detected: 8 (8.3%) of 96 patients at a detection threshold of 1% and 3 (3.1%) at a detection threshold of 20%. A total of 1184 mutations in Gag were detected, of which 51 have been associated with resistance to PI, most of them were detected at a threshold of 20%. Follow-up clinical data was available for 79 PLWH at 6 months post-ART initiation, seven PLWH failed their first ART regimen; however no major PI mutations were identified in these individuals at baseline. CONCLUSIONS: The frequency of DRM in the HIV protease was 7.3% at a detection threshold of 1% and 3.1% at a detection threshold of 20%. NGS-based HIV drug resistance genotyping provide improved detection of DRMs. Viral load was used to monitor ARV response and treatment failure was 8.9%.

Global expression profiling of CD10 + /CD19 + pre-B lymphoblasts from Hispanic B-ALL patients correlates with comparative TARGET database analysis.

Mexico City has one of the highest incidences of acute lymphoblastic leukemia (ALL) globally, with patients showing low survival, and high relapse rates. To gain more insight into the molecular features of B-ALL in Mexican children, we isolated CD10 + /CD19 + precursor B lymphoblasts from four bone marrow and nine peripheral blood samples of B-ALL patients using a fluorescence-activated cell sorting protocol. The global gene expression profile (BM vs PB) revealed 136 differentially expressed genes; 62 were upregulated (45.6%) and 74 were downregulated (54.4%). Pearson's correlation coefficient was calculated to determine the similarity between pre-B lymphoblast populations. We selected 26 highly significant genes and validated 21 by RT-qPCR (CNN3, STON2, CALN1, RUNX2, GADD45A, CDC45, CDC20, PLK1, AIDA, HCK, LY86, GPR65, PIK3CG, LILRB2, IL7R, TCL1A, DOCK1, HIST1H3G, PTPN14, CD72, and NT5E). The gene set enrichment analysis of the total expression matrix and the ingenuity pathway analysis of the 136 differentially expressed genes showed that the cell cycle was altered in the bone marrow with four overexpressed genes (PLK1, CDC20, CDC45, and GADD45A) and a low expression of IL7R and PIK3CG, which are involved in B cell differentiation. A comparative bioinformatics analysis of 15 bone marrow and 10 peripheral blood samples from Hispanic B-ALL patients collected by the TARGET program, corroborated the genes observed, except for PIK3CG. We conclude the Mexican and the Hispanic B-ALL patients studied present common driver alterations and histotype-specific mutations that could facilitate risk stratification and diagnostic accuracy and serve as potential therapeutic targets.

Primary antiphospholipid syndrome in pediatrics: beyond thrombosis. Report of 32 cases and review of the evidence.

OBJECTIVE: Describe the frequency of thrombotic and non-thrombotic clinical manifestations, laboratory, treatment and prognosis in patients with pediatric primary antiphospholipid syndrome. MATERIAL AND METHODS: A retrospective study was carried out in patients with a diagnosis of primary antiphospholipid antibody syndrome, under 16 years of age, under follow-up by the pediatric rheumatology service of the General Hospital, National Medical Center, La Raza, from January 2013 to December 2020. The antiphospholipid syndrome was defined when it met the laboratory criteria of the Sidney criteria and the presence of thrombosis or non-criteria manifestations of the disease (hematological, neurological, cutaneous, renal, cardiac or pulmonary). Demographic, clinical, laboratory, treatment, and prognosis data were collected. RESULTS: We report 32 patients, 21 female (65%) and 11 male (35%), mean age 11.75 years, evolution time 16 weeks. Thrombosis 9 patients (28%), 1 arterial and 8 venous. Non-thrombotic manifestations; Hematologic: thrombocytopenia 22 patients (69%), autoimmune hemolytic anemia 13 (40%), Fisher-Evans syndrome 6 (19%), lupus anticoagulant with hypoprothrombinemia syndrome 2 (6%). Dermatological: livedo reticularis 20 (62%), skin ulcers 2 (6%), Raynaud's phenomenon 8 (25%). Neurological: epilepsy 1 (3%), migraine 3 (9%), chorea 1 (3%) and cognitive impairment 3 (9%). Renal in 4 (13%). Laboratory: prolonged aPTT 30 (93%), lupus anticoagulant 32 (100%), positive IgG anticardiolipin 20 (62%), positive IgM anticardiolipin 19 (60%). AntiB2GPI was performed in only 3 patients, being positive in all. TREATMENT: anticoagulation in patients with thrombosis, antiplatelet in 23 (72%), steroid 30 (94%), immunosuppressant 30 (94%) and rituximab 4 (12.5%). No deaths were reported. CONCLUSIONS: The clinical characteristics of patients with pediatric primary antiphospholipid syndrome differ from those presented in adults, since non-thrombotic manifestations are more frequent in children, for which classification criteria that include these manifestations are necessary for a better characterization of the disease in pediatric population.

Association Analysis Between the Functional Single Nucleotide Variants in miR-146a, miR-196a-2, miR-499a, and miR-612 With Acute Lymphoblastic Leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is characterized by an abnormal proliferation of immature lymphocytes, in whose development involves both environmental and genetic factors. It is well known that single nucleotide polymorphisms (SNPs) in coding and noncoding genes contribute to the susceptibility to ALL. This study aims to determine whether SNPs in miR-146a, miR-196a-2, miR-499a, and miR-612 genes are associated with the risk to ALL in pediatric Mexican population. METHODS: A multicenter case-control study was carried out including patients with de novo diagnosis of ALL and healthy subjects as control group. The DNA samples were obtained from saliva and peripheral blood, and the genotyping of rs2910164, rs12803915, rs11614913, and rs3746444 was performed using the 5'exonuclease technique. Gene-gene interaction was evaluated by the multifactor dimensionality reduction (MDR) software. RESULTS: miR-499a rs3746444 showed significant differences among cases and controls. The rs3746444G allele was found as a risk factor to ALL (OR, 1.6 [95% CI, 1.05-2.5]; p = 0.028). The homozygous GG genotype of rs3746444 confers higher risk to ALL than the AA genotype (OR, 5.3 [95% CI, 1.23-23.4]; p = 0.01). Moreover, GG genotype highly increases the risk to ALL in male group (OR, 17.6 [95% CI, 1.04-298.9]; p = 0.00393). In addition, an association in a gender-dependent manner among SNPs located in miR-146a and miR-196a-2 genes and ALL susceptibility was found. CONCLUSION: Our findings suggest that SNP located in miR-499a, miR-146a, and miR-196a-2 genes confer risk to ALL in Mexican children. Experimental analysis to decipher the role of these SNPs in human hematopoiesis could improve our understanding of the molecular mechanism underlying the development of ALL.

Increase of 5-HT levels is induced both in mouse brain and HEK-293 cells following their exposure to a non-viral tryptophan hydroxylase construct.

Tryptophan hydroxylase type 2 (Tph2) is the rate-limiting enzyme for serotonin (5-HT) biosynthesis in the brain. Dysfunctional Tph2 alters 5-HT biosynthesis, leading to a deficiency of 5-HT, which could have repercussions on human behavior. In the last decade, several studies have associated polymorphisms of the TPH2 gene with suicidal behavior. Additionally, a 5-HT deficiency has been implicated in various psychiatric pathologies, including alcoholism, impulsive behavior, anxiety, and depression. Therefore, the TPH2 gene could be an ideal target for analyzing the effects of a 5-HT deficiency on brain function. The aim of this study was to use the construct pIRES-hrGFP-1a-Tph2-FLAG to treat CD1-male mice and to transfect HEK-293-cells and then to evaluate whether this treatment increases 5-HT production. 5-HT levels were enhanced 48 h post-transfection, in HEK-293 cells. Three days after the ocular administration of pIRES-hrGFP-1a-Tph2-FLAG to mice, putative 5-HT production was significantly higher than in the control in both hypothalamus and amygdala, but not in the brainstem. Further research will be needed on the possible application of this treatment for psychiatric diseases involving a Tph2 dysfunction or serotonin deficiency.

Copy Number Alterations are Associated with the Risk of Very Early Relapse in Pediatric B-lineage Acute Lymphoblastic Leukemia: A Nested Case-control MIGICCL Study.

BACKGROUND: Refining risk stratification to avoid very early relapses (VER) in Mexican patients with B-lineage acute lymphoblastic leukemia (B-ALL) could lead to better survival rates in our population. AIM OF THE STUDY: The purpose of this study was to investigate the association between the United Kingdom ALL (UKALL)-CNA classifier and VER risk in Mexican patients with childhood B-ALL. METHODS: A nested case-control study of 25 cases with VER and 38 frequency-matched controls without relapse was conducted within the MIGICCL study cohort. They were grouped into the categories of the UKALL-CNA risk classifier (good [reference], intermediate and poor), according to the results obtained by multiplex ligation dependent probe amplification. Overall and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards analyses were conducted. RESULTS: The CDKN2A/B genes were most frequently deleted in the group with relapse. According to UKALL-CNA classifier, 33 (52.4%) patients were classified as good, 21 (33.3%) intermediate and 9 (14.3%) poor-risk B-ALL. The intermediate and poor risk groups were associated with an increased risk of VER (HR = 4.94, 95% CI = 1.87-13.07 and HR = 7.42, 95% CI = 2.37-23.26, respectively) in comparison to the good-risk patients. After adjusting by NCI risk classification and chemotherapy scheme in a multivariate model, the risks remained significant. CONCLUSIONS: Our data support the clinical utility of profiling CNAs to potentially refine current risk stratification strategies of patients with B-ALL.

Therapeutic avenues for restoring the gut microbiome in HIV infection.

The interplay between the gut microbiota, the intestinal barrier and the mucosal immune system is profoundly altered in Human Immunodeficiency Virus (HIV) infection. An HIV-associated microbial dysbiotic signature has been difficult to define due to the strong impact of confounders that are intimately linked with HIV infection, namely HIV risk behaviors. When controlling for sexual preference and gender, HIV-associated microbial dysbiotic signatures are characterized by an increase in deleterious taxa and a decrease in beneficial bacteria and their respective metabolic end-products. First attempts to restore the gut microbiota of HIV subjects on Antiretroviral Therapy using Fecal Microbiota Transplantation proved to be safe and reported mild transient engraftment of donor microbiota and no effect on markers of HIV disease progression. This review focuses on the current evidence supporting a role for microbial dysbiosis in HIV pathogenesis, and reviews current microbiome-based therapeutics for restoring the gut microbiota in HIV infection.

Genotype-Environment Interaction Analysis of NQO1, CYP2E1, and NAT2 Polymorphisms and the Risk of Childhood Acute Lymphoblastic Leukemia: A Report From the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia.

Background: Acute lymphoblastic leukemia (ALL) is the main type of cancer in children. In Mexico and other Hispanic populations, the incidence of this neoplasm is one of the highest reported worldwide. Functional polymorphisms of various enzymes involved in the metabolism of xenobiotics have been associated with an increased risk of developing ALL, and the risk is different by ethnicity. The aims of the present study were to identify whether NQO1, CYP2E1, and NAT2 polymorphisms or some genotype-environmental interactions were associated with ALL risk in Mexican children. Methods: We conducted a case-control study including 478 pediatric patients diagnosed with ALL and 284 controls (children without leukemia). Ancestry composition of a subset of cases and controls was assessed using 32 ancestry informative markers. Genetic-environmental interactions for the exposure to hydrocarbons were assessed by logistic regression analysis. Results: The polymorphisms rs1801280 (OR 1.54, 95% CI 1.21-1.93), rs1799929 (OR 1.96, 95% CI 1.55-2.49), and rs1208 (OR 1.44, 95% CI 1.14-1.81) were found to increase the risk of ALL; being the risks higher under a recessive model (OR 2.20, 95% CI 1.30-1.71, OR 3.87, 95% CI 2.20-6.80, and OR 2.26, 95% CI 1.32-3.87, respectively). Gene-environment interaction analysis showed that NAT2 rs1799929 TT genotype confers high risk to ALL under exposure to fertilizers, insecticides, hydrocarbon derivatives, and parental tobacco smoking. No associations among NQO1, CYP2E1, and ALL were observed. Conclusion: Our study provides evidence for the association between NAT2 polymorphisms/gene-environment interactions, and the risk of childhood ALL in Mexican children.

Profiling FLT3 Mutations in Mexican Acute Myeloid Leukemia Pediatric Patients: Impact on Overall Survival.

Background: Acute myeloid leukemia (AML) is the second most frequent leukemia in childhood. The FLT3 gene participates in hematopoietic stem cell proliferation. FLT3 mutations are recurrent in AML and influence prognosis. In Mexican pediatric AML patients, FLT3 mutational profile, and their clinical impact have not been evaluated. Aim of the study: This study aimed to identify the profile of FLT3 mutations in pediatric patients with de novo AML and to assess their possible influence on overall survival (OS) and other clinical features. Methods: Massive parallel target sequencing of FLT3 was performed in 80 patients. Results: FLT3 mutations [internal tandem duplication (ITD) or tyrosine kinase domain (TKD)] were identified in 24% of them. OS was significantly lower in FLT3 POS cases than in FLT3 NEG (p = 0.03). The average OS for FLT3 POS was 1.2 vs. 2.2 years in FLT3 NEG. There were no significant differences in the children's sex, age, percentage of blasts in bone marrow aspirate, or white blood cell count in peripheral blood at diagnosis between both groups. No differences were identified stratifying by the mutational load (high > 0.4) or type of mutation. The negative effect of FLT3 mutations was also observed in patients with acute promyelocytic leukemia (APL). Conclusions: FLT3 mutational profile is described in Mexican pediatric AML patients for the first time. Mutated FLT3 negatively impacts the outcome of AML patients, even considering the APL group. The clinical benefit from treatment with tyrosine kinase inhibitors in the FLT3 POS pediatric patients needs to be assessed in clinical trials. FLT3 testing may contribute to better risk stratification in our pediatric AML patients.

Maternal and paternal ages at conception of index child and risk of childhood acute leukaemia: A multicentre case-control study in Greater Mexico City.

BACKGROUND: The parental age at conception has been reported to be a risk factor for childhood acute leukaemia (AL); however, the relationship is controversial. The aim of the present study was to investigate the association between parental age at conception and the risk of AL in Mexican children, a population with a high incidence of the disease and a high prevalence of pregnancies in adolescents and young adults. METHODS: A multicentre case-control study was conducted. Incident AL cases younger than 17 years of age diagnosed between 2010 and 2015 were included. Controls were matched with cases according to age, sex, and health institution. Using logistic regression analysis, adjusted odds ratios (aOR) and 95 % confidence intervals (95 % CI) were calculated for each maternal stratum after adjusting for paternal age at conception of index child. The maternal age between 25 and 29.99 years was selected as the reference category. RESULTS: In most strata where maternal and paternal ages were assessed, no association was found with the risk of developing acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in their offspring. An increased risk for AML was observed when the mother was between 20 and 24.99 years of age and the father aged 25-29.99 years (aOR, 1.94; 95 % CI, 1.03-3.67). In addition, there was a positive association for ALL when the mother´s age was between 20 and 24.99 years and the father was <20 years of age, however, a very wide confidence interval was noted (aOR, 12.26; 95 % CI, 1.41-106.83). CONCLUSION: In the present study, maternal and paternal ages assessed in different strata showed little association with risk of developing ALL and AML in children. Positive associations between risk of both types of childhood AL were observed with younger paternal and maternal ages.

Transcriptome Analysis Identifies LINC00152 as a Biomarker of Early Relapse and Mortality in Acute Lymphoblastic Leukemia.

Evidence showing the role of long non-coding RNAs (lncRNAs) in leukemogenesis have emerged in the last decade. It has been proposed that these genes can be used as diagnosis and/or prognosis biomarkers in childhood acute lymphoblastic leukemia (ALL). To know if lncRNAs are associated with early relapse and early mortality, a microarray-based gene expression analysis in children with B-lineage ALL (B-ALL) was conducted. Cox regression analyses were performed. Hazard ratios (HR) and 95% confidence intervals (95% CI) were calculated. LINC00152 and LINC01013 were among the most differentially expressed genes in patients with early relapse and early mortality. For LINC00152 high expression, the risks of relapse and death were HR: 4.16 (95% CI: 1.46-11.86) and HR: 1.99 (95% CI: 0.66-6.02), respectively; for LINC01013 low expression, the risks of relapse and death were HR: 3.03 (95% CI: 1.14-8.05) and HR: 6.87 (95% CI: 1.50-31.48), respectively. These results were adjusted by NCI risk criteria and chemotherapy regimen. The lncRNA-mRNA co-expression analysis showed that LINC00152 potentially regulates genes involved in cell substrate adhesion and peptidyl-tyrosine autophosphorylation biological processes. The results of the present study point out that LINC00152 could be a potential biomarker of relapse in children with B-ALL.

Ophthalmic Administration of a DNA Plasmid Harboring the Murine Tph2 Gene: Evidence of Recombinant Tph2-FLAG in Brain Structures.

Tryptophan hydroxylase-type 2 (Tph2) is the first rate-limiting step in the biosynthesis of serotonin (5-HT) in the brain. The ophthalmic administration (Op-Ad) is a non-invasive method that allows delivering genetic vehicles through the eye and reaches the brain. Here, the murine Tph2 gene was cloned in a non-viral vector (pIRES-hrGFP-1a), generating pIRES-hrGFP-1a-Tph2, plus the FLAG-tag. Recombinant Tph2-FLAG was detected and tested in vitro and in vivo, where 25 µg of pIRES-hrGFP-1a-Tph2-FLAG was Op-Ad to mice. The construct was capable of expressing and producing the recombinant Tph2-FLAG in vitro and in vivo. The in vivo assays showed that the construct efficiently crossed the Hemato-Ocular Barrier and the Blood-Brain Barrier, reached brain cells, passed the optical nerves, and transcribed mRNA-Tph2-FLAG in different brain areas. The recombinant Tph2-FLAG was observed in amygdala and brainstem, mainly in raphe dorsal and medial. Relative Tph2 expression of threefold over basal level was recorded three days after Op-Ad. These results demonstrated that pIRES-hrGFP-Tph2-FLAG, administrated through the eyes was capable of reaching the brain, transcribing, and translating Tph2. In conclusion, this study showed the feasibility of delivering therapeutic genes, such as the Tph2, the first enzyme, rate-limiting step in the 5-HT biosynthesis.