IKZF1 Gene Deletion in Pediatric Patients Diagnosed with Acute Lymphoblastic Leukemia in Mexico.

The IKZF1 gene is formed by 8 exons and encodes IKAROS, a transcription factor that regulates the expression of genes that control cell cycle progression and cell survival. In general, 15-20% of the patients with preB acute lymphoblastic leukemia (preB ALL) harbor IKZF1 deletions, and the frequency of these deletions increases in BCR-ABL1 or Ph-like subgroups. These deletions have been associated with poor treatment response and the risk of relapse. The aim of this descriptive study was to determine the frequency of IKZF1 deletions and the success of an induction therapy response in Mexican pediatric patients diagnosed with preB ALL in 2 hospitals from 2017 to August 2018. Thirty-six bone marrow samples from patients at the Instituto Nacional de Pediatría in Mexico City and the Centro Estatal de Cancerología in Tepic were analyzed. The IKZF1 deletion was identified by MLPA using the SALSA MLPA P335 ALL-IKZF1 probemix. Deletions of at least 1 IKZF1 exon were observed in 7/34 samples (20.6%): 3 with 1 exon deleted; 1 with 2 exons, 1 with 5 exons, 1 with 6 exons, and 1 patient with a complete IKZF1 deletion. This study was descriptive in nature; we calculated the frequency of the IKZF1 gene deletion in a Mexican pediatric population with preB ALL as 20.6%.

Antibodies and Acidic Environment Do Not Enhance HIV-1 Transcytosis.

A limited number of human immunodeficiency virus type 1 (HIV-1) variants initially infect HIV-1-naive individuals. Recent studies imply that this may occur because generally inefficient transcytosis across intact mucosal surfaces could be enhanced for specific viruses with bound antibodies and in the presence of acidic pH. We found that transcytosis of both cell-free and cell-associated viruses with diverse envelopes was significantly decreased in the presence of either antibodies or plasma from chronically infected transmitting partners regardless of pH. Transmitted variants also did not have greater transmigration as compared to chronic-infection strains. Enhanced translocation capacity is unlikely to influence which HIV-1 variant establishes infection.

Characterization of HIV-1 envelopes in acutely and chronically infected injection drug users.

BACKGROUND: Mucosally acquired human immunodeficiency virus type 1 (HIV-1) infection results from a limited number of variants, and these infecting strains potentially have unique properties, such as increased susceptibility to entry blockers, relative interferon-alpha (IFN-α) resistance, and replication differences in some primary cells. There is no data about the phenotypic properties of HIV-1 envelope variants found early after acquisition among subjects infected through injection drug use (IDU). For the first time, we compared the characteristics of virus envelopes among injection drug users sampled prior to seroconversion (HIV RNA+/Ab-), within 1 year (early), and more than 2 years (chronic) after estimated acquisition. RESULTS: Virus envelopes from 7 HIV RNA+/Ab- subjects possessed lower genetic diversity and divergence compared to 7 unrelated individuals sampled during the chronic phase of disease. Replication competent recombinant viruses incorporating the HIV RNA+/Ab- as compared to the chronic phase envelopes were significantly more sensitive to a CCR5 receptor inhibitor and IFN-α and showed a statistical trend toward greater sensitivity to a fusion blocker. The early as compared to chronic infection envelopes also demonstrated a statistical trend or significantly greater sensitivity to CCR5 and fusion inhibitor and IFN- α. The HIV RNA+/Ab- as compared to chronic envelope viruses replicated to a lower extent in mature monocyte derived dendritic cells - CD4+ T cell co-cultures, but there were no significant replication differences in other primary cells among the viruses with envelopes from the 3 different stages of infection. CONCLUSIONS: Similar to mucosal acquisition, HIV-1 envelope quasispecies present in injection drug users prior to seroconversion have unique phenotypic properties compared to those circulating during the chronic phase of disease.

Resting Energy Expenditure Prediction Equations in the Pediatric Population: A Systematic Review.

Background and Aims: The determination of energy requirements is necessary to promote adequate growth and nutritional status in pediatric populations. Currently, several predictive equations have been designed and modified to estimate energy expenditure at rest. Our objectives were (1) to identify the equations designed for energy expenditure prediction and (2) to identify the anthropometric and demographic variables used in the design of the equations for pediatric patients who are healthy and have illness. Methods: A systematic search in the Medline/PubMed, EMBASE and LILACS databases for observational studies published up to January 2021 that reported the design of predictive equations to estimate basal or resting energy expenditure in pediatric populations was carried out. Studies were excluded if the study population included athletes, adult patients, or any patients taking medications that altered energy expenditure. Risk of bias was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Results: Of the 769 studies identified in the search, 39 met the inclusion criteria and were analyzed. Predictive equations were established for three pediatric populations: those who were healthy (n = 8), those who had overweight or obesity (n = 17), and those with a specific clinical situation (n = 14). In the healthy pediatric population, the FAO/WHO and Schofield equations had the highest R 2 values, while in the population with obesity, the Molnár and Dietz equations had the highest R 2 values for both boys and girls. Conclusions: Many different predictive equations for energy expenditure in pediatric patients have been published. This review is a compendium of most of these equations; this information will enable clinicians to critically evaluate their use in clinical practice. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=226270, PROSPERO [CRD42021226270].

Humoral Immune Pressure Selects for HIV-1 CXC-chemokine Receptor 4-using Variants.

Although both C-C chemokine receptor 5 (CCR5)- and CXC chemokine receptor 4 (CXCR4)-using HIV-1 strains cause AIDS, the emergence of CXCR4-utilizing variants is associated with an accelerated decline in CD4+ T cells. It remains uncertain if CXCR4-using viruses hasten disease or if these variants only emerge after profound immunological damage. We show that exclusively CXCR4- as compared to cocirculating CCR5-utilizing variants are less sensitive to neutralization by both contemporaneous autologous plasma and plasma pools from individuals that harbor only CCR5-using HIV-1. The CXCR4-utilizing variants, however, do not have a global antigenic change because they remain equivalently susceptible to antibodies that do not target coreceptor binding domains. Studies with envelope V3 loop directed antibodies and chimeric envelopes suggest that the neutralization susceptibility differences are potentially influenced by the V3 loop. In vitro passage of a neutralization sensitive CCR5-using virus in the presence of autologous plasma and activated CD4+ T cells led to the emergence of a CXCR4-utilizing virus in 1 of 3 cases. These results suggest that in some but not necessarily all HIV-1 infected individuals humoral immune pressure against the autologous virus selects for CXCR4-using variants, which potentially accelerates disease progression. Our observations have implications for using antibodies for HIV-1 immune therapy.

Identification of the antiepileptic racetam binding site in the synaptic vesicle protein 2A by molecular dynamics and docking simulations.

Synaptic vesicle protein 2A (SV2A) is an integral membrane protein necessary for the proper function of the central nervous system and is associated to the physiopathology of epilepsy. SV2A is the molecular target of the anti-epileptic drug levetiracetam and its racetam analogs. The racetam binding site in SV2A and the non-covalent interactions between racetams and SV2A are currently unknown; therefore, an in silico study was performed to explore these issues. Since SV2A has not been structurally characterized with X-ray crystallography or nuclear magnetic resonance, a three-dimensional (3D) model was built. The model was refined by performing a molecular dynamics simulation (MDS) and the interactions of SV2A with the racetams were determined by docking studies. A reliable 3D model of SV2A was obtained; it reached structural equilibrium during the last 15 ns of the MDS (50 ns) with remaining structural motions in the N-terminus and long cytoplasmic loop. The docking studies revealed that hydrophobic interactions and hydrogen bonds participate importantly in ligand recognition within the binding site. Residues T456, S665, W666, D670 and L689 were important for racetam binding within the trans-membrane hydrophilic core of SV2A. Identifying the racetam binding site within SV2A should facilitate the synthesis of suitable radio-ligands to study treatment response and possibly epilepsy progression.

Heterogeneity of microRNAs expression in cervical cancer cells: over-expression of miR-196a.

In recent years, the study of microRNAs associated with neoplastic processes has increased. Patterns of microRNA expression in different cell lines and different kinds of tumors have been identified; however, little is known about the alterations in regulatory pathways and genes involved in aberrant set of microRNAs. The identification of these altered microRNAs in several cervical cancer cells and potentially deregulated pathways involved constitute the principal goals of the present study. In the present work, the expression profiles of cellular microRNAs in Cervical Cancer tissues and cell lines were explored using microRNA microarray, Affymetrix. The most over-expressed was miR-196a, which was evaluated by real time PCR, and HOXC8 protein as potential target by immunohistochemistry assay. One hundred and twenty three human microRNAs differentially expressed in the cell tumor, 64 (52%) over-expressed and 59 (48%) under-expressed were observed. Among the microRNAs over-expressed, we focused on miR-196a; at present this microRNA is poorly studied in CC. The expression of this microRNA was evaluated by qRT-PCR, and HOXC8 by immunohistochemistry assay. There is not a specific microRNA expression profile in the CC cells, neither a microRNA related to HPV presence. Furthermore, the miR-196a was over-expressed, while an absence of HOXC8 expression was observed. We suggest that miR-196a could be played as oncomiR in CC.

Early infection HIV-1 envelope V1-V2 genotypes do not enhance binding or replication in cells expressing high levels of α4ß7 integrin.

It has been postulated that HIV-1 envelope properties, such as shorter and less-glycosylated V1-V2 loops commonly observed among non-subtype B early-transmitted viruses, promote utilization of the gut homing integrin α4ß7. This property potentially confers an advantage to some HIV-1 variants early after acquisition. We found that replication-competent recombinant viruses incorporating HIV-1 subtype A compact and less-glycosylated early versus chronic phase V1-V2 loops demonstrated no significant difference in binding to α4ß7 high CD8⁺ T cells or replication in α4ß7 high CD4⁺ T cells. Integrin α4ß7 usage does not select for shorter less-glycosylated envelopes during transmission.