CRLF2 and IKZF1 abnormalities in childhood hematological malignancies other than B-cell Acute Lymphoblastic Leukemia.

Rearrangements and overexpression of CRLF2 are hallmarks of poor outcomes in BCR::ABL1-like B-ALL, and CRLF2 overexpression is a high-risk marker in T-ALL. However, CRLF2 alterations in pediatric hematologic malignancies other than B-ALL have not been reported. In this study, we analyzed the CRLF2 overexpression, rearrangements (P2RY8::CRLF2 and IGH::CRLF2), activation (pSTAT5 and pERK), and the expression of dominant-negative IKZF1 isoforms (Ik6 and Ik8), implied in CRLF2 dysregulation, in 16 pediatric patients (AML, n = 9; T-ALL, n = 3; LBL, n = 2; HL, n = 1; cytopenia, n = 1). A high frequency of CRLF2 rearrangements and overexpression was found in the 16 patients: 28.6% (4/14) showed CRLF2 overexpression, 93.8% (15/16) were positive for CRLF2 total protein (cell-surface and/or cytoplasmic), while 62.5% (10/16) were positive for P2RY8::CRLF2 and 12.6% (2/16) for IGH::CRLF2. In addition, 43.8% (7/16) expressed Ik6 and Ik8 isoforms. However, only a few patients were positive for the surrogate markers pSTAT5 (14.3%; 2/14) and pERK (21.4%; 3/14).

Pure Interstitial Trisomy 11q Arising from a Nonrecurrent 11q13.1q22.3 Mosaic Intrachromosomal Duplication in a Patient with Craniofacial Dysmorphism and Genital Anomalies.

Introduction: The pure interstitial trisomy 11q11q23.2 is an uncommon genomic disorder associated with nonrecurrent intrachromosomal duplications. The phenotype is characterized by intellectual disability and craniofacial abnormalities. Given their uncommonness, a comprehensive genotype-phenotype correlation has not fully been defined. Case Presentation: We report the clinical and cytogenomic characterization of a 5-year-old boy with intellectual disability, psychomotor retardation, craniofacial dysmorphism, genital anomalies, and pure interstitial trisomy 11q arising from a nonrecurrent 11q13.1q22.3 intrachromosomal duplication in a high-mosaic state (>80%). The duplicated chromosome was characterized by cytogenetics, multicolor banding FISH, and SNP array. We demonstrated the wide mosaic distribution of the 11q duplication by interphase FISH in tissues from different embryonic germ layers. The duplication involves a copy number gain of 45.3 Mb containing 22 dosage-sensitive genes. We confirmed the overexpression of dosage-sensitive genes along the duplicated region using RT-qPCR. Discussion: Only 8 patients have been described. Our patient shares clinical features with previous reports but differs from them by the presence of genital anomalies. We provide a detailed clinical review and an accurate genotype-phenotype correlation and propose PC, NDUFV1, FGF3, FGF4, and DHCR7 as dosage-sensitive genes with a possible role in the clinical spectrum of our patient; however, expression changes of FGF3/4 were not detected since they must be regulated in a spatiotemporal way. This patient contributes to the accurate description of the pure interstitial trisomy 11q. Future reports could continue to delineate the description, considering the relationship between the chromosome segment and the genes involved.

Comparison between Wright and Shukla formulas: which is better for the placement of umbilical catheters in newborns ≤ 1500 g?

BACKGROUND: Intravascular venous (VUC) or arterial (AUC) umbilical catheter placement is the most frequent invasive procedure in the neonatal intensive care unit (NICU). Either Wright's or Shukla's formula is used to introduce the catheters. However, Shukla's formula is associated with incorrect insertion, especially for newborns < 1500 g. This study aimed to determine by chest X-ray if Wright's formula is better than Shukla's formula for the correct placement of umbilical catheters in newborns ≤ 1500 g. METHODS: We included patients admitted to the NICU of a secondary-level hospital between 2021-2022 who received VUC or AUC through the Wright or Shukla formulas. RESULTS: A total of 129 newborns were included: 78 with VUC and 51 with AUC. In VUC, 50% with Wright and 36.8% with Shukla formulas had the correct location, (p = 0.24). In AUC, 56.6 % with Wright and 52.4% with Shukla formulas were placed correctly placed, (p = 0.76). VUC with weight < 1000 g were correctly placed in 36.4% with Wright and 33.3% with Shukla formulas (p = 0.58). VUC in newborns > 1000 g were correctly placed in 66.6% with Wright and 38.4% with Shukla formulas (p = 0.065). AUC in newborns < 1000 g were correctly placed in 45% using Wright and 42.9% Shukla formulas (p = 0.63). AUC in newborns > 1000 g were correctly placed in 80% using Wright and 57.1% Shukla formulas (p = 0.23). CONCLUSIONS: We found 13% more correctly placed VUC using Wright's formula. Moreover, Wright's formula was 29% above Shukla's VUC placement in neonates > 1000 g, although there was no significant difference due to the sample size.

INTRODUCCIÓN: La colocación de catéteres intravasculares venosos umbilicales (CVU) y arteriales (CAU) es el procedimiento invasivo más frecuente en la unidad de cuidados intensivos neonatales (UCIN). Para introducirlos se utilizan las fórmulas de Wright y de Shukla, aunque esta última podría estar asociada con una inserción incorrecta, especialmente en neonatos < 1500 g. El objetivo de este estudio fue determinar mediante radiografía de tórax cuál fórmula es mejor para la correcta colocación de catéteres umbilicales en recién nacidos ≤ 1500 g. MÉTODOS: Se incluyeron los pacientes ingresados en la UCIN de un hospital de segundo nivel entre 2021-2022 que recibieron CVU o CAU mediante las fórmulas de Wrigth o Shukla. RESULTADOS: Se incluyeron en total 129 recién nacidos: 78 CVU y 51 CAU. En CVU, Wright 50% y Shukla 36.8% tuvieron localización correcta, p = 0.24. En las CAU, Wright 56.6% y Shukla 52.4% tenían una ubicación correcta, p = 0.76. En CVU con peso < 1000 g, Wright 36.4% y Shukla 33.3% bien situados, p = 0.58. En CVU > 1000 g, Wright 66.6% y Shukla 38.4% bien situados, p = 0.065. En CAU < 1000 g, Wright 45% y Shukla 42.9%, p = 0.63. En CAU con peso > 1000 g, Wright 80% y Shukla 57.1%, p = 0.23. CONCLUSIONES: La colocación del CVU fue 13% mejor con la fórmula de Wright. La fórmula de Wright superó en el 29% la colocación del CVU en los neonatos > 1000 g en comparación con la de Shukla, aunque no hubo diferencia significativa debido al tamaño de la muestra.

Comparison between Wright and Shukla formulas: which is better for the placement of umbilical catheters in newborns ≤ 1500 g? / Comparación entre las fórmulas de Wright y de Shukla: ¿cuál es mejor para la colocación de catéteres umbilicales en recién nacidos ≤ 1500 g?

Abstract Background: Intravascular venous (VUC) or arterial (AUC) umbilical catheter placement is the most frequent invasive procedure in the neonatal intensive care unit (NICU). Either Wright's or Shukla's formula is used to introduce the catheters. However, Shukla's formula is associated with incorrect insertion, especially for newborns < 1500 g. This study aimed to determine by chest X-ray if Wright's formula is better than Shukla's formula for the correct placement of umbilical catheters in newborns ≤ 1500 g. Methods: We included patients admitted to the NICU of a secondary-level hospital between 2021-2022 who received VUC or AUC through the Wright or Shukla formulas. Results: A total of 129 newborns were included: 78 with VUC and 51 with AUC. In VUC, 50% with Wright and 36.8% with Shukla formulas had the correct location, (p = 0.24). In AUC, 56.6 % with Wright and 52.4% with Shukla formulas were placed correctly placed, (p = 0.76). VUC with weight < 1000 g were correctly placed in 36.4% with Wright and 33.3% with Shukla formulas (p = 0.58). VUC in newborns > 1000 g were correctly placed in 66.6% with Wright and 38.4% with Shukla formulas (p = 0.065). AUC in newborns < 1000 g were correctly placed in 45% using Wright and 42.9% Shukla formulas (p = 0.63). AUC in newborns > 1000 g were correctly placed in 80% using Wright and 57.1% Shukla formulas (p = 0.23). Conclusions: We found 13% more correctly placed VUC using Wright's formula. Moreover, Wright's formula was 29% above Shukla's VUC placement in neonates > 1000 g, although there was no significant difference due to the sample size.

Resumen Introducción: La colocación de catéteres intravasculares venosos umbilicales (CVU) y arteriales (CAU) es el procedimiento invasivo más frecuente en la unidad de cuidados intensivos neonatales (UCIN). Para introducirlos se utilizan las fórmulas de Wright y de Shukla, aunque esta última podría estar asociada con una inserción incorrecta, especialmente en neonatos < 1500 g. El objetivo de este estudio fue determinar mediante radiografía de tórax cuál fórmula es mejor para la correcta colocación de catéteres umbilicales en recién nacidos ≤ 1500 g. Métodos: Se incluyeron los pacientes ingresados en la UCIN de un hospital de segundo nivel entre 2021-2022 que recibieron CVU o CAU mediante las fórmulas de Wrigth o Shukla. Resultados: Se incluyeron en total 129 recién nacidos: 78 CVU y 51 CAU. En CVU, Wright 50% y Shukla 36.8% tuvieron localización correcta, p = 0.24. En las CAU, Wright 56.6% y Shukla 52.4% tenían una ubicación correcta, p = 0.76. En CVU con peso < 1000 g, Wright 36.4% y Shukla 33.3% bien situados, p = 0.58. En CVU > 1000 g, Wright 66.6% y Shukla 38.4% bien situados, p = 0.065. En CAU < 1000 g, Wright 45% y Shukla 42.9%, p = 0.63. En CAU con peso > 1000 g, Wright 80% y Shukla 57.1%, p = 0.23. Conclusiones: La colocación del CVU fue 13% mejor con la fórmula de Wright. La fórmula de Wright superó en el 29% la colocación del CVU en los neonatos > 1000 g en comparación con la de Shukla, aunque no hubo diferencia significativa debido al tamaño de la muestra.

Numerical Analysis of Zirconium and Titanium Implants under the Effect of Critical Masticatory Load.

Dental implants have become an alternative to replace the teeth of people suffering from edentulous and meet the physiological and morphological characteristics (recovering 95% of the chewing function). The evolution and innovation of biomaterials for dental implants have had a trajectory that dates back to prehistory, where dental pieces were replaced by ivory or seashells, to the present day, where they are replaced by metallic materials such as titanium or ceramics such as zirconium or fiberglass. The numerical evaluation focuses on comparing the stress distribution and general displacement between different dental implants and a healthy tooth when applying a force of 850 N. For the analysis, a model of the anatomical structure was developed of a healthy tooth considering three essential parts of the tooth (enamel, dentin, and pulp). The tooth biomodel was established through computed tomography. Three dental implant models were considered by changing the geometry of the abutment. A structural simulation was carried out by applying the finite element method (FEM). In addition, the material considered for the analyses was zirconium oxide (ZrO2), which was compared against titanium alloy (Ti6Al4V). The analyses were considered with linear, isotropic, and homogeneous properties. The variables included in the biomodeling were the modulus of elasticity, Poisson's ratio, density, and elastic limit. The results obtained from the study indicated a significant difference in the biomechanical behavior of the von Mises forces and the displacement between the healthy tooth and the titanium and zirconium implant models. However, the difference between the titanium implant and the zirconium implant is minimal because one is more rigid, and the other is more tenacious.

Characterization of Philadelphia-like Pre-B Acute Lymphoblastic Leukemia: Experiences in Mexican Pediatric Patients.

Ph-like subtypes with CRLF2 abnormalities are frequent among Hispano-Latino children with pre-B ALL. Therefore, there is solid ground to suggest that this subtype is frequent in Mexican patients. The genomic complexity of Ph-like subtype constitutes a challenge for diagnosis, as it requires diverse genomic methodologies that are not widely available in diagnostic centers in Mexico. Here, we propose a diagnostic strategy for Ph-like ALL in accordance with our local capacity. Pre-B ALL patients without recurrent gene fusions (104) were classified using a gene-expression profile based on Ph-like signature genes analyzed by qRT-PCR. The expressions of the CRLF2 transcript and protein were determined by qRT-PCR and flow cytometry. The P2RY8::CRLF2, IGH::CRLF2, ABL1/2 rearrangements, and Ik6 isoform were screened using RT-PCR and FISH. Surrogate markers of Jak2-Stat5/Abl/Ras pathways were analyzed by phosphoflow. Mutations in relevant kinases/transcription factors genes in Ph-like were assessed by target-specific NGS. A total of 40 patients (38.5%) were classified as Ph-like; of these, 36 had abnormalities associated with Jak2-Stat5 and 4 had Abl. The rearrangements IGH::CRLF2,P2RY8::CRLF2, and iAMP21 were particularly frequent. We propose a strategy for the detection of Ph-like patients, by analyzing the overexpression/genetic lesions of CRLF2, the Abl phosphorylation of surrogate markers confirmed by gene rearrangements, and Sanger sequencing.

High occurrence of CRLF2 abnormalities in Mexican children with B-cell acute lymphoblastic leukemia.

The P2RY8-CRLF2 and IGH-CRLF2 rearrangements induce the overexpression of cytokine receptor-like factor 2 (CRLF2) and have been associated with relapse and poor prognosis in B-cell acute lymphoblastic leukemia (B-ALL). Additionally, they are frequently documented in high-risk Hispanic populations. To better understand the potential causes of the adverse prognosis of childhood B-ALL in Mexico, we analyzed these rearrangements and the CRLF2 mRNA and protein levels in 133 Mexican children with B-ALL. We collected bone marrow samples at diagnosis and evaluated the CRLF2 gene expression by qRT-PCR and the total CRLF2 protein by flow cytometry. P2RY8-CRLF2 and IGH-CRLF2 were detected by RT-PCR and FISH, respectively. The median time of follow-up to determine the prognostic significance of the CRLF2 abnormalities was three years. In 82% of the participants, the mRNA levels correlated with the cell-surface and intracellular CRLF2 protein levels. The P2RY8-CRLF2 rearrangement was present in 31.5% (42/133) of the patients, while the IGH-CRLF2 rearrangement was detected in 13.5% (9/67) of patients with high expression of CRLF2 (6.8% of the total sample). CRLF2 copy number variations (gain) were also detected in 7.5% (5/67) of patients with high protein levels. The overall survival (OS) presented significantly lower rates in patients with high white blood cell count (≥50x109/L) regardless of CRLF2 expression, but high levels of CRLF2 gene expression appears to contribute to the reduction of OS within this group of patients. In conclusion, in our cohort, a high occurrence of CRLF2 abnormalities was documented, particularly the P2RY8-CRLF2 rearrangement, which might represent a characteristic of the Mexican population. Targeted therapy to treat this group of patients could improve OS.

Transmitted resistance in HIV-1 of patients from nine departments of Peru. / Resistencia transmitida en VIH-1 de pacientes provenientes de nueve departamentos del Perú.

The main aim of this research is to identify the transmitted resistance (RT) of the Human Immunodeficiency Virus (HIV) in subjects from nine cities of Peru. For this, a descriptive and cross-sectional study was carried out in 135 adult subjects who agreed to participate through an informed consent. Blood samples were collected to perform the CD4 / CD8 cell count, viral load and HIV Genotyping. Socio-epidemiological information was collected from the participants through surveys. The results revealed a RT frequency of 9.8% (13/132). The information from this research might help improve the intervention and monitoring programs for antiretroviral resistance in the country.

El estudio tuvo como objetivo determinar la resistencia transmitida (RT) del virus de la inmunodeficiencia humana (VIH) en pacientes procedentes de nueve departamentos del Perú. Para ello, se realizó un estudio descriptivo en 132 adultos que aceptaron participar mediante un consentimiento informado. Se colectaron muestras de sangre para realizar el recuento de células CD4/CD8, determinar la carga viral y la genotipificación del VIH. Se recabó información socioepidemiológica de los participantes mediante encuestas. Los resultados revelaron una frecuencia de RT de 9,8% (13/132). Los resultados del estudio ayudarán a mejorar los programas de intervención y monitoreo de la resistencia a los antirretrovirales en el país.

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways.

The gene fusions BCR-ABL1, TCF3-PBX1, and ETV6-RUNX1 are recurrent in B-cell acute lymphoblastic leukemia (B-ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor-like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant-negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B-ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant-negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR-ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3-PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6-RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3-PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8-CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR-ABL1 and TCF3-PBX1 patients. To obtain useful information for the assessment of treatment in B-ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant-negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.

Resistencia transmitida en VIH-1 de pacientes provenientes de nueve departamentos del Perú / Transmitted resistance in HIV-1 of patients from nine departments of Peru

RESUMEN El estudio tuvo como objetivo determinar la resistencia transmitida (RT) del virus de la inmunodeficiencia humana (VIH) en pacientes procedentes de nueve departamentos del Perú. Para ello, se realizó un estudio descriptivo en 132 adultos que aceptaron participar mediante un consentimiento informado. Se colectaron muestras de sangre para realizar el recuento de células CD4/CD8, determinar la carga viral y la genotipificación del VIH. Se recabó información socioepidemiológica de los participantes mediante encuestas. Los resultados revelaron una frecuencia de RT de 9,8% (13/132). Los resultados del estudio ayudarán a mejorar los programas de intervención y monitoreo de la resistencia a los antirretrovirales en el país.

ABSTRACT The main aim of this research is to identify the transmitted resistance (RT) of the Human Immunodeficiency Virus (HIV) in subjects from nine cities of Peru. For this, a descriptive and cross-sectional study was carried out in 135 adult subjects who agreed to participate through an informed consent. Blood samples were collected to perform the CD4 / CD8 cell count, viral load and HIV Genotyping. Socio-epidemiological information was collected from the participants through surveys. The results revealed a RT frequency of 9.8% (13/132). The information from this research might help improve the intervention and monitoring programs for antiretroviral resistance in the country.

Resistencia transmitida en VIH-1 de pacientes provenientes de nueve departamentos del Perú / Transmitted resistance in HIV-1 of patients from nine departments of Peru

RESUMEN El estudio tuvo como objetivo determinar la resistencia transmitida (RT) del virus de la inmunodeficiencia humana (VIH) en pacientes procedentes de nueve departamentos del Perú. Para ello, se realizó un estudio descriptivo en 132 adultos que aceptaron participar mediante un consentimiento informado. Se colectaron muestras de sangre para realizar el recuento de células CD4/CD8, determinar la carga viral y la genotipificación del VIH. Se recabó información socioepidemiológica de los participantes mediante encuestas. Los resultados revelaron una frecuencia de RT de 9,8% (13/132). Los resultados del estudio ayudarán a mejorar los programas de intervención y monitoreo de la resistencia a los antirretrovirales en el país.

ABSTRACT The main aim of this research is to identify the transmitted resistance (RT) of the Human Immunodeficiency Virus (HIV) in subjects from nine cities of Peru. For this, a descriptive and cross-sectional study was carried out in 135 adult subjects who agreed to participate through an informed consent. Blood samples were collected to perform the CD4 / CD8 cell count, viral load and HIV Genotyping. Socio-epidemiological information was collected from the participants through surveys. The results revealed a RT frequency of 9.8% (13/132). The information from this research might help improve the intervention and monitoring programs for antiretroviral resistance in the country.

[Identification of house dust mite fauna from allergic patients' mattress in six Mexican states]. / Identificación de la fauna de ácaros del polvo doméstico en colchones de pacientes alérgicos de seis estados mexicanos.

BACKGROUND: House dust is considered an important source of aeroallergens, and the mites living there, are the main cause of allergy to it. In México, there have been few about house dust fauna, and mostly limited to México City. OBJECTIVE: To describe the house dust fauna from mattresses of allergic patients from different cities in México. METHODS: Sixty dust samples were collected from mattresses in 6 Mexican states: Oaxaca, Tamaulipas, Veracruz, Puebla, Chiapas and Campeche. Mites were isolated under a stereomicroscope using lactic acid -0.9% NaCI solution. Identification was performed on fixed slides prepared with Hoyer solution. Skin Tests were already performed with allergen extracts of different house dust mites species in the 60 mattress' owners, whom had previously been diagnosed with respiratory allergy. RESULTS: The Pyroglyphidae family was found in 100% of dust samples. Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) were the species most frequently found (>90%). These findings were in agreement with the skin tests results, where 100% of patients were positive to Dp, whereas 70% was positive to Df. It was evidenced for the first time the presence of Blomia tropicalis in Tamaulipas, Veracruz and Campeche states, and Dermatophagoides siboney in Campeche. Both species are important allergenic sources in tropical/subtropical climates. CONCLUSIONS: These results confirm the importance of Pyroglyphid house dust mites, as indoor sensitizers in different climatic and geographical regions in México, as well as, the relevance of tropical species, particularly Blomia tropicalis and D. Siboney, in certain areas.