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The return of a migrant partner can negatively impact the sexual health of women who stayed in their communities. Understanding their sexual health needs is crucial for developing targeted interventions and support systems. Our study used a critical ethnographic approach in Agua Dulce, a rural community in Mexico, involving 50 key informants: women who stayed behind (n = 20), returnees (n = 12), community leaders (n = 12), and health care professionals (n = 6). We used participant observation, policy analysis, and interviews, using purposeful and snowball sampling methods. A gender-based thematic analysis revealed economic hardships and early separations affect the sexual well-being of women who stay behind. Infidelity, discovered through social media or calls, causes emotional distress and family disruptions. Male migrants spend an average of 8.85 years abroad, leading to fears of risky sexual behaviors. Our study highlights the urgent need for specialized support centers and comprehensive health interventions. [ABSTRACT FROM AUTHOR]

T-lineage acute lymphoblastic leukemia (ALL) is an aggressive cancer comprising diverse subtypes that are challenging to stratify using conventional immunophenotyping. To gain insights into subset-specific therapeutic vulnerabilities, we performed an integrative multiomics analysis of bone marrow samples from newly diagnosed T cell ALL, early T cell precursor ALL, and T/myeloid mixed phenotype acute leukemia. Leveraging cellular indexing of transcriptomes and epitopes in conjunction with T cell receptor sequencing, we identified a subset of patient samples characterized by activation of inflammatory and stem gene programs. These inflammatory T-lineage samples exhibited distinct biological features compared with other T-lineage ALL samples, including the production of proinflammatory cytokines, prevalence of mutations affecting cytokine signaling and chromatin remodeling, an altered immune microenvironment, and poor treatment responses. Moreover, we found that, although inflammatory T-lineage ALL samples were less sensitive to dexamethasone, they exhibited unique sensitivity to a BCL-2 inhibitor, venetoclax. To facilitate classification of patients with T-lineage ALL, we developed a computational inflammatory gene signature scoring system, which stratified patients and was associated with disease prognosis in three additional patient cohorts. By identifying a high-risk T-lineage ALL subtype on the basis of an inflammatory score, our study provides a framework for targeted therapeutic approaches for these challenging-to-treat cancers. Editor's summary: Despite advances in treatment for T-lineage acute lymphoblastic leukemia (ALL), many patients, including pediatric patients, still succumb to disease. To better stratify patients and, ideally, personalize their treatments, Gower et al. performed multiomics analysis on T-lineage ALL patient samples. The authors found that a subset of T-lineage ALL samples harbored an inflammatory phenotype and was uniquely sensitive to a clinically approved BCL-2 inhibitor, venetoclax. Using the results of their multiomics approach, the authors developed an inflammatory gene score that could be used to stratify patients into disease subtypes, offering the opportunity to personalize therapies. —Courtney Malo [ABSTRACT FROM AUTHOR]

Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed next-generation sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1) and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phenotype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that next-generation sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients.

Phosphorylation is a common form of protein modification. To understand its biological role, the site of phosphorylation has to be determined. Generally, only limited amounts of phosphorylated proteins are present in a cell, thus demanding highly sensitive procedures for phosphorylation site determination. Here, a novel method is introduced which enables the localization of tyrosine phosphorylation in gel-separated proteins in the femtomol range. The method utilizes the immonium ion of phosphotyrosine at m/z 216.043 for positive ion mode precursor ion scanning combined with the recently introduced Q2-pulsing function on quadrupole TOF mass spectrometers. The high resolving power of the quadrupole TOF instrument enables the selective detection of phosphotyrosine immonium ions without interference from other peptide fragments of the same nominal mass. Performing precursor ion scans in the positive ion mode facilitates sequencing, because there is a no need for polarity switching or changing pH of the spraying solvent. Similar limits of detection were obtained in this approach when compared to triple-quadrupole mass spectrometers but with significantly better selectivity, owing to the high accuracy of the fragment ion selection. Synthetic phosphopeptides could be detected at 1 fmol/[micro]L, and 100 fmol of a tyrosine phosphorylated protein in gel was sufficient for the detection of the phosphorylated peptide in the unseparated digestion mixture and for unambiguous phosphorylation site determination. The new method can be applied to unknown protein samples, because the identification and localization of the modification is performed on the same sample.

Noonan syndrome (NS) is a relatively common genetic disorder, characterized by typical facies, short stature, developmental delay, and cardiac abnormalities. Known causative genes account for 70-80% of clinically diagnosed NS patients, but the genetic basis for the remaining 20-30% of cases is unknown. We performed next-generation sequencing on germ-line DNA from 27 NS patients lacking a mutation in the known NS genes. We identified gain-of-function alleles in Ras-like without CAAX 1 (RIT1) and mitogen-activated protein kinase kinase 1 (MAP2K1) and previously unseen loss-of-function variants in RAS p21 protein activator 2 (RASA2) that are likely to cause NS in these patients. Expression of the mutant RASA2, MAP2K1, or RIT1 alleles in heterologous cells increased RAS-ERK pathway activation, supporting a causative role in NS pathogenesis. Two patients had more than one disease-associated variant. Moreover, the diagnosis of an individual initially thought to have NS was revised to neurofibromatosis type 1 based on an NF1 nonsense mutation detected in this patient. Another patient harbored a missense mutation in NF1 that resulted in decreased protein stability and impaired ability to suppress RAS-ERK activation; however, this patient continues to exhibit a NS-like phe-notype. In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome. Finally, we identified other potential candidates for new NS genes, as well as potential carrier alleles for unrelated syndromes. Taken together, our data suggest that next-generation sequencing can provide a useful adjunct to RASopathy diagnosis and emphasize that the standard clinical categories for RASopathies might not be adequate to describe all patients. [ABSTRACT FROM AUTHOR]

Abstract: The return of a migrant partner can negatively impact the sexual health of women who stayed in their communities. Understanding their sexual health needs is crucial for developing targeted interventions and support systems. Our study used a critical ethnographic approach in Agua Dulce, a rural community in Mexico, involving 50 key informants: women who stayed behind ( n = 20), returnees ( n = 12), community leaders ( n = 12), and health care professionals ( n = 6). We used participant observation, policy analysis, and interviews, using purposeful and snowball sampling methods. A gender-based thematic analysis revealed economic hardships and early separations affect the sexual well-being of women who stay behind. Infidelity, discovered through social media or calls, causes emotional distress and family disruptions. Male migrants spend an average of 8.85 years abroad, leading to fears of risky sexual behaviors. Our study highlights the urgent need for specialized support centers and comprehensive health interventions., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Association of Nurses in AIDS Care.)