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1.
Am J Hum Genet ; 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39288765

RESUMEN

Efforts to implement and evaluate genome sequencing (GS) as a screening tool for newborns and infants are expanding worldwide. The first iteration of the BabySeq Project (2015-2019), a randomized controlled trial of newborn sequencing, produced novel evidence on medical, behavioral, and economic outcomes. The second iteration of BabySeq, which began participant recruitment in January 2023, examines GS outcomes in a larger, more diverse cohort of more than 500 infants up to one year of age recruited from pediatric clinics at several sites across the United States. The trial aims for families who self-identify as Black/African American or Hispanic/Latino to make up more than 50% of final enrollment, and key aspects of the trial design were co-developed with a community advisory board. All enrolled families receive genetic counseling and a family history report. Half of enrolled infants are randomized to receive GS with comprehensive interpretation of pathogenic and likely pathogenic variants in more than 4,300 genes associated with childhood-onset and actionable adult-onset conditions, as well as larger-scale chromosomal copy number variants classified as pathogenic or likely pathogenic. GS result reports include variants associated with disease (Mendelian disease risks) and carrier status of autosomal-recessive and X-linked disorders. Investigators evaluate the utility and impacts of implementing a GS screening program in a diverse cohort of infants using medical record review and longitudinal parent surveys. In this perspective, we describe the rationale for the second iteration of the BabySeq Project, the outcomes being assessed, and the key decisions collaboratively made by the study team and community advisory board.

2.
Pediatr Dermatol ; 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-39308357

RESUMEN

Isotretinoin, the standard treatment for severe nodular acne, is subject to stringent iPLEDGE regulations due to its teratogenic risks, requiring monthly assessments for patients of childbearing potential. Analysis of the iPLEDGE Comprehension Assessment (iPCA) revealed an average readability score of grade 8.5, exceeding the recommended grade 6 level for optimal patient comprehension. The complex language of iPCA may hinder patients from accessing treatment, contributing to delays and potential discontinuation, especially among female patients. While the overall number of isotretinoin-exposed pregnancies has decreased since the inception of iPledge, several hundred pregnancies continue to be reported, and simplification of iPCA presents one avenue to improve patient comprehension, safety, and ensuring equitable access to isotretinoin.

3.
Diagn Microbiol Infect Dis ; 110(2): 116468, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39094237

RESUMEN

Pediatric pneumonia can be severe and result in empyema. Next-generation sequencing (NGS) may broadly detect pathogens though, optimal timing and impact of sample type on diagnostic yield is unknown. This is a prospective, single-center pilot study of children aged 3 months through 17 years admitted to the PICU with a primary diagnosis of complicated pneumonia. Plasma, endotracheal, nasopharyngeal, and pleural fluid samples were collected at three time points during hospitalization. After nucleic acid extraction, combined libraries were enriched with an NGS enrichment panel kit (RPIP, Illumina), sequenced and quantitative organism detections were analyzed. NGS identified the same bacterial pathogen as traditional testing in all samples, regardless of antibiotic pre-treatment or time collected. Conventional culture methods only identified the pathogen reliably in invasively obtained pleural fluid or endotracheal aspirates. Future application of NGS may allow for non-invasive pathogen detection at a broader range of time points and more targeted antibiotic coverage.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Niño , Lactante , Preescolar , Estudios Prospectivos , Adolescente , Proyectos Piloto , Masculino , Femenino , Bacterias/genética , Bacterias/aislamiento & purificación , Bacterias/clasificación , Neumonía Bacteriana/diagnóstico , Neumonía Bacteriana/microbiología , Nasofaringe/microbiología , Neumonía/microbiología , Neumonía/diagnóstico
4.
Am J Clin Pathol ; 2024 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-39180762

RESUMEN

OBJECTIVES: Dilated cardiomyopathy (DCM) is often hereditary, with 20% to 40% of nonischemic cases showing familial linkage, yet genetic testing is underused. This report describes an unreported pathogenic nonsense variant in the Titin (TTN) gene (NM_001267550.2:c.92603G>A) in a 24-year-old man with severe DCM and acute fibrinoid organizing pneumonia, highlighting a unique cardiopulmonary pathology. METHODS: We conducted detailed gross, histopathologic, immunophenotypic, and exome-based DNA sequencing analysis in the workup of this case. We also included the patient's clinical and radiologic findings in our study. RESULTS: With rapid clinical deterioration and complex comorbidities, including substance abuse and psychiatric conditions, which precluded transplantation, the patient's cardiac function progressively worsened. Autopsy findings included extreme cardiomegaly, biventricular hypertrophy, and acute and chronic pericarditis. Significant pulmonary pathology consistent with acute fibrinoid organizing pneumonia was also noted. Molecular testing confirmed a deleterious maternally inherited TTN variant that was absent in the sibling of the proband and the extant medical literature, highlighting its rarity and significance. CONCLUSIONS: This case contributes to the ongoing body of work on the impact of TTN variants on DCM. It suggests a potential link between genetic variants and complex cardiac injury patterns, emphasizing the need for further investigation into the interplay between cardiomyopathy and pulmonary pathology.

5.
Cureus ; 16(6): e62571, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-39027776

RESUMEN

Introduction Assisted reproductive technologies (ART) rely on endometrial receptivity (ER) for successful embryo implantation. This study aimed to compare the impact of different progesterone administration routes on ER assessed using optimal time for endometrial receptivity analysis (OpERA) and clinical outcomes in ART cycles. Methods A retrospective cohort analysis was conducted on 281 infertile women who underwent in vitro fertilization (IVF). Patients were stratified based on progesterone administration routes: oral and vaginal progesterone (Group 1) vs. intramuscular progesterone (Group 2). OpERA was performed on 257 patients to assess ER. Clinical outcomes, including biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), implantation rate (IR), and abortion rate (AR), were compared between the groups. Results OpERA results showed no significant differences between Group 1 and Group 2 in receptive (51.2% vs. 52.0%, p = 0.857), pre-receptive (44.1% vs. 44.6%, p = 0.933), or post-receptive (4.7% vs. 3.1%, p = 0.496) states. Clinical outcomes, including BPR (59.9% vs. 60.9%, p = 0.903), CPR (50.0% vs. 56.5%, p = 0.463), IR (52.5% vs. 55.3%, p = 0.748), and AR (44.3% vs. 45.6%, p = 0.882), did not significantly differ between the groups. Conclusion Progesterone administration routes did not significantly affect ER or clinical outcomes, highlighting the need to prioritize understanding and enhancing ER instead of solely focusing on progesterone delivery methods. Identifying molecular pathways or biomarkers could improve receptivity and optimize ART, ultimately improving pregnancy outcomes.

6.
Mol Biol Rep ; 51(1): 835, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39042283

RESUMEN

Glucagon-like Peptide-1 (GLP-1) receptor agonists (GLP-1RAs) emerged as a primary treatment for type-2 diabetes mellitus (T2DM), however, their multifaceted effects on various target organs beyond glycemic control opened a new era of treatment. We conducted a comprehensive literature search using databases including Scopus, Google Scholar, PubMed, and the Cochrane Library to identify clinical, in-vivo, and in-vitro studies focusing on the diverse effects of GLP-1 receptor agonists. Eligible studies were selected based on their relevance to the varied roles of GLP-1RAs in T2DM management and their impact on other physiological functions. Numerous studies have reported the efficacy of GLP-1RAs in improving outcomes in T2DM, with demonstrated benefits including glucose-dependent insulinotropic actions, modulation of insulin signaling pathways, and reductions in glycemic excursions. Additionally, GLP-1 receptors are expressed in various tissues and organs, suggesting their widespread physiological functions beyond glycemic control potentially include neuroprotective, anti-inflammatory, cardioprotective, and metabolic benefits. However, further scientific studies are still underway to maximize the benefits of GLP-1RAs and to discover additional roles in improving health benefits. This article sought to review not only the actions of GLP1RAs in the treatment of T2DM but also explore its effects on potential targets in other disorders.


Asunto(s)
Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Animales , Transducción de Señal/efectos de los fármacos , Péptido 1 Similar al Glucagón/metabolismo , Insulina/metabolismo , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Agonistas Receptor de Péptidos Similares al Glucagón
7.
Croat Med J ; 65(3): 261-267, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38868972

RESUMEN

Traditional newborn screening (NBS) serves as a critical tool in identifying conditions that may impact a child's health from an early stage. Newborn sequencing (NBSeq), the comprehensive analysis of an infant's genome, holds immense promise for revolutionizing health care throughout the lifespan. NBSeq allows for early detection of genetic disease risk and precision personalized medicine. The rapid evolution of DNA sequencing technologies and increasing affordability have spurred numerous endeavors to explore the potential of whole-genome sequencing in newborn screening. However, this transformative potential cannot be realized without challenges. Ethical aspects must be carefully navigated to safeguard individual rights and maintain public trust. Moreover, genomic data interpretation poses complex challenges due to its amount, the presence of variants of uncertain significance, and the dynamic nature of our understanding of genetics. Implementation hurdles, including cost, infrastructure, and specialized expertise, also present barriers to the widespread adoption of NBSeq. Addressing these challenges requires collaboration among clinicians, researchers, policymakers, ethicists, and stakeholders across various sectors. Robust frameworks for informed consent, data protection, and governance are essential. Advances in bioinformatics, machine learning, and genomic interpretation are crucial for translation into actionable clinical insights. Scalability and improving downstream health care access are vital for equitability, particularly in underserved communities. By fostering interdisciplinary collaboration, advancing technology and infrastructure, and upholding ethical principles, we can unlock the full potential of NBSeq as a tool for precision medicine and pave the way toward a future where every child has the opportunity for a healthier, genomics-informed start to life.


Asunto(s)
Tamizaje Neonatal , Humanos , Tamizaje Neonatal/ética , Tamizaje Neonatal/métodos , Tamizaje Neonatal/normas , Recién Nacido , Pruebas Genéticas/ética , Pruebas Genéticas/métodos , Secuenciación Completa del Genoma/ética , Genómica/ética , Medicina de Precisión/métodos
8.
J Behav Med ; 47(5): 792-803, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38735024

RESUMEN

Purpose We aimed to document the acceptability (enrollment rate) and feasibility (phone call delivery rate) of implementing a behavioral PA intervention over 12 weeks, in addition to documenting its effects on patient-reported outcomes and physical functioning. This study also describes the costs of carrying out a behavioral PA intervention. A total of 40 participants were randomized in a 1:1 ratio. The tailored behavioral PA intervention was developed based on the most recent PA guidelines in pediatric oncology and on the COM-B framework to enact PA behavior changes. The prescription (frequency, intensity, time and type (FITT)) was adjusted each week during the weekly support calls. The control group did not receive the intervention. 26 males and 14 females (13.6 years old on average and 2.9 years post-cancer treatment on average) participated in our study. The acceptability rate was 90.9% and the feasibility rate was > 85%. We found that 85% improved PA frequency, 80% improved PA intensity, 100% improved PA time, and 50.0% achieved the recommended PA guidelines. No adverse events were reported over the duration of the intervention. Physical function improved with longer 6-minute walk distances in the intervention group (465.8 ± 74.5 m) than in the control group (398.7 ± 92.9 m) (p = 0.016). PROs scores for all participants were within the limits of the normal range. The estimated cost per participant of carrying out this intervention was USD $126.57. Our 12-week behavioral PA intervention, based on the COM-B framework, was found to be acceptable, feasible and safe in childhood cancer survivors. This study is an important step in the right direction to make exercise standard practice in pediatric oncology.


Asunto(s)
Supervivientes de Cáncer , Ejercicio Físico , Estudios de Factibilidad , Neoplasias , Humanos , Femenino , Masculino , Supervivientes de Cáncer/psicología , Adolescente , Niño , Proyectos Piloto , Ejercicio Físico/psicología , Neoplasias/psicología , Neoplasias/terapia , Medición de Resultados Informados por el Paciente , Terapia Conductista/métodos , Terapia por Ejercicio/métodos
9.
Cell Biochem Biophys ; 82(2): 501-520, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38594547

RESUMEN

The Disabled-2 (DAB2) protein, found in 80-90% of various tumors, including breast cancer, has been identified as a potential tumor suppressor protein. On the contrary, some hypothesis suggests that DAB2 is associated with the modulation of the Ras/MAPK pathway by endocytosing the Grb/Sos1 signaling complex, which produces oncogenes and chemoresistance to anticancer drugs, leading to increased tumor growth and metastasis. DAB2 has multiple functions in several disorders and is typically under-regulated in several cancers, making it a potential target for treatment of cancer therapy. The primary function of DAB2 is the modulation of transforming growth factor- ß (TGF-ß) mediated endocytosis, which is involved in several mechanisms of cancer development, including tumor suppression through promoting apoptosis and suppressing cell proliferation. In this review, we will discuss in detail the mechanisms through which DAB2 leads to breast cancer and various advancements in employing DAB2 in the treatment of breast cancer. Additionally, we outlined its role in other diseases. We propose that upregulating DAB2 could be a novel approach to the therapeutics of breast cancer.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Reguladoras de la Apoptosis , Neoplasias de la Mama , Transducción de Señal , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Transducción de Señal/efectos de los fármacos , Femenino , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/metabolismo , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Animales , Endocitosis , Proteínas Supresoras de Tumor/metabolismo
10.
Langmuir ; 40(15): 7835-7842, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38574181

RESUMEN

Here, we compare the amount and morphology of silver (Ag) nanostructures electrodeposited at varied potentials and times in the presence of cetyltrimethylammonium bromide (CTAB) onto glass/indium tin oxide (glass/ITO) electrodes functionalized with mercaptopropyltrimethoxysilane (MPTMS) and coated or not coated with 4 nm average diameter Au nanoparticle (Au NP) seeds. There is a significantly larger amount of Ag deposited on the seeded electrode surface compared to that in the nonseeded electrode at potentials of -150 to -300 mV (vs Ag/AgCl) since the Au NP seeds act as catalysts for Ag deposition. At more negative overpotentials of -400 to -500 mV, the amount of Ag deposited on both electrodes is similar because the deposition kinetics are fast enough on glass/ITO that the Au seed catalyst does not make as big of a difference. Ag nanorods (NRs) and nanowires (NWs) form on the seeded surfaces, especially at more positive potentials, where deposition primarily occurs on the Au seed catalysts. Deposition of Ag onto the Au seeds appears as a separate peak in the voltammetry. This procedure mimics the seed-mediated growth of Ag NRs observed in solution in the presence of CTAB using ascorbic acid as a reducing agent. The yield, length, and aspect ratio of the Ag NRs/NWs depend on the deposition time and potential with the average length ranging from 300 nm to 3 µm for times of 30-120 min and potentials of -150 to -200 mV. The electrochemical seed-mediated growth of Ag NRs/NWs across electrode gaps could find use for resistive and surface-enhanced Raman-based sensing and molecular electronic applications.

11.
Naunyn Schmiedebergs Arch Pharmacol ; 397(8): 5533-5557, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38502243

RESUMEN

A multifunctional scaffold protein termed Disabled-2 (Dab2) has recently gained attention in the scientific community and has emerged as a promising candidate in the realm of cancer research. Dab2 protein is involved in a variety of signaling pathways, due to which its significance in the pathogenesis of several carcinomas has drawn considerable attention. Dab2 is essential for controlling the advancement of cancer because it engages in essential signaling pathways such as the Wnt/ß-catenin, epidermal growth factor receptor (EGFR), and transforming growth factor-beta (TGF-ß) pathways. Dab2 can also repress epithelial-mesenchymal transition (EMT) which is involved in tumor progression with metastatic expansion and adds another layer of significance to its possible impact on cancer spread. Furthermore, the role of Dab2 in processes such as cell growth, differentiation, apoptosis, invasion, and metastasis has been explored in certain investigative studies suggesting its significance. The present review examines the role of Dab2 in the pathogenesis of various cancer subtypes including breast cancer, ovarian cancer, gastric cancer, prostate cancer, and bladder urothelial carcinoma and also sheds some light on its potential to act as a therapeutic target and a prognostic marker in the treatment of various carcinomas. By deciphering this protein's diverse signaling, we hope to provide useful insights that may pave the way for novel therapeutic techniques and tailored treatment approaches in cancer management. Preclinical and clinical trial data on the impact of Dab2 regulation in cancer have also been included, allowing us to delineate role of Dab2 in tumor suppressor function, as well as its correlation with disease stage classification and potential therapy options. However, we observed that there is very scarce data in the form of studies on the evaluation of Dab2 role and treatment function in carcinomas, and further research into this matter could prove beneficial in the generation of novel therapeutic agents for patient-centric and tailored therapy, as well as early prognosis of carcinomas.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Reguladoras de la Apoptosis , Neoplasias , Transducción de Señal , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Animales , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Transición Epitelial-Mesenquimal
12.
Children (Basel) ; 11(3)2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38539402

RESUMEN

Opsoclonus-myoclonus ataxia syndrome (OMAS), also known as Kinsbourne syndrome, is a rare disorder that presents with myoclonus, ataxia, abnormal eye movements, irritability, and sleep disruptions, often in young children. We report a case of an infant barely 6 months old, with no significant past medical history, who presented to the emergency department with tremors, jerking motions of the head and arms, and rapid eye movements. After an extensive workup, she was found to have a neuroblastoma, which was subsequently surgically removed via thoracotomy. Despite an initial improvement in symptoms post-resection, the patient's symptoms recurred. She was subsequently treated with dexamethasone, intravenous immunoglobulin (IVIG), and rituximab. After treatment, the patient was noted to have mild global developmental delays but was otherwise well. This case report highlights the rare occurrence of OMAS in an infant barely 6 months old at diagnosis. Using the PubMed database, a systematic review was conducted to highlight the clinical presentation, diagnosis, and management of OMAS.

13.
Cureus ; 16(2): e54940, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38544578

RESUMEN

Background Infertility remains a significant global challenge, and recurrent implantation failure (RIF) poses a considerable concern in assisted reproductive technology. Understanding the factors contributing to implantation failure is essential for developing accurate diagnostic tools and treatment strategies. Endometrial receptivity (ER) during the window of implantation is crucial for successful embryo implantation in in vitro fertilization (IVF) procedures. Molecular-based endometrial receptivity analysis and next-generation sequencing provide insights into ER, but there is a lack of research on these in the Indian population, particularly in patients with RIF. This retrospective cohort study evaluates the effectiveness of Optimal Timing for Endometrial Receptivity Analysis (OpERA)-guided personalized embryo transfer (pET) in Indian patients with a history of RIF. Methodology The study includes 158 female patients with a history of failed embryo transfers who underwent OpERA testing before frozen embryo transfer. Patients were categorized based on the number of previous failed transfers. OpERA outcomes were assessed, and clinical outcomes were compared between groups undergoing preimplantation genetic testing for aneuploidy (PGT-A) with and without OpERA. Endometrial preparation involved hormone replacement therapy, and OpERA testing was performed at the Neuberg Centre for Genomic Medicine using RNA extraction, cDNA conversion, and sequencing. Results OpERA outcomes showed no significant differences in receptive rates among patient groups. Group 3, with three or more failed transfers, exhibited significantly higher biochemical pregnancy rates (BPRs), clinical pregnancy rates (CPRs), and abortion rates (ARs) compared to Groups 1 and 2. OpERA with PGT-A showed significantly higher BPR, implantation rate, CPR, and lower AR compared to OpERA without PGT-A. Conclusions OpERA-guided pET, especially with PGT-A, demonstrated improved pregnancy outcomes, particularly in patients with a history of RIF. The study emphasizes the importance of OpERA in determining optimal transfer timing, moving beyond the traditional reliance on embryo quality alone. OpERA presents promise in predicting pregnancy outcomes for Indian patients with previous IVF failures. The integration of OpERA and PGT-A represents a significant advancement in personalized reproductive medicine, offering new hope for individuals grappling with infertility complexities.

14.
Cells ; 13(6)2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38534348

RESUMEN

The integration of whole genome sequencing (WGS) into all aspects of modern medicine represents the next step in the evolution of healthcare. Using this technology, scientists and physicians can observe the entire human genome comprehensively, generating a plethora of new sequencing data. Modern computational analysis entails advanced algorithms for variant detection, as well as complex models for classification. Data science and machine learning play a crucial role in the processing and interpretation of results, using enormous databases and statistics to discover new and support current genotype-phenotype correlations. In clinical practice, this technology has greatly enabled the development of personalized medicine, approaching each patient individually and in accordance with their genetic and biochemical profile. The most propulsive areas include rare disease genomics, oncogenomics, pharmacogenomics, neonatal screening, and infectious disease genomics. Another crucial application of WGS lies in the field of multi-omics, working towards the complete integration of human biomolecular data. Further technological development of sequencing technologies has led to the birth of third and fourth-generation sequencing, which include long-read sequencing, single-cell genomics, and nanopore sequencing. These technologies, alongside their continued implementation into medical research and practice, show great promise for the future of the field of medicine.


Asunto(s)
Genómica , Medicina de Precisión , Recién Nacido , Humanos , Genómica/métodos , Secuenciación Completa del Genoma , Medicina de Precisión/métodos , Farmacogenética , Genoma Humano
15.
Res Sq ; 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38410478

RESUMEN

Aging is associated with a decline in stem cell functionality and number across the organism. In this study, we aimed to further unravel Muscle Stem Cells (MuSCs) aging by assessing how systemic factors influence MuSC fate decisions through long-term epigenetic landscape remodelling. As aging is intricately linked to a pro-inflammatory shift, we studied the epigenetic effects of inflammatory signals in MuSCs and measured decreased H4K20me1 levels. This loss disrupts MuSC quiescence, largely through epigenetic silencing of Notch target genes. In the setting of inflammatory signals or aging, the lack of Kmt5a and the subsequent absence of de novoH4K20me1 culminate in cell death by ferroptosis. Aged MuSCs manifest abnormal iron metabolism and reduced Gpx4 levels, resulting in the accumulation of intracellular iron, increased reactive oxygen species, genomic instability, and lipid peroxidation. We showed that ferroptosis is the predominant mode of cell death in aged MuSCs, with remarkably high levels of lipid peroxidation; a phenomenon we also observed in aged hematopoietic stem cells. Implementing preventative strategies to inhibit systemic inflammation prevented aged MuSC ferroptosis, preserving their numbers and regenerative capabilities. This intervention significantly enhanced aged muscle regeneration and strength recovery and extended both lifespan and healthspan in mice. This study delineates a previously underappreciated fate trajectory for stem cell aging, and offers meaningful insights into the treatment of age-related disorders.

16.
Redox Biol ; 70: 103047, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38295577

RESUMEN

Ischemic tissues accumulate succinate, which is rapidly oxidized upon reperfusion, driving a burst of mitochondrial reactive oxygen species (ROS) generation that triggers cell death. In isolated mitochondria with succinate as the sole metabolic substrate under non-phosphorylating conditions, 90 % of ROS generation is from reverse electron transfer (RET) at the Q site of respiratory complex I (Cx-I). Together, these observations suggest Cx-I RET is the source of pathologic ROS in reperfusion injury. However, numerous factors present in early reperfusion may impact Cx-I RET, including: (i) High [NADH]; (ii) High [lactate]; (iii) Mildly acidic pH; (iv) Defined ATP/ADP ratios; (v) Presence of the nucleosides adenosine and inosine; and (vi) Defined free [Ca2+]. Herein, experiments with mouse cardiac mitochondria revealed that under simulated early reperfusion conditions including these factors, total mitochondrial ROS generation was only 56 ± 17 % of that seen with succinate alone (mean ± 95 % confidence intervals). Of this ROS, only 52 ± 20 % was assignable to Cx-I RET. A further 14 ± 7 % could be assigned to complex III, with the remainder (34 ± 11 %) likely originating from other ROS sources upstream of the Cx-I Q site. Together, these data suggest the relative contribution of Cx-I RET ROS to reperfusion injury may be overestimated, and other ROS sources may contribute a significant fraction of ROS in early reperfusion.


Asunto(s)
Complejo I de Transporte de Electrón , Daño por Reperfusión , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Electrones , Transporte de Electrón , Mitocondrias Cardíacas/metabolismo , Daño por Reperfusión/metabolismo , Reperfusión , Succinatos
18.
bioRxiv ; 2023 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-38045326

RESUMEN

Ischemic tissues accumulate succinate, which is rapidly oxidized upon reperfusion, driving a burst of mitochondrial reactive oxygen species (ROS) generation that triggers cell death. In isolated mitochondria with succinate as the sole metabolic substrate under non-phosphorylating conditions, 90% of ROS generation is from reverse electron transfer (RET) at the Q site of respiratory complex I (Cx-I). Together, these observations suggest Cx-I RET is the source of pathologic ROS in reperfusion injury. However, numerous factors present in early reperfusion may impact Cx-I RET, including: (i) High [NADH]; (ii) High [lactate]; (iii) Mildly acidic pH; (iv) Defined ATP/ADP ratios; (v) Presence of the nucleosides adenosine and inosine; and (vi) Defined free [Ca2+]. Herein, experiments with mouse cardiac mitochondria revealed that under simulated early reperfusion conditions including these factors, overall mitochondrial ROS generation was only 56% of that seen with succinate alone, and only 52% of this ROS was assignable to Cx-I RET. The residual non-RET ROS could be partially assigned to complex III (Cx-III) with the remainder likely originating from other ROS sources upstream of the Cx-I Q site. Together, these data suggest the relative contribution of Cx-I RET ROS to reperfusion injury may be overestimated, and other ROS sources may contribute a significant fraction of ROS in early reperfusion.

19.
J Am Acad Dermatol ; 89(5): 1015-1021, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37451624

RESUMEN

BACKGROUND: Infantile hemangiomas (IHs) of the anogenital region remain poorly characterized. OBJECTIVE: To examine the distribution, ulceration rate, and associated congenital anomalies of anogenital IHs. METHODS: Retrospective study at 8 tertiary referral centers. RESULTS: A total of 435 infants with an IH of the anogenital region were enrolled (of which, 319 [73%] were girls). Congenital anomalies were present in 6.4% (n = 28) of infants with an anogenital IH. Segmental or partial segmental anogenital IHs ulcerated in 72% (n = 99 of 138) of infants, whereas 45% (n = 133 of 297) of focal anogenital IHs experienced ulceration (P < .001). In a multivariable logistic regression analysis, segmental or partial segmental morphology (adjusted odds ratio [aOR], 2.70; 95% CI, 1.60-4.64), mixed type (aOR, 3.44; 95% CI, 2.01-6.07), and perianal (aOR, 3.01; 95% CI, 1.53-6.12) and buttocks location (aOR, 2.08; 95% CI, 1.17-3.76) had increased odds of ulceration. Segmental or partial segmental IHs of the genitalia were confined to distinct anatomic territories and were predominantly distributed unilaterally, with a linear demarcation at the perineal raphe. LIMITATIONS: Possible selection bias, given recruitment at tertiary referral centers. CONCLUSION: This study improves our understanding of high-risk features of anogenital IHs and demonstrates that genital segmental or partial segmental IHs develop within distinct anatomic territories.

20.
Am J Hum Genet ; 110(7): 1034-1045, 2023 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-37279760

RESUMEN

Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such findings, and the downstream medical efforts in response to discovery of unanticipated genetic risk variants, are lacking. From a clinical trial of comprehensive exome sequencing in 127 apparently healthy infants and 32 infants in intensive care, we previously identified 17 infants (10.7%) with unanticipated monogenic disease risks (uMDRs). In this analysis, we assessed actionability for each of these uMDRs with a modified ClinGen actionability semiquantitative metric (CASQM) and created radar plots representing degrees of penetrance of the condition, severity of the condition, effectiveness of intervention, and tolerability of intervention. In addition, we followed each of these infants for 3-5 years after disclosure and tracked the medical actions prompted by these findings. All 17 uMDR findings were scored as moderately or highly actionable on the CASQM (mean 9, range: 7-11 on a 0-12 scale) and several distinctive visual patterns emerged on the radar plots. In three infants, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 infants, uMDRs provided risk stratification for future medical surveillance. In 13 infants, uMDRs prompted screening for at-risk family members, three of whom underwent cancer-risk-reducing surgeries. Although assessments of clinical utility and cost-effectiveness will require larger datasets, these findings suggest that large-scale comprehensive sequencing of newborns will reveal numerous actionable uMDRs and precipitate substantial, and in some cases lifesaving, downstream medical care in newborns and their family members.


Asunto(s)
Pruebas Genéticas , Genoma Humano , Humanos , Recién Nacido , Tamizaje Neonatal , Genómica , Secuenciación del Exoma
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