RESUMEN
Increased protein synthesis plays an etiologic role in diverse cancers. Here, we demonstrate that METTL13 (methyltransferase-like 13) dimethylation of eEF1A (eukaryotic elongation factor 1A) lysine 55 (eEF1AK55me2) is utilized by Ras-driven cancers to increase translational output and promote tumorigenesis in vivo. METTL13-catalyzed eEF1A methylation increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 and eEF1AK55me2 levels are upregulated in cancer and negatively correlate with pancreatic and lung cancer patient survival. METTL13 deletion and eEF1AK55me2 loss dramatically reduce Ras-driven neoplastic growth in mouse models and in patient-derived xenografts (PDXs) from primary pancreatic and lung tumors. Finally, METTL13 depletion renders PDX tumors hypersensitive to drugs that target growth-signaling pathways. Together, our work uncovers a mechanism by which lethal cancers become dependent on the METTL13-eEF1AK55me2 axis to meet their elevated protein synthesis requirement and suggests that METTL13 inhibition may constitute a targetable vulnerability of tumors driven by aberrant Ras signaling.
Asunto(s)
Metiltransferasas/metabolismo , Factor 1 de Elongación Peptídica/metabolismo , Adulto , Anciano , Animales , Carcinogénesis , Línea Celular , Transformación Celular Neoplásica/metabolismo , Femenino , Células HEK293 , Xenoinjertos , Humanos , Lisina/metabolismo , Masculino , Metilación , Metiltransferasas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Factor 1 de Elongación Peptídica/genética , Biosíntesis de Proteínas , Procesamiento Proteico-Postraduccional , Proteómica , Transducción de SeñalRESUMEN
BACKGROUND: Spanish-speakers with non-English language preference and complex medical needs suffer disparities in quality of care, safety, and health outcomes. Communication challenges during prolonged hospitalizations for complex illnesses negatively influence how this group engages in their care and decision-making while hospitalized. Limited literature capturing the perspectives of Spanish-speaking patients in this context exists. Given the impact of language barriers on care and medical decision-making, this study documents the experiences of Spanish-speaking patients with NELP and hospitalized with complex care needs as well as caregivers and community leaders. METHODS: Using community-engaged recruitment strategies and semi-structured interviews and a focus group, we gathered insights from Spanish-speaking patients hospitalized for prolonged periods, caregivers, and community leaders from three geographic regions. Data were deidentified, transcribed, translated, coded in duplicate, and analyzed guided by grounded theory using NVivo. RESULTS: We interviewed 40 participants: 27 patients, 10 caregivers and 3 community leaders. We identified four major themes: (1) Disconnected experiences impeding interactions, communication, and decision-making (2) Inadequate interpreter services (3) Benefits and consequences of family at the bedside (4) Community -informed recommendations. CONCLUSION: The study showed that in-person interpreters were preferred to virtual interpreters; yet interpreter access was suboptimal. This resulted in ad hoc family interpretation. Participants noted language negatively impacted patient's hospital experience, including decreasing confidence in medical decision-making. Recommendations from patients, caregivers, and community leaders included expanding interpreter access, bolstering interpreter quality and accuracy, and increasing resources for patient education.
Asunto(s)
Cuidadores , Barreras de Comunicación , Hispánicos o Latinos , Investigación Cualitativa , Humanos , Cuidadores/psicología , Femenino , Masculino , Persona de Mediana Edad , Hispánicos o Latinos/psicología , Anciano , Adulto , Toma de Decisiones , Grupos Focales , Hospitalización , Lenguaje , Entrevistas como Asunto , Anciano de 80 o más AñosRESUMEN
Parent-of-origin-dependent gene expression in mammals and flowering plants results from differing chromatin imprints (genomic imprinting) between maternally and paternally inherited alleles. Imprinted gene expression in the endosperm of seeds is associated with localized hypomethylation of maternally but not paternally inherited DNA, with certain small RNAs also displaying parent-of-origin-specific expression. To understand the evolution of imprinting mechanisms in Oryza sativa (rice), we analyzed imprinting divergence among four cultivars that span both japonica and indica subspecies: Nipponbare, Kitaake, 93-11, and IR64. Most imprinted genes are imprinted across cultivars and enriched for functions in chromatin and transcriptional regulation, development, and signaling. However, 4 to 11% of imprinted genes display divergent imprinting. Analyses of DNA methylation and small RNAs revealed that endosperm-specific 24-nt small RNA-producing loci show weak RNA-directed DNA methylation, frequently overlap genes, and are imprinted four times more often than genes. However, imprinting divergence most often correlated with local DNA methylation epimutations (9 of 17 assessable loci), which were largely stable within subspecies. Small insertion/deletion events and transposable element insertions accompanied 4 of the 9 locally epimutated loci and associated with imprinting divergence at another 4 of the remaining 8 loci. Correlating epigenetic and genetic variation occurred at key regulatory regions-the promoter and transcription start site of maternally biased genes, and the promoter and gene body of paternally biased genes. Our results reinforce models for the role of maternal-specific DNA hypomethylation in imprinting of both maternally and paternally biased genes, and highlight the role of transposition and epimutation in rice imprinting evolution.
Asunto(s)
Endospermo/genética , Evolución Molecular , Impresión Genómica , Oryza/genética , Metilación de ADN , Elementos Transponibles de ADN , Epigenómica , Regulación de la Expresión Génica de las Plantas , Mutación , Oryza/clasificación , Oryza/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic, immunosuppressive stroma that contributes to its resistance to immune checkpoint blockade therapies. The hypoxia-inducible factors (HIFs) mediate the cellular response to hypoxia, but their role within the PDAC tumor microenvironment remains unknown. METHODS: We used a dual recombinase mouse model to delete Hif1α or Hif2α in α-smooth muscle actin-expressing cancer-associated fibroblasts (CAFs) arising within spontaneous pancreatic tumors. The effects of CAF HIF2α expression on tumor progression and composition of the tumor microenvironment were evaluated by Kaplan-Meier analysis, reverse transcription quantitative real-time polymerase chain reaction, histology, immunostaining, and by both bulk and single-cell RNA sequencing. CAF-macrophage crosstalk was modeled ex vivo using conditioned media from CAFs after treatment with hypoxia and PT2399, an HIF2 inhibitor currently in clinical trials. Syngeneic flank and orthotopic PDAC models were used to assess whether HIF2 inhibition improves response to immune checkpoint blockade. RESULTS: CAF-specific deletion of Hif2α, but not Hif1α, suppressed PDAC tumor progression and growth, and improved survival of mice by 50% (n = 21-23 mice/group, Log-rank P = .0009). Deletion of CAF-HIF2 modestly reduced tumor fibrosis and significantly decreased the intratumoral recruitment of immunosuppressive M2 macrophages and regulatory T cells. Treatment with the clinical HIF2 inhibitor PT2399 significantly reduced in vitro macrophage chemotaxis and M2 polarization, and improved tumor responses to immunotherapy in both syngeneic PDAC mouse models. CONCLUSIONS: Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease.
Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma Ductal Pancreático/patología , Humanos , Hipoxia/metabolismo , Inhibidores de Puntos de Control Inmunológico , Terapia de Inmunosupresión , Ratones , Neoplasias Pancreáticas/patología , Microambiente Tumoral , Neoplasias PancreáticasRESUMEN
The Research Domain Criteria (RDoC) initiative was established by the US National Institute of Mental Health as a multilevel, disorder-agnostic framework for analysis of human psychopathology through designated domains and constructs, including the "Positive Valence Systems" domain focused on reward-related behavior. This study investigates the reward valuation subconstruct of "effort" and its association with genetic markers, functional neurobiological pathways, and polygenic risk scores for psychopathology in 1215 children aged 6-12 and their parents (n = 1044). All participants completed the effort expenditure for rewards task (EEfRT), which assesses "effort" according to two quantitative measures: hard-task choice and reward sensitivity. Genetic association analyses were undertaken in MAGMA, utilizing EEfRT outcome variables as genome-wide association studies phenotypes to compute SNP and gene-level associations. Genome-wide association analyses found two distinct genetic loci that were significantly associated with measures of reward sensitivity and a separate genetic locus associated with hard task choice. Gene-set enrichment analysis yielded significant associations between "effort" and multiple gene sets involved in reward processing-related pathways, including dopamine receptor signaling, limbic system and forebrain development, and biological response to cocaine. These results serve to establish "effort" as a relevant construct for understanding reward-related behavior at the genetic level and support the RDoC framework for assessing disorder-agnostic psychopathology.
RESUMEN
Reports of neurological sequelae related to colon cancer are largely restricted to rare instances of paraneoplastic syndromes, due to autoimmune reactions. Systemic inflammation associated with tumor development influences sensory neuron function in other disease models, though the extent to which this occurs in colorectal cancer is unknown. We induced orthotopic colorectal cancer via orthotopic injection of two colorectal cancer cell lines (MC38 and CT26) in two different mouse strains (C57BL/6 and Balb/c, respectively). Behavioral tests of pain sensitivity and activity did not detect significant alterations in sensory sensitivity or diminished well-being throughout tumor development. However, immunohistochemistry revealed widespread reductions in intraepidermal nerve fiber density in the skin of tumor-bearing mice. Though loss of nerve fiber density was not associated with increased expression of cell injury markers in dorsal root ganglia, lumbar dorsal root ganglia neurons of tumor-bearing animals showed deficits in mitochondrial function. These neurons also had reduced cytosolic calcium levels in live-cell imaging and reduced spontaneous activity in multi-electrode array analysis. Bulk RNA sequencing of DRGs from tumor-bearing mice detected activation of gene expression pathways associated with elevated cytokine and chemokine signaling, including CXCL10. This is consistent with the detection of CXCL10 (and numerous other cytokines, chemokines and growth factors) in MC38 and CT26 cell-conditioned media, and the serum of tumor-bearing mice. Our study demonstrates in a pre-clinical setting that colon cancer is associated with latent sensory neuron dysfunction and implicates cytokine/chemokine signaling in this process. These findings may have implications for determining risk factors and treatment responsiveness related to neuropathy in colorectal cancer.
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Animales , Neoplasias del Colon/complicaciones , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Ganglios Espinales/metabolismo , Hiperalgesia/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Receptoras Sensoriales/metabolismoRESUMEN
BACKGROUND: The Research Domain Criteria initiative was launched by the US National Institute of Mental Health to establish a multi-level framework for understanding psychological constructs relevant to human psychiatric disorders, and identified 'effort valuation/willingness to work' as a clinically useful construct worthy of further study. This construct encompasses the processes by which the cost(s) of obtaining an outcome are calculated, and the tendency to overcome response costs to obtain a reinforcer. The current study aims to examine effort valuation as a correlate of psychopathology in children and adults, and the moderating effects of sex on this relationship. METHODS: Participants were 1215 children aged 6-12 and their parents (n = 1044). All participants completed the Effort Expenditure for Rewards Task as a measure of effort expenditure. Child psychopathology was measured via the Child Behavior Checklist, while adult psychopathology was measured via the Adult Self Report. Additionally, the Social Adjustment Inventory for Children and Adolescents and Injury Behavior Checklist were used to examine child social impairments/problem behaviors. RESULTS: In children, significant interactions between reward sensitivity and sex were observed in association with anxiety and thought problems, specifically at low reward sensitivity levels. In adults, main effects of effort expenditure were seen in drug and alcohol abuse, where higher effort was associated with higher degrees of abuse. CONCLUSIONS: These results establish effort valuation as a relevant psychological construct for understanding psychopathology, but with different profiles of associated psychopathology across sex in children and adults.
Asunto(s)
Trastornos Mentales , Psicopatología , Recompensa , Adulto , Encéfalo , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Motivación , National Institute of Mental Health (U.S.) , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND/OBJECTIVES: There are no reliably effective, well-tolerated topical agents for the treatment of hyperhidrosis. We sought to evaluate the efficacy and tolerability of oxybutynin 3% gel in adolescents and young adults with primary focal hyperhidrosis. METHODS: Patients with severe axillary hyperhidrosis were treated with topical oxybutynin 3% gel for 4 weeks. Response to treatment was assessed by calculating change in Hyperhidrosis Disease Severity Score from baseline to weeks 1 and 4. Change in health-related quality of life was assessed using the Children's Dermatology Life Quality Index or the Dermatology Life Quality Index. Adverse effects were evaluated using patient diaries, investigator global review, and physical examination. RESULTS: Of 10 patients aged 13-24 enrolled, seven completed the study. Of those who completed the study, four (57.1%) reported reduction in axillary Hyperhidrosis Disease Severity Score at week 1 and all seven (100%) at week 4. Six patients (85.7%) reported reduction in Children's Dermatology Life Quality Index or Dermatology Life Quality Index score. Anticholinergic adverse effects were infrequent. The majority of treatment-related adverse events were mild to moderate in severity. One patient experienced a severe adverse event. CONCLUSION: Oxybutynin 3% gel reduced hyperhidrosis severity and improved health-related quality of life in this small pilot study. Safety and efficacy should be further evaluated in a large, prospective, placebo-controlled study.
Asunto(s)
Hiperhidrosis/tratamiento farmacológico , Ácidos Mandélicos/administración & dosificación , Parasimpatolíticos/administración & dosificación , Administración Tópica , Adolescente , Femenino , Humanos , Masculino , Ácidos Mandélicos/efectos adversos , Parasimpatolíticos/efectos adversos , Proyectos Piloto , Estudios Prospectivos , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
A key challenge in environmental remediation is the design of adsorbents bearing an abundance of accessible chelating sites with high affinity, to achieve both rapid uptake and high capacity for the contaminants. Herein, we demonstrate how two-dimensional covalent organic frameworks (COFs) with well-defined mesopore structures display the right combination of properties to serve as a scaffold for decorating coordination sites to create ideal adsorbents. The proof-of-concept design is illustrated by modifying sulfur derivatives on a newly designed vinyl-functionalized mesoporous COF (COF-V) via thiol-ene "click" reaction. Representatively, the material (COF-S-SH) synthesized by treating COF-V with 1,2-ethanedithiol exhibits high efficiency in removing mercury from aqueous solutions and the air, affording Hg2+ and Hg0 capacities of 1350 and 863 mg g-1, respectively, surpassing all those of thiol and thioether functionalized materials reported thus far. More significantly, COF-S-SH demonstrates an ultrahigh distribution coefficient value (Kd) of 2.3 × 109 mL g-1, which allows it to rapidly reduce the Hg2+ concentration from 5 ppm to less than 0.1 ppb, well below the acceptable limit in drinking water (2 ppb). We attribute the impressive performance to the synergistic effects arising from densely populated chelating groups with a strong binding ability within ordered mesopores that allow rapid diffusion of mercury species throughout the material. X-ray absorption fine structure (XAFS) spectroscopic studies revealed that each Hg is bound exclusively by two S via intramolecular cooperativity in COF-S-SH, further interpreting its excellent affinity. The results presented here thus reveal the exceptional potential of COFs for high-performance environmental remediation.
RESUMEN
In this work, the influence of the hydrophilic/hydrophobic nature of metal-organic framework (MOF) materials on the catalytic performance of supported Pd nanoparticles for biofuel upgrade was studied. We show that the introduction of hydrophilic groups on a MOF can greatly enhance the performance of the resultant catalyst. Specifically, Pd nanoparticles supported on MIL-101-SO3Na with superhydrophilicity (Pd/MIL-101-SO3Na) far outperforms pristine MIL-101 and the benchmark catalyst Pd/C in the hydrodeoxygenation reaction of vanillin, a model component of pyrolysis oil derived from the lignin fraction. This is attributed to a favorable mode of adsorption of the highly water soluble reactants on the more hydrophilic support in the vicinity of the catalytically active Pd nanoparticles, thereby promoting their transformation.
RESUMEN
The combination of two or more reactive centers working in concert on a substrate to facilitate the reaction is now considered state of the art in catalysis, yet there still remains a tremendous challenge. Few heterogeneous systems of this sort have been exploited, as the active sites spatially separated within the rigid framework are usually difficult to cooperate. It is now shown that this roadblock can be surpassed. The underlying principle of the strategy presented here is the integration of catalytic components with excellent flexibility and porous heterogeneous catalysts, as demonstrated by the placement of linear ionic polymers in close proximity to surface Lewis acid active sites anchored on the walls of a covalent organic framework (COF). Using the cycloaddition of the epoxides and CO2 as a model reaction, dramatic activity improvements have been achieved for the composite catalysts in relation to the individual catalytic component. Furthermore, they also clearly outperform the benchmark catalytic systems formed by the combination of the molecular organocatalysts and heterogeneous Lewis acid catalysts, while affording additional recyclability. The extraordinary flexibility and enriched concentration of the catalytically active moieties on linear polymers facilitate the concerted catalysis, thus leading to superior catalytic performance. This work therefore uncovers an entirely new strategy for designing bifunctional catalysts with double-activation behavior and opens a new avenue in the design of multicapable systems that mimic biocatalysis.
RESUMEN
PURPOSE: To evaluate the performance of a holographic logMAR chart for the subjective spherical refraction of the human eye. METHODS: Bland-Altman analysis was used to assess the level of agreement between subjective spherical refraction using the holographic logMAR chart and conventional autorefraction and subjective spherical refraction. RESULTS: The 95% limits of agreement (LoA) were calculated between holographic refraction and the two standard methods (subjective and autorefraction). Holographic refraction has a lower mean spherical refraction when compared to conventional refraction (LoA 0.11 ± 0.65 D) and when compared to autorefraction (LoA 0.36 ± 0.77 D). After correcting for systemic bias, this is comparable between autorefraction and conventional subjective refraction (LoA 0.45 ± 0.79 D). After correcting for differences in vergence distance and chromatic aberration between holographic and conventional refraction, approximately 65% (group 1) of measurements between holography and conventional subjective refraction were similar (MD = 0.13 D, SD = 0.00 D). The remaining 35% (group 2) had a mean difference of 0.45 D (SD = 0.12 D) between the two subjective methods. Descriptive statistics showed group 2's mean age (21 years, SD = 13 years) was considerably lower than group 1's mean age (41 years, SD = 17), suggesting accommodation may have a role in the greater mean difference of group 2. CONCLUSIONS: Overall, holographic refraction has good agreement with conventional refraction and is a viable alternative for spherical subjective refraction. A larger bias between holographic and conventional refraction was found in younger subjects than older subjects, suggesting an association between accommodation and myopic over-correction during holographic refraction.
RESUMEN
Hereditary progressive mucinous histiocytosis is a rare, benign, skin-limited form of non-Langerhans cell histiocytosis. We report on a 5-year-old boy who presented in infancy with self-resolving dermal nodules but later developed persistent and progressive erythematous papules on the face and scalp. Histologic evaluation revealed dermal aggregates of S-100/CD1a-negative histiocytes with abundant mucin. We present this case to highlight the evolution of the lesional morphology in infancy and early childhood and to stress the importance of histology in confirming this rare disorder.
Asunto(s)
Histiocitosis/diagnóstico , Neoplasias Quísticas, Mucinosas y Serosas/diagnóstico , Enfermedades Raras , Neoplasias Cutáneas/diagnóstico , Piel/patología , Preescolar , Diagnóstico Diferencial , Histiocitosis/cirugía , Humanos , Lactante , Masculino , Neoplasias Quísticas, Mucinosas y Serosas/cirugía , Neoplasias Cutáneas/cirugíaRESUMEN
Trichodysplasia spinulosa is a rare folliculocentric polyomavirus infection observed in the setting of immunosuppression. We report a 7-year-old boy with pre-B-cell lymphoblastic leukemia who presented with folliculocentric spiny papules on the face. Histologic evaluation revealed hypertrophic bulbs, an expanded inner root sheath, and numerous brightly eosinophilic trichohyalin granules. We present this case to raise awareness of this rare but recognizable entity and to highlight the availability of appropriate diagnostic and therapeutic modalities.
Asunto(s)
Dermatosis Facial/virología , Enfermedades del Cabello/virología , Folículo Piloso/virología , Huésped Inmunocomprometido , Infecciones por Polyomavirus/virología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antivirales/uso terapéutico , Niño , Cidofovir , Citosina/análogos & derivados , Citosina/uso terapéutico , Dermatosis Facial/diagnóstico , Dermatosis Facial/tratamiento farmacológico , Enfermedades del Cabello/diagnóstico , Enfermedades del Cabello/tratamiento farmacológico , Folículo Piloso/patología , Humanos , Masculino , Organofosfonatos/uso terapéutico , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológicoRESUMEN
BACKGROUND: Health care institutions are scrambling to manage the complex organizational change required for achieving meaningful use (MU) of electronic health records (EHR). Assessing baseline organizational capacity for the change can be a useful step toward effective planning and resource allocation. PURPOSE: The aim of this article is to describe an adaptable method and tool for assessing organizational capacity for achieving MU of EHR. Data on organizational capacity (people, processes, and technology resources) and barriers are presented from outpatient clinics within one integrated health care delivery system; thus, the focus is on MU requirements for eligible professionals, not eligible hospitals. METHODS: We conducted 109 interviews with representatives from 46 outpatient clinics. FINDINGS: Most clinics had core elements of the people domain of capacity in place. However, the process domain was problematic for many clinics, specifically, capturing problem lists as structured data and having standard processes for maintaining the problem list in the EHR. Also, nearly half of all clinics did not have methods for tracking compliance with their existing processes. Finally, most clinics maintained clinical information in multiple systems, not just the EHR. The most common perceived barriers to MU for eligible professionals included EHR functionality, changes to workflows, increased workload, and resistance to change. PRACTICE IMPLICATIONS: Organizational capacity assessments provide a broad institutional perspective and an in-depth clinic-level perspective useful for making resource decisions and tailoring strategies to support the MU change effort for eligible professionals.
Asunto(s)
Registros Electrónicos de Salud/organización & administración , Innovación Organizacional , Prestación Integrada de Atención de Salud/organización & administración , Administración Hospitalaria/métodos , Humanos , Entrevistas como Asunto , Modelos Organizacionales , Servicio Ambulatorio en Hospital/organización & administraciónRESUMEN
BACKGROUND: In response to COVID-19, many states revised, developed, or attempted to develop plans to allocate scarce critical care resources in the event that crisis standards of care were triggered. No prior analysis has assessed this plan development process, including whether plans were successfully adopted. RESEARCH QUESTION: How did states develop or revise scarce resource allocation plans during the COVID-19 pandemic, and what were the barriers and facilitators to their development and adoption at the state level? STUDY DESIGN AND METHODS: Plan authors and state leaders completed a semi-structured interview February to September 2022. Interview transcripts were qualitatively analyzed for themes related to plan development and adoption according to the principles of grounded theory. RESULTS: Thirty-six participants from 34 states completed an interview, from states distributed across all US regions. Among participants' states with plans that existed prior to 2020 (n = 24), 17 were revised and adopted in response to COVID-19. Six states wrote a plan de novo, with the remaining states failing to develop or adopt a plan. Thirteen states continued to revise their plans in response to disability or aging bias complaints or to respond to evolving needs. Many participants expressed that urgency in the early days of the pandemic prevented an ideal development process. Facilitators of successful plan development and adoption include: coordination or support from the state department of health and existing relationships with key community partners, including aging and disability rights groups and minoritized communities. Barriers include lack of perceived political interest in a plan and development during a public health emergency. INTERPRETATION: To avoid repeating mistakes from the early days of the COVID-19 response, states should develop or revise plans with community engagement and consider maintaining a standing committee with diverse membership and content expertise to periodically review plans and advise state officials on pandemic preparedness.
RESUMEN
Background: Autoimmune diseases have been linked to an increased risk of pregnancy-related complications. A family history of autoimmune diseases may be related to the risk of childhood cancer based on similar histocompatibility antigens. We utilized data from national registries in Denmark to examine associations between maternal autoimmune disease and cancer in their offspring. Methods: We linked data from several national registries in Denmark to identify childhood cancer cases in children <20 years diagnosed between 1977 to 2016. Controls were selected from the Central Population Register and matched to cases by birth year and sex (25:1). Mothers with autoimmune disease diagnosed in pregnancy or prior were identified from the National Patient Register. Multivariable conditional logistic regression analyses were used to estimate associations between maternal autoimmune diseases and childhood cancer in offspring. Results: Autoimmune diseases (all types) were positively associated with all childhood cancers combined (Odds Ratio (OR) = 1.25, 95% CI 1.06, 1.47), acute lymphoblastic leukemia (OR =1.52, 95% CI 1.09, 2.13), Burkitt lymphoma (OR = 2.69, 95% CI 1.04, 6.97), and central nervous system tumors (OR = 1.45, 95% CI 1.06, 1.99), especially astrocytoma (OR = 2.27, 95% CI 1.36, 3.77) and glioma (OR = 1.75, 95% CI 1.13, 2.73). When we examined mothers with rheumatoid arthritis, we observed an increased association for all cancers (OR = 2.15, 95% CI 1.40, 3.30), acute lymphoblastic leukemia (OR = 3.55, 95% CI 1.69, 7.47), and central nervous system tumors (OR = 2.91, 95% CI 1.46, 5.82), especially glioma (OR = 3.58, 95% CI 1.40, 9.18) in offspring. Conclusion: There is a positive association between maternal autoimmune disease and childhood cancer. This association is especially prominent in the offspring of women with rheumatoid arthritis.
RESUMEN
Moderating the pool of active ribosomal subunits is critical for maintaining global translation rates. A factor crucial for modulating the 60S ribosomal subunits is eukaryotic translation initiation factor 6. Release of eIF6 from 60S is essential to permit 60S interactions with 40S. Here, using the N106S mutant of eIF6, we show that disrupting eIF6 interaction with 60S leads to an increase in vacant 80S. It further highlights a dichotomy in the anti-association activity of eIF6 that is distinct from its role in 60S biogenesis and shows that the nucleolar localization of eIF6 is not dependent on uL14-BCCIP interactions. Limiting active ribosomal pools markedly deregulates translation especially in mitosis and leads to chromosome segregation defects, mitotic exit delays and mitotic catastrophe. Ribo-Seq analysis of the eIF6-N106S mutant shows a significant downregulation in the translation efficiencies of mitotic factors and specifically transcripts with long 3'UTRs. eIF6-N106S mutation also limits cancer invasion, and this role is correlated with the overexpression of eIF6 only in high-grade invasive cancers suggesting that deregulation of eIF6 is probably not an early event in cancers. Thus, this study highlights the segregation of eIF6 functions and its role in moderating 80S availability for mitotic translation and cancer progression.
RESUMEN
Follicular mucinosis (FM) and folliculotropic mycosis fungoides (MF) are rare in children, and data regarding long-term outcomes are limited. We sought to describe clinical and histopathologic findings of children with FM with and without MF, as well as treatments administered and clinical outcomes. We conducted a retrospective chart review of patients younger than 22 years (at time of diagnosis) with a biopsy demonstrating FM who were seen in the Dermatology Department at the Mayo Clinic from September 1, 1999, to September 1, 2010. Eleven patients (six male, five female) ages 11 to 19 years at the time of diagnosis met the inclusion criteria. Follow-up data were available for 10 patients, with a mean duration of 4.9 years. The head, neck, and extremities were the most common sites of involvement, and lesions were follicular-based papules (18%), scaly alopecic patches and plaques (45%), or a combination of the two (36%). Overall, three patients were confirmed to have MF. T-cell receptor gene rearrangement demonstrated clonality in two cases and was equivocal in one case. Treatments included topical corticosteroids, topical retinoids, oral minocycline, and, in patients with MF, ultraviolet light and topical bexarotene. Lesions resolved completely in seven patients, partially in one, and not at all in two (no follow-up data on one patient). Of the three patients with MF, two had complete resolution, and one has intermittent flares. To our knowledge, no patients developed other lymphoproliferative disorders. FM in children is rare. A histopathologic diagnosis of FM does not equate to folliculotropic MF in all cases. Most patients responded to treatment with topical steroids, topical retinoids, or phototherapy. In our series of patients, the disease ran a benign course.