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Muscle wasting is a universal hallmark of aging which is displayed by a wide range of organisms, although the causes and mechanisms of this phenomenon are not fully understood. We used Drosophila to characterize the phenomenon of spontaneous muscle fiber degeneration (SMFD) during aging. We found that SMFD occurs across diverse types of somatic muscles, progresses with chronological age, and positively correlates with functional muscle decline. Data from vital dyes and morphological markers imply that degenerative fibers most likely die by necrosis. Mechanistically, SMFD is driven by the damage resulting from muscle contractions, and the nervous system may play a significant role in this process. Our quantitative model of SMFD assessment can be useful in identifying and validating novel genetic factors that influence aging-related muscle wasting.
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Envejecimiento , Estrés Mecánico , Animales , Envejecimiento/genética , Envejecimiento/fisiología , Drosophila melanogaster/genética , Atrofia Muscular/genética , Atrofia Muscular/patología , Atrofia Muscular/fisiopatología , Atrofia Muscular/metabolismo , Fibras Musculares Esqueléticas/patología , Fibras Musculares Esqueléticas/metabolismo , Contracción MuscularRESUMEN
Methotrexate is a critical component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL), but is associated with neurotoxicity. Information on long-term outcomes following an acute neurotoxic event is limited. Therefore, this report compares neurocognitive performance more than 12 months post diagnosis (mean = 4 years) between ALL patients with (n = 25) and without (n = 146) a history of acute neurotoxicity. Compared to children with no documented on-treatment neurotoxic event, children who experienced a neurotoxic event during treatment exhibited poorer performance on measures of fine motor function (p = .02) and attention (p = .02). Children with ALL who experience acute neurotoxicity may be candidates for early neuropsychological screening and intervention.
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Antimetabolitos Antineoplásicos , Metotrexato , Síndromes de Neurotoxicidad , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Metotrexato/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Femenino , Masculino , Síndromes de Neurotoxicidad/etiología , Niño , Preescolar , Antimetabolitos Antineoplásicos/efectos adversos , Adolescente , Estudios de Seguimiento , Pruebas Neuropsicológicas , PronósticoRESUMEN
High-dose methotrexate (HD-MTX) is used in the treatment of children with central nervous system (CNS) tumors; however, toxicity information is limited. We characterized toxicities following 102 administrations of HD-MTX (4.6-13.5 g/m2) infused over 4 or 24 h in 38 children with a CNS tumor before 6 years of age (2010-2020). Delayed clearance of methotrexate occurred following 24% of infusions. Common Terminology Criteria for Adverse Events v5 grade 2-3 mucositis was observed in 47% of individuals, Grade 4 neutropenia in 76%, and grade 3-4 thrombocytopenia in 58%. No neurotoxicity was observed. HD-MTX can be safely used with supportive care and monitoring.
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Antimetabolitos Antineoplásicos , Neoplasias del Sistema Nervioso Central , Metotrexato , Humanos , Metotrexato/efectos adversos , Metotrexato/administración & dosificación , Femenino , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Masculino , Preescolar , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/administración & dosificación , Lactante , Niño , Estudios de Seguimiento , Estudios Retrospectivos , Pronóstico , Mucositis/inducido químicamente , Neutropenia/inducido químicamenteRESUMEN
BACKGROUND: Hearing loss (HL) is associated with worse neurocognitive outcomes among patients with medulloblastoma. We aimed to identify risk factors associated with severe HL and to evaluate the generalizability of a published HL calculator among patients treated with passive scattering proton therapy (PSPT) and cisplatin. METHODS: We identified patients aged 3-21 years who were treated at our centers between 2007-2022. Audiograms were graded using the International Society of Pediatric Oncology-Boston scale. Time to grade 3-4 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Seventy-nine patients were treated with PSPT at a median age of 7.5 years (range:3.1-21.1). The mean cochlear dose (Dmc) (±S.D.) was 31.5±8.5 Gy, and the cumulative cisplatin dose was 295±50 mg/m2. Fifty-nine patients (75%) received amifostine. Patients completed a median of 9 audiograms (range:4-22) with a median audiogram follow-up of 49 months (range:6-177). Twenty-seven patients (34%) had grade 3-4 HL. In adjusted Cox models, only higher Dmc (HR=1.12, 95% CI:1.06-1.18) was associated with grade 3-4 HL. The predicted 3-year incidence of grade 3-4 HL was 40.0% (95% CI: 21.3-66.3) and 66.7% (95% CI: 35.4-93.7) for children with Dmc ≥36 Gy and age at radiotherapy ≥7 and <7 years, respectively (p=0.042). It was 8.9% (95% CI: 2.3-31.6) and 15.6% (95% CI: 5.3-41.1) for children with Dmc <36 Gy and age at radiotherapy ≥7 and <7 years, respectively (p=0.78). CONCLUSIONS: Children <7 years at radiotherapy with a Dmc ≥36 Gy are at higher risk for HL.
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In response to ongoing coastal urbanization, it is critical to develop effective methods to improve the biodiversity and ecological sustainability of artificial shorelines. Enhancing the topographic complexity of coastal infrastructure through the mimicry of natural substrata may facilitate the establishment of ecosystem engineering species and associated biogenic habitat formation. However, interactions between ecosystem engineers and their substratum are likely determined by organismal size and resource needs, thus making responses to topography highly scale-dependent. Here, we assessed the topographic properties (rugosity, surface area, micro-surface orientations) that underpin the abundance and distribution of two ecosystem engineers (fucoids, limpets) across six spatial scales (1-500 mm). Furthermore, we assessed the 'biogenic' rugosity created by barnacle matrices across fine scales (1-20 mm). Field surveys and 3D scanning, conducted across natural and artificial substrata, showed major effects of rugosity and associated topographic variables on ecosystem engineer assemblages and spatial occupancy, while additional abiotic environmental factors (compass direction, wave exposure) and biotic associations only had weak influences. Natural substrata exhibited ≤67 % higher rugosity than artificial ones. Fucoid-covered patches were predominantly associated with high-rugosity substrata and horizontal micro-surfaces, while homescars of limpets (≥15 mm shell length) predominated on smoother substratum patches. Barnacle-driven rugosity homogenized substrata at scales ≤10 mm. Our findings suggest that scale-dependent rugosity is a key driver of fucoid habitat formation and limpet habitat use, with wider eco-engineering applications for mimicking ecologically impactful topography on coastal infrastructure.
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Biodiversidad , Ecosistema , Animales , Urbanización , Thoracica , Conservación de los Recursos Naturales/métodos , Monitoreo del Ambiente/métodosRESUMEN
As the global population ages, nurses with a positive attitude toward caring for older adults is crucial. However, studies indicate that nursing students often exhibit negative attitudes toward older adults. This study aimed to determine if a three-phased educational intervention significantly improved nursing students' attitudes toward older adults. A pre/post-test study design was used to measure the change in nursing students' attitudes toward older adults, as measured by the UCLA Geriatrics Attitudes Survey, after participating in an Artificial Intelligence in Education learning event (n = 151). Results indicate that post-intervention scores (M = 35.07, SD = 5.34) increased from pre-intervention scores (M = 34.50, SD = 4.86). This difference was statistically significant at the 0.10 significance level (t = 1.88, p = 0.06). Incorporating artificial intelligence technology in a learning event is an effective educational strategy due to its convenience, repetition, and measurable learning outcomes. Improved attitudes toward older adults are foundational for delivering competent care to a rapidly growing aging population. This study was prospectively registered with the university's Institutional Review Board (IRB) on 30 July 2021 with the registration number IRB-FY22-3.
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Topographic complexity is often considered to be closely associated with habitat complexity and niche diversity; however, complex topography per se does not imply habitat suitability. Rather, ecologically suitable habitats may emerge if topographic features interact with environmental factors and thereby alter their surrounding microenvironment to the benefit of local organisms (e.g., resource provisioning, stress mitigation). Topography may thus act as a key modulator of abiotic stressors and biotic pressures, particularly in environmentally challenging intertidal systems. Here, we review how topography can alter microhabitat conditions with respect to four resources required by intertidal organisms: a source of energy (light, suspended food particles, prey, detritus), water (hydration, buffering of light, temperature and hydrodynamics), shelter (temperature, wave exposure, predation), and habitat space (substratum area, propagule settlement, movement). We synthesize mechanisms and quantitative findings of how environmental factors can be altered through topography and suggest an organism-centered 'form-follows-ecological-function' approach to designing multifunctional marine infrastructure.
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Organismos Acuáticos , Ecosistema , AnimalesRESUMEN
Wastewater surveillance allows severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection levels to be tracked in a community. Here, we present a protocol to longitudinally quantify SARS-CoV-2 RNA in wastewater using quantitative reverse-transcription PCR (RT-qPCR) and pepper mild mottle virus (PMMoV) normalization. We describe steps for the pasteurization of wastewater samples, solids separation, supernatant filtration, viral precipitation and concentration, and RNA extraction. We then detail procedures for RT-qPCR, viral concentration extrapolation, PMMoV normalization, and longitudinal analysis. This protocol has the potential to be used for surveillance of other microorganisms. For complete details on the use and execution of this protocol, please refer to Sanchez Jimenez et al.1.
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COVID-19 , ARN Viral , SARS-CoV-2 , Tobamovirus , Aguas Residuales , Aguas Residuales/virología , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , ARN Viral/genética , ARN Viral/análisis , Tobamovirus/genética , Tobamovirus/aislamiento & purificación , COVID-19/virología , COVID-19/diagnóstico , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Humanos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
The goals of the present study were to describe the development of the first national longitudinal study of collegiate recovery programs (CRP) students; provide an updated characterization of CRP students' demographics, past problem severity, and current recovery-related functioning; and examine the perceived impact of COVID-19 on CRP students' recovery. Universities and community colleges with CRPs across the United States and Ontario, Canada, were invited to partner on this project. Launched in fall 2020, three cohorts of participants were recruited. All participants who completed the baseline survey (N = 334 from 43 CRPs) were invited to complete follow-up surveys. The sample was composed of mostly undergraduate, White, cisgender women averaging 29 years old at baseline. They reported challenging backgrounds, including high levels of polysubstance use, alcohol/substance problem severity, mental health challenges, and involvement with the criminal legal system. Despite such adversity, they evidenced high levels of recovery-related functioning. Recovery capital and quality of life were high. Students reported an average of nearly four years in recovery, with most having between two and four years of abstinence from their primary substance of choice. COVID-19 represented a substantial source of stress for many, impacting some students' abstinence and recovery-related functioning. Results generally parallel findings from the only other national study of CRP students conducted a decade ago, providing a much-needed update and novel insights into CRP students. Findings can inform our understanding of the CRP student population and can be used to tailor CRP design and service offerings to students' backgrounds and needs.
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On May 24, 2023, approximately 3.5 years into the pandemic, the World Health Organization (WHO) declared the end of the COVID-19 global health emergency. However, as there are still â¼3000 COVID-19 deaths per day in May 2023, robust surveillance systems are still warranted to return to normalcy in times of low risk and respond appropriately in times of high risk. The different phases of the pandemic have been defined by infection numbers and variants, both of which have been determined through clinical tests that are subject to many biases. Unfortunately, the end of the COVID-19 emergency threatens to exasperate these biases, thereby warranting alternative tracking methods. We hypothesized that wastewater surveillance could be used as a more accurate and comprehensive method to track SARS-CoV-2 in the post-emergency pandemic period (PEPP). SARS-CoV-2 was quantified and sequenced from wastewater between June 2022 and March 2023 to research the anticipated 2022/23 winter surge. However, in the 2022/23 winter, there was lower-than-expected SARS-CoV-2 circulation, which was hypothesized to be due to diagnostic testing biases but was confirmed by our wastewater analysis, thereby emphasizing the unpredictable nature of SARS-CoV-2 surges while also questioning its winter seasonality. Even in times of low baseline circulation, we found wastewater surveillance to be sensitive enough to detect minor changes in circulation levels â¼30-46 days prior to diagnostic tests, suggesting that wastewater surveillance may be a more appropriate early warning system to prepare for unpredictable surges in the PEPP. Furthermore, sequencing of wastewater detected variants of concern that were positively correlated with clinical samples and also provided a method to identify mutations with a high likelihood of appearing in future variants, necessary for updating vaccines and therapeutics prior to novel variant circulation. Together, these data highlight the effectiveness of wastewater surveillance in the PEPP to limit the global health burden of SARS-CoV-2 due to increases in circulation and/or viral evolution.
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The present white paper concerns the indications and recommendations of the SciSpacE Science Community to make progress in filling the gaps of knowledge that prevent us from answering the question: "How Do Gravity Alterations Affect Animal and Human Systems at a Cellular/Tissue Level?" This is one of the five major scientific issues of the ESA roadmap "Biology in Space and Analogue Environments". Despite the many studies conducted so far on spaceflight adaptation mechanisms and related pathophysiological alterations observed in astronauts, we are not yet able to elaborate a synthetic integrated model of the many changes occurring at different system and functional levels. Consequently, it is difficult to develop credible models for predicting long-term consequences of human adaptation to the space environment, as well as to implement medical support plans for long-term missions and a strategy for preventing the possible health risks due to prolonged exposure to spaceflight beyond the low Earth orbit (LEO). The research activities suggested by the scientific community have the aim to overcome these problems by striving to connect biological and physiological aspects in a more holistic view of space adaptation effects.
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RAD140 is a selective androgen receptor modulator that produces anabolic effects within skeletal muscle. Thus, RAD140 may be effective at treating sarcopenia. No long-term studies have investigated how RAD140 influences strength in ageing muscle. This study aimed to determine how 10 weeks of RAD140 supplementation impacts strength, recovery from exercise, and overall health in ageing mice. Young and adult females were assigned to receive RAD140 (5 mg/kg) or a control solution. Dorsiflexor muscles were exposed to repeated bouts of eccentric contractions, and torque was measured before and after each bout. Adaptive potential and strength gains were calculated to assess the efficacy of RAD140 in muscle, while frailty status and mortality risk were used to measure health span. Supplementation of RAD140 increased frailty status and mortality risk in the young and adult treated groups compared to the controls (p ≤ 0.042). RAD140 decreased adaptive potential in young (p = 0.040) but not adult mice (p = 0.688). Torque did not differ between groups after 2-3 weeks of recovery (p ≥ 0.135). In conclusion, long-term RAD140 supplementation reduced indices of overall health and failed to improve strength in female mice, suggesting that RAD140 (at a 5mg/kg dosage) may be more detrimental than beneficial in delaying or preventing sarcopenia.
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Fragilidad , Sarcopenia , Ratones , Femenino , Animales , Sarcopenia/prevención & control , Músculo Esquelético/fisiología , Nitrilos , Contracción Muscular/fisiología , Fuerza Muscular/fisiologíaRESUMEN
For genetic counselors to effectively meet the needs of an ever-diversifying multicultural patient population, it is vital that their genetic counseling programs (GCPs) equip future genetic counselors to recognize the impact of a patient's ethnocultural background on clinical interactions (Towards a culturally competent system of care: A monograph on effective services for minority children who are severely emotionally disturbed (p. 28). CASSP Technical Assistance Center, Georgetown University Child Development Center, 1989). Concerns about genetic counseling cultural competency training (CCT) including content and delivery have been brought up by GCP students who identify as racial and ethnic minorities (Journal of Genetic Counseling, 29, 303-314). Though GCPs must meet the Accreditation Council of Genetic Counselors' (ACGC) accreditation criteria, there is a gap in knowledge regarding the focus, type, and methods of delivery that GCPs have chosen to incorporate into their CCT, as ACGC does not dictate the exact focus, delivery, or format of training curricula. This quantitative study aimed to (1) characterize the current focus, type, and delivery of ethnocultural competency training in GCPs as perceived by second-year genetic counseling students and recent graduates and (2) highlight their perception of its impact on their levels of preparedness and comfort when interacting with ethnoculturally diverse patients. One hundred and one survey responses were analyzed using descriptive statistics, chi-square analyses, two-sample Wilcoxon rank-sum, and Fisher's exact tests. The results reveal significant variability in the format, type, and delivery of CCT provided by GCPs. Participants perceive that CCT focusing on specific traditions, medical considerations, and systemic healthcare disparities (taught to 74%, 61%, and 94% of students, respectively) related to ethnoculturally diverse patients was more likely to increase their self-reported levels of preparedness and comfort for clinical interactions than training focused on racial or ethnic stereotypes and generalizations (taught to 88% of students). Although 94% of participants perceived their CCT as helpful, 61% reported they received an insufficient amount. In light of these results, we provide suggestions for the improvement of ethnocultural CCT and highlight future opportunities for more intentional and fruitful CCT in GCPs.
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Adoption of electronic identification ear tags (EID) and DNA testing by commercial range sheep producers in the Western United States has been low, despite the availability of these technologies for over a decade. Jointly, these technologies offer an approach to provide individual animal performance data to improve flock health, genetic and reproductive management. This project involved a collaboration with five California sheep producers representing a broad geographic range, varying levels of pre-project EID adoption, and diverse operational practices. Tissue samples were collected from, and ear EIDs were placed in, a total of 2,936 rams and their potential lambs. We partnered with a commercial packing company, Superior Farms, to genotype the animals. Superior Farms used a targeted genotyping panel to assign parentage, and link individual animal identification (ID) to camera-graded carcass measurements. This enabled the collection of individual progeny carcass data and provided insight into sire performance, providing for the within-flock identification of prolific sires that were producing lambs with significantly more saleable meat as compared to their flock mates. Overall, almost 91% of lambs were successfully matched to their sire, and prolificacy ranging from 0-135 lambs per ram. There was as much as an $80 difference in the average edible product from camera-graded carcasses derived from lamb groups sired by different rams. A partial budget analysis modeling investment in an EID system coupled with an autodrafter and scale to collect individual weights and improve labor efficiency during processing, and a sheep flip chute to improve worker safety during foot trimmings, yielded a greater than 7:1 return on investment over a five-year time frame. Ideally, the data collection enabled by EIDs and DNA testing would feed into data-driven genetic evaluation programs to enable selection for more productive and profitable animals, and allow the US sheep industry to accelerate the rate of genetic improvement.
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Pruebas Genéticas , Oveja Doméstica , Ovinos/genética , Animales , Masculino , Industrias , Vendajes , ElectrónicaRESUMEN
BACKGROUND: Excessive, chronic alcohol consumption can result in muscle atrophy and weakness (i.e., alcoholic myopathy) that impairs the quality of life. However, the precise mechanisms responsible for ethanol's detrimental impact on skeletal muscle have not been fully elucidated, in part due because the time course of disease development and progression are not well established. Therefore, we examined muscle strength and body composition longitudinally using an established preclinical mouse model of chronic alcoholic myopathy. METHODS: To establish a time course of chronic alcoholic myopathy, we fed High Drinking in the Dark (HDID) female mice (n = 7) 20% ethanol for ~32 weeks (following a 2-week ethanol ramping period). We assessed in vivo isometric contractility of the left ankle dorsiflexor and lean mass via NMR every 4 weeks. Outcomes were compared with age-matched control HDID mice that did not consume ethanol (n = 8). RESULTS: At study completion, mice who consumed ethanol were 12% weaker than control mice (p = 0.015). Compared to baseline, consuming ethanol resulted in an acute transient reduction in dorsiflexion torque at Week 4 (p = 0.032) that was followed by a second, more sustained reduction at Week 20 (p < 0.001). Changes in lean mass paralleled those of dorsiflexor torque, with ~40% of the variance in dorsiflexor torque being explained by the variance in lean mass of the ethanol group (p < 0.001). Dorsiflexor torque normalized to lean mass (mN·m/g lean mass) did not differ between the ethanol and control groups from Weeks 4 to 32 (p ≥ 0.498). CONCLUSIONS: These results indicate that reductions in muscle mass and strength due to chronic, excessive ethanol intake are dynamic, not necessarily linear, processes. Moreover, the findings confirm that ethanol-induced weakness is primarily driven by muscle atrophy (i.e., loss of muscle quantity). Future studies should consider how chronic alcoholic myopathy develops and progresses rather than identifying changes after it has been diagnosed.
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BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI. METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (nâ =â 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequencyâ >â 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (Pâ <â 5â ×â 10-5) in individuals of European ancestry (nâ =â 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (Pâ <â .05) in individuals of non-European ancestries (nâ =â 78) and achieved genome-wide statistical significance (Pâ <â 5â ×â 10-8) in a meta-analysis across ancestry groups. RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at a median age of 8.3 years. Overall, 1150 neurocognitive evaluations were obtained (medianâ =â 5, range: 2-10 per participant). One of the five loci previously associated with cognitive outcomes in pediatric CNS tumors survivors demonstrated significant time-dependent IQ declines (PPARA rs6008197, Pâ =â .004). Two variants associated with IQ in the general population were associated with declines in IQ after Bonferroni correction (rs9348721, Pâ =â 1.7â ×â 10-5; rs31771, Pâ =â 7.8â ×â 10-4). In genome-wide analyses, we identified novel loci associated with accelerated declines in IQ (rs116595313, meta-Pâ =â 9.4â ×â 10-9), WM (rs17774009, meta-Pâ =â 4.2â ×â 10-9), and PS (rs77467524, meta-Pâ =â 1.5â ×â 10-8; rs17630683, meta-Pâ =â 2.0â ×â 10-8; rs73249323, meta-Pâ =â 3.1â ×â 10-8). CONCLUSIONS: Inherited genetic variants involved in baseline cognitive functioning and novel susceptibility loci jointly influence the degree of treatment-associated cognitive decline in pediatric CNS tumor survivors.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Disfunción Cognitiva , Irradiación Craneoespinal , Niño , Masculino , Humanos , Femenino , Neoplasias Encefálicas/patología , Irradiación Craneoespinal/efectos adversos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Inteligencia/genética , Inteligencia/efectos de la radiación , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/radioterapia , Disfunción Cognitiva/etiologíaRESUMEN
BACKGROUND: Downstaging has been associated with improved survival for many cancers. However, the implications of downstaging are unclear for pancreatic cancer in an era of effective neoadjuvant systemic chemotherapy. METHODS: NCDB retrospective cohort study of resected pancreatic carcinoma treated with neoadjuvant therapy. RESULTS: The study included 73,985 patients: 66,589 with no neoadjuvant therapy, 2,102 neoadjuvant radiation therapy (N-RT), 3,195 neoadjuvant multiagent chemotherapy (N-MAC) and 2.099 with both neoadjuvant radiation and multiagent chemotherapy. There was increased use of N-MAC over the period of this study. Patients selected for treatment with N-MAC had longer survival from surgery on univariate (23.1 vs. 18.7 months, p = < 0.01) and multivariate analyses HR 0.81 (0.76-0.87, p < 0.001) compared to those selected with N-RT. Downstaging was similar in N-RT and N-MAC groups (25.1 vs. 24.1%, p = 0.43). Downstaging following N-MAC was associated with a survival benefit, HR 0.85 (0.74-0.98). However, downstaging following N-RT was not associated with a survival advantage, HR 1.12 (0.99-0.99). CONCLUSION: Clinicians have rapidly adopted N-MAC for treatment of pancreatic cancer. Although the rates of downstaging are similar between treatment groups, response translates into increased survival only with N-MAC and not with N-RT.
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Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Neoplasias Pancreáticas/patología , Terapia Neoadyuvante , Quimioterapia Adyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estadificación de Neoplasias , Resultado del Tratamiento , Neoplasias PancreáticasRESUMEN
The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs. While we replicated previous findings on PKD1L1, our results do not suggest that recurrent de novo PAVs play important roles in BA susceptibility. In fact, our finding in NOTCH2, a disease gene associated with Alagille syndrome, highlights the difficulty in BA diagnosis. Notably, IFRD2 has been implicated in other gastrointestinal conditions and warrants additional study. Overall, our findings strengthen the hypothesis that the etiology of BA is complex.
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Atresia Biliar , Humanos , Atresia Biliar/epidemiología , Atresia Biliar/genética , Atresia Biliar/diagnóstico , Exoma/genética , Homocigoto , Padres , Estudios de Casos y Controles , Proteínas de la Membrana/genéticaRESUMEN
BACKGROUND: Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS. METHODS: The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical covariates. All statistical tests were two sided. We also performed stratified analyses by histological subtype (alveolar and embryonal RMS) and carried out sensitivity analyses of statistically significant SNPs by PAX3/7-FOXO1 fusion status and genetic ancestry group. RESULTS: We identified that rs17321084 was associated with worse EFS (HR = 2.01, 95% CI = 1.59 to 2.53, P = 5.39 × 10-9) and rs10094840 was associated with worse OS (HR = 1.84, 95% CI = 1.48 to 2.27, P = 2.13 × 10-8). Using publicly available data, we found that rs17321084 lies in a binding region for transcription factors GATA2 and GATA3, and rs10094840 is associated with SPAG1 and RNF19A expression. We also identified that CTNNA3 rs2135732 (HR = 3.75, 95% CI = 2.34 to 5.99, P = 3.54 × 10-8) and MED31 rs74504320 (HR = 3.21, 95% CI = 2.12 to 4.86, P = 3.60 × 10-8) were associated with worse OS among individuals with alveolar RMS. CONCLUSIONS: We demonstrated that common germline variants are associated with EFS and OS among individuals with RMS. Additional replication and investigation of these SNP effects may further support their consideration in risk stratification protocols.
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Rabdomiosarcoma Alveolar , Rabdomiosarcoma , Niño , Humanos , Estudio de Asociación del Genoma Completo , Rabdomiosarcoma/genética , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/patología , Rabdomiosarcoma Alveolar/genética , Modelos de Riesgos Proporcionales , Células Germinativas/patología , Ubiquitina-Proteína Ligasas , Complejo Mediador/genéticaRESUMEN
PURPOSE: Alcoholics develop muscle atrophy and weakness from excessive ethanol (EtOH) intake. To date, most research has examined outcomes of alcohol-induced atrophy and weakness under basal or unstressed conditions despite physical stress being a normal occurrence in a physiological setting. Therefore, this study set out to determine if recovery of torque is impaired after repetitive bouts of physical stress in skeletal muscle during excessive short-term (experiment 1) and long-term (experiment 2) EtOH consumption. METHODS: Twenty male and female mice were assigned to receive either 20% EtOH in their drinking water or 100% water. Short- and long-term consumption was predetermined to be EtOH intake starting at 4 and 26 wk, respectively. Anterior crural muscles performed repeated bouts of physical stress using in vivo eccentric contractions, with tetanic isometric torque being measured immediately pre- and postinjury. A total of 10 bouts were completed with 14 d between each bout within bouts 1-5 (experiment 1) and bouts 6-10 (experiment 2), and 12 wk between bouts 5 and 6. RESULTS: Mice consuming EtOH had blood alcohol concentrations up to 270 mg·dL -1 . In experiment 1, five bouts of eccentric contractions did not reduce recovery of torque, regardless of sex or EtOH treatment ( P ≥ 0.173). Similarly, in experiment 2, preinjury torques did not differ from day 14 values regardless of sex or treatment ( P ≥ 0.322). However, there was a group effect in female mice for bouts 6 and 10 during experiment 2, with female EtOH mice being weaker than controls ( P ≤ 0.002). CONCLUSIONS: Excessive short- or long-term EtOH misuse in a mouse model did not affect the muscle's ability to regain strength after repeated bouts of eccentric contractions, suggesting that EtOH may not be as detrimental to recovery as once predicted.