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The clinical diagnosis of patients with multisystem involvement including a pronounced neurologic damage is challenging. High-throughput sequencing methods remains crucial to provide an accurate diagnosis. In this study, we reported a Tunisian patient manifesting hypotonia and global developmental delay with visual and skin abnormalities. Exome sequencing was conducted followed by segregation analysis and, subsequently additional investigations. In silico analysis of non-synonymous variants (nsSNPs) described in COG5 in conserved positions was made. Results revealed a homozygous missense variant c.298 C > T (p.Leu100Phe) in the COG5 inherited from both parents. This variant altered both protein solubility and stability, in addition to a putative disruption of the COG5-COG7 interaction. This disruption has been confirmed using patient-derived cells in vitro in a COG5 co-immuno-precipitation, where interaction with binding partner COG7 was abrogated. Hence, we established the COG5-CDG diagnosis. Clinically, the patient shared common features with the already described cases with the report of the ichtyosis as a new manifestation. Conversely, the CADD scoring revealed 19 putatively pathogenic nsSNPs (Minor Allele Frequency MAF < 0.001, CADD > 30), 11 of which had a significant impact on the solubility and/or stability of COG5. These properties seem to be disrupted by six of the seven missense COG5-CDG variants. In conclusion, our study expands the genetic and phenotypic spectrum of COG5-CDG disease and highlight the utility of the next generation sequencing as a powerful tool in accurate diagnosis. Our results shed light on a likely molecular mechanism underlying the pathogenic effect of missense COG5 variants, which is the alteration of COG5 stability and solubility.
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Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons' origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.
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Adenocarcinoma , Neoplasias Esofágicas , Humanos , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Adenocarcinoma/genética , Adenocarcinoma/patología , Organoides/patología , Amplificación de Genes , Metilación de ADN , Oncogenes/genética , Masculino , Análisis de Secuencia de ADN/métodos , Evolución Clonal/genética , FemeninoRESUMEN
BACKGROUND: We assessed the association of hedonic hunger, self-control (impulsivity and restraint), cognitive distortion (CD), and well-being with adiposity measures such as waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body mass index (BMI), total body fat (TBF), subcutaneous fat (SF), visceral fat level (VFL), skeletal muscle percentage (SM), and resting metabolism (RM), among a sample of urban Malaysian adults at Sunway University and Sunway College, Selangor, Malaysia. METHODS: Among 186 participants (M/F = 51/135; aged 22.1 ± 5.0), psychometrics were assessed using Power of Food Scale (PFS), Brief Self-Control Scale, CD Questionnaire (CD-Quest), and WHO-5 Well-being Index. Blood pressures, anthropometrics and body compositions were also measured using standard methods and bioimpedance. RESULTS: Men had significantly higher well-being, but lower overall self-control, impulsivity and Food Available hedonic hunger. Those with moderate/severe CD had higher odds ratio (OR) of having high central adiposity, compared with those with absent/slight CD (OR: 2.52;95% CI: 1.14, 5.61; p = 0.023 for WC and OR: 2.50; 95% CI: 1.19, 5.23; p = 0.015 for WHR). Higher CD and PFS scores were strongly significantly correlated with higher systolic blood pressure (SBP), WC, WHR, WHtR, BMI, TBF, SF, VFL and RM. Lower self-control was weakly correlated with higher WC, while lower impulsivity and restraint were weakly correlated with higher VFL. Those who were overweight, obese, and in high TBF class had significantly higher PFS Aggregate Factor scores. Food Available and Food Present scores, but not Food Tasted, were also significantly higher among overweight participants. CONCLUSIONS: Higher hedonic hunger and CD were associated with higher SBP and all adiposity measures. Overweight participants had higher hedonic hunger in the context of ready availability and physical presence of highly palatable foods. Lower self-control was weakly correlated with higher central adiposity; lower impulsivity and restraint were weakly correlated with higher visceral adiposity. These findings have provided some insights into the cognitive factors underlying adiposity.
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Adiposidad , Sobrepeso , Masculino , Adulto , Humanos , Adiposidad/fisiología , Sobrepeso/complicaciones , Estudios Transversales , Hambre , Obesidad/complicaciones , Cognición , Factores de RiesgoRESUMEN
PURPOSE: DNA methylation alterations are widespread in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), some of which appear to have evolved independently of somatic mutations in epigenetic regulators. Although the presence of somatic mutations in peripheral blood can predict the risk of development of AML and MDS, its accuracy remains unsatisfactory. EXPERIMENTAL DESIGN: We performed global DNA methylation profiling in a case control study nested within the Singapore Chinese Health Study to evaluate whether DNA methylation alterations were associated with AML/MDS development. Targeted deep sequencing and methylated DNA immunoprecipitation sequencing (MeDIP-seq) were performed on peripheral blood collected a median of 9.9 years before diagnosis of AML or MDS, together with age-matched still-healthy individuals as controls. RESULTS: Sixty-six individuals who developed AML or MDS displayed significant DNA methylation changes in the peripheral blood compared with 167 age- and gender-matched controls who did not develop AML/MDS during the follow-up period. Alterations in methylation in the differentially methylation regions were associated with increased odds of developing AML/MDS. CONCLUSIONS: The epigenetic changes may be acquired independently and before somatic mutations that are relevant for AML/MDS development. The association between methylation changes and the risk of pre-AML/MDS in these individuals was considerably stronger than somatic mutations, suggesting that methylation changes could be used as biomarkers for pre-AML/MDS screening.
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Metilación de ADN , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Masculino , Femenino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/diagnóstico , Estudios de Casos y Controles , Anciano , Adulto , Epigénesis Genética , Singapur/epidemiología , Mutación , Predisposición Genética a la Enfermedad , Factores de RiesgoRESUMEN
Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful.
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Cardiopatías Congénitas , Pez Cebra , Animales , Humanos , Polaridad Celular/genética , Células Germinativas/metabolismo , Mutación de Línea Germinal/genética , Cardiopatías Congénitas/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Pez Cebra/genética , Pez Cebra/metabolismo , Proteínas de Pez Cebra/genéticaRESUMEN
OBJECTIVE: Whether gastric metaplasia (GM) of the oesophagus should be considered as Barrett's oesophagus (BO) is controversial. Given concern intestinal metaplasia (IM) may be missed due to sampling, the UK guidelines include GM as a type of BO. Here, we investigated whether the risk of misdiagnosis and the malignant potential of GM warrant its place in the UK surveillance. DESIGN: We performed a thorough pathology and endoscopy review to follow clinical outcomes in a novel UK cohort of 244 patients, covering 1854 person years of follow-up. We complemented this with a comparative genomic analysis of 160 GM and IM specimens, focused on early molecular hallmarks of BO and oesophageal adenocarcinoma (OAC). RESULTS: We found that 58 of 77 short-segment (<3 cm) GM (SS-GM) cases (75%) continued to be observed as GM-only across a median of 4.4 years of follow-up. We observed that disease progression in GM-only cases and GM+IM cases (cases with reported GM on some occasions, IM on others) was significantly lower than in the IM-only cases (Kaplan-Meier, p=0.03). Genomic analysis revealed that the mutation burden in GM is significantly lower than in IM (p<0.01). Moreover, GM does not bear the mutational hallmarks of OAC, with an absence of associated signatures and driver gene mutations. Finally, we established that GM found adjacent to OAC is evolutionarily distant from cancer. CONCLUSION: SS-GM is a distinct entity from SS-IM and the malignant potential of GM is lower than IM. It is questionable whether SS-GM warrants inclusion in BO surveillance.
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Adenocarcinoma , Esófago de Barrett , Neoplasias Esofágicas , Humanos , Esófago de Barrett/diagnóstico , Esófago de Barrett/genética , Esófago de Barrett/complicaciones , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/genética , Metaplasia , Endoscopía GastrointestinalRESUMEN
BACKGROUND: Plexiform neurofibromas (PN) are complex, benign nerve-sheath tumours that occur in 30-50% of patients with neurofibromatosis type 1 (NF1), a rare, genetic disorder. PN are associated with substantial, heterogeneous morbidities that impact health-related quality of life (HRQoL), including affecting motor function and causing pain, though HRQoL and work productivity data are scarce. This UK cross-sectional study explored HRQoL and work productivity in adult patients with NF1 PN and caregivers of paediatric patients. METHODS: Adult patients and caregivers of paediatric patients self-enrolled in an online survey (March-April 2021). Outcomes included EQ-5D-5L, PROMIS® GH and INF1-QOL (adult patients only), and EQ-5D-5L, CarerQol and WPAI (caregivers only). Utilities were estimated from EQ-5D-5L responses using the UK crosswalk value set. Linear regression models explored univariable associations between adult patient characteristics and HRQoL. RESULTS: Mean (± standard deviation) EQ-5D utility in adult patients with NF1 PN was 0.65 (± 0.29; n = 35; age-/sex-matched norm: 0.89 [± 0.04]). Moderate-extreme pain/discomfort and anxiety/depression were reported by 14/35 (40.0%) and 18/35 (51.4%) patients, respectively. Mean PROMIS® GH physical and mental health scores were 43.6 (± 9.19) and 41.7 (± 11.5; n = 35; matched norm: 50.0 [± 10.0]). Mean INF1-QOL score was 11.03 (± 6.02; n = 33). Chronic itching, at least one symptom, at least one comorbidity, PN location at extremities (arms/legs) and pain were associated with worse HRQoL scores. Mean caregiver EQ-5D utility was 0.72 (± 0.24; n = 8; age-/sex-matched norm: 0.88 [± 0.03]). Moderate pain/discomfort and moderate-severe anxiety/depression were reported by 4/8 (50.0%) and 2/8 (25.0%) caregivers, respectively. Mean CarerQol score was 69.3 (± 13.9; n = 8). Mean WPAI regular activity productivity loss was 36.3% (± 31.6%; n = 8). CONCLUSIONS: NF1 PN worsens adult patient and caregiver HRQoL compared to the general population, notably affecting pain and discomfort, anxiety and depression and caregiver productivity.
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Neurofibroma Plexiforme , Neurofibromatosis 1 , Adulto , Niño , Humanos , Cuidadores , Estudios Transversales , Estado de Salud , Neurofibroma Plexiforme/epidemiología , Neurofibromatosis 1/epidemiología , Dolor , Calidad de Vida , Encuestas y Cuestionarios , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Development, implementation and evaluation of a simulation curriculum is time and resource intensive. Limited faculty time and training are cited as primary barriers to adopting simulation into medical education. Near-peer teaching is a potential solution to manage the increased teaching demands that occur with simulation use. APPROACH: In 2022, we implemented a near-peer simulation curriculum for teaching junior physical medicine and rehabilitation (PM&R) residents high-acuity low-opportunity events commonly seen on the inpatient rehabilitation unit. The curriculum was taught by senior residents to supplement faculty lectures. Senior residents completed facilitator training on simulator logistics, debriefing and formative assessment. EVALUATION: Residents completed an end-of-course questionnaire evaluating teaching effectiveness and perceived knowledge acquisition. All items were scored on a 5-point Likert-type scale. Learners rated their near-peers as having good clinical teaching effectiveness (mean [SD], 4.66[0.38]). Senior residents (n = 6) disclosed feeling knowledgeable about the topics they instructed (baseline 3.9[3.2-4.4]; after 4.6[4.1-4.9]; p = 0.19), and junior residents (n = 6) felt they gained knowledge and improved their ability to manage patients as a result of the near-peer curriculum (baseline 2.4[2.3-2.5]; after 3.9[3.5-4.2]; p = 0.005). IMPLICATIONS: This educational programme is an example of how near-peer teaching can be used in simulation. Our simulation curriculum taught by near-peers was valued by learners as well taught and educational. Research is needed that directly compares the effectiveness of near-pear teaching to faculty instruction. We hope that by sharing our work, educators will feel inspired to use near-peer teachers for simulation instruction when faculty availability for teaching is scarce.
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Curriculum , Educación Médica , Humanos , Docentes , Escolaridad , Simulación por ComputadorRESUMEN
PURPOSE: Developmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants. METHODS: We collate clinical information of 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles. RESULTS: We identified private germline DRG1 variants, including 3 stop-gained p.Gly54∗, p.Arg140∗, p.Lys263∗, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature, and craniofacial anomalies. We show that these loss-of-function variants (1) severely disrupt DRG1 messenger RNA/protein stability in patient-derived fibroblasts, (2) impair its GTPase activity, and (3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in preweaning lethality. CONCLUSION: Our work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1's importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis.
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Proteínas de Unión al GTP , Trastornos del Neurodesarrollo , Animales , Humanos , Ratones , Proteínas Portadoras , GTP Fosfohidrolasas/genética , Mamíferos/metabolismo , Trastornos del Neurodesarrollo/genética , ARN MensajeroRESUMEN
Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1-6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.
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Adenocarcinoma , Esófago de Barrett , Carcinogénesis , ADN , Progresión de la Enfermedad , Detección Precoz del Cáncer , Neoplasias Esofágicas , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patología , Esófago de Barrett/genética , Esófago de Barrett/patología , Estudios de Casos y Controles , ADN/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinogénesis/genética , Secuenciación Completa del Genoma , Estudios de Cohortes , Biopsia , Oncogenes , Inmunomodulación , Variaciones en el Número de Copia de ADN , Amplificación de Genes , Detección Precoz del Cáncer/métodosRESUMEN
Hepatocellular carcinoma (HCC) is one of the leading cancers worldwide. Classically, HCC develops in genetically susceptible individuals who are exposed to risk factors, especially in the presence of liver cirrhosis. Significant temporal and geographic variations exist for HCC and its etiologies. Over time, the burden of HCC has shifted from the low-moderate to the high sociodemographic index regions, reflecting the transition from viral to nonviral causes. Geographically, the hepatitis viruses predominate as the causes of HCC in Asia and Africa. Although there are genetic conditions that confer increased risk for HCC, these diagnoses are rarely recognized outside North America and Europe. In this review, we will evaluate the epidemiologic trends and risk factors of HCC, and discuss the genetics of HCC, including monogenic diseases, single-nucleotide polymorphisms, gut microbiome, and somatic mutations.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/genética , Cirrosis Hepática/epidemiología , Cirrosis Hepática/genética , Cirrosis Hepática/complicaciones , Factores de Riesgo , América del Norte/epidemiologíaRESUMEN
In Japanese patients who experienced an osteoporotic fracture, 10.8% and 18.6% had a subsequent fracture within 1 and 2 years of follow-up, respectively. Although the burden of hip and vertebral fractures has been reported widely, we found that patients with non-hip non-vertebral (NHNV) fractures had a 26% higher risk of subsequent fracture than patients with hip fractures; therefore, NHNV fractures should also be considered an important risk factor for subsequent fracture. INTRODUCTION: To investigate imminent risk and odds of subsequent osteoporotic fractures and associated risk factors in patients who experienced an initial osteoporotic fracture. METHODS: Patients aged ≥ 50 years with ≥ 1 osteoporotic fracture were analyzed from Japan's Medical Data Vision (MDV) database of claims from acute-care hospitals (January 2012-January 2017). Multivariable models were constructed to explore the impact of key comorbidities and medications on the subsequent fracture risk: Cox proportional hazards model for time to subsequent fracture and logistic regression models for odds of subsequent fracture within 1 and 2 years from index fracture. RESULTS: In total, 32,926 patients were eligible with a median follow-up duration of 12.3 months. The percentage of patients experiencing subsequent fractures was 14.1% across the study duration, and 10.8% and 18.6% in patients with 1 and 2 years of follow-up, respectively. In the Cox proportional hazards model, patients with vertebral or NHNV index fractures had a higher subsequent fracture risk than patients with a hip index fracture (adjusted hazard ratio [aHR] 1.11 and 1.26, respectively); subsequent fracture risk was lower in males than females (aHR 0.89). Patients with baseline claims for tranquilizers and glucocorticoids had a higher subsequent fracture risk than those without (aHR 1.14 and 1.08, respectively). Additionally, baseline claims for anti-Parkinson's medications, alcoholism, and stage 4/5 chronic kidney disease were significantly associated with higher odds of subsequent fracture in the logistic regression models. CONCLUSION: Several clinical and demographic factors were associated with a higher risk and odds of subsequent fracture. This may help to identify patients who should be prioritized for osteoporosis treatment.
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Fracturas de Cadera , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Femenino , Fracturas de Cadera/complicaciones , Fracturas de Cadera/etiología , Humanos , Japón/epidemiología , Masculino , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/etiología , Modelos de Riesgos Proporcionales , Factores de Riesgo , Fracturas de la Columna Vertebral/complicaciones , Fracturas de la Columna Vertebral/etiologíaRESUMEN
BACKGROUND: Deletion of 1p is associated with poor prognosis in neuroblastoma, however selected 1p-intact patients still experience poor outcomes. Since mutations of 1p genes may mimic the deleterious effects of chromosomal loss, we studied the incidence, spectrum and effects of mutational variants in 1p-intact neuroblastoma. METHODS: We characterized the 1p status of 325 neuroblastoma patients, and correlated the mutational status of 1p tumor suppressors and neuroblastoma candidate genes with survival outcomes among 100 1p-intact cases, then performed functional validation of selected novel variants of 1p36 genes identified from our patient cohort. RESULTS: Among patients with adverse disease characteristics, those who additionally had 1p deletion had significantly worse overall survival. Among 100 tumor-normal pairs sequenced, somatic mutations of 1p tumor suppressors KIF1Bß and CHD5 were most frequent (2%) after ALK and ATRX (8%), and BARD1 (3%). Mutations of neuroblastoma candidate genes were associated with other synchronous mutations and concurrent 11q deletion (P = 0.045). In total, 24 of 38 variants identified were novel and predicted to be deleterious or pathogenic. Functional validation identified novel KIF1Bß I1355M variant as a gain-of-function mutation with increased expression and tumor suppressive activity, correlating with indolent clinical behavior; another novel variant CHD5 E43Q was a loss-of-function mutation with decreased expression and increased long-term cell viability, corresponding with aggressive disease characteristics. CONCLUSIONS: Our study showed that chromosome 1 gene mutations occurred frequently in 1p-intact neuroblastoma, but may not consistently abrogate the function of bonafide 1p tumor suppressors. These findings may augment the evolving model of compounding contributions of 1p gene aberrations toward tumor suppressor inactivation in neuroblastoma.
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Genes Supresores de Tumor , Neuroblastoma , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Estudios de Cohortes , ADN Helicasas/genética , Humanos , Mutación , Proteínas del Tejido Nervioso/genética , Neuroblastoma/genética , Neuroblastoma/patologíaRESUMEN
INTRODUCTION: In patients with end-stage kidney disease (ESKD) suitable for peritoneal dialysis (PD), PD should ideally be planned and initiated electively (planned-start PD). If patients present late, some centres initiate PD immediately with an urgent-start PD strategy. However, as urgent-start PD is resource intensive, we evaluated another strategy where patients first undergo emergent haemodialysis (HD), followed by early PD catheter insertion, and switch to PD 48-72 hours after PD catheter insertion (early-start PD). Conventionally, late-presenting patients are often started on HD, followed by deferred PD catheter insertion before switching to PD≥14 days after catheter insertion (deferred start PD). METHODS: This is a retrospective study of new ESKD patients, comparing the planned-start, early-start and deferred-start PD strategies. Outcomes within 1 year of dialysis initiation were studied. RESULTS: Of 148 patients, 57 (38.5%) patients had planned-start, 23 (15.5%) early-start and 68 (45.9%) deferred-start PD. Baseline biochemical parameters were similar except for a lower serum urea with planned-start PD. No significant differences were seen in the primary outcomes of technique and patient survival across all 3 subgroups. Compared to planned-start PD, early-start PD had a shorter time to catheter migration (hazard ratio [HR] 14.13, 95% confidence interval [CI] 1.65-121.04, P=0.016) while deferred-start PD has a shorter time to first peritonitis (HR 2.49, 95% CI 1.03-6.01, P=0.043) and first hospital admission (HR 2.03, 95% CI 1.35-3.07, P=0.001). CONCLUSION: Planned-start PD is the best PD initiation strategy. However, if this is not possible, early-start PD is a viable alternative. Catheter migration may be more frequent with early-start PD but does not appear to impact technique survival.
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Fallo Renal Crónico , Diálisis Peritoneal , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Diálisis Peritoneal/métodos , Diálisis Renal , Estudios Retrospectivos , Factores de TiempoRESUMEN
The RYR1 gene codes for a ryanodine receptor which is a calcium release channel in the skeletal muscle sarcoplasmic reticulum. It is associated with Malignant Hyperthermia (MH) and congenital myopathies including Central Core Disease (CCD), Multiminicore Disease (MMD) and Congenital Fibre-Type Disproportion (CFTD). There is currently little information on the epidemiology of RYR1 variants in Asians. Our study aims to describe the RYR1 variant landscape in a Singapore cohort unselected for RYR1-associated conditions. Data was retrieved from the SG10K pilot project, where whole genome sequencing was performed on volunteers unselected and undetermined for RYR1-associated conditions. Variants were classified based on pathogenicity using databases ClinVar and InterVar. Allele frequencies of pathogenic variants were compared between Chinese, Indians and Malays. Using databases ExAC, GnomAD and GenomeAsia 100k study, we further compared local allele frequencies to those in Europe, America and Asia. Data was analysed using R Commander. Significant P value was set at p < 0.05. Majority of the RYR1 variants were missense mutations. We identified four pathogenic and four likely pathogenic RYR1 variants. All were related to the aforementioned RYR1-associated conditions. There were 6 carriers of RYR1 pathogenic variants amongst 4810 individuals, corresponding to an allele frequency of 0.06%. The prevalence of pathogenic variants was the highest amongst Indians (4 in 1127 individuals) (p = 0.030). Majority of pathogenic and likely pathogenic mutations were missense and located in mutational hotspots. These variants also occurred at higher frequencies in Asians than globally. This study describes the variant landscape of the RYR1 gene in Singapore. This knowledge will facilitate genetic screening for RYR1-related conditions.
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Miopatías Estructurales Congénitas , Canal Liberador de Calcio Receptor de Rianodina , Pueblo Asiatico/genética , Humanos , Proyectos Piloto , Canal Liberador de Calcio Receptor de Rianodina/genética , Singapur/epidemiología , Secuenciación Completa del GenomaRESUMEN
Oesophageal adenocarcinoma (OAC) provides an ideal case study to characterize large-scale rearrangements. Using whole genome short-read sequencing of 383 cases, for which 214 had matched whole transcriptomes, we observed structural variations (SV) with a predominance of deletions, tandem duplications and inter-chromosome junctions that could be identified as LINE-1 mobile element (ME) insertions. Complex clusters of rearrangements resembling breakage-fusion-bridge cycles or extrachromosomal circular DNA accounted for 22% of complex SVs affecting known oncogenes. Counting SV events affecting known driver genes substantially increased the recurrence rates of these drivers. After excluding fragile sites, we identified 51 candidate new drivers in genomic regions disrupted by SVs, including ETV5, KAT6B and CLTC. RUNX1 was the most recurrently altered gene (24%), with many deletions inactivating the RUNT domain but preserved the reading frame, suggesting an altered protein product. These findings underscore the importance of identification of SV events in OAC with implications for targeted therapies.
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Adenocarcinoma , Neoplasias Esofágicas , Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Genoma Humano , Histona Acetiltransferasas/genética , Humanos , Secuenciación Completa del GenomaRESUMEN
Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here, we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near-exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling "inside-out" model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies.