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BACKGROUND: It remains an important challenge to predict the functional consequences or clinical impacts of genetic variants in human diseases, such as cancer. An increasing number of genetic variants in cancer have been discovered and documented in public databases such as COSMIC, but the vast majority of them have no functional or clinical annotations. Some databases, such as CiVIC are available with manual annotation of functional mutations, but the size of the database is small due to the use of human annotation. Since the unlabeled data (millions of variants) typically outnumber labeled data (thousands of variants), computational tools that take advantage of unlabeled data may improve prediction accuracy. RESULT: To leverage unlabeled data to predict functional importance of genetic variants, we introduced a method using semi-supervised generative adversarial networks (SGAN), incorporating features from both labeled and unlabeled data. Our SGAN model incorporated features from clinical guidelines and predictive scores from other computational tools. We also performed comparative analysis to study factors that influence prediction accuracy, such as using different algorithms, types of features, and training sample size, to provide more insights into variant prioritization. We found that SGAN can achieve competitive performances with small labeled training samples by incorporating unlabeled samples, which is a unique advantage compared to traditional machine learning methods. We also found that manually curated samples can achieve a more stable predictive performance than publicly available datasets. CONCLUSIONS: By incorporating much larger samples of unlabeled data, the SGAN method can improve the ability to detect novel oncogenic variants, compared to other machine-learning algorithms that use only labeled datasets. SGAN can be potentially used to predict the pathogenicity of more complex variants such as structural variants or non-coding variants, with the availability of more training samples and informative features.
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Algoritmos , Neoplasias , Humanos , Aprendizaje Automático , Neoplasias/genética , Bases de Datos Factuales , Aprendizaje Automático SupervisadoRESUMEN
OBJECTIVE: To evaluate factors influencing the diagnostic yield of comprehensive gene panel testing (CGPT) for hearing loss (HL) in children and to understand the characteristics of undiagnosed probands. STUDY DESIGN: This was a retrospective cohort study of 474 probands with childhood-onset HL who underwent CGPT between 2016 and 2020 at a single center. Main outcomes and measures included the association between clinical variables and diagnostic yield and the genetic and clinical characteristics of undiagnosed probands. RESULTS: The overall diagnostic yield was 44% (209/474) with causative variants involving 41 genes. While the diagnostic yield was high in the probands with congenital, bilateral, and severe HL, it was low in those with unilateral, noncongenital, or mild HL; cochlear nerve deficiency; preterm birth; neonatal intensive care unit admittance; certain ancestry; and developmental delay. Follow-up studies on 49 probands with initially inconclusive CGPT results changed the diagnostic status to likely positive or negative outcomes in 39 of them (80%). Reflex to exome sequencing on 128 undiagnosed probands by CGPT revealed diagnostic findings in 8 individuals, 5 of whom had developmental delays. The remaining 255 probands were undiagnosed, with 173 (173/255) having only a single variant in the gene(s) associated with autosomal recessive HL and 28% (48/173) having a matched phenotype. CONCLUSION: CGPT efficiently identifies the genetic etiologies of HL in children. CGPT-undiagnosed probands may benefit from follow-up studies or expanded testing.
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Sordera , Pérdida Auditiva Sensorineural , Pérdida Auditiva , Nacimiento Prematuro , Femenino , Humanos , Niño , Recién Nacido , Estudios Retrospectivos , Nacimiento Prematuro/genética , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/genética , Sordera/genética , Fenotipo , Pérdida Auditiva Sensorineural/diagnóstico , Pruebas Genéticas/métodosRESUMEN
Epigenetic mechanisms, including histone post-translational modifications, control longevity in diverse organisms. Relatedly, loss of proper transcriptional regulation on a global scale is an emerging phenomenon of shortened life span, but the specific mechanisms linking these observations remain to be uncovered. Here, we describe a life span screen in Saccharomyces cerevisiae that is designed to identify amino acid residues of histones that regulate yeast replicative aging. Our results reveal that lack of sustained histone H3K36 methylation is commensurate with increased cryptic transcription in a subset of genes in old cells and with shorter life span. In contrast, deletion of the K36me2/3 demethylase Rph1 increases H3K36me3 within these genes, suppresses cryptic transcript initiation, and extends life span. We show that this aging phenomenon is conserved, as cryptic transcription also increases in old worms. We propose that epigenetic misregulation in aging cells leads to loss of transcriptional precision that is detrimental to life span, and, importantly, this acceleration in aging can be reversed by restoring transcriptional fidelity.
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Epigénesis Genética/fisiología , Histona Demetilasas/genética , Histona Demetilasas/metabolismo , Histonas/metabolismo , Longevidad/genética , Animales , Caenorhabditis elegans/enzimología , Caenorhabditis elegans/genética , Epigénesis Genética/genética , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica , Metilación , Mutación , Procesamiento Proteico-Postraduccional/genética , Proteínas Represoras/genética , Saccharomyces cerevisiae/enzimología , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
Mitochondrial disease diagnosis requires interrogation of both nuclear and mitochondrial (mtDNA) genomes for single-nucleotide variants (SNVs) and copy number alterations, both in the proband and often maternal relatives, together with careful phenotype correlation. We developed a comprehensive mtDNA sequencing test ('MitoGenome') using long-range PCR (LR-PCR) to amplify the full length of the mtDNA genome followed by next generation sequencing (NGS) to accurately detect SNVs and large-scale mtDNA deletions (LSMD), combined with droplet digital PCR (ddPCR) for LSMD heteroplasmy quantification. Overall, MitoGenome tests were performed on 428 samples from 394 patients with suspected or confirmed mitochondrial disease. The positive yield was 11% (43/394), including 34 patients with pathogenic or likely pathogenic SNVs (the most common being m.3243A > G in 8/34 (24%) patients), 8 patients with single LSMD, and 3 patients with multiple LSMD exceeding 10% heteroplasmy levels. Two patients with both LSMD and pathogenic SNV were detected. Overall, this LR-PCR/NGS assay provides a highly accurate and comprehensive diagnostic method for simultaneous mtDNA SNV detection at heteroplasmy levels as low as 1% and LSMD detection at heteroplasmy levels below 10%. Inclusion of maternal samples for variant classification and ddPCR to quantify LSMD heteroplasmy levels further enables accurate pathogenicity assessment and clinical correlation interpretation of mtDNA genome sequence variants and copy number alterations.
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Genoma Mitocondrial , Enfermedades Mitocondriales , ADN Mitocondrial/genética , Genoma Mitocondrial/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Mitocondrias/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genéticaRESUMEN
BACKGROUND: Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma. METHODS: In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed. FINDINGS: From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported. INTERPRETATION: Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma. FUNDING: National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Adulto , Ciclobutanos/administración & dosificación , Ciclobutanos/efectos adversos , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/patología , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Dosificación RadioterapéuticaRESUMEN
Senescence is a stable proliferation arrest, associated with an altered secretory pathway, thought to promote tumor suppression and tissue aging. While chromatin regulation and lamin B1 down-regulation have been implicated as senescence effectors, functional interactions between them are poorly understood. We compared genome-wide Lys4 trimethylation on histone H3 (H3K4me3) and H3K27me3 distributions between proliferating and senescent human cells and found dramatic differences in senescence, including large-scale domains of H3K4me3- and H3K27me3-enriched "mesas" and H3K27me3-depleted "canyons." Mesas form at lamin B1-associated domains (LADs) in replicative senescence and oncogene-induced senescence and overlap DNA hypomethylation regions in cancer, suggesting that pre-malignant senescent chromatin changes foreshadow epigenetic cancer changes. Hutchinson-Gilford progeria syndrome fibroblasts (mutant lamin A) also show evidence of H3K4me3 mesas, suggesting a link between premature chromatin changes and accelerated cell senescence. Canyons mostly form between LADs and are enriched in genes and enhancers. H3K27me3 loss is correlated with up-regulation of key senescence genes, indicating a link between global chromatin changes and local gene expression regulation. Lamin B1 reduction in proliferating cells triggers senescence and formation of mesas and canyons. Our data illustrate profound chromatin reorganization during senescence and suggest that lamin B1 down-regulation in senescence is a key trigger of global and local chromatin changes that impact gene expression, aging, and cancer.
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Envejecimiento/genética , Envejecimiento/patología , Cromatina/genética , Cromatina/metabolismo , Regulación de la Expresión Génica , Lamina Tipo B/genética , Lamina Tipo B/metabolismo , Línea Celular , Proliferación Celular , Células Cultivadas , Ensamble y Desensamble de Cromatina , Epigénesis Genética , Fibroblastos/citología , Fibroblastos/metabolismo , Fibroblastos/patología , Histonas/metabolismo , Humanos , Metilación , Progeria/patología , Estructura Terciaria de ProteínaRESUMEN
We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in â¼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.
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Facies , Marcha/genética , Haploinsuficiencia/genética , Discapacidad Intelectual/genética , Proteínas/genética , Convulsiones/genética , Proteínas Adaptadoras Transductoras de Señales , Secuencia de Aminoácidos , Secuencia de Bases , Preescolar , Deleción Cromosómica , Femenino , Crecimiento y Desarrollo/genética , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Mutación/genética , Proteínas/química , Estabilidad del ARN/genética , Convulsiones/complicaciones , SíndromeRESUMEN
BACKGROUND: Molecular profiling has become essential for tumor risk stratification and treatment selection. However, cancer genome complexity and technical artifacts make identification of real variants a challenge. Currently, clinical laboratories rely on manual screening, which is costly, subjective, and not scalable. We present a machine learning-based method to distinguish artifacts from bona fide single-nucleotide variants (SNVs) detected by next-generation sequencing from nonformalin-fixed paraffin-embedded tumor specimens. METHODS: A cohort of 11278 SNVs identified through clinical sequencing of tumor specimens was collected and divided into training, validation, and test sets. Each SNV was manually inspected and labeled as either real or artifact as part of clinical laboratory workflow. A 3-class (real, artifact, and uncertain) model was developed on the training set, fine-tuned with the validation set, and then evaluated on the test set. Prediction intervals reflecting the certainty of the classifications were derived during the process to label "uncertain" variants. RESULTS: The optimized classifier demonstrated 100% specificity and 97% sensitivity over 5587 SNVs of the test set. Overall, 1252 of 1341 true-positive variants were identified as real, 4143 of 4246 false-positive calls were deemed artifacts, whereas only 192 (3.4%) SNVs were labeled as "uncertain," with zero misclassification between the true positives and artifacts in the test set. CONCLUSIONS: We presented a computational classifier to identify variant artifacts detected from tumor sequencing. Overall, 96.6% of the SNVs received definitive labels and thus were exempt from manual review. This framework could improve quality and efficiency of the variant review process in clinical laboratories.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Aprendizaje Automático , Reacciones Falso Positivas , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Cisplatin-based concurrent chemoradiotherapy is currently considered to be the standard treatment regimen for patients with advanced nasopharyngeal carcinoma, but has well known side-effects such as gastrointestinal reactions, nephrotoxicity, and ototoxicity. Nedaplatin was developed to decrease the toxic effects induced by cisplatin, and in this trial we assessed whether a nedaplatin-based concurrent chemoradiotherapy regimen was non-inferior to a cisplatin-based regimen in patients with locoregional, stage II-IVB nasopharyngeal carcinoma. METHODS: We did an open-label, non-inferiority, phase 3, randomised, controlled trial at two centres in China. Patients aged 18-65 years with non-keratinising stage II-IVB (T1-4N1-3 or T3-4N0) nasopharyngeal carcinoma, a Karnofsky score of at least 70, and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either nedaplatin 100 mg/m2 or cisplatin 100 mg/m2 on days 1, 22, and 43 for three cycles concurrently with intensity-modulated radiotherapy. Randomisation was done manually using a computer-generated random number code and patients were stratified by treatment centre and clinical stage. Patients and clinicians were not masked to treatment allocation. The primary endpoint was progression-free survival at 2 years; non-inferiority was shown if the upper limit of the 95% CI for the difference in 2-year progression-free survival between the two groups did not exceed 10%. Analyses were by both intention to treat and per protocol, including all patients who received at least one complete cycle of chemotherapy. This trial is registered with ClinicalTrials.gov, number NCT01540136, and is currently in follow-up. FINDINGS: Between Jan 16, 2012, and July 16, 2014, we randomly assigned 402 patients to nedaplatin-based (n=201) or cisplatin-based (n=201) concurrent chemoradiotherapy. In the intention-to-treat population, 2-year progression-free survival was 89·9% (95% CI 85·8-94·0) in the cisplatin group and 88·0% (83·5-94·5) in the nedaplatin group, with a difference of 1·9% (95% CI -4·2 to 8·0; pnon-inferiority=0·0048). In the per-protocol analysis (cisplatin group, n=197; nedaplatin group, n=196), 2-year progression-free survival was 89·7% (95% CI 85·4-94·0) in the cisplatin group and 88·7% (84·2-94·5) in the nedaplatin group, with a difference of 1·0% (95% CI -5·2 to 7·0; pnon-inferiority=0·0020). A significantly higher frequency of grade 3 or 4 vomiting (35 [18%] of 198 in the cisplatin group vs 12 [6%] of 200 in the nedaplatin group, p<0·0001), nausea (18 [9%] vs four [2%], p=0·0021), and anorexia (53 [27%] vs 26 [13%], p=0·00070) was observed in the cisplatin group compared with the nedaplatin group. 11 (6%) patients in the nedaplatin group had grade 3 or 4 thrombocytopenia compared with four (2%) in the cisplatin group (p=0·065). Patients in the cisplatin group had a higher frequency of any grade or grade 3 or 4 late auditory or hearing toxicities than did patients in the nedaplatin group (grade 3 or 4: three [2%] in the nedaplatin group vs 11 [6%] in the cisplatin group, p=0·030). No patients died from treatment-related causes. INTERPRETATION: Our findings show that nedaplatin-based concurrent chemoradiotherapy represents an alternative doublet treatment strategy to cisplatin-based concurrent chemoradiotherapy for patients with locoregional, advanced nasopharyngeal carcinoma. Further investigations are needed to explore the potential use of this treatment as induction or adjuvant chemotherapy or in combination with other agents. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, Sun Yat-sen University Clinical Research 5010 Program, Sci-Tech Project Foundation of Guangzhou City, National Key Basic Research Program of China, Special Support Plan of Guangdong Province, Sci-Tech Project Foundation of Guangdong Province, Health & Medical Collaborative Innovation Project of Guangzhou City, National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, PhD Start-up Fund of Natural Science Foundation of Guangdong Province, Cultivation Foundation for the Junior Teachers in Sun Yat-sen University, and Fundamental Research Funds for the Central Universities.
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Antineoplásicos/uso terapéutico , Carcinoma/terapia , Quimioradioterapia , Cisplatino/uso terapéutico , Neoplasias Nasofaríngeas/terapia , Compuestos Organoplatinos/uso terapéutico , Adolescente , Adulto , Anciano , Anorexia/inducido químicamente , Antineoplásicos/efectos adversos , Carcinoma/secundario , Cisplatino/efectos adversos , Femenino , Trastornos de la Audición/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/patología , Náusea/inducido químicamente , Compuestos Organoplatinos/efectos adversos , Supervivencia sin Progresión , Dosificación Radioterapéutica , Trombocitopenia/inducido químicamente , Vómitos/inducido químicamente , Adulto JovenRESUMEN
PURPOSE: Hereditary hearing loss is highly heterogeneous. To keep up with rapidly emerging disease-causing genes, we developed the AUDIOME test for nonsyndromic hearing loss (NSHL) using an exome sequencing (ES) platform and targeted analysis for the curated genes. METHODS: A tiered strategy was implemented for this test. Tier 1 includes combined Sanger and targeted deletion analyses of the two most common NSHL genes and two mitochondrial genes. Nondiagnostic tier 1 cases are subjected to ES and array followed by targeted analysis of the remaining AUDIOME genes. RESULTS: ES resulted in good coverage of the selected genes with 98.24% of targeted bases at >15 ×. A fill-in strategy was developed for the poorly covered regions, which generally fell within GC-rich or highly homologous regions. Prospective testing of 33 patients with NSHL revealed a diagnosis in 11 (33%) and a possible diagnosis in 8 cases (24.2%). Among those, 10 individuals had variants in tier 1 genes. The ES data in the remaining nondiagnostic cases are readily available for further analysis. CONCLUSION: The tiered and ES-based test provides an efficient and cost-effective diagnostic strategy for NSHL, with the potential to reflex to full exome to identify causal changes outside of the AUDIOME test.
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Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Patología Molecular , Exoma/genética , Femenino , Pérdida Auditiva Sensorineural/fisiopatología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Mutación , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de ADN , Secuenciación del ExomaRESUMEN
In the published version of this article, the degree of author Bo Zhang was incorrectly listed as PhD. The correct degree is BS.
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PurposeThe objective of this study was to assess the ability of our laboratory's exome-sequencing test to detect known and novel sequence variants and identify the critical factors influencing the interpretation of a clinical exome test.MethodsWe developed a two-tiered validation strategy: (i) a method-based approach that assessed the ability of our exome test to detect known variants using a reference HapMap sample, and (ii) an interpretation-based approach that assessed our relative ability to identify and interpret disease-causing variants, by analyzing and comparing the results of 19 randomly selected patients previously tested by external laboratories.ResultsWe demonstrate that this approach is reproducible with >99% analytical sensitivity and specificity for single-nucleotide variants and indels <10 bp. Our findings were concordant with the reference laboratories in 84% of cases. A new molecular diagnosis was applied to three cases, including discovery of two novel candidate genes.ConclusionWe provide an assessment of critical areas that influence interpretation of an exome test, including comprehensive phenotype capture, assessment of clinical overlap, availability of parental data, and the addressing of limitations in database updates. These results can be used to inform improvements in phenotype-driven interpretation of medical exomes in clinical and research settings.
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Exactitud de los Datos , Exoma , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis de Secuencia de ADN , Biología Computacional/métodos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Genómica/métodos , Genómica/normas , Humanos , Mutación INDEL , Polimorfismo de Nucleótido Simple , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
In the published version of this article, the name of the 18th author was misspelled as Minjie Lou. The correct name is Minjie Luo. The authors regret the error.
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BACKGROUND: To evaluate the prognostic significance of pretreatment quality of life for patients with nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. METHODS: We performed a prospective, longitudinal study on 554 newly diagnosed patients with NPC from April 2011 to January 2015. A total of 501 consecutive NPC patients were included. Patients were asked to complete the EORTC QLQ-C30 (version 3.0) and QLQ-H&N35 questionnaires before treatment. RESULTS: Global health status among QLQ-C30 correlates with EBV DNA(P = 0.019). In addition, pretreatment appetite loss was significantly correlated with EBV DNA(P = 0.02). Pretreatment teeth, opening mouth, feeding tube was significantly correlated with EBV DNA, with P value of 0.003, < 0.0001, and 0.031, respectively. In multivariate analysis, pretreatment cognitive functioning of QLQ-C30 was significantly associated with LRFS, with HR of 0.971(95%CI 0.951-0.990), P = 0.004. Among scales of QLQ-H&N35 for multivariate analysis, pretreatment teeth (P = 0.026) and felt ill (P = 0.012) was significantly associated with PFS, with HR of 0.984 (95%CI 0.971-.998) and 1.004 (95%CI 1.001-1.007), respectively. Felt ill of QLQ-H&N35 was significantly associated with DMFS, with HR of 1.004(95%CI 1.000-1.007), P = 0.043. There is no QoL scale significantly associated with OS after multivariate analysis. CONCLUSIONS: In conclusion, our analysis confirms that pretreatment teeth and felt ill was significantly associated with PFS in NPC patients treated with IMRT. In addition, the posttreatment EBV DNA was significantly associated with OS.
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Carcinoma/epidemiología , Carcinoma/radioterapia , Neoplasias Nasofaríngeas/epidemiología , Neoplasias Nasofaríngeas/radioterapia , Pronóstico , Radioterapia de Intensidad Modulada , Adolescente , Adulto , Anciano , Carcinoma/tratamiento farmacológico , Carcinoma/patología , Niño , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Estudios Prospectivos , Calidad de Vida , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Human neurodegenerative diseases have the temporal hallmark of afflicting the elderly population. Ageing is one of the most prominent factors to influence disease onset and progression, yet little is known about the molecular pathways that connect these processes. To understand this connection it is necessary to identify the pathways that functionally integrate ageing, chronic maintenance of the brain and modulation of neurodegenerative disease. MicroRNAs (miRNA) are emerging as critical factors in gene regulation during development; however, their role in adult-onset, age-associated processes is only beginning to be revealed. Here we report that the conserved miRNA miR-34 regulates age-associated events and long-term brain integrity in Drosophila, providing a molecular link between ageing and neurodegeneration. Fly mir-34 expression exhibits adult-onset, brain-enriched and age-modulated characteristics. Whereas mir-34 loss triggers a gene profile of accelerated brain ageing, late-onset brain degeneration and a catastrophic decline in survival, mir-34 upregulation extends median lifespan and mitigates neurodegeneration induced by human pathogenic polyglutamine disease protein. Some of the age-associated effects of miR-34 require adult-onset translational repression of Eip74EF, an essential ETS domain transcription factor involved in steroid hormone pathways. Our studies indicate that miRNA-dependent pathways may have an impact on adult-onset, age-associated events by silencing developmental genes that later have a deleterious influence on adult life cycle and disease, and highlight fly miR-34 as a key miRNA with a role in this process.
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Envejecimiento/genética , Modelos Animales de Enfermedad , Drosophila melanogaster/genética , Drosophila melanogaster/fisiología , Regulación de la Expresión Génica/genética , MicroARNs/genética , Enfermedades Neurodegenerativas/genética , Animales , Encéfalo/metabolismo , Encéfalo/patología , Regulación hacia Abajo , Proteínas de Drosophila/biosíntesis , Proteínas de Drosophila/genética , Femenino , Calor , Humanos , Longevidad/genética , Masculino , Mutación , Enfermedades Neurodegenerativas/patología , Biosíntesis de Proteínas , ARN Mensajero/análisis , ARN Mensajero/genética , Análisis de Supervivencia , Factores de Tiempo , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Regulación hacia ArribaRESUMEN
To compare intensity-modulated radiotherapy (IMRT) with cisplatin (CDDP) versus cetuximab (CTX) and nimotuzumab (NTZ) for Stage II-IVb Nasopharyngeal Carcinoma (NPC). A total of 1,837 patients with stage II-IVb NPC who received IMRT plus CTX or NTZ, or CDDP between January 2009 and December 2013 were included in the current analysis. Using propensity scores to adjust for potential prognostic factors, a well-balanced cohort of 715 patients was created by matching each patient who underwent IMRT plus concomitant NTZ/CTX with four patients who underwent IMRT plus concomitant CDDP (1:4). Efficacy and safety were compared between the CTX/NTZ and CDDP groups of this well-balanced cohort. Furthermore, we conducted multivariate analysis and subgroup analysis based on all the 1,837 eligible cases. There was no significant difference between CTX/NTZ group and CDDP group in terms of DFS (3-year, 86.7% vs. 86.2%, p > 0.05), LRRFS (96.2% vs. 96.3%, p > 0.05), DMFS (91.1% vs. 92.3%, p > 0.05) and OS (91.7% vs. 91.9%, p > 0.05). Subgroup analysis demonstrated a significant interaction effect between patients with IMRT plus CTX/NTZ and N3 node stage on LRRFS with the highest risk of loco-regional relapse (HR 8.85, p = 0.001). Significantly increased hematologic toxicities, gastrointestinal reactions were observed in the CDDP group (p < 0.05). Patients of 3.4-4.7% experienced severe hematologic toxicities during the treatment with concomitant CTX and NTZ. Increased rate of CTX related-skin reaction and mucositis was observed in the CTX group. CTX/NTZ used concurrently with IMRT may be comparable to those of the standard CDDP-IMRT combination for maximizing survival for patients with stage II-IVb NPC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/uso terapéutico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cetuximab/administración & dosificación , Cetuximab/efectos adversos , Quimioradioterapia , Cisplatino/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/patología , Estadificación de Neoplasias , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Estudios Retrospectivos , Adulto JovenRESUMEN
Purpose To evaluate the prognostic value of the restaging system after neoadjuvant chemotherapy (NACT) in patients with advanced-stage nasopharyngeal carcinoma (NPC). Materials and Methods This study was approved by the clinical research committee and a written informed consent was required before enrolling in the study. Prospectively enrolled were 412 consecutive patients with stage III-IVb NPC treated with NACT followed by concurrent chemotherapy and radiation therapy. Patients were staged before NACT and restaged after NACT. The progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated with the Kaplan-Meier method, and differences were compared by using the log-rank test. Results Post-NACT T classification (PFS, P = .001) and N classification (PFS, P < .001; DMFS, P = .001) resulted in better survival curve separations than pre-NACT T classification and N classification. Patients downstaged from N2-N3 to N0-N1 disease had a better prognosis than did patients who continued to have N2-N3 diseases (3-year PFS, 83.8% vs 66.6%, P = .001; 3-year DMFS, 88.0% vs 78.4%, P = .026). Multivariate analysis revealed that post-NACT T classification (hazard ratio [HR] = 1.67; 95% confidence interval [CI]: 1.18, 2.36; P = .003) and post-NACT N classification (HR = 1.54; 95% CI: 1.17, 2.03; P = .002) were independent prognostic factors for PFS; also, post-NACT N classification (HR = 1.48; 95% CI: 1.05, 2.07; P = .025) was an independent prognostic factor for DMFS. Multivariate analysis in patients with N2-N3 disease demonstrated that the N downstaging effects of NACT was the only independent prognostic factor for PFS (HR = 0.48; 95% CI: 0.29, 0.81; P = .006) and DMFS (HR = 0.52; 95% CI: 0.28, 0.97; P = .039). Conclusion The post-NACT stage is more representative of prognosis than the pre-NACT stage in advanced-stage NPC patients, which suggests that major clinical decisions should be based on the post-NACT stage. © RSNA, 2016 Online supplemental material is available for this article.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Imagen por Resonancia Magnética/métodos , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Adulto , Anciano , Biomarcadores de Tumor/análisis , Carcinoma , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Docetaxel , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/radioterapia , Terapia Neoadyuvante , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Radioterapia de Intensidad Modulada , Tasa de Supervivencia , Taxoides , Resultado del TratamientoRESUMEN
INTRODUCTION: RASopathies include disorders generally characterized by developmental delay, specific heart defects, short stature, cardiac hypertrophy, and facial dysmorphisms. Next-generation sequencing (NGS)-based panels have widespread acceptance as a diagnostic tool for RASopathies. MATERIALS AND METHODS: The first 126 patients evaluated by clinical examination and the NGS RASopathy panel at the Children's Hospital of Philadelphia were enrolled. We calculated diagnosis rate, correlated reported clinical findings with positive or negative test results, and identified final molecular diagnoses in 28/96 patients who tested negative for RASopathies. RESULTS: Twenty-four patients had pathogenic variants on the RASopathy panel, for a diagnostic yield of 19%. Reported features of pulmonic stenosis and ptosis were significantly correlated with a positive test result; no reported features were significantly correlated with a negative test result. We identified 27 different alternative diagnoses for patients originally suspected of having RASopathies. DISCUSSION: This study provides information that can assist in guiding differential diagnosis and genetic testing for patients suspected of having a RASopathy disorder.Genet Med advance online publication 20 October 2016.