RESUMO
Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.
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Epilepsia , Transtornos do Neurodesenvolvimento , Ubiquitina-Proteína Ligases , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Deficiências do Desenvolvimento/genética , Metilação de DNA/genética , Epigênese Genética , Epilepsia/genética , Histonas/metabolismo , Histonas/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
ARID1B is the most frequently mutated gene in Coffin-Siris syndrome (CSS). To date, the vast majority of causative variants reported in ARID1B are truncating, leading to nonsense-mediated mRNA decay. In the absence of experimental data, only few ARID1B amino acid substitutions have been classified as pathogenic, mainly based on clinical data and their de novo occurrence, while most others are currently interpreted as variants of unknown significance. The present study substantiates the pathogenesis of ARID1B non-truncating/NMD-escaping variants located in the SMARCA4-interacting EHD2 and DNA-binding ARID domains. Overexpression assays in cell lines revealed that the majority of EHD2 variants lead to protein misfolding and formation of cytoplasmic aggresomes surrounded by vimentin cage-like structures and co-localizing with the microtubule organisation center. ARID domain variants exhibited not only aggresomes, but also nuclear aggregates, demonstrating robust pathological effects. Protein levels were not compromised, as shown by quantitative western blot analysis. In silico structural analysis predicted the exposure of amylogenic segments in both domains due to the nearby variants, likely causing this aggregation. Genome-wide transcriptome and methylation analysis in affected individuals revealed expression and methylome patterns consistent with those of the pathogenic haploinsufficiency ARID1B alterations in CSS cases. These results further support pathogenicity and indicate two approaches for disambiguation of such variants in everyday practice. The few affected individuals harbouring EHD2 non-truncating variants described to date exhibit mild CSS clinical traits. In summary, this study paves the way for the re-evaluation of previously unclear ARID1B non-truncating variants and opens a new era in CSS genetic diagnosis.
Assuntos
Proteínas de Ligação a DNA , Face , Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Pescoço , Fatores de Transcrição , Humanos , Deficiência Intelectual/genética , Micrognatismo/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Deformidades Congênitas da Mão/genética , Pescoço/anormalidades , Face/anormalidades , Anormalidades Múltiplas/genética , Mutação , Masculino , Agregados ProteicosRESUMO
Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up.
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Anormalidades Múltiplas , Face/anormalidades , Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Adulto , Humanos , Criança , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico , Micrognatismo/genética , Micrognatismo/diagnóstico , Deformidades Congênitas da Mão/genética , Pescoço/anormalidades , Fenótipo , DNA Helicases/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genéticaRESUMO
CTNND2 encodes δ-catenin, a component of an adherens junction complex, and plays an important role in neuronal structure and function. To date, only heterozygous loss-of-function CTNND2 variants have been associated with mild neurodevelopmental delay and behavioral anomalies, a condition, which we named Rauch-Azzarello syndrome. Here, we report three siblings of a consanguineous family of Syrian descent with a homozygous deletion encompassing the last 19 exons of CTNND2 predicted to disrupt the transcript. All presented with severe neurodevelopmental delay with absent speech, profound motor delay, stereotypic behavior, microcephaly, short stature, muscular hypotonia with lower limb hypertonia, and variable eye anomalies. The parents and the fourth sibling were heterozygous carriers of the deletion and exhibited mild neurodevelopmental impairment resembling that of the previously described heterozygous individuals. The present study unveils a severe manifestation of CTNND2-associated Rauch-Azzarello syndrome attributed to biallelic loss-of-function aberrations, clinically distinct from the already described mild presentation of heterozygous individuals. Furthermore, we demonstrate novel clinical features in homozygous individuals that have not been reported in heterozygous cases to date.
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delta Catenina , Transtornos do Neurodesenvolvimento , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Alelos , Cateninas/genética , Consanguinidade , Homozigoto , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Fenótipo , Deleção de Sequência/genéticaRESUMO
The disconnected (disco)-interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase-associated protein 1 (DMAP1) binding domain, Acyl-CoA synthetase domain and AMP-binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco-interacting protein 2 homolog A (DIP2A), Disco-interacting protein 2 homolog B (DIP2B), and Disco-interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss-of-function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss-of-function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10-24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss-of-function variants in DIP2C with a neurocognitive phenotype.
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Haploinsuficiência , Transtornos do Desenvolvimento da Linguagem , Humanos , Masculino , Feminino , Haploinsuficiência/genética , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Pré-Escolar , Criança , Lactente , Fenótipo , Predisposição Genética para DoençaRESUMO
BACKGROUND: Loss-of-function variants in MME (membrane metalloendopeptidase) are a known cause of recessive Charcot-Marie-Tooth Neuropathy (CMT). A deep intronic variant, MME c.1188+428A>G (NM_000902.5), was identified through whole genome sequencing (WGS) of two Australian families with recessive inheritance of axonal CMT using the seqr platform. MME c.1188+428A>G was detected in a homozygous state in Family 1, and in a compound heterozygous state with a known pathogenic MME variant (c.467del; p.Pro156Leufs*14) in Family 2. AIMS: We aimed to determine the pathogenicity of the MME c.1188+428A>G variant through segregation and splicing analysis. METHODS: The splicing impact of the deep intronic MME variant c.1188+428A>G was assessed using an in vitro exon-trapping assay. RESULTS: The exon-trapping assay demonstrated that the MME c.1188+428A>G variant created a novel splice donor site resulting in the inclusion of an 83 bp pseudoexon between MME exons 12 and 13. The incorporation of the pseudoexon into MME transcript is predicted to lead to a coding frameshift and premature termination codon (PTC) in MME exon 14 (p.Ala397ProfsTer47). This PTC is likely to result in nonsense mediated decay (NMD) of MME transcript leading to a pathogenic loss-of-function. INTERPRETATION: To our knowledge, this is the first report of a pathogenic deep intronic MME variant causing CMT. This is of significance as deep intronic variants are missed using whole exome sequencing screening methods. Individuals with CMT should be reassessed for deep intronic variants, with splicing impacts being considered in relation to the potential pathogenicity of variants.
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Doença de Charcot-Marie-Tooth , Metaloendopeptidases , Splicing de RNA , Adulto , Feminino , Humanos , Masculino , Doença de Charcot-Marie-Tooth/genética , Íntrons , Metaloendopeptidases/genética , Mutação , LinhagemRESUMO
The expression of genes encompasses their transcription into mRNA followed by translation into protein. In recent years, next-generation sequencing and mass spectrometry methods have profiled DNA, RNA and protein abundance in cells. However, there are currently no reference standards that are compatible across these genomic, transcriptomic and proteomic methods, and provide an integrated measure of gene expression. Here, we use synthetic biology principles to engineer a multi-omics control, termed pREF, that can act as a universal molecular standard for next-generation sequencing and mass spectrometry methods. The pREF sequence encodes 21 synthetic genes that can be in vitro transcribed into spike-in mRNA controls, and in vitro translated to generate matched protein controls. The synthetic genes provide qualitative controls that can measure sensitivity and quantitative accuracy of DNA, RNA and peptide detection. We demonstrate the use of pREF in metagenome DNA sequencing and RNA sequencing experiments and evaluate the quantification of proteins using mass spectrometry. Unlike previous spike-in controls, pREF can be independently propagated and the synthetic mRNA and protein controls can be sustainably prepared by recipient laboratories using common molecular biology techniques. Together, this provides a universal synthetic standard able to integrate genomic, transcriptomic and proteomic methods.
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DNA , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , DNA/genética , Genômica , RNARESUMO
BACKGROUND: TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle. METHOD: To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling. RESULTS: We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4-mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression. CONCLUSION: Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model.
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Hiperventilação , Deficiência Intelectual , Fator de Transcrição 4 , Hiperventilação/genética , Hiperventilação/metabolismo , Hiperventilação/fisiopatologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Fator de Transcrição 4/genética , Fator de Transcrição 4/metabolismo , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Fácies , Criança , Éxons , Músculo Quadríceps/metabolismo , Músculo Quadríceps/patologiaRESUMO
Fertilization with nickel (Ni) can positively affect plant development due to the role of this micronutrient in nitrogen (N) metabolism, namely, through urease and NiFe-hydrogenase. Although the application of Ni is an emerging practice in modern agriculture, its effectiveness strongly depends on the chosen application method, making further research in this area essential. The individual and combined effects of different Ni application methods-seed treatment, leaf spraying and/or soil fertilization-were investigated in soybean plants under different edaphoclimatic conditions (field and greenhouse). Beneficial effects of the Soil, Soil + Leaf and Seed + Leaf treatments were observed, with gains of 7 to 20% in biological nitrogen fixation, 1.5-fold in ureides, 14% in shoot dry weight and yield increases of up to 1161 kg ha-1. All the Ni application methods resulted in a 1.1-fold increase in the SPAD index, a 1.2-fold increase in photosynthesis, a 1.4-fold increase in nitrogenase, and a 3.9-fold increase in urease activity. Edaphoclimatic conditions exerted a significant influence on the treatments. The integrated approaches, namely, leaf application in conjunction with soil or seed fertilization, were more effective for enhancing yield in soybean cultivation systems. The determination of the ideal method is crucial for ensuring optimal absorption and utilization of this micronutrient and thus a feasible and sustainable management technology. Further research is warranted to establish official guidelines for the application of Ni in agricultural practices.
Assuntos
Fertilizantes , Glycine max , Níquel , Solo , Glycine max/crescimento & desenvolvimento , Glycine max/efeitos dos fármacos , Glycine max/metabolismo , Fertilizantes/análise , Solo/química , Urease/metabolismo , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Folhas de Planta/efeitos dos fármacos , Fixação de Nitrogênio/efeitos dos fármacos , Nitrogênio/metabolismo , Fotossíntese/efeitos dos fármacos , Sementes/crescimento & desenvolvimento , Sementes/efeitos dos fármacos , Sementes/metabolismo , Agricultura/métodosRESUMO
Numerous contiguous gene deletion syndromes causing neurodevelopmental disorders have previously been defined using cytogenetics for which only in the current genomic era the disease-causing genes have become elucidated. One such example is deletion at Xq22.2, previously associated with a neurodevelopmental disorder which has more recently been found to be caused by de novo loss-of-function variants in TCEAL1. So far, a single study reported six unrelated individuals with this monogenetic disorder, presenting with syndromic features including developmental delay especially affecting expressive speech, intellectual disability, autistic-like behaviors, hypotonia, gait abnormalities and mild facial dysmorphism, in addition to ocular, gastrointestinal, and immunologic abnormalities. Here we report on four previously undescribed individuals, including two adults, with de novo truncating variants in TCEAL1, identified through trio exome or genome sequencing, further delineating the phenotype of the TCEAL1-related disorder. Whereas overall we identify similar features compared to the original report, we also highlight features in our adult individuals including hyperphagia, obesity, and endocrine abnormalities including hyperinsulinemia, hyperandrogenemia, and polycystic ovarian syndrome. X chromosome inactivation and RNA-seq studies further provide functional insights in the molecular mechanisms. Together this report expands the phenotypic and molecular spectrum of the TCEAL1-related disorder which will be useful for counseling of newly identified individuals and their families.
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Transtorno Autístico , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Adulto , Feminino , Humanos , Transtornos do Neurodesenvolvimento/genética , Deficiência Intelectual/genética , Transtorno Autístico/genética , Sequência de Bases , Fenótipo , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).
Assuntos
Angiotensinogênio , Humanos , Angiotensinogênio/genética , Masculino , Adolescente , Sistema Renina-Angiotensina/genética , Sistema Renina-Angiotensina/fisiologia , Progressão da Doença , Renina/genética , Renina/sangue , Renina/metabolismo , Mutação de Sentido Incorreto/genética , Sequenciamento do Exoma/métodos , Feminino , Túbulos Renais Proximais/anormalidades , Anormalidades UrogenitaisRESUMO
Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney disease in children. Although only 20% of cases can be genetically explained, the majority remain without an identified underlying etiology. The neurodevelopmental disorder Chung-Jansen syndrome (CHUJANS) is caused by haploinsufficiency of Pleckstrin homology domain-interacting protein (PHIP) and was previously associated with genital malformations. Anecdotal coincidence of CHUJANS and CAKUT prompted us to investigate whether urorenal malformations are part of the phenotypic spectrum of CHUJANS. Methods: Analysis of existing CHUJANS and CAKUT cohorts, consulting matchmaking platforms, and systematic literature review to look for additional patients with both CHUJANS and CAKUT. Prenatal expression studies in murine and human renal tissues to investigate the role for PHIP in kidney development. Results: We identified 4 novel and 8 published cases, indicating variable expressivity with a urorenogenital trait frequency of 5% to 35%. The prenatal expression studies supported a role for PHIP in normal kidney and urinary tract development. Conclusion: Pathogenic PHIP gene variants should be considered as causative in patients with syndromal CAKUT. Conversely, patients with CHUJANS should be clinically evaluated for urorenogenital manifestations. Because neurodevelopmental disorders are often associated with kidney phenotypes, an interdisciplinary re-evaluation offers promise in identifying incompletely penetrant kidney associations and uncovering novel molecular mechanisms of disturbed nephrogenesis.
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Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.
Assuntos
Histonas , Fenótipo , Humanos , Masculino , Feminino , Histonas/genética , Criança , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Pré-Escolar , Adolescente , Adulto , Deficiência Intelectual/genética , Deficiência Intelectual/patologiaRESUMO
Molecular Tumor Boards (MTBs) converge state-of-the-art next-generation sequencing (NGS) methods with the expertise of an interdisciplinary team consisting of clinicians, pathologists, human geneticists, and molecular biologists to provide molecularly informed guidance in clinical decision making to the treating physician. In the present study, we particularly focused on elucidating the factors impacting on the clinical translation of MTB recommendations, utilizing data generated from gene panel mediated comprehensive genomic profiling (CGP) of 554 patients at the MTB of the Comprehensive Cancer Center Erlangen, Germany, during the years 2016 to 2020. A subgroup analysis of cases with available follow-up data (n = 332) revealed 139 cases with a molecularly informed MTB recommendation, which was successfully implemented in the clinic in 44 (31.7%) of these cases. Here, the molecularly matched treatment was applied in 45.4% (n = 20/44) of cases for ≥6 months and in 25% (n = 11/44) of cases for 12 months or longer (median time to treatment failure, TTF: 5 months, min: 1 month, max: 38 months, ongoing at data cut-off). In general, recommendations were preferentially implemented in the clinic when of high (i.e., tier 1) clinical evidence level. In particular, this was the case for MTB recommendations suggesting the application of PARP, PIK3CA, and IDH1/2 inhibitors. The main reason for non-compliance to the MTB recommendation was either the application of non-matched treatment modalities (n = 30)/stable disease (n = 7), or deteriorating patient condition (n = 22)/death of patient (n = 9). In summary, this study provides an insight into the factors affecting the clinical implementation of molecularly informed MTB recommendations, and careful considerations of these factors may guide future processes of clinical decision making.
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SUMMARY Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic forms of diabetes mellitus with distinct clinical features. Clinical dermatological phenotypes in MODY patients are very rare in literature. This report describes a patient with HNF1A-MODY presenting with necrobiosis lipoidica (NL) and granuloma annulare (GA). A 39-year-old asymptomatic woman, with atypical diabetes diagnosed at age 17, has a confirmed HNF1A mutation on exon 2 (c.392G>A, p.R131Q), classified as Pathogenic by the ACMG guidelines. She has reasonable metabolic control using oral anti-diabetic medications and has no chronic diabetic complications. Clinical and histologic diagnoses of both NL and GA were made. We discuss these conditions and their association with MODY.
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ABSTRACT The aim of this study was to compare low- and high-viscosity bulk-fill composites for Knoop microhardness (KHN), microtensile bond strength (MTBS) to dentin in occlusal cavities, and fracture strength (FS) in molars with mesialocclusal- distal restoration. Disk-shaped samples with different thicknesses (2 or 4 mm) of low-viscosity (SDR Flow, Dentsply) and high-viscosity bulk-fill composites (Filtek BulkFill, 3M ESPE; and Tetric-N Ceram Bulk Fill, Ivoclar Vivadent) were prepared for top and bottom KHN analysis (n=10). MTBS to dentin and fracture pattern was evaluated in human molars with occlusal cavities restored with (n=10): conventional nanocomposite (Z350XT, 3M ESPE), low-viscosity (Filtek Bulk-fill Flow, 3M ESPE) or high-viscosity bulk-fill composites (Filtek BulkFill). The FS and fracture pattern of human molar with mesial-occlusal-distal restorations submitted or not to thermomechanical cycling were investigated (n=10) using: intact tooth (control), and restoration based on conventional microhybrid composite (Z250, 3M ESPE), low-viscosity (SDR Flow) or high-viscosity bulk-fill composites (Filtek BulkFill). The data were submitted to split-plot ANOVA (KHN), one-way ANOVA (MTBS), two-way ANOVA (FS) followed by Tukey's test (α=0.05). For KHN, there was no significant difference for the resin composites between the top and bottom. For MTBS, no significant differences among the materials were detected; however, the low-viscosity composite presented lower frequency of adhesive failures. For FS, there was no significant difference between composites and intact tooth regardless of thermomechanical cycling. Low- and high-viscosity bulk-fill composites have comparable microhardness and microtensile bond strength when used in occlusal restorations. Likewise, the bulk-fill composites present similar fracture strength in molars with mesio-occlusal-distal restorations.
RESUMO O objetivo deste estudo foi comparar resinas compostas bulk- -fill de baixa e alta viscosidade quanto à microdureza Knoop (KHN), resistência de união a microtração (MTBS) em cavidades oclusais e carga à fratura (FS) em molares com restauração mesio-oclusal-distal. Amostras em forma de disco com diferentes espessuras (2 ou 4 mm) de resinas bulk-fill de baixa viscosidade (SDR Flow, Dentsply) e alta viscosidade (Filtek BulkFill, 3M ESPE; e Tetric-N Ceram Bulk Fill, Ivoclar Vivadent) foram obtidas para análise de KHN no topo e na base (n = 10). A MTBS em dentina e o padrão de fratura foram avaliados em molares humanos com cavidades oclusais restauradas com (n = 10): resina composta nanoparticulada convencional (Z350XT, 3M ESPE), resinas bulk-fill de baixa viscosidade (Filtek Bulk-fill Flow, 3M ESPE) ou alta viscosidade (Filtek BulkFill). Foram investigados a FS e o padrão de fratura de molares humanos em restaurações mesial-ocluso-distais sub metidas ou não à ciclagem termomecânica (n = 10), sendo: dente íntegro (controle), e restaurações baseadas em resina composta microhíbrida convencional (Z250, 3M ESPE); resinas bulk-fill de baixa viscosidade (SDR Flow) ou alta viscosidade (Filtek BulkFill). Os dados foram submetidos a split-plot ANOVA (KHN), one-way ANOVA (MTBS), two-way ANOVA (FS) seguidos do teste de Tukey (α = 0,05). Para KHN, não houve diferença significativa entre o topo e a base para as resinas compostas. Para MTBS, não foram detectadas diferenças significativas entre os materiais; entretanto, a resina bulk-fill de baixa viscosidade apresentou menor frequência de falhas adesivas. Para FS, não houve diferença significativa entre os materiais e o dente íntegro, independentemente da ciclagem termomecânica. As resinas bulk-fill de baixa e alta viscosidade têm microdureza e resistência à microtração comparáveis quando usados em restaurações oclusais. Da mesma forma, as resinas bulk-fill apresentam resistência à fratura semelhante em molares com restaurações mesio-oclusal-distais.
RESUMO
The properly measurement of gas emissions and nutrient availability to crops using technologies such as polymer-coated urea are required to monitored the possible nitrogen (N) fertilizer pollution in the environment. This study aimed to evaluate N loss through ammonia volatilization from polymer-coated and conventional urea in maize field trials under two different environments. The study was carried out in Chapadão do Sul and Selvíria State of Mato Grosso do Sul evaluating the first and second harvest of maize plants. Nitrogen fertilizers were applied as polymer-coated, conventional urea and control plots were used as reference to evaluate N loss through volatilization (3, 6, 9, 12, and 15 days after fertilizer application). The peak of ammonia volatilization was observed during the first three days after fertilizer application corresponding up to 44% of total N supplied. Polymer-coated urea had promising results showing less ammonia volatilization during the first crop. However, the same result was not observed for second crop.
A necessidade de mensurar adequadamente a emissão de gases e também o fornecimento de nutrientes às culturas por tecnologias como o revestimento da ureia com polímeros são necessários para monitar a possível poluição de fertilizantes nitrogenados no ambiente. Assim, o objetivo desse trabalho foi determinar as perdas de nitrogênio (N) por volatilização pela ureia convencional e ureia revestida compolímero, em duas épocas de cultivo do milho (Zea mays L.), em duas regiões do cerrado brasileiro. Os trabalhos foram desenvolvidos em Chapadão do Sul e Selvíria, Mato Grosso do Sul - Brasil, na cultura do milho "primeira safra" e "segunda safra", respectivamente. Os tratamentos foram constituídos pela ureia e ureia revestida por polímero aplicada em cobertura além de um tratamento controle (sem N) em função de épocas de monitoramento das perdas de N por volatilização (3, 6, 9, 12 e 15 dias após a adubação) com 5 repetições. Foi mensurado as perdas de N por volatilização nas respectivas épocas e o total acumulado no período. O pico de volatilização ocorreu durante os três primeiros dias, atingindo patamares de até 44% do total de N fornecido. O revestimento da ureia com polímeros apresentou resultados promissores, diminuindo as perdas de N-NH3 por volatilização no milho "primeira safra". Todavia, os resultados obtidos no milho "segunda safra" não permitem generalizar tais benefícios.
Assuntos
Polímeros , Ureia , Zea mays , Fertilizantes , Amônia , PradariaRESUMO
ABSTRACT: To facilitate seeding process of forage species, a common practice is to mix seeds with fertilizers in monocropping and intercropping or in implementing integrated livestock production systems. However, in prolonged periods of contact, the fertilizer's salinity and acidity negatively affect the seeds' physiological quality. Therefore, this study intends to verify the effect of ten periods (0, 3, 6, 12, 24, 36, 48, 72, 96, and 120 hours) of exposure to granular NPK fertilizer 04-30-16 on the vigor and germination of Urochloa brizantha cv. Marandu seeds. The experiment was conducted in a completely randomized design with three replication. The fertilizer and seed mixture registered a negative effect on seed moisture content, electrical conductivity, emergence, emergence speed index, and seedling and radicle length as the period of exposure to the fertilizer increased from 3 to 120 hours.
RESUMO: Para facilitar o processo de semeadura de espécies forrageiras é comum a mistura de sementes com fertilizantes, seja em cultivo exclusivo, consorciado ou na implantação de sistemas integrados de produção agropecuária. Entretanto, a salinidade e acidez do fertilizante, em longos períodos de mistura, supõe-se ação deletéria na qualidade fisiológica das sementes. Dessa forma, o estudo teve como objetivo verificar o efeito de dez tempos de mistura (0, 3, 6, 12, 24, 36, 48, 72, 96 e 120 horas) do fertilizante granulado NPK 04-30-16, sobre vigor e germinação de sementes de Urochloa brizantha cv. Marandu. O experimento foi conduzido em delineamento experimental inteiramente casualizado, com três repetições. Houve efeito negativo da mistura de fertilizante com as sementes para o grau de umidade, condutividade elétrica, emergência, índice de velocidade de emergência, comprimentos de plântula e de radícula em função do incremento do tempo de mistura com fertilizante, de 3 a 120 horas de exposição.