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1.
Anticancer Res ; 40(1): 413-419, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892595

RESUMO

BACKGROUND/AIM: In patients with lung cancer, there has been no study that treated 'distant metastases' as 'metastatic patterns'. This study aimed to evaluate if specific 'metastatic patterns' exist in lung cancer patients. PATIENTS AND METHODS: Data were collected from lung cancer patients between 2009 and 2018. Metastatic patterns were analyzed using cluster analysis in patients with epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, those with small cell lung cancer (SCLC), and those with squamous cell lung cancer (SqCLC). RESULTS: In 313 patients (127 patients with EGFR mutation, 87 patients with SCLC, and 99 patients with SqCLC), metastatic patterns existed in each of the three subset groups, and metastatic patterns of these groups were statistically different. CONCLUSION: The knowledge of the metastatic patterns might be useful for clinical practice in the foreseeable future, as it enables a more efficient detection of metastatic disease through imaging, and a more effective treatment at predicted metastatic sites.


Assuntos
Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/genética , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Metástase Neoplásica , Probabilidade
2.
Anticancer Res ; 40(1): 421-426, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892596

RESUMO

BACKGROUND/AIM: Distant organ metastases do not occur at random in lung cancer. A retrospective study was conducted in order to evaluate 1) what kinds of metastatic patterns exist in three different types of lung cancer, and 2) whether metastatic patterns affected prognosis in the different types of lung cancer. PATIENTS AND METHODS: Data were collected from all consecutive patients with diagnosed lung cancer between April 2009 and October 2018 in our hospitals. Cluster analysis was performed to classify patients. Kaplan-Meier analysis, log-rank test, and Cox proportional hazards model were used. RESULTS: Epidermal growth factor-mutated adenocarcinoma, small cell lung cancer, and squamous cell lung cancer had different 'metastatic patterns', survival, and unfavorable prognostic factors, respectively. CONCLUSION: There might be different metastatic patterns, survival, and unfavorable prognostic factors in each pathological and genetic type of lung cancer. It is worthwhile carrying out diagnostic imaging and treatment considering information on metastatic patterns.


Assuntos
Neoplasias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação/genética , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida
3.
Anticancer Res ; 40(1): 427-433, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892597

RESUMO

BACKGROUND/AIM: The role of anti-PD1/PD-L1 therapy (IO) in NSCLC harboring driver mutations is questionable. This study aimed to examine the efficacy of IO in patients with non-small cell lung cancer (NSCLC) with a KRAS mutation (KRAS+). PATIENTS AND METHODS: We retrospectively identified NSCLC patients harboring KRAS mutation treated with IO in our Institution. We analyzed the results in comparison to non-KRAS patients. RESULTS: Among 328 consecutive KRAS+ NSCLC patients, 43 (13.1%) received IO in our Institution. In parallel 117 non-KRAS NSCLC patients treated with IO were selected for comparison. The baseline characteristics were similar between the two groups. No significant difference was observed between KRAS+ and non-KRAS patients in terms of mPFS (4.6 vs. 3.3 months, p=0.58) or OS (8.1 vs. 13.0 months, p=0.38). CONCLUSION: KRAS mutations seem to be irrelevant for selecting patients for IO that could be therefore considered an effective therapy for NSCLC patients, independently of KRAS status.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Idoso , Antígeno B7-H1/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 12-16, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922587

RESUMO

OBJECTIVE: To detect pathogenic variant of ARSA gene in an infant with late infantile metachromatic leukodystrophy (MLD). METHODS: The male proband had an onset of walking dysfunction and seizure at 28 months. Arylsulfatase A activity of his peripheral blood leucocytes was 26.9 nmol/mg.17h, and cranial MRI showed wild symmetrical demyelination. With genomic DNA extracted from his peripheral blood sample, all coding exons and splicing sites of the ARSA gene were subjected to Sanger sequencing. PubMed Protein BLAST system was employed to analyze cross-species conservation of the mutant amino acid. Ucsf chimera software was used to analyze the impact of candidate variants on the secondary structure of the protein product. Impact of potential variants was also analyzed with software including PolyPhen-2, Mutation Taster, SIFT and PROVEAN. Whole-exome sequencing was carried out to identify additional variants which may explain the patient's condition. RESULTS: The proband was found to harbor compound heterozygous variants of the ARSA gene [c.467G>A (p.Gly156Asp) and c.960G>A (p.Trp320*)], neither of which was reported previously. As predicted by Ucsf chimera software, the c.960G>A (p.Trp320*) variant may demolish important secondary structures including α-helix, ß-strand and coil of the ARSA protein, causing serious damage to its structure and loss of function. The c.467G>A (p.Gly156Asp) variant was predicted to be "probably damaging" by PolyPhen-2, Mutation Taster and SIFT software. CONCLUSION: The patient's condition may be attributed to the compound heterozygous c.467G>A (p.Gly156Asp) and c.960G>A (p.Trp320*) variants of the ARSA gene. Above results have facilitated genetic counseling and prenatal diagnosis for this family.


Assuntos
Cerebrosídeo Sulfatase , Leucodistrofia Metacromática , Cerebrosídeo Sulfatase/genética , Éxons/genética , Feminino , Humanos , Lactente , Leucodistrofia Metacromática/genética , Masculino , Mutação/genética , Gravidez , Processamento de RNA/genética
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 17-20, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922588

RESUMO

OBJECTIVE: To explore the genetic basis of a pedigree affected with hereditary spherocytosis. METHODS: Peripheral blood samples were collected from 17 members of the pedigree. Genomic DNA of the proband was subjected to next generation sequencing. Candidate variant was validated by co-segregation analysis. pCAS2(c.5798+1G) and pCAS2(c.5798+1A) plasmids were constructed by homologous recombination and transfected into 293T cells. Reverse transcription PCR, TA cloning and Sanger sequencing were used to analyze the effect of candidate variant on splicing. Meanwhile, peripheral blood RNAs were extracted to analyze the effect of candidate variant on splicing in vivo. RESULTS: The proband was found to carry a c.5798+1G>A variant of the SPTB gene. The variant has co-segregated with the phenotype in the pedigree. In vitro and in vivo splicing experiments confirmed that the mutation has significantly affected the splicing, resulting in shift of reading frame and produced a premature termination codon. CONCLUSION: The novel c.5798+1G>A variant of the SPTB gene probably underlies the pathogenesis of hereditary spherocytosis in this pedigree.


Assuntos
Espectrina , Esferocitose Hereditária , Códon sem Sentido/genética , Variação Genética , Células HEK293 , Humanos , Mutação/genética , Linhagem , Plasmídeos , Processamento de RNA , Espectrina/genética , Esferocitose Hereditária/genética , Transfecção
6.
Gene ; 725: 144164, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31639430

RESUMO

Bardet-Biedl syndrome (BBS) is a clinically and genetically heterogeneous ciliopathy with several clinical features including retinitis pigmentosa, obesity, kidney dysfunction, postaxial polydactyly, behavioral dysfunction and hypogonadism with wide spectrum of additional features. With multiple phenotypes and heterogeneous distribution, it is unlikely that BBS is caused by single gene defect. We have performed clinical and genetic diagnosis of two individuals from an Indian family with classical BBS symptoms. Whole exome sequencing identified homozygous missense mutation in BBS10 gene, hemizygous missense AR and homozygous missense PDE6B mutations in the proband and affected sibling with BBS. Identification of BBS10 mutation along with AR and PDE6B gene mutation will expand the genetic and phenotypic spectrum in individuals with BBS.


Assuntos
Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/metabolismo , Chaperoninas/genética , Chaperoninas/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Análise Mutacional de DNA , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação/genética , Linhagem , Fenótipo , Receptores Androgênicos/genética , Retinite Pigmentosa/genética , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
7.
Clin Exp Rheumatol ; 37 Suppl 121(6): 142-146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31856934

RESUMO

OBJECTIVES: To describe phenotypic and functional characteristics of patients with the homozygous c.973-2A>G splice site mutation in the adenosine deaminase 2 (ADA2) gene (rs139750129), resulting in deficiency of ADA2 (DADA2). METHODS: We present case synopses of six patients from three unrelated families. Clinical data were analysed and next-generation sequencing (NGS) was performed. We also tested for aberrant RNA splicing and measured ADA2 enzyme activity. RESULTS: One family had common DADA2 symptoms, whereas Behçet's disease-like manifestations were observed in the other two families. We detected the homozygous c.973-2A>G splice site mutation in ADA2 in all patients tested. ADA2 enzyme activity was significantly lower in patients than in healthy controls, but no correlation between ADA2 activity levels and disease severity was observed. Aberrant splicing was detected in a minority of mRNA transcripts, but the formation of other, undetected, aberrant splicing products could not be excluded. Patients were treated with TNF-α inhibitors to prevent recurrence of inflammatory findings including cerebral vasculitis-associated stroke. CONCLUSIONS: We describe three families with the same homozygous splice site mutation in ADA2 and observed a novel combination of manifestations resembling Behçet's disease. This further expands the range of phenotypes caused by ADA2 mutations, although no complete genotype-phenotype association could be determined. Even without active disease, the risk of stroke should be addressed in making decisions regarding treatment of DADA2 patients.


Assuntos
Adenosina Desaminase , Síndrome de Behçet/genética , Peptídeos e Proteínas de Sinalização Intercelular , Mutação/genética , Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Variação Biológica da População , Estudos de Associação Genética , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética
8.
Cancer Immunol Immunother ; 68(12): 2015-2027, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31705171

RESUMO

The transformation and progression of myelodysplastic syndromes (MDS) to secondary acute myeloid leukemia (sAML) involve genetic, epigenetic, and microenvironmental factors. Driver mutations have emerged as valuable markers for defining risk groups and as candidates for targeted treatment approaches in MDS. It is also evident that the risk of transformation to sAML is increased by evasion of adaptive immune surveillance. This study was designed to explore the immune microenvironment, immunogenic tumor-intrinsic mechanisms (HLA and PD-L1 expression), and tumor genetic features (somatic mutations and altered karyotypes) in MDS patients and to determine their influence on the progression of the disease. We detected major alterations of the immune microenvironment in MDS patients, with a reduced count of CD4+ T cells, a more frequent presence of markers related to T cell exhaustion, a more frequent presence of myeloid-derived suppressor cells (MDSCs), and changes in the functional phenotype of NK cells. HLA Class I (HLA-I) expression was normally expressed in CD34+ blasts and during myeloid differentiation. Only two out of thirty-six patients with homozygosity for HLA-C groups acquired complete copy-neutral loss of heterozygosity in the HLA region. PD-L1 expression on the leukemic clone was also increased in MDS patients. Finally, no interplay was observed between the anti-tumor immune microenvironment and mutational genomic features. In summary, extrinsic and intrinsic immunological factors might severely impair immune surveillance and contribute to clonal immune escape. Genomic alterations appear to make an independent contribution to the clonal evolution and progression of MDS.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Células Supressoras Mieloides/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinogênese , Senescência Celular , Progressão da Doença , Feminino , Antígenos HLA-C/genética , Humanos , Vigilância Imunológica , Masculino , Pessoa de Meia-Idade , Mutação/genética , Evasão Tumoral , Microambiente Tumoral/imunologia , Adulto Jovem
9.
Medicine (Baltimore) ; 98(44): e17749, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689829

RESUMO

RATIONALE: Early infantile epileptic encephalopathy (EIEE) 65 was recently shown to be caused by the cytoplasmic FMRP interacting protein 2 (CYFIP2) mutation. To date, only 5 cases have been reported in two articles, and all the outcomes in all cases were poor. PATIENT CONCERNS: In this study, we reported an 8-month-old girl with a 1 month-long history of seizures and developmental delay. Over 1 month later, she developed epileptic spasms in clusters with hypsarrhythmia on electroencephalography. DIAGNOSIS: The patient was diagnosed with EIEE 65 and trio-based whole-exome sequencing revealed a causative de novo CYFIP2 mutation c.260G >T (p.Arg87Leu). INTERVENTIONS: The proband was successively treated with multiple antiepileptic drugs, including levetiracetam, phenobarbital, VitB6, topiramate, methylprednisolone, prednisone, valproic acid and vigabatrin. OUTCOMES: After resistance to multiple anti-epileptic drugs over 2 months of treatment, she finally achieved seizure-free several days after vigabatrin administration and her developmental delay steadily improved. LESSONS: OUR: case confirmed that CYFIP2 was the pathogenic gene of EIEE 65. We also first demonstrated vigabatrin might be effective for control of seizures and helpful for the improved outcomes of these patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação/genética , Espasmos Infantis/genética , Anticonvulsivantes/uso terapêutico , Diagnóstico Precoce , Feminino , Humanos , Lactente , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Resultado do Tratamento
11.
Nature ; 574(7777): 273-277, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578525

RESUMO

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis.


Assuntos
Processamento Alternativo/genética , Carcinogênese/genética , Epigênese Genética , Leucemia Mieloide Aguda/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células , Metilação de DNA , Proteínas de Ligação a DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Isocitrato Desidrogenase/genética , Masculino , Mutação/genética , RNA Polimerase II/metabolismo , Fatores de Processamento de Serina-Arginina/genética , Transcriptoma
12.
Nat Neurosci ; 22(10): 1624-1634, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31551593

RESUMO

Hundreds of genes are implicated in autism spectrum disorder (ASD), but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here we analyzed leukocyte transcriptomics from 1- to 4-year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes highly expressed genes during fetal brain development. This network is dysregulated in human induced pluripotent stem cell-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS-ERK, PI3K-AKT and WNT-ß-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.


Assuntos
Transtorno do Espectro Autista/genética , Redes Reguladoras de Genes/genética , Transtorno do Espectro Autista/patologia , Encéfalo/embriologia , Encéfalo/patologia , Pré-Escolar , Desenvolvimento Fetal/genética , Humanos , Lactente , Leucócitos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Mutação/genética , Células-Tronco Neurais , Proteína Oncogênica v-akt/genética , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais/genética , Via de Sinalização Wnt/genética , beta Catenina/genética
13.
An Acad Bras Cienc ; 91(3): e20180882, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553368

RESUMO

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by dynamic mutations of a CGG repetition segment in an X chromosome's single gene. It is considered the leading hereditary cause of both Autism Spectrum Disorders and Intellectual Disability. Some authors suggest that all individuals diagnosed with some of these latter conditions to be clinically and molecularly trialled for FXS due to the high levels of comorbidity between both conditions and also due to the variable expressiveness of this syndrome. This study has focused on verifying the presence of FMR1 expanded alleles since there is a lack of information about this kind of mutation in autism patients from the northern region of Brazil. The presence of large alleles for this gene could offer new therapeutic or pharmacological methods for the treatment of these patients. Both the presence and the frequency of CGG expansions were verified in 90 autism males by molecular analysis. Four of them had intermediate alleles and four others presented premutated alleles. Premutation carriers are on the propensity of developing the late onset Fragile X-associated tremor/ataxia syndrome. No full mutation alleles were found. Further studies are necessary to obtain more accurate statistical data about this kind of dynamic mutation.


Assuntos
Transtorno do Espectro Autista/genética , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Mutação/genética , Adolescente , Alelos , Criança , Pré-Escolar , Predisposição Genética para Doença , Testes Genéticos , Humanos , Masculino , Adulto Jovem
14.
Mem Inst Oswaldo Cruz ; 114: e190120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553370

RESUMO

BACKGROUND: In recent years, South America has suffered the burden of continuous high impact outbreaks of dengue, chikungunya and Zika. Aedes aegypti is the main mosquito vector of these arboviruses and its control is the only solution to reduce transmission. OBJECTIVES: In order to improve vector control it is essential to study mosquito population genetics in order to better estimate the population structures and the geneflow among them. METHODS: We have analysed microsatellites and knockdown resistance (kdr) mutations from a trans-border region in Amazonia between the state of Amapá (Brazil) and French Guiana (overseas territory of France), to provide further knowledge on these issues. These two countries have followed distinct vector control policies since last century. For population genetic analyses we evaluated variability in 13 well-established microsatellites loci in Ae. aegypti from French Guiana (Saint Georges and Cayenne) and Brazil (Oiapoque and Macapá). The occurrence and frequency of kdr mutations in these same populations were accessed by TaqMan genotype assays for the sites 1016 (Val/Ile) and 1534 (Phe/Cys). FINDINGS: We have detected high levels of gene flow between the closest cross-border samples of Saint-Georges and Oiapoque. These results suggest one common origin of re-colonisation for the populations of French Guiana and Oiapoque in Brazil, and a different source for Macapá, more similar to the other northern Brazilian populations. Genotyping of the kdr mutations revealed distinct patterns for Cayenne and Macapá associated with their different insecticide use history, and an admixture zone between these two patterns in Saint Georges and Oiapoque, in accordance with population genetic results. MAIN CONCLUSIONS: The present study highlights the need for regional-local vector surveillance and transnational collaboration between neighboring countries to assess the impact of implemented vector control strategies, promote timely actions and develop preparedness plans.


Assuntos
Aedes/efeitos dos fármacos , Aedes/genética , Resistência a Inseticidas/genética , Mosquitos Vetores/efeitos dos fármacos , Mosquitos Vetores/genética , Mutação/genética , Animais , Biodiversidade , Brasil , Guiana Francesa , Genótipo , Resistência a Inseticidas/efeitos dos fármacos
15.
Eur J Endocrinol ; 181(5): K37-K41, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31491746

RESUMO

Objective: To screen for CLCN2 mutations in apparently sporadic cases of aldosterone-producing adenomas (APAs). Description: Recently, CLCN2, encoding for the voltage-gated chloride channel protein 2 (ClC-2), was identified to be mutated in familial hyperaldosteronism II (FH II). So far, somatic mutations in CLCN2 have not been reported in sporadic cases of APAs. We screened 80 apparently sporadic APAs for mutations in CLCN2. One somatic mutation was identified at p.Gly24Asp in CLCN2. The male patient had a small adenoma in size but high aldosterone levels preoperatively. Postoperatively, the patient had normal aldosterone levels and was clinically cured. Conclusion: In this study, we identified a CLCN2 mutation in a sporadic APA comprising about 1% of all APAs investigated. This mutation was complementary to mutations in other susceptibility genes for sporadic APAs and may thus be a driving mutation in APA formation.


Assuntos
Adenoma/genética , Adenoma/metabolismo , Aldosterona/metabolismo , Canais de Cloreto/genética , Mutação/genética , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Adenoma/cirurgia , Adulto , Frequência do Gene , Humanos , Masculino , Noruega/epidemiologia , Neoplasias Hipofisárias/cirurgia , Transcriptoma/genética
16.
Phys Chem Chem Phys ; 21(37): 20628-20640, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31495862

RESUMO

Methionine synthase (MetH) is a methylcobalamin (MeCbl)-dependent mammalian enzyme which plays a critical role in carrying out the transfer of a methyl group from methyl tetrahydrofolate to homocysteine to generate methionine and tetrahydrofolate. This catalytic cycle proceeds via cleavage of a Co-C bond which is formally heterolytic. This cleavage results in a structural change in the MeCbl cofactor bound to an enzyme. Unlike the native catalysis, upon photoexcitation, the Co-C bond in MeCbl-bound MetH generates the Co(ii)/CH3 radical pairs (RPs). Protein residues of the cap domain, particularly phenylalanine708 (F708) and leucine 715 (L715), which surrounds the upper face of the MeCbl cofactor, inhibit the photolysis of MeCbl by caging the CH3 radical and inducing the geminate recombination of the Co(ii)/CH3 RP. A molecular-level understanding of these effects requires a detailed investigation of the low-lying electronic states. Toward this, we have mutated the F708 residue with alanine (A708) and constructed the potential energy surfaces (PESs) for the low-lying S1 electronic state using a combined quantum mechanics/molecular mechanics (QM/MM) approach. The S1 PESs for the wild-type (WT) and mutant enzymes are the result of crossing of two electronic states, namely metal-to-ligand charge transfer (MLCT) and ligand field (LF) states, indicated by a seam. It is shown that the topologies of the S1 PESs are significantly modulated by introducing a mutation at the F708 position. Specifically, for the WT enzyme, the energy barrier of photoreaction and the energy difference between MLCT and LF minima are markedly higher than those of its mutant counterpart. Moreover, mutation influences the photoactivation of the Co-C bond in enzyme-bound MeCbl by decreasing the rate of geminate recombination and altering the rate of radical pair formation. This theoretical insight was also compared with transient absorption spectroscopic (TAS) studies which are in good agreement with the present findings.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , Carbono/química , Cobalto/química , Vitamina B 12/análogos & derivados , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Modelos Químicos , Estrutura Molecular , Mutação/genética , Fotólise , Domínios Proteicos/genética , Vitamina B 12/metabolismo
17.
Medicina (B Aires) ; 79(4): 265-270, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31487245

RESUMO

Malignant melanoma (MM) is the more aggressive form of skin cancer with a mortality rate in Argentina 1997-2001 = 1.1/100 000 in men and 0.6 in women. BRAF proto-oncogene is focus of intense research; its mutation is one of the main tumor promoters and occurs in approximately 50% of MM. Several drugs with clinical activity on BRAF mutations have been approved. The aim of the study is to evaluate the mutational status of BRAF (exon 15) in cutaneous MM biopsies and its relationship with histopathological characteristics. We carried out an observational, retrospective study of samples fixed in formaldehyde and paraffin embedded; reviewing age, sex, diagnosis, histopathological data, tumor size and percentage, viability for molecular analysis and melanin presence. We evaluated BRAF mutations with PCR/Sanger sequencing. For statistics we used Student's t test, Chi square, Wilcoxon and Fisher's exact test. We were able to purify and sequence 76% (38/49) samples, 13/38 (34%) from women and 25/38 (66%) from men, the median age being 70 years. Most frequent location: thorax 14/35 (40%). Histological type: Superficial spreading 18/38 (47%). Clark's levels, 11/38 (29%): I-II and 27/38 (71%): III, IV and V. Breslow's median: 1.6 mm. Radial growth phase 11/38 (29%) and 27/38 (71%) vertical. Presented mutations 16/38 (42%). As reported by other authors, no association was found between the mutational state of exon 15 and clinical or histopathological parameters.


Assuntos
Melanoma/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Neoplasias Cutâneas/patologia
18.
Gynecol Oncol ; 155(2): 270-274, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31500890

RESUMO

OBJECTIVE: To compare the survival experience of women with a BRCA1 mutation who enrolled in an ovarian cancer screening program with that of women who opted for preventive oophorectomy. METHODS: We followed 1964 women with a BRCA1 mutation and two ovaries intact in a prospective study. No women had ovarian cancer or had a bilateral oophorectomy prior to study initiation. There were 1814 women in the cohort who had at least one screening ultrasound. They were followed from the date of first ultrasound until the date of preventive oophorectomy, death or last follow-up. There were 659 women in the cohort who had preventive oophorectomy. They were followed from the date of preventive oophorectomy until death or last follow-up. RESULTS: Among the 1196 women who had one or more ultrasound examinations and no oophorectomy, there were 73 incident cancers detected and 27 deaths from ovarian/fallopian cancer. The ten year cumulative risk of death was 2.0%. Among the 659 women who had a preventive oophorectomy there were 12 incident cancers (9 detected at oophorectomy and 3 in the follow up period) and two deaths from ovarian cancer. The ten year cumulative risk of death was 0.5%. The hazard ratio for oophorectomy versus ultrasound was 0.23 (95% CI: 0.05 to 0.97; p = 0.05). CONCLUSION: The survival of women diagnosed with ovarian cancer enrolled in an ultrasound screening program is relatively poor and screening is not a viable alternative to preventive oophorectomy.


Assuntos
Neoplasias Ovarianas/mortalidade , Ovariectomia/mortalidade , Adulto , Idoso , Detecção Precoce de Câncer , Feminino , Genes BRCA1/fisiologia , Heterozigoto , Humanos , Programas de Rastreamento/mortalidade , Pessoa de Meia-Idade , Mutação/genética , Neoplasias Ovarianas/prevenção & controle , Polônia/epidemiologia , Estudos Prospectivos , Ultrassonografia , Adulto Jovem
19.
Nat Med ; 25(9): 1396-1401, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501599

RESUMO

Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date1,2. Mutations in FANCA account for more than 60% of FA cases worldwide3,4. Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70-80% of patients with FA during the first decade of life5,6. In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder.


Assuntos
Proteína do Grupo de Complementação A da Anemia de Fanconi/genética , Anemia de Fanconi/terapia , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Células da Medula Óssea/citologia , Criança , Pré-Escolar , Anemia de Fanconi/genética , Anemia de Fanconi/fisiopatologia , Feminino , Vetores Genéticos/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , Lactente , Lentivirus/genética , Masculino , Mutação/genética , Espanha/epidemiologia , Reparo Gênico Alvo-Dirigido , Transdução Genética , Adulto Jovem
20.
Phys Chem Chem Phys ; 21(37): 20951-20964, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31524891

RESUMO

As a promising drug target in the treatment of lung cancer, anaplastic lymphoma kinase (ALK) and its mutations have been studied widely through the development of multiple generations of inhibitors. Experiments have found that compared with the wild-type, the L1198F and C1156Y/L1198F mutations resulted in resistance to 5P8 inhibitors, and the C1156Y mutation resulted in resistance to VGH inhibitors. In this study, the newly developed interaction entropy (IE) method combined with the polarized protein-specific charge (PPC) force field was utilized to explore the origin of the resistance mechanism of the ALK mutant system. The calculated binding free energy was consistent with the experimental results. Per-residue binding free energy decomposition showed that the predicted hot-spot residues (LEU1122, LEU/PHE1198, MET1199, GLY1202 and LEU1256) were almost identical across systems. Especially, the GLU1197 residue played an important role in inducing drug-resistance for both inhibitors. The electrostatic interaction of GLU1197, PHE1198 and MET1199 mainly resulted in the resistances of the L1198F and C1156Y/L1198F mutations to 5P8. And the van der Waals interaction energy of LEU1256 residue, and electrostatic energy and entropy change of GLU1197 resulted in the resistances of the C1156Y mutations to VGH. The indicated origins of the drug-resistance in the ALK systems provide a theoretical foundation for the design of potent inhibitors.


Assuntos
Quinase do Linfoma Anaplásico/genética , Resistencia a Medicamentos Antineoplásicos/genética , Entropia , Mutação/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Linfoma Anaplásico de Células Grandes/enzimologia , Linfoma Anaplásico de Células Grandes/genética , Eletricidade Estática
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