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1.
Gan To Kagaku Ryoho ; 46(8): 1291-1293, 2019 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-31501372

RESUMO

A 63-year-old woman underwent right lower lobectomy and mediastinal dissection for lung cancer. At 5 years and 5 months after surgery, chest computed tomography revealed multiple liver metastasis. EGFR gene mutations of L858R and T790M were detected in both the primary lung cancer lesion and the liver metastasis specimen. Gefitinib was initiated as the first-line treatment, but the tumors increased in size. Osimertinib, as second-line treatment, was remarkably effective against the liver metastatic lesions and it maintained a partial response for approximately 1 year. Thus, osimertinib was effective for liver metastasis of lung cancer with EGFR mutations of L858R and T790M.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Neoplasias Hepáticas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases
2.
Einstein (Sao Paulo) ; 17(4): eAO4742, 2019 Sep 09.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31508660

RESUMO

OBJECTIVE: To evaluate the induction of DNA damage in peripheral blood mononuclear cells of patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea. METHODS: The study subjects were divided into two groups: one group of 22 patients with sickle cell disease, SS and SC genotypes, treated with hydroxyurea, and a Control Group composed of 24 patients with sickle cell disease who were not treated with hydroxyurea. Peripheral blood samples were submitted to peripheral blood mononuclear cell isolation to assess genotoxicity by the cytokinesis-block micronucleus cytome assay, in which DNA damage biomarkers - micronuclei, nucleoplasmic bridges and nuclear buds - were counted. RESULTS: Patients with sickle cell disease treated with hydroxyurea had a mean age of 25.4 years, whereas patients with sickle cell disease not treated with hydroxyurea had a mean age of 17.6 years. The mean dose of hydroxyurea used by the patients was 12.8mg/kg/day, for a mean period of 44 months. The mean micronucleus frequency per 1,000 cells of 8.591±1.568 was observed in the Hydroxyurea Group and 10.040±1.003 in the Control Group. The mean frequency of nucleoplasmic bridges per 1,000 cells and nuclear buds per 1,000 cells for the hydroxyurea and Control Groups were 0.4545±0.1707 versus 0.5833±0.2078, and 0.8182±0.2430 versus 0.9583±0.1853, respectively. There was no statistically significant difference between groups. CONCLUSION: In the study population, patients with sickle cell disease treated with the standard dose of hydroxyurea treatment did not show evidence of DNA damage induction.


Assuntos
Anemia Falciforme/genética , Dano ao DNA/efeitos dos fármacos , Hidroxiureia/farmacologia , Inibidores da Síntese de Ácido Nucleico/farmacologia , Adolescente , Adulto , Anemia Falciforme/tratamento farmacológico , Criança , Pré-Escolar , Citocinese , Dano ao DNA/genética , Feminino , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Testes de Mutagenicidade , Mutação/efeitos dos fármacos , Inibidores da Síntese de Ácido Nucleico/efeitos adversos , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Adulto Jovem
3.
Rinsho Ketsueki ; 60(8): 903-909, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31484887

RESUMO

A 78-year-old man with anemia (Hb 9.6 g/dl) and elevated serum immunoglobulin M (IgM 3,577 mg/dl) levels was referred to our hospital. Bone marrow aspiration yielded a dry tap, and bone marrow biopsy revealed the infiltration of CD20 positive lymphoplasmacytic lymphoma cells and myelofibrosis. The patient was diagnosed with Waldenström's macroglobulinemia complicated with myelofibrosis. TGF-ß plasma concentration was elevated. Further, after chemotherapy with bendamustine and rituximab, remission of both Waldenström's macroglobulinemia and myelofibrosis was achieved, and TGF-ß levels normalized. MYD88 L265P mutation was detected using highly sensitive digital PCR, which compared with currently used direct PCR product sequencing, has a superior sensitivity. The use of digital PCR has additional advantages toward MYD88 L265P detection, particularly when the available amount of sample DNA is limited owing to myelofibrosis.


Assuntos
Fator 88 de Diferenciação Mieloide/genética , Mielofibrose Primária , Macroglobulinemia de Waldenstrom , Idoso , Humanos , Imunoglobulina M , Masculino , Mutação , Reação em Cadeia da Polimerase , Mielofibrose Primária/complicações , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/genética
4.
Rinsho Ketsueki ; 60(8): 915-919, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31484889

RESUMO

A 83-year-old female patient was admitted to our hospital due to hematological manifestation of juvenile granulocytes and macrocytic anemia. Bone marrow (BM) examination revealed erythroid dysplasia and cytoplasmic blasts, and hence the patient was diagnosed with myelodysplastic syndrome with ring sideroblasts and with single lineage dysplasia (MDS-RS-SLD). Erythrocyte transfusion was performed as a supportive therapy, and there was a gradual increase in the number of blood cells. Therefore, BM re-examination was performed and it was confirmed that the number of megakaryocytes increased, so the patient's condition was determined as myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN with RS-T). Incidentally, gene mutation analysis showed CALR gene mutation. Thereafter, administration of hydroxycarbamide and anagrelide did not show adverse events and complications, and a good blood count control was obtained. Furthermore, it was also confirmed that an SF3B1 gene mutation is highly positive in MDS-RS. There was no report on CALR-mutant MDS/MPN in Japan, and it is a rare disease overseas.


Assuntos
Calreticulina/genética , Neoplasias Hematológicas/genética , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Trombocitose , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Mutação , Trombocitose/genética
5.
Rinsho Ketsueki ; 60(8): 960-967, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31484896

RESUMO

Myelodysplastic syndromes (MDS) constitute a group of heterogeneous disorders of hematopoietic stem cells, characterized by defective hematopoiesis and multilineage dysplasia. While low-risk subtypes normally exhibit a relatively chronic clinical course, high-risk subtypes harbor unfavorable prognosis in which hematopoietic stem cell transplantation (HCT) is the only curative therapy. Nevertheless, transplantation-related mortality is relatively high and should be weighed against the potential benefits of HCT. Hence, it is vital to precisely stratify the prognostic risks before HCT for predicting and enhancing their prognosis. Recently, our understanding of the genetic basis of MDS has substantially advanced, through which a full spectrum of major mutational targets was delineated. Moreover, its effects in the setting of HCT have also been assessed besides the conventional predictive factors. While clinical factors account for as much as 70% of the total hazard of MDS cases treated with HCT, the remaining 30% is explicated by genetic factors. The integration of genetic test and conventional clinical factors could be useful for precise stratification of the prognostic risks and, therefore, treatment decision in MDS.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas , Humanos , Mutação , Prognóstico , Transplante de Células-Tronco
6.
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
7.
Zhonghua Bing Li Xue Za Zhi ; 48(9): 682-687, 2019 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-31495087

RESUMO

Objective: To investigate the clinicopathological significance of BRAF V600E and CTNNB1 gene mutations in adamantinomatous craniopharyngiomas (ACP) and papillary craniopharyngiomas (PCP). Methods: The retrospective study included a total of 67 craniopharyngiomas diagnosed from October 2009 to August 2018 at Xuanwu Hospital, Capital Medical University. The immunohistochemical staining for ß-catenin and BRAF V600E expression, Sanger sequencing of exon 3 of CTNNB1, BRAF mutation analysis by scorpions amplification refractory mutation system (ARMS) fluorescence quantitative PCR were performed. Univariate survival analysis was used to correlate with tumor recurrence. Results: Of the 67 patients, 53 were ACPs and 14 were PCPs. Four patients underwent multiple operations and one of them presented with malignant transformation into squamous cell carcinoma. Histologically, ACPs were characterized by whorl-like cell clusters, peripheral palisaded layer, stellate reticulum, finger-shaped protrusions, ghost cells and wet keratinous substances. While PCPs usually consisted of mature squamous epithelium associated with fibrovascular stroma resulting in papillary appearance. The nuclear immunopositivity for ß-catenin was observed in 73.6% (39/53) of ACPs, and it was absent in PCPs (0/14). The nuclear translocation of ß-catenin usually presented at whorl-like structures or around ghost cells. Of all the cases, mutations analysis in exon 3 of ß-catenin gene CTNNB1 were successful in 46 cases and 42.1% (16/38) of ACP showed CTNNB1 gene mutation, while none of the PCPs harbored CTNNB1 gene mutation (0/8). The cytoplasmic immunopositivity for BRAF V600E mutant protein was found in all PCPs (14/14) and negative in all ACPs (0/53). ARMS-PCR results showed that BRAF V600E mutations were observed in 13/14 of PCPs but not seen in ACPs (0/53). Follow-up data were available in 35 patients with duration of 2 to 120 months. Ten patients experienced recurrences after the first surgery. Upon univariate survival analysis, only subtotal excision was found to be associated with increased recurrence (P=0.032), while pathological type, postoperative radiotherapy and CTNNB1 gene mutation were not (P>0.05). Conclusions: There is significant difference in the expression of BRAF V600E and CTNNB1 genes between ACP and PCP, and their immunohistochemical and molecular detection therefore can be used in the diagnosis and differential diagnoses of craniopharyngiomas.


Assuntos
Craniofaringioma , Neoplasias Hipofisárias , Proteínas Proto-Oncogênicas B-raf/genética , beta Catenina/genética , Craniofaringioma/genética , Humanos , Mutação , Recidiva Local de Neoplasia , Neoplasias Hipofisárias/genética , Estudos Retrospectivos
8.
Cancer Discov ; 9(8): 998-1000, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31371322

RESUMO

In this issue, McMahon and colleagues demonstrate that secondary clinical resistance to the FLT3 inhibitor gilteritinib in relapsed acute myeloid leukemia is often polyclonal and commonly mediated by heterogeneous mutations that activate downstream RAS-MAPK pathways. These findings and recent data from others indicate that emergence of multiple clones, each with distinct mechanisms of resistance, is a common finding at secondary failure of single-agent-targeted therapies for relapsed leukemias.See related article by McMahon et al., p. 1050.


Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms/genética , Humanos , Sistema Imunitário , Mutação , Inibidores de Proteínas Quinases
9.
Pestic Biochem Physiol ; 159: 17-21, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400779

RESUMO

Capsella bursa-pastoris is a serious broadleaf weed in winter wheat fields in China. It has evolved high levels of resistance to acetolactate synthase (ALS) inhibiting herbicides and has caused substantial losses of wheat yield in recent years. We monitored the herbicide resistance of Capsella bursa-pastoris collected from 18 regions of Shandong Province in 2009, 2013 and 2017, respectively. Compared with the 2009 populations, the number of populations resistant to florasulam had increased in 2013 and 2017. Resistance to tribenuron-methyl increased in 2013, but decreased in 2017. The 2009 and 2013 populations developed resistance only to tribenuron-methyl, but some 2017 populations developed cross-resistance to imazethapyr and florasulam as well. Mutations in ALS (Pro-197-Thr/Ser/His/Arg/Leu/Gln) were identified in the 2009 and 2013 populations; however, two ALS mutations (Pro197 and/or Trp574) were identified in 2017 plants. Meanwhile, plants containing both point mutations (Pro197 + Trp574) were identified in the 2017 populations. This study demonstrated that target site gene mutations were the main reason for Capsella bursa-pastoris resistance to ALS-inhibiting herbicides. Although target-site mutation is the reason for resistance to ALS-inhibiting herbicides in Capsella bursa-pastoris, the resistance patterns and mutations identified have changed over time.


Assuntos
Acetolactato Sintase/genética , Capsella/efeitos dos fármacos , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Proteínas de Plantas/genética , Sulfonatos de Arila/farmacologia , Capsella/enzimologia , Capsella/genética , Mutação/genética , Ácidos Nicotínicos/farmacologia , Mutação Puntual/genética , Pirimidinas/farmacologia , Sulfonamidas/farmacologia
10.
Pestic Biochem Physiol ; 159: 80-84, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400787

RESUMO

The plastid acetyl coenzyme carboxylase (ACCase) Trp1999Leu mutation was identified in a Beckmannia syzigachne population resistant to fenoxaprop-p-ethyl. The pattern of cross-resistance for the Trp1999Leu mutation is still ambiguous. In this paper, mutant homozygote (1999Leu/Leu, RR) and wild type (1999Trp/Trp, SS) B. syzigachne plants with the same genetic background were purified from the JS-26 population using the dCAPS method. The activity of ACCase in RR and SS was determined. Then, the cross-resistance pattern to ACCase inhibiting herbicides of the Trp1999Leu mutation was determined using the whole-plant method. ACCase activity showed that the Trp1999Leu mutation decreased ACCase sensitivity to fenoxaprop-p-ethyl by 2.73-fold. A dose-response experiment indicated that the Trp1999Leu mutation conferred high resistance to quizalofop-p-ethyl (20.29-fold), metamifop (12.22-fold) and pinoxaden (18.60-fold), moderate resistance to fenoxaprop-p-ethyl (8.20-fold) and sethoxydim (6.38-fold), low resistance to cyhalofop-butyl (2.73-fold) and no resistance to clodinafop-propargyl (1.42 fold) and clethodim (1.59-fold). This is the first report of the role of Trp1999Leu in fenoxaprop-p-ethyl resistance and of the patterns of cross-resistance to ACCase-inhibiting herbicides in B. syzigachne.


Assuntos
Acetil-CoA Carboxilase/genética , Herbicidas/farmacologia , Poaceae/efeitos dos fármacos , Poaceae/genética , Anilidas/farmacologia , Benzoxazóis/farmacologia , Cicloexanonas/farmacologia , Resistência a Herbicidas/genética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Mutação/genética , Propionatos/farmacologia , Piridinas/farmacologia , Quinoxalinas/farmacologia
11.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(8): 754-760, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31416498

RESUMO

Hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) syndrome is an autosomal dominant genetic disease caused by COL4A1 gene mutation, with major clinical manifestations of white matter lesion, aneurysm, retinal artery tortuosity, polycystic kidney, microscopic hematuria and muscle cramps. This article reports the clinical features and genotype of one toddler with HANAC syndrome caused by COL4A1 gene mutation. The boy, aged 1 year and 8 months, had an insidious onset, with the clinical manifestations of pyrexia and convulsion, white matter lesions in the periventricular region and the centrum semiovale on both sides, softening lesions beside the left basal ganglia, retinal arteriosclerosis, microscopic hematuria and muscle cramps. Whole exome sequencing revealed a pathogenic de novo heterozygous mutation in the COL4A1 gene, (NM_001845) c.4150+1(IVS46)G>T, and therefore, the boy was diagnosed with HANAC syndrome. COL4A1 gene mutation detection should be performed for children with unexplained white matter lesion, stroke, hematuria, polycystic kidney, cataract and retinal artery tortuosity or families with related history.


Assuntos
Aneurisma , Colágeno Tipo IV/genética , Cãibra Muscular , Genótipo , Humanos , Lactente , Masculino , Cãibra Muscular/genética , Mutação , Síndrome
12.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(8): 824-829, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31416510

RESUMO

OBJECTIVE: To construct a W203X-mutant mouse model of cblC type methylmalonic acidemia based on the CRISPR/Cas9 technology. METHODS: At first, BLAST was used to compare the conservative nature of the cblC gene and protein sequences in humans and mice, and then, the CRISPR/Cas9 technology was used for microinjection of mouse fertilized eggs to obtain heterozygous F1 mice. Hybridization was performed for these mice to obtain homozygous W203X-mutant mice. The blood level of the metabolite propionyl carnitine (C3) was measured for homozygous mutant mice, heterozygous littermates, and wild-type mice. RESULTS: The gene and protein sequences of MMACHC, the pathogenic gene for cblC type methylmalonic acidemia, were highly conserved in humans and mice. The homozygous W203X-mutant mice were successfully obtained by the CRISPR/Cas9 technology, and there was a significant increase in C3 in these mice at 24 hours after birth (P<0.001). CONCLUSIONS: A W203X-mutant mouse model of cblC type methylmalonic acidemia is successfully constructed by the CRISPR/Cas9 technology.


Assuntos
Sistemas CRISPR-Cas , Erros Inatos do Metabolismo dos Aminoácidos , Animais , Proteínas de Transporte , Heterozigoto , Camundongos , Mutação
13.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(8): 839-844, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31416513

RESUMO

Limb-girdle muscular dystrophy (LGMD) is a group of muscular dystrophies with predominantly proximal muscular weakness, and some genes associated with this disease have been identified at present. LGMD type 2Q (LGMD2Q) is a subtype of LGMD and is associated with PLEC gene mutation. Major phenotypes of PLEC gene mutation include epidermolysis bullosa with late-onset muscular dystrophy and epidermolysis bullosa with other lesions. LGMD2Q without skin lesions is rarely reported. This article reviews the pathogenic gene PLEC and clinical manifestations of LGMD2Q, so as to deepen the understanding of the pathogenic gene and phenotype of LGMD2Q.


Assuntos
Distrofia Muscular do Cíngulo dos Membros , Humanos , Mutação , Fenótipo
14.
Cancer Res ; 79(16): 4009-4010, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31416848

RESUMO

Critically important to reducing uterine cancer mortality is the development of more effective therapy for aggressive endometrial cancers, including uterine serous cancer and uterine carcinosarcoma, which together account for over half of deaths due to endometrial cancer. About one-third of these aggressive endometrial cancers harbor mutations in the protein phosphatase 2A (PP2A) Aα scaffold subunit encoded by PPP2R1A In this issue, the study by Taylor and colleagues elucidates the role of a highly recurrent PP2A-Aα-subunit mutation PPP2R1A P179R as a biological driver of aggressive endometrial cancer. Compelling data demonstrate that the P179R mutation alters PP2A-Aα protein conformation, impairing holoenzyme formation and reducing PP2A phosphatase activity to promote endometrial cancer progression. Restoration of wild-type PPP2R1A in P179R-mutant endometrial cancer cells increases phosphatase activity and inhibits tumor growth in vivo Furthermore, a small-molecule activator of PP2A (SMAP) phenocopies restoration of wild-type PPP2R1A to suppress tumor growth. These promising results are an important advance toward effective precision therapy for aggressive endometrial cancer.See related article by Taylor et al., p. 4242.


Assuntos
Cistadenocarcinoma Seroso , Neoplasias do Endométrio , Neoplasias Uterinas , Feminino , Humanos , Mutação , Proteína Fosfatase 2/genética
15.
Phys Chem Chem Phys ; 21(32): 17821-17835, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31373340

RESUMO

The rise of New Delhi metallo-beta-lactamase-1 (NDM-1) producers is a major public health concern due to carbapenem resistance. Infections caused by carbapenem-resistant enterobacteria (CRE) are classified as a serious problem. To understand the structure and function of NDM-1, an amino acid replacement approach is considered as one of the methods to get structural insight. Therefore, we have generated novel mutations (N193A, S217A, G219A and T262A) near active sites and an omega-like loop to study the role of conserved residues of NDM-1. The minimum inhibitory concentrations (MICs) of ampicillin, imipenem, meropenem, cefotaxime, cefoxitin and ceftazidime for all mutants were found to be reduced 2 to 6 fold, compared to a wild type NDM-1 producing strain. The Km values increased while Kcat and Kcat/Km values were decreased compared to wild type. The affinity as well as the catalysis properties of these mutants were reduced considerably for imipenem, meropenem, cefotaxime, cefoxitin, and ceftazidimem compared to wild type, hence the catalytic efficiencies (Kcat/Km) of all mutant enzymes were reduced owing to the poor affinity of the enzyme. The IC50 values of these mutants with respect to each drug were reduced compared to wild type NDM-1. MD simulations and docking results from the mutant protein models, along with the wild type example, showed stable and consistent RMSD, RMSF and Rg behavior. The α-helix content values of all mutant proteins were reduced by 13%, 6%, 14% and 9% compared to NDM-1. Hence, this study revealed the impact role of active sites near residues on the enzyme catalytic activity of NDM-1.


Assuntos
Antibacterianos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , beta-Lactamases/química , Antibacterianos/farmacologia , Biocatálise , Domínio Catalítico , Farmacorresistência Bacteriana , Cinética , Testes de Sensibilidade Microbiana , Mutagênese Sítio-Dirigida , Mutação , Ligação Proteica , Estrutura Secundária de Proteína , Termodinâmica , beta-Lactamases/genética , beta-Lactamases/metabolismo
16.
Rinsho Ketsueki ; 60(7): 818-823, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391372

RESUMO

Myelodysplastic syndromes (MDS), a group of heterogeneous hematopoietic disorders, are characterized by multi-lineage dysplasia and ineffective hematopoiesis. Despite identifying multiple gene mutations in patients with MDS, their main clinical features are similar. To resolve the discrepancy between genotypes and phenotypes, we performed transcriptome and epigenome analyses to ascertain the shared underlying mediator (s) of MDS etiology and identified HIF1A signaling as a central pathobiological mediator of MDS. HIF1A is a critical regulator for several physiological pathways associated with stem-cell maintenance, angiogenesis, glucose-metabolism, and immune activation. We identified dysregulated HIF1A signature in human patients with MDS. Using mouse genetic models, we demonstrated that the dysregulation of HIF1A could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS-driver mutations. The genetic disruption of HIF1A resolves MDS phenotypes. These findings suggest that HIF1A is an effective therapeutic target for a broad spectrum of patients with MDS.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Síndromes Mielodisplásicas/genética , Animais , Hematopoese , Humanos , Camundongos , Mutação , Transdução de Sinais , Transcriptoma
17.
Medicine (Baltimore) ; 98(33): e16711, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415363

RESUMO

BACKGROUND: Multiple myeloma (MM) is a clonal plasma cell malignancy associated with hypercalcemia, bone lesions, and renal failure. The prognostic significance of the mutation of miRNAs, one kind of small noncoding RNA molecules that can modulate gene expression, should be confirmed in non-Hodgkin lymphomas (NHL). This study aimed to identify the prognostic value of miRNAs in patients with MM. METHODS: A meta-analysis was performed to estimate the pooled hazard ratios and their corresponding 95% confidence intervals for the associations between levels of miRNA expression (predictive factors) and outcomes in patients with MM. We systematically searched the PubMed, Web of Science, and China National Knowledge Infrastructure databases (final search conducted January 1, 2018) to identify eligible studies. Eligible studies were included by certain inclusion and exclusion criteria, whose quality was assessed by Newcastle-Ottawa Scale. RESULTS: After performing the literature search and review, 10 relevant studies, including 1214 cases, were identified. The results of our meta-analysis revealed that upregulated miR-92a level and downregulated miR-16, miR-25, miR-744, miR-15a, let-7e, and miR-19b expression were associated with poor prognosis in MM. CONCLUSIONS: This study identified miRNAs could serve as potential prognostic biomarkers in MM. Given the limited research available, the clinical application of these findings has yet to be verified.


Assuntos
MicroRNAs/metabolismo , Mieloma Múltiplo/genética , Biomarcadores Tumorais/metabolismo , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Masculino , Mutação , Prognóstico , Modelos de Riscos Proporcionais , Regulação para Cima
18.
Medicine (Baltimore) ; 98(33): e16766, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415376

RESUMO

Patients with non-small cell lung cancer (NSCLC) and de novo brain metastasis (BM) have poor prognosis. We aim to investigate the characteristic of brain magnetic resonance (MR) imaging and the association with the treatment response of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for lung cancer with BM.EGFR-mutated NSCLC patients with BM from October 2013 to December 2017 in a tertiary referral center were retrospectively analyzed. Patient's age, sex, cell type, EGFR mutation status, treatment, and characteristics of BM were collected. Survival analysis was performed using Kaplan-Meier method. The efficacy of different EGFR-TKIs were also analyzed.Among the 257 eligible patients, 144 patients with Exon 19 deletion or Exon 21 L858R were included for analysis. The erlotinib group had the best progression free survival (PFS) (median PFS 13 months, P = .04). The overall survival (OS) revealed no significant difference between three EGFR-TKI groups. Brain MR imaging features including tumor necrosis, rim enhancement and specific tumor locations (frontal lobe, putamen or cerebellum) were factors associated with poor prognosis. Patients with poor prognostic imaging features, the high-risk group, who received erlotinib had the best PFS (median PFS 12 months, P < .001). However, the OS revealed no significant difference between 3 EGFR-TKI groups. The low risk group patients had similar PFS and OS treated with three different EGFR-TKIs.In NSCLC patients with common EGFR mutation and de novo BM, those with poor prognostic brain MR characteristics, erlotinib provided better PFS than afatinib or gefitinib.


Assuntos
Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Terapia Combinada , Intervalo Livre de Doença , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Valor Preditivo dos Testes , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Taiwan
19.
Medicine (Baltimore) ; 98(33): e16828, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415402

RESUMO

RATIONALE: Congenital glucose-galactose malabsorption (CGGM) is a rare, autosomal recessive, hereditary disease that usuallypresents in newborns. CGGM manifests as severe diarrhea, hyperosmolar dehydration, and malnutrition. It does not respond to routine treatment and often is life-threatening. PATIENT CONCERNS: We described a Chinese infant girl with refractory diarrhea, who suffered from severe dehydration and malnutrition even if with fluid replacement therapy and fed with several special formulas. DIAGNOSES: The genetic analysis identified CGGM with SLC5A1 mutations. c.1436G > C (p.R479T) was a novel mutation. INTERVENTIONS: The patient was managed by free-glucose and galactose formula, and then special low-carbohydrate dietary therapy. OUTCOMES: The patient improved immediately after starting a free-glucose and galactose formula, and kept healthy with special low-carbohydrate diet. She had been followed up with nutritional management for 20 months. LESSONS: This report highlights the importance of differential diagnosis of congenital diarrhea and enteropathies. For CGGM, free-glucose and galactose milk powder was the most effective treatment. Low-carbohydrate diet gradually introduced was still a great challenge that requires continuing guidance from child nutritionists and dietitians. Long-term nutrition management was extremely important to ensure the normal growth and development of children.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/tratamento farmacológico , Dieta com Restrição de Carboidratos/métodos , Fórmulas Infantis , Síndromes de Malabsorção/tratamento farmacológico , Erros Inatos do Metabolismo dos Carboidratos/genética , China , Feminino , Galactose , Glucose , Humanos , Recém-Nascido , Síndromes de Malabsorção/genética , Mutação , Transportador 1 de Glucose-Sódio/genética
20.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1077-1082, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418360

RESUMO

OBJECTIVE: To analyze the prevalence, clinical characteristics and prognostic significance of the isocitrate dehydrogenase 2(IDH2) mutations in patients with acute myeloid leukemia(AML). METHODS: The bone marrow samples of 223 patients with newly diagnosed AML confirmed by MICM typing from January 2015 to October 2018 were collected. The mutation of exon 4 of IDH2 gene was detected by direct sequancing of PCR product; the incidence and types of IDH2 gene mutation in AML patients were analyzed; the clinical characteristics of AML patients with IDH2 gene mutation were analyzed and the therapeutic efficacy for these patients was evaluated. RESULTS: In a cohort of 223 AML patients, mutations were detected in 23(10.31%) patients, among them, 15 with R140Q mutations(65.22%) , 6 with R172K mutations(26.09%) and 2 with R140W mutations(8.70%). The median age in IDH2 mutated group was older than that in non.mutated group(P=0.008). The platelet level at initial diagnosis in IDH2 mutated group was higher than that in non.mutated group(P=0.010). There was no significant statistical difference between IDH2 mutated group and non.mutated group in FAB subtypes of AML(P>0.05). But the rate of IDH2 mutation in M4 and M5 was higher. The rate of IDH2 mutations was higher in AML with normal karyotype and in AML with NPM1 mutations. R140Q mutations associated with NPM1 mutations(χ2=8.481,P=0.004), but R172K mutations not associated with NPM1 mutation(P>0.05). IDH2 mutated patients had a lower complete remission rate than non.mutated patients(57.14% vs 80.46%, χ2=5.927,P=0.015). The complete remission rate of R140Q mutated patients was not significantly statistically different from non.mutated patients. The complete remission rate of R172K mutated patients was very significantly lower than non.mutated patients(χ2=7.734,P=0.005). In the patients without NPM1 mutation, the 2 years overall survival in IDH2 mutated group was lower than in non.mutated group(36.36% vs 66.40%,χ2=3.958,P=0.047), the 2 years overall survival of R172K mutated group was significantly lower than non.mutated group(although P>0.05). In all patients, the 2 years overall survival between IDH2 mutated group and non.mutated group was not statistically different(50% vs 66.88%,P>0.05), the 2 years overall survival of R172K mutated group was significantly lower than non.mutated group(although P>0.05). In the patients with normal karyotype or with mutated NPM1, the 2 years overall survival between IDH2 mutated group and non.mutated group was not statistically different(P>0.05). CONCLUSION: IDH2 gene mutations are more common in AML patients at older age, higher platelets level and normal karyotype. The rate of IDH2 mutation in M4 and M5 is higher. IDH2 gene mutations associate with NPMl gene mutations, but R172K mutations not associates with NPM1mutation. IDH2 gene mutations associate with prognosis of AML patients, R140Q mutations have no effect on prognosis of patients, but R172K mutations may be the molecular markers for poor prognosis in AML patients.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda , Genótipo , Humanos , Mutação , Prognóstico
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