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1.
Georgian Med News ; (304-305): 141-147, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32965265

RESUMO

Objective - to study the ability of N-oxide-2,6-dimethylpyridine to modify the cytogenetic effects in mouse bone marrow cells caused by an alkylating antitumor cytostatic cyclophosphamide.; The cytogenetic activity and mutagen-modifying effect of the plant growth regulator N-oxide-2,6-dimethylpyridine (Ivin) were studied by the method of accounting for chromosomal aberrations in the bone marrow cells of CD-1 mice (males) with a single joint exposure to cyclophosphamide. In the first variant of the research, Ivin was administered single orally in the form of an aqueous solution at doses of 710, 71, 7.1, 0.7, and 0.07 mg/kg bw, which corresponds to 1/2, 1/20, 1/200, 1/2000 and 1/20000 from LD50. In the second variant - Ivin was administered together with Cyclophosphamide (Ivin - in the same way as in the first research variant, cyclophosphamide was administered intraperitoneally at a dose of 40 mg/kg bw the same as the positive control group). Intact animals (negative control group) were orally administered purified, UV-sterilized, deionized water.; It was shown that with isolated administration of Ivin in the studied doses did not show mutagenic activity. When combined with Cyclophosphamide, Ivin at a dose of 710 mg/kg bw did not induce the frequency of metaphases with chromosome aberrations and at a dose of 71 mg/kg bw reduced the frequency of metaphases with chromosome aberrations by 1.8 times in comparison with the positive control. In both of these dose groups, Ivin reduced the number of chromatid-type aberrations and polyploid cells but increased the number of multi-aberrant cells. This is probably due to the additional chemical load and physicochemical state of the Ivin molecule. When combined with Cyclophosphamide, Ivin at low dose levels (7.1, 0.7 and 0.07 mg/kg bw) significantly reduced the frequency of metaphases with chromosome aberrations (by 55.7%, 62.9% и 72.9%, respectively), the amount of chromatid-type aberrations, polyploid, and multi-aberrant cells. This may be due to the gene protective effect of Ivin, because of the stabilization of membranes and its antioxidant effect.


Assuntos
Células da Medula Óssea , Aberrações Cromossômicas , Animais , Ciclofosfamida/toxicidade , Análise Citogenética , Masculino , Óxidos
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1221-1227, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798402

RESUMO

OBJECTIVE: To investigate the clinical efficacy and prognosis of double-hit multiple myeloma patients with deletion P53 treated with regimen based on bortezomib. METHODS: The ethnical data from 186 newly diagnosed MM patients hospitalized in the Department of Hematology of Harrison International Peace hospital from January 2012 to January 2019 were analyzed retrospectively. The fluorescent in situ hybridization (FISH) and G-binding staining were used to detect cytogenetic abnormalities (P53 deletion, lq21 amplification and IgH rearranagement) for analyses of complete remission (CR), overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) of patients treated with bortezomib for 4 circles. RESULTS: In 186 patients, simple P53 deletion was 14 cases, 1q21 amplification and P53 deletion were found in 11 cases (A group), t (14;16) and P53 deletion in 7 cases (B group), t (4;14) and P53 deletion in 9 cases (C group). The complete remission rate (CR%) of above-mentioned three groups was 27.27%, 28.57% and 33.33% respectively, and the ORR of the three groups was 54.54%, 57.14% and 55.56%, respectively, there was no statistically significant difference between the three groups (P>0.05). The patients with 1q21 amplification and P53 deletion had shorter OS and PFS time (P=0.041, P=0.046). The double-hit patients with 1q21 amplification showed shorter OS time, compared with the patients with P53 deletion (P=0.027). The double-hit patients with t(14;16) and t(4;14) showed shorter OS time (P=0.871, P=0.276) and PFS time (P=0.955, P=0.379) than those of the patients with P53 deletion. CONCLUSION: P53 deletion and 1q21 amplification are an adverse prognostic factor of early recurrence and short lifetime in patients with newly diagnosed double-hit MM.


Assuntos
Mieloma Múltiplo , Bortezomib , Aberrações Cromossômicas , Humanos , Hibridização in Situ Fluorescente , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Proteína Supressora de Tumor p53
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1272-1277, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798411

RESUMO

OBJECTIVE: To explore the renal pathology and cytogenetic features in the multiple myeloma (MM) patients with renal impairment. METHODS: The clinical data of newly diagnosed MM patients with renal impairment in our hospital from January 2009 to January 2019 were analyzed retrospectively, and the relationship between FISH results and results of renal pathological exanimation was analyzed statistically by using SPSS 20.0. RESULTS: A total of 20 patients underwent renal biopsy, included 12 males and 8 females. FISH result showed that out of 20 patients, 7 cases presented interstitial nephritis, among which 3 cases were negative for FISH, and in the remaining cases the rate of IgH rearrangement, 1q21 amplification, RB1 deletion, D13S319 deletion, and P53 deletion detection was 42.86%, 28.57%, 28.57%, 28.57% and 14.29% respectively, the detection positive rate was statistically significantly lower as compared with total probe positive rate (P<0.01). There were 6 cases of cast nephropathy, among which IgH rearrangement, the rate of 1q21 amplification, RB1 deletion, D13S319 deletion, and P53 deletion detection was 66.67%, 50%, 66.67%, 50% and 0% respectively. Compared with the total probe positive rate, there was no statistical significance (P>0.05). There were 4 cases of acute tubular necrosis, among which the detection rates of IgH rearrangement, 1q21 amplification, RB1 deletion, D13S319 deletion, and P53 deletion was 100%, 50%, 50%, 25% and 25%, respectively. Compared with the total probe positive rate, there was no statistical significance (P>0.05). There were one case of amyloidosis, and one case of tubular nephropathy with amyloidosis, the detection with 5 probes were all positive. One case of light chain deposition disease was positive for RB1 gene deletion + D13S319 gene deletion. CONCLUSION: FISH in the MM patients with different renal pathological changes is characterized by heterogeneity, which can be used to predict the risk of renal damage and speculate possible renal pathological types to guide prognosis.


Assuntos
Mieloma Múltiplo , Aberrações Cromossômicas , Análise Citogenética , Citogenética , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Estudos Retrospectivos
4.
N Engl J Med ; 383(12): 1182-1183, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32786182
5.
Anticancer Res ; 40(7): 3759-3764, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620615

RESUMO

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is an aggressive malignancy due to its increased ability for local metastases and distant lymph node metastases. Extensive cytogenetic analyses have detected chromosome instability (CI) patterns in OSCC including gross chromosome numerical alterations, such as polysomy and sporadically monosomy that negatively affect the biological behaviour of the malignancy. Our aim was to investigate the frequency and impact of chromosome 17 (Chr 17) numerical imbalances in OSCC. MATERIALS AND METHODS: Fifty (n=50) formalin-fixed, paraffin-embedded primary OSCCs tissue sections were used. Chromogenic in situ hybridization (CISH) was implemented for detecting Chr 17 centromeric numerical imbalances. Concerning the screening process in CISH slides, a novel real-time reference and calibration grid platform was implemented. RESULTS: Chr 17 multiple copies were observed in 12/50 (24%) of the examined cases. Polysomy was observed in 10/50 (20%) tissue sections, monosomy in 2/50 (4%), whereas the rest of them demonstrated a normal, diploid pattern (38/50-76%). Chr 17 numerical differences were associated with the grade of differentiation of the examined tumors (p=0.001). CONCLUSION: Chr 17 numerical imbalances (polysomy predominantly and monosomy) are observed in sub-groups of OSCCs correlating with a progressive dedifferentiation of malignant tissues. The proposed grid-based platform on CISH slides provides a novel, fast and accurate screening-mapping mechanism for detecting chromosome numerical aberrations.


Assuntos
Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 17/genética , Neoplasias Bucais/genética , Instabilidade Cromossômica/genética , Aberrações Cromossômicas , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino
6.
Toxicol Lett ; 332: 202-212, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32659469

RESUMO

A variety of methods have been developed for accurate and systematic evaluation of chemical genotoxicity. Ceric ammonium nitrate (CAN) and 1,3-propane sultone (1,3-PS) have been extensively applied in industrial fields. Although 1,3-PS, but not CAN, has been reported as a potent carcinogen, systematic assessment of the genotoxic properties of these chemicals has not been conducted. The purpose of this study was to establish a decision tree for evaluating genotoxicity based on the good laboratory practices (GLP) system using 1,3-PS and CAN as test chemicals. In vitro studies were performed including the bacterial reverse mutation assay, chromosomal aberration assay, and micronucleus assay. We conducted in vivo studies using a combined micronucleus and alkaline comet (MN-CMT) assay and the Pig-a gene mutation assay, which is a promising method for detecting gene mutations in vivo. CAN showed negative responses in all in vitro genotoxicity assays and the in vivo combined MN-CMT assay. Meanwhile, 1,3-PS had positive results in all in vitro and in vivo genotoxicity assays. In this study, we confirmed the genotoxicity of 1,3-PS and CAN using both in vitro and in vivo assays. We propose a decision tree for evaluating chemical-induced genotoxicity.


Assuntos
Cério/toxicidade , Árvores de Decisões , Mutagênicos/toxicidade , Tiofenos/toxicidade , Animais , Bactérias/efeitos dos fármacos , Linhagem Celular/efeitos dos fármacos , Aberrações Cromossômicas/efeitos dos fármacos , Ensaio Cometa , Cricetinae , Cricetulus , Dano ao DNA , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Testes para Micronúcleos , Testes de Mutagenicidade , Ratos Sprague-Dawley
7.
PLoS Comput Biol ; 16(7): e1008012, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32658894

RESUMO

Single-cell DNA sequencing technologies are enabling the study of mutations and their evolutionary trajectories in cancer. Somatic copy number aberrations (CNAs) have been implicated in the development and progression of various types of cancer. A wide array of methods for CNA detection has been either developed specifically for or adapted to single-cell DNA sequencing data. Understanding the strengths and limitations that are unique to each of these methods is very important for obtaining accurate copy number profiles from single-cell DNA sequencing data. We benchmarked three widely used methods-Ginkgo, HMMcopy, and CopyNumber-on simulated as well as real datasets. To facilitate this, we developed a novel simulator of single-cell genome evolution in the presence of CNAs. Furthermore, to assess performance on empirical data where the ground truth is unknown, we introduce a phylogeny-based measure for identifying potentially erroneous inferences. While single-cell DNA sequencing is very promising for elucidating and understanding CNAs, our findings show that even the best existing method does not exceed 80% accuracy. New methods that significantly improve upon the accuracy of these three methods are needed. Furthermore, with the large datasets being generated, the methods must be computationally efficient.


Assuntos
Variações do Número de Cópias de DNA , Genoma Humano , Análise de Sequência de DNA/métodos , Análise de Célula Única/métodos , Algoritmos , Aberrações Cromossômicas , Biologia Computacional , Simulação por Computador , Dosagem de Genes , Humanos , Mutação , Neoplasias/genética , Ploidias , Distribuição de Poisson , Curva ROC , Reprodutibilidade dos Testes , Software
8.
Nat Cell Biol ; 22(7): 856-867, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32601372

RESUMO

The ESCRT-III membrane fission machinery maintains the integrity of the nuclear envelope. Although primary nuclei resealing takes minutes, micronuclear envelope ruptures seem to be irreversible. Instead, micronuclear ruptures result in catastrophic membrane collapse and are associated with chromosome fragmentation and chromothripsis, complex chromosome rearrangements thought to be a major driving force in cancer development. Here we use a combination of live microscopy and electron tomography, as well as computer simulations, to uncover the mechanism underlying micronuclear collapse. We show that, due to their small size, micronuclei inherently lack the capacity of primary nuclei to restrict the accumulation of CHMP7-LEMD2, a compartmentalization sensor that detects loss of nuclear integrity. This causes unrestrained ESCRT-III accumulation, which drives extensive membrane deformation, DNA damage and chromosome fragmentation. Thus, the nuclear-integrity surveillance machinery is a double-edged sword, as its sensitivity ensures rapid repair at primary nuclei while causing unrestrained activity at ruptured micronuclei, with catastrophic consequences for genome stability.


Assuntos
Núcleo Celular/patologia , Cromatina/metabolismo , Aberrações Cromossômicas , Dano ao DNA , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Instabilidade Genômica , Proteínas de Membrana/metabolismo , Proteínas Nucleares/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Cromatina/genética , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Células HeLa , Humanos
9.
Bull Environ Contam Toxicol ; 105(1): 127-133, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32548730

RESUMO

In this work the toxicity caused by explosive industries effluent (yellow water) at different levels of toxicity (genetic, cellular and organismal level) was evaluated by the Allium cepa test and the Sorghum sudanense germination. The results showed that the effluent paralyze the mitotic process, keeping the cells in the interphase, decreasing the mitotic index in A. cepa. Chromosomal abnormalities such as c-metaphases, adhesions, breaks, early ascending chromosomes and irregular nucleus were observed for this receptor species. The germination of S. sudanense was reduced, and the development of the radicles were affected, showing reduced tolerance index at the highest concentrations of the effluent. Thus, it is concluded that the effluent from the explosive industry is extremely toxic to the tested organisms, both in cellular and chromosomal level and also for seed germination.


Assuntos
Substâncias Explosivas/toxicidade , Germinação/efeitos dos fármacos , Cebolas/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Aberrações Cromossômicas , Índice Mitótico , Cebolas/genética , Cebolas/fisiologia , Sorghum
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(3): 842-848, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32552945

RESUMO

OBJECTIVE: To analyze the diagnostic value of multiple reverse transcription-polymerase chain reaction (RT-PCR) for detecting different fusion genes in children with primary acute lymphoblastic leukemia (ALL). METHODS: The clinical data of 80 children with ALL treated in the 2nd affiliated hospital of Xi'an Medical College from September 2012 to September 2017 were collected and retrospectively analyzed. Immunophenotype, chromosome karyotype and fusion gene were analyzed. RESULTS: Immunophenotyping showed that there were 2 cases of mixed expression of myeloid + B system, 2 cases with pre- B expression, 58 cases with former B expression, 11 cases with CD13 combined with pre- B expression, 4 cases with CD5 combined with pre- B expression, and 3 cases with CD2 combined with pre- B expression. The results of chromosome karyotype analysis showed that among 72 cases of karyotype analysts 5 cases could not be analyzed, 27 cases were determined to be normal karyotype, 11 cases with abnormal karyotype and 29 cases without mitotic phase. Six fusion genes were expressed in 30 cases (37.50%) of 80 ALL children, including MLL/AF9, CBF/MYH 11, BCR/ABL, TLS/ERG, MLL/ENL and TEL/AML1. Among the 3 cases with MLL/AF9 fusion gene expression [t(9;11)], 2 cases showed a poor response to early treatment, but achieved complete remission after intensive chemotherapy, and 1 case accepted bone marrow transplantation; in 1 case with CBF/MYH 11 fusion gene expression, treatment was abandoned by family members, and 4 cases with BCR/ABL fusion gene expression [t (9;22) (q34; q11)] were all showed poor response to early treatment, and achieved complete remission after intensive chemotherapy. All the fusion genes were positive during remission, including 2 cases of bone marrow transplantation; 1 case with TLS/ERG fusion gene expression [t (16;21)] displayed poor response to early treatment, and completely remitted after intensive chemotherapy; 2 cases with MLL/ENL fusion gene expression [t (11;19)] recurred during chemotherapy; 19 cases with TEL/AML1 fusion gene expression [t (12;21)] also achieved complete remission. 4 cases achieved a partial remission. CONCLUSION: Genotyping can make up for the insufficiency of MICM typing, and multiplex RT-PCR can be used to rapidly detect the fusion genes caused by chromosomal aberration in children with ALL.


Assuntos
Leucemia Linfocítica Crônica de Células B , MicroRNAs/genética , Criança , Aberrações Cromossômicas , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Proteínas de Fusão Oncogênica , Estudos Retrospectivos
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(3): 983-988, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32552969

RESUMO

OBJECTIVE: To study the potential significance and clinical application of FGFR1 gene abnormality in the diagnosis, clinical features, pathological mechanism and treatment in hematological tumors. METHODS: Clinical data of total of 29 patient with chromosome of 8 short arm (8P) abnormality who had more comprehensive medical history from 2013 to 2018 were collected. The karyotype analysis of bone marrow chromosomes in patients was carried out by using chromosome R band banding technique. FGFR1 gene was detected by using fluorescence in situ hybridization (FISH). RESULTS: Seven cases of FGFR1 gene abnormalities were decteted, including 3 cases of FGFR1 gene amplification, 2 cases of translocation, and 2 cases of deletion. Five patients with FGFR1 gene amplification or deletion not accompaned with eosinophilia, moreover the chromosome was a complex karyotype with poor prognosis; Two cases of FGFR1 gene translocation were non-complex chromosomal translocation and one of which survived for 6 years after bone marrow transplantation, the other chromosome karyotype showed no rearrangement of 8 short arm. However, FGFR1 gene rearrangement was confirmed by FISH analysis, which was a rare insertional translocation. CONCLUSION: FGFR1 gene amplification or deletion often occur in cases with complex karyotype, which not accompany eosinophilia, moreover have poor prognosis. The patients with FGFR1 gene translocation accompany eosinophilia which is consistent with the clinical characteristics of myeloid / lymphoid neoplasms with FGFR1 abnormality. Karyotype analysis combined with FISH method can improve the detection of abnormal clones.


Assuntos
Neoplasias Hematológicas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Aberrações Cromossômicas , Neoplasias Hematológicas/metabolismo , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Translocação Genética
12.
Einstein (Sao Paulo) ; 18: eRC5335, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-32578677

RESUMO

Chromosomal abnormalities are responsible for several congenital malformations in the world, some of these are associated to telomeric/subtelomeric deletions. The abnormalities involving the telomere of chromosome 12 are rare, with few reports of deletions involving 12q24.31 region in the literature, and, to our knowledge, only four of them in the 12q24.31-q24.33 region. We report a further case of interstitial deletion of bands 12q24.31-q24.33 associated with autism spectrum disorder. A 2-year-old boy with global developmental delay associated with multiple congenital anomalies. The Human Genome CGH Microarray 60K confirmed the diagnosis of 12q deletion syndrome. This study made a review of the current literature comparing our patient with previously reported cases. These detailed analyses contribute to the development of genotype/phenotype correlations for 12q deletions that will aid in better diagnosis and prognosis of this deletion.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 12/genética , Doenças Raras/genética , Anormalidades Múltiplas , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Humanos , Masculino
14.
Niger J Clin Pract ; 23(6): 864-869, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32525124

RESUMO

Background: An important component of the first-trimester scan is nuchal translucency thickness at 11 weeks to 13 weeks 6 days of gestation. A nuchal translucency ≥3.3 mm is a significant early pregnancy scan finding associated with Trisomies 13, 18, and 21 and congenital heart diseases. Aims: To determine the prevalence and outcome of increased fetal nuchal translucency among pregnant women. Subjects and Methods: A prospective cohort study at the Obstetrics and Gynaecology Department of Usmanu Danfodiyo University Teaching Hospital Sokoto. This was a prospective study of 265 consecutively recruited women in the first trimester of pregnancy who presented to antenatal clinics over a 20-week period. An NT scan was conducted at 11 weeks to 13 weeks 6 days followed by an anomaly scan at 18-22 weeks. Patients were followed up to delivery and 6-week post-partum. The neonates were examined at delivery and at 6-week postnatal life. Data entry and analysis was done with IBM SPSS version 20. The level of significance was set at less than 0.05. Frequency distribution; student t-test and Chi-squared test. Results: The 95th percentile NT was 3.3 mm and the prevalence of increased NT above 3.3 mm was 3%. The mean maternal age of the participants was 28.1 ± 5.1 years and the modal parity was Para 0. The most common anomalies associated with increased NT were ventricular septal defect and spina bifida. A congenital anomaly was significantly associated with increased NT (P < 0.001). Conclusions: The prevalence of increased fetal nuchal translucency is relatively high in our environment and is associated with congenital fetal defects. Routine screening with first-trimester ultrasound will help detect congenital anomalies early.


Assuntos
Transtornos Cromossômicos/diagnóstico por imagem , Feto/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Medição da Translucência Nucal/estatística & dados numéricos , Adulto , Aberrações Cromossômicas , Estudos de Coortes , Feminino , Idade Gestacional , Cardiopatias Congênitas , Hospitais de Ensino , Humanos , Recém-Nascido , Idade Materna , Nigéria/epidemiologia , Medição da Translucência Nucal/métodos , Gravidez , Primeiro Trimestre da Gravidez , Prevalência , Estudos Prospectivos , Ultrassonografia Pré-Natal , Adulto Jovem
15.
Nature ; 584(7819): 136-141, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581363

RESUMO

Clonally expanded blood cells that contain somatic mutations (clonal haematopoiesis) are commonly acquired with age and increase the risk of blood cancer1-9. The blood clones identified so far contain diverse large-scale mosaic chromosomal alterations (deletions, duplications and copy-neutral loss of heterozygosity (CN-LOH)) on all chromosomes1,2,5,6,9, but the sources of selective advantage that drive the expansion of most clones remain unknown. Here, to identify genes, mutations and biological processes that give selective advantage to mutant clones, we analysed genotyping data from the blood-derived DNA of 482,789 participants from the UK Biobank10. We identified 19,632 autosomal mosaic chromosomal alterations and analysed these for relationships to inherited genetic variation. We found 52 inherited, rare, large-effect coding or splice variants in 7 genes that were associated with greatly increased vulnerability to clonal haematopoiesis with specific acquired CN-LOH mutations. Acquired mutations systematically replaced the inherited risk alleles (at MPL) or duplicated them to the homologous chromosome (at FH, NBN, MRE11, ATM, SH2B3 and TM2D3). Three of the genes (MRE11, NBN and ATM) encode components of the MRN-ATM pathway, which limits cell division after DNA damage and telomere attrition11-13; another two (MPL and SH2B3) encode proteins that regulate the self-renewal of stem cells14-16. In addition, we found that CN-LOH mutations across the genome tended to cause chromosomal segments with alleles that promote the expansion of haematopoietic cells to replace their homologous (allelic) counterparts, increasing polygenic drive for blood-cell proliferation traits. Readily acquired mutations that replace chromosomal segments with their homologous counterparts seem to interact with pervasive inherited variation to create a challenge for lifelong cytopoiesis.


Assuntos
Evolução Clonal/genética , Células Clonais/metabolismo , Hematopoese/genética , Herança Multifatorial/genética , Adulto , Idoso , Alelos , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Divisão Celular/genética , Aberrações Cromossômicas , Células Clonais/citologia , Células Clonais/patologia , Feminino , Predisposição Genética para Doença , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Perda de Heterozigosidade/genética , Masculino , Pessoa de Meia-Idade , Mosaicismo , Reino Unido
16.
Nature ; 584(7819): 130-135, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581364

RESUMO

The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers1-10. Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28-91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted.


Assuntos
Envelhecimento/genética , Aberrações Cromossômicas , Cromossomos Humanos/genética , Células Clonais/metabolismo , Genoma Humano/genética , Células-Tronco Hematopoéticas/metabolismo , Mutação , Idoso de 80 Anos ou mais , Alelos , Linhagem da Célula , Células Clonais/citologia , Células Clonais/patologia , Estudos de Coortes , Feminino , Loci Gênicos/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Humanos , Japão , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia de Células T/genética , Leucemia de Células T/patologia , Masculino , Mosaicismo , Reino Unido
17.
Toxicology ; 441: 152507, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32512035

RESUMO

Vorinostat was approved as the first histone deacetylase inhibitor for the management of cutaneous T cell lymphoma. However, it's in vivo genetic and epigenetic effects on non-cancerous cells remain poorly understood. As genetic and epigenetic changes play a critical role in the pathogenesis of carcinogenesis, we investigated whether vorinostat induces genetic and epigenetic alterations in mouse bone marrow cells. Bone marrow cells were isolated 24 h following the last oral administration of vorinostat at the doses of 25, 50, or 100 mg/kg/day for five days (approximately equal to the recommended human doses). The cells were then used to assess clastogenicity and aneugenicity by the micronucleus test complemented by fluorescence in situ hybridization assay; DNA strand breaks, oxidative DNA strand breaks, and DNA methylation by the modified comet assay; apoptosis by annexin V/PI staining analysis and the occurrence of the hypodiploid DNA content; and DNA damage/repair gene expression by polymerase chain reaction (PCR) Array. The expression of the mRNA transcripts were also confirmed by real-time PCR and western blot analysis. Vorinostat caused structural chromosomal damage, numerical chromosomal abnormalities, DNA strand breaks, oxidative DNA strand breaks, DNA hypomethylation, and programed cell death in a dose-dependent manner. Furthermore, the expression of numerous genes implicated in DNA damage/repair were altered after vorinostat treatment. Accordingly, the genetic/epigenetic mechanism(s) of action of vorinostat may play a role in its carcinogenicity and support the continued study and development of new compounds with lower toxicity.


Assuntos
Antineoplásicos/toxicidade , Células da Medula Óssea/efeitos dos fármacos , Vorinostat/toxicidade , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Aberrações Cromossômicas/induzido quimicamente , Ensaio Cometa , Metilação de DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Vorinostat/administração & dosagem
18.
Anim Sci J ; 91(1): e13401, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32524695

RESUMO

The aim of this study was to examine whether a morphological approach is efficient for selecting high-quality porcine embryos produced by in vitro fertilization (IVF) under high polyspermy conditions. Frozen-thawed Meishan epididymal spermatozoa showing moderate and high polyspermy were subjected to IVF (1 × 105  sperms/ml). Under conditions of moderate polyspermy, 4-cell embryos selected at 48 hr after IVF (single selection) and 8-cell embryos selected at 79 hr after IVF from the collected 4-cell embryos (double selection) showed high developmental competence. Likewise, 4- and 8-cell embryos produced by IVF under high polyspermy conditions also showed high competence for development to blastocysts. However, blastocysts derived from high polyspermy conditions had significantly fewer cells than those produced under moderate polyspermy conditions. Furthermore, the frequency of nuclear and chromosomal abnormalities in 4- and 8-cell embryos produced under conditions of high polyspermy was significantly (p < .05) higher in comparison to moderate polyspermy conditions. These findings suggest that although high polyspermy affects the frequency of nuclear and chromosomal anomalies in porcine IVF embryos, subsequent selection based on morphological features of 4- and 8-cell embryos even under high polyspermy conditions, could be an alternative option for selecting porcine IVF embryos with high development ability.


Assuntos
Blastocisto/citologia , Desenvolvimento Embrionário , Fertilização In Vitro/veterinária , Interações Espermatozoide-Óvulo , Espermatozoides/fisiologia , Suínos/embriologia , Suínos/fisiologia , Animais , Aberrações Cromossômicas/veterinária , Feminino , Masculino
19.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(1): 73-78, 2020 Jan 30.
Artigo em Chinês | MEDLINE | ID: mdl-32376550

RESUMO

OBJECTIVE: To investigate the association of chromosomal polymorphisms with multinucleated embryos in infertile couples undergoing in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI). METHODS: This retrospective case-control study was conducted among 1145 infertile couples undergoing their first IVF/ICSI cycles. According to their karyotype, the couples were divided into chromosomal polymorphism group and control group, and the former group was divided into 3 subgroups: inversion group, D and G genome polymorphic group and 1, 9, and 16 qh+group. The blastomere multinucleation rate, clinical pregnancy rate and live birth rate were compared between the groups. RESULTS: Of the total of 1145 couples, 139 (6.10%) had chromosomal polymorphisms at least in one partner. No significant differences were found in female age, BMI, basal FSH level, total gonadotropin dose, E2 level on day of HCG, number of oocytes retrieved, fertilization rate, top quality embryo rate, clinical pregnancy rate or live birth rate among the groups (P > 0.05). The multinuclear rate of the embryos in couples with pericentric inversion of chromosomes 1, 9, and Y chromosomes and those with D and G genome polymorphisms were 8.23% and 4.65%, respectively, significantly higher than that in the control group (2.69%; P < 0.05); the multinuclear rate of the embryos was 2.77% in 1, 9, and 16 qh+ group, similar with that in the control group (P > 0.05). CONCLUSIONS: Infertile couples with pericentric inversion of chromosomes 1, 9, and Y chromosomes and in those with D and G genome polymorphism are at higher risks of blastomere multinucleation in IVF- ICSI cycles; 1, 9, and 16 qh + polymorphisms do not increase the rate of blastomere multinucleation of the embryos.


Assuntos
Blastômeros , Núcleo Celular/patologia , Aberrações Cromossômicas , Injeções de Esperma Intracitoplásmicas , Estudos de Casos e Controles , Inversão Cromossômica , Desenvolvimento Embrionário , Feminino , Fertilização In Vitro , Humanos , Cariótipo , Masculino , Gravidez , Taxa de Gravidez , Estudos Retrospectivos
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