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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1094-1096, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703133

RESUMO

OBJECTIVE: To assess the value of non-invasive prenatal testing (NIPT) for the identification of fetal chromosomal aneuploidies. METHODS: For 9470 pregnant women with a moderate-to-high risk by conventional serological screening or advanced maternal age, peripheral venous blood samples were collected and, following extraction of free fetal DNA, subjected to large-scale parallel sequencing on a Illumina Hiseq2000 platform. Those with a high risk by NIPT were validated by invasive prenatal diagnosis. RESULTS: Out of the 9470 samples, 194 cases (2.0%) were positive by NIPT testing. These included 50 trisomy 21, 11 trisomy 18, 17 trisomy 13, 44 other autosomal aneuploidies, 55 sex chromosomal aneuploidies, and 17 chromosomal copy number variations. As validated by amniotic fluid or umbilical blood chromosomal karyotyping analysis, NIPT has a false positive rate of 2.0%, 18.2%, 41.2%, 97.7%, 81.8%, 94.1%, respectively. The test has a sensitivity of 100% and a specificity of 98.79%. CONCLUSION: For common chromosomal aneuploidies such as trisomy 21 and trisomy 18, NIPT has a good sensitivity and specificity, therefore has good value for clinical application.


Assuntos
Aneuploidia , Transtornos Cromossômicos/diagnóstico , Variações do Número de Cópias de DNA , Diagnóstico Pré-Natal , Feminino , Humanos , Gravidez , Sensibilidade e Especificidade , Trissomia , Síndrome da Trissomía do Cromossomo 18
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1120-1122, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703140

RESUMO

OBJECTIVE: To report on a case of maternally derived 45,X mosaicism detected by non-invasive prenatal testing (NIPT). METHODS: Fetal sex chromosomal abnormality was detected by NIPT. Maternally derived 45,X mosaicism was confirmed by chromosome karyotype analysis. Fetal sex chromosome aneuploidy was detected by amniotic fluid chromosome microarray analysis. RESULTS: A maternal 45,X mosaicism was diagnosed. The fetus was confirmed to be normal. CONCLUSION: Maternal 45,X masaicism can be diagnosed by NIPT.


Assuntos
Mosaicismo , Diagnóstico Pré-Natal , Aberrações dos Cromossomos Sexuais , Aneuploidia , Feminino , Humanos , Cariotipagem , Gravidez
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 970-974, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598938

RESUMO

OBJECTIVE: To determine the frequency of chromosomal abnormalities and outcome of pregnancy for fetuses with increased nuchal translucency (NT). METHODS: Between July 2014 and February 2018, 247 fetuses with increased NT (>95th centile)were analyzed by chromosome microarray analysis (CMA). The fetuses were divided into ones with isolated increased NT (168 cases), increased NT with cystic hygroma (20 cases), increased NT with edema (12 cases) or increased NT with other abnormalities (47 cases). All couples were followed up by telephone calls. RESULTS: The rate of chromosomal abnormalities was 31.6% (78/247), which included 66 cases with chromosomal aneuploidies and 12 with copy number variants (CNVs). CNVs accounted for 31.4% (11/35) of total abnormalities among fetuses with isolated increased NT, whilst only 2.3% (1/43) of the total abnormalities among fetuses with non-isolated increased NT. Three fetuses with a normal CMA result had mental and physical retardation. Two of them were diagnosed with single gene disorders by whole exome sequencing. CONCLUSION: CMA can detect more chromosomal microdeletion/microduplications among fetuses with isolated increased NT. Furthermore, fetuses with increased NT and anegative CMA result during pregnancy cannot exclude all adverse outcomes.


Assuntos
Aberrações Cromossômicas , Análise em Microsséries , Medição da Translucência Nucal , Resultado da Gravidez , Diagnóstico Pré-Natal , Aneuploidia , Cromossomos , Variações do Número de Cópias de DNA , Edema , Feminino , Feto , Humanos , Linfangioma Cístico , Gravidez , Ultrassonografia Pré-Natal
4.
Rev Med Suisse ; 15(668): 1909-1913, 2019 Oct 23.
Artigo em Francês | MEDLINE | ID: mdl-31643150

RESUMO

In Switzerland, since modifications of the law regulating reproductive medicine introduced the 1rst of September 2017, preimplantation genetic testing (PGT) has been legalised. Infertile couples undergoing in vitro fertilization (IVF) can benefit from this technology by detecting which embryos are aneuploid (ie abnormal number of chromosomes, PGT-A). This is performed in order to transfer euploid embryos (normal number of chromosomes) and to optimise success, though data are limited. Couples at risk of transmitting a severe monogenic disease or unbalanced translocation can undergo PGT for monogenic disease or chromosomal structural rearrangements (PGT-M/SR). These tests are subject to strict legal criteria. Their clinical application needs to be approved through a multidisciplinary approach taking into account legal and ethical issues while respecting the autonomy of the couples.


Assuntos
Testes Genéticos/ética , Testes Genéticos/legislação & jurisprudência , Diagnóstico Pré-Implantação/ética , Aneuploidia , Feminino , Fertilização In Vitro , Testes Genéticos/métodos , Humanos , Masculino , Gravidez , Diagnóstico Pré-Implantação/métodos , Suíça
5.
Medicine (Baltimore) ; 98(39): e17342, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574874

RESUMO

RATIONALE: The karyotype 49,XXXXY is a rare form of Klinefelter syndrome usually presenting with ambiguous genitalia, facial dysmorphism, mental retardation, and a combination of cardiac, skeletal, and other malformations. PATIENT CONCERNS: We describe a 19-year-old man, whose chromosomal analysis of peripheral blood revealed a karyotype of 49,XXXXY. His mental development and motor ability were significantly delayed. At the age of 19, he had failed to develop secondary sexual characteristics. His random blood glucose level was 19.61 mmol/L, and he showed dry mouth, polydipsia, and polyuria. He had a characteristic facial appearance with prognathism, widened nasal bridge, and strabismus. His bilateral elbow rotation was limited. He had atrophic testes with micropenis. Ophthalmic examination revealed a polar cataract in both eyes. DIAGNOSIS: He was diagnosed with Klinefelter syndrome associated with cleft palate, hypothyroidism, cataracts, diabetes, and other anomalies. INTERVENTIONS: After the initial diagnosis, the patient received intensive insulin therapy to correct hyperglycemia, and he received calcium and vitamin D supplements. The patient also received testosterone and thyroid hormone replacement therapy for primary hypogonadism. OUTCOMES: The patient was discharged 12 days after receiving treatment; meanwhile, there were no clinical symptoms of dry mouth, polyuria and polyuria, and his blood glucose level was controlled. LESSONS: The combination of cleft palate, hypothyroidism, cataracts, diabetes, and osteoporosis in 49,XXXXY syndrome has not yet been reported. Early treatment and appropriate care can significantly improve the patient's quality of life and prevent serious consequences.


Assuntos
Catarata/congênito , Fissura Palatina/genética , Hipotireoidismo Congênito/genética , Diabetes Mellitus/congênito , Transtornos dos Cromossomos Sexuais/complicações , Anormalidades Múltiplas/genética , Aneuploidia , Cromossomos Humanos X/genética , Humanos , Cariotipagem , Masculino , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/genética , Adulto Jovem
6.
BMC Cancer ; 19(1): 650, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266459

RESUMO

BACKGROUND: DNA aneuploidy has attracted growing interest in clinical practice. Nevertheless, its prognostic value in gastric cancer patients remains controversial. This meta-analysis aims to explore the impact of DNA ploidy status on the survival of gastric cancer patients. METHODS: We used PubMed and Web of Science databases to retrieve relevant articles. The correlation between DNA aneuploidy and the clinicopathological features of gastric cancer, such as stage, depth of invasion (T), lymph node metastasis (N), distant metastasis (M), differentiation (G), tumor types (Lauren classification) and overall survival (OS) were evaluated. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were collected carefully from each article OS was presented with HRs. The relationships between DNA aneuploidy and each characteristic were analyzed using risk ratios (RR) and a 95% confidence interval (CI). Significance was established using P < 0.05. Funnel plot was conducted to detect the publication bias. RESULTS: After careful selection, 25 studies involving 3449 cases were eligible for further analyses. Patients with DNA aneuploidy were considered at risk of more advanced stages (stage III-IV vs. stages I-II, RR = 1.23; 95% CI, 1.07 to 1.42; P = 0.003), lymph node metastasis (N+ vs. N-: RR = 1.43; 95% CI, 1.12 to 1.82, P = 0.004), and intestinal tumor type (intestinal vs. diffuse: RR = 1.45; 95% CI, 1.02 to 2.06; P = 0.04). And an adverse relation was observed between DNA aneuploidy and tumor differentiation. While no association was found between DNA aneuploidy and distant metastasis (P = 0.42) nor depth of tumor invasion (P = 0.86). Regarding overall survival, aneuploid tumors were associated with worse survival in all patients (P < 0.00001). CONCLUSIONS: We found that DNA aneuploidy was an important predictor for gastric cancer patients, and should be used as a potential biomarker for further classification in gastric cancer.


Assuntos
Aneuploidia , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Intervalos de Confiança , DNA de Neoplasias , Humanos , Metástase Linfática , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Gástricas/patologia
7.
BMC Cancer ; 19(1): 651, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269908

RESUMO

BACKGROUND: Aneuploidy of chromosome 8 in circulating tumor cells (CTCs) has been reported correlates with therapeutic efficacy and prognosis in patients with advanced gastric cancer. However, it is not clear whether it is also appropriate for other cancer. Therefore, in this study, we evaluate the clinical application aneuploidy of CTCs for esophageal cancer. METHODS: Peripheral blood were collected for karyotyping analysis before and after first 4-cycles chemotherapy from seventy nine patients with newly diagnosed esophageal cancer. Karyotyping of chromosome 8 in CTCs detected by SET-iFISH (Subtraction Enrichment-Immunostaining fluorescence in situ hybridizatio) in those patients were grouped into two categories according to CTC number: triploid group and non-triploid group. Pearson Chi-Square were used to compare the association between different aneuploidy type and chemotherapeutic sensitivity and efficacy. RESULTS: Among the 16 patients with triploid of chromosome 8, 4 patients benefit, and of the 63 patients with non-triploid, 54 patients benefit. Chi-square test analysis found that clinical benefit of non-triploid patients was significantly higher than triploid patients, suggesting non-triploid patients were more sensitive to chemotherapy than triploid patients. After 4-cycles chemotherapy, it is found that chemotherapeutic efficacy was positively correlated with non-triploid proportion. These results suggest that non-triploid proportion could be used as a candidate maker for assessing chemotherapeutic efficacy. CONCLUSIONS: Monitoring aneuploidy of chromosome 8 in CTCs before and after chemotherapy may help predict sensitivity and efficacy of chemotherapy in patients with esophageal cancer.


Assuntos
Aneuploidia , Cromossomos Humanos Par 8 , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Cariotipagem , Células Neoplásicas Circulantes , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/patologia , Humanos , Hibridização in Situ Fluorescente/métodos , Técnicas de Hibridização Subtrativa , Resultado do Tratamento , Triploidia
8.
Cell Prolif ; 52(5): e12657, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31264311

RESUMO

OBJECTIVES: A high rate of chromosome aneuploidy is exhibited in in vitro fertilization (IVF)-derived embryos. Our previous experiments suggested that reactive oxygen species (ROS) can activate Mad2, a key protein in the spindle assembly checkpoint (SAC), and delay the first mitotic, providing time to prevent the formation of embryonic aneuploidy. We aimed to determine whether mitotic kinase Aurora B was involved in the SAC function to prevent aneuploidy in IVF-derived embryos. MATERIALS AND METHODS: We analysed aneuploidy formation and repair during embryo pre-implantation via 4',6-diamidino-2-phenylindole (DAPI) staining and karyotype analysis. We assessed Aurora B activation by immunofluorescence and investigated the effect of Aurora B inhibition on embryo injury-related variables, such as embryonic development, ROS levels, mitochondrial membrane potential and γH2AX-positive expression. RESULTS: We observed the expression and phosphorylation of Thr232 in Aurora B in oxidative stress-induced zygotes. Moreover, inhibition of Aurora B caused chromosome mis-segregation, abnormal spindle structures, abnormal chromosome number and reduced expression of Mad2 in IVF embryos. Our results suggest that Aurora B causes mitotic arrest and participates in SAC via Mad2 and H3S10P, which is required for self-correction of aneuploidies. CONCLUSIONS: We demonstrate here that oxidative stress-induced DNA damage triggers Aurora B-mediated activation of SAC, which prevents aneuploidy at the first mitotic cleavage in early mouse IVF embryos.


Assuntos
Aurora Quinase B/metabolismo , Proteínas Mad2/metabolismo , Aneuploidia , Animais , Aurora Quinase B/antagonistas & inibidores , Segregação de Cromossomos/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Feminino , Peróxido de Hidrogênio/farmacologia , Pontos de Checagem da Fase M do Ciclo Celular , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitose , Organofosfatos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Quinazolinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Zigoto/metabolismo
9.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(3): 419-424, 2019 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-31282340

RESUMO

The chromosomal aneuploidy in oocytes is one of main causes of abortion and neonatal birth defects.It is mainly due to the premature separation of sister chromatid caused by the loss of Cohesin protein complex and the non-disjunction sister chromatids caused by abnormal microtubule dynamics aneuploidy.As a pathway of protein post-translational modification,SUMO modification(or SUMOylation)involves many physiological regulation processes including cell proliferation,differentiation,apoptosis,and cycle regulation.In the oocytes,SUMOylation can regulate the localization of Cohesin protein complex on the chromosome to affect the chromosomal aneuploidy in oocytes caused by premature separation of sister chromatid.On the other hand,SUMOylation can regulate the microtubule dynamics to affect the chromosomal aneuploidy in oocytes caused by non-disjunction sister chromatids.Therefore,SUMOylation plays an important role in regulating the chromosomal aneuploidy of oocytes;the exact mechanisms via which the SUMOylated substrates affect aneuploidy in oocytes remain unclear.This articles reviews the roles of SUMOylation in premature separation and non-isolated chromatid aneuploidy in oocyte from the effects of SUMOylationon Cohesin protein complex and microtubule dynamics.


Assuntos
Aneuploidia , Cromátides , Segregação de Cromossomos , Oócitos/citologia , Sumoilação , Proteínas de Ciclo Celular , Proteínas Cromossômicas não Histona , Humanos , Microtúbulos
10.
J Korean Med Sci ; 34(24): e172, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31222985

RESUMO

BACKGROUND: Non-invasive prenatal testing (NIPT) using cell-free fetal DNA from maternal plasma for fetal aneuploidy identification is expanding worldwide. The objective of this study was to evaluate the clinical utility of NIPT for the detection of trisomies 21, 18, and 13 of high-risk fetus in a large Korean population. METHODS: This study was performed retrospectively, using stored maternal plasma from 1,055 pregnant women with singleton pregnancies who underwent invasive prenatal diagnosis because of a high-risk indication for chromosomal abnormalities. The NIPT results were confirmed by karyotype analysis. RESULTS: Among 1,055 cases, 108 cases of fetal aneuploidy, including trisomy 21 (n = 57), trisomy 18 (n = 42), and trisomy 13 (n = 9), were identified by NIPT. In this study, NIPT showed 100% sensitivity and 99.9% specificity for trisomy 21, and 92.9% sensitivity and 100% specificity for trisomy 18, and 100% sensitivity and 99.9% specificity for trisomy 13. The overall positive predictive value (PPV) was 98.1%. PPVs for trisomies 21, 18, and 13 ranged from 90.0% to 100%. CONCLUSION: This study demonstrates that our NIPT technology is reliable and accurate when applied to maternal DNA samples collected from pregnant women. Further large prospective studies are needed to adequately assess the performance of NIPT.


Assuntos
Aberrações Cromossômicas , Síndrome de Down/diagnóstico , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Adulto , Aneuploidia , Estudos de Casos e Controles , Ácidos Nucleicos Livres/metabolismo , Síndrome de Down/genética , Feminino , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Gravidez , Diagnóstico Pré-Natal , República da Coreia , Estudos Retrospectivos , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/epidemiologia , Adulto Jovem
11.
Genes Dev ; 33(15-16): 1031-1047, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31196865

RESUMO

Aneuploidy, a condition characterized by chromosome gains and losses, causes reduced fitness and numerous cellular stresses, including increased protein aggregation. Here, we identify protein complex stoichiometry imbalances as a major cause of protein aggregation in aneuploid cells. Subunits of protein complexes encoded on excess chromosomes aggregate in aneuploid cells, which is suppressed when expression of other subunits is coordinately altered. We further show that excess subunits are either degraded or aggregate and that protein aggregation is nearly as effective as protein degradation at lowering levels of excess proteins. Our study explains why proteotoxic stress is a universal feature of the aneuploid state and reveals protein aggregation as a form of dosage compensation to cope with disproportionate expression of protein complex subunits.


Assuntos
Aneuploidia , Citosol/metabolismo , Compensação de Dosagem (Genética)/fisiologia , Agregados Proteicos/genética , Humanos , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Agregação Patológica de Proteínas , Subunidades Proteicas/metabolismo , Proteólise , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
12.
Nat Commun ; 10(1): 2588, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197172

RESUMO

The brain is a genomic mosaic shaped by cellular responses to genome damage. Here, we manipulate somatic genome stability by conditional Knl1 deletion from embryonic mouse brain. KNL1 mutations cause microcephaly and KNL1 mediates the spindle assembly checkpoint, a safeguard against chromosome missegregation and aneuploidy. We find that following Knl1 deletion, segregation errors in mitotic neural progenitor cells give rise to DNA damage on the missegregated chromosomes. This triggers rapid p53 activation and robust apoptotic and microglial phagocytic responses that extensively eliminate cells with somatic genome damage, thus causing microcephaly. By leaving only karyotypically normal progenitors to continue dividing, these mechanisms provide a second safeguard against brain somatic aneuploidy. Without Knl1 or p53-dependent safeguards, genome-damaged cells are not cleared, alleviating microcephaly, but paradoxically leading to total pre-weaning lethality. Thus, mitotic genome damage activates robust responses to eliminate somatic mutant cells, which if left unpurged, can impact brain and organismal fitness.


Assuntos
Aneuploidia , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/genética , Segregação de Cromossomos/genética , Dano ao DNA/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Instabilidade Genômica , Humanos , Cinetocoros/metabolismo , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Cultura Primária de Células , Deleção de Sequência , Fuso Acromático/metabolismo
13.
Z Geburtshilfe Neonatol ; 223(3): 179-183, 2019 Jun.
Artigo em Alemão | MEDLINE | ID: mdl-31200400

RESUMO

Noninvasive prenatal testing (NIPT) is a screening test for fetal chromosome disorders. Recent studies show an incidental detection of maternal malignancies in NIPT diagnostics, where the simultaneous presence of multiple aneuploidies is described as an NIPT "anomaly". In this case, the diagnosis of a maternal tumor disease was made due to a repeat NIPT failure (no call).


Assuntos
Ácidos Nucleicos Livres , Transtornos Cromossômicos , Doenças Fetais , Neoplasias , Adulto , Aneuploidia , Transtornos Cromossômicos/diagnóstico , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Testes Genéticos , Humanos , Achados Incidentais , Programas de Rastreamento , Neoplasias/diagnóstico , Neoplasias/genética , Gravidez , Diagnóstico Pré-Natal
14.
Environ Pollut ; 252(Pt A): 388-398, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158667

RESUMO

Dibutyl phthalate (DBP), one of the most widely used plasticizers, is a known environmental endocrine disruptor that impairs male and female fertility. In this study, oral administration of DBP was given to pregnant mice on 14.5 days post coitus (dpc) for 3 days; and additionally, DBP was added into the culture of 14.5 dpc fetal ovaries for 3 days. DBP exposure during gestation disturbed the progression of meiotic prophase I of mouse oocytes, specifically from the zygotene to pachytene stages. Meanwhile, the DBP-exposed pachytene oocytes showed increased homologous recombination sites and unrepaired DNA damage. Furthermore, DBP caused DNA damage by increasing oxidative stress, decreased the expression of multiple critical meiotic regulators, and consequently induced oocyte apoptosis. Moreover, the effect of DBP on meiosis I prophase involved estrogen receptors α and ß. Collectively, these results demonstrated a set of meiotic defects in DBP-exposed fetal oocytes. As aberrations in homologous recombination can result in aneuploid gametes and embryos, this study provides new support for the deleterious effects of phthalates.


Assuntos
Dibutilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Recombinação Homóloga/efeitos dos fármacos , Prófase Meiótica I/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Plastificantes/toxicidade , Aneuploidia , Animais , Apoptose/efeitos dos fármacos , Feminino , Masculino , Prófase Meiótica I/genética , Camundongos , Oócitos/patologia , Ovário/efeitos dos fármacos , Ovário/patologia , Gravidez
15.
Medicine (Baltimore) ; 98(25): e15968, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232928

RESUMO

The aim of this study was to analyze the relationship between the percent of euploid embryo and the tolerance of embryo biopsy in preimplantation genetic screening (PGS).PubMed and trial registers were searched for clinical studies that patients were randomized to the PGS group or the control group from 1995 to October 2017. The patients of advanced maternal age, repeated implantation failure, and good prognosis with or without PGS in randomized controlled trials (RCTs) were collected.Original data from 9 RCT studies comparing in-vitro fertilization with and without PGS including 1642 patients were obtained and they were divided into 3 subgroups according to the percent of euploid embryo. PGS significantly increased live birth babies per embryo transferred (risk ratio: 2.98, 95% confidence interval: 1.54-5.75) in ≤30% of euploid embryo subgroups and but in other 2 groups, PGS has no effect. Significant negative correlation was found between the percent of euploid embryo and the tolerance of embryo biopsy in PGS (r = 0.80, P = 0.010)The tolerance of embryo biopsy in PGS was associated negatively with the percent of euploid embryo. There was a beneficial effect when PGS was used in the patients with the lowest percent of euploid embryo.


Assuntos
Aneuploidia , Transferência Embrionária , Diagnóstico Pré-Implantação , Biópsia , Feminino , Humanos , Gravidez , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Nature ; 570(7759): 117-121, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31068692

RESUMO

Aneuploidy, which refers to unbalanced chromosome numbers, represents a class of genetic variation that is associated with cancer, birth defects and eukaryotic micro-organisms1-4. Whereas it is known that each aneuploid chromosome stoichiometry can give rise to a distinct pattern of gene expression and phenotypic profile4,5, it remains a fundamental question as to whether there are common cellular defects that are associated with aneuploidy. Here we show the existence in budding yeast of a common aneuploidy gene-expression signature that is suggestive of hypo-osmotic stress, using a strategy that enables the observation of common transcriptome changes of aneuploidy by averaging out karyotype-specific dosage effects in aneuploid yeast-cell populations with random and diverse chromosome stoichiometry. Consistently, aneuploid yeast exhibited increased plasma-membrane stress that led to impaired endocytosis, and this defect was also observed in aneuploid human cells. Thermodynamic modelling showed that hypo-osmotic-like stress is a general outcome of the proteome imbalance that is caused by aneuploidy, and also predicted a relationship between ploidy and cell size that was observed in yeast and aneuploid cancer cells. A genome-wide screen uncovered a general dependency of aneuploid cells on a pathway of ubiquitin-mediated endocytic recycling of nutrient transporters. Loss of this pathway, coupled with the endocytic defect inherent to aneuploidy, leads to a marked alteration of intracellular nutrient homeostasis.


Assuntos
Aneuploidia , Pressão Osmótica , Proteoma/genética , Proteoma/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética , Estresse Fisiológico , Membrana Celular/metabolismo , Membrana Celular/patologia , Proteínas de Ligação a DNA/metabolismo , Endocitose , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Homeostase , Humanos , Cariótipo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Termodinâmica , Fatores de Transcrição/metabolismo , Transcriptoma/genética , Ubiquitina/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo
17.
Methods Mol Biol ; 1975: 407-426, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062320

RESUMO

Due to their unique cellular features, pluripotent stem cells (PSCs) acquire chromosomal aberrations at a rather high frequency during their growth in culture. Analysis of chromosomal integrity should be routinely performed and usually is done at the DNA level of the cells. RNA sequencing (RNA-Seq) has recently become the basic tool for transcriptional studies. Therefore, methods that utilize this already available data to inspect the genomic integrity are very valuable. In this chapter, we provide a practical guide to implement methods of detection of chromosomal aberrations, which are based on RNA-Seq data. The expression-based karyotyping (e-Karyotyping) method is based on global gene expression analysis, while the expressed-SNP-karyotyping (eSNP-Karyotyping) method is based on changes in the ratio between alleles.


Assuntos
Aneuploidia , Biologia Computacional/métodos , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Cariotipagem/métodos , Células-Tronco Pluripotentes/citologia , Polimorfismo de Nucleotídeo Único , Humanos
18.
Appl Microbiol Biotechnol ; 103(12): 4869-4880, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31053912

RESUMO

The yeast Saccharomyces cerevisiae has been widely used as a model system for studying the physiological and pharmacological action of small-molecular drugs. Here, a heterozygous diploid S. cerevisiae strain QSS4 was generated to determine whether drugs could induce chromosomal instability by determining the frequency of mitotic recombination. Using the combination of a custom SNP microarray and yeast screening system, the patterns of chromosomal instability induced by drugs were explored at the whole genome level in QSS4. We found that Zeocin (a member of the bleomycin family) treatment increased the rate of genomic alterations, including aneuploidy, loss of heterozygosity (LOH), and chromosomal rearrangement over a hundred-fold. Most recombination events are likely to be initiated by DNA double-stand breaks directly generated by Zeocin. Another remarkable finding is that G4-motifs and low GC regions were significantly underrepresented within the gene conversion tracts of Zeocin-induced LOH events, indicating that certain DNA regions are less preferred Zeocin-binding sites in vivo. This study provides a novel paradigm for evaluating genetic toxicity of small-molecular drugs using yeast models.


Assuntos
Instabilidade Cromossômica/efeitos dos fármacos , Cromossomos Fúngicos , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Aneuploidia , Bleomicina/farmacologia , Divisão Celular , Rearranjo Gênico , Instabilidade Genômica , Perda de Heterozigosidade , Recombinação Genética
20.
Nat Genet ; 51(5): 824-834, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31036964

RESUMO

Chromosome segregation errors cause aneuploidy and genomic heterogeneity, which are hallmarks of cancer in humans. A persistent high frequency of these errors (chromosomal instability (CIN)) is predicted to profoundly impact tumor evolution and therapy response. It is unknown, however, how prevalent CIN is in human tumors. Using three-dimensional live-cell imaging of patient-derived tumor organoids (tumor PDOs), we show that CIN is widespread in colorectal carcinomas regardless of background genetic alterations, including microsatellite instability. Cell-fate tracking showed that, although mitotic errors are frequently followed by cell death, some tumor PDOs are largely insensitive to mitotic errors. Single-cell karyotype sequencing confirmed heterogeneity of copy number alterations in tumor PDOs and showed that monoclonal lines evolved novel karyotypes over time in vitro. We conclude that ongoing CIN is common in colorectal cancer organoids, and propose that CIN levels and the tolerance for mitotic errors shape aneuploidy landscapes and karyotype heterogeneity.


Assuntos
Instabilidade Cromossômica , Neoplasias Colorretais/genética , Aneuploidia , Linhagem Celular Tumoral , Segregação de Cromossomos , Neoplasias Colorretais/patologia , Variações do Número de Cópias de DNA , Humanos , Imagem Tridimensional , Cariótipo , Cariotipagem , Instabilidade de Microssatélites , Mitose/genética , Mutação , Organoides/patologia , Análise de Célula Única
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