Hypomethylating Agent Therapy in Myelodysplastic Syndromes With Chromosome 3 Abnormalities

BackgroundAbnormalities of chromosome 3 in myelodysplastic syndromes (MDS), that is, inversion 3 (inv[3]), translocation 3q (t[3q]), or deletion 3q (del[3q]), are defined as poor-risk karyotypes in the Revised International Prognostic Scoring System (IPSS-R). The objective of this study was to further define the outcomes of patients with MDS with chromosome 3 abnormalities and address the impact of hypomethylating agent (HMA) therapy on this patient subset.Patients and MethodsThrough the MDS Clinical Research Consortium, we identified 411 patients with chromosome 3 abnormalities and MDS or oligoblastic acute myeloid leukemia (20%-30% blasts).ResultsSpecific chromosome 3 aberrations and cytogenetic complexity were predictive of survival; patients with t(3q) and isolated chromosome 3 had improved overall survival (OS), albeit still poor, whereas patients with complex cytogenetics, including those with 3p abnormalities, had inferior OS. Overall response rates to HMAs among this patient population were similar to those of patients with nonchromosome 3–MDS (52%, with a 25% complete remission rate), although with higher response rates in decitabine-treated patients (69% vs. 45%, P = .008). HMA therapy improved the OS of patients with higher-risk MDS compared with intensive chemotherapy (median OS of 15.5 vs. 8.2 months; P = .017). This improvement remained significant in multivariate analyses (hazard ratio, 0.60; P = .018); however, there were no chromosome 3 aberrations among this subgroup predictive of improved response rates to or survival from HMAs.ConclusionPatients with MDS with chromosome 3 abnormalities represent a cytogenetic cohort with poor OS, and there is an urgent need for novel therapeutic strategies.     

一例外周血染色体核型为单纯型18三体但智力正常女性的遗传学研究

目的分析1例外周血染色体核型为单纯型18三体但智力正常女性的遗传学机制。方法用G显带染色体核型分析、荧光原位杂交(fluorescence in situ hybridization,FISH)和单核苷酸多态性微阵列芯片(single nucleotide polymorphism microarray,SNP-array)技术对患者的外周血和颊粘膜细胞进行检测。结果患者的外周血染色体核型、SNP-array以及FISH检测结果均提示为47,XX,+18;颊粘膜间期细胞FISH检测结果提示为45,X合并低比例的18三体和18单体。结论胚层染色体嵌合的个体临床表现复杂,遗传学异常所造成的影响取决于相关胚层分化所形成的器官及功能。     

不良孕产史夫妇染色体核型的大样本分析

目的探讨不良孕产史夫妇染色体异常核型检出率及其分布，以及染色体异常核型与不良孕产史的关系，为优生优育及遗传咨询提供理论依据。 方法选取2016年1月1日至2017年12月31日，于济南艾迪康医学检验中心进行染色体核型检测的10 330对(20 660例)不良孕产史育龄夫妇为研究对象。采集每例受试者肘静脉血3 mL，肝素钠抗凝，取0.3 mL进行血细胞培养、标本制备，采用常规G显带技术进行染色体核型分析。对于染色体异常核型检出率、不同类型染色体异常核型占染色体异常核型总例数的比例等计数资料，采用率(%)表示。本研究遵循的程序符合2013年修订的《世界医学协会赫尔辛基宣言》要求。 结果①本组10 330对(20 660例)不良孕产史育龄夫妇中，共计检出染色体异常核型为1 119例(不含染色体多态性)，染色体异常核型检出率为5.42%(1 119/20 660)。其中，常染色体异常者为658例，占染色体异常核型的58.80%(658/1 119)，包括354例染色体平衡易位、205例染色体倒位、83例染色体罗伯逊易位、11例染色体插入、5例染色体重复，分别占染色体异常核型的31.64%、18.32%、7.41%、0.98%、0.45%。染色体倒位者中，以9号染色体倒位居多，偶见于1、4、7、11、12号染色体，并且多合并自然流产。性染色体异常者为440例，占染色体异常核型的39.32%(440/1 119)，包括365例性染色体数目异常(占染色体异常核型的32.62%)。其中，男性多表现为无精子症，以47，XXY染色体异常核型居多(144例)，女性多表现为原发性不孕，以45，X染色体异常核型居多(103例); 61例为性染色体结构异常、14例为性别反转，分别占染色体异常核型的5.45%、1.25%。其他罕见染色体异常核型者为21例，占染色体异常核型的1.88%(21/1 119)，如环状染色体、mar染色体等。②本组10 330对(20 660例)不良孕产史育龄夫妇中，11例为常染色体插入，5例为常染色体重复，54例为性染色体缺失，其主要临床表现为原发性不孕不育、胚胎停止发育、无精子症或重度少精子症。 结论染色体异常核型是导致育龄期夫妇不良孕产史的重要原因之一。对于不良孕产史夫妇，建议进行染色体核型分析和遗传咨询。临床为这类患者进行优生优育指导，可提高出生人口质量。     

DNA excision repair and double-strand break repair gene polymorphisms and the level of chromosome aberration in children with long-term exposure to radon

Purpose: To study polymorphic variants of repair genes in people affected by long-term exposure to radon. The chromosome aberration frequency in peripheral blood lymphocytes was used as the biological marker of genotoxicity.

Materials and methods: Genotyping of 12 single nucleotide polymorphisms in DNA repair genes (APE, XRCC1, OGG1, ADPRT, XpC, XpD, XpG, Lig4 and NBS1) was performed in children with long-term resident exposure to radon. Quantification of the aberrations was performed using light microscopy.

Results: The total frequency of aberrations was increased in carriers of the G/G genotype for the XpD gene (rs13181) polymorphism in recessive model confirmed by the results of ROC-analysis (‘satisfactory predictor’, AUC?=?0.609). Single chromosome fragments frequency was increased in carriers of the G/G genotype in comparison with the T/T genotype. In respect to the total frequency of aberrations, the G/G genotype for the XpG gene (rs17655) polymorphism was also identified as a ‘satisfactory predictor’ (AUC?=?0.605). Carriers of the T/C genotype for the ADPRT gene (rs1136410) polymorphism were characterized by an increased level of single fragments relative to the T/T genotype.

Conclusion: The relationships with several types of cytogenetic damage suggest these three SNP (rs13181, rs17655 and rs1136410) may be considered radiosensitivity markers.     

Interaction of RECQ4 and MCM10 is important for efficient DNA replication origin firing in human cells

DNA replication is a highly coordinated process that is initiated at multiple replication origins in eukaryotes. These origins are bound by the origin recognition complex (ORC), which subsequently recruits the Mcm2-7 replicative helicase in a Cdt1/Cdc6-dependent manner. In budding yeast, two essential replication factors, Sld2 and Mcm10, are then important for the activation of replication origins. In humans, the putative Sld2 homolog, RECQ4, interacts with MCM10. Here, we have identified two mutants of human RECQ4 that are deficient in binding to MCM10. We show that these RECQ4 variants are able to complement the lethality of an avian cell RECQ4 deletion mutant, indicating that the essential function of RECQ4 in vertebrates is unlikely to require binding to MCM10. Nevertheless, we show that the RECQ4-MCM10 interaction is important for efficient replication origin firing.     

Monosomy of Chromosome 9 Is Associated With Higher Grade,Advanced Stage,and Adverse Outcome in Clear-cell Renal Cell Carcinoma

BackgroundClear-cell renal cell carcinoma (ccRCC) is one of the most common malignancies in humans and is usually associated with poor outcomes. Cancers are considered to be genetic diseases. Therefore, a better understanding of genetic alterations that are related to disease progression or poor prognosis can help to more precisely identify high-risk patients and treat them more effectively. The aim of this study was to examine the frequency of whole chromosome 9 loss (monosomy of chromosome 9) and its prognostic value in patients with ccRCC.Materials and MethodsSingle nucleotide polymorphism-based chromosome microarray (CMA) analysis was performed on 103 resected specimens from patients with ccRCC who had undergone partial or radical nephrectomy between January 2002 and March 2017 at Fox Chase Cancer Center. Monosomy 9 was correlated with clinicopathologic parameters and recurrence-free survival.ResultsChromosome 9 loss was detected in 31 (30%) of 103 tumors. Tumors with chromosome 9 loss had higher histologic grade (3 and 4; P < .001) and pathologic stage (P < .001). In 59 patients with non-metastatic ccRCC, chromosome 9 loss was also associated with higher recurrence rate and shorter recurrence-free survival (RFS) (12-month RFS, 77.8%; 95% confidence interval, 36.5%-93.9% for chromosome 9 loss vs. 95.7%; 95% confidence interval, 84.0%-98.9% for no loss; P = .002).ConclusionsChromosome 9 loss was found in 30% of patients with ccRCC and correlated with higher grade, advanced stage, and shorter RFS in patients with Stage I to III ccRCC.     

Chronic Opioid Therapy in Cancer Survivors at a Specialty Oncology Pain Clinic: Opioid Dosing,Efficacy, and Safety During Five Years of Pain Management

There are limited data regarding long-term safety and efficacy in cancer survivors receiving chronic opioid therapy. With conflicting recommendations on opioid-prescribing practices and lack of available outcome data, this study aimed to provide a longitudinal perspective on opioid prescribing in cancer survivors. A retrospective chart review at a comprehensive cancer care center pain clinic used data from pain clinic provider notes from 2013 to 2018. Inclusion criteria were patients in clinical remission not receiving active chemotherapy or immunotherapy and receiving opioids during the study period. Opioid dosing changes and outcomes between zero and five years were evaluated by standard statistical analysis. Thirty-two patients met inclusion criteria. Solid malignancies were more common than hematologic malignancies (72% vs. 28%). Common pain complaints were related to postsurgical changes (43%), postradiation (32%), and chemotherapy-induced pain syndromes (25%). There were no serious adverse events. One patient exhibited possible aberrant behavior. At the initial visit, the median morphine milligram equivalent per day (MME/day) was 130. Median MME/day at Year 0 (study start) and Year 5 was 135 and 159, respectively (P = 0.475). Functional status was satisfactory in 58% at Year 0 and increased to 91% of patients meeting their functional goals at Year 5. In a carefully monitored group of cancer survivors with persistent pain, chronic opioid therapy was safely managed during extended periods without significant opioid escalation or evidence of serious adverse events including aberrant behaviors. This population benefited when opioid therapy was managed with a focus on function rather than reduction of pain intensity scores.     

Assessment of the cytotoxicity and genotoxicity properties of Uvaria chamae P. Beauv (Annonaceae) and Morinda lucida Benth (Rubiaceae) in mice

The toxicity profile of medicinal plants is an important preclinical requirement in the development of phytomedicines. The cytotoxic and genotoxic effects of the leaf of Uvaria chamae P. Beauv (Annonaceae) and stem bark of Morinda lucida Benth (Rubiaceae) were investigated in order to provide information on their safety as antimalarial plants. The methanol extract of U. chamae and ethanol (70%) extract of M. lucida were separately orally administered (125, 250, and 750?mg/kg/day) to mice for 10 consecutive days. Cyclophosphamide (50?mg/kg, single dose) and distilled water were used as positive and negative controls, respectively. The mice were injected with colchicine (0.04%) intra-peritoneally 24?h after the last administration of the extracts and the bone marrows harvested. Giemsa-stained slides of bone marrow cells were microscopically assessed for dividing cells to determine the mitotic index (MI) and scored for chromosomal aberrations (CA) according to standard methods. chamae exhibited dose-dependent cytotoxicity. At 750?mg/kg, the MI was significantly (p?M. lucida was not significantly different (p?>?0.05) from that of the negative control. The total CA observed from treatment with both plants at all doses were significantly (p?U. chamae showed both cytotoxicity and genotoxicity while M. lucida exerted only genotoxic effect. Nevertheless, the two plants should be used with caution in antimalarial therapy.