伴有性染色体丢失的t(8;21)急性髓系白血病实验室检测资料分析

目的 探讨12例伴有性染色体丢失的t（8；21）急性髓系白血病患者的临床和生物学特征。方法 结合临床、形态学，采用RHG显带、一组单抗、逆转录-聚合酶链反应等方法对其染色体、免疫分型和分子生物学等进行分析。结果 本组病例大多有下述形态学改变：白血病细胞有核凹陷、近核浅染区、胞浆嗜碱性、伴有成熟分化和核浆发育不平衡等；有CD13、CD33表达抗原；经逆转录-聚合酶链反应检测均检出AML1-ETO融合基因转录本。结论 性染色体丢失是t（8；21）急性髓系白血病最常见的附加异常，主要和急性粒细胞白血病有关，具有独特的形态学、免疫学和临床特征。     

UK families with children with rare chromosome disorders: Changing experiences of diagnosis and counselling (2003‐2013)

The latest United Kingdom (UK) strategy for rare diseases emphasises the need to empower affected populations to improve diagnosis, intervention, and coordination of care. Families who have a child with a rare chromosome disorder (RCD) are a challenging group to include. We report the findings of 2 large‐scale surveys, undertaken by the UK RCD Support Group Unique, of these families' experiences over a 10‐year period. Seven stages of the patient journey were examined. From pre‐testing, through diagnosis, genetics consultation, clinical follow‐up and peer support. Overall, 1158 families replied; 36.4% response rate (2003) and 53.6% (2013). Analysis of responses identifies significant differences (P < .001) over time with a decrease in results reported face to face (76%‐62%), doubling by telephone (12%‐22%), improved explanation of chromosome disorder (57%‐75%), and increased signposting to peer support group (34%‐62%). However, conduct of the consultation raises a number of important questions. Overall, 28 aspects of the patient journey are recognised as requiring improvement; only 12/28 are currently incorporated in UK service specifications. Involvement of RCD families has identified key service improvements. This approach can empower those affected by such extremely rare disorders, and also enable professionals to design improved services in partnership with “expert families.” Further surveys are planned.     

Occurrence of II and V Staphylococcal Cassette Chromosome mec Types among Coagulase-Negative Staphylococci from Northeastern Part of India

Introduction: Coagulase Negative Staphylococci, the most commonly isolated pathogen are becoming emerging threats to the community as well as to the nosocomial environment. The present study underscores the distribution of Staphylococcal cassette chromosome mec (SCCmec) types among Methicillin resistant Coagulase Negative Staphylococci from the environmental origin. Methods and Materials: Environmental and food sample (n = 460) from different location of northeastern region of India were collected for a period of one year and were phenotypically and genotypically screened using cefoxitin disc and PCR techniques for mecA and mecC gene detection. All the MR-CoNS isolates possessing mecA gene were subjected to 16srDNA sequencing for species identification. SCCmec typing was determined by evaluating using primer sets from type I to type V. Antibiotic susceptibility testing was performed for all the isolates. Statistical analysis with chi-square test using SPSS-21 statistical software. Results: Methicillin resistance shown by one hundred forty three isolates were carried out for molecular analysis, among them 53.84% serves as mecA carrier. Distribution of Staphylococcus haemolyticus was more frequent and was found that SCCmec types II and V were predominant among the study isolates. Linezolid was the drug of choice for the CoNS isolates. Statistical analysis showed an insignificant result for the tested antibiotics and SCCmec types. Conclusion: This study therefore interprets the relative importance of SCCmec types among MR-CoNS isolates.     

急性白血病和骨髓增生异常综合症染色体-7/7q-异常的细胞遗传学和临床分析

本研究探讨染色体 - 7/ 7q -异常在恶性血液学疾病的发生、发展和预后中的作用。用细胞染色体显带技术分析 4 10例初发急性白血病 (acuteleukemia ,AL)、71例骨髓增生异常综合症 (myelodysplasticsyndrome ,MDS)和36例慢性粒细胞白血病 (chronicmyelogenousleukemia acceleratedphase ,CML AP)的细胞核型。结果表明 :染色体- 7/ 7q -异常在AL ,MDS和CML AP患者中的检出率分别为 4 .88% ,9.86 %和 8.33% ,在急性髓细胞白血病(AML)和急性淋巴细胞白血病 (ALL)中均可检出染色体 - 7/ 7q -异常 ,检出率分别为 4 .70 %和 6 .2 5 % ,两者无明显差别 (P >0 .0 5 )。 9例具有单独染色体 - 7或 7q -异常 ,2 2例伴有其他染色体异常 ,如 -X、- 5、 8、t(3;3)、t(11;16 )、t(2 ;11)等。发现 1例MDS RAEB患者具有 - 7异常克隆 ,同时还有 7q -异常克隆出现 ,而且 - 7异常的细胞数高于 7q -异常的细胞数。接受化疗的 7例ALL中 4例获得完全缓解 ;13例AML患者中仅 2例获得完全缓解 ;7例MDS患者中 6例转化急性白血病 ;3例CML AP中无 1例缓解。结论 :染色体 - 7/ 7q -异常是恶性血液肿瘤常见的染色体异常 ,在髓系和淋巴细胞中均可出现 ,- 7异常和 7q异常可在同一患者共存 ;具有染色体 - 7/ 7q -异常的患者预后差。     

CHK2–BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly

BRCA1 (breast cancer type 1 susceptibility protein) is a multifunctional tumor suppressor involved in DNA damage response, DNA repair, chromatin regulation, and mitotic chromosome segregation. Although the nuclear functions of BRCA1 have been investigated in detail, its role during mitosis is little understood. It is clear, however, that loss of BRCA1 in human cancer cells leads to chromosomal instability (CIN), which is defined as a perpetual gain or loss of whole chromosomes during mitosis. Moreover, our recent work has revealed that the mitotic function of BRCA1 depends on its phosphorylation by the tumor-suppressor kinase Chk2 (checkpoint kinase 2) and that this regulation is required to ensure normal microtubule plus end assembly rates within mitotic spindles. Intriguingly, loss of the positive regulation of BRCA1 leads to increased oncogenic Aurora-A activity, which acts as a mediator for abnormal mitotic microtubule assembly resulting in chromosome missegregation and CIN. However, how the CHK2–BRCA1 tumor suppressor axis restrains oncogenic Aurora-A during mitosis to ensure karyotype stability remained an open question. Here we uncover a dual molecular mechanism by which the CHK2–BRCA1 axis restrains oncogenic Aurora-A activity during mitosis and identify BRCA1 itself as a target for Aurora-A relevant for CIN. In fact, Chk2-mediated phosphorylation of BRCA1 is required to recruit the PP6C–SAPS3 phosphatase, which acts as a T-loop phosphatase inhibiting Aurora-A bound to BRCA1. Consequently, loss of CHK2 or PP6C-SAPS3 promotes Aurora-A activity associated with BRCA1 in mitosis. Aurora-A, in turn, then phosphorylates BRCA1 itself, thereby inhibiting the mitotic function of BRCA1 and promoting mitotic microtubule assembly, chromosome missegregation, and CIN.Breast cancer type 1 susceptibility protein (BRCA1) is a major and multifunctional tumor-suppressor protein involved in the regulation of chromatin organization, gene expression, DNA damage response, and DNA repair (1–3). In addition to its functions in interphase, BRCA1 also is required for faithful execution of mitosis. Consequently, loss of BRCA1 results in abnormal mitotic progression, chromosome missegregation, and chromosomal instability (CIN), hallmark phenotypes of human cancer (4–6). However, the mitotic function of BRCA1 and its regulation during mitosis is little understood. BRCA1 localizes to centrosomes throughout the cell cycle and is phosphorylated during mitosis on S988 by the checkpoint kinase 2 (Chk2). This positive regulation is essential to ensure proper mitotic spindle assembly and chromosomal stability (5, 7, 8). Importantly, we recently have found that the loss of CHK2 or of Chk2-mediated phosphorylation on BRCA1 causes an increase in microtubule plus-end assembly rates, which results in transient spindle geometry defects facilitating the generation of erroneous microtubule–kinetochore attachments. These defects finally lead to chromosome missegregation and the induction of aneuploidy, thus constituting CIN (6).Interestingly, BRCA1 associates with the Aurora-A kinase during mitosis (6). Aurora-A is a key mitotic kinase encoded by the AURKA oncogene and is involved in various functions during mitosis, including centrosome separation and spindle assembly (9, 10). Aurora-A activation occurs at mitotic centrosomes and requires its autophosphorylation within the T-loop at threonine-288. Subsequent inactivation of Aurora-A can be mediated by the serine/threonine protein phosphatase 6 (PP6), which acts as the T-loop phosphatase for Aurora-A, and involves the catalytic subunit (PP6C) as well as regulatory subunits referred to as “Sit4-associated proteins” (SAPS1-3) and ankyrin repeat proteins (11–13). Significantly, in human cancer, AURKA frequently is overexpressed, and increased activity of AURKA is sufficient to induce enhanced microtubule plus end assembly rates, chromosome missegregation, and CIN (6). Thus, overexpression of AURKA and loss of the CHK2–BRCA1 axis result in the same mitotic abnormalities triggering CIN. Moreover, loss of the Chk2-mediated phosphorylation of BRCA1 causes an increase in BRCA1-bound Aurora-A kinase activity at mitotic centrosomes, which mediates the induction of abnormal microtubule plus end dynamics and CIN (6). However, the molecular mechanism by which the loss of the CHK2–BRCA1 tumor-suppressor axis unleashes oncogenic Aurora-A activity during mitosis and the mitotic target for Aurora-A relevant for the induction of increased microtubule dynamics and CIN remain unknown.     

热化疗对人直肠癌细胞遗传物质的损伤

将体外培养的人直肠癌细胞进行反复热化疗处理,观察处理前后癌细胞染色体和AgNOR的变化。结果显示热化疗后癌细胞染色体有明显畸变,培养后期染色体断片明显增加,且AgNOR颗粒显著减少。提示染色体是人直肠癌细胞热化疗死亡的重要靶部位之一。     

Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with 'pleasurable buzz' during early experimentation with smoking

AIMS: To extend the previously identified association between a single nucleotide polymorphism (SNP) in neuronal acetylcholine receptor subunit alpha-5 (CHRNA5) and nicotine dependence to current smoking and initial smoking-experience phenotypes. DESIGN, SETTING, PARTICIPANTS: Case-control association study with a community-based sample, comprising 363 Caucasians and 72 African Americans (203 cases, 232 controls). MEASUREMENTS: Cases had smoked > or = five cigarettes/day for > or = 5 years and had smoked at their current rate for the past 6 months. Controls had smoked between one and 100 cigarettes in their life-time, but never regularly. Participants also rated, retrospectively, pleasurable and displeasurable sensations experienced when they first smoked. We tested for associations between smoking phenotypes and the top 25 SNPs tested for association with nicotine dependence in a previous study. FINDINGS: A non-synonymous coding SNP in CHRNA5, rs16969968, was associated with case status [odds ratio (OR) = 1.5, P = 0.01] and, in Caucasians, with experiencing a pleasurable rush or buzz during the first cigarette (OR = 1.6, P = 0.01); these sensations were associated highly with current smoking (OR = 8.2, P = 0.0001). CONCLUSIONS: We replicated the observation that the minor allele of rs16969968 affects smoking behavior, and extended these findings to sensitivity to smoking effects upon experimentation. While the ability to test genetic associations was limited by sample size, the polymorphism in the CHRNA5 subunit was shown to be associated significantly with enhanced pleasurable responses to initial cigarettes in regular smokers in an a priori test. The findings suggest that phenotypes related to subjective experiences upon smoking experimentation may mediate the development of nicotine dependence.     

Megakaryopoiesis and platelet function in polycythemia vera and essential thrombocythemia patients with JAK2 V617F mutation

Patients with Ph chromosome negative myeloproliferative disease (Ph-MPD) have an increased risk of vascular complications. It remains controversial whether patients with the JAK2 V617F mutation (V617F) exhibit increased risk, while recent growing evidence has shown a critical role for V617F in clonal erythropoiesis in Ph-MPD. We studied 53 patients with Ph-MPD especially in relation to megakaryopoiesis, the thrombotic complications and the presence of V617F. Using novel mutation-specific PCR which is a highly sensitive PCR-based assay for detection of JAK2 mutated allele(s), we identified V617F in 38 Ph-MPD, which include 13 polycythemia vera (PV), 23 essential thrombocythemia (ET) and 2 chronic idiopatic myelofibrosis. The numbers of megakaryocytes were significantly increased in PV and ET patients with V617F, but the platelet counts were slightly lower. Although statistically not significant, the incidence of thrombotic events was higher in the group with V617F compared to in those without the mutation. Agonist-induced in vitro platelet aggregation and platelet adhesion were not affected by the presence of this mutation. Nonetheless, we found a hypercoagulable state in Ph-CMPD with V617F by employing whole blood thromboelastography. It suggests pre-thrombotic tendencies in CMPD are complex and JAK2 V617F mutation might have a role in vivo blood coagulation by altering not only the number, but function(s) of all three myeloid cells, including red blood cells, white blood cells and platelets in Ph-CMPD.