BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents

A critical determinant of the efficacy of antineoplastic therapy is the response of malignant cells to DNA damage induced by anticancer agents. The p53 tumor-suppressor gene is a critical component of two distinct cellular responses to DNA damage, the induction of a reversible arrest at the G1/S cell cycle checkpoint, and the activation of apoptosis, a genetic program of autonomous cell death. Expression of the BCR-ABL chimeric gene produced by a balanced translocation in chronic myeloid leukemia, confers resistance to multiple genotoxic anticancer agents. BCR-ABL expression inhibits the apoptotic response to DNA damage without altering either the p53-dependent WAF1/CIP1-mediated G1 arrest or DNA repair. BCR-ABL-mediated inhibition of DNA damage-induced apoptosis is associated with a prolongation of cell cycle arrest at the G2/M restriction point; the delay of G2/M transition may allow time to repair and complete DNA replication and chromosomal segregation, thereby preventing a mitotic catastrophe. The inherent resistance of human cancers to genotoxic agents may result not only by the loss or inactivation of the wild-type p53 gene, but also by genetic alterations such as BCR-ABL that can delay G2/M transition after DNA damage.     

血吸虫对吡喹酮抗药性的研究Ⅳ曼氏血吸虫吡喹酮敏感株与抗性株成虫对吡喹酮的体外反应性

目的　体外比较曼氏血吸虫吡喹酮敏感株与抗性株成虫阶段对吡喹酮的反应性。方法　将各虫株成熟成虫分别培养于含吡喹酮分别为 3.2× 10 - 4、8× 10 - 4、1.6× 10 - 3m ol/ L的 MEM培养液中 ,37℃孵育 15、30、4 5、6 0、75 min后 ,分别在解剖镜下观察虫体的存活状况并计算存活率。结果　当孵育于含吡喹酮 3.2× 10 - 4m ol/ L的 MEM中 75 m in,敏感株与抗性株雌虫均能存活 ;但敏感株与抗性株雄虫的存活率仅为 11.5 % - 16 .0 %和 32 .7% - 36 .5 %。孵育于含吡喹酮 8× 10 - 4m ol/L 的 MEM中 15 min,抗性株雄虫与雌虫存活率为 4 8.3% - 5 0 .0 %和 5 7.9% - 6 3.6 % ;敏感株雄虫与雌虫的存活率为 2 2 .4 % - 2 5 .9%和 38.5 % - 4 8.3% ;75 min后 ,抗性株雄虫的存活率为 13.3%- 17.3% ,敏感株雄虫的存活率则为 0。孵育于含吡喹酮 1.6× 10 - 3m ol/ L 的 MEM中 15 min,抗性株雄虫与雌虫的存活率为 11.1% - 19.6 %和 2 7.5 % - 2 9.9% ;敏感株雄虫与雌虫的存活率均为 0。结论　将曼氏血吸虫吡喹酮抗性株和敏感株成虫孵育于含一定浓度吡喹酮的 MEM中不同时间后 ,抗性株的存活率高于敏感株 ;雌虫的存活率高于雄虫     

End-of-life care for elderly patients with heart failure

The mortality rate of elderly persons with heart failure is high despite the introduction of several effective therapeutic interventions during the past decade. The management of end of life, often associated with distressing symptoms and multiple hospitalizations, is a significant clinical problem. Skillful and effective management requires expert knowledge of the heart failure syndrome, but the critical dimension of care relates to detailed knowledge about a patient's comorbidities, extent of debility, values, and desires. Discussing end-of-life issues early in the course of illness is essential for determining the appropriate levels of intensity of care and for defining the circumstances in which patients wish to be hospitalized and when hospital care offers little potential for increased comfort or longevity. Early and repeated discussions are needed to consider matters such as living wills, do-not-resuscitate orders, and power of attorney. In light of the complexity of the health care system, including involvement of multiple caregivers, end-of-life issues are among the most demanding of a physician's time, but when end-of-life care is managed effectively, health care providers often are rewarded with the gratitude of patients and their families for minimizing suffering and providing optimal opportunities for patients to participate in the affairs of family and the community.     

The NO donor DETA-NONOate reversibly activates an inward current in neurones and is not mediated by the released nitric oxide

Background and purpose:

It has been previously shown that high levels of nitric oxide (NO), from NO donors, kill neurones, but the mechanisms are unclear.

Experimental approach:

The effects of NO donors on the electrical properties of rat cultured cerebellar granule cells (CGC neurones) were investigated using the whole-cell patch-clamp technique.

Key results:

The NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate or NOC-18) caused a rapid, persistent, but fully reversible inward current that was associated with an increase in baseline noise and was concentration dependent (100 µM–10 mM). The response to 3 mM DETA-NONOate was completely inhibited by 1 mM gadolinium, but not by NO scavengers (1 mM haemoglobin or 1 mM PTIO) or glutamate receptor antagonists (10 µM MK-801 or 60 µM CNQX). Application of decomposed 3 mM DETA-NONOate or 3 mM nitrite had no effect. In contrast, the NO donor S-nitrosoglutathione (GSNO) caused a rapid, persistent, but fully reversible outward current that was also concentration dependent (1–10 mM). The 3 mM GSNO response was unaltered by NO scavengers, glutamate antagonists or gadolinium, but was mimicked by decomposed 3 mM GSNO and 3 mM oxidized glutathione.

Conclusions and implications:

These results suggest that DETA-NONOate directly activates cation-selective channels, causing an inward current in CGCs. In contrast, GSNO causes an outward current in these cells. Some of the effects of these NO donors are independent of NO, and thus caution is required in interpreting results when using high concentrations of these compounds.     

酪氨酸相关肽的合成及抗孕酮生成活性

利用固相法合成了二十个含羟基氨基酸的小肽。其中,以0.5mol·L^-1二甲二氯硅烷/1.5mol·L^-1苯酚/DCM*为脱除Boc试剂,以TFMSA为切除树脂试剂。经C-18反相柱纯化后,全部产物均通过氨基酸分析要求。体外黄体细胞分泌孕酮实验表明有八个肽化物GlyTyrAlaLys,(SarSer)₂Lys及其申酯,TyrLys,HisTyr-NH₂,ThrProTyrLys-NH₂,TyrThrProArgLys,AspHisProThr-PheLys显示较强的抑制hCG致孕酮分泌的活性,而且前三个肽还能显著抑制基础孕酮的分泌,相反,GlySerTyr能刺激基础孕酮的分泌。目前尚未建立合理的结构一活性关系。