Advances in the study of new BCR-ABL kinase inhibitors / 药学学报

The oncogenic product of BCR-ABL is an abnormal tyrosine kinase that causes chronic myeloid leukemia (CML). With further research into the pathogenesis of CML, the discovery of compounds that selectively inhibit abnormal BCR-ABL tyrosine kinases is a research focus worthy of attention. The first three generations of BCR-ABL inhibitors are orthosteric inhibitors, which competitively block the binding of ABL protein tyrosine kinase to ATP and prevent it from activating downstream signals. The fourth-generation BCR-ABL inhibitors allosterically inhibit ABL protein tyrosine kinase by binding to the myristoyl pocket, providing greater selectivity and maintaining activity against drug-resistant mutations proteins. Novel drug design strategies such as proteolytic targeting chimera (PROTAC), covalent inhibitors and dual targeting inhibitors also provide new directions for the development of BCR-ABL kinase inhibitors. This paper reviews recent research advances on BCR-ABL kinase inhibitors and discusses drug design strategies for various novel BCR-ABL inhibitors.

A 14-year multi-institutional collaborative study of Chinese pelvic floor surgical procedures related to pelvic organ prolapse / 中华医学杂志(英文版)

BACKGROUND@#It has been a global trend that increasing complications related to pelvic floor surgeries have been reported over time. The current study aimed to outline the development of Chinese pelvic floor surgeries related to pelvic organ prolapse (POP) over the past 14 years and investigate the potential influence of enhanced monitoring conducted by the Chinese Association of Urogynecology since 2011.@*METHODS@#A total of 44,594 women with POP who underwent pelvic floor surgeries between October 1, 2004 and September 30, 2018 were included from 22 tertiary academic medical centers. The data were reported voluntarily and obtained from a database. We compared the proportion of each procedure in the 7 years before and 7 years after September 30, 2011. The data were analyzed by performing Z test (one-sided).@*RESULTS@#The number of different procedures during October 1, 2011-September 30, 2018 was more than twice that during October 1, 2004-September 30, 2011. Regarding pelvic floor surgeries related to POP, the rate of synthetic mesh procedures increased from 38.1% (5298/13,906) during October 1, 2004-September 30, 2011 to 46.0% (14,107/30,688) during October 1, 2011-September 30, 2018, whereas the rate of non-mesh procedures decreased from 61.9% (8608/13,906) to 54.0% (16,581/30,688) (Z = 15.53, P < 0.001). Regarding synthetic mesh surgeries related to POP, the rates of transvaginal placement of surgical mesh (TVM) procedures decreased from 94.1% (4983/5298) to 82.2% (11,603/14,107) (Z = 20.79, P < 0.001), but the rate of laparoscopic sacrocolpopexy (LSC) procedures increased from 5.9% (315/5298) to 17.8% (2504/14,107).@*CONCLUSIONS@#The rate of synthetic mesh procedures increased while that of non-mesh procedures decreased significantly. The rate of TVM procedures decreased while the rate of LSC procedures increased significantly.@*TRIAL REGISTRATION NUMBER@#NCT03620565, https://register.clinicaltrials.gov.

Diabetes counteracts the protective effect of the diazoxide preconditioning on ischemic reperfused rat heart / 中华外科杂志

<p><b>OBJECTIVE</b>To explore the impact of diabetic condition on the protective effect of diazoxide preconditioning (DPC) on ischemic-reperfused (I/R) myocardium in rats.</p><p><b>METHODS</b>Thirty normal male Sprague-Dawley rats were divided into 3 groups, including non-diabetic control group, non-diabetic I/R group, and non-diabetic I/R DPC group. Thirty diabetic male rats were also divided into the same 3 groups. The Langendorff isolated heart perfusion models were established. The control groups had a 90 min perfusion without any intervention. The I/R groups had a 30 min equilibration period, a 30 min ischemia, and a 30 min reperfusion. The I/R DPC groups had a 10 min equilibration, two cycles of 100 micromol/L diazoxide perfusion, 5 min each, followed by a 5 min diazoxide-free period before the 30 min ischemia and a 30 min reperfusion. The recovery rate of the left ventricular function, including cardiac output, left ventricular developed pressure (LVDP), and the maximum change rate of left ventricular pressure rise and fall (+/- dp/dt(max)) were recorded. The activity of creatine kinase in coronary outflow and activities of malonyldialdehyde, and superoxide dismutase in myocardium were detected. Myocardial water content was also assessed.</p><p><b>RESULTS</b>In non-diabetic rats, the content of creatine kinase, malonyldialdehyde and water content were significantly decreased in I/R DPC group compared with those in I/R group. Furthermore, in I/R DPC group, the activity of superoxide dismutase and the recovery rate of the left ventricular function, including cardiac output, LVDP and +/- dp/dt(max), were significantly increased compared with those in I/R group (P < 0.05). By contrast, there were no significant changes between I/R DPC group and I/R group in diabetic rats (P > 0.05).</p><p><b>CONCLUSION</b>Diabetes counteracts the protective effect of the diazoxide preconditioning on ischemic reperfused rat heart, which may be related with acute insulin resistance in cardiomyocytes.</p>

Clinical analysis for 232 cases of primary heart neoplasms / 中华外科杂志

<p><b>OBJECTIVE</b>To summarize the clinical characterizations and outcome of surgical treatment of primary heart neoplasms.</p><p><b>METHODS</b>The clinical data of cardiac neoplasms were analyzed retrospectively in 232 patients. There were 14 malignant tumors (6.0%) and 218 benign tumors (94.0%), of which 200 were left atrial myxomas (86.2%). Palpitation and dyspnea on exertion added up to 87.1% (202/232) of all clinical symptoms. Two hundred and twenty-three out of 230 patients underwent complete removal of the tumors, remaining 2 patients had partial removal. Five patients received biopsy only. Other procedures had done in the same stage including 5 cases with mitral valve replacement, 1 case with pulmonary arterial valve replacement, 5 cases with thrombectomy through the Fogarty catheter.</p><p><b>RESULTS</b>Two cases died preoperatively operation. Three cases died intraoperative operation. One hundred and eighty-five cases were followed up for 6 months to 24 years, of which 10 malignant tumors died in 1 year and 1 malignant case recurred after 4 months. Of 174 benign neoplasms, 1 case recurred and 10 cases were dead, remaining were cured.</p><p><b>CONCLUSIONS</b>Left atrial myxomas are most commonly seen in patients with primary heart neoplasms. Palpitation and dyspnea on exertion are the most frequent symptoms. It is suggested that the patients should accept surgical treatment as soon as possible once the diagnosis is confirmed. Surgical treatment is effective for the benign cardiac tumors. Prognosis is poor in patients with malignant cardiac tumors.</p>