Discovery of a Potent, selective and orally bioavailable CDK9 degrader for targeting transcription regulation in Triple-Negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous and invasive subtype of breast cancer with very limited effective modalities of treatment. Degrading the critical transcription regulator cyclin-dependent kinase 9 (CDK9) by proteolysis targeting chimeras (PROTACs) has shown promising potential for treating TNBC. However, to date, CDK9-targeting PROTACs for oral administration in treatment of cancers have not been reported. We herein present the design, synthesis, and extensive biological evaluation of a series of novel PROTACs as orally bioavailable, potent and selective degraders of CDK9 for targeting transcription regulation in triple-negative breast cancer. The developed compound 29 exhibited a desired potency (DC50 = 3.94 nM) with high efficacy (Dmax = 96 %) on CDK9 degradation, and effectively inhibited the proliferation of TNBC MDA-MB-231 cells. Mechanistic investigations revealed that compound 29 is a bona fide CDK9 degrader and can substantially downregulate the downstream targets c-Myc and MCL-1. Furthermore, compound 29 displayed favorable oral bioavailability in mice, and oral administration of degrader 29 significantly depleted CDK9 protein in TNBC tumor tissues and exhibited tumor growth inhibition in TNBC xenograft mice models. Collectively, our work established that degrader 29 is a highly potent and selective degraders of CDK9 with satisfactory oral bioavailability, which holds promising potential for the treatment of TNBC.

Epidemiological survey of cystic echinococcosis in southwest China: From the Qinghai-Tibet plateau to the area of Yunnan.

BACKGROUND: Echinococcosis is prevalent in 9 provinces in Western and Northern China. An epidemiological survey of echinococcosis in 2012 and 2016 showed cases of echinococcosis in Yunnan Province. AIM: To understand the spatial distribution and epidemiological characteristics of echinococcosis in Yunnan for the prevention and control of echinococcosis and to reduce the risk of infection in Yunnan Province. METHODS: Based on the China Information System for Disease Control and Prevention (CISDCP), echinococcosis cases reported from 36 hospitals and 34 Centers for Disease Control were investigated and epidemiologically analyzed from 2021 to 2022. The exclusion criteria included suspected cases, same case only counted once and cases not from Yunnan. A total of 705 cases were investigated, of which 397 cases were suitable for statistical analysis. In these 397 cases, epidemiological investigation was tracked in 187 cases. All data were inputted using double entry in the Excel database, with error correction by double-entry comparison. The data on echinococcosis cases in Yunnan Province were analyzed by ArcGIS 10.1 software to generate a density map of echinococcosis distribution. All statistical analyses were conducted using SPSS 17.0, including the chi-square test, linear regression test and logistic univariate and multivariate regression analyses. RESULTS: A total of 397 cases were found in 89 counties in Yunnan Province. The number of cases in the top three prefectures were Dali (38.1%), Diqing (10.1%), and Kunming (8.3%), and the top five counties were Jianchuan (9.1%), Shangri La (8.3%), Eryuan (7. 6%), Heqing (6.9%), and Dali Districts (5.0%). There were significant differences between the different areas. The case reporting rate by CISDCP (33.8%) was low; the first case was reported by CISDCP in 2002, and the highest number of cases was 50 (2017). Confirmed and clinical cases accounted for 62.5% and 37.5%, respectively. However, 90.9% of the cases of hydatid disease were reported by the hospital system, and only 9.1% of the cases of hydatid disease were found in the community through active screening. The difference between the two methods of case detection was statistically significant. Most of the cases of echinococcosis were found in farmers/herdsmen (75.1%) and students (9.1%). In addition, Han (43.6%) and Bai (26.2%) had a higher incidence of infection than other nationalities, and the liver (87.7%) and lung (6.8%) were the most common sites of cyst formation. Among the analyzed cases, 187 were epidemiologically analyzed and the clinical symptoms were not obvious in the early stage in 47.1% of cases. The results of logistic regression analysis showed that the age group, education level, presence of dogs in the family (either previously or currently), and handwashing (occasionally or not) were factors related to echinococcosis infection. 55.6% of cases were in endemic areas, and 44.4% of cases were in non-endemic areas. Among 83 cases in non-endemic areas, only 4 cases had been to endemic areas and had a history of living, working, travelling, or hunting in echinococcosis epidemic areas. CONCLUSION: Cases of echinococcosis were reported throughout the entire Yunnan province, with the majority distributed in Western Yunnan, suggesting that echinococcosis control should be strengthened in this area. We suggest that an epidemiological investigation should be carried out in the future, based on the clues from newly discovered cases in hospitals or from the CISDCP. The newly discovered cases in the hospital provided clues to comprehensively determine the location of cases and where epidemic spot investigation should be conducted.

Malaria control along China-Myanmar Border during 2007-2013: an integrated impact evaluation.

BACKGROUND: Implementing effective interventions remain a lot of difficulties along all border regions. The emergence of artemisinin resistance of Plasmodium falciparum strains in the Greater Mekong Subregion is a matter of great concern. China has effectively controlled cross-border transmission of malaria and artemisinin resistance of P. falciparum along the China-Myanmar border. METHODS: A combined quantitative and qualitative study was used to collect data, and then an integrated impact evaluation was conducted to malaria control along the China-Myanmar border during 2007-2013. RESULTS: The parasite prevalence rate (PPR) in the five special regions of Myanmar was decreased from 13.6 % in March 2008 to 1.5 % in November 2013. Compared with the baseline (PPR in March 2008), the risk ratio was only 0.11 [95 % confidence interval (CI), 0.09-0. 14) in November 2013, which is equal to an 89 % reduction in the malaria burden. Annual parasite incidence (API) across 19 Chinese border counties was reduced from 19.6 per 10 000 person-years in 2006 to 0.9 per 10 000 person-years in 2013. Compared with the baseline (API in 2006), the API rate ratio was only 0.05(95 % CI, 0.04-0.05) in 2013, which equates to a reduction of the malaria burden by 95.0 %. Meanwhile, the health service system was strengthened and health inequity of marginalized populations reduced along the international border. CONCLUSION: The effective collaboration between China, Myanmar and the international non-governmental organization promptly carried out the core interventions through simplified processes. The integrated approaches dramatically decreased malaria burden of Chinese-Myanmar border.

[Survey on Malaria Epidemics in China-Myanmar Border Area].

The malaria epidemics in Laza city of Myanmar and Yingjiang county in Yunnan province of China in 2012 and 2013 was reviewed retrospectively, and a survey on malaria infection was conducted in residents in the border areas. A total of 179 malaria cases were reported in Yingjiang county from 2012 to 2013, with an average annual incidence of 2.9 per 10,000. Of the 179 cases, 77.7% were imported cases and 22.3% were local cases; 79.3% were infected with Plasmodium vivax, 20.1% with P. falciparum, and 0.6% unidentified. In Laza city of Myanmar, 2,069 malaria cases were reported, with an average annual incidence of 322.5 per 10,000. Of them, 73.4% cases were infected with P. vivax, 20.1% with P. falciparum and 6.5% unidentified. In addition, the microscopic results revealed that the malaria parasite rate in the residents in Yingjiang county was 0%, while that in Laza city was 1.5%.

[Comparison between the head-chest leads electrocardiogram and routine leads in the manifest accessory pathways in patients with Wolff-Parkinson-White syndrome].

OBJECTIVE: To observe whether there was difference between the head-chest leads electrocardiogram (HCECGs) and routine lead electrocardiogram (RLECGs) in the manifest accessory pathways in patients with Wolff-Parkinson-White syndrome. METHODS: HCECGs and RLECGs were recorded simultaneously in patients with Wolff-Parkinson-White syndrome, whose manifest accessory pathways had been confirmed by radiofrequency catheter ablation and intra-cardiac electrophysiology according to the same standard set beforehand. The diagnosis of pathways location was made by analysis of each HCECG and RLECG by two senior physicians in clinical electrophysiology. The diagnostic accuracy of the HCECGs and RLECGs was evaluated by the comparison with that of the intra-cardiac electrophysiology. The delta wave size was also compared between HCECGs and RLECGs. RESULTS: The diagnostic accuracy in the manifest accessory pathways was 86.2% (50/58) in RLECGs, and 84.4% (49/58) in HCECGs in the 58 patients with Wolff-Parkinson-White syndrome, showing no significant difference between them (P > 0.05), but each delta wave in HCECG was more evident than that in RLECG. CONCLUSION: HCECG and RLECG both have high diagnostic accuracy in the manifest accessory pathways in patients with Wolff-Parkinson-White syndrome.

[Relationship between reference point potential and potential distribution of normal electrocardial field on the thoracic surface of healthy individuals].

OBJECTIVE: To explore the effect of reference point on the potential distribution of normal cardioeleclric field of healthy individuals. METHODS: Two different reference points including central terminal and right forehead were applied to record electrocardiogram simultaneously from 15 testing points (V(1)-V(6), V(7)-V(9), V(3R)-V(8R)) of Wilson lead (RL) and the same testing points (HV(1)-HV(9), HV(3R)-HV(8R)) of head-chest (HC) lead around the torso of healthy individuals. Chi-square test was performed to observe statistical difference between the HCECGs and RLECGs according to different shapes of QRS and T waves. RESULTS: Among 120 healthy individuals, deformed ECGs appeared in V(1) and HV(3R)-HV(8R) leads, with 20% (24/120) inverted T wave in V(1) lead, 100% (120/120) in V(3R)-V(8R) leads, wide or deep Q wave 100% (120/120) in V(4R)-V(8R) leads. However, in the corresponding HC-lead system, T waves were all positive, and QRS waves were upright as the pattern of rs, RS or qRs. There was statistical difference in the form of ECG between V(1), V(3R)-V(8R) of Wilson lead and the corresponding HC-lead (P<0.05). The distribution of normal cardioeleclric field related to QRS-T wave was of all-round outward shape by HC-lead, and of roughly bipolar shape by Wilson lead for inverted QRS-T wave on the right thoracic surface. CONCLUSION: The normal distribution of electrocardial field is determined by the potential of the reference point. The forehead of HC-lead seems to be better than the central terminal as the reference point of the lead system.

[Evaluation of resultant cardiac vector based on voltage distribution of electrocardial field around ex vivo guinea pig heart].

OBJECTIVE: To evaluate the possibility of resultant cardiac vector of ex vivo guinea pig heart. METHODS: ECGs were recorded in 4 directions on every plane, and in each direction 4 points at different distances from the anterior, posterior, right and left of isolated guinea pig ventricles immersed in normal saline and distilled water. RESULTS: Main upward waves of ECGs were recorded at all points in 4 directions at 3 levels in the two media. The voltage distribution of normal electrocardial field of the QRS wave was of all-round outward shape, which did not match the resultant cardiac vectors between the left and right and between the anterior and posterior ventricular walls. CONCLUSION: There are some confusion and contradiction in the resultant cardiac vector based on the voltage distribution of electrocardial field around ex vivo guinea pig heart.

[Comparison of head-chest lead electrocardiogram and routine lead electrocardiogram in diagnosis of acute posterior wall myocardial infarction].

OBJECTIVE: To compare the value of head-chest lead electrocardiogram (HCECG) and routine lead electrocardiogram (RLECG) in diagnosis of acute positive posterior myocardial infarction. METHODS: HCECGs and RLECGs were recorded simultaneously in 68 normal individuals and 32 patients with acute posterior wall myocardial infarction confirmed by coronary angiography and echocardiography. Each HCECG and RLECG was analyzed by two senior physicians specialized in clinical electrophysiology who were blinded to the results. The HCECG- and RLECG-based diagnostic results were compared with the results of coronary angiography, and the coincidence rates and false positive rates of diagnosis based on HCECGs and RLECGs were calculated. RESULTS: The coincidence rate was 93.8% (30/32) for RLECGs and 100% (32/32) for HCECGs in the diagnosis of acute posterior wall myocardial infarction, showing no significant difference between them (P>0.05). RLECGs-based diagnosis, however, resulted in a significantly higher false positive rate than HCECGs [13.2% (9/68) vs 0% (0/68), P<0.05]. CONCLUSION: Head-chest lead system is superior to routine lead system for its low false positive rates in the diagnosis of acute posterior wall myocardial infarction.

[An efficient method for simulating ventricular electrical activity based on anatomic structure by incorporating AP model].

Conventional medical experiments can hardly simulate cardiac excitation propagation and observe the evolvement of cardiac electrical activities firsthand as is possible with computer simulation. Based on the anatomic structure of the heart, simulation of cardiac electrical activity mainly consists of the emulation of the excitation process among the cardiac cells and calculation of the electrical activities of individual cardiac cells. In this study we establish a geometric ventricular structure model demonstrating the direction of the cardiac muscle fibers and the layers of the ventricular cells, and endow different action potential models to the ventricular cells of different layers, and observe the activation process of the ventricular parts in view of the three-dimensional anatomy. This method gives attention to both enough calculation amounts and efficiency, which achieves satisfactory simulation results of ventricular electrical activity based on the anatomic structure and cell electrophysiology through an improved algorithm on personal computer.

[Fast elimination of 50-Hz noise in PC-based application system].

The interference by 50-Hz noise arising from the power supply cables is common in PC-based application system, often considerably affecting the detection of useful signals. On the basis of self-adapting correlation method, we attempt to address the problem of fast elimination of 50-Hz noise from the useful signals in PC-based application system such as digital ECG recording system.