Design and Characterization of a Novel eEF2K Degrader with Potent Therapeutic Efficacy Against Triple-Negative Breast Cancer.

Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple-negative breast cancer (TNBC), making it a plausible therapeutic target. However, specific eEF2K inhibitors with potent anti-cancer activity have not been available so far. Targeted protein degradation has emerged as a new strategy for drug discovery. In this study, a novel small molecule chemical is designed and synthesized, named as compound C1, which shows potent activity in degrading eEF2K. C1 selectively binds to F8, L10, R144, C146, E229, and Y236 of the eEF2K protein and promotes its proteasomal degradation by increasing the interaction between eEF2K and the ubiquitin E3 ligase ßTRCP in the form of molecular glue. C1 significantly inhibits the proliferation and metastasis of TNBC cells both in vitro and in vivo and in TNBC patient-derived organoids, and these antitumor effects are attributed to the degradation of eEF2K by C1. Additionally, combination treatment of C1 with paclitaxel, a commonly used chemotherapeutic drug, exhibits synergistic anti-tumor effects against TNBC. This study not only generates a powerful research tool to investigate the therapeutic potential of targeting eEF2K, but also provides a promising lead compound for developing novel drugs for the treatment of TNBC and other cancers.

Prevalence and risk factors of anal human papillomavirus infection among men with anal condyloma acuminata by HIV status in ShenZhen, Southeast China: A retrospective cohort study.

Patients with anal condyloma acuminatum (CA) are at risk of developing anal cancer which is associated with oncogenic human papillomavirus (HPV) infection. Investigation of anal HPV prevalence and risk factors can provide effective strategies for the prevention of anal cancer. A retrospective study was conducted among 549 patients with anal CA in the Third People's Hospital of Shenzhen between January 2019 and October 2021. HPV prevalence and HIV antibodies were detected by fluorescent PCR and ELISA, respectively. Logistic regression model and structural equation modeling (SEM) were conducted to analyzed the risk factors of oncogenic HPV infection. The overall prevalence of HPV was 96.72%. Both HPV6 (N = 285, 51.91%) and HPV11 (N = 300, 54.64%) were more than half infected and the most frequent Hr-HPV genotype was HPV16 (N = 138, 25.14%). HIV-positive (AOR: 5.02, 95% CI: 2.98-8.60, p < 0.0001) and history of syphilis (AOR: 4.24, 95% CI: 2.31-8.46, p < 0.0001) were independent risk factors statistically associated with oncogenic HPV infection. Ever had anal sex (AOR: 3.40, 95% CI: 1.28-11.81, p = 0.0267) and age 35 years and older (AOR: 2.79, 95% CI: 1.53-5.15, p = 0.0009) were associated with HPV16 and HPV52, respectively. SEM analyses showed that HIV-positive (b = 1.549, p < 0.001) and history of syphilis (b = 1.450, p < 0.001) had significant positive effects on oncogenic HPV infection. Ever had anal sex (b = 1.243, p = 0.025) and Age (b = 0.043, p = 0.002) positively drived HPV16 and HPV52 infection, respectively. Anal CA patients who are HIV-positive, have a history of syphilis, or at least 35 years old should be considered for Hr-HPV, cytology and other anal cancer related tests to reduce the risk of cancer development.

The correlation of lymphocytes with disease progression of COVID-19.

The aim of this study is to evaluate the potential of lymphocytes as biomarkers to predict the decline of coronavirus disease 2019 (COVID-19). Lymphocytes were counted in 164 moderate COVID-19 patients in Shenzhen, China. Among the moderate infected patients, 12.2% (20/164) progressed to severe cases after admission. Compared with the stable patients, the counts of lymphocytes, both total T lymphocytes and CD4+ T lymphocytes, in the severe patients, were lower. The aggravation of moderate infected patients was significantly associated with lymphocyte count (hazard ratio [HR] = 0.91; 95% confidence interval [CI]: 0.84-0.99), total T lymphocyte count (HR = 0.91; 95% CI: 0.84-0.99), and CD4+ T lymphocyte count (HR = 0.91; 95% CI: 0.85-0.98). Total T lymphocytes and CD4+ T lymphocytes could be important biomarkers to evaluate the risk of aggravation for moderate infected COVID-19 patients. The patients with low percentages of total T lymphocytes and CD4+ T lymphocytes need more attention.

Risk factors of oncogenic HPV infection in HIV-positive men with anal condyloma acuminata in Shenzhen, Southeast China: a retrospective cohort study.

Background: Human immunodeficiency virus (HIV)-positive patients with anal condyloma acuminata (CA) present an increased risk of anal cancer progression associated with oncogenic human papillomavirus (HPV) infection. It is essential to explore determinants of anal infection by oncogenic HPV among HIV-positive patients with CA. Methods: A retrospective cohort study was performed in HIV-positive patients with CA between January 2019 to October 2021 in Shenzhen, Southeast China. Exfoliated cells were collected from CA lesions and the anal canal of HPV genotypes detected by fluorescence PCR. Unconditional logistic regression analysis was used to probe associations of independent variables with oncogenic HPV infection. Results: Among HIV-positive patients with CA, the most prevalent oncogenic genotypes were HPV52 (29.43%), HPV16 (28.93%), HPV59 (19.20%), and HPV18 (15.96%). Risk of oncogenic HPV infection increased with age at enrollment (COR: 1.04, 95% CI: 1.01-1.07, p = 0.022). In the multivariable analysis, age ≥ 35 years (AOR: 2.56, 95% CI: 1.20-5.70, p = 0.02) and history of syphilis (AOR: 3.46, 95% CI: 1.90-6.79, p < 0.01) were independent risk factors statistically associated with oncogenic HPV infection. History of syphilis (AOR: 1.72, 95% CI: 1.08-2.73, p < 0.02) was also an independent risk factor statistically associated with HPV16 or HPV18 infection. Conclusion: In clinical practice, HIV-positive CA patients aged ≥35 years or with a history of syphilis should carry out HR-HPV testing and even anal cancer-related examinations to prevent the occurrence of anal cancer.

Aporphines: A privileged scaffold in CNS drug discovery.

Aporphine alkaloids embedded in 4H-dibenzo[de,g]quinoline four-ring structures belong to one of the largest subclasses of isoquinoline alkaloids. Aporphine is a privileged scaffold in the field of organic synthesis and medicinal chemistry for the discovery of new therapeutic agents for central nervous system (CNS) diseases, cancer, metabolic syndrome, and other diseases. In the past few decades, aporphine has attracted continuing interest to be widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS (e.g., dopamine D1/2/5, serotonin 5-HT1A/2A/2C and 5-HT7, adrenergic α/ß receptors, and cholinesterase enzymes), thereby serving as valuable pharmacological probes for mechanism studies or as potential leads for CNS drug discovery. The aims of the present review are to highlight the diverse CNS activities of aporphines, discuss their SAR, and briefly summarize general synthetic routes, which will pave the way for the design and development of new aporphine derivatives as promising CNS active drugs in the future.

Application of star poly(ethylene glycol) derivatives in drug delivery and controlled release.

Multi-arm star poly(ethylene glycol) (PEG) polymers have a number of advantages over linear PEG polymers when used as carriers for drug delivery and controlled release. For instance, they have more terminals that can be modified to form multi-functional delivery systems with significantly increased drug loading. They can form micelles with higher stability and lower critical micelle concentration (CMC), which helps to improve the blood circulation and reduce the unfavorable burst drug release. Moreover, star PEG polymers can form three-dimensional hydrogels with controllable size and adjustable functions through cross-linking. Indeed, these unique advantages of star PEG polymers have promoted investigations on star PEG-based drug delivery systems. Herein, for the first time, we carefully reviewed the advances on the research and development of star PEG polymers, especially the 4-, 6- and 8-armed star PEG polymers, in delivery and controlled release of a series of bioactive agents, including both small molecules and biomacromolecules. Opportunities and challenges for successful translation of star PEG-based drug formulations into clinical use were also discussed.

Advances in delivery of Irinotecan (CPT-11) active metabolite 7-ethyl-10-hydroxycamptothecin.

CPT-11 is a first-line chemotherapy for advanced or metastatic colorectal cancers. 7-Ethyl-10-hydroxycamptothecin (SN38), the active metabolite of CPT-11, has an anticancer efficacy 100-1000 folds more than CPT-11 in vitro. However, the drawbacks such as ultralow solubility and poor stability, greatly limit the clinical applications of SN38. Recently, SN38-based nanomedicines have greatly improved the pharmaceutical and therapeutic characteristics of SN38. In addition, these nanosized delivery systems can target tumor tissues via the EPR effect and/or active-targeting strategies, thereby significantly improving anticancer efficacy, reducing side effects and reversing drug resistance. This review focuses on the advances of nano-delivery systems for SN38. We categorize the published studies into two groups, physical encapsulation and chemical conjugation, for the development of SN38 nano-delivery systems, and particularly summarize those for active tumor targeting. The advantages and shortcomings of current SN38 nano-delivery systems, aiming to develop more potent SN38 nano-delivery systems, are also discussed.