A highly tumor-targeted nanoparticle of podophyllotoxin penetrated tumor core and regressed multidrug resistant tumors

Podophyllotoxin (PPT) exhibited significant activity against P-glycoprotein mediated multidrug resistant (MDR) tumor cell lines; however, due to its poor solubility and high toxicity, PPT cannot be dosed systemically, preventing its clinical use for MDR cancer. We developed a nanoparticle dosage form of PPT by covalently conjugating PPT and polyethylene glycol (PEG) with acetylated carboxymethyl cellulose (CMC-Ac) using one-pot esterification chemistry. The polymer conjugates self-assembled into nanoparticles (NPs) of variable sizes (20–120 nm) depending on the PPT-to-PEG molar ratio (2–20). The conjugate with a low PPT/PEG molar ratio of 2 yielded NPs with a mean diameter of 20 nm and released PPT at ∼5%/day in serum, while conjugates with increased PPT/PEG ratios (5 and 20) produced bigger particles (30 nm and 120 nm respectively) that displayed slower drug release (∼2.5%/day and ∼1%/day respectively). The 20 nm particles exhibited 2- to 5-fold enhanced cell killing potency and 5- to 20-fold increased tumor delivery compared to the larger NPs. The biodistribution of the 20 nm PPT-NPs was highly selective to the tumor with 8-fold higher accumulation than all other examined tissues, while the larger PPT-NPs (30 and 120 nm) exhibited increased liver uptake. Within the tumor, >90% of the 20 nm PPT-NPs penetrated to the hypovascular core, while the larger particles were largely restricted in the hypervascular periphery. The 20 nm PPT-NPs displayed significantly improved efficacy against MDR tumors in mice compared to the larger PPT-NPs, native PPT and the standard taxane chemotherapies, with minimal toxicity.     

妇科腹腔镜围手术期碳水化合物口服疗法对术后胰岛素抵抗影响的研究

目的观察妇科腹腔镜手术围术期碳水化合物口服疗法和传统禁饮食方案两种不同的临床处理措施对于术后胰岛素抵抗（IR）的影响。 方法选取2018年2月至8月入住徐州医科大学附属医院妇科，行腹腔镜下全子宫切除手术的非糖尿病患者共98例，将采用围术期碳水化合物口服疗法者作为观察组（50例），采用传统禁饮食方案者作为对照组（48例）。检测所有病例的术前、术后第1天及第3天的空腹血糖（FPG）及空腹胰岛素（FINS），并利用稳态模式评估法计算稳态模型胰岛素抵抗指数（HOME-IR）。对于观察组与对照组患者术前、术后第1天和术后第3天的FPG、FINS和HOME-IR等指标，组间比较采用独立样本t检验。两组患者术后腹胀、术后24 h通气、术后发热的发生情况的比较采用确切概率法检验。 结果观察组与对照组比较，术前和术后第1天FPG差异无统计学意义（P均>0.05），术后第3天FPG明显降低［（4.34±0.59）mmol/L vs （4.96±0.64）mmol/L］，差异有统计学意义（t=-4.96，P=0.002）。观察组与对照组比较，术前和术后第1天FINS差异无统计学意义（P均>0.05），术后第3天FINS明显降低［（45.39±13.55）mIU/L vs （51.18±9.34） mIU/L］，差异有统计学意义（t=-2.46，P=0.033）。观察组与对照组比较，术前HOME-IR差异无统计学意义（P>0.05），术后第1天和术后第3天HOME-IR明显降低［（13.08±4.80）vs （15.03±4.11）；（9.37±3.65）vs （11.30±2.55）］，差异有统计学意义（t=-0.69，P=0.042；t=-3.99，P=0.033）。两组患者术后其他观察指标比较，观察组术后24 h通气率与对照组比较明显增高（76.0% vs 64.6%），差异有统计学意义（P=0.045）。两组患者在术后腹胀、术后发热的发生率方面差异无统计学意义（P均>0.05）。两组患者均未发生术中误吸。 结论妇科腹腔镜手术围术期应用碳水化合物口服疗法较传统禁饮食方案，能有效减轻术后IR程度，促进术后康复进程，且不增加围术期并发症的发生率。     

HIV Protease: Historical Perspective and Current Research

The retroviral protease of human immunodeficiency virus (HIV) is an excellent target for antiviral inhibitors for treating HIV/AIDS. Despite the efficacy of therapy, current efforts to control the disease are undermined by the growing threat posed by drug resistance. This review covers the historical background of studies on the structure and function of HIV protease, the subsequent development of antiviral inhibitors, and recent studies on drug-resistant protease variants. We highlight the important contributions of Dr. Stephen Oroszlan to fundamental knowledge about the function of the HIV protease and other retroviral proteases. These studies, along with those of his colleagues, laid the foundations for the design of clinical inhibitors of HIV protease. The drug-resistant protease variants also provide an excellent model for investigating the molecular mechanisms and evolution of resistance.     

常见抗生素与新型抗菌药物在临床上的研究应用进展

摘要：抗生素的研发与使用有效杀灭和抑制了众多病原菌，挽救了无数人的生命，但由于抗生素的不合理使用，导致细菌耐 药不断出现，耐药菌的感染已严重地威胁人类的生命健康。为此，本文主要对近年来临床上常用的抗生素如β-内酰胺类、喹诺酮 类、氨基糖苷类药物以及新型抗菌药物如抗菌肽和纳米颗粒的应用研究进行总结分析与探讨，为临床上治疗疾病提供一些参考。     

Egg Intake Has No Adverse Association With Blood Lipids Or Glucose In Adolescent Girls

Objective: Longitudinal data on cardiometabolic effects of egg intake during adolescence are lacking. The current analyses aim to evaluate the impact of usual adolescent egg consumption on lipid levels, fasting glucose, and insulin resistance during late adolescence (age 17–20?years).

Methods: Data from 1392 girls, aged 9 to 10 at baseline and followed for 10?years, in the National Heart, Lung, and Blood Institute’s National Growth and Health Study were used to examine the association between usual egg intake alone and in combination with other healthy lifestyle factors and late adolescent lipid levels, fasting glucose, and insulin resistance, measured as homeostasis model assessment of insulin resistance (HOMA-IR). Diet was assessed using 3-day food records during eight examination cycles. Girls were classified according to usual weekly egg intake, ages 9–17?years:?<1 egg/wk (n?=?361), 1 to <3 eggs/wk (n?=?703), and ≥3 eggs/wk (n?=?328). Analysis of covariance modeling was used to control for confounding by other behavioral and biological risk factors.

Results: Girls with low, moderate, and high egg intakes had adjusted low-density lipoprotein cholesterol levels of 99.7, 98.8, and 95.5 mg/dL, respectively (p?=?0.0778). In combination with higher intakes of fiber, dairy, or fruits and vegetables, these beneficial effects were stronger and statistically significant. There was no evidence that ≥3 eggs/wk had an adverse effect on lipids, glucose, or HOMA-IR. More active girls who consumed ≥3 eggs/wk had the lowest levels of insulin resistance.

Conclusion: These results suggest that eggs may be included as part of a healthy adolescent diet without adverse effects on glucose, lipid levels, or insulin resistance.     

Managing cardiotoxicity associated with immune checkpoint inhibitors

Immuno-oncology is a fast evolving field of cancer therapy and immune checkpoint inhibitors (ICIs) are clearly a breakthrough in this field. Cardiotoxicity with conventional anti-cancer therapies has been well studied in the past and clear guidelines for management of these side effects are available in the literature. However, cardiotoxicity with novel agents such as ICIs has been fairly under-reported and/or underestimated and we are yet to formulate clear guidelines for management of these rare side effects. In the last few years, there has been an overall increase in the number of cases of cardiotoxicity related to ICIs. In this literature review, we describe the mechanism of action of the most widely used ICIs and their related cardiotoxicities. The increase in number of case reports about the potential of cardiotoxicities with these novel agents clearly indicates the need for a new insight into the field of cardio-immuno-oncology.     

Vaccines and autoimmunity during the COVID-19 pandemic

To control the pandemic, efficient vaccines must be applied to the population, including patients with autoimmune diseases. Therefore, one can expect that coronavirus disease 2019 (COVID-19) vaccines may influence the underlying autoimmune processes in these patients. Additionally, it is essential to understand whether COVID-19 vaccines would be effective, safe, and provide long-lasting immunological protection and memory. However, the currently available and approved COVID-19 vaccines turned out to be safe, effective, and reliable in patients with autoimmune inflammatory and rheumatic diseases. Furthermore, most patients said they felt safer after getting vaccinations for COVID-19 and reported enhanced overall quality of life and psychological wellbeing. In general, the COVID-19 vaccines have been highly tolerated by autoimmune patients. Such findings might comfort patients who are reluctant to use COVID-19 vaccines and assist doctors in guiding their patients into receiving vaccinations more easily and quickly.     

A new aspect of in vitro antimicrobial leukocyte- and platelet-rich plasma activity based on flow cytometry assessment

The current literature suggests that the antibacterial effect of leukocyte- and platelet-rich plasma (L-PRP) is directly related to platelet and leukocyte concentrations. The aim of this study was twofold: first, to evaluate the antimicrobial effect of L-PRP against selected bacterial strains in vitro, and second, to correlate this effect with leukocyte and platelet content in the final concentration. Blood was collected from 20 healthy males, and L-PRP, acellular plasma (AP), and autologous thrombin were consecutively prepared. Flow cytometry analysis of the blood, L-PRP, and AP was performed. The L-PRP gel, liquid L-PRP, and thrombin samples were tested in vitro for their antibacterial properties against seven selected bacterial strains using the Kirby–Bauer disk-diffusion method. There was notable antimicrobial activity against selected bacterial strains. No statistically significant correlations between antimicrobial activities and the platelet concentration in L-PRP were observed. Statistically significant positive correlations between selected leukocyte subtypes and antimicrobial activity were noted. A negative correlation was found between elevated monocyte count and antimicrobial activity of L-PRP against one bacterial strain studied. L-PRP possesses antimicrobial activity and can be potentially useful in the fight against certain postoperative infections. The bactericidal effect of L-PRP is caused by leukocytes, and there exists a relationship among selected leukocyte subtypes and L-PRP antimicrobial activity.     

血流感染肺炎克雷伯菌中CRISPR-Cas系统的分布及其与毒力基因和耐药的关系

的 了解血流感染肺炎克雷伯菌中CRISPR-Cas系统的分布特征并分析其与毒力基因和耐药的关系。方法 收集非重复血流感染肺炎克雷伯菌248株，使用Vitek2-Compact全自动微生物分析系统进行菌株鉴定及药物敏感性分析，PCR检测CRISPR-Cas系统3个相关基因(CRISPR1、CRISPR2和cas1)、筛查6种常见高毒力荚膜血清型(K1、K2、K5、 K20、K54和K57)、12种毒力基因及检测13种耐药基因，用χ2检验比较携带有CRISPR-Cas系统菌株与不携带CRISPR-Cas系统菌株毒力及耐药差异。结果 CRISPR-Cas系统的检出率为29.8%(74/248)；K1型是携带CRISPR-Cas系统肺炎克雷伯菌的主要荚膜血清型，占 28.4%(21/74)；除kpn基因外，携带CRISPR-Cas系统菌株的毒力基因检出率均大于不携带CRISPR-Cas系统菌株，其中7种差异有统计学意义；除对氨苄西林耐药率达100%外，携带有CRISPR-Cas系统菌株的其他抗菌药物耐药率均小于不携带有CRISPR-Cas系统菌株，其中13种差异有统计学意义；携带CRISPR-Cas系统菌株的耐药基因阳性率小于不携带CRISPR-Cas系统的菌株，且blaKPC、blaSHV、qnrS基因差异有统计学意义。结论 高毒力荚膜血清型肺炎克雷伯菌中主要为K1型携带CRISPR-Cas系统，携带CRISPR-Cas系统的肺炎克雷伯菌相对于不携带CRISPR-Cas系统菌株的毒力基因阳性率高，耐药率低，耐药基因的阳性率低。CRISPR-Cas系统可能能降低耐药基因在肺炎克雷伯菌中的水平传播，尤其是在K1型肺炎克雷伯菌。     

Review of clinical characteristics,immune responses and regulatory mechanisms of hepatitis E-associated liver failure

Hepatitis E virus (HEV) is the most common cause of acute liver failure (LF) and one of the most common factors causing acute injury in acute-on-chronic LF (ACLF). When HEV-related LF occurs, a series of changes take place in both the intrahepatic environment and extrahepatic microenvironment. The changed types and distribution of immune cells (infiltrating macrophages and increased lymphocytes) in liver tissue, as well the increased proinflammatory cytokines and chemokines in the blood, indicate that the occurrence and progression of HEV-related LF are closely related to immune imbalance. The clinical features and immune reaction in the body during HEV-related acute LF (ALF) and ACLF are complicated. This review highlights recent progress in elucidating the clinical manifestations of HEV-associated ALF and ACLF and discusses the corresponding systemic immune changes and possible regulatory mechanisms.