Rociletinib (CO-1686) enhanced the efficacy of chemotherapeutic agents in ABCG2-overexpressing cancer cells in vitro and in vivo

Overexpression of adenosine triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG2) in cancer cells is known to cause multidrug resistance (MDR), which severely limits the clinical efficacy of chemotherapy. Currently, there is no FDA-approved MDR modulator for clinical use. In this study, rociletinib (CO-1686), a mutant-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was found to significantly improve the efficacy of ABCG2 substrate chemotherapeutic agents in the transporter-overexpressing cancer cells in vitro and in MDR tumor xenografts in nude mice, without incurring additional toxicity. Mechanistic studies revealed that in ABCG2-overexpressing cancer cells, rociletinib inhibited ABCG2-mediated drug efflux and increased intracellular accumulation of ABCG2 probe substrates. Moreover, rociletinib, inhibited the ATPase activity, and competed with [¹²⁵I] iodoarylazidoprazosin (IAAP) photolabeling of ABCG2. However, ABCG2 expression at mRNA and protein levels was not altered in the ABCG2-overexpressing cells after treatment with rociletinib. In addition, rociletinib did not inhibit EGFR downstream signaling and phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK). Our results collectively showed that rociletinib reversed ABCG2-mediated MDR by inhibiting ABCG2 efflux function, thus increasing the cellular accumulation of the transporter substrate anticancer drugs. The findings advocated the combination use of rociletinib and other chemotherapeutic drugs in cancer patients with ABCG2-overexpressing MDR tumors.     

双吲哚马来酰亚胺衍生物L6诱导白血病细胞凋亡机制的研究

目的探讨双吲哚马来酰亚胺衍生物L6诱导白血病细胞的凋亡作用及其分子机制。方法采用MTT比色法检测L6对白血病细胞HEL、K562、KG1a的杀伤作用。流式细胞术检测L6对HEL细胞凋亡、周期和分化的影响。Western blotting法检测细胞凋亡相关蛋白的表达。通过体内实验研究L6治疗小鼠白血病的作用效果。结果 MTT比色法结果显示L6对HEL、K562、KG1a细胞具有比阳性对照米哚妥林(PKC412)更显著的抑制活性,半数抑制浓度(IC50)分别为(0.05±0.03)、(0.32±0.01)、(0.19±0.10)μmol/L。L6可以诱导HEL细胞发生凋亡和G2/M期阻滞,诱导HEL细胞向巨核细胞方向分化,且呈剂量效应。Western blotting检测结果表明L6主要通过激活Caspase-3执行细胞凋亡。小鼠肝组织苏木精-伊红(HE)染色显示肝组织内HEL细胞浸润有所减轻,但L6组减轻的效果更明显,表明其可延缓白血病细胞的转移,且效果优于米哚妥林。结论双吲哚马来酰亚胺衍生物L6有较强的抗白血病活性,为新型白血病药物的研发提供参考。     

A prognostic signature based on immune-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) is the fourth commonest female malignancy worldwide. CESC progresses in immune-microenvironment mainly composed of infiltrating immune and stromal cells. Here, we performed an integrated analysis incorporating the expression profiles from the Cancer Genome Atlas (TCGA) database and scores of immune and stromal cells calculated by Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm. A two-gene signature (CD1C and CD6 genes) was established to predict the prognosis of CESC. Based on this signature, patients were divided into the high- and low-risk groups, and this signature showed good prognostic performance according to the results of Kaplan-Meier analysis and receiver operating characteristic (ROC) analysis in train set and two validation sets. A nomogram was built for evaluating the clinical applicability of this signature. In addition, based on Tumor Immune Estimation Resource (TIMER) database, 2 hub genes showed negative correlations with tumor purity and positive correlations with infiltrating levels of immune filtrating cells. What’s more, we propose new treatment strategies for the two prognostic subtypes. Low- risk patients were found presenting with a higher level of immune checkpoint molecules and showing higher immunogenicity in immunophenoscore (IPS) analysis, which indicated a better response for immunotherapy. Meanwhile, estimated by Genomics of Drug Sensitivity in Cancer (GDSC) database, the high-risk patients showed sensitive responses to five chemotherapy drugs. Finally, 10 candidate small-molecule drugs for CESC were defined. In summary, the CD1C-CD6 signature can accurately predict the prognosis of CESC.     

The safety and feasibility of minimal invasive plate osteosynthesis (MIPO) of the posterior aspect of the humerus: A cadaveric study

The aim of this study was to determine the feasibility of applying MIPO of the humerus via the posterior approach and to observe the tension of the radial nerve in different elbow positions. Two separate incisions were made on the posterior aspect of the humerus in ten fresh cadavers (20 humeri). The radial nerve was identified at the proximal incision and the distances through which the nerve could be elevated from the bone with the elbow in flexion and extension were measured. A 10‐hole extra‐articular distal humeral locking compression plate was inserted and fixed through the submuscular tunnel. The tunnel was then explored to identify any entrapment of the radial nerve and to observe the anatomical relationship of the radial nerve to the plate and bone. There was no entrapment of the radial nerve or its branches. The distances through which the radial nerve could be elevated were greater with the elbow in extension than in flexion (P < 0.01). The radial nerve crossed the medial and lateral borders of the posterior surface of the humerus at 80.1–132 mm (average 104.7 mm) and 116.6–175.5 mm (average 142.7 mm) of its total length, respectively. The axillary nerve was located at 38.7–61.7 mm (average 47.9 mm) of total humeral length. MIPO of the humerus using the posterior approach is an alternative option for treating distal humeral shaft fracture. The risk of radial nerve injury can be minimized by careful dissection in the proximal incision. Clin. Anat. 32:176–182, 2019. © 2018 Wiley Periodicals, Inc.     

Toward liquid biopsies in cancer treatment: application of circulating tumor DNA

Circulating tumor DNA (ctDNA) refers to the fraction of cell‐free DNA in a patient's blood originating from tumor cells. Increased knowledge about tumor genomics, improvements in targeted therapies, and accompanying advances in DNA‐sequencing technologies have increased the interest in using ctDNA as a minimally invasive tool in cancer diagnostics and treatment. Especially, early tumor detection including identification of minimal residual disease and stratification of adjuvant therapy are promising approaches. Also, ctDNA showed to be reliable in treatment monitoring and can be used to assess therapy resistance due to the broad variety of tumor subclones captured in ctDNA. Therefore, using ctDNA in the clinical setting has the potential to improve therapeutic outcomes. In the present review, we summarize the status of ctDNA in oncology with focus of being an alternative to tissue biopsies in early detection and treatment monitoring.     

Preparation,characterization, and antibacterial activity of plaunotol and plaunoi extracts complexed with hydroxypropyl-β-cyclodextrin

Croton stellatopilosus (Plaunoi) leaves accumulate several diterpenes and possess various pharmacological activities. The present study aimed to prepare, characterize and assess the antibacterial activity of inclusion complexes prepared by mixing plaunotol (PL) or plaunoi extract (PE) with cyclodextrins (CD), including α-CD, β-CD, γ-CD, and hydroxypropyl-β-cyclodextrin (HP-β-CD). The inclusion complexes were characterized using SEM, XRD, DSC, and FT-IR and evaluated for aqueous solubility and thermal stability. The PL and PE lyophilized complexes with HP-β-CD were further evaluated for their antibacterial activity against acne-causing bacteria. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of PL, PE, and the inclusion complexes evaluated using the agar dilution method revealed that the MIC and MBC values of the inclusion complexes were lower than those of PL or PE alone. Interestingly, the complexes had a synergistic activity with clindamycin after testing with checkerboard assay. The hydrogel containing the inclusion complex and clindamycin were assessed for antibacterial activity using the agar well diffusion method. The results indicated that the hydrogels showed significant inhibition of bacterial growth. In conclusion, the prepared solid dispersion of PL or PE with HP-β-CD could enhance antibacterial activity by increasing the drug solubility. The hydrogels containing PL or PE complex and clindamycin could be considered as a candidate for the treatment of acne vulgaris.     

Abdominal access techniques

This article discusses the variety of techniques available to gain safe exposure to intra-abdominal organs. In recent years there have been significant advances in these techniques with a move towards minimally invasive strategies as the gold standard of care. This article will discuss the various options available, including laparoscopy and traditional open access, as well as the use of robotics within abdominal surgery.     

广东省慢性化脓性中耳炎患者耳分泌物的病原体分布及药物敏感性分析

目的分析广东省慢性化脓性中耳炎(CSOM)患者耳分泌物的病原体分布及药物敏感性情况,为临床CSOM的诊断和治疗提供依据。方法回顾性分析2015—2019年1892例确诊为CSOM患者耳分泌物标本的微生物学培养结果,对病原体分布、临床常用抗感染药物的敏感性进行分析。结果共检出1054株条件致病菌,检出率位于前3位的细菌是金黄色葡萄球菌、凝固酶阴性葡萄球菌和铜绿假单胞菌,真菌是近平滑念珠菌、聚多曲霉和黄曲霉。葡萄球菌对红霉素、青霉素G的敏感率较低,对其他常用抗菌药物的敏感率均高于70.0%,铜绿假单胞菌对于常用抗假单胞菌药物的敏感率均高于85.0%。近平滑念珠菌和白色念珠菌对氟康唑、伏立康唑均具有较高的敏感率;黄曲霉、土曲霉对两性霉素B的最小抑菌浓度(MIC)值较高,橘青霉对于伏立康唑的MIC值较高。结论广东省CSOM患者耳分泌物中病原体以葡萄球菌、铜绿假单胞菌、念珠菌和曲霉菌为主;真菌的检出率较其他地区高;检出的病原体对常用的治疗药物具有较高的敏感性。