miR-188-5p promotes oxaliplatin resistance by targeting RASA1 in colon cancer cells

The efficacy of chemotherapy for colon cancer is limited due to the development of chemoresistance. MicroRNA (miR)-188-5p is downregulated in various types of cancer. The aim of the present study was to explore the molecular role of miR-188 in oxaliplatin (OXA) resistance. An OXA-resistant colon cancer cell line, SW480/OXA, was used to examine the effects of miR-188-5p on the sensitivity of colon cancer cells to OXA. The target of miR-188-5p was identified using a luciferase assay. Cell cycle distribution was also assessed using flow cytometry. The measurement of p21 protein expression, Hoechst 33342 staining and Annexin V/propidium iodide staining was used to evaluate apoptosis. The expression of miR-188-5p significantly increased in SW480/OXA compared with wild-type SW480 cells. The luciferase assay demonstrated that miR-188-5p inhibited Ras GTPase-activating protein 1 (RASA1; also known as p120/RasGAP) luciferase activity by binding to the 3′-untranslated region of RASA1 mRNA, suggesting that miR-188-5p could target RASA1. In addition, miR-188-5p downregulation or RASA1 overexpression promoted the chemosensitivity of SW480/OXA, as evidenced by increased apoptosis and G₁/S cell cycle arrest. Moreover, RASA1 silencing abrogated the increase in cell apoptosis induced by the miR-188-5p inhibitor. The findings of the present study suggested that miR-188-5p could enhance colon cancer cell chemosensitivity by promoting the expression of RASA1.     

Cellular internalization and morphological analysis after intravenous injection of a highly hydrophilic octahedral rhenium cluster complex – a new promising X‐ray contrast agent

The octahedral cluster compound Na₂H₈[{Re₆Se₈}(P(C₂H₄CONH₂)(C₂H₄COO)₂)₆] has been shown to be highly radio dense, thus becoming a promising X‐ray contrast agent. It was also shown that this compound had low cytotoxic effect in vitro, low acute toxicity in vivo and was eliminated rapidly from the body through the urinary tract. The present contribution describes a more detailed cellular internalization assay and morphological analysis after intravenous injection of this hexarhenium cluster compound at different doses. The median lethal dose (LD₅₀) of intravenously administrated compound was calculated (4.67 ± 0.69 g/kg). Results of the study clearly indicated that the cluster complex H_n[{Re₆Se₈}(P(C₂H₄CONH₂)(C₂H₄COO)₂)₆]^n–10 was not internalized into cells in vitro and induced only moderate morphological alterations of kidneys at high doses without any changes in morphology of liver, spleen, duodenum, or heart of mice. Copyright © 2016 John Wiley & Sons, Ltd.     

Two-year clinical follow-up results of intracoronary radiation therapy with rhenium-188-diethylene triamine penta-acetic acid-filled balloon.

We investigated the 2-year clinical follow-up results as well as 6-month angiographic and clinical follow-up results of intracoronary radiation therapy using a rhenium-188-diethylene triamine penta-acetic acid ((188)Re-DTPA)-filled balloon system. The study comprised of 161 patients with significant de novo (83%) or in-stent restenosis (17%) lesions. Irradiation to deliver 17.6 Gy at a depth of 1.0 mm into the vessel wall was carried out after successful intervention. At 6-month follow-up, binary restenosis developed with significantly lower frequency in the radiation group than in the control group (24.3% vs. 46.3%; P = 0.009), although target lesion revascularization rate did not show significant benefit. At 2-year follow-up, cumulative target lesion revascularization rate was not significantly different between radiation group (n = 86) and control group (n = 75; 20.0% vs. 26.0%; P = 0.368). The rate of major adverse cardiac events including death, myocardial infarction, and target lesion revascularization did not show significant difference between two groups either (22.3% vs. 30.1%; P = 0.266). In conclusion, although significant reduction in restenosis rate was noted at 6-month angiographic follow-up, intracoronary radiation therapy mostly in patients with de novo lesion did not show significant clinical benefit in 6-month and 2-year follow-up results. The benefit was noted only in a small subgroup of patients with in-stent restenosis.     

Efficacy of a topical concentrated surfactant gel on microbial communities in non‐healing diabetic foot ulcers with chronic biofilm infections: A proof‐of‐concept study

This proof‐of‐concept study sought to determine the effects of standard of care (SOC) and a topically applied concentrated surfactant gel (SG) on the total microbial load, community composition, and community diversity in non‐healing diabetic foot ulcers (DFUs) with chronic biofilm infections. SOC was provided in addition to a topical concentrated SG, applied every 2 days for 6 weeks. Wound swabs were obtained from the base of ulcers at baseline (week 0), week 1, mid‐point (week 3), and end of treatment (week 6). DNA sequencing and real‐time quantitative polymerase chain reaction (qPCR) were employed to determine the total microbial load, community composition, and diversity of patient samples. Tissue specimens were obtained at baseline and scanning electron microscopy and peptide nucleic acid fluorescent in situ hybridisation with confocal laser scanning microscopy were used to confirm the presence of biofilm in all 10 DFUs with suspected chronic biofilm infections. The application of SG resulted in 7 of 10 samples achieving a reduction in mean log10 total microbial load from baseline to end of treatment (0.8 Log10 16S copies, ±0.6), and 3 of 10 samples demonstrated an increase in mean Log10 total microbial load (0.6 log10 16S copies, ±0.8) from baseline to end of treatment. Composition changes in microbial communities were driven by changes to the most dominant bacteria. Corynebacterium sp. and Streptococcus sp. frequently reduced in relative abundance in patient samples from week 0 to week 6 but did not disappear. In contrast, Staphylococcus sp., Finegoldia sp., and Fusobacterium sp., relative abundances frequently increased in patient samples from week 0 to week 6. The application of a concentrated SG resulted in varying shifts to diversity (increase or decrease) between week 0 and week 6 samples at the individual patient level. Any shifts in community diversity were independent to changes in the total microbial loads. SOC and a topical concentrated SG directly affect the microbial loads and community composition of DFUs with chronic biofilm infections.     

188Re血管内照射对新西兰白兔损伤血管内膜增生的影响

目的 研究188Re血管内照射对新西兰白兔损伤血管内膜增生的影响,探讨188Re血管内照射对预防再狭窄的可行性及作用.方法 60只新西兰白兔随机分为对照组(n=30)和照射组(n=30),均行腹主动脉球囊内皮拉伤术.照射组球囊损伤内膜后行188Re照射治疗,管腔下0.5mm处累计吸收剂量为15Gy;对照组则不行血管内照射.分别于术后1、3、6周处死动物,取病理组织学标本进行分析.结果 与对照组对比,照射组第3、6周的新生内膜面积明显减小(2.11±0.17mm2 vs 3.02±0.71mm2,P=0.003;2.63±0.84mm2 vs 3.80±0.99mm2,P=0.023),管腔面积明显增加(5.87±0.57mm2 vs 4.96±0.64mm2,P=0.009;4.74±0.59mm2 vs 4.16±0.40mm2,P=0.037),管腔周径明显增大(4.61±0.78mm vs 3.64±0.93mm,P=0.040;3.85±0.65mm vs 3.12±0.56mm,P=0.031),管腔狭窄程度明显降低(23.04±4.85mm2 vs 33.44±6.47mm2,P=0.003;30.82±7.18mm2 vs 41.46±10.95mm2,P=0.038).结论 188Re血管腔内照射能有效抑制损伤血管的新生内膜增生,改善血管重构,为预防临床PTCA术后再狭窄提供了有力的实验依据.     

Radiopharmacokinetic and dosimetric parameters of 188Re-lanreotide in athymic mice with induced human cancer tumors

Radiolabeled peptides, like the somatostatin analogs, have been used for peptide receptor-mediated radionuclide therapy (PRMRT) in metastatic neuroendocrine tumors.

The eight amino acid peptide 3-(2-naphthalenyl)-d-alanyl-l-cysteinyl-l-tyrosyl-d-tryptophyl-l-lysyl-l-valyl-l-cysteinyl-l-threoninamide,cyclic(2 → 7)-disulfide (9Cl) (lanreotide) was found to bind to the five somatostatin tumor receptors. Lanreotide has been labeled via the bifunctional chelating agent, DOTA, to ¹¹¹In, and ⁹⁰Y. A direct labeling method was used to label lanreotide with ¹⁸⁸Re. Athymic mice with implanted human cancer tumors (uterine-cervix, renal, and neuroblastoma) were injected with radiochemically pure ¹⁸⁸Re-lanreotide (1.11 MBq). The percent injected activity (%IA/g) from serial blood samples was the input data for the WinNonlin computer program to obtain radiopharmacokinetic parameters. The organs’ percent injected activity per gram of tissue (%IA/g) was extrapolated to the weights of a 70 kg male model organs and the number of nuclear transitions (N) were the input for the OLINDA/EXM program to obtain dosimetry estimates. Induced uterine-cervix tumors (HeLa cells) show a mean 2.4 %IA/g uptake up to 24 h and the tumor/blood ratio was over 1.85 (1.5–24 h post-injection) confirming ¹⁸⁸Re-lanreotide remains bound to the tumor. The estimated tumor absorbed dose was 460 mGy/MBq. Human effective dose was 0.0182 mSv/MBq. Therefore, ¹⁸⁸Re-lanreotide is a good candidate for PRMRT and a clinical trial is being planned in order to acquire individual dosimetric data.     

Stimulation of bone collagenase synthesis by mouse fibrosarcoma in resorbing bone in vitro culture.

Fragments of transplantable mouse fibrosarcoma, co-cultured with 5-day-old mouse calvaria, stimulated bone to synthesize and/or release collagenase (～0.6 units/ml) into the culture medium, whereas the tumour alone neither released nor synthesized collagenase.     

188 Re-羟乙基二膦酸与帕米膦酸二钠联合治疗乳腺癌骨转移的临床价值

目的探讨188Re-羟乙基二膦酸(188Re-HEDP)联合帕米膦酸二钠治疗乳腺癌骨转移的临床价值.方法48例乳腺癌多发骨转移患者随机分为3组,分别接受188Re-HEDP、帕米膦酸二钠的单独治疗及两者的联合治疗.结果188Re-HEDP组、帕米膦酸二钠组、联合治疗组止痛有效率分别为73.3%、80.0%和100.0%;骨转移病灶控制有效率分别为40.0%、33.3%和66.7%.联合治疗组疗效明显高于188Re-HEDP组和帕米膦酸二钠组(P均＜0.05),而188Re-HEDP组与帕米膦酸二钠组间差异无统计学意义(P＞0.05).结论188Re-HEDP联合帕米膦酸二钠治疗乳腺癌骨转移,在止痛、骨转移病灶控制方面疗效明显,优于各药单药治疗.     

用于放射性核素铼标记的fac-[^188Re（CO）3（H2O）3]^＋的制备研究

目的：探讨放化中间体fac-[188Re（CO）3（H2O）3]＋的合成条件,并对其进行优化研究。方法：参照Schibli介绍的方法进行放化中间体fac-[188Re（CO）3（H2O）3]＋的合成,分别从反应温度、反应时间和反应物BH3.NH3的用量对合成fac-[188Re（CO）3（H2O）3]＋产率的影响进行观察。结果：合成放化中间体fac-[188Re（CO）3（H2O）3]＋的最佳反应条件为：反应时间为15min,反应温度为70℃,BH3.NH3的用量为5mg;pH值〈2。在最佳的反应条件下,产物的放化产率为85%,经Sep-Pak（硅胶柱分离后,放化纯度〉95%。结论：本文结果为放化中间体fac-[188Re（CO）3（H2O）3]＋标记生物分子作为新一代治疗药物的发展提供了有力的实验基础。     

Therapeutic 188Re‐lanreotide: determination of radiopharmacokinetic parameters in rats

Objectives The radiopharmacokinetic parameters of the therapeutic radiopharmaceutical ¹⁸⁸Re‐lanreotide were compared in rats implanted with hepatocarcinoma tumours (n= 18) and healthy rats (n= 18). Methods Rats were injected with approximately 1.8 MBq ¹⁸⁸Re‐lanreotide (0.1 ml) via the tail vein and blood samples were obtained. The activity per gram of tissue (%IA/g) was calculated and the radiopharmacokinetic parameters determined. Data were fitted using a two‐compartment model. Key findings Significant differences were found between healthy and hepatoma rats for beta elimination half‐life (22.56 vs 48.14 h); transference constants K₁₀ (k_e) (6.44 vs 3.05 h^‐1) and K₁₂ (2.76 vs 7.09 h^‐1); volume of distribution (2.06 vs 5.45 ml); mean residence time (66.58 vs 95.50 h) and apparent volume of distribution at steady state (131.30 vs 810.37 ml). The tumour/organ ratios after 24 h were 11.20 for tumour/muscle, 8.00 for tumour/liver and 7.72 for tumour/bone. The scintigraphic images obtained therefore had high resolution. Conclusions ¹⁸⁸Re‐lanreotide had a prolonged beta elimination half‐life and increased volume of distribution in rats with hepatocellular carcinoma. This may be beneficial in the diagnosis and therapy of metastatic lesions in patients with cancer.