The study on changes of rectum area in proton prostate cancer therapy

The purpose of this study is to determine the changes in the rectum area during treatment and to identify the rectum area within the given field of view in order to reproduce the same pose as that presented during therapy planning to properly deliver the planned dose to the prostate. We obtained digitally reconstructed radiographs after planning treatment for 30 patients out of all patients who had been subjected to proton prostate cancer therapy from August 2012 to November 2014 at this hospital. We then obtained an image using a digital imaging positioning system (DIPS) on the first day of treatment. When planning the digitally reconstructed radiograph treatment, we determined the change in size of the rectum between the actual treatment and treatment planning by measuring the cross section of the rectum and the cross section on the image from the DIPS. The results indicated that the rectum area in the digitally reconstructed radiograph taken during treatment planning and the rectum area obtained from the DIPS image during treatment were different. As a consequence, when region targeted for proton treatment of prostate cancer does not maintain a constant volume, the position of the prostate does not receive an adequate dose due to such changes. Therefore, the results of this study will be useful to determine the corresponding volume during a prostate treatment plan.     

An amphiphilic dendrimer for effective delivery of small interfering RNA and gene silencing in vitro and in vivo

An amphiphilic dendrimer bearing a hydrophobic alkyl chain and hydrophilic poly(amidoamine) dendrons is able to combine the advantageous features of lipid and dendrimer vectors to deliver a heat shock protein?27 siRNA and produce potent gene silencing and anticancer activity in?vitro and in?vivo in a prostate cancer model. This dendrimer can be used alternatively for treating various diseases.     

Prostate‐Cancer‐Targeted N‐(2‐Hydroxypropyl)methacrylamide Copolymer/Docetaxel Conjugates

Biodistribution, pharmacokinetics, and efficacy of prostate‐cancer‐targeted HPMA copolymer/DTX conjugates are evaluated in nude mice bearing prostate cancer C4‐2 xenografts. PSMA‐specific monoclonal antibodies 3F/11 are used as the targeting moiety. Control conjugates contain either non‐specific IgG or no IgG. The ratios of tumor accumulation to total background organs (heart, lung, kidney, liver, spleen and blood) accumulation increase substantially with time for the targeted conjugate, and the ratio at 48 h is 7‐fold higher than that at 6 h. Preliminary evaluation of the efficacy of the conjugates in vivo show tumor growth inhibition for all HPMA copolymer/DTX conjugates.

     

Investigating the Role of Obesity in Prostate Cancer and Identifying Biomarkers for Drug Discovery: Systems Biology and Deep Learning Approaches

Prostate cancer (PCa) is the second most frequently diagnosed cancer for men and is viewed as the fifth leading cause of death worldwide. The body mass index (BMI) is taken as a vital criterion to elucidate the association between obesity and PCa. In this study, systematic methods are employed to investigate how obesity influences the noncutaneous malignancies of PCa. By comparing the core signaling pathways of lean and obese patients with PCa, we are able to investigate the relationships between obesity and pathogenic mechanisms and identify significant biomarkers as drug targets for drug discovery. Regarding drug design specifications, we take drug–target interaction, drug regulation ability, and drug toxicity into account. One deep neural network (DNN)-based drug–target interaction (DTI) model is trained in advance for predicting drug candidates based on the identified biomarkers. In terms of the application of the DNN-based DTI model and the consideration of drug design specifications, we suggest two potential multiple-molecule drugs to prevent PCa (covering lean and obese PCa) and obesity-specific PCa, respectively. The proposed multiple-molecule drugs (apigenin, digoxin, and orlistat) not only help to prevent PCa, suppressing malignant metastasis, but also result in lower production of fatty acids and cholesterol, especially for obesity-specific PCa.     

Insights into Aptamer–Drug Delivery Systems against Prostate Cancer

Prostate cancer is a common cancer in elderly males. Significant progress has been made in the drug therapies for prostate cancer in recent years. However, side effects are still problems that have not been overcome by the currently used anti-prostate cancer drugs. Novel technologies can be applied to reduce or even eliminate the side effects of drugs. An aptamer may be a sequence of nucleic acids or peptides that can specifically recognize proteins or cells. Taking advantage of this feature, scientists have designed aptamer–drug delivery systems for the development of anti-prostate cancer agents. Theoretically, these aptamer–drug delivery systems can specifically recognize prostate cancer cells and then induce cell death without attacking normal cells. We collected the relevant literature in this field and found that at least nine compounds have been prepared as aptamer–drug delivery systems to evaluate their precise anti-prostate cancer effects. However, the currently studied aptamer–drug delivery systems have not yet entered the market due to defects. Here, we analyze the published data, summarize the characteristics of these delivery systems, and propose ways to promote their application, thus promoting the development of the aptamer–drug delivery systems against prostate cancer.     

Effect of β Radiation on Bcl-2 and Bax Expressions in Benign Prostate Hyperplasia Tissues

The authors chose specimens from nine normal prostate tissues（NP group）, 15 benign prostate hyperplasia（BPH） prostates（BPH group）, and 35 BPH prostates that had been treated＇with ^90Sr/^90Y Prostatic Hyperplasia Applicator（exposure group）. The expressions of bcl-2 and bax in stroma and epithelia of prostate tissues were demonstrated by means of immunohistochemical staining, and the staining positive rate was semiquantatively determined, so as to observe the expression of bcl-2 and bax genes in the prostate tissues of normal individuals and BPH patients, before and after fl radiation, and to evaluate the influence of fl radiation on bcl-2 and bax expressions. The expressions of gene bcl-2 in the prostate epithelia of NP and BPH are significantly higher than those in the prostate stroma（P〈0.01）. However, the expressions of bcl-2 in the prostate epithelia and stroma of the BPH group are obviously higher than those in the NP group（P〈0.01）. The expression of gene bax in the prostate epithelia of the NP group is higher than that in the BPH group（P〈0.05）. However, bcl-2 expressions in the prostate epithelia and stroma of the BPH group are significantly higher than the bax expressions（P〈0.01）. Compared with those of the NP group, the expressions of bcl-2 in the prostate epithelia and stroma of the exposure group decrease remarkably, even as the expressions of the bax notably increase（P〈0.01）. Thus, the administration of β radiation can remarkably affect bcl-2 and bax gene expressions, to regulate cell apoptosis, in the prostate tissues of BPH.     

Production and Quality Control of [177Lu]Lu-PSMA-I&T: Development of an Investigational Medicinal Product Dossier for Clinical Trials

Since prostate cancer is the most commonly diagnosed malignancy in men, the theranostic approach has become very attractive since the discovery of urea-based PSMA inhibitors. Different molecules have been synthesized starting from the Glu-urea-Lys scaffold as the pharmacophore and then optimizing the linker and the chelate to improve functional characteristics. This article aimed to highlight the quality aspects, which could have an impact on clinical practice, describing the development of an Investigational Medicinal Product Dossier (IMPD) for clinical trials with [¹⁷⁷Lu]Lu-PSMA-I&T in prostate cancer and other solid tumors expressing PSMA. The results highlighted some important quality issues of the final preparation: radiolabeling of PSMA-I&T with lutetium-177 needs a considerably longer time compared with the radiolabeling of the well-known [¹⁷⁷Lu]Lu-PSMA-617. When the final product was formulated in saline, the stability of [¹⁷⁷Lu]Lu-PSMA-I&T was reduced by radiolysis, showing a decrease in radiochemical purity (<95% in 24 h). Different formulations of the final product with increasing concentrations of ascorbic acid have been tested to counteract radiolysis and extend stability. A solution of 20 mg/mL of ascorbic acid in saline prevents radiolysis and ensures stability over 30 h.     

Stem Extract from Momordica cochinchinensis Induces Apoptosis in Chemoresistant Human Prostate Cancer Cells (PC-3)

Natural compounds have been recognized as valuable sources for anticancer drug development. In this work, different parts from Momordica cochinchinensis Spreng were selected to perform cytotoxic screening against human prostate cancer (PC-3) cells. Chromatographic separation and purification were performed for the main constituents of the most effective extract. The content of the fatty acids was determined by Gas Chromatography-Flame Ionization Detector (GC–FID). Chemical structural elucidation was performed by spectroscopic means. For the mechanism of the apoptotic induction of the most effective extract, the characteristics were evaluated by Hoechst 33342 staining, sub-G1 peak analysis, JC-1 staining, and Western blotting. As a result, extracts from different parts of M. cochinchinensis significantly inhibited cancer cell viability. The most effective stem extract induced apoptosis in PC-3 cells by causing nuclear fragmentation, increasing the sub-G1 peak, and changing the mitochondrial membrane potential. Additionally, the stem extract increased the pro-apoptotic (caspase-3 and Noxa) mediators while decreasing the anti-apoptotic (Bcl-xL and Mcl-1) mediators. The main constituents of the stem extract are α-spinasterol and ligballinol, as well as some fatty acids. Our results demonstrated that the stem extract of M. cochinchinensis has cytotoxic and apoptotic effects in PC-3 cells. These results provide basic knowledge for developing antiproliferative agents for prostate cancer in the future.     

Pyrimidines-Based Heterocyclic Compounds: Synthesis,Cytoxicity Evaluation and Molecular Docking

A variety of structurally different pyrimidines were synthesized. Elemental analysis, FT-IR, ¹H NMR, and ¹³C NMR spectroscopy were used to confirm the chemical structures of all prepared compounds. The synthesized pyrimidines were screened against the growth of five human cancer cell lines (prostate carcinoma PC3, liver carcinoma HepG-2, human colon cancer HCT-116, human breast cancer MCF-7, human lung cancer A-549), and normal human lung fibroblasts (MRC-5) using MTT assay. Most of the screened pyrimidines have anti-proliferative activity on the growth of the PC3 cell line. Compounds 3b and 3d were more potent than the reference vinblastine sulfate (~2 to 3 × fold) and they can be considered promising leads for treating prostate cancer disease. Moreover, the screened compounds 3b, 3f, 3g, 3h, and 5 were assessed according to the values of their selectivity index (SI) and were found to be more selective and safer than vinblastine sulfate. Furthermore, using in silico computational tools, the physicochemical properties of all pyrimidine ligands were assessed, and the synthesized compounds fall within the criteria of RO5, thus having the potential to be orally bioavailable.     

细胞蛋白质组学和代谢组学整合策略表征散斑型BTB/POZ蛋白质突变调控的关键代谢通路

散斑型BTB/POZ蛋白（SPOP）是前列腺癌中突变率最高的蛋白质之一。该研究通过整合细胞蛋白质组学和代谢组学的方法，揭示SPOP突变引起的代谢紊乱及其调控的代谢通路。首先，系统地研究了LNCaP SPOP野生型及突变型高表达细胞中的代谢变化。代谢组学结果显示，SPOP野生型和突变型（SPOP_Y87N和SPOP_F133L）导入的LNCaP细胞在偏最小二乘法判别分析（PLS-DA）得分图上得到了很好的区分。进一步通过单因素方差分析发现，SPOP突变引起富马酸、苹果酸、柠檬酸、天冬氨酸和天冬酰胺等代谢物含量的增加。蛋白质组学共发现909种蛋白质在两种LNCaP SPOP突变体细胞中发生变化。分别对差异代谢物和差异蛋白质进行通路富集分析，发现三羧酸循环、氨酰基-转运核糖核酸生物合成在代谢组学和蛋白质组学分析中都发生了明显改变。最后，在SPOP敲除的Du145细胞中验证了上述研究结果。该研究证明SPOP突变可促进三羧酸循环。