Glycosylation in Indolent,Significant and Aggressive Prostate Cancer by Automated High-Throughput N-Glycan Profiling

The diagnosis and treatment of prostate cancer (PCa) is a major health-care concern worldwide. This cancer can manifest itself in many distinct forms and the transition from clinically indolent PCa to the more invasive aggressive form remains poorly understood. It is now universally accepted that glycan expression patterns change with the cellular modifications that accompany the onset of tumorigenesis. The aim of this study was to investigate if differential glycosylation patterns could distinguish between indolent, significant, and aggressive PCa. Whole serum N-glycan profiling was carried out on 117 prostate cancer patients’ serum using our automated, high-throughput analysis platform for glycan-profiling which utilizes ultra-performance liquid chromatography (UPLC) to obtain high resolution separation of N-linked glycans released from the serum glycoproteins. We observed increases in hybrid, oligomannose, and biantennary digalactosylated monosialylated glycans (M5A1G1S1, M8, and A2G2S1), bisecting glycans (A2B, A2(6)BG1) and monoantennary glycans (A1), and decreases in triantennary trigalactosylated trisialylated glycans with and without core fucose (A3G3S3 and FA3G3S3) with PCa progression from indolent through significant and aggressive disease. These changes give us an insight into the disease pathogenesis and identify potential biomarkers for monitoring the PCa progression, however these need further confirmation studies.     

PROfound研究——前列腺癌精准治疗新希望

转移性去势抵抗性前列腺癌（metastatic castrate-resistant prostate cancer,mCRPC）是前列腺癌发展的终末阶段。患者生存预后很差。尽管不断地有新的治疗手段出现，比如新型内分泌治疗以及紫杉醇类化疗，mCRPC患者的生存期依然很有限。奥拉帕利是一款聚腺苷酸二磷酸核糖基聚合酶（poly ADP-ribose polymerase,PARP）抑制剂，PARP酶在DNA修复中扮演着重要的角色。奥拉帕利已经获批用于卵巢癌和乳腺癌的治疗。目前，奥拉帕利用于mCRPC治疗的III期临床研究PROfound的结果在2019年的欧洲肿瘤内科学会（ESMO）年会与2020年的美国临床肿瘤学会-泌尿生殖系统肿瘤研讨会（ASCO-GU）已经发布。本文将带来PROfound研究的结果以及最新的结果更新。     

Perceived stress management skill mediates the relationship between optimism and positive mood following radical prostatectomy.

This study evaluated relations among optimism, perceived stress management skills (PSMS), and positive mood in 46 men who had surgical treatment for localized prostate cancer. The authors found that optimism, PSMS, and positive mood scores were positively correlated. Positive mood was unrelated to demographic and disease-related control variables. In a hierarchical regression model controlling for PSMS, the relationship between optimism and positive mood became nonsignificant, whereas PSMS remained a correlate of positive mood. Results suggest that the relationship between optimism and positive mood may be mediated by belief in being able to use stress management techniques effectively. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC.     

Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.     

基于改进3D UNet的前列腺MR图像分割

针对前列腺磁共振 (magnetic resonance, MR)图像边缘模糊、对比度较低,灰度值分布不均衡而导致分割精度较差的问题,提出了一种结合双路径注意力(dual path attention,DPA) 和多尺度特征聚合(multi-scale feature aggregation,MFA) 模块的改进3D UNet网络模型。首先,对数据集进行重采样和裁剪处理以适应模型输入。然后,在3D UNet网络的编码器各层引入DPA 并添加残差连接,加强特征的 编码能力。同时,在网络解码器中加入MFA模块,以充分利用空间上下文信息,增强语义信息。最后,在公开数据集PROMISE12上进行验证,所提出的模型的Dice系数为89.90%,Hausdorff 距离为9.37 mm。相比较于其他模型,所提出模型的分割结果更优,且参数量和运算量更少。     

Anti prostate cancer using PEGylated bombesin containing,cabazitaxel loading nano-sized drug delivery system

Context: Prostate cancer (PCa) is the second most-frequently diagnosed cancer in men. Cabazitaxel was approved for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.

Objective: In this study, bombesin (BN), a ligand reported to specifically target GRP overexpressing prostate tumor, was applied for the construction of lipid-polymer hybrid nanoparticles (LPNs), and used for the targeted delivery of cabazitaxel (CAB) to prostate cancer.

Methods: BN-polyethylene glycol-1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (BN-PEG-DSPE) was synthesized. CAB loaded, BN-PEG-DSPE contained LPNs (BN-CAB-LPNs) were prepared. Their particle size, zeta potential and drug encapsulation efficiency (EE) were evaluated. In vitro cytotoxicity study of BN-CAB-LPNs was tested in LNCaP human prostatic cancer cell line (LNCaP cells). In vivo anti-tumor efficacy of the carriers was evaluated on mice bearing prostate cancer model.

Results: The optimum BN-CAB-LPNs formulations had a particle size of 184.9?nm and a 26.5?mV positive surface charge. The growth of LNCaP cells in vitro was obviously inhibited. BN-CAB-LPNs also displayed better anti-tumor activity than the other formulations in vivo.

Conclusion: The results demonstrated that BN-CAB-LPNs can sufficiently deliver CAB to the cancer cells and enhance the anti-tumor capacity. Thus, BN-CAB-LPNs can be proved to be a superior nanomedicine which can achieve better therapeutic efficacy of prostate tumor.     

Amplification‐Free Multi‐RNA‐Type Profiling for Cancer Risk Stratification via Alternating Current Electrohydrodynamic Nanomixing

Simultaneous analysis of messenger RNA (mRNA), microRNA (miRNA), and long noncoding RNA (lncRNA)—multi‐RNA‐type profiling—is increasingly crucial in cancer diagnostics. Yet, rapid multi‐RNA‐type profiling is challenging due to enzymatic amplification reliance and RNA‐type‐dependent characteristics. Here, a nanodevice is reported to uniquely use alterable alternating current electrohydrodynamic (ac‐EHD) forces to enhance probe–target hybridization prior to direct native RNA target detection, without target amplification or surface functionalization. To exemplify clinical applicability, noninvasive screening of next‐generation prostate cancer (PCa) RNA biomarkers (of different types) in patient urine samples is performed. A strong correlation between multi‐RNA‐type expression and aggressive PCa is found, and the nanodevice performance is statistically evaluated. It is believed that this miniaturized system exhibits great potential for cancer risk stratification via multi‐RNA‐type profiling.