Immune Checkpoints,Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.     

Astragaloside IV improves melanocyte differentiation from mouse bone marrow mesenchymal stem cells

Vitiligo results in an autoimmune disorder destructing skin pigment cells, melanocytes (Mcs). This study aimed to investigate whether Astragaloside IV (AIV) could efficiently induce differentiation of bone marrow mesenchymal stem cells (BMMSCs) into Mcs. BMMSCs were induced and differentiated into Mcs with 0.1, 0.2, and 0.4 mg/L AIV during 150-day. Morphologic changes of differentiated cells were observed. Levels of some melanocytic specific genes (TRP-1, TRP-2, MART-1, Mitf) were measured with quantitative polymerase chain reaction (qPCR) at 90, 120, and 150 days of induction. After 90-day induction, the differentiated cells with 0.4 mg/L AIV demonstrated the typical morphology of Mcs, positive 3,4 dihydroxyphenylalanine staining, and positive staining of TRP-1, TRP-2, MART-1, and Mitf. After 90- and 120- days’ induction with 0.4 mg/L AIV, TRP-1 expression was significantly elevated (p < 0.01), and TRP-2 expression was significantly increased in 0.4 mg/L AIV-treated group compared to negative control (p < 0.01), 0.1 mg/L (p < 0.01), and 0.2 mg/L (p < 0.01) AIV-treated groups. Moreover, MART-1 expression was significantly up-regulated in 0.4 mg/L AIV-treated group compared to negative control, but without difference compared to 0.1 mg/L (p > 0.05) and 0.2 mg/L (p > 0.05) AIV-treated groups. During 90 to 150- day induction, there were no significant differences for Mitf levels between AIV-treated groups and negative control (p > 0.05). In conclusion, 90-day induction with 0.4 mg/L AIV up-regulated TRP-1, TRP-2, and MART-1 expression, indicating that AIV can efficiently induce Mcs differentiation from BMMSCs. These results provide experimental and theoretic evidence for AIV application in clinical vitiligo repigmentation treatment.     

Glycosyltransferase B4GALNT2 as a Predictor of Good Prognosis in Colon Cancer: Lessons from Databases

Background: glycosyltransferase B4GALNT2 and its cognate carbohydrate antigen Sd^a are highly expressed in normal colon but strongly downregulated in colorectal carcinoma (CRC). We previously showed that CRC patients expressing higher B4GALNT2 mRNA levels displayed longer survival. Forced B4GALNT2 expression reduced the malignancy and stemness of colon cancer cells. Methods: Kaplan–Meier survival curves were determined in “The Cancer Genome Atlas” (TCGA) COAD cohort for several glycosyltransferases, oncogenes, and tumor suppressor genes. Whole expression data of coding genes as well as miRNA and methylation data for B4GALNT2 were downloaded from TCGA. Results: the prognostic potential of B4GALNT2 was the best among the glycosyltransferases tested and better than that of many oncogenes and tumor suppressor genes; high B4GALNT2 expression was associated with a lower malignancy gene expression profile; differential methylation of an intronic B4GALNT2 gene position and miR-204-5p expression play major roles in B4GALNT2 regulation. Conclusions: high B4GALNT2 expression is a strong predictor of good prognosis in CRC as a part of a wider molecular signature that includes ZG16, ITLN1, BEST2, and GUCA2B. Differential DNA methylation and miRNA expression contribute to regulating B4GALNT2 expression during colorectal carcinogenesis.     

Biology of tegument associated IgG-Fc and C3 receptors inSchistosoma mansoni

Mechanisms by which schistosomes escape host immune responses are reviewed, with particular emphasis regarding the possible contributions of host or host-like Fc and C3 receptors on adult parasites.     

A群脑膜炎球菌多糖—精破类偶联抗原的制备及其主要特性

参照生物制品质量要求,连续制备3批脑膜炎球菌多糖-精破类偶联抗原,其多糖含量为19.8～24.4%(w/w),该种拟糖蛋白具有波长为245nm特征性的紫外光吸收谱,在Sepharose-CL 4B柱层析上Kd为0。偶联抗原中多糖的抗原性在火箭电泳上虽与单纯多糖相似,但其免疫原性则明显增强。偶联抗原在4℃存放3年或在37℃存放8周,其免疫原性无明显改变。加温处理过的偶联抗原经Sepharose-CL4B和SDSPAGE检查表明,多糖与蛋白共价结合是相当稳定的。     

人精浆前列腺特异抗原的分离纯化及鉴定

用PEG－SephadexG－150两步法，从精浆中分离纯化前列腺特异抗原（PSA）。精浆标本先经PEG粗提，约去除80％的杂蛋白，再经柱层析，进一步提纯，提纯产物经SDS－PAGE及ELISA法证实为免疫纯。     

人类白细胞抗原DRB等位基因多态性与克罗恩病遗传易感性的研究

目的　研究人类白细胞抗原 (HLA) DRB等位基因多态性与汉族人克罗恩病 (CD)的遗传易感性的关系。方法　应用基因芯片技术分析了 2 0例汉族CD患者和 2 0例健康对照者HLA DRB的基因分型 ,采用Fisher’s精确概率法比较两组各位点等位基因频率分布的差异。结果　CD患者DRB1 0 4和DRB1 0 7等位基因表达频率明显增高 ,OR分别为 12 6 6 7和 18 379,P <0 0 5 ;DRB1 12等位基因表达频率明显下降 ,OR为 0 14 4 4 ,P <0 0 5。其它等位基因在两组之间差异无显著意义。病变累及回肠者DRB1 0 7等位基因表达频率较病变累及其它部位者显著增加 (P <0 0 5 )。结论　DRB1 0 4和 或DRB1 0 7等位基因可能是我国汉族人群CD的易感基因 ,DRB1 12则为抵抗基因。HLA DR不同基因型的表达与疾病的临床特征有一定关系     

Comparative modelling of major house dust mite allergen Der p I: structure validation using an extended environmental amino acid propensity table

A model of the 3-D structure of a major house dust mite allergenDer p I associated with hypersensitivity reactions in humanswas built from its amino acid sequence and its homology to threeknown structures, papain, actinidin and papaya proteinase flof the cysteine proteinase family. Comparative modelling usingCOMPOSER was used to arrive at an initial model. This was refinedusing interactive graphics and energy minimization with theAMBER force field incorporated in SYBYL (Tripos Associates).Compatibility of the Der p I amino add sequence with the cysteineproteinase fold was checked using an environment-dependent aminoadd propensity table incorporated into a new program HARMONYwith a variable length windowing facility. A fiveresidue windowwas used to probe local conformational integrity. Propensitieswere derived from a structural alignment database of homologousproteins using a robust entropy-driven smoothing procedure.Der p I shares essential structural and mechanistic featureswith other papain-like cysteine proteinases, including cathepsinB. The active-site t iolate-imidazolium ion pair comprises theside chains of Cys34 and Hisl70. A cystine disulfide not presentin other known structures bridges residue 4 of an N-terminalextension and the core residue 117. Two conserved disulfidebridges are formed by residues 31 and 71 and residues 65 and103. Model building of peptide substrate analogue complexessuggests a preference for phenylalanyl or bask residues at theP₂ position, whilst selectivity may be of minor importance atthe S₁ subsite. The electrostatic influences on the Der p Iactive-site ion pair and extended peptide binding region aremarkedly different from those in known structures. A highlyimmunogenic surface exposed region (residues 107–131),comprising several overlapping T cell epitope sites, has noshared sequence identity with human liver cathepsin B and containsthree insertion-deletion sites. The structure provides a basisfor testing the substrate specificity of Der p I and the potentialrole of proteinase activity in hypersensitivity reactions. Thesestudies may offer a new treatment strategy by hyposensitizationwith inactive mutants or mutants with significantly alteredproteinase activity, either alone or complexed with antibody.     

高效液相色谱与质谱联用法分离鉴定己烯雌酚合成抗原

采用L ichrospher C-18柱,甲醇和水为流动相,流速0.3 mL/m in,甲醇从60%~100%(体积分数)梯度洗脱25 m in,液质联用,电喷雾(ESI),对己烯雌酚(DES)及其衍生物己烯雌酚-单(双)-丁酸乙酯基-醚进行了分离和结构鉴定。以混合酸酐法将己烯雌酚-单-羧丙基-醚与载体蛋白偶联形成完全抗原,并以紫外扫描分析了完全抗原的偶联比率。结果表明:在极性溶剂中,己烯雌酚和其衍生物存在着顺反异构转化现象,极性有机溶剂的溶剂化作用促使顺反异构体的转化。计算了DES-MCPE-BSA的偶联比率为10。