ABSTRACT
Claudin18.2(CLDN18.2)is a tight junction protein that is overexpressed in a variety of solid tumors such as gastrointestinal cancer and oesophageal cancer.It has been identified as a promising target and a potential biomarker to diagnose tumor,evaluate efficacy,and determine patient prognosis.TST001 is a recombinant humanized CLDN18.2 antibody that selectively binds to the extracellular loop of human Claudin18.2.In this study,we constructed a solid target radionuclide zirconium-89(89Zr)labled-TST001 to detect the expression of in the human stomach cancer BGC823CLDN18.2 cell lines.The[89Zr]Zr-des-ferrioxamine(DFO)-TST001 showed high radiochemical purity(RCP,＞99％)and specific activity(24.15±1.34 GBq/μmol),and was stable in 5％human serum albumin,and phosphate buffer saline(＞85％RCP at 96 h).The EC50 values of TST001 and DFO-TST001 were as high as 0.413±0.055 and 0.361±0.058 nM(P＞0.05),respectively.The radiotracer had a significantly higher average standard uptake values in CLDN18.2-positive tumors than in CLDN18.2-negative tumors(1.11±0.02 vs.0.49±0.03,P=0.0016)2 days post injection(p.i.).BGC823CLDN18.2 mice models showed high tumor/muscle ratios 96 h p.i.with[89Zr]Zr-DFO-TST001 was much higher than those of the other imaging groups.Immunohistochemistry results showed that BGC823CLDN18.2 tumors were highly positive(+++)for CLDN18.2,while those in the BGC823 group did not express CLDN18.2(-).The results of ex vivo biodistribution studies showed that there was a higher distribution in the BGC823CLDN18.2 tumor bearing mice(2.05±0.16％ID/g)than BGC823 mice(0.69±0.02％ID/g)and blocking group(0.72±0.02％ID/g).A dosimetry estimation study showed that the effective dose of[89Zr]Zr-DFO-TST001 was 0.0705 mSv/MBq,which is within the range of acceptable doses for nuclear medicine research.Taken together,these re-sults suggest that Good Manufacturing Practices produced by this immuno-positron emission tomog-raphy probe can detect CLDN18.2-overexpressing tumors.
ABSTRACT
@#[摘 要] 近年来，化疗基础上加用抗表皮生长因子受体2药物、抗血管生成药物及免疫检查点抑制剂，不仅可提高晚期胃癌（GC）患者治疗的有效率，而且可明显改善患者预后。然而，目前晚期GC患者治疗后的生存获益远落后于肺癌、结直肠癌及乳腺癌等实体肿瘤，靶向治疗仍需进一步探索。随着分子生物学技术的发展，新的治疗靶点如Claudin 18.2、基质金属蛋白酶（MMP）、Dickkopf相关蛋白1（DKK-1）、RAD3相关蛋白激酶（ATR）被发现在GC细胞中表达，针对这些靶点的药物逐渐在临床治疗中崭露头角，并显示出较好的临床应用前景。阐述晚期GC治疗中靶点的作用机制及靶向药物的研究进展，对提高GC的临床治疗疗效具有重要意义。
ABSTRACT
Disruption of pulmonary endothelial permeability and associated barrier integrity increase the severity of acute respiratory distress syndrome (ARDS). This study investigated the potential ability of the human immunodeficiency virus-1 (HIV-1) integrase inhibitor raltegravir to protect against acute lung injury (ALI) and the underlying mechanisms. Accordingly, the impact of raltegravir treatment on an in vitro lipopolysaccharide (LPS)-stimulated human pulmonary microvascular endothelial cell (HPMEC) model of ALI and an in vivo LPS-induced two-hit ALI rat model was examined. In the rat model system, raltegravir treatment alleviated ALI-associated histopathological changes, reduced microvascular permeability, decreased Evans blue dye extravasation, suppressed the expression of inflammatory proteins including HMGB1, TLR4, p-NF-κB, NLRP3, and MPO, and promoted the upregulation of protective proteins including claudin 18.1, VE-cadherin, and aquaporin 5 as measured via western blotting. Immunohistochemical staining further confirmed the ability of raltegravir treatment to reverse LPS-induced pulmonary changes in NLRP3, claudin 18.1, and aquaporin 5 expression. Furthermore, in vitro analyses of HPMECs reaffirmed the ability of raltegravir to attenuate LPS-induced declines in VE-cadherin and claudin 18.1 expression while simultaneously inhibiting NLRP3 activation and reducing the expression of HMGB1, TLR4, and NF-kB, thus decreasing overall vascular permeability. Overall, our findings suggested that raltegravir may represent a viable approach to treating experimental ALI that functions by maintaining pulmonary microvascular integrity.
ABSTRACT
Background:Gastric cancer is one of the malignant tumors with highest morbidity and mortality,and the early change of molecular marker in gastric mucosal lesion is the hot spot of gastric cancer study. Aims:To investigate the expressions and clinical significance of trefoil factor 2(TFF2),claudin 18(CLDN18),mucin 5AC(MUC5AC)in gastric mucosal lesions. Methods:Gastroscopy biopsies and surgery specimens from Dec. 2008 to May 2009 at Inner Mongolia People’s Hospital were collected,including 20 normal gastric mucosal tissues,20 intestinal metaplasia tissues,11 dysplasia tissues and 20 gastric cancer tissues. The protein expressions of TFF2, CLDN18, MUC5AC were determined by immunohistochemical SP method. Results:The positive expression rates of TFF2,CLDN18 and MUC5AC in normal gastric mucosal tissues were all 100% ,and were gradually decreased in the order of intestinal metaplasia,dysplasia and gastric cancer tissue,the differences were statistically significant(P < 0. 01). Conclusions:Expressions of TFF2,CLDN18 and MUC5AC protein are closely related to the degree of malignancy of gastric mucosal lesions,and can be considered as a potential biological marker for predicting the development and prognosis of gastric cancer.