• Asian Pacific Journal of Cancer Prevention
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• v.13 no.11
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• pp.5427-5432
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• 2012

Background and Purpose: Ovarian cancer is the leading cause of death among gynecologic cancers because of the lack of effective early detection methods. Accuracies of the human epididymis protein 4 (HE4) and mesothelin in detecting ovarian cancer have never been systematically assessed. The current systematic review aimed to tackle this issue. Methods: MEDLINE, EMBASE, and Cochrane databases were searched (September 1995-November 2011) for studies on the diagnostic performances of HE4 and mesothelin in differentiating ovarian cancer from other benign gynecologic diseases. QUADAS items were used to evaluate the qualities of the studies. Meta-DiSc software was used to handle data from the included studies and to examine heterogeneity. All included studies for diagnostic performance were combined with sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratios (DORs) with 95% confidence intervals (CIs), summary receiver operating characteristic (SROC) curves, and areas under the SROC curves (AUC). Results: A total of 18 studies and 3,865 patients were eligible for the final analysis. The pooled sensitivity estimates for HE4 (74.4%) were significantly higher than those for mesothelin (49.3%). The pooled specificity estimates for mesothelin (94.5%) were higher than those for HE4 (85.8%). The pooled DOR estimates for HE4 (26.22) were higher than those for mesothelin (24.01). The SROC curve for HE4 showed better diagnostic accuracy than that for mesothelin. The PLR and NLR of HE4 were 6.33 (95% CI: 3.58 to 11.18) and 0.27 (95% CI: 0.21 to 0.34), respectively. The PLR and NLR for mesothelin were 11.0 (95% CI: 6.21 to 19.59) and 0.51 (95% CI: 0.42 to 0.62), respectively. The combination of the two tumor markers or their combination with CA-125 increased sensitivity and specificity to different extents. Conclusion: The diagnostic accuracy of HE4 in differentiating ovarian cancer from other benign gynecologic diseases is better than that of soluble mesothelin-related protein. Combinations of two or more tumor markers show more sensitivity and specificity.

• Molecules and Cells
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• v.46 no.12
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• pp.764-777
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• 2023

Recombinant immunotoxins (RITs) are fusion proteins consisting of a targeting domain linked to a toxin, offering a highly specific therapeutic strategy for cancer treatment. In this study, we engineered and characterized RITs aimed at mesothelin, a cell surface glycoprotein overexpressed in various malignancies. Through an extensive screening of a large nanobody library, four mesothelin-specific nanobodies were selected and genetically fused to a truncated Pseudomonas exotoxin (PE24B). Various optimizations, including the incorporation of furin cleavage sites, maltose-binding protein tags, and tobacco etch virus protease cleavage sites, were implemented to improve protein expression, solubility, and purification. The RITs were successfully overexpressed in Escherichia coli, achieving high solubility and purity post-purification. In vitro cytotoxicity assays on gastric carcinoma cell lines NCI-N87 and AGS revealed that Meso(Nb2)-PE24B demonstrated the highest cytotoxic efficacy, warranting further characterization. This RIT also displayed selective binding to human and monkey mesothelins but not to mouse mesothelin. The competitive binding assays between different RIT constructs revealed significant alterations in IC₅₀ values, emphasizing the importance of nanobody specificity. Finally, a modification in the endoplasmic reticulum retention signal at the C-terminus further augmented its cytotoxic activity. Our findings offer valuable insights into the design and optimization of RITs, showcasing the potential of Meso(Nb2)-PE24B as a promising therapeutic candidate for targeted cancer treatment.

• Safety and Health at Work
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• v.11 no.4
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• pp.425-430
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• 2020

Background: Asbestos exposure is associated with the development of the cancer malignant mesothelioma (MM). Measurement of soluble mesothelin-related protein (SMRP) has been suggested as a method for detection of MM in its early stages. We prospectively examined SMRP levels in participants with asbestos exposure who are a group at a high risk of development of MM. Methods: This study was a follow-up of our cohort of 322 asbestos-exposed participants. No further participants developed MM or malignancy over the study period. Mean follow-up time was 22.9 months. Results: Mean (standard deviation) SMRP levels at baseline and follow-up were 0.94 (0.79) and 0.91 (0.86) nmol/L (p = 0.1033), respectively. Mean SMRP levels of the healthy individuals exposed to asbestos at baseline was significantly lower than those of participants with asbestosis and pleural plaques alone; similar patterns were found on follow-up measurements. There was a statistically significant effect of age on serial SMRP measurements. Our study confirms higher levels in participants with nonmalignant asbestos-related disorders. Levels decreased in asbestos-related disorders other than asbestosis, where a small increase was observed. We did not detect any further cases of malignancy. Conclusion: Monitoring programs for early detection of MM need to take into account increased SMRP levels found in benign asbestos-related diseases.

• Safety and Health at Work
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• v.3 no.1
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• pp.17-21
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• 2012

Objectives: Asbestos-related diseases (ARDs) have increased globally over the decades, causing an economic burden and increased health care costs. It is difficult to predict the risk of development of ARDs and of respiratory disability among workers with a history of asbestos exposure. Blood based biomarkers have been reported as promising tools for the early detection of malignant mesothelioma. This study investigated whether serum soluble mesothelin-related peptide (SMRP) would reflect severity of disablement in compensable ARDs. Methods: SMRP levels were measured in a cohort of 514 asbestos-exposed subjects. Severity of ARDs was assessed by a Medical Authority comprising four specially qualified respiratory physicians. Severity of ARDs and SMRP levels were compared. Results: Mean (standard deviation) serum SMRP level in the population with compensable ARDs (n = 150) was 0.95 (0.65) nmol/L, and was positively associated with disability assessment (p = 0.01). Mean SMRP level in healthy asbestos-exposed subjects was significantly lower than those with pleural plaques (p < 0.0001) and in subjects with ARDs who received compensation (p < 0.01). Conclusion: This study indicates that serum SMRP levels correlate with severity of compensable ARDs. Serum SMRP could potentially be applied to monitor progress of ARDs. Further prospective work is needed to confirm the relationship between SMRP and disability assessment in this population.