11. Carboxypeptidase cathepsin X defines a multifunctional role of gamma-enolase in cancerTjaša Vižin, Anja Pišlar, Ib Jarle Christensen, Hans Jørgen Nielsen, Pika Meško-Brguljan, Janko Kos, 2022, original scientific article Abstract: Gamma-enolase enzymatic activity is involved in glycolysis, a prevalent process in cancer cell metabolism. Additionally, gamma-enolase has a pro-survival function, exhibited through the active site at the C-terminal end of the molecule. This activity is regulated by cysteine peptidase cathepsin X, which cleaves two amino acids at C-terminal end of gamma-enolase. In clinical practice, the determination of gamma-enolase as a tumour marker does not differ between total, uncleaved and C-terminally cleaved forms. However, levels of uncleaved gamma-enolase alone may provide additional clinical information. In this study we analysed cathepsin X, C- terminally uncleaved and total gamma-enolase in tumour cell lines and sera from 255 patients with colorectal cancer (CRC) by western blot, immunoprecipitation, enzymatic activity, ELISAs and ECLIA. Results show that uncleaved gamma-enolase, rather than total gamma- enolase, exhibits different levels in cells, being the highest in those, derived from metastatic sites or highly invasive tumours. Gamma-enolase is secreted into the extracellular space predominantly as an uncleaved form and levels were congruent to those within the cells. Furthermore, levels of uncleaved gamma-enolase in cells are inversely related to cathepsin X protein level and its enzymatic activity. Uncleaved gamma-enolase is also predominant form in sera of patients with CRC. Both forms exhibit similar stage dependent distribution, with slightly elevated levels in stage IV patients. Higher levels of total gamma-enolase are significantly related to shorter survival in patients with metastatic CRC. Results support evidence of additional pro-survival function of gamma-enolase in cancer. Future studies should focus on analysis of uncleaved gamma-enolase in tumour samples, which may provide additional relations to clinical indicators of disease progression.
Keywords: cancer, cathepsin X, cell survival, gamma-enolase, prognosis
Published in DiRROS: 06.04.2022; Views: 860; Downloads: 478
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12. PD-L1 expression can be regarded as prognostic factor for survival of non-small cell lung cancer patients after chemoradiotherapyMartina Vrankar, Matjaž Zwitter, Izidor Kern, Karmen Stanič, 2018, original scientific article Abstract: The standard treatment for inoperable locally advanced non-small cell lung cancer (LA NSCLC) includes concurrent or sequential chemotherapy (ChT) and radiation therapy (RT). Long term survival rates with these approaches remains only in the order of 15%, therefore new treatment strategies, including immunotherapy, are under investigation, with programmed death ligand-1 (PD-L1) as one of the major players. We evaluated the clinical significance of PD-L1 expression in tumor samples from patients with inoperable LA NSCLC who underwent concurrent chemoradiotherapy (CRT) in our institution between 2005 and 2010 and correlated their expression with clinicopathological parameters and outcome of treatment. Among 107 patients treated with concurrent CRT, a total of 43 (36 males and 7 females) had sufficient tissue for immunohistochemical (IHC) staining. The expression of PD-L1 was demonstrated in 7 tumors, in 6 males and 1 female. No statistical significant differences in patient characteristics, including age, smoking status and gender, were found according to the PD-L1 expression. After a median follow up of 103.6 months, median progression free survival (PFS) was 19.9 months in patients without and 10.1 months in patients with PD-L1 expression (p=0.008). Median overall survival (OS) was 28.4 and 12.1 months for PD-L1 negative and PD-L1 positive patients, respectively (p=0.012). In conclusions, patients with PD-L1 expression had shorter PFS and OS after concurrent CRT in LA NSCLC. Unfortunately, only small number of patients had tissue available for the IHC testing, therefore no firm conclusions could be made and further investigation is warranted.
Keywords: non-small cell lung cancer, lung cancer, chemoradiotherapy, survival
Published in DiRROS: 17.12.2020; Views: 1390; Downloads: 435
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14. Pathologic grading of malignant pleural mesothelioma : an evidence-based proposalGiuseppe Pelosi, Mauro Papotti, Luisella Righi, Giulio Rossi, Stefano Ferrero, Silvano Bosari, Izidor Kern, 2018, original scientific article Abstract: Introduction: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials. Methods: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (κ > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM. Conclusions: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm2 (cutoffs as follows: 1-2 = 0 points, 3-5 = 1 point, 6-9 = 2 points, or ≥10 = 4 points), and Ki-67 labeling index based on 2000 cells (<30% = 0 points versus ≥30 = 1 point), all of which are independent factors in both patient sets after adjustment for stage and age at diagnosis. No heterogeneity was seen across the validation centers (p = 0.19). Epithelioid/biphasic MPM patterning and biopsy versus resection did not affect survival, whereas the PGS outperformed mitotic count and Ki-67 LI in both the training (area under the curve receiver operating characteristic = 0.76) and validation sets (area under the curve receiver operating characteristic = 0.73) (p < 0.01). Patient survival progressively deteriorated from a score of 0 (median times of 26.3 and 26.9 months) to a score 1 to 3 (median times of 12.8 and 14.4 months) and a score of 4 to 8 (median times of 3.7 and 7.7 months) in both sets of patients, with the hazard ratio for a 1-point increase in score being 1.46 (95% confidence interval: 1.36-1.56) in the training set and 1.28 (95% confidence interval: 1.22-1.34) in the validation set (after adjustment for age and [when available] tumor stage). The PGS was effective even in subgroup analysis (epithelioid, biphasic, and sarcomatoid tumors). Discussion: A simple and reproducible multiparametric PGS effectively predicted survival in patients with MPM.
Keywords: carcinoma, mesothehttp://dirros.openscience.si/admin/GradivoDatoteke.php?id=12688lioma, pleura, survival, grading
Published in DiRROS: 20.11.2020; Views: 1167; Downloads: 459
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