TY - JOUR AU - Kocsmár, Éva AU - Schmid, Marlene AU - Cosenza-Contreras, Miguel AU - Kocsmár, Ildikó AU - Föll, Melanie AU - Krey, Leah AU - Barta, Bálint András AU - Rácz, Gergely AU - Kiss, András AU - Werner, Martin AU - Schilling, Oliver AU - Lotz, Gábor AU - Bronsert, Peter TI - Proteome alterations in human autopsy tissues in relation to time after death JF - CELLULAR AND MOLECULAR LIFE SCIENCES J2 - CELL MOL LIFE SCI VL - 80 PY - 2023 IS - 5 PG - 15 SN - 1420-682X DO - 10.1007/s00018-023-04754-3 UR - https://m2.mtmt.hu/api/publication/33738852 ID - 33738852 AB - Protein expression is a primary area of interest for routine histological diagnostics and tissue-based research projects, but the limitations of its post-mortem applicability remain largely unclear. On the other hand, tissue specimens obtained during autopsies can provide unique insight into advanced disease states, especially in cancer research. Therefore, we aimed to identify the maximum post-mortem interval (PMI) which is still suitable for characterizing protein expression patterns, to explore organ-specific differences in protein degradation, and to investigate whether certain proteins follow specific degradation kinetics. Therefore, the proteome of human tissue samples obtained during routine autopsies of deceased patients with accurate PMI (6, 12, 18, 24, 48, 72, 96 h) and without specific diseases that significantly affect tissue preservation, from lungs, kidneys and livers, was analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). For the kidney and liver, significant protein degradation became apparent at 48 h. For the lung, the proteome composition was rather static for up to 48 h and substantial protein degradation was detected only at 72 h suggesting that degradation kinetics appear to be organ specific. More detailed analyses suggested that proteins with similar post-mortem kinetics are not primarily shared in their biological functions. The overrepresentation of protein families with analogous structural motifs in the kidney indicates that structural features may be a common factor in determining similar postmortem stability. Our study demonstrates that a longer post-mortem period may have a significant impact on proteome composition, but sampling within 24 h may be appropriate, as degradation is within acceptable limits even in organs with faster autolysis. LA - English DB - MTMT ER - TY - JOUR AU - Pesti, Adrián István AU - Danics, Krisztina AU - Glasz, Tibor AU - Várkonyi, Tibor AU - Barbai, Tamás AU - Reszegi, Andrea AU - Kovalszky, Ilona AU - Vályi-Nagy, István AU - Dobi, Deján AU - Lotz, Gábor AU - Schaff, Zsuzsa AU - Kiss, András TI - Liver alterations and detection of SARS-CoV-2 RNA and proteins in COVID-19 autopsies JF - GEROSCIENCE: OFFICIAL JOURNAL OF THE AMERICAN AGING ASSOCIATION (AGE) J2 - GEROSCIENCE VL - 45 PY - 2023 IS - 2 SP - 1015 EP - 1031 PG - 17 SN - 2509-2715 DO - 10.1007/s11357-022-00700-6 UR - https://m2.mtmt.hu/api/publication/33364402 ID - 33364402 N1 - Gábor Lotz, Zsuzsa Schaff and András Kiss contributed equally to this work AB - The most severe alterations in Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection are seen in the lung. However, other organs also are affected. Here, we report histopathologic findings in the liver and detection of viral proteins and RNA in COVID-19 autopsies performed at the Semmelweis University (Budapest, Hungary). Between March 2020 through March 2022, 150 autopsies on patients who died of COVID-19 were analyzed. Cause-of-death categories were formed based on the association with SARS-CoV-2 as strong, contributive, or weak. Samples for histopathologic study were obtained from all organs, fixed in formalin, and embedded in paraffin (FFPE). Immunohistochemical study (IHC) to detect SARS-CoV-2 spike protein and nucleocapsid protein (NP), CD31, claudin-5, factor VIII, macrosialin (CD68), and cytokeratin 7, with reverse transcriptase polymerase chain reaction (RT-PCR), and in situ hybridization (ISH, RNAscope®) for SARS-CoV-2 RNA were conducted using FFPE samples of livers taken from 20 autopsies performed ≤ 2 days postmortem. All glass slides were scanned; the digital images were evaluated by semiquantitative scoring and scores were analyzed statistically. Steatosis, single-cell and focal/zonal hepatocyte necrosis, portal fibrosis, and chronic inflammation were found in varying percentages. Sinusoidal ectasia, endothelial cell disruption, and fibrin-filled sinusoids were seen in all cases; these were assessed semiquantitatively for severity (SEF scored). SEF scores did not correlate with cause-of-death categories ( p = 0.92) or with severity of lung alterations ( p = 0.96). SARS-CoV-2 RNA was detected in 13/20 cases by PCR and in 9/20 by ISH, with IHC demonstration of spike protein in 4/20 cases and NP in 15/20. Viral RNA and proteins were located in endothelial and Kupffer cells, and in portal macrophages, but not in hepatocytes and cholangiocytes. In conclusion, endothelial damage (SEF scores) was the most common alteration in the liver and was a characteristic, but not specific alteration in COVID-19, suggesting an important role in the pathogenesis of COVID-19-associated liver disease. Detection of SARS-CoV-2 RNA and viral proteins in liver non-parenchymal cells suggests that while the most extended primary viral cytotoxic effect occurs in the lung, viral components are present in other organs too, as in the liver. The necrosis/apoptosis and endothelial damage associated with viral infection in COVID-19 suggest that those patients who survive more severe COVID-19 may face prolonged liver repair and accordingly should be followed regularly in the post-COVID period. LA - English DB - MTMT ER - TY - JOUR AU - Kocsmár, Ildikó AU - Kocsmár, Éva AU - Pajor, Gábor AU - Kulka, Janina AU - Székely, Eszter AU - Kristiansen, Glen AU - Schilling, Oliver AU - Nyirády, Péter AU - Kiss, András AU - Schaff, Zsuzsa AU - Riesz, Péter AU - Lotz, Gábor TI - Addition of Chromosome 17 Polysomy and HER2 Amplification Status Improves the Accuracy of Clinicopathological Factor-Based Progression Risk Stratification and Tumor Grading of Non-Muscle-Invasive Bladder Cancer. JF - CANCERS J2 - CANCERS VL - 14 PY - 2022 IS - 19 PG - 19 SN - 2072-6694 DO - 10.3390/cancers14194570 UR - https://m2.mtmt.hu/api/publication/33163272 ID - 33163272 N1 - * Megosztott szerzőség AB - Progression of non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive disease (MIBC) significantly worsens life expectancy. Its risk can be assessed by clinicopathological factors according to international guidelines. However, additional molecular markers are needed to refine and improve the prediction. Therefore, in the present study, we aimed to predict the progression of NMIBCs to MIBC by assessing p53 expression, polysomy of chromosome 17 (Chr17) and HER2 status in the tissue specimens of the tumors of 90 NMIBC patients. Median follow-up was 77 months (range 2-158). Patients with Chr17 polysomy or HER2 gene amplification had a higher rate of disease progression (hazard ratio: 7.44; p < 0.001 and 4.04; p = 0.033, respectively; univariate Cox regression). Multivariable Cox regression models demonstrated that the addition of either Chr17 polysomy or HER2 gene amplification status to the European Association of Urology (EAU) progression risk score increases the c-index (from 0.741/EAU/ to 0.793 and 0.755, respectively), indicating that Chr17 polysomy/HER2 amplification status information improves the accuracy of the EAU risk table in predicting disease progression. HER2/Chr17 in situ hybridization can be used to select non-progressive cases not requiring strict follow-up, by reclassifying non-HER2-amplified, non-polysomic NMIBCs from the high- and very high-risk groups of EAU to the intermediate-risk group. LA - English DB - MTMT ER - TY - JOUR AU - Szalai, Luca Karolina AU - Jakab, Ákos AU - Kocsmár, Ildikó AU - Szirtes, Ildikó AU - Kenessey, István AU - Szijártó, Attila AU - Schaff, Zsuzsa AU - Kiss, András AU - Lotz, Gábor AU - Kocsmár, Éva TI - Prognostic Ability of Tumor Budding Outperforms Poorly Differentiated Clusters in Gastric Cancer JF - CANCERS J2 - CANCERS VL - 14 PY - 2022 IS - 19 PG - 17 SN - 2072-6694 DO - 10.3390/cancers14194731 UR - https://m2.mtmt.hu/api/publication/33155952 ID - 33155952 AB - The prognostic value of histological phenomena tumor budding (TB) and poorly differentiated clusters (PDCs) have been less studied in gastric cancer (GAC) and the data provided so far are controversial. In our study, 290 surgically resected GAC cases were evaluated for TB according to the criteria of International Tumor Budding Consensus Conference (ITBCC) and PDC, and both parameters were scored on a three-grade scale as described for colorectal cancer previously (0: Grade0, 1-4: Grade1, 5-9: Grade2 and ≥10: Grade3) and classified as low (Grade0-2) and high (Grade3) TB/PDC. High TB/PDC was associated with diffuse-type morphology, higher pT status, incomplete surgical resection, poor tumor differentiation and perineural and lymphovascular invasion. Multivariable survival analyses have shown an independent prognostic role of high TB with poorer overall survival in the total cohort (p = 0.014) and in intestinal-type adenocarcinomas (p = 0.005). Multivariable model revealed high TB as an independent predictor for lymph node metastasis in both the total cohort (p = 0.019) and in the intestinal type adenocarcinomas (p = 0.038). In contrast to tumor budding, no significant association was found between PDC and the occurrence of lymph node metastasis and tumor stage and even survival. In conclusion, tumor budding is an independent prognostic factor of survival in gastric cancer, especially in intestinal-type adenocarcinomas. LA - English DB - MTMT ER - TY - JOUR AU - Tolkach, Yuri AU - Kremer, Anika AU - Lotz, Gábor AU - Schmid, Matthias AU - Mayr, Thomas AU - Foerster, Sarah AU - Garbe, Stephan AU - Hosni, Sana AU - Cronauer, Marcus V AU - Kocsmár, Ildikó AU - Kocsmár, Éva AU - Riesz, Péter AU - Alajati, Abdullah AU - Ritter, Manuel AU - Ellinger, Joerg AU - Ohlmann, Carsten-Henning AU - Kristiansen, Glen TI - Androgen Receptor Splice Variants Contribute to the Upregulation of DNA Repair in Prostate Cancer JF - CANCERS J2 - CANCERS VL - 14 PY - 2022 IS - 18 PG - 21 SN - 2072-6694 DO - 10.3390/cancers14184441 UR - https://m2.mtmt.hu/api/publication/33133656 ID - 33133656 AB - Simple Summary Ligand-independent androgen receptor splice variants emerge during androgen deprivation therapy and are suspected to render prostate carcinomas castration-resistant. In a retrospective analysis of a large cohort of primary and advanced prostate tumors, we observed increased expression of androgen receptor splice variants in therapy refractory tumors. Our hypothesis was that AR splice variants exert their tumor-promoting activity by modulating the intrinsic DNA repair machinery. In the sequence from primary over advanced tumors under androgen-deprivation therapy to castration resistance, AR splice variant expression increases and is linked to increased expression of DNA repair genes. This effect of AR splice variants appeared independent of their known impact on tumor cell proliferation. These clinical findings were validated in an androgen-sensitive prostate cancer cell line that mimics a castration-resistant phenotype by overexpression of AR-V7. Modulated DNA repair gene expression in the presence of AR splice variants is linked to increased DNA repair activity, pointing at a novel therapeutic approach for castration-resistant prostate cancer. Background: Canonical androgen receptor (AR) signaling regulates a network of DNA repair genes in prostate cancer (PCA). Experimental and clinical evidence indicates that androgen deprivation not only suppresses DNA repair activity but is often synthetically lethal in combination with PARP inhibition. The present study aimed to elucidate the impact of AR splice variants (AR-Vs), occurring in advanced or late-stage PCA, on DNA repair machinery. Methods: Two hundred and seventy-three tissue samples were analyzed, including primary hormone-naive PCA, primary metastases, hormone-sensitive PCA on androgen deprivation therapy (ADT) and castration refractory PCA (CRPC group). The transcript levels of the target genes were profiled using the nCounter platform. Experimental support for the findings was gained in AR/AR-V7-expressing LNCaP cells subjected to ionizing radiation. Results: AR-Vs were present in half of hormone-sensitive PCAs on androgen deprivation therapy (ADT) and two-thirds of CRPC samples. The presence of AR-Vs is highly correlated with increased activity in the AR pathway and DNA repair gene expression. In AR-V-expressing CRPC, the DNA repair score increased by 2.5-fold as compared to AR-V-negative samples. Enhanced DNA repair and the deregulation of DNA repair genes by AR-V7 supported the clinical data in a cell line model. Conclusions: The expression of AR splice variants such as AR-V7 in PCA patients following ADT might be a reason for reduced or absent therapy effects in patients on additional PARP inhibition due to the modulation of DNA repair gene expression. Consequently, AR-Vs should be further studied as predictive biomarkers for therapy response in this setting. LA - English DB - MTMT ER - TY - JOUR AU - Pesti, Adrián István AU - Gyömörei, Csaba AU - Juhász, Péter AU - Kálmán, Endre AU - Kiss, András AU - Kuthi, Levente AU - Lotz, Gábor AU - Méhes, Gábor AU - Schaff, Zsuzsa AU - Tiszlavicz, László TI - SARS-CoV-2-fehérjék kimutatása immunhisztokémiai módszerrel emberi szövetekben.. Patológiai körvizsgálat TS - Patológiai körvizsgálat JF - ORVOSI HETILAP J2 - ORV HETIL VL - 163 PY - 2022 IS - 25 SP - 975 EP - 983 PG - 9 SN - 0030-6002 DO - 10.1556/650.2022.32536 UR - https://m2.mtmt.hu/api/publication/33029409 ID - 33029409 N1 - Semmelweis Egyetem, Általános Orvostudományi Kar, Patológiai, Igazságügyi és Biztosítási Orvostani Intézet, Budapest, Hungary Klinikai Központ, Pécsi Tudományegyetem, Általános Orvostudományi Kar, Patológiai Intézet, Pécs, Hungary Debreceni Egyetem, Általános Orvostudományi Kar, Patológiai Intézet, Debrecen, Hungary Szegedi Tudományegyetem, Szent-Györgyi Albert Orvostudományi Kar, Patológiai Intézet, Szeged, Hungary Ülli út 93., Budapest, 1091, Hungary Cited By :1 Export Date: 29 February 2024 CODEN: ORHEA LA - Hungarian DB - MTMT ER - TY - JOUR AU - Kocsmár, Éva AU - Lotz, Gábor TI - Comment on Skrebinska et al. Who Could Be Blamed in the Case of Discrepant Histology and Serology Results for Helicobacter pylori Detection? Diagnostics 2022, 12, 133 JF - DIAGNOSTICS J2 - DIAGNOSTICS VL - 12 PY - 2022 IS - 6 PG - 2 SN - 2075-4418 DO - 10.3390/diagnostics12061424 UR - https://m2.mtmt.hu/api/publication/32950117 ID - 32950117 N1 - Cited By :2 Export Date: 15 December 2023 Correspondence Address: Lotz, G.; Department of Pathology, Üllői Street 93, Hungary; email: lotz.gabor@med.semmelweis-univ.hu AB - In their article, Skebrinska and colleagues analysed the potential pitfalls of detecting Helicobacter pylori (H. pylori) by serology, histological (Giemsa) and immunohistochemical (IHC) staining. However, in the Introduction, the authors state: " horizontal ellipsis IHC is recommended only in individuals with active gastritis without H. pylori identification by histochemistry". Although this is a widely-held view, it does not seem to hold up in view of the results of the study by Kocsmar et al., which showed that the diagnostic sensitivity of Giemsa in the absence of activity is only 33.6%, but it is 92.6% in the presence of active gastritis, which is close to the 99.4% sensitivity of IHC. Considering that chronic active gastritis with the features of H. pylori gastritis is also common in other entities, if active inflammation is present in the sample, there is a very small chance that a Giemsa-negative case will be confirmed as H. pylori-positive by IHC. Based on this, the use of IHC is more reasonable in Giemsa-negative cases with no activity in which the etiological role of H. pylori is suggested by clinical, anamnestic or other data. However, it may also be reasonable to routinely use IHC as the primary staining method instead of Giemsa. LA - English DB - MTMT ER - TY - JOUR AU - Regős, Eszter AU - Lotz, Gábor TI - Az immuncheckpoint-gátlók biomarkereinek molekuláris disgnosztikai vizsgálata JF - ORVOSKÉPZÉS J2 - ORVOSKÉPZÉS VL - 96 PY - 2021 IS - 3 SP - 469 EP - 477 PG - 9 SN - 0030-6037 UR - https://m2.mtmt.hu/api/publication/32695435 ID - 32695435 LA - Hungarian DB - MTMT ER - TY - JOUR AU - Lotz, Gábor AU - Kocsmár, Ildikó AU - Tímár, József TI - A húgyhólyagrák molekuláris klasszifikációja, 2021 JF - MAGYAR ONKOLÓGIA J2 - MAGYAR ONKOLÓGIA VL - 65 PY - 2021 IS - 4 SP - 301 EP - 306 PG - 6 SN - 0025-0244 UR - https://m2.mtmt.hu/api/publication/32603738 ID - 32603738 N1 - Semmelweis Egyetem, Klinikai Központ, II. Sz. Patológiai Intézet, Üllői út 93, Budapest, 1091, Hungary Urológiai Klinika, Budapest, Hungary Export Date: 17 January 2024 CODEN: MGONA Correspondence Address: József, T.; Semmelweis Egyetem, Üllői út 93, Hungary; email: jtimar@gmail.com Chemicals/CAS: epidermal growth factor receptor 2, 137632-09-8; fibroblast growth factor receptor 3, 306781-00-0; ERCC2 protein, human; Xeroderma Pigmentosum Group D Protein LA - Hungarian DB - MTMT ER - TY - JOUR AU - Lotz, Gábor AU - Danics, Krisztina AU - Pesti, Adrián István AU - Várkonyi, Tibor AU - Dobi, Deján AU - Vályi-Nagy, István AU - Törő, Klára Andrea AU - Glasz, Tibor AU - Kiss, András AU - Schaff, Zsuzsa TI - A COVID-19-betegség okozta szervi károsodások patológiája JF - KLINIKAI ONKOLÓGIA J2 - KLINIKAI ONKOLÓGIA VL - 8 PY - 2021 IS - 3 SP - 211 EP - 218 PG - 8 SN - 2064-5058 UR - https://m2.mtmt.hu/api/publication/32306889 ID - 32306889 LA - Hungarian DB - MTMT ER -