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  • 1
    In: Medicine, Ovid Technologies (Wolters Kluwer Health), Vol. 100, No. 36 ( 2021-09-10), p. e27094-
    Abstract: Epigenetic changes are implicated in prostate cancer (PCa) progression and resistance to therapy. Arginine residue methylation is an understudied histone post-translational modification that is increasingly associated with cancer progression and is catalyzed by enzymes called protein arginine methyltransferases (PRMTs). The molecular consequences of aberrant expression of PRMTs in PCa and the relationship between PRMTs and PCa progression are largely unknown. Using immunohistochemistry, we examined the expression of PRMT1 and CARM1, two of the best-studied PRMTs, in 288 patients across the spectrum of PCa and correlated them with markers of androgen receptor (AR) signaling, and milestones of carcinogenesis. Our findings indicate that PRMT1 and CARM1 are upregulated early in PCa progression, and that CARM1 is further upregulated after therapy. In addition, a correlation of CARM1 with AR post-translational modifications was noted in the setting of therapy resistance, highlighting CARM1 as one of the adaptation mechanisms of PCa cells in an androgen-depleted environment. Finally, CARM1 correlated with markers of cell cycle regulation, and both CARM1 and PRMT1 correlated with markers of epithelial-to-mesenchymal transition signaling. Taken together these findings indicate that an epigenetic network drives PCa progression through enhancement of milestone pathways including AR signaling, the cell cycle, and epithelial-to-mesenchymal transition.
    Type of Medium: Online Resource
    ISSN: 0025-7974 , 1536-5964
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2049818-4
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  • 2
    In: Cancers, MDPI AG, Vol. 15, No. 17 ( 2023-09-01), p. 4357-
    Abstract: Prostate cancer (PCa), the most frequent and second most lethal cancer type in men in developed countries, is a highly heterogeneous disease. PCa heterogeneity, therapy resistance, stemness, and lethal progression have been attributed to lineage plasticity, which refers to the ability of neoplastic cells to undergo phenotypic changes under microenvironmental pressures by switching between developmental cell states. What remains to be elucidated is how to identify measurements of lineage plasticity, how to implement them to inform preclinical and clinical research, and, further, how to classify patients and inform therapeutic strategies in the clinic. Recent research has highlighted the crucial role of next-generation sequencing technologies in identifying potential biomarkers associated with lineage plasticity. Here, we review the genomic, transcriptomic, and epigenetic events that have been described in PCa and highlight those with significance for lineage plasticity. We further focus on their relevance in PCa research and their benefits in PCa patient classification. Finally, we explore ways in which bioinformatic analyses can be used to determine lineage plasticity based on large omics analyses and algorithms that can shed light on upstream and downstream events. Most importantly, an integrated multiomics approach may soon allow for the identification of a lineage plasticity signature, which would revolutionize the molecular classification of PCa patients.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2527080-1
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  • 3
    In: Current Molecular Pharmacology, Bentham Science Publishers Ltd., Vol. 14, No. 6 ( 2021-12), p. 1028-1036
    Abstract: Genetic events cannot account for the complexity of human carcinogenesis alone. Mutations of epigenetic regulators and aberrations of their expression patterns have been detected in various human malignancies. Methylation of histone H3 at lysine 4 (H3K4me), is an evolutionarily conserved histone modification that marks regions of active transcription and regulates cell growth, migration, and invasion. The MLL/KMT2 family of histone methyltransferases specifically methylate histone H3 at lysine 4. Objective: The aim of this study was to explore the role of KMT2C/MLL3 as well as key histone modification activating markers, such as H3K4me2 and H3K4me3 in a cohort of surgically resected human lung adenocarcinomas in an effort to reveal possible biomarkers for lung adenocarcinoma diagnosis and prognosis and potential therapeutic targets. Method: The immunohistochemical expression of KMT2C/MLL3, H3K4me2 and H3K4me3 was analyzed in formalin fixed paraffin embedded tissue from 96 patients with lung adenocarcinoma. Results were associated with clinicopathologic parameters and patient’s prognosis. Results: Nuclear expression of KMT2C/MLL3 in epithelial cells was independently associated with shorter overall survival. Cytoplasmic H3K4me2 expression was associated withT stage and nuclear H3K4me2 expression was associated with female gender and patients’ prognosis. The latter association persisted after multivariate analysis. No association was found between H3K4me3 expression and clinicopathological data or disease outcome in our cohort of patients. Conclusion: These results suggest that the pattern of histone modifications and KMT2C/MLL3 expression can be used as an independent prognostic factor in lung adenocarcinoma, revealing that chromatin remodeling is criticallyinvolved in cancer progression.
    Type of Medium: Online Resource
    ISSN: 1874-4672
    Language: English
    Publisher: Bentham Science Publishers Ltd.
    Publication Date: 2021
    SSG: 15,3
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  • 4
    In: Cancers, MDPI AG, Vol. 13, No. 4 ( 2021-02-09), p. 713-
    Abstract: Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancer characterized by genomic complexity and therapeutic options limited to only standard chemotherapy. Although it has been suggested that stratifying TNBC patients by pathway-specific molecular alterations may predict benefit from specific therapeutic agents, application in routine clinical practice has not yet been established. There is a growing body of the literature supporting that epigenetic modifications comprised by DNA methylation, chromatin remodeling and non-coding RNAs play a fundamental role in TNBC pathogenesis. Extracellular matrix (ECM) is a highly dynamic 3D network of macromolecules with structural and cellular regulatory roles. Alterations in the expression of ECM components result in uncontrolled matrix remodeling, thus affecting its ability to regulate vital functions of cancer cells, including proliferation, migration, adhesion, invasion and epithelial-to-mesenchymal transition (EMT). Recent molecular data highlight the major role of tumor microenvironment and ECM alterations in TNBC and approaches for targeting tumor microenvironment have recently been recognized as potential therapeutic strategies. Notably, many of the ECM/EMT modifications in cancer are largely driven by epigenetic events, highlighting the pleiotropic effects of the epigenetic network in TNBC. This article presents and critically discusses the current knowledge on the epigenetic alterations correlated with TNBC pathogenesis, with emphasis on those associated with ECM/EMT modifications, their prognostic and predictive value and their use as therapeutic targets.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 5
    In: Cancers, MDPI AG, Vol. 13, No. 21 ( 2021-10-29), p. 5454-
    Abstract: (1) Background: Prognostic grade group (PGG) is an important prognostic parameter in prostate cancer that guides therapeutic decisions. The cribriform pattern and intraductal carcinoma (IDC) are two histological patterns, that have additional prognostic significance. However, discrepancies exist regarding the handling of IDC according to the guidelines published by two international genitourinary pathology societies. Furthermore, whether, in addition to its presence, the amount of IDC is also of importance has not been studied before. Lastly, the handling of tertiary patterns has also been a matter of debate in the literature. (2) Methods: A total of 129 prostatectomy cases were retrieved and a detailed histopathologic analysis was performed. (3) Results: Two cases (1.6%) upgraded their PGG, when IDC was incorporated in the grading system. The presence and the amount of IDC, as well as the presence of cribriform carcinoma were associated with adverse pathologic characteristics. Interestingly, in six cases (4.7%) there was a difference in PGG when using the different guidelines regarding the handling of tertiary patterns. In total, 6.2% of the cases would be assigned a different grade depending on the guidelines followed. (4) Conclusions: These findings highlight a potential area of confusion among pathologists and clinicians and underscore the need for a consensus grading system.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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  • 6
    In: Monaldi Archives for Chest Disease, PAGEPress Publications, ( 2023-08-29)
    Abstract: GATA3 is a transcription factor involved in embryogenesis of multiple human tissues and in maintaining cell differentiation and tissue homeostasis in the adult organism. GATA3 is also involved in carcinogenesis and regarded as a sensitive marker for urothelial and breast carcinomas, albeit expression in carcinomas of non-breast/urothelial origin has been frequently reported. We sought to examine the extent and intensity of GATA3 expression in various carcinomas, mainly lung, urothelial, and breast and various other primary sites. Patients with breast carcinoma (N=40), carcinoma of the urinary bladder/renal pelvis (N=40), lung carcinoma (N=110) and various other origins (N=45) were included in the study. One hundred and sixty-five patients had a primary tumor diagnosis, and 70 cases had a metastatic tumor diagnosis. Our results showed that GATA3 expression was significantly more common in carcinomas of the breast, urinary bladder and renal pelvis compared to all other origins. All primary and 93% of metastatic urinary bladder carcinomas and 94% of the primary and 80% of metastatic breast carcinomas expressed GATA3. Expression was lower in non-urothelial histology of urinary primaries and in triple negative breast carcinomas. Focal staining, mostly faint, was seen in 5.6% of the primary lung adenocarcinomas and 35% of the primary lung squamous cell carcinomas. More extensive and intense staining was seen in 3.7% of the primary lung adenocarcinomas and 12% of the primary lung squamous cell carcinomas. Expression, mostly focal was also seen in 30% of the metastatic lung carcinomas. Finally, high expression was seen in 12.5% of the other tumors (one metastatic pancreatic carcinoma, one metastatic salivary gland adenocarcinoma NOS, one metastatic squamous cell carcinoma of the skin, one primary uterine cervix serous carcinoma, and one squamous cell carcinoma of the head and neck) and focal expression was present in another 22% of them. No ideal cut-off for positivity for GATA3 staining could be identified. In conclusion our study shows that GATA3 staining has two caveats in its use: the first is that non classical histologies of urothelial carcinomas and TNBC may be negative for the marker and secondly carcinomas of various origins may show (although rarely) intense positivity
    Type of Medium: Online Resource
    ISSN: 2532-5264 , 1122-0643
    Language: Unknown
    Publisher: PAGEPress Publications
    Publication Date: 2023
    detail.hit.zdb_id: 2375904-5
    detail.hit.zdb_id: 2375907-0
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  • 7
    In: Pathology - Research and Practice, Elsevier BV, Vol. 235 ( 2022-07), p. 153950-
    Type of Medium: Online Resource
    ISSN: 0344-0338
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2039756-2
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  • 8
    In: Pathology, Elsevier BV, Vol. 52, No. 2 ( 2020-02), p. 218-227
    Type of Medium: Online Resource
    ISSN: 0031-3025
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1479244-8
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  • 9
    In: International Journal of Surgical Pathology, SAGE Publications, Vol. 28, No. 8 ( 2020-12), p. 918-924
    Abstract: Intraductal carcinoma of the prostate (IDCp) is a distinct neoplastic entity, and although recognized for some time, it was included for the first time in the histologic classification of prostate cancer in the 2016 publication of World Health Organization. IDCp represents an intraductal or intra-acinar proliferation of malignant cells, with preservation of the basal cell layer. Even though IDCp is usually accompanied by a high-grade invasive component, low-grade invasive carcinoma can rarely be seen adjacent to the lesion. Even rarer is the incidence of isolated IDCp in needle biopsies, while a few such cases have been reported in prostatectomy specimens. We report 2 cases with isolated IDCp without any invasive component. A review of the literature is performed including the diagnostic challenges of IDCp and its morphologic mimics, immunohistochemical markers, molecular aspects, and prognostic implications. Even though it is not yet clear whether IDCp represents an intraductal spread of invasive cancer or a precursor of invasive carcinoma, the existence of isolated IDCp reinforces the idea that, at least in some of the cases, IDCp is a precancerous lesion. Further molecular studies need to be performed in order to clarify its pathogenesis.
    Type of Medium: Online Resource
    ISSN: 1066-8969 , 1940-2465
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2020
    detail.hit.zdb_id: 2070102-0
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  • 10
    Online Resource
    Online Resource
    MDPI AG ; 2021
    In:  Cancers Vol. 14, No. 1 ( 2021-12-21), p. 13-
    In: Cancers, MDPI AG, Vol. 14, No. 1 ( 2021-12-21), p. 13-
    Abstract: Prostate cancer is the second most common malignancy in men, and prostatectomy is the treatment of choice for most patients with at least low risk of progression. The presence of positive margins in the radical prostatectomy specimen is considered an adverse pathologic feature, and may prompt additional therapeutic intervention in the patients. The absence of a distinct capsule around the prostate and intraoperative manipulations that aim to minimize postoperative adverse effects, complicate its wide removal. Proper handling of the specimen during the gross processing is essential for accurate determination of the status of margins or resection. Positive margins, defined as the presence of neoplastic glands in the highlighted-with-ink margin of resection, range from 6–38%. The surgical technique, surgeon’s expertise and tumor (i.e., grade and stage) and patients’ (i.e., BMI) characteristics affect the rate of margin positivity. Extensive or multifocal and nonanterior/nonapical positive margins are linked with higher recurrence rates, especially in organ-confined disease, underscoring the need for treating these patients more aggressively. In summary, detailed description of the status of the margins should be performed in every pathology report to determine patients’ prognosis and the most appropriate therapeutic plan.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2527080-1
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