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  • 1
    In: Pathology and Oncology Research, Frontiers Media SA, Vol. 28 ( 2022-8-1)
    Abstract: Anastomosing haemangioma (AH) is a newly described distinct vascular neoplasm that histologically may confuse with well-differentiated angiosarcoma (AS) for those who are unfamiliar with this rare entity. We aimed to identify molecular genetic differences between AHs and ASs by carrying out immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS). Immunohistochemically, all six cases showed positivity for cyclinD1 and pERK. All cases of AH showed focal weak positive reaction for p53 and MIB-1, and the IHCs for HIF-1α were all negative for all three cases. Those three cases of angiosarcoma revealed strong, diffuse positivity for p53, 50%–70% MIB-1 labelling, and multifocal, moderate to strong HIF-1α expression. To further clarify the difference in p53 expression, we carried out a FISH which revealed 17p polysomy in all three ASs whereas copy number aberration was absent in the AH group. In one AH case, the GNA11 c.627G & gt; T nucleotide variant was detected. Due to the rarity and overlapping morphological features, AH might be difficult to separate from other vascular tumours, in particular from well-differentiated AS also featured by mild hyperchromatic, hobnail-like endothelial cells. The potential molecular differences between these two entities presented here may be used in support of the correct diagnosis.
    Type of Medium: Online Resource
    ISSN: 1532-2807
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2002501-4
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  • 2
    In: BioMed Research International, Hindawi Limited, Vol. 2021 ( 2021-3-10), p. 1-11
    Abstract: Introduction. The aminopeptidase N (APN/CD13) receptor plays an important role in the neoangiogenic process and metastatic tumor cell invasion. Clinical and preclinical studies reported that bestatin and actinonin are cytotoxic to APN/CD13-positive tumors and metastases due to their APN/CD13-specific inhibitor properties. Our previous studies have already shown that 68Ga-labeled NGR peptides bind specifically to APN/CD13 expressing tumor cells. The APN/CD13 specificity of 68Ga-NGR radiopharmaceuticals enables the following of the efficacy of antiangiogenic therapy with APN/CD13-specific inhibitors using positron emission tomography (PET). The aim of this in vivo study was to assess the antitumor effect of bestatin and actinonin treatment in subcutaneous transplanted HT1080 and B16-F10 tumor-bearing animal models using 68Ga-NODAGA-c(NGR). Materials and Methods. Three days after the inoculation of HT1080 and B16-F10 cells, mice were treated with intraperitoneal injection of bestatin (15 mg/kg) or actinonin (5 mg/kg) for 7 days. On the 5th and 10th day, in vivo PET scans and ex vivo biodistribution studies were performed 90 min after intravenous injection of 5.5 ± 0.2   MBq 68Ga-NODAGA-c(NGR). Results. Control-untreated HT1080 and B16-F10 tumors were clearly visualized by the APN/CD13-specific 68Ga-NODAGA-c(NGR) radiopharmaceutical. The western blot analysis also confirmed the strong APN/CD13 positivity in the investigated tumors. We found significantly ( p ≤ 0.05 ) lower radiopharmaceutical uptake after bestatin treatment and higher radiotracer accumulation in the actinonin-treated HT1080 tumors. In contrast, significantly lower ( p ≤ 0.01 ) 68Ga-NODAGA-c(NGR) accumulation was observed in both bestatin- and actinonin-treated B16-F10 melanoma tumors compared to the untreated-control tumors. Bestatin inhibited tumor growth and 68Ga-NODAGA-c(NGR) uptake in both tumor models. Conclusion. The bestatin treatment is suitable for suppressing the neoangiogenic process and APN/CD13 expression of experimental HT1080 and B16-F10 tumors; furthermore, 68Ga-NODAGA-c(NGR) is an applicable radiotracer for the in vivo monitoring of the efficacy of the APN/CD13 inhibition-based anticancer therapies.
    Type of Medium: Online Resource
    ISSN: 2314-6141 , 2314-6133
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2021
    detail.hit.zdb_id: 2698540-8
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  • 3
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Applied Immunohistochemistry & Molecular Morphology Vol. 28, No. 1 ( 2020-01), p. 1-9
    In: Applied Immunohistochemistry & Molecular Morphology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 1 ( 2020-01), p. 1-9
    Abstract: Thymic epithelial tumors (TETs) are uncommon neoplasms of the mediastinum. The gold standard treatment is complete surgical resection which can be followed by radio/chemotherapy in selected cases. Targeted tyrosine kinase inhibition can be considered in only a limited number of aggressive or metastatic tumors as EGFR , BRAF , or c-kit mutations are rare. However, previous studies have demonstrated the efficacy of immune checkpoint inhibitors in epithelial neoplasias, such as in programmed cell death ligand 1 (PD-L1) expressing nonsmall cell lung carcinoma. Because of their rare occurrence the data on PD-L1 distribution in thymic neoplasias are limited. PD-L1 and PD-1 expression in tumor cells and tumor infiltrating immune cells was determined in TETs according to criteria published for lung carcinomas. Comparison with major clinical, pathologic, and biological features was also done. In total, 36 TETs (29 thymomas and 7 thymic carcinomas) were analyzed. PD-L1 immunohistochemical staining (Ventana PD-L1 clone SP142) was performed in all cases. The percentage of the positive tumor cells (TC value), the percentage of tumor area occupied by positive immune cells (IC value) was evaluated. Evaluation of PD-L1 expression in tumor cells showed a good reproducibility (κ-value: 0.840; Spearman r =0.966; P 〈 0.0001). About 69% of thymomas (20/29) and 43% of thymic carcinomas (3/7) showed high positivity rate (TC≥50% or IC ≥10%), which may indicate therapeutic advantage similar to nonsmall cell lung cancers defined by the same conditions. PD-L1 expression is common in different epithelial tumors of the thymus, which suggests the potential effectiveness of drugs targeting the PD-1/PD-L1 interactions in these neoplasms.
    Type of Medium: Online Resource
    ISSN: 1541-2016
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2052398-1
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  • 4
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Applied Immunohistochemistry & Molecular Morphology Vol. 31, No. 1 ( 2023-01), p. 26-32
    In: Applied Immunohistochemistry & Molecular Morphology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 1 ( 2023-01), p. 26-32
    Abstract: Hypoxia and necrosis are common features of invasive cancer. The dynamic upregulation of carbonic anhydrase IX (CAIX), triggered by hypoxia-inducible factor 1 (HIF-1) is 1 of the mechanisms supporting cellular adaptation to hypoxia in solid tumors, including breast carcinoma. CAIX activity results in extracellular acidosis and in a profound reorganization of the tumor micro-environment, influencing biological behavior and prognosis. The main focus of our study was to evaluate the mass and distribution of the immune infiltrate, more specifically of CD8+ effector T-cells, in relation with tumoral CAIX expression. Materials and Methods: Formalin-fixed and paraffin-embedded breast carcinoma sections were analyzed following double immunohistochemical staining for CAIX and CD8. Scanned digital slides were evaluated for both labelings, and CD8-related signal was determined within and outside CAIX-positive tumor areas using the HistoQuant (3DHistech) image analysis software. Statistical analysis was performed using GraphPad Prism software. Results: Of the 34 breast carcinomas, 18 tested partially positive for CAIX. The remaining 16 cases were used as the CAIX-negative control group. Necrotic foci were generally associated with CAIX overexpression, and tumors exhibiting signs of necrosis had a significantly higher rate of relative CAIX expression compared with samples without necrosis (11.47±5.505 vs. without necrosis 3.765±3.5 P -value=0.0216). On the other hand, no statistically significant difference was found when comparing relative CD8+ lymphocyte counts in cases with necrosis as opposed to those where necrosis was absent (134.7±55.7 vs. 97.70±57.25; P value=0.1579). No difference in gross CD8+ T-lymphocyte infiltrate could be measured between CAIX positive and negative samples (98.48±37.32 vs. 95.99±50 P value=0.5928). However, in CAIX-expressing tumors a statistical correlation between the CD8+ T-lymphocyte infiltrate and the extent of CAIX-positive areas was observed. Within the same tumor, CD8+ T-lymphocyte counts showed a significant difference betweeen CAIX+ and CAIX- areas (13.06±9.4 vs. 135.6±62.2 P value 〈 0.0001). Conclusion: Our measurements demonstrate for the first time that tumor areas with CAIX expression potentially hamper CD8+ T-lymphocyte infiltration in breast carcinoma. The hypoxia-driven adaptive micro-environment likely interferes with the specific response to biological and immune therapies requiring intact effector T-cell response.
    Type of Medium: Online Resource
    ISSN: 1541-2016
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2052398-1
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  • 5
    In: BMC Medical Genetics, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2020-12)
    Abstract: Wolcott-Rallison Syndrome (WRS) is a rare autosomal recessive disease that is the most common cause of neonatal diabetes in consanguineous families. WRS is caused by various genetic alterations of the Eukaryotic Translation Initiation Factor 2-Alpha Kinase 3 ( EIF2AK3 ) gene. Methods Genetic analysis of a consanguineous family where two children were diagnosed with WRS was performed by Sanger sequencing. The altered protein was investigated by in vitro cloning, expression and immunohistochemistry. Results The first cases in Hungary, − two patients in one family, where the parents were fourth-degree cousins - showed the typical clinical features of WRS: early onset diabetes mellitus with hyperglycemia, growth retardation, infection-induced multiple organ failure. The genetic background of the disease was a novel alteration in the EIF2AK3 gene involving the splice site of exon 11– intron 11–12 boundary: g.53051_53062delinsTG. According to cDNA sequencing this created a new splice site and resulted in a frameshift and the development of an early termination codon at amino acid position 633 (p.Pro627AspfsTer7). Based on in vitro cloning and expression studies, the truncated protein was functionally inactive. Immunohistochemistry revealed that the intact protein was absent in the islets of pancreas, furthermore insulin expressing cells were also dramatically diminished. Elevated GRP78 and reduced CHOP protein expression were observed in the liver. Conclusions The novel genetic alteration causing the absence of the EIF2AK3 protein resulted in insufficient handling of severe endoplasmic reticulum stress, leading to liver failure and demise of the patients.
    Type of Medium: Online Resource
    ISSN: 1471-2350
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2041359-2
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  • 6
    In: Histopathology, Wiley, Vol. 74, No. 5 ( 2019-04), p. 699-708
    Abstract: The present study evaluates the impact of hypoxia‐related carbonic anhydrase IX and XII isoenzyme expression as a basic adaptive mechanism to neutralise intracellular acidosis in classical Hodgkin's lymphoma ( cHL ). Methods and results Eighty‐one primary biopsies and 15 relapsed tissue samples diagnosed with cHL were analysed for necrosis, CAIX and CAXII expression and cell proliferation to compare hypoxia‐related histological and functional data with survival characteristics. Variable, but highly selective cell membrane CAIX expression could be demonstrated in Hodgkin–Reed–Sternberg ( HRS ) cells in 39 of 81 samples (48.1%), while virtually no staining presented in their microenvironment. In contrast, CAXII expression in HRS cells could be demonstrated in only 18 of 77 samples (23.4%), with significant stromal positivity (50 of 77, 64.9%). The CAIX + positive phenotype was strongly associated with lymphocyte depletion (four of four, 100%) and nodular sclerosis (29 of 51, 56.9%) subtypes. CAIX /Ki‐67 dual immunohistochemistry demonstrated suppressed cell proliferation in CAIX + positive compared to CAIX − negative HRS cells ( P   〈  0.001). Seventy‐two months’ progression‐free survival ( PFS ) was significantly lower for the CAIX positive group (0.192) compared with the CAIX negative group (0.771) ( P   〈  0.001), while the overall survival ( OS ) did not differ ( P  = 0.097). Conclusion Hypoxic stress‐related adaptation – highlighted by CAIX expression – results in cellular quiescence in HRS cells, potentially contributing to the short‐term failure of the standard chemotherapy in cHL .
    Type of Medium: Online Resource
    ISSN: 0309-0167 , 1365-2559
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2006447-0
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  • 7
    Online Resource
    Online Resource
    Frontiers Media SA ; 2023
    In:  Pathology and Oncology Research Vol. 29 ( 2023-6-21)
    In: Pathology and Oncology Research, Frontiers Media SA, Vol. 29 ( 2023-6-21)
    Abstract: Assessing the accurate Grade Group of a prostate needle biopsy specimen is essential for choosing the adequate therapeutic modality for prostate cancer patients. However, it is well-known that biopsy Grade Group tends to up- or downgrade significantly at radical prostatectomy. We aimed to investigate the correlation between accuracy and biopsy core number, performed immunohistochemical staining (IHC) or prostatectomy specimen sampling, with the latest also being correlated with higher detection rates of adverse pathological features, e.g., positive surgical margins, higher pathological stage or presence of perineural invasion (PnI status). The study cohort consisted of 315 consecutive patients diagnosed with prostate adenocarcinoma via transrectal ultrasound-guided needle biopsy who later underwent radical prostatectomy. We grouped and compared patients based on Grade Group accuracy, presence of IHC on biopsy, margin status, pathological stage, and PnI status. Inter-observer reproducibility was also calculated. Statistical analyzes included ANOVA, Tukey’s multiple comparisons post hoc test, Chi-squared test, and Fleiss kappa statistics. Undergraded cases harboured a significantly lower number of biopsy cores ( p & lt; 0.05), than accurately graded cases. Using IHC did not affect grading accuracy significantly, nor did the number of slides from prostatectomy specimens. The mean number of slides was virtually identical when margin status, pathological stage and PnI status of prostatectomy specimens were compared. Inter-observer reproducibility at our institute was calculated as fair (overall kappa = 0.29). Grade Group accuracy is significantly improved by obtaining more cores at biopsy but is unrelated to performed IHC. The extent of sampling prostatectomy specimens, however, did not affect accuracy and failed to significantly improve detection of adverse pathological features.
    Type of Medium: Online Resource
    ISSN: 1532-2807
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2023
    detail.hit.zdb_id: 2002501-4
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  • 8
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 310, No. 11 ( 2016-06-01), p. H1671-H1682
    Abstract: Hypertension (HTN) is a major risk factor for heart failure. We investigated the influence of HTN on cardiac contraction and relaxation in transgenic renin overexpressing rats (carrying mouse Ren-2 renin gene, mRen2, n = 6). Blood pressure (BP) was measured. Cardiac contractility was characterized by echocardiography, cellular force measurements, and biochemical assays were applied to reveal molecular mechanisms. Sprague-Dawley (SD) rats ( n = 6) were used as controls. Transgenic rats had higher circulating renin activity and lower cardiac angiotensin-converting enzyme two levels. Systolic BP was elevated in mRen2 rats (235.11 ± 5.32 vs. 127.03 ± 7.56 mmHg in SD, P 〈 0.05), resulting in increased left ventricular (LV) weight/body weight ratio (4.05 ± 0.09 vs. 2.77 ± 0.08 mg/g in SD, P 〈 0.05). Transgenic renin expression had no effect on the systolic parameters, such as LV ejection fraction, cardiomyocyte Ca 2+ -activated force, and Ca 2+ sensitivity of force production. In contrast, diastolic dysfunction was observed in mRen2 compared with SD rats: early and late LV diastolic filling ratio (E/A) was lower (1.14 ± 0.04 vs. 1.87 ± 0.08, P 〈 0.05), LV isovolumetric relaxation time was longer (43.85 ± 0.89 vs. 28.55 ± 1.33 ms, P 〈 0.05), cardiomyocyte passive tension was higher (1.74 ± 0.06 vs. 1.28 ± 0.18 kN/m 2 , P 〈 0.05), and lung weight/body weight ratio was increased (6.47 ± 0.24 vs. 5.78 ± 0.19 mg/g, P 〈 0.05), as was left atrial weight/body weight ratio (0.21 ± 0.03 vs. 0.14 ± 0.03 mg/g, P 〈 0.05). Hyperphosphorylation of titin at Ser-12742 within the PEVK domain and a twofold overexpression of protein kinase C-α in mRen2 rats were detected. Our data suggest a link between the activation of renin-angiotensin-aldosterone system and increased titin-based stiffness through phosphorylation of titin's PEVK element, contributing to diastolic dysfunction. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/diastolic-dysfunction-in-the-hypertensive-mren2-rat/ .
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2016
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 9
    In: Biochimica et Biophysica Acta (BBA) - Biomembranes, Elsevier BV, Vol. 1863, No. 10 ( 2021-10), p. 183665-
    Type of Medium: Online Resource
    ISSN: 0005-2736
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2209384-9
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2020
    In:  Pathology & Oncology Research Vol. 26, No. 4 ( 2020-10), p. 2549-2555
    In: Pathology & Oncology Research, Springer Science and Business Media LLC, Vol. 26, No. 4 ( 2020-10), p. 2549-2555
    Type of Medium: Online Resource
    ISSN: 1219-4956 , 1532-2807
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2002501-4
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