Browsing by Subject "NECROSIS"

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  • Passador-Santos, F.; Gronroos, M.; Irish, J.; Gilbert, R.; Gullane, P.; Perez-Ordonez, B.; Makitie, A.; Leivo, I. (2016)
    Myoepithelial carcinoma (MCA) is a rare malignancy of salivary glands that was included in the WHO Classification of Head and Neck Tumors in 1991. MCA has shown a broad spectrum of clinical outcomes, but attempts to identify prognostic markers for this malignancy have not resulted in significant progress. Conventional histopathological characteristics such as tumour grade, nuclear atypia, mitotic index and cell proliferation have failed to predict the outcome of MCA. In this study, we reviewed the histopathology of 19 cases of MCA focusing on nuclear atypia, mitotic count, tumour necrosis, nerve and vascular invasion and occurrence of a pre-existing pleomorphic adenoma in connection to the MCA. Histopathological characteristics and clinical information were correlated with the immunohistochemical expression of cell cycle proteins including c-Myc, p21, Cdk4 and Cyclin D3. The proportion of tumour cells immunoreactive for these markers and their intensity of staining were correlated with clinical information using logistic regression, Kaplan-Meier and Cox regression. Using logistic regression analysis, cytoplasmic c-Myc expression was associated with the occurrence of metastases (P = 0.019), but limitations of semi-quantitation of immunostaining and the limited number of cases preclude definitive conclusions. Our data show that the occurrence of tumour necrosis predicts poor disease-free survival in MCA (P = 0.035).
  • Mantula, Paula; Tietavainen, Johanna; Clement, Jan; Niemelä, Onni; Pörsti, Ilkka; Vaheri, Antti; Mustonen, Jukka; Mäkelä, Satu; Outinen, Tuula (2020)
    Transient proteinuria and acute kidney injury (AKI) are characteristics of Puumala virus (PUUV) infection. Albuminuria peaks around the fifth day and associates with AKI severity. To evaluate albuminuria disappearance rate, we quantified albumin excretion at different time points after the fever onset. The study included 141 consecutive patients hospitalized due to acute PUUV infection in Tampere University Hospital, Finland. Timed overnight albumin excretion (cU-Alb) was measured during the acute phase in 133 patients, once or twice during the convalescent phase within three months in 94 patients, and at six months in 36 patients. During hospitalization, 30% of the patients had moderately increased albuminuria (cU-Alb 20-200 mu g/min), while 57% presented with severely increased albuminuria (cU-Alb >200 mu g/min). Median cU-Alb was 311 mu g/min (range 2.2-6460)
  • Paajanen, Juuso; Laaksonen, Sanna; Kettunen, Eeva; Ilonen, Ilkka; Vehmas, Tapio; Salo, Jarmo; Räsänen, Jari; Sutinen, Eva; Ollila, Hely; Mäyränpää, Mikko I.; Myllärniemi, Marjukka; Wolff, Henrik (2020)
    Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, where the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. In order to study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival over five years (long-term survivals [LTS]) and compared the findings with 84 tumors from a reference group with average survival (RG). We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n = 34,90%) and a tubulopapillary growth pattern (n = 30,70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n = 49,61%) and solid growth pattern (n = 59,70%) were more frequent in RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (p <0.001) and the presence of necrosis (p = 0.021). In univariate survival analysis, we identified the following three novel morphological features associated with survival: exophytic polypoid growth pattern, tumor density, and single mesothelium layered tubular structures. After adjustments, low nuclear grade (p <0.001) and presence of exophytic polypoid growth (p = 0.024) were associated with prolonged survival. These results may aid in estimating DMM prognosis.
  • Sternby, Hanna; Mahle, Mariella; Linder, Nicolas; Erichson-Kirst, Laureen; Verdonk, Robert C.; Dimova, Alexandra; Ignatavicius, Povilas; Ilzarbe, Lucas; Koiva, Peeter; Penttilä, Anne; Regner, Sara; Bollen, Thomas L.; Brill, Richard; Stangl, Franz; Wohlgemuth, Walter A.; Singh, Vijay; Busse, Harald; Michl, Patrick; Beer, Sebastian; Rosendahl, Jonas (2019)
    Background: Acute pancreatitis (AP) is a frequent disorder with considerable morbidity and mortality. Obesity has previously been reported to influence disease severity. Objective The aim of this study was to investigate the association of adipose and muscle parameters with the severity grade of AP. Methods: In total 454 patients were recruited. The first contrast-enhanced computed tomography of each patient was reviewed for adipose and muscle tissue parameters at L3 level. Associations with disease severity were analysed through logistic regression analysis. The predictive capacity of the parameters was investigated using receiver operating characteristic (ROC) curves. Results: No distinct variation was found between the AP severity groups in either adipose tissue parameters (visceral adipose tissue and subcutaneous adipose tissue) or visceral muscle ratio. However, muscle mass and mean muscle attenuation differed significantly with p-values of 0.037 and 0.003 respectively. In multivariate analysis, low muscle attenuation was associated with severe AP with an odds ratio of 4.09 (95% confidence intervals: 1.61-10.36, p-value 0.003). No body parameter presented sufficient predictive capability in ROC-curve analysis. Conclusions: Our results demonstrate that a low muscle attenuation level is associated with an increased risk of severe AP. Future prospective studies will help identify the underlying mechanisms and characterise the influence of body composition parameters on AP.
  • Elmadani, Manar; Khan, Suleiman; Tenhunen, Olli; Magga, Johanna; Aittokallio, Tero; Wennerberg, Krister; Kerkelä, Risto (2019)
    Background-Small molecule kinase inhibitors (KIs) are a class of agents currently used for treatment of various cancers. Unfortunately, treatment of cancer patients with some of the KIs is associated with cardiotoxicity, and there is an unmet need for methods to predict their cardiotoxicity. Here, we utilized a novel computational method to identify protein kinases crucial for cardiomyocyte viability. Methods and Results-One hundred forty KIs were screened for their toxicity in cultured neonatal cardiomyocytes. The kinase targets of KIs were determined based on integrated data from binding assays. The key kinases mediating the toxicity of KIs to cardiomyocytes were identified by using a novel machine learning method for target deconvolution that combines the information from the toxicity screen and from the kinase profiling assays. The top kinases identified by the model were phosphoinositide 3-kinase catalytic subunit alpha, mammalian target of rapamycin, and insulin-like growth factor 1 receptor. Knockdown of the individual kinases in cardiomyocytes confirmed their role in regulating cardiomyocyte viability. Conclusions-Combining the data from analysis of KI toxicity on cardiomyocytes and KI target profiling provides a novel method to predict cardiomyocyte toxicity of KIs.
  • Turku, Ainoleena; Rinne, Maiju K.; af Gennas, Gustav Boije; Xhaard, Henri; Lindholm, Dan; Kukkonen, Jyrki P. (2017)
    Two promising lead structures of small molecular orexin receptor agonist have been reported, but without detailed analyses of the pharmacological properties. One of them, 1(3,4-dichloropheny1)-242-imino-3-(4-methylbenzy1)-2,3-dihydro-1H-benzo[climidazol-1-yl] ethan-1-ol (Yan 7874), is commercially available, and we set out to analyze its properties. As test system we utilized human OX1 and OX2 orexin receptor -expressing Chinese hamster ovary (CHO) K1 cells as well as control CHO-K1 and neuro-2a neuroblastoma cells. Gq-coupling was assessed by measurement of intracellular Ca2+ and phospholipase C activity, and the coupling to G(i) and G(s) by adenylyl cyclase inhibition and stimulation, respectively. At concentrations above 1 pM, strong Ca' and low phospholipase C responses to Yan 7874 were observed in both OX1- and OX2-expressing cells. However, a major fraction of the response was not mediated by orexin receptors, as determined utilizing the nonselective orexin receptor antagonist N-biphenyl-2-y1-1-{[(1-methyl-1H-benzimidazol-2-y1) sulfanyl]acetyl}-L-prolinamide (TCS 1102) as well as control CHO-K1 cells. Yan 7874 did not produce any specific adenylyl cyclase response. Some experiments suggested an effect on cell viability by Yan 7874, and we thus analyzed this. Within a few hours of exposure, Yan 7874 markedly changed cell morphology (shrunken, rich in vacuoles), reduced growth, promoted cell detachment, and induced necrotic cell death. The effect was equal in cells expressing orexin receptors or not. Thus, Yan 7874 is a weak partial agonist of orexin receptors. It also displays strong off -target effects in the same concentration range, culminating in necrotic cell demise. This makes Yan 7874 unsuitable as orexin receptor agonist.
  • Swanljung, Outi; Vehkalahti, Miira M. (2018)
    Introduction: The aim of this study was to assess the role of root canal irrigants and medicaments in endodontic injuries verified in Finland and to estimate the rate of such events over time. Methods: The study material comprised all endodontic injuries verified by the Patient Insurance Centre in 2002 to 2006 (n = 521) and 2011 to 2013 (n = 449). The data, based on patient documents scrutinized by 2 specialists in endodontics, included patients' and dentists' sex and age and the service sector. We recorded the use of root canal irrigants and medicaments, each as a dichotomy. Furthermore, we dichotomized the injuries as those related to root canal irrigants/medicaments and any other injuries. The injuries were also dichotomized as avoidable (could have been avoided by following good clinical practice) or unavoidable (normal treatment-related risks). Statistical evaluation used chi-square tests and t tests; logistic regression produced odds ratios (ORs). Results: The verified injuries (N = 970) comprised 635 (65%) avoidable and 335 (35%) unavoidable injuries. The number of irrigant-/medicament-related injuries was 69, accounting for 7.1% of all verified injuries; all resulted from sodium hypochlorite and calcium hydroxide, and 87% were avoidable. The overall rate of sodium hypochlorite/calcium hydroxide injuries was 4.3 cases per 100,000 endodontic patients per year. Compared with other injuries, sodium hypochlorite/calcium hydroxide injuries were more likely avoidable (OR = 3.8) and more than 5-fold likely in 2011 to 2013 than in 2002 to 2006 (OR = 5.6). Conclusions: Extreme care is needed when applying sodium hypochlorite and calcium hydroxide into root canals to avoid increasing harmful consequences.
  • Tuuminen, Raimo; Holmstrom, Emil; Raissadati, Alireza; Saharinen, Pipsa; Rouvinen, Eeva; Krebs, Rainer; Lemstrom, Karl B. (2016)
    Background: In transplantation-associated ischemia/reperfusion injury (Tx-IRI), tumor necrosis factor alpha and damage-associated molecular patterns promote caspase-8 and -9 apoptotic and receptor-interacting protein kinase-1 and-3 (RIPK1/3) necroptotic pathway activation. The extent of cell death and the counterbalance between apoptosis and regulated necrosis eventually determine the immune response of the allograft. Although simvastatin prevents Tx-IRI, its role in apoptotic and necroptotic activity remains unsolved. Methods: Rat allograft donors and recipients were treated with a single-dose of simvastatin 2 h prior to allograft procurement and reperfusion, respectively. Intragraft caspase-3, -8, and -9 and RIPK1 and-3 mRNA expression was analysed by quantitative RT-PCR and protein activity measured by immunohistochemistry and luminescent assays 6 h after reperfusion. Lactate and lactate dehydrogenase (LDH) levels were analysed from allograft recipient and from hypoxic endothelial cell cultures having treated with activated simvastatin. Results: When compared to without cold ischemia, prolonged 4-hour cold ischemia significantly enhanced intragraft mRNA expression of caspase-3 and-9, and RIPK1 and -3, and elevated protein activity of caspase-9 and RIPK1 in the allografts. Simvastatin pretreatment decreased mRNA expression of caspase-3 and -9, and RIPK1 and-3 and protein activity of caspase-9 and RIPK1 in the allografts. Intragraft caspase-8 mRNA expression remained constant regardless of cold ischemia or simvastatin pretreatment. Simvastatin pretreatment attenuated lactate and LDH levels, both in the allograft recipients and in hypoxic endothelial cell cultures. Conclusions: The beneficial effects of simvastatin pretreatment in cardiac allograft IRI may involve prevention of apoptosis and necroptosis. (C) 2016 Elsevier B.V. All rights reserved.
  • Polini, Beatrice; Carpi, Sara; Doccini, Stefano; Citi, Valentina; Martelli, Alma; Feola, Sara; Santorelli, Filippo Maria; Cerullo, Vincenzo; Romanini, Antonella; Nieri, Paola (2020)
    Background: Remarkable deregulation of several microRNAs (miRNAs) is demonstrated in cutaneous melanoma. hsa-miR-193a-3p is reported to be under-expressed in tissues and in plasma of melanoma patients, but the role of both miR-193a arms in melanoma is not known yet. Methods: After observing the reduced levels of miR-193a arms in plasma exosomes of melanoma patients, the effects of hsa-miR-193a-3p and -5p transfection in cutaneous melanoma cell lines are investigated. Results: In melanoma cell lines A375, 501Mel, and MeWo, the ectopic over-expression of miR-193a arms significantly reduced cell viability as well as the expression of genes involved in proliferation (ERBB2, KRAS, PIK3R3, and MTOR) and apoptosis (MCL1 and NUSAP1). These functional features were accompanied by a significant downregulation of Akt and Erk pathways and a strong increase in the apoptotic process. Since in silico databases revealed TROY, an orphan member of the tumor necrosis receptor family, as a potential direct target of miR-193a-5p, this possibility was investigated using the luciferase assay and excluded by our results. Conclusions: Our results underline a relevant role of miR-193a, both -3p and -5p, as tumor suppressors clarifying the intracellular mechanisms involved and suggesting that their ectopic over-expression could represent a novel treatment for cutaneous melanoma patients.