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One of the prevailing perceptions regarding the ageing of cells and organisms is the intracellular gradual accumulation of oxidatively damaged macromolecules, leading to the decline of cell and organ function (free radical theory of ageing). This chemically undefined material known as “lipofuscin,” “ceroid,” or “age pigment” is mainly formed through unregulated and nonspecific oxidative modifications of cellular macromolecules that are induced by highly reactive free radicals. A necessary precondition for reactive free radical generation and lipofuscin formation is the intracellular availability of ferrous iron (Fe2+) (“labile iron”), catalyzing the conversion of weak oxidants such as peroxides, to extremely reactive ones like hydroxyl (HO• ) or alcoxyl (RO• ) radicals. If the oxidized materials remain unrepaired for extended periods of time, they can be further oxidized to generate ultimate over-oxidized products that are unable to be repaired, degraded, or exocytosed by the relevant cellular systems. Additionally, over-oxidized materials might inactivate cellular protection and repair mechanisms, thus allowing for futile cycles of increasingly rapid lipofuscin accumulation. In this review paper, we present evidence that the modulation of the labile iron pool distribution by nutritional or pharmacological means represents a hitherto unappreciated target for hampering lipofuscin accumulation and cellular ageing. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Osteochondroma, the most common benign bone tumor, is a projection on the external surface of the bone, which can be sessile or pedunculated. 85% of osteochondromas present as solitary lesions, while 15% occur in the context of hereditary multiple exostoses (HME), a genetic disorder that is inherited in an autosomal dominant manner. Although often asymptomatic, symptoms may eventuate from compression of adjacent vessels or nerves, fractures, osseous deformities, bursa formation, or malignant transformation. Cartilage cap thickness >2 cm in adults or >3 cm in children as well as new onset of pain or growth, or rapid growth of the lesion, especially after the closure of the growth plate, might reflect cancerous transformation. Surgical resection is indicated for symptomatic lesions, complications, cosmetic reasons or malignant transformation. Excision of the tumor with free margin is the treatment of choice. Local recurrence is less than 2% if complete resection is achieved. © 2021 International Institute of Anticancer Research. All rights reserved.

Background/Aim: The mechanisms underlying the contribution of the heparan sulfate proteoglycan syndecan-1 to liver tissue injury and to crucial biological processes, such as fibrogenesis, remain to be elucidated. Therefore, we investigated the immunohistochemical expression of syndecan-1 in chronic liver diseases (CLDs) and its probable role in hepatic fibrosis. Materials and Methods: Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections of biopsy material obtained from 128 patients diagnosed with CLDs. The correlation between syndecan-1 expression and the stage of fibrosis was investigated. Results: According to the severity of fibrosis, cases were categorized into three groups: early fibrosis; intermediate fibrosis; advanced fibrosis. Syndecan-1 expression was significantly enhanced in advanced fibrosis compared to early (p

Purpose: To review the role of antigen-presenting cells (APC) in the pathogenesis of ocular surface diseases (OSD). Methods: A thorough literature search was performed in PubMed database. An additional search was made in Google Scholar to complete the collected items. Results: APCs have the ability to initiate and direct immune responses and are found in most lymphoid and non-lymphoid tissues. APCs continuously sample their environment, present antigens to T cells and co-ordinate immune tolerance and responses. Many different types of APCs have been described and there is growing evidence that these cells are involved in the pathogenesis of OSD. OSD is a complex term for a myriad of disorders that are often characterized by ocular surface inflammation, tear film instability and impairment of vision. Conclusions: This review summarizes the current knowledge concerning the immunotopographical distribution of APCs in the normal ocular surface. APCs appear to play a critical role in the pathology of a number of conditions associated with OSD including infectious keratitis, ocular allergy, dry eye disease and pterygium. © 2020, Springer Nature B.V.

The human thymus is a primary lymphoepithelial organ which supports the production of self-tolerant T cells with competent and regulatory functions. Paradoxically, despite the crucial role that it exerts in T cell-mediated immunity and prevention of systemic autoimmunity, the thymus is the first organ of the body that exhibits age-associated degeneration/regression, termed "thymic involution." A hallmark of this early phenomenon is a progressive decline of thymic mass as well as a decreased output of naïve T cells, thus resulting in impaired immune response. Importantly, thymic involution has been recently linked with cellular senescence which is a stress response induced by various stimuli. Accumulation of senescent cells in tissues has been implicated in aging and a plethora of age-related diseases. In addition, several lines of evidence indicate that oxidative stress, a well-established trigger of senescence, is also involved in thymic involution, thus highlighting a possible interplay between oxidative stress, senescence, and thymic involution. © 2020 Alexandra Barbouti et al.

Cellular senescence, an age-related process in response to damage and stress, also occurs during normal development and adult life. The thymus is a central lymphoepithelial organ of the immune system that exhibits age-related changes termed thymic involution. Since the mechanisms regulating thymic involution are still not well elucidated, we questioned whether cellular senescence is implicated in this process. We demonstrate, for the first time in situ, that cellular senescence occurs during human thymic involution using SenTraGor™ a novel chemical compound that is applicable in archival tissue material, providing thus further insights in thymus histophysiology. © 2018 Elsevier B.V.

Primary vitreoretinal lymphoma (PVRL) is a rare ocular lymphoid malignancy, which consists a subset of primary central system lymphoma (PCNSL) and the most common type of intraocular lymphoma. The involvement of eyes is estimated to be approximately 20% of PCNSL, but the brain involvement may be up to 80% of PVRL. Typically, PVRL is a high grade B-cell malignancy of the retina and needs to be assorted from choroidal low-grade B-cell lymphomas. Very often PVRL masquerades and can be erroneously diagnosed as chronic uveitis, white dot syndromes or other neoplasms. Establishing an accurate diagnosis may involve cytology/pathology, immunohistochemistry, flow cytometry, molecular pathology and cytokine profile analysis. There is inadequate information about PVRL's true incidence, ethnic/geographical variation and pathogenetic mechanisms. The therapeutic approach of PVRL involves aggressive chemotherapy and radiation therapy. Although PVRL tends to have a good response to the initial treatment, the prognosis is poor and the survival restricted due to the high relapse rates and CNS involvement. © 2019 The Authors

Senescence and apoptosis constitute types of cellular responses that normally ensure homeostasis, when endogenous or exogenous signals occur. Their deregulation is often observed in various pathologies, such as age and non-age related diseases including cancer. Although epithelial cells and fibroblasts are capable to exert both functions, under a plethora of insults, the fact that they exhibit notable intrinsic differences in cell/tissue homeostasis properties, might be a crucial determinant of the mode of response to a certain stress signal. Sparse evidence in the literature reveals that in the same tissue/organ context and under the same conditions, the cell type seems to drive the differential counteraction between epithelia and fibroblasts. Based on the above notion we propose that, upon stress insults, human fibroblasts seem to predominantly respond via senescence, while epithelial cells prefer to exert apoptosis. We suggest that considering the tissue as a whole (epithelium and stroma) would benefit research into new therapeutic strategies for chronic diseases and cancer. © 2016 Elsevier Ireland Ltd.

DNA damage responses (DDR) invoke senescence or apoptosis depending on stimulus intensity and the degree of activation of the p53-p21Cip1/Waf1 axis; but the functional impact of NF-κB signaling on these different outcomes in normal vs. human cancer cells remains poorly understood. We investigated the NF-κB-dependent effects and mechanism underlying reactive oxygen species (ROS)-mediated DDR outcomes of normal human lung fibroblasts (HDFs) and A549 human lung cancer epithelial cells. To activate DDR, ROS accumulation was induced by different doses of H2O2. The effect of ROS induction caused a G2 or G2-M phase cell cycle arrest of both human cell types. However, ROS-mediated DDR eventually culminated in different end points with HDFs undergoing premature senescence and A549 cancer cells succumbing to apoptosis. NF-κB p65/RelA nuclear translocation and Ser536 phosphorylation were induced in response to H2O2-mediated ROS accumulation. Importantly, blocking the activities of canonical NF-κB subunits with an IκBα super-repressor or suppressing canonical NF-κB signaling by IKKβ knock-down accelerated HDF premature senescence by up-regulating the p53-p21Cip1/Waf1 axis; but inhibiting the canonical NF-κB pathway exacerbated H2O2-induced A549 cell apoptosis. HDF premature aging occurred in conjunction with γ-H2AX chromatin deposition, senescence-associated heterochromatic foci and beta-galactosidase staining. p53 knock-down abrogated H2O2-induced premature senescence of vector control- and IκBαSR-expressing HDFs functionally linking canonical NF-κB-dependent control of p53 levels to ROS-induced HDF senescence. We conclude that IKKβ-driven canonical NF-κB signaling has different functional roles for the outcome of ROS responses in the contexts of normal vs. human tumor cells by respectively protecting them against DDR-dependent premature senescence and apoptosis. © 2012 Elsevier Inc.

Virchows Archiv

Modern Pathology

Gene copy number and protein expression of topoisomerase IIalpha were correlated to benefit from anthracyclines in various tumors. A retrospective series of 69 patients with DLBCL managed with CHOP chemotherapy were studied for immunohistochemical TopoIIalpha expression and numerical gene abnormalities by fluorescent in situ hybridization (FISH). The results were analyzed in relation to the expression of cell cycle proteins (Ki67, p53, HDM2, p21, p14, pRb, p16, and cyclins A, B1, D1, D2, D3, and E) and BCL6/CD10/MUM1/CD138 B-cell differentiation immunophenotype and outcome. High levels of TopoIIalpha protein were found in 91% of DLBCL cases. No evidence of TopoIIalpha gene amplification or deletion was found. The TopoIIalpha expression showed significant positive correlations with the proliferation index Ki67 (p = 0.002), cell cycle proteins pRb and cyclin D2 (p = 0.018 and p = 0.028, respectively), and the germinal center proteins bcl6 and CD10 (p = 0.010 and p0.0001, respectively). TopoIIalpha expression was significantly higher in germinal center B-cell like (GCB) DLBCL than in non-germinal center B-cell like (non-GCB) DLBCL (p = 0.048). TopoIIalpha protein was significantly associated with response to chemotherapy (chi(2), p = 0.024), but not with relapse-free or overall survival (p = 0.5). On multivariate analysis, only stage of disease retained independent prognostic significance (HR 0.33 for early stage, p = 0.008). Although TopoIIa gene copy number abnormalities were not found in DLBCL, high levels of protein expression are associated with GCB-cell differentiation immunophenotype, high proliferation, and response to treatment.

Gene copy number and protein expression of topoisomerase IIalpha were correlated to benefit from anthracyclines in various tumors. A retrospective series of 69 patients with DLBCL managed with CHOP chemotherapy were studied for immunohistochemical TopoIIalpha expression and numerical gene abnormalities by fluorescent in situ hybridization (FISH). The results were analyzed in relation to the expression of cell cycle proteins (Ki67, p53, HDM2, p21, p14, pRb, p16, and cyclins A, B1, D1, D2, D3, and E) and BCL6/CD10/MUM1/CD138 B-cell differentiation immunophenotype and outcome. High levels of TopoIIalpha protein were found in 91% of DLBCL cases. No evidence of TopoIIalpha gene amplification or deletion was found. The TopoIIalpha expression showed significant positive correlations with the proliferation index Ki67 (p = 0.002), cell cycle proteins pRb and cyclin D2 (p = 0.018 and p = 0.028, respectively), and the germinal center proteins bcl6 and CD10 (p = 0.010 and p < 0.0001, respectively). TopoIIalpha expression was significantly higher in germinal center B-cell like (GCB) DLBCL than in non-germinal center B-cell like (non-GCB) DLBCL (p = 0.048). TopoIIalpha protein was significantly associated with response to chemotherapy (chi(2), p = 0.024), but not with relapse-free or overall survival (p = 0.5). On multivariate analysis, only stage of disease retained independent prognostic significance (HR 0.33 for early stage, p = 0.008). Although TopoIIa gene copy number abnormalities were not found in DLBCL, high levels of protein expression are associated with GCB-cell differentiation immunophenotype, high proliferation, and response to treatment. Leuk Lymphoma

Normal cells divide for a limited number of generations, after which they enter a state of irreversible growth arrest termed replicative senescence. While replicative senescence is due to telomere erosion, normal human fibroblasts can undergo stress-induced senescence in response to oncogene activation, termed oncogene-induced senescence (OIS). Both, replicative and OIS, initiate a DNA damage checkpoint response (DDR) resulting in the activation of the p53-p21(Cip1/Waf1) pathway. However, while the nuclear factor-kappaB (NF-kappaB) signaling pathway has been implicated in DDR, its role in OIS has not been investigated. Here, we show that oncogenic Ha-RasV12 promoted premature senescence of IMR-90 normal human diploid fibroblasts by activating DDR, hence verifying the classical model of OIS. However, enforced expression of a constitutively active IKKbeta T-loop mutant protein (IKKbetaca), significantly delayed OIS of IMR-90 cells by suppressing Ha-RasV12 instigated DDR. Thus, our experiments have uncovered an important selective advantage in chronically activating canonical NF-kappaB signaling to overcome the anti-proliferative OIS response of normal primary human fibroblasts. Mech Ageing Dev

2-Methoxyestradiol (2-ME2) induces leukemia cells to undergo apoptosis in association with Bcl-2 inactivation but the mechanisms whereby Bcl-2 contributes to protection against programmed cell death in this context remain unclear. Here we showed that 2-ME2 inhibited the proliferation of Jurkat leukemia cells by markedly suppressing the levels of cyclins D3 and E, E2F1 and p21(Cip1/Waf1) and up-regulating p16(INK4A). Further, 2-ME2 induced apoptosis of Jurkat cells in association with down-regulation and phosphorylation of Bcl-2 (as mediated by JNK), up-regulation of Bak, activation of caspases-9 and -3 and PARP-1 cleavage. To determine the importance and mechanistic role of Bcl-2 in this process, we enforced its expression in Jurkat cells by retroviral transduction. Enforcing Bcl-2 expression in Jurkat cells abolished 2-ME2-induced apoptosis and instead produced a G1/S phase cell cycle arrest in association with markedly increased levels of p27(Kip1). Bcl-2 and p27(Kip1) were localized mainly in the nucleus in these apoptotic resistant cells. Interestingly, NF-kappaB activity and p50 levels were increased by 2-ME2 and suppression of NF-kappaB signaling reduced p27(Kip1) expression and sensitized cells to 2-ME2-induced apoptosis. Importantly, knocking-down p27(Kip1) in Jurkat Bcl-2 cells sensitized them to spontaneous and 2-ME2-induced apoptosis. Thus, Bcl-2 prevented the 2-ME2-induced apoptotic response by orchestrating a p27(Kip1)-dependent G1/S phase arrest in conjunction with activating NF-kappaB. Thus, we achieved a much better understanding of the penetrance and mechanistic complexity of Bcl-2 dependent anti-apoptotic pathways in cancer cells and why Bcl-2 inactivation is so critical for the efficacy of apoptosis and anti-proliferative inducing drugs like 2-ME2. Biochem Pharmacol

The epitope H contains an O-linked N-acetylglucosamine residue in a specific conformation and/or environment recognized by the monoclonal antibody H. It has previously been shown that the epitope H is present in several types of normal and pathological cells and in several polypeptides. In normal human brains the epitope H is present mostly to a minority of fibrous astrocytes, whereas it is greatly up-regulated in reactive astrocytes and is increased in well differentiated fibrillary astrocytomas compared to anaplastic astrocytomas and glioblastomas. In this study the expression of the epitope H was investigated in thirty cases of gemistocytic (WHO grade II), pilocytic (WHO grade I), and subependymal giant cell (WHO grade I) astrocytomas using the mAbH with the indirect immunoperoxidase method. The ten cases of gemistocytic astrocytomas revealed an overall high expression pattern. The ten cases of pilocytic astrocytomas revealed a biphasic pattern of epitope H expression. The dense tumor areas composed of elongated pilocytic cells revealed high expression of the epitope H. The loose cystic tumor areas composed of stellate cells revealed low expression of the epitope H. The ten cases of subependynal giant cell astrocytomas occurring in tuberous sclerosis revealed an overall high expression pattern. This study shows that there is high expression of the epitope H in gemistocytic, pilocytic and subependymal giant cell astrocytomas. Collectively considering, the present and our previous data, it appears that there is a spectrum of the expression levels of the epitope H ranging from the high expression in the reactive astrocytes and low grade astrocytomas to the low/null expression in the normal astrocytes and glioblastomas. Oncol Rep

Journal URL: http://www.iiar-anticancer.org/main.php?id=3