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Serglycin is a proteoglycan expressed by some malignant cells. It promotes metastasis and protects some tumor cells from complement system attack. In the present study, we show for the first time the in situ expression of serglycin by breast cancer cells by immunohistochemistry in patients' material. Moreover, we demonstrate high expression and constitutive secretion of serglycin in the aggressive MDA-MB-231 breast cancer cell line. Serglycin exhibited a strong cytoplasmic staining in these cells, observable at the cell periphery in a thread of filaments near the cell membrane, but also in filopodia-like structures. Serglycin was purified from conditioned medium of MDA-MB-231 cells, and represented the major proteoglycan secreted by these cells, having a molecular size of ~ 250 kDa and carrying chondroitin sulfate side chains, mainly composed of 4-sulfated (~ 87%), 6-sulfated (~ 10%) and non-sulfated (~ 3%) disaccharides. Purified serglycin inhibited early steps of both the classical and the lectin pathways of complement by binding to C1q and mannose-binding lectin. Stable expression of serglycin in less aggressive MCF-7 breast cancer cells induced their proliferation, anchorage-independent growth, migration and invasion. Interestingly, over-expression of serglycin lacking the glycosaminoglycan attachment sites failed to promote these cellular functions, suggesting that glycanation of serglycin is a pre-requisite for its oncogenic properties. Our findings suggest that serglycin promotes a more aggressive cancer cell phenotype and may protect breast cancer cells from complement attack supporting their survival and expansion.

Serglycin (SRGN) has been found overexpressed and secreted in glioblastoma (GBM), associated with tumorigenic signaling and poor prognosis. In this study, we aimed to elucidate the involvement of SRGN in the unfolded protein response (UPR), an oncogenic signaling pathway implicated in protein recycling and cell fate. Herein, we developed stably transduced LN-18shSCR GBM cells, expressing high levels of SRGN, and SRGN-depleted LN-18shSRGN cells. We observed significantly attenuated expression and activity of all UPR mediators upon SRGN suppression, in particular PERK, IRE1, ATF6 and downstream effectors. SRGN-expressing cells possessed a constitutively active UPR, as indicated by its active phosphorylation status and accumulated pool of nuclear ATF4 in LN-18shSCR cells. Constitutive activation of the caspase-dependent apoptotic pathway was apparent in LN-18shSRGN cells. Induction of endoplasmic reticulum (ER) stress pointed out that LN-18shSRGN cells were predisposed to ER stress-associated cell death, whereas LN-18shSCR cells activated adaptive UPR signaling and displayed resistance to apoptosis. The evaluation of TLRs, TNFRs, ILs and NF-kB also underscored that SRGN is essential for their expression and active inflammatory signaling. We concluded that SRGN-expressing cells acquire a pro-survival UPR mechanism, highlighting the novel regulatory role of SRGN in the adaptation and survival of GBM cells.

In the present pilot study, we examined the presence of serglycin in lung, breast, prostate, and colon cancer and evaluated its expression in cell lines and tissues. We found that serglycin was expressed and constitutively secreted in culture medium in high levels in more aggressive cancer cells. It is worth noticing that aggressive cancer cells that harbor KRAS or EGFR mutations secreted serglycin constitutively in elevated levels. Furthermore, we detected the transcription of an alternative splice variant of serglycin lacking exon 2 in specific cell lines. In a limited number of tissue samples analyzed, serglycin was detected in normal epithelium but was also expressed in higher levels in advanced grade tumors as shown by immunohistochemistry. Serglycin staining was diffuse, granular, and mainly cytoplasmic. In some cancer cells serglycin also exhibited membrane and/or nuclear immunolocalization. Interestingly, the stromal cells of the reactive tumor stroma were positive for serglycin, suggesting an enhanced biosynthesis for this proteoglycan in activated tumor microenvironment. Our study investigated for first time the distribution of serglycin in normal epithelial and cancerous lesions in most common cancer types. The elevated levels of serglycin in aggressive cancer and stromal cells may suggest a key role for serglycin in disease progression.

Background Mammographic density (MD) and malignant-appearing microcalcifications (MAMCs) represent the earliest mammographic findings of non-palpable breast carcinomas. Matrix proteoglycans versican and decorin are frequently over-expressed in various malignancies and are differently involved in the progression of cancer. In the present study, we have evaluated the expression of versican and decorin in non-palpable breast carcinomas and their association with high risk mammographic findings and tumor characteristics. Methods Three hundred and ten patients with non-palpable suspicious breast lesions, detected during screening mammography, were studied. Histological examination was carried out and the expression of decorin, versican, estrogen receptor α (ERα), progesterone receptor (PR) and c-erbB2 (HER-2/neu) was assessed by immunohistochemistry. Results Histological examination showed 83 out of 310 (26.8%) carcinomas of various subtypes. Immunohistochemistry was carried out in 62/83 carcinomas. Decorin was accumulated in breast tissues with MD and MAMCs independently of the presence of malignancy. In contrast, versican was significantly increased only in carcinomas with MAMCs (median ± SE: 42.0 ± 9.1) and MD (22.5 ± 10.1) as compared to normal breast tissue with MAMCs (14.0 ± 5.8), MD (11.0 ± 4.4) and normal breast tissue without mammographic findings (10.0 ± 2.0). Elevated levels of versican were correlated with higher tumor grade and invasiveness in carcinomas with MD and MAMCs, whereas increased amounts of decorin were associated with in situ carcinomas in MAMCs. Stromal deposition of both proteoglycans was related to higher expression of ERα and PR in tumor cells only in MAMCs. Conclusions The specific accumulation of versican in breast tissue with high MD and MAMCs only in the presence of malignant transformation and its association with the aggressiveness of the tumor suggests its possible use as molecular marker in non-palpable breast carcinomas.

Malignant cells exhibit elevated rates of protein synthesis and secretion to facilitate tumor growth, proliferation, and tumorigenesis. Upon malignant transformation, the endoplasmic reticulum (ER) experiences stress due to the accumulation of unfolded or misfolded proteins in the ER lumen, lack of nutrient availability and overall hostile tumor microenvironment conditions. The demand for regulated protein turnover and proteostasis reinstatement results in the activation of the unfolded protein response (UPR) pathway for cellular adaptation and survival. The UPR machinery utilizes the BiP chaperone and three ER-bound sensors, PERK, IRE1, and ATF6, to substantiate signal transduction and orchestrate gene expression associated with protein folding, degradation and recycling, inflammation, autophagy, and programmed cell death. The pleiotropic function of UPR emerges as a central mediator for tumor progression, especially in multiple myeloma and glioblastoma pathologies. Numerous studies have recently pointed out that communication of the extracellular matrix (ECM) with surrounding tumor cells dictates in part UPR activity and vice versa. In the context of this dynamic interplay, ER stress and UPR mechanisms have been proposed as potential targets to elicit novel and effective therapeutic approaches in clinical trials.

Although syndecan-4 is implicated in cancer progression, there is no information for its role in testicular germ cell tumours (TGCTs). Thus, we examined the expression of syndecan-4 in patients with TGCTs and its correlation with the clinicopathological findings. Immunohistochemical staining in 71 tissue specimens and mRNA analysis revealed significant overexpression of syndecan-4 in TGCTs. In seminomas, high percentage of tumour cells exhibited membranous and/or cytoplasmic staining for syndecan-4 in all cases. Stromal staining for syndecan-4 was found in seminomas and it was associated with nodal metastasis (P=0.04), vascular/lymphatic invasion (P=0.01), and disease stage (P=0.04). Reduced tumour cell associated staining for syndecan-4 was observed in nonseminomatous germ cell tumours (NSGCTs) compared to seminomas. This loss of syndecan-4 was associated with nodal metastasis (P=0.01), vascular/lymphatic invasion (P=0.01), and disease stage (P=0.01). Stromal staining for syndecan-4 in NSGCTs did not correlate with any of the clinicopathological variables. The stromal expression of syndecan-4 in TGCTs was correlated with microvessel density (P=0.03). Our results indicate that syndecan-4 is differentially expressed in seminomas and NSGCTs and might be a useful marker. Stromal staining in seminomas and reduced levels of syndecan-4 in tumour cells in NSGCTs are related to metastatic potential, whereas stromal staining in TGCTs is associated with neovascularization.

Antimicrobial peptides (AMPs) with antiviral activity (antiviral peptides: AVPs) have become a research hotspot and already show immense potential to become pharmaceutically available antiviral drugs. AVPs have exhibited huge potential in inhibiting viruses by targeting various stages of their life cycle. Insects are the most speciose group of animals that inhabit almost all ecosystems and habitats on the land and are a rich source of natural AMPs. However, insect AVP mining, functional research, and drug development are still in their infancy. This review aims to summarize the currently validated insect AVPs, explore potential new insect AVPs and to discuss their possible mechanism of synthesis and action, with a view to providing clues to unravel the mechanisms of insect antiviral immunity and to develop insect AVP-derived antiviral drugs.

Purpose To evaluate health-related quality of life (HRQoL) and satisfaction with iron chelation therapy (ICT) of patients with transfusion-dependent β-thalassemia (TDT) managed under routine care conditions. Patients and methods This was an observational, multicenter, cross-sectional study conducted in three hospital-based Thalassemia Units of Western Greece. Patients confidentially completed the 36-item short-form (SF-36) and the “ satisfaction with ICT” (SICT) instruments to assess HRQoL and ICT satisfaction respectively. Results One hundred and thirty-one adult TDT patients [74 female, median (IQR) age: 41 (36–47) years] were enrolled. Eighty patients (61.1%) were receiving parenteral ICT, with or without oral chelators (Group I), whereas 51 (38.9%) were only receiving oral ICT (Group II). The median SF-36 physical component summary and mental component summary scores were 76.3 and 75.7 among Group I, and 76.9 and 74.5 among Group II patients, not differing between the two groups. In their majority, Group I (84.6%) and Group II (92.9%) patients reported preferring oral ICT. Moreover, Group I patients reported greater perceived ICT effectiveness (median SICT score: 4.3 versus 4.2; p  = 0.039), whereas patients receiving deferasirox-containing ICT reported higher treatment acceptance (median SICT score: 4.0 versus 3.6, p  = 0.038) and greater satisfaction with the burden of their ICT (median SICT score: 4.4 versus 3.9, p  = 0.033). Conclusion TDT patients prefer to receive oral ICT and are more satisfied of the burden of deferasirox-containing ICT, even though those receiving parenteral ICT are more satisfied by the effectiveness of their treatment. No differences in HRQoL were not noted between patients receiving parenteral versus oral ICT.

Background-Objectives: Although considered standard of care for patients with low-/intermediate-1 risk MDS and isolated del(5q), lenalidomide is not widely used in patients exhibiting additional cytogenetic abnormalities, on top of del(5)q. The aim of this study was to provide real-world evidence for the efficacy of lenalidomide in patients with del(5q), with or without additional cytogenetic abnormalities. Methods: Patients with MDS exhibiting del(5q) in the Greek National Myelodysplastic Syndromes Registry were analyzed if they had received at least one lenalidomide dose and detailed response assessment/follow-up was available. Results: Among 238 patients analyzed, 153 (64.3%) had del(5q) syndrome (Group-I), 34 (14.3%) had an isolated del(5q) abnormality but were not 5q− syndrome (Group-II), 26 (10.9%) had del(5q) plus only one additional cytogenetic abnormality (Group-III), and 25 (10.5%) had del(5q) plus >1 additional abnormality (Group-IV). Among 218 (91.6%) evaluable patients, a major response was achieved by 146 (67.0%) patients, 114/146 (78.1%) in Group-I, 18/31 (58.1%) in Group-II, 10/20 (50.0%) in Group-III, and 4/21 (19.0%) in Group-IV. Overall, hematological response was seen in 177/218 (81.2%) patients, even among those with an excess of bone marrow blasts/frank acute myeloid leukemia. Duration of response was comparable between the four patient groups. A complete cytogenetic response was achieved by 38.0% overall, more commonly in Group-I (42.3%) and -III (35.7%). Transfusion-independent patients and those with a higher MCV or lower marrow blast cells at baseline had a higher probability of achieving a major response. With multivariate analysis, factors associated with overall survival were age, performance status, transfusion dependence, and marrow blast cell percentage at treatment start, as well as time from initial diagnosis to lenalidomide start. Conclusions: Lenalidomide was highly effective in patients with the del(5)q syndrome and also in those with isolated del(5)q, other than del(5)q syndrome, or those exhibiting del(5)q plus only one additional cytogenetic abnormality, not affecting chromosome 7.

Angioimmunoblastic T‐cell lymphoma (AITL), a rare and aggressive subtype of peripheral T‐cell lymphoma (PTCL), often demonstrates resistance to standard therapies. The optimal therapeutic approach for relapsed/refractory (R/R) AITL remains therefore uncertain and challenging, with an unmet need for effective treatment options. Given the role of epigenetic alterations in AITL lymphomagenesis, the development of drugs targeting epigenetics may present a promising therapeutic approach. Belinostat, a histone deacetylase (HDAC) inhibitor, induced durable partial remission in heavily pretreated relapsed/refractory angioimmunoblastic T‐cell lymphoma, highlighting its potential as an effective therapeutic option when standard treatments and stem cell transplantation are unsuitable. Key Clinical Message In patients with heavily pretreated relapsed/refractory AITL, HDAC inhibition can achieve long‐lasting metabolic control with minimal toxicity, even after multiple relapses. When stem cell transplantation is declined or unsuitable, belinostat as an epigenetic therapy offers a rational, patient‐centered alternative to maintain disease control and preserve quality of life.