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is observed in the principal PGB-indicated conditions which share the alteration in IL-6, TNF-α, IL-2 and IL-1β cytokines level. Yet, reports on PGB immunomodulatory and anti-inflammatory effects are a few and focused mainly on in vitro assays, local inflammatory changes within the nervous system, and attenuation of the secretion of only IL-1β and TNF-α cytokines 18-20. In addition, PGB effects on cytokines secretion in immune cells, such as isolated splenocytes and peritoneal macrophages (PMs), and its effect on lymphoid organs, were not examined before. Therefore, there is a need to perform a simultaneous assessment of the effect of PGB on the secretion of the cytokines that were commonly elevated in the aforementioned PGB-indicated conditions (IL-6, TNF-α, IL-1β and IL-2) and to expand the investigation to its effect on lymphoid organs and cytokine secretion in immune cells. As peripheral inflammation and elevated systemic cytokines levels were demonstrated in the above-mentioned PGB-indicated conditions, we investigated in this study the effect of PGB on murine models of peripheral inflammation. In this study, we used for the first time, LPS and ConA-induced murine models of inflammation to examine the effect of PGB on peripheral proinflammatory cytokine secretion (IL-6, TNF-α, IL-1β and IL-2) in vitro and in vivo in BALB/c mice. LPS-model of inflammation has been employed before to study neuroinflammatory conditions, seizure and anxiety disorders in mice 21-25 , while ConA was used to investigate T-cell function in patients with fibromyalgia 26. Additionally, in this study, the effect of PGB on mitogen-induced inflammatory changes in the spleen, as a lymphoid organ, was also examined for the first time. Regarding in vitro investigation, the lack of reports that examined the effect of PGB on the secretion of cytokines in immune cells prompted us to investigate such effects of PGB on basal and mitogen-induced proinflammatory cytokines secretion in splenocytes and peritoneal macrophages (PMs).

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Senescence is a cell stress response induced by replicative, oxidative, oncogenic, and genotoxic stresses. Tumor cells undergo senescence in response to several cancer therapeutics in vitro (Therapy-Induced Senescence, TIS), including agents utilized as neoadjuvant chemotherapy (NAC) in the treatment of invasive breast cancer. TIS has been proposed to contribute to adverse therapy outcomes including relapse. However, there is limited evidence on the induction of senescence in response to NAC in clinical cancer and its contribution to disease outcomes. In this work, the expression of three senescence-associated markers (p21CIP1, H3K9Me3 (histone H3 lysine 9 trimethylation), and Lamin B1) was investigated in breast cancer samples that developed partial or incomplete pathological response to NAC (n=37). Accordingly, 40.54% of all samples showed marker expression consistent with a senescence-like phenotype, while the remainders were either negative or inconclusive for senescence (2.70 and 56.8%, respectively). Moreover, analysis of core-needle biopsies revealed minimal changes in p21CIP1 and H3K9Me3, but significant changes in Lamin B1 expression levels following NAC, highlighting a more predictive role of Lamin B1 in senescence detection. However, our analysis did not establish an association between TIS and cancer relapse as only three patients (8.1%) with a senescence-like profile developed short-term recurrent disease. Our analysis indicates that identification of TIS in tumor samples requires large-scale transcriptomic and protein marker analyses and extended clinical follow-up. Better understanding of in vivo senescence should elucidate its contribution to therapy outcomes and pave the way for the utilization of senolytic approaches as potential adjuvant cancer therapy.

First described in 2003 as epithelioid-sarcoma-like hemangioendothelioma and later in 2011 as pseudomyogenic hemangioendothelioma, this rare vascular tumor is of intermediate malignant potential. It was officially included for the first time in the most recent World Health Organization's Classification of Tumours of Soft Tissue and Bone. It typically affects young adults with a predilection for the distal lower extremity. This tumor lacks morphologic features of vascular differentiation but shows unequivocal evidence of such differentiation with the use of relevant immunohistochemical stains such as FLI1, ERG, and CD31. Pseudomyogenic hemangioendothelioma can be diagnostically challenging and might be confused with other tumors, such as epithelioid sarcoma. In this review we discuss the clinical, morphologic, and immunohistochemical features of this tumor with particular emphasis on the differential diagnosis. Salient molecular and prognostic features are also reviewed.

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