Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4 + and CD8 + T-cells in vitro and in vivo in OvCa mouse models. In mice, ARG1-containing EVs are transported to draining lymph nodes, taken up by dendritic cells and inhibit antigen-specific T-cell proliferation. Increased expression of ARG1 in mouse OvCa cells is associated with accelerated tumor progression that can be blocked by an arginase inhibitor. Altogether, our studies show that tumor cells use EVs as vehicles to carry over long distances and deliver to immune cells a metabolic checkpoint molecule – ARG1, mitigating anti-tumor immune responses.

Lesions made in the anterior medial basal hypothalamus (MBH) in pregnant or lactating ewes caused lack of development of the mammary gland and depressed milk yield, a decrease in plasma prolactin concentration and structural changes in the prolactin cells as manifested by a lack of the expected degranulation (lack of the hormone release) or by atrophic changes and diminished cell granulation (or granule synthesis). Lesions made in the caudal MBH during pregnancy advanced development of the mammary gland, induced a rapid increase in the plasma prolactin concentration and caused extensive degranulation of prolactin cells. These results indicate that at least two functional systems controlling the secretion and production of prolactin exist in the hypothalamus of sheep: an anterior system which is stimulatory and a caudal which is inhibitory.

Serotonin or melatonin was infused into the 3rd cerebral ventricle (3rd V) or into the medial basal hypothalamus (MBH) of both intact ewes and ewes with lesions of the anterior hypothalamic area (AHA). Prolongation of the estrous cycle and delay of ovulation were obtained after infusions of melatonin or serotonin in both the intact and lesioned ewes. Statistically, serotonin proved to be more effective in this respect than melatonin in the intact ewes. The infusions also blocked the preovulatory peak of LH. Furthermore, the infusion of serotonin blocked estrous behavior, while that of melatonin did not affect this function. The effect of indoleamie infusions in the lesioned ewes, in which the inhibitory action of the AHA over the transmission of gonadotrophic releasing hormones (G-RH) had been eliminated, seems to indicate that the inhibitory action of indoleamines on the release of these neurohormones is being displayed at the level of the MBH.

Gestational diabetes mellitus (GDM) is defined as carbohydrate intolerance that appears or is for the first time diagnosed during pregnancy. It can lead to many complications in the mother and in the offspring, so diagnostics and management of GDM are important to avoid adverse pregnancy outcomes. Epigenetic studies revealed the different methylation status of genes in pregnancies with GDM compared to pregnancies without GDM. A growing body of evidence shows that the GDM can affect not only the course of the pregnancy, but also the development of the offspring, thus contributing to long-term effects and adverse health outcomes of the progeny. Epigenetic changes occur through histone modification, DNA methylation, and disrupted function of non-coding ribonucleic acid (ncRNA) including microRNAs (miRNAs). In this review, we focus on the recent knowledge about epigenetic changes in GDM. The analysis of this topic may help us to understand pathophysiological mechanisms in GDM and find a solution to prevent their consequences.

Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic studies revealed modified methylation patterns in HCC tumors, dysfunction of enzymes engaged in the DNA methylation process, and a set of histone modifications that influence gene expression. HCC cells are also influenced by the disrupted function of non-coding RNAs, such as micro RNAs and long non-coding RNAs. Moreover, a role of liver cancer stem cells in HCC development is becoming evident. The reversibility of epigenetic changes offers the possibility of influencing them and regulating their undesirable effects. All these data can be used not only to identify new therapeutic targets but also to predict treatment response. This review focuses on epigenetic changes in hepatocellular carcinoma and their possible implications in HCC therapy.

One of the potential therapeutic methods of cancer treatment is the immunotherapy with monoclonal antibodies. This kind of therapy, although devoid of serious side effects, has often insufficient efficacy. The presence of complement inhibitors on the cancer cells, which are able to inactivate complement-mediated immune response represents one of the main reasons for the inefficiency of such therapy. In our studies we investigated the expression of main membrane–bound and fluid-phase complement regulators: CD55, CD59 and factor H/factor H-like in tumour samples of ovarian and corpus uteri cancer. Tissue samples were collected from 50 patients and stained immunohistochemically, with the use of peroxidase-based immunodetection system. Immunohistochemical analysis revealed that complement inhibitors are present in examined tumors although their presence is heterogenous. The most prevalent is the presence of factor H/H-like, localized mostly in tumor stroma and within vascular structures. Membrane bound complement inhibitors are less prominently expressed by cancer cells. CD55 was detected in low percentage of cells, predominantly within cancer tubules. CD59 immunoreactivity was more prevalent in cancer cells, and was localized particularly at the margin of cancer cell tubules. Our results demonstrate that the most prominent complement inhibitor in cancer of ovary and corpus uteri origin is factor H/factor H-like. Blocking or downregulation of this inhibitor should be taken into consideration with regards to improving the efficiency of immunotherapy with monoclonal antibodies.

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Microscopic differentiation between muscularis mucosae (MM) and muscularis propria (MP) of the bladder in the material obtained during transurethral resection (TUR) remains difficult. The study was aimed at determination of the usefulness of immunohistochemical staining in this context. Forty-seven TUR specimens were stained with 5 mouse anti-human antibodies: anti-desmin, anti-filamin, anti-type IV collagen, anti-smoothelin, and anti-vimentin. Slides were assessed under light microscopy and the intensity of the immune reaction within MM and MP was evaluated on a four-level visual scale as follows: negative (0) and weakly (1), moderately (2), or strongly (3) positive. MM was identified in 27 patients (57.4%). The modal values of reaction intensity in MM and MP was 0 and 2 for desmin (p > 0.05), 2 and 2 for filamin (p = 0.01), 2 and 2 for type IV collagen (p > 0.05), 1 and 2 for smoothelin (p = 0.03), and 2 and 0 for vimentin (p = 0.02), respectively. Identical intensity within MM and MP was observed in 7.1%, 28.6%, 20%, 30.1%, 5.6%, respectively. Immunohistochemistry can help differentiate between MM and MP in TUR specimens. As of yet, no single marker can reliably differentiate between MM and MP; however, a combination of anti-filamin, anti-smoothelin, and anti-vimentin antibodies may be reasonable for diagnostic purposes.