Current Understanding on Why Ovarian Cancer Is Resistant to Immune Checkpoint Inhibitors.

The standard treatment of ovarian cancer (OC) patients, including debulking surgery and first-line chemotherapy, is unsatisfactory because of recurrent episodes in the majority (~70%) of patients with advanced OC. Clinical trials have shown only a modest (10-15%) response of OC individuals to treatment based on immune checkpoint inhibitors (ICIs). The resistance of OC to therapy is caused by various factors, including OC heterogeneity, low density of tumor-infiltrating lymphocytes (TILs), non-cellular and cellular interactions in the tumor microenvironment (TME), as well as a network of microRNA regulating immune checkpoint pathways. Moreover, ICIs are the most efficient in tumors that are marked by high microsatellite instability and high tumor mutation burden, which is rare among OC patients. The great challenge in ICI implementation is connected with distinguishing hyper-, pseudo-, and real progression of the disease. The understanding of the immunological, molecular, and genetic mechanisms of OC resistance is crucial to selecting the group of OC individuals in whom personalized treatment would be beneficial. In this review, we summarize current knowledge about the selected factors inducing OC resistance and discuss the future directions of ICI-based immunotherapy development for OC patients.

Telomeres and telomerase in risk assessment of cardiovascular diseases.

Telomeres are repetitive nucleoprotein structures located at the ends of chromosomes. Reduction in the number of repetitions causes cell senescence. Cells with high proliferative potential age with each replication cycle. Post-mitotic cells (e.g. cardiovascular cells) have a different aging mechanism. During the aging of cardiovascular system cells, permanent DNA damage occurs in the telomeric regions caused by mitochondrial dysfunction, which is a phenomenon independent of cell proliferation and telomere length. Mitochondrial dysfunction is accompanied by increased production of reactive oxygen species and development of inflammation. This phenomenon in the cells of blood vessels can lead to atherosclerosis development. Telomere damage in cardiomyocytes leads to the activation of the DNA damage response system, histone H2A.X phosphorylation, p53 activation and p21 and p16 protein synthesis, resulting in the SASP phenotype (senescence-associated secretory phenotype), increased inflammation and cardiac dysfunction. Cardiovascular cells show the activity of the TERT subunit of telomerase, an enzyme that prevents telomere shortening. It turns out that disrupting the activity of this enzyme can also contribute to the formation of cardiovascular diseases. Measurements of telomere length according to the "blood-muscle" model may help in the future to assess the risk of cardiovascular complications in people undergoing cardiological procedures, as well as to assess the effectiveness of some drugs.

Telomeres and telomerase in endometrial cancer and hyperplasia.

Introduction: The study aimed to measure telomeres length (TL) and telomerase expression in normal endometrium and endometrial hyperplasia and cancer. Methods: Total RNA and DNA were isolated from endometrium samples of 117 patients. The RT-PCR method was used to determine telomerase expression and relative telomere length. Results: The control group had the longest telomeres in comparison to the hyperplasia and endometrial cancer groups. Only in the endometrial cancer group was telomerase expressed and positively correlated with telomere length. Conclusions: Telomere extension in endometrial cancer is mediated by telomerase, but telomere length may not be an indicator of endometrioid cancer development.

[Role of CEACAM in neutrophil activation]. / Rola CEACAM w aktywacji granulocytów obojetnochlonnych.

 Neutrophils express many surface adhesion molecules, including CEACAM1, CEACAM3, CEACAM4, CEACAM6 and CEACAM8 glycoproteins, which play an important role in biological functions of neutrophils such as adhesion, phagocytosis, oxidative burst and degranulation. CEACAM3 activates neutrophils and initiates phagocytosis as a result of binding to bacterial Opa protein. In addition, CEACAM1 and CEACAM6 can delay apoptosis. All neutrophil CEACAMs, except for CEACAM3, can stimulate adhesion of neutrophils to endothelium. One CEACAM family member, CEA, which is not expressed by neutrophils, displays strong chemotactic activity, and probably can prime and/or activate neutrophils to adhesion. Induction of CEACAM signaling can be initiated by dimerization of CEACAMs and/or phosphorylation of their cytoplasmic domains. CEACAM signaling is often associated with an increase in the cytoplasmic calcium level.

The Length of Leukocyte and Femoral Artery Telomeres in Patients with Peripheral Atherosclerosis.

The length of telomeres (TLs) that protect chromosome ends may reflect the age of cells as well as the degree of genetic material damage caused by external factors. Since leukocyte telomere length is associated with cardiovascular diseases, the aim of this study was to evaluate whether leukocyte TL reflects femoral artery wall telomeres of patients with atherosclerosis and lower limb ischemia. Samples of femoral artery wall and blood were collected from 32 patients qualified to surgical revascularization. The analysis included blood and artery wall telomere length measurement and biochemical parameters. The study indicated that there was a moderate correlation between artery wall TL and leukocyte TL. Leukocyte TL was, on average, two times shorter than artery wall TL and correlated with the number of white blood cells. In turn, artery TL was impacted by total cholesterol level. The results suggest that the length of leukocyte telomeres may reflect artery wall TL and indirectly reflect the processes taking place in the artery wall in patients with atherosclerosis.

Clinical Significance of Tie-2-Expressing Monocytes/Macrophages and Angiopoietins in the Progression of Ovarian Cancer-State-of-the-Art.

Tumour growth and metastasis are specific to advanced stages of epithelial ovarian cancer (EOC). Tumour angiogenesis is an essential part of these processes. It is responsible for providing tumours with nutrients, metabolites, and cytokines and facilitates tumour and immune cell relocation. Destabilised vasculature, a distinctive feature of tumours, is also responsible for compromising drug delivery into the bulk. Angiogenesis is a complex process that largely depends on how the tumour microenvironment (TME) is composed and how a specific organ is formed. There are contrary reports on whether Tie-2-expressing monocytes/macrophages (TEMs) reported as the proangiogenic population of monocytes have any impact on tumour development. The aim of this paper is to summarise knowledge about ovarian-cancer-specific angiogenesis and the unique role of Tie-2-expressing monocytes/macrophages in this process. The significance of this cell subpopulation for the pathophysiology of EOC remains to be investigated.

The role of telomeres and telomerase in the senescence of postmitotic cells.

Senescence is a process related to the stopping of divisions and changes leading the cell to the SASP phenotype. Permanent senescence of many SASP cells contributes to faster aging of the body and development of age-related diseases due to the release of pro-inflammatory factors. Both mitotically active and non-dividing cells can undergo senescence as a result of activation of different molecular pathways. Telomeres, referred to as the molecular clock, direct the dividing cell into the aging pathway when reaching a critical length. In turn, the senescence of postmitotic cells depends not on the length of telomeres, but their functionality. Dysfunctional telomeres are responsible for triggering the signaling of DNA damage response (DDR). Telomerase subunits in post-mitotic cells translocate between the nucleus, cytoplasm and mitochondria, participating in the regulation of their activity. Among other things, they contribute to the reduction of reactive oxygen species generation, which leads to telomere dysfunction and, consequently, senescence. Some proteins of the shelterin complex also play a protective role by inhibiting senescence-initiating kinases and limiting ROS production by mitochondria.

Telomere length in leukocytes and cervical smears of women with high-risk human papillomavirus (HR HPV) infection.

OBJECTIVE: Persistent high-risk HPV (HR HPV) infection leads to the development of squamous intraepithelial lesions, which in turn may progress to cervical cancer. Telomere elongation or shortening may indicate a carcinogenesis process. In the present study, we analyzed telomere length from blood and cervical smears of women without and with high-risk HPV infection. MATERIALS AND METHODS: Telomere length was quantified by real-time PCR in blood and cervical smears from 48 women with high-risk HPV infection and HGSIL or LGSIL, 29 women HR-HPV positive without SIL, and 11 HPV-negative women. RESULTS: No correlation was found between age and telomere length in blood and cervical smears. Women with high-risk HPV infection had shorter telomeres in cervical smears, but not in blood compared to the control group. CONCLUSION: These findings suggest that telomere shortening occurs in cervical cells of women with HR HPV infection both with LGSIL and HGSIL and may indicate the onset of carcinogenesis. In turn, there is no correlation between leukocyte telomere length and cervical cancer risk in women with HR HPV infection.

Telomeres as a molecular marker of male infertility.

In recent years, male infertility has become a growing social problem. Standard diagnostic procedures, based on assessing seminological parameters, are often insufficient to explain the causes of male infertility. Because of this, new markers with better clinical application are being sought. One of the promising markers seems to be an assessment of telomere length of sperm. Sperm telomeres, in contrast to somatic cells, are elongated as men age. The results of some studies suggest that telomere length may be relevant in the case of fertilization and normal embryo development. Literature reports indicate that there is a correlation between telomere length of sperm and abnormal sperm parameters. The measurement of telomere length using the method of quantitative PCR could become a new marker of spermatogenesis, which can be useful for evaluating male reproductive age.

Telomeres and Telomerase During Human Papillomavirus-Induced Carcinogenesis.

Human papillomaviruses (HPVs) belong to a small spherical virus family and are transmitted through direct contact, most often through sexual behavior. More than 200 types of HPV are known, a dozen or so of which are classified as high-risk viruses (HR HPV) and may contribute to the development of cervical cancer. HPV is a small virus with a capsid composed of L1 and L2 proteins, which are crucial for entry to the cell. The infection begins at the basal cell layer and progresses to involve cells from higher layers of the cervical epithelium. E6 and E7 viral proteins are involved in the process of carcinogenesis. They interact with suppressors of oncogenesis, including p53 and Rb proteins. This leads to DNA replication and intensive cell divisions. The persistent HR HPV infection leads to the development of dysplasia and these changes may progress to invasive cancer. During the initial stage of carcinogenesis, telomeres shorten until telomerase activates. The activation of telomerase, the enzyme necessary to extend chromosome ends (telomeres) is the key step in cell immortalization. Analyzing the expression level of hTERT and hTERC genes encoding telomerase and telomere length measurement may constitute new markers of the early carcinogenesis.