The entanglement of extracellular matrix molecules and immune checkpoint inhibitors in cancer: a systematic review of the literature

IntroductionImmune-checkpoint inhibitors (ICIs) have emerged as a core pillar of cancer therapy as single agents or in combination regimens both in adults and children. Unfortunately, ICIs provide a long-lasting therapeutic effect in only one third of the patients. Thus, the search for predictive biomarkers of responsiveness to ICIs remains an urgent clinical need. The efficacy of ICIs treatments is strongly affected not only by the specific characteristics of cancer cells and the levels of immune checkpoint ligands, but also by other components of the tumor microenvironment, among which the extracellular matrix (ECM) is emerging as key player. With the aim to comprehensively describe the relation between ECM and ICIs’ efficacy in cancer patients, the present review systematically evaluated the current literature regarding ECM remodeling in association with immunotherapeutic approaches.MethodsThis review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and was registered at the International Prospective Register of Systematic Reviews (PROSPERO, CRD42022351180). PubMed, Web of Science, and Scopus databases were comprehensively searched from inception to January 2023. Titles, abstracts and full text screening was performed to exclude non eligible articles. The risk of bias was assessed using the QUADAS-2 tool.ResultsAfter employing relevant MeSH and key terms, we identified a total of 5070 studies. Among them, 2540 duplicates, 1521 reviews or commentaries were found and excluded. Following title and abstract screening, the full text was analyzed, and 47 studies meeting the eligibility criteria were retained. The studies included in this systematic review comprehensively recapitulate the latest observations associating changes of the ECM composition following remodeling with the traits of the tumor immune cell infiltration. The present study provides for the first time a broad view of the tight association between ECM molecules and ICIs efficacy in different tumor types, highlighting the importance of ECM-derived proteolytic products as promising liquid biopsy-based biomarkers to predict the efficacy of ICIs.ConclusionECM remodeling has an important impact on the immune traits of different tumor types. Increasing evidence pinpoint at ECM-derived molecules as putative biomarkers to identify the patients that would most likely benefit from ICIs treatments.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351180, identifier CRD42022351180

Colorectal cancer development is affected by the ECM molecule EMILIN-2 hinging on macrophage polarization via the TLR-4/MyD88 pathway

Background Colorectal cancer is one of the most frequent and deadly tumors. Among the key regulators of CRC growth and progression, the microenvironment has emerged as a crucial player and as a possible route for the development of new therapeutic opportunities. More specifically, the extracellular matrix acts directly on cancer cells and indirectly affecting the behavior of stromal and inflammatory cells, as well as the bioavailability of growth factors. Among the ECM molecules, EMILIN-2 is frequently down-regulated by methylation in CRC and the purpose of this study was to verify the impact of EMILIN-2 loss in CRC development and its possible value as a prognostic biomarker. Methods The AOM/DSS CRC protocol was applied to Emilin-2 null and wild type mice. Tumor development was monitored by endoscopy, the molecular analyses performed by IHC, IF and WB and the immune subpopulations characterized by flow cytometry. Ex vivo cultures of monocyte/macrophages from the murine models were used to verify the molecular pathways. Publicly available datasets were exploited to determine the CRC patients' expression profile; Spearman's correlation analyses and Cox regression were applied to evaluate the association with the inflammatory response; the clinical outcome was predicted by Kaplan-Meier survival curves. Pearson correlation analyses were also applied to a cohort of patients enrolled in our Institute. Results In preclinical settings, loss of EMILIN-2 associated with an increased number of tumor lesions upon AOM/DSS treatment. In addition, in the early stages of the disease, the Emilin-2 knockout mice displayed a myeloid-derived suppressor cells-rich infiltrate. Instead, in the late stages, lack of EMILIN-2 associated with a decreased number of M1 macrophages, resulting in a higher percentage of the tumor-promoting M2 macrophages. Mechanistically, EMILIN-2 triggered the activation of the Toll-like Receptor 4/MyD88/NF-kappa B pathway, instrumental for the polarization of macrophages towards the M1 phenotype. Accordingly, dataset and immunofluorescence analyses indicated that low EMILIN-2 expression levels correlated with an increased M2/M1 ratio and with poor CRC patients' prognosis. Conclusions These novel results indicate that EMILIN-2 is a key regulator of the tumor-associated inflammatory environment and may represent a promising prognostic biomarker for CRC patients

The effects of sex therapy in the treatment of women with vaginismus and their partners

Introduction: Vaginism means not allowing the insertion of the penis, finger, vibrator or other objects into the vagina and in most cases, it is caused by psychological factors. Sex therapy applied in several sessions by the expert is the best way to overcome this situation. Purpose: To present the effects of sex therapy in cases diagnosed and treated with vaginismus. Methodology: The cases of treatment of women and their partners with this type of therapy in the Specialized Ordinance of Sexology Libido in Pristina, in the period 2020-2022, were analyzed. In total, 42 such cases were handled in this time period. The data were taken from the treatment protocol. Results: In this research, the effects of sex therapy in these cases were analyzed and it was found that in 37% of cases the treatment effect was achieved with 1-3 sessions, in 43% of cases 3-5 sessions were needed, while more than 5 sessions were applied in 20% of cases. In 26 cases, the application of only sex therapy, mainly the sensate focus therapy, was sufficient, while in 16 other cases, the application of CBT therapy was also necessary. In all cases, the partner was also involved. Conclusion: Vaginismus as a quite frequent phenomenon should be treated scientifically with sex therapy, which means focusing and treating by reducing the feeling of fear for the woman and instructing the partner in the way of approach and constant support for the woman

Smoking habits among medical students: a survey at the University of Prishtina Faculty of Medicine

Background: Smoking is a common habit among the population in Kosovo. In the country, smoking occurs in public places, health and educational institutions despite being prohibited by law. Our objective was to describe smoking habits, knowledge and attitudes among medical students from all departments in the University of Prishtina, Faculty of Medicine. Methods: The present study followed the Global Health Professions Student Survey (GHPSS) standardized methodology including data processing procedures. A self-administered questionnaire used was derived from the GHPSS. A total of 600 students were invited in the study while 470 returned questionnaires and participated in the study. Descriptive statistics were used to present the data. The Fisher’s exact test was used to test the significance and a p-value<0.05 was considered significant. Results: The prevalence rate of smoking among students was 16.9% (95% CI 13.2-20). Current smokers were 79 students, 28.2 % males, and 7.7 % females. The study showed that 55.5% of students smoke less than a pack of cigarettes per day. Almost half of them (47.6%) who smoke reported to have a smoker inside the family.  This study also revealed that 74.7% of respondents smoke in the presence of non-smokers on daily bases. Conclusion: Despite threating their own health, smokers also cause noxiousness to the society and medical students should be role models for the others by not smoking. Even though the percentage doesn’t show a high rate of smokers in Medical University of Prishtina, still we need to pay attention to bad smoking habits and try..

The effects of the course on human sexuality on students\u27 knowledge and attitudes about sexual health

Sexual health is a guaranteed right that is part of human rights. However, many countries and institutions are reluctant to include programs in this field in their curricula. UBT College is the leader and the only one in the country and region that students have the Human Sexuality module as a compulsory subject. The purpose of this paper was to measure students\u27 knowledge about this field. The methodology used in this research is based on measuring the level of students\u27 knowledge before and after completing the learning module. The SKAT test (The Sex Knowledge and Attitude Test) was used, which consists of two parts: knowledge and attitudes. The research was carried out during the 2022-2023 school year and 178 students of the Department of Nursing at UBT participated. The obtained results have shown significant statistical differences in some of the areas tested in both parts, in knowledge and attitudes. The conclusion of this research states that the effect of this module in increasing knowledge and changing attitudes about sexuality has been effective

ECM Remodeling in Squamous Cell Carcinoma of the Aerodigestive Tract: Pathways for Cancer Dissemination and Emerging Biomarkers

Squamous cell carcinomas (SCC) include a number of different types of tumors developing in the skin, in hollow organs, as well as the upper aerodigestive tract (UADT) including the head and neck region and the esophagus which will be dealt with in this review. These tumors are often refractory to current therapeutic approaches with poor patient outcome. The most important prognostic determinant of SCC tumors is the presence of distant metastasis, significantly correlating with low patient survival rates. Rapidly emerging evidence indicate that the extracellular matrix (ECM) composition and remodeling profoundly affect SSC metastatic dissemination. In this review, we will summarize the current knowledge on the role of ECM and its remodeling enzymes in affecting the growth and dissemination of UADT SCC. Taken together, these published evidence suggest that a thorough analysis of the ECM composition in the UADT SCC microenvironment may help disclosing the mechanism of resistance to the treatments and help defining possible targets for clinical intervention

The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy

Multimerin-2 orchestrates the cross-talk between endothelial cells and pericytes: A mechanism to maintain vascular stability

Tumor angiogenesis is vital for the growth and development of various solid cancers and as such is a valid and promising therapeutic target. Unfortunately, the use of the currently available anti-angiogenic drugs increases the progression-free survival by only a few months. Conversely, targeting angiogenesis to prompt both vessel reduction and normalization, has been recently viewed as a promising approach to improve therapeutic efficacy. As a double-edged sword, this line of attack may on one side halt tumor growth as a consequence of the reduction of nutrients and oxygen supplied to the tumor cells, and on the other side improve drug delivery and, hence, efficacy. Thus, it is of upmost importance to better characterize the mechanisms regulating vascular stability. In this context, recruitment of pericytes along the blood vessels is crucial to their maturation and stabilization. As the extracellular matrix molecule Multimerin-2 is secreted by endothelial cells and deposited also in juxtaposition between endothelial cells and pericytes, we explored Multimerin-2 role in the cross-talk between the two cell types. We discovered that Multimerin-2 is an adhesion substrate for pericytes. Interestingly, and consistent with the notion that Multimerin-2 is a homeostatic molecule deposited in the later stages of vessel formation, we found that the interaction between endothelial cells and pericytes promoted the expression of Multimerin-2. Furthermore, we found that Multimerin-2 modulated the expression of key cytokines both in endothelial cells and pericytes. Collectively, our findings posit Multimerin-2 as a key molecule in the cross-talk between endothelial cells and pericytes and suggest that the expression of this glycoprotein is required to maintain vascular stability