Contemporary Approaches to Immunotherapy of Solid Tumors.

In recent years, the arrival of the immunotherapy industry has introduced the possibility of providing transformative, durable, and potentially curative outcomes for various forms of malignancies. However, further research has shown that there are a number of issues that significantly reduce the effectiveness of immunotherapy, especially in solid tumors. First of all, these problems are related to the protective mechanisms of the tumor and its microenvironment. Currently, major efforts are focused on overcoming protective mechanisms by using different adoptive cell therapy variants and modifications of genetically engineered constructs. In addition, a complex workforce is required to develop and implement these treatments. To overcome these significant challenges, innovative strategies and approaches are necessary to engineer more powerful variations of immunotherapy with improved antitumor activity and decreased toxicity. In this review, we discuss recent innovations in immunotherapy aimed at improving clinical efficacy in solid tumors, as well as strategies to overcome the limitations of various immunotherapies.

Influence of Extracellular Matrix Components on the Differentiation of Periodontal Ligament Stem Cells in Collagen I Hydrogel.

Regeneration of periodontal tissues requires an integrated approach to the restoration of the periodontal ligament, cementum, and alveolar bone surrounding the teeth. Current strategies in endogenous regenerative dentistry widely use biomaterials, in particular the decellularized extracellular matrix (dECM), to facilitate the recruitment of populations of resident cells into damaged tissues and stimulate their proliferation and differentiation. The purpose of our study was to evaluate the effect of the exogenous components of the extracellular matrix (hyaluronic acid, laminin, fibronectin) on the differentiation of periodontal ligament stem cells (PDLSCs) cultured with dECM (combinations of decellularized tooth matrices and periodontal ligament) in a 3D collagen I hydrogel. The immunohistochemical expression of various markers in PDLSCs was assessed quantitatively and semi-quantitatively on paraffin sections. The results showed that PDLSCs cultured under these conditions for 14 days exhibited phenotypic characteristics consistent with osteoblast-like and odontoblast-like cells. This potential has been demonstrated by the expression of osteogenic differentiation markers (OC, OPN, ALP) and odontogenic markers (DSPP). This phenomenon corresponds to the in vivo state of the periodontal ligament, in which cells at the interface between bone and cementum tend to differentiate into osteoblasts or cementoblasts. The addition of fibronectin to the dECM most effectively induces the differentiation of PDLSCs into osteoblast-like and odontoblast-like cells under 3D culture conditions. Therefore, this bioengineered construct has a high potential for future use in periodontal tissue regeneration.

Decellularized Matrix Induced Spontaneous Odontogenic and Osteogenic Differentiation in Periodontal Cells.

The regeneration of periodontal tissues is a decisive factor in the treatment of periodontitis. Currently, to achieve complete periodontal regeneration, many studies have evaluated the effectiveness of decellularized tissue-engineered constructs on periodontal regeneration. We studied the possibilities of osteogenic and odontogenic differentiation of periodontal progenitor and stem cells (SCs) of the periosteum and periodontal ligament, in decellularized tooth matrix (dTM) and periodontal ligament (dPDL), in 2D and 3D culture. The cell culture of periodontal cells without decellularized matrices was used as control. On the 14th day of cultivation of PDLSCs, PSCs, and PDLSCs + PSCs on dTM and/or dPDL scaffolds in 2D conditions, in all scaffold variants, a dense monolayer of spindle-shaped cells was intensely stained for markers of osteogenic differentiation, such as osteopontin and osteocalcin. Periodontal cells in the collagen I hydrogel (3D-dimensional culture) were more diverse in shape and, in combination of dTM and dPDL, in addition to osteogenic expression, expressed dentin sialophosphoprotein, an odontogenic differentiation marker. Thus, collagen I hydrogel contributed to the formation of conditions similar to those in vivo, and the combination of dTM with dPDL apparently formed a microenvironment that promoted osteogenic and odontogenic differentiation of periodontal cells.

Modern Approaches to Acellular Therapy in Bone and Dental Regeneration.

An approach called cell-free therapy has rapidly developed in regenerative medicine over the past decade. Understanding the molecular mechanisms and signaling pathways involved in the internal potential of tissue repair inspires the development of new strategies aimed at controlling and enhancing these processes during regeneration. The use of stem cell mobilization, or homing for regeneration based on endogenous healing mechanisms, prompted a new concept in regenerative medicine: endogenous regenerative medicine. The application of cell-free therapeutic agents leading to the recruitment/homing of endogenous stem cells has advantages in overcoming the limitations and risks associated with cell therapy. In this review, we discuss the potential of cell-free products such as the decellularized extracellular matrix, growth factors, extracellular vesicles and miRNAs in endogenous bone and dental regeneration.

Claudins as biomarkers of differential diagnosis and prognosis of tumors.

Claudins are a superfamily of transmembrane proteins, the optimal expression and localization of which are important for the normal physiological function of the epithelium and any imbalance may have pathological consequences. Not only insufficient but also excessive production of claudins in cancer cells, as well as their aberrant localization, equally manifest the formation of a malignant phenotype. Many works are distinguished by contradictory data, which demonstrate the action of the same claudins both in the role of tumor-growth suppressors and promoters in the same cancers. The most important possible causes of significant discrepancies in the results of the works are a considerable variability of sampling and the absence of a consistent approach both to the assessment of the immune reactivity of claudins and to the differential analysis of their subcellular localization. Combined, these drawbacks hinder the histological assessment of the link between claudins and tumor progression. In particular, ambiguous expression of claudins in breast cancer subtypes, revealed by various authors in immunohistochemical analysis, not only fails to facilitate the identification of the claudin-low molecular subtype but rather complicates these efforts. Research into the role of claudins in carcinogenesis has undoubtedly confirmed the potential value of this class of proteins as significant biomarkers in some cancer types; however, the immunohistochemical approach to the assessment of claudins still has limitations, needs standardization, and, to date, has not reached a diagnostic or a prognostic value.

Chelyabinsk airburst, damage assessment, meteorite recovery, and characterization.

The asteroid impact near the Russian city of Chelyabinsk on 15 February 2013 was the largest airburst on Earth since the 1908 Tunguska event, causing a natural disaster in an area with a population exceeding one million. Because it occurred in an era with modern consumer electronics, field sensors, and laboratory techniques, unprecedented measurements were made of the impact event and the meteoroid that caused it. Here, we document the account of what happened, as understood now, using comprehensive data obtained from astronomy, planetary science, geophysics, meteorology, meteoritics, and cosmochemistry and from social science surveys. A good understanding of the Chelyabinsk incident provides an opportunity to calibrate the event, with implications for the study of near-Earth objects and developing hazard mitigation strategies for planetary protection.