Mesenchymal stromal cell secretome in liver failure: Perspectives on COVID-19 infection treatment

Due to their immunomodulatory potential and release of trophic factors that promote healing, mesenchymal stromal cells (MSCs) are considered important players in tissue homeostasis and regeneration. MSCs have been widely used in clinical trials to treat multiple conditions associated with inflammation and tissue damage. Recent evidence suggests that most of the MSC therapeutic effects are derived from their secretome, including the extracellular vesicles, representing a promising approach in regenerative medicine application to treat organ failure as a result of inflammation/fibrosis. The recent outbreak of respiratory syndrome coronavirus, caused by the newly identified agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has forced scientists worldwide to use all available instruments to fight the infection, including the inflammatory cascade caused by this pandemic disease. The use of MSCs is a valid approach to combat organ inflammation in different compartments. In addition to the lungs, which are considered the main inflammatory target for this virus, other organs are compromised by the infection. In particular, the liver is involved in the inflammatory response to SARS-CoV-2 infection, which causes organ failure, leading to death in coronavirus disease 2019 (COVID-19) patients. We herein summarize the current implications derived from the use of MSCs and their soluble derivatives in COVID-19 treatment, and emphasize the potential of MSC-based therapy in this clinical setting.     

Preoperative Carcinoembryonic Antigen and Prognosis of Colorectal Cancer. An Independent Prognostic Factor Still Reliable

To evaluate whether, in a sample of patients radically treated for colorectal carcinoma, the preoperative determination of the carcinoembryonic antigen (p-CEA) may have a prognostic value and constitute an independent risk factor in relation to disease-free survival. The preoperative CEA seems to be related both to the staging of colorectal neoplasia and to the patient''s prognosis, although this—to date—has not been conclusively demonstrated and is still a matter of intense debate in the scientific community. This is a retrospective analysis of prospectively collected data. A total of 395 patients were radically treated for colorectal carcinoma. The preoperative CEA was statistically compared with the 2010 American Joint Committee on Cancer (AJCC) staging, the T and N parameters, and grading. All parameters recorded in our database were tested for an association with disease-free survival (DFS). Only factors significantly associated (P < 0.05) with the DFS were used to build multivariate stepwise forward logistic regression models to establish their independent predictors. A statistically significant relationship was found between p-CEA and tumor staging (P < 0.001), T (P < 0.001) and N parameters (P = 0.006). In a multivariate analysis, the independent prognostic factors found were: p-CEA, stages N1 and N2 according to AJCC, and G3 grading (grade). A statistically significant difference (P < 0.001) was evident between the DFS of patients with normal and high p-CEA levels. Preoperative CEA makes a pre-operative selection possible of those patients for whom it is likely to be able to predict a more advanced staging.Key words: Colorectal carcinoma, Preoperative carcinoembryonic antigen, Disease-free survival, Independent prognostic factorIn the world today, more than 1 million cases of patients with colorectal neoplasia are identified each year. Forty percent of these will have a poor prognosis for which targeted therapeutic strategies could most likely be more effective.^1–3 For this reason, finding prognostic factors that are early, reliable, and related to the extent of the tumor is of the utmost importance. Among these, the most that are considered even to this day are T and N parameters.^1,2,4,5 Less relied upon, however, is the M parameter, which is often understaged due to inadequate pretreatment diagnostic methods.⁶ However, these parameters, which are available to us only after surgery, do not represent the gold standard. In fact, the prognosis of patients with the same staging is often various and that the need to continually implement ever-changing variables in an already excessively fragmented staging is still present.^2,4,7–9Recently, in light of these needs, great attention has been paid to the study of molecular and genetic markers. At present, these markers still have not found a regular application due to the complexity of their determination, the difficulty of standardization and, last but not least, the low cost-benefit ratio.^1,3,4,9,10With this in mind, in our opinion, the carcinoembryonic antigen (CEA) maintains its position, as for over 30 years it has continued to be the most widely used marker¹¹ and whose validity, with regard to colorectal follow-up, has been sanctioned by leading organizations such as the American Society of Clinical Oncology (ASCO)¹² and the European Group on Tumor Markers.¹³ Moreover, as Herrera¹⁴ and Wanebo¹⁵ had already reported by the end of the ‘70s, the preoperative determination of the CEA (p-CEA) seems to be related both to the staging of colorectal neoplasia and to the patient''s prognosis. However, to date, none of this has been conclusively demonstrated and is still a matter of intense debate both in prestigious scientific journals^{4,7,11,16–21} as well as in different guidelines.²²The American Society of Clinical Oncology itself, if on the one hand suggests using the determination of the CEA in the preoperative staging thus justifying a worse prognosis when increased,¹² on the other, does not validate using the p-CEA in the determination of an adjuvant or neo-adjuvant therapeutic strategy.²³Regarding this issue, we believe it still pertinent to evaluate whether in a sample of patients radically treated for colorectal carcinoma, the determination of the p-CEA may have a prognostic value and constitute an independent risk factor in relation to disease-free survival (DFS).     

Immunohistochemical analysis of IL-1 Receptor 1 in the discs of patients with temporomandibular joint dysfunction

Objective Temporomandibular joint dysfunction (TMD) may affect a patient’s quality of life, and one of the etiologies can be anterior disc displacement with reduction (ADDwR) and anterior disc displacement without reduction (ADDWoR). Interleukin 1 Receptor 1 (IL-1R1) is a membrane receptor that plays an important role on initiating immune and inflammatory response by binding the agonists ligands of IL-1 alpha and IL-1 beta. Therefore, the aim of this study was to evaluate, through immunohistochemical analysis, the association of IL-1R1 with TMD.

Methods Thirty-nine human disc samples were collected and composed three different groups: ADDwR (n = 19), ADDwoR (n = 12), and control group (n = 8). The samples were immunostained with IL-1R1 antibody and evaluated on both quantity and intensity of staining.

Results There was a statistically significant difference (p < 0.05) between the control and test groups for both quantity and intensity of staining.

Conclusion IL1-R1 was associated with ADDwR and ADDwoR in TMD discs of humans.     

Fibronectin upregulation in human temporomandibular joint disks with internal derangement

Fibronectin is a large fibril-forming extracellular glycoprotein that seems to be involved in joint diseases. The objective of this study was to investigate the expression of fibronectin in human temporomandibular joint disks obtained from patients with internal derangement and varying extents of disk tissue degeneration/regeneration with that of temporomandibular joint disks free of significant morphological alterations by means of immunohistochemical methods. Twelve adult human temporomandibular joint disks (10 diseased disks and 2 normal disks) were used in this study. Temporomandibular joint disks were fixed in 10% buffered formalin. Sections were then immunohistochemically processed using a monoclonal antibody specific to human fibronectin and streptavidin-biotin detection methods. Positive reactions to fibronectin were found in normal and diseased disk tissues but to a different extent. Normal disk tissues revealed weak fibronectin expression, which was mainly located along the collagen bundles. Temporomandibular joint disks with internal derangement exhibited a higher immunoreactivity. Distinct reticular fibronectin structures were found inside the diseased disk, particularly nearby the newly formed blood vessels, tears, and clefts. In the covering layer of the disk surface, fibronectin was expressed in a fascicular pattern running parallel to the disk surface. The findings suggest that temporomandibular joint disk tissue can express fibronectin and that the expression is more pronounced in disk specimens of patients with internal derangement of the temporomandibular joint, supporting a role of this glycoprotein in the degeneration/regeneration processes of human temporomandibular joint disk tissue.     

Micronized palmitoylethanolamide reduces joint pain and glial cell activation

Objective and design

Temporomandibular disorder (TMD) is a common painful condition in the temporomandibular joint (TMJ). Joint inflammation is believed to be a chief cause of pain in patients with TMD, through the release of pro-inflammatory cytokines that induce peripheral sensitization of nerve terminals followed by microglial stimulation.

Materials and subject

TMJ was induced in rats with the injection of complete Freund’s adjuvant (CFA) emulsion into the left TMJ capsule.

Treatment

The present study would assess the effects of micronized palmitoylethanolamide (m-PEA) on glial activation and trigeminal hypersensitivity.

Methods

Ten mg/kg m-PEA or corresponding vehicle was administered 1 h after CFA and mechanical allodynia and edema were evaluated at 24 and 72 h after CFA injection.

Results

CFA-injected animals showed TMJ edema and ipsilateral mechanical allodynia accompanied by a robust growth in GFAP protein-positive satellite glial cells and activation of resident macrophages in the TG. Moreover, m-PEA administration significantly reduced the degree of TMJ damage and pain, macrophage activation in TG and up-regulation of Iba1.

Conclusions

The results confirm that m-PEA could represent a novel approach for monitoring pain during trigeminal nerve sensitization.