Search

Summary: Given recent leverage of mesenchymal stromal cells (MSCs) as a potent vaccination platform, we investigated whether forced degradation of an expressed experimental antigen fused to small degron sequences could prime potent antitumoral responses. Retrovirally gene-engineered MSCs were evaluated for their in-vitro antigen presentation capacity, nature of generated peptide repertoire and therapeutic potency in syngeneic immunocompetent mice with pre-established solid T cell lymphoma. Despite lack of noticeable changes in gene expression, MSC-UBvR-OVA vaccination triggered potent T cell activation which can be attributable to the enriched cell surface presentation of OVA-derived peptides added to elevated mitochondrial reactive oxidative species (ROS) production, the latter being associated with efficient antigen processing. Where MSC-UBvR-OVA vaccination successfully controlled tumor growth in cancer-bearing mice, the effect is further enhanced using tranylcypromine-stimulated MSCs and anti-PD-1 combination. Such anti-tumoral response relies on efferocytosis by endogenous phagocytes. Altogether, UBvR facilitated forced antigen degradation represents a plausible modality for future development of tumor antigen-expressing MSC-based vaccine.

Introduction: Myocardial dysfunction is an important complication in the context of juvenile idiopathic arthritis (JIA). Several mechanisms might be involved in the induction of myocardial injury in such a disa - bling disease. Among several factors involved, myo - cardial inflammation and cardiotoxic drugs were thought to be the most incriminated factors. The aim of this work was to determine the most important factors that implicated myocardial injury in JIA and to weigh whether the severity of inflammation varies significantly among the several subtypes or not. Methods: Sixty JIA patients as well as sixty, age and surface area, matched controls were subjected to conventional echocardiography, 3D Speckle tracking and the disease activity was measured as by Juvenile Arthritis Disease Score 27 (JADAS 27). Results: JIA cases showed statistically significant systolic and diastolic dysfunction when compared to controls. Global longitudinal strain (GLS) (index of systolic function) was lower in cases compared to controls (JIA: 16.1±6.7 vs Controls: 23.9±1.4, P<0.0001), Left Ventricular ratio of early diastolic mitral inflow velocity to average of early diastolic velocities of the mitral annulus and basal septum (LV E/E') (index of diastolic function) was higher in cases compared to controls (JIA: 14.8±7 vs. Controls: 5.9±1.3, P<0.0001). There was no statistically significant difference in echocardiographic parameters as well as JADAS 27 between subtypes of JIA patients. Multivariate analysis showed that the best predictor of both systolic and diastolic involvement of the myocardium in JIA patients was the severity of inflammation rather than the duration or the type of medications used. Conclusion: This study points out the potential of inflammation as an important inducer of myocardial injury in JIA. It also underlines the fact that this inflammation does not differ significantly according to the disease subtype. [ABSTRACT FROM AUTHOR]

Abstract Background Trans-ulnar approach was proposed primarily for elective procedures in patients not suitable for trans-radial approach that was introduced two decades ago. The trans-ulnar approach is as safe and effective as the trans-radial approach for coronary angiography and intervention. Aim This study’s aim was to assess the feasibility and safety of the trans-ulnar approach in coronary procedures as a preliminary experience for operators experienced in trans-radial approach with no/minimal trans-ulnar approach experience at an Egyptian center. Results Vascular access in 120 patients was selected randomly for coronary angiography and angioplasty—80 through radial and 40 through ulnar approach. Patients were examined for local complications and Doppler evaluation to both radial and ulnar arteries a day after the procedure was done. Ulnar approach success was 82.5% versus 93.7% in the radial group; failure of ulnar artery puncture was the only cause of crossover in the ulnar group, while occurrence of persistent spasm was the leading cause of crossover in the radial group followed by radial artery tortuosity. The procedure time of coronary angiography and percutaneous coronary intervention of the ulnar group was significantly higher than that of the radial group (P value = 0.011 and 0.034, respectively). The mean caliber of the right ulnar artery was 2.45 ± 0.38, slightly larger than that of the radial artery 2.33 ± 0.38 at the level of the wrist, but this difference was statistically non-significant. Conclusion Our study demonstrated that ulnar access with experienced radial operators and in our patients is a safe and practical approach for coronary angiography or angioplasty, without any major complications. Bearing in mind its high success rate, it can be used when a radial artery is not useful for the catheterization or as a default approach on the expense of slightly longer procedural time.

The importance of the Density Functional Theory (DFT) calculation approach lies in their ability to provide a highly accurate prediction of structural and optoelectronic properties. However, the traditional methods of DFT failed to predict optoelectronic properties satisfactorily. Therefore, it will be necessary to examine methods containing different percentages of Hartree-Fock exchange and correlation in order to find the most suitable functionals. DFT and Time-Dependent-DFT (TD-DFT) calculations was carried out using four different functionals approximations incorporating a different amount of Hartree Fock exchange (B3LYP, BHandHLYP, CAM-B3LYP and LCωPBE), in order to evaluate their accuracies to predict the geometrical, optoelectronic and charge transfer properties of four triphenylamine-based dyes for Dye-Sensitized Solar Cells (DSSCs) applications. The functional hybrid B3LYP was the best among adopted functional that reproduced the geometrical, optoelectronic and charge transfer properties. On the other hand, it has been shown that the Hartree-Fock exchange percentage for BHandHLYP, significantly improved TD-DFT results in the case of organic dyes. Moreover, the corrected long-range functionals (CAM-B3LYP and LC-wPBE) present valuable tools for giving results of comparable precision with experimental optical data. In terms of the choice of the most appropriate functional for computational calculation, the obtained results can be useful for future DSSC applications. DOI: http://dx.doi.org/10.17807/orbital.v14i1.1682

Mesenchymal stromal cells (MSCs) are largely known for their immune-suppressive capacity, hence, their common use in the control of unwanted inflammation. However, novel concepts related to their biology, combined with the urgent need to identify MSC subpopulations with enhanced suppressive properties, drive the search for isolation protocols optimized for clinical applications. We show, in this study, that MSCs expressing high CD146 levels exhibit altered surface expression profiles of CD44 and secrete elevated levels of interleukin (IL)-6, amongst other factors. In addition, CD146hi MSCs surpass the polyclonal parental populations in inhibiting alloreactive T cells in vitro, in both a soluble- and cell-contact-dependent manner. Despite the lack of CD146hi MSC-mediated activation of peritoneal macrophages to release the suppressive factor IL-10 in vitro, their administration in animals with graft-versus-host disease alleviates inflammation and leads to 40% survival rate up to 7 weeks post-transplantation. This pronounced inhibitory property is driven by CD146-mediated in situ efferocytosis by myeloid cells. Altogether, this study provides the impetus to adopt an isolation protocol for MSCs based on a CD146 expression profile before their therapeutic use and suggests a major role played by CD146 as a novel “eat-me” signal, capable of enhancing MSC uptake by competent phagocytes.

Competing Interests: Declarations. Disclosures: On behalf of all authors, the corresponding author states that there is no conflict of interest. Disclaimer: The funding source had no role in the development of this manuscript.

Within psychiatry, the proportions of individuals underrepresented in medicine (URM) are lower than are the proportions among the general U.S. population. Holistic review of residency applications may alleviate deficiencies in representation and disparities in care.  A holistic review process was implemented (2021-2022) in the University of California, San Diego, psychiatry residency program. The data (2016-2022) were extracted from the Electronic Residency Application Service to compare differences in the applicant pool before and after implementation of the holistic review.  A total of 6,602 individuals applied to the program between 2016 and 2022, increasing from 762 in 2016 to 1,148 in 2021. The proportion of women applying significantly increased (χ 2 =12.6, p<0.002), from 42.3% in 2016 to 50.6% in 2022. Across all years, a significantly greater proportion (χ 2 =22.0, p<0.001) of those selected to interview were women (55.1%), with the greatest proportion in 2022 (64.5%), after implementation of the holistic review. The proportion of applicants from URM groups significantly increased (χ 2 =28.0, p<0.001), from 13.4% in 2016 to 21.3% in 2022. There were no significant differences in the proportion of these applicants selected to interview across all years and no increase following the holistic review.  The proportion of women interviewed was greater than the proportion of women who applied, particularly after implementing the holistic review. The proportion of applicants from URM groups increased over time and, although the proportion interviewed remained greater than the number applying, that number did not change across the years studied., Competing Interests: The authors report no financial relationships with commercial interests., (Copyright © 2024 by the American Psychiatric Association.)

COVID-19 has shown a substantial variation in the rate and severity by which it impacts different demographic groups. Specifically, it has shown a predilection towards obese patients as well as well as other vulnerable groups including predilection of males over females, old age over young age and black races over Caucasian ones. Single cell sequencing studies have highlighted the role of cell polarity and the co-expression of proteases, such as Furin, along with ACE2 in the genesis of coronavirus disease rather than exclusively link tissue involvement with ACE2 levels thought previously. It has also forged a connection between the genetic and immune cellular mechanisms underlying COVID infection and the inflammatory state of obese patients, offering a more accurate explanation as to why obese patients are at increased risk of poor COVID outcomes. These commonalities encompass macrophage phenotype switching, genetic expression switching, and overexpression of the pro-inflammatory cytokines, depletion of the regulatory cytokines, in situ T cell proliferation, and T cell exhaustion. These findings demonstrate the necessity of single cell sequencing as a rapid means to identify and treat those who are most likely to need hospital admission and intensive care, in the hopes of precision medicine. Furthermore, this study underlines the use of immune modulators such as Leptin sensitizers, rather than immune suppressors as anti-inflammation therapies to switch the inflammatory response from a drastic immunological type 1 response to a beneficial type 2 effective one., Competing Interests: Authors declare that there is no conflict of interest., (© 2020 Elsevier Ltd. All rights reserved.)

Furin, a cleavage enzyme, is increasingly recognized in the pathogenesis of metabolic syndrome. Its cleavage action is an essential activation step for the endothelial pathogenicity of several viruses including SARS-CoV-2. This Furin-mediated endothelial tropism seems to underlie the multi-organ system involvement of COVID-19; which is a feature that was not recognized in the older versions of coronaviridae. Obese and diabetic patients, males, and the elderly, have increased serum levels of Furin, with its increased cellular activity; this might explain why these subgroups are at an increased risk of COVID-19 related complications and deaths. In contrast, smoking decreases cellular levels of Furin, this finding may be at the origin of the decreased severity of COVID-19 in smokers. Chinese herbal derived luteolin is suggested to be putative Furin inhibitor, with previous success against Dengue Fever. Additionally, Furin intracellular levels are largely dependent on concentration of intracellular ions, notably sodium, potassium, and magnesium. Consequently, the use of ion channel inhibitors, such as Calcium Channel blockers or Potassium Channel blockers, can prevent cellular transfection early in the course of the illness. Nicotine patches and Colchicine have also been suggested as potential therapies due to Furin mediated inhibition of COVID-19., Competing Interests: The authors declare that there is no conflict of interest., (© 2020 Elsevier Ltd. All rights reserved.)

Coronavirus disease 2019 (COVID-19) is a serious illness that has rapidly spread throughout the globe. The seriousness of complications puts significant pressures on hospital resources, especially the availability of ICU and ventilators. Current evidence suggests that COVID-19 pathogenesis majorly involves microvascular injury induced by hypercytokinemia, namely interleukin 6 (IL-6). We recount the suggested inflammatory pathway for COVID-19 and its effects on various organ systems, including respiratory, cardiac, hematologic, reproductive, and nervous organ systems, as well examine the role of hypercytokinemia in the at-risk geriatric and obesity subgroups with upregulated cytokines' profile. In view of these findings, we strongly encourage the conduction of prospective studies to determine the baseline levels of IL-6 in infected patients, which can predict a negative outcome in COVID-19 cases, with subsequent early administration of IL-6 inhibitors, to decrease the need for ICU admission and the pressure on healthcare systems. Video abstract: http://links.lww.com/CAEN/A24., Competing Interests: There are no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)