Антиангиогенный потенциал бета-адреноблокаторов в аспекте лечения ювенильных гемангиом

Juvenile hemangiomas (JH) — the most common tumor of childhood, which is estimated by various investigators found in 3–10 % of newborns resulting from the local development of significant violations of neoangiogenesis regulation. Research objective: determination of comparative antiangiogenic effectiveness and influence of beta-blockers on the level of a vascular endothelial factor of growth in an experiment. Material and methods. For determination of antiangiogenic effect of beta blockers, comparative studying of their influence on the level of a vascular endothelial factor of growth in an experiment on 72 nonlinear laboratory rats, by average weight 180 ± 20 g which were conditionally divided into 6 groups is executed: 1 — control, 2 — negative control — experimental ischemia (EI, crossing of femoral vessels), 3 — positive control (EI with bevacizumab introduction), 4 — EI with introduction of a timolol, 5 — EI with introduction of a betaksolol, 6 — EI with introduction of interferon alpha 2b. Results. The VEGF levels were: in 1 group — 1.50 ± 0.3 pg/ml, in 2 — 20.3 ± 3.2 pg/ml, 3 — 5.8 ± 0.9 pg/ml, 4 — 13.8 ± 1.4 pg/ml, 5 — 19.2 ± 2.3 pg/ml and 6 — 11.1 ± 2.2 pg/ml. Results of microscopy and immunohistochemical research demonstrate lack of activation of processes of neoangiogenesis in 1 group of animals. At animals of 2nd and 5th groups along with the expressed inflammatory processes the neoangiogenesis phenomena are established. Conclusion. Beta-blockers show the direct or mediated negative impact on synthesis of VEGF and oppression of neoangiogenesis. The activity of selective beta-blocker concerning neoangiogenesis suppression — was lower in comparison by activity non-selective that allows to consider the Timolol effective antiangiogenic remedy.Ювенильные гемангиомы (ЮГ) — наиболее распространенные опухоли детского возраста, которые, по оценкам различных исследователей, встречаются у 3–12 % новорожденных; возникающие при локальном развитии значительных нарушений регуляции неоангиогенеза. Цель исследования: определение сравнительной антиангиогенной эффективности и влияния бета-адреноблокаторов на уровень сосудистого эндотелиального фактора роста в эксперименте. Материалы и методы. Для определения антиангиогенного эффекта бета-адреноблокаторов выполнено сравнительное изучение их влияния на уровень сосудистого эндотелиального фактора роста в эксперименте на 72 нелинейных лабораторных крысах средней массой 180 ± 20 г, которые были условно разделены на 6 групп: 1 — контрольная, 2 — отрицательный контроль — экспериментальная ишемия (ЭИ, пересечение бедренных сосудов), 3 — положительный контроль (ЭИ с введением бевацизумаба), 4 — ЭИ с введением тимолола, 5 — ЭИ с введением бетаксолола, 6 — ЭИ с введением интерферона альфа-2b. Результаты. Уровни VEGF составили: в 1-й группе 1,50 ± 0,3 пг/мл, во 2-й — 20,3 ± 3,2 пг/мл, в 3-й — 5,8 ± 0,9 пг/мл, в 4-й — 13,8 ± 1,4 пг/мл, в 5-й — 19,2 ± 2,3 пг/мл и в 6-й — 11,1 ± 2,2 пг/мл. Результаты микроскопии и ИГХИ свидетельствуют об отсутствии активации процессов неоангиогенеза в 1 группе животных. У животных 2 и 5 групп наряду с выраженными воспалительными процессами установлены явления неоангиогенеза. Заключение. Бета-адреноблокаторы проявляют прямое или опосредованное негативное влияние на синтез VEGF и угнетение неоангиогенеза. Активность селективного бета-адреноблокатора в отношении подавления неоангиогенеза была ниже по сравнению активностью неселективного, что позволяет считать тимолол эффективным антиангиогенным средством

Activation of the Listeria monocytogenes Virulence Program by a Reducing Environment.

Upon entry into the host cell cytosol, the facultative intracellular pathogen Listeria monocytogenes coordinates the expression of numerous essential virulence factors by allosteric binding of glutathione (GSH) to the Crp-Fnr family transcriptional regulator PrfA. Here, we report that robust virulence gene expression can be recapitulated by growing bacteria in a synthetic medium containing GSH or other chemical reducing agents. Bacteria grown under these conditions were 45-fold more virulent in an acute murine infection model and conferred greater immunity to a subsequent lethal challenge than bacteria grown in conventional media. During cultivation in vitro, PrfA activation was completely dependent on the intracellular levels of GSH, as a glutathione synthase mutant (ΔgshF) was activated by exogenous GSH but not reducing agents. PrfA activation was repressed in a synthetic medium supplemented with oligopeptides, but the repression was relieved by stimulation of the stringent response. These data suggest that cytosolic L. monocytogenes interprets a combination of metabolic and redox cues as a signal to initiate robust virulence gene expression in vivoIMPORTANCE Intracellular pathogens are responsible for much of the worldwide morbidity and mortality from infectious diseases. These pathogens have evolved various strategies to proliferate within individual cells of the host and avoid the host immune response. Through cellular invasion or the use of specialized secretion machinery, all intracellular pathogens must access the host cell cytosol to establish their replicative niches. Determining how these pathogens sense and respond to the intracellular compartment to establish a successful infection is critical to our basic understanding of the pathogenesis of each organism and for the rational design of therapeutic interventions. Listeria monocytogenes is a model intracellular pathogen with robust in vitro and in vivo infection models. Studies of the host-sensing and downstream signaling mechanisms evolved by L. monocytogenes often describe themes of pathogenesis that are broadly applicable to less tractable pathogens. Here, we describe how bacteria use external redox states as a cue to activate virulence

Comprehensive User Engagement Sites (CUES) in Philadelphia: A Constructive Proposal

This paper is a study about Philadelphia’s comprehensive user engagement sites (CUESs) as the authors address and examine issues related to the upcoming implementation of a CUES while seeking solutions for its disputed questions and plans. Beginning with the federal drug schedules, the authors visit some of the medical and public health issues vis-à-vis safe injection facilities (SIFs). Insite, a successful Canadian SIF, has been thoroughly researched as it represents a paradigm for which a Philadelphia CUES can expand upon. Also, the existing criticisms against SIFs are revisited while critically unpackaged and responded to in favor of the establishment. In the main section, the authors propose the layout and services of the upcoming CUES, much of which would be in congruent to Vancouver’s Insite. On the other hand, the CUES would be distinct from Insite, as the authors emphasize, in that it will offer an information center run by individuals in recovery and place additional emphasis on early education for young healthcare professionals by providing them a platform to work at the site. The paper will also briefly investigate the implementation of a CUES site under an ethical scope of the Harm Reduction Theory. Lastly, the authors recommend some strategic plans that the Philadelphia City government may consider employing at this crucial stage

Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment.

Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1+PD1loCD62L- CD8+ T cells. These IFNγ-producing effector CD8+ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)+CD206- M1 phenotype. Remarkably, these LADD-Ag-induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8+ T cells

A Potent and Effective Suicidal Listeria Vaccine Platform.

Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenes recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens. Lm-RIID grows normally in broth but commits suicide inside host cells by inducing Cre recombinase and deleting essential genes flanked by loxP sites, resulting in a self-limiting infection even in immunocompromised mice. Lm-RIID vaccination of mice induces potent CD8+ T cells and protects against virulent challenges, similar to live L. monocytogenes vaccines. When combined with α-PD-1, Lm-RIID is as effective as live-attenuated L. monocytogenes in a therapeutic tumor model. This impressive efficacy, together with the increased clearance rate, makes Lm-RIID ideal for prophylactic immunization against diseases that require T cells for protection

Comprehensive User Engagement Sites (CUES): Is This a Viable Option for the Opioid Epidemic in Philadelphia?

INTRODUCTION: Opioid drug abuse has become an increasing concern throughout the United States, especially within the Philadelphia region. In 2017, the number of deaths by drug overdose were four times that of deaths by homicide. In addition, a total of 935 cases of secondary conditions due to needle sharing such as HIV and HCV occurred during the past year. The opioid epidemic has caused a public health emergency and any measures that could decrease the morbidity and mortality associated with opioid abuse are vital. A current proposal to combat this issue in Philadelphia is the implementation of a Comprehensive User Engagement Site (CUES); a site intended to offer medical resources and assistance for opioid users. This study analyzed the clinical, ethical, and economic considerations associated with a potential CUES site in Philadelphia. METHODS: A review of the literature was conducted using PubMed, EMBASE, and various public data sources. Search keywords included the history and efficacy of safe injection facilities (SIFs), their implementation to Philadelphia, and other related terms. Semi-structured discussion sessions were also conducted among members of the Institute of Clinical Bioethics at Saint Joseph’s University, resident physicians at Mercy Health System, and PCOM medical students. Topics of discussion included the risks, benefits, and ethics involved in initiating a CUES in Philadelphia, with research regarding past SIFs being uses as a comparative model. RESULTS: The impact of a CUES in Philadelphia has been estimated to avert 3-48 cases of HIV infections annually, 15-213 cases of HCV infections annually, and between 24-76 deaths. In addition, the site is estimated to reduce costs due to skin infection by $1.5-1.9 Million annually, costs due to overdose deaths by upwards of$75 Million annually, as well as costs related to ambulance and hospital visits by $123,000 and$300,000 per averted case respectively. Ethical analysis revealed that safe injection is ethically permissible given the primary intent is to limit the user’s exposure to harm. DISCUSSION: The implementation of a CUES in Philadelphia may be an effective tool to address opioid crisis. It would reduce healthcare costs through prevention of drug-related sequelae, offer treatment and resources for people seeking to overcome their opioid dependence, and act as an educational opportunity for future healthcare professionals by promoting student engagement with marginalized populations