Distant Effects Research Articles

Systemic disorders of brain functions in distant period of explosive closed brain injury: clinical case

The paper presents of clinical case of brain traumatic disease course after explosive injury. It was included about forming systemic disorders of brain in distant period based on of patient complaints, anamnesis of disease, data of neurological status as well as results neurophysiological and neuropsychological examinations. This pathology is manifested as functional impairment of non-specific system of brain on all levels of organization with domination of mediobasal temporal area dysfunction with involvement of parietal-temporal section of cortex. Case presented points to necessity of durable neurological observation of patients with this pathology for timely diagnosis and treatment of complications as well as for providing of patients psychical and social adaptation. Keywords: explosive closed brain injury, distant eff ects, systemic disorders of brain

IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase–associated lipocalin during acute kidney injury

Neutrophil gelatinase associated lipocalin (NGAL, Lcn2) is the most widely studied biomarker of acute kidney injury (AKI). Previous studies have demonstrated that NGAL is produced by the kidney and released into the urine and plasma. Consequently, NGAL is currently considered a tubule specific injury marker of AKI. However, the utility of NGAL to predict AKI has been variable suggesting that other mechanisms of production are present. IL-6 is a proinflammatory cytokine increased in plasma by two hours of AKI and mediates distant organ effects. Herein, we investigated the role of IL-6 in renal and extra-renal NGAL production. Wild type mice with ischemic AKI had increased plasma IL-6, increased hepatic NGAL mRNA, increased plasma NGAL, and increased urine NGAL; all reduced in IL-6 knockout mice. Intravenous IL-6 in normal mice increased hepatic NGAL mRNA, plasma NGAL and urine NGAL. In mice with hepatocyte specific NGAL deletion (Lcn2hep-/-) and ischemic AKI, hepatic NGAL mRNA was absent, and plasma and urine NGAL were reduced. Since urine NGAL levels appear to be dependent on plasma levels, the renal handling of circulating NGAL was examined using recombinant human NGAL. After intravenous recombinant human NGAL administration to mice, human NGAL in mouse urine was detected by ELISA during proximal tubular dysfunction, but not in pre-renal azotemia. Thus, during AKI, IL-6 mediates hepatic NGAL production, hepatocytes are the primary source of plasma and urine NGAL, and plasma NGAL appears in the urine during proximal tubule dysfunction. Hence, our data change the paradigm by which NGAL should be interpreted as a biomarker of AKI.

Changes in the Multipotent Stromal Mesenchymal Cells from the Bone Marrow of the Patients with Hematological Diseases in Debut and after the Treatment

Introduction. Stromal microenvironment of the bone marrow (BM) is essential for normal hematopoiesis; the very same cells are involved in the interaction with the leukemic stem cells. The aim of the study was to reveal the alterations in stromal microenvironment of patients in debut and after the therapy using multipotent mesenchymal stromal cells (MSC) as a model. Methods. MSC of patients with acute myeloid leukemia (AML, N=32), acute lymphoblastic leukemia (ALL, N=20), chronic myeloid leukemia (CML, N=19), and diffuse large B-cell lymphoma without BM involvement (DLBCL, N=17) were isolated by standard method from the patients' BM. Each BM sample was acquired during diagnostic aspiration after the informed signed consent was obtained from the patient. Groups of BM donors comparable by age and gender were used as controls for each nosology. Gene expression was analyzed with real-time RT-PCR. The significance of differences was evaluated with Mann-Whitney U-test. Results. The results of gene expression analysis are summarized in Table. The expression of genes regulating hematopoietic stem and precursor cells (JAG1, LIF, IL6) was significantly upregulated in MSC of the patients in debut, except for DLBCL. The latter was characterized with upregulation of osteogenic marker gene SPP1 and downregulation of FGFR1 gene. The upregulation of the expression of genes regulating proliferation of stromal cells (PDGFRA, FGFR1) and adipogenic marker gene (PPARG) was common for AML and CML. Both acute leukemias were characterized by the upregulation of genes associated with inflammation and regulation of hematopoietic precursors (CSF1, IL1B, IL1BR1) and by the downregulation of chondrogenic differentiation marker gene (SOX9). CML and DLBCL demonstrated the upregulation of FGFR2. BM of the DLBCL patients did not contain any malignant cells; nevertheless, stromal precursors from the BM were significantly affected. This indicates the distant effects of DLBCL malignant cells on the patients' BM. Myeloid malignancies seem to affect MSC more profoundly then lymphoid ones. Effect of leukemic cells on stromal microenvironment in case of myeloid leukemia was more pronounced. The treatment significantly affected gene expression in MSC of patients. In all studied nosologies the IL6 gene expression was upregulated, which may reflect the inflammation processes ongoing in the organism. The expression of LIF was upregulated and ICAM1, downregulated in MSCs of AML, ALL, and CML patients. In the MSC of patients with AML, who had received the highest doses of cytostatic drugs to achieve remission, a significant decrease in the expression of most studied genes was found. In patients with ALL with long-term continuing treatment in combination with lower doses of drugs, IL1B expression was increased, while the decrease in expression was detected for a number of genes regulating hematopoietic stem cells (SDF1, TGFB1), differentiation and proliferation (SOX9, FGFR1, FGFR2). Treatment of CML patients is based on tyrosine kinase inhibitors in doses designed for long-term use, and is less damaging for MSC. The upregulation of TGFB1, SOX9, PDGFRA genes and downregulation of IL1B gene was revealed. MCS of DLBCL patients, unlike the other samples, were analyzed after the end of treatment. Nevertheless, significant upregulation of IL8 and FGFR2 genes was found. Thus, both the malignant cells and chemotherapy affect stromal precursor cells. The changes are not transient; they are preserved for a few months at least. MSCs comprise only a minor subpopulation in the BM in vivo. When expanded in vitro, they demonstrate significant changes between groups of patients and healthy donors. Conclusions. Leukemia cells adapt the stromal microenvironment. With different leukemia, the same changes are observed in the expression of genes in MSC. MSC of patients with acute forms have a lot of changes which coincide among these two diseases. MSC of AML patients are most affected both in debut and after the therapy. Treatment depends on the nosology and in varying degrees changes the MSC. This work was supported by the Russian Foundation for Basic Research, project no. 17-00-00170. Disclosures Chelysheva: Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy; Pfizer: Consultancy. Turkina:Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; fusion pharma: Consultancy.

Static magnetic field stimulation of the supplementary motor area modulates resting-state activity and motor behavior

Focal application of a strong static magnetic field over the human scalp induces measurable local changes in brain function. Whether it also induces distant effects across the brain and how these local and distant effects collectively affect motor behavior remains unclear. Here we applied transcranial static magnetic field stimulation (tSMS) over the supplementary motor area (SMA) in healthy subjects. At a behavioral level, tSMS increased the time to initiate movement while decreasing errors in choice reaction-time tasks. At a functional level, tSMS increased SMA resting-state fMRI activity and bilateral functional connectivity between the SMA and both the paracentral lobule and the lateral frontotemporal cortex, including the inferior frontal gyrus. These results suggest that tSMS over the SMA can induce behavioral aftereffects associated with modulation of both local and distant functionally-connected cortical circuits involved in the control of speed-accuracy tradeoffs, thus offering a promising protocol for cognitive and clinical research.

Signal feedback applications in low-field NMR and MRI.

Tuned pick-up coils with high quality factors Q are used in NMR and MRI for high-sensitivity and low-noise detection. However, large Q-factors introduce bandwidth issues at low frequency and the associated enhanced currents may cause significant radiation damping effects, especially with hyperpolarised samples. Signal feedback can be used to actively control these currents and adjust the detection bandwidth without resistive losses. Capacitive and inductive coupling methods are compared using detailed models and the operating conditions for efficient feedback with negligible noise penalty are discussed. Several high-impedance commercial preamplifiers have been found to affect the resonance characteristics of tuned coils in a gain-dependent way, or could not be used in low-frequency NMR because of oscillations at large positive gain. This is attributed to an undocumented internal feedback, and could be neutralised using external feedback. The implementation of an inductive coupling scheme to feed a suitably amplified phase-adjusted signal back into the PU coils of low-field NMR systems is described, and three experimental applications are reported. One system is used for NMR studies of distant dipolar field effects in highly polarised liquid 3He without or with radiation damping. The moderate intrinsic Q-factor (≈7) could be reduced (down to 1) or increased (up to 100) to control transient maser oscillations. Another system was used for MRI of water samples around 2 mT with Q≈190 litz-wire detection coils. The detection bandwidth was increased by actively reducing the Q-factor to obtain uniform sensitivities in images and avoid artifacts introduced by intensity corrections. Finally, parallel acquisition in MRI was performed using two separately tuned detection coils placed above and below the sample. They were actively decoupled using two feedback systems. For an imaging field of view smaller than the sample, artifact-free unfolded images demonstrate the efficiency of this active coil decoupling scheme.

Oxidative and histopathological effects of the application of electrosurgical devices to the penile tissue of rats

This study was performed to evaluate the oxidative and histopathological changes that occur following the application of electrosurgical devices (monopolar or bipolar cautery) to penile tissue. Eighteen Wistar albino male rats were randomly distributed into three groups. In the control group (CG, n=6), all penile tissues were sampled without any additional process following the administration of anesthesia. In the monopolar cautery group (MPG, n=6), a 15-W cauterization process lasting 5s was performed on an approximately 2mm2 area of the ventral side of the penile shaft, 0.5cm proximal to the edge of the glans in the midline. Bipolar cautery was practiced in the third group (BPG, n=6) using the same techniques outlined in the previous statement. Penile tissues consisted of the cautery application area, the edge of the glans, and dorsal side of the penis and were sampled after 90min; then, histopathological evaluation and biochemical examination involving malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD) measurements were performed. Histopathologically, the MPG and BPG demonstrated increased inflammation, fibrosis, and epithelial loss in the urethra in the areas to which cautery was applied as compared to the CG (P<0.05). The vascular structures of the corpus cavernosa were significantly decreased in the cautery application area of both the MPG and the BPG as compared to the CG (P<0.05). In the Masson's trichrome stained samples, significant collagen deposition was observed in the cautery application area both in the MPG and the BPG as compared to the CG (P<0.05). However, S-100 staining was decreased in these groups as compared to the CG (P<0.05). S-100 staining was also decreased in the MPG as compared to the BPG on the edge of the glans (P<0.05). Biochemically, MDA values were significantly increased in the MPG as compared to the CG and the BPG (P<0.05). Monopolar and bipolar cautery both did cause oxidative changes and triggered inflammatory, vascular, and peripheral nerve alterations in the cautery application area while bipolar cautery did not cause any distant effects.

Histopathological study of upper versus lower poles of tonsil in chronic tonsillitis among pediatric age group

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; To compare the histopathological findings between upper and lower poles of tonsil in pediatric age group keeping in view the local and distant effects of chronic tonsillitis.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; Three relevant parameters, grade of inflammation (GOI), activity of inflammation and hyperplasia were histopathologically examined in the tonsils of n=60 pediatric patients with chronic tonsillitis who underwent tonsillectomy in Department of Otorhinolaryngology and Head and Neck Surgery, VIMS, Ballari, Karnataka, India. These parameters were analyzed and were subjected for statistical analysis. &lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; In our study, among 60 patients, n=32 (54.2%) were female and n=28 (45.8%) were male. Those aging 5-10 years were n=34 (57.6%) and 11-15 years were n=26 (42.4%). The tonsillar enlargement of grade 3 were present in n=46 patients (77.7%), n= 12 patients (20%) had grade 2 and n=2 patients (1.3%) had grade 4.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; The GOI and hyperplasia parameters in our study have highly significant association statistically (p&amp;lt;0.01) in histopathology of upper poles when compared with lower poles both sides. Further, the activity of inflammation when analyzed was more in upper pole when compared with lower poles both sides, However this parameter in left side upper and lower poles of tonsil was not statistically significant . Among the 60 cases studied, in all the cases, the GOI was of high grade and activity of inflammation and hyperplasia was low grade. Chronic tonsillitis and histopathology of chronically infected tonsils becomes an important step in the management of the disease.&lt;/p&gt;

Wilson disease missense mutations in ATP7B affect metal-binding domain structural dynamics

Wilson disease (WD) is caused by mutations in the gene for ATP7B, a copper transport protein that regulates copper levels in cells. A large number of missense mutations have been reported to cause WD but genotype–phenotype correlations are not yet established. Since genetic screening for WD may become reality in the future, it is important to know how individual mutations affect ATP7B function, with the ultimate goal to predict pathophysiology of the disease. To begin to assess mechanisms of dysfunction, we investigated four proposed WD-causing missense mutations in metal-binding domains 5 and 6 of ATP7B. Three of the four variants showed reduced ATP7B copper transport ability in a traditional yeast assay. To probe mutation-induced structural dynamic effects at the atomic level, molecular dynamics simulations (1.5 μs simulation time for each variant) were employed. Upon comparing individual metal-binding domains with and without mutations, we identified distinct differences in structural dynamics via root-mean square fluctuation and secondary structure content analyses. Most mutations introduced distant effects resulting in increased dynamics in the copper-binding loop. Taken together, mutation-induced long-range alterations in structural dynamics provide a rationale for reduced copper transport ability.

Oncolysis without viruses - inducing systemic anticancer immune responses with local therapies.

Local administration of oncolytic viruses to tumours can promote anticancer immune responses that lead to the abscopal regression of distant metastases, especially in patients receiving systemic immune-checkpoint inhibitors. Growing preclinical evidence indicates that non-virally induced oncolysis, defined as chemical or physical treatment administered locally to destroy malignant lesions, can promote a similar effect owing to the release of danger-associated molecular patterns that lead to the recruitment of immune cells, thus inducing a systemic response against tumour antigens that protects against local disease relapse and also mediates distant antineoplastic effects. An accumulating body of preclinical evidence supports the implementation of therapies that combine oncolysis with local or systemic immunotherapies. In this Review, we summarize the available data on innovative non-viral oncolysis strategies, including intratumorally applied cytotoxicants, photodynamic therapy, laser therapy, microwave, radiofrequency or photothermal ablation, high-intensity focused ultrasonography and cryotherapy for the local treatment of patients with solid tumours.

P1.04-43 PD-RAD: A Translational Study Investigating PD-L1 Expression After Radiotherapy for Non-Small Cell Lung Cancer - Trial in Progress

Radiotherapy (RT) is delivered to 30-50% of NSCLC patients. However, over half of patients progress following RT and mechanisms of resistance are poorly understood. RT has immune-modulatory properties such as the ability to upregulate tumour PD-L1 expression and can recalibrate the immune contexture. Blockade of the PD-1/PD-L1 axis has been shown to enhance the efficacy of RT in several pre-clinical models and the recent PACIFIC trial. Exploiting immuno-regulatory effects of RT therefore has the ability to enhance local and distant anti-cancer effects of RT, especially when combining RT with immunotherapies such as anti-PD-1 or costimulatory agonists. PDRAD is a prospective UK multi-centre feasibility study of paired pre- and post-treatment biopsies in NSCLC patients receiving palliative or radical RT. The study will recruit up to 30 patients with inoperable disease that is accessible to core biopsy by CT or bronchoscopy within the proposed RT field. Patients with archival baseline histology containing sufficient tumour material are eligible. Consented patients undergo a repeat biopsy in the second week of RT (fig.1). Blood samples will be collected at baseline, repeat biopsy, and following RT to assess immune changes that may correlate with the tumour microenvironment (TME). PDRAD opened to recruitment in November 2018 and will continue recruitment over 16 months. Research aims include investigating: Feasibility and acceptability of obtaining paired biopsies. Changes in the immune contexture in irradiated tumour and ‘out of field’ sites. Immune changes in the TME and peripheral blood. Interim feasibility results after recruitment of 15 patients will be presented at World Lung. Section not applicable We are at a pivotal point in evolving our knowledge of how the TME may influence responses to RT. The PDRAD study will help to influence further clinical trials, including combination studies with immunotherapies and predictive and prognostic biomarker development within the field.

Neo-DREAM study investigating Daromun for the treatment of clinical stage IIIB/C melanoma.

High-risk resectable melanoma poses therapeutic challenges as this subgroup remains most vulnerable for disease recurrence. Immunotherapy has established its efficacy in cases of advanced melanoma, and now is actively being investigated in the multimodal management of resectable disease. Daromun, an intralesional immunocytokine, has emerged as a unique immunotherapy in its ability to preferentially target tumor cells, resulting in direct destruction, while generating a bystander effect that leads to a distant treatment effect. On the basis of its mechanism of action, there is growing interest in delivering immune-based therapies in a neoadjuvant setting. In this review, the neo-DREAM study, a Phase III trial comparing the safety and efficacy of neoadjuvant Daromun for resectable stage IIIB/C melanoma will be described. Clinical Trial Registration Number: NCT03567889.

Introduction

Introduction

Brain Crosstalk with Other Organs in ICU Patient

AbstractCrosstalk between various organs exists in the human body. This can be part of physiological reflexes such as cardiac reflexes that protect the organs during stressful stimuli or can be part of pathological conditions where an insult to an organ releases cytokines that cause distant effects on other organs. In critically ill patients, these crosstalks are independent of pre-existing common risk factors or the presence of new risk exposure during the treatment. Crosstalk can manifest in series or parallel. The human brain, being a control center of the human body, does crosstalk with almost every organ in the body. In this narrative review, crosstalk of the brain with various organs and systems such as the heart, lungs, liver, kidneys, gut, muscle, bone, skin, adipose tissue, and immune system is being discussed along with clinical manifestations and management. Future research might help to target these pathological processes in preventing progression of single-organ dysfunction to multi-organ failures in critically ill patients.

NATURAL KILLER CELL EFFECTS UPON ANGIOGENESIS UNDER CONDITIONS OF CONTACT-DEPENDENT AND DISTANT CO-CULTURING WITH ENDOTHELIAL AND TROPHOBLAST CELLS

Regulation of angiogenesis in the utero-placental bed determines adequate trophoblast invasion, placenta formation and development, as well as successful course of pregnancy. Natural killer (NK) cells, macrophages and trophoblast have the most significant effect on angiogenesis. To date, the functions of cells participating in placenta formation have been described in detail, both individually (in vitrо) and in tissues (in situ). However, no models have yet been created that reflect the interactions of NK cells, trophoblast and endothelium during angiogenesis. It remains unclear, how each cell population contributes to placental angiogenesis regulation, and to the cross-regulation of participating cell functions. Therefore, the aim of this research was to study contact and distant effects of NK cells upon formation of tube-like structures through co-culture of endothelial and trophoblast cells influenced by various cytokines (bFGF, VEGF, PlGF, TGF-β, IL-8, IFNγ and IL-1β). Introduction of NK cells to the co-culture of endothelial and trophoblast cells under conditions of both contact and distance-dependent culturing did not change the length of tube-like structures formed by endothelial cells. During contact-dependent culturing of NK cells with co-culture of endothelial and trophoblast cells in presence of IL-1β, the length of tubule-like structures remained unchanged, compared with the length of tube-like structures formed under the same culturing conditions, but without the cytokine added. During distant culturing of NK cells with co-culture of endothelial and trophoblast cells in the presence of IL-1β, the length of tube-like structures increased as compared with those formed under the same culturing conditions but without the cytokine. During contact-dependent (but not distant) culturing of NK cells with the co-culture of endothelial and trophoblast cells in the presence of VEGF, the length of tube-like structures was greater than those formed under the same culturing conditions but without the cytokine. When used in a three-component cell system, the pro-inflammatory cytokine IFNγhad no effect upon angiogenesis. During distant (but not contact-dependent) culturing of NK cells with co-culture of endothelial and trophoblast cells in the presence of TGF-β, the length of tube-like structures was less than the length of tube-like structures formed under the same culturing conditions but without the cytokine. Under conditions of distant culturing, TGF-βtriggered a signal in NK cells that inhibited angiogenesis. Decreased length of tube-like structures under conditions of a three-component cell co-culture in the presence of the following pro-angiogenic factors was revealed: IL-8, PlGF (during contact-dependent culturing only) and bFGF (during both contact-dependent and distant culturing). Thus, the effects of cytokines upon angiogenesis in a three-component co-culture (NK cells, trophoblast and endothelium) differed from those revealed previously in single-component (endothelium only) and two-component (co-culture of endothelium and trophoblast) cell models. The results of these experiments indicated that regulation of placental cell interactions involved both cellular contacts and effects produced by cytokines.

Abstract 1474: Repurposing the yellow fever vaccine for intratumoral immunotherapy

Abstract Introduction: Yellow Fever attenuated virus vaccine (17D) induces very potent cellular and humoral immunity. Its delivery in situ in the tumor bed may induce an immune response leading to the killing of infected cells. Experimental procedures: 17D virus was propagated in Vero cells and infectious supernatants were harvested. To evaluate in vitro sensitivity of tumors to 17D infection, a panel of human and mouse tumor cell lines were infected with increasing MOIs and viability was quantified. To evaluate the antitumor efficacy of intratumor (i.t.) injection of 17D, 4x106pfu/50μl were injected (4 doses) in MC38- and in B16-OVA-tumor bearing C57BL/6 mice. Systemic antitumor effects of i.t 17D were examined in bilateral MC38 models in which one of the tumors was left uninjected. Depletion experiments were performed to assess the contribution of CD4, CD8, Gr1 and NK cells. To determine the role of conventional type-I dendritic cells (cDC1), identical experiments were performed in BATF3-/- mice. Tumor and lymph node immune infiltrates were examined by multiparametric flow cytometry. Combination with intraperitoneal anti-PD1 or anti-CD137 was performed to improve antitumor efficacy. To evaluate the effects of 17D-preexisting immunity, mice were preimmunized with 17D prior to MC38 bilateral inoculation and were subsequently treated. To assess the individual cell type contribution to the antitumor effects induced upon 17D pre-immunization, CD8, CD4, CD8+CD4 or sera from preimmunized mice were passively transferred 24h prior to first 17D i.t injection to MC38-tumor bearing mice. Results: 17D live attenuated strain is able to induce cell death of mouse and human tumor cell lines. In MC38 or B16-OVA mice models, repeated i.t. injections of 17D clearly delayed tumor progression. Regarding the systemic effect of i.t. 17D, certain contralateral therapeutic efficacy was induced upon i.t injection in bilateral MC38 models. These local and distant effects were dependent on CD8+ and cDC1 cells. 17D i.t injection increased in CD8+ T cell infiltrates and decreased in Tregs in injected tumors, while in contralateral tumors induced an increase of CD8+ and NK cells expressing key immunomodulatory receptors. I.t. 17D with anti-CD137 monoclonal antibody (mAb) induced a strong synergistic effect, while combination with anti-PD-1 mAb showed mild local additive efficacy compared to 17D monotherapy. Both combinatorial treatments delayed contralateral tumor growth. Notably, 17D preimmunization induced an important improvement of local and distant antitumor immunity. Such beneficial effects of preimmunization were transferred along with CD8+ T cells. Conclusions: 17D can be safely injected i.t. in preclinical models, giving rise to immune-mediate antitumor effects that can be combined with other immunotherapy agents. The repurposed use of this GMP-grade vaccine in preimmunized patients represents a promising and feasible immunotherapy approach. Citation Format: M. Angela Aznar, Carmen Molina, Alvaro Teijeira, Arantza Azpilikueta, Saray Garasa, Alfonso R. Sanchez-Paulete, Iñaki Etxeberria, Maite Alvarez, Pedro Berraondo, Ignacio Melero. Repurposing the yellow fever vaccine for intratumoral immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1474.

Altered Metabolism of Phospholipases, Diacylglycerols, Endocannabinoids, and N-Acylethanolamines in Patients with Mastocytosis

Background Mastocytosis is a condition characterized by the expansion and accumulation of mast cells (MCs) in various organs. The symptoms are related to the increased release of MC-derived mediators that exert local and distant effects. MCs are a source and target of phospholipase enzymes (PLs), which catalyze the cleavage of membrane phospholipids releasing lipid mediators (e.g., diacylglycerols (DAGs) and the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG)). To date, there are no data on the role of these lipid mediators in mastocytosis. Here, we analyzed plasma levels of PLA2, PLC, DAG, ECs, and EC-related N-acylethanolamines in patients with mastocytosis. Methods In 23 patients with mastocytosis and 23 healthy individuals, we measured plasma PLA2 and PLC activities, DAG, 2-AG, anandamide (AEA), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA). Results Plasma PLA2 and PLC activities were increased in mastocytosis patients compared to controls. Concentrations of DAG (18:1 20:4 and 18:0 20:4), two second messengers produced by PLC, were higher in mastocytosis compared to controls, whereas the concentrations of their metabolite, 2-AG, were not altered. AEA was decreased in mastocytosis patients compared to controls; by contrast, AEA congener, PEA, was increased. PLA2 and PLC activities were increased only in patients with mediator-related symptoms. Moreover, PLC activity was positively correlated with disease severity and tryptase concentrations. By contrast, AEA was negatively correlated with tryptase concentrations. Conclusions PLs and some lipid mediators are altered in patients with mastocytosis. Our results may pave the way for investigating the functions of these mediators in the pathophysiology of mastocytosis and provide new potential biomarkers and therapeutic targets.

The systemic immunostimulatory effects of radiation therapy producing overall tumor control through the abscopal effect

Emerging studies show that radiation therapy produces an important out of field (distant) effect known as the ‘‘abscopal effect” in nonirradiated tumor sites. The objective of this study was to provide an overview of the current state of knowledge and clinical experience of radiation therapy producing abscopal effects in the management of different types of malignant diseases. Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as Medline via PubMed and Google Scholar. The reference lists were searched in the publications that we obtained in an attempt to find additional relevant publications. Non-indexed peer-reviewed journals were manually searched and relevant information was extracted. The search was restricted to English language articles. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized. Currently, only clinical case reports and anecdotes have slowly converted into solid clinical data and interest is building in the field of radiation therapy, specifically on how local radiation can produce the abscopal effects for the management of different types of malignant tumors. Extensive clinical evidence suggests that the radiation therapy induced abscopal antitumor effects are mediated by immune cells such as the T-lymphocytes. This forms a basis for using radiation therapy in combination with immunotherapy to augment the abscopal response rates in cancer patients. Current evidence demonstrates that radiation therapy induces abscopal responses across many tumor types. Together, the clinical outcomes from published reports suggest that localized radiation therapy is capable of inducing abscopal effects in a wide variety of malignant tumors. With the advent of novel immunotherapies, the potential for immune activation by radiation defines a novel role for radiation therapy in the treatment of systemic disease. A clinical consideration of the abscopal effects produced by radiation therapy could lead to a revolutionary change in the current management of patients including radiation treatment strategies and immunotherapies for various malignant tumors.

Abscopal Outcomes: Reflections on Distant Effects

Abscopal Outcomes: Reflections on Distant Effects

Hepato‐splanchnic circulatory stress: An important effect of hemodialysis

The gastro-intestinal tract is being increasingly recognized as the site of key pathophysiological processes in the hemodialysis patient. Intestinal dysbiosis, increased intraluminal toxin production, and increased intestinal permeability are commonly observed processes which contribute to the pathogenesis of cardiovascular disease and thus elevated mortality. The acute circulatory effects of dialysis itself may contribute significantly to the development of gastrointestinal dysfunction as a result of both local and distant effects. Additionally, the liver, a relatively unknown entity in this process, has a substantial role as a functional barrier between the portal and systemic circulation and in the metabolism of pathogenic gut-derived uremic toxins. Here we summarize the evidence for acute gastro-intestinal and hepatic effects of hemodialysis and identify gaps in knowledge to date which require further study.

Рeзультати та ефективність участі студентів медичного факультету Ужгородського національного університету у винахідницькій роботі (1994–2019)

Introduction. Protection objects of intellectual property, particular inventions and utility models, their creation, applying and search have a great significance for doctors and patients.The aim of the study. carry through searching, discover and to analyze patents and inventions created by teachers along with students of the medical faculty of Uzhhorod National University during 25 years.Materials and methods. At the Patent Department of Uzhgorod National University discovered and analyzed patents for inventions and utility models, issued licenses for them and documents about their recognition in other methods.Results and discussion. 37 patents for inventions and utility models were discovered, where the authors are students and teachers of the medical faculty of Uzhhorod National University, For these patents 9 licenses were issued, 2 patents were recognized as the winners of the republican competition of students-inventors, for one work, for which then a patent for an invention and a license was obtained, student G.I. Cremeshny, Hungarian nationality, in Hungary, received the medal of Ilona Tovt, which is awarded annually by the special commission of Hungary 2 to medical students for their successes.. The experience of teaching patents is presented at the medical faculty of Uzhhorod National University.Conclusions. teaching the basics of the patent science at the Faculty of medicine gave a distant positive effect – students began to conduct together with the teachers research at the world level, Obtain patents for inventions and utility models, formalize licenses and to implement them in medical institutions and to win in competitions and recognition abroad. Patent science should be taught at medical universities to improve the search for new methods of diagnosis, treatment and prevention of diseases in the patent fund of Ukraine and other countries.