The Arabidopsis Cdk1/Cdk2 homolog CDKA;1 controls chromosome axis assembly during plant meiosis.

Meiosis is key to sexual reproduction and genetic diversity. Here, we show that the Arabidopsis cyclin-dependent kinase Cdk1/Cdk2 homolog CDKA;1 is an important regulator of meiosis needed for several aspects of meiosis such as chromosome synapsis. We identify the chromosome axis protein ASYNAPTIC 1 (ASY1), the Arabidopsis homolog of Hop1 (homolog pairing 1), essential for synaptonemal complex formation, as a target of CDKA;1. The phosphorylation of ASY1 is required for its recruitment to the chromosome axis via ASYNAPTIC 3 (ASY3), the Arabidopsis reductional division 1 (Red1) homolog, counteracting the disassembly activity of the AAA+ ATPase PACHYTENE CHECKPOINT 2 (PCH2). Furthermore, we have identified the closure motif in ASY1, typical for HORMA domain proteins, and provide evidence that the phosphorylation of ASY1 regulates the putative self-polymerization of ASY1 along the chromosome axis. Hence, the phosphorylation of ASY1 by CDKA;1 appears to be a two-pronged mechanism to initiate chromosome axis formation in meiosis.

Complement MASP-1 Modifies Endothelial Wound Healing.

Endothelial wound-healing processes are fundamental for the maintenance and restoration of the circulatory system and are greatly affected by the factors present in the blood. We have previously shown that the complement protein mannan-binding lectin-associated serine protease-1 (MASP-1) induces the proinflammatory activation of endothelial cells and is able to cooperate with other proinflammatory activators. Our aim was to investigate the combined effect of mechanical wounding and MASP-1 on endothelial cells. Transcriptomic analysis showed that MASP-1 alters the expression of wound-healing-related and angiogenesis-related genes. Both wounding and MASP-1 induced Ca2+ mobilization when applied individually. However, MASP-1-induced Ca2+ mobilization was inhibited when the treatment was preceded by wounding. Mechanical wounding promoted CREB phosphorylation, and the presence of MASP-1 enhanced this effect. Wounding induced ICAM-1 and VCAM-1 expression on endothelial cells, and MASP-1 pretreatment further increased VCAM-1 levels. MASP-1 played a role in the subsequent stages of angiogenesis, facilitating the breakdown of the endothelial capillary network on Matrigel®. Our findings extend our general understanding of endothelial wound healing and highlight the importance of complement MASP-1 activation in wound-healing processes.

Cooperation of Complement MASP-1 with Other Proinflammatory Factors to Enhance the Activation of Endothelial Cells.

Endothelial cells play an important role in sensing danger signals and regulating inflammation. Several factors are capable of inducing a proinflammatory response (e.g., LPS, histamine, IFNγ, and bradykinin), and these factors act simultaneously during the natural course of the inflammatory reaction. We have previously shown that the complement protein mannan-binding lectin-associated serine protease-1 (MASP-1) also induces a proinflammatory activation of the endothelial cells. Our aim was to investigate the possible cooperation between MASP-1 and other proinflammatory mediators when they are present in low doses. We used HUVECs and measured Ca2+ mobilization, IL-8, E-selectin, VCAM-1 expression, endothelial permeability, and mRNA levels of specific receptors. LPS pretreatment increased the expression of PAR2, a MASP-1 receptor, and furthermore, MASP-1 and LPS enhanced each other's effects in regulating IL-8, E-selectin, Ca2+ mobilization, and changes in permeability in a variety of ways. Cotreatment of MASP-1 and IFNγ increased the IL-8 expression of HUVECs. MASP-1 induced bradykinin and histamine receptor expression, and consequently, increased Ca2+ mobilization was found. Pretreatment with IFNγ enhanced MASP-1-induced Ca2+ mobilization. Our findings highlight that well-known proinflammatory mediators and MASP-1, even at low effective doses, can strongly synergize to enhance the inflammatory response of endothelial cells.

Interplay of Vitamin D and SIRT1 in Tissue-Specific Metabolism-Potential Roles in Prevention and Treatment of Non-Communicable Diseases Including Cancer.

The importance of the prevention and control of non-communicable diseases, including obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases, and cancer, is increasing as a requirement of the aging population in developed countries and the sustainability of healthcare. Similarly, the 2013-2030 action plan of the WHO for the prevention and control of non-communicable diseases seeks these achievements. Adequate lifestyle changes, alone or with the necessary treatments, could reduce the risk of mortality or the deterioration of quality of life. In our recent work, we summarized the role of two central factors, i.e., appropriate levels of vitamin D and SIRT1, which are connected to adequate lifestyles with beneficial effects on the prevention and control of non-communicable diseases. Both of these factors have received increased attention in relation to the COVID-19 pandemic as they both take part in regulation of the main metabolic processes, i.e., lipid/glucose/energy homeostasis, oxidative stress, redox balance, and cell fate, as well as in the healthy regulation of the immune system. Vitamin D and SIRT1 have direct and indirect influence of the regulation of transcription and epigenetic changes and are related to cytoplasmic signaling pathways such as PLC/DAG/IP3/PKC/MAPK, MEK/Erk, insulin/mTOR/cell growth, proliferation; leptin/PI3K-Akt-mTORC1, Akt/NFĸB/COX-2, NFĸB/TNFα, IL-6, IL-8, IL-1ß, and AMPK/PGC-1α/GLUT4, among others. Through their proper regulation, they maintain normal body weight, lipid profile, insulin secretion and sensitivity, balance between the pro- and anti-inflammatory processes under normal conditions and infections, maintain endothelial health; balance cell differentiation, proliferation, and fate; and balance the circadian rhythm of the cellular metabolism. The role of these two molecules is interconnected in the molecular network, and they regulate each other in several layers of the homeostasis of energy and the cellular metabolism. Both have a central role in the maintenance of healthy and balanced immune regulation and redox reactions; therefore, they could constitute promising targets either for prevention or as complementary therapies to achieve a better quality of life, at any age, for healthy people and patients under chronic conditions.

Assessment of Inflammation in 3D Reconstructed Human Skin Exposed to Combined Exposure to Ultraviolet and Wi-Fi Radiation.

In the human environment, the increasing exposure to radiofrequency (RF) radiation, especially that emitted by wireless devices, could be absorbed in the body. Recently, mobile and emerging wireless technologies (UMTS, DECT, LTE, and Wi-Fi) have been using higher frequencies than 2G GSM systems (900/1800 MHz), which means that most of the circulating RF currents are absorbed into the skin and the superficial soft tissue. The harmful genotoxic, cytotoxic, and mutagenic effects of solar ultraviolet (UV) radiation on the skin are well-known. This study aimed at investigating whether 2422 MHz (Wi-Fi) RF exposure combined with UV radiation in different sequences has any effect on the inflammation process in the skin. In vitro experiments examined the inflammation process by cytokines (IL-1α, IL-6, IL-8) and MMP-1 enzyme secretion in a 3D full-thickness human skin model. In the first study, UV exposure was immediately followed by RF exposure to measure the potential additive effects, while in the second study, the possible protective phenomenon (i.e., adaptive response) was investigated when adaptive RF exposure was challenged by UV radiation. Our results suggest that 2422 MHz Wi-Fi exposure slightly, not significantly increased cytokine concentrations of the prior UV exposure. We could not detect the adaptive response phenomenon.

Indications for Sleeve Gastrectomy-Is It Worth Waiting for Comorbidities to Develop?

(1) Background and Objectives: Morbid obesity significantly increases the prevalence of comorbidities, such as heart disease, restrictive lung disease, stroke, diabetes mellitus and more. (2) Methods: Patients undergoing gastric sleeve surgery were divided into three groups with BMI between 30-34.9 kg/m2 (Group I), 35-39.9 kg/m2 (Group II), and over 40 kg/m2 (Group III). Preoperative examinations included cardiac ultrasound, respiratory function and laboratory tests, and preoperative comorbidities were also recorded. Following a one-year follow-up, we compared the rate of weight loss in the three groups at six months and one year following surgery, specifically, the effect of surgery on preoperative comorbidities at one year. (3) Results: The weight loss surgeries performed were successful in all three groups. Preoperative laboratory examinations, an echocardiogram and respiratory function results showed no clinically significant difference, except moderate elevations in blood lipid levels. Hypertension was the most common comorbidity. (4) Conclusions: In our patient population, hypertension and diabetes were the only comorbidities with a high prevalence. It can be explained by the relatively younger age among the patients (mean age 44.5 years) and the fact that they had not yet developed the pathological consequences of severe obesity. Consequently, while performing the surgery at a relatively younger age, it seems far more likely that the patient will return to a more active and productive life and enjoy a better quality of life. Additionally, the perioperative risk is lower, and the burden upon health systems and health expenditure is reduced by preventing comorbidities, in particular, multimorbidity. On this basis, it may be advisable to direct patients who do not exhaust the classical indications for bariatric surgery toward the surgical solution at a younger age. Our results suggest it is not worth waiting for comorbidities, especially multimorbidity, to appear.

Methyl Donors Reduce Cell Proliferation by Diminishing Erk-Signaling and NFkB Levels, While Increasing E-Cadherin Expression in Panc-1 Cell Line.

Pancreatic cancer is an aggressive malignancy with high metastatic potential. There are several lifestyle-related determinants in its etiology, including diet. Methyl donors are dietary micronutrients which play an important role in fueling vital metabolic pathways, and as bioactive food components provide methyl groups as substrates and cofactors. The imbalanced nutritional status of methyl donors has recently been linked to pathological conditions. Therefore, we hypothesized that dietary methyl donors may improve the physiology of cancer patients, including those with pancreatic cancer, and could be used for intervention therapy. In this study, methyl-donor treatment (L-methionine, choline chloride, folic acid and vitamin B12) of an aggressive pancreatic adenocarcinoma cell line (Panc-1) resulted in significantly increased p21WAF1/Cip1 cyclin-dependent kinase inhibitor levels, along with apoptotic SubG1 fractions. At the same time, phospho-Erk1/2 levels and proliferation rate were significantly reduced. Though methyl-donor treatments also increased the pro-apoptotic protein Bak, Puma and Caspase-9, it failed to elevate cleaved Caspase-3 levels. In addition, the treatment significantly reduced the production of the pro-inflammatory cytokine IL-17a and the transcription factor NFkB. Similarly, a significant decrease in VEGF and SDF-1a levels were detected, which may indicate reduced metastatic potential. As expected, E-cadherin expression was inversely associated with these changes, showing elevated expression after methyl-donor treatment. In summary, we found that methyl donors may have the potential to reduce aggressive and proliferative phenotype of Panc-1 cells. This suggests a promising role of dietary methyl donors for complementing relevant cancer therapies, even in treatment-resistant pancreatic adenocarcinomas.

Deletion of Biliverdin Reductase A in Myeloid Cells Promotes Chemokine Expression and Chemotaxis in Part via a Complement C5a--C5aR1 Pathway.

Biliverdin reductase (BVR)-A is a pleotropic enzyme converting biliverdin to bilirubin and a signaling molecule that has cytoprotective and immunomodulatory effects. We recently showed that biliverdin inhibits the expression of complement activation fragment 5a receptor one (C5aR1) in RAW 264.7 macrophages. In this study, we investigated the role of BVR-A in determining macrophage inflammatory phenotype and function via regulation of C5aR1. We assessed expression of C5aR1, M1-like macrophage markers, including chemokines (RANTES, IP-10), as well as chemotaxis in response to LPS and C5a in bone marrow-derived macrophages from BVR fl/fl and LysM-Cre:BVR fl / fl mice (conditional deletion of BVR-A in myeloid cells). In response to LPS, macrophages isolated from LysM-Cre:BVR fl/fl showed significantly elevated levels of C5aR1 as well as chemokines (RANTES, IP10) but not proinflammatory markers, such as iNOS and TNF. An increase in C5aR1 expression was also observed in peritoneal macrophages and several tissues from LysM-Cre:BVR fl/fl mice in a model of endotoxemia. In addition, knockdown of BVR-A resulted in enhanced macrophage chemotaxis toward C5a. Part of the effects of BVR-A deletion on chemotaxis and RANTES expression were blocked in the presence of a C5aR1 neutralizing Ab, confirming the role of C5a-C5aR1 signaling in mediating the effects of BVR. In summary, BVR-A plays an important role in regulating macrophage chemotaxis in response to C5a via modulation of C5aR1 expression. In addition, macrophages lacking BVR-A are characterized by the expression of M1 polarization-associated chemokines, the levels of which depend in part on C5aR1 signaling.

A Systematic Review and Meta-Analysis of Ligation Versus Repair of Inferior Vena Cava Injuries.

OBJECTIVE: Inferior vena cava (IVC) injuries have a high mortality rate that may be related to the location of injury and type of repair. Previous studies have been either single center series or database studies lacking granular detail. These have reported conflicting results. We aimed to perform a systematic review and meta-analysis of published literature evaluating ligation versus repair. METHODS: Studies published in English on MEDLINE or EMBASE from 1946 through October 2018 were examined to evaluate mortality among patients treated with ligation versus repair of IVC injuries. Studies were included if they provided mortality associated with ligation versus repair and reported IVC injury by level. Risk of bias was assessed regarding incomplete and selective outcome reporting with Newcastle-Ottawa score of 7 or higher to evaluate study quality. We used a random-effects model with restricted maximum likelihood estimation method in R using the Metafor package to evaluate outcomes. RESULTS: Our systematic review identified 26 studies, of which 14 studies, including 855 patients, met our inclusion criteria for meta-analysis. IVC ligation was associated with higher mortality than IVC repair (OR: 3.12, P < 0.01, I2 = 49%). Ligation of infrarenal IVC injuries was not statistically associated with mortality (OR: 3.13, P = 0.09). Suprarenal injury location compared to infrarenal (OR 3.11, P < 0.01, I2 = 28%) and blunt mechanism compared to penetrating (OR: 1.91, P = 0.02, I2 = 0%) were also associated with higher mortality. CONCLUSIONS: In this meta-analysis, ligation of IVC injuries was associated with increased mortality compared to repair, but not specifically for infrarenal IVC injuries. Suprarenal IVC injury, and blunt mechanism was associated with increased mortality compared to infrarenal IVC injury and penetrating mechanism, respectively. Data are limited regarding acute renal injury and venous thromboembolic events after IVC ligation and may warrant multicenter studies. Standardized reporting of IVC injury data has not been well established and is needed in order to enable comparison of outcomes across institutions. In particular, reporting of injury location, severity, and repair type should be standardized. A contemporary prospective, multicenter study is needed in order to definitively compare surgical technique.

Methyl-Donors Can Induce Apoptosis and Attenuate Both the Akt and the Erk1/2 Mediated Proliferation Pathways in Breast and Lung Cancer Cell Lines.

Dietary methyl-donors play important roles in physiological processes catalyzed by B vitamins as coenzymes, and are used for complementary support in oncotherapy. Our hypothesis was that methyl-donors can not only assist in tolerating cancer treatment but may also directly interfere with tumor growth and proliferation. Therefore, we investigated the proposed cancer inhibitory effects of methyl-donors (in a mixture of L-methionine, choline chloride, folic acid, and vitamin B12) on MCF7 and T47D breast cancer as well as A549 and H1650 lung cancer cell lines. Indeed, methyl-donor treatment significantly reduced the proliferation in all cell lines, possibly through the downregulation of MAPK/ERK and AKT signaling. These were accompanied by the upregulation of the pro-apoptotic Bak and Bax, both in MCF7 and H1650 cells, at reduced anti-apoptotic Mcl-1 and Bcl-2 levels in MCF7 and H1650 cells, respectively. The treatment-induced downregulation of p-p53(Thr55) was likely to contribute to protecting the nuclear localization and apoptosis inducing functions of p53. The presented features are known to improve the sensitivity of cancer therapy. Therefore, these data support the hypothesis, i.e., that methyl-donors may promote apoptotic signaling by protecting p53 functions through downregulating both the MAPK/ERK and the AKT pathways both in breast and lung adenocarcinoma cell lines. Our results can emphasize the importance and benefits of the appropriate dietary supports in cancer treatments. However, further studies are required to confirm these effects without any adverse outcome in clinical settings.

GCV/VCVG prophylaxis against CMV DNAemia in pediatric renal transplant patients: A systematic review and meta-analysis.

CMV disease continues to stand as a significant threat to the longevity of renal transplants in children. More pediatric recipients are CMV-negative with CMV-positive donor serologies resulting in a HR mismatch. The length of prophylaxis with GCV or VGCV required to optimally prevent recurrence of CMVDNAemia remains unknown. This study is a meta-analysis comparing GCV/VGCV prophylaxis regimens provided for <6 months, from 6 to <12 months, and ≥12 months after transplant in order to prevent CMVDNAemia. The search conducted involved PubMed, EMBASE, ISI Web of Science, and Cochrane Central Register from inception through December 2017. Search terms Kidney Transplantation, CMV, GCV, and VGCV provided 204 studies for abstract review. Studies excluded were those which did not itemize pediatric data separately, single case reports, and duplicate studies. Pooled analysis of five retrospective studies and one prospective study identified that there is no statistically significant difference in the incidence of CMV DNAemia when comparing <6 months of prophylaxis and >12 months of prophylaxis (23% and 15%, respectively, P = 0.23). Regardless of the length of prophylaxis, there was no statistical difference in the incidence of CMV DNAemia in the HR patients (6 to <12 months vs <6 months, P = 0.62; 6 to <12 months vs ≥12 months, P = 0.78; ≥12 months vs <6 months, P = 0.83). This study identifies no optimal length of prophylaxis for HR mismatch pediatric renal transplant patients as many develop CMV DNAemia.

The Use of Tablet Technology by Older Adults in Health Care Settings-Is It Effective and Satisfying? A Systematic Review and Meta Analysis.

OBJECTIVES: This systematic review/meta-analysis examines the potential for older people to accept and use tablet technology in clinical settings by assessing satisfaction and effectiveness. METHODS: A comprehensive literature search was conducted of PubMed, SCOPUS, and CINAHL through March 2017. Inclusion criteria included studies with any clinical use of a tablet technology with a median patient age above 65 years. RESULTS: We included a total of 12 studies (4 randomized controlled trials, 4 cross-sectional studies, and 4 pre/post studies). Interventions included the use of tablet technology for medication self-management, post-surgery education, memory retention, cognitive rehabilitation, and exercise promotion. The use of tablet technology by older people in clinical settings was associated with high satisfaction with a pooled prevalence of satisfaction of 78%; 95% CI 27-100. We did not find evidence for effectiveness in improving clinical or behavioral outcomes. CONCLUSIONS: Older people can use and are satisfied with table technology in clinical settings. More studies are needed to evaluate the effectiveness of tablet technology at promoting health outcomes. CLINICAL IMPLICATIONS: Clinicians should be encouraged to utilize tablet technology in the care of older patients.

Mobile Technologies for Managing Heart Failure: A Systematic Review and Meta-analysis.

BACKGROUND: Randomized clinical trials (RCTs) conducted among heart failure (HF) patients have reported that mobile technologies can improve HF-related outcomes. Our aim was to conduct a meta-analysis to evaluate m-Health's impact on healthcare services utilization, mortality, and cost. METHODS: We searched MEDLINE, Cochrane, CINAHL, and EMBASE for studies published between 1966 and May-2017. We included studies that compared the use of m-Health in HF patients to usual care. m-Health is defined as the use of mobile computing and communication technologies to record and transmit data. The outcomes were HF-related and all-cause hospital days, cost, admissions, and mortality. RESULTS: Our search strategy resulted in 1,494 articles. We included 10 RCTs and 1 quasi-experimental study, which represented 3,109 patients in North America and Europe. Patient average age range was 53-80 years, New York Heart Association (NYHA) class III, and Left Ventricular Ejection Fraction <50%. Patients were mostly monitored daily and followed for an average of 6 months. A reduction was seen in HF-related hospital days. Nonsignificant reductions were seen in HF-related cost, admissions, and mortality and total mortality. We found no significant differences for all-cause hospital days and admissions, and an increase in total cost. CONCLUSIONS: m-Health reduced HF-related hospital days, showed reduction trends in total mortality and HF-related admissions, mortality and cost, and increased total costs related to more clinic visits and implementation of new technologies. More studies reporting consistent quality outcomes are warranted to give conclusive information about the effectiveness and cost-effectiveness of m-Health interventions for HF.

[Actor as a simulated patient in medical education at the University of Pécs]. / A színész mint szimulált páciens az oktatásban a Pécsi Tudományegyetemen.

INTRODUCTION: Medical training in the 21st century faces simulation-based education as one of the challenges that efficiently contributes to clinical skills development while moderating the burden on the clinicians and patients alike. AIM: The University of Pécs, Medical School has launched a simulation program in the MediSkillsLab based on history taking with actors to improve patient interviewing communication skills. METHOD: This new program was inspired by experiences gathered in previous medical language teaching and integrates the method of the "Standardized Patient Program". The method has been applied in America since the 1960s. RESULTS: This is the first time the program has been introduced in Hungary and implemented in an interdisciplinary design, where medical specialists, linguists, actor-patients and medical students collaborate to improve professional, language and communicative competence of the students. CONCLUSION: A course like this has its pivotal role in the medical training, and as a result more efficient and patient-oriented communication may take place at the clinical setting. Orv Hetil. 2017; 158(26): 1022-1027.

Comprehensive Cross-Linking Mass Spectrometry Reveals Parallel Orientation and Flexible Conformations of Plant HOP2-MND1.

The HOP2-MND1 heterodimer is essential for meiotic homologous recombination in plants and other eukaryotes and promotes the repair of DNA double-strand breaks. We investigated the conformational flexibility of HOP2-MND1, important for understanding the mechanistic details of the heterodimer, with chemical cross-linking in combination with mass spectrometry (XL-MS). The final XL-MS workflow encompassed the use of complementary cross-linkers, quenching, digestion, size exclusion enrichment, and HCD-based LC-MS/MS detection prior to data evaluation. We applied two different homobifunctional amine-reactive cross-linkers (DSS and BS(2)G) and one zero-length heterobifunctional cross-linker (EDC). Cross-linked peptides of four biological replicates were analyzed prior to 3D structure prediction by protein threading and protein-protein docking for cross-link-guided molecular modeling. Miniaturization of the size-exclusion enrichment step reduced the required starting material, led to a high amount of cross-linked peptides, and allowed the analysis of replicates. The major interaction site of HOP2-MND1 was identified in the central coiled-coil domains, and an open colinear parallel arrangement of HOP2 and MND1 within the complex was predicted. Moreover, flexibility of the C-terminal capping helices of both complex partners was observed, suggesting the coexistence of a closed complex conformation in solution.

Accumulation of the PX domain mutant Frank-ter Haar syndrome protein Tks4 in aggresomes.

BACKGROUND: Cells deploy quality control mechanisms to remove damaged or misfolded proteins. Recently, we have reported that a mutation (R43W) in the Frank-ter Haar syndrome protein Tks4 resulted in aberrant intracellular localization. RESULTS: Here we demonstrate that the accumulation of Tks4(R43W) depends on the intact microtubule network. Detergent-insoluble Tks4 mutant colocalizes with the centrosome and its aggregate is encaged by the intermediate filament protein vimentin. Both the microtubule inhibitor nocodazole and the histone deacetylase inhibitor Trichostatin A inhibit markedly the aggresome formation in cells expressing Tks4(R43W). Finally, pretreatment of cells with the proteasome inhibitor MG132 markedly increases the level of aggresomes formed by Tks4(R43W). Furthermore, two additional mutant Tks4 proteins (Tks4(1-48) or Tks4(1-341)) have been investigated. Whereas the shorter Tks4 mutant, Tks4(1-48), shows no expression at all, the longer Tks4 truncation mutant accumulates in the nuclei of the cells. CONCLUSIONS: Our results suggest that misfolded Frank-ter Haar syndrome protein Tks4(R43W) is transported via the microtubule system to the aggresomes. Lack of expression of Tks4(1-48) or aberrant intracellular expressions of Tks4(R43W) and Tks4(1-341) strongly suggest that these mutations result in dysfunctional proteins which are not capable of operating properly, leading to the development of FTHS.

[Clinical application of 18F-FDG PET/CT in the treatment of sarcomas]. / A 18F-FDG PET/CT klinikai alkalmazása és lehetõségei a sarcomák kezelésében.

[18F]-Fluoro-deoxyglucose positron emission tomography / computer tomography (18F-FDG PET/CT) is able to detect and assess the abnormal metabolism, enabling visualization and quantification in vivo with integration into CT anatomic information. The clinical usefulness of FDG PET/CT in the management of patients with sarcomas has been assessed by numerous investigators. Sarcomas are solid malignant tumors with distinct clinical and pathological features. Effective management of patients with sarcoma requires accurate diagnosis and staging. The authors discuss the major indications of PET/CT on the basis of literature data for diagnosis, staging, guidance of biopsy and monitoring response to therapy in both primary bone and soft tissue tumors. The consistent use of PET molecular imaging methods is of high importance in characterizing and understanding sarcoma behavior in clinical practice.

Detrimental interactions of hypoxia and complement MASP-1 in endothelial cells as a model for atherosclerosis-related diseases.

Both hypoxia and the complement lectin pathway (CLP) are involved in atherosclerosis and atherosclerosis-related stroke and acute myocardial infarction (AMI). We have previously shown that mannose-binding lectin-associated serine protease-1 (MASP-1), the most abundant enzyme of CLP, induces an inflammatory phenotype of endothelial cells (ECs) by cleaving protease activated receptors (PARs). In the absence of data, we aimed to investigate whether hypoxia and MASP-1 interact at the level of ECs, to better understand their role in atherosclerosis-related diseases. Hypoxia attenuated the wound healing ability of ECs, increased ICAM-1 and decreased ICAM-2 expression and upregulated PAR2 gene expression. Hypoxia and MASP-1 increased GROα and IL-8 production, and endothelial permeability without potentiating each other's effects, whereas they cooperatively disrupted vascular network integrity, activated the Ca2+, CREB and NFκB signaling pathways, and upregulated the expression of E-selectin, a crucial adhesion molecule in neutrophil homing. VCAM-1 expression was not influenced either by hypoxia, or by MASP-1. In summary, hypoxia potentiates the effect of MASP-1 on ECs, at least partially by increasing PAR expression, resulting in interaction at several levels, which may altogether exacerbate stroke and AMI progression. Our findings suggest that MASP-1 is a potential drug target in the acute phase of atherosclerosis-related diseases.

The effect of COVID-19 vaccination status on all-cause mortality in patients hospitalised with COVID-19 in Hungary during the delta wave of the pandemic.

The high mortality of patients with coronavirus disease 2019 (COVID-19) is effectively reduced by vaccination. However, the effect of vaccination on mortality among hospitalised patients is under-researched. Thus, we investigated the effect of a full primary or an additional booster vaccination on in-hospital mortality among patients hospitalised with COVID-19 during the delta wave of the pandemic. This retrospective cohort included all patients (n = 430) admitted with COVID-19 at Semmelweis University Department of Medicine and Oncology in 01/OCT/2021-15/DEC/2021. Logistic regression models were built with COVID-19-associated in-hospital/30 day-mortality as outcome with hierarchical entry of predictors of vaccination, vaccination status, measures of disease severity, and chronic comorbidities. Deceased COVID-19 patients were older and presented more frequently with cardiac complications, chronic kidney disease, and active malignancy, as well as higher levels of inflammatory markers, serum creatinine, and lower albumin compared to surviving patients (all p < 0.05). However, the rates of vaccination were similar (52-55%) in both groups. Based on the fully adjusted model, there was a linear decrease of mortality from no/incomplete vaccination (ref) through full primary (OR 0.69, 95% CI: 0.39-1.23) to booster vaccination (OR 0.31, 95% CI 0.13-0.72, p = 0.006). Although unadjusted mortality was similar among vaccinated and unvaccinated patients, this was explained by differences in comorbidities and disease severity. In adjusted models, a full primary and especially a booster vaccination improved survival of patients hospitalised with COVID-19 during the delta wave of the pandemic. Our findings may improve the quality of patient provider discussions at the time of admission.

Neuromonitoring with microdialysis in severe traumatic brain injury patients.

BACKGROUND: Neuromonitoring with microdialysis has the potential for early detection of metabolic derangements associated with TBI. METHODS: 1,260 microdialysis samples from 12 TBI patients were analyzed for glucose, -lactate, pyruvate, lactate/pyruvate ratio (LPR), and lactate/glucose ratio (LGR). Analytes were correlated with the Glasgow Coma Scale (GCS) before surgery and with the Glasgow Outcome Scale (GOS) at the time of discharge. The patients were divided into two groups for GCS: 3-6 and 7-9, and for GOS 1-3 and 4-5. Chi-squared test was performed for correlations. RESULTS: Glucose, lactate levels, and LGR were high in TBI patients with GCS 3-6 (p < 0.0001). Pyruvate level was lower in patients with GCS 7-9 (p < 0.001). LPR was higher in patients with GCS 3-6 (p < 0.05). High glucose, lactate level (p < 0.001), and LPR (p < 0.01) was observed in patients with GOS 1-3. Pyruvate level was low in patients with GOS 1-3 (p < 0.001). LGR was higher in patient with better outcome (GOS 4-5). CONCLUSION: After craniotomy extracellular glucose and lactate were good "biomarkers" of cerebral damage in TBI patients. We consider that high extracellular lactate and low glucose is an indicator of severe neurological damage and poor outcome, because of impaired brain metabolism.