Search

Abstract Background Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) induces transient blood-brain barrier opening (BBBO) in targeted regions. pFUS+MB, through the facilitation of neurotherapeutics’ delivery, has been advocated as an adjuvant treatment for neurodegenerative diseases and malignancies. Sterile neuroinflammation has been recently described following pFUS+MB BBBO. In this study, we used PET imaging with [18F]-DPA714, a biomarker of translocator protein (TSPO), to assess for neuroinflammatory changes following single and multiple pFUS+MB sessions. Methods Three groups of Sprague-Dawley female rats received MRI-guided pFUS+MB (Optison™; 5–8 × 107 MB/rat) treatments to the left frontal cortex and right hippocampus. Group A rats were sonicated once. Group B rats were sonicated twice and group C rats were sonicated six times on weekly basis. Passive cavitation detection feedback (PCD) controlled the peak negative pressure during sonication. We performed T1-weighted scans immediately after sonication to assess efficiency of BBBO and T2*-weighted scans to evaluate for hypointense voxels. [18F]DPA-714 PET/CT scans were acquired after the BBB had closed, 24 h after sonication in group A and within an average of 10 days from the last sonication in groups B and C. Ratios of T1 enhancement, T2* values, and [18F]DPA-714 percent injected dose/cc (%ID/cc) values in the targeted areas to the contralateral brain were calculated. Histological assessment for microglial activation/astrocytosis was performed. Results In all groups, [18F]DPA-714 binding was increased at the sonicated compared to non-sonicated brain (%ID/cc ratios > 1). Immunohistopathology showed increased staining for microglial and astrocytic markers in the sonicated frontal cortex compared to contralateral brain and to a lesser extent in the sonicated hippocampus. Using MRI, we documented BBB disruption immediately after sonication with resolution of BBBO 24 h later. We found more T2* hypointense voxels with increasing number of sonications. In a longitudinal group of animals imaged after two and after six sonications, there was no cumulative increase of neuroinflammation on PET. Conclusion Using [18F]DPA-714 PET, we documented in vivo neuroinflammatory changes in association with pFUS+MB. Our protocol (utilizing PCD feedback to minimize damage) resulted in neuroinflammation visualized 24 h post one sonication. Our findings were supported by immunohistochemistry showing microglial activation and astrocytosis. Experimental sonication parameters intended for BBB disruption should be evaluated for neuroinflammatory sequelae prior to implementation in clinical trials.

Blood-brain barrier opening (BBBO) with pulsed Focused Ultrasound (pFUS) and microbubbles (MB) has received increasing interest as a method for neurotherapeutics of the central nervous system. In general, conventional MRI [i.e., T2w, T2∗w, gadolinium (Gd) enhanced T1w] is used to monitor the effects of pFUS+MB on BBBO and/or assess whether sonication results in parenchymal damage. This study employed multimodal MRI techniques and 18F-Fludeoxyglucose (FDG) PET to evaluate the effects of single and multiple weekly pFUS+MB sessions on morphology and glucose utilization levels in the rat cortex and hippocampus. pFUS was performed with 0.548 MHz transducer with a slow infusion over 1 min of OptisonTM (5–8 × 107 MB) in nine focal points in cortex and four in hippocampus. During pFUS+MB treatment, Gd-T1w was performed at 3 T to confirm BBBO, along with subsequent T2w, T2∗w, DTI and glucose CEST (glucoCEST)-weighted imaging by high field 9.4 T and compared with FDG-PET and immunohistochemistry. Animals receiving a single pFUS+MB exhibited minimal hypointense voxels on T2∗w. Brains receiving multiple pFUS+MB treatments demonstrated persistent T2w and T2∗ abnormalities associated with changes in DTI and glucoCEST when compared to contralateral parenchyma. Decreased glucoCEST contrast was substantiated by FDG-PET in cortex following multiple sonications. Immunohistochemistry showed significantly dilated vessels and decreased neuronal glucose transporter (GLUT3) expression in sonicated cortex and hippocampus without changes in neuronal counts. These results suggest the importance to standardize MRI protocols in concert with advanced imaging techniques when evaluating long term effects of pFUS+MB BBBO in clinical trials for neurological diseases.

Antidromic stimulation of the rat trigeminal ganglion triggers the release of substance P (SP) and calcitonin gene-related peptide (CGRP) from sensory nerve terminals of the capsaicin sensitive C-fibers. These pro-inflammatory neuropeptides produce a marked hyperemia in the anterior segment of the eye, accompanied by increased intraocular pressure, breakdown of the blood-aqueous barrier and myosis. To assess the effects of neurogenic inflammation on the retina, specifically on the immunostaining of neurotransmitters and neurotrophins, as well as on the expression of neurotrophin receptors in the retina. RT-PCR was also accomplished in control and stimulated animals to confirm the immunohistochemical results. In the electrically stimulated eyes, immunostaining for SP, CGRP, VIP and nNOS demonstrated a marked increase in the RPE/POS (Retinal Pigment Epithelium/Photoreceptor Outer Segments), in the inner and outer granular layers and in the ganglion cells in comparison to the control eyes. CGRP and SP were found increased in stimulated animals and this result has been confirmed by RT- PCR. Changes in neurotrophin immunostaining and in receptor expression were also observed after electric stimulation of trigeminal ganglia. Decrease of BDNF and NT4 in the outer and inner layers and in ganglion cells was particularly marked. In stimulated rat retinas immunostaining and RT-PCR showed a NGF expression increase. Neurotrophin receptors remained substantially unchanged. These studies demonstrated, for the first time, that antidromic stimulation of the trigeminal ganglion and subsequent neurogenic inflammation affect immunostaining of retinal cell neurotransmitter/ neuropeptides and neurotrophins as well as the expression of neurotrophin receptors.

Introduction The premenstrual dysphoric disorder (PMDD) is a new distinct diagnostic entity in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). However, the severe premenstrual (PM) symptoms associated with PMDD result in functional impairment, globally, it remains highly underdiagnosed, underscoring the need for enhanced clinical recognition. Objectives This ongoing study aims to assess the prevalence and symptom profile of PMDD in a sample of Hungarian women. It is part of a comprehensive research process aiming to validate a prospective PMDD diagnostic questionnaire (Daily Record of Severity of Problems, DRSP) in order to facilitate the diagnosis of the disorder. Methods The study was performed in three steps. Firstly, retrospective data were collected from 112 women. Probable PMDD was assessed using the DSM-5 Based Screening Tool, while anxio-depressive symptoms and well-being were evaluated using the Beck Depression Inventory, the state subscale of the State-Trait Anxiety Inventory, and the WHO Well-Being Scale. Subsequently, prospective data were obtained from 9 women who completed the DRSP along with the aforementioned mood questionnaires during both their PM and follicular phases. Results In the first research phase, the sample was divided into women with probable PMDD diagnosis (PMDD group, n=68) and women without probable PMDD diagnosis (nonPMDD group, n=45) based on the DSM-5-Based Screening Tool. The PMDD group reported significantly more severe depressive (F(1; 56.2) = 19.394, p≤0.001) and anxiety (F(1; 35.6)=17.714, p≤0.001) symptoms and lower well-being (F(1; 44.3)=4.288, p=0.04) compared to the non-PMDD group, irrespective of the menstrual phase they experienced. In the second and third research phases based on the DRSP, the sample was divided into women with probable PMDD diagnosis (PMDD group, n= 3) and those without probable PMDD diagnosis (nonPMDD group, n=6). A statistically significant association was observed between the classifications according to the DSM-5 Based Screening Tool and the DRSP (p=0.048; Cramer’s V=0.79). The PMDD group showed a tendency of lower well-being and more severe anxio-depressive symptoms than the nonPMDD group (Well-being: between phases p=0.93, between groups p=0.06; BDI-II: between phases p=0.79, between groups p=0.07; STAI-S: between phases p=0.87, between groups p=0.17). Conclusions The prevalence of PMDD was high in our sample. Women with probable PMDD retrospectively reported substantial affective difficulties and a decline in subjective well-being, regardless of their menstrual cycle. Prospective preliminary findings suggest a trend toward differentiation associated with probable PMDD. These results highlight the need for prospective clinical studies addressing the psychological symptoms of women with PM issues and the importance of appropriate treatment of the clinical appearance of PMDD. Disclosure of Interest None Declared

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Polish Journal of Management Studies is the property of Czestochowa University of Technology, Faculty of Management and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction COVID-19 has increased the levels of psychological stress experienced by the dental team, and higher level of constant stress negatively impacts mental health. Objectives The study aimed to 1) assess dentists’ level of stress and compare it to normal population data; 2) identify the hierarchy of coping strategies chosen by dentists and their perception of those chosen by team members to manage psychological stress caused by the pandemic; and 3) to ascertain the effects of these coping strategies on dentists’ higher stress level. Methods Data from an electronic test battery comprising of general demographic and dental-related variables was collected from 182 licenced Hungarian dentists at the outset of the pandemic. Responses to an empirical series of questions regarding their perceived level of stress, choice of interventional coping skills and their perception of those used by team members were recorded. Results Dentists’ level of stress was significantly lower than the stress level measured in a Hungarian normal population (t (386)=-2.227, p=0.027), while financial status has a moderating effect (F(3,176)=4.851, p=0.003). The hierarchy of coping strategies chosen by the dentist indicated that physical activity and exercise, particularly in groups settings (M=4.78, SD=0.463), and socialization with family (M=4.72, SD=0.626) were the most effective coping management strategies, superior to financial compensation, shifting work patterns, systems level change, and decisions within the team structure. Inclusionary strategies with family (M=4.64, SD=0.587), participating in individual leisure activities (M=4.49, SD=0.621) and socializing with friends (M=4.44, SD=0.825) were seen by dentists as more important to team members. Regression analysis was used to ascertain whether the use of these coping strategies increased the likelihood of having higher levels of perceived stress. The model was significant (F(4,169)=8.292, p≤0.001) with R2 of 16.4%. Older age (B=-0.179, S.E.=0.050, t =-3.582, p≤0.001), gender (B=4.214, S.E.=1.423, t=2.961, p=0.004), active participation in developing COVID-19 protocols (B=-1.619, S.E.=0.575, t =-2.815, p=0.005) and socialization with family (B=-2.108, S.E.=1.058, t =-1.993, p=0.048) were the most effective coping mechanisms for having lower levels of perceived stress. Conclusions Our study provided insights into the value of importance attributed to perceived stress and a series of coping strategies used by the respondents and their perception of value ascribed to the same series by their team members. Active participation both in family life and in professional environment proved to be protective in such a highly stressful time like the COVID-19 pandemic. Disclosure of Interest None Declared

Introduction Premenstrual dysphoric disorder (PMDD) is a newly introduced category in the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and is highly underdiagnosed worldwide, despite its strong connections to anxiodepressive symptom severity and perceived well-being. Objectives Firstly in Hungary, our aim was to: (a)assess whether even a probable PMDD diagnosis is associated with elevated levels of depressive and anxiety symptoms, and decreased perception of well-being on an adult women sample; (b)to evaluate whether women with a probable PMDD diagnosis report greater fluctuation of their affect during the different phases of their menstrual cycle; (c)to examine whether the elevated levels of anxiodepressive symptoms and lower well-being increase the statistical likelihood of having a probable PMDD diagnosis. Methods An online test battery was designed to examine probable PMDD diagnosis, severity of anxiodepressive symptoms and well-being. 393 adult women were screened for eligibility in the study (exclusion criteria involved: irregular cycle; use of hormonal contraceptives), from which 112 were included in the final analyses. DSM-5-Based Screening Tool for Women’s Perceptions of Premenstrual Symptoms, Beck’s Depression Inventory, Spielberger’s State Anxiety Inventory, and the WHO-5 Well-Being Index were assessed. Results Based on the DSM-5-Based Screening Tool, the sample was divided into 1)women with probable PMDD diagnosis (PMDD group,n=67) and 2)women without probable PMDD (nonPMDD group,n=45). Menstruation cycles were sorted into menstrual, from-menstruation-to-ovulation, early luteal and late luteal phases. The PMDD group exhibited significantly higher depressive (F(1;56,2)=19.394, p≤0.001) and anxiety (F(1;35,6)=17.714,p≤0.001) symptom severity and lower scores of well-being (F(1;44,3)=4.288,p=0.0442) compared to the nonPMDD group regardless of which menstrual cycle they were in. Binomial logistic regression model was used to test whether higher anxiodepressive symptoms and lower scores of well-being increase the likelihood of having PMDD: the model was significant (χ2(2)=27.287, p≤0.001), and it explained 29.2% of the variance in PMDD. Elevated levels of anxiety (B=0.058, S.E.=0.022, Waldχ2(1)=7.142, p=0.008,OR=1.060) and depressive (B=0.085,S.E.=0.031,Waldχ2(1)=7.480,p=0.006,OR=1.089) symptoms increased significantly the likelihood of having a probable PMDD diagnosis. Conclusions Women with even a probable PMDD diagnosis exhibited significantly elevated levels of anxiodepressive symptoms and lower scores of well-being regardless of which menstrual phase they were assessed in compared to women without meeting the criteria of the PMDD screening tool. These preliminary results underscore the need for prospective clinical studies of differences in affective symptoms exhibited in PMDD. Disclosure of Interest None Declared

Introduction Elevated levels of anxio-depressive symptoms and perceived stress are widely researched in case of female factor infertility; however, there is scant information on their emergence in case of male factor infertility. Objectives The aim of the present study is to assess whether a 5-course paramedical counselling accompanying infertility treatment would have a decreasing impact on anxio-depressive symptom severity and perceived stress and would increase the level of self-esteem in infertile men. Methods 108 patients were divided into control (n = 51) and experimental (n = 57) groups, where the latter participated in the aforementioned paramedical counselling. Anxio-depressive symptom severity was measured with the Beck Depression Inventory and the Spielberger’s State Anxiety Inventory; perceived stress was registered with the Perceived Stress Scale and Brief Stress and Coping Inventory, while self-esteem was evaluated by the Rosenberg Self-Esteem Scale. Results Participation in an infertility programme itself affected positively patients’ self-esteem and decreased their levels of depressive symptom severity (t(50) = 2.738, p = 0.009, 95%CI = 0.167 – 1.088), but an additional 5-session paramedical counselling resulted in a significant lowering of state anxiety symptoms (t(106) = -2.093, p = 0.039, 95%CI = -6.372 – 0.173) contrasted with infertile men not receiving this additional counselling. Conclusions Conclusion: Screening for psychological factors is advisable in the course of an infertility treatment, and the implementation of an accompanying paramedical counselling focusing on the alleviation of concomitant psychopathological symptoms would be advisable among male infertile patients. Disclosure No significant relationships.

Non-destructive prompt gamma activation analysis (PGAA), neutron radiography (NR) and high resolution time-of-flight neutron diffraction (TOF-ND) have been applied to investigate metal archaeological artefacts belonging to the Academia Georgica Treiensis (AGT) collection. 8 archaeological items have been analysed, by using the facilities of the Budapest Neutron Centre (BNC). Some of these objects mostly dating back probably to the VI-IV century B.C. and presumed to be discovered in the Marche Region, Italy. The primary goal of the analyses was to advance the correct technological and material description of the objects, providing scientific data for further and more comprehensive comparative analyses also covering the find material from the close archaeological sites. The neutron investigations allowed determining the bulk composition, also providing either a qualitative and quantitative assessment of the phase composition and the structural properties of the constituents, or radiographic images, which would finally help to identify possible manufacturing techniques. Additional examinations, carried out by external milli-beam particle induced X-ray emission spectroscopy (PIXE), provided quantitative analyses of major and trace elements (e.g., Fe, Pb and As) in order to recognize the constitutive alloys and to supply information on the near-surface elemental composition, complementary to the data characteristic for the bulk. The obtained results, thought to be useful to set up a classification according to the chemical composition, and this way allow achieving important information related to the possible provenance of the objects.

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health., (© 2024. The Author(s).)

We investigated the association between the SDF-1-3' (c801G > A) variant and the development of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR) in a Hungarian cohort. SDF-1-3' (c801G > A) was genotyped in 103 patients with diabetic retinopathy and 31 age- and sex-matched non-diabetic controls. Central retinal and choroidal thickness was measured by swept-source optical coherence tomography. The distribution of heterozygous and homozygous SDF-1-3' (c801G > A) genotypes was similar in diabetic and control subjects. The SDF-3'(c801AA) genotype was associated with DME ( n = 94 eyes, allele distribution p = 0.006, genotype distribution p = 0.01 OR: 2.48, 95% CL: 1.21-5.08) in both univariable and multivariable modelling, independent of duration and type of diabetes, HbA1C, hypertension and microalbuminuria ( p = 0.03). DME occurred earlier in patients carrying the SDF-1 (c801A) allele (Kaplan-Meier analysis, log-rank test p = 0.02). A marginally significant association was found between the presence of the SDF-1 (c801A) allele and the development of PDR ( n = 89 eyes, p = 0.06). The SDF-1-3' (c801A) allele also showed a correlation with central retinal ( p = 0.006) and choroidal ( p = 0.08) thickness. SDF-1-3' (c801G > A) is involved in the development of macular complications in DM independent of critical clinical factors, suggesting that SDF-1 may be a future therapeutic target for high-risk patients, especially those carrying the SDF-1 (c801A) allele.

Machine learning-based systems have become instrumental in augmenting global efforts to combat cervical cancer. A burgeoning area of research focuses on leveraging artificial intelligence to enhance the cervical screening process, primarily through the exhaustive examination of Pap smears, traditionally reliant on the meticulous and labor-intensive analysis conducted by specialized experts. Despite the existence of some comprehensive and readily accessible datasets, the field is presently constrained by the limited volume of publicly available images and smears. As a remedy, our work unveils APACC (Annotated PAp cell images and smear slices for Cell Classification), a comprehensive dataset designed to bridge this gap. The APACC dataset features a remarkable array of images crucial for advancing research in this field. It comprises 103,675 annotated cell images, carefully extracted from 107 whole smears, which are further divided into 21,371 sub-regions for a more refined analysis. This dataset includes a vast number of cell images from conventional Pap smears and their specific locations on each smear, offering a valuable resource for in-depth investigation and study., (© 2024. The Author(s).)

A simple and cheap way to recognize cervical cancer is using light microscopic analysis of Pap smear images. Training artificial intelligence-based systems becomes possible in this domain, e.g., to follow the European recommendation to screen negative smears to reduce false negative cases. The first step for such a process is segmenting the cells. A large and manually segmented dataset is required for this task, which can be used to train deep learning-based solutions. We describe a corresponding dataset with accurate manual segmentations for the enclosed cells. Altogether, the APACS23 (Annotated PAp smear images for Cell Segmentation 2023) dataset contains about 37 000 manually segmented cells and is separated into dedicated training and test parts, which could be used for an official benchmark of scientific investigations or a grand challenge., (© 2024. The Author(s).)

Background: The prevalence of medical illnesses is high among patients with psychiatric disorders. The current study aimed to investigate multi-comorbidity in patients with psychiatric disorders in comparison to the general population. Secondary aims were to investigate factors associated with metabolic syndrome and treatment appropriateness of mental disorders., Methods: The sample included 54,826 subjects (64.73% females; 34.15% males; 1.11% nonbinary gender) from 40 countries (COMET-G study). The analysis was based on the registration of previous history that could serve as a fair approximation for the lifetime prevalence of various medical conditions., Results: About 24.5% reported a history of somatic and 26.14% of mental disorders. Mental disorders were by far the most prevalent group of medical conditions. Comorbidity of any somatic with any mental disorder was reported by 8.21%. One-third to almost two-thirds of somatic patients were also suffering from a mental disorder depending on the severity and multicomorbidity. Bipolar and psychotic patients and to a lesser extent depressives, manifested an earlier (15-20 years) manifestation of somatic multicomorbidity, severe disability, and probably earlier death. The overwhelming majority of patients with mental disorders were not receiving treatment or were being treated in a way that was not recommended. Antipsychotics and antidepressants were not related to the development of metabolic syndrome., Conclusions: The finding that one-third to almost two-thirds of somatic patients also suffered from a mental disorder strongly suggests that psychiatry is the field with the most trans-specialty and interdisciplinary value and application points to the importance of teaching psychiatry and mental health in medical schools and also to the need for more technocratically oriented training of psychiatric residents.

The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms., Competing Interests: Declaration of interests S.H., C.M.G., L.A.B., and J.V.H. own intellectual property on the classification of SCLC from DNA methylation and gene expression. S.H. reports consulting fees from Guardant Health, AstraZeneca, Boehringer Ingelheim, and Qiagen. C.M.G. is a member of the advisory board at Jazz Pharmaceuticals, AstraZeneca, and Bristol Myers Squibb and served as speaker for AstraZeneca and BeiGene. L.A.B. received consulting fees and research funding from AstraZeneca, GenMab, and Sierra Oncology and research funding from ToleroPharmaceuticals and served as advisor or consultant for PharmaMar, AbbVie, Bristol-Myers Squibb, Alethia, Merck, Pfizer, Jazz Pharmaceuticals, Genentech, and Debiopharm Group. J.V.H. served as advisor for AstraZeneca, EMD Serono, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion, and Chugai Pharmaceuticals and received research support from AstraZeneca, GlaxoSmithKline, and Spectrum as well as royalties and licensing fees from Spectrum., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The current study aimed to investigate the rates of anxiety, clinical depression, and suicidality and their changes in health professionals during the COVID-19 outbreak., Materials and Methods: The data came from the larger COMET-G study. The study sample includes 12,792 health professionals from 40 countries (62.40% women aged 39.76 ± 11.70; 36.81% men aged 35.91 ± 11.00 and 0.78% non-binary gender aged 35.15 ± 13.03). Distress and clinical depression were identified with the use of a previously developed cut-off and algorithm, respectively., Statistical Analysis: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses, and Factorial Analysis of Variance (ANOVA) tested relations among variables., Results: Clinical depression was detected in 13.16% with male doctors and 'non-binary genders' having the lowest rates (7.89 and 5.88% respectively) and 'non-binary gender' nurses and administrative staff had the highest (37.50%); distress was present in 15.19%. A significant percentage reported a deterioration in mental state, family dynamics, and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (24.64% vs. 9.62%; p < 0.0001). Suicidal tendencies were at least doubled in terms of RASS scores. Approximately one-third of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop clinical depression was associated with a history of Bipolar disorder (RR = 4.23)., Conclusions: The current study reported findings in health care professionals similar in magnitude and quality to those reported earlier in the general population although rates of clinical depression, suicidal tendencies, and adherence to conspiracy theories were much lower. However, the general model of factors interplay seems to be the same and this could be of practical utility since many of these factors are modifiable., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Primary open-angle glaucoma remains a global issue, lacking a definitive treatment. Increased intraocular pressure (IOP) is considered the primary risk factor of the disease and it can be caused by fibrotic-like changes in the trabecular meshwork (TM) such as increased tissue stiffness and outflow resistance. Previously, we demonstrated that the sigma-1 receptor (S1R) agonist fluvoxamine (FLU) has anti-fibrotic properties in the kidney and lung. In this study, the localization of the S1R in TM cells was determined, and the anti-fibrotic efficacy of FLU was examined in both mouse and human TM cells. Treatment with FLU reduced the F-actin rearrangement, inhibited cell proliferation and migration induced by the platelet-derived growth factor and decreased the levels of fibrotic proteins. The protective role of the S1R in fibrosis was confirmed by a more pronounced increase in alpha smooth muscle actin and F-actin bundle and clump formation in primary mouse S1R knockout TM cells. Furthermore, FLU demonstrated its protective effects by increasing the production of nitric oxide and facilitating the degradation of the extracellular matrix through the elevation of cathepsin K. These findings suggest that the S1R could be a novel target for the development of anti-fibrotic drugs and offer a new therapeutic approach for glaucoma.

The trabecular meshwork (TM) route is the principal outflow egress of the aqueous humor. Actin cytoskeletal remodeling in the TM and extracellular matrix (ECM) deposition increase TM stiffness, outflow resistance, and elevate intraocular pressure (IOP). These alterations are strongly linked to transforming growth factor-β2 (TGFβ2), a known profibrotic cytokine that is markedly elevated in the aqueous humor of glaucomatous eyes. Sigma-1 receptor (S1R) has been shown to have neuroprotective effects in the retina, but data are lacking about its role in the TM. In this study, we identified the presence of S1R in mouse TM tissue and investigated the effect of an S1R agonist fluvoxamine (FLU) on TGFβ2-induced human TM cells regarding cell proliferation; ECM-related functions, including F-actin reorganization; and the accumulation of ECM elements. TGFβ2 increased the proliferation, cytoskeletal remodeling, and protein levels of fibronectin, collagen type IV, and connective tissue growth factor, and decreased the level of matrix metalloproteinase-2. Most importantly, FLU reversed all these effects of TGFβ2, suggesting that S1R agonists could be potential candidates for preserving TM function and thus maintaining normal IOP.

Background: No targeted drugs are currently available against small cell lung cancer (SCLC). BCL-2 family members are involved in apoptosis regulation and represent therapeutic targets in many malignancies., Methods: Expression of BCL-2 family members in 27 SCLC cell lines representing all known four SCLC molecular subtypes was assessed by qPCR, Western blot and mass spectrometry-based proteomics. BCL-2 and MCL-1 inhibition (venetoclax and S63845, respectively) was assessed by MTT assay and flow cytometry and in mice bearing human SCLC tumours. Drug interactions were calculated using the Combenefit software. Ectopic BAX overexpression was achieved by expression plasmids., Results: The highest BCL-2 expression levels were detected in ASCL1- and POU2F3-driven SCLC cells. Although sensitivity to venetoclax was reflected by BCL-2 levels, not all cell lines responded consistently despite their high BCL-2 expression. MCL-1 overexpression and low BAX levels were both characteristic for venetoclax resistance in SCLC, whereas the expression of other BCL-2 family members did not affect therapeutic efficacy. Combination of venetoclax and S63845 resulted in significant, synergistic in vitro and in vivo anti-tumour activity and apoptosis induction in double-resistant cells; however, this was seen only in a subset with detectable BAX. In non-responding cells, ectopic BAX overexpression sensitised to venetoclax and S63845 and, furthermore, induced synergistic drug interaction., Conclusions: The current study reveals the subtype specificity of BCL-2 expression and sheds light on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Anti-vascular endothelial growth factor (VEGF) therapy is currently the most effective therapy of exudative age-related macular degeneration (AMD). The aim of this study was to assess long-term benefits of intensive aflibercept and ranibizumab anti-VEGF therapy in patients with exudative AMD., Methods: Two clinical trial sites recruited their original subjects for a re-evaluation 7 years after the baseline visit of the phase-3 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (VIEW 2) trial. Forty-seven eyes of 47 patients with AMD originally treated with ranibizumab (14 eyes) or aflibercept (33 eyes) were included., Results: Mean number of injections was 17.8 ± 3.0 during participation in the VIEW 2 trial. Fourteen of 47 (30%) eyes were given additional injections with a mean number of 5.7 ± 4.5 after the trial. At a mean follow-up time of 82 ± 5 months best corrected visual acuity (BCVA) remained stable or improved (≤ 10 letters lost) in 55% of patients in the entire study population, in 43% in the ranibizumab group and in 60% in the aflibercept group. In both groups combined mean BCVA was 54 ± 13 letters at baseline, 65 ± 17 letters at the end of the intensive phase and 45 ± 25 letters at the end of follow-up. There was no statistically significant difference in BCVA between the two groups at baseline (p = 0.88) and at the end of follow-up (p = 0.40). Macular atrophy was observed in 96% of eyes, average area was 7.22 ± 6.31 mm 2 with no statistically significant difference between groups (p = 0.47). Correlation between BCVA at end-of-follow-up and the area of atrophy was significant (p < 0.001). At the end of follow-up, fluid was detected in 7 of 47 eyes (15%) indicating disease activity., Conclusion: Long-term efficacy of aflibercept and ranibizumab was largely consistent. Following a two-year intensive therapy with as-needed regimen, BCVA was maintained or improved in almost half of the patients and in the ranibizumab group and more than half of the patients in the aflibercept group with very few injections. In a remarkable proportion of eyes, BCVA declined severely which underlines the need for long-term follow-ups and may indicate a more prolonged intensive therapy., Trial Registrations: VIEW 2 study: ClinicalTrials.gov ID: NCT00637377, date of registration: March 18, 2008. Long-term follow-up: IRB nr.: SE RKEB 168/2022, ClinicalTrials.gov ID: NCT05678517, date of registration: December 28, 2022, retrospectively registered., (© 2023. The Author(s).)

Serious mental illness is a chronic condition that requires long-term pharmacological treatment. Adherence to oral antipsychotic medication has specific nuances that affects patients and physicians alike. For patients with serious mental illness, nonadherence increases their risk of hospitalization and relapse. Nonadherence is a formidable barrier for physicians in accurately assessing medication efficacy and helping patients achieve their fullest potential. A digital adherence system approved by the Food and Drug Administration can provide near-real time aripiprazole ingestion information. The system records ingestions through an embedded ingestible sensor in oral aripiprazole, which sends a transient local signal to a patch worn on the patient's torso that is then stored on a paired smartphone app. With patient permission, these data can be viewed remotely by their physician, along with a patient's mood, activity, and time spent resting. Such data are able to do the following: reveal broad patterns of medication adherence behavior to the patient as well as their physician; help physicians and patients understand and create more realistic expectations for adherence; promote discussion of treatment options; and minimize therapeutic appointment time devoted to determining actual adherence, thereby maximizing the time available to address each patient's distinctive reasons for their adherence pattern. Crucially, extra time created during appointments can be used to strengthen the therapeutic relationship, which may translate into both improvements in adherence and patient attitude toward their medication. Future investigations are needed to examine how this technology impacts the development of training and best practice guidelines for its use. Otherwise, the potential benefits of this technology may be lost, or worse, inadequate and inappropriate use may harm the therapeutic relationship., (©Anabel G Richey, Ildiko Kovacs, Sara Browne. Originally published in JMIR Mental Health (https://mental.jmir.org), 02.12.2022.)

Introduction: During the COVID-19 pandemic various degrees of lockdown were applied by countries around the world. It is considered that such measures have an adverse effect on mental health but the relationship of measure intensity with the mental health effect has not been thoroughly studied. Here we report data from the larger COMET-G study pertaining to this question., Material and Methods: During the COVID-19 pandemic, data were gathered with an online questionnaire from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Anxiety was measured with the STAI, depression with the CES-D and suicidality with the RASS. Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively., Statistical Analysis: It included the calculation of Relative Risk (RR), Factorial ANOVA and Multiple backwards stepwise linear regression analysis RESULTS: Approximately two-thirds were currently living under significant restrictions due to lockdown. For both males and females the risk to develop clinical depression correlated significantly with each and every level of increasing lockdown degree (RR 1.72 and 1.90 respectively). The combined lockdown and psychiatric history increased RR to 6.88 The overall relationship of lockdown with severity of depression, though significant was small., Conclusions: The current study is the first which reports an almost linear relationship between lockdown degree and effect in mental health. Our findings, support previous suggestions concerning the need for a proactive targeted intervention to protect mental health more specifically in vulnerable groups., (Copyright © 2022. Published by Elsevier B.V.)

Background: The microanatomical steps of malignant pleural mesothelioma (MPM) vascularization and the resistance mechanisms to anti-angiogenic drugs in MPM are unclear., Methods: We investigated the vascularization of intrapleurally implanted human P31 and SPC111 MPM cells. We also assessed MPM cell's motility, invasion and interaction with endothelial cells in vitro ., Results: P31 cells exhibited significantly higher two-dimensional (2D) motility and three-dimensional (3D) invasion than SPC111 cells in vitro . In co-cultures of MPM and endothelial cells, P31 spheroids permitted endothelial sprouting (ES) with minimal spatial distortion, whereas SPC111 spheroids repealed endothelial sprouts. Both MPM lines induced the early onset of submesothelial microvascular plexuses covering large pleural areas including regions distant from tumor colonies. The development of these microvascular networks occurred due to both intussusceptive angiogenesis (IA) and ES and was accelerated by vascular endothelial growth factor A (VEGF-A)-overexpression. Notably, SPC111 colonies showed different behavior to P31 cells. P31 nodules incorporated tumor-induced capillary plexuses from the earliest stages of tumor formation. P31 cells deposited a collagenous matrix of human origin which provided "space" for further intratumoral angiogenesis. In contrast, SPC111 colonies pushed the capillary plexuses away and thus remained avascular for weeks. The key event in SPC111 vascularization was the development of a desmoplastic matrix of mouse origin. Continuously invaded by SPC111 cells, this matrix transformed into intratumoral connective tissue trunks, providing a route for ES from the diaphragm., Conclusions: Here, we report two distinct growth patterns of orthotopically implanted human MPM xenografts. In the invasive pattern, MPM cells invade and thus co-opt peritumoral capillary plexuses. In the pushing/desmoplastic pattern, MPM cells induce a desmoplastic response within the underlying tissue which allows the ingrowth of a nutritive vasculature from the pleura., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-21-828/coif). BD, BH and VL were supported by the Austrian Science Fund (FWF I2872 to BH; FWF I3522 to VL; FWF I3977 and I4677 to BD). BD, ZM, IH, SP and AC acknowledge funding from the Hungarian National Research, Development and Innovation Office (KH130356 and KKP126790 to BD; 2020-1.1.6-JÖVŐ and TKP2021-EGA-33 to BD and ZM; ANN128666 to IH; SNN 114490 to SP; ANN 132225 to AC). VL is a recipient of the Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology. ZM was supported by the UNKP-20-3 and UNKP-21-3 New National Excellence Program of the Ministry for Innovation and Technology of Hungary, and by the Hungarian Respiratory Society (MPA #2020). ZL was supported by the ESMO Translational Research Fellowship. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Candida auris is a multidrug-resistant fungus against which in some clinical situations amphotericin B (AMB) remains the alternative or first line drug. We compared daily 1 mg/kg of AMB efficacy in a neutropenic murine bloodstream infection model against 10 isolates representing four C. auris clades (South Asian n = 2; East Asian n = 2; South African n = 2; South American n = 4; two of which were of environmental origin). Five days of AMB treatment significantly increased the survival rates in mice infected with isolates of the East Asian clade, and 1 isolate each from the South African and South American clades (originated from bloodstream), but not in mice infected with the South Asian and 2 environmental isolates from the South American clades. AMB treatment decreased the fungal burden in mice infected with the 2 isolates each from East Asian and South African, and 1 out of 2 bloodstream isolates from South American clades in the hearts (p < 0.01), kidneys (p < 0.01) and brain (p < 0.05). AMB treatment, regardless of clades, significantly decreased colony forming units in the urine at day 3. However, histopathological examination in AMB-treated mice revealed large aggregates of yeast cells in the kidneys and hearts, and focal lesions in the cerebra and cerebelli, regardless of precise C. auris clade. Our clade-specific data confirm that the efficacy of AMB against C. auris is weak, explaining the therapeutic failures in clinical situations. Our results draw attention to the necessity to maximize the killing at the start of treatment to avoid later complications in the heart and central nervous system.

Loss of midbrain dopamine neurons causes the cardinal symptoms of Parkinson's disease. However, not all dopamine neurons are equally vulnerable and a better understanding of the cell-type specific properties relating to selective dopamine neuron degeneration is needed. Most midbrain dopamine neurons express the vesicular glutamate transporter VGLUT2 during development and a subset continue to express low levels of VGLUT2 in adulthood, enabling the co-release of glutamate. Moreover, VGLUT2 expression in dopamine neurons can be neuroprotective since its genetic disruption was shown to sensitize dopamine neurons to neurotoxins. Here, we show that in response to toxic insult, and in two distinct models of alpha-synuclein stress, VGLUT2 dopamine neurons were resilient to degeneration. Dopamine neurons expressing VGLUT2 were enriched whether or not insult induced dopamine neuron loss, suggesting that while VGLUT2 dopamine neurons are more resilient, VGLUT2 expression can also be transcriptionally upregulated by injury. Finally, we observed that VGLUT2 expression was enhanced in surviving dopamine neurons from post-mortem Parkinson's disease individuals. These data indicate that emergence of a glutamatergic identity in dopamine neurons may be part of a neuroprotective response in Parkinson's disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: There are few published empirical data on the effects of COVID-19 on mental health, and until now, there is no large international study., Material and Methods: During the COVID-19 pandemic, an online questionnaire gathered data from 55,589 participants from 40 countries (64.85% females aged 35.80 ± 13.61; 34.05% males aged 34.90±13.29 and 1.10% other aged 31.64±13.15). Distress and probable depression were identified with the use of a previously developed cut-off and algorithm respectively., Statistical Analysis: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses and Factorial Analysis of Variance (ANOVA) tested relations among variables., Results: Probable depression was detected in 17.80% and distress in 16.71%. A significant percentage reported a deterioration in mental state, family dynamics and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (31.82% vs. 13.07%). At least half of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop depression was associated with history of Bipolar disorder and self-harm/attempts (RR = 5.88). Suicidality was not increased in persons without a history of any mental disorder. Based on these results a model was developed., Conclusions: The final model revealed multiple vulnerabilities and an interplay leading from simple anxiety to probable depression and suicidality through distress. This could be of practical utility since many of these factors are modifiable. Future research and interventions should specifically focus on them., Competing Interests: Conflict of Interest None pertaining to the current paper., (Copyright © 2021 Elsevier B.V. and ECNP. All rights reserved.)

In trauma and orthopedic surgery, limb ischemia-reperfusion (I/R) remains a great challenge. The effect of preventive protocols, including surgical conditioning approaches, is still controversial. We aimed to examine the effects of local ischemic pre-conditioning (PreC) and post-conditioning (PostC) on limb I/R. Anesthetized rats were randomized into sham-operated (control), I/R (120-min limb ischemia with tourniquet), PreC, or PostC groups (3 × 10-min tourniquet ischemia, 10-min reperfusion intervals). Blood samples were taken before and just after the ischemia, and on the first postoperative week for testing hematological, micro-rheological (erythrocyte deformability and aggregation), and metabolic parameters. Histological samples were also taken. Erythrocyte count, hemoglobin, and hematocrit values decreased, while after a temporary decrease, platelet count increased in I/R groups. Erythrocyte deformability impairment and aggregation enhancement were seen after ischemia, more obviously in the PreC group, and less in PostC. Blood pH decreased in all I/R groups. The elevation of creatinine and lactate concentration was the largest in PostC group. Histology did not reveal important differences. In conclusion, limb I/R caused micro-rheological impairment with hematological and metabolic changes. Ischemic pre- and post-conditioning had additive changes in various manners. Post-conditioning showed better micro-rheological effects. However, by these parameters it cannot be decided which protocol is better.

Background: A link between mental health and freedom of choice has long been established, in fact, the loss of freedom of choice is one of the possible defining features of mental disorders. Freedom of choice has internal and external aspects explicitly identified within the capability approach, but received little explicit attention in capability instruments. This study aimed to develop a feasible and linguistically and culturally appropriate Hungarian version of the Oxford CAPabilities questionnaire-Mental Health (OxCAP-MH) for mental health outcome measurement., Methods: Following forward and back translations, a reconciled Hungarian version of the OxCAP-MH was developed following professional consensus guidelines of the International Society for Pharmacoeconomics and Outcomes Research and the WHO. The wording of the questionnaire underwent cultural and linguistic validation through content analysis of cognitive debriefing interviews with 11 Hungarian speaking mental health patients in 2019. Results were compared with those from the development of the German version and the original English version with special focus on linguistic aspects., Results: Twenty-nine phrases were translated. There were linguistic differences in each question and answer options due to the high number of inflected, affixed words and word fragments that characterize the Hungarian language in general. Major linguistic differences were also revealed between the internal and external aspects of capability freedom of choices which appear much more explicit in the Hungarian than in the English or German languages. A re-analysis of the capability freedom of choice concepts in the existing language versions exposed the need for minor amendments also in the English version in order to allow the development of future culturally, linguistically and conceptually valid translations., Conclusion: The internal and external freedom of choice impacts of mental health conditions require different care/policy measures. Their explicit consideration is necessary for the conceptually harmonised operationalisation of the capability approach for (mental) health outcome measurement in diverse cultural and linguistic contexts., (© 2021. The Author(s).)

The COVID-19 pandemic has had a major impact on cardiovascular emergencies. The aim of this study was to investigate the impact of the COVID-19 pandemic on a regional network for management of ST-segment elevation acute myocardial infarction (STEMI)., Methods: We report a single center's experience of patients hospitalized for ACS in a high-volume hub of a STEMI network during the lockdown (in the first pandemic trimester), compared with the same time interval of the previous year and including all consecutive patients referred for an AMI during the second trimester of 2020 (from April to June) or during the same time interval of the previous year, 2019., Results: The absolute number of hospital admissions for AMI decreased by 22.3%, while the non-AMI hospitalizations decreased by 77.14% in Q2-2020 compared to Q2-2019 (210 vs. 48, p < 0.0001). As a consequence, the percentage of AMI cases from the total number of hospital admission increased from 38% to 68% ( p < 0.0001), AMI becoming the dominant pathology. In the STEMI group there was a significant reduction of 55% in the absolute number of late STEMI presentations. Functionality of the STEMI network at the hub level did not present a significant alteration with only a minor increase in the door-to-balloon time, from 34 min to 41 min. However, at the level of the network we recorded a lower number of critical cases transferred to the interventional center, with a dramatic reduction of 56.1% in the number of critical STEMI cases arriving in the acute cardiac care unit (17.0% vs. 7.3%, p -0.04 for KILLIP class III, and 21.17% vs. 11.11%, p = 0.08 for resuscitated out of hospital cardiac arrest)., Conclusions: The COVID-19 outbreak did not have a major impact on the interventional center's functionality, but it limited the capacity of the regional STEMI network to bring the critical patient with complicated STEMI to the cathlab in time during the first months of the lockdown. Even a very well-functioning STEMI network like the one in Central Romania had difficulties bringing the most critical STEMI cases to the cathlab in time.

Aim: Migration is a constantly changing adaptation due to the climate condition evolution. The struggle for surviving during harsh winter season is different across Europe, being more complex toward the inner parts of the continent. The current approach explores the Common Buzzard number variation during the cold season and the climatic predictors of birds of prey wintering movements in relation to the possible influences of the Carpathian Mountains, which may act as a geographical barrier providing shelter from cold air outbreak from north and northeast of the continent., Location: Romania (45°N25°E)., Taxon: Birds of Prey., Methods: We applied a GLMM to investigate the relation between continental and local climatic factors with the number of Common Buzzard observations in two regions. The first region is located inside the Carpathian Arch and the other one outside, east of this large mountains chain., Results: The Common Buzzard numbers wintering Eastern from the Carpathian Mountains are highly influenced by AO ( Z  = 2.87, p  < .05%), while those wintering western are influenced by NAO ( Z  = 2.17, p  < .05%). This is the first proof of separating influences for biodiversity of AO and NAO at continental scale, outlining the influence limit placed over the Eastern Carpathian Mountains., Main Conclusions: The Carpathian Mountains act like a geographic barrier, separating the wintering Common Buzzard populations from both sides of the mountain range. While the high number of individuals in Moldova is related to their eastern and northeastern Europe origins, in Transylvania the large number of individuals observed is related to the more sheltered characteristics of the region attracting individuals from central Europe. Also, since Transylvania region is well sheltered during cold air outbreak, it represents a more favorable region for wintering. From this point of view, we can consider that the Carpathian Mountains are a geographic barrier for wintering birds of prey., Competing Interests: None declared., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

The COVID-2019 pandemic has presented a new situation affecting not only the somatic but the mental health of people worldwide and exposing the world including healthcare professionals to a challenge never experienced before. Therefore its effects on mental health, although can be estimated, but cannot be predicted, thus we are only halfways prepared for understanding as well as screening, preventing and treating the pandemic-related mental health problems. For this reason, the Mental Health Sector of the Scientific Researches Institute of the Pan-Hellenic Medical Association prepared a large, international online, general population study with participation from over 42 countries, assessing various aspects of general mental function, needs and behaviors that could occur during the COVID-19 outbreak, as a result of either the outbreak itself or the social measures adopted in order to control it. While the study is ongoing, here we present the first descriptive results from the Hungarian study sample including 738 adult participants collected during the first wave of COVID-19-associated lockdown, focusing on differences in the effect of COVID-19 on psychological and lifestyle measures, as well as attitudes towards the pandemic between mentally healthy participants and people with mental disorders.

Candida auris is an emerging worldwide concern, but comparative data about the virulence of different C. auris lineages in mammalian hosts is lacking. Different isolates of the four prevalent C. auris clades (South Asian n = 5, East Asian n = 4, South African n = 5, and South American n = 5) were compared to assess their virulence in a neutropenic murine bloodstream infection model with C. albicans as reference. C. auris , regardless of clade, proved to be less virulent than C. albicans. Highest overall mortality at day 21 was observed for the South American clade (96%), followed by the South Asian (80%), South African (45%) and East Asian (44%) clades. Fungal burden results showed close correlation with lethality. Histopathological examination revealed large aggregates of blastoconidia and budding yeast cells in the hearts, kidneys and livers but not in the spleens. The myocardium of apparently healthy sacrificed mice as well as of mice found moribund showed contraction band necrosis in case of all lineages. Regardless of clade, the heart and kidneys were the most heavily affected organs. Isolates of the same clade showed differences in virulence in mice, but a markedly higher virulence of the South American clade was clearly demonstrated.

Malignant pleural mesothelioma (MPM) has an overall poor prognosis and unsatisfactory treatment options. MPM nodules, protruding into the pleural cavity may have growth and spreading dynamics distinct that of other solid tumors. We demonstrate that multicellular aggregates can develop spontaneously in the majority of tested MPM cell lines when cultured at high cell density. Surprisingly, the nodule-like aggregates do not arise by excessive local cell proliferation, but by myosin II-driven cell contractility. Prominent actin cables, spanning several cells, are abundant both in cultured aggregates and in MPM surgical specimens. We propose a computational model for in vitro MPM nodule development. Such a self-tensioned Maxwell fluid exhibits a pattern-forming instability that was studied by analytical tools and computer simulations. Altogether, our findings may underline a rational for targeting the actomyosin system in MPM.

Nerve growth factor (NGF) gene therapy rescues and stimulates cholinergic neurons, which degenerate in Alzheimer's disease (AD). In a recent clinical trial for AD, intraparenchymal adeno-associated virus serotype 2 (AAV2)-NGF delivery was safe but did not improve cognition. Before concluding that NGF gene therapy is ineffective, it must be shown that AAV2-NGF successfully engaged the target cholinergic neurons of the basal forebrain. In this study, patients with clinically diagnosed early- to middle-stage AD received a total dose of 2 × 10 11 vector genomes of AAV2-NGF by stereotactic injection of the nucleus basalis of Meynert. After a mean survival of 4.0 years, AAV2-NGF targeting, spread, and expression were assessed by immunolabeling of NGF and the low-affinity NGF receptor p75 at 15 delivery sites in 3 autopsied patients. NGF gene expression persisted for at least 7 years at sites of AAV2-NGF injection. However, the mean distance of AAV2-NGF spread was only 0.96 ± 0.34 mm. NGF did not directly reach cholinergic neurons at any of the 15 injection sites due to limited spread and inaccurate stereotactic targeting. Because AAV2-NGF did not directly engage the target cholinergic neurons, we cannot conclude that growth factor gene therapy is ineffective for AD. Upcoming clinical trials for AD will utilize real-time magnetic resonance imaging guidance and convection-enhanced delivery to improve the targeting and spread of growth factor gene delivery.

Introduction: Atrial Fibrillation (AF) is associated with remodeling of the atrial tissue, which leads to fibrosis that can contribute to the initiation and maintenance of AF. Delayed- Enhanced Cardiac Magnetic Resonance (DE-CMR) imaging for atrial wall fibrosis detection was used in several studies to guide AF ablation. The aim of present study was to systematically review the literature on the role of atrial fibrosis detected by DE-CMR imaging on AF ablation outcome., Methods: Eight bibliographic electronic databases were searched to identify all published relevant studies until 21st of March, 2016. Search of the scientific literature was performed for studies describing DE-CMR imaging on atrial fibrosis in AF patients underwent Pulmonary Vein Isolation (PVI)., Results: Of the 763 citations reviewed for eligibility, 5 articles (enrolling a total of 1040 patients) were included into the final analysis. The overall recurrence of AF ranged from 24.4 - 40.9% with median follow-up of 324 to 540 days after PVI. With less than 5-10% fibrosis in the atrial wall there was a maximum of 10% recurrence of AF after ablation. With more than 35% fibrosis in the atrial wall there was 86% recurrence of AF after ablation., Conclusion: Our analysis suggests that more extensive left atrial wall fibrosis prior ablation predicts the higher arrhythmia recurrence rate after PVI. The DE-CMR imaging modality seems to be a useful method for identifying the ideal candidate for catheter ablation. Our findings encourage wider usage of DE-CMR in distinct AF patients in a pre-ablation setting., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aging of the microcirculatory network plays a central role in the pathogenesis of a wide range of age-related diseases, from heart failure to Alzheimer's disease. In the eye, changes in the choroid and choroidal microcirculation (choriocapillaris) also occur with age, and these changes can play a critical role in the pathogenesis of age-related macular degeneration (AMD). In order to develop novel treatments for amelioration of choriocapillaris aging and prevention of AMD, it is essential to understand the cellular and functional changes that occur in the choroid and choriocapillaris during aging. In this review, recent advances in in vivo analysis of choroidal structure and function in AMD patients and patients at risk for AMD are discussed. The pathophysiological roles of fundamental cellular and molecular mechanisms of aging including oxidative stress, mitochondrial dysfunction, and impaired resistance to molecular stressors in the choriocapillaris are also considered in terms of their contribution to the pathogenesis of AMD. The pathogenic roles of cardiovascular risk factors that exacerbate microvascular aging processes, such as smoking, hypertension, and obesity as they relate to AMD and choroid and choriocapillaris changes in patients with these cardiovascular risk factors, are also discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay AMD by targeting fundamental cellular and molecular aging processes are presented.

Introduction: While the role of inflammation in acute coronary events is well established, the impact of inflammatory-mediated vulnerability of coronary plaques from the entire coronary tree, on the extension of ventricular remodeling and scaring, has not been clarified yet., Materials and Methods: The present manuscript describes the procedures of the VIABILITY trial, a descriptive prospective single-center cohort study. The main purpose of this trial is to assess the link between systemic inflammation, pan-coronary plaque vulnerability (referring to the plaque vulnerability within the entire coronary tree), myocardial viability and ventricular remodeling in patients who had suffered a recent ST-segment elevation acute myocardial infarction (STEMI). One hundred patients with STEMI who underwent successful revascularization of the culprit lesion in the first 12 hours after the onset of symptoms will be enrolled in the study. The level of systemic inflammation will be evaluated based on the serum biomarker levels (hs-CRP, matrix metalloproteinases, interleukin-6) in the acute phase of the myocardial infarction (MI) and at 1 month. Pan-coronary plaque vulnerability will be assessed based on serum biomarkers known to be associated with increased plaque vulnerability (V-CAM or I-CAM) and at 1 month after infarction, based on computed tomographic angiography analysis of vulnerability features of all coronary plaques. Myocardial viability and remodeling will be assessed based on 3D speckle tracking echocardiography associated with dobutamine infusion and LGE-CMR associated with post-processing imaging methods. The study population will be categorized in 2 subgroups: subgroup 1 - subjects with STEMI and increased inflammatory response at 7 days after the acute event (hs-CRP ≥ 3 mg/dl), and subgroup 2 - subjects with STEMI and no increased inflammatory response at 7 days (hs-CRP < 3 mg/dl). Study outcomes will consist in the rate of post-infarction heart failure development and the major adverse events (MACE) rate., Conclusion: VIABILITY is the first prospective study designed to evaluate the influence of infarct-related inflammatory response on several major determinants of post-infarction outcomes, such as coronary plaque vulnerability, myocardial viability, and ventricular remodeling.

Introduction: Interventional ablation has been demonstrated to represent an effective therapy in patients with atrial fibrillation (AF), leading to restoration and maintenance of sinus rhythm in the majority of cases. However, recurrence of AF is encountered in 35% to 40% of cases, and the causes for this frequent complication have not been elucidated so far., Material and Methods: Here we present the study protocol of the FIBRO-RISK trial, a prospective, single-center, cohort study which aims to investigate the impact of inflammatory-mediated myocardial fibrosis on the risk of recurrence after successful catheter ablation of atrial fibrillation. The level of systemic inflammation in the pre-ablation and immediate post-ablation period will be assessed on the basis of serum levels of inflammatory biomarkers (hsCRP, matrix metalloproteases, interleukin-6), while the level of cardiac fibrosis will be determined based on cardiac magnetic resonance imaging associated with complex post-processing techniques for mapping myocardial fibrosis at the level of left atrium and left ventricle. At the same time, the amount of epicardial fat will serve as an indirect marker of localized inflammation and will be determined at different levels in the heart (surrounding left atrium, right atrium or the entire heart), while ventricular function will be assessed on the basis of serum levels of NT-proBNP prior to the procedure. All these parameters will be investigated in patients with successful ablation of AF, who will be divided into 2 groups: group 1 - patients who develop AF recurrence at 1-year, and group 2 - patients with no recurrence of AF at 1-year. In all patients, the following biomarkers will be determined: serum levels of inflammatory biomarkers and NT-proBNP at 24 hours and 1-year post procedure, the amount of myocardial fibrosis at the level of left atrium and left ventricle at baseline +/- 7 days, and the amount of epicardial fat surrounding left atrium, right atrium and the entire heart at baseline +/- 7 days.The primary endpoint of the study will be represented by the rate of AF recurrence at 1-year post ablation, documented by either ECG or Holter monitoring. The secondary endpoints of the study will consist in:In conclusion, FIBRO-RISK will be the first CMR-based study that will investigate the impact of inflammation-mediated myocardial fibrosis and ventricular remodeling on the risk of recurrence after successful ablation of AF, aiming to validate inflammatory biomarkers and myocardial fibrosis as predictors for AF recurrence.

No tyrosine kinase inhibitors are approved for malignant pleural mesothelioma (MPM). Preclinical studies identified focal adhesion kinase (FAK) as a target in MPM. Accordingly, we assessed the novel, highly selective FAK inhibitor (BI 853520) in 2D and 3D cultures and in vivo. IC 50 values were measured by adherent cell viability assay. Cell migration and 3D growth were quantified by video microscopy and spheroid formation, respectively. Phosphorylation of FAK, Akt, S6, and Erk was measured by immunoblot. The mRNA expression of the putative tumor stem cell markers SOX2, Nanog, CD44, ALDH1, c-myc, and Oct4 was analyzed by qPCR. Cell proliferation, apoptosis, and tumor tissue microvessel density (MVD) were investigated in orthotopic MPM xenografts. In all 12 MPM cell lines, IC 50 exceeded 5 μM and loss of NF2 did not correlate with sensitivity. No synergism was found with cisplatin in adherent cells. BI 853520 decreased migration in 3 out of 4 cell lines. FAK phosphorylation was reduced upon treatment but activation of Erk, Akt, or S6 remained unaffected. Nevertheless, BI 853520 inhibited spheroid growth and significantly reduced tumor weight, cell proliferation, and MVD in vivo. BI 853520 has limited effect in adherent cultures but demonstrates potent activity in spheroids and in orthotopic tumors in vivo. Based on our findings, further studies are warranted to explore the clinical utility of BI 853520 in human MPM. KEY MESSAGES: Response to FAK inhibition in MPM is independent of NF2 expression or histotype. FAK inhibition strongly interfered with MPM spheroid formation. BI 853520 has been shown to exert anti-tumor effect in MPM.

Introduction: Coronary computed tomography angiography (CCTA) has emerged as a valuable noninvasive imaging tool for assessing atheromatous plaque morphology and composition, and several CCTA features have been validated as reliable indicators of the plaque-associated risk. However, the role of lesion geometry as a CCTA feature of plaque vulnerability has not been investigated so far., Material and Methods: Here we present the study protocol of the GEOMETRY trial, a prospective, single center, cohort study in which we aim to investigate the relationship between plaque geometry (as expressed by cross-sectional and longitudinal plaque eccentricity) and the risk for major adverse cardiac events (MACE) during 2 years of follow-up, in order to validate plaque eccentricity as a new CCTA marker of coronary plaque vulnerability. One thousand patients with suspected coronary artery disease (CAD) and pretest probability of CAD between 15% and 85%, who undergo CCTA and in whom CCTA identifies the presence of at least 1 significant coronary plaque (producing a luminal narrowing of at least 50%) will be enrolled in the study. Based on the results of complex image post-processing and plaque analysis, patients will be divided into 2 groups: group 1-patients in whom CCTA analysis identifies only non-eccentric coronary plaque; and group 2-patients in whom CCTA analysis reveals the presence of at least 1 eccentric significant coronary plaque producing a significant luminal narrowing. Study outcomes will consist in the rate of major cardiovascular events and the rate of plaque progression during follow-up.The study is funded by the Romanian Ministry of European Funds, the Romanian Government and the European Union, as part of the research grant number 103544/2016 - PlaqueIMAGE (contract number 26/01.09.2016)., Conclusion: In conclusion, GEOMETRY will be the first CCTA-based study that will investigate the impact of geometric distribution of coronary atheromatous plaque on the future risk of cardiovascular events and on the rate of plaque progression, introducing and validating a new potential feature of plaque vulnerability represented by plaque geometry.

Purpose: Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting. Experimental Design: We have examined the antineoplastic activity of nintedanib in various in vitro and in vivo models of human MPM. Results: Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment in vitro Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib per os showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant in vivo antivascular and antitumor potential independently of baseline VEGF-A levels. Conclusions: Nintedanib exerts significant antitumor activity in MPM both in vitro and in vivo These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM. Clin Cancer Res; 24(15); 3729-40. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Previous works showed patients preference for herbal substances (HS) although they also highlighted a discrepancy with physicians' adherence to HS and its recommendation., Hypothesis/purpose: This study aimed to assess physician's perception and attitudes concerning the use of HS for their patients in a Family Medicine approach., Study Design: Observational cross-sectional exploratory study., Methods: A questionnaire survey was applied to National Health System physicians; 113 questionnaires were distributed in the Greater Lisbon region., Results: 80 valid questionnaires were received. The age of participants ranges from 29 to 64 with mean age of M ± SD:51.9 ± 10.0 years, mostly women (71.4%). Of these, 61.5% were unaware of traditional herbal medicinal products' (THMP) legal recognition and 67.3% of the difference between THMP and well-established use medicines. Absence of accordance between use and knowledge of herbal medicines (HM)/herbal products (HP) (p = 0.025) can be related to lack of Phytotherapy knowledge perception based on the nonexistence of specific training reported by 94.0% of physicians. Through factor analysis, three dimensions were obtained: Factor1, ``Use''; Factor2, ``Autonomy''; Factor3 ``Effort''. The overall Cronbach's α was 0.77, and 0.82 for Factor1. The evidence of use/prescription, has a correlation with ``Use'' (p < 0.0001), willingness to prescribe (p < 0.0001) and self-medication (p < 0.0001). There is a correlation (r = 0.605, p < 0.0001) between HS recommendation and self-medication. There were differences in use, perception and attitudes among Personalized-Health-Care Units and Family-Health Units physicians in relation to Factor1: p = 0.007 and Factor2: p = 0.021, age (p = 0.001), years of Medical career (p = 0.002), HM use (p = 0.014) and information about alternatives (p = 0.03). Physicians who answered correctly to the question on silymarin had higher scores in factor1 than those who did not: 1.76 vs. 1.25 (p = 0.019)., Conclusion: Low adherence to HS and little use of HM/HP were confirmed, highlighting the need for specific knowledge in Phytotherapy and its regulatory framework. This knowledge will enable the evaluation of herb-drug interactions and HM/HP adverse effects by the physicians thus justifying the integration of programmatic contents about HS in Medical Education., (Copyright © 2018. Published by Elsevier GmbH.)

Brain-derived neurotrophic factor (BDNF) gene delivery to the entorhinal cortex is a candidate for treatment of Alzheimer's disease (AD) to reduce neurodegeneration that is associated with memory loss. Accurate targeting of the entorhinal cortex in AD is complex due to the deep and atrophic state of this brain region. Using MRI-guided methods with convection-enhanced delivery, we were able to accurately and consistently target AAV2-BDNF delivery to the entorhinal cortex of non-human primates; 86 ± 3% of transduced cells in the targeted regions co-localized with the neuronal marker NeuN. The volume of AAV2-BDNF (3 × 10 8  vg/µl) infusion linearly correlated with the number of BDNF labeled cells and the volume (mm 3 ) of BDNF immunoreactivity in the entorhinal cortex. BDNF is normally trafficked to the hippocampus from the entorhinal cortex; in these experiments, we also found that BDNF immunoreactivity was elevated in the hippocampus following therapeutic BDNF vector delivery to the entorhinal cortex, achieving growth factor distribution through key memory circuits. These findings indicate that MRI-guided infusion of AAV2-BDNF to the entorhinal cortex of the non-human primate results in safe and accurate targeting and distribution of BDNF to both the entorhinal cortex and the hippocampus. These methods are adaptable to human clinical trials.

In various metabolic diseases, both the coronary circulation and cardiac metabolism are altered. Here we summarize the effects of a condition called hyperhomocysteinemia (HHcy) - which can develop due to genetic and/or environmental causes - on the function of coronary microvessels and heart. This metabolic disease is underappreciated, yet even mild or moderate elevation of plasma concentrations of homocystein (Hcy, plasma Hcy >16 µM), a sulfur-containing amino acid produced via methionine metabolism) leads to coronary and peripheral artery and even venous vessel diseases, eliciting vasomotor dysfunction and increased thrombosis, consequently increased morbidity and mortality. Yet the underlying mechanisms have not yet been revealed. Recent studies indicated that there are common pathomechanisms, which may affect several cellular functions. With methionin diet-induced HHcy two main pathomechanisms were revealed: the dysfunction of nitric oxide (NO) pathway resulting in reduced dilator responses of arteries and arterioles, and the simultaneously increased thromboxane A2 (TXA2) activity both in vessels and platelets. These changes are likely due to an increased production of reactive oxidative species (oxidative stress) due to increased NADPH oxidase assembly, which eventually lead to inflammatory processes (indicated by increases in TNFα, NFκbeta, p22phox, p67phox, and rac-1, levels) and changes in various gene expressions and morphological remodeling of vessels. Increased superoxide production and reduced availability of NO alter the regulation of mitochondrial function in the myocardium. The interactions of these pathomechanisms may explain why HHcy increases the uptake of glucose and lactate and decreases the uptake of free fatty acid by the heart. The pathological consequences of HHcy could be worsening by the simultaneous presence of other risk factors, such as hyperlipidemia, diabetes mellitus and metabolic syndrome. All in all, HHcy and associated pathometabolism lead to severe changes and dysfunctions of coronary arterial vessels and cardiac function, which may not always be apparent in clinical settings but most likely contribute to the increased prevalence of cardiovascular diseases and mortality, which however can be reduced by appropriate prevention and treatments. We believe that HHcy is an underestimated - likely due to inappropriate clinical trials - but serious disease condition because it promotes the development of atherosclerosis in large arterial vessels, vasomotor dysfunction in microvessels, hypertension and thrombosis. In this review, we will summarize previous functional findings focusing on coronary vessels and cardiac function and the underlying cellular and molecular mechanisms enabling the development of novel treatments., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Rationale: We have used a high-precision, high-efficiency method for the measurement of the 2 H/ 1 H ratios of hydrous silicates (amphiboles) and nominally anhydrous minerals (NAM) such as clinopyroxene, garnet and diamond, which are usually extremely resistant to pyrolysis. This opens up new fields of investigation to better understand the conditions of formation for deep-Earth minerals., Methods: The technique described here involves Isotope Ratio Mass Spectrometry (IRMS) on-line in continuous flow mode with an Elemental Analyser (EA) using "purge and trap" technology rather than separation by conventional packed column gas chromatography (GC). The system is equipped with a special high-temperature furnace reaching 1500°C, with a longer hot zone and improved temperature stability. Emphasis is put on the efficiency of the system to reliably pyrolyse refractory minerals difficult to analyse with other conventional systems., Results: While conventional systems usually fail to generate hydrogen suitable for isotopic analyses, with the technique presented here we were able to measure 2 H/ 1 H ratios from four diamond samples (δ 2 H = -60, -77, -84 and -79‰ V-SMOW; average SD = 4.5‰; n = 2), three garnet samples (δ 2 H from -70 to -63‰), and nine clinopyroxenes (δ 2 H from -92 to -58‰) associated with seven amphiboles (δ 2 H from -76 to -27‰) from single mantle rock., Conclusions: The possibility of using such a system to reliably measure 2 H/ 1 H ratios from refractory minerals, which are usually extremely difficult to analyse, offers a new tool of investigation for providing us with unrivaled clues to study the deep interiors of Earth., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Multiple mechanisms have been proposed for idiopathic premature ventricular contractions (PVCs) originating from the outflow tracts (OTs). Recent observations such as the coexistence of these arrhythmias with atrioventricular nodal reentrant tachycardias and the association between discrete prepotentials and successful ablation sites of ventricular arrhythmias (VAs) from the OTs suggest a common link., Objective: In this case series we draw attention to a unique association between accessory pathways (APs) and idiopathic PVCs from the OTs, disappearing after AP ablation., Methods: We identified 6 cases in collaboration with several international electrophysiology centers, which presented with pre-excitation in association with OT, and in 1 case inflow tract (IT), PVCs on 12-lead surface ECG., Results: Six cases displayed pre-excitation and PVCs, in 5 cases originating from the right ventricular outflow tract (RVOT) and in 1 case from the right ventricular inflow tract (RVIT). In all patients, PVCs were monomorphic and had fixed coupling intervals, in 3 cases presenting in bigeminy. Catheter ablation of the AP led to the simultaneous disappearance of PVCs in 5 of 6 cases. The sites of ablation were remote from the OTs in all these cases. In most cases, the occurrence of OT PVCs was closely associated with the presence of pre-excitation., Conclusion: The coexistence of pre-excitation and PVCs from the OTs and the fact that in 5 of 6 cases PVCs disappeared after AP ablation suggests a common mechanism for arrhythmia genesis., (© 2016 Wiley Periodicals, Inc.)

Resistance mechanisms against antiangiogenic drugs are unclear. Here, we correlated the antitumor and antivascular properties of five different antiangiogenic receptor tyrosine kinase inhibitors (RTKIs) (motesanib, pazopanib, sorafenib, sunitinib, vatalanib) with their intratumoral distribution data obtained by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). In the first mouse model, only sunitinib exhibited broad-spectrum antivascular and antitumor activities by simultaneously suppressing vascular endothelial growth factor receptor-2 (VEGFR2) and desmin expression, and by increasing intratumoral hypoxia and inhibiting both tumor growth and vascularisation significantly. Importantly, the highest and most homogeneous intratumoral drug concentrations have been found in sunitinib-treated animals. In another animal model, where - in contrast to the first model - vatalanib was detectable at homogeneously high intratumoral concentrations, the drug significantly reduced tumor growth and angiogenesis. In conclusion, the tumor tissue penetration and thus the antiangiogenic and antitumor potential of antiangiogenic RTKIs vary among the tumor models and our study demonstrates the potential of MALDI-MSI to predict the efficacy of unlabelled small molecule antiangiogenic drugs in malignant tissue. Our approach is thus a major technical and preclinical advance demonstrating that primary resistance to angiogenesis inhibitors involves limited tumor tissue drug penetration. We also conclude that MALDI-MSI may significantly contribute to the improvement of antivascular cancer therapies., Competing Interests: The authors have declared that no competing interest exists. The funders had no role in study design, data collection, analysis and decision to publish or preparation of the paper.

Nitric oxide (NO) has emerged as a signaling molecule in plants being involved in diverse physiological processes like germination, root growth, stomata closing and response to biotic and abiotic stress. S -nitrosoglutathione (GSNO) as a biological NO donor has a very important function in NO signaling since it can transfer its NO moiety to other proteins ( trans -nitrosylation). Such trans -nitrosylation reactions are equilibrium reactions and depend on GSNO level. The breakdown of GSNO and thus the level of S -nitrosylated proteins are regulated by GSNO-reductase (GSNOR). In this way, this enzyme controls S -nitrosothiol levels and regulates NO signaling. Here we report that Arabidopsis thaliana GSNOR activity is reversibly inhibited by H 2 O 2 in vitro and by paraquat-induced oxidative stress in vivo . Light scattering analyses of reduced and oxidized recombinant GSNOR demonstrated that GSNOR proteins form dimers under both reducing and oxidizing conditions. Moreover, mass spectrometric analyses revealed that H 2 O 2 -treatment increased the amount of oxidative modifications on Zn 2+ -coordinating Cys47 and Cys177. Inhibition of GSNOR results in enhanced levels of S -nitrosothiols followed by accumulation of glutathione. Moreover, transcript levels of redox-regulated genes and activities of glutathione-dependent enzymes are increased in gsnor-ko plants, which may contribute to the enhanced resistance against oxidative stress. In sum, our results demonstrate that reactive oxygen species (ROS)-dependent inhibition of GSNOR is playing an important role in activation of anti-oxidative mechanisms to damping oxidative damage and imply a direct crosstalk between ROS- and NO-signaling.