Dual targeting of BCL-2 and MCL-1 in the presence of BAX breaks venetoclax resistance in human small cell lung cancer.

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.

Seasonality and Delirium Tremens in Hospitalized Patients with Alcohol Dependence Syndrome.

INTRODUCTION: Due to the high rate of mortality, recognizing the contributing factors of alcohol-related delirium tremens (DT), which is the most severe form of alcohol withdrawal state (AWS) is pivotal in clinical settings. Previous studies suggested relationship between seasonality and other types of delirium; however, to our knowledge, this is the first empirical study which examined the role of seasonality in DT in alcohol dependence syndrome (ADS). METHODS: A retrospective study was undertaken between 2008 and 2015; medical records of 1,591 patients were included, which yielded 2,900 hospital appearances. Three groups were formed based on the ICD-10 diagnoses: ADS, AWS, and DT. The characteristics of the groups were analysed with one-way ANOVA and χ2 tests. Multinomial logistic regression was used to explore the potential predictors of DT, including seasonality. RESULTS: The highest incidence of DT was in spring (36.8%; χ2 (3) = 27.666; p < 0.001), especially in March (13.9%; χ2 (11) = 33.168; p < 0.001). Spring, higher mean age, higher presence of comorbid somatic disorders, and lower occurrence of comorbid psychiatric disorders were significant predictive variables for DT with the control of socio-demographic and clinical variables. CONCLUSIONS: The present study revealed that spring, especially March is a critical period in temperate climate zone regarding DT. This can be interpreted as a late winter effect since the temperature is lower in this month compared to other spring months. Furthermore, higher age and the occurrence of comorbid somatic disorders can be considered as risk factors in case of DT. These results support the need of further clinical studies to better understand the impact of seasonality on DT.

Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma.

AIMS: Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study. METHODS AND RESULTS: Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtyped. Nuclear grading and mitosis-necrosis score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis-necrosis score. The mitosis-necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours. CONCLUSIONS: Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches.

The personality profile of chronic alcohol dependent patients with comorbid gambling disorder symptoms.

BACKGROUND AND AIMS: The importance of personality characteristics in the diagnosis and treatment of gambling disorder (GD) and alcohol use disorder (AUD) is often highlighted in scientific literature. This study aimed to test predictions about the associations of temperament and character in chronic AUD patients with comorbid GD symptoms and without them. METHODS: Chronic AUD patients enrolled from an inpatient clinic were divided in two groups based on cluster analysis, AUD patients with (AUD + GD group: n = 30) and without (AUD group: n = 68) GD symptoms. Severity of GD symptoms and personality dimensions (Cloninger's Temperament and Character Inventory Revised, TCI-R) were assessed. Associations of tested variables were analysed with analysis of covariance, one-sample and independent sample t-tests. RESULTS: GD symptoms proved to be a clustering factor in terms of personality, where AUD + GD group expressed a more maladaptive personality profile. Compared to Hungarian normative TCI-R scores, both patient groups showed elevated levels of Harm Avoidance and Novelty Seeking with lower scores of Self-directedness, while the AUD + GD group scored lower on Persistence and Cooperation as well. The AUD + GD group reported significantly higher levels of Harm Avoidance, with lower scores of Reward Dependence compared to the AUD group. DISCUSSION: Comorbid GD symptom severity is an important factor in chronic AUD, where AUD patients with comorbid GD symptoms exhibited a more maladaptive personality constellation than singular AUD patients. These emphasize the need of special attention for comorbid GD symptoms in AUD, since treatment recommendations and prognosis for them may also differ.

[Gambling disorder and alcohol use disorder -- similarities and differences]. / Szerencsejáték-használati zavar és alkoholhasználat-zavar -- hasonlóságok és különbségek.

Gambling disorder has been listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM) for more than three decades. During this time, its diagnostic set of criteria has gone through significant changes. In the DSM-5, gambling disorder has been moved from Disruptive, Impulse-Control and Conduct Disorders to Substance- Related and Addictive Disorders, which acknowledges and expresses that gambling disorder has similar features compared to substance related disorders. The aim of the present review is to reveal the reasons behind this category replacement, and to examine the similarities between gambling disorder and alcohol dependence from the perspectives of symptomatology, etiology and epidemiology.

Continuous central venous oxygen saturation assisted intraoperative hemodynamic management during major abdominal surgery: a randomized, controlled trial.

BACKGROUND: Major abdominal surgery is associated with significant risk of morbidity and mortality in the perioperative period. Optimising intraoperative fluid administration may result in improved outcomes. Our aim was to compare the effects of central venous pressure (CVP), and central venous oxygen saturation (ScvO2)-assisted fluid therapy on postoperative complications in patients undergoing high risk surgery. METHODS: Patients undergoing elective major abdominal surgery were randomised into control and ScvO2 groups. The target level of mean arterial pressure (MAP) was ≥ 60 mmHg in both groups. In cases of MAP < 60 mmHg patients received either a fluid or vasopressor bolus according to the CVP < 8 mmHg in the control group. In the ScvO2 group, in addition to the MAP, an ScvO2 of <75% or a >3% decrease indicated need for intervention, regardless of the actual MAP. Data are presented as mean ± standard deviation or median (interquartile range). RESULTS: We observed a lower number of patients with complications in the ScvO2 group compared to the control group, however it did not reach statistical significance (ScvO2 group: 10 vs. CONTROL GROUP: 19; p = 0.07). Patients in the ScvO2 group (n = 38) received more colloids compared to the control group (n = 41) [279(161) vs. 107(250) ml/h; p < 0.001]. Both groups received similar amounts of crystalloid (1126 ± 471 vs. 1049 ± 431 ml/h; p = 0.46) and norepinephrine [37(107) vs. 18(73) mcg/h; p = 0.84]. Despite similar blood loss in both groups, the ScvO2 group received more blood transfusions (63% vs. 37%; p = 0.018). More patients in the control group had a postoperative PaO2/FiO2 < 200 mmHg (23 vs. 10, p < 0.01). Twenty eight day survival was significantly higher in the ScvO2 group (37/38 vs. 33/41 p = 0.018). CONCLUSION: ScvO2-assisted intraoperative haemodynamic support provided some benefits, including significantly better postoperative oxygenation and 28 day survival rate, compared to CVP-assisted therapy without a significant effect on postoperative complications during major abdominal surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT02337010.

The in vitro treatment with vitamin D3 is ineffective on the expression of PKC isoenzymes, but decreases further the impaired production of IL-2 in the T lymphocytes of SLE patients.

The objective of the study was to investigate the possibility whether the in vitro treatment with vitamin D3 can restore the impaired expression of protein kinase C (PKC) isoenzymes and IL-2 production in the lymphocytes of patients with systemic lupus erythematosus (SLE). Purified T lymphocytes from 14 patients with SLE and 13 healthy controls were cultured for 48 h in the presence and absence of 1 and 100 nM doses of vitamin D3. The expressions of various PKC isoenzymes were tested by Western blot analysis, and the amounts of various cytokines were detected by ELISA in the culture supernatants. Neither the low (1 nM) nor the high (100 nM) doses of vitamin D3 (1α,-25-dihydroxyvitamin) applied in vitro for 48 h were able to restore the decreased expression of PKC isoenzymes in the T cells of SLE patients. However, 100 nM of vitamin D3 significantly increased the release of IL-10, but suppressed the production of IL-2, IL-6, interferon γ and TNF α in the culture supernatants of both groups. As the low production of IL-2 is one of the main pathologic features of SLE, we recommend to avoid the use of high doses of vitamin D3 for treatment of lupus patients with vitamin D3 deficiency.

Premenstrual dysphoric disorder-an undervalued diagnosis? A cross-sectional study in Hungarian women.

Background: Premenstrual dysphoric disorder (PMDD) is a common but underdiagnosed mental health problem among women of reproductive age, which complicates women's daily lives with the presence of severe psychological symptoms altering everyday functioning. This study aimed to assess the prevalence of probable PMDD, the anxio-depressive symptom severity, and well-being in women affected by PMDD across the menstrual cycle. Methods: 112 women with regular menstrual periods, without hormonal contraceptives were included. The study assessed the presence of probable PMDD using a DSM-5-based screening tool, a retrospective questionnaire assessment, for the detection of premenstrual symptoms. Anxio-depressive symptoms and well-being were assessed using the Beck Depression Inventory, the state subscale of the State-Trait Anxiety Inventory, and the WHO Well-Being Scale. Results: Based on a DSM-5-based screening Tool, the sample was divided into women with probable PMDD diagnosis (PMDD group, n = 68) and women without probable PMDD diagnosis (nonPMDD group, n = 45). 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. A binomial logistic regression model was used to examine which factors predict PMDD: the model was significant (χ2(2) = 27.287, p ≤ 0.001), it explained 29.2 % of the variance in PMDD, and classified 71.4 % of the cases correctly. Anxiety (B = 0.058, S.E. = 0.022, Waldχ2(1) = 7.142, p = 0.01, OR = 1.060) and depressive (B = 0.085, S.E. = 0.031, Waldχ2(1) = 7.480, p = 0.01, OR = 1.089) symptoms predicted the likelihood of probable PMDD. Conclusion: Women even with probable PMDD experience significant affective difficulties and lower well-being, which underscore the need for attention towards psychological symptoms even in the case of probable PMDD, and consequently highlights the importance of appropriate assessment and treatment of the clinical appearance of PMDD.

Speech-related parameters are sensitive measures of acetylcholinesterase inhibitor therapy in mild Alzheimer's disease.

Our aim was to find out whether speech-related temporal parameters (SRTPs) are sensitive indicators of the clinical outcome in acetylcholinesterase (AChE) inhibitor therapy with donepezil, compared to the standard cognitive Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) used in clinical trials. In this 24-week-long, naturalistic, self-control, open-labeled, prospective pilot study with 10 mg donepezil on 20 mild AD patients, cognitive functions were evaluated using 15 different SRTPs analyzed by automatic speech recognition in the Speech-Gap Test® compared to ADAS-Cog test results. Among the SRTPs, the filled pause duration ratio significantly improved after 12 weeks of donepezil treatment. During the 24-week follow-up, additional SRTPs such as the filled pause count ratio and the filled pause frequency showed significant benefits. ADAS-Cog total scores showed a slight but not significant improvement compared to baseline after 12 and 24 weeks of donepezil treatment. Among the ADAS-Cog subtests, only orientation improved significantly after 24 weeks of donepezil treatment. Our results indicate that subtle changes in SRTPs measured by the Speech-Gap Test® could be considered as sensitive indicators of the efficacy of the pharmacotherapy in mild AD. According to our data, other cognitive domains did not show improvement in response to donepezil therapy rating by ADAS-Cog. Based on all of this, it is likely that examining and evaluating speech parameters may play an important role in determining the effects of pharmacological treatment of mild AD. The novelty of our study is that it applies the measurement of linguistic parameters as primary outcomes during a drug trial of mild AD in scientific research for the first time.

Motivational Drivers behind the Consumption of Dietary Supplements by Leisure-Time Athletes.

The prevalence of dietary supplement use has been growing continuously worldwide. Nevertheless, limited research evidence is available on dietary supplement usage related to the segment of leisure-time athletes with the determinants of motivational drivers, sport types, and demographic characteristics. This research, which was conducted in Hungary among leisure-time athletes, aims to learn about the demographic and sports characteristics of consumers who identified themselves as active dietary supplement consumers in the survey. The motivational drivers for consuming dietary supplements and their differences, as well as the frequency of dietary supplement consumption in each sports category, are examined. The findings of the study provide valuable insights into the key motivational drivers, among which health preservation, improvement in physical well-being, and cartilage protection are predominant. The results show that there are significant differences between segments taking part in different leisure-time sport activities and age groups when it comes to dietary supplement usage. Three different segments were identified based on the motivational drivers examined. As a limitation, to note is that due to the sample size, the study can be considered as prospective. In practical terms, the results of the study can be used to support marketing projects that aim to reach leisure-time sport athletes.

Entinostat Enhances the Efficacy of Chemotherapy in Small Cell Lung Cancer Through S-phase Arrest and Decreased Base Excision Repair.

PURPOSE: Acquired chemoresistance is a frequent event in small cell lung cancer (SCLC), one of the deadliest human malignancies. Histone deacetylase inhibitors (HDACi) have been shown to synergize with different chemotherapeutic agents including cisplatin. Accordingly, we aimed to investigate the dual targeting of HDAC inhibition and chemotherapy in SCLC. EXPERIMENTAL DESIGN: The efficacy of HDACi and chemotherapy in SCLC was investigated both in vitro and in vivo. Synergistic drug interactions were calculated based on the HSA model (Combenefit software). Results from the proteomic analysis were confirmed via ICP-MS, cell-cycle analysis, and comet assays. RESULTS: Single entinostat- or chemotherapy significantly reduced cell viability in human neuroendocrine SCLC cells. The combination of entinostat with either cisplatin, carboplatin, irinotecan, epirubicin, or etoposide led to strong synergy in a subset of resistant SCLC cells. Combination treatment with entinostat and cisplatin significantly decreased tumor growth in vivo. Proteomic analysis comparing the groups of SCLC cell lines with synergistic and additive response patterns indicated alterations in cell-cycle regulation and DNA damage repair. Cell-cycle analysis revealed that cells exhibiting synergistic drug responses displayed a shift from G1 to S-phase compared with cells showing additive features upon dual treatment. Comet assays demonstrated more DNA damage and decreased base excision repair in SCLC cells more responsive to combination therapy. CONCLUSIONS: In this study, we decipher the molecular processes behind synergistic interactions between chemotherapy and HDAC inhibition. Moreover, we report novel mechanisms to overcome drug resistance in SCLC, which may be relevant to increasing therapeutic success.

Impact of the three waves of COVID-19 pandemic on the HR practices of Hungarian organizations-Experience from an empirical study.

Over recent decades, the practice of human resource management in the transitional countries of Eastern Europe and in Hungary has changed significantly. Especially in local subsidiaries of foreign-owned companies and in the leading domestic large organizations, HRM has become a strategic function, while in the practice of small and medium-sized enterprises it is less common. COVID-19 hit companies, institutions and individuals unexpectedly, not only in Hungary but also in the more developed regions of the world. This crisis has also highlighted the fact that larger and better prepared organizations and public institutions have found it easier to weather this global human catastrophe. We analyze how the key tasks of HRM have changed during the successive waves, along four hypotheses. Initially, health protection, communication and home-office organization were the focus of the work of human resource professionals. In the second and third waves, securing and retaining staff became more important.

Unfolding the secrets of small cell lung cancer progression: Novel approaches and insights through rapid autopsies.

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.

Use of an Ingestible, Sensor-Based Digital Adherence System to Strengthen the Therapeutic Relationship in Serious Mental Illness.

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.

Paramedical counselling in infertility treatment: its effects on anxio-depressive symptom severity, perceived stress and self-esteem.

Aims: The importance of contributing psychological factors and stress-control in female infertility is well documented, but research on their role in male infertility is scarce. The present study aimed to evaluate the effects of a novel paramedical counselling on anxio-depressive symptom severity, perceived stress and self-esteem in infertile men participating in an infertility treatment programme. Methods: Patients were recruited from clinics of University of Szeged, Hungary between 2019 May and 2020 December, and were sorted into control (n = 51) and experimental (n = 57) groups, where patients in the experimental group received a 5-session paramedical counselling in extension to their medical treatment. The levels of anxio-depressive symptom severity, perceived stress and self-esteem were measured prior to and after receiving paramedical counselling. The control group scored lower in regards of the severity of depressive symptom, and showed an increase of self-esteem, while the experimental group resulted in a significant decrease of anxio-depressive scores with the elevation of the level of self-esteem. Results: Our results indicate that joining an infertility treatment programme alone had a positive role in reducing depressive symptoms and in the increase of self-esteem among infertile men, but receiving additional paramedical counselling throughout the treatment programme resulted in the decrease of anxio-depressive symptoms, besides the elevation of the level of self-esteem, with a significantly higher decrease in the state anxiety compared to not receiving this additional paramedical counselling. Conclusions: Thus, it would be advisable for infertility treatment programmes to incorporate screening for psychological vulnerability and implement additional paramedical counselling to alleviate these confounding symptoms detrimental to conceiving.

Temporal Speech Parameters Detect Mild Cognitive Impairment in Different Languages: Validation and Comparison of the Speech-GAP Test® in English and Hungarian.

BACKGROUND: The development of automatic speech recognition (ASR) technology allows the analysis of temporal (time-based) speech parameters characteristic of mild cognitive impairment (MCI). However, no information has been available on whether the analysis of spontaneous speech can be used with the same efficiency in different language environments. OBJECTIVE: The main goal of this international pilot study is to address the question of whether the Speech-Gap Test® (S-GAP Test®), previously tested in the Hungarian language, is appropriate for and applicable to the recognition of MCI in other languages such as English. METHODS: After an initial screening of 88 individuals, English-speaking (n = 33) and Hungarianspeaking (n = 33) participants were classified as having MCI or as healthy controls (HC) based on Petersen's criteria. The speech of each participant was recorded via a spontaneous speech task. Fifteen temporal parameters were determined and calculated through ASR. RESULTS: Seven temporal parameters in the English-speaking sample and 5 in the Hungarian-speaking sample showed significant differences between the MCI and the HC groups. Receiver operating characteristics (ROC) analysis clearly distinguished the English-speaking MCI cases from the HC group based on speech tempo and articulation tempo with 100% sensitivity, and on three more temporal parameters with high sensitivity (85.7%). In the Hungarian-speaking sample, the ROC analysis showed similar sensitivity rates (92.3%). CONCLUSION: The results of this study in different native-speaking populations suggest that changes in acoustic parameters detected by the S-GAP Test® might be present across different languages.

Externalizing personality characteristics define clinically relevant subgroups of alcohol use disorder.

AIMS: Higher levels of externalizing characteristics, i.e. impulsivity, novelty seeking and aggression, could contribute to the development, progression and severity of alcohol use disorder (AUD). The present study aims to explore whether these externalizing characteristics together have a potential group-forming role in AUD using latent profile analysis (LPA). METHODS: Externalizing characteristics of 102 AUD patients were analyzed using LPA to explore the group-forming role of externalizing symptoms; groups were compared in terms of demographic and alcohol-related variables, indices of psychopathological, depressive and anxiety symptom severity. RESULTS: LPA revealed and supported a two-group model based on externalizing symptoms. The group with higher levels of externalizing symptoms showed significantly elevated levels of alcohol-related and anxio-depressive symptoms. CONCLUSIONS: Externalizing characteristics converge and have a group-forming role in chronic AUD, and are associated with a more severe form of AUD. By making the diagnostic category less heterogeneous, these different subtypes within AUD may provide aid in tailoring treatments to patients' specific needs.

Malignant pleural mesothelioma nodules remodel their surroundings to vascularize and grow.

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.

Revealing Distress and Perceived Stress among Dentists at the Outset of the COVID-19 Pandemic: A Cross-Sectional Factor Analytic Study.

Dentists' perceptions about the stressfulness of clinical practice are well-documented, but literature on perceived stress and psychological distress experienced during the COVID-19 pandemic is scarce. This study aims to explore the emotions and attitudes, and the socio-demographic, dental, and COVID-related factors that are associated with the emergence of perceived stress and psychological distress that have been experienced by dentists during the COVID-19 pandemic. General demographic and dental-related data, and specific questions measuring the potential factors regarding dental professionals' concerns and opinions about their professional circumstances during the pandemic, were electronically collected from 182 dental practitioners. Exploratory and confirmatory factor analyses were used to assess whether dentists' emotions and attitudes during the pandemic measure the same construct: psychological distress, while linear regression models were built on the exploration of the effects of COVID-related factors on perceived stress and psychological distress. Facets of impulsiveness, lack of interest in social connections, emotional disengagement, mood swings, and acknowledgment of emotional exhaustion due to the pandemic, were measurements of the same construct and manifested in a singular factor: psychological distress. Two aspects, the fear of aerosol propagation and insecurities of financial status, increased the likelihood of the emergence of heightened levels of perceived stress and distress, while years spent in dental practice and age seemed to be protective factors against perceived stress and distress.

Internal and external aspects of freedom of choice in mental health: cultural and linguistic adaptation of the Hungarian version of the Oxford CAPabilities questionnaire-Mental Health (OxCAP-MH).

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.