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.

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.

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.

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.

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.

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.

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.

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.

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.

The Hungarian adaptation and validation of the Osteoporosis Health Belief Scale / Az Osteoporosis Health Belief Scale kérdoív magyar nyelvu validálása.

Összefoglaló. Bevezetés: A nemzetközi szakirodalomban számos betegséget illetoen elérheto betegségspecifikus tudást és attitudöt méro kérdoív. Magyarországon az osteoporosis témakörében validált kérdoívek tárháza meglehetosen hiányos. Célkituzés: Célunk volt a csontritkulás-specifikus magatartás és attitud vizsgálatára alkalmas Osteoporosis Health Belief Scale (OHBS-) kérdoív magyar nyelvre történo validációja, melynek segítségével mérhetové válna a magyar anyanyelvu nok csontritkulással kapcsolatos attitudje. Módszer: A kérdoív magyar nyelvre validálása a 2000-ben megfogalmazott hatlépcsos irányelv szerint történt. A külso validitás vizsgálatához az Osteoporosis Knowledge Assessment Tool (OKAT-) kérdoívet használtuk. Mintánkat 600 fo alkotta; statisztikai számításaink során leíró statisztikát készítettünk, különbözoségi vizsgálatokat végeztünk, a belso konzisztencia vizsgálatára Cronbach-alfa-értéket számítottunk, a konvergens validitás és a teszt-reteszt mérések vizsgálatához Spearman-féle korrelációs koefficienst számítottunk. A kérdoív belso struktúrájának vizsgálatához faktorelemzést végeztünk. Ennek megfeleloen Kaiser-Meyer-Olkin (KMO)-tesztet és Bartlett-próbát számítottunk. Eredmények: Mintánk (37,7 ± 13,15 életév) az OHBS (126,28 ± 14,85 pont) és az OKAT (8,78 ± 3,1) tekintetében egyaránt alacsony pontszámot ért el. A teljes kérdoívre kivetített Cronbach-alfa-érték 0,802 volt. A faktorelemzés (KMO = 0,886; Bartlett-próba p<0,001) 7 faktort különített el, melyek megfeleltethetok az eredeti faktoroknak. A teszt-reteszt során a Spearman-féle korrelációs koefficiens 0,921 és 1,000 közötti értéket mutatott. Az OKAT- és az OHBS-dimenziók összevetésekor számos szignifikáns kapcsolatot találtunk. Megbeszélés: A vizsgálati eredmények megfelelnek az eredeti kérdoív szerinti, továbbá a más nyelvre történt validálás során kapott eredményeknek. Következtetés: Eredményeink alapján a magyar nyelvu OHBS csontritkulás-specifikus attitudöt és magatartást vizsgáló kérdoívet megbízható és valid kérdoívnek tartjuk. Orv Hetil. 2021; 162(37): 1494-1501. INTRODUCTION: In the international literature, several disease-specific questionnaires are available for many diseases. The opportunities of validated questionnaires are incomplete about osteoporosis in Hungarian language. OBJECTIVE: The aim of the study was to validate the Osteoporosis Health Belief Scale (OHBS) into Hungarian that would make it possible to measure the osteoporosis-related attitude for Hungarian-speaking women. METHOD: The questionnaire was validated into Hungarian according to the six-step guideline outlined in 2000. The Osteoporosis Knowledge Assessment Tool (OKAT) questionnaire was used to examine external validity. Our sample consisted of 600 women. We performed descriptive statistics; Cronbach's alpha value was calculated for internal consistency, we calculated Spearman's correlation coefficient to examine external validity. We carried out factor analysis (Kaiser-Meyer-Olkin [KMO] test, Bartlett test) to examine whether the new questionnaire is suitable for measurements in the given language the same way as the original questionnaire. RESULTS: Our sample (37.7 ± 13.15 years of age) achieved low score for both OHBS (126.28 ± 14.85) and OKAT (8.78 ± 3.1). The Cronbach's alpha value was 0.802. Factor analysis (KMO = 0.886; Bartlett test p<0.001) identified 7 factors that can be similar to the original factors. During the test-retest, the Spearman correlation coefficient showed a value between 0.921 and 1.000. When comparing the OKAT and OHBS dimensions we found several significant relationships. DISCUSSION: The results of the study are similar to the results of the original questionnaire validation as well as to other OHBS validation studies. CONCLUSION: Based on the results, we consider that the Hungarian form of the OHBS is a reliable and valid questionnaire. Orv Hetil. 2021; 162(37): 1494-1501.

Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis.

Apelin, a ligand of the APJ receptor, is overexpressed in several human cancers and plays an important role in tumor angiogenesis and growth in various experimental systems. We investigated the role of apelin signaling in the malignant behavior of cutaneous melanoma. Murine B16 and human A375 melanoma cell lines were stably transfected with apelin encoding or control vectors. Apelin overexpression significantly increased melanoma cell migration and invasion in vitro, but it had no impact on its proliferation. In our in vivo experiments, apelin significantly increased the number and size of lung metastases of murine melanoma cells. Melanoma cell proliferation rates and lymph and blood microvessel densities were significantly higher in the apelin-overexpressing pulmonary metastases. APJ inhibition by the competitive APJ antagonist MM54 significantly attenuated the in vivo pro-tumorigenic effects of apelin. Additionally, we detected significantly elevated circulating apelin and VEGF levels in patients with melanoma compared to healthy controls. Our results show that apelin promotes blood and lymphatic vascularization and the growth of pulmonary metastases of skin melanoma. Further studies are warranted to validate apelin signaling as a new potential therapeutic target in this malignancy.

Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation.

Spitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sample of a 37-year-old male patient. We found that the cell line carries a rare MEK1 mutation (pGlu102_Lys104delinsGln) that belongs to the RAF- and phosphorylation-independent subgroup of MEK1 alternations supposedly insensitive to allosteric MEK inhibitors. The in vivo tumorigenicity was tested in three different models by injecting the cells subcutaneously, intravenously or into the thoracic cavity of SCID mice. In the intrapleural model, macroscopic tumors formed in the chest cavity after two months, while subcutaneously and intravenously delivered cells showed limited growth. In vitro, trametinib-but not selumentinib-and the ATP-competitive MEK inhibitor MAP855 strongly decreased the viability of the cells and induced cell death. In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib.

Evaluation of the course and treatment of Alcohol Withdrawal Syndrome with the Clinical Institute Withdrawal Assessment for Alcohol - Revised: A systematic review-based meta-analysis.

BACKGROUND: Although the Clinical Institute Withdrawal Assessment for Alcohol - Revised (CIWA-Ar) is a gold standard tool for the clinical evaluation of alcohol withdrawal syndrome (AWS), a systematic analysis using the total scores of the CIWA-Ar as a means of an objective follow-up of the course and treatment of AWS is missing. The aims of the present study were to systematically evaluate scientific data using the CIWA-Ar, to reveal whether the aggregated CIWA-Ar total scores follow the course of AWS and to compare benzodiazepine (BZD) and non-benzodiazepine (nBZD) therapies in AWS. METHODS: 1054 findings were identified with the keyword "ciwa" from four databases (PubMed, ScienceDirect, Web of Science, Cochrane Registry). Articles using CIWA-Ar in patients treated with AWS were incorporated and two measurement intervals (cumulative mean data of day 1-3 and day 4-9) of the CIWA-Ar total scores were compared. Subgroup analysis based on pharmacotherapy regimen was conducted to compare the effectiveness of BZD and nBZD treatments. RESULTS: The random effects analysis of 423 patients showed decreased CIWA-Ar scores between the two measurement intervals (BZD: d = -1.361; CI: -1.829 < δ < -0.893; nBZD: d = -0.858; CI: -1.073 < δ < -0.643). Sampling variances were calculated for the BZD (v1 = 0.215) and the nBZD (v2 = 0.106) groups, which indicated no significant group difference (z = -1.532). CONCLUSIONS: Our findings support that the CIWA-Ar follows the course of AWS. Furthermore, nBZD therapy has a similar effectiveness compared to BZD treatment based on the CIWA-Ar total scores.

Multicellular contractility contributes to the emergence of mesothelioma nodules.

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.

HDAC Inhibition Induces PD-L1 Expression in a Novel Anaplastic Thyroid Cancer Cell Line.

While papillary thyroid cancer (PTC) has largely favorable prognosis, anaplastic thyroid cancer (ATC) is a rare but extremely aggressive malignancy with grim clinical outcome. Even though new therapeutic options are emerging for ATC, additional preclinical models and novel combinations are needed for specific subsets of patients. We established a novel cell line (PF49) from the malignant pleural effusion of a 68-year-old male patient with ATC that rapidly transformed from a BRAF and TERT promoter mutant PTC. PF49 cells demonstrated a robust migratory activity in vitro and strong invasive capacity in vivo in a pleural carcinosis model. Combined BRAF and MEK inhibition decreased the proliferation and migration of PF49 cells, however could not induce cell death. Importantly, HDAC inhibitor treatment with SAHA or valproic acid induced cell cycle arrest and strongly increased PD-L1 expression of the tumor cells. Induction of PD-L1 expression was also present when paclitaxel-cisplatin chemotherapeutic treatment was combined with HDAC inhibitor treatment. Increased PD-L1 expression after HDAC inhibition was recapitulated in an international ATC cell model. Our data suggest that HDAC inhibition alone or in combination with standard chemotherapy may potentiate anaplastic thyroid cancer cells for immunotherapy.

Clustering Infertile Couples With Dyadic Approach: WHO-5-WBI as a Promising Tool for Assessing Psychological State.

Infertility may be associated with severe psychological burden and many couples need mental support. We used dyadic approach to identify couples with disturbed psychological condition and we tested the WHO-5 Well-Being Index (WHO-5-WBI) questionnaire as a possible, rapid screening method. Extensive psychological assessment of infertile couples was carried out with Beck's Depression Inventory, Spielberger State-Trait Anxiety Inventory, WHO-5-WBI, Symptom Check List-90 Revised Test, Fagerstrom Test for Nicotine Dependence, Alcohol Use Disorders Identification Test. Data of 128 patients (64 couples) were used in the statistical calculations. The Two-Step cluster analysis has revealed 2 groups, which could be separated supremely based on the level of experienced depression, anxiety and according to the general mental health. The WHO-5-WBI questionnaire showed consistent results while classifying couples into groups, which were formed. Our results indicate that infertility affects both spouses almost in the same extent in several psychological aspects. A cluster of couples with increased psychological burden could be clearly separated. The WHO-5-WBI questionnaire was a promising tool to screen reliably spouses based on their psychological state and identify couples that need psychological support during their fertility work-up and treatment.