Miracle-dz/UniFAR-FTUs huggingface dataset:
BRAF inhibitors stimulate inflammasome activation and interleukin 1 beta production in dendritic cells

Melanoma is the most dangerous form of skin cancer with a growing incidence over the last decades. Fourty percent of all melanomas harbor a mutation in the signaling adaptor BRAF (V600E) that results in ERK hyperactivity as an oncogenic driver. In these cases, treatment with the BRAFV600E inhibitors Vemurafenib (VEM) or Dabrafenib (DAB) coapplied with the MEK1/2 inhibitors Cobimetinib (COB) or Trametinib (TRA) can result in long-term suppression of tumor growth. Besides direct suppression of ERK activity, these inhibitors have been reported to also modulate tumor immune responses, and exert pro-inflammatory side effects such as fever and rash in some patients. Here we asked for potential effects of BRAFV600E inhibitors on dendritic cells (DC) which are essential for the induction of adaptive anti-tumor responses. Both splenic and bone marrow-derived (BM) mouse dendritic cells (DC) up-regulated costimulator expression (CD80, CD86) in response to DAB but not VEM treatment. Moreover, DAB and to lesser extent VEM enhanced IL-1β (interleukin 1 beta) release by splenic DC, and by LPS-stimulated BMDC. We demonstrate that DAB and VEM activated the NLRC4/Caspase-1 inflammasome. At high concentration, DAB also induced inflammasome activation independent of Caspase-1. TRA and COB elevated MHCII expression on BMDC, and modulated the LPS-induced cytokine pattern. Immunomodulatory activity of DAB and VEM was also observed in human monocyte-derived DC, and DAB induced IL-1β in human primary DC. Altogether, our study shows that BRAFV600E inhibitors upregulate IL-1β release by mouse and human DC which may affect the DC-mediated course of anti-tumor immune responses.
Feasibility and safety of combined percutaneous coronary intervention among high-risk patients with severe aortic stenosis undergoing transcatheter aortic valve implantation: a systematic review and meta-analysis

OBJECTIVES Recent reports indicated that percutaneous coronary intervention (PCI) may be correlated with increased mortality in patients undergoing transcatheter aortic valve implantation (TAVI). Therefore, we performed a meta-analysis to determine the feasibility and safety of combined PCI in high-risk patients with severe aortic stenosis undergoing TAVI. METHODS A comprehensive literature search was performed using PubMed, Embase and the Cochrane Central Register of Controlled trials through June 2016. RESULTS Five clinical trials including 1634 patients were identified. The pooled analysis revealed no significant differences in 30-day all-cause mortality [odds ratio (OR) 1.25, 95% confidence interval (CI) 0.52-3.05; P = 0.62], 30-day cardiovascular mortality rate (OR 1.59, 95% CI 0.52-4.88; P = 0.41) and 1-year mortality rate (OR 1.16, 95% CI 0.85-1.59; P = 0.34) among the patients assigned to TAVI and those undergoing TAVI+PCI. The incidence of myocardial infarction (OR 2.96, 95% CI 1.03-8.45; P = 0.04) was slightly higher in the TAVI+PCI group. Other complications, such as stroke, kidney injury, bleeding and vascular complications, were not significantly increased in the TAVI+PCI group. Patients treated with a staged procedure of TAVI and PCI but not simultaneous TAVI+PCI showed higher 30-day all-cause mortality as compared to those undergoing isolated TAVI. CONCLUSIONS Combined TAVI+PCI showed similar rates of death from any cause at 30 days and 1 year as compared to isolated TAVI. Except for myocardial infarction, the rate of operative complications in the TAVI+PCI group was not detrimental as compared to the isolated TAVI group. The simultaneous treatment of significant coronary artery lesions may be preferred in selected patients undergoing TAVI.
Neonatal Murine Engineered Cardiac Tissue Toxicology Model: Impact of Metallothionein Overexpression on Cadmium-Induced Injury

Engineered cardiac tissues (ECTs) serve as robust in vitro models to study human cardiac diseases including cardiac toxicity assays due to rapid structural and functional maturation and the ability to vary ECT composition. Metallothionein (MT) has been shown to be cardioprotective for environmental toxicants including heavy metals. To date, studies on the role of cardiomyocyte (CM)-specific MT expression and function have occurred in dissociated single cell assays or expensive in vivo small animal models. Therefore, we generated 3D ECTs using neonatal mouse ventricular cells from wild-type (WT) and the CM-specific overexpressing MT-transgenic (MT-TG) to determine the effect of MT overexpression on ECT maturation and function. Because Cadmium (Cd) is an environmentally prevalent heavy metal toxicant with direct negative impact on cardiac structure and function, we then determined the effect of MT overexpression to reduce Cd mediated CM toxicity within ECTs. We found: (1) structural and functional maturation was similar in WT and MT-TG ECTs; (2) Cd exposure negatively impacted ECT cell survival, maturation, and function; and (3) MT-ECTs showed reduced Cd toxicity as defined by reduced cleaved caspase 3, reduced Bax/Bcl2 ratio, reduced TdT-mediated dUTP nick-end labeling positive cells, reduced CM loss after Cd treatment, and delayed onset of cardiac dysfunction after Cd treatment. Thus, neonatal murine ECTs can serve as a robust in vitro model for heavy metal toxicity screening and as a platform to evaluate the role cardioprotective mechanisms, such as the MT-TG model, on environmentally relevant toxicants.
Human peroxidasin 1 promotes angiogenesis through ERK1/2, Akt, and FAK pathways

Aims The term angiogenesis refers to sprouting of new blood vessels from pre-existing ones. The angiogenic process involves cell migration and tubulogenesis requiring interaction between endothelial cells and the extracellular matrix. Human peroxidasin 1 (hsPxd01) is a multidomain heme peroxidase found embedded in the basement membranes. As it promotes the stabilization of extracellular matrix, we investigated its possible role in angiogenesis both in vitro and in vivo. Methods and results We analysed the effects of peroxidasin 1 gene silencing and supplementation by recombinant hsPxd01 in TeloHAEC endothelial cells on cell migration, tubulogenesis in matrigel, and intracellular signal transduction as assessed by kinase phosphorylation and expression of pro-angiogenic genes as measured by qRT-PCR. We further evaluated the angiogenic potential of recombinant peroxidasin in a chicken chorioallantoic membrane model. RNA silencing of endogenous hsPxd01 significantly reduced tube formation and cell migration, whereas supplementation by the recombinant peroxidase promoted tube formation in vitro and stimulated vascularization in vivo through its catalytic activity. Moreover, recombinant hsPxd01 promoted phosphorylation of Extracellular signal-Regulated Kinases (ERK1/2), Protein kinase B (Akt), and Focal Adhesion Kinase (FAK), and induced the expression of pro-angiogenic downstream genes: Platelet Derived Growth Factor Subunit B (PDGFB), endothelial-derived Heparin Binding EGF-like growth factor (HB-EGF), CXCL-1, Hairy-Related Transcription Factor 1 (HEY-1), DNA-binding protein inhibitor (ID-2), Snail Family Zinc Finger 1 (SNAI-1), as well as endogenous hsPxd01. However, peroxidasin silencing significantly reduced Akt and FAK phosphorylation but induced ERK1/2 activation after supplementation by recombinant hsPxd01. While hsPxd01 silencing significantly reduced expression of HEY-1, ID-2, and PDGFB, it did not affect expression of SNAI-1, HB-EGF, and CXCL-1 after supplementation by recombinant hsPxd01. Conclusion Our findings suggest a role of enzymatically active peroxidasin 1 as a pro-angiogenic peroxidase and a modulator of ERK1/2, Akt and FAK signalling.
Misuse of Coauthorship in Medical Theses in Sweden

The aim of this study was to explore experiences of authorship issues among persons who have recently received their doctoral degree in medicine in Sweden. A survey was mailed to all who received their PhD at a medical faculty at a Swedish university the first half of 2016. Questions concerned experiences of violations of the first three authorship criteria in the Vancouver rules and of misuse of authorship order in the articles of their thesis, and the respondents’ attitudes to these matters. The questionnaire was returned by 285 respondents (68%). According to the majority (53%), the Vancouver rules were not fully respected in the articles of their thesis. A vast majority (97%) found it important that authorship issues are handled correctly, but only 19% responded that their department has a clear and consistently applied policy. We conclude that authorship guidelines are frequently disrespected at medical faculties in Sweden. The universities seem to provide limited support on authorship issues.
Psychotic Experiences and Related Distress: A Cross-national Comparison and Network Analysis Based on 7141 Participants From 13 Countries

Psychotic experiences (PEs) are common in the general population but do not necessarily reflect a risk status if they occur in relative isolation or are not distressing. Emerging evidence suggests that PEs might be experienced as more benign for individuals from collectivistic low- and middle-income countries (LAMIC) compared with individualistic high-income countries (HIC). The aim of this study was to determine whether: (1) self-reported PEs are less distressing in community samples from LAMIC than from HIC; (2) the network of PEs is significantly less connected in a sample from LAMIC than from HIC. Adults from 8 HIC (n = 4669) and 5 LAMIC (n = 2472) were compared. The lifetime frequency of PEs and related distress were assessed with the Community Assessment of Psychic Experiences. We analyzed the associations of PEs with distress and country type. The interconnection of PEs was visualized by a network analysis and tested for differences in global connection strengths. The average endorsement rates of PEs were significantly higher in LAMIC than in HIC (χ2 = 1772.87, P < .01, Φcramer = 0.50). There was a universal positive correlation between higher frequency of PEs and more distress, but the distress levels controlled for frequency were significantly higher in HIC (R2 = 0.11; b = 0.26; SE = 0.01; T = 17.68; P < .001). Moreover, the network of PEs was significantly less connected in LAMIC (S = 0.40, P < .05). The findings indicate that PEs are of less clinical relevance in LAMIC compared with HIC. The universal use of current high-risk criteria might thus not be adequate without consideration of associated distress and cultural values.
Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: A preliminary investigation.

BACKGROUND Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is medically unexplained post-exertional fatigue associated with significant reduction in natural killer cell (NK) cytotoxicity activity. Cytotoxic activity relies on glycolytic flux and mitochondrial respiration to fulfill energetic cellular demands. While mitochondrial dysfunction has been reported in ME/CFS patients, no previous investigation has examined the bioenergetic profile of isolated NK cells from ME/CFS patients. OBJECTIVE This study was to determine the metabolic function in resting NK cells from ME/CFS patients. METHOD Six ME/CFS patients (aged 50.33±4.95) were age and sex-matched with non-fatigued healthy controls (aged 50.00±5.04). Mitochondrial stress tests measured parameters of mitochondrial function in the NK cells including basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity and bioenergetic health index. Glycolytic stress tests measured parameters of glycolytic function such as glycolytic reserve, glycolysis and glycolytic capacity in isolated NK cells from ME/CFS patients and healthy controls using an extracellular flux analyzer, Seahorse XFp. RESULT There was a significant reduction of glycolytic reserve in resting NK cells from ME/CFS patients (0.6±0.07 mpH/ min) compared with healthy control (2.25±1.3 mpH/min). Mitochondrial respiration in resting NK cells did not approach statistical significance between ME/CFS patients and healthy controls. CONCLUSION These findings suggest resting NK cells from ME/CFS patients have reduced ability to increase glycolytic flux to respond to high energetic demands for ATP production. Hence, the reduced glycolytic reserves we have identified in isolated resting isolated NK cells should be further investigated to assist in understanding ME/CFS pathogenesis.
Consumption of a Carbonated Beverage with High-Intensity Sweeteners Has No Effect on Insulin Sensitivity and Secretion in Nondiabetic Adults.

Background The effects of the regular intake of beverages containing high-intensity sweeteners on insulin sensitivity in healthy individuals remain controversial. Objective This trial compared the effects of the consumption of a carbonated beverage containing aspartame and acesulfame K (high-intensity sweeteners beverage-HISB) with those of an unsweetened, no-calorie carbonated beverage (UB) on insulin sensitivity and secretion in nondiabetic adults. Methods SEDULC was a randomized, double-blind, crossover study. Nondiabetic adults [mean age 31 y, 44% men, body mass index (BMI; kg/m²) 19-29] who did not consume high-intensity sweeteners were randomized 1:1 to drink 1 of the 2 carbonated beverages, 2 cans (330 mL each)/d, for 12 wk. After a 4-wk washout period, participants were switched to the opposite beverage for 12 wk. The primary outcome tested was the change in insulin sensitivity as assessed by the Matsuda Insulin Sensitivity Index (MISI) after an oral glucose load. Secondary outcomes were indexes of insulin secretion. Results Sixty individuals were enrolled and 50 completed the study (28 nonoverweight and 22 overweight participants). The change in MISI from baseline did not significantly differ between beverages and noninferiority was demonstrated (difference = -0.23; 95% CI: -1.31, 0.85; P < 0.0001). The change in insulinogenic (means ± SEMs: 0.23 ± 0.14 for HISB compared with 0.08 ± 0.1 for UB) and disposition indexes (2.70 ± 0.99 for HISB compared with 1.62 ± 0.90 for UB) did not differ, and no differences in insulin secretion estimates were confirmed by the Stumvoll indexes. Consuming the high-intensity sweeteners did not affect body weight, self-reported dietary consumption, or self-reported physical activity. Conclusions These findings suggest that the daily consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 wk has no significant effect on insulin sensitivity and secretion in nondiabetic adults. This trial was registered at clinicaltrials.gov as NCT02031497.
Renal Dysfunction Affects Anticoagulation Control With Warfarin and Outcomes in Japanese Elderly Patients With Non-Valvular Atrial Fibrillation.

BACKGROUND It is unclear whether renal dysfunction affects warfarin control in patients with non-valvular atrial fibrillation (NVAF). Methods and Results: Using a dataset from the J-RHYTHM Registry, time in therapeutic range (TTR) of the international normalized ratio (INR) of prothrombin time, and creatinine clearance (CrCl) were determined in elderly patients aged ≥70 years. Target INR values were 1.6-2.6 following Japanese guidelines. Incidences of thromboembolism, major hemorrhage, and all-cause death were determined over 2 years. Of 7,406 NVAF patients enrolled in the registry, 2,782 elderly patients (mean age, 75 years) had data for CrCl measured at baseline and TTR. TTR values were lower in the lower CrCl groups (P<0.001 for trend). CrCl <30 mL/min was independently associated with TTR <65% (odds ratio, 1.49; 95% confidence interval, 1.13-1.95; P=0.004). In the multivariate analysis, TTR <65% was independently associated with thromboembolism (hazard ratio, 2.26; 95% confidence interval, 1.37-3.72; P=0.001), but CrCl was not (CrCl <30 mL/min, 1.68, 0.41-6.85, P=0.473). However, CrCl <30 mL/min and TTR <65% were independently associated with all-cause death (5.32, 1.56-18.18, P=0.008 and 1.60, 1.07-2.38, P=0.022, respectively) and the composite event (thromboembolism, major hemorrhage and all-cause death) (2.03, 1.10-3.76, P=0.024 and 1.58, 1.22-2.04, P=0.001, respectively). CONCLUSIONS Elderly NVAF patients with renal dysfunction had poor warfarin control, which was associated with higher risk of thromboembolism and all-cause death.
Experiences of Self-Monitoring in Self-Directed Weight Loss and Weight Loss Maintenance: Systematic Review of Qualitative Studies

The experience and role of self-monitoring in self-directed weight loss attempts may be distinctly different from that within formal interventions, and has yet to be fully explored. We systematically reviewed qualitative studies to examine experiences of self-monitoring as an aid to self-directed weight loss. Thematic synthesis was used to construct descriptive and analytical themes from the available data. In all, 22 studies (681 participants) were included, in which the uses of self-monitoring ranged from an aid to increase adherence to a tool for facilitating analysis. Self-monitoring also influenced and was influenced by self-perception and emotions. Feelings of shame were linked with abandonment of efforts. Findings highlight the centrality of interpretation of self-monitored data, the implications this interpretation has on sense of self, and the impact of broader discourses. Explicitly framing self-monitoring as a positive tool with which to aid analysis may encourage helpful use of this technique.
Individual differences in the emotional modulation of gaze-cuing

ABSTRACT Gaze-cuing refers to the spontaneous orienting of attention towards a gazed-at location, characterised by shorter response times to gazed-at than non-gazed at targets. Previous research suggests that processing of these gaze cues interacts with the processing of facial expression cues to enhance gaze-cuing. However, whether only negative emotions (which signal potential threat or uncertainty) can enhance gaze-cuing is still debated, and whether this emotional modulation varies as a function of individual differences still remains largely unclear. Combining data from seven experiments, we investigated the emotional modulation of gaze-cuing in the general population as a function of participant sex, and self-reported subclinical trait anxiety, depression, and autistic traits. We found that (i) emotional enhancement of gaze-cuing can occur for both positive and negative expressions, (ii) the higher the score on the Attention to Detail subscale of the Autism Spectrum Quotient, the smaller the emotional enhancement of gaze-cuing, especially for happy expressions, and (iii) emotional modulation of gaze-cuing does not vary as a function of participant anxiety, depression or sex, although women display an overall larger gaze-cuing effect than men.
Reduced engagement of the anterior cingulate cortex in the dishonest decision-making of incarcerated psychopaths

Abstract A large body of research indicates that psychopathic individuals lie chronically and show little remorse or anxiety. Yet, little is known about the neurobiological substrates of dishonesty in psychopathy. In a sample of incarcerated individuals (n = 67), we tested the hypothesis that psychopathic individuals show reduced activity in the anterior cingulate cortex (ACC) when confronted with an opportunity for dishonest gain, reflecting dishonest behavior that is relatively unhindered by response conflict. During functional magnetic resonance imaging, incarcerated offenders with different levels of psychopathy performed an incentivized prediction task wherein they were given real and repeated opportunities for dishonest gain. We found that while incarcerated offenders showed a high rate of cheating, levels of psychopathic traits did not influence the frequency of dishonesty. Higher psychopathy scores predicted decreased activity in the ACC during dishonest decision‐making. Further analysis revealed that the ACC was functionally connected to the dorsolateral prefrontal cortex, and that ACC activity mediated the relationship between psychopathic traits and reduced reaction times for dishonest behavior. These findings suggest that psychopathic individuals behave dishonestly with relatively low levels of response conflict and that the ACC may play a critical role in this pattern of behavior.
Pro-arrhythmic RyR2 channels in heart failure: do their localisation and mechanism of activation really matter?

Heart failure (HF) with a reduced ejection fraction is associated with loss of co-ordinated excitation-contraction coupling (ECC) and impaired contractility. The related subcellular changes in cardiomyocyte ultra-structure and Ca 2 þ signalling cause a complex pro-arrhythmic substrate, which is difficult to target with current therapeutic approaches. 1 Physiological ECC involves Ca 2 þ release from the sarcoplasmic reticulum (SR) in response to triggered Ca 2 þ influx via voltage-gated L-type Ca 2 þ channels. To synchronize Ca 2 þ -induced Ca 2 þ release, plasmalem-mal invaginations called transverse (T)-tubules, are positioned in immedi-ate proximity to the SR, ensuring proper coupling of Ca 2 þ influx with ryanodine receptor type-2 Ca 2 þ -release channels (RyR2). 2,3 The T-tubule
Diet-Quality Indexes Are Associated with a Lower Risk of Cardiovascular, Respiratory, and All-Cause Mortality among Chinese Adults.

Background Diet-quality indexes have been associated with a lower risk of chronic disease mortality in Western populations, but it is unclear whether these indexes reflect protective dietary patterns in Asian populations. Objective We examined the association between Alternative Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), and Healthy Diet Indicator (HDI) scores and the risk of all-cause cardiovascular disease (CVD), cancer, and respiratory disease mortality. Methods We used data from a prospective cohort of 57,078 Singapore Chinese men and women (aged 45-74 y) who were free of cancer and CVD at baseline (1993-1998) and who were followed up through 2014. The diet-quality index scores were calculated on the basis of data from a validated 165-item food-frequency questionnaire. Cox regression models with adjustment for potential confounders including sociodemographic and lifestyle variables, body mass index, and medical history were used to estimate HRs and 95% CIs. Results During a total of 981,980 person-years of follow-up, 15,262 deaths (CVD: 4871; respiratory: 2690; and cancer: 5306) occurred. Comparing the highest with the lowest quintiles, the multivariable adjusted HRs (95% CIs) for all-cause mortality were 0.82 (0.78, 0.86) for AHEI-2010, 0.80 (0.76, 0.85) for aMED, 0.80 (0.75, 0.84) for DASH, and 0.88 (0.83, 0.92) for HDI scores (all P-trend < 0.001). Higher diet index scores were associated with a 14-28% lower risk of CVD and respiratory mortality, but only a 5-12% lower risk of cancer mortality. Higher consumption of vegetables, fruit, nuts, and long-chain n-3 (ω-3) fatty acids, lower consumption of red meat, and avoidance of high alcohol consumption were the diet index components associated with a lower risk of mortality. Conclusion Adherence to several recommended dietary patterns that emphasize healthy plant-based foods was associated with a substantially lower risk of chronic disease mortality in an Asian population. The Singapore Chinese Health Study was registered at www.clinicaltrials. gov as NCT03356340.