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In cancer, myeloid cells have tumor-supporting roles. We reported that the protein GPNMB (glycoprotein nonmetastatic B) was profoundly upregulated in macrophages interacting with tumor cells. Here, using mouse tumor models, we show that macrophage-derived soluble GPNMB increases tumor growth and metastasis in Gpnmb-mutant mice (DBA/2J). GPNMB triggers in the cancer cells the formation of self-renewing spheroids, which are characterized by the expression of cancer stem cell markers, prolonged cell survival and increased tumor-forming ability. Through the CD44 receptor, GPNMB mechanistically activates tumor cells to express the cytokine IL-33 and its receptor IL-1R1L. We also determined that recombinant IL-33 binding to IL-1R1L is sufficient to induce tumor spheroid formation with features of cancer stem cells. Overall, our results reveal a new paracrine axis, GPNMB and IL-33, which is activated during the cross talk of macrophages with tumor cells and eventually promotes cancer cell survival, the expansion of cancer stem cells and the acquisition of a metastatic phenotype.

IntroductionTransitional age youth (TAY), from 16 to 24 years old, are a particularly at-risk population in mental health. They have specific needs, not currently covered between child and adolescent mental health services (CAMHS) and adult mental health services (AMHS), mainly because of existing barriers.ObjectivesThis retrospective study was carried out to describe sociodemographic and clinical characteristics of 243 patients who attended a new TAY-tailored outpatient psychiatric program.MethodsOutcomes related to trajectories of psychiatric care were analysed, such as leading symptom, consultation’s referral and requester, and final orientation.ResultsThe sample was mainly composed by female; the average age was 18.7 (± 2.0) years. Leading symptoms were divided into three dimensions: internalizing (67.5%), externalizing (21.8%) and psychotic (10.7%). Leading symptom differed according to sex (p<0.001), with internalizing symptoms more frequent in women, externalizing and psychotic symptoms more frequent in men. Patients presenting psychotic symptoms were significantly older than both those with internalizing (p=0.016) and externalizing symptoms (p=0.008). After first assessment, 81.5% of youth were followed-up in our specific outpatient program, without any difference according to sex (p=0.081) or leading symptom (p=0.092). Overall and final psychiatric orientation are showed in the flowchart.ConclusionsThis TAY-tailored psychiatric outpatient program represents an innovative contribution to reinforce CAMHS-AMHS interface in French-speaking Belgium. This study enlightens the importance to enhance clinical expertise in youth mental health. Classical boundaries, determined by artificial variables such as age or type of psychopathology, do not seem to be efficient criteria to achieve a good quality psychiatric evaluation and continuity of care in TAY.DisclosureThe authors declare no potential conflicts of interest. The study was carried out as part of the University Chair “Psychiatry in Transition in a World in Transition” (Université Libre de Bruxelles - ULB) with the support of Julie Renson Fund, the Queen Fa

IntroductionStigma towards mental health has been described as a major obstacle to seek help and access to mental health services. This could result in a worsened Quality of Life (QoL). There is a little evidence of stigma in Mental Health Professionals and its consequences, especially in Early Career ones (ECMPH), who can be a more vulnerable group. There is even more lack of studies with multicultural approaches. Exploring stigma, support systems and access to these, and the link of these factors with QoL is essential to develop effective strategies to support ECMHP, for both their own mental health and providing care to patients.ObjectivesThis study aims to explore the association between ECMHP’s stigma towards mental health and their QoL, and to identify predictors of QoL among this population.MethodsIn this cross-sectional study, we designed an online survey to collect data among ECMHP, identified as having completed training since less than 7 years. QoL was assessed using the WHO-QoL. Stigma towards mental health was measured with the Opening Minds Stigma Scale for Health Care Providers (OMS-HC). Other general sociodemographic data were also collected. Descriptive results are resumed in absolute and relative frequencies for categorical variables. Student’s t-test and ANOVA were used to analyse scores in WHO-QoL and OMS-HC according to categorical variables. Pearson’s correlation coefficient was used to assess the association between WHO-QoL and OMS-HC. Simple and multiple linear regression were used to study the effect of stigma on QoL, taking into account potential confounders.ResultsWe collected data from 277 ECMHP from Europe (54.15%) and Asia (45.85%). Only 20% of our sample knew that their workplace has staff dedicated for mental health practitioners support, and among those, only 44% had visited it. OMS-HC total scores were significantly higher (p<0,05) in nurses and practitioners without a sufficient support system and without a mental disorder. WHO-QoL total scores were significantly higher in participants with sufficient support systems, and without a mental or physical illness. There was a negative correlation between OMS-HC and WHO-QoL total scores. Univariate analysis showed that OMS-HC total scores predicted WHO-QoL total scores. In the multivariate analysis, OMS-HC total scores, having a mental illness and having sufficient support, independently predicted WHO-QoL total scores, even when adjusted for sociodemographic variables.ConclusionsStigma towards mental health is related to QoL in ECMHP. Also, having sufficient support in the workplace improves QoL in this population. More studies are needed to help clarify the relationship between stigma and QoL using a longitudinal design.Disclosure of InterestNone Declared

Diabetes can elicit direct deleterious effects on the myocardium, independent of coronary artery disease or hypertension. These cardiac disturbances are termed diabetic cardiomyopathy showing increased risk of heart failure with or without reduced ejection fraction. Presently, there is no specific treatment for this type of cardiomyopathy and in the case of type I diabetes, it may start in early childhood independent of glycemic control. We hypothesized that alterations in isolated myocyte contractility and cardiac function are present in the early stages of experimental diabetes in rats before overt changes in myocardium structure occur. Diabetes was induced by single-dose injection of streptozotocin (STZ) in rats with data collected from control and diabetic animals 3 weeks after injection. Left ventricle myocyte contractility was measured by single-cell length variation under electrical stimulation. Cardiac function and morphology were studied by high-resolution echocardiography with pulsed-wave tissue Doppler imaging (TDI) measurements and three-lead surface electrocardiogram. Triglycerides, cholesterol and liver enzyme levels were measured from plasma samples obtained from both groups. Myocardial collagen content and perivascular fibrosis of atria and ventricle were studied by histological analysis after picrosirius red staining. Diabetes resulted in altered contractility of isolated cardiac myocytes with increased contraction and relaxation time intervals. Echocardiography showed left atrium dilation, increased end-diastolic LV and posterior wall thickness, with reduced longitudinal systolic peak velocity (S') of the septum mitral annulus at the apical four-chamber view obtained by TDI. Triglycerides, aspartate aminotransferase and alkaline phosphatase were elevated in diabetic animals. Intertitial collagen content was higher in atria of both groups and did not differ among control and diabetic animals. Perivascular intramyocardial arterioles collagen did not differ between groups. These results suggest that alterations in cardiac function are present in the early phase in this model of diabetes type 1 and occur before overt changes in myocardium structure appear as evaluated by intersticial collagen deposition and perivascular fibrosis of intramyocardial arterioles.

To elucidate the mechanisms behind the high sensitivity of myxoid/round cell liposarcoma (MRCL) to trabectedin and the suggested selectivity for specific subtypes, we have developed and characterized three MRCL xenografts, namely ML017, ML015 and ML004 differing for the break point of the fusion gene FUS-CHOP, respectively of type I, II and III. FUS-CHOP binding to the promoters of some target genes such as Pentraxin 3 or Fibronectin 1, assessed by chromatin immunoprecipitation, was strongly reduced in the tumor 24 h after the first or the third weekly dose of trabectedin, indicating that the drug at therapeutic doses causes a detachment of the FUS-CHOP chimera from its target promoters as previously shown in vitro . Moreover, the higher sensitivity of MRCL types I and II appears to be related to a more prolonged block of the transactivating activity of the fusion protein. Doxorubicin did not affect the binding of FUS-CHOP to target promoters. Histologically, the response to trabectedin in ML017 and ML015 was associated with a marked depletion of non-lipogenic tumoral cells and vascular component, as well as lipidic maturation as confirmed by PPARγ2 expression in western Blot. By contrast, in ML004 no major changes either in the cellularity or in the amount of mature were found, and consistently PPARγ2 was null. In conclusion, the data support the view that the selective mechanism of action of trabectedin in MRCL is specific and related to its ability to cause a functional inactivation of the oncogenic chimera with consequent derepression of the adypocytic differentiation.

Background . Benfotiamine, a synthetic analog of thiamine, offers greater bioavailability compared to other thiamine salts and increases thiamine stores upon oral intake. Thiamine is essential for energy metabolism. This study aimed to evaluate the effects of oral benfotiamine supplementation on energy metabolism, particularly the Krebs cycle function, in the muscle of endurance‐trained mice, and to assess its impact on endurance performance. Methods . Twenty‐five mice were randomly assigned to four groups: a standard diet with sedentary behavior (Sta‐Sed), a benfotiamine‐supplemented diet with sedentary behavior (Ben‐Sed), a standard diet with swimming training (Sta‐Tr), and a benfotiamine‐supplemented diet with swimming training (Ben‐Tr). The trained groups underwent five weekly swimming sessions for six weeks, followed by an exhaustive test. Thiamine and its esters were measured in erythrocytes and gastrocnemius muscle. Gene expression of pyruvate dehydrogenase (PDHa) and alpha‐ketoglutarate dehydrogenase (OGDH), along with levels of pyruvic, lactic, and hydroxybutyric acids in muscle, was analyzed. Results . The benfotiamine‐supplemented groups had higher thiamine levels in erythrocytes and muscles compared to the standard‐diet groups. No differences were observed in PDHa and OGDH gene expression. The Ben‐Tr group exhibited increased muscle lactic acid levels and a higher lactic acid to pyruvic acid ratio compared to the sedentary groups. Hydroxybutyric acid levels were also elevated in the Ben‐Tr group. No significant differences in exhaustive test duration were found between the groups. Conclusion . Benfotiamine supplementation increases thiamine levels in erythrocytes and muscle but does not affect the gene expression of thiamine‐dependent enzymes. Although it alters energy metabolism in trained muscle, it does not enhance endurance performance in mice.

Background/ObjectivesWe aimed to investigate the effects of short-term hypocaloric diet-induced weight loss on DNA methylation profile in leukocytes from women with severe obesity.MethodsEleven women with morbid obesity (age: 36.9 ± 10.3 years; BMI: 58.5 ± 10.5 kg/m2) were assessed before and after 6 weeks of a hypocaloric dietary intervention. The participants were compared with women of average weight and the same age (age: 36.9 ± 11.8 years; BMI: 22.5 ± 1.6 kg/m2). Genome-wide DNA methylation analysis was performed in DNA extracted from peripheral blood leukocytes using the Infinium Human Methylation 450 BeadChip assay. Changes (Δβ) in the methylation level of each CpGs were calculated. A threshold with a minimum value of 10%, p < 0.001, for the significant CpG sites based on Δβ and a false discovery rate of <0.05 was set.ResultsDietary intervention changed the methylation levels at 16,064 CpG sites. These CpGs sites were related to cancer, cell cycle-related, MAPK, Rap1, and Ras signaling pathways. However, regardless of hypocaloric intervention, a group of 878 CpGs (related to 649 genes) remained significantly altered in obese women when compared with normal-weight women. Pathway enrichment analysis identified genes related to the cadherin and Wnt pathway, angiogenesis signaling, and p53 pathways by glucose deprivation.ConclusionA short-term hypocaloric intervention in patients with severe obesity partially restored the obesity-related DNA methylation pattern. Thus, the full change of obesity-related DNA methylation patterns could be proportional to the weight-loss rate in these patients after dietary interventions.

Uncoupling proteins (UCPs) are located in the inner membrane of mitochondria. These proteins participate in thermogenesis and energy expenditure. This study aimed to evaluate how UCP1 and UCP3 expression influences substrate oxidation and elicits possible changes in body composition in patients submitted to bariatric surgery. This is a longitudinal study comprising 13 women with obesity grade III that underwent bariatric surgery and 10 healthy weight individuals (control group). Body composition was assessed by bioelectrical impedance. Carbohydrate and fat oxidation was determined by indirect calorimetry. Subcutaneous adipose tissue was collected for gene expression analysis. QPCR was used to evaluate UCP1 and UCP3 expression. Obese patients and the control group differed significantly in terms of lipid and carbohydrate oxidation. Six months after bariatric surgery, the differences disappeared. Lipid oxidation correlated with the percentage of fat mass in the postoperative period. Multiple linear regression analysis showed that the UCP1 and UCP3 genes contributed to lipid and carbohydrate oxidation. Additionally, UCP3 expression was associated with BMI, percentage of lean body mass, and percentage of mass in the postoperative period. UCP1 and UCP3 expression is associated with lipid and carbohydrate oxidation in patients submitted to bariatric surgery. In addition, UCP3 participates in body composition modulation six months postoperatively.

ABSTRACT Introduction: Some endourological surgeries require multiple screens to perform combined procedures, which can present ergonomic challenges (1, 2). Apple Vision Pro (AVP) is a spatial computing device developed by Apple that incorporates virtual reality (VR) for life-like simulations, realistic medical scenarios, interactive anatomical models, and augmented reality (AR) technologies (3). In health care, VR is used for pain management, physical therapy, psychological therapy, and surgical simulations, providing a controlled and safe environment for both patients and healthcare professionals (4). Objective: To demonstrate the step-by-step technique of the Mini-Endoscopic Combined Intra-Renal Surgery (Mini-ECIRS) procedure guided by ultrasound and using mixed reality technology with the Apple Vision Pro (multiscreen and 3D reconstruction). To the best of our knowledge, this is the first report of this procedure being performed with AVP assistance. Patient and Methods: We present the case of a 40-year-old female with a history of right lumbar pain for one year. A CT scan revealed a proximal ureteral stone (20mm) and a lower pole stone (14mm) on the right side, with a Guys's Score grade 2 4. In this case, we opted for Ultrasound-Guided Mini-ECIRS (5, 6). This choice allowed for precise puncture and dilation, ensuring effective treatment and minimal invasiveness, assisted by the Apple Vision Pro. This device is equipped with eight external cameras that capture the real world at a resolution of 4K, enhancing the surgeon's experience with unparalleled efficiency and ease of mixed reality. This advanced imaging allows for precise visualization and integration of digital elements into the physical environment, significantly improving the accuracy and effectiveness of surgical procedures. During this procedure, the multitude of equipment in the operating room often obstructs the view of the physical monitors, including ultrasound. However, this technology addresses these challenges by offering enhanced ergonomics, efficiency, and safety to the surgeon. By providing seamless integration of digital overlays and real-world visuals, it ensures that crucial information is always within the surgeon's line of sight, thereby improving operational precision and overall outcomes. The surgeon had no previous contact with the AVP and was assisted by an AVP expert urologist throughout the procedure. Results: The procedure was performed in the Barts flank-free position. Initially, ureterolithotomy was performed using holmium laser. After the dusting phase, an ultrasound-guided renal puncture was performed using a virtual screen, providing enhanced comfort and ergonomics for the surgeon. Throughout the procedure, the surgeon had simultaneous access to both screens (nephroscope and flexible ureteroscope), facilitating efficient location of any residual stones. The AVP functioned effectively, displaying multiple screens within its own interface, improving ergonomics during surgery and maintaining safety throughout the procedure. The surgery was performed uneventfully in 2 hours, and the patient was rendered stone-free on CT and was discharged on the first postoperative day. Conclusion: Apple Vision Pro provides multiscreen and 3D reconstruction capabilities, ensuring a comfortable, safe, and easily replicable procedure. Its advanced technology may be particularly beneficial for surgeries, such as Mini-ECIRS, which require simultaneous screens.

Weight regulation and the magnitude of weight loss after a Roux-en-Y gastric bypass (RYGB) can be genetically determined. DNA methylation patterns and the expression of some genes can be altered after weight loss interventions, including RYGB. The present study aimed to evaluate how the gene expression and DNA methylation of PIK3R1, an obesity and insulin-related gene, change after RYGB. Blood samples were obtained from 13 women (35.9 ± 9.2 years) with severe obesity before and six months after surgical procedure. Whole blood transcriptome and epigenomic patterns were assessed by microarray-based, genome-wide technologies. A total of 1966 differentially expressed genes were identified in the pre- and postoperative periods of RYGB. From these, we observed that genes involved in obesity and insulin pathways were upregulated after surgery. Then, the PIK3R1 gene was selected for further RT-qPCR analysis and cytosine-guanine nucleotide (CpG) sites methylation evaluation. We observed that the PI3KR1 gene was upregulated, and six DNA methylation CpG sites were differently methylated after bariatric surgery. In conclusion, we found that RYGB upregulates genes involved in obesity and insulin pathways.