Persistent epigenetic signals propel a senescence-associated secretory phenotype and trained innate immunity in CD34+ hematopoietic stem cells from diabetic patients.

BACKGROUND: Diabetes-induced trained immunity contributes to the development of atherosclerosis and its complications. This study aimed to investigate in humans whether epigenetic signals involved in immune cell activation and inflammation are initiated in hematopoietic stem/progenitor cells (HSPCs) and transferred to differentiated progeny. METHODS AND RESULTS: High glucose (HG)-exposure of cord blood (CB)-derived HSPCs induced a senescent-associated secretory phenotype (SASP) characterized by cell proliferation lowering, ROS production, telomere shortening, up-regulation of p21 and p27genes, upregulation of NFkB-p65 transcription factor and increased secretion of the inflammatory cytokines TNFα and IL6. Chromatin immunoprecipitation assay (ChIP) of p65 promoter revealed that H3K4me1 histone mark accumulation and methyltransferase SetD7 recruitment, along with the reduction of repressive H3K9me3 histone modification, were involved in NFkB-p65 upregulation of HG-HSPCs, as confirmed by increased RNA polymerase II engagement at gene level. The differentiation of HG-HSPCs into myeloid cells generated highly responsive monocytes, mainly composed of intermediate subsets (CD14hiCD16+), that like the cells from which they derive, were characterized by SASP features and similar epigenetic patterns at the p65 promoter. The clinical relevance of our findings was confirmed in sternal BM-derived HSPCs of T2DM patients. In line with our in vitro model, T2DM HSPCs were characterized by SASP profile and SETD7 upregulation. Additionally, they generated, after myeloid differentiation, senescent monocytes mainly composed of proinflammatory intermediates (CD14hiCD16+) characterized by H3K4me1 accumulation at NFkB-p65 promoter. CONCLUSIONS: Hyperglycemia induces marked chromatin modifications in HSPCs, which, once transmitted to the cell progeny, contributes to persistent and pathogenic changes in immune cell function and composition.

Machine-learning prediction of treatment response to stereotactic body radiation therapy in oligometastatic gynecological cancer: A multi-institutional study.

BACKGROUND AND PURPOSE: We aimed to develop and validate different machine-learning (ML) prediction models for the complete response of oligometastatic gynecological cancer after SBRT. MATERIAL AND METHODS: One hundred fifty-seven patients with 272 lesions from 14 different institutions and treated with SBRT with radical intent were included. Thirteen datasets including 222 lesions were combined for model training and internal validation purposes, with an 80:20 ratio. The external testing dataset was selected as the fourteenth Institution with 50 lesions. Lesions that achieved complete response (CR) were defined as responders. Prognostic clinical and dosimetric variables were selected using the LASSO algorithm. Six supervised ML models, including logistic regression (LR), classification and regression tree analysis (CART) and support vector machine (SVM) using four different kernels, were trained and tested to predict the complete response of uterine lesions after SBRT. The performance of models was assessed by receiver operating characteristic curves (ROC), area under the curve (AUC) and calibration curves. An explainable approach based on SHapley Additive exPlanations (SHAP) method was deployed to generate individual explanations of the model's decisions. RESULTS: 63.6% of lesions had a complete response and were used as ground truth for the supervised models. LASSO strongly associated complete response with three variables, namely the lesion volume (PTV), the type of lesions (lymph-nodal versus parenchymal), and the biological effective dose (BED10), that were used as input for ML modeling. In the training set, the AUCs for complete response were 0.751 (95% CI: 0.716-0.786), 0.766 (95% CI: 0.729-0.802) and 0.800 (95% CI: 0.742-0.857) for the LR, CART and SVM with a radial basis function kernel, respectively. These models achieve AUC values of 0.727 (95% CI: 0.669-0.795), 0.734 (95% CI: 0.649-0.815) and 0.771 (95% CI: 0.717-0.824) in the external testing set, demonstrating excellent generalizability. CONCLUSION: ML models enable a reliable prediction of the treatment response of oligometastatic lesions receiving SBRT. This approach may assist radiation oncologists to tailor more individualized treatment plans for oligometastatic patients.

Percutaneous CT-Guided Bone Biopsies: Indications, Feasibility and Diagnostic Yield in the Different Skeletal Sites-From the Skull to the Toe.

CT-guided bone biopsies are currently the diagnostic tool of choice for histopathological (and microbiological) diagnoses of skeletal lesions. Several research works have well-demonstrated their safety and feasibility in almost all skeletal regions. This comprehensive review article aims at summarizing the general concepts in regard to bone biopsy procedures, current clinical indications, the feasibility and the diagnostic yield in different skeletal sites, particularly in the most delicate and difficult-to-reach ones. The choice of the correct imaging guidance and factors affecting the diagnostic rate, as well as possible complications, will also be discussed. Since the diagnostic yield, technical difficulties, and complications risk of a CT-guided bone biopsy significantly vary depending on the different skeletal sites, subdivided analyses of different anatomical sites are provided. The information included in the current review article may be useful for clinicians assisting patients with possible bone neoplasms, as well as radiologists involved in the imaging diagnoses of skeletal lesions and/or in performing bone biopsies.

Liraglutide preserves CD34+ stem cells from dysfunction Induced by high glucose exposure.

BACKGROUND: Glucagon like peptide-1 receptor agonists (GLP-1RAs) have shown to reduce mortality and cardiovascular events in patients with type 2 diabetes mellitus (T2DM). Since the impairment in number and function of vasculotrophic circulating CD34+ hematopoietic stem progenitor cells (HSPCs) in T2D has been reported to increase cardiovascular (CV) risk, we hypothesized that one of the mechanisms whereby GLP-1 RAs exert CV protective effects may be related to the ability to improve CD34+ HSPC function. METHODS: In cord blood (CB)-derived CD34+ HSPC, the expression of GLP-1 receptor (GLP-1R) mRNA, receptor protein and intracellular signaling was evaluated by RT-qPCR and Western Blot respectively. CD34+ HSPCs were exposed to high glucose (HG) condition and GLP-1RA liraglutide (LIRA) was added before as well as after functional impairment. Proliferation, CXCR4/SDF-1α axis activity and intracellular ROS production of CD34+ HSPC were evaluated. RESULTS: CD34+ HSPCs express GLP-1R at transcriptional and protein level. LIRA treatment prevented and rescued HSPC proliferation, CXCR4/SDF-1α axis activity and metabolic imbalance from HG-induced impairment. LIRA stimulation promoted intracellular cAMP accumulation as well as ERK1/2 and AKT signaling activation. The selective GLP-1R antagonist exendin (9-39) abrogated LIRA-dependent ERK1/2 and AKT phosphorylation along with the related protective effects. CONCLUSION: We provided the first evidence that CD34+ HSPC express GLP-1R and that LIRA can favorably impact on cell dysfunction due to HG exposure. These findings open new perspectives on the favorable CV effects of GLP-1 RAs in T2DM patients.

The Long Telling Story of "Endothelial Progenitor Cells": Where Are We at Now?

Endothelial progenitor cells (EPCs): The name embodies years of research and clinical expectations, but where are we now? Do these cells really represent the El Dorado of regenerative medicine? Here, past and recent literature about this eclectic, still unknown and therefore fascinating cell population will be discussed. This review will take the reader through a temporal journey that, from the first discovery, will pass through years of research devoted to attempts at their definition and understanding their biology in health and disease, ending with the most recent evidence about their pathobiological role in cardiovascular disease and their recent applications in regenerative medicine.

Mentalization Impairment Is Associated with Problematic Alcohol Use in a Sample of Young Adults: A Cross-Sectional Study.

Background: Alcohol is one of the most widely used drugs among adolescents and young people, and problematic alcohol use (PAU) is related to significant long-term biological, clinical, and psychosocial sequelae. Although preliminary reports have linked deficits in mentalization to increased vulnerability to addiction, no studies have specifically explored this phenomenon in relation to PAU. Methods: The association between mentalization impairment and PAU severity was investigated in a sample of 271 young adults (183 females, 65.9%; mean age: 23.20 ± 3.55 years; range: 18-34). Self-report measures investigating PAU and mentalization were administered to all participants. Results: Individuals with PAU reported a more frequent use of tobacco and illicit drugs in the last 12 months. PAU severity was negatively associated with mentalization capacity (rho = -0.21; p < 0.001), and also, when possible, confounding variables (i.e., gender, age, occupation, education, tobacco and illegal drugs use) were controlled for (rho = -0.17; p = 0.004). Conclusion: The present data showed that mentalization impairment is significantly associated with PAU among young adults, suggesting that it may have a role in the development and/or maintenance of alcohol use.

The assisted suicide of Italians in Switzerland and the silence of psychiatry. / Il suicidio assistito degli italiani in Svizzera e il silenzio della psichiatria.

The debate on different forms of request of death has taken on a broad dimension in public opinion over last years, often referring on profoundly differentiated and often opposing positions of principle. Beyond cultural, political or ideal positions, a further critical issue, often underestimated or quite not considered, concerns a person's ability to express a valid consent to the request of death, according to the same criteria of validity of the informed consent to any medical act. This assumes particular importance in the case of assisted suicide. Assisted suicide represents a phenomenon in sharp growth in Western world. It is legal in many nations, and in Switzerland it is also allowed for foreign citizens, thus increasing the phenomenon of the so-called "tourism of suicide". In addition to neoplastic and neurological diseases, depression has also been accepted as a disease that makes assisted suicide possible. This imposes profound clinical and ethical considerations, since depression is unanimously recognized as a treatable disease and since in its most serious forms, such as those in which suicidal ideation dominates, it can compromise the patient's ability to express a valid consent to any medical act, including the assisted suicide. Furthermore, it is often overlooked that any serious and disabling somatic disease, source of intense and chronic suffering, carries the very high risk of the onset of unrecognized depressive conditions, able in turn to negatively influence the ability to express valid consent. Faced with this situation, which has involved a large number of Italian citizens in recent years, the personal and official voice of psychiatry is absolutely lacking, contrasting its silence with the opinions of those who do not want to take into account its potentially fundamental considerations.

Knee osteochondral autologous transplantation: long-term MR findings and clinical correlations.

We evaluated long-term magnetic resonance imaging (MRI) features of Knee Osteochondral Autologous Transplantation (OAT)-Mosaicplasty and correlated MRI findings and clinical outcome. Twenty-four patients (mean age 29.9±8.7, 70.8% male) undergoing arthroscopic OAT between 1997 and 2000 were prospectively enrolled. The International Cartilage Repair Society (ICRS)/International Knee Documentation Committee (IKDC) scores and Tegner scores were employed for clinical evaluation. The magnetic resonance observation of cartilage repair tissue (MOCART) was utilized for description and assessment of the repair tissue. Median follow up was 113 months (interquartile range [IQR] 106-122). MRI showed good survival of grafted cartilage in 62.5% of patients. The integration of the graft was complete in 75% of cases, while the repaired tissue was intact in 62.5% and had an homogeneous structure in 70.8%. The MOCART score significantly correlated with objective and subjective scores (p=0.003 and p=0.002). Contrastingly, overall MOCART showed no correlation with the Tegner score. MRI revealed to be a powerful tool for non-invasive long-term assessment of OAT.