Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression

Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets.Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)-educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography.Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFβ, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFβ-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFβ are increased in osteosarcoma patients.Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFβ-blocking agents as new therapeutic options for osteosarcoma patients

Stati depressivi, personalità di tipo D e comportamento di tipo A in pazienti cardiopatici.

Scopo dello studio \ue8 stato quello di indagare la frequenza e la comorbilit\ue0 tra diagnosi DSM dell\u2019area depressiva (depressione maggiore/minore e distimia), specifiche diagnosi DCPR (demoralizzazione e comportamento di tipo A) e personalit\ue0 di tipo D, in pazienti cardiopatici. Il campione \ue8 composto da una serie consecutiva di 161 pazienti afferenti ad un programma di cardiologia riabilitativa in seguito ad un intervento di cardiochirurgia (principalmente bypass, sostituzione/plastica valvolare e angioplastica). L\u2019assessment psicologico si \ue8 avvalso degli adattamenti italiani della SCID-I (moduli A e D), dell\u2019intervista sui DCPR (moduli riguardanti demoralizzazione e comportamento di tipo A) e del questionario DS-14 (per la diagnosi di personalit\ue0 di tipo D). All\u2019interno del campione le diagnosi DSM considerate ricorrono nel 34.8% dei casi, le diagnosi DCPR nel 31.7% e la personalit\ue0 di tipo D nel 16%. Per quanto riguarda la valutazione delle comorbilit\ue0, \ue8 emerso come i 26 soggetti con personalit\ue0 di tipo D presentino tutti una comorbilit\ue0 con o una diagnosi di demoralizzazione o di comportamento di tipo A. \uc8 emersa inoltre una comorbilit\ue0 significativa tra Depressione Maggiore e diagnosi di comportamento di tipo A e demoralizzazione. I risultati suggeriscono la necessit\ue0 di considerare, nell\u2019assessment di pazienti cardiopatici, sia gli stati depressivi e le sindromi psicosomatiche che la presenza di personalit\ue0 di tipo D, prestando particolare attenzione alle comorbilit\ue0 fra queste diagnosi. In Cardiologia Riabilitativa l\u2019assessment delle diagnosi depressive e delle sindromi psicosomatiche potrebbe condurre alla strutturazione di interventi specifici maggiormente mirati alla riduzione della sintomatologia

The role of psychiatric and psychosomatic correlates on lifestyles modification in cardiac rehabilitation.

Introduction: Cardiac rehabilitation (CR) is considered the most effective intervention for secondary prevention of patients with cardiovascular diseases. However, the role of psychiatric and psychosomatic complaints on the modification of unhealthy lifestyles is not clear. The aim of this research was to evaluate the impact of CR on risky lifestyles, considering the potential moderating role of depression, anxiety and psychosomatic syndromes on lifestyles modification. Methods: 108 patients undergone CR (experimental group) were compared with 85 people affected by cardiovascular diseases, not undergoing CR (control group). The assessment included: the Structured Clinical Interview for DSM-IV, the structured interview based on Diagnostic Criteria for Psychosomatic Research (DCPR), GOSPEL questionnaire on lifestyles, Pittsburgh Sleep Quality Index, and Morisky Medication Adherence Scale. Results: 32.1% and 19.2% of the sample suffered from depression and anxiety disorder, respectively. The most frequent DCPR syndromes were type A (31.9%), irritable mood (30.4%) and demoralization (29.3%). CR was associated with maintenance of physical activity, improvement of correct dietary behaviors and stress management, enhancement of quality of sleep. On the contrary, CR was not found to be associated with weight loss, healthy dietary habits, medications adherence. Depression and DCPR clusters of abnormal illness behavior, somatization and psychological factors affecting medical conditions mediated the modification of physical activity, stress management and pharmacological compliance. Discussion/conclusion: The findings underline the need of a psychosomatic assessment and an evaluation of psychological sub-clinical symptomatology in cardiac rehabilitation, in order to identify and address specific factors potentially associated with the clinical course of the heart disease

Trattamento cognitivo-comportamentale atto anche a promuovere il benessere in pazienti depressi affetti da sindrome coronarica acuta: il progetto TREATED-ACS.

Le Sindromi Coronariche Acute (SCA) spesso si associano a disturbi depressivi che influenzano lo stato di salute del paziente e sono associati ad esiti psicosociali negativi a lungo termine. Tali presupposti implicano la necessit\ue0 di interventi mirati alla risoluzione degli stati affettivi di questi pazienti. Sebbene i farmaci antidepressivi siano efficaci nel ridurre la depressione in pazienti con SCA, il loro uso nei setting cardiaci rimane controverso. La terapia cognitivo-comportamentale (CBT) \ue8 un trattamento di provata efficacia per la depressione. Anche se l\u2019unico studio che prevedeva un intervento di tipo comportamentale nel ridurre la morbilit\ue0 e la mortalit\ue0 cardiache in pazienti con SCA depressi (studio ENRICHD, 2003) ha mostrato che la diminuzione della depressione non \ue8 associata ad un miglioramento della sopravvivenza, \ue8 necessario verificare in studi ulteriori se il trattamento della depressione possa ridurre il rischio cardiovascolare in questi pazienti. Molti studi sottolineano l\u2019influenza del benessere psicologico nell\u2019alterare la vulnerabilit\ue0 individuale alla malattia o la qualit\ue0 di vita. Ryff e Singer hanno ridefinito la specificit\ue0 del concetto di salute in termini positivi, in base alla considerazione degli aspetti bio-psico-sociali dell\u2019individuo. Gli approcci psicoterapici che si sono focalizzati su diversi aspetti del benessere hanno dimostrato efficacia nel migliorare la qualit\ue0 di vita nei pazienti affetti da malattie croniche ed invalidanti. La terapia del Well-Being (WBT) sviluppata da GA Fava (1999) \ue8 una strategia psicoterapeutica a breve termine, basata sul modello di Ryff, che promuove il benessere. Essa pu\uf2 essere introdotta come ingrediente aggiuntivo della CBT nei setting cardiaci

Type d personality in cardiovascular psychosomatics: association with type a behavior, demoralization and depression.

Introduction: Some authors pointed out that there is the need to include personality assessment in the early identification of patients at greater risk for distress-related cardiac events. Furthermore, despite the well-known role of depression in the clinical course of cardiovascular diseases, an increasing body of literature highlights that also sub-clinical depression should be considered. Objectives of this study were: 1) to assess specific configuration of personalities (type A/D) and clinical and subclinical depression (major/minor depression, dysthymia and demoralization) among patients in cardiac rehabilitation (CR); 2) to detect overlaps among syndromes. Methods: 246 patients (72.8% males), most of whom undergone angioplasty (38.6%) or valve surgery (30.9%), were enrolled in the study. Assessment included Structured Clinical Interview for DSM\u2013IV (SCID), Interview for the Diagnostic Criteria for Psychosomatic Research (DCPR) and 14-item Type D scale (DS14). Results: Within the sample, DSM diagnoses occurred in 33.3% of cases, DCPR in 41.5% (demoralization=24.8%, type A=28%), and type D personality in 17.9%. Among type D patients, only 18.2% did not show other comorbid diagnoses: 63.6% also presented demoralization, 45.5% type A behavior and 50% DSM depression. On the contrary, 45.9% of demoralized, 29% of type A and 27.2% of depressed patients showed type D traits. Discussion/conclusion: The use of psychosomatic and personality assessments may contribute to a better understanding of patients\u2019 psychological distress than traditional psychiatric nosography. Moreover, it may help to identify early specific subgroups of patients who might be at greater risk for further psychological and cardiac problems

The modification of quality of life, well-being, psychosomatic and psychopatological distress in cardiac rehabilitation.

Introduction: Several studies documented the positive effects of cardiac rehabilitation (CR) on psychological distress. However, most of the research is focused on depression and anxiety, neglecting aspects with relevant clinical implications, such as psychosomatic diseases and well-being. The aim of this research was to evaluate the impact of CR on psychiatric and psychosomatic pathology, quality of life, psychological well-being and sub-clinical distress. Methods: The experimental group (N=108), undergoing CR, was compared to a control group (N=85) of patients affected by cardiovascular diseases, not undergoing CR. The assessment included: the Structured Clinical Interview for DSM-IV (depression and anxiety), the structured interview based on Diagnostic Criteria for Psychosomatic Research (DCPR), MOS 36-Item Short Form Health Survey (SF-36), Symptom Questionnaire (SQ) and Psychological Well-Being Scales (PWB). Results: 40.4% of the sample showed a DSM diagnosis, 62.1% suffered from at least one DCPR syndrome. Compared to the control group, CR was associated to the reduction of the most frequently observed psychiatric and psychosomatic diagnoses at baseline and to the enhancement of quality of life. On the contrary, there were no relevant effects on sub-clinical distress and well-being, except for purpose in life (PWB). Discussion/conclusion: The findings suggest that psychopathology and psychosomatic suffering observed at baseline could be reactive to the cardiac event. However, persisting residual subclinical distress and impairments in well-being should be evaluated in a comprehensive psychosomatic assessment, since they could be linked with the exacerbation of psychiatric or cardiac diseases

Psychological correlates of vasovagal versus medically unexplained syncope

Objective: Psychiatric morbidity is quite common in vasovagal syncope (VVS), but findings are sometimes contradictory. Among patients with suspected VVS, up to 40% has a negative response to Head-Up Tilt test (HUT), the cause of syncope remaining unexplained (US). The authors evaluated and compared the psychological and psychosomatic profile in patients with positive (VVS) and negative HUT (US). Method: A consecutive series of 67 patients with suspected VVS underwent HUT: 45 patients had a positive HUT, 22 negative. They were evaluated by means of observer- and self-rated measures. Results: Of the total sample, 95.5% had at least one Diagnostic and Statistical Manual of Mental Disorders diagnosis or one psychosomatic syndrome, such as specific and social phobias, illness denial and demoralization. Comparing VVS and US patients, no statistical differences on diagnoses' frequencies were found. However, the US group had significantly poorer health habits, lower levels of well-being and higher psychological distress. They also reported to be more anxious, depressed and hostile. VVS patients were significantly more blood and social phobic than US patients. Conclusion: Despite similar and remarkable observer-rated psychopathology, US patients reported higher selfperceived psychological distress than VVS patients. Psychological evaluation of patients undergoing HUT should incorporate both clinical and subclinical methods to better address syncope management