uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells.

In this manuscript, we show the involvement of the uPA/uPAR system in the regulation of aerobic glycolysis of melanoma cells. uPAR over-expression in human melanoma cells controls an invasive and glycolytic phenotype in normoxic conditions. uPAR down-regulation by siRNA or its uncoupling from integrins, and hence from integrin-linked tyrosine kinase receptors (IL-TKRs), by an antagonist peptide induced a striking inhibition of the PI3K/AKT/mTOR/HIF1α pathway, resulting into impairment of glucose uptake, decrease of several glycolytic enzymes and of PKM2, a checkpoint that controls metabolism of cancer cells. Further, binding of uPA to uPAR regulates expression of molecules that govern cell invasion, including extracellular matrix metallo-proteinases inducer (EMPPRIN) and enolase, a glycolytyc enzyme that also serves as a plasminogen receptor, thus providing a common denominator between tumor metabolism and phenotypic invasive features. Such effects depend on the α5ß1-integrin-mediated uPAR connection with EGFR in melanoma cells with engagement of the PI3K-mTOR-HIFα pathway. HIF-1α trans-activates genes whose products mediate tumor invasion and glycolysis, thus providing the common denominator between melanoma metabolism and its invasive features. These findings unveil a unrecognized interaction between the invasion-related uPAR and IL-TKRs in the control of glycolysis and disclose a new pharmacological target (i.e., uPAR/IL-TKRs axis) for the therapy of melanoma.

Suicide attempts and emergency room psychiatric consultation.

BACKGROUND: Suicidal behaviours are major public health concerns worldwide. They are associated with risk factors that vary with age and gender, occur in combination, and may change over time. The aim of our study was to investigate how frequently patients visiting a hospital emergency room (ER) require a psychiatric consultation for attempted suicide, and to outline the characteristics of this population. METHODS: Determinants of emergency room visits for psychiatric reasons were studied prospectively from 2008 to 2011 at the "Maggiore" Hospital in Novara. RESULTS: 280 out of 1888 patients requiring psychiatric consultation were referred to the ER because of suicide attempt. Suicide attempters were more often female. The rate of suicide attempters among Italian people was 14.2%, compared to 19.5% in foreigners. Subjects living with parents or own family and those having a permanent job had a higher frequency of suicide attempt. Suicide attempts were more frequent among patients with a history of psychiatric disorders; nonetheless, suicide attempts were more common among those who had not previously been hospitalized in a psychiatric ward or were not under the care of a psychiatrist. The multivariate analysis found that female gender was a risk factor for suicide attempt, while being in the colder months of the year and, surprisingly, unemployment were protective factors. CONCLUSIONS: A better understanding of patients referring to the ER due to attempted suicide may allow the identification of at-risk subjects and the implementation of targeted treatment approaches.

An observational study of Venlafaxine and CYP2D6 in clinical practice.

BACKGROUND: Venlafaxine (V) is a serotonin-norepinephrine selective reuptake inhibitor, mainly metabolized by cytochrome P4502D6 (CYP2D6). CYP2D6 polymorphisms result in a variety of phenotypes: poor (PMs), intermediate (IMs), extensive (EMs), and ultrarapid metabolizers (UMs). PMs usually show poor tolerance to drugs metabolized by CYP2D6, while UMs need greater doses. The aim of this study was to evaluate the impact of CYP2D6 genotype on V dosage, therapeutic response, and side effects in a clinical outpatient setting. METHODS: 47 patients with Major Depressive Disorder, treated with V 75 - 300 mg/day, underwent CYP2D6 genotyping using the INFINITI-CYP2D6 assay. Duration of treatment and clinical outcome (Clinical Global Impression [CGI] effectiveness index) were assessed. RESULTS: CGI assessment was performed after 6 weeks, 6 months, and 1 year of treatment with a V median dose of 150 mg/day. CYP2D6 genotyping resulted in 1 PM, 3 IMs, 42 EMs, and 1 UM. The UM took the greatest V dose (375 mg) without side effects; IMs/PMs took moderate/high doses of V (150 - 300 mg) without adverse effects; EMs displayed high response variability. CONCLUSIONS: PM/IM patients responded to V differently than expected according to genotype. However, the UM patient responded to a dosage higher than the usual therapeutic range and without developing side effects, suggesting an association between CYP2D6 gene duplication and the therapeutic efficacy of venlafaxine. The CYP2D6 genotyping may thus provide clinicians with a potential explanation for those patients requiring greater doses of CYP2D6 substrates in order to obtain the same therapeutic efficacy.

[Consultation-liaison psychiatry: strategy for care, opportunity for training]. / Psychiatrie de liaison: stratégie de soins, occasion de formation.

The liaison psychiatry defines itself as way to comprehend the psychological aspects in any situation of care, and in particular in the context of somatic care. The identification of the psychic processes, which can influence the diagnosis and the outcome of a somatic disease, is essential to adequately and globally take care of the individual. At the same time, training in the Help relationship allows to identify the difficulties of nursing, which is very often source of exhaustion and burn-out.

Cinema in the training of psychiatry residents: focus on helping relationships.

BACKGROUND: Medical schools are currently charged with a lack of education as far as empathic/relational skills and the meaning of being a health-care provider are concerned, thus leading to increased interest in medical humanities. DISCUSSION: Medical humanities can offer an insight into human illness and in a broader outlook into human condition, understanding of one self, responsibility. An empathic relation to patients might be fostered by a matching approach to humanities and sciences, which should be considered as subjects of equal relevance, complementary to one another. Recently, movies have been used in medical--psychiatric--trainees education, but mainly within the limits of teaching a variety of disorders. A different approach dealing with the use of cinema in the training of psychiatry residents is proposed, based on Jung and Hillman's considerations about the relation between images and archetypes, archetypal experience and learning. SUMMARY: Selected full-length movies or clips can offer a priceless opportunity to face with the meaning of being involved in a care-providing, helping profession.

Therapy-Induced Stromal Senescence Promoting Aggressiveness of Prostate and Ovarian Cancer.

Cancer progression is supported by the cross-talk between tumor cells and the surrounding stroma. In this context, senescent cells in the tumor microenvironment contribute to the development of a pro-inflammatory milieu and the acquisition of aggressive traits by cancer cells. Anticancer treatments induce cellular senescence (therapy-induced senescence, TIS) in both tumor and non-cancerous cells, contributing to many detrimental side effects of therapies. Thus, we focused on the effects of chemotherapy on the stromal compartment of prostate and ovarian cancer. We demonstrated that anticancer chemotherapeutics, regardless of their specific mechanism of action, promote a senescent phenotype in stromal fibroblasts, resulting in metabolic alterations and secretion of paracrine factors, sustaining the invasive and clonogenic potential of both prostate and ovarian cancer cells. The clearance of senescent stromal cells, through senolytic drug treatment, reverts the malignant phenotype of tumor cells. The clinical relevance of TIS was validated in ovarian and prostate cancer patients, highlighting increased accumulation of lipofuscin aggregates, a marker of the senescent phenotype, in the stromal compartment of tissues from chemotherapy-treated patients. These data provide new insights into the potential efficacy of combining traditional anticancer strategies with innovative senotherapy to potentiate anticancer treatments and overcome the adverse effects of chemotherapy.

Assessment of Inorganic Phosphate Intake by the Measurement of the Phosphate/Urea Nitrogen Ratio in Urine.

In chronic kidney disease (CKD) patients, it would be desirable to reduce the intake of inorganic phosphate (P) rather than limit the intake of P contained in proteins. Urinary excretion of P should reflect intestinal absorption of P(inorganic plus protein-derived). The aim of the present study is to determine whether the ratio of urinary P to urinary urea nitrogen (P/UUN ratio) helps identify patients with a high intake of inorganic P.A cross-sectional study was performed in 71 patients affected by metabolic syndrome with CKD (stages 2-3) with normal serum P concentration. A 3-day dietary survey was performed to estimate the average daily amount and the source of P ingested. The daily intake ofPwas1086.5 ± 361.3mg/day; 64% contained in animal proteins, 22% in vegetable proteins, and 14% as inorganic P. The total amount of P ingested did not correlate with daily phosphaturia, but it did correlate with the P/UUN ratio (p < 0.018). Patients with the highest tertile of the P/UUN ratio >71.1 mg/g presented more abundant inorganic P intake (p < 0.038).The P/UUN ratio is suggested to be a marker of inorganic P intake. This finding might be useful in clinical practices to identify the source of dietary P and to make personalized dietary recommendations directed to reduce inorganic P intake.

Claisened Hexafluoro Inhibits Metastatic Spreading of Amoeboid Melanoma Cells.

Metastatic melanoma is characterized by poor prognosis and a low free-survival rate. Thanks to their high plasticity, melanoma cells are able to migrate exploiting different cell motility strategies, such as the rounded/amoeboid-type motility and the elongated/mesenchymal-type motility. In particular, the amoeboid motility strongly contributes to the dissemination of highly invasive melanoma cells and no treatment targeting this process is currently available for clinical application. Here, we tested Claisened Hexafluoro as a novel inhibitor of the amoeboid motility. Reported data demonstrate that Claisened Hexafluoro specifically inhibits melanoma cells moving through amoeboid motility by deregulating mitochondrial activity and activating the AMPK signaling. Moreover, Claisened Hexafluoro is able to interfere with the adhesion abilities and the stemness features of melanoma cells, thus decreasing the in vivo metastatic process. This evidence may contribute to pave the way for future possible therapeutic applications of Claisened Hexafluoro to counteract metastatic melanoma dissemination.

Urokinase and its receptor in follicular and inflammatory cysts of the jaws.

OBJECTIVE: Proteases are considered critical in peri-cystic tissue degradation required in jaw cyst expansion. We studied the expression of the plasminogen activation system (plasminogen activators; their inhibitor type-1, PAI-1; the receptor for the urokinase-type plasminogen activator, uPAR) in follicular and inflammatory cysts of the jaw, to identify a possible role of this system in jaw cyst enlargement. MATERIALS AND METHODS: Jaw cysts were collected by therapeutic enucleation. ELISA and casein zymography were used to measure and characterize plasminogen activators in cyst fluid. By immunohistochemistry we examined the presence of uPAR in cyst walls and inflammatory cells, and by Western blotting the molecular forms of uPAR within the cyst fluid. RESULTS: Inflammatory cysts fluid contained higher amounts of plasminogen activators of the urinary-type (uPA), and lower amounts of PAI-1, when compared to follicular cysts fluid. Epithelial layers of both types of cysts and inflammatory cells expressed uPAR. Native 3-domain uPAR was scarcely detectable within cysts, where its cleavage was accounted for by uPA. CONCLUSION: These data suggest a plasminogen activation-dependent mechanism of cyst enlargement, where only the outward uPAR expressed on epithelial cells and on inflammatory cells direct the peri-cystic protease cascade, in a way similar to tumor enlargement within tissues.

ETV4 promotes late development of prostatic intraepithelial neoplasia and cell proliferation through direct and p53-mediated downregulation of p21.

BACKGROUND: ETV4 is one of the ETS proteins overexpressed in prostate cancer (PC) as a result of recurrent chromosomal translocations. In human prostate cell lines, ETV4 promotes migration, invasion, and proliferation; however, its role in PC has been unclear. In this study, we have explored the effects of ETV4 expression in the prostate in a novel transgenic mouse model. METHODS: We have created a mouse model with prostate-specific expression of ETV4 (ETV4 mice). By histochemical and molecular analysis, we have investigated in these engineered mice the expression of p21, p27, and p53. The implications of our in vivo findings have been further investigated in human cells lines by chromatin-immunoprecipitation (ChIP) and luciferase assays. RESULTS: ETV4 mice, from two independent transgenic lines, have increased cell proliferation in their prostate and two-thirds of them, by the age of 10 months, developed mouse prostatic intraepithelial neoplasia (mPIN). In these mice, cdkn1a and its p21 protein product were reduced compared to controls; p27 protein was also reduced. By ChIP assay in human prostate cell lines, we show that ETV4 binds to a specific site (-704/-696 bp upstream of the transcription start) in the CDKN1A promoter that was proven, by luciferase assay, to be functionally competent. ETV4 further controls CDKN1A expression by downregulating p53 protein: this reduction of p53 was confirmed in vivo in ETV4 mice. CONCLUSIONS: ETV4 overexpression results in the development of mPIN but not in progression to cancer. ETV4 increases prostate cell proliferation through multiple mechanisms, including downregulation of CDKN1A and its p21 protein product: this in turn is mediated through direct binding of ETV4 to the CDKN1A promoter and through the ETV4-mediated decrease of p53. This multi-faceted role of ETV4 in prostate cancer makes it a potential target for novel therapeutic approaches that could be explored in this ETV4 transgenic model.

Group Activities to Promote Early Rehabilitation in an Acute Psychiatric Ward: A Relationship-Based Approach Focusing on Movies.

Our Psychiatry Institute has a long-standing tradition of providing training in the importance of relational and emotional skills and helping relationships. Here we describe techniques that are routinely used on our psychiatric ward (Maggiore della Carità Hospital, Novara, Italy) to promote early rehabilitation of acute psychiatric inpatients. We focus on the Cinema group, which is typical of our approach to informal, therapeutic group activity. Targeting social and relational issues as adjunct to treatment as usual is useful in acute settings and can begin at an early stage of hospitalization. Our intervention is designed to improve patients' coping strategies, relational and communication skills, and overall quality of life.

HDAC1 controls CIP2A transcription in human colorectal cancer cells.

This work describes the effectiveness of HDAC-inhibitor (S)-2 towards colorectal cancer (CRC) HCT116 cells in vitro by inducing cell cycle arrest and apoptosis, and in vivo by contrasting tumour growth in mice xenografts. Among the multifaceted drug-induced events described herein, an interesting link has emerged between the oncoprotein histone deacetylase HDAC1 and the oncogenic Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) which is overexpressed in several cancers including CRCs. HDAC1 inhibition by (S)-2 or specific siRNAs downregulates CIP2A transcription in three different CRC cell lines, thus restoring the oncosuppressor phosphatase PP2A activity that is reduced in most cancers. Once re-activated, PP2A dephosphorylates pGSK-3ß(ser9) which phosphorylates ß-catenin that remains within the cytosol where it undergoes degradation. The decreased amount/activity of ß-catenin transcription factor prompts cell growth arrest by diminishing c-Myc and cyclin D1 expression and abrogating the prosurvival Wnt/ß-catenin signaling pathway. These results are the first evidence that the inhibition of HDAC1 by (S)-2 downregulates CIP2A transcription and unleashes PP2A activity, thus inducing growth arrest and apoptosis in CRC cells.

Clinical Characteristics Associated with Suicide Attempts in Clinical Settings: A Comparison of Suicidal and Non-Suicidal Depressed Inpatients.

INTRODUCTION: Both psychiatrists and psychiatric nurses are involved in the psychiatric management of suicidal inpatients. One-to-one observation by qualified nurses and the accommodation of the patient in a room close to the infirmary are usually recommended. Suicidal risk should be reassessed periodically to check response to treatment. AIM: To compare the severity of depressive symptoms in depressed inpatients admitted after an attempted suicide and those admitted for any other reason and to assess the severity of suicide attempts and the management of suicidal risk in clinical settings. MATERIALS AND METHODS: We divided the sample into two subgroups: patients with a diagnosis of depression admitted because of a recent suicide attempt and depressed patients with no recent history of attempted suicide. Socio-demographic and clinical data were gathered; assessments included the Montgomery-Asberg Depression Rating Scale and the Nurses' Global Assessment of Suicide Risk (NGASR). RESULTS: Forty-six patients were recruited over a 1-year period: 20 were admitted to the hospital following a suicide attempt; the other 26 had not attempted suicide and were admitted for other depression-related reasons. Multivariate analysis revealed a correlation between use of antidepressants and recent attempted suicide. Attempting suicide was not related to the severity of depressive symptoms. In the recent suicide attempt subgroup, NGASR suicide risk levels were lower at discharge than at admission. Patients with a recent history of attempted suicide had a higher number of suicide attempts in their clinical history than patients with no recent history of attempted suicide. CONCLUSION: There were no correlations between psychiatric diagnosis, severity of depressive symptoms, and recent suicide attempt. Antidepressant therapy protected against suicide attempts. History of suicide attempts was one of the best predictors of recent attempted suicide. A more thorough understanding of the complex phenomenon of suicide and the reasons for suicidal behavior is needed.

Immigrants' Pathways to Outpatient Mental Health: Are there Differences with the Native Population?

A poor use of mental health services has been described in immigrants. We compared the sociodemographic, clinical and treatment features of immigrants and natives attending a Community Mental Health Centre (CMHC). 191 immigrants and 191 randomly selected natives applying to the Borgomanero CMHC between 1 January 2003 and 31 August 2013 were compared. Our sample consisted mainly of the so-called "economic" immigrant. Adjustment disorders and reaction to stress were the most frequent diagnoses; in most cases symptoms onset occurred after migration. Although treatment features overlapped in the two groups (duration, number of contacts), immigrants showed a higher frequency of treatment dropout. While it is necessary to improve access to mental health services for immigrants, for the "economic" immigrant it may be more important to focus on establishing a therapeutic relationship that can be experienced as reliable and trustworthy. The finding of similar pathways to access the CMHC in natives and immigrants is encouraging.

Tumor-tropic endothelial colony forming cells (ECFCs) loaded with near-infrared sensitive Au nanoparticles: A "cellular stove" approach to the photoablation of melanoma.

In the photothermal treatments (PTs) of tumor, the localization of a high number of near-infrared (NIR) absorbing gold nanoparticles in the tumor mass is still a challenging issue. Here, we propose a promising strategy to deliver therapeutic chitosan-coated gold nanoparticles to tumor cells as hidden cargo of Endothelial Colony Forming Cells (ECFCs) endowed with an innate tumor-tropism. Remarkably, ECFC gold enrichement doesn't affect cell viability and preserves the endothelial lineage characteristics such as capillary morphogenesis and cell migration. We demonstrate that heavily Au-doped ECFCs are able to efficiently warm up the tumor environment, and kill the cancer cells via hyperthermic heating both in vitro as well as in vivo. Thus, we show an excellent thermotransductive property of gold enriched ECFCs and their capability to kill melanoma cells at moderate NIR light intensities.

Topiramate for binge eating disorder.

Topiramate is a new anti convulsant agent that acts on the voltage-activated sodium channels and on the glutamate and GABA receptors; it is furthermore able to reduce hunger and therefore contributes to loss of weight. The authors report the case of a patient suffering from binge eating disorder, who was unresponsive to several therapeutic plans but was successfully treated with topiramate.

Neuroendocrine (HPA axis) and clinical correlates during fluvoxamine and amitriptyline treatment.

The effect of amitriptyline on hypothalamic-pituitary-adrenocortical (HPA) axis activity was compared with that of fluvoxamine in 38 patients suffering from DMS-IV major depressive disorder. Basal plasma adrenocorticotropic hormone and cortisol levels were determined in the so-called "observation window" of an hour (08:00-09:00 h), and cortisol levels were determined again at 20:00 h. Clinical and biochemical assessments were performed before therapy (T0), at day 14 (T14), and at day 42 (T42) of the course of antidepressant treatment. At T0, neuroendocrine parameters did not differ in patients from those in controls, except for the ratio between cortisol levels at 20:00 h and the mean level of the "window" (ratio F20/F8), which was significantly higher, suggesting a dysregulation of the circadian pattern of cortisol. Although a decrease in the ratio F20/F8 was already apparent at T14 of both treatments, the repeated measures analysis of variance failed to demonstrate a significant variation with time (T0, T14, and T42) and with treatment (amitriptyline and fluvoxamine) for any hormonal measure. At T42, both treated groups showed a similar level of clinical improvement. Our results did not demonstrate any effect of antidepressant therapy on the cortisol circadian rhythm abnormality.

The effectiveness of a new approach using movies in the training of medical students.

INTRODUCTION: The use of movies in medical (particularly psychiatric) education has been often limited to portraits of mental illness and psychiatrists. The Psychiatric Institute of the Università del Piemonte Orientale has a longstanding tradition of working with/on movies according to a method developed by Eugenio Torre, using dynamic images as educational incitements. Our aim is to describe the preliminary results on the impact of this intervention in medical students. METHODS: The cinemeducation project lasted 6 months, and included 12 meetings. Forty randomly selected participants were assessed with: Attitudes Towards Psychiatry Scale (ATP-30), Social Distance Scale (SDS), Interpersonal Reactivity Index (IRI), and Toronto Alexithymia Scale (TAS), both at baseline and after 6 months, when the workshop was concluded. RESULTS: A significant increase was found in the ATP-30 score, and a reduction of the SDS and IRI-Personal Distress scale scores. CONCLUSIONS: Informal feedback from participants was strongly positive. Preliminary results from the assessment of participants are encouraging. Students' attitudes towards psychiatry and ability to tolerate anxiety when experiencing others' distress improved, while stigma decreased. The evocative power of movie dynamic images, developed in the group and integrated with the help of the group leader, can enrich students' knowledge, both from a cognitive and emotional standpoint.

Endothelial sphingosine kinase/SPNS2 axis is critical for vessel-like formation by human mesoangioblasts.

UNLABELLED: The interaction between endothelial cells and pericytes is crucial for the stabilization of newly formed vessels in angiogenesis. The comprehension of the mechanisms regulating pericyte recruitment might open therapeutical perspectives on vascular-related pathologies. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that derives from sphingomyelin catabolism and regulates biological functions in cell survival, proliferation, and differentiation. In this study, we aimed to identify the role of S1P axis in the intercellular communication between human mesenchymal progenitor mesoangioblasts (MAB) and endothelial cells (human microvascular endothelial cells (H-MVEC)) in the formation of capillary-like structures. We demonstrated that the S1P biosynthetic pathway brought about by sphingosine kinases (SK) SK1 and SK2 as well as spinster homolog 2 (SPNS2) transporter in H-MVEC is crucial for MAB migration measured by Boyden chambers and for the formation and stabilization of capillary-like structures in a 3D Matrigel culture. Moreover, the conditioned medium (CM) harvested from H-MVEC, where SK1, SK2, and SPNS2 were down-regulated, exerted a significantly diminished effect on MAB capillary morphogenesis and migration. Notably, we demonstrated that S1P1 and S1P3 receptors were positively involved in CM-induced capillary-like formation and migration, while S1P2 exerted a negative role on CM-induced migratory action of MAB. Finally, SK inhibition as well as MAB S1P1 and S1P3 down-regulation impaired H-MVEC-MAB cross-talk significantly reducing in vivo angiogenesis evaluated by Matrigel plug assay. These findings individuate novel targets for the employment of MAB in vascular-related pathologic conditions. KEY MESSAGE: • Down-regulation of SK1/2 in H-MVEC impaired vessel formation when cultured with MAB. • H-MVEC SPNS2 is critical for morphogenesis and migration induced by H-MVEC CM of MAB. • CM from SK1- and SK2-siRNA H-MVEC impaired morphogenesis and migration of MAB. • S1P1/3 were involved on CM-induced morphogenesis and migration of MAB. • Matrigel plug assay showed the role of S1P axis in MAB-endothelial cell interaction.

[Psychotic disorders induced by interferon alfa]. / Disturbo psicotico indotto da interferone-alfa.

The treatment with interferon-alpha is contraindicated in patients with major depression (National Institutes of Health), but a considerable number of neuropsychiatric side effects is associated with it: personality changes, impaired cognitive, mania, psychosis. In the literature limited reports of interferon-alpha-induced psychotic disorder exist. Authors report on a 46-year-old man diagnosed with alcohol induced psychotic disorder, who had been started to a treatment with Pegylated Interferon alfa-2b [Peg-Intron] and Ribavirin owing to a previous HCV-induced chronic hepatitis associated with a significant change in liver enzymes. During the first two months after the starting of therapy liver enzymes normalised, and modest side effects emerged, but the patient developed a psychotic reaction. Symptoms disappeared after discontinuation of interferon treatment.