Exploitation of new pharmacological targets for neuropathic pain reliefe

Neuropathic pain is a complex chronic condition which affects the somatosensory system, poorly managed with the conventional treatments despite the immense advances in pain treatment strategies. Damage of peripheral nervous system, due to injury or disease, leads to abnormal responses to painful and not-painful stimuli; conventional analgesics can only alleviate pain in acute situation, and finding an effective treatment which can relief chronic neuropathic pain remains still challenging. Mammalian STOML3, a MEC-2 homologue, is a member of a large family of stomatin proteins characterized by a common stomatin domain, expressed by DRG sensory neurons involved in regulation of mechanosensation, which is required for normal mechanoreceptor function. Previous data revealed that in STOML3 null mice 30-40% of Aδ and Aβ fibers lacked all mechanosensitivity; in addition, tactile behaviors are impaired and symptoms of neuropathic pain in CCI mice are also largely attenuated (Wetzel et al, 2007). Here I investigated the mechanisms by which STOML3 acts as an important contributor in the neuropathic pain symptoms and I demonstrate that small molecule modulation that both reversibly silence mechanoreceptors in vivo and attenuate touch perception in mice can reverse established neuropathic pain symptoms, making STOML3 a promising novel peripheral target for the treatment of sensory disorders

High Expression of Complement Component 5 (C5) at Tumor Site Associates with Superior Survival in Ewing's Sarcoma Family of Tumour Patients

Background. Unlike in most adult-onset cancers, an association between typical paediatric neoplasms and inflammatory triggers is rare. We studied whether immune system-related genes are activated and have prognostic significance in Ewing's sarcoma family of tumors (ESFTs). Method. Data analysis was performed on gene expression profiles of 44 ESFT patients, 11 ESFT cell lines, and 18 normal skeletal muscle samples. Differential expression of 238 inflammation and 299 macrophage-related genes was analysed by t-test, and survival analysis was performed according to gene expression. Results. Inflammatory genes are activated in ESFT patient samples, as 38 of 238 (16%) inflammatory genes were upregulated (P < 0.001) when compared to cell lines. This inflammatory gene activation was characterized by significant enrichment of macrophage-related gene expression with 58 of 299 (19%) of genes upregulated (P < 0.001). High expression of complement component 5 (C5) correlated with better event-free (P = 0.01) and overall survival (P = 0.004) in a dose-dependent manner. C5 and its receptor C5aR1 expression was verified at protein level by immunohistochemistry on an independent ESFT tumour tissue microarray. Conclusion. Immune system-related gene activation is observed in ESFT patient samples, and prognostically significant inflammatory genes (C5, JAK1, and IL8) for ESFT were identified

O monitoramento das inclusões residenciais em Psiquiatria: resultados preliminares da atividade da unidade de monitoramento e planejamento clínico

Introduction: Planning and Monitoring Unit Clinical (UMPC) has clinical epidemiological purposes, but mainly for evaluating and improving the quality of service. Objective: To describe the journeys of patients to residential care for mental health services. Method: The routes were analyzed from twopoints of view: based on the management structure and the type of intervention (these two criteria were intertwined) and based on the type of structure. 213 patients were followed. The first analysis of pathways was performed considering the residential subdivision of the Department offer residentialbased management and intervention. Results: A significant number of these patients remains inserted for several years, it can be stated that the rehabilitative program running inside the supporting structures, allow improving or at least maintaining the autonomy acquired. Conclusion: The fact thatthere are numerous passages of protected structures, administered by the Department, the support structures, such as groups of Apartment, the Accommodation Support, indicates a good capacity of rehabilitation programs, working in the community, to prepare patients to new projects characterized bygreater autonomy and personal independence.Descriptors: Psychosocial rehabilitation; Autonomy; Health Services

Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations

Standard therapy of osteosarcoma (OS) and Ewing sarcoma (EW) rests on cytotoxic regimes, which are largely unsuccessful in advanced patients. Preclinical models are needed to break this impasse. A panel of patient-derived xenografts (PDX) was established by implantation of fresh, surgically resected osteosarcoma (OS) and Ewing sarcoma (EW) in NSG mice. Engraftment was obtained in 22 of 61 OS (36%) and 7 of 29 EW (24%). The success rate in establishing primary cell cultures from OS was lower than the percentage of PDX engraftment in mice, whereas the reverse was observed for EW; the implementation of both in vivo and in vitro seeding increased the proportion of patients yielding at least one workable model. The establishment of in vitro cultures from PDX was highly efficient in both tumor types, reaching 100% for EW. Morphological and immunohistochemical (SATB2, P-glycoprotein 1, CD99, caveolin 1) studies and gene expression profiling showed a remarkable similarity between patient's tumor and PDX, which was maintained over several passages in mice, whereas cell cultures displayed a lower correlation with human samples. Genes differentially expressed between OS original tumor and PDX mostly belonged to leuykocyte-specific pathways, as human infiltrate is gradually replaced by murine leukocytes during growth in mice. In EW, which contained scant infiltrates, no gene was differentially expressed between the original tumor and the PDX. A novel therapeutic combination of anti-CD99 diabody C7 and irinotecan was tested against two EW PDX; both drugs inhibited PDX growth, the addition of anti-CD99 was beneficial when chemotherapy alone was less effective. The panel of OS and EW PDX faithfully mirrored morphologic and genetic features of bone sarcomas, representing reliable models to test therapeutic approaches

Effect of resveratrol on plasmatic molecular indicators of brain tissue response to the hypoperfusion/ reperfusion challenge

It is well-documented that endocannabinoids (eCBs) and congeners show a neuroprotective role in several experimental models of brain injury and that changes in eCB levels in peripheral blood cells may reflect the severity of neurological insult. We have previously shown that the preventive administration of dietary natural compounds may increase the plasmatic levels of palmytoylethanolamide (PEA) and oleoylethanolamide (OEA) following the transient bilateral common carotid artery occlusion (BCCAO)-induced brain tissue challenge (1). Resveratrol (RVT), (3,4’, 5-trihidroxystilbene) is a strong natural antioxidant of polyphenolic structure found in grapes and red wine, with many physiological effects, including the prevention of lipid peroxidation in human LDL, inhibition of arachidonic acid metabolism, and platelet activity. RVT has been further shown to protect cerebral tissue and cardiac muscle from tissue damage caused by oxidative stress triggered by reperfusion (2) and has been proposed as a potential neuroprotective agent in treating acute states in focal cerebral ischemia injury (3). In this line, we intend to evaluate whether exogenous administration of RVT prior to induction of BCCAO followed by reperfusion influences the molecular changes occurring in cerebral cortex and plasma, with particular focus on the eCB system. With this aim, cerebral hypoperfusion was produced by a 30 min BCCAO followed by 60 min reperfusion (BCCAO/R). Animals were starved for 12 hours before surgery and 6 hours prior to ischemia RVT (40 mg/kg/0.45 ml of sunflower oil as vehicle) was administered via gavage. Biological samples of plasma, cerebrospinal fluid (CSF), and brain tissue were examined by HPLC, gel zymography, western blot and immunohistochemistry. Data obtained indicate that RVT appears to influence the outcome of BCCAO/R cerebral injury by modulating changes in levels of lipid hydroperoxides, markers of oxidative stress, eCBs and eCB congeners, expression of CB1 and CB2 receptors, peroxisome proliferator-activated receptor- (PPAR) alpha, ciclooxygenase-2 (COX-2) protein levels and enzymatic activity of matrix-metalloproteinase- 9 (MMP-9). Interestingly, changes in brain of some of these parameters, like lipid hydroperoxides, were also found in plasma. Results obtained suggest that exogenous administration of RVT may modulate the brain tissue compensatory or repair mechanisms triggered by the hypoperfusion/reperfusion and support the possible use of this molecule as treatment to prevent the BCCAO/R-induced brain insult. In addition, the finding that changes in plasma mirrored those found in cerebral tissue, opens to the possibility to test whether RSV exerts its positive activities in humans

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 Influences Sensitivity to Anti-IGF System Agents Through the Translational Regulation of IGF1R

Insulin-like growth factor 2 (IGF2) mRNA-binding protein 3 (IGF2BP3) is an oncofetal protein that binds RNA, thereby influencing the fate of target transcripts. IGF2BP3 is synthesized de novo in cancer, where it promotes proliferation, drug resistance, and metastasis via both IGF2-dependent and IGF2-independent mechanisms. Ewing sarcoma (ES) is a rare bone and soft tissue tumor in which the IGF system plays a pivotal role. This study aimed to investigate the effect of IGF2BP3 on the regulation of the IGF system in ES. Among the components of the IGF axis, a direct significant correlation was identified between IGF2BP3 and IGF1R at mRNA and protein levels in two independent series of clinical specimens from patients with localized ES. After the formal demonstration of a direct association between IGF2BP3 and IGF1R mRNA using ribo-immunoprecipitation assay, we performed in vitro studies using A673 and TC-71 ES cell lines to demonstrate that IGF2BP3 loss promotes the downregulation of IGF1R and a decreased biological response to IGF1, represented by reduced migration and cell growth. Additionally, the compensatory activation of insulin receptor (IR) and its mitogenic ligand IGF2 is triggered in some but not all cell lines in response to IGF2BP3-mediated IGF1R loss. These findings have therapeutic implications because cells with a decreased expression of IGF2BP3/IGF1R axis but an increased expression of the IR/IGF2 loop display higher sensitivity to the dual inhibitor OSI-906 than do control cells. Therefore, studies on IGF2BP3, which was confirmed as a post-transcriptional regulator of IGF1R, provide a step forward in the identification of new mechanisms regulating the IGF system. In addition, our results demonstrate that the detection of IGF2BP3 expression should be combined with the assessment of the IGF1R/IR ratio to predict cell responses to anti-IGF1R/IR agents

Osteosarcoma of the pelvis: A monoinstitutional experience in patients younger than 41 years

Aims and background. Information is scarce on systemic treatment of pelvic osteosarcoma because most chemotherapy protocols for osteosarcoma include patients with extremity tumors and aged up to 30-40 years. Methods. Data on patients <41 years of age with high-grade pelvic osteosarcoma were prospectively collected. Patients received two chemotherapy protocols consisting of methotrexate, cisplatin, doxorubicin (MAP) and standard-dose or high-dose ifosfamide. Results. Forty patients between 11 and 36 years were included. The most frequent histological subtype was osteoblastic followed by chondroblastic (37.5%). Complete surgical remission was achieved in 65% of patients. Eighteen patients had MAP/standard- dose ifosfamide, 22 MAP/high-dose ifosfamide. Primary chemotherapy was given to 25 patients and 6 (24%) of them had a good histological response. Median follow- up was 32 months (range, 4-134). Five-year overall survival was 27.5%: 33% in localized and 0 in metastatic patients (P = 0.02); 45% in patients with complete surgical remission and 0 for patients without complete surgical remission (P = 0.001). Local recurrence rate was 46%. In patients with complete surgical remission, 5-year overall survival was 32% with MAP/standard-dose ifosfamide and 59% with MAP/high-dose ifosfamide regimen (P = 0.3). Conclusions. Local control is the major issue in the treatment of pelvic osteosarcoma. Poor pathological response and high incidence of chondroblastic variant indicate different characteristics between pelvic and extremity osteosarcoma. Chemotherapy with MAP and high-dose ifosfamide might be beneficial in patients with pelvic osteosarcoma and warrants further investigation. \ua9 II Pensiero Scientifico Editore downloaded by EXCERPTA MEDICA

Targeting ROCK2 rather than ROCK1 inhibits Ewing sarcoma malignancy

Understanding the molecular processes characterizing Ewing sarcoma (EWS) cell migration is crucial to highlight novel therapies for patients with disseminated disease. In this study we analyzed the role of ROCK kinases in the regulation of cell migration, growth and differentiation of EWS cells. Overexpression of ROCK promotes invasion and metastasis in many solid tumors. However, the effect of ROCK in EWS has not been extensively investigated. Expression of ROCK1 and ROCK2 was analyzed by western blotting in a representative panel of human EWS cell lines, in comparison with the parameters of in vitro malignancy. We investigated the effects of a ROCK2 specific inhibitor toward those of a pan-ROCK inhibitor on the growth, migration and differentiation of two EWS cell lines. ROCK2 but not ROCK1 expression was found to be associated with in vitro cell migration and anchorage-independent growth capabilities. Exposure of EWS cells to ROCK inhibitors significantly reduced migration and growth, while favoring morphology changes and neural differentiation. These effects were more striking when cells were specifically deprived of ROCK2 activity. Our findings lead to consider ROCK2, rather than ROCK1, as a possible molecular target for the treatment of EWS