Molecular and biological characterization of adipocytic neoplasm

Tra i liposarcomi, il tumore lipomatoso atipico/liposarcoma ben differenziato e il liposarcoma dedifferenziato rappresentano i sottotipi più frequenti. Spesso è difficile distinguere questi tumori da altri con caratteristiche morfologiche simili. Da un punto di vista citogenetico sono caratterizzati dalla presenza di cromosomi soprannumerari giganti e cromosomi ad anello costituiti principalmente da sequenze amplificate della regione 12q13-15. In questa regione mappano numerosi geni tra cui il gene MDM2 (murine double minute-2). La caratterizzazione molecolare di tali sottotipi diventa estremamente importante sia a fini diagnostici sia per un corretto indirizzo terapeutico, soprattutto oggi, dopo l’introduzione nella pratica clinica di terapie biologiche mirate (targeted therapies). Nel presente studio viene analizzato il ruolo dell’analisi FISH per la valutazione dello status di MDM2 nelle neoplasie lipomatose e per stabilire se questo marcatore possa essere utilizzato nella diagnosi differenziale di questi tumori. Sebbene questo studio confermi l’utilità diagnostica dell’amplificazione di MDM2 nella diagnosi del tumore lipomatoso atipico/liposarcoma ben differenziato ed il liposarcoma dedifferenziato, questo marcatore potrebbe avere in futuro anche una più ampia applicazione. Data la recente introduzione degli inibitori selettivi di MDM2 tale ricerca risulta importante non solo a fini diagnostici ma anche per la selezione dei pazienti che potranno in futuro beneficiare del trattamento con tali inibitori. Questo studio è stato effettuato anche per analizzare la rilevanza biologica del percorso che vede coinvolto il gene AKT nel liposarcoma ben differenziato e dedifferenziato e per stabilire se questo percorso possa rappresentare un utile bersaglio terapeutico in questi tumori. I dati ottenuti dimostrano che AKT è espresso ed attivato in tutti i casi di tumore lipomatoso atipico/liposarcoma ben differenziato e liposarcoma dedifferenziato.Among the liposarcomas, the atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma subtypes are more frequent. It is often difficult to distinguish these from other tumors with similar morphological characteristics. The cytogenetic hallmark of these tumors is he presence of supernumerary chromosomes and giant ring chromosomes which consist mainly of amplified sequences of the region 12q13-15. In this region mapped several genes including the gene MDM2 ( murine double Minute-2). The molecular characterization of these subtypes becomes extremely important both for diagnostic purposes and for a correct therapeutic approach , especially today, after the introduction into clinical practice of targeted biological therapies (targeted therapies). In the present study is analyzed the role of FISH analysis for the evaluation of the MDM2 status in lipomatous neoplasms and to determine whether this marker could be used in the differential diagnosis of these tumors. Although this study confirms the diagnostic utility of MDM2 amplification in the diagnosis of atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma, this marker could have in the future a wider application . Given the recent introduction of selective inhibitors of MDM2 such research is important not only for diagnostic purposes but also for the selection of patients who may in the future benefit from treatment with these inhibitors. This study was also performed to analyze the biological relevance of the pathway that involves the AKT gene in well-differentiated and dedifferentiated liposarcoma and to determine whether this pathway may represent a useful therapeutic target in these tumors . The data obtained demonstrate that AKT is expressed and activated in all cases of atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma

Assessing feature relevance in NPLS models by VIP

Multilinear PLS (NPLS) and its discriminant version (NPLS-DA) are very diffuse tools to model multi-way data arrays. Analysis of NPLS weights and NPLS regression coefficients allows data patterns, feature correlation and covariance structure to be depicted. In this study we propose an extension of the Variable Importance in Projection (VIP) parameter to multi-way arrays in order to highlight the most relevant features to predict the studied dependent properties either for interpretative purposes or to operate feature selection. The VIPs are implemented for each mode of the data array and in the case of multivariate dependent responses considering both the cases of expressing VIP with respect to each single y-variable and of taking into account all y-variables altogether. Three different applications to real data are presented: i) NPLS has been used to model the properties of bread loaves from near infrared spectra of dough, acquired at different leavening times, and corresponding to different flour formulations. VIP values were used to assess the spectral regions mainly involved in determining flour performance; ii) assessing the authenticity of extra virgin olive oils by NPLS-DA elaboration of gas chromatography/mass spectrometry data (GC–MS). VIP values were used to assess both GC and MS discriminant features; iii) NPLS analysis of a fMRI-BOLD experiment based on a pain paradigm of acute prolonged pain in healthy volunteers, in order to reproduce efficiently the corresponding psychophysical pain profiles. VIP values were used to identify the brain regions mainly involved in determining the pain intensity profile

Sirtuin 6 localization at cortical brain level of young diabetic mice

The metabolic syndrome, characterized by visceral obesity, dyslipidaemia, hyperglycaemia and hypertension, has become one of the major public-health challenges worldwide and it is strictly associated with the development of type II diabetes and neurodegenerative diseases (Alberti et al. 2005; Panza et al. 2010). Increased metabolic flux to the brain during overnutrition can orchestrate stress response, blood-brain barrier alteration, microglial cells activation and neuroinflammation (Nerurkar et al., 2011). The protein sirtuin family is a class of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that act on a variety of targets and so play a key role in central physiological regulation (Sebastian et al., 2012; Wang et al., 2012). To assess the physiopathological significance of sirtuin6 (SIRT6) at brain cortical level, we analysed its specific expression and subcellular localization in young db/db mice, animal model of type II diabetes mellitus, and respective control lean mice. In particular, we analysed the cytoarchitecture of the brain cortex, evaluated SIRT6 expression and its localization by immunohistochemistry comparing young db/db mice to lean control mice, distinguishing among the six cortical layers and between motor and somatosensory cortex. We observed that SIRT6 is mainly localized in the nucleus of both lean and db/db mice. Diabetic mice showed few SIRT6 positive cells respect to lean control mice in all cortical layers without significant differences between motor and somatosensory cortex. No morphological alteration have been find. In conclusion, our findings contribute to further understand SIRT6 protein expression in the early steps of type II diabetes mellitus and suggest its implication in the pathogenic processes of diabetes mellitus and diabetes–induced neurodegeneration

Sirtuin 6 localization at cortical brain level of young diabetic mice

The metabolic syndrome, characterized by visceral obesity, dyslipidaemia, hyperglycaemia and hypertension, has become one of the major public-health challenges worldwide and it is strictly associated with the development of type II diabetes and neurodegenerative diseases (Alberti et al. 2005; Panza et al. 2010). Increased metabolic flux to the brain during overnutrition can orchestrate stress response, blood-brain barrier alteration, microglial cells activation and neuroinflammation (Nerurkar et al., 2011). The protein sirtuin family is a class of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that act on a variety of targets and so play a key role in central physiological regulation (Sebastian et al., 2012; Wang et al., 2012). To assess the physiopathological significance of sirtuin6 (SIRT6) at brain cortical level, we analysed its specific expression and subcellular localization in young db/db mice, animal model of type II diabetes mellitus, and respective control lean mice. In particular, we analysed the cytoarchitecture of the brain cortex, evaluated SIRT6 expression and its localization by immunohistochemistry comparing young db/db mice to lean control mice, distinguishing among the six cortical layers and between motor and somatosensory cortex. We observed that SIRT6 is mainly localized in the nucleus of both lean and db/db mice. Diabetic mice showed few SIRT6 positive cells respect to lean control mice in all cortical layers without significant differences between motor and somatosensory cortex. No morphological alteration have been find. In conclusion, our findings contribute to further understand SIRT6 protein expression in the early steps of type II diabetes mellitus and suggest its implication in the pathogenic processes of diabetes mellitus and diabetes–induced neurodegeneration

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221

A global collaboRAtive study of CIC-rearranged, BCOR::CCNB3-rearranged and other ultra-rare unclassified undifferentiated small round cell sarcomas (GRACefUl)

[Background] Undifferentiated small round cell sarcomas (URCSs) represent a diagnostic challenge, and their optimal treatment is unknown. We aimed to define the clinical characteristics, treatment, and outcome of URCS patients.[Methods] URCS patients treated from 1983 to 2019 at 21 worldwide sarcoma reference centres were retrospectively identified. Based on molecular assessment, cases were classified as follows: (1) CIC-rearranged round cell sarcomas, (2) BCOR::CCNB3-rearranged round cell sarcomas, (3) unclassified URCSs. Treatment, prognostic factors and outcome were reviewed.[Results] In total, 148 patients were identified [88/148 (60%) CIC-rearranged sarcoma (median age 32 years, range 7–78), 33/148 (22%) BCOR::CCNB3-rearranged (median age 17 years, range 5–91), and 27/148 (18%) unclassified URCSs (median age 37 years, range 4–70)]. One hundred-one (68.2%) cases presented with localised disease; 47 (31.8%) had metastases at diagnosis. Male prevalence, younger age, bone primary site, and a low rate of synchronous metastases were observed in BCOR::CCNB3-rearranged cases. Local treatment was surgery in 67/148 (45%) patients, and surgery + radiotherapy in 52/148 (35%). Chemotherapy was given to 122/148 (82%) patients. At a 42.7-month median follow-up, the 3-year overall survival (OS) was 92.2% (95% CI 71.5–98.0) in BCOR::CCNB3 patients, 39.6% (95% CI 27.7–51.3) in CIC-rearranged sarcomas, and 78.7% in unclassified URCSs (95% CI 56.1–90.6; p < 0.0001).[Conclusions] This study is the largest conducted in URCS and confirms major differences in outcomes between URCS subtypes. A full molecular assessment should be undertaken when a diagnosis of URCS is suspected. Prospective studies are needed to better define the optimal treatment strategy in each URCS subtype.This work was supported by the Carisbo Foundation Call for Translational and Clinical Medical Research.Peer reviewe