Studio del coinvolgimento osseo e della mediazione del dolore in corso di Complex Regional Pain Syndrome type I

Obiettivo. Scopo della nostra indagine \ue8 stato di valutare il ruolo del tessuto osseo nella Complex Regional Pain Syndrome- type I (CRPS-I), tramite a) studio dell\u2019impatto del trattamento con bisfosfonati in una casistica real-life di pazienti con CRPS-I, volto ad identificare eventuali predittori di risposta al trattamento; b) analisi esplorativa della concentrazione sierica di Sclerostina (SOST), Dickopff-1 (DKK-1) e Nerve Growth Factor (NGF) in corso di tale sindrome. Metodi. Nella prima fase di studio sono stati valutati retrospettivamente i dati dei pazienti affetti da CRPS-I trattati con bisfosfonati endovenosi negli ultimi 5 anni. Sono state identificate le caratteristiche cliniche associate alla risposta al trattamento, definita in termini di riduzione del dolore e assenza dei criteri diagnostici della sindrome a distanza media di 40 giorni dal termine delle infusioni, tramite analisi univariata e multivariata (regressione logistica). Nella fase trasversale dello studio sono stati raccolti campioni di sangue refluo dall\u2019arto affetto e dal controlaterale in pazienti affetti da CRPS-I di mano e in un gruppo di controlli sani, appaiati per et\ue0 e sesso. \uc8 stato quindi effettuato un dosaggio della concentrazione sierica di SOST, DKK-1 e NGF tramite ELISA. I valori sono stati confrontati tra arto affetto e controlaterale e tra soggetti con CRPS-I e controlli sani. Risultati. Dei 194 pazienti inclusi nella fase retrospettiva dello studio, trattati con Clodronato, Pamidronato e Neridronato, 139 pazienti (71,6%) avevano risposto al trattamento. Una minore durata di malattia, la presenza di una forma \u201ccalda\u201d di malattia e una frattura come evento predisponente risultavano significativamente associati ad una maggiore probabilit\ue0 di risposta al trattamento, mentre il tipo di bisfosfonati non influenzava significativamente la risposta terapeutica. I risultati della fase trasversale su 17 pazienti affetti da CRPS-I hanno evidenziato una concentrazione di DKK-1 significativamente superiore su sangue refluo dall\u2019arto affetto rispetto al controlaterale nei pazienti con CRPS-I, tuttavia non statisticamente differente da quella dei controlli sani. Al contrario si sono osservati valori sierici di SOST significativamente pi\uf9 elevati nei pazienti affetti da CRPS-I rispetto ai controlli sani, senza evidenziare una differenza significativa tra il lato affetto e il non affetto. Il dosaggio di NGF non ha invece identificato differenze tra il lato affetto e quello affetto, n\ue9 rispetto ai controlli sani; tale mediatore \ue8 risultato tuttavia dosabile in un numero molto limitato di soggetti, limitando fortemente la potenza della valutazione statistica. Conclusioni. I risultati delle nostre osservazioni portano un ulteriore sostegno all\u2019ipotesi di un coinvolgimento del tessuto osseo nella patogenesi della CRPS-I. La migliore risposta al trattamento con bisfosfonati in soggetti con precedente frattura suggerisce l\u2019esistenza di un sottogruppo di pazienti in cui il ruolo del tessuto scheletrico risulti preponderante. Il riscontro di valori di DKK-1 pi\uf9 elevati su sangue refluo dall\u2019arto affetto rispetto al controlaterale potrebbe indicare un\u2019azione locale di tale regolatore del metabolismo osseo, mentre l\u2019incremento della concentrazione di SOST non \ue8 di univoco significato, ma potrebbe essere implicato nella genesi dell\u2019osteoporosi locale osservata nei soggetti affetti da CRPS-I. La valutazione dei livelli sierici di NGF non ha fornito risultati significativi per la limitata numerosit\ue0 di soggetti in cui il mediatore \ue8 risultato dosabile: successivi studi, effettuati anche con differenti metodiche, potranno fornire ulteriori evidenze sul ruolo di questo mediatore del dolore nella CRPS-I.Objective. Aim of our study was to investigate the role of bone in Complex Regional Pain Syndrome- type I (CRPS-I), by a) analyzing the impact of the treatment with bisphosphonates in a real-life population of subjects with CRPS-I, with the aim to identify predictors of response to the treatment; b) exploring the serum concentration of Sclerostin (SOST), Dickopff-1 (DKK-1) and Nerve Growth Factor (NGF) in CRPS-I. Methods. In the first phase of the study we retrospectively evaluated data of patients with CRPS-I treated with intravenous bisphosphonates in the previous 5 years. We identified clinical features associated with a response to the treatment, defined as a pain reduction and the absence of diagnostic criteria for CRPS-I at 40 days after the end of the treatment, by univariate and logistic regression analysis. In the cross-sectional phase we collected serum samples from the affected arm and the contralateral one in patients with CRPS-I and in age- and sex-matched healthy controls. Serum concentration of SOST, DKK-1 and NGF was assessed by ELISA kit and values were compared between the affected arm and the contralateral one and between subjects with CRPS-I and controls. Results. Among 194 subjects included in the retrospective phase of the study and treated with Clodronate, Pamidronate and Neridronate, 139 patients (71,6%) responded to the treatment. A shorter disease duration, a \u201cwarm\u201d clinical phase and a fracture as predisposing event were significantly associated with higher odds of response to the treatment, while the type of bisphosphonates did not significantly affect the outcome. The results of the cross-sectional phase showed a significantly higher concentration of DKK-1 in serum from the affected site compared to the contralateral one, but we did not observe a significant difference from healthy controls. Conversely serum levels of SOST in patients with CRPS-I were significantly higher than in controls, but we did not find a significant difference between the affected site and the contralateral one. NGF was detectable only in a few patients, therefore a reliable statistical analysis on its concentration was not feasible. Conclusions. Our results further support the hypothesis of a role of bone in the pathogenesis of CRPS-I. A better response to the treatment with bisphosphonates in subjects with a previous fracture suggests that a subgroup of patients with a prevalent bone involvement may exist. The finding of a higher concentration of DKK-1 in serum from the affected arm compared to the contralateral one may point out a local effect of this regulator of bone metabolism in CRPS-I, while the systemic increase of SOST concentration could be implicated in the pathogenesis of bone loss observed in patients with CRPS-I. The evaluation of serum levels of NGF did not provide significant results due to the low proportion of subjects in which this mediator was detectable: further studies with different methodologies may allow to better understand the role of NGF in CRPS-I

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 Modulates Aggressiveness of Ewing Sarcoma by Regulating the CD164-CXCR4 Axis

Ewing sarcoma (EWS) is the second most common bone and soft tissue-associated malignancy in children and young adults. It is driven by the fusion oncogene EWS/FLI1 and characterized by rapid growth and early metastasis. We have previously discovered that the mRNA binding protein IGF2BP3 constitutes an important biomarker for EWS as high expression of IGF2BP3 in primary tumors predicts poor prognosis of EWS patients. We additionally demonstrated that IGF2BP3 enhances anchorage-independent growth and migration of EWS cells suggesting that IGF2BP3 might work as molecular driver and predictor of EWS progression. The aim of this study was to further define the role of IGF2BP3 in EWS progression. We demonstrated that high IGF2BP3 mRNA expression levels correlated with EWS metastasis and disease progression in well-characterized EWS tumor specimens. EWS tumors with high IGF2BP3 levels were characterized by a specific gene signature enriched in chemokine-mediated signaling pathways. We also discovered that IGF2BP3 regulated the expression of CXCR4 through CD164. Significantly, CD164 and CXCR4 colocalized at the plasma membrane of EWS cells upon CXCL12 stimulation. We further demonstrated that IGF2BP3, CD164, and CXCR4 expression levels correlated in clinical samples and the IGF2BP3/CD164/CXCR4 signaling pathway promoted motility of EWS cells in response to CXCL12 and under hypoxia conditions. The data presented identified CD164 and CXCR4 as novel IGF2BP3 downstream functional effectors indicating that the IGF2BP3/CD164/CXCR4 oncogenic axis may work as critical modulator of EWS aggressiveness. In addition, IGF2BP3, CD164, and CXCR4 expression levels may constitute a novel biomarker panel predictive of EWS progression

HST survey of the Orion Nebula Cluster in the H2_2O 1.4 μ\mum absorption band: I. A census of substellar and planetary mass objects

In order to obtain a complete census of the stellar and sub-stellar population, down to a few M$_{Jup}$ in the $\sim1$ Myr old Orion Nebula Cluster, we used the infrared channel of the Wide Field Camera 3 of the Hubble Space Telescope with the F139M and F130N filters. These bandpasses correspond to the $1.4 \mu$m H$_2$O absorption feature and an adjacent line-free continuum region. Out of $4,504$ detected sources, $3,352$ (about $75\%$) appear fainter than m$_{130}=14$ (Vega mag) in the F130N filter, a brightness corresponding to the hydrogen-burning limit mass (M$\simeq 0.072 M_\odot$) at $\sim 1$ Myr. Of these, however, only $742$ sources have a negative F130M-139N color index, indicative of the presence of H$_2$O vapor in absorption, and can therefore be classified as bona-fide M and L dwarfs, with effective temperatures T$\lesssim 2850$ K at an assumed $1$ Myr cluster age. On our color-magnitude diagram, this population of sources with H$_2$O absorption appears clearly distinct from the larger background population of highly reddened stars and galaxies with positive F130M-F139N color index, and can be traced down to the sensitivity limit of our survey, m$_{130}\simeq 21.5$, corresponding to a $1$ Myr old $\simeq 3$M$_{Jup}$, planetary mass object under about 2 magnitudes of visual extinction. Theoretical models of the BT-Settl family predicting substellar isochrones of $1, 2$ and $3$ Myr (down to $\sim 1$M$_{Jup}$) fail to reproduce the observed H$_2$O color index at M$\lesssim 20$M$_{Jup}$. We perform a Bayesian analysis to determine extinction, mass and effective temperature of each sub-stellar member of our sample, together with its membership probability.Comment: Accepted for publication in the Astrophysical Journal. The resolution of several figures has been downgraded to comply with the size limit of arXiv submission

Efficient Walking Gait Generation via Principal Component Representation of Optimal Trajectories: Application to a Planar Biped Robot With Elastic Joints

Recently, the method of choice to exploit robot dynamics for efficient walking is numerical optimization (NO). The main drawback in NO is the computational complexity, which strongly affects the time demand of the solution. Several strategies can be used to make the optimization more treatable and to efficiently describe the solution set. In this letter, we present an algorithm to encode effective walking references, generated offline via numerical optimization, extracting a limited number of principal components and using them as a basis of optimal motions. By combining these components, a good approximation of the optimal gaits can be generated at run time. The advantages of the presented approach are discussed, and an extensive experimental validation is carried out on a planar legged robot with elastic joints. The biped thus controlled is able to start and stop walking on a treadmill, and to control its speed dynamically as the treadmill speed change

ROCK2 deprivation leads to the inhibition of tumor growth and metastatic potential in osteosarcoma cells through the modulation of YAP activity

The treatment of metastatic osteosarcoma (OS) remains a challenge for oncologists, and novel therapeutic strategies are urgently needed. An understanding of the pathways that regulate OS dissemination is required for the design of novel treatment approaches. We recently identified Rho-associated coiled-coil containing protein kinase 2 (ROCK2) as a crucial driver of OS cell migration. In this study, we explored the impact of ROCK2 disruption on the metastatic capabilities of OS cells and analyzed its functional relationship with Yes-associated protein-1 (YAP), the main transcriptional mediator of mechanotransduction signaling

Clinical Evaluation of a Custom Gene Panel as a Tool for Precision Male Infertility Diagnosis by Next-Generation Sequencing

Background: Up to 15% of couples are infertile and male factor infertility accounts for approximately 50% of these cases. Male infertility is a multifactorial pathological condition. The genetic of male infertility is very complex and at least 2000 genes are involved in its etiology. Genetic testing by next-generation sequencing (NGS) technologies can be relevant for its diagnostic value in male infertile patients. Therefore, the aim of this study was to implement the diagnostic offer with the use of an NGS panel for the identification of genetic variants. Methods: We developed an NGS gene panel that we used in 22 male infertile patients. The panel consisted of 110 genes exploring the genetic causes of male infertility; namely spermatogenesis failure due to single-gene mutations, central hypogonadism, androgen insensitivity syndrome, congenital hypopituitarism, and primary ciliary dyskinesia. Results: NGS and a subsequent sequencing of the positive pathogenic or likely pathogenic variants, 5 patients (23%) were found to have a molecular defect. In particular, pathogenic variants were identified in TEX11, CCDC39, CHD7, and NR5A1 genes. Moreover, 14 variants of unknown significance and 7 novel variants were found that require further functional studies and family segregation. Conclusion: This extended NGS-based diagnostic approach may represent a useful tool for the diagnosis of male infertility. The development of a custom-made gene panel by NGS seems capable of reducing the proportion of male idiopathic infertility

Pesquisa em ubimus na Educação Básica : um relato do Projeto Música Ubíqua no Colégio de Aplicação da UFRGS

Descrevemos aqui ações e abordagens em ensino e pesquisa em ubimus no contexto da Educação Básica, desenvolvidas no Colégio de Aplicação da UFRGS, envolvendo a participação de alunos do Ensino Médio através do Programas de Bolsa em Iniciação Científica modalidade Júnior implementadas no Colégio de Aplicação da UFRGS, bem como os trabalhos desenvolvidos em parceria com membros do g-ubimus durante o período de 2012-2018.This paper reports ubimus educational research actions and approaches carried out at the UFRGS Application School, targeting activities in basic education. These activities feature the participation of high-school students through a Brazilian undergraduate research programme called “Scientific Initiation”. It also reports collaborative research done by members of the Ubiquitous Music Group (g-ubimus), between the years 2012 and 2018

Correction to: ABCA6 affects the malignancy of Ewing sarcoma cells via cholesterol-guided inhibition of the IGF1R/AKT/MDM2 axis

In this article an incorrect affiliation had inadvertently been added. The original article has been updated