Search

IntroductionSerum biomarkers (SB) such s100B and neuron specific enolase (NSE) have been described to predict brain damage.The aim of this study is to describe SB utility to identify children at risk from adverse neurological during the perioperative period of cardiac surgery (CS) in combination with cerebral regional oxygen saturation (crSO2) measured by infrared spectroscopy.Material and methodsProspective observational study including patients undergoing CS during the first 6 months of life. crSO2 was monitored during surgery and the amount of srcO2 time below 40 was computed. s100B and NSE were collected at baseline and inmediatly after surgery. Patients were divided in groups based on age (neonatal 1 month) and type of surgery (cardiopulmonary bypass CPB vs non-CPB).Results Fifty patients were enrolled, 18 non-CBP, 11 neonatal-CBP and 19 pediatric-CBP. Two patients were excluded. Postoperative s100B was higher in neonatal-CBP patients (2.28 ugr/L) compared to non-CBP (1.40 ugr/L) and pediatric-CBP (1.65 ugr/L) (p

Altres ajuts: This work was supported by grants from Institut Català d'Oncologia (ICO), Instituto de Salud Carlos III (RD06/0020/1021 and PI11/00740), Fundació la Marató de TV3, Asociación Española Contra el Cáncer, Fundació SMALL and Fundació A. BOSCH. Rhabdomyosarcoma (RMS) is the commonest type of soft-tissue sarcoma in children. Patients with metastatic RMS continue to have very poor prognosis. Recently, several works have demonstrated a connection between Notch pathway activation and the regulation of cell motility and invasiveness. However, the molecular mechanisms of this possible relationship remain unclear. The Notch pathway was manipulated pharmacologically and genetically. The mRNA changes were analysed by quantitative PCR and protein variations by western blot and immunofluorescence. Finally, the capabilities of RMS cells to adhere, heal a wound and invade were assessed in the presence of neuronal cadherin (N-cadherin)- and α 9-integrin-blocking antibodies. Cells treated with γ -secretase inhibitor showed lower adhesion capability and downregulation of N-cadherin and α 9-integrin. Genetic manipulation of the Notch pathway led to concomitant variations in N-cadherin and α 9-integrin. Treatment with anti-N-cadherin-blocking antibody rendered marked inhibition of cell adhesion and motility, while anti- α 9-integrin-blocking antibody exerted a remarkable effect on cell adhesion and invasiveness. Neuronal cadherin and α 9-integrin are postulated as leading actors in the association between the Notch pathway and promotion of cell adhesion, motility and invasion, pointing to these proteins and the Notch pathway itself as interesting putative targets for new molecular therapies against metastases in RMS.

Natural killer (NK) cell numbers and lytic activity were determined in 40 children with various types of solid malignant neoplasias and in 25 control children by NKH-1 monoclonal antibody and cytotoxicity against K562 target cells, respectively. Patients were analyzed at the time of diagnosis before initiation of therapy and followed over a median time of 15.8 months. Mean NK cell numbers and lytic activity were similar among different types of tumor analyzed. Patients with localized disease (stages I, II; n = 25) also showed values not statistically different from those of patients in advanced disease (stages III, IV; n = 15). According to their response to therapy, patients were divided into three groups: group 1 (complete remission; n = 28), group 2 (partial remission; n = 5), and group 3 (progression of disease; n = 6). Patients in group 3 showed at the time of diagnosis a mean NK activity significantly lower than that of patients in groups 1 and 2 and control children (P = 0.007). The defect in NK cell lytic capacity in vitro observed in patients with progressive disease suggests that NK cells play a role in the control of neoplastic growth in vivo and may imply that some children with refractory progressive disease can benefit from immunomodulation destined to improve the lytic potential of NK cells.

To improve the prognosis of patients with metastatic or high-risk localized sarcoma in first CR, we explored the role of consolidation therapy with megatherapy and hematopoietic rescue. From 1986 to 1995, of 72 patients with Ewing’s sarcoma from three pediatric departments, 30 were diagnosed as high-risk patients. Of these 30 patients, six did not achieve complete remission and four refused megatherapy and received multimodal treatment (chemotherapy + surgery and/or radio- therapy). The remaining 20 patients received megatherapy. There were 15 males and five females with a median age of 10.8 years (range 2–18 years). Five patients had metastatic disease at initial diagnosis, nine patients had primary tumor in the pelvis and 13 had a tumor volume greater than 100 ml. Overall disease-free survival was 62.7 ± 11%; 40 ± 21.9% for those with metastatic disease, 76.2 ± 12.2% for those with tumor volume greater than 100 ml and 64.8 ± 16.5% for those with tumor in pelvic bones. In conclusion, megatherapy has improved the outcome of this group of patients relative to that expected following conventional therapy.

A review of the findings in seven cases of stage IV-S neuroblastoma, that have been observed between 1966 and 1984. Patients under one year stage IV-S neuroblastoma have a favorable prognosis; survival rate was 71%. Primary tumor in some may be relatively small. Chemotherapy and radiation therapy may not be necessary in the management of certain children.

Cancer; Drug development; Gene amplifications Cáncer; Desarrollo de fármacos; Amplificaciones de genes Càncer; Desenvolupament de medicaments; Amplificacions de gens The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last few years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations, and fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here, we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy-number genomic amplifications generate multiple collateral dependencies within the amplified region in most cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency led to the identification of genes, the expression of which may constitute predictive biomarkers of dependency. In conclusion, our study provides a set of druggable targets specific for each amplification, opening the possibility to specifically target amplified tumors on this basis. This research was funded by grants from Institut Català d’Oncologia (ICO), Instituto de Salud Carlos III (PI21/00640), AGAUR (2021 FI_B 00088), Fundació BOSCH, Iniciativa Tot per tu, Fundació Amics Joan Petit, and Mi compañero de viaje.

Embryonic pathways; Paediatric cancer; Soft tissue sarcomas Vies embrionàries; Càncer pediàtric; Sarcomes de teixits tous Vías embrionarias; Cáncer pediátrico; Sarcomas de tejidos blandos Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours—among them sarcomas—mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting. This article was funded by grants from: Institut Català d’Oncologia (ICO); Instituto de Salud Carlos III (PI18/00398 and FI18/00178); ACCIÓ (COMRDI15-1-0014); Fundació la Marató de TV3; Fundació Albert Bosch; Rotary Clubs Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Deutschland Gemeindienst e.V. and others from Barcelona and province; Fundation Amics Joan Petit; Del Hospital a la cathedral Initiative by Xavi Vallès; and Mi compañero de viaje Association.

Chromatin remodelling; Epigenetics; Metastasis Remodelación de cromatina; Epigenética; Metástasis Remodelació de cromatina; Epigenètica; Metàstasi Background Epigenetic programming during development is essential for determining cell lineages, and alterations in this programming contribute to the initiation of embryonal tumour development. In neuroblastoma, neural crest progenitors block their course of natural differentiation into sympathoadrenergic cells, leading to the development of aggressive and metastatic paediatric cancer. Research of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial for developing new epigenetic-based therapies against these tumours. Mammalian switch/sucrose non-fermenting (mSWI/SNF) ATP-dependent chromatin remodelling complexes act genome-wide translating epigenetic signals into open chromatin states. The present study aimed to understand the contribution of mSWI/SNF to the oncogenic epigenomes of neuroblastoma and its potential as a therapeutic target. Methods Functional characterisation of the mSWI/SNF complexes was performed in neuroblastoma cells using proteomic approaches, loss-of-function experiments, transcriptome and chromatin accessibility analyses, and in vitro and in vivo assays. Results Neuroblastoma cells contain three main mSWI/SNF subtypes, but only BRG1-associated factor (BAF) complex disruption through silencing of its key structural subunits, ARID1A and ARID1B, impairs cell proliferation by promoting cell cycle blockade. Genome-wide chromatin remodelling and transcriptomic analyses revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program involving integrins, cadherins, and key mesenchymal regulators, thereby reducing adhesion to the extracellular matrix and the subsequent invasion in vitro and drastically inhibiting the initiation and growth of neuroblastoma metastasis in vivo. Conclusions We report a novel ATPase-independent role for the BAF complex in maintaining an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging for the development of new BAF pharmacological structural disruptors for therapeutic exploitation in metastatic neuroblastoma. This work was funded by Instituto de Salud Carlos III (CP16/00006, PI17/00564 and PI20/00530 to MFS and MS17/00063 to DL-N); Asociación Española Contra el Cáncer (LABAE18009SEGU to MFS, LABAE19004LLOB to DL-N, PROYE18010POSA to FP); Generalitat de Catalunya (2017FI_B_00095 to CJ, 2017SGR799 to FP and EdN; institutional funding through CERCA Programme); La Caixa Foundation (LCF/BQ/PR20/11770001 to MN-R); Spanish Ministry of Economy and Competitiveness (PID2021-124723NB-C21 to FP and PID2021-124723NB-C22 to EdN); Spanish Ministry of Science, Innovation and Universities (institutional funding through Centres of Excellence Severo Ochoa Award); State Research Agency (institutional funding through Unidad de Excelencia María de Maeztu, CEX2018-000792-M); and the Catalan Institution for Research and Advanced Studies (Academia awards to EdN and FP). Funding was also received from NEN association; Joan Petit foundation; Asociación Pulseras Candela foundation; and the Rotary Clubs of Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Deutschland Gemeindienst, and others from Barcelona and its province.

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model., This research was supported by grants from: Institut Català d’Oncologia (ICO); Instituto de Salud Carlos III (PI18/00398 and FI18/00178); ACCIÓ (COMRDI15-1-0014); Fundació la Marató de TV3; Fundació A. BOSCH; Rotary Clubs Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Deutschland Gemeindienst e.V. and others from Barcelona and province; Eric Abidal Foundation; Del Hospital a la catedral Initiative by Xavi Vallès; and Mi compañero de viaje Association.

Dickkopf proteins; Differentiation Proteínas Dickkopf; Diferenciación Proteïnes Dickkopf; Diferenciació The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, This research was supported by grants from the following: Institut Català d’Oncologia (ICO); Instituto de Salud Carlos III (PI18/00398); Fundació A. BOSCH; Rotary Clubs Barcelona Eixample, Barcelona Diagonal, Santa Coloma de Gramanet, München-Blutenburg, Deutschland Gemeindienst e.V. and others from Barcelona and province; FERO Foundation; Eric Abidal Foundation; “del Hospital a la catedral” Initiative by Xavi Vallès; and “Mi compañero de viaje”.

MicroRNAs (miRNAs) are small non-coding endogenous RNAs, which are attracting a growing interest as therapeutic molecules due to their central role in major diseases. However, the transformation of these biomolecules into drugs is limited due to their unstability in the bloodstream, caused by nucleases abundantly present in the blood, and poor capacity to enter cells. The conjugation of miRNAs to nanoparticles (NPs) could be an effective strategy for their clinical delivery. Herein, the engineering of non-liposomal lipid nanovesicles, named quatsomes (QS), for the delivery of miRNAs and other small RNAs into the cytosol of tumor cells, triggering a tumor-suppressive response is reported. The engineered pH-sensitive nanovesicles have controlled structure (unilamellar), size (24 weeks), and are prepared by a green, GMP compliant, and scalable one-step procedure, which are all unavoidable requirements for the arrival to the clinical practice of NP based miRNA therapeutics. Furthermore, QS protect miRNAs from RNAses and when injected intravenously, deliver them into liver, lung, and neuroblastoma xenografts tumors. These stable nanovesicles with tunable pH sensitiveness constitute an attractive platform for the efficient delivery of miRNAs and other small RNAs with therapeutic activity and their exploitation in the clinics., The funding was received by Ministerio de Educación, Cultura y Deporte (Grant no. FPU16/01099), Ministerio de Economía, Industria y Competividad (Grants MAT2016-80820-R, MAT2016-80826-R and SAF2016-75241-R), the Ministry of Science and Innovation (MINECO) of Spain through grant PID2019-105622RB-I00, from Instituto de Salud Carlos III (Grant no. CP16/00006, PI17/00564, PI20/00530, DTS20/00018) (Co-funded by European Regional Development Fund/European Social Fund) “Investing in your future”), from the EuroNanoMed II platform through the NanoVax project, from CIBER-BBN through grant TAG-SMARTLY, Joan Petit Foundation, Asociación Matem Lo Bitxo and Asociación Española Contra el Cáncer (Grant no. LABAE18009SEGU), as well as, Generalitat de Catalunya through the Centres de Recerca de Catalunya (CERCA) programme and grant no. 2017-SGR-918, and from Agency for Management of University and Research Grants (AGAUR) (Grant no 2018LLAV0064 and SIFECAT IU68-010017). Furthermore, ICMAB-CSIC acknowledges support from the MINECO through the Severo Ochoa Programme for Centres of Excellence in R&D (SEV-2015-0496 and CEX2019-000917-S). Quatsome production and their physicochemical characterization was performed by the ICTS “NANBIOSIS,” more specifically in the Biomaterial Processing and Nanostructuring Unit (U6), Unit of the CIBER in Bioengineering, Biomaterials & Nanomedicne (CIBER-BBN) located at the Institute of Materials Science of Barcelona (ICMAB-CSIC). The authors thank the UAB Microscopy service for their help in recording cryo-TEM images. The authors also thank Mr. Adolfo de Hoyos-Limon for pKa measurements, Ms. Patricia Pérez for her help in in vitro experiments, the members of Laboratory Animal Service Unit of Vall d'Hebron Research Institute for their help in the in vivo experiment. The authors thank Editage (www.editage.com) and Ms. Christine O'Hara for English language correction. The authors acknowledge Biorender.com for allowing the adaptation of their templates. Retrieved from https://app.biorender.com/biorender-templates., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).