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Survival in high-risk neuroblastoma (HR-NB) patients remains poor despite multimodal treatment. We aimed to identify HR-NB patients with worse outcomes by analyzing the genomic instability derived from segmental chromosomal aberrations. We calculated 3 genomic instability indexes for primary tumor SNP array profiles from 127 HR-NB patients: (1) Copy number aberration burden (%gains length +%losses length), (2) copy number load (CNL) (%gains length -%losses length) and (3) net genomic load (NGL) (%gains amount -%losses amount). Tumors were classified according to positive or negative CNL and NGL genomic subtypes. The impact of the genomic instability indexes on overall survival (OS) was assessed with Cox regression. We identified 38% of HR-NB patients with poor 5-year OS. A negative CNL genomic background was related to poor prognosis in patients ≥18 months showing tumors with homogeneous MYCN amplification (9.5% survival probability, P < 0.05) and patients with non- MYCN amplified NB (18.8% survival probability related to >2.4% CNL, P < 0.01). A positive CNL genomic background was associated with worse outcome in patients with heterogeneous MYCN amplification (22.5% survival probability, P < 0.05). We conclude that characterizing a tumor genomic background according to predominance of genome gained or lost contributes toward improved outcome prediction and brings greater insight into the tumor biology of HR-NB patients. [ABSTRACT FROM AUTHOR]

The multiplicity of functions, substrates, and molecular partners of the two KAT3 proteins defines a complex cat's cradle of relationships. • CBP and p300 (KAT3s) interact with dozens of TFs and acetylate hundreds of substrates. • KAT3s have both unique and overlapping functions during neural development. • The relative importance of KAT3s decreases along the neuronal differentiation process. • Scaffolding and KAT functions are both part of the same mechanism of transactivation. • Novel tools can address outstanding questions regarding the neuronal role of KAT3s. The paralogous transcriptional co-activators CBP and p300 (aka KAT3A and KAT3B, respectively) contain a characteristic and promiscuous lysine acetyltransferase (KAT) domain and multiple independent protein-binding domains that enable them to interact with hundreds of proteins, possibly promoting the acetylation of thousands of target lysine residues. Both proteins play critical roles during the development of the nervous system and may also regulate stimuli-driven transcription and plasticity in postmitotic neurons. The multiplicity of functions, substrates, and molecular partners, together with the redundancy and singularity of the two KAT3 paralogs, define a complex cat's cradle of relationships. In this review, we discuss the role of the KAT3 proteins in neurons and integrate recent information regarding their function and mode of action. [ABSTRACT FROM AUTHOR]

During development, chromatin changes contribute to establishing and maintaining the distinct gene-expression profiles of each individual cell type in a multicellular organism. This feat is especially remarkable in the human brain considering the sheer number of distinct cell types that make up this organ. This epigenetic programing is sensitive to environmental influences such as the presence of toxicants, diet, temperature, maternal behavior and many other external factors that can lead to sustained differences in neuronal gene expression. Here, we review a number of studies that demonstrate the existence of these environmental fingerprints in the neuronal epigenome and discuss the current challenges and prospects of environmental neuroepigenetics research. [ABSTRACT FROM AUTHOR]

A series of azobenzene-containing peptidic boronate esters was prepared and the activity of the thermally adapted states (TAS), enriched in trans isomer, and the photostationary states (PSS), enriched in cis isomer, for each compound were evaluated against β5 and β1 proteasome subunits. Compounds with a sterically demanding phenyl-substituted azobenzene at P2 ( 4c ), and a less sterically demanding unsubstituted azobenzene at the N -terminus ( 5a ), showed the greatest difference in activity between the two states. In both cases, the more active trans -enriched TAS had activity comparable to bortezomib and delanzomib. Furthermore, cis -enriched 4c inhibited tumor growth in both breast and colorectal carcinoma cell lines. Significantly, the initial trans -enriched TAS of 4c was not cytotoxic against the non-malignant MCF-10A cells. [ABSTRACT FROM AUTHOR]

Summary During development, chromatin-modifying enzymes regulate both the timely establishment of cell-type-specific gene programs and the coordinated repression of alternative cell fates. To dissect the role of one such enzyme, the intellectual-disability-linked lysine demethylase 5C (Kdm5c), in the developing and adult brain, we conducted parallel behavioral, transcriptomic, and epigenomic studies in Kdm5c -null and forebrain-restricted inducible knockout mice. Together, genomic analyses and functional assays demonstrate that Kdm5c plays a critical role as a repressor responsible for the developmental silencing of germline genes during cellular differentiation and in fine-tuning activity-regulated enhancers during neuronal maturation. Although the importance of these functions declines after birth, Kdm5c retains an important genome surveillance role preventing the incorrect activation of non-neuronal and cryptic promoters in adult neurons. [ABSTRACT FROM AUTHOR]

The globalisation of the economy and the need for sustainable growth are having a strong influence on international sea freight transport and its infrastructures. Commercial sea ports, faced with the loss in ‘loyalty’ of their traffic and the appearance of ‘new rules in the game’, are developing new strategies in order to achieve the loyalty of their clients. The present paper is a reflection on the findings generated in recent years in the area of competitive port policies. The main focus is on the formulation of commercial and technological strategies, the new legislative framework and its consequences for the European Union in the context of the future ‘Common Ports Policy’. [Copyright &y& Elsevier]

There is a high prevalence for rhinitis with an increasing trend. However, there is a lack of specific quality of life pediatric questionnaires for sinonasal symptoms. The Sinus and Nasal Quality of Life Survey (SN-5) is the only validated instrument specifically designed with this objective. In this work we have translated and validated the Spanish version of the SN5 questionnaire. The SN5 was translated according to the World Health Organization recommendation for the translation and adaptation of instruments. The final version of the Sp-SN5 was administered twice (day 0 and day 7) to 137 participants with and without sinonasal symptoms. Reliability was measured with Cronbach α, temporal stability was measured with intraclass correlation coefficient. External validity was assessed with a ROC curve comparing a cohort of cases (children going to turbinate radiofrequency ablation) and controls (asymptomatic children). A Spearman correlation between the total result of the Sp-SN-5 questionnaire and the QOL score showed a strong negative correlation in the general sample and all the age subgroups. Internal consistency measured with Cronbach α was 0.87 for 5 items and was still over 0.83 after removing each item of the test. The intraclass correlation coefficient (ICC) for test-retest measurements was 0.94. The receiver operating characteristic (ROC) curve for all the included participants showed a very high area under the curve (0.998). The Sp–SN–5 questionnaire was successfully translated and cross-culturally adapted into Spanish, and the translated version exhibited adequate properties. The survey was effective in assessing the quality of life of pediatric patients with sinonasal complaints and can be used for this purpose both in a clinical setting and in future research. [ABSTRACT FROM AUTHOR]

Abstract: Botulinum neurotoxin A (BoNT/A) is the most potent toxin known. Unfortunately, it is also a potential bioweapon in terrorism, which is without an approved therapeutic treatment once cellular intoxication takes place. Previously, we reported how hydroxamic acid prodrug carbamates increased cellular uptake, which translated to successful inhibition of this neurotoxin. Building upon this research, we detail BoNT/A protease molecular modeling studies accompanied by the construction of small library of hydroxamic acids based on 2,4-dichlorocinnamic hydroxamic acid scaffold and their carbamate prodrug derivatization along with the evaluation of these molecules in both enzymatic and cellular models. [Copyright &y& Elsevier]

adenoidectomy is one of the most common surgical procedure in pediatric otolaryngology practice. Clinical guidelines (such as the Spanish or American) suggest adenoidectomy when the enlargement of the adenoids is associated with nasal obstruction. Nasal endoscopy and cephalograms are adequate methods to estimate the size of the adenoids. However, they do not measure nasal patency. This systematic review is designed with the objective of exploring the relationship between adenoid size and nasal ventilation through rhinomanometry. 3 authors members of the YO-IFOS rhinology study group independently analyzed the data sources (Pubmed, the Cochrane Library, EMBASE, SciELO) for papers assessing both nasal resistance and/or nasal airflow in rhinomanometry and adenoid size by any method (endoscopy, cephalogram, direct examination). A total of 10 studies with a total population of 969 participants met the inclusion criteria. 5 authors explored the size of the adenoids through endoscopy. 4 authors explored the adenoids through lateral cephalograms. Finally, a further 2 authors explored adenoid size studying the resected tissue. Five studies explored the correlation between adenoid size and nasal resistance in rhinomanometry, which ranged from 0.20 to 0.84. Finally, 5 studies used nasal decongestant. It was found higher sensitivity and specificity, a higher area under the curve for the receiver operating characteristic curve, and higher correlation with adenoid size for rhinomanometry under nasal decongestion. Up to now, there is no ideal diagnostic method for adenoid hypertrophy. Therefore, it seems prudent to use a combination of all currently available tools, as they provide complementary, rather than supplementary information. Available evidence suggests that rhinomanometry combined with nasal decongestant could help to elucidate the existence of nasal obstruction in intermediate cases of adenoid hypertrophy, as well as throw light on other possible causes for nasal obstruction, mainly turbinate hypertrophy. [ABSTRACT FROM AUTHOR]