Project description:Neuroblastoma is an embryonic malignancy of early childhood originating from neural crest cells and showing heterogeneous biological, morphological, genetic and clinical characteristics. The correct stratification of neuroblastoma patients within risk groups (low, intermediate, high and ultra-high) is critical for the adequate treatment of the patients.High-throughput technologies in the Omics disciplines are leading to significant insights into the molecular pathogenesis of neuroblastoma. Nonetheless, further study of Omics data is necessary to better characterise neuroblastoma tumour biology. In the present review, we report an update of compounds that are used in preclinical tests and/or in Phase I-II trials for neuroblastoma. Furthermore, we recapitulate a number of compounds targeting proteins associated to neuroblastoma: MYCN (direct and indirect inhibitors) and downstream targets, Trk, ALK and its downstream signalling pathways. In particular, for the latter, given the frequency of ALK gene deregulation in neuroblastoma patients, we discuss on second-generation ALK inhibitors in preclinical or clinical phases developed for the treatment of neuroblastoma patients resistant to crizotinib.We summarise how Omics drive clinical trials for neuroblastoma treatment and how much the research of biological targets is useful for personalised medicine. Finally, we give an overview of the most recent druggable targets selected by Omics investigation and discuss how the Omics results can provide us additional advantages for overcoming tumour drug resistance.
Project description:In this review I give a personal perspective of how fungal biology has changed since I started my Ph. D. in 1963. At that time we were working in the shadow of the birth of molecular biology as an autonomous and reductionistic discipline, embodied in Crick's central dogma. This first period was methodologically characterised by the fact that we knew what genes were, but we could not access them directly. This radically changed in the 70s-80s when gene cloning, reverse genetics and DNA sequencing become possible. The "next generation" sequencing techniques have produced a further qualitative revolutionary change. The ready access to genomes and transcriptomes of any microbial organism allows old questions to be asked in a radically different way and new questions to be approached. I provide examples chosen somewhat arbitrarily to illustrate some of these changes, from applied aspects to fundamental problems such as the origin of fungal specific genes, the evolutionary history of genes clusters and the realisation of the pervasiveness of horizontal transmission. Finally, I address how the ready availability of genomes and transcriptomes could change the status of model organisms.
Project description:Several studies are starting to show the power of DNA microarrays to identify interactions between animal hosts and their pathogens, and have revealed interesting correlations between host responses to different infectious agents.
Project description:Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is a Food and Drug Administration (FDA)-approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast, and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example, cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1E322K mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR.
Project description:Giardia lamblia is a causative agent of persistent diarrhea widespread in regions with low hygienic standards. Laboratory research is based on cloned lines issuing from various patient isolates typed in the late 1980s and 90s using restriction analysis and serology. In the present study, we compared the well characterized strain WBC6 with another clone of the parent WB isolate termed WBA1 and with a clone from another isolate, GS/M-83-H7, using shotgun mass spectrometry proteomics. We identified 398 proteins differentially expressed between the GS and both WB isolates and 97 proteins differentially expressed between both WB isolates. We investigated the expression levels of the predominant variant-specific surface proteins (VSPs) in each clone and matched the previously described major VSPs of each strain to the corresponding open reading frame (ORF) sequences identified by whole-genome sequencing efforts. Furthermore, since the original WB isolate comes from a patient treated with metronidazole, we compared the susceptibilities of the strains to nitro compounds, as well the expression levels of enzymes involved in nitro reduction and on the corresponding enzyme activities and found distinct differences between the three strains.
Project description:The advent of high-throughput, next-generation sequencing methods combined with advances in computational biology and bioinformatics have greatly accelerated discovery within biomedical research. This "post-genomics" era has ushered in powerful approaches allowing one to quantify RNA transcript and protein abundance for every gene in the genome - often for multiple conditions. Herein, we chronicle how the post-genomics era has advanced our overall understanding of parasitic nematodes through transcriptomics and proteomics and highlight some of the important advances made in each major nematode clade. We primarily focus on organisms relevant to human health, given that nematode infections significantly impact disability-adjusted life years (DALY) scores within the developing world, but we also discuss organisms of veterinary importance as well as those used as laboratory models. As such, we envision that this review will serve as a comprehensive resource for those seeking a better understanding of basic parasitic nematode biology as well as those interested in targets for vaccination and pharmacological intervention.
Project description:Alternative approaches complementing the existing technologies for analysis of nucleic acids and their assemblies are necessary to take on the new challenges posed by the postgenomic era. The versatility of MS in biopolymer analysis and its ability to reach beyond sequence information are the basis of ever expanding applications aimed at the elucidation of nucleic acid structure-function relationships. This Feature summarizes the current state of MS-based approaches devised to overcome the limitations of traditional techniques and to advance different facets of nucleic acids research.
Project description:Following the fanfare of initial, often dramatic, success with small molecule inhibitors in the treatment of defined genomic subgroups, it can be argued that the extension of targeted therapeutics to the majority of patients with solid cancers has stalled. Despite encouraging FDA approval rates, the attrition rates of these compounds remains high in early stage clinical studies, with single agent studies repeatedly showing poor efficacy In striking contrast, our understanding of the complexity of solid neoplasms has increased in huge increments, following the publication of large-scale genomic and transcriptomic datasets from large collaborations such as the International Cancer Genome Consortium (ICGC http://www.icgc.org/) and The Cancer Genome Atlas (TCGA http://cancergenome.nih.gov/). However, there remains a clear disconnect between these rich datasets describing the genomic complexity of cancer, including both intra- and inter-tumour heterogeneity, and what a treating oncologist can consider to be a clinically "actionable" mutation profile. Our understanding of these data is in its infancy and we still find difficulties ascribing characteristics to tumours that consistently predict therapeutic response for the majority of small molecule inhibitors. This article will seek to explore the recent studies of the patterns and impact of mutations in drug resistance, and demonstrate how we may use this data to reshape our thinking about biological pathways, critical dependencies and their therapeutic interruption.
Project description:Sugarcane is one of the most sustainable energy crops among cultivated crops presenting the highest tonnage of cultivated plants. Its high productivity of sugar, bioethanol and bioelectricity make it a promising green alternative to petroleum. Furthermore, the myriad of products that can be derived from sugarcane biomass has been driving breeding programs towards varieties with a higher yield of fiber and a more vigorous and sustainable performance: the energy cane. Here we provide an overview of the energy cane including plant description, breeding efforts, types, and end-uses. In addition, we describe recently published genomic resources for the development of this crop, discuss current knowledge of cell wall metabolism, bioinformatic tools and databases available for the community.
Project description:Nowadays, post-surgical or post-accidental bone loss can be substituted by custom-made scaffolds fabricated by additive manufacturing (AM) methods from metallic powders. However, the partially melted powder particles must be removed in a post-process chemical treatment. The aim of this study was to investigate the effect of the chemical polishing with various acid baths on novel scaffolds' morphology, porosity and mechanical properties. In the first stage, Magics software (Materialise NV, Leuven, Belgium) was used to design a porous scaffolds with pore size equal to (A) 200 µm, (B) 500 µm and (C) 200 + 500 µm, and diamond cell structure. The scaffolds were fabricated from commercially pure titanium powder (CP Ti) using a SLM50 3D printing machine (Realizer GmbH, Borchen, Germany). The selective laser melting (SLM) process was optimized and the laser beam energy density in range of 91-151 J/mm³ was applied to receive 3D structures with fully dense struts. To remove not fully melted titanium particles the scaffolds were chemically polished using various HF and HF-HNO₃ acid solutions. Based on scaffolds mass loss and scanning electron (SEM) observations, baths which provided most uniform surface cleaning were proposed for each porosity. The pore and strut size after chemical treatments was calculated based on the micro-computed tomography (µ-CT) and SEM images. The mechanical tests showed that the treated scaffolds had Young's modulus close to that of compact bone. Additionally, the effect of pore size of chemically polished scaffolds on cell retention, proliferation and differentiation was studied using human mesenchymal stem cells. Small pores yielded higher cell retention within the scaffolds, which then affected their growth. This shows that in vitro cell performance can be controlled to certain extent by varying pore sizes.