Neuroendocrine (NE) cancers are a diverse group of neoplasms typically diagnosed and treated on the basis of their site of origin. This Perspective focuses on advances in our understanding of the ...tumorigenesis and treatment of poorly differentiated neuroendocrine tumors. Recent evidence from sequencing indicates that, although neuroendocrine tumors can arise de novo, they can also develop as a result of lineage plasticity in response to pressure from targeted therapies. We discuss the shared genomic alterations of these tumors independently of their site of origin, and we explore potential therapeutic strategies on the basis of recent biological findings.
Anaerobic digestion (AD) could be considered as a mature technology and nowadays it can still play a pivot role because of the urgent need to provide renewable energy sources and efficiently manage ...the continuously growing amount of organic waste. Biochar (BC) is an extremely versatile material, which could be produced by carbonization of organic materials, including biomass and wastes, consistently with Circular Economy principles, and “tailor-made” for specific applications. The potential BC role as additive in the control of the many well-known critical issues of AD processes has been increasingly explored over the past few years. However, a clear and comprehensive understanding of the connections between BC and AD is still missing. This review paper analyses and discusses significant references (review articles, research papers and international databases and reports), mostly published in the last 10 years. This review is aimed at addressing three key issues related to the better understanding of the BC role in AD processes: 1. Investigation of the influence of BC properties on AD performances and of their ability to counteract its main challenges; 2. Assessment of the optimal BC production chain (i.e. feedstock-pyrolysis-activation) to achieve the desired features; 3. Evaluation of the economic and environmental advantages connected to BC use in AD processes, compared to conventional solutions applied to address AD challenges.
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•Biochar key properties were specific surface, pores and surface functional groups.•Lignocellulosic biomass, slow pyrolysis and physical activation made the best biochar.•Biochar addition exhibited economic and environmental advantages.•Biochar improved methane production (in average 25 %) and digestate quality.
Despite the utility of CRISPR-Cas9 nucleases for genome editing, the potential for off-target activity limits their application, especially for therapeutic purposes. We developed a yeast-based assay ...to identify optimized Streptococcus pyogenes Cas9 (SpCas9) variants that enables simultaneous evaluation of on- and off-target activity. We screened a library of SpCas9 variants carrying random mutations in the REC3 domain and identified mutations that increased editing accuracy while maintaining editing efficiency. We combined four beneficial mutations to generate evoCas9, a variant that has fidelity exceeding both wild-type (79-fold improvement) and rationally designed Cas9 variants (fourfold average improvement), while maintaining near wild-type on-target editing efficiency (90% median residual activity). Evaluating evoCas9 on endogenous genomic loci, we demonstrated a substantially improved specificity and observed no off-target sites for four of the eight single guide RNAs (sgRNAs) tested. Finally, we showed that following long-term expression (40 d), evoCas9 strongly limited the nonspecific cleavage of a difficult-to-discriminate off-target site and fully abrogated the cleavage of two additional off-target sites.
Patients with cancer carry somatic sequence variants in their tumour in addition to the germline variants in their inherited genome. Although variants in protein-coding regions have received the most ...attention, numerous studies have noted the importance of non-coding variants in cancer. Moreover, the overwhelming majority of variants, both somatic and germline, occur in non-coding portions of the genome. We review the current understanding of non-coding variants in cancer, including the great diversity of the mutation types--from single nucleotide variants to large genomic rearrangements--and the wide range of mechanisms by which they affect gene expression to promote tumorigenesis, such as disrupting transcription factor-binding sites or functions of non-coding RNAs. We highlight specific case studies of somatic and germline variants, and discuss how non-coding variants can be interpreted on a large-scale through computational and experimental methods.
The ETS family member ERG is a transcription factor with physiological roles during development and in the vascular and hematopoietic systems. ERG oncogenic activity characterizes several ...malignancies, including Ewing's sarcoma, leukemia and prostate cancer (PCa). In PCa,
rearrangements with androgen-regulated genes-mostly
-characterize a large subset of patients across disease progression and result in androgen receptor (AR)-mediated overexpression of ERG in the prostate cells. Importantly, PCa cells overexpressing ERG are dependent on ERG activity for survival, further highlighting its therapeutic potential. Here, we review the current understanding of the role of ERG and its partners in PCa. We discuss the strategies developed in recent years to inhibit ERG activity, the current therapeutic utility of ERG fusion detection in PCa patients, and the possible future approaches to target ERG fusion-positive tumors.
Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. ...Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here we show transcriptomic, histologic and cellular profiles of post mortem COVID-19 (n = 34 tissues from 16 patients) and normal lung tissues (n = 9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 are identified. One pattern shows high local expression of interferon stimulated genes (ISG
) and cytokines, high viral loads and limited pulmonary damage, the other pattern shows severely damaged lungs, low ISGs (ISG
), low viral loads and abundant infiltrating activated CD8
T cells and macrophages. ISG
patients die significantly earlier after hospitalization than ISG
patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment.
This study introduces to a one-step process for the fermentative production of L(+)-lactic acid from mixed restaurant food waste. Food waste was used as carbon and nitrogen source in simultaneous ...saccharification and fermentation (SSF) using Lactobacillus sp. or Streptococcus sp. strains for L(+)-lactic acid production. Waste consisted of (w/w) 33.5% starch, 14.8% proteins, 12.9% fat and 8.5% free sugars. Lactobacillus sp. strains showed a productivity of 0.27–0.53 g L−1 h−1 and a yield of 0.07–0.14 g g−1 of theoretically available sugars, while Streptococcus sp. more efficiently degraded the food waste material and produced lactic acid at a maximum rate of 2.16 g L−1 h−1 and a yield of 0.81 g g−1. For SSF, no enzymes were added or other hydrolytic treatments were carried out. Outcomes revealed a linear relationship between lactic acid concentration and solid-to-liquid ratio when Streptococcus sp. was applied. Statistically, from a 20% (w/w) dry food waste blend 52.4 g L−1 lactic acid can be produced. Experimentally, 58 g L−1 was achieved in presence of 20% (w/w), which was the highest solid-to-liquid ratio that could be treated using the equipment applied. Irrespective if SSF was performed at laboratory or technical scale, or under non-sterile conditions, Streptococcus sp. efficiently liquefied food waste and converted the released nutrients directly into lactic acid without considerable production of other organic acids, such as acetic acid. Downstream processing including micro- and nanofiltration, electrodialysis, chromatography and distillation gave a pure 702 g L−1 L(+)-lactic acid formulation.
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•An isolated Streptococcus sp. strain converted food waste efficiently into lactic acid.•Max. productivity was 2.16 g L−1 h−1 and yield was 0.81 g g−1 of available sugars.•Increase in solid-to-liquid ratio resulted in increased lactic acid titer.•A solid-to-liquid ratio of 20% (w/w) gave 58 g L−1 lactic acid.•Downstream processing resulted in a 702 g L−1 optical pure L(+)-lactic acid solution.
Whole exome sequencing (WES) is widely utilized both in translational cancer genomics studies and in the setting of precision medicine. Stratification of individual's ethnicity is fundamental for the ...correct interpretation of personal genomic variation impact. We implemented EthSEQ to provide reliable and rapid ethnicity annotation from whole exome sequencing individual's data, validated it on 1000 Genome Project and TCGA data (2700 samples) demonstrating high precision, and finally assessed computational performances compared to other tools. EthSEQ can be integrated into any WES based processing pipeline and exploits multi-core capabilities.
R package available at github.com/aromanel/EthSEQ and CRAN repository.
alessandro.romanel@unitn.it or f.demichelis@unitn.it.
Supplementary data are available at Bioinformatics online.
The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with ...overexpression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC. This includes an abrogation of androgen receptor signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.
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•N-Myc drives the NEPC phenotype and associated molecular program•N-Myc abrogates AR signaling, which results in enhanced AKT activity•N-Myc redirects EZH2 activity and sensitizes cells to EZH2 inhibitors•N-Myc interacts with Aurora-A, which facilitates N-Myc target gene expression
Dardenne et al. demonstrate that N-Myc overexpression in pre-clinical models drives aggressive prostate cancer that mimics human neuroendocrine prostate cancer, including reduced AR signaling and enhanced PRC2 target gene repression, and sensitizes cells to an Aurora-A inhibitor and EZH2 SET domain inhibitors.
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