Immunological Effects of Multikinase Inhibitors for Kidney Cancer: A Clue for Integration with Cellular Therapies?

The multikinase inhibitors Sunitinib and Sorafenib not only inhibit angiogenesis and tumor growth, but also have the potential of interacting with the function of the immune system

The role of noncoding RNAs in epithelial cancer

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: Fondazione Luigi Maria Monti IDI-IRCCS (RC)Abstract: Regulatory noncoding RNAs (ncRNAs) are a class of RNAs transcribed by regions of the human genome that do not encode for proteins. The three main members of this class, named microRNA, long noncoding RNA, and circular RNA play a key role in the regulation of gene expression, eventually shaping critical cellular processes. Compelling experimental evidence shows that ncRNAs function either as tumor suppressors or oncogenes by participating in the regulation of one or several cancer hallmarks, including evading cell death, and their expression is frequently deregulated during cancer onset, progression, and dissemination. More recently, preclinical and clinical studies indicate that ncRNAs are potential biomarkers for monitoring cancer progression, relapse, and response to cancer therapy. Here, we will discuss the role of noncoding RNAs in regulating cancer cell death, focusing on those ncRNAs with a potential clinical relevance

Pathophysiology of Crohn’s disease inflammation and recurrence

Chron's Disease is a chronic inflammatory intestinal disease, first described at the beginning of the last century. The disease is characterized by the alternation of periods of flares and remissions influenced by a complex pathogenesis in which inflammation plays a key role. Crohn's disease evolution is mediated by a complex alteration of the inflammatory response which is characterized by alterations of the innate immunity of the intestinal mucosa barrier together with a remodeling of the extracellular matrix through the expression of metalloproteins and increased adhesion molecules expression, such as MAcCAM-1. This reshaped microenvironment enhances leucocytes migration in the sites of inflammation, promoting a TH1 response, through the production of cytokines such as IL-12 and TNF-α. IL-12 itself and IL-23 have been targeted for the medical treatment of CD. Giving the limited success of medical therapies, the treatment of the disease is invariably surgical. This review will highlight the role of inflammation in CD and describe the surgical approaches for the prevention of the almost inevitable recurrence

Global mapping of cancers: The Cancer Genome Atlas and beyond

Cancer genomes have been explored from the early 2000s through massive exome sequencing efforts, leading to the publication of The Cancer Genome Atlas in 2013. Sequencing techniques have been developed alongside this project and have allowed scientists to bypass the limitation of costs for whole-genome sequencing (WGS) of single specimens by developing more accurate and extensive cancer sequencing projects, such as deep sequencing of whole genomes and transcriptomic analysis. The Pan-Cancer Analysis of Whole Genomes recently published WGS data from more than 2600 human cancers together with almost 1200 related transcriptomes. The application of WGS on a large database allowed, for the first time in history, a global analysis of features such as molecular signatures, large structural variations and noncoding regions of the genome, as well as the evaluation of RNA alterations in the absence of underlying DNA mutations. The vast amount of data generated still needs to be thoroughly deciphered, and the advent of machine-learning approaches will be the next step towards the generation of personalized approaches for cancer medicine. The present manuscript wants to give a broad perspective on some of the biological evidence derived from the largest sequencing attempts on human cancers so far, discussing advantages and limitations of this approach and its power in the era of machine learning

Phenotypic and functional characterization of endothelial progenitor cells isolated from peripheral blood of renal cell carcinoma patients

Endothelial progenitor cells (EPCs) are mobilized from either bone marrow or arterial walls to restore blood perfusion to ischemic organs and establish the vascular network within growing tumors [1]. The Ca2+ machinery plays a key role in EPC activation and might serve a molecular target for novel therapies of highly angiogenic tumors, such as renal cell carcinoma (RCC) [1]. The Ca2+ toolkit is remodelled in EPCs isolated from RCC patients (RCC-EPCs) as respect to healthy donors [2]. The present study was undertaken to evaluate for the first time the functional properties of EPCs isolated from tumor patients by focusing on RCC-EPCs. We extended our analysis at microscopic level by monitoring the sub-cellular structure of RCC-EPCs relative to their Ca2+ signalling fingerprint. Our results showed a striking functional and ultrastructural difference between RCC-EPCs and their normal counterparts, which might be the basis for designing novel, more specific anti-angiogenic treatments

Kiri tundmatule

Ganini, Franz, kanoonik OlomoucisKogub meieisa palve tekste erinevates keeltes, palub saata puuduvai

Mechanism of the aerobic oxidation of acetoacetate and 2- methylacetoacetate catalyzed by Mb: implications for ketogenic disorders

Acetoacetato (AA) e 2-metilacetoacetato (MAA) são compostos β-cetoácidos acumulados em diversas desordens metabólicas como no diabetes e na isoleucinemia, respectivamente. Examinamos o mecanismo de oxidação aeróbica de AA e MAA iniciada por intermediários reativos de mioglobina de coração de cavalo (Mb) gerados pela adição de H2O2. Uma rota quimioluminescente que envolve um intermediário dioxetânico cuja termólise gera espécies α-dicarbonílicas (metilglioxal e biacetilo) foi proposta e estudada. Emissão de luz ultra fraca acompanha a reação, e sua intensidade aumenta linearmente pelo aumento da concentração tanto de Mb (10-500 µM) quando AA (10-100 mM). Estudos de consumo de oxigênio mostraram que MAA é, como esperado, quase uma ordem de grandeza mais reativo que AA. Estudos de EPR com captação de spin, utilizando MNP, possibilitaram detectar adutos de MAA atribuíveis a um radical centrado no Cα (aN = 1.55 mT) e ao radical acetila (aN = 0.83 mT). O sinal do radical acetila é totalmente suprimido por sorbato, um conhecido e eficiente supressor de espécies tripletes, o que é consistente com uma rota reacional envolvendo um intermediário dioxetânico. Clivagem-α da ligação carbonila-carbonila do produto biacetilo triplete produziria, de fato, radicais acetila. Além disso, utilizando AA como substrato para Mb/H2O2, um sinal de EPR atribuível ao aduto MNP-AA• (aN = 1.46 mT e aH = 0.34 mT) foi observado e confirmado por efeito isotópico. O consumo de oxigênio e o rendimento de compostos α-dicarbonílicos foram dose-dependentes à concentração de AA ou MAA (1-50 mM) bem como à concentração de H2O2 adicionado às misturas de reação contendo Mb (até 1:10 quando medido o consumo de oxigênio, e até 1:25 quando medido o rendimento de compostos α-dicarbonílicos) e tert-butilhidroperóxido (até 1:200). Os perfis de pH (5,8-7,8) para consumo de oxigênio e rendimento de compostos α-dicarbonílicos mostraram maiores rendimentos para baixos valores de pH, indicativo de ferrilMb formada no ciclo peroxidático da proteína. Avaliando os níveis de lesão de Mb, os β-cetoácidos diminuíram o nível de desorganização protéica na estrutura secundária e terciária elicitada por H2O2. Ainda, houve maior preservação da estrutura primária da proteína, sendo que MAA protegeu mais em comparação a AA, embora quando utilizado este último composto, foi mostrado que há acetilação dose-dependente de Mb. Acetoacetato aumentou a velocidade de descoramento da hemeproteína, provavelmente por ataque de espécies tripletes geradas no sistema. Músculos de rato, plantar e sóleo, expostos ex vivo a concentrações citotóxicas de glicose oxidase (GOX, gera H2O2 em fluxo), foram protegidas pelos ésteres etílicos AAE e MAAE. Foi detectado biacetilo no meio intracelular em músculos expostos a MAAE e GOX. A concentração deste composto α-dicarbonílico é claramente relacionada à abundância de Mb em cada um dos tipos de músculos estudados. Em resumo, Mb tratada com metabólitos β-cetoácidos (AA e MAA) gera radicais centrados em carbono e produtos α-dicarbonílicos altamente reativos no estado triplete. Experimentos realizados com tecido muscular ex vivo sugerem que esta reação possivelmente ocorra in vivo. Levantamos a hipótese de que a geração de espécies carbonílicas reativas e seus adutos em condições de desbalanço metabólico possam contribuir para a compreensão das bases moleculares de desordens cetogênicas.Acetoacetate (AA) and 2-methylacetoacetate (MAA) are β-ketoacids accumulated in several metabolic disorders such as diabetes and isoleucinemia, respectively. Here we examine the mechanism of AA and MAA aerobic oxidation initiated by the reactive enzyme intermediates formed by the reaction of muscle horse myoglobin (Mb) with H2O2. A chemiluminescent route involving a dioxetane intermediate whose thermolysis yields triplet α-dicarbonyl species (methylglyoxal and diacetyl) is envisaged. Accordingly, the ultraweak light emission that accompanies the reaction increases linearly by raising the concentration of both Mb (10-500 µM) and AA (10- 100 mM). Oxygen uptake studies revealed that MAA is, expectedly, almost one order of magnitude more reactive than AA. EPR spin-trapping studies with MNP detected spin adducts from MAA attributable to an α-carbon-centered radical (aN = 1.55 mT) and to an acetyl radical (aN = 0.83 mT). As the acetyl radical signal is totally suppressed by sorbate, a well-known efficient triplet species quencher, the dioxetane hypothesis seems to be reliable. The α-cleavage of the carbonyl-carbonyl bond of a putative excited triplet diacetyl product would, in fact, leads to an acetyl radical. Furthermore, using AA as substrate for Mb/H2O2, an EPR signal assignable to a MNP-AA• adduct (aN = 1.46 mT and aH = 0.34 mT) was observed and confirmed by isotope effect. Oxygen consumption and α-dicarbonyl yield were also dependent on AA or MAA concentrations (1-50 mM) as well as on the concentration of peroxide added to the Mb-containing reaction mixtures: H2O2 (up to 1:10 when measuring oxygen uptake and up to 1:25 when measuring the α-dicarbonyl yield) and t-butOOH (up to 1:200). The pH profiles (5.8-7.8) of oxygen consumption and α-dicarbonyl yield show higher reaction rates at lower pHs, indicative of a ferrylMb intermediate. Evaluating Mb lesion, both β-ketoacids reduced disorganization of the secondary and tertiary protein structure elicited by H2O2. Therefore, Mb primary structure was more preserved, and MAA was more protective than AA. Moreover using the later compound, it was shown that Mb acetylation is dose-dependent. Acetoacetate increased the rate of the hemeprotein bleaching, probably due to the attack of triplet products generated in the system. Plantaris and soleous rat muscles exposed to damaging concentrations of glucose oxidase (GOX, generates H2O2 in flux), was cytoprotected by AAE and MAAE. Intracellular diacetyl was detected in muscle samples exposed to MAAE and GOX. The α-dicarbonyl concentration is clearly related to the Mb abundance in the muscle types. In summary, Mb treated with peroxides reacts with β-ketoacid metabolites (AA and MAA), yielding carbon-centered radicals and highly reactive α-dicarbonyl products in the triplet state. Experiments carried out ex vivo with muscle tissue showed that this reaction possibly occurs in vivo. A new route for generation and accumulation of carbonyl reactive species and adducts is here proposed to occur in unbalanced metabolic situations, such as is the case of ketogenic disorders

The role of noncoding RNAs in epithelial cancer

Regulatory noncoding RNAs (ncRNAs) are a class of RNAs transcribed by regions of the human genome that do not encode for proteins. The three main members of this class, named microRNA, long noncoding RNA, and circular RNA play a key role in the regulation of gene expression, eventually shaping critical cellular processes. Compelling experimental evidence shows that ncRNAs function either as tumor suppressors or oncogenes by participating in the regulation of one or several cancer hallmarks, including evading cell death, and their expression is frequently deregulated during cancer onset, progression, and dissemination. More recently, preclinical and clinical studies indicate that ncRNAs are potential biomarkers for monitoring cancer progression, relapse, and response to cancer therapy. Here, we will discuss the role of noncoding RNAs in regulating cancer cell death, focusing on those ncRNAs with a potential clinical relevance