609 research outputs found
Design, synthesis and biological validation of epigenetic modulators of histone/protein deacetylation and methylation
Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy
Immune checkpoint factors, such as programmed cell death protein-1/2 (PD-1, PD-2) or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) receptors, are targets for monoclonal antibodies (MAbs) developed for cancer immunotherapy. Indeed, modulating immune inhibitory pathways has been considered an important breakthrough in cancer treatment. Although immune checkpoint blockade therapy used to treat malignant diseases has provided promising results, both solid and haematological malignancies develop mechanisms that enable themselves to evade the host immune system. To overcome some major limitations and ensure safety in patients, recent strategies have shown that combining epigenetic modulators, such as inhibitors of histone deacetylases (HDACi) or DNA methyltransferases (DNMTi), with immunotherapeutics can be useful. Preclinical data generated using mouse models strongly support the feasibility and effectiveness of the proposed approaches. Indeed, co-treatment with pan- or class I-selective HDACi or DNMTi improved beneficial outcomes in both in vitro and in vivo studies. Based on the evidence of a pivotal role for HDACi and DNMTi in modulating various components belonging to the immune system, recent clinical trials have shown that both HDACi and DNMTi strongly augmented response to anti-PD-1 immunotherapy in different tumour types. This review describes the current strategies to increase immunotherapy responses, the effects of HDACi and DNMTi on immune modulation, and the advantages of combinatorial therapy over single-drug treatment
High-performance microstrip directional coupler for radio-astronomical receivers at cryogenic temperature
A microstrip directional coupler with high directivity is proposed for microwave applications requiring a weak coupling factor. This component has been used in the L-band radio-astronomical receiver of the Sardinia radio telescope. To improve the performance of the receiver, the operating temperature is lowered to 20 K. An in-house cryostat has been manufactured to perform measurements on the directional coupler, and very good agreement with the design specification is achieved
Oxidative stress and epigenetic regulation in ageing and age-related diseases
Recent statistics indicate that the human population is ageing rapidly. Healthy, but also diseased, elderly people are increasing. This trend is particularly evident in Western countries, where healthier living conditions and better cures are available. To understand the process leading to age-associated alterations is, therefore, of the highest relevance for the development of new treatments for age-associated diseases, such as cancer, diabetes, Alzheimer and cardiovascular accidents. Mechanistically, it is well accepted that the accumulation of intracellular damage determined by reactive oxygen species (ROS) might orchestrate the progressive loss of control over biological homeostasis and the functional impairment typical of aged tissues. Here, we review how epigenetics takes part in the control of stress stimuli and the mechanisms of ageing physiology and physiopathology. Alteration of epigenetic enzyme activity, histone modifications and DNA-methylation is, in fact, typically associated with the ageing process. Specifically, ageing presents peculiar epigenetic markers that, taken altogether, form the still ill-defined “ageing epigenome”. The comprehension of mechanisms and pathways leading to epigenetic modifications associated with ageing may help the development of anti-ageing therapies
Application of Small Epigenetic Modulators in Pediatric Medulloblastoma
Medulloblastoma is one of the most frequent among pediatric brain tumors, and it has been classified in various subgroups. Some of them already benefit from quite good therapeutic options, whereas others urgently need novel therapeutic approaches. Epigenetic modulators have long been studied in various types of cancer. Within this review, we summarize the main preclinical studies regarding epigenetic targets (such as HDAC, SIRT, BET, EZH2, G9a, LSD1, and DNMT) inhibitors in medulloblastoma. Furthermore, we shed light on the increasing number of applications of drug combinations as well as hybrid compounds involving epigenetic mechanisms. Nevertheless, in the studies published so far, mainly un-specific or old modulators have been used, and the PKs (brain permeability) have not been well-evaluated. Thus, these findings should be considered as a starting point for further improvement and not as a final result
Influence of the nature of the substrate on the growth of superconducting niobium films
The superconducting properties of niobium films sputtered onto the inner walls of radiofrequency cavities, including their surface resistance to 1.5 GHz microwaves, have been studied as a function of the nature of the substrate. Films grown on oxide-free copper or niobium behave differently from films grown on other substrates. The results are analysed in terms of the film texture and internal stresses
Fluxon Pinning in Niobium Films
Resistive losses induced by the presence of trapped magnetic flux in niobium superconducting films have been studied using 1.5 GHz microwaves. They are measured to span a very broad spectrum depending on the film-substrate interface and on the gas used in the sputtering discharge. An interpretation in terms of pinning by noble gas clusters is considered
Molecular mechanisms and new therapeutic targets in epithelial to mesenchymal transition (EMT) and fibrosis
Although the term “epithelial to mesenchymal transformation” was used for the first time by Betty Hay in 1968, the earliest description of the EMT process probably dates back to drawings made by the Nobel Prize Santiago Ramòn y Cajal around 1890 (López-Novoa and Nieto, 2009).
After decades of studies, EMT is now considered a key physiopathological mechanism active in embryogenesis, in fibrotic diseases and in cancer. The scope of this research topic was to provide an updated overview of EMT processes and new therapeutic strategies aimed to target EMT processes. In this Topic, Fintha et al. provided a timely survey on the “fibroblast conversion” hypothesis (with a focus on renal fibrosis), where epithelial cell transdifferentiation plays a crucial role in the generation of myofibroblasts, the main cells implicated in organ fibrosis. The ‘fibroblast conversion' hypothesis has been intensely debated over years, with some contradicting evidence in different experimental systems used
CERN studies on niobium-coated 1.5 GHz copper cavities
Studies at CERN on niobium-coated 1.5 GHz superconducting cavities are aimed at understanding and possibly curing the causes of the residual resistance increase observed when increasing the accelerating gradient above 15 MV/m. Amongst the possible causes, the surface defects and roughness, the grain size, the hydrogen content and the thermal effects are currently being investigated. The present status of understanding, together with some recent results on high field operation, are presented and discussed
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