The presence of ROS is a constant feature in living cells metabolizing O2. ROS concentration and compartmentation determine their physiological or pathological effects. ROS overproduction is a ...feature of cancer cells and plays several roles during the natural history of malignant tumor. ROS continuously contribute to each step of cancerogenesis, from the initiation to the malignant progression, acting directly or indirectly. In this review, we will (a) underline the role of ROS in the pathway leading a normal cell to tumor transformation and progression, (b) define the multiple roles of ROS during the natural history of a tumor, (c) conciliate many conflicting data about harmful or beneficial effects of ROS, (d) rethink the importance of oncogene and tumor suppressor gene mutations in relation to the malignant progression, and (e) collocate all the cancer hallmarks in a mechanistic sequence which could represent a “physiological” response to the initial growth of a transformed stem/pluripotent cell, defining also the role of ROS in each hallmark. We will provide a simplified sketch about the relationships between ROS and cancer. The attention will be focused on the contribution of ROS to the signaling of HIF, NFκB, and Sirtuins as a leitmotif of cancer initiation and progression.
The Virtual Element Method with curved edges Beirão da Veiga, L.; Russo, A.; Vacca, G.
ESAIM. Mathematical modelling and numerical analysis,
03/2019, Letnik:
53, Številka:
2
Journal Article
Recenzirano
In this paper we initiate the investigation of Virtual Elements with curved faces. We consider the case of a fixed curved boundary in two dimensions, as it happens in the approximation of problems ...posed on a curved domain or with a curved interface. While an approximation of the domain with polygons leads, for degree of accuracy k≥2, to a sub-optimal rate of convergence, we show (both theoretically and numerically) that the proposed curved VEM lead to an optimal rate of convergence.
•Treatment of EGFR mutated NSCLC is an evolving therapeutic paradigm.•EGFR mutated patients treated with 1st/2nd generation EGFR TKIs develop AR after 9–13 months.•T790M mutation is the major ...mechanism of AR to these agents.•3rd generation EGFR TKIs are emerging as a novel promising therapeutic strategy after AR.•Osimertinib is the first mutant-selective EGFR TKI approved by FDA and EMA.
The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents. Despite impressive clinical activity against EGFR-mutated NSCLCs, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant. Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M. The discovery of mutant-selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M-harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors.
The most represented group of resistance genes are those of the nucleotide binding site-leucine-rich repeat (NBS-LRR) class. These genes are very numerous in the plant genome, and they often occur in ...clusters at specific loci following gene duplication and amplification events. To date, hundreds of resistance genes and relatively few quantitative trait loci for plant resistance to pathogens have been mapped in different species, with some also cloned. When these NBS-LRR genes have been physically or genetically mapped, many cases have shown co-localization between resistance loci and NBS-LRR genes. This has allowed the identification of candidate genes for resistance, and the development of molecular markers linked to R genes. This review is focused on recent genomics studies that have described the abundance, distribution and evolution of NBS-LRR genes in plant genomes. Furthermore, in terms of their expression, NBS-LRR genes are under fine regulation by cis- and trans-acting elements. Recent findings have provided insights into the roles of alternative splicing, the ubiquitin/ proteasome system, and miRNAs and secondary siRNAs in the regulation of NBS-LRR gene expression at the post-transcriptional, post-translational and epigenetic levels. The possibility to use this knowledge for genetic improvement of plant resistance to pathogens is discussed.
Kawasaki disease is recognized as the most common cause of acquired heart disease in children in the developed world. Clinical, epidemiologic, and pathologic evidence supports an infectious agent, ...likely entering through the lung. Pathologic studies proposing an acute coronary arteritis followed by healing fail to account for the complex vasculopathy and clinical course.
Specimens from 32 autopsies, 8 cardiac transplants, and an excised coronary aneurysm were studied by light (n=41) and transmission electron microscopy (n=7). Three characteristic vasculopathic processes were identified in coronary (CA) and non-coronary arteries: acute self-limited necrotizing arteritis (NA), subacute/chronic (SA/C) vasculitis, and luminal myofibroblastic proliferation (LMP). NA is a synchronous neutrophilic process of the endothelium, beginning and ending within the first two weeks of fever onset, and progressively destroying the wall into the adventitia causing saccular aneurysms, which can thrombose or rupture. SA/C vasculitis is an asynchronous process that can commence within the first two weeks onward, starting in the adventitia/perivascular tissue and variably inflaming/damaging the wall during progression to the lumen. Besides fusiform and saccular aneurysms that can thrombose, SA/C vasculitis likely causes the transition of medial and adventitial smooth muscle cells (SMC) into classic myofibroblasts, which combined with their matrix products and inflammation create progressive stenosing luminal lesions (SA/C-LMP). Remote LMP apparently results from circulating factors. Veins, pulmonary arteries, and aorta can develop subclinical SA/C vasculitis and SA/C-LMP, but not NA. The earliest death (day 10) had both CA SA/C vasculitis and SA/C-LMP, and an "eosinophilic-type" myocarditis.
NA is the only self-limiting process of the three, is responsible for the earliest morbidity/mortality, and is consistent with acute viral infection. SA/C vasculitis can begin as early as NA, but can occur/persist for months to years; LMP causes progressive arterial stenosis and thrombosis and is composed of unique SMC-derived pathologic myofibroblasts.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lymphatic dissemination from the primary tumor is a major mechanism by which breast cancer cells access the systemic circulation, resulting in distant metastasis and mortality. Numerous studies link ...activation of hypoxia-inducible factor 1 (HIF-1) with tumor angiogenesis, metastasis, and patient mortality. However, the role of HIF-1 in lymphatic dissemination is poorly understood. In this study, we show that HIF-1 promotes lymphatic metastasis of breast cancer by direct transactivation of the gene encoding platelet-derived growth factor B (PDGF-B), which has proliferative and chemotactic effects on lymphatic endothelial cells. Lymphangiogenesis and lymphatic metastasis in mice bearing human breast cancer orthografts were blocked by administration of the HIF-1 inhibitor digoxin or the tyrosine kinase inhibitor imatinib. Immunohistochemical analysis of human breast cancer biopsies demonstrated colocalization of HIF-1α and PDGF-B, which were correlated with lymphatic vessel area and histological grade. Taken together, these data provide experimental support for breast cancer clinical trials targeting HIF-1 and PDGF-B.
Useful bio-products are obtainable viathe catalytic conversion of biomass or derived intermediates as renewable carbon sources. In particular, furanic ethers and levulinate esters (denoted bioEs) ...have wide application profiles and can be synthesised viaacid-catalysed reactions of intermediates such as fructose, 5-hydroxymethyl-2-furaldehyde (HMF) and furfuryl alcohol (FA) with ethanol. Solid acid catalysts are preferred for producing the bioEs with environmental benefits. Furthermore, the versatility of the catalyst in obtaining the bioEs from different intermediates is attractive for process economics, and in the case of porous catalysts, large pore sizes can be beneficial for operating in the kinetic regime. Carbon-based materials are attractive acid catalysts due to their modifiable surface, e.g. with relatively strong sulfonic acid groups (SO sub(3)H). Considering these aspects, here, we report the preparation of mesoporous (SO sub(3)H)-functionalised-carbon/silica (C/S) composites with large pores and high amounts of acid sites (up to 2.3 mmol g super(-1)), and their application as versatile solid acid catalysts for producing bioEs from fructose, HMF and FA. The mesoporous composites were prepared by activation of an organic compound deposited on the ordered mesoporous silicas MCF (mesostructured cellular foam) and SBA-15, where the organic compound (p-toluenesulfonic acid) acted simultaneously as the carbon and SO sub(3)H source. The atomic-level characterisation of the acid nature and strengths was performed by super(31)P solid-state NMR studies of an adsorbed base probe, in combination with FT-IR and XPS. Comparative catalytic studies showed that the C/S composites are interesting catalysts for obtaining bioEs in high yields, in comparison with classical solid acid catalysts such as sulfonic acid resin Amberlyst(TM)-15 and nanocrystalline (large pore) zeolite H-beta.
Purpose
The aim of our study is to analyse mid- to long-term severe adult spinal deformity (ASD) surgery outcomes by comparing three-column osteotomies (3CO) and multiple anterior interbody fusion ...cages (AC).
Materials and methods
The PRISMA flowchart was used to systematically review the literature. Only articles with a minimum 24-month follow-up were examined, and 11 articles were included. The following radiological parameters were observed: pelvic incidence (PI), pelvic tilt (PT), lumbar lordosis (LL), sagittal vertical axis (SVA), Cobb angle and T1-sacrum plumbline. Clinical outcome was assessed using the visual analogue scale (VAS) and Oswestry disability index (ODI) scores. The main complications were analysed, and the two groups were compared.
Results
Except for age, the two populations were homogeneous. Both techniques had the same number of posterior instrumented levels (7.4 ± 1.7). The AC group had a mean 3 ± 1.4 interbody fusions per patient. In the PSO group, all patients had 1 3CO and 89.8% of the osteotomies were performed at L2 or L3 vertebrae. No difference was observed between the two groups in terms of clinical outcomes. Both techniques were effective in sagittal parameters restoration with a final PI–LL mismatch = 4.4°. The PSO group had a statistically higher rate of intraoperative blood loss (
p
= 0.036), major complications, pseudoarthrosis and dural tears (
p
< 0.001).
Conclusion
Both PSO and multiple AC are effective in treating ASD. Multiple AC seems more suitable when treating older patients because of a lower intraoperative blood loss, lower rate of major complications and fewer number of revision surgeries.
Prior research has revealed a native-accent advantage, whereby nonnative-accented speech is more difficult to process than native-accented speech. Nonnative-accented speakers also experience more ...negative social judgments. In the current study, we asked three questions. First, does exposure to nonnative-accented speech increase speech intelligibility or decrease listening effort, thereby narrowing the native-accent advantage? Second, does lower intelligibility or higher listening effort contribute to listeners' negative social judgments of speakers? Third and finally, does increased intelligibility or decreased listening effort with exposure to speech bring about more positive social judgments of speakers? To address these questions, normal-hearing adults listened to a block of English sentences with a native accent and a block with nonnative accent. We found that once participants were accustomed to the task, intelligibility was greater for nonnative-accented speech and increased similarly with exposure for both accents. However, listening effort decreased only for nonnative-accented speech, soon reaching the level of native-accented speech. In addition, lower intelligibility and higher listening effort was associated with lower ratings of speaker warmth, speaker competence, and willingness to interact with the speaker. Finally, competence ratings increased over time to a similar extent for both accents, with this relationship fully mediated by intelligibility and listening effort. These results offer insight into how listeners process and judge unfamiliar speakers.
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