MYC is a transcription factor that can activate transcription of several targets by direct binding to their promoters at specific DNA sequences (E-box).
Recent findings have also shown that it can ...exert its biological role by repressing transcription of other set of genes. C-MYC can mediate repression on its target genes through interaction with factors bound to promoter regions but not through direct recognition of typical E-Boxes.
In this thesis, we investigated whether MYCN can also repress gene transcription and how this is mechanistically achieved.
Moreover, expression of TRKA, P75NTR and ABCC3 is attenuated in aggressive MYCN-amplified tumors, suggesting a causal link between elevated MYCN activity and transcriptional repression of these three genes.
We found that MYCN is physically associated with gene promoters in vivo in proximity of the transcriptional start sites and this association requires interactions with SP1 and/or MIZ-1.
Furthermore, we show that this interaction could interfere with SP1 and MIZ-1 activation functions by recruiting co-repressors such as DNMT3a or HDACs.
Studies in vitro suggest that MYCN interacts through distinct domains with SP1, MIZ-1 and HDAC1 supporting the idea that MYCN may form different complexes by interacting with different proteins.
Re-expression of endogenous TRKA and P75NTR with exposure to the TSA sensitizes neuroblastoma to NGF-mediated apoptosis, whereas ectopic expression of ABCC3 decreases cell motility without interfering with growth.
Finally, using shRNA whole genome library, we dissected the P75NTR repression trying to identify novel factors inside and/or outside MYCN complex for future therapeutic approaches.
Overall, our results support a model in which MYCN can repress gene transcription by direct interaction with SP1 and/or MIZ-1, and provide further lines of evidence on the importance of transcriptional repression induced by Myc in tumor biology.
EBV produces miRNAs with important functions in cancer growth, tumor invasion and host immune surveillance. The discovery of EBV miR-BARTs is recent, and most of their functions are still unknown. ...Nonetheless, some new studies underline their key roles in EBV-associated malignancies.
In EBV-associated tumors, the expression profile of miR-BARTs varies according to the cell type, autophagic process and signals received from the tumor microenvironment. By the same way of interest is the interaction between tumor cells and the tumor environment by the release of selected EBV miR-BARTs in addition to the tumor proteins trough tumor exosomes.
In this review, we discuss new findings regarding EBV miR-BARTs in Hodgkin lymphoma and gastric cancer. The recent discovery that miRNAs are released by exosomes, including miR-BARTs, highlights the importance of tumor and microenvironment interplay with more specific effects on the host immune response.
Currently-available therapies for newly-diagnosed pediatric and adolescent patients with Hodgkin lymphoma result in >95% survival at 5 years. Long-term survivors may suffer from long-term ...treatment-related side effects, however, so the past 20 years have seen clinical trials for children and adolescents with HL gradually abandon the regimens used in adults in an effort to improve this situation. Narrower-field radiotherapy can reduce long-term toxicity while maintaining good tumor control. Various risk-adapted chemo-radiotherapy strategies have been used. Early assessment of tumor response with interim positron emission tomography and/or measuring metabolic tumor volume has been used both to limit RT in patients with favorable characteristics and to adopt more aggressive therapies in patients with a poor response. Most classical Hodgkin's lymphoma relapses occur within 3 years of initial treatment, while relapses occurring 5 years or more after diagnosis are rare. As the outcome for patients with relapsed/refractory classical Hodgkin lymphoma remains unsatisfactory, new drugs have been proposed for its prevention or treatment. This review summarizes the important advances made in recent years in the management of pediatric and adolescent with classical Hodgkin lymphoma, and the novel targeted treatments for relapsed and refractory classical Hodgkin lymphoma.
Abstract
Background
Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients.
Objectives
To evaluate the pharmacokinetics of ...remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients.
Methods
Remdesivir was administered at 200 mg loading dose on the first day followed by 12 days of 100 mg in two critically ill patients. Blood samples were collected immediately after (C0) and at 1 (C1) and 24 h (C24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method.
Results
We observed higher concentrations of remdesivir at C0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C1. GS-441524 plasma concentrations reached a peak at C1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure.
Conclusions
We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.
During aging, bone marrow mesenchymal stromal cells (MSCs)-the precursors of osteoblasts-undergo cellular senescence, losing their osteogenic potential and acquiring a pro-inflammatory secretory ...phenotype. These dysfunctions cause bone loss and lead to osteoporosis. Prevention and intervention at an early stage of bone loss are important, and naturally active compounds could represent a valid help in addition to diet. Here, we tested the hypothesis that the combination of two pro-osteogenic factors, namely orthosilicic acid (OA) and vitamin K2 (VK2), and three other anti-inflammatory compounds, namely curcumin (CUR), polydatin (PD) and quercetin (QCT)-that mirror the nutraceutical BlastiMin Complex
(Mivell, Italy)-would be effective in promoting MSC osteogenesis, even of replicative senescent cells (sMSCs), and inhibiting their pro-inflammatory phenotype in vitro. Results showed that when used at non-cytotoxic doses, (i) the association of OA and VK2 promoted MSC differentiation into osteoblasts, even when cultured without other pro-differentiating factors; and (ii) CUR, PD and QCT exerted an anti-inflammatory effect on sMSCs, and also synergized with OA and VK2 in promoting the expression of the pivotal osteogenic marker ALP in these cells. Overall, these data suggest a potential role of using a combination of all of these natural compounds as a supplement to prevent or control the progression of age-related osteoporosis.
Abstract Since spring 2022, the global epidemiology of the monkeypox virus (MPXV) has changed. The unprecedented increase of human clade II MPXV cases worldwide heightened concerns about this ...emerging zoonotic disease. We analysed the positivity rates, viral loads, infectiousness, and persistence of MPXV DNA for up to 4 months in several biological samples from 89 MPXV-confirmed cases. Our data showed that viral loads and positivity rates were higher during the first two weeks of symptoms for all sample types. Amongst no-skin-samples, respiratory specimens showed higher MPXV DNA levels and median time until viral clearance, suggesting their usefulness in supporting MPXV diagnosis, investigating asymptomatic patients, and monitoring viral shedding. Infectious virus was cultured from respiratory samples, semen, and stools, with high viral loads and collected within the first 10 days. Notably, only one saliva and one semen were found positive for viral DNA after 71 and 31 days from symptoms, respectively. The focus on bloodstream samples showed the best testing sensitivity in plasma, reporting the overall highest MPXV DNA detection rate and viral loads during the 3-week follow-up as compared to serum and whole-blood. The data here presented can be useful for MPXV diagnostics and a better understanding of the potential alternative routes of its onward transmission.
In recent years, camera and computer systems have been miniaturized considerably. The market now offers several low-cost products to assemble a small scale portable stereo vision system which can be ...completely autonomous (since it can acquire and process image). However, the metrological characteristics of such a portable stereo vision device should be assessed and compared with the state of the art of stereo vision system. In this work a portable stereo vision system composed by small board cameras and a single board computer is metrologically characterized and validated with respect to fixed non-portable systems. The analysis focused on the application of such a stereo rig to DIC and stereoscopic measurements performed with commercial software. For these tests two algorithms with different correlation techniques are evaluated in Matlab and in Halcon, moreover, a 3D DIC analysis is conducted on a H-shape specimen. To perform a metrological characterization, the points clouds obtained from the triangulations are confined to a region of the scene containing only a part of the specimen, after that they are fitted with a LOWESS fitting model. The uncertainty is assessed by computing the discrepancy between the points of the cloud and the ones of the fitting model. In some algorithms more than others the errors distribute in a strongly periodic manner with a period linked to integer values of disparity. Eventually the experimental analysis demonstrated that the accuracy of such a lightweight stereo system is similar to the accuracy of traditional not-portable ones.
The use of endoscopic techniques to cure small sized, well differentiated early gastric cancer has been adopted worldwide. In the Eastern world, endoscopic resection is being increasingly utilized to ...treat small undifferentiated early gastric cancer according to the extended criteria proposed by the Japanese Gastric Cancer Associations. However, studies in the Western world reported in these tumors a rate of nodal metastasis ranging between 5% and 20%, that is higher of those observed in Eastern counterparts. A tool to predict the risk of nodal dissemination would be of great use to guide treatment toward endoscopic resection. In our study, we propose E-cadherin expression as a biological factor to predict lymph node involvement. We retrospectively reviewed the E-cadherin (E-cad) expression profile of all histological specimens of undifferentiated early gastric cancer from two Oncologic Departments and compared it with several tumor characteristics. A total of 39 patients with early gastric cancer met the inclusion criteria, of which 16 (41%) pT1a, and 23 (58.9%) pT1b SM1. Thirty-two patients (82%) underwent subtotal gastrectomy, whereas total gastrectomy was performed in only seven cases (17.9%). Patients were divided into two groups: low E-cad expression (E-cad 0/1+, 10 patients) and high E-cad expression (E-cad 2+/3+, 29 patients) according to the immunohistochemical assay (ICH). On univariate analysis, we found an association between low E-cad expression and low grading tumor (p = 0.019), pure undifferentiated histotype (PU-type) (p = 0.014), and lymph node involvement (N+) (p < 0.001). The association between low E-cad expression and lymph node metastasis was confirmed by multivariate analysis (OR = 14.5, 95% CI 3.46-60.76, p < 0.001). The loss of expression of E-cad may be a simple biological factor to predict lymph nodes metastasis in patients with undifferentiated early gastric cancer. Additional larger prospective studies are necessary to confirm these findings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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