Conjugated metallothionein-carbon-doxorubicin nanotransporter for targeted breast cancer therapy.

Metalothionein (MT) is a polypeptide of molecular weight in the range of 6-10 kDa. MT typically contains 60 to 68 amino acid residues. MT is characterized by its unique content of metal ions as well as its sulfur content. Higher MT levels were observed in proliferating cells. This fact demonstrates the importance of MT in the process of cellular regulation (relationship to cancer). The most widely used drug for patients with breast cancer metastases is an anthracycline antitumor antibiotic doxorubicin (DOX). However, the clinical use of DOX is limited by dose-related heart muscle damage (cardiomyopathy), more prevalent with increasing cumulative doses. For this reason, creation of novel pharmaceutical formulations based on using alternative methods as nanocarriers for targeted drug delivery to tumour cells is a crucial task in modern pharmacology. The aim of this work was to design a nanotechnological construct. The construct is designed as two separate nanotransporters. The nanotransporter (A) is formed by an antibody-modified AgNPs particle and a carbon nanotube with encapsulated DOX (AgNPs/Ab1/MWCNT/DOX/ODN1). The nanotransporter (B) is engineered with SPION particle modified with antibody and with bound MT (SPION/Ab2/MT/ODN2). Construct AgNPs/Ab1/MWCNT/DOX/ODN1-SPION/Ab2/MT/ODN2 is formed using an oligonucleotide anchor. Individual parts of the nanotransporter were studied using appropriate methods. The presence of MT was monitored electrochemically by Brdicka method in connection with the transfer technique (AdTSV). Characteristic MT signals RS2CO (-1.15 V), Cat1 (-1.25 V), Cat2 (-1.45 V), Cat3 (-1.75 V) were observed at accumulation time of 120s. SDS PAGE confirmed the presence of MT on SPION nanoparticles at sizes 7 to 15 kDa. The DOX signal was fluorometrically monitored (Em 590 nm, Ex 490 nm). AgNPs sizes ranged from 15-20 nm, and the SPION nanoparticles ranged from 20-50 nm. Additionally, used AgNPs nanoparticles exhibited significant antiproliferative activity (growth inhibition by 20-40%) on a model culture S. Cerevisiae. Created nanoconstruct A showed growth inhibition for S. Cerevisiae by more than 50%. The nanoconstruct after these various analysis shows a high potential as an anticancer drug and may be an innovative way how to deal with the breast cancer in a targeted therapy

Les effets de la caféine sur un épisode de sommeil nocturne et un épisode de sommeil de récupération de jour

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

Mapping the entrepreneurial university literature: a text mining approach

Since the introduction of the concept of entrepreneurial university in 1980s, the number of studies has dramatically increased, in particular since 2015. This had made the literature on the entrepreneurial university complex, fragmented and difficult to navigate. This paper provides a comprehensive review of all topics covered in the body of literature on the entrepreneurial university and identifies the most salient topics and papers within this literature, making use of text-mining techniques. Our paper employs topic modelling that reveals the underlying semantic structure of texts to identify the different underlying. Our study systematically analyses 1,110 papers over the period 1983–2020 using the Latent Dirichlet Allocation algorithm. Our analysis shows that the entrepreneurial university is fragmented around different topics that are very diverse. We find a total of 20 differentiated topics. Our study suggests that topics related to the overarching theme of academic entrepreneurship, in particular to commercialisation of research and the triple helix model are very popular within the entrepreneurial university literature. Finally, our analysis reveals that case-study type of research is losing momentum, giving path to nascent topics of research in the areas of entrepreneurial capability and university-industry alliances, which are becoming very popular within the entrepreneurial university literature

Mapping the entrepreneurial university literature: A text mining approach

Since the introduction of the concept of entrepreneurial university in 1980’s, the number of studies has dramatically increased, in particular since 2015. This had made the literature on the entrepreneurial university complex, fragmented and difficult to navigate. This paper provides a comprehensive review of all topics covered in the body of literature on the entrepreneurial university and identifies the most salient topics and papers within this literature, making use of text-mining techniques. Our paper employs topic modelling that reveals the underlying semantic structure of texts to identify the different underlying. Our study systematically analyses 1,110 papers over the period 1983-2020 using the Latent Dirichlet Allocation algorithm. Our analysis shows that the entrepreneurial university is fragmented around different topics that are very diverse. We find a total of 20 differentiated topics. Our study suggests that topics related to the overarching theme of academic entrepreneurship, in particular to commercialisation of research and the triple helix model are very popular within the entrepreneurial university literature. Finally, our analysis reveals that case-study type of research is losing momentum, giving path to nascent topics of research in the areas of entrepreneurial capability and university-industry alliances, which are becoming very popular within the entrepreneurial university literature

Zinc-modified nanotransporter of doxorubicin for targeted prostate cancer delivery.

This work investigated the preparation of chitosan nanoparticles used as carriers for doxorubicin for targeted cancer delivery. Prepared nanocarriers were stabilized and functionalized via zinc ions incorporated into the chitosan nanoparticle backbone. We took the advantage of high expression of sarcosine in the prostate cancer cells. The prostate cancer targeting was mediated by the AntiSar antibodies decorated surface of the nanocage. Formation of the chitosan nanoparticles was determined using a ninhydrin assay and differential pulse voltammetry. Obtained results showed the strong effect of tripolyphosphine on the nanoparticle formation. The zinc ions affected strong chitosan backbone coiling both in inner and outer chitosan nanoparticle structure. Zinc electrochemical signal depended on the level of the complex formation and the potential shift from -960 to -950 mV. Formed complex is suitable for doxorubicin delivery. It was observed the 20% entrapment efficiency of doxorubicin and strong dependence of drug release after 120 min in the blood environment. The functionality of the designed nanotransporter was proven. The purposed determination showed linear dependence in the concentration range of Anti-sarcosine IgG labeled gold nanoparticles from 0 to 1000 µg/mL and the regression equation was found to be y = 3.8x - 66.7 and R2 = 0.99. Performed ELISA confirmed the ability of Anti-sarcosine IgG labeled chitosan nanoparticles with loaded doxorubicin to bind to the sarcosine molecule. Observed hemolytic activity of the nanotransporter was 40%. Inhibition activity of our proposed nanotransporter was evaluated to be 0% on the experimental model of S. cerevisiae. Anti-sarcosine IgG labeled chitosan nanoparticles, with loaded doxorubicin stabilized by Zn ions, are a perspective type of nanocarrier for targeted drug therapy managed by specific interaction with sarcosine and metallothionein for prostate cancer

Zinc-modified nanotransporter of doxorubicine for multi-targeted therapy of prostate cancer cells.

Target therapy for oncologic diseases presents a big challenge for advance nanomedicine. In our work, we focused on multi-target approach development. Designed nanotransporter is based on polysaccharide chitosan which allows formation of nanoparticles. These nanoparticles can bind metal ions, mainly zinc (moreover, zinc stabilizes chitosan structure). The estimated zinc concentration was approximately 1 nmol/g of chitosan. In addition, chitosan nanoparticle (cage) irreversibly binds therapeutics which could be applied for targeted therapy of malignant tumours. Designed chitosan structure (LMQ, 10 g) encapsulation efficiency for doxorubicin was 50%. The pH change (tested interval 5 - 8) caused 20% release of doxorubicin from the nanocage. The nanotransporter is orientated to cancer tissue due the fact that the malignant cells highly express metallothionein (MT). The increased affinity of MT to zinc ions causes that the nanotransporter is preferentially bound to tumour regions with a high MT concentration. Our latest experimental results showed the changes in amino acid metabolism of prostate cancer signalized by increase in the amount of amino acid sarcosine. Therefore, the chitosan-based nanotransporter was modified by anti-sarcosine antibody. The functionality of designed nanotransporter was proved by ELISA with double detection of doxorubicin using fluorescence and by peroxidase activity of ABTS substrate. In another system, magnetic separation and identification of individual components of the nanotransporter were used. The sarcosine binding activity was estimated around 50%

Impact of sarcopenia and frailty in a multicenter cohort of polypathological patients

The prevalence, relationships and outcomes of sarcopenia and frailty in polypathological patients remain unknown. We performed a multicenter prospective observational study in six hospitals in order to assess prevalence, clinical features, outcome and associated risk factors of sarcopenia and frailty in a hospital-based population of polypathological patients. The cohort was recruited by performing prevalence surveys every 14 days during the inclusion period (March 2012-June 2016). Sarcopenia was assessed by means of EWGSOP criteria and frailty by means of Fried''s criteria. Skeletal muscle mass was measured by tetrapolar bioimpedanciometry. All patients were followed for 12 months. Factors associated with sarcopenia, frailty and mortality were analyzed by multivariate logistic regression, and Kaplan-Meier curves. A total of 444 patients (77.3 +/- 8.4 years, 55% males) were included. Sarcopenia was present in 97 patients (21.8%), this being moderate in 54 (12.2%), and severe in 43 (9.6%); frailty was present in 278 patients (62.6%), and 140 (31.6%) were pre-frail; combined sarcopenia and frailty were present in the same patient in 80 (18%) patients. Factors independently associated to the presence of both, sarcopenia and frailty were female gender, older age, different chronic conditions, poor functional status, low body mass index, asthenia and depressive disorders, and low leucocytes and lymphocytes count. Mortality in the 12-months follow-up period was 40%. Patients with sarcopenia, frailty or both survived significantly less than those without these conditions. Sarcopenia and frailty are frequent and interrelated conditions in polypathological patients, shadowing their survival. Their early recognition and management could improve health-related outcomes in this population

Tenofovir Nephrotoxicity: 2011 Update

Tenofovir is an acyclic nucleotide analogue reverse-transcriptase inhibitor structurally similar to the nephrotoxic drugs adefovir and cidofovir. Tenofovir is widely used to treat HIV infection and approved for treatment of hepatitis B virus. Despite initial cell culture and clinical trials results supporting the renal safety of tenofovir, its clinical use is associated with a low, albeit significant, risk of kidney injury. Proximal tubular cell secretion of tenofovir explains the accumulation of the drug in these mitochondria-rich cells. Tenofovir nephrotoxicity is characterized by proximal tubular cell dysfunction that may be associated with acute kidney injury or chronic kidney disease. Withdrawal of the drug leads to improvement of analytical parameters that may be partial. Understanding the risk factors for nephrotoxicity and regular monitoring of proximal tubular dysfunction and serum creatinine in high-risk patients is required to minimize nephrotoxicity. Newer, structurally similar molecular derivatives that do not accumulate in proximal tubules are under study

Epigenetic modifiers as potential therapeutic targets in diabetic kidney disease

Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio-and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.This research was funded by FIS/FEDER funds (PI15/00298, CP14/00133, PI16/01900, PI18/01386, PI18/0133, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071), ISCIII-RETIC REDinREN RD016/0009), Sociedad Española de Nefrología, FRIAT, Comunidad de Madrid en Biomedicina B2017/BMD- 3686 CIFRA2-CM. Salary support: ISCIII Miguel Servet to ABS and MDS-N, ISCIII Sara Borrell to JM-MM, REDinREN RD016/0009 to MF-B, and MICIU to JG-M

Spleen-Dependent Immune Protection Elicited by CpG Adjuvanted Reticulocyte-Derived Exosomes from Malaria Infection Is Associated with Changes in T cell Subsets' Distribution

Added corrigendum published in 2017-01-17 https://doi.org/10.3389/fcell.2016.00153Reticulocyte-derived exosomes (rex) are 30-100 nm membrane vesicles of endocytic origin released during the maturation of reticulocytes to erythrocytes upon fusion of multivesicular bodies with the plasma membrane. Combination of CpG-ODN with rex obtained from BALB/c mice infected with the reticulocyte-prone non-lethal P. yoelii 17X malaria strain (rexPy), had been shown to induce survival and long lasting protection. Here, we show that splenectomized mice are not protected upon rexPy+CpG inmunizations and that protection is restored upon passive transfer of splenocytes obtained from animals immunized with rexPy+CpG. Notably, rexPy immunization of mice induced changes in PD1- memory T cells with effector phenotype. Proteomics analysis of rexPy confirmed their reticulocyte origin and demonstrated the presence of parasite antigens. Our studies thus prove, for what we believe is the first time, that rex from reticulocyte-prone malarial infections are associated with splenic long-lasting memory responses. To try extrapolating these data to human infections, in vitro experiments with spleen cells of human transplantation donors were performed. Plasma-derived exosomes from vivax malaria patients (exPv) were actively uptaken by human splenocytes and stimulated spleen cells leading to changes in T cell subsets