Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody-“decoy” strategy

MET, a master gene sustaining "invasive growth," is a relevant target for cancer precision therapy. In the vast majority of tumors, wild-type MET behaves as a "stress-response" gene and relies on the ligand (HGF) to sustain cell "scattering," invasive growth and apoptosis protection (oncogene "expedience"). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti-MET antibody (MvDN30) inducing "shedding" (i.e., removal of MET from the cell surface), with a "decoy" (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction-and subsequent neutralization-we identified a single aminoacid in the extracellular domain of MET-lysine 842-that is critical for MvDN30 binding and engineered the corresponding recombinant decoyMET (K842E). DecoyMET(K842E) retains the ability to bind HGF with high affinity and inhibits HGF-induced MET phosphorylation. In HGF-dependent cellular models, MvDN30 antibody and decoyMET(K842E) used in combination cooperate in restraining invasive growth, and synergize in blocking cancer cell "scattering." The antibody and the decoy unbridle apoptosis of colon cancer stem cells grown in vitro as spheroids. In a preclinical model, built by orthotopic transplantation of a human pancreatic carcinoma in SCID mice engineered to express human HGF, concomitant treatment with antibody and decoy significantly reduces metastatic spread. The data reported indicate that vertical targeting of the MET/HGF axis results in powerful inhibition of ligand-dependent MET activation, providing proof of concept in favor of combined target therapy of MET "expedience.

Renal tubular function in children and adolescents with Gitelnian's syndrome, the hypocalciuric variant of Bartter's syndrome

Renal tubular function was studied in 14 patients with Gitelman's syndrome and 14 control subjects. Apart from the biochemical hallmarks of Gitelman's syndrome, namely alkalaemia, hyperbi carbonataemia, hypokalaemia, hypomagnesaemia (with increased magnesium over creatinine ratio), increased urinary chloride over creatinine ratio, and low urinary calcium over creatinine, the patients were found to have hyperproteinaemia, hypochloraemia, high total plasma calcium concentration, reduced plasma ionized calcium concentration, and high urinary sodium excretion. A statistically significant negative linear relationship between plasma magnesium concentration and magnesium excretion corrected for glomerular filtration was observed in patients. The fractional calcium clearance and the urinary excretion of calcium corrected for glomerular filtration was significantly decreased in patients. In patients the urin ary osmolality after overnight water deprivation ranged from 526 to 1067 mmol/kg. Glucosuria and aminoacid uria were similar in patients and controls. The results of the study demonstrate the renal origin of hypomag nesaemia and hypocalciuria in Gitelman's syndrome. The failure to demonstrate hyperaminoaciduria, hyperglucosuria, hyperphosphaturia, hyperuricosuria, and severely impaired urinary concentrating ability provide evidence for a defect residing in the distal convoluted tubul

From pre-and probiotics to post-biotics: A narrative review

Background and aims: Gut microbiota (GM) is a complex ecosystem containing bacteria, viruses, fungi, and yeasts. It has several functions in the human body ranging from immunomodulation to metabolic. GM derangement is called dysbiosis and is involved in several host diseases. Pre-, probiotics, and symbiotics (PRE-PRO-SYMB) have been extensively developed and studied for GM re-modulation. Herein, we review the literature data regarding the new concept of postbiotics, starting from PRE-PRO-SYMB. Methods: We conducted a search on the main medical databases for original articles, reviews, meta-analyses, randomized clinical trials, and case series using the following keywords and acronyms and their associations: Gut microbiota, prebiotics, probiotics, symbiotic, and postbiotics. Results: Postbiotics account for PRO components and metabolic products able to beneficially affect host health and GM. The deeper the knowledge about them, the greater their possible uses: The prevention and treatment of atopic, respiratory tract, and inflammatory bowel diseases. Conclusions: Better knowledge about postbiotics can be useful for the prevention and treatment of several human body diseases, alone or as an add-on to PRE-PRO-SYMB

Oxidative inactivation of SARS-CoV-2 on photoactive AgNPs@Tio2 ceramic tiles

The current SARS-CoV-2 pandemic causes serious public health, social, and economic issues all over the globe. Surface transmission has been claimed as a possible SARS-CoV-2 infection route, especially in heavy contaminated environmental surfaces, including hospitals and crowded public places. Herein, we studied the deactivation of SARS-CoV-2 on photoactive AgNPs@TiO2 coated on industrial ceramic tiles under dark, UVA, and LED light irradiations. SARS-CoV-2 inactivation is effective under any light/dark conditions. The presence of AgNPs has an important key to limit the survival of SARS-CoV-2 in the dark; moreover, there is a synergistic action when TiO2 is decorated with Ag to enhance the virus photocatalytic inactivation even under LED. The radical oxidation was confirmed as the the central mechanism behind SARS-CoV-2 damage/inactivation by ESR analysis under LED light. Therefore, photoactive AgNPs@TiO2 ceramic tiles could be exploited to fight surface infections, especially during viral severe pandemics

Antiplasmodial triterpenoids from the fruits of neem, Azadirachta indica.

J Nat Prod. 2010 Aug 27;73(8):1448-52. Antiplasmodial triterpenoids from the fruits of neem, Azadirachta indica. Chianese G, Yerbanga SR, Lucantoni L, Habluetzel A, Basilico N, Taramelli D, Fattorusso E, Taglialatela-Scafati O. Abstract Eight known and two new triterpenoid derivatives, neemfruitins A (9) and B (10), have been isolated from the fruits of neem, Azadirachta indica, a traditional antimalarial plant used by Asian and African populations. In vitro antiplasmodial tests evidenced a significant activity of the known gedunin and azadirone and the new neemfruitin A and provided useful information about the structure-antimalarial activity relationships in the limonoid class

VALUTAZIONE DELL'ESPOSIZIONE AD AGENTI MICROBICI AERODISPERSI IN 5 IMPIANTI LOMBARDI DI TRATTAMENTO DELLE ACQUE REFLUE URBANE, DIVERSI PER CAPACITA' NOMINALE E CARATTERISTICHE TECNICO-STRUTTURALI

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Effect of hypoxia on gene expression in cell populations involved in wound healing

Wound healing is a complex process regulated by multiple signals and consisting of several phases known as haemostasis, inflammation, proliferation, and remodelling. Keratinocytes, endothelial cells, macrophages, and fibroblasts are the major cell populations involved in wound healing process. Hypoxia plays a critical role in this process since cells sense and respond to hypoxic conditions by changing gene expression. This study assessed the in vitro expression of 77 genes involved in angiogenesis, metabolism, cell growth, proliferation and apoptosis in human keratinocytes (HaCaT), microvascular endothelial cells (HMEC-1), differentiated macrophages (THP-1), and dermal fibroblasts (HDF). Results indicated that the gene expression profiles induced by hypoxia were cell-type specific. In HMEC-1 and differentiated THP-1, most of the genes modulated by hypoxia encode proteins involved in angiogenesis or belonging to cytokines and growth factors. In HaCaT and HDF, hypoxia mainly affected the expression of genes encoding proteins involved in cell metabolism. This work can help to enlarge the current knowledge about the mechanisms through which a hypoxic environment influences wound healing processes at the molecular level

To explore or to exploit? Learning humans' behaviour to maximize interactions with them

Assume a robot operating in a public space (e.g., a library, a museum) and serving visitors as a companion, a guide or an information stand. To do that, the robot has to interact with humans, which presumes that it actively searches for humans in order to interact with them. This paper addresses the problem how to plan robot's actions in order to maximize the number of such interactions in the case human behavior is not known in advance. We formulate this problem as the exploration/exploitation problem and design several strategies for the robot. The main contribution of the paper than lies in evaluation and comparison of the designed strategies on two datasets. The evaluation shows interesting properties of the strategies, which are discussed

Target-Oriented Development Of Novel Antiprotozoal Agents: Celastrol Carboxamides As Inhibitors Of Leishmania Hsp90

The Leishmania isoform of the 90kDa Heat Shock Protein (LsHsp90), a chaperone known to assist the folding of more than 200 client proteins, was reported to be generally involved in parasite differentiation from promastigote to amastigote possessing a pivotal role during heat-induced cellular stress. Moreover, it was demonstrated that an impair of the native functions of LsHsp90 through the action of active-site inhibitors can exert a detrimental effect on the natural parasite life-cycle ultimately leading to its death. Celastrol is natural triterpene exhibiting a plethora of in vitro and in vivo activities. Among them, this pentacyclic compound is reported to possess a promising antiproliferative activity thanks to its ability of interacting with the chaperone cycle of the human isoform of Hsp90 (hHsp90). Moreover, celastrol derivatives (e.g. the methyl ester pristimerin, Figure 1) have also exhibited an interesting antiprotozoal activity. With the aim of building a target-oriented approach to treat Leishmania infections based on the inhibition of LsHsp90, we prepared two basic carboxamides celastrol derivatives (SS-1 and SS-2) to enhance its leishmanicidal activity and selectivity of action by deducting its unspecific cytotoxicity (measured as IC50 on HMEC-1 cell lines). Accordingly, celastrol and the two basic derivatives SS-1 and SS-2 were in vitro tested for their leishmanicidal activity against promastigotes of Leishmania tropica and L. infantum and, in parallel, their mechanism of action was investigated as well via ad hoc in vitro experiments using a recombinant Hsp90 from L. braziliensis (LbHsp90). In virtue of their pH sensitive basic heads, both SS-1 and SS-2 were found to be more potent (IC50 in the nanomolar range) and selective leishmanicidal agents than celastrol itself. Furthermore, we were able to demonstrate that SS-1 and SS-2 successfully (in vitro) inhibited the native kinase activity of LbHsp90 highlighting the key role of the inhibition of this chaperone in their mechanism of action