TRPML2 Mucolipin Channels Drive the Response of Glioma Stem Cells to Temozolomide and Affect the Overall Survival in Glioblastoma Patients

The survival of patients with glioblastoma (GBM) is poor. The main cause is the presence of glioma stem cells (GSCs), exceptionally resistant to temozolomide (TMZ) treatment. This last may be related to the heterogeneous expression of ion channels, among them TRPML2. Its mRNA expression was evaluated in two different neural stem cell (NS/PC) lines and sixteen GBM stem-like cells by qRT-PCR. The response to TMZ was evaluated in undifferentiated or differentiated GSCs, and in TRPML2-induced or silenced GSCs. The relationship between TRPML2 expression and responsiveness to TMZ treatment was evaluated by MTT assay showing that increased TRPML2 mRNA levels are associated with resistance to TMZ. This research was deepened by qRT-PCR and western blot analysis. PI3K/AKT and JAK/STAT pathways as well as ABC and SLC drug transporters were involved. Finally, the relationship between TRPML2 expression and overall survival (OS) and progression-free survival (PFS) in patient-derived GSCs was evaluated by Kaplan–Meier analysis. The expression of TRPML2 mRNA correlates with worse OS and PFS in GBM patients. Thus, the expression of TRPML2 in GSCs influences the responsiveness to TMZ in vitro and affects OS and PFS in GBM patients.     

Truncated Analogues of a G-Quadruplex-Forming Aptamer Targeting Mutant Huntingtin: Shorter Is Better!

Two analogues of the MS3 aptamer, which was previously shown to have an exquisite capability to selectively bind and modulate the activity of mutant huntingtin (mHTT), have been here designed and evaluated in their physicochemical and biological properties. Featured by a distinctive propensity to form complex G-quadruplex structures, including large multimeric aggregates, the original 36-mer MS3 has been truncated to give a 33-mer (here named MS3-33) and a 17-mer (here named MS3-17). A combined use of different techniques (UV, CD, DSC, gel electrophoresis) allowed a detailed physicochemical characterization of these novel G-quadruplex-forming aptamers, tested in vitro on SH-SY5Y cells and in vivo on a Drosophila Huntington’s disease model, in which these shorter MS3-derived oligonucleotides proved to have improved bioactivity in comparison with the parent aptamer.     

Cooperation and cooperator modeling

In this text, we argue that user modeling and system modeling should be taken into account at the same time to allow cooperativity: they are two sides of a same interaction. We focus on interlocutor modeling (the human-human homonym of user modeling) and develop three situations where interlocutor modeling is crucial: when there is a need of transforming the beliefs of the cooperator (when there is a knowledge gap or a resistance), when the interpretation of the cooperator's communication act is ambiguous and relies on implicit meaning, and when there is a specific need need of anticipating the other's understanding (in risky or irreversible situations).     

Eosinophils and serum eosinophilic cationic proteins in interleukin-2-based immunotherapy for cancer

BACKGROUND: Extramedullary hematopoiesis (EMH) occurs in many disorders, including thalassemias and other hemoglobinopathies, and commonly presents in the spleen and liver. We present a case of spinal cord compression in a patient with beta-thalassemia intermedia, and review the literature and available treatment options. PATIENT AND METHODS: A 35-year-old black female with beta-thalassemia intermedia presented with a 3-week history of back pain and lower extremity weakness. Neurologic examination was consistent with spinal cord compression, and gadolinium enhanced magnetic resonance imaging (MRI) confirmed this diagnosis. She was given intravenous steroids and radiotherapy was begun in 200 cGy fractions to a total dose of 2000 cGy. RESULTS: At the completion of radiotherapy the patient was ambulatory with mild residual weakness. MRI scans 16 months later showed smaller, but persistent masses, and she remains asymptomatic 5 years from her diagnosis. CONCLUSION: Recognition of spinal cord EMH requires prompt physical examination and MRI for accurate diagnosis. EMH can be managed with radiation, surgery, transfusions, or a combination of these therapies. Radiation in conservative doses of (750-3500 cGy) is non-invasive, avoids the surgical risks of potentially severe hemorrhage and incomplete resection, and has a high complete remission rate in the majority of patients. Relapse rates are moderate (37.5%), but retreatment provides excellent chance for second remission.     

Sourdough in gluten-free bread-making: An ancient technology to solve a novel issue?

The increasing demand for high quality gluten-free (GF) bread, clean labels and natural products is raising the need for new approaches in GF bread-making. Sourdough is the foremost fermentation used for baking purposes and it has been proven to be ideal for improving the texture, palatability, aroma, shelf life and nutritional value of wheat and rye breads. These characteristic features derive from the complex metabolic activities of the sourdough-resident lactic acid bacteria and yeasts, e.g. acidification, production of exopolysaccharides, proteolytic- amylolytic- and phytase activity, and production of antimicrobial substances. These effects have been extensively studied and well described for traditional baking, whereas little is known about the role of sourdough in GF baking. Yet, the microbiological and qualitative characterisation of local GF fermented products indicate an overlap with the microbiota of wheat/rye fermentation and suggest that the positive metabolic activities of the sourdough microbiota are still retained during fermentation of GF crops. Thus, the use of sourdough in GF baking may be the new frontier for improving the quality, safety and acceptability of GF bread.     

Machining Planning for Tolerance Synthesis

The present paper deals with the preliminary study and the prototypical implementation of an expert system to quickly define an high level manufacturing sequence able to produce the assigned part tolerances. To do so, the expert system simulates the human reasoning process by applying specific knowledge and inferences. An assembly that is widely used to test the performances of different design methods represents the case study. This module belongs to a flexible and integrated environment that aims to automatically define both the tolerance specifications and the related process plan. Its aim is to support the designer during the definition of a functional project.     

Anodic synthesis of sulfur-bridged polyaniline coatings onto Fe sheets

Sulfur-bridged polyaniline coatings are obtained onto Fe anodes by electrolyzing a basic solution of one aniline and ammonium sulfide. Their sulfur content ranges from 7% to 17%, depending on the substituents on aniline. Variously substituted anilines may be polymerized in this way and coating pollution by azobenzene formed in a side reaction is almost completely avoided. Sulfur probably enters the polymer chains through a free radical mechanism. HS^? intermediates being formed by both homogeneous and anodic oxidation of HS^? anions. Coatings from N-allylaniline, being thermally curable, show satisfactory physical properties.     

Echocardiographic evidence for a direct effect of GH/IGF-I hypersecretion on cardiac mass and function in young acromegalics

Although association of HLA-B27 with human spondyloarthropathies has been known for several years, its role in disease pathogenesis is not understood. Recently, a few investigators have proposed that presentation of B27-derived peptides by MHC class II molecules may be the underlying mechanism. HLA-B27 transgenic rat and mouse models have provided a new tool for understanding the exact role of B27 in disease pathogenesis. HLA-B27 mice lacking endogenous beta2-microglobulin (B27+ beta2m(o)) develop disease after they are transferred from the barrier facility to the conventional colony. This model was utilized to test the hypothesis that B27-derived peptide presented by MHC class II molecules is the cause of the disease. The MHC class II knockout gene, A beta(o), was bred into our B27+ beta2m(o) mice, and disease manifestation was monitored. These mice develop spontaneous disease, demonstrating that MHC class II molecules do not play a major role in B27-related disease. Thus, the disease is not manifested by presentation of B27-derived peptides by class II molecules, since these mice are devoid of H2-A and H2-E molecules. Furthermore, in vivo treatment with mAb against the heavy chain of B27 reduced the incidence of disease in B27+ beta2m(o) mice. Our results clearly demonstrate that B27 heavy chains are directly involved in the disease process.     

Development of an integrated two stage coal liquefaction process

The development of an integrated two stage liquefaction process was traced. Initial studies involved conversion of a solvent refined coal (SRC) extract in an L.C. Fining® expanded bed catalytic hydrotreater representing the second stage of a two stage process. Favorable results prompted construction of an integrated unit which incorporated a short contact time coal extraction unit, a solvent deashing unit and an L.C. Finer second stage. High yields of high quality distillate (51.7 weight percent MF coal) with reduced hydrogen consumption (4.32 weight percent) were demonstrated under steady state conditions over extended run periods.