Metformin plus PIAF combination chemotherapy for hepatocellular carcinoma

Objectives: Metformin, the most used oral antidiabetic drug for the treatment of type 2 diabetus mellitus, has proved encouraging results when used in the treatment of various types of cancer such as triple-negative breast cancer. Despite compelling evidence of a role of metformin as an anticancer drug, the mechanisms by which metformin exerts its oncostatic actions are not fully understood yet. Therefore, we tried to bring new insights by analyzing the anti-neoplastic effect of metformin for hepatocellular carcinoma-derived stem-like cells treated with conventional combination chemotherapy. Methods: Cancer stem-like cells previusly isolated from a hepatocellular carcinoma biopsy were treated with metformin, PIAF chemotherapy regimen and the combination of these two protocols. Measurements of lipid peroxidation, reduced glutathione, fluorescein diacetate and proliferation rates were determined, apart from the autophagy assay and apoptosis determination by chip flow cytometry. Results: Metformin alone and especially metformin in association with PIAF increases oxidative stress within the cells by increasing the levels of lipid peroxids as well as decreasing the levels of reduced glutathione. The MTT cell proliferation assay showed decreased prolife­ration rates for the arm treated with metformin and with the combination of drugs in comparison with the control arm, proving high correlation with the oxidative stress results. The autophagy assay and determination of apoptosis by chip flow cytometry confirmed the results obtained in the previous assays. Conclusion: Metformin could be used in chemotherapy treatments to induce reactive oxygen species and increase the cytostatics effects within the tumor cell. Still, further experiments must be carried out on murine models before we can move on and use this drugs in the adjuvant setting for unresectable primary liver cancer

Bicytopenia as a paraneoplastic syndrome for pseudomyxoma peritonei. Hematologic manifestations of a subtle disease

Ciprian Tomuleasa,1,2 Bobe Petrushev,2 Madalina Vedean,2 Alexandru Irimie,2,3 Florin Zaharie,2 Ana-Maria Rosu,1 Delia Dima,1 Andrei Cucuianu1,2 1Department of Hematology, Ion Chiricuta Oncology Institute, 2Iuliu Hatieganu University of Medicine and Pharmacy, 3Department of Surgery, Ion Chiricuta Oncology Institute, Cluj Napoca, RomaniaWe have read with great interest the paper of de Oliveira et al, in which the authors report the case of a 76-year-old woman who presented with increased abdominal girth and dyspnea for 2 weeks.1 After extensive investigations, the patient was diagnosed with an abdominal pseudomyxoma peritonei and underwent right oophorectomy, omentectomy, and pseudomyxoma debulking. View original paper by de Oliveira and colleagues&nbsp

Association of a <em>MTNR1B</em> gene variant with fasting glucose and HOMA-B in children and adolescents with high BMI-SDS.

Genome-wide association studies have shown that the melatonin receptor 1B (MTNR1B) gene locus is strongly associated with fasting glucose and &beta;-cell function. However, data are rather limited to the adult population and normal-weight children. So far, little is known whether similar associations are present in overweight and obese children and adolescents. The aim is to investigate an MTNR1B polymorphism in a sample of 310 overweight and obese children and adolescents (mean body mass index standard deviation score (BMI-SDS)): 2.74 (&plusmn; 0.55), mean age: 14 (&plusmn; 2) years), who participated in a short-term weight-loss program based on energy reduction, physical activity, and behavior therapy. We investigated an association between genotype and fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and of &beta;-cell function (HOMA-B), and anthropometric parameters and their change during intervention.The minor G allele of polymorphism rs10830963 was significantly associated with increased fasting glucose (0.205  mmol/l, P&lt;0.0001) and decreased HOMA-B (-0.353, P &lt; 0.0001). Categorizing the sample into BMI-SDS groups, these significant associations were abolished in children with BMI-SDS below 2.5 but remained in those with higher BMI-SDS values with stronger &beta;-estimates. The P value for the genotype &times; BMI-SDS category interaction was 0.012 for fasting glucose and 0.083 for HOMA-B. There was no significant association between genotype and anthropometric parameters and their change during intervention. This is the first single study, replicating the association between the MTNR1B locus and diabetes-related traits in overweight and obese children and adolescents. The effect sizes in children and adolescents seem to be stronger than in adults and differed among BMI-SDS categories

Creativity in context: the ecology of creativity evaluations and practices in an artistic craft

The present article reports a study on the use of a multiple feedback methodology for creativity evaluation in the case of Romanian Easter eggs. Four groups of evaluators —i.e. ethnographers, priests, art teachers and folk artists—all members of professional communities relevant for this particular folk art participated in the study. They almost unanimously appreciated ‘traditional’ wax decorated eggs as highly creative for their designs, aesthetics and the hard work and talent they require but opinions diverged when commenting on the creativity of other types of Easter eggs. At a more general level, two broad evaluation patters were found, corresponding to whether respondents participate or not in decoration practices. Identifying these patterns comes to reinforce the idea that creativity evaluations, as well as creative activity, are rooted in the social and cultural contexts of the participants and these contexts share important similarities but also marked differences

HLA Genotyping using Next Generation Sequencing

From an oncological perspective, the second most common malignancies in children are brain tumors. Despite the recent therapeutic breakthroughs in this field, concerning surgery, radiotherapy and chemotherapy alike, some cases still have poor outcomes in curability. This is especially the case in patients with high-risk histological types of tumors, and those suffering from residual, remitting and disseminated diseases. Due to the unique neuroanatomical emplacement of brain tumors and their aggressive infiltrative behavior, their total removal remains a demanding task. This can be perceived in the high rates of failure treatment and disease recurrence. Furthermore, the adjacent healthy brain tissue is inevitably damaged in the surgical process of effectively removing these tumors. Thus, stem cell transplantation may be a viable solution for the clinical management of these malignancies, as proven by various recent breakthroughs. In the current concise review, we present the role of next generation sequencing in HLA typing for stem cell transplantation in primary CNS pediatric malignancies

Small molecules against B-RAF (BRAF) Val600Glu (V600E) single mutation

Florin Zaharie,1,* Roxana Cojocneanu-Petric,1,* Mihai Muresan,1 Ioana Frinc,2 Delia Dima,2 Bobe Petrushev,3 Alina Tanase,4 Cristian Berce,1 Mariana Chitic,2 Ioana Berindan-Neagoe,1 Valentina Pileczki,1 Alexandru Irimie,5 Ciprian Tomuleasa2 1Iuliu Hatieganu University of Medicine and Pharmacy, 2Department of Hematology, Ion Chiricuta Oncology Institute, 3Department of Pathology, Emergency University Hospital, Cluj Napoca, 4Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, 5Department of Surgery, Ion Chiricuta Oncology Institute, Cluj Napoca, Romania *These authors contributed equally to&nbsp;this communicationWe have read with great interest the paper by Tang and Chen1 published in the most recent issue of the International Journal of Nanomedicine, in which the authors describe the protocol by which scientists constructed the ideal BRAF (V600E)-modeled structure through homology modeling and introduced the method of structure-based docking or virtual screening from a large compound database. They concluded that BRAF (V600E) has a quite prominent structural or conformational variation when compared to the wild-type BRAF protein by matrix of root mean square fluctuation and principal component analysis. On the basis of structure-based virtual screening, ligand-based quantitative structure activity relationship models, and molecular dynamics simulation, we recommend aknadicine and 16beta-hydroxy-19s-vindolinine N-oxide as potent compounds for developing novel inhibitors in the future.&nbsp;Read the original article&nbsp

Gold nanoparticles enhance the effect of tyrosine kinase inhibitors in acute myeloid leukemia therapy

Bobe Petrushev,1,* Sanda Boca,2,* Timea Simon,2 Cristian Berce,3 Ioana Frinc,4 Delia Dima,4 Sonia Selicean,3 Grigore-Aristide Gafencu,3 Alina Tanase,5 Mihnea Zdrenghea,4,6 Adrian Florea,7 Sorina Suarasan,2 Liana Dima,8 Raluca Stanciu,3 Ancuta Jurj,1 Anca Buzoianu,9 Andrei Cucuianu,4,6,&dagger; Simion Astilean,2,10 Alexandru Irimie,11,12 Ciprian Tomuleasa,1,4 Ioana Berindan-Neagoe1,131Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 2Nanobiophotonics and Laser Microscopy Center, Babes Bolyai University, 3Department of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 4Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca, 5Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, 6Department of Hematology, 7Department of Cell and Molecular Biology, 8School of Dentistry, 9Department of Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 10Faculty of Physics, Babes Bolyai University, 11Department of Surgery, Ion Chiricuta Oncology Institute, 12Department of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 13Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA*These authors contributed equally to this work&dagger;This author passed away in February 2015Background and aims: Every year, in Europe, acute myeloid leukemia (AML) is diagnosed in thousands of adults. For most subtypes of AML, the backbone of treatment was introduced nearly 40 years ago as a combination of cytosine arabinoside with an anthracycline. This therapy is still the worldwide standard of care. Two-thirds of patients achieve complete remission, although most of them ultimately relapse. Since the FLT3 mutation is the most frequent, it serves as a key molecular target for tyrosine kinase inhibitors (TKIs) that inhibit FLT3 kinase. In this study, we report the conjugation of TKIs onto spherical gold nanoparticles.Materials and methods: The internalization of TKI-nanocarriers was proved by the strongly scattered light from gold nanoparticles and was correlated with the results obtained by transmission electron microscopy and dark-field microscopy. The therapeutic effect of the newly designed drugs was investigated by several methods including cell counting assay as well as the MTT assay.Results: We report the newly described bioconjugates to be superior when compared with the drug alone, with data confirmed by state-of-the-art analyses of internalization, cell biology, gene analysis for FLT3-IDT gene, and Western blotting to assess degradation of the FLT3 protein.Conclusion: The effective transmembrane delivery and increased efficacy validate its use as a potential therapeutic.Keywords: tyrosine kinase inhibitors, gold nanoparticles, acute myeloid leukemi