Chemoresistance of glioblastoma cancer stem cells - much more complex than expected

Glioblastomas (GBM) are a paradigm for the investigation of cancer stem cells (CSC) in solid malignancies. The susceptibility of GBM CSC to standard chemotherapeutic drugs is controversial as the existing literature presents conflicting experimental data. Here, we summarize the experimental evidence on the resistance of GBM CSC to alkylating chemotherapeutic agents, with a special focus on temozolomide (TMZ). The data suggests that CSC are neither resistant nor susceptible to chemotherapy per se. Detoxifying proteins such as O6-methylguanine-DNA-methyltransferase (MGMT) confer a strong intrinsic resistance to CSC in all studies. Extrinsic factors may also contribute to the resistance of CSC to TMZ. These may include TMZ concentrations in the brain parenchyma, TMZ dosing schemes, hypoxic microenvironments, niche factors, and the re-acquisition of stem cell properties by non-stem cells. Thus, the interaction of CSC and chemotherapy is more complex than may be expected and it is necessary to consider these factors in order to overcome chemoresistance in the patient

Обґрунтування вибору обладнання сонячної електростанції потужністю 20 МВт з 3D візуалізацією об’єкту

Моделювання об’єктів енергетики у 3D та компонування розподільчого пункту та комплектних трансформаторних підстанцій Спроектовано сонячну електростанцію 20 МВт і зроблено 3D візуалізація компонентів станції. Описується де знаходиться сонячна електростанція актуальні проблеми та рішення альтернативних джерел енергії. Застосування зеленого тарифу. Що таке проектування в 3D. Показано компоновку розташування елементів енергетики. Виконані розрахунки електрообладнання. Алгоритм моделювання сонячної панелі. 3D модель кожного елемента

A Performant Web-Based Visualization, Assessment, and Collaboration Tool for Multidimensional Biosignals

Biosignal-based research is often multidisciplinary and benefits greatly from multi-site collaboration. This requires appropriate tooling that supports collaboration, is easy to use, and is accessible. However, current software tools do not provide the necessary functionality, usability, and ubiquitous availability. The latter is particularly crucial in environments, such as hospitals, which often restrict users' permissions to install software. This paper introduces a new web-based application for interactive biosignal visualization and assessment. A focus has been placed on performance to allow for handling files of any size. The proposed solution can load local and remote files. It parses data locally on the client, and harmonizes channel labels. The data can then be scored, annotated, pseudonymized and uploaded to a clinical data management system for further analysis. The data and all actions can be interactively shared with a second party. This lowers the barrier to quickly visually examine data, collaborate and make informed decisions

Histidine Residue 94 Is Involved in pH Sensing by Histidine Kinase ArsS of Helicobacter pylori

The ArsRS two-component system is the master regulator of acid adaptation in the human gastric pathogen Helicobacter pylori. Low pH is supposed to trigger the autophosphorylation of the histidine kinase ArsS and the subsequent transfer of the phosphoryl group to its cognate response regulator ArsR which then acts as an activator or repressor of pH-responsive genes. Orthologs of the ArsRS two-component system are also present in H. pylori's close relatives H. hepaticus, Campylobacter jejuni and Wolinella succinogenes which are non-gastric colonizers.In order to investigate the mechanism of acid perception by ArsS, derivatives of H. pylori 26695 expressing ArsS proteins with substitutions of the histidine residues present in its periplasmic input domain were constructed. Analysis of pH-responsive transcription of selected ArsRS target genes in these mutants revealed that H94 is relevant for pH sensing, however, our data indicate that protonatable amino acids other than histidine contribute substantially to acid perception by ArsS. By the construction and analysis of H. pylori mutants carrying arsS allels from the related epsilon-proteobacteria we demonstrate that WS1818 of W. succinogenes efficiently responds to acidic pH.We show that H94 in the input domain of ArsS is crucial for acid perception in H. pylori 26695. In addition our data suggest that ArsS is able to adopt different conformations depending on the degree of protonation of acidic amino acids in the input domain. This might result in different activation states of the histidine kinase allowing a gradual transcriptional response to low pH conditions. Although retaining considerable similarity to ArsS the orthologous proteins of H. hepaticus and C. jejuni may have evolved to sensors of a different environmental stimulus in accordance with the non gastric habitat of these bacteria

Изменение структуры и свойств покрытия на основе стали Р6М5 при воздействии импульсов лазерного излучения

Объектом исследования является покрытие на основе стали Р6М5, подверженное лазерному излучению. Целью данной работы является исследование влияния параметров режима импульсного лазерного воздействия на структуру и свойства покрытия на основе стали Р6М5. В процессе исследования подвергали лазерному излучению поверхностный слой образца, замеряли уровень твердости поверхностного слоя образца обработанного лазерным излучением.Das Ziel der Forschung basiert Beschichtung Stahl R6M5, Bestrahlung mit Laserstrahlung. Das Ziel dieser Arbeit ist der Einfluß der Parameter der gepulsten Lasermode Auswirkungen auf die Struktur und die Eigenschaften der Beschichtung auf der Basis von Stahl R6M5 zu studieren. Die Studie wurde mit Laserstrahlung mit einer Oberflächenschicht der Probe unterzogen wird, das Niveau der Härte der Oberflächenschicht der Probe mit der Laserstrahlung behandelt gemessen

Short-term effective treatment of CNS metastasis of sarcomatoid renal cell carcinoma with temozolomide and pegylated liposomal doxorubicin: A case report

Sarcomatoid renal cell carcinoma represents high-grade transformation of different subtypes of renal cell carcinoma and is associated with a dismal prognosis and high resistance to chemotherapy. We report on the course of disease of a 63 years old patient undergoing a nearly complete remission of multiple intracranial and spinal metastatic lesions of a sarcomatoid renal cell carcinoma by a combined chemotherapy with temozolomide and pegylated liposomal doxorubicin

Исследование каталитической активности высокодисперсных порошков железа в синтезе Фишера-Тропша

Объектом данного исследования являлся высокодисперсный порошок железа, полученный методом электрического взрыва проводника, с последующим таблетированием под высоким давлением. Целью данной работы являлось изучение каталитической активности железного катализатора в синтезе Фишера-Тропша.The object of study is the superfine iron powder obtained by the method of electrical explosion with subsequent tableting with high pressure. The purpose of the work is to study of the catalytic activity iron catalyst in Fischer-Tropsch synthesi

YB-1 dependent oncolytic adenovirus efficiently inhibits tumor growth of glioma cancer stem like cells

Background: The brain cancer stem cell (CSC) model describes a small subset of glioma cells as being responsible for tumor initiation, conferring therapy resistance and tumor recurrence. In brain CSC, the PI3-K/AKT and the RAS/mitogen activated protein kinase (MAPK) pathways are found to be activated. In consequence, the human transcription factor YB-1, knowing to be responsible for the emergence of drug resistance and driving adenoviral replication, is phosphorylated and activated. With this knowledge, YB-1 was established in the past as a biomarker for disease progression and prognosis. This study determines the expression of YB-1 in glioblastoma (GBM) specimen in vivo and in brain CSC lines. In addition, the capacity of Ad-Delo3-RGD, an YB-1 dependent oncolytic adenovirus, to eradicate CSC was evaluated both in vitro and in vivo. Methods: YB-1 expression was investigated by immunoblot and immuno-histochemistry. In vitro, viral replication as well as the capacity of Ad-Delo3-RGD to replicate in and, in consequence, to kill CSC was determined by real-time PCR and clonogenic dilution assays. In vivo, Ad-Delo3-RGD-mediated tumor growth inhibition was evaluated in an orthotopic mouse GBM model. Safety and specificity of Ad-Delo3-RGD were investigated in immortalized human astrocytes and by siRNA-mediated downregulation of YB-1. Results: YB-1 is highly expressed in brain CSC lines and in GBM specimen. Efficient viral replication in and virus-mediated lysis of CSC was observed in vitro. Experiments addressing safety aspects of Ad-Delo3-RGD showed that (i) virus production in human astrocytes was significantly reduced compared to wild type adenovirus (Ad-WT) and (ii) knockdown of YB-1 significantly reduced virus replication. Mice harboring othotopic GBM developed from a temozolomide (TMZ)-resistant GBM derived CSC line which was intratumorally injected with Ad-Delo3-RGD survived significantly longer than mice receiving PBS-injections or TMZ treatment. Conclusion: The results of this study supported YB-1 based virotherapy as an attractive therapeutic strategy for GBM treatment which will be exploited further in multimodal treatment concepts

RNOP-09: Pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma - a phase II study

BACKGROUND: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for. METHODS: In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression. RESULTS: The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison. CONCLUSION: Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data