Drug resistance mechanisms in a high grade glioma cell line

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour. Despite advances in GBM treatment, there is a high frequency of local relapse due to the acquisition of drug resistance. Investigation of glioma cell lines will help us to understand the molecular basis of this hard to treat tumour. In this study, the rat C6 glioma cell line was used as a model alongside two drug selected derivatives (C6-etoposide and C6-irinotecan) to investigate the mechanisms of chemo-resistance in glioma by identifying candidate proteins, genes, and key signalling pathways. Proteomic (2D gel electrophoresis) and genomic (gene array) analyses were performed to determine protein and gene expression changes. Integration of this data with cellular pathway analysis resulted in the prediction that cellular migration and the response to oxidative stress would be distinct in the drug selected C6 cell lines. Cell migration was subsequently assessed using wound scratch repair and transwell migration assays, whilst the response to oxidative stress produced by reactive oxygen species was determined fluorimetrically. The C6 cell line exposed to irinotecan (DNA topoisomerase I inhibitor) showed reduced migration, even under the influence of chemoattractant, compared to other cell lines, consistent with alterations in the expression of collagen genes. The C6 cell line exposed to etoposide (DNA topoisomerase II inhibitor) showed greater resistance to oxidative stress which was proposed to be due to alterations in the signalling pathways downstream of the PTEN/PI3Kinase. Future studies, investigating the effect of PI3Kinase pathway inhibitors are considered and it is proposed that further research into this signalling pathway will be able to uncover the molecular basis of distinct chemo-resistance in this important model cell system for aggressive glioma

Long-term exposure to irinotecan reduces cell migration in glioma cells.

In spite of considerable research into the therapies for glioblastoma multiforme this tumour type remains very difficult to treat. As well as having a tendency to be inherently resistant to chemotherapy, glioblastoma multiforme also displays local invasion. Cell line studies have a continued and important role to play in understanding the mechanisms associated with both chemotherapy resistance and invasion. In the current study we have utilized the C6 glioma cell line to investigate the response to long-term, clinically relevant application of topoisomerase I and II inhibitors. Treatment with etoposide resulted in an increase in resistance to this topoisomerase II inhibitor. By contrast, the continuous exposure to a topoisomerase I inhibitor did not result in increased drug resistance, but was associated with a reduction in cell migration. This data supports further investigation of topoisomerase I inhibition as a means to inhibit glioma invasion without the development of parallel chemoresistance

Electronic Structure of the Rare-Earth Dihydride GdH₂

With the WIEN2k simulation code, the ab initio calculations of electronic properties for the cubic stoichiometric rare-earth dihydride GdH₂ (in the cubic fluorite structure) are performed using the full-potential linearized augmented plane wave (FP-LAPW) method approach within the density functional theory (DFT) in the generalized gradient approximation (GGA) (used for the exchange—correlation potential). The lattice parameter, the bulk modulus, its pressure derivative, the density of states, and the energy band structures are determined. Two low-lying hydrogen—metal bands of GdH2 are observed. The Fermi energy EF falls at a level where most of the states are rare-earth 5d conduction states. Information on the negligible role of the H1s state contribution near EF is obtained.З використанням пакету для моделювання WIEN2k виконано ab initio розрахунки електронних властивостей для кубічного стехіометричного рідкісноземельного дигідриду GdH₂ (в структурі кубічного флюориту) із застосуванням повнопотенціяльної методи лінеаризованих приєднаних пласких хвиль в межах теорії функціоналу густини в наближенні узагальненого ґрадієнту (застосованих до обмінно-кореляційного потенціялу). Визначено сталу кристалічної ґратниці, модуль об’ємної пружности, його похідну за тиском, густину станів та структури енергетичних зон. Енергія Фермі EF розташовується поблизу рівня, де більшість станів є провідними 5d-станами рідкісноземельного елементу. Одержано інформацію щодо нехтовно малої ролі внеску стану H1s поблизу EF.С использованием пакета для моделирования WIEN2k проведены ab initio расчёты электронных свойств для кубического стехиометрического редкоземельного дигидрида GdH₂ (в структуре кубического флюорита) с применением полнопотенциального метода линеаризованных присоединённых плоских волн в рамках теории функционала плотности в приближении обобщённого градиента (применённых к обменно-корреляционному потенциалу). Определены постоянная кристаллической решётки, модуль объёмной упругости, его производная по давлению, плотность состояний и структуры энергетических зон. Энергия Ферми EF располагается вблизи уровня, где большинство состояний являются проводящими 5d-состояниями редкоземельного элемента. Получена информация о пренебрежимо малой роли вклада состояния H1s вблизи EF

Stability and magnetically induced heating behavior of lipid-coated Fe3O4 nanoparticles

Magnetic nanoparticles that are currently explored for various biomedical applications exhibit a high propensity to minimize total surface energy through aggregation. This study introduces a unique, thermoresponsive nanocomposite design demonstrating substantial colloidal stability of superparamagnetic Fe(3)O(4) nanoparticles (SPIONs) due to a surface-immobilized lipid layer. Lipid coating was accomplished in different buffer systems, pH 7.4, using an equimolar mixture of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and l-α-dipalmitoylphosphatidyl glycerol (DPPG). Particle size and zeta potential were measured by dynamic laser light scattering. Heating behavior within an alternating magnetic field was compared between the commercial MFG-1000 magnetic field generator at 7 mT (1 MHz) and an experimental, laboratory-made magnetic hyperthermia system at 16.6 mT (13.7 MHz). The results revealed that product quality of lipid-coated SPIONs was significantly dependent on the colloidal stability of uncoated SPIONs during the coating process. Greatest stability was achieved at 0.02 mg/mL in citrate buffer (mean diameter = 80.0 ± 1.7 nm; zeta potential = -47.1 ± 2.6 mV). Surface immobilization of an equimolar DPPC/DPPG layer effectively reduced the impact of buffer components on particle aggregation. Most stable suspensions of lipid-coated nanoparticles were obtained at 0.02 mg/mL in citrate buffer (mean diameter = 179.3 ± 13.9 nm; zeta potential = -19.1 ± 2.3 mV). The configuration of the magnetic field generator significantly affected the heating properties of fabricated SPIONs. Heating rates of uncoated nanoparticles were substantially dependent on buffer composition but less influenced by particle concentration. In contrast, thermal behavior of lipid-coated nanoparticles within an alternating magnetic field was less influenced by suspension vehicle but dramatically more sensitive to particle concentration. These results underline the advantages of lipid-coated SPIONs on colloidal stability without compromising magnetically induced hyperthermia properties. Since phospholipids are biocompatible, these unique lipid-coated Fe(3)O(4) nanoparticles offer exciting opportunities as thermoresponsive drug delivery carriers for targeted, stimulus-induced therapeutic interventions. PACS: 7550Mw; 7575Cd; 8185Q

Framework for Analyzing Safeguards Alarms and Response Decisions

This paper describes a quantitative approach to help evaluate and respond to safeguards alarms. These alrms may be generated internally by a facility's safeguards systems or externally by individuals claiming to possess stolen Special Nuclear Material (SNM). This approach can be used to identify the most likely cause of an alarm - theft, hoax, or error - and to evaluate alternative responses to alarms. Possible responses include conducting investigations, initiating measures to recover stolen SNM, and replying to external threats. Based on the results of each alarm investigation step, the evaluation revises the likelihoods of possible causes of an alarm, and uses this information to determine the optimal sequence of further responses. The choice of an optimal sequence of responses takes into consideration the costs and benefits of successful thefts or hoaxes. These results provide an analytical basis for setting priorities and developing contingency plans for responding to safeguards alarms

The STAR Silicon Strip Detector (SSD)

The STAR Silicon Strip Detector (SSD) completes the three layers of the Silicon Vertex Tracker (SVT) to make an inner tracking system located inside the Time Projection Chamber (TPC). This additional fourth layer provides two dimensional hit position and energy loss measurements for charged particles, improving the extrapolation of TPC tracks through SVT hits. To match the high multiplicity of central Au+Au collisions at RHIC the double sided silicon strip technology was chosen which makes the SSD a half million channels detector. Dedicated electronics have been designed for both readout and control. Also a novel technique of bonding, the Tape Automated Bonding (TAB), was used to fullfill the large number of bounds to be done. All aspects of the SSD are shortly described here and test performances of produced detection modules as well as simulated results on hit reconstruction are given.Comment: 11 pages, 8 figures, 1 tabl

Microscopics of meson degrees of freedom in nucleons and mesons in nuclei - what can be seen in the process of quasielastic knockout of mesons by high-energy electrons

Developed earlier concept of quasielastic knock out of pions from nucleons by high-energy electrons is propounded as a tool for checking microscopical model ($^3P_0$ - fluctuation) for decay of N to different channels $\pi+B$ and Preparata model of nucleus structure.Comment: 6 pages, 5 figures, Talk given at 16 Baldin Symposium in June 200

Causes of elective cesarean delivery on maternal request in Aljouf, Saudi Arabia

Background: Recently observed there is a steadily higher rate of cesarean delivery worldwide mostly due to the increasing number of women requesting an elective cesarean section on maternal request without valid indication. The aim of the study was to determine the causes of elective cesarean delivery on maternal requests in Aljouf Saudi Arabia.Methods: This was a descriptive cross-sectional study and data was evaluated by completing seven questionnaires and interviews with laboratory reports who were admitted for cesarean delivery at the Obstetrics department of Maternity and Children Hospital (MCH) Aljouf, Saudi Arabia from January 2020 to December 2020. A total of 141 Saudi women of age between 18 and over 35 years were enrolled, including those who have singleton pregnancy, no complications during pregnancy, and no medical indication for cesarean delivery.Results: 141 women reported willingness to request cesarean delivery. The mean systolic 120±6.23, diastolic 75±2.45 blood pressure mm of Hg, and fasting blood sugar level 4.1±1.1 mmol/l have been found within the normal limit. The ultrasound (US) confirmed singleton pregnancy without any abnormalities.  Data reveals that common causes of elective cesarean section on maternal request to avoid the episiotomy 77.3%, fear of labor pain 69.5%, trauma to the vagina 79.4%, uncertainty about timing 61.7%, losing a baby during vaginal delivery 54.6%, experience other members 41.8%, the risk for baby 39%, prolapse or incontinence24.1%, unsatisfactory sexual intercourse 17.7% and the undesirable experience of the previous vaginal delivery 12%.Conclusions: Maternal request for cesarean delivery is considered one of the reasons for increasing the rate of cesarean delivery in Saudi Arabia. To avoid the episiotomy and fear of labor pain may strong causes for choosing cesarean delivery

ABCB1 variants C3435T and T129C are not associated with colorectal cancer risk

Background: Colorectal cancer (CRC) is one of the most prevalent cancers in Saudi Arabia that is highly characterized with poor survival rate and advanced metastasis. Many studies contribute this poor outcome to the expression of ABC transporters on the surface of cancer cells. Objectives: In this study, two ABCB1 variants, C3435T and T129C, were examined to evaluate their contribution to CRC risk. Methods: 125 subjects (62 CRC patients and 63 healthy controls) were involved. The DNA was isolated and analyzed with PCR-RFLP to determine the different genotypes. The hardy-Weinberg equilibrium was performed to determine genotype distribution and allele frequencies. Fisher\u2019s exact test (two-tailed) was used to compare allele frequencies between patients and control subjects. Results: The study showed that for SNP C3435T, the population of both CRC patients and controls were out of Hardy-Weinberg equilibrium. Genotype distribution for CRC patients was (Goodness of fit \u3c72 = 20, df= 1, P 640.05), whereas, for the controls the genotype distribution was (Goodness of fit \u3c72 = 21, df =1, P 640.05). For SNP T129C, all subjects showed normal (TT) genotype. Conclusion: There was no significant association between ABCB1 3435C>T and 129T>C polymorphisms with CRC risk

Predictors for distant metastasis in head and neck cancer, with emphasis on age

PURPOSE: Distant metastasis (DM) in patients with head and neck squamous cell carcinoma (HNSCC) is uncommon, but strongly deteriorates prognosis. Controversy exists regarding age as a predictor for the presence and development of DM. The aim of this study was to investigate age and other predictors for DM in HNSCC patients. METHODS: From 1413 patients diagnosed with a primary HNSCC between 1999 and 2010 in a tertiary referral centre, patient, disease and pathological characteristics were extracted from patient files. Uni- and multivariable Cox regression analyses were performed to identify risk factors for DM as primary outcome. RESULTS: DM occurred in 131 (9.3%) patients, of which 27 (1.9%) were diagnosed simultaneously with the primary tumour, 27 (1.9%) were diagnosed synchronous, and 77 (5.4%) were diagnosed metachronous. The most common site of DM was lung (51.1%), followed by bone (19.1%) and liver (11.5%). Multivariable analysis identified male gender (HR = 1.95, 95% CI 1.23-3.10) hypopharyngeal tumours (HR = 3.28, 95% CI 1.75-6.14), advanced T-stage (HR = 1.61, 95% CI 1.09-2.38), poor differentiation grade (HR = 2.49, 95% CI 1.07-5.78), regional lymph node metastasis (HR = 5.35, 95% CI 3.25-8.79) and extranodal extension of regional lymph nodes metastasis (HR = 3.06, 95% CI 1.39-6.72) as independent prognostic factors for the presence or development of DM. No relation with age was found. CONCLUSION: Age is not related to the presence or development of DM. This study emphasizes the importance of screening for DM, especially in males, patients with hypopharyngeal tumours, advanced T-stage, histopathological poor differentiation grade, regional lymph node metastasis and extranodal extension