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Previously compound I showed great anti-glioblastoma activity without toxicity in a mouse xenograft study. In this study, a sensitive and rapid high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) method was developed and validated to investigate the pharmacokinetics and brain distribution of compound I in mice. The protein precipitation method was applied to extract the compound from mouse plasma and brain homogenates, and it was then separated using a Kinetex C(18) column with a mobile phase consisting of acetonitrile–0.1% formic acid water (50:50, v/v). The analytes were detected with multiple reaction monitoring for the quantitative response of the compounds. The inter- and intra-day precisions were

Cancer stem cells (CSCs) are a heterogeneous and dynamic self-renewing population that stands at the top of tumor cellular hierarchy and contribute to tumor recurrence and therapeutic resistance. As methods of CSC isolation and functional interrogation advance, there is a need for a reliable and accessible quantitative approach to assess heterogeneity and state transition dynamics in CSCs. We developed a high-throughput automated single cell imaging analysis (HASCIA) approach for the quantitative assessment of protein expression with single-cell resolution and applied the method to investigate spatiotemporal factors that influence CSC state transition using glioblastoma (GBM) CSCs (GSCs) as a model system. We were able to validate the quantitative nature of this approach through comparison of the protein expression levels determined by HASCIA to those determined by immunoblotting. A virtue of HASCIA was exemplified by detection of a subpopulation of SOX2-low cells, which expanded in fraction size during state transition. HASCIA also revealed that GSCs were committed to loose stem cell state at an earlier time point than the average SOX2 level decreased. Functional assessment of stem cell frequency in combination with the quantification of SOX2 expression by HASCIA defined a stable cutoff of SOX2 expression level for stem cell state. We also developed an approach to assess local cell density and found that denser monolayer areas possess higher average levels of SOX2, higher cell diversity, and a presence of a sub-population of slowly proliferating SOX2-low GSCs. HASCIA is an open source software that facilitates understanding the dynamics of heterogeneous cell population such as that of GSCs and their progeny. It is a powerful and easy-to-use image analysis and statistical analysis tool available at https://hascia.lerner.ccf.org. © 2019 International Society for Advancement of Cytometry.

Glioblastoma (GBM) cancer stem cells (CSCs) are insidious. They extensively infiltrate brain tissue, resist radiotherapy and chemotherapy, and are thought to represent the ultimate drivers of disease progression. New research has identified CD109, a GPI-anchored protein, on a population of perivascular CSCs. Investigation of primary human tumour tissue suggests a role for CD109-expressing CSCs in the progression from low-grade to high-grade glioma, and animal modelling reveals a critical role for CD109 in the maintenance of the GBM CSC phenotype. Furthermore, CD109-expressing CSCs appear to drive the proliferation of adjacent non-stem tumour cells (NSTCs) in a rare example of CSC-NSTC cooperative interaction. With this Commentary, we highlight the newly revealed biology of CD109, and offer a synthesis of the published information on glioma CSCs in a variety of anatomical growth zones. We also discuss the landscape of interacting cells within GBM tumours, emphasizing the few reported examples of pro-tumourigenic, interactive tumour cell partnerships, as well as a variety of tumour cell-non-transformed neural cell interactions. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Glioblastoma is a malignant brain tumor that inevitably develops resistance to standard of care drug temozolomide (TMZ) due to a population of cells called cancer stem cells (CSCs). These cells utilize progenitor cell signaling programs and develop robust DNA repair machinery. In this editorial highlight we focus on stem cell regulation of TMZ resistance and discuss findings of Happold et al. () that outline direct transcriptional regulation of DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) in glioblastoma CSCs through NFkB activation. The authors found that cells cultured in CSC propagating conditions exhibit increase in MGMT expression when compared to adherent differentiated monolayer cells. This in turn increases resistance to standard of care drug temozolomide (TMZ) in these cells. NFkB activation was found to directly activate expression of MGMT in sphere cultured GBM CSC.

Glioblastoma is the most prevalent primary brain tumor and is essentially universally fatal within 2 years of diagnosis. Glioblastomas contain cellular hierarchies with self-renewing glioblastoma stem cells (GSCs) that are often resistant to chemotherapy and radiation therapy. GSCs express high amounts of repressor element 1 silencing transcription factor (REST), which may contribute to their resistance to standard therapies. Telomere repeat-binding factor 2 (TRF2) stablizes telomeres and REST to maintain self-renewal of neural stem cells and tumor cells. Here we show viral vector-mediated delivery of shRNAs targeting TRF2 mRNA depletes TRF2 and REST from GSCs isolated from patient specimens. As a result, GSC proliferation is reduced and the level of proteins normally expressed by postmitotic neurons (L1CAM and β3-tubulin) is increased, suggesting that loss of TRF2 engages a cell differentiation program in the GSCs. Depletion of TRF2 also sensitizes GSCs to temozolomide, a DNA-alkylating agent currently used to treat glioblastoma. Targeting TRF2 significantly increased the survival of mice bearing GSC xenografts. These findings reveal a role for TRF2 in the maintenance of REST-associated proliferation and chemotherapy resistance of GSCs, suggesting that TRF2 is a potential therapeutic target for glioblastoma. GLIA 2014;62:1687–1698

Toll-like receptors (TLRs) play essential roles in innate immunity, and increasing evidence indicates that these receptors are expressed in neurons, astrocytes, and microglia in the brain, where they mediate responses to infection, stress, and injury. To address the possibility that TLR2 heterodimer activation could affect progenitor cells in the developing brain, we analyzed the expression of TLR2 throughout mouse cortical development, and assessed the role of TLR2 heterodimer activation in neuronal progenitor cell (NPC) proliferation. TLR2 mRNA and protein was expressed in the cortex in embryonic and early postnatal stages of development, and in cultured cortical NPC. While NPC from TLR2-deficient and wild type embryos had the same proliferative capacity, TLR2 activation by the synthetic bacterial lipopeptides Pam(3)CSK(4) and FSL1, or low molecular weight hyaluronan, an endogenous ligand for TLR2, inhibited neurosphere formation in vitro. Intracerebral in utero administration of TLR2 ligands resulted in ventricular dysgenesis characterized by increased ventricle size, reduced proliferative area around the ventricles, increased cell density, an increase in phospho-histone 3 cells, and a decrease in BrdU(+) cells in the sub-ventricular zone. Our findings indicate that loss of TLR2 does not result in defects in cerebral development. However, TLR2 is expressed and functional in the developing telencephalon from early embryonic stages and infectious agent-related activation of TLR2 inhibits NPC proliferation. TLR2-mediated inhibition of NPC proliferation may therefore be a mechanism by which infection, ischemia, and inflammation adversely affect brain development.

Introduction: Although much is known about the efficacy, toxicity, and direct costs of treatment for follicular lymphoma (FL), there is no data assessing the impact of this diagnosis on the work productivity of affected individuals. Methods: We conducted a cross-sectional survey study of consecutive patients attending a malignant haematology clinic at a large multi-disciplinary cancer centre. Patients with a diagnosis of FL or other indolent non-Hodgkin's lymphoma completed questionnaires assessing health status, work productivity, and activity impairment. Results: Eighty-four patients completed the survey study (95% response). Patients who continued to work reported a minimal impact on their work productivity (10%±standard deviation SD 20; 0%=no effect and 100%=complete impairment of activity) and on their daily activities (13%±SD 25) attributable to their cancer. Prior to lymphoma diagnosis, over 71% of patients were working while 14% were retired. At the time of survey administration, only 41% of patients were still able to work with a significant proportion of patients having transitioned to retirement (36%), sick leave (10%), or unemployment (4%). On multivariate analysis, significant activity impairment (daily activity impairment>50%) was predicted by poor self-rated health status (OR 32.1; 95% CI: 5.9–174.2; p

Notch is an integral membrane protein that functions as receptor for ligands such as jagged and delta that are associated with the surface of neighboring cells. Upon ligand binding, notch is proteolytically cleaved within its transmembrane domain by presenilin-1 (the enzymatic component of the γ-secretase complex) resulting in the release of a notch intracellular domain (NICD) which translocates to the nucleus where it regulates gene expression. Notch signaling plays multiple roles in the development of the central nervous system (CNS) including regulating neural stem cell (NSC) proliferation, survival, self-renewal and differentiation. Notch is also present in postmitotic neurons in the adult CNS wherein its activation influences structural and functional plasticity including processes involved in learning and memory. Recent findings suggest that notch signaling in neurons, glia and NSCs may be involved in pathological changes that occur in disorders such as stroke, Alzheimer’s disease and CNS tumors. Studies of animal models suggest the potential of agents that target notch signaling as therapeutic interventions for several different CNS disorders.

Purpose The prevalence and risk factors for thromboembolism (TE) in children with cancer are largely unknown. This retrospective cohort study aims to determine the epidemiology of TE and to identify potential risk factors for TE in children with cancer. Methods We used logistic regression to determine the association of age (

The impact of age and gender on the single-dose pharmacokinetics, safety, and tolerability of BAY 12-9566 was evaluated in healthy subjects. Volunteers were grouped according to age and gender (13 young males, 11 elderly males, and 12 elderly females) and then randomized in a 2:1 ratio to receive a single oral 50 mg dose of BAY 12-9566 or placebo. Serial plasma samples were collected up to 336 hours postdose and assayed for BAY 12-9566. Peak plasma concentration, time to reach peak plasma concentration, the area under the concentration-time curve, oral clearance, volume of distribution, and elimination half-life were calculated. BAY 12-9566 was well tolerated in all treatment groups, and no serious adverse events occurred during the study. Substantial age- or gender-related differences were not observed for any of the pharmacokinetic parameters tested. Based on these pharmacokinetic and tolerability profiles, age- or gender-related dose adjustments were not required for BAY 12-9566.

Because the olfactory system plays a major role in food consumption, and because 'food addiction' and associated morbidities have reached epidemic proportions, we tested the hypothesis that dietary energy restriction can modify adverse effects of cocaine on behavior and olfactory cellular and molecular plasticity. Mice maintained on an alternate day fasting (ADF) diet exhibited increased baseline locomotion and increased cocaine-sensitized locomotion during cocaine conditioning, despite no change in cocaine conditioned place preference, compared with mice fed ad libitum. Levels of dopamine and its metabolites in the olfactory bulb (OB) were suppressed in mice on the ADF diet compared with mice on the control diet, independent of acute or chronic cocaine treatment. The expression of several enzymes involved in dopamine metabolism including tyrosine hydroxylase, monoamine oxidases A and B, and catechol-O-methyltransferase were significantly reduced in OBs of mice on the ADF diet. Both acute and chronic administration of cocaine suppressed the production of new OB cells, and this effect of cocaine was attenuated in mice on the ADF diet. Cocaine administration to mice on the control diet resulted in up-regulation of OB genes involved in mitochondrial energy metabolism, synaptic plasticity, cellular stress responses, and calcium- and cAMP-mediated signaling, whereas multiple olfactory receptor genes were down-regulated by cocaine treatment. ADF abolished many of the effects of cocaine on OB gene expression. Our findings reveal that dietary energy intake modifies the neural substrates underlying some of the behavioral and physiological responses to repeated cocaine treatment, and also suggest novel roles for the olfactory system in addiction. The data further suggest that modification of dietary energy intake could provide a novel potential approach to addiction treatments.

A general method of grafting lignin has been developed which allows solvent extracted lignin, steam exploded lignin, and kraft lignin to be converted to complex polymers. The lignins grafted have been obtained from aspen, poplar, oak, grasses, and pine. The lignins are research samples, pilot plant products, and commerical products from paper production. Nonionic copolymers of virtually any composition and molecular weight can be made from lignin and 2-propenamide by free radical reaction of 2-propenamide in the presence of the lignin. The water soluble product is a thickening agent and has limiting viscosity number in water at 30°C that vary from 0.1 to 2.0 dL/g. The grafting reaction is rapid and yields of 80 wt % or more can be obtained in as little as 30 min from reactions run in 1,4-dioxacyclohexane or dimethylsulfoxide. The reaction is initiated by a hydroperoxide, chloride ion, and lignin.

N-Nitrosamine sind bekannt fur ihre starke Carzinogenitat Sie konnen aus der Vielzahl ubiquitar vorkommender nitrosierbarer Aminoverbindungen und Nitrosierungsmitteln wie Nitrit, Nitrat und Nitrosogasen im sauren Milieu entstehen. Eine Reihe von Untersuchungen zeigen, das einige Mikronahrstoffe wie z. B. Vitamin A, C, E und die Spurenelemente Selen und Zink bei der Krebspravention eine sehr wichtige Rolle spielen. Die Vitamine C und E sind wegen ihrer starken antioxidativen Nitritscavenger und Radikalfangereigenschaften als Inhibitoren der Peroxidations- und Nitrosierungsreaktion von groser Bedeutung. Diese Arbeit fast die bisher durchgefuhrte Forschung auf dem Gebiet der inhibitorischen Wirkung von Vitamin E zusammen. Daruber hinaus zeigt sie die neuesten Ergebnisse unserer in vitro Studie uber den hemmenden Effekt des Vitamin E und eines Mischtocopherolkonzentrats sowie die kumulative Wirkung von Vitamin e und C auf die Bildung von N-Nitroso-N-Methylanilin (NMNA). α-Tocopherol und das Mischtocopherolkonzentrat sind in der Lage, im wasrigen Reaktionsmedium unter physiologischen Bedingungen die Nitritkonzentration stark herabzusetzen und damit verbundene N-Nitrosaminbildung zu hemmen. Vitamine C und E zusammen besitzen einen starkeren Nitritscavengereffekt als das einzelne Vitamin. Die bisherigen Forschungsergebnisse weisen darauf hin, das die beiden Vitamine C und E bei der Verminderung der moglichen Exposition des Menschen gegenuber einigen carzinogenen N-Nitrosoverbindungen eine wichtige Rolle spielen konnen. Study on the Role of Vitamin E as Nitrite Scavenger and N-Nitrosamine Inhibitor N-nitrosamine are known for their powerful carcinogenicity. They may be formed under acidic conditions by interaction of nitrosable amino substrates and nitrosating agents such as nitrite, nitrate and nitroso gases. Several of recent investigations demonstrate that certain micronutrients such as vitamin A, C, and E and trace elements selenium and zinc play an important role in cancer prevention. Because of their strong antioxidative, nitrite scavenging and free radical quenching properties, vitamin C and E are capable of inhibiting the peroxidation and nitrosation reaction. This paper summarizes the research work done up to date in the field of inhibition of N-nitrosamine formation by vitamin E. It also includes the latest results of our in vitro study on the inhibitory influence of vitamin E and a mixture of tocopherols as well as the cumulative effect of vitamin C and E on the formation of N-nitroso-N-methylaniline (NMNA). α-tocopherol and the mixture of tocopherols are capable of reducing nitrite concentration in hydrophilic reaction medium and thus inhibits the formation of N-nitrosamine. Both vitamins together have a stronger nitrite scavenger effect than either of them alone. The results of research work done up to date strongly suggest that both vitamins may play an important role in reducing the health hazard of some carcinogenic N-nitroso compounds.

Phytic acid content of eight different types of leavened and unleavened flat breads was determined. It was highest in unleavened and non-fermented whole wheat chapati and lowest in the leavened and fermented white wheat flat bread roghni nan. The effect of baking conditions, bread composition and phytic acid content on in-vitro digestibility of protein was measured using a pepsin multienzyme pH stat technique. The amino acids released were separated by ultrafiltration. The rate of protein digestibility of flat bread and amino acid released depended upon the type of flour used, baking conditions, phytic acid content and other antiproteolytic constituents of breads. Leavening and fermentation of breads resulted in an increase of protein digestibility and availability of amino acids. Addition of soya flour increases the protein digestibility of breads whereas millet flour decreases it.

Synthese und Chemilumineszenz einiger 6-, 7- und 8-substituierter Benzo [f]phthalazin-l,4-(2H,3H)-dione werden beschrieben. 8-(Dimethylamino)benzo [f]phthalazin-l,4(2H,3H)-dion (7) leuchtet in wasrig-alkalischen Milieu etwa 1.5mal so stark wie Luminol. Die Chemilumineszenz der 7-(Dialkylamino)benzo[f]phthalazin-1,4(2H,3H)-dione 3a und 3b erreicht dagegen in Wasser oder in Dimethylsulfoxid nur 1–5 % der Lichtausbeute beim Luminol, was im wesentlichen auf sterische Resonanzhinderung zuruckzufuhren ist. In Dioxan als Losungsmittel chemilumineszieren die 7-Dialkylaminoderivate 3a und 3b jedoch mit etwa 1/3 der Quantenausbeute der 9-Dialkylaminoisomeren 1, die zu den am starksten leuchtenden, substituierten Benzo[f]phthalazin-l,4(2H,3H)-dionen gehoren. Constitution and Chemiluminescence, VI1). – Influence of the Positions of Substituents on the Chemiluminescence of Benzo[f]phthalazine-1,4(2H,3H)-diones Synthesis and chemiluminescence of some 6-, 7-, and 8-substituted benzo[f]phthalazine-1,4(2H,3H)-diones are described. 8-(Dimethylamino)benzo[f]phthalazine-l,4(2H,3H)-dione (7) chemiluminescences about 1.5 times as efficiently as luminol in aqueous-alkaline medium whereas 7-(dialkylamino)benzo[f]phthalazine-l,4(2H,3H)-diones 3a and 3b give only 1–5 % of the quantum yield of luminol in water as well as in dimethyl sulfoxide mainly due to steric inhibition of resonance. In dioxane the 7-dialkylamino derivatives 3a and 3b exhibit ca. 1/3 of the quantum yield of the 9-dialkylamino isomers 1 which belong to the most strongly chemiluminescing substituted benzo[f]phthalazine-l,4(2H,3H)-diones.