R1507, a fully human monoclonal antibody targeting IGF-1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts

Background The combination of rapamycin and R1507, a fully human IgG1 monoclonal antibody targeting the IGF-1 receptor (IGF-1R), in osteosarcoma xenograft tumors in vivo is evaluated in this report. Procedure Six osteosarcoma xenograft tumor models were evaluated for growth inhibition after monotherapy with R1507, rapamycin, and the combination of both drugs. Phosphorylation of proteins involved in IGF-1R signaling is evaluated at various time points by immunoblotting. Results IGF-1R was expressed in five of the six human osteosarcoma tumor lines. Objective responses to R1507 were seen in four of the six tumor lines (OS1, OS2, OS9, and OS17) including one complete response in OS1. IGF-1R protein levels did not predict degree of response to R1507 in the sensitive tumors. However, in one of the two R1507-resistant tumors (OS33), there was a minimal expression of IGF-1R. An increase in AKT phosphorylation was observed in all the osteosarcoma tumors treated with rapamycin. However, phosphorylation of AKT was inhibited when rapamycin was used in combination with R1507. In three of the xenograft tumor lines, there was an improvement in response when R1507 was used in combination with rapamycin. Conclusions IGF-1R inhibition by R1507 induced tumor growth delays and improvement in event-free survival in four of six osteosarcoma xenograft tumor lines. R1507 negates increased signaling through AKT in response to mammalian target of rapamycin inhibition, suggesting that the combination is worthy of further evaluation in patients. As R1507 and other IGF-1R inhibitors advance in clinical trials, it will be important to understand biomarkers of response and pathways of resistance. Pediatr Blood Cancer 2010;55:67–75. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75785/1/22479_ftp.pd

Socioeconomic Effect of Tourism in Nur-Sultan After EXPO-2017

Experts have studied tourism as an economic or social phenomenon but have overlooked its dual socioeconomic nature, which prevents public administrators from understanding the industry’s impact on local communities. This qualitative study conducted in a city in Central Asia addressed this problem by considering the views of tourism stakeholders related to the industry’s socioeconomic impact on the city’s local community in 2017. The theoretical framework included corporate social responsibility theory and organizational economics theory. Open-ended interviews with 15 tourism stakeholders from the city’s business, NGO, and government sectors provided data that were analyzed using two-cycle coding. Themes related to business, cultural and national identity awakening, educational revival, spatial greenification, proliferation of business and services, tourism’s multiplier effects, economic safety valve mechanisms, and boosted country name recognition. Findings may promote social-oriented officials and policies to improve the quality of tourism-development strategies, budgeting, and real-life projection. Findings may also help the city’s authorities define the pros and cons of tourism development to ensure responsible and sustainable development leading to positive social change

IRS-1: Auditing the effectiveness of mTOR inhibitors

Rapamycin analogs that inhibit mTOR signaling have antitumor activity against certain lymphomas, but treatment of solid tumors has been less encouraging despite inhibition of mTOR function. Two recent papers give insight into the potential use of mTOR inhibitors. O'Reilly et al. provide evidence that poor tumor response to rapamycins is the result of relieving mTOR-mediated feedback inhibition of insulin receptor substrate 1, and activation of Akt-mediated survival. In the second paper, Kaper et al. address the impact of pathway activation on hypoxia-mediated downregulation of mTOR signaling, raising the possibility that rapalogs could selectively inhibit hypoxic cells

Identification of Grimelysin-Like Metalloprotease Gene in the Genome of Bacterium Providencia stuartii

© 2016, Springer Science+Business Media New York.Providencia stuartii is an opportunistic pathogen often seen in patients with severe burns or long-term indwelling urinary catheters. Nowadays, the clinical significance of opportunistic microorganisms is growing and the study of their pathogenesis mechanisms is necessary. Microbial proteases are recognized as important virulence factors of diverse bacterial pathogens. We have shown that P. stuartii’s bacterial extracts have the ability to cleave actin. It is well known that metalloprotease grimelysin from Serratia grimesii is characterized by high specificity towards actin. Using the BLAST program, we identified a gene of hypothetical metalloprotease in the genome of the annotated strain P. stuartii MRSN 2154. We have constructed gene-specific primers and sequenced a homologous metalloprotease gene from clinical isolate P. stuartii NK. The amino acid sequence of this gene has the 42 % identity with grimelysin metalloprotease. In this study, we have done a comparative analysis of this novel protease from the clinical isolate of P. stuartii NK with the grimelysin from S. grimesii A2

Hydrogen sulfide inhibits giant depolarizing potentials and abolishes epileptiform activity of neonatal rat hippocampal slices

© 2016 IBROHydrogen sulfide (H2S) is an endogenous gasotransmitter with neuroprotective properties that participates in the regulation of transmitter release and neuronal excitability in various brain structures. The role of H2S in the growth and maturation of neural networks however remains unclear. The aim of the present study is to reveal the effects of H2S on neuronal spontaneous activity relevant to neuronal maturation in hippocampal slices of neonatal rats. Sodium hydrosulfide (NaHS) (100 μM), a classical donor of H2S produced a biphasic effect with initial activation and subsequent concentration-dependent suppression of network-driven giant depolarizing potentials (GDPs) and neuronal spiking activity. Likewise, the substrate of H2S synthesis L-cysteine (1 mM) induced an initial increase followed by an inhibition of GDPs and spiking activity. Our experiments indicate that the increase in initial discharge activity by NaHS is evoked by neuronal depolarization which is partially mediated by a reduction of outward K+ currents. The subsequent decrease in the neuronal activity by H2S appears to be due to the rightward shift of activation and inactivation of voltage-gated Na+ currents, thus preventing network activity. NaHS also reduced N-methyl-D-aspartate (NMDA)-mediated currents, without essential effect on AMPA/kainate or GABAA-mediated currents. Finally, H2S abolished the interictal-like events induced by bicuculline. In summary, our results suggest that through the inhibitory action on voltage-gated Na+ channels and NMDA receptors, H2S prevents the enhanced neuronal excitability typical to early hippocampal networks

Age-dependent, subunit specific action of hydrogen sulfide on GluN1/2A and GluN1/2B NMDA receptors

© 2017 Yakovlev, Kurmasheva, Ishchenko, Giniatullin and Sitdikova. Hydrogen sulfide (H 2 S) is an endogenously produced neuroactive gas implicated in many key processes in the peripheral and central nervous system. Whereas the neuroprotective role of H 2 S has been shown in adult brain, the action of this messenger in newborns remains unclear. One of the known targets of H 2 S in the nervous system is the N-methyl-D-aspartate (NMDA) glutamate receptor which can be composed of different subunits with distinct functional properties. In the present study, using patch clamp technique, we compared the effects of the H 2 S donor sodium hydrosulfide (NaHS, 100 µM) on hippocampal NMDA receptor mediated currents in rats of the first and third postnatal weeks. This was supplemented by testing effects of NaHS on recombinant GluN1/2A and GluN1/2B NMDA receptors expressed in HEK293T cells. The main finding is that NaHS action on NMDA currents is age-dependent. Currents were reduced in newborns but increased in older juvenile rats. Consistent with an age-dependent switch in NMDA receptor composition, in HEK239T cells expressing GluN1/2A receptors, NaHS increased NMDA activated currents associated with acceleration of desensitization and decrease of the deactivation rate. In contrast, in GluN1/2B NMDA receptors, which are prevalent in newborns, NaHS decreased currents and reduced receptor deactivation without effect on the desensitization rate. Adenylate cyclase inhibitor MDL-12330A (10 µM) did not prevent the age-dependent effects of NaHS on NMDA evoked currents in pyramidal neurons of hippocampus. The reducing agent dithiothreitol (DTT, 2 mM) applied on HEK293T cells prevented facilitation induced by NaHS on GluN1/2A NMDA receptors, however in GluN1/2B NMDA receptors the inhibitory effect of NaHS was still observed. Our data indicate age-dependent effect of H 2 S on NMDA receptor mediated currents determined by glutamate receptor subunit composition. While the inhibitory action of H 2 Son GluN1/2B receptors could limit the excessive activation in early age, the enhanced functionality of GluN1/2A receptor in the presence of this gasotransmitter can enlarge synaptic efficacy and promote synaptic plasticity in adults

Some Aspects of Mathematical Modeling of the Geometric Structure of Porous Vermiculite Adsorbents Used in the Refining of Vegetable Oils

Currently there are high requirements for the quality of vegetable oils and fats, which is ensured only by a highly efficient technological cleaning process. Adsorption refining has become widespread, since the resulting products not only satisfy consumer demand, but also allow the removal of oxidation products, free radicals and other carcinogenic impurities from the oil. For such oil purification, it is necessary to select not only optimal oil refining modes, but also using effective adsorbents and bleach lands. This article describes some aspects of mathematical modeling of the geometric structure of porous adsorbents, since one of the main tasks of porous adsorbents production is creation of high porosity, which is also characterized by the uniformity of the pore distribution over the volume of the layer. Ensuring optimal modes of porization processes and achieving the necessary geometric characteristics of the adsorption layer requires an understanding of the features of the layer structure formation and a theoretical description of this complex process, as well as the results of studies on the purification of cottonseed oil with expanded vermiculite from the Kulantau deposit and the characteristics of a new adsorbent for vegetable oils are presented. Practical application development of theoretical aspects of the vermiculite adsorbent porosity effect on the quality of refined vegetable oil. Key words: vegetable oil, adsorbent, Kulantau, vermiculite, porosity, geometric structure, refining

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Predicted mechanisms of resistance to mTOR inhibitors

The serine/threonine kinase, mTOR (mammalian Target of Rapamycin) has become a focus for cancer drug development. Rapamycins are highly specific inhibitors of mTOR and potently suppress tumour cell growth by retarding cells in G1 phase or potentially inducing apoptosis. Currently, both rapamycin and several analogues are being evaluated as anticancer agents in clinical trials. Results indicate that many human cancers have intrinsic resistance and tumours initially sensitive to rapamycins become refractory, demonstrating acquired resistance. Here, we consider mechanisms of resistance to inhibitors of mTOR

A simple algorithm for quantifying DNA methylation levels on multiple independent CpG sites in bisulfite genomic sequencing electropherograms

DNA methylation at cytosines is a widely studied epigenetic modification. Methylation is commonly detected using bisulfite modification of DNA followed by PCR and additional techniques such as restriction digestion or sequencing. These additional techniques are either laborious, require specialized equipment, or are not quantitative. Here we describe a simple algorithm that yields quantitative results from analysis of conventional four-dye-trace sequencing. We call this method Mquant and we compare it with the established laboratory method of combined bisulfite restriction assay (COBRA). This analysis of sequencing electropherograms provides a simple, easily applied method to quantify DNA methylation at specific CpG sites