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

Tick Extracellular Vesicles Enable Arthropod Feeding and Promote Distinct Outcomes of Bacterial Infection

Extracellular vesicles are thought to facilitate pathogen transmission from arthropods to humans and other animals. Here, we reveal that pathogen spreading from arthropods to the mammalian host is multifaceted. Extracellular vesicles from Ixodes scapularis enable tick feeding and promote infection of the mildly virulent rickettsial agent Anaplasma phagocytophilum through the SNARE proteins Vamp33 and Synaptobrevin 2 and dendritic epidermal T cells. However, extracellular vesicles from the tick Dermacentor andersoni mitigate microbial spreading caused by the lethal pathogen Francisella tularensis. Collectively, we establish that tick extracellular vesicles foster distinct outcomes of bacterial infection and assist in vector feeding by acting on skin immunity. Thus, the biology of arthropods should be taken into consideration when developing strategies to control vector-borne diseases

Priority areas for development of scientific research: domestic and foreign experience

The collective monograph describes the priority areas for development of scientific research: domestic and foreign experience. The general issues of economic theory and history, economics and business management, finance and tax policy, modern management, public management and administration, etc. are considered. The publication is intended for scholars, teachers, postgraduate students, and students, as well as a wide readership

HPLC-FLD analysis of amino acids content in Chrysanthemum morifolium

Chrysanthemum morifolium (Asteraceae family) have long been used as a tonic, antioxidant, antipyretic, analgesic, sedative, antitumor, neuroprotector, hepatoprotector and cardioprotector agent. This species should be reconsidered as possible sources of many biocompounds, especially amino acids. Thus, the aim of this study was to validate the chromatographic method for detection of amino acids and their identification in flowers and leaves of Ch. morifolium of variant Pectoral. HPLC-FLD method was evaluated in terms of linearity, precision, repeatability, accuracy, LOD and LOQ. The calibration curves of all analytical standards of amino acids were linear (R2 > 0.99) over the range of 0.015–0.625 μmol/mL, the LODs and the LOQs were in the range of 0.001–0.096 µg/mL and 0.004–0.321 µg/mL, respectively. During the HPLC-FLD assay ten amino acids in free form and fifteen amino acids after hydrolysis in Ch. morifolium flowers were identified. Besides, twelve amino acids were detected in free form and fourteen amino acids after hydrolysis in Ch. morifolium leaves. The results of HPLC-FLD analysis showed that the predominant amino acid was L-proline in both types of herbal raw materials. Its total content was 31.67±0.02 μg/mg in Ch. morifolium flowers and 18.56±0.02 μg/mg in Ch. morifolium leaves. This phytochemical study confirms that flowers and leaves of Ch. morifolium (Pectoral) are rich sources of amino acids and can exhibit a wide range of pharmacological activities

Role of carbonyl modifications on aging-associated protein aggregation

Protein aggregation is a common biological phenomenon, observed in different physiological and pathological conditions. Decreased protein solubility and a tendency to aggregate is also observed during physiological aging but the causes are currently unknown. Herein we performed a biophysical separation of aging-related high molecular weight aggregates, isolated from the bone marrow and splenic cells of aging mice and followed by biochemical and mass spectrometric analysis. The analysis indicated that compared to younger mice an increase in protein post-translational carbonylation was observed. The causative role of these modifications in inducing protein misfolding and aggregation was determined by inducing carbonyl stress in young mice, which recapitulated the increased protein aggregation observed in old mice. Altogether our analysis indicates that oxidative stress-related post-translational modifications accumulate in the aging proteome and are responsible for increased protein aggregation and altered cell proteostasis

Age-Related Oxidative Stress Compromises Endosomal Proteostasis

A hallmark of aging is an imbalance between production and clearance of reactive oxygen species and increased levels of oxidatively damaged biomolecules. Herein, we demonstrate that splenic and nodal antigen-presenting cells purified from aging mice accumulate oxidatively modified proteins with side-chain carbonylation, advanced glycation end products, and lipid peroxidation. Furthermore, we show that the endosomal accumulation of oxidatively modified proteins interferes with the efficient processing of exogenous antigens and degradation of macroautophagy-delivered proteins. In support of a causative role for oxidized products in the inefficient immune response, a decrease in oxidative stress improved the adaptive immune response to immunizing antigens. These findings underscore a previously unrecognized negative effect of age-dependent changes in cellular proteostasis on the immune response

Structural and Biological Interaction of hsc-70 Protein with Phosphatidylserine in Endosomal Microautophagy*

hsc-70 (HSPA8) is a cytosolic molecular chaperone, which plays a central role in cellular proteostasis, including quality control during protein refolding and regulation of protein degradation. hsc-70 is pivotal to the process of macroautophagy, chaperone-mediated autophagy, and endosomal microautophagy. The latter requires hsc-70 interaction with negatively charged phosphatidylserine (PS) at the endosomal limiting membrane. Herein, by combining plasmon resonance, NMR spectroscopy, and amino acid mutagenesis, we mapped the C terminus of the hsc-70 LID domain as the structural interface interacting with endosomal PS, and we estimated an hsc-70/PS equilibrium dissociation constant of 4.7 ± 0.1 μm. This interaction is specific and involves a total of 4-5 lysine residues. Plasmon resonance and NMR results were further experimentally validated by hsc-70 endosomal binding experiments and endosomal microautophagy assays. The discovery of this previously unknown contact surface for hsc-70 in this work elucidates the mechanism of hsc-70 PS/membrane interaction for cytosolic cargo internalization into endosomes