Probing the Metabolic Phenotype of Breast Cancer Cells by Multiple Tracer Stable Isotope Resolved Metabolomics

Breast cancers vary by their origin and specific set of genetic lesions, which gives rise to distinct phenotypes and differential response to targeted and untargeted chemotherapies. To explore the functional differences of different breast cell types, we performed Stable Isotope Resolved Metabolomics (SIRM) studies of one primary breast (HMEC) and three breast cancer cells (MCF-7, MDAMB-231, and ZR75-1) having distinct genotypes and growth characteristics, using 13C6-glucose, 13C-1+2-glucose, 13C5,15N2-Gln, 13C3-glycerol, and 13C8-octanoate as tracers. These tracers were designed to probe the central energy producing and anabolic pathways (glycolysis, pentose phosphate pathway, Krebs Cycle, glutaminolysis, nucleotide synthesis and lipid turnover). We found that glycolysis was not associated with the rate of breast cancer cell proliferation, glutaminolysis did not support lipid synthesis in primary breast or breast cancer cells, but was a major contributor to pyrimidine ring synthesis in all cell types; anaplerotic pyruvate carboxylation was activated in breast cancer versus primary cells. We also found that glucose metabolism in individual breast cancer cell lines differed between in vitro cultures and tumor xenografts, but not the metabolic distinctions between cell lines, which may reflect the influence of tumor architecture/microenvironment

Optical coherence tomography angiography in pediatric choroidal neovascularization

Purpose To report two cases of pediatric choroidal neovascularization (CNV) and the associated neo-vascular and retinal findings identified on Optical Coherence Tomography Angiography (OCTA) imaging. Methods: A 14-year-old boy with handheld laser-induced maculopathy-related CNV and a 13-year-old boy with idiopathic CNV were evaluated with visual acuity testing, slit-lamp exam, fundus photography, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, and OCTA. Results: Macular CNV were identified in both pediatric patients using OCTA imaging. The first case demonstrated a classic pediatric type II CNV with a “tree-like” pattern and a single vessel in-growth site, while the second case demonstrated a type I CNV with a “glomerular” pattern. Conclusion: Distinct choroidal neovascular patterns were visualized in these two cases of pediatric CNV when compared to adult subtypes. OCTA is a noninvasive imaging modality capable of evaluating and characterizing pediatric CNV and their associated vascular patterns

Pyruvate Carboxylase Is Critical for Non-Small-Cell Lung Cancer Proliferation

Anabolic biosynthesis requires precursors supplied by the Krebs cycle, which in turn requires anaplerosis to replenish precursor intermediates. The major anaplerotic sources are pyruvate and glutamine, which require the activity of pyruvate carboxylase (PC) and glutaminase 1 (GLS1), respectively. Due to their rapid proliferation, cancer cells have increased anabolic and energy demands; however, different cancer cell types exhibit differential requirements for PC- and GLS-mediated pathways for anaplerosis and cell proliferation. Here, we infused patients with early-stage non-small-cell lung cancer (NSCLC) with uniformly 13C-labeled glucose before tissue resection and determined that the cancerous tissues in these patients had enhanced PC activity. Freshly resected paired lung tissue slices cultured in 13C6-glucose or 13C5,15N2-glutamine tracers confirmed selective activation of PC over GLS in NSCLC. Compared with noncancerous tissues, PC expression was greatly enhanced in cancerous tissues, whereas GLS1 expression showed no trend. Moreover, immunohistochemical analysis of paired lung tissues showed PC overexpression in cancer cells rather than in stromal cells of tumor tissues. PC knockdown induced multinucleation, decreased cell proliferation and colony formation in human NSCLC cells, and reduced tumor growth in a mouse xenograft model. Growth inhibition was accompanied by perturbed Krebs cycle activity, inhibition of lipid and nucleotide biosynthesis, and altered glutathione homeostasis. These findings indicate that PC-mediated anaplerosis in early-stage NSCLC is required for tumor survival and proliferation

Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer

Acknowledgements: The authors thank Mr. Maron Lee Barrett and Ms. Mayra Star for their technical help. The authors thank Dr. Dejian Ma for his technical help with the NMR studies. The authors thank the UTHSC and St. Jude NMR core for their help with the NMR studies. The authors thank Drs. Robert Getzenberg and Michael Mohler for providing useful comments on the manuscript. The authors thank Ms. Brandy Grimes for her help with tissue procurement. The authors thank Dr. Daniel Johnson of UT BioCore for microarray data analysis and Mr. Lorne Rose of UT-MRC core for microarray studies. Funding Source: The research presented in this manuscript was supported by a research funding provided by GTx, Inc. Memphis, TN to R. Narayanan and by a research funding provided by West Cancer Center to R. Narayanan.Peer reviewedPostprin

Melhoramento genético de citros por meio de mutações espontâneas de gemas.

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Helminth infection protects against high fat diet-induced obesity via induction of alternatively activated macrophages

Epidemiological studies indicate an inverse correlation between the prevalence of the so-called western diseases, such as obesity and metabolic syndrome, and the exposure to helminths. Obesity, a key risk factor for many chronic health problems, is rising globally and is accompanied by low-grade inflammation in adipose tissues. The precise mechanism by which helminths modulate metabolic syndrome and obesity is not fully understood. We infected high fat diet (HFD)-induced obese mice with the intestinal nematode parasite Heligmosomoides polygyrus and observed that helminth infection resulted in significantly attenuated obesity. Attenuated obesity corresponded with marked upregulation of uncoupling protein 1 (UCP1), a key protein involved in energy expenditure, in adipose tissue, suppression of glucose and triglyceride levels, and alteration in the expression of key genes involved in lipid metabolism. Moreover, the attenuated obesity in infected mice was associated with enhanced helminth-induced Th2/Treg responses and M2 macrophage polarization. Adoptive transfer of helminth-stimulated M2 cells to mice that were not infected with H. polygyrus resulted in a significant amelioration of HFD-induced obesity and increased adipose tissue browning. Thus, our results provide evidence that the helminth-dependent protection against obesity involves the induction of M2 macrophages

The role of metallic dopants in improving the thermal stability of the electron transport layer in organic light-emitting diodes

This research was financially supported by the EPSRC NSF - CBET lead agency agreement (EP/R010595/1, 1706207), the DARPA-NESD program (N66001-17-C-4012) and by the EPSRC CDT Capital Equipment funding stream (EP/L017008/1). C.- M.K. acknowledges support from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1A6A3A03012331). C.M. acknowledges funding by the European Commission through a Marie Skłodowska Curie Individual Fellowship (703387). Y.D., W.L., and M.W. acknowledge stipends from the Chinese Scholarship Council (CSC). I.D.W.S. acknowledges support from a Royal Society Wolfson research merit award.4,7‐Diphenyl‐1,10‐phenanthroline (BPhen) is widely used to create the electron transport layer (ETL) in organic light‐emitting diodes (OLEDs) because of its high electron mobility and good compatibility with alkali metal n‐dopants. However, the morphology of these ETLs is easily altered by heating due to the relatively low glass transition temperature (Tg) of BPhen and this change often reduces the performance of OLEDs. Here, an enhancement in the thermal stability of OLEDs when doping their BPhen‐based ETLs with cesium (Cs) is reported. To investigate the role of the Cs dopant in the BPhen matrix, the crystallization features of Cs‐doped BPhen films with different doping concentrations are examined. Next, the electrical and optical properties of blue fluorescent and red phosphorescent OLEDs containing Cs‐doped BPhen ETLs are characterized after annealing the OLEDs at temperatures up to 100 °C. Cs plays a critical role in inhibiting the undesired crystallization of BPhen films, which enhances the thermal stability of OLEDs beyond the Tg of neat BPhen. Finally, highly stable BPhen‐based OLEDs encapsulated via atomic layer deposition at 80 °C are demonstrated. This work may lead to a new strategy for enhancing the intrinsic thermal durability of organic devices and their compatibility with thermally demanding processes.PostprintPeer reviewe