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Publication Open Access Activating mutations of STAT5B and STAT3 in lymphomas derived from ??-T or NK cells.(Nature Publishing Group (NPG), 2015) Kucuk, Can; Jiang, Bei; Hu, Xiaozhou; Zhang, Wenyan; Chan, John K. C.; Xiao, Wenming; Alkan, Can; Williams, John C.; Avery, Kendra N.; Kavak, Pinar; Scuto, Anna; Gaulard, Philippe; Staudt, Lou; Iqbal, Javeed; Zhang, Weiwei; Cornish, Adam; Gong, Qiang; Yang, Qunpei; Sun, Hong; d'Amore, Francesco; Leppa, Sirpa; Liu, Weiping; Fu, Kai; de Leval, Laurence; McKeithan, Timothy; Chan, Wing C.; N/A; Department of Chemical and Biological Engineering; Lack, Nathan Alan; Kılıç, Emel Şen; Faculty Member; Department of Chemical and Biological Engineering; School of Medicine; Graduate School of Sciences and Engineering; 120842; N/ALymphomas arising from NK or gamma delta-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n - 51), gamma delta-T-cell lymphomas (n - 43) and their cell lines (n = 9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of gamma delta-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy.Publication Open Access Aerogels in drug delivery: from design to application(Elsevier, 2021) García-González, C. A.; Sosnik, A.; Kalmar, J.; De Marco, I.; Concheiro, A.; Alvarez-Lorenzo, C.; Department of Chemical and Biological Engineering; Erkey, Can; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 29633Aerogels are the lightest processed solid materials on Earth and with the largest empty volume fraction in their structure. Composition versatility, modularity, and feasibility of industrial scale manufacturing are behind the fast emergence of aerogels in the drug delivery field. Compared to other 3D materials, the high porosity (interconnected mesopores) and high specific surface area of aerogels may allow faster loading of small-molecule drugs, less constrained access to inner regions of the matrix, and more efficient interactions of the biological milieu with the polymer matrix. Processing in supercritical CO2 medium for both aerogel production (drying) and drug loading (impregnation) has remarkable advantages such as absence of an oxidizing environment, clean manufacture, and easiness for the scale-up under good manufacturing practices. The aerogel solid skeleton dictates the chemical affinity to the different drugs, which in turn determines the loading efficiency and the release pattern. Aerogels can be used to increase the solubility of BCS Class II and IV drugs because the drug can be deposited in amorphous state onto the large surface area of the skeleton, which facilitates a rapid contact with the body fluids, dissolution, and release. Conversely, tuning the aerogel structure by functionalization with drug-binding moieties or stimuli-responsive components, application of coatings and incorporation of drug-loaded aerogels into other matrices may enable site-specific, stimuli-responsive, or prolonged drug release. The present review deals with last decade advances in aerogels for drug delivery. An special focus is paid first on the loading efficiency of active ingredients and release kinetics under biorelevant conditions. Subsequent sections deal with aerogels intended to address specific therapeutic demands. In addition to oral delivery, the physical properties of the aerogels appear to be very advantageous for mucosal administration routes, such as pulmonary, nasal, or transdermal. A specific section devoted to recent achievements in gene therapy and theranostics is also included. In the last section, scale up strategies and life cycle assessment are comprehensively addressed.Publication Open Access Day-time isoflurane administration suppresses circadian gene expressions in both the brain and a peripheral Organ, Liver(Turkish Society of Anaesthesiology and Reanimation, 2017) Gökmen, Necati; Barış, İbrahim; Öçmen, Elvan; Yılmaz, Osman; Günerli, Ali; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; Barış, İbrahim; Kavaklı, İbrahim Halil; Teaching Faculty; Department of Molecular Biology and Genetics; Department of Chemical and Biological Engineering; School of Medicine; College of Engineering; 111629; 40319Objective: The aim of this study is to investigate the effects of light and administration time of isoflurane on circadian gene expression in the brains and liver tissues of rats kept in light-dark cycle. Methods: Seventy tw o 15-days-old rats pups were divided into four groups. All animals were exposed to 1.5% concentration of isoflurane or to 6 L min(-1) O-2 for six hours between Zeitgeber Time (ZT) 0-ZT06 ( day-time administration) or ZT12-ZT18 ( night-time administration). Rats were sacrificed after six hours of anaesthesia with four-hour time intervals. Total RNA was isolated from brains and liver tissues. Circadian gene expression was examined using quantitative real-time Reverse transcription polymerase chain reaction (RT-PCR). Results: BMAL1, CLOCK, PER2 and CRY2 gene expression levels were markedly suppressed after day-time anaesthesia in the both brain and liver, but night-time administration caused only temporary suppression of gene expression. Conclusion: The effect of isoflurane on the circadian clock is time-dependent, and administered isoflurane anaesthesia at night had minimal effect on clock gene expression. Additionally, when the treated animals were kept in a regular light-dark cycle, isoflurane-induced phase shift was not observed, possibly because of the light.Publication Open Access Identification of interconnected markers for T-cell acute lymphoblastic leukemia(Hindawi, 2013) Ng, Özden Hatırnaz; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; N/A; 26605; 8745T-cell acute lymphoblastic leukemia (T-ALL) is a complex disease, resulting from proliferation of differentially arrested immature T cells. The molecular mechanisms and the genes involved in the generation of T-ALL remain largely undefined. In this study, we propose a set of genes to differentiate individuals with T-ALL from the nonleukemia/healthy ones and genes that are not differential themselves but interconnected with highly differentially expressed ones. We provide new suggestions for pathways involved in the cause of T-ALL and show that network-based classification techniques produce fewer genes with more meaningful and successful results than expression-based approaches. We have identified 19 significant subnetworks, containing 102 genes. The classification/prediction accuracies of subnetworks are considerably high, as high as 98%. Subnetworks contain 6 nondifferentially expressed genes, which could potentially participate in pathogenesis of T-ALL. Although these genes are not differential, they may serve as biomarkers if their loss/gain of function contributes to generation of T-ALL via SNPs. We conclude that transcription factors, zinc-ion-binding proteins, and tyrosine kinases are the important protein families to trigger T-ALL. These potential disease-causing genes in our subnetworks may serve as biomarkers, alternative to the traditional ones used for the diagnosis of T-ALL, and help understand the pathogenesis of the disease.