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Qiang Wang, Feiyang Liu, Shuang Qi, Ziping Qi, Xiao-E Yan, Beilei Wang, Aoli Wang, Wei Wang, Cheng Chen, Xiaochuan Liu, Zongru Jiang, Zhenquan Hu, Li Wang, Wenchao Wang, Tao Ren, Shanchun Zhang, Cai-Hong Yun, Qingsong Liu, Jing Liu
Through exploration of the non-highly conserved allosteric hydrophobic pocket generated by DFG-out shifting in the inactive conformation, we discovered a highly selective type II PDGFRα kinase inhibitor 15i (CHMFL-PDGFRα-159), which exhibited strong potency against purified PDGFRα (IC50 : 132 nM) but not structurally similar PDGFRβ, ABL, c-KIT and VEGFR2 kinases. In addition, it displayed a high selectivity profile (S score (10) = 0.02) at the concentration of 1 μM among 468 kinases/mutants in the KINOMEscan profiling...
March 12, 2018: European Journal of Medicinal Chemistry
Giorgio Ivan Russo, Simone Bier, Jörg Hennenlotter, Gunthild Beger, Lucretia Pavlenco, Jens van de Flierdt, Siegfried Hauch, Moritz Maas, Simon Walz, Steffen Rausch, Jens Bedke, Giuseppe Morgia, Arnulf Stenzl, Tilman Todenhöfer
OBJECTIVE: To evaluate the presence of circulating tumour cells (CTC) at different stages of prostate cancer (PC) using the ProstateCancerDetect kit. Moreover, we aimed to assess the expression of transcripts that are specific for cancer stem cells (AdnaTest StemCell) and epithelial mesenchymal transition (EMT) in CTC (AdnaTest EMT) as well as additional genes that are known to promote PC progression. PATIENTS AND METHODS: In this prospective study, we included 81 patients who underwent treatment for PC between 07/2014 and 02/2015, including A) 18 patients (22...
March 15, 2018: BJU International
N Kaji, S Nakayama, K Horiguchi, S Iino, H Ozaki, M Hori
BACKGROUND: Interstitial cells of Cajal (ICC) serve as intestinal pacemakers. Postoperative ileus (POI) is a gastrointestinal motility disorder that occurs following abdominal surgery, which is caused by inflammation-induced dysfunction of smooth muscles and enteric neurons. However, the participation of ICC in POI is not well understood. In this study, we investigated the functional changes of ICC in a mouse model of POI. METHODS: Intestinal manipulation (IM) was performed to induce POI...
March 15, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Y Liu, T Lei, Y Shi, X Y Wang, M L Sun, W X Fan, Z N Zhang, M Jiang
Objective: To explore the expression and significance of Set gene in Acute myeloid leukemia (AML) patients , and to analyze its effect for the prognosis of AML. Methods: The level of Set gene expression was detected by real-time PCR in 59 AML patients and 20 heathy people. The mutations in C-kit 8/17 gene, NPM1 gene and FLT3-TKD/ITD gene in 59 AML patients were detected by direct sequencing. Results: The level of Set gene expression[1.41(0.41-3.31)]was significantly higher in 59 AML patients.The expression of Set gene was correlated with the percentage of marrow blasts and CR in AML patients ( P =0...
March 6, 2018: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Ivan Hernandez, Jonathan M Baio, Eric Tsay, Aida F Martinez, Tania I Fuentes, Leonard L Bailey, Nahidh W Hasaniya, Mary Kearns-Jonker
The use of cardiovascular progenitor cells (CPCs) to repair damaged myocardium has been the focus of intense research. Previous reports have shown that pretreatments, including hypoxia, improve cell function. However, the age-dependent effects of short-term hypoxia on CPCs, and the role of signaling in these effects, are unknown. Cloned neonatal and adult CPCs expressing Isl1, c-Kit, KDR, PDGFRA, and CXCR4, were preconditioned using hypoxia (1% O2 for six hours). Intracellular signaling pathway changes were modeled using Ingenuity Pathway Analysis (IPA), while qRT-PCR, flow cytometry, and immunoblotting were used to measure pathway activation...
2018: American Journal of Stem Cells
Daniel Giglio, Lucie Podmolikova, Gunnar Tobin
Currently, we have assessed the neuronal control of the urinary bladder in radiation cystitis and whether interstitial cells contribute to the condition. Fourteen days following bladder irradiation (20 Gy) rats were sedated and the urinary bladder was cut in two sagittal halves where electrical field stimulation (EFS; 5-20 Hz) was applied on the pelvic nerve afferents or stretch (80 mN) on one half of the urinary bladder, while contractions were registered on the contralateral half of the urinary bladder in the absence and presence of increasing doses of imatinib (1-10 mg/kg; inhibitor of c-kit+ interstitial cells), atropine (1 mg/kg; to block muscarinic M3 receptors) or PPADS (2 mg/kg; to block P2X1 purinoceptors)...
March 12, 2018: Journal of Pharmacology and Experimental Therapeutics
Misun Kim, Takako Shibata, Soohyun Kwon, Tae Jun Park, Hee Young Kang
Ultraviolet (UV)-associated hyperpigmented skins are characterized with increased vasculature underlying pigmentation, suggestive of the possible biological role of endothelial cells in the regulation of skin pigmentation during UV irradiation. In this study, we showed that UV-irradiated endothelial cells significantly increased the pigmentation of melanocytes through epithelial-mesenchymal crosstalk. The stimulatory effect of endothelial cells was further demonstrated using ex vivo human skin. RNA sequence analysis and enzyme-linked immunosorbent assay showed that endothelial cells secrete more stem cell factor (SCF) upon UV irradiation than non-irradiated cells...
March 9, 2018: Scientific Reports
Jing Xu, Hong Xu, Yang Yu, Yi He, Qi Liu, Bo Yang
BACKGROUND The purpose of the present study was to assess the effect of luteolin and solifenacin on diabetic cystopathy (DCP) and to investigate the mechanism of action. A novel link between the overexpression of c-Kit in the bladder and voiding dysfunction was identified in rats with DCP. MATERIAL AND METHODS A rat model of DCP was successfully established by intraperitoneal injection of streptozotocin and a diet high in glucose and lipids, and animals were treated with luteolin and solifenacin. The effect of luteolin and solifenacin on urinary dysfunction in DCP rats was investigated by assessing bladder pressure and performing a volume test...
March 10, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
A Belin-Rauscent, J Lacoste, O Hermine, A Moussy, B J Everitt, David Belin
RATIONALE: Accumulating evidence shows that cocaine, and also heroin, influence several tyrosine kinases, expressed in neurons and in non-neuronal populations such as microglia, astrocytes and mast-cells. Drug-induced activation of mast cells both triggers inflammatory processes in the brain mediated by the glial cells they activate, and facilitates histamine release which may directly influence the dopamine system. Thus, by triggering the activation and degranulation of mast cells dependent on the tyrosine kinase c-kit and Fyn, the latter being also involved in NMDA-dependent synaptic plasticity, cocaine and heroin may indirectly influence the neural mechanisms that mediate their reinforcing properties...
March 8, 2018: Psychopharmacology
Brittni M Foster, Danish Zaidi, Tyler R Young, Mary E Mobley, Bethany A Kerr
Metastasis is the primary cause of cancer patient morbidity and mortality, but due to persisting gaps in our knowledge, it remains untreatable. Metastases often occur as patient tumors progress or recur after initial therapy. Tumor recurrence at the primary site may be driven by a cancer stem-like cell or tumor progenitor cell, while recurrence at a secondary site is driven by metastatic cancer stem cells or metastasis-initiating cells. Ongoing efforts are aimed at identifying and characterizing these stem-like cells driving recurrence and metastasis...
March 8, 2018: Biomedicines
Maria Rita Gaiser, Nikolas von Bubnoff, Christoffer Gebhardt, Jochen Sven Utikal
During the last six years, several innovative, systemic therapies for the treatment of metastatic malignant melanoma (MM) have emerged. Conventional chemotherapy has been superseded by novel first-line therapies, including systemic immunotherapies (anti-CTLA4 and anti-PD1; authorization of anti-PDL1 is anticipated) and therapies targeting specific mutations (BRAF, NRAS, and c-KIT). Thus, treating physicians are confronted with new challenges, such as stratifying patients for appropriate treatments and monitoring long-term responders for progression...
March 7, 2018: Journal der Deutschen Dermatologischen Gesellschaft, Journal of the German Society of Dermatology: JDDG
Feng Wang, Hongyan Li, Ela Markovsky, Ryan Glass, Elisa de Stanchina, Simon N Powell, Gary K Schwartz, Adriana Haimovitz-Friedman
Recent data in our laboratory indicate that engagement of host-derived microenvironmental elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal damage of SDRT. Using a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice we showed that activation of this enzyme by SDRT-induced damage in the endothelium is mandatory for tumor cure. ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which increased the vulnerability of tumor cells to lethal damage by radiation...
February 6, 2018: Oncotarget
Donatienne Van Weehaeghe, Olivier Gheysens, Vincent Vandecaveye, Patrick Schöffski, Koen Van Laere, Christophe M Deroose
BACKGROUND: Gastro-intestinal stromal tumors (GISTs) are very rare tumors of the gastro-intestinal tract, originating from the interstitial cells of Cajal or a common cell precursor which both express type III tyrosine kinase receptors. Regorafenib is an oral multi-kinase inhibitor used to treat gastro-intestinal stromal tumors. To our knowledge this is the first case in literature to show the response of regorafenib on PET. CASE PRESENTATION: A 37-year-old male with lower abdominal pain and weight loss was referred to our hospital...
March 5, 2018: BMC Cancer
Silvia Park, Hangseok Choi, Hee Je Kim, Jae-Sook Ahn, Hyeoung-Joon Kim, Sung-Hyun Kim, Yeung-Chul Mun, Chul Won Jung, Dennis Dong Hwan Kim
The present study attempted to build a single nucleotide polymorphism (SNP)-based risk model for predicting overall survival (OS) and event-free survival (EFS) in patients with core binding factor acute myeloid leukemia (CBF-AML). Adopting genome-wide SNP array using Affymetrix SNP array 6.0, we analyzed 868,157 SNPs with respect to OS and EFS in 104 patients with CBF-AML. Significant SNPs were identified from single SNP analysis. The risk model was constructed with incorporation of six SNPs and three clinical factors (age, c-kit exon 17 mutation, and LDH) for OS and six SNPs and three clinical factors (age, WBC, and LDH) for EFS...
March 2, 2018: Annals of Hematology
Josefina Reyes-Sebastian, Laura Arcelia Montiel-Cervantes, Elba Reyes-Maldonado, Maria Lilia Dominguez-Lopez, Rocio Ortiz-Butron, Aida Castillo-Alvarez, Ruth Angélica Lezama
Receptor tyrosine kinase (RTK) activity may contribute to carcinogenesis. The c-Kit receptor, a member of the RTK family, is expressed in immature haematopoietic system cells. Acute lymphoblastic leukaemia (ALL) presents incompletely differentiated lymphoblasts, and consequently, c-Kit expression can be detected in these cells. The BCR-ABL kinase, which is usually present in both ALL and chronic myeloid leukaemia, can trigger signalling pathways with neoplastic effects. However, a certain number of ALL patients and chronic myeloid leukaemia patients do not express this kinase, raising the question of which other proteins that intervene in signalling pathways may be involved in the development of these diseases...
March 1, 2018: Hematology (Amsterdam, Netherlands)
Masoome Jabarpour, Parviz Tajik
Background: Spermatogonial stem cells (SSCs) are undifferentiated cells which are highly reproducible and expandable. Several studies have been conducted to reproduce these cells in culture. They used growth factors, hormones and different feeder cells to improve survival and proliferation of SSCs. Objective: This study was conducted to evaluate the effects of follicular stimulating hormone (FSH) on gene expression of fibroblast growth factor (FGF2) and glial cell-derived neurotrophic factor (GDNF) in Sertoli cells...
December 2017: International Journal of Reproductive Biomedicine (Yazd, Iran)
Kenneth Yan, Jessica Yesensky, Rifat Hasina, Nishant Agrawal
Objective: To report on the current state of the literature on the genetics of mucoepidermoid and adenoid cystic carcinomas of the salivary glands with a focus on genomic screens and recently discovered genetic translocations. Methods: A PubMed based literature review was performed to query for genetics related basic science and preclinical studies about mucoepidermoid and adenoid cystic carcinomas of the salivary glands. Results and conclusions: Genetic translocations between CRTC1 and MAML2 in mucoepidermoid carcinoma and between MYB and NFIB in adenoid cystic carcinoma have been recently discovered and have therapeutic implications...
February 2018: Laryngoscope Investigative Otolaryngology
Hassan Tariq, Saba Anjum, Hafeez Ud Din, Farhan Akhtar
Background & Objective: To evaluate usefulness of immunohistochemical marker C-kit (CD117) in differentiating Adenoid cystic carcinoma (AdCC) from Polymorphous low-grade adenocarcinoma (PLGA) in patients of salivary gland carcinomas. AdCC is a malignant salivary gland neoplasm with poor prognosis. PLGA is a salivary gland malignancy with indolent growth pattern. Differentiating between the two entities is a diagnostic challenge. We evaluated the role of C-kit in differentiating the two...
November 2017: Pakistan Journal of Medical Sciences Quarterly
Chetana Chandrashekar, Subhalakshmi Sen, Venkadasalapathi Narayanaswamy, Raghu Radhakrishnan
We appraise a case of central odontogenic fibroma (COF) with unusual histologic features of entrapped neural elements and mast cells. The presence of mast cells attributed to the release of stem cell factor, the principal growth and activating factor of mast cells. A putative role for C-kit and mast cells in the pathogenesis of COF is described.
January 2018: Journal of Oral and Maxillofacial Pathology: JOMFP
Ilaria Marech, Michele Ammendola, Christian Leporini, Rosa Patruno, Maria Luposella, Nicola Zizzo, Giuseppe Passantino, Rosario Sacco, Ammad Ahmad Farooqi, Valeria Zuccalà, Silvana Leo, Rosalba Dentamaro, Mariangela Porcelli, Pietro Gadaleta, Giovambattista De Sarro, Cosmo Damiano Gadaleta, Girolamo Ranieri
C-Kit protein is a transmembrane tyrosine kinase (TK) receptor (c-KitR-TK), which is predominantly expressed on mast cells (MCs) playing a role in tumor angiogenesis. It could be also expressed on epithelial breast cancer cells (EBCCs), but no data have been published regarding the correlation between mast cells positive to c-KitR (MCs-c-KitR), EBCCs positive to c-KitR (EBCCs-c-KitR), BC angiogenesis in terms of microvessel density (MVD) and the main clinic-pathological features. This study aims to evaluate the above parameters and their correlations in a series of selected 121 female early BC patients...
January 30, 2018: Oncotarget
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