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Xiaoyu An, Jinping Liu, Na Wang, Di Wang, Liang Huang, Likun Zhang, Jie Cai, Jean-Pierre Wery, Demin Zhou, Jianfeng Zhou, Qi-Xiang Li
Engrafting a M5-AML patient bone marrow (BM) cells into immunocompromised mice (AM7577) achieved serially transferrable stable AML and eventual mortality. The disease starts at BM followed by expansion to peripherals, typical of M5 leukemogenesis, where high leukemic burden in blood is coincident with symptoms/mortality. The leukemic cells in mice have similar myeloid morphology, phenotypes and genotypes (including FLT3-ITD) as the original patient. Autocrine mechanisms of human GM-CSF/IL-3 likely support AM7577 growth in mice...
September 23, 2016: Experimental Hematology
Xin Ma, Lei Wang, Hongzhao Li, Yu Zhang, Yu Gao, Gang Guo, Kan Liu, Qingyu Meng, Chaofei Zhao, Dianjun Wang, Zhigang Song, Xu Zhang
Targeted drug decisions in metastatic renal cell carcinoma are exclusively made on the basis of clinical criteria. We investigated whether these biomarkers (HIF-1α, HIF-2α, CAIX, VEGF, VEGFR1, VEGFR2, VEGFR3, PDGFB, PDGFRA, PDGFRB, CD31, CD44, bcl-xL, KIT, p21, CXCR4, PTEN, (CSF)-1R, RET, and FLT-3) can predictive the different effects between sunitinib and sorafenib treatments and are available to guide targeted drug selection. We enrolled all patients who underwent nephrectomy with postoperative sunitinib- or sorafenib-treatment at our institution from 2007 to 2012...
2016: Scientific Reports
D L Stanculeanu, A Lazescu, D D Zob, R Bunghez, R Anghel, T D Poteca
Renal cell carcinoma (RCC) represents 3% of all cancers, with the highest incidence occurring in the most developed countries and representing the seventh most common cancer in men and the ninth most common cancer in women. The understanding of the tumor molecular biology and the discovery of new drugs that target molecular pathways have increased the arsenal against advanced renal cell carcinoma and improved the outcomes in the patients suffering from these affections. Studying the molecular signaling that controls the tumor growth and the progression has led to the development of molecular therapies targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, resulting in a significant improvement in the overall survival and quality of life...
April 2016: Journal of Medicine and Life
Natalia I Ossetrova, Patrick H Ney, Donald P Condliffe, Katya Krasnopolsky, Kevin P Hieber
Radiation accidents or terrorist attacks can result in serious consequences for the civilian population and for military personnel responding to such emergencies. The early medical management situation requires quantitative indications for early initiation of cytokine therapy in individuals exposed to life-threatening radiation doses and effective triage tools for first responders in mass-casualty radiological incidents. Previously established animal (Mus musculus, Macaca mulatta) total-body irradiation (γ-exposure) models have evaluated a panel of radiation-responsive proteins that, together with peripheral blood cell counts, create a multiparametic dose-predictive algorithm with a threshold for detection of ~1 Gy from 1 to 7 d after exposure as well as demonstrate the acute radiation syndrome severity score systems created similar to the Medical Treatment Protocols for Radiation Accident Victims developed by Fliedner and colleagues...
August 2016: Health Physics
Holger Hackstein, Inna Tschipakow, Gregor Bein, Philipp Nold, Cornelia Brendel, Nelli Baal
Plasmacytoid dendritic cells (pDCs) are rare central regulators of antiviral immunity and unsurpassed producers of interferon-α (IFN-α). Despite their crucial role as a link between innate and adaptive immunity, little is known about the modulation of pDC differentiation by other bone marrow (BM) cells. In this study, we investigated the modulation of pDC differentiation in Flt-3 ligand (Flt3L)-supplemented BM cultures, using highly purified mesenchymal stem cells (MSCs) that were FACS-isolated from murine BM based on surface marker expression and used after in vitro expansion...
May 24, 2016: Biochemical and Biophysical Research Communications
Pooja Arora, Steven A Porcelli
Dendritic cells (DCs) are professional antigen-presenting cells primarily responsible for acquiring, processing and presenting antigens on antigen presenting molecules to initiate T-cell-mediated immunity. Dendritic cells can be separated into several phenotypically and functionally heterogeneous subsets. Three important subsets of splenic dendritic cells are plasmacytoid, CD8α(Pos) and CD8α(Neg) cells. The plasmacytoid DCs are natural producers of type I interferon and are important for anti-viral T cell immunity...
2016: Journal of Visualized Experiments: JoVE
Meng Ying Sun, Su Xiang Wu, Xin Bo Zhou, Jian Ming Gu, Xiu Rong Hu
Regorafenib {systematic name: 4-[4-({[4-chloro-3-(trifluoromethy)phenyl]carbamoyl}amino)-3-fluorophenoxy]-1-methylpyridine-2-carboxamide}, C21H15ClF4N4O3, is a potent anticancer and anti-angiogenic agent that possesses various activities on the VEGFR, PDGFR, raf and/or flt-3 kinase signaling molecules. The compound has been crystallized as polymorphic form I and as the monohydrate, C21H15ClF4N4O3·H2O. The regorafenib molecule consists of biarylurea and pyridine-2-carboxamide units linked by an ether group...
April 2016: Acta Crystallographica. Section C, Structural Chemistry
Fabián Pitoia, Fernando Jerkovich
Sorafenib is a multiple kinase inhibitor (MKI) approved for the treatment of primary advanced renal cell carcinoma and advanced primary liver cancer. It was recently approved by several health agencies around the world as the first available MKI treatment for radioactive iodine-refractory advanced and progressive differentiated thyroid cancer. Sorafenib targets C-RAF, B-RAF, VEGF receptor-1, -2, -3, PDGF receptor-β, RET, c-kit, and Flt-3. As a multifunctional inhibitor, sorafenib has the potential of inhibiting tumor growth, progression, metastasis, and angiogenesis and downregulating mechanisms that protect tumors from apoptosis and has shown to increase the progression-free survival in several Phase II trials...
2016: Drug Design, Development and Therapy
Hirofumi Nakano, Tsukasa Hasegawa, Riyo Imamura, Nae Saito, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano
A non-selective inhibitor (1) of FMS-like tyrosine kinase-3 (FLT3) was identified by fragment screening and systematically modified to afford a potent and selective inhibitor 26. We confirmed that 26 inhibited the growth of FLT-3-activated human acute myeloid leukemia cell line MV4-11. Our design strategy enabled rapid development of a novel type of FLT3 inhibitor from the hit fragment in the absence of target-structural information.
May 1, 2016: Bioorganic & Medicinal Chemistry Letters
Qidong Tang, Xin Zhai, Yayi Tu, Ping Wang, Linxiao Wang, Chunjiang Wu, Wenhui Wang, Hongbo Xie, Ping Gong, Pengwu Zheng
A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50=1.21/2.15nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR) of compound 42 were evaluated in vitro...
April 1, 2016: Bioorganic & Medicinal Chemistry Letters
Jean El Cheikh, Zaher K Otrock, Abd Assalam Qannus, Mohamed A Kharfan-Dabaja, Ali Bazarbachi
BACKGROUND: Optimizing conditioning and post-transplant intervention may reduce non-relapse mortality and relapse, improving survival after allogeneic hematopoietic cell transplantation (allo-HCT). MATERIALS AND METHODS: We used a risk-adapted intensity of busulfan at 130 mg/m(2)/day for either 2, 3, or 4 days, with a fixed dose of fludarabine (30 mg/m(2)/day for 5 days), and thymoglobulin (2.5 mg/kg/day for 2 days). Our algorithm was based on age, comorbiditie(s), and disease risk...
May 2016: Clinical Lymphoma, Myeloma & Leukemia
Selahattin Çalışkan
Sorafenib is an orally active, small-molecule multikinase inhibitor that blocks tumor cell proliferation and angiogenesis. Studies have shown that it is a highly potent, selective inhibitor of vascular endothelial growth factor receptors 2 and 3, platelet-derived growth factor-β, RAF, FLT-3, and c-Kit. This drug was recently approved for the treatment of metastatic renal cell carcinoma and hepatocellular carcinoma. We report a case of a patient treated with sorafenib for metastatic renal cell carcinoma who developed scrotal eczema...
2015: Reviews in Urology
Gwilym Webb, Yung-Yi Chen, Ka-Kit Li, Desley Neil, Ye Htun Oo, Alex Richter, Venetia Bigley, Matthew Collin, David H Adams, Gideon M Hirschfield
Background & Aims Autoimmune hepatitis (AIH), an immune-mediated liver disease, originates as a consequence of interacting genetic and environmental risk factors. Treatment remains non-specific and prone to side effects. Deficiencies in regulatory T cell (Treg) function are hypothesized to contribute to the pathogenesis of AIH. Methods We describe an adult patient who presented with AIH in the context of monocytopenia. The patient was characterized by GATA2 gene sequencing, flow cytometry of peripheral blood for leucocyte subsets, ELISA for serum Flt-3 ligand, and immunohistochemistry of liver biopsy tissue...
May 2016: Journal of Hepatology
Emilia N De Melo, Livia Deda, Ronnie Har, Heather N Reich, James W Scholey, Denis Daneman, Rahim Moineddin, Laura Motran, Yesmino Elia, David Z I Cherney, Etienne B Sochett, Farid H Mahmud
AIMS: Our objective was to characterize urinary cytokine/chemokine excretion in adolescents with type 1 diabetes (T1D) and celiac disease (CD) adhering to gluten free diet (GFD) compared to matched T1D patients and healthy control (HC) group from an existing cohort. METHODS: Eighteen T1D+CD+GFD patients aged 10-16years were identified and matched 2:1 for age, sex, diabetes duration and glycated hemoglobin to 36 T1D subjects and 36 HC. T1D+CD+GFD patients were adherent with a GFD...
March 2016: Journal of Diabetes and its Complications
Vera Neubauer, Karina Wegleiter, Anna Posod, Martina Urbanek, Karina Wechselberger, Ursula Kiechl-Kohlendorfer, Matthias Keller, Elke Griesmaier
BACKGROUND: Developmental brain injury results in cognitive and motor deficits in the preterm infant. Enhanced glutamate release and subsequent receptor activation are major pathogenetic factors. The effect of haematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF) and flt-3 ligand (FL) on neonatal brain injury is controversially discussed. Timing of treatment is known to be a crucial factor. Based on the hypothesis that an exacerbation of injury is caused by administration of substances in the acute phase, the objective of this study was to evaluate the effect of delayed administration of G-CSF/SCF and FL to protect against excitotoxic brain injury in vivo...
March 1, 2016: Brain Research
Niranjan Awasthi, Roderich E Schwarz
Angiogenesis is an essential process for tumor growth and metastasis, and remains a promising therapeutic target process in cancer treatment for several cancer types. Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF), was the first antiangiogenic agent approved for cancer therapy. Novel antiangiogenic agents, such as sunitinib, sorafenib, pazopanib, or vandetanib that target additional proangiogenic signaling pathways beyond VEGF, have also been approved for the treatment of various malignant diseases...
2015: OncoTargets and Therapy
A Spencer, C Spruell, S Nandi, M Wong, M Creixell, A B Baker
The metastatic spread of cancer is a major barrier to effective and curative therapies for cancer. During metastasis, tumor cells intravasate into the vascular system, survive in the shear forces and immunological environment of the circulation, and then extravasate into secondary tumor sites. Biophysical forces are potent regulators of cancer biology and are key in many of the steps of metastasis. In particular, the adhesion of circulating cells is highly dependent upon competing forces between cell adhesion receptors and the shear stresses due to fluid flow...
January 7, 2016: Lab on a Chip
Kayo Nakamura, Noriko Nakatsuka, Masatoshi Jinnin, Takamitsu Makino, Ikko Kajihara, Katsunari Makino, Noritoshi Honda, Kuniko Inoue, Satoshi Fukushima, Hironobu Ihn
Fms-like tyrosine kinase 3 (Flt-3) is a cytokine receptor expressed on the surface of bone-marrow progenitor of hematopoietic cells. Flt-3 ligands are produced by peripheral blood mononuclear cells, and found in various human body fluids. Flt-3 signal is involved in the regulation of vessel formation as well as B cell differentiation, suggesting that Flt-3 signal contributes to the pathogenesis of vascular abnormalities and immune dysregulation in rheumatic diseases. The aim of the present study is to examine serum Flt-3 ligand levels in patients with various rheumatic diseases, and to evaluate the possibility that serum Flt-3 ligand levels can be a useful disease marker...
October 2015: Bioscience Trends
Hossein Ayatollahi, Mohammad Rafiee, Mohammad-Reza Keramati, Mahdi Balali-Mood, Ali Asgharzadeh, Mohammad Hadi Sadeghian, Maryam Sheikhi, Nafiseh Amini, Azam Moradi Zarmehri
OBJECTIVES: Sulfur mustard (SM) was used by the Iraqi army against the Iranian troops in the Iran-Iraq war from 1983-1988. This chemical gas affects different organs including the skin, lungs and the hematopoietic system. Any exposure to SM increases the risk of chromosomal breaking, hyperdiploidy and hypodiploidy. Studies have shown that the risk for acute myeloblastic and lymphoblastic leukemia increases in veterans exposed to SM. FLT3 mutations including ITD and TKD mutations had been observed in some cases of leukemia...
September 2015: Iranian Journal of Basic Medical Sciences
Daniel Delitto, Brian S Black, Heather L Sorenson, Andrea E Knowlton, Ryan M Thomas, George A Sarosi, Lyle L Moldawer, Kevin E Behrns, Chen Liu, Thomas J George, Jose G Trevino, Shannon M Wallet, Steven J Hughes
BACKGROUND: The tumor microenvironment impacts pancreatic cancer (PC) development, progression and metastasis. How intratumoral inflammatory mediators modulate this biology remains poorly understood. We hypothesized that the inflammatory milieu within the PC microenvironment would correlate with clinicopathologic findings and survival. METHODS: Pancreatic specimens from normal pancreas (n = 6), chronic pancreatitis (n = 9) and pancreatic adenocarcinoma (n = 36) were homogenized immediately upon resection...
October 24, 2015: BMC Cancer
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