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Julia Boshuizen, Louise A Koopman, Oscar Krijgsman, Aida Shahrabi, Elke Gresnigt- van den Heuvel, Maarten A Ligtenberg, David W Vredevoogd, Kristel Kemper, Thomas Kuilman, Ji-Ying Song, Nora Pencheva, Jens Thing Mortensen, Marnix Geukes Foppen, Elisa A Rozeman, Christian U Blank, Maarten L Janmaat, David Satijn, Esther C W Breij, Daniel S Peeper, Paul W H I Parren
Intratumor heterogeneity is a key factor contributing to therapeutic failure and, hence, cancer lethality. Heterogeneous tumors show partial therapy responses, allowing for the emergence of drug-resistant clones that often express high levels of the receptor tyrosine kinase AXL. In melanoma, AXL-high cells are resistant to MAPK pathway inhibitors, whereas AXL-low cells are sensitive to these inhibitors, rationalizing a differential therapeutic approach. We developed an antibody-drug conjugate, AXL-107-MMAE, comprising a human AXL antibody linked to the microtubule-disrupting agent monomethyl auristatin E...
January 15, 2018: Nature Medicine
Valeria Amendola, Ana Miljkovic, Laura Legnani, Lucio Toma, Daniele Dondi, Simone Lazzaroni
In this work, we employed for the first time a dinuclear bis[tris(2-aminoethyl)amine] cryptate to obtain the self-assembly of pseudorotaxane structures in an aqueous solution. The goal was achieved by exploiting the well-known affinity of the dicopper azacryptate with diphenyl spacers for the terephthalate anion. In particular, a series of molecular threads were synthesized by appending either alkyl or polyoxyethylene chains on both sides of the terephthalate benzene ring. The obtained dicarboxylic acids were precipitated as sodium salts, and their affinity toward the dicopper azacryptate was determined in a methanol/water mixture (pH 7)...
January 12, 2018: Inorganic Chemistry
Zhiwei Qiao, Kumiko Shiozawa, Tadashi Kondo
Pazopanib, a multitarget tyrosine kinase (TK) inhibitor, has been approved for treatment of soft tissue sarcoma. Elucidation of the molecular background of pazopanib resistance should lead to improved clinical outcomes in sarcomas; accordingly, we investigated this in synovial sarcoma using a proteomic approach. Pazopanib sensitivity was examined in four synovial sarcoma cell lines: SYO-1, HS-SYII, 1273/99, and YaFuSS. The 1273/99 cell line showed significantly higher IC50 values than the others for pazopanib...
December 12, 2017: Oncotarget
Sachindra, Lionel Larribère, Daniel Novak, Huizi Wu, Laura Hüser, Karol Granados, Elias Orouji, Jochen Utikal
Adaptive resistance to targeted therapy such as BRAF inhibitors represents in melanoma a major drawback to this otherwise powerful treatment. Some of the underlying molecular mechanisms have recently been described: hyperactivation of the BRAF-MAPK pathway, of the AKT pathway, of the TGFβ/EGFR/PDGFRB pathway, or the low MITF/AXL ratio. Nevertheless, the phenomenon of early resistance is still not clearly understood. In this report, we show that knockdown of neural crest-associated gene ID3 increases the melanoma sensitivity to vemurafenib short-term treatment...
December 15, 2017: Oncotarget
Jung Eun Kim, Youjin Kim, Gary Li, Seung Tae Kim, Kyung Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Hyuk Lee, Tae Sung Sohn, Kyoung-Mee Kim, Won Ki Kang, Jeeyun Lee
RXDX-106 is a potent and selective type II pseudo-irreversible (slow off-rate) inhibitor of TYRO3, AXL, MER and c-MET. MER tyrosine kinase (MerTK) is expressed in a variety of malignancies, including gastric cancer (GC). The oncogenic potential of MerTK is supported by various lines of evidence. First, we surveyed 10 GC cell lines for MerTK protein overexpression and MerTk phosphorylation. We next evaluated the change of downstream signaling molecules including (p)-ERK and (p)-AKT, following RXDX-106 treatment...
December 1, 2017: Oncotarget
Takaaki Fujino, Hirotake Naitoh, Shinobu Miyagawa, Masaki Kimura, Tsuneomi Kawasaki, Kazuyuki Yoshida, Hajime Inoue, Hiroaki Takagawa, Yuji Tokunaga
An efficient synthesis of a doubly stranded [3]rotaxane has been developed through bridging of a pseudo[3]rotaxane featuring two axle components. Reversible azine formation was effective as the bridging reaction. Kinetic and thermodynamic conditions provided the [2]- and [3]rotaxanes, respectively.
December 28, 2017: Organic Letters
Chi Young Jung, So-Young Kim, Chuhee Lee
BACKGROUND/AIM: AXL has been reported to be overexpressed and highly activated in various cancer types. In this study, we demonstrated the effect of carvacrol on cell proliferation and migration in non-small cell lung cancer (NSCLC) cells by impeding the expression and activation of AXL. MATERIALS AND METHODS: The levels of AXL protein, mRNA and promoter activity were evaluated by western blot, reverse transcription polymerase chain reaction (RT-PCR) and luciferase assay, respectively...
January 2018: Anticancer Research
Shao-Chi Cheng, Kai-Jen Chen, Yuji Suzaki, Yoshitaka Tsuchido, Ting-Shen Kuo, Kohtaro Osakada, Masaki Horie
This study investigated the dynamic photoresponse of pseudorotaxane crystals with azobenzene and ferrocenyl groups in the axle component. X-ray crystallography showed pseudorotaxanes with a methylazobenzene group and a dibromophenylene ring in the cyclic component to exhibit twisting of the trans-azobenzene groups at torsion angles of 17° and 38°, respectively. Repeated alternating laser irradiation of the crystals at 360 and 445 nm produced bending of 20-30° in opposite directions, with no evidence of decay...
December 23, 2017: Journal of the American Chemical Society
Xiaoming Sun, Stephane Hua, Hsiao-Rong Chen, Zhengyu Ouyang, Kevin Einkauf, Samantha Tse, Kevin Ard, Andrea Ciaranello, Sigal Yawetz, Paul Sax, Eric S Rosenberg, Mathias Lichterfeld, Xu G Yu
Although dendritic cells are among the human cell population best equipped for cell-intrinsic antiviral immune defense, they seem highly susceptible to infection with the Zika virus (ZIKV). Using highly purified myeloid dendritic cells isolated from individuals with naturally acquired acute infection, we here show that ZIKV induces profound perturbations of transcriptional signatures relative to healthy donors. Interestingly, we noted a remarkable downregulation of antiviral interferon-stimulated genes and innate immune sensors, suggesting that ZIKV can actively suppress interferon-dependent immune responses...
December 19, 2017: Cell Reports
Mariacristina Parravano, Fabio Scarinci, Marta Gilardi, Lea Querques, Monica Varano, Francesco Oddone, Francesco Bandello, Giuseppe Querques
Purpose: To investigate the potential role of ranibizumab treatment on the development or enlargement of chorioretinal atrophy (CRA) at the posterior pole in eyes with myopic choroidal neovascularization (mCNV). Methods: This observational case series included patients having high myopia spherical equivalent refractive error ≥ -6.00 diopters, axial length (AxL) ≥ 26.0 mm in both eyes, and mCNV treated with ranibizumab 0.5 mg in one eye, who were retrospectively enrolled...
December 1, 2017: Investigative Ophthalmology & Visual Science
Keisuke Iida, Ryo Sakai, Shota Yokoyama, Naritaka Kobayashi, Shodai Togo, Hiroshi Y Yoshikawa, Anchalee Rawangkan, Kozue Namiki, Masami Suganuma
To study the role of cell softening in malignant progression, Transwell assay and atomic force microscope were used to classify six human non-small cell lung cancer cell lines into two groups: a high motility-low stiffness (HMLS) group and a low motility-high stiffness (LMHS) group. We found a significant role of activity of the AXL receptor tyrosine kinase, which belongs to the TAM (Tyro3, AXL, Mer) family, in the stimulation of motility and cell softening. HMLS cells expressed higher AXL levels than LMHS cells and contained phosphorylated AXL...
December 19, 2017: Scientific Reports
Che-Feng Chang, Brittany A Goods, Michael H Askenase, Matthew D Hammond, Stephen C Renfroe, Arthur F Steinschneider, Margaret J Landreneau, Youxi Ai, Hannah E Beatty, Luís Henrique Angenendt da Costa, Matthias Mack, Kevin N Sheth, David M Greer, Anita Huttner, Daniel Coman, Fahmeed Hyder, Sourav Ghosh, Carla V Rothlin, J Christopher Love, Lauren H Sansing
Macrophages are a source of both proinflammatory and restorative functions in damaged tissue through complex dynamic phenotypic changes. Here, we sought to determine whether monocyte-derived macrophages (MDMs) contribute to recovery after acute sterile brain injury. By profiling the transcriptional dynamics of MDMs in the murine brain after experimental intracerebral hemorrhage (ICH), we found robust phenotypic changes in the infiltrating MDMs over time and demonstrated that MDMs are essential for optimal hematoma clearance and neurological recovery...
December 18, 2017: Journal of Clinical Investigation
Muhammad Altaf, Helen Stoeckli-Evans
Tranexamic acid [systematic name: trans-4-(amino-meth-yl)cyclo-hexane-1-carb-oxy-lic acid], is an anti-fibrinolytic amino acid that exists as a zwitterion [trans-4-(ammonio-meth-yl)cyclo-hexane-1-carboxyl-ate] in the solid state. Its reaction with copper chloride leads to the formation of a compound with a copper(II) paddle-wheel structure that crystallizes as a hexa-hydrate, [Cu2Cl2(C8H15NO2)4]2+·2Cl-·6H2O. The asymmetric unit is composed of a copper(II) cation, two zwitterionic tranexamic acid units, a coordinating Cl- anion and a free Cl- anion, together with three water mol-ecules of crystallization...
October 1, 2017: Acta Crystallographica. Section E, Crystallographic Communications
Pinar Kanlikilicer, Bulent Ozpolat, Burcu Aslan, Recep Bayraktar, Nilgun Gurbuz, Cristian Rodriguez-Aguayo, Emine Bayraktar, Merve Denizli, Vianey Gonzalez-Villasana, Cristina Ivan, Ganesh L R Lokesh, Paola Amero, Silvia Catuogno, Monika Haemmerle, Sherry Yen-Yao Wu, Rahul Mitra, David G Gorenstein, David E Volk, Vittorio de Franciscis, Anil K Sood, Gabriel Lopez-Berestein
Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK) has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database...
December 15, 2017: Molecular Therapy. Nucleic Acids
Chiara Fedeli, Giulia Torriani, Clara Galan-Navarro, Marie-Laurence Moraz, Hector Moreno, Gisa Gerold, Stefan Kunz
Fatal infection with the highly pathogenic Lassa virus (LASV) is characterized by extensive viral dissemination, indicating broad tissue tropism. The major cellular receptor for LASV is the highly conserved extracellular matrix receptor dystroglycan (DG). Binding of LASV depends on DG's tissue-specific post-translational modification with the unusual O-linked polysaccharide matriglycan. Interestingly, functional glycosylation of DG does not always correlate with viral tropism observed in vivo The broadly expressed phosphatidylserine (PS) receptors Axl and Tyro3 were recently identified as alternative LASV receptor candidates...
December 13, 2017: Journal of Virology
Paola Magnaghi, Barbara Salom, Liviana Cozzi, Nadia Amboldi, Dario Ballinari, Elena Tamborini, Fabio Gasparri, Alessia Montagnoli, Laura Raddrizzani, Alessio Somaschini, Roberta Bosotti, Christian Orrenius, Fabio Bozzi, Silvana Pilotti, Arturo Galvani, Josh Sommer, Silvia Stacchiotti, Antonella Isacchi
Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in Phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRβ and EGFR tyrosine kinases, and assessed their anti-proliferative activity against a panel of chordoma cell lines...
December 13, 2017: Molecular Cancer Therapeutics
Sudip Pan, Susmita Kar, Ranajit Saha, Edison Osorio, Ximena Zarate, Lili Zhao, Gabriel Merino, Pratim K Chattaraj
The viability of noble gas axled boron nanowheel, NgnMB10- (Ng = Ar-Rn, M = Nb, Ta; n = 1, 2), is explored via ab initio computations. In the resulting Ng2-M complexes, the Ng-M-Ng nanorod passes through the center of B10- ring, providing them with an inverse sandwich like structure. While in single Ng bound analogue, the Ng binding enthalpy (Hb) at 298 K ranges from 2.5 to 10.6 kcal/mol, in two Ng bound cases it becomes very low for Ng2MB10- -> Ng + NgMB10- dissociation channel, except for Rn case. For a given Ng, Ta has slightly higher Ng binding ability than Nb...
December 11, 2017: Chemistry: a European Journal
Ramón Ruiz-Mesa, Antonio Abengózar-Vela, María Ruiz-Santos
PURPOSE: To evaluate the repeatability of a new biometer using Scheimpflug technology combined with partial coherence interferometry (PCI) (Pentacam AXL) and its agreement with a device based on optical low-coherence reflectometry (OLCR), the Allegro Biograph. SETTING: Oftalvist Centro Integral Ocular Jerez, Jerez de la Frontera, Spain. DESIGN: Evaluation of a diagnostic test. METHODS: The mean keratometry (K), central corneal thickness (CCT), anterior chamber depth (ACD), and axial length (AL) were measured with the 2 devices 3 times by the same examiner in 2 groups (patients with cataract and patients without cataract)...
November 2017: Journal of Cataract and Refractive Surgery
Marcela Alcántara-Hernández, Rebecca Leylek, Lisa E Wagar, Edgar G Engleman, Tibor Keler, M Peter Marinkovich, Mark M Davis, Garry P Nolan, Juliana Idoyaga
Given the limited efficacy of clinical approaches that rely on ex vivo generated dendritic cells (DCs), it is imperative to design strategies that harness specialized DC subsets in situ. This requires delineating the expression of surface markers by DC subsets among individuals and tissues. Here, we performed a multiparametric phenotypic characterization and unbiased analysis of human DC subsets in blood, tonsil, spleen, and skin. We uncovered previously unreported phenotypic heterogeneity of human cDC2s among individuals, including variable expression of functional receptors such as CD172a...
November 28, 2017: Immunity
HyeRim Shin, Dayoung Kim, David M Helfman
Metastasis dissemination is the result of various processes including cell migration and cell aggregation. These processes involve alterations in the expression and organization of cytoskeletal and adhesion proteins in tumor cells. Alterations in actin filaments and their binding partners are known to be key players in metastasis. Downregulation of specific tropomyosin (Tpm) isoforms is a common characteristic of transformed cells. In this study, we examined the role of Tpm2.1 in non-transformed MCF10A breast epithelial cells in cell migration and cell aggregation, because this isoform is downregulated in primary and metastatic breast cancer as well as various breast cancer cell lines...
November 10, 2017: Oncotarget
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