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Milka Kostic
Every month the editors of Cell Chemical Biology bring you highlights of the most recent chemical biology literature. Our October 2016 selection includes systematic structural, biochemical, and cellular characterization of B-RAF inhibitors; connecting bacterial transporters with their physiologically relevant ligands; and rewiring yeast metabolism for industrial scale production of isoprenoids.
October 20, 2016: Cell Chemical Biology
Silvia Laura Locatelli, Giuseppa Careddu, Giuliano Giuseppe Stirparo, Luca Castagna, Armando Santoro, Carmelo Carlo-Stella
PI3K/AKT and RAF/MEK/ERK pathways are constitutively activated in Hodgkin lymphoma (HL) patients, thus representing attractive therapeutic targets. Here we report that the PI3K/ERK dual inhibitor AEZS-136 induced significant cell proliferation inhibition in L-540, SUP-HD1, KM-H2 and L-428 HL cell lines, but a significant increase in necroptotic cell death was observed only in two out of four cell lines (L-540 and SUP-HD1). In these cells, AEZS-136-induced necroptosis was associated with mitochondrial dysfunction and reactive oxygen species (ROS) production...
October 21, 2016: Scientific Reports
Hong Zhang, Zheng Dan, Zhi-Jie Ding, Yuan-Zhi Lao, Hong-Sheng Tan, Hong-Xi Xu
A UPLC-PDA-QTOFMS-guided isolation strategy was employed to screen and track potentially new compounds from Garcinia oblongifolia. As a result, two new prenylated xanthones, oblongixanthones D and E (1-2), six new prenylated benzoylphloroglucinol derivatives, oblongifolins V-Z (3-7) and oblongifolin AA (8), as well as a known compound oblongifolin L (9), were isolated from the EtOAc-soluble fraction of an acetone extract of the leaves of Garcinia oblongifolia guided by UPLC-PDA-QTOFMS analysis. The structures of the new compounds were elucidated by 1D- and 2D-NMR spectroscopic analysis and mass spectrometry...
October 21, 2016: Scientific Reports
Masaru Ide, Shinichi Koba, Naoko Sueoka-Aragane, Akemi Sato, Yuri Nagano, Takuya Inoue, Noriyuki Misago, Yutaka Narisawa, Shinya Kimura, Eisaburo Sueoka
: BRAF gene mutations have been observed in 30-50 % of malignant melanoma patients. Recent development of therapeutic intervention using BRAF inhibitors requires an accurate and rapid detection system for BRAF mutations. In addition, the clinical characteristics of the melanoma associated with BRAF mutations in Japanese patients have not been investigated on a large scale evaluation. We recently established quenching probe system (QP) for detection of an activating BRAF mutation, V600E and evaluated 113 melanoma samples diagnosed in Saga University Hospital from 1982 to 2011...
October 21, 2016: Pathology Oncology Research: POR
Ahmed Bulldan, Mazen Shihan, Sandra Goericke-Pesch, Georgios Scheiner-Bobis
A gonadotropin-releasing hormone agonist (GnRH-A) implant induces hormonal castration in dogs that is associated with reduced prostate and testes size. We address the molecular events associated with hormonal castration by examining GnRH-A effects on expression and phosphorylation of a number of key signaling proteins. Male beagles were treated for 5 months with a GnRH-A implant, and then surgically castrated at 0, 3, 6, 12, and 24 weeks after implant removal; untreated animals served as controls. GnRH-A treatment led to activation of c-Raf, Erk1/2, and p53 in the testes...
October 20, 2016: Molecular Reproduction and Development
Peter J Gawthrop, Edmund J Crampin
Bond graphs can be used to build thermodynamically-compliant hierarchical models of biomolecular systems. As bond graphs have been widely used to model, analyse and synthesise engineering systems, this study suggests that they can play the same rôle in the modelling, analysis and synthesis of biomolecular systems. The particular structure of bond graphs arising from biomolecular systems is established and used to elucidate the relation between thermodynamically closed and open systems. Block diagram representations of the dynamics implied by these bond graphs are used to reveal implicit feedback structures and are linearised to allow the application of control-theoretical methods...
October 2016: IET Systems Biology
Xiaoyan Kang, Nan Zhu, Xia Song
In recent years, targeted drugs occupy a pivotal position in the treatment of non-small cell lung cancer (NSCLC), drugs targeting epidermal growth factor receptor (EGFR) has been widely used in clinical practice, it is of milestone significance. V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors targeted at BRAF gene have obviously clinical efficacy to specific advantages populations with little side-effect, and be well tolerated. It is discovered recently that drug resistance also exists in BRAF inhibitors like other targeted drugs, the mechanism of drug resistance is being studied...
October 20, 2016: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
Lisa Brenan, Aleksandr Andreev, Ofir Cohen, Sasha Pantel, Atanas Kamburov, Davide Cacchiarelli, Nicole S Persky, Cong Zhu, Mukta Bagul, Eva M Goetz, Alex B Burgin, Levi A Garraway, Gad Getz, Tarjei S Mikkelsen, Federica Piccioni, David E Root, Cory M Johannessen
Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants...
October 18, 2016: Cell Reports
Janghyun Yoo, Tae-Sun Lee, Byungsan Choi, Min Ju Shon, Tae-Young Yoon
Extremely weak protein-protein interactions (PPIs), signified by micromolar or even millimolar dissociation constants, are one of the keys to understanding the rapid responses of cellular systems. Although single-molecule methods are particularly useful in determining kinetics of biological processes, their application is largely limited to rather strong interactions because of the diffraction-limited observation volume. In this study, we report a single-molecule method that allows the characterization of PPIs using a prey concentration four orders of magnitude lower than the dissociation constant...
October 19, 2016: Journal of the American Chemical Society
Anne Rochtus, Raf Winand, Griet Laenen, Elise Vangeel, Benedetta Izzi, Christine Wittevrongel, Yves Moreau, Carla Verpoorten, Katrien Jansen, Chris Van Geet, Kathleen Freson
BACKGROUND: Neural tube defects (NTDs) are severe congenital malformations that arise from failure of neurulation during early embryonic development. The molecular basis underlying most human NTDs still remains largely unknown. Based on the hypothesis that folic acid prevents NTDs by stimulating methylation reactions, DNA methylation changes could play a role in NTDs. We performed a methylome analysis for patients with myelomeningocele (MMC). Using a candidate CpG analysis for HOX genes, a significant association between HOXB7 hypomethylation and MMC was found...
2016: Clinical Epigenetics
Piotr T Filipczak, Cynthia L Thomas, Wenshu Chen, Andrew Salzman, Jacob D McDonald, Yong Lin, Steven A Belinsky
Tuberous sclerosis complex (TSC) is a genetic multi-organ disorder characterized by the development of neoplastic lesions in kidney, lung, brain, heart and skin. It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1/TSC2 complex, resulting in hyperactivation of mTOR- and Raf/MEK/MAPK-dependent signaling that stimulates tumor cell proliferation and metastasis. Despite its oncogenic effect, cells with TSC deficiency were more sensitive to oxidative stress and dependent on mitochondrial metabolism, providing a rationale for a new therapeutic approach...
October 18, 2016: Cancer Research
Weibin Wang, Helen Kang, Yinu Zhao, Irene Min, Brian Wyrwas, Maureen Moore, Lisong Teng, Rasa Zarnegar, Xuejun Jiang, Thomas J Fahey
CONTEXT: The RAF inhibitor vemurafenib has provided a major advance for the treatment of patients with BRAF-mutant metastatic melanoma. However, BRAF-mutant thyroid cancer is relatively resistant to vemurafenib, and the reason for this disparity remains unclear. Anti-cancer therapy induced autophagy can trigger adaptive drug resistance in a variety of cancer types and treatments. To date, role of autophagy during BRAF inhibition in thyroid cancer remains unknown. OBJECTIVE: In this study, we investigate if autophagy is activated in vemurafenib treated BRAF-mutant thyroid cancer cells, and whether autophagy inhibition improves or impairs the treatment efficacy of vemurafenib...
October 18, 2016: Journal of Clinical Endocrinology and Metabolism
Yanling Zhang, Junyan Wu, Trefor Morgan
OBJECTIVE: Recently, some findings support the (pro) renin-(Pro) renin receptor (P) RR interaction at exceptionally high (pro) renin levels in vitro. The aim of this study was to investigate the roles of cardiac (P) RR and its downward signals on mean arterial pressure (MAP) in rats with abdominal aortic constriction, following treatment of handle region peptide (HRP) and phospholipase C-β3 (PLC-b3) inhibitor, U73122. DESIGN AND METHOD: Seventy-five SD rats were divided into 5 groups (n=15 each group) as following: sham operated (SO), rats with the aortic ligation (AL), AL rats were given HRP (4 μg kg d, SC), AL rats given U73122 (40 μg kg d, SC) and AL rats given HRP+U73122...
September 2016: Journal of Hypertension
Naftali Stern
As both the rate of hypertension and cancer rise with age, concomitant hypertension in patients receiving treatment for cancer is very common. Increase in blood pressure during cancer treatment requires careful clinical assessment. Distinction between discontinuation or malabsorption of antihypertensive treatment due to factors such as nausea/vomiting/diarrhea and anti-cancer drug specific effects must be first made. De-novo hypertension during cancer treatment is likely related to anticancer drugs per se. Classical chemotherapeutic agents such as cyclophosphamide, cisplatin and busulfan have been previously linked to rising blood pressure...
September 2016: Journal of Hypertension
Meidi Gu, Zhiyong Liu, Rongrong Lai, Si Liu, Wenlong Lin, Chuan Ouyang, Sheng Ye, He Huang, Xiaojian Wang
TANK-binding kinase 1 (TBK1) activation is a central event in type I interferon production in anti-virus innate immunity. However, the regulatory mechanism underlying TBK1 activation remains unclear. Here we report that Raf kinase inhibitory protein (RKIP) is essential for TBK1 activation and type I interferon production triggered by viral infection. Upon viral infection, RKIP is phosphorylated at serine 109 (S109) by TBK1. Phosphorylation of RKIP enhances its interaction with TBK1 and in turn promotes TBK1 autophosphorylation...
October 17, 2016: EMBO Journal
Maike Zimmermann, Aruni P S Arachchige-Don, Michaela S Donaldson, Tommaso Patriarchi, Mary C Horne
Definition of cell cycle control proteins that modify tumor cell resistance to estrogen (E2) signaling antagonists could inform clinical choice for estrogen receptor positive (ER+) breast cancer (BC) therapy. Cyclin G2 (CycG2) is upregulated during cell cycle arrest responses to cellular stresses and growth inhibitory signals and its gene, CCNG2, is directly repressed by E2-bound ER complexes. Our previous studies showed that blockade of HER2, PI3K and mTOR signaling upregulates CycG2 expression in HER2+ BC cells, and that CycG2 overexpression induces cell cycle arrest...
October 18, 2016: Cell Cycle
Kento Kurata, Naoyoshi Onoda, Satoru Noda, Shinichiro Kashiwagi, Yuka Asano, Kosei Hirakawa, Masaichi Ohira
Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated...
October 7, 2016: International Journal of Oncology
Brij Bharti, Sachin Shukla, Ratnakar Tripathi, Suman Mishra, Mohan Kumar, Manoj Pandey, Rajnikant Mishra
BACKGROUND & OBJECTIVES: The PAX5, a paired box transcription factor and B-cell activator protein (BSAP), activates B-cell commitment genes and represses non-B-cell lineage genes. About 14 transcript variants of PAX5 have been observed in human. Any alteration in its expression pattern leads to lymphogenesis or associated diseases and carcinogenesis in non-lymphoid tissues. Its mechanisms of function in pathophysiology of non-Hodgkin's lymphoma (NHL) are unclear. This study was intended to explore influence of PAX5 in cascade of NHL pathogenesis and diagnosis...
May 2016: Indian Journal of Medical Research
Tyler Friedrich, Stephen Leong, Christopher H Lieu
Despite numerous breakthroughs in the understanding of colorectal cancer and identification of many oncogenic mutations, the treatment of metastatic colorectal cancer remains relatively more empiric than targeted. Testing for mutations in rat sarcoma virus (RAS) and rapidly growing fibrosarcoma (RAF) are routinely performed, though identification of these mutations currently offers little more than a negative predictive marker for response to EGFR inhibitor treatment and, in the case of RAF mutation, a poor prognostic indicator...
October 2016: Journal of Gastrointestinal Oncology
Raf Donders, Kathleen Sanen, Rik Paesen, Eli Slenders, Wilfried Gyselaers, Piet Stinissen, Marcel Ameloot, Niels Hellings
In situ detection of MSCs remains difficult and warrants additional methods to aid with their characterization in vivo. Two-photon confocal laser scanning microscopy (TPM) and second harmonic generation (SHG) could fill this gap. Both techniques enable the detection of cells and extracellular structures, based on intrinsic properties of the specific tissue and intracellular molecules under optical irradiation. TPM imaging and SHG imaging have been used for label-free monitoring of stem cells differentiation, assessment of their behavior in biocompatible scaffolds, and even cell tracking in vivo...
2016: Stem Cells International
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