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https://www.readbyqxmd.com/read/28543695/mechanisms-and-strategies-to-overcome-resistance-to-molecularly-targeted-therapy-for-melanoma
#1
REVIEW
Su Yin Lim, Alexander M Menzies, Helen Rizos
The identification of driver mutations in melanoma has changed the field of cancer treatment. BRAF and NRAS mutations are predominant in melanoma and lead to overactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. Selective inhibitors targeting key effectors of the MAPK pathway have revolutionized the treatment of patients with advanced metastatic BRAF-mutant melanoma. However, resistance to therapy is almost universal and remains a major challenge in clinical care, with the majority of patients progressing within 1 year...
June 1, 2017: Cancer
https://www.readbyqxmd.com/read/28542559/fluvastatin-inhibits-age-induced-cell-proliferation-and-migration-via-an-erk5-dependent-nrf2-pathway-in-vascular-smooth-muscle-cells
#2
Ae-Rang Hwang, Jung-Hwa Han, Jae Hyang Lim, Young Jin Kang, Chang-Hoon Woo
Advanced glycation endproduct (AGE)-induced vascular smooth muscle cell (VSMC) proliferation and reactive oxygen species (ROS) production are emerging as important mechanisms of diabetic vasculopathy, but little is known about the molecular mechanism responsible for the antioxidative effects of statins on AGEs. It has been reported that statins exert pleiotropic effects on the cardiovascular system due to decreases in AGE-induced cell proliferation, migration, and vascular inflammation. Thus, in the present study, the authors investigated the molecular mechanism by which statins decrease AGE-induced cell proliferation and VSMC migration...
2017: PloS One
https://www.readbyqxmd.com/read/28539634/the-plasmodium-pi-4-k-inhibitor-kdu691-selectively-inhibits-dihydroartemisinin-pretreated-plasmodium-falciparum-ring-stage-parasites
#3
L Dembele, X Ang, M Chavchich, G M C Bonamy, J J Selva, M Yi-Xiu Lim, C Bodenreider, B K S Yeung, F Nosten, B M Russell, M D Edstein, J Straimer, D A Fidock, T T Diagana, P Bifani
Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type) Plasmodium falciparum strain is exposed to ART derivatives such as dihydroartemisinin (DHA), a small population of the early ring-stage parasites can survive drug treatment by entering cell cycle arrest or dormancy. After drug removal, these parasites can resume growth. Dormancy has been hypothesized to be an adaptive physiological mechanism that has been linked to recrudescence of parasites after monotherapy with ART and, possibly contributes to ART resistance...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28524178/transcriptome-analyses-of-chronic-traumatic-encephalopathy-show-alterations-in-protein-phosphatase-expression-associated-with-tauopathy
#4
Jeong-Sun Seo, Seungbok Lee, Jong-Yeon Shin, Yu Jin Hwang, Hyesun Cho, Seong-Keun Yoo, Yunha Kim, Sungsu Lim, Yun Kyung Kim, Eun Mi Hwang, Su Hyun Kim, Chong-Hyun Kim, Seung Jae Hyeon, Ji-Young Yun, Jihye Kim, Yona Kim, Victor E Alvarez, Thor D Stein, Junghee Lee, Dong Jin Kim, Jong-Il Kim, Neil W Kowall, Hoon Ryu, Ann C McKee
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder that is associated with repetitive head injury and has distinctive neuropathological features that differentiate this disease from other neurodegenerative diseases. Intraneuronal tau aggregates, although they occur in different patterns, are diagnostic neuropathological features of CTE, but the precise mechanism of tauopathy is not known in CTE. We performed whole RNA sequencing analysis of post-mortem brain tissue from patients with CTE and compared the results to normal controls to determine the transcriptome signature changes associated with CTE...
May 19, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28515457/crystal-structure-of-taz-tead-complex-reveals-a-distinct-interaction-mode-from-that-of-yap-tead-complex
#5
Hung Yi Kristal Kaan, Siew Wee Chan, Siew Kim Joyce Tan, Fusheng Guo, Chun Jye Lim, Wanjin Hong, Haiwei Song
The Hippo pathway is a tumor suppressor pathway that is implicated in the regulation of organ size. The pathway has three components: the upstream regulatory factors, the kinase core, and the downstream transcriptional machinery, which consists of YAP, TAZ (transcription co-activators) and TEAD (transcription factor). Formation of YAP/TAZ-TEAD complexes leads to the transcription of growth-promoting genes. Herein, we report the crystal structure of TAZ-TEAD4 complex, which reveals two binding modes. The first is similar to the published YAP-TEAD structure...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28514723/genomic-profiling-of-pelvic-genital-type-leiomyosarcoma-in-a-woman-with-a-germline-chek2-c-1100delc-mutation-and-a-concomitant-diagnosis-of-metastatic-invasive-ductal-breast-carcinoma
#6
My Linh Thibodeau, Caralyn Reisle, Eric Zhao, Lee Ann Martin, Yazeed Alwelaie, Karen L Mungall, Carolyn Ch'ng, Ruth Thomas, Tony Ng, Stephen Yip, Howard Lim, Sophie Sun, Sean S Young, Aly Karsan, Yongjun Zhao, Andrew J Mungall, Richard A Moore, Daniel Renouf, Karen Gelmon, Yussanne P Ma, Malcolm Hayes, Janessa Laskin, Marco A Marra, Kasmintan A Schrader, Steven J M Jones
INTRODUCTION: We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumour suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximate 2-fold increase in breast cancer risk...
May 16, 2017: Cold Spring Harbor Molecular Case Studies
https://www.readbyqxmd.com/read/28504693/cyclin-dependent-kinase-7-is-a-therapeutic-target-in-high-grade-glioma
#7
S A Greenall, Y C Lim, C B Mitchell, K S Ensbey, B W Stringer, A L Wilding, G M O'Neill, K L McDonald, D J Gough, B W Day, T G Johns
High-grade glioma (HGG) is an incurable brain cancer. The transcriptomes of cells within HGG tumors are highly heterogeneous. This renders the tumors unresponsive or able to adapt to therapeutics targeted at single pathways, thereby causing treatment failure. To overcome this, we focused on cyclin-dependent kinase 7 (CDK7), a ubiquitously expressed molecule involved in two major drivers of HGG pathogenesis: cell cycle progression and RNA polymerase-II-based transcription. We tested the activity of THZ1, an irreversible CDK7 inhibitor, on patient-derived primary HGG cell lines and ex vivo HGG patient tissue slices, using proliferation assays, microarray analysis, high-resolution respirometry, cell cycle analysis and in vivo tumor orthografts...
May 15, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28504362/synthesis-and-structure-elucidation-of-polyphenols-containing-the-n-methyleneformohydrazide-scaffold-as-aurora-kinase-inhibitors
#8
Dongsoo Koh, Yearam Jung, Seunghyun Ahn, Kenneth Hun Mok, Soon Young Shin, Yoongho Lim
No abstract text is available yet for this article.
May 15, 2017: Magnetic Resonance in Chemistry: MRC
https://www.readbyqxmd.com/read/28501511/identification-of-quinazoline-based-inhibitors-of-irak4-for-the-treatment-of-inflammation
#9
Graham F Smith, Michael D Altman, Brian Andresen, James Baker, Jason D Brubaker, Hongmin Chen, Yiping Chen, Matthew Childers, Anthony Donofrio, Heidi Ferguson, Christian Fischer, Thierry O Fischmann, Craig Gibeau, Alexander Hicks, Sue Jin, Sam Kattar, Melanie A Kleinschek, Erica Leccese, Charles Lesburg, Chaomin Li, Jongwon Lim, Duan Liu, John K F Maclean, Faruk Mansoor, Lilly Y Moy, Erin F Mulrooney, Antoaneta S Necheva, Jeremy Presland, Larissa Rakhilina, Ruojing Yang, Luis Torres, Jie Zhang-Hoover, Alan Northrup
Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity...
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28500843/bmpr2-promotes-invasion-and-metastasis-via-the-rhoa-rock-limk2-pathway-in-human-osteosarcoma-cells
#10
Shidong Wang, Tingting Ren, Guangjun Jiao, Yi Huang, Xing Bao, Fan Zhang, Kuisheng Liu, Bingxin Zheng, Kunkun Sun, Wei Guo
Bone morphogenetic protein receptor 2 (BMPR2) has been identified in several types of cancer. However, its role in osteosarcoma is largely unknown. We systematically investigated the role of BMPR2 in osteosarcoma cell lines, human tissue samples and xenograft models. The relationship between BMPR2 expression and osteosarcoma patients' survival was investigated by bioinformatics and clinical data. Wound healing assay and transwell assay were used to detect the changes of cell migration and invasion ability after BMPR2 transfection...
April 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28497946/nanopillar-surface-topology-promotes-cardiomyocyte-differentiation-through-cofilin-mediated-cytoskeleton-rearrangement
#11
Ha-Rim Seo, Hyung Joon Joo, Dae Hwan Kim, Long-Hui Cui, Seung-Cheol Choi, Jong-Ho Kim, Sung Woo Cho, Kyu Back Lee, Do-Sun Lim
Nanoscaled surface patterning is an emerging potential method of directing the fate of stem cells. We adopted nanoscaled pillar gradient patterned cell culture plates with three diameter gradients [280-360 (GP 280/360), 200-280 (GP 200/280), and 120-200 nm (GP 120/200)] and investigated their cell fate-modifying effect on multipotent fetal liver kinase 1-positive mesodermal precursor cells (Flk1(+) MPCs) derived from embryonic stem cells. We observed increased cell proliferation and colony formation of the Flk1(+) MPCs on the nanopattern plates...
May 12, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28495617/the-adaptor-protein-ara55-and-the-nuclear-kinase-hipk1-assist-c-myb-in-recruiting-p300-to-chromatin
#12
Mads Bengtsen, Linda Sørensen, Linn Aabel, Marit Ledsaak, Vilborg Matre, Odd Stokke Gabrielsen
LIM-domain proteins, containing multiple cysteine-rich zinc finger-like motifs, have been shown to play diverse roles in several cellular processes. A common theme is that they mediate important protein-protein interactions that are key to their function. Androgen receptor-associated protein 55 (ARA55) belongs to this family of bridging proteins containing four C-terminal LIM domains. It has a dual role with functions both at focal adhesions and in the nucleus, apparently shuttling between the two compartments...
May 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28483666/docosahexaenoic-acid-inhibits-il-6-expression-via-ppar%C3%AE-mediated-expression-of-catalase-in-cerulein-stimulated-pancreatic-acinar-cells
#13
Eun Ah Song, Joo Weon Lim, Hyeyoung Kim
Cerulein pancreatitis mirrors human acute pancreatitis. In pancreatic acinar cells exposed to cerulein, reactive oxygen species (ROS) mediate inflammatory signaling by Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, and cytokine induction. Docosahexaenoic acid (DHA) acts as an agonist of peroxisome proliferator activated receptor γ (PPARγ), which mediates the expression of some antioxidant enzymes. We hypothesized that DHA may induce PPARγ-target catalase expression and reduce ROS levels, leading to the inhibition of JAK2/STAT3 activation and IL-6 expression in cerulein-stimulated acinar cells...
May 5, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28482641/bryostatin-effects-on-cognitive-function-and-pkc%C3%A9-in-alzheimer-s-disease-phase-iia-and-expanded-access-trials
#14
Thomas J Nelson, Miao-Kun Sun, Chol Lim, Abhik Sen, Tapan Khan, Florin V Chirila, Daniel L Alkon
Bryostatin 1, a potent activator of protein kinase C epsilon (PKCɛ), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 μg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1-2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCɛ was measured (p = 0.0185) within 1 h from the onset of infusion...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28480589/quantification-and-tracking-of-genetically-engineered-dendritic-cells-for-studying-immunotherapy
#15
Amnon Bar-Shir, Lina Alon, Michael J Korrer, Hong Seo Lim, Nirbhay N Yadav, Yoshinori Kato, Arvind P Pathak, Jeff W M Bulte, Assaf A Gilad
PURPOSE: Genetically encoded reporters can assist in visualizing biological processes in live organisms and have been proposed for longitudinal and noninvasive tracking of therapeutic cells in deep tissue. Cells can be labeled in situ or ex vivo and followed in live subjects over time. Nevertheless, a major challenge for reporter systems is to identify the cell population that actually expresses an active reporter. METHODS: We have used a nucleoside analog, pyrrolo-2'-deoxycytidine, as an imaging probe for the putative reporter gene, Drosophila melanogaster 2'-deoxynucleoside kinase...
May 7, 2017: Magnetic Resonance in Medicine: Official Journal of the Society of Magnetic Resonance in Medicine
https://www.readbyqxmd.com/read/28474336/comparative-genomic-expression-signatures-of-signal-transduction-pathways-and-targets-in-paediatric-burkitt-lymphoma-a-children-s-oncology-group-report
#16
Sanghoon Lee, Nancy S Day, Rodney R Miles, Sherrie L Perkins, Megan S Lim, Janet Ayello, Carmella van de Ven, Lauren Harrison, Nader K El-Mallawany, Stanton Goldman, Mitchell S Cairo
Burkitt lymphoma (BL) is the most common histological subtype of non-Hodgkin lymphoma (NHL) in children and adolescents. Through the introduction of short intensive multi-agent chemoimmunotherapy, survival has improved significantly over the past 30 years. However, this successful approach is limited by significant chemotherapy-induced acute toxicity and risk of developing resistant disease, demonstrating the need to identify less toxic and targeted therapies. We analysed the comparative genomic signature and targetable signalling pathways in paediatric BL (PEBL) samples from the Children's Oncology Group study (ANHL01P1) by genomic profiling and selected genes were confirmed by quantitative real time polymerase chain reaction...
May 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28467813/a-systematic-review-and-meta-analysis-of-individual-patient-data-on-the-impact-of-the-bim-deletion-polymorphism-on-treatment-outcomes-in-epidermal-growth-factor-receptor-mutant-lung-cancer
#17
Sheila X Soh, Fahad J Siddiqui, John C Allen, Go Woon Kim, Jae Cheol Lee, Yasushi Yatabe, Manabu Soda, Hiroyuki Mano, Ross A Soo, Tan-Min Chin, Hiromichi Ebi, Seiji Yano, Keitaro Matsuo, Xiaomin Niu, Shun Lu, Kazutoshi Isobe, Jih-Hsiang Lee, James C Yang, Mingchuan Zhao, Caicun Zhou, June-Koo Lee, Se-Hoon Lee, Ji Yun Lee, Myung-Ju Ahn, Tira J Tan, Daniel S Tan, Eng-Huat Tan, S Tiong Ong, Wan-Teck Lim
BACKGROUND: A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue. RESULTS: In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1...
April 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28465421/hyperactive-locomotion-in-a-drosophila-model-is-a-functional-readout-for-the-synaptic-abnormalities-underlying-fragile-x-syndrome
#18
Risa Kashima, Patrick L Redmond, Prajakta Ghatpande, Sougata Roy, Thomas B Kornberg, Thomas Hanke, Stefan Knapp, Giorgio Lagna, Akiko Hata
Fragile X syndrome (FXS) is the most common cause of heritable intellectual disability and autism and affects ~1 in 4000 males and 1 in 8000 females. The discovery of effective treatments for FXS has been hampered by the lack of effective animal models and phenotypic readouts for drug screening. FXS ensues from the epigenetic silencing or loss-of-function mutation of the fragile X mental retardation 1 (FMR1) gene, which encodes an RNA binding protein that associates with and represses the translation of target mRNAs...
May 2, 2017: Science Signaling
https://www.readbyqxmd.com/read/28464435/management-of-epidermal-growth-factor-receptor-tyrosine-kinase-inhibitor-related-cutaneous-and-gastrointestinal-toxicities
#19
REVIEW
Derrick Chen-Wee Aw, Eng Huat Tan, Tan Min Chin, Hong Liang Lim, Haur Yueh Lee, Ross A Soo
Patients with advanced stage non-small cell lung cancer with sensitizing epidermal growth factor receptor (EGFR) mutations using EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib and afatinib as first-line treatment had better progression-free survival, overall response rate and quality of life than those on chemotherapy. Although EGFR TKIs are commonly associated with skin-related (rash, xerosis and paronychia) and gastrointestinal-related (diarrhea and stomatitis) adverse events (AEs), these effects are usually mild...
May 2, 2017: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/28453848/association-of-the-emergence-of-acyclovir-resistant-herpes-simplex-virus-type-1-with-prognosis-in-hematopoietic-stem-cell-transplantation-patients
#20
Satsuki Kakiuchi, Masanori Tsuji, Hidekazu Nishimura, Tomoki Yoshikawa, Lixin Wang, Mutsuyo Takayama-Ito, Hitomi Kinoshita, Chang-Kweng Lim, Hikaru Fujii, Souichi Yamada, Shizuko Harada, Akira Oka, Masashi Mizuguchi, Shuichi Taniguchi, Masayuki Saijo
Background.: Antiviral-resistant herpes simplex virus type 1 (HSV-1) has been recognized as an emerging clinical problem among patients undergoing hematopoietic stem cell transplantation (HSCT). Methods.: A prospective observational study was conducted at a hematological center over a 2-year period. Oropharyngeal swab samples were serially collected each week from 1 week before and up to 100 days after HSCT and were tested for virus isolation. The HSV-1 isolates were tested for sensitivity to acyclovir (ACV)...
March 15, 2017: Journal of Infectious Diseases
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