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K Shitara, T Yamanaka, T Denda, Y Tsuji, K Shinozaki, Y Komatsu, Y Kobayashi, J Furuse, H Okuda, M Asayama, K Akiyoshi, Y Kagawa, T Kato, E Oki, T Ando, Y Hagiwara, Y Ohashi, T Yoshino
Background: The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, as the current standard sequence for metastatic colorectal cancer (mCRC) patients. Patients and methods: Patients with KRAS exon 2 wild-type mCRC after failure of fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive sequential treatment with regorafenib followed by cetuximab ± irinotecan (R-C arm), or the reverse sequence (cetuximab ± irinotecan followed by regorafenib; C-R arm)...
December 3, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Susan M Hiatt, Matthew B Neu, Ryne C Ramaker, Andrew A Hardigan, Jeremy W Prokop, Miroslava Hancarova, Darina Prchalova, Marketa Havlovicova, Jan Prchal, Viktor Stranecky, Dwight K C Yim, Zöe Powis, Boris Keren, Caroline Nava, Cyril Mignot, Marlene Rio, Anya Revah-Politi, Parisa Hemati, Nicholas Stong, Alejandro D Iglesias, Sharon F Suchy, Rebecca Willaert, Ingrid M Wentzensen, Patricia G Wheeler, Lauren Brick, Mariya Kozenko, Anna C E Hurst, James W Wheless, Yves Lacassie, Richard M Myers, Gregory S Barsh, Zdenek Sedlacek, Gregory M Cooper
Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase...
November 30, 2018: PLoS Genetics
Hideto Koso, Asano Tsuhako, Daisuke Matsubara, Yasuyuki Fujita, Sumiko Watanabe
The RAS gene family members, H-RAS, K-RAS, and N-RAS, are frequently mutated in human cancer. A subset of retinal tumors displays K-RAS mutations; however, the specific role of RAS activation on retinal tumor formation is unclear. To examine the role of RAS in retinal development, we overexpressed the mutant H-RAS gene (G12V) in retinal progenitor cells (RPCs), a multipotent progenitor cell population that gives rise to all six neuron types in the retina and to the Muller glia. The Msi1CreER mouse strain was used to induce mosaic activation of Ras (RasV12) in the RPCs of the postnatal retina...
November 27, 2018: Experimental Eye Research
Viktoriya Mozolevska, Anna Schwartz, David Cheung, Vineet Goyal, Bilal Shaikh, Bella Dingman, Esther Kim, Ishika Mittal, Chantal Y Asselin, Andrea L Edel, Amir Ravandi, James Thliveris, Pawan K Singal, Piotr Czaykowski, Davinder S Jassal
Although anti-cancer systemic therapy agents clearly lead to improved survival in cancer patients, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor Bevacizumab (BVZ) and the tyrosine kinase inhibitor Sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction...
November 30, 2018: American Journal of Physiology. Heart and Circulatory Physiology
Luis Alberto Anguiano-Sevilla, Eugenia Lugo-Cervantes, Cynthia Ordaz-Pichardo, Jorge Luis Rosas-Trigueros, María Eugenia Jaramillo-Flores
In this study, an ethanol extract of Agave lechuguilla was evaluated against six carcinogenic cell lines (HCT-15, MCF-7, PC-3, U-251, SK-LU-1 and K-562) with an inhibition of 75.7 ± 2.3% against the SK-LU-1 line. Based on the previous result, the extract was hydrolyzed and fractionated, to which the IC50 was determined; the cell line was more sensitive to the fractionated extract with an IC50 6.96 ± 0.15 µg/mL. Characterization by mass spectrometry showed the presence of kaempferol, quercetin and a flavonoid dimer formed by afzelechin-4β-8-quercetin, according to the generated fragmentation pattern...
November 27, 2018: International Journal of Molecular Sciences
Xiao-Xiao Li, Shi-Jie Zhang, Amy P Chiu, Lilian H Lo, Jeffery C To, He-Ning Cui, Dewi K Rowlands, Vincent W Keng
The neuromuscular junction (NMJ) consists of three components, namely presynaptic motor neurons, postsynaptic muscle fibers and perisynaptic Schwann cells (PSCs). The role of Schwann cells (SCs) in regulating NMJ structural and functional development remains unclear. In this study, mice with conditional inactivation of neurofibromin 1 ( Nf1 ) and phosphatase and tensin homolog ( Pten ), specifically in SCs, resulted in delayed NMJ maturation that led to delayed muscle growth, recapitulating the muscular dystrophy condition observed in human neurofibromatosis type I syndrome (NF1) patients...
November 26, 2018: G3: Genes—Genomes—Genetics
Satoru Munakata, Eisuke Tomiyama, Hitoshi Takayama
Juxtaglomerular cell tumor (JGCT) is a rare renal tumor, producing renin and behaving almost in a benign fashion. So far, only three cases have been reported as malignant. We report a rare case with atypical JGCT. A 74-year-old male was referred to our hospital due to hypertension, proteinuria, and hematuria. Abdominal CT revealed a mass measured in 9.7×7.0 cm in the lower portion of the right kidney. Right kidney was removed laparoscopically. Grossly, white to tan tumor with massive hemorrhage and necrosis occupied the lower portion of the right kidney...
2018: Case Reports in Pathology
Ramesh Rijal, Kristen M Consalvo, Christopher K Lindsey, Richard H Gomer
Eukaryotic chemoattraction signal transduction pathways, such as those used by Dictyostelium discoideum to move towards cAMP, use a G protein-coupled receptor to activate multiple conserved pathways such as PI3 kinase/Akt/PKB to induce actin polymerization and pseudopod formation at the front of a cell, and PTEN to localize myosin II to the rear of a cell. Relatively little is known about chemorepulsion. We previously found that AprA is a chemorepellent protein secreted by Dictyostelium cells. Here we used 29 cell lines with disruptions of cAMP and/or AprA signal transduction pathway components, and delineated the AprA chemorepulsion pathway...
November 21, 2018: Molecular Biology of the Cell
C M Parseghian, J M Loree, V K Morris, X Liu, K K Clifton, S Napolitano, J T Henry, A A Pereira, E Vilar, B Johnson, B Kee, K Raghav, A Dasari, J Wu, N Garg, V M Raymond, K C Banks, A A Talasaz, R B Lanman, J H Strickler, D S Hong, R B Corcoran, M J Overman, S Kopetz
Background: Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to EGFR inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay, however the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. Patients and Methods: We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS/BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy...
November 21, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Qian Fei, Jianjia Xiao, Ling Gai, Jianwei Zhu
HMGB1-RAGE signaling plays an integral role in inflammation-driven carcinogenesis. In the present study, we showed that RAGE has direct association with K-Ras following HMGB1 exposure in colorectal cancer (CRC) cells. Immunofluorescence analysis revealed a significant co-localization between RAGE and K-Ras in HMGB1-exposed CRC cells. Moreover, we uncovered that HMGB1-mediated RAGE activation led to Yap1 accumulation in a Ras-dependent mechanism in CRC cells. HMGB1 activated the expression of Yap1 downstream stemness marker proteins CD44 and Sox2 in RAGE- and Ras-dependent manners...
November 19, 2018: Molecular Carcinogenesis
Kari Kopra, Tanja Seppälä, Dana Rabara, Maria Abreu-Blanco, Sakari Kulmala, Matthew Holderfield, Harri Härmä
A new label-free molecular probe for luminescent nucleotide detection in neutral aqueous solution is presented. Phosphate-containing molecules, such as nucleotides possess vital role in cell metabolism, energy economy, and various signaling processes. Thus, the monitoring of nucleotide concentration and nucleotide related enzymatic reactions is of high importance. Two component lanthanide complex formed from Tb(III) ion carrier and light harvesting antenna, readily distinguishes nucleotides containing different number of phosphates and enable direct detection of enzymatic reactions converting nucleotide triphosphate (NTP) to nucleotide di/monophosphate or the opposite...
November 16, 2018: Sensors
M Steklov, S Pandolfi, M F Baietti, A Batiuk, P Carai, P Najm, M Zhang, H Jang, F Renzi, Y Cai, L Abbasi Asbagh, T Pastor, M De Troyer, M Simicek, E Radaelli, H Brems, E Legius, J Tavernier, K Gevaert, F Impens, L Messiaen, R Nussinov, S Heymans, S Eyckerman, A A Sablina
The LZTR1 protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan Syndrome phenotypes; whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine 170...
November 15, 2018: Science
Z J Gao, Q Jiang, X L Chen, Q Chen, X N Ji, Y Y Mao, S Feng, J J Dong, K M Xu
Objective: To analyze the de novo point mutations in known genes among patients with unexplained intellectual disability (ID) or developmental retardation (DD). Methods: A total of 120 outpatients with ID or DD were recruited in the Department of Neurology, Affiliated Children's Hospital of Capital Institute of Pediatrics between September 2015 and April 2017. Target gene sequencing was used to screen the candidate gene. The sequencing data were analyzed by a variety of bioinformatics software. Combining with the phenotypes of the patients, the candidate genetic/genomic variants were identified from next-generation sequencing data...
November 13, 2018: Zhonghua Yi Xue za Zhi [Chinese medical journal]
Karlijn M C Cornel, Kim Wouters, Koen K Van de Vijver, Anneke A M van der Wurff, Manon van Engeland, Roy F P M Kruitwagen, Johanna M A Pijnenborg
Up to 60% of untreated atypical hyperplastic endometrium will develop into endometrial carcinoma (EC), and for those who underwent a hysterectomy a coexisting EC is found in up to 50%. Gene promoter methylation might be related to the EC development. The aim of this study is to determine changes in gene promoter profiles in normal endometrium, atypical hyperplasia (AH) and EC in relation to K-Ras mutations. A retrospective study was conducted in patients diagnosed with endometrial hyperplasia with and without subsequent EC...
November 14, 2018: Pathology Oncology Research: POR
Leila Kaeid Sharaf, Mridul Sharma, Deepika Chandel, Geeta Shukla
BACKGROUND: Colorectal cancer has been found to be attenuated either with prophylactic manipulation of gut microbiome with probiotics or celecoxib, a non-steroidal anti-inflammatory drug mainly by suppressing early pro-carcinogenic markers in various experimental studies. Therefore, the present study was designed to assess the prophylactic potential of combinatorial administration of probiotics (Lactobacillus rhamnosus GG, Lactobacillus acidophilus) and celecoxib in experimental colon carcinogenesis...
November 13, 2018: BMC Cancer
Jaesik Jeong, Kwangok Seo, Eung-Sam Kim
BACKGROUND: Various efforts to understand the relationship between biological information and disease have been done using many different types of highthroughput data such as genomics and metabolomics. However, information obtained from previous studies was not satisfactory, implying that new direction of studies is in need. Thus, we have tried profiling intracellular free amino acids in normal and cancerous cells to extract some information about such relationship by way of the change in IFAA levels in response to the treatment of three kinase inhibitors...
November 13, 2018: BMC Cancer
Yuri Ishigaki, Kae Sato
The fluorescence in situ hybridization (FISH)-based padlock probe and rolling circle amplification (RCA) method allows for the detection of point mutations. However, it requires multiple reaction steps and solution exchanges, making it costly, labor-intensive, and time-consuming. In this study, we aimed to improve the efficiency of padlock/RCA by determining the effects of microchannel shape and ultrasonic solution mixing. Using a circular-shaped microchamber and ultrasonic mixing, the efficiency of microfluidic padlock/RCA was improved, and the consumption of the expensive probe solution was reduced from 10 µL to approximately 3...
May 30, 2018: Micromachines
Di Qu, Feng Cui, Dan Lu, Yu Yang, Yuqing Xu
DEP domain containing 1 (DEPDC1) protein is a novel oncoantigen up-regulated in multi-type of cancers which presents oncogenic activity and high immunogenicity. However, the functional discovery and therapeutic potential of DEPDC1 in hepatocellular carcinoma (HCC) remain unclear. In this study, we demonstrated that DEPDC1 was frequently up-regulated in HCC and associated with cancer diagnosis and poor prognosis for HCC patients. Moreover, DEPDC1 promotes HCC cell proliferation in vitro as well as carcinogenesis in vivo...
November 12, 2018: Cancer Science
Stella Liong, Gillian Barker, Martha Lappas
Heightened placental inflammation and dysfunction are commonly associated in pregnant obese women compared to their pregnant lean counterparts. The small GTPase superfamily members known as the rat sarcoma viral oncogene homolog (Ras) proteins, in particular, the K-Ras and H-Ras isoforms, have been implicated to regulate inflammation. The aims were to determine the placental Ras expression and activity with maternal obesity and its role in regulating placental inflammation. Human placenta was obtained at term Caesarean section from lean and obese pregnant women to determine the effect of maternal obesity on Ras protein expression and activity...
2018: Mediators of Inflammation
Anke Van Herck, Stijn E Verleden, Annelore Sacreas, Tobias Heigl, Bart M Vanaudenaerde, Lieven J Dupont, Jonas Yserbyt, Eric K Verbeken, Arne P Neyrinck, Dirk Van Raemdonck, Geert M Verleden, Robin Vos
BACKGROUND: Long-term survival after lung transplantation (LTx) is hampered by chronic lung allograft dysfunction (CLAD). Our study evaluated the prevalence and prognostic importance of obstructive and restrictive CLAD phenotypes, with or without an identifiable underlying cause, to validate the recently proposed classification system for CLAD. METHODS: Data for patients who underwent LTx between 2004 and 2015 with a minimal survival of 180 days post-LTx were retrospectively collected...
October 4, 2018: Journal of Heart and Lung Transplantation
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