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Mutational load

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https://www.readbyqxmd.com/read/29350327/hypermutated-tumors-and-immune-checkpoint-inhibition
#1
Kristen K Ciombor, Richard M Goldberg
Microsatellite instability-high/DNA mismatch repair deficient tumors are found across the cancer spectrum and often harbor markedly increased numbers of mutations when compared to microsatellite stable/DNA mismatch repair proficient tumors. As a result of this high mutational load, tumor-infiltrating lymphocyte density is increased and more immunogenic neoepitopes are expressed, leading to upregulation of immune checkpoints in these tumors. Checkpoint inhibitors such as pembrolizumab and nivolumab, both immunoglobulin G4 (IgG4) monoclonal antibodies that block interactions between the programmed cell death receptor-1 and its ligands, have significant activity in this tumor class...
January 19, 2018: Drugs
https://www.readbyqxmd.com/read/29349598/phase-ib-study-evaluating-safety-and-clinical-activity-of-the-anti-her3-antibody-lumretuzumab-combined-with-the-anti-her2-antibody-pertuzumab-and-paclitaxel-in-her3-positive-her2-low-metastatic-breast-cancer
#2
Andreas Schneeweiss, Tjoung-Won Park-Simon, Joan Albanell, Ulrik Lassen, Javier Cortés, Veronique Dieras, Marcus May, Christoph Schindler, Frederik Marmé, Juan Miguel Cejalvo, Maria Martinez-Garcia, Iria Gonzalez, Jose Lopez-Martin, Anja Welt, Christelle Levy, Florence Joly, Francesca Michielin, Wolfgang Jacob, Céline Adessi, Annie Moisan, Georgina Meneses-Lorente, Tomas Racek, Ian James, Maurizio Ceppi, Max Hasmann, Martin Weisser, Andrés Cervantes
Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts)...
January 19, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29348202/molecular-characterization-of-latent-gdf8-reveals-mechanisms-of-activation
#3
Ryan G Walker, Jason C McCoy, Magdalena Czepnik, Melanie J Mills, Adam Hagg, Kelly L Walton, Thomas R Cotton, Marko Hyvönen, Richard T Lee, Paul Gregorevic, Craig A Harrison, Thomas B Thompson
Growth/differentiation factor 8 (GDF8), or myostatin, negatively regulates muscle mass. GDF8 is held in a latent state through interactions with its N-terminal prodomain, much like TGF-β. Using a combination of small-angle X-ray scattering and mutagenesis, we characterized the interactions of GDF8 with its prodomain. Our results show that the prodomain:GDF8 complex can exist in a fully latent state and an activated or "triggered" state where the prodomain remains in complex with the mature domain. However, these states are not reversible, indicating the latent GDF8 is "spring-loaded...
January 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29346601/accumulation-of-mutational-load-at-the-edges-of-a-species-range
#4
Yvonne Willi, Marco Fracassetti, Stefan Zoller, Josh Van Buskirk
Why species have geographically restricted distributions is an unresolved question in ecology and evolutionary biology. Here we test a new explanation, that mutation accumulation due to small population size or a history of range expansion can contribute to restricting distributions by reducing population growth rate at the edge. We examined genomic diversity and mutational load across the entire geographic range of the North American plant Arabidopsis lyrata, including old, isolated populations predominantly at the southern edge and regions of postglacial range expansion at the northern and southern edges...
January 15, 2018: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/29343598/coadaptation-of-mitochondrial-and-nuclear-genes-and-the-cost-of-mother-s-curse
#5
Tim Connallon, M Florencia Camus, Edward H Morrow, Damian K Dowling
Strict maternal inheritance renders the mitochondrial genome susceptible to accumulating mutations that harm males, but are otherwise benign or beneficial for females. This 'mother's curse' effect can degrade male survival and fertility if unopposed by counteracting evolutionary processes. Coadaptation between nuclear and mitochondrial genomes-with nuclear genes evolving to compensate for male-harming mitochondrial substitutions-may ultimately resolve mother's curse. However, males are still expected to incur a transient fitness cost during mito-nuclear coevolution, and it remains unclear how severe such costs should be...
January 31, 2018: Proceedings. Biological Sciences
https://www.readbyqxmd.com/read/29342281/phenotypic-analysis-of-hiv-1-e157q-integrase-polymorphism-and-impact-on-virological-outcome-in-patients-initiating-an-integrase-inhibitor-based-regimen
#6
Charlotte Charpentier, Isabelle Malet, Elisabeth Andre-Garnier, Alexandre Storto, Laurence Bocket, Corinne Amiel, Laurence Morand-Joubert, Camille Tumiotto, Thuy Nguyen, Anne Maillard, Audrey Rodallec, Marie Leoz, Brigitte Montes, Véronique Schneider, Jean-Christophe Plantier, Julia Dina, Coralie Pallier, Audrey Mirand, Catherine Roussel, Anne Signori-Schmuck, Stéphanie Raymond, Vincent Calvez, Constance Delaugerre, Anne-Geneviève Marcelin, Diane Descamps
Objectives: To assess the phenotypic susceptibility of the E157Q polymorphism in HIV-1 integrase (IN) and the virological outcome of patients infected with E157Q-mutated virus initiating an IN inhibitor (INI)-based regimen. Methods: This was a multicentre study assessing IN sequences from INI-naive patients among 17 French HIV clinical centres. E157Q site-directed mutants in pNL4.3 and pCRF02_AG contexts were assessed in a recombinant phenotypic assay. Results: Prevalence of the E157Q polymorphism was 2...
January 12, 2018: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29339483/hells-and-cdca7-comprise-a-bipartite-nucleosome-remodeling-complex-defective-in-icf-syndrome
#7
Christopher Jenness, Simona Giunta, Manuel M Müller, Hiroshi Kimura, Tom W Muir, Hironori Funabiki
Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29339376/tumor-immunity-and-survival-as-a-function-of-alternative-neopeptides-in-human-cancer
#8
Andrew J Rech, David Balli, Alejandro Mantero, Hemant Ishwaran, Katherine L Nathanson, Ben Z Stanger, Robert H Vonderheide
The immune system exerts antitumor activity via T cell-dependent recognition of tumor-specific antigens. Although the number of tumor neopeptides - peptides derived from somatic mutations - often correlates with immune activity and survival, most classically defined high-affinity neopeptides (CDNs) are not immunogenic, and only rare CDNs have been linked to tumor rejection. Thus, the rules of tumor antigen recognition remain incompletely understood. Here, we analyzed neopeptides, immune activity, and clinical outcome from 6,324 patients across 27 tumor types...
January 16, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29331843/performance-of-genotypic-algorithms-for-predicting-tropism-for-hiv-1-crf01_ae-recombinant
#9
C Soulie, L Morand-Joubert, J Cottalorda, C Charpentier, P Bellecave, L Le Guen, S Yerly, B Montes, S Fafi-Kremer, J Dina, V Avettand-Fenoel, C Amiel, C Roussel, C Pallier, K Zafilaza, S Sayon, A Signori-Schmuck, A Mirand, M A Trabaud, S Berger, V Calvez, A G Marcelin
OBJECTIVES: There is no consensus about the performances of genotypic rules for predicting HIV-1 non-B subtype tropism. Three genotypic methods were compared for CRF01_AE HIV-1 tropism determination. METHODS: The V3 env region of 207 HIV-1 CRF01_AE and 178 B subtypes from 17 centers in France and 1 center in Switzerland was sequenced. Tropism was determined by Geno2Pheno algorithm with false positive rate (FPR) 5% or 10%, the 11/25 rule or the combined criteria of the 11/25, net charge rule and NXT/S mutations...
January 8, 2018: Journal of Clinical Virology: the Official Publication of the Pan American Society for Clinical Virology
https://www.readbyqxmd.com/read/29331515/mhc-class-i-loaded-ligands-from-breast-cancer-cell-lines-a-potential-hla-i-typed-antigen-collection
#10
Dmitri V Rozanov, Nikita D Rozanov, Kami Chiotti, Ashok Reddy, Phillip A Wilmarth, Larry L David, Seung W Cha, Sunghee Woo, Pavel Pevzner, Vineet Bafna, Gregory G Burrows, Juha K Rantala, Trevor Levin, Pavana Anur, Katie Johnson-Camacho, Shaadi Tabatabaei, Daniel J Munson, Tullia C Bruno, Jill E Slansky, John W Kappler, Naoto Hirano, Sebastian Boegel, Bernard A Fox, Colt Egelston, Diana L Simons, Grecia Jimenez, Peter P Lee, Joe W Gray, Paul T Spellman
To build a catalog of peptides presented by breast cancer cells, we undertook systematic MHC class I immunoprecipitation followed by elution of MHC class I-loaded peptides in breast cancer cells. We determined the sequence of 3196 MHC class I ligands representing 1921 proteins from a panel of 20 breast cancer cell lines. After removing duplicate peptides, i.e., the same peptide eluted from more than one cell line, the total number of unique peptides was 2740. Of the unique peptides eluted, more than 1750 had been previously identified, and of these, sixteen have been shown to be immunogenic...
January 10, 2018: Journal of Proteomics
https://www.readbyqxmd.com/read/29328915/retrovirus-like-gag-protein-arc1-binds-rna-and-traffics-across-synaptic-boutons
#11
James Ashley, Benjamin Cordy, Diandra Lucia, Lee G Fradkin, Vivian Budnik, Travis Thomson
Arc/Arg3.1 is required for synaptic plasticity and cognition, and mutations in this gene are linked to autism and schizophrenia. Arc bears a domain resembling retroviral/retrotransposon Gag-like proteins, which multimerize into a capsid that packages viral RNA. The significance of such a domain in a plasticity molecule is uncertain. Here, we report that the Drosophila Arc1 protein forms capsid-like structures that bind darc1 mRNA in neurons and is loaded into extracellular vesicles that are transferred from motorneurons to muscles...
January 11, 2018: Cell
https://www.readbyqxmd.com/read/29326804/occult-hepatitis-b-virus-infection-and-associated-genotypes-among-hbsag-negative-subjects-in-burkina-faso
#12
Birama Diarra, Albert Théophane Yonli, Pegdwendé Abel Sorgho, Tegwindé Rebeca Compaore, Abdoul Karim Ouattara, Wendpagnangdé Arsène Zongo, Issoufou Tao, Lassina Traore, Serge Théophile Soubeiga, Florencia Wendkuuni Djigma, Dorcas Obiri-Yeboah, Bolni-Marius Nagalo, Virginio Pietra, Rokia Sanogo, Jacques Simpore
Background: The presence of HBV DNA in the liver (with detectable or undetectable HBV DNA in the serum) of individuals tested HBsAg negative by currently available assays is defined occult B Infection (OBI). It remains a potential transmission threat and risk to HBV chronic infection. The purpose of this study was to determine the OBI prevalence among HBsAg negative subjects and to characterize associated genotypes. Methods: Blood samples of 219 HBsAg-negative subjects tested by ELISA were collected...
2018: Mediterranean Journal of Hematology and Infectious Diseases
https://www.readbyqxmd.com/read/29322427/immunophenotyping-of-pediatric-brain-tumors-correlating-immune-infiltrate-with-histology-mutational-load-and-survival-and-assessing-clonal-t-cell-response
#13
Ashley S Plant, Shohei Koyama, Claire Sinai, Isaac H Solomon, Gabriel K Griffin, Keith L Ligon, Pratiti Bandopadhayay, Rebecca Betensky, Ryan Emerson, Glenn Dranoff, Mark W Kieran, Jerome Ritz
There is little known regarding the immune infiltrate present in pediatric brain tumors and how this compares to what is known about histologically similar adult tumors and its correlation with survival. Here, we provide a descriptive analysis of the immune infiltrate of 22 fresh pediatric brain tumor tissue samples of mixed diagnoses and 40 peripheral blood samples. Samples were analyzed using a flow cytometry panel containing markers for immune cell subtypes, costimulatory markers, inhibitory signals, and markers of activation...
January 10, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29321356/the-connexin-46-mutant-v44m-impairs-gap-junction-function-causing-congenital-cataract
#14
Lijuan Chen, Dongmei Su, Sijia Li, Lina Guan, Cuige Shi, Dianjun Li, Shanshan Hu, Xu Ma
Connexin 46 (Cx46) is important for gap junction channels formation which plays crucial role in the preservation of lens homeostasis and transparency. Previously, we have identified a missense mutation (p.V44M) of Cx46 in a congenital cataract family. This study aims at dissecting the potential pathogenesis of the causative mutant of cataract. Plasmids carrying wild-type (wt) and mutant (V44M) of Cx46 were constructed and expressed in Hela cells respectively.Western blotting and fluorescence microscopy were applied to analyse the expression and subcellular localization of recombinant proteins, respectively...
December 2017: Journal of Genetics
https://www.readbyqxmd.com/read/29321316/two-residues-in-nsp9-contribute-to-the-enhanced-replication-and-pathogenicity-of-highly-pathogenic-porcine-reproductive-and-respiratory-syndrome-virus
#15
Kuan Zhao, Jia-Cong Gao, Jun-Yao Xiong, Jin-Chao Guo, Yong-Bo Yang, Cheng-Gang Jiang, Yan-Dong Tang, Zhi-Jun Tian, Xue-Hui Cai, Guang-Zhi Tong, Tong-Qing An
Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) possesses greater replicative capacity and pathogenicity than classical PRRSV. However, the factors that lead to enhanced replication and pathogenicity remain unclear. In our study, an alignment of all available full-length sequences of North-American type PRRSVs (n = 204) revealed two consistent amino acid mutations that differed between HP-PRRSV and classical PRRSV and were located at positions 519 and 544 in non-structural protein 9...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29320991/an-oncogenic-mutant-of-rheb-rheb-y35n-exhibits-an-altered-interaction-with-braf-resulting-in-cancer-transformation
#16
Jeffrey J Heard, Ivy Phung, Mark I Potes, Fuyuhiko Tamanoi
BACKGROUND: RHEB is a unique member of the RAS superfamily of small GTPases expressed in all tissues and conserved from yeast to humans. Early studies on RHEB indicated a possible RHEB-RAF interaction, but this has not been fully explored. Recent work on cancer genome databases has revealed a reoccurring mutation in RHEB at the Tyr35 position, and a recent study points to the oncogenic potential of this mutant that involves activation of RAF/MEK/ERK signaling. These developments prompted us to reassess the significance of RHEB effect on RAF, and to compare mutant and wild type RHEB...
January 10, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29320758/polymerase-epsilon-mutations-and-concomitant-%C3%AE-2-microglobulin-mutations-in-cancer
#17
Ioannis A Voutsadakis
Mutations in the exonuclease domain of polymerase epsilon (POLE), an enzyme of DNA synthesis, are involved in a newly described syndrome of colorectal polyposis and cancer, and have been associated with a high mutation burden with or without microsatellite instability (MSI) phenotype. The exonuclease domain of POLE executes a proofreading function that decreases the mutation rate during DNA replication by an estimated of one to two orders. The high mutation burden resulting from its loss of function could create a load of neo-antigens that would put the neoplastic cells in severe disadvantage of an immune attack if properly presented to the immune system...
January 7, 2018: Gene
https://www.readbyqxmd.com/read/29320474/high-response-rate-to-pd-1-blockade-in-desmoplastic-melanomas
#18
Zeynep Eroglu, Jesse M Zaretsky, Siwen Hu-Lieskovan, Dae Won Kim, Alain Algazi, Douglas B Johnson, Elizabeth Liniker, Ben Kong, Rodrigo Munhoz, Suthee Rapisuwon, Pier Federico Gherardini, Bartosz Chmielowski, Xiaoyan Wang, I Peter Shintaku, Cody Wei, Jeffrey A Sosman, Richard W Joseph, Michael A Postow, Matteo S Carlino, Wen-Jen Hwu, Richard A Scolyer, Jane Messina, Alistair J Cochran, Georgina V Long, Antoni Ribas
Desmoplastic melanoma is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, and is highly associated with ultraviolet light-induced DNA damage. We analysed sixty patients with advanced desmoplastic melanoma who had been treated with antibodies to block programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1). Objective tumour responses were observed in forty-two of the sixty patients (70%; 95% confidence interval 57-81%), including nineteen patients (32%) with a complete response...
January 10, 2018: Nature
https://www.readbyqxmd.com/read/29316259/fatal-outcome-after-reactivation-of-inherited-chromosomally-integrated-hhv-6a-icihhv-6a-transmitted-through-liver-transplantation
#19
P Bonnafous, J Marlet, D Bouvet, E Salamé, A-C Tellier, S Guyetant, A Goudeau, H Agut, A Gautheret-Dejean, C Gaudy-Graffin
HHV-6A and HHV-6B are found as inherited and chromosomally integrated forms (iciHHV-6A and -6B) into all germinal and somatic cells and vertically transmitted in a Mendelian manner in about 1% of the population. They were occasionally shown to be horizontally transmitted through hematopoietic stem cell transplantation. Here, we present a clinical case of horizontal transmission of iciHHV-6A from donor to recipient through liver transplantation. Molecular analysis performed on three viral genes (7.2 kb) in the recipient and donor samples supports transmission of iciHHV-6A from the graft...
January 9, 2018: American Journal of Transplantation
https://www.readbyqxmd.com/read/29311238/bacterial-pathogen-emergence-required-more-than-direct-contact-with-a-novel-passerine-host
#20
Molly Staley, Geoffrey E Hill, Chloe C Josefson, Jonathan W Armbruster, Camille Bonneaud
While direct contact may sometimes be sufficient to allow a pathogen to jump into a new host species, in other cases fortuitously adaptive mutations that arise in the original donor host are also necessary. Viruses have been the focus of most host shift studies, so less is known about the importance of ecological versus evolutionary processes to successful bacterial host shifts. Here we tested whether direct contact with the novel host was sufficient to enable the mid-1990s jump of the bacterium Mycoplasma gallisepticum from domestic poultry into house finches (Haemorhous mexicanus)...
January 8, 2018: Infection and Immunity
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