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2. Author Correction: The plasmidome associated with Gram-negative bloodstream infections: a large-scale observational study using complete plasmid assemblies

Author

Lipworth, Samuel, Matlock, William, Shaw, Liam, Vihta, Karina-Doris, Rodger, Gillian, Chau, Kevin, Barker, Leanne, George, Sophie, Kavanagh, James, Davies, Timothy, Vaughan, Alison, Andersson, Monique, Jeffery, Katie, Oakley, Sarah, Morgan, Marcus, Hopkins, Susan, Peto, Timothy, Crook, Derrick, Walker, A. Sarah, and Stoesser, Nicole

Published
2024
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3. The plasmidome associated with Gram-negative bloodstream infections: A large-scale observational study using complete plasmid assemblies

Author

Lipworth, Samuel, Matlock, William, Shaw, Liam, Vihta, Karina-Doris, Rodger, Gillian, Chau, Kevin, Barker, Leanne, George, Sophie, Kavanagh, James, Davies, Timothy, Vaughan, Alison, Andersson, Monique, Jeffery, Katie, Oakley, Sarah, Morgan, Marcus, Hopkins, Susan, Peto, Timothy, Crook, Derrick, Walker, A. Sarah, and Stoesser, Nicole

Published
2024
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5. MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Author

Ghukasyan, Razmik, Liang, Keke, Chau, Kevin, Li, Luyi, Chan, Charlotte, Abt, Evan R, Le, Thuc, Park, Joon Y, Wu, Nanping, Premji, Alykhan, Damoiseaux, Robert, Luu, Tony, Labora, Amanda, Rashid, Khalid, Link, Jason M, Radu, Caius G, and Donahue, Timothy R

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Digestive Diseases, Pancreatic Cancer, Rare Diseases, 5.1 Pharmaceuticals, Humans, Interferon Type I, Antineoplastic Agents, Signal Transduction, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal, Mitogen-Activated Protein Kinase Kinases, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

PurposeStimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity.Experimental designWe screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo.ResultsWe found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation.ConclusionsOur results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition.

Published
2023

6. Reorganization in the macaque interoceptive-allostatic network following anterior cingulate cortex damage

Author

Charbonneau, Joey A, Bennett, Jeffrey L, Chau, Kevin, and Bliss-Moreau, Eliza

Subjects
Biological Psychology, Psychology, Neurosciences, Behavioral and Social Science, 1.1 Normal biological development and functioning, Animals, Gyrus Cinguli, Cerebral Cortex, Brain, Brain Mapping, Macaca mulatta, amygdala, brain damage, insula, plasticity, rhesus monkey, Cognitive Sciences, Experimental Psychology, Biological psychology, Cognitive and computational psychology
Abstract

Accumulating evidence indicates that the adult brain is capable of significant structural change following damage-a capacity once thought to be largely limited to developing brains. To date, most existing research on adult plasticity has focused on how exteroceptive sensorimotor networks compensate for damage to preserve function. Interoceptive networks-those that represent and process sensory information about the body's internal state-are now recognized to be critical for a wide range of physiological and psychological functions from basic energy regulation to maintaining a sense of self, but the extent to which these networks remain plastic in adulthood has not been established. In this report, we used detailed histological analyses to pinpoint precise changes to gray matter volume in the interoceptive-allostatic network in adult rhesus monkeys (Macaca mulatta) who received neurotoxic lesions of the anterior cingulate cortex (ACC) and neurologically intact control monkeys. Relative to controls, monkeys with ACC lesions had significant and selective unilateral expansion of the ventral anterior insula and significant relative bilateral expansion of the lateral nucleus of the amygdala. This work demonstrates the capacity for neuroplasticity in the interoceptive-allostatic network which, given that changes included expansion rather than atrophy, is likely to represent an adaptive response following damage.

Published
2023

7. Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

Author

Owen, Mallory J, Wright, Meredith S, Batalov, Sergey, Kwon, Yonghyun, Ding, Yan, Chau, Kevin K, Chowdhury, Shimul, Sweeney, Nathaly M, Kiernan, Elizabeth, Richardson, Andrew, Batton, Emily, Baer, Rebecca J, Bandoli, Gretchen, Gleeson, Joseph G, Bainbridge, Matthew, Chambers, Christina D, and Kingsmore, Stephen F

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Pediatric, Genetics, Minority Health, Perinatal Period - Conditions Originating in Perinatal Period, Clinical Research, Infant Mortality, Health Disparities, Preterm, Low Birth Weight and Health of the Newborn, American Indian or Alaska Native, Good Health and Well Being, Child, Female, Humans, Infant, Infant, Newborn, Causality, Cohort Studies, Infant Death, Male, Whole Genome Sequencing, California, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceUnderstanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood.ObjectiveTo determine the association of genetic diseases with infant mortality.Design, setting, and participantsThis cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022.ExposureInfants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation.Main outcomes and measuresProportion of infant deaths associated with single-locus genetic diseases.ResultsAmong 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission.Conclusions and relevanceIn this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality.

Published
2023

8. Scalable, high quality, whole genome sequencing from archived, newborn, dried blood spots

Author

Ding, Yan, Owen, Mallory, Le, Jennie, Batalov, Sergey, Chau, Kevin, Kwon, Yong Hyun, Van Der Kraan, Lucita, Bezares-Orin, Zaira, Zhu, Zhanyang, Veeraraghavan, Narayanan, Nahas, Shareef, Bainbridge, Matthew, Gleeson, Joe, Baer, Rebecca J, Bandoli, Gretchen, Chambers, Christina, and Kingsmore, Stephen F

Subjects
Human Genome, Pediatric, Clinical Research, Biotechnology, Genetics, Perinatal Period - Conditions Originating in Perinatal Period
Abstract

Universal newborn screening (NBS) is a highly successful public health intervention. Archived dried bloodspots (DBS) collected for NBS represent a rich resource for population genomic studies. To fully harness this resource in such studies, DBS must yield high-quality genomic DNA (gDNA) for whole genome sequencing (WGS). In this pilot study, we hypothesized that gDNA of sufficient quality and quantity for WGS could be extracted from archived DBS up to 20 years old without PCR (Polymerase Chain Reaction) amplification. We describe simple methods for gDNA extraction and WGS library preparation from several types of DBS. We tested these methods in DBS from 25 individuals who had previously undergone diagnostic, clinical WGS and 29 randomly selected DBS cards collected for NBS from the California State Biobank. While gDNA from DBS had significantly less yield than from EDTA blood from the same individuals, it was of sufficient quality and quantity for WGS without PCR. All samples DBS yielded WGS that met quality control metrics for high-confidence variant calling. Twenty-eight variants of various types that had been reported clinically in 19 samples were recapitulated in WGS from DBS. There were no significant effects of age or paper type on WGS quality. Archived DBS appear to be a suitable sample type for WGS in population genomic studies.

Published
2023

9. Optimization of a Real-Time Wavelet-Based Algorithm for Improving Speech Intelligibility

Author

Kang, Tianqu, Dinh, Anh-Dung, Wang, Binghong, Du, Tianyuan, Chen, Yijia, and Chau, Kevin

Subjects
Computer Science - Sound, Computer Science - Computation and Language, Electrical Engineering and Systems Science - Audio and Speech Processing
Abstract

The optimization of a wavelet-based algorithm to improve speech intelligibility along with the full data set and results are reported. The discrete-time speech signal is split into frequency sub-bands via a multi-level discrete wavelet transform. Various gains are applied to the sub-band signals before they are recombined to form a modified version of the speech. The sub-band gains are adjusted while keeping the overall signal energy unchanged, and the speech intelligibility under various background interference and simulated hearing loss conditions is enhanced and evaluated objectively and quantitatively using Google Speech-to-Text transcription. A universal set of sub-band gains can work over a range of noise-to-signal ratios up to 4.8 dB. For noise-free speech, overall intelligibility is improved, and the Google transcription accuracy is increased by 16.9 percentage points on average and 86.7 maximum by reallocating the spectral energy toward the mid-frequency sub-bands. For speech already corrupted by noise, improving intelligibility is challenging but still realizable with an increased transcription accuracy of 9.5 percentage points on average and 71.4 maximum. The proposed algorithm is implementable for real-time speech processing and comparatively simpler than previous algorithms. Potential applications include speech enhancement, hearing aids, machine listening, and a better understanding of speech intelligibility., Comment: 16 pages, 7 figures, 4 tables

Published
2022

11. Contact map dependence of a T cell receptor binding repertoire

Author

Chau, Kevin Ng, George, Jason T., Onuchic, José N., Lin, Xingcheng, and Levine, Herbert

Subjects
Physics - Biological Physics
Abstract

The T cell arm of the adaptive immune system provides the host protection against unknown pathogens by discriminating between host and foreign material. This discriminatory capability is achieved by the creation of a repertoire of cells each carrying a T cell receptor (TCR) specific to non-self antigens displayed as peptides bound to the major histocompatibility complex (pMHC). The understanding of the dynamics of the adaptive immune system at a repertoire level is complex, due to both the nuanced interaction of a TCR-pMHC pair and to the number of different possible TCR-pMHC pairings, making computationally exact solutions currently unfeasible. To gain some insight into this problem, we study an affinity-based model for TCR-pMHC binding in which a crystal structure is used to generate a distance-based contact map that weights the pairwise amino acid interactions. We find that the TCR-pMHC binding energy distribution strongly depends both on the number of contacts and the repeat structure allowed by the topology of the contact map of choice; this in turn influences T cell recognition probability during negative selection, with higher variances leading to higher survival probabilities. In addition, we quantify the degree to which neoantigens with mutations in sites with higher contacts are recognized at a higher rate., Comment: 10 pages, 4 figures, to be submitted to Physical Review E

Published
2021

12. Wastewater influent and population-level surveillance of antimicrobial resistance in Oxfordshire using metagenomic sequencing

Author

Chau, Kevin Kaibond, Stoesser, Nicole, Walker, Sarah Ann, Crook, Derrick, and Read, Daniel

Subjects
Drug resistance in microorganisms, Metagenomics, Public health surveillance, Sewage
Abstract

Antimicrobial resistance (AMR) represents a significant challenge to global health comprising substantial complexity driving its emergence and spread. Thus, surveillance efforts are essential to monitor trends, identify emergence and develop interventions, and of particular importance in curtailing rapid global dissemination facilitated by plasmids and other mobile genetic elements. Accordingly, the development and deployment of novel surveillance approaches is prioritised in the World Health Organisation's global AMR action plan. Wastewater-based epidemiology (WBE) is of increasing interest as a convenient surveillance approach, leveraging the pooling of human excreta to generate information on human populations at scale. Whilst WBE has found success in the surveillance of polioviruses and SARS-CoV-2, its application to monitoring population-level AMR prevalence remains limited to date. Part of the challenge lies in the paucity of clearly reported studies and validation of methodology which hinders effective iterative development. In this thesis, I employed metagenomic sequencing methods to investigate several fundamental questions of methodology and study design regarding the application of WBE to population-level AMR surveillance. By initially conducting a comprehensive synthesis of shortcomings and knowledge gaps in the existing literature, I tailored my experimental chapters to specifically address gaps in knowledge whilst employing best practices gleaned from the review. I benchmarked the performance of multiple sequencing and bioinformatic approaches in the context of WBE AMR surveillance. I also investigated the impact of initial wastewater sampling methods on profiling taxonomic and resistome composition, with parallel characterisation of short-term temporal fluctuation and associated drivers. Lastly, I conducted a multi-site longitudinal survey to explore factors associated with wastewater composition such as antibiotic prescribing and residue concentrations. A common recurring theme throughout this thesis is the importance of validating individual methods to systematically identify sources of variation when developing workflows for WBE. The work I have conducted highlights the complexity involved in the analysis and deconvolution of wastewater for AMR surveillance, and demonstrates the need for clearer reporting of high-quality metadata to facilitate Iterative development of optimal practice. Additionally, interdisciplinary collaboration is vital for this field where insight from colleagues in areas of chemical and viral surveillance as well as the often- overlooked expertise of individuals working outside of research but within the wastewater industry is invaluable. Future work underscored by collaboration and the sharing of granular metadata will significantly accelerate the development of wastewater-based epidemiology into a robust surveillance tool for the mitigation of antimicrobial resistance.

Published
2022

13. An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases

Author

Owen, Mallory J, Lefebvre, Sebastien, Hansen, Christian, Kunard, Chris M, Dimmock, David P, Smith, Laurie D, Scharer, Gunter, Mardach, Rebecca, Willis, Mary J, Feigenbaum, Annette, Niemi, Anna-Kaisa, Ding, Yan, Van Der Kraan, Luca, Ellsworth, Katarzyna, Guidugli, Lucia, Lajoie, Bryan R, McPhail, Timothy K, Mehtalia, Shyamal S, Chau, Kevin K, Kwon, Yong H, Zhu, Zhanyang, Batalov, Sergey, Chowdhury, Shimul, Rego, Seema, Perry, James, Speziale, Mark, Nespeca, Mark, Wright, Meredith S, Reese, Martin G, De La Vega, Francisco M, Azure, Joe, Frise, Erwin, Rigby, Charlene Son, White, Sandy, Hobbs, Charlotte A, Gilmer, Sheldon, Knight, Gail, Oriol, Albert, Lenberg, Jerica, Nahas, Shareef A, Perofsky, Kate, Kim, Kyu, Carroll, Jeanne, Coufal, Nicole G, Sanford, Erica, Wigby, Kristen, Weir, Jacqueline, Thomson, Vicki S, Fraser, Louise, Lazare, Seka S, Shin, Yoon H, Grunenwald, Haiying, Lee, Richard, Jones, David, Tran, Duke, Gross, Andrew, Daigle, Patrick, Case, Anne, Lue, Marisa, Richardson, James A, Reynders, John, Defay, Thomas, Hall, Kevin P, Veeraraghavan, Narayanan, and Kingsmore, Stephen F

Subjects
Human Genome, Pediatric, Genetics, Biotechnology, Pediatric Research Initiative, Good Health and Well Being, Child, DNA Copy Number Variations, Humans, Infant, Retrospective Studies, Whole Genome Sequencing
Abstract

While many genetic diseases have effective treatments, they frequently progress rapidly to severe morbidity or mortality if those treatments are not implemented immediately. Since front-line physicians frequently lack familiarity with these diseases, timely molecular diagnosis may not improve outcomes. Herein we describe Genome-to-Treatment, an automated, virtual system for genetic disease diagnosis and acute management guidance. Diagnosis is achieved in 13.5 h by expedited whole genome sequencing, with superior analytic performance for structural and copy number variants. An expert panel adjudicated the indications, contraindications, efficacy, and evidence-of-efficacy of 9911 drug, device, dietary, and surgical interventions for 563 severe, childhood, genetic diseases. The 421 (75%) diseases and 1527 (15%) effective interventions retained are integrated with 13 genetic disease information resources and appended to diagnostic reports ( https://gtrx.radygenomiclab.com ). This system provided correct diagnoses in four retrospectively and two prospectively tested infants. The Genome-to-Treatment system facilitates optimal outcomes in children with rapidly progressive genetic diseases.

Published
2022

14. Cortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism

Author

Urresti, Jorge, Zhang, Pan, Moran-Losada, Patricia, Yu, Nam-Kyung, Negraes, Priscilla D, Trujillo, Cleber A, Antaki, Danny, Amar, Megha, Chau, Kevin, Pramod, Akula Bala, Diedrich, Jolene, Tejwani, Leon, Romero, Sarah, Sebat, Jonathan, Yates III, John R, Muotri, Alysson R, and Iakoucheva, Lilia M

Subjects
Biomedical and Clinical Sciences, Neurosciences, Stem Cell Research - Induced Pluripotent Stem Cell, Pediatric, Mental Health, Intellectual and Developmental Disabilities (IDD), Human Genome, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research, Autism, Brain Disorders, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Neurological, Autism Spectrum Disorder, Autistic Disorder, Brain, Chromosome Deletion, Chromosomes, Human, Pair 16, DNA Copy Number Variations, Humans, Neurogenesis, Organoids, Proteomics, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

Reciprocal deletion and duplication of the 16p11.2 region is the most common copy number variation (CNV) associated with autism spectrum disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV dosage affects neuronal maturation, proliferation, and synapse number, in addition to its effect on organoid size. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with a significant excess of neurons and depletion of neural progenitors observed in deletions. Transcriptomic and proteomic profiling revealed multiple pathways dysregulated by the 16p11.2 CNV, including neuron migration, actin cytoskeleton, ion channel activity, synaptic-related functions, and Wnt signaling. The level of the active form of small GTPase RhoA was increased in both, deletions and duplications. Inhibition of RhoA activity rescued migration deficits, but not neurite outgrowth. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.

Published
2021

15. Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

Author

Amar, Megha, Pramod, Akula Bala, Yu, Nam-Kyung, Herrera, Victor Munive, Qiu, Lily R, Moran-Losada, Patricia, Zhang, Pan, Trujillo, Cleber A, Ellegood, Jacob, Urresti, Jorge, Chau, Kevin, Diedrich, Jolene, Chen, Jiaye, Gutierrez, Jessica, Sebat, Jonathan, Ramanathan, Dhakshin, Lerch, Jason P, Yates, John R, Muotri, Alysson R, and Iakoucheva, Lilia M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Mental Health, Genetics, Human Genome, Autism, Intellectual and Developmental Disabilities (IDD), Neurosciences, Biotechnology, Brain Disorders, Behavioral and Social Science, Pediatric, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Mental health, Animals, Autism Spectrum Disorder, Autistic Disorder, Cullin Proteins, Cytoskeleton, Germ Cells, Haploinsufficiency, Mice, Neurogenesis, Proteomics, autism spectrum disorder, CRISPR/Cas9 mouse model, Cullin 3 ubiquitin ligase, Cul3, Transcriptomics, TMT quantitative proteomics, neurodevelopmental diseases, brain development, genomics, small GTPase RhoA, cytoskeleton, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for autism spectrum disorder (ASD) and developmental delay (DD). To investigate how Cul3 mutations impact brain development, we generated a haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of embryonic, early postnatal and adult brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified defects in neuronal cytoskeleton and Rho signaling as the primary targets of Cul3 mutation during brain development.

Published
2021

16. Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer

Author

O’Brien, Neil A, McDermott, Martina SJ, Conklin, Dylan, Luo, Tong, Ayala, Raul, Salgar, Suruchi, Chau, Kevin, DiTomaso, Emmanuelle, Babbar, Naveen, Su, Faye, Gaither, Alex, Hurvitz, Sara A, Linnartz, Ronald, Rose, Kristine, Hirawat, Samit, and Slamon, Dennis J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Biotechnology, Cancer, Breast Cancer, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Good Health and Well Being, Animals, Breast Neoplasms, Cell Line, Tumor, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Drug Evaluation, Preclinical, Drug Resistance, Neoplasm, Estrogen Receptor alpha, Female, Humans, Mice, Nude, Molecular Targeted Therapy, Phosphatidylinositol 3-Kinases, Pregnancy, Protein Kinase Inhibitors, Signal Transduction, TOR Serine-Threonine Kinases, Xenograft Model Antitumor Assays, Palbociclib, Alpelisib, Translational, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundCombined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.MethodsIn this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.ResultsWe show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models.ConclusionsThese data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

Published
2020

17. Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer.

Author

O'Brien, Neil A, McDermott, Martina SJ, Conklin, Dylan, Luo, Tong, Ayala, Raul, Salgar, Suruchi, Chau, Kevin, DiTomaso, Emmanuelle, Babbar, Naveen, Su, Faye, Gaither, Alex, Hurvitz, Sara A, Linnartz, Ronald, Rose, Kristine, Hirawat, Samit, and Slamon, Dennis J

Subjects
Cell Line, Tumor, Animals, Humans, Mice, Nude, Breast Neoplasms, Estrogen Receptor alpha, Protein Kinase Inhibitors, Drug Evaluation, Preclinical, Xenograft Model Antitumor Assays, Signal Transduction, Pregnancy, Drug Resistance, Neoplasm, Female, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Molecular Targeted Therapy, Alpelisib, Palbociclib, Translational, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundCombined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.MethodsIn this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.ResultsWe show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models.ConclusionsThese data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

Published
2020

18. Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19

Author

Ahern, David J, Ai, Zhichao, Ainsworth, Mark, Allan, Chris, Allcock, Alice, Angus, Brian, Ansari, M Azim, Arancibia-Cárcamo, Carolina, Aschenbrenner, Dominik, Attar, Moustafa, Baillie, J Kenneth, Barnes, Eleanor, Bashford-Rogers, Rachael, Bashyal, Archana, Beer, Sally, Berridge, Georgina, Beveridge, Amy, Bibi, Sagida, Bicanic, Tihana, Blackwell, Luke, Bowness, Paul, Brent, Andrew, Brown, Andrew, Broxholme, John, Buck, David, Burnham, Katie, Byrne, Helen, Camara, Susana, Ferreira, Ivan Candido, Charles, Philip, Chen, Wentao, Chen, Yi-Ling, Chong, Amanda, Clutterbuck, Elizabeth, Coles, Mark, Conlon, Christopher, Cornall, Richard, Cribbs, Adam, Curion, Fabiola, Davenport, Emma, Davidson, Neil, Davis, Simon, Dendrou, Calliope, Dequaire, Julie, Dib, Lea, Docker, James, Dold, Christina, Dong, Tao, Downes, Damien, Drakesmith, Hal, Dunachie, Susanna, Duncan, David, Eijsbouts, Chris, Esnouf, Robert, Espinosa, Alexis, Etherington, Rachel, Fairfax, Benjamin, Fairhead, Rory, Fang, Hai, Fassih, Shayan, Felle, Sally, Fernandez Mendoza, Maria, Ferreira, Ricardo, Fischer, Roman, Foord, Thomas, Forrow, Aden, Frater, John, Fries, Anastasia, Gallardo Sanchez, Veronica, Garner, Lucy, Geeves, Clementine, Georgiou, Dominique, Godfrey, Leila, Golubchik, Tanya, Gomez Vazquez, Maria, Green, Angie, Harper, Hong, Harrington, Heather, Heilig, Raphael, Hester, Svenja, Hill, Jennifer, Hinds, Charles, Hird, Clare, Ho, Ling-Pei, Hoekzema, Renee, Hollis, Benjamin, Hughes, Jim, Hutton, Paula, Jackson-Wood, Matthew, Jainarayanan, Ashwin, James-Bott, Anna, Jansen, Kathrin, Jeffery, Katie, Jones, Elizabeth, Jostins, Luke, Kerr, Georgina, Kim, David, Klenerman, Paul, Knight, Julian, Kumar, Vinod, Kumar Sharma, Piyush, Kurupati, Prathiba, Kwok, Andrew, Lee, Angela, Linder, Aline, Lockett, Teresa, Lonie, Lorne, Lopopolo, Maria, Lukoseviciute, Martyna, Luo, Jian, Marinou, Spyridoula, Marsden, Brian, Martinez, Jose, Matthews, Philippa, Mazurczyk, Michalina, McGowan, Simon, McKechnie, Stuart, Mead, Adam, Mentzer, Alexander, Mi, Yuxin, Monaco, Claudia, Montadon, Ruddy, Napolitani, Giorgio, Nassiri, Isar, Novak, Alex, O'Brien, Darragh, O'Connor, Daniel, O'Donnell, Denise, Ogg, Graham, Overend, Lauren, Park, Inhye, Pavord, Ian, Peng, Yanchun, Penkava, Frank, Pereira Pinho, Mariana, Perez, Elena, Pollard, Andrew, Powrie, Fiona, Psaila, Bethan, Quan, T Phuong, Repapi, Emmanouela, Revale, Santiago, Silva-Reyes, Laura, Richard, Jean-Baptiste, Rich-Griffin, Charlotte, Ritter, Thomas, Rollier, Christine, Rowland, Matthew, Ruehle, Fabian, Salio, Mariolina, Sansom, Stephen Nicholas, Sanches Peres, Raphael, Santos Delgado, Alberto, Sauka-Spengler, Tatjana, Schwessinger, Ron, Scozzafava, Giuseppe, Screaton, Gavin, Seigal, Anna, Semple, Malcolm, Sergeant, Martin, Simoglou Karali, Christina, Sims, David, Skelly, Donal, Slawinski, Hubert, Sobrinodiaz, Alberto, Sousos, Nikolaos, Stafford, Lizzie, Stockdale, Lisa, Strickland, Marie, Sumray, Otto, Sun, Bo, Taylor, Chelsea, Taylor, Stephen, Taylor, Adan, Thongjuea, Supat, Thraves, Hannah, Todd, John, Tomic, Adriana, Tong, Orion, Trebes, Amy, Trzupek, Dominik, Tucci, Felicia Anna, Turtle, Lance, Udalova, Irina, Uhlig, Holm, van Grinsven, Erinke, Vendrell, Iolanda, Verheul, Marije, Voda, Alexandru, Wang, Guanlin, Wang, Lihui, Wang, Dapeng, Watkinson, Peter, Watson, Robert, Weinberger, Michael, Whalley, Justin, Witty, Lorna, Wray, Katherine, Xue, Luzheng, Yuen Yeung, Hing, Yin, Zixi, Young, Rebecca, Youngs, Jonathan, Zhang, Ping, Zurke, Yasemin-Xiomara, Banning, Adrian, Antonopoulos, Alexios, Bajaj, Amrita, Kelion, Andrew, Deshpande, Aparna, Kardos, Attila, Hudson, Benjamin, Koo, Bon-Kwon, Shirodaria, Cheerag, Xie, Cheng, Kotanidis, Christos, Mahon, Ciara, Berry, Colin, Adlam, David, Newby, David, Connolly, Derek, Scaletta, Diane, Alexander, Donna, Nicol, Ed, McAlindon, Elisa, Oikonomou, Evangelos, Pugliese, Francesca, Pontone, Gianluca, Benedetti, Giulia, He, Guo-Wei, West, Henry, Kondo, Hidekazu, Benedek, Imre, Das, Intrajeet, Deanfield, John, Graby, John, Greenwood, John, Rodrigues, Jonathan, Ge, Junbo, Channon, Keith, Fabritz, Larissa, Fan, Li-Juan, Kingham, Lucy, Guglielmo, Marco, Lyasheva, Maria, Schmitt, Matthias, Beer, Meinrad, Anderson, Michelle, Desai, Milind, Marwan, Mohamed, Takahashi, Naohiko, Mehta, Nehal, Dai, Neng, Screaton, Nicholas, Sabharwal, Nikant, Maurovich-Horvat, Pál, Rao, Praveen, Kotronias, Rafail, Kharbanda, Rajesh, Preston, Rebecca, Wood, Richard, Blankstein, Ron, Rajani, Ronak, Mirsadraee, Saeed, Munir, Shahzad, Thomas, Sheena, Neubauer, Stefan, Klömpken, Steffen, Petersen, Steffen, Achenbach, Stephan, Anthony, Susan, Mak, Sze, Mittal, Tarun, Benedek, Theodora, Sharma, Vinoda, Lin, Wen-Hua, Kotanidis, Christos P, Rodrigues, Jonathan C L, O’Connor, Daniel, Siddique, Muhammad, Lockstone, Helen, Oikonomou, Evangelos K, Badi, Ileana, Lumley, Sheila F, Constantinides, Bede, Sanderson, Nicholas, Rodger, Gillian, Chau, Kevin K, Lodge, Archie, Tsakok, Maria, Gleeson, Fergus, Indrajeet, Das, Hudson, Benjamin J, Srivastava, Vivek, Farid, Shakil, Krasopoulos, George, Sayeed, Rana, Newby, David E, Channon, Keith M, and Antoniades, Charalambos

Published
2022
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20. Epidemiological data and genome sequencing reveals that nosocomial transmission of SARS-CoV-2 is underestimated and mostly mediated by a small number of highly infectious individuals

Author

Lumley, Sheila F, Constantinides, Bede, Sanderson, Nicholas, Rodger, Gillian, Street, Teresa L, Swann, Jeremy, Chau, Kevin K, O'Donnell, Denise, Warren, Fiona, Hoosdally, Sarah, O'Donnell, Anne-Marie, Walker, Timothy M, Stoesser, Nicole E, Butcher, Lisa, Peto, Tim EA, Crook, Derrick W, Jeffery, Katie, Matthews, Philippa C, and Eyre, David W

Published
2021
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21. Molecular epidemiology and antimicrobial resistance phenotype of paediatric bloodstream infections caused by Gram-negative bacteria

Author

Lipworth, Sam, Vihta, Karina-Doris, Davies, Tim, Wright, Sarah, Tabirao, Merline, Chau, Kevin, Vaughan, Alison, Kavanagh, James, Barker, Leanne, George, Sophie, Segal, Shelley, Paulus, Stephane, Barrett, Lucinda, Oakley, Sarah, Jeffery, Katie, Butcher, Lisa, Peto, Tim, Crook, Derrick, Walker, Sarah, Kadambari, Seilesh, and Stoesser, Nicole

Published
2022
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23. COVID-19: Rapid antigen detection for SARS-CoV-2 by lateral flow assay: A national systematic evaluation of sensitivity and specificity for mass-testing

Author

Affron, Dominic, Afrough, Babak, Agasu, Anita, Ainsworth, Mark, Allanson, Alison, Allen, Katherine, Allen, Collette, Archer, Lorraine, Ashbridge, Natasha, Aurfan, Iman, Avery, Miriam, Badenoch, Ellena, Bagga, Priya, Balaji, Rishab, Baldwin, Ella, Barraclough, Sophie, Beane, Carol, Bell, John, Benford, Tracy, Bird, Susan, Bishop, Marina, Bloss, Angela, Body, Richard, Boulton, Rosie, Bown, Abbie, Bratten, Carla, Bridgeman, Chris, Britton, Dominic, Brooks, Tim, Broughton-Smith, Margaret, Brown, Pauline, Buck, Beverley, Butcher, Elaine, Byrne, Wendy, Calderon, Gloria, Campbell, Siobhan, Carr, Olivia, Carter, Penny, Carter, Daniel, Cathrall, Megan, Catton, Matthew, Chadwick, Jim, Chapman, David, Chau, Kevin K., Chaudary, Tanzina, Chidavaenzi, Shaolin, Chilcott, Samatha, Choi, Bea, Claasen, Hannah, Clark, Simon, Clarke, Richard, Clarke, Dawn, Clayton, Richard, Collins, Kayleigh, Colston, Rima, Connolly, James, Cook, Eloïse, Corcoran, Marie, Corley, Ben, Costello, Laura, Coulson, Caroline, Crook, Ant, Crook, Derrick W., D'Arcangelo, Silvia, Darby, Mary-Anne, Davis, John, de Koning, Rosaline, Derbyshire, Pauline, Devall, Pam, Dolman, Mark, Draper, Natalie, Driver, Mark, Dyas, Sarah, Eaton, Emily, Edwards, Joy, Elderfield, Ruth, Ellis, Kate, Ellis, Graham, Elwell, Sue, Evans, Rachel, Evans, Becky, Evans, Marion, Evans, Ranoromanana, Eyre, David, Fahey, Codie, Fenech, Vanessa, Field, Janet, Field, Alice, Foord, Tom, Fowler, Tom, French, Mollie, Fuchs, Hannah, Gan, Jasmine, Gernon, Joseph, Ghadiali, Geeta, Ghuman, Narindar, Gibbons, Kerry, Gill, Gurvinder, Gilmour, Kate, Goel, Anika, Gordon, Sally, Graham, Tillie, Grassam-Rowe, Alexander, Green, David, Gronert, Anna, Gumsley-Read, Tegan, Hall, Claire, Hallis, Bassam, Hammond, Sally, Hammond, Peter, Hanney, Beth, Hardy, Victoria, Harker, Gabriella, Harris, Andrew, Havinden-Williams, May, Hazell, Elena, Henry, Joanne, Hicklin, Kim, Hollier, Kelly, Holloway, Ben, Hoosdally, Sarah J., Hopkins, Susan, Hughes, Lucy, Hurdowar, Steve, Hurford, Sally-Anne, Jackman, Joanne, Jackson, Harriet, Johns, Ruth, Johnston, Susan, Jones, Juliet, Kanyowa, Tinashe, Keating-Fedders, Katie, Kempson, Sharon, Khan, Iftikhar, Khulusi, Beinn, Knight, Thomas, Krishna, Anuradha, Lahert, Patrick, Lampshire, Zoe, Lasserson, Daniel, Lee, Kirsten, Lee, Lennard Y.W., Legard, Arabella, Leggio, Cristina, Liu, Justin, Lockett, Teresa, Logue, Christopher, Lucas, Vanessa, Lumley, Sheila F., Maripuri, Vindhya, Markham, Des, Marshall, Emma, Matthews, Philippa C., Mckee, Sarah, McKee, Deborah F., McLeod, Neil, McNulty, Antoinette, Mellor, Freddie, Michel, Rachel, Mighiu, Alex, Miller, Julie, Mirza, Zarina, Mistry, Heena, Mitchell, Jane, Moeser, Mika Erik, Moore, Sophie, Muthuswamy, Akhila, Myers, Daniel, Nanson, Gemma, Newbury, Mike, Nicol, Scott, Nuttall, Harry, Nwanaforo, Jewel Jones, Oliver, Louise, Osbourne, Wendy, Osbourne, Jake, Otter, Ashley, Owen, Jodie, Panchalingam, Sulaksan, Papoulidis, Dimitris, Pavon, Juan Dobaldo, Peace, Arro, Pearson, Karen, Peck, Liam, Pegg, Ashley, Pegler, Suzannah, Permain, Helen, Perumal, Prem, Peto, Leon, Peto, Tim E.A., Pham, Thanh, Pickford, Hayleah L., Pinkerton, Mark, Platton, Michelle, Price, Ashley, Protheroe, Emily, Purnell, Hellen, Rawden, Lottie, Read, Sara, Reynard, Charles, Ridge, Susan, Ritter, Tom G., Robinson, James, Robinson, Patrick, Rodger, Gillian, Rowe, Cathy, Rowell, Bertie, Rowlands, Alexandra, Sampson, Sarah, Saunders, Kathryn, Sayers, Rachel, Sears, Jackie, Sedgewick, Richard, Seeney, Laura, Selassie, Amanda, Shail, Lloyd, Shallcross, Jane, Sheppard, Lucy, Sherkat, Anna, Siddiqui, Shelha, Sienkiewicz, Alex, Sinha, Lavanya, Smith, Jennifer, Smith, Ella, Stanton, Emma, Starkey, Thomas, Stawiarski, Aleksander, Sterry, Amelia, Stevens, Joe, Stockbridge, Mark, Stoesser, Nicole, Sukumaran, Anila, Sweed, Angela, Tatar, Sami, Thomas, Hema, Tibbins, Carly, Tiley, Sian, Timmins, Julie, Tomas-Smith, Cara, Topping, Oliver, Turek, Elena, Neibler, Toi, Trigg-Hogarth, Kate, Truelove, Elizabeth, Turnbull, Chris, Tyrrell, David, Vaughan, Alison, Vertannes, John, Vipond, Richard, Wagstaff, Linda, Waldron, Joanne, Walker, Philip, Walker, Ann Sarah, Walters, Mary, Wang, Jenny Y, Watson, Ellie, Webberley, Kate, Webster, Kimerbley, Westland, Grace, Wickens, Ian, Willcocks, Jane, Willis, Herika, Wilson, Stephen, Wilson, Barbara, Woodhead, Louise, Wright, Deborah, Xavier, Bindhu, Yelnoorkar, Fiona, Zeidan, Lisa, Zinyama, Rangeni, and Peto, Tim

Published
2021
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24. Population-level faecal metagenomic profiling as a tool to predict antimicrobial resistance in Enterobacterales isolates causing invasive infections: An exploratory study across Cambodia, Kenya, and the UK

Author

Auguet, Olga Tosas, Niehus, Rene, Gweon, Hyun Soon, Berkley, James A., Waichungo, Joseph, Njim, Tsi, Edgeworth, Jonathan D., Batra, Rahul, Chau, Kevin, Swann, Jeremy, Walker, Sarah A., Peto, Tim E.A., Crook, Derrick W., Lamble, Sarah, Turner, Paul, Cooper, Ben S., and Stoesser, Nicole

Published
2021
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25. Community prevalence of SARS-CoV-2 in England from April to November, 2020: results from the ONS Coronavirus Infection Survey

Author

Pouwels, Koen B., Walker, A. Sarah, Crook, Derrick, Matthews, Philippa C., Peto, Tim, Pritchard, Emma, Stoesser, Nicole, Vihta, Karina-Doris, Howarth, Alison, Doherty, George, Kavanagh, James, Chau, Kevin K., Hatch, Stephanie B., Ebner, Daniel, Martins Ferreira, Lucas, Christott, Thomas, Marsden, Brian D., Dejnirattisai, Wanwisa, Mongkolsapaya, Juthathip, Hoosdally, Sarah, Cornall, Richard, Stuart, David I., Screaton, Gavin, Eyre, David, Bell, John, Cox, Stuart, Paddon, Kevin, James, Tim, House, Thomas, Newton, John N., Robotham, Julie V., Birrell, Paul, Jordan, Helena, Sheppard, Tim, Athey, Graham, Moody, Dan, Curry, Leigh, Brereton, Pamela, Hay, Jodie, Vansteenhouse, Harper, Bell, Iain, Diamond, Ian, Lambert, Alex, Benton, Pete, Rourke, Emma, Hawkes, Stacey, Henry, Sarah, Scruton, James, Stokes, Peter, Thomas, Tina, Allen, John, Black, Russell, Bovill, Heather, Braunholtz, David, Brown, Dominic, Collyer, Sarah, Crees, Megan, Daglish, Colin, Davies, Byron, Donnarumma, Hannah, Douglas-Mann, Julia, Felton, Antonio, Finselbach, Hannah, Fordham, Eleanor, Ipser, Alberta, Jenkins, Joe, Jones, Joel, Kent, Katherine, Kerai, Geeta, Lloyd, Lina, Masding, Victoria, Osborn, Ellie, Patel, Alpi, Pereira, Elizabeth, Pett, Tristan, Randall, Melissa, Reeve, Donna, Shah, Palvi, Snook, Ruth, Studley, Ruth, Sutherland, Esther, Swinn, Eliza, Thomas, Heledd, Tudor, Anna, Weston, Joshua, Leib, Shayla, Tierney, James, Farkas, Gabor, Cobb, Raf, Van Galen, Folkert, Compton, Lewis, Irving, James, Clarke, John, Mullis, Rachel, Ireland, Lorraine, Airimitoaie, Diana, Nash, Charlotte, Cox, Danielle, Fisher, Sarah, Moore, Zoe, McLean, James, Kerby, Matt, Pouwels, Koen B, Robotham, Julie V, Birrell, Paul J, Gelman, Andrew, Bowers, Nikola, Boreham, Ian, Lewis, James, Bell, John I, Newton, John N, Farrar, Jeremy, and Walker, Ann Sarah

Published
2021
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26. Performance characteristics of five immunoassays for SARS-CoV-2: a head-to-head benchmark comparison

Author

Ainsworth, Mark, Andersson, Monique, Auckland, Kathryn, Baillie, J Kenneth, Barnes, Eleanor, Beer, Sally, Beveridge, Amy, Bibi, Sagida, Blackwell, Luke, Borak, Martyna, Bown, Abbie, Brooks, Tim, Burgess-Brown, Nicola A, Camara, Susana, Catton, Matthew, Chau, Kevin K., Christott, Thomas, Clutterbuck, Elizabeth, Coker, Jesse, Cornall, Richard J, Cox, Stuart, Crawford-Jones, David, Crook, Derrick W, D'Arcangelo, Silvia, Dejnirattsai, Wanwisa, Dequaire, Julie M M, Dimitriadis, Stavros, Dingle, Kate E, Doherty, George, Dold, Christina, Dong, Tao, Dunachie, Susanna J, Ebner, Daniel, Emmenegger, Marc, Espinosa, Alexis, Eyre, David W, Fairhead, Rory, Fassih, Shayan, Feehily, Conor, Felle, Sally, Fernandez-Cid, Alejandra, Fernandez Mendoza, Maria, Foord, Thomas H, Fordwoh, Thomas, Fox McKee, Deborah, Frater, John, Gallardo Sanchez, Veronica, Gent, Nick, Georgiou, Dominique, Groves, Christopher J, Hallis, Bassam, Hammond, Peter M, Hatch, Stephanie B., Harvala, Heli J, Hill, Jennifer, Hoosdally, Sarah J, Horsington, Bryn, Howarth, Alison, James, Tim, Jeffery, Katie, Jones, Elizabeth, Justice, Anita, Karpe, Fredrik, Kavanagh, James, Kim, David S, Kirton, Richard, Klenerman, Paul, Knight, Julian C, Koukouflis, Leonidas, Kwok, Andrew, Leuschner, Ullrich, Levin, Robert, Linder, Aline, Lockett, Teresa, Lumley, Sheila F, Marinou, Spyridoula, Marsden, Brian D, Martinez, Jose, Martins Ferreira, Lucas, Mason, Lara, Matthews, Philippa C, Mentzer, Alexander J, Mobbs, Alexander, Mongkolsapaya, Juthathip, Morrow, Jordan, Mukhopadhyay, Shubhashish M M, Neville, Matthew J, Oakley, Sarah, Oliveira, Marta, Otter, Ashley, Paddon, Kevin, Pascoe, Jordan, Peng, Yanchun, Perez, Elena, Perumal, Prem K, Peto, Timothy E A, Pickford, Hayleah, Ploeg, Rutger J, Pollard, Andrew J, Richardson, Anastasia, Ritter, Thomas G, Roberts, David J, Rodger, Gillian, Rollier, Christine S, Rowe, Cathy, Rudkin, Justine K, Screaton, Gavin, Semple, Malcolm G, Sienkiewicz, Alex, Silva-Reyes, Laura, Skelly, Donal T, Sobrino Diaz, Alberto, Stafford, Lizzie, Stockdale, Lisa, Stoesser, Nicole, Street, Teresa, Stuart, David I, Sweed, Angela, Taylor, Adan, Thraves, Hannah, Tsang, Hoi P, Verheul, Marije K, Vipond, Richard, Walker, Timothy M, Wareing, Susan, Warren, Yolanda, Wells, Charlie, Wilson, Clare, Withycombe, Kate, and Young, Rebecca K

Published
2020
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29. Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia

Author

Wang, Lili, Brooks, Angela N, Fan, Jean, Wan, Youzhong, Gambe, Rutendo, Li, Shuqiang, Hergert, Sarah, Yin, Shanye, Freeman, Samuel S, Levin, Joshua Z, Fan, Lin, Seiler, Michael, Buonamici, Silvia, Smith, Peter G, Chau, Kevin F, Cibulskis, Carrie L, Zhang, Wandi, Rassenti, Laura Z, Ghia, Emanuela M, Kipps, Thomas J, Fernandes, Stacey, Bloch, Donald B, Kotliar, Dylan, Landau, Dan A, Shukla, Sachet A, Aster, Jon C, Reed, Robin, DeLuca, David S, Brown, Jennifer R, Neuberg, Donna, Getz, Gad, Livak, Kenneth J, Meyerson, Matthew M, Kharchenko, Peter V, and Wu, Catherine J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Hematology, Lymphatic Research, Human Genome, Genetics, Rare Diseases, Cancer, Lymphoma, 2.1 Biological and endogenous factors, Alternative Splicing, Cell Line, Tumor, Dishevelled Proteins, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Phosphoproteins, RNA Splicing Factors, Receptors, Notch, Signal Transduction, CLL, Notch signaling, RNA sequencing, SF3B1, alternative splicing, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways.

Published
2016

30. Does environmental exposure to pharmaceutical and personal care product residues result in the selection of antimicrobial-resistant microorganisms, and is this important in terms of human health outcomes?

Author

Stanton, Isobel C., Tipper, Holly J., Chau, Kevin, Klümper, Uli, Subirats, Jessica, Murray, Aimee K., Stanton, Isobel C., Tipper, Holly J., Chau, Kevin, Klümper, Uli, Subirats, Jessica, and Murray, Aimee K.

Abstract

The environment plays a critical role in the development, dissemination, and transmission of antimicrobial resistance (AMR). Pharmaceuticals and personal care products (PPCPs) enter the environment through direct application to the environment and through anthropogenic pollution. Although there is a growing body of evidence defining minimal selective concentrations (MSCs) of antibiotics and the role antibiotics play in horizontal gene transfer (HGT), there is limited evidence on the role of non-antibiotic PPCPs. Existing data show associations with the development of resistance or effects on bacterial growth rather than calculating selective endpoints. Research has focused on laboratory-based systems rather than in situ experiments, although PPCP concentrations found throughout wastewater, natural water, and soil environments are often within the range of laboratory-derived MSCs and at concentrations shown to promote HGT. Increased selection and HGT of AMR by PPCPs will result in an increase in total AMR abundance in the environment, increasing the risk of exposure and potential transmission of environmental AMR to humans. There is some evidence to suggest that humans can acquire resistance from environmental settings, with water environments being the most frequently studied. However, because this is currently limited, we recommend that more evidence be gathered to understand the risk the environment plays in regard to human health. In addition, we recommend that future research efforts focus on MSC-based experiments for non-antibiotic PPCPS, particularly in situ, and investigate the effect of PPCP mixtures on AMR.

Published
2024

34. Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers

Author

O'Brien, Neil A., primary, McDermott, Martina S.J., additional, Zhang, Jun, additional, Gong, Ke Wei, additional, Lu, Ming, additional, Hoffstrom, Benjamin, additional, Luo, Tong, additional, Ayala, Raul, additional, Chau, Kevin, additional, Liang, Min, additional, Madrid, Athena M., additional, Donahue, Timothy R., additional, Glaspy, John A., additional, Presta, Leonard, additional, and Slamon, Dennis J., additional

Published
2023
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35. Data from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Author

Ghukasyan, Razmik, primary, Liang, Keke, primary, Chau, Kevin, primary, Li, Luyi, primary, Chan, Charlotte, primary, Abt, Evan R., primary, Le, Thuc, primary, Park, Joon Y., primary, Wu, Nanping, primary, Premji, Alykhan, primary, Damoiseaux, Robert, primary, Luu, Tony, primary, Labora, Amanda, primary, Rashid, Khalid, primary, Link, Jason M., primary, Radu, Caius G., primary, and Donahue, Timothy R., primary

Published
2023
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36. Supplementary Fig. 2 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Author

Ghukasyan, Razmik, primary, Liang, Keke, primary, Chau, Kevin, primary, Li, Luyi, primary, Chan, Charlotte, primary, Abt, Evan R., primary, Le, Thuc, primary, Park, Joon Y., primary, Wu, Nanping, primary, Premji, Alykhan, primary, Damoiseaux, Robert, primary, Luu, Tony, primary, Labora, Amanda, primary, Rashid, Khalid, primary, Link, Jason M., primary, Radu, Caius G., primary, and Donahue, Timothy R., primary

Published
2023
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37. Supplementary Fig. 5 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Author

Ghukasyan, Razmik, primary, Liang, Keke, primary, Chau, Kevin, primary, Li, Luyi, primary, Chan, Charlotte, primary, Abt, Evan R., primary, Le, Thuc, primary, Park, Joon Y., primary, Wu, Nanping, primary, Premji, Alykhan, primary, Damoiseaux, Robert, primary, Luu, Tony, primary, Labora, Amanda, primary, Rashid, Khalid, primary, Link, Jason M., primary, Radu, Caius G., primary, and Donahue, Timothy R., primary

Published
2023
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38. Supplementary Fig. 1 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Author

Ghukasyan, Razmik, primary, Liang, Keke, primary, Chau, Kevin, primary, Li, Luyi, primary, Chan, Charlotte, primary, Abt, Evan R., primary, Le, Thuc, primary, Park, Joon Y., primary, Wu, Nanping, primary, Premji, Alykhan, primary, Damoiseaux, Robert, primary, Luu, Tony, primary, Labora, Amanda, primary, Rashid, Khalid, primary, Link, Jason M., primary, Radu, Caius G., primary, and Donahue, Timothy R., primary

Published
2023
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39. Supplementary Fig. 4 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Author

Ghukasyan, Razmik, primary, Liang, Keke, primary, Chau, Kevin, primary, Li, Luyi, primary, Chan, Charlotte, primary, Abt, Evan R., primary, Le, Thuc, primary, Park, Joon Y., primary, Wu, Nanping, primary, Premji, Alykhan, primary, Damoiseaux, Robert, primary, Luu, Tony, primary, Labora, Amanda, primary, Rashid, Khalid, primary, Link, Jason M., primary, Radu, Caius G., primary, and Donahue, Timothy R., primary

Published
2023
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40. Supplementary Fig. 3 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Author

Ghukasyan, Razmik, primary, Liang, Keke, primary, Chau, Kevin, primary, Li, Luyi, primary, Chan, Charlotte, primary, Abt, Evan R., primary, Le, Thuc, primary, Park, Joon Y., primary, Wu, Nanping, primary, Premji, Alykhan, primary, Damoiseaux, Robert, primary, Luu, Tony, primary, Labora, Amanda, primary, Rashid, Khalid, primary, Link, Jason M., primary, Radu, Caius G., primary, and Donahue, Timothy R., primary

Published
2023
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41. Supplementary Data 1 from MEK Inhibition Sensitizes Pancreatic Cancer to STING Agonism by Tumor Cell–intrinsic Amplification of Type I IFN Signaling

Author

Ghukasyan, Razmik, primary, Liang, Keke, primary, Chau, Kevin, primary, Li, Luyi, primary, Chan, Charlotte, primary, Abt, Evan R., primary, Le, Thuc, primary, Park, Joon Y., primary, Wu, Nanping, primary, Premji, Alykhan, primary, Damoiseaux, Robert, primary, Luu, Tony, primary, Labora, Amanda, primary, Rashid, Khalid, primary, Link, Jason M., primary, Radu, Caius G., primary, and Donahue, Timothy R., primary

Published
2023
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43. Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing

Author

Owen, Mallory J., primary, Wright, Meredith S., additional, Batalov, Sergey, additional, Kwon, Yonghyun, additional, Ding, Yan, additional, Chau, Kevin K., additional, Chowdhury, Shimul, additional, Sweeney, Nathaly M., additional, Kiernan, Elizabeth, additional, Richardson, Andrew, additional, Batton, Emily, additional, Baer, Rebecca J., additional, Bandoli, Gretchen, additional, Gleeson, Joseph G., additional, Bainbridge, Matthew, additional, Chambers, Christina D., additional, and Kingsmore, Stephen F., additional

Published
2023
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46. Reorganization in the macaque interoceptive-allostatic network following anterior cingulate cortex damage.

Author

Charbonneau, Joey, Charbonneau, Joey, Chau, Kevin, Bliss-Moreau, Eliza, Bennett, Jeffrey, Charbonneau, Joey, Charbonneau, Joey, Chau, Kevin, Bliss-Moreau, Eliza, and Bennett, Jeffrey

Abstract

Accumulating evidence indicates that the adult brain is capable of significant structural change following damage-a capacity once thought to be largely limited to developing brains. To date, most existing research on adult plasticity has focused on how exteroceptive sensorimotor networks compensate for damage to preserve function. Interoceptive networks-those that represent and process sensory information about the bodys internal state-are now recognized to be critical for a wide range of physiological and psychological functions from basic energy regulation to maintaining a sense of self, but the extent to which these networks remain plastic in adulthood has not been established. In this report, we used detailed histological analyses to pinpoint precise changes to gray matter volume in the interoceptive-allostatic network in adult rhesus monkeys (Macaca mulatta) who received neurotoxic lesions of the anterior cingulate cortex (ACC) and neurologically intact control monkeys. Relative to controls, monkeys with ACC lesions had significant and selective unilateral expansion of the ventral anterior insula and significant relative bilateral expansion of the lateral nucleus of the amygdala. This work demonstrates the capacity for neuroplasticity in the interoceptive-allostatic network which, given that changes included expansion rather than atrophy, is likely to represent an adaptive response following damage.

Published
2023

47. High-resolution characterization of short-term temporal variability in the taxonomic and resistome composition of wastewater influent

Author

Chau, Kevin K., Goodall, T., Bowes, M., Easterbrook, K., Brett, H., Hughes, J., Crook, D.W., Read, D.S., Walker, A.S., Stoesser, N., Chau, Kevin K., Goodall, T., Bowes, M., Easterbrook, K., Brett, H., Hughes, J., Crook, D.W., Read, D.S., Walker, A.S., and Stoesser, N.

Abstract

Wastewater-based epidemiology (WBE) for population-level surveillance of antimicrobial resistance (AMR) is gaining significant traction, but the impact of wastewater sampling methods on results is unclear. In this study, we characterized taxonomic and resistome differences between single-timepoint-grab and 24 h composites of wastewater influent from a large UK-based wastewater treatment work [WWTW (population equivalent: 223 435)]. We autosampled hourly influent grab samples (n=72) over three consecutive weekdays, and prepared additional 24 h composites (n=3) from respective grabs. For taxonomic profiling, metagenomic DNA was extracted from all samples and 16S rRNA gene sequencing was performed. One composite and six grabs from day 1 underwent metagenomic sequencing for metagenomic dissimilarity estimation and resistome profiling. Taxonomic abundances of phyla varied significantly across hourly grab samples but followed a repeating diurnal pattern for all 3 days. Hierarchical clustering grouped grab samples into four time periods dissimilar in both 16S rRNA gene-based profiles and metagenomic distances. 24H-composites resembled mean daily phyla abundances and showed low variability of taxonomic profiles. Of the 122 AMR gene families (AGFs) identified across all day 1 samples, single grab samples identified a median of six (IQR: 5–8) AGFs not seen in the composite. However, 36/36 of these hits were at lateral coverage <0.5 (median: 0.19; interquartile range: 0.16–0.22) and potential false positives. Conversely, the 24H-composite identified three AGFs not seen in any grab with higher lateral coverage (0.82; 0.55–0.84). Additionally, several clinically significant human AGFs (bla VIM, bla IMP, bla KPC) were intermittently or completely missed by grab sampling but captured by the 24 h composite. Wastewater influent undergoes significant taxonomic and resistome changes on short timescales potentially affecting interpretation of results based on sampling strategy. Grab sa

Published
2023

48. Enterobacterales plasmid sharing amongst human bloodstream infections, livestock, wastewater, and waterway niches in Oxfordshire, UK

Author

Matlock, William, Lipworth, Samuel, Chau, Kevin K., AbuOun, Manal, Barker, Leanne, Kavanagh, James, Andersson, Monique, Oakley, Sarah, Morgan, Marcus, Crook, Derrick W., Read, Daniel S., Anjum, Muna, Shaw, Liam P., Stoesser, Nicole, REHAB Consortium, Matlock, William, Lipworth, Samuel, Chau, Kevin K., AbuOun, Manal, Barker, Leanne, Kavanagh, James, Andersson, Monique, Oakley, Sarah, Morgan, Marcus, Crook, Derrick W., Read, Daniel S., Anjum, Muna, Shaw, Liam P., Stoesser, Nicole, and REHAB Consortium

Abstract

Plasmids enable the dissemination of antimicrobial resistance (AMR) in common Enterobacterales pathogens, representing a major public health challenge. However, the extent of plasmid sharing and evolution between Enterobacterales causing human infections and other niches remains unclear, including the emergence of resistance plasmids. Dense, unselected sampling is highly relevant to developing our understanding of plasmid epidemiology and designing appropriate interventions to limit the emergence and dissemination of plasmid-associated AMR. We established a geographically and temporally restricted collection of human bloodstream infection (BSI)-associated, livestock-associated (cattle, pig, poultry, and sheep faeces, farm soils) and wastewater treatment work (WwTW)-associated (influent, effluent, waterways upstream/downstream of effluent outlets) Enterobacterales. Isolates were collected between 2008-2020 from sites <60km apart in Oxfordshire, UK. Pangenome analysis of plasmid clusters revealed shared 'backbones', with phylogenies suggesting an intertwined ecology where well-conserved plasmid backbones carry diverse accessory functions, including AMR genes. Many plasmid 'backbones' were seen across species and niches, raising the possibility that plasmid movement between these followed by rapid accessory gene change could be relatively common. Overall, the signature of identical plasmid sharing is likely to be a highly transient one, implying that plasmid movement might be occurring at greater rates than previously estimated, raising a challenge for future genomic One Health studies.

Published
2023

49. A longitudinal study reveals persistence of antimicrobial resistance on livestock farms is not due to antimicrobial usage alone

Author

Smith, Richard P., May, Hannah E., AbuOun, Manal, Stubberfield, Emma, Gilson, Daniel, Chau, Kevin K., Crook, Derrick, Shaw, Liam P., Read, Daniel S., Stoesser, Nicole, Vilar, Maria Jose, Anjum, Muna F., Smith, Richard P., May, Hannah E., AbuOun, Manal, Stubberfield, Emma, Gilson, Daniel, Chau, Kevin K., Crook, Derrick, Shaw, Liam P., Read, Daniel S., Stoesser, Nicole, Vilar, Maria Jose, and Anjum, Muna F.

Abstract

•Introduction: There are concerns that antimicrobial usage (AMU) is driving an increase in multi-drug resistant (MDR) bacteria so treatment of microbial infections is becoming harder in humans and animals. The aim of this study was to evaluate factors, including usage, that affect antimicrobial resistance (AMR) on farm over time. •Methods: A population of 14 cattle, sheep and pig farms within a defined area of England were sampled three times over a year to collect data on AMR in faecal Enterobacterales flora; AMU; and husbandry or management practices. Ten pooled samples were collected at each visit, with each comprising of 10 pinches of fresh faeces. Up to 14 isolates per visit were whole genome sequenced to determine presence of AMR genes. •Results: Sheep farms had very low AMU in comparison to the other species and very few sheep isolates were genotypically resistant at any time point. AMR genes were detected persistently across pig farms at all visits, even on farms with low AMU, whereas AMR bacteria was consistently lower on cattle farms than pigs, even for those with comparably high AMU. MDR bacteria was also more commonly detected on pig farms than any other livestock species. •Discussion: The results may be explained by a complex combination of factors on pig farms including historic AMU; co-selection of AMR bacteria; variation in amounts of antimicrobials used between visits; potential persistence in environmental reservoirs of AMR bacteria; or importation of pigs with AMR microbiota from supplying farms. Pig farms may also be at increased risk of AMR due to the greater use of oral routes of group antimicrobial treatment, which were less targeted than cattle treatments; the latter mostly administered to individual animals. Also, farms which exhibited either increasing or decreasing trends of AMR across the study did not have corresponding trends in their AMU. Therefore, our results suggest that factors other than AMU on individual farms are important for p

Published
2023

50. Figure S8 from Preclinical Efficacy of the Antibody–Drug Conjugate CLDN6–23-ADC for the Treatment of CLDN6-Positive Solid Tumors

Author

McDermott, Martina S.J., primary, O'Brien, Neil A., primary, Hoffstrom, Benjamin, primary, Gong, KeWei, primary, Lu, Ming, primary, Zhang, Jun, primary, Luo, Tong, primary, Liang, Min, primary, Jia, Weiping, primary, Hong, Jenny J., primary, Chau, Kevin, primary, Davenport, Simon, primary, Xie, Bin, primary, Press, Michael F., primary, Panayiotou, Richard, primary, Handly-Santana, Abram, primary, Brugge, Joan S., primary, Presta, Leonard, primary, Glaspy, John, primary, and Slamon, Dennis J., primary

Published
2023
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