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1. Functional inversion of circadian regulator REV-ERBα leads to tumorigenic gene reprogramming

Author

Yang, Yatian, Zhang, Xiong, Cai, Demin, Zheng, Xingling, Zhao, Xuan, Zou, June X, Zhang, Jin, Borowsky, Alexander D, Dall’Era, Marc A, Corey, Eva, Mitsiades, Nicholas, Kung, Hsing-Jien, Chen, Xinbin, Li, Jian Jian, Downes, Michael, Evans, Ronald M, and Chen, Hong-Wu

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Cancer, Human Genome, Genetics, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Nuclear Receptor Subfamily 1, Group D, Member 1, Humans, Animals, Circadian Rhythm, Carcinogenesis, Mice, Gene Expression Regulation, Neoplastic, Transcription Factors, Hepatocyte Nuclear Factor 3-alpha, Signal Transduction, Cell Line, Tumor, Neoplasms, Cell Cycle Proteins, Nuclear Receptor Co-Repressor 1, Bromodomain Containing Proteins, REV-ERB alpha, prostate, CRPC, liver, antagonist, REV-ERBα
Abstract

Profound functional switch of key regulatory factors may play a major role in homeostasis and disease. Dysregulation of circadian rhythm (CR) is strongly implicated in cancer with mechanisms poorly understood. We report here that the function of REV-ERBα, a major CR regulator of the orphan nuclear receptor subfamily, is dramatically altered in tumors in both its genome binding and functional mode. Loss of CR is linked to a functional inversion of REV-ERBα from a repressor in control of CR and metabolic gene programs in normal tissues to a strong activator in different cancers. Through changing its association from NCoR/HDAC3 corepressor complex to BRD4/p300 coactivators, REV-ERBα directly activates thousands of genes including tumorigenic programs such as MAPK and PI3K-Akt signaling. Functioning as a master transcriptional activator, REV-ERBα partners with pioneer factor FOXA1 and directly stimulates a large number of signaling genes, including multiple growth factors, receptor tyrosine kinases, RASs, AKTs, and MAPKs. Moreover, elevated REV-ERBα reprograms FOXA1 to bind new targets through a BRD4-mediated increase in local chromatin accessibility. Pharmacological targeting with SR8278 diminishes the function of both REV-ERBα and FOXA1 and synergizes with BRD4 inhibitor in effective suppression of tumorigenic programs and tumor growth. Thus, our study revealed a functional inversion by a CR regulator in driving gene reprogramming as an unexpected paradigm of tumorigenesis mechanism and demonstrated a high effectiveness of therapeutic targeting such switch.

Published
2024

2. The Proteogenomics of Prostate Cancer Radioresistance

Author

Haas, Roni, Frame, Gavin, Khan, Shahbaz, Neilsen, Beth K, Hong, Boon Hao, Yeo, Celestia PX, Yamaguchi, Takafumi N, Ong, Enya HW, Zhao, Wenyan, Carlin, Benjamin, Yeo, Eugenia LL, Tan, Kah Min, Bugh, Yuan Zhe, Zhu, Chenghao, Hugh-White, Rupert, Livingstone, Julie, Poon, Dennis JJ, Chu, Pek Lim, Patel, Yash, Tao, Shu, Ignatchenko, Vladimir, Kurganovs, Natalie J, Higgins, Geoff S, Downes, Michelle R, Loblaw, Andrew, Vesprini, Danny, Kishan, Amar U, Chua, Melvin LK, Kislinger, Thomas, Boutros, Paul C, and Liu, Stanley K

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Precision Medicine, Prostate Cancer, Human Genome, Genetics, Biotechnology, Aging, Urologic Diseases, Cancer Genomics, Radiation Oncology, Male, Humans, Prostatic Neoplasms, Radiation Tolerance, Proteogenomics, Cell Line, Tumor, DNA Polymerase theta, Genomic Instability, DNA Mismatch Repair, Gene Expression Regulation, Neoplastic, DNA-Directed DNA Polymerase, Radiation Dose Hypofractionation
Abstract

Prostate cancer is frequently treated with radiotherapy. Unfortunately, aggressive radioresistant relapses can arise, and the molecular underpinnings of radioresistance are unknown. Modern clinical radiotherapy is evolving to deliver higher doses of radiation in fewer fractions (hypofractionation). We therefore analyzed genomic, transcriptomic, and proteomic data to characterize prostate cancer radioresistance in cells treated with both conventionally fractionated and hypofractionated radiotherapy. Independent of fractionation schedule, resistance to radiotherapy involved massive genomic instability and abrogation of DNA mismatch repair. Specific prostate cancer driver genes were modulated at the RNA and protein levels, with distinct protein subcellular responses to radiotherapy. Conventional fractionation led to a far more aggressive biomolecular response than hypofractionation. Testing preclinical candidates identified in cell lines, we revealed POLQ (DNA Polymerase Theta) as a radiosensitizer. POLQ-modulated radioresistance in model systems and was predictive of it in large patient cohorts. The molecular response to radiation is highly multimodal and sheds light on prostate cancer lethality.SignificanceRadiation is standard of care in prostate cancer. Yet, we have little understanding of its failure. We demonstrate a new paradigm that radioresistance is fractionation specific and identified POLQ as a radioresistance modulator.

Published
2024

3. Guidance for prevention and management of COVID-19 in children and adolescents: A consensus statement from the Pediatric Infectious Diseases Society Pediatric COVID-19 Therapies Taskforce.

Author

Willis, Zachary, Oliveira, Carlos, Abzug, Mark, Anosike, Brenda, Ardura, Monica, Bio, Laura, Boguniewicz, Juri, Chiotos, Kathleen, Downes, Kevin, Grapentine, Steven, Hersh, Adam, Heston, Sarah, Hijano, Diego, Huskins, W, James, Scott, Jones, Sarah, Lockowitz, Christine, Lloyd, Elizabeth, MacBrayne, Christine, Maron, Gabriela, Hayes McDonough, Molly, Miller, Christine, Morton, Theodore, Olivero, Rosemary, Orscheln, Rachel, Schwenk, Hayden, Singh, Prachi, Soma, Vijaya, Sue, Paul, Vora, Surabhi, Nakamura, Mari, and Wolf, Joshua

Subjects
COVID-19, evidence-based, guidance, management, pediatric, Adolescent, Child, Humans, Antiviral Agents, COVID-19, COVID-19 Drug Treatment, Risk Factors, SARS-CoV-2
Abstract

BACKGROUND: Since November 2019, the SARS-CoV-2 pandemic has created challenges for preventing and managing COVID-19 in children and adolescents. Most research to develop new therapeutic interventions or to repurpose existing ones has been undertaken in adults, and although most cases of infection in pediatric populations are mild, there have been many cases of critical and fatal infection. Understanding the risk factors for severe illness and the evidence for safety, efficacy, and effectiveness of therapies for COVID-19 in children is necessary to optimize therapy. METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacology, and pediatric intensive care medicine from 21 geographically diverse North American institutions was re-convened. Through a series of teleconferences and web-based surveys and a systematic review with meta-analysis of data for risk factors, a guidance statement comprising a series of recommendations for risk stratification, treatment, and prevention of COVID-19 was developed and refined based on expert consensus. RESULTS: There are identifiable clinical characteristics that enable risk stratification for patients at risk for severe COVID-19. These risk factors can be used to guide the treatment of hospitalized and non-hospitalized children and adolescents with COVID-19 and to guide preventative therapy where options remain available.

Published
2024

4. Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes.

Author

Hitti-Malin, Rebekkah, Panneman, Daan, Corradi, Zelia, Boonen, Erica, Astuti, Galuh, Dhaenens, Claire-Marie, Stöhr, Heidi, Weber, Bernhard, Sharon, Dror, Banin, Eyal, Karali, Marianthi, Banfi, Sandro, Ben-Yosef, Tamar, Glavač, Damjan, Farrar, G, Ayuso, Carmen, Liskova, Petra, Dudakova, Lubica, Vajter, Marie, Ołdak, Monika, Szaflik, Jacek, Matynia, Anna, Gorin, Michael, Kämpjärvi, Kati, Bauwens, Miriam, De Baere, Elfride, Hoyng, Carel, Li, Catherina, Klaver, Caroline, Inglehearn, Chris, Fujinami, Kaoru, Rivolta, Carlo, Allikmets, Rando, Zernant, Jana, Lee, Winston, Podhajcer, Osvaldo, Fakin, Ana, Sajovic, Jana, AlTalbishi, Alaa, Valeina, Sandra, Taurina, Gita, Vincent, Andrea, Roberts, Lisa, Ramesar, Raj, Sartor, Giovanna, Luppi, Elena, Downes, Susan, van den Born, L, McLaren, Terri, De Roach, John, Lamey, Tina, Thompson, Jennifer, Chen, Fred, Tracewska, Anna, Kamakari, Smaragda, Sallum, Juliana, Bolz, Hanno, Kayserili, Hülya, Roosing, Susanne, and Cremers, Frans

Subjects
inherited, macula, maculopathies, penetrance, retinal, sequencing, Humans, Mutation, Penetrance, Pedigree, Macular Degeneration, Retina, Phenotype, ATP-Binding Cassette Transporters, Eye Proteins, Cadherin Related Proteins, Nerve Tissue Proteins
Abstract

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G>A and CNGB3:c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

Published
2024

5. Targeting nuclear receptor corepressors for reversible male contraception.

Author

Hong, Suk-Hyun, Castro, Glenda, Wang, Dan, Nofsinger, Russell, Kane, Maureen, Folias, Alexandra, Atkins, Annette, Yu, Ruth, Napoli, Joseph, Sassone-Corsi, Paolo, de Rooij, Dirk, Liddle, Christopher, Downes, Michael, and Evans, Ronald

Subjects
retinoic acid signaling, spermatogenesis, transcriptional corepression, Humans, Female, Male, Animals, Mice, DNA-Binding Proteins, Repressor Proteins, Co-Repressor Proteins, Nuclear Receptor Co-Repressor 2, Tretinoin, Contraception, Nuclear Receptor Co-Repressor 1
Abstract

Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)-dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.

Published
2024

6. Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation

Author

Xia, Wenmin, Veeragandham, Preethi, Cao, Yu, Xu, Yayun, Rhyne, Torrey E, Qian, Jiaxin, Hung, Chao-Wei, Zhao, Peng, Jones, Ying, Gao, Hui, Liddle, Christopher, Yu, Ruth T, Downes, Michael, Evans, Ronald M, Rydén, Mikael, Wabitsch, Martin, Wang, Zichen, Hakozaki, Hiroyuki, Schöneberg, Johannes, Reilly, Shannon M, Huang, Jianfeng, and Saltiel, Alan R

Subjects
Medical Biochemistry and Metabolomics, Medical Physiology, Biomedical and Clinical Sciences, Nutrition and Dietetics, Diabetes, Liver Disease, Digestive Diseases, Nutrition, Obesity, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Metabolic and endocrine, Stroke, Cardiovascular, Adipose Tissue, Animals, Humans, Mice, Insulin Resistance, Weight Gain, Male, Adipocytes, White, Medical biochemistry and metabolomics, Medical physiology, Nutrition and dietetics
Abstract

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

Published
2024

7. RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1β- and RNA-dependent co-activator of osteoclast gene expression

Author

Abe, Yohei, Kofman, Eric R, Almeida, Maria, Ouyang, Zhengyu, Ponte, Filipa, Mueller, Jasmine R, Cruz-Becerra, Grisel, Sakai, Mashito, Prohaska, Thomas A, Spann, Nathanael J, Resende-Coelho, Ana, Seidman, Jason S, Stender, Joshua D, Taylor, Havilah, Fan, Weiwei, Link, Verena M, Cobo, Isidoro, Schlachetzki, Johannes CM, Hamakubo, Takao, Jepsen, Kristen, Sakai, Juro, Downes, Michael, Evans, Ronald M, Yeo, Gene W, Kadonaga, James T, Manolagas, Stavros C, Rosenfeld, Michael G, and Glass, Christopher K

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Humans, Mice, Animals, Co-Repressor Proteins, RNA, Osteoclasts, RANK Ligand, Nuclear Receptor Co-Repressor 1, Gene Expression, AP-1, H3K27ac, HDAC3, NCoR, NF-κB, PGC1β, RANK, co-activator, deacetylation, gene expression, non-coding RNA, osteoclast, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1β with the NCoR/HDAC3 complex, resulting in the activation of PGC1β and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.

Published
2023

8. A Carrier Female Manifesting an Unusual X-Linked Retinoschisis Phenotype Associated with the Pathogenic Variant c.266delA, p.(Tyr89LeufsTer37) in RS1, and Skewed X-Inactivation.

Author

Gait, Anthony, Jenkins, Lucy, Clouston, Penny, Patel, Chetan, Downes, Susan, Kirkby, Jennifer, Halford, Stephanie, Shanks, Morag, and Moore, Anthony

Subjects
X-inactivation, X-linked retinoschisis, carrier, female, heterozygous, Female, Humans, Eye Proteins, Phenotype, Retina, Retinoschisis, X Chromosome Inactivation, Child, Preschool
Abstract

X-linked retinoschisis (XLRS) is the most common juvenile macular degeneration in males. Unlike most other X-linked retinal dystrophies, carrier heterozygous females are very rarely reported to show clinical features of the disease. Herein, we describe unusual retinal features in a 2-year-old female infant with family history and genetic testing consistent with XLRS.

Published
2023

9. FXR mediates ILC-intrinsic responses to intestinal inflammation

Author

Fu, Ting, Li, Yuwenbin, Oh, Tae Gyu, Cayabyab, Fritz, He, Nanhai, Tang, Qin, Coulter, Sally, Truitt, Morgan, Medina, Paul, He, Mingxiao, Yu, Ruth T, Atkins, Annette, Zheng, Ye, Liddle, Christopher, Downes, Michael, and Evans, Ronald M

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Vaccine Related, Biodefense, Digestive Diseases, Autoimmune Disease, Prevention, Crohn's Disease, Inflammatory Bowel Disease, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Oral and gastrointestinal, Humans, Immunity, Innate, Lymphocytes, Inflammatory Bowel Diseases, Cytokines, Inflammation, inflammatory bowel disease, bile acids, FXR, innate lymphoid cells, IL17
Abstract

The pleiotropic actions of the Farnesoid X Receptor (FXR) are required for gut health, and reciprocally, reduced intestinal FXR signaling is seen in inflammatory bowel diseases (IBDs). Here, we show that activation of FXR selectively in the intestine is protective in inflammation-driven models of IBD. Prophylactic activation of FXR restored homeostatic levels of pro-inflammatory cytokines, most notably IL17. Importantly, these changes were attributed to FXR regulation of innate lymphoid cells (ILCs), with both the inflammation-driven increases in ILCs, and ILC3s in particular, and the induction of Il17a and Il17f  in ILC3s blocked by FXR activation. Moreover, a population of ILC precursor-like cells increased with treatment, implicating FXR in the maturation/differentiation of ILC precursors. These findings identify FXR as an intrinsic regulator of intestinal ILCs and a potential therapeutic target in inflammatory intestinal diseases.

Published
2022

10. Gut metagenome‐derived signature predicts hepatic decompensation and mortality in NAFLD‐related cirrhosis

Author

Sharpton, Suzanne R, Oh, Tae Gyu, Madamba, Egbert, Wang, Chenjingyi, Yu, Ruth T, Atkins, Annette R, Huan, Tao, Downes, Michael, Evans, Ronald M, and Loomba, Rohit

Subjects
Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Chronic Liver Disease and Cirrhosis, Liver Disease, Digestive Diseases, Clinical Research, Oral and gastrointestinal, Good Health and Well Being, Adult, Humans, Non-alcoholic Fatty Liver Disease, Hepatic Encephalopathy, Esophageal and Gastric Varices, Ascites, Prospective Studies, End Stage Liver Disease, Metagenome, Rifaximin, Lactulose, Gastrointestinal Hemorrhage, Severity of Illness Index, Liver Cirrhosis, Gastroenterology & Hepatology, Clinical sciences, Pharmacology and pharmaceutical sciences
Abstract

BackgroundThere are limited data on the diagnostic accuracy of gut microbial signatures for predicting hepatic decompensation in patients with cirrhosis.AimsTo determine whether a stool metagenome-derived signature accurately detects hepatic decompensation and mortality risk in cirrhosis secondary to non-alcoholic fatty liver disease (NAFLD) METHODS: Shotgun metagenomic sequencing was performed on faecal samples collected at study entry from a prospective cohort of adults with NAFLD-related cirrhosis. A Random Forest machine learning algorithm was utilised to identify a metagenomic signature of decompensated cirrhosis (defined by ascites, hepatic encephalopathy or variceal haemorrhage) and subsequently validated in an external cohort. A Cox proportional hazards regression model was used to examine predictors of all-cause mortality.ResultsIn all, 25 adults with NAFLD-related cirrhosis (training cohort) were included. Among the 16 participants with decompensated cirrhosis, 33% had ascites, 56% had hepatic encephalopathy and 22% had experienced a variceal haemorrhage (not mutually exclusive). We identified a stool metagenomic signature comprising 13 discriminatory species that reliably distinguished decompensated NAFLD-related cirrhosis (diagnostic accuracy, 0.97, 95% confidence interval [CI] 0.96-0.99). Diagnostic accuracy of the 13-species signature remained high after adjustment for lactulose (area under the curve [AUC] 0.99) and rifaximin use (AUC 0.93). The discriminative ability of 13-species metagenomic signature was robust in an independent test cohort (AUC 0.95, 95% CI 0.81-1.00). The 13-species metagenomic signature (hazard ratio [HR] 1.54, 95% CI 1.10-2.15, p = 0.01) was a stronger predictor of mortality than the Model for End-Stage Liver Disease score (HR 1.25, 95% CI 1.03-1.53, p = 0.03).ConclusionsThis study provides evidence for a gut metagenome-derived signature with high diagnostic accuracy for hepatic decompensation that predicts risk of mortality in NAFLD-related cirrhosis.

Published
2022

11. Shared Mechanisms between Cardiovascular Disease and NAFLD

Author

Huang, Daniel Q, Downes, Michael, Evans, Ronald M, Witztum, Joseph L, Glass, Christopher K, and Loomba, Rohit

Subjects
Heart Disease, Hepatitis, Digestive Diseases, Heart Disease - Coronary Heart Disease, Chronic Liver Disease and Cirrhosis, Liver Disease, Atherosclerosis, Cardiovascular, Prevention, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Non-alcoholic Fatty Liver Disease, Cardiovascular Diseases, Risk Factors, Insulin Resistance, Inflammation, nonalcoholic fatty liver disease, pathogenesis, atherosclerosis, coronary artery disease, Clinical Sciences, Gastroenterology & Hepatology
Abstract

The burden of nonalcoholic fatty liver disease (NAFLD) is rising globally. Cardiovascular disease is the leading cause of death in patients with NAFLD. Nearly half of individuals with NAFLD have coronary heart disease, and more than a third have carotid artery atherosclerosis. Individuals with NAFLD are at a substantially higher risk of fatal and nonfatal cardiovascular events. NAFLD and cardiovascular disease share multiple common disease mechanisms, such as systemic inflammation, insulin resistance, genetic risk variants, and gut microbial dysbiosis. In this review, we discuss the epidemiology of cardiovascular disease in NAFLD, and highlight common risk factors. In addition, we examine recent advances evaluating the shared disease mechanisms between NAFLD and cardiovascular disease. In conclusion, multidisciplinary collaborations are required to further our understanding of the complex relationship between NAFLD and cardiovascular disease and potentially identify therapeutic targets.

Published
2022

12. Estrogen-Related Receptor γ Maintains Pancreatic Acinar Cell Function and Identity by Regulating Cellular Metabolism

Author

Choi, Jinhyuk, Oh, Tae Gyu, Jung, Hee-Won, Park, Kun-Young, Shin, Hyemi, Jo, Taehee, Kang, Du-Seock, Chanda, Dipanjan, Hong, Sujung, Kim, Jina, Hwang, Hayoung, Ji, Moongi, Jung, Minkyo, Shoji, Takashi, Matsushima, Ayami, Kim, Pilhan, Mun, Ji Young, Paik, Man-Jeong, Cho, Sung Jin, Lee, In-Kyu, Whitcomb, David C, Greer, Phil, Blobner, Brandon, Goodarzi, Mark O, Pandol, Stephen J, Rotter, Jerome I, Consortium, North American Pancreatitis Study 2, Fan, Weiwei, Bapat, Sagar P, Zheng, Ye, Liddle, Chris, Yu, Ruth T, Atkins, Annette R, Downes, Michael, Yoshihara, Eiji, Evans, Ronald M, and Suh, Jae Myoung

Subjects
Digestive Diseases, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Acinar Cells, Animals, Estrogens, Humans, Mice, Mice, Knockout, Pancreas, Pancreas, Exocrine, Pancreatitis, Chronic, ERR gamma, Pancreatic Acinar Cells, Mitochondrial Oxidative Phosphorylation, Reactive Oxygen Species, Acinar-to-Ductal Metaplasia, North American Pancreatitis Study 2 (NAPS2) Consortium, ERRγ, Clinical Sciences, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology
Abstract

Background & aimsMitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production.MethodsTwo models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in 2 distinct human pancreatitis cohorts.ResultsBlocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss of ERRγ in primary acini abrogates messenger RNA expression and protein levels of mitochondrial oxidative phosphorylation complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared with normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants for ERRγ that are associated with chronic pancreatitis.ConclusionsCollectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Published
2022

13. Updated Guidance on Use and Prioritization of Monoclonal Antibody Therapy for Treatment of COVID-19 in Adolescents

Author

Wolf, Joshua, Abzug, Mark J, Anosike, Brenda I, Vora, Surabhi B, Waghmare, Alpana, Sue, Paul K, Olivero, Rosemary M, Oliveira, Carlos R, James, Scott H, Morton, Theodore H, Maron, Gabriela M, Young, Jennifer L, Orscheln, Rachel C, Schwenk, Hayden T, Bio, Laura L, Willis, Zachary I, Lloyd, Elizabeth C, Hersh, Adam L, Huskins, Charles W, Soma, Vijaya L, Ratner, Adam J, Hayes, Molly, Downes, Kevin, Chiotos, Kathleen, Grapentine, Steven P, Wattier, Rachel L, Lamb, Gabriella S, Zachariah, Philip, and Nakamura, Mari M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Biodefense, Pneumonia & Influenza, Pediatric Research Initiative, Lung, Pediatric, Vaccine Related, Pneumonia, Prevention, Patient Safety, Biotechnology, Emerging Infectious Diseases, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Good Health and Well Being, Adolescent, Adult, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, Antibodies, Viral, Child, Drug Combinations, Humans, Practice Guidelines as Topic, SARS-CoV-2, COVID-19 Drug Treatment, bamlanivimab and etesevimab, COVID-19, pediatric, REGEN-COV, sotrovimab, Medical microbiology, Paediatrics
Abstract

BackgroundStarting in November 2020, the US Food and Drug Administration (FDA) has issued Emergency Use Authorizations (EUAs) for multiple novel virus-neutralizing monoclonal antibody therapies, including bamlanivimab monotherapy (now revoked), bamlanivimab and etesivimab, casirivimab and imdevimab (REGEN-COV), and sotrovimab, for treatment or postexposure prophylaxis of Coronavirus disease 2019 (COVID-19) in adolescents (≥12 years of age) and adults with certain high-risk conditions. Previous guidance is now updated based on new evidence and clinical experience.MethodsA panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacotherapy, and pediatric critical care medicine from 18 geographically diverse US institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on a review of the best available evidence and expert opinion.ResultsThe course of COVID-19 in children and adolescents is typically mild, though more severe disease is occasionally observed. Evidence supporting risk stratification is incomplete. Randomized controlled trials have demonstrated the benefit of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific monoclonal antibody therapies in adults, but data on safety and efficacy in children or adolescents are limited. Potential harms associated with infusion reactions or anaphylaxis are reportedly low in adults.ConclusionsBased on evidence available as of August 31, 2021, the panel suggests a risk-based approach to administration of SARS-CoV-2 monoclonal antibody therapy. Therapy is suggested for the treatment of mild to moderate COVID-19 in adolescents (≥12 years of age) at the highest risk of progression to hospitalization or severe disease. Therapeutic decision-making about those at moderate risk of severe disease should be individualized. Use as postexposure prophylaxis could be considered for those at the highest risk who have a high-risk exposure but are not yet diagnosed with COVID-19. Clinicians and health systems should ensure safe and timely implementation of these therapeutics that does not exacerbate existing healthcare disparities.

Published
2022

14. Elucidating mechanisms of genetic cross-disease associations at the PROCR vascular disease locus

Author

Stacey, David, Chen, Lingyan, Stanczyk, Paulina J, Howson, Joanna MM, Mason, Amy M, Burgess, Stephen, MacDonald, Stephen, Langdown, Jonathan, McKinney, Harriett, Downes, Kate, Farahi, Neda, Peters, James E, Basu, Saonli, Pankow, James S, Tang, Weihong, Pankratz, Nathan, Sabater-Lleal, Maria, de Vries, Paul S, Smith, Nicholas L, Gelinas, Amy D, Schneider, Daniel J, Janjic, Nebojsa, Samani, Nilesh J, Ye, Shu, Summers, Charlotte, Chilvers, Edwin R, Danesh, John, and Paul, Dirk S

Subjects
Biological Sciences, Genetics, Prevention, Cardiovascular, Atherosclerosis, Hematology, Heart Disease - Coronary Heart Disease, Heart Disease, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Antigens, CD, Crosses, Genetic, Endothelial Cells, Endothelial Protein C Receptor, Humans, Protein C, Receptors, Cell Surface, Thrombosis, Venous Thromboembolism, CHARGE Hemostasis Working Group
Abstract

Many individual genetic risk loci have been associated with multiple common human diseases. However, the molecular basis of this pleiotropy often remains unclear. We present an integrative approach to reveal the molecular mechanism underlying the PROCR locus, associated with lower coronary artery disease (CAD) risk but higher venous thromboembolism (VTE) risk. We identify PROCR-p.Ser219Gly as the likely causal variant at the locus and protein C as a causal factor. Using genetic analyses, human recall-by-genotype and in vitro experimentation, we demonstrate that PROCR-219Gly increases plasma levels of (activated) protein C through endothelial protein C receptor (EPCR) ectodomain shedding in endothelial cells, attenuating leukocyte-endothelial cell adhesion and vascular inflammation. We also associate PROCR-219Gly with an increased pro-thrombotic state via coagulation factor VII, a ligand of EPCR. Our study, which links PROCR-219Gly to CAD through anti-inflammatory mechanisms and to VTE through pro-thrombotic mechanisms, provides a framework to reveal the mechanisms underlying similar cross-phenotype associations.

Published
2022

15. BRD9 regulates interferon-stimulated genes during macrophage activation via cooperation with BET protein BRD4

Author

Ahmed, Nasiha S, Gatchalian, Jovylyn, Ho, Josephine, Burns, Mannix J, Hah, Nasun, Wei, Zong, Downes, Michael, Evans, Ronald M, and Hargreaves, Diana C

Subjects
Biochemistry and Cell Biology, Biological Sciences, Human Genome, Genetics, Infectious Diseases, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, Antiviral Agents, Cell Cycle Proteins, Chromatin Assembly and Disassembly, Humans, Interferon-Stimulated Gene Factor 3, gamma Subunit, Interferon-alpha, Interferons, Macrophage Activation, Promoter Regions, Genetic, Protein Domains, STAT1 Transcription Factor, STAT2 Transcription Factor, Transcription Factors, Transcriptional Activation, inflammation, macrophages, BRD9, bromodomain protein 9, BRD4
Abstract

Macrophages induce a number of inflammatory response genes in response to stimulation with microbial ligands. In response to endotoxin Lipid A, a gene-activation cascade of primary followed by secondary-response genes is induced. Epigenetic state is an important regulator of the kinetics, specificity, and mechanism of gene activation of these two classes. In particular, SWI/SNF chromatin-remodeling complexes are required for the induction of secondary-response genes, but not primary-response genes, which generally exhibit open chromatin. Here, we show that a recently discovered variant of the SWI/SNF complex, the noncanonical BAF complex (ncBAF), regulates secondary-response genes in the interferon (IFN) response pathway. Inhibition of bromodomain-containing protein 9 (BRD9), a subunit of the ncBAF complex, with BRD9 bromodomain inhibitors (BRD9i) or a degrader (dBRD9) led to reduction in a number of interferon-stimulated genes (ISGs) following stimulation with endotoxin lipid A. BRD9-dependent genes overlapped highly with a subset of genes differentially regulated by BET protein inhibition with JQ1 following endotoxin stimulation. We find that the BET protein BRD4 is cobound with BRD9 in unstimulated macrophages and corecruited upon stimulation to ISG promoters along with STAT1, STAT2, and IRF9, components of the ISGF3 complex activated downstream of IFN-alpha receptor stimulation. In the presence of BRD9i or dBRD9, STAT1-, STAT2-, and IRF9-binding is reduced, in some cases with reduced binding of BRD4. These results demonstrate a specific role for BRD9 and the ncBAF complex in ISG activation and identify an activity for BRD9 inhibitors and degraders in dampening endotoxin- and IFN-dependent gene expression.

Published
2022

16. Proteomic discovery of non-invasive biomarkers of localized prostate cancer using mass spectrometry

Author

Khoo, Amanda, Liu, Lydia Y, Nyalwidhe, Julius O, Semmes, O John, Vesprini, Danny, Downes, Michelle R, Boutros, Paul C, Liu, Stanley K, and Kislinger, Thomas

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Urologic Diseases, Prevention, Aging, Prostate Cancer, Cancer, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 4.2 Evaluation of markers and technologies, Good Health and Well Being, Biomarkers, Tumor, Early Detection of Cancer, Humans, Male, Mass Spectrometry, Prognosis, Prostatic Neoplasms, Proteomics, Risk Assessment, Urology & Nephrology, Clinical sciences
Abstract

Prostate cancer is the second most frequently diagnosed non-skin cancer in men worldwide. Patient outcomes are remarkably heterogeneous and the best existing clinical prognostic tools such as International Society of Urological Pathology Grade Group, pretreatment serum PSA concentration and T-category, do not accurately predict disease outcome for individual patients. Thus, patients newly diagnosed with prostate cancer are often overtreated or undertreated, reducing quality of life and increasing disease-specific mortality. Biomarkers that can improve the risk stratification of these patients are, therefore, urgently needed. The ideal biomarker in this setting will be non-invasive and affordable, enabling longitudinal evaluation of disease status. Prostatic secretions, urine and blood can be sources of biomarker discovery, validation and clinical implementation, and mass spectrometry can be used to detect and quantify proteins in these fluids. Protein biomarkers currently in use for diagnosis, prognosis and relapse-monitoring of localized prostate cancer in fluids remain centred around PSA and its variants, and opportunities exist for clinically validating novel and complimentary candidate protein biomarkers and deploying them into the clinic.

Published
2021

17. Glycogen metabolism links glucose homeostasis to thermogenesis in adipocytes

Author

Keinan, Omer, Valentine, Joseph M, Xiao, Haopeng, Mahata, Sushil K, Reilly, Shannon M, Abu-Odeh, Mohammad, Deluca, Julia H, Dadpey, Benyamin, Cho, Leslie, Pan, Austin, Yu, Ruth T, Dai, Yang, Liddle, Christopher, Downes, Michael, Evans, Ronald M, Lusis, Aldons J, Laakso, Markku, Chouchani, Edward T, Rydén, Mikael, and Saltiel, Alan R

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Nutrition, Diabetes, Obesity, 2.1 Biological and endogenous factors, Adaptation, Physiological, Adipocytes, Adipocytes, Beige, Animals, Cold Temperature, Energy Metabolism, Female, Glucose, Glycogen, Homeostasis, Humans, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, Knockout, Thermogenesis, Uncoupling Protein 1, p38 Mitogen-Activated Protein Kinases, General Science & Technology
Abstract

Adipocytes increase energy expenditure in response to prolonged sympathetic activation via persistent expression of uncoupling protein 1 (UCP1)1,2. Here we report that the regulation of glycogen metabolism by catecholamines is critical for UCP1 expression. Chronic β-adrenergic activation leads to increased glycogen accumulation in adipocytes expressing UCP1. Adipocyte-specific deletion of a scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels in beige adipocytes, attenuating UCP1 expression and responsiveness to cold or β-adrenergic receptor-stimulated weight loss in obese mice. Unexpectedly, we observed that glycogen synthesis and degradation are increased in response to catecholamines, and that glycogen turnover is required to produce reactive oxygen species leading to the activation of p38 MAPK, which drives UCP1 expression. Thus, glycogen has a key regulatory role in adipocytes, linking glucose metabolism to thermogenesis.

Published
2021

18. Reactivation of a developmentally silenced embryonic globin gene.

Author

King, Andrew J, Songdej, Duantida, Downes, Damien J, Beagrie, Robert A, Liu, Siyu, Buckley, Megan, Hua, Peng, Suciu, Maria C, Marieke Oudelaar, A, Hanssen, Lars LP, Jeziorska, Danuta, Roberts, Nigel, Carpenter, Stephanie J, Francis, Helena, Telenius, Jelena, Olijnik, Aude-Anais, Sharpe, Jacqueline A, Sloane-Stanley, Jacqueline, Eglinton, Jennifer, Kassouf, Mira T, Orkin, Stuart H, Pennacchio, Len A, Davies, James OJ, Hughes, Jim R, Higgs, Douglas R, and Babbs, Christian

Subjects
Chromatin, Erythroid Cells, Animals, Humans, Mice, DNA-Binding Proteins, Transcription Factors, Repressor Proteins, Gene Expression Regulation, Developmental, Gene Silencing, Acetylation, Enhancer Elements, Genetic, Transcriptional Activation, alpha-Globins, zeta-Globins, Histone Deacetylase Inhibitors
Abstract

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.

Published
2021

19. Initial Guidance on Use of Monoclonal Antibody Therapy for Treatment of COVID-19 in Children and Adolescents

Author

Wolf, Joshua, Abzug, Mark J, Wattier, Rachel L, Sue, Paul K, Vora, Surabhi B, Zachariah, Philip, Dulek, Daniel E, Waghmare, Alpana, Olivero, Rosemary, Downes, Kevin J, James, Scott H, Pinninti, Swetha G, Yarbrough, April, Aldrich, Margaret L, MacBrayne, Christine E, Soma, Vijaya L, Grapentine, Steven P, Oliveira, Carlos R, Hayes, Molly, Kimberlin, David W, Jones, Sarah B, Bio, Laura L, Morton, Theodore H, Hankins, Jane S, Marόn-Alfaro, Gabriella M, Timberlake, Kathryn, Young, Jennifer L, Orscheln, Rachel C, Schwenk, Hayden T, Goldman, David L, Groves, Helen E, Huskins, W Charles, Rajapakse, Nipunie S, Lamb, Gabriella S, Tribble, Alison C, Lloyd, Elizabeth E, Hersh, Adam L, Thorell, Emily A, Ratner, Adam J, Chiotos, Kathleen, and Nakamura, Mari M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Pediatric Research Initiative, Infectious Diseases, Hematology, Biotechnology, Health Services, Patient Safety, Clinical Research, Pediatric, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Good Health and Well Being, Adolescent, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antiviral Agents, COVID-19, Child, Drug Approval, Female, Humans, Male, Pandemics, Pneumonia, Viral, SARS-CoV-2, United States, United States Food and Drug Administration, COVID-19 Drug Treatment, bamlanivimab, casirivimab, imdevimab, pediatric, Medical microbiology, Paediatrics
Abstract

BackgroundIn November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for 2 novel virus-neutralizing monoclonal antibody therapies, bamlanivimab and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products.MethodsA panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion.ResultsThe course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high-risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis.ConclusionsBased on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence and ensure the implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities.

Published
2021

20. Proton pump inhibitor use status does not modify the microbiome signature for cirrhosis

Author

Oh, Tae Gyu, Kim, Susy M, Atkins, Annette R, Yu, Ruth T, Downes, Michael, Evans, Ronald M, and Loomba, Rohit

Subjects
Microbiology, Biological Sciences, Liver Disease, Clinical Research, Genetics, Digestive Diseases, Chronic Liver Disease and Cirrhosis, Human Genome, Cohort Studies, Gastrointestinal Microbiome, Humans, Liver Cirrhosis, Microbiota, Proton Pump Inhibitors, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

Oh et al. address concerns about the influence of proton pump inhibitor (PPI) use on a gut microbiome signature for cirrhosis. By removing PPI using subjects from the training cohort and retraining a 19-species Random Forest model, they demonstrate the impact of PPI usage on the signature's diagnostic accuracy is minimal.

Published
2021

21. Multicenter interim guidance on use of antivirals for children with COVID-19/SARS-CoV-2

Author

Chiotos, Kathleen, Hayes, Molly, Kimberlin, David W, Jones, Sarah B, James, Scott H, Pinninti, Swetha G, Yarbrough, April, Abzug, Mark J, MacBrayne, Christine E, Soma, Vijaya L, Dulek, Daniel E, Vora, Surabhi B, Waghmare, Alpana, Wolf, Joshua, Olivero, Rosemary, Grapentine, Steven, Wattier, Rachel L, Bio, Laura, Cross, Shane J, Dillman, Nicholas O, Downes, Kevin J, Oliveira, Carlos R, Timberlake, Kathryn, Young, Jennifer, Orscheln, Rachel C, Tamma, Pranita D, Schwenk, Hayden T, Zachariah, Philip, Aldrich, Margaret L, Goldman, David L, Groves, Helen E, Rajapakse, Nipunie S, Lamb, Gabriella S, Tribble, Alison C, Hersh, Adam L, Thorell, Emily A, Denison, Mark R, Ratner, Adam J, Newland, Jason G, and Nakamura, Mari M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Lung, Emerging Infectious Diseases, Infectious Diseases, Clinical Research, Pediatric, Good Health and Well Being, Adenosine Monophosphate, Alanine, Antiviral Agents, COVID-19, Child, Evidence-Based Medicine, Humans, Immunocompromised Host, Risk Factors, Severity of Illness Index, Systemic Inflammatory Response Syndrome, COVID-19 Drug Treatment, antiviral, pediatric, SARS-CoV-2, Medical microbiology, Paediatrics
Abstract

BackgroundAlthough coronavirus disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data describing agents with potential antiviral activity continue to expand such that updated guidance is needed regarding use of these agents in children.MethodsA panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion.ResultsGiven the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or noninvasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children.ConclusionsAntiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.

Published
2021

22. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2

Author

Chiotos, Kathleen, Hayes, Molly, Kimberlin, David W, Jones, Sarah B, James, Scott H, Pinninti, Swetha G, Yarbrough, April, Abzug, Mark J, MacBrayne, Christine E, Soma, Vijaya L, Dulek, Daniel E, Vora, Surabhi B, Waghmare, Alpana, Wolf, Joshua, Olivero, Rosemary, Grapentine, Steven, Wattier, Rachel L, Bio, Laura, Cross, Shane J, Dillman, Nicholas O, Downes, Kevin J, Timberlake, Kathryn, Young, Jennifer, Orscheln, Rachel C, Tamma, Pranita D, Schwenk, Hayden T, Zachariah, Philip, Aldrich, Margaret, Goldman, David L, Groves, Helen E, Lamb, Gabriella S, Tribble, Alison C, Hersh, Adam L, Thorell, Emily A, Denison, Mark R, Ratner, Adam J, Newland, Jason G, and Nakamura, Mari M

Subjects
Clinical Research, Emerging Infectious Diseases, Patient Safety, Pediatric, Infectious Diseases, Lung, Good Health and Well Being, Antiviral Agents, Child, Humans, Risk Assessment, Severity of Illness Index, COVID-19 Drug Treatment, antiviral, COVID-19, guidance, pediatric, SARS-CoV-2
Abstract

BackgroundAlthough coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics.MethodsA panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion.ResultsGiven the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available.ConclusionsAntiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.

Published
2020

23. Return to School for Pediatric Solid Organ Transplant Recipients in the United States During the Coronavirus Disease 2019 Pandemic: Expert Opinion on Key Considerations and Best Practices

Author

Downes, Kevin J, Danziger-Isakov, Lara A, Cousino, Melissa K, Green, Michael, Michaels, Marian G, Muller, William J, Orscheln, Rachel C, Sharma, Tanvi S, Statler, Victoria A, Wattier, Rachel L, and Ardura, Monica I

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Organ Transplantation, Prevention, Pediatric, Transplantation, Good Health and Well Being, COVID-19, Child, Coronavirus Infections, Disease Transmission, Infectious, Humans, Pandemics, Pneumonia, Viral, Risk Factors, Safety, Schools, Transplant Recipients, United States, coronavirus, pediatric transplant, return to school, SARS-CoV-2, school reopening, Medical microbiology, Paediatrics
Abstract

The coronavirus disease 2019 (COVID-19) pandemic has created many challenges for pediatric solid organ transplant (SOT) recipients and their families. As the pandemic persists, patients and their families struggle to identify the best and safest practices for resuming activities as areas reopen. Notably, decisions about returning to school remain difficult. We assembled a team of pediatric infectious diseases (ID), transplant ID, public health, transplant psychology, and infection prevention and control specialists to address the primary concerns about school reentry for pediatric SOT recipients in the United States. Based on available literature and guidance from national organizations, we generated consensus statements pertaining to school reentry specific to pediatric SOT recipients. Although data are limited and the COVID-19 pandemic is highly dynamic, our goal was to create a framework from which providers and caregivers can identify the most important considerations for each pediatric SOT recipient to promote a safe return to school.

Published
2020

24. A Universal Gut-Microbiome-Derived Signature Predicts Cirrhosis

Author

Oh, Tae Gyu, Kim, Susy M, Caussy, Cyrielle, Fu, Ting, Guo, Jian, Bassirian, Shirin, Singh, Seema, Madamba, Egbert V, Bettencourt, Ricki, Richards, Lisa, Yu, Ruth T, Atkins, Annette R, Huan, Tao, Brenner, David A, Sirlin, Claude B, Downes, Michael, Evans, Ronald M, and Loomba, Rohit

Subjects
Microbiology, Biological Sciences, Biomedical and Clinical Sciences, Medical Biochemistry and Metabolomics, Digestive Diseases, Human Genome, Hepatitis, Clinical Research, Liver Disease, Chronic Liver Disease and Cirrhosis, Genetics, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Adult, Aged, Aged, 80 and over, Aspartate Aminotransferases, Cohort Studies, Feces, Female, Gastrointestinal Microbiome, Humans, Liver Cirrhosis, Male, Metabolome, Metagenome, Middle Aged, Non-alcoholic Fatty Liver Disease, Serum Albumin, Human, NAFLD, NASH, biomarker, cirrhosis, fatty liver, liver fibrosis, metabolomics, metagenomics, microbiome, microbiota, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, Biochemistry and Cell Biology, Endocrinology & Metabolism, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

Dysregulation of the gut microbiome has been implicated in the progression of non-alcoholic fatty liver disease (NAFLD) to advanced fibrosis and cirrhosis. To determine the diagnostic capacity of this association, we compared stool microbiomes across 163 well-characterized participants encompassing non-NAFLD controls, NAFLD-cirrhosis patients, and their first-degree relatives. Interrogation of shotgun metagenomic and untargeted metabolomic profiles by using the random forest machine learning algorithm and differential abundance analysis identified discrete metagenomic and metabolomic signatures that were similarly effective in detecting cirrhosis (diagnostic accuracy 0.91, area under curve [AUC]). Combining the metagenomic signature with age and serum albumin levels accurately distinguished cirrhosis in etiologically and genetically distinct cohorts from geographically separated regions. Additional inclusion of serum aspartate aminotransferase levels, which are increased in cirrhosis patients, enabled discrimination of cirrhosis from earlier stages of fibrosis. These findings demonstrate that a core set of gut microbiome species might offer universal utility as a non-invasive diagnostic test for cirrhosis.

Published
2020

25. Genomic and Epigenomic Landscaping Defines New Therapeutic Targets for Adenosquamous Carcinoma of the Pancreas

Author

Lenkiewicz, Elizabeth, Malasi, Smriti, Hogenson, Tara L, Flores, Luis F, Barham, Whitney, Phillips, William J, Roesler, Alexander S, Chambers, Kendall R, Rajbhandari, Nirakar, Hayashi, Akimasa, Antal, Corina E, Downes, Michael, Grandgenett, Paul M, Hollingsworth, Michael A, Cridebring, Derek, Xiong, Yuning, Lee, Jeong-Heon, Ye, Zhenqing, Yan, Huihuang, Hernandez, Matthew C, Leiting, Jennifer L, Evans, Ronald M, Ordog, Tamas, Truty, Mark J, Borad, Mitesh J, Reya, Tannishtha, Von Hoff, Daniel D, Fernandez-Zapico, Martin E, and Barrett, Michael T

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Bioinformatics and Computational Biology, Genetics, Oncology and Carcinogenesis, Rare Diseases, Biotechnology, Cancer, Digestive Diseases, Human Genome, Pancreatic Cancer, Aetiology, 2.1 Biological and endogenous factors, Carcinoma, Adenosquamous, Carcinoma, Pancreatic Ductal, Chromatin, Epigenome, Humans, Mutation, Organoids, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Receptor, Fibroblast Growth Factor, Type 1, Single-Cell Analysis, Smad4 Protein, Exome Sequencing, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer. SIGNIFICANCE: These data provide a unique description of the ASCP genomic and epigenomic landscape and identify candidate therapeutic targets for this dismal cancer.

Published
2020

26. Global chemical effects of the microbiome include new bile-acid conjugations

Author

Quinn, Robert A, Melnik, Alexey V, Vrbanac, Alison, Fu, Ting, Patras, Kathryn A, Christy, Mitchell P, Bodai, Zsolt, Belda-Ferre, Pedro, Tripathi, Anupriya, Chung, Lawton K, Downes, Michael, Welch, Ryan D, Quinn, Melissa, Humphrey, Greg, Panitchpakdi, Morgan, Weldon, Kelly C, Aksenov, Alexander, da Silva, Ricardo, Avila-Pacheco, Julian, Clish, Clary, Bae, Sena, Mallick, Himel, Franzosa, Eric A, Lloyd-Price, Jason, Bussell, Robert, Thron, Taren, Nelson, Andrew T, Wang, Mingxun, Leszczynski, Eric, Vargas, Fernando, Gauglitz, Julia M, Meehan, Michael J, Gentry, Emily, Arthur, Timothy D, Komor, Alexis C, Poulsen, Orit, Boland, Brigid S, Chang, John T, Sandborn, William J, Lim, Meerana, Garg, Neha, Lumeng, Julie C, Xavier, Ramnik J, Kazmierczak, Barbara I, Jain, Ruchi, Egan, Marie, Rhee, Kyung E, Ferguson, David, Raffatellu, Manuela, Vlamakis, Hera, Haddad, Gabriel G, Siegel, Dionicio, Huttenhower, Curtis, Mazmanian, Sarkis K, Evans, Ronald M, Nizet, Victor, Knight, Rob, and Dorrestein, Pieter C

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Chemical Sciences, Microbiology, Medical Biochemistry and Metabolomics, Genetics, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Animals, Bile Acids and Salts, Cholic Acid, Cystic Fibrosis, Germ-Free Life, Humans, Inflammatory Bowel Diseases, Metabolomics, Mice, Microbiota, Receptors, Cytoplasmic and Nuclear, General Science & Technology
Abstract

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease1-9. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units10), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches11-13 to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry14. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis.

Published
2020

27. Temporal Stability and Prognostic Biomarker Potential of the Prostate Cancer Urine miRNA Transcriptome

Author

Jeon, Jouhyun, Olkhov-Mitsel, Ekaterina, Xie, Honglei, Yao, Cindy Q, Zhao, Fang, Jahangiri, Sahar, Cuizon, Carmelle, Scarcello, Seville, Jeyapala, Renu, Watson, John D, Fraser, Michael, Ray, Jessica, Commisso, Kristina, Loblaw, Andrew, Fleshner, Neil E, Bristow, Robert G, Downes, Michelle, Vesprini, Danny, Liu, Stanley, Bapat, Bharati, and Boutros, Paul C

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Cancer, Urologic Diseases, Clinical Research, Biotechnology, Aging, Prostate Cancer, Prevention, 4.2 Evaluation of markers and technologies, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Good Health and Well Being, Biomarkers, Tumor, Carcinogenesis, Cohort Studies, Humans, Longitudinal Studies, Male, MicroRNAs, Neoplasm Grading, Prognosis, Prostatic Neoplasms, Reproducibility of Results, Transcriptome, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe development of noninvasive tests for the early detection of aggressive prostate tumors is a major unmet clinical need. miRNAs are promising noninvasive biomarkers: they play essential roles in tumorigenesis, are stable under diverse analytical conditions, and can be detected in body fluids.MethodsWe measured the longitudinal stability of 673 miRNAs by collecting serial urine samples from 10 patients with localized prostate cancer. We then measured temporally stable miRNAs in an independent training cohort (n = 99) and created a biomarker predictive of Gleason grade using machine-learning techniques. Finally, we validated this biomarker in an independent validation cohort (n = 40).ResultsWe found that each individual has a specific urine miRNA fingerprint. These fingerprints are temporally stable and associated with specific biological functions. We identified seven miRNAs that were stable over time within individual patients and integrated them with machine-learning techniques to create a novel biomarker for prostate cancer that overcomes interindividual variability. Our urine biomarker robustly identified high-risk patients and achieved similar accuracy as tissue-based prognostic markers (area under the receiver operating characteristic = 0.72, 95% confidence interval = 0.69 to 0.76 in the training cohort, and area under the receiver operating characteristic curve = 0.74, 95% confidence interval = 0.55 to 0.92 in the validation cohort).ConclusionsThese data highlight the importance of quantifying intra- and intertumoral heterogeneity in biomarker development. This noninvasive biomarker may usefully supplement invasive or expensive radiologic- and tissue-based assays.

Published
2020

28. Neutralization of Oxidized Phospholipids Ameliorates Non-alcoholic Steatohepatitis

Author

Sun, Xiaoli, Seidman, Jason S, Zhao, Peng, Troutman, Ty D, Spann, Nathanael J, Que, Xuchu, Zhou, Fangli, Liao, Zhongji, Pasillas, Martina, Yang, Xiaohong, Magida, Jason A, Kisseleva, Tatiana, Brenner, David A, Downes, Michael, Evans, Ronald M, Saltiel, Alan R, Tsimikas, Sotirios, Glass, Christopher K, and Witztum, Joseph L

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Chronic Liver Disease and Cirrhosis, Hepatitis, Digestive Diseases, Liver Disease, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Animals, Apoptosis, Carcinoma, Hepatocellular, Diet, High-Fat, Fatty Liver, Gene Ontology, Hepatocytes, Humans, Inflammation, Liver Cirrhosis, Liver Neoplasms, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Transmission, Mitochondria, Non-alcoholic Fatty Liver Disease, Obesity, Oxidation-Reduction, Oxidative Stress, Phospholipids, RNA-Seq, Reactive Oxygen Species, Single-Chain Antibodies, MnSOD, atherosclerosis, fibrosis, inflammation, mitochondria, natural antibody, nonalcoholic steatohepatitis, oxidative stress, oxidized phospholipids, steatosis, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

Oxidized phospholipids (OxPLs), which arise due to oxidative stress, are proinflammatory and proatherogenic, but their roles in non-alcoholic steatohepatitis (NASH) are unknown. Here, we show that OxPLs accumulate in human and mouse NASH. Using a transgenic mouse that expresses a functional single-chain variable fragment of E06, a natural antibody that neutralizes OxPLs, we demonstrate the causal role of OxPLs in NASH. Targeting OxPLs in hyperlipidemic Ldlr-/- mice improved multiple aspects of NASH, including steatosis, inflammation, fibrosis, hepatocyte death, and progression to hepatocellular carcinoma. Mechanistically, we found that OxPLs promote ROS accumulation to induce mitochondrial dysfunction in hepatocytes. Neutralizing OxPLs in AMLN-diet-fed Ldlr-/- mice reduced oxidative stress, improved hepatic and adipose-tissue mitochondrial function, and fatty-acid oxidation. These results suggest targeting OxPLs may be an effective therapeutic strategy for NASH.

Published
2020

29. Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS

Author

Bravo-Hernandez, Mariana, Tadokoro, Takahiro, Navarro, Michael R, Platoshyn, Oleksandr, Kobayashi, Yoshiomi, Marsala, Silvia, Miyanohara, Atsushi, Juhas, Stefan, Juhasova, Jana, Skalnikova, Helena, Tomori, Zoltan, Vanicky, Ivo, Studenovska, Hana, Proks, Vladimir, Chen, PeiXi, Govea-Perez, Noe, Ditsworth, Dara, Ciacci, Joseph D, Gao, Shang, Zhu, Wenlian, Ahrens, Eric T, Driscoll, Shawn P, Glenn, Thomas D, McAlonis-Downes, Melissa, Da Cruz, Sandrine, Pfaff, Samuel L, Kaspar, Brian K, Cleveland, Don W, and Marsala, Martin

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Neurosciences, Gene Therapy, Brain Disorders, Traumatic Head and Spine Injury, ALS, Genetics, Spinal Cord Injury, Rare Diseases, Biotechnology, Neurodegenerative, Physical Injury - Accidents and Adverse Effects, Neurological, Amyotrophic Lateral Sclerosis, Animals, Atrophy, Dependovirus, Disease Progression, Evoked Potentials, Motor, Female, Gene Expression Regulation, Gene Silencing, Gene Transfer Techniques, Humans, Inflammation, Interneurons, Male, Mice, Inbred C57BL, Mice, Transgenic, Motor Neurons, Muscle Development, Nerve Degeneration, Pia Mater, Primates, Protein Folding, RNA, Messenger, RNA, Small Interfering, Spinal Cord, Superoxide Dismutase-1, Swine, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences
Abstract

Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.

Published
2020

30. MicroRNA-198 suppresses prostate tumorigenesis by targeting MIB1

Author

Ray, Jessica, Hoey, Christianne, Huang, Xiaoyong, Jeon, Jouhyun, Taeb, Samira, Downes, Michelle R, Boutros, Paul C, and Liu, Stanley K

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Aging, Cancer, Genetics, Biotechnology, Urologic Diseases, Prostate Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Nude, MicroRNAs, Prognosis, Prostatic Neoplasms, Transcriptome, Tumor Cells, Cultured, Ubiquitin-Protein Ligases, Xenograft Model Antitumor Assays, microRNA, miR-198, prostate cancer, MIB1, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

MicroRNAs are small non‑coding RNA molecules which act as modulators of gene function, and have been identified as playing important roles in cancer as both tumor suppressors and oncogenes. The present study aimed to examine the role of miR‑198 in prostate cancer aggression by analyzing how it influences several hallmarks of cancer. Abundance of miR‑198 in prostate cancer and association with clinical characteristics was analyzed using a CPC‑Gene prostate cancer dataset. Overexpression of miR‑198 was performed using transient transfection of miR‑198 mimic prior to assaying proliferation, cell cycle, and colony formation in LNCaP and DU145 cell lines using standard protocols. In vivo tumor formation in athymic nude mice was examined using LNCaP xenografts with stable overexpression conferred using lentiviral miR‑198 transduction. Protein and mRNA abundance of MIB1 was determined using western blotting and RT‑qPCR respectively, while miR‑198 binding to MIB1 was validated using a luciferase reporter assay. miR‑198 abundance was lower in high Gleason grade prostate cancer relative to intermediate and low‑grade cancer. Overexpression of miR‑198 diminished proliferation of prostate cancer cell lines, increased G0/G1 cell cycle arrest, and significantly impaired colony formation. Elevated miR‑198 abundance was also demonstrated to impair tumor formation in vivo using LNCaP xenografts. Mindbomb E3 ubiquitin protein ligase 1 (MIB1) was demonstrated to be directly targeted by miR‑198, and knockdown of MIB1 recapitulated the effects of miR‑198 on proliferation and colony formation. The present evidence supports miR‑198 as an important tumor suppressor in prostate cancer, and demonstrates for the first time that it acts by targeting MIB1. The present study reinforces the importance and complexity of miRNA in regulating prostate cancer aggression.

Published
2019

31. YIPF6 controls sorting of FGF21 into COPII vesicles and promotes obesity

Author

Wang, Lirui, Mazagova, Magdalena, Pan, Chuyue, Yang, Song, Brandl, Katharina, Liu, Jun, Reilly, Shannon M, Wang, Yanhan, Miao, Zhaorui, Loomba, Rohit, Lu, Na, Guo, Qinglong, Liu, Jihua, Yu, Ruth T, Downes, Michael, Evans, Ronald M, Brenner, David A, Saltiel, Alan R, Beutler, Bruce, and Schnabl, Bernd

Subjects
Biochemistry and Cell Biology, Biological Sciences, Chronic Liver Disease and Cirrhosis, Obesity, Nutrition, Digestive Diseases, Liver Disease, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Oral and gastrointestinal, Animals, Body Temperature, COP-Coated Vesicles, Diet, High-Fat, Endoplasmic Reticulum, Energy Metabolism, Fibroblast Growth Factors, Gene Expression Regulation, Hepatocytes, Humans, Lipolysis, Liver, Membrane Proteins, Metabolic Syndrome, Mice, Mice, Knockout, Non-alcoholic Fatty Liver Disease, Protein Binding, Signal Transduction, Thermogenesis, Vesicular Transport Proteins, obesity, YIPF6, FGF21, COPII vesicles, sorting receptor
Abstract

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates glucose, lipid, and energy homeostasis. While gene expression of FGF21 is regulated by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha in the fasted state, little is known about the regulation of trafficking and secretion of FGF21. We show that mice with a mutation in the Yip1 domain family, member 6 gene (Klein-Zschocher [KLZ]; Yipf6KLZ/Y ) on a high-fat diet (HFD) have higher plasma levels of FGF21 than mice that do not carry this mutation (controls) and hepatocytes from Yipf6KLZ/Y mice secrete more FGF21 than hepatocytes from wild-type mice. Consequently, Yipf6KLZ/Y mice are resistant to HFD-induced features of the metabolic syndrome and have increased lipolysis, energy expenditure, and thermogenesis, with an increase in core body temperature. Yipf6KLZ/Y mice with hepatocyte-specific deletion of FGF21 were no longer protected from diet-induced obesity. We show that YIPF6 binds FGF21 in the endoplasmic reticulum to limit its secretion and specifies packaging of FGF21 into coat protein complex II (COPII) vesicles during development of obesity in mice. Levels of YIPF6 protein in human liver correlate with hepatic steatosis and correlate inversely with levels of FGF21 in serum from patients with nonalcoholic fatty liver disease (NAFLD). YIPF6 is therefore a newly identified regulator of FGF21 secretion during development of obesity and could be a target for treatment of obesity and NAFLD.

Published
2019

32. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring

Author

Shi, Yu, Gao, Weina, Lytle, Nikki K, Huang, Peiwu, Yuan, Xiao, Dann, Amanda M, Ridinger-Saison, Maya, DelGiorno, Kathleen E, Antal, Corina E, Liang, Gaoyang, Atkins, Annette R, Erikson, Galina, Sun, Huaiyu, Meisenhelder, Jill, Terenziani, Elena, Woo, Gyunghwi, Fang, Linjing, Santisakultarm, Thom P, Manor, Uri, Xu, Ruilian, Becerra, Carlos R, Borazanci, Erkut, Von Hoff, Daniel D, Grandgenett, Paul M, Hollingsworth, Michael A, Leblanc, Mathias, Umetsu, Sarah E, Collisson, Eric A, Scadeng, Miriam, Lowy, Andrew M, Donahue, Timothy R, Reya, Tannishtha, Downes, Michael, Evans, Ronald M, Wahl, Geoffrey M, Pawson, Tony, Tian, Ruijun, and Hunter, Tony

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Pancreatic Cancer, Cancer, Rare Diseases, Orphan Drug, Digestive Diseases, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Animals, Antibodies, Monoclonal, Carcinogenesis, Carcinoma, Pancreatic Ductal, Cell Differentiation, Cell Line, Tumor, Disease Progression, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, Female, Humans, Leukemia Inhibitory Factor, Male, Mass Spectrometry, Mice, Pancreatic Neoplasms, Paracrine Communication, Receptors, OSM-LIF, Tumor Microenvironment, General Science & Technology
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.

Published
2019

33. A gut microbiome signature for cirrhosis due to nonalcoholic fatty liver disease.

Author

Caussy, Cyrielle, Tripathi, Anupriya, Humphrey, Greg, Bassirian, Shirin, Singh, Seema, Faulkner, Claire, Bettencourt, Ricki, Rizo, Emily, Richards, Lisa, Xu, Zhenjiang Z, Downes, Michael R, Evans, Ronald M, Brenner, David A, Sirlin, Claude B, Knight, Rob, and Loomba, Rohit

Subjects
Feces, Humans, Bacteria, Liver Cirrhosis, ROC Curve, Family, Female, Male, Non-alcoholic Fatty Liver Disease, Gastrointestinal Microbiome
Abstract

The presence of cirrhosis in nonalcoholic-fatty-liver-disease (NAFLD) is the most important predictor of liver-related mortality. Limited data exist concerning the diagnostic accuracy of gut-microbiome-derived signatures for detecting NAFLD-cirrhosis. Here we report 16S gut-microbiome compositions of 203 uniquely well-characterized participants from a prospective twin and family cohort, including 98 probands encompassing the entire spectrum of NAFLD and 105 of their first-degree relatives, assessed by advanced magnetic-resonance-imaging. We show strong familial correlation of gut-microbiome profiles, driven by shared housing. We report a panel of 30 features, including 27 bacterial features with discriminatory ability to detect NAFLD-cirrhosis using a Random Forest classifier model. In a derivation cohort of probands, the model has a robust diagnostic accuracy (AUROC of 0.92) for detecting NAFLD-cirrhosis, confirmed in a validation cohort of relatives of proband with NAFLD-cirrhosis (AUROC of 0.87). This study provides evidence for a fecal-microbiome-derived signature to detect NAFLD-cirrhosis.

Published
2019

34. Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis.

Author

Ling, Shuo-Chien, Dastidar, Somasish Ghosh, Tokunaga, Seiya, Ho, Wan Yun, Lim, Kenneth, Ilieva, Hristelina, Parone, Philippe A, Tyan, Sheue-Houy, Tse, Tsemay M, Chang, Jer-Cherng, Platoshyn, Oleksandr, Bui, Ngoc B, Bui, Anh, Vetto, Anne, Sun, Shuying, McAlonis-Downes, Melissa, Han, Joo Seok, Swing, Debbie, Kapeli, Katannya, Yeo, Gene W, Tessarollo, Lino, Marsala, Martin, Shaw, Christopher E, Tucker-Kellogg, Greg, La Spada, Albert R, Lagier-Tourenne, Clotilde, Da Cruz, Sandrine, and Cleveland, Don W

Subjects
Lysosomes, Animals, Mice, Inbred C57BL, Humans, RNA-Binding Protein FUS, RNA, Gene Expression Profiling, Homeostasis, Autophagy, Mutant Proteins, FUS, RNA metabolism, amyotrophic lateral sclerosis, autophagy-lysosome, frontotemporal degeneration, homeostasis, mouse, neuroscience, Mice, Inbred C57BL, Biochemistry and Cell Biology
Abstract

Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We show here that broad expression within the nervous system of wild-type or either of two ALS-linked mutants of human FUS in mice produces progressive motor phenotypes accompanied by characteristic ALS-like pathology. FUS levels are autoregulated by a mechanism in which human FUS downregulates endogenous FUS at mRNA and protein levels. Increasing wild-type human FUS expression achieved by saturating this autoregulatory mechanism produces a rapidly progressive phenotype and dose-dependent lethality. Transcriptome analysis reveals mis-regulation of genes that are largely not observed upon FUS reduction. Likely mechanisms for FUS neurotoxicity include autophagy inhibition and defective RNA metabolism. Thus, our results reveal that overriding FUS autoregulation will trigger gain-of-function toxicity via altered autophagy-lysosome pathway and RNA metabolism function, highlighting a role for protein and RNA dyshomeostasis in FUS-mediated toxicity.

Published
2019

35. FXR Regulates Intestinal Cancer Stem Cell Proliferation

Author

Fu, Ting, Coulter, Sally, Yoshihara, Eiji, Oh, Tae Gyu, Fang, Sungsoon, Cayabyab, Fritz, Zhu, Qiyun, Zhang, Tong, Leblanc, Mathias, Liu, Sihao, He, Mingxiao, Waizenegger, Wanda, Gasser, Emanuel, Schnabl, Bernd, Atkins, Annette R, Yu, Ruth T, Knight, Rob, Liddle, Christopher, Downes, Michael, and Evans, Ronald M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Stem Cell Research - Nonembryonic - Non-Human, Cancer, Nutrition, Digestive Diseases, Prevention, Colo-Rectal Cancer, Stem Cell Research, Animals, Bile Acids and Salts, Cell Line, Cell Proliferation, Colorectal Neoplasms, Deoxycholic Acid, Gene Expression Regulation, Neoplastic, Humans, Intestinal Neoplasms, Intestines, Liver, Mice, Mice, Inbred C57BL, Neoplastic Stem Cells, Organoids, Receptors, Cytoplasmic and Nuclear, Risk Factors, Signal Transduction, Taurocholic Acid, Wnt Signaling Pathway, BA-FXR axis, Lgr5(+) intestinal stem cells, colon cancer progression, genetic and dietary risk factors, Biological Sciences, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5+) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5+ cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5+ cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.

Published
2019

36. ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS.

Author

López-Erauskin, Jone, Tadokoro, Takahiro, Baughn, Michael W, Myers, Brian, McAlonis-Downes, Melissa, Chillon-Marinas, Carlos, Asiaban, Joshua N, Artates, Jonathan, Bui, Anh T, Vetto, Anne P, Lee, Sandra K, Le, Ai Vy, Sun, Ying, Jambeau, Mélanie, Boubaker, Jihane, Swing, Deborah, Qiu, Jinsong, Hicks, Geoffrey G, Ouyang, Zhengyu, Fu, Xiang-Dong, Tessarollo, Lino, Ling, Shuo-Chien, Parone, Philippe A, Shaw, Christopher E, Marsala, Martin, Lagier-Tourenne, Clotilde, Cleveland, Don W, and Da Cruz, Sandrine

Subjects
Hippocampus, Axons, Cells, Cultured, Animals, Mice, Inbred C57BL, Mice, Transgenic, Humans, Mice, Amyotrophic Lateral Sclerosis, RNA-Binding Protein FUS, Protein Biosynthesis, Pregnancy, Female, Male, Frontotemporal Dementia, Loss of Function Mutation, ALS, FTD, FUS, Frontotemporal dementia, RNA-binding proteins, TLS, axonal translation, neurodegenerative disease, protein synthesis, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Dementia, Genetics, Alzheimer's Disease Related Dementias (ADRD), Behavioral and Social Science, Brain Disorders, Aging, Frontotemporal Dementia (FTD), Acquired Cognitive Impairment, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Neurological, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Through the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. VIDEO ABSTRACT.

Published
2018

37. The potential value of probabilistic tractography-based for MR-guided focused ultrasound thalamotomy for essential tremor

Author

Tsolaki, Evangelia, Downes, Angela, Speier, William, Elias, W Jeff, and Pouratian, Nader

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Biomedical Imaging, Clinical Research, Brain Mapping, Diffusion Tensor Imaging, Essential Tremor, Female, Follow-Up Studies, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Predictive Value of Tests, Probability, Severity of Illness Index, Thalamus, Ultrasonography, Magnetic resonance imaging-guided focused ultrasound, Tremor, Tractography, Biological psychology, Clinical and health psychology
Abstract

Magnetic Resonance-guided Focused UltraSound (MRgFUS) offers an incisionless approach to treat essential tremor (ET). Due to lack of evident internal anatomy on traditional structural imaging, indirect targeting must still be used to localize the lesion. Here, we investigate the potential predictive value of probabilistic tractography guided thalamic targeting by defining how tractography-defined targets, lesion size and location, and clinical outcomes interrelate. MR imaging and clinical outcomes from 12 ET patients that underwent MRgFUS thalamotomy in a pilot study at the University of Virginia were evaluated in this analysis. FSL was used to evaluate each patient's voxel-wise thalamic connectivity with FreeSurfer generated pre- and post-central gyrus targets, to generate thalamic target maps. Using Receiver Operating Characteristic curves, the overlap between these thalamic target maps and the MRgFUS lesion was systematically evaluated relative to clinical outcome. To further define the connectivity characteristics of effective MRgFUS thalamotomy lesions, we evaluated whole brain probabilistic tractography of lesions (using post-treatment imaging to define the lesion pre-treatment diffusion tensor MRI). The structural connectivity difference was explored between subjects with the best clinical outcome relative to all others. Ten of twelve patients presented high percentage of overlapping between connectivity-based thalamic segmentation maps and lesion area. The improvement of clinical score was predicted (AUC: 0.80) using the volume of intersection between the thalamic target (precentral gyrus) map and MRgFUS induced lesion as feature. The main structural differences between those with different magnitudes of response were observed in connectivity to the pre- and post-central gyri and brainstem/cerebellum. MRgFUS thalamotomy lesions characterized by strong structural connectivity to precentral gyrus demonstrated better responses in a cohort of patients treated with MRgFUS for ET. The intersection between lesion and thalamic-connectivity maps to motor - sensory targets proved to be effective in predicting the response to the therapy. These imaging techniques can be used to increase the efficacy and consistency of outcomes with MRgFUS and potentially shorten treatment times by identifying optimal targets in advance of treatment.

Published
2018

38. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity

Author

Shalapour, Shabnam, Lin, Xue-Jia, Bastian, Ingmar N, Brain, John, Burt, Alastair D, Aksenov, Alexander A, Vrbanac, Alison F, Li, Weihua, Perkins, Andres, Matsutani, Takaji, Zhong, Zhenyu, Dhar, Debanjan, Navas-Molina, Jose A, Xu, Jun, Loomba, Rohit, Downes, Michael, Yu, Ruth T, Evans, Ronald M, Dorrestein, Pieter C, Knight, Rob, Benner, Christopher, Anstee, Quentin M, and Karin, Michael

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Rare Diseases, Digestive Diseases, Aging, Cancer, Liver Cancer, Liver Disease, Chronic Liver Disease and Cirrhosis, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Good Health and Well Being, Animals, B7-H1 Antigen, CD8 Antigens, Carcinoma, Hepatocellular, Cell Proliferation, Clone Cells, Disease Progression, Female, Gastrointestinal Microbiome, Humans, Immune Tolerance, Immunoglobulin A, Inflammation, Interleukin-10, Liver Cirrhosis, Liver Neoplasms, Lymphocyte Activation, Male, Mice, Non-alcoholic Fatty Liver Disease, Plasma Cells, T-Lymphocytes, Cytotoxic, General Science & Technology
Abstract

The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.

Published
2017

39. Misfolded SOD1 is not a primary component of sporadic ALS

Author

Da Cruz, Sandrine, Bui, Anh, Saberi, Shahram, Lee, Sandra K, Stauffer, Jennifer, McAlonis-Downes, Melissa, Schulte, Derek, Pizzo, Donald P, Parone, Philippe A, Cleveland, Don W, and Ravits, John

Subjects
Biomedical and Clinical Sciences, Neurosciences, ALS, Rare Diseases, Brain Disorders, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Animals, Cerebral Cortex, Disease Models, Animal, Female, Humans, Immunohistochemistry, Immunoprecipitation, Male, Mice, Transgenic, Middle Aged, Protein Folding, Spinal Cord, Superoxide Dismutase-1, Young Adult, Amyotrophic lateral sclerosis, Superoxide dismutase, Misfolding, Sporadic, Neurodegeneration, Human patients, Neuropathology, Clinical Sciences, Neurology & Neurosurgery
Abstract

A common feature of inherited and sporadic ALS is accumulation of abnormal proteinaceous inclusions in motor neurons and glia. SOD1 is the major protein component accumulating in patients with SOD1 mutations, as well as in mutant SOD1 mouse models. ALS-linked mutations of SOD1 have been shown to increase its propensity to misfold and/or aggregate. Antibodies specific for monomeric or misfolded SOD1 have detected misfolded SOD1 accumulating predominantly in spinal cord motor neurons of ALS patients with SOD1 mutations. We now use seven different conformationally sensitive antibodies to misfolded human SOD1 (including novel high affinity antibodies currently in pre-clinical development) coupled with immunohistochemistry, immunofluorescence and immunoprecipitation to test for the presence of misfolded SOD1 in high quality human autopsy samples. Whereas misfolded SOD1 is readily detectable in samples from patients with SOD1 mutations, it is below detection limits for all of our measures in spinal cord and cortex tissues from patients with sporadic or non-SOD1 inherited ALS. The absence of evidence for accumulated misfolded SOD1 supports a conclusion that SOD1 misfolding is not a primary component of sporadic ALS.

Published
2017

40. Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes

Author

Oral, Elif A, Reilly, Shannon M, Gomez, Andrew V, Meral, Rasimcan, Butz, Laura, Ajluni, Nevin, Chenevert, Thomas L, Korytnaya, Evgenia, Neidert, Adam H, Hench, Rita, Rus, Diana, Horowitz, Jeffrey F, Poirier, BreAnne, Zhao, Peng, Lehmann, Kim, Jain, Mohit, Yu, Ruth, Liddle, Christopher, Ahmadian, Maryam, Downes, Michael, Evans, Ronald M, and Saltiel, Alan R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Digestive Diseases, Clinical Research, Obesity, Nutrition, Clinical Trials and Supportive Activities, Prevention, Chronic Liver Disease and Cirrhosis, Diabetes, Liver Disease, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Oral and gastrointestinal, Metabolic and endocrine, Aged, Aminopyridines, Blood Glucose, Diabetes Mellitus, Type 2, Double-Blind Method, Energy Metabolism, Female, Glycated Hemoglobin, Humans, I-kappa B Kinase, Male, Middle Aged, Non-alcoholic Fatty Liver Disease, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, amlexanox, clinical trial, energy expenditure, fatty liver, gene expression, inflammation, obesity, protein kinase, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism, Biochemistry and cell biology, Medical biochemistry and metabolomics
Abstract

Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.

Published
2017

41. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

Author

Ditsworth, Dara, Maldonado, Marcus, McAlonis-Downes, Melissa, Sun, Shuying, Seelman, Amanda, Drenner, Kevin, Arnold, Eveline, Ling, Shuo-Chien, Pizzo, Donald, Ravits, John, Cleveland, Don W, and Da Cruz, Sandrine

Subjects
Biomedical and Clinical Sciences, Neurosciences, Rare Diseases, Neurodegenerative, Genetics, Brain Disorders, ALS, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Aged, 80 and over, Aging, Amyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, Disease Models, Animal, Disease Progression, Female, Humans, Inflammation, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Motor Activity, Motor Neurons, Mutation, Neuromuscular Junction, Young Adult, Amyotrophic lateral sclerosis, TDP-43, Frontotemporal dementia, RanGAP1, Motor neuron, Non-cell autonomous, Neurodegeneration, Mouse model, Clinical Sciences, Neurology & Neurosurgery
Abstract

Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

Published
2017

42. Meta‐analysis of individual‐patient data from EVAR‐1, DREAM, OVER and ACE trials comparing outcomes of endovascular or open repair for abdominal aortic aneurysm over 5 years

Author

Powell, JT, Sweeting, MJ, Ulug, P, Blankensteijn, JD, Lederle, FA, Becquemin, J‐P, Greenhalgh, RM, Beard, JD, Buxton, MJ, Brown, LC, Harris, PL, Rose, JDG, Russell, IT, Sculpher, MJ, Thompson, SG, Lilford, RJ, Bell, PRF, Whitaker, SC, Poole‐Wilson, the late PA, Ruckley, CV, Campbell, WB, Dean, MRE, Ruttley, MST, Coles, EC, Halliday, A, Gibbs, SJ, Epstein, D, Hannon, RJ, Johnston, L, Bradbury, AW, Henderson, MJ, Parvin, SD, Shepherd, DFC, Mitchell, AW, Edwards, PR, Abbott, GT, Higman, DJ, Vohra, A, Ashley, S, Robottom, C, Wyatt, MG, Byrne, D, Edwards, R, Leiberman, DP, McCarter, DH, Taylor, PR, Reidy, JF, Wilkinson, AR, Ettles, DF, Clason, AE, Leen, GLS, Wilson, NV, Downes, M, Walker, SR, Lavelle, JM, Gough, MJ, McPherson, S, Scott, DJA, Kessell, DO, Naylor, R, Sayers, R, Fishwick, NG, Gould, DA, Walker, MG, Chalmers, NC, Garnham, A, Collins, MA, Gaines, PA, Ashour, MY, Uberoi, R, Braithwaite, B, Davies, JN, Travis, S, Hamilton, G, Platts, A, Shandall, A, Sullivan, BA, Sobeh, M, Matson, M, Fox, AD, Orme, R, Yusef, W, Doyle, T, Horrocks, M, Hardman, J, Blair, PHB, Ellis, PK, and Morris, G

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Clinical Research, Clinical Trials and Supportive Activities, Cardiovascular, Evaluation of treatments and therapeutic interventions, 6.4 Surgery, Good Health and Well Being, Aged, Aged, 80 and over, Aortic Aneurysm, Abdominal, Elective Surgical Procedures, Endovascular Procedures, Female, Humans, Male, Middle Aged, Models, Statistical, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, Reoperation, Treatment Outcome, Vascular Grafting, EVAR-1, DREAM, OVER and ACE Trialists, Medical and Health Sciences, Surgery, Clinical sciences
Abstract

BackgroundThe erosion of the early mortality advantage of elective endovascular aneurysm repair (EVAR) compared with open repair of abdominal aortic aneurysm remains without a satisfactory explanation.MethodsAn individual-patient data meta-analysis of four multicentre randomized trials of EVAR versus open repair was conducted to a prespecified analysis plan, reporting on mortality, aneurysm-related mortality and reintervention.ResultsThe analysis included 2783 patients, with 14 245 person-years of follow-up (median 5·5 years). Early (0-6 months after randomization) mortality was lower in the EVAR groups (46 of 1393 versus 73 of 1390 deaths; pooled hazard ratio 0·61, 95 per cent c.i. 0·42 to 0·89; P = 0·010), primarily because 30-day operative mortality was lower in the EVAR groups (16 deaths versus 40 for open repair; pooled odds ratio 0·40, 95 per cent c.i. 0·22 to 0·74). Later (within 3 years) the survival curves converged, remaining converged to 8 years. Beyond 3 years, aneurysm-related mortality was significantly higher in the EVAR groups (19 deaths versus 3 for open repair; pooled hazard ratio 5·16, 1·49 to 17·89; P = 0·010). Patients with moderate renal dysfunction or previous coronary artery disease had no early survival advantage under EVAR. Those with peripheral artery disease had lower mortality under open repair (39 deaths versus 62 for EVAR; P = 0·022) in the period from 6 months to 4 years after randomization.ConclusionThe early survival advantage in the EVAR group, and its subsequent erosion, were confirmed. Over 5 years, patients of marginal fitness had no early survival advantage from EVAR compared with open repair. Aneurysm-related mortality and patients with low ankle : brachial pressure index contributed to the erosion of the early survival advantage for the EVAR group. Trial registration numbers: EVAR-1, ISRCTN55703451; DREAM (Dutch Randomized Endovascular Aneurysm Management), NCT00421330; ACE (Anévrysme de l'aorte abdominale, Chirurgie versus Endoprothèse), NCT00224718; OVER (Open Versus Endovascular Repair Trial for Abdominal Aortic Aneurysms), NCT00094575.

Published
2017

43. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration

Author

Arno, Gavin, Carss, Keren J, Hull, Sarah, Zihni, Ceniz, Robson, Anthony G, Fiorentino, Alessia, Hardcastle, Alison J, Holder, Graham E, Cheetham, Michael E, Plagnol, Vincent, Moore, Anthony, Raymond, F Lucy, Matter, Karl, Balda, Maria S, Webster, Andrew R, Black, Graeme, Hall, Georgina, Ingram, Stuart, Gillespie, Rachel, Manson, Forbes, Sergouniotis, Panagiotis, Inglehearn, Chris, Toomes, Carmel, Ali, Manir, McKibbin, Martin, Poulter, James, Khan, Kamron, Lord, Emma, Nemeth, Andrea, Downes, Susan, Halford, Stephanie, Yu, Jing, Lise, Stefano, Ponitkos, Nikos, Michaelides, Michel, Webster, Andrew, van Heyningen, Veronica, Aitman, Timothy, Alachkar, Hana, Ali, Sonia, Allen, Louise, Allsup, David, Ambegaonkar, Gautum, Anderson, Julie, Antrobus, Richard, Armstrong, Ruth, Arumugakani, Gururaj, Ashford, Sofie, Astle, William, Attwood, Antony, Austin, Steve, Bacchelli, Chiara, Bakchoul, Tamam, Bariana, Tadbir K, Baxendale, Helen, Bennett, David, Bethune, Claire, Bibi, Shahnaz, Bitner-Glindzicz, Maria, Bleda, Marta, Boggard, Harm, Bolton-Maggs, Paula, Booth, Claire, Bradley, John R, Brady, Angie, Brown, Matthew, Browning, Michael, Bryson, Christine, Burns, Siobhan, Calleja, Paul, Canham, Natalie, Carmichael, Jenny, Carss, Keren, Caulfield, Mark, Chalmers, Elizabeth, Chandra, Anita, Chinnery, Patrick, Chitre, Manali, Church, Colin, Clement, Emma, Clements-Brod, Naomi, Clowes, Virginia, Coghlan, Gerry, Collins, Peter, Cooper, Nichola, Creaser-Myers, Amanda, DaCosta, Rosa, Daugherty, Louise, Davies, Sophie, Davis, John, De Vries, Minka, Deegan, Patrick, Deevi, Sri VV, and Deshpande, Charu

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Ophthalmology and Optometry, Human Genome, Rare Diseases, Neurosciences, Eye Disease and Disorders of Vision, Aetiology, 2.1 Biological and endogenous factors, Eye, Adult, Alleles, Amino Acid Sequence, Cell Polarity, Epithelial Cells, Exome, Eye Proteins, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Membrane Proteins, Middle Aged, Mutation, Missense, Nerve Tissue Proteins, Pedigree, Phenotype, Retina, Retinal Degeneration, Retinal Dystrophies, Rho Guanine Nucleotide Exchange Factors, rhoA GTP-Binding Protein, UK Inherited Retinal Disease Consortium, NIHR Bioresource - Rare Diseases Consortium, ARHGEF18, apicobasal polarity, inherited retinal dystrophy, p114RhoGEF, retinal degeneration, retinitis pigmentosa, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs∗63), c.1996C>T (p.Arg666∗), c.2632G>T (p.Glu878∗), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.

Published
2017

44. Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

Author

Arno, Gavin, Agrawal, Smriti A, Eblimit, Aiden, Bellingham, James, Xu, Mingchu, Wang, Feng, Chakarova, Christina, Parfitt, David A, Lane, Amelia, Burgoyne, Thomas, Hull, Sarah, Carss, Keren J, Fiorentino, Alessia, Hayes, Matthew J, Munro, Peter M, Nicols, Ralph, Pontikos, Nikolas, Holder, Graham E, UKIRDC, Black, Graeme, Hall, Georgina, Ingram, Stuart, Gillespie, Rachel, Manson, Forbes, Sergouniotis, Panagiotis, Inglehearn, Chris, Toomes, Carmel, Ali, Manir, McKibbin, Martin, Poulter, James, Khan, Kamron, Lord, Emma, Nemeth, Andrea, Downes, Susan, Yu, Jing, Lise, Stefano, Ponitkos, Nikos, Plagnol, Vincent, Michaelides, Michel, Hardcastle, Alison J, Cheetham, Michael E, Webster, Andrew R, van Heyningen, Veronica, Asomugha, Chinwe, Raymond, F Lucy, Moore, Anthony T, Li, Yumei, Cukras, Catherine, and Chen, Rui

Subjects
Genetics, Biotechnology, Neurodegenerative, Rare Diseases, Clinical Research, Eye Disease and Disorders of Vision, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Eye, Adolescent, Alleles, Animals, Child, Child, Preschool, Eye Proteins, Female, Genes, Recessive, Humans, Induced Pluripotent Stem Cells, Male, Membrane Proteins, Membrane Transport Proteins, Mice, Mutation, Mutation, Missense, Phenotype, Photoreceptor Cells, Vertebrate, Retinitis Pigmentosa, Young Adult, UKIRDC, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Retinitis pigmentosa (RP) is the most frequent form of inherited retinal dystrophy. RP is genetically heterogeneous and the genes identified to date encode proteins involved in a wide range of functional pathways, including photoreceptor development, phototransduction, the retinoid cycle, cilia, and outer segment development. Here we report the identification of biallelic mutations in Receptor Expression Enhancer Protein 6 (REEP6) in seven individuals with autosomal-recessive RP from five unrelated families. REEP6 is a member of the REEP/Yop1 family of proteins that influence the structure of the endoplasmic reticulum but is relatively unstudied. The six variants identified include three frameshift variants, two missense variants, and a genomic rearrangement that disrupts exon 1. Human 3D organoid optic cups were used to investigate REEP6 expression and confirmed the expression of a retina-specific isoform REEP6.1, which is specifically affected by one of the frameshift mutations. Expression of the two missense variants (c.383C>T [p.Pro128Leu] and c.404T>C [p.Leu135Pro]) and the REEP6.1 frameshift mutant in cultured cells suggest that these changes destabilize the protein. Furthermore, CRISPR-Cas9-mediated gene editing was used to produce Reep6 knock-in mice with the p.Leu135Pro RP-associated variant identified in one RP-affected individual. The homozygous knock-in mice mimic the clinical phenotypes of RP, including progressive photoreceptor degeneration and dysfunction of the rod photoreceptors. Therefore, our study implicates REEP6 in retinal homeostasis and highlights a pathway previously uncharacterized in retinal dystrophy.

Published
2016

45. Higher dose corticosteroids in patients admitted to hospital with COVID-19 who are hypoxic but not requiring ventilatory support (RECOVERY)

Author

Obbina Abani, Ali Abbas, Fatima Abbas, Joshua Abbas, Kasim Abbas, Mustafa Abbas, Sadia Abbasi, Hakam Abbass, Alfie Abbott, Alison Abbott, Nabeel Abdallah, Ammar Abdelaziz, Ashraf Abdelaziz, Mohamed Abdelfattah, Bushra Abdelqader, Audrey Abdul, Basir Abdul, Siddiqui Abdul, Althaf Abdul Rasheed, Ajibode Abdulakeem, Rezan Abdul-Kadir, Abdullah Abdullah, Abdulfatahi Abdulmumeen, Rasheed Abdul-Raheem, Niyaz Abdulshukkoor, Kula Abdusamad, Yazeed Abed El Khaleq, Mai Abedalla, Abeer Abeer Ul Amna, Lynn Abel, Katrina Abernethy, Movin Abeywickrema, Chandra Abhinaya, Affyarsyah Abidin, Adebanke Aboaba, Abigail Aboagye-Odei, Christopher Aboah, Heba Aboelela, Hani Abo-Leyah, Karim Abouelela, Ahmed Abou-Haggar, Mahmoud Abouibrahim, Ahmed Abousamra, Mona Abouzaid, Miriam Abraham, Tizzy Abraham, Abraheem Abraheem, Judith Abrams, Rebecca Abrams, Hyacinth-John Abu, Ahmed Abu-Arafeh, Syed M Abubacker, Akata Abung, Yousuf Abusamra, Yaa Aceampong, Amaka Achara, Devikumar Acharya, Faustina Acheampong, Prince Acheampong, Sarah Acheampong, Janet Acheson, Shiella Achieng, Andres Acosta, Rebecca Acquah, Catherine Acton, Jacqueline Adabie-Ankrah, Paul Adair, Fiona Adam, Matthew Adam, Huzaifa Adamali, Marta Adamczyk, Carol Adams, Charlotte Adams, Daniel Adams, Kate Adams, Laura Adams, Nikkita Adams, Richard Adams, Tim Adams, Laura Adamu-Ikeme, Krishma Adatia, Kirsty Adcock, Lawrence Addai-Boampong, Afua Addo, Oluwatobi Adeagbo, Ade Adebiyi, Ogunlana Adedeji, Yewande Adegeye, Ken Adegoke, Vicki Adell, Sherna Adenwalla, Femi W Adeoye, Oluwasegun A Adesemoye, Emmanuel O Adewunmi, Adedamola Adeyanju, Joyce Adeyemi, Tenifayo Adeyemo, Binay Adhikari, Shanti A Adhikari, Rina Adhikary, Adhikarla Aditya, Patience Adjepong, Gabrielle Adkins, Adnan Adnan, Marguerite Adriaanse, John Aeron-Thomas, Debbie Affleck, Carmel Afnan, Muhammad Afridi, Patricia Afrim, Felicia Akua Afriyie, Zainab A Aftab, Meenakshi Agarwal, Rachel Agbeko, Chris Agbo, Sunil Aggarwal, Arameh Aghababaie, Laura Aguilar Jimenez, Jacqueline Afrakomah Agyekum, Kwame Agyen, Shafana Ahamed Sadiq, Mohamed H Ahammed Nazeer, Mohammad Ahmad, Syed Ahmad, Afshan Ahmed, Ashar Ahmed, Asim Ahmed, Basheer A R Ahmed, Bilal Ahmed, Forizuddin Ahmed, Hamze Ahmed, Hanad Ahmed, Irshad Ahmed, Khaled Ahmed, Khalil Ahmed, Liban Ahmed, Mahin Ahmed, Maria C Ahmed, Muhammad S Ahmed, Naseer Ahmed, Nausheen Ahmed, Osama Ahmed, Rajia A Ahmed, Rawya Ahmed, Rizwan Ahmed, Saif Ahmed, Sammiya Ahmed, Sana G Ahmed, Syed Ahmed, Syed H Ahmed, Roa Ahmed Ali, Bilal Ahmed Mohamud, Sana Ahmed, Sana Ahmer, Augustine Ahonia, Christine Aiken, Dhiraj Ail, Mark Ainsworth, Myriam Aissa, Lindianne Aitken, Bini Ajay, Abdulakeem Ajibode, Ayesha Ajmi, Nasim Akhtar, Nauman Akhtar, Suha Akili, Bolutito Akinbiyi, Oludoyinsola Akindolie, Yinka Akinfenwa, Olugbenga Akinkugbe, Ibrahim Akinpelu, Mohammad Akram, Olugbenro Aktinade, Uzayr Akudi, Ahmad S A R Al Aaraj, Asma Al Balushi, Majd Al Dakhola, Aladdin Al Swaifi, Eslam Al-Abadi, Adegoke Alabi, Narendra Aladangady, Mohamed Alafifi, Ayaz Alam, Sajid Alam, Abbas Al-Asadi, Kyriaki Alatzoglou, Paul Albert, Albertus Albertus, Lorraine Albon, Angela Alcala, Gemma Alcorn, Stephen Alcorn, Aggie Aldana, David Alderdice, Abdullah Aldesouki, Rayan Aldouri, Jonathan Aldridge, Nicolas Aldridge, Ram Maya Ale, Ana Alegria, Alison Alexander, Courtney Alexander, John Alexander, Peter D G Alexander, Julyan Al-fori, Laith Alghazawi, Osama Alhabsha, Bahij Al-Hakim, Rafil Alhameed, Mohammed Al-Hayali, Shams Al-Hity, Ali Ali, Amanda Ali, Asad Ali, Fawzia R Ali, Jawad Ali, Mariam Ali, Mohamed Ali, Mohammad Ali, Muhammad S Ali, Nayab Ali, Oudai Ali, Ramla Ali, Sakina Ali, Syed Ali, Emilio Aliberti, Jade Alin, Abid Alina, Analyn Alipustain, Bachti Alisjahbana, Fine Aliyuda, Katrin Alizadeh, Maithem Al-Jibury, Saba Al-Juboori, Majid Al-Khalil, Abdullah Alkhudhayri, Moutaz Alkhusheh, Fiona Allan, Nataliya Allan, Alison Allanson, Robert Allcock, Eireann Allen, Jade Allen, Kerry Allen, Louise Allen, Poppy Allen, Rebecca Allen, Sam Allen, Sharon Allen, Simon Allen, Tania Allen, Abiola Alli, Kathryn Allison, Bethan Allman, Helen K Allsop, Lynne Allsop, David Allsup, Amal F T Almahroos, Hassan Al-Moasseb, Magda Al-Obaidi, Lina Alomari, Akram Al-Rabahi, Bahar Al-Ramadhani, Zayneb Al-Saadi, Riyam Al-Sammarraie, Inji Alshaer, Rustam Al-Shahi Salman, Warkaq Al-Shamkhani, Fadia Alsheikh, Bashar Al-Sheklly, Sara Altaf, Amanda Alty, Mary Alvarez, Maria Alvarez Corral, Edward Alveyn, Maysaa Alzetani, Susan Amamou, Noor Amar, Sakkarai Ambalavanan, Robert Ambrogetti, Chris Ambrose, Amir Ameen, Amel Amelia Ganefianty, Katharine Ames, Maria R Amezaga, Allison Amin, Amina Amin, Kanish Amin, Syed Amin, Tara Amin, Badshah Amit, Amjad Amjad, Neelma Amjad, James Amoah-Dankwa, Victoria Amosun, Muhammad Amsal, Khaled Amsha, John Amuasi, Noelia Amutio Martin, Pugh Amy, Ann Anada, Atul Anand, Samantha Anandappa, Satya D Anantapatnaikuni, Ellen Anderson, Julie Anderson, Laura Anderson, Marina Anderson, Michelle Anderson, Nicola Anderson, Rachel Anderson, Rebecca Anderson, Rory Anderson, Samantha Anderson, Wendy Anderson, Prematie Andreou, Angela Andrews, Antonette Andrews, Jill Andrews, Joyann Andrews, Kanayochukwu Aneke, Andrew Ang, Wan Wei Ang, Tammy Angel, Aramburo Angela, Paola Angelini, Lazarus Anguvaa, Oleg Anichtchik, Millicent Anim-Somuah, Krishnan Aniruddhan, Jessica Annett, Louise Anning, Maldwyn Ansah, Patrick J Anstey, Rebekah Anstey, Alpha Anthony, Aaron Anthony-Pillai, Philip Antill, Zhelyazkova Antonina, Varghese Anu, Muhammad Anwar, Elena Apetri, Aristeidis Apostolopoulos, Sarah Appleby, Diane Appleyard, Maia F Aquino, Bianca Araba, Samuel Aransiola, Mariana Araujo, Ann Archer, Denise Archer, Samuel Archer, Simon Archer, Daniele Arcoria, Christian Ardley, Ana-Maria Arias, Oluwatoyin Aribike, Ryoki Arimoto, Charlotte Arkley, Charlotte Armah, Ilianna Armata, Jennifer Armistead, Adam Armitage, Ceri Armstrong, Maureen Armstrong, Sonia Armstrong, Wendy Armstrong, Philippa Armtrong, Heike Arndt, Clare Arnison-Newgass, David Arnold, Rachael Arnold, Andrew Arnott, Dhawal Arora, Kavan Arora, Pardeep Arora, Rishi Arora, Arslam Arter, Armena Arumaithurai, Ayush Arya, Rita Arya, Diptesh Aryal, Denisa Asandei, Adeeba Asghar, Malik Asghar, Arif Ashab, Catherine Ashbrook-Raby, Helen Ashby, Jan Ashcroft, John Ashcroft, Samuel Ashcroft, Georgia Asher, Zakariya Ashfak, Ayesha Ashfaq, Abdul Ashish, Dawn Ashley, Sally Ashman-Flavell, Sundar Ashok, Abd-El-Aziz Ashour, Muhammad Z Ashraf, Saima Ashraf, Mohammad B Ashraq, Deborah Ashton, Susan Ashton, Andrew Ashworth, Fiona J Ashworth, Rebecca Ashworth, Arshia Aslam, I Aslam, Suhail Aslam, Laura Aslett, Harshini Asogan, Atif Asrar, Omar Assaf, Raine Astin-Chamberlain, Deborah Athorne, Billie Atkins, Christopher Atkins, Stacey Atkins, John Atkinson, Vicki Atkinson, Abolaji Atomode, Brygitta Atraskiewicz, Abdul A Attia, Eva Attubato, Marie Attwood, Paula Aubrey, Zoltan Auer, Avinash Aujayeb, Aye Chan Thar Aung, Hnin Aung, Hnin Wint Wint Aung, Ko Ko Aung, Kyaw Thu Aung, Nwe Aung, Yin Aung, Zaw Myo Aung, Emily Austin, Karen Austin, Abdusshakur Auwal, Malcolm Avari, Miriam Avery, Nicholas Aveyard, Joanne Avis, Georgina Aviss, Cristina Avram, Paula Avram, Abuzar Awadelkareem, Gabriel Awadzi, Mahmoud Awaly, Atia Awan, Aszad Aya, Eman Ayaz, John Maximilian Ayerh, Amanda Ayers, Jawwad Azam, Ahmed Azeem, Mohammed Azharuddin, Ammar Aziz, Ghazala Aziz, Imran Aziz, N Aziz, Ali Azkoul, Ashaari Azman Shah, Giada Azzopardi, Hocine Azzoug, Fiyinfoluwa Babatunde, Melvin Babi, Babiker Babiker, Gayna Babington, Matthew Babirecki, Marta Babores, Adetona O Babs-Osibodu, Sammy Bacciarelli, Roudi Bachar, Michel-Elie Bachour, Alisjahbana Bachti, Gina Bacon, Jenny Bacon, Bibi Badal, Aysha Badat, Maryuma Bader, Gurpreet R Badhan, Shreya Badhrinarayanan, Joseph P Bae, Alice Baggaley, Amy Baggott, Graham Bagley, Dinesh Bagmane, Lynsey Bagshaw, Kasra Bahadori, Angela Bailey, James Bailey, Katie Bailey, Lindsey Bailey, Liz Bailey, Lucy Bailey, Maria A Bailey, Morgan Bailey, Pippa Bailey, Sarah Bailey, Hamish Baillie, J Kenneth Baillie, Jennifer Bain, Vikram Bains, David Baird, Eilidh Baird, Kevin Baird, Susan Baird, Tracy Baird, Yolanda Baird, Aiysha Bajandouh, Danielle C Baker, Evelyn Baker, Johanne Baker, Josephine Baker, Kenneth Baker, Mark Baker, Rebecca Baker, Terri-Anne Baker, Victoria Baker, Hugh Bakere, Nawar Bakerly, Michelle Baker-Moffatt, Ameet Bakhai, Nauman Bakhtiar, Panos Bakoulas, Dhanalakshmi Bakthavatsalam, Niranjan Balachandran, Andrea Balan, Prasath Balasingam, Theodosios Balaskas, Madhu Balasubramaniam, Nicola Balatoni, Alison Balcombe, Alexander Baldwin, Ashley Baldwin, Caron Baldwin, Danielle Baldwin, Fiona Baldwin, Rebekah Baldwin-Jones, Nichola Bale, James Balfour, Matthew Ball, Robert Ball, K Ballard, Ismael Balluz, Craig Balmforth, Emese Balogh, Abeir Baltmr, Amir Baluwala, Gabby Bambridge, Alasdair Bamford, Amy Bamford, Peter Bamford, Adefunke Bamgboye, Elizabeth Bancroft, Hollie Bancroft, Joyce Banda, Krishna Bandaru, Srini Bandi, Nageswar Bandla, Somaditya Bandyopadhyam, Amit Banerjee, Ritwik Banerjee, Santosh Baniya, Omar Bani-Saad, Harrison Banks, Luke Banks, Paul Banks, Claudia Bann, Helen Bannister, Oliver Bannister, Laura Banton, Tran Bao, Mariamma Baptist, Tanya Baqai, Ananya M Baral, Sharad Chandra Baral, Desislava Baramova, Russel Barber, Emma Barbon, Monica Barbosa, Jamie Barbour, Alexander Barclay, Amanda Barclay, Claire Barclay, George Bardsley, Stephanie Bareford, Shahedal Bari, Morris Barimbing, Amy Barker, Debbie Barker, Erandi Barker, Helen Barker, Joseph Barker, Leon Barker, Lesley Barker, Oliver Barker, Kerry Barker-Williams, Sinha Barkha, Juliana Barla, Gavin Barlow, Richard Barlow, Valerie Barlow, James Barnacle, Alex Barnard, Debi Barnes, Nicky Barnes, Rory Barnes, Theresa Barnes, Calum Barnetson, Amy Barnett, Ashton Barnett-Vanes, Prince Gyenti Barning, William Barnsley, Andrew Barr, David Barr, James Barr, Charlotte Barr, Nina Barratt, Shaney Barratt, Manuella Barrera, Amy Barrett, Fiona Barrett, Jessica Barrett, Sue Barrett, Esther Barrow, Jazz Bartholomew, Claire Bartlett, Georgina Bartlett, James Bartlett, Louise Bartlett, Shauna Bartley, Sandra Bartolmeu-Pires, Anna Barton, Greg Barton, Jill Barton, Lorna Barton, Rachael Barton, Rosaleen Baruah, Sonia Baryschpolec, Hannah Bashir, Archana Bashyal, Betsy Basker, Sudha Basnet, Buddha Basnyat, Ayten Basoglu, Alexander Basran, John Bassett, G Bassett, Chris Bassford, Bengisu Bassoy, Victoria Bastion, Anup Bastola, Anupam Basumatary, Precious Basvi, Jireh A Batac, Vipula R Bataduwaarachchi, Tristan Bate, Harry J Bateman, Kathryn Bateman, Vhairi Bateman, Eleanor Bates, Hayley Bates, Michelle Bates, Simon Bates, Sally Batham, Ana Batista, Amit Batla, Dushyant Batra, Harry Batty, Thomas Batty, Alice Batty, Miranda Baum, Rachel Baumber, Carina Bautista, Fareha Bawa, Tanveer Bawa, Fatima S Bawani, Simon Bax, Matt Baxter, Nicola Baxter, Zachary Baxter, Hannah Bayes, Lee-Ann Bayo, Farid Bazari, Rohit Bazaz, Ahmad Bazli, Laura Beacham, Wendy Beadles, Kirsten Beadon, Philip Beak, Andy Beale, Kathy Beard, Jack Bearpark, Alanna Beasley, Sandee Beattie, Karen Beaumont, Dawn Beaumont-Jewell, Theresa Beaver, Sarah Beavis, Christy Beazley, Sarah Beck, Virginia Beckett, Rosie Beckitt, Sarah Beckley, Heidi Beddall, Seonaid Beddows, Deborah Beeby, Sophia Beeby, Gail Beech, Michelle Beecroft, Nigel Beer, Sally Beer, Jane Beety, Gabriela Bega, Alison Begg, Susan Begg, Sara Beghini, Ayesha Begum, Salman Begum, Selina Begum, Teresa Behan, Roya Behrouzi, Jon Beishon, Claire Beith, James Belcher, Holly Belfield, Katherine Belfield, Ajay Belgaumkar, Dina Bell, Gareth Bell, Gillian Bell, Jessica Bell, Lauren Bell, Louise Bell, Nicholas Bell, Pippa Bell, Stephanie Bell, Jennifer Bellamu, Mary Bellamy, Tammy Bellamy, Arianna Bellini, Amanda Bellis, Fionn Bellis, Lesley Bendall, Naveena Benesh, Nicola Benetti, Leonie Benham, Guy Benison-Horner, Sarah Benkenstein, Tracey Benn, Ann Bennett, Caroline Bennett, Denise Bennett, Gillian Bennett, Kaytie Bennett, Kristopher Bennett, Lorraine Bennett, Miriam R Bennett, Sara Bennett, Karen Bennion, Gautham Benoy, Vivienne Benson, Andrew Bentley, James Bentley, Ian Benton, Eva Beranova, Matthew Beresford, Colin Bergin, Malin Bergstrom, Jolanta Bernatoniene, Thomas Berriman, Zoe Berry, Frida Best, Kimberley Best, Ans-Mari Bester, Yvonne Beuvink, Emily Bevan, Sarah Bevins, Tom Bewick, Andrew Bexley, Sonay Beyatli, Fenella Beynon, Arjun Bhadi, Sanjay Bhagani, Shiv Bhakta, Rekha Bhalla, Khushpreet Bhandal, Kulbinder Bhandal, Ashwin Bhandari, Lila Nath Bhandari, Sangam Bhandari, Jennifer Bhanich Supapol, Aashutosh Bhanot, Ravina Bhanot, Swati Bhasin, Abdul Bhat, Prashanth Bhat, Rahul Bhatnagar, Karan Bhatt, Janki Bhayani, Deepika Bhojwani, Parminder Bhuie, M S Bhuiyan, Salimuzzaman Bhuiyan, Anna Bibby, Fatima Bibi, Naheeda Bibi, Salma Bibi, Tihana Bicanic, Sarah Bidgood, Julie Bigg, Sarah Biggs, Alphonsa Biju, Andras Bikov, Sophie Billingham, Jessica Billings, Prof Binh, Alice Binns, Muhammad BinRofaie, Oliver Bintcliffe, Catherine Birch, Janine Birch, Jenny Birch, Katherine Birchall, Sam Bird, Sumedha Bird, Sarah Bird, Mark Birt, Claire Bishop, Kilanalei Bishop, Linda Bishop, Lisa Bishop, Karen Bisnauthsing, Nibedan Biswas, Mustapha Bittaye, Sahar Biuk, Karen Blachford, Ethel Black, Helen Black, Karen Black, Mairead Black, Polly Black, Virginia Black, Hayley Blackgrove, Bethan Blackledge, Joanne Blackler, Samantha Blackley, Helen Blackman, Caroline Blackstock, Cameron Blair, Francesca Blakemore, Helen Blamey, Alison Bland, Sujata Blane, Simon Blankley, Parry Blaxill, Katie Blaylock, Jane Blazeby, Natalie Blencowe, Ben Bloom, Jack Bloomfield, Angela Bloss, Alex Blowers, Samuel Blows, Hannah Bloxham, Susan Blrd, Louise Blundell, Andrew Blunsum, Mark Blunt, Tadhg Blunt, Ian Blyth, Kevin Blyth, Andrew Blythe, Karen Blythe, Kwabena Appiah Boahen, Marilyn Boampoaa, Sarah Board, Boniface Bobie, Karen Bobruk, 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Zain Chaudhry, Nazia Chaudhuri, Muhammad Chaudhury, Anoop Chauhan, Ruchi S Chauhan, Alexander Chavasse, Nicola Chavasse, Vipal Chawla, Lindsay Cheater, James Cheaveau, Charlotte Cheeld, Michelle Cheeseman, Fang Chen, Hui Min Chen, Terence Chen, Floria Cheng, Lok Yin Cheng, Zhihang Cheng, Helen Chenoweth, Chun How Cheong, Shiney Cherian, Mary Cherrie, Helen Cheshire, Chee Kay Cheung, Elaine Cheung, Kayan Cheung, Michelle Cheung, Claire Cheyne, Swati Chhabra, Wei Ling Chia, Eric Chiang, Angela Chiapparino, Rosavic Chicano, Moses Chikungwa, Zviedzo A Chikwanha, Gemma Chilcott, Sam Chilcott, Alison Chilvers, Phillipa Chimbo, KokWai Chin, Wen Jie Chin, Rumbidzai Chineka, Amol Chingale, Ezomike Chinonso, Chloe Chin-Saad, Margaret Chirgwin, Heather Chisem, Claire Chisenga, Catherine Chisholm, Ben Chisnall, Carolyn Chiswick, Sunder Chita, Nihil Chitalia, Matthew Chiu, Laura Chiverton, Brenda Chivima, Catherine Chmiel, Soha Choi, Willy Choon Kon Yune, Meena Chopra, Michelle Chopra, Vandana 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Tak-Yan Ellis, Yvette Ellis, Alison C Ellwood, Rahma Elmahdi, Einas Elmahi, Hannah-May Elmasry, Mohammed El-Naggar, Najla Elndari, Omer Elneima, Mohamed Elokl, Ahmed Elradi, Mohamed Elsaadany, Mohammed A S A Elsayed, Sally El-Sayeh, Hana El-Sbahi, Mohammad Elsebaei, Tarek Elsefi, Karim El-Shakankery, Alguili Elsheikh, Hosni El-Taweel, Sarah Elyoussfi, Jonathan Emberey, Jonathan R Emberson, John Emberton, Anna Emery, Julian Emmanuel, Ingrid Emmerson, Michael Emms, Florence Emond, Marieke Emonts, Nicu Enachi, Dickson Enenche, Angila Engden, Katy English, Emma Entwistle, Hene Enyi, Marios Erotocritou, Peter Eskander, Hanif Esmail, Fatheha Essa, Brynach Evans, Chris Evans, Debra Evans, E Evans, Emrys Evans, Gail Evans, Gareth Evans, Isabel Evans, Jack Evans, Jacqueline Evans, Jennifer Evans, John Evans, Jolanta Evans, Lisa Evans, Lynn Evans, Mim Evans, Morgan Evans, Ranoromanana Evans, Sharon Evans, Sian Evans, Teriann Evans, Tomos Evans, Caroline Everden, Serenydd Everden, Lynette Every, 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Flanagan, Charles Flanders, Nikolaos Flaris, Gail Fleming, Julie Fleming, Lucy Fleming, Paul Fleming, William Flesher, Alison Fletcher, Anna Fletcher, Jonathan Fletcher, Lucy Fletcher, Simon Fletcher, Sophie Fletcher, Fiona Flett, Karen Flewitt, Sarah Flockhart, Christopher Flood, Ian Floodgate, Jonathan Flor, Vincent Florence, Mary Flowerdew, Sharon Floyd, Margaret J Flynn, Rachel Flynn, Claire Foden, Adama Fofana, Georgina Fogarty, Paul Foley, Linda Folkes, Tracey Fong, Daniela M Font, Aiwyne Foo, Jane Foo, Andrew Foot, Helen R Foot, Jayne Foot, Jane Forbes, Amber Ford, Jamie Ford, Imogen Fordham, Jennifer Foreman, Matthew Forester, Mohammad Forkan, Caroline Fornolles, Adam Forrest, Ellie Forsey, Miranda Forsey, Thomas Forshall, Elliot Forster, Abigail Forsyth, Julian Forton, Conrad Foster, Emily Foster, Joseph Foster, Rachel A Foster, Tracy Foster, Angela Foulds, Ian Foulds, Folakemi Fowe, Natasha Fowkes, Emily Fowler, Robert Fowler, Stephen Fowler, Amy Fox, Claire Fox, Heather Fox, Jonathan Fox, Laura Fox, Lauren Fox, Natalie Fox, Olivia Fox, Simon Fox, Sarah-Jane Foxton, Eva Fraile, Rebecca Frake, Alex Francioni, Olesya Francis, Rebecca Francis, Sarah Francis, Theodora Francis-Bacon, Helen Frankland, Jessica Franklin, Siobhan Franklin, Catherine Fraser, Andi Fratila, Sharon Frayling, Martyn Fredlund, Anna Freeman, Carol Freeman, Elaine Freeman, Hannah Freeman, Nicola Freeman, Clare Freer, Eleanor French, Thomas French, Karen Freshwater, Matthew Frise, Renate Fromson, Adam Frosh, John Frost, Victoria Frost, Oliver Froud, Rachel Frowd, Arun Fryatt, Andrzej Frygier, Bridget Fuller, Liz Fuller, Lucy Fuller, Tracy Fuller, Duncan Fullerton, Carrie Fung, Gayle Fung, Sarah Funnell, John Furness, Andrew Fyfe, Nytianandan G, Elizabeth Gabbitas, Claire Gabriel, Zoë Gabriel, Hadiza Gachi, Sophie Gaffarena, Sarah Gage, Joshua Gahir, Sarveen Gajebasia, Katarzyna Gajewska-Knapik, Babita Gajmer, Zacharoula Galani, Christopher Gale, Hugo Gale, Linda Gale, Rebecca Gale, Swetha Gali, Bernadette Gallagher, Jude Gallagher, Rosie Gallagher, William Gallagher, Feroze Gallam, Joanne Galliford, Catherine Galloway, Chris Galloway, Emma Galloway, Jacqui Galloway, James Galloway, Anna Galvin, Victoria Galvis, Gareth Gamble, Laura Gamble, Liz Gamble, Brian Gammon, Chien N Gan, Muhammad B Ganaie, Jaikumar Ganapathi, Ramesh Ganapathy, Kaminiben Gandhi, Sarah Gandhi, Usha Ganesh, Thenugan Ganeshanathan, Saibal Ganguly, Abrar Gani, Pauline Ganley, Ukraina Garcia, Emma-James Garden, Antoni D Gardener, Emma Gardiner, Michael Gardiner, Phil Gardiner, Siobhan Gardiner, Caroline Gardiner-Hill, Jonathan Gardner, Louis Gardner, Mark Garfield, Atul Garg, Isha Garg, Nathan Garlick, Daniel Garner, Justin Garner, Lucie Garner, Zoe Garner, Rosaline Garr, Kathryn A Garrero, Manisha Gartaula, Florence Garty, Rachel Gascoyne, Hyeriju Gashau, Aoife Gatenby, Erin Gaughan, Alok Gaurav, Mariana Gavrila, Jane Gaylard, Sophie Gayle, Catherine Geddie, Ian Gedge, Sarah Gee, Fartuun Geele, Kalaichelvi Geerthan, Minnie Gellamucho, Karzan Gelly, Leila Gelmon, Sandra Gelves-Zapata, Gemma Genato, Neal Gent, Susan Gent, Natalie Geoghegan, Aparna George, Bini George, Sam George, Susan George, Tina George, Valerie P George, Simon Georges, Domonique Georgiou, Peter Gerard, Leigh Gerdes, Louise Germain, Helen Gerrish, Abel Getachew, Louise Gethin, Siobhan Gettings, Hisham Ghanayem, Bijan Ghavami Kia, Shaista Ghazal, Anca Gherman, Alison Ghosh, Dipansu Ghosh, Justin Ghosh, Subhamay Ghosh, Sarra Giannopoulou, Malick Gibani, Chris Gibb, Ben Gibbison, Kerry Gibbons, Alex Gibson, Bethan Gibson, Jamie Gibson, Kimberley Gibson, Kirsty Gibson, Sian Gibson, Mary Gigi, Cat Gilbert, Jeanette Gilbert, Kayleigh Gilbert, Benjamin Giles, James Gilham, Mandy Gill, Lynne Gill, Paul Gillen, Annelies Gillesen, Katherine Gillespie, Elizabeth Gillham, Andrew Gillian, Deborah Gilliland, Robert Gillott, Danielle Gilmour, Kate Gilmour, Lesley Gilmour, Louis Ginn, Franciscus Ginting, Theodora Giokanini-Royal, Anna Gipson, Barbie Giri, Joanna Girling, Rhian Gisby, Angelena Gkioni, Aikaterini Gkoritsa, Effrossyni Gkrania-Klotsas, Amy Gladwell, James Glanville, Jessica Glasgow, Susannah Glasgow, Jon Glass, Lynn Glass, Sharon Glaysher, Lisa Gledhill, Eleanor Glenday, Ana Glennon, Jodie Glossop, John Glover, Kyle Glover, Michelle Glover, Jan Glover Bengtsson, Deborah Glowski, Sharon Glynn, Chevanthy Gnanalingam, Julie Goddard, Wendy Goddard, Emily Godden, Jo Godden, Sarah Godlee, Emma Godson, Gillian Godwin, Sukanya Gogoi, Aiky Goh, Manjinder Gohel, Rebeca Goiriz, Sriya Gokaraju, Raphael Goldacre, Arthur Goldsmith, Portia Goldsmith, Darren Gomersall, Lucia Gomez, Raquel Gomez-Marcos, Ali Gondal, Celia Gonzalez, Jack Goodall, Vicky Goodall, Bob Goodenough, Anna Goodfellow, Laura Goodfellow, James Goodlife, Camelia Goodwin, Elizabeth Goodwin, Jayne Goodwin, Paula Goodyear, Rajiv Gooentilleke, Michelle Goonasekara, Sheila Gooseman, Shameer Gopal, Chris Gordon, Sally Gordon, Robin 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Hale, Jennie Hale, Carmel Halevy, Paul Halford, William Halford, Alaina Halim, Alistair Hall, Anthony Hall, Claire Hall, Elizabeth Hall, Fiona Hall, Helen Hall, Jennifer Hall, Kathryn Hall, Laura Hall, Jan Hallas, Kyle Hallas, Charles Hallett, Jackie Halliday, Akmal Hallman, Heather Halls, Maryam Hamdollah-Zadeh, Ifedadepo A Hamed-Adekale, Bilal Hameed, Mohammed Hameed, Raph L Hamers, Imran Hamid, Mohamad Hamie, Raymond Hamill, Bethany Hamilton, Fergus Hamilton, Gus Hamilton, Leigh Hamilton, Melanie Hamilton, Nicola Hamilton, Sara Hamilton, Ruth Hamlin, Eleanor Hamlyn, Beatrice Hammans, Shirley Hammersley, Kate Hammerton, Bev Hammond, Emily Hammond, Leah Hammond, Sally Hammond, Fiona Hammonds, Ibrahim Hamoodi, Karen Hampshire, James A Hampson, Jude Hampson, Lucy Hampson, Lisa Hamzah, Jenny Han, Ozan Hanci, Sadiyah Hand, Lala Handayani, Jasmine Handford, Soran Handrean, Nina K Handzewniak, Sarah Haney, Vu Thi Kim Hang, Sheharyar Hanif, E Hanison, Esther Hanison, Jennifer Hannah, Amy Hannington, Merhej Hannun, Aidan Hanrath, Helena Hanratty, Daniel Hansen, Anita Hanson, Ashley Hanson, Helen Hanson, Jane Hanson, Kathryn Hanson, Steve Hanson, Ala Haqiqi, Monjurul Haque, Henry Harcourt, Lesley Harden, Zoe Harding, Simon Hardman, Marc Hardwick, Gareth Hardy, Joanna Hardy, Yasmine Hardy, Kumar Haresh, Rachel Harford, Beverley Hargadon, James Hargraves, Carolyn Hargreaves, Alice Harin, Mohammed Haris, Edward Harlock, Paula Harman, Tracy Harman, Mark Harmer, Muhammad A Haroon, Charlie Harper, Heather Harper, James Harper, Peter Harper, Rosemary Harper, Sarah Harrhy, Kate Harrington, Sian Harrington, Yasmin Harrington-Davies, Jade Harris, Jess Harris, John Harris, Laura Harris, Marie-Clare Harris, Nichola Harris, Sophie Harris, David Harrison, Laura Harrison, Melanie Harrison, Olakunbi A Harrison, Rachael Harrison, Rowan Harrison, Susie Harrison, Thomas Harrison, Wendy Harrison, Elizabeth Harrod, Ciaran Hart, Dominic Hart, Jessica Hartley, Lisa Hartley, Rosemary Hartley, Ruth Hartley, Tom Hartley, William Hartrey, Phillipa Hartridge, Stuart Hartshorn, Alice Harvey, Angela Harvey, Anna Harvey, Max Harvey, Catherine Harwood, Helen Harwood, Zoe Harzeli, Brigitte Haselden, Kazi Hashem, Mohammed Hashimm, Tadaaki Hashimoto, Imranullah Hashmi, Jack Haslam, Zena Haslam, Grace Hasnip, Adil Hassan, Ali Hassan, Amro Hassan, Awab Hassan, Zeinab Hassan, Sapna Hassasing, Jane Hassell, Philip Hassell, Alex Hastings, Bethany Hastings, Janice Hastings, Sarah Hathaway-Lees, Jonathan Hatton, Jennifer Hau, May Havinden-Williams, Stefan Havlik, Daniel B Hawcutt, Kadean Hawes, Liz Hawes, Nicola Hawes, Lydia Hawker, Annie Hawkins, Joe Hawkins, Nancy Hawkins, W John Hawkins, Dan Hawley, Ed Hawley-Jones, Edward Haworth, Alasdair W Hay, Cathy Hay, Amna Hayat, Jamal Hayat, Mohamed-Riyal Hayathu, Anne Hayes, Jonas Hayes, Kate Hayes, Melony Hayes, Fiona Hayes, Patrick Hayle, Chloe Haylett, Antara Hayman, Melanie Hayman, Matthew Haynes, Richard Haynes, Rachel Hayre, Carole Hays, Sarah Haysom, James Hayward, Patrick Haywood, Hazel Haywood Hasford, Tracy Hazelton, Phoebe Hazenberg, Zhengmai He, Elizabeth Headon, Carrie Heal, Brendan Healy, Jessica L Healy, Amy Hearn, David Heasman, Angela Heath, Debbie Heath, Rowan Heath, Diane Heaton, Adam Heavens, Kerry Hebbron, Catherine Heckman, Gemma Hector, Sadie Heddon, Andy Hedges, Katrine Hedges, Cheryl Heeley, Elaine Heeney, Richard Heinink, Rajdeep Heire, Ingvild Helgesen, Joanne Hemingway, Ulla Hemmila, Beth Hemmings, Scott Hemphill, Deborah Hemsley, Abigail Henderson, Eilidh Henderson, Jennifer Henderson, Steven Henderson, Joanne Henry, Karol Henry, Lavinia Henry, Margo Henry, Natalie Henry, David Henshall, Gillian Herdman, Rosaleen Herdman-Grant, Morag Herkes, Lucas E Hermans, Fe Marie Hernandez, Emma Heron, Lisa Heron, William Herrington, Emilia Heselden, Peta Heslop, Tracey Heslop, Simon Hester, Emily Hetherington, Joseph Hetherington, Chamila Hettiarachchi, Pramodh Hettiarachchi, Hayley Hewer, John Hewertson, Anna Hewetson, Sue Hewins, Nicola Hewitson, Claire Hewitt, Davina Hewitt, Richard Hewitt, Samuel Hey, Robert S Heyderman, Mathis Heydtmann, Joseph Heys, Jonathan Heywood, Meg Hibbert, John Hickey, Naomi Hickey, Peter Hickey, Nicky Hickman, Alex Hicks, Jenny Hicks, Scott R Hicks, Phan Thi Thu Hien, Daniel Higbee, Lucy Higgins, Andrew Higham, Martin Highcock, Judith Highgate, Mondy Hikmat, Amanda Hill, Helen Hill, Joanne Hill, Lisa Hill, Lucy Hill, Phoebe Hill, Uta Hill, Annette Hilldrith, Catherine Hillman-Cooper, Jon Hilton, Zoe Hilton, Sarah Hinch, Andrew Hindle, Esther Hindley, Alice Hindmarsh, Paul Hine, Kim Hinshaw, Clare Hird, Claire Hirst, Lindsay Hirst, Jemma Hives, Htet M Hlaing, Benson Ho, David K K Ho, Rosemary Ho, Michaela Hoare, David Hobden, Gill Hobden, Maria Hobrok, Simon Hobson, Christopher Hodge, Simon Hodge, Lesley Hodgen, George Hodgetts, Holly Hodgkins, Sally Hodgkinson, David Hodgson, Helen Hodgson, Luke Hodgson, Sheila Hodgson, Gemma Hodkinson, Kenneth Hodson, Mike Hodson, Alison Hogan, Matthew Hogben, Lucy Hogg, Lee Hoggett, Abigail Holborow, Catherine Holbrook, Rebecca Holbrook, Catherine Holden, Jill Holden, Melinda Holden, Sophie Holden, Thomas Holder, Niels Holdhof, Hannah Holdsworth, Lisa Holland, Maureen Holland, Nicky Holland, Poppy Holland, Susan Holland, Marie L Hollands, Elizabeth Holliday, Kyra Holliday, Mark Holliday, Nina Holling, Laszlo Hollos, Nora Hollos, Leah Holloway, Simon Holloway, Max Hollowday, Marcus Hollyer, Amy Holman, Ann Holmes, Megan Holmes, Raphael Holmes, Rebecca Holmes, Kelly Holroyd, Beth Holroyd-Hind, Lyndsey Holt, Siobhan Holt, Susie Holt, Alexandra Holyome, Marie Home, Renate Homewood, Kate Hong, Louise Hoole, Clare Hooper, Samantha Hope, Susan Hope, Bridget Hopkins, Peter W Horby, Stephanie Horler, Anil Hormis, Daniel Hornan, Nicola Hornby, Thomas Horne, Zoey Horne, Rebecca Horner, Caroline Horrobin, Latoya Horsford, Megan Horsford, Mark Horsford, Valana Horsham, Alexander Horsley, Ashley Horsley, Elizabeth Horsley, Sarah Horton, Jane Hosea, Toby Hoskins, Muhammad S Hossain, Rashed Hossain, Maxine Hough, Sarah Hough, Catherine Houghton, Kathryn Houghton, Rebecca Houlihan, Kay Housely, Hamish Houston, Roseanna Hovvels, Lee How, Laura Howaniec, Joanne Howard, Kate Howard, Laura Howard, Linda Howard, Lucy Howard, Megan Howard, Sarah Howard, Stuart Howard, Richard Howard-Griffin, Louise Howard-Sandy, Serena Howe, Alice Howell, Mark Howells, Lyn Howie, Kerry Howlett, Sophie Howlett, Ruth Howman, Josh Hrycaiczuk, Hein Htet, Naing Z Htoon, Su Htwe, Ying Hu, Chiang O H Huah, Sylvia Huang, Kelly Hubbard, Abby Huckle, Shahzya Huda, Alison Hudak, Lisa Hudig, Heather Hudson, Suzanne Hudson, Oli Hudson, Alison Hufton, Connor Huggins, Alistair Hughes, Caitlin Hughes, Emma Hughes, Gareth Hughes, Heather Hughes, Luke Hughes, Martin Hughes, Rachel Hughes, Rebecca Hughes, Samantha Hughes, Stephen Hughes, Vikki Hughes, Wesley Hughes, Lukas Huhn, Ching Hui, Ruth Hulbert, Diana Hull, Grace Hull, Robert Hull, Amanda Hulme, Peter Hulme, Wendy Hulse, George Hulston, Ryan Hum, Megan Hume, Charlotte Humphrey, Alasdair Humphries, Amy Humphries, Joanne Humphries, Charlotte Hunt, Fiona Hunt, Jane Hunt, Jonquil Hunt, Kristen Hunt, Luke Hunt, Molly Hunt, Sophie Hunt, Alexandra Hunter, Catherine Hunter, Ewan Hunter, Karl Hunter, Neil Hunter, Ross Hunter, Sophie Hunter, George Huntington, Fuad Huq, Elizabeth Hurditch, Judith Hurdman, Cian Hurley, Katrina Hurley, Mohammed A Husain, Syeda Y Husaini, Coralie Huson, Afreen Hussain, Chreif Hussain, Ibraar Hussain, Ifza Hussain, Mohammad Hussain, Mohammed Hussain, Muhammad Hussain, Reda Hussain, Rizwana Hussain, Samia Hussain, Sanniah Hussain, Yasmin Hussain, Mohammed Hussam El-Din, Samahir F E M Hussein, Ziad Hussein, Rebecca Hussey, Adiel Haqiq Hussien, Anja Hutchinson, Camille Hutchinson, Dorothy Hutchinson, Elizabeth Hutchinson, John Hutchinson, Claire Hutsby, Paula Hutton, Nguyen Quang Huy, Thuong Huyen, Tran Bang Huyen, Nguyen Thi Huyen 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Jennings, Jacqui Jennings, Louise Jennings, Virginia Jennings, Ellen Jerome, Douglas Jerry, Greame Jervis, Ellen Jessup-Dunton, Jorge A Jesus Silva, Champa Jetha, Kishan Jethwa, Roshan Kumar Jha, Shaman Jhanji, Khoo Jian, Zhixin Jiao, Laura Jimenez, Ana Jimenez Gil, Jithin Jith, Teishel Joefield, Navraj Johal, Simran Johal, Karine Johannessen, Aisyah Johari, Annie John, Anu John, Maya John, Navin John, Emma Johns, Margaret Johns, Antoinette Johnson, Emma Johnson, Gillian Johnson, Kathryn Johnson, Katie Johnson, Luke Johnson, Mark Johnson, Nelsonseelan Johnson, Oliver Johnson, Rachel Johnson, Brogan Johnston, Claire Johnston, Janet Johnston, Susan Johnston, Victoria Johnston, Dawn Johnstone, Ed Johnstone, Janet Johnstone, Manohar Joishy, Adam Jones, Alistair Jones, Amy Jones, Angela Jones, Annabel Jones, Ben Jones, Bryony Jones, Carys Jones, Ceri Jones, Charlotte Jones, Christine E Jones, Debra Jones, Emily Jones, Gareth Jones, Geraldine Jones, Jac Jones, James Jones, Jonathon Jones, Julie Jones, Kate E Jones, Kimberly Jones, Laura Jones, Laura M Jones, Louise Jones, Mathew Jones, Nancy Jones, Nicola Jones, Olivia Jones, Paul Jones, Philip H Jones, Rhianna Jones, Ruth E Jones, Samantha Jones, Sophie Jones, Stefanie Jones, Steve Jones, Susan Jones, Taya Jones, Thomas Jones, Tim Jones, Tracey Jones, Ramya Jonnalagadda, Rebecca Jordache, Michele Jordan, Sarah Jordan, Abi Jose, Litty Jose, Louise Jose, Sanal Jose, Anna Joseph, Gigee Joseph, P Aiden Joseph, Rosane Joseph, Sibet Joseph, Dhaara Joshi, Mehul Joshi, Pratichi Joshi, Tushar Joshi, Benz Josiah, Lijo Joy, Tiffany Joyce, Hong Ju, Adriel Ju Wen Kwek, Andrew Judd, Edward Jude, Parminder Judge, Jessica Juhl, Sirisha Jujjavarapu, Mark Juniper, Edmund Juszczak, Deepthi Jyothish, Kasamu Kabiru Dawa, Mark Kacar, Nikhil Kadam, Nicole Kader, Ajai Kailey, Matthew Kain, Gail Kakoullis, Azad Kala Bhushan, Richard J K Kalayi, Roobala Kaliannan Periyasami, Efthymia Kallistrou, Thomas Kalmus Eliasz, Seika Kalsoom, Elisa Kam, 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Laybourne, Christine Laycock, Reina Layug, Maria Lazo, Thi Thao Le, Vietland Le, Amelia Lea, William Lea, Louisa E Leach, Ian Leadbitter, Thomas Leahy, Richard Lean, Lorna Leandro, Darren Leaning, Ruth Leary, Sandra Leason, Marie A Ledingham, Caroline Lee, Emma Lee, Hannah Lee, Irish Lee, Joshua Lee, Judith Lee, Sam Lee, Shannon Lee, Shi Han Lee, Simon Lee, Sindy Lee, Stephanie Lee, Tracey Lee, Xiang Lee, Robyn Lee, Diana Lees, Jennifer Lees, Helen Legge, Julian Leggett, Katie Leigh-Ellis, David Leitch, Nicky Leitch, Eleni Lekoudis, Petula Lemessy, Nicholas Lemoine, Rebecca Lenagh, Katy Leng, Katrina Lennon, Liz Lennon, Beth Leonard, Kelly Leonard, Wen Leong, Nicky Leopold, Oskar Lepiarczyk, Isla Leslie, Eva Noviani Lestari, Eleni Lester, Emma Levell, Chris Levett, Anastasia Levynska, Alice Lewin, Alison Lewis, Christopher Lewis, David Lewis, Dee Lewis, Heather Lewis, Joanne Lewis, Joseph Lewis, Kathryn Lewis, Keir Lewis, Leon Lewis, Mandy Lewis, Marissa Lewis, Nicolas Lewis, Robert 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Infection and Global Health Division, University of St Andrews. School of Medicine, and Group, RECOVERY Collaborative

Subjects
Adult, Male, Hypoxia/etiology, SARS-CoV-2, COVID-19, 3rd-DAS, General Medicine, Adrenal Cortex Hormones/therapeutic use, AC, Dexamethasone/therapeutic use, Hospitals, Oxygen, Treatment Outcome, SDG 3 - Good Health and Well-being, MCP, Humans, Female
Abstract

Background Low-dose corticosteroids have been shown to reduce mortality for patients with COVID-19 requiring oxygen or ventilatory support (non-invasive mechanical ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation). We evaluated the use of a higher dose of corticosteroids in this patient group. Methods This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing multiple possible treatments in patients hospitalised for COVID-19. Eligible and consenting adult patients with clinical evidence of hypoxia (ie, receiving oxygen or with oxygen saturation Findings Between May 25, 2021, and May 13, 2022, 1272 patients with COVID-19 and hypoxia receiving no oxygen (eight [1%]) or simple oxygen only (1264 [99%]) were randomly allocated to receive usual care plus higher dose corticosteroids (659 patients) versus usual care alone (613 patients, of whom 87% received low-dose corticosteroids during the follow-up period). Of those randomly assigned, 745 (59%) were in Asia, 512 (40%) in the UK, and 15 (1%) in Africa. 248 (19%) had diabetes and 769 (60%) were male. Overall, 123 (19%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio 1·59 [95% CI 1·20–2·10]; p=0·0012). There was also an excess of pneumonia reported to be due to non-COVID infection (64 cases [10%] vs 37 cases [6%]; absolute difference 3·7% [95% CI 0·7–6·6]) and an increase in hyperglycaemia requiring increased insulin dose (142 [22%] vs 87 [14%]; absolute difference 7·4% [95% CI 3·2–11·5]). Interpretation In patients hospitalised for COVID-19 with clinical hypoxia who required either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared with usual care, which included low-dose corticosteroids. The RECOVERY trial continues to assess the effects of higher dose corticosteroids in patients hospitalised with COVID-19 who require non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation. Funding UK Research and Innovation (Medical Research Council), National Institute of Health and Care Research, and Wellcome Trust.

Published
2023
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46. Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS

Author

Sun, Shuying, Sun, Ying, Ling, Shuo-Chien, Ferraiuolo, Laura, McAlonis-Downes, Melissa, Zou, Yiyang, Drenner, Kevin, Wang, Yin, Ditsworth, Dara, Tokunaga, Seiya, Kopelevich, Alex, Kaspar, Brian K, Lagier-Tourenne, Clotilde, and Cleveland, Don W

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Digestive Diseases, Rare Diseases, Neurodegenerative, Brain Disorders, ALS, Genetics, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Gene Expression Profiling, Humans, Mice, Motor Neurons, Mutation, Neuroglia, Protein Biosynthesis, Superoxide Dismutase, Superoxide Dismutase-1, SOD1, cell type selective toxicity, bacTRAP, RNA profiling
Abstract

Ubiquitous expression of amyotrophic lateral sclerosis (ALS)-causing mutations in superoxide dismutase 1 (SOD1) provokes noncell autonomous paralytic disease. By combining ribosome affinity purification and high-throughput sequencing, a cascade of mutant SOD1-dependent, cell type-specific changes are now identified. Initial mutant-dependent damage is restricted to motor neurons and includes synapse and metabolic abnormalities, endoplasmic reticulum (ER) stress, and selective activation of the PRKR-like ER kinase (PERK) arm of the unfolded protein response. PERK activation correlates with what we identify as a naturally low level of ER chaperones in motor neurons. Early changes in astrocytes occur in genes that are involved in inflammation and metabolism and are targets of the peroxisome proliferator-activated receptor and liver X receptor transcription factors. Dysregulation of myelination and lipid signaling pathways and activation of ETS transcription factors occur in oligodendrocytes only after disease initiation. Thus, pathogenesis involves a temporal cascade of cell type-selective damage initiating in motor neurons, with subsequent damage within glia driving disease propagation.

Published
2015

47. Calcipotriol Targets LRP6 to Inhibit Wnt Signaling in Pancreatic Cancer

Author

Arensman, Michael D, Nguyen, Phillip, Kershaw, Kathleen M, Lay, Anna R, Ostertag-Hill, Claire A, Sherman, Mara H, Downes, Michael, Liddle, Christopher, Evans, Ronald M, and Dawson, David W

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Cancer, Rare Diseases, Digestive Diseases, Colo-Rectal Cancer, Pancreatic Cancer, Nutrition, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Aetiology, 2.1 Biological and endogenous factors, Adaptor Proteins, Signal Transducing, Antineoplastic Agents, Calcitriol, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Cell Proliferation, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Molecular Targeted Therapy, Wnt Signaling Pathway, Oncology and Carcinogenesis, Developmental Biology, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledPancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy in need of more effective treatment approaches. One potential therapeutic target is Wnt/β-catenin signaling, which plays important roles in PDAC tumor initiation and progression. Among Wnt inhibitors with suitable in vivo biologic activity is vitamin D, which is known to antagonize Wnt/β-catenin signaling in colorectal cancer and have antitumor activity in PDAC. For this study, the relationship between vitamin D signaling, Wnt/β-catenin activity, and tumor cell growth in PDAC was investigated through the use of calcipotriol, a potent non-hypercalcemic vitamin D analogue. PDAC tumor cell growth inhibition by calcipotriol was positively correlated with vitamin D receptor expression and Wnt/β-catenin activity. Furthermore, vitamin D and Wnt signaling activity were found to be reciprocally linked through feedback regulation. Calcipotriol inhibited autocrine Wnt/β-catenin signaling in PDAC cell lines in parallel with decreased protein levels of the low-density lipoprotein receptor-related protein 6 (LRP6), a requisite coreceptor for ligand-dependent canonical Wnt signaling. Decrease in LRP6 protein seen with calcipotriol was mediated through a novel mechanism involving transcriptional upregulation of low-density lipoprotein receptor adaptor protein 1 (LDLRAP1). Finally, changes in LRP6 or LDLRAP1 expression directly altered Wnt reporter activity, supporting their roles as regulators of ligand-dependent Wnt/β-catenin signaling.ImplicationsThis study provides a novel biochemical target through which vitamin D signaling exerts inhibitory effects on Wnt/β-catenin signaling, as well as potential biomarkers for predicting and following tumor response to vitamin D-based therapy.

Published
2015

48. Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder.

Author

Abrams, Alexander J, Hufnagel, Robert B, Rebelo, Adriana, Zanna, Claudia, Patel, Neville, Gonzalez, Michael A, Campeanu, Ion J, Griffin, Laurie B, Groenewald, Saskia, Strickland, Alleene V, Tao, Feifei, Speziani, Fiorella, Abreu, Lisa, Schüle, Rebecca, Caporali, Leonardo, La Morgia, Chiara, Maresca, Alessandra, Liguori, Rocco, Lodi, Raffaele, Ahmed, Zubair M, Sund, Kristen L, Wang, Xinjian, Krueger, Laura A, Peng, Yanyan, Prada, Carlos E, Prows, Cynthia A, Schorry, Elizabeth K, Antonellis, Anthony, Zimmerman, Holly H, Abdul-Rahman, Omar A, Yang, Yaping, Downes, Susan M, Prince, Jeffery, Fontanesi, Flavia, Barrientos, Antonio, Németh, Andrea H, Carelli, Valerio, Huang, Taosheng, Zuchner, Stephan, and Dallman, Julia E

Subjects
COS Cells, Embryo, Nonmammalian, Animals, Animals, Genetically Modified, Zebrafish, Humans, Optic Atrophy, Autosomal Dominant, Charcot-Marie-Tooth Disease, Genetic Predisposition to Disease, Phosphate Transport Proteins, Muscle Proteins, Saccharomyces cerevisiae Proteins, Membrane Proteins, Mitochondrial Proteins, Microscopy, Confocal, Microscopy, Electron, Transmission, Pedigree, Sequence Analysis, DNA, RNA Interference, Protein Binding, Mutation, Female, Male, Mitochondrial Membranes, HEK293 Cells, Exome, Chlorocebus aethiops, Brain Disorders, Genetics, Neurosciences, Rare Diseases, Eye Disease and Disorders of Vision, Neurological, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

Published
2015

49. Macrophage Migration Inhibitory Factor as a Chaperone Inhibiting Accumulation of Misfolded SOD1

Author

Israelson, Adrian, Ditsworth, Dara, Sun, Shuying, Song, SungWon, Liang, Jason, Hruska-Plochan, Marian, McAlonis-Downes, Melissa, Abu-Hamad, Salah, Zoltsman, Guy, Shani, Tom, Maldonado, Marcus, Bui, Anh, Navarro, Michael, Zhou, Huilin, Marsala, Martin, Kaspar, Brian K, Da Cruz, Sandrine, and Cleveland, Don W

Subjects
Biomedical and Clinical Sciences, Neurosciences, Neurodegenerative, Rare Diseases, ALS, Brain Disorders, 2.1 Biological and endogenous factors, Aetiology, Neurological, Acid Phosphatase, Animals, Cell Differentiation, Cells, Cultured, Choline O-Acetyltransferase, Endoplasmic Reticulum, Green Fluorescent Proteins, Humans, Induced Pluripotent Stem Cells, Isoenzymes, Liver, Macrophage Migration-Inhibitory Factors, Mice, Mice, Transgenic, Mitochondria, Motor Neurons, Mutation, Nerve Tissue Proteins, Protein Folding, Protein Transport, Rats, Rats, Transgenic, Ribosomal Proteins, Spinal Cord, Superoxide Dismutase, Superoxide Dismutase-1, Tartrate-Resistant Acid Phosphatase, Psychology, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Mutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons and accompanied by accumulation of misfolded SOD1 onto the cytoplasmic faces of intracellular organelles, including mitochondria and the endoplasmic reticulum (ER). Using inhibition of misfolded SOD1 deposition onto mitochondria as an assay, a chaperone activity abundant in nonneuronal tissues is now purified and identified to be the multifunctional macrophage migration inhibitory factor (MIF), whose activities include an ATP-independent protein folding chaperone. Purified MIF is shown to directly inhibit mutant SOD1 misfolding. Elevating MIF in neuronal cells suppresses accumulation of misfolded SOD1 and its association with mitochondria and the ER and extends survival of mutant SOD1-expressing motor neurons. Accumulated MIF protein is identified to be low in motor neurons, implicating correspondingly low chaperone activity as a component of vulnerability to mutant SOD1 misfolding and supporting therapies to enhance intracellular MIF chaperone activity.

Published
2015

50. A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

Author

Reilly, Shannon M, Ahmadian, Maryam, Zamarron, Brian F, Chang, Louise, Uhm, Maeran, Poirier, BreAnne, Peng, Xiaoling, Krause, Danielle M, Korytnaya, Evgenia, Neidert, Adam, Liddle, Christopher, Yu, Ruth T, Lumeng, Carey N, Oral, Elif A, Downes, Michael, Evans, Ronald M, and Saltiel, Alan R

Subjects
Liver, 3T3-L1 Cells, Adipocytes, Animals, Mice, Inbred C57BL, Humans, Mice, Insulin Resistance, Inflammation, Aminopyridines, Glucose-6-Phosphatase, p38 Mitogen-Activated Protein Kinases, Receptors, Adrenergic, beta, Cyclic AMP, Interleukin-6, Signal Transduction, Gluconeogenesis, Adult, Aged, Middle Aged, Female, Male, Subcutaneous Fat, STAT3 Transcription Factor, Gene Knockdown Techniques, Young Adult, Inbred C57BL, Receptors, Adrenergic, beta
Abstract

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.

Published
2015

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