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Gurwith M.,Paxvax, Inc. | Lock M.,Paxvax, Inc. | Taylor E.M.,Paxvax, Inc. | Ishioka G.,Paxvax, Inc. | And 8 more authors.
The Lancet Infectious Diseases | Year: 2013

Background: Replication-competent virus vector vaccines might have advantages compared with non-replicating vector vaccines. We tested the safety and immunogenicity of an oral adenovirus serotype 4 vector vaccine candidate (Ad4-H5-Vtn) expressing the haemagglutinin from an avian influenza A H5N1 virus. Methods: We did this phase 1 study at four sites in the USA. We used a computer-generated randomisation list (block size eight, stratified by site) to assign healthy volunteers aged 18-40 years to receive one of five doses of Ad4-H5-Vtn (107 viral particles [VP], 108 VP, 109 VP, 1010 VP, 1011 VP) or placebo (3:1). Vaccine or placebo was given on three occasions, about 56 days apart. Participants, investigators, and study-site personnel were masked to assignment throughout the study. Subsequently, volunteers received a boost dose with 90 μg of an inactivated parenteral H5N1 vaccine. Primary immunogenicity endpoints were seroconversion by haemagglutination-inhibition (HAI), defined as a four-times rise compared with baseline titre, and HAI geometric mean titre (GMT). We solicited symptoms of reactogenicity daily for 7 days after each vaccination and recorded symptoms that persisted beyond 7 days as adverse events. Primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01006798. Findings: We enrolled 166 participants (125 vaccine; 41 placebo) between Oct 19, 2009, and Sept 9, 2010. HAI responses were low: 13 of 123 vaccinees (11%, 95% CI 6-17) and three of 41 placebo recipients (7%, 2-20) seroconverted. HAI GMT was 6 (95% CI 5-7) for vaccinees, and 5 (5-6) for placebo recipients. However, when inactivated H5N1 vaccine became available, one H5N1 boost was offered to all participants. In this substudy, HAI seroconversion occurred in 19 of 19 participants in the 1011 VP cohort (100%; 95% CI 82-100) and eight of 22 placebo recipients (36%; 17-59); 17 of 19 participants in the 1011 VP cohort (89%; 67-99) achieved seroprotection compared with four of 22 placebo recipients (18%; 5-40); GMT was 135 (89-205) with 1011 VP, compared with 13 (7-21) with placebo. The cumulative frequency of abdominal pain, diarrhoea, and nasal congestion after all three vaccinations was significantly higher in vaccinees than placebo recipients (21 [16·8%] of 125 vs one [2·4%] of 41, p=0·017; 24 [19·2%] of 125 vs two [4·9%] of 41, p=0·027; 41 [32·8%] of 125 vs six [14·6%] of 41, p=0·028; respectively). No serious treatment-related adverse events occurred. Interpretation: Oral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1. Funding: Wellcome Trust Foundation, PaxVax. © 2013 Elsevier Ltd.


Youm Y.-H.,Yale University | Nguyen K.Y.,Yale University | Grant R.W.,Purdue University | Goldberg E.L.,Yale University | And 13 more authors.
Nature Medicine | Year: 2015

The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K + efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome. © 2015 Nature America, Inc. All rights reserved.


Annett R.D.,University of Mississippi Medical Center | Patel S.K.,Beckman Research Institute | Phipps S.,St Jude Childrens Hospital
Pediatric Blood and Cancer | Year: 2015

Central nervous system cancers or exposure to CNS-directed therapies increase risk for neuropsychological deficits. There are no accepted guidelines for assessment of neuropsychological functioning in this population. A multifaceted literature search was conducted and relevant literature reviewed to inform the guidelines. Studies of neuropsychological outcomes are widely documented in the pediatric oncology literature. There is strong evidence of need for neuropsychological assessment, but insufficient evidence to guide the timing of assessment, nor to recommend specific interventions. Children with brain tumors and others at high risk for neuropsychological deficits should be monitored and assessed for neuropsychological deficits. Pediatr Blood Cancer 2015;9999:1-52. © 2015 Wiley Periodicals, Inc.


Barton S.E.,Harvard University | Najita J.S.,Dana-Farber Cancer Institute | Ginsburg E.S.,Harvard University | Leisenring W.M.,Fred Hutchinson Cancer Research Center | And 6 more authors.
The Lancet Oncology | Year: 2013

Background: Previous studies have shown decreased pregnancy rates and early menopause in female cancer survivors; however, infertility rates and reproductive interventions have not been studied. We investigated infertility and time to pregnancy in female childhood cancer survivors, and analysed treatment characteristics associated with infertility and subsequent pregnancy. Methods: The Childhood Cancer Survivor Study (CCSS) is a cohort study including 5 year cancer survivors from 26 Canadian and US institutions who were younger than 21 years at the time of diagnosis between Jan 1, 1970, and Dec 31, 1986, and a sibling control group. We included women aged 18-39 years who had ever been sexually active. We gathered demographic, medical, and reproductive data via a baseline questionnaire, and quantified exposure to alkylating agents and radiation therapy. Self-reported infertility, medical treatment for infertility, time to first pregnancy in survivors and siblings, and the risk of infertility in survivors by demographic, disease, and treatment variables were analysed. Findings: 3531 survivors and 1366 female sibling controls who enrolled between Nov 3, 1992, and April 4, 2004, were included. Compared with their siblings, survivors had an increased risk (relative risk [RR] 1·48 [95% CI 1·23-1·78]; p<0·0001) of clinical infertility (ie, >1 year of attempts at conception without success), which was most pronounced at early reproductive ages (RR 2·92 [95% CI 1·18-7·20], p=0·020, in participants ≤24 years; 1·61 [1·05-2·48], p=0·029, in those aged 25-29 years; and 1·37 [1·11-1·69], p=0·0035, in those aged 30-40 years). Despite being equally likely to seek treatment for infertility, survivors were less likely than were their siblings to be prescribed drugs for treatment of infertility (0·57 [95% CI 0·46-0·70], p<0·0001). Increasing doses of uterine radiation and alkylating agent chemotherapy were strongly associated with infertility. Although survivors had an increased time to pregnancy compared with their siblings (p=0·032), 292 (64%) of 455 participants with self-reported clinical infertility achieved a pregnancy. Interpretation: A more comprehensive understanding of infertility after cancer is crucial for counselling and decision making about future conception attempts and fertility preservation. Funding: National Cancer Institute, American Lebanese Syrian Associated Charities, Swim Across America. © 2013 Elsevier Ltd.


Kutteh W.H.,Vanderbilt University | Kutteh W.H.,St Jude Childrens Hospital
Seminars in Reproductive Medicine | Year: 2015

This article discusses the current trends in the diagnosis and treatment of recurrent pregnancy loss. Genetic testing of the miscarriage tissue by 23-chromosome microarray and the ability to identify maternal cell contamination have increased our awareness of the role of aneuploidy as a cause of recurrent pregnancy loss. This increasing influence and the role of genetic testing in developing a strategy for the evaluation of recurrent pregnancy loss are described and discussed. The most common questions that practicing physicians ask about recurrent pregnancy loss include how many losses are needed to make the diagnosis, what counts as a pregnancy loss, what constitutes a full workup, should we get karyotypes on the parents and the miscarriage, and what is the prognosis for a live birth? This review attempts to answer those questions based on current research and clinical experience to expand our current understanding of recurrent pregnancy loss. © 2015 by Thieme Medical Publishers, Inc.


O'Reilly M.C.,Vanderbilt University | Scott S.A.,Vanderbilt University | Brown K.A.,Vanderbilt University | Oguin T.H.,St Jude Childrens Hospital | And 5 more authors.
Journal of Medicinal Chemistry | Year: 2013

An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC50 > 20 000 nM, PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor, ML299 (PLD1 IC50 = 6 nM, PLD2 IC50 = 20 nM). SAR studies revealed that a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma cells. © 2013 American Chemical Society.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Research Grant | Award Amount: 1.09M | Year: 2011

In the proposed study we wish to test a new approach called gene therapy for the treatment of patients with haemophilia A. This inherited disorder in which life threatening bleeding occurs without trauma results from an absence or defect of a blood clotting protein called Factor FVIII (FVIII) that arises due to mutations in the FVIIIX gene. The goal of our gene therapy approach, therefore, is to treat the disease by transferring to the patient?s liver, a normal copy of the FVIII gene so that normal FVIII protein can be continuously produced by the patient?s own cells. To this end we have developed a novel vector based on adeno-associated virus (rAAV8-HLP-codop-hFVIII) which is highly efficient at transferring the normal FVIII gene to the liver, its natural site of synthesis. Importantly, AAV has the best safety profile among gene transfer vectors of viral origin. In murine models we have consistently achieved long-term expression of human FVIII at levels that would be sufficient to prevent spontaneous life threatening bleeding in haemophilia A patients following a single injection of rAAV8-HLP-codop-hFVIII. Prior to evaluating this new vector in patients with haemophilia A, we have to establish its safety and efficacy to the rigorous standards required by the regulators using high quality clinical grade vector as opposed to research grade vector. This application is therefore designed to generate sufficient quantities of clinical grade rAAV8-HLP-codop-hFVIII vector and then carefully and critically evaluate its safety and efficacy in a context relevant to humans. The results of this study will be used to support the initiation of a clinical trial in patients with severe haemophilia A. Success with our approach could significantly impact on a wide variety of life threatening genetic disorders including alpha-1 antitrypsin deficiency, lysosomal storage and urea cycle disorders.


Kim J.,University of California at San Diego | Kundu M.,St Jude Childrens Hospital | Viollet B.,University of Paris Descartes | Guan K.L.,University of California at San Diego
Nature Cell Biology | Year: 2011

Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling. © 2011 Macmillan Publishers Limited. All rights reserved.


Pelletier S.,St Jude Childrens Hospital | Gingras S.,St Jude Childrens Hospital | Green D.,St Jude Childrens Hospital
Immunity | Year: 2015

Clustered regularly interspaced palindromic repeats (CRISPR)-associated (Cas9) technology has proven a formidable addition to our armory of approaches for genomic editing. Derived from pathways in archaea and bacteria that mediate the resistance to exogenous genomic material, the CRISPR-Cas9 system utilizes a short single guide RNA (sgRNA) to direct the endonuclease Cas9 to virtually anywhere in the genome. Upontargeting, Cas9 generates DNA double-strand breaks (DSBs) and facilitates the repair or insertion of mutations, insertion of recombinase recognition sites, or large DNA elements. Here, we discuss the practical advantages of the CRISPR-Cas9 system over conventional and other nuclease-based targeting technologies and provide suggestions for the use of this technology to address immunological questions. CRISPR-Cas9 is a targetable nuclease technology that allows genomic manipulation in many species. Green and colleagues discuss the practical advantages of the CRISPR-Cas9 system over conventional and other nuclease-based targeting technologies and provide suggestions for the use of this technology to address immunological questions. © 2015 Elsevier Inc.


Tait S.W.G.,University of Glasgow | Green D.R.,St Jude Childrens Hospital
Cold Spring Harbor Perspectives in Biology | Year: 2013

Although required for life, paradoxically, mitochondria are often essential for initiating apoptotic cell death. Mitochondria regulate caspase activation and cell death through an event termed mitochondrial outer membrane permeabilization (MOMP); this leads to the release of various mitochondrial intermembrane space proteins that activate caspases, resulting in apoptosis.MOMPis often considered a point of no return because it typically leads to cell death, even in the absence of caspase activity. Because of this pivotal role in deciding cell fate, deregulation of MOMP impacts on many diseases and represents a fruitful site for therapeutic intervention. Here we discuss the mechanisms underlying mitochondrial permeabilization and how this key event leads to cell death through caspase-dependent and -independent means. We then proceed to explore how the release of mitochondrial proteins may be regulated following MOMP. Finally, we discuss mechanisms that enable cells sometimes to survive MOMP, allowing them, in essence, to return from the point of no return. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.

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