Hemphill L

References (5)

Title : Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome - Witztum_2019_N.Engl.J.Med_381_531
Author(s) : Witztum JL , Gaudet D , Freedman SD , Alexander VJ , Digenio A , Williams KR , Yang Q , Hughes SG , Geary RS , Arca M , Stroes ESG , Bergeron J , Soran H , Civeira F , Hemphill L , Tsimikas S , Blom DJ , O'Dea L , Bruckert E
Ref : N Engl J Med , 381 :531 , 2019
Abstract : BACKGROUND: Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels. METHODS: We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months. RESULTS: Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began. CONCLUSIONS: Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, NCT02211209.).
ESTHER : Witztum_2019_N.Engl.J.Med_381_531
PubMedSearch : Witztum_2019_N.Engl.J.Med_381_531
PubMedID: 31390500

Title : Subtle genetic changes enhance virulence of methicillin resistant and sensitive Staphylococcus aureus - Highlander_2007_BMC.Microbiol_7_99
Author(s) : Highlander SK , Hulten KG , Qin X , Jiang H , Yerrapragada S , Mason EO, Jr. , Shang Y , Williams TM , Fortunov RM , Liu Y , Igboeli O , Petrosino J , Tirumalai M , Uzman A , Fox GE , Cardenas AM , Muzny DM , Hemphill L , Ding Y , Dugan S , Blyth PR , Buhay CJ , Dinh HH , Hawes AC , Holder M , Kovar CL , Lee SL , Liu W , Nazareth LV , Wang Q , Zhou J , Kaplan SL , Weinstock GM
Ref : BMC Microbiol , 7 :99 , 2007
Abstract : BACKGROUND: Community acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) increasingly causes disease worldwide. USA300 has emerged as the predominant clone causing superficial and invasive infections in children and adults in the USA. Epidemiological studies suggest that USA300 is more virulent than other CA-MRSA. The genetic determinants that render virulence and dominance to USA300 remain unclear. RESULTS: We sequenced the genomes of two pediatric USA300 isolates: one CA-MRSA and one CA-methicillin susceptible (MSSA), isolated at Texas Children's Hospital in Houston. DNA sequencing was performed by Sanger dideoxy whole genome shotgun (WGS) and 454 Life Sciences pyrosequencing strategies. The sequence of the USA300 MRSA strain was rigorously annotated. In USA300-MRSA 2658 chromosomal open reading frames were predicted and 3.1 and 27 kilobase (kb) plasmids were identified. USA300-MSSA contained a 20 kb plasmid with some homology to the 27 kb plasmid found in USA300-MRSA. Two regions found in US300-MRSA were absent in USA300-MSSA. One of these carried the arginine deiminase operon that appears to have been acquired from S. epidermidis. The USA300 sequence was aligned with other sequenced S. aureus genomes and regions unique to USA300 MRSA were identified. CONCLUSION: USA300-MRSA is highly similar to other MRSA strains based on whole genome alignments and gene content, indicating that the differences in pathogenesis are due to subtle changes rather than to large-scale acquisition of virulence factor genes. The USA300 Houston isolate differs from another sequenced USA300 strain isolate, derived from a patient in San Francisco, in plasmid content and a number of sequence polymorphisms. Such differences will provide new insights into the evolution of pathogens.
ESTHER : Highlander_2007_BMC.Microbiol_7_99
PubMedSearch : Highlander_2007_BMC.Microbiol_7_99
PubMedID: 17986343
Gene_locus related to this paper: staa3-q2fkj0 , staau-LIP , staau-lipas , staau-MW0741 , staau-MW2456 , staau-q6gfm6 , staau-SA0011 , staau-SA0569 , staau-SA0572 , staau-SA0897 , staau-SA1143 , staau-SA2240 , staau-SA2306 , staau-SA2367 , staau-SA2422 , staau-SAV0321 , staau-SAV0446 , staau-SAV0457 , staau-SAV0655 , staau-SAV1014 , staau-SAV1765 , staau-SAV1793 , staau-SAV2188 , staau-SAV2350 , staau-SAV2594

Title : Chromosome rearrangement and diversification of Francisella tularensis revealed by the type B (OSU18) genome sequence - Petrosino_2006_J.Bacteriol_188_6977
Author(s) : Petrosino JF , Xiang Q , Karpathy SE , Jiang H , Yerrapragada S , Liu Y , Gioia J , Hemphill L , Gonzalez A , Raghavan TM , Uzman A , Fox GE , Highlander S , Reichard M , Morton RJ , Clinkenbeard KD , Weinstock GM
Ref : Journal of Bacteriology , 188 :6977 , 2006
Abstract : The gamma-proteobacterium Francisella tularensis is one of the most infectious human pathogens, and the highly virulent organism F. tularensis subsp. tularensis (type A) and less virulent organism F. tularensis subsp. holarctica (type B) are most commonly associated with significant disease in humans and animals. Here we report the complete genome sequence and annotation for a low-passage type B strain (OSU18) isolated from a dead beaver found near Red Rock, Okla., in 1978. A comparison of the F. tularensis subsp. holarctica sequence with that of F. tularensis subsp. tularensis strain Schu4 (P. Larsson et al., Nat. Genet. 37:153-159, 2005) highlighted genetic differences that may underlie different pathogenicity phenotypes and the evolutionary relationship between type A and type B strains. Despite extensive DNA sequence identity, the most significant difference between type A and type B isolates is the striking amount of genomic rearrangement that exists between the strains. All but two rearrangements can be attributed to homologous recombination occurring between two prominent insertion elements, ISFtu1 and ISFtu2. Numerous pseudogenes have been found in the genomes and are likely contributors to the difference in virulence between the strains. In contrast, no rearrangements have been observed between the OSU18 genome and the genome of the type B live vaccine strain (LVS), and only 448 polymorphisms have been found within non-transposase-coding sequences whose homologs are intact in OSU18. Nonconservative differences between the two strains likely include the LVS attenuating mutation(s).
ESTHER : Petrosino_2006_J.Bacteriol_188_6977
PubMedSearch : Petrosino_2006_J.Bacteriol_188_6977
PubMedID: 16980500
Gene_locus related to this paper: fratt-q5ng35 , fratt-q5nga8 , fratt-q5ngu5 , fratu-q7wvf7

Title : The genome sequence of Mannheimia haemolytica A1: insights into virulence, natural competence, and Pasteurellaceae phylogeny - Gioia_2006_J.Bacteriol_188_7257
Author(s) : Gioia J , Qin X , Jiang H , Clinkenbeard K , Lo R , Liu Y , Fox GE , Yerrapragada S , McLeod MP , McNeill TZ , Hemphill L , Sodergren E , Wang Q , Muzny DM , Homsi FJ , Weinstock GM , Highlander SK
Ref : Journal of Bacteriology , 188 :7257 , 2006
Abstract : The draft genome sequence of Mannheimia haemolytica A1, the causative agent of bovine respiratory disease complex (BRDC), is presented. Strain ATCC BAA-410, isolated from the lung of a calf with BRDC, was the DNA source. The annotated genome includes 2,839 coding sequences, 1,966 of which were assigned a function and 436 of which are unique to M. haemolytica. Through genome annotation many features of interest were identified, including bacteriophages and genes related to virulence, natural competence, and transcriptional regulation. In addition to previously described virulence factors, M. haemolytica encodes adhesins, including the filamentous hemagglutinin FhaB and two trimeric autotransporter adhesins. Two dual-function immunoglobulin-protease/adhesins are also present, as is a third immunoglobulin protease. Genes related to iron acquisition and drug resistance were identified and are likely important for survival in the host and virulence. Analysis of the genome indicates that M. haemolytica is naturally competent, as genes for natural competence and DNA uptake signal sequences (USS) are present. Comparison of competence loci and USS in other species in the family Pasteurellaceae indicates that M. haemolytica, Actinobacillus pleuropneumoniae, and Haemophilus ducreyi form a lineage distinct from other Pasteurellaceae. This observation was supported by a phylogenetic analysis using sequences of predicted housekeeping genes.
ESTHER : Gioia_2006_J.Bacteriol_188_7257
PubMedSearch : Gioia_2006_J.Bacteriol_188_7257
PubMedID: 17015664
Gene_locus related to this paper: pasha-a7jrr2 , pasha-a7js08 , pasha-a7jsd4 , pasha-a7jsj9 , pasha-a7ju47 , pasmu-q9cjt9

Title : The genome of the social amoeba Dictyostelium discoideum - Eichinger_2005_Nature_435_43
Author(s) : Eichinger L , Pachebat JA , Glockner G , Rajandream MA , Sucgang R , Berriman M , Song J , Olsen R , Szafranski K , Xu Q , Tunggal B , Kummerfeld S , Madera M , Konfortov BA , Rivero F , Bankier AT , Lehmann R , Hamlin N , Davies R , Gaudet P , Fey P , Pilcher K , Chen G , Saunders D , Sodergren E , Davis P , Kerhornou A , Nie X , Hall N , Anjard C , Hemphill L , Bason N , Farbrother P , Desany B , Just E , Morio T , Rost R , Churcher C , Cooper J , Haydock S , van Driessche N , Cronin A , Goodhead I , Muzny D , Mourier T , Pain A , Lu M , Harper D , Lindsay R , Hauser H , James K , Quiles M , Madan Babu M , Saito T , Buchrieser C , Wardroper A , Felder M , Thangavelu M , Johnson D , Knights A , Loulseged H , Mungall K , Oliver K , Price C , Quail MA , Urushihara H , Hernandez J , Rabbinowitsch E , Steffen D , Sanders M , Ma J , Kohara Y , Sharp S , Simmonds M , Spiegler S , Tivey A , Sugano S , White B , Walker D , Woodward J , Winckler T , Tanaka Y , Shaulsky G , Schleicher M , Weinstock G , Rosenthal A , Cox EC , Chisholm RL , Gibbs R , Loomis WF , Platzer M , Kay RR , Williams J , Dear PH , Noegel AA , Barrell B , Kuspa A
Ref : Nature , 435 :43 , 2005
Abstract : The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal-fungal lineage after the plant-animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.
ESTHER : Eichinger_2005_Nature_435_43
PubMedSearch : Eichinger_2005_Nature_435_43
PubMedID: 15875012
Gene_locus related to this paper: dicdi-abhd , dicdi-ACHE , dicdi-apra , dicdi-cinbp , dicdi-CMBL , dicdi-crysp , dicdi-DPOA , dicdi-P90528 , dicdi-ppme1 , dicdi-Q8MYE7 , dicdi-q54cf7 , dicdi-q54cl7 , dicdi-q54cm0 , dicdi-q54ct5 , dicdi-q54cu1 , dicdi-q54d54 , dicdi-q54d66 , dicdi-q54dj5 , dicdi-q54dy7 , dicdi-q54ek1 , dicdi-q54eq6 , dicdi-q54et1 , dicdi-q54et7 , dicdi-q54f01 , dicdi-q54g24 , dicdi-q54g47 , dicdi-q54gi7 , dicdi-q54gw5 , dicdi-q54gx3 , dicdi-q54h23 , dicdi-q54h73 , dicdi-q54i38 , dicdi-q54ie5 , dicdi-q54in4 , dicdi-q54kz1 , dicdi-q54l36 , dicdi-q54li1 , dicdi-q54m29 , dicdi-q54n21 , dicdi-q54n35 , dicdi-q54n85 , dicdi-q54qe7 , dicdi-q54qi3 , dicdi-q54qk2 , dicdi-q54rl3 , dicdi-q54rl8 , dicdi-q54sy6 , dicdi-q54sz3 , dicdi-q54t49 , dicdi-q54t91 , dicdi-q54th2 , dicdi-q54u01 , dicdi-q54vc2 , dicdi-q54vw1 , dicdi-q54xe3 , dicdi-q54xl3 , dicdi-q54xu1 , dicdi-q54xu2 , dicdi-q54y48 , dicdi-q54yd0 , dicdi-q54ye0 , dicdi-q54yl1 , dicdi-q54yr8 , dicdi-q54z90 , dicdi-q55bx3 , dicdi-q55d01 , dicdi-q55d81 , dicdi-q55du6 , dicdi-q55eu1 , dicdi-q55eu8 , dicdi-q55fk4 , dicdi-q55gk7 , dicdi-Q54ZA6 , dicdi-q86h82 , dicdi-Q86HC9 , dicdi-Q86HM5 , dicdi-Q86HM6 , dicdi-q86iz7 , dicdi-q86jb6 , dicdi-Q86KU7 , dicdi-q550s3 , dicdi-q552c0 , dicdi-q553t5 , dicdi-q555e5 , dicdi-q555h0 , dicdi-q555h1 , dicdi-q557k5 , dicdi-q558u2 , dicdi-Q869Q8 , dicdi-u554 , dicdi-y9086 , dicdi-q54r44 , dicdi-f172a