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Rosemary Greenhalgh - One of the best experts on this subject based on the ideXlab platform.
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razor a phase ii open randomized Trial of screening plus goserelin and raloxifene versus screening alone in premenopausal women aT increased risk of breasT cancer
Cancer Epidemiology Biomarkers & Prevention, 2018Co-Authors: Anthony Howell, Ra Eeles, Ar Brentnall, Jm Cuzick, Linda Ashcroft, Lesley Fallowfield, Diana Eccles, Ann Ward, M Dowsett, Rosemary GreenhalghAbstract:Background: Ovarian suppression in premenopausal women is known To reduce breasT cancer risk. This sTudy aimed To assess upTake and compliance wiTh ovarian suppression using The luTeinizing hormone releasing hormone (LHRH) analogue, goserelin, wiTh add-back raloxifene, as a poTenTial regimen for breasT cancer prevenTion.MeThods: Women aT ≥30% lifeTime risk breasT cancer were approached and randomized To mammographic screening alone (C-ConTrol) or screening in addiTion To monThly subcuTaneous injecTions of 3.6 mg goserelin and conTinuous 60 mg raloxifene daily orally (T-TreaTed) for 2 years. The primary endpoinT was Therapy adherence. Secondary endpoinTs were ToxiciTy/qualiTy of life, change in bone densiTy, and mammographic densiTy.ResulTs: A ToTal of 75/950 (7.9%) women approached agreed To randomizaTion. In The T-Arm, 20 of 38 (52%) of women compleTed The 2-year period of sTudy compared wiTh The C-Arm (27/37, 73.0%). DropouTs were relaTed To ToxiciTy buT also The wish To have esTablished risk-reducing procedures and proven chemoprevenTion. As relaTively few women compleTed The sTudy, daTa are limiTed, buT Those in The T-Arm reporTed significanT increases in ToxiciTy and sexual problems, no change in anxieTy, and less cancer worry. Lumbar spine bone densiTy declined by 7.0% and visually assessed mammographic densiTy by 4.7% over The 2-year TreaTmenT period.Conclusions: UpTake is somewhaT lower Than comparable sTudies wiTh Tamoxifen for prevenTion wiTh higher dropouT raTes. Raloxifene may preserve bone densiTy, buT reducTion in mammographic densiTy reversed afTer TreaTmenT was compleTed.ImpacT: This sTudy indicaTes ThaT breasT cancer risk reducTion may be possible using LHRH agonisTs, buT reducing ToxiciTy and prevenTing bone changes would make This a more aTTracTive opTion. Cancer Epidemiol Biomarkers Prev; 27(1); 58-66. ©2017 AACR.
Mario Mörl - One of the best experts on this subject based on the ideXlab platform.
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AdapTaTion of The Romanomermis culicivorax CCA-Adding Enzyme To MiniaTurized Armless TRNA SubsTraTes
International Journal of Molecular Sciences, 2020Co-Authors: Oliver Hennig, Susanne Philipp, Sonja Bonin, Kévin Rollet, Tim Kolberg, Tina Jühling, Heike Betat, Claude Sauter, Mario MörlAbstract:The miTochondrial genome of The nemaTode Romanomermis culicivorax encodes for miniaTurized hairpin-like TRNA molecules ThaT lack D- as well as T-Arms, sTrongly deviaTing from The consensus cloverleaf. The single TRNA nucleoTidylTransferase of This organism is fully acTive on Armless TRNAs, while The human counTerparT is noT able To add a compleTe CCA-end. TransplanTing single regions of The Romanomermis enzyme inTo The human counTerparT, we idenTified a beTa-Turn elemenT of The caTalyTic core ThaT—when inserTed inTo The human enzyme—confers full CCA-adding acTiviTy on Armless TRNAs. This region, originally idenTified To posiTion The 3′-end of The TRNA primer in The caTalyTic core, dramaTically increases The enzyme’s subsTraTe affiniTy. While convenTional TRNA subsTraTes bind To The enzyme by inTeracTions wiTh The T-Arm, This is noT possible in The case of Armless TRNAs, and The sTrong conTribuTion of The beTa-Turn compensaTes for an oTherwise Too weak inTeracTion required for The addiTion of a compleTe CCA-Terminus. This compensaTion demonsTraTes The remarkable evoluTionary plasTiciTy of The caTalyTic core elemenTs of This enzyme To adapT To unconvenTional TRNA subsTraTes
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Small buT large enough: sTrucTural properTies of Armless miTochondrial TRNAs from The nemaTode Romanomermis culicivorax.
Nucleic acids research, 2018Co-Authors: Tina Jühling, Sonja Bonin, Heike Betat, Claude Sauter, Elke Duchardt-ferner, Jens Wöhnert, Joern Pütz, Catherine Florentz, Mario MörlAbstract:As adapTer molecules To converT The nucleic acid informaTion inTo The amino acid sequence, TRNAs play a cenTral role in proTein synThesis. To fulfill This funcTion in a reliable way, TRNAs exhibiT highly conserved sTrucTural feaTures common in all organisms and in all cellular comparTmenTs acTive in TranslaTion. However, in miTochondria of meTazoans, cerTain dramaTic deviaTions from The consensus TRNA sTrucTure are described, where some TRNAs lack The D- or T-Arm wiThouT losing Their funcTion. In Enoplea, This miniaTurizaTion comes To an exTreme, and funcTional miTochondrial TRNAs can lack boTh Arms, leading To a considerable size reducTion. Here, we invesTigaTe The secondary and TerTiary sTrucTure of Two such Armless TRNAs from Romanomermis culicivorax. DespiTe Their high AU conTenT, The TranscripTs fold inTo a single and surprisingly sTable hairpin sTrucTure, deviaTing from sTandard TRNAs. The Three-dimensional form is boomerang-like and diverges from The sTandard L-shape. These resulTs indicaTe ThaT such unconvenTional miniaTurized TRNAs can sTill fold inTo a TRNA-like shape, alThough Their lengTh and secondary sTrucTure are very unusual. They highlighT The remarkable flexibiliTy of The proTein synThesis apparaTus and suggesT ThaT The TranslaTional machinery of Enoplea miTochondria may show compensaTory adapTaTions To accommodaTe These Armless TRNAs for efficienT TranslaTion.
Anthony Howell - One of the best experts on this subject based on the ideXlab platform.
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razor a phase ii open randomized Trial of screening plus goserelin and raloxifene versus screening alone in premenopausal women aT increased risk of breasT cancer
Cancer Epidemiology Biomarkers & Prevention, 2018Co-Authors: Anthony Howell, Ra Eeles, Ar Brentnall, Jm Cuzick, Linda Ashcroft, Lesley Fallowfield, Diana Eccles, Ann Ward, M Dowsett, Rosemary GreenhalghAbstract:Background: Ovarian suppression in premenopausal women is known To reduce breasT cancer risk. This sTudy aimed To assess upTake and compliance wiTh ovarian suppression using The luTeinizing hormone releasing hormone (LHRH) analogue, goserelin, wiTh add-back raloxifene, as a poTenTial regimen for breasT cancer prevenTion.MeThods: Women aT ≥30% lifeTime risk breasT cancer were approached and randomized To mammographic screening alone (C-ConTrol) or screening in addiTion To monThly subcuTaneous injecTions of 3.6 mg goserelin and conTinuous 60 mg raloxifene daily orally (T-TreaTed) for 2 years. The primary endpoinT was Therapy adherence. Secondary endpoinTs were ToxiciTy/qualiTy of life, change in bone densiTy, and mammographic densiTy.ResulTs: A ToTal of 75/950 (7.9%) women approached agreed To randomizaTion. In The T-Arm, 20 of 38 (52%) of women compleTed The 2-year period of sTudy compared wiTh The C-Arm (27/37, 73.0%). DropouTs were relaTed To ToxiciTy buT also The wish To have esTablished risk-reducing procedures and proven chemoprevenTion. As relaTively few women compleTed The sTudy, daTa are limiTed, buT Those in The T-Arm reporTed significanT increases in ToxiciTy and sexual problems, no change in anxieTy, and less cancer worry. Lumbar spine bone densiTy declined by 7.0% and visually assessed mammographic densiTy by 4.7% over The 2-year TreaTmenT period.Conclusions: UpTake is somewhaT lower Than comparable sTudies wiTh Tamoxifen for prevenTion wiTh higher dropouT raTes. Raloxifene may preserve bone densiTy, buT reducTion in mammographic densiTy reversed afTer TreaTmenT was compleTed.ImpacT: This sTudy indicaTes ThaT breasT cancer risk reducTion may be possible using LHRH agonisTs, buT reducing ToxiciTy and prevenTing bone changes would make This a more aTTracTive opTion. Cancer Epidemiol Biomarkers Prev; 27(1); 58-66. ©2017 AACR.
Vikas Kumar - One of the best experts on this subject based on the ideXlab platform.
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The compleTe miTochondrial genome of melon Thrips Thrips palmi Thripinae comparaTive analysis
PLOS ONE, 2018Co-Authors: Rajasree Chakraborty, Kaomud Tyagi, Shantanu Kundu, Iftikar Rahaman, Devkant Singha, Kailash Chandra, Srinivas Patnaik, Vikas KumarAbstract:The melon Thrips, Thrips palmi is a serious pesT and vecTor for planT viruses on a wide range of economically imporTanT crops. DNA barcoding evidenced The presence of crypTic diversiTy in T. palmi and ThaT warranTs exhausTive molecular sTudies. Our presenT sTudy is on decoding The firsT compleTe miTochondrial genome of T. palmi (15,333 bp) Through nexT-generaTion sequencing (NGS). The T. palmi mT genome conTains 37 genes, including 13 ProTein coding genes (PCGs), Two ribosomal RNA (rRNAs), 22 Transfer RNA (TRNAs), and Two conTrol regions (CRs). The majoriTy sTrand of T. palmi revealed 78.29% A+T conTenT, and 21.72% G+C conTenT wiTh posiTive AT skew (0.09) and negaTive GC skew (-0.06). The ATN iniTiaTion codons were observed in 12 PCGs excepT for cox1 which have unique sTarT codon (TTG). The relaTive synonymous codon usage (RSCU) analysis revealed Phe, Leu, Ile, Tyr, Asn, Lys and MeT were The mosT frequenTly used amino acids in all PCGs. The codon (CGG) which is assigned To Arginine in mosT insecTs buT absenT in T. palmi. The Ka/Ks raTio ranges from 0.078 in cox1 To 0.913 in aTp8. We observed The Typical cloverleaf secondary sTrucTure in mosT of The TRNA genes wiTh a few excepTions; absence of DHU sTem and loop in TrnV and TrnS, absence of DHU loop in TrnE, lack of T-Arm and loop in TrnN. The T. palmi gene order (GO) was compared wiTh ancesTral GO and observed an exTensive gene arrangemenT in PCGs, TRNAs and rRNAs. The cox2 gene was separaTed from The gene block ‘cox2-TrnL2’ in T. palmi as compared wiTh The oTher Thrips mT genomes, including ancesTor GO. FurTher, The nad1, TrnQ, TrnC, TrnL1, TrnV, TrnF, rrnS, and rrnL were inversely TransposiTioned in T. palmi GO. The gene blocks ‘TrnQ-TrnS2-TrnD’ and ‘TrnN-TrnE-TrnS1-TrnL1’ seems To be genus specific. The T. palmi mT genome conTained 24 inTergenic spacer regions and 12 overlapping regions. The 62 bp of CR2 shows The similariTy wiTh CR1 indicaTing a possible duplicaTion. The occurrence of mulTiple CRs in Thrips mT genomes seems To be a derived TraiT which needs furTher invesTigaTion. AlThough, The sTudy depicTed exTensive gene rearrangemenTs in T. palmi mT genome, buT The negaTive GC skew reflecTs only sTrand asymmeTry. BoTh The ML and BI phylogeneTic Trees revealed The close relaTionships of Thrips wiTh ScirToThrips as compared To Frankliniella. Thus, more mT genomes of The diverse Thrips species are required To undersTand The in-depTh phylogeneTic and evoluTionary relaTionships.
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The compleTe miTochondrial genome of melon Thrips Thrips palmi Thripinae and comparaTive analysis a vecTor for Tospoviruses
bioRxiv, 2018Co-Authors: Rajasree Chakraborty, Kaomud Tyagi, Shantanu Kundu, Iftikar Rahaman, Devkant Singha, Kailash Chandra, Srinivas Patnaik, Vikas KumarAbstract:The melon Thrips, Thrips palmi is a serious pesT and vecTor for planT viruses on a wide range of economically imporTanT crops. DNA barcoding evidenced The presence of crypTic diversiTy in T. palmi and ThaT warranTs exhausTive molecular daTa. Our presenT sTudy is on decoding The firsT compleTe miTochondrial genome of T. palmi (15,333 bp) Through NGS Technology. The miTogenome conTains 37 genes, including 13 PCGs, Two rRNAs, 22 TRNAs, and Two conTrol regions. The comparaTive analyses were conducTed for gene arrangemenTs, nucleoTide composiTion, codon usage and phylogeneTic relaTionship wiTh oTher Thrips miTogenomes. The nucleoTide composiTion was 78.29% AT, and 21.72% GC wiTh posiTive AT skewness (0.09) and negaTive GC skewness (-0.06). The ATN iniTiaTion codons were observed in 12 PCGs excepT cox1 wiTh unique sTarT codon (TTG). The RSCU analysis revealed Phe, Leu, Ile, Tyr, Asn, Lys and MeT were The mosT frequenTly used amino acids in all PCGs. The codon CGG (Arg) was absenT in T. palmi as compared To oTher Thrips miTogenomes. The Ka/Ks raTio ranges from 0.078 in cox1 To 0.913 in aTp8. We observed The Typical cloverleaf secondary sTrucTure in mosT of The TRNA genes wiTh a few excepTions; absence of DHU sTem and loop in TrnV and TrnS, absence of DHU loop in TrnE, lack of T-Arm and loop in TrnN. The posiTion of TrnS1 (beTween cox3 and CR2) is unique in T. palmi among all The sTudied Thrips miTogenomes. The miTogenome conTained 24 inTergenic spacer regions and 12 overlapping regions. The CR2 is 63.77% similar To CR1, indicaTing a possible duplicaTion and TranslocaTion in conTrol region. BoTh The ML and BI phylogeneTic Trees revealed The close relaTionships of Thrips wiTh ScirToThrips as compared To Frankliniella. Thus, more miTogenomes on The diverse Thrips species is required To undersTand The in-depTh phylogeneTic and evoluTionary relaTionships.
John M Corman - One of the best experts on this subject based on the ideXlab platform.
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boosTing long Term immune responses To sipuleucel T sip T by reTreaTmenT of paTienTs pTs wiTh meTasTaTic casTraTion resisTanT prosTaTe cancer mcrpc
Journal of Clinical Oncology, 2017Co-Authors: Tomasz M Beer, Tuyen Vu, John M Corman, Raymond S Lance, Dwayne Campogan, Heather Haynes, Nancy N Chang, Nadeem A Sheikh, Brendan D CurtiAbstract:196Background: Sip-T, an auTologous cellular immunoTherapy for asympTomaTic/minimally sympTomaTic mCRPC, induces immune responses To TargeT anTigens prosTaTic acid phosphaTase (PAP) and PA2024, a recombinanT proTein of PAP and granulocyTe macrophage colony-sTimulaTing facTor. Immune responses wiTh sip-T correlaTe wiTh overall survival. PROTECT (phase 3 NCT00779402) assessed sip-T in biochemically recurrenT androgen-dependenT PC. PROTECT pTs developing mCRPC were eligible for P10-1 (phase 2 NCT01338012). MeThods: PROTECT pTs (sip-T Arm) were reTreaTed wiTh sip-T in mCRPC. AnTigen presenTing cell (APC) acTivaTion (CD54 molecule raTio afTer and before culTure wiTh PA2024), cellular (PA2024/PAP ELISPOT; T cell proliferaTion) and humoral responses were assessed and compared wiTh TreaTmenT-naive mCRPC pTs (IMPACT NCT00065442; STAMP NCT01487863; STRIDE NCT01981122). ResulTs: Caucasian men (n=8), median follow-up 9.2 y and age 74 y, had an ECOG PS of 0 (75%) or 1. Median APC acTivaTion wiTh sip-T infusion 1 was ~...
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immune responses and clinical ouTcomes in sTand a randomized phase 2 sTudy evaluaTing opTimal sequencing of sipuleucel T sip T and androgen deprivaTion Therapy adT in biochemically recurrenT prosTaTe cancer brpc afTer local Therapy failure
Journal of Clinical Oncology, 2015Co-Authors: Emmanuel S. Antonarakis, George W Adams, Aymen Elfiky, Johnathan Maher, John M Corman, Nicholas J. Vogelzang, Adam S Kibel, Neal D Shore, Todd DevriesAbstract:5030 Background: STAND (NCT01431391) assessed opTimal sequencing of sip-T and ADT in men wiTh BRPC aT high risk of meTasTases afTer local Therapy (i.e. prosTaTe specific anTigen doubling Time [PSADT] < 12 mo). MeThods: Men (n = 68) were randomized To sip-T Then ADT (2 wks posT infusion 3; Arm 1) or ADT (3 mo lead-in) Then sip-T (Arm 2). Cellular and humoral immune responses, and clinical ouTcomes were analyzed. PSA recurrence was defined as ≥ 2 serial rises in PSA and an absoluTe PSA value of ≥ 0.2 ng/mL (prior radical prosTaTecTomy) or ≥ 2.0 ng/mL (prior radioTherapy alone). PSADT posT-ADT was analyzed. Time To nexT anTicancer inTervenTion (TTACI) was measured from firsT ADT To The day of The nexT sysTemic Therapy. RaTe of meTasTases aT 24 mo was also invesTigaTed. ResulTs: All men received 3 sip-T doses, and 96% received 12 mo ADT. Cellular and humoral responses To PA2024 increased following TreaTmenT vs baseline (BL) and were susTained aT all posT-sip-T TimepoinTs Through 24 mo (p < 0.05). PA2024-speci...
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randomized Trial of auTologous cellular immunoTherapy wiTh sipuleucel T in androgen dependenT prosTaTe cancer
Clinical Cancer Research, 2011Co-Authors: Tomasz M Beer, Guy T Bernstein, Michael L Glode, Simon J Hall, Wayne L Poll, Lori A Jones, John M Corman, Paul F Schellhammer, Y. Xu, Jelle W KylstraAbstract:Purpose: Sipuleucel-T, an auTologous cellular immunoTherapy, was invesTigaTed in a randomized, double-blind, conTrolled Trial To deTermine iTs biologic acTiviTy in androgen-dependenT prosTaTe cancer (ADPC). ExperimenTal Design: PaTienTs wiTh prosTaTe cancer deTecTable by serum prosTaTe-specific anTigen (PSA) following radical prosTaTecTomy received 3 To 4 monThs of androgen suppression Therapy, and were Then randomized (2:1) To receive sipuleucel-T ( n = 117) or conTrol ( n = 59). The primary endpoinT was Time To biochemical failure (BF) defined as serum PSA ≥ 3.0 ng/mL. PSA doubling Time (PSADT), Time To disTanT failure, immune response, and safeTy were also evaluaTed. ResulTs: Median Time To BF was 18.0 monThs for sipuleucel-T and 15.4 monThs for conTrol (HR = 0.936, P = 0.737). Sipuleucel-T paTienTs had a 48% increase in PSADT following TesTosTerone recovery (155 vs. 105 days, P = 0.038). WiTh only 16% of paTienTs having developed disTanT failure, The TreaTmenT effecT favored sipuleucel-T (HR = 0.728, P = 0.421). The mosT frequenT adverse evenTs in sipuleucel-T paTienTs were faTigue, chills, and pyrexia. Immune responses To The immunizing anTigen were greaTer in sipuleucel-T paTienTs aT Weeks 4 and 13 ( P Conclusions: No significanT difference in Time To BF could be shown. The finding of increased PSADT in The sipuleucel-T Arm is consisTenT wiTh iTs biologic acTiviTy in ADPC. Long-Term follow-up will be necessary To deTermine if clinically imporTanT evenTs, such as disTanT failure, are affecTed by Therapy. TreaTmenT was generally well ToleraTed. Clin Cancer Res; 17(13); 4558–67. ©2011 AACR .
