103 research outputs found
Targeting targeted agents: open issues for clinical trial design
- Author
- A Bagnato
- A Di Leo
- A Hoering
- A Morabito
- A Stone
- AJ Vickers
- B Freidlin
- BP Schneider
- C Bokemeyer
- CS Karapetis
- DG Altman
- Diana Giannarelli
- DJ Slamon
- E Van Cutsem
- Emilio Bria
- FA Shepherd
- Federica Cuppone
- Francesco Cognetti
- GL Rosner
- JA Kopec
- JK Chan
- JM Llovet
- K Kelly
- K Miller
- L Paz-Ares
- Massimo Di Maio
- Michele Milella
- MJ Moore
- MJ Ratain
- MJ Ratain
- MW Karaman
- N Thatcher
- Paolo Carlini
- R Simon
- RA Betensky
- RE Carter
- RG Amado
- RH El-Maraghi
- RJ Motzer
- ST Brookes
- SW Lagakos
- Publication venue
- BioMed Central
- Publication date
- 01/01/2009
- Field of study
Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present). Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources
Marked anti-tumour activity of the combination of YM155, a novel survivin suppressant, and platinum-based drugs
- Author
- A Badran
- A Chakravarti
- A Hirao
- A Kita
- A Krieg
- AW Tolcher
- BB Zhou
- BZ Carter
- C Adida
- C Mahotka
- C Mahotka
- CP Diggle
- D Grossman
- D Hanahan
- DC Altieri
- DC Altieri
- DC Altieri
- DC Altieri
- DS OâConnor
- E Hatashita
- EA Noton
- EP Rogakou
- F Bunz
- F Li
- F Rodel
- G Ambrosini
- G Chu
- G Giaccone
- G Jiang
- H Caldas
- H Caldas
- H Koutoku
- H Marusawa
- H Zhao
- I Okamoto
- JP Banath
- K Kuwata
- K Nakagawa
- K Takezawa
- K Yamanaka
- KK Khanna
- M Fukuoka
- M Milella
- M Monzo
- M Sasamata
- N Taneja
- NK Sah
- NR Wall
- RA Olie
- S De Schepper
- SP Wheatley
- T Iwasa
- T Iwasa
- T Nakahara
- T Nakahara
- T Satoh
- Y Shiloh
- Y Yamada
- ZH Siddik
- Publication venue
- Nature Publishing Group
- Publication date
- Field of study
Elevated calpain activity in acute myelogenous leukemia correlates with decreased calpastatin expression
- Author
- A Glading
- A Glading
- A Goy
- A Herry
- AS Galvez
- BG Rosser
- BJ Perrin
- C Delmas
- D Bonnet
- DC Taussig
- DE Goll
- DM Zhu
- E Matsubara
- F Demarchi
- F Ferrara
- G Mulligan
- GW Hassen
- H Li
- H Shao
- H Zhu
- J Inazawa
- J Soboloff
- J Takano
- J Wu
- JL Hood
- JM Witkowski
- K Kojima
- K Tanaka
- KA Kim
- KB Kindle
- KK Wang
- L Leloup
- M Averna
- M Dicato
- M Hirano
- M Milella
- M Niapour
- M Niapour
- M Vermaelen
- MA Morgan
- MR Ricciardi
- MS Tallman
- N Guan
- NC Gutierrez
- NO Carragher
- P Razeghi
- PM Yang
- R Benetti
- R Benetti
- R Betts
- R Betts
- R Stifanese
- RA Hanna
- RL Mellgren
- S Frohling
- S Samantaray
- SJ Storr
- T Lapidot
- T Sasaki
- V Bardet
- W Zhu
- Y Dai
- Y Yajima
- Z Chen
- Publication venue
- Nature Publishing Group
- Publication date
- Field of study
Calpains are intracellular cysteine proteases that have crucial roles in many physiological and pathological processes. Elevated calpain activity has been associated with many pathological states. Calpain inhibition can be protective or lethal depending on the context. Previous work has shown that c-myc transformation regulates calpain activity by suppressing calpastatin, the endogenous negative regulator of calpain. Here, we have investigated calpain activity in primary acute myelogenous leukemia (AML) blast cells. Calpain activity was heterogeneous and greatly elevated over a wide range in AML blast cells, with no correlation to FAB classification. Activity was particularly elevated in the CD34+CD38â enriched fraction compared with the CD34+CD38+ fraction. Treatment of the cells with the specific calpain inhibitor, PD150606, induced significant apoptosis in AML blast cells but not in normal equivalent cells. Sensitivity to calpain inhibition correlated with calpain activity and preferentially targeted CD34+CD38â cells. There was no correlation between calpain activity and p-ERK levels, suggesting the ras pathway may not be a major contributor to calpain activity in AML. A significant negative correlation existed between calpain activity and calpastatin, suggesting calpastatin is the major regulator of activity in these cells. Analysis of previously published microarray data from a variety of AML patients demonstrated a significant negative correlation between calpastatin and c-myc expression. Patients who achieved a complete remission had significantly lower calpain activity than those who had no response to treatment. Taken together, these results demonstrate elevated calpain activity in AML, anti-leukemic activity of calpain inhibition and prognostic potential of calpain activity measurement
Pan-cancer analysis of whole genomes
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- The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium View Correspondence (jump link)
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- Publication venue
- Publication date
- 11/12/2019
- Field of study
Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe
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- Ălvarez FernĂĄndez A
- Ăzçelik Ă
- Publication venue
- Springer Nature on behalf of SISSA
- Publication date
- 09/10/2022
- Field of study
A preprint version of the article is available at arXiv:2206.09466v2 [hep-ex], https://arxiv.org/abs/2206.09466v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at httpS://cms-results.web.cern.ch/cms-results/public-results/publications/HIG-20-013 (CMS Public Pages). Report number: CMS-HIG-20-013, CERN-EP-2022-120.Production cross sections of the standard model Higgs boson decaying to a pair of W bosons are measured in proton-proton collisions at a center-of-mass energy of 13 TeV. The analysis targets Higgs bosons produced via gluon fusion, vector boson fusion, and in association with a W or Z boson. Candidate events are required to have at least two charged leptons and moderate missing transverse momentum, targeting events with at least one leptonically decaying W boson originating from the Higgs boson. Results are presented in the form of inclusive and differential cross sections in the simplified template cross section framework, as well as couplings of the Higgs boson to vector bosons and fermions. The data set collected by the CMS detector during 2016-2018 is used, corresponding to an integrated luminosity of 138 fb^â1. The signal strength modifier ÎŒ, defined as the ratio of the observed production rate in a given decay channel to the standard model expectation, is measured to be ÎŒ = 0.95 +0.10â0.09. All results are found to be compatible with the standard model within the uncertainties.SCOAP3
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Measurement of inclusive and differential cross sections for single top quark production in association with a W boson in proton-proton collisions at sâ = 13 TeV
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- Zuolo D
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- Ălvarez FernĂĄndez A
- Publication venue
- Springer Nature
- Publication date
- 06/11/2022
- Field of study
A preprint version of the article is available at arXiv:2208.00924v2 [hep-ex], https://arxiv.org/abs/2208.00924v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables, including additional supplementary figures, can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/TOP-21-010 (CMS Public Pages). Report number: CMS-TOP-21-010, CERN-EP-2022-158.Measurements of the inclusive and normalised differential cross sections are presented for the production of single top quarks in association with a W boson in proton-proton collisions at a centre-of-mass energy of 13 TeV. The data used were recorded with the CMS detector at the LHC during 2016-2018, and correspond to an integrated luminosity of 138 fb^{â1}. Events containing one electron and one muon in the final state are analysed. For the inclusive measurement, a multivariate discriminant, exploiting the kinematic properties of the events is used to separate the signal from the dominant ttÂŻ background. A cross section of 79.2 ± 0.9 (stat) +7.7â8.0 (syst) ± 1.2 (lumi) pb is obtained, consistent with the predictions of the standard model. For the differential measurements, a fiducial region is defined according to the detector acceptance, and the requirement of exactly one jet coming from the fragmentation of a bottom quark. The resulting distributions are unfolded to particle level and agree with the predictions at next-to-leading order in perturbative quantum chromodynamics.SCOAP3
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- Springer Science and Business Media LLC
- Publication date
- 07/07/2022
- Field of study
A Correction to this paper has been published (18 October 2023) : https://doi.org/10.1038/s41586-023-06164-8.Data availability:
Tabulated results are provided in the HEPData record for this analysis. Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS data preservation, re-use and open acess policy.Code availability:
The CMS core software is publicly available on GitHub (https://github.com/cms-sw/cmssw).In July 2012, the ATLAS and CMS collaborations at the CERN Large Hadron Collider announced the observation of a Higgs boson at a mass of around 125âgigaelectronvolts. Ten years later, and with the data corresponding to the production of a 30-times larger number of Higgs bosons, we have learnt much more about the properties of the Higgs boson. The CMS experiment has observed the Higgs boson in numerous fermionic and bosonic decay channels, established its spinâparity quantum numbers, determined its mass and measured its production cross-sections in various modes. Here the CMS Collaboration reports the most up-to-date combination of results on the properties of the Higgs boson, including the most stringent limit on the cross-section for the production of a pair of Higgs bosons, on the basis of data from protonâproton collisions at a centre-of-mass energy of 13âteraelectronvolts. Within the uncertainties, all these observations are compatible with the predictions of the standard model of elementary particle physics. Much evidence points to the fact that the standard model is a low-energy approximation of a more comprehensive theory. Several of the standard model issues originate in the sector of Higgs boson physics. An order of magnitude larger number of Higgs bosons, expected to be examined over the next 15 years, will help deepen our understanding of this crucial sector.BMBWF and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, FAPERGS, and FAPESP (Brazil); MES and BNSF (Bulgaria); CERN; CAS, MoST, and NSFC (China); MINCIENCIAS (Colombia); MSES and CSF (Croatia); RIF (Cyprus); SENESCYT (Ecuador); MoER, ERC PUT and ERDF (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Germany); GSRI (Greece); NKFIH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); MSIP and NRF (Republic of Korea); MES (Latvia); LAS (Lithuania); MOE and UM (Malaysia); BUAP, CINVESTAV, CONACYT, LNS, SEP, and UASLP-FAI (Mexico); MOS (Montenegro); MBIE (New Zealand); PAEC (Pakistan); MES and NSC (Poland); FCT (Portugal); MESTD (Serbia); MCIN/AEI and PCTI (Spain); MOSTR (Sri Lanka); Swiss Funding Agencies (Switzerland); MST (Taipei); MHESI and NSTDA (Thailand); TUBITAK and TENMAK (Turkey); NASU (Ukraine); STFC (United Kingdom); DOE and NSF (USA). Individuals have received support from the Marie-Curie programme and the European Research Council and Horizon 2020 Grant, contract Nos. 675440, 724704, 752730, 758316, 765710, 824093, 884104, and COST Action CA16108 (European Union); the Leventis Foundation; the Alfred P. Sloan Foundation; the Alexander von Humboldt Foundation; the Belgian Federal Science Policy Office; the Fonds pour la Formation Ă la Recherche dans lâIndustrie et dans lâAgriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); the F.R.S.-FNRS and FWO (Belgium) under the âExcellence of Science â EOSâ â be.h project n. 30820817; the Beijing Municipal Science & Technology Commission, No. Z191100007219010; the Ministry of Education, Youth and Sports (MEYS) of the Czech Republic; the Stavros Niarchos Foundation (Greece); the Deutsche Forschungsgemeinschaft (DFG), under Germanyâs Excellence Strategy â EXC 2121 âQuantum Universeâ â 390833306, and under project number 400140256 - GRK2497; the Hungarian Academy of Sciences, the New National Excellence Program - ĂNKP, the NKFIH research grants K 124845, K 124850, K 128713, K 128786, K 129058, K 131991, K 133046, K 138136, K 143460, K 143477, 2020-2.2.1-ED-2021-00181, and TKP2021-NKTA-64 (Hungary); the Council of Science and Industrial Research, India; the Latvian Council of Science; the Ministry of Education and Science, project no. 2022/WK/14, and the National Science Center, contracts Opus 2021/41/B/ST2/01369 and 2021/43/B/ST2/01552 (Poland); the Fundação para a CiĂȘncia e a Tecnologia, grant CEECIND/01334/2018 (Portugal); the National Priorities Research Program by Qatar National Research Fund; MCIN/AEI/10.13039/501100011033, ERDF âa way of making Europeâ, and the Programa Estatal de Fomento de la InvestigaciĂłn CientĂfica y TĂ©cnica de Excelencia MarĂa de Maeztu, grant MDM-2017-0765 and Programa Severo Ochoa del Principado de Asturias (Spain); the Chulalongkorn Academic into Its 2nd Century Project Advancement Project, and the National Science, Research and Innovation Fund via the Program Management Unit for Human Resources & Institutional Development, Research and Innovation, grant B05F650021 (Thailand); the Kavli Foundation; the Nvidia Corporation; the SuperMicro Corporation; the Welch Foundation, contract C-1845; and the Weston Havens Foundation (USA)
Recommended from our members
Search for new heavy resonances decaying to WW, WZ, ZZ, WH, or ZH boson pairs in the all-jets final state in proton-proton collisions at sâ = 13 TeV
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- Ăzçelik Ă
- Publication venue
- Elsevier
- Publication date
- 26/02/2023
- Field of study
A preprint version of this article is available at arXiv:2210.00043v2 [hep-ex], https://arxiv.org/abs/2210.00043v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables, including additional supplementary figures, can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/B2G-20-009 (CMS Public Pages). Report number: CMS-B2G-20-009, CERN-EP-2022-152.Data availability: see: https://cms-results.web.cern.ch/cms-results/public-results/publications/B2G-20-009 .A search for new heavy resonances decaying to WW, WZ, ZZ, WH, or ZH boson pairs in the all-jets final state is presented. The analysis is based on proton-proton collision data recorded by the CMS detector in 2016-2018 at a centre-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 138 fb^{-1}. The search is sensitive to resonances with masses between 1.3 and 6 TeV, decaying to bosons that are highly Lorentz-boosted such that each of the bosons forms a single large-radius jet. Machine learning techniques are employed to identify such jets. No significant excess over the estimated standard model background is observed. A maximum local significance of 3.6 standard deviations, corresponding to a global significance of 2.3 standard deviations, is observed at masses of 2.1 and 2.9 TeV. In a heavy vector triplet model, spin-1 Z' and W' resonances with masses below 4.8 TeV are excluded at the 95% confidence level (CL). These limits are the most stringent to date. In a bulk graviton model, spin-2 gravitons and spin-0 radions with masses below 1.4 and 2.7 TeV, respectively, are excluded at 95% CL. Production of heavy resonances through vector boson fusion is constrained with upper cross section limits at 95% CL as low as 0.1 fb.SCOAP3
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Measurement of the Higgs boson production via vector boson fusion and its decay into bottom quarks in proton-proton collisions at sâ = 13 TeV
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- Publication venue
- Springer Nature on behalf of SISSA
- Publication date
- 30/01/2024
- Field of study
A preprint version of the article is available at arXiv:2308.01253v2 [hep-ex], https://arxiv.org/abs/2308.01253v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/HIG-22-009 (CMS Public Pages). Report number: CMS-HIG-22-009, CERN-EP-2023-110.A measurement of the Higgs boson (H) production via vector boson fusion (VBF) and its decay into a bottom quark-antiquark pair (bbÂŻ) is presented using proton-proton collision data recorded by the CMS experiment at sâ = 13 TeV and corresponding to an integrated luminosity of 90.8 fbâ1. Treating the gluon-gluon fusion process as a background and constraining its rate to the value expected in the standard model (SM) within uncertainties, the signal strength of the VBF process, defined as the ratio of the observed signal rate to that predicted by the SM, is measured to be ÎŒqqHHbbÂŻ = 1.01 +0.55â0.46. The VBF signal is observed with a significance of 2.4 standard deviations relative to the background prediction, while the expected significance is 2.7 standard deviations. Considering inclusive Higgs boson production and decay into bottom quarks, the signal strength is measured to be ÎŒincl.HbbÂŻ = 0.99 +0.48â0.41, corresponding to an observed (expected) significance of 2.6 (2.9) standard deviations.SCOAP3, STFC; Marie-Curie program and the European Research Council and Horizon 2020 Gran
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Search for new Higgs bosons via same-sign top quark pair production in association with a jet in proton-proton collisions at âs = 13 TeV
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- Aarup Petersen H
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- Yoo J
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- Yuldashev BS
- Yusuff I
- Zabi A
- Zabolotny W
- Zacharopoulou A
- Zaleski S
- Zalewski P
- Zanetti M
- Zarubin A
- Zarucki M
- Zaza A
- Zecchinelli AG
- Zehetner P
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- Zejdl P
- Zeuner WD
- Zghiche A
- Zhang F
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- Zhizhin I
- Zhokin A
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- Ziemons T
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- Zorbakir IS
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- Zucchetta A
- Zumerle G
- Zuo X
- Zuolo D
- Zygala L
- Publication venue
- Elsevier
- Publication date
- 02/02/2024
- Field of study
Data availability:
Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS policy as stated in âCMS data preservation, re-use and open access policyâ available online at: https://cms-docdb.cern.ch/cgi-bin/PublicDocDB/RetrieveFile?docid=6032&filename=CMSDataPolicyV1.2.pdf&version=2 .A preprint of this article is available online at arXiv:2311.03261v2 [hep-ex] https://arxiv.org/abs/2311.03261v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/TOP-22-010 (CMS Public Pages)A search is presented for new Higgs bosons in proton-proton (pp) collision events in which a same-sign top quark pair is produced in association with a jet, via the pp â tH/A â ttÂŻc and pp â tH/A â ttÂŻu processes. Here, H and A represent the extra scalar and pseudoscalar boson, respectively, of the second Higgs doublet in the generalized two-Higgs-doublet model (g2HDM). The search is based on pp collision data collected at a center-of-mass energy of 13 TeV with the CMS detector at the LHC, corresponding to an integrated luminosity of 138 fbâ1. Final states with a same-sign lepton pair in association with jets and missing transverse momentum are considered. New Higgs bosons in the 200-1000 GeV mass range and new Yukawa couplings between 0.1 and 1.0 are targeted in the search, for scenarios in which either H or A appear alone, or in which they coexist and interfere. No significant excess above the standard model prediction is observed. Exclusion limits are derived in the context of the g2HDM.SCOAP3
- âŠ