To advance preclinical testing of novel targeted drugs in colorectal cancer (CRC) we established a panel of 133 mouse xenograft models from fresh tumor specimens of 239 patients with CRC of all four UICC stages. A sub...To advance preclinical testing of novel targeted drugs in colorectal cancer (CRC) we established a panel of 133 mouse xenograft models from fresh tumor specimens of 239 patients with CRC of all four UICC stages. A subgroup of 67 xenograft models was treated with cetuximab, bevacizumab and oxaliplatin as single agents. Mutation status of KRAS (G12, G13, A146T), BRAF (V600E) and PIK3CA (E542K, E545K, H1047R) was assessed in all xenografts by allelespecific real-time PCR. KRAS codon 61 was assessed by conventional sequencing. AREG and EREG expression levels were analyzed by real-time PCR expression assays. In the treatment experiment we observed response rates of 27% (18/67) for cetuximab, 3% (2/67) for bevacizumab, and 6% (4/67) for oxaliplatin. Classification based on KRAS, BRAF and PIK3CA mutation status identified 15 of the responders (sensitivity 83%, confidence interval at p = 0.05 (CI): 59% - 96%), and 38 nonresponders (specificity 78%, CI: 63% - 88%). If any mutation except in KRAS codon 13 were considered, the classifier reached sensitivity of 94% and specificity of 69%. We improved specificity of the classifiers to 90% and 86% respectively by adding AREG and EREG RNA expression thresholds retrospectively. In patient-derived xenograft models, we found a predictive classifier for response to cetuximab that is more accurate than established biomarkers. We confirmed its potential performance in primary human tumors. For patients, the classifier’s sensitivity promises increased response rates and its specificity limits unnecessary toxicity. Given the scope of our xenograft models across all UICC stages, this applies not only to mCRC but also to the adjuvant setting of earlier stages. The xenograft collection allows to mimic randomized phase II trials and to test novel drugs effectively as single agents or in combinations. It also enables the development of highly accurate companion diagnostics as demonstrated by us for cetuximab.展开更多
First evidence of a structure in the J/ψΛinvariant mass distribution is obtained from an amplitude analysis of■b^(-)J/ψΛK^(-)decays.The observed structure is consistent with being due to a charmonium pentaquark w...First evidence of a structure in the J/ψΛinvariant mass distribution is obtained from an amplitude analysis of■b^(-)J/ψΛK^(-)decays.The observed structure is consistent with being due to a charmonium pentaquark with strangeness with a significance of 3.1r including systematic uncertainties and lookelsewhere effect.Its mass and width are determined to be 4458:8±2:9t4:7-1:1 MeV and 17:3±6:5t8:0-5:7 MeV,respectively,where the quoted uncertainties are statistical and systematic.The structure is also consistent with being due to two resonances.In addition,the narrow excited■^(-)states,N■(1690)and■(1820),are seen for the first time in a■b^(-)decay,and their masses and widths are measured with improved precision.The analysis is performed using pp collision data corresponding to a total integrated luminosity of 9 fb^(-1),collected with the LHCb experiment at centre-of-mass energies of 7,8 and 13 TeV.展开更多
A search for the doubly charmed baryon ■^+cc is performed through its decay to theΛ^+c K^-π^+ final state,using proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7,8 and 13...A search for the doubly charmed baryon ■^+cc is performed through its decay to theΛ^+c K^-π^+ final state,using proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7,8 and 13 TeV.The data correspond to a total integrated luminosity of 9 fb^-1.No significant signal is observed in the mass range from 3.4 to 3.8 GeV/c^2.Upper limits are set at 95%credibility level on the ratio of the ■^+cc production cross-section times the branching fraction to that ofΛ^+c and ■^++cc baryons.The limits are determined as functions of the ■^+cc mass for different lifetime hypotheses,in the rapidity range from 2.0 to 4.5 and the transverse momentum range from 4 to 15 GeV/c.展开更多
The production of ■baryons in proton-proton collisions at a centre-of-mass energy of √s = 13 TeV is measured in the transverse-momentum range 4<pT<15GeV/c and the rapidity range2.0<y<4.5.The data used in...The production of ■baryons in proton-proton collisions at a centre-of-mass energy of √s = 13 TeV is measured in the transverse-momentum range 4<pT<15GeV/c and the rapidity range2.0<y<4.5.The data used in this measurement correspond to an integrated luminosity of 1.7fb^-1,recorded by the LHCb experiment during 2016.The ratio of the ■ production cross-section times the branching fraction of the■→∧^+cK^-π^+ π^+decay relative to the prompt ∧^+c production cross-section is found to be(2.22±0.27±0.29)×10^-4,assuming the central value of the measured lifetime,where the first uncertainty is statistical and the second systematic.展开更多
A first search for the Ξ_(bc)^(+)J/ψΞ_(c)^(+) decay is performed by the LHCb experiment with a data sample of proton-proton collisions, corresponding to an integrated luminosity of 9 fb−1 recorded at centre-of-mass...A first search for the Ξ_(bc)^(+)J/ψΞ_(c)^(+) decay is performed by the LHCb experiment with a data sample of proton-proton collisions, corresponding to an integrated luminosity of 9 fb−1 recorded at centre-of-mass energies of 7, 8, and 13 TeV. Two peaking structures are seen with a local (global) significance of 4.3(2.8) and 4.1(2.4) standard deviations at masses of 6571 and 6694 MeV/c2, respectively. Upper limits are set on the Ξ+bc baryon production cross-section times the branching fraction relative to that of the B+c→J/ψD+s decay at centre-of-mass energies of 8 and 13 TeV, in the Ξ+bc and in the B+c rapidity and transverse-momentum ranges from 2.0 to 4.5 and 0 to 20GeV/c, respectively. Upper limits are presented as a function of the Ξ+bc mass and lifetime.展开更多
The first search for the doubly heavyΩ^(0)_(bc)baryon and a search for the E^(0)_(bc)baryon are performed using pp collision data collected via the LHCb experiment from 2016 to 2018 at a centre-of-mass energy of 13 T...The first search for the doubly heavyΩ^(0)_(bc)baryon and a search for the E^(0)_(bc)baryon are performed using pp collision data collected via the LHCb experiment from 2016 to 2018 at a centre-of-mass energy of 13 TeV,corresponding to an integrated luminosity of 5.2 fb^(-1).The baryons are reconstructed via their decays to Λ^(+)_(c)π^(-)and E^(+)_(c)π^(-).No significant excess is fbund for invariant masses between 6700 and 7300 MeV/c^(2),in a rapidity range from 2.0 to 4.5 and a transverse momentum range from 2 to 20 MeV/c.Upper limits are set on the ratio of the Ω^(0)_(bc)and E^(0)_(bc)production cross-section times the branching fraction to Λ^(+)_(c)π^(-)(E^(+)_(c)π^(-))relative to that of the Λ^(0)_(b)(E^(0)_(b))baryon,for different lifetime hypotheses,at 95%confidence level.The upper limits range from 0.5 x 10^(-4)to 2.5 x 10^(-4)for theΩ^(0)_(bc)→Λ^(+)_(c)π^(-)(E^(0)_(bc)→Λ^(+)_(c)π^(-))decay,and from 1.4x 10^(-3)to 6.9 x 10^(-3)for theΩ^(0)_(bc)→E^(+)_(c)π^(-)(E^(0)_(bc)→E^(+)_(c)π^(-))decay,depending on the considered mass and lifetime of theΩ^(0)_(bc)(E^(0)_(bc))baryon.展开更多
A search for the rare decays W^(+)→D_(s)^(+)γ and Z→D0γis performed using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of 13TeV,corresponding to an integrated luminosity...A search for the rare decays W^(+)→D_(s)^(+)γ and Z→D0γis performed using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of 13TeV,corresponding to an integrated luminosity of 2.0fb−1.No significant signal is observed for either decay mode and upper limits on their branching fractions are set using W^(+)→D_(s)^(+)γ and Z→μ+μ−decays as normalization channels.The upper limits are 6.5×10^(−4) and 2.1×10^(−3) at 95% confidence level for the W^(+)→D_(s)^(+)γ and Z→D^(0)γ decay modes,respectively.This is the first reported search for the Z→D^(0)γ decay,while the upper limit on the W+→D+sγbranching fraction improves upon the previous best limit.展开更多
Bioactive glasses(BGs)are promising bone substitute materials.However,under certain circumstances BGs such as the well-known 45S5 Bioglass®(composition in wt%:45.0 SiO2,24.5 Na2O,24.5 CaO,6.0 P2O5)act cytotoxic d...Bioactive glasses(BGs)are promising bone substitute materials.However,under certain circumstances BGs such as the well-known 45S5 Bioglass®(composition in wt%:45.0 SiO2,24.5 Na2O,24.5 CaO,6.0 P2O5)act cytotoxic due to a strong increase in pH caused by a burst release of sodium ions.A potential alternative is a sodiumreduced fluoride-containing BG belonging to the CaO–MgO–SiO2 system,namely BG1d-BG(composition in wt%:46.1 SiO2,28.7 CaO,8.8 MgO,6.2 P2O5,5.7 CaF2,4.5 Na2O),that has already been evaluated in-vitro,in-vivo and in preliminary clinical trials.Before further application,however,BG1d-BG should be compared to the benchmark amongst BGs,the 45S5 Bioglass®composition,to classify its effect on cell viability,proliferation and osteogenic differentiation of human mesenchymal stem cells(MSCs).Therefore,in this study,the biocompatibility and osteogenic potential of both BGs were investigated in an indirect and direct culture setting to assess the effect of the ionic dissolution products and the BGs’physical presence on the cells.The results indicated an advantage of BG1d-BG over 45S5 Bioglass®regarding cell viability and proliferation.Both BGs induced an earlier onset of osteogenic differentiation and accelerated the expression of late osteoblast marker genes compared to the control group.In conclusion,BG1d-BG is an attractive candidate for further experimental investigation.The basic mechanisms behind the different impact on cell behavior should be assessed in further detail,e.g.by further alteration of the BG compositions.展开更多
A search for the rare decay B^(0)→J/ψФis performed using Pp collision data collected with the LHCb dete-ctor at centre-of-mass energies of 7,8 and 13 TeV,corresponding to an integrated luminosity of9 fb.No signific...A search for the rare decay B^(0)→J/ψФis performed using Pp collision data collected with the LHCb dete-ctor at centre-of-mass energies of 7,8 and 13 TeV,corresponding to an integrated luminosity of9 fb.No significant signal of the decay is observed and an upper limitof 1.1x 10^(-7)at 90%confidence level is set on the branching fraction.展开更多
文摘To advance preclinical testing of novel targeted drugs in colorectal cancer (CRC) we established a panel of 133 mouse xenograft models from fresh tumor specimens of 239 patients with CRC of all four UICC stages. A subgroup of 67 xenograft models was treated with cetuximab, bevacizumab and oxaliplatin as single agents. Mutation status of KRAS (G12, G13, A146T), BRAF (V600E) and PIK3CA (E542K, E545K, H1047R) was assessed in all xenografts by allelespecific real-time PCR. KRAS codon 61 was assessed by conventional sequencing. AREG and EREG expression levels were analyzed by real-time PCR expression assays. In the treatment experiment we observed response rates of 27% (18/67) for cetuximab, 3% (2/67) for bevacizumab, and 6% (4/67) for oxaliplatin. Classification based on KRAS, BRAF and PIK3CA mutation status identified 15 of the responders (sensitivity 83%, confidence interval at p = 0.05 (CI): 59% - 96%), and 38 nonresponders (specificity 78%, CI: 63% - 88%). If any mutation except in KRAS codon 13 were considered, the classifier reached sensitivity of 94% and specificity of 69%. We improved specificity of the classifiers to 90% and 86% respectively by adding AREG and EREG RNA expression thresholds retrospectively. In patient-derived xenograft models, we found a predictive classifier for response to cetuximab that is more accurate than established biomarkers. We confirmed its potential performance in primary human tumors. For patients, the classifier’s sensitivity promises increased response rates and its specificity limits unnecessary toxicity. Given the scope of our xenograft models across all UICC stages, this applies not only to mCRC but also to the adjuvant setting of earlier stages. The xenograft collection allows to mimic randomized phase II trials and to test novel drugs effectively as single agents or in combinations. It also enables the development of highly accurate companion diagnostics as demonstrated by us for cetuximab.
文摘First evidence of a structure in the J/ψΛinvariant mass distribution is obtained from an amplitude analysis of■b^(-)J/ψΛK^(-)decays.The observed structure is consistent with being due to a charmonium pentaquark with strangeness with a significance of 3.1r including systematic uncertainties and lookelsewhere effect.Its mass and width are determined to be 4458:8±2:9t4:7-1:1 MeV and 17:3±6:5t8:0-5:7 MeV,respectively,where the quoted uncertainties are statistical and systematic.The structure is also consistent with being due to two resonances.In addition,the narrow excited■^(-)states,N■(1690)and■(1820),are seen for the first time in a■b^(-)decay,and their masses and widths are measured with improved precision.The analysis is performed using pp collision data corresponding to a total integrated luminosity of 9 fb^(-1),collected with the LHCb experiment at centre-of-mass energies of 7,8 and 13 TeV.
基金support from CERN and from the national agencies:CAPES,CNPq，FAPERJ and FINEP(Brazil)MOST and NSFC(China)+11 种基金CNRS/IN2P3(France)BMBF,DFG and MPG(Germany)INFN(Italy)KWO(Netherlands)MNiSW and NCN(Poland)MEN/IFA(Romania)MinES and FASO(Russia)MinECo(Spain)SNSF and SER(Switzerland)NASU(Ukraine)STFC(United Kingdom)NSF(USA).
文摘A search for the doubly charmed baryon ■^+cc is performed through its decay to theΛ^+c K^-π^+ final state,using proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7,8 and 13 TeV.The data correspond to a total integrated luminosity of 9 fb^-1.No significant signal is observed in the mass range from 3.4 to 3.8 GeV/c^2.Upper limits are set at 95%credibility level on the ratio of the ■^+cc production cross-section times the branching fraction to that ofΛ^+c and ■^++cc baryons.The limits are determined as functions of the ■^+cc mass for different lifetime hypotheses,in the rapidity range from 2.0 to 4.5 and the transverse momentum range from 4 to 15 GeV/c.
基金Supported by CERNnational agencies:CAPES+30 种基金CNPqFAPERJFINEP(Brazil)MOSTNSFC(China)CNRS/IN2P3(France)BMBFDFGMPG(Germany)INFN(Italy)NWO(Netherlands)MNiSWNCN(Poland)MEN/IFA(Romania)MSHE(Russia)MinECo(Spain)SNSFSER(Switzerland)NASU(Ukraine)STFC(United Kingdom)DOE NPNSF(USA)Key Research Program of Frontier Sciences of CAS,CAS PIFIthe Thousand Talents Program(China)RFBRRSFYandex LLC(Russia)GVAXuntaGalGENCAT(Spain)the Royal Society and the Leverhulme Trust(United Kingdom)
文摘The production of ■baryons in proton-proton collisions at a centre-of-mass energy of √s = 13 TeV is measured in the transverse-momentum range 4<pT<15GeV/c and the rapidity range2.0<y<4.5.The data used in this measurement correspond to an integrated luminosity of 1.7fb^-1,recorded by the LHCb experiment during 2016.The ratio of the ■ production cross-section times the branching fraction of the■→∧^+cK^-π^+ π^+decay relative to the prompt ∧^+c production cross-section is found to be(2.22±0.27±0.29)×10^-4,assuming the central value of the measured lifetime,where the first uncertainty is statistical and the second systematic.
基金The project support from CERN and from the national agencies:CAPES,CNPq,FAPERJ and FINEP(Brazil)MOST and NSFC(China)+18 种基金CNRS/IN2P3(France)BMBF,DFG and MPG(Germany)INFN(Italy)NWO(Netherlands)MNiSW and NCN(Poland)MEN/IFA(Romania)MICINN(Spain)SNSF and SER(Switzerland)NASU(Ukraine)STFC(United Kingdom)DOE NP and NSF(USA).We acknowledge the computing resources that are provided by CERN,IN2P3(France),KIT and DESY(Germany),INFN(Italy),SURF(Netherlands),PIC(Spain),GridPP(United Kingdom),CSCS(Switzerland),IFIN-HH(Romania),CBPF(Brazil),Polish WLCG(Poland)and NERSC(USA).Individual groups or members have received support from ARC and ARDC(Australia)Minciencias(Colombia)AvH Foundation(Germany)EPLANET,Marie Sklodowska-Curie Actions and ERC(European Union)A*MIDEX,ANR,IPhU and Labex P2IO,and Région Auvergne-RhôneAlpes(France)Key Research Program of Frontier Sciences of CAS,CAS PIFI,CAS CCEPP,Fundamental Research Funds for the Central Universities,and Sci.&Tech.Program of Guangzhou(China)GVA,XuntaGal,GENCAT and Prog.Atracción Talento,CM(Spain)SRC(Sweden)the Leverhulme Trust,the Royal Society and UKRI(United Kingdom).
文摘A first search for the Ξ_(bc)^(+)J/ψΞ_(c)^(+) decay is performed by the LHCb experiment with a data sample of proton-proton collisions, corresponding to an integrated luminosity of 9 fb−1 recorded at centre-of-mass energies of 7, 8, and 13 TeV. Two peaking structures are seen with a local (global) significance of 4.3(2.8) and 4.1(2.4) standard deviations at masses of 6571 and 6694 MeV/c2, respectively. Upper limits are set on the Ξ+bc baryon production cross-section times the branching fraction relative to that of the B+c→J/ψD+s decay at centre-of-mass energies of 8 and 13 TeV, in the Ξ+bc and in the B+c rapidity and transverse-momentum ranges from 2.0 to 4.5 and 0 to 20GeV/c, respectively. Upper limits are presented as a function of the Ξ+bc mass and lifetime.
基金CAPES,CNPq,FAPERJ and FINEP(Brazil)MOST and NSFC(China)+18 种基金CNRS/IN2P3(France)BMBF,DFG,MPG(Germany)INFN(Italy)NWO(Netherlands)MNiSW,NCN(Poland)MEN/IFA(Romania)MSHE(Russia)MICINN(Spain)SNSF,SER(Switzerland)NASU(Ukraine)STFC(United Kingdom)DOE NP,NSF(USA).We acknowledge the computing resources that are provided by CERN,IN2P3(France),KIT and DESY(Germany),INFN(Italy),SURF(Netherlands),PIC(Spain),GridPP(United Kingdom),RRCKI and Yandex LLC(Russia),CSCS(Switzerland),IFIN-HH(Romania),CBPF(Brazil),PL-GRID(Poland)and NERSC(USA)AvH Foundation(Germany)EPLANET,Marie Sklodowska-Curie Actions and ERC(European Union)A*MIDEX,ANR,Labex P2IO and OCEVU,Region Auvergne-Rhdne-Alpes(France)Key Research Program of Frontier Sciences of CAS,CAS PIFI,CAS CCEPP,Fundamental Research Funds for the Central Universities,and Sci.Tech.Program of Guangzhou(China)RFBR,RSF and Yandex LLC(Russia)GVA,XuntaGal,GENCAT(Spain)the Leverhulme Trust,the Royal Society and UKRI(United Kingdom)。
文摘The first search for the doubly heavyΩ^(0)_(bc)baryon and a search for the E^(0)_(bc)baryon are performed using pp collision data collected via the LHCb experiment from 2016 to 2018 at a centre-of-mass energy of 13 TeV,corresponding to an integrated luminosity of 5.2 fb^(-1).The baryons are reconstructed via their decays to Λ^(+)_(c)π^(-)and E^(+)_(c)π^(-).No significant excess is fbund for invariant masses between 6700 and 7300 MeV/c^(2),in a rapidity range from 2.0 to 4.5 and a transverse momentum range from 2 to 20 MeV/c.Upper limits are set on the ratio of the Ω^(0)_(bc)and E^(0)_(bc)production cross-section times the branching fraction to Λ^(+)_(c)π^(-)(E^(+)_(c)π^(-))relative to that of the Λ^(0)_(b)(E^(0)_(b))baryon,for different lifetime hypotheses,at 95%confidence level.The upper limits range from 0.5 x 10^(-4)to 2.5 x 10^(-4)for theΩ^(0)_(bc)→Λ^(+)_(c)π^(-)(E^(0)_(bc)→Λ^(+)_(c)π^(-))decay,and from 1.4x 10^(-3)to 6.9 x 10^(-3)for theΩ^(0)_(bc)→E^(+)_(c)π^(-)(E^(0)_(bc)→E^(+)_(c)π^(-))decay,depending on the considered mass and lifetime of theΩ^(0)_(bc)(E^(0)_(bc))baryon.
文摘A search for the rare decays W^(+)→D_(s)^(+)γ and Z→D0γis performed using proton-proton collision data collected by the LHCb experiment at a centre-of-mass energy of 13TeV,corresponding to an integrated luminosity of 2.0fb−1.No significant signal is observed for either decay mode and upper limits on their branching fractions are set using W^(+)→D_(s)^(+)γ and Z→μ+μ−decays as normalization channels.The upper limits are 6.5×10^(−4) and 2.1×10^(−3) at 95% confidence level for the W^(+)→D_(s)^(+)γ and Z→D^(0)γ decay modes,respectively.This is the first reported search for the Z→D^(0)γ decay,while the upper limit on the W+→D+sγbranching fraction improves upon the previous best limit.
基金We thank Dr.Jorg Fellenberg for technical support and inspiring scientific discussion and Sebastian Wilkesmann and Frederike Hohenbild for their support in designing the figuresThis study was funded by the research fund of the Heidelberg Orthopedic University Hospital.Dr.Fabian Westhauser is supported by the“Physician Scientist Program”-scholarship introduced by the Medical Faculty of the University of HeidelbergThis study contains parts of Sarah Isabelle Schmitz's doctoral thesis.
文摘Bioactive glasses(BGs)are promising bone substitute materials.However,under certain circumstances BGs such as the well-known 45S5 Bioglass®(composition in wt%:45.0 SiO2,24.5 Na2O,24.5 CaO,6.0 P2O5)act cytotoxic due to a strong increase in pH caused by a burst release of sodium ions.A potential alternative is a sodiumreduced fluoride-containing BG belonging to the CaO–MgO–SiO2 system,namely BG1d-BG(composition in wt%:46.1 SiO2,28.7 CaO,8.8 MgO,6.2 P2O5,5.7 CaF2,4.5 Na2O),that has already been evaluated in-vitro,in-vivo and in preliminary clinical trials.Before further application,however,BG1d-BG should be compared to the benchmark amongst BGs,the 45S5 Bioglass®composition,to classify its effect on cell viability,proliferation and osteogenic differentiation of human mesenchymal stem cells(MSCs).Therefore,in this study,the biocompatibility and osteogenic potential of both BGs were investigated in an indirect and direct culture setting to assess the effect of the ionic dissolution products and the BGs’physical presence on the cells.The results indicated an advantage of BG1d-BG over 45S5 Bioglass®regarding cell viability and proliferation.Both BGs induced an earlier onset of osteogenic differentiation and accelerated the expression of late osteoblast marker genes compared to the control group.In conclusion,BG1d-BG is an attractive candidate for further experimental investigation.The basic mechanisms behind the different impact on cell behavior should be assessed in further detail,e.g.by further alteration of the BG compositions.
基金support from AvH Foundation(Germany)EPLANET,Marie Sk lodowska-Curie Actions and ERC(European Union)+11 种基金A*MIDEXANRLabex P2IOOCEVURégion Auvergne-Rh?ne-Alpes(France)Key Research Program of Frontier Sciences of CASCAS PIFIThousand Talents ProgramSci.&Tech.Program of Guangzhou(China)RFBR,RSF and Yandex LLC(Russia)GVA,Xunta Gal and GENCAT(Spain)the Royal Society and the Leverhulme Trust(United Kingdom)。
文摘A search for the rare decay B^(0)→J/ψФis performed using Pp collision data collected with the LHCb dete-ctor at centre-of-mass energies of 7,8 and 13 TeV,corresponding to an integrated luminosity of9 fb.No significant signal of the decay is observed and an upper limitof 1.1x 10^(-7)at 90%confidence level is set on the branching fraction.
