Building prognostic models for breast cancer patients using clinical variables and hundreds of gene expression signatures

<p>Abstract</p> <p>Background</p> <p>Multiple breast cancer gene expression profiles have been developed that appear to provide similar abilities to predict outcome and may outperform clinical-pathologic criteria; however, the extent to which seemingly disparate profiles provide additive prognostic information is not known, nor do we know whether prognostic profiles perform equally across clinically defined breast cancer subtypes. We evaluated whether combining the prognostic powers of standard breast cancer clinical variables with a large set of gene expression signatures could improve on our ability to predict patient outcomes.</p> <p>Methods</p> <p>Using clinical-pathological variables and a collection of 323 gene expression "modules", including 115 previously published signatures, we build multivariate Cox proportional hazards models using a dataset of 550 node-negative systemically untreated breast cancer patients. Models predictive of pathological complete response (pCR) to neoadjuvant chemotherapy were also built using this approach.</p> <p>Results</p> <p>We identified statistically significant prognostic models for relapse-free survival (RFS) at 7 years for the entire population, and for the subgroups of patients with ER-positive, or Luminal tumors. Furthermore, we found that combined models that included both clinical and genomic parameters improved prognostication compared with models with either clinical or genomic variables alone. Finally, we were able to build statistically significant combined models for pathological complete response (pCR) predictions for the entire population.</p> <p>Conclusions</p> <p>Integration of gene expression signatures and clinical-pathological factors is an improved method over either variable type alone. Highly prognostic models could be created when using all patients, and for the subset of patients with lymph node-negative and ER-positive breast cancers. Other variables beyond gene expression and clinical-pathological variables, like gene mutation status or DNA copy number changes, will be needed to build robust prognostic models for ER-negative breast cancer patients. This combined clinical and genomics model approach can also be used to build predictors of therapy responsiveness, and could ultimately be applied to other tumor types.</p

Following damage, the majority of bone marrow-derived airway cells express an epithelial marker

<p>Abstract</p> <p>Background</p> <p>Adult-derived bone marrow stem cells are capable of reconstituting the haematopoietic system. However there is ongoing debate in the literature as to whether bone marrow derived cells have the ability to populate other tissues and express tissue specific markers. The airway has been an organ of major interest and was one of the first where this was demonstrated. We have previously demonstrated that the mouse airway can be repopulated by side population bone marrow transplanted cells. Here we investigate the frequency and phenotypic nature of these bone marrow derived cells.</p> <p>Methods</p> <p>Female mice were engrafted with male whole bone marrow or side population (SP) cells and subjected to detergent-induced damage after 3 months. Donor cells were identified by Y chromosome fluorescence in situ hybridisation and their phenotype was assessed by immunohistochemistry on the same sections. Slides were visualised by a combination of widefield and deconvolved microscopy and whole cells were analysed on cytospin preparations.</p> <p>Results</p> <p>The frequencies of engraftment of male cells in the airway of mice that show this (9/10), range from 1.0 – 1.6% with whole marrow and 0.6 – 1.5% with SP cells. Undamaged controls have only between 0.1 and 0.2% male cells in the trachea. By widefield microscopy analysis we find 60.2% (53/88) of male donor derived cells express cytokeratins as a marker of epithelial cells. These results were reinforced using deconvolved microscopy and scored by two independent investigators. In addition cytospin analysis of cells dissociated from the damaged trachea of engrafted mice also reveals donor derived Y chromosome positive cells that are immunopositive for cytokeratin. Using cytokeratin and the universal haematopoietic marker CD45 immunohistochemistry, we find the donor derived cells fall into four phenotypic classes. We do not detect cytokeratin positive cells in whole bone marrow using cytokeratin immunostaining and we do not detect any cytokeratin mRNA in SP or bone marrow samples by RT-PCR.</p> <p>Conclusion</p> <p>The appearance of bone marrow derived cells in the tracheal epithelium is enriched by detergent-induced tissue damage and the majority of these cells express an epithelial marker. The cytokeratin positive donor derived cells in the tracheal epithelium are not present in the injected donor cells and must have acquired this novel phenotype <it>in vivo</it>.</p

Test of lepton universality in b→sℓ+ℓ−b \rightarrow s \ell^+ \ell^- decays

The first simultaneous test of muon-electron universality using $B^{+}\rightarrow K^{+}\ell^{+}\ell^{-}$ and $B^{0}\rightarrow K^{*0}\ell^{+}\ell^{-}$ decays is performed, in two ranges of the dilepton invariant-mass squared, $q^{2}$. The analysis uses beauty mesons produced in proton-proton collisions collected with the LHCb detector between 2011 and 2018, corresponding to an integrated luminosity of 9 $\mathrm{fb}^{-1}$. Each of the four lepton universality measurements reported is either the first in the given $q^{2}$ interval or supersedes previous LHCb measurements. The results are compatible with the predictions of the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-046.html (LHCb public pages

Precision measurement of CP\it{CP} violation in the penguin-mediated decay Bs0→ϕϕB_s^{0}\rightarrow\phi\phi

A flavor-tagged time-dependent angular analysis of the decay $B_s^{0}\rightarrow\phi\phi$ is performed using $pp$ collision data collected by the LHCb experiment at % at $\sqrt{s}=13$ TeV, the center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 6 fb^{-1}. The $\it{CP}$-violating phase and direct $\it{CP}$-violation parameter are measured to be $\phi_{s\bar{s}s} = -0.042 \pm 0.075 \pm 0.009$ rad and $|\lambda|=1.004\pm 0.030 \pm 0.009$, respectively, assuming the same values for all polarization states of the $\phi\phi$ system. In these results, the first uncertainties are statistical and the second systematic. These parameters are also determined separately for each polarization state, showing no evidence for polarization dependence. The results are combined with previous LHCb measurements using $pp$ collisions at center-of-mass energies of 7 and 8 TeV, yielding $\phi_{s\bar{s}s} = -0.074 \pm 0.069$ rad and $|lambda|=1.009 \pm 0.030$. This is the most precise study of time-dependent $\it{CP}$ violation in a penguin-dominated $B$ meson decay. The results are consistent with $\it{CP}$ symmetry and with the Standard Model predictions.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-001.html (LHCb public pages

First observation of a doubly charged tetraquark and its neutral partner

A combined amplitude analysis is performed for the decays $B^0 \rightarrow \overline{D}^0 D^+_s\pi^-$ and $B^+\rightarrow D^- D^+_s\pi^+$, which are related by isospin symmetry. The analysis is based on data collected by the LHCb detector in proton-proton collisions at center-of-mass energies of 7, 8 and 13$\,\rm{TeV}$. The full data sample corresponds to an integrated luminosity of 9$\,\rm{fb^{-1}}$. Two new resonant states with masses of $2.908\pm0.011\pm0.020\,\rm{GeV}$ and widths of $0.136\pm0.023\pm0.011\,\rm{GeV}$ are observed, which decay to $D^+_s\pi^+$ and $D^+_s\pi^-$ respectively. The former state indicates the first observation of a doubly charged open-charm tetraquark state with minimal quark content $[c\bar{s}u\bar{d}]$, and the latter state is a neutral tetraquark composed of $[c\bar{s}\bar{u}d]$ quarks. Both states are found to have spin-parity $0^+$, and their resonant parameters are consistent with each other, which suggests that they belong to an isospin triplet.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-026.html (LHCb public pages

Observation of Two New Excited Ξb0 States Decaying to Λb0 K-π+

Two narrow resonant states are observed in the Λb0K-π+ mass spectrum using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV, collected by the LHCb experiment and corresponding to an integrated luminosity of 6 fb-1. The minimal quark content of the Λb0K-π+ system indicates that these are excited Ξb0 baryons. The masses of the Ξb(6327)0 and Ξb(6333)0 states are m[Ξb(6327)0]=6327.28-0.21+0.23±0.12±0.24 and m[Ξb(6333)0]=6332.69-0.18+0.17±0.03±0.22 MeV, respectively, with a mass splitting of Δm=5.41-0.27+0.26±0.12 MeV, where the uncertainties are statistical, systematic, and due to the Λb0 mass measurement. The measured natural widths of these states are consistent with zero, with upper limits of Γ[Ξb(6327)0]&lt;2.20(2.56) and Γ[Ξb(6333)0]&lt;1.60(1.92) MeV at a 90% (95%) credibility level. The significance of the two-peak hypothesis is larger than nine (five) Gaussian standard deviations compared to the no-peak (one-peak) hypothesis. The masses, widths, and resonant structure of the new states are in good agreement with the expectations for a doublet of 1D Ξb0 resonances

Observation of a resonant structure near the Ds+Ds−D_s^+ D_s^- threshold in the B+→Ds+Ds−K+B^+\to D_s^+ D_s^- K^+ decay

An amplitude analysis of the $B^+\to D_s^+ D_s^- K^+$ decay is carried out to study for the first time its intermediate resonant contributions, using proton-proton collision data collected with the LHCb detector at centre-of-mass energies of 7, 8 and 13 TeV. A near-threshold peaking structure, referred to as $X(3960)$, is observed in the $D_s^+ D_s^-$ invariant-mass spectrum with significance greater than 12 standard deviations. The mass, width and the quantum numbers of the structure are measured to be $3956\pm5\pm10$ MeV, $43\pm13\pm8$ MeV and $J^{PC}=0^{++}$, respectively, where the first uncertainties are statistical and the second systematic. The properties of the new structure are consistent with recent theoretical predictions for a state composed of $c\bar{c}s\bar{s}$ quarks. Evidence for an additional structure is found around 4140 MeV in the $D_s^+ D_s^-$ invariant mass, which might be caused either by a new resonance with the $0^{++}$ assignment or by a $J/\psi \phi\leftrightarrow D_s^+ D_s^-$ coupled-channel effect.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-018.html (LHCb public pages

Measurement of the Λb0→Λ(1520)μ+μ−\Lambda_{b}^{0}\to \Lambda(1520) \mu^{+}\mu^{-} differential branching fraction

The branching fraction of the rare decay $\Lambda_{b}^{0}\to \Lambda(1520) \mu^{+}\mu^{-}$ is measured for the first time, in the squared dimuon mass intervals, $q^2$, excluding the $J/\psi$ and $\psi(2S)$ regions. The data sample analyzed was collected by the LHCb experiment at center-of-mass energies of 7, 8, and 13 TeV, corresponding to a total integrated luminosity of $9\ \mathrm{fb}^{-1}$. The result in the highest$q^{2}$interval,$q^{2} >15.0\ \mathrm{GeV}^2/c^4$, where theoretical predictions have the smallest model dependence, agrees with the predictions.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-050.html (LHCb public pages

Precise determination of the B-s(0)-B-s(-0) oscillation frequency

Mesons comprising a beauty quark and a strange quark can oscillate between particle (B0s) and antiparticle (B0s) flavour eigenstates, with a frequency given by the mass difference between heavy and light mass eigenstates, deltams. Here we present ameasurement of deltams using B0s2DsPi decays produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The oscillation frequency is found to be deltams = 17.7683 +- 0.0051 +- 0.0032 ps-1, where the first uncertainty is statistical and the second systematic. This measurement improves upon the current deltams precision by a factor of two. We combine this result with previous LHCb measurements to determine deltams = 17.7656 +- 0.0057 ps-1, which is the legacy measurement of the original LHCb detector.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2021-005.html (LHCb public pages