Combining single-cell tracking and omics improves blood stem cell fate regulator identification.

Molecular programs initiating cell fate divergence (CFD) are difficult to identify. Current approaches usually compare cells long after CFD initiation, therefore missing molecular changes at its start. Ideally, single cells that differ in their CFD molecular program but are otherwise identical are compared early in CFD. This is possible in diverging sister cells, which were identical until their mother's division and thus differ mainly in CFD properties. In asymmetrically dividing cells, divergent daughter fates are prospectively committed during division, and diverging sisters can thus be identified at the start of CFD. Using asymmetrically dividing blood stem cells, we developed a pipeline (ie, trackSeq) for imaging, tracking, isolating, and transcriptome sequencing of single cells. Their identities, kinship, and histories are maintained throughout, massively improving molecular noise filtering and candidate identification. In addition to many identified blood stem CFD regulators, we offer here this pipeline for use in CFDs other than asymmetric division.

Search for an Axionlike Particle in B Meson Decays.

Axionlike particles (ALPs) are predicted in many extensions of the standard model, and their masses can naturally be well below the electroweak scale. In the presence of couplings to electroweak bosons, these particles could be emitted in flavor-changing B meson decays. We report herein a search for an ALP, a, in the reaction B^{±}→K^{±}a, a→γγ using data collected by the BABAR experiment at SLAC. No significant signal is observed, and 90% confidence level upper limits on the ALP coupling to electroweak bosons are derived as a function of ALP mass, improving current constraints by several orders of magnitude in the range 0.175 GeV

Search for Darkonium in e

Collider searches for dark sectors, new particles interacting only feebly with ordinary matter, have largely focused on identifying signatures of new mediators, leaving much of dark sector structures unexplored. In particular, the existence of dark matter bound states (darkonia) remains to be investigated. This possibility could arise in a simple model in which a dark photon (A^{'}) is light enough to generate an attractive force between dark fermions. We report herein a search for a J^{PC}=1^{--} darkonium state, the ϒ_{D}, produced in the reaction e^{+}e^{-}→γϒ_{D}, ϒ_{D}→A^{'}A^{'}A^{'}, where the dark photons subsequently decay into pairs of leptons or pions, using 514 fb^{-1} of data collected with the BABAR detector. No significant signal is observed, and we set bounds on the γ-A^{'} kinetic mixing as a function of the dark sector coupling constant for 0.001

Search for Lepton Flavor Violation in ϒ(3S)→e

We report on the first search for electron-muon lepton flavor violation (LFV) in the decay of a b quark and b antiquark bound state. We look for the LFV decay ϒ(3S)→e^{±}µ^{∓} in a sample of 118 million ϒ(3S) mesons from 27 fb^{-1} of data collected with the BABAR detector at the SLAC PEP-II e^{+}e^{-} collider operating with a 10.36 GeV center-of-mass energy. No evidence for a signal is found, and we set a limit on the branching fraction B[ϒ(3S)→e^{±}µ^{∓}]<3.6×10^{-7} at 90% C. L. This result can be interpreted as a limit Λ_{NP}/g_{NP}^{2}>80 TeV on the energy scale Λ_{NP} divided by the coupling-squared g_{NP}^{2} of relevant new physics (NP).

First-line high-dose therapy and autologous blood stem cell transplantation in patients with primary central nervous system non-Hodgkin lymphomas-a single-centre experience in 61 patients.

Primary central nervous system non-Hodgkin lymphomas (PCNS-NHLs) are extranodal B-cell lymphomas with poor prognosis. The role of high-dose therapy (HDT) followed by autologous blood stem cell transplantation (ASCT) as first-line therapy is still not clear. We retrospectively collected long-term follow up data of 61 consecutive patients with PCNS-NHL at the University Hospital Düsseldorf from January 2004 to December 2016. Thirty-six patients were treated with conventional chemoimmunotherapy (cCIT) only (CT-group). Seventeen patients received an induction cCIT followed by HDT and ASCT. In the CT-group, the overall response rate (ORR) was 61% (CR 47%, PR 14%), and there were 8% treatment-related deaths (TRD). Progression-free survival (PFS) was 31.8 months, and overall survival (OS) was 57.3 months. In the HDT-group, the ORR was 88% (59% CR, 29% PR), and there were 6% TRD. Median PFS and OS were not reached at 5 years. The 5-year PFS and OS were 64.7%. After a median follow up of 71 months, 10 patients (59%) were still alive in CR/PR following HDT and ASCT, one patient was treated for progressive disease (PD), and 7 had died (41%, 6 PD, 1 TRD). All patients achieving CR prior to HDT achieved durable CR. In the CT-group, 8 patients (22%) were alive in CR/PR after a median follow-up of 100 months. Twenty-eight patients died (78%, 24 PD, 2 TRD, 2 deaths in remission). In the univariate analysis, the HDT-group patients had significantly better PFS (not reached vs 31.8 months, p = 0.004) and OS (not reached vs 57.3 months, p = 0.021). The multivariate analysis showed HDT was not predictive for survival. Treatment with HDT + ASCT is feasible and offers the chance for long-term survival with low treatment-related mortality in younger patients. In this analysis, ORR, PFS and OS were better with HDT than with conventional cCIT alone. This result was not confirmed in the multivariate analysis, and further studies need to be done to examine the role of HDT in PCNSL.

Therapy-related myeloid neoplasms following treatment for multiple myeloma-a single center analysis.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) can be late complications following mutagenic treatment. Limited data is available on the outcome of patients developing therapy-related MDS and AML after treatment for multiple myeloma (MM). We identified 250 patients with therapy-associated MDS or AML in the Duesseldorf MDS registry. Of those, 50 patients were previously diagnosed with multiple myeloma (mm-MDS/AML). We compared them to patients with de novo MDS (n = 4862) and to patients with MDS following other underlying diseases (tMDS) (n = 200). mm-MDS patients and tMDS patients showed similar karyotypes and degrees of cytopenia. However, mm-MDS patients had significantly higher blast counts and more often belonged to the high-risk group according to the International Prognostic Scoring System (IPSS) (both p < 0.05). Although the rate of progression to AML was similar in mm-MDS and tMDS, both transformed significantly more often than de novo MDS (p < 0.05). Median overall survival of patients with mm-MDS (13 months; range: 1-99) and tMDS (13 months; range 0-160) was also similar yet significantly shorter than patients with de novo MDS (32 months; range 0-345 months; p < 0.05). Furthermore, survival of mm-MDS patients was not affected by myeloma activity. Despite significantly more high-risk disease and higher blast cell counts, myeloma-associated MDS-patients show features akin to other tMDS. Survival is similar to other tMDS and irrespective of myeloma remission status or transformation to AML. Thus, patient outcome is not determined by competing clones but rather by MDS governing the stem cell niche.

Analysis of the impact of adherence to guidelines and expert advice in patients with myelodysplastic syndromes.

The European Leukemia Net (ELN) guidelines for treatment of myelodysplastic syndromes (MDS) connect heterogeneous MDS subgroups with a number of therapeutic options ranging from best supportive care to allogeneic stem cell transplantation (alloSCT). However, it is currently unknown whether adherence to guideline recommendations translates into improved survival. The sizeable database of the Duesseldorf MDS Registry allowed us to address this question. We first performed a retrospective analysis including 1698 patients (cohort 1) to whom we retrospectively applied the ELN guidelines. We compared patients treated according to the guidelines with patients who deviated from it, either because they received a certain treatment though it was not recommended or because they did not receive that treatment despite being eligible. We also performed a prospective study with 381 patients (cohort 2) who were seen in our department and received guideline-based expert advice. Again, we compared the impact of subsequent guideline-adherent versus non-adherent treatment. For the majority of treatment options (best supportive care, lenalidomide, hypomethylating agents, low-dose chemotherapy, and intensive chemotherapy), we found that adherence to the ELN guidelines did not improve survival in cohort 1. The same was true when patient management was prospectively enhanced through guideline-based treatment advice given by MDS experts (cohort 2). The only exceptions were alloSCT and iron chelation (ICT). Patients receiving ICT and alloSCT as recommended fared significantly better than those who were eligible but received other treatment. Our analysis underscores the limited survival impact of most MDS therapies and suggests to pursue alloSCT in all suitable candidates. Graphical abstract.

Precision Measurement of the Ratio B(ϒ(3S)→τ

We report on a precision measurement of the ratio R_{τµ}^{ϒ(3S)}=B(ϒ(3S)→τ^{+}τ^{-})/B(ϒ(3S)→µ^{+}µ^{-}) using data collected with the BABAR detector at the SLAC PEP-II e^{+}e^{-} collider. The measurement is based on a 28 fb^{-1} data sample collected at a center-of-mass energy of 10.355 GeV corresponding to a sample of 122 million ϒ(3S) mesons. The ratio is measured to be R_{τµ}^{ϒ(3S)}=0.966±0.008_{stat}±0.014_{syst} and is in agreement with the standard model prediction of 0.9948 within 2 standard deviations. The uncertainty in R_{τµ}^{ϒ(3S)} is almost an order of magnitude smaller than the only previous measurement.

Search for a Dark Leptophilic Scalar in e

Many scenarios of physics beyond the standard model predict the existence of new gauge singlets, which might be substantially lighter than the weak scale. The experimental constraints on additional scalars with masses in the MeV to GeV range could be significantly weakened if they interact predominantly with leptons rather than quarks. At an e^{+}e^{-} collider, such a leptophilic scalar (ϕ_{L}) would be produced predominantly through radiation from a τ lepton. We report herein a search for e^{+}e^{-}→τ^{+}τ^{-}ϕ_{L}, ϕ_{L}→ℓ^{+}ℓ^{-} (ℓ=e, µ) using data collected by the BABAR experiment at SLAC. No significant signal is observed, and we set limits on the ϕ_{L} coupling to leptons in the range 0.04

Search for Rare or Forbidden Decays of the D

We present a search for nine lepton-number-violating and three lepton-flavor-violating neutral charm decays of the type D^{0}→h^{'-}h^{-}ℓ^{'+}ℓ^{+} and D^{0}→h^{'-}h^{+}ℓ^{'±}ℓ^{∓}, where h and h^{'} represent a K or π meson and ℓ and ℓ^{'} an electron or muon. The analysis is based on 468 fb^{-1} of e^{+}e^{-} annihilation data collected at or close to the ϒ(4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. No significant signal is observed for any of the twelve modes, and we establish 90% confidence level upper limits on the branching fractions in the range (1.0-30.6)×10^{-7}. The limits are between 1 and 3 orders of magnitude more stringent than previous measurements.

Measurements of the Absolute Branching Fractions of B

A study of the two-body decays B^{±}→X_{cc[over ¯]}K^{±}, where X_{cc[over ¯]} refers to one charmonium state, is reported by the BABAR Collaboration using a data sample of 424 fb^{-1}. The absolute determination of branching fractions for these decays are significantly improved compared to previous BABAR measurements. Evidence is found for the decay B^{+}→X(3872)K^{+} at the 3σ level. The absolute branching fraction B[B^{+}→X(3872)K^{+}]=[2.1±0.6(stat)±0.3(syst)]×10^{-4} is measured for the first time. It follows that B[X(3872)→J/ψπ^{+}π^{-}]=(4.1±1.3)%, supporting the hypothesis of a molecular component for this resonance.

Mapping distribution of brain metastases: does the primary tumor matter?

PURPOSE: Prior reports on the location and sizes of brain metastases almost entirely focus on patients with primary breast and pulmonary cancer. This is the first study comparing multiple other types of cancer that metastasize to the brain. METHODS: This monocentric retrospective study includes 369 untreated patients with 3313 intraaxial brain metastases. Following semi-manual segmentation of metastases on post-contrast T1WI, cumulative spatial probability distribution maps of brain metastases were created for the whole group and for all primary tumors. Furthermore, mixed effects logistic regression model analysis was performed to determine if the primary tumor, patient age, and patient sex influence lesion location. RESULTS: The cerebellum as location of brain metastases was proportionally overrepresented. Breast and pulmonary cancer caused higher number of brain metastases to what would normally be expected. Multivariate analyses revealed a significant accumulation of brain metastases from skin cancer in a frontal and from breast and gastrointestinal cancer in a cerebellar location. CONCLUSION: Distribution of brain metastases is very heterogeneous for the distinct primaries, possibly reflecting the diversity of mechanisms involved in brain metastases formation. In daily clinical practice distribution patters may be beneficial to predict the primary cancer site, if unknown.

Extraction of form Factors from a Four-Dimensional Angular Analysis of B[over ¯]→D

An angular analysis of the decay B[over ¯]→D^{*}ℓ^{-}ν[over ¯]_{ℓ}, ℓ∈{e,µ}, is reported using the full e^{+}e^{-} collision data set collected by the BABAR experiment at the ϒ(4S) resonance. One B meson from the ϒ(4S)→BB[over ¯] decay is fully reconstructed in a hadronic decay mode, which constrains the kinematics and provides a determination of the neutrino momentum vector. The kinematics of the semileptonic decay is described by the dilepton mass squared, q^{2}, and three angles. The first unbinned fit to the full four-dimensional decay rate in the standard model is performed in the so-called Boyd-Grinstein-Lebed approach, which employs a generic q^{2} parametrization of the underlying form factors based on crossing symmetry, analyticity, and QCD dispersion relations for the amplitudes. A fit using the more model-dependent Caprini-Lellouch-Neubert (CLN) approach is performed as well. Our form factor shapes show deviations from previous fits based on the CLN parametrization. The latest form factors also provide an updated prediction for the branching fraction ratio R(D^{*})≡B(B[over ¯]→D^{*}τ^{-}ν[over ¯]_{τ})/B(B[over ¯]→D^{*}ℓ^{-}ν[over ¯]_{ℓ})=0.253±0.005. Finally, using the well-measured branching fraction for the B[over ¯]→D^{*}ℓ^{-}ν[over ¯]_{ℓ} decay, a value of |V_{cb}|=(38.36±0.90)×10^{-3} is obtained that is consistent with the current world average for exclusive B[over ¯]→D^{(*)}ℓ^{-}ν[over ¯]_{ℓ} decays and remains in tension with the determination from inclusive semileptonic B decays to final states with charm.

Observation of the Decay D

We report the observation of the rare charm decay D^{0}→K^{-}π^{+}e^{+}e^{-}, based on 468 fb^{-1} of e^{+}e^{-} annihilation data collected at or close to the center-of-mass energy of the ϒ(4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. We find the branching fraction in the invariant mass range 0.675

Search for a Stable Six-Quark State at BABAR.

Recent investigations have suggested that the six-quark combination uuddss could be a deeply bound state (S) that has eluded detection so far, and a potential dark matter candidate. We report the first search for a stable, doubly strange six-quark state in ϒ→SΛ[over ¯]Λ[over ¯] decays based on a sample of 90×10^{6}ϒ(2S) and 110×10^{6}ϒ(3S) decays collected by the BABAR experiment. No signal is observed, and 90% confidence level limits on the combined ϒ(2S,3S)→SΛ[over ¯]Λ[over ¯] branching fraction in the range (1.2-1.4)×10^{-7} are derived for m_{S}<2.05 GeV. These bounds set stringent limits on the existence of such exotic particles.

Search for B

We search for the rare flavor-changing neutral current process B^{+}→K^{+}τ^{+}τ^{-} using data from the BABAR experiment. The data sample, collected at the center-of-mass energy of the ϒ(4S) resonance, corresponds to a total integrated luminosity of 424 fb^{-1} and to 471×10^{6} BB[over ¯] pairs. We reconstruct one B meson, produced in the ϒ(4S)→B^{+}B^{-} decay, in one of many hadronic decay modes and search for activity compatible with a B^{+}→K^{+}τ^{+}τ^{-} decay in the rest of the event. Each τ lepton is required to decay leptonically into an electron or muon and neutrinos. Comparing the expected number of background events with the data sample after applying the selection criteria, we do not find evidence for a signal. The resulting upper limit, at the 90% confidence level, is B(B^{+}→K^{+}τ^{+}τ^{-})<2.25×10^{-3}.

Search for Invisible Decays of a Dark Photon Produced in e

We search for single-photon events in 53 fb^{-1} of e^{+}e^{-} collision data collected with the BABAR detector at the PEP-II B-Factory. We look for events with a single high-energy photon and a large missing momentum and energy, consistent with production of a spin-1 particle A^{'} through the process e^{+}e^{-}→γA^{'}; A^{'}→invisible. Such particles, referred to as "dark photons," are motivated by theories applying a U(1) gauge symmetry to dark matter. We find no evidence for such processes and set 90% confidence level upper limits on the coupling strength of A^{'} to e^{+}e^{-} in the mass range m_{A^{'}}≤8 GeV. In particular, our limits exclude the values of the A^{'} coupling suggested by the dark-photon interpretation of the muon (g-2)_{µ} anomaly, as well as a broad range of parameters for the dark-sector models.

Measurement of the D

We measure the mass difference, Δm_{+}, between the D^{*}(2010)^{+} and the D^{+} using the decay chain D^{*}(2010)^{+}→D^{+}π^{0} with D^{+}→K^{-}π^{+}π^{+}. The data were recorded with the BABAR detector at center-of-mass energies at and near the ϒ(4S) resonance, and correspond to an integrated luminosity of approximately 468 fb^{-1}. We measure Δm_{+}=(140 601.0±6.8[stat]±12.9[syst]) keV. We combine this result with a previous BABAR measurement of Δm_{0}≡m(D^{*}(2010)^{+})-m(D^{0}) to obtain Δm_{D}=m(D^{+})-m(D^{0})=(4824.9±6.8[stat]±12.9[syst]) keV. These results are compatible with and approximately five times more precise than the Particle Data Group averages.

Assessment of Competence in EVAR Stent Graft Sizing and Selection.

OBJECTIVES AND BACKGROUND: The aims of this study were to develop a test of competence in endovascular aortic repair (EVAR) stent graft sizing and selection; to examine the test for evidence of validity; and to explore the experience required for the task. METHODS: The test was developed based on a literature review resulting in 22 anatomical assessment points and a graft selection. Validity evidence was explored in an international cross sectional study. Twenty-two consultants with varying levels of experience in the field (novices, intermediates, and experts) were presented with computed tomography angiography of the aortic vessels from three patients. Test scores were based on summed z-scores using the anatomical measurements and graft choices of the experts as a reference. A proficiency score was established using the contrasting groups standard setting method. RESULTS: The assessment was shown to be reliable with an intraclass correlation coefficient of 0.83 (p<.001) and high internal consistency with a Cronbach's α of .91 (p<.001). Mann-Whitney U test showed that experts performed significantly better than novices and intermediates (p<.002 and p<.005, respectively). Regarding anatomical measurements, Mann-Whitney U test could discriminate between experts and novices (p=.002), between experts and intermediates (p=.010), and between novices and intermediates (p=.036). In stent selection the experts performed significantly better than both the novices and the intermediates (p=.002 and p=.007, respectively), while there was no significant difference between the two non-expert groups (p=1). A credible passing standard with appropriate consequences was established using the contrasting groups methods. CONCLUSION: This study presents a standardised and objective assessment tool of competence in vessel analysis and stent graft selection for endovascular aortic repair. This was supported by strong validity evidence with good internal consistency and discriminatory ability. The tool may be used to facilitate training and certification of future endovascular specialists.

Assessment of Competence in EVAR Procedures: A Novel Rating Scale Developed by the Delphi Technique.

OBJECTIVE/BACKGROUND: To develop a procedure specific global rating scale for assessment of operator competence in endovascular aortic repair (EVAR). METHODS: A Delphi approach was used to achieve expert consensus. A panel of 32 international experts (median 300 EVAR procedures, range 200-3000) from vascular surgery (n = 21) and radiology (n = 11) was established. The first Delphi round was based on a review of endovascular skills assessment papers, stent graft instructions for use, and structured interviews. It led to a primary pool of 83 items that were formulated as global rating scale items with tentative anchors. Iterative Delphi rounds were executed. The panellists rated the importance of each item on a 5 point Likert scale. Consensus was defined as 80% of the panel rating an item 4 or 5 in the primary round and 90% in subsequent rounds. Consensus on the final assessment tool was defined as Cronbach's alpha > .8 after a minimum of three rounds. RESULTS: Thirty-two of 35 invited experts participated. Three rounds of surveys were completed with a completion rate of 100% in the first two rounds and 91% in round three. The 83 primary assessment items were supplemented with five items suggested by the panel and reduced to seven pivotal assessment items that reached consensus, Cronbach's alpha = 0.82. The seven item rating scale covers key elements of competence in EVAR stent placement and deployment. Each item has well defined grades with explicit anchors at unacceptable, acceptable, and superior performance on a 5 point Likert scale. CONCLUSION: The Delphi methodology allowed for international consensus on a new procedure specific global rating scale for assessment of competence in EVAR. The resulting scale, EndoVascular Aortic Repair Assessment of Technical Expertise (EVARATE), represents key elements in the procedure. EVARATE constitutes an assessment tool for providing structured feedback to endovascular operators in training.