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An event by event analysis is carried out for all charged particles observed in central collisions of 40Ar + KCl and 40Ar + Pb at 1.808 and 0.772 GeV/nucleon, respectively. Total transverse energy is used for impact parameter selection within the central trigger condition. The central Ar + KCl reaction exhibits a forward-backward oriented momentum flux. The flux distribution of the most central Ar + Pb events is approximately isotropic in the fireball center of mass.
Proton emission in relativistic nuclear collisions is examined for events of low and high multiplicity, corresponding to large and small impact parameters. Peripheral reactions exhibit distributions of protons in agreement with spectator-participant decay modes. Central collisions of equal-size nuclei are dominated by the formation and decay of a fireball system. Central collisions of light projectiles with heavy targets exhibit an enhancement in sideward emission which is predicted by recent hydrodynamical calculations.
Inclusive energy spectra of protons, deuterons, and tritons were measured with a telescope of silicon and germanium detectors with a detection range for proton energies up to 200 MeV. Fifteen sets of data were taken using projectiles ranging from protons to 40Ar on targets from 27Al to 238U at bombarding energies from 240 MeV/nucleon to 2.1 GeV/nucleon. Particular attention was paid to the absolute normalization of the cross sections. For three previously reported reactions, He fragment cross sections have been corrected and are presented. To facilitate a comparison with theory the sum of nucleonic charges emitted as protons plus composite particles was estimated and is presented as a function of fragment energy per nucleon in the interval from 15 to 200 MeV/nucleon. For low-energy fragments at forward angles the protons account for only 25% of the nucleonic charges. The equal mass 40Ar plus Ca systems were examined in the center of mass. Here at 0.4 GeV/nucleon 40Ar plus Ca the proton spectra appear to be nearly isotropic in the center of mass over the region measured. Comparisons of some data with firestreak, cascade, and fluid dynamics models indicate a failure of the first and a fair agreement with the latter two. In addition, associated fast charged particle multiplicities (where the particles had energies larger than 25 MeV/nucleon) and azimuthal correlations were measured with an 80 counter array of plastic scintillators. It was found that the associated multiplicities were a smooth function of the total kinetic energy of the projectile. NUCLEAR REACTIONS U(20Ne,X), E / A=240 MeV/nucleon; U(40Ar,X), Ca(40Ar,X), U(20Ne,X), Au(20Ne,X), Ag(20Ne,X), Al(20Ne,X), U(4He,X), Al(4He,X), E / A=390 MeV/nucleon; U(40Ar,X), Ca(40Ar,X), U(20Ne,X), U(4He,X), U(p,X), E / A=1.04 GeV/nucleon; U(20Ne,X), E / A=2.1 GeV/nucleon; measured sigma (E, theta ), X=p,d,t.
Pion-production cross sections have been measured for the reaction 40Ar+40Ca--> pi ++X at a laboratory energy of 1.05 GeV/nucleon. A maximum in the pi + cross section occurs at mid-rapidity, which is anomalous relative to p+p and p+nucleus reactions and compared to many other heavy-ion reactions. Calculations based on cascade and thermal models fail to fit the data.
The negative-pion multiplicity is measured for central collisions of 40Ar with KCl at eight energies from 0.36 to 1.8 GeV/nucleon and for 4He on KCl and 40Ar on BaI2 at 977 and 772 MeV/nucleon, respectively. A systematic discrepancy with a cascade-model calculation which fits proton- and pion-nucleus cross sections but omits potential-energy effects is used to derive the energy going into bulk compression of the system. A value of the incompressibility constant of K=240 MeV is extracted in a parabolic form of the nuclear-matter equation of state.
Pion production and charged-particle multiplicity selection in relativistic nuclear collisions
(1982)
Spectra of positive pions with energies of 15-95 MeV were measured for high energy proton, 4He, 20Ne, and 40Ar bombardments of targets of 27Al, 40Ca, 107,109Ag, 197Au, and 238U. A Si-Ge telescope was used to identify charged pions by dE / dx-E and, in addition, stopped pi + were tagged by the subsequent muon decay. In all, results for 14 target-projectile combinations are presented to study the dependence of pion emission patterns on the bombarding energy (from E / A=0.25 to 2.1 GeV) and on the target and the projectile masses. In addition, associated charged-particle multiplicities were measured in an 80-paddle array of plastic scintillators, and used to make impact parameter selections on the pion-inclusive data. NUCLEAR REACTIONS U(20Ne, pi +), E / A=250 MeV; U(40Ar, pi +), Ca(40Ar, pi +), U(20Ne, pi +), Au(20Ne, pi +), Ag(20Ne, pi +), Al(20Ne, pi +), U(4He, pi +), Al(4He, pi +). E / A=400 MeV; Ca(40Ar, pi +), U(20Ne, pi +), U(4He, pi +), U(p, pi +), E / A=1.05), GeV; U(20Ne, pi +), E / A=2.1 GeV; measured sigma (E, theta ), inclusive and selected on associated charged-particle multiplicity.
Lambda 's produced in central collisions of 40Ar+KC1 at 1.8-GeV/u incident energy were detected in a streamer chamber by their charged-particle decay. For central collisions with impact parameters b<2.4 fm the Lambda production cross section is 7.6±2.2 mb. A calculation in which Lambda production occurs in the early stage of the collision qualitatively reproduces the results but underestimates the transverse momenta. An average Lambda polarization of -0.10±0.05 is observed. PACS numbers: 25.70 Bc
Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at sqrt[sNN] = 130 GeV using the STAR Time Projection Chamber at the Relativistic Heavy Ion Collider. The elliptic flow signal, v2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.
Pion and proton production are measured to investigate thermal equilibrium in central collisions of 40Ar+KCl at 1.8 GeV/nucleon. The bulk of the pion yield is isotropic in the c.m. system, with an apparent temperature of 58±3 MeV, much lower than the 118±2 MeV of the protons. It is shown that the low pion "temperature" can be explained by the decay kinematics of delta resonances in thermal equilibrium. A (5±1)% component in the pion spectrum is, however, found to have a temperature of 110±10 MeV. The effect on the spectra of possible contributions from collective radial flow is discussed.
Background: We analyzed whether co-occurring mutations influence the outcome of systemic therapy in ALK-rearranged non-small-cell lung cancer (NSCLC).
Patients and methods: ALK-rearranged stage IIIB/IV NSCLC patients were analyzed with next-generation sequencing and fluorescence in situ hybridization analyses on a centralized diagnostic platform. Median progression-free survival (PFS) and overall survival (OS) were determined in the total cohort and in treatment-related sub-cohorts. Cox regression analyses were carried out to exclude confounders.
Results: Among 216 patients with ALK-rearranged NSCLC, the frequency of pathogenic TP53 mutations was 23.8%, while other co-occurring mutations were rare events. In ALK/TP53 co-mutated patients, median PFS and OS were significantly lower compared with TP53 wildtype patients [PFS 3.9 months (95% CI: 2.4–5.6) versus 10.3 months (95% CI: 8.6–12.0), P < 0.001; OS 15.0 months (95% CI: 5.0–24.9) versus 50.0 months (95% CI: 22.9–77.1), P = 0.002]. This difference was confirmed in all treatment-related subgroups including chemotherapy only [PFS first-line chemotherapy 2.6 months (95% CI: 1.3–4.1) versus 6.2 months (95% CI: 1.8–10.5), P = 0.021; OS 2.0 months (95% CI: 0.0–4.6) versus 9.0 months (95% CI: 6.1–11.9), P = 0.035], crizotinib plus chemotherapy [PFS crizotinib 5.0 months (95% CI: 2.9–7.2) versus 14.0 months (95% CI: 8.0–20.1), P < 0.001; OS 17.0 months (95% CI: 6.7–27.3) versus not reached, P = 0.049] and crizotinib followed by next-generation ALK-inhibitor [PFS next-generation inhibitor 5.4 months (95% CI: 0.1–10.7) versus 9.9 months (95% CI: 6.4–13.5), P = 0.039; OS 7.0 months versus 50.0 months (95% CI: not reached), P = 0.001).
Conclusions: In ALK-rearranged NSCLC co-occurring TP53 mutations predict an unfavorable outcome of systemic therapy. Our observations encourage future research to understand the underlying molecular mechanisms and to improve treatment outcome of the ALK/TP53 co-mutated subgroup.
Rho GTPases are involved in homing and mobilization of hematopoietic stem and progenitor cells due to their impact on cytoskeleton remodeling. We have previously shown that inhibition of Rho, Rac and Cdc42 clearly impairs adhesion of normal and leukemic hematopoietic progenitor cells (HPC) to fibronectin and migration in a three-dimensional stromal cell model. Here, we identified the Ras GTPase-Activating Protein SH3 Domain-Binding Protein (G3BP) as a target gene of Rho GTPases and analysed its role in regulating HPC motility. Overexpression of G3BP significantly enhanced adhesion of murine 32D HPC to fibronectin and human umbilical vein endothelial cells, increased the proportion of adherent cells in a flow chamber assay and promoted cell migration in a transwell assay and a three-dimensional stromal cell model suggesting a strong impact on the cytoskeleton. Immunofluorescent staining of G3BP-overexpressing fibroblasts revealed a Rho-like phenotype characterized by formation of actin stress fibers in contrast to the Rac-like phenotype of control fibroblasts. This is the first report implicating a role for G3BP in Rho GTPase-mediated signalling towards adhesion and migration of HPC. Our results may be of clinical importance, since G3BP was found overexpressed in human cancers.
Exclusive pi - and charged-particle production in collisions of Ar+KCl is studied at incident energies from 0.4 to 1.8 GeV/u. Complete disintegration of both nuclei is observed. The correlation between pi - and total charge multiplicity shows no islands of anomalous pion production. For constant numbers of proton participants the pi - multiplicity distributions are Poissons. For central collisions <n pi -> increases smoothly and to first order linearly with the c.m. energy. Disagreement with the firestreak model is found. Pacs numbers: 25.70.Hi, 24.10.Dp
Elliptic flow from nuclear collisions is a hadronic observable sensitive to the early stages of system evolution. We report first results on elliptic flow of charged particles at midrapidity in Au+Au collisions at sqrt(s_NN)=130 GeV using the STAR TPC at RHIC. The elliptic flow signal, v_2, averaged over transverse momentum, reaches values of about 6% for relatively peripheral collisions and decreases for the more central collisions. This can be interpreted as the observation of a higher degree of thermalization than at lower collision energies. Pseudorapidity and transverse momentum dependence of elliptic flow are also presented.
Background: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date.
Patients and methods: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions).
Results: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1.
Conclusions: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.
Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.
Background: While recent data show that crizotinib is highly effective in patients with ROS1 rearrangement, few data is available about the prognostic impact, the predictive value for different treatments, and the genetic heterogeneity of ROS1- positive patients.
Patients and methods: 1137 patients with adenocarcinoma of the lung were analyzed regarding their ROS1 status. In positive cases, next-generation sequencing (NGS) was performed. Clinical characteristics, treatments and outcome of these patients were assessed. Overall survival (OS) was compared with genetically defined subgroups of ROS1-negative patients.
Results: 19 patients of 1035 evaluable (1.8%) had ROS1-rearrangement. The median OS has not been reached. Stage IV patients with ROS1-rearrangement had the best OS of all subgroups (36.7 months, p < 0.001). 9 of 14 (64.2%) patients had at least one response to chemotherapy. Estimated mean OS for patients receiving chemotherapy and crizotinib was 5.3 years. Ten patients with ROS1-rearrangement (52.6%) harbored additional aberrations.
Conclusion: ROS1-rearangement is not only a predictive marker for response to crizotinib, but also seems to be the one of the best prognostic molecular markers in NSCLC reported so far. In stage IV patients, response to chemotherapy was remarkable high and overall survival was significantly better compared to other subgroups including EGFR-mutated and ALK-fusion-positive NSCLC.
Children’s and adolescents’ lives drastically changed during COVID lockdowns worldwide. To compare accident- and injury-related admissions to pediatric intensive care units (PICU) during the first German COVID lockdown with previous years, we conducted a retrospective multicenter study among 37 PICUs (21.5% of German PICU capacities). A total of 1444 admissions after accidents or injuries during the first lockdown period and matched periods of 2017–2019 were reported and standardized morbidity ratios (SMR) were calculated. Total PICU admissions due to accidents/injuries declined from an average of 366 to 346 (SMR 0.95 (CI 0.85–1.05)). Admissions with trauma increased from 196 to 212 (1.07 (0.93–1.23). Traffic accidents and school/kindergarten accidents decreased (0.77 (0.57–1.02 and 0.26 (0.05–0.75)), whereas household and leisure accidents increased (1.33 (1.06–1.66) and 1.34 (1.06–1.67)). Less neurosurgeries and more visceral surgeries were performed (0.69 (0.38–1.16) and 2.09 (1.19–3.39)). Non-accidental non-suicidal injuries declined (0.73 (0.42–1.17)). Suicide attempts increased in adolescent boys (1.38 (0.51–3.02)), but decreased in adolescent girls (0.56 (0.32–0.79)). In summary, changed trauma mechanisms entailed different surgeries compared to previous years. We found no evidence for an increase in child abuse cases requiring intensive care. The increase in suicide attempts among boys demands investigation.