678 research outputs found
Compatibility of phenomenological dipole cross sections with the Balitsky-Kovchegov equation
Phenomenological models of the dipole cross section that enters in the
description of for instance deep inelastic scattering at very high energies
have had considerable success in describing the available small-x data in both
the saturation region and the so-called extended geometric scaling (EGS)
region. We investigate to what extent such models are compatible with the
numerical solutions of the Balitsky-Kovchegov (BK) equation which is expected
to describe the nonlinear evolution in x of the dipole cross section in these
momentum regions. We find that in the EGS region the BK equation yields results
that are qualitatively different from those of phenomenological studies. In
particular, geometric scaling around the saturation scale is only obtained at
asymptotic rapidities. We find that in this limit, the anomalous dimension
\gamma(r,x) of phenomenological models approaches a limiting function that is
universal for a large range of initial conditions. At the saturation scale,
this function equals approximately 0.44, in contrast to the value 0.628
commonly used in the models. We further investigate the dependence of these
results on the starting distribution, the small-r limit of the anomalous
dimension for fixed rapidities and the x-dependence of the saturation scale.Comment: 14 pages, 8 figures. Extensive revisions, several new results, plots,
references and conclusions added; to appear in Phys.Rev.
Geometric Scaling at RHIC and LHC
We present a new phenomenological model of the dipole scattering amplitude to
demonstrate that the RHIC data for hadron production in d-Au collisions for all
available rapidities are compatible with geometric scaling, just like the
small-x inclusive DIS data. A detailed comparison with earlier geometric
scaling violating models of the dipole scattering amplitude in terms of an
anomalous dimension gamma is made. In order to establish whether the geometric
scaling violations expected from small-x evolution equations are present in the
data a much larger range in transverse momentum and rapidity must be probed.
Predictions for hadron production in p-Pb and p-p collisions at LHC are given.
We point out that the fall-off of the transverse momentum distribution at LHC
is a sensitive probe of the variation of gamma in a region where x is much
smaller than at RHIC. In this way, the expectation for the rise of gamma from
small-x evolution can be tested.Comment: 11 pages, 6 figures, minor changes, references added; version to
appear in Phys.Rev.
The saturation scale and its x-dependence from Lambda polarization studies
The transverse polarization of forward Lambda hyperons produced in
high-energy p-A collisions is expected to display an extremum at a transverse
momentum around the saturation scale. This was first observed within the
context of the McLerran-Venugopalan model which has an x-independent saturation
scale. The extremum arises due to the k_t-odd nature of the polarization
dependent fragmentation function, which probes approximately the derivative of
the dipole scattering amplitude. The amplitude changes most strongly around the
saturation scale, resulting in a peak in the polarization. We find that the
observation also extends to the more realistic case in which the saturation
scale Q_s is x dependent. Since a range of x and therefore Q_s values is probed
at a given transverse momentum and rapidity, this result is a priori not
expected. Moreover, the measurement of Lambda polarization over a range of x_F
values actually provides a direct probe of the x dependence of the saturation
scale. This novel feature is demonstrated for typical LHC kinematics and for
several phenomenological models of the dipole scattering amplitude. We show
that although the measurement will be challenging, it may be feasible at LHC.
The situation at RHIC is not favorable, because the peak will likely be at too
low transverse momentum of the Lambda to be a trustworthy measure of the
saturation scale.Comment: 11 pages, 6 figure
Intrinsic Resistance to MEK Inhibition in KRAS Mutant Lung and Colon Cancer through Transcriptional Induction of ERBB3
Summary There are no effective therapies for the ∼30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors. We show that MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance. Drugs targeting both EGFR and ERBB2, each capable of forming heterodimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM. Moreover, ERBB3 protein level is a biomarker of response to combinatorial treatment. These data suggest a combination strategy for treating KRAS mutant colon and lung cancers and a way to identify the tumors that are most likely to benefit from such combinatorial treatment
The Tumor Immune Landscape and Architecture of Tertiary Lymphoid Structures in Urothelial Cancer
Candidate immune biomarkers have been proposed for predicting response to immunotherapy in urothelial cancer (UC). Yet, these biomarkers are imperfect and lack predictive power. A comprehensive overview of the tumor immune contexture, including Tertiary Lymphoid structures (TLS), is needed to better understand the immunotherapy response in UC. We analyzed tumor sections by quantitative multiplex immunofluorescence to characterize immune cell subsets in various tumor compartments in tumors without pretreatment and tumors exposed to preoperative anti-PD1/CTLA-4 checkpoint inhibitors (NABUCCO trial). Pronounced immune cell presence was found in UC invasive margins compared to tumor and stroma regions. CD8+PD1+ T-cells were present in UC, particularly following immunotherapy. The cellular composition of TLS was assessed by multiplex immunofluorescence (CD3, CD8, FoxP3, CD68, CD20, PanCK, DAPI) to explore specific TLS clusters based on varying immune subset densities. Using a k-means clustering algorithm, we found five distinct cellular composition clusters. Tumors unresponsive to anti-PD-1/CTLA-4 immunotherapy showed enrichment of a FoxP3+ T-cell-low TLS cluster after treatment. Additionally, cluster 5 (macrophage low) TLS were significantly higher after pre-operative immunotherapy, compared to untreated tumors. We also compared the immune cell composition and maturation stages between superficial (submucosal) and deeper TLS, revealing that superficial TLS had more pronounced T-helper cells and enrichment of early TLS than TLS located in deeper tissue. Furthermore, superficial TLS displayed a lower fraction of secondary follicle like TLS than deeper TLS. Taken together, our results provide a detailed quantitative overview of the tumor immune landscape in UC, which can provide a basis for further studies
Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers
Background: Genomic gains and losses are a result of genomic instability in many types of cancers. BRCA1- and BRCA2-mutated breast cancers are associated with increased amounts of chromosomal aberrations, presumably due their functions in genome repair. Some of these genomic aberrations may harbor genes whose absence or overexpression may give rise to cellular growth advantage. So far, it has not been easy to identify the driver genes underlying gains and losses. A powerful approach to identify these driver genes could be a cross-species comparison of array comparative genomic hybridization (aCGH) data from cognate mouse and human tumors. Orthologous regions of mouse and human tumors that are commonly gained or lost might represent essential genomic regions selected for gain or loss during tumor development. Methods: To identify genomic regions that are associated with BRCA1- and BRCA2-mutated breast cancers we compared aCGH data from 130 mouse Brca1?/?;p53?/?, Brca2?/?;p53?/? and p53?/? mammary tumor groups with 103 human BRCA1-mutated, BRCA2-mutated and non-hereditary breast cancers. Results: Our genome-wide cross-species analysis yielded a complete collection of loci and genes that are commonly gained or lost in mouse and human breast cancer. Principal common CNAs were the well known MYCassociated gain and RB1/INTS6-associated loss that occurred in all mouse and human tumor groups, and the AURKA-associated gain occurred in BRCA2-related tumors from both species. However, there were also important differences between tumor profiles of both species, such as the prominent gain on chromosome 10 in mouse Brca2?/?;p53?/? tumors and the PIK3CA associated 3q gain in human BRCA1-mutated tumors, which occurred in tumors from one species but not in tumors from the other species. This disparity in recurrent aberrations in mouse and human tumors might be due to differences in tumor cell type or genomic organization between both species. Conclusions: The selection of the oncogenome during mouse and human breast tumor development is markedly different, apart from the MYC gain and RB1-associated loss. These differences should be kept in mind when using mouse models for preclinical studies.MediamaticsElectrical Engineering, Mathematics and Computer Scienc
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer
BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.
METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.
RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.
CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.)
Albumin-derived peptides efficiently reduce renal uptake of radiolabelled peptides
Contains fulltext :
88022.pdf (publisher's version ) (Closed access)PURPOSE: In peptide-receptor radionuclide therapy (PRRT), the maximum activity dose that can safely be administered is limited by high renal uptake and retention of radiolabelled peptides. The kidney radiation dose can be reduced by coinfusion of agents that competitively inhibit the reabsorption of radiolabelled peptides, such as positively charged amino acids, Gelofusine, or trypsinised albumin. The aim of this study was to identify more specific and potent inhibitors of the kidney reabsorption of radiolabelled peptides, based on albumin. METHODS: Albumin was fragmented using cyanogen bromide and six albumin-derived peptides with different numbers of electric charges were selected and synthesised. The effect of albumin fragments (FRALB-C) and selected albumin-derived peptides on the internalisation of (111)In-albumin, (111)In-minigastrin, (111)In-exendin and (111)In-octreotide by megalin-expressing cells was assessed. In rats, the effect of Gelofusine and albumin-derived peptides on the renal uptake and biodistribution of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide was determined. RESULTS: FRALB-C significantly reduced the uptake of all radiolabelled peptides in vitro. The albumin-derived peptides showed different potencies in reducing the uptake of (111)In-albumin, (111)In-exendin and (111)In-minigastrin in vitro. The most efficient albumin-derived peptide (peptide #6), was selected for in vivo testing. In rats, 5 mg of peptide #6 very efficiently inhibited the renal uptake of (111)In-minigastrin, by 88%. Uptake of (111)In-exendin and (111)In-octreotide was reduced by 26 and 33%, respectively. CONCLUSIONS: The albumin-derived peptide #6 efficiently inhibited the renal reabsorption of (111)In-minigastrin, (111)In-exendin and (111)In-octreotide and is a promising candidate for kidney protection in PRRT.1 februari 201
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