Safety and preliminary activity results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody gatipotuzumab with the anti-EGFR tomuzotuximab in patients with refractory solid tumors

Colorectal cancer; Lung cancer; Monoclonal antibodyCáncer colorrectal; Cáncer de pulmón; Anticuerpo monoclonalCàncer colorectal; Càncer de pulmó; Anticòs monoclonalBackground The phase I GATTO study (NCT03360734) explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab, a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin 1 (TA-MUC1) and an anti-epidermal growth factor receptor (anti-EGFR) antibody in refractory solid tumors. Patients and methods Initially the study enrolled primary phase (PP) patients with EGFR-positive metastatic solid tumors, for whom no standard treatment was available. Patients received gatipotuzumab administered at 1400 mg every 2 weeks, 6 weeks after the start of the glyco-optimized anti-EGFR antibody tomuzotuximab at 1200 mg every 2 weeks. As this regimen was proven safe, enrollment continued in an expansion phase (EP) of patients with refractory metastatic colorectal cancer, non-small-cell lung cancer, head and neck cancer and breast cancer. Tomuzotuximab and gatipotuzumab were given at the same doses and gatipotuzumab treatment started 1 week after the first dose of the anti-EGFR antibody. Additionally, investigators could use a commercial anti-EGFR antibody in place of tomuzotuximab. Results A total of 52 patients were enrolled, 20 in the PP and 32 in the EP. The combined treatment was well tolerated and no dose-limiting toxicity was observed in the whole study, nor related serious adverse event or death. Preliminary activity of the combination was observed, with one and four RECIST partial responses in the PP and EP, all in colorectal cancer patients. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 (sTA-MUC1) in serum. In the EP, patients with baseline sTA-MUC1 levels above the median appeared to have improved progression-free survival and overall survival. Conclusions Combination of a TA-MUC1-targeting antibody and an EGFR-targeting antibody is safe and feasible. Interesting antitumor activity was observed in heavily pretreated patients. Future studies should test this combination together with chemotherapy and explore the potential of sTA-MUC1 as a companion biomarker for further development of the combination.This work was supported by Glycotope GmbH (no grant number)

Hierarchical Graph Transformation

If systems are specified by graph transformation, large graphs should be structured in order to be comprehensible. In this paper, we present an approach for the rule-based transformation of hierarchically structured (hyper)graphs. In these graphs, distinguished hyperedges contain graphs that can be hierarchical again. Our framework extends the well-known double-pushout approach from at to hierarchical graphs. In particular, we show how pushouts and pushout complements of hierarchical graphs and graph morphisms can be constructed recursively. Moreover, we make rules more expressive by introducing variables which allow to copy and to remove hierarchical subgraphs in a single rule application

A Lattice Study of the Gluon Propagator in Momentum Space

We consider pure glue QCD at beta=5.7, beta=6.0 and beta=6.3. We evaluate the gluon propagator both in time at zero 3-momentum and in momentum space. From the former quantity we obtain evidence for a dynamically generated effective mass, which at beta=6.0 and beta=6.3 increases with the time separation of the sources, in agreement with earlier results. The momentum space propagator G(k) provides further evidence for mass generation. In particular, at beta=6.0, for k less than 1 GeV, the propagator G(k) can be fit to a continuum formula proposed by Gribov and others, which contains a mass scale b, presumably related to the hadronization mass scale. For higher momenta Gribov's model no longer provides a good fit, as G(k) tends rather to follow an inverse power law. The results at beta=6.3 are consistent with those at beta=6.0, but only the high momentum region is accessible on this lattice. We find b in the range of three to four hundred MeV and the exponent of the inverse power law about 2.7. On the other hand, at beta=5.7 (where we can only study momenta up to 1 GeV) G(k) is best fit to a simple massive boson propagator with mass m. We argue that such a discrepancy may be related to a lack of scaling for low momenta at beta=5.7. {}From our results, the study of correlation functions in momentum space looks promising, especially because the data points in Fourier space turn out to be much less correlated than in real space.Comment: 19 pages + 12 uuencoded PostScript picture

Analytic properties of the Landau gauge gluon and quark propagators

We explore the analytic structure of the gluon and quark propagators of Landau gauge QCD from numerical solutions of the coupled system of renormalized Dyson--Schwinger equations and from fits to lattice data. We find sizable negative norm contributions in the transverse gluon propagator indicating the absence of the transverse gluon from the physical spectrum. A simple analytic structure for the gluon propagator is proposed. For the quark propagator we find evidence for a mass-like singularity on the real timelike momentum axis, with a mass of 350 to 500 MeV. Within the employed Green's functions approach we identify a crucial term in the quark-gluon vertex that leads to a positive definite Schwinger function for the quark propagator.Comment: 42 pages, 16 figures, revtex; version to be published in Phys Rev

Mood Induction in Depressive Patients: A Comparative Multidimensional Approach

Anhedonia, reduced positive affect and enhanced negative affect are integral characteristics of major depressive disorder (MDD). Emotion dysregulation, e.g. in terms of different emotion processing deficits, has consistently been reported. The aim of the present study was to investigate mood changes in depressive patients using a multidimensional approach for the measurement of emotional reactivity to mood induction procedures. Experimentally, mood states can be altered using various mood induction procedures. The present study aimed at validating two different positive mood induction procedures in patients with MDD and investigating which procedure is more effective and applicable in detecting dysfunctions in MDD. The first procedure relied on the presentation of happy vs. neutral faces, while the second used funny vs. neutral cartoons. Emotional reactivity was assessed in 16 depressed and 16 healthy subjects using self-report measures, measurements of electrodermal activity and standardized analyses of facial responses. Positive mood induction was successful in both procedures according to subjective ratings in patients and controls. In the cartoon condition, however, a discrepancy between reduced facial activity and concurrently enhanced autonomous reactivity was found in patients. Relying on a multidimensional assessment technique, a more comprehensive estimate of dysfunctions in emotional reactivity in MDD was available than by self-report measures alone and this was unsheathed especially by the mood induction procedure relying on cartoons. The divergent facial and autonomic responses in the presence of unaffected subjective reactivity suggest an underlying deficit in the patients' ability to express the felt arousal to funny cartoons. Our results encourage the application of both procedures in functional imaging studies for investigating the neural substrates of emotion dysregulation in MDD patients. Mood induction via cartoons appears to be superior to mood induction via faces and autobiographical material in uncovering specific emotional dysfunctions in MDD

the gatto study a phase i of the anti egfr tomuzotuximab to in combination with the anti muc1 gatipotuzumab gat in patients with egfr positive solid tumors

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Microallopatry Caused Strong Diversification in Buthus scorpions (Scorpiones: Buthidae) in the Atlas Mountains (NW Africa)

The immense biodiversity of the Atlas Mountains in North Africa might be the result of high rates of microallopatry caused by mountain barriers surpassing 4000 meters leading to patchy habitat distributions. We test the influence of geographic structures on the phylogenetic patterns among Buthus scorpions using mtDNA sequences. We sampled 91 individuals of the genus Buthus from 51 locations scattered around the Atlas Mountains (Antiatlas, High Atlas, Middle Atlas and Jebel Sahro). We sequenced 452 bp of the Cytochrome Oxidase I gene which proved to be highly variable within and among Buthus species. Our phylogenetic analysis yielded 12 distinct genetic groups one of which comprised three subgroups mostly in accordance with the orographic structure of the mountain systems. Main clades overlap with each other, while subclades are distributed parapatrically. Geographic structures likely acted as long-term barriers among populations causing restriction of gene flow and allowing for strong genetic differentiation. Thus, genetic structure and geographical distribution of genetic (sub)clusters follow the classical theory of allopatric differentiation where distinct groups evolve without range overlap until reproductive isolation and ecological differentiation has built up. Philopatry and low dispersal ability of Buthus scorpions are the likely causes for the observed strong genetic differentiation at this small geographic scale