Extracellular matrix features discriminate aggressive HER2-positive breast cancer patients who benefit from trastuzumab treatment

We previously identified an extracellular matrix (ECM) gene expression pattern in breast cancer (BC), called ECM3, characterized by a high expression of genes encoding structural ECM proteins. Since ECM is reportedly implicated in response to therapy of BCs, the aim of this work is to investigate the prognostic and predictive value of ECM3 molecular classification in HER2-positive BCs. ECM3 resulted in a robust cluster that identified a subset of 25-37% of HER2-positive tumors with molecular aggressive features. ECM3 was significantly associated with worse prognosis in two datasets of HER2-positive BCs untreated with adjuvant therapy. Analyses carried out on two of our cohorts of patients treated or not with adjuvant trastuzumab showed association of ECM3 with worse prognosis only in patients not treated with trastuzumab. Moreover, investigating a dataset that includes gene profile data of tumors treated with neoadjuvant trastuzumab plus chemotherapy or chemotherapy alone, ECM3 was associated with increased pathological complete response if treated with trastuzumab. In the in vivo experiments, increased diffusion and trastuzumab activity were found in tumors derived from injection of HER2-positive cells with Matrigel that creates an ECM-rich tumor environment. Taken together, these results indicate that HER2-positive BCs classified as ECM3 have an aggressive phenotype but they are sensitive to trastuzumab treatment

Gravity in the 3+1-Split Formalism II: Self-Duality and the Emergence of the Gravitational Chern-Simons in the Boundary

We study self-duality in the context of the 3+1-split formalism of gravity with non-zero cosmological constant. Lorentzian self-dual configurations are conformally flat spacetimes and have boundary data determined by classical solutions of the three-dimensional gravitational Chern-Simons. For Euclidean self-dual configurations, the relationship between their boundary initial positions and initial velocity is also determined by the three-dimensional gravitational Chern-Simons. Our results imply that bulk self-dual configurations are holographically described by the gravitational Chern-Simons theory which can either viewed as a boundary generating functional or as a boundary effective action.Comment: 25 pages; v2: minor improvements, references adde

Elements Related to Heterogeneity of Antibody-Dependent Cell Cytotoxicity in Patients Under Trastuzumab Therapy for Primary Operable Breast Cancer Overexpressing Her2

Preliminary results from a pilot trial on trastuzumab's mechanism of action against operable breast tumors overexpressing Her2 suggested a role for antibody-dependent cell cytotoxicity (ADCC). To examine factors affecting ADCC intensity and variability, we extended this study to the phenotypic and functional analysis of circulating mononuclear cells in 18 patients. ADCC was induced by trastuzumab therapy in 15 of 18 patients (83%). Inability to develop ADCC in three patients did not depend on inadequate levels of trastuzumab because further increase in its concentration in vitro was ineffective. Rather, susceptibility to develop ADCC was fairly predicted by test with trastuzumab before therapy and was correlated to the number of lymphocytes coexpressing CD16 and CD56. Phenotypic analysis at the end of ADCC evaluating down-regulation of CD16, and up-regulation of CD69 and CD107a, confirmed that natural killer (NK) cells and CD56+ T cells were involved in productive engagement of trastuzumab. Also, the killing efficiency of CD16+ lymphocytes was influenced by 158 V/F polymorphism of FcγRIII (CD16), whereas variations of CD247 on NK cells were consistent with trends between ADCC before and after therapy. Complete pathologic response was observed in one patient showing ADCC of outstanding intensity, whereas four cases of partial response showed intermediate ADCC; none of the three patients unable to mount ADCC had significant tumor regression. These data indicate that quantity and lytic efficiency of CD16+ lymphocytes are major factors for ADCC induction by trastuzumab, and confirm that breast cancer responses to short-term trastuzumab monotherapy may depend on involvement of the ADCC mechanism. [Cancer Res 2007;67(24):11991–9

Transcranial optical monitoring for detecting intracranial pressure alterations in children with benign external hydrocephalus: a proof-of-concept study

Hydrocephalus; Optical techniques; PathophysiologyHidrocefalia; Técnicas ópticas; FisiopatologíaHidrocefàlia; Tècniques òptiques; FisiopatologiaSignificance Benign external hydrocephalus (BEH) is considered a self-limiting pathology with a good prognosis. However, some children present a pathological intracranial pressure (ICP) characterized by quantitative and qualitative alterations (the so-called B-waves) that can lead to neurological sequelae. Aim Our purpose was to evaluate whether there were cerebral hemodynamic changes associated with ICP B-waves that could be evaluated with noninvasive neuromonitoring. Approach We recruited eleven patients (median age 16 months, range 7 to 55 months) with BEH and an unfavorable evolution requiring ICP monitoring. Bedside, nocturnal monitoring using near-infrared time-resolved and diffuse correlation spectroscopies synchronized to the clinical monitoring was performed. Results By focusing on the timing of different ICP patterns that were identified manually by clinicians, we detected significant tissue oxygen saturation (StO2) changes (p = 0.002) and blood flow index (BFI) variability (p = 0.005) between regular and high-amplitude B-wave patterns. A blinded analysis looking for analogs of ICP patterns in BFI time traces achieved 90% sensitivity in identifying B-waves and 76% specificity in detecting the regular patterns. Conclusions We revealed the presence of StO2 and BFI variations—detectable with optical techniques—during ICP B-waves in BEH children. Finally, the feasibility of detecting ICP B-waves in hemodynamic time traces obtained noninvasively was shown.This work was realized with the support of the Department of Cirugía and Ciencias Morfológicas of the Universitat Autònoma de Barcelona. The work was supported by the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie (Grant No. 675332) (BitMap: brain injury and trauma monitoring using advanced photonics) and the European Union’s Horizon 2020 Research and Innovation Program [Grant No. 101017113 (TinyBrains) and Grant No. 101016087 (VASCOVID)]; Fondo de Investigación Sanitaria (Instituto de Salud Carlos III) (Grant No. PI18/00468); Fundació CELLEX Barcelona, Fundació Mir Puig, Agencia Estatal de Investigación (PHOTOMETABO, Grant No. PID2019106481RBC31); the “Severo Ochoa” Program for Centers of Excelence in R&D (Grant No. CEX2019-000910-S); the Obra social “La Caixa” Foundation (LlumMedBcn), Generalitat de Catalunya (CERCA, AGAUR-2017-SGR-1380, RIS3CAT-001-P-001682 CECH), FEDER EC and LASERLAB EUROPE V (EC H2020 No. 871124); KidsBrainIT (ERANET NEURON); Fundació La Marató de TV3 (Grant Nos. 201724.31 and 201709.31)

Mutual heavy ion dissociation in peripheral collisions at ultrarelativistic energies

We study mutual dissociation of heavy nuclei in peripheral collisions at ultrarelativistic energies. Earlier this process was proposed for beam luminosity monitoring via simultaneous registration of forward and backward neutrons in zero degree calorimeters at Relativistic Heavy Ion Collider. Electromagnetic dissociation of heavy ions is considered in the framework of the Weizsacker-Williams method and simulated by the RELDIS code. Photoneutron cross sections measured in different experiments and calculated by the GNASH code are used as input for the calculations of dissociation cross sections. The difference in results obtained with different inputs provides a realistic estimation for the systematic uncertainty of the luminosity monitoring method. Contribution to simultaneous neutron emission due to grazing nuclear interactions is calculated within the abrasion model. Good description of CERN SPS experimental data on Au and Pb dissociation gives confidence in predictive power of the model for AuAu and PbPb collisions at RHIC and LHC.Comment: 46 pages with 7 tables and 13 figures, numerical integration accuracy improved, next-to-leading-order corrections include

Particle emission following Coulomb excitation in ultrarelativistic heavy-ion collisions

We study nuclear reactions induced by virtual photons associated with Lorentz-boosted Coulomb fields of ultrarelativistic heavy ions. Evaporation, fission and multifragmentation mechanisms are included in a new RELDIS code, which describes the deexcitation of residual nuclei formed after single and double photon absorption in peripheral heavy-ion collisions. Partial cross sections for different dissociation channels, including the multiple neutron emission ones, are calculated and compared with data when available. Rapidity and transverse momentum distributions of nucleons, nuclear fragments and pions, produced electromagnetically, are also calculated. These results provide important information for designing large-rapidity detectors and zero-degree calorimeters at RHIC and LHC. The electromagnetic dissociation of nuclei imposes some constrains on the investigation of exotic particle production in gamma-gamma fusion reactions.Comment: 26 LaTeX pages including 8 figures, uses epsf.st