Silent universes with a cosmological constant

We study non-degenerate (Petrov type I) silent universes in the presence of a non-vanishing cosmological constant L. In contrast to the L=0 case, for which the orthogonally spatially homogeneous Bianchi type I metrics most likely are the only admissible metrics, solutions are shown to exist when L is positive. The general solution is presented for the case where one of the eigenvalues of the expansion tensor is 0.Comment: 11 pages; several typos corrected which were still present in CGQ version; minor change

Purely radiative perfect fluids

We study `purely radiative' (div E = div H = 0) and geodesic perfect fluids with non-constant pressure and show that the Bianchi class A perfect fluids can be uniquely characterized --modulo the class of purely electric and (pseudo-)spherically symmetric universes-- as those models for which the magnetic and electric part of the Weyl tensor and the shear are simultaneously diagonalizable. For the case of constant pressure the same conclusion holds provided one also assumes that the fluid is irrotational.Comment: 12 pages, minor grammatical change

Frame dragging, vorticity and electromagnetic fields in axially symmetric stationary spacetimes

We present a general study about the relation between the vorticity tensor and the Poynting vector of the electromagnetic field for axially symmetric stationary electrovacuum metrics. The obtained expressions allow to understand the role of the Poynting vector in the dragging of inertial frames. The particular case of the rotating massive charged magnetic dipole is analyzed in detail. In addition, the electric and magnetic parts of the Weyl tensor are calculated and the link between the later and the vorticity is established. Then we show that, in the vacuum case, the necessary and sufficient condition for the vanishing of the magnetic part is that the spacetime be static.Comment: 16 pages Latex. Some minor changes in the text and typos correcte

Isotropic singularity in inhomogeneous brane cosmological models

We discuss the asymptotic dynamical evolution of spatially inhomogeneous brane-world cosmological models close to the initial singularity. By introducing suitable scale-invariant dependent variables and a suitable gauge, we write the evolution equations of the spatially inhomogeneous $G_{2}$ brane cosmological models with one spatial degree of freedom as a system of autonomous first-order partial differential equations. We study the system numerically, and we find that there always exists an initial singularity, which is characterized by the fact that spatial derivatives are dynamically negligible. More importantly, from the numerical analysis we conclude that there is an initial isotropic singularity in all of these spatially inhomogeneous brane cosmologies for a range of parameter values which include the physically important cases of radiation and a scalar field source. The numerical results are supported by a qualitative dynamical analysis and a calculation of the past asymptotic decay rates. Although the analysis is local in nature, the numerics indicates that the singularity is isotropic for all relevant initial conditions. Therefore this analysis, and a preliminary investigation of general inhomogeneous ($G_0$) models, indicates that it is plausible that the initial singularity is isotropic in spatially inhomogeneous brane-world cosmological models and consequently that brane cosmology naturally gives rise to a set of initial data that provide the conditions for inflation to subsequently take place.Comment: 32 pages with 8 pictures. submitted to Class. Quant. Gra

Pharmacological Modulation of Dopamine Receptor D2-Mediated Transmission Alters the Metabolic Phenotype of Diet Induced Obese and Diet Resistant C57Bl6 Mice

High fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced dopamine receptor D2 (DRD2) mediated tone. We hypothesized that this differing dopaminergic tone contributes to the distinct metabolic profiles of these animals. C57Bl6 mice were classified as DIO or DR based on their weight gain during 10 weeks of high fat feeding. Subsequently DIO mice were treated with the DRD2 agonist bromocriptine and DR mice with the DRD2 antagonist haloperidol for 2 weeks. Compared to DR mice, the bodyweight of DIO mice was higher and their insulin sensitivity decreased. Haloperidol treatment reduced the voluntary activity and energy expenditure of DR mice and induced insulin resistance in these mice. Conversely, bromocriptine treatment tended to reduce bodyweight and voluntary activity, and reinforce insulin action in DIO mice. These results show that DRD2 activation partly redirects high fat diet induced metabolic anomalies in obesity-prone mice. Conversely, blocking DRD2 induces an adverse metabolic profile in mice that are inherently resistant to the deleterious effects of high fat food. This suggests that dopaminergic neurotransmission is involved in the control of metabolic phenotype

Combined osimertinib, dabrafenib and trametinib treatment for advanced non-small-cell lung cancer patients with an osimertinib-induced BRAF V600E mutation

INTRODUCTION: Previous studies have reported an acquiredBRAF V600E mutation as a potential resistance mechanism to osimertinib treatment in advanced NSCLC patients with an activating mutation in EGFR. However, the therapeutic effect of combining dabrafenib and trametinib with osimertinib remains unclear. Here we report treatment efficacy in two cases with acquired BRAF V600E mutations. METHODS: Two patients with anEGFR exon 19 deletion and a T790 M mutation, both treated with osimertinib, acquired a BRAF V600E mutation at disease progression. Following the recommendation of the molecular tumor board, a concurrent combination of dabrafenib and trametinib plus osimertinib was administered. RESULTS: Because of toxicity, one patient ultimately received a reduced dose of dabrafenib and trametinib combined with a normal dose of osimertinib. Clinical response in this patient lasted for 13.4 months. Re-biopsy upon tumor progression revealed loss ofBRAF V600E and emergence of EGFR C797S. The other patient, treated with full doses of the combined therapy, had progression with metastases in lung and brain one month after starting therapy. CONCLUSION: BRAF V600E may be a resistance mechanism induced by osimertinib in EGFR-mutated advanced NSCLC. Combined treatment using dabrafenib/trametinib concurrently with osimertinib needs to be explored for osimertinib-induced BRAF V600E mutation

Mast Cells in Kidney Transplant Biopsies With Borderline T Cell-mediated Rejection and Their Relation to Chronicity

Background. Mast cells are potential contributors to chronic changes in kidney transplants (KTx). Here, the role of mast cells (MCs) in KTx is investigated in patients with minimal inflammatory lesions. Methods. Fourty-seven KTx biopsies (2009-2018) with borderline pathological evidence for T cell-mediated rejection according to the Banff'17 Update were retrospectively included and corresponding clinical data was collected. Immunohistochemistry for tryptase was performed on formalin-fixed paraffin-embedded sections. Cortical MCs were counted and corrected for area (MC/mm²). Interstitial fibrosis was assessed by Sirius Red staining and quantified using digital image analysis (QuPath). Results. Increased MC number was correlated to donor age (spearman's r = 0.35, P = 0.022), deceased donor kidneys (mean difference = 0.74, t [32.5] = 2.21, P = 0.035), and delayed graft function (MD = 0.78, t [33.9] = 2.43, P = 0.020). Increased MC number was also correlated to the amount of interstitial fibrosis (r = 0.42, P = 0.003) but did not correlate with transplant function over time (r = -0.14, P = 0.36). Additionally, transplant survival 2 y post-biopsy was not correlated to MC number (mean difference = -0.02, t [15.36] = -0.06, P = 0.96). Conclusions. MC number in suspicious (borderline) for acute T cell-mediated rejection is correlated to interstitial fibrosis and time post-transplantation, suggesting MCs to be a marker for cumulative burden of tissue injury. There was no association between MCs and transplant function over time or transplant survival 2 y post-biopsy. It remains unclear whether MCs are just a bystander or have pro-inflammatory or anti-inflammatory effects in the KTx with minimal lesions.</p

Ortho-Carborane-modified N-substituted Deoxynojirimycins

Medical Biochemistr

Actionability of on-target ALK Resistance Mutations in Patients With Non-Small Cell Lung Cancer:Local Experience and Review of the Literature

Introduction Non-small cell lung cancer (NSCLC) patients with Anaplastic Lymphoma Kinase (ALK) gene fusions respond well to ALK inhibitors but commonly develop on-target resistance mutations. The objective of this study is to collect clinical evidence for subsequent treatment with ALK inhibitors. Patients and methods Local experience with on-target ALK resistance mutations and review of the literature identified 387 patients with ALK inhibitor resistance mutations. Clinical benefit of mutation-inhibitor combinations was assessed based on reported response, progression-free survival and duration of treatment. Furthermore, this clinical evidence was compared to previously reported in vitro sensitivity of mutations to the inhibitors. Results Of the pooled population of 387 patients in this analysis, 239 (62%) received at least one additional line of ALK inhibition after developing on-target resistance to ALK inhibitor therapy. Clinical benefit was reported for 177 (68%) patients, but differed for each mutation-inhibitor combination. Agreement between in vitro predicted sensitivity of six published models and observed clinical benefit ranged from 64 to 87%. The observed clinical evidence for highest probability of response in the context of specific on-target ALK inhibitor resistance mutations is presented. Conclusion Molecular diagnostics performed on tissue samples that are refractive to ALK inhibitor therapy can reveal new options for targeted therapy for NSCLC patients. Our comprehensive overview of clinical evidence of drug actionability of ALK on-target resistance mechanisms may serve as a practical guide to select the most optimal drug for individual patients

Energetics of the Einstein-Rosen spacetime

A study covering some aspects of the Einstein--Rosen metric is presented. The electric and magnetic parts of the Weyl tensor are calculated. It is shown that there are no purely magnetic E--R spacetimes, and also that a purely electric E--R spacetime is necessarily static. The geodesics equations are found and circular ones are analyzed in detail. The super--Poynting and the ``Lagrangian'' Poynting vectors are calculated and their expressions are found for two specific examples. It is shown that for a pulse--type solution, both expressions describe an inward radially directed flow of energy, far behind the wave front. The physical significance of such an effect is discussed.Comment: 19 pages Latex.References added and updated.To appear in Int.J.Theor.Phy