237 research outputs found
Gaussian noise and time-reversal symmetry in non-equilibrium Langevin models
We show that in driven systems the Gaussian nature of the fluctuating force
and time-reversibility are equivalent properties. This result together with the
potential condition of the external force drastically restricts the form of the
probability distribution function, which can be shown to satisfy
time-independent relations. We have corroborated this feature by explicitly
analyzing a model for the stretching of a polymer and a model for a suspension
of non-interacting Brownian particles in steady flow.Comment: 6 pages, submitted to PR
The role of phagocytic cells in enhanced susceptibility of broilers to colibacillosis after Infectious Bronchitis Virus infection
Delta--Excitation and Exchange Corrections for NN--Bremsstrahlung
The role of the relativistic amplitudes for a number of
processes usually neglected in potential model calculations of
NN--bremsstrahlung is investigated. In particular, we consider the
--excitation pole contributions related to the one--pion and one--rho
exchange and in addition include the exchange contributions induced by the
radiative decays. The contributions are
calculated from relativistic Born amplitudes fitted to --production and
absorption data in the energy range up to 1 GeV and then used to supplement
potential model and soft photon calculations for nucleon--nucleon
bremsstrahlung. The effects on --observables, although moderate in
general, are found to be important in some kinematic domains.Comment: 15 pages in LaTex, using Revtex, 6 figures as uufile'd, compressed
Postscript file included, TRIUMF preprint TRI-PP-94-9
Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment
Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agencyβapproved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease β₯ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P β€ 0.001) or BRAF inhibitors (9% vs. 1%; P β€ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer
Progress in Classical and Quantum Variational Principles
We review the development and practical uses of a generalized Maupertuis
least action principle in classical mechanics, in which the action is varied
under the constraint of fixed mean energy for the trial trajectory. The
original Maupertuis (Euler-Lagrange) principle constrains the energy at every
point along the trajectory. The generalized Maupertuis principle is equivalent
to Hamilton's principle. Reciprocal principles are also derived for both the
generalized Maupertuis and the Hamilton principles. The Reciprocal Maupertuis
Principle is the classical limit of Schr\"{o}dinger's variational principle of
wave mechanics, and is also very useful to solve practical problems in both
classical and semiclassical mechanics, in complete analogy with the quantum
Rayleigh-Ritz method. Classical, semiclassical and quantum variational
calculations are carried out for a number of systems, and the results are
compared. Pedagogical as well as research problems are used as examples, which
include nonconservative as well as relativistic systems
The RECAP Test Rapidly and Reliably Identifies Homologous Recombination-Deficient Ovarian Carcinomas
Recent studies have shown that the efficacy of PARP inhibitors in epithelial ovarian
carcinoma (EOC) is related to tumor-specific defects in homologous recombination (HR) and extends
beyond BRCA1/2 deficient EOC. A robust method with which to identify HR-deficient (HRD)
carcinomas is therefore of utmost clinical importance. In this study, we investigated the proficiency of
a functional HR assay based on the detection of RAD51 foci, the REcombination CAPacity (RECAP)
test, in identifying HRD tumors in a cohort of prospectively collected epithelial ovarian carcinomas
(EOCs). Of the 39 high-grade serous ovarian carcinomas (HGSOC), the RECAP test detected 26%
(10/39) to be HRD, whereas ovarian carcinomas of other histologic subtypes (n = 10) were all
HR-proficient (HRP). Of the HRD tumors that could be sequenced, 8/9 showed pathogenic BRCA1/2
variants or BRCA1 promoter hypermethylation, indicating that the RECAP test reliably identifies
HRD, including but not limited to tumors related to BRCA1/2 deficiency. Furthermore, we found a
trend towards better overall survival (OS) of HGSOC patients with RECAP-identified HRD tumors
compared to patients with HRP tumors. This study shows that the RECAP test is an attractive alternative to DNA-based HRD tests, and further development of a clinical grade RECAP test is
clearly warranted
The ETS Family Member TEL Binds to Nuclear Receptors RAR and RXR and Represses Gene Activation
Retinoic acid receptor (RAR) signaling is important for regulating transcriptional activity of genes involved in growth, differentiation, metabolism and reproduction. Defects in RAR signaling have been implicated in cancer. TEL, a member of the ETS family of transcription factors, is a DNA-binding transcriptional repressor. Here, we identify TEL as a transcriptional repressor of RAR signaling by its direct binding to both RAR and its dimerisation partner, the retinoid x receptor (RXR) in a ligand-independent fashion. TEL is found in two isoforms, created by the use of an alternative startcodon at amino acid 43. Although both isoforms bind to RAR and RXR in vitro and in vivo, the shorter form of TEL represses RAR signaling much more efficiently. Binding studies revealed that TEL binds closely to the DNA binding domain of RAR and that both Helix Loop Helix (HLH) and DNA binding domains of TEL are mandatory for interaction. We have shown that repression by TEL does not involve recruitment of histone deacetylases and suggest that polycomb group proteins participate in the process
Autoantibody Epitope Spreading in the Pre-Clinical Phase Predicts Progression to Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability. Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear. To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA. To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1β12 years prior to disease onset. We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines. We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing). We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes. At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA. Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-Ξ±, IL-6, IL-12p70, and IFN-Ξ³. Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread. Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis
The crystal structure of titanium dioxide nanoparticles influences immune activity in vitro and in vivo
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