330 research outputs found
Optical to UV spectra and birefringence of SiO and TiO: First-principles calculations with excitonic effects
A first principles approach is presented for calculations of optical --
ultraviolet (UV) spectra including excitonic effects. The approach is based on
Bethe-Salpeter equation calculations using the \textsc{NBSE} code combined with
ground-state density-functional theory calculations from the electronic
structure code \textsc{ABINIT}. Test calculations for bulk Si are presented,
and the approach is illustrated with calculations of the optical spectra and
birefringence of -phase SiO and the rutile and anatase phases of
TiO. An interpretation of the strong birefringence in TiO is presented.Comment: 8 figure
Frequency dependent specific heat of viscous silica
We apply the Mori-Zwanzig projection operator formalism to obtain an
expression for the frequency dependent specific heat c(z) of a liquid. By using
an exact transformation formula due to Lebowitz et al., we derive a relation
between c(z) and K(t), the autocorrelation function of temperature fluctuations
in the microcanonical ensemble. This connection thus allows to determine c(z)
from computer simulations in equilibrium, i.e. without an external
perturbation. By considering the generalization of K(t) to finite wave-vectors,
we derive an expression to determine the thermal conductivity \lambda from such
simulations. We present the results of extensive computer simulations in which
we use the derived relations to determine c(z) over eight decades in frequency,
as well as \lambda. The system investigated is a simple but realistic model for
amorphous silica. We find that at high frequencies the real part of c(z) has
the value of an ideal gas. c'(\omega) increases quickly at those frequencies
which correspond to the vibrational excitations of the system. At low
temperatures c'(\omega) shows a second step. The frequency at which this step
is observed is comparable to the one at which the \alpha-relaxation peak is
observed in the intermediate scattering function. Also the temperature
dependence of the location of this second step is the same as the one of the
peak, thus showing that these quantities are intimately connected to
each other. From c'(\omega) we estimate the temperature dependence of the
vibrational and configurational part of the specific heat. We find that the
static value of c(z) as well as \lambda are in good agreement with experimental
data.Comment: 27 pages of Latex, 8 figure
Improved Endpoints for Cancer Immunotherapy Trials
Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation
Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B)
Background To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naive patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy.Methods Eligible patients with treatment-naive nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies.Results 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of = 5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death.Conclusions Nivolumab monotherapy has limited activity in treatment-naive nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity
Patient-centric trials for therapeutic development in precision oncology
An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine
Propriedades ópticas de amostras policristalinas LiGaSiO4 contendo Fe3+ como impureza substitucional
Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies
Optimum efficacy is the primary goal for any cancer therapy, and entails controlling tumour growth and prolonging survival as far as possible. The prognosis for patients with metastatic renal cell carcinoma (mRCC) has greatly improved with the introduction of targeted therapies. This review examines the development and efficacy of targeted agents for the management of mRCC, the challenges offered by their rapid emergence, and discusses how mRCC treatment may evolve in the future. Improvements in progression-free survival and overall survival rates, observed with targeted agents, indicate that it may now be possible to change mRCC from a rapidly fatal and largely untreatable condition into a chronic disease. The major challenges to further advances in targeted therapy for mRCC include overcoming drug resistance, identifying the most effective sequence or combination of targeted agents, optimising clinical trial design and managing the cost of treatment
Photoactivatable prodrugs of antimelanoma agent Vemurafenib
In this study, we report on novel
photoactivatable caged prodrugs
of vemurafenib. This kinase inhibitor was the first approved drug
for the personalized treatment of BRAF-mutated melanoma and showed
impressive results in clinical studies. However, the occurrence of
severe side effects and drug resistance illustrates the urgent need
for innovative therapeutic approaches. To conquer these limitations,
we implemented photoremovable protecting groups into vemurafenib.
In general, this caging concept provides spatial and temporal control
over the activation of molecules triggered by ultraviolet light. Thus,
higher inhibitor concentrations in tumor tissues might be reached
with less systemic effects. Our study describes the first development
of caged vemurafenib prodrugs useful as pharmacological tools. We
investigated their photochemical characteristics and photoactivation. <i>In vitro</i> evaluation proved the intended loss-of-function
and the light-dependent recovery of efficacy in kinase and cellular
assays. The reported vemurafenib photo prodrugs represent a powerful
biological tool for novel pharmacological approaches in cancer research
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