30 research outputs found
Multi-level Protocol for Mechanistic Reaction Studies Using Semi-local Fitted Potential Energy Surfaces
In this work, we propose a multi-scale protocol for routine theoretical
studies of chemical reaction mechanisms. The initial reaction paths of our
investigated systems are sampled using the Nudged-Elastic Band (NEB) method
driven by a cheap electronic structure method. Forces recalculated at the more
accurate electronic structure theory for a set of points on the path are fitted
with a machine-learning technique (in our case symmetric gradient domain
machine learning or sGDML) to produce a semi-local reactive Potential Energy
Surface (PES), embracing reactants, products and transition state (TS) regions.
This approach has been successfully applied to a unimolecular (Bergman
cyclization of enediyne) and a bimolecular (S2 substitution)
reaction. In particular, we demonstrate that with only 50 to 150 energy-force
evaluations with the accurate reference methods (here CASSCF and CCSD) it is
possible to construct a semi-local PES giving qualitative agreement for
stationary-point geometries, intrinsic reaction-coordinates and barriers.
Furthermore, we find a qualitative agreement in vibrational frequencies and
reaction rate coefficients. The key aspect of the method's performance is its
multi-scale nature, which not only saves computational effort but also allows
extracting meaningful information along the reaction path, characterized by
zero gradients in all but one direction. Agnostic to the nature of the TS and
computationally economic, the protocol can be readily automated and routinely
used for mechanistic reaction studies
Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial
Background
Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane.
Methods
In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0â2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436.
Findings
Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6â13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7â46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment.
Interpretation
Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations
PROGRESS IN CALCULATIONS OF THE SUPERCONDUCTING PROPERTIES OF TRANSITION METALS
First principles calculations of the electron--phonon parameters of d-band metals can now be performed to an accuracy of about 10% for averaged quantities such as the mass enhancement or the room temperature resistivity. Quantities such as the spectral function ..cap alpha../sup 2/F(..omega..) or the phonon linewidth which describe the electron--phonon interaction in more detail can also be calculated. Agreement between calculated and experimental phonon linewidths is generally good but there are differences between the experimental and calculated versions of ..cap alpha../sup 2/F(..omega..). Calculations of the thermodynamic critical field and the upper critical field for Nb agree well with experiment
Assessment of DLPNO-MP2 Approximations in Double-Hybrid DFT
The unfavorable scaling (N5) of conventional second-order MĂžller-Plesset theory (MP2) typically prevents the application of double-hybrid (DH) density functionals to large systems with more than 100 atoms. A prominent approach to reduce the computational demand of electron correlation methods is the domain-based local pair natural orbital (DLPNO) approximation that is successfully used in the framework of DLPNO-CCSD(T). Its extension to MP2 [P. Pinski, C. Riplinger, E. F. Valeev and F. Neese, J. Chem. Phys. 143, 034108 (2015)] paved the way for DLPNO-MP2-based double-hybrid methods. In this work, we assess the accuracy of the DLPNO-MP2 approximation compared to conventional double-hybrids on a large number of 7925 data points for thermochemistry and 239 data points for structural features, including main-group and transition-metal systems. It is shown that DLPNO-DH-DFT can be applied successfully to perform energy calculations and geometry optimizations for large molecules at a drastically reduced computational cost. Furthermore, PNO space extrapolation is shown to be applicable, similar to its DLPNO-CCSD(T) counterpart, to reduce the remaining error
Glucose Metabolism of Human Prostate Cancer Mouse Xenografts
We hypothesized that the glucose metabolism of prostate cancer is modulated by androgen. We performed in vivo biodistribution and imaging studies of [F-18] fluorodeoxyglucose (FDG) accumulation in androgen-sensitive (CWR-22) and androgen-independent (PC-3) human prostate cancer xenografts implanted in castrated and noncastrated male athymic mice. The growth pattern of the CWR-22 tumor was best approximated by an exponential function (tumor size in mm 3 = 14.913 e 0.108 Ă days , R 2 = .96, n = 5). The growth pattern of the PC-3 tumor was best approximated by a quadratic function (tumor size in mm 3 = 0.3511 Ă days 2 + 49.418 Ă day â753.33, R 2 = .96, n = 3). The FDG accumulation in the CWR-22 tumor implanted in the castrated mice was significantly lower, by an average of 55%, in comparison to that implanted in the noncastrated host (1.27 vs. 2.83, respectively, p < .05). The 3-week maximal standardized uptake value (SUV max ) was 0.99 ± 0.43 (mean ± SD ) for CWR-22 and 1.21 ± 0.32 for PC-3, respectively. The 5-week SUV max was 1.22 ± 0.08 for CWR-22 and 1.35 ± 0.17 for PC-3, respectively. The background muscle SUV max was 0.53 ± 0.11. Glucose metabolism was higher in the PC-3 tumor than in the CWR-22 tumor at both the 3-week (by 18%) and the 5-week (by 9.6%) micro-PET imaging sessions. Our results support the notions that FDG PET may be useful in the imaging evaluation of response to androgen ablation therapy and in the early prediction of hormone refractoriness in men with metastatic prostate cancer
Preliminary updated results of a phase I/II trial using trimodality therapy in patients with post-prostatectomy high-risk pathologic (p) T2-3N0M0 prostate cancer.
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Multilevel Approaches within the Local Pair Natural Orbital Framework
The
linear-scaling local coupled cluster method DLPNO-CCSDÂ(T) allows
calculations on systems containing hundreds of atoms to be performed
while reproducing canonical CCSDÂ(T) energies typically with chemical
accuracy (<1 kcal/mol). The accuracy of the method is determined
by two main truncation thresholds that control the number of electron
pairs included in the CCSD iterations and the size of the pair natural
orbital virtual space for each electron pair, respectively. While
the results of DLPNO-CCSDÂ(T) calculations converge smoothly toward
their canonical counterparts as the thresholds are tightened, the
improved accuracy is accompanied by a fairly steep increase of the
computational cost. Many applications study events that are confined
to a relatively small region of the system of interest. Hence, it
is viable to develop methods that allow the user to treat different
parts of a large system at various levels of accuracy. In this work
we present an extension to the native DLPNO method that fragments
the system into preselected molecular parts and uses different thresholds
or even different levels of theory for the interaction between individual
fragments. Thereby chemical intuition can be used to focus computational
resources on a more accurate evaluation of the properties at the center
of interest, while permitting a less demanding description of the
surrounding moieties. The strategy was implemented within the DLPNO-CCSDÂ(T)
framework. We tested the scheme for a series of realistic quantum
chemical applications such as the calculation of the dimerization
energies, potential energy surfaces, enantiomeric excess in organometallic
catalysis, and the binding energy of the anticancer drug ellipticine
to DNA. This work demonstrates the power of the approach and offers
guidance to its setup