NWChem: Past, present, and future
Journal of chemical physics online/The Journal of chemical physics/Journal of chemical physics,
05/2020
Journal Article
Historically, lung cancer was long considered a poorly immunogenic malignancy. In recent years, however, immune checkpoint inhibitors have emerged as promising therapeutic agents in non‐small cell ...lung cancer (NSCLC). To date, the best characterized and most therapeutically relevant immune checkpoints have been cytotoxic T‐lymphocyte‐associated antigen 4 (CTLA‐4) and the programmed cell death protein‐1 (PD‐1) pathway. In early studies, PD‐1/programmed cell death ligand‐1 (PD‐L1) inhibitors demonstrated promising antitumor activity and durable clinical responses in a subset of patients. Based on these encouraging results, multiple different PD‐1/PD‐L1 inhibitors have entered clinical development, and two agents (nivolumab and pembrolizumab) have gained regulatory approval in the United States for the treatment of NSCLC. In several large, randomized studies, PD‐1/PD‐L1 inhibitors have produced significant improvements in overall survival compared with single‐agent docetaxel delivered in the second‐line setting, effectively establishing a new standard of care in NSCLC. In the present report, we provide an overview of the rationale for checkpoint inhibitors in lung cancer, recent clinical trial data, and the need for predictive biomarkers.
Implications for Practice
Strategies targeting negative regulators (i.e., checkpoints) of the immune system have demonstrated significant antitumor activity across a range of solid tumors. In non‐small cell lung cancer (NSCLC), programmed cell death protein‐1 (PD‐1) pathway inhibitors have entered routine clinical use because of the results from recent randomized studies demonstrating superiority against single‐agent chemotherapy in previously treated patients. The present report provides an overview of immune checkpoint inhibitors in lung cancer for the practicing clinician, focusing on the rationale for immunotherapy, recent clinical trial data, and future directions.
Immune checkpoint inhibitors have emerged as promising therapeutic agents in non‐small cell lung cancer (NSCLC). Programmed cell death protein‐1/programmed cell death ligand‐1 inhibitors have produced significant improvements in overall survival compared with single‐agent docetaxel, effectively establishing a new standard of care in NSCLC. An overview of the rationale for checkpoint inhibitors in lung cancer, recent clinical trial data, and the need for predictive biomarkers is provided.
Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater ...antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy.
An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50mg/day) or cetuximab (250mg/m2/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR).
A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab.
Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.
•Wind turbine towers can be critically affected by wind and seismic loading.•We evaluated these effects by using fragility surfaces/contours.•We considered the wind turbine blades parked and in ...operation.•The methodology employed can be used for other structural analysis cases.
The scenario of growing demand for construction of wind turbine structures in Mexico poses the need of analyzing the hazards that affect this kind of structures in that country. Current Mexican standards include wind turbine support structures in their earthquake design chapter, but no information is included regarding the wind design. This work focuses on the analysis of an onshore 5 MW wind turbine structure, similar to those currently installed in Mexico, under the simultaneous action of wind and earthquake for different intensities. The analyses performed consider the rotor in both: parked and in operation conditions. Wind speed records are obtained from simulations based on an Auto Regressive and Moving Average model and the Veers’ method, while the ground motion records are simulated to be consistent with design spectra for a zone in the Southwest of Mexico, near the coast of the Pacific Ocean, which happens to be the region with the greatest installed wind capacity in Mexico and also a region of strong seismic hazard. The numerical results obtained are employed in a multi-hazard fragility analysis, which shows that the critical action for the structure depends on the operational state of the turbine.
Abstract Patients with psychosis display alterations in social cognition as well as in the realm of neurocognition. It is unclear, however, to what degree these cognitive domains represent two ...separate dimensions of liability or the pleiotropic expression of a single deficit. The purpose of the present study was to investigate (i) to what extent alterations in social cognition represent an independent area of vulnerability to psychosis, separate from neurocognitive deficits and (ii) whether social cognition is one construct or can be divided into several subcomponents. Five social cognition and three neurocognitive tasks were completed by 186 participants with different levels of vulnerability for psychosis: 44 patients with psychotic disorder; 47 subjects at familial risk; 41 subjects at psychometric risk and 54 control subjects. The social cognition tasks covered important basic subcomponents of social cognition, i.e. mentalisation (or theory of mind), data gathering bias (jumping to conclusions), source monitoring and attribution style. Neurocognitive tasks assessed speed of information processing, inhibition, cognitive shifting and strategy-driven retrieval from semantic memory. The results of factor analysis suggested that neurocognition and social cognition are two separate areas of vulnerability in psychosis. Furthermore, the social cognition measures lacked significant overlap, suggesting a multidimensional construct. Cognitive liabilities to psychosis are manifold, and include key processes underlying basic person–environment interactions in daily life, independent of cognition quantified by neuropsychological tests.
Summary
Adherence is key for achieving the optimal benefits from a weight loss intervention. Despite the number of studies on factors that promote adherence, their findings suggest inconsistent and ...fragmented evidence. The aim of this study was to review the existing factors of adherence to weight loss interventions and to find factors that facilitate the design of effective intervention programs. Six databases were searched for this umbrella review; after the screening process, 21 studies were included. A total of 47 factors were identified in six groups as relevant for adherence: (i) sociodemographic (n = 7), (ii) physical activity (n = 2), (iii) dietary (n = 8), (iv) behavioral (n = 4), (v) pharmacological (n = 3), and (vi) multi‐intervention (n = 23). In addition, a map of adherence factors was created. The main findings are that with respect to demographic factors, the development of personalized intervention strategies based on the characteristics of specific populations is encouraged. Moreover, self‐monitoring has been shown to be effective in behavioral, dietary, and multi‐interventions, while technology has shown potential in dietary, behavioral, and multi‐interventions. In addition, multi‐interventions are adherence‐promoting strategies, although more evidence is required on adherence to pharmacological interventions. Overall, the factor map can be controlled and modified by researchers and practitioners to improve adherence to weight loss interventions.
The peak factor is an analytical development for estimating the expected maximum response caused by aerodynamic forces on wind-sensitive structures. It expresses the likelihood of how above the mean ...is the maximum amplitude of a stationary process in terms of its standard deviation. Such a process represents the structural response of a wind-sensitive structure in conventional applications. The methods and solutions used to approximate it in the along-wind direction have become ordinary to structural engineers. Notwithstanding, the structural response in combined orthogonal directions is often omitted since a criterion for such an estimation is still absent. This communication seeks to contribute to fill the gap in practical criteria for estimating response maxima in symmetric structures. It is done by proposing models to estimate the parameters describing the probability distribution of the maxima from the Euclidean norm of two correlated Gaussian variables. Although the applications to structural engineering are emphasized, the proposed models apply to other problems where the maxima from the norm of two Gaussian variables is relevant.
The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on ...endometrial cancer was held on 11–13 December 2014 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of endometrial cancer. Before the conference, the expert panel prepared three clinically relevant questions about endometrial cancer relating to the following four areas: prevention and screening, surgery, adjuvant treatment and advanced and recurrent disease. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. Results of this consensus conference, together with a summary of evidence supporting each recommendation, are detailed in this article. All participants have approved this final article.
Aliment Pharmacol Ther 2011; 34: 297–305
Summary
Background A higher baseline homeostasis model assessment of insulin resistance (HOMA‐IR) score has sometimes predicted a poorer sustained ...virological response (SVR) rate to peginterferon/ribavirin therapy in treatment‐naïve chronic hepatitis C patients.
Aim To perform a meta‐analysis to evaluate the impact of HOMA‐IR on SVR in hepatitis C.
Methods Relevant studies were identified by searching Medline and EMBASE. We identified 17 publications that addressed the influence of insulin resistance on SVR. The random effect model of Der Simonian and Laird method were used for heterogeneous studies using the Meta‐Disc software 1.4, Madrid, Spain.
Results Normal insulin sensitivity was associated with a higher rate of SVR odds ratio (OR) 2.86 (95%CI: 1.97–4.16) in comparison with insulin resistance. Moreover, in separate analysis by genotype selecting studies that used HOMA‐IR > 2 as cut‐off defining insulin resistance, SVR was higher in patients with HOMA‐IR < 2 in all genotypes: HCV‐1 OR: 2.16 (95%CI: 1.51–3.08), HCV‐2&3 OR: 3.06 (95%CI: 1.06–8.82) and HCV‐4 OR: 6.65(95%CI: 2.51–17.61). Studies reporting no association between HOMA and SVR included easy‐to‐cure cohorts, analysed variables strongly related with insulin resistance like body mass index, steatosis, hyper γGT, age and fibrosis and reported differences in handling and interpretation of HOMA‐IR.
Conclusion Elevated HOMA‐IR was associated with a lower cure rate of patients with hepatitis C treated with Peg‐IFN‐α/ribavirin irrespective of genotype, and the more difficult‐to‐treat cohort, the better the HOMA‐IR prediction. HOMA‐IR is, as a surrogate marker of insulin resistance, susceptible to some biases derived from both handling and interpretation.
RTS,S/AS01E has been tested in a phase 3 malaria vaccine study with partial efficacy in African children and infants. In a cohort of 1028 subjects from one low (Bagomoyo) and two high (Nanoro, ...Kintampo) malaria transmission sites, we analysed IgG plasma/serum concentration and avidity to CSP (NANP-repeat and C-terminal domains) after a 3-dose vaccination against time to clinical malaria events during 12-months. Here we report that RTS,S/AS01E induces substantial increases in IgG levels from pre- to post-vaccination (p < 0.001), higher in NANP than C-terminus (2855 vs 1297 proportional change between means), and higher concentrations and avidities in children than infants (p < 0.001). Baseline CSP IgG levels are elevated in malaria cases than controls (p < 0.001). Both, IgG magnitude to NANP (hazard ratio 95% confidence interval 0.61 0.48-0.76) and avidity to C-terminus (0.07 0.05-0.90) post-vaccination are significantly associated with vaccine efficacy. IgG avidity to the C-terminus emerges as a significant contributor to RTS,S/AS01E-mediated protection.
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