The MiniBooNE Collaboration observes unexplained electronlike events in the reconstructed neutrino energy range from 200 to 475 MeV. With 6.46x10;{20} protons on target, 544 electronlike events are ...observed in this energy range, compared to an expectation of 415.2+/-43.4 events, corresponding to an excess of 128.8+/-20.4+/-38.3 events. The shape of the excess in several kinematic variables is consistent with being due to either nu_{e} and nuover _{e} charged-current scattering or nu_{mu} neutral-current scattering with a photon in the final state. No significant excess of events is observed in the reconstructed neutrino energy range from 475 to 1250 MeV, where 408 events are observed compared to an expectation of 385.9+/-35.7 events.
Oral cancer incidence is higher in individuals between the fifth and seventh decades of life, but some studies indicate a decreasing age trend. From the epidemiological point of view, alcohol ...consumption is associated with the emergence of oral cancer by interfering with mechanisms of DNA synthesis and repair. From a genetic standpoint, variant alleles in genes encoding the enzymes of alcohol (CYP2E1 and ADH) and acetaldehyde (ALDH2) metabolism may play an important role in the genesis of oral cancer. This study aimed to assess the relation of polymorphisms ADH1B (rs1229984 and rs2066702), ADH1C (rs698), ALDH2 (rs671) and CYP2E1 96bp insertion and the risk of squamous cell carcinoma of the mouth floor, as well as its clinicopathological and prognostic characteristics in relation to alcohol consumption. Our sample group was made of 301 patients, with 159 controls without a previous history of cancer and 142 patients with oral cancer. Genomic DNA was extracted from peripheral blood samples and genotypes were determined by PCR-RFLP. Our results suggest that the presence of ALDH2 Lys504 allele and 96bp insertion CYP2E1 were significantly associated with oral cancer risk. ADH1C gene Ile350 allele was associated with the presence of positive lymph nodes, and lymphatic invasion was related to the presence of polymorphic alleles ADH1B*1, ADH1C Ile350 and ALDH2 Lys504. In conclusion, these results reveal potential markers of oral cancer risk and behavior.
Abstract
New tools enable new ways of working, and materials science is no exception. In materials discovery, traditional manual, serial, and human-intensive work is being augmented by automated, ...parallel, and iterative processes driven by Artificial Intelligence (AI), simulation and experimental automation. In this perspective, we describe how these new capabilities enable the acceleration and enrichment of each stage of the discovery cycle. We show, using the example of the development of a novel chemically amplified photoresist, how these technologies’ impacts are amplified when they are used in concert with each other as powerful, heterogeneous workflows.
Sotorasib for Lung Cancers with KRAS p.G12C Mutation Skoulidis, Ferdinandos; Li, Bob T; Dy, Grace K ...
New England journal of medicine/The New England journal of medicine,
06/2021, Letnik:
384, Številka:
25
Journal Article
Recenzirano
Odprti dostop
Sotorasib showed anticancer activity in patients with
p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients ...with non-small-cell lung cancer (NSCLC).
In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with
p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy.
Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval CI, 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in
,
, or
.
In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated
p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).
Aims: The incidence of head and neck cancer (HNC) in Brazil has increased substantially in recent years. This increase is likely to be strongly associated with alcohol and tobacco consumption, but ...genetic susceptibility also should be investigated in this population. The aim of this study was to evaluate the association of polymorphisms in genes of alcohol metabolism enzymes and the risk of HNC. Methods: A hospital-based case–control study was conducted in São Paulo, Brazil. We here investigated ADH1C Ile350Val, ADH1B Arg48His, ADH1B Arg370Cys and CYP2E1*5A PstI polymorphisms by PCR-RFLP Polymerase Chain Reaction - Restriction Fragment Length Polymorphism in 207 histopathologically confirmed HNC cases (184 males and 23 females) and 244 cancer-free controls (225 males and 19 females) admitted as in-patients in the same hospital. Results: Chronic alcohol intake increased approximately four times the risk of HNC. The mutant genotype ADH1B Arg48His was more frequent in controls (12.7%) than HNC patients (5.8%) conferring protection for the disease (odds ratio (OR) = 0.42; 95% confidence interval (CI ), 0.21–0.85). Similar results were observed for individuals with ADH1B*2 (OR = 0.41; 95% CI , 0.20–0.82) or ADH1B*2/ADH1C*1 (OR = 0.32; 95% CI , 0.13–0.79) mutated haplotypes. Multiple regression analyses showed that individuals with the mutant genotype ADH1B Arg48His who consume alcohol >30 g/L/day have more than four times the risk for HNC (OR = 4.42; 95% CI, 1.21–16.11). Conclusions: The fast alcohol metabolizing genotypes may prevent HNC when the amount of alcohol intake is <30.655 g/L/day.
Cheese odour-active compounds identified by gas chromatography-olfactometry (GC-O) are compiled in nine tables dealing with alcohols, aldehydes, ketones, esters, lactones, furans, nitrogen-containing ...compounds together with pyrazines and sulphur-containing compounds, terpenes and miscellaneous compounds, and, finally, aromatic compounds and free fatty acids. For each component, the odour descriptors, the cheese variety in which it was evaluated, the concentration (or an indication of the odour intensity), the extraction method, the GC-O type of analysis, and, if available, the perception threshold values are also provided. The sensory properties and metabolic origin of major cheese aroma compounds are discussed in the text, explaining to a certain extent the discrepancies between different authors.
The sidereal time dependence of MiniBooNE νe and ν¯e appearance data is analyzed to search for evidence of Lorentz and CPT violation. An unbinned Kolmogorov–Smirnov (K–S) test shows both the νe and ...ν¯e appearance data are compatible with the null sidereal variation hypothesis to more than 5%. Using an unbinned likelihood fit with a Lorentz-violating oscillation model derived from the Standard Model Extension (SME) to describe any excess events over background, we find that the νe appearance data prefer a sidereal time-independent solution, and the ν¯e appearance data slightly prefer a sidereal time-dependent solution. Limits of order 10−20 GeV are placed on combinations of SME coefficients. These limits give the best limits on certain SME coefficients for νμ→νe and ν¯μ→ν¯e oscillations. The fit values and limits of combinations of SME coefficients are provided.
Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic ...alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.
We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation.
We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n=271), EGFR (n=125), BRAF (n=43), MET (n=36), HER2 (n=29), ALK (n=23), RET (n=16), ROS1 (n=7), and multiple drivers (n=1). Median age was 60years, gender ratio was 1:1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, and ALK=0%. In the entire cohort, median PFS was 2.8months, OS 13.3months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).
: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.
Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterised by limited treatment options and a poor prognosis. At relapse after platinum-based chemotherapy, single-agent ...chemotherapy is commonly used and single-arm trials of immune-checkpoint inhibitors have demonstrated encouraging activity.
PROMISE-meso is an open-label 1:1 randomised phase III trial investigating the efficacy of pembrolizumab (200 mg/Q3W) versus institutional choice single-agent chemotherapy (gemcitabine or vinorelbine) in relapsed MPM patients with progression after/on previous platinum-based chemotherapy. Patients were performance status 0–1 and unselected for programmed cell death ligand 1 (PD-L1) status. At progression, patients randomly assigned to receive chemotherapy were allowed to crossover to pembrolizumab. The primary end point was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary end points were overall survival (OS), investigator-assessed PFS, objective response rate (ORR), and safety. Efficacy by PD-L1 status was investigated in exploratory analyses.
Between September 2017 and August 2018, 144 patients were randomly allocated (pembrolizumab: 73; chemotherapy: 71). At data cut-off 20 February 2019, median follow-up of 11.8 months (interquartile range: 9.9–14.5), 118 BICR-PFS events were observed. No difference in BICR-PFS was detected hazard ratio = 1.06, 95% confidence interval (CI): 0.73–1.53; P = 0.76, and median BICR-PFS (95% CI) for pembrolizumab was 2.5 (2.1–4.2), compared with 3.4 (2.2–4.3) months for chemotherapy. A difference in ORR for pembrolizumab was identified (22%, 95% CI: 13% to 33%), over chemotherapy (6%, 95% CI: 2% to 14%; P = 0.004). Forty-five patients (63%) assigned to chemotherapy received pembrolizumab at progression. With follow-up to 21 August 2019 17.5 months: (14.8–19.7), no difference in OS was detected between groups (HR = 1.12, 95% CI: 0.74–1.69; P = 0.59), even after adjusting for crossover. Pembrolizumab safety was consistent with previous observations. Exploratory efficacy analyses by PD-L1 status demonstrated no improvements in ORR/PFS/OS.
This is the first randomised trial evaluating the efficacy of pembrolizumab in MPM patients progressing after/on previous platinum-based chemotherapy. In biologically unselected patients, although associated with an improved ORR, pembrolizumab improves neither PFS nor OS over single-agent chemotherapy.
•First randomised, controlled trial evaluating efficacy of an anti-PD1 agent versus chemotherapy in relapsed MPM, with immunotherapy crossover allowed.•Objective response rate was significantly improved for pembrolizumab (22% versus 6%, P = 0.004).•No improvement for independently reviewed PFS for pembrolizumab over chemotherapy (HR = 1.06, 95% CI: 0.73–1.53, P = 0.76).•No overall survival improvement for pembrolizumab over chemotherapy (HR = 1.04, 95% CI: 0.66–1.67, P = 0.85).
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