•Recommended phase II dose is binimetinib 30 mg BID with carboplatin/pemetrexed in non-squamous NSCLC.•Manageable toxicities observed with the combination of carboplatin, pemetrexed and ...binimetinib.•Objective response rate 50 % and disease control rate 83.3 % with chemotherapy plus binimetinib.
MEK inhibition is a potential therapeutic strategy in non-small cell lung cancer (NSCLC). This phase I study evaluates the MEK inhibitor binimetinib plus carboplatin and pemetrexed in stage IV non-squamous NSCLC patients (NCT02185690).
A standard 3 + 3 dose-escalation design was used. Binimetinib 30 mg BID (dose level 1 DL1) or 45 mg BID (dose level 2 DL2) was given with standard doses of carboplatin and pemetrexed using an intermittent dosing schedule. The primary outcome was determination of the recommended phase II dose (RP2D) and safety of binimetinib. Secondary outcomes included efficacy, pharmacokinetics, and an exploratory analysis of response based on mutation subtype.
Thirteen patients (6 DL1, 7 DL2) were enrolled: 7 KRAS, 5 EGFR, and 1 NRAS mutation. The RP2D was binimetinib 30 mg BID. Eight patients (61.5%) had grade 3/4 adverse events, with dose limiting toxicities in 2 patients at DL2. Twelve patients were evaluated for response, with an investigator-assessed objective response rate (ORR) of 50% (95% CI 21.1%-78.9%; ORR 33.3% by independent-review, IR), and disease control rate 83.3% (95% CI 51.6%-97.9%). Median progression free survival (PFS) was 4.5 months (95% CI 2.6 months–NA), with a 6-month and 12-month PFS rate of 38.5% (95% CI 19.3%-76.5%) and 25.6% (95% CI 8.9%-73.6%), respectively. In an exploratory analysis, KRAS/NRAS-mutated patients had an ORR of 62.5% (ORR 37.5% by IR) vs. 25% in KRAS/NRAS wild-type patients. In MAP2K1–mutated patients, the ORR was 42.8%.
The addition of binimetinib to carboplatin and pemetrexed appears to have manageable toxicity with evidence of activity in advanced non-squamous NSCLC.
This paper presents the results of experimental studies on the transport of water-sandy mixtures with the content of very fine non-cohesive fractions in steady flow. The flow and shear velocity ...measurements as well as the measurements of sediment amount in the trap and control area were conducted. A theoretical model of the vertical structure of both velocity and concentration of sediment non-cohesive fractions as well as vertical mixing and sorting is presented here for transport calculations. The interaction effects between fractions are included, especially the influence of fine fractions in the mixture on transport of coarser fractions. The model provides an agreement between measurements and calculations of transport rate and grain size distributions of poorly sorted mixtures within plus/minus a coefficient of two. Further, the present model is used for calculating the limited contribution of very fine fractions in sediment due to deficit of those fractions in the bed. Again, the compliance of the calculations of sediment transport according to measurements is achieved. The satisfactory agreement between the calculations of grain size distributions and measurements is also found.
The aim of the study was a comprehensive assessment of metastatic breast cancer patients’ needs in Poland. We conducted and culturally adapted and validated “Count Us, Know Us, Join Us” Metastatic ...Breast Cancer Survey between November 2018 and July 2019. Two hundred ten patients treated in Tarnów completed the paper questionnaires distributed conveniently by healthcare professionals, and 110 patients completed the online survey. Almost all patients believe that new therapies are necessary, and over a half find their options of treatment limited. Support from family, friends, and healthcare professionals seems sufficient. Most patients declare a negative impact of the disease on their emotional status and ability to maintain their lifestyle, finances, and job with one-third of respondents being employed. Three-quarters of patients actively seek data about cancer. The main source of information for Polish patients is the Internet, and they are primarily interested in the ways of managing side effects and available treatment options. We identified factors related to satisfaction with communication with the healthcare professionals. The results are generally consistent with similar studies across the universe. This may indicate that several issues have not been addressed over the years, and there is an urgent need to join international forces to raise awareness and support for metastatic breast cancer patients and lobby for better treatment outcomes.
The aim of this study is to adapt culturally and validate a questionnaire assessing experiences of metastatic breast cancer (MBC) patients in Poland. The questionnaire development was divided into ...three phases: bidirectional translation of the survey, testing it for acceptability and relevance, and field testing. In the field study, 320 women with MBC completed the questionnaire, 50 of them twice for retest. Basic psychometric properties of the items used in questionnaire were analyzed. Test-retest reliability was assessed using kappa coefficient. In case of some items, known-group validity was verified. We made minor revisions to the construction and wording of the questionnaire. The analysis of the variables distributions used in the final version of the questionnaire showed that there were no redundant response categories across items. We checked for the floor and ceiling effect. It was found that there were a total of < 40% respondents selecting the lowest or the highest possible score. The observed values of the Kappa coefficients indicated high tool’s stability. We compared predefined groups for known-group validity; few expected associations reached statistical significance, which supported the overall validity of the tool. The questionnaire has been successfully developed. The results confirm the validity, reliability, and applicability.
The paper presents results of experimental and theoretical studies on transport of water-sand mixtures in steady flow with small amounts of cohesive fractions. The experiments were carried out for ...sand alone and with cohesive admixtures in the form of clay in the amount of 5, 10, 15 and 20% by weight. The amount of sand fractions retained in the trap and along the control area was measured. The experimental results were compared with the calculation results for transport rate of sand fractions. An intended model of the vertical structure of both sand velocity and concentration as well as vertical mixing and sorting is proposed here in order to determine the influence of cohesive admixtures on the transport of sand fractions. Hence the reduction of sand fractions transport due to cohesion forces is included. The agreement of sand transport calculations according to the extended model with measured results and experimental data from literature was achieved within plus/minus a factor of 2.
The purpose of the study was to collect experimental data on the vertical structure of sediment fluxes during the wave crest and trough phase over sloped bed. The first stage of the experimental work ...included measurements of these fluxes using the particle image method, while the second stage, measurements of sediment transport rates and granulometric distributions of sediments collected in the traps on both sides of the sloped initial area. The experimental data were compared both with the results collected previously over flat bed as well as with a theoretical analysis based on a three-layer model of graded sediment transport. This model does not take into account the effects related to the presence of fine and very fine fractions and neglects the effects related to the bed slope, i.e., to gravitational forces and to additional pressure gradients. Hence, a modification of this model is proposed that is based on four coefficients that corrected for sediment fluxes over sloped bed. The consistency of the sediment transport calculations according to the modified model with measurements was achieved within plus/minus a factor of 2 of the measurements.
The purpose of the study was to collect experimental data on the vertical structure of sediment fluxes during the wave crest and trough phase. The first stage of the experimental work included ...measurements of these fluxes using the particle image method, while in the second stage, measurements of sediment transport rates and granulometric distributions of sediments were collected in the traps on both sides of the initial area. The experimental data were compared with the results of a theoretical analysis based on a three-layer model of graded sediment transport. The comparison of the calculations with the measurements was conducted separately for fluxes of fine and very fine fractions in the diameter range di < 0.20 mm, coarse, and total fractions all outgoing in the crest and trough phase from the initial area and deposited in adjacent control areas. As this model did not take into account both the effects of vertical mixing and the phase-lag effects related to the presence of fine and very fine fractions, a modification of this model was proposed that was based on four coefficients that corrected for fluxes. The consistency of the sediment transport calculations according to the modified model with measurements was achieved within plus/minus a factor of 2 of the measurements.
Over the past few decades, the frequency and number of large fires has increased in the western United States following a paucity of fire activity in many forests during most of the 20th century. ...Areas of repeated burning are of particular interest for understanding where there may be qualitative shifts in fire severity and the ecological consequences related to ecosystem resilience and climate change. In the context of recent increases in fire activity, we evaluated the relative importance of potential factors contributing to reburn severity (fire severity in areas that have burned twice) from 1985 to 2012 in the Klamath Mountains ecoregion of California. A unique component of our study was the evaluation of different scales of analysis within the ecoregion. The variables prior burn severity (continuous relative difference‐normalized burn ratio values from 1 to 1300), time since fire, biophysical setting, and average monthly weather were evaluated using generalized additive models to identify the relative importance of factors related to reburn severity patterns for 28 individual repeat fires (>375 ha), shorter (<15 yr) and longer (≥19 yr) fire interval categories, and across all repeat fires combined (79,112 ha). We found that evaluation of all repeat fires combined had masked important trends occurring across individual reburn areas of study particularly when dominated by one or more large fires. Averaging the variance of reburn severity explained across individual reburn areas (equal representation) yielded more explanatory power of predictor variables compared to the composite of all reburn areas combined. Over the period of analysis, topographic controls were relatively consistent regardless of fire interval, but vegetation characteristics had a stronger relationship than weather on reburn severity at longer fire intervals compared to shorter intervals. Likewise, we found greater similarity between prior and reburn severity at longer fire intervals than at shorter fire intervals. Our results underscore the presence of a self‐reinforcing pattern of fire severity related to the biophysical setting in the Klamath Mountains ecoregion, but also highlight the importance of spatial and temporal scale of evaluation and the interactions of vegetation characteristics, time since fire, and fire weather on reburn fire severity.
Differential capacity, charge density measurements, and polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) were employed to study the fusion of small unilamellar vesicles ...of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) on a Au(111) electrode surface. The differential capacity and charge density data showed that the vesicles fuse onto the gold surface at charge densities between −10 μC/cm2 < σM < 10 μC/cm2 to form a bilayer. When σM < −10 μC/cm2, the film is detached from the surface but it remains in close proximity to the surface. PM-IRRAS experiments provided IR spectra for the bilayer in the adsorbed and the desorbed state. Ab initio normal coordinate calculations were performed to assist interpretation of the IR spectra. The IR bands were analyzed quantitatively, and this analysis provided information concerning the conformation and orientation of the acyl chains and the polar head region of the DMPC molecule. The orientation of the chains, hydration, and conformation of the headgroup of the DMPC molecule strongly depend on the electrode potential.
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