15 research outputs found
Preferential flow systems amended with biogeochemical components: imaging of a two-dimensional study
The vadose zone is a highly interactive heterogeneous system through which
water enters the subsurface system by infiltration. This paper details the
effects of simulated plant exudate and soil component solutions upon unstable
flow patterns in a porous medium (ASTM silica sand; US Silica, Ottawa, IL,
USA) through the use of two-dimensional tank light transmission method
(LTM). The contact angle (Ξ) and surface tension (γ) of two
simulated plant exudate solutions (i.e., oxalate and citrate) and two soil
component solutions (i.e., tannic acid and Suwannee River natural organic matter, SRNOM) were analyzed to determine the liquidâgas and liquidâsolid
interface characteristics of each. To determine if the unstable flow
formations were dependent on the type and concentration of the simulated
plant exudates and soil components, the analysis of the effects of the
simulated plant exudate and soil component solutions were compared to a
control solution (Hoagland nutrient solution with 0.01Â MÂ NaCl). Fingering
flow patterns, vertical and horizontal water saturation profiles, water
saturation at the fingertips, finger dimensions and velocity, and number of
fingers were obtained using the light transmission method. Significant
differences in the interface properties indicated a decrease between the
control and the plant exudate and soil component solutions tested;
specifically, the control (Ξâ=ââŻ64.5° and Îłâ=ââŻ75.75âŻmNâŻmâ1) samples exhibited a higher contact
angle and surface tension than the low concentration of citrate (Ξâ=ââŻ52.6° and Îłâ=ââŻ70.8âŻmNâŻmâ1). Wetting front
instability and fingering flow phenomena were reported in all infiltration
experiments. The results showed that the plant exudates and soil components
influenced the soil infiltration as differences in finger geometries,
velocities, and water saturation profiles were detected when compared to the
control. Among the tested solutions and concentrations of soil components,
the largest finger width (10.19âŻcm) was generated by the lowest tannic acid
solution concentration (0.1âŻmgâŻLâ1), and the lowest finger width
(6.00âŻcm) was induced by the highest SRNOM concentration (10âŻmgâŻLâ1).
Similarly, for the plant exudate solutions, the largest finger width
(8.36âŻcm) was generated by the lowest oxalate solution concentration
(0.1âŻmgâŻLâ1), and the lowest finger width (6.63âŻcm) was induced by the
lowest citrate concentration (0.1âŻmgâŻLâ1). The control solution
produced fingers with average width of 8.30âŻcm. Additionally, the
wettability of the medium for the citrate, oxalate, and SRNOM solutions
increased with an increase in concentration. Our research demonstrates that
the plant exudates and soil components which are biochemical compounds
produced and released in soil are capable of influencing the process of
infiltration in soils. The results of this research also indicate that soil
wettability, expressed as cosΞ1â2, should be
included in the scaling of the finger dimension, i.e., finger width, when
using the Miller and Miller (1956) scaling theory for the scaling of flow in
porous media
Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial
Background: Ramucirumabâan IgG1 vascular endothelial growth factor receptor 2 antagonistâplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5â13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3â4·8] vs 2·8 months [2·6â2·9]; HR 0·696 [95% CI 0·573â0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9â11·4) in the ramucirumab group versus 7·9 months (7·0â9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724â1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company
Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity
Fibrotic diseases are still a serious concern for public health, due to their high prevalence, complex etiology and lack of successful treatments. Fibrosis consists of excessive accumulation of extracellular matrix components. As a result, the structure and function of tissues are impaired, thus potentially leading to organ failure and death in several chronic diseases. Myofibroblasts represent the principal cellular mediators of fibrosis, due to their extracellular matrix producing activity, and originate from different types of precursor cells, such as mesenchymal cells, epithelial cells and fibroblasts. Profibrotic activation of myofibroblasts can be triggered by a variety of mechanisms, including the transforming growth factor-ÎČ signalling pathway, which is a major factor driving fibrosis. Interestingly, preclinical and clinical studies showed that fibrotic degeneration can stop and even reverse by using specific antifibrotic treatments. Increasing scientific evidence is being accumulated about the role of sirtuins in modulating the molecular pathways responsible for the onset and development of fibrotic diseases. Sirtuins are NAD+-dependent protein deacetylases that play a crucial role in several molecular pathways within the cells, many of which at the crossroad between health and disease. In this context, we will report the current knowledge supporting the role of sirtuins in the balance between healthy and diseased myofibroblast activity. In particular, we will address the signalling pathways and the molecular targets that trigger the differentiation and profibrotic activation of myofibroblasts and can be modulated by sirtuins.</p
Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial
Background: Ramucirumabâan IgG1 vascular endothelial growth factor receptor 2 antagonistâplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5â13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3â4·8] vs 2·8 months [2·6â2·9]; HR 0·696 [95% CI 0·573â0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9â11·4) in the ramucirumab group versus 7·9 months (7·0â9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724â1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company. © 2020 Elsevier Lt