Amino acids are the currency of nitrogen exchange between source and sink tissues in plants and constitute a major source of the components used for cellular growth and differentiation. The ...characterization of a new amino acid transporter belonging to the amino acid permease (AAP) family, AAP11, expressed in the perennial species Populus trichocarpa is reported here. PtAAP11 expression analysis was performed by semi-quantitative RT-PCR and GUS activity after poplar transformation. PtAAP11 function was studied in detail by heterologous expression in yeast. The poplar genome contains 14 putative AAPs which is quite similar to other species analysed except Arabidopsis. PtAAP11 was mostly expressed in differentiating xylem cells in different organs. Functional characterization demonstrated that PtAAP11 was a high affinity amino acid transporter, more particularly for proline. Compared with other plant amino acid transporters, PtAAP11 represents a novel high-affinity system for proline. Thus, the functional characterization and expression studies suggest that PtAAP11 may play a major role in xylogenesis by providing proline required for xylem cell wall proteins. The present study provides important information highlighting the role of a specific amino acid transporter in xylogenesis in poplar.
Several guidelines dedicated to metastatic colorectal cancer (mCRC) are available. Since 2013 no recent guidelines are specifically dedicated to older patients and based on a systematic review.
A ...multidisciplinary Task Force with digestive oncologists, geriatricians and methodologists from the SoFOG was formed in 2016 to update recommendations on medical treatment of mCRC based on a systematic review of publications from 2000 to 2018. Search strategy has followed a standardized protocol from the formulation of clinical questions and definition of a search algorithm to the selection of complete articles for recommendations.
The four selected key questions were: For which older patients with mCRC can we considered: (1) Any chemotherapy, (2) Mono or poly-chemotherapy, (3) Anti-angiogenic therapy, (4) Other targeted therapy. Main recommendations for older patients are: (1) Omission of chemotherapy should be discussed with a geriatrician for patients with severe comorbidities, advanced dementia, uncontrolled psychiatric disorder or severe loss of autonomy. (2) If tumor response is not the main aim, a mono-chemotherapy with 5-fluorouracil combined with bevacizumab is recommended as first-line. (3) For patients with symptoms related to metastases or with a planned metastasis ablation, a doublet chemotherapy combined with bevacizumab or anti-EGFR antibody in the context of a RAS wild type tumor is recommended as first-line. Preliminary data suggest that regorafenib may be used, in its registered indication, in patients under 80 with a performance status of 0 and no autonomy alterations and that trifluridine-tipiracil may be used with a tight supervising of hematological function.
The aim of this ancillary study of the SARAH trial is to compare health-related quality of life (HRQoL) in patients with locally advanced or inoperable hepatocellular carcinoma (HCC) treated with ...transarterial radioembolisation (TARE) or sorafenib.
This study included randomised patients who received either TARE or at least one dose of sorafenib with no major deviation in the protocol and who had at least one QoL follow-up assessment in addition to the baseline evaluation. QoL was assessed from the date of randomisation using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire, until disease progression or other reasons for stopping study participation. Data were analysed using linear mixed and time-dependent models.
A total of 285 patients were included (122 and 163, in the TARE and sorafenib groups, respectively). Questionnaire completion rates were similar (77.5% versus 80.4%, in the TARE and sorafenib groups, respectively, p = 0.25). Longitudinal HRQoL analysis showed a significant treatment and time effects for fatigue and global health status, and significant treatment, time and treatment by time interaction effects for appetite loss, diarrhoea and social functioning. The median time to deterioration for the global health status was 3.9 months (95% confidence interval CI 3.7–4.3) versus 2.6 months (95% CI 2.0–3.0) in the TARE and sorafenib groups, respectively.
HRQoL was preserved longer with TARE than with sorafenib in locally advanced HCC. These data could be used to optimise management of patients with advanced or inoperable HCC.
•Deterioration for global health status was lower in the TARE group compared to sorafenib.•Deterioration in physical functioning was lower in the TARE group compared to sorafenib.•Deterioration in role functioning was lower in the TARE group compared to sorafenib.•Deterioration in social functioning was lower in the TARE group compared to sorafenib.•TARE and tumour burden ≤25% were associated with a lower risk of deterioration.
Summary
CD81 is a major receptor for Hepatitis C Virus (HCV). It belongs to the tetraspanin family whose members form dynamic clusters with numerous partner proteins and with one another, forming ...tetraspanin‐enriched areas in the plasma membrane. In our study, we combined single‐molecule microscopy and biochemistry experiments to investigate the clustering and membrane behaviour of CD81 in the context of cells expressing EWI‐2wint, a natural inhibitor of HCV entry. Interestingly, we found that EWI‐2wint reduces the global diffusion of CD81 molecules due to a decrease of the diffusion rate of mobile CD81molecules and an increase in the proportion of confined molecules. Indeed, we demonstrated that EWI‐2wint promotes CD81 clustering and confinement in CD81‐enriched areas. In addition, we showed that EWI‐2wint influences the colocalization of CD81 with Claudin‐1 – a co‐receptor required for HCV entry. Together, our results indicate that a change in membrane partitioning of CD81 occurs in the presence of EWI‐2wint. This study gives new insights on the mechanism by which HCV enters into its target cells, namely by exploiting the dynamic properties of CD81.
Background and Objective
Chronic pain is associated with significant functional and social impairment. The objective of this review was to assess the characteristics and quality of randomized ...controlled trials (RCTs) evaluating pain management interventions in children and adolescents with chronic pain.
Methods
We performed a systematic search of PubMed, Embase and the Cochrane Library up to July 2017. We included RCTs that involved children and adolescents (3 months‐18 years) and evaluated the use of pharmacological or non‐pharmacological intervention(s) in the context of pain persisting or re‐occurring for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias (ROB) Tool.
Results
A total of 58 RCTs were identified and numbers steadily increased over time. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 47.5 participants (Q1,Q3: 32, 70). Forty‐five percent of RCTs included both adults and children and the median of the mean ages at inclusion was 12.9 years (Q1,Q3: 11, 15). Testing of non‐pharmacological interventions was predominant and only 5 RCTs evaluated analgesics or co‐analgesics. Abdominal pain, headache/migraine and musculoskeletal pain were the most common types of chronic pain among participants. Methodological quality was poor with 90% of RCTs presenting a high or unclear ROB.
Conclusions
Evaluation of analgesics targeting chronic pain relief in children and adolescents through RCTs is marginal. Infants and children with long‐lasting painful conditions are insufficiently represented in RCTs. We discuss possible research constraints and challenges as well as methodologies to circumvent them.
Significance
There is a substantial research gap regarding analgesic interventions for children and adolescents with chronic pain. Most clinical trials in the field focus on the evaluation of non‐pharmacological interventions and are of low methodological quality. There is also a specific lack of trials involving infants and children and adolescents with long‐lasting diseases.
In France, two therapeutic strategies can be offered after fingolimod (FNG) withdrawal to highly active relapsing–remitting multiple sclerosis (RRMS) patients: natalizumab (NTZ) or anti-CD20. We ...compared the effectiveness of these two strategies as a switch for FNG within the OFSEP database. The primary endpoint was the time to first relapse. Other outcomes were the relapse rates over 3-month periods, time to worsening the EDSS score, proportion of patients with worsened 24-month MRI, time to treatment discontinuation, and incidence rates of serious adverse events. The dynamics of event rates over time were modeled using multidimensional penalized splines, allowing the possibility to model the effects of covariates in a flexible way, considering non-linearity and interactions. A total of 740 patients were included (337 under anti-CD20 and 403 under NTZ). There was no difference between the two treatments regarding the dynamic of the first occurrence of relapse, with a monthly probability of 5.0% at initiation and 1.0% after 6 months. The rate of EDSS worsening increased in both groups until 6 months and then decreased. No difference in the proportion of patients with new T2 lesions at 24 months was observed. After 18 months of follow-up, a greater risk of NTZ discontinuation was found compared to anti-CD20. This study showed no difference between NTZ and anti-CD20 after the FNG switch regarding the clinical and radiological activity. The effect of these treatments was optimal after 6 months and there was more frequent discontinuation of NTZ after 18 months, probably mainly related to JC virus seroconversions.
The SARAH (Sorafenib Versus Radioembolization in Advanced Hepatocellular Carcinoma) trial (ClinicalTrials.gov Identifier NCT01482442) did not show a significant survival benefit for patients treated ...with transarterial radioembolization (TARE) compared with continuous oral sorafenib. The improved toxicity profile of patients treated with TARE in the trial, however, could result in a quality of life benefit in economic evaluations. Our objective was to perform a cost-utility analysis of TARE versus sorafenib for locally advanced and inoperable hepatocellular carcinoma.
This study used patient-level data of the SARAH trial regarding resource use, progression-free and overall survival, and quality of life for the within-trial period for the patients who received at least 1 dose of sorafenib or 1 treatment with TARE according to their randomization arm. Data were extrapolated by using a partitioned survival model that incorporated costs and health outcomes, measured in life-years and quality-adjusted life-years (QALYs).
The use of TARE resulted in an average loss of 0.036 life-year and a gain of 0.006 QALY compared with sorafenib. The aerage cost for the TARE arm was €17,179 (95% CI, 9,926–24,280) higher than the sorafenib arm, for an incremental cost-effectiveness ratio of €3,153,086/QALY. The probabilistic sensitivity analysis revealed a 50% risk that the TARE strategy was dominated. TARE was consistently dominated by sorafenib or had an incremental cost-effectiveness ratio more than €450,000/QALY in all sensitivity analyses.
This economic evaluation of SARAH found that using radioembolization with yttrium-90 microspheres for the treatment of hepatocellular carcinoma was not a cost-effective option at the usually accepted willingness-to-pay thresholds.
Abstract
Background
Sparing of antiretroviral drug classes could reduce the toxicity and cost of maintenance treatment for HIV infection.
Objectives
To evaluate the non-inferiority of efficacy and ...the safety of lopinavir/ritonavir (r) monotherapy versus a single-tablet regimen of efavirenz, emtricitabine and tenofovir (EFV/FTC/TDF) over 2 years.
Methods
Adults on stable ART with plasma HIV-1 RNA viral load <50 copies/mL for the past 12 months and no documented treatment failure were randomized to receive either lopinavir/r or EFV/FTC/TDF for 2 years. The primary endpoint was the proportion of patients without treatment failure at week 96 (viral load <50 copies/mL at week 96, confirmed at week 98), without study treatment discontinuation, a new AIDS-defining illness, or death.
Results
In the ITT analysis, the primary endpoint was reached by, respectively, 64% and 71% of patients in the lopinavir/r (n = 98) and EFV/FTC/TDF arms (n = 97), yielding a difference of –6.8% (lower limit of the 95% two-sided CI: –19.9%). Sanger and UltraDeep sequencing showed the occurrence of PI mutations in the lopinavir/r arm (n = 4) and of NNRTI and/or NRTI mutations in the EFV/FTC/TDF arm (n = 2). No unexpected serious clinical events occurred.
Conclusions
Lopinavir/r monotherapy cannot be considered non-inferior to EFV/FTC/TDF. PI resistance rarely emerged in the lopinavir/r arm and did not undermine future PI options. Two years of lopinavir/r monotherapy had no deleterious clinical impact when compared with EFV/FTC/TDF.
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