Fate of yeast and grape pectic polysaccharides of a young red wine in the cross-flow microfiltration process

Cross-flow microfiltration of a young red wine through a mineral membrane of zirconium oxide (average pore size 0.2 μm) laid over a support of agglomerated microporous carbon reduced by 44 % the concentration of the starting wine in soluble polysaccharides. These carbohydrate polymers were mainly constituted of mannose, arabinose, galactose and galacturonic acid associated with minor amounts of rhamnose, glucose, xylose and fucose. The polysaccharides from starting wine and final permeate were separated by gel filtration on Ultrogel AcA 34 (exclusion limit for globular proteins 750,000) in at least four fractions (I-IV) of respective Kav 0.22, 0.50, 0.75 and 0.90. Each polysaccharidic population contained various proportions of yeast mannans, while grape polysaccharides were unequally distributed, fraction I containing neutral type II arabinogalactans and fractions II to IV being complex mixtures of type II arabinogalactans, arabinans and degraded forms of acidic rhamnogalactumnans (pectins). Losses due to microfiltration were positively correlated to hydrodynamic volume (molecular weight) of molecules: (I) "" 79 %, (II) "" 58 %, (III) "" 38 % and (IV) no loss. Yeast and grape polysaccharides coexisting in a given fraction (having the same Kav) were not equally affected by the microfiltration process, yeast mannans passing preferentially the membrane, while grape polymers were more retained. This differential retention was only observed in fractions of high molecular weights (I and II) and was discussed in relation with possible modifications at the molecular level (size and shape of polysaccharides) occurring in the concentration polarisation layer. Application of a back-flush pulse destined to unplug the membrane resulted in a reenrichment of the permeate in the polysaccharides present in the starting wine at a 82 % level

Long-term Safety of Sunitinib in Metastatic Renal Cell Carcinoma

Background Metastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to ≥6 yr. Objective To analyze long-term safety with sunitinib in mRCC patients. Design, setting, and participants Data were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g. cytokine refractory or treatment-naïve). Outcome measurements and statistical analysis Interval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (≥2 yr) sunitinib treatment. Results and limitations Among long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-<6 mo to 42% at 5-<6 yr and by cumulative analysis from 14% at 0-<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ≥3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients. Conclusions Prolonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative. Patient summary More than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk

Reuse of treated wastewater in viticulture: Can it be an alternative source of nutrient-rich water?

Water scarcity is a global problem, which leads to unprecedented pressure on water supply in arid and semi-arid regions. Treating wastewater is an alternative and valuable water resource, therefore its reuse for agricultural irrigation has been growing worldwide since the beginning of the 21st century. In several regions of the wine-producing countries subject to significant water stress (e.g., Australia, California-USA, Spain), wastewater recycling appears to be the most accessible alternative, both financially and technically, for the agricultural uses that notably not requiring drinking water. Therefore, this research was planned to quantify the contribution of treated wastewater (TWW) to fertilization-needs of the vine, evaluate the impact of irrigation with TWW on the soil, vegetative growth, yield, and wine and grape juice composition. The results provide scientific and technical knowledge on a strategy of water management with high added value. The fertilizer contribution of the TWW would be important, according to the plant's nutrient needs (e.g., in this study 19–39 Unit N, 0.5–1.1 Unit P and 14–28 Unit K ha−1 were supplied with TWW). Ensuring treated wastewater microbiological quality is essential, but without reducing of its nutrients. These nutrients would be a valuable input for crop growth and yield, and could reduce the need to resort for inorganic/synthetic fertilizers. A sustainable use of treated wastewater over the long term would, however, necessitate a good practice guidelines and an integrated vision of treated wastewater quality, crops, irrigation and post-harvest practices

Sunitinib and other targeted therapies for renal cell carcinoma

Targeted therapy has radically altered the way metastatic renal cancer is treated. Six drugs are now licensed in this setting, with several other agents under evaluation. Sunitinib is currently the most widely used in the first line setting with impressive efficacy and an established toxicity profile. However, as further randomised studies report and as newer drugs become available this may change. In this review, we address our current understanding of targeted therapy in renal cancer. We also discuss areas in which our knowledge is incomplete, including the identification of correlative biomarkers and mechanisms of drug resistance. Finally, we will describe the major areas of clinical research that will report over the next few years

Maitrise de la salinité des eaux d'irrigation pour la viticulture

Même si la vigne reste parmi les plantes cultivées une des plus économes en eau, se pose maintenant la question de la disponibilité et de l'accessibilité à la ressource en eau naturelle de qualité: eaux souterraines (infiltration, nappes), eaux de surface stagnantes (lacs, retenues de barrages) ou en écoulement (rivières, fleuves), eaux de mer, eaux usées traitées (REUT). Certaines de ces eaux peuvent contenir des composés d'intérêts nutritionnels pour les plantes, mais aussi être riches en sels dissous. L'objet de cette communication est d'étudier les technologies permettant d'affiner la teneur en sel de l'eau d'irrigation pour la vigne, quel que soit son origine et son niveau initial. Les techniques membranaires, osmose inverse, nanofiltration et électrodialyse sont ainsi comparées techniquement et évaluées économiquement. Les unes, nanofiltration et osmose inverse, à partir de membranes poreuses ou denses sous pression, consiste en une séparation de quasi tous les éléments dissous de l'eau (anions, cations, mais y compris les nutriments azotés, et minéraux) et ce quel que soit, pour l'osmose inverse, la salinité de l'eau initiale (e.g. eau de mer). L'autre l'électrodialyse, à partir de membranes denses ne filtre pas l'eau, mais extrait une quantité pilotable en ligne, de sels dissous (Na+ et Cl− en particulier sélectionnables) sous l'effet d'un champ électrique, afin de l'adapter aux sols ou plantes concerné

Chromophobe renal cell carcinoma with prolonged response to targeted therapy: a case report

Abstract Introduction Chromophobe renal cell carcinoma is universally accepted as a distinct subtype of renal cell carcinoma. There are conflicting reports on prognosis, and few data on response to treatment exist. Currently, we do not have any effective treatment for the metastatic disease apart from surgical procedures. Current strategies are based on results obtained in the context of clear cell-type renal cell carcinoma. Separate trials for rare histologies seem unfeasible and are unlikely to be performed. For these cases, clinical observations are an important part for advancing therapeutic insight. In recent years, novel tyrosine kinase inhibitors have been shown to have significant clinical benefit in advanced renal cell carcinoma. Case presentation We present the case of a 43-year-old Caucasian man with advanced chromophobe renal cell carcinoma treated with the tyrosine kinase inhibitor sunitinib and subsequently with sorafenib and the mammalian target of the rapamycin inhibitor everolimus, achieving a prolonged response and significant clinical benefit. We report an unexpectedly high efficacy of everolimus as a third-line treatment in a patient with metastatic chromophobe renal cell carcinoma. Conclusions Up to now, no published data from randomized clinical studies have addressed the question of efficacy of everolimus as a third-line treatment after failure of tyrosine kinase inhibitors. To the best of our knowledge, this case is the first report of chromophobe renal cell carcinoma treated successfully with sequential tyrosine kinase and mammalian target of rapamycin inhibitor therapy. Notably, the time on treatment with sunitinib exceeded four years. The case presented here implies that everolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma.</p

Cabozantinib versus everolimus, nivolumab, axitinib, sorafenib and best supportive care: A network meta-analysis of progression-free survival and overall survival in second line treatment of advanced renal cell carcinoma

Background Relative effect of therapies indicated for the treatment of advanced renal cell carcinoma (aRCC) after failure of first line treatment is currently not known. The objective of the present study is to evaluate progression-free survival (PFS) and overall survival (OS) of cabozantinib compared to everolimus, nivolumab, axitinib, sorafenib, and best supportive care (BSC) in aRCC patients who progressed after previous VEGFR tyrosine-kinase inhibitor (TKI) treatment. Methodology & findings Systematic literature search identified 5 studies for inclusion in this analysis. The assessment of the proportional hazard (PH) assumption between the survival curves for different treatment arms in the identified studies showed that survival curves in two of the studies did not fulfil the PH assumption, making comparisons of constant hazard ratios (HRs) inappropriate. Consequently, a parametric survival network meta-analysis model was implemented with five families of functions being jointly fitted in a Bayesian framework to PFS, then OS, data on all treatments. The comparison relied on data digitized from the Kaplan-Meier curves of published studies, except for cabozantinib and its comparator everolimus where patient level data were available. This analysis applied a Bayesian fixed-effects network meta-analysis model to compare PFS and OS of cabozantinib versus its comparators. The log-normal fixed-effects model displayed the best fit of data for both PFS and OS, and showed that patients on cabozantinib had a higher probability of longer PFS and OS than patients exposed to comparators. The survival advantage of cabozantinib increased over time for OS. For PFS the survival advantage reached its maximum at the end of the first year’s treatment and then decreased over time to zero. Conclusion With all five families of distributions, cabozantinib was superior to all its comparators with a higher probability of longer PFS and OS during the analyzed 3 years, except with the Gompertz model, where nivolumab was preferred after 24 months

A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer

Background: Serum interleukin (IL)-6 levels correlate with disease outcomes in renal cell carcinoma (RCC) patients. Siltuximab, a chimeric, murine-human mAb against IL-6, was evaluated in a three-part phase I/II study in patients with progressive metastatic RCC. Methods: In part 1, 11 patients received 1, 3, 6, or 12 mg kg–1 at weeks 1, 4 and q2w × 2 thereafter; in part 2, 37 patients randomly received 3 or 6 mg kg–1 q3w × 4; in part 3, 20 low-risk patients received 6 mg kg–1 q2w × 6. Modified WHO response criteria were assessed at weeks 7, 11, the 6-week follow-up, and when clinically indicated. Results: Siltuximab was well tolerated overall, with no maximum tolerated dose or immune response observed. In all, 5 out of 11, 17 out of 37, and 9 out of 20 patients in parts 1, 2, and 3, respectively, received extended treatment beyond 4–6 initial infusions. In part 2, stable disease (SD) (greater than or equal to11weeks) or better was achieved by 11 out of 17 (65%) 3 mg kg–1 treated patients (one partial response (PR) ~8 months, 10 SD) and 10 out of 20 (50%) 6 mg kg–1 treated patients (10 SD). In part 3, documented complete or PR was not observed, but 13 out of 20 (65%) patients achieved SD. Conclusion: Siltuximab stabilised disease in >50% of progressive metastatic RCC patients. One PR was observed. Given the favourable safety profile of siltuximab and poor correlation of tumour shrinkage with clinical benefit demonstrated for other non-cytotoxic therapies, further evaluation of dose-escalation strategies and/or combination therapy may be considered for patients with RCC

Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse: Results From the SORCE Randomized Phase III Intergroup Trial

PURPOSE: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence. / PATIENTS AND METHODS: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo. / RESULTS: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, −0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib. / CONCLUSION: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART