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

An examination of semantic impairment in amnestic MCI and AD : What can we learn from verbal fluency?

Introduction The Verbal Fluency Test (VF) is commonly used in neuropsychology. Some studies have demonstrated a marked impairment of semantic VF compared to phonemic VF in Alzheimer’s disease (AD). Since amnestic Mild Cognitive Impairment (aMCI) is associated with increased risk of conversion to incident AD, it is relevant to examine whether a similar impairment is observed in this population. The objective of the present empirical study is to compare VF performance of aMCI patients to those of AD and elderly controls matched one-to-one for age and education. Method Ninety-six participants divided into three equal groups (N = 32: AD, aMCI and Controls) were included in this study. Participants in each group were, on average, 76 years of age and had 13 years of education. A repeated measures ANOVA with the Group (AD, aMCI, NC) as between-subject factor and the Fluency condition (“P” and “animals”) as within-subject factor was performed. T-tests and simple ANOVAs were also conducted to examine the interaction. Results There was a significant interaction between the groups and the verbal fluency condition. In AD, significantly fewer words were produced in both conditions. In contrast, participants with aMCI demonstrated a pattern similar to controls in the phonemic condition, but generated significantly fewer words in the semantic condition. Conclusion These results indicate a semantic memory impairment in aMCI revealed by a simple, commonly-used neuropsychological test. Future studies are needed to investigate if semantic fluency deficits can help predict future conversion to AD

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

Colloquium: Theory of Drag Reduction by Polymers in Wall Bounded Turbulence

The flow of fluids in channels, pipes or ducts, as in any other wall-bounded flow (like water along the hulls of ships or air on airplanes) is hindered by a drag, which increases many-folds when the fluid flow turns from laminar to turbulent. A major technological problem is how to reduce this drag in order to minimize the expense of transporting fluids like oil in pipelines, or to move ships in the ocean. It was discovered in the mid-twentieth century that minute concentrations of polymers can reduce the drag in turbulent flows by up to 80%. While experimental knowledge had accumulated over the years, the fundamental theory of drag reduction by polymers remained elusive for a long time, with arguments raging whether this is a "skin" or a "bulk" effect. In this colloquium review we first summarize the phenomenology of drag reduction by polymers, stressing both its universal and non-universal aspects, and then proceed to review a recent theory that provides a quantitative explanation of all the known phenomenology. We treat both flexible and rod-like polymers, explaining the existence of universal properties like the Maximum Drag Reduction (MDR) asymptote, as well as non-universal cross-over phenomena that depend on the Reynolds number, on the nature of the polymer and on its concentration. Finally we also discuss other agents for drag reduction with a stress on the important example of bubbles.Comment: Invited Colloquium Paper for Reviews of Modern Physics, 24 pages, 18 Figs., submitte

Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials

A subset of patients with metastatic renal cell carcinoma treated with sunitinib achieved long-term response (ie, progression-free survival [PFS] > 18 months). Long-term responders had improved objective response rate, PFS, and overall survival versus others. Patient baseline characteristics predictive of long-term response to sunitinib were identified. Background: We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months. Patients and Methods: A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤ 18 months (“others”). PFS and overall survival (OS) were summarized using Kaplan–Meier methodology. Results: Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P <.0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan (67.1% vs. 51.2%; P =.0018) and greater median maximum on-study tumor shrinkage from baseline (−56.9 vs. −27.1; P <.0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase ≤ 1.5 upper limit of normal (ULN), corrected calcium ≤ 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index ≥ 25 kg/m2, and low neutrophil-to-lymphocyte ratio were associated with LTR. Conclusion: A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS

First-line treatment of metastatic clear cell renal cell carcinoma: a decision-making analysis among experts

Background: The treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has been transformed by targeted therapies with tyrosine kinase inhibitors (TKI) and more recently by the incorporation of immune checkpoint inhibitors (ICI). Today, a spectrum of single agent TKI to TKI/ICI and ICI/ICI combinations can be considered and the choice of the best regimen is complex. Materials and methods: We performed an updated decision-making analysis among 11 international kidney cancer experts. Each expert provided their treatment strategy and relevant decision criteria in the first line treatment of mccRCC. After the collection of all input a list of unified decision criteria was determined and compatible decision trees were created. We used a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees, to determine the most common treatment recommendations as well as deviations. Results: Diverse parameters were considered relevant for treatment selection, various drugs and drug combinations were recommended by the experts. The parameters, chosen by the experts, were performance status, International Metastatic renal cell carcinoma Database Consortium (IMDC) risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. The systemic therapies selected for first line treatment were sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib. Conclusion: A wide spectrum of treatment recommendations based on multiple decision criteria was demonstrated. Significant inter-expert variations were observed. This demonstrates how data from randomized trials are implemented differently when transferred into daily practice

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

How clinical practice is changing the rules: the sunitinib 2/1 schedule in metastatic renal cell carcinoma.

Introduction Currently, sunitinib is a standard of care in first-line treatment for metastatic renal cell carcinoma (mRCC). However, with the standard 4/2 schedule (sunitinib 50 mg/day; 4 consecutive weeks on treatment; 2 weeks' rest), 50% of patients require dose reductions to mitigate toxicity, highlighting the need to investigate alternative dosing schedules that improve tolerability without compromising efficacy. Areas covered: We present a concise critical review of published studies comparing the efficacy and safety of the 4/2 and 2/1 schedule (2 weeks on treatment; 1 week rest) for sunitinib. While all studies evaluating the 2/1 schedule have a low level of evidence, the results indicate that the 2/1 schedule improves tolerability compared with the 4/2 schedule, including significant reductions in the incidence of specific adverse events. It was not possible to make any definitive conclusions regarding efficacy due to methodologic limitations of these studies. Expert commentary: In the absence of strong evidence supporting the safety and efficacy of the 2/1 schedule, we recommend that patients should be initiated on sunitinib therapy with the standard 4/2 schedule and only be switched to the 2/1 schedule after the development of dose-limiting toxicities from weeks 3-4 (cycle 1) of the 4/2 schedule cycle