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•Fermentation of maqui juice with kombucha consortium of different ages enhances its co-pigmentation effect.•Sucrose concentration influences anthocyanin co-pigmentation in kombucha ...analogs of maqui juice.•Fermented beverages rich in stable anthocyanins favor antioxidant responses and inhibit digestive enzymes.
The fermentation of maqui juice (MJ), by incorporating kombucha as a starter culture, produces beverages with variable and stable anthocyanin contents. The metabolic effect of kombucha starter cultures obtained at different fermentation times was explored on the anthocyanin stability of maqui (Aristotelia chilensis (Mol.) Stuntz) juice supplemented at different concentrations of sucrose and fermented at different times. The stability of anthocyanins was associated with the levels of catechin detected in the fermentation system. This study concludes that the fermentation of MJ with sucrose (10%) and kombucha consortium of 7-days old, promotes the release and accumulation of phenolic compounds that act as co-pigments, with the best response in quality parameters of beverages such as color intensity, tone, hyperchromic effect, and a significant bathochromic shift. Finally, the additive effect of phenolic constituents with stable anthocyanins, confers to kombucha analogs an outstanding antioxidant quality and inhibitory effects on key enzymes in digestive processes.
A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + ...Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial.
Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks.
Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively.
This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.
MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody–drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody ...conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE).
This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3–3.2mg/kg) or weekly (Q1W, 0.8–1.6mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken.
Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC.
DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required.
NCT01335958.
Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral ...small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed.
In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000mg/m2 (arm 2a) or 500mg/m2 (arm 2b), followed by GDC-0575 (45 or 80mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts.
Of 102 patients treated, 70% were female, the median age was 59years (range 27–85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2hours of dosing, and half-life was ∼23hours. No pharmacokinetic drug–drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2.
GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine.
NCT01564251.
Recent results have demonstrated that live yeast in diets improved gut maturation in sea bass larvae. In this study, we tested the absence and two levels of live yeast in sea bass larvae diets. ...Specimens were fed from time of mouth opening to 37 days after hatching a diet of 0%, 1.1%, or 5.7% wet weight of live yeast (Debaryomyces hansenii CBS 8339). Yeast incorporation improved survival 10%, and reduced malformed larvae. In groups fed 1.1% yeast, only 1% of larvae were malformed, compared to 14% in the control group. Final mean weight in groups fed 1.1% yeast was twice that of other groups. Activities and concentrations of mRNA trypsin and lipase were higher in the two groups fed yeast than in the control group, whereas activity and concentration of mRNA amylase were lower. This suggests that the pancreas matured faster in the two groups fed yeast. Activities of intestinal enzymes alkaline phosphatase, aminopeptidase N, and maltase in the group fed 1.1% yeast were higher than those in the two other groups, revealing earlier development of intestinal digestion. The best results were obtained with the diet containing 1.1% yeast cell biomass, corresponding approximately to 106 CFU g−1 in the diet and 1.1×104 CFU per larva 30 days after hatching. The dose-dependent effect of yeast on rearing performance could be attributed to the amount of polyamines secreted by live yeast in the gut lumen of larvae.
Background
Sedation might improve tolerability and adherence to endoscopic procedures in patients with eosinophilic esophagitis (EoE). Propofol administration is often contraindicated in patients ...with hypersensitivity to egg, soy, or peanut.
Objective
To investigate the safety of propofol administration for procedural sedation in EoE patients sensitized/allergic to egg, soy, peanut.
Methods
A retrospective observational study in adult EoE patients undergoing esophagogastroduodenoscopy with propofol sedation was conducted between January 2009 and March 2013. Food‐specific serum IgE and skin prick tests for egg, soy, peanut, and cross‐reactant foods were performed in all patients.
Results
Sixty EoE adult patients, mostly on food elimination diets (91%), were evaluated (age: 28 years (14–56), male gender (90%)). Atopy was present in 88% of patients, being the most prevalent comorbidities rhinoconjunctivitis (78%) and asthma (67%). Fifty‐two patients (86%) were sensitized to either egg, soy, or peanut. Eighteen patients (28%) had a history of allergic reactions to egg, legumes, and nuts and strictly avoided these foods. A total of 404 upper endoscopies were performed under propofol sedation. No allergic adverse events were reported, except a transient bronchospasm after orotracheal intubation in an asthmatic adolescent receiving multiple drugs for anesthesia, in whom no sensitization to either propofol or its lipid vehicle was confirmed.
Conclusions
Propofol was safely administered for procedural sedation in a large series of adult EoE patients multisensitized to egg, soy, peanut, showing one‐third clinical allergy to these foods.
Aliment Pharmacol Ther 31, 1077–1084
Summary
Background Helicobacter pylori eradication rates with standard triple therapy have declined to unacceptable levels.
Aim To compare clarithromycin and ...levofloxacin in triple and sequential first‐line regimens.
Methods A total of 460 patients were randomized into four 10‐day therapeutic schemes (115 patients per group): (i) standard OCA, omeprazole, clarithromycin and amoxicillin; (ii) triple OLA, omeprazole, levofloxacin and amoxicillin; (iii) sequential OACM, omeprazole plus amoxicillin for 5 days, followed by omeprazole plus clarithromycin plus metronidazole for 5 days; and (iv) modified sequential OALM, using levofloxacin instead of clarithromycin. Eradication was confirmed by 13C‐urea breath test. Adverse effects and compliance were assessed by a questionnaire.
Results Per protocol cure rates were: OCA (66%; 95% CI: 57–74%), OLA (82.6%; 75–89%), OACM (80.8%; 73–88%) and OALM (85.2%; 78–91%). Intention‐to‐treat cure rates were: OCA (64%; 55–73%), OLA (80.8%; 73–88%), OACM (76.5%; 69–85%) and OALM (82.5%; 75–89%). Eradication rates were lower with OCA than with all the other regimens (P < 0.05). No differences in compliance or adverse effects were demonstrated among treatments.
Conclusions Levofloxacin‐based and sequential therapy are superior to standard triple scheme as first‐line regimens in a setting with high clarithromycin resistance. However, all of these therapies still have a 20% failure rate.
The present work aims to study the interactive effect of drought stress and high vapour pressure deficit (VPD) on leaf gas exchange, and especially on mesophyll conductance to CO₂ (gm), in two woody ...species of great agronomical importance in the Mediterranean basin: Vitis vinifera L. cv. Tempranillo and Olea europaea L. cv. Manzanilla. Plants were grown in specially designed outdoor chambers with ambient and below ambient VPD, under both well-irrigated and drought conditions. gm was estimated by the variable J method from simultaneous measurements of gas exchange and fluorescence. In both species, the response to soil water deficit was larger in gs than in gm, and more important than the response to VPD. Olea europaea was apparently more sensitive to VPD, so that plants growing in more humid chambers showed higher gs and gm. In V. vinifera, in contrast, soil water deficit dominated the response of gs and gm. Consequently, changes in gm/gs were more related to VPD in O. europaea and to soil water deficit in V. vinifera. Most of the limitations of photosynthesis were diffusional and especially due to stomatal closure. No biochemical limitation was detected. The results showed that structural parameters played an important role in determining gm during the acclimation process. Although the relationship between leaf mass per unit area (MA) with gm was scattered, it imposed a limitation to the maximum gm achievable, with higher values of MA in O. europaea at lower gm values. MA decreased under water stress in O. europaea but it increased in V. vinifera. This resulted in a negative relationship between MA and the CO₂ draw-down between substomatal cavities and chloroplasts in O. europaea, while being positive in V. vinifera.
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