Insight In Efficacy Research Articles

Effects of a short‐term Mediterranean diet on mental health, cognition and cerebral blood flow in UK adults: MediMood study protocol

AbstractBackgroundDementias and mental health disorders (i.e. depression, anxiety) are significant public health challenges. Chronic consumption of a Mediterranean diet (MD) has been associated with lower incident dementia, improved cognitive performance, and reduced brain atrophy. Yet, short‐term studies and randomised clinical trials (RCT) are lacking. Our systematic review of RCTs showed that in only four available studies, a MD can improve attention, alertness and contentment in up to 10 days (1). In a controlled efficacy study with all foods provided, we aim to explore postprandial, 24‐h and 5 days impacts of a MD and a Western diet (WD) on mood, anxiety and cognition, cerebral blood flow as assessed by MRI.MethodMediMood is an efficacy crossover RCT. Individuals (n = 25) over 18 years with mild to moderate anxiety and/or depression will complete a 5‐day MD and a 5‐day WD intervention with a 4‐week wash‐out period, with foods, meal plans and instructions provided. Biological samples (blood, urine, faeces) will be collected. The primary outcomes are mood and anxiety assessed using Bond‐Lader and POMS questionnaires. Secondary outcomes include cognitive outcomes assessed through computerised neuropsychology tests, brain perfusion assessed by MRI, select cardiometabolic and inflammatory biomarkers, ketones, brain‐derived neurotrophic factor, several hormones (e.g. serotonin, dopamine), gut microbiome speciation, sleep quality and behaviour change. The assessment time points during each arm are baseline (day 1 morning), postprandial (post day 1 lunch), 24‐h (day 2 morning) and day 6 morning.ResultNAConclusionThis will be the first well‐controlled RCT examining the acute and short‐term impacts of a MD and a WD on mental health and cognition in a targeted risk group. MediMood considers interfaces between sleep quality and the gut‐brain axis as modifiable determinants of mental health. We expect the findings to provide novel insights in efficacy of a MD on daily and short‐term well‐being in those with existing mild‐moderate mental health difficulties and to provide an initial mechanistic understanding of any observed benefits. Funding:Medical Research Council (MRC, UK), NuBrain Consortium (MR/T001852/1); Turkish Government personal PhD scholarship

CLRM-09. INCORPORATING EXTERNAL CONTROL ARM IN MDNA55 RECURRENT GLIOBLASTOMA REGISTRATION TRIAL

BACKGROUNDDrug development in recurrent glioblastoma multiforme (rGBM) is challenging. For randomized controlled trials (RCTs) short survival horizons and limited life-prolonging treatment options may delay accrual and introduce bias through differential dropout of control patients. Comparing results of a single-arm Phase 2b trial of intratumoral delivery of MDNA55 (an interleukin-4 receptor targeted fusion protein) to an external control arm, we sought early efficacy insights and consideration by the FDA of incorporating an ECA in a Phase 3 registrational trial.METHODSUsing propensity score weighting, we compared rGBM patients from the Phase 2b trial (NCT02858895) (2017-2019) to patients from rGBM registries who had received standard of care therapies (2011-2019) and met eligibility requirements. Propensity scores were estimated using a logistic regression model with 11 covariates. We compared the propensity score weighted groups according to demographic and disease attributes before and after weighting and compared overall survival between the two groups.RESULTSThrough propensity score weighting, 43 (98%, 43/44) MDNA55 patients and 40.80 weighted ECA patients (from 62 unweighted registry patients) were identified for comparison. MDNA55 and ECA patients were balanced on all baseline characteristics (i.e., standardized mean difference ≤ 0.15). Compared to ECA patients, MDNA55 patients had a 37% lower hazard of death (hazard ratio 0.63, 95% confidence interval: 0.39,1.02).CONCLUSIONIn advance of a Phase 3 trial, comparison of Phase 2b trial results to an ECA suggests that MDNA55 may be efficacious in rGBM. In view of the known challenges associated with drug development for rGBM, these results provided a proof-of-concept for the design of a novel hybrid Phase 3 trial. This planned Phase 3 trial incorporates propensity score weighting to create a composite hybrid randomized and external control arm, an approach preferred by the FDA over full replacement of a randomized control with an external control.

Inhomogeneous Solubility-Diffusion Model Gives Insight in Efficacy of Counting Crossings Method to Calculate the Membrane Permeability

Passive permeation of substances through the cell membrane is one of the key biological processes. Determining this property can extensively assist various fields of studies, including drug delivery. In this contribution, the conditions are investigated under which the number of crossings has sufficiently high statistics to be used to predict membrane permeability. To assess this, 16 systems of dipalmitoylphosphatidylcholine (DPPC) membranes with different permeant types were simulated with coarse-grained molecular dynamics (CGMD).

183. Retrospective analysis of Tomotherapy dose-of-the-day: Results and effectiveness on adaptive strategies

PurposeAnalysis of dose-of-the-day (DoDa) for patients during treatment represents the first step to Adaptive-radiotherapy (ART). In our Institute DoDa for Tomotherapy plans is computed for first fraction for all patients, daily for SRT, weekly for all other treatments. This workflow aiming to ensure a control of delivered dose, check inter-fraction patient set-up and follow patient anatomical changes that may require a replanning. In this work we retrospectively reviewed DoDa of last 100 therapy courses in order to have an insights of efficacy and effectiveness of procedure. MethodsPatients included were 83. For each patient the associated plans (different courses and corresponding adaptive plans) were included (total of 137 plans included). For each plan, delivered fractions number, computed DoDa number, DoDa passed and failed numbers were reported. Results1507 delivered fraction were considered, 23% were checked computing DoDa. Passing rate was 78%. 10.9% DoDa outlined problems that need a plan reevaluation, while 10.3% showed problems of set-up but doses were adequately comparable to planned dose. All results are summarized in table. ConclusionsAlthough DoDa analysis process is demanding in terms of workload and computation time, our results show that may have a high impact on daily dose delivery quality shifting the paradigma from planned dose to actual delivered dose. [Display omitted]

New insights in efficacy of different dosages of enzyme replacement therapy due to treatment switch in Fabry disease

El genograma y el árbol genealógico son herramientas de representación gráfica de la familia que, aunque comparten similitudes, tienen una funcionalidad y significados diferentes. Si bien el objetivo básico del primero es representar la estructura familiar y las relaciones entre sus miembros, el segundo pretende la identificación del patrón de herencia y de rasgos heredables, aunque su uso y aplicaciones van mucho más allá. Por otra parte, la representación gráfica en ambas herramientas se encuentra normalizada con símbolos similares, aunque algunos de ellos con significado distinto. Tanto una como otra, son utilizadas por el médico de familia, y éste debe tener las competencias necesarias para su manejo efectivo. En este trabajo se pretende mejorar dichas competencias al definir las principales diferencias de una y otra herramienta, establecer los elementos básicos para la construcción e interpretación del árbol genealógico, además de señalar su utilidad clínica y sus usos más frecuentes.A genogram and a genealogical tree are graphic representations of families that share similarities but have different functionality and meanings. While the first basic objective is to represent the family structure and the relationships between its members, the second seeks to identify the inheritance pattern and inheritable traits, although its use and applications go much further. Graphic representation is normalized with similar symbols, although some of them have different meanings. Both are used by family doctors, and they must have the necessary skills for their effective management. This work aims to improve these skills by defining the main differences between the two tools, establishing the basic elements for the construction and interpretation of a genealogical tree, and pointing out its clinical utility and its most frequent uses.

Fabry disease under enzyme replacement therapy-new insights in efficacy of different dosages.

Fabry patients on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in estimated glomerular filtration rate (eGFR) and an increase of the Mainz Severity Score Index. In this prospective observational study, we assessed end-organ damage and clinical symptoms in 112 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, who were (i) non-randomly assigned to continue this treatment regime (regular-dose group, n = 37); (ii) received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n = 38); or (iii) were re-switched to agalsidase-beta after receiving agalsidase-alfa for at least 12 months (re-switch group, n = 37) with a median follow-up of 53 (38-57) months. eGFR of patients in the regular-dose group remained stable. Patients in the switch group showed an annual eGFR loss of - 4.6 ± 9.1 mL/min/1.73 m2 (P < 0.05). Patients in the re-switch group also had an eGFR loss of - 2.2 ± 4.4 mL/min/1.73 m2 after re-switch to agalsidase-beta, but to a lower degree compared with the switch group (P < 0.05). Patients in the re-switch group suffered less frequently from diarrhoea (relative risk 0.42; 95% confidence interval 0.19-0.93; P = 0.02). Lyso-Gb3 remained stable in the switch (P = 0.97) and the regular-dose (P = 0.48) groups, but decreased in the re-switch group after change of the therapy regimen (P < 0.05). After switch to agalsidase-alfa, Fabry patients experienced a continuous decline in eGFR, while this decline was attenuated in patients who were re-switched to agalsidase-beta. Decreasing lyso-Gb3 levels may indicate a better treatment response in the latter group.

Electrophoretic Studies of Isozymes of Glutamate Dehydrogenase (EC 1.4.1.3) (GDH) and Aspartate aminotransferase (EC: 2.6.1.1) AspAT (GOT) inSesuvium portulacastrum(L.), An Associate Halophyte.

Sesuvium portulacastrum L. (Aizoaceae) is a pioneer, psammophytic associate halophyte of subtropical, Mediterranean regions. It dominates coastal and warmer zones of the world. Apart from being utilized as a vegetable and forage by local people, it is also utilized for bioreclamation of saline soil in the arid and semiarid regions. Coastal soils has poor nitrogen content whereas halophytes which inhabit these areas have high protein content due to the ability to conserve nitrogen and recycle it through their body metabolism. In present investigation, Sesuvium portulacastrum (L.) is used as a model system representing an associate halophyte with efficacy in Nitrogen utilization in saline conditions. The plant has adapted to nitrogen stress by evolving efficient nitrogen assimilating isoenzymes. Isoenzymes of glutamate dehydrogenase (GDH) and Aspartate aminotransferase (AspAT) are separated electrophoretically from the leaves and roots of Sesuvium portulacastrum L. Presence of Isozymes for nitrogen assimilating and distributing enzymes like GDH and AspAT indicates the physiological adaptation of plants growing in saline nitrogen deficient conditions. The same study would be extended to other important enzymes of Nitrogen metabolism to get an insight in efficacy of such halophytes to conserve available Nitrogen from saline soils and help in phytoremediation of saline soils.

Abstract 4421: Onco Vasculomics(tm): A 3-d tumor vasculature assessment methodology for quantifying mechanism and efficacy of discovery-stage anti-cancer compounds.

Abstract Conventional methods for evaluating tumor vasculature, such as microvessel density, do not capture critical 3-dimensional properties such as their spatial distribution, tortuosity, and distribution of different vessel sizes on a population basis. Such parameters are critical for understanding the biological effects of agents targeting tumor vasculature by different mechanisms. To address this critical unmet need, we developed a novel system platform which enables high-resolution 3-D, structural microvascular-pattern analysis and biomarker mining in support of preclinical and translational oncology discovery space. The OncoVasculomics™ platform captures, reconstructs, and then automatically and quantitatively analyzes microvascular structures and patterns indicative of response to targeted drug therapy. Methods: The effect of two different anti-angiogenic therapeutic agents, bevacizumab and sunitinib, were assessed using OncoVasculomicsTM platform in Colo205 human colorectal cancer xenograft model. Animals bearing ∼200 mm3 sized tumors were treated for 7 days either with the appropriate vehicle, bevacizumab at 5 mg/kg (i.p. daily) or sunitinib at 30 mg/kg (p.o. daily). Mice were then systemically perfused with Mercox, the tissue was macerated and the resulting vascular tumor cast was imaged using a microCT. 3-dimensional tumor vascular tree was derived using proprietary segmentation and reconstruction software. OncoVasculomicsTM vascular mining software was then used to derive various vascular morphology parameters. Results: Mean tumor sizes did not significantly differ between the Bevacizumab, sutent or vehicle treatment groups at the end of the experiment. Whole tumor 3D micro vessel density (MVD) was similar between the treatment groups: vehicle (bevacizumab) 2.7+/-0.6 % of total tumor volume, bevacizumab 2.2+/-0.4%, vehicle (sunitinib) 2.9+/-0.3% and sunitinib 2.5+/-0.3%. Bevacizumab and sunitinib treatments resulted in 20% and 16% decrease in total tumor MVD, respectively. Bevacizumab treatment resulted in 8.2 % “cold spot” or low vascular density region generation. In contrast, sunitinib was ∼5-fold more efficient in generating “cold spots” at a rate of 37% (sunitinib vs. vehicle tumors). Bevacizumab's anti-vascular activity targeted vessels of 28 um in diameter and larger. However, the majority of sunitinib's activity had effect on vessels 21-35 um in diameter. This study demonstrates that a comprehensive 3d OncoVasculomic™ analysis may provide important mechanistic and efficacy insights into the vascular effects of different classes of drugs targeting tumor vasculature. Citation Format: Raul A. Brauner, Kongbin Kang, Yanchun Wu, George N. Naumov, John V. Heymach. Onco Vasculomics(tm): A 3-d tumor vasculature assessment methodology for quantifying mechanism and efficacy of discovery-stage anti-cancer compounds. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4421. doi:10.1158/1538-7445.AM2013-4421

Targeting the Endothelin Axis with Atrasentan, in combination with IFN-alpha, in metastatic renal cell carcinoma

Background:The endothelin system is involved in tumour growth. Atrasentan, a selective endothelin-A-receptor antagonist, blocks endothelin signalling. This phase I trial studied combining treatment of interferon-alpha (IFN-α) with atrasentan in renal cell carcinoma (RCC).Patients and methods:This study evaluated the safety and tolerance of IFN-α (9MU subcutaneously (s.c.) three times a week) in combination with atrasentan (2.5, 5 and 10 mg orally once daily) in untreated metastatic RCC. Cohort 10 mg was extended to obtain insights in efficacy and pharmacodynamics.Results:Observed toxicities mainly consisted of known IFN-like toxicities (anorexia, chills, fever, fatigue and nausea), and of nasal congestion (associated to atrasentan). None of these toxicities were considered dose limiting. Cohort 10 mg was extended up to 32 patients; in a subset of patients treated according to the protocol (n=27), median overall survival (OS) was 17.3 months. One patient (3.1%) showed a partial response lasting 14.3 months. In an exploratory analysis, we observed that in the subset of patients with declining vascular endothelial growth factor (VEGF) levels (in combination with rising Endothelin-1 levels), median OS was 22.2 months compared with 2.2 months in patients with increasing VEGF levels.Conclusion:Combination treatment of IFN-α 9MU-α s.c. three times a week and atrasentan 10 mg once daily is tolerated. Clinical activity, especially OS, and biomarkers in our view warrant further studies targeting the endothelin axis.

Focus on ecological weed management: what is hindering adoption?

SummaryDespite increased concerns regarding the heavy reliance of many cropping systems on chemical weed control, adoption of ecological weed management practices is only steadily progressing. For this reason, this paper reflects on both the possibilities and limitations of cultural weed control practices. Cultural weed control utilises a number of principles, predominantly: (i) a reduced recruitment of weed seedlings from the soil seedbank, (ii) an alteration of crop–weed competitive relations to the benefit of the crop and (iii) a gradual reduction of the size of the weed seedbank. Compared with chemical control, the general applicability, reliability and efficacy of most measures is only moderate, and consequently, cultural control strategies need to consist of a combination of measures, resulting in increased systems complexity. Combined with the trade‐offs connected to some of the measures, this hampers large‐scale implementation. It is argued that tailoring cultural weed management strategies to the needs and skills of individual farmers would be an important step forward. Research can aid in improving the utilisation of cultural weed control strategies by focussing on a broadening of the range of available measures and by providing clear quantitative insight in efficacy, variability in outcome and trade‐offs of these measures.