Co-Development of Three Dietary Indices to Facilitate Dietary Intake Assessment of Pediatric Crohn's Disease Patients.

Literature on dietary behaviours of the pediatric Crohn's Disease (CD) population and the relationship between dietary intake and CD activity is limited. Three dietary indices were developed and tested to conduct dietary pattern analysis in pediatric patients with CD consuming a free diet following remission induction via exclusive enteral nutrition (n = 11). Index scores underwent descriptive and inferential analysis. The mean adjusted scores (out of 100) for the Pediatric Western Diet Index, Pediatric Prudent Diet Index, and Pediatric-Adapted 2010 Alternate Healthy Eating Index (PA2010-AHEI) were 29.82 ± 15.22, 34.25 ± 15.18, and 51.50 ± 11.69, respectively. The mean Western-to-Prudent ratio was 0.94 ± 0.55. A significant correlation (r = -0.71) and relationship (F[1, 9] = 9.04, P < 0.05, R2 = 0.501) between the Western-to-Prudent ratio and PA2010-AHEI was found. The results suggest participants were not following a Western or Prudent diet, and were consuming foods not captured by the indices. More research is needed to describe dietary intake of individuals with CD, validate dietary indices in diverse samples, and explore the utility of these indices in CD assessment and treatment. The co-authors hope this work will stimulate/inspire subsequent interprofessional, dietitian-led research on this topic.

Sex differences in the relationship between dietary pattern adherence and cognitive function among older adults: findings from the NuAge study.

BACKGROUND: Consumption of a prudent dietary pattern rich in healthy nutrients is associated with enhanced cognitive performance in older adulthood, while a Western dietary pattern low in healthy nutrients is associated with poor age-related cognitive function. Sex differences exist in dietary intake among older adults; however, there is a paucity of research examining the relationship between sex-specific dietary patterns and cognitive function in later life. METHODS: The current study aimed to investigate sex differences in the relationship between sex-specific dietary pattern adherence and global cognitive function at baseline and over a 3-year follow-up in 1268 community-dwelling older adults (Mage = 74 years, n = 664 women, n = 612 men) from the Quebec Longitudinal Study on Nutrition and Successful Aging (NuAge). A 78-item Food Frequency Questionnaire was used to estimate dietary intake over the previous year. Sex-specific dietary pattern scores were derived using principal component analysis. Global cognition was assessed using the Modified Mini-Mental State Examination (3MS). RESULTS: Adjusted linear mixed effects models indicated that a healthy, prudent dietary pattern was not associated with baseline cognitive performance in men or women. No relationship was found between Western dietary pattern adherence and baseline cognitive function in women. Among men, adherence to an unhealthy, Western dietary pattern was associated with poorer baseline cognitive function (ß = - 0.652, p = 0.02, 95% CI [- 1.22, - 0.65]). No association was found between prudent or Western dietary patterns and cognitive change over time in men or women. CONCLUSIONS: These findings highlight the importance of conducting sex-based analyses in aging research and suggest that the relationship between dietary pattern adherence and cognitive function in late life may be sex-dependent.

Synthesis and Characterization of Cetuximab-Docetaxel and Panitumumab-Docetaxel Antibody-Drug Conjugates for EGFR-Overexpressing Cancer Therapy.

The safety and efficacy of anticancer antibody-drug conjugates (ADCs) depend on the selection of tumor-targeting monoclonal antibody (mAb), linker, and drug, as well as their specific chemical arrangement and linkage chemistry. In this study, we used a heterobifunctional cross-linker to conjugate docetaxel (DX) to cetuximab (CET) or panitumumab (PAN). The resulting ADCs were investigated for their in vitro EGFR-specific cytotoxicity and in vivo anticancer activity. Reaction conditions, such as reducing agent, time, temperature, and alkylation buffer, were optimized to yield potent and stable ADCs with consistent batch-to-batch drug-to-antibody ratios (DARs). ADCs were synthesized with DARs from 0.4 to 3.0, and all retained their EGFR affinity and specificity after modification. ADCs were sensitive to cell surface wildtype EGFR expression, demonstrating more cytotoxicity in EGFR-expressing A431 and MDA-MB-231 cell lines compared to U87MG cells. A431 tumor-bearing mice treated once weekly for four weeks with 100 mg/kg cetuximab-docetaxel ADC (C-SC-DX, DAR 2.5) showed durable anticancer responses and improved overall survival compared to the same treatment regimen with 1 mg/kg DX, 100 mg/kg CET, or a combination 1 mg/kg DX and 100 mg/kg CET. New treatment options are emerging for patients with both wild-type and mutated EGFR-overexpressing cancers, and these studies highlight the potential role of EGFR-targeted ADC therapies as a promising new treatment option.

Nutrition as a component of dementia risk reduction strategies.

According to the Alzheimer Society of Canada, within the next generation, Canada will experience a more than doubling of individuals living with dementia and a potentially economically crippling 10-fold increase in costs to Canadians. Up to 50% of cases with dementia can be attributed to seven modifiable, predominantly vascular and/or lifestyle-associated, risk factors. Multi-modal dementia risk reduction strategies, targeting diet, exercise, mental stimulation, and vascular risk monitoring, are likely to be the most successful. Diet-related strategies need to focus on overall diet quality and not on individual foods or nutrients. High-quality diets that are associated with better cognitive function and lower dementia risk with aging are high in vegetables, fruits, nuts, whole grains, and fish and low in red meat, high-fat dairy products, sweets, and highly processed foods. It is the time to embed risk reduction strategies into our public health and healthcare infrastructure to proactively address the challenges posed by population aging.

The Interplay of Antigen Affinity, Internalization, and Pharmacokinetics on CD44-Positive Tumor Targeting of Monoclonal Antibodies.

Monoclonal antibodies (mAbs) offer promise as effective tumor targeting and drug delivery agents for cancer therapy. However, comparative biological and clinical characteristics of mAbs targeting the same tumor-associated antigen (TAA) often differ widely. This study examined the characteristics of mAbs that impact tumor targeting using a panel of mAb clones specific to the cancer-associated cell-surface receptor and cancer stem cell marker CD44. CD44 mAbs were screened for cell-surface binding, antigen affinity, internalization, and CD44-mediated tumor uptake by CD44-positive A549 cells. It was hypothesized that high-affinity, rapidly internalizing CD44 mAbs would result in high tumor uptake and prolonged tumor retention. Although high-affinity clones rapidly bound and were internalized by A549 cells in vitro, an intermediate-affinity clone demonstrated significantly greater tumor uptake and retention than high-affinity clones in vivo. Systemic exposure, rather than high antigen affinity or rapid internalization, best associated with tumor targeting of CD44 mAbs in A549 tumor-bearing mice.

Subtumoral analysis of PRINT nanoparticle distribution reveals targeting variation based on cellular and particle properties.

The biological activity of nanoparticle-directed therapies critically depends on cellular targeting. We examined the subtumoral fate of Particle Replication in Non-Wetting Templates (PRINT) nanoparticles in a xenografted melanoma tumor model by multi-color flow cytometry and in vivo confocal tumor imaging. These approaches were compared with the typical method of whole-organ quantification by radiolabeling. In contrast to radioactivity based detection which demonstrated a linear dose-dependent accumulation in the organ, flow cytometry revealed that particle association with cancer cells became dose-independent with increased particle doses and that the majority of the nanoparticles in the tumor were associated with cancer cells despite a low fractional association. In vivo imaging demonstrated an inverse relationship between tumor cell association and other immune cells, likely macrophages. Finally, variation in particle size nonuniformly affected subtumoral association. This study demonstrates the importance of subtumoral targeting when assessing nanoparticle activity within tumors. FROM THE CLINICAL EDITOR: Particle Replication in Non-Wetting Templates (PRINT) technology allows the production of nanoparticles with uniform size. The authors in the study utilized PRINT-produced nanoparticles to investigate specific tumor uptake by multi-color flow cytometry and in vivo confocal tumor imaging. This approach allowed further in-depth correlation between nanoparticle properties and tumor cells and should improve future design.

The erotetic theory of delusional thinking.

INTRODUCTION: In this paper, we argue for a novel account of one cognitive factor implicated in delusional cognition. According to the erotetic theory of delusion we present, the central cognitive factor in delusion is impaired endogenous question raising. METHOD: After presenting the erotetic theory, we draw on it to model three distinct patterns of reasoning exhibited by delusional and schizophrenic patients, and contrast our explanations with Bayesian alternatives. RESULTS: We argue that the erotetic theory has considerable advantages over Bayesian models. Specifically, we show that it offers a superior explanation of three phenomena: the onset and persistence of the Capgras delusion; recent data indicating that schizophrenic subjects manifest superior reasoning with conditionals in certain contexts; and evidence that schizophrenic and delusional subjects have a tendency to "jump to conclusions." Moreover, since the cognitive mechanisms we appeal to are independently motivated, we avoid having to posit distinct epistemic states that are intrinsically irrational in order to fit our model to the variety of data. CONCLUSION: In contrast to Bayesian models, the erotetic theory offers a simple, unified explanation of a range of empirical data. We therefore conclude that it offers a more plausible framework for explaining delusional cognition.

Plasmonic gold nanostars for multi-modality sensing and diagnostics.

Gold nanostars (AuNSs) are unique systems that can provide a novel multifunctional nanoplatform for molecular sensing and diagnostics. The plasmonic absorption band of AuNSs can be tuned to the near infrared spectral range, often referred to as the "tissue optical window", where light exhibits minimal absorption and deep penetration in tissue. AuNSs have been applied for detecting disease biomarkers and for biomedical imaging using multi-modality methods including surface-enhanced Raman scattering (SERS), two-photon photoluminescence (TPL), magnetic resonance imaging (MRI), positron emission tomography (PET), and X-ray computer tomography (CT) imaging. In this paper, we provide an overview of the recent development of plasmonic AuNSs in our laboratory for biomedical applications and highlight their potential for future translational medicine as a multifunctional nanoplatform.

Relationship between diet quality and cognition depends on socioeconomic position in healthy older adults.

Both diet quality and socioeconomic position (SEP) have been linked to age-related cognitive changes, but there is little understanding of how the socioeconomic context of dietary intake may shape its cognitive impact. We examined whether equal adherence to "prudent" and "Western" dietary patterns, identified by principal components analysis, was associated with global cognitive function [Modified Mini-Mental State Examination (3MS)] in independently living older adults with different SEPs (aged 68-84 y; n = 1099). The interaction of dietary pattern adherence with household income, educational attainment, occupational prestige, and a composite indicator of SEP combining all 3 was examined in multiple-adjusted mixed models over 3 y of follow-up in participants of the NuAge study (Quebec Longitudinal Study on Nutrition and Successful Aging). Adherence to the prudent pattern (vegetables, fruits, fish, poultry, and lower-fat dairy products) was related to higher 3MS scores at recruitment only in the upper categories of income [parameter estimate (B): 0.56; 95% CI: 0.11, 1.01], education (B: 0.44; 95% CI: 0.080, 0.80), or composite SEP (B: 0.37; 95% CI: 0.045, 0.70). High prudent pattern adherence was associated with less cognitive decline only in those with low composite SEP (B: 0.25; 95% CI: 0.0094, 0.50). Conversely, adherence to the Western pattern (meats, potatoes, processed foods, and higher-fat dairy products) was associated with more cognitive decline (B: -0.23; 95% CI: -0.43, -0.032) only in those with low educational attainment. In summary, among individuals with equivalent diet quality, the magnitude and characteristics of the diet-cognition relationship depended on their socioeconomic circumstances. These results suggest that interventions promoting retention of cognitive function through improved diet quality would provide maximum benefit to those with relatively low SEP.

Incorporation and controlled release of silyl ether prodrugs from PRINT nanoparticles.

Asymmetric bifunctional silyl ether (ABS) prodrugs of chemotherapeutics were synthesized and incorporated within 200 nm × 200 nm particles. ABS prodrugs of gemcitabine were selected as model compounds because of the difficulty to encapsulate a water-soluble drug within a hydrogel. The resulting drug delivery systems were degraded under acidic conditions and were found to release only the parent or active drug. Furthermore, changing the steric bulk of the alkyl substituents on the silicon atom could regulate the rate of drug release and, therefore, the intracellular toxicity of the gemcitabine-loaded particles. This yielded a family of novel nanoparticles that could be tuned to release drug over the course of hours, days, or months.

Combining elements of the CO-OP Approach™ with education to promote healthy eating among older adults: A pilot study.

This paper describes an exploratory study developing the Baycrest Brain-healthy Eating Approach (BBEA). Poor diet is a modifiable risk factor for many health problems including dementia. Mediterranean type diets, high in plant-based foods, rich in poly- and mono- unsaturated fatty acids with minimal consumption of saturated fat, red meat, and processed foods, are considered brain healthful. While several dementia prevention trials randomized controlled trials have included nutritional counselling in favor of these diets as one component of their interventions, the extent to which dietary change occurred is not known. Based on observations that a strategy training approach, the Cognitive Orientation to daily Occupational Performance (CO-OP) Approach, was beneficial for promoting lifestyle changes in older adults with complaints of cognitive changes, we undertook to develop the BBEA combining elements of CO-OP with didactic nutrition education. This exploratory, descriptive study assesses the feasibility and acceptability of the BBEA. Healthy community dwelling older adults (n = 5) were recruited using convenience sampling. Participants received five, 2 h, group sessions. During these sessions participants were supported in adopting dietary practices consistent with brain healthy eating. Each participant set specific dietary goals important to them. Feasibility of the intervention was demonstrated through high levels of attendance and by the findings that at each session, all participants set personally meaningful goals and received education on selected brain healthy eating topics. Acceptability was demonstrated through participants' positive reports of their experiences and perspectives obtained via semi-structured interviews. Thus, the BBEA appears to be feasible and acceptable.

Spatial and Temporal Distribution of Information Processing in the Human Dorsal Anterior Cingulate Cortex.

The dorsal anterior cingulate cortex (dACC) is a key node in the human salience network. It has been ascribed motor, pain-processing and affective functions. However, the dynamics of information flow in this complex region and how it responds to inputs remain unclear and are difficult to study using non-invasive electrophysiology. The area is targeted by neurosurgery to treat neuropathic pain. During deep brain stimulation surgery, we recorded local field potentials from this region in humans during a decision-making task requiring motor output. We investigated the spatial and temporal distribution of information flow within the dACC. We demonstrate the existence of a distributed network within the anterior cingulate cortex where discrete nodes demonstrate directed communication following inputs. We show that this network anticipates and responds to the valence of feedback to actions. We further show that these network dynamics adapt following learning. Our results provide evidence for the integration of learning and the response to feedback in a key cognitive region.

The Association Between Dietary Pattern Adherence, Cognitive Stimulating Lifestyle, and Cognitive Function Among Older Adults From the Quebec Longitudinal Study on Nutrition and Successful Aging.

OBJECTIVES: This study examined the effect of dietary patterns and engagement in cognitive stimulating lifestyle (CSL) behaviors on the trajectory of global cognition, executive function (EF), and verbal episodic memory (VEM). METHODS: Western and prudent dietary patterns were empirically derived using food frequency questionnaire responses from 350 community-dwelling older adults (mean age: 73.7 years) participating in the Quebec Longitudinal Study on Nutrition and Successful Aging. CSL was represented by a binary composite indicator based on education, occupational complexity, and social engagement. Global cognition, EF, and VEM were assessed prospectively. RESULTS: Primary effect models revealed an association between higher Western dietary pattern score and a greater rate of decline in global cognition and EF. Higher Western dietary pattern adherence was also associated with poorer baseline VEM. Primary effect models also revealed that CSL was independently associated with baseline global cognition and EF. Effect modification models suggested an interactive effect between Western dietary pattern and CLS on global cognition only. No associations were found for prudent dietary pattern score. DISCUSSION: Contributing to existing research supporting the negative impact of consuming an unhealthy diet on cognitive function, the current study suggests increased vulnerability among older adults who do not engage in a CSL. These findings can inform the development of lifestyle intervention programs that target brain health in later adulthood.

Tunable bifunctional silyl ether cross-linkers for the design of acid-sensitive biomaterials.

Responsive polymeric biomaterials can be triggered to degrade using localized environments found in vivo. A limited number of biomaterials provide precise control over the rate of degradation and the release rate of entrapped cargo and yield a material that is intrinsically nontoxic. In this work, we designed nontoxic acid-sensitive biomaterials based on silyl ether chemistry. A host of silyl ether cross-linkers were synthesized and molded into relevant medical devices, including Trojan horse particles, sutures, and stents. The resulting devices were engineered to degrade under acidic conditions known to exist in tumor tissue, inflammatory tissue, and diseased cells. The implementation of silyl ether chemistry gave precise control over the rate of degradation and afforded devices that could degrade over the course of hours, days, weeks, or months, depending upon the steric bulk around the silicon atom. These novel materials could be useful for numerous biomedical applications, including drug delivery, tissue repair, and general surgery.

Synthesis, radiolabeling, and bio-imaging of high-generation polyester dendrimers.

A series of aliphatic polyester dendrons, generations 1 through 8, were prepared with a core p-toluenesulfonyl ethyl (TSe) ester as an easily removable protecting group that can be efficiently replaced with a variety of nucleophiles. Using amidation chemistry, a tridentate bis(pyridyl)amine ligand which is known to form stable complexes with both Tc(I) and Re(I) was introduced at the dendrimer core. Metalation of the core ligand with (99m)Tc was accomplished for generations 5 through 7, and resulted in regioselective radiolabeling of the dendrimers. The distribution of the radiolabeled dendrimers was evaluated in healthy adult Copenhagen rats using dynamic small-animal single photon emission computed tomography (SPECT). The labeled dendrimers were cleanly and rapidly eliminated from the bloodstream via the kidneys with negligible nonspecific binding to organs or tissues being observed. These data were corroborated by a quantitative biodistribution study on the generation 7 dendrimer following necropsy. The quantitative biodistribution results were in excellent agreement with the data obtained from the dynamic SPECT images.

Zapped assembly of polymeric (ZAP) nanoparticles for anti-cancer drug delivery.

The starting hypothesis for this work was that microwave synthesis could enable the rapid assembly of polymers into size-specific nanoparticles (NPs). The Zapped Assembly of Polymeric (ZAP) NPs was initially realized using poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) block copolymers and distinct microwave reaction parameters. A library of polymeric NPs was generated with sizes ranging from sub-20 nm to 350 nm and low polydispersity. Select ZAP NPs were synthesized in 30 seconds at different scales and concentrations, up to 200 mg and 100 mg mL-1, without substantial size variation. ZAP NPs with diameters of 25 nm, 50 nm, and 100 nm were loaded with the chemotherapeutic paclitaxel (PXL), demonstrated unique release profiles, and exhibited dose-dependent cytotoxicity similar to Taxol. Incorporation of d-alpha tocopheryl polyethylene glycol succinate (TPGS) and PLGA33k allowed for the production of a sub-40 nm NP with an exceptionally high loading of PXL (12.6 wt%, ca. 7 times the original NP) and a slower release profile. This ZAP NP platform demonstrated scalable, flexible, and tunable synthesis with potential toward clinical scale production of size-specific drug carriers.

A systematic review of existing peripheral biomarkers of cognitive aging: Is there enough evidence for biomarker proxies in behavioral modification interventions?: An initiative in association with the nutrition, exercise and lifestyle team of the Canadian Consortium on Neurodegeneration in Aging.

Peripheral biomarkers have shown significant value in predicting brain health and may serve as a useful proxy measurement in the assessment of evidence-based lifestyle behavior modification programs, including physical activity and nutrition programs, that aim to maintain cognitive function in late life. The aim of this systematic review was to elucidate which peripheral biomarkers are robustly associated with cognitive function among relatively healthy non-demented older adults. Following the standards for systematic reviews (PICO, PRIMSA), and employing MEDLINE and Scopus search engines, 222 articles were included in the review. Based on the review of biomarker proxies of cognitive health, it is recommended that a comprehensive biomarker panel, or biomarker signature, be developed as a clinical end point for behavior modification trials aimed at enhancing cognitive function in late life. The biomarker signature should take a multisystemic approach, including lipid, immune/inflammatory, and metabolic biomarkers in the biological signature index of cognitive health.

Immuno-PET imaging of tumor-infiltrating lymphocytes using zirconium-89 radiolabeled anti-CD3 antibody in immune-competent mice bearing syngeneic tumors.

The ability to non-invasively monitor tumor-infiltrating T cells in vivo could provide a powerful tool to visualize and quantify tumor immune infiltrates. For non-invasive evaluations in vivo, an anti-CD3 mAb was modified with desferrioxamine (DFO) and radiolabeled with zirconium-89 (Zr-89 or 89Zr). Radiolabeled 89Zr-DFO-anti-CD3 was tested for T cell detection using positron emission tomography (PET) in both healthy mice and mice bearing syngeneic bladder cancer BBN975. In vivo PET/CT and ex vivo biodistribution demonstrated preferential accumulation and visualization of tracer in the spleen, thymus, lymph nodes, and bone marrow. In tumor bearing mice, 89Zr-DFO-anti-CD3 demonstrated an 11.5-fold increase in tumor-to-blood signal compared to isotype control. Immunological profiling demonstrated no significant change to total T cell count, but observed CD4+ T cell depletion and CD8+ T cell expansion to the central and effector memory. This was very encouraging since a high CD8+ to CD4+ T cell ratio has already been associated with better patient prognosis. Ultimately, this anti-CD3 mAb allowed for in vivo imaging of homeostatic T cell distribution, and more specifically tumor-infiltrating T cells. Future applications of this radiolabeled mAb against CD3 could include prediction and monitoring of patient response to immunotherapy.

Dietary influences on cognitive function with aging: from high-fat diets to healthful eating.

Human epidemiologic studies provide convincing evidence that dietary patterns practiced during adulthood are important contributors to age-related cognitive decline and dementia risk. Diets high in fat, especially trans and saturated fats, adversely affect cognition, while those high in fruits, vegetables, cereals, and fish are associated with better cognitive function and lower risk of dementia. While the precise physiologic mechanisms underlying these dietary influences are not completely understood, modulation of brain insulin activity and neuroinflammation likely contribute. Not surprisingly, deficits in cognitive functions, especially those dependent on the medial temporal lobes, are apparent in type 2 diabetes mellitus (T2DM). Special care in food selection at meals should be exercised by those with T2DM since ingestion of rapidly absorbed, high-glycemic index carbohydrate foods further impairs medial temporal lobe function, with food-induced increases in oxidative stress and cytokine release likely explaining the association between food ingestion and reduction in cognitive function in those with T2DM.