Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Micronutrient deficiencies in children with coeliac disease; a double-edged sword of both untreated disease and treatment with gluten-free diet.

INTRODUCTION: In coeliac disease (CD) micronutrient deficiencies may occur due to malabsorption in active disease and diminished intake during treatment with a gluten-free diet (GFD). This study assessed the micronutrient status in children with CD at diagnosis and follow-up. METHODS: Fifteen micronutrients were analysed in 106 blood samples from newly diagnosed CD and from patients on a GFD for <6 months, 6-12 months and with longstanding disease (>12 months). Predictors of micronutrient status included: demographics, disease duration, anthropometry, gastrointestinal symptoms, raised tissue transglutaminase antibodies (TGA), multivitamin use and faecal gluten immunogenic peptide (GIP). Micronutrient levels were compared against laboratory reference values. RESULTS: At CD diagnosis (n = 25), low levels in ≥10% of patients were observed for: vitamins E (88%), B1 (71%), D (24%), K (21%), A (20%) and B6 (12%), ferritin (79%), and zinc (33%). One year post-diagnosis, repletion of vitamins E, K, B6 and B1 was observed (<10% patients). In contrast, deficiencies for vitamins D, A and zinc did not change significantly post-diagnosis. Copper, selenium and magnesium did not differ significantly between diagnosis and follow-up. All samples for B2, folate, vitamin C (except for one sample) and B12 were normal. A raised TGA at follow-up was associated with low vitamins A and B1 (raised vs normal TGA; vitamin A: 40% vs 17%, p = 0.044, vitamin B1: 37% vs 13%, p = 0.028). Low vitamin A (p = 0.009) and vitamin D (p = 0.001) were more common in samples collected during winter. There were no associations between micronutrient status with GIP, body mass index, height, socioeconomic status, or gastrointestinal symptom. Multivitamin use was less common in patients with low vitamin D. CONCLUSIONS: Several micronutrient deficiencies in CD respond to a GFD but others need to be monitored long-term and supplemented where indicated.

Ferric Carboxymaltose Across All Ages in Paediatric Gastroenterology Shows Efficacy Without Increased Safety Concerns.

OBJECTIVES: The aim of the study was to assess the efficacy, safety and side-effect profile of ferric carboxymaltose (FCM) for correcting IDA in children and adolescents in paediatric gastroenterology, hepatology, and nutrition. METHOD: This was a retrospective study of all gastroenterology patients <18 years who had FCM (October 2015 to October 2017). Haematological and biochemical parameters were recorded pre-infusion, at 4 weeks, 3 months, 6 months, and 1 year post-infusion. Recognised side-effects were documented. RESULTS: Sixty-six children received FCM during this period. Data was analysed on 61 children, 5 excluded because of inadequate data. The median age at administration was 14 years (IQR 7). Thirty-two (52%) were boys. Twenty-six (42%) were <14 years old. Seven (11.5%) were <5 years old. Seventeen (28%) were switched from oral iron supplements to FCM. The median dose of FCM delivered was 19 mg/kg. The median haemoglobin increased from 108 to 126 g/L at 1 month post-infusion (P value <0.00001). The mean cell volume also improved from 80 to 84 fL at 1 month post-infusion (P value = 0.0007). Forty-eight (94%) children corrected their anaemia after receiving FCM. Two patients (3%) reported side-effects with skin bruising and staining. CONCLUSIONS: FCM appears to be effective in correcting IDA in children across a wide range of gastroenterology indications and all ages. It is effective and generally well tolerated including in very young patients. Potential side-effects can be avoided by careful monitoring during infusions.

Analysis of 61 exclusive enteral nutrition formulas used in the management of active Crohn's disease-new insights into dietary disease triggers.

BACKGROUND: Exclusive enteral nutrition (EEN) is an effective treatment for Crohn's disease. AIMS: To investigate the hypothesis that ingredients of EEN formulas are unlikely to initiate a disease flare and that their dietary elimination is not essential for disease amelioration. METHODS: We performed compositional analysis of EEN formulas with evidence of efficacy in management of active Crohn's disease. Macronutrient content was compared against the dietary reference values (DRV), the UK National Diet and Nutrition Survey (NDNS) and intake of Crohn's disease children. Food additives were cross-referenced against the FAO/WHO database. RESULTS: Sixty-one formulas were identified with variable composition (carbohydrates [22.8%-89.3%], protein [7.8%-30.1%], fat [0%-52.5%]). Maltodextrin, milk protein and vegetable/plant oils were the commonest macronutrient sources. Their n-6:n-3 fatty acid ratio varied from 0.25 to 46.5. 56 food additives were identified (median per formula: 11). All formulas were lactose-free, gluten-free, and 82% lacked fibre. The commonest food additives were emulsifiers, stabilisers, antioxidants, acidity regulators and thickeners. Food additives, implicated in Crohn's disease aetiology, were present in formulas (modified starches [100%], carrageenan [22%], carboxymethyl cellulose [13%] and polysorbate 80 [5%]). Remission rates did not differ between EEN formulas with and without those food additives. Analysis including only formulas from randomised controlled trials (RCTs) retained in the latest Cochrane meta-analysis produced similar findings. EEN formulas contained less energy from saturated fat than NDNS intake. CONCLUSION: We have identified food ingredients which are present in EEN formulas that are effective in Crohn's disease and challenge perceptions that these ingredients might be harmful.

A Double-Blind, Placebo-Controlled Trial to Assess Safety and Tolerability of (Thetanix) Bacteroides thetaiotaomicron in Adolescent Crohn's Disease.

INTRODUCTION: Thetanix (gastroresistant capsules containing lyophilized Bacteroides thetaiotaomicron) is a live biotherapeutic, under development for Crohn's disease, that antagonizes transcription factor nuclear factor kappa B, reducing proinflammatory cytokines, particularly tumor necrosis factor alpha. We aimed to assess safety and tolerability in adolescents with Crohn's disease in remission. METHODS: Subjects who were 16-18 years with Crohn's in remission (weighted pediatric Crohn's disease activity index <12.5) were recruited. Each active dose comprised ∼108.2±1.4 colony forming units of B. thetaiotaomicron (randomized 4:1 active:placebo). Part A was single dose. Part B involved 7.5 days twice daily dosing. Serial stools were analyzed for calprotectin, 16S rRNA sequencing, and B. thetaiotaomicron real-time polymerase chain reaction. Bloods were taken serially. Subjects reported adverse events and recorded temperature twice daily. RESULTS: Fifteen subjects were treated-8 in part A (75% men, median 17.1 years) and 10 in part B, including 3 from part A (80% men, median 17.1 years); all 18 completed. Seventy percent took concurrent immunosuppression. Reported compliance was >99% in part B. Two subjects reported adverse events deemed related-one in part A with eructation, flatulence, and reflux; one in part B with dizziness, abdominal pain, and headache. No serious adverse events were reported. There was no significant change in median calprotectin across part B (87.8 [4.4-447] to 50.5 [5.3-572], P = 0.44 by the Fisher exact test in the active group). No significant differences were found in microbiota profiles, but diversity seemed to increase in treated subjects. DISCUSSION: Thetanix, after single and multiple doses, was well tolerated. Although the numbers in this study were small, the safety profile seems good. Future studies should explore efficacy.

British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

Screening for CYP3A4 inhibition and induction coupled to parallel artificial membrane permeability assay (PAMPA) for prediction of botanical-drug interactions: The case of açaí and maca.

BACKGROUND: The consumption of botanical dietary supplements (BDS) is a common practice among the US population. However, the potential for botanical-drug interactions exists, and their mechanisms have not been thoroughly studied. CYP3A4 is an important enzyme that contributes to the metabolism of about 60% of clinically used drugs. PURPOSE: To investigate the potential for botanical-drug interactions of Lepidium meyenii Walpers (maca) root and Euterpe oleracea Mart. (açaí) berries, two commonly used BDS, when co-administered with CYP3A4-metabolized drugs. METHODS: In an attempt to decrease the general discrepancy between in vivo and in vitro studies, the absorption profiles, particularly for passive diffusion, of plant extracts were investigated. Specifically, the parallel artificial membrane permeability assay (PAMPA) model was utilized to simulate intestinal filtration of passively diffused constituents of açaí and maca extracts. These were subsequently screened for in vitro liver CYP3A4 inhibition and induction. In the inhibition assay, midazolam was used as the probe substrate on genotyped human liver microsomes (CYP3A5 null), and the production of its 1'-substituted metabolite when co-cultured with extract treatments was monitored. In the induction assay, extract treatments were applied to human primary hepatocytes, and quantitative PCR analysis was performed to determine CYP3A4 mRNA expression. RESULTS: Passively diffused constituents of the methanol açaí extract (IC50 of 28.03 µg/µl) demonstrated the highest inhibition potential, and, at 1.5 µg/µl, induced significant changes in CYP3A4 gene expression. The composition of this extract was further investigated using the chemometric tool Mass Profiler Professional (MPP) on liquid chromatography-mass spectroscopy (LC-MS) data. Subsequently, five compounds of interest characterized by high abundance or high permeability were extracted for further study. This included efforts in effective passive permeability determination and structural elucidation by tandem mass spectrometry (MS/MS). CONCLUSION: The passively absorbable portion of a methanol açaí extract exhibited inhibition and induction effects on CYP3A4 suggesting the potential to produce botanical-drug interactions.

Treatment of Active Crohn's Disease With an Ordinary Food-based Diet That Replicates Exclusive Enteral Nutrition.

BACKGROUND & AIMS: Exclusive enteral nutrition (EEN) is the only established dietary treatment for Crohn's disease (CD), but its acceptability is limited. There is a need for novel dietary treatments for CD. METHODS: We evaluated the effects of an individualized food-based diet (CD-TREAT), with similar composition to EEN, on the gut microbiome, inflammation, and clinical response in a rat model, healthy adults, and children with relapsing CD. Twenty-five healthy adults randomly received EEN or CD-TREAT for 7 days, followed by a 14-day washout period, followed by the alternate diet. Fecal microbiome and metabolome were assessed before and after each diet. HLA-B7 and HLA-B27 transgenic rats with gut inflammation received EEN, CD-TREAT, or standard chow for 4 weeks. Fecal, luminal, and tissue microbiome, fecal metabolites, and gut inflammation were assessed. Five children with active CD activity received CD-TREAT and their clinical activity and calprotectin were evaluated after 8 weeks of treatment. RESULTS: For healthy adults, CD-TREAT was easier to comply with and more acceptable than EEN. CD-TREAT induced similar effects to EEN (EEN vs CD-TREAT) on fecal microbiome composition, metabolome, mean total sulfide (increase 133.0 ± 80.5 vs 54.3 ± 47.0 nmol/g), pH (increase 1.3 ± 0.5 vs 0.9 ± 0.6), and the short-chain fatty acids (µmol/g) acetate (decrease 27.4 ± 22.6 vs 21.6 ± 20.4), propionate (decrease 5.7 ± 7.8 vs 5.2 ± 7.9), and butyrate (decrease 7.0 ± 7.4 vs 10.2 ± 8.5). In the rat model, CD-TREAT and EEN produced similar changes in bacterial load (decrease 0.3 ± 0.3 log10 16S rRNA gene copies per gram), short-chain fatty acids, microbiome, and ileitis severity (mean histopathology score decreases of 1.25 for EEN [P = .015] and 1.0 for CD-TREAT [P = .044] vs chow). In children receiving CD-TREAT, 4 (80%) had a clinical response and 3 (60%) entered remission, with significant concurrent decreases in fecal calprotectin (mean decrease 918 ± 555 mg/kg; P = .002). CONCLUSION: CD-TREAT replicates EEN changes in the microbiome, decreases gut inflammation, is well tolerated, and is potentially effective in patients with active CD. ClinicalTrials.gov, numbers NCT02426567 and NCT03171246.

Adverse event reporting patterns of concomitant botanical dietary supplements with CYP3A4 interactive & CYP3A4 non-interactive anticancer drugs in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).

BACKGROUND: To examine the adverse event (AE) reporting patterns for concomitant Botanical Dietary Supplements (BDS) and anticancer drugs. RESEARCH DESIGN AND METHODS: Using the 2004-2015 U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, AEs involving commonly used BDS and anticancer drugs (categorized into CYP3A4 interactive and CYP3A4 non-interactive) were examined. Disproportionality analyses using reporting odds ratios (RORs) assessed the relative reporting rates of 1) serious AEs (i.e., mortality and morbidity) with concomitant use of BDS (overall and by type) and anticancer drugs compared to anticancer drugs only; and 2) AEs by specific System Organ Classes (SOCs). RESULTS: A total of 3,264 AEs were reported involving concomitant BDS and CYP3A4 interactives, and 3,885 involving concomitant BDS and non-interactive anticancer drugs. ROR of serious AEs with concomitant all BDS and anticancer drugs compared to anticancer drugs alone showed a potential protective signal (ROR = 0.65, 95% CI = 0.62,0.68), but ROR for açaí and non-interactive anticancer drugs indicated potential risk (ROR = 1.70, 95% CI = 1.01,2.86). Heterogeneity of reporting patterns of AEs related to certain SOCs was observed for use of BDS along with anticancer drugs. CONCLUSION: This study identified potential protective and risk signals for AEs with concomitant use of BDS and anticancer drugs.

Trends in botanical dietary supplement use among US adults by cancer status: The National Health and Nutrition Examination Survey, 1999 to 2014.

BACKGROUND: Patients with cancer may use botanical dietary supplements (BDS) in an attempt to manage the side effects of chemotherapy, yet evidence about BDS use among patients with cancer is limited. The authors examined trends in BDS use among US adults according to cancer status and patient characteristics. METHODS: A serial, cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey from 1999 through 2014 (n = 43,644). Self-reported cancer diagnosis history and any BDS use in the preceding 30 days were determined. The prevalence of BDS use was calculated in each cycle for respondents with and without cancer, both overall and by patient characteristics. Simple linear regression models were applied to test for trends in BDS use at a 2-sided P value < .05. Multiple logistic regression models were performed to identify the patient factors associated with BDS use. The results were weighted to represent national estimates. RESULTS: The prevalence of BDS use was greater among participants who had cancer compared with participants who did not have cancer, but trends remained stable during 1999 through 2014 for both groups. Trends in BDS use declined in patients with cancer who were older (Ptrend = .047), had a low annual family income (Ptrend = .028), and had a lower education level (Ptrend = .004). Among the respondents without cancer, trends in BDS use declined in those who were middle-aged (Ptrend = .025), non-Hispanic whites (Ptrend = .025), those with a lower education level (Ptrend = .011), and those who were not receiving prescription medication (Ptrend = .036). Patient age, sex, race/ethnicity, income, education, and health conditions were associated with BDS use. CONCLUSIONS: The overall use of BDS remained stable during 1999 through 2014 for US adults with and without cancer, but it varied by individual characteristics. Cancer 2018;124:1207-15. © 2017 American Cancer Society.

Dietary treatment of Crohn's disease: perceptions of families with children treated by exclusive enteral nutrition, a questionnaire survey.

BACKGROUND: Diet is strongly associated with the aetiology of Crohn's Disease (CD) and exclusive enteral nutrition (EEN) is the primary induction treatment in paediatric CD. This study explored opinions around the use of EEN and alternative novel, solid food-based diets (SFDs) expressed by paediatric patients with CD, previously treated with EEN and their parents. METHODS: This anonymous questionnaire surveyed families of CD patients treated with EEN over 1 year. Two questionnaire forms were completed; one asking the patients' opinions and another referring to their main carer. This questionnaire explored participants' demographic characteristics; acceptability of a repeat EEN course to treat a future flare (EEN repeat); their opinion on how difficult EEN would be compared to an example SFD; and their intention to participate in a future clinical trial assessing the therapeutic efficacy of an SFD in CD. RESULTS: Forty-one families of CD patients were approached with 29 sending replies (71%). Most of our participants were positive on completing another EEN course, however the majority would choose an SFD alternative (Patients:66, Parents:72%). Both patients and their parents rated EEN to be more difficult to adhere to compared to an example SFD (p < 0.05), and their ratings were strongly correlated (EEN:r = 0.83, SFD:r = 0.75, p < 0.001). The majority of our respondents would agree to participate in a clinical trial assessing an SFD's effectiveness (Patients:79, Parents:72%) for the management of active CD. CONCLUSIONS: While patients with CD and their families would accept an EEN repeat, the majority would prefer an SFD alternative. CD families surveyed are supportive of the development of solid food-based dietary treatments.

Observational study of adjuvant therapy with capecitabine in colon cancer.

OBJECTIVE: This observational study was conducted to document the safety of capecitabine-based adjuvant therapy in patients with resected colon cancer under routine clinical conditions. RESEARCH AND DESIGN METHODS: ML20431 was a prospective, multicenter, non-interventional, observational study. It was designed to answer five research questions relating to safety, dosage and administration, and discontinuation from capecitabine-based adjuvant therapy. Patients were required to have R0 resected stage III colon cancer and have started treatment with capecitabine-based adjuvant therapy based on a decision by the investigator. Patients were followed over an observation period of ≤6 months after initiation of therapy. Investigators were required to complete the study case report form at study entry, each treatment cycle, and at the final examination. MAIN OUTCOME MEASURES: A total of 1485 patients were included in the study, and 1481 patients were treated with capecitabine and formed the analysis population. Most patients had colon cancer (78.3%), followed by rectal cancer (16.4%). Most patients had stage III disease (69.3%); the remaining patients had stage II disease (30.7%). The most common all-grade adverse reactions were hand-foot syndrome (46.9%), diarrhea (34.4%), and hemoglobin decreases (31.5%). Grade 3/4 adverse reactions were infrequent (<4%). Serious adverse events were reported in 96 patients (6.5%). Six or more cycles of treatment were completed by 77.9% of patients. Approximately two-thirds of patients (67.3%) received capecitabine monotherapy and the remainder (32.7%) received capecitabine in combination with ≥1 drugs, most commonly oxaliplatin (460 cases). Discontinuation of capecitabine was documented in 344 patients (23.2%). STUDY LIMITATIONS: no efficacy data were collected; the questionnaires for patients' expectations and satisfaction were not formally validated; and a few patients (<1.5%) had some retrospective data. CONCLUSIONS: The safety profile of capecitabine-based adjuvant therapy in a broad patient population with colon cancer is similar to that previously documented in phase III clinical trials.

Utilization patterns of antihypertensive drugs among the chronic kidney disease population in the United States: a cross-sectional analysis of the national health and nutrition examination survey.

PURPOSE: Antihypertensive drugs are prescribed to patients with chronic kidney disease (CKD) for their cardioprotective and renoprotective effects. Nationally representative information on the use of antihypertensive drugs among CKD patients is limited. The purpose of this study was to assess the utilization patterns of antihypertensive drugs among the CKD population (stages I-IV) in the United States. METHODS: We conducted a retrospective cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) panels from 2005-2006, 2007-2008, and 2009-2010. The estimated glomerular filtration rate was calculated and kidney damage was assessed to identify participants with CKD. The demographic and clinical characteristics of the participants with CKD were reported, as were the antihypertensive drugs they used. FINDINGS: A total weighted sample of 116,231,361 participants representative of the CKD population in the United States (stages I-IV) was identified. Less than one half of the participants with CKD in the NHANES were using antihypertensive drugs. ß-blockers were the most commonly used and angiotensin II receptor blockers were the least used antihypertensive agents among participants with CKD. Age (≥70 years), awareness of hypertension or diabetes, and higher stage of CKD were associated with an increased likelihood of antihypertensive drug use among participants with CKD. IMPLICATIONS: The results of our analyses suggest that antihypertensive drugs are underused in the CKD population, and the use of preferred agents (ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) is low. Efforts should be directed toward emphasizing the importance of using antihypertensive drugs in the CKD population.

Orally administered particulate beta-glucan modulates tumor-capturing dendritic cells and improves antitumor T-cell responses in cancer.

PURPOSE: The beneficial properties of ß-glucans have been recognized for centuries. Their proposed mechanisms of action in cancer therapy occur via stimulation of macrophages and priming of innate neutrophil complement receptor 3 for eliciting complement receptor 3-dependent cellular cytotoxicity of iC3b-opsonized tumor cells. The current study is to investigate whether ß-glucan therapy has any effect on antitumor adaptive T-cell responses. EXPERIMENTAL DESIGN: We first examined the trafficking of orally administered particulate yeast-derived ß-glucan and its interaction with dendritic cells (DC) that captured tumor materials. Antigen-specific T cells were adoptively transferred into recipient mice to determine whether oral ß-glucan therapy induces augmented T-cell responses. Lewis lung carcinoma and RAM-S lymphoma models were used to test oral ß-glucan therapeutic effect. Further mechanistic studies including tumor-infiltrating T cells and cytokine profiles within the tumor milieu were determined. RESULTS: Orally administered particulate ß-glucan trafficked into spleen and lymph nodes and activated DCs that captured dying tumor cells in vivo, leading to the expansion and activation of antigen-specific CD4 and CD8 T cells. In addition, IFN-γ production of tumor-infiltrating T cells and CTL responses were significantly enhanced on ß-glucan treatment, which ultimately resulted in significantly reduced tumor burden. Moreover, ß-glucan-treated tumors had significantly more DC infiltration with the activated phenotype and significant levels of Th1-biased cytokines within the tumor microenvironment. CONCLUSIONS: These data highlight the ability of yeast-derived ß-glucan to bridge innate and adaptive antitumor immunity and suggest that it can be used as an adjuvant for tumor immunotherapy.

Therapeutic potential of various beta-glucan sources in conjunction with anti-tumor monoclonal antibody in cancer therapy.

Combined beta-glucan with anti-tumor mAb therapy has demonstrated therapeutic efficacy in murine tumor models. The current study was designed to compare the therapeutic efficacy of various sources of beta-glucans. Our studies demonstrated that yeast beta-glucan, in combination with anti-tumor mAb, resulted in significantly smaller tumor burdens and achieved enhanced long-term survival compared to mAb alone or beta-glucan extracts from mushrooms. Further studies indicated that yeast beta-glucan particle was superior to mushroom extracts in inducing cytokine secretion, particularly IL-12 production in dendritic cells (DCs). In addition, results showed that cytokine production was markedly decreased in MyD88-deficient macrophages and DCs but not in complement receptor 3 (CR3)-deficient mice. Our data suggest that yeast beta-glucan demonstrates much stronger adjuvant activity compared to mushroom beta-glucan extracts in tumor therapy. This effect of yeast beta-glucan may be in part ascribed to the cytokine secretion by DCs and macrophages and bioavailability of active beta-glucan moiety.

An infrastructure for high-throughput microscopy: instrumentation, informatics, and integration.

High-throughput, image-based cell assays are rapidly emerging as valuable tools for the pharmaceutical industry and academic laboratories for use in both drug discovery and basic cell biology research. Access to commercially available assay reagents and automated microscope systems has made it relatively straightforward for a laboratory to begin running assays and collecting image-based cell assay data, but doing so on a large scale can be more challenging. Challenges include process bottlenecks with sample preparation, image acquisition, and data analysis as well as day-to-day assay consistency, managing unprecedented quantities of image data, and fully extracting useful information from the primary assay data. This chapter considers many of the decisions needed to build a robust infrastructure that addresses these challenges. Infrastructure components described include integrated laboratory automation systems for sample preparation and imaging, as well as an informatics infrastructure for multilevel image and data analysis. Throughout the chapter we describe a variety of strategies that emphasize building processes that are scaleable, highly efficient, and rigorously quality controlled.

Resorptive drug use among community-dwelling women in Minnesota.

PURPOSE: The frequency of and factors associated with the use of resorptive medications among community-dwelling women age 45 years or older in Minnesota were studied. METHODS: The study was a secondary analysis of a cross-sectional survey mailed to 1700 community-dwelling women age 45 years or older in Minnesota. The survey was designed to collect information about women's attitudes and beliefs regarding osteoporosis and antiresorptive medications. Respondents were also asked to give a detailed list of all prescription medications they currently used, including the quantity and directions for use. Descriptive statistics were calculated for the demographic, health, and medication-use characteristics of all respondents and for the subset of those using resorptive medications. Chi-square analysis and logistic regression were used to test bivariate and multivariate relationships. RESULTS: Of the 990 usable surveys returned (adjusted response rate of 61.1%), 84 respondents (8.5%) reported using a resorptive drug. Age, health status, and the use of health care services (monthly physician visits and prescription use) were associated with resorptive drug use, controlling for other variables in the model. Women using resorptive medications were nearly 2.5 times more likely to report osteoporosis and osteopenia than women not using these medications. CONCLUSION: The use of resorptive medications in community-dwelling women in Minnesota was highest among those 75-84 years of age, women who were in poor health, and those frequently using health care services. These women were more likely to report using newer antiresorptive medications but were not more likely to use hormone therapy or calcium supplementation.