Impact of Elimination or Reduction of Dietary Animal Proteins on Cancer Progression and Survival: Protocol of an Online Pilot Cohort Study.

BACKGROUND: Current evidence suggests that the incidence of cancer is low in vegan populations, and experimental studies have revealed a significant role of dietary proteins in cancer development and progression. However, little data currently exists regarding the effect of a plant-based diet on the progression of diagnosed cancer. OBJECTIVE: The main objective of this study is to determine if a reduction or total elimination of animal protein from the diet can positively influence the outcome of an existing cancer and, in addition to standard oncological therapies, increase remission rates. METHODS: The primary aim of this online study is to test the effect on remission rates in cancer patients (primary outcome) with distinct self-selected dietary patterns (omnivore, lacto-ovo-vegetarian, vegan), and allow for an estimation of the effect size. Secondary outcomes are tumor behavior, relapse-free interval, therapies, therapy tolerability and side-effects, comorbidities, medication, quality of life, acceptance, and feasibility of the selected diet. Safety concerns exist for vegan diets (especially in cancer patients) and the study will carefully monitor for deterioration of health, tumor progression, or malnutrition. Furthermore, the study will evaluate the online portal as a study platform (technical and safety aspects, and sequence of displayed questionnaires) as well as the validity of self-reported and online-generated data. RESULTS: The study was performed between April, 2015 and June, 2016, and a preliminary evaluation of safety aspects was undertaken after June, 2016. Primary and secondary outcomes will be evaluated when the final patients complete the study in December, 2016. CONCLUSIONS: This study will reveal information about the effects of dietary patterns on cancer disease and progression. The methodology of the study addresses several aspects and limitations of nutrition studies in cancer patients, such as precision of nutrition data, acceptance criteria, online methodology, and safety aspects. CLINICALTRIAL: Clinicaltrials.gov NCT02437474; https://clinicaltrials.gov/ct2/show/NCT02437474 (Archived by WebCite at http://www.webcitation.org/6jL7UUCVq).

Changes of dietary patterns during participation in a web-based weight-reduction programme.

OBJECTIVE: To examine the weight-loss success associated with distinct dietary patterns and to determine changes of these dietary patterns during participation in a web-based weight-reduction programme. DESIGN: Factor analysis was used to identify the dietary patterns of twenty-two food groups that were administered in 14 d dietary protocols at baseline and after 3 months. Successful weight loss (≥5% of initial weight) and BMI were calculated. Logistic regression analyses were used to assess the rates of weight-loss success from each dietary pattern and changing or remaining in the initial dietary pattern. A generalised linear mixed model was used to estimate the effects of changing or staying in a dietary pattern on change in BMI. SUBJECTS: Adults (n 1635) aged 18-81 years. SETTING: Users of a web-based weight-reduction programme (2006-2012). RESULTS: Participants who aligned to a healthful dietary pattern at baseline (OR=1·8; 95% CI 1·5, 2·3) and after 3 months (OR=1·5; 95% CI 1·2, 1·9) had a greater chance of successfully losing weight. After adjusting for age, sex, initial dietary pattern and BMI, participants who started with or changed to the healthful dietary pattern had a greater chance of being successful (OR=1·4; 95% CI 1·1, 1·7) and a higher BMI reduction of 0·30 (95% CI 0·2, 0·5) kg/m(2) compared with those who started with or changed to the energy-dense or high-carbohydrate dietary pattern. CONCLUSIONS: A favourable healthful dietary pattern at the beginning and after 3 months was positively associated with anthropometry. However, successful weight loss was feasible in each dietary pattern.

Determinants of successful weight loss after using a commercial web-based weight reduction program for six months: cohort study.

BACKGROUND: The Internet is widely available and commonly used for health information; therefore, Web-based weight loss programs could provide support to large parts of the population in self-guided weight loss. Previous studies showed that Web-based weight loss interventions can be effective, depending on the quality of the program. The most effective program tools are visual progress charts or tools for the self-monitoring of weight, diet, and exercises. KiloCoach, a commercial program currently available in German-speaking countries, incorporates these features. A previous investigation showed that the program effectively supports users in losing weight. OBJECTIVE: We investigated weight loss dynamics stratified by weight loss success after 6-month use of KiloCoach. Furthermore, we analyzed possible associations between intensity of program use and weight loss. The results are intended for tailoring user recommendations for weight-loss Internet platforms. METHODS: Datasets of KiloCoach users (January 1, 2008 to December 31, 2011) who actively used the platform for 6 months or more were assigned to this retrospective analysis. Users (N=479) were 42.2% men, mean age of 44.0 years (SD 11.7), with a mean body mass index (BMI) of 31.7 kg/m² (SD 3.2). Based on the weight loss achieved after 6 months, 3 success groups were generated. The unsuccessful group lost <5%, the moderate success group lost 5%-9.9%, and the high success group lost ≥10% of their baseline body weight. At baseline, the unsuccessful (n=261, 54.5%), moderate success (n=133, 27.8%), and high success (n=85, 17.8%) groups were similar in age, weight, BMI, and gender distribution. RESULTS: After 6 months, the unsuccessful group lost 1.2% (SD 2.4), the moderate success group lost 7.4% (SD 1.5), and the high success group lost 14.2% (SD 3.8) of their initial weight (P<.001). Multivariate regression showed that early weight loss (weeks 3-4), the total number of dietary protocols, and the total number of weight entries were independent predictors for 6-month weight reduction (all P<.001) explaining 52% of the variance in weight reduction. Sensitivity analysis by baseline carried forward method confirmed all independent predictors of 6-month weight loss and reduced the model fit by only 11%. The high success group lost weight faster and maintained weight loss more efficiently than the other groups (P<.001). Early weight loss was associated with weight maintenance after 1 year and 2 years (both P<.001). Weight dynamics did not differ between men and women over 6 months when adjusted for baseline and usage parameters (P=.91). The percentage of male long-term users was unusually high (42.2%). CONCLUSIONS: Our results suggest that early weight loss and close program adherence (ie, 5 dietary protocols per week and weekly entering of current weight), especially in the early phase of program usage, can improve weight loss outcome.

Effectiveness of the online weight reduction program KiloCoach™ and comparison with other evaluated commercial direct intervention and online programs.

OBJECTIVE: Preliminary results indicated effectiveness of the online weight reduction program KiloCoach. The current study presents a large collection of user data and compares KiloCoach with other evaluated commercial weight loss programs. Furthermore, potential factors influencing the effectiveness of internet weight loss programs should be identified. METHOD: 4,310 data sets of KiloCoach users were available, 3,150 of them were suitable for further analysis. 946 program users were considered completers (at least 60 days of continuous protocol). For comparison with other programs, different subsamples were drawn that matched to the inclusion criteria of reference studies. RESULTS: On average, KiloCoach overweight and obese completers lost 4.5 % of initial body weight. KiloCoach was as effective as the commercial program Weight Watchers® after 1 year (6.4% vs. 5.3% weight loss; p = 0.11) and 2 years (5.1% vs. 3.2% weight loss; p = 0.15). KiloCoach proved to be more effective than other online programs (Viktklubb, eDiets.com) as well as an in-person behavioral program, but less effective than Vtrim®, an online behavioral program providing intensive support. CONCLUSION: In comparison to reference programs, KiloCoach proved to be effective for weight reduction. The effect of online weight reduction programs seems to depend on methods and features applied.

Defective T-cell activation caused by impairment of the TNF receptor 2 costimulatory pathway in common variable immunodeficiency.

BACKGROUND: Patients with common variable immunodeficiency have defective T-cell activation after stimulation via T-cell receptor (TCR)/CD28 or by recall antigens. OBJECTIVE: In the current study, we investigated whether TNF-receptor 2 (RII) costimulation, which is important for sufficient TCR/CD28 stimulation, was significantly impaired in common variable immunodeficiency (CVID). METHODS: We studied T-cell activation events such as CD69 induction, calcium flux through store operated calcium channels, protein kinase C-theta translocation, and costimulation via TNF-RII compared with costimulation via CD28. RESULTS: By measuring TNF receptor-associated factor 1 expression, which is induced by TCR alone and can be upregulated by either CD28 or TNF-RII costimulation, we show that costimulation via CD28 is intact, whereas costimulation via TNF-RII in these patients is impaired. The ras-activation pathway as tested by CD69 induction, calcium flux through store operated calcium channels, and protein kinase C-theta translocation were comparable in CVID and control T cells. CONCLUSION: Taken together, these data indicate that the primary TCR signal as well as the signal derived from CD28 are normal but that TNF-RII-supported TCR costimulation is defective, most likely leading to impairment of an important amplification loop, such as TNF-RII augmented nuclear factor-kappaB activation. CLINICAL IMPLICATIONS: The finding of defective TNF-RII cosignaling in patients with CVID may help to define the activation pathway affected, thus potentially leading to a characterization of the molecular defect and molecular diagnosis in at least some of these patients.

Characterization of novel Bruton's tyrosine kinase gene mutations in Central European patients with agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is an immunodeficiency disorder caused by mutations in the gene coding for Bruton's tyrosine kinase (BTK). In this study we investigated 10 male patients with XLA-compatible phenotype (agammaglobulinemia and undetectable B cells in peripheral blood) from 9 unrelated Central European families. We identified seven different mutations, six of which were novel. One previously described point mutation caused a premature stop codon (p.C464X), two point mutations resulted in amino acid exchanges (p.W588R; p.G419E), and two point mutations affected splice sites (c.305-1G>A; c.391+1G>A). We further detected one deletion (c.1921_1927del CGTCCCA) and one large duplication. The duplication resulted from Alu element-induced unequal homologous recombination, which was only detectable by extended analysis of cDNA, while direct sequencing of genomic DNA gave a false negative result. Western blot analysis revealed that the patients with the p.W588R and the p.G419E amino acid substitutions, respectively, produced full length BTK, but in clearly diminished amounts. The patient with the 7bp deletion expressed low amounts of protein which might represent truncated BTK. All other genomic alterations resulted in complete loss of BTK protein. In two patients from unrelated families BTK protein expression was normal and no Btk gene mutation was detected. The results of this study further substantiate the importance of using elaborate molecular analysis with different detection techniques to obtain an explicit molecular diagnosis in patients with suspected XLA.

Chronic TNF-alpha exposure impairs TCR-signaling via TNF-RII but not TNF-RI.

Chronic exposure to TNF-alpha has been shown to impair T cell-activation in mice and in humans. In the present study, we investigated a possible role of TNF-RII in this long-term effect of TNF-alpha. Chronic TNF-alpha exposure led to suppression of subsequent TCR stimulation (e.g., TCR/CD28-induced proliferation, cytokine production (IFN-gamma, TNF-alpha)) but left TCR independent restimulation unaffected. Activation of T cells during TNF-alpha exposure was required for the inhibitory effect on TCR stimulation. In contrast to the mouse model, the inhibitory effect of long-term TNF-alpha exposure was mediated via TNF-RII but not TNF-receptor I, and surface expression of the TCR/CD3 complex remained unchanged. Chronic TNF-RII triggering downregulated T cell activation at an early level, as TCR-induced calcium flux and IL-2 mRNA expression were impaired after preculture in the presence of anti-TNF-RII mAbs. Furthermore, chronic TNF-RII-stimulation specifically downregulated store operated calcium channels, which contribute to sustained TCR-induced calcium influx.

Regulation of TCR-mediated T cell activation by TNF-RII.

In the present study, we investigated the role of tumor necrosis factor receptor II (TNF-RII) in human T cell activation induced via the T cell receptor (TCR) in an antigen-presenting cell-independent system. Our results confirm that interaction of TNF-alpha with TNF-RII but not TNF-RI is directly costimulatory to TCR-mediated T cell activation, thereby augmenting T cell proliferation, expression of T cell activation markers (CD25, human leukocyte antigen-DR, TNF-RII), and secretion of cytokines such as interferon-gamma and TNF-alpha. In contrast to the well-defined costimulatory molecule CD28, costimulation via TNF-RII showed significant differences in kinetics, requirement for cross-linking, redundancy of intracellular signaling pathways involved, and the capacity to induce interleukin (IL)-2, IL-10, and IL-13 secretion. In addition, cross-linking TNF-RII had the capacity to down-regulate TCR/CD28-induced Ca++ mobilization, IL-2 mRNA expression, and IL-2 and IL-10 secretion. Taken together, our findings demonstrate that TNF-RII plays a unique role among the T cell costimulatory molecules, as TNF-RII ligation can have positive and negative effects on TCR-dependent signaling. TNF-RII cross-linking has an inhibitory effect on early TCR signaling events proximal to induction of Ca++ flux, which ultimately leads to modulation of the T cell cytokine pattern expressed.