Effects of butyrate on the colon cancer cell phenotype-chemosensitization and upregulation of proteins implicated in cancer progression

Colon cancer is the second leading cause of cancer mortality in the U.S. Surgery is the only truly effective human colon cancer (HCC) therapy due to marked intrinsic drug resistance. The inefficacy of therapies developed for metastatic HCC suggests that advances in colon cancer chemoprevention and chemotherapy will be needed to reduce HCC mortality. The dietary fiber metabolite butyrate (NaB) is a candidate cancer chemopreventive agent that inhibits growth, promotes differentiation and stimulates apoptosis of HCC cells. Epidemiological and experimental studies suggest that dietary fiber protects against the development of HCC, however, recent large prospective trials have not found significant protection. ^ The first central hypothesis of this dissertation project is that the diversity of phenotypic changes induced by NaB in HCC cells includes molecular alterations that oppose its chemopreventive action and thereby limit its efficacy. We investigated the effect of NaB on the expression/activity of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in HCC HT29 cells. NaB treatment induced a 13-fold increase in EGFR expression in concert with its chemopreventive action in vitro, i.e., induction of growth suppression and G1 arrest, apoptosis and a differentiated phenotype. NaB-induced EGFR was active based on multiple lines of evidence. The EGFR was: (1) heavily phosphorylated at Tyrosine (P-Tyr); (2) associated with the cytoskeleton; (3) localized at the cell surface, and activated in response to EGF; and (4) NaB treatment of the cells induced activation of the EGFR effector Erk1/2. NaB treatment also induced a 7-fold increase in COX-2 expression. The NaB-induced COX-2 was active based on significantly increased PGE2 production. ^ The second central hypothesis is that NaB treatment would render HCC cells more chemosensitive to chemotherapy agents based on the increased apoptotic index induced by NaB. NaB treatment chemosensitized HT29 cells to 5-FU and doxorubicin, despite increases in the expression of P-glycoprotein and a related drug resistance protein (MRP). ^ These results raise the intriguing possibility that the chemopreventive effects of fiber may require concomitant treatment with EGFR and/or COX-2 inhibitors. Similarly, NaB may be a rational drug to combine with existing chemotherapeutic agents for the management of advanced HCC patients. ^

Delivery of health care at the end of life in cancer patients of four swiss cantons a retrospective database study (SAKK 89/09)

Background The use of cancer related therapy in cancer patients at the end-of-life has increased over time in many countries. Given a lack of published Swiss data, the objective of this study was to describe delivery of health care during the last month before death of cancer patients. Methods Claims data were used to assess health care utilization of cancer patients (identified by cancer registry data of four participating cantons), deceased between 2006-2008. Primary endpoints were hospitalization rate and delivery of cancer related therapies during the last 30 days before death. Multivariate logistic regression assessed the explanatory value of patient and geographic characteristics. Results 3809 identified cancer patients were included. Hospitalization rate (mean 68.5%, 95%CI 67.0-69.9) and percentage of patients receiving anti-cancer drug therapies (ACDT, mean 14.5%, 95%CI 13.4-15.6) and radiotherapy (mean 7.7%, 95%CI 6.7-8.4) decreased with age. Canton of residence and insurance type status most significantly influenced the odds for hospitalization or receiving ACDT. Conclusions The intensity of cancer specific care showed substantial variation by age, cancer type, place of residence and insurance type status. This may be partially driven by cultural differences within Switzerland and the cantonal organization of the Swiss health care system.

Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer.

Head and neck cancer constitutes the 6th most common malignancy worldwide and affects the crucial anatomical structures and physiological functions of the upper aerodigestive tract. Classical therapeutic strategies such as surgery and radiotherapy carry substantial toxicity and functional impairment. Moreover, the loco-regional control rates as well as overall survival still need to be improved in subgroups of patients. The scatter-factor/hepatocyte growth factor receptor tyrosine kinase MET is an established effector in the promotion, maintenance and progression of malignant transformation in a wide range of human malignancies, and has been gaining considerable interest in head and neck cancer over the last 15 years. Aberrant MET activation due to overexpression, mutations, tumor-stroma paracrine loops, and cooperative/redundant signaling has been shown to play prominent roles in epithelial-to-mesenchymal transition, angiogenesis, and responses to anti-cancer therapeutic modalities. Accumulating preclinical and translational evidence highly supports the increasing interest of MET as a biomarker for lymph node and distant metastases, as well as a potential marker of stratification for responses to ionizing radiation. The relevance of MET as a therapeutic molecular target in head and neck cancer described in preclinical studies remains largely under-evaluated in clinical trials, and therefore inconclusive. Also in the context of anti-cancer targeted therapy, a large body of preclinical data suggests a central role for MET in treatment resistance towards multiple therapeutic modalities in malignancies of the head and neck region. These findings, as well as the potential use of combination therapies including MET inhibitors in these tumors, need to be further explored.

Examination of the influence of behavioral, normative and control beliefs on the adherence to a prescribed renal diet among elderly populations with chronic to end-stage renal disease

The 1999-2004 prevalence of chronic kidney disease in adults 20 year or older (15.5 million) is an estimated 7.69%. The risk of developing CKD is exacerbated by diabetes, hypertension and/or a family history of kidney disease. African Americans, Hispanics, Pacific Islanders, Native Americans, and the elderly are more susceptible to higher incidence of CKD. The challenges of aging coupled with co-morbidities such as kidney disease raises the potential for malnutrition among elderly (for the purpose of this study 55 years or older) populations. Lack of adherence to prescribed nutrition guidelines specific to renal failure jeopardizes body homeostasis and increases the likelihood of future morbidity and resultant mortality. The relationship and synergy that exists between diet and disease is evident. Clinical experience with renal patients has indicated the importance of adherence to diet therapy specific to kidney disease. Extension investigation of diet adherence among endstage renal disease patients revealed a sizeable dearth in the current literature. This thesis study was undertaken to help reduce that void. The study design is qualitative and descriptive. Support, cooperation, and collaboration were provided by the University of Texas Nephrology Department, University of Texas Physicians, and DaVita Dialysis Centers. Approximately 105 male and female chronic to end-stage kidney disease patients were approached to participate in elicitation interviews in dialysis treatment facilities regarding their present diet beliefs and practices. Eighty-five were recruited and agreed to participate. Inclusion criteria required individuals to be between 35-90 years of age; capable of completing a 5-10 minute interview; and English speaking. Each kidney patient was asked seven (7) non-leading questions developed from the constructs of the Theory of Planned Behavior. The study presents a descriptive comparison of behavioral, normative, and control beliefs that influence adherence to renal diets by age, race, and gender. The study successfully concluded that behavioral, normative, and control beliefs of chronic to end-stage renal patients promoted execution and adherence to prescribed nutrition. This study provides valuable information for dietitians, technicians, nurses, and physicians to assess patient compliance toward prescribed nutrition and the means to support or improve that performance. ^

Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using IL-12, pro-IL-18, and IL-1β converting enzyme cDNA

We report here that a cancer gene therapy protocol using a combination of IL-12, pro-IL-18, and IL-1β converting enzyme (ICE) cDNA expression vectors simultaneously delivered via gene gun can significantly augment antitumor effects, evidently by generating increased levels of bioactive IL-18 and consequently IFN-γ. First, we compared the levels of IFN-γ secreted by mouse splenocytes stimulated with tumor cells transfected with various test genes, including IL-12 alone; pro-IL-18 alone; pro-IL-18 and ICE; IL-12 and pro-IL-18; and IL-12, pro-IL-18, and ICE. Among these treatments, the combination of IL-12, pro-IL-18, and ICE cDNA resulted in the highest level of IFN-γ production from splenocytes in vitro, and similar results were obtained when these same treatments were delivered to the skin of a mouse by gene gun and IFN-γ levels were measured at the skin transfection site in vivo. Furthermore, the triple gene combinatorial gene therapy protocol was the most effective among all tested groups at suppressing the growth of TS/A (murine mammary adenocarcinoma) tumors previously implanted intradermally at the skin site receiving DNA transfer by gene gun on days 6, 8, 10, and 12 after tumor implantation. Fifty percent of mice treated with the combined three-gene protocol underwent complete tumor regression. In vivo depletion experiments showed that this antitumor effect was CD8+ T cell-mediated and partially IFN-γ-dependent. These results suggest that a combinatorial gene therapy protocol using a mixture of IL-12, pro-IL-18, and ICE cDNAs can confer potent antitumor activities against established TS/A tumors via cytotoxic CD8+ T cells and IFN-γ-dependent pathways.

Creation of drug-specific herpes simplex virus type 1 thymidine kinase mutants for gene therapy.

Herpes simplex virus type 1 (HSV-1) thymidine kinase is currently used as a suicide agent in the gene therapy of cancer. This therapy is based on the preferential phosphorylation of nucleoside analogs by tumor cells expressing HSV-1 thymidine kinase. However, the use of HSV-1 thymidine kinase is limited in part by the toxicity of the nucleoside analogs. We have used random sequence mutagenesis to create new HSV-1 thymidine kinases that, compared with wild-type thymidine kinase, render cells much more sensitive to specific nucleoside analogs. A segment of the HSV-1 thymidine kinase gene at the putative nucleoside binding site was substituted with random nucleotide sequences. Mutant enzymes that demonstrate preferential phosphorylation of the nucleoside analogs, ganciclovir or acyclovir, were selected from more than one million Escherichia coli transformants. Among the 426 active mutants we have isolated, 26 demonstrated enhanced sensitivity to ganciclovir, and 54 were more sensitive to acyclovir. Only 6 mutant enzymes displayed sensitivity to both ganciclovir and acyclovir when expressed in E. coli. Analysis of 3 drug-sensitive enzymes demonstrated that 1 produced stable mammalian cell transfectants that are 43-fold more sensitive to ganciclovir and 20-fold more sensitive to acyclovir.

Bibliographies on nursing; books, pamphlets, articles, audio-visual aids.

Vol. 5 issued by the National League for Nursing, Division of Nursing Education.

Sickroom cookery and hospital diet; with special recipes for convalescent and diabetic patients,

Mode of access: Internet.

A prospective study of the use of alternative therapies by men with localized prostate cancer

Although the use of alternative therapies is highly prevalent amongst men with prostate cancer, research about the predictors of such use is limited. The current study aimed to describe prospectively the use of alternative therapies by men diagnosed with localized prostate cancer and identify predictors of alternative therapy use. In all, 111 men newly diagnosed with localized prostate cancer (93% response) were recruited to the study prior to treatment. Men's use of alternative therapies and psychological variables including: psychological distress, orientation to health care, decisional conflict, and health locus of control, were assessed at three time points-(1) before treatment; (2) 2 months after completion of treatment; and (3) 12 months after completion of treatment. Demographic information was also obtained. The percentage of men using alternative therapies was 25, 17 and 14% before treatment, 2 and 12 months after treatment, respectively. In general, the most commonly used therapies were dietary changes, vitamins and herbal and nutrient remedies. Alternative therapy use was not related to final treatment choices. Before treatment, men who used alternative therapies were more uncertain about prostate cancer compared to men who were not using these therapies. Men who were using alternative therapies 12 months after treatment were less psychologically distressed that men who were not using these therapies. Health locus of control and orientation to health care were not found to be related to men's use of alternative therapies. In conclusion, men's use of alternative therapies after localized prostate cancer varied across time in terms of the incidence of use, the types of therapies used, and the psychological correlates of therapy use. Informational support that targets uncertainty about prostate cancer may assist men at diagnosis who are considering alternative therapy use. The potential for alternative therapies to have a supportive function in patient care requires further investigation. (C) 2003 Elsevier Ireland Ltd. All rights reserved.

The Challenges Faced in Developing Novel Drug Radiation Combinations in Non-small Cell Lung Cancer

Lung cancer is the most common cancer diagnosed in the UK. Outcomes for patients with this disease remain poor and new strategies to treat this disease require investigation. One potential option is to combine novel agents with radiotherapy in clinical studies. Here we discuss some of the important issues to consider when combining novel agents with radiotherapy, together with potential solutions as discussed at a recent Clinical Translational Radiotherapy Group (CTRad) workshop.

Gene therapy tools: oligonucleotides and peptides

Genetic mutations can cause a wide range of diseases, e.g. cancer. Gene therapy has the potential to alleviate or even cure these diseases. One of the many gene therapies developed so far is RNA-cleaving deoxyribozymes, short DNA oligonucleotides that specifically bind to and cleave RNA. Since the development of these synthetic catalytic oligonucleotides, the main way of determining their cleavage kinetics has been through the use of a laborious and error prone gel assay to quantify substrate and product at different time-points. We have developed two new methods for this purpose. The first one includes a fluorescent intercalating dye, PicoGreen, which has an increased fluorescence upon binding double-stranded oligonucleotides; during the course of the reaction the fluorescence intensity will decrease as the RNA is cleaved and dissociates from the deoxyribozyme. A second method was developed based on the common denominator of all nucleases, each cleavage event exposes a single phosphate of the oligonucleotide phosphate backbone; the exposed phosphate can simultaneously be released by a phosphatase and directly quantified by a fluorescent phosphate sensor. This method allows for multiple turnover kinetics of diverse types of nucleases, including deoxyribozymes and protein nucleases. The main challenge of gene therapy is often the delivery into the cell. To bypass cellular defenses researchers have used a vast number of methods; one of these are cell-penetrating peptides which can be either covalently coupled to or non-covalently complexed with a cargo to deliver it into a cell. To further evolve cell-penetrating peptides and understand how they work we developed an assay to be able to quickly screen different conditions in a high-throughput manner. A luciferase up- and downregulation experiment was used together with a reduction of the experimental time by 1 day, upscaling from 24- to 96-well plates and the cost was reduced by 95% compared to commercially available assays. In the last paper we evaluated if cell-penetrating peptides could be used to improve the uptake of an LNA oligonucleotide mimic of GRN163L, a telomerase-inhibiting oligonucleotide. The combination of cell-penetrating peptides and our mimic oligonucleotide lead to an IC50 more than 20 times lower than that of GRN163L.

A systematic review of the cost-effectiveness of targeted therapies for metastatic non-small cell lung cancer (NSCLC)

Background: Non-small cell lung cancer (NSCLC) imposes a substantial burden on patients, health care systems and society due to increasing incidence and poor survival rates. In recent years, advances in the treatment of metastatic NSCLC have resulted from the introduction of targeted therapies. However, the application of these new agents increases treatment costs considerably. The objective of this article is to review the economic evidence of targeted therapies in metastatic NSCLC. Methods: A systematic literature review was conducted to identify cost-effectiveness (CE) as well as cost-utility studies. Medline, Embase, SciSearch, Cochrane, and 9 other databases were searched from 2000 through April 2013 (including update) for full-text publications. The quality of the studies was assessed via the validated Quality of Health Economic Studies (QHES) instrument. Results: Nineteen studies (including update) involving the MoAb bevacizumab and the Tyrosine-kinase inhibitors erlotinib and gefitinib met all inclusion criteria. The majority of studies analyzed the CE of first-line maintenance and second-line treatment with erlotinib. Five studies dealt with bevacizumab in first-line regimes. Gefitinib and pharmacogenomic profiling were each covered by only two studies. Furthermore, the available evidence was of only fair quality. Conclusion: First-line maintenance treatment with erlotinib compared to Best Supportive Care (BSC) can be considered cost-effective. In comparison to docetaxel, erlotinib is likely to be cost-effective in subsequent treatment regimens as well. The insights for bevacizumab are miscellaneous. There are findings that gefitinib is cost-effective in first- and second-line treatment, however, based on only two studies. The role of pharmacogenomic testing needs to be evaluated. Therefore, future research should improve the available evidence and consider pharmacogenomic profiling as specified by the European Medicines Agency. Upcoming agents like crizotinib and afatinib need to be analyzed as well. © Lange et al.

Theranostic multimodular potential of zinc-doped ferrite-saturated metal-binding protein-loaded novel nanocapsules in cancers

The present study successfully developed orally deliverable multimodular zinc (Zn) iron oxide (Fe3O4)-saturated bovine lactoferrin (bLf)-loaded polymeric nanocapsules (NCs), and evaluated their theranostic potential (antitumor efficacy, magnetophotothermal efficacy and imaging capability) in an in vivo human xenograft CpG-island methylator phenotype (CIMP)-1(+)/CIMP2(-)/chromosome instability-positive colonic adenocarcinoma (Caco2) and claudin-low, triple-negative (ER(-)/PR(-)/HER2(-); MDA-MB-231) breast cancer model. Mice fed orally on the Zn-Fe-bLf NC diet showed downregulation in tumor volume and complete regression in tumor volume after 45 days of feeding. In human xenograft colon cancer, vehicle-control NC diet-group (n=5) mice showed a tumor volume of 52.28±11.55 mm(3), and Zn-Fe-bLf NC diet (n=5)-treated mice had a tumor-volume of 0.10±0.073 mm(3). In the human xenograft breast cancer model, Zn-Fe-bLf NC diet (n=5)-treated mice showed a tumor volume of 0.051±0.062 mm(3) within 40 days of feeding. Live mouse imaging conducted by near-infrared fluorescence imaging of Zn-Fe-bLf NCs showed tumor site-specific localization and regression of colon and breast tumor volume. Ex vivo fluorescence-imaging analysis of the vital organs of mice exhibited sparse localization patterns of Zn-Fe-bLf NCs and also confirmed tumor-specific selective localization patterns of Zn-Fe-bLf NCs. Dual imaging using magnetic resonance imaging and computerized tomography scans revealed an unprecedented theranostic ability of the Zn-Fe-bLf NCs. These observations warrant consideration of multimodular Zn-Fe-bLf NCs for real-time cancer imaging and simultaneous cancer-targeted therapy.

Nurses knowledge of health effects of dietary fibre

Introduction: Nurses accompany patients throughout their health care to prevent and treat disease, so their knowledge about diet and dietary fibre is key to successful diet therapy, which is an essential part of a patient's non-pharmacological treatment. It is known from the literature that a high proportion of nurses have limited knowledge about diet therapy and about sources of soluble fibre and other foods that can prevent or treat certain diseases. Given the position of nurses as key providers of dietary guidance, and given the health benefits of dietary fibre, we wanted to assess the level of fibre-related knowledge among nurses in Croatia. Material and Methods: Cross-sectional study based on data collected between October 2014 and March 2015 using a survey developed by the CI&DETS Polytechnic Institute in Viseu, Portugal. The survey contains questions about demographic characteristics as well as about knowledge of sources of dietary fibre, recommended daily intake and effects of fibre intake on particular diseases. The study included a total of 369 nurses from two health institutions and one nursing school from Croatia older than 18 years. Differences in knowledge were assessed for significance using the non-parametric Mann-Whitney U test. Possible associations among variables were explored using Spearman's rank correlation. For all statistical analyses, the threshold of significance was defined as P<0.05. Results: The level of knowledge among nurses in Croatia about dietary fibre varied from «undecided» to «partial knowledge». The median for level of knowledge ranged from 3 to 4 with low variability ranging from 0.11 to 0.33. Average levels of knowledge in percentages varied from 57.6% to 82.1%. Nurses with higher education levels showed significantly higher knowledge levels about the influence of dietary fiber intake on the risk of certain diseases (p = 0.007), constipation (p = 0.016), bowel cancer (p = 0.005) and breast cancer (p = 0.039). Conclusion: The level of nurses’ knowledge about dietary fiber is suboptimal. This indicates the need to strengthen nurse education in the areas of diet and diet therapy. Increase the level of knowledge of nurses about nutrition can positively influence the quality of care.

A low fermentable oligo-di-mono saccharides and polyols (FODMAP) diet reduced pain and improved daily life in fibromyalgia patients

Fibromyalgia (FM) is a chronic, rheumatic disease characterized by widespread myofascial pain, of unknown aetiology, having a major impact on quality of life (QOL). Available pharmacotherapy for FM is marginally effective. FM is associated with co-morbidities of gastrointestinal (GI) disorders and Irritable Bowel Syndrome (IBS). There is growing evidence that diets low in FODMAPs, “fermentable oligo-, di- or mono-saccharides and polyols” [Low FODMAP Diet (LFD)], are effective in treating IBS. The aim of this pilot study was to examine the effects of LFDs on symptoms of FM, especially with regard to pain, QOL and GI disorders. Methods A longitudinal study using LFD intervention was performed on 38, 51 ± 10 year-old, female patients diagnosed with FM for an average of 10 years, based on ACR (American College of Rheumatology) 2010 criteria. The study was conducted from January through May, 2015, using a four-week, repeated-assessment model, as follows: Moment 0 – introduction of the protocol to participants; Moment 1 – first assessment and delivery of individual LFD dietary plans; Moment 2 – second assessment and reintroduction of FODMAPs; Moment 3 – last assessment and final nutritional counselling. Assessment tools used were the following: RFIQ (Revised Fibromyalgia Impact Questionnaire), FSQ (Fibromyalgia Survey Questionnaire), IBS-SSS (Severity Score System), EQ-5D (Euro-QOL quality of life instrument), and VAS (Visual Analogue Scale). Daily consumption of FODMAPs was quantified based on published food content analyses. Statistical analyses included ANOVA, non-parametric Friedman, t-student and Chi-square tests, using SPSS 22 software. Results The mean scores of the 38 participants at the beginning of the study were: FSQ (severity of FM, 0–31) – 22 ± 4.4; RFIQ (0–100) – 65 ± 17; IBS-SSS (0–500) – 275 ± 101; and EQ-5D (0–100) – 48 ± 19. Mean adherence to dietary regimens was 86%, confirmed by significant difference in FODMAP intakes (25 g/day vs. 2.5 g/day; p < 0.01). Comparisons between the three moments of assessment showed significant (p < 0.01) declines in scores in VAS, FSQ, and RFIQ scores, in all domains measured. An important improvement was observed with a reduction in the severity of GI symptoms, with 50% reduction in IBS scores to 138 ± 117, following LFD therapy. A significant correlation (r = 0.36; p < 0.05) was found between improvements in FM impact (declined scores) and gastrointestinal scores. There was also a significant correlation (r = 0.65; p < 0.01) between “satisfaction with improvement” after introduction of LFDs and “diet adherence”, with satisfaction of the diet achieving 77% among participants. A significant difference was observed between patients who improved as compared to those that did not improve (Chi-square χ2 = 6.16; p < .05), showing that the probability of improvement, depends on the severity of the RFIQ score. Conclusions Implementation of diet therapy involving FODMAP restrictions, in this cohort of FM patients, resulted in a significant reduction in GI disorders and FM symptoms, including pain scores. These results need to be extended in future larger studies on dietary therapy for treatment of FM. Implications According to current scientific knowledge, these are the first relevant results found in an intervention with LFD therapy in FM and must be reproduced looking for a future dietetic approach in FM.