Home parenteral nutrition with an omega-3-fatty-acid-enriched MCT/LCT lipid emulsion in patients with chronic intestinal failure (the HOME study):study protocol for a randomized, controlled, multicenter, international clinical trial

BACKGROUND: Home parenteral nutrition (HPN) is a life-preserving therapy for patients with chronic intestinal failure (CIF) indicated for patients who cannot achieve their nutritional requirements by enteral intake. Intravenously administered lipid emulsions (ILEs) are an essential component of HPN, providing energy and essential fatty acids, but can become a risk factor for intestinal-failure-associated liver disease (IFALD). In HPN patients, major effort is taken in the prevention of IFALD. Novel ILEs containing a proportion of omega-3 polyunsaturated fatty acids (n-3 PUFA) could be of benefit, but the data on the use of n-3 PUFA in HPN patients are still limited. METHODS/DESIGN: The HOME study is a prospective, randomized, controlled, double-blind, multicenter, international clinical trial conducted in European hospitals that treat HPN patients. A total of 160 patients (80 per group) will be randomly assigned to receive the n-3 PUFA-enriched medium/long-chain triglyceride (MCT/LCT) ILE (Lipidem/Lipoplus® 200 mg/ml, B. Braun Melsungen AG) or the MCT/LCT ILE (Lipofundin® MCT/LCT/Medialipide® 20%, B. Braun Melsungen AG) for a projected period of 8 weeks. The primary endpoint is the combined change of liver function parameters (total bilirubin, aspartate transaminase and alanine transaminase) from baseline to final visit. Secondary objectives are the further evaluation of the safety and tolerability as well as the efficacy of the ILEs. DISCUSSION: Currently, there are only very few randomized controlled trials (RCTs) investigating the use of ILEs in HPN, and there are very few data at all on the use of n-3 PUFAs. The working hypothesis is that n-3 PUFA-enriched ILE is safe and well-tolerated especially with regard to liver function in patients requiring HPN. The expected outcome is to provide reliable data to support this thesis thanks to a considerable number of CIF patients, consequently to broaden the present evidence on the use of ILEs in HPN. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03282955. Registered on 14 September 2017

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe

Effectiveness of a mobile smoking cessation service in reaching elderly smokers and predictors of quitting

<p>Abstract</p> <p>Background</p> <p>Different smoking cessation programmes have been developed in the last decade but utilization by the elderly is low. We evaluated a pilot mobile smoking cessation service for the Chinese elderly in Hong Kong and identified predictors of quitting.</p> <p>Methods</p> <p>The Mobile Smoking Cessation Programme (MSCP) targeted elderly smokers (aged 60 or above) and provided service in a place that was convenient to the elderly. Trained counsellors provided individual counselling and 4 week's free supply of nicotine replacement therapy (NRT). Follow up was arranged at 1 month by face-to-face and at 3 and 6 months by telephone plus urinary cotinine validation. A structured record sheet was used for data collection. The service was evaluated in terms of process, outcome and cost.</p> <p>Results</p> <p>102 governmental and non-governmental social service units and private residential homes for the elderly participated in the MSCP. We held 90 health talks with 3266 elderly (1140 smokers and 2126 non-smokers) attended. Of the 1140 smokers, 365 (32%) received intensive smoking cessation service. By intention-to-treat, the validated 7 day point prevalence quit rate was 20.3% (95% confidence interval: 16.2%–24.8%). Smoking less than 11 cigarettes per day and being adherent to NRT for 4 weeks or more were significant predictors of quitting. The average cost per contact was US$54 (smokers only); per smoker with counselling: US$168; per self-reported quitter: US$594; and per cotinine validated quitter: US$827.</p> <p>Conclusion</p> <p>This mobile smoking cessation programme was acceptable to elderly Chinese smokers, with quit rate comparable to other comprehensive programmes in the West. A mobile clinic is a promising model to reach the elderly and probably other hard to reach smokers.</p

The DAC system and associations with multiple myeloma

Despite the clear progress achieved in recent years in the treatment of MM, most patients eventually relapse and therefore novel therapeutic options are still necessary for these patients. In this regard, several drugs that target specific mechanisms of the tumor cells are currently being explored in the preclinical and clinical setting. This manuscripts offers a review of the rationale and current status of the antimyeloma activity of one of the most relevant examples of these targeted drugs: deacetylase inhibitors (DACi). Several studies have demonstrated the prooncogenic activity of deacetylases (DACs) through the targeting not only of histones but also of non histone proteins relevant to tumor progression, such as p53, E2F family members, Bcl-6, Hsp90, HIF-1α or Nur77. This fact together with the DACs overexpression present in several tumors, has prompted the development of some DACi with potential antitumor effect. This situation is also evident in the case of MM as two mechanisms of DACi, the inhibition of the epigenetic inactivation of p53 and the blockade of the unfolded protein response, through the inhibition of the aggressome formation (by targeting DAC6) and the inactivation of the chaperone system (by acetylating HSP-90), provides the rationale for the exploration of the potential antimyeloma activity of these compounds. Several DACi with different chemical structure and different selectivity for targeting the DAC families have been tested in MM. Their preclinical activity in monotherapy has been quite exciting and has been described to be mediated by various mechanisms: the induction of apoptosis and cell cycle arrest mainly by the upregulation of p21; the interferece with the interaction between plasma cells and the microenvironment, by reducing the expression and signalling of several cytokines or by inhibiting angiogenesis. Finally they also have a role in protecting murine models from myeloma bone disease. Neverteless, the clinical activity in monotherapy of these drugs in relapsed/refractory MM patients has been very modest. This has prompted the development of combinations such as the one with bortezomib or lenalidomide and dexamethasone, which have already been taken into the clinics with positive preliminary results

Cancer cell sensitivity to bortezomib is associated with survivin expression and p53 status but not cancer cell types

<p>Abstract</p> <p>Background</p> <p>Survivin is known playing a role in drug resistance. However, its role in bortezomib-mediated inhibition of growth and induction of apoptosis is unclear. There are conflicting reports for the effect of bortezomib on survivin expression, which lacks of a plausible explanation. Methods: In this study, we tested cancer cells with both p53 wild type and mutant/null background for the relationship of bortezomib resistance with survivin expression and p53 status using MTT assay, flow cytometry, DNA fragmentation, caspase activation, western blots and RNAi technology.</p> <p>Results</p> <p>We found that cancer cells with wild type p53 show a low level expression of survivin and are sensitive to treatment with bortezomib, while cancer cells with a mutant or null p53 show a high level expression of survivin and are resistant to bortezomib-mediated apoptosis induction. However, silencing of survivin expression utilizing survivin mRNA-specific siRNA/shRNA in p53 mutant or null cells sensitized cancer cells to bortezomib mediated apoptosis induction, suggesting a role for survivin in bortezomib resistance. We further noted that modulation of survivin expression by bortezomib is dependent on p53 status but independent of cancer cell types. In cancer cells with mutated p53 or p53 null, bortezomib appears to induce survivin expression, while in cancer cells with wild type p53, bortezomib downregulates or shows no significant effect on survivin expression, which is dependent on the drug concentration, cell line and exposure time.</p> <p>Conclusions</p> <p>Our findings, for the first time, unify the current inconsistent findings for bortezomib treatment and survivin expression, and linked the effect of bortezomib on survivin expression, apoptosis induction and bortezomib resistance in the relationship with p53 status, which is independent of cancer cell types. Further mechanistic studies along with this line may impact the optimal clinical application of bortezomib in solid cancer therapeutics.</p

How does the tobacco industry attempt to influence marketing regulations? A systematic review

BACKGROUND: The Framework Convention on Tobacco Control makes a number of recommendations aimed at restricting the marketing of tobacco products. Tobacco industry political activity has been identified as an obstacle to Parties' development and implementation of these provisions. This study systematically reviews the existing literature on tobacco industry efforts to influence marketing regulations and develops taxonomies of 1) industry strategies and tactics and 2) industry frames and arguments. METHODS: Searches were conducted between April-July 2011, and updated in March 2013. Articles were included if they made reference to tobacco industry efforts to influence marketing regulations; supported claims with verifiable evidence; were written in English; and concerned the period 1990-2013. 48 articles met the review criteria. Narrative synthesis was used to combine the evidence. RESULTS: 56% of articles focused on activity in North America, Europe or Australasia, the rest focusing on Asia (17%), South America, Africa or transnational activity. Six main political strategies and four main frames were identified. The tobacco industry frequently claims that the proposed policy will have negative unintended consequences, that there are legal barriers to regulation, and that the regulation is unnecessary because, for example, industry does not market to youth or adheres to a voluntary code. The industry primarily conveys these arguments through direct and indirect lobbying, the promotion of voluntary codes and alternative policies, and the formation of alliances with other industrial sectors. The majority of tactics and arguments were used in multiple jurisdictions. CONCLUSIONS: Tobacco industry political activity is far more diverse than suggested by existing taxonomies of corporate political activity. Tactics and arguments are repeated across jurisdictions, suggesting that the taxonomies of industry tactics and arguments developed in this paper are generalisable to multiple jurisdictions and can be used to predict industry activity

Cell-to-Cell Signaling Influences the Fate of Prostate Cancer Stem Cells and Their Potential to Generate More Aggressive Tumors

An increasing number of malignancies has been shown to be initiated and propelled by small subpopulations of cancer stem cells (CSC). However, whether tumor aggressiveness is driven by CSC and by what extent this property may be relevant within the tumor mass is still unsettled. To address this issue, we isolated a rare tumor cell population on the basis of its CD44+CD24− phenotype from the human androgen-independent prostate carcinoma cell line DU145 and established its CSC properties. The behavior of selected CSC was investigated with respect to the bulk DU145 cells. The injection of CSC in nude mice generated highly vascularized tumors infiltrating the adjacent tissues, showing high density of neuroendocrine cells and expressing low levels of E-cadherin and β-catenin as well as high levels of vimentin. On the contrary, when a comparable number of unsorted DU145 cells were injected the resulting tumors were less aggressive. To investigate the different features of tumors in vivo, the influence of differentiated tumor cells on CSC was examined in vitro by growing CSC in the absence or presence of conditioned medium from DU145 cells. CSC grown in permissive conditions differentiated into cell populations with features similar to those of cells held in aggressive tumors generated from CSC injection. Differently, conditioned medium induced CSC to differentiate into a cell phenotype comparable to cells of scarcely aggressive tumors originated from bulk DU145 cell injection. These findings show for the first time that CSC are able to generate differentiated cells expressing either highly or scarcely aggressive phenotype, thus influencing prostate cancer progression. The fate of CSC was determined by signals released from tumor environment. Moreover, using microarray analysis we selected some molecules which could be involved in this cell-to-cell signaling, hypothesizing their potential value for prognostic or therapeutic applications

Stromal Interferon-γ Signaling and Cross-Presentation Are Required to Eliminate Antigen-Loss Variants of B Cell Lymphomas in Mice

To study mechanisms of T cell-mediated rejection of B cell lymphomas, we developed a murine lymphoma model wherein three potential rejection antigens, human c-MYC, chicken ovalbumin (OVA), and GFP are expressed. After transfer into wild-type mice 60–70% of systemically growing lymphomas expressing all three antigens were rejected; lymphomas expressing only human c-MYC protein were not rejected. OVA expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation, and lost antigen expression, indicating immune escape. In contrast to wild-type recipients, 80–100% of STAT1-, IFN-γ-, or IFN-γ receptor-deficient recipients died of lymphoma, indicating that host IFN-γ signaling is critical for rejection. Lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice had invariably lost antigen expression, suggesting that poor overall survival of these recipients was due to inefficient elimination of antigen-negative lymphoma variants. Antigen-dependent eradication of lymphoma cells in wild-type animals was dependent on cross-presentation of antigen by cells of the tumor stroma. These findings provide first evidence for an important role of the tumor stroma in T cell-mediated control of hematologic neoplasias and highlight the importance of incorporating stroma-targeting strategies into future immunotherapeutic approaches

Prostate Cancer Cell Lines under Hypoxia Exhibit Greater Stem-Like Properties

Hypoxia is an important environmental change in many cancers. Hypoxic niches can be occupied by cancer stem/progenitor-like cells that are associated with tumor progression and resistance to radiotherapy and chemotherapy. However, it has not yet been fully elucidated how hypoxia influences the stem-like properties of prostate cancer cells. In this report, we investigated the effects of hypoxia on human prostate cancer cell lines, PC-3 and DU145. In comparison to normoxia (20% O2), 7% O2 induced higher expressions of HIF-1α and HIF-2α, which were associated with upregulation of Oct3/4 and Nanog; 1% O2 induced even greater levels of these factors. The upregulated NANOG mRNA expression in hypoxia was confirmed to be predominantly retrogene NANOGP8. Similar growth rates were observed for cells cultivated under hypoxic and normoxic conditions for 48 hours; however, the colony formation assay revealed that 48 hours of hypoxic pretreatment resulted in the formation of more colonies. Treatment with 1% O2 also extended the G0/G1 stage, resulting in more side population cells, and induced CD44 and ABCG2 expressions. Hypoxia also increased the number of cells positive for ABCG2 expression, which were predominantly found to be CD44bright cells. Correspondingly, the sorted CD44bright cells expressed higher levels of ABCG2, Oct3/4, and Nanog than CD44dim cells, and hypoxic pretreatment significantly increased the expressions of these factors. CD44bright cells under normoxia formed significantly more colonies and spheres compared with the CD44dim cells, and hypoxic pretreatment even increased this effect. Our data indicate that prostate cancer cells under hypoxia possess greater stem-like properties