Modifiable lifestyle factors associated with risk of sessile serrated polyps, conventional adenomas, and hyperplastic polyps

ObjectiveTo identify modifiable factors associated with sessile serrated polyps (SSPs) and compare the association of these factors with conventional adenomas (ADs) and hyperplastic polyps (HPs).DesignWe used data from the Tennessee Colorectal Polyp Study, a colonoscopy-based case–control study. Included were 214 SSP cases, 1779 AD cases, 560 HP cases and 3851 polyp-free controls.ResultsCigarette smoking was associated with increased risk for all polyps and was stronger for SSPs than for ADs (OR 1.74, 95% CI 1.16 to 2.62, for current vs never, ptrend=0.008). Current regular use of non-steroidal anti-inflammatory drugs was associated with a 40% reduction in SSP risk in comparison with never users (OR 0.68, 95% CI 0.48 to 0.96, ptrend=0.03), similar to the association with AD. Red meat intake was strongly associated with SSP risk (OR 2.59, 95% CI 1.41 to 4.74 for highest vs lowest intake, ptrend&lt;0.001) and the association with SSP was stronger than with AD (ptrend=0.003). Obesity, folate intake, fibre intake and fat intake were not associated with SSP risk after adjustment for other factors. Exercise, alcohol use and calcium intake were not associated with risk for SSPs.ConclusionsSSPs share some modifiable risk factors for ADs, some of which are more strongly associated with SSPs than ADs. Thus, preventive efforts to reduce risk for ADs may also be applicable to SSPs. Additionally, SSPs have some distinctive risk factors. Future studies should evaluate the preventive strategies for these factors. The findings from this study also contribute to an understanding of the aetiology and biology of SSPs.</jats:sec

Comparison of Biomarker Expression between Proximal and Distal Colorectal Adenomas: The Tennessee-Indiana Adenoma Recurrence Study

It is unclear if proximal and distal traditional adenomas present with differences in molecular events which contribute to cancer heterogeneity by tumor anatomical subsite. Participants from a colonoscopy-based study (n=380) were divided into subgroups based on the location of their most advanced adenoma: proximal, distal, or “equivalent both sides”. Eight biomarkers in the most advanced adenomas were evaluated by immunohistochemistry (Ki-67, COX-2, TGFβRII, EGFR, β-catenin, cyclin D1, c-Myc) or TUNEL (apoptosis). After an adjustment for pathological features, there were no significant differences between proximal and distal adenomas for any biomarker. Conversely, expression levels did vary by other features, such as their size, villous component, and synchronousness. Large adenomas had higher expression levels of Ki-67(P<0.001), TGFβRII (P<0.0001), c-Myc (P<0.001), and cyclin D1 (P<0.001) in comparison to small adenomas, and tubulovillous/villous adenomas also were more likely to have similar higher expression levels in comparison to tubular adenomas. Adenoma location is not a major determinant of the expression of these biomarkers outside of other pathological features. This study suggests similarly important roles of Wnt/β-catenin and TGF-β pathways in carcinogenesis in both the proximal and distal colorectum

Dissidents and God-Talk in the Johannine Epistles

Peer reviewe

Prenylation Inhibition-Induced Cell Death in Melanoma: Reduced Sensitivity in BRAF Mutant/PTEN Wild-Type Melanoma Cells.

While targeted therapy brought a new era in the treatment of BRAF mutant melanoma, therapeutic options for non-BRAF mutant cases are still limited. In order to explore the antitumor activity of prenylation inhibition we investigated the response to zoledronic acid treatment in thirteen human melanoma cell lines with known BRAF, NRAS and PTEN mutational status. Effect of zoledronic acid on proliferation, clonogenic potential, apoptosis and migration of melanoma cells as well as the activation of downstream elements of the RAS/RAF pathway were investigated in vitro with SRB, TUNEL and PARP cleavage assays and videomicroscopy and immunoblot measurements, respectively. Subcutaneous and spleen-to-liver colonization xenograft mouse models were used to evaluate the influence of zoledronic acid treatment on primary and disseminated tumor growth of melanoma cells in vivo. Zoledronic acid more efficiently decreased short-term in vitro viability in NRAS mutant cells when compared to BRAF mutant and BRAF/NRAS wild-type cells. In line with this finding, following treatment decreased activation of ribosomal protein S6 was found in NRAS mutant cells. Zoledronic acid demonstrated no significant synergism in cell viability inhibition or apoptosis induction with cisplatin or DTIC treatment in vitro. Importantly, zoledronic acid could inhibit clonogenic growth in the majority of melanoma cell lines except in the three BRAF mutant but PTEN wild-type melanoma lines. A similar pattern was observed in apoptosis induction experiments. In vivo zoledronic acid did not inhibit the subcutaneous growth or spleen-to-liver colonization of melanoma cells. Altogether our data demonstrates that prenylation inhibition may be a novel therapeutic approach in NRAS mutant melanoma. Nevertheless, we also demonstrated that therapeutic sensitivity might be influenced by the PTEN status of BRAF mutant melanoma cells. However, further investigations are needed to identify drugs that have appropriate pharmacological properties to efficiently target prenylation in melanoma cells

Pan-RAF and MEK vertical inhibition enhances therapeutic response in non-V600 BRAF mutant cells

BACKGROUND: Currently, there are no available targeted therapy options for non-V600 BRAF mutated tumors. The aim of this study was to investigate the effects of RAF and MEK concurrent inhibition on tumor growth, migration, signaling and apoptosis induction in preclinical models of non-V600 BRAF mutant tumor cell lines. METHODS: Six BRAF mutated human tumor cell lines CRL5885 (G466 V), WM3629 (D594G), WM3670 (G469E), MDAMB231 (G464 V), CRL5922 (L597 V) and A375 (V600E as control) were investigated. Pan-RAF inhibitor (sorafenib or AZ628) and MEK inhibitor (selumetinib) or their combination were used in in vitro viability, video microscopy, immunoblot, cell cycle and TUNEL assays. The in vivo effects of the drugs were assessed in an orthotopic NSG mouse breast cancer model. RESULTS: All cell lines showed a significant growth inhibition with synergism in the sorafenib/AZ628 and selumetinib combination. Combination treatment resulted in higher Erk1/2 inhibition and in increased induction of apoptosis when compared to single agent treatments. However, single selumetinib treatment could cause adverse therapeutic effects, like increased cell migration in certain cells, selumetinib and sorafenib combination treatment lowered migratory capacity in all the cell lines. Importantly, combination resulted in significantly increased tumor growth inhibition in orthotropic xenografts of MDAMB231 cells when compared to sorafenib - but not to selumetinib - treatment. CONCLUSIONS: Our data suggests that combined blocking of RAF and MEK may achieve increased therapeutic response in non-V600 BRAF mutant tumors

Age dating of an early Milky Way merger via asteroseismology of the naked-eye star ν Indi

Over the course of its history, the Milky Way has ingested multiple smaller satellite galaxies1. Although these accreted stellar populations can be forensically identified as kinematically distinct structures within the Galaxy, it is difficult in general to date precisely the age at which any one merger occurred. Recent results have revealed a population of stars that were accreted via the collision of a dwarf galaxy, called Gaia–Enceladus1, leading to substantial pollution of the chemical and dynamical properties of the Milky Way. Here we identify the very bright, naked-eye star ν Indi as an indicator of the age of the early in situ population of the Galaxy. We combine asteroseismic, spectroscopic, astrometric and kinematic observations to show that this metal-poor, alpha-element-rich star was an indigenous member of the halo, and we measure its age to be 11.0±0.7 (stat) ±0.8 (sys) billion years. The star bears hallmarks consistent with having been kinematically heated by the Gaia–Enceladus collision. Its age implies that the earliest the merger could have begun was 11.6 and 13.2 billion years ago, at 68% and 95% confidence, respectively. Computations based on hierarchical cosmological models slightly reduce the above limits

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Aspects of dietary carbohydrate intake are not related to risk of colorectal polyps in the Tennessee Colorectal Polyp Study

PURPOSE: High digestible carbohydrate intakes can induce hyperglycemia and hyperinsulinemia, and collectively have been implicated in colorectal tumor development. Our aim was to explore the association between aspects of dietary carbohydrate intake and risk of colorectal adenomas and hyperplastic polyps in a large case-control study. METHODS: Colorectal polyp cases (n=1,315 adenomas only, n=566 hyperplastic polyps only and n=394 both) and controls (n=3,184) undergoing colonoscopy were recruited between 2003 and 2010 in Tennessee, USA. Dietary intakes were estimated by a 108-item food frequency questionnaire. Unconditional logistic regression analysis was applied to determine odds ratios (OR) and corresponding 95% confidence intervals (CI) for colorectal polyps according to dietary carbohydrate intakes, after adjustment for potential confounders. RESULTS: No significant associations were detected for risk of colorectal adenomas when comparing the highest versus lowest quartiles of intake for total sugars (OR 1.03; 95% CI 0.84–1.26), starch (OR 1.01; 95% CI 0.81–1.26), total or available carbohydrate intakes. Similar null associations were observed between dietary carbohydrate intakes and risk of hyperplastic polyps, or concurrent adenomas and hyperplastic polyps. CONCLUSION: In this US population, digestible carbohydrate intakes were not associated with risk of colorectal polyps, suggesting that dietary carbohydrate does not have an etiological role in the early stages of colorectal carcinogenesis