Octreotide LAR significantly lengthens time to tumor progression compared with placebo in patients with functionally active and inactive metastatic midgut NETs. Because of the low number of observed deaths, survival analysis was not confirmatory.

Luke Matthews is an anthropologist and primatologist whose interests include the evolution of primate behavior, primate traditions, and human cultural evolution. He has conducted primatological fieldwork in Ecuador and Argentina. He employs phylogenetics, network analysis, and cluster analysis to study inheritance systems that range from DNA sequences to primate foraging traditions and human material culture. Importantly, the 10,000 trees that we provide are not random, but instead use recent systematic methods to create a plausible set of topologies that reflect our certainty about some nodes on the tree and uncertainty about other nodes given the dataset.The trees also reflect uncertainty about branch lengths.The comparative method has undergone a revolution in the past 20 years. 2,[14][15][16] Specifically, new phylogenetic methods provide a way to incorporate evolutionary history directly into comparative research. Phylogeny is essential to comparative research because related species tend to resemble one another, resulting in non-independent data points. 2,[17][18] Phylogenetic comparative methods can be used to investigate whether two traits change in tandem through time, while also providing the historical scaffolding to identify independent evolutionary origins of the traits of interest. More recently, phylogenetic methods have provided a toolkit to investigate the tempo and mode of evolution, [19][20] to quantify phylogenetic signal in comparative data, [21][22] and to study the factors that influence diversification rates. [23][24] Computer simulations have revealed that it is usually preferable to conduct comparative tests with some form of phylogenetic method because this reduces false positives (Type I errors) and increases statistical power. [17][18][25][26] This latter point is often under-appreciated, but it is a logical outcome of phylogenetic comparative analyses that reduce error associated with the estimation of statistics and thus enhance the probability of detecting real effects. 26Researchers generally want to include as many species as possible in a comparative analysis. To incorporate phylogeny in comparative studies of primates, previous researchers have used either published primate-wide "supertrees" such as the Purvis phylogeny, 27 or they compiled smaller trees from the literature, often patching these together from among existing phylogenies based on morphology or genetics. 28-29More recently, Bininda-Emonds et al. [30][31] produced a new supertree of mammals, and researchers have begun to use the primate portion of this tree in comparative studies of primates. 32-34The actual tree topology and timing of speciation events is, however, never known with certainty. In addition, phylogenetic relationships should be continually proportion to their posterior probability (see Box 1). The set of trees obtained reflects uncertainty in the phylogeny given the substitution model and data; more certain nodes are found across a greater proportion of the sample of trees, while less certain nodes ...

The associations between methylation frequencies at CIMP-related markers and MSI or MSI-/LOH- sporadic CRCs suggest that the majority of these tumors evolve through CIMP. These findings suggest that CIN and CIMP represent 2 independent and inversely related mechanisms of genetic and epigenetic instability in sporadic CRCs and confirm that MSI cancers arise as a consequence of CIMP.

Loss of PTEN tumor suppressor function is observed in tumors of breast, prostate, thyroid, and endometrial origin. Allelic losses in the proximity of the PTEN locus (10q23) also occur in sporadic colorectal cancers (CRCs), but biallelic inactivation of this site has not been frequently demonstrated. We hypothesized that alternative mechanisms of PTEN allelic inactivation, such as promoter hypermethylation, might be operative in CRC and that PTEN inactivation may be related to recognized forms of genomic instability. We characterized a cohort of 273 sporadic CRCs by determining their microsatellite instability (MSI) status. Of these, 146 cancers were examined for PTEN promoter methylation by methylation-specific PCR. Mutations at the poly(A) 6 repeat sequences in PTEN exons 7 and 8 and deletions at the 10q23 locus were also identified using microsatellite analysis. The presence of PTEN protein was determined by immunostaining, and the results were correlated with the promoter methylation status. We observed that PTEN promoter hypermethylation was a frequent occurrence in MSI-high (MSI-H) tumors (19.1% of MSI-H versus 2.2% of MSI-low/microsatellite stable tumors; P ‫؍‬ 0.002). A PTEN mutation or a deletion event was present in 60% of the tumors with promoter region hypermethylation. Hypermethylation of the PTEN promoter correlated significantly with either decreased or complete loss of PTEN protein expression (P ‫؍‬ 0.004). This is the first demonstration of PTEN inactivation as a result of promoter hypermethylation in MSI-H sporadic CRCs. These data suggest that this silencing mechanism plays a major role in PTEN inactivation and, in colon cancer, may be more important than either allelic losses or inactivating mutations. The significant correlation of PTEN hypermethylation with MSI-H tumors further suggests that PTEN is an additional important "target" of methylation along with the hMLH1 gene in the evolution of MSI-H CRCs and also confers the "second hit" in the biallelic inactivation mechanism for some proportion of tumors.

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Highlights d diffTF estimates differential TF activity based on chromatin data (basic mode) d Integration with RNA-seq identifies activator/repressor TFs (classification mode) d We applied diffTF to subtypes of CLL and hematopoietic differentiation d The TF classification was experimentally validated in both case studies

Loss of DNA mismatch repair (MMR) occurs in 10 -15% of sporadic colorectal cancer, is usually caused by hMLH1 hypermethylation, and has been shown to confer resistance to various chemotherapeutic reagents, including 5-fluorouracil (5-FU). We tested the hypothesis that demethylation of the hMLH1 promoter in hypermethylated colorectal cancer cells would restore MMR proficiency and drug sensitivity to 5-FU.

Although the relevance of particle size reduction in herbivore digestion is widely appreciated, few studies have investigated digesta particle size across species in relation to body mass or digestive strategy. We investigated faecal particle size, which reflects the size of ingesta particles after both mastication and specialized processes such as rumination. Particle size was measured by wet sieving samples from more than 700 captive individuals representing 193 mammalian species. Using phylogenetic generalized least squares, faecal particle size scaled to body mass with an exponent of 0.22 (95% confidence interval: 0.160.28). In comparisons among different digestive strategies, we found that (1) equids had smaller faecal particles than other hindgut fermenters, (2) non-ruminant foregut fermenters and hindgut fermenters had similar-sized faecal particles (not significantly different), and (3) ruminants had finer faecal particles than non-ruminants. These results confirm that the relationship between chewing efficiency and body mass is modified by morphological adaptations in dental design and physiological adaptations to chewing, such as rumination. This allometric relationship should be considered when investigating the effect of body size on digestive physiology, and digestion studies should include a measure of faecal particle size.