Phylogenomic perspectives on speciation and reproductive isolation in a North American biodiversity hotspot: An example using California sages (Salvia subg. Audibertia; Lamiaceae).

BACKGROUND AND AIMS: The California Floristic Province (CA-FP) is the most species-rich region of North America north of Mexico. One of several proposed hypotheses explaining the exceptionally diversity of the region is that the CA-FP harbors myriad recently diverged lineages with nascent reproductive barriers. Salvia subgenus Audibertia is a conspicuous element of the CA-FP, with multiple sympatric and compatible species. METHODS: Using 305 nuclear loci and both organellar genomes, we reconstruct species trees, examine genomic discordance, conduct divergence-time estimation, and analyze contemporaneous patterns of gene flow and mechanical reproductive isolation. KEY RESULTS: Despite strong genomic discordance, an underlying bifurcating tree is supported. Organellar genomes capture additional introgression events not detected in the nuclear genome. Most interfertility is found within clades, indicating that reproductive barriers are coincident with genetic divergence. Species are generally not mechanically isolated, suggesting that it is unlikely to be the primary factor leading to reproductive isolation. CONCLUSIONS: Rapid, recent speciation with some interspecific gene flow in conjunction with the onset of a Mediterranean-like climate is the underlying cause of extant diversity in Salvia subgenus Audibertia. Speciation has largely not been facilitated by gene flow. Its signal in the nuclear genome seems to mostly be erased by backcrossing, but organellar genomes each capture different instances of historical gene flow, likely characteristic of many CA-FP lineages. Mechanical reproductive isolation appears to be only part of a mosaic of factors limiting gene flow.

Phylogeography and genetic variation in Western Jacob's ladder (Polemonium occidentale) provide insights into the origin and conservation of rare species in the Great Lakes region.

The perennial herb Western Jacob's Ladder (Polemonium occidentale, Polemoniaceae) is widespread in the mountains of western North America but reappears as a disjunct in the Great Lakes Region in Minnesota and Wisconsin, USA as the narrow endemic P. occidentale subsp. lacustre. This distribution is shown by a diverse assemblage of angiosperms. It has been hypothesized that these species became isolated just after the Last Glacial Maximum, but this has not been tested. Additionally, the genetic diversity and population connectivity of the endemic Great Lakes flora has been understudied, with important conservation implications. Using genotyping-by-sequencing, we examined the relationship of P. occidentale subsp. lacustre to its closest relatives, relationships among all known populations, and genetic diversity within these populations. Polemonium occidentale subsp. lacustre represents an isolated, unique lineage that diverged from its closest relatives 1.3 Ma and arrived in the Great Lakes Region by at least 38 ka. Nearly all extant populations diverged prior to the Last Glacial Maximum, are genetically distinct, and show little within-population genetic diversity. Clonality may mitigate reduction in diversity due to drift. Mixed population signal between Wisconsin and some Minnesota populations may be due to gene flow during the Late Pleistocene. While populations of P. occidentale subsp. lacustre may be relictual from a now extinct western relative, it is best treated as a distinct species. Conservation efforts should focus more on ensuring that current populations remain rather than maintaining large populations sizes across a few populations. However, encouraging habitat heterogeneity may accomplish both simultaneously.

East Asian-North American disjunctions and phylogenetic relationships within subtribe Nepetinae (Lamiaceae).

Biogeographic disjunctions, including intercontinental disjunctions, are frequent across plant lineages and have been of considerable interest to biologists for centuries. Their study has been reinvigorated by molecular dating and associated comparative methods. One of the "classic" disjunction patterns is that between Eastern Asia and North America. It has been speculated that this pattern is the result of vicariance following the sundering of a widespread Acrto-Teritary flora. Subtribe Nepetinae in the mint family (Lamiaceae) is noteworthy because it contains three genera with this disjunction pattern: Agastache, Dracocephalum, and Meehania. These disjunctions are ostensibly the result of three separate events, allowing for concurrent testing of the tempo, origin, and type of each biogeographic event. Using four plastid and four nuclear markers, we estimated divergence times and analyzed the historical biogeography of Nepetinae, including comprehensive sampling of all major clades for the first time. We recover a well-supported and largely congruent phylogeny of Nepetinae between genomic compartments, although several cases of cyto-nuclear discordance are evident. We demonstrate that the three disjunctions are pseudo-congruent, with unidirectional movement from East Asia at slightly staggered times during the late Miocene and early Pliocene. With the possible exception of Meehania, we find that vicariance is likely the underlying driver of these disjunctions. The biogeographic history of Meehania in North America may be best explained by long-distance dispersal, but a more complete picture awaits deeper sampling of the nuclear genome and more advanced biogeographical models.

The evolution of Ericaceae flowers and their pollination syndromes at a global scale.

PREMISE: Floral evolution in large clades is difficult to study not only because of the number of species involved, but also because they often are geographically widespread and include a diversity of outcrossing pollination systems. The cosmopolitan blueberry family (Ericaceae) is one such example, most notably pollinated by bees and multiple clades of nectarivorous birds. METHODS: We combined data on floral traits, pollination ecology, and geography with a comprehensive phylogeny to examine the structuring of floral diversity across pollination systems and continents. We focused on ornithophilous systems to test the hypothesis that some Old World Ericaceae were pollinated by now-extinct hummingbirds. RESULTS: Despite some support for floral differentiation at a continental scale, we found a large amount of variability within and among landmasses, due to both phylogenetic conservatism and parallel evolution. We found support for floral differentiation in anther and corolla traits across pollination systems, including among different ornithophilous systems. Corolla traits show inconclusive evidence that some Old World Ericaceae were pollinated by hummingbirds, while anther traits show stronger evidence. Some major shifts in floral traits are associated with changes in pollination system, but shifts within bee systems are likely also important. CONCLUSIONS: Studying the floral evolution of large, morphologically diverse, and widespread clades is feasible. We demonstrate that continent-specific radiations have led to widespread parallel evolution of floral morphology. We show that traits outside of the perianth may hold important clues to the ecological history of lineages.

Out of Sight, Out of Mind: Widespread Nuclear and Plastid-Nuclear Discordance in the Flowering Plant Genus Polemonium (Polemoniaceae) Suggests Widespread Historical Gene Flow Despite Limited Nuclear Signal.

Phylogenomic data from a rapidly increasing number of studies provide new evidence for resolving relationships in recently radiated clades, but they also pose new challenges for inferring evolutionary histories. Most existing methods for reconstructing phylogenetic hypotheses rely solely on algorithms that only consider incomplete lineage sorting (ILS) as a cause of intra- or intergenomic discordance. Here, we utilize a variety of methods, including those to infer phylogenetic networks, to account for both ILS and introgression as a cause for nuclear and cytoplasmic-nuclear discordance using phylogenomic data from the recently radiated flowering plant genus Polemonium (Polemoniaceae), an ecologically diverse genus in Western North America with known and suspected gene flow between species. We find evidence for widespread discordance among nuclear loci that can be explained by both ILS and reticulate evolution in the evolutionary history of Polemonium. Furthermore, the histories of organellar genomes show strong discordance with the inferred species tree from the nuclear genome. Discordance between the nuclear and plastid genome is not completely explained by ILS, and only one case of discordance is explained by detected introgression events. Our results suggest that multiple processes have been involved in the evolutionary history of Polemonium and that the plastid genome does not accurately reflect species relationships. We discuss several potential causes for this cytoplasmic-nuclear discordance, which emerging evidence suggests is more widespread across the Tree of Life than previously thought. [Cyto-nuclear discordance, genomic discordance, phylogenetic networks, plastid capture, Polemoniaceae, Polemonium, reticulations.].

Evolving Role of Liver Resection in Selected Patients With Metastatic Breast Cancer.

BACKGROUND: More effective chemotherapy regimens combined with metastasectomy have improved overall survival (OS) in several cancer populations. The value of liver resection (LR) in breast cancer liver metastasis (BCLM) remains controversial. We sought to investigate the role of LR in BCLM as a therapeutic option in patients with isolated liver metastasis. METHODS: The National Cancer Data Base (NCDB) was queried for patients with BCLM diagnosed from 2010 to 2014. The primary outcome was the OS. Kaplan-Meier and Cox proportional hazards regression were performed for intergroup comparison. RESULTS: A total of 9244 patients with BCLM were included. The median age was 58 y (IQR 49-68 y). Of them, 2632 (28.5%) patients had isolated liver metastasis, 1957 (78.2%) received chemotherapy, 93 (3.6%) underwent LR, and only 83 (3.2%) received chemotherapy and LR. Median OS for the entire cohort and for patients with isolated BCLM was 18.3 mo and 29 mo, respectively. Chemotherapy with LR was associated with superior OS compared to chemotherapy alone (69.7 versus 49.2 mo, P < 0.001) in patients with BCLM: ER+ (69.6 versus 54.1 mo, P = 0.002) and triple-negative BC (49.2 versus 17.6 mo, P = 0.006). Cox regression showed that LR, chemotherapy, and positive hormone receptor status (ER+, PR+, and/or HER2+) were independent predictors of improved OS. Advanced age and comorbidity score negatively impacted OS. CONCLUSIONS: This is the largest series thus far assessing the role of LR in patients with BCLM. LR plus chemotherapy may be associated with acceptable outcomes in selected patients with BCLM. LR should be considered in patients with isolated BCLM who had a good response to systemic therapy.

Adaptive associations among life history, reproductive traits, environment, and origin in the Wisconsin angiosperm flora.

PREMISE: We tested 25 classic and novel hypotheses regarding trait-origin, trait-trait, and trait-environment relationships to account for flora-wide variation in life history, habit, and especially reproductive traits using a plastid DNA phylogeny of most native (96.6%, or 1494/1547 species) and introduced (87.5%, or 690/789 species) angiosperms in Wisconsin, USA. METHODS: We assembled data on life history, habit, flowering, dispersal, mating system, and occurrence across open/closed/mixed habitats across species in the state phylogeny. We used phylogenetically structured analyses to assess the strength and statistical significance of associations predicted by our models. RESULTS: Introduced species are more likely to be annual herbs, occupy open habitats, have large, visually conspicuous, hermaphroditic flowers, and bear passively dispersed seeds. Among native species, hermaphroditism is associated with larger, more conspicuous flowers; monoecy is associated with small, inconspicuous flowers and passive seed dispersal; and dioecy is associated with small, inconspicuous flowers and fleshy fruits. Larger flowers with more conspicuous colors are more common in open habitats, and in understory species flowering under open (spring) canopies; fleshy fruits are more common in closed habitats. Wind pollination may help favor dioecy in open habitats. CONCLUSIONS: These findings support predictions regarding how breeding systems depend on flower size, flower color, and fruit type, and how those traits depend on habitat. This study is the first to combine flora-wide phylogenies with complete trait databases and phylogenetically structured analyses to provide powerful tests of evolutionary hypotheses about reproductive traits and their variation with geographic source, each other, and environmental conditions.

Tracking temporal shifts in area, biomes, and pollinators in the radiation of Salvia (sages) across continents: leveraging anchored hybrid enrichment and targeted sequence data.

PREMISE OF THE STUDY: A key question in evolutionary biology is why some clades are more successful by being widespread geographically, biome diverse, or species-rich. To extend understanding of how shifts in area, biomes, and pollinators impact diversification in plants, we examined the relationships of these shifts to diversification across the mega-genus Salvia. METHODS: A chronogram was developed from a supermatrix of anchored hybrid enrichment genomic data and targeted sequence data for over 500 of the nearly 1000 Salvia species. Ancestral areas and biomes were reconstructed using BioGeoBEARS. Pollinator guilds were scored, ancestral pollinators determined, shifts in pollinator guilds identified, and rates of pollinator switches compared. KEY RESULTS: A well-resolved phylogenetic backbone of Salvia and updated subgeneric designations are presented. Salvia originated in Southwest Asia in the Oligocene and subsequently dispersed worldwide. Biome shifts are frequent from a likely ancestral lineage utilizing broadleaf and/or coniferous forests and/or arid shrublands. None of the four species diversification shifts are correlated to shifts in biomes. Shifts in pollination system are not correlated to species diversification shifts, except for one hummingbird shift that precedes a major shift in diversification near the crown of New World subgen. Calosphace. Multiple reversals back to bee pollination occurred within this hummingbird clade. CONCLUSIONS: Salvia diversified extensively in different continents, biomes, and with both bee and bird pollinators. The lack of tight correlation of area, biome, and most pollinator shifts to the four documented species diversification shifts points to other important drivers of speciation in Salvia.

Synthesis of Semicrystalline Polyolefin Materials: Precision Methyl Branching via Stereoretentive Chain Walking.

We report the discovery of C2-symmetric nickel catalysts capable of the regio- and isoselective polymerization of 1-butene to produce isotactic 4,2-poly(1-butene), a new semi-crystalline polyolefin. The catalyst exhibits enantioface selectivities as high as 84% and the resulting polymers display melting temperatures up to 86 °C. This system marks a rare example of preserving stereochemistry through a chain walking polymerization process.

Phylogeny, historical biogeography, and diversification of angiosperm order Ericales suggest ancient Neotropical and East Asian connections.

Inferring interfamilial relationships within the eudicot order Ericales has remained one of the more recalcitrant problems in angiosperm phylogenetics, likely due to a rapid, ancient radiation. As a result, no comprehensive time-calibrated tree or biogeographical analysis of the order has been published. Here, we elucidate phylogenetic relationships within the order and then conduct time-dependent biogeographical and diversification analyses by using a taxon and locus-rich supermatrix approach on one-third of the extant species diversity calibrated with 23 macrofossils and two secondary calibration points. Our results corroborate previous studies and also suggest several new but poorly supported relationships. Newly suggested relationships are: (1) holoparasitic Mitrastemonaceae is sister to Lecythidaceae, (2) the clade formed by Mitrastemonaceae + Lecythidaceae is sister to Ericales excluding balsaminoids, (3) Theaceae is sister to the styracoids + sarracenioids + ericoids, and (4) subfamilial relationships with Ericaceae suggest that Arbutoideae is sister to Monotropoideae and Pyroloideae is sister to all subfamilies excluding Arbutoideae, Enkianthoideae, and Monotropoideae. Our results indicate Ericales began to diversify 110 Mya, within Indo-Malaysia and the Neotropics, with exchange between the two areas and expansion out of Indo-Malaysia becoming an important area in shaping the extant diversity of many families. Rapid cladogenesis occurred along the backbone of the order between 104 and 106 Mya. Jump dispersal is important within the order in the last 30 My, but vicariance is the most important cladogenetic driver of disjunctions at deeper levels of the phylogeny. We detect between 69 and 81 shifts in speciation rate throughout the order, the vast majority of which occurred within the last 30 My. We propose that range shifting may be responsible for older shifts in speciation rate, but more recent shifts may be better explained by morphological innovation.

Spatial phylogenetics reveals evolutionary constraints on the assembly of a large regional flora.

PREMISE OF THE STUDY: We used spatial phylogenetics to analyze the assembly of the Wisconsin flora, linking processes of dispersal and niche evolution to spatial patterns of floristic and phylogenetic diversity and testing whether phylogenetic niche conservatism can account for these patterns. METHODS: We used digitized records and a new molecular phylogeny for 93% of vascular plants in Wisconsin to estimate spatial variation in species richness and phylogenetic α and ß diversity in a native flora shaped mainly by postglacial dispersal and response to environmental gradients. We developed distribution models for all species and used these to infer fine-scale variation in potential diversity, phylogenetic distance, and interspecific range overlaps. We identified 11 bioregions based on floristic composition, mapped areas of neo- and paleo-endemism to establish new conservation priorities and predict how community-assembly patterns should shift with climatic change. KEY RESULTS: Spatial phylogenetic turnover most strongly reflects differences in temperature and spatial distance. For all vascular plants, assemblages shift from phylogenetically clustered to overdispersed northward, contrary to most other studies. This pattern is lost for angiosperms alone, illustrating the importance of phylogenetic scale. CONCLUSIONS: Species ranges and assemblage composition appear driven primarily by phylogenetic niche conservatism. Closely related species are ecologically similar and occupy similar territories. The average level and geographic structure of plant phylogenetic diversity within Wisconsin are expected to greatly decline over the next half century, while potential species richness will increase throughout the state. Our methods can be applied to allochthonous communities throughout the world.

Shape analysis of moss (Bryophyta) sporophytes: Insights into land plant evolution.

PREMISE OF THE STUDY: The alternation of generations life cycle represents a key feature of land-plant evolution and has resulted in a diverse array of sporophyte forms and modifications in all groups of land plants. We test the hypothesis that evolution of sporangium (capsule) shape of the mosses-the second most diverse land-plant lineage-has been driven by differing physiological demands of life in diverse habitats. This study provides an important conceptual framework for analyzing the evolution of a single, homologous character in a continuous framework across a deep expanse of time, across all branches of the tree of life. METHODS: We reconstruct ancestral sporangium shape and ancestral habitat on the largest phylogeny of mosses to date, and use phylogenetic generalized least squares regression to test the association between habitat and sporangium shape. In addition, we examine the association between shifts in sporangium shape and species diversification. RESULTS: We demonstrate that sporangium shape is convergent, under natural selection, and associated with habitat type, and that many shifts in speciation rate are associated with shifts in sporangium shape. CONCLUSIONS: Our results suggest that natural selection in different microhabitats results in the diversity of sporangium shape found in mosses, and that many increasing shifts in speciation rate result in changes in sporangium shape across their 480 million year history. Our framework provides a way to examine if diversification shifts in other land plants are also associated with massive changes in sporophyte form, among other morphological traits.

Positive selection of lactase persistence among people of Southern Arabia.

OBJECTIVE: Frequency patterns of the lactase persistence (LP)-associated -13,915 G allele and archaeological records pointing to substantial role played by southern regions in the peopling and domestication processes that involved the Arabian Peninsula suggest that Southern Arabia plausibly represented the center of diffusion of such adaptive variant. Nevertheless, a well-defined scenario for evolution of Arabian LP is still to be elucidated and the burgeoning archaeological picture of complex human migrations occurred through the peninsula is not matched by an equivalent high-resolution description of genetic variation underlying this adaptive trait. To fill this gap, we investigated diversity at a wide genomic interval surrounding the LCT gene in different Southern Arabian populations. METHODS: 40 SNPs were genotyped to characterize LCT profiles of 630 Omani and Yemeni individuals to perform population structure, linkage disequilibrium, population differentiation-based and haplotype-based analyses. RESULTS: Typical Arabian LP-related variation was found in Dhofaris and Yemenis, being characterized by private haplotypes carrying the -13,915 G allele, unusual differentiation with respect to northern groups and conserved homozygous haplotype-blocks, suggesting that the adaptive allele was likely introduced in the Arabian gene pool in southern populations and was then subjected to prolonged selective pressure. CONCLUSION: By pointing to Yemen as one of the best candidate centers of diffusion of the Arabian-specific adaptive variant, obtained results indicate the spread of indigenous groups as the main process underlying dispersal of LP along the Arabian Peninsula, supporting a refugia model for Arabian demic movements occurred during the Terminal Pleistocene and Early Holocene.

Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo.

The discovery that circulating nucleic acid-containing complexes in the serum of autoimmune lupus patients can stimulate B cells and plasmacytoid dendritic cells via Toll-like receptors 7 and 9 suggested that agents that block these receptors might be useful therapeutics. We identified two compounds, AT791 {3-[4-(6-(3-(dimethylamino)propoxy)benzo[d]oxazol-2-yl)phenoxy]-N,N-dimethylpropan-1-amine} and E6446 {6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole}, that inhibit Toll-like receptor (TLR)7 and 9 signaling in a variety of human and mouse cell types and inhibit DNA-TLR9 interaction in vitro. When administered to mice, these compounds suppress responses to challenge doses of cytidine-phosphate-guanidine (CpG)-containing DNA, which stimulates TLR9. When given chronically in spontaneous mouse lupus models, E6446 slowed development of circulating antinuclear antibodies and had a modest effect on anti-double-stranded DNA titers but showed no observable impact on proteinuria or mortality. We discovered that the ability of AT791 and E6446 to inhibit TLR7 and 9 signaling depends on two properties: weak interaction with nucleic acids and high accumulation in the intracellular acidic compartments where TLR7 and 9 reside. Binding of the compounds to DNA prevents DNA-TLR9 interaction in vitro and modulates signaling in vivo. Our data also confirm an earlier report that this same mechanism may explain inhibition of TLR7 and 9 signaling by hydroxychloroquine (Plaquenil; Sanofi-Aventis, Bridgewater, NJ), a drug commonly prescribed to treat lupus. Thus, very different structural classes of molecules can inhibit endosomal TLRs by essentially identical mechanisms of action, suggesting a general mechanism for targeting this group of TLRs.

Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients.

PURPOSE: Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance. PATIENTS AND METHODS: This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC. Thirteen patients were enrolled and received cetuximab in combination with pertuzumab at several dose levels in a 3 + 3 design. Patients were assessed for dose-limiting toxicity (DLT) during the first cycle. A phase II portion was planned, but not initiated due to toxicity. RESULTS: Six of the thirteen patients (46 %) experienced DLTs, therefore the study was terminated early. Grade 3 or higher DLTs included dermatitis with desquamation and/or acneiform rash (n = 6), mucositis or stomatitis (n = 5), and diarrhea (n = 2). There was one Grade 5 event (myocardial infarction) attributed to underlying disease. Among the 13 patients, seven (54 %) were evaluable for response. The objective response rate was 14 %: one patient had a partial response lasting 6 months. Two patients had stable disease (29 %), and four had progressive disease (57 %). Median progression free survival was 2.1 months (95 % CI, 1.5-4.9) and median overall survival was 3.7 months (95 % CI, 1.6-7.9). CONCLUSION: Combination pertuzumab and cetuximab in refractory CRC was associated with potential antitumor activity; however, the combination was not tolerable due to overlapping toxicities.

Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria.

Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.

Model selection, hummingbird natural history, and biological hypotheses: a response to Sazatornil et al.

We have previously suggested that a shift from bee to hummingbird pollination, in concert with floral architecture modifications, occurred at the crown of Salvia subgenus Calosphace in North America ca. 20 mya (Kriebel et al. 2020 and references therein). Sazatornil et al. (2022), using a hidden states model, challenged these assertions, arguing that bees were the ancestral pollinator of subg. Calosphace and claiming that hummingbirds could not have been the ancestral pollinator of subg. Calosphace because hummingbirds were not contemporaneous with crown subg. Calosphace in North America. Here, using a variety of models, we demonstrate that most analyses support hummingbirds as ancestral pollinators of subg. Calosphace and show that Sazatornil et al. (2022) erroneously concluded that hummingbirds were absent from North America ca. 20 mya. We contend that "biological realism" - based on timing and placement of hummingbirds in Mexico ca. 20 mya and the correlative evolution of hummingbird associated floral traits - must be considered when comparing models based on fit and complexity, including hidden states models.

Influence of KRAS mutation status in metachronous and synchronous metastatic colorectal adenocarcinoma.

BACKGROUND: Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are present in approximately 30% to 40% of colorectal adenocarcinomas. Wild-type (WT) KRAS mutation status is predictive of tumor response with epidermal growth factor receptor-directed therapies, but the results from studies evaluating the prognostic value of KRAS status in localized disease have been contradictory. The prognostic value of KRAS in metastatic disease, specifically according to whether patients have synchronous or metachronous disease at presentation, is less understood. METHODS: One-hundred ten consecutive patients with metastatic colorectal adenocarcinoma underwent testing for KRAS exon 2 mutations by polymerase chain reaction amplification and direct nucleotide sequencing. The clinical characteristics, treatments, and outcomes of these patients were then analyzed retrospectively, stratified according to whether patients presented with synchronous or metachronous metastasis and according to KRAS mutation status (WT or mutated). RESULTS: For the entire cohort, the median overall survival from the date of diagnosis of metastatic disease was 34.3 months (95% confidence interval, 28.3-49.4 months) for patients with WT KRAS (n = 70). The median overall survival for patients with mutated KRAS (n = 40) was 40.3 months (95% confidence interval, 27.9-51.1 months; log-rank P = .91). Kaplan-Meier survival analysis indicated that 3-year overall survival and 5-year overall survival were not statistically different. Within the subgroups of patients with synchronous and metachronous metastatic disease, no significant differences were observed in median overall survival, 3-year overall survival, or 5-year overall survival between the WT KRAS and mutated KRAS groups. CONCLUSIONS: In this study, KRAS mutation status did not influence overall survival in either synchronous or metachronous metastatic colorectal adenocarcinoma and, as such, had no prognostic role in this disease setting.

Antiemetic control with palonosetron in patients with gastrointestinal cancer receiving a fluoropyrimidine-based regimen in addition to either irinotecan or oxaliplatin: a retrospective study.

BACKGROUND: For moderately emetogenic chemotherapy, palonosetron (PALO) is reported to provide complete control of chemotherapy-induced nausea and vomiting (CINV) in 69% of patients. Prior to August 2009, our gastrointestinal (GI) cancer patients receiving the moderately emetogenic compounds oxaliplatin or irinotecan plus a fluoropyrimidine regimen received ondansetron and dexamethasone orally on day 1 of chemotherapy for CINV prevention. Beginning in August of 2009, ondansetron was replaced by PALO 0.25 mg (intravenous push). METHODS: This is a single-institution retrospective study of GI cancer patients who received oxaliplatin or irinotecan plus a fluoropyrimidine. Failure of an antiemetic regimen was defined as grade ≥1 vomiting or grade ≥2 nausea (Common Terminology Criteria for Adverse Events, version 3) on days 1 through 5 following chemotherapy. Patients were divided for analysis into pre-PALO and post-PALO cohorts. Fisher's exact test compared cohort differences. RESULTS: A total of 305 patients were included in the study, with 157 patients in the pre-PALO cohort and 148 in the post-PALO cohort. For all patients, the risk of antiemetic failure was reduced from 50.3% [95% confidence interval (CI) 42.2-58.4%] to 28.4% (95% CI 21.3-36.4%) with PALO. This reduction in the relative risk of antiemetic failure was observed in all subgroups. CONCLUSION: The addition of PALO may provide increased control of CINV for the moderately emetogenic regimens of oxaliplatin or irinotecan plus a fluoropyrimidine in GI cancer patients.