Search

Background: Dietary restraint has been linked to deficits in the ability to recall detailed memories of personally experienced events (referred to as autobiographical memory specificity). As priming with healthy foods increases the salience of restraint it would be expected to lead to greater deficits in memory specificity. Objective: To determine if priming word cues with images of healthy or unhealthy foods would influence the specificity of memory retrieval, and if deficits in memory specificity would be more evident in those reporting higher levels of dietary restraint, or currently dieting. Methods: Sixty female undergraduates self-reported if they were currently dieting and completed measures of mood, restraint, and disinhibition, and a modified version of the autobiographical memory task. Participants were presented with positive and negative words (unrelated to eating concerns) and asked to retrieve a specific memory in response to each cue. A food image was shown prior to each word cue; half of the participants were primed with images of healthy foods and half with images of unhealthy foods. Results: As expected, participants primed with healthy foods retrieved fewer specific memories than did those primed with unhealthy foods. However, neither restraint nor current dieting behaviour were associated with memory specificity. Conclusions: Differences in memory specificity between the priming conditions cannot be explained in terms of increased salience of restraint. However, it is plausible that unhealthy images led to an increase in positive affect, which in turn improved memory specificity. Level of evidence: Level I: Evidence obtained from: at least one properly designed experimental study

How should we set about understanding epistêmê and doxa? Plato in fact offers us explicit instructions, in the famous “powers” argument of Republic V: he seems to say that each is to be defined as the cognition of a special kind of object. But there is a difficulty: over the past half-century, this interpretation—the “Two Worlds” or “Distinct Objects” reading—has been so widely questioned as to now be declared “outrageous.” The aim of this chapter is to shift the burden of proof onto those who reject that reading. I explain the debate, mount textual evidence and, through a survey of Plato scholarship over the past 2400 years, and a brief discussion of Distinct Objects epistemologies in other thinkers, argue that resistance to the Distinct Objects reading is motivated largely by the assumption that Plato must be talking about knowledge and belief as we understand them now.

The Caribbean spiny lobster Panulirus argus supports important fisheries throughout the greater Caribbean and is also the only known host for the pathogenic virus Panulirus argus virus 1 (PaV1). While discovered nearly 2 decades ago, gaps still exist in our knowledge of PaV1, such as the dose required to establish infection and its viability outside of the host. To help answer such questions and to enhance diagnostic capabilities, we developed a TaqMan real-time quantitative polymerase chain reaction (qPCR) assay for PaV1. Of the advantages offered by qPCR, one of the most important benefits is its ability to accurately quantify viral DNA copies in a clinical sample. The qPCR assay was found to be efficient (mean ± SD: 99.19 ± 4.67%) and sensitive, detecting as few as 10 copies of PaV1 plasmid DNA. Its diagnostic sensitivity and specificity determined using a set of 165 lobster samples (138 from Florida, USA, and 27 from across the Caribbean) were 100 and 84%, respectively. The qPCR assay should thus prove useful as a research tool and for detecting and quantifying PaV1 infection severity in Caribbean spiny lobsters.

Eastern oyster, Crassostrea virginica , aquaculture has expanded greatly in recent years, but further growth of the industry is constrained by disease-related losses. Oyster breeding programs supporting the oyster aquaculture industry along the east coast of the US have targeted resistance to three prominent diseases: MSX, Dermo, and ROD, caused by Haplosporidium nelsoni , Perkinsus marinus , and Roseovarius crassostreae respectively. Consequently, selected oyster lines possess some level of resistance and/or tolerance but the extent to which these lines, derived from various programs, perform across diverse growing environments used by industry has not been tested. The performance of six selected eastern oyster lines was evaluated at five sites along the east coast of the US (Maine to Virginia) to 1) identify differences in performance among lines at each site, and 2) identify lines that perform well across all sites. Performance measures included growth, mortality, and yield over a 15-month evaluation period. During unusually high mortality events, subsets of oysters were processed for disease diagnosis. Growth trajectories were similar among lines within a site, but varied significantly across sites (78% of random variance explained). Oysters grown in Rhode Island were largest while oysters grown in Maine were smallest at the end of the study. Mortality varied greatly among lines at each site as well as among sites. Line × site interaction explained 61% of the total random variance in the mortality data. In Maine, extensive mortality was observed early in the year for all lines, coincident with increased ROD prevalence. In New Jersey and Virginia, unusually high mortality was evident in the UMFS, Clinton, and NEH-RI lines during the final months of the experiment when the prevalence of both Dermo and MSX were 100% and Statement of relevance First to evaluate multiple oyster lines across diverse sites.

On the US east coast, Eastern oyster (Crassostrea virginica) aquaculture has grown substantially over the last century. As aquaculture expands into previously unexploited areas, there is a need for oyster lines bred for specific environmental conditions. In the Maryland portion of the Chesapeake Bay, and in other coastal areas, salinity tends to be below optimal for typical aquaculture productivity, and these areas frequently experience periods of acute low salinity following heavy rain events. While these areas may hinder oyster growth, they provide a refuge from common oyster diseases. Selective breeding focusing on survival in acute low salinity conditions could expand areas suitable for aquaculture, but the genetic framework underlying this trait is currently unknown. In this study, we estimated the heritability of survival at acute low salinity (

Mass mortalities of cultured triploid Crassostrea virginica in late spring, or “triploid mortality,” have been reported on farms in the Chesapeake Bay since 2012. Typical causes, such as disease or poor husbandry, were not responsible, and mortalities occurred without clear signs of biological or physical stressors. Previous comparisons of the effects of genetic origin on triploid mortality have been uncontrolled, initiating this investigation of the effect of brood stock source and ploidy on triploid mortality. Four triploid and four diploid crosses, produced by crossing different combinations of brood stock of Virginia, Louisiana, and Maine origin in early 2015, were tested at four commercial oyster farms in Virginia throughout 2016. From February to November, oysters from all crosses and sites were regularly sampled, and growth (shell height), condition (meat weight), and pathology were monitored, as were environmental conditions. Compared to diploids made from Virginia brood stock, diploids with Maine genetic origin had high mortality and Virginia-Maine diploid hybrids exhibited mid-parent heterosis. A triploid mortality event occurred in late spring at only one site and only affected the triploid crosses. Evidence for substantial disease pressure from Haplosporidium nelsoni or Perkinsus marinus or of especially stressful environmental conditions based on temperature, salinity, pH, and dissolved oxygen was absent during the triploid mortality event. At 18 months, shell height was similar in the diploids and triploids with the most similar genetic origin. Triploids maintained meat weight through the summer, while meat weight in diploids dropped sharply. Triploids may be especially susceptible to late spring mortality events in the Chesapeake Bay, which justifies their classification as “triploid mortality,” and warrants further investigation on traits in triploids that may affect susceptibility.

For commercial oyster aquaculture, triploidy has significant advantages. To produce triploids, the principal technology uses diploid × tetraploid crosses. The development of tetraploid brood stock for this purpose has been successful, but as more is understood about tetraploids, it seems clear that chromosome instability is a principal feature in oysters. This paper is a continuation of work to investigate chromosome instability in polyploid Crassostrea virginica. We established families between tetraploids—apparently stable (non-mosaic) and unstable (mosaic)—and normal reference diploids, creating triploid groups, as well as tetraploids between mosaic and non-mosaic tetraploids. Chromosome loss was about the same for triploid juveniles produced from either mosaic or non-mosaic tetraploids or from either male or female tetraploids. However, there was a statistically significant difference in chromosome loss in tetraploid juveniles produced from mosaic versus non-mosaic parents, with mosaics producing more unstable progeny. These results confirm that chromosome instability, as manifested in mosaic tetraploids, is of little concern for producing triploids, but it is clearly problematic for tetraploid breeding. Concordance between the results from cytogenetics and flow cytometry was also tested for the first time in oysters, by assessing the ploidy of individuals using both techniques. Results between the two were non-concordant.

ABSTRACT Background: Targeting growth factor and survival pathways may delay endocrine-resistance in estrogen receptor-positive breast cancer. Materials & methods: A pilot Phase II study adding sorafenib to endocrine therapy in 11 patients with metastatic estrogen receptor-positive breast cancer was conducted. Primary end point was response by RECIST after 3 months of sorafenib. Secondary end points included safety, time to progression and biomarker modulation. The study closed early owing to slow accrual. Results: Eight out of 11 patients had progressive disease on study entry and three had stable disease. Of the ten evaluable patients, seven experienced stable disease (70%) and three experienced progressive diseas (30%), with a median time to progression of 6.1 months (8.4 months in the seven patients on tamoxifen). The serum samples demonstrated a significant reduction in VEGF receptor 2 and PDGF receptor-α. Microarray analysis identified 32 suppressed genes, no induced genes and 29 enriched Kyoto Encyclopedia of Genes and Genomes pathways. Conclusion: The strategy of adding a targeted agent to endocrine therapy upon resistance may be worthwhile testing in larger studies.

Since 2012, aquacultured eastern oysters Crassostrea virginica have been reported by oyster farmers to display mortality approaching 30%, and in some cases 85%, in areas of the lower Chesapeake Bay, VA. Based on accounts from industry, this mortality has typically affected 1-y-old oysters between May and early July, and has tended to occur in triploid oysters, which represent the vast bulk of production in the area. During this period, samples submitted for pathology have not revealed the presence of major pathogens as a cause. In 2015, to gain deeper insight into this mortality and determine whether specific sites, ploidy condition, or genetic lines were affected, oyster seed commercially produced in early 2014 were obtained from four lines, one diploid (2N DEBY) and three triploid (3N DEBY, 3N hANA, and 3N Northern). These lines were deployed in July 2014 at aquaculture farms at five Chesapeake Bay locations: Locklies Creek and Milford Haven on the western shore, and Pungoteague Creek, Nassawadox Creek, and Cherrystone Creek on the Eastern Shore. During this study, mortality was observed to peak in June at most sites, reaching a mean mortality across all tested lines of 17.0% and a cumulative mortality for the study period of 32.0% at Nassawadox Creek, the site most severely affected by mortality that followed the expected early summer mortality pattern. Interval mortality at all sites decreased to under 5% after June, but cumulative levels for the study period reached from 8.8% to 18.6% even at the sites least affected by mortality. This represents a high level of mortality given the documented absence of material involvement by major oyster pathogens such as Hapolosporidium nelsoni and Perkinsus marinus. Infiltration of gill tissues by hemocytes, observed in up to 33% of individuals at Nassawadox Creek coincident with the increase in mortality, was the only pathology observed. Harmful algal blooms were not associated with the mortality, nor were abnormal temperatures or salinities. There was no clear relationship of mortality to oyster genetic heritage, although there was variability in susceptibility among oyster lines and interactions between lines and specific sites. At some locations and in comparison with diploids, triploid oysters appeared to be more susceptible to mortality. Mortality in triploids was coincident with the timing of peak gametogenic development in diploids. Given the lack of involvement by major pathogens and the possible association of mortality with oyster gametogenesis, future work should seek to better understand the suite of environmental stressors potentially impacting cultured oysters in these systems and their interactions with the physiology and energetics of these animals.

The pathogenic virus Panulirus argus virus 1 (PaV1) was first discovered in Caribbean spiny lobsters Panulirus argus from the Florida Keys (USA) in 1999 and has since been reported in Belize, Mexico, and Cuba; its distribution in the wider Caribbean is unknown. We col- lected tissue samples from adult spiny lobsters from 30 locations in 14 countries bordering the Caribbean Sea and used molecular diagnostics to assay for the presence of PaV1. PaV1 occurred primarily in the northern areas of the Caribbean, where its prevalence was highest. The virus was not found in lobsters from the southeastern Caribbean, and its prevalence was lowest in the south- western Caribbean. DNA sequence analysis was performed on a fragment of the viral DNA to examine the genetic diversity of PaV1 on a Caribbean-wide scale. Sequence variation in the viral DNA fragment was high, with 61 unique alleles identified from 9 areas. The sharing of viral alleles in lobsters from distant locations supports the hypothesis of a strong genetic connectivity among lobsters within the Caribbean, and further supports the hypothesis that postlarvae infected with PaV1 may serve to disperse the virus over long distances.

Aristotle repeatedly claims that character-virtue “makes the goal right”, while Phronesis is responsible for working out how to achieve the goal. Many argue that these claims are misleading: it must be intellect that tells us what ends to pursue. I argue that Aristotle means just what he seems to say: despite putative textual evidence to the contrary, virtue is (a) a wholly non-intellectual state, and (b) responsible for literally supplying the contents of our goals. Furthermore, there are no good textual or philosophical reasons to reject this straightforward interpretation. Contrary to widespread opinion, Aristotle does not characterize Phronesis as supplying ends. Instead, its ethical import lies wholly in its ability to “determine the mean”. Moreover, because character involves non-rational cognition of the end as good, Aristotle can restrict practical intellect to deliberation without abandoning his anti-Humean view that we desire our ends because we find them good.

The emergence of epizootic shell disease in the American lobster (Homarus americanus) has been devastating to the fishing industry in southern New England. In response, research was initiated to understand the roles of the environment, pathogens, and pollutants in the ecology and etiology of the disease. A comprehensive project was initiated in which tissues and hemolymph from 100 lobsters were collected from an endemic area of disease, Narragansett Bay, RI. The project has moved forward with the purpose of compiling, synthesizing, and propagating the findings from the ''100 Lobsters'' Project. The resulting tissue bank and Web-based data repository and instructional tools serve as a nascent demonstration project to both the scientific community working on this disease as well as to members of the lobster industry.

The emergence of epizootic shell disease in the American lobster (Homarus americanus) has been devastating to the industry in the coastal waters of southern New England. A comprehensive assessment of the disease syndrome, known as the ''100 Lobsters'' Project, was initiated to examine health and physiological parameters among laboratories involved in the research on lobster shell disease. A histological study of the 100 lobsters was undertaken as part of that assessment. Tissues from 90 lobsters from Rhode Island and 19 lobsters from Maine were examined as a general health assessment of the 100 lobsters. Approximately half the lobsters from Rhode Island were selected because they had frank epizootic shell disease, whereas none of the lobsters from Maine exhibited the syndrome. In addition to epizootic shell disease, the histological findings revealed 3 other idiopathic syndromes—necrotizing hepatopancreatitis, idiopathic blindness, and nonspecific granulomas—in higher prevalences in lobsters from Rhode Island compared with those from Maine. Necrotizing hepatopancreatitis, a newly described disease syndrome in lobsters, was observed in 15% of the lobsters from Rhode Island. Idiopathic blindness was present in 54% of the lobsters from Rhode Island, and 16% of the animals from Maine. This is the first report of the syndrome in lobsters from Maine. None of the idiopathic syndromes was associated with epizootic shell disease. The detection of multiple disease syndromes such as epizootic shell disease, necrotizing hepatopancreatitis, and idiopathic blindness may be indicative of exposure to environmental stressors in Narragansett Bay, RI.

Panulirus argus virus 1 (PaV1) is an unclassified, pathogenic virus first discovered in Caribbean spiny lobsters Panulirus argus from the Florida Keys, USA, and has since been con- firmed in lobsters in other parts of the Caribbean. Several studies have examined the prevalence, pathogenicity, and population dynamics of the pathogen in the lobster host, but little is known about the genetic diversity of the virus. We analyzed a fragment of viral DNA from lobsters col- lected in the Florida Keys, which provided the first insight into the genetic diversity of PaV1. The variation in viral sequences, both within and between individual lobsters, indicates that lobsters can be infected with multiple viral strains. Laboratory experiments in which uninfected lobsters were serially exposed to lobsters inoculated with PaV1 implied that rapid mutation of strains is unlikely and suggest that there may be endemic strains of PaV1. In addition, we discovered PaV1 in P. argus postlarvae (pueruli), suggesting that the virus may disperse through the Caribbean within the long-lived (5 to 7 mo) planktonic phyllosoma larvae — a novel mechanism for dispersal of viruses in the sea.

Following a brief introduction about the need for businesses to respond to climate change, this paper considers the development of the phrase ‘carbon footprint’. Widely used definitions are considered before the authors offer their own interpretation of how the term should be used. The paper focuses on the contribution small and medium sized enterprises (SMEs) make to the economy and their level of influence in stimulating change within organisations. The experience of an outreach team from the Engineering Department of a UK university is used which draws on the experience of delivering regional economic growth projects funded principally through the European Regional Development Fund. Case studies are used including the development of bespoke carbon footprints for SMEs from an initiative delivered by the outreach team. Limitations of current carbon footprints are identified based on this higher education‐industry knowledge exchange mechanism around three main themes of scope, the assessment method and co...

Plato links pleasure with illusion, and this link explains his rejection of the view that all desires are rational desires for the good. The Protagoras and Gorgias show connections between pleasure and illusion; the Republic develops these into a psychological theory. One part of the soul is not only prone to illusions, but also incapable of the kind of reasoning that can dispel them. Pleasure appears good; therefore this part of the soul (the appetitive part) desires pleasures qua good but ignores reasoning about what is really good. Hence the new moral psychology of the Republic, not all desires are rational, and thus virtue depends on bringing one's non-rational desires under the control of reason.

The Suminoe oyster, Crassostrea ariakensis, has been under investigation since the early 1990s for potential use in restoring the commercial harvest or for aquaculture of oysters in the Chesapeake Bay, USA. Initial studies focusing on C. ariakensis documented a significant level of tolerance to the protozoan parasite Perkinsus marinus, a pathogen found in almost all reaches of the Bay and widely acknowledged as one of the main reasons for the decline in the eastern oyster, Crassostrea virginica, harvest since the late 1980s. Crassostrea ariakensis was demonstrated to acquire P. marinus, however infection intensities, as measured using Ray's thioglycollate medium assay indices, generally were found to be light. As part of a series of experiments to study potential impacts on the Chesapeake Bay region of pathogens found in C. ariakensis in Asia, a challenge experiment was conducted to study the pathogenicity of Perkinsus olseni to C. ariakensis. During this study, we observed the acquisition of mod...

Angiosarcomas are exceedingly rare tumors that are often difficult to diagnose. Exceptionally unusual is the presentation of these tumors with Kasabach-Merritt Syndrome, a curious form of intratumoral coagulation that can be impossible to distinguish from intravascular coagulation, which is more common. Instant recognition of this clinical association can help making a prompt diagnosis and timely initiation of therapy.

In 2000, a pathogenic virus was discovered in juvenile Caribbean spiny lobsters Pan- ulirus argus from the Florida Keys, USA. Panulirus argus virus 1 (PaV1) is the first naturally occurring pathogenic virus reported from lobsters, and it profoundly affects their ecology and physiology. PaV1 is widespread in the Caribbean with infections reported in Florida (USA), St. Croix, St. Kitts, Yucatan (Mexico), Belize, and Cuba. It is most prevalent and nearly always lethal in the smallest juvenile lob- sters, but this declines with increasing lobster size; adults harbor the virus, but do not present the characteristic signs of the disease. No other PaV1 hosts are known. The prevalence of PaV1 in juve- nile lobsters from the Florida Keys has been stable since 1999, but has risen to nearly 11% in the east- ern Yucatan since 2001. Heavily infected lobsters become sedentary, cease feeding, and die of meta- bolic exhaustion. Experimental routes of viral transmission include ingestion, contact, and for newly settled juveniles, free virus particles in seawater. Prior to infectiousness, healthy lobsters tend to avoid diseased lobsters and so infected juvenile lobsters mostly dwell alone, which appears to reduce disease transmission. However, avoidance of diseased individuals may result in increased shelter competition between healthy and diseased lobsters, and greater predation on infected lobsters. Little is known about PaV1 outside of Mexico and the USA, but it poses a potential threat to P. argus fish- eries throughout the Caribbean.

de Anima III. 10 characterizes akrasia as a conflict between phantasia ("imagination") on one side and rational cognition on the other: the akratic agent is torn between an appetite for what appears good to her phantasia and a rational desire for what her intellect believes good. This entails that akrasia is parallel to certain cases of perceptual illusion. Drawing on Aristotle's discussion of such cases in the de Anima and de Insomniis, I use this parallel to illuminate the difficult discussion of akrasia in Nicomachean Ethics VII.3, arguing that its account of akrasia as involving ignorance is compatible with, and in fact crucially supplements, the more straightforward account we find elsewhere in the corpus of akrasia as a struggle between desires.

With the drastic decline of eastern oyster Crassostrea virginica populations in the Chesapeake Bay due to over-fishing, diseases and habitat destruction, there is interest in Maryland and Virginia in utilizing the non-native oyster species Crassostrea ariakensis for aquaculture, fishery resource enhancement, and ecological restoration. The International Council for the Exploration of the Sea (ICES) recommends that non-native species be examined for ecological, genetic and disease relationships in the native range prior to a deliberate introduction to a new region. Therefore, a pathogen survey of C. ariakensis and other sympatric oyster species was conducted on samples collected in the PR China, Japan and Korea using molecular diagnostics and histopathology. Molecular assays focused on 2 types of pathogens: protistan parasites in the genus Perkinsus and herpesviruses, both with known impacts on commercially important molluscan species around the world, including Asia. PCR amplification and DNA sequence data from the internal transcribed spacer region of the rRNA gene complex revealed the presence of 2 Perkinsus species not currently found in USA waters: P. olseni and an undescribed species. In addition, 3 genetic strains of molluscan herpesviruses were detected in oysters from several potential C. ariakensis broodstock acquisition sites in Asia. Viral gametocytic hypertrophy, Chlamydia-like organisms, a Steinhausia-like microsporidian, Perkinsus sp., Nematopsis sp., ciliates, and cestodes were also detected by histopathology.

Parasitic dinoflagellates in the genus Hematodinium infect a number of decapod crustaceans in waters off the UK, including the Norway lobster Nephrops norvegicus and the edible crab Cancer pagurus. This study investigated sequence variability in the first internal transcribed spacer (ITS1) region of the ribosomal RNA complex of Hematodinium spp. infecting N. norvegicus, C. pagurus, and Pagurus bernhardus from 4 locations in the UK and from the Hematodinium sp. infecting Chionoecetes opilio from the province of Newfoundland and Labrador, Canada. Phylogenetic analysis of the Hematodinium ITS1 sequences from N. norvegicus, C. pagurus, P. bernhardus and C. opilio suggest that these crustaceans are infected with the same species of Hematodinium. Length variability of the ITS1 region was observed (324 to 345 bp) and attributed to 4 variable microsatellite regions (CATG)n' (GCC)nTCCGC(TG)n' (TA)n' and (GAA)n(GGA)n within the sequenced ITS1 fragment. The observed variation may be due to co-infection of the host crustacean with several different strains of Hematodinium or differences among copies of ITS1 region within the genome of a single parasite cell. The Hematodinium ITS1 sequence from N. norvegicus, C. pagurus, P. bernhardus and C. opilio isolates was sufficiently conserved in primer binding regions targeted by previous molecular diagnostic assays; therefore, we suggest that this assay could be used to screen for Hematodinium infections in these crustacean hosts.

Sociality has evolved in a wide range of animal taxa but infectious diseases spread rapidly in populations of aggregated individuals, potentially negating the advantages of their social interactions. To disengage from the coevolutionary struggle with pathogens, some hosts have evolved various forms of "behavioral immunity"; yet, the effectiveness of such behaviors in controlling epizootics in the wild is untested. Here we show how one form of behavioral immunity (i.e., the aversion of diseased conspecifics) practiced by Caribbean spiny lobsters (Panulirus argus) when subject to the socially transmitted PaV1 virus, appears to have prevented an epizootic over a large seascape. We capitalized on a "natural experiment" in which a die-off of sponges in the Florida Keys (USA) resulted in a loss of shelters for juvenile lobsters over a ~2500km2 region. Lobsters were thus concentrated in the few remaining shelters, presumably increasing their exposure to the contagious virus. Despite this spatial reorganization of the population, viral prevalence in lobsters remained unchanged after the sponge die-off and for years thereafter. A field experiment in which we introduced either a healthy or PaV1-infected lobster into lobster aggregations in natural dens confirmed that spiny lobsters practice behavioral immunity. Healthy lobsters vacated dens occupied by PaV1-infected lobsters despite the scarcity of alternative shelters and the higher risk of predation they faced when searching for a new den. Simulations from a spatially-explicit, individual-based model confirmed our empirical results, demonstrating the efficacy of behavioral immunity in preventing epizootics in this system.

Background Resistance to antiestrogens is a major problem in metastatic breast cancer. Preclinical data suggest that growth factor signaling and angiogenesis may promote endocrine resistance and blocking such pathways may delay resistance. Methods: We conducted a phase II clinical trial of adding sorafenib, a VEGFR and Ras/Raf/MAPK inhibitor, to antiestrogen therapy in patients with metastatic ER-positive breast cancer. Patients were required to have progressive disease on an anstiestrogen or have maximum response with residual measurable disease. A core biopsy of accessible breast disease was offered at entry and after 28 days of sorafenib. Microarray experiments were performed on frozen tissue obtained from 4 paired biopsies using Affymetrix Gene Chip HG-U133 Plus 2. Data was normalized based on the GCRMA method and Expression values of each gene were analyzed based on the significant analysis of microarray (SAM) method for paired data. Gene set analysis on KEGG pathways was performed using the gene set enrichment analysis (GSEA) method, where genes were ranked based on the absolute values of their SAM test statistics. Serum was collected on day 1 and day 28 for biomarker comparison using ELISA. Primary study endpoint was response rate by RECIST criteria after 3 months of sorafenib and secondary endpoints were safety, time to progression (TTP), and biomarker assessment. Results: Planned sample size was 43 but the study closed after 11 patients because of slow accrual. Median age was 45 years (Range 39–72). 7 patients were on tamoxifen, 3 on an aromatase inhibitor, and 1 on fulvestrant. Of the 11 patients enrolled, 8 had progressive disease (PD) on entry and 3 had confirmed stable disease (SD) on antiestrogen alone. One patient with SD at entry discontinued sorafenib after 2 weeks because of a grade 3 rash. Of the 10 patients evaluable for response, 7 had SD (70%) and 3 had PD. Median TTP after adding sorafenib was 182 days (6 months) and in the 8 patients who entered the study with PD, 5 converted to SD (62%) with a median TTP of 192 days (6.4 months). One patient remains on treatment after 16 months of enrollment. Most common adverse events were rash in 9 patients, weight loss in 8 and hypertension in 6. Hypophosphatemia was seen in 11 patients, hypokalemia in 9, and elevated ALT/AST in 4. The majority of toxicities were grade 1. There were 6 grade 3 toxicities; rash, anorexia, hypokalemia, colitis, and 2 hypophosphatemia. No grade 4 toxicities occurred. Microarray analysis identified 29 enriched pathways with a false discovery rate of less than 25%. There was a significant reduction in mean serum Transforming growth factor beta (TGF-β) and platelet derived growth factor receptor alpha ( PDGFR-α) on day 28 (P values= < 0.0001 and 0. 0.017, respectively). Tissue and serum biomarker correlates will be presented in detail at the meeting. Conclusions: Sorafenib can overcome resistance to antiestrogens, particularly tamoxifen, and may help avoid the routine early use of chemotherapy for endocrine resistant disease. Further study of strategies to overcome endocrine resistance is warranted to help preserve patient quality of life and to investigate mechanisms of resistance. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-05.

Abstract 1624 Tumor suppressor gene silencing via mechanisms including DNA hypermethylation is a recognized event in lymphomagenesis and lymphoma recurrence and transformation. DNA methyltransferase inhibitor, azacitidine, reduces epigenetic methylation in lymphoma and numerous other tumor models. Given the poor outcome of patients with transformed or refractory lymphoma, there is an immediate need to find novel therapies. We report the first results of an ongoing Phase I trial evaluating the maximal tolerated dose (MTD) of azacitidine given in a schedule intended to sensitize lymphoma to a regimen of oral cyclophosphamide, intravenous vincristine, and rituximab (for those patients whose lymphoma expresses CD20) for patients with recurrent or refractory lymphoma. Participants receive azacitidine (days 1–5, starting with 25 mg/m2) followed by oral cyclophosphamide (days 6–9, 300 mg/m2), vincristine (day 8, 1.4 mg/m2, maximum of 2 mg), and rituximab (day 8, 375 mg/m2). All patients receive pegfilgrastim (day 10, 6 mg) with each cycle. Cycles are repeated every 21 days for up to eight cycles if participants continue to benefit from therapy. To determine the MTD, a “3+3” design was employed. Dose limiting toxicity (DLT) is assessed during cycle 1. DLT is defined as the following: grade 3 or 4 non-hematologic toxicity (excluding emesis or isolated elevation of alkaline phosphatase); grade 4 neutropenia or thrombocytopenia of ≥7 days duration; increased serum creatinine > 2.0 times upper limit of normal; inability to receive all doses of azacitidine or cyclophosphamide within the first cycle or inability to initiate cycle 2 within two weeks of completing cycle 1 due to drug-related toxicity. Of the first 10 patients enrolled (8 patients in 25 mg/m2 azacitidine cohort, and 2 patients in 50 mg/m2 cohort), median age was 56 years (range 39–73). Median number of prior lines of therapy was 3 (range 2–4). Lymphoma subtypes included diffuse large B cell lymphoma (DLBCL; n=4), follicular lymphoma (FL; n=3), Hodgkins lymphoma (HL; n=1), small lymphocytic lymphoma (SLL; n=1), and cutaneous T-cell lymphoma (CTCL; n=1). A median of 2 cycles (range 1–6) have been received. The MTD has not yet been reached. One patient experienced thrombocytopenia as a DLT. The DLT criteria were subsequently revised to allow grade 4 thrombocytopenia of < 7 days after initially noting that some patients experienced asymptomatic grade 4 thrombocytopenia lasting only a short duration. An additional three patients were accrued to the first dose level after this adjustment to the current DLT, with no additional patients experiencing a DLT. Grade 3–4 toxicities during any cycle of therapy were as follows: neutropenia (n=5); thrombocytopenia (n=4); anemia (n=2); and abscess, anorexia, bacteremia, hypoalbuminemia, and nausea (n=1 each). Additionally, grade 3 cardiac ischemia and deep venous thrombosis each occurred in one patient but were considered unrelated to treatment by the investigator. Of the 8 patients who have completed treatment, 1 patient with FL achieved a complete response (CR), 1 patient with FL achieved a partial response (PR), 2 had stable disease (SD), 2 experienced progressive disease (PD), and 2 were not evaluable (NE) for response. Interestingly, the CR was maintained for 7 months and the PR has been ongoing for 6 months since completion of therapy. These preliminary data suggest the therapeutic potential of this novel combination and enrollment remains ongoing to define the MTD. Additional correlative assessments of tumor and peripheral blood mononuclear cells are also underway. Disclosures: Off Label Use: Azacitidine is the test article in this study and is not FDA approved for the treatment of lymphoma. Hayslip:Celgene: Research Funding.

Background: Endocrine therapy for metastatic estrogen receptor (ER) positive breast cancer is effective and relatively nontoxic, but resistance eventually develops in all patients. Preclinical data suggest that growth factor signaling and angiogenesis may promote endocrine resistance and blocking such pathways may restore endocrine sensitivity and delay resistance. Methods: We conducted a phase II trial of administering sorafenib, which inhibits VEGFR and Ras/Raf/MAPK, to patients with metastatic ER-positive breast cancer after at least 3 months of antiestrogen use. Patients were required to have either stable disease or progressive non-visceral metastasis. Measurable disease was required. Sorafenib 400 mg BID was administered along with the same antiestrogen patients were already taking. A core biopsy of accessible disease was offered at entry and after 28 days of sorafenib. Serum was collected on day 1 and day 28 for VEGF, VEGFR, and VEGFR2 analysis. Primary endpoint was response rate by RECIST criteria after 3 months of sorafenib. Secondary endpoints were safety, time to progression (TTP), and biomarker assessment. Planned sample size was 43 but the study closed after 11 patients because of slow accrual. Results: Median age at entry was 45 years (Range 39-72). 7 patients were on tamoxifen, 3 on an aromatase inhibitor, and 1 on fulvestrant. Of the 11 patients enrolled, 8 had progressive disease (PD) on entry and 3 had confirmed stable disease (SD). One patient with SD at entry discontinued sorafenib after 2 weeks because of a grade 3 rash. Of the 10 patients evaluable for response, 7 had SD (70%) and 3 had PD. Two of the SD patients had minor responses, but no partial responses were seen. Median TTP after adding sorafenib was 182 days (6 months). Of the 8 patients who entered the study with progressive disease, 5 converted to stable disease (62%) with a median TTP of 136 days (4.5 months). There was a significant reduction in mean serum VEGFR2 on day 28 (P 0.0035) with borderline significant reduction of VEGFR (P 0.08). In the 7 patients with SD as best response, mean VEGFR and VEGFR2 levels were significantly reduced (P 0.016 and 0.038, respectively). There was no significant change in serum VEGF in any of the groups tested. Most common adverse events were rash in 9 patients, weight loss in 8, and hypertension in 6. Most common laboratory abnormalities were hypophosphatemia in 11 patients, hypokalemia in 9, and elevated ALT/AST in 4. The majority of toxicities were grade 1. There were 5 grade 3 toxicities; rash, anorexia, hypokalemia, and 2 hypophosphatemia. No grade 4 toxicities occurred. Overall, treatment was well tolerated and all toxicities were reversible upon sorafenib discontinuation. Tissue biomarkers including 4 paired biopsies will be examined. Conclusions: Sorafenib may prolong antiestrogen benefit in patients with metastatic ERpositive breast cancer and in particular can restore endocrine sensitivity in patients with disease progression on such therapy. Clinical trials that target endocrine resistance remain critical for understanding mechanisms of resistance and can help preserve patient quality of life by avoiding the early use of more toxic treatments. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-19.