The Effect of Focusing and Caustics on Exit Phenomena in Systems Lacking Detailed Balance

We study the trajectories followed by a particle subjected to weak noise when escaping from the domain of attraction of a stable fixed point. If detailed balance is absent, a _focus_ may occur along the most probable exit path, leading to a breakdown of symmetry (if present). The exit trajectory bifurcates, and the exit location distribution may become `skewed' (non-Gaussian). The weak-noise asymptotics of the mean escape time are strongly affected. Our methods extend to the study of skewed exit location distributions in stochastic models without symmetry.Comment: REVTEX macros (latest version). Two accompanying PS figures, one of which is large (over 600K unpacked

Remarkable fly (Diptera) diversity in a patch of Costa Rican cloud forest : Why inventory is a vital science

Study of all flies (Diptera) collected for one year from a four-hectare (150 x 266 meter) patch of cloud forest at 1,600 meters above sea level at Zurqui de Moravia, San Jose Province, Costa Rica (hereafter referred to as Zurqui), revealed an astounding 4,332 species. This amounts to more than half the number of named species of flies for all of Central America. Specimens were collected with two Malaise traps running continuously and with a wide array of supplementary collecting methods for three days of each month. All morphospecies from all 73 families recorded were fully curated by technicians before submission to an international team of 59 taxonomic experts for identification. Overall, a Malaise trap on the forest edge captured 1,988 species or 51% of all collected dipteran taxa (other than of Phoridae, subsampled only from this and one other Malaise trap). A Malaise trap in the forest sampled 906 species. Of other sampling methods, the combination of four other Malaise traps and an intercept trap, aerial/hand collecting, 10 emergence traps, and four CDC light traps added the greatest number of species to our inventory. This complement of sampling methods was an effective combination for retrieving substantial numbers of species of Diptera. Comparison of select sampling methods (considering 3,487 species of non-phorid Diptera) provided further details regarding how many species were sampled by various methods. Comparison of species numbers from each of two permanent Malaise traps from Zurqui with those of single Malaise traps at each of Tapanti and Las Alturas, 40 and 180 km distant from Zurqui respectively, suggested significant species turnover. Comparison of the greater number of species collected in all traps from Zurqui did not markedly change the degree of similarity between the three sites, although the actual number of species shared did increase. Comparisons of the total number of named and unnamed species of Diptera from four hectares at Zurqui is equivalent to 51% of all flies named from Central America, greater than all the named fly fauna of Colombia, equivalent to 14% of named Neotropical species and equal to about 2.7% of all named Diptera worldwide. Clearly the number of species of Diptera in tropical regions has been severely underestimated and the actual number may surpass the number of species of Coleoptera. Various published extrapolations from limited data to estimate total numbers of species of larger taxonomic categories (e.g., Hexapoda, Arthropoda, Eukaryota, etc.) are highly questionable, and certainly will remain uncertain until we have more exhaustive surveys of all and diverse taxa (like Diptera) from multiple tropical sites. Morphological characterization of species in inventories provides identifications placed in the context of taxonomy, phylogeny, form, and ecology. DNA barcoding species is a valuable tool to estimate species numbers but used alone fails to provide a broader context for the species identified.Peer reviewe

Statistical techniques to construct assays for identifying likely responders to a treatment under evaluation from cell line genomic data

<p>Abstract</p> <p>Background</p> <p>Developing the right drugs for the right patients has become a mantra of drug development. In practice, it is very difficult to identify subsets of patients who will respond to a drug under evaluation. Most of the time, no single diagnostic will be available, and more complex decision rules will be required to define a sensitive population, using, for instance, mRNA expression, protein expression or DNA copy number. Moreover, diagnostic development will often begin with in-vitro cell-line data and a high-dimensional exploratory platform, only later to be transferred to a diagnostic assay for use with patient samples. In this manuscript, we present a novel approach to developing robust genomic predictors that are not only capable of generalizing from in-vitro to patient, but are also amenable to clinically validated assays such as qRT-PCR.</p> <p>Methods</p> <p>Using our approach, we constructed a predictor of sensitivity to dacetuzumab, an investigational drug for CD40-expressing malignancies such as lymphoma using genomic measurements of cell lines treated with dacetuzumab. Additionally, we evaluated several state-of-the-art prediction methods by independently pairing the feature selection and classification components of the predictor. In this way, we constructed several predictors that we validated on an independent DLBCL patient dataset. Similar analyses were performed on genomic measurements of breast cancer cell lines and patients to construct a predictor of estrogen receptor (ER) status.</p> <p>Results</p> <p>The best dacetuzumab sensitivity predictors involved ten or fewer genes and accurately classified lymphoma patients by their survival and known prognostic subtypes. The best ER status classifiers involved one or two genes and led to accurate ER status predictions more than 85% of the time. The novel method we proposed performed as well or better than other methods evaluated.</p> <p>Conclusions</p> <p>We demonstrated the feasibility of combining feature selection techniques with classification methods to develop assays using cell line genomic measurements that performed well in patient data. In both case studies, we constructed parsimonious models that generalized well from cell lines to patients.</p

Microenvironmental Influence on Pre-Clinical Activity of Polo-Like Kinase Inhibition in Multiple Myeloma: Implications for Clinical Translation

Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers

Comprehensive inventory of true flies (Diptera) at a tropical site

Peer reviewe

Comprehensive inventory of true flies (Diptera) at a tropical site

Estimations of tropical insect diversity generally suffer from lack of known groups or faunas against which extrapolations can be made, and have seriously underestimated the diversity of some taxa. Here we report the intensive inventory of a four-hectare tropical cloud forest in Costa Rica for one year, which yielded 4332 species of Diptera, providing the first verifiable basis for diversity of a major group of insects at a single site in the tropics. In total 73 families were present, all of which were studied to the species level, providing potentially complete coverage of all families of the order likely to be present at the site. Even so, extrapolations based on our data indicate that with further sampling, the actual total for the site could be closer to 8000 species. Efforts to completely sample a site, although resource-intensive and time-consuming, are needed to better ground estimations of world biodiversity based on limited sampling

Estimating duration in partnership studies: issues, methods and examples

BACKGROUND AND OBJECTIVES: Understanding the time course of sexual partnerships is important for understanding sexual behaviour, transmission risks for sexually transmitted infections (STI) and development of mathematical models of disease transmission. STUDY DESIGN: The authors describe issues and biases relating to censoring, truncation and sampling that arise when estimating partnership duration. Recommendations for study design and analysis methods are presented and illustrated using data from a sexual-behaviour survey that enrolled individuals from an adolescent-health clinic and two STD clinics. Survey participants were queried, for each of (up to) four partnerships in the last 3 months, about the month and year of first sex, the number of days since last sex and whether partnerships were limited to single encounters. Participants were followed every 4 months for up to 1 year. RESULTS: After adjustment for censoring and truncation, the estimated median duration of sexual partnerships declined from 9 months (unadjusted) to 1.6 months (adjusted). Similarly, adjustment for censoring and truncation reduced the bias in relative risks for the effect of age in a Cox model. Other approaches, such as weighted estimation, also reduced bias in the estimated duration distribution. CONCLUSION: Methods are available for estimating partnership duration from censored and truncated samples. Ignoring censoring, truncation and other sampling issues results in biased estimates

SAT0187 DISCRIMINATION OF SYSTEMIC LUPUS (SLE) PATIENTS WITH CLINICAL RESPONSE TO OBEXELIMAB (XMAB®5871) BASED ON A PATTERN OF IMMUNOLOGIC MARKERS

Background:We recently reported Phase 2 SLE trial results of obexelimab, an FcγRIIb agonist (suppressor of B cell activation). Obexelimab did not meet the primary endpoint (% of patients without flare at Day 225) (p=0.183) but other endpoints such as time to flare (p=0.025) were met.Objectives:1. To assign SLE patients to phenotypic subsets based on patterns of gene expression in immune-related pathways.12. To explore the association of immune patterns and clinical response to obexelimab.Methods:This analysis included 71 of the 104 participants in the obexelimab study, those who either completed the protocol or terminated for disease flare, if there were adequate blood samples (biomarker subset). At screening, patients were assigned to clusters based on 41 SLE co-expression signature modules from the Human Immune Phenotyping Consortium via unsupervised random forest and K-means clustering.2Other markers of SLE disease were also examined. TheBOLD3study design mandated withdrawal of background immunosuppressants, supporting less ambiguous pharmacodynamic analysis as the trial progressed.Results:Immune pathway expression patterns of 7 patient clusters (Fig 1a) confirmed our prior characterization of 200 non-overlapping SLE patients.2The biomarker subset retained a trend of longer time to first flare in patients receiving obexelimab (n=38) vs placebo (n=33) (Fig1b, HR 0.61, p=0.11). A smaller set of only Clusters 3 and 6 demonstrated marked increased time to flare in the obexelimab group (n=13) compared to placebo (n=14) (Fig 1c, HR 0.22, p=0.025). Obexelimab had no effect on other clusters (Fig 1d). The responder clusters shared low expression of inflammation modules (p &lt; 0.001) compared to other clusters and high expression of T Cell, immune response, cell cycle, mitochondrial modules (all p &lt; 0.001) and B Cell modules (p=0.006). We therefore sorted patients by these specific features regardless of cluster assignment. Figure 2 shows significant impact of obexelimab on time to flare in 64 patients with B Cell pathway activation (HR 0.5, p=0.038), although less robust by itself than found in Clusters 3 and 6. In a group with high B or plasma cell modules but low inflammation (n=46), treatment effect increased (HR 0.35, p=0.019). Between Screening and Baseline, as brief steroids were given and background treatments withdrawn, expression of B Cell and Plasma Cell pathways increased. Both then decreased after treatment with obexelimab but not placebo (p&lt; 0.0001 and p&lt; 0.001 respectively), an effect not seen with other immune pathway modules.Conclusion:Precision medicine for SLE has been hampered by heterogenous immune signals with variable expression. Clustering of patients by gene co-expression pathways enabled an efficient, hierarchical array that reduplicated results of a prior SLE cohort, suggesting these are not random phenotypes. Of these 7 reproducible SLE subsets, the combination of clusters 3 and 6 distinguished an obexelimab responder population of 27 out of 71 subjects (38%) with high expression of B and T Cell modules and cell activation pathways. Focus on the defining features shared by these clusters revealed specific factors associated with response, enabling inclusion of some patients from other clusters in an optimized responder population of 46/71 (65% of subjects). B Cell and Plasma Cell pathways demonstrated mechanism-related pharmacodynamic effects of obexelimab. Lack of responders with high expression of inflammation modules could implicate inhibitory factors to obexelimab within inflammatory pathways, potentially targetable by complementary treatments.References:[1]Banchereau Cell 165:1548 2016[2]Lu ACR Abstract #2977 2017[3]Merrill Arthritis Rheumatol 69: 1257 2017Disclosure of Interests: :Joan T Merrill Grant/research support from: Xencor, Bristol Myers Squibb, Glaxo Smith Kline, Consultant of: Xencor, Abbvie, UCB, Glaxo Smith Kline, EMD Serono, Astellas, Remegen, Celgene/Bristol Myers Squibb, Exagen, Astra Zeneca, Amgen, Jannsen, Servier, ILTOO, Daitchi Sankyo, Lilly, Paid instructor for: Abbvie, Bristol Myers Squibb, Joel Guthridge Grant/research support from: Xencor, Bristol Myers Squibb, DXterity, Debra Zack Shareholder of: Xencor, Employee of: Xencor, Paul Foster Shareholder of: Xencor Inc, Employee of: Xencor Inc, Bart Burington Shareholder of: Xencor Inc, Employee of: Xencor Inc, Ly Tran: None declared, Miles Smith: None declared, Judith A. James Grant/research support from: Progentec Diagnostics, Inc, Consultant of: Abbvie, Novartis, Jannsen</jats:sec

Evaluation of a gene signature to predict single agent dacetuzumab (SGN-40) activity in patients with DLBCL

11063 Background: Dacetuzumab (SGN-40) is a humanized IgG1 monoclonal antibody that binds to CD40, mediates effector cell functions, and activates downstream apoptosis signaling pathways. Dacetuzumab has shown single-agent activity in relapsed/refractory DLBCL in phase I and phase II trials, with multiple objective responses and 1/3 of patients demonstrating tumor shrinkage, defined as a decrease in tumor volume (SPD) of at least 10%. We previously reported a 14-gene signature (ASH 2008 #1593) that was strongly associated with dacetuzumab sensitivity in DLBCL cell lines. Here, we report an initial evaluation of the gene signature as a classifier of patients likely to demonstrate tumor shrinkage after dacetuzumab therapy. Methods: The original 14 microarray probes were chosen for high correlation with in vitro dacetuzumab sensitivity (IC25) in 31 NHL cell line models. Matching qRT-PCR probes were developed and confirmed to correlate with the microarray probes in paired cell line samples. In this retrospective analysis, archived paraffin blocks from a 26 patient subset of the phase I and II trials, with a diagnosis of DLBCL and available tumor measurements, were assayed by qRT-PCR. Results: Overall, 42% of patients (11/26) exhibited decreased SPD of at least 10%. Of those who were marker +, 10 out of 13 (78%) had 10% or better decreases in SPD, whereas only 1 of 13 patients who were marker - demonstrated tumor shrinkage (8%). The overall accuracy for predicting tumor shrinkage was 85% (one-sided P=0.002, by permutation test). Among the 14 genes contributing to the multivariate signature, CD22 and VNN2 were the most strongly down-regulated in specimens from patients without at least a 10% decrease in SPD (P=0.14 and P=0.10, respectively), while IGF1R and CTSC were the most strongly up-regulated (P=0.05 and P=0.08, respectively). Conclusions: A 14-gene signature appears to predict tumor shrinkage in DLBCL patients receiving dacetuzumab in single-agent clinical trials (P=0.002). A larger clinical data set will be analyzed to further evaluate the correlation of this gene signature with objective clinical response rates.. [Table: see text] </jats:p