A phase II trial of intraperitoneal interleukin-2 in patients with platinum-resistant or platinum-refractory ovarian cancer

Ovarian cancer patients with persistent (platinum-resistant) or progressive (platinum-refractory) disease respond poorly to second line chemotherapy and have low survival expectancy. New and improved therapeutic approaches are needed and immune biologics are one possibility. Interleukin-2 (IL-2) is a T-cell growth factor believed to be important in anti-tumor immunity. We performed a phase II clinical trial with intraperitoneal (IP) recombinant IL-2 administered in weekly infusions of 6 × 10⁵ IU/m². Thirty-one subjects were sequentially entered into the study and clinical responses were surgically confirmed in 24 patients. The primary end point of this study was clinical response with immunologic measurements as secondary end points. The IP regimen was generally well tolerated. Of the 24 patients assessed for response, there were 6 (4 complete, 2 partial) responses for an overall response rate of 25.0% [95% confidence interval (CI) of 11–45]. The median survival of the 31 patient cohort was 2.1 years (95% CI of 1.3–4.4), but for the 6 patients with responses the median survival has not been reached (range 24–120+ months). Eosinophil and lymphocyte numbers were continuously monitored during treatment. Peripheral blood eosinophils were markedly increased at the completion of treatment (p < 0.0001) and associated with increased circulating eotaxin (p = 0.03). We also found significant associations between changes in CD3 counts and survival (p = 0.05) and between IFNγ-secreting CD8 T cells at early time points and survival (p = 0.04). This study provides important evidence for IP IL-2 in platinum-resistant ovarian cancer and identifies several immune correlates of survival.     

Preparative separation and bioactivity of oligomeric proanthocyanidins

Phytochemistry Reviews - Oligomeric proanthocyanidins are among the most widely distributed polyphenols in the plant kingdom, being endowed with antioxidant, anti-inflammatory, antimicrobial,...     

Biogeography and systematics of Aricia butterflies (Lepidoptera,Lycaenidae)

Butterflies of the Aricia species group represent a paradigm of unresolved taxonomy, both at the genus and species levels. We studied phylogenetic relationships, biogeography, and systematics based on genetic – nuclear and mitochondrial – and morphometric – external (wings) and internal (genitalia) – data. We show that Aricia is a monophyletic genus comprising the taxa Pseudoaricia, Ultraaricia and Umpria, which are here considered junior synonyms of Aricia. The taxa allous, inhonora, issekutzi, mandzhuriana, myrmecias and transalaica, which have often been raised to species rank, are shown to probably represent subspecies or synonyms. We show that montensis is likely a good species that is sister to all A. artaxerxes populations across the Palearctic region. The species A. anteros and A. morronensis are shown to display deep intraspecific divergences and they may harbor cryptic species. We also discovered that A. cramera and A. agestis exhibit a pattern of mutual exclusion on islands, and a parapatric distribution in mainland with a narrow contact zone where potential hybrids were detected. The lack of a prezygotic barrier that prevents their coexistence could explain this phenomenon. This study will hopefully contribute to the stability of the systematics of Aricia, a group with potential for the study of the link between speciation and biogeography.     

Finding disease variants in Mendelian disorders by using sequence data: methods and applications

Many sequencing studies are now underway to identify the genetic causes for both Mendelian and complex traits. Via exome-sequencing, genes harboring variants implicated in several Mendelian traits have already been identified. The underlying methodology in these studies is a multistep algorithm based on filtering variants identified in a small number of affected individuals and depends on whether they are novel (not yet seen in public resources such as dbSNP), shared among affected individuals, and other external functional information on the variants. Although intuitive, these filter-based methods are nonoptimal and do not provide any measure of statistical uncertainty. We describe here a formal statistical approach that has several distinct advantages: (1) it provides fast computation of approximate p values for individual genes, (2) it adjusts for the background variation in each gene, (3) it allows for incorporation of functional or linkage-based information, and (4) it accommodates designs based on both affected relative pairs and unrelated affected individuals. We show via simulations that the proposed approach can be used in conjunction with the existing filter-based methods to achieve a substantially better ranking of a gene relevant for disease when compared to currently used filter-based approaches, this is especially so in the presence of disease locus heterogeneity. We revisit recent studies on three Mendelian diseases and show that the proposed approach results in the implicated gene being ranked first in all studies, and approximate p values of 10⁻⁶ for the Miller Syndrome gene, 1.0 × 10⁻⁴ for the Freeman-Sheldon Syndrome gene, and 3.5 × 10⁻⁵ for the Kabuki Syndrome gene.     

Histone tails cooperate to control the breathing of genomic nucleosomes

Genomic DNA is packaged in chromatin, a dynamic fiber variable in size and compaction. In chromatin, repeating nucleosome units wrap 145–147 DNA basepairs around histone proteins. Genetic and epigenetic regulation of genes relies on structural transitions in chromatin which are driven by intra- and inter-nucleosome dynamics and modulated by chemical modifications of the unstructured terminal tails of histones. Here we demonstrate how the interplay between histone H3 and H2A tails control ample nucleosome breathing motions. We monitored large openings of two genomic nucleosomes, and only moderate breathing of an engineered nucleosome in atomistic molecular simulations amounting to 24 μs. Transitions between open and closed nucleosome conformations were mediated by the displacement and changes in compaction of the two histone tails. These motions involved changes in the DNA interaction profiles of clusters of epigenetic regulatory aminoacids in the tails. Removing the histone tails resulted in a large increase of the amplitude of nucleosome breathing but did not change the sequence dependent pattern of the motions. Histone tail modulated nucleosome breathing is a key mechanism of chromatin dynamics with important implications for epigenetic regulation.     

Rgtsp: a generalized top scoring pairs package for class prediction

SUMMARY: A top scoring pair (TSP) classifier consists of a pair of variables whose relative ordering can be used for accurately predicting the class label of a sample. This classification rule has the advantage of being easily interpretable and more robust against technical variations in data, as those due to different microarray platforms. Here we describe a parallel implementation of this classifier which significantly reduces the training time, and a number of extensions, including a multi-class approach, which has the potential of improving the classification performance. AVAILABILITY AND IMPLEMENTATION: Full C++ source code and R package Rgtsp are freely available from http://lausanne.isb-sib.ch/~vpopovic/research/. The implementation relies on existing OpenMP libraries.     

High Resolution 3D Imaging of Ex-Vivo Biological Samples by Micro CT

Non-destructive volume visualization can be achieved only by tomographic techniques, of which the most efficient is the x-ray micro computerized tomography (μCT).High resolution μCT is a very versatile yet accurate (1-2 microns of resolution) technique for 3D examination of ex-vivo biological samples^{1, 2}. As opposed to electron tomography, the μCT allows the examination of up to 4 cm thick samples. This technique requires only few hours of measurement as compared to weeks in histology. In addition, μCT does not rely on 2D stereologic models, thus it may complement and in some cases can even replace histological methods^{3, 4}, which are both time consuming and destructive. Sample conditioning and positioning in μCT is straightforward and does not require high vacuum or low temperatures, which may adversely affect the structure. The sample is positioned and rotated 180° or 360°between a microfocused x-ray source and a detector, which includes a scintillator and an accurate CCD camera, For each angle a 2D image is taken, and then the entire volume is reconstructed using one of the different available algorithms^5-7. The 3D resolution increases with the decrease of the rotation step. The present video protocol shows the main steps in preparation, immobilization and positioning of the sample followed by imaging at high resolution.