A bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer

© 2014 Chan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear

Peptide microarrays for the profiling of cytotoxic T-lymphocyte activity using minimum numbers of cells

The identification of epitopes that elicit cytotoxic T-lymphocyte activity is a prerequisite for the development of cancer-specific immunotherapies. However, especially the parallel characterization of several epitopes is limited by the availability of T cells. Microarrays have enabled an unprecedented miniaturization and parallelization in biological assays. Here, we developed peptide microarrays for the detection of CTL activity. MHC class I-binding peptide epitopes were pipetted onto polymer-coated glass slides. Target cells, loaded with the cell-impermeant dye calcein, were incubated on these arrays, followed by incubation with antigen-expanded CTLs. Cytotoxic activity was detected by release of calcein and detachment of target cells. With only 200,000 cells per microarray, CTLs could be detected at a frequency of 0.5% corresponding to 1,000 antigen-specific T cells. Target cells and CTLs only settled on peptide spots enabling a clear separation of individual epitopes. Even though no physical boundaries were present between the individual spots, peptide loading only occurred locally and cytolytic activity was confined to the spots carrying the specific epitope. The peptide microarrays provide a robust platform that implements the whole process from antigen presentation to the detection of CTL activity in a miniaturized format. The method surpasses all established methods in the minimum numbers of cells required. With antigen uptake occurring on the microarray, further applications are foreseen in the testing of antigen precursors that require uptake and processing prior to presentation

Capecitabine and mitomycin C as third-line therapy for patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan

Protracted venous infusion 5-fluorouracil (5FU) combined with mitomycin C (MMC) has demonstrated significant activity against metastatic colorectal cancer. Owing to potential synergy based upon upregulation of thymidine phosphorylase by MMC, the combination of capecitabine and MMC may improve outcomes in irinotecan-refractory disease. Eligible patients with progressive disease during or within 6 months of second-line chemotherapy were treated with capecitabine (1250 mg m−2 twice daily) days 1–14 every 3 weeks and MMC (7 mg m−2 IV bolus) once every 6 weeks. A total of 36 patients were recruited, with a median age of 64 years (range 40–77), and 23 patients (78%) were performance status 0–1. The objective response rate was 15.2%. In all, 48.5% of patients had stable disease. Median failure-free survival was 5.4 months (95% CI 4.6–6.2). Median overall survival was 9.3 months (95% CI: 6.9–11.7). Grade 3 toxicities were palmar-plantar erythema 16.7%, vomiting 8.3%, diarrhoea 2.8%, anaemia 8.3%, and neutropenia 2.8%. No patients developed haemolytic uraemic syndrome. Symptomatic improvement occurred for pain, bowel symptoms, and dyspnoea. Capecitabine in combination with MMC is an effective regimen for metastatic colorectal cancer resistant to 5FU and irinotecan with an acceptable toxicity profile and a convenient administration schedule

Estrogen and progesterone receptors have distinct roles in the establishment of the hyperplastic phenotype in PR-A transgenic mice

Introduction: Expression of the A and B forms of progesterone receptor (PR) in an appropriate ratio is critical for mammary development. Mammary glands of PR-A transgenic mice, carrying an additional A form of PR as a transgene, exhibit morphological features associated with the development of mammary tumors. Our objective was to determine the roles of estrogen (E) and progesterone (P) in the genesis of mammary hyperplasias/preneoplasias in PR-A transgenics.Methods: We subjected PR-A mice to hormonal treatments and analyzed mammary glands for the presence of hyperplasias and used BrdU incorporation to measure proliferation. Quantitative image analysis was carried out to compare levels of latency-associated peptide and transforming growth factor beta 1 (TGFβ1) between PR-A and PR-B transgenics. Basement membrane disruption was examined by immunofluorescence and proteolytic activity by zymography.Results: The hyperplastic phenotype of PR-A transgenics is inhibited by ovariectomy, and is reversed by treatment with E + P. Studies using the antiestrogen ICI 182,780 or antiprogestins RU486 or ZK 98,299 show that the increase in proliferation requires signaling through E/estrogen receptor alpha but is not sufficient to give rise to hyperplasias, whereas signaling through P/PR has little impact on proliferation but is essential for the manifestation of hyperplasias. Increased proliferation is correlated with decreased TGFβ1 activation in the PR-A transgenics. Analysis of basement membrane integrity showed loss of laminin-5, collagen III and collagen IV in mammary glands of PR-A mice, which is restored by ovariectomy. Examination of matrix metalloproteases (MMPs) showed that total levels of MMP-2 correlate with the steady-state levels of PR, and that areas of laminin-5 loss coincide with those of activation of MMP-2 in PR-A transgenics. Activation of MMP-2 is dependent on treatment with E and P in ovariectomized wild-type mice, but is achieved only by treatment with P in PR-A mice.Conclusions: These data establish a link between hormonal response, proliferation, modulation of MMP activity and maintenance of basement membrane integrity that depend on a balance in the expression levels of PR-A and PR-B isoforms. Notably, concomitant increased proliferation, due to inhibition of TGFβ1 activation, and loss of basement membrane integrity, via increased MMP-2 activity, appear to be prerequisites for the PR-A hyperplastic phenotype.Fil: Simian, Marina. Lawrence Berkeley National Laboratory; Estados Unidos. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Bissell, Mina J.. Lawrence Berkeley National Laboratory; Estados UnidosFil: Barcellos Hoff, Mary H.. Lawrence Berkeley National Laboratory; Estados Unidos. NYU Langone Medical Center; Estados UnidosFil: Shyamala, Gopalan. Lawrence Berkeley National Laboratory; Estados Unido

Phase I trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer

The objective of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of S-1, an oral fluorouracil derivative, combined with gemcitabine, the current standard treatment for advanced pancreatic cancer (APC). The subjects were histopathologically proven APC patients with distant metastasis. S-1 was administered orally twice daily each day for 14 days and gemcitabine on days 8 and 15 of each cycle, and this was repeated every 21 days. Doses of each drug were planned as follows: level 1: 800/60, level 2a: 800/80, level 2b: 1000/60, level 3: 1000/80 (gemcitabine (mg m−2)/S-1 (mg m−2 day−1)). In all, 21 patients with APC were enrolled. The main grade 3–4 toxicities observed during first cycle were neutropenia (33%), anaemia (10%), thrombocytopenia (14%) and anorexia (10%). There were no DLT observed in level 1. Three of six patients in level 2a had DLT and this level was considered the MTD. In all, 12 patients in level 2b had no DLT and this level was selected as the recommended dose. Applicable responses were one complete response and nine partial responses (48%). As toxicities were well tolerated and antitumour activities seem to be promising, this combination can be recommended for further phase II studies with APC

Membrane Docking Geometry of GRP1 PH Domain Bound to a Target Lipid Bilayer: An EPR Site-Directed Spin-Labeling and Relaxation Study

The second messenger lipid PIP3 (phosphatidylinositol-3,4,5-trisphosphate) is generated by the lipid kinase PI3K (phosphoinositide-3-kinase) in the inner leaflet of the plasma membrane, where it regulates a broad array of cell processes by recruiting multiple signaling proteins containing PIP3-specific pleckstrin homology (PH) domains to the membrane surface. Despite the broad importance of PIP3-specific PH domains, the membrane docking geometry of a PH domain bound to its target PIP3 lipid on a bilayer surface has not yet been experimentally determined. The present study employs EPR site-directed spin labeling and relaxation methods to elucidate the membrane docking geometry of GRP1 PH domain bound to bilayer-embedded PIP3. The model target bilayer contains the neutral background lipid PC and both essential targeting lipids: (i) PIP3 target lipid that provides specificity and affinity, and (ii) PS facilitator lipid that enhances the PIP3 on-rate via an electrostatic search mechanism. The EPR approach measures membrane depth parameters for 18 function-retaining spin labels coupled to the PH domain, and for calibration spin labels coupled to phospholipids. The resulting depth parameters, together with the known high resolution structure of the co-complex between GRP1 PH domain and the PIP3 headgroup, provide sufficient constraints to define an optimized, self-consistent membrane docking geometry. In this optimized geometry the PH domain engulfs the PIP3 headgroup with minimal bilayer penetration, yielding the shallowest membrane position yet described for a lipid binding domain. This binding interaction displaces the PIP3 headgroup from its lowest energy position and orientation in the bilayer, but the headgroup remains within its energetically accessible depth and angular ranges. Finally, the optimized docking geometry explains previous biophysical findings including mutations observed to disrupt membrane binding, and the rapid lateral diffusion observed for PIP3-bound GRP1 PH domain on supported lipid bilayers

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Hierarchically Structured Lipid Systems (Part of 2nd Edition)

No abstract available

Growth of breast cancer recurrences assessed by consecutive MRI

<p>Abstract</p> <p>Background</p> <p>Women with a personal history of breast cancer have a high risk of developing an ipsi- or contralateral recurrence. We aimed to compare the growth rate of primary breast cancer and recurrences in women who had undergone prior breast magnetic resonance imaging (MRI).</p> <p>Methods</p> <p>Three hundred and sixty-two women were diagnosed with breast cancer and had undergone breast MRI at the time of diagnosis in our institution (2005 - 2009). Among them, 37 had at least one prior breast MRI with the lesion being visible but not diagnosed as cancer. A linear regression of tumour volume measured on MRI scans and time data was performed using a generalized logistic model to calculate growth rates. The primary objective was to compare the tumour growth rate of patients with either primary breast cancer (no history of breast cancer) or ipsi- or contralateral recurrences of breast cancer.</p> <p>Results</p> <p>Twenty women had no history of breast cancer and 17 patients were diagnosed as recurrences (7 and 10 were ipsi- and contralateral, respectively). The tumour growth rate was higher in contralateral recurrences than in ipsilateral recurrences (growth rate [10^-3days^-1] 3.56 vs 1.38, p < .001) or primary cancer (3.56 vs 2.09, p = 0.01). Differences in tumour growth were not significant for other patient-, tumour- or treatment-related characteristics.</p> <p>Conclusions</p> <p>These findings suggest that contralateral breast cancer presents accelerated growth compared to ipsilateral recurrences or primary breast events.</p

Local control by radiotherapy: is that all there is?

Radiotherapy is a local treatment modality employed in breast cancer to reduce local recurrence following surgery. The observed association of optimal local control with improved survival was not expected in a disease characterized by early systemic spread. The underlying mechanisms whereby the application of ionizing radiation to the primary tumor site can have systemic effects remain unclear and are the subject of much debate. In the present article we discuss the hypothesis that radiotherapy has unique biological effects and that, in addition to killing residual neoplastic cells after surgery is performed, it might favorably alter the microenvironment at the primary tumor site during the process of wound healing and the development of antitumor immune responses