Combination immunotherapy induces distinct T-cell repertoire responses when administered to patients with different malignancies.

BackgroundCTLA-4 blockade with ipilimumab is Food and Drug Administration-approved for melanoma as a monotherapy and has been shown to modulate the circulating T-cell repertoire. We have previously reported clinical trials combining CTLA-4 blockade with granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic melanoma patients and in metastatic castration resistant prostate cancer (mCRPC) patients. Here, we investigate the effect that cancer type has on circulating T cells in metastatic melanoma and mCRPC patients, treated with ipilimumab and GM-CSF.MethodsWe used next-generation sequencing of T-cell receptors (TCR) to compare the circulating T cells of melanoma and mCRPC patients receiving the same treatment with ipilimumab and GM-CSF by Wilcoxon rank sum test. Flow cytometry was utilized to investigate specific T-cell populations. TCR sequencing results were correlated with each T-cell subpopulation by Spearman's rank correlation coefficient. Of note, 14 metastatic melanoma patients had samples available for TCR sequencing and 21 had samples available for flow cytometry analysis; 37 mCRPC patients had samples available for sequencing of whom 22 have TCR data available at both timepoints; 20 of these patients had samples available for flow cytometry analysis and 16 had data available at both timepoints.ResultsWhile melanoma and mCRPC patients had similar pretreatment circulating T-cell counts, treatment induces greater expansion of circulating T cells in melanoma patients. Metastatic melanoma patients have a higher proportion of clones that increased more than fourfold after the treatment compared with mCRPC patients (18.9% vs 11.0%, p=0.017). Additionally, melanoma patients compared with mCRPC patients had a higher ratio of convergent frequency (1.22 vs 0.60, p=0.012). Decreases in clonality induced by treatment are associated with baseline CD8+ T-cell counts in both patient groups, but are more pronounced in the melanoma patients (r=-0.81, p<0.001 vs r=-0.59, p=0.02).Trial registration numbersNCT00064129; NCT01363206

PENGEMBANGAN SISTEM INFORMASI EKSPEDISI PT.PANCA UTAMA EXPRESS DENGAN METODE PERANCANGAN BERORIENTASI OBJEK

PT Panca Utama Express adalah sebuah perusahaan yang bergerak dibidang jasa pengiriman barang jalur darat di palembang. Dalam proses bisnisnya PT Panca Utama Express tidak terlepas dari kendala yang dihadapi, seperti kesalahan pengangkutan barang milik pelanggan, terlewatnya waktu untuk pengambilan barang di bandara, barang-barang yang mengalami keterlambatan tidak diambil, pengiriman yang urgent terlambat untuk diantarkan dan lain-lain. Sehubung dengan permasalahan diatas, penulis ingin menyelesaikan permasalahan yang dihadapi perusahaan dengan membangun sistem informasi yang berorientasi objek sebagai teknologi informasi untuk menyelesaikan masalah yang ada seperti pengaturan informasi pengangkutan barang dengan memberikan informasi rute-rute lokasi pengiriman. Pengingat untuk pengambilan barang dibandara, Pemilahan informasi untuk barang yang urgent. Dalam pengembangan ini, penulis akan mengunakan metodologi RUP (Rational Unified Process) sebagai metodologi pengembangan sistem dan untuk membangun sistem ini penulis menggunakan Visual Basic.Net dan Microsoft SQL Server 2008. Dengan dibangunnya sistem ini masalah-masalah yang ada diperusahaan dapat diselesaikan, pekerjaan pada setiap bagian juga akan dipermudah dan selain itu proses bisnis perusahaan juga akan menjadi lebih baik

Environment mediated multipartite and multidimensional entanglement

Quantum entanglement is usually considered a fragile quantity and decoherence through coupling to an external environment, such as a thermal reservoir, can quickly destroy the entanglement resource. This doesn't have to be the case and the environment can be engineered to assist in the formation of entanglement. We investigate a system of qubits and higher dimensional spins interacting only through their mutual coupling to a reservoir. We explore the entanglement of multipartite and multidimensional system as mediated by the bath and show that at low temperatures and intermediate coupling strengths multipartite entanglement may form between qubits and between higher spins, i.e., qudits. We characterise the multipartite entanglement using an entanglement witness based upon the structure factor and demonstrate its validity versus the directly calculated entanglement of formation, suggesting possible experiments for its measure.Comment: 9 pages, 10 figure

Src Family Kinases and p38 Mitogen-Activated Protein Kinases Regulate Pluripotent Cell Differentiation in Culture

Multiple pluripotent cell populations, which together comprise the pluripotent cell lineage, have been identified. The mechanisms that control the progression between these populations are still poorly understood. The formation of early primitive ectoderm-like (EPL) cells from mouse embryonic stem (mES) cells provides a model to understand how one such transition is regulated. EPL cells form from mES cells in response to l-proline uptake through the transporter Slc38a2. Using inhibitors of cell signaling we have shown that Src family kinases, p38 MAPK, ERK1/2 and GSK3β are required for the transition between mES and EPL cells. ERK1/2, c-Src and GSK3β are likely to be enforcing a receptive, primed state in mES cells, while Src family kinases and p38 MAPK are involved in the establishment of EPL cells. Inhibition of these pathways prevented the acquisition of most, but not all, features of EPL cells, suggesting that other pathways are required. L-proline activation of differentiation is mediated through metabolism and changes to intracellular metabolite levels, specifically reactive oxygen species. The implication of multiple signaling pathways in the process suggests a model in which the context of Src family kinase activation determines the outcomes of pluripotent cell differentiation

Unconditional and conditional standards for fetal abdominal circumference and estimated fetal weight in an ethnic Chinese population: a birth cohort study

10.1186/s12884-015-0569-1BMC Pregnancy and Childbirth151411-11GUSTO (Growing up towards Healthy Outcomes

Inflammatory Aetiology of Human Myometrial Activation Tested Using Directed Graphs

There are three main hypotheses for the activation of the human uterus at labour: functional progesterone withdrawal, inflammatory stimulation, and oxytocin receptor activation. To test these alternatives we have taken information and data from the literature to develop causal pathway models for the activation of human myometrium. The data provided quantitative RT-PCR results on key genes from samples taken before and during labour. Principal component analysis showed that pre-labour samples form a homogenous group compared to those during labour. We therefore modelled the alternative causal pathways in non-labouring samples using directed graphs and statistically compared the likelihood of the different models using structural equations and D-separation approaches. Using the computer program LISREL, inflammatory activation as a primary event was highly consistent with the data (p = 0.925), progesterone withdrawal, as a primary event, is plausible (p = 0.499), yet comparatively unlikely, oxytocin receptor mediated initiation is less compatible with the data (p = 0.091). DGraph, a software program that creates directed graphs, produced similar results (p = 0.684, p = 0.280, and p = 0.04, respectively). This outcome supports an inflammatory aetiology for human labour. Our results demonstrate the value of directed graphs in determining the likelihood of causal relationships in biology in situations where experiments are not possible

Incremental cost-effectiveness analysis of gestational diabetes mellitus screening strategies in Singapore

10.1177/1010539515612908Asia-Pacific Journal of Public Health28115-25GUSTO (Growing up towards Healthy Outcomes

Maternal blood pressure during pregnancy and early childhood blood pressures in the offspring

10.1097/MD.0000000000001981Medicine94451-9GUSTO (Growing up towards Healthy Outcomes