High-throughput genomic technology in research and clinical management of breast cancer. Plasma-based proteomics in early detection and therapy

Protein-based breast cancer biomarkers are a promising resource for breast cancer detection at the earliest and most treatable stages of the disease. Plasma is well suited to proteomic-based methods of biomarker discovery because it is easily obtained, is routinely used in the diagnosis of many diseases, and has a rich proteome. However, due to the vast dynamic range in protein concentration and the often uncertain tissue and cellular origin of plasma proteins, proteomic analysis of plasma requires special consideration compared with tissue and cultured cells. This review briefly touches on the search for plasma-based protein biomarkers for the early detection and treatment of breast cancer

Low-temperature spin dynamics of a valence bond glass in Ba<sub style="font-size: smaller; vertical-align: baseline; position: relative; top: 0.25em;">2YMoO<sub style="font-size: smaller; vertical-align: baseline; position: relative; top: 0.25em;">6</sub></sub>

We carried out AC magnetic susceptibility measurements and muon spin relaxation spectroscopy on the cubic double perovskite Ba2YMoO6, down to 50 mK. Below ~1 K the muon relaxation is typical of a magnetic insulator with a spin-liquid type ground state, i.e. without broken symmetries or frozen moments. However, the AC susceptibility revealed a dilute-spin-glass like transition below ~ 1 K. Antiferromagnetically coupled Mo5+ 4d1 electrons in triply degenerate t2g orbitals are in this material arranged in a geometrically frustrated fcc lattice. Bulk magnetic susceptibility data has previously been interpreted in terms of a freezing to a heterogeneous state with non-magnetic sites where 4d^1 electrons have paired in spin-singlets dimers, and residual unpaired Mo5+ 4d1 electrons. Based on the magnetic heat capacity data it has been suggested that this heterogeneity is the result of kinetic constraints intrinsic to the physics of the pure system (possibly due to topological overprotection), leading to a self-induced glass of valence bonds between neighbouring 4d1 electrons. The muSR relaxation unambiguously points to a static heterogeneous state with a static arrangement of unpaired electrons isolated by spin-singlet (valence bond) dimers between the majority of Mo5+ 4d electrons. The AC susceptibility data indicate that the residual magnetic moments freeze into a dilute-spin-glass-like state. This is in apparent contradiction with the muon-spin decoupling at 50 mK in fields up to 200 mT, which indicates that, remarkably, the time scale of the field fluctuations from the residual moments is ~ 5 ns. Comparable behaviour has been observed in other geometrically frustrated magnets with spin-liquid-like behaviour and the implications of our observations on Ba2YMoO6 are discussed in this context.Comment: 11 pages, 3 Figures. Published in New Journal of Physic

THE HUPO Human Plasma Proteome Project

The Human Proteomics Organization (HUPO) Human Plasma Proteome Project (PPP) is a prominent example of the inherently collaborative nature of the overall community effort to characterize the proteome of humans in health and disease. The PPP Pilot Phase, called “Exploring the Human Plasma Proteome”, engaged 55 laboratories, four technical committees, and vendors and sponsors on an international scale. Among other outcomes, the PPP generated a Core Dataset of 3020 proteins identified with two or more peptides, fully accessible at EBI/PRIDE, ISB/PeptideAtlas, and University of Michigan websites, a rich resource for follow-on analyses. The PPP provided extensive annotation, correlation of number of peptides with protein concentrations measured by immunoassay, an algorithm for choice of a representative protein for multiple proteins matching a given peptide, and independent analyses from the raw spectra. The next phase of the PPP will emphasize standardized procedures for specimen handling, potent new technology platforms for discovery and for targeted proteomics, and robust informatics efforts, including comparative analyses of other biofluids.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56177/1/769_ftp.pd

Potentials of Plasma NGAL and MIC-1 as Biomarker(s) in the Diagnosis of Lethal Pancreatic Cancer

Pancreatic cancer (PC) is lethal malignancy with very high mortality rate. Absence of sensitive and specific marker(s) is one of the major factors for poor prognosis of PC patients. In pilot studies using small set of patients, secreted acute phase proteins neutrophil gelatinase associated lipocalin (NGAL) and TGF-β family member macrophage inhibitory cytokine-1 (MIC-1) are proposed as most potential biomarkers specifically elevated in the blood of PC patients. However, their performance as diagnostic markers for PC, particularly in pre-treatment patients, remains unknown. In order to evaluate the diagnostic efficacy of NGAL and MIC-1, their levels were measured in plasma samples from patients with pre-treatment PC patients (n = 91) and compared it with those in healthy control (HC) individuals (n = 24) and patients with chronic pancreatitis (CP, n = 23). The diagnostic performance of these two proteins was further compared with that of CA19-9, a tumor marker commonly used to follow PC progression. The levels of all three biomarkers were significantly higher in PC compared to HCs. The mean (± standard deviation, SD) plasma NGAL, CA19-9 and MIC-1 levels in PC patients was 111.1 ng/mL (2.2), 219.2 U/mL (7.8) and 4.5 ng/mL (4.1), respectively. In comparing resectable PC to healthy patients, all three biomarkers were found to have comparable sensitivities (between 64%-81%) but CA19-9 and NGAL had a higher specificity (92% and 88%, respectively). For distinguishing resectable PC from CP patients, CA19-9 and MIC-1 were most specific (74% and 78% respectively). CA19-9 at an optimal cut-off of 54.1 U/ml is highly specific in differentiating resectable (stage 1/2) pancreatic cancer patients from controls in comparison to its clinical cut-off (37.1 U/ml). Notably, the addition of MIC-1 to CA19-9 significantly improved the ability to distinguish resectable PC cases from CP (p = 0.029). Overall, MIC-1 in combination with CA19-9 improved the diagnostic accuracy of differentiating PC from CP and HCs

Gene expression profiling of breast cancer in Lebanese women

MPP grants MPP320046 and MPP320061

Chapter 6 Protein Sorting in the Secretory Pathway

This chapter focuses on protein sorting in the secretory pathway. From primary and secondary biosynthetic sites in the cytosol and mitochondrial matrix, respectively, proteins and lipids are distributed to more than 30 final destinations in membranes or membrane-bound spaces, where they carry out their programmed function. Molecular sorting is defined, in its most general sense, as the sum of the mechanisms that determine the distribution of a given molecule from its site of synthesis to its site of function in the cell. The final site of residence of a protein in a eukaryotic cell is determined by a combination of various factors, acting in concert: (1) site of synthesis, (2) sorting signals or zip codes, (3) signal recognition or decoding mechanisms, (4) cotranslational or posttranslational mechanisms for translocation across membranes, (5) specific fusion–fission interactions between intracellular vesicular compartments, and (6) restrictions to the lateral mobility in the plane of the bilayer. Improvements in cell fractionation, protein separation, and immune precipitation procedures in the past decade have made them possible. Very little is known about the mechanisms that mediate the localization and concentration of specific proteins and lipids within organelles. Various experimental model systems have become available for their study. The advent of recombinant DNA technology has shortened the time needed for obtaining the primary structure of proteins to a few months