We profiled receptor tyrosine kinase pathway activation and key gene mutations in eight human lung tumor cell lines and 50 human lung tumor tissue samples to define molecular pathways. A panel of eight kinase inhibitors was used to determine whether blocking pathway activation affected the tumor cell growth. The HER1 pathway in HER1 mutant cell lines HCC827 and H1975 were found to be highly activated and sensitive to HER1 inhibition. H1993 is a c-MET amplified cell line showing c-MET and HER1 pathway activation and responsiveness to c-MET inhibitor treatment. IGF-1R pathway activated H358 and A549 cells are sensitive to IGF-1R inhibition. The downstream PI3K inhibitor, BEZ-235, effectively inhibited tumor cell growth in most of the cell lines tested, except the H1993 and H1650 cells, while the MEK inhibitor PD-325901 was effective in blocking the growth of KRAS mutated cell line H1734 but not H358, A549 and H460. Hierarchical clustering of primary tumor samples with the corresponding tumor cell lines based on their pathway signatures revealed similar profiles for HER1, c-MET and IGF-1R pathway activation and predict potential treatment options for the primary tumors based on the tumor cell lines response to the panel of kinase inhibitors.

Hua C. Gong

Sean Wang

Gary Mayer

Guoan Chen

Glen Leesman

 Sharat Singh

David G. Beer

Signatures of Drug Sensitivity in Nonsmall Cell Lung Cancer

Technological and scientific innovations over the last decade have greatly contributed to improved diagnostics, predictive models, and prognosis among cancers affecting women. In fact, an explosion of information in these areas has almost assured future generations that outcomes in cancer will continue to improve. Herein we discuss the current status of breast, cervical, and ovarian cancers as it relates to screening, disease diagnosis, and treatment options. Among the differences in these cancers, it is striking that breast cancer has multiple predictive tests based upon tumor biomarkers and sophisticated, individualized options for prescription therapeutics while ovarian cancer lacks these tools. In addition, cervical cancer leads the way in innovative, cancer-preventative vaccines and multiple screening options to prevent disease progression. For each of these malignancies, emerging proteomic technologies based upon mass spectrometry, stable isotope labeling with amino acids, high-throughput ELISA, tissue or protein microarray techniques, and click chemistry in the pursuit of activity-based profiling can pioneer the next generation of discovery. We will discuss six of the latest techniques to understand proteomics in cancer and highlight research utilizing these techniques with the goal of improvement in the management of women&#39;s cancers.

Eun-Kyoung Yim Breuer

Mandi M. Murph

The Role of Proteomics in the Diagnosis and Treatment of Women&#39;s Cancers: Current Trends in Technology and Future Opportunities

Cerebrospinal fluid (CSF) has been used for biomarker discovery of neurodegenerative diseases in humans since biological changes in the brain can be seen in this biofluid. Inactivation of A-T-mutated protein (ATM), a multifunctional protein kinase, is responsible for A-T, yet biochemical studies have not succeeded in conclusively identifying the molecular mechanism(s) underlying the neurodegeneration seen in A-T patients or the proteins that can be used as biomarkers for neurologic assessment of A-T or as potential therapeutic targets. In this study, we applied a high-throughput LC/MS-based label-free protein quantification technology to quantitatively characterize the proteins in CSF samples in order to identify differentially expressed proteins that can serve as potential biomarker candidates for A-T. Among 204 identified CSF proteins with high peptide-identification confidence, thirteen showed significant protein expression changes. Bioinformatic analysis revealed that these 13 proteins are either involved in neurodegenerative disorders or cancer. Future molecular and functional characterization of these proteins would provide more insights into the potential therapeutic targets for the treatment of A-T and the biomarkers that can be used to monitor or predict A-T disease progression. Clinical validation studies are required before any of these proteins can be developed into clinically useful biomarkers.

Monika Dzieciatkowska

Guihong Qi

Jinsam You

Kerry G. Bemis

Heather Sahm

Howard M. Lederman

Thomas O. Crawford

Lawrence M. Gelbert

Cynthia Rothblum-Oviatt

Mu Wang

Proteomic Characterization of Cerebrospinal Fluid from Ataxia-Telangiectasia (A-T) Patients Using a LC/MS-Based Label-Free Protein Quantification Technology

In a high-resolution MALDI-TOF mass spectrum, a peptide produces multiple
peaks, corresponding to the isotopic variants of the molecules. An overlap occurs when two peptides appear in the vicinity of the mass coordinate, resulting in the difficulty of quantifying the relative abundance and the exact masses of these peptides. To address the problem, two factors need to be considered: (1) the variability pertaining to the abundances of the isotopic variants (2) extra information content needed to supplement the information contained in data. We propose a Bayesian model for the incorporation of prior information. Such information exists, for example, for the distribution of the masses of peptides and the abundances of the isotopic variants. The model we develop allows for the correct estimation of the parameters of interest. The validity of the modeling approach is verified by a real-life case study from a controlled mass spectrometry experiment and by a simulation study.

Qi Zhu

Adetayo Kasim

Dirk Valkenborg

Tomasz Burzykowski

A Bayesian Model Averaging Approach to the Quantification of Overlapping Peptides in an MALDI-TOF Mass Spectrum

Repair of double-stranded breaks (DSBs) is vital to maintaining genomic stability. In mammalian cells, DSBs are resolved in one of the following complex repair pathways: nonhomologous end-joining (NHEJ), homologous recombination (HR), or the inclusive DNA damage response (DDR). These repair pathways rely on factors that utilize reversible phosphorylation of proteins as molecular switches to regulate DNA repair. Many of these molecular switches overlap and play key roles in multiple pathways. For example, the NHEJ pathway and the DDR both utilize DNA-PK phosphorylation, whereas the HR pathway mediates repair with phosphorylation of RPA2, BRCA1, and BRCA2. Also, the DDR pathway utilizes the kinases ATM and ATR, as well as the phosphorylation of H2AX and MDC1. Together, these molecular switches regulate repair of DSBs by aiding in DSB recognition, pathway initiation, recruitment of repair factors, and the maintenance of repair mechanisms.

K. C. Summers

F. Shen

E. A. Sierra Potchanant

E. A. Phipps

R. J. Hickey

L. H. Malkas

Phosphorylation: The Molecular Switch of Double-Strand Break Repair

We present a versatile user-friendly software tool, PolyAlign, for the alignment of multiple LC-MS signal maps with the option of manual landmark setting or automated alignment. One of the spectral images is selected as a reference map, and after manually setting the landmarks, the program warps the images using either polynomial or Hermite transformation. The software provides an option for automated landmark finding. The software includes a very fast zoom-in function synchronized between the images, which facilitate detecting correspondences between the adjacent images. Such an interactive visual process enables the analyst to decide when the alignment is satisfactory and to correct known irregularities. We demonstrate that the software provides significant improvements in the alignment of LC-MALDI data, with 10–15 landmark pairs, and it is also applicable to correcting electrospray LC-MS data. The results with practical data show substantial improvement in peak alignment compared to MZmine, which was among the best analysis packages in a recent assessment. The PolyAlign software is freely available and easily accessible as an integrated component of the popular MZmine software, and also as a simpler stand-alone Perl implementation to preview data and apply landmark directed polynomial transformation.

Heidi Vähämaa

Ville R. Koskinen

Waltteri Hosia

Robert Moulder

Olli S. Nevalainen

Riitta Lahesmaa

Tero Aittokallio

Jussi Salmi

PolyAlign: A Versatile LC-MS Data Alignment Tool for Landmark-Selected and -Automated Use

Myogenesis, the formation of skeletal muscle, is a multistep event that commences with myoblast proliferation, followed by cell-cycle arrest, and finally the formation of multinucleated myotubes via fusion of mononucleated myoblasts. Each step is orchestrated by well-documented intracellular factors, such as cytoplasmic signalling molecules and nuclear transcription factors. Regardless, the key step in getting a more comprehensive understanding of the regulation of myogenesis is to explore the extracellular factors that are capable of eliciting the downstream intracellular factors. This could further provide valuable insight into the acute cellular response to extrinsic cues in maintaining normal muscle development. In this paper, we survey the intracellular factors that respond to extracellular cues that are responsible for the cascades of events during myogenesis: myoblast proliferation, cell-cycle arrest of myoblasts, and differentiation of myoblasts into myotubes. This focus on extracellular perspective of muscle development illustrates our mass spectrometry-based proteomic approaches to identify differentially expressed secreted factors during skeletal myogenesis.

C. Y. X'avia Chan

John C. McDermott

K. W. Michael Siu

Secretome Analysis of Skeletal Myogenesis Using SILAC and Shotgun Proteomics


		The grass family Poaceae includes annual species cultivated as major grain crops and perennial species cultivated as forage or turf grasses. Heat stress is a primary factor limiting growth and productivity of cool-season grass species and is becoming a more significant problem in the context of global warming. Plants have developed various mechanisms in heat-stress adaptation, including changes in protein metabolism such as the induction of heat shock proteins (HSPs). This paper summarizes the structure and function of major HSPs, recent research progress on the association of HSPs with grass tolerance to heat stress, and incorporation of HSPs in heat-tolerant grass breeding.

Yan Xu

Chenyang Zhan

Bingru Huang

Heat Shock Proteins in Association with Heat Tolerance in Grasses

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International Journal of Proteomics