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Clinical Proteomics

Stephanie Heinzlmeir, Denis Kudlinzki, Sridhar Sreeramulu, Susan Klaeger, Santosh Lakshmi Gande, Verena Linhard, Mathias Wilhelm, Huichao Qiao, Dominic Helm, Benjamin Ruprecht, Krishna Saxena, Guillaume Médard, Harald Schwalbe, Bernhard Kuster
The receptor tyrosine kinase EPHA2 (Ephrin type-A receptor 2) plays important roles in oncogenesis, metastasis and treatment resistance yet therapeutic targeting, drug discovery or investigation of EPHA2 biology is hampered by the lack of appropriate inhibitors and structural information. Here, we used chemical proteomics to survey 235 clinical kinase inhibitors for their kinase selectivity and identified 24 drugs with sub-micromolar affinities for EPHA2. NMR-based conformational dynamics together with nine new co-crystal structures delineated drug-EPHA2 interactions in full detail...
October 21, 2016: ACS Chemical Biology
Joan Yw Liu, Cheryl Reeves, Beate Diehl, Antonietta Coppola, Aliya Al-Hajri, Chandrashekar Hoskote, Salim Al Mughairy, Mohamed Tachrount, Michael Groves, Zuzanna Michalak, Kevin Mills, Andrew W McEvoy, Anna Miserocchi, Sanjay M Sisodiya, Maria Thom
OBJECTIVE: This study reports on a novel brain pathology in young patients with Frontal Lobe Epilepsy that is distinct from Focal Cortical Dysplasia. METHODS: Surgical specimens from twenty young adults with frontal lobe epilepsy (mean age, 30 years) were investigated with histological/immunohistochemical markers for cortical laminar architecture, mammalian target of rapamycin pathway activation and inhibition, cellular autophagy, and synaptic vesicle-mediated trafficking as well as proteomics analysis...
October 20, 2016: Annals of Neurology
David Gurwitz
The development and clinical implementation of personalized medicine crucially depends on the availability of high-quality human biosamples; animal models, although capable of modeling complex human diseases, cannot reflect the large variation in the human genome, epigenome, transcriptome, proteome, and metabolome. Although the biosamples available from public biobanks that store human tissues and cells may represent the large human diversity for most diseases, these samples are not always sufficient for developing biomarkers for patient-tailored therapies for neuropsychiatric disorders...
September 2016: Dialogues in Clinical Neuroscience
Martino Deidda, Rosalinda Madonna, Ruggiero Mango, Pasquale Pagliaro, Pier P Bassareo, Lucia Cugusi, Silvio Romano, Maria Penco, Francesco Romeo, Giuseppe Mercuro
Despite advances in supportive and protective therapy for myocardial function, heart failure caused by various clinical conditions, including cardiomyopathy due to antineoplastic therapy, remains a major cause of morbidity and mortality. Because of the limitations associated with current therapies, investigators have been searching for alternative treatments that can effectively repair the damaged heart and permanently restore its function. Damage to the heart can result from both traditional chemotherapeutic agents, such as anthracyclines, and new targeted therapies, such as trastuzumab...
May 2016: Journal of Cardiovascular Medicine
Alessio Soggiu, Cristian Piras, Viviana Greco, Paola Devoto, Andrea Urbani, Luigino Calzetta, Marco Bortolato, Paola Roncada
The enzyme 5α-reductase (5αR) catalyzes the conversion of progesterone and testosterone into neuroactive steroids implicated in a wide array of behavioral functions. The prototypical 5αR inhibitor, finasteride (FIN), is clinically approved for the treatment of androgenic alopecia and benign prostatic hyperplasia. Recent evidence has shown that FIN, albeit generally well tolerated, can induce untoward psychological effects in a subset of patients; furthermore, this drug may have therapeutic efficacy for a number of different neuropsychiatric conditions, ranging from Tourette syndrome to schizophrenia...
October 6, 2016: Psychoneuroendocrinology
Alberto Papi, Maria Sandra Magnoni, Carmelo Caio Muzzio, Gianmarco Benso, Andrea Rizzi
The Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) study was a large 3-year observational multicentre international study aimed at defining COPD phenotypes and identifying biomarkers and/or genetic parameters that help to predict disease progression. The study has contributed to a better understanding of COPD heterogeneity, with the characterization of clinically important subtypes/phenotypes of patients, such as the frequent exacerbators or patient with persistent systemic inflammation, who may have different prognosis or treatment requirements...
October 14, 2016: Monaldi Archives for Chest Disease, Archivio Monaldi Per le Malattie del Torace
Clizia Chinello, Vincenzo L'Imperio, Martina Stella, Andrew James Smith, Giorgio Bovo, Angelica Grasso, Marco Grasso, Francesca Raimondo, Marina Pitto, Fabio Pagni, Fulvio Magni
Renal cell carcinoma (RCC) is the most fatal of the common urologic cancers, with approximately 35% of patients dying within 5 years following diagnosis. Therefore, there is a need for non-invasive markers that are capable of detecting and determining the severity of small renal masses at an early stage in order to tailor treatment and follow-up. Proteomic studies have proved to be very useful in the study of tumors. Areas covered: In this review, we will detail the current knowledge obtained by the different proteomic approaches, focusing on MS-based strategies, used to investigate RCC biology in order to identify diagnostic, prognostic and predictive biomarkers on tissue, cultured cells and biological fluids...
October 17, 2016: Expert Review of Proteomics
Jürgen Böhm, Frank Pianka, Nina Stüttgen, Junghyun Rho, Biljana Gigic, Yuzheng Zhang, Nina Habermann, Petra Schrotz-King, Clare Abbenhardt-Martin, Lin Zielske, Paul D Lampe, Alexis Ulrich, Markus K Diener, Cornelia M Ulrich
BACKGROUND: Ventral incisional hernia is the most common long-term complication after an abdominal operation. Among newly diagnosed colorectal cancer patients, we screened the preoperative plasma proteome to explore predictive markers for the development of an incisional hernia. METHODS: We utilized preoperative plasma samples of 72 newly diagnosed colorectal cancer patients who underwent midline incision for tumor resection between 2010 and 2013. A total of 21 patients with incisional hernia occurrence were matched with 51 patients with at least 18 months follow-up without an incisional hernia by sex, age, and body mass index...
October 13, 2016: Surgery
Tino W Sanchez, Guangyu Zhang, Jitian Li, Liping Dai, Saied Mirshahidi, Nathan R Wall, Clayton Yates, Colwick Wilson, Susanne Montgomery, Jian-Ying Zhang, Carlos A Casiano
African American (AA) men suffer from a disproportionately high incidence and mortality of prostate cancer (PCa) compared to other racial/ethnic groups. Despite these disparities, African American men are underrepresented in clinical trials and in studies on PCa biology and biomarker discovery. We used immunoseroproteomics to profile anti-tumor autoantibody responses in AA and European American (EA) men with PCa, and explored differences in these responses. This minimally invasive approach detects autoantibodies to tumor-associated antigens that could serve as clinical biomarkers and immunotherapeutic agents...
October 14, 2016: Molecular & Cellular Proteomics: MCP
Maria Bruzelius, Maria Jesus Iglesias, Mun-Gwan Hong, Laura Sanchez-Rivera, Beata Gyorgy, Juan Carlos Souto, Mattias Frånberg, Claudia Fredolini, Rona J Strawbridge, Margareta Holmström, Anders Hamsten, Mathias Uhlén, Angela Silveira, Jose Manuel Soria, David M Smadja, Lynn M Butler, Jochen M Schwenk, Pierre-Emmanuel Morange, David-Alexandre Trégouët, Jacob Odeberg
There is a clear clinical need for high specificity plasma biomarkers for predicting risk of venous thromboembolism (VTE), but thus far such markers have remained elusive. Utilising affinity reagents from the human protein atlas (HPA) project and multiplexed immuoassays we extensively analysed plasma samples from two individual cohorts to identify candidate protein markers associated with VTE risk. We screened plasma samples from 88 VTE cases and 85 matched controls, collected as part of the Swedish 'Venous Thromboembolism Biomarker Study' (VEBIOS), using suspension bead arrays composed of 755 antibodies targeting 408 candidate proteins...
October 14, 2016: Blood
Caron Jacobson, Nadja Kopp, Jacob V Layer, Robert A Redd, Sebastian Tschuri, Sarah Haebe, Diederik van Bodegom, Liat Bird, Amanda L Christie, Alexandra Christodoulou, Amy Saur, Trevor Tivey, Stefanie Zapf, Deepak Bararia, Ursula Zimber-Strobl, Scott J Rodig, Oliver Weigert, David M Weinstock
The BTK inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma. Intrinsic resistance can occur through activation of the non-classical NFκB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer HSP90 inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IKKα in MCL lines and CD40-dependent B cells, with downstream loss of MAP kinase and non-classical NFκB signaling...
October 14, 2016: Blood
Travis C Salzillo, Jingzhe Hu, Linda Nguyen, Nicholas Whiting, Jaehyuk Lee, Joseph Weygand, Prasanta Dutta, Shivanand Pudakalakatti, Niki Zacharias Millward, Seth T Gammon, Frederick F Lang, Amy B Heimberger, Pratip K Bhattacharya
This article reviews existing and emerging techniques of interrogating metabolism in brain cancer from well-established proton magnetic resonance spectroscopy to the promising hyperpolarized metabolic imaging and chemical exchange saturation transfer and emerging techniques of imaging inflammation. Some of these techniques are at an early stage of development and clinical trials are in progress in patients to establish the clinical efficacy. It is likely that in vivo metabolomics and metabolic imaging is the next frontier in brain cancer diagnosis and assessing therapeutic efficacy; with the combined knowledge of genomics and proteomics a complete understanding of tumorigenesis in brain might be achieved...
November 2016: Magnetic Resonance Imaging Clinics of North America
Priyakshi Kalita-de Croft, Fares Al-Ejeh, Amy E McCart Reed, Jodi M Saunus, Sunil R Lakhani
Our understanding of the natural history of breast cancer has evolved alongside technologies to study its genomic, transcriptomic, proteomic, and metabolomics landscapes. These technologies have helped decipher multiple molecular pathways dysregulated in breast cancer. First-generation 'omics analyses considered each of these dimensions individually, but it is becoming increasingly clear that more holistic, integrative approaches are required to fully understand complex biological systems. The 'omics represent an exciting era of discovery in breast cancer research, although important issues need to be addressed to realize the clinical utility of these data through precision cancer care...
November 2016: Advances in Anatomic Pathology
Michael Henry, Paula Meleady
Liquid chromatography-mass spectrometry (LC-MS) has become a routine powerful technology in clinical proteomic studies for protein identification, protein characterization and the discovery of biomarkers. In this chapter, we describe two protocol methods to analyze clinical patient samples using a resin based depletion column followed by either protein In-gel enzymatic digestion or protein in-solution enzymatic digestion and then analysis by one-dimensional reverse-phase chromatography or two-dimensional strong cation exchange (SCX)-reverse-phase chromatography (RPC)...
2017: Methods in Molecular Biology
Changwon Kang, Yejin Lee, J Eugene Lee
The last decade has witnessed remarkable technological advances in mass spectrometry-based proteomics. The development of proteomics techniques has enabled the reliable analysis of complex proteomes, leading to the identification and quantification of thousands of proteins in gastric cancer cells, tissues, and sera. This quantitative information has been used to profile the anomalies in gastric cancer and provide insights into the pathogenic mechanism of the disease. In this review, we mainly focus on the advances in mass spectrometry and quantitative proteomics that were achieved in the last five years and how these up-and-coming technologies are employed to track biochemical changes in gastric cancer cells...
October 7, 2016: World Journal of Gastroenterology: WJG
Nikolaos Tziolos, Evangelos J Giamarellos-Bourboulis
Introduction Although the administration of appropriate antimicrobials within the very first hour remains the mainstay of sepsis management, the correct selection of antimicrobials is hampered by the delay of conventional microbiology providing results after at least 48 hours. Methods of rapid detection of pathogens are an approach to overcome these difficulties. Areas covered This review analyzes the advantages and the disadvantages of these approaches with major emphasis on technologies based on multiplex PCR for the rapid detection of pathogens using whole blood...
October 11, 2016: Expert Review of Molecular Diagnostics
Dominik Domanski, Oliwia Zegrocka-Stendel, Anna Perzanowska, Malgorzata Dutkiewicz, Magdalena Kowalewska, Iwona Grabowska, Dorota Maciejko, Anna Fogtman, Michal Dadlez, Katarzyna Koziak
β-escin is a mixture of triterpene saponins isolated from the horse chestnut seeds (Aesculus hippocastanum L.). The anti-edematous, anti-inflammatory and venotonic properties of β-escin have been the most extensively clinically investigated effects of this plant-based drug and randomized controlled trials have proved the efficacy of β-escin for the treatment of chronic venous insufficiency. However, despite the clinical recognition of the drug its pharmacological mechanism of action still remains largely elusive...
2016: PloS One
A Brian Mochon, Den Sussland, Michael A Saubolle
The group of Gram-positive bacillary organisms broadly known as "aerobic actinomycetes" consists of heterogeneous and taxonomically divergent genera. They are found in a wide variety of natural and man-made environments but are rarely considered a part of the normal human flora, with infections normally originating from exogenous sources. An extensive number of genera have been described, but only a minority of these has been associated with human or veterinary health. The association with human disease is usually of an opportunistic nature, either through accidental means of inoculation or through involvement with immunocompromising conditions in the host...
August 2016: Microbiology Spectrum
Fred Saad, Mathieu Latour, Jean-Baptiste Lattouf, Hugues Widmer, Kevin C Zorn, Anne-Marie Mes-Masson, Veronique Ouellet, Genevieve Saad, Amol Prakash, Sibgat Choudhury, Gang Han, Pierre Karakiewicz, Jerome P Richie
PURPOSE: Current clinicopathologic parameters are insufficient to predict the likelihood of biochemical recurrence in patients with prostate cancer after radical prostatectomy. Such information may help to identify patients who would likely benefit from adjuvant radiotherapy rather than active surveillance. A multiplex proteomic assay, previously tested on biopsies and found to be predictive of favorable or unfavorable pathology at radical prostatectomy, was assessed for its predictive value to identify patients at higher risk of biochemical relapse...
October 7, 2016: Journal of Urology
Joelle M Fenger, Ryan D Roberts, O Hans Iwenofu, Misty D Bear, Xiaoli Zhang, Jason I Couto, Jaime F Modiano, William C Kisseberth, Cheryl A London
BACKGROUND: MicroRNAs (miRNAs) regulate the expression of networks of genes and their dysregulation is well documented in human malignancies; however, limited information exists regarding the impact of miRNAs on the development and progression of osteosarcoma (OS). Canine OS exhibits clinical and molecular features that closely resemble the corresponding human disease and it is considered a well-established spontaneous animal model to study OS biology. The purpose of this study was to investigate miRNA dysregulation in canine OS...
October 10, 2016: BMC Cancer
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