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Proteomic Profiling Of Serum Derived Exosomes From Prostate Cancer Patients, David Turay 2018 Selected Works

Proteomic Profiling Of Serum Derived Exosomes From Prostate Cancer Patients, David Turay

David Turay, MD

Touted among the major achievements in the diagnosis and management of Prostate cancer (PCa) in the past few decades has been, the dramatic decline of men with advanced/metastatic PCa at diagnosis coupled with a significant improvement ( >90%) in the five and ten year survival rates of the disease. Non-palpable PCa (potentially clinically treatable disease) now accounts for 70-80% of all newly diagnosed cases of PCa. Preceding these changes by about a decade was the introduction of Prostatic Specific Antigen (PSA) into clinical practice; first as biomarker for monitoring response to therapy and subsequently as a complementary screening tool. It ...


Interleukin-1 Receptor-Associated Kinase 4 (Irak4) Plays A Dual Role In Myddosome Formation And Toll-Like Receptor Signaling, Dominic De Nardo, Katherine R. Balka, Yamel Cardona Gloria, Vikram R. Rao, Eicke Latz, Seth L. Masters 2018 University of Melbourne

Interleukin-1 Receptor-Associated Kinase 4 (Irak4) Plays A Dual Role In Myddosome Formation And Toll-Like Receptor Signaling, Dominic De Nardo, Katherine R. Balka, Yamel Cardona Gloria, Vikram R. Rao, Eicke Latz, Seth L. Masters

Open Access Articles

Toll-like receptors (TLRs) form part of the host innate immune system, in which they act as sensors of microbial and endogenous danger signals. Upon TLR activation, the intracellular Toll/interleukin-1 receptor domains of TLR dimers initiate oligomerization of a multiprotein signaling platform comprising myeloid differentiation primary response 88 (MyD88) and members of the interleukin-1 receptor-associated kinase (IRAK) family. Formation of this myddosome complex initiates signal transduction pathways, leading to the activation of transcription factors and the production of inflammatory cytokines. To date, little is known about the assembly and disassembly of the myddosome and about the mechanisms by which these ...


Intestinal P-Glycoprotein Exports Endocannabinoids To Prevent Inflammation And Maintain Homeostasis, Rose L. Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, Christine Tuohy, Zachary Demma, Sage Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall J. Mrsny, Beth A. McCormick 2018 University of Massachusetts Medical School

Intestinal P-Glycoprotein Exports Endocannabinoids To Prevent Inflammation And Maintain Homeostasis, Rose L. Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, Christine Tuohy, Zachary Demma, Sage Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall J. Mrsny, Beth A. Mccormick

Open Access Articles

Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted ...


Identification Of A Novel Anoikis Signalling Pathway Using The Fungal Virulence Factor Gliotoxin, Florian Haun, Simon Neumann, Lukas Peintner, Katrin Wieland, Juri Habicht, Carsten Schwan, Kristine Ostevold, Maria Magdalena Koczorowska, Martin Biniossek, Matthias Kist, Hauke Busch, Melanie Boerries, Roger J. Davis, Ulrich Maurer, Oliver Schilling, Klaus Aktories, Christoph Borner 2018 Albert Ludwigs University

Identification Of A Novel Anoikis Signalling Pathway Using The Fungal Virulence Factor Gliotoxin, Florian Haun, Simon Neumann, Lukas Peintner, Katrin Wieland, Juri Habicht, Carsten Schwan, Kristine Ostevold, Maria Magdalena Koczorowska, Martin Biniossek, Matthias Kist, Hauke Busch, Melanie Boerries, Roger J. Davis, Ulrich Maurer, Oliver Schilling, Klaus Aktories, Christoph Borner

Open Access Articles

Anoikis is a form of apoptosis induced by cell detachment. Integrin inactivation plays a major role in the process but the exact signalling pathway is ill-defined. Here we identify an anoikis pathway using gliotoxin (GT), a virulence factor of the fungus Aspergillus fumigatus, which causes invasive aspergillosis in humans. GT prevents integrin binding to RGD-containing extracellular matrix components by covalently modifying cysteines in the binding pocket. As a consequence, focal adhesion kinase (FAK) is inhibited resulting in dephosphorylation of p190RhoGAP, allowing activation of RhoA. Sequential activation of ROCK, MKK4/MKK7 and JNK then triggers pro-apoptotic phosphorylation of Bim. Cells in ...


Select Gp120 V2 Domain Specific Antibodies Derived From Hiv And Siv Infection And Vaccination Inhibit Gp120 Binding To Alpha4beta7, Sakaorat Lertjuthaporn, Shan Lu, Yang Lou, Shixia Wang, James Arthos 2018 Mahidol University

Select Gp120 V2 Domain Specific Antibodies Derived From Hiv And Siv Infection And Vaccination Inhibit Gp120 Binding To Alpha4beta7, Sakaorat Lertjuthaporn, Shan Lu, Yang Lou, Shixia Wang, James Arthos

Open Access Articles

The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin alpha4beta7, a gut-homing receptor. Using both cell-surface expressed alpha4beta7 and a soluble alpha4beta7 heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of alpha4beta7 in a cation -sensitive manner and is inhibited ...


An Asymmetric Centromeric Nucleosome, Yuichi Ichikawa, Noriko Saitoh, Paul D. Kaufman 2018 University of Massachusetts Medical School

An Asymmetric Centromeric Nucleosome, Yuichi Ichikawa, Noriko Saitoh, Paul D. Kaufman

Open Access Articles

Nucleosomes contain two copies of each core histone, held together by a naturally symmetric, homodimeric histone H3-H3 interface. This symmetry has complicated efforts to determine the regulatory potential of this architecture. Through molecular design and in vivo selection, we recently generated obligately heterodimeric H3s, providing a powerful tool for discovery of the degree to which nucleosome symmetry regulates chromosomal functions in living cells (Ichikawa et al., 2017). We now have extended this tool to the centromeric H3 isoform (Cse4/CENP-A) in budding yeast. These studies indicate that a single Cse4 N- or C-terminal extension per pair of Cse4 molecules is ...


Modulating Viscoelasticity, Stiffness, And Degradation Of Synthetic Cellular Niches Via Stoichiometric Tuning Of Covalent Versus Dynamic Noncovalent Cross-Linking, Yu Tan, Henry Huang, David C. Ayers, Jie Song 2018 University of Massachusetts Medical School

Modulating Viscoelasticity, Stiffness, And Degradation Of Synthetic Cellular Niches Via Stoichiometric Tuning Of Covalent Versus Dynamic Noncovalent Cross-Linking, Yu Tan, Henry Huang, David C. Ayers, Jie Song

Open Access Articles

Viscoelasticity, stiffness, and degradation of tissue matrices regulate cell behavior, yet predictive synergistic tuning of these properties in synthetic cellular niches remains elusive. We hypothesize that reversible physical cross-linking can be quantitatively introduced to synthetic hydrogels to accelerate stress relaxation and enhance network stiffness, while strategic placement of isolated labile linkages near cross-linking sites can predict hydrogel degradation, both of which are essential for creating adaptive cellular niches. To test these hypotheses, chondrocytes were encapsulated in hydrogels formed by biorthogonal covalent and noncovalent physical cross-linking of a pair of hydrophilic building blocks. The stiffer and more viscoelastic hydrogels with DBCO-DBCO ...


Measurement And Protection Of Lung Health In Poultry Farmers Of Southwestern Ontario, Rose-Marie Doyon Dolinar 2018 The University of Western Ontario

Measurement And Protection Of Lung Health In Poultry Farmers Of Southwestern Ontario, Rose-Marie Doyon Dolinar

Electronic Thesis and Dissertation Repository

Chronic obstructive lung disease (COPD), develops gradually, and tends to be noticed by farmers only after there has been a significant loss of lung function. People with symptoms of COPD often present for health care in later stages of disease, because they accept cough or breathlessness as “normal”.

Measurement of lung health for those at risk of developing COPD provides an opportunity for early detection of lung disease, and deter the progression toward irreversible damage to the lungs. COPD is, however, under-diagnosed.

The importance of bringing primary care providers and farmers together, and acknowledging the high-risk nature of occupational exposures ...


Effects Of Reproductive Period Duration And Number Of Pregnancies On Midlife Ecg Indices: A Secondary Analysis From The Women's Health Initiative Clinical Trial, Nisha I. Parikh, Kristopher Kapphahn, Haley Hedlin, Jeffrey E. Olgin, Matthew A. Allison, Jared W. Magnani, Kelli R. Ryckman, Molly E. Waring, Marco Valentin Perez, Barbara V. Howard 2018 University of California, San Francisco

Effects Of Reproductive Period Duration And Number Of Pregnancies On Midlife Ecg Indices: A Secondary Analysis From The Women's Health Initiative Clinical Trial, Nisha I. Parikh, Kristopher Kapphahn, Haley Hedlin, Jeffrey E. Olgin, Matthew A. Allison, Jared W. Magnani, Kelli R. Ryckman, Molly E. Waring, Marco Valentin Perez, Barbara V. Howard

Open Access Articles

OBJECTIVES: Pregnancy, menses and menopause are related to fluctuations in endogenous sex hormones in women, which cumulatively may alter cardiac electrical conduction. Therefore, we sought to study the association between number of pregnancies and reproductive period duration (RD, time from menarche to menopause) with ECG intervals in the Women's Health Initiative Clinical Trials.

DESIGN: Secondary analysis of multicentre clinical trial.

SETTING: USA.

PRIMARY OUTCOME MEASURES: ECGintervals: PR interval, P-wave duration, P-wave dispersion, QTc interval.

PARTICIPANTS: n=40 687 women (mean age=62 years) participating in the Women's Health Initiative Clinical Trials. 82.5% were white, 9.3% black ...


Ripk1-Ripk3-Mlkl-Associated Necroptosis Drives Leishmania Infantum Killing In Neutrophils, Laiana A. Barbosa, Paloma P. Fiuza, Leticia J. Borges, Fellipe A. Rolim, Mayara B. Andrade, Nivea F. Luz, Graziele Quintela-Carvalho, Jonilson B. Lima, Roque P. Almeida, Francis Ka-Ming Chan, Marcelo T. Bozza, Valeria M. Borges, Deboraci B. Prates 2018 Federal University of Bahia

Ripk1-Ripk3-Mlkl-Associated Necroptosis Drives Leishmania Infantum Killing In Neutrophils, Laiana A. Barbosa, Paloma P. Fiuza, Leticia J. Borges, Fellipe A. Rolim, Mayara B. Andrade, Nivea F. Luz, Graziele Quintela-Carvalho, Jonilson B. Lima, Roque P. Almeida, Francis Ka-Ming Chan, Marcelo T. Bozza, Valeria M. Borges, Deboraci B. Prates

Open Access Articles

Necroptosis is a pro-inflammatory cell death, which happens in the context of caspase-8 inhibition, allowing activation of the receptor interacting protein kinase 1-receptor interacting protein kinase 3-mixed lineage kinase domain-like (RIPK1-RIPK3-MLKL) axis. Recently, necroptosis has emerged as a key component of resistance against pathogens including infected macrophage by Leishmania infantum, the ethiologic agent of Visceral leishmaniasis (VL). VL is the most severe form of Leishmaniasis, characterized by systemic inflammation and neutropenia. However, the role of neutrophil cell death in VL has not been characterized. Here, we showed that VL patients exhibited increased lactate dehydrogenase levels in the serum, a hallmark ...


Il-16/Mir-125a Axis Controls Neutrophil Recruitment In Pristane-Induced Lung Inflammation, Siobhan Smith, Hardy Kornfeld, Caroline A. Jefferies 2018 Royal College of Surgeons in Ireland

Il-16/Mir-125a Axis Controls Neutrophil Recruitment In Pristane-Induced Lung Inflammation, Siobhan Smith, Hardy Kornfeld, Caroline A. Jefferies

Open Access Articles

Severe lung inflammation and alveolar hemorrhage can be life-threatening in systemic lupus erythematosus (SLE) patients if not treated early and aggressively. Neutrophil influx is the driver key of this pathology, but little is known regarding the molecular events regulating this recruitment. Here, we uncover a role for IL-16/mir-125a in this pathology and show not only that IL-16 is a target for miR-125a but that reduced miR-125a expression in SLE patients associates with lung involvement. Furthermore, in the pristane model of acute "SLE-like" lung inflammation and alveolar hemorrhage, we observed reduced pulmonary miR-125a and enhanced IL-16 expression. Neutrophil infiltration was ...


A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder 2018 Mayo Clinic

A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder

Open Access Articles

Enterochromaffin (EC) cells constitute the largest population of intestinal epithelial enteroendocrine (EE) cells. EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion. However, it is unknown whether EE and EC cells are directly mechanosensitive, and if so, what the molecular mechanism of their mechanosensitivity is. Consequently, the role of EE and EC cells in gastrointestinal mechanobiology is unclear. Piezo2 mechanosensitive ion channels are important for some specialized epithelial mechanosensors, and they are expressed in mouse and human EC cells. Here, we use EC and EE cell ...


Are Membranes Non-Apoptotic Compartments For Apoptotic Caspases, Andreas Bergmann 2018 University of Massachusetts Medical School

Are Membranes Non-Apoptotic Compartments For Apoptotic Caspases, Andreas Bergmann

Open Access Articles

Critical mediators of apoptotic cell death are caspases, a highly specialized class of Cys-proteases that cleave substrates after Asp residues. Under normal conditions, caspases are cytosolic proteins. After their activation, they cleave a large number of cytosolic proteins and execute apoptosis (Figure 1, left). However, in addition to their well-studied role in apoptosis, caspases also have many non-apoptotic functions [1, 2]. It is not very well understood how cells escape the potential harmful action of caspases when they perform nonapoptotic functions. In our recent work, we now show that epithelial cells may prevent apoptosis by sequestration of caspases at the ...


Jnk Regulates Muscle Remodeling Via Myostatin/Smad Inhibition, Sarah J. Lessard, Tara L. MacDonald, Prerana Pathak, Myoung Souk Han, Vernon G. Coffey, Johann Edge, Donato A. Rivas, Michael F. Hirshman, Roger J. Davis, Laurie J. Goodyear 2018 Harvard Medical School

Jnk Regulates Muscle Remodeling Via Myostatin/Smad Inhibition, Sarah J. Lessard, Tara L. Macdonald, Prerana Pathak, Myoung Souk Han, Vernon G. Coffey, Johann Edge, Donato A. Rivas, Michael F. Hirshman, Roger J. Davis, Laurie J. Goodyear

Open Access Articles

Skeletal muscle has a remarkable plasticity to adapt and remodel in response to environmental cues, such as physical exercise. Endurance exercise stimulates improvements in muscle oxidative capacity, while resistance exercise induces muscle growth. Here we show that the c-Jun N-terminal kinase (JNK) is a molecular switch that when active, stimulates muscle fibers to grow, resulting in increased muscle mass. Conversely, when muscle JNK activation is suppressed, an alternative remodeling program is initiated, resulting in smaller, more oxidative muscle fibers, and enhanced aerobic fitness. When muscle is exposed to mechanical stress, JNK initiates muscle growth via phosphorylation of the transcription factor ...


Unfolded Protein Response Pathways In Skeletal Muscle Homeostasis., Kyle R. Bohnert 2018 University of Louisville

Unfolded Protein Response Pathways In Skeletal Muscle Homeostasis., Kyle R. Bohnert

Electronic Theses and Dissertations

Skeletal muscle mass, contractile properties, and metabolic function are regulated through the coordinated activation of multiple intracellular signaling pathways and genetic reprogramming. The endoplasmic reticulum (ER) plays a pivotal role in protein folding and calcium homeostasis in many cell types, including skeletal muscle. Disruption of calcium levels or accumulation of misfolded proteins in the ER lumen leads to stress, which results in the activation of a signaling network called the unfolded protein response (UPR). Further, recent studies have suggested that in certain conditions, UPR pathways can be activated independent of ER stress. However, the role of ER stress and the ...


Peptide Antigen Concentration Modulates Digital Nfat1 Activation In Primary Mouse Naive Cd8(+) T Cells As Measured By Flow Cytometry Of Isolated Cell Nuclei, Michael P. Gallagher, James M. Conley, Leslie J. Berg 2018 University of Massachusetts Medical School

Peptide Antigen Concentration Modulates Digital Nfat1 Activation In Primary Mouse Naive Cd8(+) T Cells As Measured By Flow Cytometry Of Isolated Cell Nuclei, Michael P. Gallagher, James M. Conley, Leslie J. Berg

Open Access Articles

Circulating naive T cells exist in a quiescent state. After TCR contact with the cognate peptide presented by APCs in secondary lymphoid structures, T cells undergo a period of rapid transcriptional changes that set the stage for fate-determining effector or memory programming. We describe a novel method to analyze TCR signaling pathway activation in nuclei isolated from primary mouse naive T cells after stimulation with natural peptide Ags. We prelabeled cells with cell tracking dye to easily distinguish CD8(+) T cell nuclei from APC nuclei by conventional flow cytometry. Using this approach, we observed clear digital activation of NFAT1 transcription ...


Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr. 2018 University of Mogi das Cruzes

Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr.

Open Access Articles

Cancer cachexia (CC) is a multifactorial syndrome with an unknown etiology. The primary symptom is the progressive reduction of the body weight. Recently, down-regulation of adipogenic and lipogenic genes were demonstrated to be early affected during cachexia progression in adipose tissue (AT), resulting in AT remodeling. Thus, this study aimed to evaluate in a co-culture system the influence of the Lewis Lung Carcinoma (LLC) tumor cells (c/c-LLC) in an established pre-adipocyte cell line 3T3-L1 adipogenic capacity. c/c-LLC in the presence of 3T3-L1 caused a reduction in lipids accumulation, suggesting that secretory tumor cells products may affect adipogenesis. Interestingly ...


Quantitative Profiling Of The Lymph Node Clearance Capacity, Cristina C. Clement, Wei Wang, Monika Dzieciatkowska, Marco Cortese, Kirk C. Hansen, Aniuska Becerra, Sangeetha Thangaswamy, Irina Nizamutdinova, Jee-Young Moon, Lawrence J. Stern, Anatoliy A. Gashev, David Zawieja, Laura Santambrogio 2018 Albert Einstein College of Medicine

Quantitative Profiling Of The Lymph Node Clearance Capacity, Cristina C. Clement, Wei Wang, Monika Dzieciatkowska, Marco Cortese, Kirk C. Hansen, Aniuska Becerra, Sangeetha Thangaswamy, Irina Nizamutdinova, Jee-Young Moon, Lawrence J. Stern, Anatoliy A. Gashev, David Zawieja, Laura Santambrogio

Open Access Articles

Transport of tissue-derived lymphatic fluid and clearance by draining lymph nodes are pivotal for maintenance of fluid homeostasis in the body and for immune-surveillance of the self- and non-self-proteomes. Yet a quantitative analysis of nodal filtration of the tissue-derived proteome present in lymphatic fluid has not been reported. Here we quantified the efficiency of nodal clearance of the composite proteomic load using label-free and isotope-labeling proteomic analysis of pre-nodal and post-nodal samples collected by direct cannulation. These results were extended by quantitation of the filtration efficiency of fluorophore-labeled proteins, bacteria, and beads infused at physiological flow rates into pre-nodal lymphatic ...


Primary Cardiac Lymphoma: Importance Of Tissue Diagnosis, Lauren Mendelson, Emily Hsu, Hojune Chung, Andrew Hsu 2018 University of Massachusetts Medical School

Primary Cardiac Lymphoma: Importance Of Tissue Diagnosis, Lauren Mendelson, Emily Hsu, Hojune Chung, Andrew Hsu

Open Access Articles

Primary cardiac lymphoma (PCL) is a rare disease entity that can present with severe cardiac and cardioembolic symptoms. We present a 79-year-old male with history of polymalgia rheumatica on chronic prednisone who presented with a two-week history of progressively worsening dyspnea, cough, and a 10 pound weight loss. Transthoracic echocardiogram (TTE) and computed tomography (CT) of the chest showed a large mediastinal mass with invasion of the pericardium. A biopsy of an abdominal soft-tissue mass confirmed the diagnosis of PCL. The patient was treated with two cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) which was complicated by ...


Neurexin Directs Partner-Specific Synaptic Connectivity In C. Elegans, Alison Philbrook, Shankar Ramachandran, Christopher M. Lambert, Devyn Oliver, Jeremy Florman, Mark J. Alkema, Michele Lemons, Michael M. Francis 2018 University of Massachusetts Medical School

Neurexin Directs Partner-Specific Synaptic Connectivity In C. Elegans, Alison Philbrook, Shankar Ramachandran, Christopher M. Lambert, Devyn Oliver, Jeremy Florman, Mark J. Alkema, Michele Lemons, Michael M. Francis

Open Access Articles

In neural circuits, individual neurons often make projections onto multiple postsynaptic partners. Here, we investigate molecular mechanisms by which these divergent connections are generated, using dyadic synapses in C. elegans as a model. We report that C. elegans nrx-1/neurexin directs divergent connectivity through differential actions at synapses with partnering neurons and muscles. We show that cholinergic outputs onto neurons are, unexpectedly, located at previously undefined spine-like protrusions from GABAergic dendrites. Both these spine-like features and cholinergic receptor clustering are strikingly disrupted in the absence of nrx-1. Excitatory transmission onto GABAergic neurons, but not neuromuscular transmission, is also disrupted. Our ...


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