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Modification of lipid rafts by extracellular vesicles carrying HIV-1 protein Nef induces redistribution of APP and Tau causing neuronal dysfunction.

Michael Ditiatkovski, Nigora Mukhamedova, Dragana Dragoljevic, Anh Hoang, Hann Low, Tatiana Pushkarsky, Ying Fu, Irena Carmichael, Andrew F Hill, Andrew J Murphy, Michael Bukrinsky, Dmitri Sviridov,

HIV-associated neurocognitive disorders (HAND) are a frequent outcome of HIV infection. Effective treatment of HIV infection has reduced the rate of progression and severity, but not the overall prevalence of HAND, suggesting ongoing pathological process even when viral replication is supressed. In this study, we investigated how HIV-1 protein Nef ... Read more >>

J. Biol. Chem. (The Journal of biological chemistry)
[2020, :]

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Pancreaticoduodenectomy for the treatment of pancreatic neoplasms in children: A Pediatric Surgical Oncology Research Collaborative study.

Sanjeev A Vasudevan, Tu-Anh N Ha, Huirong Zhu, Todd E Heaton, Michael P LaQuaglia, Joseph T Murphy, Wesley E Barry, Catherine Goodhue, Eugene S Kim, Jennifer H Aldrink, Stephanie F Polites, Harold J Leraas, Henry E Rice, Elisabeth T Tracy, Timothy B Lautz, Riccardo A Superina, Andrew M Davidoff, Max R Langham, Andrew J Murphy, Andreana Bütter, Jacob Davidson, Richard D Glick, James Grijalva, Kenneth W Gow, Peter F Ehrlich, Erika A Newman, Dave R Lal, Marcus M Malek, Annie Le-Nguyen, Nelson Piché, David H Rothstein, Scott S Short, Rebecka Meyers, Roshni Dasgupta,

BACKGROUND:To better characterize short-term and long-term outcomes in children with pancreatic tumors treated with pancreaticoduodenectomy (PD). METHODS:Patients 21 years of age or younger who underwent PD at Pediatric Surgical Oncology Collaborative (PSORC) hospitals between 1990 and 2017 were identified. Demographic, clinical information, and outcomes (operative complications, long-term pancreatic function, recurrence, ... Read more >>

Pediatr Blood Cancer (Pediatric blood & cancer)
[2020, :e28425]

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Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses.

Asiel A Benitez, Sara Khalil-Agüero, Anjali Nandakumar, Namita T Gupta, Wen Zhang, Gurinder S Atwal, Andrew J Murphy, Matthew A Sleeman, Sokol Haxhinasto,

The endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. ... Read more >>

Commun Biol (Communications biology)
[2020, 3(1):355]

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Activin A does not drive post-traumatic heterotopic ossification.

Charles Hwang, Chase A Pagani, Nanditha Das, Simone Marini, Amanda K Huber, LiQin Xie, Johanna Jimenez, Susannah Brydges, Wei Keat Lim, Kalyan C Nannuru, Andrew J Murphy, Aris N Economides, Sarah J Hatsell, Benjamin Levi,

Heterotopic ossification (HO), the formation of ectopic bone in soft tissues, has been extensively studied in its two primary forms: post-traumatic HO (tHO) typically found in patients who have experienced musculoskeletal or neurogenic injury and in fibrodysplasia ossificans progressiva (FOP), where it is genetically driven. Given that in both diseases ... Read more >>

Bone (Bone)
[2020, 138:115473]

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XAF1 as a modifier of p53 function and cancer susceptibility.

Emilia M Pinto, Bonald C Figueiredo, Wenan Chen, Henrique C R Galvao, Maria Nirvana Formiga, Maria Candida B V Fragoso, Patricia Ashton-Prolla, Enilze M S F Ribeiro, Gabriela Felix, Tatiana E B Costa, Sharon A Savage, Meredith Yeager, Edenir I Palmero, Sahlua Volc, Hector Salvador, Jose Luis Fuster-Soler, Cinzia Lavarino, Guillermo Chantada, Dominique Vaur, Vicente Odone-Filho, Laurence Brugières, Tobias Else, Elena M Stoffel, Kara N Maxwell, Maria Isabel Achatz, Luis Kowalski, Kelvin C de Andrade, Alberto Pappo, Eric Letouze, Ana Claudia Latronico, Berenice B Mendonca, Madson Q Almeida, Vania B Brondani, Camila M Bittar, Emerson W S Soares, Carolina Mathias, Cintia R N Ramos, Moara Machado, Weiyin Zhou, Kristine Jones, Aurelie Vogt, Payal P Klincha, Karina M Santiago, Heloisa Komechen, Mariana M Paraizo, Ivy Z S Parise, Kayla V Hamilton, Jinling Wang, Evadnie Rampersaud, Michael R Clay, Andrew J Murphy, Enzo Lalli, Kim E Nichols, Raul C Ribeiro, Carlos Rodriguez-Galindo, Marta Korbonits, Jinghui Zhang, Mark G Thomas, Jon P Connelly, Shondra Pruett-Miller, Yoan Diekmann, Geoffrey Neale, Gang Wu, Gerard P Zambetti,

Cancer risk is highly variable in carriers of the common TP53-R337H founder allele, possibly due to the influence of modifier genes. Whole-genome sequencing identified a variant in the tumor suppressor XAF1 (E134*/Glu134Ter/rs146752602) in a subset of R337H carriers. Haplotype-defining variants were verified in 203 patients with cancer, 582 relatives, and ... Read more >>

Sci Adv (Science advances)
[2020, 6(26):eaba3231]

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Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies.

Alina Baum, Benjamin O Fulton, Elzbieta Wloga, Richard Copin, Kristen E Pascal, Vincenzo Russo, Stephanie Giordano, Kathryn Lanza, Nicole Negron, Min Ni, Yi Wei, Gurinder S Atwal, Andrew J Murphy, Neil Stahl, George D Yancopoulos, Christos A Kyratsous,

Antibodies targeting the spike protein of SARS-CoV-2 present a promising approach to combat the COVID19 pandemic; however, concerns remain that mutations can yield antibody resistance. We investigate the development of resistance against four antibodies to the spike protein that potently neutralize SARS-CoV-2, individually as well as when combined into cocktails. ... Read more >>

Science (Science (New York, N.Y.))
[2020, :]

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Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis.

Michelle C Flynn, Michael J Kraakman, Christos Tikellis, Man Ks Lee, Nordin Mj Hanssen, Helene L Kammoun, Raelene Pickering, Dragana Dragoljevic, Annas Al-Sharea, Tessa J Barrett, Fiona Hortle, Frances L Byrne, Ellen Olzomer, Domenica A McCarthy, Casper G Schalkwijk, Josephine M Forbes, Kyle Hoehn, Liza Makowski, Graeme I Lancaster, Assam El-Osta, Edward A Fisher, Ira J Goldberg, Mark E Cooper, Prabhakara R Nagareddy, Merlin C Thomas, Andrew J Murphy,

Rationale: Treatment efficacy for diabetes is largely determined by assessment of HbA1c levels, which poorly reflects direct glucose variation. People with pre-diabetes and diabetes spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH) appear to be an independent risk-factor for cardiovascular ... Read more >>

Circ. Res. (Circulation research)
[2020, :]

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Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop.

Senem Aykul, Richard A Corpina, Erich J Goebel, Camille J Cunanan, Alexandra Dimitriou, Hyon Jong Kim, Qian Zhang, Ashique Rafique, Raymond Leidich, Xin Wang, Joyce McClain, Johanna Jimenez, Kalyan C Nannuru, Nyanza J Rothman, John B Lees-Shepard, Erik Martinez-Hackert, Andrew J Murphy, Thomas B Thompson, Aris N Economides, Vincent Idone,

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC). Although the former property has been studied extensively, the roles of the NSC remain unexplored. The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a ... Read more >>

Elife (eLife)
[2020, 9:]

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Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy.

Janelle C Waite, Bei Wang, Lauric Haber, Aynur Hermann, Erica Ullman, Xuan Ye, Drew Dudgeon, Rabih Slim, Dharani K Ajithdoss, Stephen J Godin, Ilyssa Ramos, Qi Wu, Erin Oswald, Patrick Poon, Jacquelynn Golubov, Devon Grote, Jennifer Stella, Arpita Pawashe, Jennifer Finney, Evan Herlihy, Hassan Ahmed, Vishal Kamat, Amanda Dorvilliers, Elizabeth Navarro, Jenny Xiao, Julie Kim, Shao Ning Yang, Jacqueline Warsaw, Clarissa Lett, Lauren Canova, Teresa Schulenburg, Randi Foster, Pamela Krueger, Elena Garnova, Ashique Rafique, Robert Babb, Gang Chen, Nicole Stokes Oristian, Chia-Jen Siao, Christopher Daly, Cagan Gurer, Joel Martin, Lynn Macdonald, Douglas MacDonald, William Poueymirou, Eric Smith, Israel Lowy, Gavin Thurston, William Olson, John C Lin, Matthew A Sleeman, George D Yancopoulos, Andrew J Murphy, Dimitris Skokos,

Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti-PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T ... Read more >>

Sci Transl Med (Science translational medicine)
[2020, 12(549):]

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Attack of the NETs! NETosis primes IL-1β-mediated inflammation in diabetic foot ulcers.

Man K S Lee, Gopalkrishna Sreejit, Prabhakara R Nagareddy, Andrew J Murphy,

In volume 133 issue 4 of Clinical Science, Liu et al. showed that neutrophils release extracellular traps (NETs) in the setting of diabetes which acts as a stimulus for NLRP3 inflammasome activation in macrophages to promote IL1β-dependent exacerbation of inflammation. They also provide evidence to show that degrading NETs improves ... Read more >>

Clin. Sci. (Clinical science (London, England : 1979))
[2020, 134(12):1399-1401]

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Incidence of and risk factors for late cholecystectomy in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Bryan V Dieffenbach, Nan Li, Arin L Madenci, Andrew J Murphy, Dana Barnea, Todd M Gibson, Emily S Tonorezos, Wendy M Leisenring, Rebecca M Howell, Lisa R Diller, Qi Liu, Eric J Chow, Gregory T Armstrong, Yutaka Yasui, Kevin C Oeffinger, Christopher B Weldon, Brent R Weil,

BACKGROUND:Gallbladder disease and need for cholecystectomy are common and significant contributors to patient morbidity and healthcare costs. Childhood cancer survivors are at elevated risk for developing cholelithiasis. However, their incidence of and risk factors for late (>5 years from diagnosis) cholecystectomy have not been studied. METHODS:A total of 25,549 survivors ... Read more >>

Eur. J. Cancer (European journal of cancer (Oxford, England : 1990))
[2020, 133:4-13]

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S100 family proteins in inflammation and beyond.

Gopalkrishna Sreejit, Michelle C Flynn, Mallikarjun Patil, Prasanna Krishnamurthy, Andrew J Murphy, Prabhakara R Nagareddy,

The S100 family proteins possess a variety of intracellular and extracellular functions. They interact with multiple receptors and signal transducers to regulate pathways that govern inflammation, cell differentiation, proliferation, energy metabolism, apoptosis, calcium homeostasis, cell cytoskeleton and microbial resistance. S100 proteins are also emerging as novel diagnostic markers for identifying ... Read more >>

Adv Clin Chem (Advances in clinical chemistry)
[2020, 98:173-231]

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Single-site retroperitoneoscopy in pediatric metastatic lymphadenopathy.

Yousef El-Gohary, Sara Mansfield, Lindsay Talbot, Andrew J Murphy, Andrew M Davidoff, Abdelhafeez Abdelhafeez,

Retroperitoneoscopic surgery (RS) is increasingly used for the diagnosis, staging, and treatment of solid tumors, but rarely in pediatric surgical oncology for retroperitoneal lymph node dissection (RPLND). Herein, we use single-site RS for RPLND in children and compare the perioperative outcomes with those for the transperitoneal laparoscopic approach (TPLA). A ... Read more >>

J. Pediatr. Surg. (Journal of pediatric surgery)
[2020, :]

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Alternative approaches to retroperitoneal lymph node dissection for paratesticular rhabdomyosarcoma.

Sara A Mansfield, Andrew J Murphy, Lindsay Talbot, Hasmukh Prajapati, Vinod Maller, Alberto Pappo, Sunil Singhal, Matthew J Krasin, Andrew M Davidoff, Abdelhafeez Abdelhafeez,

PURPOSE:The aim of this study was to evaluate outcomes based on surgical approach for retroperitoneal lymph node dissection (RPLND) in patients with paratesticular rhabdomyosarcoma (PT-RMS). METHODS:Patients undergoing RPLND for PT-RMS over 10 years at a single institution were retrospectively reviewed. Length of stay (LOS), complications, oral morphine equivalents per kilogram (OME/Kg), ... Read more >>

J. Pediatr. Surg. (Journal of pediatric surgery)
[2020, :]

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Combined reduction in the expression of MCL-1 and BCL-2 reduces organismal size in mice.

Francine Ke, Graeme I Lancaster, Stephanie Grabow, Andrew J Murphy, Andreas Strasser,

The intrinsic apoptotic pathway is controlled by the BCL-2 family of proteins, which exhibit either a pro-death or pro-survival function. Gene knockout studies revealed that different pro-survival BCL-2 proteins are critical for the survival of distinct cell types, although overlapping functions amongst such proteins have also been identified. In the ... Read more >>

Cell Death Dis (Cell death & disease)
[2020, 11(3):185]

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Pneumonectomy for Pediatric Tumors-a Pediatric Surgical Oncology Research Collaborative Study.

Stephanie F Polites, Todd E Heaton, Michael P LaQuaglia, Eugene S Kim, Wesley E Barry, Catherine J Goodhue, Andrew J Murphy, Andrew M Davidoff, Max R Langham, Rebecka L Meyers, Scott S Short, Timothy B Lautz, Richard D Glick, Sanjeev A Vasudevan, Christina M Bence, Dave R Lal, Reto M Baertschiger, Bryanna Emr, Marcus M Malek, Roshni Dasgupta,

OBJECTIVE:To describe utilization and long-term outcomes of pneumonectomy in children and adolescents with cancer. SUMMARY BACKGROUND DATA:Pneumonectomy in adults is associated with significant morbidity and mortality. Little is known about the indications and outcomes of pneumonectomy for pediatric tumors. METHODS:The Pediatric Surgical Oncology Research Collaborative (PSORC) identified pediatric patients <21 ... Read more >>

Ann. Surg. (Annals of surgery)
[2020, :]

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Interplay between Clonal Hematopoiesis of Indeterminate Potential and Metabolism.

Man K S Lee, Dragana Dragoljevic, Camilla Bertuzzo Veiga, Nan Wang, Laurent Yvan-Charvet, Andrew J Murphy,

Clonal hematopoiesis of indeterminate potential (CHIP), defined as a clone of hematopoietic cells consisting of a single acquired mutation during a lifetime, has recently been discovered to be a major risk factor for atherosclerotic cardiovascular disease (CVD). As such, this phenomenon has sparked interest into the role that these single ... Read more >>

Trends Endocrinol. Metab. (Trends in endocrinology and metabolism: TEM)
[2020, 31(7):525-535]

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The anti-IgE mAb omalizumab induces adverse reactions by engaging Fcγ receptors.

Bianca Balbino, Pauline Herviou, Ophélie Godon, Julien Stackowicz, Odile Richard-Le Goff, Bruno Iannascoli, Delphine Sterlin, Sébastien Brûlé, Gael A Millot, Faith M Harris, Vera A Voronina, Kari C Nadeau, Lynn E Macdonald, Andrew J Murphy, Pierre Bruhns, Laurent L Reber,

Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are ... Read more >>

J. Clin. Invest. (The Journal of clinical investigation)
[2020, 130(3):1330-1335]

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Splenic function is not maintained long-term after partial splenectomy in children with sickle cell disease.

Yousef El-Gohary, Sidrah Khan, Erica Hodgman, Lynn Wynn, Amy Kimble, Abdelhafeez Abdelhafeez, Lindsay Talbot, Winfred Wang, Andrew M Davidoff, Andrew J Murphy,

BACKGROUND:Partial splenectomy (PS) may allow preservation of splenic function in cases where splenectomy is indicated for hematologic diseases; however, the long-term outcomes are uncertain. We investigated the long-term outcomes of PS in patients with sickle cell disease (SCD). METHODS:A single-institution retrospective chart review was performed for children with SCD who ... Read more >>

J. Pediatr. Surg. (Journal of pediatric surgery)
[2020, :]

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Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation.

Audrey Le Floc'h, Jeanne Allinne, Kirsten Nagashima, George Scott, Dylan Birchard, Seblewongel Asrat, Yu Bai, Wei Keat Lim, Joel Martin, Tammy Huang, Terra B Potocky, Jee H Kim, Ashique Rafique, Nicholas J Papadopoulos, Neil Stahl, George D Yancopoulos, Andrew J Murphy, Matthew A Sleeman, Jamie M Orengo,

BACKGROUND:Dupilumab, a fully human monoclonal antibody that binds IL-4Rα and inhibits signaling of both IL-4 and IL-13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis, and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis ... Read more >>

Allergy (Allergy)
[2020, 75(5):1188-1204]

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Kappa-on-Heavy (KoH) bodies are a distinct class of fully-human antibody-like therapeutic agents with antigen-binding properties.

Lynn E Macdonald, Karoline A Meagher, Matthew C Franklin, Natasha Levenkova, Johanna Hansen, Ashok T Badithe, Maggie Zhong, Pamela Krueger, Ashique Rafique, Naxin Tu, James Shevchuk, Saurabh Wadhwa, George Ehrlich, Joannie Bautista, Craig Grant, Lakeisha Esau, William T Poueymirou, Wojtek Auerbach, Lori Morton, Robert Babb, Gang Chen, Tammy Huang, Douglas MacDonald, Kenneth Graham, Cagan Gurer, Vera A Voronina, John R McWhirter, Chunguang Guo, George D Yancopoulos, Andrew J Murphy,

We describe a Kappa-on-Heavy (KoH) mouse that produces a class of highly diverse, fully human, antibody-like agents. This mouse was made by replacing the germline variable sequences of both the Ig heavy-chain (IgH) and Ig kappa (IgK) loci with the human IgK germline variable sequences, producing antibody-like molecules with an ... Read more >>

Proc. Natl. Acad. Sci. U.S.A. (Proceedings of the National Academy of Sciences of the United States of America)
[2020, 117(1):292-299]

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A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies.

Dimitris Skokos, Janelle C Waite, Lauric Haber, Alison Crawford, Aynur Hermann, Erica Ullman, Rabih Slim, Stephen Godin, Dharani Ajithdoss, Xuan Ye, Bei Wang, Qi Wu, Ilyssa Ramos, Arpita Pawashe, Lauren Canova, Kristin Vazzana, Priyanka Ram, Evan Herlihy, Hassan Ahmed, Erin Oswald, Jacquelynn Golubov, Patrick Poon, Lauren Havel, Danica Chiu, Miguel Lazo, Kathleen Provoncha, Kevin Yu, Julie Kim, Jacqueline J Warsaw, Nicole Stokes Oristian, Chia-Jen Siao, Drew Dudgeon, Tammy Huang, Terra Potocky, Joel Martin, Douglas MacDonald, Adelekan Oyejide, Ashique Rafique, William Poueymirou, Jessica R Kirshner, Eric Smith, William Olson, John Lin, Gavin Thurston, Matthew A Sleeman, Andrew J Murphy, George D Yancopoulos,

T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide-major histocompatibility complexes ("signal 1"); activation is enhanced by engagement of a second "costimulatory" receptor, such as the CD28 receptor on T cells binding to its cognate ligand(s) on the target cell ("signal 2"). CD3-based ... Read more >>

Sci Transl Med (Science translational medicine)
[2020, 12(525):]

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Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction.

Gopalkrishna Sreejit, Ahmed Abdel-Latif, Baskaran Athmanathan, Rahul Annabathula, Ashish Dhyani, Sunil K Noothi, Gregory A Quaife-Ryan, Annas Al-Sharea, Gerard Pernes, Dragana Dragoljevic, Hind Lal, Kate Schroder, Beatriz Y Hanaoka, Chander Raman, Maria B Grant, James E Hudson, Susan S Smyth, Enzo R Porrello, Andrew J Murphy, Prabhakara R Nagareddy,

BACKGROUND:Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear. METHODS:Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial ... Read more >>

Circulation (Circulation)
[2020, 141(13):1080-1094]

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Chronic allergen exposure drives accumulation of long-lived IgE plasma cells in the bone marrow, giving rise to serological memory.

Seblewongel Asrat, Navneet Kaur, Xia Liu, Li-Hong Ben, Daisuke Kajimura, Andrew J Murphy, Matthew A Sleeman, Andre Limnander, Jamie M Orengo,

Immunoglobulin E (IgE) plays an important role in allergic diseases. Nevertheless, the source of IgE serological memory remains controversial. We reexamined the mechanism of serological memory in allergy using a dual reporter system to track IgE+ plasma cells in mice. Short-term allergen exposure resulted in the generation of IgE+ plasma ... Read more >>

Sci Immunol (Science immunology)
[2020, 5(43):]

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Management of pancreatic pseudocysts in pediatric oncology patients.

Yousef El-Gohary, Sara Mansfield, Jessica Staszak, Abdelhafeez Abdelhafeez, Lindsay Talbot, Ching-Hon Pui, Robert Gold, Andrew J Murphy, Andrew M Davidoff,

BACKGROUND:Management of children with pancreatic pseudocysts has historically been adopted from the adult experience where pancreatic pseudocysts greater than 6 cm are unlikely to resolve without intervention. We reviewed the clinical course of pediatric oncology patients with pancreatic pseudocysts. METHODS:A retrospective review of patients treated over a 15-year period was performed. ... Read more >>

J. Pediatr. Surg. (Journal of pediatric surgery)
[2019, :]

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