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American Journal of Pathology

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https://www.readbyqxmd.com/read/28739343/inhibition-of-cell-apoptosis-and-amelioration-of-pulmonary-fibrosis-by-thrombomodulin
#1
Kentaro Fujiwara, Tetsu Kobayashi, Hajime Fujimoto, Hiroki Nakahara, Corina N D'Alessandro-Gabazza, Josephine A Hinneh, Yoshinori Takahashi, Taro Yasuma, Kota Nishihama, Masaaki Toda, Masahiro Kajiki, Yoshiyuki Takei, Osamu Taguchi, Esteban C Gabazza
Pulmonary fibrosis is the terminal stage of a group of idiopathic interstitial pneumonias, of which idiopathic pulmonary fibrosis is the most frequent and fatal form. Recent studies have shown that recombinant human thrombomodulin improves exacerbation and clinical outcome of idiopathic pulmonary fibrosis, but the mechanism remains unknown. This study evaluated the mechanistic pathways of the inhibitory activity of recombinant human thrombomodulin in pulmonary fibrosis. Transgenic mice overexpressing human transforming growth factor β1 that develop spontaneously pulmonary fibrosis and wild-type mice treated with bleomycin were used as model of lung fibrosis...
July 21, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28739342/a-pro-inflammatory-function-of-toll-like-receptor-2-in-the-retinal-pigment-epithelium-as-a-novel-target-for-reducing-choroidal-neovascularization-in-age-related-macular-degeneration
#2
Lili Feng, Meihua Ju, Kei Ying Vivian Lee, Ashley Mackey, Mariasilvia Evangelista, Daiju Iwata, Peter Adamson, Kameran Lashkari, Richard Foxton, David Shima, Yin Shan Ng
Current treatments for choroidal neovascularization, a major cause of blindness for patients with age-related macular degeneration, treat symptoms but not the underlying causes of the disease. Inflammation has been strongly implicated in the pathogenesis of choroidal neovascularization. We examined the inflammatory role of toll-like receptor 2 (TLR2) in age-related macular degeneration. TLR2 was robustly expressed by the retinal pigment epithelium in mouse and human eyes, both normal and with macular degeneration/choroidal neovascularization...
July 21, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28736317/next-generation-proteomics-and-its-application-to-clinical-breast-cancer-research
#3
REVIEW
Mariya Mardamshina, Tamar Geiger
Proteomics technology aims to map the protein landscapes of biological samples, and can be applied to a variety of samples, including cells, tissues, and body fluids. As the proteins are the main functional molecules in the cells, their levels reflect much more accurately the cellular phenotype and the regulatory processes within them than gene levels, mutations, and even mRNA levels. With the advancement in the technology, it is possible nowadays to obtain comprehensive views of the biological systems, and study large patient cohorts in a streamlined manner...
July 20, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28736316/early-actions-of-anti-vascular-endothelial-growth-factor-vascular-endothelial-growth-factor-receptor-drugs-on-angiogenic-blood-vessels
#4
Basel Sitohy, Sunghee Chang, Tracey E Sciuto, Elizabeth Masse, Mei Shen, Peter M Kang, Shou-Ching Jaminet, Laura E Benjamin, Rupal S Bhatt, Ann M Dvorak, Janice A Nagy, Harold F Dvorak
Tumors induce their heterogeneous vasculature by secreting vascular endothelial growth factor (VEGF)-A. Anti-VEGF/VEGF receptor (VEGFR) drugs may treat cancer but the underlying mechanisms remain unclear. An adenovirus expressing VEGF-A (Ad-VEGF-A(164)) replicates the tumor vasculature in mice without tumor cells. Mother vessels (MV) are the first angiogenic vessel type to form in tumors and following Ad-VEGF-A(164). Multiday treatments with a VEGF trap reverted MV back to normal microvessels. We now show that, within hours, a single dose of several anti-VEGF drugs collapsed MV to form glomeruloid microvascular proliferations (GMP), accompanied by only modest endothelial cell death...
July 20, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28736315/the-spectrum-of-triple-negative-breast-disease-high-and-low-grade-lesions
#5
REVIEW
Felipe C Geyer, Fresia Pareja, Britta Weigelt, Emad Rakha, Ian O Ellis, Stuart J Schnitt, Jorge S Reis-Filho
Triple-negative breast cancer is viewed clinically as an aggressive subgroup of breast cancer. In fact, the majority of triple-negative breast cancers are poor-prognosis tumors with a complex genomic landscape. However, triple-negative disease is vastly heterogeneous, encompassing multiple entities with marked genetic, transcriptional, histological, and clinical differences, with neoplasms in this group ranging from low- to high-grade. Among the less common low-grade triple-negative lesions, two large subgroups, both with a rather indolent behavior, can be distinguished: a low-grade triple-negative breast neoplasia family, which includes nonobligate precursors of triple-negative breast cancer, and, despite being low-grade, harbor the complex genomic landscape of usual triple-negative breast cancer, and the salivary gland-like tumors of the breast, lacking all of the cardinal molecular features of conventional triple-negative breast cancer and underpinned by specific fusion-genes or hotspot mutations, which may be of diagnostic and possibly therapeutic utility...
July 20, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28734730/multifaceted-c-x-c-chemokine-receptor-4-inhibition-interferes-with-anti-vascular-endothelial-growth-factor-therapy-induced-glioma-dissemination
#6
Jean-Pierre Gagner, Yasmeen Sarfraz, Valerio Ortenzi, Fawaz M Alotaibi, Luis A Chiriboga, Awab T Tayyib, Garry J Douglas, Eric Chevalier, Barbara Romagnoli, Gérald Tuffin, Michel Schmitt, Guillaume Lemercier, Klaus Dembowsky, David Zagzag
Resistance to antiangiogenic therapy glioblastoma (GBM) patients may involve hypoxia-induced expression of stromal cell-derived factor (SDF)-1α receptor C-X-C chemokine receptor 4 (CXCR4) on invading tumor, macrophage/microglial cells (MGCs), and glioma stem cells (GSCs). We determined whether antagonizing CXCR4 with peptide epitope mimetic POL5551 disrupts anti-vascular endothelial growth factor therapy-induced glioma growth and dissemination. Mice bearing orthotopic CT-2A or GL261 gliomas received POL5551 and/or anti-vascular endothelial growth factor antibody B20-4...
July 20, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28734947/platelet-derived-growth-factor-receptor-alpha-contributes-to-human-hepatic-stellate-cell-proliferation-and-migration
#7
Alexander Kikuchi, Tirthadipa Pradhan-Sundd, Sucha Singh, Shanmugam Nagarajan, Nick Loizos, Satdarshan Monga
Platelet-derived growth factor receptor alpha (PDGFRα), a tyrosine kinase receptor, is up-regulated in hepatic stellate cells (HSCs) during chronic liver injury. HSCs mediate hepatic fibrosis through their activation from a quiescent state partially in response to pro-fibrotic growth factors. HSC activation entails enhanced expression of pro-fibrotic genes, increase in proliferation, and increase in motility, which facilitates migration within the hepatic lobule. We show co-localization of PDGFRα in murine carbon tetrachloride, bile duct ligation (BDL), and 0...
July 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28734946/impaired-rhodopsin-generation-in-the-rat-model-of-diabetic-retinopathy
#8
Volha V Malechka, Gennadiy Moiseyev, Yusuke Takahashi, Younghwa Shin, Jian-Xing Ma
Diabetic retinopathy is a common complication of diabetes mellitus. Diabetic patients experience functional deficits in dark adaptation, contrast sensitivity, and color perception before microvascular pathologies become apparent. Here, we evaluated early changes in neural retinal function and in retinoid metabolism in the eye in diabetes. Streptozotocin-induced diabetic rats showed decreased a-wave and b-wave amplitudes of scotopic and photopic electroretinography responses four months after diabetes induction compared to nondiabetic controls...
July 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28734945/the-epigenomic-revolution-in-breast-cancer-from-single-gene-to-genome-wide-next-generation-approaches
#9
REVIEW
Veronica Davalos, Anna Martinez-Cardus, Manel Esteller
From the first identification of aberrant DNA methylation in primary human tumors more than three decades ago, exponential progress in cancer epigenetics research has been made. For many years, cancer epigenetics studies relied on identification of DNA methylation and histone modifications at specific genes. These studies laid the foundation for the field and revealed the epigenetic alterations as hallmark of cancer, as well as the crucial role of epigenetic mechanisms in tumorigenesis. The introduction of next-generation sequencing and array-based technologies for analyzing epigenetic states has accelerated our understanding about cancer and nowadays have become potent tools in our fight against the disease...
July 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28734944/triple-negative-breast-cancer-next-generation-sequencing-for-target-identification
#10
REVIEW
Jonathan D Marotti, Francine B de Abreu, Wendy A Wells, Gregory J Tsongalis
Our ability to now study disease at the most fundamental molecular level has led to a reclassification of human cancers into numerous subtypes that vary in disease progression and response to therapy. Like most solid tumors, breast cancer is a heterogeneous disease with considerable variation in histological and biological features. Triple negative breast cancer (TNBC) is a subtype of breast cancer in which estrogen receptor and progesterone receptor are not expressed, and human epidermal growth factor receptor 2 is not amplified or overexpressed...
July 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28734943/deficits-in-col5a2-expression-result-in-novel-skin-and-adipose-abnormalities-and-predisposition-to-aortic-aneurysms-and-dissections
#11
Arick C Park, Noel Phan, Dawiyat Massoudi, Zhenjie Liu, John F Kernien, Sheila M Adams, Jeffrey M Davidson, David E Birk, Bo Liu, Daniel S Greenspan
Classic Ehlers-Danlos syndrome (cEDS) is characterized by fragile, hyperextensible skin and hypermobile joints. cEDS can be caused by heterozygosity for missense mutations in genes COL5A2 and COL5A1, which encode the α2(V) and α1(V) chains, respectively, of collagen V, and is most often caused by COL5A1 null alleles. However, COL5A2 null alleles have yet to be associated with cEDS or other human pathologies. We previously showed that mice homozygous null for the α2(V) gene Col5a2 are early embryonic lethal, whereas haploinsufficiency caused aberrancies of adult skin, but not a frank cEDS-like phenotype, as skin hyperextensibility at low strain and dermal "cauliflower"-contoured collagen fibril aggregates, two cEDS hallmarks, were absent...
July 19, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28733195/the-evolving-role-of-companion-diagnostics-for-breast-cancer-in-an-era-of-next-generation-omics
#12
REVIEW
Jason N Rosenbaum, Paul Weisman
A companion diagnostic is a test for a specific biomarker-approved by the United States Food and Drug Administration-qualifying a patient to receive a specific, associated therapy. As interest has grown in precision medicine over the last decade, the principle of companion diagnostics has gained increasing purchase among laboratory professionals, clinicians, regulators, and even patients. The evolution of the biomarkers used to stratify and treat breast cancer illustrates the history of companion diagnostics, and provides a lens through which to examine potential challenges...
July 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28733194/breast-cancer-molecular-stratification-from-intrinsic-subtypes-to-integrative-clusters
#13
REVIEW
Hege G Russnes, Ole Christian Lingjærde, Anne-Lise Børresen-Dale, Carlos Caldas
Breast carcinomas can be stratified into different entities based on clinical behavior, histological features and/or by biological properties. A classification of breast cancer should be based on underlying biology, which we know must be determined by the somatic genomic landscape of mutations. Moreover, as the latest generations of anti-cancer agents are founded on biological mechanisms, a detailed molecular stratification is a requirement for appropriate clinical management. Such stratification, based on genomic drivers, will be important for selecting patients for clinical trials...
July 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28727987/associations-of-autoimmunity-immunodeficiency-lymphomagenesis-and-gut-microbiota-in-mice-with-knockins-for-a-pathogenic-autoantibody
#14
Shweta Jain, Jerrold M Ward, Dong-Mi Shin, Hongsheng Wang, Zohreh Naghashfar, Alexander L Kovalchuk, Herbert C Morse
A number of mouse strains transgenic for B-cell receptors specific for nucleic acids or other autoantigens have been generated to understand how autoreactive B cells are regulated in normal and autoimmune mice. Previous studies of nonautoimmune C57BL/6 mice heterozygous for both the IgH and IgL knockins of the polyreactive autoantibody, 564, produced high levels of autoantibodies in a largely Toll-like receptor 7-dependent manner. Herein, we describe studies of mice homozygous for the knockins that also expressed high levels of autoantibodies but, unlike the heterozygotes, exhibited a high incidence of mature B-cell lymphomas and enhanced susceptibility to bacterial infections...
July 17, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28727986/this-month-in-ajp
#15
(no author information available yet)
The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
July 17, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28710904/m1-macrophage-induced-endothelial-to-mesenchymal-transition-promotes-infantile-hemangioma-regression
#16
Keith Q Wu, Christopher S Muratore, Eui Y So, Changqi Sun, Patrycja M Dubielecka, Anthony M Reginato, Olin D Liang
Infantile hemangiomas are benign tumors of vascular endothelial cells (ECs), characterized by three distinct stages: proliferating phase, involuting phase, and involuted phase. The mechanisms that trigger involution of hemangioma into fibro-fatty tissue remain unknown. We report a novel mechanism by which M1-polarized macrophages induce endothelial-to-mesenchymal transition (EndMT) and promote hemangioma regression. M1- but not M2-polarized macrophages induced EndMT in ECs. Tumor necrosis factor-α and, to a lesser extent, IL-1β and interferon-γ were the most potent cytokines produced by the M1 macrophages that induce in vitro EndMT...
July 12, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28710903/stellate-cells-orchestrate-concanavalin-a-induced-acute-liver-damage
#17
Richa Rani, Ashish Tandon, Jiang Wang, Sudhir Kumar, Chandrashekhar R Gandhi
Concanavalin A (ConA) causes immune cell-mediated liver damage, but the contribution of resident nonparenchymal cells is also evident. Hepatic stellate cells (HSCs) induce hepatic inflammation and immunological reactions; we therefore investigated their role in ConA-induced liver injury. ConA was administered i.v. to control or HSC-depleted mice; hepatic histopathology and cytokines/chemokines were determined after 6 hours. In vitro, the effects of ConA-conditioned HSC medium on hepatocytes were determined...
July 12, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28711154/western-diet-induced-dysbiosis-in-farnesoid-x-receptor-knockout-mice-causes-persistent-hepatic-inflammation-after-antibiotic-treatment
#18
Prasant K Jena, Lili Sheng, Hui-Xin Liu, Karen M Kalanetra, Annie Mirsoian, William J Murphy, Samuel W French, Viswanathan V Krishnan, David A Mills, Yu-Jui Yvonne Wan
Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin)...
July 11, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28708972/uv-irradiation-of-skin-enhances-glycolytic-flux-and-reduces-migration-capabilities-in-bone-marrow-differentiated-dendritic-cells
#19
Terence A McGonigle, Kevin N Keane, Simon Ghaly, Kim W Carter, Denise Anderson, Naomi M Scott, Helen S Goodridge, Amy Dwyer, Eloise Greenland, Fiona J Pixley, Philip Newsholme, Prue H Hart
A systemic immunosuppression follows UV irradiation of the skin of humans and mice. In this study, dendritic cells (DCs) differentiating from the bone marrow of UV-irradiated mice had a reduced ability to migrate toward the chemokine (C-C motif) ligand 21. Fewer DCs also accumulated in the peritoneal cavity of UV-chimeric mice (ie, mice transplanted with bone marrow from UV-irradiated mice) after injection of an inflammatory stimulus into that site. We hypothesized that different metabolic states underpin altered DC motility...
July 11, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28708971/short-term-alcohol-abstinence-improves-antibacterial-defenses-of-chronic-alcohol-consuming-mice-against-gut-bacteria-associated-sepsis-caused-by-enterococcus-faecalis-oral-infection
#20
Makiko Kobayashi, Akira Asai, Ichiaki Ito, Sumihiro Suzuki, Kazuhide Higuchi, Fujio Suzuki
The effects of short-term alcohol abstinence on host antibacterial resistance against Enterococcus faecalis oral infection was investigated in chronic alcohol-consuming mice [mice with 0.1 g/day of 20% ethanol consumption for 12 or 16 weeks (CAC-mice)]. These mice were highly susceptible to the infection; however, after 7 days of alcohol abstinence (aaCAC-mice), their antibacterial resistances were completely restored to the normal mouse level. Normal mice inoculated with CAC-mouse hepatic macrophages were shown to be susceptible to the infection, whereas the same macrophage preparation from aaCAC-mice did not impair the antibacterial resistance of normal mice...
July 11, 2017: American Journal of Pathology
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