Genomic and Epigenomic Alterations in Cancer.
Abstract Multiple genetic and epigenetic events characterize tumor progression and define the identity of the tumors. Advances in high-throughput technologies, like gene expression profiling, next-generation sequencing, proteomics, and metabolomics, have enabled detailed molecular characterization of various tumors. The integration and analyses of these high-throughput data have unraveled many novel molecular aberrations and network alterations in tumors. These molecular alterations include multiple cancer-driving mutations, gene fusions, amplification, deletion, and post-translational modifications, among others....
Source: The American Journal of Pathology - June 25, 2016 Category: Pathology Authors: Chakravarthi BV, Nepal S, Varambally S Tags: Am J Pathol Source Type: research

Targeting Platelet-Derived Growth Factor Receptor β(+) Scaffold Formation Inhibits Choroidal Neovascularization.
Targeting Platelet-Derived Growth Factor Receptor β(+) Scaffold Formation Inhibits Choroidal Neovascularization. Am J Pathol. 2016 Jul;186(7):1890-9 Authors: Strittmatter K, Pomeroy H, Marneros AG Abstract Neovascular age-related macular degeneration is among the most common causes of irreversible blindness and manifests with choroidal neovascularization (CNV). Anti-vascular endothelial growth factor-A therapies are only partially effective and their chronic administration may impair functions of the choriocapillaris and retina. Thus, novel therapeutic targets are needed urgently. We have observe...
Source: The American Journal of Pathology - June 25, 2016 Category: Pathology Authors: Strittmatter K, Pomeroy H, Marneros AG Tags: Am J Pathol Source Type: research

Overexpression of Protocadherin-10 in Transthyretin-Related Familial Amyloidotic Polyneuropathy.
va MJ Abstract Overwhelming data suggest that oncogenic and neurodegenerative pathways share several altered cellular responses to insults such as oxidative stress, extracellular matrix remodeling, inflammation, or cell dyscommunication. Protocadherin-10 (Pcdh10) is an adhesion molecule found to protect against tumorigenesis and essential for axonal elongation and actin dynamics during development. Here, by using genome microarrays we identified for the first time Pcdh10 up-regulation in tissues from transgenic mouse models, cultured Schwann cells, and human samples from a familial form of peripheral neuropathy (f...
Source: The American Journal of Pathology - June 25, 2016 Category: Pathology Authors: Gonçalves NP, Martins D, Saraiva MJ Tags: Am J Pathol Source Type: research

Spleen Tyrosine Kinase Signaling Promotes Myeloid Cell Recruitment and Kidney Damage after Renal Ischemia/Reperfusion Injury.
Abstract Ischemia/reperfusion (I/R) injury is an important cause of acute and chronic renal failure. Neutrophils and macrophages, by integrin-based recruitment, play a key role in renal I/R injury. Integrin-based activation of spleen tyrosine kinase (Syk) contributes to myeloid cell adhesion to activated endothelial cells in vitro; however, whether Syk is required for myeloid cell recruitment and tubular damage in I/R injury is unknown. Therefore, we investigated the function of Syk in mouse I/R injury using two different approaches. C57Bl/6J mice underwent bilateral warm ischemia and were sacrificed after 30...
Source: The American Journal of Pathology - June 17, 2016 Category: Pathology Authors: Ryan J, Kanellis J, Blease K, Ma FY, Nikolic-Paterson DJ Tags: Am J Pathol Source Type: research

Splenic Damage during SIV Infection: Role of T-Cell Depletion and Macrophage Polarization and Infection.
Abstract The effects of HIV infection on spleen and its cellular subsets have not been fully characterized, particularly for macrophages in which diverse populations exist. We used an accelerated SIV-infected macaque model to examine longitudinal effects on T-cell and macrophage populations and their susceptibilities to infection. Substantial lymphoid depletion occurred, characterized by follicular burn out and a loss of CD3 T lymphocytes, which was associated with cellular activation and transient dysregulations in CD4/CD8 ratios and memory effector populations. In contrast, the loss of CD68 and CD163(+)CD68(+) m...
Source: The American Journal of Pathology - June 17, 2016 Category: Pathology Authors: Williams DW, Engle EL, Shirk EN, Queen SE, Gama L, Mankowski JL, Zink MC, Clements JE Tags: Am J Pathol Source Type: research

Aggregated α-Synuclein Increases SOD1 Oligomerization in a Mouse Model of Amyotrophic Lateral Sclerosis.
Aggregated α-Synuclein Increases SOD1 Oligomerization in a Mouse Model of Amyotrophic Lateral Sclerosis. Am J Pathol. 2016 Jun 17; Authors: Koch Y, Helferich AM, Steinacker P, Oeckl P, Walther P, Weishaupt JH, Danzer KM, Otto M Abstract Aggregation of misfolded disease-related proteins is a hallmark of neurodegenerative diseases. Aggregate propagation accompanying disease progression has been demonstrated for different proteins (eg, for α-synuclein). Additional evidence supports aggregate cross-seeding activity for α-synuclein. For mutated superoxide dismutase 1 (SOD1), which causes ...
Source: The American Journal of Pathology - June 17, 2016 Category: Pathology Authors: Koch Y, Helferich AM, Steinacker P, Oeckl P, Walther P, Weishaupt JH, Danzer KM, Otto M Tags: Am J Pathol Source Type: research

Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling.
Abstract The Bcl2-associated anthanogene (BAG) 3 protein is a member of the BAG family of cochaperones, which supports multiple critical cellular processes, including critical structural roles supporting desmin and interactions with heat shock proteins and ubiquitin ligases intimately involved in protein quality control. The missense mutation P209L in exon 3 results in a primarily cardiac phenotype leading to skeletal muscle and cardiac complications. At least 10 other Bag3 mutations have been reported, nine resulting in a dilated cardiomyopathy for which no specific therapy is available. We generated αMHC-h...
Source: The American Journal of Pathology - June 16, 2016 Category: Pathology Authors: Quintana MT, Parry TL, He J, Yates CC, Sidorova TN, Murray KT, Bain JR, Newgard CB, Muehlbauer MJ, Eaton SC, Hishiya A, Takayama S, Willis MS Tags: Am J Pathol Source Type: research

Interleukin-11 Receptor Is a Candidate Target for Ligand-Directed Therapy in Lung Cancer: Analysis of Clinical Samples and BMTP-11 Preclinical Activity.
asqualini R Abstract We previously isolated an IL-11-mimic motif (CGRRAGGSC) that binds to IL-11 receptor (IL-11R) in vitro and accumulates in IL-11R-expressing tumors in vivo. This synthetic peptide ligand was used as a tumor-targeting moiety in the rational design of BMTP-11, which is now a drug candidate in clinical trials. Here, we investigated the specificity and accessibility of IL-11R as a target and the efficacy of BMTP-11 as a ligand-targeted drug in lung cancer. We observed high expression levels of IL-11R in a large cohort of patients (n = 368). In matching surgical specimens (i.e., ...
Source: The American Journal of Pathology - June 15, 2016 Category: Pathology Authors: Cardó-Vila M, Marchiò S, Sato M, Staquicini FI, Smith TL, Bronk JK, Yin G, Zurita AJ, Sun M, Behrens C, Sidman RL, Lee JJ, Hong WK, Wistuba II, Arap W, Pasqualini R Tags: Am J Pathol Source Type: research

CD4(+)CD25(hi)Foxp3(+) Cells Exacerbate Bleomycin-Induced Pulmonary Fibrosis.
Abstract Idiopathic pulmonary fibrosis is a fatal lung disease with a median survival of 2 to 5 years. A decade of studies has downplayed inflammation contributing to its pathogenesis. However, these studies preceded the discovery of regulatory T cells (Tregs) and all of their functions. On the basis of human studies demonstrating Tregs can decrease graft-versus-host disease and vasculitides, there is consideration of their use to treat idiopathic pulmonary fibrosis. We hypothesized that Treg therapy would attenuate the fibroplasia involved in a preclinical murine model of pulmonary fibrosis. IL-2 complex was used...
Source: The American Journal of Pathology - June 15, 2016 Category: Pathology Authors: Birjandi SZ, Palchevskiy V, Xue YY, Nunez S, Kern R, Weigt SS, Lynch JP, Chatila TA, Belperio JA Tags: Am J Pathol Source Type: research

Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy.
Reduced Krüppel-Like Factor 2 Aggravates Glomerular Endothelial Cell Injury and Kidney Disease in Mice with Unilateral Nephrectomy. Am J Pathol. 2016 Jun 15; Authors: Zhong F, Mallipattu SK, Estrada C, Menon M, Saleem F, Jain MK, Chen H, Wang Y, Lee K, He JC Abstract Loss of functional nephrons induces compensatory glomerular hyperfiltration and hypertrophy, leading to the progression of chronic kidney disease. Krüppel-like factor 2 (KLF2), a shear-stress-inducible transcription factor, confers protection against endothelial injury. Because glomerular hyperfiltration is associated with shear...
Source: The American Journal of Pathology - June 15, 2016 Category: Pathology Authors: Zhong F, Mallipattu SK, Estrada C, Menon M, Saleem F, Jain MK, Chen H, Wang Y, Lee K, He JC Tags: Am J Pathol Source Type: research

Proatherosclerotic Effect of the α1-Subunit of Soluble Guanylyl Cyclase by Promoting Smooth Muscle Phenotypic Switching.
This study sought to decipher the role of Gucy1a3 in atherosclerosis in mice. At age 32 weeks and after 20 weeks of standard or high-fat diet, Gucy1a3(-/-)/Ldlr(-/-) mice exhibited a significant reduction of the atherosclerotic plaque size at the aortic root and in the aorta for high-fat diet animals as compared to respective Ldlr(-/-) control mice. Collagen content in plaques in the aortic root was reduced, suggesting an alteration of smooth muscle cell function. Proliferation and migration were reduced in Gucy1a3(-/-) primary aortic smooth muscle cells (AoSMCs) and proliferation was also reduced in human AoSMCs after inh...
Source: The American Journal of Pathology - June 14, 2016 Category: Pathology Authors: Segura-Puimedon M, Mergia E, Al-Hasani J, Aherrahrou R, Stoelting S, Kremer F, Freyer J, Kösling D, Erdmann J, Schunkert H, de Wit C, Aherrahrou Z Tags: Am J Pathol Source Type: research

Prominent Lymphatic Vessel Hyperplasia with Progressive Dysfunction and Distinct Immune Cell Infiltration in Lymphedema.
Abstract Lymphedema is a common complication that occurs after breast cancer treatment in up to 30% of the patients undergoing surgical lymph node excision. It is associated with tissue swelling, fibrosis, increased risk of infection, and impaired wound healing. Despite the pronounced clinical manifestations of the disease, little is known about the morphological and functional characteristics of the lymphatic vasculature during the course of lymphedema progression. We used an experimental murine tail lymphedema model where sustained fluid stasis was generated on disruption of lymphatic flow, resulting in chronic ...
Source: The American Journal of Pathology - June 14, 2016 Category: Pathology Authors: Gousopoulos E, Proulx ST, Scholl J, Uecker M, Detmar M Tags: Am J Pathol Source Type: research

The Role of Integrins αMβ2 (Mac-1, CD11b/CD18) and αDβ2 (CD11d/CD18) in Macrophage Fusion.
The Role of Integrins αMβ2 (Mac-1, CD11b/CD18) and αDβ2 (CD11d/CD18) in Macrophage Fusion. Am J Pathol. 2016 Jun 14; Authors: Podolnikova NP, Kushchayeva YS, Wu Y, Faust J, Ugarova TP Abstract The subfamily of β2 integrins is implicated in macrophage fusion, a hallmark of chronic inflammation. Among β2 family members, integrin Mac-1 (αMβ2, CD11b/CD18) is abundantly expressed on monocyte/macrophages and mediates critical adhesive reactions of these cells. However, the role of Mac-1 in macrophage fusion leading to the formation of multinucleated giant cells rem...
Source: The American Journal of Pathology - June 14, 2016 Category: Pathology Authors: Podolnikova NP, Kushchayeva YS, Wu Y, Faust J, Ugarova TP Tags: Am J Pathol Source Type: research

Jagged1 DNA Copy Number Variation Is Associated with Poor Outcome in Liver Cancer.
In conclusion, amplification of Jagged1 contributed to mRNA expression that activates the Jagged1-Notch signaling pathway in liver cancer and led to poor outcome. PMID: 27315779 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - June 14, 2016 Category: Pathology Authors: Kawaguchi K, Honda M, Yamashita T, Okada H, Shirasaki T, Nishikawa M, Nio K, Arai K, Sakai Y, Yamashita T, Mizukoshi E, Kaneko S Tags: Am J Pathol Source Type: research

Estrogen Stimulates Homing of Endothelial Progenitor Cells to Endometriotic Lesions.
Abstract The incorporation of endothelial progenitor cells (EPCs) into microvessels contributes to the vascularization of endometriotic lesions. Herein, we analyzed whether this vasculogenic process is regulated by estrogen. Estrogen- and vehicle-treated human EPCs were analyzed for migration and tube formation. Endometriotic lesions were induced in irradiated FVB/N mice, which were reconstituted with bone marrow from FVB/N-TgN (Tie2/green fluorescent protein) 287 Sato mice. The animals were treated with 100 μg/kg β-estradiol 17-valerate or vehicle (control) over 7 and 28 days. Lesion growth, cyst formatio...
Source: The American Journal of Pathology - June 14, 2016 Category: Pathology Authors: Rudzitis-Auth J, Nenicu A, Nickels RM, Menger MD, Laschke MW Tags: Am J Pathol Source Type: research

EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain.
Abstract Microglial cells play a key role in neuronal damage in neurodegenerative disorders. Overactivated microglia induce detrimental neurotoxic effects through the excess production of proinflammatory cytokines. However, the mechanisms of microglial activation are poorly understood. We focused on prostaglandin E2 type 4 receptor-associated protein (EPRAP), which suppresses macrophage activation. We demonstrated that EPRAP exists in microglia in the brain. Furthermore, EPRAP-deficient mice displayed less microglial accumulation, and intraperitoneal administration of lipopolysaccharide (LPS) led to reduced expres...
Source: The American Journal of Pathology - June 14, 2016 Category: Pathology Authors: Fujikawa R, Higuchi S, Nakatsuji M, Yasui M, Ikedo T, Nagata M, Yokode M, Minami M Tags: Am J Pathol Source Type: research

Effects of IL-8 Up-Regulation on Cell Survival and Osteoclastogenesis in Multiple Myeloma.
In conclusion, our results implicate IL-8 in myeloma bone disease and point to the potential utility of an anti-IL-8 therapy to prevent unwanted effects of IL-8 up-regulation on survival, angiogenesis, and osteolysis in MM. PMID: 27301357 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - June 11, 2016 Category: Pathology Authors: Herrero AB, García-Gómez A, Garayoa M, Corchete LA, Hernández JM, San Miguel J, Gutierrez NC Tags: Am J Pathol Source Type: research

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II-Induced Aortic Aneurysm in Male Apoe(-/-) Mice.
Abstract Cytochrome P450 (CYP) 1B1 is implicated in vascular smooth muscle cell migration, proliferation, and hypertension. We assessed the contribution of CYP1B1 to angiotensin (Ang) II-induced abdominal aortic aneurysm (AAA). Male Apoe(-/-)/Cyp1b1(+/+) and Apoe(-/-)/Cyp1b1(-/-) mice were infused with Ang II or its vehicle for 4 weeks; another group of Apoe(-/-)/Cyp1b1(+/+) mice was coadministered the CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS) every third day for 4 weeks. On day 28 of Ang II infusion, AAAs were analyzed by ultrasound and ex vivo by Vernier calipers, mice were euthanized, and tissu...
Source: The American Journal of Pathology - June 11, 2016 Category: Pathology Authors: Thirunavukkarasu S, Khan NS, Song CY, Ghafoor HU, Brand DD, Gonzalez FJ, Malik KU Tags: Am J Pathol Source Type: research

Suppression of Ischemia-Induced Hippocampal Pyramidal Neuron Death by Hyaluronan Tetrasaccharide through Inhibition of Toll-Like Receptor 2 Signaling Pathway.
Abstract Toll-like receptors (TLRs) are one of the main contributors that induce inflammation under tissue injury and infection. Because excessive inflammation can aggravate disease states, it is important to control inflammation at a moderate level. Herein, we show that hyaluronan (HA) oligomer, HA tetrasaccharide (HA4), could suppress the expression of proinflammatory cytokine IL-1β when stimulated with both TLR2- and TLR4-specific agonists in primary hippocampal neurons. To understand the effect of HA4 against ischemic insult, we performed hypoxic-ischemic (H/I) brain injury against neonatal mice. HA4 trea...
Source: The American Journal of Pathology - June 11, 2016 Category: Pathology Authors: Sunabori T, Koike M, Asari A, Oonuki Y, Uchiyama Y Tags: Am J Pathol Source Type: research

The Complement Regulatory Protein CD46 Deficient Mouse Spontaneously Develops Dry-Type Age-Related Macular Degeneration-Like Phenotype.
Abstract In the mouse, membrane cofactor protein (CD46), a key regulator of the alternative pathway of the complement system, is only expressed in the eye and on the inner acrosomal membrane of spermatozoa. We noted that although Cd46(-/-) mice have normal systemic alternative pathway activating ability, lack of CD46 leads to dysregulated complement activation in the eye, as evidenced by increased deposition of C5b-9 in the retinal pigment epithelium (RPE) and choroid. A knockout of CD46 induced the following cardinal features of human dry age-related macular degeneration (AMD) in 12-month-old male and female mice...
Source: The American Journal of Pathology - June 10, 2016 Category: Pathology Authors: Lyzogubov VV, Bora PS, Wu X, Horn LE, de Roque R, Rudolf XV, Atkinson JP, Bora NS Tags: Am J Pathol Source Type: research

Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2(-) Tumor Related to Lymphangioleiomyomatosis.
Abstract Angiomyolipoma (AML) is a tumor closely related to lymphangioleiomyomatosis (LAM). Both entities are characterized by the proliferation of smooth muscle actin and melanocytic glycoprotein 100 (recognized by antibody HMB-45)-positive spindle-shaped and epithelioid cells. AML and LAM are etiologically linked to mutations in the tsc2 and tsc1 genes in the case of LAM. These genes encode the proteins tuberous sclerosis complex (TSC)-1 and TSC2, which are directly involved in suppressing the mechanistic target of rapamycin cell growth signaling pathway. Although significant progress has been made in characteri...
Source: The American Journal of Pathology - June 2, 2016 Category: Pathology Authors: Yue M, Pacheco G, Cheng T, Li J, Wang Y, Henske EP, Schuger L Tags: Am J Pathol Source Type: research

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope.
Abstract Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis a...
Source: The American Journal of Pathology - May 26, 2016 Category: Pathology Authors: Caron JM, Ames JJ, Contois L, Liebes L, Friesel R, Muggia F, Vary CP, Oxburgh L, Brooks PC Tags: Am J Pathol Source Type: research

Corrections.
Authors: PMID: 27216149 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - May 26, 2016 Category: Pathology Tags: Am J Pathol Source Type: research

Huntington Disease: A Disease of DNA Methylation or DNA Breaks?
Abstract This commentary highlights the article by Mollica et al that describes an interesting model for the clinical evolution of Huntington disease. PMID: 27219493 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - May 21, 2016 Category: Pathology Authors: Ferlazzo ML, Foray N Tags: Am J Pathol Source Type: research

Mouse Models of NMNAT1-Leber Congenital Amaurosis (LCA9) Recapitulate Key Features of the Human Disease.
Abstract The nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) enzyme is essential for regenerating the nuclear pool of NAD(+) in all nucleated cells in the body, and mounting evidence also suggests that it has a separate role in neuroprotection. Recently, mutations in the NMNAT1 gene were associated with Leber congenital amaurosis, a severe retinal degenerative disease that causes blindness during infancy. Availability of a reliable mammalian model of NMNAT1-Leber congenital amaurosis would assist in determining the mechanisms through which disruptions in NMNAT1 lead to retinal cell degeneration and would pr...
Source: The American Journal of Pathology - May 17, 2016 Category: Pathology Authors: Greenwald SH, Charette JR, Staniszewska M, Shi LY, Brown SD, Stone L, Liu Q, Hicks WL, Collin GB, Bowl MR, Krebs MP, Nishina PM, Pierce EA Tags: Am J Pathol Source Type: research

α3 Integrin of Cell-Cell Contact Mediates Kidney Fibrosis by Integrin-Linked Kinase in Proximal Tubular E-Cadherin Deficient Mice.
α3 Integrin of Cell-Cell Contact Mediates Kidney Fibrosis by Integrin-Linked Kinase in Proximal Tubular E-Cadherin Deficient Mice. Am J Pathol. 2016 May 13; Authors: Zheng G, Zhang J, Zhao H, Wang H, Pang M, Qiao X, Lee SR, Hsu TT, Tan TK, Lyons JG, Zhao Y, Tian X, Loebel DA, Rubera I, Tauc M, Wang Y, Wang Y, Wang YM, Cao Q, Wang C, Lee VW, Alexander SI, Tam PP, Harris DC Abstract Loss of E-cadherin marks a defect in epithelial integrity and polarity during tissue injury and fibrosis. Whether loss of E-cadherin plays a causal role in fibrosis is uncertain. α3β1 Integrin has been ident...
Source: The American Journal of Pathology - May 13, 2016 Category: Pathology Authors: Zheng G, Zhang J, Zhao H, Wang H, Pang M, Qiao X, Lee SR, Hsu TT, Tan TK, Lyons JG, Zhao Y, Tian X, Loebel DA, Rubera I, Tauc M, Wang Y, Wang Y, Wang YM, Cao Q, Wang C, Lee VW, Alexander SI, Tam PP, Harris DC Tags: Am J Pathol Source Type: research

Cytoplasmic Cyclin E and Phospho-Cyclin-Dependent Kinase 2 Are Biomarkers of Aggressive Breast Cancer.
We examined the specificity of different cyclin E antibodies and concordance between immunohistochemical and Western blot analyses for each antibody in a panel of 14 breast cell lines. Nuclear versus cytoplasmic staining of cyclin E readily differentiated full-length from LMW-E, respectively. We also evaluated the expression of cyclin E and p-CDK2 in 1676 human breast carcinoma cases by using immunohistochemical analysis. Cytoplasmic cyclin E correlated strongly with cytoplasmic p-CDK2 (P 
Source: The American Journal of Pathology - May 13, 2016 Category: Pathology Authors: Karakas C, Biernacka A, Bui T, Sahin A, Yi M, Akli S, Schafer J, Alexander A, Adjapong O, Hunt KK, Keyomarsi K Tags: Am J Pathol Source Type: research

DNA Methylation Leads to DNA Repair Gene Down-Regulation and Trinucleotide Repeat Expansion in Patient-Derived Huntington Disease Cells.
Abstract Huntington disease (HD) is an autosomal dominantly inherited disease that exhibits genetic anticipation of affected progeny due to expansions of a trinucleotide repeat (TNR) region within the HTT gene. DNA repair machinery is a known effector of TNR instability; however, the specific defects in HD cells that lead to TNR expansion are unknown. We hypothesized that HD cells would be deficient in DNA repair gene expression. To test this hypothesis, we analyzed expression of select DNA repair genes involved in mismatch/loop-out repair (APEX1, BRCA1, RPA1, and RPA3) in patient-derived HD cells and found each w...
Source: The American Journal of Pathology - May 13, 2016 Category: Pathology Authors: Mollica PA, Reid JA, Ogle RC, Sachs PC, Bruno RD Tags: Am J Pathol Source Type: research

Divergent Inflammatory, Fibrogenic, and Liver Progenitor Cell Dynamics in Two Common Mouse Models of Chronic Liver Injury.
This study revealed remarkable differences between the models. It identified periportal injury and fibrosis with an early peak and slow normalization of all parameters in the CDE regimen, whereas TAA-treated mice had pericentral patterns of progressive injury and fibrosis, resulting in a more severe hepatic injury phenotype. This study is the first to resolve two different patterns of injury and fibrosis in the CDE and TAA model and to indisputably identify the fibrosis pattern in the TAA model as driven from the pericentral vein region. Our data provide a valuable foundation for future work using the CDE and TAA regimens ...
Source: The American Journal of Pathology - May 12, 2016 Category: Pathology Authors: Köhn-Gaone J, Dwyer BJ, Grzelak CA, Miller G, Shackel NA, Ramm GA, McCaughan GW, Elsegood CL, Olynyk JK, Tirnitz-Parker JE Tags: Am J Pathol Source Type: research

PERK Activation Promotes Medulloblastoma Tumorigenesis by Attenuating Premalignant Granule Cell Precursor Apoptosis.
Abstract Evidence suggests that activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress negatively or positively influences cell transformation by regulating apoptosis. Patched1 heterozygous deficient (Ptch1(+/-)) mice reproduce human Gorlin's syndrome and are regarded as the best animal model to study tumorigenesis of the sonic hedgehog subgroup of medulloblastomas. It is believed that medulloblastomas in Ptch1(+/-) mice results from the transformation of granule cell precursors (GCPs) in the developing cerebellum. Here, we determined the role of PERK sig...
Source: The American Journal of Pathology - May 12, 2016 Category: Pathology Authors: Ho Y, Li X, Jamison S, Harding HP, McKinnon PJ, Ron D, Lin W Tags: Am J Pathol Source Type: research

Intrahepatic Xenograft of Cutaneous T-Cell Lymphoma Cell Lines: A Useful Model for Rapid Biological and Therapeutic Evaluation.
Abstract Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases primarily involving the skin that could have an aggressive course with circulating blood cells, especially in Sézary syndrome and transformed mycosis fungoides. So far, few CTCL cell lines have been adapted for in vivo experiments and their tumorigenicity has not been adequately assessed, hampering the use of a reproducible model for CTCL biological evaluation. In fact, both patient-derived xenografts and cell line xenografts at subcutaneous sites failed to provide a robust tool, because engraftment was dependent on mice ...
Source: The American Journal of Pathology - May 12, 2016 Category: Pathology Authors: Andrique L, Poglio S, Prochazkova-Carlotti M, Kadin ME, Giese A, Idrissi Y, Beylot-Barry M, Merlio JP, Chevret E Tags: Am J Pathol Source Type: research

Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development.
Abstract The highly orchestrated interactions between the epithelium and mesenchyme required for normal lung development can be disrupted by perinatal inflammation in preterm infants, although the mechanisms are incompletely understood. We used transgenic (inhibitory κB kinase transactivated) mice that conditionally express an activator of the NF-κB pathway in airway epithelium to investigate the impact of epithelial-derived inflammation during lung development. Epithelial NF-κB activation selectively impaired saccular stage lung development, with a phenotype comprising rapidly progressive distal...
Source: The American Journal of Pathology - May 12, 2016 Category: Pathology Authors: Benjamin JT, van der Meer R, Im AM, Plosa EJ, Zaynagetdinov R, Burman A, Havrilla ME, Gleaves LA, Polosukhin VV, Deutsch GH, Yanagisawa H, Davidson JM, Prince LS, Young LR, Blackwell TS Tags: Am J Pathol Source Type: research

Dynein Dysfunction Reproduces Age-Dependent Retromer Deficiency: Concomitant Disruption of Retrograde Trafficking Is Required for Alteration in β-Amyloid Precursor Protein Metabolism.
We report that aging itself affects retromer trafficking in cynomolgus monkey brains. In addition, dynein dysfunction reproduces this type of age-dependent retromer deficiency (ie, the endosomal accumulation of retromer-related proteins and Aβ precursor protein. Moreover, we found that knockdown of Rab7, Rab9, or Rab11 did not alter endogenous Aβ precursor protein metabolism, such as that observed in aged monkey brains and in dynein-depleted cells. These findings suggest that dynein dysfunction can cause retromer deficiency and that concomitant disruption of retrograde trafficking may be the key factor underlying...
Source: The American Journal of Pathology - May 11, 2016 Category: Pathology Authors: Kimura N, Samura E, Suzuki K, Okabayashi S, Shimozawa N, Yasutomi Y Tags: Am J Pathol Source Type: research

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice.
Abstract Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)-ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein (GFP)-chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow-derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capil...
Source: The American Journal of Pathology - May 10, 2016 Category: Pathology Authors: Dominguez JM, Hu P, Caballero S, Moldovan L, Verma A, Oudit GY, Li Q, Grant MB Tags: Am J Pathol Source Type: research

Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Protective for Injured Epithelia.
Abstract Acute lung injury is a life-threatening condition caused by disruption of the alveolar-capillary barrier leading to edema, influx of inflammatory leukocytes, and impaired gas exchange. Specialized proresolving mediators biosynthesized from essential fatty acids, such as docosahexaenoic acid, have tissue protective effects in acute inflammation. Herein, we found that the docosahexaenoic acid-derived mediator resolvin D3 (RvD3): 4S, 11R, 17S-trihydroxydocosa-5Z, 7E, 9E, 13Z, 15E, 19Z-hexaenoic acid was present in uninjured lungs, and increased significantly 24 to 72 hours after hydrochloric acid-initiated i...
Source: The American Journal of Pathology - May 9, 2016 Category: Pathology Authors: Colby JK, Abdulnour RE, Sham HP, Dalli J, Colas RA, Winkler JW, Hellmann J, Wong B, Cui Y, El-Chemaly S, Petasis NA, Spite M, Serhan CN, Levy BD Tags: Am J Pathol Source Type: research

Repair Mechanisms in Oxidant-Driven Chronic Inflammatory Disease.
Abstract The interplay that governs chronic diseases through pathways specifically associated with chronic inflammation remains undefined. Many metabolic events have been identified during the injury and repair process. Nonetheless, the cellular events that control the pathogenesis of inflammation-induced disease have not been fully characterized. We and others reason that chronic inflammatory diseases associated with a cascade of complex network mediators, such as nitric oxide, arachidonic acid metabolites, cytokines, and reactive oxygen species, play a significant role in the governance of alterations in homeost...
Source: The American Journal of Pathology - May 9, 2016 Category: Pathology Authors: Deeb RS, Hajjar DP Tags: Am J Pathol Source Type: research

Delta-Like Ligand 4 Modulates Liver Damage by Down-Regulating Chemokine Expression.
HL Abstract Disrupting Notch signaling ameliorates experimental liver fibrosis. However, the role of individual Notch ligands in liver damage is unknown. We investigated the effects of Delta-like ligand 4 (Dll4) in liver disease. DLL4 expression was measured in 31 human liver tissues by immunohistochemistry. Dll4 function was examined in carbon tetrachloride- and bile duct ligation-challenged mouse models in vivo and evaluated in hepatic stellate cells, hepatocytes, and Kupffer cells in vitro. DLL4 was expressed in patients' Kupffer and liver sinusoidal endothelial cells. Recombinant Dll4 protein (rDll4...
Source: The American Journal of Pathology - May 9, 2016 Category: Pathology Authors: Shen Z, Liu Y, Dewidar B, Hu J, Park O, Feng T, Xu C, Yu C, Li Q, Meyer C, Ilkavets I, Müller A, Stump-Guthier C, Munker S, Liebe R, Zimmer V, Lammert F, Mertens PR, Li H, Dijke PT, Augustin HG, Li J, Gao B, Ebert MP, Dooley S, Li Y, Weng HL Tags: Am J Pathol Source Type: research

α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy.
α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy. Am J Pathol. 2016 May 5; Authors: Lakritz JR, Thibault D, Robinson JA, Campbell J, Miller AD, Williams K, Burdo TH Abstract Traffic of activated monocytes into the dorsal root ganglia (DRG) is critical for pathology in HIV peripheral neuropathy. We have shown that accumulation of recently recruited (bromodeoxyuridine-positive MAC387(+)) monocytes is associated with severe DRG pathology...
Source: The American Journal of Pathology - May 5, 2016 Category: Pathology Authors: Lakritz JR, Thibault D, Robinson JA, Campbell J, Miller AD, Williams K, Burdo TH Tags: Am J Pathol Source Type: research

Epithelial p85 and p53 Regulate Survivin Expression during Adaptation to Ileocecal Resection.
Abstract Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial p85α-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of β-catenin target gene expression, activated caspase-3, survivin, p85α, and p53. Healthy and post-resection human infant small-bowel sections ...
Source: The American Journal of Pathology - May 5, 2016 Category: Pathology Authors: Cohran V, Managlia E, Bradford EM, Goretsky T, Li T, Katzman RB, Cheresh P, Brown JB, Hawkins J, Liu SX, De Plaen IG, Weitkamp JH, Helmrath M, Zhang Z, Barrett TA Tags: Am J Pathol Source Type: research

Severe Reduction in Number and Function of Peripheral T Cells Does Not Afford Protection toward Emphysema and Bronchial Remodeling Induced in Mice by Cigarette Smoke.
Abstract The protein Lck (p56(Lck)) is a Src family tyrosine kinase expressed at all stages of thymocyte development and is required for maturation of T cells. The targeted disruption of Lck gene in mice results in severe block in thymocyte maturation with substantial reduction in the development of CD4(+)CD8(+) thymocytes, severe reduction of peripheral T cells, and disruption of T-cell receptor signaling with defective function of T-cell responses. To investigate the role of T lymphocyte in the development of cigarette smoke-induced pulmonary changes, Lck(-/-) mice and corresponding congenic wild-type mice were ch...
Source: The American Journal of Pathology - May 5, 2016 Category: Pathology Authors: De Cunto G, Lunghi B, Bartalesi B, Cavarra E, Fineschi S, Ulivieri C, Lungarella G, Lucattelli M Tags: Am J Pathol Source Type: research

Lipid-Induced Endoplasmic Reticulum Stress Impairs Selective Autophagy at the Step of Autophagosome-Lysosome Fusion in Hepatocytes.
Abstract Blockage of hepatic autophagic degradation system occurs in obesity and is associated with the development of nonalcoholic fatty liver disease. However, the mechanism of this blockage remains unclear. We found a high-fat diet induced accumulation of autophagosomes in the mice livers. However, autophagy substrates such as p62 and ubiquitinated proteins also accumulated in the livers in this model. These findings indicate the possibility that a high-fat diet impairs autophagic flux in the liver. Then, to assess the autophagic flux in more detail, we performed analyses of autophagic flux in cultured hepatocy...
Source: The American Journal of Pathology - May 5, 2016 Category: Pathology Authors: Miyagawa K, Oe S, Honma Y, Izumi H, Baba R, Harada M Tags: Am J Pathol Source Type: research

Prohibitin-2 Depletion Unravels Extra-Mitochondrial Functions at the Kidney Filtration Barrier.
kkoetter PT Abstract Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Loss of the stomatin/PHB/flotillin/HflK/C (SPFH) domain containing protein PHB2 causes mitochondrial dysfunction and defective mitochondria-mediated signaling, which is implicated in a variety of human diseases, including progressive renal disease. Here, we provide evidence of additional, extra-mitochondrial functions of this membrane-anchored protein. Immunofluorescence and immunogold labeling detected PHB2 at mit...
Source: The American Journal of Pathology - April 25, 2016 Category: Pathology Authors: Ising C, Bharill P, Brinkkoetter S, Brähler S, Schroeter C, Koehler S, Hagmann H, Merkwirth C, Höhne M, Müller RU, Fabretti F, Schermer B, Bloch W, Kerjaschki D, Kurschat CE, Benzing T, Brinkkoetter PT Tags: Am J Pathol Source Type: research

To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease.
Abstract Despite similar components, the heterogeneity of skin characteristics across the human body is enormous. It is classically believed that site-specific fibroblasts in the dermis control postnatal skin identity by modulating the behavior of the surface-overlying keratinocytes in the epidermis. To begin testing this hypothesis, we characterized the gene expression differences between volar (ventral; palmoplantar) and nonvolar (dorsal) human skin. We show that KERATIN 9 (KRT9) is the most uniquely enriched transcript in volar skin, consistent with its etiology in genetic diseases of the palms and soles. In ad...
Source: The American Journal of Pathology - April 25, 2016 Category: Pathology Authors: Kim D, Hossain MZ, Nieves A, Gu L, Ratliff TS, Mi Oh S, Park A, Han S, Yang NB, Qi J, Taube JM, Kang S, Garza LA Tags: Am J Pathol Source Type: research

Protein Tyrosine Phosphatase-1B Negatively Impacts Host Defense against Pseudomonas aeruginosa Infection.
Abstract Pseudomonas aeruginosa is a major opportunistic pathogen in immune-compromised individuals. Mechanisms governing immune responses to P. aeruginosa infection remain incompletely defined. Herein, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator in P. aeruginosa infection. PTP1B-deficient mice display greatly enhanced bacterial clearance and reduced disease scores, which are accompanied by increased neutrophil infiltration and cytokine production. Interestingly, PTP1B deficiency mainly up-regulates the production of interferon-stimulated response elements-regulated...
Source: The American Journal of Pathology - April 25, 2016 Category: Pathology Authors: Yue L, Xie Z, Li H, Pang Z, Junkins RD, Tremblay ML, Chen X, Lin TJ Tags: Am J Pathol Source Type: research

Epithelial Cell Transforming 2 and Aurora Kinase B Modulate Formation of Stress Granule-Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells.
Epithelial Cell Transforming 2 and Aurora Kinase B Modulate Formation of Stress Granule-Containing Transcripts from Diverse Cellular Pathways in Astrocytoma Cells. Am J Pathol. 2016 Apr 20; Authors: Weeks A, Agnihotri S, Lymer J, Chalil A, Diaz R, Isik S, Smith C, Rutka JT Abstract Stress granules are small RNA-protein granules that modify the translational landscape during cellular stress to promote survival. The RhoGTPase RhoA is implicated in the formation of RNA stress granules. Our data demonstrate that the cytokinetic proteins epithelial cell transforming 2 and Aurora kinase B (AurkB) are l...
Source: The American Journal of Pathology - April 20, 2016 Category: Pathology Authors: Weeks A, Agnihotri S, Lymer J, Chalil A, Diaz R, Isik S, Smith C, Rutka JT Tags: Am J Pathol Source Type: research

Geranylgeranyl Diphosphate Synthase Modulates Fetal Lung Branching Morphogenesis Possibly through Controlling K-Ras Prenylation.
Abstract G proteins play essential roles in regulating fetal lung development, and any defects in their expression or function (eg, activation or posttranslational modification) can lead to lung developmental malformation. Geranylgeranyl diphosphate synthase (GGPPS) can modulate protein prenylation that is required for protein membrane-anchoring and activation. Here, we report that GGPPS regulates fetal lung branching morphogenesis possibly through controlling K-Ras prenylation during fetal lung development. GGPPS was continuously expressed in lung epithelium throughout whole fetal lung development. Specific delet...
Source: The American Journal of Pathology - April 19, 2016 Category: Pathology Authors: Jia WJ, Jiang S, Tang QL, Shen D, Xue B, Ning W, Li CJ Tags: Am J Pathol Source Type: research

Blockade of Glucocorticoid-Induced Tumor Necrosis Factor-Receptor-Related Protein Signaling Ameliorates Murine Collagen-Induced Arthritis by Modulating Follicular Helper T Cells.
Blockade of Glucocorticoid-Induced Tumor Necrosis Factor-Receptor-Related Protein Signaling Ameliorates Murine Collagen-Induced Arthritis by Modulating Follicular Helper T Cells. Am J Pathol. 2016 Apr 19; Authors: Ma J, Feng D, Wei Y, Tian J, Tang X, Rui K, Lu L, Xu H, Wang S Abstract Recent studies have shown that glucocorticoid-induced tumor necrosis factor-receptor-related protein (GITR) and its ligand (GITRL) are critically involved in the pathogenesis of autoimmune arthritis, but the role of GITRL/GITR signaling in modulating CD4(+) follicular helper T (Tfh) cell response during autoimmune a...
Source: The American Journal of Pathology - April 19, 2016 Category: Pathology Authors: Ma J, Feng D, Wei Y, Tian J, Tang X, Rui K, Lu L, Xu H, Wang S Tags: Am J Pathol Source Type: research

The Myoblast C2C12 Transfected with Mutant Valosin-Containing Protein Exhibits Delayed Stress Granule Resolution on Oxidative Stress.
Abstract Mutations in valosin-containing protein (VCP) cause inclusion body myopathy with Paget disease and frontotemporal dementia. However, the mechanisms by which mutant VCP triggers degeneration remain unknown. Here, we investigated the role of VCP in cellular stress both in vitro and in vivo. We found that two different stressors-the oxidative stressor arsenite and heat shock-activated stress responses evident by T-intracellular antigen-1-positive granules in C2C12 myoblasts. Granules also contained phosphorylated transactive response DNA-binding protein 43, ubiquitin, and the autophagosome and lyso...
Source: The American Journal of Pathology - April 19, 2016 Category: Pathology Authors: Rodriguez-Ortiz CJ, Flores JC, Valenzuela JA, Rodriguez GJ, Zumkehr J, Tran DN, Kimonis VE, Kitazawa M Tags: Am J Pathol Source Type: research

Fas Regulates Macrophage Polarization and Fibrogenic Phenotype in a Model of Chronic Ethanol-Induced Hepatocellular Injury.
Abstract The role of Fas-mediated apoptosis and its effect on proinflammatory cytokine production in early alcoholic liver disease has not been addressed. Wild-type mice (C57Bl/6) or mice with a functional mutation in the Fas ligand (B6.gld) were given either high-fat control diet or ethanol diet by intragastric cannulation for 2 or 4 weeks. Liver injury, hepatic lipid accumulation, and proinflammatory cytokine production associated with chronic ethanol consumption were largely prevented in B6.gld mice compared with wild-type mice. Conversely, B6.gld mice given ethanol exhibited increases in collagen deposition, h...
Source: The American Journal of Pathology - April 18, 2016 Category: Pathology Authors: Isayama F, Moore S, Hines IH, Wheeler MD Tags: Am J Pathol Source Type: research

Treatment with ActRIIB-mFc Produces Myofiber Growth and Improves Lifespan in the Acta1 H40Y Murine Model of Nemaline Myopathy.
We report a study of ActRIIB-mFc treatment in the Acta1 H40Y mouse model of NM. Treatment of Acta1 H40Y mice produced significant increases in body mass, muscle mass, quadriceps myofiber size, and survival, but other measurements of strength (forelimb grip strength, ex vivo measurements of contractile function) did not improve. Our studies also identified that the complications of urethral obstruction are associated with the mortality seen in male hemizygote Acta1 H40Y mice. The incidence of urethral obstruction and histologic evidence of chronic obstruction (inflammation) were significantly lower in Acta1 H40Y mice t...
Source: The American Journal of Pathology - April 18, 2016 Category: Pathology Authors: Tinklenberg J, Meng H, Yang L, Liu F, Hoffmann RG, Dasgupta M, Allen KP, Beggs AH, Hardeman EC, Pearsall RS, Fitts RH, Lawlor MW Tags: Am J Pathol Source Type: research