Murine Double Minute-2 Inhibition Ameliorates Established Crescentic Glomerulonephritis.
Abstract Rapidly progressive glomerulonephritis is characterized by glomerular necroinflammation and crescent formation. Its treatment includes unspecific and toxic agents; therefore, the identification of novel therapeutic targets is required. The E3-ubiquitin ligase murine double minute (MDM)-2 is a nonredundant element of NF-κB signaling and the negative regulator of tumor suppressor gene TP53-mediated cell cycle arrest and cell death. We hypothesized that the MDM2 would drive crescentic glomerulonephritis by NF-κB-dependent glomerular inflammation and by p53-dependent parietal epithelial ...
Source: The American Journal of Pathology - April 18, 2016 Category: Pathology Authors: Mulay SR, Romoli S, Desai J, Honarpisheh MM, Kumar SV, Anders HJ, Thomasova D Tags: Am J Pathol Source Type: research

TET2 Negatively Regulates Nestin Expression in Human Melanoma.
Abstract Although melanoma is an aggressive cancer, the understanding of the virulence-conferring pathways involved remains incomplete. We have demonstrated that loss of ten-eleven translocation methylcytosine dioxygenase (TET)-2-mediated 5-hydroxymethylcytosine (hmC) is an epigenetic driver of melanoma growth and a biomarker of clinical virulence. We also have determined that the intermediate filament protein nestin correlates with tumorigenic and invasive melanoma growth. Here we examine the relationships between these two biomarkers. IHC staining of nestin and 5-hmC in 53 clinically annotated primary and metast...
Source: The American Journal of Pathology - April 18, 2016 Category: Pathology Authors: Ferreira Gomes CB, Zechin KG, Xu S, Stelini RF, Nishimoto IN, Zhan Q, Xu T, Qin G, Treister NS, Murphy GF, Lian CG Tags: Am J Pathol Source Type: research

Isolation of Pancreatic Cancer Cells from a Patient-Derived Xenograft Model Allows for Practical Expansion and Preserved Heterogeneity in Culture.
Abstract Commercially available, highly passaged pancreatic cancer (PC) cell lines are of limited translational value. Attempts to overcome this limitation have primarily consisted of cancer cell isolation and culture directly from human PC specimens. However, these techniques are associated with exceedingly low success rates. Here, we demonstrate a highly reproducible culture of primary PC cell lines (PPCLs) from patient-derived xenografts, which preserve, in part, the intratumoral heterogeneity known to exist in PC. PPCL expansion from patient-derived xenografts was successful in 100% of attempts (5 of 5). Pheno...
Source: The American Journal of Pathology - April 18, 2016 Category: Pathology Authors: Pham K, Delitto D, Knowlton AE, Hartlage ER, Madhavan R, Gonzalo DH, Thomas RM, Behrns KE, George TJ, Hughes SJ, Wallet SM, Liu C, Trevino JG Tags: Am J Pathol Source Type: research

Interferon-γ-Induced Unfolded Protein Response in Conjunctival Goblet Cells as a Cause of Mucin Deficiency in Sjögren Syndrome.
Interferon-γ-Induced Unfolded Protein Response in Conjunctival Goblet Cells as a Cause of Mucin Deficiency in Sjögren Syndrome. Am J Pathol. 2016 Apr 13; Authors: Coursey TG, Henriksson JT, Barbosa FL, de Paiva CS, Pflugfelder SC Abstract Goblet cells (GCs) are specialized secretory cells that produce mucins and a variety of other proteins. Significant conjunctival GC loss occurs in both experimental dry eye models and patients with keratoconjunctivitis sicca due to the induction of interferon (IFN)-γ. With the use of a primary murine culture model, we found that GCs are highly sensit...
Source: The American Journal of Pathology - April 13, 2016 Category: Pathology Authors: Coursey TG, Henriksson JT, Barbosa FL, de Paiva CS, Pflugfelder SC Tags: Am J Pathol Source Type: research

Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages.
Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages. Am J Pathol. 2016 Apr 13; Authors: Okizaki SI, Ito Y, Hosono K, Oba K, Ohkubo H, Kojo K, Nishizawa N, Shibuya M, Shichiri M, Majima M Abstract The persistence of proinflammatory macrophages, which are recruited to the granulation tissue, impairs the healing of diabetic wounds. Herein, we examined the role of vascular endothelial growth factor receptor type 1 (VEGFR1) signaling in streptozotocin (STZ)-induced diabeti...
Source: The American Journal of Pathology - April 13, 2016 Category: Pathology Authors: Okizaki SI, Ito Y, Hosono K, Oba K, Ohkubo H, Kojo K, Nishizawa N, Shibuya M, Shichiri M, Majima M Tags: Am J Pathol Source Type: research

Neutrophil-Epithelial Interactions: A Double-Edged Sword.
Abstract In recent years, it has become clear that innate immune cells termed neutrophils act as double-edged swords by playing essential roles in clearing infection but also causing tissue damage, yet being critical for wound healing. Neutrophil recruitment to sites of injured tissue or infection has been well studied, and many of the molecular events that regulate passage of leukocytes out of the microcirculation are now understood. However, after exiting the circulation, the molecular details that regulate neutrophil passage to end targets, such mucosal surfaces, are just beginning to be appreciated. Given that...
Source: The American Journal of Pathology - April 12, 2016 Category: Pathology Authors: Parkos CA Tags: Am J Pathol Source Type: research

Presymptomatic Alterations in Amino Acid Metabolism and DNA Methylation in the Cerebellum of a Murine Model of Niemann-Pick Type C Disease.
Abstract The fatal neurodegenerative disorder Niemann-Pick type C (NPC) is caused in most cases by mutations in NPC1, which encodes the late endosomal NPC1 protein. Loss of NPC1 disrupts cholesterol trafficking from late endosomes to the endoplasmic reticulum and plasma membrane, causing cholesterol accumulation in late endosomes/lysosomes. Neurons are particularly vulnerable to this cholesterol trafficking defect, but the pathogenic mechanisms through which NPC1 deficiency causes neuronal dysfunction remain largely unknown. Herein, we have investigated amino acid metabolism in cerebella of NPC1-deficient mice at ...
Source: The American Journal of Pathology - April 12, 2016 Category: Pathology Authors: Kennedy BE, Hundert AS, Goguen D, Weaver IC, Karten B Tags: Am J Pathol Source Type: research

Runx2 Controls Bone Resorption through the Down-regulation of the Wnt Pathway in Osteoblasts.
Runx2 Controls Bone Resorption through the Down-regulation of the Wnt Pathway in Osteoblasts. Am J Pathol. 2016 Apr 12; Authors: Haxaire C, Haÿ E, Geoffroy V Abstract The transcription factor Runx2 and the Wnt/β-catenin pathway are major regulators of bone formation. Our aim was to assess the potential interactions between the Wnt/β-catenin pathway and Runx2 that contribute to bone resorption. Our results indicate that the activity of the canonical Wnt/β-catenin pathway depends on Runx2. Runx2 overexpression inhibited β-catenin levels and activity in vitro and i...
Source: The American Journal of Pathology - April 12, 2016 Category: Pathology Authors: Haxaire C, Haÿ E, Geoffroy V Tags: Am J Pathol Source Type: research

Transient Receptor Potential Channel 4 Encodes a Vascular Permeability Defect and High-Frequency Ca(2+) Transients in Severe Pulmonary Arterial Hypertension.
Abstract The canonical transient receptor potential channel 4 (TRPC4) comprises an endothelial store-operated Ca(2+) entry channel, and TRPC4 inactivation confers a survival benefit in pulmonary arterial hypertension (PAH). Endothelial Ca(2+) signals mediated by TRPC4 enhance vascular permeability in vitro, but the contribution of TRPC4-dependent Ca(2+) signals to the regulation of endothelial permeability in PAH is poorly understood. We tested the hypothesis that TRPC4 increases vascular permeability and alters the frequency of endothelial Ca(2+) transients in PAH. We measured permeability in isolated lungs,...
Source: The American Journal of Pathology - April 12, 2016 Category: Pathology Authors: Francis M, Xu N, Zhou C, Stevens T Tags: Am J Pathol Source Type: research

Local Glucocorticoid Activation by 11β-Hydroxysteroid Dehydrogenase 1 in Keratinocytes: The Role in Hapten-Induced Dermatitis.
Local Glucocorticoid Activation by 11β-Hydroxysteroid Dehydrogenase 1 in Keratinocytes: The Role in Hapten-Induced Dermatitis. Am J Pathol. 2016 Apr 9; Authors: Terao M, Itoi S, Matsumura S, Yang L, Murota H, Katayama I Abstract Over the past decade, extra-adrenal cortisol production was reported in various tissues. The enzyme that catalyzes the conversion of hormonally inactive cortisone into active cortisol in cells is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is also expressed in keratinocytes and regulates inflammation and keratinocy...
Source: The American Journal of Pathology - April 9, 2016 Category: Pathology Authors: Terao M, Itoi S, Matsumura S, Yang L, Murota H, Katayama I Tags: Am J Pathol Source Type: research

Enhanced Muscular Dystrophy from Loss of Dysferlin Is Accompanied by Impaired Annexin A6 Translocation after Sarcolemmal Disruption.
We examined the same loss-of-function Dysf mutation in two different mouse strains, 129T2/SvEmsJ (Dysf(129)) and C57BL/6J (Dysf(B6)). Although there are many genetic differences between these two strains, we focused on polymorphisms in Anxa6 because these variants were previously associated with modifying a pathologically distinct form of muscular dystrophy and increased the production of a truncated annexin A6 protein. Dysferlin deficiency in the C57BL/6J background was associated with increased Evan's Blue dye uptake into muscle and increased serum creatine kinase compared to the 129 background. In the C57BL/6J backgroun...
Source: The American Journal of Pathology - April 9, 2016 Category: Pathology Authors: Demonbreun AR, Allen MV, Warner JL, Barefield DY, Krishnan S, Swanson KE, Earley JU, McNally EM Tags: Am J Pathol Source Type: research

Nuclear Factor Erythroid 2-Related Factor 2 Down-Regulation in Oral Neutrophils Is Associated with Periodontal Oxidative Damage and Severe Chronic Periodontitis.
We report, for the first time, Nrf2 pathway down-regulation in oPMNs of patients with severe CP. PMNs of CP patients may be primed for low antioxidant response in the context of high recruitment in the oral cavity, resulting in increased oxidative tissue damage. PMID: 27070823 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - April 9, 2016 Category: Pathology Authors: Sima C, Aboodi GM, Lakschevitz FS, Sun C, Goldberg MB, Glogauer M Tags: Am J Pathol Source Type: research

Generation of Novel Thyroid Cancer Stem-Like Cell Clones: Effects of Resveratrol and Valproic Acid.
Abstract Anaplastic thyroid cancer is an aggressive and highly lethal cancer for which conventional therapies have proved ineffective. Cancer stem-like cells (CSCs) represent a small fraction of cells in the cancer that are resistant to chemotherapy and radiation therapy and are responsible for tumor reoccurrence and metastasis. We characterized CSCs in thyroid carcinomas and generated clones of CSC lines. Our study showed that anaplastic thyroid cancers had significantly more CSCs than well-differentiated thyroid cancers. We also showed that Aldefluor-positive cells revealed significantly higher expression of ste...
Source: The American Journal of Pathology - April 6, 2016 Category: Pathology Authors: Hardin H, Yu XM, Harrison AD, Larrain C, Zhang R, Chen J, Chen H, Lloyd RV Tags: Am J Pathol Source Type: research

Diagnostic and Biological Significance of KIR Expression Profile Determined by RNA-Seq in Natural Killer/T-Cell Lymphoma.
an T, Chan WC Abstract Natural killer/T-cell lymphoma (NKTCL) is a rare, aggressive form of non-Hodgkin lymphoma that is generally incurable at more advanced stages with systemic involvement. Clonal diagnostic markers (eg, unique T- or B-cell receptor rearrangements) are not available for NKTCLs. Killer cell immunoglobulin like receptors (KIRs) are a family of type I transmembrane glycoproteins involved in the inhibition or activation of NK cells. A restricted expression profile of KIRs has been proposed as clonal markers of NK-cell proliferations. Here we evaluated the transcription profile of all KIR family...
Source: The American Journal of Pathology - April 6, 2016 Category: Pathology Authors: Küçük C, Hu X, Gong Q, Jiang B, Cornish A, Gaulard P, McKeithan T, Chan WC Tags: Am J Pathol Source Type: research

This Month in AJP.
Authors: Abstract The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID: 27012189 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - March 27, 2016 Category: Pathology Tags: Am J Pathol Source Type: research

The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded.
Abstract Since our proposal of a dualistic model of epithelial ovarian carcinogenesis more than a decade ago, a large number of molecular and histopathologic studies were published that have provided important insights into the origin and molecular pathogenesis of this disease. This has required that the original model be revised and expanded to incorporate these findings. The new model divides type I tumors into three groups: i) endometriosis-related tumors that include endometrioid, clear cell, and seromucinous carcinomas; ii) low-grade serous carcinomas; and iii) mucinous carcinomas and malignant Brenner t...
Source: The American Journal of Pathology - March 27, 2016 Category: Pathology Authors: Kurman RJ, Shih IeM Tags: Am J Pathol Source Type: research

Saturated and Unsaturated Dietary Fats Differentially Modulate Ethanol-Induced Changes in Gut Microbiome and Metabolome in a Mouse Model of Alcoholic Liver Disease.
Saturated and Unsaturated Dietary Fats Differentially Modulate Ethanol-Induced Changes in Gut Microbiome and Metabolome in a Mouse Model of Alcoholic Liver Disease. Am J Pathol. 2016 Apr;186(4):765-76 Authors: Kirpich IA, Petrosino J, Ajami N, Feng W, Wang Y, Liu Y, Beier JI, Barve SS, Yin X, Wei X, Zhang X, McClain CJ Abstract Alcoholic liver disease (ALD) ranks among major causes of morbidity and mortality. Diet and crosstalk between the gut and liver are important determinants of ALD. We evaluated the effects of different types of dietary fat and ethanol on the gut microbiota composition and m...
Source: The American Journal of Pathology - March 27, 2016 Category: Pathology Authors: Kirpich IA, Petrosino J, Ajami N, Feng W, Wang Y, Liu Y, Beier JI, Barve SS, Yin X, Wei X, Zhang X, McClain CJ Tags: Am J Pathol Source Type: research

IL-6 Overexpression in ERG-Positive Prostate Cancer Is Mediated by Prostaglandin Receptor EP2.
, Nowak M Abstract Prostate cancer is the most diagnosed cancer in men and multiple risk factors and genetic alterations have been described. The TMPRSS2-ERG fusion event and the overexpression of the transcription factor ERG are present in approximately 50% of all prostate cancer patients, however, the clinical outcome is still controversial. Prostate tumors produce various soluble factors, including the pleiotropic cytokine IL-6, regulating cellular processes such as proliferation and metastatic segregation. Here, we used prostatectomy samples in a tissue microarray format and analyzed the co-expression and the ...
Source: The American Journal of Pathology - March 27, 2016 Category: Pathology Authors: Merz C, von Mässenhausen A, Queisser A, Vogel W, Andrén O, Kirfel J, Duensing S, Perner S, Nowak M Tags: Am J Pathol Source Type: research

A Unique Role for Endothelial Cell Kinesin Light Chain 1, Variant 1 in Leukocyte Transendothelial Migration.
Abstract A reservoir of parajunctional membrane in endothelial cells, the lateral border recycling compartment (LBRC), is critical for transendothelial migration (TEM). We have previously shown that targeted recycling of the LBRC to the site of TEM requires microtubules and a kinesin molecular motor. However, the identity of the kinesin and mechanism of cargo binding were not known. We show that microinjection of endothelial cells with a monoclonal antibody specific for kinesin-1 significantly blocked LBRC-targeted recycling and TEM. In complementary experiments, knocking down KIF5B, a ubiquitous kinesin-1 isoform...
Source: The American Journal of Pathology - March 16, 2016 Category: Pathology Authors: Cyrus BF, Muller WA Tags: Am J Pathol Source Type: research

Mouse Osteoblasts Play a Crucial Role in the Immune System.
Abstract This commentary highlights the article by Tu et al describing mechanisms in immune-mediated arthritis that may propel strategies to treat diseases involving the bone and immune system. PMID: 26993206 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - March 15, 2016 Category: Pathology Authors: Kotake S, Nanke Y Tags: Am J Pathol Source Type: research

Establishment of a Novel Histopathological Classification of High-Grade Serous Ovarian Carcinoma Correlated with Prognostically Distinct Gene Expression Subtypes.
Abstract Recently, The Cancer Genome Atlas data revealed four molecular subtypes of high-grade serous ovarian cancer (HGSOC) that exhibited distinct prognoses on the basis of a transcriptome analysis. We developed a novel histopathological classification dividing HGSOC into four subtypes: mesenchymal transition, defined by remarkable desmoplastic reaction, immune reactive by lymphocytes surrounding and infiltrating tumor, solid and proliferative by a solid growth pattern, and papilloglandular by a papillary architecture. Unsupervised hierarchical clustering revealed four clusters correlated with histopathological ...
Source: The American Journal of Pathology - March 15, 2016 Category: Pathology Authors: Murakami R, Matsumura N, Mandai M, Yoshihara K, Tanabe H, Nakai H, Yamanoi K, Abiko K, Yoshioka Y, Hamanishi J, Yamaguchi K, Baba T, Koshiyama M, Enomoto T, Okamoto A, Murphy SK, Mori S, Mikami Y, Minamiguchi S, Konishi I Tags: Am J Pathol Source Type: research

Transgenic Disruption of Glucocorticoid Signaling in Osteoblasts Attenuates Joint Inflammation in Collagen Antibody-Induced Arthritis.
Abstract The role of endogenous glucocorticoids (GCs) in rheumatoid arthritis remains unclear. Herein, we examined the role of osteoblastic GC signaling in collagen antibody-induced arthritis. Intracellular GC signaling was abrogated exclusively in mature osteoblasts via transgenic (tg) expression of 11ß-hydroxysteroid dehydrogenase type 2. Arthritis was induced in 8-week-old male tg mice and their wild-type (WT) littermates. Paw swelling was scored daily from induction to end point (day 14). Inflammation, cartilage degradation, and local bone erosion were assessed at the wrist, knee, and ankle joints. Syste...
Source: The American Journal of Pathology - March 14, 2016 Category: Pathology Authors: Tu J, Zhang Y, Kim S, Wiebe E, Spies CM, Buttgereit F, Cooper MS, Seibel MJ, Zhou H Tags: Am J Pathol Source Type: research

Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2-Dependent Bladder Cancer Cell Migration and Invasion.
Transforming Growth Factor-β Is an Upstream Regulator of Mammalian Target of Rapamycin Complex 2-Dependent Bladder Cancer Cell Migration and Invasion. Am J Pathol. 2016 Mar 14; Authors: Gupta S, Hau AM, Al-Ahmadie HA, Harwalkar J, Shoskes AC, Elson P, Beach JR, Hussey GS, Schiemann WP, Egelhoff TT, Howe PH, Hansel DE Abstract Our prior work identified the mammalian target of rapamycin complex 2 (mTORC2) as a key regulator of bladder cancer cell migration and invasion, although upstream growth factor mediators of this pathway in bladder cancer have not been well delineated. We tested whether trans...
Source: The American Journal of Pathology - March 14, 2016 Category: Pathology Authors: Gupta S, Hau AM, Al-Ahmadie HA, Harwalkar J, Shoskes AC, Elson P, Beach JR, Hussey GS, Schiemann WP, Egelhoff TT, Howe PH, Hansel DE Tags: Am J Pathol Source Type: research

Hepatic Oncostatin M Receptor β Regulates Obesity-Induced Steatosis and Insulin Resistance.
In conclusion, hepatic OSMRβ expression alleviates obesity-induced hepatic insulin resistance and steatosis through the activation of JAK2/STAT3 signaling cascades. PMID: 26976243 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - March 11, 2016 Category: Pathology Authors: Luo P, Wang PX, Li ZZ, Zhang XJ, Jiang X, Gong J, Qin JJ, Guo J, Zhu X, Yang S, Li H Tags: Am J Pathol Source Type: research

Modulation of Decidual Macrophage Polarization by Macrophage Colony-Stimulating Factor Derived from First-Trimester Decidual Cells: Implication in Preeclampsia.
Abstract During human pregnancy, immune tolerance of the fetal semiallograft occurs in the presence of abundant maternal leukocytes. At the implantation site, macrophages comprise approximately 20% of the leukocyte population and act as primary mediators of tissue remodeling. Decidual macrophages display a balance between anti-inflammatory and proinflammatory phenotypes. However, a shift to an M1 subtype is reported in preeclampsia. Granulocyte-macrophage colony-stimulating-factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are major differentiating factors that mediate M1 and M2 polarization, respec...
Source: The American Journal of Pathology - March 9, 2016 Category: Pathology Authors: Li M, Piao L, Chen CP, Wu X, Yeh CC, Masch R, Chang CC, Huang SJ Tags: Am J Pathol Source Type: research

Trehalose 6,6-Dimycolate Induction of Hypercoagulation.
Abstract Tuberculosis (TB) remains a global health concern. Trehalose 6'6-dimycolate (TDM) activates innate inflammation and likely stimulates the chronic inflammation observed during disease progression. Noninfectious models using purified TDM oil/water emulsions elicit pathologic findings observed in patients with TB. We introduce a new TDM model that promotes inflammatory lung pathologic findings and vascular occlusion and hemorrhage. C57BL/6 and BALB/c mice were injected with 10 μg of i.p. TDM in light mineral oil (TDM-IP). At 7 days, another injection of 10 μg of i.v. TDM in oil/water emulsion was given...
Source: The American Journal of Pathology - March 8, 2016 Category: Pathology Authors: Donnachie E, Fedotova EP, Hwang SA Tags: Am J Pathol Source Type: research

Cardiac Tropism of Borrelia burgdorferi: An Autopsy Study of Sudden Cardiac Death Associated with Lyme Carditis.
Abstract Fatal Lyme carditis caused by the spirochete Borrelia burgdorferi rarely is identified. Here, we describe the pathologic, immunohistochemical, and molecular findings of five case patients. These sudden cardiac deaths associated with Lyme carditis occurred from late summer to fall, ages ranged from young adult to late 40s, and four patients were men. Autopsy tissue samples were evaluated by light microscopy, Warthin-Starry stain, immunohistochemistry, and PCR for B. burgdorferi, and immunohistochemistry for complement components C4d and C9, CD3, CD79a, and decorin. Post-mortem blood was tested by serology....
Source: The American Journal of Pathology - March 8, 2016 Category: Pathology Authors: Muehlenbachs A, Bollweg BC, Schulz TJ, Forrester JD, DeLeon Carnes M, Molins C, Ray GS, Cummings PM, Ritter JM, Blau DM, Andrew TA, Prial M, Ng DL, Prahlow JA, Sanders JH, Shieh WJ, Paddock CD, Schriefer ME, Mead P, Zaki SR Tags: Am J Pathol Source Type: research

An Essential Role for SHARPIN in the Regulation of Caspase 1 Activity in Sepsis.
Abstract Sepsis is burdened by high mortality due to uncontrolled inflammatory response to pathogens. Increased caspase 1 activation causing maturation of IL1β/18 cytokines remains a therapeutic challenge in sepsis. SHARPIN (shank-associated regulator of G-protein signaling homology domain-interacting protein), a component of the LUBAC (linear ubiquitin chain-assembly complex), regulates inflammation, with unknown effects on caspase 1 activation. Mice lacking Casp1, Casp11, or both in a Sharpin-deficient background were generated, exposed to lipopolysaccharide-induced endotoxemia, and injected with caspase 1 ...
Source: The American Journal of Pathology - March 8, 2016 Category: Pathology Authors: Nastase MV, Zeng-Brouwers J, Frey H, Tzung-Harn Hsieh L, Poluzzi C, Beckmann J, Schroeder N, Pfeilschifter J, Lopez-Mosqueda J, Mersmann J, Ikeda F, Iozzo RV, Dikic I, Schaefer L Tags: Am J Pathol Source Type: research

Glucocorticoid Receptor as a Potential Target to Decrease Aromatase Expression and Inhibit Leydig Tumor Growth.
ano S Abstract Leydig cell tumors are the most frequent interstitial neoplasms of the testis with apparent recent increased incidence. They are hormonally active and are considered one of the steroid-secreting tumors. Although usually benign, the malignant phenotype responds poorly to conventional chemotherapy or radiation, highlighting the need to identify new therapeutic targets for treatment. Here, we identified a novel glucocorticoid-mediated mechanism that controls cell growth in Leydig cell tumors. We found that a synthetic glucocorticoid receptor agonist, dexamethasone, significantly reduces cell proliferat...
Source: The American Journal of Pathology - March 8, 2016 Category: Pathology Authors: Panza S, Malivindi R, Chemi F, Rago V, Giordano C, Barone I, Bonofiglio D, Gelsomino L, Giordano F, Andò S, Catalano S Tags: Am J Pathol Source Type: research

Deficiency of IκB Kinase in Myeloid Cells Reduces Severity of Experimental Autoimmune Encephalomyelitis.
Deficiency of IκB Kinase in Myeloid Cells Reduces Severity of Experimental Autoimmune Encephalomyelitis. Am J Pathol. 2016 Mar 8; Authors: Hao W, Decker Y, Schnöder L, Schottek A, Li D, Menger MD, Fassbender K, Liu Y Abstract In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), peripherally developed myelin-reactive T lymphocytes stimulate myeloid cells (ie, microglia and infiltrated macrophages) to trigger an inflammatory reaction in the central nervous system, resulting in demyelination and neurodegeneration. IκB kinase (IKKβ) is ...
Source: The American Journal of Pathology - March 8, 2016 Category: Pathology Authors: Hao W, Decker Y, Schnöder L, Schottek A, Li D, Menger MD, Fassbender K, Liu Y Tags: Am J Pathol Source Type: research

Targeted Recycling of the Lateral Border Recycling Compartment Precedes Adherens Junction Dissociation during Transendothelial Migration.
Abstract Leukocyte transendothelial migration (TEM) requires two major events: local dissociation of adherens junctions manifested as gaps in vascular endothelial (VE)-cadherin staining at the site of TEM and targeted trafficking of the lateral border recycling compartment (LBRC) to the site of TEM. However, the association between LBRC recycling and VE-cadherin gaps remains unknown. We found that when targeting of the LBRC is selectively inhibited using established methods, such as a function blocking anti-platelet endothelial cell adhesion molecule 1 antibody, depolymerizing microtubules, or microinjection of an...
Source: The American Journal of Pathology - March 8, 2016 Category: Pathology Authors: Gonzalez AM, Cyrus BF, Muller WA Tags: Am J Pathol Source Type: research

Serum Osteopontin as a Novel Biomarker for Muscle Regeneration in Duchenne Muscular Dystrophy.
In conclusion, OPN is a promising biomarker for muscle regeneration in dystrophic dogs and can be applicable to boys with Duchenne muscular dystrophy. PMID: 26963343 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - March 7, 2016 Category: Pathology Authors: Kuraoka M, Kimura E, Nagata T, Okada T, Aoki Y, Tachimori H, Yonemoto N, Imamura M, Takeda S Tags: Am J Pathol Source Type: research

Circulating miRNAs as Biomarkers of Acute Muscle Damage in Rats.
Abstract Skeletal muscle damage is an often-occurring event. Diagnosis using the classic blood marker creatine kinase sometimes yields unsatisfactory results due to great interindividual variability. Therefore, the identification of reliable biomarkers is important. Our aim was to detect and characterize circulating miRNAs in plasma in response to acute notexin-induced muscle damage in rats. Real-time quantitative RT-PCR profiling led to the identification of miRNAs that were highly increased in plasma in response to notexin injection into several muscles, namely miR-1-3p, -133a-3p, -133b-3p, -206-3p, -208b-3...
Source: The American Journal of Pathology - March 4, 2016 Category: Pathology Authors: Siracusa J, Koulmann N, Bourdon S, Goriot ME, Banzet S Tags: Am J Pathol Source Type: research

IL-19 Halts Progression of Atherosclerotic Plaque, Polarizes, and Increases Cholesterol Uptake and Efflux in Macrophages.
Abstract Atherosclerosis regression is an important clinical goal, and treatments that can halt or reverse atherosclerotic plaque formation are actively being sought. Our aim was to determine whether administration of exogenous IL-19, a Th2 cytokine, could attenuate progression of preformed atherosclerotic plaque and to identify molecular mechanisms. LDLR(-/-) mice were fed a Western diet for 12 weeks, then administered rIL-19 or phosphate-buffered saline concomitant with Western diet for an additional 8 weeks. Analysis of atherosclerosis burden showed that IL-19-treated mice were similar to baseline mice, in cont...
Source: The American Journal of Pathology - March 4, 2016 Category: Pathology Authors: Gabunia K, Ellison S, Kelemen S, Kako F, Cornwell WP, Rogers TJ, Data PK, Ouimet M, Moore KJ, Autieri MV Tags: Am J Pathol Source Type: research

Interaction between Esophageal Squamous Cell Carcinoma and Adipose Tissue in Vitro.
Interaction between Esophageal Squamous Cell Carcinoma and Adipose Tissue in Vitro. Am J Pathol. 2016 Mar 4; Authors: Nakayama A, Aoki S, Uchihashi K, Nishijima-Matsunobu A, Yamamoto M, Kakihara N, Iwakiri R, Fujimoto K, Toda S Abstract Esophageal squamous cell carcinoma (ESCC) develops within the squamous epithelial layer and progressively invades the submucosa to the subadventitia that has abundant adipose tissue (AT). AT seems critical to ESCC progression, but the underlying mechanism is unknown. We aimed to address the association between ESCC and AT in vitro. ESCC cells were cultured on...
Source: The American Journal of Pathology - March 4, 2016 Category: Pathology Authors: Nakayama A, Aoki S, Uchihashi K, Nishijima-Matsunobu A, Yamamoto M, Kakihara N, Iwakiri R, Fujimoto K, Toda S Tags: Am J Pathol Source Type: research

TNF-α Modulation of Intestinal Tight Junction Permeability Is Mediated by NIK/IKK-α Axis Activation of the Canonical NF-κB Pathway.
In conclusion, our data show that NIK/IKK-α/regulates the activation of NF-κB p50/p65 and plays an integral role in the TNF-α-induced activation of MLCK gene and increase in intestinal TJ permeability. PMID: 26948423 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - March 4, 2016 Category: Pathology Authors: Al-Sadi R, Guo S, Ye D, Rawat M, Ma TY Tags: Am J Pathol Source Type: research

Induction of Colonic M Cells during Intestinal Inflammation.
Abstract Intestinal M (microfold) cells are specialized epithelial cells overlying lymphoid tissues in the small intestine. Unlike common enterocytes, M cells lack an organized apical brush border, and are able to transcytose microparticles across the mucosal barrier to underlying antigen-presenting cells. We found that in both the dextran sodium sulfate and Citrobacter rodentium models of colitis, significantly increased numbers of Peyer's patch (PP) phenotype M cells were induced at the peak of inflammation in colonic epithelium, often accompanied by loosely organized lamina propria infiltrates. PP type M cells ...
Source: The American Journal of Pathology - March 3, 2016 Category: Pathology Authors: Bennett KM, Parnell EA, Sanscartier C, Parks S, Chen G, Nair MG, Lo DD Tags: Am J Pathol Source Type: research

Myocardial Galectin-3 Expression Is Associated with Remodeling of the Pressure-Overloaded Heart and May Delay the Hypertrophic Response without Affecting Survival, Dysfunction, and Cardiac Fibrosis.
Abstract The β-galactoside-binding animal lectin galectin-3 is predominantly expressed by activated macrophages and is a promising biomarker for patients with heart failure. Galectin-3 regulates inflammatory and fibrotic responses; however, its role in cardiac remodeling remains unclear. We hypothesized that galectin-3 may be up-regulated in the pressure-overloaded myocardium and regulate hypertrophy and fibrosis. In normal mouse myocardium, galectin-3 was constitutively expressed in macrophages and was localized in atrial but not ventricular cardiomyocytes. In a mouse model of transverse aortic constriction,...
Source: The American Journal of Pathology - March 3, 2016 Category: Pathology Authors: Frunza O, Russo I, Saxena A, Shinde AV, Humeres C, Hanif W, Rai V, Su Y, Frangogiannis NG Tags: Am J Pathol Source Type: research

miR-133b Regulation of Connective Tissue Growth Factor: A Novel Mechanism in Liver Pathology.
Abstract miRNAs are involved in liver regeneration, and their expression is dysregulated in hepatocellular carcinoma (HCC). Connective tissue growth factor (CTGF), a direct target of miR-133b, is crucial in the ductular reaction (DR)/oval cell (OC) response for generating new hepatocyte lineages during liver injury in the context of hepatotoxin-inhibited hepatocyte proliferation. Herein, we investigate whether miR-133b regulation of CTGF influences HCC cell proliferation and migration, and DR/OC response. We analyzed miR-133b expression and found it to be down-regulated in HCC patient samples and induced in the ra...
Source: The American Journal of Pathology - March 2, 2016 Category: Pathology Authors: Gjymishka A, Pi L, Oh SH, Jorgensen M, Liu C, Protopapadakis Y, Patel A, Petersen BE Tags: Am J Pathol Source Type: research

Glioma-Derived Platelet-Derived Growth Factor-BB Recruits Oligodendrocyte Progenitor Cells via Platelet-Derived Growth Factor Receptor-α and Remodels Cancer Stroma.
Glioma-Derived Platelet-Derived Growth Factor-BB Recruits Oligodendrocyte Progenitor Cells via Platelet-Derived Growth Factor Receptor-α and Remodels Cancer Stroma. Am J Pathol. 2016 Mar 2; Authors: Zheng Y, Yamamoto S, Ishii Y, Sang Y, Hamashima T, Van De N, Nishizono H, Inoue R, Mori H, Sasahara M Abstract Glioma is an aggressive and incurable disease, and is frequently accompanied by augmented platelet-derived growth factor (PDGF) signaling. Overexpression of PDGF-B ligand characterizes a specific subclass of glioblastoma multiforme, but the significance of the ligand remains to be elucidated...
Source: The American Journal of Pathology - March 2, 2016 Category: Pathology Authors: Zheng Y, Yamamoto S, Ishii Y, Sang Y, Hamashima T, Van De N, Nishizono H, Inoue R, Mori H, Sasahara M Tags: Am J Pathol Source Type: research

IL-33 Interleukin-33 Drives Eosinophil Infiltration and Pathogenic Type 2 Helper T-Cell Immune Responses Leading to Chronic Experimental Ileitis.
Abstract Although a clear association has been established between IL-33 and inflammatory bowel disease, mechanistic studies to date, primarily using acute murine models of colitis, have yielded contradicting results, demonstrating both pathogenic and protective roles. We used a well-characterized, spontaneous model of inflammatory bowel disease [ie, SAMP1/YitFc (SAMP) mice] to investigate the role of IL-33 during chronic intestinal inflammation. Our results showed marked eosinophil infiltration into the gut mucosa with increased levels of eotaxins and type 2 helper T-cell (Th2) cytokines as disease progressed and...
Source: The American Journal of Pathology - February 20, 2016 Category: Pathology Authors: De Salvo C, Wang XM, Pastorelli L, Mattioli B, Omenetti S, Buela KA, Chowdhry S, Garg RR, Goodman WA, Rodriguez-Palacios A, Smith DE, Abbott DW, Cominelli F, Bamias G, Xin W, Lee JJ, Vecchi M, Pizarro TT Tags: Am J Pathol Source Type: research

Cellular Mechanism for Impaired Hepatitis C Virus Clearance by Interferon Associated with IFNL3 Gene Polymorphisms Relates to Intrahepatic Interferon-λ Expression.
Cellular Mechanism for Impaired Hepatitis C Virus Clearance by Interferon Associated with IFNL3 Gene Polymorphisms Relates to Intrahepatic Interferon-λ Expression. Am J Pathol. 2016 Feb 16; Authors: Ferraris P, Chandra PK, Panigrahi R, Aboulnasr F, Chava S, Kurt R, Pawlotsky JM, Wilkens L, Osterlund P, Hartmann R, Balart LA, Wu T, Dash S Abstract The single nucleotide polymorphism located within the IFNL3 (also known as IL28B) promoter is one of the host factors associated with hepatitis C virus (HCV) clearance by interferon (IFN)-α therapy; however the mechanism remains unknown. We inves...
Source: The American Journal of Pathology - February 16, 2016 Category: Pathology Authors: Ferraris P, Chandra PK, Panigrahi R, Aboulnasr F, Chava S, Kurt R, Pawlotsky JM, Wilkens L, Osterlund P, Hartmann R, Balart LA, Wu T, Dash S Tags: Am J Pathol Source Type: research

Mice Homozygous for a Deletion in the Glaucoma Susceptibility Locus INK4 Show Increased Vulnerability of Retinal Ganglion Cells to Elevated Intraocular Pressure.
Abstract A genomic region located on chromosome 9p21 is associated with primary open-angle glaucoma and normal tension glaucoma in genome-wide association studies. The genomic region contains the gene for a long noncoding RNA called CDKN2B-AS, two genes that code for cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/p16(INK4A) and CDKN2B/p15(INK4B)) and an additional protein (p14(ARF)). We used a transgenic mouse model in which 70 kb of murine chromosome 4, syntenic to human chromosome 9p21, are deleted to study whether this deletion leads to a discernible phenotype in ocular structures implicated in glaucoma. ...
Source: The American Journal of Pathology - February 13, 2016 Category: Pathology Authors: Gao S, Jakobs TC Tags: Am J Pathol Source Type: research

The Protectin PCTR1 Is Produced by Human M2 Macrophages and Enhances Resolution of Infectious Inflammation.
Abstract Inflammation and its natural resolution are host-protective responses triggered by infection or injury. The resolution phase of inflammation is regulated by enzymatically produced specialized pro-resolving mediators. We recently identified a new class of peptide-conjugated specialized pro-resolving mediators that carry potent tissue regenerative actions that belong to the protectin family and are coined protectin conjugates in tissue regeneration (PCTR). Herein, with the use of microbial-induced peritonitis in mice and liquid chromatography-tandem mass spectrometry-based lipid mediator metabololipidomics,...
Source: The American Journal of Pathology - February 13, 2016 Category: Pathology Authors: Ramon S, Dalli J, Sanger JM, Winkler JW, Aursnes M, Tungen JE, Hansen TV, Serhan CN Tags: Am J Pathol Source Type: research

Plasmalemma Vesicle-Associated Protein Has a Key Role in Blood-Retinal Barrier Loss.
In conclusion, PLVAP is an essential cofactor in VEGF-induced BRB permeability and may become an interesting novel target for diabetic macular edema therapy. PMID: 26878208 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - February 12, 2016 Category: Pathology Authors: Wisniewska-Kruk J, van der Wijk AE, van Veen HA, Gorgels TG, Vogels IM, Versteeg D, Van Noorden CJ, Schlingemann RO, Klaassen I Tags: Am J Pathol Source Type: research

αB-Crystallin Regulates Subretinal Fibrosis by Modulation of Epithelial-Mesenchymal Transition.
αB-Crystallin Regulates Subretinal Fibrosis by Modulation of Epithelial-Mesenchymal Transition. Am J Pathol. 2016 Feb 12; Authors: Ishikawa K, Sreekumar PG, Spee C, Nazari H, Zhu D, Kannan R, Hinton DR Abstract Subretinal fibrosis is an end stage of neovascular age-related macular degeneration, characterized by fibrous membrane formation after choroidal neovascularization. An initial step of the pathogenesis is an epithelial-mesenchymal transition (EMT) of retinal pigment epithelium cells. αB-crystallin plays multiple roles in age-related macular degeneration, including cytoprotection and ...
Source: The American Journal of Pathology - February 12, 2016 Category: Pathology Authors: Ishikawa K, Sreekumar PG, Spee C, Nazari H, Zhu D, Kannan R, Hinton DR Tags: Am J Pathol Source Type: research

Dynamic Change of Polarity in Primary Cultured Spheroids of Human Colorectal Adenocarcinoma and Its Role in Metastasis.
Abstract Intestinal epithelial cells possess apical-basal polarity, which governs the exchange of nutrients and waste. Perturbation of cell polarity appears to be a general feature of cancers, although most colorectal cancers are differentiated adenocarcinomas, in which polarity is maintained to some extent. Little is known about the role of dysregulated polarity in cancer. The cancer tissue-originated spheroid method was applied to the preparation and culture of spheroids. Spheroids were cultured in suspension or in type I collagen gel. Polarity was assessed by IHC of apical markers and electron microscopy. Two t...
Source: The American Journal of Pathology - February 12, 2016 Category: Pathology Authors: Okuyama H, Kondo J, Sato Y, Endo H, Nakajima A, Piulats JM, Tomita Y, Fujiwara T, Itoh Y, Mizoguchi A, Ohue M, Inoue M Tags: Am J Pathol Source Type: research

Circulating Extracellular Histones Are Clinically Relevant Mediators of Multiple Organ Injury.
Abstract Extracellular histones are a damage-associated molecular pattern (DAMP) involved in the pathogenesis of various diseases. The mechanisms of histone-mediated injury in certain organs have been extensively studied, but an understanding of the pathophysiological role of histone-mediated injury in multiple organ injury remains elusive. To elucidate this role, we systemically subjected C57BL/6 mice to various doses of histones and performed a chronological evaluation of the morphological and functional changes in the lungs, liver, and kidneys. Notably, histone administration ultimately led to death after a dos...
Source: The American Journal of Pathology - February 12, 2016 Category: Pathology Authors: Kawai C, Kotani H, Miyao M, Ishida T, Jemail L, Abiru H, Tamaki K Tags: Am J Pathol Source Type: research

Actin-Depolymerizing Factor and Cofilin-1 Have Unique and Overlapping Functions in Regulating Intestinal Epithelial Junctions and Mucosal Inflammation.
We examined the roles of ADF and cofilin-1 in regulating the structure and functions of AJs and TJs in the intestinal epithelium. Knockdown of either ADF or cofilin-1 by RNA interference increased the paracellular permeability of human colonic epithelial cell monolayers to small ions. Additionally, cofilin-1, but not ADF, depletion increased epithelial permeability to large molecules. Loss of either ADF or cofilin-1 did not affect the steady-state morphology of AJs and TJs but attenuated de novo junctional assembly. The observed defects in AJ and TJ formation were accompanied by delayed assembly of the perijunctional filam...
Source: The American Journal of Pathology - February 12, 2016 Category: Pathology Authors: Wang D, Naydenov NG, Feygin A, Baranwal S, Kuemmerle JF, Ivanov AI Tags: Am J Pathol Source Type: research

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis.
Abstract Although ethanol causes acute pancreatitis (AP) and lipolytic fatty acid (FA) generation worsens AP, the contribution of ethanol metabolites of FAs, that is, FA ethyl esters (FAEEs), to AP outcomes is unclear. Previously, pancreata of dying alcoholics and pancreatic necrosis in severe AP, respectively, showed high FAEEs and FAs, with oleic acid (OA) and its ethyl esters being the most abundant. We thus compared the toxicities of FAEEs and their parent FAs in severe AP. Pancreatic acini and peripheral blood mononuclear cells were exposed to FAs or FAEEs in vitro. The triglyceride of OA (i.e., glyceryl...
Source: The American Journal of Pathology - February 12, 2016 Category: Pathology Authors: Patel K, Durgampudi C, Noel P, Trivedi RN, de Oliveira C, Singh VP Tags: Am J Pathol Source Type: research