Pancreatic and Islet Remodeling in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Knockout Ferrets.
Abstract In cystic fibrosis (CF) there is early destruction of the exocrine pancreas and this results in a unique form of diabetes that affects approximately half of adult CF individuals. An animal model of cystic fibrosis-related diabetes has been developed in the ferret which progresses through phases of glycemic abnormalities due to islet remodeling during and after exocrine destruction. Here, we quantified the pancreatic histopathologic changes that occur during these phases. There was an increase in percent ductal, fat, and islet area in CF ferrets over time compared to age-matched WT controls. We also quanti...
Source: The American Journal of Pathology - January 20, 2018 Category: Pathology Authors: Rotti PG, Xie W, Poudel A, Yi Y, Sun X, Tyler SR, Uc A, Norris AW, Hara M, Engelhardt JF, Gibson-Corley KN Tags: Am J Pathol Source Type: research

Syndecan-1 controls lung tumorigenesis by regulating microRNAs packaged in exosomes.
Abstract Syndecan-1 is a transmembrane proteoglycan expressed prominently by lung epithelium and has pleiotropic functions such as regulating cell migration, proliferation, and survival. Loss of syndecan-1 expression by lung cancer cells is associated with higher-grade cancers and worse clinical prognosis. We evaluated the effect of syndecan-1 in various cell-based and animal models of lung cancer and found that lung tumorigenesis was moderated by syndecan-1. We also demonstrate that syndecan-1 (or lack thereof) altered the microRNA (miRNA) cargo carried within exosomes exported from lung cancer cells. Analysis of...
Source: The American Journal of Pathology - January 17, 2018 Category: Pathology Authors: Parimon T, Brauer R, Schlesinger SY, Xie T, Jiang D, Ge L, Huang Y, Birkland T, Parks WC, Habiel D, Hogaboam C, Gharib SA, Deng N, Liu Z, Chen P Tags: Am J Pathol Source Type: research

A Shared Pattern of β-catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis.
A Shared Pattern of β-catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis. Am J Pathol. 2018 Jan 16;: Authors: Sucre JMS, Deutsch GH, Jetter C, Ambalavanan N, Benjamin JT, Gleaves LA, Millis BA, Young LR, Blackwell TS, Kropski JA, Guttentag SH Abstract Wnt/β-catenin signaling is necessary for normal lung development, and abnormal Wnt signaling contributes to the pathogenesis of both bronchopulmonary dysplasia (BPD) and idiopathic pulmonary fibrosis (IPF), fibrotic lung diseases that occur during infancy and aging, respectively. Using a library of human normal a...
Source: The American Journal of Pathology - January 16, 2018 Category: Pathology Authors: Sucre JMS, Deutsch GH, Jetter C, Ambalavanan N, Benjamin JT, Gleaves LA, Millis BA, Young LR, Blackwell TS, Kropski JA, Guttentag SH Tags: Am J Pathol Source Type: research

Spliceosome-associated protein 130 exacerbates alcohol-induced liver injury by inducing NLRP3 inflammasome-mediated IL1 β in mice.
Spliceosome-associated protein 130 exacerbates alcohol-induced liver injury by inducing NLRP3 inflammasome-mediated IL1β in mice. Am J Pathol. 2018 Jan 16;: Authors: Kim JW, Roh YS, Jeong H, Yi HK, Lee MH, Lim CW, Kim B Abstract Excessive alcohol consumption leads to chronic liver diseases. Macrophage-inducible C-type lectin (Mincle) is a C-type lectin receptor that recognizes spliceosome-associated protein 130 (SAP130) known as an endogenous ligand released from dying cells. Our aim was to examine the role of Mincle-SAP130 in the pathogenesis of alcoholic liver disease. Alcohol-induced liver inj...
Source: The American Journal of Pathology - January 16, 2018 Category: Pathology Authors: Kim JW, Roh YS, Jeong H, Yi HK, Lee MH, Lim CW, Kim B Tags: Am J Pathol Source Type: research

Mechanisms of enhanced osteoclastogenesis in Alkaptonuria.
In conclusion, the altered osteoclastogenesis was observed already in AKU children despite the absence of evident injury. Thus, a preventive approach in young patients, targeting osteoclast activity, may prevent the macroscopic bone disease which appears in adult AKU. PMID: 29353057 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - January 15, 2018 Category: Pathology Authors: Brunetti G, Tummolo A, D'Amato G, Gaeta A, Ortolani F, Piacente L, Giordano P, Colucci S, Grano M, Papadia F, Faienza MF Tags: Am J Pathol Source Type: research

Chd7 Is Critical for Early T-Cell Development and Thymus Organogenesis in Zebrafish.
Abstract CHARGE syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations in CHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T-cells have been noted in CHARGE syndrome. However, the mechanisms underlying T-lymphopenia are largely unexplored. Here, we observed dramatic decrease of T cells in both chd7-knockdown and -knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas in chd7-deficient embryos, unlikely to contribute to the T cel...
Source: The American Journal of Pathology - January 15, 2018 Category: Pathology Authors: Liu ZZ, Wang ZL, Choi TI, Huang WT, Wang HT, Han YY, Zhu LY, Kim HT, Choi JH, Lee JS, Kim HG, Zhao J, Chen Y, Lu Z, Tian XL, Pan BX, Li BM, Kim CH, Xu H Tags: Am J Pathol Source Type: research

ASK Family Kinases Are Required for Optimal NLRP3 Inflammasome Priming.
Abstract Activation of the multimeric inflammasome complex leads to inflammatory responses to biotic and abiotic triggers. The inflammasome sensor, Nod-like receptor family Pyrin domain containing 3 (NLRP3), is activated by a range of stimuli and is tightly regulated to restrict excessive inflammation. Because NLRP3 responds broadly to cellular insults and regulates cell death similar to the stress-activated apoptosis signal-regulating kinases 1 and 2 (ASK1/2), we hypothesized that ASK1/2 may regulate NLRP3 activity. Though essential for mediating NLRP3 inflammasome activation, ASK1/2 were not required for NLRC4 o...
Source: The American Journal of Pathology - January 15, 2018 Category: Pathology Authors: Place DE, Samir P, Karki R, Briard B, Vogel P, Kanneganti TD Tags: Am J Pathol Source Type: research

Parathyroid hormone-related protein contributes to early healing of Habu-SnakeVenom-induced glomerulonephritis in mice.
ebs M Abstract Proliferative glomerulonephritis is characterized by local inflammation and mesangial cell deterioration, followed by mesangial proliferation and glomerular healing. Parathyroid-hormone-related peptide (PTHrP) is a mesangial cytokine-like growth factor implicated in mesangial proliferation and survival. No data are available about its role in glomerulonephritis. Herein, we analyzed the expression and role of PTHrP in glomerular inflammation and healing in an experimental model of glomerulonephritis induced by intravenous injection of Habu-snake venom in mice. The temporal analysis showed marked rena...
Source: The American Journal of Pathology - January 15, 2018 Category: Pathology Authors: Hochane M, Raison D, Coquard C, Béraud C, Danilin S, Bethry A, Massfelder T, Barthelmebs M Tags: Am J Pathol Source Type: research

Next-generation sequencing to detect deletion of RB1 and ERBB4 genes in chromophobe renal cell carcinoma: A potential role in distinguishing chromophobe renal cell carcinoma from renal oncocytoma.
Abstract Overlapping morphological, immunohistochemical, and ultrastructural features make it difficult to diagnose chromophobe renal cell carcinoma (ChRCC) and renal oncocytoma (RO). Since ChRCC is a malignant tumor, whereas RO is a tumor with benign behavior, it is important to distinguish these two entities. We aimed to identify genetic markers that distinguish ChRCC from RO by using next-generation sequencing (NGS). NGS for hotspot mutations or gene copy number changes was performed on 12 renal neoplasms including seven ChRCC and five RO cases. Matched normal tissues from the same patients were used to exclude...
Source: The American Journal of Pathology - January 15, 2018 Category: Pathology Authors: Liu Q, Cornejo KM, Cheng L, Hutchinson L, Wang M, Zhang S, Tomaszewicz K, Cosar EF, Woda BA, Jiang Z Tags: Am J Pathol Source Type: research

microRNA in Rat Liver Sinusoidal Endothelial Cells and Hepatocytes and Application to Circulating Biomarkers that Discern Pathogenesis of Liver Injuries.
In conclusion, we identified miR-511-3p in plasma as a possible biomarker for LSEC damage. PMID: 29353062 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - January 15, 2018 Category: Pathology Authors: Oda S, Takeuchi M, Akai S, Shirai Y, Tsuneyama K, Yokoi T Tags: Am J Pathol Source Type: research

Protection against the Neurotoxic Effects of β-Amyloid Peptide on Cultured Neuronal Cells by Lovastatin Involves Elevated Expression of α7 Nicotinic Acetylcholine Receptors and Activating Phosphorylation of Protein Kinases.
Protection against the Neurotoxic Effects of β-Amyloid Peptide on Cultured Neuronal Cells by Lovastatin Involves Elevated Expression of α7 Nicotinic Acetylcholine Receptors and Activating Phosphorylation of Protein Kinases. Am J Pathol. 2018 Jan 13;: Authors: Zhao L, Xiao Y, Xiu J, Tan LC, Guan ZZ Abstract The treatment of neurodegenerative diseases with statins has drawn increasing attention, but the related molecular mechanisms remain elusive. To examine the pleiotropic cholesterol-independent effects of statins in connection with the treatment of Alzheimer disease, we probed the influenc...
Source: The American Journal of Pathology - January 13, 2018 Category: Pathology Authors: Zhao L, Xiao Y, Xiu J, Tan LC, Guan ZZ Tags: Am J Pathol Source Type: research

Adventitial Activation in the Pathogenesis of Injury-Induced Arterial Remodeling: Potential Implications in Transplant Vasculopathy.
Abstract Transplant vasculopathy is one of the major causes of chronic rejection following solid organ transplantation. The pathogenic mechanisms of transplant vasculopathy are still poorly understood. Here we summarize current evidence suggesting that activation of the tunica adventitia may be involved in the pathogenesis of transplant vasculopathy. Adventitia is an early responder to various vascular injuries and plays an integral role in eliciting vascular inflammation and remodeling. Accumulation of macrophages in the adventitia promotes the development of vascular remodeling by releasing a variety of paracrin...
Source: The American Journal of Pathology - January 13, 2018 Category: Pathology Authors: Wang J, Wang Y, Wang J, Guo X, Chan EC, Jiang F Tags: Am J Pathol Source Type: research

Patched 1 Expression Correlates with Biochemical Relapse in High-Risk Prostate Cancer Patients.
In this study potential associations between Hh pathway protein expression and clinico-pathological factors, including time to biochemical recurrence (BCR), were investigated using a tissue microarray constructed from benign and malignant prostate samples from 75 predominantly high-risk PCa patients who underwent radical prostatectomy. Hh signaling activity was found to differ between benign and malignant prostate tissue, with a greater amount of active Hh signaling present in malignant than benign prostate epithelium. High expression of PTCH1 in malignant prostate epithelium was found to be an independent predictor of BCR...
Source: The American Journal of Pathology - January 12, 2018 Category: Pathology Authors: Gonnissen A, Isebaert S, Perneel C, McKee CM, Van Utterbeeck F, Lerut E, Verrill C, Bryant RJ, Joniau S, Muschel RJ, Haustermans K 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: 29331321 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - January 10, 2018 Category: Pathology Tags: Am J Pathol Source Type: research

Prognostic Value of the Expression of DNA Repair-Related Biomarkers Mediated by Alcohol in Gastric Cancer Patients.
Abstract Alcohol consumption likely induces gastric carcinogenesis through deregulation of RNA polymerase (Pol) III genes and oxidative damage. Transcription factor IIB-related factor 1 (BRF1) overexpression alleviates RNA Pol III transcription inhibition through breast cancer susceptibility gene 1 (BRCA1). Myeloperoxidase (MPO) involvement in cancer is induced by alcohol-mediated oxidative damage. BRCA1/2 and MPO play key roles in DNA repair. BRCA1 and BRCA2 exert different roles in homologous recombination repair. By using human gastric cancer (GC) biopsies, we investigated the prognostic value of these proteins...
Source: The American Journal of Pathology - January 5, 2018 Category: Pathology Authors: Zhang Y, Wu H, Yang F, Ning J, Li M, Zhao C, Zhong S, Gu K, Wang H Tags: Am J Pathol Source Type: research

Alterations of Ocular Hemodynamics Impair Ophthalmic Vascular and Neuroretinal Function.
In conclusion, hypertension sustained for four weeks causes ophthalmic vascular dysfunction, retinal glial cell activation, oxidative stress, and neuroretinal impairment. Although ophthalmic vasoregulation is insensitive to hypotensive insult, the ocular hypoperfusion causes neuroretinal dysfunction. PMID: 29309745 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - January 5, 2018 Category: Pathology Authors: Tsai SH, Xie W, Zhao M, Rosa RH, Hein TW, Kuo L Tags: Am J Pathol Source Type: research

Role of A-Kinase Anchoring Protein Phosphorylation in Alcohol-Induced Liver Injury and Hepatic Stellate Cell Activation.
Abstract Alcoholic liver injury is associated with hepatic stellate cell (HSC) activation. A-kinase anchoring protein 12 (AKAP12) scaffolds protein kinase C (PKC-α) and cyclin-D1, which is regulated by its phosphorylation, and spatiotemporally controls cell proliferation, invasiveness, and chemotaxis. HSC activation induces AKAP12 expression but the role of AKAP12's scaffolding activity in liver function is unknown. Since AKAP12 phosphorylation is enhanced in ethanol-treated HSCs, we examined AKAP12's scaffolding functions in alcohol-mediated HSC activation and liver injury. AKAP12 expression, interaction, a...
Source: The American Journal of Pathology - January 2, 2018 Category: Pathology Authors: Ramani K, Tomasi ML, Berlind J, Mavila N, Sun Z Tags: Am J Pathol Source Type: research

Correction.
Authors: PMID: 29249253 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - December 20, 2017 Category: Pathology Tags: Am J Pathol Source Type: research

Note of Concern.
Authors: PMID: 29249254 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - December 20, 2017 Category: Pathology Tags: Am J Pathol Source Type: research

Reduced Expression of Hydrogen Sulfide-Generating Enzymes Down-Regulates 15-Hydroxyprostaglandin Dehydrogenase in Chorion  during Term and Preterm Labor.
Reduced Expression of Hydrogen Sulfide-Generating Enzymes Down-Regulates 15-Hydroxyprostaglandin Dehydrogenase in Chorion during Term and Preterm Labor. Am J Pathol. 2018 Jan;188(1):63-71 Authors: Sun Q, Chen Z, He P, Li Y, Ding X, Huang Y, Gu H, Ni X Abstract Chorionic NAD-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) plays a pivotal role in controlling the amount of prostaglandins in the uterus and has been implicated in the process of labor. Prior studies identified hydrogen sulfide-generating enzymes cystathionine-β-synthetase (CBS) and cystathionine-γ-lyase (CSE) in ...
Source: The American Journal of Pathology - December 20, 2017 Category: Pathology Authors: Sun Q, Chen Z, He P, Li Y, Ding X, Huang Y, Gu H, Ni X Tags: Am J Pathol Source Type: research

Fibrosis in Preeclamptic Placentas Is Associated with Stromal Fibroblasts Activated by the Transforming Growth Factor Beta 1 (TGFB1) Signaling Pathway.
Abstract Although fibrosis is one of the most prominent pathological features of preeclamptic (PE) placentas, its mechanism remains largely unknown. Consistent with previous reports, we observed overexpression of collagen; actin, alpha 2, smooth muscle, aorta; connective tissue growth factor; and fibronectin in PE placentas compared with control ones. To investigate the mechanism of fibrosis in PE placentas, placental fibroblasts were isolated from PE placentas or normal pregnancies at delivery. The expression of fibrosis-related factors in fibroblasts was evaluated by real-time reverse transcription PCR, western ...
Source: The American Journal of Pathology - December 15, 2017 Category: Pathology Authors: Ohmaru-Nakanishi T, Asanoma K, Fujikawa M, Fujita Y, Yagi H, Onoyama I, Hidaka N, Sonoda K, Kato K Tags: Am J Pathol Source Type: research

MicroRNA-31-3p Is Involved in Substance P (SP)-Associated Inflammation in Human Colonic Epithelial Cells and Experimental Colitis.
Abstract Substance P (SP) mediates colitis. SP signaling regulates the expression of several microRNAs (miRNAs), including miR-31-3p, in human colonocytes. However, the role of miR-31-3p in colitis and the underlying mechanisms has not been elucidated. We performed real time PCR analysis of miR-31-3p expression in human colonic epithelial cells overexpressing neurokinin-1 receptor (NCM460 NK-1R) in response to SP stimulation and in NCM460 cells following interleukin (IL)-6, IL8, tumor necrosis factor (TNF)-α, and interferon-γ exposure. Functions of miR-31-3p were tested in NCM460-NK-1R cells and the TN...
Source: The American Journal of Pathology - December 15, 2017 Category: Pathology Authors: Fang K, Law IKM, Padua D, Sideri A, Huang V, Kevil CG, Iliopoulos D, Pothoulakis C Tags: Am J Pathol Source Type: research

Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice.
In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis via orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC, and displayed a striking acquisition of CC-related pathological and molecular features, which was absent in the primary HCC tumors. Our study directly demo...
Source: The American Journal of Pathology - December 14, 2017 Category: Pathology Authors: Li L, Qian M, Chen IH, Finkelstein D, Onar-Thomas A, Johnson M, Calabrese C, Bahrami A, López-Terrada DH, Yang JJ, Tao WA, Zhu L Tags: Am J Pathol Source Type: research

A large set of miRNAs is dysregulated since the earliest steps of human hepatocellular carcinoma development.
Abstract Hepatocellular carcinoma (HCC) mostly results from a stepwise process characterized by the development of premalignant lesions, such as low- or high-grade dysplastic nodules (LGDN and HGDN, respectively) in a cirrhotic setting. MicroRNAs (miRNAs) are small noncoding RNAs involved in post-transcriptional regulation of gene expression that can act as oncogenes or tumor suppressors. Whether and which miRNAs are involved in the early stages of HCC development remains elusive. Here, small RNA sequencing was applied to profile miRNA expression in 55 samples (cirrhotic nodules, CNs), LGDNs, HGDNs, early HCCs, an...
Source: The American Journal of Pathology - December 14, 2017 Category: Pathology Authors: Sulas P, Di Tommaso L, Novello C, Rizzo F, Rinaldi A, Weisz A, Columbano A, Roncalli M Tags: Am J Pathol Source Type: research

Endothelin-2 injures the blood-retinal barrier and macroglial M üller cells:: interactions with angiotensin II, aldosterone, and NADPH oxidase.
In conclusion, Edn2 has detrimental effects on the BRB and Müller cells that involve interactions with the renin-angiotensin aldosterone system and Nox1/4. PMID: 29248456 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - December 14, 2017 Category: Pathology Authors: Alrashdi SF, Deliyanti D, Talia DM, Wilkinson-Berka JL Tags: Am J Pathol Source Type: research

Malnutrition in pancreatic ductal adenocarcinoma (PDA): dietary pancreatic enzymes improve short-term health but stimulate tumor growth.
Abstract Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that resists efforts to identify better chemotherapeutics. PDA is associated with chronic pancreatitis and acinar cell dedifferentiation. This reduces enzyme production by the exocrine pancreas, resulting in digestive insufficiencies. Malabsorption of partially digested food can cause bloating, overfilled intestines, abdominal pain, excessive feces, steatorrhea, and malnutrition. These maladies affect quality of life and restrict treatment options for pancreatitis and PDA. Here, we characterize the health benefits and risks of dietary pancreatic en...
Source: The American Journal of Pathology - December 14, 2017 Category: Pathology Authors: Zolghadri Y, Choudhuri SP, Ocal O, Ghalehsoukhteh SL, Berhe F, Hale MA, Wilkie TM Tags: Am J Pathol Source Type: research

Hepatic stem/progenitor cell activation differs between primary sclerosing and primary biliary cholangitis.
In conclusion, progenitor cell activation differs between primary sclerosing cholangitis and primary biliary cholangitis and is characterized by a divergent fate commitment and different signaling pathway predominance. In primary biliary cholangitis, ductular reaction represents a relevant histologic prognostic marker. PMID: 29248458 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - December 14, 2017 Category: Pathology Authors: Carpino G, Cardinale V, Folseraas T, Overi D, Floreani A, Franchitto A, Onori P, Cazzagon N, Berloco PB, Karlsen TH, Alvaro D, Gaudio E Tags: Am J Pathol Source Type: research

Discrete pools of oligomeric amyloid- β track with spatial learning deficits in a mouse model of Alzheimer amyloidosis.
Discrete pools of oligomeric amyloid-β track with spatial learning deficits in a mouse model of Alzheimer amyloidosis. Am J Pathol. 2017 Dec 14;: Authors: Chiang ACA, Fowler SW, Reddy R, Pletnikova O, Troncoso JC, Sherman MA, Lesne SE, Jankowsky JL Abstract Despite increasing appreciation that oligomeric amyeloid beta (Aβ) may contribute to cognitive decline of Alzheimer disease, defining the most critical forms has been thwarted by the changeable nature of these aggregates and the varying methods used for detection. Here, using a broad approach, we quantified Aβ oligomers during the ev...
Source: The American Journal of Pathology - December 14, 2017 Category: Pathology Authors: Chiang ACA, Fowler SW, Reddy R, Pletnikova O, Troncoso JC, Sherman MA, Lesne SE, Jankowsky JL Tags: Am J Pathol Source Type: research

γδ T cells contribute to injury in the developing brain.
γδ T cells contribute to injury in the developing brain. Am J Pathol. 2017 Dec 14;: Authors: Albertsson AM, Zhang X, Vontell R, Bi D, Bronson RT, Supramaniam V, Baburamani AA, Hua S, Nazmi A, Cardell S, Zhu C, Cantor H, Mallard C, Hagberg H, Leavenworth JW, Wang X Abstract Brain injury in premature infants, especially periventricular leukomalacia, is an important cause of neurological disabilities. Inflammation contributes to the development of perinatal brain injury, but the essential mediators leading to brain injury in early life remain largely unknown. Neonates have reduced capacity fo...
Source: The American Journal of Pathology - December 14, 2017 Category: Pathology Authors: Albertsson AM, Zhang X, Vontell R, Bi D, Bronson RT, Supramaniam V, Baburamani AA, Hua S, Nazmi A, Cardell S, Zhu C, Cantor H, Mallard C, Hagberg H, Leavenworth JW, Wang X Tags: Am J Pathol Source Type: research

Knockout of l-Histidine Decarboxylase (HDC-/-) Prevents Cholangiocyte Damage and Hepatic Fibrosis in Mice Subjected to High-Fat Diet Feeding via Disrupted Histamine/Leptin Signaling.
Abstract Administration of a high-fat diet (HFD) coupled with sugar, mimicking a Western diet, causes fatty liver disease in mice. Histamine induces biliary proliferation and fibrosis, and regulates leptin signaling. Wild-type (WT) and l-histidine decarboxylase (Hdc-/-) mice were fed a control diet or a HFD coupled with a high fructose corn syrup equivalent. H&E and Oil Red O staining were performed to determine steatosis. Intrahepatic biliary mass and cholangiocyte proliferation were evaluated by immunohistochemistry. Senescence and fibrosis were measured by qPCR and immunohistochemistry. Hepatic stellate cel...
Source: The American Journal of Pathology - December 14, 2017 Category: Pathology Authors: Kennedy L, Hargrove L, Demieville J, Bailey J, Dar W, Polireddy K, Chen Q, Nevah Rubin MI, Sybenga A, DeMorrow S, Meng F, Stockton L, Alpini G, Francis H Tags: Am J Pathol Source Type: research

Fibroblasts Promote Inflammation and Pain via Interleukin-1 α-Induction of the Monocyte Chemoattractant CCL2.
Fibroblasts Promote Inflammation and Pain via Interleukin-1α-Induction of the Monocyte Chemoattractant CCL2. Am J Pathol. 2017 Dec 14;: Authors: Paish HL, Kalson NS, Smith GR, Del Carpio Pons A, Baldock TE, Smith N, Swist-Szulik K, Weir DJ, Bardgett M, Deehan DJ, Mann DA, Borthwick LA Abstract Fibroblasts persist within fibrotic scar tissue and exhibit considerable phenotypic and functional plasticity. Here, we hypothesized that scar-associated fibroblasts may be a source of stress-induced inflammatory exacerbations and pain. To test this idea we used a human model of surgery-induced fibrosis, t...
Source: The American Journal of Pathology - December 14, 2017 Category: Pathology Authors: Paish HL, Kalson NS, Smith GR, Del Carpio Pons A, Baldock TE, Smith N, Swist-Szulik K, Weir DJ, Bardgett M, Deehan DJ, Mann DA, Borthwick LA 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: 29246494 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - December 12, 2017 Category: Pathology Tags: Am J Pathol Source Type: research

Elevated peripheral myelin protein 22, reduced mitotic potential, and proteasome impairment in dermal fibroblasts from Charcot-Marie-Tooth disease type 1A patients.
Abstract A common form of hereditary autosomal dominant demyelinating neuropathy known as Charcot-Marie-Tooth disease type 1A (CMT1A) is linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Although studies from animal models have led to better understanding of the pathobiology of these neuropathies, there continues to be a gap in the translation of findings from rodents to humans. As PMP22 was originally identified in fibroblasts as growth arrest specific gene 3 (gas3) and is expressed broadly in the body, it was tested whether skin cells from neuropathic patients would display the cellular p...
Source: The American Journal of Pathology - December 12, 2017 Category: Pathology Authors: Lee S, Bazick H, Chittoor-Vinod V, Al Salihi MO, Xia G, Notterpek L Tags: Am J Pathol Source Type: research

microRNAs as Biomarkers for Predicting the Progression of Ductal Carcinoma in Situ.
Abstract Ductal carcinoma in situ (DCIS) is defined as a proliferation of neoplastic cells within the duct of the mammary gland that have not invaded into the surrounding stroma. DCIS is considered a precursor to invasive ductal carcinoma (IDC); however, approximately only half of DCIS may progress to IDC, if left untreated. Current research has shown that the genomic and transcriptomic changes are present in DCIS prior to the emergence of invasive disease, indicating that the malignant nature of the DCIS is defined prior to invasion. However, important questions remain surrounding the specific changes and process...
Source: The American Journal of Pathology - December 12, 2017 Category: Pathology Authors: Hannafon BN, Ding WQ Tags: Am J Pathol Source Type: research

Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Post-Treatment in Rhesus Macaques.
Abstract Non-human primates currently serve as the best experimental model for Lyme disease due to their close genetic homology with humans and demonstration of all three phases of disease following infection with Borreliella (Borrelia) burgdorferi (Bb). We investigated the pathology associated with late disseminated Lyme disease (12 to 13 months following tick inoculation) in doxycycline-treated (28 days; 5mg/kg, oral, 2x/day) and untreated rhesus macaques (Rm). Minimal to moderate lymphoplasmacytic inflammation, with a predilection for perivascular spaces and collagenous tissues, was observed in multiple tissues...
Source: The American Journal of Pathology - December 11, 2017 Category: Pathology Authors: Crossland NA, Alvarez X, Embers ME Tags: Am J Pathol Source Type: research

Lymphocyte-Dominant Encephalitis and Meningitis in Simian Immunodeficiency Virus-Infected Macaques Receiving Antiretroviral Therapy.
Abstract A retrospective neuropathologic review of 30 SIV-infected pigtailed macaques receiving combination antiretroviral therapy (cART) was conducted. Seventeen animals with lymphocyte-dominant inflammation in the brain and/or meninges that clearly was morphologically distinct from prototypic SIV encephalitis and human immunodeficiency virus encephalitis were identified. Central nervous system (CNS) infiltrates in cART-treated macaques primarily comprised CD20+ B cells and CD3+ T cells with fewer CD68+ macrophages. Inflammation was associated with low levels of SIV RNA in the brain as shown by in situ hybridizat...
Source: The American Journal of Pathology - December 5, 2017 Category: Pathology Authors: Mangus LM, Beck SE, Queen SE, Brill SA, Shirk EN, Metcalf Pate KA, Muth DC, Adams RJ, Gama L, Clements JE, Mankowski JL Tags: Am J Pathol Source Type: research

Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression.
Abstract Lipopolysaccharides (LPSs) are a major component of the Gram-negative bacterial cell wall and play an important role in mediating intestinal inflammatory responses in inflammatory bowel disease. Although recent studies suggested that physiologically relevant concentrations of LPS (0 to 1 ng/mL) cause an increase in intestinal epithelial tight junction (TJ) permeability, the mechanisms that mediate an LPS-induced increase in intestinal TJ permeability remain unclear. Herein, we show that myosin light chain kinase (MLCK) plays a central role in the LPS-induced increase in TJ permeability. Filter-grown Caco-...
Source: The American Journal of Pathology - November 22, 2017 Category: Pathology Authors: Nighot M, Al-Sadi R, Guo S, Rawat M, Nighot P, Watterson MD, Ma TY Tags: Am J Pathol Source Type: research

Clinical Evidence Supports a Protective Role for CXCL5 in Coronary Artery Disease.
Abstract Our goal was to measure the association of CXCL5 and molecular phenotypes associated with coronary atherosclerosis severity in patients at least 65 years old. CXCL5 is classically defined as a proinflammatory chemokine, but its role in chronic inflammatory diseases, such as coronary atherosclerosis, is not well defined. We enrolled individuals who were at least 65 years old and undergoing diagnostic cardiac catheterization. Coronary artery disease (CAD) severity was quantified in each subject via coronary angiography by calculating a CAD score. Circulating CXCL5 levels were measured from plasma, and both ...
Source: The American Journal of Pathology - November 15, 2017 Category: Pathology Authors: Ravi S, Schuck RN, Hilliard E, Lee CR, Dai X, Lenhart K, Willis MS, Jensen BC, Stouffer GA, Patterson C, Schisler JC Tags: Am J Pathol Source Type: research

Porphyromonas gingivalis differentially modulates apoptosome APAF-1 in epithelial cells and fibroblasts.
In this study, Apaf-1 and X-linked inhibitor of apoptosis protein (Xiap) mRNA were differentially expressed between gingival samples harvested from human healthy and chronic periodontitis tissues (Apaf-1: 19.2-fold; caspase-9: 14.5-fold; caspase-3: 6.8-fold; Xiap: 2.5-fold in chronic periodontitis) (P
Source: The American Journal of Pathology - November 15, 2017 Category: Pathology Authors: Bugueno IM, Batool F, Korah L, Benkirane-Jessel N, Huck O Tags: Am J Pathol Source Type: research

Inhibition of cyclooxygenase (COX)-2 suppresses the recruitment of endothelial progenitor cells in the microvasculature of endometriotic lesions.
Abstract The incorporation of endothelial progenitor cells (EPCs) into newly developing blood vessels contributes to the vascularization of endometriotic lesions. here, we analyzed whether cyclooxygenase (COX)-2 signaling regulates this vasculogenic process. Endometriotic lesions were surgically induced in irradiated FVB/N mice, which were reconstituted with bone marrow from FVB/N-TgN (Tie2/green fluorescent protein (GFP)) 287 Sato mice. The animals received β-estradiol 17-valerate once a week and were daily treated with the selective COX-2 inhibitor parecoxib (25 mg/kg) or vehicle (control) over 7 and 28 day...
Source: The American Journal of Pathology - November 15, 2017 Category: Pathology Authors: Rudzitis-Auth J, Nickels RM, Menger MD, Laschke MW Tags: Am J Pathol Source Type: research

A Novel Type 2 Diabetes Mouse Model of Combined Diabetic Kidney Disease and Atherosclerosis.
Abstract Diabetic kidney disease and atherosclerotic disease are major causes of morbidity and mortality associated with type 2 diabetes (T2D), and diabetic kidney disease is a major cardiovascular risk factor. The BTBR mouse strain with leptin-deficiency (Lep(ob)) has emerged as one of the best models of human diabetic kidney disease. However, no T2D mouse model of combined diabetic kidney disease and atherosclerosis exists. Our goal was to generate such a model. To this end, the LDL receptor was targeted for degradation via IDOL (inducible degrader of the LDL receptor) overexpression, using a liver-targeted aden...
Source: The American Journal of Pathology - November 15, 2017 Category: Pathology Authors: Bornfeldt KE, Kramer F, Batorsky A, Choi J, Hudkins KL, Tontonoz P, Alpers CE, Kanter JE Tags: Am J Pathol Source Type: research

Extracellular lipids accumulate in human carotid arteries as distinct three-dimensional structures and have proinflammatory properties.
vanen PT, Öörni K Abstract Lipid accumulation is a key characteristic of advancing atherosclerotic lesions. Here we analyzed the ultrastructure of the accumulated lipids in endarterectomized human carotid atherosclerotic plaques using three-dimensional (3D) electron microscopy, a method never used in this context before. 3D-electron microscopy revealed intracellular lipid droplets and extracellular lipoprotein particles. The majority of the particles were aggregated and some connected to needle-shaped or sheet-like cholesterol crystals. Proteomic analysis of isolated extracellular lipoprotein particles r...
Source: The American Journal of Pathology - November 14, 2017 Category: Pathology Authors: Lehti S, Nguyen SD, Belevich I, Vihinen H, Heikkilä HM, Soliymani R, Käkelä R, Saksi J, Jauhiainen M, Grabowski GA, Kummu O, Hörkkö S, Baumann M, Lindsberg PJ, Jokitalo E, Kovanen PT, Öörni K Tags: Am J Pathol Source Type: research

Distinct effects of interleukin-6 classic and trans-signaling in bone fracture healing.
Abstract Bone healing is a complex process with closely linked phases of inflammation, regeneration, and remodeling. Interleukin-6 (IL-6) may crucially regulate this process; however, the underlying mechanisms are presently unclear. IL-6 signals are transmitted via the transmembrane glycoprotein 130 by two distinct mechanisms: classic signaling employing the membrane-anchored IL-6 receptor, and trans-signaling using its soluble form. Here, we investigated the hypothesis that IL-6 classic and trans-signaling have different functions during bone healing. To investigate fracture healing, 12-week-old C57BL/6J mice rec...
Source: The American Journal of Pathology - November 13, 2017 Category: Pathology Authors: Prystaz K, Kaiser K, Kovtun A, Haffner-Luntzer M, Fischer V, Rapp AE, Liedert A, Strauss G, Waetzig GH, Rose-John S, Ignatius A Tags: Am J Pathol Source Type: research

Analysis of Tumor Biology to Advance Cancer Health Disparity Research.
Abstract Cancer mortality rates in the US continue to decline. Reductions in tobacco use, uptake of preventive measures, adoption of early detection methods, and better treatments have resulted in improved cancer outcomes for men and women. Despite this progress, some population groups continue to experience an excessive cancer burden when compared with other population groups. One of the most prominent cancer health disparities exists in prostate cancer. Prostate cancer mortality rates are highest among men of African ancestry when compared with other men, both in the US and globally. This disparity and other can...
Source: The American Journal of Pathology - November 11, 2017 Category: Pathology Authors: Smith CJ, Minas TZ, Ambs S Tags: Am J Pathol Source Type: research

The Science of Cancer Health Disparities.
Abstract This Guest Editorial highlights the reviews in Race in Cancer Health Disparities Theme Issue that improve our understanding of the complex role of race in disparities in cancer frequency and outcome. PMID: 29137949 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 11, 2017 Category: Pathology Authors: Gardner K Tags: Am J Pathol Source Type: research

Linking Race, Cancer Outcomes and Tissue Repair.
Abstract The burden of cancer in the United States is unevenly spread across its different populations, with stark differences in both disease prevalence and outcome based on race and ethnicity. Although a large portion of these differences can be explained by a variety of socio-behavioral and socio-economic factors, even after these exposures are taken into consideration, significant disparities persist. In this review, we explore a conceptual framework of biological theories and unifying concepts, based on an evolutionary perspective, that may help better define common guiding principles for exploration of under...
Source: The American Journal of Pathology - November 11, 2017 Category: Pathology Authors: Byun JS, Park S, Caban A, Jones A, Gardner K Tags: Am J Pathol Source Type: research

Triple-Negative Breast Cancer, Stem Cells, and African Ancestry.
Abstract Triple-negative breast cancers (TNBC) are more common among African ancestry populations, such as African Americans and western, sub-Saharan Africans, compared to European ancestry populations. This phenotype prevalence contributes to breast cancer outcome disparities between African Americans and Caucasian Americans. Breast cancer stem cells represent the tumor subpopulation responsible for metastatic virulence and ongoing research seeks to characterize the extent to which TNBC versus non-TNBC stem cells may differ. This review summarizes the existing literature regarding TNBC and stem cells as they pert...
Source: The American Journal of Pathology - November 11, 2017 Category: Pathology Authors: Jiagge E, Chitale D, Newman LA Tags: Am J Pathol Source Type: research

Neural EGFL like 1 regulates cartilage maturation through runt-related transcription factor 3-mediated Indian hedgehog signaling.
In this study, we further revealed that the pro-chondrogenic activities of Nell-1 also rely on Ihh signaling, by showing: [1] Nell-1 significantly elevated Ihh signal transduction, [2] Nell-1 deficiency markedly reduced Ihh activation in chondrocytes, and [3] Nell-1-stimulated chondrogenesis was significantly reduced by the specific hedgehog inhibitor, cyclopamine. Importantly, we demonstrated that Nell-1-responsive Ihh signaling and chondrogenic differentiation extended to Runx2(-/-) models in vitro and in vivo. In Runx2(-/-) chondrocytes, Nell-1 stimulated the expression and signal transduction of Runx3, another transcri...
Source: The American Journal of Pathology - November 11, 2017 Category: Pathology Authors: Li C, Zheng Z, Jiang J, Jiang W, Lee K, Berthiaume EA, Chen EC, Culiat CT, Zhou YH, Zhang X, Ting K, Soo C 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: 29132928 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 10, 2017 Category: Pathology Tags: Am J Pathol Source Type: research

A New Scope and a New Editorial Team for The American Journal of Pathology.
PMID: 29132929 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 10, 2017 Category: Pathology Authors: Furie MB Tags: Am J Pathol Source Type: research