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The Role of Substance P in Pulmonary Clearance of Bacteria in Comparative Injury Models.
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The Role of Substance P in Pulmonary Clearance of Bacteria in Comparative Injury Models.

Am J Pathol. 2016 Dec;186(12):3236-3245

Authors: Hsieh T, Vaickus MH, Stein TD, Lussier BL, Kim J, Stepien DM, Duffy ER, Chiswick EL, Remick DG

Abstract
Neural input to the immune system can alter its ability to clear pathogens effectively. Patients suffering mild traumatic brain injury (mTBI) have shown reduced rates of pneumonia and a murine model replicated these findings, with better overall survival of TBI mice compared with sham-injured mice. To further investigate the mechanism of improved host response in TBI mice, this study developed and characterized a mild tail trauma model of similar severity to mild TBI. Both mild tail trauma and TBI induced similar systemic changes that normalized within 48 hours, including release of substance P. Examination of tissues showed that injuries are limited to the target tissue (ie, tail in tail trauma, brain in mTBI). Pneumonia challenge showed that mild TBI mice showed improved immune responses, characterized by the following: i) increased survival, ii) increased pulmonary neutrophil recruitment, iii) increased bacterial clearance, and iv) increased phagocytic cell killing of bacteria compared with tail trauma. Administration of a neurokinin-1-receptor antagonist to block substance P signaling eliminated the improved survival of mTBI mice. Neurokinin-1-receptor antagonism did not alter pneumonia mortality in tail trauma mice. These data show that immune benefits of trauma are specific to mTBI and that tail trauma is an appropriate control for future studies aimed at elucidating the mechanisms of improved innate immune responses in mTBI mice.

PMID: 27876152 [PubMed - indexed for MEDLINE]




Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice.
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Identification of an Epitope from Adenine Nucleotide Translocator 1 That Induces Inflammation in Heart in A/J Mice.

Am J Pathol. 2016 Dec;186(12):3160-3175

Authors: Basavalingappa RH, Massilamany C, Krishnan B, Gangaplara A, Kang G, Khalilzad-Sharghi V, Han Z, Othman S, Li Q, Riethoven JJ, Sobel RA, Steffen D, Reddy J

Abstract
Heart failure, a leading cause of death in humans, can emanate from myocarditis. Although most individuals with myocarditis recover spontaneously, some develop chronic dilated cardiomyopathy. Myocarditis may result from both infectious and noninfectious causes, including autoimmune responses to cardiac antigens. In support of this notion, intracellular cardiac antigens, like cardiac myosin heavy chain-α, cardiac troponin-I, and adenine nucleotide translocator 1 (ANT1), have been identified as autoantigens in cardiac autoimmunity. Herein, we demonstrate that ANT1 can induce autoimmune myocarditis in A/J mice by generating autoreactive T cells. We show that ANT1 encompasses multiple immunodominant epitopes (namely, ANT1 21-40, ANT1 31-50, ANT1 171-190, and ANT1 181-200). Although all four peptides induce comparable T-cell responses, only ANT1 21-40 was found to be a major myocarditogenic epitope in immunized animals. The myocarditis-inducing ability of ANT1 21-40 was associated with the generation of T cells producing predominantly IL-17A, and the antigen-sensitized T cells could transfer the disease to naïve recipients. These data indicate that cardiac mitochondrial proteins can be target autoantigens in myocarditis, supporting the notion that the antigens released as a result of primary damage may contribute to the persistence of chronic inflammation through autoimmunity.

PMID: 27876151 [PubMed - indexed for MEDLINE]




Transfusion of CD206(+) M2 Macrophages Ameliorates Antibody-Mediated Glomerulonephritis in Mice.
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Transfusion of CD206(+) M2 Macrophages Ameliorates Antibody-Mediated Glomerulonephritis in Mice.

Am J Pathol. 2016 Dec;186(12):3176-3188

Authors: Du Q, Tsuboi N, Shi Y, Ito S, Sugiyama Y, Furuhashi K, Endo N, Kim H, Katsuno T, Akiyama S, Matsuo S, Isobe KI, Maruyama S

Abstract
Macrophages are multifunctional immune cells that may either drive or modulate disease pathogenesis, depending on the activated phenotype. In this study, we investigated the protective effects of CD206(+) M2 macrophages against nephrotoxic serum nephritis in mice. We found that these immunosuppressive macrophages, derived from bone marrow and stimulated with IL-4/IL-13 [CD206(+) M2 bone marrow-derived macrophages (M2BMMs)], protected against renal injury, decreased proteinuria, and diminished the infiltration of CD68(+) macrophages, neutrophils, and T cells into glomerular tissue. Comparable therapeutic results were obtained with CD206(+) M2 cells derived from induced pluripotent stem cells. Notably, CD206(+) M2BMMs, which retained an M2 signature, could elicit a switch of M1 to M2 phenotype in co-cultured macrophages. Moreover, these cells were found to induce the production of regulatory T cells in the spleen and renal draining lymph node. Accordingly, mRNA expression of the T helper 1 cytokines tumor necrosis factor-α, interferon-β, interferon-γ, and IL-12 was significantly reduced in kidneys from mice treated with CD206(+) M2BMMs. Taken together, the data suggest that CD206(+) M2 may have therapeutic potential against antibody-mediated glomerular injury and presents its therapeutic value for the treatment of crescentic nephritis in humans.

PMID: 27855848 [PubMed - indexed for MEDLINE]




p15 Expression Differentiates Nevus from Melanoma.
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p15 Expression Differentiates Nevus from Melanoma.

Am J Pathol. 2016 Dec;186(12):3094-3099

Authors: Taylor LA, O'Day C, Dentchev T, Hood K, Chu EY, Ridky TW, Seykora JT

Abstract
Most melanomas are driven by BRAF(V600E)-activating mutations, while nevi harboring the same mutations have growth arrest. Although decreased p16 expression has been associated with melanoma formation, in recent work, p15 represented a primary effector of oncogene-induced senescence in nevomelanocytes that was diminished in melanomas. This study determined whether decreased p15 levels represent a general biomarker for the transition from nevus to melanoma. We performed p15 and p16 IHC analyses on a random series of nevi and melanomas. Staining was evaluated and graded for percentage and intensity to determine the H score. For real-time quantitative RT-PCR analysis of p15, RNA was extracted from FFPE sections from 14 nevus and melanoma samples via macrodissection. A two-sided t-test was used to evaluate between-group differences in mean H scores and qΔCt values. p15 Expression was significantly increased in melanocytic nevi compared with melanomas (mean H scores, 254.8 versus 132.3; P < 0.001). On p15 staining, the H score differential was greater than that with p16 staining [122.5 (P < 0.001) and 64.8 (P = 0.055), respectively]. Real-time quantitative RT-PCR analysis revealed a lower mean qΔCt value in melanomas, consistent with lower p15 expression (P = 0.018). Together, these data support the hypothesis that decreased p15 expression is a robust biomarker for distinguishing nevus from melanoma.

PMID: 27855847 [PubMed - indexed for MEDLINE]




The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation: Implications for Thyroid Eye Disease.
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The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation: Implications for Thyroid Eye Disease.

Am J Pathol. 2016 Dec;186(12):3189-3202

Authors: Woeller CF, Roztocil E, Hammond CL, Feldon SE, Phipps RP

Abstract
Thyroid eye disease (TED) is a degenerative disease that manifests with detrimental tissue remodeling, myofibroblast accumulation, and scarring in the orbit of affected individuals. Currently, there are no effective therapies for TED that target or prevent the excessive tissue remodeling caused by myofibroblast formation and activation. The canonical cytokine that induces myofibroblast formation is transforming growth factor (TGF)-β. The TGF-β signaling pathway is influenced by aryl hydrocarbon receptor (AHR) signaling pathways. We hypothesized that AHR agonists can prevent myofibroblast formation in fibroblasts from patients with TED, and thus AHR ligands are potential therapeutics for the disease. Orbital fibroblasts explanted from patients with TED were treated with TGF-β to induce myofibroblast formation, contraction, and proliferation. We found that AHR ligands prevent TGF-β-dependent myofibroblast formation, and this ability is dependent on AHR expression. The AHR and AHR ligands block profibrotic Wnt signaling by inhibiting the phosphorylation of GSK3β to prevent myofibroblast formation. These results provide new insight into the molecular pathways underlying orbital scarring in TED. These novel studies highlight the potential of the AHR and AHR ligands as future therapeutic options for eye diseases and possibly also for other scarring conditions.

PMID: 27842700 [PubMed - indexed for MEDLINE]




Lymphoid Aggregates Remodel Lymphatic Collecting Vessels that Serve Mesenteric Lymph Nodes in Crohn Disease.
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Lymphoid Aggregates Remodel Lymphatic Collecting Vessels that Serve Mesenteric Lymph Nodes in Crohn Disease.

Am J Pathol. 2016 Dec;186(12):3066-3073

Authors: Randolph GJ, Bala S, Rahier JF, Johnson MW, Wang PL, Nalbantoglu I, Dubuquoy L, Chau A, Pariente B, Kartheuser A, Zinselmeyer BH, Colombel JF

Abstract
Early pathological descriptions of Crohn disease (CD) argued for a potential defect in lymph transport; however, this concept has not been thoroughly investigated. In mice, poor healing in response to infection-induced tissue damage can cause hyperpermeable lymphatic collecting vessels in mesenteric adipose tissue that impair antigen and immune cell access to mesenteric lymph nodes (LNs), which normally sustain appropriate immunity. To investigate whether analogous changes might occur in human intestinal disease, we established a three-dimensional imaging approach to characterize the lymphatic vasculature in mesenteric tissue from controls or patients with CD. In CD specimens, B-cell-rich aggregates resembling tertiary lymphoid organs (TLOs) impinged on lymphatic collecting vessels that enter and exit LNs. In areas of creeping fat, which characterizes inflammation-affected areas of the bowel in CD, we observed B cells and apparent innate lymphoid cells that had invaded the lymphatic vessel wall, suggesting these cells may be mediators of lymphatic remodeling. Although TLOs have been described in many chronic inflammatory states, their anatomical relationship to preestablished LNs has never been revealed. Our data indicate that, at least in the CD-affected mesentery, TLOs are positioned along collecting lymphatic vessels in a manner expected to affect delivery of lymph to LNs.

PMID: 27746181 [PubMed - indexed for MEDLINE]




Basic Fibroblast Growth Factor Induces Angiogenic Properties of Fibrocytes to Stimulate Vascular Formation during Wound Healing.
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Basic Fibroblast Growth Factor Induces Angiogenic Properties of Fibrocytes to Stimulate Vascular Formation during Wound Healing.

Am J Pathol. 2016 Dec;186(12):3203-3216

Authors: Nakamichi M, Akishima-Fukasawa Y, Fujisawa C, Mikami T, Onishi K, Akasaka Y

Abstract
The role of fibrocytes in wound angiogenesis remains unclear. We therefore demonstrated the specific changes in fibrocyte accumulation for angiogesis in basic fibroblast growth factor (bFGF)-treated wounds. bFGF-treated wounds exhibited marked formation of arterioles and inhibition of podoplanin(+) lymph vessels that were lacking in vascular endothelial growth factor-A-treated wounds. Real-time PCR in bFGF-treated wounds manifested enhanced expression of CD34, CD31, and bFGF mRNA and reduced expression of podoplanin and collagen type I, III, and IV mRNA. Double immunofluorescence staining focusing on fibrocyte detection in bFGF-treated wounds showed increased formation of capillary-like structures composed of CD34(+)/procollagen I(+) fibrocytes, with a lack of capillary-like structures formed by CD45(+)/procollagen I(+) or CD11b(+)/procollagen I(+) fibrocytes. However, vascular endothelial growth factor-A-treated wounds lacked capillary-like structures composed of CD34(+)/procollagen I(+) fibrocytes, with increased numbers of CD34(+)/fetal liver kinase-1(+) endothelial progenitor cells. Furthermore, fibroblast growth factor receptor 1 siRNA injection into wounds, followed by bFGF, inhibited the formation of capillary-like structures composed of CD34(+)/procollagen I(+) fibrocytes, together with inhibited mRNA expression of CD34 and CD31 and enhanced mRNA expression of collagen type I, indicating the requirements of bFGF/fibroblast growth factor receptor 1 system for capillary structure formation. This study highlights the angiogenic properties of CD34(+)/procollagen I(+) fibrocytes specifically induced by bFGF, providing new insight into the active contribution of fibrocytes for vascular formation during wound healing.

PMID: 27773739 [PubMed - indexed for MEDLINE]




Lysosomal Storage of Subunit c of Mitochondrial ATP Synthase in Brain-Specific Atp13a2-Deficient Mice.
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Lysosomal Storage of Subunit c of Mitochondrial ATP Synthase in Brain-Specific Atp13a2-Deficient Mice.

Am J Pathol. 2016 Dec;186(12):3074-3082

Authors: Sato S, Koike M, Funayama M, Ezaki J, Fukuda T, Ueno T, Uchiyama Y, Hattori N

Abstract
Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of early-onset parkinsonism linked to the PARK9 locus. The causative gene for KRS is Atp13a2, which encodes a lysosomal type 5 P-type ATPase. We recently showed that KRS/PARK9-linked mutations lead to several lysosomal alterations, including reduced proteolytic processing of cathepsin D in vitro. However, it remains unknown how deficiency of Atp13a2 is connected to lysosomal impairments. To address this issue, we analyzed brain tissues of Atp13a2 conditional-knockout mice, which exhibited characteristic features of neuronal ceroid lipofuscinosis, including accumulation of lipofuscin positive for subunit c of mitochondrial ATP synthase, suggesting that a common pathogenic mechanism underlies both neuronal ceroid lipofuscinosis and Parkinson disease.

PMID: 27770614 [PubMed - indexed for MEDLINE]




Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling.
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Ornithine Decarboxylase Is Sufficient for Prostate Tumorigenesis via Androgen Receptor Signaling.

Am J Pathol. 2016 Dec;186(12):3131-3145

Authors: Shukla-Dave A, Castillo-Martin M, Chen M, Lobo J, Gladoun N, Collazo-Lorduy A, Khan FM, Ponomarev V, Yi Z, Zhang W, Pandolfi PP, Hricak H, Cordon-Cardo C

Abstract
Increased polyamine synthesis is known to play an important role in prostate cancer. We aimed to explore its functional significance in prostate tumor initiation and its link to androgen receptor (AR) signaling. For this purpose, we generated a new cell line derived from normal epithelial prostate cells (RWPE-1) with overexpression of ornithine decarboxylase (ODC) and used it for in vitro and in vivo experiments. We then comprehensively analyzed the expression of the main metabolic enzymes of the polyamine pathway and spermine abundance in 120 well-characterized cases of human prostate cancer and high-grade prostate intraepithelial neoplasia (HGPIN). Herein, we show that the ODC-overexpressing prostate cells underwent malignant transformation, revealing that ODC is sufficient for de novo tumor initiation in 94% of injected mice. This oncogenic capacity was acquired through alteration of critical signaling networks, including AR, EIF2, and mTOR/MAPK. RNA silencing experiments revealed the link between AR signaling and polyamine metabolism. Human prostate cancers consistently demonstrated up-regulation of the main polyamine enzymes analyzed (ODC, polyamine oxidase, and spermine synthase) and reduction of spermine. This phenotype was also dominant in HGPIN, rendering it a new biomarker of malignant transformation. In summary, we report that ODC plays a key role in prostate tumorigenesis and that the polyamine pathway is altered as early as HGPIN.

PMID: 27770613 [PubMed - indexed for MEDLINE]




Choroidal Involution Is Associated with a Progressive Degeneration of the Outer Retinal Function in a Model of Retinopathy of Prematurity: Early Role for IL-1β.
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Choroidal Involution Is Associated with a Progressive Degeneration of the Outer Retinal Function in a Model of Retinopathy of Prematurity: Early Role for IL-1β.

Am J Pathol. 2016 Dec;186(12):3100-3116

Authors: Zhou TE, Rivera JC, Bhosle VK, Lahaie I, Shao Z, Tahiri H, Zhu T, Polosa A, Dorfman A, Beaudry-Richard A, Costantino S, Lodygensky GA, Lachapelle P, Chemtob S

Abstract
Retinopathy of prematurity (ROP), the most common cause of blindness in premature infants, has long been associated with inner retinal alterations. However, recent studies reveal outer retinal dysfunctions in patients formerly afflicted with ROP. We have recently demonstrated that choroidal involution occurs early in retinopathy. Herein, we investigated the mechanisms underlying the choroidal involution and its long-term impact on retinal function. An oxygen-induced retinopathy (OIR) model was used. In vitro and ex vivo assays were applied to evaluate cytotoxic effects of IL-1β on choroidal endothelium. Electroretinogram was used to evaluate visual function. We found that proinflammatory IL-1β was markedly increased in retinal pigment epithelium (RPE)/choroid and positively correlated with choroidal degeneration in the early stages of retinopathy. IL-1β was found to be cytotoxic to choroid in vitro, ex vivo, and in vivo. Long-term effects on choroidal involution included a hypoxic outer neuroretina, associated with a progressive loss of RPE and photoreceptors, and visual deterioration. Early inhibition of IL-1β receptor preserved choroid, decreased subretinal hypoxia, and prevented RPE/photoreceptor death, resulting in life-long improved visual function in IL-1 receptor antagonist-treated OIR animals. Together, these findings suggest a critical role for IL-1β-induced choroidal degeneration in outer retinal dysfunction. Neonatal therapy using IL-1 receptor antagonist preserves choroid and prevents protracted outer neuroretinal anomalies in OIR, suggesting IL-1β as a potential therapeutic target in ROP.

PMID: 27768863 [PubMed - indexed for MEDLINE]




Inactivation of Tsc2 in Mesoderm-Derived Cells Causes Polycystic Kidney Lesions and Impairs Lung Alveolarization.
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Inactivation of Tsc2 in Mesoderm-Derived Cells Causes Polycystic Kidney Lesions and Impairs Lung Alveolarization.

Am J Pathol. 2016 Dec;186(12):3261-3272

Authors: Ren S, Luo Y, Chen H, Warburton D, Lam HC, Wang LL, Chen P, Henske EP, Shi W

Abstract
The tuberous sclerosis complex (TSC) proteins are critical negative regulators of the mammalian/mechanistic target of rapamycin complex 1 pathway. Germline mutations of TSC1 or TSC2 cause TSC, affecting multiple organs, including the kidney and lung, and causing substantial morbidity and mortality. The mechanisms of organ-specific disease in TSC remain incompletely understood, and the impact of TSC inactivation on mesenchymal lineage cells has not been specifically studied. We deleted Tsc2 specifically in mesoderm-derived mesenchymal cells of multiple organs in mice using the Dermo1-Cre driver. The Dermo1-Cre-driven Tsc2 conditional knockout mice had body growth retardation and died approximately 3 weeks after birth. Significant phenotypes were observed in the postnatal kidney and lung. Inactivation of Tsc2 in kidney mesenchyme caused polycystic lesions starting from the second week of age, with increased cell proliferation, tubular epithelial hyperplasia, and epithelial-mesenchymal transition. In contrast, Tsc2 deletion in lung mesenchyme led to decreased cell proliferation, reduced postnatal alveolarization, and decreased differentiation with reduced numbers of alveolar myofibroblast and type II alveolar epithelial cells. Two major findings thus result from this model: inactivation of Tsc2 in mesoderm-derived cells causes increased cell proliferation in the kidneys but reduced proliferation in the lungs, and inactivation of Tsc2 in mesoderm-derived cells causes epithelial-lined renal cysts. Therefore, Tsc2-mTOR signaling in mesenchyme is essential for the maintenance of renal structure and for lung alveolarization.

PMID: 27768862 [PubMed - indexed for MEDLINE]




Cigarette Smoke Mediates Nuclear to Cytoplasmic Trafficking of Transcriptional Inhibitor Kaiso through MUC1 and P120-Catenin.
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Cigarette Smoke Mediates Nuclear to Cytoplasmic Trafficking of Transcriptional Inhibitor Kaiso through MUC1 and P120-Catenin.

Am J Pathol. 2016 Dec;186(12):3146-3159

Authors: Zhang L, Gallup M, Zlock L, Feeling Chen YT, Finkbeiner WE, McNamara NA

Abstract
Lung cancer is the leading cause of cancer-related death, and 87% of these deaths are directly attributable to smoking. Using three-dimensional cultures of primary human bronchial epithelial cells, we demonstrated that loss of adherens junction protein, epithelial cadherin, and the aberrant interaction of its adherens junction binding partner, p120-catenin (p120ctn), with the cytoplasmic tail of apical mucin-1 (MUC1-CT) represent initiating steps in the epithelial-to-mesenchymal transition. Smoke provoked the rapid nuclear entry of p120ctn in complex with MUC1-CT that was inhibited using the MUC1-CT inhibitory peptides, PMIP and GO-201. Nuclear entry of p120ctn promoted its interaction with transcriptional repressor kaiso and the rapid shuttling of kaiso to the cytoplasm. Nuclear exit of kaiso permitted the up-regulation of oncogenic transcription factors Fos/phospho-Ser(32) Fos, FosB, Fra1/phospho-Ser(265) Fra1, which was inhibited through suppression of p120ctn's nuclear export using leptomycin-B. These data indicated that smoke-induced nuclear-to-cytoplasmic translocation of kaiso depends on the nuclear import of p120ctn in complex with MUC1-CT and the nuclear export of kaiso in complex with p120ctn. The presence of MUC1-CT/p120ctn and p120ctn/kaiso complexes in lung squamous cell carcinoma and adenocarcinoma specimens from human patients confirms the clinical relevance of these events. Thus, enhancing kaiso's suppressor role of protumor genes by sequestering kaiso in the nucleus of a smoker's airway epithelium may represent a novel approach of treating lung cancer.

PMID: 27765636 [PubMed - indexed for MEDLINE]




Molecular Analysis of Hybrid Neurofibroma/Schwannoma Identifies Common Monosomy 22 and α-T-Catenin/CTNNA3 as a Novel Candidate Tumor Suppressor.
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Molecular Analysis of Hybrid Neurofibroma/Schwannoma Identifies Common Monosomy 22 and α-T-Catenin/CTNNA3 as a Novel Candidate Tumor Suppressor.

Am J Pathol. 2016 Dec;186(12):3285-3296

Authors: Stahn V, Nagel I, Fischer-Huchzermeyer S, Oyen F, Schneppenheim R, Gesk S, Bohring A, Chikobava L, Young P, Gess B, Werner M, Senner V, Harder A

Abstract
Neurofibromas and schwannomas are benign Schwann cell-derived peripheral nerve sheath tumors arising sporadically and within neurofibromatoses. Multiple tumors are a hallmark of neurofibromatosis type 1 (NF1) and type 2 (NF2) and schwannomatosis. Neurofibromas in NF1 and schwannomas in NF2 or schwannomatosis are defined by distinctive molecular hits. Among these, multiple hybrid neurofibromas/schwannomas may also appear, not yet being defined by a molecular background. We therefore performed molecular analysis of 22 hybrid neurofibromas/schwannomas using array comparative genomic hybridization, immunohistochemistry, quantitative RT-PCR, and functional analyses of cultured Schwann cells. Furthermore, we analyzed SMARCB1 by fluorescence in situ hybridization and multiplex ligation-dependent probe. Monosomy 22 was identified in 44% of tumors of tested patients with hybrid neurofibromas/schwannomas. In addition, in a single case, we detected focal deletion of the α-T-catenin/CTNNA3 gene (10q21.3). To further characterize this candidate, transient knockdown of α-T-catenin in Schwann cells was performed. CTNNA3 depleted cells showed cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like abnormalities. To conclude, we uncovered loss of chromosome 22 in almost half of all cases with hybrid neurofibromas/schwannomas of patients with multiple peripheral nerve sheath tumors. We tagged α-T-catenin/CTNNA3 as a novel candidate gene. Our functional investigations might indicate involvement of α-T-catenin/CTNNA3 in the biology of peripheral nerve sheath tumors.

PMID: 27765635 [PubMed - indexed for MEDLINE]




Low-Dose Acetylsalicylic Acid Treatment Modulates the Production of Cytokines and Improves Trophoblast Function in an in Vitro Model of Early-Onset Preeclampsia.
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Low-Dose Acetylsalicylic Acid Treatment Modulates the Production of Cytokines and Improves Trophoblast Function in an in Vitro Model of Early-Onset Preeclampsia.

Am J Pathol. 2016 Dec;186(12):3217-3224

Authors: Panagodage S, Yong HE, Da Silva Costa F, Borg AJ, Kalionis B, Brennecke SP, Murthi P

Abstract
Preeclampsia (PE), a serious hypertensive disorder of pregnancy, remains a leading cause of perinatal morbidity and mortality worldwide. Perturbed trophoblast function and impaired placental development early in pregnancy are key features. Low-dose acetylsalicylic acid (LDA) administered before 16 weeks' gestation significantly reduces the risk for PE. However, the exact mechanisms of action of LDA, particularly on trophoblast function, are unclear. We hypothesized that LDA influences placental trophoblast function and reverses PE-associated abnormalities. This study aimed to determine the effects of serum from normotensive women and from those with PE with or without LDA treatment on a model of placental syncytium. On cytokine profiling, LDA increased placental growth factor production and selectively restored PE serum-induced alterations in levels of cytokines [activated leukocyte cell adhesion molecule, CXCL-16, and ErbB3] to those in normotensive serum-treated cells. PE serum-induced increases in the apoptotic markers P53 mRNA expression, IKBKE mRNA expression, caspase 3 activity, and decreased BIRC8 mRNA expression, were attenuated by LDA treatment. LDA treatment also reduced abnormal differentiation caused by PE serum administration. Possible mechanisms by which LDA influences PE-affected trophoblast cells in vitro are by modulating cytokine secretion, reducing apoptosis to levels seen in normotensive serum-treated cells, and preventing the premature trophoblast differentiation commonly observed in PE.

PMID: 27750048 [PubMed - indexed for MEDLINE]




BGP-15 Improves Aspects of the Dystrophic Pathology in mdx and dko Mice with Differing Efficacies in Heart and Skeletal Muscle.
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BGP-15 Improves Aspects of the Dystrophic Pathology in mdx and dko Mice with Differing Efficacies in Heart and Skeletal Muscle.

Am J Pathol. 2016 Dec;186(12):3246-3260

Authors: Kennedy TL, Swiderski K, Murphy KT, Gehrig SM, Curl CL, Chandramouli C, Febbraio MA, Delbridge LM, Koopman R, Lynch GS

Abstract
Duchenne muscular dystrophy is a severe and progressive striated muscle wasting disorder that leads to premature death from respiratory and/or cardiac failure. We have previously shown that treatment of young dystrophic mdx and dystrophin/utrophin null (dko) mice with BGP-15, a coinducer of heat shock protein 72, ameliorated the dystrophic pathology. We therefore tested the hypothesis that later-stage BGP-15 treatment would similarly benefit older mdx and dko mice when the dystrophic pathology was already well established. Later stage treatment of mdx or dko mice with BGP-15 did not improve maximal force of tibialis anterior (TA) muscles (in situ) or diaphragm muscle strips (in vitro). However, collagen deposition (fibrosis) was reduced in TA muscles of BGP-15-treated dko mice but unchanged in TA muscles of treated mdx mice and diaphragm of treated mdx and dko mice. We also examined whether BGP-15 treatment could ameliorate aspects of the cardiac pathology, and in young dko mice it reduced collagen deposition and improved both membrane integrity and systolic function. These results confirm BGP-15's ability to improve aspects of the dystrophic pathology but with differing efficacies in heart and skeletal muscles at different stages of the disease progression. These findings support a role for BGP-15 among a suite of pharmacological therapies for Duchenne muscular dystrophy and related disorders.

PMID: 27750047 [PubMed - indexed for MEDLINE]




Hypophysitis Secondary to Cytotoxic T-Lymphocyte-Associated Protein 4 Blockade: Insights into Pathogenesis from an Autopsy Series.
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Hypophysitis Secondary to Cytotoxic T-Lymphocyte-Associated Protein 4 Blockade: Insights into Pathogenesis from an Autopsy Series.

Am J Pathol. 2016 Dec;186(12):3225-3235

Authors: Caturegli P, Di Dalmazi G, Lombardi M, Grosso F, Larman HB, Larman T, Taverna G, Cosottini M, Lupi I

Abstract
Hypophysitis that develops in cancer patients treated with monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4; an inhibitory molecule classically expressed on T cells) is now reported at an incidence of approximately 10%. Its pathogenesis is unknown, in part because no pathologic examination of the pituitary gland has been reported to date. We analyzed at autopsy the pituitary glands of six cancer patients treated with CTLA-4 blockade, one with clinical and pathologic evidence of hypophysitis, one with mild lymphocytic infiltration in the pituitary gland but no clinical signs of hypophysitis, and four with normal pituitary structure and function. CTLA-4 antigen was expressed by pituitary endocrine cells in all patients but at different levels. The highest levels were found in the patient who had clinical and pathologic evidence of severe hypophysitis. This high pituitary CTLA-4 expression was associated with T-cell infiltration and IgG-dependent complement fixation and phagocytosis, immune reactions that induced an extensive destruction of the adenohypophyseal architecture. Pituitary CTLA-4 expression was confirmed in a validation group of 37 surgical pituitary adenomas and 11 normal pituitary glands. The study suggests that administration of CTLA-4 blocking antibodies to patients who express high levels of CTLA-4 antigen in the pituitary can cause an aggressive (necrotizing) form of hypophysitis through type IV (T-cell dependent) and type II (IgG dependent) immune mechanisms.

PMID: 27750046 [PubMed - indexed for MEDLINE]




B-Lymphoblastic Lymphomas Evolving from Follicular Lymphomas Co-Express Surrogate Light Chains and Mutated Gamma Heavy Chains.
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B-Lymphoblastic Lymphomas Evolving from Follicular Lymphomas Co-Express Surrogate Light Chains and Mutated Gamma Heavy Chains.

Am J Pathol. 2016 Dec;186(12):3273-3284

Authors: Slot LM, Hoogeboom R, Smit LA, Wormhoudt TA, Biemond BJ, Oud ME, Schilder-Tol EJ, Mulder AB, Jongejan A, van Kampen AH, Kluin PM, Guikema JE, Bende RJ, van Noesel CJ

Abstract
Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma able to transform into germinal center-type diffuse large B-cell lymphoma. We describe four extraordinary cases of FL, which progressed to TdT(+)CD20(-) precursor B-lymphoblastic lymphoma (B-LBL). Fluorescence in situ hybridization analysis showed that all four B-LBLs had acquired a MYC translocation on transformation. Comparative genomic hybridization analysis of one case demonstrated that in addition to 26 numerical aberrations that were shared between the FL and B-LBL, deletion of CDKN2A/B and 17q11, 14q32 amplification, and copy-neutral loss of heterozygosity of 9p were gained in the B-LBL cells. Whole-exome sequencing revealed mutations in FMN2, NEB, and SYNE1 and a nonsense mutation in KMT2D, all shared by the FL and B-LBL, and TNFRSF14, SMARCA2, CCND3 mutations uniquely present in the B-LBL. Remarkably, all four FL-B-LBL pairs expressed IgG. In two B-LBLs, evidence was obtained for ongoing rearrangement of IG light chain variable genes and expression of the surrogate light chain. IGHV mutation analysis showed that all FL-B-LBL pairs harbored identical or near-identical somatic mutations. From the somatic gene alterations found in the IG and non-IG genes, we conclude that the FLs and B-LBLs did not develop in parallel from early t(14;18)-positive IG-unmutated precursors, but that the B-LBLs developed from preexistent FL subclones that accumulated additional genetic damage.

PMID: 27750045 [PubMed - indexed for MEDLINE]




CK2α/CSNK2A1 Phosphorylates SIRT6 and Is Involved in the Progression of Breast Carcinoma and Predicts Shorter Survival of Diagnosed Patients.
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CK2α/CSNK2A1 Phosphorylates SIRT6 and Is Involved in the Progression of Breast Carcinoma and Predicts Shorter Survival of Diagnosed Patients.

Am J Pathol. 2016 Dec;186(12):3297-3315

Authors: Bae JS, Park SH, Jamiyandorj U, Kim KM, Noh SJ, Kim JR, Park HJ, Kwon KS, Jung SH, Park HS, Park BH, Lee H, Moon WS, Sylvester KG, Jang KY

Abstract
Recently, the roles of sirtuins (SIRTs) in tumorigenesis have been of interest to oncologists, and protein kinase CK2 α1 (CSNK2A1) has been shown to be involved in tumorigenesis by phosphorylating various proteins, including SIRT1. Therefore, we evaluated the roles of CSNK2A1, SIRT6, and phosphorylated SIRT6 and their relationships in breast carcinoma. Nuclear expression of CSNK2A1 and SIRT6 predicted shorter overall survival and relapse-free survival by multivariate analysis. Inhibition of CSNK2A1 decreased the proliferative and invasive activity of cancer cells. In addition, CSNK2A1 was bound to SIRT6 and phosphorylated SIRT6; evidence for this is provided from immunofluorescence staining, co-immunoprecipitation of CSNK2A1 and SIRT6, a glutathione S-transferase pull-down assay, an in vitro kinase assay, and transfection of mutant CSNK2A1. Knockdown of SIRT6 decreased the proliferation and invasiveness of cancer cells. Overexpression of SIRT6 increased proliferation, but mutation at the Ser338 phosphorylation site of SIRT6 inhibited the proliferation of MCF7 cells. Moreover, both knockdown of SIRT6 and a mutation at the phosphorylation site of SIRT6 decreased expression of matrix metallopeptidase 9, β-catenin, cyclin D1, and NF-κB. Especially, SIRT6 expression was associated with the nuclear localization of β-catenin. This study demonstrates that CSNK2A1 and SIRT6 are indicators of poor prognosis for breast carcinomas and that CSNK2A1-mediated phosphorylation of SIRT6 might be involved in the progression of breast carcinoma.

PMID: 27746184 [PubMed - indexed for MEDLINE]




Inhibition of Poly(ADP-Ribose) Polymerase-1 Protects Chronic Alcoholic Liver Injury.
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Inhibition of Poly(ADP-Ribose) Polymerase-1 Protects Chronic Alcoholic Liver Injury.

Am J Pathol. 2016 Dec;186(12):3117-3130

Authors: Zhang Y, Wang C, Tian Y, Zhang F, Xu W, Li X, Shu Z, Wang Y, Huang K, Huang D

Abstract
Activation of Kupffer cells (KCs) by gut-derived endotoxin plays a pivotal role in the pathogenesis of alcoholic liver diseases (ALD). Limiting the activation of resident KCs attenuates chronic ethanol-induced liver steatosis and injury. Poly (ADP-ribose) polymerase (PARP)-1 is suggested to play a role in a number of chronic inflammatory diseases. In this study, we found a significant increase of hepatic PARP activity in mice with short-term and long-term ethanol-induced ALD. Male mice on a long-term ethanol diet exhibited severe hepatic steatosis and apoptosis and enhanced KC activation and neutrophil infiltration. However, pharmacologic inhibition of PARP activity or genetic depletion of PARP1 significantly attenuated these detrimental effects in vivo. We found that inhibition of PARP1 effectively reduced hepatic expression of genes involved in lipogenesis and elevated hepatic expression of genes involved in lipolysis. Moreover, limited KC activation and neutrophil infiltration were observed in PARP1 knockout mice or PARP inhibitor-treated mice. Furthermore, in vitro experiments found that LPS-induced macrophage activation was limited by PARP inhibitor, and exposure of ethanol-treated hepatocytes to this conditioned medium further decreased the number of apoptotic and steatotic cells. Taken together, these findings suggest that PARP1 inhibition protects against long-term ethanol-induced liver injury, as indicated by limited hepatocytes steatosis, apoptosis, inflammation levels, and neutrophil infiltration, mainly by limiting KC activation during the initiation of ALD.

PMID: 27746183 [PubMed - indexed for MEDLINE]




HIV Interferes with Mycobacterium tuberculosis Antigen Presentation in Human Dendritic Cells.
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HIV Interferes with Mycobacterium tuberculosis Antigen Presentation in Human Dendritic Cells.

Am J Pathol. 2016 Dec;186(12):3083-3093

Authors: Singh SK, Andersson AM, Ellegård R, Lindestam Arlehamn CS, Sette A, Larsson M, Stendahl O, Blomgran R

Abstract
HIV coinfection is the most prominent risk factor for progression of Mycobacterium tuberculosis (Mtb) infection into active tuberculosis (TB) disease. The mechanisms behind the increased transition from latent to active TB in coinfected individuals have not been well elucidated at the cellular level. We hypothesized that HIV infection contributes to Mtb pathogenesis by interfering with the dendritic cell (DC)-mediated immune control. Mtb-antigen processing and presentation are key events in the immune response against TB. Human immature DCs coinfected with HIV/Mtb had decreased expression of human leukocyte antigen antigen D related and the costimulatory molecules CD40, CD80, and CD86. In addition, Mtb-infected DCs triggered a significant release of the proinflammatory cytokines IL-6, IL-1β, and tumor necrosis factor-α, whereas coinfected DCs did not. To assess the DC antigen presentation capacity, we measured interferon-γ from co-cultures of DCs and autologous Mtb antigen-specific CD4(+) T cells. Interferon-γ release was significantly reduced when purified protein derivative- and Ag85B-specific CD4(+) T cells had been activated with coinfected DCs compared to Mtb-infected DCs, and this effect was attributed to Mtb antigen processing rather than peptide-major histocompatibility complex class II loading. Evaluating autophagy as a measure of vesicular processing and maturation further revealed that HIV efficiently blocks initiation of this pathway during coinfection. Overall, our results demonstrate that HIV impairs Mtb antigen presentation in DCs, thereby suppressing an important cell linking innate and adaptive immune response in TB.

PMID: 27746182 [PubMed - indexed for MEDLINE]