TABLE OF CONTENTS

Volume 97, Issue 9 (September 2017)

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Inside the USCAP Journals

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Research Articles

Hepatic and Pancreatic Systems

Roflumilast reverses polymicrobial sepsis-induced liver damage by inhibiting inflammation in mice

In this paper, the authors show that roflumilast, a selective phosphodiesterase-4 inhibitor, exerts a protective effect against sepsis-induced liver injury, restoring the levels of cAMP, and subsequently activating PKA/CREB signaling. In addition, roflumilast exerts an anti-inflammatory effect by inhibiting JAK/STAT and nuclear NF-kB signaling pathways.

Hongfang Feng, Jiajia Chen, Haitao Wang, Yufang Cheng, Zhengqiang Zou, Qiuping Zhong and Jiangping Xu

97: 1008-1019; advance online publication, June 26, 2017; doi:10.1038/labinvest.2017.59

Paired related homeobox protein 1 regulates PDGF-induced chemotaxis of hepatic stellate cells in liver fibrosis

This study demonstrates that paired related homeobox protein 1 (Prrx1) acts as a critical downstream molecule in PDGF signaling pathway and plays a major role in the recruitment of PDGF-dependent hepatic stellate cells via modulation of matrix metalloproteinases 2 and 9. Additionally, knockdown of Prrx1 attenuates liver fibrosis in animal models.

Jin Gong, Jian Han, Jiayi He, Jingmei Liu, Ping Han, Yunwu Wang, Mengke Li, Dongxiao Li, Xiangming Ding, Zhipeng Du, Jiazhi Liao and Dean Tian

97: 1020-1032; advance online publication, July 24, 2017; doi:10.1038/labinvest.2017.65

Angiogenesis, Cardiovascular and Pulmonary Systems

Endothelial fibrosis induced by suppressed STAT3 expression mediated by signaling involving the TGF-β1/ALK5/Smad pathway

Inflammatory mediators change endothelial cells (ECs) into activated fibroblasts via TGF-β1-meditaed epithelial-to-mesenchymal transition. Although decreased STAT3 can induce TGF-β1-mediated fibrosis, it is not known whether suppression of STAT3 expression induces EC fibrosis. This study shows that suppressed expression of STAT3 stimulates fibrotic conversion in ECs via the TGF-β1/ALK5/Smad4 signaling pathway.

Alvaro Becerra, Macarena Rojas, Alejandro Vallejos, Vicente Villegas, Lorena Pérez, Claudio Cabello-Verrugio and Felipe Simon

97: 1033-1046; advance online publication, July 24, 2017; doi:10.1038/labinvest.2017.61

Phenotypic screening identifies Axl kinase as a negative regulator of an alveolar epithelial cell phenotype

Molecular mechanisms underlying loss of epithelial integrity in human lung diseases are incompletely understood. This study identifies the role of Axl kinase signaling pathway in pulmonary epithelial morphology and function by regulation of epithelial-to-mesenchymal transition transcription factors. Furthermore, in idiopathic pulmonary fibrosis, abnormal expression of Axl kinase in regions of lung epithelium was observed, indication the loss of barrier integrity.

Naoya Fujino, Hiroshi Kubo and Rose A Maciewicz

97: 1047-1062; advance online publication, May 29, 2017; doi:10.1038/labinvest.2017.52

Breast, Skin, Soft Tissue and Bone

Melanoma subtypes demonstrate distinct PD-L1 expression profiles

The authors compared PD-L1 expression across four melanoma subtypes. They found that the proportion of PD-L1+ tumors was highest in chronic sun-damaged melanomas and lowest in uveal melanomas. PD-L1 expression in acral and mucosal subtypes was comparable to cutaneous disease. These findings are commensurate with anti-PD-1 response rates and support combinatorial regimens in PD-L1-poor subtypes.

Genevieve J Kaunitz, Tricia R Cottrell, Mohammed Lilo, Valliammai Muthappan, Jessica Esandrio, Sneha Berry, Haiying Xu, Aleksandra Ogurtsova, Robert A Anders, Alexander H Fischer, Stefan Kraft, Meg R Gerstenblith, Cheryl L Thompson, Kord Honda, Jonathan D Cuda, Charles G Eberhart, James T Handa, Evan J Lipson and Janis M Taube

97: 1063-1071; advance online publication, July 24, 2017; doi:10.1038/labinvest.2017.64

Adrenocorticotropic hormone and 1,25-dihydroxyvitamin D3 enhance human osteogenesis in vitro by synergistically accelerating the expression of bone-specific genes

Adrenocorticotropic hormone and 1,25-dihydroxyvitaminD3 dramatically improve human osteoblast differentiation in vitro via synergistic mechanisms. Osteoblasts express the calcium sensing receptor and respond to calcium, but at non-physiological concentrations. Cortisol accelerates expression of some osteoblast-specific proteins, but blunts bone formation and other processes, and various hormone effects.

Irina L Tourkova, Li Liu, Nareerat Sutjarit, Quitterie C Larrouture, Jianhua Luo, Lisa J Robinson and Harry C Blair

97: 1072-1083; advance online publication, July 24, 2017; doi:10.1038/labinvest.2017.62

Oral and Gastrointestinal Systems

α-Actinin-4 promotes metastasis in gastric cancer

This study indicates that α-actinin 4 (ACTN4) is significantly upregulated in patients with metastatic gastric cancer. In vitro, ACTN4 reduces cell adhesion and enhances migration and invasion of gastric cancer cells. Because ACTN4 promotes metastasis of gastric cancer, it may be a novel therapeutic target.

Xin Liu and Kent-Man Chu

97: 1084-1094; advance online publication, June 5, 2017; doi:10.1038/labinvest.2017.28

Blood, Lymphatics, Immune System and Stem Cells

EMMPRIN (CD147) is induced by C/EBPβ and is differentially expressed in ALK+ and ALK− anaplastic large-cell lymphoma

This study demonstrates that the transcription factor C/EBPβ contributes to the activated phenotype of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) cells and may be involved in suppressing anti-tumor response through induction of PD-L1. Furthermore, EMMPRIN (CD147) is differentially expressed in ALK+ and ALK− ALCL and may contribute to the oncogenic role of C/EBPβ by promoting invasiveness through induction of matrix metalloproteinase expression.

Janine Schmidt, Irina Bonzheim, Julia Steinhilber, Ivonne A Montes-Mojarro, Carlos Ortiz-Hidalgo, Wolfram Klapper, Falko Fend and Leticia Quintanilla-Martínez

97: 1095-1102; advance online publication, June 5, 2017; doi:10.1038/labinvest.2017.54

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Technical Reports

Models and Techniques

Assessment of tumor characteristics based on glycoform analysis of membrane-tethered MUC1

A new and robust methodology for differential O-glycome profiling on an endogenous tumor-associated glycoprotein, MUC1, is proposed in this paper. This method enables glycome analysis of small quantities of samples collected from single formalin-fixed, paraffin-embedded tissue sections and is applicable to other O-glycosylated proteins. This technique is promising for discovery of biomarkers and therapeutic targets for a large number of diseases.

Atsushi Matsuda, Michiyo Higashi, Tomomi Nakagawa, Seiya Yokoyama, Atsushi Kuno, Suguru Yonezawa and Hisashi Narimatsu

97: 1103-1113; advance online publication, June 5, 2017; doi:10.1038/labinvest.2017.53

Sensitive and non-invasive method for the in vivo analysis of membrane permeability in small animals

Current experimental techniques to quantify membrane permeability in small animals have limited precision and temporal specificity. This study shows the efficacy of a novel, non-invasive imaging analysis-based measurement method that significantly improves the quantification of tissue membrane permeability in small animals, while mitigating the adverse effects experienced by the animals.

Andrea Fernandez-Carrera, Eva Vigo, Carla Regueiro-Rodríguez, África González-Fernández, David Olivieri and Luiz S Aroeira

97: 1114-1120; advance online publication, July 24, 2017; doi:10.1038/labinvest.2017.66

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Corrigendum

Increased expression of latent TGF-β-binding protein 4 affects the fibrotic process in scleroderma by TGF-β/SMAD signaling FREE

Jiaying Lu, Qingmei Liu, Lei Wang, Wenzhen Tu, Haiyan Chu, Weifeng Ding, Shuai Jiang, Yanyun Ma, Xiangguang Shi, Weilin Pu, Xiaodong Zhou, Li Jin, Jiucun Wang and Wenyu Wu

97: 1121; doi:10.1038/labinvest.2017.43