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American Journal of Pathology

Asoka Banno, Sowmya P Lakshmi, Aravind T Reddy, Seong C Kim, Raju C Reddy
The transcription factor nuclear receptor 77 (Nur77) belongs to the NR4A subfamily of nuclear hormone receptors. It features an atypical ligand-binding site that precludes canonical ligand binding, leading to the designation "orphan nuclear receptor." However, recent studies show that small molecules can interact with the receptor and modulate its activity by inducing a conformational change in the Nur77 ligand-binding site. Nur77 expression and activation are rapidly induced by a wide range of physiological and pathological stimuli...
November 7, 2018: American Journal of Pathology
Qiaoli Li, Koen van de Wetering, Jouni Uitto
Ectopic mineralization is a global problem and leading cause of morbidity and mortality. The pathomechanisms of ectopic mineralization are poorly understood. Recent studies on heritable ectopic mineralization disorders with defined gene defects have been helpful in elucidation of the mechanisms of ectopic mineralization in general. The prototype of such disorders is pseudoxanthoma elasticum (PXE), a late-onset, slowly progressing disorder with multi-system clinical manifestations. Other conditions include generalized arterial calcification of infancy (GACI) characterized by severe, early-onset mineralization of the cardiovascular system often with early postnatal demise...
November 7, 2018: American Journal of Pathology
Hirokazu Kameyama, Kenji Uchimura, Taro Yamashita, Kaori Kuwabara, Mineyuki Mizuguchi, Shang-Cheng Hung, Keiichiro Okuhira, Tomohiro Masuda, Tomoki Kosugi, Takashi Ohgita, Hiroyuki Saito, Yukio Ando, Kazuchika Nishitsuji
The highly sulfated domains of heparan sulfate (HS), also called HS S-domains, are made up of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)-] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Here, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis (ATTR amyloidosis). In in vitro assays with cells stably expressing human Sulfs, heparin, a structural analog of HS S-domains, promoted aggregation of TTR in an HS S-domain-dependent manner...
November 7, 2018: American Journal of Pathology
Souzan Sanati
Ductal carcinoma in situ (DCIS) encompasses a highly heterogeneous group of lesions that differ with regard to their clinical presentations, histologic features, biomarker profiles, genetic abnormalities, and potential for progression. DCIS is a non-obligatory precursor for invasive carcinoma. With the advent of screening mammography the incidence of DCIS has significantly increased. There is an argument that many of these lesions will not progress to invasive carcinoma within the lifetime of a patient. In addition, many studies have shown enormous heterogeneity within DCIS...
October 29, 2018: American Journal of Pathology
Kevin Shee, Kristen E Muller, Jonathan Marotti, Todd W Miller, Wendy A Wells, Gregory J Tsongalis
Historically, ductal carcinoma in situ (DCIS) of the breast has been managed aggressively with surgery and radiation due to a risk of progression to invasive ductal carcinoma. However, this treatment paradigm has been challenged by overtreatment concerns and evidence suggesting that DCIS can be stratified according to risk of recurrence, or risk of progression to invasive disease. Traditional methods of risk stratification include histologic grade and hormone receptor status. Recent technological advancements have enabled an era of precision medicine, where DCIS can be molecularly analyzed by tools such as next-generation DNA and RNA sequencing to identify molecular biomarkers for risk stratification...
October 29, 2018: American Journal of Pathology
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The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology.
October 19, 2018: American Journal of Pathology
Hong Pan, Huifen Xiang, Jing Wang, Zhaolian Wei, Yiran Zhou, Beihong Liu, Tengyan Li, Xu Ma, Yunxia Cao, Binbin Wang
Recurrent pregnancy loss (RPL) is a major concern for women's reproductive health. Several studies have proved that genetics is a major factor leading to unexplained RPL, but the maternal pathogenic genes involved in RPL remain largely unknown. A consanguineous family, including the parents who were cousins and their three daughters who had been diagnosed as having nonsyndromic unexplained RPL, was recruited in this study. A rare homozygous variant in calcyphosine (CAPS; ENST00000588776: c.377delC, p.Leu127Trpfs) might be the potential candidate variant for this RPL family through whole-exome sequencing...
October 17, 2018: American Journal of Pathology
Yvonne Mödinger, Anna E Rapp, Anna Vikman, Zhaozhou Ren, Verena Fischer, Stephanie Bergdolt, Melanie Haffner-Luntzer, Wen-Chao Song, John D Lambris, Markus Huber-Lang, Cornelia Neidlinger-Wilke, Rolf Brenner, Anita Ignatius
The terminal complement complex (TCC) is formed upon activation of the complement system, a crucial arm of innate immunity. TCC formation on cell membranes results in a transmembrane pore leading to cell lysis. In addition, sublytic TCC concentrations can modulate various cellular functions. TCC-induced effects may play a role in the pathomechanisms of inflammatory disorders of the bone, including rheumatoid arthritis and osteoarthritis. In this study we investigated the effect of the TCC on bone turnover and repair...
October 16, 2018: American Journal of Pathology
Qiying Fan, Hua Mao, Liang Xie, Xinchun Pi
Acute lung injury and its more severe form, the acute respiratory distress syndrome, are life-threatening respiratory disorders. Overwhelming pulmonary inflammation and endothelium disruption are commonly observed. Endothelial cells (ECs) are well recognized as key regulators in leukocyte adhesion and migration in response to bacterial infection. Prolyl hydroxylase domain (PHD)-2 protein, a major PHD in ECs, plays a critical role in intracellular oxygen homeostasis, angiogenesis, and pulmonary hypertension...
October 16, 2018: American Journal of Pathology
Tais Berelli Saito, Jeremy Bechelli, Claire Smalley, Shahid Karim, David H Walker
Many aspects of rickettsial infections have been characterized, including pathogenic and immune pathways, as well as mechanisms of rickettsial survival within the vertebrate host and tick vector. However, there is a remarkable paucity of studies focused on the complex pathogen-vector-host interactions during tick feeding. Therefore, our objective was to develop a tick transmission model of spotted fever group rickettsial infection to study the initial events in disease development. The most appropriate strain of mouse was identified to be evaluated as a transmission model, and the course of infection, bacterial levels, histopathologic changes, and antibody response during tick transmission in mice infested with Amblyomma maculatum ticks carrying the emerging pathogen, Rickettia parkeri, were further studied...
October 10, 2018: American Journal of Pathology
Ambart E Covarrubias, Edouard Lecarpentier, Agnes Lo, Saira Salahuddin, Kathryn J Gray, S Ananth Karumanchi, Zsuzsanna K Zsengellér
Although the etiology of preeclampsia, a pregnancy complication with significant maternal and neonatal morbidity, has not been fully characterized, placental ischemia due to impaired spiral artery remodeling and abnormal secretion of anti-angiogenic factors are thought to be important in the pathogenesis of the disease. Placental ischemia could impair trophoblast mitochondrial function and energy production leading to the release of reactive oxygen species (ROS). ROS has been shown to stabilize hypoxia inducible factor (HIF-1α), which in turn may induce transcription of anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFLT1) and soluble endoglin in trophoblasts...
October 10, 2018: American Journal of Pathology
Po-Ku Chen, Chun-Hung Hua, Hui-Ting Hsu, Tzer-Min Kuo, Chia-Min Chung, Chi-Pin Lee, Ming-Hsui Tsai, Kun-Tu Yeh, Ying-Chin Ko
Oral squamous cell carcinoma (OSCC) is the most common malignant cancer with high mortality rates in advanced stages. Recent studies have shown that the expression of ALPK1 mRNA and its inhibitory differentiation function are associated with cancer progression. However, the expression and clinicopathological features of ALPK1 in OSCC remain unexplored. Here we investigated the expression patterns of ALPK1 in 39 matched OSCC patients and examined the relationship between ALPK1 protein expression and clinicopathological factors using immunohistochemical scores...
October 10, 2018: American Journal of Pathology
Tiina Rasila, Olga Saavalainen, Hesham Attalla, Petri Lankila, Caj Haglund, Erkki Hölttä, Leif C Andersson
Our group originally found and cloned cDNA for a 98-kDa type 1 transmembrane glycoprotein of unknown function. Because of its abundant expression in astrocytes, it was called the protein astroprincin (APCN). Two thirds of the evolutionarily conserved protein is intracytoplasmic, whereas the extracellular domain carries two N-glycosidic side chains. APCN is physiologically expressed in placental trophoblasts, skeletal and hearth muscle, and kidney and pancreas. Overexpression of APCN (cDNA) in various cell lines induced sprouting of slender projections, whereas knockdown of APCN expression by siRNA caused disappearance of actin stress fibers...
October 10, 2018: American Journal of Pathology
John Hanna, Angel Guerra-Moreno, Jessie Ang, Yagmur Micoogullari
The abundance of any protein is determined by the balance of protein synthesis and protein degradation. Regulated protein degradation has emerged as a powerful means of precisely controlling individual protein abundance within cells and is largely mediated by the ubiquitin-proteasome system (UPS). By controlling the levels of key regulatory proteins, the UPS contributes to nearly every aspect of cellular function. The UPS also functions in protein quality control, rapidly identifying and destroying misfolded or otherwise aberrant proteins that may be toxic to cells...
October 10, 2018: American Journal of Pathology
Wenjun Luo, Cuiyun Sun, Junhu Zhou, Qian Wang, Lin Yu, Xiu-Wu Bian, Xuexia Zhou, Dan Hua, Run Wang, Chun Rao, Zhendong Jiang, Cuijuan Shi, Shizhu Yu
miR-135a-5p has been reported as a tumor suppressor in several extracranial tumors. However, its exact roles in gliomagenesis and relevance to the patients' prognoses are largely unknown. Here, we detected the miR-135a-5p and TRAF5 levels in 120 human glioma specimens and 20 nontumoral brain tissues, and found the miR-135a-5p level decreased, whereas the TRAF5 level increased with the elevation of glioma grade. Their labeling indexes were inversely correlated with each other, and showed strong negative (miR-135a-5p) and positive (TRAF5) correlation with the Ki-67 index...
October 9, 2018: American Journal of Pathology
Hanaa K B Motawea, Maqsood A Chotani, Mehboob Ali, William Ackerman, Guomao Zhao, Amany A E Ahmed, Catalin S Buhimschi, Irina A Buhimschi
α2 -Adrenergic receptors (α2 ARs) are G-protein-coupled receptors involved in catecholamine signaling by extracellular regulated protein kinase 1 and 2 (ERK1/2) pathways. We examined placental expression and function of α2 AR subtypes in women with severe preeclampsia (sPE) with and without intrauterine growth restriction (IUGR). Placental biopsies were analyzed from 52 women with i) sPE [n = 8; median ± SEM gestational age (GA), 31 ± 1 weeks]; ii) sPE + IUGR (n = 9; median ± SEM GA, 30 ± 1 weeks); iii) idiopathic IUGR (n = 8; median ± SEM GA, 31 ± 1 weeks); iv) idiopathic preterm birth (n = 16; median ± SEM GA, 31 ± 1 weeks); and v) healthy term controls (n = 11; median ± SEM GA, 39 ± 1 weeks)...
September 29, 2018: American Journal of Pathology
Yanling Zhang, Kerri Thai, David M Kepecs, Daniel Winer, Richard E Gilbert
The excessive accumulation of extracellular matrix material in the kidney is a histopathologic hallmark of diabetic kidney disease that correlates closely with declining function. Although considerable research has focused on the role of profibrotic factors, comparatively little attention has been paid to the possibility that a diminution in endogenous antifibrotic factors may also contribute. Among the latter, the ELR- CXC chemokines, CXCL9, CXCL10, and CXCL11, have been shown to provide a stop signal to prevent excessive fibrosis...
September 29, 2018: American Journal of Pathology
Yoshihito Oura, Machiko Nakamura, Tohru Takigawa, Yoko Fukushima, Taku Wakabayashi, Motokazu Tsujikawa, Kohji Nishida
Age-related macular degeneration (AMD) is an important cause of blindness. It is characterized by a retinal pigment epithelium (RPE) disorder that leads to death of photoreceptor cells (PRCs). AMD has a strong genetic association with high-temperature requirement A 1 (HTRA1). The relationship between HTRA1 and the AMD phenotype is unknown. In this study, we show that the expression of HTRA1 in PRCs, as well as in RPE, is increased by the disease-associated HTRA1 mutation and aging. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and quantitative PCR of apoptosis-associated caspases confirmed that PRC-specific overexpression of HTRA1 induced PRC death...
September 29, 2018: American Journal of Pathology
Xinxu Yuan, Owais Bhat, Nan Meng, Hannah Lohner, Pin-Lan Li
We hypothesized that autophagy and associated lysosome function serve as a critical modulator during Nod-like receptor family pyrin domain containing 3 (Nlrp3) inflammasome activation on proatherogenic stimuli. We first demonstrated that 7-ketocholesterol stimulated Nlrp3 inflammasome formation and activation as shown by increased colocalization of inflammasome components [Nlrp3 versus apoptosis associated speck-like protein (Asc) or caspase-1] and enhanced cleavage of caspase-1 into active caspase-1 to generate IL-1β in coronary artery smooth muscle cells...
September 29, 2018: American Journal of Pathology
Riikka Huhtaniemi, Riikka Oksala, Matias Knuuttila, Arfa Mehmood, Eija Aho, Teemu D Laajala, Daniel Nicorici, Tero Aittokallio, Asta Laiho, Laura Elo, Claes Ohlsson, Pekka Kallio, Sari Mäkelä, Mika V J Mustonen, Petra Sipilä, Matti Poutanen
The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P4 ) and moderate levels of androgens, such as androstenedione, testosterone, and dihydrotestosterone, in the adrenal glands of both intact and orchectomized (ORX) mice...
September 28, 2018: American Journal of Pathology
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