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3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine

Clement, Cristina C; D'Alessandro, Angelo; Thangaswamy, Sangeetha; Chalmers, Samantha; Furtado, Raquel; Spada, Sheila; Mondanelli, Giada; Ianni, Federica; Gehrke, Sarah; Gargaro, Marco; Manni, Giorgia; Cara, Luisa Carlota Lopez; Runge, Peter; Tsai, Wanxia Li; Karaman, Sinem; Arasa, Jorge; Fernandez-Rodriguez, Ruben; Beck, Amanda; Macchiarulo, Antonio; Gadina, Massimo; Halin, Cornelia; Fallarino, Francesca; Skobe, Mihaela; Veldhoen, Marc; Moretti, Simone; Formenti, Silvia; Demaria, Sandra; Soni, Rajesh K; Galarini, Roberta; Sardella, Roccaldo; Lauvau, Gregoire; Putterman, Chaim; Alitalo, Kari; Grohmann, Ursula; Santambrogio, Laura
Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-L-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1β, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.
PMID: 34290243
ISSN: 2041-1723
CID: 4951192

Machine learning identifies histologic features associated with regression of cirrhosis in treatment for chronic hepatitis B [Meeting Abstract]

Juyal, D; Shukla, C; Pokkalla, H; Taylor, A; Zevallos, O; Resnick, M; Montalto, M; Beck, A; Wapinski, I; Marcellin, P; Flaherty, J F; Suri, V; Gaggar, A; Subramanian, M; Jacobson, I; Gane, E; Buti, M
Background and aims: Machine learning (ML) may facilitate interpretation of histologic changes associated with treatment of chronic hepatitis B virus (HBV) infection. We developed ML models that identify and quantify histologic features in a clinical study of HBV patients receiving antiviral therapy.
Method(s): ML models were developed using H&E histology images from 330 patients enrolled in registrational studies for tenofovir disoproxil fumarate for HBV (GS-US-174-0102, GS-US-174-0103). Histological improvement and regression of cirrhosis were assessed by a central pathologist at baseline (BL) and weeks 48 and 240 according to the Ishak/Knodell necroinflammatory scoring and Ishak fibrosis staging systems. Images were split into training (N = 1090) and testing sets (N = 1061). Models were trained using the PathAI research platform (Boston, MA) to identify inflamed regions and immune cells (lymphocytes and plasma cells) using annotations from 40 board-certified pathologists. Additional annotations of steatosis and ballooning from previous models were included in training. Slide-level, quantitative ML features were computed and correlated with pathologist scores to assess accuracy. Regression analysis was performed to determine associations of ML features at BL and changes from BL with cirrhosis regression at week 240. Results were generated using the testing image set.
Result(s): ML % area of portal inflammation correlated strongly with Ishak portal inflammation scores (rho = 0.643; p < 0.001) and ML % area of interface inflammation correlated strongly with Ishak periportal necrosis scores (rho = 0.716; p < 0.001). Of the 48 patients in the testing set with cirrhosis at BL, 36 patients (75%) no longer had cirrhosis at week 240. Lower ML % area of steatosis (Figure) and greater ML % area of lobular inflammation at BL were predictive of cirrhosis regression (p = 0.006, p = 0.047, respectively), indicating the presence of underlying fatty liver in those who do not resolve cirrhosis. Change from baseline in ML % area of portal and lobular inflammation as well as change in lymphocyte density correlated with regression of cirrhosis at week 240 (p = 0.010, p = 0.026, p = 0.031 respectively). [Figure presented]
Conclusion(s): An ML approach accurately classified histopathologic features in H&E images from HBV clinical trial biopsies. ML features at BL and changes in ML features with treatment were significant associated with cirrhosis regression. An ML approach for evaluating liver histology in patients with HBV can provide mechanistic insight into both HBV disease pathogenesis and cirrhosis regression.
ISSN: 1600-0641
CID: 4781822

Targeting the pregnane X receptor using microbial metabolite mimicry

Dvořák, Zdeněk; Kopp, Felix; Costello, Cait M; Kemp, Jazmin S; Li, Hao; Vrzalová, Aneta; Štěpánková, Martina; Bartoňková, Iveta; Jiskrová, Eva; Poulíková, Karolína; Vyhlídalová, Barbora; Nordstroem, Lars U; Karunaratne, Chamini V; Ranhotra, Harmit S; Mun, Kyu Shik; Naren, Anjaparavanda P; Murray, Iain A; Perdew, Gary H; Brtko, Julius; Toporova, Lucia; Schön, Arne; Wallace, Bret D; Walton, William G; Redinbo, Matthew R; Sun, Katherine; Beck, Amanda; Kortagere, Sandhya; Neary, Michelle C; Chandran, Aneesh; Vishveshwara, Saraswathi; Cavalluzzi, Maria M; Lentini, Giovanni; Cui, Julia Yue; Gu, Haiwei; March, John C; Chatterjee, Shirshendu; Matson, Adam; Wright, Dennis; Flannigan, Kyle L; Hirota, Simon A; Sartor, Ryan Balfour; Mani, Sridhar
The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXR-specific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space.
PMID: 32153125
ISSN: 1757-4684
CID: 4349712

Overview of chromium (III) toxicology

Chapter by: Costa, Max; Murphy, A
in: Nutritional biochemisty of chromium (III) by Vincent JB [Eds]
Amsterdam : Elsevier, 2007
pp. 341-359
ISBN: 9780444641229
CID: 5046702

Allgrove syndrome (triple a syndrome): Two cases and the fourth "a" [Meeting Abstract]

Murphy, A B; Palma, J A; Kaufmann, H
Background: Allgrove syndrome (triple A syndrome) is a rare autosomal recessive disorder first described by endocrinologist Jeremy Allgrove in 1978 in two siblings with adrenal insufficiency, achalasia, and alacrima. Onset is usually within the first decade of life. Other features include adrenocorticotropic hormone (ACTH) unresponsiveness, and varying degrees of neurologic dysfunction. In 2002, mutations in the AAAS gene located on chromosome 12q13, which encodes for the nuclear pore protein ALADIN, were reported as the cause of the disease. The autonomic features of the disorder remain poorly understood with only ~ 100 cases in the literature, most of which were described before the availability of genetic testing. Methods: Case series of 2 patients with genetically confirmed Allgrove syndrome. Results: Case # 1: 9-year-old girl of East Indian descent presented with alacrima since birth. At age 6, she developed adrenal insufficiency manifesting as hyperpigmentation and fatigue. Genetic testing confirmed she was homozygous for the pathogenic variant c.1432C>T p.Arg478Ter. The patient had no achalasia and neurological exam was normal. Cardiovascular autonomic testing was normal. Case # 2: 39-year-old Hispanic woman presented with alacrima, achalasia, ACTH resistance, and sensorimotor polyneuropathy at the age of 13 years. Autonomic testing revealed adrenergic impairment with orthostatic hypotension together with cholinergic dysfunction and decreased heart rate variability. Genetic testing confirmed two heterozygous mutations: 1) Heterozygous Exon 6, R155P, base 464 CGT to CCT; 2) Heterozygous IVSC14 + 1G to A. Mutation 1 had not been previously reported. Conclusions: Allgrove syndrome is a rare pediatric-onset disorder with variable presentation. Neurological signs (autonomic dysfunction, hyperreflexia, dysarthria, ataxia, sensory impairment, weakness, cognitive deficits) and ACTH resistance may only manifest after many years or decades. As the number of genetically confirmed cases grows, there is a need to understand the autonomic phenotype, which should perhaps be considered the 4th A
ISSN: 1619-1560
CID: 2859922

Plasma osteopontin velocity differentiates lung cancers from controls in a CT screening population

Joseph, Sasha; Harrington, Ryan; Walter, Dawn; Goldberg, Judith D; Li, Xiaochun; Beck, Amanda; Litton, Tyler; Hirsch, Nathalie; Blasberg, Justin; Slomiany, Mark; Rom, William; Pass, Harvey; Donington, Jessica
INTRODUCTION: As CT screening is integrated into non-small cell lung cancer (NSCLC) care, additional parameters are needed to help distinguish cancers from benign nodules. Osteopontin (OPN), a secreted phosphoprotein, has elevated plasma levels in NSCLC. We hypothesize that changes in plasma OPN over time (i.e., OPN velocity [OPNV]) can differentiate NSCLC patients from those without cancer in a CT screening population. METHODS: A nested case-control study was conducted within a NSCLC CT screening trial. Incident cancers with serial plasma were matched to controls. OPN was measured by ELISA. Demographic, OPN, and OPNV were compared between cancers and controls using Wilcoxon Signed Rank tests. RESULTS: Ten incident cancers were identified. The pack years distributions were similar, but cancers were older (median of the paired difference: 5.35 years; p=0.002) and their surveillance intervals were shorter (median of the paired difference: -2 months; p=0. 03) than matched controls. Baseline OPN was similar (median of the paired difference: -5.15 ng/ml, p=0.50), but OPNV in the cancers was significantly greater than that of matched controls, (median of the paired difference: 1.06 ng/ml/month, p=0.01). Accuracy rate for prediction of disease status based on OPNV (adjusted for age and surveillance) was 83%. CONCLUSIONS: These are early evidence for utility of monitoring plasma OPN during CT screening to assist in identification of NSCLCs.
PMID: 23568008
ISSN: 1574-0153
CID: 287312


Donington, Jessica S; Harrington, Ryan; Walter, Dawn; Beck, Amanda; Litton, Tyler; Hirsch, Nathalie; Goldberg, Judith; Blasberg, Justin D; Rom, William; Pass, Harvey I
ISSN: 1556-1380
CID: 1675512

Tumorigenic properties of alternative osteopontin isoforms in mesothelioma

Ivanov, Sergey V; Ivanova, Alla V; Goparaju, Chandra M V; Chen, Yuanbin; Beck, Amanda; Pass, Harvey I
Osteopontin (SPP1) is an inflammatory cytokine that we previously characterized as a diagnostic marker in patients with asbestos-induced malignant mesothelioma (MM). While SPP1 shows both pro- and anti-tumorigenic biological effects, little is known about the molecular basis of these activities. In this study, we demonstrate that while healthy pleura possesses all three differentially spliced SPP1 isoforms (A-C), in clinical MM specimens isoform A is markedly up-regulated and predominant. To provide a clue to possible functions of the SPP1 isoforms we next performed their functional evaluation via transient expression in MM cell lines. As a result, we report that isoforms A-C demonstrate different activities in cell proliferation, wound closure, and invasion assays. These findings suggest different functions for SPP1 isoforms and underline pro-tumorigenic properties of isoforms A and B
PMID: 19285954
ISSN: 1090-2104
CID: 99136

Protumorigenic role of HAPLN1 and its IgV domain in malignant pleural mesothelioma

Ivanova, Alla V; Goparaju, Chandra M V; Ivanov, Sergey V; Nonaka, Daisuke; Cruz, Christina; Beck, Amanda; Lonardo, Fulvio; Wali, Anil; Pass, Harvey I
PURPOSE: Tumor extracellular matrix (ECM) plays a crucial role in cancer progression mediating and transforming host-tumor interactions. Targeting the ECM is becoming an increasingly promising therapeutic approach in cancer treatment. We find that one of the ECM proteins, HAPLN1, is overexpressed in the majority of mesotheliomas. This study was designed to characterize the protumorigenic role of HAPLN1 in mesothelioma. EXPERIMENTAL DESIGN: Overexpression of HAPLN1 was assessed and validated on a large set of normal/mesothelioma specimens on the RNA and protein levels. We also analyzed DNA copy number alterations in the HAPLN1 genomic locus using the array-based comparative genomic hybridization representational oligonucleotide microarray analysis tool. Tumorigenic activities of the HAPLN1 domains were evaluated in vitro on mesothelioma cells transfected with HAPLN1-expressing constructs. RESULTS: We found that HAPLN1 is 23-fold overexpressed in stage I mesothelioma and confirmed it for 76% samples (n = 53) on RNA and 97% (n = 40) on protein levels. The majority of lung cancers showed no differential expression of HAPLN1. Analysis of DNA copy number alterations identified recurrent gain in the 5q14.3 HAPLN1 locus in approximately 27% of tumors. Noteworthy, high expression of HAPLN1 negatively correlated with time to progression (P = 0.05, log-rank test) and overall survival (P = 0.006). Proliferation, motility, invasion, and soft-agar colony formation assays on mesothelioma cells overexpressing full-length HAPLN1 or its functional domains strongly supported the protumorigenic role of HAPLN1 and its SP-IgV domain. CONCLUSION: Overexpression of HAPLN1 and its SP-IgV domain increases tumorigenic properties of mesothelioma. Thus, targeting the SP-IgV domain may be one of the therapeutic approaches in cancer treatment
PMID: 19351750
ISSN: 1078-0432
CID: 101351

Genomic events associated with progression of pleural malignant mesothelioma

Ivanov, Sergey V; Miller, Jeremy; Lucito, Robert; Tang, Chunlao; Ivanova, Alla V; Pei, Jianming; Carbone, Michele; Cruz, Christina; Beck, Amanda; Webb, Craig; Nonaka, Daisuke; Testa, Joseph R; Pass, Harvey I
Pleural malignant mesothelioma (MM) is an aggressive cancer with a very long latency and a very short median survival. Little is known about the genetic events that trigger MM and their relation to poor outcome. The goal of our study was to characterize major genomic gains and losses associated with MM origin and progression and assess their clinical significance. We performed Representative Oligonucleotide Microarray Analysis (ROMA) on DNA isolated from tumors of 22 patients who recurred at variable interval with the disease after surgery. The total number of copy number alterations (CNA) and frequent imbalances for patients with short time (<12 months from surgery) and long time to recurrence were recorded and mapped using the Analysis of Copy Errors algorithm. We report a profound increase in CNA in the short-time recurrence group with most chromosomes affected, which can be explained by chromosomal instability associated with MM. Deletions in chromosomes 22q12.2, 19q13.32 and 17p13.1 appeared to be the most frequent events (55-74%) shared between MM patients followed by deletions in 1p, 9p, 9q, 4p, 3p and gains in 5p, 18q, 8q and 17q (23-55%). Deletions in 9p21.3 encompassing CDKN2A/ARF and CDKN2B were characterized as specific for the short-term recurrence group. Analysis of the minimal common areas of frequent gains and losses identified candidate genes that may be involved in different stages of MM: OSM (22q12.2), FUS1 and PL6 (3p21.3), DNAJA1 (9p21.1) and CDH2 (18q11.2-q12.3). Imbalances seen by ROMA were confirmed by Affymetrix genome analysis in a subset of samples. (c) 2008 Wiley-Liss, Inc
PMID: 18973227
ISSN: 1097-0215
CID: 90030