Faculty Bibliography

Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus, cardiovascular disease, and all-cause mortality. Previously, we demonstrated that lipocalin-type prostaglandin D₂ synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in mediating NAFLD utilizing L-PGDS knockout (KO) and control C57BL/6 mice fed either low fat (LFD) or high fat diet (HFD) for 14 weeks. Our present study demonstrates that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster and eventually progress to the more severe non-alcoholic steatohepatitis (NASH). We found increased lipid accumulation in the liver of KO mice over time on both diets, as compared to control mice. The L-PGDS KO mice showed elevated fasting glucose and insulin levels and developed insulin resistance on both LFD and HFD. Lipogenesis marker proteins such as SREBP-1c and LXRα were increased in L-PGDS KO mice after 14 weeks on both diets, when compared to control mice. We replicated our in vivo findings in vitro using HepG2 cells treated with a combination of free fatty acids (oleic and palmitic acid) and exposure to a L-PGDS inhibitor and prostaglandin D₂ receptor (DP1) antagonists. We conclude that the absence or inhibition of L-PGDS results in dyslipidemia, altered expression of lipogenesis genes and the acceleration of NAFLD to NASH, independent of diet and obesity. We propose L-PGDS KO mice as a useful model to explore the pathogenesis of NAFLD and NASH, and L-PGDS as a potential therapeutic target for treatment.

Objectives: Digital innovation has the potential to transform both the science and practice of child mental health. Creation of pediatric digital health tools requires that bioethics, human-centered design, and clinical and scientific expertise are integrated with digital tool development, digital data collection, and data analytics. In this talk, we will describe the opportunities for innovations in pediatric digital mental health and the concurrent ethical and security risks. We will then present a framework and design methodology for creating ethical, human-centered, clinically informed, and evidence-based digital tools for children's mental health.
Method(s): The data presented will come from our experience founding and leading the New York University Langone Department of Child and Adolescent Psychiatry's WonderLab, which creates pediatric digital mental health tools that are evidence based, scalable, and ethical, as well as beautiful and fun so that parents and children would want to use them. The WonderLab brings clinical, scientific, digital engineering, digital design, data science, and bioethics expertise together with user engagement and a "build, measure, learn" agile development culture and methodology. We will use the WonderLab team's development and launch of our first app-based study, "When to Wonder: Picky Eating," to illustrate our framework and methodology.
Result(s): We will describe the innovation opportunities in pediatric digital mental health, including innovation in measurement, engagement, access, and collaborative methodologies. We will then present the ethical, privacy, security, and safety risks related to digital health applications and app-based data collection with children and their families. Finally, we will describe how the WonderLab team, methodology, and products innovate across multiple domains within an explicit ethical and clinically informed framework.
Conclusion(s): Digital innovation and data science have great potential to address the challenges facing our patients and our field. To build ethical and useful digital health tools for children's mental health requires multidisciplinary teams, user engagement, collaborative agile methodology, and a framework that ensures that innovations are integrated with and reflect our ethics and commitment to children. R, COMP, DAM
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Objectives: We will: 1) describe the WonderLab, a digital health initiative within the New York University Langone Health Department of Child and Adolescent Psychiatry; 2) introduce When to Wonder: Picky Eating, which is the WonderLab's first early childhood mental health digital study; and 3) present preliminary data from this study. Our first objective is to demonstrate how smartphone-based tools developed to assess children in their homes and the use of advanced data analytics can transform how, when, and where we assess young children's development and mental health. Our second objective is to share how our multidisciplinary team and agile development methodology enable us to build and launch a consumer-facing pediatric health app within an academic medical center.
Method(s): The WonderLab creates scalable mobile digital health tools to collect multimodal data in children's homes at the individual, family, and population levels. In December 2018, we released When to Wonder: Picky Eating, a national study with consent, enrollment, study activities, and feedback fully integrated in iOS and Android apps that parents download from the app stores. When to Wonder: Picky Eating focuses on the emotions and behaviors related to picky eating in children under the age of 7 years. Data sources include parent-report, video, audio, and an active task that children and parents play independently to quantify children's food preferences.
Result(s): We will present preliminary data from When to Wonder: Picky Eating to characterize normative and clinically significant emotions and behaviors related to picky eating. We will also share data on recruitment and engagement using social media, app performance, and "lessons learned" about digital pediatric health.
Conclusion(s): We create clinically and scientifically valid digital tools that parents and children want to use. We integrate clinical, scientific, engineering, design, data science, and bioethics expertise with collaborative user engagement and a "build, measure, learn" agile development culture. Our app-based study demonstrates how to build digital health tools that collect and analyze population-level and individual-level, multimodal data about children and families in the home. These new tools and approaches have the potential to transform our engagement with families and our delivery of care. EA, EC, MED
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Background The number of people migrating for labour is growing around the world, particularly in low- and middleincome countries. Parents often move for work, leaving their children behind. In China alone there are 61 million leftbehind children and adolescents (LBCA). Methods We conducted a systematic review including studies on parental migration and LBCA aged 0-19 years in low- and middle-income countries. Our outcomes were the 10 main causes of disability-adjusted life years in the under-5, 5-9 and 10-19 year age groups. These included nutrition, mental health, unintentional injuries, infectious disease, substance use, unprotected sex, early pregnancy and abuse among. We searched databases including MEDLINE, EMBASE and CINAHL from inception to April 2017, with no language restrictions. We conducted meta-analyses, sensitivity analyses based on the quality of studies, subgroup analyses (internal and international migration and one or two parent absence), and meta-regression to investigate child gender and age. A revised version of the Newcastle-Ottawa tool was used to assess bias. The protocol was registered with PROSPERO (CRD42017064871). Results We identified 111 studies, including 2 64 967 children and adolescents. 91 studies were conducted in China, all of which focused on internal migration. The other 20 studies were largely related to international migration in Asia. LBCA had an increased risk of depression (risk ratio (RR) 1.52; 95% confidence interval (CI) 1.27,1.82) and higher depression scores (standardised mean difference (SMD) 0.16; 0.10,0.21), anxiety (RR 1.85;95% CI 1.36,2.53 and SMD 0.18; 95% CI 0.11,0.26), suicidal ideation (RR 1.70; 95% CI 1.28,2.26), conduct disorder (SMD 0.16; 95% CI 0.04,0.28) and substance use (RR 1.24; 95% CI 1.00,1.52). There was an increased risk of malnutrition: wasting (RR 1.13; 95% CI 1.02,1.24) and stunting (RR 1.12; 95% CI 1.00,1.26). We found no difference for other nutrition outcomes, unintentional injury, abuse or diarrhoea. Removing low quality studies made little difference to the outcomes, as did subgroup analyses. Meta-regression showed no significant effect of gender or mean age on any outcomes. Conclusions Parental labour migration is associated with morbidity in LBCA, with no evidence of any benefit. The strongest evidence exists in China, with more research required in the rest of the world

The tumor microenvironment regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. Increased expression of type X collagen α-1 (ColXalpha1) in tumor-associated stroma correlates with poor pathologic response to neoadjuvant chemotherapy in estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Evaluation of ColXα1 expression patterns suggests a potential connection with elastin fibers. To investigate the possible interaction between ColXα1 and elastin, we evaluated the expression of ColXα1 in relation to elastin fibers in normal breast tissue, ductal carcinoma in situ, and invasive breast carcinomas at cellular and subcellular levels. Our findings demonstrate that ColXα1 colocalizes with elastin in invasive breast cancer-associated stroma by immunohistochemistry, immunofluorescence, and electron microscopy. In 212 invasive breast carcinomas, this complex was aberrantly and selectively expressed in tumor extracellular matrix in 79% of ER+/HER2-, 80% of ER+/HER2+, 76% of ER-/HER2+, and 58% of triple negative breast cancers. In contrast, ColXα1 was generally absent, while elastin was present perivascularly in normal breast tissue. ColXα1 and elastin were coexpressed in 58% of ductal carcinoma in situ (DCIS) in periductal areas. In mass-forming DCIS with desmoplastic stroma, the complex was intensely expressed in periductal areas as well as within the tumor-associated stroma in all cases. Our data suggest that the breast carcinoma neoplastic process may involve aberrant expression of ColXalpha1 and elastin in the tumor microenvironment emerging early at the DCIS stage. Enrichment of these complexes in tumor-associated stroma may represent a stromal signature indicative of intrinsic differences between breast cancers. These findings shed light on investigation into the role of aberrant collagen complex expression in tumorigenesis and tumor progression which may be leveraged in therapeutic and theranostic applications.

Giant cell arteritis (GCA) primarily involves medium-to-large arteries. Small-vessel inflammation is a recognized phenomenon occurring in association with GCA. However, its significance is poorly elucidated. Histologic sections and medical records of105 temporal artery specimens were retrospectively reviewed between 2008 and 2017 to examine associated clinical manifestations and laboratory data including antinuclear antibody and p-antineutrophilic cytoplasmic antibody titers. Immunohistochemical staining for CD4 and CD8 was performed in select cases to assess the nature of the inflammatory response. Seventy-eight patients meeting the diagnostic criteria of temporal arteritis were included in the analysis. Twenty-eight specimens demonstrated temporal arteritis with small arterial inflammation (SAI), and 50 specimens showed temporal arteritis without SAI. Eight (28.6%) of 28 patients with SAI presented with jaw claudication, whereas 5 (17.9%) were febrile at presentation. In contrast, in 50 patients without SAI, jaw claudication and fever were seen in 11 and 2 cases, respectively (P = .01 and P = .0047, respectively). No statistically significant difference was noted between other symptoms and laboratory indices between the 2 groups. Elevated p-antineutrophilic cytoplasmic antibody titers in GCA may be associated with concomitant polymyalgia rheumatica or treatment-resistant disease. We also identified a higher count of CD4 and CD8 T cells in SAI cases, although the ratio of CD4/CD8 T lymphocytes was within normal limits. In conclusion, simultaneous involvement of arterioles and medium- to large-sized arteries is common in GCA and may be associated with treatment-refractory disease. Documentation of small arterial involvement in GCA will help the clinicians to manage the disease more effectively.

Arginase-1 has been demonstrated as a marker for hepatocellular carcinoma (HCC) with higher sensitivity and specificity than HepPar-1 and glypican-3. However, its sensitivity is diminished in moderately and poorly differentiated HCCs. In the current study, we evaluated the utility of AGXT1 as a diagnostic marker. Immunostains for AGXT1 and arginase-1 were performed in tissue microarrays of 139 HCCs and 374 gastrointestinal and nongastrointestinal carcinomas. AGXT1 exhibited granular cytoplasmic immunoreactivity in contrast to the diffuse cytoplasmic staining characteristic of arginase-1 in nonneoplastic and neoplastic hepatocytes. Sensitivities of AGXT1 for all HCCs were 90.0% compared to 87.8% for arginase-1. A small number of tumors expressed only 1 of the 2 markers. Sensitivity increased to 92.1% when the presence of either marker was considered positive. Excepting 5 cases of cholangiocarcinoma, both AGXT1 and arginase-1 were negative in all non-HCC tumors with specificities of 98.7%. Our data support the consideration of AGXT1 as a novel hepatocellular marker with equally high specificity and slightly higher sensitivity as compared to arginase-1. AGXT1 may aid in diagnostic workup especially in conjunction with arginase-1 for HCCs that may otherwise defy conventional immunostaining patterns.

BACKGROUND:The G protein-coupled bile acid receptor (TGR5) is a cell surface receptor which induces the production of intracellular cAMP and promotes epithelial-mesenchymal transition in gastric cancer cell lines. TGR5 is found in a wide variety of tissues including the kidney. However, the patterns of TGR5 expression have not been well characterized in physiologic kidney or renal neoplasms. We explore the expression of TGR5 in benign renal tissue and renal neoplasms and assess its utility as a diagnostic marker. METHODS:Sixty-one renal cortical neoplasms from 2000 to 2014 were retrieved. TGR5 protein expression was examined by immunohistochemistry. TGR5 mRNA was also measured by real-time PCR. RESULTS:In normal renal tissue, TGR5 was strongly positive in collecting ducts, distal convoluted tubules and thin loop of Henle. Proximal convoluted tubules showed absent or focal weak staining. In clear cell renal cell carcinomas (RCCs), 25 of 27 cases (92%) were negative for TGR5 (p < 0.001). TGR5 mRNA was also significantly decreased in clear cell RCCs, suggesting that decreased TGR5 protein expression may be attributable to the downregulation of TGR5 mRNA in these tumors. All 11 papillary RCCs expressed TGR5 with 45% (5/11) exhibiting moderate to strong staining. All chromophobe RCCs and oncocytomas were positive for TGR5 with weak to moderate staining. TGR5 mRNA expression in these tumors was similar to normal kidney. All urothelial carcinomas of the renal pelvis strongly expressed TGR5 including a poorly differentiated urothelial carcinoma with sarcomatoid features. CONCLUSION/CONCLUSIONS:TGR5 is strongly expressed in collecting ducts, distal convoluted tubules and thin loop of Henle. TGR5 protein and mRNA expression were notably decreased in clear cell RCCs and may be helpful in differentiating these tumors from other RCCs.

Several markers of pancreatobiliary lineage have been described in the literature. However, none have demonstrated sufficient specificity and sensitivity to warrant diagnostic use. We evaluated the utility of T-complex-associated-testis-expressed 3 (TCTE3) as a pancreatobiliary marker. A set of 247 adenocarcinomas from the gastrointestinal (GI) tract was identified including 18 from the gastroesophageal junction (GEJ), 29 stomach, 17 ampullary, 62 pancreatic, and 16 common bile duct and gallbladder (CBD/GB), 13 non-ampullary small intestine, 32 colon, and 24 rectum. The remainder consisted of 16 cholangiocarcinomas and 20 hepatocellular carcinomas (HCC). Additionally, 163 adenocarcinomas from the breast, gynecologic tract, prostate, urothelium, kidney, and lung were stained for comparison. Immunohistochemistry for TCTE3 and other gastrointestinal markers was performed. Positive expression of TCTE3 was characterized by a strong, well-defined membranous pattern with or without weak cytoplasmic staining. Expression was identified in the normal epithelial cells of pancreatobiliary tree, but staining was absent in normal epithelial cells of esophagus, stomach, and intestine. Hepatocytes, pancreatic acini and islets and other non-epithelial cells were also negative for staining. TCTE3 was expressed in 93.5% of pancreatic ductal adenocarcinomas, 37.5% of CBD/GB adenocarcinomas, 50% of cholangiocarcinomas, 76.4% of ampullary adenocarcinomas, and 33.3% of GEJ adenocarcinomas. Only 3.5% of the gastric, 7.7% of non-ampullary small intestinal and 6.25% of colonic tumors exhibited positive staining. Expression was absent in rectal carcinomas and HCCs. These results suggest that TCTE3 is a useful marker of pancreatobiliary differentiation and may aid in distinguishing these tumors from gastric and intestinal primary tumors.

Methamphetamine (meth) is a potent psychostimulant known to cause neurotoxicity. Clinical reports suggest meth abuse is a risk factor for Parkinson's disease. We investigated changes in the blood-brain barrier and cerebral vasculature as a mechanism underlying this risk in rats treated acutely and trained to self-administer meth. We observed blood-brain barrier leakage in rats treated acutely with meth. Hypoperfusion in the striatum was detected with acute and chronic meth treatment and was associated with hypoxia. This was correlated with reductions in striatal tyrosine hydroxylase in rats trained to self-administer meth. These findings suggest a new mechanism of meth-induced neurotoxicity involving striatal vasoconstriction resulting in hypoxia and dopamine reductions leading to an increased risk for Parkinson's disease for meth abusers.