Belinda Sun

Interests

Teaching

Teaching medical students, pathology residents, and GI/liver fellows.

Research

Novel biomarkers for prostate cancer progression. Pancreatic cancer treatment effects in response to chemoradiation. Rectal cancer disagnosis and stratification in response to chemoradiation.

Courses

Scholarly Contributions

Journals/Publications

• Lynn, H., Sun, X., Casanova, N. G., Bime, C., Reyes Hernon, V., Lanham, C., Oita, R. C., Ramos, N., Sun, B., Coletta, D. K., Camp, S. M., Karnes, J. H., Ellis, N. A., & Garcia, J. G. (2023). Linkage of NAMPT promoter variants to eNAMPT secretion, plasma eNAMPT levels, and ARDS severity. Therapeutic advances in respiratory disease, 17, 17534666231181262.
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  eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel DAMP and TLR4 ligand, is a druggable ARDS therapeutic target with promoter SNPs associated with ARDS severity. This study assesses the previously unknown influence of promoter SNPs on transcription, eNAMPT secretion, and ARDS severity.
• Peterson, T., Mann, S., Sun, B. L., Peng, L., Cai, H., & Liang, R. (2023). Motionless volumetric structured light sheet microscopy. Biomedical optics express, 14(5), 2209-2224.
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  To meet the increasing need for low-cost, compact imaging technology with cellular resolution, we have developed a microLED-based structured light sheet microscope for three-dimensional and imaging of biological tissue in multiple modalities. All the illumination structure is generated directly at the microLED panel-which serves as the source-so light sheet scanning and modulation is completely digital, yielding a system that is simpler and less prone to error than previously reported methods. Volumetric images with optical sectioning are thus achieved in an inexpensive, compact form factor without any moving parts. We demonstrate the unique properties and general applicability of our technique by imaging of porcine and murine tissue from the gastrointestinal tract, kidney, and brain.
• Sun, B. L., Sun, X., Kempf, C. L., Song, J. H., Casanova, N. G., Camp, S. M., Reyes Hernon, V., Fallon, M., Bime, C., Martin, D. R., Travelli, C., Zhang, D. D., & Garcia, J. G. (2023). Involvement of eNAMPT/TLR4 inflammatory signaling in progression of non-alcoholic fatty liver disease, steatohepatitis, and fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37(3), e22825.
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  Although the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to steatohepatitis (NASH) and cirrhosis remains poorly understood, a critical role for dysregulated innate immunity has emerged. We examined the utility of ALT-100, a monoclonal antibody (mAb), in reducing NAFLD severity and progression to NASH/hepatic fibrosis. ALT-100 neutralizes eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel damage-associated molecular pattern protein (DAMP) and Toll-like receptor 4 (TLR4) ligand. Histologic and biochemical markers were measured in liver tissues and plasma from human NAFLD subjects and NAFLD mice (streptozotocin/high-fat diet-STZ/HFD, 12 weeks). Human NAFLD subjects (n = 5) exhibited significantly increased NAMPT hepatic expression and significantly elevated plasma levels of eNAMPT, IL-6, Ang-2, and IL-1RA compared to healthy controls, with IL-6 and Ang-2 levels significantly increased in NASH non-survivors. Untreated STZ/HFD-exposed mice displayed significant increases in NAFLD activity scores, liver triglycerides, NAMPT hepatic expression, plasma cytokine levels (eNAMPT, IL-6, and TNFα), and histologic evidence of hepatocyte ballooning and hepatic fibrosis. Mice receiving the eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg/week, IP, weeks 9 to 12) exhibited marked attenuation of each index of NASH progression/severity. Thus, activation of the eNAMPT/TLR4 inflammatory pathway contributes to NAFLD severity and NASH/hepatic fibrosis. ALT-100 is potentially an effective therapeutic approach to address this unmet NAFLD need.
• Sun, X., Sammani, S., Hufford, M., Sun, B. L., Kempf, C. L., Camp, S. M., Garcia, J. G., & Bime, C. (2023). Targeting P-selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the promoter. Pulmonary circulation, 13(1), e12206.
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  We previously identified a missense single nucleotide polymorphism rs2228315 (G>A, Met62Ile) in the selectin-P-ligand gene (), encoding P-selectin glycoprotein ligand 1 (PSGL-1), to be associated with increased susceptibility to acute respiratory distress syndrome (ARDS). These earlier studies demonstrated that lung tissue expression was increased in mice exposed to lipopolysaccharide (LPS)- and ventilator-induced lung injury (VILI) suggesting that inflammatory and epigenetic factors regulate promoter activity and transcription. In this report, we used a novel recombinant tandem PSGL1 immunoglobulin fusion molecule (TSGL-Ig), a competitive inhibitor of PSGL1/P-selectin interactions, to demonstrate significant TSGL-Ig-mediated decreases in lung tissue expression as well as highly significant protection from LPS- and VILI-induced lung injury. In vitro studies examined the effects of key ARDS stimuli (LPS, 18% cyclic stretch to simulate VILI) on promoter activity and showed LPS-mediated increases in promoter activity and identified putative promoter regions associated with increased expression. promoter activity was strongly regulated by the key hypoxia-inducible transcription factors, HIF-1α, and HIF-2α as well as NRF2. Finally, the transcriptional regulation of promoter by ARDS stimuli and the effect of DNA methylation on expression in endothelial cell was confirmed. These findings indicate transcriptional regulation by clinically-relevant inflammatory factors with the significant TSGL-Ig-mediated attenuation of LPS and VILI highly consistent with PSGL1/P-selectin as therapeutic targets in ARDS.
• Casanova, N. G., Reyes-Hernon, V., Gregory, T., Sun, B., Bermudez, T., Hufford, M. K., Oita, R. C., Camp, S. M., Hernandez-Molina, G., Serrano, J. R., Sun, X., Fimbres, J., Mirsaeidi, M., Sammani, S., Bime, C., & Garcia, J. G. (2022). Biochemical and genomic identification of novel biomarkers in progressive sarcoidosis: HBEGF, eNAMPT, and ANG-2. Frontiers in medicine, 9, 1012827.
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  Progressive pulmonary fibrosis is a serious complication in subjects with sarcoidosis. The absence of reliable, non-invasive biomarkers that detect early progression exacerbates the difficulty in predicting sarcoidosis severity. To potentially address this unmet need, we evaluated a panel of markers for an association with sarcoidosis progression (HBEGF, NAMPT, IL1-RA, IL-6, IL-8, ANG-2). This panel encompasses proteins related to inflammation, vascular injury, cell proliferation, and fibroblast mitogenesis processes.
• Sammani, S., Bermudez, T., Kempf, C. L., Song, J. H., Fleming, J. C., Reyes Hernon, V., Hufford, M., Tang, L., Cai, H., Camp, S. M., Natarajan, V., Jacobson, J. R., Dudek, S. M., Martin, D. R., Karmonik, C., Sun, X., Sun, B., Casanova, N. G., Bime, C., & Garcia, J. G. (2022). eNAMPT Neutralization Preserves Lung Fluid Balance and Reduces Acute Renal Injury in Porcine Sepsis/VILI-Induced Inflammatory Lung Injury. Frontiers in physiology, 13, 916159.
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  Numerous potential ARDS therapeutics, based upon preclinical successful rodent studies that utilized LPS challenge without mechanical ventilation, have failed in Phase 2/3 clinical trials. Recently, ALT-100 mAb, a novel biologic that neutralizes the TLR4 ligand and DAMP, eNAMPT (extracellular nicotinamide phosphoribosyltransferase), was shown to reduce septic shock/VILI-induced porcine lung injury when delivered 2 h after injury onset. We now examine the ALT-100 mAb efficacy on acute kidney injury (AKI) and lung fluid balance in a porcine ARDS/VILI model when delivered 6 h post injury. Compared to control PBS-treated pigs, exposure of ALT-100 mAb-treated pigs (0.4 mg/kg, 2 h or 6 h after injury initiation) to LPS-induced pneumonia/septic shock and VILI (12 h), demonstrated significantly diminished lung injury severity (histology, BAL PMNs, plasma cytokines), biochemical/genomic evidence of NF-kB/MAP kinase/cytokine receptor signaling, and AKI (histology, plasma lipocalin). ALT-100 mAb treatment effectively preserved lung fluid balance reflected by reduced BAL protein/tissue albumin levels, lung wet/dry tissue ratios, ultrasound-derived B lines, and chest radiograph opacities. Delayed ALT-100 mAb at 2 h was significantly more protective than 6 h delivery only for plasma eNAMPT while trending toward greater protection for remaining inflammatory indices. Delayed ALT-100 treatment also decreased lung/renal injury indices in LPS/VILI-exposed rats when delivered up to 12 h after LPS. These studies indicate the delayed delivery of the eNAMPT-neutralizing ALT-100 mAb reduces inflammatory lung injury, preserves lung fluid balance, and reduces multi-organ dysfunction, and may potentially address the unmet need for novel therapeutics that reduce ARDS/VILI mortality.
• Dawley, J. C., Ahmad, Y. H., Riall, T. S., & Sun, B. (2021). Gastric mixed large cell neuroendocrine-adenosquamous carcinoma with heterogenous MSH6 loss in Lynch syndrome. Human Pathology Report, 26, 300579. doi:https://doi.org/10.1016/j.hpr.2021.300579
• Dawley, J. C., Gavini, H. K., & Sun, B. L. (2021). Submucosal gastric heterotopia presenting as an upper esophageal nodule. Journal of surgical case reports, 2021(6), rjab251.
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  Esophageal gastric heterotopia (GH), the presence of differentiated gastric tissue in the esophagus, is estimated in up to 14% of populations worldwide and has always been reported on the surface of the esophagus, where it is also known as inlet patch. However, submucosal GH, in any tissue, is a rare finding. We report the case of a 50 year-old male presenting with chronic cough, heartburn and raspy vocalizations. Endoscopic examination showed a single 7 mm esophageal nodule, 20 cm from the incisors, interpreted as a submucosal mass. Pathologic examination of the endoscopically excised nodule showed well-differentiated gastric mucosa within the submucosa underneath the overlying squamous mucosa, consistent with submucosal GH. This case raises the awareness of an atypical presentation and location of GH seen as a submucosal mass on endoscopy.
• Singh, N., Ramnarine, V. R., Song, J. H., Pandey, R., Padi, S. K., Nouri, M., Olive, V., Kobelev, M., Okumura, K., McCarthy, D., Hanna, M. M., Mukherjee, P., Sun, B., Lee, B. R., Parker, J. B., Chakravarti, D., Warfel, N. A., Zhou, M., Bearss, J. J., , Gibb, E. A., et al. (2021). The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer. Nature communications, 12(1), 7349.
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  Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.
• Sun, B. L. (2021). Immunotherapy in treatment of metastatic prostate cancer: An approach to circumvent immunosuppressive tumor microenvironment. The Prostate, 81(15), 1125-1134.
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  Prostate cancer is the second most common cause of cancer-related death in men in the United States and the fifth worldwide. Most prostate cancer arises as an androgen-dependent tumor but eventually progresses into castration-resistance prostate cancer, incurable by the current androgen deprivation therapy and chemotherapy. The development of immunotherapy in cancer treatment has brought an exciting era of antiprostate cancer therapy through antitumor immune responses. Prostate cancer is recognized as a poorly immunogenic tissue with immunological ignorance showing low levels of antigen-presenting process and cytotoxic T-cell activation, high levels of immune checkpoint molecules and immunosuppressive cytokines/chemokines, and recruitment of immunosuppressive cells. Immunotherapies for prostate cancer have been developed to activate the innate and adaptive immune responses, such as vaccines and adoptive CAR-T cells, or to inhibit immunosuppressive molecules, such as immune checkpoint inhibitors or antibodies. The U.S Food and Drug Administration has approved Sipuleucel-T for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC) and immune checkpoint inhibitor pembrolizumab for the treatment of all solid tumors, including prostate cancer, with impaired mismatch repair genes/microsatellite instability; however, the current clinical outcomes still need to be improved. As various immunosuppressive mechanisms coexist and cross-interact within the tumor microenvironment, different immunotherapy approaches may have to be combined and selected in a highly personalized way. It is hoped that this rapidly evolving field of immunotherapy will achieve successful treatment for mCRPC and will be applied to a wider range of prostate cancer patients.
• Sun, B. L. (2021). Submucosal lifting agent ORISE gel causes extensive foreign body granuloma post endoscopic resection. International journal of colorectal disease, 36(2), 419-422.
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  Submucosal injection of lifting solution is often performed to facilitate endoscopic mucosal resection or endoscopic submucosal dissection. ORISE gel is a synthetic solution recently approved by the US Food and Drug Administration (FDA) in 2018 for use as submucosal lifting solution for endoscopic resection procedures and has gained popularity for its convenient pre-filled syringe. However, here the present two cases show that ORISE gel induces marked foreign body giant cell granulomatous reaction in the submucosa and muscularis propria following endoscopic resection.
• Sun, B. L., Tang, L., Sun, X., Garcia, A. N., Camp, S. M., Posadas, E., Cress, A. E., & Garcia, J. G. (2021). A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression. Pharmaceuticals (Basel, Switzerland), 14(12).
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  Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. In the current study, we further investigate the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody (ALT-100 mAb) in preclinical PCa orthotopic xenograft models. We utilized human aggressive PCa cells (DU145 or PC3) for prostate implantation in SCID mice receiving weekly intraperitoneal injections of either ALT-100 mAb or IgG/PBS (control) for 12 weeks. Prostatic tumors and solid organs were examined for tumor growth, invasion, and metastasis and for biochemical and immunohistochemistry evidence of NFκB activation. ALT-100 mAb treatment significantly improved overall survival of SCID mice implanted with human PCa orthotopic prostate xenografts while inducing tumor necrosis, decreasing PCa proliferation and reducing local invasion and distal metastases. The ALT-100 mAb inhibits NFκB phosphorylation and signaling in PCa cells both in vitro and in vivo. This study demonstrates that eNAMPT neutralization effectively prevents human PCa aggressive progression in preclinical models, indicating its high potential to directly address the unmet need for an effective targeted therapy for patients with aggressive PCa.
• Sun, X., Sun, B. L., Sammani, S., Bermudez, T., Dudek, S. M., Camp, S. M., & Garcia, J. G. (2021). Genetic and epigenetic regulation of the non-muscle myosin light chain kinase isoform by lung inflammatory factors and mechanical stress. Clinical science (London, England : 1979), 135(7), 963-977.
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  The myosin light chain kinase gene, MYLK, encodes three proteins via unique promoters, including the non-muscle isoform of myosin light chain kinase (nmMLCK), a cytoskeletal protein centrally involved in regulation of vascular integrity. As MYLK coding SNPs are associated with severe inflammatory disorders (asthma, acute respiratory distress syndrome (ARDS)), we explored clinically relevant inflammatory stimuli and promoter SNPs in nmMLCK promoter regulation.
• Sun, X., Sun, B., Dudek, S., Camp, S., & Garcia, J. G. (2020). Genetic and Epigenetic Regulation of the Non-Muscle Myosin Light Chain Kinase Isoform by Lung Inflammatory Factors and Mechanical Stress. Clinical Science.
• Carlson, Q., Golconda, U., & Sun, B. (2020). Gastric heterotopia with perforation mimicking neoplastic process in ileum. Journal of surgical case reports, 2020(7), rjaa224.
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  Gastric heterotopia (GH) is rare in ileum except in Meckel's diverticulum and rarely causes severe symptoms in adults. Here, we report a 31-year-old male patient with GH in ileum presented with bowel perforation and mass formation in the mesentery mimicking perforated small bowel tumor. Microscopic examination of the lesion showed completely differentiated gastric body-type mucosa with mucosal ulceration, fistula formation and bowel perforation. This case raises the awareness that GH may cause severe complications and should be included in the differential diagnosis for acute abdominal pain especially in patients with a mass lesion at an unusual location.
• Casanova, N. G., Gonzalez-Garay, M. L., Sun, B., Bime, C., Sun, X., Knox, K. S., Crouser, E. D., Sammani, N., Gonzales, T., Natt, B., Chaudhary, S., Lussier, Y., & Garcia, J. G. (2020). Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas. Respiratory research, 21(1), 321.
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  Despite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures.
• Elliott, A. S., Sun, B., & Bhattachayya, A. (2020). Benign Intestinal Epithelization on Serosa Mimicking Stage IV Tumor Post Bowel Perforation in Colonic Adenocarcinoma Following Neoadjuvant Therapy.. Journal of Case Reports in Medicine, 19(1), 14-17. doi:10.25149/jocrm.v9i1.222
• Quijada, H., Bermudez, T., Kempf, C. L., Valera, D. G., Garcia, A. N., Camp, S. M., Song, J. H., Franco, E., Burt, J. K., Sun, B., Mascarenhas, J. B., Burns, K., Gaber, A., Oita, R. C., Reyes Hernon, V., Barber, C., Moreno-Vinasco, L., Sun, X., Cress, A. E., , Martin, D., et al. (2020). Endothelial eNAMPT Amplifies Preclinical Acute Lung Injury: Efficacy of an eNAMPT-Neutralising mAb. The European respiratory journal.
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  The SARS-CoV-2/COVID-19 pandemic has highlighted the serious unmet need for effective therapies that reduce ARDS mortality. We explored whether extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a ligand for Toll-like receptor 4 and a master regulator of innate immunity and inflammation, is a potential ARDS therapeutic target.
• Sun, B. (2020). Endoscopic tattooing: a risk for tumor implantation. International Journal of Colorectal Disease, 1-4. doi:https://doi.org/10.1007/s00384-019-03495-9
• Sun, B. (2020). Endoscopic tattooing: a risk for tumor implantation. International journal of colorectal disease, 35(3), 571-574.
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  Endoscopic tattooing is considered to be a safe procedure to mark a lesion for subsequent surgical resection, and the reported complications are relatively minor. However, here the present case shows tumor traveling through needle tract with tumor inoculation following endoscopic tattooing.
• Sun, B. L. (2020). Current Microsatellite Instability Testing in Management of Colorectal Cancer. Clinical colorectal cancer.
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  Colorectal cancer (CRC) is the third most common cancer worldwide. In the past decade, mismatch repair deficiency (dMMR), manifested as microsatellite instability-high (MSI-H), has been recognized as a distinct mechanism promoting tumorigenesis in 15% of CRCs including 3% Lynch syndrome and 12% sporadic CRCs. As the molecular classifications of CRCs are continuously evolving, MSI-H CRCs appear to be the most homogeneous CRCs with distinct molecular, morphologic, and clinical features. MSI-H CRCs have dMMR causing MSI-H and genetic hypermutation but with diploid chromosomes. Morphologically, MSI-H CRCs appear as poorly differentiated or mucinous adenocarcinoma with characteristic lymphocytic infiltration. Most importantly, MSI-H CRCs have better stage-adjusted survival, do not respond well to standard 5-fluorouracil-based adjuvant chemotherapy, but do respond to immunotherapy. The United States Food and Drug Administration granted accelerated approval to immune checkpoint inhibitors, anti-programmed cell death protein-1 antibodies pembrolizumab and nivolumab, and the combination of nivolumab with anti-CTLA4 antibody ipilimumab for the second-line treatment of patients with stage IV MSI-H CRCs in 2017. There are still ongoing phase III clinical trials evaluating pembrolizumab and anti-programmed death-ligand 1 antibody atezolizumab as the first-line treatment in stage IV MSI-H CRCs and a phase I study on the combination of nivolumab and ipilimumab in patients with early stage CRC. These ongoing clinical studies on immunotherapy may lead to practice-changing results in the management of MSI-H CRCs. The National Comprehensive Cancer Network 2018 guidelines recommended MSI to be tested in all newly diagnosed CRCs. The MSI test will become increasingly vital in guiding adjuvant chemotherapy and immunotherapy in the management of CRCs.
• Sun, B. L., Sun, X., Casanova, N., Garcia, A. N., Oita, R., Algotar, A. M., Camp, S. M., Hernon, V. R., Gregory, T., Cress, A. E., & Garcia, J. G. (2020). Role of secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in prostate cancer progression: Novel biomarker and therapeutic target. EBioMedicine, 61, 103059.
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  There remains a serious need to prevent the progression of invasive prostate cancer (PCa). We previously showed that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator via TLR4 ligation which has been implicated in PCa progression. Here we investigate the role of eNAMPT as a diagnostic biomarker and therapeutic target in the progression of PCa.
• Sun, X., Sun, B. L., Babicheva, A., Vanderpool, R., Oita, R. C., Casanova, N., Tang, H., Gupta, A., Lynn, H., Gupta, G., Rischard, F., Sammani, S., Kempf, C. L., Moreno-Vinasco, L., Ahmed, M., Camp, S. M., Wang, J., Desai, A. A., Yuan, J. X., & Garcia, J. G. (2020). Direct Extracellular NAMPT Involvement in Pulmonary Hypertension and Vascular Remodeling. Transcriptional Regulation by SOX and HIF-2α. American journal of respiratory cell and molecular biology, 63(1), 92-103.
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  We previously demonstrated involvement of (nicotinamide phosphoribosyltransferase) in pulmonary arterial hypertension (PAH) and now examine regulation and extracellular NAMPT's (eNAMPT's) role in PAH vascular remodeling. transcription and protein expression in human lung endothelial cells were assessed in response to PAH-relevant stimuli (PDGF [platelet-derived growth factor], VEGF [vascular endothelial growth factor], TGF-β1 [transforming growth factor-β1], and hypoxia). Endothelial-to-mesenchymal transition was detected by SNAI1 (snail family transcriptional repressor 1) and PECAM1 (platelet endothelial cell adhesion molecule 1) immunofluorescence. An eNAMPT-neutralizing polyclonal antibody was tested in a PAH model of monocrotaline challenge in rats. Plasma eNAMPT concentrations, significantly increased in patients with idiopathic pulmonary arterial hypertension, were highly correlated with indices of PAH severity. eNAMPT increased endothelial-to-mesenchymal transition, and each PAH stimulus significantly increased endothelial cell promoter activity involving transcription factors STAT5 (signal transducer and activator of transcription 5), SOX18 (SRY-box transcription factor 18), and SOX17 (SRY-box transcription factor 17), a PAH candidate gene newly defined by genome-wide association study. The hypoxia-induced transcription factor HIF-2α (hypoxia-inducible factor-2α) also potently regulated promoter activity, and HIF-2α binding sites were identified between -628 bp and -328 bp. The PHD2 (prolyl hydroxylase domain-containing protein 2) inhibitor FG-4592 significantly increased promoter activity and protein expression in an HIF-2α-dependent manner. Finally, the eNAMPT-neutralizing polyclonal antibody significantly reduced monocrotaline-induced vascular remodeling, PAH hemodynamic alterations, and NF-κB activation. eNAMPT is a novel and attractive therapeutic target essential to PAH vascular remodeling.
• Wanes, P., Daley, S., & Sun, B. (2020). Persistent Lymph Node Metastasis Post Imatinib Treatment in Low Grade Gastrointestinal Stromal Tumor with PDGFRA Mutation. American Journal of Surgical Case Reports, 2(3), 1-4. doi:10.31487/j.AJSCR.2020.03.10
• Gravbrot, N., Brasiliense, L. B., Alswied, A., Sun, B., & Lemole, G. M. (2019). Multiple Extraaxial Cavernous Hemangiomas: Rare Entity. World neurosurgery, 130, 364-368.
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  Cavernous hemangiomas arising in the extraaxial space are rarely encountered, often mimicking other more common pathologies. Furthermore, multiple coexisting lesions and posterior fossa involvement are scarcely reported. Herein, we present the case of a patient with concurrent frontal bone and posterior fossa extraaxial cavernous hemangiomas. We also review the challenges associated with the diagnosis and management of these entities.
• Sun, B., & Bhatachryya, A. (2019). Diagnosis of Hepatoid Carcinoma of Extrahepatic Origins: Cell Markers and Pathologic Standards. Biomedical Journal of Scientific & Technical Research, 15(2), 11182-11187. doi:10.26717/BJSTR.2019.15.002666
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  Background: Hepatoid adenocarcinoma (HAC) is a rare carcinoma showing hepatocellular differentiation but arising from extrahepatic organs. We herein have reported four HAC cases and reviewed literature to summarize the pathologic standards and biomarkers for diagnosis of HACs.Objectives and Methods: Cases diagnosed as HAC at the University of Arizona Medical Center Tucson were retrospectively reviewed. Relevant literature in the PubMed database prior to October, 2018 were reviewed and summarized.Results and conclusion: About 72% of reported HACs were originated from stomach, 9% from ovary, 7% from lung, 6% from pancreas, 2% from gallbladder or urinary bladder and rare cases from uterus, esophagus, jejunum, colon, rectum, or extrahepatic bile duct. Diagnosis of HAC can be challenging especially at the metastatic stage of disease with multiple organs’ involvement. Hepatocellular markers identify hepatocellular differentiation with variable sensitivity for the diagnosis of HACs from different origins. AFP expression was found in more than 90% of gastric, ovarian and urinary gallbladder HACs but only in 57% of pancreatic HACs. HepPar-1 was positive in 100% of pancreatic, gallbladder and urinary gallbladder HACs but only in 31% of gastric HACs. Glypican-3 is positive in almost all HACs tested except one gastric HAC. Differentiating HAC versus hepatocellular carcinoma is challenging due to the striking similarity in morphology and immunoprofile. Some tumor markers may help to make differentiation: serum tumor marker CA125 was elevated in 75% of ovarian HACs, and serum CEA was increased in 63% of gastric HACs; CK19 and CK7 were often strongly positive in HACs but rarely positive in hepatocellular carcinomas. Some newly identified markers such as bile salt export pump (BSEP) and multidrug-resistance protein 3 (MDR3) have been reported in distinguishing HAC from hepatocellular carcinoma but need to be further validated.
• Sun, B. L., Jain, R., Patel, C., & Bhattacharyya, A. K. (2018). Graft-Versus-Host Disease With Early Cytomegalovirus Infection in Gastrointestinal Tract Biopsies. International journal of surgical pathology, 26(4), 347-352.
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  Gastrointestinal (GI) graft-versus-host disease (GVHD) and cytomegalovirus (CMV) infection often simulate each other. However, distinction between GVHD and CMV infection is critical in the management of immunosuppression for transplant recipients. This study retrospectively reviewed 16 patients diagnosed with GVHD from 2010 to 2016 and found 4 cases (25%) coinfected with CMV. Two cases were initially diagnosed as GVHD only but found to have CMV infection by serological testing within 3 days after immunosuppression treatment for GVHD. The remarkable histological feature of CMV infection appeared to be significant acute inflammation in addition to apoptotic epithelial injuries, and particularly in an early stage of CMV replication, acute inflammation is possibly the only detectable feature of CMV infection.
• Sun, B., Lapetino, S. R., Diffalha, S. A., Yong, S., Gaba, R. C., Bui, J. T., Koppe, S., Garzon, S., & Guzman, G. (2016). Microvascular injury in persistent gastric ulcers after yttrium-90 microsphere radioembolization for liver malignancies. Human pathology, 50, 11-4.
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  Yttrium-90 microsphere radioembolization ((90)Y MRE) is a therapy for liver malignancies by permanently implanting (90)Y-containing microspheres into tumors via hepatic artery. The etiology of persistent gastric ulcerations in patients presenting months after treatment remains unclear. Three patients who presented with gastric ulceration 4 to 13 months after (90)Y MRE were examined by esophagogastroduodenoscopy and biopsies. Pathological examinations showed multiple (90)Y microspheres scattered within the lamina propria and submucosa. Most of the microspheres were distributed in a linear fashion, consistent with an intravascular location; however, the vascular lumen and endothelial cells were not present. The microspheres were surrounded by fibrotic tissue infiltrated by chronic inflammatory cells and rare neutrophils. Epithelial granulation without pititis and miniaturized glands with intervening fibrosis were noted, compatible with chronic ischemic changes. These findings suggest that the persistent gastric ulceration is a result of localized ischemic injury in response to (90)Y MRE-induced vascular damage.
• Ulrich, F., Carretero-Ortega, J., Menéndez, J., Narvaez, C., Sun, B., Lancaster, E., Pershad, V., Trzaska, S., Véliz, E., Kamei, M., Prendergast, A., Kidd, K. R., Shaw, K. M., Castranova, D. A., Pham, V. N., Lo, B. D., Martin, B. L., Raible, D. W., Weinstein, B. M., & Torres-Vázquez, J. (2016). Reck enables cerebrovascular development by promoting canonical Wnt signaling. Development (Cambridge, England), 143(6), 1055.
• Leiderman, Y. I., Andreoli, M. T., Sun, B., & Dawood, S. (2015). PARS PLANA VITRECTOMY COMBINED WITH CATARACT EXTRACTION: A Comparison of Surgical Outcomes Using Single-Piece and Multipiece Foldable Intraocular Lenses. Retina (Philadelphia, Pa.), 35(6), 1059-64.
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  To assess whether complication rates are comparable between phacovitrectomy using multipiece lenses versus single-piece foldable intraocular lenses.
• Sun, B. L., Abern, M., Garzon, S., & Setty, S. (2015). Cystic nephroma/mixed epithelial stromal tumor: a benign neoplasm with potential for recurrence. International journal of surgical pathology, 23(3), 238-42.
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  Cystic nephroma (CN) is a rare, benign, renal neoplasm composed of epithelial and stromal elements. Only about 200 cases have been reported since 1892 and recurrence has rarely been observed. We report a 32-year-old Hispanic woman, with a history of a right, complex cystic, renal mass treated by robotic decortication 2 years ago, who presented with flank pain, hematuria, and recurrent urinary tract infection. A magnetic resonance imaging study showed a 3.4-cm multicystic lesion with thickened septa and enhancement at the right kidney. The partial nephrectomy specimen revealed a well-circumscribed, multicystic tumor abutting the renal pelvis, with thick septa and smooth walls, filled with clear fluid. Microscopic examination showed variably sized cysts lined by cuboidal epithelium with focal hobnailing, without significant cytologic atypia and mitosis. The epithelial lining was positive for CK19, high molecular weight cytokeratin, and α-methylacyl-CoA racemase suggesting a primitive tubular epithelial phenotype. Primitive glomeruli-like structures were also present. The ovarian-like stroma was condensed around the cysts and was variably cellular with areas of muscle differentiation and thick-walled vessels. The stroma was positive for desmin, estrogen receptor, progesterone receptor, and CD10. We suggest that CN represents a variable mixture of epithelial and stromal elements, immature glomerular, tubular, muscle, and vascular elements, which may be present in variable proportions creating a spectrum of lesions previously described as CN and mixed epithelial and stromal tumors (MEST). This case emphasizes that CN/MEST clinically/radiologically mimics other cystic renal neoplasms, especially cystic renal cell carcinoma and tubulocystic carcinoma, necessitating histopathological examination and immunohistochemial studies for definitive diagnosis. Additionally, CN has the tendency to recur when not completely excised initially.
• Sun, B. L., Pearl, R., Sharifi, R., & Guzman, G. (2015). Metachronous bilateral testicular seminoma developing after an interval of 31 years: case report and review of the literature. International journal of surgical pathology, 23(2), 156-60.
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  Men diagnosed with testicular germ cell tumors are at higher risk for development of a second germ cell tumor in the contralateral testis. Metachronous bilateral testicular germ cell tumors usually occur within 5 years. Here, we report a case of a 63-year-old man previously diagnosed with testicular seminoma and treated with a left orchiectomy followed by radiation, developing contralateral testicular seminoma after an interval of 31 years. The patient was asymptomatic and found to have an enlarged, nontender right testis on routine urological examination. Further workup did not reveal evidence of metastatic disease or lymphadenopathy. The surgery specimen revealed a 4.2 × 3.1 × 1.8 cm distinct mass without tumor involvement of tunica albuginea or the tunica vaginalis. Microscopy showed classic seminoma with venous/lymphatic tumor invasion. The current case underscores the importance of recommending lifelong follow-up for patients with testicular germ cell tumors.

Presentations

• Sun, B. (2023, March).

  Grade 3 Well Differentiated Neuroendocrine Tumor versus Neuroendocrine Carcinoma: Landscape Genomics Showing Heterogeneity and Distinct Bioreaction Pathways.

  . USCAP 2023. New Orlean: USCAP.
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  Background: The current WHO classification separates high grade neuroendocrine neoplasm (Ki67>20%) into grade 3 well differentiated neuroendocrine tumor (G3-NET) and poorly differentiated neuroendocrine carcinoma (NEC). However, pathologic diagnosis of G3 NET versus NEC is often challenging especially in cases with ambiguous morphology. We have explored the possibility of distinguishing G3-NET versus NEC through genomics.   Design: The genomic data from 194 neuroendocrine neoplasm were met-analyzed for the distinct significant coding mutations and bioreaction pathways between G3 NET and NEC.Results: The landscape genomics of 57 G1-NET, 105 G2-NET, 16 G3-NET and 16-NEC showed broad heterogeneity among each group. The number of coding mutations are in average 23 per G1-NET, 33 per G2-NET, 45 per G3-NET and 170 per NEC, suggesting an increase in high grade NET and marked increase in NEC. Comparing NEC and NET, 92% of coding mutations were different among each group; and comparing G3N-ET and NEC, 86% to 95% of coding mutations were different with 777 genes unique in G3-NET and 1927 genes unique in NEC.  Bioreaction analysis of significant coding mutations showed significant pathways in G3-NET involving MET/RAS, RAS/NTRK3, IGFR1/SHC, FGFRs signaling and TP53-regulated transcriptions, and NEC involving  MET/PTK2, PKA, GRB7/ERBB signaling, and TP53 expression.Conclusion: The distinct coding mutations and bioreactions may provide potential signature genes or pathways to differentiate G3-NET versus NEC through genetic approaches.  

Poster Presentations

• Garcia, J. G., Casanova, N., Sun, X., Gonzalez-Garay, M. L., Sun, B., Sun, B., Gonzalez-Garay, M. L., Sun, X., Casanova, N., & Garcia, J. G. (2019, May). Sarcoidosis And Coccidioidomycosis Share Common Tissue Transcriptome Expression Profiles. ATS International Conference. Dallas: American Thoracic Society.
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  In this study we compared sarcoidosis gene expression profiles of lung and lymph node granulomas to tissues from patients with tuberculosis and coccidioidomycosis or Valley Fever (VF), a soil-dwelling fungi disease endemic in the southwest. We also aimed to compare sarcoidosis tissue gene expression to our previous gene signatures derived from peripheral blood mononuclear (PBMC). Incorporation of precise approaches like molecular biomarkers in the differential diagnosis will facilitate and expedite the diagnosis.

Case Studies

• Bhattacharyya, A. K., Sun, B., & Elliott, A. (2020. Benign Intestinal Epithelization on Serosa Mimicking Stage IV Tumor Post Bowel Perforation in Colonic Adenocarcinoma Following Neoadjuvant Therapy(pp Volume 9(1):14-17).
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  Abstract:Differentiation between benign intestinal epithelium and neoplastic epithelium is critical in staging intestinal tumors, especially complicated colorectal cancer. We present a case of treated advanced colon adenocarcinoma in a 72-year- old female who was clinically diagnosed with colo-vaginal-ileal fistula formation and intraperitoneal carcinomatosis following neoadjuvant chemotherapy and vEGFR targeted therapy. She presented acutely with abdominal pain, was found to have bowel perforation on imaging and underwent total colectomy. Pathologic examination revealed rectosigmoid perforation and terminal ileum with fistula. Microscopic examination identified a small amount of residual adenocarcinoma in the rectosigmoid and no tumor in the remaining colon, ileum, fistula and perforated areas; instead, benign reactive intestinal epithelium and related mucosa were present on the serosa adjacent to the perforations, mimicking stage IV carcinoma and carcinomatosis. This case report raises the awareness that benign intestinal mucosa may colonize the serosa, challenging the diagnosis of tumor involvement and significantly impacting tumor staging, treatment and prognosis.