Cindy Wang

All Publications

• Corrigendum to "Analysis of AI foundation model features decodes the histopathologic landscape of HPV-positive head and neck squamous cell carcinomas". [Oral Oncol. 163 (2025) 107207]. Oral oncology Hieromnimon, H. M., Trzcinska, A., Wen, F. T., Howard, F. M., Dolezal, J. M., Dyer, E., Kochanny, S., Schulte, J. J., Wang, C., Chen, H., Chin, J., Blair, E., Agrawal, N., Rosenberg, A., Vokes, E., Katipally, R., Juloori, A., Izumchenko, E., Lingen, M. W., Cipriani, N., Jalaly, J. B., Basu, D., Riesenfeld, S. J., Pearson, A. T. 2025: 107510

  View details for DOI 10.1016/j.oraloncology.2025.107510

  View details for PubMedID 40721367

• Analysis of AI foundation model features decodes the histopathologic landscape of HPV-positive head and neck squamous cell carcinomas. Oral oncology Hieromnimon, H. M., Trzcinska, A., Wen, F. T., Howard, F. M., Dolezal, J. M., Dyer, E., Kochanny, S., Schulte, J. J., Wang, C., Chen, H., Chin, J., Blair, E., Agrawal, N., Rosenberg, A., Vokes, E., Katipally, R., Juloori, A., Izumchenko, E., Lingen, M. W., Cipriani, N., Jalaly, J. B., Basu, D., Riesenfeld, S. J., Pearson, A. T. 2025; 163: 107207

  Abstract

  OBJECTIVES: Human papillomavirus (HPV) influences the pathobiology of Head and Neck Squamous Cell Carcinomas (HSNCCs). While deep learning shows promise in detecting HPV from hematoxylin and eosin (H&E) stained slides, the histologic features utilized remain unclear. This study leverages artificial intelligence (AI) foundation models to characterize histopathologic features associated with HPV presence and objectively describe patterns of variability in the HPV-positive space.MATERIALS AND METHODS: H&E images from 981 HNSCC patients across public and institutional datasets were analyzed. We used UNI, a foundation model based on self-supervised learning (SSL), to map the landscape of HNSCC histology and identify the axes of SSL features that best separate HPV-positive and HPV-negative tumors. To interpret the histologic features that vary across different regions of this landscape, we used HistoXGAN, a pretrained generative adversarial network (GAN), to generate synthetic histology images from SSL features, which a pathologist rigorously assessed.RESULTS: Analyzing AI-generated synthetic images found distinctive features of HPV-positive histology, such as smaller, paler, more monomorphic nuclei; purpler, amphophilic cytoplasm; and indistinct cell borders with rounded tumor contours. The SSL feature axes we identified enabled accurate prediction of HPV status from histology, achieving validation sensitivity and specificity of 0.81 and 0.92, respectively. Our analysis subdivided image tiles from HPV-positive histology into three overlapping subtypes: border, inflamed, and stroma.CONCLUSION: Foundation-model-derived synthetic pathology images effectively capture HPV-related histology. Our analysis identifies distinct subtypes within HPV-positive HNSCCs and enables accurate, explainable detection of HPV presence directly from histology, offering a valuable approach for low-resource clinical settings.

  View details for DOI 10.1016/j.oraloncology.2025.107207

  View details for PubMedID 40043423

• Some Drugs Have Two Faces: Paradoxical Colitis in a Patient with Psoriatic Arthritis Previously Treated with Etanercept and IL-17 Inhibitors. Digestive diseases and sciences Huynh, S., Achalu, S., Berry, R., Lin, J., Wang, C. X., Gubatan, J., Cheng, A. G. 2024

  Abstract

  Tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) inhibitors are among the most potent treatments for inflammatory arthropathies including rheumatoid arthritis, psoriasis, and spondyloarthropathies. The availability of these biologic agents have revolutionized the management of these conditions and improved patient outcomes. Though generally safe, these biologics may contribute to the induction or exacerbation of colitis. This paradoxical colitis has been observed in patients on TNF-α inhibitor etanercept and IL-17 inhibitors (secukinumab and ixekizumab). We report a case of a 46-year-old female with psoriasis and psoriatic arthritis who presented with gastrointestinal symptoms after treatment with etanercept and IL-17 inhibitors. She was later diagnosed with paradoxical indeterminate colitis that was masked and treated by subsequent biologics given for her RA and psoriatic arthritis. In this report, we will discuss the importance of considering paradoxical colitis in the differential diagnosis for patients even several years after TNF-α/IL-17 inhibitor initiation and explain why careful consideration must be made when initiating these colitis-inducing agents to treat patients with inflammatory disorders.

  View details for DOI 10.1007/s10620-024-08380-2

  View details for PubMedID 38502378

  View details for PubMedCentralID 3886036

• A Picture is Worth 1000 Pathological Learning Points: Creating Visual Pathology Teaching Materials Appropriate for Pre-Clerkship Medical Student Learning Afifi, A., Cobos, J., Hammer, P., Gilbert, A., Bharani, K., Wang, C., Kuhlmann, R., Ernst, K. ELSEVIER SCIENCE INC. 2024: S1978-S1979

  View details for Web of Science ID 001302363407082

• Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation JCI INSIGHT Manoli, I., Sysol, J. R., Head, P. E., Epping, M. W., Gavrilova, O., Crocker, M. K., Sloan, J. L., Koutsoukos, S. A., Wang, C., Ktena, Y. P., Mendelson, S., Pass, A. R., Zerfas, P. M., Hoffmann, V., Vernon, H. J., Fletcher, L. A., Reynolds, J. C., Tsokos, M. G., Stratakis, C. A., Voss, S. D., Chen, K. Y., Brown, R. J., Hamosh, A., Berry, G. T., Chen, X., Yanovski, J. A., Venditti, C. P. 2024; 9 (4)

  Abstract

  A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.

  View details for DOI 10.1172/jci.insight.174097

  View details for Web of Science ID 001174841400001

  View details for PubMedID 38271099

• Clinicopathological features and clinical outcomes in individuals with Krukenberg tumors of colorectal origin. Bergstrom, C. P., Wang, C., King, D., Lin, A. Y., Fisher, G. A. LIPPINCOTT WILLIAMS & WILKINS. 2024: 191

  View details for DOI 10.1200/JCO.2024.42.3_suppl.191

  View details for Web of Science ID 001266680500518

• Milky Way: Management of Primary Intestinal Lymphangiectasia Digestive Diseases and Sciences Norman, J. S., Testa, S., Wang, C., Savage, T. 2023

  View details for DOI 10.1007/s10620-023-08077-y

  View details for PubMedCentralID 7789053

• Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin. Science translational medicine Head, P. E., Myung, S., Chen, Y., Schneller, J. L., Wang, C., Duncan, N., Hoffman, P., Chang, D., Gebremariam, A., Gucek, M., Manoli, I., Venditti, C. P. 2022; 14 (646): eabn4772

  Abstract

  Organic acidemias such as methylmalonic acidemia (MMA) are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino and fatty acids. Accretion of acyl-CoA species is postulated to underlie disease pathophysiology, but the mechanism(s) remain unknown. Here, we surveyed hepatic explants from patients with MMA and unaffected donors, in parallel with samples from various mouse models of methylmalonyl-CoA mutase deficiency. We found a widespread posttranslational modification, methylmalonylation, that inhibited enzymes in the urea cycle and glycine cleavage pathway in MMA. Biochemical studies and mouse genetics established that sirtuin 5 (SIRT5) controlled the metabolism of MMA-related posttranslational modifications. SIRT5 was engineered to resist acylation-driven inhibition via lysine to arginine mutagenesis. The modified SIRT5 was used to create an adeno-associated viral 8 (AAV8) vector and systemically delivered to mutant and control mice. Gene therapy ameliorated hyperammonemia and reduced global methylmalonylation in the MMA mice.

  View details for DOI 10.1126/scitranslmed.abn4772

  View details for PubMedID 35613279

  View details for PubMedCentralID PMC10468269

• Morphologic and molecular analysis of early-onset gastric cancer. Cancer Setia, N., Wang, C. X., Lager, A., Maron, S., Shroff, S., Arndt, N., Peterson, B., Kupfer, S. S., Ma, C., Misdraji, J., Catenacci, D., Hart, J. 2021; 127 (1): 103-114

  Abstract

  Evidence suggests that early-onset gastric cancers are distinct from traditional gastric cancers; however, detailed genomic and morphologic characterization of these cancers has not been performed.Genomic analysis was performed for 81 patients with gastric cancer who were 50 years old or younger; pathology slides were available for 53 of these patients, and they were re-reviewed to perform a morphologic-molecular correlation analysis. The results were compared with corresponding cBioPortal data and The Cancer Genome Atlas (TCGA) analysis, which represent traditional gastric cancers. The TP53 molecular signature was established to determine the pattern of somatic mutational damage. Variants of potential germline origin were also identified from next-generation sequencing data.A higher rate of CDH1 mutations (22.2% of early-onset gastric cancers vs 11.4% of traditional gastric cancers; P = .0042) but a similar rate of TP53 mutations (63% of early-onset gastric cancers vs 56.6% of traditional gastric cancers; P = .2674) were seen in early-onset cancers in comparison with traditional gastric cancers. The diffuse/mixed types correlated with the TCGA genomically stable type, and the remaining Lauren types correlated with the TCGA chromosomal instability type. Diffuse and indeterminate histologic types (overall survival, 26.25 months for the intestinal type, 20.5 months for the mixed type, 12.62 months for the diffuse type, and 9 months for the indeterminate type; P = .027) and the presence of a CDH1 gene mutation (overall survival, 9 months for mutant CDH1 and 22 months for wild-type CDH1; P = .013) significantly correlated with worse survival. The TP53 gene frequently showed transition mutations (65.5%) involving the CpG sites (49%). Variants of potential germline origin were seen in high-penetrance genes (CDH1 and APC) and moderate-penetrance genes (ATM, NBN, and MUTYH) in 9.9% of cancers.Early-onset gastric cancer has distinct genomic alterations, such as CDH1 mutations, but shares with traditional gastric cancers a high frequency of TP53 mutations and the TP53 mutagenic signature. Diffuse and indeterminate histologic types and the presence of a CDH1 mutation are associated with worse overall survival. Endogenous factors leading to cytosine deamination and potential germline alterations in moderate-penetrance cancer susceptibility genes may be implicated in the pathogenesis of these cancers.

  View details for DOI 10.1002/cncr.33213

  View details for PubMedID 33048355

• FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia. JCI insight Manoli, I., Sysol, J. R., Epping, M. W., Li, L., Wang, C., Sloan, J. L., Pass, A., Gagne, J., Ktena, Y. P., Li, L., Trivedi, N. S., Ouattara, B., Zerfas, P. M., Hoffmann, V., Abu-Asab, M., Tsokos, M. G., Kleiner, D. E., Garone, C., Cusmano-Ozog, K., Enns, G. M., Vernon, H. J., Andersson, H. C., Grunewald, S., Elkahloun, A. G., Girard, C. L., Schnermann, J., DiMauro, S., Andres-Mateos, E., Vandenberghe, L. H., Chandler, R. J., Venditti, C. P. 2018; 3 (23)

  Abstract

  Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.

  View details for PubMedID 30518688

• Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Manoli, I., Sysol, J. R., Li, L., Houillier, P., Garone, C., Wang, C., Zerfas, P. M., Cusmano-Ozog, K., Young, S., Trivedi, N. S., Cheng, J., Sloan, J. L., Chandler, R. J., Abu-Asab, M., Tsokos, M., Elkahloun, A. G., Rosen, S., Enns, G. M., Berry, G. T., Hoffmann, V., DiMauro, S., Schnermann, J., Venditti, C. P. 2013; 110 (33): 13552-13557

  Abstract

  Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.

  View details for DOI 10.1073/pnas.1302764110

  View details for Web of Science ID 000323069200075

  View details for PubMedID 23898205

  View details for PubMedCentralID PMC3746875