68Ga-MY6349 PET/CT imaging to assess Trop2 expression in multiple types of cancer

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Abstract

Background Considering trophoblast cell surface antigen 2 (Trop2) is overexpressed in a wide range of human epithelial cancers, it presents an attractive target for the diagnosis and treatment of multiple types of cancer. Herein, we have developed a Trop2-specific radiotracer, 68Ga-MY6349, and present a prospective, investigator-initiated trial to explore the clinical values of 68Ga-MY6349 PET/CT. Methods In this translational study, 90 patients with 15 types of cancer, who underwent 68Ga-MY6349 PET/CT, were enrolled prospectively. Among them, 78 patients underwent paired 68Ga-MY6349 and 18F-FDG PET/CT, and 12 patients with prostate cancer underwent paired 68Ga-MY6349 and 68Ga-PSMA-11 PET/CT. Results Among the 90 patients across 15 types of cancer, 68Ga-MY6349 uptake in tumors was generally high but heterogeneous, varying among lesions, patients, and cancer types. Trop2 expression level determined by immunohistochemistry was highly correlated with 68Ga-MY6349 uptake at primary and metastatic tumor sites. 68Ga-MY6349 PET/CT showed higher tumor uptake (quantified by SUVmax) than 18F-FDG PET/CT in certain types of cancer, including breast (7.2 vs. 5.4, P < 0.001), prostate (9.2 vs. 3.0, P < 0.001), and thyroid cancers (8.5 vs. 3.7, P < 0.001). When compared with 68Ga-PSMA-11, 68Ga-MY6349 PET/CT exhibited comparable lesion uptake (12.2 vs. 12.5, P = 0.223) but a better tumor-to-background contrast (15.8 vs. 12.2, P < 0.001) for primary and metastatic prostate cancer, allowing visualization of more metastatic lesions. Conclusion 68Ga-MY6349 PET/CT is a non-invasive method for comprehensively assessing Trop2 expression in tumors, which can improve the diagnosis and staging for cancer patients, and aid in the decision-making for Trop2-targeted therapies and advancing personalized treatment.

Authors

Haojun Chen, Liang Zhao, Yizhen Pang, Jiyun Shi, Hannan Gao, Yining Sun, Jianhao Chen, Hao Fu, Jiayu Cai, Lingyu Yu, Ru Zeng, Long Sun, Hua Wu, Zhanxiang Wang, Fan Wang

Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer

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BACKGROUND. Despite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive ten or more years after standard treatment. METHODS. We evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared to medium-term (MTS; 5–7.99 years; n = 433) and short-term survivors (STS; 2–4.99 years; n = 416). Primary tumor samples were immunostained and scored for intra-epithelial and intra-stromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content. RESULTS. Positive associations with LTS compared to STS were seen for 9/10 immune-cell subsets. In particular, the combination of intra-epithelial CD8+ T cells and intra-stromal B cells showed near five-fold increased odds of LTS compared to STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype. CONCLUSIONS. The tumor microenvironment of HGSC long-term survivors is distinguished by the intersection of T and B cell co-infiltration, high epithelial content and C4/Differentiated molecular subtype, features which may inspire new approaches to immunotherapy. FUNDING. Ovarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; MRC; National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.

Authors

Brad H. Nelson, Phineas T. Hamilton, Minh Tung Phung, Katy Milne, Bronwyn Harris, Shelby Thornton, Donald L.I. Stevens, Shreena Kalaria, Karanvir Singh, Céline M. Laumont, Elena Moss, Aliya Alimujiang, Nicola S. Meagher, Adelyn Bolithon, Sian Fereday, Catherine J. Kennedy, Joy Hendley, Dinuka Ariyaratne, Kathryn Alsop, Nadia Traficante, Ellen L. Goode, Anthony N. Karnezis, Hui Shen, Jean Richardson, Cindy McKinnon Deurloo, Anne Chase, Bronwyn Grout, Jennifer A. Doherty, Holly R. Harris, Kara L. Cushing-Haugen, Michael S. Anglesio, Karolin Heinze, David Huntsman, Aline Talhouk, Gillian E. Hanley, Jennifer Alsop, Mercedes Jimenez-Linan, Paul D.P. Pharoah, Jessica Boros, Alison H. Brand, Paul R. Harnett, Raghwa Sharma, Jonathan L. Hecht, Naoko Sasamoto, Kathryn L. Terry, Beth Y. Karlan, Jenny Lester, Michael E. Carney, Marc T. Goodman, Brenda Y. Hernandez, Lynne R. Wilkens, Sabine Behrens, Renée Turzanski Fortner, Peter A. Fasching, Christiani Bisinotto, Francisco José Candido dos Reis, Prafull Ghatage, Martin Köbel, Esther Elishaev, Francesmary Modugno, Linda S. Cook, Nhu D. Le, Aleksandra Gentry-Maharaj, Usha Menon, María J. García, Cristina Rodriguez-Antona, Kyo M. Farrington, Linda E. Kelemen, Stefan Kommoss, Annette Staebler, Dale W. Garsed, James D. Brenton, Anna M. Piskorz, David D.L. Bowtell, Anna DeFazio, Susan J. Ramus, Malcolm C. Pike, Celeste Leigh Pearce

Attenuated kidney oxidative metabolism in young adults with type 1 diabetes

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BACKGROUND. In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism. METHODS. Young adults with T1D (n = 30) and healthy controls (HC, n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA sequencing, and spatial metabolomics to assess this relationship. RESULTS. Participants with T1D had significantly higher glomerular basement membrane thickness compared to HC. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HC, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, GBM, and lower insulin sensitivity and cortical oxidative metabolism. CONCLUSION. These early structural and metabolic changes in T1D kidneys may precede clinical DKD. TRIAL REGISTRATION. ClinicalTrials.gov NCT04074668

Authors

Ye Ji Choi, Gabriel Richard, Guanshi Zhang, Jeffrey B. Hodgin, Dawit S. Demeke, Yingbao Yang, Jennifer A. Schaub, Ian M. Tamayo, Bhupendra K. Gurung, Abhijit S. Naik, Viji Nair, Carissa Birznieks, Alexis MacDonald, Phoom Narongkiatikhun, Susan Gross, Lynette Driscoll, Maureen Flynn, Kalie Tommerdahl, Kristen J. Nadeau, Viral N. Shah, Tim Vigers, Janet K. Snell-Bergeon, Jessica Kendrick, Daniel H. van Raalte, Lu-Ping Li, Pottumarthi Prasad, Patricia Ladd, Bennett B. Chin, David Z. Cherney, Phillip J. McCown, Fadhl Alakwaa, Edgar A. Otto, Frank C. Brosius, Pierre Jean Saulnier, Victor G. Puelles, Jesse A. Goodrich, Kelly Street, Manjeri A. Venkatachalam, Aaron Ruiz, Ian H. de Boer, Robert G. Nelson, Laura Pyle, Denis P. Blondin, Kumar Sharma, Matthias Kretzler, Petter Bjornstad

Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures

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BACKGROUND Immune-related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). Prospective evaluation of the drivers of irAEs in a diverse pan-tumor cohort is needed to identify patients at greatest risk and to develop rational treatment and interception strategies.METHODS In an observational study, we prospectively collected blood samples and performed regular clinical evaluations for irAEs in patients receiving ICI therapy as standard of care for solid tumors. We performed in-parallel analysis of cytokines by Luminex immunoassay and circulating immune cells by cytometry by time-of-flight (CyTOF) at baseline and on treatment to investigate mechanisms of irAEs.RESULTS We enrolled 111 patients, of whom 40.5% developed a symptomatic irAE (grade ≥ 2). Development of a grade ≥ 2 irAE was positively associated with the use of combination ICI and a history of an autoimmune disorder. Early changes in T helper 17 (Th17) (IL-6, IL-17f), type 2 (IL-5, IL-13, IL-25), and type 1 (TNF-α) cytokine signatures and congruent on-treatment expansions of Th17 and Th2 effector memory (Th2EM) T cell populations in peripheral blood were positively associated with the development of grade ≥2 irAEs. IL-6 levels were also associated with inferior cancer-specific survival and overall survival.CONCLUSIONS In a diverse, prospective pan-tumor cohort, Th17 and Th2 skewing during early ICI treatment was associated with the development of clinically relevant irAEs but not antitumor responses, providing possible targets for monitoring and therapeutic interventions.FUNDING Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, the NCI SPORE in Gastrointestinal Cancers (P50 CA062924), NCI grant (R50CA243627 to LD), the NIH Center Core Grant (P30 CA006973), Swim Across America (to MY), NIAMS (K23AR075872 to LC), and imCORE-Genentech grant 137515 (to Johns Hopkins Medicine on behalf of MY).

Authors

Chester J. Kao, Soren Charmsaz, Stephanie L. Alden, Madelena Brancati, Howard L. Li, Aanika Balaji, Kabeer Munjal, Kathryn Howe, Sarah Mitchell, James Leatherman, Ervin Griffin, Mari Nakazawa, Hua-Ling Tsai, Ludmila Danilova, Chris Thoburn, Jennifer Gizzi, Nicole E. Gross, Alexei Hernandez, Erin M. Coyne, Sarah M. Shin, Jayalaxmi Suresh Babu, George W. Apostol, Jennifer Durham, Brian J. Christmas, Maximilian F. Konig, Evan J. Lipson, Jarushka Naidoo, Laura C. Cappelli, Aliyah Pabani, Yasser Ged, Marina Baretti, Julie Brahmer, Jean Hoffman-Censits, Tanguy Y. Seiwert, Rachel Garonce-Hediger, Aditi Guha, Sanjay Bansal, Laura Tang, Elizabeth M. Jaffee, G. Scott Chandler, Rajat Mohindra, Won Jin Ho, Mark Yarchoan

Genomic and transcriptomic features of androgen receptor signaling inhibitor resistance in metastatic castration-resistant prostate cancer

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BACKGROUND Androgen receptor signaling inhibitors (ARSIs) have improved outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), but their clinical benefit is limited by treatment resistance.METHODS To investigate the mechanisms of ARSI resistance, we analyzed the whole-genome (n = 45) and transcriptome (n = 31) sequencing data generated from paired metastatic biopsies obtained before initiation of first-line ARSI therapy for mCRPC and after radiographic disease progression. We investigated the effects of genetic and pharmacologic modulation of SSTR1 in 22Rv1 cells, a representative mCRPC cell line.RESULTS We confirmed the predominant role of tumor genetic alterations converging on augmenting androgen receptor (AR) signaling and the increased transcriptional heterogeneity and lineage plasticity during the emergence of ARSI resistance. We further identified amplifications involving a putative enhancer downstream of the AR and transcriptional downregulation of SSTR1, encoding somatostatin receptor 1, in ARSI-resistant tumors. We found that patients with SSTR1-low mCRPC tumors derived less benefit from subsequent ARSI therapy in a retrospective cohort. We showed that SSTR1 was antiproliferative in 22Rv1 cells and that the FDA-approved drug pasireotide suppressed 22Rv1 cell proliferation.CONCLUSION Our findings expand the knowledge of ARSI resistance and point out actionable next steps, exemplified by potentially targeting SSTR1, to improve patient outcomes.FUNDING National Cancer Institute (NCI), NIH; Prostate Cancer Foundation; Conquer Cancer, American Society of Clinical Oncology Foundation; UCSF Benioff Initiative for Prostate Cancer Research; Netherlands Cancer Institute.

Authors

Xiaolin Zhu, Tatyanah Farsh, Daniël Vis, Ivan Yu, Haolong Li, Tianyi Liu, Martin Sjöström, Raunak Shrestha, Jeroen Kneppers, Tesa Severson, Meng Zhang, Arian Lundberg, Thaidy Moreno Rodriguez, Alana S. Weinstein, Adam Foye, Niven Mehra, Rahul R. Aggarwal, Andries M. Bergman, Eric J. Small, Nathan A. Lack, Wilbert Zwart, David A. Quigley, Michiel S. van der Heijden, Felix Y. Feng

Proteogenomic analysis integrated with electronic health records data reveals disease-associated variants in Black Americans

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BACKGROUND. Most genome wide association studies (GWAS) of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry enriched protein quantitative loci (pQTL). METHODS. We conducted a discovery GWAS of ~3,000 plasma proteins measured by the antibody based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS), and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs were further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome wide association study (PheWAS) across two large multi-ethnic electronic health record (EHR) systems in All of Us and BioMe. RESULTS. We identified 1002 pQTLs for 925 proteins. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for Cathepsin L (CTSL) and Siglec-9 that were linked with sarcoidosis and non-Hodgkin’s lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, white blood cell count, and multiple sclerosis. CONCLUSIONS. Our findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.

Authors

Usman A. Tahir, Jacob L. Barber, Daniel E. Cruz, Meltem Ece Kars, Shuliang Deng, Bjoernar Tuftin, Madeline G. Gillman, Mark D. Benson, Jeremy M. Robbins, Zsu-Zsu Chen, Prashant Rao, Daniel H. Katz, Laurie Farrell, Tamar Sofer, Michael E. Hall, Lynette Ekunwe, Russell P. Tracy, Peter Durda, Kent D. Taylor, Yongmei Liu, W. Craig Johnson, Xiuqing Guo, Yii-Der Ida Chen, Ani W. Manichaikul, Deepti Jain, Thomas J. Wang, Alex P. Reiner, Pradeep Natarajan, Yuval Itan, Stephen S. Rich, Jerome I. Rotter, James G. Wilson, Laura M. Raffield, Robert E. Gerszten

Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance

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BACKGROUND Metastatic hormone-sensitive prostate cancer (mHSPC) is androgen dependent, and its treatment includes androgen deprivation therapy (ADT) with gonadal testosterone suppression. Since 2014, overall survival (OS) has been prolonged with addition of other systemic therapies, such as adrenal androgen synthesis blockers, potent androgen receptor blockers, or docetaxel, to ADT. HSD3B1 encodes the rate-limiting enzyme for nongonadal androgen synthesis, 3β-hydroxysteroid dehydrogenase-1, and has a common adrenal-permissive missense-encoding variant that confers increased synthesis of potent androgens from nongonadal precursor steroids and poorer prostate cancer outcomes.METHODS Our prespecified hypothesis was that poor outcome associated with inheritance of the adrenal-permissive HSD3B1 allele with ADT alone is reversed in patients with low-volume (LV) mHSPC with up-front ADT plus addition of androgen receptor (AR) antagonists to inhibit the effect of adrenal androgens. HSD3B1 genotype was obtained in 287 patients with LV disease treated with ADT + AR antagonist only in the phase III Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) trial and was associated with clinical outcomes.RESULTS Patients who inherited the adrenal-permissive HSD3B1 allele had more favorable 5-year clinical progression-free survival and OS when treated with ADT plus enzalutamide or ADT plus nonsteroidal antiandrogen compared with their counterparts who did not have adrenal-permissive HSD3B1 inheritance. HSD3B1 was also associated with OS after accounting for known clinical variables. Patients with both genotypes benefited from early enzalutamide.CONCLUSION These data demonstrated an inherited physiologic driver of prostate cancer mortality is associated with clinical outcomes and is potentially pharmacologically reversible.FUNDING National Cancer Institute, NIH; Department of Defense; Prostate Cancer Foundation, Australian National Health and Medical Research Council.

Authors

Nima Sharifi, Robert Diaz, Hui-Ming Lin, Evan Roberts, Lisa G. Horvath, Andrew Martin, Martin R. Stockler, Sonia Yip, Vinod V. Subhash, Neil Portman, Ian D. Davis, Christopher J. Sweeney

Natural TCRs targeting KRAS^G12V display fine specificity and sensitivity to human solid tumors

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BACKGROUND. Neoantigens derived from KRASMUT have been described, but the fine antigen specificity of T cell responses directed against these epitopes are poorly understood. Here, we explore KRASMUT immunogenicity and the properties of 4 TCRs specific for KRASG12V restricted to HLA-A3 superfamily of class I alleles. METHODS. A phase I clinical vaccine trial targeting KRASMUT was conducted. TCRs targeting KRASG12V restricted to HLA-A*03:01 or HLA-A*11:01 were isolated from vaccinated patients or healthy individuals. A comprehensive analysis of TCR antigen specificity, affinity, cross-reactivity, and CD8 coreceptor dependence was performed. TCR lytic activity was evaluated, and target antigen density was determined by quantitative immunopeptidomics. RESULTS. Vaccination against KRASMUT resulted in the priming of CD8+ and CD4+ T cell responses. KRASG12V -specific natural (not affinity-enhanced) TCRs exhibited exquisite specificity to mutated protein with no discernable reactivity against KRASWT. TCR-recognition motifs were determined and used to identify and exclude cross-reactivity to non-cognate peptides derived from the human proteome. Both HLA-A*03:01 and HLA-A*11:01 restricted TCR-redirected CD8+ T cells exhibited potent lytic activity against KRASG12V cancers, while only HLA-A*11:01 restricted TCR-T CD4+ T cells exhibited anti-tumor effector functions consistent with partial co-receptor dependence. All KRASG12V-specific TCRs displayed high sensitivity for antigen as demonstrated by their ability to eliminate tumor cell lines expressing low levels of of peptide/HLA (4.4 to 242) complexes per cell. CONCLUSION. This study identifies KRASG12V-specific TCRs with high therapeutic potential for the development of TCR-T cell therapies. TRIAL REGISTRATION. ClinicalTrials.gov NCT03592888. FUNDING. AACR SU2C / Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, and NIH (R01 CA204261, P01 CA217805, P30 CA016520).

Authors

Adham S. Bear, Rebecca B. Nadler, Mark H. O'Hara, Kelsey L. Stanton, Chong Xu, Robert J. Saporito, Andrew J. Rech, Miren L. Baroja, Tatiana Blanchard, Maxwell H. Elliott, Michael J. Ford, Richard C. Jones, Shivang Patel, Andrea L. Brennan, Zachary O'Neil, Daniel J. Powell Jr., Robert H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno

Prebiotics improve frailty status in community-dwelling older individuals in a double-blind, randomized, controlled trial

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BACKGROUND Frailty significantly affects morbidity and mortality rates in the older population (age >65 years). Age-related degenerative diseases are influenced by the intestinal microbiota. However, limited research exists on alterations in the intestinal microbiota in frail older individuals, and the effectiveness of prebiotic intervention for treating frailty remains uncertain.OBJECTIVE We sought to examine the biological characteristics of the intestinal microbiome in frail older individuals and assess changes in both frailty status and gut microbiota following intervention with a prebiotic blend consisting of inulin and oligofructose.METHODS The study consisted of 3 components: an observational analysis with a sample size of 1,693, a cross-sectional analysis (n = 300), and a multicenter double-blind, randomized, placebo-controlled trial (n = 200). Body composition, commonly used scales, biochemical markers, intestinal microbiota, and metabolites were examined in 3 groups of older individuals (nonfrail, prefrail, and frail). Subsequently, changes in these indicators were reevaluated after a 3-month intervention using the prebiotic mixture for the prefrail and frail groups.RESULTS The intervention utilizing a combination of prebiotics significantly improved frailty and renal function among the older population, leading to notable increases in protein levels, body fat percentage, walking speed, and grip strength. Additionally, it stimulated an elevation in gut probiotic count and induced alterations in microbial metabolite expression levels as well as corresponding metabolic pathways.CONCLUSIONS The findings suggest a potential link between changes in the gut microbiota and frailty in older adults. Prebiotics have the potential to modify the gut microbiota and metabolome, resulting in improved frailty status and prevention of its occurrence.TRIAL REGISTRATION ClinicalTrials.gov NCT03995342.

Authors

Jie Yang, Liming Hou, Anhui Wang, Lei Shang, Xin Jia, Rong Xu, Xiaoming Wang

Postprandial metabolomics analysis reveals disordered serotonin metabolism in post-bariatric hypoglycemia

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BACKGROUND. Bariatric surgery is a potent therapeutic approach for obesity and type 2 diabetes but can be complicated by post-bariatric hypoglycemia (PBH). PBH typically occurs 1 to 3 hours after meals, in association with exaggerated postprandial levels of incretins and insulin. METHODS. To identify mediators of disordered metabolism in PBH, we analyzed plasma metabolome in fasting state and 30 and 120 minutes after mixed meal in 3 groups: PBH (n = 13), asymptomatic post-RYGB (n = 10), and non-surgical controls (n = 8). RESULTS. In the fasting state, multiple tricarboxylic acid cycle intermediates and the ketone beta-hydroxybutyrate were increased by 30% to 80% in PBH vs. asymptomatic. Conversely, multiple amino acids (BCAA, tryptophan) and polyunsaturated lipids were reduced by 20% to 50% in PBH versus asymptomatic. Tryptophan-related metabolites, including kynurenate, xanthurenate, and serotonin, were reduced by 2- to 10-fold in PBH in fasting state. Postprandially, plasma serotonin was uniquely increased by 1.9-fold in PBH versus asymptomatic post-RYGB. In mice, serotonin administration lowered glucose and increased plasma insulin and GLP-1. Moreover, serotonin-induced hypoglycemia in mice was blocked by the nonspecific serotonin receptor antagonist cyproheptadine and the specific serotonin receptor 2 antagonist ketanserin. CONCLUSION. Together these data suggest that increased postprandial serotonin may contribute to the pathophysiology of PBH and provide a potential therapeutic target. FUNDING. NIH grant R01 DK121995, NIH grant P30 DK036836 (Diabetes Research Center grant, Joslin Diabetes Center), and Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP grant 2018/22111-2.

Authors

Rafael Ferraz-Bannitz, Berkcan Ozturk, Cameron J. Cummings, Vissarion Efthymiou, Pilar Casanova Querol, Lindsay Poulos, Hanna J. Wang, Valerie Navarrete, Hamayle Saeed, Christopher M. Mulla, Hui Pan, Jonathan M. Dreyfuss, Donald C. Simonson, Darleen A. Sandoval, Mary-Elizabeth Patti