Clinical Research and Public Health
Abstract
Background Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS. Methods Paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNAseq) on kidney biopsies from five youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics, were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n=64). Results Post-VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNAseq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and Forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. JAK-STAT pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data. Conclusion MBS/VSG prompts kidney molecular adaptations, providing potential targets for non-surgical interventions against obesity- and diabetes-associated kidney disease.
Authors
Abhijit S. Naik, Fadhl M. Alakwaa, Viji Nair, Phillip J. McCown, Jennifer A. Schaub, Edgar A. Otto, Rajasree Menon, Francesca Annese, Ye Ji Choi, Hailey E. Hampson, Thomas H. Inge, John Hartman, Sean Eddy, Cathy Smith, Jeffrey B. Hodgin, Ken Inoki, Swayam Prakash Srivastava, Kareem Al-Fagih, Shota Yoshida, Jesse A. Goodrich, Melanie G. Cree, Phoom Narongkiatikhun, Long Yuan, Kalie L. Tommerdahl, Pottumarthi Prasad, Daniël H. van Raalte, Megan M. Kelsey, Justin R. Ryder, Tyler J. Dobbs, Patricia Ladd, Subramaniam Pennathur, Robert G. Nelson, Yusuke Okabayashi, Victor G. Puelles, Jenna Ferrence-Salo, Jeffrey A. Beamish, Frank C. Brosius, Kristen J. Nadeau, Laura Pyle, Matthias Kretzler, Petter Bjornstad
Abstract
BACKGROUND. MASLD has a substantial inherited component. Rare variants in Apolipoprotein B gene (APOB) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear. METHODS. We investigated APOB rare variants in a case-control cohort of people with advanced MASLD vs. healthy controls (n = 510/261), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program cohort (MVP, n = 94,885) and the UK Biobank (UKBB, n = 417,657). RESULTS. In the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% c.i. 2.7-70.7, P = 0.002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (P < 0.05). In the family study, APOB variants segregated with hepatic steatosis and fibrosis (P < 0.05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma of 1.82, 95% c.i. 1.33-2.49 and 3.53, 95% c.i. 2.09-5.98, respectively. Variants affecting specifically ApoB100 had a three-fold greater impact on hepatic lipid metabolism compared to those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). Variants affected cirrhosis risk similarly, but ApoB48/100 had a larger impact on hepatocellular carcinoma (P < 0.05). CONCLUSIONS. Rare APOB variants predispose to advanced MASLD and HCC, with distinct contributions from disrupted VLDL and chylomicrons secretion. These findings highlight the interplay between hepatic and intestinal lipid handling, suggesting that APOB genotyping may enhance MASLD risk stratification and case identification. FUNDING. European Union, Italian Ministry of Health, Swedish Research Council, Veteran health administration, NIH.
Authors
Matteo Mureddu, Serena Pelusi, Oveis Jamialahmadi, Marijana Vujkovic, Lorenzo Miano, Hadi Eidgah Torghabehei, Luisa Ronzoni, Francesco Malvestiti, Marco Saracino, Giulia Periti, Vittoria Moretti, Craig C. Teerlink, Julie A. Lynch, Philip S. Tsao, Josephine P. Johnson, Vincenzo La Mura, Robertino Dilena, Saleh A. Alqahtani, Alessandro Cherubini, Francesco Paolo Russo, Roberta D'Ambrosio, Mirella Fraquelli, Salvatore Petta, Luca Miele, Umberto Vespasiani-Gentilucci, Elisabetta Bugianesi, Rosellina M. Mancina, Paolo Parini, Daniele Prati, Kyong-Mi Chang, Carolin V. Schneider, Stefano Romeo, Luca V.C. Valenti
Abstract
Cervical cancer (CC) remains the fourth leading cause of cancer-related deaths in women globally, with poor prognosis for metastatic and recurrent cases. Although genomic alterations have been extensively characterized, global proteogenomic landscape of the disease is largely under-explored. Here, we present the first genome-wide proteogenomic characterization of CC, analyzing 139 tumor-normal tissue pairs using whole-genome sequencing, transcriptomics, proteomics, and phosphoproteomics. We identified four distinct molecular subtypes with unique clinical outcomes: epithelial-mesenchymal transition (EMT, C1), proliferation (C2), immune response (C3), and epithelial differentiation (C4). A four-protein classifier (CDH13, TP53BP1, NNMT, HSPB1) was developed with strong prognostic and predictive value, particularly for immunotherapy response in subtype C3. Phosphoproteomic profiling uncovered subtype-specific kinase activity, identifying actionable therapeutic targets. Our findings further revealed previously uncharacterized somatic copy number alterations, extrachromosomal DNA landscape, and human-HPV fusion peptides, with implications for genetic heterogeneity and therapeutic targets. This study enhances the understanding of cervical cancer through deeper proteogenomic insights, and facilitates the development of personalized therapeutic strategies to improve patient outcomes.
Authors
Xun Tian, Mansheng Li, Zhi Wang, Tian Fang, Yi Liu, Jin Fang, Lejing Wang, Zhichao Jiang, Xingyu Zhao, Chen Cao, Zhiqiang Yu, Meiying Yang, Songfeng Wu, Yifan Wu, Rui Tian, Hui Wang, Yunping Zhu, Zheng Hu
Abstract
BACKGROUND. Infection by Trypanosoma cruzi, the agent of Chagas disease, is endemic to the Americas and can irreparably damage the cardiac and gastrointestinal systems during decades of parasite persistence. Diagnosis of chronic infection requires confirmation by multiple serological assays due to the imperfect performance of existing tests. Current serology tests were developed using small specimen sets predominantly from South America, and lower performance has been observed in patients who acquired infection in Central America and Mexico. METHODS. To improve Chagas disease serology, we evaluated antibody responses against the entire T. cruzi proteome with phage display immunoprecipitation sequencing and further evaluated high prevalence antigens by immunoassay. We utilized specimen sets representing Mexico, Central America and South America and varying cardiac disease presentations, from 185 cases and 143 controls. RESULTS. We identified over 1,300 antigenic T. cruzi peptides. A trans-sialidase antigen demonstrated high seroprevalence across all regions and has not previously been described as a diagnostic target. Orthogonal validation of this peptide demonstrated increased antibody reactivity for infections originating from Central America. CONCLUSION. This study provides proteome-wide identification of seroreactive T. cruzi peptides across a range of endemic populations not previously represented in antigen discovery and identifies a trans-sialidase peptide antigen (TS23) with potential for translation into diagnostic serological assays. TRIAL REGISTRATION. Not Applicable.
Authors
Hannah M. Kortbawi, Ryan J. Marczak, Jayant V. Rajan, Nash L. Bulaong, John E. Pak, Wesley Wu, Grace Wang, Anthea Mitchell, Aditi Saxena, Aditi Maheshwari, Rachel Alfaro Leone, Charles J. Fleischmann, Emily A. Kelly, Evan Teal, Rebecca L. Townsend, Susan L. Stramer, Emi E. Okamoto, Jacqueline E. Sherbuk, Eva H. Clark, Robert H. Gilman, Rony Pedro Colanzi, Efstathios D. Gennatas, Caryn Bern, Joseph L. DeRisi, Jeffrey D. Whitman
Abstract
BACKGROUND. Plasma heparan sulfate, a glycosaminoglycan released during endothelial glycocalyx degradation, predicts sepsis mortality. Chondroitin sulfate is a circulating glycosaminoglycan not specific to glycocalyx degradation; its relevance to sepsis is unknown. METHODS. We studied the associations of plasma chondroitin sulfate with (a) mortality in patients with sepsis-associated hypotension and (b) the relative effectiveness of a randomly-assigned liberal versus restrictive intravenous fluid resuscitation strategy. We selected 574 patients enrolled in the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis trial using an outcome-enriched sampling strategy. We used liquid chromatography-mass spectrometry to quantify plasma chondroitin sulfate. In comparison, we measured hyaluronic acid as a glycocalyx degradation marker and IL-6 as an inflammatory biomarker. We conducted Cox proportional hazards regression analyses to examine associations of baseline biomarker concentrations with mortality and resuscitation strategy effectiveness. We used inverse probability of selection weights and generalized raking to account for the non-representative sampling design. RESULTS. Plasma chondroitin sulfate, hyaluronic acid, and IL-6 were associated with mortality within 90 days. As baseline chondroitin sulfate increased, subsequent randomization to a restrictive strategy was increasingly beneficial (p = 0.022): treatment effect hazard ratio (restrictive versus liberal) for mortality was estimated as 1.49 (95% CI 0.98–2.27), 1.30 (1.00–1.69), 1.09 (0.82–1.44), 0.88 (0.66–1.16), and 0.71 (0.52–0.97) for 10th, 25th, 50th, 75th and 90th percentiles of baseline chondroitin sulfate. CONCLUSIONS. Plasma chondroitin sulfate predicts sepsis mortality and may modify the response to a subsequent liberal vs. restrictive intravenous fluid resuscitation strategy. TRIAL. ClinicalTrials.gov NCT03434028.
Authors
Kaori Oshima, Bailu Yan, Ran Tao, Gustavo Amorim, Chiara Di Gravio, Sarah A. McMurtry, Ryan C. Burke, Yunbi Nam, Ina Nikolli, Max S. Kravitz, Daniel Stephenson, Aaron Issaian, Kirk C. Hansen, Angelo D'Alessandro, Ivor S. Douglas, Wesley H. Self, Christopher J. Lindsell, Carolyn Leroux, Angelika Ringor, Michael A. Matthay, Jonathan S. Schildcrout, Nathan I. Shapiro, Eric P. Schmidt
Abstract
BACKGROUND. Chronic alcohol use leads to synaptic dysfunction in preclinical studies. However, whether in vivo synaptic density deficits are found in people with alcohol use disorder (AUD) remains unclear. METHODS. Thirty-two people with AUD (17 women) and 29 controls (17 women) completed one positron emission tomography (PET) brain imaging scan with the radiotracer [11C]UCB-J, which binds to SV2A, a marker of synaptic density. Levels of synaptic density were quantified by estimating binding potential (BPND) across four regions of interest: frontal cortex, striatum, hippocampus, and cerebellum. RESULTS. People with AUD were on average(±SD) 43±13 years old and most met criteria for mild or moderate AUD. Controls were 37±12 years old. People with AUD had on average 11% lower [11C]UCB-J BPND than controls in the frontal cortex (F(1,62)=13.074, p<0.001), striatum (F(1,60)=10.283, p=0.002), hippocampus (F(1,60)=5.964, p=0.018), and trending in the same direction in cerebellum (F(1,50)=3.438, p=0.070). Among people with AUD, lower [11C]UCB-J BPND was significantly related to more drinks per drinking day in the frontal cortex (p=0.022) and striatum (p=0.026). People with AUD performed worse on executive function than controls (p=0.020), but this was not related to [11C]UCB-J BPND. CONCLUSION. Synaptic density deficits are evident, even in people with mild-to-moderate AUD, with greater deficits in those with greater drinking severity. These findings underscore the potential of synaptic restoration as a therapeutic target for AUD. TRIAL REGISTRATION. N/A. FUNDING. This work was supported by the National Institute of Health.
Authors
Yasmin Zakiniaeiz, Nakul R. Raval, Will Riordan, Nabeel Nabulsi, Yiyun Huang, Brian Pittman, David Matuskey, Gustavo A. Angarita, Robin Bonomi, Sherry A. McKee, Ansel T. Hillmer, Kelly P. Cosgrove
Abstract
BACKGROUND. Infection is an important complication of implanted devices and prosthetics. Identifying infections sufficiently early to salvage implants and avoid reconstructive failure is a persistent medical challenge. METHODS. Two female cohorts >21 years undergoing breast implant reconstruction were recruited. Seroma fluid (82 breasts, 70 patients) was collected upon implant removal for infectious or non-infectious causes. Post-implantation drain fluid (100 samples, 44 breasts, 32 patients) was collected at routine visits prior to implant removal. A liquid-chromatography/mass spectrometry-based metabolomic approach was used to identify infection correlates. RESULTS. In seroma fluid specimens, infection was associated with a diverse set of small molecules including acetylated polyamines, defensins, glucosyl-sphingosine, and several peptide-like features (all P<0.001, diagnostic areas under the receiver operating curve 0.82-0.93). Notably, a subset of these markers were significantly elevated (p<0.05) in post-implantation drain fluid before recorded infection symptoms and diagnosis. Pseudomonas aeruginosa and its specialized exometabolites in drain specimens were also associated with subsequent P. aeruginosa infections. CONCLUSION. Tissue fluid from infected patients has a distinctive metabolome reflecting human and bacterial physiologic processes that often precede clinical diagnoses. A diagnostic based on these findings has potential to improve patient outcomes through early recognition of infection. TRIAL REGISTRATION. Not applicable. FUNDING. Work was supported by U54CK000609 from the CDC and an unencumbered research gift to TMM from Sientra. Metabolomic approaches were supported by RO1DK125860 and RO1DK111930 to JPH. The contents are solely the responsibility of the authors and do not necessarily represent the official views of CDC.
Authors
John A. Wildenthal, Margaret A. Olsen, Hung D. Tran, John I. Robinson, Terence M. Myckatyn, David K. Warren, Keith E. Brandt, Marissa M. Tenenbaum, Joani M Christensen, Thomas H. Tung, Justin M. Sacks, Rachel A. Anolik, Katelin B. Nickel, Hideji Fujiwara, Peter J. Mucha, Jeffrey P. Henderson
Abstract
BACKGROUND. Amino acid (AA) concentrations are increased in prediabetes and diabetes. Since AA stimulate glucagon secretion which should then increase hepatic AA catabolism, it has been hypothesized that hepatic resistance (associated with hepatic fat content) to glucagon’s actions on AA metabolism leads to hyperglucagonemia and hyperglycemia. METHODS. To test this hypothesis, we therefore studied lean and obese individuals, the latter group with and without hepatic steatosis as defined by Proton Density Fat Fraction (PDFF) > 5%. After an overnight fast, femoral vein, femoral artery, and hepatic vein catheters were placed. [3-3H] glucose and L-[1-13C,15N]-leucine were used to measure glucose turnover and leucine oxidation respectively. During a hyperglycemic clamp, an amino acid mixture was infused together with insulin and glucagon (1.5 ng/kg/min 0 – 120 min; 3.0 ng/kg/min 120 – 240 min). Tracer-based measurement of hepatic leucine oxidation in response to rising glucagon concentrations and splanchnic balance (measured using arterio-venous differences across the liver), of the other AA were the main outcomes measured. RESULTS. The presence of hepatic steatosis did not alter hepatic glucose metabolism and leucine oxidation in response to insulin and rising concentrations of glucagon. Splanchnic balance of a few amino acids, and related metabolites differed amongst the groups. However, across-group differences of AA splanchnic balance in response to glucagon were unaffected by the presence of hepatic steatosis. CONCLUSION. The action of glucagon on hepatic amino acid metabolism is unaffected by hepatic steatosis in humans. TRIAL REGISTRATION. This study was registered at Clinical Trials.Gov: NCT05500586. FUNDING. This work was funding by the NIH.
Authors
Hannah E. Christie, Sneha Mohan, Aoife M. Egan, Federica Boscolo, Chiara Dalla Man, Scott M. Thompson, Michael Jundt, Chad J. Fleming, James C. Andrews, Kent R. Bailey, Michael D. Jensen, K. Sree Nair, Adrian Vella
Abstract
BACKGROUND. Among antiretroviral therapy (ART)-suppressed people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the broader effect of sex on the inflammatory proteome, and whether these differences are modified by age, remains unclear. METHODS. 363 plasma inflammatory protein levels (Olink Inflammation Explore) were assessed in ART-suppressed PWH sampled from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). The relationship between sex and 363 plasma proteins – including 22 in the interferon-α response pathway – was assessed with linear regression models adjusting for confounders, assessing interactions by age. FINDINGS. Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age impacted the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 (P = 0.024), but higher in women in those > 47 (P = 0.005, p-interaction < 0.001). Among the 131 proteins associated with mortality risk (q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women . Women had decreased mortality than men ≤47 (P < 0.001) but had similar mortality > 47 (P = 0.84). INTERPRETATION. The menopausal transition appears to have a dramatic effect on systemic Type I interferon responses and the broader inflammatory proteome in women with HIV. Among older PWH, women have greater inflammation than men, including the majority of proteins linked with mortality risk.
Authors
Rebecca A. Abelman, Samuel R. Schnittman, Natalia Faraj Murad, Adam Olshen, Gabriele B. Beck-Engeser, Noah Aquino, Gabrielle C. Ambayec, Edward R. Cachay, Joseph J. Eron, Michael Saag, Robin M. Nance, Joseph A. Delaney, Stephanie A. Ruderman, Richard D. Moore, Kenneth H. Mayer, Jeffrey M. Jacobson, Heidi M. Crane, Peter W. Hunt
Abstract
BACKGROUND. Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a pilot study. METHODS. We performed integrative multi-omics analysis of blood samples from 160 ARDS patients in the ROSE trial, randomly selecting 80 patients from each latent class analysis-defined inflammatory phenotype (Hyperinflammatory and Hypoinflammatory) with phenotype probability >0.9. Untargeted plasma metabolomics and whole blood transcriptomics at Day 0 and Day 2 were analyzed using multi-modal factor analysis (MEFISTO). The primary outcome was 90-day mortality, with validation in an independent critically ill sepsis cohort (EARLI). RESULTS. Multi-omics integration revealed four molecular signatures associated with mortality: (1) enhanced innate immune activation coupled with increased glycolysis (associated with Hyperinflammatory phenotype), (2) hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation (associated with Hyperinflammatory phenotype), (3) interferon program suppression coupled with altered mitochondrial respiration (associated with Hyperinflammatory phenotype), and (4) redox impairment and cell proliferation pathways (not associated with inflammatory phenotype). These signatures persisted through Day 2 of trial enrollment. Within-phenotype analysis revealed distinct mortality-associated pathways in each group. All molecular signatures were validated in the independent EARLI cohort. CONCLUSIONS. Inflammatory phenotypes of ARDS reflect distinct underlying biological processes with both phenotype-specific and phenotype-independent pathways influencing patient outcomes, all characterized by mitochondrial dysfunction. These findings suggest potential therapeutic targets for precise treatment strategies in critical illness. FUNDING. This work is the result of NIH funding.
Authors
Narges Alipanah-Lechner, Lucile Neyton, Pratik Sinha, Carolyn Leroux, Kim Bardillon, Sidney A. Carrillo, Suzanna Chak, Olivia Chao, Taarini Hariharan, Carolyn Hendrickson, Kirsten Kangelaris, Charles R. Langelier, Deanna Lee, Chelsea Lin, Kathleen Liu, Liam Magee, Angelika Ringor, Aartik Sarma, Emma Schmiege, Natasha Spottiswoode, Kathryn Sullivan, Melanie F. Weingart, Andrew Willmore, Hanjing Zhuo, Angela J. Rogers, Kathleen A. Stringer, Michael A. Matthay, Carolyn S. Calfee
No posts were found with this tag.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)