BACKGROUND. Whether airspace biomarkers add value to plasma biomarkers in studying ARDS is not well understood. Mesenchymal stromal cells (MSCs) are an investigational therapy for ARDS, and airspace biomarkers may provide mechanistic evidence for MSCs' impact in patients with ARDS. METHODS. We carried out a nested cohort study within a phase 2a safety trial of treatment with allogeneic MSCs for moderate to severe ARDS. Non-bronchoscopic bronchoalveolar lavage and plasma samples were collected 48 hours after study drug infusion. Airspace and plasma biomarker concentrations were compared between the MSC (n = 17) and placebo (n = 10) treatment arms, and correlation between the two compartments was tested. Airspace biomarkers were also tested for associations with clinical and radiographic outcomes. RESULTS. Compared to placebo, MSC treatment significantly reduced airspace total protein, angiopoietin-2 (Ang-2), interleukin-6 (IL-6), and soluble tumor necrosis factor receptor-1 concentrations. Plasma biomarkers did not differ between groups. Each 10-fold increase in airspace Ang-2 was independently associated with 6.7 fewer days alive and free of mechanical ventilation (95% CI -12.3 to -1.0, p = 0.023), and each 10-fold increase in airspace receptor for advanced glycation end-products (RAGE) was independently associated with a 6.6 point increase in day 3 radiographic assessment of lung edema score (95% CI 2.4 to 10.7, p = 0.004). CONCLUSIONS. MSCs reduced biological evidence of lung injury in patients with ARDS. Biomarkers from the airspaces provide additional value for studying pathogenesis, treatment effects, and outcomes in ARDS. TRIAL REGISTRATION. NCT02097641 FUNDING. National Heart, Lung, and Blood Institute
Katherine D. Wick, Aleksandra Leligdowicz, Hanjing Zhuo, Lorraine B. Ware, Michael A. Matthay
BACKGROUND. Assessment of risk for chronic kidney disease (CKD) after acute kidney injury (AKI) is based on a limited set of markers primarily reflecting glomerular function. We evaluated markers of cell integrity (EGF) and inflammation (monocyte chemoattractant protein-1 [MCP-1]) for predicting long-term kidney outcomes after cardiac surgery. METHODS. We measured the urinary biomarkers EGF and MCP-1 in pre- and post-operative urine samples from 865 adult patients who underwent cardiac surgery from 2007–2010 at 2 sites in Canada and the United States and assessed their associations with the composite outcome of CKD incidence or progression. We also used single-cell (Sc) RNAseq of biopsies from patients with AKI to perform a transcriptomic analysis of programs that are coregulated with the genes encoding the 2 biomarkers. RESULTS. Over a median (IQR) follow-up of 5.8 (4.2-7.1) years, 266 (30.8%) patients developed the composite CKD outcome. Post-operatively, higher levels of urinary EGF were protective and higher levels of MCP-1 were associated with the composite CKD outcome (adjusted HR 0.83, 95% CI 0.73-0.95 and 1.10, 95% CI 1.00-1.21, respectively). Intrarenal scRNAseq transcriptomes in patients with AKI-defined cell populations revealed concordant changes in EGF and MCP-1 levels and identified underlying molecular processes associated with loss of EGF expression and gain of CCL2 (encoding MCP-1) expression. CONCLUSION. Urinary EGF and MCP-1 were each independently associated with CKD incidence or progression after cardiac surgery. These markers may serve as noninvasive indicators of tubular damage, supported by tissue transcriptomes and provide opportunity for novel interventions in cardiac surgery. TRIAL REGISTRATION. ClinicalTrials.gov NCT00774137 FUNDING. NIH (R01HL085757 to CRP) funded the TRIBE-AKI Consortium.
Steven Menez, Wenjun Ju, Rajasree Menon, Dennis G. Moledina, Heather Thiessen Philbrook, Eric McArthur, Yaqi Jia, Wassim Obeid, Sherry G. Mansour, Jay K. Koyner, Michael G. Shlipak, Steven G. Coca, Amit X. Garg, John A. Kellum, Andrew S Bomback, Matthias Kretzler, Chirag R. Parikh
Adipocytes were long considered to be inert components of the bone marrow niche, but both mouse and human models suggest that bone marrow adipose tissue (BMAT) is dynamic and responsive to hormonal and nutrient cues. In this study of healthy volunteers, we investigated how BMAT responds to acute nutrient changes, including analyses of endocrine determinants and paracrine factors from marrow aspirates. Study participants underwent a 10-day high-calorie protocol followed by a 10-day fast. We demonstrate three novel findings: 1) vertebral BMAT increased significantly during both high-calorie feeding and fasting, suggesting that BMAT may have different functions in states of caloric excess compared to caloric deprivation; 2) Ghrelin, which decreased in response to both high-calorie feeding and fasting, was inversely associated with changes in BMAT; 3) In response to high-calorie feeding, resistin levels in the marrow sera, but not the circulation, rose significantly. In addition, TNF-a expression in marrow adipocytes increased with high-calorie feeding and decreased upon fasting. Therefore, high-calorie feeding, but not fasting, induces an immune response in the bone marrow similar to what has been reported in peripheral adipose tissue. Understanding the immunomodulatory regulators in the marrow may provide further insight into the homeostatic function of this unique adipose tissue depot.
Pouneh K. Fazeli, Miriam A. Bredella, Olga Gisela Pachon-Peña, Wenxiu Zhao, Xun Zhang, Alexander T. Faje, Megi Resulaj, Sai P. Polineni, Tara M. Holmes, Hang Lee, Elizabeth K. O’Donnell, Ormond A. MacDougald, Mark C. Horowitz, Clifford J. Rosen, Anne Klibanski
BACKGROUND. Continued androgen receptor (AR) signaling constitutes a key target for treatment in metastatic castration-resistant prostate cancer (CRPC). Studies have identified 11-ketotestosterone (11KT) as a potent AR agonist, but it is unknown if 11KT is present at physiologically-relevant concentrations in CRPC patients to drive AR activation. The goal of this study was to investigate the circulating steroid metabolome including all active androgens in CRPC patients. METHODS. Metastatic CRPC patients (n=29) starting a new line of systemic therapy were included. Sequential plasma samples were obtained for measurement of circulating steroid concentrations by multi-steroid profiling employing liquid chromatography-tandem mass spectrometry. Metastatic tumor biopsy samples were obtained at baseline and subjected to RNA sequencing. RESULTS. 11KT was the most abundant circulating active androgen in 97% of CRPC patients (median 0.39 nmol/L, range: 0.03–2.39 nmol/L), constituting 60% (IQR 43-79%) of the total active androgen (TA) pool. Treatment with glucocorticoids reduced 11KT by 84% (49-89%) and testosterone (T) by 68% (38-79%). Circulating TA concentrations at baseline were associated with a distinct intratumoral gene expression signature comprising AR-regulated genes. CONCLUSIONS. The potent AR agonist 11KT is the predominant circulating active androgen in CRPC patients and, therefore, one of the potential drivers of AR activation in CRPC. Assessment of androgen status should be extended to include 11KT, as current clinical approaches likely underestimate androgen abundance in CRPC patients. Trial registrationNetherlands TRIAL REGISTRATION. NL5625(NTR5732) FUNDING. Daniel den Hoed foundation (Hofland) and Wellcome Trust (Investigator Award WT209492/Z/17/Z, Arlt)
Gido Snaterse, Lisanne F. van Dessel, Job van Riet, Angela E. Taylor, Michelle van der Vlugt-Daane, Paul Hamberg, Ronald de Wit, Jenny A. Visser, Wiebke Arlt, Martijn P. Lolkema, Johannes Hofland
BACKGROUND. Little is known about pathogen-specific humoral immunity in individuals with long-term remission after treatment with chimeric antigen receptor-modified T-cells (CAR-T-cells) for B-cell lineage malignancies. METHODS. We conducted a prospective cross-sectional study of CD19-targeted or BCMA-targeted CAR-T-cell therapy recipients ≥6 months post-treatment and in remission. We measured lymphocyte subsets, immunoglobulins, pathogen-specific IgG for 12 vaccine-preventable infections, and the total number of viral and bacterial epitopes to which IgG was detected (‘epitope hits’) using a serological profiling assay. The primary outcome was the proportion of participants with IgG levels above a threshold correlated with seroprotection for vaccine-preventable infections. RESULTS. We enrolled 65 children and adults a median of 20 months after CD19- (n=54) or BCMA- (n=11) CAR-T-cell therapy. Among 30 adults without IgG replacement therapy (IGRT) in the prior 16 weeks, 27 (90%) had hypogammaglobulinemia. Despite this, these individuals had seroprotection to a median of 67% (IQR, 59-73%) of tested vaccine-preventable infections. Proportions of participants with seroprotection per-pathogen were comparable to population-based studies, but most individuals lacked seroprotection to specific pathogens. Compared to CD19-CAR-T-cell recipients, BCMA-CAR-T-cell recipients were half as likely to have seroprotection to vaccine-preventable infections (prevalence ratio, 0.47; 95% CI, 0.18-1.25) and had fewer pathogen-specific epitope hits (mean difference, -90 epitope hits; 95% CI, -157 to -22). CONCLUSIONS. Seroprotection for vaccine-preventable infections in adult CD19-CAR-T-cell recipients was comparable to the general population, but BCMA-CAR-T-cell recipients have fewer pathogen-specific antibodies. Deficits in both groups support the need for randomized vaccine and IGRT trials to determine efficacy and risk-benefit.
Carla S. Walti, Elizabeth M. Krantz, Joyce Maalouf, Jim Boonyaratanakornkit, Jacob Keane-Candib, Laurel Joncas-Schronce, Terry Stevens-Ayers, Sayan Dasgupta, Justin J. Taylor, Alexandre V. Hirayama, Merav Bar, Rebecca A. Gardner, Andrew J. Cowan, Damian J. Green, Michael J. Boeckh, David G. Maloney, Cameron J. Turtle, Joshua A. Hill
BACKGROUND. Identifying a quantitative biomarker of neuropsychiatric dysfunction in people with HIV (PWH) remains a significant challenge in the neuroHIV field. The strongest evidence to date implicates the role of monocytes in central nervous system (CNS) dysfunction in HIV, yet no study has examined monocyte subsets in blood as a correlate and/or predictor of neuropsychiatric function in virally suppressed PWH. METHODS. In two independent cohorts of virologically suppressed women with HIV (vsWWH; n=25 and n=18), whole blood samples were obtained either in conjunction with neuropsychiatric assessments (neuropsychological [NP] test battery, self-report depression and stress-related symptom questionnaires) or one year prior to assessments. Immune cell subsets were assessed by flow cytometry. RESULTS. A higher proportion of intermediate monocytes (CD14+CD16+) was associated with lower global NP function when assessing monocytes concurrently and approximately one year before (predictive) NP testing. The same pattern was seen for executive function (mental flexibility) and processing speed. Conversely, there were no associations with monocyte subsets and depression or stress-related symptoms. Additionally, we found that a higher proportion of classical monocytes was associated with better cognition. CONCLUSION. Although it is widely accepted that lentiviral infection of the CNS targets cells of monocyte-macrophage-microglial lineage, is associated with an increase in intermediate monocytes in the blood and monocyte migration into brain, the percentage of intermediate monocytes in blood of vsWWH has not been associated with neuropsychiatric outcomes. Our findings provide evidence for a new, easily measured blood-based cognitive biomarker in vsWWH. FUNDING. R01-MH113512, R01-MH113512-S, P30-AI094189, R01-MH112391, R01-AI127142, R00-DA044838, U01-AI35004, and P30-MH075673.
Rebecca T. Veenhuis, Dionna W. Williams, Erin N. Shirk, Celina Monteiro Abreu, Edna A. Ferreira, Jennifer M. Coughlin, Todd T. Brown, Pauline M. Maki, Kathryn Anastos, Joan W. Berman, Janice E. Clements, Leah H. Rubin
BACKGROUND. Early diagnosis and treatment are key to the long-term survival of lung cancer patients. Although CT has significantly contributed to the early diagnosis of lung cancer, there are still consequences of excessive or delayed treatment. By improving the sensitivity and specificity of circulating tumour cell (CTC) detection, a new solution was proposed for differentiating benign from malignant pulmonary nodules. METHODS. In this study, we used telomerase reverse transcriptase-based CTC detection (TBCD) to distinguish benign from malignant pulmonary nodules <2 cm and compared this method with the pathological diagnosis as the gold standard. FlowSight and FISH were used to confirm the CTCs detected by TBCD. RESULTS. Our results suggest that CTCs based on TBCD can be used as an independent biomarker to distinguish benign from malignant nodules and are significantly superior to serum tumour markers. When the detection threshold was 1, the detection sensitivity and specificity of CTC diagnosis were 0.854 and 0.839, respectively. For pulmonary nodules ≦1 cm and 1-2 cm, the sensitivity and specificity of CTCs were both higher than 77%. Additionally, the diagnostic ability of CTC-assisted CT was compared by CT detection. The results showed that CT combined with CTCs could significantly improve the differentiation ability of benign and malignant nodules in lung nodules <2 cm, and the sensitivity and specificity could reach 0.899 and 0.839, respectively. CONCLUSIONS. In conclusion, TBCD can effectively diagnose pulmonary nodules and be used as an effective auxiliary diagnostic scheme for CT diagnosis. FUNDING. National Key Research and Development Project grants No. 2019YFC1315700 and No. 2017YFC1308702, CAMS Initiative for Innovative Medicine grants No. 2017-I2M-1-005, and National Natural Science Foundation of China grants No. 81472013.
Wen Zhang, Xinchun Duan, Zhenrong Zhang, Zhenrong Yang, Changyun Zhao, Chunzi Liang, Zhidong Liu, Shujun Cheng, Kaitai Zhang
BACKGROUND [18F]FluorThanatrace ([18F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODS Two single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via [18F]FTT PET before and after initiation of PARPi treatment and in vitro via [125I]KX1 (an analog of [18F]FTT) binding to surgically removed breast cancer.RESULTS Thirteen patients had baseline [18F]FTT PET. Nine of these then had resection and in vitro evaluation of [18F]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [18F]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [18F]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [18F]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [125I]KX1 binding.CONCLUSION [18F]FTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test [18F]FTT PET as a predictive and pharmacodynamic biomarker.TRIAL REGISTRATION ClinicalTrials.gov identifiers NCT03083288 and NCT03846167.FUNDING Metavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge.
Elizabeth S. McDonald, Austin R. Pantel, Payal D. Shah, Michael D. Farwell, Amy S. Clark, Robert K. Doot, Daniel A. Pryma, Sean D. Carlin
BACKGROUND. Serum creatinine concentrations (SCr) are used to determine the presence and severity of acute kidney injury (AKI). SCr is primarily eliminated by glomerular filtration; however, most mechanisms of AKI in critical illness involve kidney proximal tubules, where tubular secretion occurs. Proximal tubular secretory clearance is not currently estimated in the ICU. Our objective was to estimate the kidney clearance of secretory solutes in critically ill adults. METHODS. We collected matched blood and spot urine samples from 170 ICU patients and from a comparison group of 70 adults with normal kidney function. We measured seven endogenously produced secretory solutes using liquid chromatography-tandem mass spectrometry. We computed a composite secretion score incorporating all seven solutes, and evaluated associations with 28-day major adverse kidney events (MAKE28), defined as doubling of SCr, dialysis dependence, or death. RESULTS. The urine/plasma ratio of six of seven secretory solutes were lower in critically ill patients compared with normal individuals after adjustment for SCr. The composite secretion score was moderately correlated with SCr and cystatin C (r = -0.51 and r = -0.53, respectively). Each standard deviation higher composite secretion score was associated with a 25% lower risk of MAKE28 (95% CI 9% - 38% lower) independent of severity of illness, SCr and tubular injury markers. Higher urine to plasma ratios of individual secretory solutes isovalerylglycine and tiglylglycine were associated with MAKE28 after accounting for multiple testing. CONCLUSIONS. Among critically ill adults, tubular secretory clearance is associated with adverse outcomes and measurement could improve assessment of kidney function and dosing of essential ICU medications. TRIAL REGISTRATION. None. FUNDING. PKB was supported by grants from the Digestive and Kidney Diseases K23DK116967, the University of Washington Diabetes Research Center P30DK017047, and an unrestricted gift to the Kidney Research Institute from the Northwest Kidney Centers. EDS was supported by the Vanderbilt O’Brien Kidney Center (NIDDK 5P30 DK114809-03) The funding sources had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Pavan K. Bhatraju, Xin-Ya Chai, Neha A. Sathe, John Ruzinski, Edward D. Siew, Jonathan Himmelfarb, Andrew N. Hoofnagle, Mark M. Wurfel, Bryan R. Kestenbaum
BACKGROUND. High circulating levels of ceramides (Cer) and sphingomyelins (SM) have been associated with cardiometabolic diseases. The consumption of whole-fat dairy products, which naturally contain such polar lipids (PL), is associated with health benefits, but the impact on sphingolipidome remains unknown. We investigated how milk PL supplementation impacts circulating and intestinal SM and Cer composition in association with improvement of cardiovascular markers. METHODS. In a 4 week-randomized double-blind controlled study, 58 postmenopausal women consumed daily a cream cheese containing 0, 3 or 5 g of milk PL. Postprandial metabolic explorations were performed before and after the supplementation. SM and Cer species were analyzed in serum, intestine-derived chylomicrons and feces. The ileal content of 4 ileostomy patients was also explored after milk PL intake in a crossover double-blind study. RESULTS. Milk PL consumption decreased serum atherogenic C24:1 Cer (Pgroup = 0.033), C16:1 (Pgroup = 0.007) and C18:1 (Pgroup = 0.003) SM species. Changes in serum C16+18 SM species were positively correlated with the reduction of total cholesterol (r = 0.706, P < 0.001), LDL-C (r = 0.666, P < 0.001) and ApoB (r = 0.705, P < 0.001). Milk PL decreased the concentration in chylomicrons of total SM (Pgroup < 0.0001) and of C24:1 Cer (Pgroup = 0.001). Saturated SM and Cer species, which are also the major species found in milk PL-enriched cheeses, increased in ileal efflux and feces. There was a marked increase in total fecal Cer after milk PL supplementation (Pgroup = 0.0002). Milk PL also modulated the abundance of some specific SM and Cer species in ileal efflux and feces, suggesting differential absorption and metabolization processes in the gut. CONCLUSION. These data demonstrate that milk PL supplementation decreases atherogenic SM and Cer species associated with an improvement of cardiovascular risk markers. Our findings bring new insights on sphingolipid metabolism in the gastrointestinal tract, especially Cer as such signaling molecules potentially participating in the beneficial effect of milk PL. ClinicalTrials.gov, NCT02099032, NCT02146339. FUNDINGS. Agence Nationale de la Recherche, ANR-11-ALID-007-01; Regional Hospital Clinical Research Program (PHRCI-2014: VALOBAB, n°14-007); French Dairy Interbranch Organization (CNIEL); Groupe Lipides et Nutrition (GLN 2018-11-07), Hospices Civils de Lyon as sponsor.
Mélanie Le Barz, Cécile Vors, Emmanuel Combe, Laurie Joumard-Cubizolles, Manon Lecomte, Florent Joffre, Michèle Trauchessec, Sandra Pesenti, Emmanuelle Loizon, Anne-Esther Breyton, Emmanuelle Meugnier, Karène Bertrand, Jocelyne Drai, Chloé Robert, Annie Durand, Charlotte Cuerq, Patrice Gaborit, Nadine Leconte, Annick Bernalier-Donadille, Eddy Cotte, Martine Laville, Stéphanie Lambert-Porcheron, Lemlih Ouchchane, Hubert Vidal, Corinne Malpuech-Brugère, David Cheillan, Marie-Caroline Michalski
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