Background: Mitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined. Methods: We measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. ICU admission, intubation, vasopressor and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristics and area under-the-curve assessment were used to compare MT-DNA levels to established and emerging inflammatory markers of COVID-19. Results: Circulating MT-DNA levels were highly elevated in patients who eventually died, required ICU admission, intubation, vasopressor use or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA is an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels have a similar or superior area-under-the curve when compared against clinically-established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy. Conclusions: These results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes. Funding: This project was supported by Washington University Institute of Clinical Translational Sciences COVID-19 Research Program. Sample procurement and patient outcome data collection was supported by the Washington University ICTS NIH grant UL1TR002345.
Davide Scozzi, Marlene Cano, Lina Ma, Dequan Zhou, Ji Hong Zhu, Jane A. O’Halloran, Charles W. Goss, Adriana M. Rauseo, Zhiyi Liu, Sanjaya Kumar Sahu, Valentina Peritore, Monica Rocco, Alberto Ricci, Rachele Amodeo, Laura Aimati, Mohsen Ibrahim, Ramsey R. Hachem, Daniel Kreisel, Philip A. Mudd, Hrishikesh S. Kulkarni, Andrew E. Gelman
BACKGROUND Although CDK4/6 inhibitors are an established treatment for hormone receptor–positive, HER2-negative metastatic breast cancers, their benefit in other malignancies remains limited.METHODS We investigated factors associated with clinical outcomes from CDK4/6 inhibitor–based therapy among patients with G1/S phase cell-cycle alterations (CDK4/6 amplifications, CCND1/2/3 amplifications, or CDKN2A/B alterations).RESULTS Overall, 2457 patients with diverse solid tumors that underwent clinical-grade, next-generation sequencing (182–465 genes) and therapy outcome of (non–breast cancer) patients treated with matched CDK4/6 inhibitors were analyzed. G1/S phase cell-cycle alterations occurred in 20.6% (507 of 2457) of patients; 99% of those patients (n = 501) harbored ≥1 characterized co-alteration (median, 4; range, 0–24). In 40 patients with G1/S phase cell-cycle alterations given CDK4/6 inhibitors as part of their regimen, significantly longer median progression-free survival (PFS) was observed when CDK4/6 inhibitor–based therapies matched a larger proportion of tumor alterations, often because CDK4/6 inhibitors were administered together with other drugs that were matched to genomic co-alterations, hence achieving a high matching score (high vs. low [≥50% vs. <50%] matching score, PFS, 6.2 vs. 2.0 months, P < 0.001 [n = 40] [multivariate]) and higher rate of stable disease ≥6 months or an objective response (57% vs. 21%, P = 0.048).CONCLUSION In summary, in cell-cycle–altered cancers, matched CDK4/6 inhibitors, as part of an individualized regimen targeting a majority of genomic alterations, was independently associated with longer PFS.TRIAL REGISTRATION ClinicalTrials.gov NCT02478931.FUNDING Joan and Irwin Jacobs Fund, National Cancer Institute (P30 CA023100, R01 CA226803), and the FDA (R01 FD006334).
Shumei Kato, Ryosuke Okamura, Jacob J. Adashek, Noor Khalid, Suzanna Lee, Van Nguyen, Jason K. Sicklick, Razelle Kurzrock
Background. Neuronal hyper-excitability characterizes the early stages of Alzheimer’s disease (AD). In animals, early misfolded tau and amyloid-beta (Aβ) protein accumulation, both central to AD neuropathology, promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aβ aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau, and its associated neuroinflammation, and cortical Aβ aggregations remains unknown. Methods. We probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late middle-aged individuals (50-69 y; 45 women). We assessed whole-brain [18F]THK5351 positron emission tomography (PET) uptake as a proxy measure of tau/neuroinflammation, and whole-brain Aβ burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers. Results. We find that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment is associated with increased cortical excitability (r = .29, p = .02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (pFWE-corrected < .001), was not significantly associated with cortical excitability (r = .14, p = .25). Importantly, no significant association was found between early Aβ cortical deposits and cortical excitability (r = -.20, p = .11). Conclusion. These findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans. Trial registration. EudraCT 2016-001436-35. Funding. F.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund.
Maxime Van Egroo, Daphne O. Chylinski, Justinas Narbutas, Gabriel Besson, Vincenzo Muto, Christina Schmidt, Davide Marzoli, Paolo Cardone, Nora Vandeleene, Martin Grignard, André Luxen, Eric Salmon, Christian Lambert, Christine Bastin, Fabienne Collette, Christophe Phillips, Pierre Maquet, Mohamed Ali Bahri, Evelyne Balteau, Gilles Vandewalle
BACKGROUND Identifying factors conferring responses to therapy in cancer is critical to select the best treatment for patients. For immune checkpoint inhibition (ICI) therapy, mounting evidence suggests that the gut microbiome can determine patient treatment outcomes. However, the extent to which gut microbial features are applicable across different patient cohorts has not been extensively explored.METHODS We performed a meta-analysis of 4 published shotgun metagenomic studies (Ntot = 130 patients) investigating differential microbiome composition and imputed metabolic function between responders and nonresponders to ICI.RESULTS Our analysis identified both known microbial features enriched in responders, such as Faecalibacterium as the prevailing taxa, as well as additional features, including overrepresentation of Barnesiella intestinihominis and the components of vitamin B metabolism. A classifier designed to predict responders based on these features identified responders in an independent cohort of 27 patients with the area under the receiver operating characteristic curve of 0.625 (95% CI: 0.348–0.899) and was predictive of prognosis (HR = 0.35, P = 0.081).CONCLUSION These results suggest the existence of a fecal microbiome signature inherent across responders that may be exploited for diagnostic or therapeutic purposes.FUNDING This work was funded by the Knut and Alice Wallenberg Foundation, BioGaia AB, and Cancerfonden.
Angelo Limeta, Boyang Ji, Max Levin, Francesco Gatto, Jens Nielsen
BACKGROUND Surgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%–40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib.METHODS ccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment.RESULTS Twenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations.CONCLUSION Neoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response.FUNDING Support was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study.
Christopher G. Wood, James E. Ferguson III, Joel S. Parker, Dominic T. Moore, Jennifer G. Whisenant, Susan J. Maygarden, Eric M. Wallen, William Y. Kim, Mathew I. Milowsky, Kathryn E. Beckermann, Nancy B. Davis, Scott M. Haake, Jose A. Karam, Dante S. Bortone, Benjamin G. Vincent, Thomas Powles, W. Kimryn Rathmell
Background Severe acute malnutrition (SAM) is a major contributor to global mortality in children under 5 years. Mortality has decreased, however the long-term cardiometabolic consequences of SAM and its subtypes, severe wasting (SW) and edematous malnutrition (EM), are not well understood. We evaluated the metabolic profiles of adult SAM survivors using targeted metabolomic analyses. Methods This cohort study of 122 adult SAM survivors (SW=69, EM=53) and 90 age, sex and BMI-matched community participants (CPs) quantified serum metabolites using direct flow injection mass spectrometry combined with reverse-phase liquid chromatography. Univariate and sparse partial least square discriminant analyses (sPLS-DA) assessed differences in metabolic profiles and identified the most discriminative metabolites. Results 77 metabolite variables were significant in distinguishing between SAM survivors (28.4 ± 8.8 years, 24.0 ± 6.1 kg/m2) and CPs (28.4 ± 8.9 years, 23.3 ± 4.4 kg/m2) (mean ± SDs) in univariate and sPLS-DA models. Compared to CPs, SAM survivors had less liver fat, higher branched-chained amino acids (BCAAs), urea cycle metabolites and kynurenine-tryptophan (KT) ratio (p<0.001) and lower β-hydroxybutyric acid and acylcarnitine:free carnitine ratio (p<0.001) which were both associated with hepatic steatosis (p<0.001). SW and EM survivors had similar metabolic profiles as did stunted and non-stunted SAM survivors. Conclusions Adult SAM survivors have distinct metabolic profiles that suggest reduced β-oxidation and greater risk of type 2 diabetes (BCAAs, KT ratio, urea cycle metabolites) compared to community participants. This indicates that early childhood SAM exposure has long-term metabolic consequences that may worsen with age and require targeted clinical management. Funding Health Research Council of New Zealand Caribbean Public Health Agency Centre for Global Child Health, Hospital for Sick Children. DST is an Academic Fellow and a Restracomp Fellow at the Centre for Global Child Health GBG is a postdoctoral fellow of the Research Foundation Flanders (FWO).
Debbie S. Thompson, Celine Bourdon, Paraskevi Massara, Michael S. Boyne, Terrence Forrester, Gerard Bryan Gonzales, Robert HJ Bandsma
Background: Psoriasis is a chronic inflammatory skin disease with increased obesity, non-calcified coronary artery burden (NCB), and incident myocardial infarction. We sought to assess the relationship between inflammation, visceral adipose tissue (VAT), and NCB. Furthermore, we evaluated whether improvement in VAT would be associated with reduction in NCB over time in psoriasis. Methods: Consecutive psoriasis patients (PSO) underwent coronary computed-tomography angiography to quantify NCB and abdominal computed tomography to calculate VAT, at baseline (n=237), one year (n=176), and four-years (n=50). Results: Patients with high hs-CRP had significantly greater visceral adiposity (17952.9±849.2 vs 13370.7±806.8 cc3, p<0.001) and non-calcified coronary burden (1.26±0.03 vs 1.07±0.02 mm2) than those with low hs-CRP. Those with higher VAT had more systemic inflammation [hs-CRP: 2.5 (1.0-5.3) vs 1.2 (0.6-2.9) mg/L] with ~50% higher NCB (1.42±0.6 vs 0.91±0.2 mm2 , p<0.001). VAT associated with NCB in fully adjusted models (β=0.47, p<0.001). At one-year follow up, patients who had worsening hs-CRP had an increase in VAT (14748.7±878.1 to 15158.7±881.5 cc3; p=0.03), whereas those who improved hs-CRP improved their VAT (16876.1±915.2 to 16310.4±889.6 cc3; p=0.04). At one-year, in those who decreased VAT, there was 10.3% reduction in NCB (β=0.26, p<0.0001), which persisted in a subset at four-years (β=0.39, p=0.003). Conclusions: Inflammation drives development of VAT, increased cardiometabolic risk, and NCB in psoriasis. Reduction of inflammation associated with reduction in VAT, and associated with longitudinal improvement in NCB. These findings demonstrate the important role of inflammation in the development of VAT in humans and its impact on early atherogenesis.
Aparna Sajja, Khaled M. Abdelrahman, Aarthi S. Reddy, Amit K. Dey, Domingo E. Uceda, Sundus S. Lateef, Alexander V. Sorokin, Heather L. Teague, Jonathan H. Chung, Joshua P. Rivers, Aditya A. Joshi, Youssef A. Elnabawi, Aditya Goyal, Justin Rodante, Andrew Keel, Julie A. Erb-Alvarez, Benjamin Lockshin, Ronald Prussick, Evan L. Siegel, Martin P. Playford, Marcus Y. Chen, David A. Bluemke, Joel M. Gelfand, Nehal N. Mehta
BACKGROUND Hyperglycemia, insulin insensitivity, and low IGF1 levels in extremely preterm infants are associated with an increased risk of retinopathy of prematurity (ROP), but the interactions are incompletely understood.METHODS In 117 extremely preterm infants, serum glucose levels and parenteral glucose intake were recoded daily in the first postnatal week. Serum IGF1 levels were measured weekly. Mice with oxygen-induced retinopathy alone versus oxygen-induced retinopathy plus streptozotocin-induced hyperglycemia/hypoinsulinemia were assessed for glucose, insulin, IGF1, IGFBP1, and IGFBP3 in blood and liver. Recombinant human IGF1 was injected to assess the effect on glucose and retinopathy.RESULTS The highest mean plasma glucose tertile of infants positively correlated with parenteral glucose intake [r(39) = 0.67, P < 0.0001]. IGF1 plasma levels were lower in the high tertile compared with those in low and intermediate tertiles at day 28 (P = 0.038 and P = 0.03). In high versus lower glucose tertiles, ROP was more prevalent (34 of 39 versus 19 of 39) and more severe (ROP stage 3 or higher; 71% versus 32%). In oxygen-induced retinopathy, hyperglycemia/hypoinsulinemia decreased liver IGF1 expression (P < 0.0001); rh-IGF1 treatment improved normal vascular regrowth (P = 0.027) and reduced neovascularization (P < 0.0001).CONCLUSION In extremely preterm infants, high early postnatal plasma glucose levels and signs of insulin insensitivity were associated with lower IGF1 levels and increased ROP severity. In a hyperglycemia retinopathy mouse model, decreased insulin signaling suppressed liver IGF1 production, lowered serum IGF1 levels, and increased neovascularization. IGF1 supplementation improved retinal revascularization and decreased pathological neovascularization. The data support IGF1 as a potential treatment for prevention of ROP.TRIAL REGISTRATION ClinicalTrials.gov NCT02760472 (Donna Mega).FUNDING This study has been supported by the Swedish Medical Research Council (14940, 4732, 20144-01-3, and 21144-01-3), a Swedish government grant (ALFGB2770), Lund medical faculty grants (ALFL, 11615 and 11601), the Skåne Council Foundation for Research and Development, the Linnéa and Josef Carlsson Foundation, the Knut and Alice Wallenberg Foundation, the NIH/National Eye Institute (EY022275, EY017017, EY017017-13S1, and P01 HD18655), European Commission FP7 project 305485 PREVENT-ROP, Deutsche Forschungsgemeinschaft (CA-1940/1-1), and Stiftelsen De Blindas Vänner.
Bertan Cakir, William Hellström, Yohei Tomita, Zhongjie Fu, Raffael Liegl, Anna Winberg, Ingrid Hansen-Pupp, David Ley, Ann Hellström, Chatarina Löfqvist, Lois E.H. Smith
Background: Physical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies, but their presence or link to EI in the frail older adult is unknown. Methods: Three groups of ambulatory, community-dwelling adults with no history of significant coronary disease were studied: frail, older individuals (FO, 81±2.7 years, mean±SEM), non-frail, older individuals (NFO, 79±2.0 years), and healthy middle-aged controls (CONT, 51±2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded, multistage plantar flexion exercise (PFE). EI was quantified by six-minute walk and peak oxygen consumption during cardiopulmonary testing (peak-VO2). Results: During graded exercise, frail older (FO), non-frail older (NFO), and healthy middle-aged individuals all fatigued at similar SM HEP levels measured by 31P MR. However, FO fatigued fastest with several-fold higher rates of PFE-induced HEP decline, which correlated closely with shorter exercise duration in the MR scanner and with six-minute walk distance and lower peak oxygen consumption on cardiopulmonary testing (p<0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI. Conclusions: Several-fold faster skeletal muscle energetic decline during exercise occurs in frail older individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.
Sabra C. Lewsey, Kilian Weiss, Michael Schär, Yi Zhang, Paul A. Bottomley, T. Jake Samuel, Qian-Li Xue, Angela Steinberg, Jeremy Walston, Gary Gerstenblith, Robert G. Weiss
Background: Patients infected with SARS-CoV-2 differ in the severity of disease. We hypothesized that characteristics of SARS-CoV-2 specific immunity correlate with disease severity. Methods: In this study, SARS-CoV-2 specific T-cells and antibodies were characterized in uninfected controls and patients with different COVID-19 related disease severity. SARS-CoV-2 specific T-cells were flow-cytometrically quantified after stimulation with SARS-CoV-2 peptide pools and analyzed for expression of cytokines (IFNγ, IL-2 and TNFα) and markers for activation, proliferation and functional anergy. SARS-CoV-2 specific IgG and IgA antibodies were quantified using ELISA. Moreover, global characteristics of lymphocyte subpopulations were compared between patient groups and uninfected controls Results: Despite severe lymphopenia affecting all major lymphocyte subpopulations, patients with severe disease mounted significantly higher levels of SARS-CoV-2 specific T-cells as compared to convalescent individuals. SARS-CoV-2 specific CD4 T-cells dominated over CD8 T-cells and closely correlated with the number of plasmablasts and SARS-CoV-2 specific IgA- and IgG-levels. Unlike in convalescents, SARS-CoV-2 specific T-cells in patients with severe disease showed marked alterations in phenotypical and functional properties, which also extended to CD4 and CD8 T-cells in general. Conclusion: Given the strong induction of specific immunity to control viral replication in patients with severe disease, the functionally altered characteristics may result from the need for contraction of specific and general immunity to counteract excessive immunopathology in the lung. Trial registration: n.a. Funding: The study was supported by institutional funds by M.S., and in part by grants of Saarland University (to M.S. and. R.B), the State of Saarland, and the Dr. Rolf M. Schwiete Stiftung to R.B.
David Schub, Verena Klemis, Sophie Schneitler, Janine Mihm, Philipp M. Lepper, Heinrike Wilkens, Robert Bals, Hermann Eichler, Barbara C. Gärtner, Sören L. Becker, Urban Sester, Martina Sester, Tina Schmidt
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