BACKGROUND. The heterogeneity of tinnitus is thought to underlie the lack of objective diagnostic measures. METHODS. Longitudinal data from 20,349 participants of the Swedish Longitudinal Occupational Survey of Health (SLOSH) cohort from 2008 to 2018 was used to understand the dynamics of transition between occasional and constant tinnitus. The second part of the study included electrophysiological data from 405 participants of the Swedish Tinnitus Outreach Project (STOP) cohort. RESULTS. We determined that with increasing frequency of the occasional perception of self-reported tinnitus, the odds of reporting constant tinnitus after 2 years increases from 5 for previous tinnitus (sometimes) to 30 for previous tinnitus (often). When previous tinnitus was reported to be constant, the odds of reporting it as constant after 2 years rose to 603, suggesting that once transitioned to constant tinnitus, the likelihood of tinnitus to persist was much greater. Auditory brainstem responses (ABRs) from subjects reporting non-tinnitus (controls), occasional tinnitus, and constant tinnitus show that wave V latency increased in constant tinnitus when compared to occasional tinnitus or non-tinnitus. The ABR from occasional tinnitus was indistinguishable from that of the non-tinnitus controls. CONCLUSIONS. Our results support the hypothesis that the transition from occasional to constant tinnitus is accompanied by neuronal changes in the midbrain leading to a persisting tinnitus, which is then less likely to remit. TRIAL REGISTRATION. Not applicable FUNDING. This study was supported by the GENDER-Net Co-Plus Fund (GNP-182), the European Union’s Horizon 2020 Grant No. 848261 (UNITI) and No. 722046 (ESIT).
Niklas K. Edvall, Golbarg Mehraei, Martin Claeson, Andra Lazar, Jan Bulla, Constanze Leineweber, Inger Uhlén, Barbara Canlon, Christopher R. Cederroth
BACKGROUND The temporal clustering of a cancer diagnosis with dermatomyositis (DM) onset is strikingly associated with autoantibodies against transcriptional intermediary factor 1-γ (TIF1-γ). Nevertheless, many patients with anti–TIF1-γ antibodies never develop cancer. We investigated whether additional autoantibodies are found in anti–TIF1-γ–positive patients without cancer.METHODS Using a proteomic approach, we defined 10 previously undescribed autoantibody specificities in 5 index anti–TIF1-γ–positive DM patients without cancer. These were subsequently examined in discovery (n = 110) and validation (n = 142) cohorts of DM patients with anti–TIF1-γ autoantibodies.RESULTS We identified 10 potentially novel autoantibodies in anti–TIF1-γ–positive DM patients, 6 with frequencies ranging from 3% to 32% in 2 independent DM cohorts. Autoantibodies recognizing cell division cycle and apoptosis regulator protein 1 (CCAR1) were the most frequent, and were significantly negatively associated with contemporaneous cancer (discovery cohort OR 0.27 [95% CI 0.7–1.00], P = 0.050; validation cohort OR 0.13 [95% CI 0.03–0.59], P = 0.008). When cancer did emerge, it occurred significantly later in anti-CCAR1–positive compared with anti-CCAR1–negative patients (median time from DM onset 4.3 vs. 0.85 years, respectively; P = 0.006). Cancers that emerged were more likely to be localized (89% of anti-CCAR1–positive cancers presenting at stage 0 or 1 compared with 42% of patients without anti-CCAR1 antibodies, P = 0.02). As the number of additional autoantibody specificities increased in anti–TIF1-γ–positive DM patients, the frequency of cancer decreased (P < 0.001).CONCLUSION As the diversity of immune responses in anti–TIF1-γ DM patients increases, the likelihood of cancer emerging decreases. Our findings have important relevance for cancer risk stratification in DM patients and for understanding natural immune regulation of cancer in humans.TRIAL REGISTRATION Not applicable.FUNDING SOURCES The NIH, the Donald B. and Dorothy L. Stabler Foundation, and the Huayi and Siuling Zhang Discovery Fund.
David F. Fiorentino, Christopher A. Mecoli, Matthew C. Rosen, Lorinda S. Chung, Lisa Christopher-Stine, Antony Rosen, Livia Casciola-Rosen
BACKGROUND. Fasting and NAD+-boosting compounds including NAD+ precursor nicotinamide riboside (NR) confer anti-inflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined. METHODS. We explored the underlying biology in myeloid cells from healthy volunteers following in-vivo placebo or NR administration and subsequently tested the findings in-vitro in monocytes extracted from subjects with systemic lupus erythematosus (SLE). RESULTS. RNA sequencing of unstimulated and lipopolysaccharide (LPS)-activated monocytes implicate NR in the regulation of autophagy and type I interferon signaling. In primary monocytes NR blunts LPS-induced IFNβ production and genetic or pharmacologic disruption of autophagy phenocopies this effect. Given NAD+ is a co-enzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased inosine level. Inosine supplementation similarly blunts autophagy and IFNβrelease. Finally, as SLE exhibits type I interferon dysregulation, we assessed the NR effect on SLE patient monocytes and found that NR reduces autophagy and interferon-β release. CONCLUSION. We conclude that NR, in an NAD+-dependent manner and in part via inosine-signaling, mediates suppression of autophagy and attenuates type I interferon in myeloid cells and identifies NR as a potential adjunct for SLE management. TRIAL REGISTRATION. ClinicalTrails.gov registration numbers: NCT02812238, NCT00001846 and NCT00001372. FUNDING. This work was supported by the NHLBI and NIAMS Divisions of Intramural Research.
Jing Wu, Komudi Singh, Amy Lin, Allison M. Meadows, Kaiyuan Wu, Vivian Shing, Maximilian Bley, Shahin Hassanzadeh, Rebecca D. Huffstutler, Mark S. Schmidt, Luz P. Blanco, Rong Tian, Charles Brenner, Mehdi Pirooznia, Mariana J. Kaplan, Michael N. Sack
BACKGROUND. Curative gene therapies for sickle cell disease (SCD) are currently undergoing clinical evaluation. The occurrence of myeloid malignancies in these trials has prompted safety concerns. Individuals with SCD are predisposed to myeloid malignancies, but the underlying causes remain undefined. Clonal hematopoiesis (CH) is a pre-malignant condition that also confers significant predisposition to myeloid cancers. While it has been speculated that CH may play a role in SCD-associated cancer predisposition, limited data addressing this issue have been reported. METHODS. Here, we leveraged 74,190 whole genome sequences to robustly study CH in SCD. Somatic mutation calling methods were used to assess CH in all samples and comparisons between individuals with and without SCD were performed. RESULTS. While we had sufficient power to detect a greater than 2-fold increased rate of CH, we found no detectable variation in rate or clone properties between individuals affected by SCD and controls. The rate of CH in individuals with SCD was unaltered by hydroxyurea use. CONCLUSIONS. We did not observe an increased risk for acquiring detectable CH in SCD, at least as measured by whole genome sequencing. These results should help guide ongoing efforts and further studies that seek to better define the risk factors underlying myeloid malignancy predisposition in SCD and help ensure that curative therapies can be more safely applied.FUNDING. Funding was provided by the New York Stem Cell Foundation and National Institutes of Health. The funders had no role in study design or reporting.
L. Alexander Liggett, Liam D. Cato, Joshua S. Weinstock, Yingze Zhang, S. Mehdi Nouraie, Mark T. Gladwin, Melanie E. Garrett, Allison Ashley-Koch, Marilyn Telen, Brian Custer, Shannon Kelly, Carla Dinardo, Ester C. Sabino, Paula Loureiro, Anna Carneiro-Proietti, Cláudia Maximo, Alexander P. Reiner, Gonçalo R. Abecasis, David A. Williams, Pradeep Natarajan, Alexander G. Bick, Vijay G. Sankaran
The KRAS proto-oncogene is among the most frequently mutated genes in cancer, yet for 40 years it remained an elusive therapeutic target. Recently, allosteric inhibitors that covalently bind to KRAS G12C mutations have been approved for use in lung adenocarcinomas. Although responses are observed they are often short-lived, thus making in-depth characterization of the mechanisms of resistance of paramount importance. Here, we present a rapid-autopsy case of a patient who had a KRASG12C-mutant lung adenocarcinoma who initially responded to a KRAS G12C inhibitor but then rapidly developed resistance. Using deep RNA and whole exome sequencing comparing pre-treatment, post-treatment and matched normal tissues, we uncover numerous mechanisms of resistance to direct KRAS inhibition. In addition to decreased KRAS G12C mutant allele frequency in refractory tumors, we also found reactivation of the MAPK pathway despite no new mutations in KRAS or its downstream mediators. Tumor cell intrinsic and non-cell autonomous mechanisms included increased complement activation, coagulation and tumor angiogenesis, and several lines of evidence of immunologic evasion. Together, our findings reveal numerous mechanisms of resistance to current KRAS G12C inhibitors through enrichment of clonal populations, KRAS-independent downstream signaling and diverse remodeling of the tumor microenvironment.
Yihsuan S. Tsai, Mark G. Woodcock, Salma H. Azam, Leigh B. Thorne, Krishna L. Kanchi, Joel S. Parker, Benjamin G Vincent, Chad V. Pecot
BACKGROUND. Presbyosmia, or aging related olfactory loss, occurs in a majority of humans over age 65 years, yet remains poorly understood, with no specific treatment options. The olfactory epithelium (OE) is the peripheral organ for olfaction, and is subject to acquired damage, suggesting a likely site of pathology in aging. Adult stem cells reconstitute the neuroepithelium in response to cell loss under normal conditions. In aged OE, patches of respiratory-like metaplasia have been observed histologically, consistent with a failure in normal neuroepithelial homeostasis. METHODS. Accordingly, we have focused on identifying cellular and molecular changes in presbyosmic OE. The study combined psychophysical testing with olfactory mucosa biopsy analysis, single cell RNA-sequencing (scRNA-seq), and culture studies. RESULTS. We identified evidence for inflammation-associated changes in the OE stem cells of presbyosmic patients. The presbyosmic basal stem cells exhibited increased expression of genes involved in response to cytokines or stress, or the regulation of proliferation and differentiation. Using a culture model, cytokine exposure drove increased TP63, a transcription factor acting to prevent OE stem cell differentiation. CONCLUSIONS. Our data suggest aging-related inflammatory changes in OE stem cells may contribute to presbyosmia, via the disruption of normal epithelial homeostasis. OE stem cells may represent a therapeutic target for restoration of olfaction. TRIAL REGISTRATION. Not applicable FUNDING. National Institutes of Health grants DC018371 (BJG), NS121067 (EAM), DC016224 (HM);Office of Physician-Scientist Development, Burroughs-Wellcome Fund Research Fellowship for Medical Students Award, Duke University School of Medicine (AO).
Allison D. Oliva, Rupali Gupta, Khalil Issa, Ralph Abi Hachem, David W. Jang, Sebastian A. Wellford, E. Ashley Moseman, Hiroaki Matsunami, Bradley J. Goldstein
BACKGROUND. Care management of Parkinson’s disease (PD) patients currently remains symptomatic, mainly because diagnosis relying on the expression of the cardinal motor symptoms is made too late. Earlier detecting PD therefore represents a key step for developing therapies able to delay or slow down its progression. METHODS. We investigated metabolic markers in three different animal models of PD, mimicking different phases of the disease assessed by behavioral and histological evaluation, and in 3 cohorts of de novo PD patients and matched controls (n = 129). Serum and brain tissue samples were analyzed by nuclear magnetic resonance spectroscopy and data submitted to advanced multivariate statistics. RESULTS. Our translational strategy reveals common metabolic dysregulations in serum of the different animal models and PD patients. Some of them were mirrored in the tissue samples, possibly reflecting pathophysiological mechanisms associated with PD development. Interestingly, some metabolic dysregulations appeared before motor symptom emergence, and could represent early biomarkers of PD. Finally, we built a composite biomarker with a combination of 6 metabolites. This biomarker discriminated animals mimicking PD from controls, even from the first, non-motor signs and very interestingly, also discriminated PD patients from healthy subjects. CONCLUSION. From our translational study which included three animal models and three de novo PD patient cohorts, we propose a promising biomarker exhibiting a high accuracy for de novo PD diagnosis and may possibly predict early PD development, before motor symptoms appearance. FUNDINGS. ANR, DOPALCOMP, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes.
David Mallet, Thibault Dufourd, Mélina Decourt, Carole Carcenac, Paola Bossù, Laure Verlin, Pierre-Olivier Fernagut, Marianne Benoit-Marand, Gianfranco Spalletta, Emmanuel L. Barbier, Sebastien Carnicella, Véronique Sgambato, Florence Fauvelle, Sabrina Boulet
BACKGROUND Hepatic de novo lipogenesis (DNL) is elevated in nonalcoholic fatty liver disease (NAFLD). Improvements in hepatic fat by dietary sugar reduction may be mediated by reduced DNL, but data are limited, especially in children. We examined the effects of 8 weeks of dietary sugar restriction on hepatic DNL in adolescents with NAFLD and correlations between DNL and other metabolic outcomes.METHODS Adolescent boys with NAFLD (n = 29) participated in an 8-week, randomized controlled trial comparing a diet low in free sugars versus their usual diet. Hepatic DNL was measured as percentage contribution to plasma triglyceride palmitate using a 7-day metabolic labeling protocol with heavy water. Hepatic fat was measured by magnetic resonance imaging–proton density fat fraction.RESULTS Hepatic DNL was significantly decreased in the treatment group (from 34.6% to 24.1%) versus the control group (33.9% to 34.6%) (adjusted week 8 mean difference: –10.6% [95% CI: –19.1%, –2.0%]), which was paralleled by greater decreases in hepatic fat (25.5% to 17.9% vs. 19.5% to 18.8%) and fasting insulin (44.3 to 34.7 vs. 35.5 to 37.0 μIU/mL). Percentage change in DNL during the intervention correlated significantly with changes in free-sugar intake (r = 0.48, P = 0.011), insulin (r = 0.40, P = 0.047), and alanine aminotransferase (ALT) (r = 0.39, P = 0.049), but not hepatic fat (r = 0.13, P = 0.532).CONCLUSION Our results suggest that dietary sugar restriction reduces hepatic DNL and fasting insulin, in addition to reductions in hepatic fat and ALT, among adolescents with NAFLD. These results are consistent with the hypothesis that hepatic DNL is a critical metabolic abnormality linking dietary sugar and NAFLD.TRIAL REGISTRY ClinicalTrials.gov NCT02513121.FUNDING The Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation, Ambrose Monell Foundation, and individual donors), the UCSD Altman Clinical and Translational Research Institute, the NIH, Children’s Healthcare of Atlanta and Emory University’s Children’s Clinical and Translational Discovery Core, Children’s Healthcare of Atlanta and Emory University Pediatric Biostatistical Core, the Georgia Clinical and Translational Science Alliance, and the NIH National Institute of Diabetes, Digestive, and Kidney Disease.
Catherine C. Cohen, Kelvin W. Li, Adina L. Alazraki, Carine Beysen, Carissa A. Carrier, Rebecca L. Cleeton, Mohamad Dandan, Janet Figueroa, Jack Knight-Scott, Cynthia J. Knott, Kimberly P. Newton, Edna M. Nyangau, Claude B. Sirlin, Patricia A. Ugalde-Nicalo, Jean A. Welsh, Marc K. Hellerstein, Jeffrey B. Schwimmer, Miriam B. Vos
BACKGROUND MEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODS This open-label phase II study randomized patients with BTC to atezolizumab (anti–PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTS Seventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35–0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination.CONCLUSION The combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs.TRIAL REGISTRATION ClinicalTrials.gov NCT03201458.FUNDING National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI’s Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation.
Mark Yarchoan, Leslie Cope, Amanda N. Ruggieri, Robert A. Anders, Anne M. Noonan, Laura W. Goff, Lipika Goyal, Jill Lacy, Daneng Li, Anuj K. Patel, Aiwu R. He, Ghassan K. Abou-Alfa, Kristen Spencer, Edward J. Kim, S. Lindsey Davis, Autumn J. McRee, Paul R. Kunk, Subir Goyal, Yuan Liu, Lauren Dennison, Stephanie Xavier, Aditya A. Mohan, Qingfeng Zhu, Andrea Wang-Gillam, Andrew Poklepovic, Helen X. Chen, Elad Sharon, Gregory B. Lesinski, Nilofer S. Azad
BACKGROUND. It is unclear how excess adiposity and insulin resistance affect β-cell function, insulin secretion, and insulin clearance in people with obesity. METHODS. We used a hyperinsulinemic-euglycemic clamp procedure and a modified oral glucose tolerance test to evaluate the interrelationships among obesity, insulin sensitivity, insulin kinetics, and glycemic status in five groups: normoglycemic lean and obese with: i) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), ii) NFG and impaired glucose tolerance (Ob-NFG-IGT), iii) impaired fasting glucose and IGT (Ob-IFG-IGT), and iv) type 2 diabetes (Ob-T2D). RESULTS. Glucose-stimulated insulin secretion (GSIS), an assessment of β-cell function, was greater in the Ob-NFG-NGT and Ob-NFG-IGT groups than in the lean group, even when insulin sensitivity was matched in the obese and lean groups. Insulin sensitivity, not GSIS, was decreased in the Ob-NFG-IGT group compared with the Ob-NFG-NGT group, whereas GSIS, not insulin sensitivity, was decreased in the Ob-IFG-IGT and Ob-T2D groups compared with the Ob-NFG-NGT and Ob-NFG-IGT groups. Insulin clearance was directly related to insulin sensitivity and inversely related to the postprandial increase in insulin secretion and plasma insulin concentration. CONCLUSION. Increased adiposity per se, not insulin resistance, enhances insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raise plasma insulin concentrations needed to maintain normoglycemia in people with moderate, but not severe insulin resistance. A deterioration in β-cell function, not a decrease in insulin sensitivity, is a determinant of IFG and ultimately leads to T2D. CLINICAL TRIALS REGISTRATION. NCT02706262; NCT04131166; NCT01977560 FUNDING. This study was supported by NIH grants P30 DK056341 (Washington University Nutrition and Obesity Research Center), P30 DK020579 (Washington University Diabetes Research Center), and UL1 TR000448 (Washington University Institute of Clinical and Translational Sciences), and grants from the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation, the Pershing Square Foundation, and the Washington University-Centene ARCH Personalized Medicine Initiative (P19-00559). ROLE OF THE FUNDERS/SPONSOR. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Bettina Mittendorfer, Bruce W. Patterson, Gordon I. Smith, Mihoko Yoshino, Samuel Klein
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