Too Much of a Good Thing? An Evolutionary Theory to Explain the Role of Ceramides in NAFLD.
Front Endocrinol (Lausanne). 2020;11:505
Authors: Poss AM, Summers SA
Abstract
Non-alcoholic fatty liver disease (NAFLD), which ranges from the relatively benign and reversible fatty liver (NAFL) to the more advanced and deadly steatohepatitis (NASH), affects a remarkably high percentage of adults in the population. Depending upon severity, NAFLD can increase one's risk for diabetes, cardiovascular disease, and hepatocellular carcinoma. Though the dominant histological feature of all forms of the disease is the accumulation of liver triglycerides, these molecules are likely not pathogenic, but rather serve to protect the liver from the damaging consequences of overnutrition. We propose herein that the less abundant ceramides, through evolutionarily-conserved actions intended to help organisms adapt to nutrient excess, drive the cellular events that define NAFL/NASH. In early stages of the disease process, they promote lipid uptake and storage, whilst inhibiting utilization of glucose. In later stages, they stimulate hepatocyte apoptosis and fibrosis. In rodents, blocking ceramide synthesis ameliorates all stages of NAFLD. In humans, serum and liver ceramides correlate with the severity of NAFLD and its comorbidities diabetes and heart disease. These studies identify key roles for ceramides in these hepatic manifestations of the metabolic syndrome.
PMID: 32849291 [PubMed - in process]
Neuroimmunogastroenterology: At the Interface of Neuroimmunology and Gastroenterology.
Front Neurol. 2020;11:787
Authors: Sanchez JMS, McNally JS, Cortez MM, Hemp J, Pace LA, Clardy SL
Abstract
The central nervous system (CNS) is an important regulator of the gastrointestinal tract, and CNS dysfunction can result in significant and disabling gastrointestinal symptom manifestation. For patients with neuroimmunologic and neuroinflammatory conditions, the recognition of gastrointestinal symptoms is under-appreciated, yet the gastrointestinal manifestations have a dramatic impact on quality of life. The current treatment strategies, often employed independently by the neurologist and gastroenterologist, raise the question of whether such patients are being treated optimally when siloed in one specialty. Neuroimmunogastroenterology lies at the borderlands of medical specialties, and there are few resources to guide neurologists in this area. Here, we provide an overview highlighting the potential mechanisms of crosstalk between immune-mediated neurological disorders and gastrointestinal dysfunction.
PMID: 32849234 [PubMed]
Hyperphosphatemia Secondary to the Selective Fibroblast Growth Factor Receptor 1-3 Inhibitor Infigratinib (BGJ398) Is Associated with Antitumor Efficacy in Fibroblast Growth Factor Receptor 3-altered Advanced/Metastatic Urothelial Carcinoma.
Eur Urol. 2020 Aug 23;:
Authors: Lyou Y, Grivas P, Rosenberg JE, Hoffman-Censits J, Quinn DI, Petrylak DP, Galsky M, Vaishampayan U, De Giorgi U, Gupta S, Burris H, Rearden J, Li A, Wang H, Reyes M, Moran S, Daneshmand S, Bajorin D, Pal SK
Abstract
BACKGROUND: Infigratinib (BGJ398) is a potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor with significant activity in metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. It can cause hyperphosphatemia due to the "on-target" class effect of FGFR1 inhibition.
OBJECTIVE: To investigate the relationship between hyperphosphatemia and treatment response in patients with mUC.
INTERVENTION: Oral infigratinib 125 mg/d for 21 d every 28 d.
DESIGN, SETTING, AND PARTICIPANTS: Data from patients treated with infigratinib in a phase I trial with platinum-refractory mUC and activating FGFR3 alterations were retrospectively analyzed for clinical efficacy in relation to serum hyperphosphatemia. The relationship between plasma infigratinib concentration and phosphorous levels was also assessed.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical outcomes were compared in groups with/without hyperphosphatemia.
RESULTS AND LIMITATIONS: Of the 67 patients enrolled, 48 (71.6%) had hyperphosphatemia on one or more laboratory tests. Findings in patients with versus without hyperphosphatemia were the following: overall response rate 33.3% (95% confidence interval [CI] 20.4-48.4) versus 5.3% (95% CI 0.1-26.0); disease control rate 75.0% (95% CI 60.4-86.4) versus 36.8% (95% CI 16.3-61.6). This trend was maintained in a 1-mo landmark analysis. Pharmacokinetic/pharmacodynamic analysis showed that serum phosphorus levels and physiologic infigratinib concentrations were correlated positively. Key limitations include retrospective design, lack of comparator, and limited sample size.
CONCLUSIONS: This is the first published study to suggest that hyperphosphatemia caused by FGFR inhibitors, such as infigratinib, can be a surrogate biomarker for treatment response. These findings are consistent with other reported observations and will need to be validated further in a larger prospective trial.
PATIENT SUMMARY: Targeted therapy is a new paradigm in treating bladder cancer. In a study using infigratinib, a drug that targets mutations in a gene called fibroblast growth factor receptor 3 (FGFR3), we found that elevated levels of phosphorous were associated with greater clinical benefit. In the future, these data may help inform treatment strategies.
PMID: 32847703 [PubMed - as supplied by publisher]
miR-125a-5p Regulates Megakaryocyte Proplatelet Formation Via the Actin Bundling Protein L-Plastin.
Blood. 2020 Jul 07;:
Authors: Bhatlekar S, Manne BK, Basak I, Edelstein LC, Tugolukova E, Stoller ML, Cody MJ, Morley SC, Nagalla S, Weyrich AS, Rowley JW, O'Connell RM, Rondina MT, Campbell RA, Bray PF
Abstract
There is heritability to inter-individual variation in platelet count, and better understanding of the regulating genetic factors may provide insights for thrombopoiesis. MicroRNAs (miRs) regulate gene expression in health and disease, and megakaryocytes (MKs) deficient in miRs have lower platelet counts, but there is a limited information about the role of miRs in normal human MK and platelet production. Using genome-wide miR profiling, we observed strong correlations among human bone marrow MKs, platelets and differentiating cord blood-derived MK cultures, and identified MK miR-125a-5p as associated with human platelet number but not leukocyte or hemoglobin levels. Overexpression and knock-down studies showed miR-125a-5p positively regulated human MK proplatelet (PP) formation in vitro. Inhibition of miR-125a-5p in vivo lowered murine platelet counts. Analyses of MK and platelet transcriptomes identified LCP1 as a miR-125a-5p target. LCP1 encodes the actin-bundling protein, L-plastin, not previously studied in MKs. We show miR-125a-5p directly targets and reduces expression of MK L-plastin. Overexpression and knock-down studies show L-plastin promotes MK progenitor migration, but negatively correlates with human platelet count and inhibits MK PP formation. This work provides the first evidence for the actin-bundling protein, L-plastin, as a regulator of human MK PP formation via inhibition of the late-stage MK invagination system, podosome and PP formation, and PP branching. We also provide resources of primary and differentiating MK transcriptomes and miRs associated with platelet counts. miR-125a-5p and L-plastin may be relevant targets for increasing in vitro platelet manufacturing and for managing quantitative platelet disorders.
PMID: 32844999 [PubMed - as supplied by publisher]
The long-term effects of anti-vascular endothelial growth factor therapy on the optical coherence tomography angiographic appearance of neovascularization in age-related macular degeneration.
Int J Retina Vitreous. 2020;6:39
Authors: Levine ES, Custo Greig E, Mendonça LSM, Gulati S, Despotovic IN, Alibhai AY, Moult E, Muakkassa N, Quaranta-El Maftouhi M, El Maftouhi A, Chakravarthy U, Fujimoto JG, Baumal CR, Witkin AJ, Duker JS, Hartnett ME, Waheed NK
Abstract
Background: The short-term effects of anti-vascular endothelial growth factor (anti-VEGF) treatment on macular neovascularization (MNV) morphology is well described, but long-term studies on morphologic changes and correlation of such changes to the type of MNV have not been conducted. This study aims to determine if different types of MNVs in neovascular AMD (nAMD) behave differently with anti-VEGF treatment as visualized on optical coherence tomography angiography (OCTA).
Methods: Treatment-naïve nAMD patients were retrospectively screened for baseline and follow-up OCTA imaging 10 or more months after initial treatment. Images were graded for MNV type, area, activity, mature versus immature vessels, vessel density, presence of atrophy, atrophy location and area. Growth rate was calculated as the percent change in lesion area from baseline over the years of follow-up. In addition, the occurrence of complete regression and the percent of lesions that grew, remained stable, and shrunk per type was also evaluated.
Results: Forty-three eyes from 43 patients with a mean follow-up of 2 years were evaluated. On structural OCT, 26 lesions were classified as pure type 1 MNVs, 12 MNVs had a type 2 component, and 5 MNVs had a type 3 component. Of these cases, 2 mixed-type MNVs were considered to have completely regressed. There was no significant differences in MNV area and growth rate between type 1 and type 2 lesions, but all cases of type 3 lesions shrunk in the follow-up period. There was no correlation between the number of injections per year and growth rate, endpoint MNV area or endpoint activity status for any MNV type. There was no significant association between the development of atrophy and the number of injections, baseline MNV area, baseline vessel density, or lesion growth rate.
Conclusions: In nAMD, complete regression of an MNV network exposed to anti-VEGF is rare. This work emphasizes the role of anti-VEGF as anti-leakage rather than vascular regression agents in nAMD.
PMID: 32844038 [PubMed]
In vitro studies provide insight into effects of Dicer-2 helicase mutations in Drosophila melanogaster.
RNA. 2020 Aug 25;:
Authors: Donelick HM, Talide L, Bellet M, Aruscavage J, Lauret E, Aguiar E, Marques JT, Meignin C, Bass BL
Abstract
In vitro, Drosophila melanogaster Dicer-2 (Dcr-2) uses its helicase domain to initiate processing of dsRNA with blunt (BLT) termini, and its Platform•PAZ domain to initiate processing of dsRNA with 3' overhangs (ovrs). To understand the relationship of these in vitro observations to roles of Dcr-2 in vivo, we compared in vitro effects of two helicase mutations to their impact on production of endogenous and viral siRNAs in flies. Consistent with the importance of the helicase domain in processing BLT dsRNA, both point mutations eliminated processing of BLT, but not 3'ovr, dsRNA in vitro. However, the mutations had different effects in vivo. A point mutation in the Walker A motif of the Hel1 subdomain, G31R, largely eliminated production of siRNAs in vivo, while F225G, located in the Hel2 subdomain, showed reduced levels of endogenous siRNAs, but did not significantly affect virus-derived siRNAs. In vitro assays monitoring dsRNA cleavage, dsRNA binding, ATP hydrolysis, and binding of the accessory factor Loquacious-PD, provided insight into the different effects of the mutations on processing of different sources of dsRNA in flies. Our in vitro studies suggest effects of the mutations in vivo relate to their effects on ATPase activity, dsRNA binding, and interactions with Loquacious-PD. Our studies emphasize the importance of future studies to characterize dsRNA termini as they exist in drosophila and other animals.
PMID: 32843367 [PubMed - as supplied by publisher]
Comparison of International Classification of Diseases and Related Health Problems, Tenth Revision Codes With Electronic Medical Records Among Patients With Symptoms of Coronavirus Disease 2019.
JAMA Netw Open. 2020 08 03;3(8):e2017703
Authors: Crabb BT, Lyons A, Bale M, Martin V, Berger B, Mann S, West WB, Brown A, Peacock JB, Leung DT, Shah RU
Abstract
Importance: International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes are used to characterize coronavirus disease 2019 (COVID-19)-related symptoms. Their accuracy is unknown, which could affect downstream analyses.
Objective: To compare the performance of fever-, cough-, and dyspnea-specific ICD-10 codes with medical record review among patients tested for COVID-19.
Design, Setting, and Participants: This cohort study included patients who underwent quantitative reverse transcriptase-polymerase chain reaction testing for severe acute respiratory syndrome coronavirus 2 at University of Utah Health from March 10 to April 6, 2020. Data analysis was performed in April 2020.
Main Outcomes and Measures: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ICD-10 codes for fever (R50*), cough (R05*), and dyspnea (R06.0*) were compared with manual medical record review. Performance was calculated overall and stratified by COVID-19 test result, sex, age group (<50, 50-64, and >64 years), and inpatient status. Bootstrapping was used to generate 95% CIs, and Pearson χ2 tests were used to compare different subgroups.
Results: Among 2201 patients tested for COVD-19, the mean (SD) age was 42 (17) years; 1201 (55%) were female, 1569 (71%) were White, and 282 (13%) were Hispanic or Latino. The prevalence of fever was 66% (1444 patients), that of cough was 88% (1930 patients), and that of dyspnea was 64% (1399 patients). For fever, the sensitivity of ICD-10 codes was 0.26 (95% CI, 0.24-0.29), specificity was 0.98 (95% CI, 0.96-0.99), PPV was 0.96 (95% CI, 0.93-0.97), and NPV was 0.41 (95% CI, 0.39-0.43). For cough, the sensitivity of ICD-10 codes was 0.44 (95% CI, 0.42-0.46), specificity was 0.88 (95% CI, 0.84-0.92), PPV was 0.96 (95% CI, 0.95-0.97), and NPV was 0.18 (95% CI, 0.16-0.20). For dyspnea, the sensitivity of ICD-10 codes was 0.24 (95% CI, 0.22-0.26), specificity was 0.97 (95% CI, 0.96-0.98), PPV was 0.93 (95% CI, 0.90-0.96), and NPV was 0.42 (95% CI, 0.40-0.44). ICD-10 code performance was better for inpatients than for outpatients for fever (χ2 = 41.30; P < .001) and dyspnea (χ2 = 14.25; P = .003) but not for cough (χ2 = 5.13; P = .16).
Conclusions and Relevance: These findings suggest that ICD-10 codes lack sensitivity and have poor NPV for symptoms associated with COVID-19. This inaccuracy has implications for any downstream data model, scientific discovery, or surveillance that relies on these codes.
PMID: 32797176 [PubMed - indexed for MEDLINE]
