tbuckley/cabot-search huggingface dataset:
APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa
Authors: Raymond J. Cho, Ludmil B. Alexandrov, Nicoline Y. den Breems, Velina S. Atanasova, Mehdi Farshchian, Elizabeth Purdom, Tran N. Nguyen, Cristian Coarfa, Kimal Rajapakshe, Marco Prisco, Joya Sahu, Patrick Tassone, Evan J. Greenawalt, Eric A. Collisson, Wei Wu, Hui Yao, Xiaoping Su, Christina Guttmann-Gruber, Josefina Piñón Hofbauer, Raabia Hashmi, Ignacia Fuentes, Stephen C. Benz, Justin Golovato, Erik A. Ehli, Christel M. Davis, Gareth E. Davies, Kyle R. Covington, Dedee F. Murrell, Julio C. Salas-Alanis, Francis Palisson, Anna L. Bruckner, William Robinson, Cristina Has, Leena Bruckner-Tuderman, Matthias Titeux, Marcel F. Jonkman, Elham Rashidghamat, Su M. Lwin, Jemima E. Mellerio, John A. McGrath, Johann W. Bauer, Alain Hovnanian, Kenneth Y. Tsai, Andrew P. South
Journal: Science Translational Medicine (2018)

Early-onset squamous cell carcinoma in recessive dystrophic epidermolysis bullosa patients is characterized by APOBEC mutagenesis.
Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular Disease
Authors: Shuaib M. Abdullah, Laura F. Defina, David Leonard, Carolyn E. Barlow, Nina B. Radford, Benjamin L. Willis, Anand Rohatgi, Darren K. McGuire, James A. de Lemos, Scott M. Grundy, Jarett D. Berry, Amit Khera
Journal: Circulation (2018)

Background: The associations of low-density lipoprotein cholesterol (LDL-C) with cardiovascular disease (CVD) and coronary heart disease mortality in an exclusively low estimated 10-year risk group are not well delineated. We sought to determine the long-term associations of various LDL-C and non–high-density lipoprotein cholesterol (HDL-C) thresholds and CVD and coronary heart disease mortality in a large, low 10-year risk cohort. Methods: The study sample included participants of the CCLS (Cooper Center Longitudinal Study) without a history of CVD or diabetes mellitus and defined as low risk (&lt;7.5%) for 10-year atherosclerotic CVD events at baseline based on Pooled Cohort Risk Assessment Equations. The associations of fasting LDL-C and non–HDL-C with CVD mortality were tested with Cox proportional hazards models. Results: In 36 375 participants (72% men, median age 42) followed for a median of 26.8 years, 1086 CVD and 598 coronary heart disease deaths occurred. Compared with LDL-C &lt;100 mg/dL, LDL-C categories 100 to 129 mg/dL, 130 to 159 mg/dL, 160 to 189.9 mg/dL, and ≥190 mg/dL were associated with a significantly higher risk of CVD death, with hazard ratios of 1.4 (95% CI, 1.1–1.7), 1.3 (95% CI, 1.1–1.6), 1.9 (95% CI, 1.5–2.4), and 1.7 (95% CI, 1.3–2.3), and mean reductions in years free of CVD death of 1.8, 1.1, 4.3, and 3.9, respectively. After adjustment for atherosclerotic CVD risk factors, LDL-C categories 160 to 189 mg/dL and ≥190 mg/dL remained independently associated with CVD mortality, with hazard ratios of 1.7 (95% CI, 1.4–2.2) and 1.5 (95% CI, 1.2–2.1), respectively. In multivariable-adjusted models using non–HDL-C &lt;130 mg/dL as the reference, non–HDL-C 160 to 189 mg/dL, 190 to 219 mg/dL, and ≥220 mg/dL were significantly associated with CVD death, with hazard ratios of 1.3 (95% CI, 1.1–1.6), 1.8 (95% CI, 1.4–2.2), and 1.5 (95% CI, 1.2–2.0), respectively. Restricting the cohort to those with 10-year risk &lt;5% did not diminish the associations of LDL-C and non–HDL-C with CVD mortality. Conclusions: In a low 10-year risk cohort with long-term follow-up, LDL-C and non–HDL-C ≥160 mg/dL were independently associated with a 50% to 80% increased relative risk of CVD mortality. These findings may have implications for future cholesterol treatment paradigms.
Reply to Shanthikumar <i>et al.</i>: Azithromycin for Early <i>Pseudomonas</i> Infection in Cystic Fibrosis: Do the Benefits Outweigh the Harms?
Authors: George Retsch-Bogart, Nicole Mayer-Hamblett, Bonnie W. Ramsey
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Self‐Assembled Fluorescent Organic Nanomaterials for Biomedical Imaging
Authors: Kuo Zhang, Yu‐Juan Gao, Pei‐Pei Yang, Guo‐Bin Qi, Jing‐Ping Zhang, Lei Wang, Hao Wang
Journal: Advanced Healthcare Materials (2018)

Fluorescent nanomaterials, self-assembled from building blocks through multiple intermolecular interactions show diversified structures and functionalities, and are potential fluorescence contrast agents/probes for high-performance biomedical imaging. Self-assembled nanomaterials exhibit high stability, long circulation time, and targeted biological distribution. This review summarizes recent advances of self-assembled nanomaterials as fluorescence contrast agents/probes for biomedical imaging. The self-assembled nanomaterials are classified into two groups, i.e., ex situ and in situ construction of self-assembled nanomaterials. The advantages of ex situ as well as in situ constructed nanomaterials for biomedical applications are discussed thoroughly. The directions of future developments for self-assembled nanomaterials are provided.
Attenuated Joint Tissue Damage Associated With Improved Synovial Lymphatic Function Following Treatment With Bortezomib in a Mouse Model of Experimental Posttraumatic Osteoarthritis
Authors: Wensheng Wang, Xi Lin, Hao Xu, Wen Sun, Echoe M. Bouta, Michael J. Zuscik, Di Chen, Edward M. Schwarz, Lianping Xing
Journal: Arthritis & Rheumatology (2018)

To investigate the roles of the synovial lymphatic system in the severity and progression of joint tissue damage and functional responses of synovial lymphatic endothelial cells (LECs) to macrophage subsets, and to evaluate the therapeutic potential of the proteasome inhibitor bortezomib (BTZ) in a mouse model of experimental posttraumatic osteoarthritis (OA).C57BL/6J wild-type mice received a meniscal ligamentous injury to induce posttraumatic knee OA. Lymphangiogenesis was blocked by a vascular endothelial growth factor receptor 3 (VEGFR-3) neutralizing antibody. Synovial lymphatic drainage was examined by near-infrared imaging. Joint damage was assessed by histology. RNA-sequencing and pathway analyses were applied to synovial LECs. Macrophage subsets in the mouse synovium were identified by flow cytometry and immunofluorescence staining. M1 and M2 macrophages were induced from mouse bone marrow cells, and their effects on LECs were examined in cocultures in the presence or absence of BTZ. The effects of BTZ on joint damage, LEC inflammation, and synovial lymphatic drainage were examined.Injection of a VEGFR-3 neutralizing antibody into the joints of mice with posttraumatic knee OA reduced synovial lymphatic drainage and accelerated joint tissue damage. Synovial LECs from the mouse OA joints had dysregulated inflammatory pathways and expressed high levels of inflammatory genes. The number of M1 macrophages was increased in the knee joints of mice with posttraumatic OA, thereby promoting the expression of inflammatory genes by LECs; this effect was blocked by BTZ. Treatment with BTZ decreased cartilage loss, reduced the expression of inflammatory genes by LECs, and improved lymphatic drainage in the knee joints of mice with posttraumatic OA.Experimental posttraumatic knee OA is associated with decreased synovial lymphatic drainage, increased numbers of M1 macrophages, and enhanced inflammatory gene expression by LECs, all of which was improved by treatment with BTZ. Intraarticular administration of BTZ may represent a new therapy for the restoration of synovial lymphatic function in subjects with posttraumatic knee OA.
Relationship Among Fatty Liver, Specific and Multiple‐Site Atherosclerosis, and 10‐Year Framingham Score
Authors: Raluca Pais, Alban Redheuil, Philippe Cluzel, Vlad Ratziu, Philippe Giral
Journal: Hepatology (2018)

Despite a well‐documented increase in the prevalence of subclinical atherosclerosis in patients with steatosis, the relationship among steatosis and atherosclerosis, specific atherosclerotic sites, multiple‐site atherosclerosis, and cardiovascular risk prediction is incompletely understood. We studied the relationship among steatosis, atherosclerosis site, multiple‐site atherosclerosis, coronary artery calcification (CAC), and 10‐year Framingham Risk Score (FRS) in 2,554 patients with one or more cardiovascular risk factors (CVRF), free of cardiovascular events and other chronic liver diseases, and drinking less than 50 g alcohol/day. All patients underwent arterial ultrasound (carotid [CP] and femoral [FP] plaques defined as intima‐media thickness (IMT) &gt; 1.5 mm), coronary computed tomography scan (severe CAC if ≥ 100), 10‐year FRS calculation, and steatosis detection by the fatty liver index (FLI, present if score ≥ 60). Patients with steatosis (36% of total) had higher prevalence of CP (50% versus 45%, P = 0.004) and higher CAC (181 ± 423 versus 114 ± 284, P &lt; 0.001) but similar prevalence of FP (53% versus 50%, P = 0.099) than patients without steatosis. Steatosis was associated with carotid IMT and CAC, but not with FP, independent of age, diabetes, hypertension, and tobacco use ( P &lt; 0.001). Fifty‐three percent of patients had at least 2‐site atherosclerosis and steatosis was associated with at least 2‐site atherosclerosis independent of age and CVRF (odds ratio = 1.21, 95% confidence interval 1.01‐1.45, P = 0.035). Sixty‐four percent of patients with steatosis had a FRS score of 10% or more. FLI was associated with FRS beyond the CVRF or the number of atherosclerosis sites ( P &lt; 0.001). Adding FLI to CVRF predicted an FRS greater than or equal to 10% better than CVRF alone (area under the receiver operating characteristic curve = 0.848 versus 0.768, P &lt; 0.001). Conclusion: Steatosis is associated with carotid and coronary, but not femoral atherosclerosis, and with cardiovascular mortality risk. The multiple‐site involvement and quantitative tonic relationship could reinforce the prediction of cardiovascular mortality or events over classical CVRF or imaging‐based detection of atherosclerosis.
Abstract 16008: Association Between Statin Exposure and Diabetes Incidence in a Nationwide Claims Database
Authors: Tariq Ali Ahmad, Guodong Liu, Peter Alagona Jr, Cynthia H Chuang, Andrew J Foy, Syeda M Bokhari, Douglas Leslie
Journal: Circulation (2015)

Background: Statins reduce risk for cardiovascular events; however, concerns have been raised about their association with diabetes mellitus (DM). We used a national health insurance claims database, which captures the health care experiences of &gt;50 million privately insured individuals, to determine if there was a significant association between statin exposure and incidence of DM when controlling for multiple covariates not accounted for in prior analyses. Method: A cohort of non-diabetic patients who initiated treatment with a statin was matched with a control group of patients who did not receive a statin based on age, gender and geographic location. Patients were then followed for a minimum of 2 years to determine whether they developed DM (i.e. ≥2 ICD-9 code for DM and/or pharmacy claim for DM medications). In addition to Pearson chi-square tests for unadjusted comparisons, Cox proportional hazard models were used to examine the relationship between statin exposed and unexposed groups adjusting for HTN, CAD, PAD, CVA, CHF, hyperlipidemia and healthcare costs in the prior year. Predefined subgroup analyses were performed based on age, gender, obesity status and statin type. Results: The study population included 231,478 matched pairs of exposed and unexposed subjects (age 51.3 ±7.5 years; follow up duration of 1140 ±212.77 days). Statin exposure was associated with an increased DM incidence [adjusted HR 2.236 (2.182, 2.291)]. However, the effect was significant only after the age of ≥50 years [for age groups 30-39, 1.0 (0.86, 1.163); 40-49, 1.053 (0.91, 1.22); 50-59, 1.19 (1.028, 1.374); 60-69, 1.276 (1.101, 1.478) with age group 20-29 as reference]. Compared to males, statin-exposed females had an increased incidence of DM [HR 1.08 (1.06, 1.10)]. In obese individuals DM incidence was 1.820 (1.610, 2.057) in statin exposed versus unexposed. All statin types were associated with increased DM incidence without any statistically significant differences between them. Conclusion: In this large study, there was an association between statin exposure and diabetes incidence. These findings are consistent with other data reported in literature and strengthen the causal link between statin exposure and diabetes.
Abstract 15410: ACE Gene Dosage Influences the Magnitude of Blood Pressure Increase After Chronic High Fructose Intake: Role of Resistance Arteries
Authors: Ivana C Moraes-Silva, Leandro E de Souza, Maria Claudia Irigoyen, Dulce E Casarini
Journal: Circulation (2015)

We investigated the mechanisms involved in blood pressure (BP) increase induced by chronic high fructose (F) intake and its association with angiotensin converting enzyme (ACE) dosage. Male mice harbouring 1, 2 or 3 copies of the ACE gene received F (100g/l) or tap water (C) for 8 weeks. Glucose tolerance and BP were evaluated. BP variability was analyzed in frequency domain. Mesenteric resistance artery reactivity to noradrenaline (Nor; 0.1nM - 1μM), and acetylcholine (Ach; 1nM - 10μM, after or not L-NAME incubation, 100 μM) were studied in an isometric myograph (DMT, 620M). Glucose intolerance was seen in all F groups vs. C (1 copy: 100+3 vs. F=198+5; 2 copies: 121+4 vs. F=201+8; 3 copies: 86+4 vs. F=212+5 mg/dl at the 120thmin after 1.5 g/Kg ip glucose overload). Systolic BP increased in all F-fed mice (mean C=112+2; F:1 copy=119+3, 2 copies=123+2, 3 copies=129+2 mmHg), with a significant augment in 3-copy group vs. 1 and 2-copy mice. Not only BP variability (1 copy: 39+3 vs. F=57+2; 2 copies: 38+2 vs. F=59+3; 3 copies: 40+3 vs. F=73+7 mmHg 2 ) but also its sympathetic component (LF; 1 copy: 5+1 vs. F=12+3; 2 copies: 6+2 vs. F=19+3; 3 copies: 7+2 vs. F=31+5 %) increased in all F groups, with a more pronounced augment in 3-copy mice vs. 1 and 2. Moreover, F-fed 3-copy mice reactivity to Nor was superior than the other groups (1 copy: 170+5; 2 copies: 190+7; 3 copies: 214+10 %) while Ach-induced relaxation was more reduced in 3-copy mice than 1 and 2 (mean C: 76+5%; F: 1 copy=58+8, 2 copies=47+6, 3 copies=36+5 %). L-NAME in F-fed groups significantly blocked ~95% of Ach relaxation in 3-copy mice vs. 75 and 82% in 1 and 2-copy mice, respectively. Additionally, BP variability was negatively correlated to Ach maximal relaxation (r 2 =0.75) and positively correlated to Nor maximal constriction (r 2 =0.78) while glucose levels in the tolerance test were also negatively correlated to Ach maximal relaxation (r 2 =0.72) and positively correlated to Nor maximal constriction (r 2 =0.9). In conclusion, F-induced BP increase is influenced by ACE levels in mice. Increased BP variability and glucose intolerance are highly associated with microvascular dysfunction.
Abstract 12831: Coupling Factor 6 Accelerates Aging by Synchronizing Primary Aging Hallmarks Such as Telomere Attrition and a Blocking Effect of Atpase Inhibitory Factor 1
Authors: Tomohiro Osanai, Makoto Tanaka, Hirofumi Tomita, Akihiro Kobayashi, Ken Okumura
Journal: Circulation (2016)

Introduction: A transient low pH stressor gives great impacts to the nucleus, but little is known about the effect of chronic pH stressor on aging and lifespan. We identified that coupling factor 6 (CF6) induces long-term low pH in the cells by enhanced proton import through ecto-F 1 F o complex and by reduced proton export through inhibition of Na + -K + ATPase. We analyzed whether and how CF6-induced acidosis affects aging and lifespan, being focused on primary aging hallmarks of genomic instability, telomere attrition, epigenetic alterations, and defective proteostasis. Methods and Results: CF6 overexpressing transgenic mice (TG, n=20) manifested early senescence-associated phenotypes such as signs of hair graying and sparseness, resulting in shortened lifespan compared with wild-type mice (WT, n=13) (median values; 108±2 vs 131±11 weeks, p&lt;0.05). Long-term low pH disturbed nuclear envelope protein emerin as genomic instability and elevated aging-associated markers of global hypo-methylated DNA, histone 3 lysine 4 (H3K4) and H4K20 trimethylation, and H4K5 acetylation by decreased nucleoplasmic HDAC3, a binding partner of emerin. Leukocyte telomere length was shorter in TG compared with WT at the age of 100 weeks. Microarray analysis showed that a target molecule of three primary hallmarks was autophagy-related Atg7 that is commonly decreased in TG tissues. Chronic acidosis decreased and acetylated Atg7 protein in the TG heart and kidney without affecting insulin signaling. In TG cells, LC3 II and lysosome were located more weakly and diffusely in the cytoplasm compared with strong peri-nuclear staining in WT, being dependent on acetylation of LC3 II that inhibits cytoplasmic translocation. ATPase inhibitory factor 1 (IF1), an endogenous inhibitor for CF6, repaired subcellular localization of LC3 II and lamp1, and restored the decrease in Atg7 and emerin and the increase in H4K5ac. ChIP assay revealed that PCR in the repressor-binding region of Atg7 promoter at -441 through -763 was increased by CF6 after immuneprecipitated with anti-acetyl H4K5, anti-trimethyl H3K4, and H4K20 antibodies. Conclusions: Long-term low pH switches on aging by onset and synchronization of primary aging hallmarks, and provides a novel target for anti-aging therapy.
Ethical Considerations in the Manufacture, Sale, and Distribution of Genome Editing Technologies
Authors: Jeremy Sugarman, Supriya Shivakumar, Martha Rook, Jeanne F. Loring, Christoph Rehmann-Sutter, Jochen Taupitz, Jutta Reinhard-Rupp, Steven Hildemann
Journal: The American Journal of Bioethics (2018)
Enterocolitis due to immune checkpoint inhibitors: a systematic review
Authors: Emilie Soularue, Patricia Lepage, Jean Frederic Colombel, Clelia Coutzac, David Faleck, Lysiane Marthey, Michael Collins, Nathalie Chaput, Caroline Robert, Franck Carbonnel
Journal: Gut (2018)

Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1 (PD-1)/ligand are increasingly used to treat several types of cancer. These drugs enhance antitumour T-cell activity and therefore induce immune-related adverse effects (irAE), of which gastrointestinal (GI) irAE are among the most frequent and severe. This systematic literature review summarises the clinical manifestations, management and pathophysiology of GI irAE due to immune checkpoint inhibitors. GI irAE induced by anti-CTLA-4 are frequent, potentially severe and resemble IBD, whereas those induced by PD-1 blockade seem to be less frequent and clinically more diverse. Baseline symbiotic gut microbiota is associated with an enhanced antitumour response to immune checkpoint inhibitors and an increased susceptibility to developing enterocolitis, in patients treated with anti-CTLA-4. These findings open new perspectives for possible manipulation of the gut microbiota in order to better identify responders to immune checkpoint inhibitors and to increase their efficacy and safety.
Interaction between the microbiome and TP53 in human lung cancer
Authors: K. Leigh Greathouse, James R. White, Ashely J. Vargas, Valery V. Bliskovsky, Jessica A. Beck, Natalia von Muhlinen, Eric C. Polley, Elise D. Bowman, Mohammed A. Khan, Ana I. Robles, Tomer Cooks, Bríd M. Ryan, Noah Padgett, Amiran H. Dzutsev, Giorgio Trinchieri, Marbin A. Pineda, Sven Bilke, Paul S. Meltzer, Alexis N. Hokenstad, Tricia M. Stickrod, Marina R. Walther-Antonio, Joshua P. Earl, Joshua C. Mell, Jaroslaw E. Krol, Sergey V. Balashov, Archana S. Bhat, Garth D. Ehrlich, Alex Valm, Clayton Deming, Sean Conlan, Julia Oh, Julie A. Segre, Curtis C. Harris
Journal: Genome biology (2018)

Abstract Background Lung cancer is the leading cancer diagnosis worldwide and the number one cause of cancer deaths. Exposure to cigarette smoke, the primary risk factor in lung cancer, reduces epithelial barrier integrity and increases susceptibility to infections. Herein, we hypothesize that somatic mutations together with cigarette smoke generate a dysbiotic microbiota that is associated with lung carcinogenesis. Using lung tissue from 33 controls and 143 cancer cases, we conduct 16S ribosomal RNA (rRNA) bacterial gene sequencing, with RNA-sequencing data from lung cancer cases in The Cancer Genome Atlas serving as the validation cohort. Results Overall, we demonstrate a lower alpha diversity in normal lung as compared to non-tumor adjacent or tumor tissue. In squamous cell carcinoma specifically, a separate group of taxa are identified, in which Acidovorax is enriched in smokers. Acidovorax temporans is identified within tumor sections by fluorescent in situ hybridization and confirmed by two separate 16S rRNA strategies. Further, these taxa, including Acidovorax , exhibit higher abundance among the subset of squamous cell carcinoma cases with TP53 mutations, an association not seen in adenocarcinomas. Conclusions The results of this comprehensive study show both microbiome-gene and microbiome-exposure interactions in squamous cell carcinoma lung cancer tissue. Specifically, tumors harboring TP53 mutations, which can impair epithelial function, have a unique bacterial consortium that is higher in relative abundance in smoking-associated tumors of this type. Given the significant need for clinical diagnostic tools in lung cancer, this study may provide novel biomarkers for early detection.
Abstract 13651: Angiotensin-Converting Enzyme Inhibitors Preserve Limb Function and Decrease Myofibrosis and Oxidative Damage in the Calf Muscle of Patients With Peripheral Artery Disease
Authors: Duy Ha, George Casale, Panagiotis Koutakis, Mina Hanna, Stanley Swanson, Zhen Zhu, Evlampia Papoutsi, Iraklis Pipinos
Journal: Circulation (2015)

Introduction: A six-month treatment with the Angiotensin-Converting Enzyme Inhibitor (ACEI) Ramipril improved the walking ability of Peripheral Artery Disease (PAD) patients, but the mechanism remains unknown. ACEI have been shown to reduce fibrosis in heart and kidney and improve arterial compliance. We have identified a myopathy in calf muscles of PAD patients, characterized by fibrosis and increased TGF-β1 produced exclusively in smooth muscle cells (SMC) of microvessels. These events were linked to myofiber oxidative damage and reduced myofiber cross-sectional area. Hypothesis: The myopathy of PAD patients taking ACEI is improved compared to patients who are not taking ACEI and this improvement is associated with improved walking ability. Methods: Calf muscle biopsies, from PAD patients (Fontaine Stage II) taking ACEI (ACEI+) and those who were not (ACEI-), were fixed, embedded in paraffin, sectioned at 4 microns and slide mounted. Oxidative damage (carbonyl groups) (N=13 for ACEI- and 22 for ACEI+) and TGF-β1 (N=13 for ACEI- and 20 for ACEI+) were analyzed by quantitative fluorescence microscopy and expressed as grey scale units (gsu). Myofiber cross-sectional area was determined from fluorescence-labeled sarcolemma. Fibrosis was determined as collagen density (gsu) by multi-spectral analysis of slide specimens (N=13 for ACEI- and 20 for ACEI+) stained with Mason Trichrome. Limb function was assessed by the six-minute walking distance (N=28 for ACEI- and 20 for ACEI+). Results: Compared to ACEI- patients, ACEI+ patients had reduced TGF-β1 (4.25 gsu +/- 0.69 vs. 1.51 gsu +/- 0.23; p = 0.001) and decreased collagen density (2067 gsu +/- 88 vs. 1671 gsu +/- 51; p &lt; 0.001). Carbonyl adducts were reduced in myofibers of ACEI+ compared to ACEI- patients (1584 gsu +/- 55 vs. 1779 gsu +/- 58; p = 0.019) and myofiber cross sectional area was increased (4629 μm2 +/- 285 vs. 3816 μm2 +/- 267; p = 0.023). Six-minute walking distance was greater in ACEI+ compared to ACEI- patients (333 m +/- 20 vs. 266 m +/- 16; p = 0.011). Conclusions: Improved walking distance of PAD patients taking ACEI is associated with improved calf muscle myopathy, determined as reduced TGF-β1 production, collagen density, and myofiber oxidative damage, and increased myofiber cross-sectional area.