Emery-Dreifuss muscular dystrophy with dilated cardiomyopathy preceding skeletal muscle symptoms

Emery-Dreifuss muscular dystrophy is a slowly progressive skeletal muscle and joint disorder associated with cardiac complications. Dilated cardiomyopathy was the initial manifestation of Emery-Dreifuss muscular dystrophy in an 8-year-old girl. Despite normal muscle and myocardial biopsies, genetic testing revealed LMNA mutations. As Emery-Dreifuss muscular dystrophy is associated with minimal skeletal muscle weakness, cardiac complications can facilitate its diagnosis.

Transcriptomic analysis for pork color – the ham halo effect in biceps femoris

Pork color is a major indicator of product quality that guides consumerpurchasing decisions. Recently, industry has received an increase in consumercomplaints about the lightness and non-uniformity of ham color, primarilylighter color in the periphery termed “ham halo” that is not caused bymanufacturing procedures. This effect is seen in fresh and processed hams andthe outer, lighter muscle is associated with lower myoglobin concentration, pHand type I fibers. The objective of this study was to identify differences ingene expression profiles between light and normal colored portions of biceps femoris muscle from pork hams.RNA-sequencing was performed for paired light and normal colored muscle samplesfrom 10 animals showing the ham halo effect. Over 50 million paired-end reads(2x75bp) per library were obtained. An average of 99.74% of trimmed high-qualityreads were mapped to the Sscrofa 11.1 genome assembly. Differentially expressedgenes (DEGs) were identified using both the DESeq2 and GFOLD software packages.A total of 14,049 genes were expressed in bicepsfemoris; 13,907 were expressed in both light and normal muscle, while 56and 86 genes were only expressed in light and normal muscle, respectively. Analysiswith DESeq2 identified 392 DEGs with 359 genes being more highly expressed innormal colored muscle. A total of 61 DEGs were identified in the DESeq2analysis and also were identified in at least 7 of the 10 individual animalanalyses. All 61 of these DEGs were up-regulated in normal colored muscle. Geneontology (GO) enrichment analysis of DEGs identified the transition betweenfast and slow fibers, and skeletal muscle adaptation and contraction as themost significant biological process terms. The evaluation of gene expression byRNA-Seq identified DEGs between regions of the biceps femoris with the ham halo effect that are associated with thevariation in pork color.

Association of plasma FGF21 levels with muscle mass and muscle strength in a national multicentre cohort study: Korean Frailty and Aging Cohort Study

Background despite of the beneficial effects of fibroblast growth factor (FGF) 21 in several metabolic diseases, the association of plasma FGF21 with muscle mass and muscle strength is still unclear. Methods a total of 386 community-dwelling older adults aged 70–84 years were analysed. Appendicular skeletal muscle mass was measured using dual-energy X-ray absorptiometry and normalised to the square of height (ASM/ht2). Muscle strength was assessed using the hand grip strength (HGS) test. The definitions of low muscle mass (LMM) and low muscle strength (LMS) were based on the Asian Working Group for Sarcopenia. Results plasma FGF21 was significantly lower in participants with LMM than in those with normal muscle mass (289.7 [192.4–448.3] vs. 345.6 [238.6–503.2] pg/ml, P = 0.008). In contrast, the LMS group had a significantly higher plasma FGF21 level than the normal muscle strength group (369.7 [244.4–591.1] vs. 309.7 [205.3–444.8] pg/ml, P = 0.006). In the partial correlation analysis, following adjustment for age, sex and body mass index, FGF21 levels had no significant association with ASM/ht2, but were negatively associated with HGS (r = −0.112, P = 0.029). Furthermore, after multivariate adjustment for confounding variables, the odds ratio for the risk of LMS was 2.32 (95% confidence interval 1.20–4.46) when comparing the highest with the lowest FGF21 quartile. Conclusions circulating FGF21 levels are negatively associated with muscle strength but are not independently correlated with muscle mass.

Surfaceome Profiling of Rhabdomyosarcoma Reveals B7-H3 as a Mediator of Immune Evasion

Novel therapeutic strategies are needed for the treatment of rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children. By using a combination of cell surface proteomics and transcriptomic profiling of RMS and normal muscle, we generated a catalog of targetable cell surface proteins enriched in RMS tumors. Among the top candidates, we identified B7-H3 as the major immunoregulatory molecule expressed by RMS tumors. By using a large cohort of tissue specimens, we demonstrated that B7-H3 is expressed in a majority of RMS tumors while not detected in normal human tissues. Through a deconvolution analysis of the RMS tumor RNA-seq data, we showed that B7-H3-rich tumors are enriched in macrophages M1, NK cells, and depleted in CD8+-T cells. Furthermore, in vitro functional assays showed that B7-H3 knockout in RMS tumor cells increases T-cell mediated cytotoxicity. Altogether, our study uncovers new potential targets for the treatment of RMS and provides the first biological insights into the role of B7-H3 in RMS biology, paving the way for the development of next-generation immunotherapies.

OS05.3.A Temporal muscle thickness as surrogate parameter of sarcopenia in newly diagnosed glioblastoma patients:translational imaging analysis of the CENTRIC EORTC 26071-22072 and CORE trials

BACKGROUND Temporal muscle thickness (TMT) was described as surrogate parameter of skeletal muscle mass. This study aimed to investigate the prognostic relevance of TMT in patients with newly diagnosed glioblastoma. MATERIAL AND METHODS TMT was assessed in cranial magnetic resonance images (MRI) of 755 pts enrolled in the CENTRIC EORTC 26071-22072 study (n=508) and CORE study (n=247). Predefined sex-specific TMT cutoff values were used to categorize “patients at risk of sarcopenia” and “patients with normal muscle status” at baseline. Furthermore, patients were categorized according to the extent of TMT loss over time. Cox models adjusted for other explanatory variables were used to evaluate the associations with progression-free survival (PFS) and overall survival (OS). RESULTS Overall, 510/755 (67.6%) patients were categorized as “at risk of sarcopenia” and 245/755 (32.4%) patients had normal muscle status at baseline. In both study cohorts patient at risk of sarcopenia at baseline had significantly higher risk of progression and death than patients with normal muscle status (CENTRIC: PFS = HR 0.16, 95% CI: 0.12, 0.21, p<0.001; OS = HR 0.341, 95% CI: 0.27, 0.44, p < 0.001; CORE: PFS = HR 0.29, 95% CI: 0.21, 0.39, p<0.001; OS = HR 0.365, 95% CI: 0.27, 0.49, p<0.001). In multivariate Cox models adjusted for other important prognostic parameters similar results were obtained. In patients at risk for sarcopenia the extent of TMT loss over time showed a significant inverse correlation with median OS times (CENTRIC: p < 0.001, CORE: p = 0.005, log-rank test), but not in patients with normal baseline muscle mass in both study cohorts (CENTRIC: p = 0.538, CORE: p = 0.28, log-rank test). CONCLUSION TMT identifies patients with newly diagnosed glioblastoma at risk for progressive sarcopenia and adverse outcomes. Early intervention for muscle mass preservation including exercise and resistance training as well as nutritional support may prevent skeletal muscle loss and improve patient outcome in this group of patients.

A Retrospective Cohort Study of Myosteatosis and Quality of Life in Head and Neck Cancer Patients

Head and neck cancer (HNC) treatment-related morbidity can be detrimental to quality of life (QOL). Myosteatosis is associated with poor QOL in multiple cancers. If predictive of poor QOL trajectories, myosteatosis would be a tool for clinicians to determine which patients may require additional support during treatment. The purpose of this study was to determine if pretreatment myosteatosis is associated with a poor QOL trajectory following treatment completion. Methods: In a retrospective cohort design, myosteatosis was determined from pretreatment CT scans. Both physical and global QOL score was assessed through patient interview on follow-up appointment. Demographic, cancer-specific, and social covariates were collected, reported, and considered as potential confounders. Results: The population of 163 patients was mostly male (82.2%) and white (91.4%) with oropharyngeal cancer (55.8%). Males with myosteatosis had a physical QOL score 46.84 points lower at one-year following treatment completion (p = 0.01) than those with normal muscle density (p = 0.01). Males with myosteatosis averaged 57.57 points lower at one-year post-treatment (p = 0.01) in global QOL scores. Conclusions: Over one year following completion of treatment, patients with myosteatosis reported worse physical and global QOL scores than patients with normal muscle density.

POS0832 A NOVEL GREY SCALE AND POWER DOPPLER ULTRASONOGRAPHIC SCORE FOR IDIOPATHIC INFLAMMATORY MYOPATHIES: SIENA MYOSITIS ULTRASOUND GRADING SCALE

Background:No clear-cut guidelines exist about the use of diagnostic procedures for idiopathic inflammatory myopathies (IIM) and only scanty and conflicting data report the use of ultrasound (US).Objectives:We aimed to assess if grey-scale (GS) and Power Doppler (PD) US, graded with a 0-3-points-scale, may be a reliable tool in a cohort of patients affected by IIM.Methods:We prospectively collected, since July to October 2020, all patients referred to Vasculitis and Myositis clinic, Rheumatology Unit, University of Siena, for suspected IIM, as well as patients with a previous, definite diagnosis of IIM and evaluated during follow-up or referred from other centers for a second opinion. All patients underwent US examination of both thighs in axial and longitudinal scans. Edema and atrophy, both assessed in GS, and PD, were graded with a 0-3-points-scale. Spearman test was used to identify the correlations between US and clinical and serological variables.Results:A total of 18 patients was included. Four of them were evaluated twice, at baseline and within 3 months of therapy. Muscle edema was found to be directly correlated with physician global assessment (PhGA), serum myoglobin and PD and negatively with disease duration. PD score was positively correlated to PhGA and negatively to disease duration. Muscle atrophy directly correlated with Myositis Damage Index and patients’ age. The single-thigh sub-analysis evidenced a direct correlation between PD score and Manual Muscle Test.Conclusion:In our cohort, we found that edema and PD are strictly related to early, active myositis, suggesting that an inflamed muscle should appear swollen, thickened and with Doppler signal. Conversely, muscle atrophy reflects the age of the patient and the overall severity of the disease. Such findings shed a new, promising, light in the role of US in diagnosis and monitoring of IIMs.Table 1.Siena Myositis Ultrasound Grading Scale (SMUGS).Grey-scale edemaGrey-scale atrophyPower Doppler0Normal muscle echotexture with hyperechoic septa and hypoechoic muscle fibers, conserved thickness.Normal muscle echotexture, with hyperechoic septa and hypoechoic muscle fibers, conserved thickness.No PD signal.1Focal hypoechoic areas, where septa are less evident. Conserved thickness.Focal heterogeneously hyperechoic areas, where septa are thicker and more evident, and muscle fibers are thinner. Conserved muscle thickness.One or two PD signals in at least one muscle (PD vascular spots, small vessels of homogenous diameters, vessel diameters approximately not superior to fibrous intramuscular septa)2Diffuse and heterogeneous hypo echogenicity (rectus femoris as hypoechoic or more than vastus intermedius), septa diffusely less evident. Conserved thickness.Diffuse and heterogeneously hyperechoic muscle, with thicker septa and thinner muscle fibers. Conserved muscle thickness.More than 2 PD signals for each muscle (as vascular spots, small vessels of homogenous diameters, vessel diameters approximately not superior to fibrous intramuscular septa).3Diffuse and heterogeneous hypo echogenicity (rectus femoris as hypoechoic or more than vastus intermedius), septa diffusely less evident. Increased thickness (rectus femoris became thicker than vastus intermedius).Diffuse and heterogeneously hyperechoic muscle, with thicker septa and thinner muscle fibers. Reduced muscle thickness.More than 2 PD signals for each muscle with larger diameter of the vessel (at least superior to fibrous intramuscular septa), or vessels with different diameters or branched vessels.Figure 1.Different PD findings (clockwise) in longitudinal anterior scans of the thigh: PD 3 in a patient with a recent diagnosis of anti-Mi2 DM; PD 2 in the same patient after one month of treatment with steroids and Methotrexate; PD 1 in a patient affected by anti-SAE DM, with a suspected disease flare; PD 0 in a patient affected by an advanced polymyositis diagnosed in 2000, currently not in treatment.Disclosure of Interests:None declared

Drug interaction evaluation of [99mTc]Tc-ketoconazole uptake with ketoconazole administration in Candidiasis mice model

The use of radiopharmaceuticals for infection detection has gained increasing attention for their application in nuclear medicine. The administration of [99mTc]Tc-ketoconazole may altere pharmacological aspects including interaction data with some antifungals especially ketoconazole as a common drug for candidiasis treatment. The current study investigated the ex vivo biodistribution and pharmacokinetic interaction of [99mTc]Tc-ketoconazole after ketoconazole administration in BALB/c mice. In this research,The [99mTc]Tc-ketoconazole was prepared with radiochemical purity 94.59% (n=3). The ex vivo biodistribution uptake in infected muscle as a target organ showed 0.16±0.13%ID/g for control, 0.17±0.12 for 1 h, and 0.05±0.04 for 3 h after ketoconazole administration. The Target/Non-Target (T/NT) ratio between infected muscle compared with normal muscle showed 1.19±0.13 for the control group, 2.56±1.71 for 1 h and 0.86±0.67 for 3 h. The ex vivo biodistribution also showed high radioactivity uptake on the liver, lung, spleen and kidney. Pharmacokinetics analysis using PKSolver showed [99mTc]Tc-ketoconazole half-life elimination (t1/2 beta) for the therapy group showed shorter elimination time 13.78±4.77 h compared with the control group 44.77±2.74 h after ketoconazole administration. Pharmacokinetics parameter change also occurred on the area under the curve of therapy group (AUC 0-inf) that is 26.10±18.97 %ID/g*h and maximum concentration (Cmax) 13.05±9.48 %ID/g which was related with radiopharmaceutical absorption rate. This study proves that based on biodistribution and pharmacokinetics evaluation, the [99mTc]Tc-ketoconazole application was recommended at 1 h post ketoconazole administration.

Histone H3K4me3 and H3K9me3 are super over-methylated in soft tissue sarcoma compared to normal muscle in patient-derived xenograft (PDX) mouse models: an indicator of cancer methionine addiction

Methionine addiction is a fundamental and general hallmark of cancer discovered by us almost a half-century ago [Proc Natl Acad Sci U S A 73 (1976) 1523-1527]. Methionine addiction is defined as the requirement, specific for cancer cells of all types, for exogenous methionine despite the normal ability to synthesize methionine from homocysteine. The methionine addiction of cancer is termed the Hoffman-effect, analogous to the Warburg-effect of the high glucose requirement of cancer cells. Methionine addiction is due to excess transmethylation reactions resulting in high methionine flux in cancer cells, which causes them to selectively arrest under methionine restriction due to depletion of free methionine and S-adenosyl methionine. Recently we have shown methionine-addicted cancer cells over-methylate histone H3 lysine marks which are not over-methylated in normal cells or in low-malignancy methionine-independent revertants derived from methionine-addicted cancer cells. In the present report, we show that in patient-derived xenograft (PDX) mouse models of the most common soft tissue sarcomas: myxofibrosarcoma, undifferentiated pleomorphic sarcoma (UPS) and liposarcoma, histone H3K4me3 and H3K9me3 are super over-methylated compared to normal muscle tissue. This new result is discussed along with our previous reports, regarding the potential of histone H3 over-methylation as a basis of malignancy.