The correspondence address for author Ping Hu were previously incomplete. The complete correspondence address for Ping Hu is shown below:
Department of Pediatric Orthopedics, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Guangzhou Laboratory, Guangzhou, China; Max Planck Center for Tissue Stem Cells and Regenerative Medicine, Bioland Laboratory, Guangzhou, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
{"title":"Corrigendum to Yang et al. J of Cachexia, Sarcopenia and Muscle, 13, 728–742. https://doi.org/10.1002/jcsm.12882","authors":"","doi":"10.1002/jcsm.13232","DOIUrl":"https://doi.org/10.1002/jcsm.13232","url":null,"abstract":"<p>The correspondence address for author Ping Hu were previously incomplete. The complete correspondence address for Ping Hu is shown below:</p><p>Department of Pediatric Orthopedics, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Guangzhou Laboratory, Guangzhou, China; Max Planck Center for Tissue Stem Cells and Regenerative Medicine, Bioland Laboratory, Guangzhou, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1586"},"PeriodicalIF":8.9,"publicationDate":"2023-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6183863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wouter R.P.H. van de Worp, Jan Theys, Alba Sanz González, Brent van der Heyden, Frank Verhaegen, Duncan Hauser, Florian Caiment, Hubertus J.M. Smeets, Annemie M.W.J. Schols, Ardy van Helvoort, Ramon C.J. Langen
Introduction
Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia.
Methods
Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-rasG12D; p53R172HΔG) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.
Results
Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (−13.7 ± 5.7%; P < 0.01), muscle mass (−13.8 ± 8.1%; P < 0.01) and muscle strength (−25.5 ± 10.5%; P < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32 and Trim63) and autophagy-lysosomal pathway (Gabarapl1 and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (P < 0.001) and CXCL1/KC (P < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal
{"title":"A novel orthotopic mouse model replicates human lung cancer cachexia","authors":"Wouter R.P.H. van de Worp, Jan Theys, Alba Sanz González, Brent van der Heyden, Frank Verhaegen, Duncan Hauser, Florian Caiment, Hubertus J.M. Smeets, Annemie M.W.J. Schols, Ardy van Helvoort, Ramon C.J. Langen","doi":"10.1002/jcsm.13222","DOIUrl":"https://doi.org/10.1002/jcsm.13222","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (<i>K-ras</i><sup><i>G12D</i></sup>; <i>p53</i><sup><i>R172HΔG</i></sup>) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (−13.7 ± 5.7%; <i>P</i> < 0.01), muscle mass (−13.8 ± 8.1%; <i>P</i> < 0.01) and muscle strength (−25.5 ± 10.5%; <i>P</i> < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (<i>Fbxo32</i> and <i>Trim63</i>) and autophagy-lysosomal pathway (<i>Gabarapl1</i> and <i>Bnip3</i>), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (<i>P</i> < 0.001) and CXCL1/KC (<i>P</i> < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (<i>P</i> < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1410-1423"},"PeriodicalIF":8.9,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13222","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6097676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tanja Krauss, Simone Heisz, Julius Honecker, Olga Prokopchuk, Marc Martignoni, Klaus-Peter Janssen, Melina Claussnitzer, Hans Hauner, Claudine Seeliger
Background
Cancer cachexia (CCx) is a complex and multi-organ wasting syndrome characterized by substantial weight loss and poor prognosis. An improved understanding of the mechanisms involved in the onset and progression of cancer cachexia is essential. How microRNAs contribute to the clinical manifestation and progression of CCx remains elusive. The aim of this study was to identify specific miRNAs related to organ-specific CCx and explore their functional role in humans.
Methods
miRNA patterns in serum and in cachexia target organs (liver, muscle and adipose tissue) from weight stable (N ≤ 12) and cachectic patients (N ≤ 23) with gastrointestinal cancer were analysed. As a first step, a miRNA array (158 miRNAs) was performed in pooled serum samples. Identified miRNAs were validated in serum and corresponding tissue samples. Using in silico prediction, related genes were identified and evaluated. The findings were confirmed in vitro by siRNA knock-down experiments in human visceral preadipocytes and C2C12 myoblast cells and consecutive gene expression analyses.
Results
Validating the results of the array, a 2-fold down-regulation of miR-122-5p (P = 0.0396) and a 4.5-fold down-regulation of miR-194-5p (P < 0.0001) in serum of CCx patients in comparison with healthy controls were detected. Only miR-122-5p correlated with weight loss and CCx status (P = 0.0367). Analysing corresponding tissues six muscle and eight visceral adipose tissue (VAT) cachexia-associated miRNAs were identified. miR-27b-3p, miR-375 and miR-424-5p were the most consistently affected miRNAs in tissues of CCx patients correlating negatively with the severity of body weight loss (P = 0.0386, P = 0.0112 and P = 0.0075, respectively). We identified numerous putative target genes of the miRNAs in association with muscle atrophy and lipolysis pathways. Knock-down experiments in C2C12 myoblast cells revealed an association of miR-27b-3p and the in silico predicted atrophy-related target genes IL-15 and TRIM63. Both were up-regulated in miR-27b-3p knock-down cells (P < 0.05). Concordantly, in muscle tissue of CCx individuals, significant higher expression levels of IL-15 (P = 0.0237) and TRIM63 (P = 0.0442) were detected. miR-424-5p was identified to regulate the expression of lipase genes. Knock-down experiments in human visceral preadipocytes revealed an inverse association of miR-424-5p with its predicted target genes LIPE, PNPLA2, MGLL and <
{"title":"Specific miRNAs are associated with human cancer cachexia in an organ-specific manner","authors":"Tanja Krauss, Simone Heisz, Julius Honecker, Olga Prokopchuk, Marc Martignoni, Klaus-Peter Janssen, Melina Claussnitzer, Hans Hauner, Claudine Seeliger","doi":"10.1002/jcsm.13224","DOIUrl":"https://doi.org/10.1002/jcsm.13224","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cancer cachexia (CCx) is a complex and multi-organ wasting syndrome characterized by substantial weight loss and poor prognosis. An improved understanding of the mechanisms involved in the onset and progression of cancer cachexia is essential. How microRNAs contribute to the clinical manifestation and progression of CCx remains elusive. The aim of this study was to identify specific miRNAs related to organ-specific CCx and explore their functional role in humans.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>miRNA patterns in serum and in cachexia target organs (liver, muscle and adipose tissue) from weight stable (<i>N</i> ≤ 12) and cachectic patients (<i>N</i> ≤ 23) with gastrointestinal cancer were analysed. As a first step, a miRNA array (158 miRNAs) was performed in pooled serum samples. Identified miRNAs were validated in serum and corresponding tissue samples. Using <i>in silico</i> prediction, related genes were identified and evaluated. The findings were confirmed <i>in vitro</i> by siRNA knock-down experiments in human visceral preadipocytes and C2C12 myoblast cells and consecutive gene expression analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Validating the results of the array, a 2-fold down-regulation of miR-122-5p (<i>P</i> = 0.0396) and a 4.5-fold down-regulation of miR-194-5p (<i>P</i> < 0.0001) in serum of CCx patients in comparison with healthy controls were detected. Only miR-122-5p correlated with weight loss and CCx status (<i>P</i> = 0.0367). Analysing corresponding tissues six muscle and eight visceral adipose tissue (VAT) cachexia-associated miRNAs were identified. miR-27b-3p, miR-375 and miR-424-5p were the most consistently affected miRNAs in tissues of CCx patients correlating negatively with the severity of body weight loss (<i>P</i> = 0.0386, <i>P</i> = 0.0112 and <i>P</i> = 0.0075, respectively). We identified numerous putative target genes of the miRNAs in association with muscle atrophy and lipolysis pathways. Knock-down experiments in C2C12 myoblast cells revealed an association of miR-27b-3p and the <i>in silico</i> predicted atrophy-related target genes <i>IL-15</i> and <i>TRIM63</i>. Both were up-regulated in miR-27b-3p knock-down cells (<i>P</i> < 0.05). Concordantly, in muscle tissue of CCx individuals, significant higher expression levels of <i>IL-15</i> (<i>P</i> = 0.0237) and <i>TRIM63</i> (<i>P</i> = 0.0442) were detected. miR-424-5p was identified to regulate the expression of lipase genes. Knock-down experiments in human visceral preadipocytes revealed an inverse association of miR-424-5p with its predicted target genes <i>LIPE, PNPLA2, MGLL</i> and <","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1381-1394"},"PeriodicalIF":8.9,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5994003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nadjia Amini, Jolan Dupont, Laurence Lapauw, Laura Vercauteren, Leen Antonio, Terence W. O'Neill, Dirk Vanderschueren, Neil Pendleton, Giulia Rastrelli, Mario Maggi, Felipe F. Casanueva, Jolanta S?owikowska-Hilczer, Margus Punab, Ilpo T. Huhtaniemi, Frederick C.W. Wu, Sabine Verschueren, Jos Tournoy, Evelien Gielen
Background
Previous research suggests that sarcopenia is associated with lower cognitive functioning. Evidence on the longitudinal relationship between cognition and sarcopenia, according to the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2), is scarce. This study aimed to investigate both cross-sectional and longitudinal associations between sarcopenia and its defining parameters (muscle strength, muscle mass and physical performance) and cognitive performance in middle-aged and older men.
Methods
This was a secondary analysis of data from the European Male Ageing Study (EMAS), a multicentre cohort study of men aged 40–79 years, recruited from population registers in eight European centres. Cognitive functioning was assessed by using a battery of three neuropsychological tests, measuring fluid intelligence: Rey–Osterrieth Complex Figure (ROCF-Copy and ROCF-Recall), Camden Topographical Recognition Memory (CTRM) and Digit Symbol Substitution Test (DSST). Sarcopenia-defining parameters appendicular lean mass (aLM), gait speed (GS), chair stand test (CST) and handgrip strength (HGS) were measured. Sarcopenia was diagnosed according to the criteria of the EWGSOP2. All measurements were performed at baseline and after a follow-up of 4.3 years. Cross-sectional associations between cognition, sarcopenia-defining parameters and prevalent sarcopenia (EWGSOP2) were analysed. Longitudinally, the predictive value of baseline cognition on decline in sarcopenia-defining parameters, onset of new sarcopenia and vice versa was examined. Linear and logistic regression were used and adjusted for putative confounders.
Results
In the whole cohort (n = 3233), ROCF-Copy (β = 0.016; P < 0.05), ROCF-Recall (β = 0.010; P < 0.05), CTRM (β = 0.015; P < 0.05), DSST score (β = 0.032; P < 0.05) and fluid cognition (β = 0.036; P < 0.05) were significantly and independently associated with GS at baseline. In the Leuven + Manchester subcohorts (n = 456), ROCF-Copy (β = 1.008; P < 0.05), ROCF-Recall (β = 0.908; P < 0.05) and fluid cognition (β = 1.482; P < 0.05) were associated with HGS. ROCF-Copy (β = 0.394; P < 0.05), ROCF-Recall (β = 0.316; P < 0.05), DSST (β = 0.393; P < 0.05) and fluid cognition (β = 0.765; P < 0.05) were associated with aLM. The prevalence of sarcopenia in this population was 17.8%. No associations were detected between cognition and prevalent or incident sarcopenia. Longitudinal analy
{"title":"Sarcopenia-defining parameters, but not sarcopenia, are associated with cognitive domains in middle-aged and older European men","authors":"Nadjia Amini, Jolan Dupont, Laurence Lapauw, Laura Vercauteren, Leen Antonio, Terence W. O'Neill, Dirk Vanderschueren, Neil Pendleton, Giulia Rastrelli, Mario Maggi, Felipe F. Casanueva, Jolanta S?owikowska-Hilczer, Margus Punab, Ilpo T. Huhtaniemi, Frederick C.W. Wu, Sabine Verschueren, Jos Tournoy, Evelien Gielen","doi":"10.1002/jcsm.13229","DOIUrl":"https://doi.org/10.1002/jcsm.13229","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Previous research suggests that sarcopenia is associated with lower cognitive functioning. Evidence on the longitudinal relationship between cognition and sarcopenia, according to the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2), is scarce. This study aimed to investigate both cross-sectional and longitudinal associations between sarcopenia and its defining parameters (muscle strength, muscle mass and physical performance) and cognitive performance in middle-aged and older men.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This was a secondary analysis of data from the European Male Ageing Study (EMAS), a multicentre cohort study of men aged 40–79 years, recruited from population registers in eight European centres. Cognitive functioning was assessed by using a battery of three neuropsychological tests, measuring fluid intelligence: Rey–Osterrieth Complex Figure (ROCF-Copy and ROCF-Recall), Camden Topographical Recognition Memory (CTRM) and Digit Symbol Substitution Test (DSST). Sarcopenia-defining parameters appendicular lean mass (aLM), gait speed (GS), chair stand test (CST) and handgrip strength (HGS) were measured. Sarcopenia was diagnosed according to the criteria of the EWGSOP2. All measurements were performed at baseline and after a follow-up of 4.3 years. Cross-sectional associations between cognition, sarcopenia-defining parameters and prevalent sarcopenia (EWGSOP2) were analysed. Longitudinally, the predictive value of baseline cognition on decline in sarcopenia-defining parameters, onset of new sarcopenia and vice versa was examined. Linear and logistic regression were used and adjusted for putative confounders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In the whole cohort (<i>n</i> = 3233), ROCF-Copy (β = 0.016; <i>P</i> < 0.05), ROCF-Recall (β = 0.010; <i>P</i> < 0.05), CTRM (β = 0.015; <i>P</i> < 0.05), DSST score (β = 0.032; <i>P</i> < 0.05) and fluid cognition (β = 0.036; <i>P</i> < 0.05) were significantly and independently associated with GS at baseline. In the Leuven + Manchester subcohorts (<i>n</i> = 456), ROCF-Copy (β = 1.008; <i>P</i> < 0.05), ROCF-Recall (β = 0.908; <i>P</i> < 0.05) and fluid cognition (β = 1.482; <i>P</i> < 0.05) were associated with HGS. ROCF-Copy (β = 0.394; <i>P</i> < 0.05), ROCF-Recall (β = 0.316; <i>P</i> < 0.05), DSST (β = 0.393; <i>P</i> < 0.05) and fluid cognition (β = 0.765; <i>P</i> < 0.05) were associated with aLM. The prevalence of sarcopenia in this population was 17.8%. No associations were detected between cognition and prevalent or incident sarcopenia. Longitudinal analy","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1520-1532"},"PeriodicalIF":8.9,"publicationDate":"2023-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5719499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy-induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha-like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy-induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy-induced cachexia in tumour-bearing mice.
Methods
Anti-GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15-induced signalling was evaluated using western blotting. To investigate the in vivo function of A11, a tumour-bearing mouse model was established by inoculating 8-week-old male C57BL/6 mice with B16F10 cells (n = 10–16 mice per group). A11 was administered subcutaneously (10 mg/kg) 1 day before intraperitoneal treatment with cisplatin (10 mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis.
Results
A11 reduced serum response element-luciferase reporter activity up to 74% (P < 0.005) in a dose-dependent manner and blocked RET phosphorylation up to 87% (P = 0.0593), AKT phosphorylation up to 28% (P = 0.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (P = 0.0636). A11 inhibited the action of cisplatin-induced GDF15 on the brainstem and decreased GFRAL-positive neuron population expressing c-Fos in the area postrema and nucleus of the solitary tract by 62% in vivo (P < 0.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (P < 0.05) and tumour-free body weight loss by 13% (P < 0.05). A11 significantly improved the cisplatin-induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, P < 0.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, P < 0.05).
{"title":"GDNF family receptor alpha-like antagonist antibody alleviates chemotherapy-induced cachexia in melanoma-bearing mice","authors":"Beom Yong Lee, Jongwon Jeong, Inseong Jung, Hanchae Cho, Dokyung Jung, Jiwon Shin, Jun-kook Park, Eunju Park, Soojeong Noh, Sanghee Shin, Sungmin Kang, Jong-Ik Heo, Moon-Chang Baek, Kyungmoo Yea","doi":"10.1002/jcsm.13219","DOIUrl":"https://doi.org/10.1002/jcsm.13219","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Patients with cancer undergoing chemotherapy experience cachexia with anorexia, body weight loss, and the depletion of skeletal muscles and adipose tissues. Effective treatment strategies for chemotherapy-induced cachexia are scarce. The growth differentiation factor 15 (GDF15)/GDNF family receptor alpha-like (GFRAL)/rearranged during transfection (RET) axis is a critical signalling pathway in chemotherapy-induced cachexia. In this study, we developed a fully human GFRAL antagonist antibody and investigated whether it inhibits the GDF15/GFRAL/RET axis, thereby alleviating chemotherapy-induced cachexia in tumour-bearing mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Anti-GFRAL antibodies were selected via biopanning, using a human combinatorial antibody phage library. The potent GFRAL antagonist antibody A11 was selected via a reporter cell assay and its inhibitory activity of GDF15-induced signalling was evaluated using western blotting. To investigate the <i>in vivo</i> function of A11, a tumour-bearing mouse model was established by inoculating 8-week-old male C57BL/6 mice with B16F10 cells (<i>n</i> = 10–16 mice per group). A11 was administered subcutaneously (10 mg/kg) 1 day before intraperitoneal treatment with cisplatin (10 mg/kg). Animals were assessed for changes in food intake, body weight, and tumour volume. Plasma and key metabolic tissues such as skeletal muscles and adipose tissues were collected for protein and mRNA expression analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A11 reduced serum response element-luciferase reporter activity up to 74% (<i>P</i> < 0.005) in a dose-dependent manner and blocked RET phosphorylation up to 87% (<i>P</i> = 0.0593), AKT phosphorylation up to 28% (<i>P</i> = 0.0593) and extracellular signal regulatory kinase phosphorylation up to 75% (<i>P</i> = 0.0636). A11 inhibited the action of cisplatin-induced GDF15 on the brainstem and decreased GFRAL-positive neuron population expressing c-Fos in the area postrema and nucleus of the solitary tract by 62% <i>in vivo</i> (<i>P</i> < 0.05). In a melanoma mouse model treated with cisplatin, A11 recovered anorexia by 21% (<i>P</i> < 0.05) and tumour-free body weight loss by 13% (<i>P</i> < 0.05). A11 significantly improved the cisplatin-induced loss of skeletal muscles (quadriceps: 21%, gastrocnemius: 9%, soleus: 13%, <i>P</i> < 0.05) and adipose tissues (epididymal white adipose tissue: 37%, inguinal white adipose tissue: 51%, <i>P</i> < 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1441-1453"},"PeriodicalIF":8.9,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5705321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jong Hyuk Lee, Seung Ho Choi, Keum Ji Jung, Jin Mo Goo, Soon Ho Yoon
Background
The prognostic role of increased visceral fat attenuation (VFA) remains underexplored. We investigated the long-term prognostic implications of computed tomography (CT)-derived VFA in a health check-up population.
Methods
This study included consecutive individuals who had positron-emission tomography/CT scans for health check-ups between January 2004 and December 2010. The primary outcome was overall survival (OS), and the secondary outcomes were cancer-specific survival (CSS) and non-cancer-specific survival (NCS). Commercially available body composition analysis software was used to obtain abdominal waist VFA, visceral fat volume index (VFI) and skeletal muscle index (SMI) at the L3 level. Sarcopenia was determined using sex-specific SMI references. VFA and VFI were dichotomized using the thresholds for the highest quartiles. The relationship between CT-derived body composition parameters and body mass index (BMI) was evaluated with Pearson correlation coefficients. The prognostic implications of VFA and sarcopenic obesity (SO) defined by VFA were assessed by multivariable Cox regression analysis and Kaplan–Meier plots with log-rank tests.
Results
A total of 2720 individuals (1530 men [56.3%] and 1190 women [43.7%]; median age: 53 years, inter-quartile range: 47–60 years) were included. During the median follow-up of 138 months, 128 individuals (5%) died (cancer mortality: 2%; non-cancer mortality: 3%), with 0.2% (5 of 2720) and 1.1% (30 of 2720) of 1- and 5-year mortality rates. VFA was negatively correlated with BMI (r = −0.62; P < 0.001) and VFI (r = −0.69; P < 0.001). After adjusting for clinical variables, sarcopenia and VFI, high VFA was a negative prognostic factor for OS (hazard ratio [HR]: 1.05 per Hounsfield unit; 95% confidence interval [CI]: 1.02, 1.08; P = 0.001), CSS (HR: 1.07 per Hounsfield unit; 95% CI: 1.02, 1.12; P = 0.006) and NCS (HR: 1.03 per Hounsfield unit; 95% CI: 1.01, 1.06; P = 0.009). Individuals with high VFA had higher high-sensitivity C-reactive protein levels than those with low VFA (0.11 vs. 0.03 mg/dL; P < 0.001). Individuals with SO defined by VFA had worse OS (9% vs. 4%; P < 0.001), CSS (3% vs. 2%; P = 0.02) and NCS (6% vs. 3%; P < 0.001) than those without SO, even in the same BMI (underweight-to-normal BMI, OS: 8% vs. 4%; overweight-to-obese BMI, OS: 38% vs. 4%; P < 0.001 in both) or VFI category (high VFI, OS: 43% vs. 6%; low VFI, OS: 8% vs. 3%; P < 0.001 in both).
{"title":"High visceral fat attenuation and long-term mortality in a health check-up population","authors":"Jong Hyuk Lee, Seung Ho Choi, Keum Ji Jung, Jin Mo Goo, Soon Ho Yoon","doi":"10.1002/jcsm.13226","DOIUrl":"https://doi.org/10.1002/jcsm.13226","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The prognostic role of increased visceral fat attenuation (VFA) remains underexplored. We investigated the long-term prognostic implications of computed tomography (CT)-derived VFA in a health check-up population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study included consecutive individuals who had positron-emission tomography/CT scans for health check-ups between January 2004 and December 2010. The primary outcome was overall survival (OS), and the secondary outcomes were cancer-specific survival (CSS) and non-cancer-specific survival (NCS). Commercially available body composition analysis software was used to obtain abdominal waist VFA, visceral fat volume index (VFI) and skeletal muscle index (SMI) at the L3 level. Sarcopenia was determined using sex-specific SMI references. VFA and VFI were dichotomized using the thresholds for the highest quartiles. The relationship between CT-derived body composition parameters and body mass index (BMI) was evaluated with Pearson correlation coefficients. The prognostic implications of VFA and sarcopenic obesity (SO) defined by VFA were assessed by multivariable Cox regression analysis and Kaplan–Meier plots with log-rank tests.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 2720 individuals (1530 men [56.3%] and 1190 women [43.7%]; median age: 53 years, inter-quartile range: 47–60 years) were included. During the median follow-up of 138 months, 128 individuals (5%) died (cancer mortality: 2%; non-cancer mortality: 3%), with 0.2% (5 of 2720) and 1.1% (30 of 2720) of 1- and 5-year mortality rates. VFA was negatively correlated with BMI (<i>r</i> = −0.62; <i>P</i> < 0.001) and VFI (<i>r</i> = −0.69; <i>P</i> < 0.001). After adjusting for clinical variables, sarcopenia and VFI, high VFA was a negative prognostic factor for OS (hazard ratio [HR]: 1.05 per Hounsfield unit; 95% confidence interval [CI]: 1.02, 1.08; <i>P</i> = 0.001), CSS (HR: 1.07 per Hounsfield unit; 95% CI: 1.02, 1.12; <i>P</i> = 0.006) and NCS (HR: 1.03 per Hounsfield unit; 95% CI: 1.01, 1.06; <i>P</i> = 0.009). Individuals with high VFA had higher high-sensitivity C-reactive protein levels than those with low VFA (0.11 vs. 0.03 mg/dL; <i>P</i> < 0.001). Individuals with SO defined by VFA had worse OS (9% vs. 4%; <i>P</i> < 0.001), CSS (3% vs. 2%; <i>P</i> = 0.02) and NCS (6% vs. 3%; <i>P</i> < 0.001) than those without SO, even in the same BMI (underweight-to-normal BMI, OS: 8% vs. 4%; overweight-to-obese BMI, OS: 38% vs. 4%; <i>P</i> < 0.001 in both) or VFI category (high VFI, OS: 43% vs. 6%; low VFI, OS: 8% vs. 3%; <i>P</i> < 0.001 in both).</p>\u0000 ","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1495-1507"},"PeriodicalIF":8.9,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6094740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xinrong Zuo, Xuehong Li, Kuo Tang, Rui Zhao, Minming Wu, Yang Wang, Tao Li
Sarcopenia is an age-related disease and is often accompanied by other diseases. Now, many studies have shown that cardiovascular diseases (CVDs) may raise the incidence rate of sarcopenia. Therefore, the purpose of this study was to conduct a systematic review and meta-analysis to investigate the prevalence of sarcopenia in patients with CVDs compared with the general population, defined as relatively healthy non-hospitalized subjects. The databases of PubMed, Embase, Medline and Web of Science were searched for eligible studies published up to 12 November 2022. Two assessment tools were used to evaluate study quality and the risk of bias. Statistical analysis was conducted using STATA 14.0 and R Version 4.1.2. Thirty-eight out of the 89 629 articles retrieved were included in our review. The prevalence of sarcopenia ranged from 10.1% to 68.9% in patients with CVDs, and the pooled prevalence was 35% (95% confidence interval [95% CI]: 28–42%). The pooled prevalence of sarcopenia was 32% (95% CI: 23–41%) in patients with chronic heart failure (CHF), 61% (95% CI: 49–72%) in patients with acute decompensated heart failure (ADHF), 43% (95% CI: 2–85%) in patients with coronary artery disease, 30% (95% CI: 25–35%) in patients with cardiac arrhythmia (CA), 35% (95% CI: 10–59%) in patients with congenital heart disease and 12% (95% CI: 7–17%) in patients with unclassed CVDs. However, in the general population, the prevalence of sarcopenia varied from 2.9% to 28.6% and the pooled prevalence was 13% (95% CI: 9–17%), suggesting that the prevalence of sarcopenia in patients with CVDs was about twice compared with the general population. The prevalence of sarcopenia was significantly higher only in patients with ADHF, CHF and CA compared with the general population. There is a positive correlation between CVDs and sarcopenia. The prevalence of sarcopenia is higher in patients with CVDs than that in the general population. With global aging, sarcopenia has brought a heavy burden to individuals and society. Therefore, it is important to identify the populations with high-risk or probable sarcopenia in order to do an early intervention, such as exercise, to counteract or slow down the progress of sarcopenia.
{"title":"Sarcopenia and cardiovascular diseases: A systematic review and meta-analysis","authors":"Xinrong Zuo, Xuehong Li, Kuo Tang, Rui Zhao, Minming Wu, Yang Wang, Tao Li","doi":"10.1002/jcsm.13221","DOIUrl":"https://doi.org/10.1002/jcsm.13221","url":null,"abstract":"<p>Sarcopenia is an age-related disease and is often accompanied by other diseases. Now, many studies have shown that cardiovascular diseases (CVDs) may raise the incidence rate of sarcopenia. Therefore, the purpose of this study was to conduct a systematic review and meta-analysis to investigate the prevalence of sarcopenia in patients with CVDs compared with the general population, defined as relatively healthy non-hospitalized subjects. The databases of PubMed, Embase, Medline and Web of Science were searched for eligible studies published up to 12 November 2022. Two assessment tools were used to evaluate study quality and the risk of bias. Statistical analysis was conducted using STATA 14.0 and R Version 4.1.2. Thirty-eight out of the 89 629 articles retrieved were included in our review. The prevalence of sarcopenia ranged from 10.1% to 68.9% in patients with CVDs, and the pooled prevalence was 35% (95% confidence interval [95% CI]: 28–42%). The pooled prevalence of sarcopenia was 32% (95% CI: 23–41%) in patients with chronic heart failure (CHF), 61% (95% CI: 49–72%) in patients with acute decompensated heart failure (ADHF), 43% (95% CI: 2–85%) in patients with coronary artery disease, 30% (95% CI: 25–35%) in patients with cardiac arrhythmia (CA), 35% (95% CI: 10–59%) in patients with congenital heart disease and 12% (95% CI: 7–17%) in patients with unclassed CVDs. However, in the general population, the prevalence of sarcopenia varied from 2.9% to 28.6% and the pooled prevalence was 13% (95% CI: 9–17%), suggesting that the prevalence of sarcopenia in patients with CVDs was about twice compared with the general population. The prevalence of sarcopenia was significantly higher only in patients with ADHF, CHF and CA compared with the general population. There is a positive correlation between CVDs and sarcopenia. The prevalence of sarcopenia is higher in patients with CVDs than that in the general population. With global aging, sarcopenia has brought a heavy burden to individuals and society. Therefore, it is important to identify the populations with high-risk or probable sarcopenia in order to do an early intervention, such as exercise, to counteract or slow down the progress of sarcopenia.</p>","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1183-1198"},"PeriodicalIF":8.9,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6015112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huijing He, Li Pan, Dingming Wang, Feng Liu, Jianwei Du, Lize Pa, Xianghua Wang, Ze Cui, Xiaolan Ren, Hailing Wang, Xia Peng, Jingbo Zhao, Guangliang Shan
Background
Hand grip strength (HGS) is a powerful indicator of sarcopenia and other adverse health outcomes. Normative values for HGS for general Chinese people with a broad age spectrum are lacking. This study aims to establish normative values of HGS and explore the correlations between HGS and body composition among unselected people aged 8–80 in China.
Methods
From 2012 to 2017, 39 655 participants aged 8–80 years in the China National Health Survey were included. Absolute HGS was measured using a Jamar dynamometer. The relative HGS was normalized by body mass index. Body composition indexes included body mass index, body fat percentage, muscle mass, fat mass index (FMI) and muscle mass index (MMI). Sex-specific smoothed centile tables for the P1, P5, P25, P50, P75, P95 and P99 centiles of HGS and body composition were generated using lambda-mu-sigma method. The correlations between muscle strength and body composition were estimated by partial Spearman correlation analysis.
Results
The median values (25th and 75th percentile) of HGS in boys and girls (8–19 years old) were 22 (14, 34) kg and 18 (12, 22) kg, respectively; in men and women aged 20–80 were 39 (33, 44) kg and 24 (20, 27) kg, respectively. Values of upper and lower HGS across ages had three periods: an increase to a peak in the 20 s in men (with the 5th and 95th values of 30 and 55 kg, respectively) and 30 s in women (with the 5th and 95th values of 18 and 34 kg, respectively), preservation through midlife (20s–40 s), and then a decline after their 50 s. The lowest HGS values in both sexes were in the 70- to 80-year-old group, with the 5th and 95th percentile values of 16 and 40 kg in men, and 10 and 25 kg in women. There were substantial sex differences in body composition in the life course (all P values <0.001). In ageing, the decrease of muscle strength was faster than that of muscle mass in both sexes. The correlations between muscle mass and HGS were most robust than other correlations, especially in women (0.68 vs. 0.50), children and adolescents.
Conclusions
Our study established the age- and sex-specific percentile reference values for hand grip strength in an unselected Chinese population across a broad age-spectrum. The rich data can facilitate the practical appraisal of muscle strength and promote early prediction of sarcopenia and other impairm
{"title":"Normative values of hand grip strength in a large unselected Chinese population: Evidence from the China National Health Survey","authors":"Huijing He, Li Pan, Dingming Wang, Feng Liu, Jianwei Du, Lize Pa, Xianghua Wang, Ze Cui, Xiaolan Ren, Hailing Wang, Xia Peng, Jingbo Zhao, Guangliang Shan","doi":"10.1002/jcsm.13223","DOIUrl":"https://doi.org/10.1002/jcsm.13223","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hand grip strength (HGS) is a powerful indicator of sarcopenia and other adverse health outcomes. Normative values for HGS for general Chinese people with a broad age spectrum are lacking. This study aims to establish normative values of HGS and explore the correlations between HGS and body composition among unselected people aged 8–80 in China.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>From 2012 to 2017, 39 655 participants aged 8–80 years in the China National Health Survey were included. Absolute HGS was measured using a Jamar dynamometer. The relative HGS was normalized by body mass index. Body composition indexes included body mass index, body fat percentage, muscle mass, fat mass index (FMI) and muscle mass index (MMI). Sex-specific smoothed centile tables for the P<sub>1</sub>, P<sub>5</sub>, P<sub>25</sub>, P<sub>50</sub>, P<sub>75</sub>, P<sub>95</sub> and P<sub>99</sub> centiles of HGS and body composition were generated using lambda-mu-sigma method. The correlations between muscle strength and body composition were estimated by partial Spearman correlation analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The median values (25th and 75th percentile) of HGS in boys and girls (8–19 years old) were 22 (14, 34) kg and 18 (12, 22) kg, respectively; in men and women aged 20–80 were 39 (33, 44) kg and 24 (20, 27) kg, respectively. Values of upper and lower HGS across ages had three periods: an increase to a peak in the 20 s in men (with the 5th and 95th values of 30 and 55 kg, respectively) and 30 s in women (with the 5th and 95th values of 18 and 34 kg, respectively), preservation through midlife (20s–40 s), and then a decline after their 50 s. The lowest HGS values in both sexes were in the 70- to 80-year-old group, with the 5th and 95th percentile values of 16 and 40 kg in men, and 10 and 25 kg in women. There were substantial sex differences in body composition in the life course (all <i>P</i> values <0.001). In ageing, the decrease of muscle strength was faster than that of muscle mass in both sexes. The correlations between muscle mass and HGS were most robust than other correlations, especially in women (0.68 vs. 0.50), children and adolescents.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study established the age- and sex-specific percentile reference values for hand grip strength in an unselected Chinese population across a broad age-spectrum. The rich data can facilitate the practical appraisal of muscle strength and promote early prediction of sarcopenia and other impairm","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1312-1321"},"PeriodicalIF":8.9,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13223","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5908715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cardiac wasting is a detrimental consequence of cancer that has been traditionally ignored and often misinterpreted as an iatrogenic effect.
Methods
We conducted a retrospective study on 42 chemo-naive patients affected by locally advanced head and neck cancer (HNC). Based on unintentional weight loss, patients were divided into cachectic and non-cachectic. Left ventricular mass (LVM), LV wall thickness (LVWT), interventricular septal (IVS) thickness, left ventricular internal diameter diastolic (LVIDd), left ventricular internal diameter systolic (LVIDs), internal ventricular septum diastolic (IVSd), left ventricular posterior wall thickness diastolic (LVPWd) and LV ejection fraction (LVEF) were analysed by echocardiography. In parallel, we retrospectively analysed 28 cardiac autoptic specimens of patients who either died of cancer before chemotherapy or with a diagnosis of cancer at autopsy. Presence or absence of myocardial fibrosis at microscopic observation was used for sample stratification. Conventional histology was performed.
Results
Cachectic and non-cachectic patients had a significantly different value of LVWT and IVS thickness and LVPWd. LVWT was 9.08 ± 1.57 versus 10.35 ± 1.41 mm (P = 0.011) in cachectic and non-cachectic patients, IVS was 10.00 mm (8.50–11.00) versus 11.00 mm (10.00–12.00) (P = 0.035), and LVPWd was 9.0 (8.5–10.0) and 10.00 mm (9.5–11.0) (P = 0.019) in cachectic and non-cachectic patients.
LVM adjusted for body surface area or height squared did not differ between the two populations. Similarly, LVEF did not show any significant decline. At multivariate logistic regression analysis for some independent predictors of weight loss, only LVWT maintained significant difference between cachectic and non-cachectic patients (P = 0.035, OR = 0.240; P = 0.019). The secondary analysis on autoptic specimens showed no significant change in heart weight, whereas LVWT declined from 9.50 (7.25–11.00) to 7.50 mm (6.00–9.00) in cardiac specimens with myocardial fibrosis (P = 0.043). These data were confirmed in multivariate logistic regression analysis (P = 0.041, OR = 0.502). Histopathological analysis confirmed severe atrophy of cardiomyocytes, fibrosis and oedema as compared with controls.
Conclusions
Subtle changes in heart structure and function occur early in HNC patients. These can be detect
背景:心脏衰竭是癌症的一个有害后果，传统上一直被忽视，并经常被误解为医源性效应。方法对42例局部晚期头颈癌(HNC)患者进行回顾性研究。根据非故意体重减轻，将患者分为恶病质和非恶病质。超声心动图分析左室质量(LVM)、左室壁厚度(LVWT)、室间隔厚度(IVS)、左室舒张内径(LVIDd)、左室收缩内径(LVIDs)、室间隔舒张内径(IVSd)、左室舒张后壁厚度(LVPWd)和左室射血分数(LVEF)。同时，我们回顾性分析了28例化疗前死于癌症或尸检诊断为癌症的患者的心脏自噬标本。显微镜下观察心肌纤维化的存在与否用于样品分层。进行常规组织学检查。结果病毒症患者与非病毒症患者LVWT、IVS厚度及LVPWd值差异有统计学意义。恶病质和非恶病质患者LVWT分别为9.08±1.57 mm和10.35±1.41 mm (P = 0.011)， IVS分别为10.00 mm(8.50-11.00)和11.00 mm (10.00 - 12.00) (P = 0.035)， LVPWd分别为9.0 mm(8.5-10.0)和10.00 mm (9.5-11.0) (P = 0.019)。经体表面积或身高平方调整后的LVM在两个人群之间没有差异。同样，LVEF也没有明显下降。在对一些体重减轻的独立预测因素进行多因素logistic回归分析时，只有LVWT在恶病质和非恶病质患者之间保持显著差异(P = 0.035, OR = 0.240;p = 0.019)。自噬标本的二次分析显示心脏重量无明显变化，而心肌纤维化标本的LVWT从9.50(7.25-11.00)下降到7.50 mm (6.00-9.00) (P = 0.043)。这些数据经多因素logistic回归分析证实(P = 0.041, OR = 0.502)。组织病理学分析证实，与对照组相比，心肌细胞严重萎缩，纤维化和水肿。结论HNC患者心脏结构和功能早期发生细微变化。这些可以通过常规超声心动图检测到，可能有助于为这些患者选择合适的癌症治疗方案。组织病理学分析提供了确凿的证据，表明心肌细胞萎缩、水肿和纤维化发生在癌症进展过程中，可能先于明显的心脏病理发生。据我们所知，这是第一个在HNCs中建立肿瘤进展和心脏重构之间直接关系的临床研究，也是第一个对选定chemo-naïve癌症患者的人类心脏尸检进行的病理研究。
{"title":"Cardiac wasting in head and neck cancer and in cardiac autopsies from different cancer types: A study in a chemo-naïve setting","authors":"Sara Calamelli, Samantha Noto, Alessandra Baldoni, Alessandra Casarin, Alessandro Calzavara, Irene Bolgan, Silvia Coccato, Salvatore Saccà, Licia Laurino, Giuseppe Azzarello, Simonetta Ausoni","doi":"10.1002/jcsm.13217","DOIUrl":"https://doi.org/10.1002/jcsm.13217","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cardiac wasting is a detrimental consequence of cancer that has been traditionally ignored and often misinterpreted as an iatrogenic effect.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a retrospective study on 42 chemo-naive patients affected by locally advanced head and neck cancer (HNC). Based on unintentional weight loss, patients were divided into cachectic and non-cachectic. Left ventricular mass (LVM), LV wall thickness (LVWT), interventricular septal (IVS) thickness, left ventricular internal diameter diastolic (LVIDd), left ventricular internal diameter systolic (LVIDs), internal ventricular septum diastolic (IVSd), left ventricular posterior wall thickness diastolic (LVPWd) and LV ejection fraction (LVEF) were analysed by echocardiography. In parallel, we retrospectively analysed 28 cardiac autoptic specimens of patients who either died of cancer before chemotherapy or with a diagnosis of cancer at autopsy. Presence or absence of myocardial fibrosis at microscopic observation was used for sample stratification. Conventional histology was performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Cachectic and non-cachectic patients had a significantly different value of LVWT and IVS thickness and LVPWd. LVWT was 9.08 ± 1.57 versus 10.35 ± 1.41 mm (<i>P</i> = 0.011) in cachectic and non-cachectic patients, IVS was 10.00 mm (8.50–11.00) versus 11.00 mm (10.00–12.00) (<i>P</i> = 0.035), and LVPWd was 9.0 (8.5–10.0) and 10.00 mm (9.5–11.0) (<i>P</i> = 0.019) in cachectic and non-cachectic patients.</p>\u0000 \u0000 <p>LVM adjusted for body surface area or height squared did not differ between the two populations. Similarly, LVEF did not show any significant decline. At multivariate logistic regression analysis for some independent predictors of weight loss, only LVWT maintained significant difference between cachectic and non-cachectic patients (<i>P</i> = 0.035, OR = 0.240; <i>P</i> = 0.019). The secondary analysis on autoptic specimens showed no significant change in heart weight, whereas LVWT declined from 9.50 (7.25–11.00) to 7.50 mm (6.00–9.00) in cardiac specimens with myocardial fibrosis (<i>P</i> = 0.043). These data were confirmed in multivariate logistic regression analysis (<i>P</i> = 0.041, OR = 0.502). Histopathological analysis confirmed severe atrophy of cardiomyocytes, fibrosis and oedema as compared with controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Subtle changes in heart structure and function occur early in HNC patients. These can be detect","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1286-1298"},"PeriodicalIF":8.9,"publicationDate":"2023-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5940822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Haiming L. Kerr, Kora Krumm, Ian (In-gi) Lee, Barbara Anderson, Anthony Christiani, Lena Strait, Beatrice A. Breckheimer, Brynn Irwin, Alice (Siyi) Jiang, Artur Rybachok, Amanda Chen, Lucas Caeiro, Elizabeth Dacek, Daniel B. Hall, Caroline H. Kostyla, Laura M. Hales, Tarik M. Soliman, Jose M. Garcia
Background
Ghrelin is a potential therapy for cachexia due to its orexigenic properties and anabolic effects on muscle and fat. However, its clinical use is limited by the short half-life of active (acylated) ghrelin (~11 min in humans). EXT418 is a novel long-acting, constitutively active ghrelin analog created by covalently linking it to a vitamin D derivative. Here, we evaluated the effects and mechanisms of action of EXT418 on Lewis lung carcinoma (LLC)-induced cachexia in mice.
Methods
Male C57BL/6J mice (5- to 7-month-old) were implanted with 1 × 106 heat-killed (HK) or live LLC cells. When the tumour was palpable, mice were injected with vehicle (T + V) or EXT418 daily (T + 418 Daily, 0.25 mg/kg/day) or every other day (T + 418 EOD, 0.5 mg/kg/EOD) for up to 14 days, whereas HK-treated mice were given vehicle (HK + V). Subsets of T + 418 Daily or EOD-treated mice were pair-fed to the T + V group. Body composition and grip strength were evaluated before tumour implantation and at the end of the experiment. Molecular markers were probed in muscles upon termination.
Results
In tumour-bearing mice, administration of EXT418 daily or EOD partially prevented weight loss (T + V vs. T + 418 Daily, P = 0.030; and vs. T + 418 EOD, P = 0.020). Similar effects were observed in whole body fat and lean body mass. Grip strength in tumour-bearing mice was improved by EXT418 daily (P = 0.010) or EOD (P = 0.008) administration compared with vehicle-treated mice. These effects of EXT418 on weight and grip strength were partially independent of food intake. EXT418 daily administration also improved type IIA (P = 0.015), IIB (P = 0.037) and IIX (P = 0.050) fibre cross-sectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; P = 0.005). In skeletal muscles, tumour-induced increases in atrogenes Fbxo32 and Trim63 were ameliorated by EXT418 treatments (TA and GAS/plantaris, PL), which were independent of food intake. EXT418 administration decreased expression of the mitophagy marker Bnip3 (GAS/PL; P ≤ 0.010). Similar effects of EXT418 EOD were observed in p62 (GAS/PL; P = 0.039). In addition, EXT418 treatments ameliorated the tumour-induced elevation in muscle Il6 transcript levels (TA and GAS/PL), independently of food intake. Il-6 transcript levels in adipose tissue and circulating IL-10 were elevated in response to the tumour but these increases were not signifi
{"title":"EXT418, a novel long-acting ghrelin, mitigates Lewis lung carcinoma induced cachexia in mice","authors":"Haiming L. Kerr, Kora Krumm, Ian (In-gi) Lee, Barbara Anderson, Anthony Christiani, Lena Strait, Beatrice A. Breckheimer, Brynn Irwin, Alice (Siyi) Jiang, Artur Rybachok, Amanda Chen, Lucas Caeiro, Elizabeth Dacek, Daniel B. Hall, Caroline H. Kostyla, Laura M. Hales, Tarik M. Soliman, Jose M. Garcia","doi":"10.1002/jcsm.13211","DOIUrl":"https://doi.org/10.1002/jcsm.13211","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ghrelin is a potential therapy for cachexia due to its orexigenic properties and anabolic effects on muscle and fat. However, its clinical use is limited by the short half-life of active (acylated) ghrelin (~11 min in humans). EXT418 is a novel long-acting, constitutively active ghrelin analog created by covalently linking it to a vitamin D derivative. Here, we evaluated the effects and mechanisms of action of EXT418 on Lewis lung carcinoma (LLC)-induced cachexia in mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Male C57BL/6J mice (5- to 7-month-old) were implanted with 1 × 10<sup>6</sup> heat-killed (HK) or live LLC cells. When the tumour was palpable, mice were injected with vehicle (T + V) or <i>EXT418</i> daily (T + 418 Daily, 0.25 mg/kg/day) or every other day (T + 418 EOD, 0.5 mg/kg/EOD) for up to 14 days, whereas HK-treated mice were given vehicle (HK + V). Subsets of T + 418 Daily or EOD-treated mice were pair-fed to the T + V group. Body composition and grip strength were evaluated before tumour implantation and at the end of the experiment. Molecular markers were probed in muscles upon termination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In tumour-bearing mice, administration of <i>EXT418</i> daily or EOD partially prevented weight loss (T + V vs. T + 418 Daily, <i>P</i> = 0.030; and vs. T + 418 EOD, <i>P</i> = 0.020). Similar effects were observed in whole body fat and lean body mass. Grip strength in tumour-bearing mice was improved by <i>EXT418</i> daily (<i>P</i> = 0.010) or EOD (<i>P</i> = 0.008) administration compared with vehicle-treated mice. These effects of EXT418 on weight and grip strength were partially independent of food intake. <i>EXT418</i> daily administration also improved type IIA (<i>P</i> = 0.015), IIB (<i>P</i> = 0.037) and IIX (<i>P</i> = 0.050) fibre cross-sectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; <i>P =</i> 0.005). In skeletal muscles, tumour-induced increases in atrogenes <i>Fbxo32</i> and <i>Trim63</i> were ameliorated by EXT418 treatments (TA and GAS/plantaris, PL), which were independent of food intake. EXT418 administration decreased expression of the mitophagy marker <i>Bnip3</i> (GAS/PL; <i>P</i> ≤ 0.010). Similar effects of EXT418 EOD were observed in p62 (GAS/PL; <i>P</i> = 0.039). In addition, EXT418 treatments ameliorated the tumour-induced elevation in muscle <i>Il6</i> transcript levels (TA and GAS/PL), independently of food intake. <i>Il-6</i> transcript levels in adipose tissue and circulating IL-10 were elevated in response to the tumour but these increases were not signifi","PeriodicalId":186,"journal":{"name":"Journal of Cachexia, Sarcopenia and Muscle","volume":"14 3","pages":"1337-1348"},"PeriodicalIF":8.9,"publicationDate":"2023-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13211","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5736448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号