Serum Metabolite Profiles Are Altered by Erlotinib Treatment and the Integrin α1-Null Genotype but Not by Post-Traumatic Osteoarthritis

The risk of developing post-traumatic osteoarthritis (PTOA) following joint injury is high. Furthering our understanding of the molecular mechanisms underlying PTOA and/or identifying novel biomarkers for early detection may help to improve treatment outcomes. Increased expression of integrin α1β1 and inhibition of epidermal growth factor receptor (EGFR) signaling protect the knee from spontaneous OA; however, the impact of the integrin α1β1/EGFR axis on PTOA is currently unknown. We sought to determine metabolic changes in serum samples collected from wild-type and integrin α1-null mice that underwent surgery to destabilize the medial meniscus and were treated with the EGFR inhibitor erlotinib. Following ¹H nuclear magnetic resonance spectroscopy, we generated multivariate statistical models that distinguished between the metabolic profiles of erlotinib- versus vehicle-treated mice and the integrin α1-null versus wild-type mouse genotype. Our results show the sex-dependent effects of erlotinib treatment and highlight glutamine as a metabolite that counteracts this treatment. Furthermore, we identified a set of metabolites associated with increased reactive oxygen species production, susceptibility to OA, and regulation of TRP channels in α1-null mice. Our study indicates that systemic pharmacological and genetic factors have a greater effect on serum metabolic profiles than site-specific factors such as surgery

Additional file 2: of Development of metabolic and inflammatory mediator biomarker phenotyping for early diagnosis and triage of pediatric sepsis

Results of the metabolomic and protein mediator biomarker phenotyping in the two age subgroups. This file contains six figures depicting the results for the age subgroups and a seventh figure showing the loading plots that demonstrate which metabolites and/or inflammatory protein mediators contribute most to each component in the PCA models for the age 2–17-year-old cohort. (PDF 4020 kb

Sarcopenia and myosteatosis are accompanied by distinct biological profiles in patients with pancreatic and periampullary adenocarcinomas

<div><p>Introduction</p><p>Pancreatic and periampullary adenocarcinomas are associated with abnormal body composition visible on CT scans, including low muscle mass (sarcopenia) and low muscle radiodensity due to fat infiltration in muscle (myosteatosis). The biological and clinical correlates to these features are poorly understood.</p><p>Methods</p><p>Clinical characteristics and outcomes were studied in 123 patients who underwent pancreaticoduodenectomy for pancreatic or non-pancreatic periampullary adenocarcinoma and who had available preoperative CT scans. In a subgroup of patients with pancreatic cancer (n = 29), <i>rectus abdominus</i> muscle mRNA expression was determined by cDNA microarray and in another subgroup (n = 29) ¹H-NMR spectroscopy and gas chromatography-mass spectrometry were used to characterize the serum metabolome.</p><p>Results</p><p>Muscle mass and radiodensity were not significantly correlated. Distinct groups were identified: sarcopenia (40.7%), myosteatosis (25.2%), both (11.4%). Fat distribution differed in these groups; sarcopenia associated with lower subcutaneous adipose tissue (P<0.0001) and myosteatosis associated with greater visceral adipose tissue (P<0.0001). Sarcopenia, myosteatosis and their combined presence associated with shorter survival, Log Rank P = 0.005, P = 0.06, and P = 0.002, respectively. In muscle, transcriptomic analysis suggested increased inflammation and decreased growth in sarcopenia and disrupted oxidative phosphorylation and lipid accumulation in myosteatosis. In the circulating metabolome, metabolites consistent with muscle catabolism associated with sarcopenia. Metabolites consistent with disordered carbohydrate metabolism were identified in both sarcopenia and myosteatosis.</p><p>Discussion</p><p>Muscle phenotypes differ clinically and biologically. Because these muscle phenotypes are linked to poor survival, it will be imperative to delineate their pathophysiologic mechanisms, including whether they are driven by variable tumor biology or host response.</p></div

Biological functions associated with differentially abundant genes for muscle radiodensity and sarcopenia.

<p>Biological functions associated with differentially abundant genes for muscle radiodensity and sarcopenia.</p

Kaplan-Meier plots.

<p>(A) Disease-free survival (DFS) as a function of sarcopenia. (B) Overall survival (OS) as a function of sarcopenia. (C) DFS as a function of myosteatosis. (D) OS as a function of myosteatosis. (E) DFS in individuals with both sarcopenia and myosteatosis. (F) OS in individuals with both sarcopenia and myosteatosis.</p

Metabolomic models that distinguish body composition phenotypes in pancreatic cancer patients.

<p>(A) OPLS-DA scores plots and metabolite lists for NMR and GC-MS metabolites: sarcopenia vs. no sarcopenia or myosteatosis. (B) OPLS-DA scores plots and metabolite lists for NMR and GC-MS metabolites: myosteatosis vs. no sarcopenia or myosteatosis. For the metabolite lists: metabolites in <b>bold</b> are shared in 1H-NMR spectroscopy and GC-MS datasets; metabolites in red have a VIP>1.</p

Patient characteristics as a function of low muscle mass and radiodensity.

<p>Data are expressed as mean ± SD, or as N (%).</p