👤 Christopher Husted

Osteosarcoma (OS) is the most common bone tumor in both dogs and humans. It predominantly occurs in the appendicular skeleton, with about 25% of cases occurring within the axial skeleton. Progression of local disease is often the life-limiting factor for patients with axial OS, in contrast to appendicular OS, where local disease is addressed surgically, and metastatic disease remains the primary obstacle. While OS is a rare human cancer, limiting the availability of samples, its higher incidence in dogs provides a valuable comparative model for study. Both canines and humans share commonalities in clinical presentation, but dogs have an accelerated progression. Similarly, complex structural genetic changes define appendicular OS in both dogs and people, but it is unclear whether the genomic landscape of axial OS exhibits different alterations that may separate it from appendicular OS. We performed pilot whole genome sequencing of canine primary oral (maxillary or mandibular) OS tumors (n = 8) and matched normal tissue. We found that the genetics of canine oral OS largely parallel the genetics of canine appendicular OS, including an overall low number of recurrent point mutations affecting the same gene (TP53 and SETD2, 3/8 samples). Structural variants dominated the landscape of mutational changes, with recurrent variants in DMD (4/8) and DLG2 (3/8) found at a similar incidence to appendicular OS. This pilot suggests genomic similarities between oral and appendicular OS. Show less

Acute prolonged sitting increases blood pressure (BP) and arterial stiffness (AS). Both of these may be mitigated via light physical activity (LPA). Whether long COVID (LC), which partly manifests as vascular sequelae, predisposes a heightened sensitivity to sitting or diminished benefits from its interruption is unknown. The aims of this study were to identify whether individuals with LC: (i) exhibit a worse BP/AS response to uninterrupted sitting and (ii) a diminished mitigation of BP/AS response to sitting interrupted with LPA, compared to healthy controls. Thirty participants with LC and 15 controls completed 2 h of uninterrupted sitting and sitting interrupted with LPA. Central and peripheral systolic and diastolic BP and carotid-femoral pulse wave velocity (cfPWV) were determined pre and post sitting. Linear mixed-effects models demonstrated no three-way or two-way interactions for any variable. There was a significant main effect of time, with increases in central systolic (MD = 3.37 mmHg, SE = 0.93 mmHg, p < 0.001) and central diastolic (MD = 3.00 mmHg, SE = 0.58 mmHg, p < 0.001) BP. cfPWV was not altered in sitting in either group (MD = 0.13 m/s, SE = 0.09 m/s, p = 0.170). Uninterrupted sitting increases BP similarly, but AS is unchanged. Interrupting sitting with LPA did not mitigate sitting-induced increase in BP regardless of LC diagnosis. Show less

Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass. Show less