The tumor microenvironment is emerging as an important therapeutic target. Most studies, however, are focused on the protein components, and relatively little is known of how the microenvironmental metabolome might influence tumor survival. In this study, we examined the metabolic profiles of paired bone marrow (BM) and peripheral blood (PB) samples from 10 children with acute lymphoblastic leukemia (ALL). BM and PB samples from the same patient were collected at the time of diagnosis and after 29 days of induction therapy, at which point all patients were in remission. We employed two analytical platforms, high-resolution magnetic resonance spectroscopy and gas chromatography-mass spectrometry, to identify and quantify 102 metabolites in the BM and PB. Standard ALL therapy, which includes l-asparaginase, completely removed circulating asparagine, but not glutamine. Statistical analyses of metabolite correlations and network reconstructions showed that the untreated BM microenvironment was characterized by a significant network-level signature: a cluster of highly correlated lipids and metabolites involved in lipid metabolism (p<0.006). In contrast, the strongest correlations in the BM upon remission were observed among amino acid metabolites and derivatives (p<9.2×10-10). This study provides evidence that metabolic characterization of the cancer niche could generate new hypotheses for the development of cancer therapies.

SYNOPSIS Introduction The size and shape of joints markedly affect their biomechanical properties, but the macroscopic 3-dimensional (3-D) mechanism and extent of cartilage and joint maturation during normal growth are largely unknown. Aims The purposes of this study were to qualitatively illustrate the development of the cartilage-bone interface in the knee during postnatal growth in humans and C57BL/6 wild-type mice, and to quantitatively define the 3-D shape using statistical shape modeling as well as to assess growth strain rates in the mouse distal femur. Methods Clinical computed tomography (CT) scans of asymptomatic knees (0.3–0.6mm in-plane resolution, 0.63mm slice thickness) were obtained from six patients between 4 to 12 years old. Micro-CT scans of mouse knees (9μm isotropic resolution) were from twenty-one mice between 12 to 120 days postnatal. Human and mouse images were compared qualitatively with 2-D images and 3-D reconstructions. Mouse femora shape parameters were determined with statistical shape modeling, and strain rates and directions during growth were mapped. Results The attainment of cartilage-bone interface shape of the distal femur and proximal tibia were qualitatively similar in humans and mice, with marked differences in growth plate morphology. Mouse distal femur shape was described by 11 independent parameters that accounted for >90% of total shape variation during growth. Each shape parameter described changes in specific anatomical regions of the distal femur and varied with age. Shape parameters and strains in the medial and lateral condyles, as well as intercondylar notch, varied greatly between postnatal days 16 to 30. Directions of growth strain across ages corresponded well with the appearance of anatomical landmarks within the distal femur. Conclusion Accurate quantification of the cartilage-bone interface geometry is imperative for furthering the understanding of the macroscopic mechanisms of cartilage maturation and overall joint development.

Background The rapid plasma reagin (RPR) assay is commonly used as a surrogate marker of infectious syphilis, but is non-specific, slow to change and variable in its rate of decline post treatment. Methods: Within an urban sexual health service testing predominantly men who have sex with men, a file review of RPR changes was undertaken in all subjects who had a dilution level of ≥1:4, between January 2015 to the end of December 2018. Results: Overall, 248 cases of infectious syphilis were identified in 215 subjects (165 HIV seropositive, 50 HIV seronegative). Among unique-subject cases with follow-up RPR recorded, seroreversion to a non-reactive titre was achieved in only 42.3% (71/168) cases at a median of 235 days (interquartile range: 138–348 days) and was significantly less likely if patients had HIV infection (P = 0.02), late latent syphilis (P = 0.003) or a subsequent syphilis infection (P &lt; 0.0001). Having HIV infection (P = 0.03) or a subsequent episode of syphilis (P = 0.01) were associated with a lower likelihood of documented cure. Conclusions: The slow decay in RPR titres post therapy and the inability of a significant number of subjects to achieve a non-reactive result over time makes RPR a poor test for assessing the adequacy of treatment or in diagnosing re-infection, especially in populations having repeated and frequent risk exposures. As the number of syphilis cases continue to climb, better tests that accurately assess pathogen presence are urgently needed.