The Molecular Pathogenesis of Osteosarcoma: A Review

Osteosarcoma is the most common primary malignancy of bone. It arises in bone during periods of rapid growth and primarily affects adolescents and young adults. The 5-year survival rate for osteosarcoma is 60%–70%, with no significant improvements in prognosis since the advent of multiagent chemotherapy. Diagnosis, staging, and surgical management of osteosarcoma remain focused on our anatomical understanding of the disease. As our knowledge of the molecular pathogenesis of osteosarcoma expands, potential therapeutic targets are being identified. A comprehensive understanding of these mechanisms is essential if we are to improve the prognosis of patients with osteosarcoma through tumour-targeted therapies. This paper will outline the pathogenic mechanisms of osteosarcoma oncogenesis and progression and will discuss some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management

Global application of an unoccupied aerial vehicle photogrammetry protocol for predicting aboveground biomass in non‐forest ecosystems

P. 1-15Non-forest ecosystems, dominated by shrubs, grasses and herbaceous plants, provide ecosystem services including carbon sequestration and forage for grazing, and are highly sensitive to climatic changes. Yet these ecosystems are poorly represented in remotely sensed biomass products and are undersampled by in situ monitoring. Current global change threats emphasize the need for new tools to capture biomass change in non-forest ecosystems at appropriate scales. Here we developed and deployed a new protocol for photogrammetric height using unoccupied aerial vehicle (UAV) images to test its capability for delivering standardized measurements of biomass across a globally distributed field experiment. We assessed whether canopy height inferred from UAV photogrammetry allows the prediction of aboveground biomass (AGB) across low-stature plant species by conducting 38 photogrammetric surveys over 741 harvested plots to sample 50 species. We found mean canopy height was strongly predictive of AGB across species, with a median adjusted R2 of 0.87 (ranging from 0.46 to 0.99) and median prediction error from leave-one-out cross-validation of 3.9%. Biomass per-unit-of-height was similar within but different among, plant functional types. We found that photogrammetric reconstructions of canopy height were sensitive to wind speed but not sun elevation during surveys. We demonstrated that our photogrammetric approach produced generalizable measurements across growth forms and environmental settings and yielded accuracies as good as those obtained from in situ approaches. We demonstrate that using a standardized approach for UAV photogrammetry can deliver accurate AGB estimates across a wide range of dynamic and heterogeneous ecosystems. Many academic and land management institutions have the technical capacity to deploy these approaches over extents of 1–10 ha−1. Photogrammetric approaches could provide much-needed information required to calibrate and validate the vegetation models and satellite-derived biomass products that are essential to understand vulnerable and understudied non-forested ecosystems around the globe.S

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Bioengineering of articular cartilage: past, present and future

The treatment of cartilage defects poses a clinical challenge owing to the lack of intrinsic regenerative capacity of cartilage. The use of tissue engineering techniques to bioengineer articular cartilage is promising and may hold the key to the successful regeneration of cartilage tissue. Natural and synthetic biomaterials have been used to recreate the microarchitecture of articular cartilage through multilayered biomimetic scaffolds. Acellular scaffolds preserve the microarchitecture of articular cartilage through a process of decellularization of biological tissue. Although promising, this technique often results in poor biomechanical strength of the graft. However, biomechanical strength could be improved if biomaterials could be incorporated back into the decellularized tissue to overcome this limitation

AMPK activation is fiber type specific in human skeletal muscle: effects of exercise and short-term exercise training

AMP-activated protein kinase (AMPK) has been extensively studied in whole muscle biopsy samples of humans, yet the fiber type-specific expression and/or activation of AMPK is unknown. We examined basal and exercise AMPK-α Thr172 phosphorylation and AMPK subunit expression (α1, α2, and γ3) in type I, IIa, and IIx fibers of human skeletal muscle before and after 10 days of exercise training. Before training basal AMPK phosphorylation was greatest in type IIa fibers (P type IIa > type I), irrespective of training status. Thus skeletal muscle AMPK phosphorylation and AMPK expression are fiber type specific in humans in the basal state, as well as during exercise. Our findings reveal fiber type-specific differences that have been masked in previous studies examining mixed muscle samples

Mechanisms of palmitate-induced lipotoxicity in osteocytes

Background: Lipotoxicity is defined as cellular toxicity observed in the presence of an abnormal accumulation of fat and adipocyte-derived factors in non-fat tissues. Palmitic acid (PA), an abundant fatty acid in the bone marrow and particularly in osteoporotic bones, affects osteoblastogenesis and osteoblast function, decreasing their survival through induction of apoptosis and dysfunctional autophagy. In this study, we hypothesized that PA also has a lipotoxic effect on osteocytes in vitro. Methods: Initially, we tested the effect of PA on osteocyte-derived factors DKK1, sclerostin and RANKL. Then, we tested whether PA affects survival and causes apoptosis in osteocytes. Subsequently, we investigated the effect of PA on autophagy by detecting the membrane component LC3-II (Western blot) and staining them and lysosomes with Lysotracker Red dye. Results: PA decreases RANKL, DKK1 and sclerostin expression in osteocytes. In addition, we found that PA induces apoptosis and reduces osteocyte survival. PA also caused autophagy failure identified by a significant increase in LC3-II and a reduced number of autophagosomes/lysosomes in the cytoplasm. Conclusion: In addition to the effects of PA on RANKL, DKK1 and sclerostin expression, which could have significant deleterious impact on bone cell coupling and bone turnover, PA also induced apoptosis and reduced autophagy in osteocytes. Considering that apoptosis and cell dysfunction are two common changes occurring in the osteocytes of osteoporotic bone, our findings suggest that PA could play a role in the pathogenesis of the disease. Suppression of these effects could bring new potential targets for therapeutic interventions in the future

The molecular pathogenesis of osteosarcoma: a review,” Sarcoma, vol

Osteosarcoma is the most common primary malignancy of bone. It arises in bone during periods of rapid growth and primarily affects adolescents and young adults. The 5-year survival rate for osteosarcoma is 60%-70%, with no significant improvements in prognosis since the advent of multiagent chemotherapy. Diagnosis, staging, and surgical management of osteosarcoma remain focused on our anatomical understanding of the disease. As our knowledge of the molecular pathogenesis of osteosarcoma expands, potential therapeutic targets are being identified. A comprehensive understanding of these mechanisms is essential if we are to improve the prognosis of patients with osteosarcoma through tumour-targeted therapies. This paper will outline the pathogenic mechanisms of osteosarcoma oncogenesis and progression and will discuss some of the more frontline translational studies performed to date in search of novel, safer, and more targeted drugs for disease management

Chondrogenesis of human infrapatellar fat pad stem cells on acellular dermal matrix

Acellular dermal matrix (ADM) has been in clinical use for decades in numerous surgical applications. The ability for ADM to promote cellular repopulation and revascularisation, and tissue regeneration is well documented. Adipose stem cells have the ability to differentiate into mesenchymal tissue types, including bone and cartilage. The aim of this study was to investigate the potential interaction between ADM and adipose stem cells in vitro using TGFβ3 and BMP6.Human infrapatellar fat pad derived adipose stem cells (IPFP-ASC) were cultured with ADM derived from rat dermis under chondrogenic (TGFβ3 and BMP6) in vitro for 2 and 4 weeks. Histology, qPCR and immunohistochemistry were performed to assess for markers of chondrogenesis (collagen Type II, SOX9 and proteoglycans). At 4 weeks, cell-scaffold constructs displayed cellular changes consistent with chondrogenesis, with evidence of stratification of cell layers and development of a hyaline-like cartilage layer superficially which stained positively for collagen Type II and proteoglycans. Significant cell-matrix interaction was seen between the cartilage layer and the ADM itself with seamless integration between each layer. Real time qPCR showed significantly increases of COL2A1, SOX9, and ACAN gene expression over 4 weeks when compared to control. COL1A2 gene expression remained unchanged over 4 weeks.We believe the principles which make ADM versatile and successful for tissue regeneration are application to cartilage regeneration. This study demonstrates in vitro the ability for IPFP-ASCs to undergo chondrogenesis, infiltrate and interact with ADM. These outcomes serve as a platform for in vivo modelling of ADM for cartilage repair