No abstract

Bone tissue, by definition, is an organic–inorganic nanocomposite, where metabolically active cells are embedded within a matrix that is heavily calcified on the nanoscale. Currently, there are no strategies that replicate these definitive characteristics of bone tissue. Here we describe a biomimetic approach where a supersaturated calcium and phosphate medium is used in combination with a non-collagenous protein analog to direct the deposition of nanoscale apatite, both in the intra- and extrafibrillar spaces of collagen embedded with osteoprogenitor, vascular, and neural cells. This process enables engineering of bone models replicating the key hallmarks of the bone cellular and extracellular microenvironment, including its protein-guided biomineralization, nanostructure, vasculature, innervation, inherent osteoinductive properties (without exogenous supplements), and cell-homing effects on bone-targeting diseases, such as prostate cancer. Ultimately, this approach enables fabrication of bone-like tissue models with high levels of biomimicry that may have broad implications for disease modeling, drug discovery, and regenerative engineering.

Although this study did not produce the outcomes desired, the literature supports a potential to use canines for human cancer detection. Better management of urine samples and a more stringent training protocol during our study may have provided new evidence as to the feasibility of using canines for cancer detection. A comparison of the 3 dog cancer scenting studies is also presented.

Dysregulation of the dopamine system is linked to various aberrant behaviors, including addiction, compulsive exercise, and hyperphagia leading to obesity. The goal of the present experiments was to determine how dopamine contributes to the expression of opposing phenotypes, excessive exercise and obesity. We hypothesized that similar alterations in dopamine and dopamine-related gene expression may underly obesity and excessive exercise, as competing traits for central reward pathways. Moreover, we hypothesized that selective breeding for high levels of exercise or obesity may have influenced genetic variation controlling these pathways, manifesting as opposing complex traits. Dopamine, dopamine-related peptide concentrations, and gene expression were evaluated in dorsal striatum (DS) and nucleus accumbens (NA) of mice from lines selectively bred for high rates of wheel running (HR) or obesity (M16), and the non-selected ICR strain from which these lines were derived. HPLC analysis showed significantly greater neurotransmitter concentrations in DS and NA of HR mice compared to M16 and ICR. Microarray analysis showed significant gene expression differences between HR and M16 compared to ICR in both brain areas, with changes revealed throughout the dopamine pathway including D1 and D2 receptors, associated G-proteins (eg. Golf), and adenylate cyclase (eg. Adcy5). The results suggest similar modifications within the dopamine system may contribute to the expression of opposite phenotypes in mice, demonstrating that alterations within central reward pathways can contribute to both obesity and excessive exercise.

Innate or acquired resistance to cancer therapeutics remains an important area of biomedical investigation that has clear ramifications for improving cancer specific death rates. Importantly, clues to key resistance mechanisms may lie in the well-orchestrated and highly conserved cellular and systemic responses to injury and stress. Many anti-neoplastic therapies typically rely on DNA damage, which engages potent DNA damage response signaling pathways that culminate in apoptosis or growth arrest at checkpoints to allow for damage repair. However, an alternative cellular response, senescence, can also be initiated when challenged with these internal/external pressures and in ideal situations acts as a self-protecting mechanism. Senescence-induction therapies are an attractive concept in that they represent a normal, highly conserved and commonly-invoked tumor-suppressing response to overwhelming genotoxic stress or oncogene activation. Yet, such approaches should ensure that senescence by-pass or senescence re-emergence does not occur, as emergent cells appear to have highly drug resistant phenotypes. Further, cell non-autonomous senescence responses may contribute to therapy-resistance in certain circumstances. Here we provide an overview of mechanisms by which cellular senescence plausibly contributes to therapy resistance and concepts by which senescence responses can be influenced to improve cancer treatment outcomes.

High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F(2) mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F(2) mice either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL x diet interaction effects. Here we describe effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer latency but increased tumor growth and pulmonary metastases occurrence over an equivalent time. We identified 25 modifier loci for mammary cancer and pulmonary metastasis, likely representing 13 unique loci after accounting for pleiotropy, and novel QTL x diet interactions at a majority of these loci. These findings highlight the importance of accurately modeling not only the human cancer characteristics in mice but also the environmental exposures of human populations.

Bone is an active organ that continuously undergoes an orchestrated process of remodeling throughout life. Bone tissue is uniquely capable of adapting to loading, hormonal, and other changes happening in the body, as well as repairing bone that becomes damaged to maintain tissue integrity. On the other hand, diseases such as osteoporosis and metastatic cancers disrupt normal bone homeostasis leading to compromised function. Historically, the ability to investigate processes related to either physiologic or diseased bone tissue is limited by traditional models that fail to emulate the complexity of native bone. Organ‐on‐a‐chip models are based on technological advances in tissue engineering and microfluidics, enabling the reproduction of key features specific to tissue microenvironments within a microfabricated device. Compared to conventional in vitro and in vivo bone models, microfluidic models, and especially organ‐on‐a‐chip platforms, provide more biomimetic tissue culture conditions, with increased predictive power for clinical assays. In this review, microfluidic and organ‐on‐a‐chip technologies designed for understanding the biology of bone as well as bone‐related diseases and treatments are reported. Finally, the authors discuss the limitations of the current models and point toward future directions for microfluidics and organ‐on‐a‐chip technologies in bone research.

Metastatic prostate cancers generally rely on androgen receptor (AR) signaling for growth and survival, even following systemic androgen deprivation therapy (ADT). However, recent evidence suggests that some advanced prostate cancers escape ADT by utilizing signaling programs and growth factors that bypass canonical AR ligand-mediated mechanisms. We utilized an in vitro high-throughput RNAi screen to identify pathways in androgen-dependent prostate cancer cell lines whose loss of function promotes androgen ligand-independent growth. We identified 40 genes where knockdown promoted proliferation of both LNCaP and VCaP prostate cancer cells in the absence of androgen. Of these, 14 were down-regulated in primary and metastatic prostate cancer, including two subunits of the protein phosphatase 2 (PP2A) holoenzyme complex: PPP2R1A, a structural subunit with known tumor-suppressor properties in several tumor types; and PPP2R2C, a PP2A substrate-binding regulatory subunit that has not been previously identified as a tumor suppressor. We demonstrate that loss of PPP2R2C promotes androgen ligand depletion-resistant prostate cancer growth without altering AR expression or canonical AR-regulated gene expression. Furthermore, cell proliferation induced by PPP2R2C loss was not inhibited by the AR antagonist MDV3100, indicating that PPP2R2C loss may promote growth independently of known AR-mediated transcriptional programs. Immunohistochemical analysis of PPP2R2C protein levels in primary prostate tumors determined that low PPP2R2C expression significantly associated with an increased likelihood of cancer recurrence and cancer-specific mortality. These findings provide insights into mechanisms by which prostate cancers resist AR-pathway suppression, and support inhibiting PPP2R2C complexes or the growth pathway(s) activated by PPP2R2C as a therapeutic strategy.