Decreased bone mass, osteoporosis, and increased fracture rates are common skeletal complications in patients with insulin-dependent diabetes mellitus (IDDM; type I diabetes). IDDM develops from little or no insulin production and is marked by elevated blood glucose levels and weight loss. In this study we use a streptozotocin-induced diabetic mouse model to examine the effect of type I diabetes on bone. Histology and microcomputed tomography demonstrate that adult diabetic mice, exhibiting increased plasma glucose and osmolality, have decreased trabecular bone mineral content compared with controls. Bone resorption could not completely account for this effect, because resorption markers (tartrate-resistant acid phosphatase 5b, urinary deoxypyridinoline excretion, and tartrate-resistant acid phosphatase 5 mRNA) are unchanged or reduced at 2 and/or 4 wk after diabetes induction. However, osteocalcin mRNA (a marker of late-stage osteoblast differentiation) and dynamic parameters of bone formation were decreased in diabetic tibias, whereas osteoblast number and runx2 and alkaline phosphatase mRNA levels did not differ. These findings suggest that the final stages of osteoblast maturation and function are suppressed. We also propose a second mechanism contributing to diabetic bone loss: increased marrow adiposity. This is supported by increased expression of adipocyte markers [peroxisome proliferator-activated receptor gamma2, resistin, and adipocyte fatty acid binding protein (alphaP2)] and the appearance of lipid-dense adipocytes in diabetic tibias. In contrast to bone marrow, adipose stores at other sites are depleted in diabetic mice, as indicated by decreased body, liver, and peripheral adipose tissue weights. These findings suggest that IDDM contributes to bone loss through changes in marrow composition resulting in decreased mature osteoblasts and increased adipose accumulation.

Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with poor prognosis and rising incidence. Late detection and a particularly aggressive biology are the major challenges which determine therapeutic failure. In this review, we present the current status and the recent advances in PDAC treatment together with the biological and immunological hallmarks of this cancer entity. On this basis, we discuss new concepts combining distinct treatment modalities in order to improve therapeutic efficacy and clinical outcome – with a specific focus on protocols involving radio(chemo)therapeutic approaches.

Mechanical loads can lead to matrix damage and chondrocyte death in articular cartilage. This damage has been implicated in the pathogenesis of secondary osteoarthritis. Studies on cartilage explants with the attachment of underlying bone at high rates of loading have documented cell death adjacent to surface lesions. On the other hand, studies involving explants removed from bone at low rates of loading suggest no clear spatial association between cell death and matrix damage. The current study hypothesized that the observed differences in the distribution of cell death in these studies are attributed to the rate of loading. Ninety bovine cartilage explants were cultured for two days. Sixty explants were loaded in unconfined compression to 40 MPa in either a fast rate of loading experiment (-900 MPa/s) or a low rate of loading experiment (40 MPa/s). The remaining 30 explants served as a control population. All explants were cultured for four days after loading. Matrix damage was assessed by measuring the total length and average depth of surface lesions and the release of glycosaminoglycans to the culture media. Explants were sectioned and stained with calcein and ethidium bromide homodimer to document the number of live and dead cells. Greater matrix damage was documented in explants subjected to a high rate of loading, compared to explants exposed to a low rate of loading. The high rate of loading experiments resulted in cell death adjacent to fissures, whereas more dead cells were observed in the low rate of loading experiments and a more diffuse distribution of dead cells was observed away from the fissures. In conclusion, this study indicated that the rate of loading can significantly affect the degree of inatrix damage, the distribution of dead cells, and the amount of cell death in unconfined compression experiments on explants of articular cartilage.

The induction of tumor cell death is one of the major goals of radiotherapy and has been considered to be the central determinant of its therapeutic outcome for a long time. However, accumulating evidence suggests that the success of radiotherapy does not only derive from direct cytotoxic effects on the tumor cells alone, but instead might also depend – at least in part – on innate as well as adaptive immune responses, which can particularly target tumor cells that survive local irradiation. The clearance of dying tumor cells by phagocytic cells of the innate immune system represents a crucial step in this scenario. Dendritic cells and macrophages, which engulf, process and present dying tumor cell material to adaptive immune cells, can trigger, skew, or inhibit adaptive immune responses, respectively. In this review we summarize the current knowledge of different forms of cell death induced by ionizing radiation, the multi-step process of dying cell clearance, and its immunological consequences with special regard toward the potential exploitation of these mechanisms for the improvement of tumor radiotherapy.

Our results indicate that physiologically relevant concentrations of GLN and CS can regulate gene expression and synthesis of NO and PGE(2), providing a plausible explanation for their purported anti-inflammatory properties.

Based on its potent capacity to induce tumor cell death and to abrogate clonogenic survival, radiotherapy is a key part of multimodal cancer treatment approaches. Numerous clinical trials have documented the clear correlation between improved local control and increased overall survival. However, despite all progress, the efficacy of radiation-based treatment approaches is still limited by different technological, biological, and clinical constraints. In principle, the following major issues can be distinguished: (1) The intrinsic radiation resistance of several tumors is higher than that of the surrounding normal tissue, (2) the true patho-anatomical borders of tumors or areas at risk are not perfectly identifiable, (3) the treatment volume cannot be adjusted properly during a given treatment series, and (4) the individual heterogeneity in terms of tumor and normal tissue responses toward irradiation is immense. At present, research efforts in radiation oncology follow three major tracks, in order to address these limitations: (1) implementation of molecularly targeted agents and ‘omics’-based screening and stratification procedures, (2) improvement of treatment planning, imaging, and accuracy of dose application, and (3) clinical implementation of other types of radiation, including protons and heavy ions. Several of these strategies have already revealed promising improvements with regard to clinical outcome. Nevertheless, many open questions remain with individualization of treatment approaches being a key problem. In the present review, the current status of radiation-based cancer treatment with particular focus on novel aspects and developments that will influence the field of radiation oncology in the near future is summarized and discussed.

Objective To determine whether glucosamine inhibits experimentally induced degradation of equine articular cartilage explants. Methods Articular cartilage was obtained from the antebrachio-carpal and middle joints of horses (2-8 years old) killed for reasons unrelated to lameness. Cartilage discs were harvested from the weight-bearing region of the articular surface and cultured. Media were exchanged daily and the recovered media stored at 4 degrees C. Explants were maintained in basal media 2 days prior to the start of four treatment days. On days 1-4 lipopolysaccharide (LPS, 10 microg/ml) or recombinant human interleukin-1 (rhIL-1, 50 ng/ml) were added to induce cartilage degradation. To test the potential protective effects of glucosamine, the compound was added in three concentrations (0.25, 2.5, or 25 mg/ml) and treatments were performed in triplicate. Controls included wells without LPS, rhIL-1beta, or glucosamine. Nitric oxide, proteoglycan and matrix metalloproteinases (MMP) released into conditioned media and tissue proteoglycan synthesis were measured as indicators of cartilage metabolism. Results Maximal nitric oxide production, proteoglycan release, and MMP activity were detected 1 day after the addition of LPS or rhIL-1beta to the media. The addition of 25 mg/ml of glucosamine prevented the increase in nitric oxide production, proteoglycan release and MMP activity induced by LPS or rhIL-1. Conclusions These data indicate that glucosamine can prevent experimentally induced cartilage degradation in vitro.

SUMMARY Faithful transmission of genomic information requires tight spatiotemporal regulation of DNA replication factors. In the licensing step of DNA replication CDT-1 is loaded onto chromatin to subsequently promote the recruitment of additional replication factors including CDC-45 and GINS. During the elongation step the CDC-45/GINS complex moves with the replication fork, however it is largely unknown how its chromatin association is regulated. Here, we show that the chaperone-like ATPase CDC-48/p97 coordinates degradation of CDT-1 with release of the CDC-45/GINS complex. C. elegans embryos lacking CDC-48 or its cofactors UFD-1/NPL-4 accumulate CDT-1 on mitotic chromatin, indicating a critical role of CDC-48 in CDT-1 turnover. Strikingly, CDC-48UFD-1/NPL-4 deficient embryos show persistent chromatin association of CDC-45/GINS, which is a consequence of CDT-1 stabilization. Moreover, our data confirmed a similar regulation in Xenopus egg extracts, emphasizing a conserved coordination of licensing and elongation events during eukaryotic DNA replication by CDC-48/p97.