One Dog,but Which Dog? How Researchers Guide Participants to Select Dogs in Surveys of Human–Dog Relationships

Surveys and questionnaires are regularly used in studies of human–animal relationships. However, little attention has been given to understanding how survey participants are provided with instructions for the selection of a single animal within a multi-pet household, let alone the implications for reporting and interpreting data. We reviewed the instructions for the selection of an individual animal in studies addressing emotional or psychological attachment between people and dogs. By searching multidisciplinary journals from the year 2000 onwards, we identified a total of 128 papers, of which 63 met the inclusion criteria. Where selection criteria/instructions were not clear, authors were contacted. One in five studies (21%, or n = 13) did not report their instructions. When provided, instructions varied considerably. The most commonly provided direction was “favorite/closest relationship” (n = 12, or 19%). The remainder (n = 38, or 60%) were spread across eight different categories. Around half of the studies used a validated questionnaire that already contained an instruction, though a similar proportion of studies implemented author-designed instruments. Overall, the common absence and inconsistency of instructions for individual dog selection is taken to imply that there is no standard expectation or approach for instructions to be reported in studies of human relationships with dogs, or human–animal relationships more generally. We recommend further research on the implication of selection methods to ensure that instructions can be matched with specific research aims.     

Engineered exosomes: A new promise for the management of musculoskeletal diseases

Background

Exosomes are nanovesicles actively secreted by potentially all cell types, including tumour cells, with the primary role of extracellular systemic communication mediators, both at autocrine and paracrine levels, at short and long distances. Recently, different studies have used exosomes as a delivery system for a plethora of different molecules, such as drugs, microRNAs and proteins. This has been made possible thanks to the simplicity in exosomes engineering, their great stability and versatility for applications in oncology as well as in regenerative medicine.

Stochastic modeling of cellular colonies with quiescence: an application to drug resistance in cancer

Several cancers are thought to be driven by cells with stem cell like properties. An important characteristic of stem cells, which also applies to primitive tumor cells, is the ability to undergo quiescence, where cells can temporarily stop the cell cycle. Cellular quiescence can affect the kinetics of tumor growth, and the susceptibility of the cells to therapy. To study how quiescence affects treatment, we formulate a stochastic birth-death process with quiescence, on a combinatorial cellular mutation network, and consider the pre-treatment (growth) and treatment (decay) regimes. We find that, in the absence of mutations, treatment (if sufficiently strong) will proceed as a biphasic decline with the first (faster) phase driven by the elimination of the cycling cells and the second (slower) phase limited by the process of cell awakening. Other regimes are possible for weaker treatments. We also describe how the process of mutant generation is influenced by quiescence. Interestingly, for single-drug treatments, the probability to have resistance at start of treatment is independent of quiescence. For two or more drugs, the probability to have generated resistant mutants before treatment grows with quiescence. Finally, we study the influence of quiescence on the treatment phase. Starting from a given composition of mutants, the chances of treatment success are not influenced by the presence of quiescence.     

Structure,function, aging and turnover of aggrecan in the intervertebral disc

Background

Aggrecan is the major non-collagenous component of the intervertebral disc. It is a large proteoglycan possessing numerous glycosaminoglycan chains and the ability to form aggregates in association with hyaluronan. Its abundance and unique molecular features provide the disc with its osmotic properties and ability to withstand compressive loads. Degradation and loss of aggrecan result in impairment of disc function and the onset of degeneration.

Scope of review

This review summarizes current knowledge concerning the structure and function of aggrecan in the normal intervertebral disc and how and why these change in aging and degenerative disc disease. It also outlines how supplementation with aggrecan or a biomimetic may be of therapeutic value in treating the degenerate disc.

Major conclusions

Aggrecan abundance reaches a plateau in the early twenties, declining thereafter due to proteolysis, mainly by matrix metalloproteinases and aggrecanases, though degradation of hyaluronan and non-enzymic glycation may also participate. Aggrecan loss is an early event in disc degeneration, although it is a lengthy process as degradation products may accumulate in the disc for decades. The low turnover rate of the remaining aggrecan is an additional contributing factor, preventing protein renewal. It may be possible to retard the degenerative process by restoring the aggrecan content of the disc, or by supplementing with a bioimimetic possessing similar osmotic properties.

General significance

This review provides a basis for scientists and clinicians to understand and appreciate the central role of aggrecan in the function, degeneration and repair of the intervertebral disc.     

Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia

The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL⁺ CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL⁺ CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL⁺ cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL⁺ cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.     

Bortezomib and sphingosine kinase inhibitor interact synergistically to induces apoptosis in BCR/ABl cells sensitive and resistant to STI571 through down-regulation Mcl-1

Interactions between the proteasome inhibitor, bortezomib, and the sphingosine kinase (SPK1) inhibitor, SKI, were examined in BCR/ABL human leukemia cells. Coexposure of K562 or chronic myeloid leukemia (CML) cells from patients to subtoxic concentrations of SKI (10 μM) and bortezomib (100 nM) resulted in a synergistic increase in caspase-3 cleavage and apoptosis. These events were associated with the downregulation of BCR–ABL and Mcl-1, and a marked reduction in SPK1 expression. In imatinib mesylate-resistant K562 cells that displayed decreased BCR–ABL expression, bortezomib/SKI treatment markedly increased apoptosis and inhibited colony-formation in association with the downregulation of Mcl-1. Finally, the bortezomib/SKI regimen also potently induced the downregulation of BCR/ABL and Mcl-1 in human leukemia cells. Collectively, these findings suggest that combining SKI and bortezomib may represent a novel strategy in leukemia, including apoptosis-resistant BCR–ABL⁺ hematologic malignancies.