The Role of Extracellular Vesicles in Cancer

Intercellular communication is a key feature of cancer progression and metastasis. Extracellular vesicles (EVs) are generated by all cells, including cancer cells, and recent studies have identified EVs as key mediators of cell-cell communication via packaging and transfer of bioactive constituents to impact the biology and function of cancer cells and cells of the tumor microenvironment. Here, we review recent advances in understanding the functional contribution of EVs to cancer progression and metastasis, as cancer biomarkers, and the development of cancer therapeutics

Cell culture metabolomics in the diagnosis of lung cancer - The influence of cell culture conditions

Lung cancer is the leading cause of cancer deaths. Unfortunately, lung cancer is often diagnosed only when it becomes symptomatic or at an advanced stage when few treatment options are available. Hence, a diagnostic test suitable for screening widespread populations is required to enable earlier diagnosis. Analysis of exhaled breath provides a non-invasive method for early detection of lung cancer. Analysis of volatile organic compounds (VOCs) by various mass spectral techniques has identified potential biomarkers of disease. Nevertheless, the metabolic origins and the disease specificity of VOCs need further elucidation. Cell culture metabolomics can be used as a bottom-up approach to identify biomarkers of pathological conditions and can also be used to study the metabolic pathways that produce such compounds. This paper summarizes the current knowledge of lung cancer biomarkers in exhaled breath and emphasizes the critical role of cell culture conditions in determining the VOCs produced in vitro. Hypoxic culture conditions more closely mimic the conditions of cancer cell growth in vivo. We propose that since hypoxia influences cell metabolism and so potentially the VOCs that the cancer cells produce, the cell culture metabolomics projects should consider culturing cancer cells in hypoxic conditions

The epithelial–mesenchymal transition: new insights in signaling, development, and disease

The conversion of an epithelial cell to a mesenchymal cell is critical to metazoan embryogenesis and a defining structural feature of organ development. Current interest in this process, which is described as an epithelial–mesenchymal transition (EMT), stems from its developmental importance and its involvement in several adult pathologies. Interest and research in EMT are currently at a high level, as seen by the attendance at the recent EMT meeting in Vancouver, Canada (October 1–3, 2005). The meeting, which was hosted by The EMT International Association, was the second international EMT meeting, the first being held in Port Douglas, Queensland, Australia in October 2003. The EMT International Association was formed in 2002 to provide an international body for those interested in EMT and the reverse process, mesenchymal–epithelial transition, and, most importantly, to bring together those working on EMT in development, cancer, fibrosis, and pathology. These themes continued during the recent meeting in Vancouver

An analysis of isothermal, bithermal, and thermomechanical fatigue data of Haynes 188 and B1900+Hf by energy considerations

The low-cycle fatigue behavior of Haynes 188 and B1900+Hf under isothermal, bithermal, and thermomechanical loading conditions has been analyzed on the basis of the total hysteresis energy expended per cycle. It has been observed that in the case of isothermal fatigue the total hysteresis energy correlates well with the fatigue life. In the case of bithermal 'high rate' fatigue, for a given total hysteresis energy per cycle, the fatigue life is equal to or greater than the isothermal fatigue life at the maximum bithermal temperature. This observation could be used to establish a lower bound on life for design purposes. In one case of bithermal creep-fatigue and in thermomechanical fatigue, the life is shorter than that corresponding to the isothermal life at the maximum temperature. The energy supplied, per se, may not always give a systematic correlation with the fatigue life in the cases where time-dependent creep and environmental effects are encountered. Thus, in bithermal creep-fatigue and thermomechanical fatigue, the role of creep and environment and their dependence on the energy supplied have to be properly accounted for before the energy term can be used for life prediction

Genome-wide analysis of Aux/IAA and ARF gene families in Populus trichocarpa

<p>Abstract</p> <p>Background</p> <p>Auxin/Indole-3-Acetic Acid (Aux/IAA) and Auxin Response Factor (ARF) transcription factors are key regulators of auxin responses in plants. We identified the suites of genes in the two gene families in <it>Populus </it>and performed comparative genomic analysis with <it>Arabidopsis </it>and rice.</p> <p>Results</p> <p>A total of 35 <it>Aux/IAA </it>and 39 <it>ARF </it>genes were identified in the <it>Populus </it>genome. Comparative phylogenetic analysis revealed that several Aux/IAA and ARF subgroups have differentially expanded or contracted between the two dicotyledonous plants. Activator <it>ARF </it>genes were found to be two fold-overrepresented in the <it>Populus </it>genome. <it>PoptrIAA </it>and <it>PoptrARF </it>gene families appear to have expanded due to high segmental and low tandem duplication events. Furthermore, expression studies showed that genes in the expanded <it>PoptrIAA3 </it>subgroup display differential expression.</p> <p>Conclusion</p> <p>The present study examines the extent of conservation and divergence in the structure and evolution of <it>Populus Aux/IAA </it>and <it>ARF </it>gene families with respect to <it>Arabidopsis </it>and rice. The gene-family analysis reported here will be useful in conducting future functional genomics studies to understand how the molecular roles of these large gene families translate into a diversity of biologically meaningful auxin effects.</p

New compartment model analysis of lean-mass and fat-mass growth with overfeeding

Objectives: Mathematical models of lean- and fat-mass growth with diet are useful to help describe and potentially predict the fat- and lean-mass change with different diets as a function of consumed protein and fat calories. Most of the existing models do not explicitly account for interdependence of fat-mass on the lean-mass and vice versa. The aim of this study was to develop a new compartmental model to describe the growth of lean and fat mass depending on the input of dietary protein and fat, and accounting for the interdependence of adipose tissue and muscle growth. Methods: The model was fitted to existing clinical data of an overfeeding trial for 23 participants (with a high-protein diet, a normal-protein diet, and a low-protein diet) and compared with the existing Forbes model. Results: Qualitatively and quantitatively, the compartment model data fit was smoother with less overall error than the Forbes model. The root means square error were 0.39, 0.93 and 0.72 kg for the new model, the Forbes model, and the modified Forbes model, respectively. Additionally, for the present model, the differences between some of the coefficients (on the cross dependence of fat and lean mass as well as on the intake diet dependence) across different diets were statistically significant (P \u3c 0.05). Conclusions: Our new Dey-model showed excellent fit to overfeeding data for 23 normal participants with some significant differences of model coefficients across diets, enabling further studies of the model coefficients for larger groups of participants with obesity or other diseases

Test Methodology Development for Experimental Structural Assessment of ASC Planar Spring Material for Long-Term Durability

A vibration-based testing methodology has been developed that will assess fatigue behavior of the metallic material of construction for the Advanced Stirling Convertor displacer (planar) spring component. To minimize the testing duration, the test setup is designed for base-excitation of a multiplespecimen arrangement, driven in a high-frequency resonant mode; this allows completion of fatigue testing in an accelerated period. A high performance electro-dynamic exciter (shaker) is used to generate harmonic oscillation of cantilever beam specimens, which are clasped on the shaker armature with specially-designed clamp fixtures. The shaker operates in closed-loop control with dynamic specimen response feedback provided by a scanning laser vibrometer. A test coordinator function synchronizes the shaker controller and the laser vibrometer to complete the closed-loop scheme. The test coordinator also monitors structural health of the test specimens throughout the test period, recognizing any change in specimen dynamic behavior. As this may be due to fatigue crack initiation, the test coordinator terminates test progression and then acquires test data in an orderly manner. Design of the specimen and fixture geometry was completed by finite element analysis such that peak stress does not occur at the clamping fixture attachment points. Experimental stress evaluation was conducted to verify the specimen stress predictions. A successful application of the experimental methodology was demonstrated by validation tests with carbon steel specimens subjected to fully-reversed bending stress; high-cycle fatigue failures were induced in such specimens using higher-than-prototypical stresse

CNS demyelinating events in primary Sjogren's syndrome: A single-center case series on the clinical phenotype

ObjectiveThe study aimed to assess the prevalence, clinical characteristics, and therapeutic outcomes of the central nervous system (CNS) demyelinating disease in a large cohort of primary Sjogren's syndrome (pSS). MethodsThis is an explorative cross-sectional study of patients with pSS seen in the departments of rheumatology, otorhinolaryngology, or neurology of a tertiary university center between January 2015 and September 2021. ResultsIn a cohort of 194 pSS patients, 22 patients had a CNS manifestation. In this CNS group, 19 patients had a lesion pattern suggestive of demyelination. While there were no obvious differences in the patients' epidemiological disposition or rate of other extraglandular manifestations, the CNS group differed from the remaining patients with pSS by having less glandular manifestations but a higher seroprevalence for anti-SSA/Ro antibodies. Notably, patients with CNS manifestations were often diagnosed with multiple sclerosis (MS) and treated as such, although age and disease course were atypical of MS. Many first-line MS agents were ineffective in these MS look-alikes;however, the disease course was benign with B-cell-depleting agents. ConclusionNeurological symptoms of pSS are common and clinically manifest mainly as myelitis or optic neuritis. Notably, in the CNS, the pSS phenotype can overlap with MS. The prevailing disease is crucial since it has a major impact on the long-term clinical outcome and the choice of disease-modifying agents. Although our observations neither confirm pSS as a more appropriate diagnosis nor rule out simple comorbidity, physicians should consider pSS in the extended diagnostic workup of CNS autoimmune diseases

'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention