Metastatic carcinoma of the prostate mimicking primary carcinoid tumor of the lung and mediastinum

AIMS: To investigate the current use of thrombolytic therapy in the management of patients with acute myocardial infarction and to determine the potential for an increased use of thrombolysis or percutaneous transluminal coronary angioplasty (PTCA). METHODS AND RESULTS: All hospitalised cases of acute myocardial infarction were identified in three health districts in the UK (population of 960,000) in patients under the age of 76 years during a 2-year period; 2439 patients had acute myocardial infarction, of whom 1264 (52%) received thrombolytic therapy. Failure to administer thrombolytic therapy was a result of the absence of diagnostic electrocardiograms in 712 (29.2%) patients, late presentation in 127 (5.2%), therapeutic error in 112 (4.6%), presence of a bleeding risk in 139 (5.7%) and other miscellaneous reasons in 80 (3.3%) patients. Thirty-eight of the 139 patients in whom bleeding risk was reported as a contra-indication could, in retrospect, have received thrombolytic therapy and a further 76 would have been suitable for primary PTCA. CONCLUSIONS: The potential for increasing the use of thrombolytic therapy seems to be limited and is unlikely to make a major impact on the in-hospital mortality from acute myocardial infarction. However, primary PTCA should be considered in those who are ineligible for thrombolysis because of bleeding risk as a contra-indication.     

Phosphatidylinositol 3-kinase-gamma activates Bruton's tyrosine kinase in concert with Src family kinases

Bruton's tyrosine kinase (Btk) is essential for normal B lymphocyte development and function. The activity of Btk is partially regulated by transphosphorylation within its kinase domain by Src family kinases at residue Tyr-551 and subsequent autophosphorylation at Tyr-223. Activation correlates with Btk association with cellular membranes. Based on specific loss of function mutations, the Btk pleckstrin homology (PH) domain plays an essential role in this activation process. The Btk PH domain can bind in vitro to several lipid end products of the phosphatidylinositol 3-kinase (PI 3-kinase) family including phosphatidylinositol 3,4,5-trisphosphate. Activation of Btk as monitored by elevation of phosphotyrosine content and a cellular transformation response was dramatically enhanced by coexpressing a weakly activated allele of Src (E378G) and the two subunits of PI 3-kinase-gamma. This activation correlates with new sites of phosphorylation on Btk identified by two-dimensional phosphopeptide mapping. Activation of Btk was dependent on the catalytic activity of all three enzymes and an intact Btk PH domain and Src transphosphorylation site. These combined data define Btk as a downstream target of PI 3-kinase-gamma and Src family kinases.     

Extracorporeal photochemotherapy (photopheresis) induces apoptosis in lymphocytes: a possible mechanism of action of PUVA therapy

The mechanism of action of psoralen plus UVA (PUVA) and photopheresis is not entirely understood. These therapies are assumed to be immunomodulating partly by gradually decreasing leukocyte viability. We investigated whether this delayed form of cell death was due to apoptosis. Untreated and treated (PUVA exposed) leukocytes obtained from six patients with systemic sclerosis and (untreated) leukocytes from healthy control individuals were studied. Qualitative gel electrophoresis and quantitative in situ nick translation analysis of DNA fragmentation was performed. Apoptosis of the treated cells did occur (gel electrophoresis) after 24 h. At t = 0 h, immediately after exposure to PUVA, there was no evidence of DNA fragmentation in the treated cells. The percentage of treated cells undergoing apoptosis was 20-55% at t = 24 h (in situ nick translation). The untreated leukocytes of the patients and the healthy individuals showed no distinctive rise in apoptotic cells. Apoptosis of the leukocytes after PUVA or photopheresis treatment might be a mechanism of action and might explain the therapeutic response.     

An analytical method for selecting the optimal nozzle external geometry for fluid dynamic gauging

Fluid dynamic gauging (FDG) was developed to measure, in situ and in real time, the thickness of a soft deposit layer immersed in a liquid without contacting the surface of the layer. An analysis based on the lubrication assumption for the flow patterns in the space between the nozzle and the surface being gauged yielded analytical expressions for the relationships between the main flow variables and system parameters. Nozzle shapes for particular pressure, pressure gradient and shear stress profiles could then be identified. The effect of flow rate, nozzle geometry and nozzle position on the pressure beneath the nozzle and shear stress on the gauged surface showed very good agreement with computational fluid dynamics (CFD) simulations. Case studies presented include nozzle shapes for uniform pressure and shear stress profiles, which are useful for measuring the strength of soft deposit layers.     

A Fragrance Prediction Model for Molecules Using Rough Set-based Machine Learning

In this work, a novel machine learning based methodology was developed to predict fragrance from the molecular structure and the effect of the subjects attributes on odour perception. As fragrance is linked to the molecular structure and interactions, topological indices are used to develop a predictive model. Rough set-based machine learning is used to generate rule-based models that link the topology of fragrant molecules and dilution to their respective odour characteristics. The results show that the generated models are effective in determining the odour characteristic of molecules.     

Intrusive probes in riser applications

Many of the probes used to understand hydrodynamics in circulating fluidized bed risers intrude into the environment they are measuring, although assumptions are typically asserted that the intrusive probes do not affect the data collected. This could be a poor assumption in some cases and conditions. We found that intrusive fiber‐optic probe measurements consistently mis‐predicted the solids concentration compared to the nonintrusive pressure drop measurements outside the fully developed flow region of a riser containing fluid catalytic cracking catalyst or glass bead particles. The discrepancy was sensitive to superficial gas velocity, solid circulation rate, probe position, and flow direction. Barracuda VR? computational fluid dynamics simulations confirmed this, and indicated that particle momentum was lost at the leading edge of the probe and particles were spilling over to the probe tip. Accordingly, new probe designs were proposed to mitigate the intrusiveness of a fiber‐optic probe for more accurate characterization. © 2017 American Institute of Chemical Engineers AIChE J, 63: 5361–5374, 2017     

Influence of Fillers on Sizing Efficiency and Hydrolysis of Alkyl Ketene Dimer

The influence of various fillers on sizing efficiency, adsorption and hydrolysis of alkyl ketene dimer (AKD) has been investigated. Results indicated that the precipitated calcium carbonate (PCC) improved AKD retention, both bound and unbound. The sizing efficiency was reduced as PCC contents increased, which might be attributed to the decrease in the relative AKD dosage to fibres and AKD hydrolysis promoted by PCC. Less amount of AKD was adsorbed on PCC, compared with calcined clay and TiO₂ fillers under the same conditions. Hydrolysis studies indicated that PCC had a more detrimental effect on AKD hydrolysis than clay and TiO₂.     

Investigating T Cell Immunity in Cancer: Achievements and Prospects

T cells play a key role in tumour surveillance, both identifying and eliminating transformed cells. However, as tumours become established they form their own suppressive microenvironments capable of shutting down T cell function, and allowing tumours to persist and grow. To further understand the tumour microenvironment, including the interplay between different immune cells and their role in anti-tumour immune responses, a number of studies from mouse models to clinical trials have been performed. In this review, we examine mechanisms utilized by tumour cells to reduce their visibility to CD8⁺ Cytotoxic T lymphocytes (CTL), as well as therapeutic strategies trialled to overcome these tumour-evasion mechanisms. Next, we summarize recent advances in approaches to enhance CAR T cell activity and persistence over the past 10 years, including bispecific CAR T cell design and early evidence of efficacy. Lastly, we examine mechanisms of T cell infiltration and tumour regression, and discuss the strengths and weaknesses of different strategies to investigate T cell function in murine tumour models.     

Outer Membrane Vesicle Production by Helicobacter pylori Represents an Approach for the Delivery of Virulence Factors CagA,VacA and UreA into Human Gastric Adenocarcinoma (AGS) Cells

Helicobacter pylori infection is the etiology of several gastric-related diseases including gastric cancer. Cytotoxin associated gene A (CagA), vacuolating cytotoxin A (VacA) and α-subunit of urease (UreA) are three major virulence factors of H. pylori, and each of them has a distinct entry pathway and pathogenic mechanism during bacterial infection. H. pylori can shed outer membrane vesicles (OMVs). Therefore, it would be interesting to explore the production kinetics of H. pylori OMVs and its connection with the entry of key virulence factors into host cells. Here, we isolated OMVs from H. pylori 26,695 strain and characterized their properties and interaction kinetics with human gastric adenocarcinoma (AGS) cells. We found that the generation of OMVs and the presence of CagA, VacA and UreA in OMVs were a lasting event throughout different phases of bacterial growth. H. pylori OMVs entered AGS cells mainly through macropinocytosis/phagocytosis. Furthermore, CagA, VacA and UreA could enter AGS cells via OMVs and the treatment with H. pylori OMVs would cause cell death. Comparison of H. pylori 26,695 and clinical strains suggested that the production and characteristics of OMVs are not only limited to laboratory strains commonly in use, but a general phenomenon to most H. pylori strains.