Effects of a Rehabilitation Program Combined with Pain Management That Targets Pain Perception and Activity Avoidance in Older Patients with Acute Vertebral Compression Fracture: a Randomised Controlled Trial

This study aimed to investigate the efect of a rehabilitation program combined with pain management targeting pain perception and activity avoidance on multifaceted outcomes in older patients with acute vertebral compression fractures (VCFs). We randomised 65 older adults with acute VCFs to either an intervention group (n = 32), involving usual rehabilitation combined with pain management that targeted pain perception and activity avoidance, or a control group (n = 33), involving only usual rehabilitation. Te usual rehabilitation was initiated immediately after admission. All patients were treated conservatively. Pain management aimed to improve the patients’ daily behaviour by increasing their daily activities despite pain, rather than by focusing on eliminating the pain. Pain intensity and psychological statuses such as depression, pain catastrophising, and physical activity levels were assessed on admission. Two weeks postadmission and at discharge, physical performance measures were assessed along with the above-given measurements. A signifcant main efect of the group was observed for the intensity of lower back pain, favouring the intervention group (F = 5.135, p = 0.027). At discharge, it was signifcantly better in the intervention group than in the control group (p = 0.011). A time-by-group interaction emerged for magnifcation of the pain catastrophising scale (p = 0.012), physical activity levels (p < 0.001), and six-minute walking distance (p = 0.006), all favouring the intervention group. Rehabilitation programs combined with pain management targeting pain perception and activity avoidance could be an efective conservative treatment for older patients with acute VCFs

Relationship of Grade of Malignant Brain Tumor to Cancer Stem Cells and Survivin Expression

Glioblastoma (GBM) is difficult to completely cure by surgical treatment alone, and it is generally treated with a combination of surgery, radiotherapy, and chemotherapy. However, GBM is resistant to radiotherapy and chemotherapy, and complete cure cannot be achieved. Cancer stem cells (CSC) and survivin, which inhibit apoptosis, are considered as factors underlying tumor recurrence and the radiation- and drug-resistance of these tumors. We analyzed CSC and survivin expression in surgically excised specimens of malignant brain tumors to establish the relationships between the grades and CSC and survivin expression and between MIB-1 (Ki-67) expression and resistance. No relationship was noted between the grades and CSC or survivin expression, or between MIB-1 and CSC expression or between Grade 3 and 4 MIB-1 and survivin expression, although a correlation was noted between MIB-1 and survivin expression in Grade II tumors. These findings suggested that CSC are consistently contained in tumor tissue at a specific rate regardless of the histological grade, and the apoptosis of cells with low-level proliferative and cell cycling activities does not occur because these cells do not respond to chemotherapy or radiation, being resistant to treatment

Characterization of the novel mutant A78T-HERG from a long QT syndrome type 2 patient: Instability of the mutant protein and stabilization by heat shock factor 1

Background:The human ether-a-go-go-related gene (HERG) encodes the α-subunit of rapidly activating delayed-rectifier potassium channels. Mutations in this gene cause long QT syndrome type 2 (LQT2). In most cases, mutations reduce the stability of the channel protein, which can be restored by heat shock (HS). Methods: We identified the novel mutant A78T-HERG in a patient with LQT2. The purpose of the current study was to characterize this mutant protein and test whether HS and heat shock factors (HSFs) could stabilize the mutant protein. A78T-HERG and wild-type HERG (WT-HERG) were expressed in HEK293 cells and analyzed by immunoblotting, immunoprecipitation, immunofluorescence, and whole-cell patch clamping. Results: When expressed in HEK293 cells, WT-HERG gave rise to immature and mature forms of the protein at 135 and 155 kDa, respectively. A78T-HERG gave rise only to the immature form, which was heavily ubiquitinated. The proteasome inhibitor MG132 increased the expression of immature A78T-HERG and increased both the immature and mature forms of WT-HERG. WT-HERG, but not A78T-HERG, was expressed on the plasma membrane. In whole-cell patch clamping experiments, depolarizing pulses evoked E4031-sensitive HERG channel currents in cells transfected with WT-HERG, but not in cells transfected with A78T-HERG. The A78V mutant, but not A78G mutant, remained in the immature form similarly to A78T. Maturation of the A78T-HERG protein was facilitated by HS, expression of HSF-1, or exposure to geranyl geranyl acetone. Conclusions: A78T-HERG was characterized by protein instability and reduced expression on the plasma membrane. The stability of the mutant was partially restored by HSF-1, indicating that HSF-1 is a target for the treatment for LQT2 caused by the A78T mutation in HERG

Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells

The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis

Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness

Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes

Ring-Opening Fluorination of Isoxazoles

A ring-opening fluorination of isoxazoles has been developed. By treating isoxazoles with an electrophilic fluorinating agent (Selectfluor®), fluorination followed by deprotonation leads to tertiary fluorinated carbonyl compounds. The present method features mild reaction conditions, good functional group tolerance, and simple experimental procedure. Diverse transformations of the resulting α-fluorocyanoketones were also demonstrated, furnishing a variety of fluorinated compounds

Syntheses of Various Hydrophobic Substrates for Enzyme Model Kinetics

Successful preparations of novel p-nitrophenyl esters and p-nitroanilides of various caboxylic acids have been presented. All the esters and anilides have a hydrophobic alkyl group, which would be expected as a suitable substrate for the enzyme-model reactions such as macrocyclic or aqueous micellar system. In addition to the above substrates three pseudo-substrates commonly bearing a p-nitrophenyl moiety with different alkyl chain residues have also been prepared. These newly prepared compounds were characterized by means of IR and NMR spectroscopy and elemental analysis as well. Satisfactory results have been obtained for each compound