Interleukin-1α enhances the aggressive behavior of pancreatic cancer cells by regulating the α(6)β(1)-integrin and urokinase plasminogen activator receptor expression

BACKGROUND: In human pancreatic cancer progression, the α(6)β(1)-integrin is expressed on cancer cell surface during invasion and metastasis formation. In this study, we investigated whether interleukin (IL)-1α induces the alterations of integrin subunits and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) expression in pancreatic cancer cells. We hypothesize that the alterations of integrin subunits and uPA/uPAR expression make an important role in signaling pathways responsible for biological behavior of pancreatic cancer cells. RESULTS: IL-1α upregulated the expression of α(6 )and β(1 )integrins without any alterations of α(5 )and α(v )integrins expression. IL-1α also induced enhancement in the expression of uPA/uPAR in pancreatic cancer cells. IL-1α enhanced the proliferation, adhesion, and migration in pancreatic cancer cells, and IL-1α-induced alterations of uPA/uPAR expression correlated with the increased the migration of pancreatic cancer cells. Upregulation of α(6 )integrin subunit and uPA/uPAR correlated with the activation of Ras and downstream extracellular signal-regulated kinase (ERK) pathways. IL-1α-induced activation of Ras and downstream ERK can be inhibited by using inhibitory antibodies against α(6 )and β(1 )integrin and uPAR, consistent with the inhibition of proliferation, adhesion and migration of pancreatic cancer cells. Immunohistochemical analysis demonstrated a significant association between strong expressions of α(6 )integrin with uPAR in pancreatic cancer specimens. Furthermore, the strong expression of α(6 )integrin and uPAR was found to be independent prognosticator in pancreatic cancer patients. CONCLUSION: Based on these findings, we conclude that IL-1α can induce selective upregulation of α(6)β(1)-integrin and uPA/uPAR in pancreatic cancer cells and these changes may modulate the aggressive functions of pancreatic cancer

Role of cysteine residues in the V(V)-reductase activity of Vanabin2

Ascidians (tunicates or sea squirts) accumulate extremely high levels of vanadium as the reduced form V(III) in extremely acidic vacuoles in their blood cells. Several key proteins related to vanadium accumulation have been isolated from vanadium-rich ascidians and their physiological functions characterized. Of these, vanabins are small, cysteine-rich proteins that have been identified only in vanadium-rich ascidians. Our previous study revealed that Vanabin2 can act as a V(V)-reductase. The current study examines the role of cysteine and several other amino acid residues of Vanabin2 in V(V)-reduction. When all eighteen cysteine residues of Vanabin2 were substituted with serine residues, the V(V)-reductase activity was lost. Substitutions of three, structurally clustered cysteines in three different regions resulted in a moderate decrease in reductase activity, suggesting that more than a single cysteine pair is responsible for the V(V)-reductase activity of Vanabin2. Mutations in the V(IV)-binding domains caused either an increase or decrease in activity but no mutation caused the complete loss of activity. These results suggest that some pairs, but more than a single pair, of cysteine residues are necessary for the V(V)-reductase activity of Vanabin2

Expression in E. coli of finger-domain lacking tissue-type plasminogen activator with high fibrin affinity

AbstractTissue-type plasminogen activator (t-PA) has a high affinity for fibrin and induces lysis of fibrin (fibrinolysis) on the surface of fibrin without degrading circulating fibrinogen. cDNA for t-PA which lacks the ‘fingerdomain’ (the site for fibrin affinity) was isolated from Detroit 562 cells. Analysis of the nucleotide sequence revealed a lack of the sequences which code for the finger-domain. A plasmid (pDPAT 1) containing the Escherichia coli tac promoter/operator and the cDNA sequence coding for ‘finger-domain lacking t-PA’ was constructed for expression in E. Coli. The polypeptide so produced was a new type of t-PA lacking finger-domain, but revealed plasminogen activator activity with the function of fibrin affinity.Tissue-type plasminogen activatorFinger-domainFibrin affinityPlasmid E. coli tac promoter/operatorDetroit 562 cel

Selective metal binding by Vanabin2 from the vanadium-rich ascidian, Ascidia sydneiensis samea

Vanadium-binding proteins, or Vanabins, have recently been isolated from the vanadium-rich ascidian, Ascidia sydneiensis samea. Recent reports indicate that Vanabin2 binds twenty V(IV) ions at pH 7.5, and that it has a novel bow-shaped conformation. However, the role of Vanabin2 in vanadium accumulation by the ascidian has not yet been determined. In the present study, the effects of acidic pH on selective metal binding to Vanabin2 and on the secondary structure of Vanabin2 were examined. Vanabin2 selectively bound to V(IV), Fe(III), and Cu(II) ions under acidic conditions. In contrast, Co(II), Ni(II), and Zn(II) ions were bound at pH 6.5 but not at pH 4.5. Changes in pH had no detectable effect on the secondary structure of Vanabin2 under acidic conditions, as determined by circular dichroism spectroscopy, and little variation in the dissociation constant for V(IV) ions was observed in the pH range 4.5-7.5, suggesting that the binding state of the ligands is not affected by acidification. Taken together, these results suggest that the reason for metal ion dissociation upon acidification is attributable not to a change in secondary structure but, rather, that it is caused by protonation of the amino acid ligands that complex with V(IV) ions

A severe skeletal Class III malocclusion treated with Le Fort I combined with sagittal split ramus osteotomy, mandibular body ostectomy and tongue reduction surgery. A case report

This case report describes the orthodontic-orthognathic management of a 17-year-old male patient with extremely severe skeletal Class III malocclusion due to a marked mandibular protrusion with a small and narrowed upper jaw which increased the remarkable concave facial profile. Dental articulation was entirely lacking, resulting in great difficulty in masticating food. A two-jaw surgery combined with mandibular body ostectomy was performed to correct mandibular asymmetry and the severe sagittal skeletal discrepancy (Wits appraisal –36.5 mm and ANB angle –14.3°). Bi-maxillary surgery was performed in two-stages; the first surgery consisted of maxillary advancement with Le Fort I osteotomy followed by a second surgery where a combination of sagittal split ramus osteotomy (SSRO) and mandibular body ostectomy was performed to correct the severe mandibular prognathism. A partial glossectomy was also carried out to address macroglossia. After a total treatment time of 32 months, a Class I occlusion with a favorable facial profile and lip competence were obtained. The occlusion was made approximately ideal, and mastication improved remarkably. Three years after retention, the occlusion was stable and no relapse was observed. The patient’s complaints and orthodontic problems were completely resolved. Therefore, a combination of two-jaw surgeries with Le Fort I maxillary osteotomy, mandibular SSRO, mandibular ostectomy, and glossectomy may be a viable option in the correction of extremely severe anteroposterior skeletal discrepancy

Comparison of Cerebral Blood Volume during Cold and Warm Stimulation in Elderly and Young Subjects

Background: Dementia involves a neuronal loss in the primary somatosensory cortex of the parietal lobe, causing dementia patients to perceive pain stimuli hardly. The function of temperature sensation declines. Studies measuring brain blood volume using near-infrared light have reported that patients suffering from dementia have less activation than healthy elderly people. However, the majority of these studies used tests related to cognitive function and the frontal lobe, and few have examined thermal sensation.Objective: The present study aimed to investigate the effect of cold and warm stimulation on cerebral blood volume in elderly and young subjects.Material and Methods: This observational study measured changes in oxygenated hemoglobin concentrations in the frontal cortex during cold and warm stimulation in elderly and young subjects using a near-infrared light device. The mean and standard deviation of the change in oxygenated hemoglobin concentration before and after cold and warm stimulation, as well as the center-of-gravity values, were compared between the young and the elderly.Results: During warm stimulation, the younger subjects showed an increase in blood oxygenated hemoglobin levels; however, the difference was not significant. For the elderly, no change was observed during the task. The center of gravity values was lower in the young compared to the elderly which was similar to the reaction threshold. No significant changes were observed during cold stimulation. Conclusion: Thermal sensation thresholds were impaired in the elderly compared to the young; however, cerebral blood volume changes were unclear

A novel fiber-optic based 0.014 '' pressure wire: Designs of the OptoWire (TM), development phases, and the O-2 first-in-man results

Objectives To review the technical limitations of available pressure-wires, present the design evolution of a nitinol fiber-optic pressure wire and to summarize the First-in-Man (FIM) O-2 pilot study results. Background Despite increasing use of physiology assessment of coronary lesions, several technical limitations persist. We present technical details, design evolution and early clinical results with a novel 0.014 '' nitinol fiber-optic based pressure-wire. Methods and Results The 0.014' OptoWire (TM) (Opsens Medical, Quebec, Canada) was designed to combine improved handling properties compared to standard pressure-wires and to offer extremely reliable pressure recording and transmission due to fiber-optic properties compared to piezo-electric sensors and electrical wires. In vitro assessment showed that OptoWire (TM) steerability, pushability and torquability properties were closer to regular PCI wires than standard electrical pressure wires. In the First-in-Man O(2)study, 60 patients were recruited at 2 centers in Canada. A total of 103 lesions were assessed with the OptoWire (TM) and OptoMonitor (TM), 75 lesions at baseline and 28 lesions post-PCI (without disconnection). In all crossed lesions (n = 100, 97%), mean Pd/Pa and FFR could be adequately measured. In 11 cases assessed successively with OptoWire (TM) and Aegis (TM) (Abbott Vascular, USA) bland-Altman analysis showed a mean difference of 0.002 +/- 0.052 mmHg (p = .91) for Pd/Pa and 0.01 +/- 0.06 for FFR calculation (p= .45). There was no device-related complication. Upon these initial results, several design changes aimed to improve overall performance including torquability, stiffness, resistance to kink and pressure drift were completed. Conclusion The novel 0.014 '' fiber-optic OptoWire (TM) provides superior wire handling with reduced risk of pressure drift allowing reliable pre- and post-PCI physiology assessment

GlmS and NagB Regulate Amino Sugar Metabolism in Opposing Directions and Affect Streptococcus mutans Virulence

Streptococcus mutans is a cariogenic pathogen that produces an extracellular polysaccharide (glucan) from dietary sugars, which allows it to establish a reproductive niche and secrete acids that degrade tooth enamel. While two enzymes (GlmS and NagB) are known to be key factors affecting the entrance of amino sugars into glycolysis and cell wall synthesis in several other bacteria, their roles in S. mutans remain unclear. Therefore, we investigated the roles of GlmS and NagB in S. mutans sugar metabolism and determined whether they have an effect on virulence. NagB expression increased in the presence of GlcNAc while GlmS expression decreased, suggesting that the regulation of these enzymes, which functionally oppose one another, is dependent on the concentration of environmental GlcNAc. A glmS-inactivated mutant could not grow in the absence of GlcNAc, while nagB-inactivated mutant growth was decreased in the presence of GlcNAc. Also, nagB inactivation was found to decrease the expression of virulence factors, including cell-surface protein antigen and glucosyltransferase, and to decrease biofilm formation and saliva-induced S. mutans aggregation, while glmS inactivation had the opposite effects on virulence factor expression and bacterial aggregation. Our results suggest that GlmS and NagB function in sugar metabolism in opposing directions, increasing and decreasing S. mutans virulence, respectively