Tyrosine-kinase inhibition results in EGFR clustering at focal adhesions and consequent exocytosis in uPAR down-regulated cells of Head and Neck cancers

<p>Abstract</p> <p>Background</p> <p>Antisense (AS) induced down-regulation of uPAR in ACCS adenoid-cyctic carcinoma cells decreased the cellular adhesion and invasion on various extracellular matrices. Additionally, ACCS-AS cells showed an increased EGFR expression and other behavioral similarities to NA-SCC, a typical highly proliferative but less invasive squamous cell carcinoma (SCC) cell line of the head and neck. ACCS, ACCS-AS and NA-SCC cells were used to elucidate the relationships between uPAR down-regulation and EGFR inhibition.</p> <p>Results</p> <p>Tyrosine kinase inhibitor Gefitinib (IRESSA, ZD 1839) significantly reduced the chemotactic cell migration and adhesion. This was associated with reduced EGFR and ERK activation. In addition, anti-proliferative effect of gefitinib in uPAR down-regulated ACCS-AS was significantly higher than parental ACCS, to levels comparable to gefitinib-sensitive NA-SCC cells. This was evidenced by both reduced dosage and duration of treatment. Furthermore, time-lapse videography showed that treatment with gefitinib was also associated with cell rounding and loss of pseudopodia, mostly in ACCS-AS rather than parental ACCS cells. There were also evidences of formation and exocytosis of vacuole-like structures in ACCS-AS, as well as NA-SCC, but not in parental ACCS cells. Interestingly, immunocytochemistry showed that the exocytotic vacuoles actually contained de-activated EGFR.</p> <p>Conclusion</p> <p>Our results suggested that down-regulation of uPAR affected the fate of EGFR in high EGFR expressing cells. Furthermore, combining the uPAR down-regulation with EGFR inhibition showed a synergistic anti-tumor effect and might provide an alternative method to increase anti-proliferative effect of tyrosine kinase inhibitors with lower doses and duration to reduce their side effects during cancer control.</p

Two-stage Method for the Extraction of a Horizontally Impacted Lower Third Molar

AbstractA modification of the surgical technique for extracting impacted lower third molars is required to decrease the rate of complications including inferior alveolar nerve injury. In this study, a new two-stage extraction method for the horizontally impacted lower third molar was developed. During the first stage, only the crown was removed after separating the impacted tooth at the neck. Thereafter, the root(s) was pulled toward the anterior direction with an elastic band at 130–150 g over a 7-day period. Next, the root(s) was extracted. This method was firstly attempted for 20 horizontally impacted lower third molars, the roots of which had been close to the mandibular canal in panoramic radiographs and were pulled for 20.8 ± 11.5 (n = 20) days. The roots in 17 of 20 cases (85%) were loosened from the sockets and extracted easily without any complications. These outcomes suggest that this two-stage method is useful for the extraction of a horizontally impacted lower third molar in order to decrease the rate of inferior alveolar nerve injury

Primary meningioma of the mandible

SummaryWe reported a case of primary extracranial meningioma in the mandible of a 10 year-old-boy with basal cell nevus syndrome. The tumor had a well-delineated large round shaped radiolucency including an impacted canine in the mandible. Microscopic examination revealed a fibrous tumor composed of uniform spindle-shaped cells and fine collagen bundles. The spindle-shaped cells were arranged in whorls and interconnecting fascicles, and some nuclear pseudoinclusion and psammoma bodies were detected. Immunohistochemically, the tumor cells were stained for epithelial membrane antigen, vimentin and desmoplakin, but not for S-100 protein. No recurrence of the tumor was detected for 4 years

Evidence that polymorphonuclear neutrophils infiltrate into the developing corpus luteum and promote angiogenesis with interleukin-8 in the cow

<p>Abstract</p> <p>Background</p> <p>After ovulation in the cow, the corpus luteum (CL) rapidly develops within a few days with angiogenesis and progesterone production. CL formation resembles an inflammatory response due to the influx of immune cells. Neutrophils play a role in host defense and inflammation, and secrete chemoattractants to stimulate angiogenesis. We therefore hypothesized that neutrophils infiltrate in the developing CL from just after ovulation and may play a role in angiogenesis of the CL.</p> <p>Methods and Results</p> <p>Polymorphonuclear neutrophils (PMN) were detected in CL tissue by Pas-staining, and interleukin-8 (IL-8, a neutrophil-specific chemoattractant) was measured in supernatant of the CL tissue culture: considerable amounts of PMNs and the high level of IL-8 were observed during the early luteal phase (days 1-4 of the estrous cycle). PMNs and IL-8 were low levels in the mid and late luteal phases, but IL-8 was increased during luteal regression. The PMN migration in vitro was stimulated by the supernatant from the early CL but not from the mid CL, and this activity was inhibited by neutralizing with an anti-IL-8 antibody, indicating the major role of IL-8 in inducing active PMN migration in the early CL. Moreover, IL-8 stimulated proliferation of CL-derived endothelial cells (LECs), and both the supernatant of activated PMNs and IL-8 stimulated formation of capillary-like structures of LECs.</p> <p>Conclusion</p> <p>PMNs migrate into the early CL partially due to its major chemoattractant IL-8 produced at high levels in the CL, and PMNs is a potential regulator of angiogenesis together with IL-8 in developing CL in the cow.</p

Do People Explicitly Make a Frame Choice Based on the Reference Point?

Previous studies have shown that when choosing one of two logically equivalent frames (e.g., “half full” or “half empty”), people tend to choose based on a reference point. For example, when the amount of water in a glass with 500 ml capacity was originally 0 ml (or 500 ml), and then increased (or decreased) to 250 ml, people tend to express the amount of water in the glass as “half full” (or “half empty”). In the present study, we examined whether participants explicitly made a frame choice based on the reference point. We conducted four behavioral experiments relating to frame choice tasks. Specifically, participants were presented with a story-based or prime-based reference point and then made a frame choice. Furthermore, participants provided their reasons for the choice. Our findings on frame choices and their reasons can be summarized as follows. First, when participants were presented with a story-based reference point, some of them reported that they made frame choices based on the reference point. Second, when a reference point was presented as a prime, participants’ frame choices were affected by this reference point. However, almost no participants reported that they made frame choices based on the reference point. These results indicate that the effect of reference points on frame choices is robust and that people do not always explicitly make frame choices based on the reference point

Retrospective Study of Selective Submandibular Neck Dissection versus Radical Neck Dissection for N0 or N1 Necks in Level I Patients with Oral Squamous Cell Carcinoma

Objective. To evaluate the efficacy of selective submandibular neck dissection (SMND) in patients with oral squamous cell carcinoma (OSCC) with or without nodal metastasis. Patients. From a total of 384 patients with untreated OSCC who underwent radical excision, we identified 229 with clinically N0 necks and 68 with clinically N1 necks in level I. Main Outcome Measures. The Kaplan-Meier 5-year regional control and 5-year disease specific survival (DSS) were compared for SMND, radical neck dissection (RND), and modified radical neck dissection (MRND). Results. In clinically node-negative necks, the regional control rates were 85.2% with SMND and 83.3% with MRND (P = 0.89), and 5-year DSS rates were 86.5% and 87.0%, respectively, (P = 0.94). In clinically N1 necks, the regional control rates were 81.3% with SMND and 83.0% with RND (P = 0.72), and the DSS rates were 81.3% and 80.0%, respectively, (P = 0.94). Type of neck dissection was not significantly associated with regional control or DSS on either univariate or multivariate analysis using Cox's proportional hazard model. Conclusions. SMND can be effectively applied in elective and therapeutic management to patients with OSCC that are clinically assessed as N0 or N1 to level I of the neck

Deficiency of the RIβ subunit of protein kinase A causes body tremor and impaired fear conditioning memory in rats

The RIβ subunit of cAMP-dependent protein kinase (PKA), encoded by Prkar1b, is a neuronal isoform of the type I regulatory subunit of PKA. Mice lacking the RIβ subunit exhibit normal long-term potentiation (LTP) in the Schaffer collateral pathway of the hippocampus and normal behavior in the open-field and fear conditioning tests. Here, we combined genetic, electrophysiological, and behavioral approaches to demonstrate that the RIβ subunit was involved in body tremor, LTP in the Schaffer collateral pathway, and fear conditioning memory in rats. Genetic analysis of WTC-furue, a mutant strain with spontaneous tremors, revealed a deletion in the Prkar1b gene of the WTC-furue genome. Prkar1b-deficient rats created by the CRISPR/Cas9 system exhibited body tremor. Hippocampal slices from mutant rats showed deficient LTP in the Schaffer collateral–CA1 synapse. Mutant rats also exhibited decreased freezing time following contextual and cued fear conditioning, as well as increased exploratory behavior in the open field. These findings indicate the roles of the RIβ subunit in tremor pathogenesis and contextual and cued fear memory, and suggest that the hippocampal and amygdala roles of this subunit differ between mice and rats and that rats are therefore beneficial for exploring RIβ function

Luteal angiogenesis and its control

Angiogenesis, the formation of new blood vessels from pre-existing ones, is critical to luteal structure and function; In addition, it is a complex and tightly regulated process. Not only does rapid and extensive angiogenesis occur to provide the corpus luteum (CL) with an unusually high blood flow and support its high metabolic rate, but in the absence of pregnancy the luteal vasculature must rapidly regress to enable the next cycle of ovarian activity. This review describes a number of the key endogenous stimulatory and inhibitory factors, which act in a delicate balance to regulate luteal angiogenesis and ultimately luteal function. In vitro luteal angiogenesis cultures have demonstrated critical roles for fibroblast growth factor 2 (FGF2) in endothelial cell proliferation and sprouting, whilst other factors such as vascular endothelial growth factor (VEGFA) and platelet derived growth factor (PDGF) were important modulators in the control of luteal angiogenesis. Post-transcriptional regulation by small non-coding micro-RNAs, is also likely to play a central role in the regulation of luteal angiogenesis. Appropriate luteal angiogenesis requires the coordinated activity of numerous factors expressed by several cell types at different times and this review will also describe the role of perivascular pericytes and the importance of vascular maturation and stability. It is hoped that a better understanding of the critical processes underlying the transition from follicle to CL, and subsequent luteal development will benefit the management of luteal function in the future

Rapid Accumulation of Polymorphonuclear Neutrophils in the Corpus luteum during Prostaglandin F2α-Induced Luteolysis in the Cow

Prostaglandin F2α (PGF2α) induces luteolysis within a few days in cows, and immune cells increase in number in the regressing corpus luteum (CL), implying that luteolysis is an inflammatory-like immune response. We investigated the rapid change in polymorphonuclear neutrophil (PMN) numbers in response to PGF2α administration as the first cells recruited to inflammatory sites, together with mRNA of interleukin-8 (IL-8: neutrophil chemoattractant) and P-selectin (leukocyte adhesion molecule) in the bovine CL. CLs were collected by ovariectomy at various times after PGF2α injection. The number of PMNs was increased at 5 min after PGF2α administration, whereas IL-8 and P-selectin mRNA increased at 30 min and 2 h, respectively. PGF2α directly stimulated P-selectin protein expression at 5–30 min in luteal endothelial cells (LECs). Moreover, PGF2α enhanced PMN adhesion to LECs, and this enhancement by PGF2α was inhibited by anti-P-selectin antibody, suggesting that P-selectin expression by PGF2α is crucial in PMN migration. In conclusion, PGF2α rapidly induces the accumulation of PMNs into the bovine CL at 5 min and enhances PMN adhesion via P-selectin expression in LECs. It is suggested that luteolytic cascade by PGF2α may involve an acute inflammatory-like response due to rapidly infiltrated PMNs