Inhibition of p600 Expression Suppresses Both Invasiveness and Anoikis Resistance of Gastric Cancer

Background  

Advanced gastric cancers often metastasize to distant organs and the peritoneum, leading to a poor prognosis. Both invasiveness and resistance to anchorage-independent cell death (anoikis) are important factors in the process of metastasis. p600 (600-kDa protein), recently identified from a cervical cancer cell line, plays a role in both anoikis resistance and cell migration. In this study, we examined whether p600 is involved in the progression of gastric cancer.     

Development of a novel antiadhesive material,alginate flakes,ex vivo and in vivo

Purpose  

Postoperative intra-abdominal adhesion sometimes causes significant morbidity. The aim of this study was to compare the efficacy of our newly developed antiadhesive material, alginate flakes, to the most commonly used combination of hyaluronic acid and carboxymethyl cellulose film.     

Zoledronic acid - a multiplicity of anti-cancer action

Bisphosphonates (BPs) are inhibitors of bone-resorption and have become the current standard of care for preventing skeletal complications associated with bone metastases. Among BPs, zoledronic acid (ZOL) has the strongest activity of anti-bone resorption and shows diverse direct anti-cancer effects in vitro. Some chemical and biological characteristics of ZOL indicate the potential for in vivo growth inhibition and the mechanisms responsible for the observed anti-cancer effects are beginning to be elucidated. ZOL inhibits farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway. Consequently, it inhibits the prenylation of small G-proteins such as Ras, Rap1, Rho and Rab, reduces the signals they mediate, and thereby prevents the growth, adhesion/spreading, and invasion of cancer cells. ZOL, which has a high affinity for mineralized bone, rapidly localizes to bone, resulting in therapeutically effective local concentrations for the cancer cells in bone. ZOL also blocks osteolysis and osteoclastgenesis, thus preventing the release of various growth factors which are abundantly stored in bone. Moreover, ZOL stimulates gammadelta T cells, which play important roles in innate immunity against cancer. In addition, ZOL is also a potent inhibitor of angiogenesis, probably due to the modification of various angiogenic properties of endothelial cells. Furthermore, ZOL synergizes with a variety of anticancer agents including chemotherapeutic drugs, molecular targeted agents, and other biological agents. Based on these potential anti-cancer properties, several clinical trials have been initiated to test the combination of ZOL and other agents. The accumulated encouraging evidence to date indicate that ZOL is an attractive anti-cancer agent which promises to be the next exciting therapy for patients with various cancers.     

Differential mechanisms underlie the regulation of serotonergic transmission in the dorsal and median raphe nuclei by mirtazapine: a dual probe microdialysis study

Rationale

Blockade of α₂ adrenoceptors and histamine H₁ receptors plays important roles in the antidepressant and hypnotic effects of mirtazapine.

Objectives

However, it remains unclear how mirtazapine’s actions at these receptors interact to affect serotonergic transmission in the dorsal (DRN) and median (MRN) raphe nuclei.

Method

Using dual-probe microdialysis, we determined the roles of α₂ and H₁ receptors in the effects of mirtazapine on serotonergic transmission in the DRN and MRN and their respective projection regions, the frontal (FC) and entorhinal (EC) cortices.

Results

Mirtazapine (<30 μM) failed to alter extracellular serotonin levels when perfused alone into the raphe nuclei, but when co-perfused with a 5-HT_1A receptor antagonist, mirtazapine increased serotonin levels in the DRN, MRN, FC, and EC. Serotonin levels in the DRN and FC were decreased by blockade and increased by activation of H₁ receptors in the DRN. Serotonin levels in the MRN and EC were not affected by H₁ agonists/antagonists perfused in the MRN. The increase in serotonin levels in the DRN and FC induced by DRN H₁ receptor activation was attenuated by co-perfusion with mirtazapine. Furthermore, the increase in serotonin levels (DRN/FC) induced by DRN α₂ adrenoceptor blockade was attenuated by concurrent DRN H₁ blockade, whereas the increase in serotonin levels (MRN/EC) induced by MRN α₂ adrenoceptor inhibition was unaffected by concurrent MRN H₁ receptor blockade.

Conclusion

These results suggest that enhanced serotonergic transmission resulting from α₂ adrenoceptor blockade is offset by subsequent activation of 5-HT_1A receptors and, in the DRN but not MRN, H₁ receptor inhibition. These pharmacological actions of mirtazapine may explain its antidepressant and hypnotic actions.     

B cell activation regulates exosomal HLA production

Exosomes are nanovesicles produced constitutively and inducibly by several types of cells. They are generated as intraluminal vesicles of multivesicular bodies and express MHC and several endosomal/lysosomal proteins. In spite of their potential role in cellular immunity, the regulatory mechanisms of exosome production are largely unknown. In this study, we have established a novel ELISA system to quantify exosomal HLA using a combination of anti-HLA class I and anti-HLA-DR mAb. We found that exosomal HLA production of B cells was enhanced by contact with CD4(+) T cells. Neutralizing anti-CD154 (CD40L) mAb inhibited this effect, and a soluble CD40L significantly increased production of exosomal HLA in B cells. In addition, B cell stimulation via BCR and TLR9 enhanced their production while IL-4 stimulation alone failed to do so. Strikingly, an inhibitor of the classical NF-kappaB pathway drastically inhibited exosomal HLA production in stimulated B cells, indicating that the classical NF-kappaB pathway is critical for exosomal HLA production in B cells. Together, these findings suggest a pivotal role of B cell activation in exosomal HLA production in vivo.     

A case of pedunculated colonic adenoma with pseudocarcinomatous invasion and squamous metaplasia occurring in the sigmoid colon

A case of pedunculated colonic adenoma with pseudocarcinomatous invasion and squamous metaplasia occurring in the sigmoid colon is reported. The patient was a 65-year-old man who visited our hospital for further evaluation of a positive fecal occult blood test. Colonoscopy revealed a pedunculated polyp with a thick swollen stalk in the sigmoid colon. EUS revealed a hyperechoic lesion in the stalk. However, endosonographically, the third and fourth layers of the colonic wall were shown to be normal. It was suspected to be a colonic adenoma with pseudocarcinomatous invasion from these endoscopic findings. Endoscopic polypectomy was performed. Histological examination of the specimen revealed tubular adenoma with moderate epithelial atypia and submucosal displacement of adenomatous glands with variable cystic changes. Squamous metaplasia and hemosiderin deposition were also seen in the mucosal and submucosal layer, respectively. This polyp was diagnosed as a colonic adenoma with pseudocarcinomatous invasion with squamous metaplasia.     

'Clover technique' for tricuspid regurgitation due to pacemaker lead

Whilst tricuspid regurgitation (TR) secondary to severe mitral regurgitation (MR) is a common problem, organic TR caused by pacemaker leads is also frequently encountered. In a 63-year-old patient who developed TR attributable to both MR and a pacemaker lead inserted 12 years previously, the regurgitation could not be controlled satisfactorily using a normal ring annuloplasty. Consequently, the 'clover technique' provided an efficient correction to the TR.     

Spontaneous and visually driven high-frequency oscillations in the occipital cortex: intracranial recording in epileptic patients

High-frequency oscillations (HFOs) at ≥80 Hz of nonepileptic nature spontaneously emerge from human cerebral cortex. In 10 patients with extraoccipital lobe epilepsy, we compared the spectral-spatial characteristics of HFOs spontaneously arising from the nonepileptic occipital cortex with those of HFOs driven by a visual task as well as epileptogenic HFOs arising from the extraoccipital seizure focus. We identified spontaneous HFOs at ≥80 Hz with a mean duration of 330 ms intermittently emerging from the occipital cortex during interictal slow-wave sleep. The spectral frequency band of spontaneous occipital HFOs was similar to that of visually driven HFOs. Spontaneous occipital HFOs were spatially sparse and confined to smaller areas, whereas visually driven HFOs involved the larger areas including the more rostral sites. Neither spectral frequency band nor amplitude of spontaneous occipital HFOs significantly differed from those of epileptogenic HFOs. Spontaneous occipital HFOs were strongly locked to the phase of delta activity, but the strength of δ-phase coupling decayed from 1 to 3 Hz. Conversely, epileptogenic extraoccipital HFOs were locked to the phase of delta activity about equally in the range from 1 to 3 Hz. The occipital cortex spontaneously generates physiological HFOs which may stand out on electrocorticography traces as prominently as pathological HFOs arising from elsewhere; this observation should be taken into consideration during presurgical evaluation. Coupling of spontaneous delta and HFOs may increase the understanding of significance of δ-oscillations during slow-wave sleep. Further studies are warranted to determine whether δ-phase coupling distinguishes physiological from pathological HFOs or simply differs across anatomical locations.