AN ENDOCRINE CELL CARCINOMA WITH GASTRIC‐AND‐INTESTINAL MIXED PHENOTYPE ADENOCARCINOMA COMPONENT IN THE STOMACH

A 77‐year‐old man complained of bodyweight loss, and a Borrmann 3 type lesion was observed endoscopically in the anterior wall of angular region of the stomach. The endocrine cell carcinoma (ECC) having the cytoplasmic staining of chromogranin A (CgA) was detected pathologically in the biopsy samples. The patient underwent distal gastrectomy plus systemic lymph node (LN) dissection (D2 LN dissection), and pathological examination revealed ECC invading the subserosa, and no LN metastasis (pT2N0M0). None of the gastric and intestinal endocrine cell marker expression was apparent in the ECC cells. The lesion also contained a moderately differentiated type tubular adenocarcinoma component, which was judged to be gastric‐and‐intestinal mixed (GI type) phenotype, using gastric and intestinal exocrine cell markers. After the surgery, he left the hospital and started oral doxifluridine (600 mg/day). The patient now (March 2008, about 19 months since the surgery) continues this chemotherapy with no recurrence. In conclusion, we experienced ECC with a GI type adenocarcinoma component. The ECC cases with the GI type adenocarcinoma component may have a relatively good prognosis, being similar to the results of advanced gastric cancers from the viewpoint of gastric and intestinal phenotypic expression.     

GASTRIC SCHWANNOMA WITH ADJACENT EXTERNAL PROGRESSION HARBORED ABERRANT NF2 GENE

Gastric schwannomas are rare benign mesenchymal tumors. We describe a schwannoma of gastric origin with adjacent external progression. Sections showed a spindle cell tumor arranged in interlaced bundles and fascicles that was S‐100 and CD34 positive but c‐KIT protein negative. Histology and immunohistochemistry revealed the typical appearance of a gastric schwannoma. Genetic evaluation revealed that the tumor harbored a point mutation in exon 6 of the tumor suppressor neurofibromatosis 2 (NF2) gene, which resulted in an amino acid substitution of NF2 protein, and no mutation in exon 4b of the NF1 gene. In conclusion, we identified a rare mutation of the NF2 gene in gastric schwannoma. A diagnosis can only be definitive when based on histological and immunohistochemical findings. Digestive tract schwannomas are rare mesenchymal tumors that are differentiated from gastrointestinal stromal tumors by the absence of KIT protein. Follow up suggested that complete resection is an effective long‐term treatment strategy.     

Gastric cancer risk and erythrocyte composition of docosahexaenoic acid with anti-inflammatory effects.

Infection with Helicobacter pylori is linked to inflammation and is the main cause of peptic ulcer, gastritis, and gastric malignancies. To examine associations between gastric cancer risk and the erythrocyte composition of docosahexaenoic acid (DHA), a fatty acid with anti-inflammatory and apoptosis-inducing effects, here we conducted a case-control study of 179 incident gastric cancer cases and 357 noncancer controls (matched by age, sex, and season of sample collection). Dietary information and blood samples were collected from all subjects, and erythrocyte fatty acid levels were measured using accelerated solvent extraction and gas-liquid chromatography. Gastric cancer risk did not seem to be directly associated with dietary intake of fish and n-3 highly unsaturated fatty acids (HUFAs), such as DHA, derived from fish. However, risk was inversely associated with erythrocyte compositions of n-3 HUFAs [the highest to the lowest tertile, odds ratio (OR), 0.39; 95% confidence interval (95% CI), 0.23-0.68; P(trend)<0.005] and DHA (OR, 0.47; 95% CI, 0.28-0.79; P(trend)<0.01). Particularly strong associations were noted for well-differentiated type lesions and n-3 HUFAs (OR, 0.10; 95% CI, 0.03-0.35; P(trend)=0.0005) as well as DHA (OR, 0.20; 95% CI, 0.07-0.58; P(trend)<0.01) values. In conclusion, the erythrocyte composition of DHA was found to be negatively linked to risk of gastric cancer, especially of well-differentiated adenocarcinoma. Further studies are needed to investigate mechanisms of action of DHA relevant to antitumor effects in the stomach.     

Kinetic Analysis of Aggregated Amyloid-β Peptide Clearance in Adult Bone-marrow-derived Macrophages from APP and CCL2 Transgenic Mice

Accumulating evidence suggests that bone-marrow (BM)-derived mononuclear phagocytes have an important role in the clearance of soluble and aggregated amyloid-β peptides (Aβ) in Alzheimer’s disease (AD) brains. However, the exact kinetics of Aβ clearance in mononuclear phagocytes derived from transgenic animal models of AD expressing β-amyloid precursor protein (APP) mutants have been poorly characterized. We have examined whether CCL2 and APP expression affects the clearance of Aβ in conjunction with our control, acetylated low-density lipoprotein (AcLDL), using primary cultured BM-derived macrophages derived from adult APP, CCL2, APP/CCL2, and control littermates. Pulse-chase analysis demonstrated three distinct destinations for Aβ40 and AcLDL: intracellular retention, degradation, and secretion. As predicted, 50% of Aβ remained intracellularly contained even 5 days after pulse, while 40% of degraded and 14% of nondegraded Aβ were secreted. APP/CCL2 macrophages show reduced intracellular Aβ retention, along with enhanced secretion of both degraded and nondegraded Aβ. Aβ accumulation in aggresome is also partially reduced in APP/CCL2 macrophages as compared to other APP, CCL2, or control groups, suggesting impaired sorting of aggregated Aβ in aggresomes. The degradation of intracranially injected ¹²⁵I-Aβ40 aggregates was also enhanced in adult APP/CCL2 mice as compared to APP littermates in vivo. These data suggest that APP and CCL2 synergistically enhance BM-derived macrophage-mediated clearance of Aβ. In contrast, the clearance of AcLDL by BM-derived macrophages was not significantly enhanced by the presence of either APP or CCL2.     

Maturation of dendritic cells induced by Candida beta-D-glucan

We investigated whether Candida beta-D-glucan (CSBG) alters the maturation of dendritic cells (DCs). DC phenotypes were analyzed using FACScan. The expression of surface molecules, including major histocompatibility complex (MHC) classes I and II, as well as CD80 and CD86, increased on DCs that were stimulated with lipopolysaccaride (DCs/LPS), in comparison with unstimulated bone marrow-derived DCs (BM-DCs). Furthermore, the level of surface molecule expression on DCs stimulated with CSBG (DCs/CSBG) was between that of DCs and DCs/LPS. Phagocytosis was assessed by the uptake of FITC-dextran. There were no differences in the uptake of dextran among DCs/LPS and DCs/CSBG. The ability of BM-DCs to uptake dextran was higher than that of DCs/LPS and DCs/CSBG. We analyzed the concentration of IL-12 secreted by DCs using ELISA. BM-DCs secreted a low concentration of IL-12, while DCs/LPS and DCs/CSBG secreted higher levels of IL-12 than BM-DCs. There were no remarkable differences in the concentrations of IL-12 produced by DCs/LPS and DCs/CSBG. This data suggests that CSBG may augment DC maturation.     

Relationship between pediatric sinusitis and middle turbinate pneumatization--ethmoidal sinus pyocele thought to be caused by middle turbinate pneumatization

OBJECTIVE: To investigate whether the presence of pediatric middle turbinate pneumatization causes narrowing of the ostiomeatal complex (OMC) and is associated with the development of paranasal sinusitis. METHODS: CT scans of 190 nasal sides of 95 children (1-15 years old) were analyzed for the presence of middle turbinate pneumatization and mucosal thickness in the paranasal sinus. RESULTS: Middle turbinate pneumatization was detected in nine (4.6%) of the nasal cavities. Only one of these sides was in a patient younger than 10 years of age, while the other eight sides were in patients at least 13 years old. In six of those nine sides with pneumatization, paranasal sinusitis was also found. However, the images showed that in five sides the middle turbinate pneumatization itself did not obstruct the OMC. In addition, the mean +/- standard deviation (S.D.) of the total score for the paranasal sinus opacification on the side which had the middle turbinate pneumatization was 5.67 +/- 2.95. The corresponding value for the 76 sides without pneumatization was 5.29 +/- 2.53, and the difference between these mean total scores was not statistically significant. However, in one side, the OMC was obstructed or narrowed due to the middle turbinate pneumatization, and an ethmoidal sinus pyocele formed on this side. CONCLUSION: A causal relationship was not found between middle turbinate pneumatization and the mechanism of development of paranasal sinusitis in children. However, in the event that the OMU becomes obstructed at some time, frequent cycles of improvement and aggravation of pediatric paranasal sinusitis may occur and lead to the development of a serious condition.     

AAV1/2-mediated CNS Gene Delivery of Dominant-negative CCL2 Mutant Suppresses Gliosis, ��-amyloidosis, and Learning Impairment of APP/PS1 Mice

Accumulation of aggregated amyloid-β (Aβ) peptide was studied as an initial step for Alzheimer''s disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause neuroinflammation. Here brain chemokines play a major role for the glial accumulation. We have previously shown that transgenic overexpression of chemokine CCL2 in the brain results in increased microglial accumulation and diffuse amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish amyloid precursor protein (APP) mutant. Here, we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in a dose–response manner and express >1,000-fold higher recombinant CCL2 than basal levels after a single administration. AAV1/2 hybrid virus principally infected neurons without neuroinflammation with sustained expression for 6-months. 7ND expressed in APP/presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, β-amyloidosis, including suppression of both fibrillar and oligomer Aβ accumulation, and improved spatial learning. Our data support the idea that the AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related neuroinflammation.     

GPU-based fast pencil beam algorithm for proton therapy

Performance of a treatment planning system is an essential factor in making sophisticated plans. The dose calculation is a major time-consuming process in planning operations. The standard algorithm for proton dose calculations is the pencil beam algorithm which produces relatively accurate results, but is time consuming. In order to shorten the computational time, we have developed a GPU (graphics processing unit)-based pencil beam algorithm. We have implemented this algorithm and calculated dose distributions in the case of a water phantom. The results were compared to those obtained by a traditional method with respect to the computational time and discrepancy between the two methods. The new algorithm shows 5-20 times faster performance using the NVIDIA GeForce GTX 480 card in comparison with the Intel Core-i7 920 processor. The maximum discrepancy of the dose distribution is within 0.2%. Our results show that GPUs are effective for proton dose calculations.     

The Comorbidity of HIV-Associated Neurocognitive Disorders and Alzheimer’s Disease: A Foreseeable Medical Challenge in Post-HAART Era

Although the introduction of highly active antiretroviral therapy (HAART) has led to a strong reduction of HIV-associated dementia (HAD) incidence, the prevalence of minor HIV-1-associated neurocognitive disorder (HAND) is rising among AIDS patients. HAART medication has shifted neuropathology from a subacute encephalitic condition to a subtle neurodegenerative process involving synaptic and dendritic degeneration, particularly of hippocampal neurons that are spared prior to HAART medication. Considerable neuroinflammation coupled with mononuclear phagocyte activation is present in HAART-medicated brains, particularly in the hippocampus. Accumulating evidence suggests that the resultant elevated secretion of pro-inflammatory cytokines such as interferon-γ, tumor necrosis factor-α, and interleukin-1β can increase amyloid-β peptide (Aβ) generation and reduce Aβ clearance. Recent advancements in Alzheimer’s disease (AD) research identified Aβ biogenesis and clearance venues that are potentially influenced by HIV viral infection, providing new insights into beta-amyloidosis segregation in HIV patients. Our study suggests enhanced beta-amyloidosis in ART-treated HAD and HIV-associated encephalitis brains and suppression of Aβ clearance by viral infection of human primary macrophages. A growing awareness of potential convergent mechanisms leading to neurodegeneration shared by HIV and Aβ points to a significant chance of comorbidity of AD and HAND in senile HIV patients, which calls for a need of basic studies.