Computed tomography lymphography for the detection of sentinel nodes in patients with gastric carcinoma

The sentinel node (SN) concept has been found to be feasible in gastric cancer. However, the lymphatic network of gastric cancer may be more complex, and it may be difficult to visualize all the SN distributed in unexpected areas by conventional modalities. In this study, we evaluate the feasibility and efficacy of CT lymphography for the detection of SN in gastric cancer. A total 24 patients with early gastric cancer were enrolled in the study. Three modalities (CT lymphography, dye and radioisotope [RI] methods) were used for the detection of SN. The images of CT lymphography were obtained at 10 min after injection of contrast agents. The SN were successfully identified by CT lymphography in 83.3% of patients; detection rates by the dye and RI methods were 95% and 100%, respectively. Most patients, in whom SN were successfully detected by CT lymphography, had positive results at 5 min after injection of the contrast material. The SN stations detected by CT lymphography were consistent with or included those detected by dye and/or RI methods. In conclusion, CT lymphography for the detection of SN in gastric cancer is feasible and has several advantages. However, based on this initial experience, CT lymphography had a relatively low detection rate compared with conventional methods, and further efforts will be necessary to improve the detection rate and widen the clinical application of CT lymphography for the detection of SN in gastric cancer. (Cancer Sci 2010; 101: 2586–2590)     

SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1-dependent reduction of esterified cholesterol

We previously reported that the inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor function of CD8⁺ T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8⁺ T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8⁺ T cells. In vitro treatment of CD8⁺ T cells with SCD1 inhibitors enhanced IFN-γ production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl-CoA acetyltransferase 1 (ACAT1), in CD8⁺ T cells. The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8⁺ T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor-bearing mice enhanced IFN-γ production of tumor-infiltrating CD8⁺ T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased. These results indicated that SCD1 suppressed effector functions of CD8⁺ T cells through the increased esterified cholesterol in an ACAT1-dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol. Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti-PD-1 antibody therapy or CAR-T cell therapy in mouse tumor models. Therefore, the SCD1–ACAT1 axis is regulating effector functions of CD8⁺ T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.     

The Expression of Endothelin-1 and Its Binding Sites in Mouse Skin Increased after Ultraviolet B Irradiation or Local Injection of Tumor Necrosis Factor α

Endothelin (ET)-1 is a 21-amino acid peptide which has vasoconstrictor and growth regulatory activity. Recently, cultured keratinocytes have been reported to express ET-1 and its receptor when irradiated by ultraviolet (UV) B. In order to further understand the role of ET-1 in vivo during UVB-induced inflammation, we examined the localization, intensity and time course of the expression levels of ET-1 and its binding sites in UVB-exposed BALB/c mouse skin. Frozen and paraffin sections prepared from mouse skin 48 h after treatment with UVB irradiation (0.36 or 0.72 J/cm²) or after injection with tumor necrosis factor (TNF)-α (1.0 μg) or interleukin (IL)-1α (0.05 μg) were incubated with monoclonal anti-ET-1 IgG and then visualized by peroxidase staining. In normal skin, faint ET-1 immunoreactivity was observed in the epidermis, pilosebaceous structures and blood vessels. Upon exposure to UVB irradiation or administration of TNF-α injection or IL-1α injection, such immunoreactivity was found to be significantly enhanced. Subsequently, the frozen sections were incubated with ¹²⁵I ET-1 for 30 min, and visualized by autoradiographic technique. In normal skin, ET-1 weakly bound to the skin, while UVB irradiation and TNF-α injection significantly enhanced ET-1 binding in the epidermis, pilosebaceous structures and blood vessels. Time course experiments (1, 2, 4 and 7 days) indicated that ET-1 immunoreactivity and ET-1 binding peaked 1 or 2 days after UVB irradiation or TNF-α injection. These results suggest that the up-regulated expression of ET-1 and its binding sites in the epidermis and pilosebaceous structures may act as an autocrine/paracrine factor during UVB-induced inflammation.     

1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine improves cognitive decline by enhancing long-term depression

1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPhtCho) (1 μM) enhanced long-term depression (LTD), a synaptic plasticity relevant to learning and memory, in the CA1 region of rat hippocampal slices, where expression of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit GluR1 on the plasma membrane was decreased. In the water maze test, oral administration with POPhtCho (5 mg/kg) significantly shortened the prolonged retention latency for rats intraperitoneally injected with scopolamine (1 mg/kg), while the acquisition latency was not affected. For humans with mild cognitive impairment and dementia (average of Mini Mental State Examination score, 18), oral intake with POPhtCho (300 mg/day, once after breakfast) everyday raised the score to over 20, corresponding to normal cognitive functions, throughout 6 months after intake. The results of the present study, thus, indicate that POPhtCho could ameliorate cognitive disorders, possibly by enhancing LTD.     

An fMRI study of musicians with focal dystonia during tapping tasks

Musician’s dystonia is a type of task specific dystonia for which the pathophysiology is not clear. In this study, we performed functional magnetic resonance imaging to investigate the motor-related brain activity associated with musician’s dystonia. We compared brain activities measured from subjects with focal hand dystonia and normal (control) musicians during right-hand, left-hand, and both-hands tapping tasks. We found activations in the thalamus and the basal ganglia during the tapping tasks in the control group but not in the dystonia group. For both groups, we detected significant activations in the contralateral sensorimotor areas, including the premotor area and cerebellum, during each tapping task. Moreover, direct comparison between the dystonia and control groups showed that the dystonia group had greater activity in the ipsilateral premotor area during the right-hand tapping task and less activity in the left cerebellum during the both-hands tapping task. Thus, the dystonic musicians showed irregular activation patterns in the motor-association system. We suggest that irregular neural activity patterns in dystonic subjects reflect dystonic neural malfunction and consequent compensatory activity to maintain appropriate voluntary movements.     

A case of double-chambered right ventricle associated with an interventricular septal aneurysm in an elderly patient

Double-chambered right ventricle is a congential malformation caused by an anomalous muscle band obstructing the right ventricular outflow tract. Most reported cases of this condition have been diagnosed in infants, or adolescents. We encountered a 61-year-old woman with a double-chambered right ventricle, associated with a large interventricular septal aneurysm, which is a rare complication. The right ventricular obstruction was corrected with surgery.     

Impact of transgenic overexpression of SH2-containing inositol 5'-phosphatase 2 on glucose metabolism and insulin signaling in mice

SH2-containing inositol 5'-phosphatase 2 (SHIP2) is a 5'-lipid phosphatase hydrolyzing the phosphatidylinositol (PI) 3-kinase product PI(3,4,5)P(3) to PI(3,4)P(2) in the regulation of insulin signaling, and is shown to be increased in peripheral tissues of diabetic C57BL/KSJ-db/db mice. To clarify the impact of SHIP2 in the pathogenesis of insulin resistance with type 2 diabetes, we generated transgenic mice overexpressing SHIP2. The body weight of transgenic mice increased by 5.0% (P < 0.05) compared with control wild-type littermates on a normal chow diet, but not on a high-fat diet. Glucose tolerance and insulin sensitivity were mildly but significantly impaired in the transgenic mice only when maintained on the normal chow diet, as shown by 1.2-fold increase in glucose area under the curve over control levels at 9 months old. Insulin-induced phosphorylation of Akt was decreased in the SHIP2-overexpressing fat, skeletal muscle, and liver. In addition, the expression of hepatic mRNAs for glucose-6-phosphatase and phosphoenolpyruvate carboxykinase was increased, that for sterol regulatory element-binding protein 1 was unchanged, and that for glucokinase was decreased. Consistently, hepatic glycogen content was reduced in the 9-month-old transgenic mice. Structure and insulin content were histologically normal in the pancreatic islets of transgenic mice. These results indicate that increased abundance of SHIP2 in vivo contributes, at least in part, to the impairment of glucose metabolism and insulin sensitivity on a normal chow diet, possibly by attenuating peripheral insulin signaling and by altering hepatic gene expression for glucose homeostasis.