Exogenous vascular endothelial growth factor can induce preeclampsia-like symptoms in pregnant mice

It is reported that expression of vascular endothelial growth factor (VEGF) in trophoblasts increases in cases with preeclampsia. Recently, we demonstrated that the lack of cyclin-dependent kinase inhibitor, p57kip2, expression in the fetus and the placenta plays a role in the development of preeclampsia-like symptoms in pregnant mice. Furthermore, we observed that VEGF mRNA and protein levels, especially VEGF (164), were higher and its expression was stronger in placentas of p57kip2-null embryos than in placentas of wild-type embryos. In this study we investigated whether exogenous murine VEGF (164) induced preeclampsia-like symptoms in pregnant mice, and anti-VEGF neutralized antibody could suppress these symptoms. Administration of VEGF induced hypercoagulation in the placental circulation and a significant elevation of systolic blood pressure in pregnant mice. Furthermore, we demonstrated that treatment with anti-VEGF antibody could suppress the hypercoagulability in placenta and the elevation of systolic blood pressure. These data suggest that VEGF is related to the pathophysiology of preeclampsia.     

The role of a mutation of the CXCR4 gene in WHIM syndrome

We investigated the role of a mutation of the CXCR4 gene in 11-year-old twin sisters with WHIM syndrome. The mutated gene may result in production of the mutant CXCR4 protein causing abnormal apoptosis and migratory function, which are thought to be related to the cause of chronic neutropenia in WHIM syndrome.     

A Huge Primary Peritoneal Papillary Adenocarcinoma Which Demonstrated Imaging Findings Similar to Those of Extrahepatic-Growing Type Hepatic Tumor: Report of a Case

We herein report a 69-year-old woman who presented with a huge intra-abdominal tumor which demonstrated imaging findings similar to those of extrahepatic-growing type hepatic tumor, but turned out to be primary peritoneal papillary adenocarcinoma. Computed tomography showed a well-demarcated mass, measuring 12.0cm in diameter, which came in contact with the lateral segment of the liver and invaded the diaphragm and abdominal wall. Distant lymph node metastasis was also detected. A fine-needle aspiration biopsy of the tumor showed poorly differentiated adenocarcinoma of unknown origin. After chemotherapy with 5-fluorouracil and cisplatin, the maximal diameter of the tumor decreased to 6.0cm. The patient then underwent a tumorectomy together with a lateral segmentectomy of the liver, a splenectomy, a partial resection of the diaphragm and abdominal wall, and a left oophorectomy. Histological and immunohistochemical examinations demonstrated the tumor to be primary peritoneal papillary adenocarcinoma.     

Representation of immediate and final behavioral goals in the monkey prefrontal cortex during an instructed delay period

We examined neuronal activity in the lateral prefrontal cortex of monkeys performing a path-planning task in a maze that required the planning of actions in multiple steps. The animals received an instruction that prompted them to prepare to move a cursor in the maze stepwise from a starting position to a goal position by operating manipulanda with either arm. During a delay period in which the animal prepared to start the first of three cursor movements to approach the pre-instructed goal, we identified two types of neuronal activity: the first type reflected the position within the maze to which the animal intended to move the cursor as an initial step (an immediate goal) and the second type reflected the position within the maze that was to be captured as a final goal. Neither type reflected motor responses. We propose that these two types of neuronal activity are neuronal correlates that represent immediate and ultimate behavioral goals. This finding implicates the prefrontal cortex in governing goal-oriented sequential behavior rather than sensorimotor transformation.     

Dietary supplementation of soybean kunitz trypsin inhibitor reduces lipopolysaccharide-induced lethality in mouse model

We examined the modifying effects of a Kunitz trypsin inhibitor (KTI) and a Bowman-Birk trypsin inhibitor (BBI), purified from soybean, as intraperitoneal (i.p.) injection and dietary supplements on bacterial lipopolysaccharide (LPS)-induced lethality in mice. We initially examined the suppressing effects of i.p. injection of KTI (50 mg/kg) and BBI (50 mg/kg) on LPS-induced lethality after i.p. injection of LPS. Furthermore, groups of female C57BL/6 were fed a basal diet (control group) or the basal diet supplemented with KTI (50 g/kg) or BBI (50 g/kg). Here, we show that i.p. and daily oral administration of KTI, but not BBI, caused a significant reduction of the LPS-induced lethality; that LPS significantly induced plasma TNF-alpha, IL-1beta, and IL-6 levels in mice after LPS challenge; that concomitant administration of KTI, but not BBI, inhibits the LPS-induced plasma levels of these cytokines; and that KTI, but not BBI, suppressed LPS-induced upregulation of cytokine expression through suppression of phosphorylation of three mitogen-activated protein (MAP) kinase pathways, ERK1/2, JNK, and p38, in peritoneal macrophages. These data allow us to speculate that i.p. injection and dietary supplementation of a soybean KTI may play a role as a potent anti-inflammatory agent by inhibiting activation of MAP kinases, leading to the suppression of cytokine expression.     

Hypoxic culture induces expression of sialin, a sialic acid transporter, and cancer-associated gangliosides containing non-human sialic acid on human cancer cells

Tumor hypoxia figures heavily in malignant progression by altering the intracellular glucose metabolism and inducing angiogenic factor production, thus, selecting and expanding more aggressive cancer cell clones. Little is known, however, regarding hypoxia-induced antigenic changes in cancers. We investigated the expression of N-glycolyl sialic acid (NeuGc)-G(M2), a cancer-associated ganglioside containing non-human sialic acid, NeuGc, in human cancers. Cancer tissues prepared from patients with colon cancers frequently expressed NeuGc-G(M2), whereas it was virtually absent in nonmalignant colonic epithelia. Studies on cultured cancer cells indicated that the non-human sialic acid was incorporated from culture medium. Hypoxic culture markedly induced mRNA for a sialic acid transporter, sialin, and this accompanied enhanced incorporation of NeuGc as well as N-acetyl sialic acid. Transfection of cells with sialin gene conferred accelerated sialic acid transport and induced cell surface expression of NeuGc-G(M2). We propose that the preferential expression of NeuGc-G(M2) in cancers is closely associated with tumor hypoxia. Hypoxic culture of tumor cells induces expression of the sialic acid transporter, and enhances the incorporation of non-human sialic acid from the external milieu. A consequence of this is the acquisition of cancer-associated cell surface gangliosides, typically G(M2), containing non-human sialic acid (NeuGc), which is not endogenously synthesized through CMP-N-acetyl sialic acid hydroxylase because humans lack the gene for the synthetic enzyme. As hypoxia is associated with diminished response to radiotherapy and chemotherapy, NeuGc-G(M2) is a potential therapeutic target for hypoxic cancer cells.     

Two cases of gastric cancer with peritoneal dissemination that responded to TS-1 without progression or recurrence for over 3 years

for over 3 years. A 67-year-old woman underwent distal gastrectomy for advanced gastric cancer. Histological examination of several nodules in the posterior gastric wall led to suspicion of peritoneal dissemination. Low-dose FP treatment was performed for only 5 days after surgery. Peritoneal dissemination was diagnosed at the time of surgery for postoperative abdominal hernia 20 months after the gastrectomy. TS-1 was administered postoperatively, and recurrence or progression has not been detected for 3 years 4 months. Another patient, a 68-year-old woman,underwent distal gastrectomy for advanced gastric cancer with multiple lymph node metastasis and peritoneal dissemination. TS-1 was administered after surgery, and no recurrence or progression has been detected for 3 years and 7 months. These cases suggest that TS-1 is a promising treatment for gastric cancer with peritoneal dissemination.     

Proton magnetic resonance spectroscopy (MRS) of metastatic brain tumors: variations of metabolic profile

Background Spectroscopic imaging can be helpful for the noninvasive identification of parenchymal brain tumors. The objective of the present study was the characterization of the metabolic profile of intracranial metastases, based on proton magnetic resonance spectroscopy (MRS). Methods One hundred and four metastatic brain tumors were evaluated by long-echo (TR, 2000 ms; TE, 136 ms) single-voxel volume-selected proton MRS. In 83 patients the tumor fraction within the MRS voxel constituted more than 50%. Results Compared to normal brain, the tumors showed statistically significant decreases of N-acetylaspartate (P < 0.0001), creatine (P < 0.0001), and the [NAA]/choline-containing compounds ratio (P < 0.0001), increases of [Cho] (P < 0.0001) and the mobile lipids/[Cr] ratio (P < 0.0001) and the lactate/[Cr] ratio (P < 0.05), and the more frequent presence of [Lip] (P < 0.0001) and [Lac] (P < 0.0001) resonances. However, the majority of these differences were lost when data for patients whose tumor fraction within the MRS voxel constituted less than 50% were analyzed separately. Determination of the predominant metabolite peak on the MR spectrum [NAA, Cho, Lip] permitted us to define three general metabolic patterns of brain metastases, which, showed statistically significant associations with the size of the neoplasm (P < 0.001), type of its contrast enhancement (P < 0.01), and the extent of perilesional edema (P < 0.05). Conclusion Proton MRS can define metabolically different subsets of metastatic brain tumors, and these characteristics should be taken into consideration during the differential diagnosis of parenchymal brain lesions. The results of this study were presented in part during 64^th Annual Meeting of the Japan Neurosurgical Society, October 5–7, 2005, Yokohama, Japan