Leukemia cell to endothelial cell communication via exosomal miRNAs.

Recent findings indicate that specific microRNAs (miRNAs), such as those of the miR-17-92 cluster, may be responsible for regulating endothelial gene expression during tumor angiogenesis. Secreted miRNAs enclosed in exosomes also have an important role in cell-cell communication. To elucidate whether miRNAs secreted from neoplastic cells transfer into endothelial cells and are functionally active in the recipient cells, we investigated the effect of exosomal miRNAs derived from leukemia cells (K562) on human umbilical vein endothelial cells (HUVECs). As K562 cells released the miR-17-92 cluster, especially miR-92a, into the extracellular environment, K562 cells, transfected with Cy3-labeled pre-miR-92a, were co-cultured with HUVECs. Cy3-miR-92a derived from K562 cells was detected in the cytoplasm of HUVECs, and the Cy3-miR-92a co-localized with the signals of an exosomal marker, CD63. The expression of integrin α5, a target gene for miR-92a, was significantly reduced in HUVECs by exosomal miR-92a, indicating that exogenous miRNA via exosomal transport can function like endogenous miRNA in HUVECs. The most salient feature of this study is the exosome, derived from K562 cells with enforced miR-92a expression, did not affect the growth of HUVECs but did enhance endothelial cell migration and tube formation. Our results support the idea that exosomal miRNAs have an important role in neoplasia-to-endothelial cell communication.

High expression of N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma.

BACKGROUND: Gestational trophoblastic diseases (GTDs) are related to trophoblasts, and human chorionic gonadotropin (hCG) is secreted by GTDs as well as normal placentas. However, the asparagine-linked sugar chains on hCG contain abnormal biantennary structures in invasive mole and choriocarcinoma, but not normal pregnancy or hydatidiform mole. N-acetylglucosaminyltransferase-IV (GnT-IV) catalyses ß1,4-N-acetylglucosamine branching on asparagine-linked oligosaccharides, which are consistent with the abnormal sugar chain structures on hCG. METHODS: We investigated GnT-IVa expression in GTDs and placentas by immunohistochemistry, western blot, and RT-PCR. We assessed the effects of GnT-IVa knockdown in choriocarcinoma cells in vitro and in vivo. RESULTS: The GnT-IVa was highly expressed in trophoblasts of invasive mole and choriocarcinoma, and moderately in extravillous trophoblasts during the first trimester, but not in hydatidiform mole or other normal trophoblasts. The GnT-IVa knockdown in choriocarcinoma cells significantly reduced migration and invasive capacities, and suppressed cellular adhesion to extracellular matrix proteins. The extent of ß1,4-N-acetylglucosamine branching on ß1 integrin was greatly reduced by GnT-IVa knockdown, although the expression of ß1 integrin was not changed. In vivo studies further demonstrated that GnT-IVa knockdown suppressed tumour engraftment and growth. CONCLUSION: These findings suggest that GnT-IVa is involved in regulating invasion of choriocarcinoma through modifications of the oligosaccharide chains of ß1 integrin.

Downregulated plasma miR-92a levels have clinical impact on multiple myeloma and related disorders.

Recent studies have demonstrated that one-third of known microRNAs (miRNAs) are stably detectable in plasma. Therefore, we assessed plasma miRNAs to investigate the dynamics of oncomir 17-92a, which is highly expressed in multiple myeloma (MM) patients. The plasma miR-92a level in symptomatic MM patients was significantly downregulated compared with normal subjects (P<0.0001), regardless of immunoglobulin subtypes or disease stage at diagnosis. In contrast, miR-92a levels in peripheral blood CD8(+) or CD4(+) cells from MM patients were lower than those of normal subjects, and the miR-92a levels of the cells tended to correlate with plasma miR-92a levels. The plasma miR-92a level in the complete remission group became normalized, whereas the partial response (PR) and very good PR groups did not reach the normal range. In smoldering MM, the plasma miR-92a level did not show a significant difference compared with normal subjects. Our findings suggest that measurement of the plasma miR-92a level in MM patients could be useful for initiation of chemotherapy and monitoring disease status, and the level may represent, in part, the T-cell immunity status of these patients.

Long-term survival of young women receiving fertility-sparing surgery for ovarian cancer in comparison with those undergoing radical surgery.

OBJECTIVES: To compare the clinical outcome of patients with stage I epithelial ovarian cancer (EOC) who received with fertility-sparing surgery (FSS) with those who underwent radical surgery (RS). METHODS: After a central pathological review and search of the medical records from multiple institutions, a total of 572 patients were retrospectively evaluated. All patients were divided into three groups: group A {FSS (n=74); age, ≤ 40}; groups B and C [RS; age, 40 ≥{(B), n=52}; 40<{(C), n=446}]. RESULTS: Five-year overall survival (OS) and disease-free survival (DFS) rates of patients in the groups were as follows: group A, 90.8% (OS)/87.9% (DFS); group B, 88.3% (OS)/84.4% (DFS); group C, 90.6% (OS)/85.3% (DFS), respectively (OS, P=0.802; DFS, P=0.765). Additionally, there was no significant difference in OS and DFS among the three groups stratified to stage IA or IC (OS (IA), P=0.387; DFS (IA), P=0.314; OS (IC), P=0.993; DFS (IC), P=0.990, respectively). Furthermore, patients with a grade 1-2 or 3 tumours in the FSS group did not have a poorer prognosis than those in the RS group. CONCLUSIONS: Stage I EOC patients treated with FSS showed an acceptable prognosis compared with those who underwent RS.

Ambulation-promoting effect of peppermint oil and identification of its active constituents.

Various plant-derived essential oils (EOs) have traditionally been used in the treatment of mental disorders, despite a lack of scientific evidence. In a previous study, we demonstrated that certain EOs possess behavioral effects, a finding that supports our original hypotheses that EOs possess psychoactive actions. The present study was conducted in order to obtain further evidence to support our hypothesis. Peppermint oil, a type of EO, is believed to be effective for treating mental fatigue. When the oil was administered intraperitoneally to ICR mice, the ambulatory activity of mice increased dramatically. We identified alpha-pinene, beta-pinene, (R)-(+)-limonene, 1,8-cineol, isomenthone, menthone, menthol, (R)-(+)-pulegone, menthyl acetate and caryophyllene as constituent elements of peppermint oil by GC-MS analysis. We then examined the effect of each constituent element of peppermint oil on ambulatory activity in mice. Intraperitoneal administration of 1,8-cineol, menthone, isomenthone, menthol, (R)-(+)-pulegone, menthyl acetate and caryophyllene significantly increased ambulatory activity in mice, suggesting that these chemicals are the behaviorally active elements of peppermint oil. Intravenous administration of these substances to mice induced a significant increase in ambulatory activity at much lower doses. The present study provides further evidence demonstrating that EOs possess pharmacological actions on behavior. In addition, our finding revealed that the action of peppermint oil comes from its constituent elements.

Effects of psychoactive drugs in the Vogel conflict test in mice.

This study examined effects of various psychoactive drugs on the Vogel conflict test, where drinking behavior is punished by electric shocks, in ICR mice to clarify the pharmacological features of this method in mice. A benzodiazepine anxiolytic diazepam and a barbiturate pentobarbital produced significant anticonflict effects, which mean that these drugs increased the number of electric shocks mice received during 40-min test session. On the other hand, yohimbine (alpha2-receptor antagonist), caffeine (adenosine-receptor antagonist), scopolamine (muscarinic cholinergic antagonist), cyclazocine (sigma-receptor antagonist), cimetidine (H2-receptor antagonist), baclofen (GABA(B)-receptor agonist), MK-801 (NMDA-receptor antagonist), buspirone (5-HT1A-receptor agonist), chlorpromazine (dopamine-receptor antagonist) and haloperidol (dopamine-receptor and sigma-receptor antagonist) all did not produce anticonflict effects in this test using ICR mice. The results suggest that the Vogel conflict test is applicable to ICR mice and that this test in mice is appropriate as a screening method for drugs that have apparent anti-anxiety actions.

Circadian behavior and plasticity of light-induced c-fos expression in SCN of tau mutant hamsters.

In hamsters homozygous for the circadian clock mutation tau, the photic history dramatically affects the magnitude of light-induced circadian phase shifts. The maximum amplitude of phase shifts produced by 1-h light pulses presented at CT 14 was less than 2 h in animals that had been in DD for 2 days, whereas animals that had been kept in DD for 49 days could be shifted by more than 8 h. In this study, the authors compared the effect of previous light history on the amplitude of circadian phase shifts and on c-fos expression in the SCN of tau mutant hamsters. Although the maximum amplitude of behavioral phase shifts was drastically different between animals that had been held for either 2 or 49 days in DD, maximal fos induction was not significantly different in these two groups. However, photic thresholds for light-induced behavioral phase shifts, c-fos mRNA, and Fos immunoreactivity were closely correlated within both groups, and these thresholds were lower (more sensitive to light) after 49 than after 2 days in DD. The correlation between phase shifting and Fos induction thresholds, under conditions where both responses are dramatically altered by the previous light history, demonstrates an association between changes in circadian behavioral phase-shifting responses of tau mutant hamsters and plasticity of light-induced c-fos expression in SCN. However, because the maximum amplitudes of Fos induction and phase shifting were not correlated in animals that had been in DD for 2 days, we speculate that the level of c-fos expression does not directly determine phase shift amplitude.

Hypersensitivity reactions to cisplatin following multiple uncomplicated courses: a report on two cases.

Two patients with ovarian cancer who had received multiple courses of cisplatin without complications experienced hypersensitivity reactions to cisplatin: one, involving intrahepatic artery infusion, manifested general erythema, dyspnea, and hypotension; the other, involving intravenous infusion, manifested abdominal pain, general erythema, and fever. When platinum-containing agents are administered, patients should be closely monitored for hypersensitivity reactions, even in previously uncomplicated cases.

Malignant mixed Müllerian tumor of the fallopian tube: report of two cases and review of literature.

Malignant mixed Müllerian tumors are usually found in the endometrium, vagina, cervix, and ovary. It is extremely rare for this tumor to arise in the fallopian tube, and to date only 37 tubal cases have been reported. We recently experienced 2 such cases. The clinical features, pathologic findings, diagnosis, therapy, and outcome of these 39 cases were reviewed. The clinical features and diagnosis were similar to those of primary carcinoma of the fallopian tube. Correct preoperative diagnosis was difficult. Histologically, 18 patients had homologous elements and 21 had heterologous elements in the sarcomatous components. The most common type of heterologous element was cartilage, followed by striated muscle and bone. The clinical stage (FIGO staging of ovarian carcinoma) was stage I in 15 cases, stage II in 11 cases, stage III in 8 cases, stage IV in 3 cases, and unknown in 2 cases. In all the patients except 1, the tumor was surgically removed. Postoperatively, radiotherapy was given to 9 patients, chemotherapy to 9 patients, and both to 2 patients. Sixteen patients died of the disease, after a mean period of 16.1 months. Of the 15 stage I patients, 10 survived more than 12 months. The most important prognostic factor was spread of the tumor at diagnosis.

[Effects of nicotine on circadian rhythm of ambulatory activity and drinking in rats].

Effects of the intake of nicotine solution and/or forced administration of nicotine at a fixed time-of-day on circadian rhythm of ambulatory activity and drinking in rats were observed under various conditions. Rats showed nocturnal pattern under the light-dark cycle (L: D = 12:12, light period 6:00-18:00), and the patterns scarcely altered while the rats were given 150 micrograms/ml of nicotine solution. When a restricted feeding only for 1 h per day (10:00-11:00) was loaded to the rats, the ambulatory activity and drinking appeared in the light period, especially around the feeding time. While rats were given 15-150 micrograms/ml of nicotine solution under the restricted feeding condition, they demonstrated a marked phase-shift in the circadian rhythm in the concentration-dependent manner. Rats showed free-running rhythms with tau value of longer than 24 h under the constant red dim light condition (CRDL), and such rhythm was scarcely modified by the intake of nicotine solution of 50-150 micrograms/ml. However, when nicotine (1.5 mg/kg po), but not tap water, was administered at 10:00 every day under the CRDL condition, it also produced phase-shift which was similar to that induced by the nicotine ingestion under the redose of nicotine is administered or taken at a fixed time-of-day.

Early gastric cancer following gastrojejunostomy without gastrectomy.

Two rare cases involving distal gastrectomies for gastric cancer after an earlier gastrojejunostomies without gastrectomy for duodenal or gastric stricture due to a duodenal or pre-pyloric ulcer are reported. The time interval between the initial gastrojejunostomy and the resection of the distal stomach with gastrojejunal stoma were 17 and 36 years. One patient underwent reconstruction by Billroth II and the other by Roux-en-Y end-to-side gastrojejunostomies, both retrocolically without any peri or postoperative complications. The histological classification was confirmed for both as type IIc mucosal early gastric cancer. Only 6 other primary early gastric cancers following gastrojejunostomies without gastrectomy have been reported in the Japanese literature.

Postoperative subphrenic abscess following gastrectomy for gastric cancer.

From 1985 to 1989, a total of 598 gastric cancer patients underwent gastrectomies in the First Department of Surgery at Kurume University School of Medicine. Of these, 24 patients (4.0%) incurred a subphrenic abscess, postoperatively. Subphrenic abscesses occurred most frequently after total gastrectomies at a rate of 17 of 197 (8.8%) cases. Leaking gastrointestinal anastomoses were responsible for 12 of the 17 (70.5%) abscesses. In 384 cases of distal gastrectomy, only 6 (1.6%) cases with a subphrenic abscess occurred, and only 3 were due to anastomotic leakage. Among the total of 24 cases with subphrenic abscesses, 16 (67%) were related to an anastomotic leakage including a pancreatic fistula, while the other 8 (33%) showed no leakage by contrast roentgenography. When chest roentgenography shows a pleural effusion and an elevation of the diaphragm, then a subphrenic abscess must be suspected. The majority of patients were treated by replacing the intraabdominal drainage catheter inserted during the gastrectomy with a larger catheter. The overall operative mortality rate was 4.1% due to a death in only one (MOF) patient.

Esophageal invasion by an upper gastric cancer: retrospective evaluation and prognosis.

From 1975 to 1984, 894 patients with gastric cancer were operated on in the Department of Surgery at Kurume University School of Medicine. Of these, 86 (10%) had upper gastric cancer invading the esophagus. The 86 resected tumors were divided into two groups according to the surgical approach, thoraco-abdominal or abdominal. Twenty-three (27%) were resected through the abdominal approach and 63 (73%) were resected by the thoraco-abdominal approach. The overall positive mediastinal lymphnode metastasis rates for the 55 patients who underwent mediastinal lymphnode dissection by the thoraco-abdominal approach were 22% for differentiated type and 37% for undifferentiated type. The positive mediastinal lymphnode metastasis and the correlation to the extent of esophageal cancer invasion were observed at a minimal 7 mm distance from the esophago-gastric (E-G) junction for the undifferentiated type, and 2.2 cm for the differentiated type. Sixteen patients with cancer invading the esophagus were radically resected by the abdominal approach with an overall survival rate of 39%, while 48 were resected by the thoraco-abdominal approach with a 5 year survival rate of 40%. The 86 resected tumors were further subdivided into two groups according to the year of surgery. From 1975 to 1979, the abdominal approach was employed in 36% and the thoraco-abdominal approach in 64% of the surgeries, with an overall curative resection rate of 47%. However, from 1980 to 1984, the abdominal approach was employed in only 17% and the thoraco-abdominal approach in 83% of the surgeries and the curative resection rate increased to 59%.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgical management of residual gastric cancer.

From 1966 to 1985, 2130 patients with gastric cancer were admitted to our surgical department. Among these cancers, gastric cancer following partial gastrectomy for benign gastroduodenal lesion were present in 22 (1%) patients. The original pathology was gastric ulcers in 64% (14 patients), duodenal ulcers in 23% (5 patients), combined gastric and duodenal ulcers in 9% (2 patients), and leiomyoma of the gastric cardia in 4% (1 patient). Fourteen patients were reconstructed by Billroth II, 7 by Billroth I, and one had an esophagogastrostomy after a proximal gastrectomy. The cancer in 19 (86%) patients was resected and 3 (14%) could not be resected. Only 2 (9%) were early cancer, 20 (89%) were advanced cancer including 11 (50%) with Borrmann type 3. A higher proportion of positive lymphnode metastasis was observed for residual gastric cancer (84%) than for primary gastric cancer (49%). The overall 5-year survival rate was 32%, with a 5-year survival rate of 45% for those who underwent curative resection.