Overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induced acute leukemia in p210BCR/ABL transgenic mice.

Chronic myelogenous leukemia (CML) is a hematopoietic disorder, which begins as indolent chronic phase but inevitably progresses to fatal blast crisis. p210BCR/ABL, a constitutively active tyrosine kinase, is responsible for disease initiation but molecular mechanism(s) underlying disease evolution remains largely unknown. To explore this process, we employed retroviral insertional mutagenesis to CML-exhibiting p210BCR/ABL transgenic mice (Tg). Virus infection induced acute lymphoblastic leukemia (ALL) in p210BCR/ABL Tg with a higher frequency and in a shorter latency than wild-type littermates, and inverse PCR detected two retrovirus common integration sites (CISs) in p210BCR/ABL Tg tumors. Interestingly, one CIS was the transgene itself, where retrovirus integrations induced upregulation of p210BCR/ABL and production of truncated BCR/ABL with an enhanced kinase activity. Another CIS was Notch1 gene, where retrovirus integrations resulted in overexpression of Notch1 and generation of Notch1 lacking the C-terminal region (Notch1DeltaC) associated with stable expression of its activated product, C-terminal-truncated Notch intracellular domain (NICD Delta C). In addition, generation of Tg for both p210BCR/ABL and Notch1DeltaC developed ALL in a shortened period with Stat5 activation, demonstrating the cooperative oncogenicity of Notch1DeltaC/NICD Delta C with p210BCR/ABL involving Stat5-mediated pathway. These results demonstrated that overexpression/enhanced kinase activity of BCR/ABL and altered expression of Notch1 induces acute leukemia in a transgenic model for CML.

Inhibitory effects of suplatast tosilate on the differentiation and function of monocyte-derived dendritic cells from patients with asthma.

BACKGROUND: Dendritic cells (DCs) are antigen-presenting cells that efficiently activate T cells. OBJECTIVE: We examined the effects of suplatast tosilate, which prevents T-helper type 2 responses, on the differentiation and function of monocyte-derived DCs (moDCs). METHODS: DCs were differentiated in vitro from peripheral monocytes from patients with asthma by the addition of granulocyte macrophage colony-stimulating factor and IL-4 in the presence or absence of suplatast tosilate. Cell surface molecules (CD1a, CD14, CD80, CD83, CD86, HLA-DR) on immature and mature DCs were analysed with flow cytometry, and the secretion of CC chemokine ligand (CCL)17 (thymus and activation-regulated chemokine), IL-12p70, IL-12p40, and IL-10 was measured with an ELISA. We also studied the proliferative responses of allogeneic CD4(+) T cells from healthy subjects to DCs differentiated in the presence of suplatast tosilate. In addition, the production of IFN-gamma and IL-5 by CD4(+) T cells after coculture with untreated DCs or suplatast tosilate-treated DCs was measured with ELISA. RESULTS: Suplatast tosilate significantly inhibited the expression of CD1a, CD80, and CD86 on immature DCs and of CD1a, CD80, CD83, and CD86 on mature DCs. Suplatast tosilate also significantly inhibited the secretion of CCL17, IL-12p70, and IL-12p40; however, the secretion of IL-10 was not affected. The proliferative responses of allogeneic CD4(+) T cells to suplatast tosilate-treated DCs were suppressed. Moreover, suplatast tosilate-treated DCs had an impaired capacity to stimulate CD4(+) T cells to produce IFN-gamma and IL-5. CONCLUSION: Suplatast tosilate inhibits the differentiation, maturation, and function of moDCs.

Comparative studies on Philippine Paragonimus westermani and Japanese Paragonimus westermani

Paragonimus westermani in the Philippines has been reconfirmed to develop to sexual maturity in albino rats. The migration route of this species in albino rats have also been studied in detail and compared with that of Paragonimus westermani in Japan in ratsAs the result it was found that the course of migration of the larvae of Philippine P. westermani in rats was quite different from that of Japanese P. westermani in ratsIt has shown that it is possible to differentiate the species of Paragonimus westermani in the Philippines and Japan by means of immunoserological techniques such as compliment fixation test, double diffusion test and immunoelectrophoresis. The Philippine P. westermani from Japanese P. westermani not only morphology but also biological and immunological chararcteristics, therefore we reiterate the new name paragonimus philippinensis, (Ito, 1978) Philippine P. westermaniA new theory by Miyazaki (1977) concerning the taxonomy of Paragonimus westermani is also discussed. (Summary)

[A multicenter cooperative study on supplementary chemotherapy of uterocervical cancer. The Kyushu UFT Study Group of Uterocervical Cancer].

A randomized study was carried out by means of multicentered cooperation in respect to 5-FU and UFT administration, which was used as the supplementary chemotherapy after treatment of uterocervical cancer. Five years later, the improvement in prognosis was examined. Out of all the cases with radical operation + supplementary chemotherapy as well as with radical operation + postoperative radiotherapy + supplementary chemotherapy, 98 cases were ratable. The analysis of 98 cases led to no significant difference in the survival rate between the 5-FU administration group and the UFT administration group. As to the cases with supplementary chemotherapy + postoperative radiotherapy only, the survival rate was significantly higher in the UFT administration group than in the 5-FU administration group. During the administration, severe adverse side effects developed neither in the 5-FU administration group nor in the UFT administration group. These results suggest that UFT may be useful as a factor in supplementary chemotherapy of uterocervical cancer in combination with radiotherapy.

Detection of human papillomavirus (HPV) infections in Japanese women with and without abnormal cervical cytology by dot blot and Southern blot hybridization.

The frequency of human papillomavirus (HPV) was investigated in 245 Japanese women (100 showing normal cytology and 145 showing abnormal cytology). A previously presented method for the detection and typing of HPV DNA was used, where a dot blot test excluded samples that did not hybridize with HPV DNA. Positive samples were further analyzed by a southern blot procedure, to give the HPV type. A mixture of subgenomic probes of the types 6, 11, 16, 18, 31, 33 and 35 was used. HPV DNA was detected in only 2% (2/100) of patients without abnormal cytology. In patients with abnormal cytology, the frequency was 30% (43/145). HPV was detected in 100% (2/2) of the patients with condyloma acuminatum, 39% (26/66) of those with mild to moderate dysplasia, 44% (7/16) of those with severe dysplasia to carcinoma in situ, and 70% (7/10) of those with invasive carcinoma. Young women (20-29 yr.) had the highest HPV frequency (71%). HPV types 16 and 18 were found in 39% of the patients with mild to moderate dysplasia, in 71% of those with severe dysplasia to carcinoma in situ and in 86% of those with invasive carcinoma. These may be considered as high risk types for development to cancer. HPV type 31 may be considered as a moderate risk, as it was detected in 37% (16/43) of the patients. HPV types 6 and 11 were found in 100% of patients with condyloma acuminatum (2/2). To clarify the natural history of the HPV infection in the uterine cervix, it is necessary to conduct further studies.

The current therapeutic approaches to advanced ovarian cancer.

One hundred and fifty-nine cases of stage III or IV ovarian cancer treated at Kurume University and affiliated hospitals over the decade from 1978 to 1987 were analysed for their clinical outcome in relation to the therapeutic methods. The following results were obtained. 1) Two definite groups of patients were identified, one having a favourable prognosis with all patients surviving for at least three years after the initial treatment and the other, group of patients with poor prognosis who died within two years. There were significant differences in the clinical features of the two groups mentioned, i.e. in the performance status, the clinical stage, the type of operation carried out, the residual tumor, the application of second look laparotomy (SLO), the type of anti-cancer drug given and the use of maintenance chemotherapy. 2) The operations performed were primary surgery, including hysterectomy, bilateral adnexectomy and omentectomy or exploratory laparotomy. There was also a significant difference in the prognosis of those who received primary surgery compared to those given exploratory laparotomy. 3) A significant difference was also noted in the prognosis of cases with residual tumors less than 1 cm in diameter when compared to those which had larger residual tumors. 4) The application of SLO did not affect the prognosis. 5) Favourable results were obtained in the survival rate of cases who received cisplatin and also, 6) Favourable results were obtained in the survival rate of those patients who were given maintenance chemotherapy.

[Histomorphological studies of Krukenberg tumor on early ovarian metastatic lesion].

In ten cases of "early" Krukenberg tumor with only slight swelling of the ovary, histomorphological studies were performed to clarify the process of the formation of Krukenberg tumor. 1) The histological features of early metastatic lesion were classified into 3 types; lymph vessel permeation only, solid alveolar structure, and diffuse infiltration type. 2) Lymph vessel permeation in the ovarian hilum was observed in all cases. 3) In the diffuse infiltration type, signet-ring cells extended diffusely and radially via the lymph vessels, and, in the periphery, tumor cells leaked from the lymph vessels, infiltrating the stroma. At this stage, the response of ovarian stroma was slight, and signet-ring cells were present more abundantly in the vicinity of the infiltrated area. 4) In the solid alveolar type, the stroma was interposed in these lesions. 5) CEA staining revealed many CEA positive tumor cells in the proliferated stroma in which tumor cells failed to be detected. In summary, tumor cells infiltrate via the lymph vessels and leak into the stroma. Following the destruction of signet-ring cells, the mucus leaks into the stroma and it produces stromal edema and proliferation, eventually leading to a swollen ovary.

Respiratory function in handicapped children.

The aim of this study was to evaluate respiratory function of severely handicapped children. Tidal volumes and respiratory rates were determined in a total of 130 children with different clinical motor abilities. Tidal volume of non-sitters (n = 39) was significantly lower than ambulators (n = 49) or sitters (n = 42) (p less than 0.01). There was no difference in respiratory rate among the three groups. Among 45 children whose vital capacity could be determined, the tidal volumes showed a significant correlation with vital capacity (r = 0.56, p less than 0.001). Among four children whose tidal volume was less than 200 ml and respiratory rate was more than 30 cpm, blood gas analysis revealed hypoxia in three of them. The tidal volumes, therefore, would be a useful guide to estimate respiratory functions. It was concluded that the respiratory function in a non-sitter with reduced tidal volume is impaired, and that preventive measures must be taken against respiratory infection.

Effects of butoctamide hydrogen succinate and nitrazepam on psychomotor function and EEG in healthy volunteers.

We studied the effects of butoctamide hydrogen succinate and nitrazepam on psychomotor function and EEG in eight male volunteers aged 19-32. The hypnotic effects, effects on psychomotor performance, EEG activity and standing steadiness between BAHS 1000 mg and nitrazepam 5 mg were compared at regular intervals for 10 h. The serum levels of both drugs were also assayed. The hypnotic effects of BAHS were very weak compared to those of nitrazepam. BAHS did not exert any effects on psychomotor performance and standing steadiness during the test period. In contrast, nitrazepam impaired psychomotor performance and standing steadiness as the serum drug levels increased. Nitrazepam decreased the alpha activity and increased the beta activity in a concentration-dependent manner. BAHS did not change the alpha activity but increased beta-2 activity at Fz and Cz at 10 h of the post-drug period. BAHS was eliminated more rapidly than nitrazepam. These results indicated that BAHS, at the dose used, was less potent than nitrazepam and the effects on psychomotor performance and standing steadiness were minimal.

Severe cardiovascular changes associated with pancuronium after cardiopulmonary resuscitation and after brain injury.

Severe hypertension, tachycardia or ECG changes have been reported following i.v. administration of pancuronium to patients with pheochromocytoma or bronchial asthma. These cardiovascular changes were explained by an interaction between autonomic effects of pancuronium and elevated serum catecholamines or aminophylline. We noted similar cardiovascular changes associated with i.v. administration of pancuronium in two patients after successful cardiopulmonary resuscitation and in two with midbrain hemorrhage and epidural hematoma. In these patients, pancuronium produced no abnormal cardiovascular changes when given during elective surgery or before the occurrence of midbrain hemorrhage. Thus, ischemic brain damage may play a role in producing the severe cardiovascular changes associated with pancuronium.

Krukenberg tumors of the ovary: a clinicopathologic analysis of 112 cases.

The records from 1965 to 1985 in the Department of Obstetrics and Gynecology Kurume University Hospital were reviewed. In this period, 112 cases were fulfilled the criteria of Krukenberg tumor and they were carefully screened to clinical history, physical findings, operative findings, and histologic character of the lesion. The incidence of Krukenberg tumors in all ovarian cancer was 17.8%. The average age was 45.4 years with ranged from 23 to 71. As expected from this age distribution, 73 patients (65%) were 50 years of age or younger. A primary carcinoma of the stomach was found in 78 (69.6%) of 112 patients. In three cases, the Krukenberg tumors were associated with a recent pregnancy. Two cases were associated with ovarian dermoid cyst. Microscopically, both ovaries were involved in all cases that could be evaluated for bilaterality. The relation between age distribution and histological characteristics was examined. Signet-ring type carcinomas were observed frequently in young women and gland-formation type carcinomas in older women. Stromal hyperplasia of the tumors were remarkably common in younger women. In the patients with a recent pregnancy, the abdominal mass developed rapidly after delivery. In addition, estrogen receptors were present in all experimented cases. The above results suggested that estrogen influences tumor development and the histological character many of Krukenberg tumor.

[Transfer of cefmenoxime to lung tissue and thoracic muscle in thoracic surgery].

Twenty patients who were performed pulmonary resection for the disease of the lung were administered 2 g of cefmenoxime (CMX) intravenously during the operation. The CMX levels in serum, lung tissue and thoracic muscle were measured by agar-well technique. The CMX levels in lung tissue and thoracic muscle were higher than the MIC80 of CMX for Klebsiella pneumoniae, Haemophilus influenzae and Streptococcus pneumoniae which were commonly as isolated causative organisms from the patients with pulmonary infection. These results indicate that CMX will be useful agent for the prevention and treatment of pulmonary infection.

[Studies of immunological function in patients with ovarian cancer].

Immunological function in patients with ovarian cancer was studied using parameters including peripheral blood lymphocyte counts, lymphocyte subsets, PHA-induced lymphoproliferative (PHA-LP) reaction, PPD skin test and immunoglobulin levels. The following results were obtained: The number of total lymphocytes, T cells (OKT 11+) and B cells (OKIa 1+) in peripheral blood were found to be decreased in patients with advanced carcinoma. The positive rate of PPD skin test was also lower in the patients. OKT8+ cells were significantly increased in the disseminated carcinoma (DC) group and the OKT4+/OKT8+ ratio in the DC group was markedly decreased when the results were compared with the control and the patients in the localized carcinoma (LC) group. PHA-LP reaction and serum IgM level in the patients in the LC and DC groups were found to be significantly lower than in the control group. The percentage of T cell (OKT11+), serum IgG and IgA levels were not altered in any clinical stage of the patients.