Platelet-derived growth factor, basic fibroblast growth factor, and interferon gamma increase type IV collagen production in human fetal mesangial cells via a transforming growth factor-beta-dependent mechanism.

BACKGROUND: Glomerulosclerosis is characterized by glomerular accumulation of extracellular matrix following mesangial cell proliferation. The precise pathomechanism of glomerulosclerosis is still undetermined. Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (b-FGF) are known to be mitogenic for mesangial cells, and interferon gamma (IFN-gamma) is known to have an inhibitory effect on mesangial cell proliferation. We attempted to clarify the role of these cytokines on mesangial matrix production using cultured human fetal mesangial cells (HMC). METHODS: HMC were incubated with these cytokines for 24-72 h and the levels of type IV collagen and TGF-beta in the cell supernatants were measured by enzyme immunoassay. RESULTS: PDGF, b-FGF, and IFN-gamma stimulated type IV collagen production by HMC in a dose- and time-dependent manner. The anti-TGF-beta neutralizing antibody clearly inhibited their stimulatory effect on type IV collagen production. PDGF and b-FGF also stimulated TGF-beta production by HMC in a dose-dependent manner, although IFN-gamma did not. CONCLUSION: PDGF, b-FGF, and IFN-gamma stimulate type IV collagen production in cultured HMC via a TGF-beta-dependent mechanism.     

Genetic Changes and Histopathological Grades in Human Hepatocellular Carcinomas

Loss of heterozygosity (LOH) on chromosomes 1p, 4q, 5q, 8p, 13q, 16q, 17p, and 22q, and mutation of the p53 gene were simultaneously analyzed in 63 hepatocellular carcinomas (HCCs) with distinct histopathological grades, 80% of the tumors being from patients who had been exposed to hepatitis B virus (HBV) or hepatitis C virus (HCV). The frequencies of LOH on 8 chromosomes were 0–25% in 10 well differentiated HCCs, LOH being observed on 4q, 5q and 17p, 21–53% in 26 moderately differentiated HCCs, LOH on 8p and 17p being high, and 29–75% in 27 poorly differentiated HCCs, LOH on 17p, 4q and 8p heing the most frequent. p53 gene mutation was detected in moderately and poorly differentiated HCCs at 15% and 52%, respectively, but not at all in well differentiated HCCs. Of the mutations detected, 42% were transition mutation and only 5% were CpG transition, in contrast to the high frequencies of these types of mutations in colon tumors (78% and 54%, respectively). LOH on every chromosome and p53 mutation were more frequent in more advanced tumors, and accumulation of genetic changes increased with increase of the histopathological grade. Frequency of genetic changes in HCCs from HBV-positive patients was comparable to that from HCV-positive patients. The present results suggest that accumulation of genetic changes in multiple tumor suppressor genes, especially LOH on 17p, 4q and 8p, and mutation in p53 gene, are involved in the progression of liver cancer, and LOH on 17p and 4q precedes other genetic changes. Differences in the direction of p53 mutation between HCC and colon carcinoma suggest that liver carcinogens are distinct from colon carcinogens. Furthermore, mechanisms affecting the frequency of LOH in HCCs in HBV-infected patients may be similar to those in HCV-infected patients.     

Head-and-neck stages I and II extranodal non-Hodgkin's lymphomas: real classification and selection for treatment modality

PURPOSE: We re-evaluated histopathological specimens of head and neck early-stage extranodal non-Hodgkin's lymphoma (NHL) using the revised European and American lymphoma (REAL) classification, and also investigated the relationship between the clinical characteristics and histopathological classification in an attempt to evaluate the usefulness of this new classification system in selecting treatment modalities. MATERIALS AND METHODS: Between 1979 and 1995, 117 patients with histologically confirmed stages I and II NHL of head-and-neck extranodal regions were treated. Of these patients, 110 specimens were available for re-evaluation. Sixty-four patients had Stage I, and 46 had Stage II diseases. All but 3 had received radiation therapy, and 59 patients were also treated with intensive combination chemotherapy. RESULTS: There were 32 extranodal marginal-zone B-cell lymphomas, 57 diffuse large B-cell lymphomas, 11 peripheral T/NK-cell lymphomas, and 10 others. The 5- and 10-year cause-specific survival rates for all patients were 72% and 62%, respectively. Patients with extranodal marginal-zone B-cell lymphoma or other low-grade B-cell lymphomas demonstrated higher survival rates than patients with other lymphomas. Patients with peripheral T/NK lymphomas showed the lowest survival rate. CONCLUSION: The REAL classification accurately indicated the prognosis of patients with NHL. These results suggest that appropriate treatment modalities can be selected using this classification.     

ADULT T CELL LEUKEMIA HISTOLOGICAL CLASSIFICATION AND CHARACTERISTICS

Adult T cell leukemia was classified into two distinct types, monomorphic and pleomorphic, according to their histological and cytological features. The former type is composed of uniform neoplastic cells with round or slightly indented nuclei without any marked deformation. The latter type, on the other hand, occupies a unique position in lymphocytic leukemias with the following characteristics: a) onset in adulthood, b) an acute and subacute course, c) well-differentiated T cell origin of the neoplastic cells, d) pleomor-phism of the neoplstic cells with markedly deformed nuclei, e) difkuse proliferation of the neoplastic cells without nodular pattern, f) histologically heterogeneous features of lymph nodes frequently admixing a cluster of normal lymphocytes, proliferation of macrophages and dendritic cells, and well-developed high endothelium venules, g) high incidence of skin lesions due to the infiltration of neoplastic cells, and h) exclusively limited localization of patients' birth places.     

A case of advanced gastric cancer with lymphangitis carcinomatosa after operation of Krukenberg tumor treated by TS-1 plus CPT-11 as third-line chemotherapy

Chemotherapies for recurrent gastric cancer have not yet been established. Here we report a case of type 4 gastric cancer associated with lymphangitis carcinomatosis which became refractory to the previous chemotherapies. The case was a 40-year-old woman. She had been diagnosed with gastric cancer after a Krukenberg tumor operation. Chemotherapies (TS-1 plus CDDP as first-line, and TS-1 plus taxanes as second-line) were performed, and a partial response was achieved. Disease activity has been well controlled until this time. Since recurrence of left pleural effusion and lymphangitis carcinomatosis was recognized, we changed the chemotherapy TS-1 plus CPT-11. Pleural effusion decreased and lymphangitis carcinomatosis improved. The serum CA 19-9 level rose transiently after CPT-11 administration, and tended to fall at the second week of chemotherapy. However, the patient died 2 years 4 months after the onset. TS-1 plus CPT-11 combination chemotherapy would be effective for lymphangitis carcinomatosis and also useful as third-line chemotherapy for recurrent gastric cancer.     

Involvement of supraspinal imidazoline receptors and descending monoaminergic pathways in tizanidine-induced inhibition of rat spinal reflexes

The neuronal pathways involved in the muscle relaxant effect of tizanidine were examined by measurement of spinal reflexes in rats. Tizanidine (i.v. and intra-4th ventricular injection) decreased the mono- and disynaptic (the fastest polysynaptic) reflexes (MSR and DSR, respectively) in non-spinalized rats. Depletion of central noradrenaline by 6-hydroxydopamine abolished the depressant effect of tizanidine on the MSR almost completely and attenuated the effect on the DSR. Co-depletion of serotonin by 5,6-dihydroxytryptamine and noradrenaline resulted in more prominent attenuation of tizanidine-induced inhibition of the DSR. Supraspinal receptors were then studied using yohimbine- and some imidazoline-receptor ligands containing an imidazoline moiety. Idazoxan (I1, I2, I3, and alpha2), efaroxan (I1, I3, and alpha2), and RX821002 (I3 and alpha2), but not yohimbine, an alpha2-adrenergic receptor antagonist with no affinity for I receptors, antagonized the inhibitory effects of tizanidine. Thus, supraspinal I receptors (most likely I3) and descending monoaminergic influences are necessary for tizanidine-induced inhibition of spinal segmental reflexes.     

Centrally mediated antihyperalgesic and antiallodynic effects of zonisamide following partial nerve injury in the mouse

Some antiepileptic drugs are used clinically to relieve neuropathic pain. We have evaluated the effects and investigated the possible mechanisms of action of zonisamide, an antiepileptic drug, on thermal hyperalgesia and tactile allodynia in a murine chronic pain model that was prepared by partial ligation of the sciatic nerve. Subcutaneously administered zonisamide (10 and 30 mg/kg) produced antihyperalgesic and antiallodynic effects in a dose-dependent manner; these effects were manifested by elevation of the withdrawal threshold in response to a thermal (plantar test) or mechanical (von Frey) stimulus, respectively. Similar analgesic effects were obtained in both the plantar and von Frey tests when zonisamide was injected either intracerebroventricularly (i.c.v., 10 and 30 μg) or intrathecally (i.t., 10 and 30 μg). It is thought that this elevation of the thermal and mechanical withdrawal thresholds after local injection of zonisamide is not generated secondarily via impaired motor activity, since zonisamide (30 μg, i.c.v. or i.t.) did not affect locomotor activity, as assessed in sciatic-nerve-ligated mice. Moreover, the nitric oxide synthase inhibitor L-NAME, when injected either i.c.v. or i.t., potentiated the analgesic effects of zonisamide. In contrast, neither i.c.v. nor i.t. zonisamide produced antinociceptive effects against acute thermal and mechanical nociception in non-ligated mice. Together, following peripheral nerve injury, it appears that zonisamide produces centrally mediated antihyperalgesic and antiallodynic effects partly via the blockade of nitric oxide synthesis.     

HMOCC-1, a human monoclonal antibody that inhibits adhesion of ovarian cancer cells to human mesothelial cells

OBJECTIVES: Ovarian carcinoma is one of the most common gynecologic cancers and shows the worst prognosis since current therapies are not sufficiently effective at achieving and maintaining remission. To develop new treatment, a monoclonal antibody recognizing human ovarian cancer cells was raised in KM mice. METHODS: A human monoclonal antibody targeting RMG-I (an ovarian carcinoma cell line) was established with hybridomas of myeloma cells and spleen cells from KM mice. The immunohistochemical reactivity of various types of ovarian carcinoma and other tumors was investigated. RMG-I cells were treated with N-glycosidase F, NaOH, H(2)SO(4), and Gal NAC-alpha-benzyl to investigate the target antigens by Western blotting. The effect of HMOCC-1 on adhesion of RMG-I cells to cultured human mesothelial cells was also investigated. RESULTS: The new human monoclonal antibody, HMOCC-1, was an immunoglobulin M that recognized ovarian epithelial carcinoma. Immunohistochemical staining revealed HMOCC-1 positivity in 83.2% of ovarian carcinomas. The antigen recognized by HMOCC-1 was apparently a glycoprotein since Western blotting yielded a broad band (34.8-49.1 kDa). HMOCC-1 inhibited the attachment of RMG-I cells to monolayers of cultured peritoneal mesothelial cells in a concentration-dependent manner. CONCLUSIONS: This new human monoclonal antibody reacted with most ovarian cancers tested. The antigen recognized by HMOCC-1 is a glycoprotein located on the cell membrane. Inhibition of the attachment of RMG-1 cells to mesothelial cells by HMOCC-1 suggests a potential role for this antibody in the treatment of ovarian cancer.