Taiji Nishimura

A possible mechanism of intravesical BCG therapy for human bladder carcinoma: involvement of innate effector cells for the inhibition of tumor growth.

Intravesical bacillus Calmette-Guerin (BCG) therapy is considered the most successful immunotherapy against solid tumors of human bladder carcinoma. To determine the actual effector cells activated by intravesical BCG therapy to inhibit the growth of bladder carcinoma, T24 human bladder tumor cells, expressing very low levels of class I MHC, were co-cultured with allogeneic peripheral blood mononuclear cells (PBMCs) with live BCG. The proliferation of T24 cells was markedly inhibited when BCG-infected dendritic cells (DCs) were added to the culture although the addition of either BCG or uninfected DCs alone did not result in any inhibition. The inhibitory effect was much stronger when the DCs were infected with live BCG rather than with heat-inactivated BCG. The live BCG-infected DCs secreted TNF-α and IL-12 within a day and this secretion continued for at least a week, while the heat-inactivated BCG-infected DCs secreted no IL-12 and little TNF-α. Such secretion of cytokines may activate innate alert cells, and indeed NKT cells expressing IL-12 receptors apparently proliferated and were activated to produce cytocidal perforin among the PBMCs when live BCG-infected DCs were externally added. Moreover, depletion of γδ T-cells from PBMCs significantly reduced the cytotoxic effect on T24 cells, while depletion of CD8β cells did not affect T24 cell growth. Furthermore, the innate effectors seem to recognize MICA/MICB molecules on T24 via NKG2D receptors. These findings suggest the involvement of innate alert cells activated by the live BCG-infected DCs to inhibit the growth of bladder carcinoma and provide a possible mechanism of intravesical BCG therapy.

Citrate enhances the protective effect of orally administered bismuth subnitrate against the nephrotoxicity of cis-diamminedichloroplatinum.

Attenuation of the renal toxicity of cis-diamminedichloroplatinum (CDDP) is important in the use of this effective but cytotoxic anticancer agent. We have previously shown that the renal toxicity of CDDP can be efficiently reduced by the induction of metallothionein (MT) by preadministration of bismuth compounds in mice. Bismuth subnitrate (BSN) is used as an antigastric ulcer agent and as an antidiarrheic agent, and is suitable for inducing MT in the kidney in cancer patients. However, due to the low absorption rate of Bi from the gastrointestinal tract, the efficacy of BSN in inducing renal MT is low. In the present study, we examined the effects of citrate as a vehicle for oral administration of BSN on the tissue distribution of Bi and induction of MT in the kidneys and tumors in mice inoculated with Meth-A fibrosarcoma. Renal levels of MT and Bi were markedly increased in the mice given BSN dissolved in citrate solution compared with those given BSN suspended in saline. On the other hand, the use of citrate increased Bi accumulation in the tumor only slightly and did not increase tumor MT levels. Administration of BSN with citrate efficiently depressed the renal toxicity of CDDP, but did not affect its antitumor activity. Since both BSN and citrate are used clinically as pharmaceuticals, the combination regimen of BSN and citrate may be readily applicable as a countermeasure against the adverse side effects of CDDP without affecting its antitumor activity.

Association of common missense changes in ELAC2 (HPC2) with prostate cancer in a Japanese case-control series

AbstractThe recently identified prostate cancer susceptibility gene ELAC2 (HPC2) harbors two common missense variants, a serine to leucine substitution at residue 217 (Leu217) and an alanine to threonine substitution at residue 541 (Thr541). We genotyped the two variants in a Japanese cohort consisting of 350 prostate cancer patients 242 male population controls, and 114 male low-risk controls. Both missense alleles, Leu217 and Thr541, were carried at higher frequency in Japanese patients than in the controls (Leu217, P = 0.0012; Thr541, P = 0.0145), and the odds ratios associated with carrying these sequence variants were higher in Japanese than in Caucasians. Although the Leu217 and Thr541 variants of ELAC2 are less common in Japanese than in Caucasians, both variants confer significantly increased risk of prostate cancer in Japanese. Carriage of these variants was not associated with age at diagnosis, tumor stage, or tumor grade in these Japanese prostate cancer patients. The allele-specific pattern of risk observed in Japanese and familial Caucasian patients was qualitatively similar; however, the magnitude of that risk was considerably greater in Japanese than in Caucasians.

IL-1ra versus IL-1 Levels in Prostatic Fluid from Prostatitis Patients

Recent papers reported that the balance between the production of IL-1ra and IL-1 probably influences the regulation of host responses, the severity and prolongation of the inflammatory reaction in some diseases. Therefore, in our continuing investigation to clarify the significance of leukocytosis and its prolongation in prostatic fluid from prostatitis patients, we investigated whether low levels of IL-1ra versus IL-1β secreted in prostatic fluid were the cause of prolonged prostatitis, especially nonbacterial prostatitis (NBP). As a result of the present study, we concluded that a low level of IL-1ra in relation to that of IL-1 secreted in prostatic fluid is unlikely to cause prolongation of NBP for the following reasons: (1) IL-1β was detected in 5 of 10 cases (50.0%), but was slightly elevated in only 2 cases (20.0%) at 14 and 17 pg/ml; (2) the average IL-1ra level was not statistically low compared with that in prostatic fluid from acute bacterial prostatitis (ABP) patients who were cured promptly with antibiotics, and (3) in 5 cases of NBP in which IL-1β was detected, the average IL-1ra/IL-1β ratio was 118 which was comparable to or even higher than that in 3 ABP and 14 acute bacterial cystitis cases in which IL-1β was detected and the ratios were 40 and 88, respectively.

Cystosarcoma phyllodes of the seminal vesicle

Background: We report here an extremely rare case of cystosarcoma phyllodes of the seminal vesicle.

Longitudinal study of macrophages in prostatic fluid from nonbacterial prostatitis patients

Longitudinal study of percentage of macrophages among leukocytes in prostatic fluid from 10 patients with nonbacterial prostatitis did not show correlation between percentage of macrophages and severity of clinical symptoms.

Study of macrophages in prostatic fluid from nonbacterial prostatitis patients. V. Relation between activation of macrophages and stage of prostatitis.

Relationship between activation of macrophages in prostatic fluid and stage of nonbacterial prostatitis was studied by observing the rate of adherence of leukocytes, percentage of macrophages among adherent leukocytes and presence of spreading of macrophages. As a result, it was found that macrophages in the early stage of NBP were more activated than macrophages in the chronic stage.

Renal masses detected by general health checkup.

Abstract Background A total of 60 604 persons underwent a general health checkup at Toma Hospital, Saitama, Japan, between January 1993 and June 1997, and transabdominal ultrasonography (US) was performed on all persons. We investigated the usefulness of transabdominal US in detecting renal tumors during general health checkups.

Effect of the hsp90 inhibitor geldanamycin on androgen response of prostate cancer under hypoxic conditions

Objectives:  To investigate the androgen response of hormone‐dependent prostate cancer cells under hypoxia and to examine the effect of geldanamycin (GA), a heat shock protein 90 (Hsp90)‐specific inhibitor, on the androgen response.

Nucleotide variations in genes encoding plasminogen activator inhibitor-2 and serine proteinase inhibitor B10 associated with prostate cancer

AbstractGenes encoding the serine proteinase inhibitor B family (SERPINBs) are mainly clustered on human chromosome 18 (18q21). Several serpins are known to affect malignant phenotypes of tumor cells, so aberrant genetic variants in this molecular family are candidates for conferring susceptibility for risk of cancer. We investigated whether eight selected non-synonymous variations within SERPINB loci at 18q21 might be associated with risk of prostate cancer in Japanese men. A case-control study involving 292 prostate-cancer patients and 384 controls revealed significant differences in regard to distribution of four missense variations in genes encoding plasminogen activator inhibitor 2 (PAI2) and SERPINB10. The most significant association was detected for the N120D polymorphism in the PAI2 gene (P=5.0×10−5); men carrying the 120-N allele (120-N/N and 120-N/D genotypes) carried a 2.4-fold increased risk of prostate cancer (95% confidence interval 1.45-4.07). Associations were also detected for three other missense polymorphisms in those two genes. Strong linkage disequilibrium in the region encompassing PAI2 and SERPINB10 extended to about 50 kbp. The results suggested that missense variations in one or both of these genes confer important risks for prostate cancer, and may be themselves tumorigenic. Although confirmative replication studies on larger cohorts are awaited, clinical examination of these variations may become useful for identifying individuals at high risk for prostate cancer.