Tadaichi Kitamura

INCREASED INCIDENTAL DETECTION AND REDUCED MORTALITY IN RENAL CANCER—RECENT RETROSPECTIVE ANALYSIS AT EIGHT INSTITUTIONS

A retrospective survey of renal cell carcinoma between 1975 and 1993 at eight collaborating institutions was conducted with special reference to the incidental detection and mortality of renal cancer. The analysis demonstrated a recent dramatic increase in the frequency of incidental renal cancer, which now comprises two‐thirds of all renal cancers, and a simultaneous recession in non‐incidental or suspected renal cancer. Incidental renal cancer has remained unchanged during the last decade as far as patient demographics, occasion and method of detection, and the degree of tumor extension are concerned. On the other hand, the annual number of deaths from renal cancer has significantly decreased, and kidney‐sparing surgery has been more frequently performed. These results indicate that incidental renal cancers are now in the majority, and earlier detection may contribute to improving the mortality and morbidity from the disease as a whole.

Habitual Intake of Lactic Acid Bacteria and Risk Reduction of Bladder Cancer

Introduction: A kind of lactic acid bacteria, Lactobacillus casei strain Shirota, shows antitumor activity in experimental animals. One clinical trial using L. casei showed a significant decrease in the recurrence of superficial bladder cancer. So, to assess the preventive effect of the intake of L. casei, widely taken as fermented milk products in Japan, against bladder cancer, we conducted a case-control study. Methods: A total of 180 cases (mean age: 67 years, SD 10) were selected from 7 hospitals, and 445 population-based controls matched by gender and age were also selected. Interviewers asked them 81 items. The conditional logistic regression was used to estimate adjusted odds ratios (OR). Results: The OR of smoking was 1.61 (95% confidence interval: 1.10–2.36). Those of previous (10–15 years ago) intake of fermented milk products were 0.46 (0.27–0.79) for 1–2 times/week and 0.61 (0.38–0.99) for 3–4 or more times/week, respectively. Conclusion: It was strongly suggested that the habitual intake of lactic acid bacteria reduces the risk of bladder cancer.

Adenovirus Is a Key Pathogen in Hemorrhagic Cystitis Associated with Bone Marrow Transplantation

Late-onset hemorrhagic cystitis (HC) is a well-known complication of bone marrow transplantation (BMT) that is mainly attributed to infection with BK virus (BKV) and adenovirus (AdV). From 1986 through 1998, 282 patients underwent BMT, and 45 of them developed HC. Urine samples tested positive for AdV in 26 patients, of which 22 showed virus type 11. Among patients who underwent allogeneic BMT, logistic regression analysis revealed acute graft-versus-host disease (grade, > or = 2) to be the most significant predictive factor for HC (P < .0001). In addition, a total of 193 urine samples regularly obtained from 26 consecutive patients who underwent allogeneic BMT were examined for BKV, JC virus (JCV), and AdV by means of polymerase chain reaction. Of patients without HC, approximately 30% of the specimens tested positive for BKV (58 samples) and JCV (55 samples), whereas 5 (3%) tested positive for AdV. Of the 3 samples obtained from patients with HC, the numbers of positive results for BKV, JCV, and AdV were 3, 1, and 1, respectively; the numbers of positive results increased to 14 of 17, 9 of 17, and 10 of 17, respectively, when we added another 14 samples obtained from 14 patients with HC (P < .0001, P = .026, and P < .0001, respectively). In conclusion, there was significant correlation between AdV and HC in the patients we studied.

Persistence of archetypal JC virus DNA in normal renal tissue derived from tumor-bearing patients

JC virus DNAs derived from the urine of nonimmunosuppressed individuals generally contain an archetypal regulatory region which may have generated various regulatory regions of JC virus from from the brain with progressive multifocal leukoencephalopathy (PML). In this study, we examined whether JC virus persisting in normal human kidney tissue contains the archetypal regulatory region. Renal medulla, cortex, and tumor from 32 patients bearing renal tumors were screened for JC virus DNA by blot hybridization. Viral DNA was detected in the medulla in 13 cases (41%), in the cortex in 2 cases (6%), but not at all from the tumor. A number of viral DNA-positive specimens (8 from the medulla and 2 from the cortex) were used to amplify and sequence viral regulatory regions by polymerase chain reaction. Structures of the regulatory regions from all the specimens were, with a few nucleotide variations, identical with that of the archetypal region which was previously detected in the JC virus DNA from urine. This finding supports the hypothesis that the JC virus associated with PML evolved from the archetypal JC virus during persistence in human hosts. Furthermore, we present evidence that renal JCV is replicating and that progeny virions are excreted into the urine.

Age-related urinary excretion of BK polyomavirus by nonimmunocompromised individuals.

ABSTRACT Two polyomaviruses, BK virus (BKV) and JC virus (JCV), are ubiquitous in the human population, generally infecting children asymptomatically and then persisting in renal tissue. It is generally thought that reactivation leads to productive infection for both viruses, with progeny shed in the urine. Several studies have shown that the rate of JC viruria increases with the age of the host, but a systematic approach to examine the shedding of BKV has not been developed. To elucidate the relationship between BK viruria and host age, we obtained urine from donors (healthy volunteers or nonimmunocompromised patients) who were divided into nine age groups, each containing 50 members. A high-sensitivity PCR was used to detect BKV and JCV DNA from urinary samples, and the specificity of amplification was confirmed by sequencing or restriction analysis of the amplified fragments. The rate of BK viruria was relatively low in subjects aged <30 years but gradually increased with age in subjects aged ≥30 years. However, BK viruria was less frequent than JC viruria in adults. The detected BKV isolates were classified into subtypes, and detection rates for individual subtypes were compared among age groups; this analysis showed that viruria of subtypes I (the most prevalent subtype) and IV (the second most prevalent subtype) occurred more frequently in older subjects. Therefore, our results reveal new aspects of BK viruria in nonimmunocompromised individuals.

Promoter Methylation of TSLC1 and Tumor Suppression by Its Gene Product in Human Prostate Cancer

We recently identified TSLC1, a tumor suppressor gene in human lung cancer. Gene silencing by promoter methylation has been observed frequently in adenocarcinoma of the lung, liver, and pancreas. Here, we demonstrate that TSLC1 expression is also absent or markedly reduced in 3 of 4 prostate cancer cell lines. Promoter sequences of TSLC1 were heavily methylated in PPC‐1 cells that lacked TSLC1 expression, supporting the idea that promoter methylation is strongly correlated with complete loss of gene expression. Promoter sequences of TSLC1 were also methylated significantly in 7 of 22 (32%) primary prostate cancers. Hypermethylation of the promoter occurred not only in advanced tumors, but also in relatively early‐stage tumors. Restoration of TSLC1 expression substantially suppressed tumor formation of PPC‐1 cells in nude mice. These findings indicate that alteration of TSLC1 is involved in prostate cancer.

Significance of nocturia in the International Prostate Symptom Score for benign prostatic hyperplasia.

PURPOSE We studied the relationship of nocturia with the International Prostate Symptom Score in men with lower urinary tract symptoms due to benign prostatic hyperplasia (BPH). MATERIALS AND METHODS Baseline symptom score and the change in the score by treatment were analyzed in 219 consecutive Japanese men with BPH using basic statistics, and correlation, cluster and principal component analyses. RESULTS The average nocturia score was the middle of that of the 7 symptoms at baseline and by far the highest after treatment. Hence, the score change was the smallest. Analysis of baseline scores demonstrated that all symptoms were the initial component in principal component analysis with individual symptom scores correlating with the total symptom score and quality of life index. However, the correlation was least for nocturia. Observations were similar when analyzing the score change by treatment. These results indicate that the nocturia score is least specific to symptoms associated with BPH or least sensitive to the therapeutic effect on symptoms. This finding may be related to the high nocturia score in the age matched control population. CONCLUSIONS The nocturia score of the International Prostate Symptom Score behaves differently in the symptom complex of BPH in Japanese men, partially because it is most confounded by the aging factor.

BMP signals inhibit proliferation and in vivo tumor growth of androgen-insensitive prostate carcinoma cells

Prostate cancer is one of the most common cancers in men. Several lines of evidence have suggested that bone morphogenetic protein (BMP) signals play important roles in the generation and progression of prostate cancers. In the present study, we show that BMP-7 inhibits the proliferation of androgen-insensitive PC-3 and DU-145 prostate cancer cells in a medium containing 1% fetal bovine serum, observed as decreased incorporation of [3H]thymidine and decreased cell number. Cell cycle analysis by flow cytometry showed an increased fraction of cells in the G1 phase and subsequent decrease in both S and G2/M phase after BMP-7 stimulation. BMP-7 caused an upregulation of the cyclin-dependent kinase inhibitor (CDKI) p21CIP1/WAF1, and decreased the activity of Cdk2, leading to hypophosphorylation of Rb proteins. Furthermore, in order to evaluate the impact of BMP signals on prostate tumor growth, we generated the PC-3 cell lines expressing a constitutively active BMP type I receptor (constitutively active (c.a.) activin receptor-like kinase (ALK)-6) in a tetracycline (Tet)-regulated manner. Tet/doxycycline-regulated expression of c.a.ALK-6 resulted in the inhibition of in vitro cell proliferation and reduction of the size of tumors derived from the PC-3 cells subcutaneously injected into immune-deficient mice. Collectively, these findings suggest that BMP signals inhibit growth and proliferation of prostate tumor cells through induction of CDKI. Furthermore, this is the first report of a role for BMP signaling in reducing growth kinetics of androgen-insensitive prostate tumors.

Disruption of Spermatogenic Cell Adhesion and Male Infertility in Mice Lacking TSLC1/IGSF4, an Immunoglobulin Superfamily Cell Adhesion Molecule

ABSTRACT TSLC1/IGSF4, an immunoglobulin superfamily molecule, is predominantly expressed in the brain, lungs, and testes and plays important roles in epithelial cell adhesion, cancer invasion, and synapse formation. We generated Tslc1/Igsf4-deficient mice by disrupting exon 1 of the gene and found that Tslc1−/− mice were born with the expected Mendelian ratio but that Tslc1−/− male mice were infertile. In 11-week-old adult Tslc1−/− mice, the weight of a testis was 88% that in Tslc1+/+ mice, and the number of sperm in the semen was approximately 0.01% that in Tslc1+/+ mice. Histological analysis revealed that the round spermatids and the pachytene spermatocytes failed to attach to the Sertoli cells in the seminiferous tubules and sloughed off into the lumen with apoptosis in the Tslc1−/− mice. On the other hand, the spermatogonia and the interstitial cells, including Leydig cells, were essentially unaffected. In the Tslc1+/+ mice, TSLC1/IGSF4 expression was observed in the spermatogenic cells from the intermediate spermatogonia to the early pachytene spermatocytes and from spermatids at step 7 or later. These findings suggest that TSLC1/IGSF4 expression is indispensable for the adhesion of spermatocytes and spermatids to Sertoli cells and for their normal differentiation into mature spermatozoa.

Evolution of Human Polyomavirus JC: Implications for the Population History of Humans

The polyomavirus JC virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy, is ubiquitous in the human population, infecting children asymptomatically, then persisting in the kidney. The main mode of transmission of JCV is from parents to children through long-term cohabitation. Twelve JCV subtypes that occupy unique domains in Europe, Africa, and Asia have been identified. Here, we attempted to elucidate the evolutionary relationships among JCV strains worldwide using the whole-genome approach with which a highly reliable phylogeny of JCV strains can be reconstructed. Sixty-five complete JCV DNA sequences, derived from various geographical regions and belonging to 11 of the 12 known subtypes, were subjected to phylogenetic analysis using three independent methods: the neighbor-joining, maximum parsimony, and maximum likelihood methods. The trees obtained with these methods consistently indicated that ancestral JCVs were divided into three superclusters, designated as Types A, B, and C. A split in Type A generated two subtypes, EU-a and -b, mainly containing European and Mediterranean strains. The first split in Type B generated Af2 (the major African subtype). Subsequent splits in Type B generated B1-c (a minor European subtype) and all seven Asian subtypes (B1-a, -b, -d, B2, MY, CY, and SC). Type C generated a single subtype (Af1), consisting of strains derived from western Africa. While the present findings provided a basis on which to classify JCV into types or subtypes, they have several implications for the divergence and migration of human populations.