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The androgen receptor (AR) is implicated in prostate cancer growth, progression, and angiogenesis. Hypoxia-inducible factor-1 (HIF-1), which transcriptionally regulates hypoxia-inducible angiogenic factors, is up-regulated in prostate cancers compared with adjacent normal tissues. HIF-1 may be involved in prostate cancer as well as the AR, but the involvement of HIF-1 in prostate cancer angiogenesis and progression has not been fully elucidated. In the present study, we found that in prostate cancer LNCaP cells dihydrotestosterone enhanced the expression of GLUT-1, one of the HIF-1 target genes, and also that hypoxia enhanced the expression of prostate-specific antigen (PSA) that is one of the AR target genes and is involved in tumor invasion. Small interfering RNA that specifically inhibits HIF-1 reduced the expression levels of PSA as well as GLUT-1. Reporter gene analysis showed that dihydrotestosterone activated the HIF-1–mediated gene expression and hypoxia enhanced the AR-induced promoter activity of human PSA gene. Deletion and site-directed mutation of the 5′-flanking region of human PSA gene revealed that the sequence ACGTG between −3951 and −3947 was essential in the response to hypoxia. Furthermore, chromatin immunoprecipitation assay indicated that HIF-1 interacts with the AR on the human PSA gene promoter. These results indicated that in prostate cancers, HIF-1 might cooperate with the AR to activate the expression of several genes related to tumor angiogenesis, invasion, and progression. (Mol Cancer Res 2007;5(4):383–91)

Objectives: While reassessing the value of exfoliative cytologic examination of prostatic fluid (PF) for the diagnosis of prostate cancer, we found that PF is easily obtained with transrectal ultrasonography during prostate biopsy and that cytologic examination of PF is useful for the diagnosis of prostate cancer. Methods: The cohort included 53 consecutive patients who underwent transrectal prostate biopsy from May through September 2005. Patient age was 66.7 � 7.24 years, and the mean concentration of prostate-specific antigen (PSA) was 15.1 � 25.8 ng ml .T he PF for cytologic examination was obtained before biopsy, and Papanicolaous staining was performed. The results of cytologic examination are expressed as class 1 to 5. Results of cytologic examination and prostate tissue pathologic examination were analyzed. Patient age, PSA levels, total prostate volume (TPV), and PF volume were compared with cytologic class by means of analysis of variance. Results: The mean PF volume was 378.4 � 245.3 µl, and the mean TPV was 38.0 � 18.8 ml. The numbers of patient in classes 1 to 5 were 1 (1.9%), 37 (69.8%), 11 (20.7%), 1 (1.9%), and 3 (5.7%), respectively. Pathologic examination showed 23 (43.4%) cases of cancer, 27 (50.9%) cases of benign prostatic hyperplasia, and 3 (5.7%) cases of high-grade prostatic intraepithelial neoplasia. All three patients with class 5 results had prostate cancer (Gleason score, 7 to 10). All 9 patients with a PSA level greater than 16 ng ml had biopsy-proven cancer, and 3 of these 9 patients (33.3%) were in cytology class 5. Therefore, PF cytologic examination showed a specificity of 100% and a sensitivity of 33.3% in patients with PSA levels higher than 16 ng ml. The cytologic classes differed in PSA levels (F=8.271, P=0.000) but not in patient age, TPV, or PF volume. Conclusions: Exfoliative cytologic examination of PF is a valuable, noninvasive method for detecting prostate cancer, especially in patients with high PSA levels. (J Nippon Med Sch 2006; 73: 129135)

Background: We assessed the outcome and prognostic factors in men with prostate cancer after luteinizing hormone‑releasing hormone agonist monotherapy. Methods: Between April 1998 and August 2002 62 men with prostate cancer who were treated with monotherapy at our institution were included in this analysis. Prostate‑specific antigen(PSA)failure‑free(bNED)survival was calculated using Kaplan‑Meier methods. Prognostic factors were evaluated using Cox proportional hazards regression model. Results: We reviewed the data of patients with a median follow‑up from the commencement of monotherapy of 26 months. The overall survival rate at 3 years was 89.9%. The bNED survival rate was 63.7% at 3 years. Of the 20 patients with clinical stage B 2 progressed to PSA failure whereas PSA failure was seen in 8 of 30 patients with stage C and 8 of 12 patients with stage D. The significant factors for bNED status were an initial PSA level of

Purpose: Hypoxia-inducible factor-1α (HIF-1α) is a transcriptional factor that regulates genes involved in the response to hypoxia. We evaluated the effects of HIF-1α over expression on the tumorigenic potency of renal cell carcinoma VMRC cells and bladder cancer EJ cells in vitro and in vivo. Materials and Methods: We introduced HIF-1α expression vectors into VMRC and EJ cells, and generated the HIF-1α over expressing cell lines VMRC-HIF1α and EJ-HIF1α, and the vector only transfected cell lines VMRC-neo and EJ-neo. We then evaluated in vitro cell proliferation and in vivo tumor growth of these cell lines after subcutaneous injection into athymic nude mice. Results: In vitro studies showed that HIF-1α over expression in VMRC and EJ cells accelerated cell proliferation during the confluent growth phase and rendered these cells resistant to hypoxic stress. Furthermore, in vivo studies revealed that all 4 types of cancer cells (VMRC-neo, VMRC-HIF1α, EJ-neo and EJ-HIF1α) formed tumors in nude mice and the size of VMRC-HIF1α cell derived xenografts was much larger than that of VMRC-neo cell derived xenografts. Although HIF-1α over expression did not affect the size of EJ cell derived xenografts, histological examination showed that there was only a small area of necrosis in EJ-HIF1α cell derived xenografts, whereas a large area of central necrosis was observed in EJ-neo cell derived xenografts. It was also found that HIF-1α over expression increased intratumor microvessel density in the xenografts. Conclusions: These results suggest that HIF-1α may have important roles in bladder and renal cancer angiogenesis and proliferation.

We report four patients on maintenance hemodialysis (HD) with transitional cell carcinoma (TCC) of the bladder. Three patients underwent transurethral resection (TUR) of their tumors, which were grade 2 or 3, stage pT1 TCC. Among them, one patient underwent repeat TUR for recurrent superficial TCC. The remaining one patient underwent total cystectomy for grade 3, stage pT4 TCC and squamous cell carcinoma of the bladder. Subsequently, he died suddenly without evidence of local recurrence or systemic metastasis. We discuss the relationship between the duration of HD and the tumor grade and stage of primary bladder TCC in maintenance HD patients.

Background: Laparoscopic partial nephrectomy has been recently applied as a minimally invasive procedure. Several non‑ischemic operation devices in partial nephrectomy have been developed. However the problem related to maintenance of renal homeostasis remains. We investigated the efficacy and safety of a microwave tissue coagulator in laparoscopic partial nephrectomy. Methods: Between April 2001 and February 2003 eleven patients with small renal tumors underwent laparoscopic partial nephrectomy using a microwave tissue coagulator. Seven patients underwent hand‑assisted laparoscopic procedure and 4 pure laparoscopic procedure. Results: The mean tumor size on preoperative CT scan was 2.5 cm（range: 2.0 to 4.0 cm） the mean operative time was 307 minutes（range: 160 to 580 minutes） and the mean estimated blood loss was 154.4 ml （range: 50 to 1140 ml ） . The microwave tissue coagulator well controlled the renal bleeding and maintained renal function. All patients safely underwent partial nephrectomy without inducing renal ischemia. A complication of urine leakage was recognized in only one patient with hypoproteinemia caused by nephrotic syndrome. Conclusions: Laparoscopic partial nephrectomy using a microwave tissue coagulator wa sa useful method for achieving homeostasis and was less invasive for treating small renal tumors. （J Nippon Med Sch 2004; 71: 392―398）

Endoscopic surgery in the urological field begins with cystoscopy and transurethral resection, and it develops into laparoscopic surgery. The indication of laparoscopic surgery for a malignant tumor also gradually expands. It is virtually impossible to search for urological cancer using laparoscopic procedures. In particular, out laparoscopic nephrectomy for renal cancer and transurethral resection for bladder cancer used widely in Japan. In the future, laparoscopic partial nephrectomy and the laparoscopic procedure for adrenal cancer and prostate cancer are considered to become widespread.

Aims: Cyclooxygenase (COX), which catalyses the synthesis of prostaglandins from arachidonic acid, has two isoforms; COX-1 and COX-2. There is ample evidence to suggest an important role for COX-2 in cancer. The aim of this study was to evaluate the clinical significance of COX-2 expression and its localization in the development and progression of human renal cell carcinoma (RCC). Methods and results: The expression and localization of COX-2 were evaluated in human RCC tissues from 75 patients by immunohistochemistry. Immunoreactive COX-2 protein was observed in all cases of RCC, and the levels of COX-2 expression were correlated with tumour grade and pathological stage. Expression of COX-2 was higher in the granular cell subtype than in the clear cell subtype of RCC. Immunoelectron microscopy revealed that COX-2 was expressed in the nuclear membrane, rough endoplasmic reticulum, Golgi complex and mitochondrial membrane of RCC cells. Conclusion: COX-2 overexpression within these intracellular organelles in RCC may be associated with renal cell carcinogenesis and COX-2 may be a useful biomarker in RCC.

In summary, we have showed that levels of COX-2 are increased in both TCC and RCC derived from urinary tract epithelium as well as gastrointestinal cancer. These results raised the possibility that selective inhibitors of COX-2 may be useful in the prevention or treatment of these diseases.

Cyclooxygenase (COX) catalyses the synthesis of prostaglandins from arachidonic acid. There are two isoforms of COX (DuBois et al., 1998; vane et al., 1998). One is constitutively expressed (COX-1) and the other is inducible (COX-2). The COX-2 gene is an immediate, early-response gene that is induced by growth factors, oncogenes, carcinogens, and tumor-promoting phorbol esters (Inoue et al., 1995; Nanayama et al., 1995; Herschman, 1996). The constitutive isoform, COX-1, is essentially unaffected by these factors.

207 Background: Zoledronic acid (ZA) reduces the onset risk of skeletal-related events (SRE) caused by bone metastasis in prostate cancer (PCa) patients and improves the QOL. Therefore ZA has become a standard supportive therapy for PCa with bone metastasis. However, it remains unclear when the physicians should start ZA treatment. In the present study, we investigated whether combination of ZA could delay PSA relapse of PCa and prevent SREs. Methods: The patients were randomly classified in two groups (combined androgen blockade (CAB) alone group and CAB + ZA treatment group). In the CAB + ZA group, 4 mg ZA was intravenously administered every 4 weeks with the start of treatment. The first end point was a period to PSA relapse, and the secondary end point was SREs rate. Results: Untreated 60 PCa patients with bone metastasis were enrolled by 2011 from 2006. Thirty one patients were treated with CAB alone and 29 patients were treated with CAB + ZA. There were no significant differences in the baseline characteristics in the both groups, and the mean observation period was 27.4 months and 32.1 months, respectively. Although there was no significant difference in progression free survival (PFS) (p=0.073), tendency that CAB + ZA shows better PFS than CAB alone group was observed (time to 50% PFS was extended 11.6 months than CAB alone group). Moreover, the sub analysis using the patients with more than Gleason score 7, CAB +ZA group showed significantly longer PFS than the CAB group (p=0.021). And statistically significant difference was recognized in SRE rate between the two groups (p=0.019), ZA tended to delay the occurrence of SRE in PCa patients. Conclusions: This result indicates that the use of ZA at the beginning of hormonal therapy have not only a preventive effect on the occurrence of SREs but also a relapse-delaying effect, especially in the patients with high Gleason score and severe bone metastasis. Though careful observation is essential, since the long-term use of ZA may increase the incidence of adverse effects, CAB-ZA treatment may be recommended for the treatment of PCa patients with bone metastasis.

Background: Although it is an established surgical technique, transurethral resection (TUR) is associated with a certain incidence of postoperative bacteriuria. Assessment was made whether the urothelial mucosal concentration of an antibiotic administered before TUR was high enough to decrease the incidence of urinary tract infection (UTI). Also investigated were factors predicting the organ concentration. Methods: Forty-nine patients (45 men and four women aged 51–79 years with a median age of 70 years) who underwent TUR between August 1996 and September 1997 were enrolled in the study. Each patient received 200 mg of levofloxacin (LVFX) about two hours before surgery. Blood and bladder urine were collected and urothelial mucosa was harvested at the time of TUR. Then the LVFX concentration in these samples was measured using high-performance liquid chromatography. The association between drug levels, or the ratio to the serum concentration, and factors likely to affect the vascular system that delivers the drug (age, bodyweight, blood pressure, pulse rate, total cholesterol and diabetes mellitus) were investigated. Results: The mean serum drug level was 2.4 μg/mL, and it was 206.4 μg/mL in the urine and 5.7 μg/mL in the urothelial mucosa. The mean ratio of the mucosal to serum concentrations was 2.6. The urinary drug concentration showed no association with any of the factors assessed, while the serum concentration decreased with increasing bodyweight (P = 0.03). As the diastolic blood pressure increased, both the mucosal drug concentration and the mucosa/serum ratio decreased (P < 0.01). When the relationship between the serum and mucosal concentrations was investigated, no correlation was found. However, the mucosa/serum ratio (indicating the transfer of LVFX from the blood) was positively correlated with the mucosal concentration. Conclusion: Preoperative administration of LVFX was demonstrated to have potential value for the prophylaxis of UTI after TUR. Both the mucosal concentration and the mucosa/serum ratio were correlated with the diastolic blood pressure. As the diastolic blood pressure seems to be an indicator of the tissue concentration of LVFX, it may be possible to set the optimum dose based on the diastolic pressure.

Because the up-regulation of telomerase in most cancer tissues is considered to be responsible for the unlimited proliferation of cancer cells, suppression of telomerase activity is an attractive potential target for cancer therapy. The mechanism for the activation of telomerase in cancer cells, however, is still unclear. In the present study, we demonstrated that Zn induces an enhancement of telomerase activity in the human renal cell carcinoma (NRC-12) and prostatic cancer (DU145) cell lines. The maximum elevation of the activity was observed 6 hr after treatment with 100 microM Zn; it was diminished by the addition of either metal chelator or cycloheximide. Other metals such as Cd and Cu also enhanced telomerase activity but to a lesser extent, and no correlation between the activation of telomerase and the induction of metallothionein was observed. Our findings provide the first evidence that metals, especially Zn, can modulate telomerase activity in cancer cells.

Metallothionein (MT) is known to play a predominant role in the protection of cells from cadmium (Cd) toxicity. To investigate other factors involved in Cd resistance, we established Cd-resistant cell lines from simian virus 40-transformed MT null fibroblasts. Cd-resistant MT null cells, Cd-rA7 and Cd-rB5, developed approximately 10-fold resistance to Cd compared to parental cells, but showed no cross-resistance to Zn, Cu, Hg, Ni, As, cisplatin or H 2 O 2 . Accumulation of Cd in the resistant cells was 13–18% of that of parental cells after treatment with Cd for 24 h. A short-term experiment revealed that the rate of Cd incorporation into the Cd-resistant cells was suppressed, and the rate of Cd release was enhanced in the resistant cells compared with that of parental cells. These results indicate that the altered transport of Cd, slow uptake and rapid release, may confer resistance to Cd on the Cd-resistant cells established from MT null fibroblasts.

We examined the carcinogenicity of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in transgenic mice deficient in the metallothionein (MT) I and II genes and in control (129/Sv) mice. Both strains of mice were given BBN for 8 weeks with or without Zn treatment. All mice were killed at 12 weeks after the cessation of BBN administration. BBN induced bladder tumors in 75% of MT null mice and in 43% of 129/Sv mice. The average number of bladder tumors per mouse was significantly higher in MT null mice (1. 18 +/- 0.27) than in 129/Sv mice (0.43 +/- 0.20). Zn treatment suppressed the carcinogenicity of BBN in 129/Sv mice but not in MT null mice. Histopathological examination of the tumors revealed that the malignant potential of bladder tumors in 129/Sv mice was greater than that in MT null mice. These results indicate that MT is an important modulator of carcinogenicity of BBN in the bladder of mice.

In higher eukaryotic cells, it is generally thought that nuclear pore complex disassembles at the beginning of mitosis and reassembles at the end. Using a monoclonal antibody that recognizes nuclear pore antigens, we found that, at mitosis of mammalian somatic Hela cells, the nuclear pore complex disassembles into at least three subcomplexes, termed subcomplexes A, B and C (molecular mass; 2 MDa, approximately 660 kDa, and approximately 440 kDa, respectively). The direct partial amino acid sequencing of the components of these subcomplexes indicates that the A subcomplex contains CAN/Nup214/p250 and p62 and the B subcomplex also contains p62, indicating that p62 is contained in two different subcomplexes. Subcomplex C was shown to consist of Nup98 and human RAE1, a human homolog of yeast Rae1p/Gle2p. Since Nup98 and Rae1p/Gle2p have been reported to be involved in mRNA export, this suggests that some of the mitotic subcomplex may be formed by functionally related proteins.

Disseminated intravascular coagulation (DIC) is the most frequent coagulation disorder in patients with prostate cancer. However, renal involvement in DIC associated with prostate cancer has rarely been documented. Herein, we present a case of metastatic prostate cancer presenting with acute renal failure (RF) triggered by DIC. An 80 year old man with metastatic prostate cancer was treated with antihormone therapy at an outpatient clinic. He was admitted to our hospital because of severe dyspnea and progressive RF. A hemorrhagic tendency was not clinically evident. Laboratory tests exhibited a significant coagulation disorder, suggestive of DIC. Despite treatment, his RF and dyspnea worsened, and he eventually passed away. An autopsy study revealed hypertensive nephrosclerosis superimposed by fibrin rich thrombi formation involving glomerular capillaries and arterioles characteristic of DIC. Additionally, focal segmental glomerulosclerosis was identified, which was presumably secondary to the glomerular endothelial and/or podocyte injury augmented by DIC. Those findings showed that glomerular injury, which was induced and subsequently exacerbated by DIC associated with prostate cancer, highly contributed to the progression of RF in our case. A differential diagnosis of DIC should be considered when a patient with prostate cancer presents with renal dysfunction.

We describe a prostate cancer patient whose initial symptom was intermittent double vision. Intracranial magnetic resonance imaging demonstrated a pituitary mass extending to the cavernous sinus, which caused the double vision. After hormonal therapy for prostate cancer, the pituitary mass disappeared, and double vision was completely resolved without local therapy for the brain. In the 19 months of follow-up after hormone treatment, the prostate cancer remained stable, and the patient remained neurologically intact.

BACKGROUND: In this paper we demonstrate the relationship between the antitumor activity of cis-diamminedichloroplatinum (II) (CDDP) and inducibility of metallothionein (MT) and glutathione (GSH) of genitourinary tumors. METHODS: The chemosensitivity test was performed in athymic mice bearing tumors derived from the human tumor cell lines: ACHN (renal cell carcinoma), NMB-1 (urinary bladder transitional cell carcinoma), and NMT-1 (testicular embryonal cell carcinoma). A single dose of CDDP (25 mumol/kg body weight), was administered i.p. to athymic tumor bearing mice. Concentrations of platinum, MT, and GSH were measured in organ and tumor homogenates 24 h after CDDP administration. RESULTS: We observed that tumors derived from NMB-1 and NMT-1 were very sensitive to CDDP, but ACHN derived tumors were resistant to CDDP. Measurement of platinum concentrations in tumor tissues revealed no correlation to the observed chemosensitivities of the tumors. Furthermore, 24 h after CDDP administration, the levels of MT and GSH in NMB-1 and NMT-1 derived tumors were lower them or equal to those of control mice. In contrast, mice bearing tumors derived from ACHN exhibited a 1.7-fold and a 2.1-fold increase in MT and GSH, respectively, as compared to control mice. CONCLUSION: These findings suggest that the inducibility of MT and GSH in tumor tissues following CDDP administration may be a contributing factor in the development of CDDP resistance in renal cell carcinoma.

A new Iµ-amino protecting group, 2-adamantyloxycarbonyl (2-Adoc), was developed, and its application to the solid-phase synthesis of protected peptides was demonstrated in combination with Nα-fluoren-9-ylmethoxycarbonyl (Fmoc) protection and trifluoroacetic acid (TFA)-cleavable resin support. The 2-Adoc group was applied successfully also to the solution-phase peptide synthesis depending on tert-butoxycarbonyl (Boc)-chemistry.

Embryonic cells from transgenic mice with targeted disruption of metallothionein I and II genes expressed no detectable metallothionein either constitutively or after treatment with cadmium, in contrast to cultured cells that were wild type or heterozygous for the loss of the metallothionein genes. Metallothionein null cells were most sensitive to the cytotoxic effects of cadmium, the membrane permeant oxidant tert-butylhydroperoxide, and the redox cycling toxin paraquat. No marked differences were seen among the wild type, heterozygous, or metallothionein null cells in glutathione levels or in the activity of CuZn-superoxide dismutase, glutathione peroxidase, or catalase. Nevertheless, metallothionein null cells were more sensitive to tert-butylhydroperoxide-induced oxidation as ascertained by confocal microscopic imaging of dichlorofluoroscein fluorescence. These results indicate basal metallothionein levels can function to regulate intracellular redox status in mammalian cells.

48 Background: Zoledronic acid (ZA) eventually reduces risk of skeletal morbidity carries beneficial effect on bone pain. Moreover, ZA eventually extends a period to bone pain and the SRE onset after CRPC (castration-resistant prostate cancer) and improves the QOL of the patients. ZA, therefore, has become a standard supportive therapy for CRPC with bone metastasis. However, it remains unclear when the physicians should start ZA treatment for prostate cancer (PCa) patients with bone metastasis. In the present study, we investigated whether we could extend a period before androgen sensitive PCa with bone metastasis becoming CRPC by ZA treatment. Methods: The patients were randomly classified in two groups (combined androgen blockade (CAB) alone group and CAB + ZA treatment group) based on Gleason score (less than 7 or more) EOD score (less than 2 or more). Four mg ZA treatment was conducted every 4 weeks. We evaluated serum PSA value, bone-related markers, and SRE. The first end point was a period before androgen sensitive PCa with bone metastasis becoming CRPC. Results: Untreated 59 PCa patients with bone metastasis were enrolled by 2011 from 2006. Thirty patients were classified in the CAB alone group and 29 patients in the CAB + ZA group. There were no significant difference in age (72,5 and 71.7 yo, respectively), PSA (381.3 ng/ml and 399.0 ng/ml, respectively), Gleason score, and EOD score between CAB alone group and CAB + ZA group. Although there was no significant difference in PSA-progression free survival (PFS) (p=0.14), tendency that CAB + ZA shows better PFS than CAB alone group was observed (time to 50% PFS was extended 9.4 months than CAB alone group). Moreover, the sub analysis using the patients with more than Gleason score 7 or with more than EOD score 1, CAB +ZA group showed better PFS (p=0.074 in Gleason score and p=0.028 in EOD score. Conclusions: This result indicates that CAB with ZA from initial treatment can extend a period before PCa, especially high advanced PCa recurring.

Erratum to: Ann Nucl MedDOI 10.1007/s12149-011-0551-6The fifth coauthor’s name was incorrectly given as NaohisaYoshihara. It should be Hisashi Yoshihara. In the affiliationline, it should be shown as H. Yoshihara, not N. Yoshihara.Also, the title and the contents of Table 2 were incor-rect. They should be given as shown below.

In period of April, 1982 to March, 1987 for 5 years, fifty-four patients with superficial bladder tumors were treated at the Department of Urology, Nippon Medical School. There were 42 males and 12 females with age ranged from 28 to 85 years old. All patient underwent TUR-Bt (trans urethral resection-bladder tumor) as an initial treatment. The rather long term follow-up study after initial treatment was 47 months in average. Recurrence rate at 2 years after TUR-Bt was 30%. The risk factors of recurrence were analysed in connection with sex, age, tumor number, histological grade and stage, and infiltration pattern. In conclusion, significantly higher recurrence rate were observed in G2 than G1 and G3, and in pT1b rather than pTa and pT1a. Other factors were not distinctly correlated with incidence of recurrence.

We studied subsets and cytotoxicity of recombinant interleukin-2 (rIL-2)-expanded tumor-infiltrating lymphocytes (TIL) from renal cell cancer (RCC) patients. TIL were successfully expanded in 13 of 14 RCC cases using anti-CD3 during the initial 48 h of culture. Percentages of CD8-positive cells among rIL-2-expanded TIL at 1-4 week(s) of culture were 56.2 +/- 15.1% (range 26.2-79.8%, n = 13) and not necessarily predominant over CD4-positive cells. Natural killer and lymphokine-activated killer (LAK) activities of TIL at 3-6 weeks of culture were 31.6 +/- 15.8% (range 1.4-57.4%, n = 9) and 16.6 +/- 11.6% (range 3.8-35.6%, n = 6), respectively. Autologous and allogeneic RCC cytotoxicity of TIL at 3-4 weeks of culture were 17.9 +/- 19.7% (range 0-47.6%, n = 4) and 18.9 +/- 14.8% (range 0-47.3%, n = 12), respectively. Since there was no statistical difference between them, autologous specific cytotoxicity was not demonstrated. From these result of the present study, it is unlikely that most of effector cells of rIL-2-expanded TIL in autologous RCC lysis are major histocompatibility complex-restricted cytotoxic T cells. We concluded that it is doubtful whether TIL is significantly superior over LAK cells in immunotherapy of human RCC.

An advanced thin‐film field emitter array (FEA) with self‐feedback function which suppresses the fluctuation of emission current was fabricated by self‐aligned processing. Each starlike miniature field emitter in the FEA has a double layer of a resistive and an electron emitting layer. 200‐μm‐square FEAs of Mo or W emitters, both had a threshold voltage of about 50 V, emitted the current of 4 μA at a gate voltage of 90 V. The emission current of a 5‐mm‐sq FEA was 300 μA at 85 V. Insertion of the resistive layer with 2.4 MΩ worked to stabilize the current fluctuations, but insufficient for practical applications. However, it was found that the resistive value should be above 50 MΩ to suppress the emission current fluctuations less than 5%. It is confirmed that the electron emission in a 5‐mm‐sq FEA was stably continued during ∼1200 h.

The Nim-2-adamantyloxycarbonyl (2-Adoc) group is suitable for the protection of the imidazole function of the histidine residue in peptide synthesis in terms of its stability to trifluoroacetic acid (TFA), tertiary amines and 1-hydroxybenzotriazole (HOBt), and its reduction of racemization rate during the coupling reaction.

A new Iµ-amino protecting group, 2-adamantyloxycarbonyl (2-Adoc), was developed, and its application to the solid-phase synthesis of protected peptides was demonstrated in combination with Nα-fluoren-9-ylmethoxycarbonyl (Fmoc) protection and trifluoroacetic acid (TFA)-cleavable resin support. The 2-Adoc group was applied successfully also to the solution-phase peptide synthesis depending on tert-butoxycarbonyl (Boc)-chemistry.

The relationship between the frequency of the use of drugs and diseases at respective departments of Kumamoto University Hospital was discussed. In the study on the relationship between agents affecting digestive organs and diseases, it was found that for various reasons such agents were used for the diseases other than their own indications. The complexity of the contents of prescriptions in some departments was due to the treatment for complications.

Metallothionein (MT), a low molecular weight, cysteine-rich metal binding protein, has been associated with cytoprotection from heavy metals and cellular oxidants. As MT has the ability to scavenge hydroxyl radicals, MT may control intracellular redox status. In the present study, we examined whether MT regulates the activity of nuclear factor-kappaB (NF-kappaB), which is one of the redox-regulated transcription factors, using the MT null embryonic cell lines established from MT null mice. We first found that tumor necrosis factor (TNF)-induced activation of the binding of NF-kappaB protein to DNA in wild type MT+/+ cells was lower than that in MT-/- cells. The NF-kappaB activation in MT-expressing cells established from MT-/- cells by the transfection of mouse MT-1 gene was also significantly lower than that in MT-/- cells. In addition, transfection of the MT gene inhibited TNF-induced IkappaB degradation and suppressed NF-kappaB-dependent gene expression induced by TNF. These results demonstrate that MT may function as a negative regulator of NF-kappaB activity.