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Biomedical subjects

S Koga

Publications and source records attributed to S Koga.

At least 37 records · Page 2Linked to original sources
PubMed2001

Treatment of bladder cancer cells in vitro and in vivo with 2-5A antisense telomerase RNA.

Bladder cancer is the most common malignant tumor of the urinary tract. Novel treatment approaches are essential because of the failure of current treatment options to cure a high percentage of patients. Telomerase, a ribonucleoprotein, is detected in almost all bladder cancer, but not in normal bladder tissues. Therefore, telomerase is expected to be a very promising candidate for targeted therapy of bladder cancer. In this study, we synthesized a 19-mer antisense oligonucleotide against the RNA component of human telomerase (hTR) linked to a 2-5A molecule (2-5A-anti-hTR) and investigated its antitumor effect against bladder cancer cells. The 2-5A antisense strategy relies on the recruitment and activation of RNase L at the site of targeted RNA sequence. Here we demonstrate that treatment with 2-5A-anti-hTR reduced the viability of seven bladder cancer cell lines (UM-UC-2, UM-UC-3, UM-UC-6, UM-UC-9, UM-UC-14, RT4 and T24) expressing telomerase activity to 21-55% within 4 days. The cytotoxicity was mainly due to induction of caspase-dependent apoptosis. In contrast, normal fibroblast WI38 cells lacking telomerase activity were resistant to the treatment. Furthermore, treatment of subcutaneous UM-UC-2 tumors in nude mice with 2-5A-anti-hTR significantly suppressed the tumor growth through induction of apoptosis (P < 0.001). These findings may offer a strong support to the feasibility of the 2-5A-anti-hTR treatment for human bladder cancer.

Animals↗
PubMed2001

Relationship between serum ferritin levels and tumour status in patients with renal cell carcinoma.

OBJECTIVE: To assess the relationship between serum ferritin levels (a useful marker for diagnosing and staging renal cell carcinoma, RCC) and tumour status in RCC of <or=7 cm diameter. PATIENTS AND METHODS: Serum ferritin levels were measured using an enzyme immunoassay in 101 patients before treatment for RCC. The largest diameter of the primary tumour was measured in the pathological specimens. The correlation between serum ferritin levels and histopathological status was assessed retrospectively in all patients, and separately in the 67 patients with tumours of <or=7 cm diameter. RESULTS: For the whole group, lymph node metastasis, distant metastasis, extracapsular invasion, vascular invasion and nuclear grade were significantly different (P < 0.001) between patients with normal and those with elevated ferritin levels. However, in patients with tumours of <or=7 cm, only the presence of distant metastasis was significantly different (P < 0.001) between the groups. CONCLUSIONS: Elevated serum ferritin levels in patients with RCC of <or=7 cm may suggest the presence of distant metastasis.

Biomarkers, Tumor↗
PubMed2001

OK432-induced killer cell activity: potential method for monitoring immunological complications after renal transplantation.

BACKGROUND: Various clinical and biochemical parameters are currently in use for monitoring allograft rejection. However, the mechanism of allograft rejection is complex and it is frequently difficult to obtain a prompt and accurate diagnosis. We examined the usefulness of OK432-induced killer cell activity as an immunological monitoring system for acute renal rejection after renal transplantation. METHODS: Twenty-four renal transplant recipients, seven patients on haemodialysis, and 10 normal volunteers were enrolled in our study. The killer cell activity of peripheral blood mononuclear cells was induced by culturing these cells with the immunopotentiator, OK432, a heat and penicillin-treated lyophilized powder of the Su-strain of Streptococcus pyogenes. RESULTS: The OK432-induced killer cell activity of renal transplant recipients without acute rejection (stable recipients) was significantly lower than in normal volunteers. In four renal transplant recipients with acute rejection, the killer cell activity was significantly higher than in stable recipients. In three recipients suffering from opportunistic infections, killer cell activity was significantly suppressed compared with stable recipients. CONCLUSIONS: Our new test utilizing OK432-induced killer cell activity is potentially useful for monitoring the immunological state and complications after renal transplantation.

Adjuvants, Immunologic↗
PubMed2001

Effect of muscle mass on V(O(2)) kinetics at the onset of work.

The dependence of O(2) uptake (V(O(2))) kinetics on the muscle mass recruited under conditions when fiber and muscle recruitment patterns are similar following the onset of exercise has not been determined. We developed a motorized cycle ergometer that facilitated one-leg (1L) cycling in which the electromyographic (EMG) profile of the active muscles was not discernibly altered from that during two-leg (2L) cycling. Six subjects performed 1L and 2L exercise transitions from unloaded cycling to moderate [ VT) exercise. The 1L condition yielded kinetics that was unchanged from the 2L condition [the phase 2 time constants (tau(1), in s) for 0.05; for >VT: 1L = 26.8 +/- 12.0; 2L = 27.8 +/- 16.1, P > 0.05]. The overall V(O(2)) kinetics (mean response time) was not significantly different for the two exercise conditions. However, the gain of the fast component (the amplitude/work rate) during the 1L exercise was significantly higher than that for the 2L exercise for both moderate and heavy work rates. The slow-component responses evident for heavy exercise were temporally and quantitatively unaffected by the 1L condition. These data demonstrate that, when leg muscle recruitment patterns are unchanged as assessed by EMG analysis, on-transient V(O(2)) kinetics for both moderate and heavy exercise are not dependent on the muscle mass recruited.

Electromyography↗
PubMed2001

Function of human eccrine sweat glands during dynamic exercise and passive heat stress.

The purpose of this study was to identify the pattern of change in the density of activated sweat glands (ASG) and sweat output per gland (SGO) during dynamic constant-workload exercise and passive heat stress. Eight male subjects (22.8 +/- 0.9 yr) exercised at a constant workload (117.5 +/- 4.8 W) and were also passively heated by lower-leg immersion into hot water of 42 degrees C under an ambient temperature of 25 degrees C and relative humidity of 50%. Esophageal temperature, mean skin temperature, sweating rate (SR), and heart rate were measured continuously during both trials. The number of ASG was determined every 4 min after the onset of sweating, whereas SGO was calculated by dividing SR by ASG. During both exercise and passive heating, SR increased abruptly during the first 8 min after onset of sweating, followed by a slower increase. Similarly for both protocols, the number of ASG increased rapidly during the first 8 min after the onset of sweating and then ceased to increase further (P > 0.05). Conversely, SGO increased linearly throughout both perturbations. Our results suggest that changes in forearm sweating rate rely on both ASG and SGO during the initial period of exercise and passive heating, whereas further increases in SR are dependent on increases in SGO.

Acclimatization↗
PubMed2001

A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter.

Telomerase activity has a close relationship with malignancies in many cell types and it is tightly regulated at the transcriptional level of human telomerase reverse transcriptase (hTERT). Utilizing the hTERT promoter, the authors developed a gene delivery system of Fas associated protein with death domain (FADD) (hTERT/FADD). FADD is a protein which plays an important role in the apoptotic pathway of Fas. Over-expression of FADD induces apoptosis in the cells regardless of Fas expression on the cell surface. We hypothesized that we might be able to restrict the expression of FADD in malignant glioma cells if we use the gene transfer system under the control of hTERT promoter. This study was designed to investigate whether the hTERT/FADD construct induces apoptosis effectively in malignant glioma cells while keeping normal cells intact. First, using the reverse transcription-polymerase chain reaction (RT-PCR) technique, we confirmed that hTERT mRNA was expressed in human malignant glioma cells (U373-MG, A172 and GB-1), but not in cultured astrocytes (TEN) or fibroblasts (MRC5). After transient transfection with the hTERT/FADD construct, a significant number of FADD-positive cells and apoptotic cells were detected in hTERT-positive malignant glioma cells. In contrast, hTERT-negative astrocytes and fibroblasts remained intact. Furthermore, subcutaneously implanted U373-MG tumors treated with the hTERT/FADD construct reduced in volume significantly compared to the conrol treatment (p=0.0001). Gene transfer of FADD under the control of the hTERT promoter may be a novel and promising therapy to kill hTERT-positive malignant glioma cells while sparing normal brain cells lacking hTERT.

Animals↗
PubMed2001

[Evaluation of bone metastases from renal cell carcinoma].

Forty-two cases of bone metastasis from renal cell carcinoma were examined. Thirty of the cases had bone metastases at the time of renal cell carcinoma. Bone metastasis appeared after treatment of the primary site in 12 cases. Fifteen cases had only bone metastasis and another 27 had metastasis in multiple organs. The total cause-specific survival curve of these patients was 10% at 5 years. All patients with bone metastases died of cancer within 5 years after the bone metastases had developed. There was no significant difference in the survival rate between patients with bone metastases and patients with lung metastases. We investigated the prognostic value of laboratory studies in bone metastases of renal cell carcinoma. However, no significant markers were detected for bone metastases. The 6 patients were treated with decompressed laminectomy (2), wide resection (3) and excision of the metastatic lesions (3). The quality of life was improved in all the patients although they died of cancer.

Adult↗
PubMed2001

[Long-term experience with renal transplantation in systemic amyloidosis: a case report].

Renal transplantation was performed on a 39-year old woman with secondary amyloidosis due to rheumatoid arthritis. She remains alive and renal function has been maintained satistfactorily with the exception of proteinuria ten years after transplantation. Recent renal biopsy showed no amyloid recurrence, but the presence of chronic rejection reaction and mild cyclosporin arteriolopathy. Symptoms related to systemic amyloidosis and rheumatoid arthritis improved after transplantation. Renal transplantation is the recommended therapy for the type AA systemic amyloidosis. This is the second report of long-term experience with renal transplantation in systemic amyloidosis in Japan.

Aged↗
PubMed2001

The diagnostic value of bone scan in patients with renal cell carcinoma.

PURPOSE: Bone scan is performed as part of the evaluation of bone metastasis. We assessed the diagnostic value of bone scan in patients with renal cell carcinoma. MATERIALS AND METHODS: Bone scan was performed at presentation in 205 patients with confirmed renal cell carcinoma. Abnormal hot areas were further evaluated by x-ray, computerized tomography or surgery. RESULTS: Of the 56 patients (27%) with an abnormal bone scan 32 (57%) had osseous metastatic lesions. Overall bone metastasis was present in 34 of the 205 patients (17%). Bone scan had 94% sensitivity and 86% specificity. Of the 124 patients with clinically localized, stages T1-2N0M0 disease exclusive of bone metastasis 6 (5%) had bone metastasis only, whereas 28 of 81 (35%) with locally advanced or metastatic disease had bone metastasis, including 12 (35%) who complained of bone pain and 19 (56%) who presented with other symptoms due to local tumor growth or metastasis at other sites. Three patients (9%) were asymptomatic. There was osseous metastasis without other metastasis, enlarged regional lymph nodes or bone pain in 7 patients, including 1 with stage T1b (2% of all with that stage), 2 with stage T2 (5%), 1 with stage T3a (4%), 1 with stage T3b (6%), 1 with stage T3c (14%) and 1 with stage T4 (6%) disease. CONCLUSIONS: Bone scan may be omitted in patients with stages T1-3aN0M0 tumors and no bone pain because of the low proportion of missed cases with bone metastasis.

Adult↗
PubMed2001

[Clinical evaluation of renal angiomyolipoma].

Between April 1980 and December 1999, 23 kidneys in 20 patients were diagnosed as having renal angiomyolipoma at our institution. The patients were 6 males and 14 females aged 24 to 79 years, with a mean age of 55.4 years. Two patients had associated tuberous sclerosis and 3 had bilateral disease. Of all patients the main clinical symptoms were pain (45%) and palpable mass (40%); 5 patients (25%) had asymptomatic lesions. The size of the tumor ranged from 1.3 to 24 cm (mean 7.7 cm). Treatment consisted of nephrectomy in 9 patients, partial nephrectomy in 6 and selective embolization in one. Pre-operative diagnosis was renal cell carcinoma in 5 of the 9 patients who underwent nephrectomy. Six patients with 7 diseased kidneys were followed radiologically. One patient underwent percutaneous biopsy to confirm the diagnosis. We suggest that nephron-sparing surgery for patients with renal angiomyolipoma should be the first step if tumor size is 4 cm < or = or increasing rapidly. Selective embolization is also a useful method. However, we need long-term follow-up to evaluate the effectiveness of embolization.

Adult↗
PubMed2001

[A case of bilateral synchronous renal cell carcinoma treated with left partial nephrectomy and laparoscopic right nephrectomy].

We describe a case of bilateral synchronous renal cell carcinoma. A 70-year-old female was admitted to our department because of further examination for bilateral renal masses. Computed tomographic scanning and ultrasound examinations revealed bilateral solid enhanced renal masses, and bilateral renal cell carcinomas were suspected. First, partial left nephrectomy was performed. On the 21th day after the first operation, we confirmed the recovery of the left kidney, and performed right nephrectomy laparoscopically. The histopathological diagnosis revealed bilateral renal cell carcinomas. The patient is alive with no metastatic lesions and no recurrence at 16 months after the operations.

Aged↗
PubMed2000

Inhibition of the allograft response by donor specific blood transfusion: association with reduced local TH1 cytokines and nitric oxide but enhanced prostaglandin E2 production.

BACKGROUND: Donor-specific blood transfusion (DST) may improve allograft survival in human and animal models, but the mechanisms for this graft protective effect are incompletely understood. The sponge matrix allograft model was used to determine if DST induces regulatory factors within the allograft. METHODS: C57BL/6 (H-2b) recipients received donor-specific (DBA/2J, H-2d) or syngeneic (C57BL/6) blood 7 days before sponge matrix allograft (DBA/2J) implantation. Fourteen days postgrafting, the sponge infiltrating cells (SIC) were examined for cytotoxic T cell (CTL) and natural killer (NK) activity, and sponge exudate fluid (SEF) was assessed for nitric oxide (.N=O) and prostaglandin E2 (PGE2) content. Interleukin- (IL) 2, IL-4, IL-10, and interferon-gamma (IFN-gamma) production by SIC was also determined. Recipient splenocytes were simultaneously assessed for anti-donor cytotoxic and proliferative responses and .N=O production. RESULTS: SIC from mice receiving syngeneic transfusions (ST) acquired both CTL and NK activity postgrafting, with maximal activity by day 14. DST suppressed both CTL and NK activity throughout the postgrafting period. Limiting dilution analysis (LDA) of SIC to determine precursor and native CTL frequency showed significantly lower responder cell frequency after DST compared with ST. SEF .N=O levels and SIC production of IL-2 and IFN-gamma in grafted DST mice were significantly lower than in grafted mice receiving ST. No significant amounts of IL-4 and very low levels of IL-10 were produced by SIC from grafted mice after either ST or DST. Conversely, PGE2 content of sponge fluid and serum from DST mice was higher than in mice receiving ST. Antigen stimulated splenocyte proliferation and CTL development assessed by LDA were also inhibited by DST. CONCLUSIONS: Reduction in local TH1 cytokines, absence of detectable TH2 cytokines, with enhanced PGE2 and depressed .N=O were observed in the local graft environment after DST. These data support the hypothesis that DST induces donor-specific intragraft suppressor factors, accompanied by reduced local and systemic immune activation.

Animals↗
PubMed2000

2-5A antisense telomerase RNA therapy for intracranial malignant gliomas.

Malignant gliomas are the most common intracranial tumors and are considered incurable. Therefore, exploration of novel therapeutic modalities is essential. Telomerase is a ribonucleoprotein enzyme that is detected in the vast majority of malignant gliomas but not in normal brain tissues. We, therefore, hypothesized that telomerase inhibition could be a very promising approach for the targeted therapy of malignant gliomas. Thus, 2-5A (5'-phosphorylated 2'-5'-linked oligoadenylate)-linked antisense against human telomerase RNA component (2-5A-anti-hTER) was investigated for its antitumor effect on an intracranial malignant glioma model. 2-5A is a mediator of one pathway of IFN actions by activating RNase L, resulting in RNA degradation. By linking 2-5A to antisense, RNase L degrades the targeted RNA specifically and effectively. Prior to the experiments using intracranial tumor models in nude mice, we modified the in vitro and in vivo treatment modality of 2-5A-anti-hTER using a cationic liposome to enhance the effect of 2-5A-anti-hTER. Here we demonstrate that 2-5A-anti-hTER complexed with a cationic liposome reduced the viability of five malignant glioma cell lines to 20-43% within 4 days but did not influence the viability of cultured astrocytes lacking telomerase. Furthermore, treatment of intracranial malignant gliomas in nude mice with 2-5A-anti-hTER was therapeutically effective compared with the control (P < 0.01). These findings clearly suggest the therapeutic potentiality of 2-5A-anti-hTER as a novel approach for the treatment of intracranial malignant gliomas.

Adenine Nucleotides↗
PubMed2000

A novel telomerase-specific gene therapy: gene transfer of caspase-8 utilizing the human telomerase catalytic subunit gene promoter.

Apoptosis is a genetically encoded cell death process and is a pathway that may be disrupted in tumor cells. Therefore, therapies that restore the ability to undergo apoptosis are promising for the treatment of tumor cells. We have demonstrated that the transfer of apoptosis-inducible genes inhibits the growth of tumors in vitro and in vivo through induction of apoptosis. However, to restrict induction of apoptosis to tumor cells, we need to explore a tumor-specific expression system of these genes. In the present study, we developed the telomerase-specific transfer system of apoptosis-inducible genes, utilizing the promoter of the human telomerase catalytic subunit (hTERT) gene. Approximately 90% of tumors have telomerase activity whereas most normal cells do not express the activity. These observations indicate that telomerase is a particularly attractive target for the tumor-specific expression system of vectors. We demonstrate here that by using the hTERT promoter-driven caspase-8 expression vector (hTERT/caspase-8), apoptosis is restricted to telomerase-positive tumor cells of wide range, and is not seen in normal fibroblast cells without telomerase activity. Furthermore, treatment of subcutaneous tumors in nude mice with the hTERT/caspase-8 construct inhibited tumor growth significantly because of induction of apoptosis (p < 0.01). The telomerase-specific expression of apoptosis-inducible genes afforded by the hTERT promoter, therefore, may be a novel and promising targeting approach for the treatment of tumors with telomerase activity.

Animals↗
PubMed2000

Intraallograft chemokine RNA and protein during rejection of MHC-matched/multiple minor histocompatibility-disparate skin grafts.

Chemokines direct leukocyte recruitment into sites of tissue inflammation and may facilitate recruitment of leukocytes into allografts following transplantation. Although the expression of chemokines during rejection of MHC-disparate allografts has been examined, chemokine expression in MHC-matched/multiple minor histocompatibility Ag-disparate allografts has not been tested. The intraallograft RNA expression of several C-X-C and C-C chemokines was tested during rejection of full thickness skin grafts from B10. D2 donors on control Ig-, anti-CD4 mAb-, and anti-CD8 mAb-treated BALB/c recipients. In all recipients, two patterns of intragraft chemokine expression were observed during rejection of these grafts: 1) macrophage-inflammatory protein-1alpha, macrophage-inflammatory protein-1beta, GRO-alpha (KC), JE, and IFN-gamma-inducible protein (IP-10) were expressed at equivalent levels in allo- and isografts for 2-4 days posttransplant and then returned to low or undetectable levels; and 2) IP-10 and monokine induced by IFN-gamma (Mig) were expressed in the allografts 3 days before rejection was completed, suggesting a possible role in recruiting primed T cells into the allograft. Three days before completion of rejection, intraallograft IP-10 protein was restricted to the epidermis, whereas Mig was located in the lower dermis and associated with the intense infiltration of mononuclear cells. Treatment of B10.D2 recipients with rabbit antiserum to Mig, but not to IP-10, delayed rejection of the allografts 3-4 days. The results suggest that Mig mediates optimal recruitment of T cells into MHC-matched/multiple minor histocompatibility Ag-disparate allografts during rejection.

Amino Acid Sequence↗
PubMed2000

Treatment of prostate cancer in vitro and in vivo with 2-5A-anti-telomerase RNA component.

Prostate cancer is the most common malignancy of elderly men in the United States. Since there is no curative treatment for advanced prostate cancer, exploration of novel modalities of treatment is essential. Telomerase, a ribonucleoprotein, is detected in the vast majority of prostate cancer, but not in normal or benign prostatic hyperplasia tissues. Thus, telomerase is expected to be a very strong candidate for targeted therapy of prostate cancer. In this study, we synthesized a 19-mer antisense oligonucleotide against the RNA component of human telomerase (hTR) linked to a 2-5A molecule (2-5A-anti-hTR) and examined its cytotoxic effect on prostate cancer cells. The 2-5A antisense strategy relies on the recruitment and activation of RNase L at the site of targeted RNA sequence. We here show that treatment with 2-5A-anti-hTR in the presence of a cationic liposome reduced cell viability of tumor cell lines tested to 9-18% within 6 days. In contrast, normal fibroblast cells were resistant to the treatment. Its effect was mainly due to induction of apoptosis by activated caspase family members. Furthermore, treatment of subcutaneous tumors in nude mice with 2-5A-anti-hTR significantly suppressed the tumor growth through induction of apoptosis (P<0.001). The treatment with 2-5A-anti-hTR may be a promising strategy for the treatment modality of prostate cancer with telomerase activity.

Animals↗
PubMed2000

Multiendoscope-assisted treatment for blue rubber bleb nevus syndrome.

Blue rubber bleb nevus syndrome is characterized by gastrointestinal and cutaneous hemangiomas and gastrointestinal bleeding causing anemia. We report a unique case of this syndrome in an adult woman. It was associated with congenital heart disease, for which the patient underwent surgery at 12 months of age, and cutaneous hemangiomas, for which surgery was performed later in childhood. Gastrointestinal bleeding was diagnosed and treated when she was 21 years of age after a workup for iron deficiency anemia. Successful total resection of all gastrointestinal hemangiomas was performed by minimally invasive surgery with gastric, small intestinal, and colonic fiberscopy and laparoscopy. The postoperative course was uneventful. The patient could walk the day after surgery, and she was discharged from the hospital 14 days after surgery. Our experience and findings given in other reports suggest that total resection of hemangiomas should be the final goal and that minimal skin incision is preferable for this benign disease, with multiendoscope-assisted treatment to ensure that any hemangiomas remaining in the gastrointestinal tract are not overlooked.

Adult↗