Biomedical subjects

Go Watanabe

Publications and source records attributed to Go Watanabe.

At least 73 records · Page 4Linked to original sources

PubMed2004

Skeletonization of gastroepiploic artery graft in off-pump coronary artery bypass grafting: early clinical and angiographic assessment.

BACKGROUND: Recently skeletonization has been recognized as an alternative to pedicle harvesting of the internal thoracic artery as a technique that increases the length and caliber size of the graft compared with pedicled internal thoracic artery grafts; however, this is not yet popular for harvesting the gastroepiploic artery (GEA). We report here our experience of skeletonized GEA grafting in off-pump coronary artery bypass grafting with early clinical and angiographic results. The purpose of this study was to evaluate skeletonization of GEA grafting in off-pump coronary artery bypass grafting with a large patient volume. METHODS: One hundred sixty-eight patients including 131 men and 37 women (mean age, 65 years; range, 45 to 87 years) underwent the skeletonized GEA grafting in off-pump coronary artery bypass grafting. These patients represent 41% (168 of 407 patients) of those who underwent off-pump coronary artery bypass grafting operations during the same period. We used the GEA graft of choice in patients with right coronary artery lesion. Skeletonization was performed in a unique manner we developed. RESULTS: There were no in-hospital deaths among the study patients. One patient had a perioperative myocardial infarction, which was considered a result of vasospasm of the GEA graft. None of the other patients had severe morbidity. The patency rate of the skeletonized GEA graft was 98.1% (151 of 154 distal anastomoses). CONCLUSIONS: This study suggests that skeletonization of the GEA graft can enlarge its caliber size and improve its flow capacity. In addition, the acceptable early clinical and angiographic outcome suggests that use of the skeletonized GEA graft in off-pump coronary artery bypass grafting surgery is safe and effective.

Aged↗

PubMed2004

Instant myocardial blood flow monitor: its calibration and assessment of flow capacity of the intracoronary shunt tube.

BACKGROUND: We developed a new instant regional myocardial blood flow (RMBF) monitor utilizing the thermal diffusion method in which the RMBF value is presented as the value inversely proportional to the thermocouple voltage output (1/V). The purposes of this study were (1) to validate the accuracy of RMBF measurement by the instant RMBF monitor in comparison with the colored microsphere method for calibration; (2) to investigate influences of it on the RMBF; and (3) to assess changes in RMBF caused by the shunt tube insertion. METHODS: Twenty pigs were used for this study: 4 for comparison between the instant RMBF meter and the colored microsphere method, 4 for validation of reproducibility, and 6 for measurement of RMBF during shunt tube. RESULTS: The relation between RMBF values obtained by the colored microsphere method and 1/V values by instant RMBF monitor was colored microsphere = 140,992 (1/V)--231 in epicardial layer (R2 = 0.819) and colored microsphere = 111,381 (1/V)--165 in endocardial layer (R2 = 0.693). The correlation coefficient and R2 values between RMBF values measured by both methods were 0.985 and 0.839 in epicardial layer, and 0.963 and 0.679 in endocardial layer, respectively. The RMBF at each layer did not change after the attachment of the monitor. Fifteen minutes after shunt tube insertion, RMBF measured by the colored microsphere method decreased to 31.1% (p = 0.0001) and 33.7% (p = 0.0001) in epicardium and endocardium, respectively, and no difference was observed from the value measured by the instant RMBF monitor. CONCLUSIONS: This instant RMBF monitor can provide instantaneous and continuous information of RMBF without requiring tissue examination.

Animals↗

PubMed2004

Efficacy of FK633, an ultra-short acting glycoprotein IIb/IIIa antagonist on platelet preservation during and after cardiopulmonary bypass.

OBJECTIVE: Temporary pharmacologic inhibition of platelet function during and after cardiopulmonary bypass (CPB) (platelet anesthesia) is an attractive strategy for preserving platelets during CPB. We examined the efficacy of FK633, an ultra-short acting glycoprotein IIb/IIIa antagonist. METHODS: The study was carried out in six mongrel dogs that received an intravenous bolus of 0.1 mg/kg of FK633 at the time of administration of heparin (group F), and six control dogs (group C). All animals underwent 60 min of normothermic CPB followed by a 2-h observation period. Blood samples for platelet count, platelet aggregation to adenosine diphosphate and parameters concerning the coagulation system were obtained at eight time points. Hemodynamics, bleeding time, and postoperative blood loss were assessed serially. Scanning electron micrograph of the oxygenator's membrane was investigated. RESULTS: FK633 significantly protected platelet number (group F, 59+/-10% versus group C, 38+/-15% of the pre-CPB value; P < 0.01), and inhibited platelet aggregation to adenosine diphosphate (group F, 13+/-12% versus group C, 35+/-9% of the pre-CPB value; P < 0.01) during CPB. Postoperative blood loss did not significantly differ between the two groups, but there was a tendency of less bleeding in group F (group F, 73+/-23 ml versus group C, 111+/-44 ml; P = 0.09). In group F, scanning electron micrograph of the oxygenator's membrane showed that its surface was free from platelets. There were no significant differences between the groups in hemodynamics. CONCLUSIONS: An ultra-short acting glycoprotein IIb/IIIa antagonist, FK633, is effective in preventing both platelet aggregation and thrombocytopenia during CPB, and may be effective for minimizing postoperative bleeding.

Adenosine Diphosphate↗

PubMed2004

Total arterial revascularization with composite skeletonized gastroepiploic artery graft in off-pump coronary artery bypass grafting.

BACKGROUND: Total arterial revascularization in coronary artery bypass grafting has recently become of great interest to many surgeons. At the same time, off-pump coronary bypass grafting has also become a popular procedure because of its low morbidity and mortality. Here we report our recent series of off-pump coronary bypass grafting performed with a grafting technique we developed by using the skeletonized gastroepiploic artery and the radial artery composite graft to achieve total arterial revascularization. METHODS: From September 2000 to April 2003, 98 patients underwent total arterial revascularization with the skeletonized gastroepiploic artery and radial artery composite graft on the beating heart. We used the gastroepiploic artery graft of choice in patients with a right coronary artery lesion. When multiple grafting was required in inferior, posterolateral, or lateral ventricular walls and the gastroepiploic artery graft was too short to cover these areas, we used the composite grafting technique. RESULTS: There were no in-hospital deaths and there was no severe morbidity among the study patients. Postoperative angiography showed graft occlusion at the anastomosis site between the gastroepiploic and radial arteries. The patency rate of the gastroepiploic arterial composite graft was 98.3% (118/120 distal anastomoses). CONCLUSIONS: A composite graft with the skeletonized gastroepiploic artery and the radial artery ensured sufficient caliber size and length for myocardial revascularization on inferior, posterolateral, and lateral ventricular walls. This composite graft can be used safely and effectively even in off-pump coronary bypass surgery with excellent early clinical and angiographic outcome in selected patients, although longer follow-up periods are necessary to draw definitive conclusions.

Aged↗

PubMed2004

Experimental study of extracorporeal lung resection in dogs: ex situ sleeve resection and autotransplantation of the pulmonary lobe after extended pneumonectomy for central lung cancer.

OBJECTIVE: Extracorporeal lung resection as an alternative to pneumonectomy for central lung cancer is a procedure in which the unilateral lung is extirpated, removing the pulmonary lobe with the cancers and replanting the residual pulmonary lobe. The aim of this study was to investigate whether extracorporeal lung resection for lung cancer can be performed safely. METHODS: Nineteen dogs were divided into the control and extracorporeal lung resection groups. The former (n = 5) underwent lung autotransplantion, and the latter was subdivided into ND1 (n = 7) and ND2 (n = 7) groups on the basis of the manner of lymph node dissection. By comparing the 3 groups, the adverse effects of lymph node dissection were examined. RESULTS: All dogs in the control group had no complications. Four dogs in the ND1 group survived for 90 to 630 days after the operation. In the ND2 group 5 dogs succumbed within 30 days after the operation, although the other 2 dogs survived for 391 and 573 days, respectively. Bronchopulmonary fistulas were seen in 1 of the ND1 dogs and 3 of the ND2 dogs. Two of the latter were free of thrombus formation in the pulmonary arteries and veins of the autografts. In the ND2 group, compared with the control and ND1 group, the tissue blood flow at the bronchial anastomotic site indicated reduction between the 3rd and 14th postoperative days. CONCLUSION: The extensive lymph node dissection had severe adverse effects on bronchial anastomotic healing in extracorporeal lung resection. Therefore extracorporeal lung resection can be applied to only a very limited number of patients with N0 or N1 disease.

Anastomosis, Surgical↗

PubMed2004

Vascular endothelial growth factor expression in metastatic pulmonary tumor from colorectal carcinoma: utility as a prognostic factor.

OBJECTIVE: To define the most reliable prognostic factor, we studied the 5-year survival of patients after resection of pulmonary metastases from colorectal cancer in relation to various prognostic factors, including vascular endothelial growth factor expression in primary and metastatic tumors. METHODS: A retrospective study was undertaken in 49 patients who had undergone complete resection of pulmonary metastasis from colorectal carcinoma. All patients were retrospectively analyzed for sex, age, location and stage of primary tumor, number of pulmonary metastases, type of pulmonary resection, size of metastatic tumor, lymph node metastasis, and prethoracotomy carcinoembryonic antigen level. Furthermore, vascular endothelial growth factor expression of both primary and metastatic tumors was investigated. RESULTS: Overall 5-year survival was 34.3%. In the univariate analysis the number of pulmonary metastases (P =.007) and vascular endothelial growth factor expression in metastatic tumors (P =.008) and primary colorectal tumors (P =.011) were significantly associated with poor survival. In the multivariate analysis the number of pulmonary metastases (P =.0031), vascular endothelial growth factor expression in metastatic tumors (P =.0057), and stage of primary tumor (P =.0321) were characteristics that retained a significant independent prognostic effect on overall survival. A statistically significant difference was not found in the 5-year survival of patients with solitary and negative vascular endothelial growth factor expression in metastatic tumors (59.1%) versus those with multiple and positive vascular endothelial growth factor expression in metastatic tumors (10.0%; P <or=.0001). CONCLUSIONS: Vascular endothelial growth factor expression in metastatic pulmonary tumors is an important prognostic marker for patients with pulmonary metastasis from colorectal carcinoma. Our results suggested that patients with multiple and positive vascular endothelial growth factor expression in the metastatic tumor will not receive benefit from metastasectomy.

Biomarkers, Tumor↗

PubMed2004

Primary chondromatous osteosarcoma of the pulmonary artery.

Primary pulmonary sarcoma is an extremely rare malignancy, pulmonary osteogenic sarcoma is even more rare and has a poor prognosis. We present a report of a 58-year-old woman with primary pulmonary osteosarcoma occupying the right main pulmonary artery and extending to the main pulmonary artery. Right pneumonectomy was performed with total right main pulmonary artery resection under cardiopulmonary bypass. Microscopic examination demonstrated that tumor cells contained mainly chondromatous components and were atypical cells that became osteoid. There is no sign of recurrence 24 months postoperatively. The present case is the only case yet reported with even an intermediate-term survival without recurrence.

Female↗

PubMed2004

Increased matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase activity and expression in heterotopically transplanted murine tracheas.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the most common long-term cause of morbidity and mortality after heart-lung or lung transplantation. One pathologic feature of BOS is infiltration of fibroblasts and connective tissue products into the airway lumen, which form a fibrous, collagen-rich occlusion. Heterotopically transplanted allogeneic murine tracheal stenosis resemble BOS in the development of obliterans airway disease. Matrix metalloproteinases (MMPs) are key enzymes involved in tissue remodeling and, clinically, have several roles in pulmonary diseases. Among the MMP family, type IV collagenases, MMP-2 and MMP-9, have high gelatinolytic activity and are thought to play a role in several pulmonary diseases. Membrane type 1 MMP (MT1-MMP) activates the zymogen of MMP-2 (proMMP-2, 72 kd), and activated MMP-2 (active MMP-2, 62 kd) degrades type IV collagen and plays an important role in clinical pulmonary disease. In this study, we examine the expression of MMP-2, its activator MT1-MMP and MMP-9 in BOS using murine trachea transplantation models. METHODS: Rats were divided into 5 experimental groups (n = 10 in each group). Group I was a control group with intact tracheas. Animals with tracheal grafts underwent heterotopically syngeneic (Groups II and III) or allogeneic (Groups IV and V) transplantation. The recipient rats were killed 7 days (Groups II and IV) or 28 days (Groups III and V) after transplantation. The harvested tracheal grafts were examined histologically. MMP activity was assessed using gelatin zymography analysis, and MMP-2 and MT1-MMP gene expression was examined by quantitative real-time polymerase chain reaction analysis. Distribution of gelatinolytic activity was studied using in situ zymography. RESULTS: There was little histologic change in the intact trachea (Group I) and in all isografts (Groups II and III). Fibrotic tissues in Group V significantly occluded the tracheal lumen, and there was severe lymphocyte infiltration in Group IV. According to gelatin zymography, proMMP-9 was faint at 7 days, but activated MMP-9 was not present in all groups. The MMP-2 gelatinolytic bands were predominant; the activation in Group V was significantly greater than that in Group IV, and in Group III it was significantly greater than that in Group II. Gene expression of both MMP-2 and MT1-MMP were significantly higher in Group V than in the other groups (p < 0.01), and MMP-2 was clearly activated. Gelatinolytic activity was localized in the fibrotic tissues or lymphocytes of thickening lumen after destruction of the epithelium by stenosis. CONCLUSIONS: These results demonstrate that MMP-2, together with its activator MT1-MMP, may have an important role in the development of BOS, which is associated with destruction of the tracheal epithelium, leading to fibrosis.

Animals↗

PubMed2004

Optimal continuous retrograde coronary perfusion flow rate with beating heart in normal temperature.

PURPOSE: We were led to the premise that with retrograde oxygenated blood perfusion, it would be possible to perform operations on the beating heart. METHODS: The experiment consisted of two stages: procedure 1 and 2. In procedure 1, six pigs were used. Retrograde perfusion flow was controlled to be in the range of 5.0-10.0 mL/kg/min and was gradually increased. In procedure 2, six pigs were used. Retrograde perfusion was continued for 120 min at the optimal flow rate obtained from procedure 1. RESULTS: The optimal flow rate was 7.0 mL/kg/min in procedure 1. In procedure 2, retrograde perfusions for 120 min were performed with perfusion flows set at optimal flow rate. CONCLUSIONS: The procedure used in this study made it possible to maintain empty beating heart with normal sinus rhythm for 120 min, and the results suggest the possibility of clinical application to open heart surgery.

Animals↗

PubMed2004

Prognostic significance of dysadherin expression in esophageal squamous cell carcinoma.

OBJECTIVE: Dysadherin is a cancer-associated cell membrane glycoprotein that has been reported to downregulate E-cadherin expression and promote metastasis. To evaluate the role of dysadherin in metastasis of esophageal squamous cell carcinoma (ESCC), we examined dysadherin and E-cadherin expression in patients with this cancer. METHODS: Dysadherin and E-cadherin expression was evaluated in 117 ESCC patients (pT1, 31; pT2, 30; pT3, 39; pT4, 17) by immunohistochemistry. The findings were compared with the clinicopathological data of the patients. RESULTS: Both dysadherin and E-cadherin were localized to the cell membrane. Thirty patients (29.1%) had tumors positive for dysadherin and 41 patients (35.0%) had tumors positive for E-cadherin. Tumors showing dysadherin positivity and negative E-cadherin expression had a significantly worse prognosis than other tumors. When the patients with dysadherin- positive tumors were combined with E-cadherin-negative patients, this group had a worse prognosis (p < 0.0001). Cox multivariate analysis revealed that dysadherin expression was an independent prognostic factor for ESCC (p = 0.003), but E-cadherin expression was not. CONCLUSION: Combined analysis of dysadherin and E-cadherin expression may help to predict the prognosis of patients with ESCC. Our results suggested that expression of dysadherin by this cancer may partly explain the poor prognosis of patients with preservation of E-cadherin expression.

Aged↗

PubMed2004

A new technique of fixing a costal coaptation pin after resection of rib segment.

The Poly-L-lactide costal coaptation pin is an effective device in chest wall reconstruction. However, fixation is sometimes incomplete, despite the use of the costal coaptation pin. We report here the use of two suture techniques for the fixation of the incised ribs with costal coaptation and discuss the effectiveness of these procedures. We used the Poly-L-lactide costal coaptation pin in 174 cases of posterolateral thoracotomies with two suture methods. In one method the rib was generally fixed with suture only (L-method, n = 30), and in the H-method pairs of holes were made at the end of the incised ribs for ligating with sutures (H-method, n = 144). The effectiveness of each method was evaluated based on the degree of fixation and lateral shift 24 months postoperatively. Lateral shift was none in 114 (79.2%) cases using the H-method and 18 (60.0%) cases using the L-method. Fixation was good in 131 (91.0%) cases using the H-method but in only 20 (66.7%) cases using the L-method. H-method was significantly more effective than the L-method of costal coaptation. The H-method was very effective for fixing incised ribs and is convenient for use by thoracic surgeons.

Aged↗

PubMed2004

Chest CT and serum vascular endothelial growth factor-C level to diagnose lymph node metastasis in patients with primary non-small cell lung cancer.

STUDY OBJECTIVE: Accurate tumor staging is essential for choosing the appropriate treatment strategy for lung cancer. CT of the chest is the most commonly used noninvasive staging method of the lymph node metastasis, but it is far from satisfying. We evaluated whether circulating vascular endothelial growth factor (VEGF)-C could give additional information for diagnosing lymph node metastasis in patients with lung cancer. PATIENTS AND METHOD: Serum samples were obtained from 116 patients with primary non-small cell lung cancer (NSCLC). All patients underwent preoperative CT of the thorax. Clinical T and N stages were compared to the final T and N stages obtained from pathologic findings. Serum VEGF-C concentration was assayed by commercially available sandwich enzyme-linked immunosorbent assay. We evaluated the utility of serum VEGF-C level as a marker for nodal metastasis comparing the utility of CT. RESULTS: Preoperative and final T categories completely agreed in 82.8%. Regarding nodal metastasis, the accuracy of CT was 68.1%. Patients with lymph node metastasis showed higher serum VEGF-C concentrations than those without lymph node metastasis (p = 0.0007). Serum VEGF-C reached the highest sensitivity and specificity in diagnosing lymph node metastasis when a cut-off value of 1,850.6 pg/mL was applied (sensitivity, 70.0%; specificity, 77.3%). Serum VEGF-C visually correlated with CT scan in the detection of lymph node metastasis (sensitivity, 74.0%; specificity, 80.3%; positive predictive value, 74.0%; negative predictive value, 80.3%; accuracy, 77.6%). When the cases were limited to adenocarcinoma, better results could be obtained. CONCLUSIONS: Serum VEGF-C is a reliable marker for lymph node metastasis in NSCLC. Serum VEGF-C evaluation and CT examination are complementary to each other for accurate lymph node staging in NSCLC.

Adenocarcinoma↗

PubMed2004

Hypermethylation of the MYOD1 gene is a novel prognostic factor in patients with colorectal cancer.

MYOD1 promoter methylation occurs in various malignancies including colorectal cancer. We analyzed MYOD1 methylation in 80 colorectal cancer and 74 adjacent normal tissues using MethyLight, which enabled quantitative DNA methylation analysis. The measured methylation value was expressed as a percentage of methylated reference (PMR). The results were compared with clinicopathological features and patient prognosis in order to investigate whether MYOD1 methylation may serve as an independent prognostic factor of colorectal cancer. MYOD1 promoter methylation was detectable in all samples and was significantly higher in tumor compared to normal mucosa, where the median level of methylation was 5.3 PMR (range 0.03-133.4) in normal mucosa and 42.3 PMR (range 0.44-742.9) in tumor. The methylation value of MYOD1 was higher with elder patients both in normal colonic mucosa (p=0.034) and in cancer tissues (p=0.0012). Patients without MYOD1 hypermethylation showed significantly longer survival than those with hypermethylation (p=0.0077). In multivariate analysis of prognostic factors, MYOD1 hypermethylation was a significant prognostic factor (p=0.015) independent to patients' age. These results suggest that MYOD1 hypermethylation plays an important role in colorectal cancer and may be a novel prognostic factor. In addition, quantitative methylation analysis by MethyLight is encouraged for other genes showing age-related and non-cancer-specific methylation.

Aged↗

PubMed2004

[The association of expression and gene polymorphism of the thymidylate synthase gene with 5-fluoro-5'-deoxyuridine sensitivity in gastric cancer cell lines].

Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil (5-FU), and the TS expression level of cancer tissues is a potential predictor of the response to 5-FU-based chemotherapy. The TS gene has a polymorphic tandem-repeat sequence, which is associated with its protein expression. Therefore, the TS polymorphism may also be a predictor of the response to 5-FU-based chemotherapy. In this study, we analyzed the TS genotype, TS protein level, and sensitivity to 5-fluoro-5'-deoxyuridine (5'-dFUrd) in 10 human gastric cancer cell lines. TS genotype was classified into 2R-homozygote (2R/2R, n=3), 3R-homozygote (3R/3R, n=5), and 2R/3R-heterozygote (2R/3R, n=2). The cell lines with 3R/3R showed a significantly higher IC50 value compared to those with 2R/2R or 2R/3R genotype. There was no relationship between TS protein level and 5'-dFUrd sensitivity. However, a statistically significant relationship was revealed between them when the subgroup with the genotypes of 2R/2R or 2R/3R was considered (r=0.815, p<0.05). In this subgroup, the cell lines with higher TS protein showed higher IC50 value for 5'-dFUrd, indicating less sensitivity to 5'-dFUrd. An identical relationship between the TS protein level and IC50 was also observed in the subgroup with 3R/3R genotype, although it did not reach statistical significance (r=0.745, p=0.09). These results suggest that the TS gene polymorphism and TS protein level may be independent predictors for 5-FU-based chemotherapy.

Antimetabolites, Antineoplastic↗

PubMed2003

Outcomes and indications of segmental pancreatectomy. Comparison with distal pancreatectomy.

BACKGROUND/AIM: To preserve pancreatic function, segmental pancreatectomy has been proposed for benign or low-malignancy tumors in the pancreatic body. Indications for the procedure, however, are still controversial. METHODS: In this study, we investigated the advantages and disadvantages of segmental pancreatectomy compared with distal pancreatectomy and subsequently determined indications for segmental pancreatectomy. RESULTS: The distal pancreatectomy patients had shorter operation times, lower incidence of operative complications, and shorter hospital stays compared to segmental pancreatectomy patients. Endocrine function in distal pancreatectomy patients deteriorated compared to that of segmental pancreatectomy patients. The postoperative 75-gram oral glucose tolerance test showed a diabetic pattern in 3 of 7 distal pancreatectomy patients, whereas none of the segmental pancreatectomy patients became diabetic after surgery. The relation between the length of the removed pancreas and plasma glucose at 2 h after the 75-gram glucose intake showed a significant correlation. CONCLUSION: According to our results, if the length of removed pancreas is longer than 12 cm, the patients will have a risk of acquiring diabetes. In those cases, the segmental pancreatectomy should be considered.

4-Aminobenzoic Acid↗

PubMed2003

The folate pool in colorectal cancers is associated with DNA hypermethylation and with a polymorphism in methylenetetrahydrofolate reductase.

PURPOSE: Aberrant DNA methylation occurs in a subset of colorectal cancers and is characterized by regional areas of hypermethylation at CpG islands. The aims of this study were firstly to evaluate the levels of folate intermediates (FIs) in tumors with aberrant DNA methylation and secondly to determine whether these levels are affected by polymorphisms in key genes involved in folate metabolism. EXPERIMENTAL DESIGN: The concentrations of two major intracellular FIs, 5,10-methylenetetrahydrofolate and tetrahydrofolate (FH4), were measured in 103 surgically resected colorectal cancers. DNA hypermethylation at seven different CpG islands was measured using the MethylLight assay. Genotyping for polymorphisms in the thymidylate synthase, cystathionine beta-synthase, methionine synthase, and methylenetetrahydrofolate reductase (MTHFR) genes was carried out using PCR and PCR-RFLP. RESULTS: Significantly higher levels of FH4 were found in tumors from the proximal colon compared with those originating in the distal colon and rectum. Tumors with aberrant DNA methylation of CpG islands within promoter regions of the hMLH1, TIMP3, and ARF genes also contained higher levels of both 5,10-methylenetetrahydrofolate and FH4. In contrast, patients who were homozygous for the C667T polymorphism of the MTHFR gene had significantly lower concentrations of both these FIs in their tumor tissue. CONCLUSIONS: The concentrations of FIs in colorectal tumors are directly related to the presence of frequent DNA hypermethylation and inversely related to the presence of a common polymorphism in the MTHFR gene. FIs could serve as biochemical markers for the risk of developing this disease, as well as for the prediction of toxicity and efficacy of fluorouracil-based treatments.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed2003

Involvement of TSLC1 in progression of esophageal squamous cell carcinoma.

Frequent allelic losses of 11q23 in esophageal squamous cell carcinoma (ESCC) have been reported previously, but no tumor suppressor genes in this region have been identified in ESCC. TSLC1 was identified on chromosome 11q23.2 as a tumor suppressor gene in non-small cell lung cancer by functional complementation of a lung adenocarcinoma cell line. The purpose of this study is to evaluate the role of TSLC1 in ESCC. Loss of TSLC1 expression was observed by reverse transcription-PCR in 75% of the cell lines (27 of 36) and 50% of the primary tumors from ESCC patients (28 of 56). In a clinicopathological analysis, loss of TSLC1 expression correlated significantly with depth of invasion (pT) and status of metastasis (pM; P = 0.012 and 0.036, respectively). Patients with tumors lacking TSLC1 expression tended to have a poorer prognosis than those with tumors expressing TSLC1. (P = 0.079). Moreover, TSLC1 expression was an independent prognostic factor in a multivariate analysis (P = 0.049). Methylation analyses revealed that TSLC1 expression or loss correlated with the promoter methylation status, as determined by bisulfite sequencing, and that TSLC1 expression could be restored by a demethylating agent in certain cell lines. The growth of TSLC1-transfected ESCC cells was significantly suppressed both in vitro and in vivo (P < 0.01), possibly by a G(1) cell cycle arrest. TSLC1 expression also suppressed motility and invasion of ESCC cells in vitro significantly (P < 0.01). These findings suggest that loss of TSLC1 expression has an important role in tumor growth, cell motility, and invasion and is associated with aggressive tumor behavior in ESCC.

Aged↗

PubMed2003

Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene.

The variable number of tandem repeat (VNTR) of thymidylate synthase (TS) gene, mainly 2 repeat (2R) and 3 repeat (3R), is one of the genetic variations that can potentially predict the effectiveness of 5-fluorouracil-based chemotherapy. In this study we identified an additional single nucleotide polymorphism (SNP) in the VNTR of TS, followed by functional and clinical analysis of the SNP. Two-hundred fifty eight tumor samples were obtained from patients with primary colorectal adenocarcinoma. We observed three different patterns of electrophoresis by analysis of the VNTR with 2R/3R heterozygote. The sequencing results revealed a SNP, G/C polymorphism, within the 28-bp repeat component of TS VNTR. Each polymorphic allele was assigned as 2G, 2C, 3G, or 3C according to the combination of SNP and VNTR. Functional analysis showed that the plasmid construct with 3G sequence had three to four times greater efficiency of translation than other polymorphic sequences. 3R allele in colorectal cancer was subdivided into around half by the SNP, indicating its commonness among Japanese. TS genotypes of the patients with colorectal cancer were classified into high expression type (2R/3G, 3C/3G, and 3G/3G) and low expression type (2R/2R, 2R/3C, and 3C/3C). The patients who received oral fluoropyrimedines survived longer than the patients with no treatment in the group of low expression type. No benefit of oral fluoropyrimedines was observed in the group of high expression type. These results suggest that the double polymorphism in the TS tandem repeat sequence, the SNP and the VNTR, may provide a potential for more effective prediction of the clinical outcome of 5-fluorouracil-based chemotherapy.

Adenocarcinoma↗