Biomedical subjects

Dan D Hershko

Publications and source records attributed to Dan D Hershko.

At least 19 recordsLinked to original sources

PubMed2006

Prognostic role of p27Kip1 deregulation in colorectal cancer.

p27Kip1, an inhibitor of cyclin-dependent kinases, is a negative cell cycle regulator that plays an important role in tumor suppression. Deregulation of p27 is commonly observed in many human cancers secondary to enhanced ubiquitin-mediated degradation, mediated and rate-limited by its specific ubiquitin ligase subunits Skp2 and Cks1. In the present study the prognostic implications of p27 and the mechanisms that down-regulate its expression in colorectal cancer (CRC) are reviewed. A review and analysis of the English literature was conducted. Loss of p27 was strongly associated with aggressive tumor behavior and poor clinical outcome in CRC. Overexpression of Skp2 and Cks1 was observed in aggressive CRC and is responsible for down-regulation of p27 levels. Both Skp2 and Cks1 were found to be independent prognostic markers for survival and provide predictive information additional to that provided by p27 alone. Deregulation of p27 has a profound effect on tumor progression in CRC and was found to be an accurate and independent prognostic marker. Thus, determination of levels of p27 and of its ubiquitin ligase subunits by readily available immunohistochemical studies may be a useful tool in the assessment of prognosis, especially in patients with intermediate disease, and may potentially assist in the planning of adjuvant therapy and development of novel interventional therapy.

Biomarkers, Tumor↗

PubMed2006

The "Sentinel Chain": a new concept for prediction of axillary node status in breast cancer patients.

BACKGROUND AND OBJECTIVES: More than half the breast cancer patients with positive sentinel lymph nodes (SLN) do not harbor additional metastases in non-sentinel nodes (NSN). The aim of this study was to identify a subgroup of patients with positive SLNs and negative NSNs, on the basis of tumor involvement patterns in multiple radioactive nodes. METHODS: Between 2000 and 2004, 290 patients with primary invasive breast cancer and clinically negative axillary nodes had a SLN biopsy in our breast unit. Radiotracer was identified intraoperatively in the axilla. All radioactive nodes were removed and radioactivity was measured in each node extracorporeally. Nodes were ranked according to radioactivity, constituting a "Sentinel Chain", and the histopathological status of each node was reported. The different metastatic involvement patterns of the Sentinel Chain were correlated with the metastatic status of the NSNs after axillary dissection. Information was charted in a prospective database. RESULTS: Of 290 patients, 216 (74.5%) had multiple radioactive nodes. Ninety patients (31%) had SLN metastases. Fifty patients had multiple ranked radioactive nodes and positive SLNs. Twenty-five of these patients had a sequential involvement pattern, with tumor-bearing high radioactivity nodes, and uninvolved low-radioactivity nodes. In the 23 of these 25 patients who had axillary dissection, NSN involvement was detected in only one patient (4.3%), whereas in 24 patients with other involvement patterns of the Sentinel Chain, NSN involvement reached 54.2% (p<0.001). CONCLUSION: Tumor-free status of NSN may be predicted using the Sentinel Chain concept in some breast cancer patients with positive SLNs.

Axilla↗

PubMed2006

Laparoscopic diagnostic peritoneal lavage (L-DPL): A method for evaluation of penetrating abdominal stab wounds.

BACKGROUND: The management of penetrating abdominal stab wounds has been the subject of continued reappraisal and controversy. In the present study a novel method which combines the use of diagnostic laparoscopy and DPL, termed laparoscopic diagnostic peritoneal lavage (L-DPL) is described METHOD: Five trauma patients with penetrating injuries to the lower chest or abdomen were included. Standard videoscopic equipment is utilized for the laparoscopic trauma evaluation of the injured patient. When no significant injury is detected, the videoscope is withdrawn and 1000 mL of normal saline is infused through the abdominal trochar into the peritoneal cavity, and the effluent fluid studied for RBCs, WBC, amylase debry, bile as it is uced in regular diagnostic peritoneal lavage RESULTS: Laparoscopic peritoneal lavage (L-DPL) was then performed and proved to be negative in all 5 patients. RBC lavage counts above 100,000/mcrl were not considered as a positive lavage result, because the bleeding source was directly observed and controlled laparoscopically. All patients recovered uneventfully and were released within 3 days. This procedure combines the visual advantages of laparoscopy together with the sensitivity and specificty of DPL for the diagnosis of significant penetrating intra-abdominal injury, when the diagnostic strategy of selective consevatism for abdominal stab wounds is adopted. CONCLUSION: A method of laparoscopic diagnostic peritoneal lavage (L-DPL) in hemodynamically stable patients with penetrating lower thoracic or abdominal stab wounds is described. The method is especially applicable for trauma surgeons with only basic experience in laparoscopic technique. This procedure is used to obtain conclusive evidence of significant intra-abdominal injury, confirm peritoneal penetration, control intra-abdominal bleeding, and repair lacerations to the diaphragm and abdominal wall. The combination of laparoscopy and DPL afforded by the L-DPL method adds to the sensitivity and specificity of DPL, and avoids under or over sesitivty, that have limited the use of DPL in the hemodynamically stable trauma patients with suspicious or proven peritoneal penetration.

Journal Article↗

PubMed2006

Sentinel lymph node biopsy in thin melanoma patients.

BACKGROUND: We sought to determine the incidence of positive sentinel lymph nodes in thin melanoma ( or= III and thicker lesions (mean 0.77 mm vs. 0.47 mm), but were not different in regards to age, sex, or lesion location. Eight percent and 58% of sentinel nodes were positive by routine histology and RT-PCR, respectively. Among mapped patients, younger age was the only significant prognostic factor for node positivity. With a median follow-up of 18 months among all patients, one regional recurrence (at 2 years) has been identified. CONCLUSIONS: Given the low morbidity of sentinel lymph node biopsy, this procedure should be discussed with selected thin melanoma patients to detect microscopic disease, however PCR positivity by our methods is too commonly seen to be clinically significant in thin melanoma patients and requires additional study.

Adult↗

PubMed2006

Expression of the ubiquitin ligase subunit cyclin kinase subunit 1 and its relationship to S-phase kinase protein 2 and p27Kip1 in prostate cancer.

PURPOSE: Loss of the cell cycle inhibitory protein p27Kip1 in cancer is associated with tumor aggressiveness and poor prognosis in the prostate. The decrease in p27(Kip1) results from increased proteasome dependent degradation, which is mediated by its specific ubiquitin ligase subunits S-phase kinase protein 2 and cyclin dependent kinase subunit 1. S-phase kinase protein 2 was found to be over expressed in aggressive prostate cancers but to our knowledge the role of cyclin dependent kinase subunit 1 in these cancers is unknown. MATERIALS AND METHODS: The expression of cyclin dependent kinase subunit 1, S-phase kinase protein 2 and p27Kip1 was examined by immunohistochemistry in tissue sections from 45 patients with prostate cancer. The expression of cyclin dependent kinase subunit 1 was compared to that of S-phase kinase protein 2 and p27Kip1, and patient clinical and histological characteristics. RESULTS: Cyclin dependent kinase subunit 1 expression was strongly associated with S-phase kinase protein 2 expression (r = 0.666, p = 0.001) and inversely with p27Kip1 expression (r = -0.737, p < 0.001). Cyclin dependent kinase subunit 1 over expression was associated with loss of tumor differentiation (r = 0.631, p = 0.001), high serum prostate specific antigen (r = 0.627, p < 0.001) and metastatic disease (p < 0.001). CONCLUSIONS: These results suggest that cyclin dependent kinase subunit 1 is involved in p27Kip1 down-regulation and it may have an important causative role in the development of aggressive tumor behavior in prostate cancer.

Aged↗

PubMed2006

The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells.

INTRODUCTION: Loss of the cyclin-dependent kinase inhibitor p27 is associated with poor prognosis in breast cancer. The decrease in p27 levels is mainly the result of enhanced proteasome-dependent degradation mediated by its specific ubiquitin ligase subunit S phase kinase protein 2 (Skp2). The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphoinositol 3' kinase (PI3K)/Akt pathway that down-regulates p27 levels in breast cancer. Rapamycin was found to stabilize p27 levels in breast cancer, but whether this effect is mediated through changes in Skp2 expression is unknown. METHODS: The expression of Skp2 mRNA and protein levels were examined in rapamycin-treated breast cancer cell lines. The effect of rapamycin on the degradation rate of Skp2 expression was examined in cycloheximide-treated cells and in relationship to the anaphase promoting complex/Cdh1 (APC\C) inhibitor Emi1. RESULTS: Rapamycin significantly decreased Skp2 mRNA and protein levels in a dose and time-dependent fashion, depending on the sensitivity of the cell line to rapamycin. The decrease in Skp2 levels in the different cell lines was followed by cell growth arrest at G1. In addition, rapamycin enhanced the degradation rate of Skp2 and down-regulated the expression of the APC\C inhibitor Emi1. CONCLUSION: These results suggest that Skp2, an important oncogene in the development and progression of breast cancer, may be a novel target for rapamycin treatment.

Breast Neoplasms↗

PubMed2005

The expression of the ubiquitin ligase subunit Cks1 in human breast cancer.

INTRODUCTION: Loss of the cell-cycle inhibitory protein p27Kip1 is associated with a poor prognosis in breast cancer. The decrease in the levels of this protein is the result of increased proteasome-dependent degradation, mediated and rate-limited by its specific ubiquitin ligase subunits S-phase kinase protein 2 (Skp2) and cyclin-dependent kinase subunit 1 (Cks1). Skp2 was recently found to be overexpressed in breast cancers, but the role of Cks1 in these cancers is unknown. The present study was undertaken to examine the role of Cks1 expression in breast cancer and its relation to p27Kip1 and Skp2 expression and to tumor aggressiveness. METHODS: The expressions of Cks1, Skp2, and p27Kip1 were examined immunohistochemically on formalin-fixed, paraffin-wax-embedded tissue sections from 50 patients with breast cancer and by immunoblot analysis on breast cancer cell lines. The relation between Cks1 levels and patients' clinical and histological parameters were examined by Cox regression and the Kaplan-Meier method. RESULTS: The expression of Cks1 was strongly associated with Skp2 expression (r = 0.477; P = 0.001) and inversely with p27Kip1 (r = -0.726; P < 0.0001). Overexpression of Cks1 was associated with loss of tumor differentiation, young age, lack of expression of estrogen receptors and of progesterone receptors, and decreased disease-free (P = 0.0007) and overall (P = 0.041) survival. In addition, Cks1 and Skp2 expression were increased by estradiol in estrogen-dependent cell lines but were down-regulated by tamoxifen. CONCLUSION: These results suggest that Cks1 is involved in p27Kip1 down-regulation and may have an important role in the development of aggressive tumor behavior in breast cancer.

Breast Neoplasms↗

PubMed2005

The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma.

BACKGROUND: Loss of the cell-cycle inhibitory protein p27Kip1 is associated with poor prognosis in colorectal carcinoma. The decrease in p27Kip1 levels is the result of increased proteasome-dependent degradation, mediated and rate-limited by its specific ubiquitin ligase subunits S-phase kinase protein (Skp) 2 and cyclin-dependent kinase subunit (Cks) 1. Recently, Skp2 and Cks1 expression were found to be increased in some colorectal carcinomas, but their potential role as prognostic markers for survival is unknown. The present study was undertaken to assess the prognostic value of both Skp2 and Cks1 in colorectal carcinoma. MATERIALS AND METHODS: The expression of Skp2, Cks1, and p27Kip1 was examined by immunohistochemistry using highly specific antibodies on formalin-fixed, paraffin-embedded tissue sections from 80 patients with colorectal carcinoma. RESULTS: Overexpression of Skp2 and Cks1 strongly correlated with loss of p27Kip1 and loss of tumor differentiation. A significant decrease in overall survival was observed in patients expressing high Skp2 or Cks1 levels, and in particular, patients with Stage II and III disease. Each protein provided significant additional prognostic information to that given by disease stage, tumor grade, or p27Kip1 expression. CONCLUSIONS: Results suggest that overexpression of Skp2 or Cks1 is strongly associated with poor prognosis and may thus be used as prognostic markers for overall survival in colorectal carcinoma.

Aged↗

PubMed2005

Transanal endoscopic microsurgery for rectal cancer.

BACKGROUND: Transanal endoscopic microsurgery has recently gained acceptance as an alternative minimally invasive surgical technique for the curative management of large rectal adenomas and selected early rectal carcinomas. OBJECTIVES: To analyze our 8 year experience using TEM for the management of rectal cancer. METHODS: Local resection by TEM was performed in patients with benign tumors and early rectal cancer. In addition, selected patients with T2 and T3 rectal cancers who were either medically unfit or unwilling to undergo radical surgery were also treated with this modality. Radical surgery was offered to all patients with incomplete tumor excision by TEM. RESULTS: Overall, 116 TEM operations for rectal tumors were carried out between 1995 and 2003, including 74 patients with rectal adenomas and 42 patients with rectal carcinomas. In 25 patients, TEM successfully removed all T1 tumors with clear tumor margins. Fourteen patients had T2 cancer and 3 of them (21%) required additional radical surgery due to incomplete excision. Local recurrence was observed in one patient with T2 cancer. There was no mortality. Major surgery or radiotherapy-related complications requiring additional surgical intervention was needed in five patients with T2 cancer. CONCLUSIONS: Local excision by TEM is a safe surgical procedure and should be offered to highly selected patients with early rectal cancer.

Adenoma↗

PubMed2004

Alterations in the expression of the cell cycle regulatory protein cyclin kinase subunit 1 in colorectal carcinoma.

BACKGROUND: Low levels of p27(Kip1) are associated with high aggressiveness and poor prognosis in various malignancies, including colorectal carcinoma. The authors showed that S phase kinase protein 2 (Skp2), the specific ubiquitin ligase subunit that targets p27(Kip1) for degradation, was overexpressed and was inversely related to p27(Kip1) levels in patients with colorectal carcinoma. The essential role of cyclin kinase subunit 1 (Cks1) in Skp2-dependent p27 degradation was recently discovered, but its role in human malignancies is unknown. METHODS: Quick-frozen colorectal tumor samples from 30 patients were separated by electrophoresis on sodium dodecyl sulfate-polyacrylamide gels, transferred to nitrocellulose, and probed with highly specific monoclonal antibodies directed against Cks1, Skp2, and p27(Kip1). The expression of Cks1 was also examined by immunohistochemistry using formalin-fixed, paraffin-embedded tissue sections from the same patients. RESULTS: A strong correlation was found between Cks1 levels and Skp2 expression and loss of tumor differentiation. A significant inverse relation was also observed between levels of Cks1 and p27(Kip1) and overall survival. CONCLUSIONS: The results of the current study suggest that increased expression of Cks1 may have an important causative role in decreasing levels of p27 in patients with aggressive colorectal carcinoma.

Aged↗

PubMed2004

Superinduction of IL-6 by cycloheximide is associated with mRNA stabilization and sustained activation of p38 map kinase and NF-kappaB in cultured caco-2 cells.

Protein synthesis inhibitors paradoxically increase the expression of early-gene products, including various cytokines, through a process known as superinduction. Superinduction is cell-specific and the mechanisms involved are not fully understood but are usually attributed to decreased mRNA degradation. There is, however, increasing evidence that activation of signaling cascades and increased transcriptional activation may be involved as well. Recent studies suggest that IL-6 production in the intestinal mucosa is particularly important due to its anti-inflammatory and protective effects. The effect of protein synthesis inhibitors on IL-6 production in enterocytes, however, is unknown. Treatment of Caco-2 cells with cycloheximide (10 microg/ml) increased IL-6 mRNA and protein levels in IL-1beta-treated cells and this was associated with increased mRNA stabilization. In addition, cycloheximide suppressed IkappaBalpha resynthesis and prolonged p38MAP kinase activation and these changes were associated with sustained activation of the transcription factor NF-kappaB. NF-kappaB activation, in turn, was prevented by the specific p38MAP kinase inhibitor SB208350. Our results suggest that superinduction of IL-6 by cycloheximide in enterocytes results from both increased mRNA stabilization and upregulated transcriptional activity mediated by prolonged activation of the p38 MAP kinase and NF-kappaB.

Blotting, Western↗

PubMed2004

Omentopexy improves vascularization and decreases stricture formation of esophageal anastomoses in a dog model.

BACKGROUND: Anastomotic strictures are common after primary esophageal anastomosis in pediatric patients. Recent studies provided evidence that omentopexy may improve vascularization of gastroesophageal anastomoses and decrease the rate of stricture-related complications. The effect of omentopexy on primary esophago-esophageal anastomosis, however, is unknown. The aim of the current study was to examine the role of omentopexy on the healing process of primary midesopageal anastomoses. METHODS: Six dogs were operated on. A 5-cm portion of the midesophagus was resected, and continuity was restored by end-to-end anastomosis. In 3 dogs, an omental pedicle was placed around the anastomotic region. Eating patterns were recorded and functional swallowing was evaluated by fluoroscopic studies. Eight weeks after the operations, the experimental animals were killed and anastomotic lumen diameters and vascularization of the anastomotic sites were evaluated by radiographic studies and histologic examination, respectively. RESULTS: Two dogs in the omentopexy group were able to resume regular feeding, whereas none of the dogs in the control group were able to tolerate solid food intake. Fluoroscopic studies found preserved motility patterns of the esophagus in the omentoesophagopexy group, while prestenotic dilatation and delayed food clearance through the anastomosis were observed in the control group. Histologically, neovascularization was observed at the anastomotic site in the omentoesophagopexy group in contrast to the marked degree of fibrosis displayed in the control group. CONCLUSIONS: Omentopexy may improve vascularization and decrease stricture formation after primary esophagoesophageal anastomosis.

Anastomosis, Surgical↗

PubMed2003

Sodium arsenite downregulates transcriptional activity of AP-1 and CRE binding proteins in IL-1beta-treated Caco-2 cells by increasing the expression of the transcriptional repressor CREMalpha.

In recent studies, sodium arsenite (SA) inhibited IL-6 production in cultured intestinal epithelial cells, at least in part by downregulating the activity of nuclear factor-kappaB (NF-kappaB). The influence of SA on the activity of other transcription factors regulating the interleukin-6 (IL-6) gene in enterocytes is not known. We tested the effect of SA on the activity of CCAAT/enhancer binding protein (C/EBP), activating protein-1 (AP-1), and CRE binding proteins in IL-1beta-treated Caco-2 cells. DNA binding activity was determined by electrophoretic mobility shift assay (EMSA) and transcriptional activity by transfecting cells with luciferase reporter plasmids containing promoter constructs with binding sites for the individual transcription factors. DNA binding activity for all three transcription factors was increased after treatment with SA or IL-1beta. In contrast, SA inhibited transcriptional activity of AP-1 and CRE binding proteins but not C/EBP. Additional experiments provided evidence that the inhibition of AP-1 and CRE mediated transcriptional activity was associated with, and probably caused by, increased expression of the transcriptional repressor cyclic AMP response element modulator (CREM)alpha. The present results are consistent with the concept that SA inhibits IL-6 production in stimulated enterocytes by downregulating the transcriptional activity of several, but not all, IL-6-related transcription factors. Because of the multiple important biological functions of IL-6 in the enterocyte and gut mucosa, methods to regulate enterocyte IL-6 production have significant clinical implications.

Arsenites↗

PubMed2003

Interleukin-6 induces thermotolerance in cultured Caco-2 cells independent of the heat shock response.

In recent studies, induction of the heat shock response increased IL-6 production in gut mucosa in vivo and in cultured Caco-2 cells in vitro. The heat shock response is associated with increased survival of cells exposed to otherwise lethal hyperthermia, so called thermotolerance, but the role of IL-6 in the induction of thermotolerance is not known. We tested the hypothesis that treatment of cultured Caco-2 cells with IL-6 results in the development of thermotolerance. Cells were treated with human recombinant IL-6 for 1h followed by 3 h recovery in cytokine-free medium whereafter cells were exposed to heat stress (48 degrees C for 2 h). In untreated cells, the heat stress resulted in an approximately 80% cell death. In cells treated with IL-6, cell viability after heat stress was significantly improved and was doubled at an IL-6 concentration of 20 ng/ml. Treatment of the cells with other cytokines (IL-4, IL-10, IL-1beta, or TNFalpha) did not induce thermotolerance, suggesting that the effect of IL-6 may be specific for this cytokine. The induction of thermotolerance by IL-6 was blocked by an IL-6 receptor antibody, suggesting that the development of thermotolerance was receptor-mediated. Treatment of cells with IL-6 did not induce an heat shock response as suggested by unaltered heat shock protein 70 and 90 levels and unaffected heat shock factor DNA binding activity. In addition, the IL-6-induced thermotolerance was not inhibited by quercetin. The present study provides the first evidence of IL-6-induced thermotolerance and suggests that this effect of IL-6 is independent of the heat shock response.

Animals↗

PubMed2003

Restorative proctocolectomy with ileal pouch-anal anastomosis in very young patients with refractory ulcerative colitis.

BACKGROUND/PURPOSE: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the standard surgical treatment for ulcerative colitis (UC). The purpose of the current study was to determine the outcome of very young patients (< or =10 years of age) with UC undergoing IPAA. METHODS: Between 1978 and 2002, 13 patients 10 years of age or younger underwent IPAA for management of UC at the authors' institution. Charts were reviewed for patient characteristics, and a standardized telephone interview was performed. RESULTS: Average age at diagnosis was 4.0 years (range, 1.0 to 8.4 years), and patients underwent IPAA at a mean of 6.8 years (range, 3.7 to 10.8 years). Pancolitis was present in 100%. The mean follow-up was 9.1 years (1.0 to 16.1 years), the average number of stools per day was 5 (3 to 8). All patients are continent while awake. Pouchitis was documented in 9 patients (75%). All patients or their parents rated the outcome of their procedures as "excellent." CONCLUSIONS: When compared with older children, very young patients with UC tend to have more frequent total colonic involvement and a greater frequency of pouchitis after IPAA. The functional outcome and patient/family satisfaction with the procedure endorse IPAA as an attractive procedure even in the very young population with UC.

Anal Canal↗

PubMed2003

Sepsis upregulates the gene expression of multiple ubiquitin ligases in skeletal muscle.

Muscle wasting during sepsis reflects increased expression and activity of the ubiquitin-proteasome proteolytic pathway and is at least in part mediated by glucocorticoids. The ubiquitination of proteins destined to be degraded by the proteasome is regulated by multiple enzymes, including ubiquitin ligases. We tested the hypothesis that sepsis upregulates the gene expression of the newly described ubiquitin ligases, MuRF1 and atrogin-1/MAFbx. Sepsis was induced in rats by cecal ligation and puncture. Control rats were sham-operated. In some experiments, rats were treated with the glucocorticoid receptor antagonist RU 38486 before induction of sepsis. At various time points after induction of sepsis, mRNA levels for MuRF1 and atrogin-1/MAFbx were determined in extensor digitorum longus muscles by real-time PCR. Sepsis resulted in a 10-16-fold increase in gene expression of the ubiquitin ligases studied here. These changes were much greater than those observed previously for another ubiquitin ligase, E3alpha, in muscle during sepsis. Treatment of rats with RU 38486 prevented the sepsis-induced increase in mRNA levels for MuRF1 and atrogin-1/MAFbx, suggesting that glucocorticoids participate in the upregulation of these genes in muscle during sepsis. The present results lend further support to the concept that the ubiquitin-proteasome pathway plays an important role in sepsis-induced muscle proteolysis and suggest that multiple ubiquitin ligases may participate in the development of muscle wasting during sepsis.

Animals↗

PubMed2003

IL-1beta stimulates IL-6 production in cultured skeletal muscle cells through activation of MAP kinase signaling pathway and NF-kappa B.

Recent studies suggest that the skeletal muscle may be a significant site of IL-6 production in various conditions, including exercise, inflammation, hypoperfusion, denervation, and local muscle injury. The mediators and molecular mechanisms regulating muscle IL-6 production are poorly understood. We tested the hypothesis that IL-6 production in muscle cells is regulated by IL-1beta and that mitogen-activated protein (MAP) kinase signaling and NF-kappaB activation are involved in IL-1beta-induced IL-6 production. Cultured C2C12 cells, a mouse skeletal muscle cell line, were treated with different concentrations (0.1-2 ng/ml) of IL-1beta in the absence or presence of the p38 MAP kinase inhibitor SB-208350 or the p42/44 inhibitor PD-98059. Protein and gene expression of IL-6 were determined by ELISA and real-time PCR, respectively. NF-kappaB DNA binding activity was determined by electrophoretic mobility shift assay and by transfecting myocytes with a luciferase reporter plasmid containing a promoter construct with multiple repeats of NF-kappaB binding site. Treatment of myotubes with IL-1beta resulted in a dose- and time-dependent increase of IL-6 production accompanied by an approximately 25-fold increase in IL-6 mRNA levels. IL-1beta stimulated NF-kappaB DNA binding activity and gene activation. SB-208350 and PD-98059 inhibited the increase in IL-6 production induced by IL-1beta. The present results support the concept that skeletal muscle is an important site of IL-6 production. In addition, the results suggest the IL-1beta regulates muscle IL-6 production at least in part by activating the MAP kinase pathway and NF-kappaB.

Animals↗

PubMed2003

Sentinel lymph node biopsy in early breast cancer: the first 100 cases performed in a teaching institute.

BACKGROUND: The histologic status of axillary lymph nodes is one of the most important prognostic factors in breast cancer and influences the management of these patients. Axillary lymph node dissection was traditionally performed in all patients to obtain this information but this procedure carries a considerable rate of complications. Recently, sentinel lymph node biopsy has emerged as an accurate and minimally invasive tool for predicting the axillary nodal status and has become the standard of care in selected patients with breast cancer. OBJECTIVE: To examine the accuracy of SLN biopsies performed by surgical residents during surgical resident training. METHODS: This prospective, randomized controlled study included 100 consecutive patients with clinically early breast cancer (T1-T2, N0, M0). Lymphatic mapping was performed using radiotracers, blue dye, or both. Formal axillary lymph node dissection completed the operations in all patients. All operations were performed by surgical residents under the supervision of senior surgeons. RESULTS: The overall rate of identification of sentinel lymph nodes was 92%. The accuracy of SLN biopsy in reflecting the axillary nodal status was 96% with a false negative rate of 5.7%. CONCLUSIONS: Sentinel lymph node biopsy is an accurate method for the evaluation and staging of regional lymph nodes in breast cancer patients. A dedicated instruction program for surgical residents may increase the standard of care and lead to highly trained surgeons in the management of early breast cancer.

Adult↗