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R J Goulet

Publications and source records attributed to R J Goulet.

At least 19 recordsLinked to original sources
PubMed2006

Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion.

Chemokine receptor CXCR4 and its ligand CXCL12 are suggested to be involved in migration, invasion and metastasis of breast cancer cells. Mutation of the tumor suppressor gene p53 in breast cancer is associated with metastasis and aggressive clinical phenotype. In this report, we demonstrate that wild type but not the dominant-negative mutant (V143A) or cancer-specific mutants (R175H or R280K) of p53 repress CXCR4 expression. Recently described cancer-specific p53 isoform, Delta133p53, also failed to repress CXCR4 promoter activity. Short-interfering RNA-mediated depletion of p53 increased endogenous CXCR4 expression in MCF-7 breast cancer cells that contain wild-type p53. Basal CXCR4 promoter activity in HCT116 colon carcinoma cells deleted of p53 [HCT116(p53KO)] was 10-fold higher compared to that in parental HCT116 cells with functional wild-type p53. Deletion analysis of CXCR4 promoter identified a seven-base pair p53-repressor element homologous to cyclic AMP/AP-1 response (CRE/AP-1) element. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed binding of ATF-1 and cJun to the CRE/AP-1 element. The p53 rescue drug PRIMA-1 reduced CXCR4 mRNA and cell surface expression in MDA-MB-231 cells, which express R280K mutant p53. CP-31398, another p53 rescue drug, similarly reduced cell surface levels of CXCR4. PRIMA-1-mediated decrease in CXCR4 expression correlated with reduced invasion of MDA-MB-231 cells through matrigel. These results suggest a mechanism for elevated CXCR4 expression and metastasis of breast cancers with p53 mutations or isoform expression. We propose that p53 rescue drugs either alone or in combination with chemotherapeutic drugs may be effective in reducing CXCR4-mediated metastasis.

Breast Neoplasms↗
PubMed2001

Biopsy of sentinel lymph nodes guided by lymphoscintigraphic mapping in patients with breast cancer.

OBJECTIVE: The purpose of this study was to determine the technical success rate of sentinel node biopsy with lymphoscintigraphy in women with breast cancer and the frequency with which sentinel node biopsy obviated axillary dissection. Factors affecting the success rate of sentinel node biopsy and lymphoscintigraphy were also evaluated. MATERIALS AND METHODS: Retrospective review revealed 119 women with breast cancer who underwent lymphoscintigraphy and sentinel node biopsy at our institution during the study period. A planned axillary dissection was performed in 13 of the first 16 patients; otherwise, axillary dissection was only performed if tumor was present in sentinel nodes or if the sentinel node biopsy was unsuccessful. RESULTS: Sentinel node biopsy was successful in 96% of patients, and sentinel node metastases were found in 20%. In 78% of patients, a negative sentinel node biopsy obviated axillary dissection. Prior excisional biopsy was not associated with a failed sentinel node biopsy (p = 0.750) but was associated with failed lymphoscintigraphy (p = 0.01). Successful lymphoscintigraphy was associated with successful sentinel node biopsy (p < 0.0001). No association was found between the histology or size of the tumor and a failed sentinel node biopsy (p = 0.46 and p = 0.1, respectively) or failed lymphoscintigraphy (p = 0.36 and p = 0.47, respectively). CONCLUSION: Sentinel node biopsy guided by lymphoscintigraphy, intraoperative gamma probe, and isosulfan blue dye is an effective alternative to axillary dissection in patients with breast cancer. Lymphoscintigraphy improved the success rate of sentinel node biopsy. Large tumor size or prior excisional biopsy should not prevent patients from having sentinel node biopsy.

Adult↗
PubMed2000

Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide.

The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-kappaB remains sequestered in an inactive state by cytoplasmic inhibitor-of-kappaB (IkappaB) proteins. NF-kappaB translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines. We and others have shown previously that NF-kappaB is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-kappaB leads to overexpression of the anti-apoptotic genes c-inhibitor of apoptosis 2 (c-IAP2) and manganese superoxide dismutase (Mn-SOD) in breast cancer cells. Furthermore, expression of the anti-apoptotic tumor necrosis factor receptor associated factor 1 (TRAF1) and defender-against cell death (DAD-1) is regulated by NF-kappaB in certain breast cancer cells. We also demonstrate that NF-kappaB-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modified to overexpress IkappaBalpha required lower concentrations of paclitaxel to arrest at the G2/M phase of the cell cycle and undergo apoptosis when compared to parental cells. The effect of NF-kappaB on paclitaxel-sensitivity appears to be specific to cancer cells because normal fibroblasts derived from embryos lacking p65 subunit of NF-kappaB and wild type littermate embryos were insensitive to paclitaxel-induced G2/M cell cycle arrest. Parthenolide, an active ingredient of herbal remedies such as feverfew (tanacetum parthenium), mimicked the effects of IkappaBalpha by inhibiting NF-kappaB DNA binding activity and Mn-SOD expression, and increasing paclitaxel-induced apoptosis of breast cancer cells. These results suggest that active ingredients of herbs with anti-inflammatory properties may be useful in increasing the sensitivity of cancers with constitutively active NF-kappaB to chemotherapeutic drugs. Oncogene (2000) 19, 4159 - 4169

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

The orphan receptor COUP-TFII regulates G2/M progression of breast cancer cells by modulating the expression/activity of p21(WAF1/CIP1), cyclin D1, and cdk2.

The orphan receptors COUP-TFI and COUP-TFII play an important role in development and differentiation by activating specific genes and by modulating the activity of nuclear receptors including estrogen receptor alpha (ERalpha) and retinoic acid receptors (RARs). Previously, it was demonstrated that the expression and activity of ERalpha and RARs are lost or impaired in anti-estrogen-resistant breast cancers. Here we show that, similar to ERalpha and RARs, the expression of COUP-TFII but not COUP-TFI is reduced in approximately 30% of breast cancer cell lines. Introduction of COUP-TFII to MDA-MB-435 cells resulted in reduced growth and plating efficiency. Interestingly, COUP-TFII increased the expression of cyclin D1 and p21(WAF1/CIP1) in MDA-MB-435 cells. Although parental and COUP-TFII-transduced cells progressed through the G1-S phase at a similar rate, progression of COUP-TFII cells through the G2/M transition phase was delayed. The activity of cdk2 required for G2/M progression was reduced in COUP-TFII cells compared to parental cells. This property of COUP-TFII is distinct from that of ERalpha and RARs, which usually modulate the G1 phase of breast cancer cells. Furthermore, these results reveal an important physiological function of COUP-TFII, which correlates with its ability to induce gene expression rather than modulation of nuclear receptor activity.

Breast Neoplasms↗
PubMed1999

Negative regulation of transactivation function but not DNA binding of NF-kappaB and AP-1 by IkappaBbeta1 in breast cancer cells.

The transcription factor NF-kappaB regulates the expression of genes involved in cancer cell invasion, metastasis, angiogenesis, and resistance to chemotherapy. In normal cells NF-kappaB is maintained in the cytoplasm by protein-protein interaction with inhibitor IkappaBs. In contrast, in cancer cells a substantial amount of NF-kappaB is in the nucleus and constitutively activates target genes. To understand the mechanisms of constitutive NF-kappaB activation, we have analyzed the function of IkappaBalpha and IkappaBbeta in breast cancer cells. In most cases, constitutive NF-kappaB DNA binding correlated with reduced levels of either IkappaBalpha or IkappaBbeta isoforms. Overexpression of IkappaBalpha but not IkappaBbeta1 resulted in reduced constitutive DNA binding of NF-kappaB in MDA-MB-231 cells. Unexpectedly, IkappaBbeta1 overexpression moderately increased 12-O-tetradecanoylphorbol-13-acetate- and interleukin-1-inducible NF-kappaB DNA binding. 12-O-Tetradecanoylphorbol-13-acetate- and interleukin-1-induced transactivation by NF-kappaB, however, was lower in IkappaBbeta1-overexpressing cells. Mutants of IkappaBbeta1 lacking the C-terminal casein kinase II phosphorylation sites, which form a stable complex with DNA bound NF-kappaB without inhibiting its transactivation in other cell types, repressed the transactivation by NF-kappaB in MDA-MB-231 cells. Consistent with the results of transient transfections, the expression of urokinase plasminogen activator, an NF-kappaB target gene, was reduced in IkappaBbeta1-overexpressing cells. These results suggest that depending on the cell type, IkappaBbeta1 represses the expression of NF-kappaB-regulated genes by inhibiting either DNA binding or transactivation function of NF-kappaB.

Breast Neoplasms↗
PubMed1997

An analysis of perioperative cholangiography in one thousand laparoscopic cholecystectomies.

BACKGROUND: We undertook this retrospective study to ascertain the proper role of perioperative cholangiography in the management of 1002 patients undergoing laparoscopic cholecystectomy for symptomatic cholelithiasis. METHODS: Nine hundred forty-one patients were categorized as being at high or low risk for choledocholithiasis according to the presence or absence of jaundice, pancreatitis, elevated bilirubin, alkaline phosphatase, serum glutamic-oxaloacetic transaminase, or radiographic evidence of common bile duct stones (CBDSs). RESULTS: Intraoperative cholangiography (IOCG) and preoperative endoscopic retrograde cholangiopancreatography (ERCP) were equivalent in the detection of CBDSs, and laparoscopic common bile duct exploration (CBDE) was successful in 12 of the 21 patients (57%) in whom it was attempted. The ducts of the other 52 patients with CBDSs were successfully cleared by preoperative or postoperative ERCP. CONCLUSIONS: Laparoscopic IOCG is successful in detecting CBDS in high-risk patients and half of these ducts can be cleared laparoscopically. The incidence of CBDS in low-risk patients is 1.7%, a risk that does not warrant routine cholangiography. These data suggest ERCP should be reserved for those at-risk individuals in whom IOCG or laparoscopic duct clearance has been unsuccessful.

Alkaline Phosphatase↗
PubMed1997

Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth.

Breast cancers often progress from a hormone-dependent, nonmetastatic, antiestrogen-sensitive phenotype to a hormone-independent, antiestrogen- and chemotherapy-resistant phenotype with highly invasive and metastatic growth properties. This progression is usually accompanied by altered function of the estrogen receptor (ER) or outgrowth of ER-negative cancer cells. To understand the molecular mechanisms responsible for metastatic growth of ER-negative breast cancers, the activities of the transcription factor NF-kappaB (which modulates the expression of genes involved in cell proliferation, differentiation, apoptosis, and metastasis) were compared in ER-positive (MCF-7 and T47-D) and ER-negative (MDA-MB-231 and MDA-MB-435) human breast cancer cell lines. NF-kappaB, which is usually maintained in an inactive state by protein-protein interaction with inhibitor IkappaBs, was found to be constitutively active in ER-negative breast cancer cell lines. Constitutive DNA binding of NF-kappaB was also observed with extracts from ER-negative, poorly differentiated primary breast tumors. Progression of the rat mammary carcinoma cell line RM22-F5 from an ER-positive, nonmalignant phenotype (E phenotype) to an ER-negative, malignant phenotype (F phenotype) was also accompanied by constitutive activation of NF-kappaB. Analysis of individual subunits of NF-kappaB revealed that all ER-negative cell lines, including RM22-F5 cells of F phenotype, contain a unique 37-kDa protein which is antigenically related to the RelA subunit. Cell-type-specific differences in IkappaB alpha, -beta, and -gamma were also observed. In transient-transfection experiments, constitutive activity of an NF-kappaB-dependent promoter was observed in MDA-MB-231 and RM22-F5 cells of F phenotype, and this activity was efficiently repressed by cotransfected ER. Since ER inhibits the constitutive as well as inducible activation function of NF-kappaB in a dose-dependent manner, we propose that breast cancers that lack functional ER overexpress NF-kappaB-regulated genes. Furthermore, since recent data indicate that NF-kappaB protects cells from tumor necrosis factor alpha-, ionizing radiation-, and chemotherapeutic agent daunorubicin-mediated apoptosis, our results provide an explanation for chemotherapeutic resistance in ER-negative breast cancers.

Animals↗
PubMed1997

Factors influencing effect of mammography screening in a university workplace.

The purpose of this study was to examine the relationship between theoretically identified variables and participation in mammography screening in a university workplace. A sample of 1093 women 50 and over returned a questionnaire following the offer of a free workplace breast cancer screening. Anderson's Behavioral Model of Health Services Use identified factors predisposing and enabling women to have mammograms. Predisposing variables included attitudes and experience related to mammography. Enabling variables included income, willingness to pay for mammography, health insurance coverage, and regular source of health care. Comparisons were made among: (i) those who were screened in the workplace, (ii) those who were screened elsewhere, and (iii) those who were not screened. Differences in perceived barriers, perceived benefits, practice of breast self-examination (BSE), and education surfaced. Results indicated, among other things, that women who were older, had no more than 12 years of education, had a family member with breast cancer, and were proficient with breast self-examination were more likely to have participated in the university work-site screening.

Breast Neoplasms↗
PubMed1996

Conversion of laparoscopic to open cholecystectomy. An analysis of risk factors.

BACKGROUND: Identifying patients who are at risk for conversion from laparoscopic (LC) to open cholecystectomy (OC) has proven to be difficult. The purpose of this review was to identify factors that may be predictive of cases which will require conversion to laparotomy for completion of cholecystectomy. METHODS: We reviewed 581 LCs initiated between July 1990 and August 1993 at a university medical center and recorded reasons for conversion to OC. Statistical analysis was then performed to identify factors predictive of increased risk for conversion. RESULTS: Of the 581 LC initiated, 45 (8%) required OC for completion. Reasons for conversion included technical and mandatory reasons and equipment failure. By multivariate analysis, statistically significant risk factors for conversion included increasing age, acute cholecystitis, a history of previous upper abdominal surgery, and being a patient at the Veterans Affairs Medical Center (VAMC). Factors not increasing risk of conversion included gender and operating surgeon. CONCLUSIONS: We conclude that no factor alone can reliably predict unsuccessful LC, but that combinations of increasing age, acute cholecystitis, previous upper abdominal surgery, and VAMC patient result in high conversion rates. Patients with the defined risk factors may be counseled on the increased likelihood of conversion. However, LC can be safely initiated for gallbladder removal with no excess morbidity or mortality should conversion be required.

Adolescent↗
PubMed1995

Classification and treatment of local septic complications in acute pancreatitis.

BACKGROUND: An international symposium on acute pancreatitis recently developed a clinical classification system for severe acute pancreatitis that classifies all local septic complications into three groups: infected necrosis (IN), sterile necrosis (SN), and pancreatic abscess (PA). Despite the appeal of having three distinct, well-defined labels for this complex process, the clinical utility of this schema has yet to be determined. The purpose of this study was to investigate the prognostic and therapeutic utility of applying this clinical classification system to a large group of surgical patients with local septic complication from acute pancreatitis. PATIENTS AND METHODS: We reviewed the cases of 62 patients with complicated pancreatitis, classifying them into IN (n = 20), SN (n = 14), or PA (n = 28) groups. Ranson's score, APACHE II score, and computed tomography grading were calculated within the first 48 hours of admission. Information on patient demographics, etiology of pancreatitis, operative procedures, timing of intervention, bacteriology, blood loss, intensive care unit days, ventilator days, and morbidity and mortality were also accrued and analyzed. RESULTS: Despite similar demographics and etiology of pancreatitis, patients with necrosis, both IN and SN, were more critically ill than were patients with PA (APACHE II score > 15, 21% versus 0%, respectively), required earlier operative intervention (mean 14 days versus 29 days, P = 0.02), required necrosectomy with drainage (65% versus 4%, P < 0.001) rather than simple drainage (3% versus 86%, P < 0.001), more reoperations (2.3 versus 1.1, P < 0.05), and had a significantly higher mortality rate (35% versus 4%, P < 0.05). In addition, patients with IN required significantly more hospital days, ventilator days, and blood transfusions than either patients with SN or PA (P < 0.05). CONCLUSIONS: We conclude that this classification system allows for the stratification of patients into three distinct groups--infected necrosis, sterile necrosis, and pancreatic abscess--and has both therapeutic and prognostic usefulness.

Abscess↗
PubMed1993

Unique pancreatic carcinoma cDNA found via subtracted libraries with limited normal tissue and tumor from the same patient.

We have approached the problem of isolating clones unique to specific malignancies such as T-cell acute lymphoblastic leukemia (ALL) and pancreatic adenocarcinoma by using subtractive hybridization techniques. Our initial studies involved using normal donor tissue (i.e., normal blood donors for ALL and cadaver renal transplant donors for normal pancreatic tissue) and cultured malignant cell lines. It occurred to us that normal pancreatic tissue from the same patient source as that of the malignant tissue might subtract out normal sequences more readily and enrich clones unique to pancreatic adenocarcinoma because of patient/donor identity. Using such a method meant that the amounts of tissue for overcoming this obstacle. We constructed independent UNI-ZAP-XR cDNA libraries (normal and malignant) and used them to amplify either the normal or malignant cDNA prior to subtractive hybridization. We then obtained rescued single stranded cDNA from the malignant ZAP library. The RNA which was not hybridized was isolated. The process was repeated and a double subtraction was effected. The residual non-hybridized RNA was used as a template for first and second strand synthesis. After the EcoRI adaptors were ligated to the double stranded cDNA it was cloned into Lambda ZAP II arms to form a double subtracted malignant cDNA library. A subtracted probe was prepared from the double subtracted cDNA library. Single stranded cDNA was rescued, double stranded plasmid was made, the plasmid DNA was digested with EcoRI, the digested DNA was run on a 1% SeaPlaque gel, and the insert cDNA was recovered using Ultra-Free MC and Ultra-Free Probind filters. The subtracted malignant cDNA library was probed with the subtracted probe and with normal cDNA (obtained from the normal ZAP library) and those plaques which were positive per the subtracted probe and negative per the normal cDNA were isolated; their cDNA inserts are being further characterized.

Actins↗
PubMed1993

Vascular injuries during pancreatobiliary surgery.

Fourteen cases of vascular injury during pancreatobiliary surgery have been treated at our institution. The patients' mean age was 49 years, and nine were males. Six operations were performed for chronic pancreatitis, six for cancer, and two for an inflammatory process. Operations included 11 pancreatic resections and one laparoscopic cholecystectomy, one sphincteroplasty, and one pseudocyst drainage. Vessels injured included the portal vein (7), superior mesenteric vein (6), superior mesenteric artery (3), hepatic arteries (4), splenic vein (3). Six patients experienced more than one vascular injury. In all but one case, the injury was recognized and repaired during the initial operation. Primary repair was possible in seven cases. Six cases utilized autogenous tissue for repair. The one unrecognized injury was a right hepatic artery ligation, and a delayed repair was not possible. Follow-up demonstrated two occlusions, one following a portal vein repair without clinical sequela and a superior mesenteric artery repair which resulted in a small bowel stricture. The one unrecognized hepatic artery injury resulted in necrosis of the proximal common hepatic duct. Vascular injury following pancreatobiliary injury tends to occur in the presence of pancreatitis or cancer with its associated dense adhesions and inflammatory process. The variable anatomy of this area contributes to vascular injuries. Immediate recognition of the injury and repair appears to yield excellent results.

Adolescent↗
PubMed1992

Chronic constipation with encopresis persisting beyond 15 years of age.

Childhood constipation with encopresis is a common malady. Previous reports suggest that essentially all patients either respond to standard treatments or have spontaneous recovery before 16 years of age. In this paper, we describe the results of anorectal function studies and treatment outcome in four patients in whom constipation and encopresis persisted beyond 15 years of age. Abnormalities in the ability to defecate water-filled balloons, in external sphincter relaxation with straining, in rectal sensation and development of the urge to defecate, and in maximum anal resting pressure were seen in some or all of these patients. In addition, two patients had impaired voluntary squeeze strength. Two patients responded to standard therapy; a colostomy was needed in one; and one failed therapy and has become a recluse.

Adolescent↗
PubMed1991

Duodenal webs in the adult.

Duodenal webs and diaphragms in the adult are congenital in origin and are rare. They are explained embryologically by the process of duodenal epithelial plugging and subsequent revacuolization. The symptoms may be insidious and appear late in life and consist of partial gastric outlet complaints. Two thirds of the patients will have other upper GI problems, some of which may be related to the antral distension and stasis produced by the web. Peptic ulcer disease is common but may resolve when the web is excised. Diagnosis can be made by contrast duodenography but is more definitive with endoscopy. Therapy should be directed at web excision if possible. Associated ulcer disease should be selectively approached. The results of therapy in the reported cases have been successful when the web is surgically excised without additional ulcer procedures.

Adult↗
PubMed1990

Ruptured mycotic pseudoaneurysm of the gastroduodenal artery presenting with hemoperitoneum and subcapsular liver hematoma.

We report a case of a patient with mycotic pseudoaneurysm of the gastroduodenal artery who presented with hemoperitoneum and subcapsular hematoma of the liver. The diagnosis was established with contrasted abdominal CT scanning. Visceral angiography was not needed. Prompt recognition and surgical intervention led to a favorable outcome. Pseudoaneurysm of visceral vessels is an uncommon disease process, and to our knowledge, this is the first reported case that has presented with free blood in the peritoneal cavity and beneath the liver capsule. This case may also represent a rare complication of therapeutic ERCP procedures. Mycotic aneurysm or pseudoaneurysm of visceral vessels may develop from bacteremia and its dissection or rupture should be suspected in patients presenting with sepsis and abdominal pain.

Aged↗
PubMed1990

Hepatic resection for disseminated germ cell carcinoma.

Improvements in operative technique and perioperative management have expanded the application of hepatic resection for metastatic cancer. Although a policy of aggressive surgical resection of residual pulmonary and retroperitoneal disease following chemotherapy and normalization of serum tumor markers has been adopted for disseminated germ cell carcinoma, resection of residual hepatic disease in these cases has not been addressed. This report concerns a series of prospectively randomized patients who received systemic cisplatin-based chemotherapy for testis cancer during the past 13 years. Twenty-eight patients underwent resection of residual hepatic disease after serologic remission. Most (23 of 28 patients) of these procedures were performed concomitantly with other cytoreductive procedures. There were no operative deaths, although 28% of the patients developed complications. The 2-year survival rate was 54%, with an average follow-up of 34 months. Patients were stratified into three groups based on the most aggressive histology noted in the resected specimen. Survival is predicted by this histologic classification system. Hepatic resection can be performed safely and is an important component in the treatment of disseminated testicular carcinoma.

Adolescent↗
PubMed1990

Percutaneous cholecystolithotomy with endoscopic lithotripsy by using a pulsed-dye laser: preliminary experience.

Percutaneous cholecystolithotomy with endoscopically directed lithotripsy with a pulsed-dye laser was performed in eight patients for the treatment of symptomatic gallstones. All patients had stones that were not amenable to therapy by less invasive techniques. During the first stage of a two-stage procedure, a cholecystostomy catheter was placed percutaneously. During the second stage, performed at least 10 days later, the stones were fragmented with a laser and removed. Fragmentation of the stones was successful in all patients. In six patients, the gallbladder was completely cleared of stones, as assessed with endoscopy and cholecystography. In two patients, residual fragments remained in the gallbladder. No laser-related complications occurred. This preliminary experience suggests that the pulsed-dye laser is safe and effective in endoscopically directed lithotripsy of gallbladder stones.

Adult↗