PubMed Health⌕ Search

Biomedical subjects

Robert Gryfe

Publications and source records attributed to Robert Gryfe.

13 recordsLinked to original sources
PubMed2007

Transcriptional cooperation between the transforming growth factor-beta and Wnt pathways in mammary and intestinal tumorigenesis.

Transforming growth factor-beta (TGF-beta) and Wnt ligands function in numerous developmental processes, and alterations of both signaling pathways are associated with common pathologic conditions, including cancer. To obtain insight into the extent of interdependence of the two signaling cascades in regulating biological responses, we used an oligonucleotide microarray approach to identify Wnt and TGF-beta target genes using normal murine mammary gland epithelial cells as a model. Combination treatment of TGF-beta and Wnt revealed a novel transcriptional program that could not have been predicted from single ligand treatments and included a cohort of genes that were cooperatively induced by both pathways. These included both novel and known components or modulators of TGF-beta and Wnt pathways, suggesting that mutual feedback is a feature of the coordinated activities of the ligands. The majority of the cooperative targets display increased expression in tumors derived from either Min (many intestinal neoplasia) or mouse mammary tumor virus (MMTV)-Wnt1 mice, two models of Wnt-induced tumors, with nine of these genes (Ankrd1, Ccnd1, Ctgf, Gpc1, Hs6st2, IL11, Inhba, Mmp14, and Robo1) showing increases in both. Reduction of TGF-beta signaling by expression of a dominant-negative TGF-beta type II receptor in bigenic MMTV-Wnt1/DNIIR mice increased mammary tumor latency and was correlated with a decrease in expression of Gpc1, Inhba, and Robo1, three of the TGF-beta/Wnt cooperative targets. Our results indicate that the TGF-beta and Wnt/beta-catenin pathways are firmly intertwined and generate a unique gene expression pattern that can contribute to tumor progression.

Adenoma↗
PubMed2006

Clinical implications of our advancing knowledge of colorectal cancer genetics: inherited syndromes, prognosis, prevention, screening and therapeutics.

Recent genetic advances in our knowledge of colorectal cancer genetics are beginning to pay translational dividends in the management of this common clinical problem. We are now able to accurately screen and counsel individuals at risk of rare inherited cancer syndromes. We have recently introduced two of what are sure to be numerous biologic-based therapies, and have shown that colorectal neoplasia risk can be modestly reduced by various chemopreventative agents. Finally, our advancing knowledge has led to significant inroads into understanding what genetic alterations define prognosis and predict response to specific chemotherapeutic agents, and we are beginning to explore the utility of this knowledge in mass genetic-based clinical screening efforts. Enthusiasm must be tempered, however, by the extraordinary cost that often accompanies relatively modest gains. Finally, although genetic-based therapy often receives the greatest attention, molecular genetics, will likely have the greatest cost-effective impact in primary prevention and early diagnosis.

Adenomatous Polyposis Coli↗
PubMed2005

Prevalence of male and female sexual dysfunction is high following surgery for rectal cancer.

OBJECTIVE: To measure sexual function and quality of life (QOL) after rectal cancer treatment. SUMMARY BACKGROUND DATA: Previous studies on sexual function after rectal cancer treatment have focused on males and have not used validated instruments. METHODS: Patients undergoing curative rectal cancer surgery from 1980 to 2003 were administered a questionnaire, including the Female Sexual Function Index (FSFI) or International Index of Erectile Function (IIEF), and the EORTC QLQ-C30/CR-38. Multiple logistic regression was used to test associations of clinical factors with outcomes. RESULTS: Eighty-one women (81.0%) and 99 men (80.5%) returned the questionnaire; 32% of women and 50% of men are sexually active, compared with 61% and 91% preoperatively (P < 0.04); 29% of women and 45% of men reported that "surgery made their sexual lives worse." Mean (SD) FSFI and IIEF scores were 17.5 (11.9) and 29.3 (22.8). Specific sexual problems in women were libido 41%, arousal 29%, lubrication 56%, orgasm 35%, and dyspareunia 46%, and in men libido 47%, impotence 32%, partial impotence 52%, orgasm 41%, and ejaculation 43%. Both genders reported a negative body image. Patients seldom remembered discussing sexual risks preoperatively and seldom were treated for dysfunction. Current age (P < 0.001), surgical procedure (P = 0.003), and preoperative sexual activity (P = 0.001) were independently associated with current sexual activity. Gender (male, P = 0.014), surgical procedure (P = 0.005), and radiation therapy (P = 0.0001) were independently associated with the outcome "surgery made sexual life worse." Global QOL scores were high. CONCLUSIONS: Sexual problems after surgery for rectal cancer are common, multifactorial, inadequately discussed, and untreated. Therefore, sexual dysfunction should be discussed with rectal cancer patients, and efforts to prevent and treat it should be increased.

Aged↗
PubMed2004

Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk.

The MutY human homologue (MYH) gene encodes a member of the base excision repair pathway that is involved in repairing oxidative damage to DNA. Two germline MYH gene mutations that result in Myh proteins containing amino acid substitutions Y165C and G382D (hereafter called the Y165C and G382D mutations) are associated with adenomatous poly-posis and colorectal cancer among patients from several European poly-posis registries. We used a population-based series of 1238 colorectal cancer patients and 1255 healthy control subjects from Ontario, Canada, to examine the risk of colorectal cancer among biallelic and monoallelic germline MYH Y165C and G382D mutation carriers. The entire MYH gene coding region was screened in all MYH Y165C and G382D mutation carriers. Compared with noncarriers, biallelic and monoallelic germline MYH gene mutation carriers had an increased risk of colorectal cancer and were more likely to have first-or second-degree relatives with colorectal cancer (relative risk = 1.54, 95% confidence interval = 1.10 to 2.16). The increased risk of colorectal cancer in biallelic and monoallelic MYH gene mutation carriers was not consistently associated with the development of multiple adenomatous polyps. Loss of heterozygosity in at least one of four loci in MYH was detected in eight (47%) of 17 colorectal tumors from monoallelic MYH gene mutation carriers but in only two (20%) of 10 colorectal tumors from biallelic MYH gene mutation carriers. These two MYH gene mutations may account for a substantial fraction of hereditary colorectal cancer.

Adenomatous Polyposis Coli↗
PubMed2004

Microsatellite instability as a prognostic factor in resected colorectal cancer liver metastases.

BACKGROUND: Two distinct genetic mutational pathways characterized by either chromosomal instability or high-frequency microsatellite instability (MSI-H) are currently recognized in the pathogenesis of colorectal cancer (CRC). Recently, it has been shown that patients with primary CRC that displays MSI-H have a significant, stage-independent, multivariate survival advantage. Untreated CRC hepatic metastases are incurable and are associated with a median survival of 4 to 12 months. Conversely, surgical resection in selected patients results in a 20% to 50% cure rate. The aim of this study was to investigate the prognostic importance of MSI-H in patients undergoing resection of hepatic CRC metastases. METHODS: DNA was extracted from paraffin-embedded, resected metastatic CRC liver lesions and corresponding normal liver parenchyma from 190 patients. MSI-H status was determined by polymerase chain reaction-based evaluation of the noncoding mononucleotide repeats BAT-25 and BAT-26. RESULTS: MSI was detected in tumors from 5 (2.7%) of the 190 CRC patients. All MSI-H tumors were in patients with node-positive CRC primary tumors. The median survival after hepatic resection of MSI-H and non-MSI-H tumors was 67 and 61 months, respectively (P = .9). CONCLUSIONS: These data suggest that MSI-H is not a common feature in resected CRC liver metastases and do not suggest a role for MSI in stratifying good versus poor prognosis in these patients.

Aged↗
PubMed2004

Chromosome 7q31 allelic imbalance and somatic mutations of RAY1/ST7 gene in colorectal cancer.

ST7 is a putative tumor suppressor gene on chromosome 7q31. However, the role of ST7 as a tumor suppressor is uncertain as somatic mutations have been difficult to demonstrate. In order to investigate the genetic role of RAY1/ST7 in tumorigenesis, we have screened 135 colorectal cancers for loss of heterozygosity (LOH) at chromosome 7q31. The entire RAY1/ST7 gene, including intron/exon boundaries and alternate 5' and 3' sequences of 15/124 (12%) informative cancers with LOH were characterized. No somatic mutations of the RAY1/ST7 gene were observed. Our results do not support a role for RAY1/ST7 as a colorectal cancer tumor suppressor gene.

Adenocarcinoma↗
PubMed2004

Prognostic factors in resected pancreatic adenocarcinoma: analysis of actual 5-year survivors.

BACKGROUND: Pancreatic cancer is a rapidly fatal disease with very few 5-year survivors even after aggressive surgical treatment. Our objective was to determine the actual 5-year survival rate of patients with pancreatic adenocarcinoma who underwent a resection with curative intent in 5 teaching hospitals within the University of Toronto system. We then sought to determine clinical and histopathologic features of 5-year survivors to determine factors associated with a favorable prognosis. STUDY DESIGN: A retrospective chart review was performed using surgeon and hospital databases to identify patients who had a surgical resection for pancreatic adenocarcinoma between January 1, 1988, and December 31, 1996. RESULTS: One hundred twenty-three patients who had a resection and a pathologic diagnosis of pancreatic adenocarcinoma with complete followup were identified from seven surgical practices. Mean survival (+/- standard error) in this series was 31.7 +/- 3.5 months (median 13.6 months). There were 18 5-year survivors (14.6%), including 5 patients (4.1%) who survived longer than 10 years. The survivors included 13 patients who had undergone a Whipple resection, 4 who had undergone a distal pancreatectomy, and 1 who had undergone a total pancreatectomy. Tumor size, lack of jaundice at presentation, negative nodal disease, low tumor grade, and a low tumor stage were all significant predictors of survival in univariate analysis (all p < 0.05). Only tumor stage (hazard ratio [95% confidence interval]: stage IIA 1.5 [0.8 to 2.8], stage IIB 2.6 [1.4 to 4.7], stage III 1.8 [0.8 to 4.3]) and tumor grade (hazard ratio [95% confidence interval]: moderately differentiated 1.6 [0.9 to 2.9], and poorly differentiated 3.1 [1.6 to 6.2]) were independently associated with survival differences in a multivariate Cox proportional hazards model. CONCLUSIONS: We conclude that longterm survival from pancreatic adenocarcinoma is possible if the disease is identified in its early stages. These and other similar data should provide further stimulus for the development and evaluation of novel screening strategies to improve early detection of this disease.

Adenocarcinoma↗
PubMed2004

Robotic-assisted laparoscopic colorectal surgery.

Robotic assistance provides a number of potential benefits for laparoscopic surgery by addressing several inherent limitations. However, its utility in colorectal surgery has not been determined. This is a report of our initial experience with robot-assisted colon resections. We prospectively followed 10 patients who underwent robotic-assisted laparoscopic colorectal surgery using Zeus Microwrist System. Surgical outcomes were compared with those of 10 consecutive patients who underwent laparoscopic colorectal surgery in the same institution for similar indications prior to the start of robotic-assisted surgery. Six patients in each group had surgery for colorectal malignancy. All 10 robotic-assisted procedures were completed with no intraoperative complications, conversions, or mortality. The average blood loss was less than 150 mL in all cases. Morbidity and hospital stay were comparable to those for the patients undergoing standard laparoscopic procedures. Robotic surgery was associated with a significant increase in operative time of almost 1 hour. This time was reduced significantly after the first 4 cases. The value of robotic assistance in colorectal surgery needs to be further evaluated in a larger comparative study.

Aged↗
PubMed2003

Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer.

BACKGROUND: Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer. METHODS: Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers. RESULTS: Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 [95 percent confidence interval, 0.14 to 0.72]; P=0.004). Among patients who received adjuvant chemotherapy, high-frequency microsatellite instability was not correlated with increased overall survival (hazard ratio for death, 1.07 [95 percent confidence interval, 0.62 to 1.86]; P=0.80). The benefit of treatment differed significantly according to the microsatellite-instability status (P=0.01). Adjuvant chemotherapy improved overall survival among patients with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (hazard ratio for death, 0.72 [95 percent confidence interval, 0.53 to 0.99]; P=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high-frequency microsatellite instability. CONCLUSIONS: Fluorouracil-based adjuvant chemotherapy benefited patients with stage II or stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability but not those with tumors exhibiting high-frequency microsatellite instability.

Analysis of Variance↗
PubMed2003

Heterozygosity for the BLM(Ash) mutation and cancer risk.

Bloom syndrome is an autosomal recessive disorder whose characteristics include an increased risk for many types of cancers. In contrast to the homozygous mutations of Bloom syndrome, heterozygous carriers of BLM mutations may be at increased risk for developing colorectal cancer. We have screened 2,333 Jewish individuals, including 497 individuals with colorectal cancer, 125 with adenomatous polyps, 767 with noncolorectal cancers and 944 controls for the truncating BLM(Ash) founder mutation. The BLM(Ash) mutation was carried by 0.80% of individuals with colorectal neoplasia, 0.87% of those with any type of cancer and 0.85% of controls. In addition to case-control data, we found no evidence to support a significant relationship between increased cancer risk and heterozygous BLM(Ash) mutations with respect to age of cancer diagnosis, tumor multiplicity or family cancer history.

Aged↗
PubMed2002

Mutation profiling of mismatch repair-deficient colorectal cncers using an in silico genome scan to identify coding microsatellites.

Human colorectal, endometrial, and gastric cancers with defective DNA mismatch repair (MMR) have microsatellite instability, a unique molecular alteration characterized by widespread frameshift mutations of repetitive DNA sequences. We developed "Kangaroo," a bioinformatics program for searches in nucleotide and protein sequence databases, and performed an in silico genome scan for DNA coding microsatellites that may have novel mutations in MMR-deficient cancers. Examination of 29 previously untested coding polyadenines revealed widespread mutations in MMR-deficient colorectal cancers, with the highest frequencies in ERCC5, CASP8AP2, p72, RAD50, CDC25, RECQL1, CBF2, RACK7, GRK4, and DNAPK (range, 10-33%). This algorithm allows comprehensive mutation profiling of MMR-deficient cancers, an important step in understanding the pathogenesis of these neoplasms.

Algorithms↗