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Biomedical subjects

G H Farr

Publications and source records attributed to G H Farr.

At least 19 recordsLinked to original sources
PubMed2004

Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial.

BACKGROUND: Insulin sensitizing agents may be useful in treatment of non-alcoholic fatty liver disease. AIM: A pilot study to evaluate the efficacy and safety of metformin in non-alcoholic fatty liver disease. METHODS: In an open labelled study, patients with histologically confirmed non-alcoholic fatty liver disease were given metformin (20 mg/kg) for 1 year. Insulin resistance (by log homeostasis assessment model analysis for insulin resistance and Quantitative Insulin Sensitivity Check Index) and post-treatment hepatic histology were compared with pre-treatment histology. RESULTS: Fifteen patients completed 1 year of treatment. During the initial 3 months, there was improvement in alanine aminotransferase and aspartate aminotransferase (P-value 0.01 and 0.02, respectively) along with improvement in insulin sensitivity. However, after 3 months, there was no further improvement in insulin sensitivity and there was gradual rise in aspartate aminotransferase and alanine aminotransferase back to pre-treatment levels. Among the 10 patients with post-treatment biopsy, three (33%), showed improvement in steatosis, two (20%) showed improvement in inflammation score and one (10%) showed improvement in fibrosis. CONCLUSION: Metformin treatment was associated with only a transient improvement in liver chemistries. A progressive, sustainable reduction in insulin sensitivity was not noted during treatment.

Alanine Transaminase↗
PubMed2001

Low-density lipoprotein receptor-related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway.

To understand how the Wnt coreceptor LRP-5 is involved in transducing the canonical Wnt signals, we identified Axin as a protein that interacts with the intracellular domain of LRP-5. LRP-5, when expressed in fibroblast cells, showed no effect on the canonical Wnt signaling pathway by itself, but acted synergistically with Wnt. In contrast, LRP-5 mutants lacking the extracellular domain functioned as constitutively active forms that bind Axin and that induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin. Addition of Wnt caused the translocation of Axin to the membrane and enhanced the interaction between Axin and LRP-5. In addition, the LRP-5 sequences involved in interactions with Axin are required for LEF-1 activation. Thus, we conclude that the binding of Axin to LRP-5 is an important part of the Wnt signal transduction pathway.

3T3 Cells↗
PubMed2001

A mass on breast imaging predicts coexisting invasive carcinoma in patients with a core biopsy diagnosis of ductal carcinoma in situ.

An image-guided core-needle breast biopsy (IGCNBB) diagnosis of ductal carcinoma in situ (DCIS) is often upgraded to invasive carcinoma (IC) after complete excision. When IC is identified after excision patients must be returned to the operating room for evaluation of their axillary nodes. We performed this study to identify histologic or mammographic features that would predict the presence of invasion when DCIS is documented by IGCNBB. Patients with an IGCNBB diagnosis of DCIS were identified from a prospective database. Imaging abnormalities were classified as either calcification only or mass with or without calcifications. IGCNBB specimens were reviewed to document nuclear grade and the presence of comedo-type necrosis, periductal fibrosis, and periductal inflammation. Patients were divided into two groups, DCIS and IC, on the basis of the final diagnosis after complete excision. From July 1993 through May 2000, 148 of 2995 (4.9%) IGCNBBs demonstrated DCIS; eight were excluded after pathologic review. Of the remaining 140 patients 36 (26%) demonstrated IC after complete excision. The presence of a mass on breast imaging was the only significant predictor of IC (P = 0.04). On the basis of the results of this study we now perform sentinel lymph node mapping and biopsy at the initial surgical procedure for patients with an IGCNBB diagnosis of DCIS and an associated mass on breast imaging.

Biopsy, Needle↗
PubMed2000

Interaction among GSK-3, GBP, axin, and APC in Xenopus axis specification.

Glycogen synthase kinase 3 (GSK-3) is a constitutively active kinase that negatively regulates its substrates, one of which is beta-catenin, a downstream effector of the Wnt signaling pathway that is required for dorsal-ventral axis specification in the Xenopus embryo. GSK-3 activity is regulated through the opposing activities of multiple proteins. Axin, GSK-3, and beta-catenin form a complex that promotes the GSK-3-mediated phosphorylation and subsequent degradation of beta-catenin. Adenomatous polyposis coli (APC) joins the complex and downregulates beta-catenin in mammalian cells, but its role in Xenopus is less clear. In contrast, GBP, which is required for axis formation in Xenopus, binds and inhibits GSK-3. We show here that GSK-3 binding protein (GBP) inhibits GSK-3, in part, by preventing Axin from binding GSK-3. Similarly, we present evidence that a dominant-negative GSK-3 mutant, which causes the same effects as GBP, keeps endogenous GSK-3 from binding to Axin. We show that GBP also functions by preventing the GSK-3-mediated phosphorylation of a protein substrate without eliminating its catalytic activity. Finally, we show that the previously demonstrated axis-inducing property of overexpressed APC is attributable to its ability to stabilize cytoplasmic beta-catenin levels, demonstrating that APC is impinging upon the canonical Wnt pathway in this model system. These results contribute to our growing understanding of how GSK-3 regulation in the early embryo leads to regional differences in beta-catenin levels and establishment of the dorsal axis.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Benign diagnosis by image-guided core-needle breast biopsy.

Image-guided core-needle breast biopsy (IGCNBB) is widely used to evaluate patients with abnormal mammograms; however, information is limited regarding the reliability of a benign diagnosis. The goal of this study was to demonstrate that a benign diagnosis obtained by IGCNBB is accurate and amenable to mammographic surveillance. Records of all patients evaluated by IGCNBB from July 1993 through July 1996 were reviewed. Biopsies were classified as malignant, atypical, or benign. All benign cases were followed by surveillance mammography beginning 6 months after IGCNBB. Of the 1110 patients evaluated by IGCNBB during the study period, 855 revealed benign pathology. A total of 728 of the 855 patients (85%) complied with the recommendation for surveillance mammography. A total of 196 IGCNBBs were classified as malignant; 59 cases were classified as atypical. The atypical cases were excluded from the statistical analysis. Only two patients have demonstrated carcinoma after a benign IGCNBB during the 2-year minimum follow-up period. The sensitivity and specificity of a benign result were 100.0 and 98.9 per cent, respectively. A benign diagnosis obtained by IGCNBB is accurate and therefore amenable to mammographic surveillance. The results of this study support IGCNBB as the preferred method of evaluating women with abnormal mammograms.

Adult↗
PubMed1999

Microsatellite instability and 8p allelic imbalance in stage B2 and C colorectal cancers.

BACKGROUND: Microsatellite instability (MSI) and allelic imbalance involving chromosome arms 5q, 8p, 17p, and 18q are genetic alterations commonly found in colorectal cancer. We investigated whether the presence or absence of these genetic alterations would allow stratification of patients with Astler-Coller stage B2 or C colorectal cancer into favorable and unfavorable prognostic groups. METHODS: Tumors from 508 patients were evaluated for MSI and allelic imbalance by use of 11 microsatellite markers located on chromosome arms 5q, 8p, 15q, 17p, and 18q. Genetic alterations involving each of these markers were examined for associations with survival and disease recurrence. All P values are two-sided. RESULTS: In univariate analyses, high MSI (MSI-H), i.e., MSI at 30% or more of the loci examined, was associated with improved survival (P =.02) and time to recurrence (P =.01). The group of patients whose tumors exhibited allelic imbalance at chromosome 8p had decreased survival (P =.02) and time to recurrence (P =.004). No statistically significant associations with survival or time to recurrence were observed for markers on chromosome arms 5q, 15q, 17p, or 18q. In multivariate analyses, MSI-H was an independent predictor of improved survival (hazard ratio [HR] = 0.51; 95% confidence interval [CI] = 0.31-0.82; P =.006) and time to recurrence (HR = 0.42; 95% CI = 0.24-0.74; P =.003), and 8p allelic imbalance was an independent predictor of decreased survival (HR = 1.89; 95% CI = 1.25-2.83; P =. 002) and time to recurrence (HR = 2.07; 95% CI = 1.32-3.25; P =.002). CONCLUSIONS: Patients whose tumors exhibited MSI-H had a favorable prognosis, whereas those with 8p allelic imbalance had a poor prognosis; both alterations served as independent prognostic factors. To our knowledge, this is the first report of an association between 8p allelic imbalance and survival in patients with colorectal cancer.

Adult↗
PubMed1999

Axin and Frat1 interact with dvl and GSK, bridging Dvl to GSK in Wnt-mediated regulation of LEF-1.

Wnt proteins transduce their signals through dishevelled (Dvl) proteins to inhibit glycogen synthase kinase 3beta (GSK), leading to the accumulation of cytosolic beta-catenin and activation of TCF/LEF-1 transcription factors. To understand the mechanism by which Dvl acts through GSK to regulate LEF-1, we investigated the roles of Axin and Frat1 in Wnt-mediated activation of LEF-1 in mammalian cells. We found that Dvl interacts with Axin and with Frat1, both of which interact with GSK. Similarly, the Frat1 homolog GBP binds Xenopus Dishevelled in an interaction that requires GSK. We also found that Dvl, Axin and GSK can form a ternary complex bridged by Axin, and that Frat1 can be recruited into this complex probably by Dvl. The observation that the Dvl-binding domain of either Frat1 or Axin was able to inhibit Wnt-1-induced LEF-1 activation suggests that the interactions between Dvl and Axin and between Dvl and Frat may be important for this signaling pathway. Furthermore, Wnt-1 appeared to promote the disintegration of the Frat1-Dvl-GSK-Axin complex, resulting in the dissociation of GSK from Axin. Thus, formation of the quaternary complex may be an important step in Wnt signaling, by which Dvl recruits Frat1, leading to Frat1-mediated dissociation of GSK from Axin.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Radial scar of the breast: radiologic-pathologic correlation in 22 cases.

Twenty-two cases were reviewed in which the diagnosis of radial scar (complex sclerosing lesion) of the breast was suspected preoperatively. At mammography, the lesions had a "black star" appearance with long, thin spicules radiating from a radiolucent central area. Excisional rather than core needle biopsy was recommended in all cases. In 13 of 22 cases, including one case of atypical ductal hyperplasia, the lesions proved benign at pathologic analysis. The remaining nine cases were malignant and included one case with a low-nuclear-grade cribriform and micropapillary ductal carcinoma in situ adjacent to the lesion. Results of this study confirm the previously reported association of atypical ductal hyperplasia and carcinoma with radial scar. Furthermore, they demonstrate that a mammographic finding suggestive of radial scar may represent a malignancy that mimics the typical imaging findings in these entities. In cases of mammographically suspected radial scar, all members of the management team as well as the patient should be made aware preoperatively of the potential for benign as well as malignant pathologic findings.

Adult↗
PubMed1998

GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis.

Dorsal accumulation of beta-catenin in early Xenopus embryos is required for body axis formation. Recent evidence indicates that beta-catenin is dorsally stabilized by the localized inhibition of the kinase Xgsk-3, utilizing a novel Wnt ligand-independent mechanism. Using a two-hybrid screen, we identified GBP, a maternal Xgsk-3-binding protein that is homologous to a T cell protooncogene in three well-conserved domains. GBP inhibits in vivo phosphorylation by Xgsk-3, and ectopic GBP expression induces an axis by stabilizing beta-catenin within Xenopus embryos. Importantly, antisense oligonucleotide depletion of the maternal GBP mRNA demonstrates that GBP is required for the establishment of the dorsal-ventral axis in Xenopus embryos. Our results define a family of GSK-3-binding proteins with roles in development and cell proliferation.

Amino Acid Sequence↗
PubMed1998

Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1.

Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colorectal cancer and in a large number of sporadic tumors. To further characterize the type of alterations at these loci and their frequency of involvement in colon cancer, we studied DNA extracted from paraffin-embedded tissue from 508 patients using 11 microsatellites localized to chromosomes 5, 8, 15, 17, and 18. Overall, MSI at each locus varied in character and frequency and was observed with at least one marker in 191 cases (37.6%). Based on the number of markers displaying instability per tumor, three groups of patients were defined: those with <30% of the markers showing instability (MSI-L,, n = 109, 21.5%); those with > or = 30% (MSI-H, n = 82, 16.1%); and those showing no instability (MSS, n = 317, 62.4%). These groups were tested for correlations with a number of clinical and pathological parameters, including age, sex, stage, ploidy status, and site of tumor. Comparing across the three groups and verified by pair-wise comparisons, the MSI-H group was associated with tumor site (proximal colon, P = 0.001), sex (females, P = 0.005), stage (Dukes' B, P = 0.01), and ploidy status (diploid, P = 0.03). No significant differences were noted between the MSI-L and MSS group for any of the parameters tested. An additional 188 consecutive surgical colorectal cancer cases were examined for the presence of MSI and for the immunohistochemical expression of hMLH1 and hMSH2 proteins. Of this group, 129 (68.6%) were classified as MSS, 17 (9.0%) as MSI-L, and 42 (22.3%) as MSI-H. None of the MSS and none of the MSI-L tumors had altered expression of either hMLH1 or hMSH2. However, the majority of MSI-H (40 of 42, 95%) cases demonstrated absence of staining for these proteins. The most frequently altered protein was hMLH1, occurring in 95% of the tumors with altered expression. Cumulatively, these data suggest that the tumor phenotype MSI-H is distinct from tumor phenotypes MSI-L and MSS, with no apparent differences between MSI-L and MSS. Furthermore, altered hMLH1 protein expression appears to be responsible for the mutator phenotype in the vast majority of MSI-H tumors.

Adaptor Proteins, Signal Transducing↗
PubMed1998

A core breast biopsy diagnosis of invasive carcinoma allows for definitive surgical treatment planning.

BACKGROUND: We reviewed our image-guided core needle breast biopsy (IGCNBB) experience with patients diagnosed with invasive carcinoma (IC) to determine the accuracy of a core biopsy diagnosis of invasion and our ability to perform a single definitive cancer operation. METHODS: All IGCNBBs between July 1993 and July 1997 were reviewed to identify patients diagnosed with IC. Data included initial surgical treatment, surgical pathology, and subsequent surgical treatment. RESULTS: Of the 1,676 biopsies, invasive carcinoma was diagnosed in 208 with follow-up in 204 cases. Invasive carcinoma diagnosis was confirmed in 202 of 204 cases (99%). One hundred ninety-two patients had surgical treatment. Of these 192 patients, 173 (90%) could have achieved definitive surgical treatment with a single operation. CONCLUSIONS: An IGCNBB diagnosis of IC is accurate and allows for definitive breast cancer therapy. The potential impact on patient management is that a single operation can usually accomplish what traditionally has required at least two surgical procedures.

Biopsy↗
PubMed1998

Image-guided core-needle breast biopsy is an accurate technique to evaluate patients with nonpalpable imaging abnormalities.

OBJECTIVE: The goal was to evaluate one institution's experience with image-guided core-needle breast biopsy (IGCNBB) and compare the pathologic results with wire-localized excisional breast biopsy (WLEBB) for patients with positive cores and the mammographic surveillance results for patients with negative cores. SUMMARY BACKGROUND DATA: IGCNBB is becoming a popular, minimally invasive alternative to WLEBB in the evaluation of patients with nonpalpable abnormalities. METHODS: This study includes all patients with nonpalpable breast imaging abnormalities evaluated by IGCNBB from July 1993 to February 1997. Patients with positive cores (atypical hyperplasia, carcinoma in situ, or invasive carcinoma) were evaluated by WLEBB. Patients with negative cores (benign histology) were followed with a standard mammographic protocol. IGCNBB results were compared with WLEBB results to determine the sensitivity and specificity for each IGCNBB pathologic diagnosis. RESULTS: Of 1440 IGCNBBs performed during the study period, 1106 were classified as benign, and during surveillance follow-up only a single patient was demonstrated to have a carcinoma in the index part of the breast evaluated by IGCNBB (97.3% sensitivity, 99.7% specificity). IGCNBB demonstrated atypical hyperplasia in 72 patients, 5 of whom refused WLEBB. The remaining 67 patients were evaluated by WLEBB: nonmalignant findings were found in 31, carcinoma in situ was found in 25, and invasive carcinoma was found in 11 (100% sensitivity, 88.8% specificity). IGCNBB demonstrated carcinoma in situ in 84 patients; WLEBB confirmed carcinoma in situ in 54 and invasive carcinoma in 30 (65.4% sensitivity, 97.7% specificity). IGCNBB demonstrated invasive carcinoma in 178 patients. Three were lost to follow-up. On WLEBB, 173 of the remaining 175 had invasive carcinoma; the other 2 patients had carcinoma in situ (80.8% sensitivity, 99.8% specificity). CONCLUSIONS: An IGCNBB that demonstrates atypical hyperplasia or carcinoma in situ requires WLEBB to define the extent of breast pathology. Mammographic surveillance for a patient with a benign IGCNBB is supported by nearly 100% specificity. An IGCNBB diagnosis of invasive carcinoma is also associated with nearly 100% specificity; therefore, these patients can have definitive surgical therapy, including axillary dissection or mastectomy, without waiting for the pathologic results of a WLEBB. Based on the authors' findings, IGCNBB can safely replace WLEBB in evaluating patients with nonpalpable breast abnormalities.

Biopsy, Needle↗
PubMed1997

Appropriate management of atypical ductal hyperplasia diagnosed by stereotactic core needle breast biopsy.

BACKGROUND: Stereotactic core needle breast biopsy (SCNBB) is a minimally invasive technique used to sample nonpalpable mammographic abnormalities. The optimal management of atypical ductal hyperplasia (ADH) diagnosed by SCNBB is unknown. We hypothesized that ADH diagnosed by SCNBB should be evaluated by excisional breast biopsy (EBB) because of the risk of identifying carcinoma in association with ADH that would be missed if a diagnostic sampling technique alone was utilized. METHODS: To test this hypothesis, a prospective diagnostic protocol was created which called for SCNBB instead of EBB for patients with mammographic abnormalities considered suspicious for malignancy. If ADH was noted on histologic evaluation of the cores, patients were advised to undergo an EBB. RESULTS: A review of the initial 900 patients evaluated by SCNBB yielded 39 patients (4.3%) with ADH detected by SCNBB. Thirty-six of these 39 patients agreed to proceed with EBB: 19 patients demonstrated benign findings including atypical ductal hyperplasia, 13 patients demonstrated noninvasive ductal carcinoma, and 4 patients had evidence of invasive carcinoma. CONCLUSIONS: A 47% rate of detecting noninvasive or invasive breast carcinoma supports the hypothesis that ADH detected by a sampling technique, such as SCNBB, should be managed by EBB.

Biopsy, Needle↗
PubMed1996

Comparison of estrogen receptor determinations by a biochemical ligand-binding assay and immunohistochemical staining with monoclonal antibody ER1D5 in females with lymph node positive breast carcinoma entered on two prospective clinical trials.

BACKGROUND: The measurement of estrogen receptors (ER) in breast cancer specimens has traditionally been assessed with a dextran-coated charcoal assay (DCCA). More recently the immunohistochemical staining (IHC) method has gained increasing popularity because of its ability to use fixed tissue, assess needle biopsies, and reduce cost. Controversy exists over the accuracy of IHC compared with that of DCCA in determining ER. We compared these two techniques using tumor tissue obtained from a large group of females with lymph node positive breast carcinoma with long term follow-up. METHODS: Breast carcinoma tissue was obtained from a large group of females with node positive breast carcinoma participating in two adjuvant chemotherapy trials. ER was determined by the traditional DCCA method and by IHC using the ER1D5 antibody. Disease free survival (DFS) and overall survival (OS) were assessed by each of these methods. RESULTS: ER status was determined by DCCA and IHC in tumor tissue obtained from 316 females. A concordance of 79% was observed for the determination of ER-positive tumors. Of the discordant results, the majority of DCCA-negative, IHC-positive tumors could be explained by a low level of DCCA positivity (< 10 fmol) or IHC staining of nonmalignant cells. A much higher rate of discordant results was observed in premenopausal females. Of the DCCA-negative, IHC-positive patients 97% were premenopausal and of the DCCA-positive, IHC-negative patients 79% were premenopausal. ER by DCC appears to perform better than ER by IHC as a prognostic factor in terms of DFS and OS. CONCLUSIONS: When compared with DCCA, IHC with monoclonal antibody ER1D5 appears to be a reasonable substitute for the determination of ER. Although DCCA appeared to perform better as a determinant of prognosis, ER detection is used primarily for deciding on hormonal therapy. Review of discordant cases indicates IHC may more accurately reflect the ER status of malignant cells in some patients. Attention must be paid to quality control considerations in performance of IHC staining.

Adenocarcinoma↗
PubMed1996

Flow-cytometric analysis of deoxyribonucleic acid content in advanced ovarian carcinoma: its importance in long-term survival.

OBJECTIVE: Our purpose was to evaluate the importance of deoxyribonucleic acid content to long-term survival from advanced epithelial ovarian carcinoma. STUDY DESIGN: Clinical and pathologic prognostic factors, including deoxyribonucleic acid content measured by means of flow cytometry, were analyzed for 282 patients. RESULTS: In 80% of the patients, the deoxyribonucleic acid patterns were nondiploid. In univariate analysis stage (p < 0.0001), residual disease (p < 0.0001), deoxyribonucleic acid index (p = 0.01), and deoxyribonucleic acid ploidy (p = 0.02) significantly predicted progression-free survival. In multivariate analysis stage (p < 0.001), residual tumor (p = 0.001), deoxyribonucleic acid ploidy (p = 0.02), and deoxyribonucleic acid index (p = 0.02) retained independent prognostic value. Residual disease and deoxyribonucleic acid content retained independent prognostic value for stage III tumors but not for stage IV tumors. CONCLUSION: Deoxyribonucleic acid analysis with flow cytometry provides prognostic information about long-term progression-free survival from advanced ovarian carcinoma and should be considered in the stratification processes of patients in future clinical trials. This prognostic information appears to be inversely related to tumor burden.

Adult↗