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PubMed2004

Utilization of beef from different cattle phenotypes to produce a guaranteed tender beef product.

Cattle (n = 303) were visually selected from four feed yards to represent six phenotypes (English [EN; n = 50], 3/4 English-1/4 Brahman [ENB; n = 52], 1/2 English-1/2 Exotic [ENEX; n = 56], 1/2 English-1/4 Exotic-1/4 Brahman [ENEXB; n = 47], 3/4 Exotic-1/4 Brahman [EXB; n = 49], and 1/2 Exotic-1/4 English-1/4 Brahman [EXENB; n = 49]). Carcasses were processed at a commercial beef packing facility, and strip loins were collected after 48-h chilling. Strip loins were aged for 14 d at 2 degrees C and frozen at -20 degrees C for 3 to 5 d before three 2.5-cm-thick steaks were cut for Warner-Bratzler shear force (WBSF) determinations and sensory evaluations. Phenotype EN had the highest (P < 0.05) adjusted fat thickness, and EXB had adjusted fat thickness that was lower (P < 0.05) than all other phenotypes except EXENB. Carcasses of EN and ENB had smaller (P < 0.05) longissimus muscle areas than phenotypes ENEX, EXB, and EXENB. Phenotype EN produced carcasses with the highest (P < 0.05) numerical yield grade, whereas carcasses originating from phenotype EXB had lower (P < 0.05) numerical yield grades than all other phenotypes except ENEX. No differences (P > 0.05) were found among phenotypes for mean WBSF values or sensory panel ratings for initial and sustained tenderness, initial and sustained juiciness, beef flavor characteristics, and overall mouthfeel. More than 90% of steaks from carcasses of all phenotypes had WBSF values less than 3.6 kg when cooked to an internal cooked temperature of 70 degrees C. Results from this study indicated that all phenotypes represented in this study could be managed to produce tender beef.

Animals↗
PubMed2006

Tumor differentiation phenotype in gastric differentiated-type tumors and its relation to tumor invasion and genetic alterations.

AIM: To clarify the relations between tumor differentiation phenotype and tumor invasion or genetic alterations in gastric differentiated-type tumors. METHODS: We examined the tumor differentiation phenotype, the presence of mutations in APC and p53, and the microsatellite instability (MSI) status in 48 gastric adenomas and 171 differentiated-type carcinomas. The tumor differentiation phenotype was determined by examining the expression of human gastric mucin (HGM), MUC6, MUC2 and CD10. The tumors were then classified into gastric- (G-), gastric and intestinal mixed- (GI-), or intestinal- (I-) phenotypes, according to the immunopositivity of the above markers. The presence of mutations in APC and p53 and the MSI status were also investigated in all the tumors. RESULTS: Gastric adenomas were significantly associated with CD10 expression, I-phenotype tumors and the presence of APC mutations, compared with carcinomas (66.7% vs 25.1%, P < 0.0001; 56.3% vs 14.6%, P < 0.0001; 39.6% vs 14.0%, P < 0.0001, respectively) and inversely associated with expressions of HGM and MUC6 and the presence of p53 mutations (10.4% vs 62.6%, P < 0.0001; 39.6% vs 64.3%, P = 0.003; 2.0% vs 26.3%, P = 0.001, respectively). The frequency of APC mutations was significantly higher in HGM-negative tumors, MUC6-negative tumors, CD10-positive tumors and I-phenotype tumors than in HGM-positive tumors, MUC6-positive tumors, CD10-negative tumors and G-phenotype tumors (32.7% vs 7.1%, P < 0.0001; 27.8% vs 14.0%, P = 0.0182; 37.3% vs 10.4%, P < 0.0001; and 38.5% vs 9.5%, P = 0.0017, respectively). The frequency of MSI was significantly higher in MUC6-positive tumors, CD10-negative tumors and G-phenotype tumors than in MUC6-negative tumors, CD10-positive tumors and I-phenotype tumors (24.8% vs 6.7%, P = 0.0009; 22.2% vs 8.0%, P = 0.0143; and 28.6% vs 9.6%, P = 0.0353, respectively). CONCLUSION: The tumor differentiation phenotype is closely related to tumor invasion and genetic alterations in gastric differentiated-type tumors.

Adenocarcinoma↗
PubMed2002

[LDL phenotype A and B in ischemic stroke].

The role of the lipid abnormalities as a risk factor for stroke remains controversial; very likely because only the standard lipid fractions are measured and because different causes of stroke are not considered. LDL phenotype B promotes atherogenesis and is recognized as a risk factor for ischemic heart disease, but its prevalence in ischemic stroke of distinct causes is unknown. Therefore we designed the study to investigate the prevalence of LDL phenotype B in stroke survivors with large vessel disease (LVD) or small vessel disease (SVD) and to establish the relationship between LDL phenotypes and basic lipid fractions in this group of patients. 59 patients (24 patients with LVD and 35 patients with SVD) being at least 3 months after ischemic stroke were included into the study. 30 sex- and age-matched subject served as controls. The concentrations of total cholesterol, HDL- and LDL-cholesterol, as well as triglycerides were measured and the LDL phenotype was determined using the potassium bromide density gradient ultracentrifugation. The LDL phenotype B was more frequent in patients with LVD (67%, p < 0.05) compared to patients with SVD and with controls. LDL phenotype B was also more frequent in patients with SVD (40%) and in all stroke survivors combined (51%), when compared with control group (17%, p < 0.05; chi-square test). Among stroke survivors, controls and studied subjects as a whole, those with LDL phenotype B revealed the lower concentration of HDL-cholesterol (1.19 +/- 0.33 vs. 1.46 +/- 0.42; 1.16 +/- 0.29 vs. 1.53 +/- 0.3 and 1.19 +/- 0.32 vs. 1.49 +/- 0.37, respectively; p < 0.05, Student t-test) when compared with carriers of LDL A phenotype. The LDL phenotype B is more frequent in ischemic stroke survivors compared to controls, and within the group of stroke survivors, LDL B is more prevalent in patients with LVD. The LDL phenotype B is associated with lower concentration of HDL-cholesterol.

Brain↗
PubMed2003

[Biochemical phenotypes and phage types of Salmonella enteriditis strains isolated in Antofagasta during the period 1997-2000].

BACKGROUND: PhP-S48 (Phene Plate Techniques AB), a method based on biochemical phenotypes has been developed and used successfully to typify S enteritidis strains in epidemiological studies. AIM: To identify phenotypes of S enteritidis isolated from eggs, chicken meat and infected humans in Antofagasta during the period 1997-2000. MATERIAL AND METHODS: PhP-S48 and phage typing were used to identify phenotypes of 33 S enteritidis strains, sixteen isolated from poultry and 17 from clinical sources. S enteritidis ATCC17036 was used as control strain. RESULTS: Twelve biochemical phenotypes (BTs) including 4 common (C) and 8 single (S) were identified. BTs C1 y C3 containing 16 and 5 strains, respectively, accounted for 63.6% of the isolates. BT C1 was found in poultry and human sources in the period 1997-2000, and BT C3 was isolated from humans, in the period 1999-2000. Using phage typing, 5 phage types (PT) and 3 strains could be not typed (NTs). PT1 and PT21 were the dominant phage types, with 14 and 13 strains respectively. Strains of PT1 were isolated from poultry and human sources in the period 1997-2000. PT21 was found in poultry samples in the period 1997-1998 and in clinical samples, in the period 1997-1998. Combination of biochemical phenotypes and phage typing divided the strains into 5 phenotypes (BT:PT). Two phenotypes were the most frequently isolated, phenotype C1:1 with 8 isolates found in eggs and humans in 1999, and phenotype C1:21 with 5 strains isolated in 1997-1999. CONCLUSIONS: These results indicate the presence of one persistent and one recently emerged phenotype among S enteritidis in Antofagasta, Chile. PhP-S48 also provided information about a relationship among the strains.

Animals↗
PubMed2006

Phenotypic resistance of resistant strains of HIV type-1 subtype B in China.

BACKGROUND: This study was aim to explore the characteristics of phenotypic resistance of resistant strains of HIV type-1 (HIV-1) subtype B and to compare the concordance between the phenotypic resistance and genotypic resistance. METHODS: The genotypic resistance assay for the HIV-1 clinical isolates was performed. One isolate without resistance mutation was chosen as a drug-sensitive reference strain and seven subtype B isolates with resistance mutations were phenotypically tested. Fifty percent inhibitory concentrations (IC50) between resistant and sensitive viruses were compared. The resistance extent was determined by the folds of the increased IC50. The concordance between the phenotypic resistance and genotypic resistance was also analyzed. RESULTS: IC50 of resistant isolates were 0.0006 - 0.1300 micromol/L for zidovudine (AZT), 0.0016 - 0.0390 micromol/L for lamivudine (3TC), 0.0104 - 0.4234 micromol/L for nevirapine (NVP), and 0.0163 - 0.1142 micromol/L for indinavir (IDV), respectively. Genotypic and phenotypic resistance assays indicated that the resistant strains were intermediately and highly resistant to nucleotide analog reverse transcriptase inhibitors and non-nucleotide analog reverse transcriptase inhibitors. The phenotypic assay was consistent with the genotypic assay. For measuring the potential resistance, the genotypic assay was more sensitive than the phenotypic. In evaluating the resistance to protease inhibitors, these two assays were discrepant. CONCLUSIONS: Both the phenotypic and genotypic assays indicate that the resistant viruses exist in HIV-infected patients in China who have received treatment. Phenotypic and genotypic assays have high concordance, and the genotypic assay could replace the phenotypic assay to predict the HIV-1 resistance.

Anti-Retroviral Agents↗
PubMed1988

Demonstration of phenotypic abnormalities of thymic epithelium in thymoma including two cases with abundant Langerhans cells.

A panel of monoclonal antibodies that phenotypically define stages of normal human thymic epithelial (TE) cell maturation was used to compare thymic epithelium of nine thymomas with hyperplastic thymic epithelium in myasthenia gravis (MG) and thymic epithelium of normal thymuses. It has been shown previously that normal thymic epithelial cells express antigens of early TE cell maturation (A2B5, TE-4) throughout thymic ontogeny and acquire antigens 12/1-2, TE8, and TE-15 at 14 to 16 weeks of fetal gestation. Hyperplastic MG thymic epithelial cells expressed TE antigens in phenotypic patterns similar to that seen in normal postnatal thymus, ie, TE in subcapsular cortex and medulla was TE4+, A2B5+, and 12/1 - 2+ and Hassall's bodies were reactive with antibodies TE8 and TE15. In contrast, thymic epithelium in primary mediastinal thymomas was TE4+, A2B5+, TE8-, and greater than 75% of thymoma epithelium was 12/1 - 2-, a thymic epithelial phenotype similar to that seen on normal fetal thymic epithelium at 14 to 16 weeks fetal gestation. In one subject with a mature epithelial histologic pattern, thymoma epithelium was found to be strongly TE8+, a phenotype suggestive of a later stage of TE maturation. Lymphocytes in five of seven thymomas with immature thymic epithelial cells predominantly expressed immature thymocyte phenotype while two thymomas with immature epithelial phenotype showed a predominance of Langerhans cells and surrounding lymphocytes expressing a mature phenotype. Lymphocytes in the thymoma with differentiated epithelial cells expressed a mature thymocyte phenotype. Thus, in thymomas of varying histologic types, phenotypic abnormalities of thymic epithelium are present; these phenotypic abnormalities may reflect abnormal thymic epithelial maturation.

Adult↗
PubMed1984

Alterations in cell surface phenotype of T- and B-cell chronic lymphocytic leukemia cells following in vitro differentiation by phorbol ester.

The phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) was used for the induction of in vitro differentiation in primary cultures of chronic lymphocytic leukemia cells to study its effects on B-cell antigens [surface IgG, HLA-DR, and the mouse erythrocyte receptor (MR)] and on T-cell antigens [T65 and Lyt-3 (sheep erythrocyte receptor)] found on these cells. Three distinct phenotypes were studied: 1) the common phenotype (slg+, HLA-DR+, MR+, T65+, Lyt-3-); 2) the T-cell phenotype (slg-, HLA-DR-, MR-, T65+, Lyt-3+); and 3) a unique phenotype (slg-, HLA-DR+, MR+, T65+, Lyt-3-). In both the common and unique phenotypes, TPA increased the expression of T65 and HLA-DR, decreased the formation of MR, and induced cytoplasmic immunoglobulin, but it did not induce Lyt-3. In the unique phenotype, TPA also induced surface immunoglobulin. These data suggest that both the common and unique phenotypes are derived from the same lineage, probably B-cell. In the T-cell phenotype, TPA increased the expression of T65 and Lyt-3, but it did not induce any B-cell antigens. These data suggest that the T-cell phenotype is derived from a T-cell lineage distinct from the two B-cell phenotypes.

Antigens, Surface↗
PubMed1997

Changes in phenotypes of apolipoprotein E and apolipoprotein(a) in liver transplant recipients.

The aim of this study has been to confirm that liver is the main site of apolipoprotein (apo) E and apo(a) synthesis, based in the changes of their phenotypes after transplantation. Apo E phenotypes were studied in 34 patients and apo(a) phenotypes in 27 of them before and after liver transplant. Thirteen patients changed the apo E phenotype after transplantation. Eight patients with E3/3 phenotype changed to the others with 2 or 4 alleles. Three patients with E4/3 phenotype changed to E3/3, one changed from E3/2 to E3/3 and another one changed from E4/2 to E3/2 phenotype after transplantation. Twenty one of the 27 patients changed the apo(a) phenotype. Thirteen of them also changed lipoprotein (Lp)(a) serum concentration at least twofold, showing in 11 an increase and in 2 a decrease, in relation with the change to phenotype associated with high and low Lp(a) concentration, respectively. Changes in apo E and apo(a) phenotypes in liver transplant recipients studied show that most of these apolipoproteins are synthesized by the liver.

Alleles↗
PubMed1999

Molecular composition of drusen as related to substructural phenotype.

Age-related macular degeneration (AMD) is characterized in part by the deposition of extracellular deposits, including drusen, in the aging macula. A number of clinical studies have revealed a strong association between the number, size, and degree of confluency of drusen and AMD. Although a number of distinct morphological classes, or phenotypes, of drusen can be resolved at the ultrastructural level, very little is known about the compositional and etiological relationship between these phenotypes. A number of recent studies have begun to provide insight into the composition of drusen at the light microscopic level of resolution. Out of 33 extracellular matrix proteins evaluated, vitronectin was identified in hard and soft drusen [FASEB J 1999; 13:477-84]. Drusen have also been found to contain carbohydrate moieties which are labeled by wheat germ agglutinin (WGA), and Limax flavus agglutinin (LFA). We have recently extended these histochemical, immunohistochemical, and biochemical investigations to examine the relationship between substructural drusen phenotype and composition. The initial results of these observations, generated from a repository of human donor eyes processed within four hours of death, are reported herein. Five distinct substructural drusen phenotypes were identified in tissue sections from eyes of approximately 400 donors; all five phenotypes were observed in eyes from donors with and without clinically documented AMD. Interestingly, no strict relationship between size (one important discriminator between "hard" and "soft" drusen class) and morphology was noted for four out of the five drusen phenotypes. Sections from the same donors were incubated with antibodies directed against vitronectin and with the lectins WGA and LFA, three probes recently shown to label hard and soft drusen at the light microscopic level of resolution. As anticipated, all of these probes bound to all phenotypes of drusen examined. These data suggest that different phenotypes of drusen, although they may differ significantly with respect to their substructural morphology, may possess a similar complement of extracellular matrix-associated proteins and saccharides. Ongoing investigations are directed toward determining whether there exist specific drusen constituents, not yet identified, that impart phenotypic and/or ontogenic specificity to drusen. It is anticipated that a more complete understanding of drusen composition, as it relates to phenotype, will provide significant new insight into the biology and etiology of various clinically manifested forms of AMD.

History, 19th Century↗
PubMed2001

Rhesus D-phenotype does not provide prognostic information additional to TNM staging in gastric cancer patients.

Recently, the Rhesus D-negative phenotype was identified in multivariate analysis as an important independent risk factor in gastric cancer patients who underwent curative resection. The distribution of Rhesus (Rh) D phenotype was investigated in a group of 268 patients who underwent gastrectomy for gastric cancer from June 1988 to April 1999. After excluding patients with short, potentially guaranteed follow-up or who deceased in the postoperative period, the prognostic significance of Rh D phenotype was evaluated in a subgroup of 239 patients by Cox regression model controlling for gender, age, site, histology, depth of tumor invasion (T), node metastasis (N), and type of resection (R). Two hundred and thirty-six patients (88.1%) presented an Rh+ phenotype and 32 (11.9%) presented an Rh- phenotype. A significant association was found between Rh D- phenotype and the presence of residual tumor after surgery (P = .01). The cumulative 5-year survival rate (95% confidence interval) was 37.3% (18.1-56.6) in patients with Rh- phenotype and 47.0% (39.2-54.4) in patients with Rh+ phenotype. The Rh D phenotype did not affect survival independently either in univariate analysis (P = .27) or in multivariate analysis (P = .55). The relative risk of death in D-negative versus D-positive patients decreased from 1.36 (95% confidence interval, 0.80-2.30) in univariate analysis to 0.84 (0.47-1.49) in multivariate analysis after controlling for depth of tumor invasion, lymph node metastases, and type of resection. Our study did not confirm the prognostic significance of Rh D phenotype in gastric cancer patients.

Adult↗
PubMed2001

Provision of phenotype-matched blood units: no need for pre-transfusion antibody screening.

BACKGROUND AND OBJECTIVES: The Hong Kong government is planning to introduce an electronic smart identity card for all seven million citizens in 2003. If the smart card contains the full red cell phenotype/genotype of the individual, it may be possible to transfuse phenotype-matched blood units without pre-transfusion antibody screening. We conducted a feasibility study. DESIGN AND METHODS: Red cell phenotype was determined for 407 donor blood units and 493 patients for whom an antibody screen had been ordered. The computer program selected phenotype-matched blood from the donor stock for the patients according to actual transfusion request. For patients with a positive antibody screen, full crossmatching was carried out with the computer-selected phenotype units. The frequencies of the various red cell phenotypes in the population were calculated from Red Cross data of antigen frequencies. The probabilities of finding at least one unit of phenotype-matched blood from a 300-unit hospital stock and a 4,000-unit Red Cross stock were determined for each phenotype. Cost analysis was performed. RESULTS: Ninety-two out of 493 patients received a total of 395 blood units. The required number of phenotype-matched blood units could be found for 92 patients using a 300-unit pool and for all patients using a 4,000-unit pool. We calculated that phenotype-matched blood could be provided for more than 98% of patients without antibody screening. The total cost of the project is US$ 98 million with potential savings of US$ 14 million per year. INTERPRETATION AND CONCLUSIONS: It is feasible and cost-effective to transfuse patients with phenotype-matched blood without antibody screening using a smart card system.

Blood Group Antigens↗
PubMed2024

Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.

PURPOSE: Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations. METHODS: A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups. RESULTS: The study models the natural history of the HPDL-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span. CONCLUSION: Quantitative and unbiased natural history modeling in HPDL-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies.

Humans↗
PubMed1996

Engrailed gene dosage determines whether certain recessive cubitus interruptus alleles exhibit dominance of the adult wing phenotype in Drosophila.

The cubitus interruptus (ci) locus of Drosophila melanogaster is needed for normal development. Some mutants of this gene result in embryonic lethality, while others just disrupt adult wing veins. While undertaking a genetic screen for additional ci mutations that affect the wing veins, we recovered a modifier mutation on chromosome two that produced a ci phenotype in recessive ci heterozygotes (ci(recessive)/+). We identified the modifier mutation as an allele of engrailed and have called it engrailed-enhancer of cubitus interruptus (enEnci). As a double heterozygote (en-/+; ci-/+) this new en allele dominantly generates a ci wing vein phenotype. As a double heterozygote, it also enhances the ci wing vein phenotype of the dominant alleles ciW and ciCe2, but not ciD. Other loss-of-function en alleles also enhance the ci phenotype, with the en lethal alleles (and deletions) showing the strongest effect, while the homozygous viable en alleles show weaker enhancement. Strong en- alleles failed to induce a ci phenotype with heterozygotes of ci recessive lethal alleles l(4)13, l(4)17, or ciDrev, which are loss-of-function mutations. This supports a previous proposal that the ci wing vein phenotype is not due to loss of ci+ function, as would be expected for most recessive alleles. Instead, the adult wing vein abnormality is due to ectopic expression (or de-repression) of the ci transcript in the posterior compartment of the wing disc. We also observed that en-/+ heterozygotes could induce a ci phenotype in situations where the ci+ locus is either unpaired or hemizygous. Since loss of one en+ gene dose enhanced the ci phenotype, three doses of en+ were tested and found to suppress expression of the ci phenotype in ci1 homozygotes and ciW heterozygotes. These observations show that correct regulation of the ci gene involves more than the simple interaction of upstream regulatory elements. some pairing, pairing dependent gene repression, position effects.

Alleles↗
PubMed1992

Lack of increase in heterozygous alpha 1-antitrypsin deficiency phenotypes among patients with hepatocellular and bile duct carcinoma.

Homozygous alpha 1-antitrypsin deficiency (PiZZ phenotype) is known to be associated with increased risk of cirrhosis and primary liver cancer. Although a relationship between heterozygous alpha 1-antitrypsin deficiency and chronic liver disease was suggested recently, it is still a matter of controversy whether such patients are at increased risk of liver cancer. The goal of this study was to determine the prevalence of heterozygous alpha 1-antitrypsin deficiency of different phenotypes among patients with primary hepatobiliary cancers. We studied 82 patients with primary hepatobiliary cancer; 59 had hepatocellular carcinoma and 23 had bile duct carcinoma. alpha 1-Antitrypsin quantitation and phenotyping were performed in each patient using standard methods. The distribution of the various Pi phenotypes was compared with that found in a normal population and reported elsewhere. Odds-ratio and chi 2 tests were used to measure the relative risk and the significance of association, respectively, between primary hepatobiliary cancers and heterozygous alpha 1-antitrypsin deficiency. Four patients in each of the cancer groups were heterozygous. Among the hepatocellular carcinoma patients, three had the PiMS phenotype and one had the PiMZ phenotype. Of these four heterozygous patients, only two had cirrhosis; one had cryptogenic cirrhosis and the other had hepatitis B virus-related cirrhosis. One noncirrhotic patient with a PiMZ phenotype had a fibrolamellar carcinoma. Of the four patients with bile duct carcinoma, three had the PiMS phenotype and one had the PiMZ phenotype. Of the four heterozygous patients, two had primary sclerosing cholangitis without associated inflammatory bowel disease and one patient had had previous biliary operations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Bile Duct↗
PubMed2001

MHC class I negative phenotype of disseminated tumor cells in bone marrow is associated with poor survival in R0M0 breast cancer patients.

Changing the major histocompatibility complex (MHC) class I phenotype is a pivotal strategy of tumor cells to circumvent an effective immune response and is associated with tumor progression in cancer patients. Epithelial cells in bone marrow have been detected in various tumor types, but the clinical observation that only a portion of the patients with a positive bone marrow status develops solid bone metastasis suggests a certain molecular equipment of the isolated tumor cells as a prerequisite for metastatic formation. In the present study the prognostic impact of the MHC class I phenotype of disseminated epithelial cells in bone marrow was evaluated in a cohort of 30 curatively resected (R0) patients without distant metastases (M0) (designated R0M0) who had minimal residual disease. Immunocytochemical analysis using the alkaline/anti-alkaline immunogold double staining procedure revealed a heterogeneous MHC class I expression profile [monoclonal antibody (mAb) W6/32] of the epithelial cells (mAb CK2). In 16 patients (53.3%) all epithelial cells were human leukocyte antigen (HLA) class I-positive (CK2+//W6/32+ phenotype). Eight patients (26.7%) showed complete loss of the HLA class I molecules (CK2+//W6/32- phenotype) and in 6 patients (20%) partial loss of HLA class I expression was found (CK2+//W6/32+ and - phenotype). CK2+ cells with the HLA class I negative phenotype (CK2+//W6/32- phenotype and CK2+//W6/32+ and - phenotype) were often derived from poorly differentiated (G3) primary breast carcinomas (p = 0.036) and were associated with short survival of the R0M0 patients (follow-up 15-98 months, log rank p = 0.072). These findings support the necessity to develop immmunotherapeutic strategies leading to the restoration of MHC class I positive phenotype.

Antibodies, Monoclonal↗
PubMed2006

Modeling tumor predisposing FH mutations in yeast: effects on fumarase activity, growth phenotype and gene expression profile.

Heterozygous mutations in the fumarase (FH) gene cause the tumor predisposition syndrome hereditary leiomyomatosis and renal cell cancer (MIM 605839). While most families segregate a benign phenotype of multiple leiomyomas, others display a phenotype with early-onset renal cancer and leiomyosarcoma. Modifier genes may play a role in this, but an alternative explanation is simple genotype-phenotype association. FH mutations predisposing to cancer appear to be truncating or in fully conserved amino acids, suggesting that mutations severely affecting FH activity might predispose to malignancy. In the present study, we analyzed 2 conserved fumarase mutations in yeast. H153R has been described in 3 cancer predisposition families; whereas all 3 reported K187R families have displayed the benign phenotype. Examining H153R and K187R should clarify whether cancer-related FH mutations differ from their benign phenotype-associated counterparts. Yeast strains containing the 2 mutations, and knockout and wild type (WT) references, were created and the growth phenotypes studied on selected carbon sources to assess mitochondrial function. Additionally, Fum1 protein production and activity were measured, and the strains were subjected to transcriptional profiling. On nonfermentable lactate medium, the fumarase knockout strains did not grow, whereas the mutants showed no differences, as compared to WT yeast. Although both mutant strains produced fumarase, a considerable decrease in enzyme activity was seen in mutants with respect to WT. Transcription of the majority of Krebs cycle enzymes was downregulated in response to mutations in fumarase. In conclusion, both mutants displayed some, albeit greatly reduced, fumarase activity. This activity was sufficient to support normal growth on nonfermentable carbon source, unlike the deletion phenotype, demonstrating the significance of the residual activity. The findings support the hypothesis that modifier gene(s), rather than phenotype-genotype effects, display a major role in determining tumor phenotypes in families segregating FH mutations.

Cell Division↗
PubMed1999

Phase variable switching of in vivo and environmental phenotypes of Salmonella typhimurium.

Previously it was shown that S. typhimurium strain 798, which is known to cause persistent asymptomatic infections in pigs, exists in two phenotypes. One phenotype, which is called adhesive, was shown to produce pili, is adhesive to porcine enterocytes, is readily phagocytized, and then survives intracellularly in phagocytes. The other phenotype, termed non-adhesive, does not produce pili, does not attach to enterocytes, is phagocytized less efficiently, and does not survive within the phagocyte. Cells in each phenotype can freely switch to the other phenotype at a fairly high frequency and thus the shift between each phenotype is phase variation. Further analysis of these phenotypes identified 4 additional characteristics that were co-regulated by phase variation. The first is the enterocyte-specific adhesin, which was shown to be type 1 fimbriae. Mutations in fimA, the major pilin molecule, led to a decreased ability to colonize the gut of pigs and mice. The second characteristic is O-antigen production. Adhesive cells produce a long O-antigen (up to 18 subunits) while non-adhesive cells do not (only 1-2 subunits). The long O-antigen produced by the adhesive cells leads to resistance to serum and appears to be the result of phase variable expression of rfaL. A third locus, ebu, has been identified based on differential color production of colonies growing on Evans blue-Uranine plates. The relationship of this trait to in vivo survival or virulence is not known but ebu is genetically related to a family of transcriptional activators. The fourth locus, prv is located on the virulence plasmid and a mutation in prv results in delayed time to death in mice. It is hypothesized that the adhesive phenotype is the in vivo, virulent form, while the non-adhesive phenotype is the environmental, avirulent form. By modulating the fraction of cells in each phase, persistent asymptomatic infections can be promoted.

Animals↗
PubMed1993

Expression of connexin43 gap junctions between cultured vascular smooth muscle cells is dependent upon phenotype.

The smooth muscle cell is the predominant cell type of the arterial media. In the adult vascular system, smooth muscle cells are found primarily in the contractile phenotype, but following injury or during atherosclerotic plaque formation the secretory synthetic phenotype is expressed. Recently it has been shown that gap junction connexin43 messenger RNA levels are six times higher in cultured smooth muscle cells in the synthetic phenotype than in intact aorta. We have modulated rabbit aortic smooth muscle cells in culture between the synthetic phenotype and one resembling the contractile phenotype, and correlated gap junction expression with phenotype. A dual labelling technique with antibodies against smooth muscle myosin and a synthetic peptide constructed to match a portion of the connexin43 gap junction protein was used for these experiments. Gap junctions are numerous between synthetic phenotype cells but few are observed between contractile cells. Rat aortic smooth muscle cells were also cultured and the growth and structure of gap junctions followed in the synthetic phenotype by use of freeze-fracture electron microscopy and immunohistochemical techniques. Junctional plaques are similar in structure to those observed in cardiac muscle, their size and number increasing with time in culture. The increased numbers of gap junctions between synthetic phenotype smooth muscle cells may be important during vessel development, following injury, or in atherosclerotic plaque formation.

Animals↗