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Biomedical subjects

H Feiner

Publications and source records attributed to H Feiner.

At least 19 recordsLinked to original sources
PubMed2001

Delta N89 beta-catenin induces precocious development, differentiation, and neoplasia in mammary gland.

To investigate the role of beta-catenin in mammary gland development and neoplasia, we expressed a stabilized, transcriptionally active form of beta-catenin lacking the NH(2)-terminal 89 amino acids (Delta N 89 beta-catenin) under the control of the mouse mammary tumor virus long terminal repeat. Our results show that Delta N 89 beta-catenin induces precocious lobuloalveolar development and differentiation in the mammary glands of both male and female mice. Virgin Delta N 89 beta-catenin mammary glands resemble those found in wild-type (wt) pregnant mice and inappropriately express cyclin D1 mRNA. In contrast to wt mammary glands, which resume a virgin appearance after cessation of lactation, transgenic mammary glands involute to a midpregnant status. All transgenic females develop multiple aggressive adenocarcinomas early in life. Surprisingly, the Delta N89 beta-catenin phenotype differs from those elicited by overexpression of Wnt genes in this gland. In particular, Delta N 89 beta-catenin has no effect on ductal side branching. This suggests that Wnt induction of ductal branching involves additional downstream effectors or modulators.

Adenocarcinoma↗
PubMed2000

Initiation of translation from a downstream in-frame AUG codon on BRCA1 can generate the novel isoform protein DeltaBRCA1(17aa).

Expression of the breast and ovarian cancer gene BRCA1 is regulated at both the transcriptional and post-transcriptional levels. We found that the expression of the BRCA1 protein may also be regulated at the translational level. In addition to an AUG start codon at position 1, BRCA1 mRNA has a second in-frame AUG (+17) that acts as an alternative start codon to generate a novel BRCA1 protein that lacks the first 17 amino acids (DeltaBRCA1(17aa)). We fused cDNAs encoding the second exon of BRCA1 of the wild-type BRCA1 gene (wt-BRCA1) and a mutated BRCA1 gene (mt-BRCA1), in which the first initiation site and its Kozak consensus sequence were abolished, with the nucleophosmin (NPM) reporter gene and used them for in vitro and in vivo translation assays. In both systems, the wt-BRCA1-NPM constructs produced two distinct proteins (18 and 16 kD) begun from the first and second AUGs. The mt-BRCA1-NPM constructs produced only the shorter 16-kD protein lacking the first 17 amino acids of the BRCA1 gene. Next, we analysed the N-terminal protein sequence of purified BRCA1 protein from normal thymocytes and found two different BRCA1 proteins, derived from translation of the first and second in-frame AUGs. Thus, BRCA1 protein expression can be regulated at the translation level in normal cells. Characterization of DeltaBRCA1(17aa) may shed light on the function and regulation of BRCA1 in normal cells as well as the pathogenesis of breast and ovarian cancers. Oncogene (2000).

Amino Acid Sequence↗
PubMed2000

Multiplex genotype analysis of invasive carcinoma and accompanying proliferative lesions microdissected from breast tissue.

To understand the genetic basis of breast cancer in a comprehensive way, purported precursor lesions need to be analyzed at a large number of genetic marker loci and compared with each other and with the invasive components. However, the microscopic size of most of these lesions and the very small amount of material that can be obtained through microdissection limit the number of loci that can be included in the analysis. To address this issue, a multiplex genotyping approach has been developed. With this approach, polymorphic sequences at 28 marker loci were amplified simultaneously from the micro-dissected components in 5-microm paraffin-embedded breast tissue sections. The genotypes of the lesions were determined after resolving the amplified allelic products by denaturing gradient gel electrophoresis. Because the material isolated from each lesion in a single 5-microm section was sufficient for several 28-locus assays and several successive tissue sections with the same set of lesions may be prepared, it is possible to determine the genotype of each lesion at hundreds of genetic marker loci that may well cover the human genome. Analyzing a sufficient number of cases may yield information that could be used to understand the genetic basis of breast cancer development in a comprehensive way.

Alleles↗
PubMed1999

gamma-heregulin is the product of a chromosomal translocation fusing the DOC4 and HGL/NRG1 genes in the MDA-MB-175 breast cancer cell line.

gamma-heregulin is a recently described novel isoform of the heregulin/neuregulin class of EGF-like ligands that bind to and activate receptors of the ErbB family. Deregulated signaling through the heregulin-ErbB pathway is thought to be implicated in the development of a subset of human breast cancers. gamma-heregulin has been found to be expressed in the culture supernatant of MDA-MB-175, a breast carcinoma cell line. gamma-heregulin is characterized by the presence of a large N-terminal peptide extension that is not found in other heregulin isoforms. Here we report that this unique N-terminal extension of gamma-heregulin is identical to the N-terminus of DOC4, a product of a recently identified CHOP-dependent stress-induced gene. Human DOC4 and the heregulin-encoding genes map to different chromosomes and the MDA-MB-175 cell line contains a chromosomal translocation that leads to the fusion of DOC4 and HGL, on chromosomes 11 and 8, respectively. Thus, gamma-heregulin is a product of a mutant fusion gene and not a bona fide normal isoform. We speculate that the mutation may be selected for by virtue of its ability to activate ErbB signaling through the production of an autocrine ligand.

Breast Neoplasms↗
PubMed1998

Repression of interleukin-2 mRNA translation in primary human breast carcinoma tumor-infiltrating lymphocytes.

Human breast carcinoma tumor-infiltrating lymphocytes (TIL) express activation antigens in situ indicative of ongoing immune response-CD28, CD45RO, CD69, CD71, and DR. However, interleukin 2 (IL-2) receptor was poorly expressed: CD25 was detected in only 1/24 samples and CD122 in only 2/24 samples. Furthermore, isolated breast cancer TIL were defective in proliferative response but recover when treated with recombinant IL-2. Nineteen of 24 tumor samples expressed B7-1, B7-2, and CD28 protein, showing that absence of costimulator proteins or counter ligand was not the basis for TIL proliferative deficit. Expression of IL-2 activity was not detected; however, mRNA encoding IL-2 was produced and translatable in vitro. These findings show that human breast cancer tumor-induced repression of IL-2 RNA translation is the basis of failure of TIL to express the IL-2 receptor and subsequent T cell hyporesponsiveness.

Breast Neoplasms↗
PubMed1996

Cytology of extranodal Ki-1 anaplastic large cell lymphoma.

Ki-1-positive anaplastic large-cell lymphoma (ALCL) is an uncommon neoplasm which may present with extranodal as well as nodal disease. By definition, the tumor cells are immunoreactive for Ki-1 or Ber-H2 antigen (CD30). There have been few published cytologic descriptions of this lymphoma, or of its detection in extranodal sites. We describe the cytologic findings in five cases of extranodal Ki-1 lymphoma. Cytologic findings in all five cases were similar and consisted of a heterogeneous population of lymphocytes and bizarre, pleomorphic tumor cells. These cells were characterized by generous amounts of vacuolated, basophilic cytoplasm, eccentric, multilobulated nuclei with some showing "wreath-like" configurations. Some nuclei contained huge nucleoli simulating Reed-Sternberg cells. All cases showed the characteristic surface membrane and cytoplasmic paranuclear dot-like staining for CD30. Our findings indicate that fine-needle aspiration and exfoliative cytology have a useful role in the diagnosis of Ki-1 ALCL in extranodal sites. Furthermore, effusions containing anaplastic cells suspicious for lymphoma, particularly in AIDS patients, should be immunostained with antibodies to CD30.

Adolescent↗
PubMed1996

Morphological and biological characteristics of mammogram-detected invasive breast cancer.

Thirty-nine mammographically detected, (M-detected) small invasive carcinomas of the breast (< or = 5 mm) were compared with 78 consecutive clinical cancers (> or = 10 mm) for a variety of morphological and biological markers of prognostic importance. There were more tubular carcinomas in the M-detected group (12.8% v 3.8%), but this did not reach statistical significance. Incidences of other histological types were similar. The types of associated in situ component were similar in the two groups. M-detected cancers were of lower overall grade (P < .001), lower architectural and nuclear grades (P = .0164 and P < .0001 respectively), and had fewer mitotic cells (P < .0001). None showed positive lymph nodes (P < .0001). Estrogen and progesterone receptor expression was similar in both groups. M-detected cancers expressed p53 nuclear protein less frequently than clinical cancers (P = .0398), had lower levels of microvessel density (P = .0001), and were more often diploid (P = .0131). S-phase of diploid tumors in the two groups was similar, but S-phase of aneuploid tumors was lower in the M-detected group (P = .0057). Ki67 expression was lower in M-detected cancers (P < .0001). In conclusion, M-detected small breast cancers, although invasive, represent an evolutionary phase of breast cancer that generally lacks morphological and biologic markers of aggressive behavior. The presence or absence of these markers, collectively, may explain the influence of tumor size on survival in patients with breast cancer.

Breast Neoplasms↗
PubMed1996

Effects of amlodipine on glomerular filtration, growth, and injury in experimental hypertension.

The objective of this study was to determine whether the calcium antagonist amlodipine could slow the progression of chronic renal disease. We examined the effects of amlodipine on kidney structure and function in two experimental models of hypertension. In the first study, adult, male Munich Wistar rats underwent uninephrectomy and were given weekly injections of desoxycorticosterone and 1% saline for drinking. Rats ingested normal chow or chow containing amlodipine for 8 weeks. The drug reduced systemic blood pressure, but glomerular filtration rate, kidney weight, proteinuria, and morphological evidence of glomerular injury were not affected. In the second study, male spontaneously hypertensive rats underwent uninephrectomy at 5 weeks of age and were followed for 6 months, during which they received no therapy or amlodipine. The drug dose was determined in preliminary studies to be the highest dose not associated with marked growth retardation. Again, although systemic blood pressure was significantly reduced by amlodipine, proteinuria and the prevalence of glomerulosclerosis were similar in amlodipine-treated and control spontaneously hypertensive rats. Micropuncture studies revealed that glomerular pressure remained elevated in amlodipine-treated spontaneously hypertensive rats. Kidney weight and glomerular volume were also similar in amlodipine-treated and control rats. Amlodipine also failed to inhibit platelet aggregation. Therefore, antihypertensive therapy with amlodipine fails to reduce glomerular pressure in spontaneously hypertensive rats as well as glomerular size and injury in spontaneously hypertension rats and desoxycorticosterone-salt hypertension. Although other dihydropyridine calcium antagonists have been found to reduce experimental glomerular injury, these data suggest that amlodipine may not prevent hypertensive nephrosclerosis.

Amlodipine↗
PubMed1995

Mycosis fungoideslike T-cell cutaneous lymphoid infiltrates in patients with HIV infection.

Cutaneous patch and plaque lesions, and erythroderma may suggest mycosis fungoides both clinically and histopathologically in HIV+ patients. However, in some cases, this diagnosis is questionable. Five such cases are presented. When we compared these cases with cases of mycosis fungoides unassociated with HIV infection, we found less concordance among dermatopathologists in making a histopathological diagnosis, a greater proportion of CD8 than CD4 T cells in the cutaneous infiltrates, and no instances of demonstrated clonality of the cutaneous T-cell infiltrates in the HIV+ group. We conclude that CD8 T-cell predominant dermatoses may simulate mycosis fungoides in HIV+ patients.

CD4-Positive T-Lymphocytes↗
PubMed1995

Primary lymphomatous effusions in AIDS: a morphological, immunophenotypic, and molecular study.

Lymphomas were documented in pleural effusions or ascites in 18 human immunodeficiency virus-positive (HIV+) patients. Eleven of 12 with clinical data had acquired immunodeficiency syndrome before the diagnosis of lymphoma. In 13 of 15 with data available, a body cavity was the site of initial presentation of lymphoma. Cytological subtypes were large cell immunoblastic, n = 7; large cell anaplastic, n = 6; and large cell NOS, n = 5. The high incidence of anaplastic large cell lymphoma and the conspicuous absence of Burkitt's lymphoma differ strikingly from HIV-associated lymphomas generally. Immunophenotypically, two cases were B-cell (CD19/20+, sIg+, CD/5-), one was T-cell (CD3+, CD5+, CD4+, CD8-, CD19/20-, sIg-), and 15 were null (CD45+, HLA-DR+ CD19/20-, sIg-, CD3/5-). This 83% incidence of null immunophenotype contrasts sharply with a 9% incidence among 35 tissue-based lymphomas in HIV+ patients that were similarly studied and a 0% null immunophenotype among 11 lymphomatous effusions in patients without HIV risk factors. Seven of the 18 HIV-associated lymphomas expressed CD30. Four of five cases with null immunophenotype showed Ig heavy-chain gene rearrangement, two had clonal Epstein-Barr virus integration, and none had MYC protooncogene rearrangement. These cases belong to a subgroup of high-grade HIV-associated lymphomas that occur in the setting of profound immunosuppression in which immunoblastic morphology predominates and MYC rearrangement is encountered only infrequently.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Visceral leishmaniasis in the acquired immunodeficiency syndrome: report of two cases.

Core biopsies of the bone marrow are indispensable in the evaluation of fever of unknown etiology in human immunodeficiency virus-positive patients. We report two patients in whom visceral leishmaniasis was diagnosed based on the typical morphology, staining characteristics, and ultrastructure of the organisms.

AIDS-Related Opportunistic Infections↗
PubMed1992

Proto-oncogene analysis in multiple myeloma.

The genetic basis for the development of multiple myeloma (MM) remains poorly understood, in part because MM has thus far been relatively refractory to cytogenetic analysis. The few cases karyotyped have pointed to involvement of 11q13, site of the BCL1 proto-oncogene, or of 8q24, site of the MYC proto-oncogene. A recent molecular study detected rearrangements distal to the MYC gene in 16% of MM, using the MLVI-4 probe. The immunocytochemical demonstration of BCL2 protein overexpression in at least some cases of MM has suggested the possibility of translocation-mediated deregulation of the BCL2 proto-oncogene. The configuration of the BCL2 gene in MM, however, has not yet been defined using all available breakpoint probes. To address these issues, we studied 17 patients with plasma cell dyscrasias (16 MM, 1 plasmacytoma) by Southern blotting using the major breakpoint region (MBR), minor cluster region (MCR), and 5' cDNA (pB16) BCL2 breakpoint probes; with the BCL1 major translocation cluster (MTC) breakpoint probe; and with a probe to the MYC-associated MLVI-4 region (PA1.3SB). In all 17 cases, rearrangement of one or both alleles of the immunoglobulin heavy chain gene had been demonstrated, thereby confirming the presence of tumor DNA in the samples studied. None of the cases tested showed a rearrangement with the MBR BCL2 (0/16), MCR BCL2 (0/17), 5' cDNA BCL2 (0/16), BCL1 MTC (0/15), or MLVI-4 (0/15) probes. These results suggest that if BCL2 deregulation does indeed occur in MM, a mechanism other than translocation must be involved in most cases. Furthermore, rearrangements distal to the MYC gene, in the region of the MLVI-4 probe, may be less common than previously thought. Finally, a significant proportion of translocation breakpoints in band 11q13 may not be detected by the BCL1 MTC probe in MM, as is true in lymphomas.

Aged↗
PubMed1990

Lymphomatoid granulomatosis in the acquired immunodeficiency syndrome. Evidence of Epstein-Barr virus infection and B-cell clonal selection without myc rearrangement.

A case of lymphomatoid granulomatosis of lung that occurred in a patient with the acquired immunodeficiency syndrome (AIDS) was studied by light microscope, electron microscope, cell surface markers, and Southern blot test. Clonal selection of two clones of B-cells was seen. Two clones were infected with Epstein-Barr virus. There was no c-myc rearrangement. Lymphomatoid granulomatosis in patients with AIDS may represent multiclonal selection of B-lymphocytes in association with Epstein-Barr virus infection.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Clinical evaluation of high-frequency (ultrasonic) mechanical débridement in the surgical treatment of calcific aortic stenosis.

Repair of aortic valve stenosis due to calcific degeneration may lead to hemodynamic and clinical improvement without the problems inherent with prosthetic valves. We have evaluated the use of a device capable of débriding calcium, the Cavitron ultrasonic aspirator (CUSA), as an adjunct to mechanical débridement in the repair of calcific aortic stenosis. Ten patients (five women), ages 63 to 83 years, were studied by M-mode, two-dimensional, and Doppler echocardiography before and an average of 26 (range 3 to 124) days after this procedure. The degree of calcification of the valve cusps was clearly reduced. The maximal cusp excursion increased from 0.7 +/- 0.1 cm preoperatively to 1.5 +/- 0.4 cm postoperatively (p = 0.006). The peak aortic gradient fell from 80 +/- 36 mm Hg to 28 +/- 10 mm Hg (p = 0.0007). The mean aortic gradient fell from 53 +/- 20 mm Hg to 16 +/- 5 mm Hg (p less than 0.0001). Aortic valve area calculated by the continuity equation increased from 0.6 + 0.2 cm2 to 1.6 +/- 0.6 cm2 (p = 0.0009). No patient had more than mild aortic insufficiency preoperatively. Postoperatively, color Doppler flow mapping revealed severe aortic insufficiency in two patients. Seven patients had further echocardiographic evaluation 99 (range 33 to 196) days after the procedure. These studies revealed the development of severe aortic insufficiency in an additional four patients. Four patients with severe symptomatic aortic insufficiency eventually underwent aortic valve replacement. Pathology revealed scarring and retraction of the aortic cusps. Widening of the commissures was responsible for the severe aortic insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

The role of liver biopsies in psoriatic patients receiving long-term methotrexate treatment. Improvement in liver abnormalities after cessation of treatment.

Liver biopsy specimens from 168 patients who underwent a total of 364 biopsies were examined. Of 83 patients receiving biopsies before methotrexate treatment, 14 had one or more risk factors predictive of liver abnormality but they had normal pretreatment biopsy specimens. Among 17 patients with abnormal biopsy specimens before methotrexate treatment, only 1 had an identifiable risk factor and 5 had abnormal results of liver function tests. The probability of a normal biopsy specimen after methotrexate treatment dropped below 50% at a cumulative methotrexate dose of 3115 mg for the 31 patients with biopsy specimens from before and after methotrexate treatment and 5776 mg for those who had biopsies only after methotrexate treatment; this difference was statistically significant and is thought to be related to the fact that the patients who had biopsies before and after methotrexate treatment had received most of their medication by the parenteral rather than the oral route. A significant association existed between biopsy grade after methotrexate treatment and obesity. Other risk factors were not correlated with biopsy grade. Blood chemistry tests were not predictive of histopathologic findings. Eight of 11 patients with fibrosis or cirrhosis showed meaningful improvement in liver histologic findings after methotrexate treatment had been withdrawn for 6 months or more; none had progression of abnormalities.

Adolescent↗