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Biomedical subjects

L Sherman

Publications and source records attributed to L Sherman.

At least 55 records · Page 3Linked to original sources
PubMed1996

Serum- and calcium-induced differentiation of human keratinocytes is inhibited by the E6 oncoprotein of human papillomavirus type 16.

Transfection of the E6 and E7 genes of the high-risk human papillomaviruses (HPVs) into primary genital keratinocytes generates colonies of proliferating cells which are resistant to calcium- and serum-induced terminal differentiation. To genetically map the HPV gene(s) responsible for this cellular phenotype, we cloned cDNAs for full-length E6, full-length E7, four truncated E6 splice variants (E6I to E6IV), and a series of E6 C-terminal truncation mutants into a simian virus 40 expression vector. The E6 proteins were tagged with the AU1 epitope at the C terminus to verify their expression in COS cells by immunoprecipitation and immunofluorescence. Transfection of the full-length E6 protein, either wild type or epitope tagged, induced calcium- and serum-resistant keratinocyte colonies, but the truncated E6 variants and full-length E7 protein did not. E6-induced colonies, while altered in response to serum and calcium, could not be established into cell lines without the combined presence of the E7 protein, further exemplifying the independent roles of E6 and E7 in cell differentiation and cell proliferation. The E6 C-terminal deletion mutants defined two distinct functional domains between amino acids 120 and 151. Amino acids 120 to 151 contained an apparent bipartite nuclear localization signal, whereas amino acids 132 to 141 were required for the induction of resistance to calcium- and serum-induced differentiation and for immortalization of human keratinocytes in conjunction with E7.

Alternative Splicing↗
PubMed1996

Insulin resistance and development of diabetes mellitus associated with megestrol acetate therapy.

We describe a case of diabetes mellitus induced by megestrol acetate in a patient with the acquired immunodeficiency syndrome. Metabolic studies including an arginine infusion test excluded an insulinopenic state and suggested insulin resistance as the underlying mechanism for hyperglycaemia. Withdrawal of megestrol acetate resulted in rapid correction of all metabolic abnormalities and eliminated the need for exogenous insulin therapy.

Adult↗
PubMed1995

The role of CD44 splice variants in human metastatic cancer.

The large family of CD44 splice variants are likely to serve multiple functions in the embryo and in the adult organism. This is reflected in their complex patterns of expression. In molecular terms these functions are largely unknown. Certain splice variants (CD44v) can promote the metastatic behaviour of cancer cells. In human colon and breast cancer the presence of epitopes encoded by exon v6 on primary resected tumour material indicates poor prognosis. Metastasis-promoting splice variants differ from those that seem not to have a role in the induction of metastasis by the formation of homomultimeric complexes in the plasma membrane of cells. This may increase their affinity to ligands such as hyaluronate. The affinity can be further regulated over a range from low to very high by cell-specific modification. The fact that CD44v epitopes are found on normal epithelial cells such as skin, cervical epithelium and bladder enforces cautious evaluation of the significance of CD44v expression in human cancer. Nevertheless, certain epitopes can serve as tools in early diagnosis of certain cancers and will facilitate the development of specific targeted therapy.

Biomarkers, Tumor↗
PubMed1995

Regulated expression of neurofibromin in migrating neural crest cells of avian embryos.

Neurofibromatosis type 1 (NF1) is a common human genetic disease involving various neural crest (NC)-derived cell types, in particular, Schwann cells and melanocytes. The gene responsible for NF1 encodes the protein neurofibromin, which contains a domain with amino acid sequence homology to the ras-guanosine triphosphatase activating protein, suggesting that neurofibromin may play a role in intracellular signaling pathways regulating cellular proliferation or differentiation, or both. To determine whether neurofibromin plays a role in NC cell development, we used antibodies raised against human neurofibromin fusion proteins in western blot and immunocytochemical studies of early avian embryos. These antibodies specifically recognized the 235 kD chicken neurofibromin protein, which was expressed in migrating trunk and cranial NC cells of early embryos (E1.5 to E2), as well as in endothelial and smooth muscle cells of blood vessels and in a subpopulation of non-NC-derived cells in the dermamyotome. At slightly later stages (E3 to E5), neurofibromin immunostaining was observed in various NC derivatives, including dorsal root ganglia and peripheral nerves, as well as non-NC-derived cell types, including heart, skeletal muscle, and kidney. At still later stages (E7 to E9), neurofibromin immunoreactivity was found in almost all tissues in vivo. To determine whether the levels of neurofibromin changed during melanocyte and Schwann cell development, tissue culture experiments were performed. Cultured NC cells were found to express neurofibromin at early time points in culture, but the levels of immunoreactivity decreased as the cells underwent pigmentation. Schwann cells, on the other hand, continued to express neurofibromin in culture. These data suggest, therefore, that neurofibromin may play a role in the development of both NC cells and a variety of non-NC-derived tissues.

Animals↗
PubMed1995

Schwann cell tumors express characteristic patterns of CD44 splice variants.

Members of the CD44 family of cell surface hyaluronate-binding proteins have been implicated in cell migration, cell-matrix interactions and tumor progression. To determine whether these proteins might play a role in the normal functions of Schwann cells and in their tumorigenesis, we examined the patterns of CD44 expression in Schwann cells from rat peripheral nerve, rat Schwann cell tumor lines, and human schwannomas. Normal rat spinal nerves and primary Schwann cell cultures expressed standard CD44 (CD44s) but not alternatively spliced variant isoforms. In contrast, rat Schwann cell tumor lines expressed both CD44s and a number of variants, including proteins containing sequences encoded by exon v6. Furthermore, we found that these cell lines bind hyaluronate, and that their cell surface hyaluronate binding correlates with CD44 expression. All of the human schwannomas also expressed CD44 variants, especially epitopes encoded by exon v5, the border between v7 and v8, and v9-10. These data indicate that Schwann cells normally express CD44s, that Schwann cell tumors express both CD44s and particular variants of CD44, and that CD44s and possibly variants of CD44 are involved in hyaluronate recognition by Schwann cell tumors.

Alternative Splicing↗
PubMed1995

Comparative analysis of HLA polymorphism at the serologic and molecular level in Moroccan and Ashkenazi Jews.

The Jewish people comprise two major groups, one encompassing the Jews of Ashkenazi (Central and Eastern European) origin and the other including those of Sephardic (Middle Eastern and North African) descent. To the latter belong the Jews of Moroccan stock, who form the largest Jewish subgroup among the non-Ashkenazi population living in Israel. As the members of each of these groups differ in physiognomy and life style, it was of interest to investigate whether these differences are also reflected in their respective HLA compositions. To this end, 132 subjects of Ashkenazi and 113 individuals of Moroccan origin residing in Israel were tested and the results compared with data for other populations made available by the 11th International Histocompatibility Workshop. Comparison between their HLA profiles and those of non-Jews revealed that the Jewish groups in some aspects resembled one another but in others showed disparities. The dissimilarities between the various groups are expressed in terms of gene and haplotype frequencies, as well as in HLA-disease associations (as for example rheumatoid arthritis, erosive lichen planus, primary Sjögren's syndrome, pemphigus vulgaris). However, both Jewish groups shared some unique features with respect to HLA class II allelic frequencies, pointing to a common ancestry.

Adolescent↗
PubMed1995

Functional and mobility impairments associated with Paget's disease of bone.

OBJECTIVE: To determine if patients with Paget's disease of bone involving the tibia, femur, and/or acetabular portion of the ilium had more impairments in function and mobility than age- and sex-matched control subjects. PATIENTS AND METHODS: A case control study with Paget's disease patients selected from a center for bone disease at a tertiary medical center; control subjects were volunteers from the Duke University Aging Center subject registry. Demographic characteristics, physical examination and serum alkaline phosphatase levels were obtained. Radiographs of the pelvis and lower extremities were evaluated by a radiologist. All participants completed a Functional Status Questionnaire (FSQ). Mobility measures included mobility skills protocol, 10-foot walk time, 360-degree turn left (number of steps), and 6-minute walk distance. RESULTS: The 12 Paget's disease patients were no different in age (70.7 +/- 6.2 years) than the 12 control subjects (69.5 +/- 6.2 years). Serum alkaline phosphatase levels were elevated in Paget's patients (539 +/- 530 IU/L), and normal in control subjects (85 +/- 17 IU/L). In addition to Paget's disease, radiographs showed joint space loss in joints proximate to the diseased bone. On the FSQ scales Paget's disease patients had significantly lower scores in basic activities of daily living (P < .05), instrumental activities of daily living (P < .001), and social activity than control subjects (P < .05). There was no difference between the groups on scales measuring mental health and quality of social interaction. On mobility measurements, Paget's disease patients showed significant impairments when compared with control subjects: mobility skills protocol score (22.5 +/- 2.5 vs 25.6 +/- 0.7, P < .001); 10-foot walk (3.96 +/- 1.3 vs 2.55 +/- 0.5 seconds, P < .001); 360 degree turn left (8.0 +/- 1.0 vs 5.9 +/- 0.6 steps, P < .001); and 6-minute walk (342.0 +/- 108.5 vs 519.4 +/- 100 meters, P < .001). CONCLUSION: When compared with control subjects, patients who have Paget's disease of bone involving the tibia, femur, or acetabular portion of the ilium have clinically and statistically significant functional and mobility impairments compared to age- and gender-matched controls.

Activities of Daily Living↗
PubMed1995

How short is too short?

A review of growth parameters should be a routine part of pediatric care. Children and parents need to be helped in understanding normal growth and development. Variations in growth should be explained, and concerns of parents and children openly discussed. Age appropriate educational materials are often helpful. Children with abnormal growth should be referred promptly for definitive diagnosis, selection of treatable candidates, and monitoring.

Adolescent↗
PubMed1994

Characterization of cDNAs species encoding the Tat protein of caprine arthritis encephalitis virus.

Two distinct species of caprine arthritis encephalitis virus (CAEV) tat cDNAs were isolated early after infection of a Himalayan tahr cell line. Sequence analyses predicted that one cDNA (pCEV/e1) represented a polycistronic transcript that encodes Tat and Rev as well as an N-terminally truncated transmembrane protein and a protein, designated X, whose function is unknown; whereas the other cDNA (pCEV/f1) encodes Tat and the env gene products. pCEV/e1 trans-activated a CAEV LTR-chloramphenicol acetyltransferase reporter gene in goat synovial membrane cells. This activity was shown to be encoded by the Tat open reading frame by analysis of a deletion mutant. Because the pCAEV/f1 insert was unstable in plasmid form, its Tat activity could not be convincingly demonstrated. The target sequences for Tat within the CAEV LTR were localized to the U3 region which, when placed in either orientation upstream of heterologous promoters, was able to confer responsiveness to Tat.

Amino Acid Sequence↗
PubMed1994

Cellular distribution, subcellular localization and possible functions of basic and acidic fibroblast growth factors.

The distribution in the rat nervous system of acidic and basic fibroblast growth factors (FGFs) was analysed by a combination of biochemical and anatomical methods. Acidic FGF (aFGF) was found to be present exclusively in specific neuronal populations, such as motor neurons and basal forebrain cholinergic neurons. Basic FGF (bFGF) was found in astrocytes and in neurons in hippocampal area CA2. Within labelled astrocytes and CA2-neurons, bFGF was detected in both the cytoplasm and the nucleus. The levels of intracellular bFGF were manipulated by antisense oligonucleotide treatment of cultures of developing neural crest cells. Results indicated that the amount of melanogenesis in the cultures is likely to be regulated by intracellular, possibly nuclear bFGF.

Animals↗
PubMed1994

HLA polymorphism in Moroccan Jewry.

The Moroccan Jewish community living in Israel shows a relatively large genetic distance from other North African Jewish communities. In this work the polymorphism of HLA class I and class II determinants, as defined by serology and oligotyping, is analyzed in 113 healthy unrelated Jews of Moroccan stock. The class I antigens HLA-A1, -B44, and -Cw7 showed the highest frequency, while the most prevalent class II variants were DRB1*0701 and *1104, DQA1*0501, and DQB1*0201 and *0301. HLA A1-B13-DR7, A2-B51-DR10, and A1-B44-DR13 were the most typical three-locus haplotypes. Although the antigen frequency distribution of the Moroccan Jews falls within the Caucasian diversity range, this community has a unique pattern in terms of antigen, gene, and haplotype frequencies. Thus, in the Moroccan Jews DRB1*1305, an allele believed to be the result of a recombination event between DRB1*1301-1302 and DRB1*1101, is represented to a much larger extent than in all the other population groups studied at the 11th IHWS. This allele may therefore be a typical Jewish variant. A particular finding was the high frequencies of HLA-B13, B52, and DR10, alleles common among some Oriental populations. The answer to this enigmatic phenomenon probably must be sought in the tortuous history of this community.

Alleles↗
PubMed1994

Hyaluronate receptors: key players in growth, differentiation, migration and tumor progression.

Hyaluronate (HA) is an abundant component of extracellular matrix that is believed to be crucial in many cellular processes, including tissue remodeling, the creation of cell-free spaces, inflammation and tumorigenesis. Although several well characterized proteins within the extracellular matrix associate with HA, it is now clear that cells can also bind and respond to HA directly, via cell-surface HA-binding proteins. The cDNAs coding for two families of such proteins, CD44 and RHAMM, have been cloned and characterized. These proteins have been implicated in a number of physiological processes, including cell migration, lymphocyte activation and tumor progression. Although many of these processes depend on an association with HA, some are apparently HA-independent, suggesting that other ligands for these receptors may be involved.

Animals↗
PubMed1994

Detection of interleukin-1 receptors in human epidermis. Induction of the type II receptor after organ culture and in psoriasis.

Normal human epidermis is a rich source of biologically active interleukin-1 alpha (IL-1 alpha). Keratinocytes both synthesize this cytokine and respond to it via cell surface receptors (IL-1R), suggesting that the IL-1 system may play an important role in normal epidermal physiology and inflammation. In this study, we have examined the expression of IL-1R in normal and psoriatic epidermis, as judged at a functional level by the capacity to bind 125I-labeled IL-1 alpha (the principal IL-1 species present in epidermis) and by immunostaining with antibodies specific for each species of IL-1R. IL-1R was not readily detectable by either technique in normal, freshly isolated human epidermis. However, in lesional psoriasis or normal epidermis after 24 hours of organ culture, expression of IL-1R was dramatically induced, especially in basal keratinocytes. Immunostaining and antibody blocking studies demonstrated the induced IL-1R to be the type II species, a nonsignal transducing molecule previously demonstrated only on leukocytes. The Ka of this receptor was comparable to that previously demonstrated in vitro. mRNA for both species of IL-1R could be demonstrated by reverse transcriptase-polymerase chain reaction in fresh and cultured epidermis. These in vivo findings were confirmed in culture, where normal human keratinocytes expressed few IL-1R at rest but large numbers of type II IL-1R after activation by phorbol ester or interferon-gamma. We conclude that under resting conditions, epidermal expression of IL-1R is low. However, the potential for keratinocytes in vivo to express large numbers of the nonsignal transducing type II IL-1R is evident from both organ cultured and psoriatic epidermis. The in vitro induction of keratinocyte IL-1R by interferon-gamma suggests that this cytokine may be involved in the induction of type II IL-1R in inflammatory skin disease. The presence of bioactive IL-1 in epidermis, coupled with the inducible expression of the decoy type II IL-1R, indicates the existence of a highly regulated system of autocrine stimulation of keratinocytes by IL-1.

Autoradiography↗
PubMed1994

Analysis of molecular functions of the tumor metastasis promoting surface molecule CD44v4-v7 using transgenic mice.

In certain circumstances, metastatic tumor cells may mimic the molecular properties and behaviour of lymphocytes. Support for this hypothesis has come from the observation that activated lymphocytes and some tumor cells need a CD44 variant isoform (CD44v) to survive and/or expand in the lymphatic system. CD44 variant (CD44v) isoforms are created by differential splicing from a pool of at least ten variant exons (v1-v10), the encoded sequences of which are absent in the CD44 standard isoform (CD44s). To dissect the molecular interactions of CD44v, transgenic animals have been generated that constitutively express a variant of CD44 containing sequences encoded by exons v4 to v7 on the surface of T cells. Lymphocytes derived from these transgenic animals show accelerated entry into S phase upon antigenic stimulation, and a subpopulation of the cells constitutively express early lymphocyte activation markers. Our data support the hypothesis that the presence of CD44v4-v7 on the surface of T cells mediates intercellular or intracellular processes which result in the promotion of T cells towards a preactivated state.

Animals↗
PubMed1993

Basic fibroblast growth factor (bFGF) acts intracellularly to cause the transdifferentiation of avian neural crest-derived Schwann cell precursors into melanocytes.

We previously found that cultured neural crest-derived cells from embryonic quail peripheral nerves, which consist mostly of Schwann cell precursors, gave rise to melanocytes following treatment with basic fibroblast growth factor (bFGF) or 12-O-tetradecanoyl phorbol-13-acetate (TPA). Here, we show that antisense deoxyoligonucleotides targeted against two regions of the bFGF mRNA transcript blocked this TPA-induced transdifferentiation of Schwann cell precursors. Neither sense nor scrambled antisense control oligonucleotides had any effect in this regard. TPA increased bFGF protein expression in cell lysates but not in conditioned media from these cultures, and this expression was localized to the nucleus and cytoplasm. Furthermore, bFGF-neutralizing antibodies and inositol-hexakisphosphate (InsP6) both inhibited pigmentation caused by exogenous bFGF, but had no affect on TPA-induced melanogenesis, suggesting that bFGF is not released by these cells. These data indicate that bFGF is necessary for the TPA-induced transdifferentiation of Schwann cell precursors into melanocytes and that bFGF acts via an intracrine mechanism.

Animals↗
PubMed1993

A study on financial viability of clinics and physician practices in under-served areas of Wisconsin: summary of results with recommendations.

A survey of 21 physicians and clinic managers located in Health Professional Shortage Areas (HPSAs) and other under-served areas in Wisconsin found that to combat increasing costs, low reimbursement rates, and increasing charity care demands, several practices rely on outside sources of funding to remain financially viable. Also, the financial viability of physician practices in under-served areas of Wisconsin is threatened more by the low reimbursement rates of Medicaid and Medicare than by the provision of charity care. Though few are limiting the number of Medicare and uninsured patients they will treat, many have begun implementing cost containment measures, including more strict collection policies. There are also indications of restricted access for Medicaid patients.

Health Services Accessibility↗
PubMed1993

A study on financial viability of clinics and physician practices in under-served areas of Wisconsin: the primary care physician shortage problem and collection issues.

A survey of 21 physicians and clinic managers in Health Professional Shortage Areas (HPSAs) and other under-served areas in Wisconsin found that to combat increasing costs, low reimbursement rates and increasing charity care demands, several practices rely on outside sources of funding. Also, the financial viability of physician practices in underserved areas of Wisconsin is threatened more by the low reimbursement rates of Medicaid and Medicare than by the provision of charity care. Though few are limiting the number of Medicare and uninsured patients they will treat, many have begun implementing cost containment measures, including more strict collection policies. There are also indications of restricted access for Medicaid patients.

Cost-Benefit Analysis↗