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Biomedical subjects

J A Reed

Publications and source records attributed to J A Reed.

At least 19 recordsLinked to original sources
PubMed2005

Case-mix fails to explain variation in mastectomy rates: management of screen-detected breast cancer in a UK region 1997-2003.

Wide variation in the surgical management of breast cancer exists at hospital, regional, national and international level. To demonstrate whether variation in surgical practice observed at aggregate level between breast units persists following adjustment for case-mix, individual patient-level data from the Trent Breast Screening Programme Quality Assurance database (1997-2003) was analysed. Expected case-mix adjusted mastectomy rates were derived by logistic regression using the variables tumour size, site and grade, patient age and year of presentation, employing the region's overall case-mix adjusted practice as the reference population. The region's 11 breast screening units detected 5109 (3989 invasive) surgically managed primary breast cancers over the 6-year period. A total of 1828 mastectomies (Mx) were performed (Mx rate 35.8%, 95% confidence interval: 34.5-37.1%). Significant variation in mastectomy rates were observed between units (range 25-45%, P<0.0001), and persists following case-mix adjustment (P<0.0001). Two-fold variation in observed to expected unit mastectomy rate coefficient is demonstrated overall (range 0.66-1.36), increasing to almost four-fold variation in cancers less than 15 mm diameter (range 0.55-1.95). Significant variation in surgery for screen-detected primary breast cancer is not explained by case-mix. Further research is required to investigate potential patient and professional causative factors.

Aged↗
PubMed2004

Carcinoma with thymus-like differentiation arising in the dermis of the head and neck.

Carcinoma exhibiting thymus-like differentiation (CASTLE) is a rare, distinct tumor of the thyroid gland or soft tissue of the head and neck that may simulate primary squamous cell carcinoma or lymphoepithelioma, and which contains features reminiscent of thymic differentiation including Hassall's corpuscles, occasional perivascular spaces, and the presence of lymphocytes. Ectopic thymic tissue may result from incomplete descent or persistence of the cervical portion of the thymus and may occur anywhere along the course of the embryonic descent from the angle of the mandible to the sternal notch. Herein, we report two cases of dermal extrathyroidal CASTLE. The differential diagnosis of squamoid carcinoma with features of thymic differentiation includes extrathyroidal CASTLE, a primary squamous cell carcinoma with thymic differentiation, lymphoepithelioma-like carcinoma of the skin, and metastatic squamous cell carcinoma of unknown primary. It is essential that the latter two be ruled out before accepting the diagnosis of an extrathyroidal carcinoma with thymus-like differentiation.

Adult↗
PubMed2001

Cytoplasmic localization of the oncogenic protein Ski in human cutaneous melanomas in vivo: functional implications for transforming growth factor beta signaling.

The oncogenic protein Ski associates with Smad proteins and counteracts their activation of gene expression and growth inhibition in response to transforming growth factor beta (TGF-beta). Here we show that Ski protein levels are increased in all 44 human melanoma tumor tissues analyzed in vivo. In addition, Ski subcellular localization changes from nuclear, in preinvasive melanomas (melanomas in situ), to nuclear and cytoplasmic in primary invasive and metastatic melanomas. Furthermore, Ski/Smad association in the cytoplasm seems to prevent Smad3 nuclear translocation in response to TGF-beta. The biological significance of Ski overexpression in melanomas was established by showing that down-regulation of Ski levels, by antisense Ski vectors, restored TGF-beta-mediated growth inhibition. Such inhibition is apparently mediated by up-regulation of the cyclin-dependent kinase-I p21(Waf-1) and inhibition of cyclin-dependent kinase 2 activity. Our results suggest that high levels of Ski in human melanomas produce a disruption of TGF-beta signaling phenotypically similar to that in cells harboring mutations in TGF-beta receptors or Smad proteins, and this may represent a significant event in the progression of melanomas in vivo.

Cell Division↗
PubMed2001

S100A6 expression in fibrohistiocytic lesions.

BACKGROUND: S100A6, an S100 calcium-binding protein, has been found in a variety of cutaneous and extracutaneous lesions including: melanocytic nevi, melanoma, some salivary gland and epithelial tumors, and malignant fibrous histiocytoma (MFH). Dermal dendrocytes (DD) in the papillary dermis of skin also express S100A6 protein. We evaluated a variety of cutaneous fibrohistiocytic lesions to determine if the immunophenotype of S100A6 positivity can be expanded to include some or all of these lesions. METHODS: Formalin-fixed, paraffin-embedded tissues from fibrous papules (FP, 20), dermatofibromas (DF, 20), dermatofibrosarcoma protuberans (DFSP, 5), atypical fibroxanthomas (AFX, 5), oral fibromas (3), digital fibroma (1), and dermatomyofibroma (1) were evaluated with antibodies to S100A6, S100B, factor XIIIa, and MAC387 using a one-hour capillary action-based immunohistochemical procedure. RESULTS: DD in 20/20 FP, 19/20 DF, and 4/4 fibromas stained positively with anti-S100A6 in a pattern similar to anti-factor XIIIa. No DFSP cases stained with anti-S100A6. Anti-S100A6 showed superior staining to anti-factor XIIIa in 4/5 AFX cases. CONCLUSIONS: The immunophenotypes of some fibrohistiocytic lesions can be expanded to include S100A6 protein. With the exception of AFX, the use of anti-S100A6 does not appear to offer added benefit over anti-factor XIIIa in the differential diagnosis of fibrohistiocytic lesions.

Antibodies, Monoclonal↗
PubMed2001

S100A6 preferentially labels type C nevus cells and nevic corpuscles: additional support for Schwannian differentiation of intradermal nevi.

BACKGROUND: Melanocytic nevi typically show a morphologic sequence of maturation from epithelioid "type A" cells to fusiform, Schwann cell-like "type C" cells with dermal descent. Nevi may also produce Wagner-Meissner-like structures (nevic corpuscles). Previous studies have shown that this maturation of intradermal nevi recapitulates intermediate stages in Schwann cell development. In intradermal nevi, we have evaluated the pattern of S100A6 protein, a form of S100 found in Schwann cells. METHODS: Formalin-fixed, paraffin-embedded archival tissues were evaluated by immunohistochemistry using antibodies specific for S100A6 and S100B in 38 intradermal nevi (IDN). Ten neurofibromas (NF), 3 Schwannomas (SCH), 2 palisaded and encapsulated neuromas (PEN), and 2 granular cell tumors (GCT) were included as positive controls since these lesions have large numbers of Schwann cells. RESULTS: Melanocytic nevi demonstrated preferential anti-S100A6 staining of "type C" cells (36/38; 28 strong, 8 weak) and nevic corpuscles (25/38; 19 strong, 6 weak) compared to "type A" cells (17/38; 17 weak) and "type B" cells (17/38; 4 strong, 13 weak). All NF, SCH, and PEN stained strongly with anti-S100A6. Both GCT were negative with anti-S100A6 but positive with anti-S100B. CONCLUSIONS: The pattern of S100A6 expression in intradermal nevi further supports the hypothesis that maturation in these lesions recapitulates features of Schwann cell differentiation. The lack of S100A6 expression by both GCT suggests that these lesions have lost this feature of Schwann cells, which may play a role in their peculiar phenotypic appearance.

Cell Cycle Proteins↗
PubMed2001

Loss of expression of protein kinase C beta is a common phenomenon in human malignant melanoma: a result of transformation or differentiation?

As with most cancers, the aetiology of human cutaneous melanoma is likely to be multifactorial and to include the accumulation of irreversible alterations in an unknown number of genes. Elucidating this molecular progression necessitates both the identification of genetic perturbations at each clinically relevant stage, and the assessment of their impact on the normal melanocyte. The observation that the epidermal melanocyte, in contrast to metastatic melanoma cells, requires activation of the protein kinase C (PKC) pathway to facilitate growth in vitro indicates that one or more isoforms (or substrates) of this large and complex family of proteins are among those that undergo alteration during the development of malignant melanoma. Consequently, a number of studies have investigated the expression of various PKC family members in both melanocyte and melanoma cell lines, without a consensus of opinion as to which isoforms are of biological significance in melanoma development and progression. The present study involved a comprehensive evaluation of the PKC profile in normal melanocytes and in 16 metastatic melanoma cell lines. The results show that the major difference in isoform expression between epidermal melanocytes and melanoma cells is the loss of PKCbeta protein expression in 90% of melanoma cell lines. Examination of PKCbeta in benign and malignant melanocytic lesions revealed that this protein is either downregulated or absent in both naevi and metastatic melanomas. We conjecture that, although the loss of PKCbeta expression is a common phenomenon in malignant melanocytes, it may be related more to a normal process of melanocytic differentiation than to malignant transformation.

Blotting, Western↗
PubMed2001

GM-CSF regulates protein and lipid catabolism by alveolar macrophages.

Metabolism of surfactant protein (SP) A and dipalmitoylphosphatidylcholine (DPPC) was assessed in alveolar macrophages isolated from granulocyte-macrophage colony-stimulated factor (GM-CSF) gene-targeted [GM(-/-)] mice, wild-type mice, and GM(-/-) mice expressing GM-CSF under control of the SP-C promoter element (SP-C-GM). Although binding and uptake of (125)I-SP-A were significantly increased in alveolar macrophages from GM(-/-) compared with wild type or SP-C-GM mice, catabolism of (125)I-SP-A was markedly decreased in GM(-/-) mice. Association of [(3)H]DPPC with alveolar macrophages from GM(-/-), wild-type, and SP-C-GM mice was similar; however, catabolism of DPPC was markedly reduced in cells from GM(-/-) mice. Fluorescence-activated cell sorter analysis demonstrated decreased catabolism of rhodamine-labeled dipalmitoylphosphatidylethanolamine by alveolar macrophages from GM(-/-) mice. GM-CSF deficiency was associated with increased SP-A uptake by alveolar macrophages but with impaired surfactant lipid and SP-A degradation. These findings demonstrate the important role of GM-CSF in the regulation of alveolar macrophage lipid and SP-A catabolism.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2001

Acantholytic dermatosis of the vulvocrural area.

Acantholytic dermatosis of the vulvocrural area is a rare skin disorder characterized by solitary or multiple skin-colored to white, smooth papules or plaques. Histopathological features of both Hailey-Hailey disease and Darler's disease are present. There is acantholysis, which may involve the full thickness of the epidermis, and dyskeratosis with corps ronds and grains. There may be marked hyperkeratosis and focal parakeratosis. We report a case of this rare disease and discuss its differential diagnosis and treatment.

Acantholysis↗
PubMed2000

Granulocyte-macrophage colony-stimulating factor in the innate immune response to Pneumocystis carinii pneumonia in mice.

Innate immunity plays an important role in pulmonary host defense against Pneumocystis carinii, an important pathogen in individuals with impaired cell-mediated immunity. We investigated the role of GM-CSF in host defense in a model of P. carinii pneumonia induced by intratracheal inoculation of CD4-depleted mice. Lung GM-CSF levels increased progressively during the infection and were significantly greater than those in uninfected controls 3, 4, and 5 wk after inoculation. When GM-CSF gene-targeted mice (GM-/-) depleted of CD4+ cells were inoculated with P. carinii, the intensities of infection and inflammation were increased significantly compared with those in CD4-depleted wild-type mice. In contrast, transgenic expression of GM-CSF directed solely in the lungs of GM-/- mice (using the surfactant protein C promoter) dramatically decreased the intensity of infection and inflammation 4 wk after inoculation. The concentrations of surfactant proteins A and D were greater in both uninfected and infected GM-/- mice compared with those in wild-type controls, suggesting that this component of the innate response was preserved in the GM-/- mice. However, alveolar macrophages (AM) from GM-/- mice demonstrated impaired phagocytosis of purified murine P. carinii organisms in vitro compared with AM from wild-type mice. Similarly, AM production of TNF-alpha in response to P. carinii in vitro was totally absent in AM from GM-/- mice, while GM-CSF-replete mice produced abundant TNF in this setting. Thus, GM-CSF plays a critical role in the inflammatory response to P. carinii in the setting of impaired cell-mediated immunity through effects on AM activation.

Animals↗
PubMed2000

Expression of the intermediate filament peripherin in extraskeletal myxoid chondrosarcoma.

The embryologic histogenesis of cartilage is not well characterized. While cranial cartilage is believed to be derived from pluripotential precursor cells of the neural crest, chondrocytes found elsewhere in the body are thought to be derived from mesoderm. As such, soft tissue tumors with cartilaginous differentiation may be related to neural crest or mesoderm. Peripherin is an intermediate filament encoded on chromosome 12, involved in growth and development of the peripheral nervous system. Peripherin is apparently expressed exclusively in cells derived from the neural crest and neural tube. A group of six soft tissue tumor types was selected because they are either of controversial differentiation or cytogenetically related to chromosome 12. A total of 41 cases was evaluated with antibodies against the intermediate filament peripherin. A panel of neural and neuroendocrine differentiation markers was used in selected cases. Three of five extraskeletal myxoid chondrosarcomas showed strong cytoplasmic reactivity with anti-peripherin. No peripherin expression was noted in any of eleven epithelioid sarcomas, eight liposarcomas, seven conventional chondrosarcomas, four neurothekeomas, three alveolar soft part sarcomas, or three clear cell sarcomas. The finding of peripherin expression in some extraskeletal myxoid chondrosarcomas may suggest the ability of some tumors to demonstrate both neural and chondroid differentiation.

Adolescent↗
PubMed2000

IL-4 increases surfactant and regulates metabolism in vivo.

Mice that express interleukin (IL)-4 in Clara cells (CCSP-IL-4) develop chronic airway inflammation and an alveolar proteinosis-like syndrome. To identify the role of IL-4 in surfactant homeostasis, we measured lipid and protein metabolism in the lungs of CCSP-IL-4 mice in vivo. Alveolar saturated phosphatidylcholine (Sat PC) pools were increased 6.5-fold and lung tissue Sat PC pools were increased 4. 8-fold in the IL-4 transgenic mice. Whereas surfactant protein (SP) A was increased proportionately to Sat PC, SP-D was increased approximately 90-fold in the IL-4 mice compared with wild-type mice and was associated with 2.8-fold increase in SP-D mRNA. The incorporation of palmitate and choline into Sat PC was increased about twofold in CCSP-IL-4 mice. Although trace doses of radiolabeled Sat PC were cleared from the air spaces and lungs of CCSP-IL-4 mice more slowly than in wild-type mice, net clearance of Sat PC from the lungs of CCSP-IL-4 mice was sixfold higher in the IL-4 mice than in wild-type mice because of the larger Sat PC pool sizes. Expression of IL-4 in Clara cells increased surfactant lipid synthesis and clearance, establishing a new equilibrium with increased surfactant pools and an alveolar proteinosis associated with a selective increase in SP-D protein, demonstrating a previously unexpected effect of IL-4 in pulmonary surfactant homeostasis.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2000

Distinct changes in pulmonary surfactant homeostasis in common beta-chain- and GM-CSF-deficient mice.

Pulmonary alveolar proteinosis (PAP) is caused by inactivation of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM receptor common beta-chain (beta(c)) genes in mice [GM(-/-), beta(c)(-/-)], demonstrating a critical role of GM-CSF signaling in surfactant homeostasis. To distinguish possible phenotypic differences in GM(-/-) and beta(c)(-/-) mice, surfactant metabolism was compared in beta(c)(-/-), GM(-/-), and wild-type mice. Although lung histology in beta(c)(-/-) and GM(-/-) mice was indistinguishable, distinct differences were observed in surfactant phospholipid and surfactant protein concentrations and clearance from lungs of beta(c)(-/-) and GM(-/-) mice. At 1-2 days of age, lung saturated phosphatidylcholine (Sat PC) pool sizes were higher in wild-type, beta(c)(-/-), and GM(-/-) mice compared with wild-type adult mice. In wild-type mice, Sat PC pool sizes decreased to adult levels by 7 days of age; however, Sat PC increased with advancing age in beta(c)(-/-) and GM(-/-) mice. Postnatal changes in Sat PC pool sizes were different in GM(-/-) compared with beta(c)(-/-) mice. After 7 days of age, the increased lung Sat PC pool sizes remained constant in beta(c)(-/-) mice but continued to increase in GM(-/-) mice, so that by 56 days of age, lung Sat PC pools were increased three- and sixfold, respectively, compared with wild-type controls. After intratracheal injection, the percent recovery of [(3)H]dipalmitoylphosphatidylcholine and (125)I-recombinant surfactant protein (SP) C was higher in beta(c)(-/-) compared with wild-type mice, reflecting decreased clearance in the receptor-deficient mice. The defect in clearance was significantly more severe in GM(-/-) than in beta(c)(-/-) mice. The ratio of SP Sat PC to SP-A, -B, and -C was similar in bronchoalveolar lavage fluid (BALF) from adult mice of all genotypes, but the ratio of SP-D to Sat PC was markedly increased in beta(c)(-/-) and GM(-/-) mice (10- and 5-fold, respectively) compared with wild-type mice. GM-CSF concentrations were increased in BALF but not in serum of beta(c)(-/-) mice, consistent with a pulmonary response to the lack of GM-CSF signaling. The observed differences in surfactant metabolism suggest the presence of alternative clearance mechanisms regulating surfactant homeostasis in beta(c)(-/-) and GM(-/-) mice and may provide a molecular basis for the range in severity of PAP symptoms. surfactant metabolism; alveolar macrophage; granulocyte-macrophage colony-stimulating factor

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2000

Update of diagnostic and prognostic markers in cutaneous malignant melanoma.

The biomolecules described in this article generally have been studied as possible diagnostic or clinically prognostic markers in the context of melanoma disease progression as measured by the gold standards of tumor thickness and development of metastasis. Most of the markers showed variations in expression phenotype only during the deeply invasive or metastatic stage of tumor progression and were thus predictive of clinical outcome only for these subgroups of patients. Some of the markers may have utility in identifying patients with deeply invasive primary tumors who are likely to develop metastasis and thus should receive earlier, more aggressive treatments. In addition, some of the markers may identify patients likely to respond better to a new type of therapy (e.g., anti-angiogenic therapy in a patient whose tumor is overexpressing VEGF or immunotherapy for a patient whose tumor is expressing high levels of MART-1). In the future, it will probably be possible to employ new techniques, such as laser-guided microdissection of tissues, to isolate individual melanocytes in order to identify the earliest stage-specific defects that contribute to an aggressive biological behavior. Identifying the subset of patients with superficially invasive melanomas who will develop metastatic disease will continue to provide a challenge.

Biomarkers, Tumor↗
PubMed1999

Divergent cellular differentiation pathways during the invasive stage of cutaneous malignant melanoma progression.

Melanocytic nevus cells in the dermis adopt many morphological features of Schwann cells. These differentiation-related changes typically are not observed in melanomas. However, nevus cells do not fully recapitulate a Schwann cell phenotype, because they lack expression of mature myelin-associated proteins. In this study, melanocytic nevi and malignant melanomas were examined by immunohistochemistry for expression of low-affinity nerve growth factor receptor (p75NGFR), neural cell adhesion molecule (CD56/N-CAM), and growth-associated phosphoprotein-43 (GAP-43). These three proteins define the earliest stages of Schwann cell development but are not expressed in myelinated Schwann cells or normal melanocytes. p75NGFR was expressed in 25 of 25 (100%) and CD56/N-CAM and GAP-43 in 23 of 25 (92%) nevi, predominantly in type C nevus cells and nevic corpuscles. Most (84%) of the nevi expressed all three proteins. In primary invasive and metastatic melanoma, expression of each of the three proteins was limited to </=20% of lesions but was not observed in any melanoma in situ (chi(2 )P < 0.0001). None of the melanomas expressed all three proteins (ANOVA P < 0.0001). These data confirm and extend earlier studies by showing that terminal differentiation of melanocytes in the dermis recapitulates some aspects observed in the earliest stages of Schwann cell development and that invasive melanomas follow a divergent pathway. Studying these early differentiation events may help to identify specific defects in the relevant signaling pathways and establish tenable targets for therapy of advanced-stage melanoma.

Biomarkers, Tumor↗