Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design.

Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells.

Multiple schwannomas of the upper limb related exclusively to the ulnar nerve in a patient with segmental schwannomatosis.

Schwannomas are benign encapsulated tumours arising from the sheaths of peripheral nerves. They present as slowly enlarging solitary lumps, which may cause neurological defects. Multiple lesions are rare, but occur in patients with neurofibromatosis type 2 or schwannomatosis.

Tyrosine phosphate in melanoma progression.

Background: Cellular tyrosine phosphorylation is regulated by two large families of enzymes. Protein tyrosine kinases (PTK) mediate addition, and protein tyrosine phosphatases (PTP), removal of phosphate from protein substrates. PTKs are oncogenes and PTPs have been hypothesized to function as tumour suppressor genes.

Expression of beta-catenin in basal cell carcinoma.

Background beta-Catenin is a crucial member of the E-cadherin/catenin complex, which plays a major role in cell-cell adhesion. beta-Catenin is also known to be involved in signal transduction pathways. Many studies have demonstrated changes in the expression of beta-catenin in colorectal carcinomas, suggesting a role for beta-catenin in neoplastic development.

Up-regulation of ephrin-A1 during melanoma progression.

Ephrin-A1, formerly called B61, is a new melanoma growth factor; it is angiogenic and chemoattractant for endothelial cells. EPH-A2, or ECK (a receptor for ephrin-A1), is ectopically expressed in most melanoma cell lines; the pathology where this expression is first manifested and the possible role of the receptor in tumor progression are unknown. To determine these, we studied the expression of this ligand and receptor in biopsies of benign and malignant melanocytic lesions.

Transepidermal elimination of urate-like crystals: a new perforating disorder?

We report two men who developed a transient perforating disorder characterized by transepidermal elimination of negatively birefringent needle-shaped crystals similar to monosodium urate. This striking clinical presentation has not previously been described and we propose that it be added to the group of diseases known as the primary perforating disorders.

Lichen planus associated with milia.

The formation of milia is well recognized in both bullous and inflammatory dermatoses. There are several reports of milia developing in a rare variant of lichen planus pilaris known as lichen planus follicularis tumidus (LPFT), but the association of milia with other types of lichen planus (LP) has not been documented in the literature. We report five patients who developed milia during the course of either drug-induced or idiopathic LP and one in whom milia developed in a lichenoid tattoo reaction.

Cutaneous malignant melanoma in Scotland: incidence, survival, and mortality, 1979-94. The Scottish Melanoma Group.

Objective: To determine the changing incidence of and mortality from cutaneous malignant melanoma in Scotland from 1979 to 1994.

Design: Detailed registration of clinical and pathological features, surgical and other treatment, and follow up of all cases of cutaneous malignant melanoma diagnosed from 1979 to 1994 and registered with specialist database for Scotland.

Setting: Scotland.

Cutaneous manifestations of fucosidosis.

Angiokeratoma corporis diffusum (ACD) is still often thought to be synonymous with Anderson-Fabry disease, a deficiency of alpha-galactosidase. It is important, however, to consider other possible enzyme deficiencies in patients with ACD. We report an 8-year-old boy with neurodevelopmental delay who was diagnosed as having fucosidosis following recognition of ACD in the dermatology department.

Localized argyria caused by silver earrings.

We report a patient with localized cutaneous argyria following the wearing of silver earrings in pierced ears.

Papular mucinosis: is the inflammatory cell infiltrate neoplastic? The presence of a monotypic plasma cell population demonstrated by in situ hybridization.

Papular mucinosis is a condition reported to be associated with abnormal serum paraproteins and plasma cell dyscrasias. We report a patient with papular mucinosis, without a serum paraprotein or bone marrow plasmacytosis, in whom the affected skin contained a prominent perivascular plasma cell infiltrate. Using in situ hybridization, for kappa and lambda light chain mRNA, these plasma cells were demonstrably monotypic for lambda light chain and, therefore, presumably monoclonal and putatively neoplastic.

Expression of NM23 in human melanoma progression and metastasis.

NM23 is a putative metastasis-suppressor gene for some human cancers. Here we have studied NM23 expression during melanoma progression using Northern blotting and immunocytochemistry. There was no significant difference in the average amounts of NM23 mRNA between cell lines derived from metastatic and primary melanomas.

Evidence based assessment?

There have been many calls recently for a more 'evidence based' approach to clinical dentistry. This article argues the need for a similar approach to be adopted by the private dental schemes when setting criteria for practice inspection. The author recognises the laudable attempt to revise the 'quality' of dental practice but questions whether the methods adopted to date are justifiable.

Sebaceous carcinoma of the periorbital and extraorbital regions.

Sebaceous carcinomas are uncommon amongst cutaneous malignancies. These lesions can broadly be classified into 2 groups; (i) periorbital, which behave aggressively, and (ii) extraorbital, which are reported to metastasize rarely. A retrospective review has identified 12 cases of primary sebaceous carcinoma treated at Canniesburn Hospital over the decade from mid-1983 to mid-1993.

Aneuploidy in atypical fibroxanthoma: DNA content quantification of 10 cases by image analysis.

It has recently been reported that atypical fibroxanthoma (AFX) is a predominantly diploid lesion in contrast to malignant fibrous hystiocytoma (MFH) which is usually aneuploid. To test this hypothesis, DNA content quantification was undertaken on Feulgen-stained cytology and tissue section preparations from 10 cases of AFX by image analysis. The large atypical cells which characterize AFX were aneuploid in each case.