The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes.

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis.

A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors.

BACKGROUND: AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). PATIENTS AND METHODS: AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained. RESULTS: Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m(2)/day). At 40 mg/m(2)/day, one patient developed hypotension and ST segment elevation. At 34 mg/m(2)/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m(2). CONCLUSION: AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.

A history of dermatologic surgery in the United States.

BACKGROUND: Dermatologic surgery has a long and distinguished history in the United States. OBJECTIVE: To examine the specific contributions of American dermatologic surgeons. METHOD: The medical literature on cutaneous reconstructive and cosmetic surgery for the last century and a half was researched. RESULTS: Numerous American dermatologic surgeons have had a major impact on scientific and technological discoveries in cutaneous surgery. Dermatologic surgeons have been significantly involved in cutaneous surgery since the second half of the 19th century. Dermatologic surgeons have contributed many important advances to the fields of chemical peeling, cryosurgery, dermabrasion, electrosurgery, hair transplantation, soft tissue augmentation, tumescent liposuction, laser surgery, phlebology, Mohs chemosurgery, cutaneous reconstruction, wound healing, botulium toxin, blepharoplasty, and rhytidectomy. CONCLUSION: Dermatologic surgeons in the United States have contributed significantly to the history of reconstructive and cosmetic surgery. Dermatologic surgeons have been leaders in advancing this field and are poised to continue in the future.

Comparison of matrix vesicles derived from normal and osteoarthritic human articular cartilage.

Articular cartilage matrix vesicles (MVs) from normal human adult articular cartilage were examined for protein and enzyme content and biomineralizing capacity for comparison to MVs derived from human osteoarthritic (OA) cartilage. Femoral condylar and tibial plateau cartilage from each of 9 healthy donors ages 17-37 y was enzymatically digested and serially ultracentrifuged to pellet MV's at 3 x 10(6) g-min. MV protein content, nucleoside triphosphate pyrophospho hydrolase (NTPPPH) specific activity (SA) and capacity for 45Ca precipitation were determined. MV precipitated mineral was examined using Fourier transform infrared spectroscopy (FTIR). Normal human cartilage yields 50% less MV protein/g cartilage than OA cartilage (p < .01). Normal human articular MVs possess 30-70x higher NTPPPH SA than cell-free digest. Mean NTPPPH SAs of MVs derived from normal human cartilage are 3x higher than that of OA MVs (p < .05) and normal MV NTPPPH SA appears to decrease with age (p < .01). Normal human MVs support significantly higher calcium precipitation/mg MV protein in both ATP-dependent (p < .01) and -independent (p = .05) systems. The FTIR spectrum of MV mineral generated in the presence of ATP strongly resembles the standard spectrum for calcium pyrophosphate dihydrate (CPPD). The FTIR spectrum of MV mineral generated without ATP resembles that of carbonate-substituted apatite (AP). The fact that isolated MVs from normal cartilage generate pathologically relevant crystal phases in vitro implies that matrix integrity and substrate availability may be crucial factors in the control of pathologic biomineralization.

Clinical tools for success in managing care.

Managing care effectively requires a coalition of services that are sensitive to individual needs, promote effective resource use, support physician practice, and ensure coordination of services across the continuum. Several clinical tools exist to establish structures, systems, and processes that integrate management of expected and unexpected patient and family needs across the life span and throughout the health care continuum. System evaluation; unrelenting communication; continuous improvement; case management; empowerment; standards-based clinical practice; and satisfaction of the patient, family, and care provider are some of the tools available to develop systems that effectively manage health and illness. This article provides some examples of several of these "tools," the process of development and implementation, and evaluation strategies.

An unusual histopathologic response to an insect bite.

A lesion with the histologic features of a cutaneous plasmacytoma formed on the cheek of a woman bitten by an insect six months previously. The significance of cutaneous plasmacytoma, its differential diagnosis, and the importance of clinical versus histologic diagnosis are discussed.

Lichen nitidus of the palms.

A case is presented of lichen nitidus that evolved into an acquired palmar keratoderma in a fifty year old woman; this is a rare manifestation of the disease. Lichen nitidus must be considered in the differential diagnosis of keratoderma palmaris.

"Polywater": a hydrosol?

Measurements of the dielectric constant and the effective parallel conductance of a specimen of anomalous water suggest that anomalous water is a hydrosol consisting of finely divided particulate matter suspended in ordinary water. Scanning electron micrography confirms the presence of particulate matter. These new experimental data provide an alternative explanation for the properties of anomalous water.

Wideband optical heterodyne performance of extrinsic photoconductive infrared radiation detectors.

Heterodyne detection of infrared radiation by cryogenically cooled extrinsic photoconductors is reviewed. Operational characteristics of a highly compensated Ge : Hg detector are calculated from experimentally determined material parameters. In many cases wideband, quantum noise limited performance can be obtained only if substantial refrigeration capacity is available at detector operating temperature.