Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

PURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.     

Evaluation of a Short,On-Plate Formic Acid Extraction Method for Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry-Based Identification of Clinically Relevant Yeast Isolates

This report describes a short, on-plate formic acid (FA) extraction method for the identification of clinical yeast isolates using matrix-assisted laser desorption ionization–time-of-flight mass spectrometry (MALDI-TOF MS). A total of 41.1% (78/190) and 63.7% (121/190) of yeasts were identified using species log score thresholds of >2.0 and >1.9, respectively. Overall, 97.4% (185/190) of yeasts were identified in combination with conventional FA extraction.     

Biochemical Variability in a Team Sports Situation

Abstract

Using 13 members of an amateur softball team during the last seven games of the regular season, associations were determined between overall offensive and defensive performance and levels of serum uric acid (SUA) and cholesterol, and urinary adrenaline and noradrenaline. Skilled players were found to have significantly lower cholesterol and noradrenaline levels than less skilled players whether the games were won or lost. Adrenaline and SUA levels did not differ between the two groups nor between losing or winning outcomes. The elevated cholesterol and noradrenaline levels found among the less skilled players may indicate that although they were stressed by the discrepancy between their expectations and their performance, they nonetheless maintained perceived control over performance because of the social support and reinforcement received from the other players and the coach.     

A modified sharp score demonstrates disease progression in established psoriatic arthritis

Objective

To use a modified Sharp score (MSS) to measure radiologic progression and to assess its relationship to other radiologic features, peripheral joint disease, and physical function in psoriatic arthritis (PsA).

Methods

Two sets of hand radiographs (median interval 5.75 years) in 139 patients with established PsA were scored using an MSS. Seventy‐four patients had standardized clinical joint and Health Assessment Questionnaire (HAQ) scores and other radiologic features of PsA documented at baseline and followup (median interval 5 years).

Results

Radiologic damage was present in 58% of patients at baseline and 74% at followup. The median MSS and its components, erosion score and joint space abnormality score, were significantly greater at followup (P < 0.001). The median MSS progression was +1.08 units/year. There was strong correlation between MSS and clinical joint scores at baseline and followup (r = 0.72 and r = 0.81, respectively). There was weak correlation between MSS and HAQ at baseline (r = 0.29), but stronger correlation at followup (r = 0.48). There was a strong association between MSS and other characteristic radiologic features of PsA (bony proliferation, periostitis, bony ankylosis) at baseline and followup (P < 0.001). However, the presence of soft‐tissue swelling on radiographs at baseline was the only radiologic parameter associated with an increased rate of change of MSS (corrected P < 0.006).

Conclusion

The MSS shows good construct validity with measures of peripheral joint involvement such as clinical joint scores and other radiologic features of PsA, and is able to demonstrate that radiologic damage is progressive beyond early disease.