Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K i s of 5.2 and 2.9 nmol/L, respectively.The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d  10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.poly(ADP-ribose) polymerase (PARP)-1 is the founding member of a family of poly(ADP-ribosyl)ating proteins. All PARP family members are characterized by the ability to poly(ADP-ribosyl)ate protein substrates and all share a catalytic PARP homology domain (1). PARP-1 and the closely related PARP-2 are nuclear proteins and the only PARPs with DNA binding domains. These DNA binding domains localize PARP-1 and PARP-2 to the site of DNA damage serving as DNA damage sensors and signaling molecules for repair. The knockout of PARP-1 is sufficient to significantly impair DNA repair following damage via radiation (2) or cytotoxic (3) insult. The residual PARP-dependent repair activity (f10%) is due to PARP-2 (4, 5). These data imply that inhibition of only PARP-1 and PARP-2 will impair DNA repair following damage and that inhibition of other PARP family members is not required in the process. The functions of other PARP family members remain to be elucidated, but poly(ADP-ribosyl)ation has been implicated in many cellular processes, including differentiation, gene regulation, protein degradation, spindle maintenance, as well as replication and transcription (6).Higher expression of PARP in cancer compared with normal cells has been linked to...

BackgroundAllograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure.MethodsThis multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis.FindingsavddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%–9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6–19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable.InterpretationLung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure.FundNational Institutes of Health.

This study investigated the effect of abnormal autonomic cardiovascular function on heart rate variability (HRV) in individuals classified into four groups: complete quadriplegia, incomplete quadriplegia, low paraplegia, and non-spinal cord injury (SCI) controls. Measurements were collected at baseline and during provocative maneuvers. Spectral analysis using a fast-Fourier transform algorithm revealed two spectral components of HRV, termed low frequency (LF) and high frequency (HF); the LF-to-HF ratio (estimate of sympathovagal balance) was also calculated. Each group of subjects with quadriplegia exhibited significantly lower spectral components for both baseline and composite provocative measures compared with the non-SCI controls (P < 0.05). In addition, the group with paraplegia demonstrated significantly lower HF baseline and LF composite levels than controls (P < 0.05). No differences were observed among all groups for the LF-to-HF ratio. This consistency in the LF-to-HF ratio suggests that the two autonomic divisions that regulate the cardiovascular system maintain homeostasis even when one component is severely compromised. This is supported by the additional findings of decreased parasympathetic activity in the two groups with quadriplegia and the absence of significant differences among any of the four groups at rest in either heart rate or blood pressure.

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Persons with spinal cord injury (SCI) have been recognized to have several metabolic changes that adversely impact their risk for cardiovascular disease. An increased prevalence of disorders of carbohydrate metabolism and dyslipidemia may be related predominantly to paralysis with immobilization and associated loss of lean body tissue and gain in relative adiposity. Studies have reported an increased risk of vascular disease in those with SCI. As such, an understanding of the constellation of carbohydrate and lipid changes that occur after SCI is relevant to the clinical practice of medicine in this population. Oral glucose tolerance testing and associated studiesImpaired glucose tolerance and diabetes mellitus are more prevalent in individuals with SCI than in those who are able-bodied. 1 ± 4 In most of the individuals with SCI and abnormal carbohydrate tolerance, resistance to insulin mediation of glucose uptake by peripheral tissues may be demonstrable. In the presence of insulin resistance, the normal homeostatic response to glucose challenge is increased pancreatic b-cell secretion of insulin. If the compensatory response of the pancreas is insu cient to control the serum glucose concentration, worsening of carbohydrate tolerance will ensue.Bauman et al 3 performed a 75 g oral glucose tolerance test in 100 male veterans with SCI and in 50 able-bodied veteran controls. According to criteria established by the World Health Organization, 5 22% of those with SCI were diabetic whereas only 6% of the control group were diabetic. Eighty-two per cent of the controls had normal oral glucose tolerance, compared with 38% of those with quadriplegia and 50% of those with paraplegia. Subjects with SCI had signi®cantly higher mean plasma glucose and insulin values at several points during the oral glucose tolerance test when compared with controls ( Figure 1). In subgroups, determinants of insulin sensitivity were measured: per cent lean body mass, per cent fat mass, and cardiopulmonary ®tness. Values for insulin sensitivity were linearly related with those of ®tness (VO 2 max) determined from a progressive incremental upper-body exercise stress test. Insulin sensitivity was suggestively correlated with lean body mass, and negatively correlated with body fat. Thus, in a relatively small subgroup of untrained subjects with paraplegia, the strongest determinant of insulin sensitivity was cardiopulmonary ®tness.In 201 non-veteran subjects with SCI, Bauman et al 2 studied the relationship of oral carbohydrate tolerance after a 75 g glucose load to several variables, including level and completeness of lesion, gender, ethnicity, age, duration of injury, and anthropometric measures. Of the total group, 27 (13%) had diabetes mellitus and 56 (29%) had impaired glucose tolerance. 2,6 The subjects with complete tetraplegia had sign®cantly worse carbohydrate tolerance (Figure 2) and were more frequently classi®ed with a disorder of carbohydrate tolerance than the other neurological de®cit subgroups. 2 There were no signi®cant gend...

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