Differential effects of ionizing radiation and platinum-derivative chemotherapy on apoptotic pathways in testicular germ cells

PURPOSE: The purpose here was to identify whether ionizing radiation and oxaliplatin triggered testicular germ cells apoptosis through different executionary pathways. MATERIALS AND METHODS: Adult male mice are treated with oxaliplatin (0.5 mg/kg, Ox) 4 h before being locally irradiated (0.5 Gy, IR, considered as time 0 h). RESULTS: The number of apoptotic germ cells was significantly higher for IR (p < 0.008), Ox (p < 0.0001) and Ox + IR (p < 0.0001) groups compared to the untreated mice group. Similarly, the different treatments induced an increase of p53 expression. Downstream p53, IR and Ox used different pathways. Indeed, IR increased effector caspase-3 expression in terms of mRNA (p < 0.002), pro-enzyme p < 0.0001) and active (3.7-fold, p < 0.003) protein levels but not the inhibitors of apoptosis proteins (IAP) including cIAP1, cIAP2 and XIAP. In contrast, while oxaliplatin treatment had no apparent effect on caspase-3 expression, it significantly decreased the cIAP1 (p < 0.005), cIAP2 (p < 0.008) and XIAP (p < 0.02) proteins levels. Finally, the combination of both treatments decreased IAP expression but did not modify caspase-3 levels while it increased the AIF (apoptosis-inducing factor) protein levels (5.5-fold, p < 0.003). No modification of AIF levels was observed with OX or IR alone. CONCLUSIONS: Together, these results indicate that the platinum analogue oxaliplatin and the ionizing radiations trigger apoptosis in the testicular germ cells, probably through different pathways.     

Serum Interleukin-6, Soluble Interleukin-6 Receptor and Crohn’s Disease Activity

The relationship between plasma interleukin-6 (IL-6) concentration and its soluble receptor in Crohn’s disease (CD) is not well elucidated. Twenty healthy volunteers and 94 consecutive patients with CD (44 in relapse and 50 in remission) were studied. Plasma IL-6 concentrations in patients with active disease [80 ± 9 pg/ml; mean ± standard error of the mean (SEM)] were significantly higher than in patients with inactive disease (50 ± 4 pg/ml; P < 0.001) or controls (3 ± 1 pg/ml; P < 0.001). However, concentrations did not vary with the severity of CD attacks. Plasma concentrations of soluble interleukin-6 receptor (sIL-6R) in active-CD patients (77 ± 5 ng/ml) did not differ significantly from those with inactive disease (82 ± 5 ng/ml), while both groups had significantly raised concentrations compared with those of controls (58 ± 6 ng/ml; P < 0.03 and P < 0.01, respectively). Plasma IL-6 concentrations correlated significantly with serum C-reactive protein (CRP) (r = 0.34; P < 0.001), whereas plasma sIL-6R concentrations did not. Taken together, these data suggest that, although IL6 and sIL6-R are both involved in the inflammatory process of CD, they are poor markers of disease activity.     

Tacrolimus induction followed by maintenance monotherapy is useful in selected patients with moderate-to-severe ulcerative colitis refractory to prior treatment

Background

Tacrolimus in refractory ulcerative colitis often serves as a bridge to long-term maintenance therapy with thiopurines. Our aim was to review efficacy and safety of tacrolimus in active ulcerative colitis resistant to conventional therapies, including anti-tumour necrosis factor.

Methods

Charts of consecutive outpatients with refractory ulcerative colitis, in whom tacrolimus was orally administered as a 12 week-induction (target trough levels 10–15 ng/mL) followed by a maintenance therapy (target trough levels 5–10 ng/mL), were retrospectively reviewed. Clinical remission and response at weeks 4, 12 and 52 as well as adverse events within 1-year therapy were reported.

Results

Twelve (40%) and six (20%) of the 30 patients included (14 males, mean age 37.1 ± 1.4 years) achieved a clinical remission and response, respectively, at week 12. Three responders to tacrolimus initiation experienced drug-related adverse events requiring discontinuation. Among the 18 remaining initial responders who tolerated tacrolimus, 8 (27%) were in clinical remission at week 52, whereas the remainder either experienced adverse events requiring drug withdrawal (n = 4) or relapsed (n = 6). Overall adverse events were recorded in 14 patients (46%), mainly finger tremor and urinary infections.

Conclusion

Oral monotherapy with tacrolimus may be a valuable long-term therapeutic option in selected patients with moderate-to-severe active refractory ulcerative colitis.