The success of chemotherapy in cancer treatment is limited by scarce drug delivery to the tumor and severe side-toxicity. Prolyl hydroxylase domain protein 2 (PHD2) is an oxygen/redox-sensitive ...enzyme that induces cellular adaptations to stress conditions. Reduced activity of PHD2 in endothelial cells normalizes tumor vessels and enhances perfusion. Here, we show that tumor vessel normalization by genetic inactivation of Phd2 increases the delivery of chemotherapeutics to the tumor and, hence, their antitumor and antimetastatic effect, regardless of combined inhibition of Phd2 in cancer cells. In response to chemotherapy-induced oxidative stress, pharmacological inhibition or genetic inactivation of Phd2 enhances a hypoxia-inducible transcription factor (HIF)-mediated detoxification program in healthy organs, which prevents oxidative damage, organ failure, and tissue demise. Altogether, our study discloses alternative strategies for chemotherapy optimization.
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► Combined loss of Phd2 in stromal and cancer cells sensitizes tumors to chemotherapy ► Loss of Phd2 protects healthy organs against chemotherapy-induced oxidative damage ► Loss of Phd2 in healthy organs unleashes a HIF-mediated anti-oxidative response
Objective To evaluate the precision of methods used to assess renal function in patients with neurogenic voiding dysfunction. Materials and Methods This multicenter prospective study, which was set ...in Toulouse and Lyon, France, included 60 patients (mean age, 48.9 ± 15.2 years) with neurogenic bladder and sphincter dysfunction. The correlation and the concordance with the inulin clearance of each method of renal function evaluation were assessed. Results The correlation of serum creatinine with inulin clearance was low when using serum creatinine-based equations such as the Modification of Diet in Renal Disease (simplified and complete) and Cockcroft-Gault equations. The r and r2 coefficients were higher for creatinine-based methods, such as 24-hour ( r = 0.72) and 3-hour creatinine clearance ( r = 0.78). The strongest correlation was found for serum cystatin C–based equations: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine/cystatin C combined equation ( r = 0.78) and the CKD-EPI cystatin C equation ( r = 0.80). Mean bias of serum creatinine–based equations estimating glomerular filtration rate, the Cockcroft-Gault, and the simplified and complete Modification of Diet in Renal Disease equations, was 27.5 ± 28.6, 17.48 ± 29.40, and 21.98 ± 30.40 mL/min, respectively. Mean bias of creatinine clearance was 19.89 ± 15.30 mL/min at 3 hours and 19.00 ± 31.08 mL/min at 24 hours. Mean bias of the CKD-EPI cystatin C and the CKD-EPI creatinine/cystatin C combined equations was 11.98 ± 17.68 mL/min and 18.62 ± 17.85 mL/min, respectively. Limitations are the numerous types of neurologic diseases. Conclusion The CKD-EPI equation using cystatin C was the most precise method of renal function evaluation in patients with neurogenic bladder.
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