Summary Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo.

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Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival.BD donors were maintained for 20 hours; kidneys were procured and stored at 4°C for 43-48 hours prior to implantation into ABO-compatible, nonsensitized, MHC-mismatched recipients. Animals were divided into 3 donor-treatment groups: G1 -vehicle, G2 -rhC1INH+heparin, and G3 -heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor α and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P = .008). In addition, G2 recipients showed superior renal function, reduced sC5b-9, and reduced urinary neutrophil gelatinase-associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor-management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD-induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation. 1514 | DANOBEITIA ET Al. K E Y W O R D S animal models: nonhuman primate, complement biology, delayed graft function (DGF), donors and donation: donation after brain death (DBD), immunosuppression/immune modulation, ischemia reperfusion injury (IRI), kidney transplantation/nephrology, translational research/ science 1 | INTRODUC TI ON Delayed graft function (DGF) manifests as a consequence of ischemia-reperfusion injury (IRI) and is characterized by acute kidney injury (AKI) within 7 days of transplant, requiring life-sustaining dialysis. 1 The incidence of DGF in kidney transplants from brain dead (BD) donors is approximately 26% in the United States, and this rate can reach as high as 37% in kidneys from older donors and those subjected to extended cold ischemia >36 hours. 2-4 In addition to complications related to AKI in the peritransplant period, development of DGF is an important risk factor for acute cellular rejection, antibody-mediated rejection (AMR), and reduced

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