Impact of Prolonged Cold Ischemia Time on One Year Kidney Transplant Outcomes.

BACKGROUND: Prolonged cold ischemia times (CIT) of kidney allografts remains a significant reason for graft refusal in the new allocation system. We sought to investigate the effect of prolonged CIT on kidney transplant outcomes at a center without an international airport. METHODS: Retrospective study of kidney transplant patients treated at an academic medical center from January 1, 2018 to May 1, 2020. The 117 patients were divided into 2 categories. Fifty-four patients (46%) had CIT of 30-35.99 hours, and 63 (54%) had CIT of 36± hours. Kidney function was evaluated using creatinine and at 12 months, which was the primary endpoint. RESULTS: All of the transplanted allografts were carefully selected and had ≤ 20% glomerulosclerosis and an average kidney donor profile index of 54%. Among the 117 patients analyzed in this study, there was no significant difference in creatinine at 12 months between groups with CIT above 36 hours and < 35.99 hours (2.07 vs 1.78; P value .2339). There were a total of 18 rejection events (15%) and no cases of primary non-function in either group. Patients that were able to be maintained on calcineurin inhibitors had improved graft function at 12 months (1.69 vs 2.96; P value .0267). CONCLUSIONS: Our study indicated that prolonged CITs over 36 hours were not associated with poorer patient outcomes at 1 year when using creatinine as an endpoint. They also had similar rates of rejection, consistent with previously published rates for kidney transplantation.

Phospho-valproic acid (MDC-1112) suppresses glioblastoma growth in preclinical models through the inhibition of STAT3 phosphorylation.

New therapeutic strategies against glioblastoma multiforme (GBM) are urgently needed. Signal transducer and activator of transcription 3 (STAT3), constitutively active in many GBM tumors, plays a major role in GBM tumor growth and represents a potential therapeutic target. We have documented previously that phospho-valproic acid (MDC-1112), which inhibits STAT3 activation, possesses strong anticancer properties in multiple cancer types. In this study, we explored the anticancer efficacy of MDC-1112 in preclinical models of GBM, and evaluated its mode of action. MDC-1112 inhibited the growth of multiple human GBM cell lines in a concentration- and time-dependent manner. Normal human astrocytes were resistant to MDC-1112, indicating selectivity. In vivo, MDC-1112 reduced the growth of subcutaneous GBM xenografts in mice by up to 78.2% (P < 0.01), compared with the controls. Moreover, MDC-1112 extended survival in an intracranial xenograft model. Although all vehicle-treated mice died by 19 days of treatment, 7 of 11 MDC-1112-treated mice were alive and healthy by the end of 5 weeks, with many showing tumor regression. Mechanistically, MDC-1112 inhibited STAT3 phosphorylation at the serine 727 residue, but not at tyrosine 705, in vitro and in vivo. STAT3 overexpression rescued GBM cells from the cell growth inhibition by MDC-1112. In addition, MDC-1112 reduced STAT3 levels in the mitochondria and enhanced mitochondrial levels of reactive oxygen species, which triggered apoptosis. In conclusion, MDC-1112 displays strong efficacy in preclinical models of GBM, with the serine 727 residue of STAT3 being its key molecular target. MDC-1112 merits further evaluation as a drug candidate for GBM. New therapeutic options are needed for glioblastoma. The novel agent MDC-1112 is an effective anticancer agent in multiple animal models of glioblastoma, and its mechanism of action involves the inhibition of STAT3 phosphorylation, primarily at its Serine 727 residue.