Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.

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Background. End-stage liver disease (ESLD) patients requiring intensive care unit (ICU) care before liver transplantation (LT) often experience significant muscle mass loss, which has been associated with mortality. In this exploratory study, we primarily aimed to assess the feasibility of serial ultrasound (US) rectus femoris muscle area (RFMA) measurements for the evaluation of progressive muscle loss in ICU-bound potential LT candidates and describe the rate of muscle loss as assessed by sequential US RFMA measurements. Secondarily, we sought to identify patient characteristics associated with muscle loss and determine how muscle loss is associated with survival. Methods. We prospectively enrolled 50 ESLD adults (≥18 y old) undergoing evaluation for LT candidacy in the ICU. A baseline computed tomography measurement of psoas muscle area (PMA) and serial bedside US measurements of RFMA were obtained. The associations between patient characteristics, PMA, RFMA, ICU stay, and survival were analyzed. Results. Rapid decline in muscle mass by RFMA measurements was ubiquitously present and correlated to baseline PMA and length of ICU stay. RFMA normalized by body surface area decreased by 0.013 cm2/m2 (95% confidence interval, 0.010-0.016; P < 0.001) for each day in the ICU. Decreased RFMA normalized by body surface area was associated with poor overall survival (adjusted hazard ratio, 0.42; 95% confidence interval, 0.18-0.99; P = 0.047). Conclusions. In this exploratory, prospective study, serial US RFMA measurements in ESLD patients in the ICU are feasible, demonstrate progressive time-dependent muscle loss, and are associated with mortality. Further large-scale assessment of this modality compared with static PMA or performance-based dynamic assessments should be performed.

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What problem will this proposal solve? Current OPTN policy prioritizes candidates seeking a simultaneous liver kidney (SLK) transplant before pediatric and adult transplant candidates who are listed only for a kidney ("kidney alone candidates") when the liver candidate and the deceased donor are in the same Donation Service Area (DSA) 1. Unlike kidney alone allocation, in SLK allocation, the kidney is not allocated based on medical criteria assessing the kidney function of the candidate. Instead, geographic proximity between the liver-kidney candidate and the donor is the single factor in allocating the kidney with the liver. OPOs are not required to allocate the kidney with the liver regionally, although they are given the discretion to do so. The Kidney Transplantation Committee ("the Committee"),has identified several problems with this current policy: