Organ Utilization Rates from Non-Ideal Donors for Solid Organ Transplant in the United States.

Background: Non-ideal donors provide acceptable allografts and may expand the donor pool. This study evaluates donor utilization across solid organs over 15-years in the United States. Methods: We analyzed the OPTN STAR database to identify potential donors across three donor eras: 2005-2009, 2010-2014, and 2015-2019. Donors were analyzed by a composite Donor Utilization Score (DUS), comprised of donor age and comorbidities. Outcomes of interest were overall and organ-specific donor utilization. Descriptive analyses and multivariable logistic regression modeling were performed. p-values < 0.01 considered significant. Results: Of 132,465 donors, 32,710 (24.7%) were identified as non-ideal donors (NID), based on a DUS ≥ 3. Compared to ideal donors (ID), NID were older (median 56 years, IQR 51-64 years vs. 35 years, 22-48 years, p < 0.001) and more frequently female (44.3% vs. 39.1%, p < 0.001), Black (22.1% vs. 14.6%, p < 0.001) and obese (60.7% vs. 19.6%, p < 0.001). The likelihood of overall DBD utilization from NID increased from Era 1 to Era 2 (OR 1.227, 95% CI 1.123-1.341, p < 0.001) and Era 3 (OR 1.504, 1.376-1.643, p < 0.001), while DCD donor utilization in NID was not statistically different across Eras. Compared to Era 1, the likelihood of DBD utilization from NID for kidney transplantation was lower in Era 2 (OR 0.882, 0.822-0.946) and Era 3 (OR 0.938, 0.876-1.004, p = 0.002). The likelihood of NID utilization increased in Era 3 compared to Era 1 for livers (OR 1.511, 1.411-1.618, p < 0.001), hearts (OR 1.623, 1.415-1.862, p < 0.001), and lungs (OR 2.251, 2.011-2.520, p < 0.001). Conclusions: Using a universal definition of NID across organs, NID donor utilization is increasing; however, use of DUS may improve resource utilization in identifying donors at highest likelihood for multi-organ donation.

Implications of drug intoxication on donor utilization and outcomes in liver transplantation.

INTRODUCTION: This study evaluates the implications of drug intoxication (DI) on donor utilization and outcomes in liver transplantation (LT). METHODS: The UNOS STAR database was evaluated for all potential donors and adult, first-time, whole LT between 2005 and 2019. Logistic regression analyses evaluated liver utilization; proportional hazards modeling assessed risk of 1-year graft loss. RESULTS: A total of 132 783 potential donors (10 205, 7.7% from DI), and 90 612 adult LT were identified (7490, 8.3% from DI). DI donors had median age 32 years (IQR 26-40 years, p < .001), were 42.6% female (n = 4346), and 15.5% were DCD donors (n = 1583). Utilization of DI donors changed over time, such that by 2015-2019 they were the most likely donor cause of death (COD) to be utilized. Among LT recipients, there were insignificant differences (<2% variance) in age, gender, ethnicity, and etiology of liver disease according to donor COD. Recipients with MELD scores >30 more frequently received grafts from donors with trauma (23.8%) and DI (21.8%) versus cardiovascular (20.0%) and CVA/stroke (19.9%, p < .001). Among DBD donors, DI-COD was associated with superior 1-year graft survival compared to donors from trauma (HR 1.172, 95% CI 1.057-1.300) and CVA/stroke (HR 1.404, 95% CI 1.264-1.561, p < .001). Donor COD was not significantly associated with 1-year graft loss among DCD donors. CONCLUSIONS: There is an increased likelihood of donor utilization when COD is drug overdose and an increased likelihood of 1-year graft survival compared to donors from trauma, CVA/stroke, and other COD.

The Promise of Complement Therapeutics in Solid Organ Transplantation.

Transplantation is the ideal therapy for end-stage organ failure, but outcomes for all transplant organs are suboptimal, underscoring the need to develop novel approaches to improve graft survival and function. The complement system, traditionally considered a component of innate immunity, is now known to broadly control inflammation and crucially contribute to induction and function of adaptive T-cell and B-cell immune responses, including those induced by alloantigens. Interest of pharmaceutical industries in complement therapeutics for nontransplant indications and the understanding that the complement system contributes to solid organ transplantation injury through multiple mechanisms raise the possibility that targeting specific complement components could improve transplant outcomes and patient health. Here, we provide an overview of complement biology and review the roles and mechanisms through which the complement system is pathogenically linked to solid organ transplant injury. We then discuss how this knowledge has been translated into novel therapeutic strategies to improve organ transplant outcomes and identify areas for future investigation. Although the clinical application of complement-targeted therapies in transplantation remains in its infancy, the increasing availability of new agents in this arena provides a rich environment for potentially transformative translational transplant research.

Incidence and Outcomes of Simultaneous Thoracoabdominal Triple Organ Transplantation in the United States.

BACKGROUND: This study aims to evaluate patient outcomes of simultaneous triple organ transplants, which may provide insight into optimal donor allocation while maximizing recipient benefit. METHODS: Triple organ transplants and their corollary dual organ transplants were identified using the United Network for Organ Sharing database. Triple organ transplants evaluated included heart-lung-kidney (n = 12) and heart-liver-kidney (n = 37). Heart-lung-kidney recipients were compared with heart-lung (n = 325), lung-kidney (n = 91), and heart-kidney (n = 2022) groups. Heart-liver-kidney recipients were compared with heart-liver (n = 451), liver-kidney (n = 10422), and heart-kidney (n = 2517) recipients. Patient survival outcomes were calculated using the Kaplan-Meier method and compared using log-rank tests. RESULTS: Patients undergoing triple organ transplants showed similar 10-year survival as their corresponding dual organ transplant cohorts. Patient survival estimate at 10 years for the heart-lung-kidney group was 45%, with no statistically significant difference in survival when compared with dual organ groups (P = .16). Survival estimates at 10 years for the heart-liver-kidney group was 49%, with no statistically significant difference in survival when compared with dual organ groups (P = .06). CONCLUSION: Despite the surgical burden of adding a third organ transplant, heart-liver-kidney and heart-lung-kidney have similar survival outcomes to dual organ equivalents and represent a reasonable allocation option in well-selected patients.

Corrigendum: Regulatory network and interplay of hepatokines, stellakines, myokines and adipokines in nonalcoholic fatty liver diseases and nonalcoholic steatohepatitis.

[This corrects the article DOI: 10.3389/fendo.2022.1007944.].

Preserved 2-y Liver Transplant Outcomes Following Simultaneous Thoracoabdominal DCD Organ Procurement Despite Effects on Liver Utilization Rate.

Background: Current techniques for donation after circulatory determination of death (DCD) heart procurement, through either direct procurement and machine perfusion or thoracoabdominal normothermic regional perfusion (NRP), have demonstrated excellent heart transplant outcomes. However, the impact of thoracoabdominal DCD (TA-DCD) heart procurement on liver allograft outcomes and utilization is poorly understood. Methods: One hundred sixty simultaneous heart and liver DCD donors were identified using the United Network for Organ Sharing/Organ Procurement and Transplantation Network database between December 2019 and July 2021. Liver outcomes from TA-DCD donors were stratified by heart procurement technique and evaluated for organ utilization, graft survival, and patient survival. Results were compared with abdominal-only DCD (A-DCD; n = 1332) and donation after brain death (DBD; n = 12 891) liver transplants during the study interval. Kaplan-Meier methods with log-rank testing were used to evaluate patient and graft survival. Results: One hundred thirty-three of 160 livers procured from TA-DCD donors proceeded to transplant. TA-DCD donors were younger (mean 28.26 y; P < 0.0001) with lower body mass index (mean 26.61; P < 0.0001) than A-DCD and DBD donors. TA-DCD livers had equivalent patient survival ( P = 0.893) and superior graft survival (P = 0.009) compared with A-DCD. TA-DCD livers had higher rates of organ discard for long warm ischemia time (37.0%) than A-DCD (20.5%) and DBD (0.5%; P < 0.0001), with direct procurement and machine perfusion procurements leading to a higher discard rate (18.5%) than NRP procurements (7.4%). Conclusions: Liver transplants after TA-DCD donation demonstrated equivalent patient outcomes and excellent graft outcomes. NRP procurements resulted in the lowest rate of organ discard after DCD donation and may represent an optimal strategy to maximize organ utilization.

Drug Overdose and Cardiovascular Deaths Among Deceased Organ Donors: Implications for Donor Utilization and Data Reporting.

BACKGROUND The present study evaluated expanded cause of death (COD) definitions and its implications on donor utilization for solid organ transplantation. MATERIAL AND METHODS The OPTN Standard Transplant and Research file was queried for potential donors between 2005 and 2019. Donor- and organ-specific utilization were evaluated. Expanded donor COD were identified: trauma, cardiovascular (CV), cerebrovascular accident (CVA) or stroke, drug intoxication (DI), anoxia not otherwise specified (NOS), and other. Descriptive analyses and multivariable logistic regression analyses for donor utilization were performed. RESULTS Among 132 783 potential donors identified, the most common COD was CVA/Stroke (n=44 707, 33.7%), followed by trauma (n=43 356, 32.7%), CV (n=20 053, 15.1%), anoxia-NOS (n=12 261, 9.2%), DI (n=10 205, 7.7%), and other causes (n=2201, 1.7%). Significant differences between CV, DI, and anoxia-NOS groups existed for donor age, sex, ethnicity, body mass index, and comorbidities. Donors from trauma had the highest unadjusted utilization rate (97.2%) while CV donors had the lowest (90.1%). Multivariable analysis of brain-dead donors (DBD) showed that compared to trauma, donors from DI had higher likelihood of utilization (odds ratio 1.217, 95% 1.025-1.446) while CV donors were lower (OR 0.717, 95% CI 0.642-0.800, P<0.001). Among donation after circulatory death (DCD) donors, there was decreased utilization compared to trauma for both CV (OR 0.607, 95% CI 0.523-0.705) and DI (OR 0.754, 95% CI 0.603-0.914, P<0.001). CONCLUSIONS Current COD definitions should be expanded to capture significant differences in the donor population. DI donors are the fastest growing cohort and the most likely utilized DBD donors, while trauma donors remain the most likely utilized DCD donors.

CSNK2A1-mediated MAX phosphorylation upregulates HMGB1 and IL-6 expression in cholangiocarcinoma progression.

BACKGROUND: We established a novel diethylnitrosamine (DEN) -induced mouse model that reflected the progression of cholangiocarcinoma (CCA) from atypical cystic hyperplasia. METHODS: BALB/c mice were administered DEN by oral gavage. Cells isolated from livers were analyzed for expression of CSNK2A1, MAX and MAX-interacting proteins. Human CCA cell lines (MzChA-1, HuCCT1), normal human cholangiocyte (H69), human hepatic stellate cells (LX-2), macrophages (RAW 264.7), and primary hepatic cells were used for cellular and molecular biology assays. RESULTS: Expression of MAX, CSNK2A1, C-MYC, ß-catenin, HMGB1, and IL-6 was upregulated in hepatic cells from CCA liver tissue. The half-life of MAX is higher in CCA cells, and this favors their proliferation. Overexpression of MAX increased growth, migration, and invasion of MzChA-1, whereas silencing of MAX had the opposite effect. MAX positively regulated IL-6 and HMGB1 through paracrine signaling in HepG2, LX2, and RAW cells and autocrine signaling in MzChA-1 cells. CSNK2A1-mediated MAX phosphorylation shifts MAX-MAX homodimer to C-MYC-MAX and ß-catenin-MAX heterodimers and increases the HMGB1 and IL-6 promoter activities. Increase of MAX phosphorylation promotes cell proliferation, migration, invasion, and cholangiocarcinogenesis. The casein kinase 2 inhibitor CX-4945 induces cell cycle arrest and inhibits cell proliferation, migration, invasion, and carcinogenesis in MzChA-1 cells through the downregulation of CSNK2A1, MAX, and MAX-interaction proteins. CONCLUSION: C-MYC-MAX and ß-catenin-MAX binding to E-box site or ß-catenin-MAX bound to TCFs/LEF1 enhanced HMGB1 or IL-6 promoter activities, respectively. IL-6 and HMGB1 secreted by hepatocytes, HSCs, and KCs exert paracrine effects on cholangiocytes to promote cell growth, migration, and invasion and lead to the progression of cholangiocarcinogenesis. CX-4945 provides perspectives on therapeutic strategies to attenuate progression from atypical cystic hyperplasia to cholangiocarcinogenesis.

A Retrospective Evaluation of Changing Health Characteristics Amongst Deceased Organ Donors in the United States.

BACKGROUND: The availability of suitable donor organs remains a limiting factor to performing life-saving transplant operations. This study evaluates changes in the health of the donor population and its influence on organ use in the United States. METHODS: A retrospective analysis was performed using the OPTN STAR data file from 2005 to 2019. Three donor eras were defined: 1) 2005 to 2009, 2) 2010 to 2014, and 3) 2015 to 2019. The primary outcome was donor use, defined as transplantation of at least one solid organ. Descriptive analyses were performed, and associations of donor use were examined with multivariable logistic regression models. P values <.01 were considered significant. RESULTS: The cohort included 132,783 potential donors of which 124,729 (93.9%) were used for transplantation. Donor median age was 42 years (interquartile range 26-54), 53,566 (40.3%) were female, and 88,209 (66.4%) were White, 21,834 (16.4%) were black, and 18,509 (13.9%) were Hispanic. Compared with donors from Eras 1 and 2, donors in Era 3 were younger (P < .001), had higher body mass index (BMI) (P < .001), increased rates of diabetes mellitus (DM) (P < .001), hepatitis C virus (HCV) positivity (P < .001) and more comorbidities (P < .001). Multivariable modeling found donor BMI, DM, hypertension, and HCV status as health factors significantly associated with donor use. Compared with Era 1, there was increased use in Era 3 of donors with BMI ≥30 kg/m2, DM, hypertension, HCV-positive status, and donors with ≥3 comorbidities. CONCLUSIONS: Despite an increasing prevalence of chronic health problems in the donor population, donors with multiple comorbid conditions are more likely to be used for transplantation in recent years.

Regulatory Networks, Management Approaches, and Emerging Treatments of Nonalcoholic Fatty Liver Disease.

The pathogenesis of NAFLD is complex and diverse, involving multiple signaling pathways and cytokines from various organs. Hepatokines, stellakines, adipokines, and myokines secreted by hepatocytes, hepatic stellate cells, adipose tissue, and myocytes play an important role in the occurrence and development of nonalcoholic fatty liver disease (NAFLD). The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) contributes to the progression of NAFLD by mediating liver inflammation, immune response, hepatocyte death, and later compensatory proliferation. In this review, we first discuss the crosstalk and interaction between hepatokines, stellakines, adipokines, and myokines and NF-κB in NAFLD. The characterization of the crosstalk of NF-κB with these factors will provide a better understanding of the molecular mechanisms involved in the progression of NAFLD. In addition, we examine new expert management opinions for NAFLD and explore the therapeutic potential of silymarin in NAFLD/NASH.

Regulatory network and interplay of hepatokines, stellakines, myokines and adipokines in nonalcoholic fatty liver diseases and nonalcoholic steatohepatitis.

Fatty liver disease is a spectrum of liver pathologies ranging from simple hepatic steatosis to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and culminating with the development of cirrhosis or hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is complex and diverse, and there is a lack of effective treatment measures. In this review, we address hepatokines identified in the pathogenesis of NAFLD and NASH, including the signaling of FXR/RXR, PPARα/RXRα, adipogenesis, hepatic stellate cell activation/liver fibrosis, AMPK/NF-κB, and type 2 diabetes. We also highlight the interaction between hepatokines, and cytokines or peptides secreted from muscle (myokines), adipose tissue (adipokines), and hepatic stellate cells (stellakines) in response to certain nutritional and physical activity. Cytokines exert autocrine, paracrine, or endocrine effects on the pathogenesis of NAFLD and NASH. Characterizing signaling pathways and crosstalk amongst muscle, adipose tissue, hepatic stellate cells and other liver cells will enhance our understanding of interorgan communication and potentially serve to accelerate the development of treatments for NAFLD and NASH.

Donor-derived duodenal adenocarcinoma of a bladder-drained pancreas allograft.

The subset of the population that received bladder-drained allograft pancreata during peak utilization of the technique in the 1990s is approaching 20-30 postoperative years. This time frame is salient, as it parallels the time in which patients in the urologic literature develop adenocarcinomas after bladder reconstruction using gastrointestinal segments. We present the case of a 57-year-old simultaneous pancreas/kidney recipient who presented with microhematuria twenty-four years after transplantation and was found to have an adenocarcinoma of the duodenum of his failed, bladder-drained pancreas. After allograft pancreatectomy/duodenectomy, he remains disease-free eleven months postoperatively. As this patient population ages, practitioners should consider pathology of the donor duodenum and pancreas in recipients who present with gross or microscopic hematuria.

Use of a donor-derived cell-free DNA assay to monitor treatment response in pediatric renal transplant recipients with allograft rejection.

BACKGROUND: Detection of donor-derived cell-free DNA (dd-cfDNA) reliably identifies allograft rejection in pediatric and adult kidney transplant (KT) recipients. Here, we evaluate the utility of dd-cfDNA for monitoring response to treatment among pediatric renal transplant recipients suffering graft rejection. METHODS: 58 pediatric transplant recipients were enrolled between April 2018 and March 2020 and underwent initial dd-cfDNA testing to monitor for rejection. Allograft biopsy was performed for dd-cfDNA scores >1.0%. Patients with histologically proven rejection formed the study cohort and underwent appropriate treatment. Results of dd-cfDNA, serum creatinine (SCr), biopsy findings, and treatment outcomes were evaluated. Standard statistical analyses were applied. RESULTS: Nineteen of 58 (31%) patients had dd-cfDNA score >1.0%, of which 18 (94.7%) had biopsy-proven rejection. Median dd-cfDNA value was 1.90% (interquartile range 1.43%-3.23%), and biopsy results showed 11 patients (61.1%) with antibody-mediated rejection (AMR), 2 patients (11.1%) with T-cell mediated rejection (TCMR), and 5 patients (27.7%) with mixed AMR/TCMR. SCr at time of biopsy was 1.28 ± 1.09 mg/dl. Following treatment, dd-cfDNA scores decreased for all types of rejection but still remained >1.0% in both AMR (1.50% [0.90%-3.10%]) and mixed (1.40% [0.95%-4.15%]) groups. Repeat dd-cfDNA values were <1.0% for patients with TCMR (0.20%-0.28%). SCr showed minimal change from pre-treatment levels regardless of rejection subtype. CONCLUSIONS: Patients with TCMR may be reliably followed by dd-cfDNA; however, it remains unclear whether persistently elevated dd-cfDNA levels in AMR is a reflection of ongoing subclinical rejection or an inherent limitation of the assay's utility.

A Clinical Tool to Guide Selection and Utilization of Marginal Donor Livers With Graft Steatosis in Liver Transplantation.

BACKGROUND: Donor liver biopsy (DLBx) in liver transplantation provides information on allograft quality; however, predicting outcomes from these allografts remains difficult. METHODS: Between 2006 and 2015, 16 691 transplants with DLBx were identified from the Standard Transplant Analysis and Research database. Cox proportional hazard regression analyses identified donor and recipient characteristics associated with 30-d, 90-d, 1-y, and 3-y graft survival. A composite model, the Liver Transplant After Biopsy (LTAB) score, was created. The Mini-LTAB was then derived consisting of only donor age, macrosteatosis on DLBx, recipient model for end-stage liver disease score, and cold ischemic time. Risk groups were identified for each score and graft survival was evaluated. P values <0.05 were considered significant. RESULTS: The LTAB model used 14 variables and 5 risk groups and identified low-, mild-, moderate-, high-, and severe-risk groups. Compared with moderate-risk recipients, severe-risk recipients had increased risk of graft loss at 30 d (hazard ratio, 3.270; 95% confidence interval, 2.568-4.120) and at 1 y (2.258; 1.928-2.544). The Mini-LTAB model identified low-, moderate-, and high-risk groups. Graft survival in Mini-LTAB high-risk transplants was significantly lower than moderate- or low-risk transplants at all time points. CONCLUSIONS: The LTAB and Mini-LTAB scores represent guiding principles and provide clinically useful tools for the successful selection and utilization of marginal allografts in liver transplantation.

Clinical considerations in the management of non-alcoholic steatohepatitis cirrhosis pre- and post-transplant: A multi-system challenge.

Non-alcoholic steatohepatitis (NASH) is the most common chronic liver disease worldwide, and the fastest growing indication for liver transplantation in the United States. NASH is now the leading etiology for liver transplantation in women, the second leading indication for men, and the most common cause amongst recipients aged 65 years and older. Patients with end-stage liver disease related to NASH represent a unique and challenging patient population due the high incidence of associated comorbid diseases, including obesity, type 2 diabetes (T2D), and hypertension. These challenges manifest in the pre-liver transplantation period with increased waitlist times and waitlist mortality. Furthermore, these patients carry considerable risk of morbidity and mortality both before after liver transplantation, with high rates of T2D, cardiovascular disease, chronic kidney disease, poor nutrition, and disease recurrence. Successful transplantation for these patients requires identification and management of their comorbidities in the face of liver failure. Multidisciplinary evaluations include a thorough pre-transplant workup with a complete cardiac evaluation, control of diabetes, nutritional support, and even, potentially, consultation with a bariatric surgeon. This article provides a comprehensive review of the conditions and challenges facing patients with NASH cirrhosis undergoing liver transplantation and provides recommendations for evaluation and management to optimize them before liver transplantation to produce successful outcomes.

Higher thresholds for the utilization of steatotic allografts in liver transplantation: Analysis from a U.S. national database.

BACKGROUND: Historically, liver allografts with >30% macrosteatosis (MaS) on donor biopsy have been associated with early allograft dysfunction and worse graft survival; however, successful outcomes have been reported in small cohorts. This study proposes an elevated MaS threshold for organ utilization without detriment to graft survival. METHODS: The UNOS Standard Transplant Analysis and Research database was evaluated for transplants between 2006-2015. Graft survival up to 1-year was evaluated by Kaplan-Meier (KM) survival analyses, and by univariate and multivariable logistic regression analyses, including donor and recipient characteristics. Odds ratios (OR) with 95% confidence intervals (CI) for risk of graft loss are reported. RESULTS: Thirty-day risk of graft loss was increased with MaS as low as 10-19% (OR [95% CI] 1.301 [1.055-1.605], p<0.0001) and peaked with MaS 50-59% (2.921 [1.672-5.103]). At 1-year, risk of graft loss remained elevated with MaS 40-49% (1.465 [1.002-2.142]) and MaS 50-59% (1.978 [1.281-3.056], p = 0.0224). Multivariable models were created for Lower and Higher MELD recipients and MaS cutoffs were established. In Lower MELD recipients, organs with ≥50% MaS had increased risk of graft loss at 30 days (2.451 [1.541-3.897], p = 0.0008) and 1-year post-transplant (1.720 [1.224-2.418], p = 0.0125). Higher MELD recipients had increased risk of graft loss at 30 days with allografts showing MaS ≥40% (4.204 [1.440-5.076], p = 0.0016). At 1-year the risk remained increased, but MaS was not significant predictor of graft loss.048 [1.131-3.710], p = 0.0616). In both MELD cohorts, organs with MaS levels below threshold had similar survival to those transplanted without a donor biopsy. CONCLUSIONS: In conjunction with recipient selection, organs with MaS up to 50% may be safely used without detriment to outcomes.

Reciprocal Regulation Between Forkhead Box M1/NF-κB and Methionine Adenosyltransferase 1A Drives Liver Cancer.

BACKGROUND AND AIMS: Forkhead box M1 (FOXM1) and nuclear factor kappa B (NF-ĸB) are oncogenic drivers in liver cancer that positively regulate each other. We showed that methionine adenosyltransferase 1A (MAT1A) is a tumor suppressor in the liver and inhibits NF-ĸB activity. Here, we examined the interplay between FOXM1/NF-κB and MAT1A in liver cancer. APPROACH AND RESULTS: We examined gene and protein expression, effects on promoter activities and binding of proteins to promoter regions, as well as effects of FOXM1 inhibitors T0901317 (T0) and forkhead domain inhibitory-6 (FDI-6) in vitro and in xenograft and syngeneic models of liver cancer. We found, in both hepatocellular carcinoma and cholangiocarcinoma, that an induction in FOXM1 and NF-κB expression is accompanied by a fall in MATα1 (protein encoded by MAT1A). The Cancer Genome Atlas data set confirmed the inverse correlation between FOXM1 and MAT1A. Interestingly, FOXM1 directly interacts with MATα1 and they negatively regulate each other. In contrast, FOXM1 positively regulates p50 and p65 expression through MATα1, given that the effect is lost in its absence. FOXM1, MATα1, and NF-κB all bind to the FOX binding sites in the FOXM1 and MAT1A promoters. However, binding of FOXM1 and NF-κB repressed MAT1A promoter activity, but activated the FOXM1 promoter. In contrast, binding of MATα1 repressed the FOXM1 promoter. MATα1 also binds and represses the NF-κB element in the presence of p65 or p50. Inhibiting FOXM1 with either T0 or FDI-6 inhibited liver cancer cell growth in vitro and in vivo. However, inhibiting FOXM1 had minimal effects in liver cancer cells that do not express MAT1A. CONCLUSIONS: We have found a crosstalk between FOXM1/NF-κB and MAT1A. Up-regulation in FOXM1 lowers MAT1A, but raises NF-κB, expression, and this is a feed-forward loop that enhances tumorigenesis.

Current status of hepatocellular carcinoma detection: screening strategies and novel biomarkers.

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide. Delayed diagnosis is a major factor responsible for the poor prognosis of HCC. Several advances have been made in the field of liver imaging with the use of novel imaging contrasts, improving current imaging techniques with contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI), introduction of new technologies such as contrast liver ultrasound, and development of novel biomarkers with the goal of early detection of HCC and improving outcomes of patients with HCC. This review focuses on current surveillance strategies and development of biomarkers with the goal of early detection of HCC.