Summary Colorectal cancer primarily metastasizes to the liver and kills over 600,000 people annually. By functionally screening 661 miRNAs in parallel during liver colonization, we have identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of extracellular phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP—fueling metastatic survival. Combinatorial therapeutic viral delivery of miR-551a and miR-483-5p through single-dose adeno-associated viral (AAV) delivery significantly suppressed colon cancer metastatic colonization, as did CKB inhibition with a small-molecule inhibitor. Importantly, human liver metastases express higher CKB and SLC6A8 levels and reduced miR-551a/miR-483 levels relative to primary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting.

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Nanophthalmos is a rare disorder of eye development characterized by extreme hyperopia (farsightedness), with refractive error in the range of ؉8.00 to ؉25.00 diopters. Because the cornea and lens are normal in size and shape, hyperopia occurs because insufficient growth along the visual axis places these lensing components too close to the retina. Nanophthalmic eyes show considerable thickening of both the choroidal vascular bed and scleral coat, which provide nutritive and structural support for the retina. Thickening of these tissues is a general feature of axial hyperopia, whereas the opposite occurs in myopia. We have mapped recessive nanophthalmos to a unique locus at 11q23.3 and identified four independent mutations in MFRP, a gene that is selectively expressed in the eye and encodes a protein with homology to Tolloid proteases and the Wnt-binding domain of the Frizzled transmembrane receptors. This gene is not critical for retinal function, as patients entirely lacking MFRP can still have good refraction-corrected vision, produce clinically normal electroretinograms, and show only modest anomalies in the dark adaptation of photoreceptors. MFRP appears primarily devoted to regulating axial length of the eye. It remains to be determined whether natural variation in its activity plays a role in common refractive errors.eye ͉ genetics ͉ morphology ͉ nanophthalmos

HIV/HCV coinfection leads to accelerated hepatic fibrosis progression, with higher rates of cirrhosis, liver failure, and liver death than does HCV mono-infection. However, the profibrogenic role of HIV on hepatocytes and hepatic stellate cells (HSC) has not been fully clarified. We hypothesized that HIV, HCV induce liver fibrosis through altered regulation of the production of extracellular matrix and matrix metalloproteinases. We examined the fibrogenesis- and fibrolysis-related gene activity in LX2 HSC and Huh7.5.1 cells in the presence of inactivated CXCR4 and CCR5 HIV, as well as HCV JFH1 virus. The role of reactive oxygen species (ROS) upon fibrosis gene expression was assessed using the ROS inhibitor. Fibrosis-related transcripts including procollagen α1(I) (CoL1A), TIMP1, and MMP3 mRNA were measured by qPCR. TIMP1 and MMP3 protein expression were assessed by ELISA. We found that inactivated CXCR4 HIV and CCR5 HIV increased CoL1A, and TIMP1 expression in both HSC and Huh7.5.1 cells; the addition of JFH1 HCV further increased CoL1A and TIMP1 expression. CXCR4 HIV and CCR5 HIV induced ROS production in HSC and Huh7.5.1 cells which was further enhanced by JFH1 HCV. The ROS inhibitor DPI abrogated HIV-and HCV-induced CoL1A and TIMP1 expression. HIV and HCV-induced CoL1A and TIMP1 expression were also blocked by NFκB siRNA. Our data provide further evidence that HIV and HCV independently regulate hepatic fibrosis progression through the generation of ROS; this regulation occurs in an NFκB-dependent fashion. Strategies to limit the viral induction of oxidative stress are warranted to inhibit fibrogenesis.

Human immunodeficiency virus (HIV) infection is a major cause of acceleration of hepatitis C virus-related liver disease, cirrhosis, and death. However, studies of liver disease pathogenesis in HIV/HCV coinfection have thus far been limited. Emerging data support multiple derangements attending HIV coinfection, including increases in profibrogenic cytokine expression and secretion, generation of enhanced oxidative stress, and increases in hepaotcyte apoptosis. These derangements may be further augmented in the presence of increased microbial translocation in the setting of HIV disease. New insight into the mechanisms of HIV/HCV pathogenesis causing accelerated liver fibrosis could lead to new therapeutic strategies designed to retard ths process.

Background and Aims Outcomes with anticoagulation (AC) are understudied in advanced liver disease. We investigated effects of AC with warfarin and direct oral anticoagulants (DOACs) on all‐cause mortality and hepatic decompensation as well as ischemic stroke, major adverse cardiovascular events, splanchnic vein thrombosis, and bleeding in a cohort with cirrhosis and atrial fibrillation (AF). Approach and Results This was a retrospective, longitudinal study using national data of U.S. veterans with cirrhosis at 128 medical centers, including patients with cirrhosis with incident AF, from January 1, 2012 to December 31, 2017 followed through December 31, 2018. To assess the effects of AC on outcomes, we applied propensity score (PS) matching and marginal structural models (MSMs) to account for confounding by indication and time‐dependent confounding. The final cohort included 2,694 veterans with cirrhosis with AF (n = 1,694 and n = 704 in the warfarin and DOAC cohorts after PS matching, respectively) with a median of 4.6 years of follow‐up. All‐cause mortality was lower with warfarin versus no AC (PS matched: hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.55‐0.76; MSM models: HR, 0.54; 95% CI, 0.40‐0.73) and DOACs versus no AC (PS matched: HR, 0.68; 95% CI, 0.50‐0.93; MSM models: HR, 0.50; 95% CI, 0.31‐0.81). In MSM models, warfarin (HR, 0.29; 95% CI, 0.09‐0.90) and DOACs (HR, 0.23; 95% CI, 0.07‐0.79) were associated with reduced ischemic stroke. In secondary analyses, bleeding was lower with DOACs compared to warfarin (HR, 0.49; 95% CI, 0.26‐0.94). Conclusions Warfarin and DOACs were associated with reduced all‐cause mortality. Warfarin was associated with more bleeding compared to no AC. DOACs had a lower incidence of bleeding compared to warfarin in exploratory analyses. Future studies should prospectively investigate these observed associations.

Colorectal cancer (CRC) is a major cause of human death. Mortality is primarily due to metastatic organ colonization, with the liver being the main organ affected. We modeled metastatic CRC (mCRC) liver colonization using patient-derived primary and metastatic tumor xenografts (PDX). Such PDX modeling predicted patient survival outcomes. In vivo selection of multiple PDXs for enhanced metastatic colonization capacity upregulated the gluconeogenic enzyme PCK1, which enhanced liver metastatic growth by driving pyrimidine nucleotide biosynthesis under hypoxia. Consistently, highly metastatic tumors upregulated multiple pyrimidine biosynthesis intermediary metabolites. Therapeutic inhibition of the pyrimidine biosynthetic enzyme DHODH with leflunomide substantially impaired CRC liver metastatic colonization and hypoxic growth. Our findings provide a potential mechanistic basis for the epidemiologic association of anti-gluconeogenic drugs with improved CRC metastasis outcomes, reveal the exploitation of a gluconeogenesis enzyme for pyrimidine biosynthesis under hypoxia, and implicate DHODH and PCK1 as metabolic therapeutic targets in CRC metastatic progression.

Background/Aims The response rates of HCV infection to interferon therapy vary depending on viral and host factors. We hypothesized that key regulators of the IFN signaling pathway are predictive of treatment outcome. Methods We measured the expression of signal transducer and activator of transcription 1 (STAT1) and suppressor of cytokine signaling 3 (SOCS3) in pretreatment liver biopsies. Staining quantitation was compared to treatment outcomes. Results Forty-nine patients with HCV and 25 patients with HCV/HIV infection treated with peginterferon/ribavirin were analyzed. Pretreatment hepatic SOCS3 expression was higher in non-responders than responders. Genotype 1 responders had similar levels of SOCS3 as genotype 2/3 responders. African Americans (AA) had higher hepatic SOCS3 than non-AA. Pretreatment hepatic SOCS3 was the most powerful independent predictor of sustained virologic response (SVR), even more so than genotype by logistic regression analysis. Failure to achieve SVR and AA race were independently associated with high hepatic SOCS3 levels. The hepatic expression of STAT-1 did not differ between responders and non-responders. Conclusions Our data indicate that hepatic SOCS3 is a stronger baseline predictor of antiviral response than viral genotype. Poor response to antiviral therapy in AA may be associated with higher hepatic SOCS3 expression.