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"Strom, Stephen"
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The Greater San Rafael Swell
A landscape of great natural beauty, Utah's red rock country is a
place where the passage from deep time to the present is revealed
in stunningly sculpted and colorful geological strata that span 350
million years of Earth's history. At the heart of this dramatic
landscape is the Greater San Rafael Swell-a land of both geologic
and human tumult. Natural and human history come together in
The Greater San Rafael Swell , which spans much of Emery
County in Utah. Authors Stephen Strom and Jonathan Bailey paint a
multi-faceted picture of a singular place through photographs,
along with descriptions of geology, paleontology, archaeology,
history, and dozens of interviews with individuals who devoted more
than two decades to developing a shared vision of the future of
both the Swell and the County. At its core, the book relates the
important story of how a coalition of ranchers, miners, off-road
enthusiasts, conservationists, recreationists, and Native American
tribal nations worked together for nearly 25 years to forge and
pass the Emery County Public Lands Management Act in 2019. This
book chronicles hopeful stories for our times: how citizens of
Emery and three other counties in the rural West worked to resolve
perhaps the most volatile issue in the region - the future of
public lands. Both their successes and the processes by which they
found common ground serve as beacons in today's uncertain landscape
- beacons that can illuminate paths toward rebuilding our shared
democracy from the ground up.
eBook
Earth and Mars : a reflection
\"Earth and Mars relates in images and words the life story of two planets: both born in the dusty disk surrounding the young sun; each shaped by volcanic activity, wind, and water; but only one home to life\"--Provided by publisher.
Book
Oleocanthal exerts antitumor effects on human liver and colon cancer cells through ROS generation
The beneficial health properties of the Mediterranean diet are well recognized. The principle source of fat in Mediterranean diet is extra-virgin olive oil (EVOO). Oleocanthal (OC) is a naturally occurring minor phenolic compound isolated from EVOO, which has shown a potent anti-inflammatory activity, by means of its ability to inhibit the cyclooxygenase (COX) enzymes COX-1 and COX-2. A large body of evidence indicates that phenols exhibit anticancer activities. The aim of the present study was to evaluate the potential anticancer effects of OC in hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) models. A panel of human HCC (HepG2, Huh7, Hep3B and PLC/PRF/5) and CRC (HT29, SW480) cell lines was used. Cells were treated with OC, and cell viability and apoptosis were evaluated. Compared with classical commercially available COX inhibitors (ibuprofen, indomethacin, nimesulide), OC was more effective in inducing cell growth inhibition in HCC and CRC cells. Moreover, OC inhibited colony formation and induced apoptosis, as confirmed by PARP cleavage, activation of caspases 3/7 and chromatin condensation. OC treatment in a dose dependent-manner induced expression of γH2AX, a marker of DNA damage, increased intracellular ROS production and caused mitochondrial depolarization. Moreover, the effects of OC were suppressed by the ROS scavenger N-acetyl-L-cysteine. Finally, OC was not toxic in primary normal human hepatocytes. In conclusion, OC treatment was found to exert a potent anticancer activity against HCC and CRC cells. Taken together, our findings provide preclinical support of the chemotherapeutic potential of EVOO against cancer.
Journal Article
Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes
Three decades of hepatocyte transplantation have confirmed such a cell-based approach as an adjunct or alternative treatment to solid organ transplantation. Donor cell survival and engraftment were indirectly measured by hepatospecific secretive or released metabolites, such as ammonia metabolism in urea cycle defects. In cases of sepsis or viral infection, ammonia levels can significantly and abruptly increase in these recipients, erroneously implying rejection. Pro-inflammatory cytokines associated with viral or bacterial infections are known to affect many liver functions, including drug-metabolizing enzymes and hepatic transport activities. We examined the influence of pro-inflammatory cytokines in primary human hepatocytes, isolated from both normal donors or patients with metabolic liver diseases. Different measures of hepatocyte functions, including ammonia metabolism and phase 1–3 metabolism, were performed. All the hepatic functions were profoundly and significantly suppressed after exposure to concentrations of from 0.1 to 10 ng/mL of different inflammatory cytokines, alone and in combination. Our data indicate that, like phase I metabolism, suppression of phase II/III and ammonia metabolism occurs in hepatocytes exposed to pro-inflammatory cytokines in the absence of cell death. Such inflammatory events do not necessarily indicate a rejection response or loss of the cell graft, and these systemic inflammatory signals should be carefully considered when the immunosuppressant regiment is reduced or relieved in a hepatocyte transplantation recipient in response to such alleged rejection.
Journal Article
Gene Editing Correction of a Urea Cycle Defect in Organoid Stem Cell Derived Hepatocyte-like Cells
Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. In severe cases, currently available therapies are marginally effective, with liver transplantation being the only definitive treatment. Donor liver availability can limit even this therapy. Identification of novel therapeutics for genetic-based liver diseases requires models that provide measurable hepatic functions and phenotypes. Advances in stem cell and genome editing technologies could provide models for the investigation of cell-based genetic diseases, as well as the platforms for drug discovery. This report demonstrates a practical, and widely applicable, approach that includes the successful reprogramming of somatic cells from a patient with a urea cycle defect, their genetic correction and differentiation into hepatic organoids, and the subsequent demonstration of genetic and phenotypic change in the edited cells consistent with the correction of the defect. While individually rare, there is a large number of other genetic-based liver diseases. The approach described here could be applied to a broad range and a large number of patients with these hepatic diseases where it could serve as an in vitro model, as well as identify successful strategies for corrective cell-based therapy.
Journal Article
Mapping the Genetic Architecture of Gene Expression in Human Liver
Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.
Journal Article
Maintenance of Human Hepatocyte Function In Vitro by Liver-Derived Extracellular Matrix Gels
Tissue engineering and regenerative medicine (TE&RM) approaches to treating liver disease have the potential to provide temporary support with biohybrid-liver-assist devices or long-term therapy by replacing the diseased liver with functional constructs. A rate-limiting step for TE&RM strategies has been the loss of hepatocyte-specific functions after hepatocytes are isolated from their highly specialized in vivo microenvironment and placed in in vitro culture systems. The identification of a biologic substrate that can maintain a functional hepatocyte differentiation profile during in vitro culture would advance potential TE&RM therapeutic strategies. The present study compared two different biologic substrates for their ability to support human hepatocyte function in vitro: porcine-liver-derived extracellular matrix (PLECM) or MatrigelTM. Because Matrigel has been shown to be the most useful matrix for static, traditional hepatocyte culture, we directly compared PLECM with Matrigel in each experiment. Albumin secretion, hepatic transport activity, and ammonia metabolism were used to determine hepatocyte function. Hepatocytes cultured between two layers of PLECM or Matrigel showed equally high levels of albumin expression and secretion, ammonia metabolism, and hepatic transporter expression and function. We conclude that like Matrigel, PLECM represents a favorable substrate for in vitro culture of human hepatocytes.
Journal Article
Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice
Mice that could be highly repopulated with human hepatocytes would have many potential uses in drug development and research applications. The best available model of liver humanization, the uroplasminogen-activator transgenic model, has major practical limitations. To provide a broadly useful hepatic xenorepopulation system, we generated severely immunodeficient, fumarylacetoacetate hydrolase (Fah)-deficient mice. After pretreatment with a urokinase-expressing adenovirus, these animals could be highly engrafted (up to 90%) with human hepatocytes from multiple sources, including liver biopsies. Furthermore, human cells could be serially transplanted from primary donors and repopulate the liver for at least four sequential rounds. The expanded cells displayed typical human drug metabolism. This system provides a robust platform to produce high-quality human hepatocytes for tissue culture. It may also be useful for testing the toxicity of drug metabolites and for evaluating pathogens dependent on human liver cells for replication.
Journal Article
Clinical Hepatocyte Transplantation: Practical Limits and Possible Solutions
Since the first human hepatocyte transplants (HTx) in 1992, clinical studies have clearly established proof of principle for this therapy as a treatment for patients with acquired or inherited liver disease. Although major accomplishments have been made, there are still some specific limitations to this technology, which, if overcome, could greatly enhance the efficacy and implementation of this therapy. Here, we describe what in our view are the most significant obstacles to the clinical application of HTx and review the solutions currently proposed. The obstacles of significance include the limited number and quality of liver tissues as a cell source, the lack of clinical grade reagents, quality control evaluation of hepatocytes prior to transplantation, hypothermic storage of cells prior to transplantation, preconditioning treatments to enhance engraftment and proliferation of donor cells, tracking or monitoring cells after transplantation, and the optimal immunosuppression protocols for transplant recipients.
Journal Article