Publications by authors named "Amanda J Craig"

23 Publications

  • Page 1 of 1

Transcriptomic characterization of cancer-testis antigens identifies MAGEA3 as a driver of tumor progression in hepatocellular carcinoma.

PLoS Genet 2021 Jun 24;17(6):e1009589. Epub 2021 Jun 24.

Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, United States of America.

Cancer testis antigens (CTAs) are an extensive gene family with a unique expression pattern restricted to germ cells, but aberrantly reactivated in cancer tissues. Studies indicate that the expression (or re-expression) of CTAs within the MAGE-A family is common in hepatocellular carcinoma (HCC). However, no systematic characterization has yet been reported. The aim of this study is to perform a comprehensive profile of CTA de-regulation in HCC and experimentally evaluate the role of MAGEA3 as a driver of HCC progression. The transcriptomic analysis of 44 multi-regionally sampled HCCs from 12 patients identified high intra-tumor heterogeneity of CTAs. In addition, a subset of CTAs was significantly overexpressed in histologically poorly differentiated regions. Further analysis of CTAs in larger patient cohorts revealed high CTA expression related to worse overall survival and several other markers of poor prognosis. Functional analysis of MAGEA3 was performed in human HCC cell lines by gene silencing and in a genetic mouse model by overexpression of MAGEA3 in the liver. Knockdown of MAGEA3 decreased cell proliferation, colony formation and increased apoptosis. MAGEA3 overexpression was associated with more aggressive tumors in vivo. In conclusion MAGEA3 enhances tumor progression and should be considered as a novel therapeutic target in HCC.
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http://dx.doi.org/10.1371/journal.pgen.1009589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224860PMC
June 2021

Experimental Models of Liquid Biopsy in Hepatocellular Carcinoma Reveal Clone-Dependent Release of Circulating Tumor DNA.

Hepatol Commun 2021 Jun 23;5(6):1095-1105. Epub 2021 Mar 23.

Division of Liver Diseases Liver Cancer Program Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA.

Liquid biopsy, the molecular analysis of tumor components released into the bloodstream, has emerged as a noninvasive and resourceful means to access genomic information from cancers. Most data derived from translational studies showcase its numerous potential clinical applications. However, data from experimental models are scarce, and little is known about the underlying mechanisms and factors controlling the release of circulating tumor DNA (ctDNA) and cells (CTCs). This study aimed to model liquid biopsy in hepatocellular carcinoma xenografts and to study the dynamics of release of ctDNA and CTCs; this included models of intratumoral heterogeneity (ITH) and metastatic disease. We quantified ctDNA by quantitative polymerase chain reaction (PCR) targeting human long interspersed nuclear element group 1; targeted mutation analysis was performed with digital droplet PCR. CTCs were traced by flow cytometry. Results demonstrated the feasibility of detecting ctDNA, including clone-specific mutations, as well as CTCs in blood samples of mice. In addition, the concentration of ctDNA and presence of tumor-specific mutations reflected tumor progression, and detection of CTCs was associated with metastases. Our ITH model suggested differences in the release of DNA fragments impacted by the cell-clone origin and the treatment. These data present new models to study liquid biopsy and its underlying mechanisms and highlighted a clone-dependent release of ctDNA into the bloodstream.
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http://dx.doi.org/10.1002/hep4.1692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183169PMC
June 2021

Toward a Liver Cell Atlas: Understanding Liver Biology in Health and Disease at Single-Cell Resolution.

Semin Liver Dis 2021 Jun 15. Epub 2021 Jun 15.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Single-cell technologies are revolutionizing our understanding of cellular heterogeneity and functional diversity in health and disease. Here, we review the current knowledge and advances in liver biology using single-cell approaches. We focus on the landscape of the composition and the function of cells in a healthy liver in the context of its spatial organization. We also highlight the alterations of the molecular landscape in chronic liver disease and liver cancer, which includes the identification of disease-related cell types, altered cellular functions, dynamic cell-cell interactions, the plasticity of malignant cells, the collective behavior of a cell community, and microenvironmental reprogramming. We anticipate that the uncovered liver cell atlas will help deciphering the molecular and cellular mechanisms driving a healthy liver into a disease state. It also offers insight into the detection of new therapeutic targets and paves the way for effective disease interventions.
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http://dx.doi.org/10.1055/s-0041-1729970DOI Listing
June 2021

Hypoxia is a key regulator in liver cancer progression.

J Hepatol 2021 Jun 19. Epub 2021 Jun 19.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, USA.

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http://dx.doi.org/10.1016/j.jhep.2021.05.032DOI Listing
June 2021

Understanding tumour cell heterogeneity and its implication for immunotherapy in liver cancer using single-cell analysis.

J Hepatol 2021 Mar 30;74(3):700-715. Epub 2020 Nov 30.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, USA. Electronic address:

Over the last decade, precision medicine and immunotherapeutic approaches have become increasingly popular in oncology. Early clinical trials reported promising results, but response rates in phase III clinical trials have been suboptimal. Knowledge gained from subsequent translational studies indicates the importance of targeting the tumour microenvironment to overcome resistance to immunotherapy. In this era of precision medicine, it is crucial to consider inter- as well as intratumoural heterogeneity. Single-cell analysis is a cutting-edge technology that enables us to better define the tumour cell community and to identify potential targets for immunotherapy or combination treatments. This review focuses on single-cell analysis in the context of immunotherapy in liver cancer, including the rationale behind studying hepatocellular carcinoma biology at a single-cell level. Single-cell technologies have the potential to revolutionise our understanding of resistance mechanisms and to guide drug discovery efforts, leading to further advances in personalised medicine.
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http://dx.doi.org/10.1016/j.jhep.2020.11.036DOI Listing
March 2021

DNA Methylation Profiling of Human Hepatocarcinogenesis.

Hepatology 2021 Jul 15;74(1):183-199. Epub 2021 Jun 15.

Division of Liver Diseases, Liver Cancer Program, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.

Background And Aims: Mutations in TERT (telomerase reverse transcriptase) promoter are established gatekeepers in early hepatocarcinogenesis, but little is known about other molecular alterations driving this process. Epigenetic deregulation is a critical event in early malignancies. Thus, we aimed to (1) analyze DNA methylation changes during the transition from preneoplastic lesions to early HCC (eHCC) and identify candidate epigenetic gatekeepers, and to (2) assess the prognostic potential of methylation changes in cirrhotic tissue.

Approach And Results: Methylome profiling was performed using Illumina HumanMethylation450 (485,000 cytosine-phosphateguanine, 96% of known cytosine-phosphateguanine islands), with data available for a total of 390 samples: 16 healthy liver, 139 cirrhotic tissue, 8 dysplastic nodules, and 227 HCC samples, including 40 eHCC below 2cm. A phylo-epigenetic tree derived from the Euclidean distances between differentially DNA-methylated sites (n = 421,997) revealed a gradient of methylation changes spanning healthy liver, cirrhotic tissue, dysplastic nodules, and HCC with closest proximity of dysplasia to HCC. Focusing on promoter regions, we identified epigenetic gatekeeper candidates with an increasing proportion of hypermethylated samples (beta value > 0.5) from cirrhotic tissue (<1%), to dysplastic nodules (≥25%), to eHCC (≥50%), and confirmed inverse correlation between DNA methylation and gene expression for TSPYL5 (testis-specific Y-encoded-like protein 5), KCNA3 (potassium voltage-gated channel, shaker-related subfamily, member 3), LDHB (lactate dehydrogenase B), and SPINT2 (serine peptidase inhibitor, Kunitz type 2) (all P < 0.001). Unsupervised clustering of genome-wide methylation profiles of cirrhotic tissue identified two clusters, M1 and M2, with 42% and 58% of patients, respectively, which correlates with survival (P < 0.05), independent of etiology.

Conclusions: Genome-wide DNA-methylation profiles accurately discriminate the different histological stages of human hepatocarcinogenesis. We report on epigenetic gatekeepers in the transition between dysplastic nodules and eHCC. DNA-methylation changes in cirrhotic tissue correlate with clinical outcomes.
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http://dx.doi.org/10.1002/hep.31659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144238PMC
July 2021

Mutations in circulating tumor DNA predict primary resistance to systemic therapies in advanced hepatocellular carcinoma.

Oncogene 2021 01 23;40(1):140-151. Epub 2020 Oct 23.

Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Little is known about the mutational landscape of advanced hepatocellular carcinoma (HCC), and predictive biomarkers of response to systemic therapies are lacking. We aimed to describe the mutational landscape of advanced HCC and to identify predictors of primary resistance to systemic therapies using circulating tumor DNA (ctDNA). We prospectively enrolled 121 patients between October 2015 and January 2019. We performed targeted ultra-deep sequencing of 25 genes and Digital Droplet PCR of TERT promoter, including sequential samples throughout treatment. Primary endpoint was progression-free survival (PFS) stratified by mutation profiles in ctDNA. Secondary endpoints were overall survival and objective response rate. The most frequent mutations in ctDNA of advanced HCC were TERT promoter (51%), TP53 (32%), CTNNB1 (17%), PTEN (8%), AXIN1, ARID2, KMT2D, and TSC2 (each 6%). TP53 and CTNNB1 mutations were mutually exclusive. Patients with mutations in the PI3K/MTOR pathway had significantly shorter PFS than those without these mutations after tyrosine kinase inhibitors (2.1 vs 3.7 months, p < 0.001), but not after immune checkpoint inhibition (CPI). WNT pathway mutations were not associated with PFS, overall survival, or objective response after CPI. Serial profiling of ctDNA in a subset correlated with treatment response. Mutation profiling of ctDNA in advanced HCC shows similar mutation frequencies for known HCC drivers compared to early stages and identifies predictive biomarkers of response to systemic therapies.
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http://dx.doi.org/10.1038/s41388-020-01519-1DOI Listing
January 2021

Intratumoral heterogeneity and clonal evolution in liver cancer.

Nat Commun 2020 01 15;11(1):291. Epub 2020 Jan 15.

Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Clonal evolution of a tumor ecosystem depends on different selection pressures that are principally immune and treatment mediated. We integrate RNA-seq, DNA sequencing, TCR-seq and SNP array data across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. We investigate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. We detect different clonal expansion of the adaptive immune system in distant regions of the same tumor. An ITH-based gene signature improves single-biopsy patient survival predictions and an expression survey of 38,553 single cells across 7 regions of 2 patients further reveals heterogeneity in liver cancer. These data quantify transcriptomic ITH and how the different components of the HCC ecosystem interact during cancer evolution.
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http://dx.doi.org/10.1038/s41467-019-14050-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962317PMC
January 2020

Tumour evolution in hepatocellular carcinoma.

Nat Rev Gastroenterol Hepatol 2020 03 2;17(3):139-152. Epub 2019 Dec 2.

Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, typically develops on the background of chronic liver disease and is an aggressive disease with dismal prognosis. Studies using next-generation sequencing of multiple regions of the same tumour nodule suggest different patterns of HCC evolution and confirm the high molecular heterogeneity in a subset of patients. Different hypotheses have been proposed to explain tumour evolution, including clonal selection or neutral and punctuated acquisition of genetic alterations. In parallel, data indicate a fundamental contribution of nonmalignant cells of the tumour microenvironment to cancer clonal evolution. Delineating these dynamics is crucial to improve the treatment of patients with HCC, and particularly to help understand how HCC evolution drives resistance to systemic therapies. A number of new minimally invasive techniques, such as liquid biopsies, could help track cancer evolution in HCC. These tools might improve our understanding of how systemic therapies affect tumour clonal composition and could facilitate implementation of real-time molecular monitoring of patients with HCC.
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http://dx.doi.org/10.1038/s41575-019-0229-4DOI Listing
March 2020

Phenotype-Based Screens with Conformation-Specific Inhibitors Reveal p38 Gamma and Delta as Targets for HCC Polypharmacology.

Mol Cancer Ther 2019 09 18;18(9):1506-1519. Epub 2019 Jun 18.

Department of Oncological Sciences, The Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, New York.

The approved kinase inhibitors for hepatocellular carcinoma (HCC) are not matched to specific mutations within tumors. This has presented a daunting challenge; without a clear target or mechanism, no straightforward path has existed to guide the development of improved therapies for HCC. Here, we combine phenotypic screens with a class of conformation-specific kinase inhibitors termed type II to identify a multikinase inhibitor, AD80, with antitumoral activity across a variety of HCC preclinical models, including mouse xenografts. Mass spectrometry profiling found a number of kinases as putative targets for AD80, including several receptor and cytoplasmic protein kinases. Among these, we found p38 gamma and delta as direct targets of AD80. Notably, a closely related analog of AD80 lacking p38δ/γ activity, but retaining several other off-target kinases, lost significant activity in several HCC models. Moreover, forced and sustained MKK6 → p38→ATF2 signaling led to a significant reduction of AD80 activity within HCC cell lines. Together with HCC survival data in The Cancer Genome Atlas and RNA-seq analysis, we suggest p38 delta and gamma as therapeutic targets in HCC and an "AD80 inhibition signature" as identifying those patients with best clinical outcomes.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017390PMC
September 2019

The Impact of Translational Research in Hepatology.

Clin Liver Dis (Hoboken) 2019 Jan 21;13(1):29-33. Epub 2019 Feb 21.

Division of Liver Diseases, Department of Medicine, Liver Cancer Program Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai New York NY.

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http://dx.doi.org/10.1002/cld.805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465783PMC
January 2019

Mitohormesis Primes Tumor Invasion and Metastasis.

Cell Rep 2019 05;27(8):2292-2303.e6

Tisch Cancer Institute, Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Moderate mitochondrial stress can lead to persistent activation of cytoprotective mechanisms - a phenomenon termed mitohormesis. Here, we show that mitohormesis primes a subpopulation of cancer cells to basally upregulate mitochondrial stress responses, such as the mitochondrial unfolded protein response (UPR) providing an adaptive metastatic advantage. In this subpopulation, UPR activation persists in the absence of stress, resulting in reduced oxidative stress indicative of mitohormesis. Mechanistically, we showed that the SIRT3 axis of UPR is necessary for invasion and metastasis. In breast cancer patients, a 7-gene UPR signature demonstrated that UPR patients have significantly worse clinical outcomes, including metastasis. Transcriptomic analyses revealed that UPR patients have expression profiles characterized by metastatic programs and the cytoprotective outcomes of mitohormesis. While mitohormesis is associated with health and longevity in non-pathological settings, these results indicate that it is perniciously used by cancer cells to promote tumor progression.
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http://dx.doi.org/10.1016/j.celrep.2019.04.095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579120PMC
May 2019

A phenotypical map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites.

Histopathology 2019 Apr 21;74(5):718-730. Epub 2019 Feb 21.

Liver Cancer Research Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Aims: Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation of molecular drivers of HCC dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages, and paired primary-metastatic comparisons between samples from the same patient are difficult.

Methods And Results: We report the evaluation of 88 patients with HCC who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules analysed. The study included morphological assessment, immunohistochemistry and mutation status of the TERT promoter, the most frequently mutated gene in HCC. We confirm a strong predilection of HCC for lung dissemination, including subclinical micrometastases (unrecognised during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; macrovascular invasion; high histological, nuclear and architectural grades; and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significantly higher K19 and EpCAM expression than primary liver tumours. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumour, sometimes to a specific hepatic nodule.

Conclusions: This study suggests limited heterogeneity in metastatic sites compared to primary tumour sites.
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http://dx.doi.org/10.1111/his.13809DOI Listing
April 2019

Role of circulating tumor DNA to help decision-making in hepatocellular carcinoma.

Oncoscience 2018 Jul 22;5(7-8):209-211. Epub 2018 Aug 22.

Division of Liver Diseases, Division of Hematology and Medical Oncology, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.

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http://dx.doi.org/10.18632/oncoscience.446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142901PMC
July 2018

A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma.

Oncogene 2018 07 9;37(27):3740-3752. Epub 2018 Apr 9.

Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Graduate School of Biomedical Sciences, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, USA.

Cellular components of solid tumors including DNA are released into the bloodstream, but data on circulating-free DNA (cfDNA) in hepatocellular carcinoma (HCC) are still scarce. This study aimed at analyzing mutations in cfDNA and their correlation with tissue mutations in patients with HCC. We included 8 HCC patients treated with surgical resection for whom we collected paired tissue and plasma/serum samples. We analyzed 45 specimens, including multiregional tumor tissue sampling (n = 24), peripheral blood mononuclear cells (PMBC, n = 8), plasma (n = 8) and serum (n = 5). Ultra-deep sequencing (5500× coverage) of all exons was performed in a targeted panel of 58 genes, including frequent HCC driver genes and druggable mutations. Mutations detected in plasma included known HCC oncogenes and tumor suppressors (e.g., TERT promoter, TP53, and NTRK3) as well as a candidate druggable mutation (JAK1). This approach increased the detection rates previously reported for mutations in plasma of HCC patients. A thorough characterization of cis mutations found in plasma confirmed their tumoral origin, which provides definitive evidence of the release of HCC-derived DNA fragments into the bloodstream. This study demonstrates that ultra-deep sequencing of cfDNA is feasible and can confidently detect somatic mutations found in tissue; these data reinforce the role of plasma DNA as a promising minimally invasive tool to interrogate HCC genetics.
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http://dx.doi.org/10.1038/s41388-018-0206-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035113PMC
July 2018

Focal Ischaemic Infarcts Expand Faster in Cerebellar Cortex than Cerebral Cortex in a Mouse Photothrombotic Stroke Model.

Transl Stroke Res 2018 12 17;9(6):643-653. Epub 2018 Feb 17.

Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, UNSW Sydney, Sydney, NSW, 2052, Australia.

It is generally accepted that the cerebellum is particularly vulnerable to ischaemic injury, and this may contribute to the high mortality arising from posterior circulation strokes. However, this has not been systematically examined in an animal model. This study compared the development and resolution of matched photothrombotic microvascular infarcts in the cerebellar and cerebral cortices in adult 129/SvEv mice of both sexes. The photothrombotic lesions were made using tail vein injection of Rose Bengal with a 532 nm laser projected onto a 2 mm diameter aperture over the target region of the brain (with skull thinning). Infarct size was then imaged histologically following 2 h to 30-day survival using serial reconstruction of haematoxylin and eosin stained cryosections. This was complemented with immunohistochemistry for neuron and glial markers. At 2 h post-injury, the cerebellar infarct volume averaged ~ 2.7 times that of the cerebral cortex infarcts. Infarct volume reached maximum in the cerebellum in a quarter of the time (24 h) taken in the cerebral cortex (4 days). Remodelling resolved the infarcts within a month, leaving significantly larger residual injury volume in the cerebellum. The death of neurons in the core lesion at 2 h was confirmed by NeuN and Calbindin immunofluorescence, alongside activation of astrocytes and microglia. The latter persisted in the region within and surrounding the residual infarct at 30 days. This comparison of acute focal ischaemic injuries in cerebellar and cerebral cortices provides direct confirmation of exacerbation of neuropathology and faster kinetics in the cerebellum.
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http://dx.doi.org/10.1007/s12975-018-0615-1DOI Listing
December 2018

Divergent evolutionary trajectories in transplanted tumor models.

Nat Genet 2017 Oct;49(11):1565-1566

Liver Cancer Research Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Human-derived tumor models are becoming popular in the context of personalized medicine, but a new study shows that these models could be less representative of primary tumors than previously thought, particularly when using late passages.
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http://dx.doi.org/10.1038/ng.3983DOI Listing
October 2017

Molecular profiling of liver cancer heterogeneity.

Discov Med 2017 09;24(131):117-125

Liver Cancer Research Program, Division of Liver Diseases, Tisch Cancer Institute, Department of Medicine, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Liver cancer has the highest increase in incidence and mortality of all cancers in the United States in recent decades. A major effort has been taken over the last 10 years to understand molecular heterogeneity between tumors of different patients through the development of mutation signatures and molecular classifications. More recently, attention has shifted to understanding intra-tumor heterogeneity (ITH). Several possibilities exist as to the underlying mechanisms that drive ITH in liver cancer, including cancer stem cells (CSCs) and neutral and clonal evolution. Tracking ITH changes in patients over treatment courses will become imperative as precision medicine comes to the forefront of cancer management. Here we review the models of ITH development in liver cancer and the impact ITH assessment can have on clinical management.
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September 2017

Evaluation of Gene Therapy as an Intervention Strategy to Treat Brain Injury from Stroke.

Front Mol Neurosci 2016 24;9:34. Epub 2016 May 24.

Translational Neuroscience Facility & Department of Physiology, School of Medical Sciences, University of New South Wales, Sydney NSW, Australia.

Stroke is a leading cause of death and disability, with a lack of treatments available to prevent cell death, regenerate damaged cells and pathways, or promote neurogenesis. The extended period of hours to weeks over which tissue damage continues to occur makes this disorder a candidate for gene therapy. This review highlights the development of gene therapy in the area of stroke, with the evolution of viral administration, in experimental stroke models, from pre-injury to clinically relevant timeframes of hours to days post-stroke. The putative therapeutic proteins being examined include anti-apoptotic, pro-survival, anti-inflammatory, and guidance proteins, targeting multiple pathways within the complex pathology, with promising results. The balance of findings from animal models suggests that gene therapy provides a viable translational platform for treatment of ischemic brain injury arising from stroke.
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http://dx.doi.org/10.3389/fnmol.2016.00034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877374PMC
June 2016

Liver capsule: Molecular-based signatures in hepatocellular carcinoma.

Hepatology 2016 06 25;63(6):2018. Epub 2016 Mar 25.

Division of Liver Diseases, Liver Cancer Program.

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http://dx.doi.org/10.1002/hep.28489DOI Listing
June 2016

The neuroprotective efficacy of cell-penetrating peptides TAT, penetratin, Arg-9, and Pep-1 in glutamic acid, kainic acid, and in vitro ischemia injury models using primary cortical neuronal cultures.

Cell Mol Neurobiol 2014 Mar 9;34(2):173-81. Epub 2013 Nov 9.

Centre for Neuromuscular and Neurological Disorders, The University of Western Australia and Australian Neuromuscular Research Institute, A Block, 4th Floor, QEII Medical Centre, Verdun St, Nedlands, WA, 6009, Australia,

Cell-penetrating peptides (CPPs) are small peptides (typically 5-25 amino acids), which are used to facilitate the delivery of normally non-permeable cargos such as other peptides, proteins, nucleic acids, or drugs into cells. However, several recent studies have demonstrated that the TAT CPP has neuroprotective properties. Therefore, in this study, we assessed the TAT and three other CPPs (penetratin, Arg-9, Pep-1) for their neuroprotective properties in cortical neuronal cultures following exposure to glutamic acid, kainic acid, or in vitro ischemia (oxygen-glucose deprivation). Arg-9, penetratin, and TAT-D displayed consistent and high level neuroprotective activity in both the glutamic acid (IC50: 0.78, 3.4, 13.9 μM) and kainic acid (IC50: 0.81, 2.0, 6.2 μM) injury models, while Pep-1 was ineffective. The TAT-D isoform displayed similar efficacy to the TAT-L isoform in the glutamic acid model. Interestingly, Arg-9 was the only CPP that displayed efficacy when washed-out prior to glutamic acid exposure. Neuroprotection following in vitro ischemia was more variable with all peptides providing some level of neuroprotection (IC50; Arg-9: 6.0 μM, TAT-D: 7.1 μM, penetratin/Pep-1: >10 μM). The positive control peptides JNKI-1D-TAT (JNK inhibitory peptide) and/or PYC36L-TAT (AP-1 inhibitory peptide) were neuroprotective in all models. Finally, in a post-glutamic acid treatment experiment, Arg-9 was highly effective when added immediately after, and mildly effective when added 15 min post-insult, while the JNKI-1D-TAT control peptide was ineffective when added post-insult. These findings demonstrate that different CPPs have the ability to inhibit neurodamaging events/pathways associated with excitotoxic and ischemic injuries. More importantly, they highlight the need to interpret neuroprotection studies when using CPPs as delivery agents with caution. On a positive note, the cytoprotective properties of CPPs suggests they are ideal carrier molecules to deliver neuroprotective drugs to the CNS following injury and/or potential neuroprotectants in their own right.
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http://dx.doi.org/10.1007/s10571-013-9999-3DOI Listing
March 2014

Comparison of pharmacokinetic variables for creatinine and iohexol in dogs with various degrees of renal function.

Am J Vet Res 2012 Nov;73(11):1841-7

Unité de recherche clinique, Institut national polytechnique de Toulouse, Université de Toulouse, F-31076 Toulouse, France.

Objective: To compare pharmacokinetics and clearances of creatinine and iohexol as estimates of glomerular filtration rate (GFR) in dogs with various degrees of renal function.

Animals: 50 Great Anglo-Francais Tricolor Hounds with various degrees of renal function.

Procedures: Boluses of iohexol (40 mg/kg) and creatinine (647 mg/kg) were injected IV. Blood samples were collected before administration and 5 and 10 minutes and 1, 2, 4, 6, and 8 hours after administration. Plasma creatinine and iohexol concentrations were assayed via an enzymatic method and high-performance liquid chromatography, respectively. A noncompartmental approach was used for pharmacokinetic analysis. Pharmacokinetic variables were compared via a Bland-Altman plot and an ANOVA.

Results: Compared with results for creatinine, iohexol had a significantly higher mean ± SD plasma clearance (3.4 ± 0.8 mL/min/kg vs 3.0 ± 0.7 mL/min/kg) and a significantly lower mean volume of distribution at steady state (250 ± 37 mL/kg vs 539 ± 73 mL/kg), mean residence time (80 ± 31 minutes vs 195 ± 73 minutes), and mean elimination half-life (74 ± 20 minutes vs 173 ± 53 minutes). Despite discrepancies between clearances, especially for high values, the difference was < 0.6 mL/min/kg for 34 (68%) dogs. Three dogs with a low GFR (< 2 mL/min/kg) were classified similarly by both methods.

Conclusions And Clinical Relevance: Plasma iohexol and creatinine clearances can be used interchangeably for screening patients suspected of having chronic kidney disease (ie, low GFR), but large differences may exist for dogs with a GFR within or above the reference range.
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http://dx.doi.org/10.2460/ajvr.73.11.1841DOI Listing
November 2012

High level over-expression of different NCX isoforms in HEK293 cell lines and primary neuronal cultures is protective following oxygen glucose deprivation.

Neurosci Res 2012 Jul 27;73(3):191-8. Epub 2012 Apr 27.

Centre for Neuromuscular and Neurological Disorders, University of Western Australia and Australian Neuromuscular Research Institute, Western Australia, Australia.

In this study we have assessed sodium-calcium exchanger (NCX) protein over-expression on cell viability in primary rat cortical neuronal and HEK293 cell cultures when subjected to oxygen-glucose deprivation (OGD). In cortical neuronal cultures, NCX2 and NCX3 over-expression was achieved using adenoviral vectors, and following OGD increased neuronal survival from ≈20% for control vector treated cultures to ≈80% for both NCX isoforms. In addition, we demonstrated that NCX2 and NCX3 over-expression in cortical neuronal cultures enables neurons to maintain intracellular calcium at significantly lower levels than control vector treated cultures when exposed to high (9mM) extracellular calcium challenge. Further assessment of NCX activity during OGD was performed using HEK293 cell lines generated to over-express NCX1, NCX2 or NCX3 isoforms. While it was shown that NCX isoform expression differed considerably in the different HEK293 cell lines, high levels of NCX over-expression was associated with increased resistance to OGD. Taken together, our findings show that high levels of NCX over-expression increases neuronal and HEK293 cell survival following OGD, improves calcium management in neuronal cultures and provides additional support for NCX as a therapeutic target to reduce ischemic brain injury.
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http://dx.doi.org/10.1016/j.neures.2012.04.007DOI Listing
July 2012
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