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1. Evolutional transition of HBV genome during the persistent infection determined by single-molecule real-time sequencing

Author

Soichi Arasawa, Haruhiko Takeda, Atsushi Takai, Eriko Iguchi, Yuji Eso, Takahiro Shimizu, Ken Takahashi, Taiki Yamashita, Yoshihide Ueda, Hiroyuki Marusawa, and Hiroshi Seno

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background. Although HBV infection is a serious health issue worldwide, the landscape of HBV genome dynamics in the host has not yet been clarified. This study aimed to determine the continuous genome sequence of each HBV clone using a single-molecule real-time sequencing platform, and clarify the dynamics of structural abnormalities during persistent HBV infection without antiviral therapy. Patients and Methods. Twenty-five serum specimens were collected from 10 untreated HBV-infected patients. Continuous whole-genome sequencing of each clone was performed using a PacBio Sequel sequencer; the relationship between genomic variations and clinical information was analyzed. The diversity and phylogeny of the viral clones with structural variations were also analyzed. Results. The whole-genome sequences of 797,352 HBV clones were determined. The deletion was the most common structural abnormality and concentrated in the preS/S and C regions. Hepatitis B e antibody (anti-HBe)-negative samples or samples with high alanine aminotransferase levels have significantly diverse deletions than anti-HBe-positive samples or samples with low alanine aminotransferase levels. Phylogenetic analysis demonstrated that various defective and full-length clones evolve independently and form diverse viral populations. Conclusions. Single-molecule real-time long-read sequencing revealed the dynamics of genomic quasispecies during the natural course of chronic HBV infections. Defective viral clones are prone to emerge under the condition of active hepatitis, and several types of defective variants can evolve independently of the viral clones with the full-length genome.

Published
2023
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2. Mutational spectrum of hepatitis C virus in patients with chronic hepatitis C determined by single molecule real-time sequencing

Author

Fumiyasu Nakamura, Haruhiko Takeda, Yoshihide Ueda, Atsushi Takai, Ken Takahashi, Yuji Eso, Soichi Arasawa, Eriko Iguchi, Takahiro Shimizu, Masako Mishima, Ken Kumagai, Taiki Yamashita, Shinji Uemoto, Nobuyuki Kato, Hiroyuki Marusawa, Akihiro Sekine, and Hiroshi Seno

Subjects
Medicine, Science
Abstract

Abstract The emergence of hepatitis C virus (HCV) with resistance-associated substitution (RAS), produced by mutations in the HCV genome, is a major problem in direct acting antivirals (DAA) treatment. This study aimed to clarify the mutational spectrum in HCV-RNA and the substitution pattern for the emergence of RASs in patients with chronic HCV infection. HCV-RNA from two HCV replicon cell lines and the serum HCV-RNA of four non-liver transplant and four post-liver transplant patients with unsuccessful DAA treatment were analyzed using high-accuracy single-molecule real-time long-read sequencing. Transition substitutions, especially A>G and U>C, occurred prominently under DAAs in both non-transplant and post-transplant patients, with a mutational bias identical to that occurring in HCV replicon cell lines during 10-year culturing. These mutational biases were reproduced in natural courses after DAA treatment. RASs emerged via both transition and transversion substitutions. NS3-D168 and NS5A-L31 RASs resulted from transversion mutations, while NS5A-Y93 RASs was caused by transition substitutions. The fidelity of the RNA-dependent RNA polymerase, HCV-NS5B, produces mutational bias in the HCV genome, characterized by dominant transition mutations, notably A>G and U>C substitutions. However, RASs are acquired by both transition and transversion substitutions, and the RASs-positive HCV clones are selected and proliferated under DAA treatment pressure.

Published
2022
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3. Cancer imaging and therapy utilizing a novel NIS-expressing adenovirus: The role of adenovirus death protein deletion

Author

Matthew Glen Robertson, Benjamin Bruce Eidenschink, Eriko Iguchi, Stanislav O. Zakharkin, Christopher J. LaRocca, Ezequiel J. Tolosa, Mark J. Truty, Kari Jacobsen, Martin E. Fernandez-Zapico, and Julia Davydova

Subjects
Oncolytic Virus, Adenovirus, Sodium-iodide symporter, Adenovirus Death Protein, Cancer imaging, Radiotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Encoding the sodium iodide symporter (NIS) by an adenovirus (Ad) is a promising strategy to facilitate non-invasive imaging and radiotherapy of pancreatic cancer. However, insufficient levels of NIS expression in tumor cells have limited its clinical translation. To optimize Ad-based radiotherapy and imaging, we investigated the effect of Ad death protein (ADP) deletion on NIS expression. We cloned two sets of oncolytic NIS-expressing Ads that differed only in the presence or absence of ADP. We found that ADP expression negatively affected NIS membrane localization and inhibited radiotracer uptake. ADP deletion significantly improved NIS-based imaging in pancreatic cancer models including patient-derived xenografts, where effective imaging was possible for up to 6 weeks after a single virus injection. This study demonstrates that improved oncolysis may hinder the therapeutic effect of oncolytic viruses designed to express NIS. In vivo studies in combination with 131I showed potential for effective radiotherapy. This also highlights the need for further investigation into optimal timing of 131I administration and suggests that repeated doses of 131I should be considered to improve efficacy in clinical trials. We conclude that ADP deletion is essential for effective NIS-based theranostics in cancer.

Published
2021
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4. LPCAT1-TERT fusions are uniquely recurrent in epithelioid trophoblastic tumors and positively regulate cell growth.

Author

Gavin R Oliver, Sofia Marcano-Bonilla, Jonathan Quist, Ezequiel J Tolosa, Eriko Iguchi, Amy A Swanson, Nicole L Hoppman, Tanya Schwab, Ashley Sigafoos, Naresh Prodduturi, Jesse S Voss, Shannon M Knight, Jin Zhang, Numrah Fadra, Raul Urrutia, Michael Zimmerman, Jan B Egan, Anthony G Bilyeu, Jin Jen, Ema Veras, Rema'a Al-Safi, Matthew Block, Sarah Kerr, Martin E Fernandez-Zapico, John K Schoolmeester, and Eric W Klee

Subjects
Medicine, Science
Abstract

Gestational trophoblastic disease (GTD) is a heterogeneous group of lesions arising from placental tissue. Epithelioid trophoblastic tumor (ETT), derived from chorionic-type trophoblast, is the rarest form of GTD with only approximately 130 cases described in the literature. Due to its morphologic mimicry of epithelioid smooth muscle tumors and carcinoma, ETT can be misdiagnosed. To date, molecular characterization of ETTs is lacking. Furthermore, ETT is difficult to treat when disease spreads beyond the uterus. Here using RNA-Seq analysis in a cohort of ETTs and other gestational trophoblastic lesions we describe the discovery of LPCAT1-TERT fusion transcripts that occur in ETTs and coincide with underlying genomic deletions. Through cell-growth assays we demonstrate that LPCAT1-TERT fusion proteins can positively modulate cell proliferation and therefore may represent future treatment targets. Furthermore, we demonstrate that TERT upregulation appears to be a characteristic of ETTs, even in the absence of LPCAT1-TERT fusions, and that it appears linked to copy number gains of chromosome 5. No evidence of TERT upregulation was identified in other trophoblastic lesions tested, including placental site trophoblastic tumors and placental site nodules, which are thought to be the benign chorionic-type trophoblast counterpart to ETT. These findings indicate that LPCAT1-TERT fusions and copy-number driven TERT activation may represent novel markers for ETT, with the potential to improve the diagnosis, treatment, and outcome for women with this rare form of GTD.

Published
2021
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6. Cancer imaging and therapy utilizing a novel NIS-expressing adenovirus: The role of adenovirus death protein deletion

Author

Benjamin Bruce Eidenschink, Martin E. Fernandez-Zapico, Julia Davydova, Stanislav O. Zakharkin, Mark J. Truty, Eriko Iguchi, Christopher J. LaRocca, Ezequiel J. Tolosa, Kari Jacobsen, and Matthew Glen Robertson

Subjects
0301 basic medicine, Sodium-iodide symporter, Cancer Research, medicine.medical_treatment, lcsh:RC254-282, Virus, 03 medical and health sciences, 0302 clinical medicine, Pancreatic cancer, medicine, Adenovirus, Pharmacology (medical), health care economics and organizations, Radiotherapy, business.industry, Adenovirus Death Protein, Cancer, Translation (biology), lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Oncolytic virus, Oncolytic Virus, Radiation therapy, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Original Article, Cancer imaging, business
Abstract

Encoding the sodium iodide symporter (NIS) by an adenovirus (Ad) is a promising strategy to facilitate non-invasive imaging and radiotherapy of pancreatic cancer. However, insufficient levels of NIS expression in tumor cells have limited its clinical translation. To optimize Ad-based radiotherapy and imaging, we investigated the effect of Ad death protein (ADP) deletion on NIS expression. We cloned two sets of oncolytic NIS-expressing Ads that differed only in the presence or absence of ADP. We found that ADP expression negatively affected NIS membrane localization and inhibited radiotracer uptake. ADP deletion significantly improved NIS-based imaging in pancreatic cancer models including patient-derived xenografts, where effective imaging was possible for up to 6 weeks after a single virus injection. This study demonstrates that improved oncolysis may hinder the therapeutic effect of oncolytic viruses designed to express NIS. In vivo studies in combination with 131I showed potential for effective radiotherapy. This also highlights the need for further investigation into optimal timing of 131I administration and suggests that repeated doses of 131I should be considered to improve efficacy in clinical trials. We conclude that ADP deletion is essential for effective NIS-based theranostics in cancer., Graphical abstract, Sodium iodide symporter (NIS)-expressing oncolytic viruses enable tumor-specific imaging and radiotherapy for infected tumors. We designed a novel NIS-expressing adenoviral vector with deletion of the adenovirus death protein (ADP) gene. ADP deletion improved NIS expression and subsequent imaging capabilities highlighting the role of vector design in effective transgene expression.

Published
2021

7. LPCAT1-TERT fusions are uniquely recurrent in epithelioid trophoblastic tumors and positively regulate cell growth

Author

Eriko Iguchi, Raul Urrutia, Eric W. Klee, Ashley N. Sigafoos, Michael Zimmerman, Jesse S. Voss, Sarah E. Kerr, Jin Zhang, Anthony G. Bilyeu, Amy A. Swanson, Jin Jen, Matthew S. Block, Tanya L. Schwab, Numrah Fadra, Shannon M. Knight, Jan B. Egan, Ema Veras, John K. Schoolmeester, Martin E. Fernandez-Zapico, Nicole L. Hoppman, Gavin R. Oliver, Naresh Prodduturi, Sofia Marcano-Bonilla, Rema'a Al-Safi, Jonathan Quist, and Ezequiel J. Tolosa

Subjects
Oncogene Proteins, Fusion, Trophoblastic Tumor, Uterus, Cancer Treatment, Lung and Intrathoracic Tumors, Cell Fusion, Pregnancy, Medicine and Health Sciences, Gestational Trophoblastic Disease, DNA extraction, Telomerase, Multidisciplinary, Gestational trophoblastic disease, Epithelioid Cells, 1-Acylglycerophosphocholine O-Acyltransferase, Genomics, Middle Aged, medicine.anatomical_structure, Oncology, Uterine Neoplasms, embryonic structures, Medicine, Female, Research Article, Adult, Cell Physiology, Science, Biology, Trophoblastic Neoplasms, Malignant Tumors, Extraction techniques, Downregulation and upregulation, Diagnostic Medicine, medicine, Carcinoma, Genetics, Cancer Detection and Diagnosis, Biomarkers, Tumor, Humans, Placental site trophoblastic tumor, Epithelioid Trophoblastic Tumor, Cell Proliferation, Trophoblast, Biology and Life Sciences, Cancers and Neoplasms, Cell Biology, medicine.disease, Research and analysis methods, Cancer research
Abstract

Gestational trophoblastic disease (GTD) is a heterogeneous group of lesions arising from placental tissue. Epithelioid trophoblastic tumor (ETT), derived from chorionic-type trophoblast, is the rarest form of GTD with only approximately 130 cases described in the literature. Due to its morphologic mimicry of epithelioid smooth muscle tumors and carcinoma, ETT can be misdiagnosed. To date, molecular characterization of ETTs is lacking. Furthermore, ETT is difficult to treat when disease spreads beyond the uterus. Here using RNA-Seq analysis in a cohort of ETTs and other gestational trophoblastic lesions we describe the discovery of LPCAT1-TERT fusion transcripts that occur in ETTs and coincide with underlying genomic deletions. Through cell-growth assays we demonstrate that LPCAT1-TERT fusion proteins can positively modulate cell proliferation and therefore may represent future treatment targets. Furthermore, we demonstrate that TERT upregulation appears to be a characteristic of ETTs, even in the absence of LPCAT1-TERT fusions, and that it appears linked to copy number gains of chromosome 5. No evidence of TERT upregulation was identified in other trophoblastic lesions tested, including placental site trophoblastic tumors and placental site nodules, which are thought to be the benign chorionic-type trophoblast counterpart to ETT. These findings indicate that LPCAT1-TERT fusions and copy-number driven TERT activation may represent novel markers for ETT, with the potential to improve the diagnosis, treatment, and outcome for women with this rare form of GTD.

Published
2021

8. DNA methyltransferase 3B plays a protective role against hepatocarcinogenesis caused by chronic inflammation via maintaining mitochondrial homeostasis

Author

Soichi Arasawa, Yoshihide Ueda, Yuji Eso, Atsushi Takai, Ken Kumagai, Hiroshi Seno, Haruhiko Takeda, Takahiro Shimizu, Hiroyuki Marusawa, and Eriko Iguchi

Subjects
0301 basic medicine, Methyltransferase, Carcinoma, Hepatocellular, Hepatocellular carcinoma, Bisulfite sequencing, DNMT3B, Biology, Article, Epigenesis, Genetic, Hepatitis, Transcriptome, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Animals, Homeostasis, Humans, Epigenetics, DNA (Cytosine-5-)-Methyltransferases, Author Correction, Cells, Cultured, Inflammation, Multidisciplinary, DNA methylation, Reverse Transcriptase Polymerase Chain Reaction, Liver Neoplasms, HCCS, medicine.disease, Immunohistochemistry, Mitochondria, 030104 developmental biology, Differentially methylated regions, 030220 oncology & carcinogenesis, embryonic structures, Cancer research
Abstract

Most hepatocellular carcinomas (HCCs) develop on the basis of chronic hepatitis, but the mechanism of epigenetic regulation in inflammatory hepatocarcinogenesis has yet to be elucidated. Among de novo DNA methyltransferases (DNMTs), DNMT3B has lately been reported to act specifically on actively transcribed genes, suggesting the possibility that it plays a role in the pathogenesis of cancer. We confirmed that DNMT3B isoforms lacking its catalytic domain were highly expressed in HCCs compared with non-tumorous liver tissue. To elucidate the role of DNMT3B in hepatocarcinogenesis, we generated a genetically engineered mouse model with hepatocyte-specific Dnmt3b deletion. The liver of the Dnmt3b-deficient mice exhibited an exacerbation of thioacetamide-induced hepatitis, progression of liver fibrosis and a higher incidence of HCC compared with the liver of the control mice. Whole-genome bisulfite sequencing verified a lower CG methylation level in the Dnmt3b-deficient liver, demonstrating differentially methylated regions throughout the genome. Transcriptome analysis revealed decreased expression of genes related to oxidative phosphorylation in the Dnmt3b-deficient liver. Moreover, primary hepatocytes isolated from the Dnmt3b-deficient mice showed reduced mitochondrial respiratory capacity, leading to the enhancement of oxidative stress in the liver tissue. Our findings suggest the protective role of DNMT3B against chronic inflammation and HCC development via maintaining mitochondrial homeostasis.

Published
2020

9. Author Correction: DNA methyltransferase 3B plays a protective role against hepatocarcinogenesis caused by chronic inflammation via maintaining mitochondrial homeostasis

Author

Ken Kumagai, Eriko Iguchi, Hiroshi Seno, Atsushi Takai, Haruhiko Takeda, Soichi Arasawa, Hiroyuki Marusawa, Yuji Eso, Yoshihide Ueda, and Takahiro Shimizu

Subjects
Multidisciplinary, DNA METHYLTRANSFERASE 3B, Science, medicine, Medicine, Inflammation, Mitochondrial homeostasis, Biology, medicine.symptom, Cell biology
Published
2021

10. Dose Intensity/Body Surface Area Ratio is a Novel Marker Useful for Predicting Response to Lenvatinib against Hepatocellular Carcinoma

Author

Fumiyasu Nakamura, Hiroshi Seno, Soichi Arasawa, Haruhiko Takeda, Atsushi Takai, Ken Takahashi, Yuji Eso, Shigeharu Nakano, Eriko Iguchi, Masako Mishima, and Kojiro Taura

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Multivariate analysis, dose intensity, relative dose intensity, lenvatinib, lcsh:RC254-282, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Treatment intensity, medicine, Body surface area, Receiver operating characteristic, business.industry, body surface area, molecular-targeted therapy, hepatocellular carcinoma, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Dose intensity, chemistry, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, 030211 gastroenterology & hepatology, albi grade, Lenvatinib, business, After treatment
Abstract

Lenvatinib was recently approved as a novel first-line molecular targeted agent (MTA) for treating hepatocellular carcinoma (HCC). The importance of relative dose intensity (RDI) has been shown in the treatment of various types of cancers. However, RDI may not accurately reflect the treatment intensity of lenvatinib, as it is the first oral MTA where the dose is based on the patient&rsquo, s weight. We aimed to evaluate the utility of 2M-DBR (the delivered dose intensity/body surface area ratio at 60 days) by comparing the relationship between 2M-DBR, 2M-RDI (RDI at 60 days), and the therapeutic response. The therapeutic response to lenvatinib was evaluated in 45 patients who underwent computed tomography 8&ndash, 12 weeks after treatment initiation. We also investigated the clinical factors associated with high 2M-DBR. The area under the receiver operating characteristic of 2M-DBR that predicts the response to lenvatinib was higher than that of 2M-RDI (0.8004 vs. 0.7778). Patients with high 2M-DBR achieved significantly better objective responses and disease control rates than those with low 2M-DBR (p &lt, 0.0001 and 0.0008). Patients with high 2M-DBR experienced significantly longer progression-free survival (PFS) than those with low 2M-DBR (p = 0.0001), while there was no significant correlation between 2M-RDI levels and PFS (p = 0.2198). Patients who achieved higher levels of 2M-DBR had a significantly better modified ALBI grade (p = 0.0437), better CONUT score (p = 0.0222), and higher BTR (p = 0.0281). Multivariate analysis revealed that high 2M-DBR was the only significant factor associated with longer PFS. In conclusion, 2M-DBR could be an important factor that reflects treatment intensity and useful for predicting the response to lenvatinib against HCC, instead of 2M-RDI.

Published
2019

11. Molecular Modeling and Functional Analysis of Exome Sequencing–Derived Variants of Unknown Significance Identify a Novel, Constitutively Active FGFR2 Mutant in Cholangiocarcinoma

Author

Konstantinos N. Lazaridis, Ryan M. Carr, Amulya A. Nageswara Rao, Gavin R. Oliver, Karl J. Clark, Stephen M. Ansell, Eriko Iguchi, Thorvardur R. Halfdanarson, Robert R. McWilliams, Heidi D. Finnes, Animesh Pardanani, Sarah E. Kerr, Tara L. Hogenson, Jean Pierre A. Kocher, Ramesh K. Ramanathan, Mitesh J. Borad, Richard W. Joseph, Aryan Ala'Aldeen, Steven I. Robinson, Aaron S. Mansfield, Ronald S. Go, Raoul Tibes, Colleen M. Tagtow, Chelsea D. Gawryletz, Eric D. Wieben, Anne M. Vrabel, Naresh Prodduturi, Alvin C. Silva, Grzegorz S. Nowakowski, David W. Mead, Aminah Jatoi, Prashant Kapoor, Tammy M. McAllister, Elisa Enriquez Hesles, Luciana L. Almada, Eric W. Klee, Eileen J. Kennedy, David L. Marks, John C. Cheville, Sikander Ailawadhi, Asif Hossain, Kandelaria M. Rumilla, Mrinal M. Patnaik, Stephanie L. Safgren, Ernesto Resnik, Jan B. Egan, Estrella M. Carballido, Asher Chanan-Khan, Martin E. Fernandez-Zapico, Paola A. Romecin-Duran, Thai H. Ho, Andrew L. Feldman, Norine E. Huneke, Nathalie Meurice, Kelly K. Curtis, Michaela S. Banck, Jennifer B. McCormick, Alan H. Bryce, Ashley N. Sigafoos, A. Keith Stewart, Sameer A. Parikh, Ezequiel J. Tolosa, and Gianrico Farrugia

Subjects
Genetics, Cancer Research, Point mutation, In silico, Mutant, Biology, Receptor tyrosine kinase, Article, Oncology, biology.protein, Coding region, Gene, Exome sequencing, Function (biology)
Abstract

Purpose Genomic testing has increased the quantity of information available to oncologists. Unfortunately, many identified sequence alterations are variants of unknown significance (VUSs), which thus limit the clinician’s ability to use these findings to inform treatment. We applied a combination of in silico prediction and molecular modeling tools and laboratory techniques to rapidly define actionable VUSs. Materials and Methods Exome sequencing was conducted on 308 tumors from various origins. Most single nucleotide alterations within gene coding regions were VUSs. These VUSs were filtered to identify a subset of therapeutically targetable genes that were predicted with in silico tools to be altered in function by their variant sequence. A subset of receptor tyrosine kinase VUSs was characterized by laboratory comparison of each VUS versus its wild-type counterpart in terms of expression and signaling activity. Results The study identified 4,327 point mutations of which 3,833 were VUSs. Filtering for mutations in genes that were therapeutically targetable and predicted to affect protein function reduced these to 522 VUSs of interest, including a large number of kinases. Ten receptor tyrosine kinase VUSs were selected to explore in the laboratory. Of these, seven were found to be functionally altered. Three VUSs (FGFR2 F276C, FGFR4 R78H, and KDR G539R) showed increased basal or ligand-stimulated ERK phosphorylation compared with their wild-type counterparts, which suggests that they support transformation. Treatment of a patient who carried FGFR2 F276C with an FGFR inhibitor resulted in significant and sustained tumor response with clinical benefit. Conclusion The findings demonstrate the feasibility of rapid identification of the biologic relevance of somatic mutations, which thus advances clinicians’ ability to make informed treatment decisions.

Published
2017

12. Transcriptional Induction of Periostin by a Sulfatase 2-TGFβ1-SMAD Signaling Axis Mediates Tumor Angiogenesis in Hepatocellular Carcinoma

Author

Ikuo Nakamura, Shaoshan Han, Mengtao Zhou, Yong Fang, Dongye Yang, Hassan M. Shaleh, Martin E. Fernandez-Zapico, Tao Song, Ezequiel J. Tolosa, Ju Seog Lee, Yichun Chen, Alexander G. Miamen, Luciana L. Almada, Gang Chen, Chunling Hu, Roongruedee Chaiteerakij, Abdul M. Oseini, Eriko Iguchi, Eric Chevet, Dehai Wu, Catherine D. Moser, Michael K. Asiedu, Paola A. Romecin, Lewis R. Roberts, Vijay H. Shah, Renumathy Dhanasekaran, Bubu A. Banini, Renzo E. Vera, Snorri S. Thorgeirsson, Shaoqing Wang, CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Schulze Center for Novel Therapeutics, Division of Oncology Research [Rochester], Mayo Clinic [Rochester], CA165076, National Institutes of Health, P30DK084567, National Institute of Diabetes and Digestive and Kidney Diseases, 81201953, National Natural Science Foundation of China, CA15083, Mayo Clinic Cancer Center, and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cancer Research, Pathology, Angiogenesis, Smad Proteins, SMAD, Kaplan-Meier Estimate, ANGIOGENESIS, purl.org/becyt/ford/1 [https], Extracellular matrix, Mice, 0302 clinical medicine, Oligonucleotide Array Sequence Analysis, Tube formation, Mice, Knockout, Neovascularization, Pathologic, SULFATASE 2, Liver Neoplasms, Bioquímica y Biología Molecular, Immunohistochemistry, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Gene Knockdown Techniques, Sulfatases, Sulfotransferases, CIENCIAS NATURALES Y EXACTAS, Signal Transduction, medicine.medical_specialty, Chromatin Immunoprecipitation, Carcinoma, Hepatocellular, Blotting, Western, Enzyme-Linked Immunosorbent Assay, [SDV.CAN]Life Sciences [q-bio]/Cancer, Periostin, Biology, Real-Time Polymerase Chain Reaction, Article, Ciencias Biológicas, Transforming Growth Factor beta1, 03 medical and health sciences, Paracrine signalling, Downregulation and upregulation, medicine, Biomarkers, Tumor, Gene silencing, Animals, Humans, HEPATOCELLULAR CARCINOMA, purl.org/becyt/ford/1.6 [https], digestive system diseases, 030104 developmental biology, Cancer research, Cell Adhesion Molecules
Abstract

Existing antiangiogenic approaches to treat metastatic hepatocellular carcinoma (HCC) are weakly effectual, prompting further study of tumor angiogenesis in this disease setting. Here, we report a novel role for sulfatase 2 (SULF2) in driving HCC angiogenesis. Sulf2-deficient mice (Sulf2 KO) exhibited resistance to diethylnitrosamine-induced HCC and did not develop metastases like wild-type mice (Sulf2 WT). The smaller and less numerous tumors formed in Sulf2 KO mice exhibited a markedly lower microvascular density. In human HCC cells, SULF2 overexpression increased endothelial proliferation, adhesion, chemotaxis, and tube formation in a paracrine fashion. Mechanistic analyses identified the extracellular matrix protein periostin (POSTN), a ligand of avb3/5 integrins, as an effector protein in SULF2-induced angiogenesis. POSTN silencing in HCC cells attenuated SULF2-induced angiogenesis and tumor growth in vivo. The TGFb1/SMAD pathway was identified as a critical signaling axis between SULF2 and upregulation of POSTN transcription. In clinical HCC specimens, elevated levels of SULF2 correlated with increased microvascular density, POSTN levels, and relatively poorer patient survival. Together, our findings define an important axis controlling angiogenesis in HCC and a mechanistic foundation for rational drug development. Fil: Chen, Gang. Mayo Clinic; Estados Unidos. Wenzhou Medical University; China Fil: Nakamura, Ikuo. Mayo Clinic; Estados Unidos Fil: Dhanasekaran, Renumathy. Mayo Clinic; Estados Unidos. University of Stanford; Estados Unidos Fil: Iguchi, Eriko. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos Fil: Tolosa, Ezequiel Julian. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina Fil: Romecin, Paola A.. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos Fil: Vera, Renzo Emanuel. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Almada, Luciana Victoria. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos Fil: Miamen, Alexander G.. Mayo Clinic; Estados Unidos Fil: Chaiteerakij, Roongruedee. Mayo Clinic; Estados Unidos Fil: Zhou, Mengtao. Wenzhou Medical University; China Fil: Asiedu, Michael K.. Mayo Clinic; Estados Unidos Fil: Moser, Catherine D.. Mayo Clinic; Estados Unidos Fil: Han, Shaoshan. Mayo Clinic; Estados Unidos Fil: Hu, Chunling. Mayo Clinic; Estados Unidos Fil: Banini, Bubu A.. Mayo Clinic; Estados Unidos Fil: Oseini, Abdul M.. Mayo Clinic; Estados Unidos Fil: Chen, Yichun. Mayo Clinic; Estados Unidos Fil: Fang, Yong. Mayo Clinic; Estados Unidos Fil: Yang, Dongye. Mayo Clinic; Estados Unidos Fil: Shaleh, Hassan M.. Mayo Clinic; Estados Unidos Fil: Wang, Shaoqing. Mayo Clinic; Estados Unidos Fil: Wu, Dehai. Mayo Clinic; Estados Unidos Fil: Song, Tao. Mayo Clinic; Estados Unidos Fil: Lee, Ju-Seog. Anderson Cancer Center; Estados Unidos Fil: Thorgeirsson, Snorri S.. National Cancer Institute; Estados Unidos Fil: Chevet, Eric. Université Rennes; Francia Fil: Shah, Vijay H.. Mayo Clinic; Estados Unidos Fil: Fernandez-Zapico, Martin E.. Schulze Center For Novel Therapeutics, Mayo Clinic; Estados Unidos Fil: Roberts, Lewis R.. Mayo Clinic; Estados Unidos

Published
2017

13. The effect of pegylated interferon-alpha2b and ribavirin combination therapy for chronic hepatitis C infection in elderly patients

Author

Azusa Sakamoto, Ryuichi Kita, Jun Nakajima, Soichiro Ako, Sinichiro Henmi, Fumihiro Matsuda, Toru Kimura, Tadashi Inuzuka, Hiroki Nishikawa, Yorimitsu Koshikawa, Sumio Saito, Eriko Iguchi, Yukio Osaki, Keiichi Hatamaru, Haruhiko Takeda, and Tetsuro Ishikawa

Subjects
Male, Hepacivirus, lcsh:Medicine, Virus Replication, medicine.disease_cause, Chronic hepatitis C, Treatment response, Gastroenterology, Polyethylene Glycols, chemistry.chemical_compound, Pegylated interferon, Medicine, lcsh:QH301-705.5, Medicine(all), biology, General Medicine, Hepatitis C, Middle Aged, Viral Load, Recombinant Proteins, Treatment Outcome, Hepatocellular carcinoma, Drug Therapy, Combination, Female, Viral load, Research Article, medicine.drug, Blood Platelets, medicine.medical_specialty, Hepatitis C virus, Alpha interferon, Interferon alpha-2, Antiviral Agents, Drug Administration Schedule, General Biochemistry, Genetics and Molecular Biology, Sex Factors, Internal medicine, Ribavirin, Humans, lcsh:Science (General), Aged, Biochemistry, Genetics and Molecular Biology(all), Platelet Count, business.industry, lcsh:R, Interferon-alpha, Hepatitis C, Chronic, biology.organism_classification, medicine.disease, Molecular Typing, Elderly patients, chemistry, lcsh:Biology (General), Multivariate Analysis, Immunology, business, lcsh:Q1-390
Abstract

Background The clearance of hepatitis C virus infection by interferon therapy significantly reduces the incidence of hepatocellular carcinoma and death in elderly chronic hepatitis patients. However, there are few reports concerning the efficacy and safety of pegylated interferon-alpha2b plus ribavirin combination therapy in elderly patients. The aims of the present study were to examine the effect and safety of pegylated interferon-alpha2b plus ribavirin combination therapy in 427 patients with chronic hepatitis C infection. We compared the rates of sustained virological response--defined as the absence of detectable hepatitis C virus in serum 24 weeks after the treatment ended--and the treatment discontinuation rate between 319 younger patients aged < 65 years and 108 elderly patients aged ≥ 65 years. We also examined the factors contributing to a sustained virological response. Results There was no significant difference in the sustained virological response rate between younger patients and elderly patients according to their hepatitis C virus genotype (41.5% (100/241) and 40.7% (35/86) for genotype 1; P = 0.899, 89.7% (70/78) and 86.4% (19/22) for genotype 2; P = 0.703, respectively). There was also no significant difference in the treatment discontinuation rate between the two age groups (10.3% (33/319) and 13.9% (15/108), respectively; P = 0.378). There were no serious adverse events requiring hospitalization. The factors contributing significantly to a sustained virological response in elderly patients were gender, hepatitis C virus genotype, platelet count, and the presence of a rapid or early virological response (undetectable hepatitis C virus in serum at weeks 4 or 12 of treatment, respectively). However, upon multivariate analysis, the presence of an early virological response was the only significant factor (odds ratio: 0.115, 95% confidence interval: 0.040- 0.330, P < 0.001). Conclusions The efficacy and safety of pegylated interferon-alpha2b plus ribavirin combination therapy in elderly patients are not always inferior to those in younger patients. Obtaining an early virological response may be essential to achieve a sustained virological response in elderly patients with chronic hepatitis C infection.

Published
2012

14. Molecular Modeling and Functional Analysis of Exome Sequencing-Derived Variants of Unknown Significance Identify a Novel, Constitutively Active FGFR2 Mutant in Cholangiocarcinoma.

Author

Egan JB, Marks DL, Hogenson TL, Vrabel AM, Sigafoos AN, Tolosa EJ, Carr RM, Safgren SL, Hesles EE, Almada LL, Romecin-Duran PA, Iguchi E, Ala'Aldeen A, Kocher JA, Oliver GR, Prodduturi N, Mead DW, Hossain A, Huneke NE, Tagtow CM, Ailawadhi S, Ansell SM, Banck MS, Bryce AH, Carballido EM, Chanan-Khan AA, Curtis KK, Resnik E, Gawryletz CD, Go RS, Halfdanarson TR, Ho TH, Joseph RW, Kapoor P, Mansfield AS, Meurice N, Nageswara Rao AA, Nowakowski GS, Pardanani A, Parikh SA, Cheville JC, Feldman AL, Ramanathan RK, Robinson SI, Tibes R, Finnes HD, McCormick JB, McWilliams RR, Jatoi A, Patnaik MM, Silva AC, Wieben ED, McAllister TM, Rumilla KM, Kerr SE, Lazaridis KN, Farrugia G, Stewart AK, Clark KJ, Kennedy EJ, Klee EW, Borad MJ, and Fernandez-Zapico ME

Abstract

Purpose: Genomic testing has increased the quantity of information available to oncologists. Unfortunately, many identified sequence alterations are variants of unknown significance (VUSs), which thus limit the clinician's ability to use these findings to inform treatment. We applied a combination of in silico prediction and molecular modeling tools and laboratory techniques to rapidly define actionable VUSs., Materials and Methods: Exome sequencing was conducted on 308 tumors from various origins. Most single nucleotide alterations within gene coding regions were VUSs. These VUSs were filtered to identify a subset of therapeutically targetable genes that were predicted with in silico tools to be altered in function by their variant sequence. A subset of receptor tyrosine kinase VUSs was characterized by laboratory comparison of each VUS versus its wild-type counterpart in terms of expression and signaling activity., Results: The study identified 4,327 point mutations of which 3,833 were VUSs. Filtering for mutations in genes that were therapeutically targetable and predicted to affect protein function reduced these to 522VUSs of interest, including a large number of kinases. Ten receptortyrosine kinase VUSs were selected to explore in the laboratory. Of these, seven were found to be functionally altered. Three VUSs (FGFR2 F276C, FGFR4 R78H, and KDR G539R) showed increased basal or ligand-stimulated ERK phosphorylation compared with their wild-type counterparts, which suggests that they support transformation. Treatment of a patient who carried FGFR2 F276C with an FGFR inhibitor resulted in significant and sustained tumor response with clinical benefit., Conclusion: The findings demonstrate the feasibility of rapid identification of the biologic relevance of somatic mutations, which thus advances clinicians' ability to make informed treatment decisions., Competing Interests: AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relation-ships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or po.ascopubs.org/site/ifc. Jan B. Egan No relationship to disclose David L. Marks Stock and Other Ownership Interests: WebMD, Cardinal Health (I), Prothena (I), Perrigo (I) Tara L. Hogenson No relationship to disclose Anne M. Vrabel No relationship to disclose Ashley N. Sigafoos No relationship to disclose Ezequiel J. Tolosa No relationship to disclose Ryan M. Carr No relationship to disclose Stephanie L. Safgren No relationship to disclose Elisa Enriquez Hesles No relationship to disclose Luciana L. Almada No relationship to disclose Paola A. Romecin-Duran No relationship to disclose Eriko Iguchi No relationship to disclose Aryan Ala’Aldeen No relationship to disclose Jean-Pierre A. Kocher No relationship to disclose Gavin R. Oliver No relationship to disclose Naresh Prodduturi No relationship to disclose David W. Mead No relationship to disclose Asif Hossain No relationship to disclose Norine E. Huneke No relationship to disclose Colleen M. Tagtow No relationship to disclose Sikander Ailawadhi Consulting or Advisory Role: Amgen, Takeda Pharmaceuticals, Novartis Research Funding: Pharmacyclics (Inst) Travel, Accommodations, Expenses: Amgen, Takeda Pharmaceuticals, Novartis Stephen M. Ansell Honoraria: WebMD, Research To Practice Research Funding: Bristol-Myers Squibb (Inst), Celldex Therapeutics (Inst), Seattle Genetics (Inst), Merck (Inst), Affimed (Inst), Trillium Therapeutics (Inst) Michaela S. Banck No relationship to disclose Alan H. BryceNo relationship to disclose Estrella M. Carballido No relationship to disclose Asher A. Chanan-Khan No relationship to disclose Kelly K. Curtis Employment: INC Research Stock and Other Ownership Interests: INC Research Travel, Accommodations, Expenses: INC Research Ernesto ResnikNo relationship to disclose Chelsea D. Gawryletz No relationship to disclose Ronald S. Go Speakers’ Bureau: OnLive, Takeda Pharmaceuticals Thorvardur R. Halfdanarson Consulting or Advisory Role: Lexicon (Inst), Ipsen (Inst), Merrimack (Inst) Research Funding: Esanex (Inst), Ipsen (Inst), Boston Biomedical (Inst) Thai H. Ho No relationship to disclose Richard W. Joseph Consulting or Advisory Role: Bristol-Myers Squibb, Nektar, Genoptix, Eisai, Bristol-Myers Squibb Research Funding: Merck, Bristol-Meyers Squibb, Roche (Inst), Genentech (Inst), X4P Pharmaceuticals (Inst), Amgen (Inst) Prashant Kapoor Consulting or Advisory Role: Sanofi (Inst) Research Funding: Amgen (Inst), Takeda Pharmaceuticals (Inst) Aaron S. Mansfield Consulting or Advisory Role: TrovaGene (Inst), Genentech (Inst), Bristol-Myers Squibb (Inst) Travel, Accommodations, Expenses: Bristol-Myers Squibb Nathalie Meurice No relationship to disclose Amulya A. Nageswara Rao No relationship to disclose Grzegorz S. Nowakowski Consulting or Advisory Role: Celgene (Inst), MorphoSys (Inst), Genentech (Inst) Research Funding: Celgene (Inst) Animesh Pardanani No relationship to disclose Sameer A. Parikh Research Funding: Pharmacyclics (Inst) John C. Cheville No relationship to disclose Andrew L. Feldman Consulting or Advisory Role: Infinity Pharmaceuticals Patents, Royalties, Other Intellectual Property: Inventor of technology for which the Mayo Clinic holds an unlicensed patent or has submitted a patent application (Inst) Ramesh K. Ramanathan Honoraria: Taiho Pharmaceutical, Cerulean Pharma, Pharmacyclics, Insys Therapeutics, Novocure Consulting or Advisory Role: Cerulean Pharma, Novocure, INSYS Therapeutics, Pharmacyclics Research Funding: AbbVie (Inst), Celgene (Inst), Merck (Inst), Schering Plough (Inst), Merrimack (Inst), Boston Biomedical (Inst), BERG (Inst), Superlab Far East (Inst) Steven I. Robinson Travel, Accommodations, Expenses: Tricon Pharmaceuticals Raoul Tibes Research Funding: Novartis (Inst), Merck (Inst), Seattle Genetics (Inst), Boehringer Ingelheim (Inst), Astellas Pharma (Inst), Astex Pharmaceuticals (Inst)Heidi D. Finnes Jennifer B. McCormick No relationship to disclose Robert R. McWilliams Consulting or Advisory Role: Merrimack (Inst) Research Funding: PRISM BioLab (Inst), Genentech (Inst), Novartis (Inst), NewLink Genetics (Inst), Eli Lilly (Inst), Aduro Biotech (Inst), Pfizer (Inst), Sanofi (Inst) Travel, Accommodations, Expenses: AstraZeneca Aminah Jatoi Research Funding: Entera Health, Boston Biologics Mrinal M. Patnaik No relationship to disclose Alvin C. Silva No relationship to disclose Eric D. Wieben Patents, Royalties, Other Intellectual Property: Champions Oncology–licensed IP-targeted therapy with abiraterone acetate ($0 received), WuXi AppTec–licensed IP-breast cancer xenografts ($12,737 to Mayo Clinic; Inst), Affymetrix-licensed IP on several variants in drug processing enzymes ($0 in past 2 years), Life Technologies–licensed IP on several variants in drug processing enzymes ($0 in past 2 years) Tammy M. McAllister No relationship to disclose Kandelaria M. Rumilla No relationship to disclose Sarah E. Kerr Research Funding: Abbott Molecular Konstantinos N. Lazaridis No relationship to disclose Gianrico Farrugia No relationship to disclose A. Keith Stewart Consulting or Advisory Role: Celgene, Bristol-Myers Squibb, Janssen Pharmaceuticals, Roche, Amgen Karl J. Clark Patents, Royalties, Other Intellectual Property: Inventor on patents associated with the Sleeping Beauty transposon system Eileen J. Kennedy Patents, Royalties, Other Intellectual Property: Patent on unrelated work (US patent 9,458,189) for “ligation of stapled polypeptides” issued October 4, 2016 Eric W. Klee Patents, Royalties, Other Intellectual Property: Royalties on software development Mitesh J. Borad Stock and Other Ownership Interests: GlaxoSmithKline, Gilead Sciences Consulting or Advisory Role: G1 Therapeutics, TD2, Fujifilm (Inst), Agios (Inst), INSYS Therapeutics (Inst), Novartis (Inst), ArQule (Inst), Celegene (Inst), Inspyr Therapeutics, Halozyme Therapeutics (Inst) Research Funding: Boston Biomedical (Inst), miRNA Therapeutics (Inst), Senhwa Biosciences (Inst), Medimmune (Inst), Bioline (Inst), Agios (Inst), Halozyme Therapeutics (Inst), Celgene (Inst), Threshold Pharmaceuticals (Inst), Toray (Inst), Dicerna Pharmaceuticals (Inst), Sillajen (Inst), Eisai (Inst), Taiho Pharmaceuticals (Inst), EMD Serono (Inst), Isis Pharmaceuticals (Inst), Incyte (Inst), Sun BioPharma (Inst), ARIAD Pharmaceuticals (Inst), ImClone Systems (Inst) Travel, Accommodations, Expenses: ArQule, Celgene, AstraZeneca Martin E. Fernandez-Zapico No relationship to disclose

Published
2017
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