Subjects -> MEDICAL SCIENCES (Total: 8810 journals)
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INTERNAL MEDICINE (180 journals)                     

Showing 1 - 180 of 180 Journals sorted alphabetically
Abdomen     Open Access  
ACP Hospitalist     Full-text available via subscription   (Followers: 9)
ACP Internist     Full-text available via subscription   (Followers: 10)
ACP Journal Club     Full-text available via subscription   (Followers: 11)
Acta Clinica Belgica     Hybrid Journal   (Followers: 1)
Acute and Critical Care     Open Access   (Followers: 11)
Acute Medicine     Full-text available via subscription   (Followers: 9)
Advances in Hepatology     Open Access   (Followers: 4)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6)
African Journal of Primary Health Care & Family Medicine     Open Access   (Followers: 6)
African Journal of Thoracic and Critical Care Medicine     Open Access  
American Family Physician     Full-text available via subscription   (Followers: 38)
American Journal of Hypertension     Hybrid Journal   (Followers: 31)
Anales de Medicina Interna     Open Access   (Followers: 1)
Anatomy & Physiology : Current Research     Open Access   (Followers: 9)
Angiology     Hybrid Journal   (Followers: 5)
Annals of Colorectal Research     Open Access   (Followers: 1)
Annals of Internal Medicine     Full-text available via subscription   (Followers: 392)
AORN Journal     Hybrid Journal   (Followers: 27)
Apollo Medicine     Open Access  
Archives of Drug Information     Hybrid Journal   (Followers: 5)
Archivos de Medicina Interna     Open Access   (Followers: 1)
Asia Oceania Journal of Nuclear Medicine & Biology     Open Access   (Followers: 4)
Asian Pacific Journal of Tropical Disease     Full-text available via subscription   (Followers: 3)
Australasian Physical & Engineering Sciences in Medicine     Hybrid Journal   (Followers: 1)
BMI Journal : Bariátrica & Metabólica Iberoamericana     Open Access   (Followers: 1)
BMJ Open Diabetes Research & Care     Open Access   (Followers: 35)
BMJ Quality & Safety     Hybrid Journal   (Followers: 69)
Bone & Joint Journal     Hybrid Journal   (Followers: 138)
Brain Communications     Open Access   (Followers: 4)
Brain Science Advances     Open Access  
Canadian Journal of General Internal Medicine     Open Access   (Followers: 2)
Cardiovascular Medicine in General Practice     Full-text available via subscription   (Followers: 7)
Case Reports in Internal Medicine     Open Access   (Followers: 1)
Cell Death & Disease     Open Access   (Followers: 3)
Cellular and Molecular Gastroenterology and Hepatology     Open Access   (Followers: 3)
Cephalalgia     Hybrid Journal   (Followers: 8)
Cephalalgia Reports     Open Access   (Followers: 4)
Chronic Diseases and Injuries in Canada     Free   (Followers: 1)
Clinical Ethics     Hybrid Journal   (Followers: 13)
Clinical Liver Disease     Open Access   (Followers: 5)
Clinical Nutrition     Hybrid Journal   (Followers: 98)
Clinical Thyroidology     Full-text available via subscription   (Followers: 1)
CNE Pflegemanagement     Hybrid Journal  
Communication Law and Policy     Hybrid Journal   (Followers: 5)
Current Diabetes Reports     Hybrid Journal   (Followers: 30)
Current Hepatology Reports     Hybrid Journal  
Current Research: Integrative Medicine     Open Access  
CVIR Endovascular     Open Access   (Followers: 1)
Der Internist     Hybrid Journal   (Followers: 12)
Diabetes     Full-text available via subscription   (Followers: 603)
Diabetes Care     Full-text available via subscription   (Followers: 578)
Diabetes Internacional     Open Access  
Diabetes Spectrum     Full-text available via subscription   (Followers: 17)
Diagnosis     Hybrid Journal   (Followers: 1)
Egyptian Journal of Bronchology     Open Access  
Egyptian Journal of Internal Medicine     Open Access   (Followers: 1)
Egyptian Journal of Neurosurgery     Open Access  
Egyptian Liver Journal     Open Access   (Followers: 2)
Egyptian Spine Journal     Open Access  
EMC - Aparato Locomotor     Hybrid Journal  
Endovascular Neuroradiology / Ендоваскулярна нейрорентгенохірургія     Open Access   (Followers: 1)
eNeuro     Open Access   (Followers: 3)
Ergonomics     Hybrid Journal   (Followers: 24)
European Journal of Inflammation     Open Access   (Followers: 2)
European Journal of Internal Medicine     Full-text available via subscription   (Followers: 10)
European Journal of Translational Myology     Open Access  
European Radiology Experimental     Open Access   (Followers: 2)
Head and Neck Tumors     Open Access   (Followers: 1)
Health Sociology Review     Hybrid Journal   (Followers: 14)
HemaSphere     Open Access   (Followers: 2)
Hepatology Communications     Open Access  
Hepatoma Research     Open Access   (Followers: 3)
Human Physiology     Hybrid Journal   (Followers: 5)
ImmunoHorizons     Open Access  
Immunological Medicine     Open Access  
Infectious Diseases: Research and Treatment     Open Access   (Followers: 5)
Inflammation and Regeneration     Open Access   (Followers: 2)
Inflammatory Intestinal Diseases     Open Access  
Innere Medizin up2date     Hybrid Journal   (Followers: 1)
Internal and Emergency Medicine     Hybrid Journal   (Followers: 5)
Internal Medicine Journal     Hybrid Journal   (Followers: 9)
International Journal of Abdominal Wall and Hernia Surgery     Open Access   (Followers: 1)
International Journal of Anatomy and Research     Open Access   (Followers: 2)
International Journal of Angiology     Hybrid Journal  
International Journal of Artificial Organs     Hybrid Journal   (Followers: 3)
International Journal of Hyperthermia     Open Access  
International Journal of Internal Medicine     Open Access   (Followers: 3)
International Journal of Noncommunicable Diseases     Open Access  
International Journal of Psychiatry in Clinical Practice     Hybrid Journal   (Followers: 6)
Iranian Journal of Neurosurgery     Open Access   (Followers: 1)
Italian Journal of Anatomy and Embryology     Open Access   (Followers: 1)
JAC-Antimicrobial Resistance     Open Access   (Followers: 4)
JAMA Internal Medicine     Full-text available via subscription   (Followers: 364)
JCSM Clinical Reports     Open Access   (Followers: 3)
JHEP Reports     Open Access  
JIMD Reports     Open Access  
JMV - Journal de Médecine Vasculaire     Hybrid Journal   (Followers: 1)
Joint Commission Journal on Quality and Patient Safety     Hybrid Journal   (Followers: 41)
JOP. Journal of the Pancreas     Open Access   (Followers: 2)
Journal of Basic & Clinical Physiology & Pharmacology     Hybrid Journal   (Followers: 1)
Journal of Bone Oncology     Open Access   (Followers: 1)
Journal of Cancer & Allied Specialties     Open Access  
Journal of Clinical and Experimental Hepatology     Full-text available via subscription   (Followers: 3)
Journal of Clinical Movement Disorders     Open Access   (Followers: 3)
Journal of Community Hospital Internal Medicine Perspectives     Open Access  
Journal of Cutaneous Immunology and Allergy     Open Access  
Journal of Developmental Origins of Health and Disease     Hybrid Journal   (Followers: 2)
Journal of Endoluminal Endourology     Open Access  
Journal of Gastroenterology and Hepatology Research     Open Access   (Followers: 4)
Journal of General Internal Medicine     Hybrid Journal   (Followers: 23)
Journal of Hypertension     Hybrid Journal   (Followers: 14)
Journal of Infectious Diseases     Hybrid Journal   (Followers: 48)
Journal of Interdisciplinary Medicine     Open Access  
Journal of Internal Medicine     Hybrid Journal   (Followers: 11)
Journal of Liver : Disease & Transplantation     Hybrid Journal   (Followers: 7)
Journal of Medical Internet Research     Open Access   (Followers: 24)
Journal of Movement Disorders     Open Access   (Followers: 2)
Journal of Pain and Symptom Management     Hybrid Journal   (Followers: 46)
Journal of Pancreatic Cancer     Open Access  
Journal of Renal and Hepatic Disorders     Open Access  
Journal of Solid Tumors     Open Access   (Followers: 1)
Journal of Sports Medicine and Allied Health Sciences : Official Journal of the Ohio Athletic Trainers Association     Open Access   (Followers: 1)
Journal of the American Board of Family Medicine     Open Access   (Followers: 11)
Journal of the European Mosquito Control Association     Open Access  
Journal of Translational Internal Medicine     Open Access  
Jurnal Vektor Penyakit     Open Access  
La Revue de Medecine Interne     Full-text available via subscription   (Followers: 3)
Lege artis - Das Magazin zur ärztlichen Weiterbildung     Hybrid Journal   (Followers: 1)
Liver Cancer International     Open Access  
Liver Research     Open Access  
Molecular Diagnosis & Therapy     Hybrid Journal   (Followers: 3)
Molecular Therapy - Oncolytics     Open Access  
Multiple Sclerosis and Demyelinating Disorders     Open Access   (Followers: 7)
MYOPAIN. A journal of myofascial pain and fibromyalgia     Hybrid Journal   (Followers: 18)
Neuro-Oncology Advances     Open Access   (Followers: 1)
Neurobiology of Pain     Open Access   (Followers: 2)
Neurointervention     Open Access   (Followers: 6)
Neuromuscular Diseases     Open Access  
Nigerian Journal of Gastroenterology and Hepatology     Full-text available via subscription  
OA Alcohol     Open Access   (Followers: 5)
Oncological Coloproctology     Open Access  
Open Journal of Internal Medicine     Open Access  
Pleura and Peritoneum     Open Access  
Pneumo News     Full-text available via subscription  
Polish Archives of Internal Medicine     Full-text available via subscription   (Followers: 2)
Preventing Chronic Disease     Free   (Followers: 2)
Progress in Transplantation     Hybrid Journal   (Followers: 1)
Prostate International     Open Access   (Followers: 2)
Psychiatry and Clinical Psychopharmacology     Open Access   (Followers: 1)
Pulmonary Therapy     Open Access   (Followers: 2)
Quality of Life Research     Hybrid Journal   (Followers: 20)
Research and Practice in Thrombosis and Haemostasis     Open Access  
Revista Chilena de Fonoaudiología     Open Access   (Followers: 1)
Revista de la Sociedad Peruana de Medicina Interna     Open Access   (Followers: 4)
Revista del Instituto de Medicina Tropical     Open Access  
Revista Hispanoamericana de Hernia     Open Access   (Followers: 1)
Revista Médica Internacional sobre el Síndrome de Down     Full-text available via subscription   (Followers: 1)
Revista Virtual de la Sociedad Paraguaya de Medicina Interna     Open Access   (Followers: 1)
Romanian Journal of Diabetes Nutrition and Metabolic Diseases     Open Access   (Followers: 1)
Romanian Journal of Internal Medicine     Open Access  
Russian Journal of Child Neurology     Open Access   (Followers: 1)
Scandinavian Journal of Primary Health Care     Open Access   (Followers: 8)
Schlaf     Hybrid Journal  
Schmerzmedizin     Hybrid Journal  
Scientific Journal of the Foot & Ankle     Open Access   (Followers: 1)
SciMedicine Journal     Open Access   (Followers: 3)
SEMERGEN - Medicina de Familia     Full-text available via subscription   (Followers: 1)
The Journal of Critical Care Medicine     Open Access   (Followers: 9)
Therapeutic Advances in Chronic Disease     Open Access   (Followers: 8)
Therapeutic Advances in Musculoskeletal Disease     Hybrid Journal   (Followers: 6)
Thieme Case Report     Hybrid Journal   (Followers: 1)
Tijdschrift voor Urologie     Hybrid Journal  
Tissue Barriers     Hybrid Journal   (Followers: 1)
Transactions of the Royal Society of Tropical Medicine and Hygiene     Hybrid Journal   (Followers: 3)
Transgender Health     Open Access   (Followers: 3)
Trends in Anaesthesia and Critical Care     Full-text available via subscription   (Followers: 23)
US Cardiology Review     Open Access  
Vascular and Endovascular Review     Open Access   (Followers: 1)
Ожирение и метаболизм     Open Access  


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Molecular Therapy - Oncolytics
Journal Prestige (SJR): 1.193
Citation Impact (citeScore): 3
Number of Followers: 0  

  This is an Open Access Journal Open Access journal
ISSN (Online) 2372-7705
Published by Elsevier Homepage  [3303 journals]
  • Matrix metalloproteinase 11 as a Potential Therapeutic Target in Lung

    • Abstract: Publication date: Available online 6 April 2019Source: Molecular Therapy - OncolyticsAuthor(s): Haoran Yang, Peng Jiang, Dongyan Liu, Hong-Qiang Wang, Qingmei Deng, Xiaojie Niu, Li Lu, Haiming Dai, Hongzhi Wang, Wulin Yang Lung cancer is one of the leading causes of cancer associated death with the etiology largely unknown. The aim of this study is to identify key driver genes with therapeutic potentials in lung adenocarcinoma (LUAD). Transcriptome microarray data from four GEO datasets (GSE7670, GSE10072, GSE68465 and GSE43458) were jointly analyzed for differentially expressed genes (DEGs). Ontologic analysis showed that most of upregulated DEGs enriched in collagen catabolic/fibril organization processes regulated by matrix metalloproteinases (MMPs). Matrix metalloproteinase 11 (MMP11) was the highest upregulated MMPs member in LUAD transformed cells acting in an autocrine manner and significantly increased in sera from LUAD patients. MMP11-depletion severely impaired LUAD cell proliferation, migration and invasion in vitro, in line with retarded tumor growth in xenograft models. Treatment of different human LUAD cell lines with anti-MMP11 antibody significantly retarded cell growth and migration. Administration of Anti-MMP11 antibody in a dose of 1 μg/g body weight significantly suppressed tumor growth in xenograft models. These findings indicate that MMP11 is one of key cancer driver genes in LUAD and owns the potential as an appealing target for antibody therapy.
  • Sulforaphane induces miR135b-5p and its target gene RASAL2, thereby
           inhibiting the progression of pancreatic cancer

    • Abstract: Publication date: Available online 6 April 2019Source: Molecular Therapy - OncolyticsAuthor(s): Libo Yin, Xi Xiao, Christina Georgikou, Yiqiao Luo, Li Liu, Jury Gladkich, Wolfgang Gross, Ingrid Herr Pancreatic ductal adenocarcinoma is one of the most lethal tumors, with poor therapeutic options in the advanced state. The broccoli-derived antiinflammatory agent sulforaphane was shown to inhibit the progression of pancreatic cancer and other tumor entities. We examined the involvement of pancreatic cancer cell lines were evaluated by microRNA and gene expression arrays, bioinformatics, in silico analysis, qRT-PCR, western blotting, immunohistochemistry, in situ hybridization, self-renewal and differentiation assays, and in vivo xenograft studies. We selected the top 9 differentially expressed microRNAs, and miR135b-5p was chosen as the most important candidate for the sulforaphane-induced upregulation of the tumor suppressor gene RASAL2. The expression of miR135b-5p and RASAL2 was almost absent in malignant pancreatic tissues and cell lines but not in their normal counterparts. Lipofection of miR135b-5p enhanced RASAL2 expression and inhibited ERK1/2 signaling, viability, self-renewal capacity and tumor growth. These results indicate that miR135b-5p acts as a tumor suppressor via the induction of RASAL2 in PDA.
  • Recombinant Oncolytic Vaccinia Viruses Expressing Human β-Defensin 2
           Enhance Anti-tumor Immunity

    • Abstract: Publication date: Available online 4 April 2019Source: Molecular Therapy - OncolyticsAuthor(s): Ting Sun, Yanxi Luo, Minglong Wang, Hui Yan Cancer is still a leading of cause of deaths worldwide. Among the bio-therapy strategies for cancer, vaccinia virus (VV) has been widely used as an expression vector because of its potent oncolytic activities besides its large capacity for insertion of foreign genes and excellent safety records. In the present study, a novel recombinant vaccinia virus VV-HBD2-lacZ expressing human β-defensin 2 (HBD2), an antimicrobial peptide of the innate immune system, was constructed. Firstly, the chemotaxis characteristics of HBD2 expressed on VV-HBD2-lacZ-infected cells towards DCs in vitro and in vivo were demonstrated. The anti-tumor effects of VV-HBD2-lacZ in vitro and in vivo in a mouse malenoma cancer model were then investigated. It was found that VV-HBD2-lacZ was able to inhibit tumor growth and metastasis significantly. It was further demonstrated that VV-HBD2-lacZ induced potent cytotoxic activity by increasing the tumor-infiltrating CD4+ and CD8+ T cells. These results indicate that HBD2-expressing VV recruited plasmacytoid dendritic cells (pDCs) to the tumor location, leading to cytotoxic T cell response against tumor, and thus inhibited tumor growth in vitro and in vivo. In conclusion, oncolytic HBD2-expressing VV provides an effective treatment for tumors by triggering innate and adaptive immunity.
  • Bp-Bs, a novel T-cell engaging bispecific antibody with biparatopic Her2
           binding, has potent anti-tumor activities

    • Abstract: Publication date: Available online 2 April 2019Source: Molecular Therapy - OncolyticsAuthor(s): Jiayu Liu, Xiaoqiong Wu, Limin Lin, Haitao Pan, Yanlan Wang, Yumei Li, Yining Zhao, Zhong Wang Patients with Her2 overexpression are associated with aggressive tumor growth and poor clinical outcomes. Bispecific antibodies targeting Her2 have recently exhibited potent effects on Her2 signal inhibition. In this study, a novel biparatopic anti-Her2 bispecific antibody (Bp-Bs) was constructed by linking a single anti-CD3 Fab with two different anti-Her2 single domain antibodies targeting non-overlapping epitopes of Her2. The Bp-Bs antibody demonstrated strong binding on Her2 positive cells and potent cytotoxicity on Her2 positive tumor cells, even Her2 low expression cells, suggesting that biparatopic bispecific antibodies may have improved therapeutic benefits on broad Her2 patient populations.
  • Oncolytic Herpes Simplex Virus and Phosphoinositide 3-kinase Inhibitor
           BKM120 Synergize to Promote Killing of Prostate Cancer Stem-like Cells

    • Abstract: Publication date: Available online 29 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Lei Wang, Jianfang Ning, Hiroaki Wakimoto, Shulin Wu, Chin-lee Wu, Melissa R. Humphrey, Samuel D. Rabkin, Robert L. Martuza Novel therapies to override chemo-radiation resistance in prostate cancer (PCa) are needed. Prostate cancer sphere-forming cells (PCSCs) (also termed prostate cancer stem-like cells) likely participate in tumor progression and recurrence and are important therapeutic targets. We established PCSC-enriched spheres by culturing human (DU145) and murine (TRAMP-C2) PCa cells in growth factor-defined serum-free medium and characterized stem-like properties of clonogenicity and tumorigenicity. The efficacy of two different oHSVs (G47Δ and MG18L) in PCSCs was tested alone and in combination with radiation, chemotherapy, and inhibitors of PI3K, Wnt, and NOTCH in vitro, and G47Δ with the PI3K inhibitor BKM120 in a PCSC-derived tumor model in vivo. PCSCs were more tumorigenic than serum-cultured parental cells. Human and murine PCSCs were sensitive to oHSV and BKM120 killing in vitro, while the combination was synergistic. oHSV combined with radiation, docetaxel, Wnt, or NOTCH inhibitors was not. In athymic mice bearing DU145 PCSC-derived tumors, combination intra-tumoral G47Δ and systemic BKM120 induced complete regression of tumors in 2 of 7 animals and exhibited superior anti-tumor activity compared to either monotherapy alone, with no detectable toxicity. oHSV synergizes with BKM120 in killing PCSCs in vitro and the combination markedly inhibits tumor growth even inducing regression in vivo.
  • High expression of pseudogene PTTG3P indicates a poor prognosis in human
           breast cancer

    • Abstract: Publication date: Available online 27 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Weiyang Lou, Bisha Ding, Weimin Fan Pseudogenes play pivotal roles in tumorigenesis. Previous studies suggested that pituitary tumour-transforming 3, pseudogene (PTTG3P) served as an oncogene in human cancers. However, its expression pattern, biological function and underlying mechanism in breast cancer remain unknown. In this study, we demonstrated an elevated expression of PTTG3P in breast cancer and discovered that PTTG3P expression was negatively correlated with estrogen receptor (ER) or progesterone receptor (PR) status; but positively linked to basal-like status, triple-negative breast cancer status, Nottingham prognostic index (NPI) and Scarff Bloom & Richardson criterion. Besides, high expression of PTTG3P was also found to be associated with poor prognosis of breast cancer. To explore the potential mechanisms of PTTG3P, a PTTG3P-miRNA-mRNA regulatory network was established. Co-expressed genes of PTTG3P were also obtained. Enrichment analysis for these co-expressed genes revealed that they were significantly enriched in mitotic nuclear division and cell cycle. Subsequent research on mechanism of PTTG3P indicated that its expression was positively correlated with PTTG1 expression. However, no significant expression correlation between PTTG3P and PTTG2 was observed. Taken together, our findings suggest that increased expression of pseudogene PTTG3P may be utilized as a promising prognostic biomarker and novel therapeutic target for breast cancer.
  • The enhanced tumor specificity of TG6002, an armed-oncolytic vaccinia
           virus deleted in two genes involved in nucleotide metabolism

    • Abstract: Publication date: Available online 27 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Johann Foloppe, Juliette Kempf, Nicolas Futin, Jacqueline Kintz, Pascale Cordier, Christelle Pichon, Annie Findeli, Fabien Vorburger, Eric Quemeneur, Philippe Erbs Oncolytic vaccinia viruses are currently in clinical development. However, the safety and the tumor selectivity of these oncolytic viruses must be improved. We previously constructed a first-generation oncolytic vaccinia virus by expressing the suicide gene FCU1 inserted in the J2R locus that encodes thymidine kinase. We demonstrated that the combination of this thymidine kinase-deleted vaccinia virus and the FCU1/5-fluocytosine system is a potent vector for cancer therapy. We here developed a second generation of vaccinia virus, named TG6002, expressing FCU1 and with targeted deletions of the J2R gene and the I4L gene that encodes the large subunit of the ribonucleotide reductase. Compared to the previously used single thymidine kinase-deleted vaccinia virus, TG6002 is highly attenuated in normal cells yet it displays tumor-selective replication and tumor cell killing. TG6002 replication is highly dependent on cellular ribonucleotide reductase levels and is less pathogenic than the single deleted vaccinia virus. Tumor selective viral replication, prolonged therapeutic levels of 5-fluorouracil in tumors and significant antitumor effects were observed in multiple human xenograft tumor models after systemic injection of TG6002 and 5-fluorocytosine. TG6002 displays a convincing safety profile and is a promising candidate for treatment of cancer in humans.
  • Fludarabine as an Adjuvant Improves Newcastle Disease Virus-Mediated
           Antitumor Immunity in Hepatocellular Carcinoma

    • Abstract: Publication date: Available online 27 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Gang Meng, Ziwei Fei, Mingyue Fang, Binghua Li, Anxian Chen, Chun Xu, Mao Xia, Decai Yu, Jiwu Wei In addition to direct oncolysis, oncolytic viruses (OVs) also induce antitumor immunity, also called viro-immunotherapy. Limited viral replication and immune negative feedback are the major hurdles to effective viro-immunotherapy. In this study, we found that use of an adjuvant of fludarabine, a chemotherapeutic drug for chronic myeloid leukemia, increased the replication of Newcastle disease virus (NDV) by targeting signal transducer and activator of transcription 1 (STAT1), which led to enhanced oncolysis of hepatocellular carcinoma (HCC) cells. Moreover, fludarabine accelerated ubiquitin-proteasomal degradation by enhancing ubiquitylation rather than proteasomal activity. This resulted in accelerated degradation of phosphorylated signal transducer and activator of transcription 3 (STAT3) and Indoleamine 2, 3-dioxygenase 1 (IDO1), whose expression was induced by NDV infection. In addition, fludarabine significantly increased the NDV-induced infiltration of NK cells, and decreased the number of NDV-induced myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. The aforementioned effects of fludarabine significantly improved NDV-mediated antitumor immunity and prolonged survival in mouse model of HCC. Our findings indicate the utility of fludarabine as an adjuvant for oncolytic anticancer viro-immunotherapy.
  • Enhancing Dendritic cell Therapy in Solid Tumors with Immune Modulating
           Conventional Treatment

    • Abstract: Publication date: Available online 27 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): R.A. Belderbos, J.G.J.V. Aerts, H. Vroman Dendritic cells (DCs) are the most potent antigen presenting cells and are the key initiator of tumor-specific immune responses. These characteristics are exploited by DC therapy, were DCs are ex vivo loaded with tumor-associated antigens (TAAs) and used to induce tumor-specific immune responses. Unfortunately, clinical responses remain limited to a proportion of the patients. Tumor characteristics and the immunosuppressive tumor microenvironment (TME) of the tumor are likely hampering efficacy of DC therapy. Therefore, reducing the immunosuppressive TME by combining DC therapy with other treatments could be a promising strategy. Initially, conventional cancer therapies, such as chemotherapy and radiotherapy, were thought to specifically target cancerous cells. Recent insights indicate that these therapies additionally augment tumor immunity. Therefore, combining DC therapy with registered therapies such as chemotherapy, radiotherapy or checkpoint inhibitors to target immunosuppressive cell subsets in the TME, inducing immunogenic cell death (ICD) or blocking of inhibitory molecules, could be a promising treatment strategy to improve efficacy of DC therapy. In this review, we will evaluate various clinical applicable combination strategies to improve efficacy of DC therapy.
  • LncRNA UCA1-mediated Cdc42 signaling promotes oncolytic vaccinia virus
           cell-to-cell spread in ovarian cancer

    • Abstract: Publication date: Available online 26 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Kosuke Horita, Hajime Kurosaki, Motomu Nakatake, Nozomi Kuwano, Tetsuro Oishi, Hiroaki Itamochi, Sho Sato, Hiromichi Kono, Mai Ito, Kosei Hasegawa, Tasuku Harada, Takafumi Nakamura Oncolytic vaccinia virus (OVV) has demonstrated appropriate safety profiles for clinical development. Although designed to kill cancer cells efficiently, OVV sensitivity varies in individual cancers and predictive biomarkers of therapeutic responses have not been identified. Here, we found that OVV was much more efficient in KFTX paclitaxel-resistant ovarian cancer cells, compared to that in KFlow paclitaxel-sensitive cells. Microarray analysis identified long non-coding RNA urothelial carcinoma-associated 1 (UCA1) upregulation, which contributed to both enhanced paclitaxel resistance and OVV spread. In addition, UCA1 expression correlated with efficient OVV spread in other ovarian cell lines and primary cancer cell cultures. When host pathways underlying OVV spread were analyzed, differences were detected in the activation of the Rho GTPase Cdc42, suggesting that filopodia formation enhances OVV cell-to-cell spread and tumor migration. Moreover, we established a clinically-relevant mouse model of peritoneal metastasis using KFTX or KFlow cells. Paclitaxel exerted anti-tumor effects on KFlow, but not KFTX, tumors. In mice bearing KFTX cells after paclitaxel failure, OVV treatment induced the regression of residual tumors and improved survival. Our findings demonstrated that UCA1 promotes OVV cell-to-cell spread in ovarian cancer, resulting in enhanced therapeutic outcome.Graphical Graphical abstract for this article
  • Functional Analysis of an Inducible Promoter Driven by Activation Signals
           from a Chimeric Antigen Receptor

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Ryosuke Uchibori, Takeshi Teruya, Hiroyuki Ido, Ken Ohmine, Yoshihide Sehara, Masashi Urabe, Hiroaki Mizukami, Junichi Mineno, Keiya OzawaAdoptive transfer of T cells expressing a chimeric antigen receptor (CAR) is a promising cell-based anticancer therapy. Although clinical studies of this approach show therapeutic efficacy, additional genetic modification is necessary to enhance the efficacy and safety of CAR-T cells. For example, production of an antitumor cytokine from CAR-T cells can potentially enhance their tumor-killing activity, but there are concerns that constitutive expression of anticancer molecules will cause systemic side effects. Therefore, it is important that exogenous gene expression is confined to the tumor locality. Here, we aimed to develop an inducible promoter driven by activation signals from a CAR. Transgene expression in T cells transduced with the CD19-targeted CAR and an inducible promoter, including inducible reporter genes (CAR-T/iReporter), was only induced strongly by co-culture with CD19-positive target cells. CAR-T/iReporter cells also showed redirected cytolysis toward CD19-positive, but not CD19-negative, tumor cells. Overall, our study indicated that the inducible promoter was selectively driven by activation signals from the CAR, and transduction with the inducible promoter did not affect original effector activities including interleukin-2 and interferon-γ production and the antitumor activity of CAR-redirected cytotoxic T lymphocytes. Moreover, this inducible promoter permits visualization and quantification of the activation status in CAR-T cells.
  • Updates on Oncolytic Virus Immunotherapy for Cancers

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Cole Peters, Paola Grandi, Fares NigimThe 2018 annual Cambridge Healthtech Institute’s International Immuno-Oncology Summit in Boston, MA convened late August, and academic and industry researchers were allowed to debate and discuss oncolytic virology during the virus immunotherapy portion of the conference. The breakthrough agent, TVEC/IMLYGIC, as well as most other oncolytic viruses (OVs) in clinical trials, are demonstrating an immense synergy with T cell checkpoint inhibitors. To this extent, the marriage of T cell checkpoint inhibitors and OV is now vastly accepted, indicating the next phase in OVs is the recruitment of the immune system, and tailoring the immune response toward tumor clearance is a far better strategy than directly lysing the tumor outright with virus. The next field-shaping question for OVs is how to convert a patient’s immune response against their tumor. The talks this year focused on whether OVs can cause the emergence of a strong anti-tumor immunity intrinsically or whether vectors, which educate the immune system to detect tumor antigens, were more efficacious. Speakers presented novel transgenes to arm OVs and systems biology approaches to discover the best viral backbones to engineer into vectors. Here we summarize the meeting’s keynote talks, thematic principles running through the summit, and current developments in the OV field.
  • MAPK Inhibitors Enhance HDAC Inhibitor-Induced Redifferentiation in
           Papillary Thyroid Cancer Cells Harboring BRAF V600E: An In Vitro Study

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Hao Fu, Lingxiao Cheng, Yuchen Jin, Lin Cheng, Min Liu, Libo ChenClinical efficacy of redifferentiation therapy with histone deacetylase inhibitor (HDACi) for lethal radioiodine-refractory papillary thyroid cancer (RR-PTC) is urgently needed to be improved. Given that the impairment of histone acetylation is a mechanism in BRAFV600E-mitogen-activated protein kinase (MAPK)-induced aberrant silencing of thyroid iodine-metabolizing genes, dual inhibition of HDAC and MAPK may produce a more favorable effect. In this study, we treated BRAFV600E-mutant (BCPAP and K1) and BRAF-wild-type (BHP 2-7) cells with HDACi (panobinostat) and MAPK inhibitor (dabrafenib or selumetinib), alone or in combination, and we tested the expression of iodine- and glucose-metabolizing genes, radioiodine uptake and efflux, and toxicity. We found that panobinostat alone increased iodine-metabolizing gene expression, promoted radioiodine uptake and toxicity, and suppressed GLUT1 expression in all the cells. However, MAPKi (dabrafenib or selumetinib) induced these effects only in BRAFV600E-mutant cells. Combined treatment with panobinostat and MAPKi (dabrafenib or selumetinib) displayed a more robust BRAFV600E-dependent redifferentiation effect than panobinostat alone via further improving the acetylation level of histone at the sodium-iodide symporter (NIS) promoter. In conclusion, MAPK inhibitors enhance HDACi-induced redifferentiation in PTC cells harboring BRAFV600E, warranting animal and clinical trials.
  • Nitidine Chloride Inhibits SIN1 Expression in Osteosarcoma Cells

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Hui Xu, Tong Cao, Xiaoqing Zhang, Ying Shi, Qing Zhang, Shuo Chai, Li Yu, Guoxi Jin, Jia Ma, Peter Wang, Yuyun LiNitidine chloride (NC) has been demonstrated to exert a tumor-suppressive function in various types of human cancers. However, the detailed mechanism of NC-mediated anti-tumor effects remains elusive. It has been reported that SIN1, a component of mTORC2 (mammalian target of rapamycin complex C2), plays an oncogenic role in a variety of human cancers. Therefore, the inhibition of SIN1 could be useful for the treatment of human cancers. In this study, we explored whether NC triggered an anti-cancer function via the inhibition of SIN1 in osteosarcoma (OS) cells. An MTT assay was performed to measure the effect of NC on the cell growth of osteosarcoma cells, and flow cytometry was used to detect the apoptotic rate of the cells after NC treatment. The expression of SIN1 was detected by western blotting. Wound-healing assay and Transwell chamber invasion assay were conducted to analyze the motility of osteosarcoma cells following NC exposure. We found that exposure to NC led to the inhibition of cell growth, migration, and invasion and the induction of apoptosis. Mechanistically, we found that NC inhibited the expression of SIN1 in osteosarcoma cells. Overexpression of SIN1 abrogated the inhibition of cell growth and motility induced by NC in osteosarcoma cells. Our results indicate that NC exhibits its tumor-suppressive activity via the inhibition of SIN1 in osteosarcoma cells, suggesting that NC could be a potential inhibitor of SIN1 in osteosarcoma.
  • Skp2 Expression Is Inhibited by Arsenic Trioxide through the Upregulation
           of miRNA-330-5p in Pancreatic Cancer Cells

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Jiankun Gao, Gu Wang, Jingrong Wu, Yu Zuo, Jing Zhang, Xintian JinArsenic trioxide (ATO) has been found to exert its anti-cancer activity in various human malignancies. In our previous report, we have shown that ATO inhibited cell growth and invasion via downregulation of Skp2 in pancreatic cancer (PC) cells. It has been extensively demonstrated that microRNAs (miRNAs) play a pivotal role in tumorigenesis. ATO might induce PC cell apoptosis and regulate Skp2 downregulation through the regulation of miRNAs. One study has demonstrated that miR-330-5p exerts a tumor-suppressive function in PC cell lines. Here, we investigated the role of miRNA-330-5p in ATO-mediated anti-tumor activity and explored whether ATO could regulate miR-330-5p in PC cells. We found that ATO treatment upregulated the expression of miR-330-5p. Moreover, miR-330-5p inhibitor rescued the ATO-mediated tumor-suppressive function. The combination of miR-330-5p mimic with ATO reduced cell growth, motility, and invasion, and enhanced apoptosis to a greater degree in PC cells. This study suggests that the combination of miR-330-5p mimic with ATO may be a potential therapeutic strategy for the treatment of PC.
  • ZNF280A Promotes Proliferation and Tumorigenicity via Inactivating the
           Hippo-Signaling Pathway in Colorectal Cancer

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Xu Wang, Di Sun, Jiandong Tai, Si Chen, Sen Hong, Lei WangAberrant expression of zinc-finger proteins has been extensively reported to contribute to malignant progression in a variety of cancers. However, clinical significance and biological roles of ZNF280A in the field of cancer are poorly known. In this study, the expression of ZNF280A was detected in clinical colorectal cancer (CRC) tissues. Functional experiments in vitro and animal experiment in vivo were performed to measure the effect of ZNF280A on the proliferation and tumorigenesis in CRC cells. Western blot and luciferase assays were used to identify the underlying pathway mediating the biological roles of ZNF280A in CRC. Here we report that ZNF280A was upregulated in CRC tissues and cells and a high expression of ZNF280A correlated with tumor, lymph node, and metastasis (TNM) classifications, clinical stage, and predicted poor prognosis and disease progression in CRC patients. Moreover, silencing ZNF280A repressed proliferation and induced G0 and/or G1 arrest in vitro, and it inhibited tumorigenesis of CRC cells in vivo. Our results further demonstrate that silencing ZNF280A inhibited the proliferation of CRC cells by activating Hippo signaling. Therefore, our results uncover a novel mechanistic understanding of ZNF280A-mediated tumor progression in CRC, and meanwhile they provide a novel prognostic factor in CRC patients and a potential therapeutic target for the treatment of CRC.
  • Cathelicidin Suppresses Colon Cancer Metastasis via a P2RX7-Dependent

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Jiani Wang, Michelle Cheng, Ivy K.M. Law, Christina Ortiz, Mingjun Sun, Hon Wai KoonThe antimicrobial peptide cathelicidin inhibits development of colitis-associated colon cancer. However, the role of cathelicidin in colon cancer metastasis remains unknown. We hypothesized that cathelicidin is effective in inhibiting colon cancer metastasis. Human colon cancer HT-29 cells were injected intravenously into nude mice. Control HA-tagged adeno-associated virus (HA-AAV) or cathelicidin-overexpressing AAV (CAMP-HA-AAV) were injected intravenously into nude mice on the same day. Four weeks later, the nude mice were assessed for lung and liver metastases. Human colon cancer SW620 cells were used to study the effect of cathelicidin on cell migration and cytoskeleton. Incubation of SW620 cells with cathelicidin dose-dependently reduced cell migration, disrupted cytoskeletal structure, and reduced βIII-tubulin (TUBB3) mRNA expression. The addition of the P2RX7 antagonist KN62, but not the FPRL1 antagonist WRW4, prevented the LL-37-mediated inhibition of cell migration and TUBB3 mRNA expression. The CAMP-HA-AAV-overexpressing group showed significantly reduced human CK20 protein (by 60%) and TUBB3 mRNA expression (by 40%) in the lungs and liver of the HT-29-loaded nude mice, compared to the HA-AAV control group. Intraperitoneal injection of KN62 reversed the CAMP-HA-AAV-mediated inhibition of human CK20 and TUBB3 expression in the lungs and liver of HT-29-loaded nude mice. In conclusion, cathelicidin inhibits colon cancer metastasis via a P2RX7-dependent pathway.
  • A Systematic Review of miR-29 in Cancer

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Jason J. Kwon, Tricia D. Factora, Shatovisha Dey, Janaiah KotaMicroRNAs (miRNA) are small non-coding RNAs (∼22 nt in length) that are known as potent master regulators of eukaryotic gene expression. miRNAs have been shown to play a critical role in cancer pathogenesis, and the misregulation of miRNAs is a well-known feature of cancer. In recent years, miR-29 has emerged as a critical miRNA in various cancers, and it has been shown to regulate multiple oncogenic processes, including epigenetics, proteostasis, metabolism, proliferation, apoptosis, metastasis, fibrosis, angiogenesis, and immunomodulation. Although miR-29 has been thoroughly documented as a tumor suppressor in the majority of studies, some controversy remains with conflicting reports of miR-29 as an oncogene. In this review, we provide a systematic overview of miR-29’s functional role in various mechanisms of cancer and introspection on the contradictory roles of miR-29.
  • Systemically Administered Reovirus-Induced Downregulation of Hypoxia
           Inducible Factor-1α in Subcutaneous Tumors

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Takuma Hotani, Hiroyuki Mizuguchi, Fuminori SakuraiReovirus, which possesses a 10-segmented double-stranded RNA genome, mediates superior antitumor effects via not only virus replication in a tumor cell-specific manner but also other mechanisms distinct from virus replication. Several groups, including ours, reported the reovirus-mediated downregulation of hypoxia inducible factor-1α (HIF-1α) following infection in cultured tumor cells; however, it remained to be clarified whether reovirus downregulates the expression of HIF-1α and its target genes in tumor-bearing hosts. We found that reovirus induced significant downregulation of protein levels of HIF-1α and its target genes in the subcutaneous tumors at 120 h post-systemic administration. Expression of reovirus capsid protein σ3 was found in the pimonidazole-positive hypoxic area in the tumor. Significant levels of tumor cell apoptosis were not found in the tumors of reovirus-treated mice at this time point, suggesting that reovirus-mediated tumor cell killing did not largely contribute to the downregulation of HIF-1α protein levels in the tumors. UV-inactivated reovirus did not induce downregulation of HIF-1α expression in the tumors, indicating that virus replication was indispensable for downregulation of HIF-1α expression in the subcutaneous tumors. This study provides important information for the development of reovirus-mediated virotherapy against various types of tumors.
  • Measles Virus-Based Treatments Trigger a Pro-inflammatory Cascade and a
           Distinctive Immunopeptidome in Glioblastoma

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Srinath Rajaraman, Denis Canjuga, Michael Ghosh, Marius Cosmin Codrea, Raika Sieger, Florian Wedekink, Marcos Tatagiba, Marilin Koch, Ulrich M. Lauer, Sven Nahnsen, Hans-Georg Rammensee, Michael D. Mühlebach, Stefan Stevanovic, Ghazaleh TabatabaiGlioblastoma is an aggressive primary brain tumor with bad prognosis. On the other hand, oncolytic measles virus (MeV) therapy is an experimental glioma treatment strategy with clinical safety and first evidence of anti-tumoral efficacy. Therefore, we investigated the combination of MeV with conventional therapies by cytotoxic survival assays in long-term glioma cell lines LN229, LNZ308, and glioma stem-like GS8 cells, as well as the basal viral infectivity in primary glioblastoma cultures T81/16, T1094/17, and T708/16. We employed Chou-Talalay analysis to identify the synergistic treatment sequence chemotherapy, virotherapy, and finally radiotherapy (CT-VT-RT). RNA sequencing and immunopeptidome analyses were used to delineate treatment-induced molecular and immunological profiles. CT-VT-RT displayed synergistic anti-glioma activity and initiated a type 1 interferon response, along with canonical Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling, and downstream interferon-stimulated genes were induced, resulting in apoptotic cascades. Furthermore, antigen presentation along with immunostimulatory chemokines was increased in CT-VT-RT-treated glioma cells, indicating a treatment-induced pro-inflammatory phenotype. We identified novel treatment-induced viral and tumor-associated peptides through HLA ligandome analysis. Our data delineate an actionable treatment-induced molecular and immunological signature of CT-VT-RT, and they could be exploited for the design of novel tailored treatment strategies involving virotherapy and immunotherapy.
  • Efficient Prostate Cancer Therapy with Tissue-Specific Homing Peptides
           Identified by Advanced Phage Display Technology

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Akinori Wada, Tomoya Terashima, Susumu Kageyama, Tetsuya Yoshida, Mitsuhiro Narita, Akihiro Kawauchi, Hideto KojimaSelective targeting of drugs to tumor cells is a key goal in oncology. Here, we performed an in vivo phage display to identify peptides that specifically target xenografted prostate cancer cells. This yielded three peptide candidates, LN1 (C-TGTPARQ-C), LN2 (C-KNSMFAT-C), and LN3 (C-TNKHSPK-C); each of these peptides was synthesized and evaluated for binding and biological activity. LN1 showed the highest avidity for LNCaP prostate cancer cells in vitro and was thus administered to tumor-bearing mice to evaluate in vivo binding. Strikingly, LN1 specifically bound to the tumor tissue and exhibited very low reactivity with normal liver and kidney tissues. To demonstrate that LN1 could specifically deliver drugs to prostate cancer tissue, a therapeutic peptide, LN1-KLA (C-TGTPARQ-C-GGG-D[KLAKLAK]2), was prepared and used to treat LNCaP cells in vitro and was also administered to tumor-bearing mice. The therapeutic peptide significantly suppressed growth of the cells both in vitro and in vivo. Our study shows that a selective homing peptide strategy could facilitate cell-specific targeting of therapeutics while avoiding adverse reactions in normal tissues.
  • Two-Dimensional Regulation of CAR-T Cell Therapy with Orthogonal Switches

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): MyLinh T. Duong, Matthew R. Collinson-Pautz, Eva Morschl, An Lu, Slawomir P. Szymanski, Ming Zhang, Mary E. Brandt, Wei-Chun Chang, Kelly L. Sharp, Steven M. Toler, Kevin M. Slawin, Aaron E. Foster, David M. Spencer, J. Henri BayleUse of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow in vivo elimination of CAR-T cells. iMC costimulation induced by systemic rimiducid administration enhanced CAR-T cell proliferation, cytokine secretion, and antitumor efficacy in both in vitro assays and xenograft tumor models. Conversely, rapamycin-mediated iRC9 dimerization rapidly induced apoptosis in a dose-dependent fashion as an approach to mitigate therapy-related toxicity. This novel, regulatable dual-switch system may promote greater CAR-T cell expansion and prolonged persistence in a drug-dependent manner while providing a safety switch to mitigate toxicity concerns.
  • COMMD7 Regulates NF-κB Signaling Pathway in Hepatocellular Carcinoma
           Stem-like Cells

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Lu Zheng, Nan You, Xiaobing Huang, Huiying Gu, Ke Wu, Na Mi, Jing LiPrevious studies showed that the COpper Metabolism gene MURR1 Domain (COMMD) family of proteins was abnormally expressed in hepatocellular carcinoma (HCC). This study aimed to explore the roles of COMMD1 and COMMD7 in regulating nuclear factor κB (NF-κB) signaling in HCC stem cells (HCSCs). In vivo, the expression of COMMD7 and COMMD1 was determined in 35 pairs of HCC cancer tissues and adjacent tissues, and the effect of COMMD7 silencing on xenograft tumor growth was evaluated. In vitro, the effects of COMMD7 silencing and COMMD1 overexpression on HCSC function were assessed. Results found that the expression levels of COMMD7 were higher, whereas COMMD1 levels were lower in HCC tissues and HCSCs. COMMD7 silencing or COMMD1 overexpression inhibited cell proliferation, migration, and invasion through suppression of NF-κB p65. Furthermore, COMMD7 positively regulated NF-κB by upregulating protein inhibitor for activated stat 4 (PIAS4). This study demonstrates that COMMD7 has a dual regulatory role in the NF-κB signaling pathway in Nanog+ HCSCs.Graphical Graphical abstract for this article
  • Expression and Prognosis Analyses of Runt-Related Transcription Factor
           Family in Human Leukemia

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Cheng-Cao Sun, Shu-Jun Li, Zhen-Long Chen, Guang Li, Qian Zhang, De-Jia LiDespite advances in early diagnosis and treatment, cancer remains the major reason for mortality worldwide. The Runt-related transcription factor (RUNX) family has been reported to participate in diverse human diseases. However, little is known about their expression and prognostic values in human leukemia. Herein, we conducted a detailed cancer versus normal analysis. The mRNA expression levels of the RUNX family in various kinds of cancers, including leukemia, were analyzed via the ONCOMINE and GEPIA (Gene Expression Profiling Interactive Analysis) databases. We observed that the mRNA expression levels of RUNX1, RUNX2, and RUNX3 were all increased in most cancers compared with normal tissues, especially in leukemia. Moreover, the expression levels of RUNX1, RUNX2, and RUNX3 are also highly expressed in almost all cancer cell lines, particularly in acute myeloid leukemia (AML) cell lines, analyzed by Cancer Cell Line Encyclopedia (CCLE) and European Bioinformatics Institute (EMBL-EBI) databases. Further, the LinkedOmics and GEPIA databases were used to evaluate the prognostic values. In survival analyses based on LinkedOmics, higher expression of RUNX1 and RUNX2 indicated a better overall survival (OS), but with no significance, whereas increased RUNX3 revealed a poor OS in leukemia. In addition, the GEPIA dataset was also used to perform survival analyses, and results manifested that the expression of RUNX1 and RUNX2 had no remarkable correction with OS in leukemia, but it showed highly expressed RUNX3 was significantly related with poor OS in leukemia. In conclusion, the RUNX family showed significant expression differences between cancer and normal tissues, especially leukemia, and RUNX3 could be a promising prognostic biomarker for leukemia.
  • Suppression of HMGB1 Released in the Glioblastoma Tumor Microenvironment
           Reduces Tumoral Edema

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Bangxing Hong, Kamaldeen Muili, Chelsea Bolyard, Luke Russell, Tae Jin Lee, Yeshavanth Banasavadi-Siddegowda, Ji Young Yoo, Yuanqing Yan, Leomar Y. Ballester, Kurt H. Bockhorst, Balveen KaurHMGB1 is a ubiquitously expressed intracellular protein that binds DNA and transcription factors and regulates chromosomal structure and function. Under conditions of cell death or stress, it is actively or passively released by cells into the extracellular environment, where it functions as damage-associated molecular pattern (DAMP) that orchestrates pro-inflammatory cytokine release and inflammation. Our results demonstrate that HMGB1 is secreted in the tumor microenvironment after oncolytic HSV (oHSV) infection in vitro and in vivo. The impact of secreted HMGB1 on tumor growth and response to oncolytic viral therapy was evaluated by using HMGB1-blocking antibodies in vitro and in mice bearing intracranial tumors. IVIS and MRI imaging was utilized to visualize in real time virus spread, tumor growth, and changes in edema in mice. Our data showed that HMGB1 released in tumor microenvironment orchestrated increased vascular leakiness and edema. Further HMGB1 blocking antibodies rescued vascular leakiness and enhanced survival of intracranial glioma-bearing mice treated with oHSV.
  • Enhanced Delivery of Oncolytic Adenovirus by Neural Stem Cells for
           Treatment of Metastatic Ovarian Cancer

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Rachael Mooney, Asma Abdul Majid, Jennifer Batalla-Covello, Diana Machado, Xueli Liu, Joanna Gonzaga, Revathiswari Tirughana, Mohamed Hammad, Maciej S. Lesniak, David T. Curiel, Karen S. AboodyOncolytic virotherapy is a promising approach for treating recurrent and/or drug-resistant ovarian cancer. However, its successful application in the clinic has been hampered by rapid immune-mediated clearance or neutralization of the virus, which reduces viral access to tumor foci. To overcome this barrier, patient-derived mesenchymal stem cells have been used to deliver virus to tumors, but variability associated with autologous cell isolations prevents this approach from being broadly clinically applicable. Here, we demonstrate the ability of an allogeneic, clonal neural stem cell (NSC) line (HB1.F3.CD21) to protect oncolytic viral cargo from neutralizing antibodies within patient ascites fluid and to deliver it to tumors within preclinical peritoneal ovarian metastases models. The viral payload used is a conditionally replication-competent adenovirus driven by the survivin promoter (CRAd-S-pk7). Because the protein survivin is highly expressed in ovarian cancer, but not in normal differentiated cells, viral replication should occur selectively in ovarian tumor cells. We found this viral agent was effective against cisplatin-resistant ovarian tumors and could be used as an adjunct treatment with cisplatin to decrease tumor burden without increasing toxicity. Collectively, our data suggest NSC-delivered CRAd-S-pk7 virotherapy holds promise for improving clinical outcome, reducing toxicities, and improving quality of life for patients with advanced ovarian cancer.Graphical Graphical abstract for this article
  • In Vivo Imaging of Oncolytic Measles Virus Propagation with
           Single-Cell Resolution

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Iris Kemler, Matthew K. Ennis, Claudia M. Neuhauser, David DingliRecombinant measles viruses (MVs) have oncolytic activity against a variety of human cancers. However, their kinetics of spread within tumors has been unexplored. We established an intravital imaging system using the dorsal skin fold chamber, which allows for serial, non-invasive imaging of tumor cells and replication of a fusogenic and a hypofusogenic MV. Hypofusogenic virus-infected cells were detected at the earliest 3 days post-infection (dpi), with peak infection around 6 dpi. In contrast, the fusogenic virus replicated faster: infected cells were detectable 1 dpi and cells were killed quickly. Infection foci were significantly larger with the fusogenic virus. Both viruses formed syncytia. The spatial relationships between cells have a major influence on the outcome of therapy with oncolytic viruses.
  • A Phase I-II Study Using Rexin-G Tumor-Targeted Retrovector Encoding a
           Dominant-Negative Cyclin G1 Inhibitor for Advanced Pancreatic Cancer

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Sant P. Chawla, Howard Bruckner, Michael A. Morse, Nupur Assudani, Frederick L. Hall, Erlinda M. GordonRexin-G is a replication-incompetent retroviral vector displaying a cryptic SIG-binding peptide for targeting abnormal Signature (SIG) proteins in tumors and encoding a dominant-negative human cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT. No patient tested positive for vector-neutralizing antibodies, antibodies to gp70, replication-competent retrovirus (RCR), or vector integration into genomic DNA of peripheral blood lymphocytes (PBLs). For the efficacy analysis (n = 15), one patient achieved a complete response (CR), two patients had a partial response (PR), and 12 had stable disease (SD). Median progression-free survival (PFS) was 2.7, 4.0, and 5.6 months at doses 0–I, II, and III, respectively. Median overall survival (OS) and 1-year OS rate at dose 0–I were 4.3 months and 0%, and at dose II–III they were 9.2 months and 33.3%. To date, one patient is still alive with no evidence of cancer 10 years after the start of Rexin-G treatment. Taken together, these data suggest that Rexin-G, the first targeted gene delivery system, is uniquely safe and exhibits significant antitumor activity, for which the FDA granted fast-track designation.
  • Hypoxia-Induced Upregulation of HE4 Is Responsible for Resistance to
           Radiation Therapy of Gastric Cancer

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Chunwei Peng, Guangjie Liu, Kai Huang, Qiang Zheng, Yunsong Li, Changjun YuUpregulation of human epididymis protein 4 (HE4) is often observed in different types of cancers, including gastric cancer (GC), but the association of elevated HE4 level with radiation resistance in GC remains unclear. The expression of HE4 and hypoxia-inducible factor 1α subunit (HIF1α) was assessed in GC patient samples and cell lines. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to reveal the regulation between HE4 and HIF1α. Stable HE4 knockdown and HIF1α overexpression were introduced into GC cell lines to study the role of HE4 in the resistance of GC to radiation therapy. Colony formation assay and the xenograft mouse model were used to investigate the effects of radiation on GC cells. HE4 and HIF1α were upregulated in both GC patient tissues and GC cells. Hypoxia and HIF1α upregulated HE4 by directly targeting the hypoxia response element in its promoter region. Stable HE4 knockdown significantly sensitized GC cells and xenograft tumors to radiation. HIF1α overexpression markedly elevated the radiation resistance of GC cells, which was almost completely abolished by HE4 knockdown. Hypoxia-induced upregulation of HE4 is responsible for resistance to radiation therapy of GC, suggesting that HE4 knockdown or inhibition, combined with radiation therapy, holds great potential in the clinical treatment of GC.
  • Recombinant AAV-CEA Tumor Vaccine in Combination with an Immune Adjuvant
           Breaks Tolerance and Provides Protective Immunity

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Jonathan A. Hensel, Vinayak Khattar, Reading Ashton, Selvarangan PonnazhaganCarcinoembryonic antigen (CEA) is a human glycoprotein involved in cellular adhesion and expressed during human fetal development. Although expression of CEA largely ceases prior to birth, several human epithelial cancers, including colorectal, gastric, squamous esophageal, and breast carcinomas have been known to overexpress CEA, suggesting its potential as an immunotherapeutic target. Using a transgenic mouse model constitutively expressing human CEA in a spatiotemporal manner as a self-protein and a syngeneic mouse colon cancer cell line, MC38-CEA, overexpressing CEA, we tested the potential of a novel genetic immunotherapy approach against CEA-expressing tumors, using recombinant adeno-associated virus vector encoding CEA (rAAV-CEA) and appropriately timed immune adjuvant application. Results of the study demonstrated breaking of immune tolerance for CEA with this vaccine regimen and an anti-tumor response, resulting in tumor-free survival. Furthermore, tumor challenge of CEA-vaccinated mice with parental MC38 cells not expressing CEA did not result in protection from tumor development, confirming that the protection against tumor development is CEA specific. The study illustrates the feasibility of utilizing rAAV vectors in combination with an immunostimulatory adjuvant to break tolerance to weakly immunogenic self-antigens and for an anti-tumor response.
  • Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with
           T Cell Receptor Transgenic T Cells as Carriers

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Michael Karl Melzer, Lisa Zeitlinger, Sabine Mall, Katja Steiger, Roland M. Schmid, Oliver Ebert, Angela Krackhardt, Jennifer AltomonteVesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as neurotoxicity. We hypothesized that we could overcome these limitations and simultaneously enhance the therapy, by combining VSV with adoptively transferred T cell receptor (TCR) transgenic T cells as carrier cells. We show that CD8+ T central memory cells (CD8+ T cm) can be efficiently loaded with VSV, they support intracellular virus production, and they can efficiently transfer VSV to tumor cells without compromising their own viability or antitumor reactivity. Loading VSV onto CD8+ T cm not only improves the safety compared with systemic administration of naked virus, but this approach also allows for an effective delivery of virus to its tumor target, resulting in an effective combination therapy in NSG mice bearing subcutaneous human acute myeloid leukemia (AML) tumors. We conclude that the combination of potent tumor debulking provided by the oncolytic VSV with the added effector functions afforded by the cytotoxic immune carrier cells results in a potent and safer immunotherapeutic, which can be further developed for clinical translation.
  • Extremely Low Organ Toxicity and Strong Antitumor Activity of
           miR-34-Regulated Oncolytic Coxsackievirus B3

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Yang Jia, Shohei Miyamoto, Yasushi Soda, Yuto Takishima, Miyako Sagara, Jiyuan Liao, Lisa Hirose, Yasuki Hijikata, Yoshie Miura, Kenichiro Hara, Atsufumi Iwanaga, Yasunori Ota, Kenzaburo TaniOncolytic virotherapies have emerged as new modalities for cancer treatment. We previously reported that coxsackievirus B3 (CVB3) is a novel oncolytic virus (OV) with a strong ability to lyse human non-small cell lung cancer cells; however, its non-specific toxicity against normal cells remains to be resolved. To improve its safety profile, microRNA target sequences complementary to miR-34a/c, which is expressed preferentially in normal cells, were inserted into the 5′ UTR or 3′ UTR of the CVB3 genome. In the presence of miR-34a/c, the gene-modified CVB3 could not replicate in normal cells. We also found that the pathogenicity of CVB3 was reduced to a greater extent by targeting miR-34a than miR-34c; in addition, it was more effective to insert the target sequences into the 3′ UTR rather than the 5′ UTR of the viral genome. Ultimately, we developed a double-miR-34a targeting virus (53a-CVB) by inserting miR-34a targets in both the 5′ UTR and 3′ UTR of the virus. 53a-CVB was minimally toxic to cells in normal tissue, but maintained nearly its full oncolytic activity in mice xenografted with human lung cancer. 53a-CVB is the first miR-34-regulated OV and represents a promising platform for the development of safe and effective anti-cancer therapies.Graphical Graphical abstract for this article
  • The Expression of MicroRNA-598 Inhibits Ovarian Cancer Cell Proliferation
           and Metastasis by Targeting URI

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Feng Xing, Shuo Wang, Jianhong ZhouUnconventional prefoldin RPB5 interactor (URI, or RMP, a member of the prefoldin family of molecular chaperones) exhibits oncogenic activity in several types of cancer, including ovarian cancer. However, the underlying regulatory mechanism in ovarian cancer remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To elucidate the role of miRNAs in URI-induced ovarian cancer, miR-598 and URI were overexpressed in the SKOV3 ovarian cancer cell line. The CCK8 kit was used to determine cell proliferation, and the Transwell assay was used to measure cell invasion and migration. RT-PCR and western blotting were used to analyze the expression of miR-598 and URI, and the luciferase reporter assay was used to examine the interaction between miR-598 and URI. Nude mice were used to characterize the regulation of tumor growth in vivo. The results showed that the expression of miR-598 inhibited the proliferation, invasion, and migration of ovarian cancer cells by targeting URI. The inhibitory effect of miR-598 was reversed by overexpression of URI. The luciferase reporter assay showed that miR-598 downregulated URI by directly targeting the 3′ UTR of URI. In vivo studies showed that the expression of miR-598 significantly inhibited the growth of tumors. Taken together, the results suggested that miR-598 inhibited tumor growth and metastasis by targeting URI.
  • Impact of a Chinese Medicinal Formula, Xiao Liu Fang, on the “3A”
           Ability of Endometrial Stromal Cells in Patients with Endometriosis

    • Abstract: Publication date: 29 March 2019Source: Molecular Therapy - Oncolytics, Volume 12Author(s): Hua Zhou, Qian Zhang, Cong QiThe pathogenesis of endometriosis (EMS) is complicated, and treatment results are unsatisfactory. It has become the focus of gynecological research. Analysis targeting the pathogenesis of EMS is the key to providing more effective treatments. In recent years, the superiority of traditional Chinese medicine in treating EMS has been highlighted, so we investigated the impact of a Chinese medicinal formula (Xiao Liu Fang) on the “3A” ability, in situ, of ectopic endometrial stromal cells in patients with EMS. Primary endometrial stromal cells were isolated using a modified net filtration method, cultured, and identified in different groups. Endometrial cell attachment was measured using the methyl thiazolyl tetrazolium (MTT) colorimetric assay, cell aggression was detected by the transwell cell-invasion assay, and angiogenesis was defined by evaluating the mRNA concentrations of intercellular cell adhesion molecule 1 (ICAM-1), cyclooxygenase 2 (COX-2), matrix metallo peptidase 9 (MMP-9), and vascular endothelial growth factor (VEGF). Attachment, aggression, and angiogenesis (AAA) plays an important role in EMS, and a high dose of the Xiao Liu Fang extract can be used for the treatment of EMS owing to its inhibition of the AAA of endometrial stromal cells. Therefore, in-depth studies targeting the effective mechanisms and targets of traditional Chinese medicine (TCM) are of great significance for the prevention and treatment of EMS.
  • Chimeric antigen receptor T cell bearing herpes virus entry mediator
           co-stimulatory signal domain exhibits high functional potency

    • Abstract: Publication date: Available online 23 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Jun-ichi Nunoya, Michiaki Masuda, Chaobaihui Ye, Lishan Su Chimeric antigen receptor (CAR) is a hybrid molecule consisting of an antigen-binding domain and a signal transduction domain. The artificial T cells expressing CAR (CAR-T cells) are expected to be a useful tool for treatment of various diseases, such as cancer. Addition of co-stimulatory signal domain (CSSD) to CAR is shown to be critical for modulating CAR-T cell activities. However, the interplay among types of CSSDs, effector functions and characteristics of CAR-T cells are largely unknown. To elucidate these interplay, we analyzed effector functions, differentiation to memory T cell subsets, exhaustion and energy metabolism of the CAR-T cells with different CSSDs. Comparing to the CAR-T cells bearing CD28- or 4-1BB-derived CSSD which were currently used for CAR-T cell development, we found that the CAR-T cells with herpes virus entry mediator (HVEM)-derived CSSD exhibited enhanced effector functions, efficient and balanced differentiation to both central and effector memory subsets, associated with an elevated energy metabolism and a reduced level of exhaustion. Thus, we developed the CAR-T cells bearing the CSSD derived from HVEM with high functional potency. The HVEM-derived CSSD may be useful for developing effective CAR-T cells.Graphical Graphical abstract for this article
  • Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck

    • Abstract: Publication date: Available online 20 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Renjith Parameswaran Nair, Prakash Srinivasan Timiri Shanmugam, Gulshan Sunavala-Dossabhoy Oral radiotoxicity is often a limiting factor in cancer treatment. Previously, we demonstrated that transfer of cell-permeable TAT-TLK1B protein in salivary glands effectively mitigates radiation-induced salivary dysfunction. However similar to most radioprotectors, TLK1B can carry the risk of limiting cancer treatment efficacy. The central goal of the study was, therefore, to reengineer TLK1B as a selective radioprotector of normal cells. Degradation of the extracellular matrix by proteases such as matrix metalloproteinases (MMPs) is a hallmark of aggressive tumors. Increased expression of membrane type 1-MMP (MT1-MMP; also called MMP14) is observed in a variety of cancers including head and neck squamous cell carcinoma (HNSCC). To limit TLK1B transduction to normal cells, we rendered the protein susceptible to MT1-MMP cleavage on the premise that high expression of MT1-MMP on cell surface of HNSCC will suppress TLK1B internalization. Two optimal MT1-MMP-sensitive (MS) motifs were identified, which when incorporated in TAT-TLK1B excluded its cellular entry in HNSCC, SCC40, but not immortalized salivary acinar cells, NS-SV-AC. Importantly, administration of MS-harboring TAT-TLK1B did not affect sensitivity of tumors to radiation in a nude mouse xenograft tumor model. We conclude that MT1-MMP-sensitive TLK1B can be an attractive therapeutic to allay salivary radiotoxicity without compromising cancer treatment efficacy.
  • Oncolytic Virus-based Cytokine Expression to Improve Immune Activity in
           Brain and Solid Tumors

    • Abstract: Publication date: Available online 20 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Taylor M. Pearl, James M. Markert, Kevin A. Cassady, Mohammed G. Ghonime Oncolytic viral therapy has gained significant traction as cancer therapy over the past two decades. Oncolytic viruses are uniquely designed to both lyse tumor cells through their replication and to recruit immune responses against viral infected cells. Increasingly, investigators are leveraging this immune response to target the immunosuppressive tumor microenvironment and improve immune effector response against bystander tumor cells. In this article we review the spectrum of preclinical, early stage clinical, and potential future efforts with cytokine secreting oncolytic viruses with a focus on the treatment of brain tumors and solid tumors.
  • The Antiviral Apparatus: STING and Oncolytic Virus Restriction

    • Abstract: Publication date: Available online 20 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Joel Lee, M.G. Ghonime, Ruoning Wang, K.A. Cassady
  • Combined checkpoint inhibition and chemotherapy: new era of 1st line
           treatment for non-small cell lung cancer

    • Abstract: Publication date: Available online 19 March 2019Source: Molecular Therapy - OncolyticsAuthor(s): Chongkai Wang, Prakash Kulkarni, Ravi Salgia Platinum-based chemotherapy has long been the first-line treatment of choice for metastatic non-small-cell lung cancer (NSCLC) patients who lack targetable gene mutations. The arrival of checkpoint blockade has led to a vast shift in the treatment landscape of NSCLC. Among NSCLC patients with PD-L1 expression in ≥50% of tumor cells, treatment with pembrolizumab leads to a superior progression-free and overall survival compared to platinum-doublet chemotherapy in the first-line setting. Furthermore, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significant longer progression-free survival and overall survival irrespective to PD-L1 expression. In this review, we focus on the molecular rational for the combination therapy and the results of completed clinical studies.
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
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