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Translational Oncology

Signe Holm Nielsen, Nicholas Willumsen, Diana Julie Leeming, Samuel Joseph Daniels, Susanne Brix, Morten Asser Karsdal, Federica Genovese, Mette Juul Nielsen
OBJECTIVES: Remodeling of the extracellular matrix (ECM) is a key event in different lung disorders, such as fibrosis and cancer. The most common cell type in the connective tissue is fibroblasts, which transdifferentiate into myofibroblasts upon activation. All myofibroblasts express α-SMA, which has been found to be upregulated in lung fibrosis and cancer. We evaluated the potential of α-SMA as a noninvasive biomarker of activated fibroblasts in lung fibrosis and cancer. METHODS: A monoclonal antibody was raised against the N-terminal of α-SMA, and a novel competitive enzyme-linked immunosorbent assay (ELISA) measuring α-SMA was developed and technically characterized...
November 29, 2018: Translational Oncology
Marc Eissing, Lise Ripken, Gerty Schreibelt, Harm Westdorp, Marjolijn Ligtenberg, Romana Netea-Maier, Mihai G Netea, I Jolanda M de Vries, Nicoline Hoogerbrugge
Carriers of a pathogenic germline mutations in the PTEN gene, a well-known tumor suppressor gene, are at increased risk of multiple benign and malignant tumors, e.g. breast, thyroid, endometrial and colon cancer. This is called PTEN Hamartomous Tumor Syndrome (PHTS). PHTS patients may also have an increased risk of immunological dysregulation, such as autoimmunity and immune deficiencies. The effects of PTEN on the immune system have been studied in murine knockout models demonstrating that loss of PTEN function leads to dysregulation of the immune response...
November 29, 2018: Translational Oncology
Gabriela M Wiedemann, Celina Aithal, Angelina Kraechan, Constanze Heise, Bruno L Cadilha, Jin Zhang, Peter Duewell, Robert Ballotti, Stefan Endres, Corine Bertolotto, Sebastian Kobold
Microphthalmia-associated transcription factor (MITF) is a key transcription factor in melanoma development and progression. MITF amplification and downregulation have been observed in a significant proportion of melanoma patients and correlate with clinical outcomes. Here, we have investigated the effect of MITF on melanoma chemokine expression and immune cell attraction. In B16F10 melanoma cells, MITF knockdown reduced expression of CXCL10, with concomitantly decreased attraction of immune cells and accelerated tumor outgrowth...
November 28, 2018: Translational Oncology
Ayako Nogami, Keigo Okada, Shinya Ishida, Hiroki Akiyama, Yoshihiro Umezawa, Osamu Miura
FLT3-ITD and FLT3-TKD are the most frequent tyrosine kinase mutations in acute myeloid leukemia (AML), with the former conferring a poor prognosis. We have recently revealed that FLT3-ITD confers resistance to the PI3K/AKT pathway inhibitors by protecting the mTORC1/4EBP1/Mcl-1 pathway through Pim kinases induced by STAT5 activation in AML. The proteasome inhibitor bortezomib has recently been reported as a promising agent for treatment of AML. Here, we show that the proteasome inhibitor bortezomib as well as carfilzomib induces apoptosis through the intrinsic pathway more conspicuously in cells transformed by FLT3-TKD than FLT3-ITD...
November 22, 2018: Translational Oncology
Rheal A Towner, Nataliya Smith, Debra Saunders, Chase A Brown, Xue Cai, Jadith Ziegler, Samantha Mallory, Mikhail G Dozmorov, Patricia Coutinho De Souza, Graham Wiley, Kyeongsoon Kim, Shinwook Kang, Doo-Sik Kong, Young-Tae Kim, Kar-Ming Fung, Jonathan D Wren, James Battiste
Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines...
November 20, 2018: Translational Oncology
Nadine Wiesmann, Rita Gieringer, Franz Grus, Juergen Brieger
To fight resistances to radiotherapy, the understanding of escape mechanisms of tumor cells is crucial. The aim of this study was to identify phosphoproteins that are regulated upon irradiation. The comparative analysis of the phosphoproteome before and after irradiation brought nucleophosmin (NPM1) into focus as a versatile phosphoprotein that has already been associated with tumorigenesis. We could show that knockdown of NPM1 significantly reduces tumor cell survival after irradiation. NPM1 is dephosphorylated stepwise within 1 hour after irradiation at two of its major phosphorylation sites: threonine-199 and threonine-234/237...
November 16, 2018: Translational Oncology
Young Mi Seol, Chae Hwa Kwon, So Jeong Lee, Seon Jin Lee, Yuri Choi, Young Jin Choi, Hyojeong Kim, Do Youn Park
With the advent of next-generation sequencing (NGS), targeted sequencing is now contributing to decision making for which chemotherapeutics to administer to cancer patients, especially in refractory and metastatic cancer. Given that most patients with refractory cancer develop resistance to chemotherapy and have few treatment options, we performed NGS test to evaluate the efficacy and clinical feasibility of NGS-based targeted anticancer therapy. We used a gene panel for capturing target regions covering 83 cancer-related genes...
November 15, 2018: Translational Oncology
Leilei Zhou, Zuoheng Zhang, Yu-Chen Chen, Zhen-Yu Zhao, Xin-Dao Yin, Hong-Bing Jiang
OBJECTIVES: To investigate the effect of transfer learning on computed tomography (CT) images for the benign and malignant classification on renal tumors and to attempt to improve the classification accuracy by building patient-level models. METHODS: One hundred ninety-two cases of renal tumors were collected and identified by pathologic diagnosis within 15 days after enhanced CT examination (66% male, 70% malignant renal tumors, average age of 62.27 ± 12...
November 15, 2018: Translational Oncology
Matteo Fassan, Ri Cui, Pierluigi Gasparini, Claudia Mescoli, Vincenza Guzzardo, Caterina Vicentini, Giada Munari, Fotios Loupakis, Sara Lonardi, Chiara Braconi, Marco Scarpa, Edoardo D'Angelo, Salvatore Pucciarelli, Imerio Angriman, Marco Agostini, Renata D'Incá, Fabio Farinati, Roberta Gafà, Giovanni Lanza, Wendy L Frankel, Carlo Maria Croce, Nicola Valeri, Massimo Rugge
miR-224 has recently emerged as a driver oncomiR in sporadic colorectal carcinogenesis, but its pathogenetic role is still controversial. A large phenotypical and molecularly characterized series of preinvasive and invasive colorectal lesions was investigated for miR-224 expression by qRT-PCR and in situ hybridization. The caspase-3 and caspase-7 status was also assessed and correlated to miR-224 dysregulation. miR-224 was significantly upregulated during the adenoma-carcinoma sequence and in the context of inflammatory bowel disease dysplastic lesions, whereas its expression was significantly downregulated among BRAF-mutated tumors and in the presence of a DNA mismatch repair deficiency...
November 15, 2018: Translational Oncology
Eun Byeol Jo, Doopyo Hong, Young Sang Lee, Hyunjoo Lee, Jae Berm Park, Sung Joo Kim
The patient-derived xenograft (PDX) model has been adopted as a major tool for studying tumorigenesis and differentiation in various carcinomas. In addition, it has been used in the development of anticancer agents. PDX models have been among the most meaningful tools used to understand the role of stromal cells and vascular cells in the body, which are major factors in cancer development and the application of therapeutic agents. Also, the establishment of PDX models from liposarcoma patients is considered to be important for understanding lipomagenesis and following drugs development...
November 14, 2018: Translational Oncology
Nicole Golob-Schwarzl, Kira Bettermann, Anita Kuldeep Mehta, Sonja M Kessler, Julia Unterluggauer, Stefanie Krassnig, Kensuke Kojima, Xintong Chen, Yujin Hoshida, Nabeel M Bardeesy, Heimo Müller, Vendula Svendova, Michael G Schimek, Clemens Diwoky, Alexandra Lipfert, Vineet Mahajan, Cornelia Stumptner, Andrea Thüringer, Leopold F Fröhlich, Tatjana Stojakovic, K P R Nilsson, Thomas Kolbe, Thomas Rülicke, Thomas M Magin, Pavel Strnad, Alexandra K Kiemer, Richard Moriggl, Johannes Haybaeck
BACKGROUND & AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termed Mallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: We analyzed livers of aged Krt18-/- mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex...
November 12, 2018: Translational Oncology
Ken Tawara, Hannah Scott, Jacqueline Emathinger, Alex Ide, Ryan Fox, Daniel Greiner, Dollie LaJoie, Danielle Hedeen, Madhuri Nandakumar, Andrew J Oler, Ryan Holzer, Cheryl Jorcyk
Breast cancer cell-response to inflammatory cytokines such as interleukin-6 (IL-6) and oncostatin M (OSM) may affect the course of clinical disease in a cancer subtype-dependent manner. Furthermore, vascular endothelial growth factor A (VEGF) secretion induced by IL-6 and OSM may also be subtype-dependent. Utilizing datasets from Oncomine, we show that poor survival of invasive ductal carcinoma (IDC) breast cancer patients is correlated with both high VEGF expression and high cytokine or cytokine receptor expression in tumors...
November 12, 2018: Translational Oncology
Yanyun Xie, Linfeng Zheng, Lijian Tao
IQGAP2 was recently reported as a tumor suppressor of prostate cancer (PC). Nonetheless, its clinical implications remain unknown. To address this issue, we extracted data related to IQGAP2 mRNA expression and genomic alterations from multiple large datasets within the Oncomine and cBioPortal databases and performed in silico analyses to determine a potential association of IQGAP2 mRNA expression and its genomic alterations with PC progression. In 4 cohorts consisting of 118 normal prostate tissues and 277 PCs, IQGAP2 mRNA expression was significantly elevated particularly in low-grade (primary Gleason score ≤3) PCs; these changes separate PC from normal tissues with area under curve values of 0...
November 11, 2018: Translational Oncology
Sang Mun Bae, Dong-Jun Bae, Eun-Ju Do, Gyungseok Oh, Su Woong Yoo, Gil-Je Lee, Ji Soo FChae, Youngkuk Yun, Sungjee Kim, Ki Hean Kim, Euiheon Chung, Jun Ki Kim, Sung Wook Hwang, Sang Hyoung Park, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Suk-Kyun Yang, Jinmyoung Joo, Sang-Yeob Kim, Seung-Jae Myung
BACKGROUND AND STUDY AIM: To develop a molecular imaging endoscopic system that eliminates tissue autofluorescence and distinguishes multiple fluorescent markers specifically on the cancerous lesions. METHODS: Newly developed multi-spectral fluorescence endoscope device has the potential to eliminate signal interference due to autofluorescence and multiplex fluorophores in fluorescent probes. The multiplexing capability of the multi-spectral endoscope device was demonstrated in the phantom studies and multi-spectral imaging with endoscopy and macroscopy was performed to analyze fluorescence signals after administration of fluorescent probe that targets cancer in the colon...
November 9, 2018: Translational Oncology
Kulthida Vaeteewoottacharn, Ryusho Kariya, Phattarin Pothipan, Sawako Fujikawa, Chawalit Pairojkul, Sakda Waraasawapati, Kazuhiko Kuwahara, Chaisiri Wongkham, Sopit Wongkham, Seiji Okada
The involvement of chronic inflammation in cholangiocarcinoma (CCA) progression is well established. Cluster of differentiation 47 (CD47) is mutually expressed in various cancers and serves as a protective signal for phagocytic elimination. CD47 signaling blockage is a recent treatment strategy; however, little is known regarding CD47 in CCA. Therefore, the potential use of CD47 targeting in CCA was focused. CD47 was highly expressed in CCA compared to hepatocellular carcinoma (HCC). Disturbance of CD47-signal regulatory protein-α (SIRPα) interaction by blocking antibodies promoted the macrophage phagocytosis...
November 8, 2018: Translational Oncology
Kyle C Cuneo, Ranjit K Mehta, Himabindu Kurapati, Dafydd G Thomas, Theodore S Lawrence, Mukesh K Nyati
INTRODUCTION: C-Met plays important roles in treatment resistance, tumor invasion, and metastasis. In this study, we used a small molecule inhibitor of c-Met, crizotinib, in cetuximab-resistant, mutant KRAS-driven colorectal cancer cell lines and assessed radiosensitization. MATERIALS AND METHODS: A tissue microarray containing colorectal tumors was used to study the relationship between KRAS mutations and c-Met expression. For in vivo studies, we used the KRAS mutant cell lines HCT116, DLD1, and LoVo...
November 6, 2018: Translational Oncology
Laura L Stafman, Adele P Williams, Evan F Garner, Jamie M Aye, Jerry E Stewart, Karina J Yoon, Kimberly Whelan, Elizabeth A Beierle
Hepatoblastoma is the most common primary liver tumor in children, but treatment has not changed significantly in the past 20 years. We have previously demonstrated that Proviral Integration site for Moloney murine leukemia (PIM) kinases promote tumorigenesis in hepatoblastoma. Stem cell-like cancer cells (SCLCCs) are a subset of cells thought to be responsible for chemoresistance, metastasis, relapse, and recurrence. The aim of this study was to identify SCLCCs in hepatoblastoma and determine the role of PIM kinases in SCLCCs...
November 6, 2018: Translational Oncology
Daisuke Kyuno, Kun Zhao, Nathalie Bauer, Eduard Ryschich, Margot Zöller
AIM: Transfer of exosomes (Exo) miRNA was described interfering with tumor progression. We here explored for claudin7 (cld7) and EpCAM (EpC), cancer-initiating-cell markers in colorectal and pancreatic cancer, the efficacy of Exo loading with miRNA and miRNA transfer. METHODS: Exo were collected from nontransformed mouse (NIH3T3) and rat lung fibroblasts (rFb), which were transfected with Tspan8 cDNA (NIH3T3-Tspan8, rFb-Tspan8). Exo were loaded by electroporation with miRNA...
October 27, 2018: Translational Oncology
Sofia Aakko, Anne Hege Straume, Einar Elvbakken Birkeland, Ping Chen, Xi Qiao, Per Eystein' 'Lønning, Marko J Kallio
Taxanes are chemotherapeutic agents used in the treatment of solid tumors, particularly of breast, ovarian, and lung origin. However, patients show divergent therapy responses, and the molecular determinants of taxane sensitivity have remained elusive. Especially the signaling pathways that promote death of the taxane-treated cells are poorly characterized. Here we describe a novel part of a signaling route in which c-Myc enhances paclitaxel sensitivity through upregulation of miR-203b-3p and miR-203a-3p; two clustered antiapoptosis protein Bcl-xL controlling microRNAs...
October 22, 2018: Translational Oncology
Zhongjie Chen, Zhiqiang Wu, Wen Ning
Radiation-induced pulmonary fibrosis (RIPF) is a common complication in patients with lung cancer and breast cancer after receiving thoracic radiotherapy. The average incidence of RIPF is 16%-28% after radiotherapy. RIPF includes a heterogeneous group of lung disorders characterized by progressive and irreversible destruction of lung architecture and disruption of gas exchange. The clinical signs of RIPF include increasing dyspnea, deteriorating lung function, and accumulation of interstitial fluid, eventually leading to respiratory failure...
October 17, 2018: Translational Oncology
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