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Background Tumor cells progress to evade immunological attacks and prohibit activity of CD8+ T cells. Irradiation damages tumor cells and augments tumor immunotherapy in clinical application. However, the detail mechanism remains elusive. We aimed to uncover the mechanism of irradiation augmenting cytotoxic CD8+ T cells to suppress tumor progression in non-small-cell lung cancer (NSCLC). Methods EGFR-positive NSCLC cell lines were co-cultured with isolated PBMCs from healthy volunteers, cell viability and apoptosis were measured. RNAseq was used to screen the IFNγ-mediated gene expression in A549 cells. Irradiation was used to augment PBMCs-mediated anti-tumor effect and the irradiation effect to IFNγ-mediated gene expression was investigated using qPCR and Western blots. Results Co-culture of tumor cells stimulates increase of granzyme B and IFNγ in CD8+ T, but A549 exhibits resistance against CD8+ T cytotoxicity. Irradiation inhibits A549 proliferation and enhances apoptosis, augmenting PBMCs-mediated cytotoxicity against A549. IFNγ simultaneously increased phosphorylation on STAT1 and STAT3 in EGFR-positive lung cancer, resulting in overexpression of PD-L1. In RNAseq analysis, MCL1 was identified and increased by IFNγ-STAT3 axis in A549 cells, we found that irradiation specifically inhibits phosphorylation on STAT1 and STAT3 in IFNr-treated A549, resulting in reductions of PD-L1 and MCL1. Moreover, knockdowns of STAT3 and MCL1 increased PBMCs against irradiated A549 cells. Conclusion This study demonstrated that A549 expressed MCL1 against CD8+ T cell-mediated apoptosis. In addition, we found that irradiation suppressed STAT3 phosphorylation and IFNγ-mediated PD-L1 and MCL1 expression, revealing a potential mechanism of irradiation augmenting immune surveillance.

Objectives YM155, an inhibitor of interleukin enhancer-binding factor 3 (ILF3), significantly suppresses cancer stemness property, implying that ILF3 contributes to cell survival of cancer stem cells. However, the molecular function of ILF3 inhibiting cancer stemness remains unclear. This study aimed to uncover the potential function of ILF3 involving in cell survival of epidermal growth factor receptor (EGFR)-positive lung stem-like cancer, and to investigate the potential role to improve the efficacy of anti-EGFR therapeutics. Materials and methods The association of EGFR and ILF3 in expression and regulations was first investigated in this study. Lung cancer A549 cells with deprivation of ILF3 were created by the gene-knockdown method and then RNAseq was applied to identify the putative genes regulated by ILF3. Meanwhile, HCC827- and A549-derived cancer stem-like cells were used to investigate the role of ILF3 in the formation of cancer stem-like tumorspheres. Results We found that EGFR induced ILF3 expression, and YM155 reduced EGFR expression. The knockdown of ILF3 reduced not only EGFR expression in mRNA and protein levels, but also cell proliferation in vitro and in vivo, demonstrating that ILF3 may play an important role in contributing to cancer cell survival. Moreover, the knockdown and inhibition of ILF3 by shRNA and YM155, respectively, reduced the formation and survival of HCC827- and A549-derived tumorspheres through inhibiting ErbB3 (HER3) expression, and synergized the therapeutic efficacy of afatinib, a tyrosine kinase inhibitor, against EGFR-positive A549 lung cells. Conclusion This study demonstrated that ILF3 plays an oncogenic like role in maintaining the EGFR-mediated cellular pathway, and can be a therapeutic target to improve the therapeutic efficacy of afatinib. Our results suggested that YM155, an ILF3 inhibitor, has the potential for utilization in cancer therapy against EGFR-positive lung cancers.

Background Epidermal growth factor receptor (EGFR) overexpressed in colorectal cancer (CRC) is a tumor target for developing the anti-tumor theranostic agents. Cetuximab, an anti-EGFR monoclonal antibody against EGFR-positive tumors, inhibits cell proliferation and growth was labeled with radioactive 111indium (111In) in this study for diagnosing EGFR-positive CRC. The aim of this study was to evaluate the efficacy of noninvasive nuclear imaging agent 111In-cetuximab and investigate the biological distribution of 111In-cetuximab in the HCT-15-induced EGFR-positive CRC tumor xenografts. Methods We conjugated cetuximab with an isotope chelator, diethylene triamine penta acetic acid (DTPA), and consequently labeled cetuximab-DTPA with 111In and measured the labeling efficacy by an instant thin layer chromatography (iTLC). Furthermore, the 111In-cetuximab was investigated and compared for imaging small (50 mm3) and large (250 mm3) tumor of CRC xenografts, respectively. Results The conjugated ratio between cetuximab and DTPA was 1:6 measured by MALDI-TOF-MS. The better labeling concentration of cetuximab with 10 mCi of 111In was calculated and experimented as 48 μg, resulting in labeling efficacy >80% detected by iTLC. The results revealed that the 111In-cetuximab accumulated in the both sizes of tumors as a reliable noninvasive diagnostic agent, whereas the ratio of tumor to muscle in the large tumor was 7.5-fold. The biodistribution data indicated that the 111In-cetuximab bound to tumor specifically that was higher than that in other organs. Conclusion We suggested that the 111In-cetuximab was potential for early diagnosis and prognostic monitor of EGFR-positive CRC in further clinical practice.

Hypoxic microenvironment is a common situation in solid tumors. Carbonic anhydrase IX (CA9) is one of the reliable cellular biomarkers of hypoxia. The role of CA9 in colorectal cancer (CRC) remains to be clarified. CA9 inhibitor such as sulfonamides is known to block CA9 activation and reduce tumor growth consequently. Here, we aimed to investigate the CA9 expression in serum and tumor from different stages of CRC patients and utilize sulfonamide derivative with indium-111 labeling as a probe for CRC nuclear imaging detection in vivo. The serum CA9 was correlated with the tumor CA9 levels in different stages of CRC patients. Hypoxia increased cell viability and CA9 expression in colorectal cancer HCT-15 cells. Sulfonamide derivative 5-(2-aminoethyl)thiophene-2-sulfonamide (ATS) could bind with CA9 in vitro under hypoxia. Moreover, tumor tissues in HCT-15-induced xenograft mice possessed higher hypoxic fluorescence signal as compared with other organs. We also found that the radioisotope signal of indium-111 labeled ATS, which was utilized for CRC detection in HCT-15-induced xenograft mice, was markedly enhanced in tumors as compared with non-ATS control. Taken together, these findings suggest that CA9 is a potential hypoxic CRC biomarker and measurement of serum CA9 can be as a potential tool for diagnosing CA9 expressions in CRC clinical practice. The radioisotope-labeled sulfonamide derivative (ATS) may be useful to apply in CRC patients for nuclear medicine imaging.

Summary Background Statins are a class of drugs used to lower cholesterol levels, accompanying increased high-density lipoprotein (HDL) levels. Previous studies have suggested that statins can inhibit inflammation, and also reduce tumor proliferation. We therefore hypothesized that pravastatin, a member of the statins, mediating the inhibitory functions in tumor growth may be associated with the upregulated HDL constituent, apolipoprotein A1 (ApoA1). Methods Pravastatin-induced inhibition in tumor proliferation in vitro and in xenografts was investigated. Reduced ApoA1 expressions were detected in the tumor regions in specimens from tumor patients as well in xenografts using Western Blotting. Moreover, ApoA1 was administered to inhibit tumor proliferation, and pravastatin was given to enhance the chemotherapeutic efficacy of doxorubicin (DOX). Results We found a significant statistical reduction of ApoA1 in the tumor regions of specimens from gastric cancer and colorectal cancer patients. MKN45 cells proliferation was inhibited by 18% under the growing medium containing pravastatin. ApoA1 levels were elevated in liver Clone 9 cells administered pravastatin, but not in MKN45 cells. In vitro studies revealed that ApoA1 can reduce MKN45 tumor proliferation. Moreover, the tumor volume was significantly reduced in in vivo xenografts after the administration of pravastatin. Combined treatments of pravastatin with DOX significantly minimized the size of tumors, leading to a better therapeutic efficacy. Conclusion This study demonstrated that pravastatin elevated ApoA1, an HDL major constituent with anti-inflammatory characteristics, which displayed strong adversary associations with tumor developments and growth. Increasing the amounts of ApoA1 by pravastatin coupled with DOX may improve the therapeutic efficacy for cancer treatment.

// Siao-Syun Guan 1,2 , Jungshan Chang 3 , Chun-Chia Cheng 2,3 , Tsai-Yueh Luo 2 , Ai-Sheng Ho 4 , Chia-Chi Wang 5 , Cheng-Tien Wu 1 and Shing-Hwa Liu 1,6,7 1 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 2 Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan 3 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan 4 Division of Gastroenterology, Cheng Hsin General Hospital, Taipei, Taiwan 5 Division of Hepatology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan 6 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 7 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan Correspondence: Shing-Hwa Liu, email: // Keywords : colorectal cancer / HER2 / afatinib / micelles Received : March 31, 2014 Accepted : May 30, 2014 Published : June 1, 2014 Abstract Colorectal cancer (CRC) is known as a common malignant neoplasm worldwide. The role of EGFR/HER2 in CRC is unclear. Afatinib is an irreversible EGFR/HER2 inhibitor. There were few studies of afatinib on CRC. Here, we investigated the protein levels/expressions of HER2 in sera and tumors from CRC patients and the therapeutic effect of afatinib on HER2-overexpressed CRC in vitro and in vivo . The increased HER2 levels were detected in the collected sera and tumors of patients with CRC. The serological HER2 levels were correlated with the tumor HER2 expressions in patients. Afatinib also inhibited the HER2-positive tumor cell growth and caused apoptosis in HER2-overexpressed human colorectal cancer HCT-15 cells but not in low HER2 expressed human gastric cancer MKN45 cells. In vivo study showed that afatinib reduced tumor growth in HER2-overexpressed xenografts. Moreover, afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT-15 cells and were more effective for tumor growth suppression in HCT-15-induced tumor xenografts than afatinib performance alone. Taken together, these findings suggest that higher serum HER2 levels reflect the higher HER2 contents in tumors of CRC patients, and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in HER2-overexpressed CRC in vitro and in vivo .

HER3 exerts resistance against epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), resulting in tumor relapse in lung cancers. Previously, we have demonstrated that EGFR induces HER3 overexpression and that contributes to the formation of cancer stem-like tumorspheres. However, the cellular mechanism of EGFR in regulating HER3 expression was obscure. We hypothesized that EGFR-downstream STAT3 participates in HER3 expression since STAT3 contributes to cancer stemness and surviving EGFR-TKIs. First, RNAseq was used to uncover the potential genes involving in formation of lung cancer HCC827-derived stem-like tumorspheres. EGFR-positive lung cancer cell lines (HCC827, A549, H1975) were individually treated with a panel containing 172 compounds which targeting to stem cell-associated genes in order to searching potential agents against EGFR-positive lung cancers. In addition, gene knockdown and RNAseq were used for investigating the molecular mechanism of STAT3 on regulating tumor progression and survival of lung cancers. We found that BBI608, a STAT3 inhibitor, was a potential therapeutic agent specifically reducing the cell viability of EGFR-positive lung cancers. Interestingly, the inhibitory effects caused by BBI608 were similar with that derived from YM155, an ILF3 inhibitor, both compounds reduced G9a-mediated HER3 expression. We, furthermore, demonstrated that STAT3 upregulated G9a to silence miR-145-5p for exacerbating HER3 expression in this study. In conclusion, this study figured out the potential cellular function of STAT3 in EGFR-positive lung cancers. We also evaluated that BBI608 was potential to eradicate EGFR-positive lung cancers and demonstrated that STAT3 regulated expression of HER3, indicating that STAT3 was a reliable therapeutic target against EGFR-TKI-resistant lung cancers. Note: This abstract was not presented at the meeting. Citation Format: Chun-Chia Cheng, Ya-Wen Chiang, Ken-Hong Lim, Jungshan Chang, Ai-Sheng Ho, Yi-Fang Chang. STAT3 represses miR-145-5p to exacerbate HER3 expression for surviving EGFR-TKIs in lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3028.

Background Although rare, psychosis can emerge during interferon (IFN)-alpha therapy and persist after therapy is completed. Objective The authors report the case of a 30-year-old man with hepatitis C infection treated with IFN-alpha and ribavirin who developed acute psychosis with persecutory delusions and auditory hallucinations, resulting in a suicide attempt. Method The patient was treated with amisulpride for 6 weeks and then with risperidone for 6 weeks. Results There was no improvement in symptoms until the patient was treated with quetiapine; he then had a marked recovery from the psychotic symptoms. The duration of the psychosis was 28 weeks. Conclusion Hepatitis C can be successfully treated with IFN therapy, and the risk of IFN-induced psychosis is low, with psychotic symptoms resolving in most cases after completion of IFN therapy with or without antipsychotic treatment. In prolonged psychosis induced by IFN, quetiapine might also be of benefit.

In contrast to Western countries, erosiveesophagitis has been considered less common, Barrett'sesophagus presumed less frequent, and hiatal herniaextremely uncommon in the Orient. However, accelerated modernization and adoption of Western customshave resulted in marked life-style changes in manyAsians in the Orient that may potentially affect thefrequency of erosive esophagitis and Barrett's esophagus in this population. Our aim was to determinethe current frequency of erosive esophagitis, Barrett'sesophagus, and other gastroesophageal reflux diseasecomplications in self-referred Chinese patients undergoing upper gastrointestinal endoscopy inTaipei, Taiwan. Between July 1991 and June 1992, 464consecutive patients underwent endoscopy for a varietyof upper gastrointestinal symptoms at a major medical center. The presence of erosive esophagitis,strictures, Barrett's esophagus, and hiatal hernia wasrecorded. The extent of mucosal injury was determined byusing the Savary-Miller grading system. Sixty-six (14.5%) patients were found to have erosiveesophagitis, 9 (2%), Barrett's esophagus, and 32 (7%)hiatal hernias. Erosive esophagitis showed amale-to-female preponderance of 3.1:1. Disease severityincreased with age and peaked during the sixth andseventh decades. We concluded that in contrast toprevious experience, the Chinese population in Taiwanappears to have a higher frequency of erosiveesophagitis, Barrett's esophagus, and hiatal hernia.Increased fat consumption, aging, and other possiblefactors are suggested as possible mechanisms.