bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolated Jejunal Perforation and Mesentery Injury following a Kick on the Abdomen of a College Student: A Case Report from a District Hospital in Northern Ghana
Authors: Nonterah Engelbert A. , Atindama Solomon , Achumbowina Emmanuel , Kaburise Michael B. , Saanwie Edwin , Ewura Aziz , Al-Hassan Majeedallahi
Published: March 2020

Introduction. Isolated jejunal perforation from blunt abdominal trauma is an extremely rare intra-abdominal injury that poses a huge diagnostic challenge. Delay in diagnosis and initiation of treatment often leads to significant morbidity and mortality. Diagnosis particularly in resource-poor settings may be extremely challenging and often relies on a high index of suspicion. This is due to lack of adequate diagnostic facilities and human resource to deal with the condition with resulting high occurrence of adverse outcomes. Case Presentation. We report a case of isolated jejunal perforation with associated mesentery injury in a young college student who sustained a kick to his abdomen while playing soccer. This is an unusual presentation since most reported cases often resulted from motor vehicular accidents, bicycle handlebar, and fall from a height. We emphasized the role of critical level of suspicion with a good history and physical examination as the major source of diagnosis since diagnostic procedures, such as abdominal ultrasonography and computed tomography, are largely unavailable in most resource-constraint settings. Early surgical intervention following diagnosis leads to good recovery and reduced mortality. Conclusion. Sufficient vigilance and suspicions of small bowel perforation should always be considered after blunt trauma even when symptoms and physical findings are minimal and when diagnostic capacity is limited.
A Sudden Onset of Severe Thrombocytopenia While Using Evolocumab
Authors: Inoue Ikuo , Takenaka Yasuhiro , Kin Yoshitora , Yamazaki Satoshi , Ikegami Yuichi , Saito Daigo , Shimada Akira
Published: March 2020

A 72-year-old man with a 10-year history of coronary heart disease started evolocumab treatment once a month after developing excess myalgia due to therapy with a 3-hydroxy-methylglutaryl CoA reductase inhibitor. No side effects such as myalgia symptoms had been reported during the first 14 months of evolocumab treatment; however, he suddenly presented with acute severe thrombocytopenia following the 14th treatment. His platelet count continued to decrease to a nadir of 1,000/μL. His platelet-associated immunoglobulin G level had elevated to 790 ng/107 cells. He started receiving a combination of steroid therapy, high-dose immunoglobulin therapy, and platelet transfusions, but the first-line therapy was ineffective. He was subsequently treated with a thrombopoietin receptor agonist, and his platelet count recovered to 250,000/μL.
Overexpression of BMPER in Ovarian Cancer and the Mechanism by which It Promotes Malignant Biological Behavior in Tumor Cells
Authors: Xi Yong , Nie Xin , Wang Jing , Gao Lingling , Lin Bei
Published: March 2020

Background. BMPER has been reported to be associated with the biological behavior of a few malignant tumors, but the mechanism is still unclear. We aimed to detect BMPER expression in ovarian epithelial tumor tissues and its effects on their biological behaviors, as well as to elucidate the possible mechanism. Methods. BMPER expression in ovarian epithelial tumor tissues was detected by immunohistochemistry. BMPER expression in ovarian cancer cell lines was inhibited via RNA interference. Changes in the malignant behaviors of ovarian cancer cells were detected by MTT, wound healing, Transwell, and flow cytometry assays. Changes in proteins in the MAPK and autophagy‐related signaling pathways were detected by Western blot analysis. Results. The expression of BMPER was significantly upregulated in ovarian epithelial malignant tumors and was related to increased lymph node metastasis and lower survival rate. High BMPER expression is an independent risk factor for poor prognosis in patients. Inhibition of BMPER inhibited the proliferation, invasion, and migration of ovarian cancer cells and promoted apoptosis. In addition, BMPER downregulation decreased the expression of PCNA, Bcl‐2, MMP2, and MMP9 and increased the expression of Bax. Moreover, the levels of p‐ERK, p‐MEK, and the autophagy‐related protein p‐mTOR were decreased, and Beclin 1 levels and the LC3II/I ratio were increased. Conclusions. Our findings indicated that BMPER is closely related to poor prognosis in ovarian cancer. BMPER plays a role in promoting the malignant biological behavior of tumor cells through the MAPK and autophagy‐related signaling pathways.
TiO2 Nanoparticles Decorated Graphene Nanoribbons for Voltammetric Determination of an Anti-HIV Drug Nevirapine
Authors: Apath Daniel , Moyo Mambo , Shumba Munyaradzi
Published: March 2020

In the present study, electrochemical behavior of nevirapine on a glassy carbon electrode (GCE) modified with TiO2 nanoparticles decorated graphene nanoribbons was investigated. Characterization of different components used for modifications was achieved using Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The electrochemical behavior of nevirapine on the modified electrodes was examined using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), chronoamperometry (CA), and differential pulse voltammetry (DPV). A considerable oxidation potential decrease of +352 mV for nevirapine in 0.1 M phosphate-buffered saline (PBS), pH 11.0, was achieved due to synergy offered by graphene nanoribbons and TiO2 compared to graphene nanoribbons (+252 mV) and TiO2 (−37 mV), all with respect to the glassy carbon electrode. Under optimized conditions, DPV gave linear calibrations over the range of 0.020–0.14 µM. The detection limit was calculated as 0.043 µM. The developed sensor was used for determination of nevirapine in a pharmaceutical formulation successfully.
A Novel Approach to Fabricate Foam Ceramics from Steel Slag
Authors: Zheng Yu , Luo Xudong , Yang Jinlong , Huo Wenlong , Kang Chi
Published: March 2020

A novel approach is used for fabricating steel slag foam ceramics based on the particle‐stabilized foaming method. In this work, steel slag was used as the raw material and propyl gallate (PG) was used as the surface modifier. For the first time, steel slag ceramic foams were successfully fabricated based on particle‐stabilized foams. The results show that the stability of the ceramic foams was closely related to the pH value and PG concentration. The porosity and compressive strength could be controlled by changing the solid loading of steel slag and sintering temperature. The porosity of steel slag foam ceramics ranged from 85.6% to 62.53%, and the compressive strength was from 1.74 MPa to 10.42 MPa. The thermal conductivity of steel slag foam ceramics was only 0.067 W (m·K)−1, which shows that it could be used as a thermal insulation material.
The Discriminative Efficacy of Retinal Characteristics on Two Traditional Chinese Syndromes in Association with Ischemic Stroke
Authors: Zhuo Y. Y. , Wu J. M. , Kuang L. , Qu Y. M. , Zee B. , Lee J. , Yang Z. X.
Published: March 2020

We aimed to investigate the efficacy of an objective method using AI‐based retinal characteristic analysis to automatically differentiate between two traditional Chinese syndromes that are associated with ischemic stroke. Inpatient clinical and retinal data were retrospectively retrieved from the archive of our hospital. Patients diagnosed with cerebral infarction in the department of acupuncture and moxibustion between 2014 and 2018 were examined. Of these, the patients with Qi deficiency blood stasis syndrome (QDBS) and phlegm stasis in channels (PSIC) syndrome were selected. Those without retinal photos were excluded. To measure and analyze the patients’ retinal vessel characteristics, we applied a patented AI‐assisted automated retinal image analysis system developed by the Chinese University of Hong Kong. The demographic, clinical, and retinal information was compared between the QDBS and PSIC patients. The t‐test and chi‐squared test were used to analyze continuous data and categorical data, respectively. All the selected clinical information and retinal vessel measures were used to develop different discriminative models for QDBS and PSIC using logistic regression. Discriminative efficacy and model performances were evaluated by plotting a receiver operating characteristic curve. As compared to QDBS, the PSIC patients had a lower incidence of insomnia problems (46% versus 29% respectively, p = 0.023) and a higher tortuosity index (0.45 ± 0.07 versus 0.47 ± 0.07, p = 0.027). Moreover, the area under the curve of the logistic model showed that its discriminative efficacy based on both retinal and clinical characteristics was 86.7%, which was better than the model that employed retinal or clinical characteristics individually. Thus, the discriminative model using AI‐assisted retinal characteristic analysis showed statistically significantly better performance in QDBS and PSIC syndrome differentiation among stroke patients. Therefore, we concluded that retinal characteristics added value to the clinical differentiation between QDBS and PSIC.
Electronic Medical Record Inaccuracies: Multicenter Analysis of Challenges with Modified Lung Cancer Screening Criteria
Authors: Wilshire Candice L. , Fuller Carson C. , Gilbert Christopher R. , Handy John R. , Costas Kimberly E. , Louie Brian E. , Aye Ralph W. , Farivar Alexander S. , Vallières Eric , Gorden Jed A.
Published: March 2020

The National Comprehensive Cancer Network expanded their lung cancer screening (LCS) criteria to comprise one additional clinical risk factor, including chronic obstructive pulmonary disease (COPD). The electronic medical record (EMR) is a source of clinical information that could identify high-risk populations for LCS, including a diagnosis of COPD; however, an unsubstantiated COPD diagnosis in the EMR may lead to inappropriate LCS referrals. We aimed to detect the prevalence of unsubstantiated COPD diagnosis in the EMR for LCS referrals, to determine the efficacy of utilizing the EMR as an accurate population-based eligibility screening “trigger” using modified clinical criteria. We performed a multicenter review of all individuals referred to three LCS programs from 2012 to 2015. Each individual’s EMR was searched for COPD diagnostic terms and the presence of a diagnostic pulmonary functionality test (PFT). An unsubstantiated COPD diagnosis was defined by an individual’s EMR containing a COPD term with no PFTs present, or the presence of PFTs without evidence of obstruction. A total of 2834 referred individuals were identified, of which 30% (840/2834) had a COPD term present in their EMR. Of these, 68% (571/840) were considered unsubstantiated diagnoses: 86% (489/571) due to absent PFTs and 14% (82/571) due to PFTs demonstrating no evidence of postbronchodilation obstruction. A large proportion of individuals referred for LCS may have an unsubstantiated COPD diagnosis within their EMR. Thus, utilizing the EMR as a population-based eligibility screening tool, employing expanded criteria, may lead to individuals being referred, potentially, inappropriately for LCS.
Experimental Observation on the Pure Torsional Ratchetting of Polycarbonate Polymer at Room Temperature
Authors: Lu Fucong , Zhang Bencheng , Wu Bo , Wu Zhiwen , Suo Xiao
Published: March 2020

The stress‐controlled pure torsional cyclic tests are carried out to investigate the torsional ratchetting of polycarbonate (PC) polymer at room temperature. The effects of applied shear mean stress, stress amplitude, stress rate, peak stress hold, and stress history on the torsional ratchetting are discussed. The shear strain of tubular specimen is measured by a noncontact digital image correlation (DIC) apparatus. The results show that the torsional ratchetting of the polymer obviously depends on the applied shear stress level, stress rate, and peak stress hold; the shear ratchetting strain and its rate increase with the increasing mean stress, stress amplitude, and peak stress hold time and with the decreasing stress rate. Moreover, the torsional ratchetting depends on the stress history. A higher stress level cyclic loading history restrains the evolution of torsional ratchetting in the subsequent lower stress level cyclic loading, while the lower stress level cyclic loading history promotes the torsional ratchetting of the subsequent higher level cyclic loading.
Heredity Indexes for Estimating Heritability Using Known and Unknown Family Data Based on the Model of Polygenic Inheritance
Authors: Liu Hui
Published: March 2020

Objective. To establish a model for estimating genetic risk using known and unknown family data. Methods. Four simulated datasets were generated for four paternal and maternal chromosomes. The simulated data for children were generated from the parental data according to the Mendelian law. The correlation coefficient between the children’s and paternal data was calculated, and 2R was defined as the heredity index for continuous data (HIC). The simulated continuous data were transformed into binary data according to the gene accumulation threshold (incidence); the incidences of children in the parental no-disease group and the disease onset group were obtained; the correlation coefficient (R) was calculated as expected R (Re). The ratio of observed R (Ro) and Re was defined as the Heredity index for binary data (HIB). Results. Different actual pedigree data (lunula and holding a hammer in the right or left hand) were successfully used to verify the accuracy of the model. The genetic risk was estimated according to the incidence in a population using a lookup table. Conclusion. Our findings indicate the reliability of the model based on the fact that the multigene effect constitutes the normal distribution. Thus, this model can be used for comprehensive analysis of the influence of genetic and nongenetic factors on the genetic phenotype and to estimate genetic risk using known and unknown family data.
Microstructure, Mechanical, and Electrical Properties and Corrosion Analysis of Lead‐Free Solder CSI Joints on Cu Substrate Using Novel Concentrated Solar Energy Soldering (CSES) Method
Authors: Sonawane Pushkaraj D. , Bupesh Raja V. K. , Gupta Manoj
Published: March 2020

In this study, “Concentrated Solar Energy (CSE)” is applied for soldering and is named as the “Concentrated Solar Energy Soldering (CSES) technique.” Lead‐free solders are used for comparing novel CSES technique solder joints with CSI (Conventional Soldering Iron) solder joints. Tensile strength, bending/flexural strength, microhardness, electrical resistivity, fractography, optical microstructures, SEM microstructures, and EDS analysis were used to compare CSES solder joints with CSI solder joints. The salt spray test (SST) was used for corrosion analysis of CSES and CSI solder joints. Experimental results reveal that the tensile response, bending strength, and microhardness of the CSES solder joints were almost equal to those of the CSI solder joints. It was observed that after corrosion, the tensile strength, bending strength, and microhardness for CSES and CSI solder joints reduced. CSES solder joints were found to be slightly better than CSI solder joints for electrical resistivity. Electrical resistivity for all the cases studied was found to increase slightly after corrosion. Interfacial integrity and effect of corrosion were clearly observed on CSES and CSI solder joint microstructures. The intermetallic compounds (IMC) formed in case of CSES solder joints were found to be having slightly less thickness than that of CSI solder joints. The results demonstrate CSES technique as a green technology and a potential substitute to the CSI method.
Effects of Ethanol Blending on the Formation of Soot in n-Heptane/Air Coflow Diffusion Flame
Authors: Ya Yuchen , Nie Xiaokang , Peng Licheng , Xiang Longkai , Hu Jialong , Dong Wenlong , Chu Huaqiang
Published: March 2020

Laminar diffusion flame was used to study the effect of ethanol on n-heptane flame in terms of the morphology and microstructure of soot under atomization combustion. For the same carbon mass flux at the outlet of the burner, the ratio of ethanol doping in n-heptane was changed, and the soot was collected from the axial positions of the flame at different heights using the thermophoresis probe method. The results showed that the flame height increased significantly with the increasing ratio of ethanol doping. When the ratio of ethanol and n-heptane (CE/CN) was 1.5, the flame height increased by 10 mm compared with that of pure n-heptane flame. Besides, the temperature in the center of the flame decreased with the increasing ratio of ethanol doping, but the temperature in the low position was higher than that in the pure n-heptane flame, and the temperature in the high position was lower than that in the pure n-heptane flame. However, the flame temperature was the highest when the proportion of ethanol in the mixture was greater than that of n-heptane. The temperature at the flame center decreased with the increasing ratio of ethanol doping, while the temperature at the flame edge increased with the ratio. The primary particle size of soot (soot size hereafter) in all working conditions increased with the increase of flame height, which was in line with the general growth law of soot. Moreover, the soot size at the same height decreased with the increasing ratio of ethanol doping, and this trend was most obvious at the flame height of 20 mm and 30 mm. Compared with pure n-heptane, when CE/CN was 1.5, the soot size at 20 mm and 30 mm decreased by an average of 34.83%, indicating that ethanol could inhibit the surface growth of soot particle. Furthermore, the density of soot particles collected by a single copper net decreased significantly, indicating that ethanol could reduce the production amount of soot.
Chemopreventive Effects and Antioxidant Capacity of Combined Leaf Extracts of Sesamum angustifolium (Oliv.) Engl. and Hibiscus articulatus on Rhabdomyosarcoma
Authors: Siamayuwa Clayton E. , Nyanga Loveness K. , Chidewe Cathrine
Published: March 2020

Sesamum angustifolium (Oliv.) Engl. and Hibiscus articulatus contain compounds that have antimutagenic properties. The rise in rhabdomyosarcoma in paediatrics and prognosis of the disease in infants compared to adults calls for newer, less toxic alternatives in treatment of the disease. The aim of this study was to determine the anticancer activity and antioxidant capacity of combined leaf extracts of Sesamum angustifolium (Oliv.) Engl. and Hibiscus articulatus (SAHA), against rhabdomyosarcoma (RMS) using rhabdomyosarcoma (RD) cell line and mouse (L20B) cell line. Cytotoxicity, morphology, apoptosis induction, and antioxidant capacity assays were done. Of the four solvents used for extraction, the dichloromethane SAHA extract was the most cytotoxic with IC50 of 106 μg/mL after doxorubicin, the reference anticancer drug with IC50 of 0.8 μg/mL. The SAHA extracts had a stronger cytotoxicity effect on the cancerous RD cells than on normal L20B cells. Morphological assessment showed untreated cells maintained their normal striated appearance of muscle cells whereas cells treated with doxorubicin or SAHA extracts exhibited cell shrinkage, loss of surface adherence, reduced cell density along with cell debris, which is a characteristic of apoptosis. Normal L20B cells when treated with doxorubicin or SAHA extracts, maintained their cell shape, and remained adherent to the surface. The apoptotic enzyme caspase‐3 was induced in a concentration dependent manner upon treatment of the RD cells with SAHA extracts or doxorubicin. Induction of caspase‐3 was ten times less in treated L20B cells compared to the RD cells. Low induction of caspase‐9 enzyme was observed in both treated RD and L20B cells. Treatment of both RD and L20B cells with SAHA extracts or doxorubicin resulted in increased activity of peroxidase and reduction of oxidative stress. Results of the study show that the SAHA extracts are potential sources of compounds that may serve as useful agents for treatment of rhabdomyosarcoma.
Acute Lymphoblastic Leukemia Presenting Initially as Spinal Cord Compression: When Chemotherapy Alone Is Enough
Authors: Jang Albert , Kram Kallie N. , Berger Scott N. , Gaballa Mahmoud R. , Lu Lee B. , Dunaway David R. , Miller-Chism Courtney N.
Published: March 2020

Spinal cord compression (SCC) is a rare initial presentation and complication of acute lymphoblastic leukemia (ALL) with nearly all reported cases occurring in the pediatric population. We report a 38-year-old previously healthy man who presented with acute on chronic lower back pain, gait instability, urinary retention, and severe thrombocytopenia. Radiologic examination revealed two soft tissue masses of the thoracic spine associated with compression fractures causing spinal canal narrowing and cord compression. Bone marrow biopsy confirmed the diagnosis of ALL. Immediate initiation of high-dose corticosteroids and systemic chemotherapy resolved the patient’s symptoms without radiation therapy or surgical intervention. After two courses of chemotherapy, the patient achieved complete remission in the bone marrow. Rapid administration of chemotherapy alone in this case resulted in a complete resolution of SCC. Given the rarity of this complication in adults, no standardized treatment has been established. The success of this case recommends chemotherapy as the initial management of SCC in chemotherapy-naïve ALL.
Modeling and Risk Analysis Using Parametric Distributions with an Application in Equity-Linked Securities
Authors: Choi Sun-Yong , Yoon Ji-Hun
Published: March 2020

In this study, we model the returns of a stock index using various parametric distribution models. There are four indices used in this study: HSCEI, KOSPI 200, S&P 500, and EURO STOXX 50. We applied 12 distributions to the data of these stock indices—Cauchy, Laplace, normal, Student’s t, skew normal, skew Cauchy, skew Laplace, skew Student’s t, hyperbolic, normal inverse Gaussian, variance gamma, and general hyperbolic—for the parametric distribution model. In order to choose the best-fit distribution for describing the stock index, we used the information criteria, goodness-of-fit test, and graphical tail test for each stock index. We estimated the value-at-risk (VaR), one of the most popular management concepts in the area of risk management, for the return of stock indices. Furthermore, we applied the parametric distributions to the risk analysis of equity-linked securities (ELS) as they are a very popular financial product on the Korean financial market. Relevant risk measures, such as VaR and conditional tail expectation, are calculated using various distributions. For calculating the risk measures, we used Monte Carlo simulations under the best-fit distribution. According to the empirical results, investing in ELS is more risky than investing in securities, and the risk measure of the ELS heavily depends on the type of security.
Abstract A010: Development of OVA-expressing immunogenic syngeneic mouse tumor models: CT26-OVA and B16-OVA
Authors: Jin Ying , Wang Phillip Shuzong , Li Zhongliang , An Annie Xiaoyu , Zhou Jiahua , Li Henry Qixiang , Ouyang Davy Xuesong
Published: March 2020

Background: Syngeneic homograft mouse tumor models have been the workhorse for investigating immuno-oncology (I/O) therapeutics. However, there are limited number of such models available, and among them, only a few respond to immune checkpoint inhibitors (ICI). One potential reason for the ICI-insensitivity may be their intrinsic low-/non-immunogenicity. Chicken ovalbumin (OVA) is a protein known to be highly immunogenic, and engineered syngeneic cell line expressing OVA could potentially render the cell more immunogenic, thus providing further tools for I/O research. To this end, we developed immunogenic variants of both colon cancer CT26.WT and melanoma B16-F10 syngeneic tumors by introducing the OVA transgene. Method: CT26.WT and B16-F10 cells were transduced by lentiviral vector (pLVX-EF1a-IRES-PURO) with a chicken ovalbumin coding cDNA and selected in culture in the presence of the antibiotic puromycin. OVA expression was confirmed by Western blotting analysis and the cells denoted as CT26-OVA and B16-OVA. The engineered cells were evaluated for tumorigenicity following subcutaneous (SC) implantation in immune competent mice and for in vivo/in vitro response to anti-PD-1 treatment. Mice bearing CT26-OVA and B16-OVA tumors were treated with anti-PD-1 antibodies (10mg/kg) or vehicle (intraperitoneally (IP) twice weekly for 3 weeks). Tumors were collected at termination and subjected to flow analysis for the frequency of total tumor-infiltrating CD8+T cells and H-2Kb-restricted OVA tetramer (SIINFEKL)-positive cells. Results: OVA-expressing models showed slower SC tumor growth compared to the parental lines, which was probably due to immune-mediated rejection. Both B16-OVA and CT26-OVA produced a higher sensitivity to anti-PD-1 treatment, superior to corresponding untransduced parental models. In addition, adoptive T cell transfer was conducted by isolating CD3+ T cells from the cured mice and subsequent inoculation into recipient mice in order to verify the presence of tumor-specific memory T cells. Conclusion: Our preliminary results indicate that CT26.WT and B16-F10 OVA-expressing engineered syngeneic models had a higher immunogenic profile, which resulted in enhanced response to ICI, thus providing additional models for I/O research.

Citation Format: Ying Jin, Phillip Shuzong Wang, Zhongliang Li, Annie Xiaoyu An, Jiahua Zhou, Henry Qixiang Li, Davy Xuesong Ouyang. Development of OVA-expressing immunogenic syngeneic mouse tumor models: CT26-OVA and B16-OVA [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A010. doi:10.1158/1535-7163.TARG-19-A010
Abstract A020: 1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one from Betula platyphylla impairs autophagy and induces apoptosis in lung cancer cells
Authors: Jung Hyun Jin , Kang Ju-Hee , Oh Seung Hyun
Published: March 2020

Aim of the Study: Betula platyphylla (BP) is a representative medicinal herb used in the treatment of various inflammatory diseases in East Asia. The purpose of this study was to identify the active components of BP extracts and examine the cytotoxic effect of constituents through specific biological mechanisms that regulate the chemotherapeutic activity in lung cancer cells. Materials and Methods: We performed MTT assays, colony formation assays, flow cytometry assays, western blot analysis, and used fluorescence microscopy after transfection with plasmids to study the molecular mechanisms and chemotherapeutic effects of BP extracts and its active components. Results: We observed that BP extracts and 1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one (BE1), one of the components of BP, effectively decreased the cell viability of several lung cancer cell lines. BE1-treated cells exhibited apoptosis induction and cell cycle arrest at the G2/M phase. Further examination demonstrated that BE1 treatment resulted in suppression of autophagy, as evidenced by increased protein expression levels of both LC3 II and p62/SQSTM1. Interestingly, the pharmacological induction of autophagy with rapamycin remarkably reduced the BE1-induced apoptosis, indicating that apoptosis induced by BE1 was associated with autophagy inhibition. Our data also demonstrated that BE1 exposure activated the p38 pathway resulting in regulation of the pro-apoptotic activity. Conclusion: Taken together, we believe that BE1 is a potential anticancer agent for human lung cancer, which exerts its effect by enhancing apoptosis via regulating autophagy and the p38 pathway.

Citation Format: Hyun Jin Jung, Ju-Hee Kang, Seung Hyun Oh. 1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one from Betula platyphylla impairs autophagy and induces apoptosis in lung cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A020. doi:10.1158/1535-7163.TARG-19-A020
Abstract A046: Pre-clinical assessment of neratinib sensitivity and biomarkers of response
Authors: Conlon Neil T , Kooijman Jeffrey J , Zaman Guido JR , Diala Irmina , Lalani Alshad , Crown John , Collins Denis M
Published: March 2020

Introduction: Neratinib is an irreversible pan-HER inhibitor that has shown clinical activity against HER2-amplified (HER2+) and HER2-mutated cancers. Alteration in HER2 is currently the only biomarker of sensitivity to neratinib. To examine other potential biomarkers of sensitivity, we evaluated neratinib as a single agent in a panel of 108 cancer cell lines from 25 different primary tumour sites. In order to determine possible biomarkers of response, correlation analysis was performed to assess the relationship between genomic alterations or gene expression levels of oncogenes and neratinib response. Methods: Sensitivity to neratinib was assessed in 108 cancer cell lines (Oncolines™) by ATPlite assay after 72-hour treatment. Pearson correlation analysis was carried out between the gene expression profile of 361 relevant cancer genes for 94 of the 108 cell lines (CCLE) and neratinib sensitivity (10logIC50 values). The neratinib gene expression profile was then compared to > 160 reference compound profiles to exclude false positives. The mutation and copy number status of established oncogenes and tumour suppressor genes was sourced from COSMIC cell lines project and CCLE and compared to neratinib IC50 values by ANOVA and t-test. Results: Neratinib had a potent anti-proliferative effect across numerous cancer types, achieving an IC50 value of < 500 nM in 18 of the 108 cell lines; including breast, lung, pancreatic, colorectal, bladder, head and neck, and cervical cancers. Overall, no significant difference was observed between solid and haematological cancers. As expected, ERBB2-amplification, over-expression, and mutation correlated with neratinib response. However, sensitivity was also significantly correlated with EGFR mutations/ amplification/over-expression, amplification of MRPS28 (p=5.2 x 10-5), mutations in BRCA2 (p=0.02) and FBXW7 (p=0.008), and with both CNVs and mutations in SMAD4 (p=0.007) and PTEN (p=0.02). Gene expression of ERBB2 and RAC1, which can be activated downstream of HER2, positively correlated to neratinib response compared to reference compounds. Conclusions: Neratinib displayed broad-spectrum pre-clinical efficacy across numerous cancer types outside of HER2+ breast cancer. This study identified several novel markers of response to neratinib, which warrant further validation.

Citation Format: Neil T Conlon, Jeffrey J Kooijman, Guido JR Zaman, Irmina Diala, Alshad Lalani, John Crown, Denis M Collins. Pre-clinical assessment of neratinib sensitivity and biomarkers of response [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A046. doi:10.1158/1535-7163.TARG-19-A046
Abstract A053: Significance of Transglutaminase 2 expression on clinical outcome in metastatic renal cell carcinoma
Authors: Beom Seung-Hoon , Park Sejung , Kwon Woo Sun , Shin Sang Joon , Kim Soo-Youl , Cho Nam Hoon , Rha Sun Young
Published: March 2020

Background: A few recent studies have demonstrated a possible role of transglutaminase 2 (TG2) in tumorigenesis or progression of renal cell carcinoma (RCC). The aim of this study was to examine TG2 expression and its clinical significance in patients with metastatic clear cell RCCs (ccRCCs). Methods: We analyzed 206 metastatic ccRCC patients who received the first-line vascular endothelial growth factor (VEGF) targeted therapy including sunitinib (n = 33), pazopanib (n = 120), and sorafenib (n = 53) between 2006 and 2016. The expression of TG2 was determined by immunohistochemistry and categorized into four groups, according to membranous staining intensity: negative (0), mild (1+), moderate (2+), and strong (3+). Results: TG2 staining intensity was negative in 20.9% of ccRCC (n = 43), 1+ in 46.6% (n = 96), 2+ in 9.71% (n = 20), and 3+ in 22.8% (n = 47). The survival analysis showed a significant association between stronger TG2 expression (≥ 2+) and worse progression-free survival (PFS) (P = 0.032) in the 1st line VEGF-targeted therapy. On multivariate analysis including previous nephrectomy, number of metastatic organs, and International Metastatic RCC Database Consortium Risk Score, stronger TG2 expression was a significant independent predictive indicator for poor PFS (P = 0.004). Conclusions: Our study is the first to demonstrate the significance of TG2 expression on clinical outcome in metastatic ccRCCs. TG2 expression was a significant negative predictive marker for PFS in 1st line VEGF-targeted therapy and targeting TG2 may be a new therapeutic approach to metastatic ccRCC.

Citation Format: Seung-Hoon Beom, Sejung Park, Woo Sun Kwon, Sang Joon Shin, Soo-Youl Kim, Nam Hoon Cho, Sun Young Rha. Significance of Transglutaminase 2 expression on clinical outcome in metastatic renal cell carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A053. doi:10.1158/1535-7163.TARG-19-A053
Abstract A054: Extracellular vesicles modulate glioblastoma intratumor heterogeneity and treatment resistance
Authors: Schweiger Markus W , Tabet Elie , Li Mao , Tian Tian , Zinter Max , Fleming Renata , Carvalho Litia A , Saad Michael J , Tannous Bakhos A
Published: March 2020

Glioblastoma (GBM) is the most common primary malignant brain tumor and despite optimal treatment, long-term survival remains uncommon. GBM can be roughly divided into three different molecular subtypes, each varying in aggressiveness and treatment resistance. Interestingly, recent evidence shows plasticity between these subtypes in which the proneural (PN) glioma stem-like cells undergo transition into the more aggressive mesenchymal (MES) subtype leading to therapeutic resistance. Extracellular vesicles (EVs) are membranous structures secreted by nearly every cell and have been shown to play a key role in GBM progression by acting as multifunctional signaling complexes. Here we show that EVs derived from MES cells educate PN cells to increase stemness, cell proliferation, tumor aggressiveness, and therapeutic resistance by modulating mesenchymal transition through NF-κB activation. Our findings could potentially help to explore new treatment strategies for GBM and indicate that EVs may also play a role in the mesenchymal transition of different tumor types.

Citation Format: Markus W Schweiger, Elie Tabet, Mao Li, Tian Tian, Max Zinter, Renata Fleming, Litia A Carvalho, Michael J Saad, Bakhos A Tannous. Extracellular vesicles modulate glioblastoma intratumor heterogeneity and treatment resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A054. doi:10.1158/1535-7163.TARG-19-A054
Abstract A069: Mechanisms governing the transcriptional regulation of the liver-specific transporter OATP1B3 in prostate cancer
Authors: Barbier Roberto H , McCrea Edel M , Strope Jonathan D , Huang Phoebe A , Sissung Tristan M , Price Douglas K , Chau Cindy H , Figg William D
Published: March 2020

Background: The testosterone uptake transporter OATP1B3 is expressed de novo in prostate tumors and SLCO1B3 gene (encoding OATP1B3) variants are associated with clinical outcomes in patients with prostate cancer receiving androgen deprivation therapy (ADT) and in castration-resistant disease. These findings support the role of OATP1B3 as a major physiologic contributor to androgen distribution and a contributor to resistance to ADT. We have previously shown CBP/p300-mediated SLCO1B3 expression; however, specific transcriptional regulation of de novo expression remains to be elucidated. We characterized the SLCO1B3 promoter in order to better understand the regulatory mechanisms that govern its expression in prostate cancer. Methods: Functional analysis of the SLCO1B3 promoter was conducted using 5’ deletion mutagenesis. Transcriptional activity of the SLCO1B3 gene was measured using the SLCO1B3 promoter-luciferase reporter plasmids, transient transfections and luciferase reporter assays. Promoter activity was modulated by co-transfection with the p300 expression plasmid or treatment with various p300 inhibitor compounds (chetomin, HATi II, or C646). Results: We detected different transcriptional profiles across multiple prostate cancer cells (22Rv1, LNCaP, PC3) and identified a conserved domain responsible for SLCO1B3 transcriptional activity. Variable transcriptional changes in response to p300 inhibitor treatments were observed in both the conserved domain plasmid and the full-length reporter with the HATi II compound showing a consistent 2 to 3-fold increase in luciferase activity. Putative transcription factor binding sites are being evaluated by site-directed mutagenesis to determine potential regulatory elements involved in transcriptional activity of the gene. Conclusions: Our data suggest that several multi-protein transcription factor complexes assemble at distinct regulatory elements in the SLCO1B3 promoter, driving tissue-specific expression of OATP1B3 in prostate cancer. Understanding the underlying regulatory mechanisms of OATP1B3 expression and the transporter’s role in prostate cancer progression will aid in its development as a potential therapeutic target.

Citation Format: Roberto H Barbier, Edel M McCrea, Jonathan D Strope, Phoebe A Huang, Tristan M Sissung, Douglas K Price, Cindy H Chau, William D Figg. Mechanisms governing the transcriptional regulation of the liver-specific transporter OATP1B3 in prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A069. doi:10.1158/1535-7163.TARG-19-A069
Abstract A081: Phase I study of mesothelin-targeted immunotoxin LMB-100 given as a long infusion
Authors: Alewine Christine , Ahmad Mehwish Iqra , Peer Cody J , Steinberg Seth , Figg William D , Hassan Raffit , Pastan Ira
Published: March 2020

Purpose: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting and a modified Pseudomonas exotoxin A payload. Previous Phase 1 clinical testing of a 30-minute LMB-100 infusion format identified dose-limiting toxicity (DLT) of capillary leak syndrome (CLS) and a serum half-life of ~60 minutes. Pre-clinical data suggested that extending infusion time could improve anti-tumor efficacy by increasing tumor cell duration of exposure to LMB-100. The primary objective of this study was to determine the safety and tolerability of administering LMB-100 over a longer infusion time. We hypothesized that reduced CMAX would result in decreased severity of off-target toxicities like CLS without decreasing anti-tumor activity. Patients and Methods: Patients (n = 15) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; mesothelioma, colon adenocarcinoma, ampullary carcinoma) treated on 3 dose levels received long infusion (24-48 hours) LMB-100 (65 or 100 mcg/kg/day) with or without a loading dose (40 mcg/kg over 30 minutes) for up to 2 cycles. Safety and tolerability, pharmacokinetics, immunogenicity and anti-tumor activity were assessed. Results: DLT of proteinuria (grade 3) was observed in 1 of 6 patients receiving 100 mcg/kg/day over 48 hours with pre-load. Three of 6 patients at this dose level developed significant CLS (>5 kg weight gain from fluid edema) that was not dose-limiting. No CLS was observed in the 6 patients who received 100 mcg/kg over 24 hours on days 1 and 4 with pre-load. Increased immunogenicity was observed with the long infusion compared to standard administration format: 8 of 9 patients receiving 2nd cycle treatment had undetectable plasma LMB-100 concentration during this cycle that was associated with the development of high titer anti-LMB-100 antibodies. Progressive disease was observed in 11 of 12 evaluable patients, and none of 8 evaluable patients with pancreatic adenocarcinoma had a clinically significant decline in CA 19-9 tumor marker. Conclusions: Long infusion format of delivery for LMB-100 can reduce CLS but increases immunogenicity. No anti-tumor activity was observed.

Citation Format: Christine Alewine, Mehwish Iqra Ahmad, Cody J Peer, Seth Steinberg, William D Figg, Raffit Hassan, Ira Pastan. Phase I study of mesothelin-targeted immunotoxin LMB-100 given as a long infusion [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A081. doi:10.1158/1535-7163.TARG-19-A081
Abstract A104: Nanoformulations of PARP and CDK inhibitors for cancer therapy
Authors: Singh Bijay , Yang Shicheng , Baldwin Paige , Ven Anne van de , Sridhar Srinivas
Published: March 2020

Poly(ADP-ribose) polymerase (PARP) inhibitors have been majorly utilized in cancers with BRCA1/2 mutations that have deficiencies in the homologous recombination (HR) DNA repair pathway. Traditionally, PARP inhibitors have been administered through oral route in the clinic but they have resulted in poor bioavailability, low tumor accumulation and high systemic toxicity. Moreover, tumors develop resistance to PARP inhibitors necessitating the development of strategies to re-sensitize these resistant tumors. To overcome these limitations, nanoparticle drug formulation has demonstrated a great potential to increase the drug concentration and accumulation at tumor sites with low systemic toxicities. Here we report the development of several nanoformulations of PARP inhibitors and observe their efficacies by systemic administration to treat various cancer diseases. We used two FDA approved PARP inhibitors (Olaparib or Talazoparib) for nanoformulations of NanoOlaparib and NanoTalazoparib, decorated with EpCAM or EGFR antibody, and tested on breast, ovarian, prostate and lung cancer with or without irradiation. In HR deficient models, the nanoformulations showed significant inhibition of tumor cell growth in vitro and in vivo. Above all, combination of PARP inhibitor with irradiation resulted in greater efficacy in lung and prostate cancer models. To overcome PARP inhibitor resistance, we formulated nanoparticles, NanoDinaciclib of cyclin-dependent kinase 12 (CDK12) inhibitor (dinaciclib) and used in combination with nanoformulation of PARP inhibitor to arrest the tumor growth in animal model. Our current research reveals that the use of CDK12 inhibitor in PARP resistant tumors further arrests tumor growth compared with monotherapy alone. Further studies will help clarify to achieve clear understanding of the mechanism of action CDK12 inhibitor to determine the best way to use PARP inhibitors beyond HR deficiency.

Citation Format: Bijay Singh, Shicheng Yang, Paige Baldwin, Anne van de Ven, Srinivas Sridhar. Nanoformulations of PARP and CDK inhibitors for cancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A104. doi:10.1158/1535-7163.TARG-19-A104
Abstract A106: A peptide based on transmembrane domain of S1PR4 as a tumor cell growth inhibitor
Authors: Yoshida Tetsuhiko , Tanaka Kenichi , Asakawa Shuichi , Sawada Makoto , Hasegawa Yoshinori , Nakase Ikuhiko , Kobayashi Nahoko Bailey
Published: March 2020

Background: Many anti-tumor agents are used in chemotherapy for cancers. However, they also have serious side effects because they express similar growth inhibitory activity in normal cells. Meanwhile, the development of molecular target drugs inhibiting biomolecules relating to tumor growth, invasion, and metastasis has been proceeding with the goal of selectively attacking cancer cells. It has been revealed that the proliferation of cancer stem cells involved in redevelopment, invasion, and metastasis is promoted by sphingosine-1-phosphate (S1P). We focused on the transmembrane domains of sphingosine 1 phosphate receptor 4 (S1PR4), and hypothesized that peptides which utilized these domains would exhibit a selective anti-tumor effect in cancer cells. We designed peptides based on the transmembrane domains of S1PR4 and evaluated whether the peptides showed tumor cell growth inhibitory activity against various kinds of human tumor cells. Material and methods: We chemically synthesized conjugation peptides of the human S1PR4 transmembrane domain sequences and a cell-penetrating peptide HIV TAT. The peptides were evaluated for growth inhibitory activity against human melanoma, non-small cell lung cancer (NSCLC),kidney cancer by WST assay. Results: The peptide based on the S1PR4 transmembrane domain 2 exhibited the strongest anti-tumor activity in the synthesized peptides based on the domain from 1 to 7. The result was that more than 95% of the tumor cells were inhibited in cells treated with a concentration of 25μM for 48 hours. Conclusions: We demonstrated a novel strategy for discovering an anti-tumor molecule by focusing on transmembrane domains of proteins involved in the proliferation of cancer cells. In particular, the peptide based on the transmembrane domain 2 of S1PR4 exhibits remarkable anti-tumor activity against human melanoma, NSCLC, kidney cancer which suggests that the peptide could be a candidate for a new anti-tumor agent. COI: I/we (in case of co-authors) have no potential conflict of interest to disclose

Citation Format: Tetsuhiko Yoshida, Kenichi Tanaka, Shuichi Asakawa, Makoto Sawada, Yoshinori Hasegawa, Ikuhiko Nakase, Nahoko Bailey Kobayashi. A peptide based on transmembrane domain of S1PR4 as a tumor cell growth inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A106. doi:10.1158/1535-7163.TARG-19-A106