tbuckley/cabot-search huggingface dataset:
Abstract 365: Targeted Delivery of IGF-1 Following Acute Myocardial Infarction
Authors: Raffay S Khan, Jay C Sy, Milton Brown, Mario D Martinez, Niren Murthy, Michael E Davis
Journal: Circulation Research (2012)

During acute myocardial infarction (MI) there is excessive necrosis of myocardial cells, leading to the release of large amounts of DNA, representing a potential target for drug delivery. Hoechst, a commonly used molecule for staining nuclei, binds to the minor groove of double-stranded DNA and can be functionalized to contain reactive groups such as free amines, sulfhydryls, and biotin moieties. Insulin-like growth factor-1 (IGF-1), a small molecule with a short half-life is protective immediately following MI, though there is potential for long-term toxicity and off-target effects. Therefore, we hypothesized that conjugating IGF-1 to Hoechst would increase targeting of IGF-1 to the injured myocardium. Hoechst-IGF1 (H-IGF1) was synthesized by binding Hoechst-biotin to biotinylated IGF-1 via a fluorescent streptavidin linker. Intact cells did not show nuclear staining with H-IGF1, while permeabilized cells had a significant increase in blue fluorescent Hoechst staining, indicating H-IGF1 was cell impermeable but could still bind DNA. Activity of H-IGF1 was demonstrated by Akt phosphorylation in cultured cardiac progenitor cells and was similar to native IGF-1. To determine in-vivo targeting of H-IGF1 to MI, mice underwent 30 minutes of coronary artery ligation followed by reperfusion (I/R). Six hours following MI, mice were injected intravenously with 70ng of H-IGF1, S-IGF1 (streptavidin bound IGF-1 only) or PBS followed by in vivo imaging at 30 and 120 minutes post-injection. At 30 minutes post-injection, we found 3.2% (2.2 of 70ng) of the injected dose of H-IGF1 in infarcted hearts compared with 1.8% (1.3 of 70ng) of S-IGF1 (n=5-7; p&lt;0.05). To confirm that targeting of H-IGF1 was dependent on binding DNA, H-IGF1 pre-bound to double-stranded DNA was injected intravenously after I/R. This led to a significant (p&lt;0.05) decrease in targeted IGF-1 levels. IGF-1 levels determined by ELISA 2 hours post-injection demonstrated a similar trend with increased targeting of H-IGF1 compared with S-IGF1 treated mice (4.2±0.6 ng vs. 2.4±0.2 ng; p&lt;0.05). In conclusion, our data demonstrate that intravenous delivery of Hoechst-conjugated IGF-1 increases myocardial targeting. This provides a novel strategy for delivery of growth factors for the treatment of MI.
Abstract 3106: Targeted delivery via Elastin Like Polypeptide: Biodistribution of a doxorubicin derivative in MDA-MB231 human breast cancer xenografts in mice
Authors: Sonja Dragojevic, Jung Su Ryu, Felix Kratz, Drazen Raucher
Journal: Cancer Research (2017)

Abstract The anticancer agent doxorubicin has been widely used in the treatment of a variety of hematological malignancies and solid tumors. Despite doxorubicin’s efficiency in eradicating tumor cells, severe damage to healthy tissues, along with cardiotoxicity, limits its use in clinics. To overcome adverse side effects, improve patient safety, and enhance therapeutic efficacy, we have designed a thermally responsive biopolymer doxorubicin carrier that can be specifically targeted to tumor tissue by locally applying mild hyperthermia (41 degrees C). The developed drug vehicle is composed of: a cell penetrating peptide (SynB1) to promote tumor and cellular uptake; thermally responsive Elastin like polypeptide (ELP); and the (6-maleimidocaproyl) hydrazone derivative of doxorubicin (DOXO-EMCH) containing a pH-sensitive hydrazine linker that releases dox in the acidic tumor environment. We used the in vivo imaging system, IVIS, to determine the biodistribution of doxorubicin-delivered ELP in MDA-MB231 triple negative human breast cancer cell line xenografts in nude mice. Tumor bearing mice were treated with a single IV injection of 10 mg/kg doxorubicin equivalent dose with free doxorubicin, thermally responsive SynB1 ELP 1-DOXO, and a thermally nonresponsive control biopolymer, SynB1 ELP 2-DOXO. Following a 2 hour treatment with hyperthermia, tumors showed a 2-fold higher uptake when treated with SynB1 ELP 1-DOXO compared to free doxorubicin. Accumulation of the thermally non-responsive control SynB1 ELP2 -DOXO was comparable to free doxorubicin, indicating that an increase in dox accumulation with ELP is due to aggregation in response to thermal targeting. Higher levels of SynB1 ELP1 -DOXO and SynB1 ELP2 -DOXO with respect to free doxorubicin were observed in kidneys. Fluorescence intensity from hearts of animals treated with SynB1 ELP1 - DOXO show a 5-fold lower accumulation of doxorubicin than the same dose of free doxorubicin. SynB1-ELP1-DOXO biopolymers demonstrated a 6-fold increase in tumor/heart ratio in comparison to free doxorubicin, indicating preferential accumulation of the drug carrier in tumors. Overall, thermally targeted polymers are a promising therapy to enhance tumor targeting and uptake of anticancer drugs and to minimize free drug toxicity in healthy tissues, representing a great potential for clinical application. Citation Format: Sonja Dragojevic, Jung Su Ryu, Felix Kratz, Drazen Raucher. Targeted delivery via Elastin Like Polypeptide: Biodistribution of a doxorubicin derivative in MDA-MB231 human breast cancer xenografts in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3106. doi:10.1158/1538-7445.AM2017-3106
Abstract 2205: Identification of potential biomarker related to EGFR mutation by functional proteome profiling in primary non-small cell lung cancer
Authors: Yuan-Ling Hsu, Szu-Hua Pan
Journal: Cancer Research (2017)

Abstract Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers which the leading cause of cancer-related death worldwide. Recently, epidermal growth factor receptor (EGFR) activating mutations have been proved relevant to NSCLC and let treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs) become an alternative therapy for NSCLC patients. Despite excellent clinical response to EGFR-TKIs, the intrinsic and acquired resistance to EGFR-TKI created challenges in clinical practice. Although several mechanisms may contribute to solve EGFR-TKIs resistance, there still have 20% to 30% of these patients that how the resistance developed remain unclear. Studies indicated that the increment of membrane efflux may be associated with drug resistance. In this study, we use differential membrane proteomic analysis to identify potential biomarkers for therapeutics of EGFR-TIKs resistance in NSCLC patients.Several primary NSCLC cell lines with different EGFR status were be isolated by our laboratory. Identification of modulators on membrane of primary cancer cells with different EGFR status was analyzed by membrane proteomic assay using LC-MS/ MS. The expression patterns of EGFR mutation cells would compare with that of wild type groups and the potential candidates would be selected by cross the results of interactome profiles of EGFR mutation cell lines. The expression patterns and functional role of these candidates were be examined in NSCLC cells by several molecular, cellular and biochemical analysis; and demonstrated the clinical relevance of these specific targets with EGFR mutation. The expressions of 100 modulators up-regulated in EGFR mutation cells compared with that of wild type group. After cross reacted with the 474 interaction proteins of mutated EGFR, 8 proteins were selected as potential candidates that related to EGFR-TKI resistance, especially the expression of a protein we called SHX in EGFR mutation cells. We demonstrated the real expression levels of SHX in different lung cancer cells, and performed network analysis of SHX and EGFR in translational level.The analysis of differential membrane proteomic found several novelbiomarkers and potential regulation mechanisms that related to the development of EGFR-TKIs resistance in NSCLC. These identification may provide us new direction for exploiting therapeutic strategy for NSCLC treatment in the future. Citation Format: Yuan-Ling Hsu, Szu-Hua Pan. Identification of potential biomarker related to EGFR mutation by functional proteome profiling in primary non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2205. doi:10.1158/1538-7445.AM2017-2205
Abstract 5027: Exome sequencing of cancer-related genes to identify genetic markers for sensitivity to cytotoxic anticancer drugs
Authors: Chihiro Udagawa, Yasushi Sasaki, Hiroshi Suemizu, Yasuyuki Ohnishi, Hiroshi Ohnishi, Takashi Tokino, Hitoshi Zembutsu
Journal: Cancer Research (2017)

Abstract Although the progress in moving from a one-size-fits-all cytotoxic approach to personalized molecular medicine, majority of the patients with cancer receive chemotherapy with cytotoxic anticancer drugs. Exome sequencing of 409 cancer related genes was conducted using 59 DNAs extracted from human tumor xenografts implanted into nude mice, of which sensitivity to nine cytotoxic anticancer drugs (5-fluorouracil (5FU), Nimustine (ACNU), adriamycin (ADR), cyclophosphamide (CPM), cisplatin (DDP), mitomycin C (MMC), methotrexate (MTX), vincristine (VCR), and vinblastine (VLB)) had been examined. We investigated the relationship between the sensitivities of the xenografts to the nine anticancer drugs and single nucleotide variants (SNVs) by classifying them into three groups according to the allele frequency (≤10%, 10-90%, ≥90%). We further carried out replication study using additional set of 20 xenografts. We also estimated the correlation between the expression levels of the 409 genes and sensitivities to the nine drugs in the above xenografts. In the screening stage using 59 xenografts, three SNVs, which were associated with sensitivity to VCR or MMC, showed P &amp;lt; 0.001. We further carried out a replication study of 596 SNVs showing P &amp;lt; 0.05 in the screening stage using independent samples of 20 xenografts. A combined result of the screening and replication studies suggested possible associations of 35 SNVs with sensitivities to the nine anticancer drugs (Pcombined = 0.0011 - 0.035). A total of 35 SNVs showed possible association with sensitivity to at least one of the nine drugs. Of the 35 SNVs, SNV-1 and SNV-2 in a tumor suppressor gene and a oncogene were commonly associated with sensitivity to two or four anticancer drugs, respectively. These findings provide new insights into precision anticancer therapy for the patients with cancer. Citation Format: Chihiro Udagawa, Yasushi Sasaki, Hiroshi Suemizu, Yasuyuki Ohnishi, Hiroshi Ohnishi, Takashi Tokino, Hitoshi Zembutsu. Exome sequencing of cancer-related genes to identify genetic markers for sensitivity to cytotoxic anticancer drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5027. doi:10.1158/1538-7445.AM2017-5027
Conceptualization, development and validation of T‐QoL<sup>©</sup>(Teenagers’ Quality of Life): a patient‐focused measure to assess quality of life of adolescents with skin diseases
Authors: M.K.A. Basra, M.S. Salek, D. Fenech, A.Y. Finlay
Journal: British Journal of Dermatology (2017)

Skin disease can affect the quality of life (QoL) of teenagers in a variety of different ways, some being unique to this age group. To develop and validate a dermatology‐specific QoL instrument for adolescents with skin diseases. Qualitative semistructured interviews were conducted with adolescents with skin disease to gain in‐depth understanding of how skin diseases affect their QoL. A prototype instrument based on the themes identified from content analysis of interviews was tested in several stages, using classical test theory and item response theory models to develop this new tool and conduct its psychometric evaluation. Thirty‐three QoL issues were identified from semistructured interviews with 50 adolescents. A questionnaire based on items derived from content analysis of interviews was subjected to Rasch analysis: factor analysis identified three domains, therefore not supporting the validity of T‐QoL as a unidimensional measure. Psychometric evaluation of the final 18‐item questionnaire was carried out in a cohort of 203 adolescents. Convergent validity was demonstrated by significant correlation with Skindex‐Teen and Dermatology Life Quality Index (DLQI) or Children's DLQI. The T‐QoL showed excellent internal consistency reliability: Cronbach's α = 0·89 for total scale score and 0·85, 0·60 and 0·74, respectively, for domains 1, 2 and 3. Test–retest reliability was high in stable volunteers. T‐QoL showed sensitivity to change in two subgroups of patients who indicated change in their self‐assessed disease severity. Built on rich qualitative data from patients, the T‐QoL is a simple and valid tool to quantify the impact of skin disease on adolescents' QoL; it could be used as an outcome measure in both clinical practice and clinical research.
Abstract 269: The descriptive epidemiology of gynecologic cancers: an international comparison of incidence, survival and mortality
Authors: Zoubida Zaidi, Mokhtar Hamdi Cherif
Journal: Cancer Research (2017)

Abstract Introduction: Gynecologic Cancers are the most common cancers in women, in 2012, Cervical Cancer (CC) is ranking as the fourth with an estimated 528.000 new cases and Ovarian Cancer (OC) is the seventh most common for females with nearly 239.000 new cases worldwide. Aim: this communication presents the latest international descriptive epidemiological data for invasive GC, including incidence, survival and mortality in the worldwide. Methods: -The incidence and mortality statistics presented for GC worldwide were taken from the International Agency for Research on Cancer IARC: * the Cancer Incidence in five Continents Vol X and * GLOBOCAN database, 2012. -The data of cancer survival are taken from: * Cancer survival in five continents, a worldwide population-based study (CONCORD) version 2, 1995-2009. Estimated five-year net survival, adjusted for background mortality by single year of age, sex, calendar year in each country. Results: CC is the most common cancer among women in 45 countries mainly in sub-Saharan Africa, part of Asia and some countries in Central and South America, the lowest incidence rates in western Europe, North America, Australia and the eastern Mediterranean. Almost 55% of all new cases of OC occurred in countries very high level of human development mainly northern Europe and America and Oceanic, Africa presents the lowest incidence. -Data for CC are available for 602 225 women, CC survival was 50% or higher in most countries, except for Libya (Benghazi, 39%) and India (Karunagappally, 46%). During 2005-09, age-standardised 5-year net survival was 70% or higher in Iceland, Mauritius, Norway, South Korea, and Taiwan, for Qatar is also above 70% (based on only 16 cases and is not age-standardised). -Data for ovarian cancer are available for 779 302 women, during 2005-09, age-standardised 5-year net survival was 40% or higher in Ecuador, the USA, nine countries in Asia, and eight countries in Europe. Survival in other countries was mostly in the range 30-40%, except for Libya (22%). Conclusions: The evolution of cancers in women shows a consistent and very striking pattern during the epidemiological transition with rapid declines in the incidence of cervical cancer. Comparison of population-based cancer survival CONCORD study 2 showed very wide variations in survival from gynecologic cancer worldwide. Note: This abstract was not presented at the meeting. Citation Format: Zoubida Zaidi, Mokhtar Hamdi Cherif. The descriptive epidemiology of gynecologic cancers: an international comparison of incidence, survival and mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 269. doi:10.1158/1538-7445.AM2017-269
Abstract LB-241: Quantification of EGFR allele frequency predicts tumor response to EGFR tyrosine kinase inhibitors
Authors: Jin-Soo Kim, Mi Young Kim, Sung-Su Kim, Hyun-jeung Choi, Yunsu Lee, In-Seon Lee, Jin-Hyun Park, Ki Hwan Kim, Hoon Gu Kim, Bong Seog Kim, Young Kee Shin
Journal: Cancer Research (2017)

Abstract Background: EGFR tyrosine kinase inhibitors (TKIs) are current standard treatments for non-small cell lung cancers (NSCLCs) with EGFR mutation. Current diagnostic tests for EGFR mutation include direct sequencing, pyrosequencing or real-time PCR based technology. We have developed a digital droplet PCR based analysis, GenesWell™ ddEGFR Mutation Test (IUO version 5.2. Gencurix Inc., Seoul, Korea). Methods: We have analyzed a total of 325 archived tissue from 233 lung cancer patients treated with gefitinib or erlotinib in the participating 3 hospitals from 2008 to 2013. Samples were analyzed with GenesWell™ ddEGFR Mutation Test and the results were compared with in-house results recorded in each institutional EMR. Results: Since we have analyzed left-over archived tissue, the amount of DNA was inappropriate for analysis in few cases (n=5, 1.5%), which had less than 2ng/uL concentration of DNA. ddEGFR test detected additional EGFR mutations in patients with EGFR wild-type (WT) (N=4), exon 19 deletion (19del) (N=4) and exon 21 L858R (L858R) (N=3) by in-house EGFR test. ddEGFR test detected EGFR mutations in cytology-base samples, such as pleural effusion or ascites. Small amount of sample from CSF and plasma was also detectable with ddEGFR test. Based on in-house EGFR mutation results, response rates (RRs) and disease control rates (DCRs) were as follows: 15.8% and 26.9% in WT, 71.4% and 91.8% in 19del, and 55.9% and 91.2% in L858R. Similarly, RRs and DCRs were as follows, based on ddEGFR results: 13.4% and 43.9% in wild-type (WT), 77.6% and 93.9% in 19del and 54.1% and 86.5% in exon 21 L858R (L858R). Mean allele frequencies were 48.6 (0 - 180.5) in PR, 27.4 (0 - 287.5) in SD, and 9.5 (0-159.6) in PD (P-value, PR vs SD: .0078, PR vs PD: &amp;lt;.000001, SD vs. PD: .029, respectively, Student T-test) Conclusion: The GenesWell™ ddEGFR Mutation demonstrate a high sensitivity for EGFR mutation detection. RRs and DCRs were comparable between in-house EGFR test and ddEGFR. Quantitative analysis of EGFR mutant allele could predict responses to EGFR TKIs. Plasma-based detection of EGFR mutations with ddEGFR are being tested in patients with EGFR mutant lung cancers. Supported by the R&amp;D Program for Society of the National Research Foundation (NRF) funded by the Ministry of Science, ICT &amp; Future Planning (Grant number : 2013M3C8A1078499) Citation Format: Jin-Soo Kim, Mi Young Kim, Sung-Su Kim, Hyun-jeung Choi, Yunsu Lee, In-Seon Lee, Jin-Hyun Park, Ki Hwan Kim, Hoon Gu Kim, Bong Seog Kim, Young Kee Shin. Quantification of EGFR allele frequency predicts tumor response to EGFR tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-241. doi:10.1158/1538-7445.AM2017-LB-241
Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis
Authors: Chandramohan Chitraju, Niklas Mejhert, Joel T. Haas, L. Grisell Diaz-Ramirez, Carrie A. Grueter, Jason E. Imbriglio, Shirly Pinto, Suneil K. Koliwad, Tobias C. Walther, Robert V. Farese
Journal: Cell Metabolism (2017)
Abstract 4899: The small molecule cathepsin L and K inhibitor KGP-94 impairs the metastatic phenotype of osteosarcoma cells
Authors: Henrietta Fasanya, Dietmar Siemann
Journal: Cancer Research (2017)

Abstract Osteosarcoma (OS) is the most common primary malignant bone cancer and primarily affects adolescents between the ages 10-20 years old. Today, OS remains the second leading cause of cancer-related death for patients in this age group. With current therapy, the 5-year survival for patients with clinically metastatic disease has remained unchanged at 20% since the early 1970s. There is a significant need for novel therapies that will increase overall survival for patients with metastatic OS. Proteases secreted within the tumor microenvironment enable primary tumor development and potentiate the ability of OS cells to metastasize. Typically, cysteine proteases under normal physiologic conditions function primarily within the lysosome to facilitate protein cell turnover. During tumorigenesis, Cathepsin L (CTSL) is secreted into the tumor environment by the tumor. CTSL secretion potentiates metastasis through its regulation of cell motility, extracellular matrix degradation, angiogenesis, and bone remodeling. Cathepsin K (CTSK) is overexpressed in OS and is secreted during bone remodeling by osteoclast to degrade the bone matrix. The bone environment is hypoxic which induces proteomic changes that enable OS cells to survive in a nutrient deprived environment and increase CTSL/CTSK secretion by the tumor cells. The goal of these studies was to determine if CTSL/CTSK inhibition via KPG-94 (3-bromophenyl-3-hydroxyphenyl-ketone thiosemicarbazone) could decrease the metastatic phenotype of human osteosarcoma cells under normoxic and hypoxic conditions. The Hu09 cell line has been characterized as an osteoblastic cell line with the potential to grow orthotopically in vivo. Hu09 and its metastatic sublines Hu09-L6 and Hu09-M112 have been characterized to low and high metastatic capacity, respectively. Treatment with KGP-94 at 10 and 25 uM effectively decreases cell motility and invasion of Hu09 and its metastatic sublines under normoxic and hypoxic conditions. Our results demonstrate that dual CTSL/CTSK inhibition is effective at decreasing two signature methods of measuring metastasis: 1) cell motility and 2) invasiveness. Targeting CTSL/CTSK may provide a novel therapeutic approach for patients with metastatic OS. Citation Format: Henrietta Fasanya, Dietmar Siemann. The small molecule cathepsin L and K inhibitor KGP-94 impairs the metastatic phenotype of osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4899. doi:10.1158/1538-7445.AM2017-4899