tbuckley/cabot-search huggingface dataset:
Abstract 4858: LADR™: A novel linker activated drug release technology for drug delivery
Authors: Khalid Abu Ajaj, Stephan David Koester, Friederike Inga Nollmann, Simon Waltzer, Olga Fuchs, André Warnecke, Felix Kratz
Journal: Cancer Research (2016)

Abstract Drug delivery systems in oncology for treating cancer are based on different drug release mechanisms at the tumor site including primarily hydrolytic, reductive, enzymatic and/or acid-sensitive cleavage. Drug carrier conjugates that incorporate an acid-sensitive breaking-point exploit the extra- and intracellular acidic environment of the tumor. Important requirements for acid-sensitive bonds are high stability of the carrier-bound drug in the blood circulation and an effective or sustained release of the active drug in the acidic tumor interstitium and acidic endosomes/lysosomes of tumor cells. In addition, sufficient stability of the acid-sensitive bond is a prerequisite for galenic formulation and reconstitution. As a continuation of our development of aldoxorubicin, an acid-sensitive albumin-binding drug of doxorubicin, which is being clinically assessed in advanced clinical trials (www.cytrx.com), we have set out to design a novel acid-sensitive drug release platform that is applicable to carriers such as serum proteins and antibodies. The key components of this specific drug delivery system are linkers containing a thiol-binding maleimide group and a substituted aromatic hydrazine to form an acid-cleavable hydrazone bond with suitable carbonyl-containing drugs. For establishing and fine-tuning the pH-dependent release profiles, the aromatic moiety of the linker was substituted with a spectrum of electron-withdrawing groups, and reacted with the anthracyclines doxorubicin and nemorubicin. The resulting hydrazone derivatives were conjugated to the cysteine-34 position of albumin as a model protein. Subsequently, the drug release was determined at physiological and acidic conditions as well as in human plasma. It was discovered that by variation of the electron-withdrawing groups, the pH dependent release of the drug could be substantially varied between 1-50 h in the pH range of 4-5. The technology using these linkers was coined LADR™ (Linker Activated Drug Release) and has the additional advantage that the galenic formulation and reconstitution of LADR™-based drugs is facilitated. We have applied the LADR™ technology to several anticancer drugs such as vinblastine and gemcitabine. In summary, LADR™ is an innovative and versatile linker technology creating a platform for developing acid-sensitive drug carrier conjugates that allow the carrier-bound drug to be released in a controlled manner resulting in sustained exposure to cancer cells. Citation Format: Khalid Abu Ajaj, Stephan David Koester, Friederike Inga Nollmann, Simon Waltzer, Olga Fuchs, André Warnecke, Felix Kratz. LADR™: A novel linker activated drug release technology for drug delivery. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4858.
Abstract 1025: A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells
Authors: Wei Li, Guixue Hou, Dianrong Zhou, Xiaomin Lou, Yang Xu, Siqi Liu, Xiaohang Zhao
Journal: Cancer Research (2016)

Abstract The protocatechuic acid ethyl ester ethyl-3,4-dihydroxybenzoate (EDHB) is an antioxidant found in the testa of peanut seeds. The cytotoxic effect of EDHB on esophageal squamous cell carcinoma (ESCC) cells was investigated and 46 up- and down-regulated genes involved in several signaling pathways associated with cell cycle regulation and cellular metabolism were identified. Our studies have shown that EDHB can effectively induce autophagy and apoptosis of esophageal cancer cells by BNIP3 and NDRG1 respectively, and AKR1C family were one of the differentially expressed genes after cells treated with EDHB. We also found that the esophageal cancer cells with higher (KYSE 180) and lower (KYSE 510) AKR1C expressing levels were selected, and the cell proliferation was found inhibited more effectively in KYSE 180 than KYSE 510 cells after treated with EDHB. Furthermore, at the same condition, the effective subunits of AKR1C superfamily, AKR1C1/C2, were identified quantitatively by multiple reaction monitoring (MRM) assays. And the involvement of AKR1C1/C2 in the metabolism of the EDHB in ESCC cells and induced cell death. When autophagy was inhibited using 3-methyladenine (3-MA), KYSE 180 cells exhibited higher sensitivity to EDHB and it may act as metabolic substrate of AKR1C1/C2. These results indicate that esophageal cancer patients with high expression of AKR1C1/C2 are more sensitive to EDHB and facilitate its induced autophagy and apoptosis that providing potential guidance for the chemoprevention of ESCC. Citation Format: Wei Li, Guixue Hou, Dianrong Zhou, Xiaomin Lou, Yang Xu, Siqi Liu, Xiaohang Zhao. A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces cell autophagy and apoptosis in esophageal squamous cell carcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1025.
Disinfection By-Product Exposures and the Risk of Specific Cardiac Birth Defects
Authors: J. Michael Wright, Amanda Evans, John A. Kaufman, Zorimar Rivera-Núñez, Michael G. Narotsky
Journal: Environmental Health Perspectives (2016)

Epidemiological studies suggest that women exposed to disinfection by-products (DBPs) have an increased risk of delivering babies with cardiovascular defects (CVDs).We examined nine CVDs in relation to categorical DBP exposures including bromoform, chloroform, dibromochloromethane (DBCM), bromodichloromethane (BDCM), monobromoacetic acid (MBAA), dichloroacetic acid (DCAA), trichloroacetic acid (TCAA), and summary DBP measures (HAA5, THMBr, THM4, and DBP9).We calculated adjusted odds ratios (aORs) in a case-control study of birth defects in Massachusetts with complete quarterly 1999-2004 trihalomethane (THM) and haloacetic acid (HAA) data. We randomly matched 10 controls each to 904 CVD cases based on week of conception. Weight-averaged aggregate first-trimester DBP exposures were assigned to individuals based on residence at birth.We detected associations for tetralogy of Fallot and the upper exposure categories for TCAA, DCAA, and HAA5 (aOR range, 3.34-6.51) including positive exposure-response relationships for DCAA and HAA5. aORs consistent in magnitude were detected between atrial septal defects and bromoform (aOR = 1.56; 95% CI: 1.01, 2.43), as well as DBCM, chloroform, and THM4 (aOR range, 1.26-1.67). Ventricular septal defects (VSDs) were associated with the highest bromoform (aOR = 1.85; 95% CI: 1.20, 2.83), MBAA (aOR = 1.81; 95% CI: 0.85, 3.84), and DBCM (aOR = 1.54; 95% CI: 1.00, 2.37) exposure categories.To our knowledge, this is the first birth defect study to develop multi-DBP adjusted regression models as well as the first CVD study to evaluate HAA exposures and the second to evaluate bromoform exposures. Our findings, therefore, inform exposure specificity for the consistent associations previously reported between THM4 and CVDs including VSDs. Citation: Wright JM, Evans A, Kaufman JA, Rivera-Núñez Z, Narotsky MG. 2017. Disinfection by-product exposures and the risk of specific cardiac birth defects. Environ Health Perspect 125:269-277; http://dx.doi.org/10.1289/EHP103.
Variation in Health-Related Quality of Life by Line of Therapy of Patients with Chronic Lymphocytic Leukemia
Authors: Neil E. Kay, Christopher R. Flowers, Mark Weiss, Nicole Lamanna, Ian W. Flinn, David Grinblatt, Thomas J. Kipps, Mark Kozloff, Susan Lerner, Jeff Sharman, Ren Yu, Zeba M. Khan, Thomas K. Street, Arlene S. Swern, Kristen A. Sullivan, Chris L Pashos
Journal: Blood (2012)
The Outcome of Mantle Cell Lymphoma patients after Treatment Failure and Prognostic value of Secondary Mantle Cell International Prognostic Index (sec MIPI)
Authors: Marek Trneny, Pavel Klener, David Belada, Heidi Mocikova, Vit Prochazka, Samuel Vokurka, Jan Pirnos, Katerina Kubackova, Juraj Duras, Jana Salkova, David Salek, Robert Pytlik, Lucie Barsova, Petr Kessler, Ludmila Boudova, Vit Campr, Radek Jaksa, Jitka Dlouha, Katerina Benesova
Journal: Blood (2014)
Impact Of Anthracycline Dose Intensification On Minimal Residual Disease and Outcome Of Core Binding Factors Acute Myeloid Leukemias
Authors: Thomas Prebet, Sarah Bertoli, Eric Delabesse, Marie-Joelle Mozziconacci, Anne Etienne, Christian Recher, Françoise Huguet, Norbert Vey
Journal: Blood (2013)
Referendum anger with<i>The BMJ</i>is misdirected
Authors: Jay Ilangaratne
Journal: BMJ (2016)

Some people are irate or irritated at The BMJ ’s view on the EU referendum, which is well referenced and not mendacious.1 The BMJ need not provide any explanation or defence.

It’s well known that, though owned by the BMA, The BMJ has been granted …
A feasibility and safety study of vaccination with Poly-ICLC and peptide-pulsed dendritic cells in patients with advanced pancreatic adenocarcinoma.
Authors: Shikhar Mehrotra, Carolyn D. Britten, Steve Hsukwo Chin, Mohamed L. Salem, Colleen Cloud, Michelle H. Nelson, Chrystal Paulos, Elizabeth Garrett-Mayer, Mark P. Rubinstein, Zihai Li, David J. Cole
Journal: Journal of Clinical Oncology (2016)

e14579 Background: Dendritic cells (DCs) shape the quantity and quality of anti-tumor immunity in patients with cancer. We hypothesized that DC-based immunotherapy, in conjunction with a novel long-lasting TLR3 agonist, Poly-ICLC, is a promising approach against metastatic or locally advanced unrespectable pancreatic cancer (PC). Methods: To address our clinical concept, we generated autologous DCs from peripheral blood monocytes from HLA-A2+ patients with pancreatic cancer (PC) and pulsed DCs with three immunogenic A2-restricted epitopes: human telomerase reverse transcriptase (hTERT, TERT572Y), carcinoembryonic antigen (CEA; Cap1-6D) and survivin (SRV.A2). Patients received four intradermal injections of 1 x 107peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28 and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 µg/Kg on vaccination days (Day 0, 14, 28, and 42), as well as on Days 3, 17, 21, 31, 37 and 45). Our primary objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells. Results: A total of 12 patients underwent leukapheresis: 9 patients with metastatic disease, and 3 with locally advanced unresectable PC. Manufacturing of vaccines was uniformly successful. Study treatment was well tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the 8 patients who underwent imaging on Day 56, 4 had stable disease and 4 had disease progression. Overall, the median survival was 7.7 months from date of leukapheresis. One patient has survived for 28 months. IFN-gamma ELISPOT and MHC class I – tetramer analysis, before and after vaccination, revealed effective generation of antigen-specific T cells in 3 patients with stable disease. Conclusions: Vaccination with Poly-ICLC and peptide-pulsed dendritic cells is safe and induces a measurable tumor specific T cell population in patients with advanced PC. Clinical trial information: NCT01410968.
Abstract 4426: The PEAK1/ZEB1/ITGA1 pathway mediates survival, stemness and TGFbeta-induced EMT in pancreatic cancer
Authors: Armen Gharibi, Sa La Kim, Daniel Brambilla, Yvess Adamian, Malachia Hoover, Joy Lin, Megan Agajanian, Laurelin Wolfenden, Jonathan A. Kelber
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States with a five-year survival rate of approximately 7%. Its highly invasive characteristics, lack of biomarkers for early detection, limited therapeutic targets and inherent resistance to chemotherapy are the central factors that lead to an overall poor prognosis for this malignancy. Since most cancer-related deaths are a result of metastatic tumors, we reasoned that our previously published proteomic signature of the cell pseudopodium (PD) may be a good pool from which to identify novel protein biomarkers or therapeutic targets in pancreatic cancer. We cross-referenced PD enriched proteins with Oncomine and identified 37 genes that are upregulated in pancreatic cancer. The function of integrin alpha 1 (ITGA1), a cell surface receptor for collagen and regulator of cell adhesion, has not been previously characterized in the context of PDAC. Our results indicate that ITGA1 is required for PDAC cell viability, promoting cell survival and tumor growth. We further analyzed ITGA1 cell-surface levels and discovered that ITGA1hi cells represent a subpopulation of Aldehyde Dehyrogenase high (ALDH1hi) cells, and that ITGA1 knockdown reduces the ALDH1hi cell population. One mechanism by which PDAC cells acquire metastatic potential is via epithelial-mesenchymal transition (EMT). Thus, we searched for prominent EMT genes among the top ITGA1 co-expressors using RNA-Seq data from the Cancer Bio Portal. Interestingly, ZEB1 (a transforming growth factor beta, TGFbeta, response gene and central regulator of EMT) and PEAK1 kinase (a protein we’ve shown to be required for pancreatic cancer progression and TGFbeta/ZEB1-induced EMT) co-expresses with ITGA1. We tested the function of ITGA1 on TGFbeta-induced EMT and found that ITGA1 is upregulated by TGFbeta during EMT, and required for metastasis and a complete EMT response to TGFbeta. We also demonstrate that PEAK1 is required for TGFbeta-induced ITGA1 in PDAC cells. Finally, we demonstrate that ITGA1 is responsible for collagen-induced spreading and an EMT-like shift in PDAC cell morphology. Taken together, these results point to a novel TGFbeta/PEAK1/ZEB1/ITGA1 signaling cascade that when targeted can abrogate PDAC cell survival, stemness, EMT and tumor growth/metastasis. Citation Format: Armen Gharibi, Sa La Kim, Daniel Brambilla, Yvess Adamian, Malachia Hoover, Joy Lin, Megan Agajanian, Laurelin Wolfenden, Jonathan A. Kelber. The PEAK1/ZEB1/ITGA1 pathway mediates survival, stemness and TGFbeta-induced EMT in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4426.
Abstract 3643: Flow cytometry multiplexing used to analyze metabolic activity and assess pharmaceutical compound toxicity as a high throughput screening tool
Authors: Mike OGrady, Leticia A. Montoya, Michelle Yan, Scott T. Clarke, Quentin Low, Carolyn DeMarco, April Anderson, Kathy Kihn, Carmen Finnessy, Marcy Wickett, Veronica Calderon
Journal: Cancer Research (2016)

Abstract High throughput screening (HTS) is an extremely effective method for allowing researchers to identify putative active compounds for therapeutics. Recently, flow cytometry has emerged as a powerful HTS tool with the added benefit of cell-by-cell analysis. Flow cytometry allows a researcher to study protein-protein interactions, metabolic activities, as well as DNA content in a single or multiplexed assay format. For this study, we screened the Tocriscreen Total compound library and compared HTS using a plate reader with flow cytometer multiplexing. Peripheral blood mononuclear (PBMCs) and Jurkat cells were used as cell models. Cells were cultured under standard conditions and either at normoxic (5%) or hyperoxic (19%) oxygen levels. We also varied length of time the cells were treated with compound library (24, 48, or 72 hrs). Membrane integrity and metabolic activity were measured as an output for evaluating cellular viability. To further assess cellular activity, post-screening analysis was implemented to establish EC50s of “hits” from compound library. Screening analysis identified target drugs that were further analyzed using cell health readouts with different mechanisms of action to assess compound toxicity. Results indicate that compound “hits” and potency differed in the screen depending on cell type, the mechanistic readout, length of compound exposure, and mode of readout used to perform the HTS experiments. Citation Format: Mike OGrady, Leticia A. Montoya, Michelle Yan, Scott T. Clarke, Quentin Low, Carolyn DeMarco, April Anderson, Kathy Kihn, Carmen Finnessy, Marcy Wickett, Veronica Calderon. Flow cytometry multiplexing used to analyze metabolic activity and assess pharmaceutical compound toxicity as a high throughput screening tool. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3643.
Genomic analysis of Andamanese provides insights into ancient human migration into Asia and adaptation
Authors: Mayukh Mondal, Ferran Casals, Tina Xu, Giovanni M Dall'Olio, Marc Pybus, Mihai G Netea, David Comas, Hafid Laayouni, Qibin Li, Partha P Majumder, Jaume Bertranpetit
Journal: Nature Genetics (2016)
Abstract 2057: Dual peptide-mediated targeted delivery of siRNAs for the treatment of oral cancer
Authors: Angela A. Alexander-Bryant, Haiwen Zhang, William Pugh, Lu Dinh, Christopher Attaway, Laurence Eggart, Robert Sansevere, Liliana Cantini, Andrew Jakymiw
Journal: Cancer Research (2016)

Abstract Two major hurdles for small interfering RNA (siRNA)-mediated therapies are cell/tissue-type targeted delivery and endosomal entrapment of siRNAs, resulting in inefficient gene silencing. As a result, the objective of this study was to examine the feasibility of utilizing two peptides, one with cancer cell-targeting specificity and the second with endosome-disruptive properties, to co-deliver bioactive siRNAs into oral cancer cells overexpressing the epidermal growth factor receptor (EGFR) and induce silencing of the targeted oncoprotein, CIP2A. Previously, we designed a novel endosome-disruptive peptide, termed 599, that was demonstrated to mediate intracellular delivery of bioactive siRNAs targeting CIP2A (siCIP2A) in vitro. Furthermore, we recently demonstrated that 599 peptide-mediated delivery of siCIP2A into tumor tissues via intratumoral injections reduced the expression of CIP2A and significantly inhibited tumor growth. In order to induce targeted uptake via systemic administration, we designed the EGFR targeting peptide, GE11R9, which was found to deliver siRNAs specifically to EGFR-overexpressing oral cancer cells; however, it was incapable of mediating the delivery of bioactive siRNAs due to endosomal entrapment. Consequently, we developed a novel dual peptide delivery strategy, combining the 599 peptide, with the GE11R9 peptide and examined their ability to co-deliver siRNAs. Our results demonstrated that the dual peptide complex exhibited effective binding and specific uptake of siRNAs into EGFR-overexpressing cells compared to low-EGFR-expressing cells. The co-addition of the 599 peptide with the GE11R9 peptide also restored siRNA functionality. Furthermore, when administered systemically to mice bearing xenograft oral tumors, the dual peptide complex mediated increased targeted delivery of siRNAs into tumor tissues in comparison to the 599 peptide alone. Together, these data demonstrate the clinical potential of the dual peptide strategy for RNAi-based therapeutics by synergistically mediating the effective targeting and delivery of bioactive siRNAs into EGFR-overexpressing cancer cells. Citation Format: Angela A. Alexander-Bryant, Haiwen Zhang, William Pugh, Lu Dinh, Christopher Attaway, Laurence Eggart, Robert Sansevere, Liliana Cantini, Andrew Jakymiw. Dual peptide-mediated targeted delivery of siRNAs for the treatment of oral cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2057.
Brexit from current guideline recommendations?
Authors: Paolo Angeli, Salvatore Piano, Vicente Arroyo
Journal: Gut (2016)

Dear Editor,

We appreciate the interest of O'Brien et al in our position paper recently published in Gut .1 O'Brien et al raised a very important question: is human serum albumin (HSA) the best resuscitation fluid in patients with cirrhosis and acute kidney injury (AKI)? In our minds, as in that of almost all experts in this field, the answer is absolutely yes. This certainty is based on several clinical and experimental evidences and cannot be challenged by studies performed in critically ill patients that are inconsistent for this purpose considering (a) the low percentage of patients with cirrhosis who were included and (b) the modest doses of …
Abstract 1618: Thromboxane A2 receptor controls migration and metastasis of triple-negative breast cancer cells
Authors: Yuanqin Zhang, Xuejing Zhang, Daotai Nie
Journal: Cancer Research (2016)

Abstract Background: Triple negative breast cancers (TNBCs) have poor prognosis and there are no effective targeted therapies available. Thromboxane A2 receptor (TBXA2R) is a G protein coupled receptor whose ligand is a prostanoid produced by cyclooxygenase and thromboxane A2 synthase. There are two isoforms of TBXA2R as results of alternative splicing. TBXA2Rα and β differ in the cytoplasmic tail distal at amino acid residue 328. High expression of TBXA2R has been linked with poor progression free survival of breast cancer cells, but it is unknown how TBXA2R contributes to the progression of breast cancers and which isoform(s) is involved. Methods: TBXA2R expression in breast cancer was determined by RT-PCR, Western blot and immunohistochemistry using isoform specific primer sets or antibodies. Small hairpin RNAs and CRISPR-CAS9 were used to knock down or knock out TBXA2R expression. Tumor cell migration was evaluated by wound healing and Boyden chamber assays. Cell proliferation and survival was evaluated by MTS and trypan blue based cell counting. Xenograft models were used to assess breast tumor growth, progression, and metastasis. Results: While TBXA2Rα is ubiquitously expressed in breast cancer cells, TBXA2Rβ is selectively expressed in triple negative breast cancer. Activation of TBXA2R had no discernible effects on proliferation or survival of MDA-MB-231 cells. However, TBXA2R activation led to rapid activation of RhoA and cytoskeletal reorganizations of TNBC cells. TBXA2R activation also led to rapid activation of protein kinase N1 (PKN1), a kinase frequently amplified in TNBCs. Inhibition or depletion of TBXA2R led to reduced tumor cell migration in vitro and prevented breast cancer metastasis in vivo. Further analyses found that inhibition or depletion of TBXA2R compromised the ability of TNBC cells to extravasate in an animal model. Conclusions: Our data suggest that TBXA2R can contribute to TNBC progression and metastasis by controlling tumor cell cytoskeleton reorganization and motility. Citation Format: Yuanqin Zhang, Xuejing Zhang, Daotai Nie. Thromboxane A2 receptor controls migration and metastasis of triple-negative breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1618.