tbuckley/cabot-search huggingface dataset:
341. Nucleic Acid Delivery Using Vesicular Stomatitis Virus-Based Vesicles
Authors: Mathias Mangion, Alexandre Audy, Igor Slivac, Rénald Gilbert, Bruno Gaillet
Journal: Molecular Therapy (2016)

Gene delivery methods are essential to understand fundamental cellular mechanisms and to develop new therapies. Recombinant viruses are efficient to transfer nucleic acids but their safety is a concern. In addition, some commercial transfection reagents (including lipids and cationic polymers) and electroporation methods are cytotoxic. Interestingly, the sole expression of G envelope protein of the vesicular stomatitis virus (VSV) in mammalian cells can lead to the formation of VSV-G pseudotyped vesicles (V-VSV-G). In presence of polybrene, these vesicles are able to transfer plasmids in a large panel of animal cells. Unfortunately, the production of V-VSV-G and their use for nucleic acid delivery is poorly documented. Here we propose to improve this promising method of transfection. At first we developed a V-VSV-G production process by transient transfection of HEK-293 cells using polyethylenimine (PEI). Three modes of production were compared: cells cultivated in adherence, in suspension and on micro-carriers. Also we demonstrated that the quantity of vesicles produced depends on the VSV-G sequence used. The harvest of V-VSV-G from cell culture media was also optimized. Then, several parameters potentially involved in the formation and the transfer efficiency of V-VSV-G/DNA complex were studied: polybrene concentration, order of addition of mix transfection components, incubation time of the complexes, medium of transfection, etc. Stability studies also demonstrated that V-VSV-G are robust particles: DNA transfer capacity of V-VSV-G is efficient after 10 freezing and thawing cycles and V-VSV-G can be stored for long term at +4 °C, -20 °C and -80 °C. Finally, V-VSV-G/DNA ratio was optimized for three different cell types. Transfection efficiency of 70 % and 55 % were obtained for HEK-293 and HeLa cells respectively, with 1 µg of V-VSV-G and 0.4 µg of DNA. Transfection of refractory cells such as human myoblasts, reached 25 % with 5 µg of V-VSV-G and 0.8 µg of DNA. V-VSV-G can also deliver large plasmids (18 kb). Furthermore, no cytotoxicity was observed in cells transfected with these complexes. Presently, the potential of V-VSV-G to transfer siRNA is investigated. In conclusion, V-VSV-G is a powerful tool for nucleic acid delivery which could be useful for several applications oriented toward cell and gene therapies.
Abstract 4230: Targeting lung cancer stem cells through fatty acid metabolism
Authors: Alessia Noto, Maria Elena Pisanu, Claudia De Vitis, Debora Malpicci, Luigi Fattore, Nadia Lobello, Barbara Bonacci, Gennaro Ciliberto, Rita Mancini
Journal: Cancer Research (2015)

Abstract Distinctive features of CSC are capacity of self renewal, increased resistance to chemotherapy and the ability to form three dimensional non adherent spheroids in appropriate conditions. We have recently demonstrated that cell cultures derived from malignant pleural effusion (MPE’s) of patients with adenocarcinoma of the lung efficiently form spheroids in non-adherent conditions supplemented with growth factors. By expression profiling, we identified 18 genes whose expression is significantly upregulated in lung tumor spheroids versus adherent cultures. Among the upregulated genes we found five genes involved in lipid metabolism. SCD1, the enzyme involved in the conversion of saturated into monounsaturated fatty acids, was one of those strongly upregulated. We demonstrated that SCD1 inhibition leads to lung cancer spheroid collapse and to the selective apoptosis of ALDH+ cells, a marker enriched in cells with stem like properties. In line with these results we demonstrated by cell sorting that ALDH positive cells were more sensitive to SCD1 inhibition than ALDH negative cells and that treatment with an SCD1 inhibitor strongly enhanced sensitivity of spheroids cells to Cisplatin. Furthermore, we observed that SCD1 inhibited spheroids were strongly impaired in their in vivo tumorigenicity. Using public datasets from lung cancer we conducted a bioinformatics analysis demonstrating that the survival rate of patients expressing SCD1-high levels was significantly lower than that of the patients expressing low level in lung adenocarcinoma. Moreover, we found that the correlation of SCD1 and stemness markers (nanog, CD44, CD24) selects the patients with bad prognosis. These results overall, indicate that SCD1 could be considered a prognostic markers for lung adenocarcinoma and a potential target for therapeutic intervention. Our studies are currently directed to dissect the mechanism pathways leading to SCD1 upregulation in lung cancer stem cells. Citation Format: Alessia Noto, Maria Elena Pisanu, Claudia De Vitis, Debora Malpicci, Luigi Fattore, Nadia Lobello, Barbara Bonacci, Gennaro Ciliberto, Rita Mancini. Targeting lung cancer stem cells through fatty acid metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4230. doi:10.1158/1538-7445.AM2015-4230
Abstract 5028: CXCL10 within the tumor microenvironment induces gemcitabine resistance in pancreatic cancer cells
Authors: Daniel Delitto, Chelsey Perez, Brian S. Black, Heather L. Sorenson, Andrea E. Knowlton, Song Han, Dongyu Zhang, George A. Sarosi, Lyle L. Moldawer, Kevin E. Behrns, Chen Liu, Thomas J. George, Ryan M. Thomas, Jose G. Trevino, Shannon M. Wallet, Steven J. Hughes
Journal: Cancer Research (2015)

Abstract Background: The systemic treatment of pancreatic cancer (PC) is hindered by the rapid development of chemoresistance to current cytotoxic therapies. Mechanisms governing the development of chemoresistance remain poorly characterized, particularly with respect to contributions from the tumor microenvironment. Thus, the goal of this study was to identify novel mechanisms acting within the tumor microenvironment which lead to PC chemoresistance. Methods: Intratumoral soluble mediator concentrations from resected PC specimens (n = 26) as well as supernatants from co-cultures of primary tumor-associated pancreatic stellate cells (PSCs) and PC cells (n = 12) were evaluated using a panel of 41 growth factors, chemokines and cytokines. The effect of CXCL10, a highly expressed soluble mediator during co-culture, on viability, proliferation, and apoptosis of PC cells was evaluated with and without gemcitabine treatment. In addition, the contribution of CXCL10 on migration patterns of peripheral blood mononuclear cells (PBMCs) was assessed. Results: Co-culture of tumor-associated PSCs with PC cells revealed increased CXCL10 levels compared to either cell type cultured alone. In addition, high intratumoral CXCL10 concentrations correlated with reduced overall survival (HR 6.9; P = .006). While CXCL10 treatment had a small effect on the viability of PC cells, it led to significantly increased PC cell viability in the presence of gemcitabine. Further, gemcitabine treatment induced the expression of the CXCL10 receptor, CXCR3, and this induction of CXCR3 was associated with the absence of apoptotic markers in PC cells. Finally, constitutive expression of CXCL10 by PC cells preferentially led to the migration of regulatory immune cell subsets. Conclusion: Paracrine CXCL10 signaling between stromal, PC and immune cells may be responsible not only for chemoresistance to gemcitabine, but also the recruitment and potential polarization of regulatory immune cell subsets in the pancreatic cancer microenvironment. Citation Format: Daniel Delitto, Chelsey Perez, Brian S. Black, Heather L. Sorenson, Andrea E. Knowlton, Song Han, Dongyu Zhang, George A. Sarosi, Lyle L. Moldawer, Kevin E. Behrns, Chen Liu, Thomas J. George, Ryan M. Thomas, Jose G. Trevino, Shannon M. Wallet, Steven J. Hughes. CXCL10 within the tumor microenvironment induces gemcitabine resistance in pancreatic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5028. doi:10.1158/1538-7445.AM2015-5028
Abstract 4553: Substituted monocyclic pyrimidines as potent tubulin inhibitors that circumvent P-glycoprotein mediated resistance
Authors: Rishabh Mohan, Aleem Gangjee, Ruoli Bai, Ernest Hamel
Journal: Cancer Research (2015)

Abstract Tubulin is involved in several critical cellular functions, including cell division, cell motility and development and maintenance of cell shape. Although microtubule disrupting agents like paclitaxel are highly successful chemotherapeutic agents, these compounds are easily recognized by P-glycoprotein (Pgp) and are pumped out of cancer cells, resulting in resistance to the agent. Thus, these compounds have major limitations against multidrug resistant tumors. Recently, we reported simple, monocyclic pyrimidines with the N-methyl-4′-methoxyaniline moiety at the 4-position. These compounds circumvent some of the important limitations of paclitaxel while preserving its antimitotic activity. To further evaluate the SAR at the 4-position of the pyrimidine scaffold, a series of compounds were designed and synthesized that involved replacing the chloro moiety of the 5-amino-4,6-dichloro-2-methylpyrimidine with various anilines. The replacement of the N-methyl-4′-methoxyaniline moiety of the lead molecule with a conformationally restricted 6′-methoxy-tetrahydroquinoline moiety resulted in potent tubulin assembly inhibition (IC50 = 3.0 ± 0.03 μM) comparable to that observed with combretastatin A-4 (CSA4, IC50 = 1.1 ± 0.1 μM), of which the phosphorylated derivative is currently in clinical trials. It is a potent inhibitor of [3H]colchicine binding (65% at 5 μM concentration) indicating that it binds at the colchicine binding site on tubulin similar to CSA4. Similarly, the monocyclic pyrimidine with a conformationally restricted 4-N-methyl 2′,3′-dihydrobenzofuran moiety was also a potent inhibitor of bovine tubulin assembly. Replacement of the 4′-methoxy of the lead with a 4′-thiomethyl retained potency against tubulin assembly (IC50 = 2.6 ± 0.1 μM). In Pgp overexpressing NCI/ADR-RES cell line, three of the newly synthesized compounds were found to be 1.5-5-fold more potent (IC50 = 170-630 nM) than in the wild type OVCAR-8 cell line, thus, overcoming an important mechanism associated with clinical resistance to paclitaxel. These attributes of the 4-N-substituted monocyclic pyrimidines provide the impetus for further preclinical development of these compounds. Citation Format: Rishabh Mohan, Aleem Gangjee, Ruoli Bai, Ernest Hamel. Substituted monocyclic pyrimidines as potent tubulin inhibitors that circumvent P-glycoprotein mediated resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4553. doi:10.1158/1538-7445.AM2015-4553
Agelastatin A (AgA), a Marine Sponge Derived Alkaloid, Inhibits Wnt/Beta-Catenin Signaling and Selectively Induces Apoptosis in Chronic Lymphocytic Leukemia Independently of p53
Authors: Michael Y. Choi, Johanna Melo Cardenas, Desheng Lu, Jian Yu, E. Paige Stout, Raymond P. Wu, John M Horton, Allison Gomez, Julio A. Diaz-Perez, Dennis A. Carson, Tadeusz F. Molinski, Thomas J. Kipps, Januario E. Castro
Journal: Blood (2011)
Review of RAISE, a Randomized, Double-Blind, Multicenter Phase III Study of Irinotecan, Folinic Acid, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab (RAM) or Placebo (PBO) in Patients (pts) With Metastatic Colorectal Carcinoma (mCRC) Progressive During or Following First-Line Combination Therapy With Bevacizumab (bev), Oxaliplatin (ox), and a Fluoropyrimidine (fp): Primary Results and Subgroup Analysis by KRAS Status
Authors: A. Sobrero, L. Latini, C. Barone, F. Capuzzo, M. Banzi, F. Nasroulah, L. Sims, J. Tabernero
Journal: Annals of Oncology (2015)
Abstract 3919: Inhibition of HER2 and IGF2 in trastuzumab-resistant HER2 positive JIMT1 cells decreases cell growth and reduces activation of MAPK and AKT
Authors: Xousaen M. Helu, Daisy DeLeon
Journal: Cancer Research (2015)

Abstract Breast cancer is the second leading cause of death in women. Overexpression of human epidermal growth factor receptor 2 (HER2) is detected in 20-30% of breast cancers. Increased levels of HER2 are linked to poor prognosis, more aggressive phenotype, and resistance to chemotherapy and hormonal treatment. HER2 is part of a four-member family of cell surface receptors that are implicated in transmission of signals controlling cell growth and differentiation. HER2 has an intracellular domain with tyrosine kinase catalytic activity. Dimerization of HER2 activates the MAPK and AKT pathways. The HER2 receptor also hetero-dimerizes with the IGF1 receptor (IGF1R) in trastuzumab-resistant cells. The insulin-like growth factor 2 (IGF2) has an important role in fetal and cancer development signaling through the IGF1R, insulin receptor (InsR), and a cross-talk with the estrogen receptors alpha and beta (ERα, ERß). Trastuzumab resistance occurs in 70% of patients with HER2 positive breast cancer. Therefore it is important to understand the mechanism of resistance so we can develop new therapies to help patients with trastuzumab-resistant rumors. Previous findings in our lab demonstrate an increased expression of IGF2 in the trastuzumab-resistant cell line JIMT1 when compared to trastuzumab-sensitive cell lines BT474, SKBR3, and ZR75-30. We hypothesize that to overcome trastuzumab-resistance in JIMT1 cells, dual inhibition of the HER2 and IGF2 is necessary to induce cell death. When JIMT1 cells were treated with trastuzumab and an IGF2 blocking antibody (IBA) a decrease in cell viability was observed, but changes in PARP cleavage were not present. We also analyzed the protein and phosphorylation levels of HER2, IGF1R, MAPK, and AKT. Our studies suggest that blocking both HER2 and IGF2 decreases cell viability and reduces phosphorylation of MAPK and AKT. Citation Format: Xousaen M. Helu, Daisy DeLeon. Inhibition of HER2 and IGF2 in trastuzumab-resistant HER2 positive JIMT1 cells decreases cell growth and reduces activation of MAPK and AKT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3919. doi:10.1158/1538-7445.AM2015-3919
72. A Phase l Study of RB94 in Genitourinary Cancers Using a Tumor-Targeted Systemic Nanodelivery System
Authors: Arlene Siefker-Radtke, Xin-qiao Zhang, Charles C. Guo, Kathleen F. Pirollo, Chris P. Leung, Esther H. Chang, Randall E. Millikan, William F. Benedict
Journal: Molecular Therapy (2016)

RB-94 is a truncated form of the RB tumor suppressor gene which has shown marked cytotoxicity in every human tumor type tested to date without affecting normal cells. A systemically administered, tumor-targeted nanocomplex for systemic gene delivery (termed SGT) has been developed. In the SGT nanocomplex, the payload is encapsulated within a cationic liposome. The surface of the liposome is decorated with an anti-transferrin receptor (TfR) single chain antibody fragment (scFv) designed to target cancer cells by binding to the TfR which is highly expressed on tumor cells. Here we describe the results of a DNA dose escalating first-in-man Phase l study of SGT encapsulated RB-94 (SGT-94) for the treatment of metastatic genitourinary tumors. The majority of the cancers treated in this study were bladder cancers. Treatment with SGT-94 was well tolerated with minimal side effects observed. Moreover, among the 11 evaluable patients of 13 treated, a complete remission (CR) in a lung metastasis, two partial remissions (PRs) and three incidences of stable disease (SD) were observed. The CR and PRs occurred at the highest dose (2.4 mg DNA) tested. In addition, there is strong evidence for tumor-specific targeting including data from two resected lung metastases. In these metastatic lesions, the presence of RB94 was documented by both PCR and Western blotting in the tumors. However, RB94 was absent in contiguous normal lung tissue. Therefore, this Phase I study demonstrates not only the safety, but also the anti-cancer potential of the SGT-94 nanocomplex and suggests that additional studies using SGT-94 alone or in combination with chemotherapy, radiation or other modalities are warranted.
Health economic assessments of anticancer agents: A comparison of assessment technologies applied to end-stage cancer.
Authors: S. Kobina, W. R. Simons
Journal: Journal of Clinical Oncology (2011)

e16623 Background: The availability of newer therapeutic options to treat patients with cancer often depend on falling at or below economic value thresholds; namely, dollars per quality adjusted life years (QALY). The issue is that for patients with end stage cancer, these economic values (Cost/ QALY) tend to infinity as life expectancy diminishes. We compare and contrast the application and implications of life years gained (LYG) and Quality Adjusted Life Years (QALYs), when overall survival is less than one year for end stage cancer. Methods: We conducted a systematic search of published and publically available literature using Medline (1980-2010) and Google for: “End Stage Cancer (ESC),” “Life Years Gained (LYG),” and “Quality Adjusted Life Years (QALYs)” and their combinations. Extracted citations were reviewed by two researchers for relevance. Results: The Medline search yielded 7,488 citations for ESC, 2,920 for LYG and 7,138 for QALYs, and 3 and 20 for the combinations of ESC, LYG and QALY. The Google search yield 5 citations, all more on-target to the study aims. LYG is a mortality measure quantifying the incremental net benefit (INB) of two treatment strategies in terms of changes in life expectancy while QALYs weigh life expectancy by a value between 0 (death) and 1 (perfect health). In reviewing quality-weighting survival time, the literature found QALYs were biased with age, disease and how those weights were assessed. Social and personal aversion to risk also sway thQALY measure. LYG lack those design biases, although LYG cannot differentiate safety profiles among anticancer agents. The cancer literature with LYG and QALY did not differentiate between their application to end-stage versus earlier stage, missing economic inefficiencies and a violation of the fundamental axiom of health economic assessments, life is a ‘good’ thing. Conclusions: LYG, a mortality measure, is better suited for end stage cancer than QALY because even small changes in utility weights result in inefficiencies which can under or overestimate the QALY measure and as survival diminishes standard economic theory would predict that any resource use becomes unaffordable.
Abstract 1297: Increases in the numbers of myeloid-derived suppressor cells in Egyptian children with acute lymphoid leukemia
Authors: Mohamed L. Salem
Journal: Cancer Research (2015)

Abstract Background: Acute lymphoblastic leukemia (ALL) or acute lymphoid leukemia is an acute form of leukemia. Although the mechanism behind the relapse in ALL is not clearly known, one possible mechanism could be the accumulation of immune regulatory cells, in particular myeloid-derived suppressor cells (MDSCs). We and others have reported that MDSCs cause suppression of host immune responses through several mechanisms. Aim: The main goal of this study was to determine whether these cells accumulate in ALL patients and whether they are affected by chemotherapy. Materials and Methods: Upon informed consent, patients with B-Linage Acute Lymphoblastic Leukemia “B-ALL” (n = 20) were recruited in this study along with healthy volunteers (n = 20). Patients included in this study were risk stratified according to risk classification system and treated according to treatment protocols including high risk pre B-ALL protocol, standard risk pre B-ALL. MDSCs were characterized as HLA-DR-Lin-CD33+CD11b+ cells. Results: Our preliminary results showed significant increases in the numbers of myeloid population with MDSC-like phenotype in B-ALL patients at different stages of chemotherapy treatment when compared with healthy control volunteers (Mean = 1.01%). The increases in the numbers of these cells were higher after treatment of the patients with induction chemotherapy. Further, the increased numbers of MDSCs associated with high numbers of circulating leukemic stem cells (LSCs). Conclusion: Our preliminary data suggest that cells with MDSCs like-phenotype emerge in ALL patients and possibly play a critical role in establishing an immune suppressive environment in children with ALL. Further research is needed to determine if circulating MDSCs like-phenotype populations are a immunosuppressive and whether they can be modulated. Acknowledgment: This work has been supported by a grant (ID# 5245) funded from the Science and Technology Development Fund (STDF), Ministry of Scientific Research and Technology, Egypt to Mohamed L. Salem, the Principal investigator of this project. Note: This abstract was not presented at the meeting. Citation Format: Mohamed L. Salem. Increases in the numbers of myeloid-derived suppressor cells in Egyptian children with acute lymphoid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1297. doi:10.1158/1538-7445.AM2015-1297
The Toll of Death and Disability From Traumatic Injury in the United States—The “Neglected Disease” of Modern Society, Still Neglected After 50 Years
Authors: Kimberly A. Davis, Timothy C. Fabian, William G. Cioffi
Journal: JAMA Surgery (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal