tbuckley/cabot-search huggingface dataset:
Abstract 566: Therapeutic targeting of the polyamine pathway and EIF5A1 hypusination in endometrial cancer with DFMO and GC7
Authors: HongIm Kim, Chad Schultz, Andre Bachmann, John I. Risinger
Journal: Cancer Research (2020)

Abstract The polyamines putrescine, spermidine, and spermine are well-characterized oncometabolites upregulated in cancers and drive their proliferation and spread. Endometrial cancers (ECs) express high levels of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis and decreased levels of spermidine/spermine N1-acetyltransferase (SAT1), a key negative regulator of polyamines. In addition, the deoxyhypusine synthase (DHPS) enzyme necessary for spermidine-dependent hypusination of eIF5A1 is highly expressed in ECs. Hypusinated EIF5A1 is needed by cancer cells to support their increased protein translation needs. Collectively, these findings suggest that the polyamine pathway is particularly active and necessary in EC. Here we evaluated the effect of ODC inhibitor difluoromethylornithine (DFMO) and DHPS inhibitor N1-Guanyl-1,7-Diaminoheptane (GC7) alone or in combination on the growth of ECs. GC7 and DFMO were effective in suppressing growth in EC cell lines in vitro as measured by MTS viability and proliferation assays. These effects were accompanied by decreased hypusinated EIF5A1 in treated cells. However, neither compound induced apoptotic cell death when applied singly. We did note that when non-apoptotic inducing doses of DFMO and GC7 were combined, EC cells showed a marked combinatorial decrease in viability, proliferation, and hypusinated EIF5A1 levels. Importantly we found that combined DFMO/GC7 treatment caused apoptotic cell death of EC cells as measured by cleaved PARP. Furthermore, levels of cleaved caspases 3 and 7 were increased in these cells while caspases 5 or 9 were not cleaved. In summary we found for the first time that pharmacologically increased depression of the polyamine pathway as measured by decreased hypusinated EIFA1 can lead to apoptotic cell death in ECs. These data suggest that targeting the polyamine pathway and particularly its role in protein translation through EIF5A1 hypusination may be an effective treatment strategy. Citation Format: HongIm Kim, Chad Schultz, Andre Bachmann, John I. Risinger. Therapeutic targeting of the polyamine pathway and EIF5A1 hypusination in endometrial cancer with DFMO and GC7 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 566.
Abstract 4475: Site-specific profiling of TCR signaling
Authors: Zaw Phyo, Rohan Verma, Won J. Ho, Elizabeth M. Jaffee
Journal: Cancer Research (2020)

Abstract Background: T cell exhaustion is a hyporesponsive state commonly found in cancer and is characterized by overexpression of inhibitory receptors and secretion of immunosuppressive cytokines. Immune checkpoint inhibitors (ICIs) target inhibitory receptors such as PD-1 and CTLA-4 to reinvigorate exhausted T cells and promote anti-tumor responses. While ICIs have improved clinical outcomes, no biomarker to date reliably determines the extent of T cell exhaustion. Since robust T cell receptor (TCR) signaling is critical for effective antitumor immunity, we hypothesized that interrogating the phospho-signaling states within the T cells along with their functional states will enhance our understanding of T cell exhaustion and yield potential biomarkers. Methods: In this study, we developed a validated mass cytometry panel of 24 markers to quantify phosphorylation states of 8 intracellular kinases involved in the TCR signaling within multiple CD8+ T cell subtypes. To identify potential differences between the local and peripheral immunological responses, we profiled CD8+ T cells derived from four sites (tumor, tumor draining lymph node, spleen and peripheral blood) in mice bearing MC38-induced flank tumors. We performed a clustering analysis of the dataset in aggregate using FlowSOM and visualized the results with UMAP, a dimensionality reduction algorithm, to compare the phospho-profiles of CD8+ T cell subtypes in all four sites. Results: Bulk analysis of CD8+ T cells demonstrates site-specific concordance between phosphoprotein markers and T cell functional markers (i.e. Ki67 and Granzyme B) with the highest expression in tumor followed by tumor draining lymph node, spleen and peripheral blood. Based on the results from the clustering analysis, site-specific breakdown of CD8+ T cells revealed high prevalence of effector, memory, and exhausted memory T cells in tumors compared to other sites where naïve T cells predominated. Despite these variations in CD8+ T cell immunophenotypic distribution, TCR signaling profiles correlated strongly with specific T cell subtypes across all sites. Conclusion: These data demonstrate that subtype-specific TCR signaling is preserved systemically and that phospho-immune subtyping of CD8+ T cells in the peripheral blood may be used to identify T cell exhaustion states that are found in the tumor microenvironment. Further studies will be conducted to investigate the changes in the TCR phospho-profiles in response to ICI treatment and their associated functions. Citation Format: Zaw Phyo, Rohan Verma, Won J. Ho, Elizabeth M. Jaffee. Site-specific profiling of TCR signaling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4475.
The wild grape genome sequence provides insights into the transition from dioecy to hermaphroditism during grape domestication
Authors: Hélène Badouin, Amandine Velt, François Gindraud, Timothée Flutre, Vincent Dumas, Sonia Vautrin, William Marande, Jonathan Corbi, Erika Sallet, Jérémy Ganofsky, Sylvain Santoni, Dominique Guyot, Eugenia Ricciardelli, Kristen Jepsen, Jos Käfer, Hélène Berges, Eric Duchêne, Franck Picard, Philippe Hugueney, Raquel Tavares, Roberto Bacilieri, Camille Rustenholz, Gabriel A. B. Marais
Journal: Genome biology (2020)

A key step in domestication of the grapevine was the transition from separate sexes (dioecy) in wild Vitis vinifera ssp. sylvestris (V. sylvestris) to hermaphroditism in cultivated Vitis vinifera ssp. sativa (V. vinifera). It is known that V. sylvestris has an XY system and V. vinifera a modified Y haplotype (Yh) and that the sex locus is small, but it has not previously been precisely characterized.We generate a high-quality de novo reference genome for V. sylvestris, onto which we map whole-genome re-sequencing data of a cross to locate the sex locus. Assembly of the full X, Y, and Yh haplotypes of V. sylvestris and V. vinifera sex locus and examining their gene content and expression profiles during flower development in wild and cultivated accessions show that truncation and deletion of tapetum and pollen development genes on the X haplotype likely causes male sterility, while the upregulation of a Y allele of a cytokinin regulator (APRT3) may cause female sterility. The downregulation of this cytokinin regulator in the Yh haplotype may be sufficient to trigger reversal to hermaphroditism. Molecular dating of X and Y haplotypes is consistent with the sex locus being as old as the Vitis genus, but the mechanism by which recombination was suppressed remains undetermined.We describe the genomic and evolutionary characterization of the sex locus of cultivated and wild grapevine, providing a coherent model of sex determination in the latter and for transition from dioecy to hermaphroditism during domestication.
Abstract 4485: Comparison of two commercially available T cell receptor repertoire sequencing assays
Authors: Jennifer Mason, Martin Buchkovich, Jennifer Sims, Patrick Hurban
Journal: Cancer Research (2020)

Abstract Background: Deep sequencing of the T-cell receptor complementarity-determining regions assists with resolving T-cell diversity, and, in oncology, detects specific clones or changes in clonality associated with anti-tumor responses. However, the extreme diversity of the T-cell repertoire represents a major analytical challenge, while a gold standard method for the repertoire analysis has not yet been identified. Here, we evaluated performance of the Oncomine TCR Beta squencing assay in PBMC and formalin-fixed paraffin-embedded (FFPE) tissues, and compared it to another commercially available TCR sequencing assay. Method: RNA derived from PBMCs or tumor FFPE tissue were prepared using the Oncomine TCR Beta-SR (short read) and LR (long read) assays, and a comparator assay. Library preparation using the TCR Beta SR and LR assays required cDNA synthesis followed by TCR gene specific amplification, sample barcoding, and sequencing on the Ion Torrent S5. Comparator assay entailed gene specific cDNA synthesis, preparation of sequencing libraries, TCR gene specific amplification, sample barcoding and 2 × 150 bp sequencing on Illumina's NextSeq. Libraries generated from RNA derived from PBMCs and FFPE were sequenced to a depth of 25M and 10M reads, respectively, for the TCR Beta-SR and a comparator assay. All samples prepared with the TCR Beta-LR assay were sequenced to 3M reads. On target reads, reproducibility, sensitivity, and robustness of input were used to measure assay performance. Results: Higher fractions of on target TCR reads were identified in PBMC and FFPE libraries generated with the TCR Beta-SR and LR assays. The TCR Beta-SR and LR assays had mean pairwise correlations for replicate samples of 0.95 and 0.99, respectively, and 0.86 for a comparator assay. Rare clones at frequencies 10−5 and 10−6 in PBMC samples were detected by the Oncomine TCR Beta-SR and LR assays in samples with an input of 50 - 300 ng, where a comparator assay had inconsistent detection of the rare clones at a frequency of 10−5, independent of input. Conclusions: Thermo Fisher's Oncomine TCR Beta assay reproducibly amplifies TCR specific sequences with high sensitivity. The assay is suitable for characterization of TCR clones from RNA derived from PBMC and tissue FFPEs. Citation Format: Jennifer Mason, Martin Buchkovich, Jennifer Sims, Patrick Hurban. Comparison of two commercially available T cell receptor repertoire sequencing assays [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4485.
Abstract 1151: Inclusion of cholesterol and A549 lipid extract in CLENs improved cellular uptake in adenocarcinoma non-small cell lung cancer target cells
Authors: Maxime Langlois, Guo-Yun Kao, Diana Lasker
Journal: Cancer Research (2020)

Abstract Purpose:The purpose of this investigation was to determine the optimal amount of cholesterol and A549-derived lipid extract (LE) included in the initial design and development of A-549-cell membrane lipid extracted nanoliposomes (A549-CLENs) for cell targeting studies. Methods and Materials:A549 (ATCC® CCL-185™), used as a positive control and NCI-H1703 (ATCC® CRL-5889™), used as a negative control, and respective growth media were purchased from ATCC (Manassas, VA). A549-GFP (green fluorescent protein) cell line was purchased from AntiCancer, Inc. DOPC, DOTAP, cholesterol, and DSPE-PEG5000 were obtained from Avanti Polar Lipids (Alabastar, AL). Cellular membrane lipids of A549 cells were extracted by modified Bligh &amp; Dyer method. CLENs were fluorescently labeled with rhodamine-B. Particle sizes and zeta potentials were performed using ZetaPALS (Brookhaven Instruments Corporation, Holtsville, NY, USA). For cellular uptake studies cells were seeded at 2.0 x 104 cells in a 48-well plate followed by incubation for 24 hours. A fluorescence microplate reader and/or fluorescence microscopy were used to evaluate cellular uptake as a function of relative amount of cholesterol and A549-lipid extract inclusion in CLENs. Results:In general, an increase in the inclusion of cholesterol reduced the particle size of CLENs. Amount of 10 mol% of cholesterol content in CLENs demonstrated the smallest mean size diameters and a zeta potential value recorded at 243 ± 4.4 nm and 1 ± 2.61 mV, respectively. The finding correlated also with a relatively high degree of cellular uptake of the preparation type for part I of the physicochemical characterization studies. We next maintained 10 mol% cholesterol content consistent in all future preparations and increased the total A-549 lipid extract material at the expense of DOPC. In general, the mean diameter and zeta potential for A549-CLENs were 246 ± 3.8 nm and 20.4 ± 0.84 mV, respectively. Approximately 10-15 mol% of A-549 lipid extract inclusion resulted in a consistently high degree of overall cellular uptake by GFP-A549 and A549 target cells compared to control and the non-target cell population, NCI-H1703. Conclusion: Preparation of A549-CLENs consisting of DOPC/ DOTAP/ Chol/ LE/PEG (65/10/10/10/5) established the greatest increase in cellular uptake and overall selectivity. Future studies will consider antibody conjugation and development of tumor-specific biomarkers for serodiagnostic detection and lung cancer treatment. Citation Format: Maxime Langlois, Guo-Yun Kao, Diana Lasker. Inclusion of cholesterol and A549 lipid extract in CLENs improved cellular uptake in adenocarcinoma non-small cell lung cancer target cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1151.
Horace Barlow. Scientist of vision
Authors: Colin Blakemore
Journal: Nature Neuroscience (2020)

Horace Basil Barlow, Fellow of the Royal Society, winner of the Australia Prize, the Royal Medal of the Royal Society and the Schwartz Prize of the Society for Neuroscience, died on 5 July 2020 at the age of 98, 10 days after suffering a stroke. As news spread among his former students and collaborators, one phrase recurred again and again in the messages of nostalgic reflection: ‘the end of an era’.
Abstract 1981: Cell free DNA promotes malignant transformation in non-tumor cells
Authors: Aline Gomes Souza, Mario Machado Martins, Victor Alexandre Bastos, Natassia Caroline Resende, Paula Sousa Santos, Karina Marangoni, Luiz Ricardo Goulart, Vivian Alonso Goulart
Journal: Cancer Research (2020)

Abstract Cell free DNA (cfDNA) are present at various biological fluids and when released by tumor cells it can contribute with the induction of pro-tumorigenic events, such as malignant transformations and metastasis. In this work we evaluated the effects of tumor derived cfDNA, isolated from blood of prostate cancer patients, in the non-tumoral prostate cellular linages RWPE-1 and PNT-2. We quantified, characterized and evaluated the function of the isolated cfDNA by qPCR of tumor progression related genes and MS-metabolomics. The results showed that the isolated cfDNA was able to induce the increase expression of MMP9 and CD44 in the normal prostate cellular linages, as well as to alter the consumption of tryptophan by the cells, these changes can indicate the sifting of the cells metabolism in favor of a tumoral profile. Those results demonstrate the potential of tumor derived cfDNA to alter receptor cells profiles, triggering malignant transformation events, making them a good target for new therapies and molecular targets for diagnosis. Citation Format: Aline Gomes Souza, Mario Machado Martins, Victor Alexandre Bastos, Natassia Caroline Resende, Paula Sousa Santos, Karina Marangoni, Luiz Ricardo Goulart, Vivian Alonso Goulart. Cell free DNA promotes malignant transformation in non-tumor cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1981.
Abstract 1221: Novel strategies to target autophagy to improve cancer therapy
Authors: Yuanpei Li, Zhao Ma, Dailn Zhang, Mythili Ramachandran, Tzu-yin Lin
Journal: Cancer Research (2020)

Abstract In cancer research, autophagy is thought to be a double-edged sword because it can either prevent malignant transformation during cancer initiation or sustain tumor metabolism, growth and survival in cancer establishment and progression. For established tumors, especially the advanced or metastatic types, the harsh intercellular conditions activate autophagy so that tumor cells can adapt to the stressful conditions and efficiently recycle their nutrients, while also allowing them to respond to anti-tumor therapeutics. Therefore, interventions that deliberately inhibit autophagy in cancer therapy have been used to reduce cancer cell survival, overcome drug resistance and improve clinical outcomes. The vast majority of autophagy inhibitors used in these therapies are lysosomotopic alkaline agents, such as chloroquine (CQ) and hydroxychloroquine (HCQ). However, their efficacy is considered to be imperfect. New strategy to target autophagy for cancer therapy is needed. Through introducing nanotechnology into initial new drug entity design, we developed a series of new chemical entities, BAQ12-18, and all of them are potential building blocks to self-assemble into the single new-chemical-entity nanomedicines (BAQ SNNs). The selected BAQ12 NP and BAQ13 NP not only improve drug delivery and tumor-targeted biodistribution but also endow unique proton sponge effect to dramatically enhance the existing functions of lysosomal disruption and autophagy blockade, and thus generate significant therapeutic efficacy both in vitro and in vivo. The more striking finding is that BAQ13 NP can potently provide both a uniform drug delivery platform and synergistic effect to the combination drug, indicating a new-generation strategy of combination therapy. Considering their capacity to encapsulate different drugs and broad synergistic effect with various treatments, BAQ SNNs may make a tremendous contribution to the outcome of cancer treatment. To the best of our knowledge, this is the first attempt to extend nanotechnology into the design stage of new small-molecule drug entity. The seamless connection between new drug discovery and nanomedicine-based drug delivery will absolutely inspire researchers to develop increasingly advanced nanomedicines with a wide range of practical values and market for improved the therapy against challenging diseases. Citation Format: Yuanpei Li, Zhao Ma, Dailn Zhang, Mythili Ramachandran, Tzu-yin Lin. Novel strategies to target autophagy to improve cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1221.
Abstract 1659: Development of an orthotopic murine model of a patient-derived pancreatic adenocarcinoma to evaluate the tissue specificity of two novel fluorescent compounds
Authors: Olivier Duchamp, Cyril Berthet, Peggy Provent, Elodie Marie Dit Chatel, Jordan Longin, Stanislas Urbain, François Scherninski
Journal: Cancer Research (2020)

Abstract Fluorescent dyes have been used in medical diagnostics for over 50 years. The emergence of new fluorescent imaging technology in support of surgery and the need for increased sensitivity and precision have driven the search for novel fluorescent molecules. Orthotopic patient-derived pancreatic tumor models provide a closely related human tumor within organ-specific tumor microenvironment, which was well suited to the evaluation of the tissue specificity of two novel fluorescent compounds. To this end, we have developed an orthotopic tumor model of IM-PAN-15 (PDX model developed within the IMODI consortium), a patient derived pancreatic adenocarcinoma, in mice. Tumor cells were amplified subcutaneously in SCID mice and the resulting fragments subsequently surgically implanted into the pancreas of irradiated BALB/c nude mice. Tumor development was monitored in vivo by MRI at three time points. Fluorescent compounds were injected intravenously 36 days after tumor fragment implantation, when mean tumor volumes were approximately 70 mm³. Ex-vivo fluorescent imaging showed that 2h after injection, the two novel fluorescent compounds were present in the pancreas and tumor at roughly equivalent amounts. However, 48h after injection, a clear preferential distribution for the tumor was observed, with both compounds producing an approximately four-fold higher fluorescent signal in the tumor than in the surround pancreatic tissue. This effect persisted six days after injection, although the signal decreased over time. In comparison, indocyanine green, a dye widely used in medical diagnostics, showed no specific accumulation in either the pancreas or tumor. In conclusion, we report the development of a clinically relevant, patient-derived orthotopic tumor model and demonstrate its use in the investigation of tissue specificity of two novel fluorescent compounds. Keywords: PDX, fluorescent dyes, orthotopic pancreatic model, MRI Citation Format: Olivier Duchamp, Cyril Berthet, Peggy Provent, Elodie Marie Dit Chatel, Jordan Longin, Stanislas Urbain, François Scherninski. Development of an orthotopic murine model of a patient-derived pancreatic adenocarcinoma to evaluate the tissue specificity of two novel fluorescent compounds [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1659.