tbuckley/cabot-search huggingface dataset:
Abstract 4255: Reliable identification of both known and novel gene fusions using a high-efficiency amplicon-based NGS panel
Authors: Chenyu LI
Journal: Cancer Research (2020)

Abstract Gene fusions and RNA splicing errors are important events frequently involved in tumorigenesis, and often represent clinically addressable targets for various cancers. The reliable detection of such mutations via NGS requires the development of cutting-edge technologies capable of overcoming many challenges. These include detecting fusion mutations regardless of the complexity of fusion structures, removing the length and quantity constraints of FFPE RNA, reducing ribosomal RNA interference, eliminating false negatives and positives, revealing the existing copies of mutations, and improving the reproducibility and ease of workflow. Here we describe the development and validation of a fast and user-friendly RNA-based fusion detection technology - CleanPlex® Fusion. Adding a universal primer at the 3' end of single-stranded cDNA via template switching allows us to eliminate the constraint of template length, and hence amplify damaged RNA fragments, such as FFPE RNA. The presence of a target-specific primer on one side enables the detection of any mutations on the RNA fragments, including novel ones. With a panel of 61 primers (covering most of fusion mutations of NSCLC) annealing to the 3' end portion of RNA, we demonstrated the high on-target rate, mapping rate, and low rRNA rate and primer-dimer rate. We validated the amplification of each amplicon by using fragmented total RNA. Additionally, we also made a dual-primer multiplex PCR panel covering the same set of fusion mutations as defined by the single-primer panel, confirmed its coverage of all fusion mutations using a synthetic pool of fusion targets, and detected all commercial reference fusion mutations targeted by the panel. We again demonstrated the detection of such reference fusion mutations using the single-primer mPCR panel, and demonstrated that the single-primer method even detected fusion mutations outside the boundary of the dual primers. Moreover, we showed that the detected fusion reads significantly correlate with copy numbers determined by digital PCR. Lastly, we validated detection of fusion mutations in cell lines and FFPE RNA. CleanPlex® Fusion therefore represent a robust and efficient NGS method for detecting fusion mutations. Citation Format: Chenyu LI. Reliable identification of both known and novel gene fusions using a high-efficiency amplicon-based NGS panel [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 4255.
Abstract 528: EMB-01: An innovative bispecific antibody targeting EGFR and cMet on tumor cells mediates a novel mechanism to improve anti-tumor efficacy
Authors: Fang Ren, Xuan Wu, Dandan Yang, Danqing Wu, Shiyong Gong, Yingxi Zhang, Stephan Lensky, Chengbin Wu
Journal: Cancer Research (2020)

Abstract Interruption of EGFR signaling, either by blocking EGFR binding sites on the extracellular domain of the receptor or by inhibiting intracellular tyrosine kinase activity, can prevent the growth of EGFR-expressing tumors. EGFR tyrosine kinase inhibitors (TKIs) provide a favorable treatment outcome in EGFR mutation positive NSCLC patients. However, many patients eventually develop progressive disease after treatment. Such acquired resistance limits the long-term efficacy of these EGFR TKIs in the clinic. The mechanisms of acquired resistance include a variety of mutations of the EGFR and crosstalk with the adjacent cMet receptors that allow the tumor to partially compensate the EGFR activity. EMB-01 is an innovative bispecific antibody developed based on EpimAb's proprietary FIT-Ig® platform to target EGFR and cMET on tumor cells simultaneously. The anti-EGFR and anti-cMet Fab-domains in each EMB-01 arm are fused directly in-tandem in a unique crisscross orientation without any mutations or use of peptide linkers to form a final tetravalent binding complex with the corresponding receptors on cell surface. We have demonstrated that EMB-01 can maintain all the biological activity from parental monoclonal antibody (mAb) to block ligand binding and the downstream signal pathway. In addition, such tetravalent binding feature is found to induce significant co-degradation of EGFR and cMET in various tumor cells, and such effect is unattainable by either mAb alone or in combination, demonstrating a unique synergistic function of EMB-01. At equivalent doses, EMB-01 induces significantly stronger anti-tumor activity in PDX and CDX tumor models than that of anti-EGFR mAb or anti-cMet mAb alone. Furthermore, EMB-01 shows significant anti-tumor activity in anti-EGFR mAb resistant tumor model. These results demonstrate the potential benefit of EMB-01 in treating EGFR and/or cMET driven cancers, particularly in cases where patients develop acquired resistance due to secondary EGFR mutations in the kinase domain or cMET activation. Currently, EMB-01 has initiated a Phase I/II clinical trial with advanced/metastatic solid tumors. Citation Format: Fang Ren, Xuan Wu, Dandan Yang, Danqing Wu, Shiyong Gong, Yingxi Zhang, Stephan Lensky, Chengbin Wu. EMB-01: An innovative bispecific antibody targeting EGFR and cMet on tumor cells mediates a novel mechanism to improve anti-tumor efficacy [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 528.
TCT-303 Balloon Predilation in Transcatheter Aortic Valve Replacement with Self-Expanding Valves
Authors: Hasan Rehman, Ankur Kalra, John Cochran, Leif Peterson, Rishi Puri, Sahil Khera, Tanush Gupta, Dhaval Kolte, Colin Barker, Deepak Bhatt, Michael J. Reardon, Neal Kleiman
Journal: Journal of the American College of Cardiology (2017)
Cancer recurrence with severe fibrosis after cold snare polypectomy resected by means of endoscopic submucosal dissection
Authors: Hiroaki Kitae, Naohisa Yoshida, Ken Inoue
Journal: Endoscopy (2020)

Generally, local recurrence is a major problem after various endoscopic resections for colorectal tumors, and we have previously reported a recurrence rate after cold snare polypectomy (CSP) of 1.9 % [1]. Endoscopic salvage treatment for recurrent neoplasms is sometimes difficult due to fibrosis.
Abstract 6288: A high-throughput <i>in vitro</i> characterization method of CAR T cells using image cytometry
Authors: Leo Li-Ying Chan, Colby Maldini, Andrea Love, Kevin Tosh, Kevin Gayout, Tim Smith, James Riley
Journal: Cancer Research (2020)

Abstract Since the FDA approval of two CAR T cell therapies, Kymriah (Tisagenlecleucel, Novartis) and Yescarta (Axicabtagene ciloleucel, Kite) for CD19+ malignancies, there has been a significant interest for developing new CARs targeting other disease indications. As such, the ability to simultaneously monitor manufacturing criteria and functional characteristics of multiple CAR T cell products would likely be critical to accelerate candidate therapies into clinical trials. Here, we demonstrate that image-based cytometry using the Celigo Image Cytometer (Nexcelom Bioscience LLC) yields high-throughput measurements of CAR T cell proliferation and size throughout the cell-manufacturing process, and captures the kinetics of antigen-specific CAR T cell-mediated killing in vitro. The data acquired and analyzed by the Celigo Image Cytometer were congruent with results from conventional instruments when tested contemporaneously, such as the Multisizer 3 (Beckman Coulter) which monitored the properties of CAR T cell expansion, and a luciferase-based assay which measured the cytotoxic potential of CAR T cells. More importantly, the use of bright field and fluorescent imaging by the Celigo Image Cytometer provided kinetic measurements and rapid data acquisition and analysis which were direct advantages over the conventional technologies described herein. Together, the Celigo Image Cytometer enabled fast, reproducible, and high-throughput assessment of CAR T cell manufacturing criteria and effector function, which could greatly facilitate the identification and evaluation of novel CARs with therapeutic potential. Citation Format: Leo Li-Ying Chan, Colby Maldini, Andrea Love, Kevin Tosh, Kevin Gayout, Tim Smith, James Riley. A high-throughput in vitro characterization method of CAR T cells using image cytometry [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 6288.
THU0215 Asymptomatic gastrocnemius muscle biopsy: an extremely sensitive and specific test in the histologic confirmation of sarcoidosis presenting wth hilar adenopathy
Authors: AP Andonopoulos, C Papadimitriou, M Melachrinou, N Meimaris, C Vlahanastasi, A Bounas, P Georgiou
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The purpose of our study was to evaluate asymptomatic gastrocnemius muscle biopsy as a tool in the histologic confirmation of the diagnosis of sarcoidosis. <h3>Methods</h3> Consequently, twenty two patients, admitted over a two year period to our department, with bilateral hilar adenopathy and a variety of symptoms compatible with sarcoidosis, were studied prospectively. Besides a complete history, physical and routine laboratory, serum angiotensin converting enzyme (SACE) determination, pulmonary function, slit lamp eye examination, PPD skin test, gallium 67 scan, and gastrocnemius muscle biopsy under local anaesthesia, after informed consent, were performed. <h3>Results</h3> The biopsy revealed non caseating granuloma in all the patients, confirming the diagnosis of sarcoidosis. No other patient in our department received this diagnosis over the two year period of the study. The procedure was well tolerated by all patients and almost zero morbidity was noted. Erythema nodosum was present in 68.2% of the patients, PPD was negative in all of them, SACE was elevated in 59.1%, and pulmonary function was normal in the majority. <h3>Conclusion</h3> The impressive sensitivity of the employed biopsy, its safety and ease of performance, along with the extreme rarity of muscle involvement by other granulomatous diseases, included in the differential diagnosis, may render it the procedure of choice for the histologic confirmation of sarcoidosis, presenting with hilar adenopathy.
CTRP13 Mitigates Abdominal Aortic Aneurysm Formation via NAMPT1
Authors: Wenjing Xu, Yuelin Chao, Minglu Liang, Kai Huang, Cheng Wang
Journal: Molecular Therapy (2020)

Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease characterized by localized dilation of the abdominal aorta. C1q/tumor necrosis factor (TNF)-related protein-13 (CTRP13) is a secreted adipokine that plays important roles in the cardiovascular system. However, the functional role of CTRP13 in the formation and development of AAA has yet to be explored. In this study, we determined that serum CTRP13 levels were significantly downregulated in blood samples from patients with AAA and in rodent AAA models induced by Angiotensin II (Ang II) in ApoE-/- mice or by CaCl2 in C57BL/6J mice. Using two distinct murine models of AAA, CTRP13 was shown to effectively reduce the incidence and severity of AAA in conjunction with reduced aortic macrophage infiltration, expression of proinflammatory cytokines (interleukin-6 [IL-6], TNF-α, and monocyte chemoattractant protein 1 [MCP-1]), and vascular smooth muscle cell (SMC) apoptosis. Mechanistically, nicotinamide phosphoribosyl-transferase 1 (NAMPT1) was identified as a new target of CTRP13. The decreased in vivo and in vitro expression of NAMPT1 was markedly reversed by CTRP13 supplementation in a ubiquitination-proteasome-dependent manner. NAMPT1 knockdown further blocked the beneficial effects of CTRP13 on vascular inflammation and SMC apoptosis. Overall, our study reveals that CTRP13 management may be an effective treatment for preventing AAA formation.
Recommendations for measuring HIV reservoir size in cure-directed clinical trials
Authors: Mohamed Abdel-Mohsen, Douglas Richman, Robert F. Siliciano, Michel C. Nussenzweig, Bonnie J. Howell, Javier Martinez-Picado, Nicolas Chomont, Katharine J. Bar, Xu G. Yu, Mathias Lichterfeld, Jose Alcami, Daria Hazuda, Frederic Bushman, Janet D. Siliciano, Michael R. Betts, Adam M. Spivak, Vicente Planelles, Beatrice H. Hahn, Davey M. Smith, Ya-Chi Ho, Maria J. Buzon, Christian Gaebler, Mirko Paiardini, Qingsheng Li, Jacob D. Estes, Thomas J. Hope, Jay Kostman, Karam Mounzer, Marina Caskey, Lawrence Fox, Ian Frank, James L. Riley, Pablo Tebas, Luis J. Montaner, Mohamed Abdel-Mohsen, Douglas Richman, Robert F. Siliciano, Michel C. Nussenzweig, Bonnie J. Howell, Javier Martinez-Picado, Nicolas Chomont, Katharine J. Bar, Xu G. Yu, Mathias Lichterfeld, Jose Alcami, Daria Hazuda, Frederic Bushman, Janet D. Siliciano, Michael R. Betts, Adam M. Spivak, Vicente Planelles, Beatrice H. Hahn, Davey M. Smith, Ya-Chi Ho, Maria J. Buzon, Christian Gaebler, Mirko Paiardini, Qingsheng Li, Jacob D. Estes, Thomas J. Hope, Jay Kostman, Karam Mounzer, Marina Caskey, Lawrence Fox, Ian Frank, James L. Riley, Pablo Tebas, Luis J. Montaner
Journal: Nature Medicine (2020)
Abstract 4867: Using a fragment based approach for the identification of TEAD S3 pocket binders
Authors: Laure Delarbre, Olivier Venier, Iris Valtingojer, Jacques Houtmann, Maryse Lowinski, Annick Parent, Françoise Bégassat, Angelique Lasbleiz, Catherine Seys, Philippe Bombart, Laurent Debussche, Alexey Rak
Journal: Cancer Research (2020)

Abstract YAP1 and TEAD are transcriptional regulators involved in organ size control and cell proliferation. Aberrant activation of YAP1 has been reported for multiple tumor types and inhibiting the interaction of YAP1 with its partner protein TEAD is thought to be a means of targeting aberrant YAP1 activity. In order to identify small molecule inhibitors of YAP1 interaction with TEAD, we have performed a fragment-based-screening looking for ligands binding to TEAD at its interface with YAP1 (TEAD pocket S3). We have employed three techniques for fragment screening (NMR, SPR, DSF) and have cross tested positive hits identified by one technique with the respective orthogonal method. Using this strategy on Sanofi proprietary fragment libraries, three different fragment series have been identified. X-Ray co-structures with TEAD have been obtained for all three fragment series confirming binding to the S3 pocket of TEAD. Binding mode determination by X-Ray crystallography has set the stage for subsequent fragment optimization. Citation Format: Laure Delarbre, Olivier Venier, Iris Valtingojer, Jacques Houtmann, Maryse Lowinski, Annick Parent, Françoise Bégassat, Angelique Lasbleiz, Catherine Seys, Philippe Bombart, Laurent Debussche, Alexey Rak. Using a fragment based approach for the identification of TEAD S3 pocket binders [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 4867.
Abstract LB-309: Comprehensive genomic insights into dynamic mechanism underlying the development of non-malignant human liver disease into hepatocellular carcinoma
Authors: Xiangyu Zhang, Ran Cao, Kaiqian Zhou, Xinyu Wang, Cheng Zhou, Feiyu Chen, Hua Bao, Xue Wu, Yang W. Shao, Jia Fan, Jian Zhou, Zheng Wang
Journal: Cancer Research (2020)

Abstract Aim: Hepatocellular carcinoma (HCC) is a dynamically developing disease. However, the molecular and evolutionary mechanism underlying the development of human non-malignant liver disease into HCC remains largely unknown. Methods: We performed whole-genome sequencing studies on 3 different types of samples (e.g. liver cirrhosis (LC), dysplastic liver nodules (DN), and hepatocellular carcinoma (HCC)) which were collected simultaneously from each of 8 liver cancer patients. Bioinformatics analysis was performed on somatic mutations, mutational signatures, copy number alterations, structure variants, telomere length, and phylogenetic trees. Results: Surprisingly, few passenger mutations were shared across LC, DN and HCC samples within each patient. Compared with the non-malignant LC and DN samples, HCC was characterized by significantly greater number of somatic mutations (particularly oncogenic mutations), copy number alterations, genomic rearrangements, as well as shorter telomeres. HCC exhibited much similar mutational signatures as dysplastic nodules but different from background cirrhotic liver. Several mutational signatures (e.g. COSMIC signatures 16, 22, 24) were substantially more active in tumor and DN samples than LC, while some mutational signatures (e.g. signatures 5, 8) were universal and equally active in both non-malignant hepatocytes and HCC. Most somatic copy number alterations (SCNAs) were only observed in HCC and no overlap across different samples was found. In contrast to universal subclonal SCNAs, minimal subclonal diversification of mutations was identified in HCC, implying the majority of mutations are acquired at the earliest stages. Conclusions: HCC can be characterized by punctuated evolution of mutations in short bursts followed by subclonal diversification driven by SCNAs. Despite little overlap of mutations, the mutational context indicates a common mutagenesis mechanism underlying HCC and DN, which is different from LC. Citation Format: Xiangyu Zhang, Ran Cao, Kaiqian Zhou, Xinyu Wang, Cheng Zhou, Feiyu Chen, Hua Bao, Xue Wu, Yang W. Shao, Jia Fan, Jian Zhou, Zheng Wang. Comprehensive genomic insights into dynamic mechanism underlying the development of non-malignant human liver disease into hepatocellular carcinoma [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 LB-309.
Abstract 6012: Cancer stem cells could be responsible for the chimeras of hematopoietic cells in the cancer microenvironment
Authors: Ghmkin Hassan, Said M Afify, Kazuki Kumon, Amira Osman, Maram H Zahra, Akimasa Seno, Masaharu Seno
Journal: Cancer Research (2020)

Abstract Development of cancer stem cells (CSCs) model from iPSCs for different types of cancers will help to investigate the tumorigenesis and designing new therapies applicable to CSCs. In this context, our lab has developed a novel method to generate CSCs from iPSCs under cancer microenvironment using conditioned medium from different cancer cell lines. In our previous study, BT549 cell line conditioned media was used to convert iPSCs to CSCs (miPSCs-BTcscs). Here, we investigated the potential of adherent CSCs converted from iPSCs to give hematopoietic like cells. Cancer stem cells, miPSCs-BTcscs, were obtained by conversion of miPSCs (iPS MEF-Ng-20D-17) cells in the presence of conditioned medium from breast cancer cell line BT549 cells followed by the primary culture of the tumor formed in Balb/c nude mice. The stemness and tumorigenicity of miPSCs-BTcscs cells had previously been confirmed. miPSCs-BTcscs cells were cultured on gelatin coated dish in absence of Leukemia Inhibitory Factor (LIF) and select undifferentiated cells was done using puromycin. Non-adherent cells (NACs) arising from adherent CSCs collected and their viability, the morphology and the expression of hematopoietic cells markers were investigated using Giemsa staining, flow cytometry, immunofluorescence staining, and RT-PCR. Moreover, to assess the potential of clonogenicity in vivo and the engraftment of NACs, NACs were injected into the tail vein of busulfan conditioned Balb/c nude mice. The round nucleated NACs were found to be viable, positive for Lin markers and CD34 and expressed hematopoietic markers just like homing to the bone marrow. When NACs were injected into a mouse, Wright-Giemsa staining showed that the number of white blood cells got higher than those in the control mice after 4 weeks. As conclusion, CSCs were demonstrated to have the potential to provide progenies with hematopoietic markers, morphology and homing ability to bone marrow, which could give a new insight into tumor microenvironment according to the plasticity of CSCs. Citation Format: Ghmkin Hassan, Said M Afify, Kazuki Kumon, Amira Osman, Maram H Zahra, Akimasa Seno, Masaharu Seno. Cancer stem cells could be responsible for the chimeras of hematopoietic cells in the cancer microenvironment [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 6012.
Abstract 5108: Investigation of how extracellular matrix composition affects pancreatic cancer chemoresistance through the use of biomimetic models
Authors: Weikun Xiao, Chae-Young Eun, Charlene Dekalb, Kexin Zhang, Reginald Hill
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and malignant type of cancer with few effective treatments. Despite recent advancement in knowledge of cancer treatment, median survival of PDAC patients remains within 2 years, and less than 8% patients live beyond 5 years after diagnosis. The main factor that drives PDAC lethality is the development of chemoresistance in nearly all clinical PDACs. While intrinsic factors that facilitates chemoresistance have been studied extensively, few studies have illustrated how complex and unique microenvironment surrounding the PDAC tumor affects therapeutic responses. Moreover, a physiologically relevant co-culture model of PDAC and stromal cells remained challenging. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to culture established human PDAC cell lines, cancer-associated fibroblast (CAF) cells and mouse model-derived organoids. Individual matrix parameters can be customized to mimic actual tumor matrix composition and mechanical properties. Moreover, we have optimized a co-culture medium to maintain viability of both organoid tumor and cancer associated fibroblasts. Through our 3D culture system, our data suggests that matrix-induced exosome secretion directly facilitate gemcitabine resistance in PDAC cells. By directly increasing stiffness of our 3D culture platform, we have observed that PDAC cells potentially display more invasive phenotype. Moreover, in the co-culture systems, we have seen that CAF cells cultured in different stiffness substrates affect PDAC drug response in organoid cultures. Our investigation provides insight into how matrix composition and stiffness together affect therapeutic outcome in PDAC. We believe that specific therapeutic strategies aimed at targeting the matrix microenvironment will be instrumental in order to overcome matrix-mediated chemoresistance in PDAC. Citation Format: Weikun Xiao, Chae-Young Eun, Charlene Dekalb, Kexin Zhang, Reginald Hill. Investigation of how extracellular matrix composition affects pancreatic cancer chemoresistance through the use of biomimetic models [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 5108.