tbuckley/cabot-search huggingface dataset:
Abstract 2123: Chromatin profiling of glioblastoma tissues identifies core oncogenic dependency and therapeutic opportunities
Authors: Liang Xu, Ye Chen, Yulun Huang, Edwin Sandanaraj, John S. Yu, Ruby Yu-Tong Lin, Pushkar Dakle, Xin-Yu Ke, Yuk Kien Chong, Lynnette Koh, Anand Mayakonda, Kassoum Nacro, Jeffrey Hill, Mo-Li Huang, Sigal Gery, See Wee Lim, Zhengyun Huang, Ying Xu, Jianxiang Chen, Longchuan Bai, Shaomeng Wang, Hiroaki Wakimoto, Tseng Tsai Yeo, Beng Ti Ang, Markus Müschen, Carol Tang, Tuan Zea Tan, Phillip H. Koeffler
Journal: Cancer Research (2021)

Abstract Background: Glioblastoma (GBM) is the most aggressive and therapy-refractory brain tumor in adults. Molecular profiling of GBM on the basis of gene expression, DNA methylation and genomic variations has advanced both cancer research and clinical diagnosis. However, the enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive. Methods: Chromatin immunoprecipitation followed by sequencing analysis was applied to examine H3K27ac deposition and to map the active regulatory landscapes across 95 GBM biopsies and 12 normal brain tissues. RNA-sequencing analysis was performed to measure transcriptome and to classify transcriptional subtypes. Super-enhancer associated genes and master transcriptional factors were identified. Function of novel cancer associated genes was explored using both patient-derived GBM propagating cells and orthotopic xenograft models. Results: Analyses of differentially regulated enhancers and super-enhancers uncovered previously unrecognized layers of inter-tumor heterogeneity. Integrative analysis of variant enhancer loci and transcriptome identified topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors: AC1-mesenchymal, AC1-classical, AC2-proneural and AC3-proneural. Subtype-specific enhancer domains contributed to transcriptional diversity and shaped subtype identity. Moreover, this study reveals novel oncogenic dependency of GBM on various super-enhancer-driven transcriptional factors and druggable targets (e.g., BRD4). Conclusion: Through profiling of transcriptional enhancers, we provide clinically relevant insights into the molecular classification, pathogenesis and therapeutic intervention of GBM. Citation Format: Liang Xu, Ye Chen, Yulun Huang, Edwin Sandanaraj, John S. Yu, Ruby Yu-Tong Lin, Pushkar Dakle, Xin-Yu Ke, Yuk Kien Chong, Lynnette Koh, Anand Mayakonda, Kassoum Nacro, Jeffrey Hill, Mo-Li Huang, Sigal Gery, See Wee Lim, Zhengyun Huang, Ying Xu, Jianxiang Chen, Longchuan Bai, Shaomeng Wang, Hiroaki Wakimoto, Tseng Tsai Yeo, Beng Ti Ang, Markus Müschen, Carol Tang, Tuan Zea Tan, Phillip H. Koeffler. Chromatin profiling of glioblastoma tissues identifies core oncogenic dependency and therapeutic opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2123.
Injectable polymeric nanoparticle hydrogel system for long-term anti-inflammatory effect to treat osteoarthritis
Authors: Bo-Bae Seo, Youngjoong Kwon, Jun Kim, Ki Hyun Hong, Sung-Eun Kim, Hae-Ryong Song, Young-Min Kim, Soo-Chang Song
Journal: Bioactive Materials (2021)

Treatment of osteoarthritis (OA) by administration of corticosteroids is a commonly used method in clinics using anti-inflammatory medicine. Oral administration or intra-articular injection of corticosteroids can reduce the pain and progress of cartilage degeneration, but they are usually insufficient to show local and long-term anti-inflammatory effects because of their fast clearance in the body. In this study, we suggest an injectable anti-OA drug depot system for sustained drug release that provides long-term effective therapeutic advantages. Amphiphilic poly(organophosphazene), which has temperature-dependent nanoparticle forming and sol-gel transition behaviors when dissolved in aqueous solution, was synthesized for triamcinolone acetonide (TCA) delivery. Because hydrophobic parts of the polymer can interact with hydrophobic parts of the TCA, the TCA was encapsulated into the self-assembled polymeric nanoparticles. The TCA-encapsulated polymeric nanoparticles (TePNs) were well dispersed in an aqueous solution below room temperature so that they can be easily injected as a sol state into an intra-articular region. However, the TePNs solution transforms immediately to a viscose 3D hydrogel like a synovial fluid in the intra-articular region via the conducted body temperature. An in vitro TCA release study showed sustained TCA release for six weeks. One-time injection of the TePN hydrogel system in an early stage of OA-induced rat model showed a great inhibition effect against further OA progression. The OA-induced knees completely recovered as a healthy cartilage without any abnormal symptoms.
Differences in Clinician Electronic Health Record Use Across Adult and Pediatric Primary Care Specialties
Authors: Lisa S. Rotenstein, A. Jay Holmgren, N. Lance Downing, Christopher A. Longhurst, David W. Bates
Journal: JAMA Network Open (2021)

Clinicians spend a large proportion of their days using the electronic health record (EHR). There are known negative associations between measures of EHR use and clinician experience.1 Primary care clinicians spend significantly more total and after-hours time in the EHR than medical specialty and surgical colleagues.2 However, little is known regarding variation in EHR use across primary care specialties, such as between adult and pediatric care. In this cross-sectional study, we compared EHR use across general pediatrics, general internal medicine, and family medicine clinicians.
Abstract 216: Functional annotations of membrane transport genes using genetic perturbation screens
Authors: Heba Sailem
Journal: Cancer Research (2021)

Abstract Dysregulation of membrane transport and ion channels genes have been associated with through their role in cellular communication, regulation of cell size through osmoregulation and inflammation. However, a systematic profiling of the biological functions that are affected downstream of ion channels is not well studied due to challenges in monitoring their activity. Depleting known ligand-gated and voltage-gated ion channels has been shown to have a distinct phenotypic signature in HCT116 colorectal cells which is associated with their size and collective arrangement. These results were based on data from a genome-wide image-based siRNA screen where more than 500 million cells were segmented, and their shape and organisation were quantified. Single cells data were aggregated for each gene to capture cell heterogeneity and partial penetrance effects resulting in more than 1700 features per gene. Predictions of multiple functions for each gene were generated using KCML, a machine learning platform that automatically links gene perturbation phenotypes to molecular and biological function. Here we analysed the predicted functions for known ligand-gated and voltage-gated ion channel genes using KCML. Top predicted functions included ubiquitin protein ligase activity, phosphatase activity, stress-activated protein kinase signalling cascade, positive regulation of inflammatory response and cellular response to starvation. To validate these predictions, we applied KCML to independent genome-wide CRISPR screens measuring cell viability in 60 cancer cell lines from different tissue types. We focused on the functional association between ion channels and inflammatory response which is well recognised. We confirmed the prediction of 62/86 ion channel genes role in positive regulation of inflammatory response based on viability phenotypes. Many of these genes are documented to play a role in inflammation but has not annotated with inflammatory function in the gene ontology including GAS1, CHRNA2, and TMEM37. Pathway analysis revealed that seven of these genes are associated with gastric acid secretion (p-value =3.4E-5) including KCNQ1 gene that its loss that has been linked to the expression of inflammatory genes in colon cancer and worse patient outcomes. These results show that a comprehensive analysis of gene perturbation screens utilising siRNA or CRISPR technologies allows functional annotation of different roles for known ion channel genes. In particular, we identify 62 ion channel genes to be associated with inflammation and therefore would be promising therapeutic targets in colorectal cancer. Citation Format: Heba Sailem. Functional annotations of membrane transport genes using genetic perturbation screens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 216.
Abstract 2420: Characterizing the oncogenic activity of ERBB4 mutations and their sensitivity to neratinib
Authors: Peppi Suominen, Deepankar Chakroborty, Kari J. Kurppa, Irmina Diala, Lisa D. Eli, Alshad S. Lalani, Klaus Elenius
Journal: Cancer Research (2021)

Abstract Hundreds of somatic ERBB4 mutations have been described in cancer tissues with very limited information about their functional significance. However, analyses of individual mutants have indicated that activating ERBB4 mutations, such as ERBB4 K935I, do exist. Understanding the functional consequences of ERBB4 mutations is needed in order to assess the relevance of targeting ERBB4 in human cancers with matched therapies such as neratinib. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that binds to and potently inhibits ERBB4 kinases activity in-vitro, and is currently approved clinically for the treatment of early stage and metastatic HER2+ breast cancers. We set up to address the transforming potential of individual ERBB4 variants by selecting 18 mutations (Table 1) from cBioPortal data (www.cbioportal.org) using the following criteria: 1) the mutations were recurrent, 2) they were analogous to activating mutations described for other oncogenic ERBB family members and/or 3) their position at receptor dimerization interfaces suggested functional relevance. Retroviral pBABE-puro-gateway vector was used to achieve functional, but still near-physiological expression levels of ERBB4 in different cell backgrounds. A screen for optimal cellular background to assess the transforming potential of ERBB4 variants indicated that 1) IL-3 independent growth of mouse lymphoid Ba/F3 cells, 2) focus formation analysis of mouse NIH-3T3 fibroblasts, and 3) ligand-induced proliferation of human mammary epithelial MCF-10A provided read-outs with robust differences when the effects of the positive control mutant ERBB4 K935I was compared to wild-type ERBB4. These models are now being used to address the transforming potential of the 18 mutations (Table 1). Table 1.Somatic ERBB4 mutations chosen for functional analyses.R106CE452KR711CL798RG870RK1223TS303FR524CG741EV840IG907ES1289AR393WR544WS774GR847HR992CR1304W Citation Format: Peppi Suominen, Deepankar Chakroborty, Kari J. Kurppa, Irmina Diala, Lisa D. Eli, Alshad S. Lalani, Klaus Elenius. Characterizing the oncogenic activity of ERBB4 mutations and their sensitivity to neratinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2420.
Papillary renal cell carcinoma type I and II: Two distinct diseases with different clinical and therapeutical implications
Authors: G. Rosiello, G. Fallara, A. Martini, A. Boletta, D. Cignoli, L. Nocera, G. Basile, G. Colandrea, G. Baiamonte, I. Rowe, D. Canibus, G. Musso, F. Cei, C. Giancristofaro, M. Romani, A. Briganti, R. Bertini, F. Montorsi, A. Necchi, A. Salonia, A. Larcher, U. Capitanio
Journal: European Urology (2021)
Abstract 3092: Effect of cancer stem cell-specific progerin expression on metastatic potential
Authors: Philipp Morgenroth, Christoph Söhnchen, Alf Spitschak, Brigitte M. Puetzer, Stella Logotheti
Journal: Cancer Research (2021)

Abstract Metastasis signals the final and treatment-refractory stage of cancer disease. Formation of metastases is fueled by a small cell subpopulation within the tumor, the so-called cancer stem cells (CSCs), which have the ability to rejuvenate the heterogeneous tumor population and support self-renewal, survival and tumor cell heterogeneity. Stemness is a cell property rather than a distinct subpopulation of the tumor structure. In this respect, even if CSCs are specifically targeted to be killed, their surrounding cells dedifferentiate to replace assaulted CSCs. Herein, we sought to target CSCs with progerin, a truncated form of lamin A, which causes the Hutchinson-Gilford childhood progeria syndrome, a rare genetic disease of accelerated aging. We combined a promoter responsive to two stemness factors (Yamanaka factors) with the progerin gene and produced a lentiviral construct, where progerin is set under the transcriptional control of stemness cascades. Stable transduction of cancer cells with this construct establishes a dynamic gene modification of the tumor cell population, where all tumor cells carry the progerin gene, but only the ones where the levels of stemness factors are initially high or secondarily upregulated are able to express it. This way, stemness programs are transcriptionally linked with a gene that, when expressed in normal stem cells, causes premature exhaustion of adult stem cells, inhibits the regenerative capacity of tissues and accelerates senescence. We monitor the effects of CSC-specific progerin expression on the CSC reservoir and the tumor cell population dynamics over time, in comparison with CSC-specific expression of its wild-type laminA counterpart, as well as non CSC-specific progerin expression. We further examine how targeting the CSC turnover within the tumor population projects into metastasis-initiating processes, such as cell invasion, migration, epithelial-mesenchymal transition, and tumor metabolism. Our approach provides a model for addressing the potential crosstalk between stemness and senescence in the context of CSCs and holds promise to translate the findings into anti-metastatic therapeutic solutions. Funding: This project is funded by FORUN (889040) and P.M. has a scholarship from the German Cancer Aid (70114135). Citation Format: Philipp Morgenroth, Christoph Söhnchen, Alf Spitschak, Brigitte M. Puetzer, Stella Logotheti. Effect of cancer stem cell-specific progerin expression on metastatic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3092.
MRI-targeted or systematic biopsies in prostate cancer screening: The STHLM3MRI trial
Authors: M. Eklund, F. Jäderling, A. Discacciati, M. Bergman, M. Annerstedt, M. Aly, A. Glaessgen, S. Carlsson, H. Grönberg, T. Nordström
Journal: European Urology (2021)
Global burden of cancer in 2020 attributable to alcohol consumption: a population-based study
Authors: Harriet Rumgay, Kevin Shield, Hadrien Charvat, Pietro Ferrari, Bundit Sornpaisarn, Isidore Obot, Farhad Islami, Valery E P P Lemmens, Jürgen Rehm, Isabelle Soerjomataram
Journal: The Lancet Oncology (2021)

Alcohol use is causally linked to multiple cancers. We present global, regional, and national estimates of alcohol-attributable cancer burden in 2020 to inform alcohol policy and cancer control across different settings globally.
Abstract 2956: Humanized IL17A/hIL17F mouse model provides a preclinical tool for the evaluation of therapeutic drugs targeting to IL-17 pathway
Authors: Chong Li, Lei Zhao, Tao Zhu, Yichao Chen, Leila Kokabee, Chaoshe Guo
Journal: Cancer Research (2021)

Abstract Interleukin 17 (IL-17) is described as a pro-inflammatory cytokine produced by activated CD4 cells. Evidence shows that IL-17 is highly up-regulated at sites of inflammatory tissues of autoimmune diseases and amplifies the inflammation through synergy with other cytokines, such as TNF (tumor necrosis factor) α. Therefore, targeting IL-17/IL-17R, IL-17-producing pathways or IL-17-mediated signaling pathways can be considered for future therapy in autoimmune diseases. To evaluate the efficacy of IL17A and IL17F antibodies, we generated a double humanized B-hIL17A/hIL17F mouse in Biocytogen. In this model, the sequences encoding the extracellular domains of the mouse IL17A gene and the IL17F gene were replaced with the corresponding human sequences. IL17A and IL17F protein expression was detected in B-hIL17A/hIL17F mice by ELISA using a species-specific IL17A ELISA kit. In efficacy study of anti-human IL17A and IL17F antibody with psoriasis model induced in B-hIL17A/hIL17F mice, mice were treated with different dose of bimekizumab produced in house. Erythema and scaling score of the skin was significantly reduced compared with non-treatment group. The results suggest B-hIL17A/hIL17F mouse model is an effective tool for in vivo efficacy evaluation, which may represent a promising model for screening IL17 related drug candidates for the treatment of psoriasis disease. Citation Format: Chong Li, Lei Zhao, Tao Zhu, Yichao Chen, Leila Kokabee, Chaoshe Guo. Humanized IL17A/hIL17F mouse model provides a preclinical tool for the evaluation of therapeutic drugs targeting to IL-17 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2956.
Assessing in-hospital morbidity after urethroplasty using the EAU quality criteria for standardized reporting
Authors: M. Bandini, G. Barbagli, P.M. Joshi, R. Leni, G.O. Cirulli, G. Basile, S. Balò, F. Montorsi, S. Sansalone, A. Salonia, A. Briganti, D. Butnaru, S.B. Kulkarni, M. Lezzeri
Journal: European Urology (2021)
Response to ‘COVID‐19‐associated multisystem inflammatory syndrome in adults with Kawasaki disease‐like cutaneous manifestations’: reply from the authors
Authors: T.P. Afra, M.M. Siraj, M. Razmi T
Journal: British Journal of Dermatology (2021)

We appreciate the interest shown by Pathania regarding our manuscript,1 and enjoyed reading his additional comments on multisystem inflammatory syndrome in adults (MIS-A)/children (MIS-C) and kawasaki disease (KD). Our patient had a 3-days history of fever, and the rash appeared within a day of fever. Fever and rash subsided promptly with intravenous steroids (hydrocortisone 100mg Q8H) which was given from emergency suspecting drug rash (azithromycin and mefenamic acid taken for the fever).
In vivo printing of growth factor-eluting adhesive scaffolds improves wound healing
Authors: Kristo Nuutila, Mohamadmahdi Samandari, Yori Endo, Yuteng Zhang, Jacob Quint, Tannin A. Schmidt, Ali Tamayol, Indranil Sinha
Journal: Bioactive Materials (2021)

Acute and chronic wounds affect millions of people around the world, imposing a growing financial burden on patients and hospitals. Despite the application of current wound management strategies, the physiological healing process is disrupted in many cases, resulting in impaired wound healing. Therefore, more efficient and easy-to-use treatment modalities are needed. In this study, we demonstrate the benefit of in vivo printed, growth factor-eluting adhesive scaffolds for the treatment of full-thickness wounds in a porcine model. A custom-made handheld printer is implemented to finely print gelatin-methacryloyl (GelMA) hydrogel containing vascular endothelial growth factor (VEGF) into the wounds. In vitro and in vivo results show that the in situ GelMA crosslinking induces a strong scaffold adhesion and enables printing on curved surfaces of wet tissues, without the need for any sutures. The scaffold is further shown to offer a sustained release of VEGF, enhancing the migration of endothelial cells in vitro. Histological analyses demonstrate that the administration of the VEGF-eluting GelMA scaffolds that remain adherent to the wound bed significantly improves the quality of healing in porcine wounds. The introduced in vivo printing strategy for wound healing applications is translational and convenient to use in any place, such as an operating room, and does not require expensive bioprinters or imaging modalities.
Mucomucosal Anastomotic Non-Transecting Augmentation (MANTA) urethroplasty: Patient-reported outcomes and mid-term success rates of a surgical modification for obliterative bulbar strictures
Authors: P. Marks, R. Dahlem, M. Khonsari, L. Kühnke, F. König, M. Fisch, M.W. Vetterlein
Journal: European Urology (2021)
Dietary and Physiological Effects of Zinc on the Immune System
Authors: Inga Wessels, Henrike Josephine Fischer, Lothar Rink
Journal: Annual Review of Nutrition (2021)

Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency.