tbuckley/cabot-search huggingface dataset:
Abstract 326: Structural dynamics-based hit generation to disrupt YAP/TAZ-TEAD protein-protein interaction
Authors: Lin Du, Jing Liu, Qinglong Zeng, Ming Xu, Jiting Lu, Qiangang Zheng, Jidong Zhu
Journal: Cancer Research (2021)

Abstract The Hippo pathway is an evolutionarily conserved pathway involved in developmental biology. The biological functions of Hippo pathway are executed by the downstream transcriptional coactivator YAP/TAZ, which shuttle between the cytoplasm and the nucleus and have to interact with TEADs in nucleus for transcription activation. YAP/TAZ are master transcriptional factors widely activated in human cancers to promote cancer initiation, progression, metastasis and therapy resistance. It has been shown that aberrant YAP/TAZ activation is also associated with the adapted tumor microenvironment (TME) for tumor growth. Dysregulation in Hippo pathway and YAP/TAZ-TEADs transcriptional activity is pervasively associated with various types of cancers, including mesothelioma, squamous cell cancers, liver cancer and lung cancer, making it an attractive target for cancer therapy. Therefore, inhibition of YAP/TAZ oncogenic activity by blocking YAP/TAZ-TEADs interaction is an effective approach for cancer treatment. In this study, we aim to discover small molecule inhibitors that bind to TEADs and disrupt YAP/TAZ-TEADs interaction for cancer therapy. With superposition of all the available crystal structures of four TEAD subtypes in the public database, we found the YAP Ω loop binding site of TEADs is relatively rigid (of backbone atoms), but the side chain flexibility of K289, K265 and V406 in TEAD1 affects the shape of the binding site significantly. Notably, in two TEAD2 structures, e.g. PDB ID: 5dqe and 5dq8, K301 (K274 of TEAD1) adopts an open conformation and accommodates a flufenamic acid to bind in an induced pocket. Using 5dq8 as the protein model, we virtually screened a fragment library, and identified a hit compound that is suitable to combine with flufenamic acid. Interaction between the hit compound and TEAD1 was confirmed by 1D-NMR (STD). Based on the docking poses, we combined the hit and flufenamic acid, designed and synthesized several compounds. Interaction with TEAD1 of the compounds were confirmed by 1D-NMR, SPR and HTRF. Crystal structures of representative compounds confirmed the predicted binding mode in TEAD1. With further medicinal chemistry efforts, we have discovered a series of novel YAP/TAZ-TEAD PPI inhibitors bound at the Ω loop site of TEAD1. Citation Format: Lin Du, Jing Liu, Qinglong Zeng, Ming Xu, Jiting Lu, Qiangang Zheng, Jidong Zhu. Structural dynamics-based hit generation to disrupt YAP/TAZ-TEAD protein-protein interaction [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 326.
Abstract 498: ZL-1201, a differentiated CD47 therapeutic antibody with improved hematological safety profile
Authors: Bing Wan, Xu Fang, Shou Li, Wenhua Shi, Holly Li, David Bellovin, Lei Wang, Yusong Zhu, Yuan Lin, Shali Qi, Sophia Yin, Frank Tao, Lishan Kang, Omar Kabbarah, Haiying Zhou, Petter Veiby, James Yan, Karl Hsu
Journal: Cancer Research (2021)

Abstract The interaction between CD47 that is overexpressed on tumor cells and SIRPα on macrophages facilitates a “don't-eat-me” signal that inhibits macrophage-mediated phagocytosis of tumor cells. Blockade of the CD47/SIRPα interaction using antibodies against CD47 or SIRPα-Fc fusion proteins promotes phagocytosis and tumor cell destruction, which represents a promising strategy for tumor immunotherapy. However, CD47 is ubiquitously expressed on all cells including erythrocytes and platelets, which form a large antibody sink and lead to potential hematological toxicities. In fact, anemia and thrombocytopenia have been observed in non-human primates and tumor patients that are subjected to anti-CD47 treatment in preclinical and clinical studies. We have developed ZL-1201, a recombinant, humanized monoclonal antibody that specifically targets CD47. ZL-1201 was engineered to reduce Fc-mediated antibody effector function. Preclinical in vitro studies show that ZL-1201 displays potent binding to CD47 thereby blocking interaction with SIRPα and effectively facilitates macrophage-mediated phagocytosis of hematological and solid tumor cells. Importantly, ZL-1201 induces minimal red blood cell (RBC) phagocytosis and does not induce hemagglutination, though it does bind to human RBCs and platelets. In vivo studies demonstrate that ZL-1201 possesses potent antitumor efficacy in rodent xenograft tumor models, while displaying remarkably improved hematological safety profile as compared with the benchmark antibody in a toxicology study in cynomolgus monkeys. Thus, ZL-1201 treatment represents an effective CD47-targeting therapy with improved hematological safety consequences. A Ph1 dose escalation study to assess the safety of ZL-1201 is currently ongoing in patients with solid tumors, and future combination studies are planned for both hematologic and solid tumor indications. Citation Format: Bing Wan, Xu Fang, Shou Li, Wenhua Shi, Holly Li, David Bellovin, Lei Wang, Yusong Zhu, Yuan Lin, Shali Qi, Sophia Yin, Frank Tao, Lishan Kang, Omar Kabbarah, Haiying Zhou, Petter Veiby, James Yan, Karl Hsu. ZL-1201, a differentiated CD47 therapeutic antibody with improved hematological safety profile [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 498.
Abstract 2795: Estimation of cell lineage and inter-cell interactions from spatial transcriptomics data
Authors: Beibei Ru, Jinlin Huang, Yu Zhang, Kenneth Aldape, Peng Jiang
Journal: Cancer Research (2021)

Abstract The spatial transcriptomics (ST) technology has enabled geographical profiling of tumor gene expression. However, each ST spot may detect mixture signals from diverse immune or malignant cells of unknown lineages, and local tissue densities may vary significantly across regions. Therefore, the decomposition of ST cell lineages remains a challenge that cannot be resolved by previous decomposition methods for fixed cell types in bulk tumors. We developed the Spatial Cell Estimator (SpaCE) to infer the cell identities and intercellular interactions for tumor ST data. SpaCE first estimates the cancer cell clonal abundance through modeling the copy number segmental variations across ST spots. Then, we utilized a constrained regression to determine the hierarchy of immune cell lineages and local tissue densities. The prediction accuracy was validated through both simulation and double-blinded pathology annotations on hematoxylin and eosin images. Based on reliable cell lineage inference, SpaCE can further reveal how intercellular interactions affect the pathway and gene activities in distinct regions to modulate the cancer progression. Citation Format: Beibei Ru, Jinlin Huang, Yu Zhang, Kenneth Aldape, Peng Jiang. Estimation of cell lineage and inter-cell interactions from spatial transcriptomics data [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 2795.
Helen Salisbury: No room for growth at general practices
Authors: Helen Salisbury
Journal: BMJ (2021)

There aren’t enough GPs to meet patient demand, and we’ve been invited to plug the gaps with other health professionals funded though the Additional Roles Reimbursement Scheme (ARRS). The plan is that by 2024 an extra 26 000 staff—including physiotherapists, pharmacists, paramedics, social prescribers, and dietitians—will work in general practice teams, offering a better service to patients and (if all goes to plan) lightening the load for GPs.

So far around 9000 of these allied health professionals are in post, but it remains unclear whether the 2024 target will be reached. Lack of suitably trained personnel is an issue—we really can’t solve …
Covid-19: Vaccine centres operating at 30% capacity as young people stay away
Authors: Ingrid Torjesen
Journal: BMJ (2021)

Covid-19: Vaccine centres operating at 30% capacity as young people stay away Ingrid TorjesenCovid-19 vaccination centres are working at 30% capacity because many young adults think they are "invincible" and don't need the vaccine to protect themselves, a healthcare leader in London has said. 1 NHS England.Half a million covid jabs booked in "Glastonbury rush" this morning.8 Jun 2021.https://
Abstract 10939: C1q/tnf-related Protein5 (ctrp5) as a Novel Molecule Contributing to Diabetic Vascular Endothelium Dysfunction Through Suppressing Rhoa/rock Signaling
Authors: Yajing Wang, Jing Liu, Gan Lu, Demin Liu, Ling Zhang, Devin Kolmetzky, Bernard Lopez, Theodore Christopher, Xin L Ma
Journal: Circulation (2019)

Objective: Dysregulated adipokine profiles contribute to the pathogenesis of diabetic cardiovascular complications. Endothelial cell (EC) dysfunction, a common pathologic alteration in cardiovascul...
Abstract 13973: Efficacy and Safety of Cryoballoon versus Radiofrequency Ablation of Atrial Fibrillation in the VA Healthcare System
Authors: Zaid Gheith, Bilal Alqam, Fuad Habash, Khaldia Khaled, Amjad Abualsuod, Mohammed Madmani, Srikanth Vallurupalli, Waddah Maskoun
Journal: Circulation (2018)

Background: Prior randomized studies suggested similar efficacy of cryoballoon (CB) and radiofrequency (RF) ablation of atrial fibrillation (AF) with a slightly different complication profile (more...
Clinical Deployment of Explainable Artificial Intelligence of SPECT for Diagnosis of Coronary Artery Disease
Authors: Yuka Otaki, Ananya Singh, Paul Kavanagh, Robert J.H. Miller, Tejas Parekh, Balaji K. Tamarappoo, Tali Sharir, Andrew J. Einstein, Mathews B. Fish, Terrence D. Ruddy, Philipp A. Kaufmann, Albert J. Sinusas, Edward J. Miller, Timothy M. Bateman, Sharmila Dorbala, Marcelo Di Carli, Sebastien Cadet, Joanna X. Liang, Damini Dey, Daniel S. Berman, Piotr J. Slomka
Journal: JACC. Cardiovascular imaging (2021)
Abstract 2188: Urothelial cancer-GENOmic analysis to improve patient outcomes and research (UC-GENOME): a bladder cancer advocacy network (BCAN) led collaborative research study
Authors: Jeffrey S. Damrauer, Jeff Klomp, Wolfgang Beck, Mi Zhou, Elizabeth Plimack, Matthew Galsky, Petros Grivas, Noah Hahn, Peter O'Donnell, Gopa Iyer, David I. Quinn, Katherine A. Hoadley, William Y. Kim, Matthew I. Milowsky
Journal: Cancer Research (2021)

Abstract The UC-GENOME study was designed to capitalize on The Cancer Genome Atlas (TCGA) findings in real world patients with metastatic urothelial carcinoma (UC) with co-equal aims: 1) to provide targeted DNA sequencing for potential clinical decision making at no cost to patients; and 2) to create a clinically annotated biorepository (including tissue, plasma, and PBMCs) for collaborative research. Patients with metastatic UC (n=209, median age 68 y, 74% male) were accrued at 8 academic medical centers between 2016-2019. We report on the first analysis of the targeted DNAseq (n=191) and total RNAseq (n=176) from FFPE specimens (n=169 overlap). Recurrently mutated genes were observed in a similar frequency to TCGA, including TP53 (54%), KMT2D (30%), ARID1A (26%) and FGFR3 (18%). Somatic variant patterns were correlated with previously annotated mutational signatures (COSMICv3), revealing a subset of tumors enriched for APOBEC signatures. Molecular subtypes were defined using the Bladder Cancer Molecular Taxonomy Group's consensus subtyping schema (Ba_Sq=54 [31%], Stroma-rich=64 [36%], LumP=26 [15%], LumU=24 [14%], LumNS=4 [2%], NE=4 [2%]). To further understand the tumor immune features and whether they correlate with durable clinical response, tumor microenvironment deconvolution was performed by applying MiXCR and immune gene signatures. An inflamed phenotype and enhanced T cell receptor richness but not clonality was observed within Ba_Sq and Stroma-rich subtypes, which also had the highest disease control rate (CR/PR + SD ~75%) to immunotherapy. The Stroma-rich subtype had the highest disease control rate (~88%) to chemotherapy. Future efforts will leverage the clinical, DNA and RNAseq data along with other biobanked specimens for collaborative research initiatives. Citation Format: Jeffrey S. Damrauer, Jeff Klomp, Wolfgang Beck, Mi Zhou, Elizabeth Plimack, Matthew Galsky, Petros Grivas, Noah Hahn, Peter O'Donnell, Gopa Iyer, David I. Quinn, Katherine A. Hoadley, William Y. Kim, Matthew I. Milowsky. Urothelial cancer-GENOmic analysis to improve patient outcomes and research (UC-GENOME): a bladder cancer advocacy network (BCAN) led collaborative research study [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 2188.
A Phase II Trial of the Bruton Tyrosine-Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Relapsed/Refractory Waldenström Macroglobulinemia
Authors: Gang An, Daobin Zhou, Shu Cheng, Keshu Zhou, Jianyong Li, Jianfeng Zhou, Liping Xie, Jie Jin, Liye Zhong, Lingzhi Yan, Haiyi Guo, Chenmu Du, Jinhua Zhong, Yiling Yu, Binghao Wu, Lugui Qiu
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Although Bruton tyrosine kinase (BTK) inhibitors have demonstrated promising efficacy in patients with Waldenström macroglobulinemia (WM), data in Asian populations are scarce. This trial is the first to investigate the effect of a BTK inhibitor in Chinese patients with relapsed/refractory (R/R) WM. Patients and Methods: Patients with R/R WM with at least one prior regimen were enrolled into this single-arm, multicenter, phase II study (NCT03332173) and received zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR), as assessed by an independent review committee. Secondary endpoints included progression-free survival, overall response rate, duration of major response, and safety. Results: Forty-four patients were enrolled. After a median follow-up of 33.0 (range, 3.2–36.5) months, MRR in all patients was 69.8%, with very good partial response or better in 32.6% of patients. All mutation groups benefited from zanubrutinib treatment (MRR in patients with MYD88L265P mutation, 73%; MRR in patients with MYD88 wild type mutation, 50%). A higher response rate was seen in the MYD88L265P/CXCR4WT population, compared with the other populations. Median progression-free survival and median duration of major response were not reached. The most frequently reported grade ≥3 treatment-emergent adverse events (AEs) were neutrophil count decreased (31.8%), and platelet count decreased and pneumonia (20.5% each). No case of atrial fibrillation/flutter occurred. Conclusions: Zanubrutinib achieved a high rate of response that was durable and deep in patients with R/R WM across all subgroups, and potentially confers a positive benefit–risk profile for WM.
Abstract 1431: Role of emt biomarkers in mediating osimertinib resistance in non-small cell lung cancer
Authors: Kavya Sri Racherla, Katrina Dovalovsky, Neelu Puri
Journal: Cancer Research (2021)

Abstract Osimeritinib (OR), a Tyrosine Kinase Inhibitor is a first-line therapy in EGFR-mutant NSCLC patients. Resistance to OR treatment may occur due to acquired C797S mutations, MET amplifications and ALK rearrangements and other mechanisms not clearly defined. EMT may be one of the reasons for TKI resistance. EMT is a process by which epithelial cells acquire mesenchymal characteristics that increase invasiveness. We hypothesize that loss of E-cadherin during EMT, results in abnormal localization of p120 catenin, an E-cadherin regulating protein, and Kaiso factor, a repressor of Wnt signaling, promoting oncogenesis. Protein arginine methyl transferase 1 (PRMT1) an EMT regulator catalyzes methylation of Twist1, which represses E-cadherin. However, their role in OR resistance is still unknown. We have made parental (P) NSCLC cells, H2170, H358, H1975 and H3255 resistant to OR. MTT assays were performed on the parental cells and OR resistant cells which showed that the H2170OR, H3255OR, H358OR, H1975OR cells had IC50 for OR, 2.8-14 fold higher in comparison to parental cells, respectively. We further performed qPCR to study the modulation of EMT biomarkers in OR cells as compared to parental cells and found upregulation of PRMT1, p120 catenin and Kaiso factor by 1.5-3.67 fold respectively in H1975 cells and 1.5-5.73 fold in H3255 cells. Immunofluorescence studies in H1975OR cells for expression of PRMT1 showed that there was 3.18 fold increase as compared to 2.21 fold increase in Erlotinib resistant H1975 (H1975ER) and 4.77 fold increase in H3255OR as compared to 2.27 fold increase in H3255ER. After transfection with p120 siRNA we found that OR efficacy was increased by 33% in comparison to mock siRNA and OR treated cells. The percentage wound closure after 24 hours was found to be 26.2% in the p120-catenin siRNA transfected cells as compared to 7.4%.in mock siRNA transfected cells (p&amp;lt;0.05) indicating its role in EMT and cell migration. Furthermore, our results showed increased expression of p120 catenin in smokers with 50% of smokers showing high expression compared to 0% and 5.8% of quit smokers and nonsmokers indicating that high p-120 expression was associated with smoking (P=0.002). In conclusion, biomarkers like PRMT1 may mediate the process of EMT by methylation of Twist1 and upregulation of p120 that prevents transcriptional repression of Kaiso factor target genes, promoting EMT in OR and ER resistant cells. p-120 expression was found to be higher in smokers compared to quit/nonsmokers indicating that it may have a potential role in lung cancer. Citation Format: Kavya Sri Racherla, Katrina Dovalovsky, Neelu Puri. Role of emt biomarkers in mediating osimertinib resistance in non-small cell lung cancer [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 1431.
Continuous monitoring of deep-tissue haemodynamics with stretchable ultrasonic phased arrays
Authors: Chonghe Wang, Baiyan Qi, Muyang Lin, Zhuorui Zhang, Mitsutoshi Makihata, Boyu Liu, Sai Zhou, Yi-hsi Huang, Hongjie Hu, Yue Gu, Yimu Chen, Yusheng Lei, Taeyoon Lee, Shu Chien, Kyung-In Jang, Erik B. Kistler, Sheng Xu
Journal: Nature Biomedical Engineering (2021)
There is no way to compensate a non-timely use of early salvage radiation therapy in men with recurrent Prostate Cancer after Radical Prostatectomy. A retrospective, multi-centre analyses on oncological and toxicity outcomes
Authors: E. Mazzone, N. Fossati, R.J. Karnes, S.A. Boorjan, G. Motterle, A. Bossi, T. Kumar, N. Di Muzio, C. Cozzarini, B. Noris Chiorda, G. Gandaglia, A. Stabile, S. Scuderi, D. Bartkowiak, S. Shariat, G. Goldner, S. Joniau, H. Van Poppel, C. Berghen, G. De Meerleer, F. Montorsi, T. Wiegel, A. Briganti
Journal: European Urology (2021)
EAU recommendations for the diagnosis and treatment of human papillomavirus infections in men
Authors: T. Cai, W. Devlies, A. Pilatz, R. Veeratterapillay, B. Pradere, M. Tunde, F. Bruyère, R. Bartoletti, B. Koves, S. Geerlings, S. Schubert, F. Wagenlehner, G. Mantica, E. James Smith, G. Bonkat
Journal: European Urology (2021)
Optimal timing of cholecystectomy after necrotising biliary pancreatitis
Authors: Nora D Hallensleben, Hester C Timmerhuis, Robbert A Hollemans, Sabrina Pocornie, Janneke van Grinsven, Sandra van Brunschot, Olaf J Bakker, Rogier van der Sluijs, Matthijs P Schwartz, Peter van Duijvendijk, Tessa Römkens, Martijn W J Stommel, Robert C Verdonk, Marc G Besselink, Stefan A W Bouwense, Thomas L Bollen, Hjalmar C van Santvoort, Marco J Bruno
Journal: Gut (2021)

Following an episode of acute biliary pancreatitis, cholecystectomy is advised to prevent recurrent biliary events. There is limited evidence regarding the optimal timing and safety of cholecystectomy in patients with necrotising biliary pancreatitis.A post hoc analysis of a multicentre prospective cohort. Patients with biliary pancreatitis and a CT severity score of three or more were included in 27 Dutch hospitals between 2005 and 2014. Primary outcome was the optimal timing of cholecystectomy in patients with necrotising biliary pancreatitis, defined as: the optimal point in time with the lowest risk of recurrent biliary events and the lowest risk of complications of cholecystectomy. Secondary outcomes were the number of recurrent biliary events, periprocedural complications of cholecystectomy and the protective value of endoscopic sphincterotomy for the recurrence of biliary events.Overall, 248 patients were included in the analysis. Cholecystectomy was performed in 191 patients (77%) at a median of 103 days (P25-P75: 46-222) after discharge. Infected necrosis after cholecystectomy occurred in four (2%) patients with persistent peripancreatic collections. Before cholecystectomy, 66 patients (27%) developed biliary events. The risk of overall recurrent biliary events prior to cholecystectomy was significantly lower before 10 weeks after discharge (risk ratio 0.49 (95% CI 0.27 to 0.90); p=0.02). The risk of recurrent pancreatitis before cholecystectomy was significantly lower before 8 weeks after discharge (risk ratio 0.14 (95% CI 0.02 to 1.0); p=0.02). The complication rate of cholecystectomy did not decrease over time. Endoscopic sphincterotomy did not reduce the risk of recurrent biliary events (OR 1.40 (95% CI 0.74 to 2.83)).The optimal timing of cholecystectomy after necrotising biliary pancreatitis, in the absence of peripancreatic collections, is within 8 weeks after discharge.
Phenotyping long COVID
Authors: Robert Naeije, Sergio Caravita
Journal: European Respiratory Journal (2021)

<b>Patients who recover from an acute SARS-CoV-2 infection often present with persistent symptoms lasting for months. The cardiopulmonary exercise test profile of those with "long COVID" is suggestive of deconditioning with a tendency to hyperventilation.</b>https://bit.ly/3y8n0Bt
Long non-coding RNA ANRIL promotes homologous recombination-mediated DNA repair by maintaining ATR protein stability to enhance cancer resistance
Authors: Lei Liu, Yuanyuan Chen, Yijuan Huang, Kun Cao, Tingting Liu, Hui Shen, Jianguo Cui, Bailong Li, Jianming Cai, Fu Gao, Yanyong Yang
Journal: Molecular Cancer (2021)