tbuckley/cabot-search huggingface dataset:
Abstract A15: Uninflamed immunologic microenvironment of muscle-invasive bladder cancer associates with activating FGFR3 gene alterations
Authors: Veronika Weyerer, Robert Stoehr, Pamela Strissel, Reiner Strick, Christian Bolenz, Arndt Hartmann, Philipp Erben, Markus Eckstein
Journal: Clinical Cancer Research (2020)

Abstract Background and Objective: Muscle-invasive bladder cancer (MIBC) is a complex disease for which perioperative chemotherapy followed by radical cystectomy is a standard treatment. In recent years new therapy options for advanced urothelial tumors have emerged, representing a personalized medicine approach for patients. For example, targeting fibroblast growth factor receptors (FGFR) as well as restoring antitumor activity using PD-1/PD-L1 inhibitors are currently being evaluated in clinical trials and show promising results. Our present goal in this study was to assess the relationship of FGFR3-gene alterations, immune cell types, gene expression of checkpoint inhibitors like PD-L1/PD-1, and immune-related genes in MIBC to gain insight into significant differential expression. Materials and Methods: We analyzed the TCGA cohort (n=407). Tumors were identified with activating FGFR3-gene alterations (FGFR3-altered: mutation, amplification, fusion, gain). A comparison was performed between tumors with FGFR3-altered or wild-type tumors and tumor mutational burden (TMB), neoantigen load, immune checkpoint, and immune-related gene expression as well as specific immune cell populations using the CIBERSORT-algorithm. Results: Activating FGFR3-altered tumors showed significantly less TMB and neoantigen load compared to wild-type cases (p=0.037 and p=0.04). Tumors with high expression of PD-1, PD-L1, CTLA4, and IDO1 were predominately not FGFR3-altered (p&amp;lt;0.0001). Additionally, expression of immune-related genes like CD3Z, CD8A, FOXP3 and amounts of specific immune cell populations were significantly inversely associated with an FGFR3-altered status. Conclusion: Strikingly, our analysis demonstrates that activating FGFR3 gene alterations in MIBC show low immune checkpoint and immune-related gene expression as well as low amounts of immune cells, demonstrating association with an uninflamed tumor microenvironment. Therefore, combination therapies targeting FGFR3 and, e.g., PD-1/PD-L1 might not be effective. It will be essential to validate these results in another MIBC cohort as well as unravel the role of aberrant signaling of FGFR3. Citation Format: Veronika Weyerer, Robert Stoehr, Pamela Strissel, Reiner Strick, Christian Bolenz, Arndt Hartmann, Philipp Erben, Markus Eckstein. Uninflamed immunologic microenvironment of muscle-invasive bladder cancer associates with activating FGFR3 gene alterations [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A15.
Work visas: foreign doctors in the US have more than covid-19 to fear
Authors: Kim Painter
Journal: BMJ (2020)

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A high-affinity antibody against the CSP N-terminal domain lacks <i>Plasmodium falciparum</i> inhibitory activity
Authors: Elaine Thai, Giulia Costa, Anna Weyrich, Rajagopal Murugan, David Oyen, Yevel Flores-Garcia, Katherine Prieto, Alexandre Bosch, Angelo Valleriani, Nicholas C. Wu, Tossapol Pholcharee, Stephen W. Scally, Ian A. Wilson, Hedda Wardemann, Jean-Philippe Julien, Elena A. Levashina
Journal: The Journal of Experimental Medicine (2020)

Malaria is a global health concern, and research efforts are ongoing to develop a superior vaccine to RTS,S/AS01. To guide immunogen design, we seek a comprehensive understanding of the protective humoral response against Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP). In contrast to the well-studied responses to the repeat region and the C-terminus, the antibody response against the N-terminal domain of PfCSP (N-CSP) remains obscure. Here, we characterized the molecular recognition and functional efficacy of the N-CSP–specific monoclonal antibody 5D5. The crystal structure at 1.85-Å resolution revealed that 5D5 binds an α-helical epitope in N-CSP with high affinity through extensive shape and charge complementarity and the unusual utilization of an antibody N-linked glycan. Nevertheless, functional studies indicated low 5D5 binding to live Pf sporozoites and lack of sporozoite inhibition in vitro and in vivo. Overall, our data do not support the inclusion of the 5D5 N-CSP epitope into the next generation of CSP-based vaccines.
p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease
Authors: Zhengwei Ma, Lin Li, Man J. Livingston, Dongshan Zhang, Qingsheng Mi, Ming Zhang, Han-Fei Ding, Yuqing Huo, Changlin Mei, Zheng Dong
Journal: Journal of Clinical Investigation (2020)

Dysregulation of autophagy in diabetic kidney disease (DKD) has been reported, but the underlying mechanism and its pathogenic role remain elusive. We show that autophagy was inhibited in DKD models and in human diabetic kidneys. Ablation of autophagy-related gene 7 (Atg7) from kidney proximal tubules led to autophagy deficiency and worse renal hypertrophy, tubular damage, inflammation, fibrosis, and albuminuria in diabetic mice, indicating a protective role of autophagy in DKD. Autophagy impairment in DKD was associated with the downregulation of unc-51-like autophagy-activating kinase 1 (ULK1), which was mediated by the upregulation of microRNA-214 (miR-214) in diabetic kidney cells and tissues. Ablation of miR-214 from kidney proximal tubules prevented a decrease in ULK1 expression and autophagy impairment in diabetic kidneys, resulting in less renal hypertrophy and albuminuria. Furthermore, blockade of p53 attenuated miR-214 induction in DKD, leading to higher levels of ULK1 and autophagy, accompanied by an amelioration of DKD. Compared with nondiabetic samples, renal biopsies from patients with diabetes showed induction of p53 and miR-214, associated with downregulation of ULK1 and autophagy. We found a positive correlation between p53/miR-214 and renal fibrosis, but a negative correlation between ULK1/LC3 and renal fibrosis in patients with diabetes. Together, these results identify the p53/miR-214/ULK1 axis in autophagy impairment in diabetic kidneys, pinpointing possible therapeutic targets for DKD.
Hematopoietic-Specific CSNK2B Loss in Mice Causes Impaired Erythropoiesis
Authors: Laura Quotti Tubi, Sara Canovas Nunes, Marilena Carrino, Ketty Gianesin, Sabrina Manni, Odile Filhol-Cochet, Brigitte Boldyreff, Livio Trentin, Gianpietro Semenzato, Francesco Piazza
Journal: Blood (2017)
FRI0005 Safety of new cox-2 inhibitors in nsaid-intolerant patients
Authors: M Sánchez-Borges, A Capriles-Hulett, F Caballero, C Pérez
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Non-steroidal anti-inflammatory drug (NSAID)-triggered urticaria and angioedema occurrs in up to 3% of the population. The tolerance to new COX-2 selective inhibitors in intolerant patients has not been determined. <h3>Objectives</h3> To study the clinical tolerance to Rofecoxib and Celecoxib in patients sensitive to conventional NSAIDs who develop urticaria and/or angioedema when exposed to these drugs. <h3>Methods</h3> Sixty three subjects (female 44, male 19, mean age 33.0 ± 16.7 years, range 11 – 74 years) with challenge-proved urticaria/angioedema were studied. These patients were challenged by means of the single-blinded oral method, controlled with placebo. <h3>Results</h3> Positive challenges were observed in 4 out of 53 subjects challenged with Rofecoxib (7.5%) and in 13 out of 47 individuals submitted to oral provocation with Celecoxib (27.6%) (p = 0.01). <h3>Conclusion</h3> We conclude that: 1) The clinical tolerance to selective COX-2 inhibitors in NSAID-sensitive patients with skin manifestations differs between new drugs, which may be due to different degrees of enzyme selectivity or to other, not yet determined reasons.2) COX-1 inhibition would be involved in the production of cutaneous adverse reactions to NSAIDs.3) Controlled oral challenges are indicated especially for the management of sensitive individuals with chronic inflammatory and/or painful diseases.
AB1016 RATE OF PREDEFINING DISEASE ACTIVITY, REMISSION AND RELAPSE OF ADULT-ONSET STILL’S DISEASE: SYSTEMATIC LITERATURE REVIEW
Authors: E. Bilgin, U. Kalyoncu
Journal: Annals of the Rheumatic Diseases (2020)

Background: Adult-onset Still’s disease (AOSD) is a rare, multisystem and auto-inflammatory disorder. Although several scoring systems are proposed to describe AOSD disease activity, there is no agreement on the definition of disease activity, remission or relapse of AOSD. Objectives: Aim of this literature review was to determine the rates of defining ‘’disease activity’’, ‘’remission’’ and ‘’relapse’’ of AOSD. Methods: We performed a systematic review (May 2019) on Pubmed by using the MeSh word ‘’ Adult-onset Still’s disease’’; results were restricted to human studies and English language. We excluded case reports, reviews and studies including less than 10 patients; 215 articles were recruited for final assessment. Of this 215 article, we reached the full-texts of the 181 articles. Final assessment was done with 181 articles. In these articles, we searched whether the definitions of disease activity, remission or relaps were made or not. Results: Total of 181 articles were included to analysis. Mean age was 37.2±6.6 and 73.6% of patients was female. Articles were devided to 4 main groups according to main focus related to AOSD: Observational studies, laboratory studies, genetic studies and clinical trials. Diagnosis of AOSD was according to Yamaguchi criteria in 159 (87.8%) of articles and Yamaguchi criteria was the most commonly used criteria set. Disease activity was defined in 96 (54.1%) of articles. Remission and relapse were defined in 52 (28.7%) and 18 (10%) of articles, respectively. Most commonly used definition of disease activity was the ‘’systemic score’’ which was defined by Pouchet et al. Rates of defining ‘’disease activity’’, ‘’remission’’ and ‘’relapse’’ according to 4 main groups were given in Table 1. Table 1. Rates of disease activity, remission and relapse reporting based on 4 main article groups Article group n (%) Disease activity (n,%) p Remission (n,%) p Relapse (n,%) p Observational Studies 70 (38.7) 18 (25.7) &lt;0.001 17 (24.3) &lt;0.001 8 (11.4) &lt;0.001 Laboratory Studies 72 (39.8) 46 (63.9) 15 (20.8) 2 (2.8) Genetic Studies 17 (9.4) 5 (29.4) 2 (11.8) 0 (0) Clinical Trial 22 (12.2) 14 (63.6) 18 (81.8) 8 (36.4) Conclusion: In recent years, new treatment options become available for AOSD. However, data about how to measure the AOSD activity in largely missing. Definitions of disease activity, remission or relapse are missing in the most of the studies, including clinical trials, in current literature. Future studies are needed for this issue. References: None Disclosure of Interests: Emre Bilgin: None declared, Umut Kalyoncu Consultant of: Abbvie, Amgen, Janssen, Lilly, Novartis, UCB
Abstract PR01: Novel role of ketone body metabolism in acquired gemcitabine resistance
Authors: Krizia Rohena-Rivera, Neil Bhowmick
Journal: Clinical Cancer Research (2020)

Abstract Urinary bladder cancer accounts for 81,000 new cases per year and 4.7% of the new cancer diagnosis in the US. Even though most of the patients suffer from noninvasive lesions, around 70% will recur following surgical intervention. Chemotherapy with gemcitabine in combination with cisplatin is a common treatment option for recurrent disease; however, 60% of the patients will relapse due to resistance. Gemcitabine is a synthetic pyrimidine nucleoside prodrug, without a known mechanism for resistance. In examining mechanisms of resistance, we identified ketone body metabolism to be important. OXCT1, a rate-limiting enzyme in ketone metabolism, was found to be highly associated with bladder cancer death—Hoglund et al, P = 2.3 × 10-3 and TCGA, P = 6.5 × 10-4. We measured the expression of OXCT1 in RT4, UMUC3, T24, and 5637 bladder cancer cell lines and observed that expression correlated with gemcitabine resistance. The generation of gemcitabine resistance of otherwise sensitive 5637 cells (5637GR) resulted in elevation of OXCT1 expression, as well as PGC1a and SIRT1 involved in mitochondrial biogenesis. Conversely, the CRISPR/Cas9 knockout of OXCT1 was able to sensitize inherently resistant UMUC3 and generated 5637GR lines. Given that OXCT1 is a rate-limiting enzyme in ketone metabolism, we evaluated oxygen consumption rate among parental and resistant cells with Seahorse. Surprisingly, resistant cells were found to be metabolically quiescent. We evaluated the role OXCT1 has on cancer stemness through sphere-forming assays (hanging drop and forced floating methods) to reveal that the OXCT1-KO lines had reduced spheres compared to their parental lines. We identified bone morphogenic protein (BMP) signaling to be induced in promoting SOX9 expression, in OXTC1-dependent manner. Gene expression analysis further corroborated the novel role of ketone metabolism in stemness and therapeutic resistance. This abstract is also being presented as Poster B28. Citation Format: Krizia Rohena-Rivera, Neil Bhowmick. Novel role of ketone body metabolism in acquired gemcitabine resistance [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr PR01.
miR-552-3p modulates transcriptional activities of FXR and LXR to ameliorate hepatic glycolipid metabolism disorder
Authors: Lei Fan, Rongtao Lai, Ningning Ma, Yunxia Dong, Yu Li, Qian Wu, Junwen Qiao, Henglei Lu, Likun Gong, Zhouteng Tao, Jing Chen, Qing Xie, Jin Ren
Journal: Journal of Hepatology (2020)
Abstract 6098: Gut microbiome predicts response to immunotherapy in advanced NSCLC
Authors: Lu Yang, Huihui Yin, Yan Wang, Yuchen Jiao
Journal: Cancer Research (2020)

Abstract Introduction: It has demonstrated that gut microbiome could affect the response to anti-programmed death 1 (PD-1) immunotherapy in the Western population. And one study has suggested that the diversity of gut microbiome was associated with responses to immunotherapy in China. However, there were some conflicts in these previous studies. This study is aimed to further explore the relationship between gut microbiome and clinical response in advanced non-small cell lung cancer (NSCLC) patients. Methods: From 30th/January/2018, advanced NSCLC patients with anti-PD-1 immunotherapy were enrolled. Fecal samples were collected prior to starting therapy and serially after immunotherapy. Total DNA was extracted and 16S ribosome RNA gene sequencing was applied to assess gut microbiome composition. Results: Clinical response rate was determined by radiography according to Response Evaluation Criteria in Solid Tumor Version 1.1. There were sixteen responders (referred to as R, thirteen with stable disease and three with partial response), and thirteen non-responders (NR), yielding a response rate of 55.2%. Firmicutes, Bacteroidetes, Actinobacteria and Proteobacoteria were the main microbial composition in baseline stool samples. Gut microbiome diversity at baseline was not statistically different between responders and non-responders. However, the relative abundance of Akkermansia genus at baseline was significantly enriched in R cohort (p=0.0363). The count of OTUs at progression increased significantly during the treatment. (p=0.012). Of note, Alloprevotellal and Capnocytophaga were overrepresented significantly at progression, indicating that they were associated with unfavorable clinical outcome. Conclusions: This study illustrated that the relationship between clinical outcomes and gut microbiome by dynamic monitoring. Akkermansia present at baseline feces was related with better clinical response to immunotherapy. The increase of some bacteria abundance, especially Alloprevotellal and Capnocytophaga, may predict disease progression during the immunotherapy. This study will continue to collect fecal samples and further verify these conclusions. Citation Format: Lu Yang, Huihui Yin, Yan Wang, Yuchen Jiao. Gut microbiome predicts response to immunotherapy in advanced NSCLC [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 6098.
Abstract IA09: Collagen microenvironment in the modulation of local invasion and distal metastasis
Authors: Yu Cheng, Keith Syson Chan
Journal: Clinical Cancer Research (2020)

Abstract Metastasis is a multistep process that includes, but is not limited to, local invasion, intravasation of tumor cells into the circulation, and extravasation of circulating tumor cells from the circulation into distal organs for metastatic colonization. The 5-year survival rate of patients diagnosed with metastatic bladder urothelial carcinomas is less than 10%, posing a major clinical challenge. Previous studies in human bladder urothelial carcinomas have elegantly investigated the mechanistic contribution of tumor cell intrinsic properties that promote metastasis. However, the contribution of tumor microenvironments at both the primary tumor and metastatic sites to the metastatic process is not as well characterized. Historically, the extracellular matrix (ECM) was considered a passive scaffold, enclosing neighboring cancer cells and other cell types to support tissue architecture. Intriguingly, recent studies, including ours, revealed the emerging roles of ECMs as a dynamic component of the tumor microenvironment, which crosstalks with cancer cells. Here, we showed that bladder cancer cells expressing the collagen receptor CD167a or discoidin domain receptor 1 responded to collagen stimulation at the primary tumor to promote local invasion and utilized the same receptor to preferentially colonize at airway smooth muscle cells—another rich source of collagen and a newly identified metastatic niche in lung. Morphologically, these collagen-CD167a-driven metastatic foci are uniquely distinct from typical lung alveolar metastatic lesions and exhibited activation of the CD167a-HSP90-Stat3 axis. Interestingly, metastatic lung colonization could be abrogated using an investigational drug that attenuates Stat3 activity, implicating this seed-and-soil interaction as a therapeutic target for abrogating lung metastases. Together with our recent study demonstrating prevalent Stat3 expression in the primary basal bladder carcinomas (J Natl Cancer Inst 2018 May 1;110[5]:448-59), these findings implicate Stat3 as a valid target for metastatic bladder carcinoma patients with a basal molecular subtype, thus opening a new avenue for potential clinical intervention. Citation Format: Yu Cheng, Keith Syson Chan. Collagen microenvironment in the modulation of local invasion and distal metastasis [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA09.
Fertility preservation and timing of cancer treatment
Authors: A. Kumar, A. Mhaskar, S. Vadaparampil, B. Djulbegovic, G. Quinn
Journal: Journal of Clinical Oncology (2009)

e20629 Background: Cancer survival rates have increased steadily over time and young cancer survivors desire quality of life, including the ability to have a family. Cancer treatments, due to its toxic nature, can permanently or temporarily affect fertility. However, advanced fertility preservation measures are available and should be pursued before toxic chemo or radiation therapy. Evidence from observational studies indicate patients want to be informed of the adverse effects of cancer treatments on their fertility. Despite conflicting evidence on the efficacy of early treatment, the urgency of starting treatment early for maximum benefit has been cited as the most common reason for not discussing fertility preservation with patients.Accordingly, we conducted a systematic review and meta-analysis to assess if early treatment leads to better outcomes. Methods: A comprehensive literature search was performed of MEDLINE and Cochrane databases from 1966–2008 for all phase III randomized controlled trials (RCT) comparing early versus late treatment in cancer patients as first line therapy. Data were extracted and pooled on benefits (overall survival) and harms (treatment related mortality). Results: Initial search yielded 570 trials, of which 8 RCTs met the inclusion criteria. 3 RCTs assessed the efficacy of early versus deferred treatment in prostate cancer, 3 in multiple myeloma, and 1 each in lung cancer and chronic lymphocytic leukemia (CLL). Overall, pooled data showed survival benefit with early treatment (Hazard ratio [HR]=1.16,95%CI 1.05–1.28). However, the benefit with early treatment was restricted to prostate cancer(HR=1.21,95%CI 1.09–1.35). There was no survival difference between early and deferred treatment in multiple myeloma (HR=1.11,95%CI 0.67–1.84), CLL (HR=0.89,95%CI 0.49–1.59) or lung cancer (HR=0.95,95%CI 0.72–1.24). Pooled results excluding prostate cancer RCTs did not show a survival benefit with early treatment (HR=0.97,95%CI 0.78–1.21). No trial reported data on harms. There was no significant heterogeneity among trials. Conclusions: The totality of the evidence shows except in prostate cancer, deferment of treatment does not lead to decreased survival, and provides a unique window to oncologists to address the issues related to fertility preservation if desired by patients. No significant financial relationships to disclose.
The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy
Authors: Jimin Yuan, Xiaoduo Dong, Jiajun Yap, Jiancheng Hu
Journal: Journal of Hematology & Oncology (2020)

Abstract Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.
Th1/17 Cells Are Expanded in Bronchial Alveolar Lavage (BAL) Fluid from Leukemia Patients with Checkpoint Inhibitor-Induced Pneumonitis
Authors: Sang Kim, Vickie Shannon, Ajay Sheshadri, Hagop M. Kantarjian, Guillermo Garcia-Manero, Jin S Im, Farhad Ravandi, Aung Naing, Padmanee Sharma, Dimitrios P. Kontoyiannis, Andrew Futreal, Naval Daver
Journal: Blood (2017)