tbuckley/cabot-search huggingface dataset:
Abstract 2: Discovery of BAY 2402234 by phenotypic screening: A human Dihydroorotate Dehydrogenase (DHODH) inhibitor in clinical trials for the treatment of myeloid malignancies
Authors: Stefan N. Gradl, Thomas Mueller, Steven Ferrara, Sherif El Sheikh, Andreas Janzer, Han-Jie Zhou, Anders Friberg, Judith Guenther, Martina Schaefer, Timo Stellfeld, Knut Eis, Michael Kroeber, Duy Nguyen, Claudia Merz, Michael Niehues, Detlef Stoeckigt, Sven Christian, Katja Zimmermann, Pascal Lejeune, Michael Bruening, Hanna Meyer, Vera Puetter, David T. Scadden, David B. Sykes, Henrik Seidel, Ashley Eheim, Martin Michels, Andrea Haegebarth, Marcus Bauser
Journal: Cancer Research (2019)

Abstract DHODH is a key enzyme in the biosynthesis of pyrimidines and recent studies have renewed interest in this old anti-cancer target. Here, we disclose the discovery of 4-triazolosalicylamides as inhibitors of DHODH and their structure activity relationship (SAR). The hit cluster was discovered during a phenotypic high throughput screen (HTS) of 2.5 million compounds where proliferation of H460 lung cancer cells was used as read-out. DHODH was successfully identified as the molecular target by comparing the activity profile of the hits in a panel of cell lines to a set of inhibitors with known pharmacological activity. The hit compounds showed good cellular potency but had undesirable DMPK properties. Interestingly, the compounds are non-ionizable in contrast to many other DHODH inhibitors and show no potency shift from biochemical to cellular assays. Structural modifications lead to compounds with sub-nanomolar potency in cellular assays and increased metabolic stability enabling the proof of concept in vivo xenograft experiments. Further optimization guided by lipophilicity efficiency and identification of metabolic hot spots resulted in molecules with low clearance and improved solubility. BAY 2402234 was selected as the clinical candidate after side by side comparison of a number of promising compounds. It shows great oral bioavailability, target engagement in all preclinical species tested, induces differentiation in AML models, and has excellent activity in a variety of leukemia models. A clinical phase I study has been initiated in patients with myeloid malignancies. (NCT03404726) Citation Format: Stefan N. Gradl, Thomas Mueller, Steven Ferrara, Sherif El Sheikh, Andreas Janzer, Han-Jie Zhou, Anders Friberg, Judith Guenther, Martina Schaefer, Timo Stellfeld, Knut Eis, Michael Kroeber, Duy Nguyen, Claudia Merz, Michael Niehues, Detlef Stoeckigt, Sven Christian, Katja Zimmermann, Pascal Lejeune, Michael Bruening, Hanna Meyer, Vera Puetter, David T. Scadden, David B. Sykes, Henrik Seidel, Ashley Eheim, Martin Michels, Andrea Haegebarth, Marcus Bauser. Discovery of BAY 2402234 by phenotypic screening: A human Dihydroorotate Dehydrogenase (DHODH) inhibitor in clinical trials for the treatment of myeloid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2.
Different endotypes and phenotypes drive the heterogeneity in severe asthma
Authors: P. Jane McDowell, Liam G. Heaney
Journal: Allergy (2019)

Abstract The identification of sputum eosinophilia indicating corticosteroid responsiveness in subjects with severe asthma heralded the beginning of phenotyping asthmatic subjects based on airways inflammation. Since then, the heterogeneity of severe asthma has been explored and the importance of immunobiology has come sharply into focus with the identification of the key type‐2 cytokine pathways driving eosinophilic inflammation. The development of molecules targeting these type‐2 pathways has transformed severe asthma treatment, but necessitates robust clinical evaluation, biomarker profiling and assessment of comorbid factors to identify subjects most likely to benefit from these therapies. It has also become clear that targeting these pathways does not eradicate asthma symptoms and exacerbation risk; further work is needed to clarify underlying non‐type‐2 mechanisms in severe asthma pathways and possible therapeutic targets. This review addresses progress to date in clinical assessment and management of severe asthma and some of the challenges and unmet needs in severe asthma to achieve the goal of delivering individualized patient care.
Abstract 2484: An online tool to validate predictive biomarkers of therapy response using transcriptomic data of 3,651 ovarian cancer patients
Authors: Balazs Györffy, Janos Fekete, Agnes Osz, Imre Pete, Marcell Szasz
Journal: Cancer Research (2019)

Abstract Systemic therapy of ovarian cancer can include chemotherapy and targeted therapy. Prognostic biomarkers are capable to predict survival and predictive biomarkers are capable to predict therapy response. To date, multiple online tools were established to identify prognostic biomarkers, but no platform is yet available for predictive biomarkers. In this study, we describe the first release of an online available tool capable to validate gene expression based predictive biomarkers using transcriptomic data of a large set of ovarian cancer patients. Published gene expression data of 35 independent datasets was integrated with treatment data into a unified database. The classification is based on either author-reported pathological complete response (n=1,022) or relapse-free survival status at six months (n=1,347) or relapse-free survival status at twelve months (n=1,282). Treatment data includes chemotherapy (platin, taxol, docetaxel, paclitaxel, gemcitabine, topotecan) and targeted therapy (avastin). The transcriptomic database includes 54,675 probe sets corresponding to 20,089 distinctive genes. Finally, we performed a sample collection at the National Institute of Oncology (NIO cohort), and used these patient samples to validate the top six genes in ovarian cancer patients. Gene expression and therapy response were compared using receiver operating characteristics and Mann-Whitney tests. In the validation of the tool we focused on paclitaxel-resistance associated genes. We selected the top genes after running the analysis across all samples and validated these by PCR in the NIO cohort of patients (n=80). The best performing paclitaxel-resistance biomarker candidates were ARAF (AUC=0.743, p=4.1E-09), PPCS (AUC=0.733, p=4.2E-07), GNL2 (AUC=0.718, p=2.7E-08), TFE3 (AUC=0.718, p=4.8E-06), PDXK (AUC=0.717, p=1.1E-05) and TOP1 (AUC=0.716, p=4.6E-05). The analysis pipeline enables to validate and rank predictive biomarker nominees. By analyzing the candidate genes in a large set of independent patients, we can select the most reliable candidate and abolish those which are most likely to fail in a clinical setting. The registration-free interface of the online analysis platform is accessible at www.rocplot.org/ovar. Citation Format: Balazs Györffy, Janos Fekete, Agnes Osz, Imre Pete, Marcell Szasz. An online tool to validate predictive biomarkers of therapy response using transcriptomic data of 3,651 ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2484.
Glyphosate induces benign monoclonal gammopathy and promotes multiple myeloma progression in mice
Authors: Lei Wang, Qipan Deng, Hui Hu, Ming Liu, Zhaojian Gong, Shanshan Zhang, Zijun Y. Xu-Monette, Zhongxin Lu, Ken H. Young, Xiaodong Ma, Yong Li
Journal: Journal of Hematology & Oncology (2019)

Glyphosate is the most widely used herbicide in the USA and worldwide. There has been considerable debate about its carcinogenicity. Epidemiological studies suggest that multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) have a positive and statistically significant association with glyphosate exposure. As a B cell genome mutator, activation-induced cytidine deaminase (AID) is a key pathogenic player in both MM and B cell NHL. Vk*MYC is a mouse line with sporadic MYC activation in germinal center B cells and considered as the best available MM animal model. We treated Vk*MYC mice and wild-type mice with drinking water containing 1000 mg/L of glyphosate and examined animals after 72 weeks. Vk*MYC mice under glyphosate exposure developed progressive hematological abnormalities and plasma cell neoplasms such as splenomegaly, anemia, and high serum IgG. Moreover, glyphosate caused multiple organ dysfunction, including lytic bone lesions and renal damage in Vk*MYC mice. Glyphosate-treated wild-type mice developed benign monoclonal gammopathy with increased serum IgG, anemia, and plasma cell presence in the spleen and bone marrow. Finally, glyphosate upregulated AID in the spleen and bone marrow of both wild-type and Vk*MYC mice. These data support glyphosate as an environmental risk factor for MM and potentially NHL and implicate a mechanism underlying the B cell-specificity of glyphosate-induced carcinogenesis observed epidemiologically.
Salivary mycobiome dysbiosis and its potential impact on bacteriome shifts and host immunity in oral lichen planus
Authors: Yan Li, Kun Wang, Bo Zhang, Qichao Tu, Yufei Yao, Bomiao Cui, Biao Ren, Jinzhi He, Xin Shen, Joy D. Van Nostrand, Jizhong Zhou, Wenyuan Shi, Liying Xiao, Changqing Lu, Xuedong Zhou
Journal: International Journal of Oral Science (2019)

The biodiversity of the mycobiome, an important component of the oral microbial community, and the roles of fungal–bacterial and fungal–immune system interactions in the pathogenesis of oral lichen planus (OLP) remain largely uncharacterized. In this study, we sequenced the salivary mycobiome and bacteriome associated with OLP. First, we described the dysbiosis of the microbiome in OLP patients, which exhibits lower levels of fungi and higher levels of bacteria. Significantly higher abundances of the fungi Candida and Aspergillus in patients with reticular OLP and of Alternaria and Sclerotiniaceae_unidentified in patients with erosive OLP were observed compared to the healthy controls. Aspergillus was identified as an "OLP-associated" fungus because of its detection at a higher frequency than in the healthy controls. Second, the co-occurrence patterns of the salivary mycobiome–bacteriome demonstrated negative associations between specific fungal and bacterial taxa identified in the healthy controls, which diminished in the reticular OLP group and even became positive in the erosive OLP group. Moreover, the oral cavities of OLP patients were colonized by dysbiotic oral flora with lower ecological network complexity and decreased fungal–Firmicutes and increased fungal–Bacteroidetes sub-networks. Third, several keystone fungal genera (Bovista, Erysiphe, Psathyrella, etc.) demonstrated significant correlations with clinical scores and IL-17 levels. Thus, we established that fungal dysbiosis is associated with the aggravation of OLP. Fungal dysbiosis could alter the salivary bacteriome or may reflect a direct effect of host immunity, which participates in OLP pathogenesis. Imbalance in the oral fungal community could lead to the development of oral lichen planus (OLP), a chronic inflammatory disease that affects the mucous membranes in the mouth. The exact cause of OLP is uncertain, which is a major obstacle to therapeutic development. Using salivary samples, a team headed by Xuedong Zhou at Sichuan University in China investigated the composition and diversity of the fungal community in OLP patients and healthy individuals. The authors found that the oral fungal community was less diverse and that there were higher levels of bacteria in OLP patients. The team concluded that fungal community imbalance could affect the bacterial community in the saliva and the host immunity in the mucous membrane, thereby constituting a direct or indirect cause of the development of OLP.
Mismatch Repair–Proficient Colorectal Cancer: Finding the Right TiME to Respond
Authors: Jason A. Willis, Michael J. Overman, Eduardo Vilar
Journal: Clinical Cancer Research (2019)

Abstract New approaches are required for addressing the important and unmet need to expand the benefits of checkpoint blockade to patients with mismatch repair proficient colorectal cancer. Systematic profiling of the tumor immune microenvironment provides insights into potential mechanisms of resistance, predictive biomarkers, and novel combinatorial strategies for overcoming resistance. See related article by Llosa et al., p. 5250
Abstract 2134: Niraparib combined with abiraterone acetate inhibits the growth of BRCA2wt prostate tumors
Authors: Rajendra N. Damle, Rebecca Hawkins, Jennifer Hosbach, Georges Habineza Ndikuyeze, Jenny Driscoll, Natalie L. Fulton, David Derosa, Anna Hughes, Gerald Chu, Karl Calara-Nielsen, Denis Smirnov, Dong Shen, Linda A. Snyder
Journal: Cancer Research (2019)

Abstract Patients with metastatic prostate cancer may initially respond well to first- and second-generation androgen receptor (AR)-targeted therapies, but many will experience disease progression, indicating a need for alternative therapies. A subset of these patients bears prostate tumors that harbor deleterious mutations in DNA damage repair (DDR) pathway genes, such as BRCA2. These DDR mutations render the tumors sensitive to drugs that inhibit poly (ADP-ribose) [PAR] polymerase-1 (PARP1), inducing synthetic lethality. Studies indicate that there are interactions between AR signaling pathways and DDR pathways in prostate cancer cells, supporting the hypothesis that dual AR/PARP inhibition could inhibit prostate tumor growth more potently than single agents, regardless of the DDR status of the tumor. This hypothesis was tested using well-known human and mouse prostate tumor models that are sensitive to androgen deprivation. Genotyping of the models confirmed that none of them carried homozygous pathogenic mutations in DDR genes, including BRCA1, BRCA2, and ATM. When the cell lines were incubated in vitro with niraparib, a potent and highly selective PARP1/2 inhibitor, PAR formation was significantly inhibited, and there was induction of γH2AX in treated cells, indicating the drug induced DNA double-stranded breaks. In addition, the cytotoxicity IC50 values for niraparib were in the range of 1-10 µM, as expected for cells that are DDRwt. In vivo efficacy studies demonstrated that the VCaP and Myc-CaP tumor models were insensitive or modestly sensitive to single agent treatment with niraparib or abiraterone acetate (AA). In contrast, the combination treatment of niraparib plus AA significantly reduced tumor growth and increased survival (p&amp;lt;0.05) as compared with control or single agent arms. Studies are ongoing to understand the mechanisms of tumor growth control mediated by the combination of these two agents. The results support the hypothesis that prostate tumors may respond to a combination treatment with niraparib, a PARP inhibitor, and AA, an androgen synthesis inhibitor, even in the absence of DDR anomalies. A Phase 3 study is planned to evaluate this hypothesis and the safety and efficacy of this combination in humans. Citation Format: Rajendra N. Damle, Rebecca Hawkins, Jennifer Hosbach, Georges Habineza Ndikuyeze, Jenny Driscoll, Natalie L. Fulton, David Derosa, Anna Hughes, Gerald Chu, Karl Calara-Nielsen, Denis Smirnov, Dong Shen, Linda A. Snyder. Niraparib combined with abiraterone acetate inhibits the growth of BRCA2wt prostate tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2134.
Epigenetic programming underpins B cell dysfunction in human SLE
Authors: Christopher D. Scharer, Emily L. Blalock, Tian Mi, Benjamin G. Barwick, Scott A. Jenks, Tsuneo Deguchi, Kevin S. Cashman, Bridget E. Neary, Dillon G. Patterson, Sakeenah L. Hicks, Arezou Khosroshahi, F. Eun-Hyung Lee, Chungwen Wei, Iñaki Sanz, Jeremy M. Boss
Journal: Nature Immunology (2019)
Ability of routine blood tests (RBTs) in asymptomatic patients (pts) with indolent non-Hodgkin lymphoma (iNHL) to detect relapse or clinically significant disease progression.
Authors: Oliver Piercey, Zoe Loh, Joanna Chan, Geoffrey Chong, Andrew Grigg, Steven Cheema, Tania Cushion, Gurjot Gill, Matthew Whybird, Eliza Anne Hawkes
Journal: Journal of Clinical Oncology (2019)

e19027 Background: Pts with iNHL undergo active surveillance to detect disease relapse or progression. International guidelines recommend regular RBTs for surveillance but evidence for this practice is lacking. Methods: We conducted a retrospective analysis of pts aged ≥16 yrs from 2008-17 undergoing routine surveillance at 2 Australian centres for grade 1-3a follicular lymphoma (FL) or marginal zone lymphoma (MZL), to assess the utility of full blood count, lactate dehydrogenase &amp; beta-2-microglobulin to detect progression events; (i.e relapse or progression) or to change management. Abnormal results were defined as acute deviations from local laboratory normal ranges not explained by a concurrent medical condition. Eligible pts were either treatment-naive or had achieved a response to lymphoma-directed therapy, had ≥6 mths follow up and an absence of progression events within 3 mths of prior therapy. Demographic data were collected as well as treatment, follow up appointment (appt) details including presence of signs/symptoms, RBT results, survival status &amp; further therapy. The study was ethically approved. Results: 180 eligible pts (FL:142, MZL:38) underwent 1757 follow up appts (median follow up 38 months). RBTs were done at 83% of appts. 74 progression events occurred in a total of 62 pts; 48/74 (65%) had immediate therapy. 2/74 (3%) were detected by RBTs alone, (both treatment naïve pts); 88% by signs/symptoms &amp; 9% by routine imaging. 20/243 (8%) of abnormal RBTs in asymptomatic pts led to a change in subsequent management (10 had imaging; 8 earlier appts; 2 repeat RBTs alone). The sensitivity &amp; positive predictive value of abnormal RBTs to detect progression events were 39% &amp; 9% respectively. In asymptomatic patients, the number of RBTs required to change management and to detect a progression event were 64 and 644 respectively. Conclusions: RBTs rarely detect clinically significant disease progression or relapse and seldom solely lead to a change in management in asymptomatic pts with iNHL. Clinical signs/symptoms are far more likely to detect progression or relapse. Guidelines should reflect the benefit &amp; risk of RBTs in the clinical setting.
Abstract 375: MCL-1 Regulates Mitochondrial Dynamics and Mitophagy
Authors: Alexandra G Moyzis, Leonardo Leon, Robert L Thomas, Åsa B Gustafsson
Journal: Circulation Research (2016)

The anti-apoptotic BCL-2 family protein Myeloid Cell Leukemia-1 (MCL-1) is essential for maintaining mitochondrial integrity and cardiac function in the adult heart. Recently, we reported that cardiac-specific deletion of MCL-1 in mice leads to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Surprisingly, MCL-1 ablation does not result in apoptotic cell death, but rather cells show signs of mitochondrial deterioration and necrotic cell death. This suggests that in addition to its anti-apoptotic role, MCL-1 has unidentified roles in maintaining mitochondrial function in cardiac myocytes. MCL-1 exists in two distinct locations in myocytes: one form is localized to the outer mitochondrial membrane (MCL-1 OM ) and a shorter cleaved form exists in the mitochondrial matrix (MCL-1 Matrix ). Interestingly, overexpression of MCL-1 WT or MCL-1 OM , but not MCL-1 Matrix , leads to translocation of Drp1 to mitochondria, which correlates with fission and perinuclear aggregation of mitochondria. We also found that Drp1 co-immunoprecipitates with MCL-1 in heart lysates and that MCL-1-deficient hearts lack mitochondrial Drp1. Additionally, the interaction between Drp1 and MCL-1 and mitochondrial fission increase in response to serum starvation in neonatal myocytes. This suggests that MCL-1 OM recruits Drp1 to mitochondria to induce fission. Since there is a strong link between mitochondrial fission and degradation, we examined the effect of MCL-1 on mitophagy. Parkin is an E3 ubiquitin ligase that plays an important role in mitophagy. MEFs, which lack detectable Parkin, do not efficiently clear their depolarized mitochondria in response to FCCP treatment. However, overexpression of Parkin or MCL-1 increased the efficiency of mitophagy in MEFs in response to FCCP treatment. MCL-1-mediated mitophagy is abrogated in autophagy-deficient Atg5 -/- MEFs, confirming that the clearance occurs via enhanced autophagy. Thus, our data suggest that MCL-1 OM has dual actions in coordinating Drp1-mediated fission and mitophagy, which allows for more efficient removal of damaged mitochondria.
Abstract 11797: Evaluation of Progress Made in a Learning Network by Early Performance Level
Authors: Garick D Hill, Michael Bingler, Allison B McCoy, Matt Oster, Taylor Pitcher, Karen Uzark, Katherine E Bates
Journal: Circulation (2018)

Introduction: The National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) is a learning network that has demonstrated a reduction in interstage mortality and growth failure after ...