tbuckley/cabot-search huggingface dataset:
Abstract 1466: Molecular insights of resistin associated proliferation by inducing hypercholesterolemia in breast cancer
Authors: Ankita Deb, Manoj Bhat
Journal: Cancer Research (2020)

Abstract Introduction: Breast cancer is the most prevalent cancer in women impacting ~2.1 million women each year (WHO, 2019). It is the second leading cause of death after lung cancer in women. In spite of several therapeutic advances, further improvement in prognosis and survivability is still desired. According to numerous studies, Resistin, a proinflammatory cytokine, has a positive correlation with breast tumor progression. It plays multifaceted roles in diabetes, obesity, cardiovascular diseases as well as in several cancers. Despite several epidemiological studies showing an increase in serum resistin level in breast cancer patients, its relevance is not clearly understood. In the present study, we have focused on the role of resistin in breast cancer and emphasized on metabolic alterations occurring in this process. Methods: In vitro studies include long term colony formation and LDL estimation assays, immunoblotting, immunofluorescence . For in vivo studies, female Balb/C mice were used as isograft breast cancer model. Results: In vitro studies show that resistin facilitates progression of breast cancer through activation of JAK-STAT pathway. Downstream targets, c-Myc and cdc25A are also regulated via Resistin. Inhibition of JAK-STAT pathway abrogates resistin induced growth in breast cancer cells. Moreover, resistin also promotes cholesterol accumulation thereby inducing a hypercholesterolemic environment. In vivo studies indicate that with increase in tumor progression, resistin as well as LDL levels are also elevated in serum. Conclusions: In vitro as well as in vivo studies show that increase in serum resistin level is positively correlated with breast cancer progression and induction of hypercholesterolemia. Insights into resistin associated molecular events contributing to metabolic changes might facilitate progression of breast cancer. Targeting this pathway might contribute to a better therapeutic outcomes. Citation Format: Ankita Deb, Manoj Bhat. Molecular insights of resistin associated proliferation by inducing hypercholesterolemia in breast cancer [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 1466.
Abstract 2585: Tools for the discovery of KRAS pathway inhibitors
Authors: Ekaterina Kuznetsova, Lauren McCauley, Elaine Steinke-Neal, Timothy Sullivan, Louis Primavera, Haiching Ma
Journal: Cancer Research (2020)

Abstract The small GTPase, KRAS, is a known oncogene that is frequently mutated in a large percentage of cancers and is associated with poor disease prognosis. Mutated KRAS is locked in the activated GTP bound state and facilitates enhanced Ras signaling in cancer cells. While being a desirable target, absence of good druggable binding pockets has made modulator compound discovery challenging and unsuccessful. There has been a resurgence of interest in discovery of KRAS modulators after recent identification of unique binding pockets and successful inhibition of the KRAS G12C mutant by covalent chemical modifiers. With five molecules in clinical trials, many researchers are joining the efforts to find new inhibitors. Ras-mediated signaling commonly occurs through the receptor tyrosine kinase SOS-Ras pathway. To facilitate drug discovery activities targeting this pathway, we have produced the full spectrum of pathway proteins including kinases, wild type and mutated KRAS, and the upstream guanine nucleotide exchange factor protein SOS1. We have also developed and validated a number of biochemical and biophysical assays for these targets. This poster will summarize our most recent assay development efforts for the KRAS mutants including two different assays that monitor SOS1-mediated KRAS nucleotide exchange activities. Molecules that target SOS1 can be characterized using nucleotide exchange and KRAS::SOS1 protein-protein interaction assays. Binding of molecules to KRAS and SOS1 can also be assessed with biophysical methods. These tools and assays will significantly advance the drug discovery efforts of the industry. Citation Format: Ekaterina Kuznetsova, Lauren McCauley, Elaine Steinke-Neal, Timothy Sullivan, Louis Primavera, Haiching Ma. Tools for the discovery of KRAS pathway inhibitors [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 2585.
Profibrotic Circulating Proteins and Risk of Early Progressive Renal Decline in Patients With Type 2 Diabetes With and Without Albuminuria
Authors: Katsuhito Ihara, Jan Skupien, Hiroki Kobayashi, Zaipul I. Md Dom, Jonathan M. Wilson, Kristina O’Neil, Hannah S. Badger, Lenden M. Bowsman, Eiichiro Satake, Matthew D. Breyer, Kevin L. Duffin, Andrzej S. Krolewski
Journal: Diabetes Care (2020)

OBJECTIVE The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and matrix metalloproteinase 7 (MMP-7; Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 were monitored for 6–12 years to ascertain fast early progressive renal decline, defined as eGFR loss ≥5 mL/min/1.73 m2/year. RESULTS A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and albumin-to-creatinine ratio (ACR) at baseline were 97 mL/min/1.73 m2 and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups, the risk of renal decline increased with increasing baseline levels of WFDC2 (P &amp;lt; 0.0001) and MMP-7 (P &amp;lt; 0.0001). After adjustment for relevant clinical characteristics and known biomarkers, an increase by one quartile in the fibrosis index (combination of levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (odds ratio 1.63; 95% CI 1.30–2.04). The association was similar and statistically significant among patients with and without albuminuria. CONCLUSIONS Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in the development of early renal decline.
Abstract 10912: Lambl’s Excrescences: Embolic Risk and Pathogenesis
Authors: Alex Schevchuck, Leonardo Macias, Kirsten Tolstrup, Paola C Roldan, Emerest R Greene, Rex Jung, Clifford R Qualls, Reyad Hayek, Wilmer Sibbitt, Carlos A Roldan
Journal: Circulation (2013)

Background: Lambl’s excrescences (LEx) are commonly detected by transesophageal echocardiography (TEE) in patients with suspected cardioembolism. However, LEx are detected in healthy subjects and p...
Immune-Related Adverse Events (irAEs): Implications for Immune Checkpoint Inhibitor Therapy
Authors: Nanruoyi Zhou, Maria A. Velez, Dwight Owen, Aaron E. Lisberg
Journal: Journal of the National Comprehensive Cancer Network (2020)

I mmune checkpoint inhibitors (ICIs) have revolutionized the treatment of ad- vanced malignancies, including non-small cell lung cancer (NSCLC).2][3] irAEs are the result of nonspecific immune activation and can affect any organ system, although they most commonly occur in the skin, liver, gastrointestinal tract, and endocrine systems. 47][8][9] The authors used individual patient data from these trials to explore the incidence and timing of single-organ and multiorgan irAEs, the latter defined as either concurrent or sequential depending on whether irAEs arose within 7 days of one another.The primary objectives were to evaluate the incidence, grade, and time course of irAEs, in addition to assessing correlation with clinical outcomes (overall and progression-free survival).Kichenadasse et al 5 also conducted an in-depth evaluation of multiorgan irAEs, which is of particular interest because information regarding these types of AEs is currently sparse.Among the 4 atezolizumab NSCLC trials evaluated, multiorgan irAEs occurred in 5.4% of patients.To date, very little information is available on the frequency, significance, and management of multiorgan irAEs.1][12][13][14][15][16][17][18] Interestingly, previously published reports have shown that the development of irAEs correlates with patient response rate and survival. 19,20In a 2019 study, Cortellini et al 12 found that overall survival, progression-free survival, and objective response rates were higher among patients with NSCLC who experienced irAEs during treatment with anti-PD-1 agents; however, no significant difference in these endpoints was observed when comparing single-site versus multiple-site irAEs.In contrast, Kichenadasse et al 5 found that multiorgan involvement was associated with better survival outcomes than were observed with single-organ involvement.The question of whether multiorgan irAEs are associated with improved survival in patients with NSCLC is important because this information could potentially help guide decisions about whether to continue treatment with ICIs in the face of treatment-related toxicity.If multiorgan irAEs are truly associated with improved survival outcomes, clinicians and patients may choose to forge ahead with ICI treatment despite multiorgan toxicity, when possible.To assist with this critical decision, effective tools are needed to predict which patients are most likely to experience serious and/or fatal toxicities.Currently, however, no refined tools are available to predict development of ICI-induced irAEs, and surveillance for occurrence generally relies on traditional laboratory markers. 21At the very least, developing predictive tools would allow for more relevant discussion between clinicians and patients during ICI therapy.Given the dramatic improvement in See page 1191 for related article.
First trimester miscarriage in a pregnant woman infected with COVID-19 in Pakistan
Authors: Muhammad Suleman Rana, Muhammad Usman, Muhammad Masroor Alam, Amara Khalid, Aamer Ikram, Muhammad Salman, Syed Sohail Zahoor Zaidi, Rani Faryal, Mehmood Qadir, Massab Umair, None Roohullah, Mian Muhammad Sufian
Journal: Journal of Infection (2020)
Abstract 3308: SUMOylation-mediated enhancer activity regulates type I interferon pathway
Authors: Li Du, Yuan Chen, Steven Rosen
Journal: Cancer Research (2020)

Abstract Type I interferon (IFN) pathway plays an important role in innate immunity and anti-tumor immune response. Previous study has reported that SUMOylation represses type I interferon production, and that deletion of the E2 enzyme Ubc9 or SUMO2 or 3 greatly enhanced type I interferon response. However, the detailed mechanism of how SUMOylation regulates type I interferon response in controversial in the literature. In this study, we found that inhibition of the SUMO E1 enzyme with ML-792 significant enhanced type I cytokine IFNβ expression in human monocytes THP1 cell line, up to 1,500 folds. Similar induction was observed in human peripheral blood mononuclear cells (PBMCs). However, ML-792 treatment showed no effect in IFNβ promoter reporter assay, indicating that ML-792 induced IFNβ expression is not through activation of the transcription factors, such as through the STING pathway, that act on the promoter region. Genome browser ENCODE analysis showed SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1) binds at a ifnb1 enhancer region, known as L2, located ~9kb upstream of ifnb1 transcription start site (TSS). Knockdown of SETDB1 increased IFNβ level resulting in enhanced type I IFN downstream gene expression, indicating that SETDB1 is a transcriptional suppressor of ifnb1 gene. Chromatin immunoprecipitation (ChIP) assay determined that ML-792 treatment or knockdown of the catalytic subunit of the SUMO E1 greatly reduced SETDB1 SUMOylation and occupancy at ifnb1 gene enhancer region. Mutation of SETDB1 SUMOylation sites (4KR, with all 4 SUMOylation sites mutated: K355R, K1032R, K1050R, K1069R) also reduced SETDB1 binding at ifnb1 gene enhancer region shown by ChIP assay, demonstrating that SUMOylation is required for SETDB1 binding to ifnb1 gene enhancer region. In conclusion, our study identified SETDB1 as a novel transcriptional suppressor of ifnb1gene. In addition, we found that at least one mechanism of SUMOylation in preventing type I IFN production is through regulating SETDB1 binding to the enhancer of ifnb1 and consequently histone methylation. Citation Format: Li Du, Yuan Chen, Steven Rosen. SUMOylation-mediated enhancer activity regulates type I interferon pathway [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 3308.
Abstract 4419: Subtyping of HNSCC single-cell RNA-seq identifies transcriptional programs characterized by suppression of Mtorc1 and Wnt signaling pathways and better patient prognosis
Authors: Eric Reed, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti
Journal: Cancer Research (2020)

Abstract Single-cell RNA-seq (scRNA-seq) is an emerging platform for high-throughput profiling of individual cells in a sample and is routinely employed to investigate the transcriptional landscapes of the cellular constituents of tumors. To this end, many scRNA-seq specific clustering algorithms have emerged to analytically partition cells into modules of comparatively similar profiles. To facilitate data driven molecular subtyping of such scRNA-seq clustering results and other large-scale-omics studies, we have developed K2 Taxonomer. K2 Taxonomer is an R package built around a novel top-down hierarchical clustering algorithm, utilizing repeated perturbations of the data to generate robust taxonomical partitions of observations. The software runs additional analyses to define gene co-expression signatures of these modules, as well as to integrate user-input annotations of genes and/or observations. An interactive web portal has been generated to assist in the interrogation of the full compendium of results. We applied K2 Taxonomer to publicly available HNSCC scRNA-seq data, identifying pertinent tumor cell subtypes, distinguished by cell cycle and epithelial-to-mesenchymal transition, and with analytical projection of this signature onto TCGA-HNSCC bulk RNA-seq data exhibiting association with worse survival in TCGA-HNSCC patients. A transcriptional signature corresponding to suppression of Mtorc1 and Wnt/β-catenin signaling was also identified in a sub-population of HNSCCs, and shown to be associated with improved patient survival. Of notice, highly ranked markers of this signature are significantly associated with gene expression changes altered by E7386 - a novel β-catenin/CBP modulator with an activity profile that closely overlaps with that of ICG-001, but exhibits ~50-100-fold lower EC50 values - suggesting a role for this signaling axis in subsets of HNSCC. In conclusion, taxonomical subtyping with K2 Taxonomer provides a novel framework to expand the scope of applicability of scRNA-seq clustering results, and has revealed potentially novel HNSCC subtypes that offer directions for future studies. Citation Format: Eric Reed, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Maria Kukuruzinska, Stefano Monti. Subtyping of HNSCC single-cell RNA-seq identifies transcriptional programs characterized by suppression of Mtorc1 and Wnt signaling pathways and better patient prognosis [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 4419.
Abstract 6056: A next-gen anti-CD73 Antibody with potential to show better efficacy and safety profile than existing approach
Authors: Xin Gan, Lei Shi, Qianqian Shan, Fei Chen, Yun He, Yiping Rong, Qiumei Du
Journal: Cancer Research (2020)

Abstract CD73, an ecto-5'-nucleotidase, plays a major role in de-phosphorylation of the extracellular adenosine monophosphate (AMP) to adenosine, which in turn is a potent immunosuppressive metabolite that modulates the immune reaction within the tumor microenvironment (TME). High concentration of adenosine, predominantly signaling through the A2A receptor, suppress innate and adaptive immune cell responses, leading to tumor escape of immune surveillance. Recent studies have shown a significant overexpression of CD73 in solid tumors alongside it's functional upregulation by inflammatory mediators and hypoxia. Thus, inhibition of CD73 enzymatic activity and its surface expression in the TME may improve anti-tumor immune activity. To test this hypothesis, we designed and developed a fully human antibody with unique structure to recognize CD73. This antibody can block the enzymatic activity of CD73 in addition to reducing the surface expression of CD73. Both enzymatic and non-enzymatic dependent functions of CD73 were significantly dampened. The antibody demonstrates a superior anti-tumor activity over reference antibodies in in-vitro and in-vivo models. Our findings indicate that the antibody has promising potential as an effective therapy for PD-1/PD-L1 nonresponsive or refractory patients, as well as a broader patient population that may benefit from a unique mechanism of action of CD73-targeting antibody. Citation Format: Xin Gan, Lei Shi, Qianqian Shan, Fei Chen, Yun He, Yiping Rong, Qiumei Du. A next-gen anti-CD73 Antibody with potential to show better efficacy and safety profile than existing approach [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 6056.
Abstract 2059: Exploiting machine learning in local treatment strategies in cancer patients with bone metastases: A real world clinical trial
Authors: Hui Zhao, zhiyu wang, jing Sun, yifeng Gu, mengdi Yang, guangyu Yao
Journal: Cancer Research (2020)

Abstract With rising life expectancy in cancer patients with bone metastases, the need for local treatment (LT) is expanding. Machine learning (ML) could create reasonable generalizations, the purpose of this article was to evaluate the use of ML model in LT strategies. Patients were treated by an interdisciplinary team in Shanghai Sixth People's Hospital. Visual analog scale (VAS) and Quality of Life (QoL) Questionnaire Bone Metastases Module scores were analyzed before, 1 week, 1, 3, and 6 months after treatments. ML models were used to calculate LT probability, and confusion matrix was used to calculate the accuracy, precision, recall and F1 score of models. ML models were further used to calculate pathological fracture (PF) probability in lung cancer patients. Of 386 patients enrolled between 2016 and 2017, 101 patients underwent LT. Significant improved VAS and pain domains scores were observed in 27 surgery patients at 1, 3 and 6m, while functional domains scores at 3 and 6m. All five scores improved significantly in 46 percutaneous osteoplasty patients at 1w, 1 and 3m. Significant improved VAS and pain domains scores were observed in 28 radiation patients at 1 and 3m, while functional domains scores at 3m. Compared with team decision-making, decision tree was superior to support vector machine and Bayesian neural networks in model building. The VAS scale, primary cancer, Frankel classification, Mirels score, C-terminal telopeptide of type I collagen (CTx), age, mid-fragment of osteocalcin (MID), character of bone metastases, CA153, and visceral metastases were included in the DT model. In 386 patients, the values of decision tree for the accuracy, precision, recall and F1 score were 86.53%, 78.44%, and 64.90% and 0.69 respectively. 124 lung cancer patients were used to calculate PF probability by decision tree. We also put driving gene mutation and five differentially expressed proteins into the model. The VAS scale, character of bone metastases, age, driving gene mutation, C-terminal telopeptide of type I collagen (CTx), mid-fragment of osteocalcin (MID) and enolase 1 (ENO1) were included in the DT model. The sensitivity, specificity and accuracy of DT model was 90.52%, 87.19% and 77.72%. Appropriate LT provided significant pain relief and improvement in QoL. The ML model is effective in helping physicians determine which patient may be the candidate for LT. Citation Format: Hui Zhao, zhiyu wang, jing Sun, yifeng Gu, mengdi Yang, guangyu Yao. Exploiting machine learning in local treatment strategies in cancer patients with bone metastases: A real world clinical trial [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 2059.
Abstract 4349: Comparison of Psychosocial Wellbeing among African American and Caucasian Metastatic Cancer Survivors
Authors: Jayla M. Caffey, Jennifer Bail
Journal: Cancer Research (2020)

Abstract Introduction: Approximately 5 million Americans are living with metastatic cancer and are at an increased risk for psychosocial distress (e.g., hopelessness). Hope is vital to life and is essential for effectively coping with illness. Among early-stage cancer survivors, previous studies indicate that African Americans (AA) experience greater cancer burden than Caucasians (CAU). The aim of this study was to compare psychosocial wellbeing between AA and CAU MCS residing in the Deep South. Methods: MCS were identified via UAB Cancer Registry and I2B2.Using a modified Dilman's method, eligible MCS (&amp;gt;21 years and physician permission to contact) were mailed a survey. Psychosocial wellbeing (i.e. physical and mental wellbeing, anxiety, depression, social isolation, emotional support, and hopefulness) of MCS were assessed via PROMIS® measures. Returned surveys were double-key entered into REDCap®. Data were analyzed using Excel. Descriptive statistics were used to characterize the study sample and instrument scores. Between group difference, between AA and CAU MCS, was examined via independent-samples t-test. Results: To date, 100 surveys have been returned (AA=18; CAU=82; Mage=67 years; Msurvivorship=3 years) with a broad representation of primary cancer sites (breast=23%; prostate=10%; gynecological=16%; colorectal=13%; lung=10%; kidney=11%; other=17%). Mean instrument scores were similar between AA and CAU MCS for physical wellbeing (44.57 vs 44.81), mental wellbeing (48.1 vs 48.46), anxiety (45.76 vs 48.45), depression (44.85 vs 46.77), social isolation (39.96 vs 40.89), and emotional support (39.96 vs 40.89). However, AA MCS reported significantly better feelings of hopefulness than CAU MCS (61.34 vs 55.39, p&amp;gt;0.01, d=0.73). Discussion: Findings suggest that AA MCS may be more hopeful than CAU MCS. These preliminary findings warrant further analysis after data collection is complete (an additional 300 returned surveys are anticipated). Citation Format: Jayla M. Caffey, Jennifer Bail. Comparison of Psychosocial Wellbeing among African American and Caucasian Metastatic Cancer Survivors [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 4349.