tbuckley/cabot-search huggingface dataset:
Abstract 6576: DNA methylation reveals alternative promoter usage in genes critical to pediatric tumors
Authors: Justin Williams, Beisi Xu, Daniel Putnam, Xiang Chen
Journal: Cancer Research (2020)

Abstract Transcriptional regulation is fundamental for cell identity and function, and it's deregulation is a defining feature for common diseases, including cancers. Besides directly modifying the canonical promoter activities, tumors frequently utilize alternative promoters to increase the isoform diversity, activate oncogenes when the canonical promoters are repressed, and to evade host immune attacks by immune-editing. However, fresh-tissue availability and technical challenges represent major obstacles in genomewide promoter activity assessment in patient tumors by ChIP-seq experiments. Here, we presented MethylToActivity (M2A), a deep-learning framework that reveals promoter activities (H3K4me3 and H3K27ac) from DNA methylation (DNAm) patterns, a relatively stable epigenetic regulatory mechanism that can be robustly and accurately profiled in various tissues, including retrospective tumor samples archived using the formalin-fixed paraffin-embedded (FFPE) method. Trained from a cohort of neuroblastomas (N = 6), we demonstrate that M2A 1) approaches the accuracies of ChIP-seq experiments in revealing promoter activities, 2) is generalizable to various pediatric and adult cancers, 3) captures changes of promoter activity associated with differentially methylated regions, and 4) faithfully recapitulates differential promoter usages among tumor subtypes. Importantly, M2A uncovers oncogenic activation of alternative promoters in genes critical for tumor survival while the canonical promoter remains inactive. These results substantiate that M2A is capable of accurately measuring promoter activities, which will be of great use not only to functionally interpret differential DNAm patterns, but to unveil alternative promoter usages in patient tumors, which will facilitate precision medicine by tailoring treatments based on both epigenetic deregulations and genetic variants. Citation Format: Justin Williams, Beisi Xu, Daniel Putnam, Xiang Chen. DNA methylation reveals alternative promoter usage in genes critical to pediatric tumors [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 6576.
Mechanisms of Environment-Induced Autoimmunity
Authors: K. Michael Pollard, David M. Cauvi, Jessica M. Mayeux, Christopher B. Toomey, Amy K. Peiss, Per Hultman, Dwight H. Kono
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Although numerous environmental exposures have been suggested as triggers for preclinical autoimmunity, only a few have been confidently linked to autoimmune diseases. For disease-associated exposures, the lung is a common site where chronic exposure results in cellular toxicity, tissue damage, inflammation, and fibrosis. These features are exacerbated by exposures to particulate material, which hampers clearance and degradation, thus facilitating persistent inflammation. Coincident with exposure and resulting pathological processes is the posttranslational modification of self-antigens, which, in concert with the formation of tertiary lymphoid structures containing abundant B cells, is thought to promote the generation of autoantibodies that in some instances demonstrate major histocompatibility complex restriction. Under appropriate gene-environment interactions, these responses can have diagnostic specificity. Greater insight into the molecular and cellular requirements governing this process, especially those that distinguish preclinical autoimmunity from clinical autoimmunedisease, may facilitate determination of the significance of environmental exposures in human autoimmune disease.
Injuries and illnesses among competitive Norwegian rhythmic gymnasts during preseason: a prospective cohort study of prevalence, incidence and risk factors
Authors: Marte Charlotte Dobbertin Gram, Benjamin Clarsen, Kari Bø
Journal: British Journal of Sports Medicine (2020)

Objectives Rhythmic gymnastics is an Olympic sport that demands high training volume from early age. We investigated the extent of, and risk factors for, injuries among competitive Norwegian rhythmic gymnasts. Methods One hundred and seven of 133 (80.5%) female rhythmic gymnasts (mean age: 14.5 years (SD 1.6), mean body mass index: 18.9 (SD 2.2)) participated. All gymnasts completed a baseline questionnaire and the ‘Triad-Specific Self-Report Questionnaire’. Injuries, illnesses and training hours were recorded prospectively for 15 weeks during preseason using the ‘Oslo Sports Trauma Research Center Questionnaire on Health Problems’ (OSTRC-H2). Results Response rate to OSTRC-H2 was 97%. Mean overuse and acute injury prevalence were 37% (95% CI: 36% to 39%) and 5% (95% CI: 4% to 6%), respectively. Incidence was 4.2 overuse injuries (95% CI: 3.6 to 4.9) and 1.0 acute injuries (95% CI: 0.5 to 1.6) per gymnast per year. Overuse injuries in knees, lower back and hip/groin represented the greatest burdens. Previous injury increased the odds of injury (OR 30.38, (95% CI: 5.04 to 183.25)), while increased age (OR 0.61 per year, (95% CI: 0.39 to 0.97)) and presence of menarche (OR: 0.20, (95% CI: 0.06 to 0.71)) reduced the odds of all injuries and substantial injuries, respectively. Conclusions Overuse injuries were common among Norwegian rhythmic gymnasts. Younger gymnasts had higher all-injury risk. Gymnasts who were not menstruating had higher substantial injury risk. Injury prevention interventions should start at an early age and focus on preventing knee, lower back and hip/groin injuries.
Reducing Vasopressor Exposure in Patients With Vasodilatory Hypotension—Reply
Authors: François Lamontagne, Paul R. Mouncey
Journal: JAMA (2020)

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Functional Identification of the Plasmodium Centromere and Generation of a Plasmodium Artificial Chromosome
Authors: Shiroh Iwanaga, Shahid M. Khan, Izumi Kaneko, Zoe Christodoulou, Chris Newbold, Masao Yuda, Chris J. Janse, Andrew P. Waters
Journal: Cell Host & Microbe (2010)

(Cell Host & Microbe 7, 245–255; March 18, 2010) In the author attributions of the above article, the affiliation of Andrew P. Waters was listed as Leiden University Medical Centre and present address as the University of Glasgow. In fact, both institutions should have been listed as affiliations, indicating that contributions to the production of the manuscript had been made at both locations. Any inconvenience caused by this error is regretted. This has been corrected in the original article online. Functional Identification of the Plasmodium Centromere and Generation of a Plasmodium Artificial ChromosomeIwanaga et al.Cell Host & MicrobeMarch 18, 2010In BriefThe artificial chromosome represents a useful tool for gene transfer, both as cloning vectors and in chromosome biology research. To generate a Plasmodium artificial chromosome (PAC), we had to first functionally identify and characterize the parasite's centromere. A putative centromere (pbcen5) was cloned from chromosome 5 of the rodent parasite P. berghei based on a Plasmodium gene-synteny map. Plasmids containing pbcen5 were stably maintained in parasites during a blood-stage infection with high segregation efficiency, without drug pressure. Full-Text PDF Open Access
Abstract 6312: Use of differential sensing-based biosensors to quantify ERK kinase activity in complex biological samples
Authors: Diana Zamora-Olivares, Jacey R. Pridgen, Lingyu Zeng, Tamer S. Kaoud, Eric V. Anslyn, Kevin N. Dalby
Journal: Cancer Research (2020)

Abstract The expeditious quantification of signalling in complex biological system by novel technologies will aid in the development of biological models, help to identify targets for treatment, and assess treatment plans. The biochemical process of protein phosphorylation, which underlies almost all aspects of cell signaling, is typically evaluated by immunoblotting procedures like western blot. More recently, proteomics procedures, which provide qualitative estimates of the concentration of proteins and their modifications in cells have also been used. However, enzyme activity can be difficult to correlate to protein modifications.vRecently we reported a differential sensing-based approach to differentiate nine MAPKs from each other. From this we developed a cabilbration regression model to measure ERK activation and inhibition while both JNK and p38 MAPKs were present. Our previous studies were carried out using purified MAPKs, which do not necessarily reflect endogenous activity. Here, we report a similar approach to rapidly quantify unknown levels of endogenous ERK activity in biological samples. To do so, a library of cross-reactive SOX-peptide-based biosensors along with chemometric analysis, was used to quantify nanograms of active ERK in micrograms of unfractionated cell lysates and tumor extracts. This approach can be used to measure multiple samples quickly, allowing for faster analysis of the response of actual ERK activity in treatments in cell lines or animal models than other methods. This approach might also provide an alternative to assessing ERK activity in human tumor biopsies, which would be valuable for evaluating treatments and inhibitor resistance. Citation Format: Diana Zamora-Olivares, Jacey R. Pridgen, Lingyu Zeng, Tamer S. Kaoud, Eric V. Anslyn, Kevin N. Dalby. Use of differential sensing-based biosensors to quantify ERK kinase activity in complex biological samples [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 6312.
Antibacterial nanotruffles for treatment of intracellular bacterial infection
Authors: Marwa G. Elnaggar, Kunyu Jiang, Hassan E. Eldesouky, Yihua Pei, Jinho Park, Simseok A. Yuk, Fanfei Meng, Alexandra M. Dieterly, Haroon T. Mohammad, Youssef A. Hegazy, Hesham M. Tawfeek, Aly A. Abdel-Rahman, Ahmed E. Aboutaleb, Mohamed N. Seleem, Yoon Yeo
Journal: Biomaterials (2020)
Abstract 5091: TIMP-1 in tumor-associated fibroblasts drives tumor progression in lung adenocarcinoma through CD63 interaction
Authors: Paula Duch, Marta Gabasa, Rafael Ikemori, Marselina Arshakyan, Frank Hillberg, Noemí Reguart, Derek Radisky, Jordi Alcaraz
Journal: Cancer Research (2020)

Abstract Tumor associated fibroblasts (TAFs) are important regulators of tumor growth and resistance to therapies. We have recently shown that lung TAFs in vitro respond to the antifibrotic drug nintedanib in adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). We also showed that the tumor-promoting effects of TAFs are driven by different mechanisms in ADC and SCC, which remain to be elucidated. Tissue inhibitor of metalloproteinases 1 (TIMP-1) has been associated with poor prognosis in lung cancer, its expression is downregulated by nintedanib, and our preliminary results reveal that its putative receptor, CD63, is overexpressed in ADC patients compared to SCC, supporting a selective crosstalk between TAFs and cancer cells in ADC through TIMP-1 and CD63. The aim of this study was to test this hypothesis using in vitro preclinical models. Primary fibroblasts were obtained with the patient informed consent, and using protocols approved by the Ethics Committee of the Hospital Clinic. ADC-TAFs and SCC-TAFs were stimulated with TGF-β1 in the presence or absence of nintedanib, and the TIMP-1 content in their conditioned medium was determined by ELISA. TIMP-1 was knocked-down in ADC-TAFs by siRNA, and the corresponding conditioned medium was used to stimulate growth and invasion of the high-CD63 ADC cell line, H1437. Likewise, CD63 expression in H1437 cells was reduced by siRNA. Our in vitro results showed that TIMP-1 secretion induced by TGF-β1 is significantly larger in ADC-TAFs compared to SCC-TAFs. Likewise, nintedanib elicited a higher downregulation of secreted TIMP-1 in ADC-TAFs compared to SCC-TAFs. Of note, TIMP-1 from ADC-TAFs was necessary to induce growth and invasion of H1437 cells. Likewise, knocking-down CD63 in H1437 ADC cells was sufficient to reduce the growth and invasion elicited by the conditioned medium of TGF-β1 activated ADC-TAFs. Collectively, our results unveil a novel stroma-carcinoma crosstalk driven by TIMP-1 and CD63 selectively in lung ADC, and support that such heterotypic crosstalk may underlie the aberrant tumor-promoting effects of ADC-TAFs that are selectively downregulated by nintedanib. Citation Format: Paula Duch, Marta Gabasa, Rafael Ikemori, Marselina Arshakyan, Frank Hillberg, Noemí Reguart, Derek Radisky, Jordi Alcaraz. TIMP-1 in tumor-associated fibroblasts drives tumor progression in lung adenocarcinoma through CD63 interaction [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 5091.
Association of sex and APOE ε4 with brain tau deposition and atrophy in older adults with Alzheimer's disease
Authors: Shaozhen Yan, Chaojie Zheng, Manish D Paranjpe, Jian Li, Tammie L S Benzinger, Jie Lu, Yun Zhou
Journal: Theranostics (2020)

The objective of this study was to assess the association of sex and the apolipoprotein E (APOE) ε4 allele with brain tau deposition and atrophy in older adults with Alzheimer's disease (AD) using quantitative
Comparing measures of hematologic response after high-dose melphalan and stem cell transplantation in AL amyloidosis
Authors: Shayna Sarosiek, Luke Zheng, J. Mark Sloan, Karen Quillen, Dina Brauneis, Vaishali Sanchorawala
Journal: Blood Cancer Journal (2020)

Abstract Hematologic complete response (hemCR) in AL amyloidosis requires absence of monoclonal protein by immunofixation electrophoreses (IFE) and normal serum free light chain ratio (FLCR). Recent literature suggests that an involved free light chain (iFLC) &lt;20 mg/L or difference in free light chains (dFLC) &lt;10 mg/L may more accurately predict outcomes after treatment. We evaluated overall survival in 340 patients treated with high-dose melphalan and stem cell transplantation (SCT). Of 305 patients evaluable 6 months after SCT, 90 (30%) achieved hemCR, 132 (43%) dFLC &lt;10 mg/L, 118 (39%) iFLC &lt;20 mg/L, and 176 (58%) normal FLCR. Of 215 patients without hemCR, 65 (30%) had dFLC &lt;10 mg/L and 86 (40%) had normal FLCR. Overall survival (OS) in those achieving dFLC &lt;10 mg/L or normal FLCR without hemCR was inferior to those achieving hemCR ( p = 0.013 and p = 0.001). OS was not significantly different in patients achieving iFLC &lt;20 mg/L without hemCR compared with hemCR ( p = 0.243). Of those with hemCR, OS was not significantly improved if dFLC &lt;10 mg/L was also achieved ( p = 0.852), but OS was improved for those with hemCR who also attained iFLC &lt;20 mg/L ( p = 0.009). Multivariate analysis demonstrated absence of monoclonal protein in IFE and iFLC &lt;20 mg/L as independent predictors of survival. Attainment of hemCR remains a treatment goal, although achieving iFLC &lt;20 mg/L may also predict improved OS.
Abstract 2891: Targeting breast cancer stem cells with anti-EMP2 immunotoxins delivering granzyme b
Authors: Khalid A. Mohamedali, Kok Su-yin, Lawrence H. Cheung, Naina Dhawan, Michael G. Rosenblum, Madhuri Wadehra
Journal: Cancer Research (2020)

Abstract Despite new therapies, breast cancer remains one of the leading causes of cancer-related death in women worldwide. Part of the issue remains the inability of these therapies to target cancer stem cells (CSCs). These cells show unique resistance to chemotherapy and have enhanced capacity for self-renewal. Recently, our group has shown that Epithelial membrane protein-2, or EMP2, is expressed on CSCs defined by increased aldehyde dehydrogenase activity (ALDH+). Clinical data supports the role of EMP2 in advanced breast cancer as increased expression of the protein is observed in metastatic lesions compared to primary tumors and its expression is enhanced in chemotherapy resistant tumors. In parallel, EMP2 expression correlated with enhanced mammosphere formation, an accepted surrogate for cells with enriched stem cell capacity. We have recently developed a novel IgG1 monoclonal antibody to EMP2, which has been shown to reduce tumor load. As the antibody-antigen complex rapidly internalizes, we hypothesized that its anti-tumor effects could be enhanced through the creation of a fusion protein. Granzyme B (GrB) is a serine protease that plays a critical role in the body's defense against viral infection and tumor development by initiating the apoptotic cascade via both caspase-dependent and -independent mechanisms. We developed novel fusion proteins composed of the anti-EMP2 backbone as the targeting moiety and granzyme B as the cytotoxic payload. Our initial design comprised of the active GrB fused to the IgG heavy chain (Fc) domain containing 2 single-chain antibodies against EMP2, a format that results in a longer plasma retention time. This new construct showed high and specific affinity for EMP2 (10−10M) using both flow cytometry and ELISA based formats. Moreover, treatment with these agents induced cell death to EMP2 positive cells, including those characterized by high ALDEFLUOR activity. Preclinical assessment of the anti-EMP2 immunotoxins showed no acute toxicity and acceptable plasma retention. Preliminary results using a 4T1 model system produced a significant reduction in tumor burden. Our results suggest that continued development of these agents may be successful at targeting advanced disease. Research supported, in part, by NCI R21 CA234642 and the Clayton Foundation for Research. Citation Format: Khalid A. Mohamedali, Kok Su-yin, Lawrence H. Cheung, Naina Dhawan, Michael G. Rosenblum, Madhuri Wadehra. Targeting breast cancer stem cells with anti-EMP2 immunotoxins delivering granzyme b [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 2891.
Abstract 5488: Prediction of target receptor occupancy for ALX148, a CD47 blocker, using mechanistic PK/RO modeling
Authors: Elena Vasileva, Oleg Demin
Journal: Cancer Research (2020)

Abstract Background: ALX148 is one of the anti-CD47 antibodies that are currently in clinical development. Understanding the target receptor occupancy (RO) in tumor can help with dose selection for ALX148 and other anti-CD47 antibodies. However, RO can be challenging to determine through direct experimental measurements. A mechanistic PK/RO model was developed to predict CD47 occupancy in tumor tissues and periphery for ALX148 based on its properties (PK, structure, and affinity). Methods: Developed mechanistic PK/RO model describes PK of ALX148 in blood plasma, distribution to tumor tissues of Non-Hodgkin lymphoma (lymph nodes, spleen), non-linear clearance of ALX148 due to the binding with CD47 and further complex internalization. RO was described on red blood cells and tumor cells. The model takes into account CD47 expression (molecules per cell) and a number of cells expressing CD47. Parameters were fitted against clinical PK data. Clinical data on RO in the periphery was used for model validation. Results: The model successfully described ALX148 clinical data on PK and RO in blood plasma. Concentrations in lymph nodes and spleen were predicted to be similar and in approximately 3 times lower than in blood plasma. Such high concentration in tumor tissues is caused by small size of ALX148 (molecular weight is 78 kDa). Dose and regimen chosen for combination treatment (10 mg/kg QW) result in 90-95% trough steady-state RO in tumor tissues. The model predicted that trough steady-state RO in lymph nodes and spleen was more than 95% after administration of maximal dose 30 mg/kg Q2W. Conclusions: A mechanistic PK/RO model was built to capture ALX148 clinical PK data and then predicted more than 90% RO at the dose used in combination treatment cohort. This approach has the potential to be used to inform dose selection for other anti-CD47 antibodies taking into account their specific features as binding properties, size, etc. Citation Format: Elena Vasileva, Oleg Demin Jr. Prediction of target receptor occupancy for ALX148, a CD47 blocker, using mechanistic PK/RO modeling [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 5488.