tbuckley/cabot-search huggingface dataset:
Abstract 1673: Uveal melanoma study patients with low CD163:CD3 ratio in tumor biopsy and low serum IL-6 showed enhanced tumor shrinkage (TS) and overall survival (OS) on tebentafusp
Authors: Jessica C. Hassel, Adel Benlahrech, Sarah Stanhope, Revashnee Naidoo, Emma Leach, Laura Collins, Shaad Abdullah, Koustubh Ranade, Joseph Sacco
Journal: Cancer Research (2021)

Abstract Background: Tebentafusp, an investigational TCR–anti-CD3 bispecific fusion protein (ImmTAC) that targets gp100 and activates T cells, has shown monotherapy activity in metastatic melanoma [1-3]. In a phase I/II trial enrolling metastatic uveal melanoma patients we explored biomarkers of clinical outcomes. Methods: The effect of CD163+ macrophages on ImmTAC-mediated T cell proliferation and melanoma cell killing was assessed in vitro. Advanced uveal melanoma HLA-A*02:01+ patients (N = 127) were treated with weekly 68mcg tebentafusp after intra-patient dose escalation (NCT02570308). Serum samples (up to N=123) were profiled for 11 cytokines and chemokines. Digital image analysis of IHC enumerated immune cells per mm2 in tumor biopsies (up to N=112). Median cutoff was used for biomarker correlations with outcomes. Results: In vitro, increasing numbers of CD163+ macrophages resulted in greater inhibition of ImmTAC-mediated T cell proliferation and killing of MEL624 melanoma cells. The numbers of tumor infiltrating T cells (CD3, CD4, CD8) and CD163+ macrophages at baseline were not associated with TS. However, below median CD163:CD3 ratio was associated with greater TS (odds ratio OR=2.9, p=0.014) and OS (hazard ratio HR=0.4, p=0.001), attributable to CD163:CD8 (OR=3.6, p=0.004) but not CD163:CD4 (OR=1.9, p=0.2). Low serum IL-6 levels at baseline trended with TS (OR=2.1, p=0.09) and OS (HR=0.3, p&amp;lt;0.001). Subset with below median CD163:CD3 in tumor biopsies and serum IL-6 had the best outcomes (Table). Conclusions: Uveal melanoma patients with low levels of pre-treatment CD163:CD3 in tumor biopsy and serum IL-6 may derive the most benefit from tebentafusp. This hypothesis will be tested in samples from a randomized trial of tebentafusp (NCT03070392). [1] NCT01211262; ASCO 2019 [2] Clinical Cancer Research; 2020[3] #195; ESMO IO; 2020 Subset% with tumor shrinkageMean change in tumor SLD ± S.E.1-year OS %All biomarker evaluable43 (N=95)5.4 ± 3 (N=95)58 (N=105)Low IL-6/Low CD163:CD370 (N=27)-9.4 ± 6.1 (N=27)93 (N=30)Low IL-6/High CD163:CD330 (N=20)10.2 ± 5.0 (N=20)64 (N=22)High IL-6/Low CD163:CD340 (N=20)14.2 ± 7.7 (N=20)41 (N=22)High IL-6/High CD163:CD329 (N=28)9.9 ± 4.0 (N=28)32 (N=31) Citation Format: Jessica C. Hassel, Adel Benlahrech, Sarah Stanhope, Revashnee Naidoo, Emma Leach, Laura Collins, Shaad Abdullah, Koustubh Ranade, Joseph Sacco. Uveal melanoma study patients with low CD163:CD3 ratio in tumor biopsy and low serum IL-6 showed enhanced tumor shrinkage (TS) and overall survival (OS) on tebentafusp [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 1673.
Abstract 2831: Exosome gene signatures characterize metastatic dynamicity
Authors: Amber Gonda, Jay V. Shah, Jake N. Siebert, Nanxia Zhao, Mi Jung Kwon, Prabhas V. Moghe, Nicola Francis, Vidya Ganapathy
Journal: Cancer Research (2021)

Abstract Early diagnosis and effective tumor monitoring can significantly alter clinical outcomes of ovarian cancer patients. Innovative tools are needed to enhance the sensitivity and specificity of current monitoring modalities. Extracellular vesicles, or exosomes, have shown to be promising conduits of diagnostic biomarkers to aid in tumor detection as evidenced by Exosome Diagnostics' new ExoDx Prostate (IntelliScore) test that uses exosomal markers to differentiate between benign prostate disease and early cancer (Tutrone, R., Donovan, M.J., Torkler, P. et al. Clinical utility of the exosome based ExoDx Prostate(IntelliScore) EPI test in men presenting for initial Biopsy with a PSA 2-10 ng/mL. Prostate Cancer Prostatic Dis 23, 607-614 (2020)). The potential of these vesicles however goes beyond simple diagnostic power of cancer detection. Due to the onco-specific contents packaged and the minimally invasive, low risk accessibility, exosomes have the capacity to be used as longitudinal monitoring tools to characterize early molecular changes at all stages of the disease. We hypothesized that the dynamicity of ovarian tumors during progression and metastatic development is reflected in exosomes. In order to test this we isolated exosomes and used qPCR to analyze exosomal gene signatures from a mouse model of ovarian cancer. SKOV3 ovarian cancer tumor cells were injected into mice and allowed to grow for 3 weeks. Plasma was collected from mice at 5-7 day increments and exosomes were extracted. Multiple established metastatic genes in ovarian cancer were evaluated and 4 genes, Lox, THBS1, TIMP3, and β-actin, were found to be differentially expressed in correlation with 3 translationally pertinent assessments: presence or absence of tumors, levels of metastatic burden, and longitudinal tumor progression. Gene expression patterns were compared with exosomal gene signatures extracted from human ovarian patient plasma and found to express similar patterns. These results support the diagnostic potential of using exosomal genetic signatures to detect early metastatic development and to facilitate longitudinal tracking of tumor progression. Citation Format: Amber Gonda, Jay V. Shah, Jake N. Siebert, Nanxia Zhao, Mi Jung Kwon, Prabhas V. Moghe, Nicola Francis, Vidya Ganapathy. Exosome gene signatures characterize metastatic dynamicity [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 2831.
Abstract 2551: The development of cancer digital videos to increase participation in marginalized communities
Authors: Pamela Valera, Luis Alzate-Duque, Nicholas Acuna
Journal: Cancer Research (2021)

Abstract Social media, in the form of digital videos, targeted people with limited health literacy, as well as disadvantaged or marginalized groups, may help reduce cancer health disparities and improve health outcomes in these populations. In this article, we document the process of adapting the content from the Cancer 101 curriculum to create animated scripts about the cancer care continuum that is clear, straightforward, and in plain language. The development of the Cancer 101 digital videos required a multidisciplinary collaboration from - public health, medicine, technology, and expertise in correctional health, smoking cessation, web development, video producers, and individuals directly impacted by cancer disparities. The Cancer 101 videos were showcased at a community health fair where the videos were viewed by attendants waiting to be seen by a medical provider. While waiting for their cancer screening, thirteen individuals were selected and invited to watch all eleven videos totaling less than 60-minutes of viewing time. Overall, participants agreed that they would recommend the videos to friends/family and that they plan to watch other video modules to learn more information about cancer. Additionally, participants enjoyed the graphics and audio of the videos presented. Furthermore, participants noted that Cancer 101 digital videos described cancer in plain language, leading to a better understanding of the disease. Future research is needed to implement Cancer 101 digital videos in healthcare clinics to increase cancer information and improve cancer screening rates in marginalized communities. Citation Format: Pamela Valera, Luis Alzate-Duque, Nicholas Acuna. The development of cancer digital videos to increase participation in marginalized communities [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 2551.
AIAP: A Quality Control and Integrative Analysis Package to Improve ATAC-Seq Data Analysis
Authors: Shaopeng Liu, Daofeng Li, Cheng Lyu, Paul M. Gontarz, Benpeng Miao, Pamela A.F. Madden, Ting Wang, Bo Zhang
Journal: Genomics Proteomics & Bioinformatics (2021)

Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) is a technique widely used to investigate genome-wide chromatin accessibility. The recently published Omni-ATAC-seq protocol substantially improves the signal/noise ratio and reduces the input cell number. High-quality data are critical to ensure accurate analysis. Several tools have been developed for assessing sequencing quality and insertion size distribution for ATAC-seq data; however, key quality control (QC) metrics have not yet been established to accurately determine the quality of ATAC-seq data. Here, we optimized the analysis strategy for ATAC-seq and defined a series of QC metrics for ATAC-seq data, including reads under peak ratio (RUPr), background (BG), promoter enrichment (ProEn), subsampling enrichment (SubEn), and other measurements. We incorporated these QC tests into our recently developed ATAC-seq Integrative Analysis Package (AIAP) to provide a complete ATAC-seq analysis system, including quality assurance, improved peak calling, and downstream differential analysis. We demonstrated a significant improvement of sensitivity (20%-60%) in both peak calling and differential analysis by processing paired-end ATAC-seq datasets using AIAP. AIAP is compiled into Docker/Singularity, and it can be executed by one command line to generate a comprehensive QC report. We used ENCODE ATAC-seq data to benchmark and generate QC recommendations, and developed qATACViewer for the user-friendly interaction with the QC report. The software, source code, and documentation of AIAP are freely available at https://github.com/Zhang-lab/ATAC-seq_QC_analysis.
Topological analysis of hepatocellular carcinoma tumour microenvironment based on imaging mass cytometry reveals cellular neighbourhood regulated reversely by macrophages with different ontogeny
Authors: Jianpeng Sheng, Junlei Zhang, Lin Wang, Vincent Tano, Jianghui Tang, Xun Wang, Jiangchao Wu, Jinyuan Song, Yaxing Zhao, Jingxia Rong, Fei Cheng, Jianfeng Wang, Yinan Shen, Liang Wen, Junjun He, Hui Zhang, Taohong Li, Qi Zhang, Xueli Bai, Zhimin Lu, Tingbo Liang
Journal: Gut (2021)

Hepatocellular carcinoma (HCC) tumour microenvironment (TME) is highly complex with diverse cellular components organising into various functional units, cellular neighbourhoods (CNs). And we wanted to define CN of HCC while preserving the TME architecture, based on which, potential targets for novel immunotherapy could be identified.A highly multiplexed imaging mass cytometry (IMC) panel was designed to simultaneously quantify 36 biomarkers of tissues from 134 patients with HCC and 7 healthy donors to generate 562 highly multiplexed histology images at single-cell resolution. Different function units were defined by topological analysis of TME. CN relevant to the patients' prognosis was identified as specific target for HCC therapy. Transgenic mouse models were used to validate the novel immunotherapy target for HCC.Three major types of intratumour areas with distinct distribution patterns of tumorous, stromal and immune cells were identified. 22 cellular metaclusters and 16 CN were defined. CN composed of various types of cells formed regional function units and the regional immunity was regulated reversely by resident Kupffer cells and infiltrating macrophages with protumour and antitumour function, respectively. Depletion of Kupffer cells in mouse liver largely enhances the T cell response, reduces liver tumour growth and sensitises the tumour response to antiprogrammed cell death protein-1 treatment.Our findings reveal for the first time the various topological function units of HCC TME, which also presents the largest depository of pathological landscape for HCC. This work highlights the potential of Kupffer cell-specific targeting rather than overall myeloid cell blocking as a novel immunotherapy for HCC treatment.
Autologous bone marrow transplantation in acute leukemia: a phase I study of in vitro treatment of marrow with 4- hydroperoxycyclophosphamide to purge tumor cells
Authors: H Kaizer, RK Stuart, R Brookmeyer, WE Beschorner, HG Braine, WH Burns, DJ Fuller, M Korbling, KF Mangan, R Saral
Journal: Blood (1985)
Abstract 1526: Single-step precision genome engineering platform enables versatile generation of personalized (neoTCR) adoptive cell therapy T cells with supplementary anti-tumor attributes
Authors: Michael M. Dubreuil, Charles W. Tran, Bhamini Purandare, William Lu, James Byers, Michal Mass, Kyle Jacoby, Barbara Sennino, Alex Franzusoff, Stefanie J. Mandl
Journal: Cancer Research (2021)

Abstract Personalized autologous TCR-T cell therapies targeting neoE-specific neoepitopes (NeoE) derived from tumor-exclusive mutations are a compelling approach for the treatment of patients with solid tumors. Using the ultra-sensitive imPACT Isolation Technology®, antigen-experienced neoE-specific CD8 T cells are captured from the blood of patients with solid cancers followed by cloning of the cognate neoepitope-specific HLA class I-restricted T cell receptors (HLA-I neoTCRs). Using DNA-mediated (non-viral) precision genome engineering technology, fresh CD8 and CD4 T cells from the same patient with cancer are engineered to express the HLA-I neoTCR. We have further innovated this platform of precision genome engineering to confer neoTCR-T cells with supplementary gene edits to address the array of potential sources for tumor immune evasion. Two examples of the versatility of this single step gene editing platform are described in this study: 1) concurrent expression of a CD8 co-receptor (CD8coR) to augment activity of CD4 T cells engineered with lower affinity HLA-I neoTCRs; and 2) simultaneous disruption of TET2 expression in T cells, which has previously been reported to positively affect T cell differentiation and persistence. The data shows that these simultaneous supplemental gene modifications were achieved with high efficiency, resulting in fully functional CD8 and CD4 neoTCR-T cells. Surface expression of CD8coR together with the neoE-targeted TCR increased T cell effector function and antigen-specific tumor cell killing. NeoTCR-T cells with concomitant deletion of TET2-expression exhibited enhanced cytotoxicity against neoantigen-expressing tumor cells. Together, these results demonstrate the applicability of this versatile precision genome engineering platform technology to yield enhanced next generation neoTCR-T cell therapies to expand the potential for clinical benefit in treating persons with solid cancers. Citation Format: Michael M. Dubreuil, Charles W. Tran, Bhamini Purandare, William Lu, James Byers, Michal Mass, Kyle Jacoby, Barbara Sennino, Alex Franzusoff, Stefanie J. Mandl. Single-step precision genome engineering platform enables versatile generation of personalized (neoTCR) adoptive cell therapy T cells with supplementary anti-tumor attributes [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 1526.
Abstract 520: Potential role of serum proteome in predicting immune-related adverse events from immunotherapy in non-small cell lung cancer
Authors: Myungwoo Nam, Leeseul Kim, William Cheng, William H. Bae, Jin Young Hwang, Yoonhee Choi, Yeun Ho Lee, Won Kyung Hur, Chan Mi Jung, Heayoon S. Cho, Young Kwang Chae
Journal: Cancer Research (2021)

Abstract Early recognition of immune-related adverse events (irAEs) of immunotherapy is important. Circulating proteome reflects host response to diseases and is being explored as a marker for response to immunotherapy. We used a serum-based proteomics test, Primary Immune Response (PIR), to explore the associations between developing irAEs and immunotherapy in non-small cell lung cancer (NSCLC) patients. Data of 38 consented NSCLC patients with baseline PIR test done within one week prior to the start of immunotherapy were collected. Samples were grouped into either sensitive or intermediate/resistant (not sensitive) by PIR classification. We analyzed the durations from the immunotherapy initiation to the first episode of irAE, each individual irAE, and each irAE above grade 1 using log-rank test. IrAEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Among the 38 NSCLC patients, 21 patients (55%) experienced one or more irAEs. The total number of irAEs was 33 with the majority classified as either grade 1 (n=18, 55%) or grade 2 (n=11, 33%) (Table 1). PIR-sensitive group showed longer irAE free period with the median ‘Time to first irAE' being 54 weeks compared to 9.5 weeks in PIR-not sensitive (p=0.22, HR=0.56, 95% CI=0.24-1.34). The median ‘Time to each irAE' were 45 weeks and 12 weeks in PIR-sensitive and PIR-not sensitive, respectively (p=0.1, HR=0.55, 95% CI=0.28-1.1). The median ‘Time to each irAE above grade 1' demonstrated similar results with less differences between the two groups with median values of 54 weeks and 30 weeks in PIR-sensitive and PIR-not sensitive, respectively (p=0.28, HR=0.57, 95% CI=0.21-1.56). Our results demonstrated a trend that PIR-sensitive patients are more likely to tolerate immunotherapy longer without developing irAEs. It implies the potential value of the baseline PIR test in predicting the development of irAEs and selecting subsets of patients who need close monitoring with immunotherapy. Distribution of irAEs by PIR classificationVariablesSensitiveNot-sensitiveTotal number of patients, n1325Patients without irAE, n (%)7 (54%)10 (40%)Patients with irAE, n (%)6 (46%)15 (60%)Total number of irAEs, n1023Grade 1, n (%)5 (50%)13 (57%)Grade 2, n (%)5 (50%)6 (26%)Grade 3, n (%)02 (8%)Grade 4, n (%)01 (4%)Grade 5, n (%)01 (4%) Citation Format: Myungwoo Nam, Leeseul Kim, William Cheng, William H. Bae, Jin Young Hwang, Yoonhee Choi, Yeun Ho Lee, Won Kyung Hur, Chan Mi Jung, Heayoon S. Cho, Young Kwang Chae. Potential role of serum proteome in predicting immune-related adverse events from immunotherapy 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 520.
Haemodynamic frailty – A risk factor for acute kidney injury in the elderly
Authors: Neil G. Docherty, Christian Delles, Patrick D’Haese, Anita T. Layton, Carlos Martínez-Salgado, Benjamin A. Vervaet, Francisco J. López-Hernández
Journal: Ageing Research Reviews (2021)

Clinical frailty in the elderly is defined by a composite measure of functional psychomotor decline. Herein, we develop the concept of haemodynamic frailty (HDF), a state of increased predisposition to disease prevalent in the elderly and characterised by impairment of the network of compensatory responses governing the defence of circulatory volume and adaptive haemodynamic function. We review the factors predisposing the elderly to HDF, with a focus on the impaired capacity to sustain total body water balance. As a component of HDF, dehydration generates vulnerability to diseases caused by tissue hypoperfusion, including acute kidney injury. We provide a detailed mechanistic explanation of how dehydration and depletion of the intravascular volume impacts on renal blood flow to become an important element of the heightened risk of acute kidney injury (AKI) in the elderly. We bring these mechanistic considerations into the clinical context with reference to examples of how pre-renal (haemodynamic) and intrinsic (involving renal parenchymal damage) AKI risk is elevated in the setting of dehydration. Finally, we present HDF as a state of opportunity to prevent disease, for which diagnostic and interventional standards need to be refined. Further prospective studies are warranted to help clarify the clinical utility of assessing and managing HDF with regard to the mitigation of AKI risk in the elderly.
Assessing and Addressing Cardiovascular Health in People Who Are Transgender and Gender Diverse: A Scientific Statement From the American Heart Association
Authors: Carl G. Streed, Lauren B. Beach, Billy A. Caceres, Nadia L. Dowshen, Kerrie L. Moreau, Monica Mukherjee, Tonia Poteat, Asa Radix, Sari L. Reisner, Vineeta Singh
Journal: Circulation (2021)

There is growing evidence that people who are transgender and gender diverse (TGD) are impacted by disparities across a variety of cardiovascular risk factors compared with their peers who are cisgender. Prior literature has characterized disparities in cardiovascular morbidity and mortality as a result of a higher prevalence of health risk behaviors. Mounting research has revealed that cardiovascular risk factors at the individual level likely do not fully account for increased risk in cardiovascular health disparities among people who are TGD. Excess cardiovascular morbidity and mortality is hypothesized to be driven in part by psychosocial stressors across the lifespan at multiple levels, including structural violence (eg, discrimination, affordable housing, access to health care). This American Heart Association scientific statement reviews the existing literature on the cardiovascular health of people who are TGD. When applicable, the effects of gender-affirming hormone use on individual cardiovascular risk factors are also reviewed. Informed by a conceptual model building on minority stress theory, this statement identifies research gaps and provides suggestions for improving cardiovascular research and clinical care for people who are TGD, including the role of resilience-promoting factors. Advancing the cardiovascular health of people who are TGD requires a multifaceted approach that integrates best practices into research, health promotion, and cardiovascular care for this understudied population.