tbuckley/cabot-search huggingface dataset:
Abstract 133: Micro-environment on demand (MOD): A versatile technology for cognate T-cell receptor - neoantigen discovery
Authors: Maithreyan Srinivasan, Justin Madrigal, Nathan Schoepp, Russell Cole
Journal: Cancer Research (2020)

Abstract NCI estimates that cancer will be the leading cause of death in 2030, worldwide. Checkpoint inhibitors and adoptive cell therapies (ACTs) cost up to ~$2 million/patient and have shown durable responses in a few patients while many patients experience life-threatening side-effects. So, there is a critical need to identify cost-effective therapies to treat cancer with minimal to no side-effects. Deep mapping of cancer antigens and their cognate immune cells is one approach that has the potential for a more universal/targeted treatment. However, systematic methods do not exist to identify cancer antigens and their cognate immune cells functionally and link phenotypic readouts to antigen and immune cell DNA sequences. Here we present a single cell handling and analysis platform based on Printed Droplet Microfluidics, a new droplet microfluidic technology that enables the precise construction of cell-cell interaction experiments with single cell resolution, followed by functional and genomic analysis. At the core of the technology is a fluorescence-activated flow sorter repurposed to deterministically sort and merge droplets containing single cells, beads, reagents, and drugs, collect and assay merged droplets and resort assay-positive droplets for downstream genomic analyses. The selectivity of the sorting/merging technology enables both the construction of experiments with up to one million precise cell combinations and the performance of flexible multi-step molecular biology workflows. We will show proof-of-concept for the MOD platform that integrates three technologies after fluorescently labeled single-cells are encapsulated in droplets - droplet-based cell-sorting and merging, single-cell-based cytokine assays and selective sequencing of T-cell receptor variable regions based on cytokine signals. The technology has the potential to rapidly accelerate the rate of immunotherapy discovery by enabling a larger number of experiments to be performed with higher precision, more modes of analysis, and less starting material than competing bulk technologies. Citation Format: Maithreyan Srinivasan, Justin Madrigal, Nathan Schoepp, Russell Cole. Micro-environment on demand (MOD): A versatile technology for cognate T-cell receptor - neoantigen discovery [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 133.
Assessment of Brain Injury Using Portable, Low-Field Magnetic Resonance Imaging at the Bedside of Critically Ill Patients
Authors: Kevin N. Sheth, Mercy H. Mazurek, Matthew M. Yuen, Bradley A. Cahn, Jill T. Shah, Adrienne Ward, Jennifer A. Kim, Emily J. Gilmore, Guido J. Falcone, Nils Petersen, Kevin T. Gobeske, Firas Kaddouh, David Y. Hwang, Joseph Schindler, Lauren Sansing, Charles Matouk, Jonathan Rothberg, Gordon Sze, Jonathan Siner, Matthew S. Rosen, Serena Spudich, W. Taylor Kimberly
Journal: JAMA Neurology (2020)

Neuroimaging is a key step in the clinical evaluation of brain injury. Conventional magnetic resonance imaging (MRI) systems operate at high-strength magnetic fields (1.5-3 T) that require strict, access-controlled environments. Limited access to timely neuroimaging remains a key structural barrier to effectively monitor the occurrence and progression of neurological injury in intensive care settings. Recent advances in low-field MRI technology have allowed for the acquisition of clinically meaningful imaging outside of radiology suites and in the presence of ferromagnetic materials at the bedside.
Severe mental illness and health service utilisation for nonpsychiatric medical disorders: A systematic review and meta-analysis
Authors: Amy Ronaldson, Lotte Elton, Simone Jayakumar, Anna Jieman, Kristoffer Halvorsrud, Kamaldeep Bhui
Journal: PLoS Medicine (2020)

Background Psychiatric comorbidity is known to impact upon use of nonpsychiatric health services. The aim of this systematic review and meta-analysis was to assess the specific impact of severe mental illness (SMI) on the use of inpatient, emergency, and primary care services for nonpsychiatric medical disorders. Methods and findings PubMed, Web of Science, PsychINFO, EMBASE, and The Cochrane Library were searched for relevant studies up to October 2018. An updated search was carried out up to the end of February 2020. Studies were included if they assessed the impact of SMI on nonpsychiatric inpatient, emergency, and primary care service use in adults. Study designs eligible for review included observational cohort and case-control studies and randomised controlled trials. Random-effects meta-analyses of the effect of SMI on inpatient admissions, length of hospital stay, 30-day hospital readmission rates, and emergency department use were performed. This review protocol is registered in PROSPERO (CRD42019119516). Seventy-four studies were eligible for review. All were observational cohort or case-control studies carried out in high-income countries. Sample sizes ranged from 27 to 10,777,210. Study quality was assessed using the Newcastle-Ottawa Scale for observational studies. The majority of studies (n = 45) were deemed to be of good quality. Narrative analysis showed that SMI led to increases in use of inpatient, emergency, and primary care services. Meta-analyses revealed that patients with SMI were more likely to be admitted as nonpsychiatric inpatients (pooled odds ratio [OR] = 1.84, 95% confidence interval [CI] 1.21–2.80, p = 0.005, I2 = 100%), had hospital stays that were increased by 0.59 days (pooled standardised mean difference = 0.59 days, 95% CI 0.36–0.83, p < 0.001, I2 = 100%), were more likely to be readmitted to hospital within 30 days (pooled OR = 1.37, 95% CI 1.28–1.47, p < 0.001, I2 = 83%), and were more likely to attend the emergency department (pooled OR = 1.97, 95% CI 1.41–2.76, p < 0.001, I2 = 99%) compared to patients without SMI. Study limitations include considerable heterogeneity across studies, meaning that results of meta-analyses should be interpreted with caution, and the fact that it was not always possible to determine whether service use outcomes definitively excluded mental health treatment. Conclusions In this study, we found that SMI impacts significantly upon the use of nonpsychiatric health services. Illustrating and quantifying this helps to build a case for and guide the delivery of system-wide integration of mental and physical health services.
Abstract 4024: NAMPT inhibitor decreases NAMPT capture by an antibody directed against the 5-phosphoribosyl-1-pyrophosphate-binding loop: Rationale for an NAMPT occupancy assay
Authors: Maysoun Shomali, Sandrine Hilairet, Marianne Duhamel, Frederico Nardi, Thomas Bertrand, Geraldine Penarier, Laurent Debussche, Monsif Bouaboula
Journal: Cancer Research (2020)

Abstract Nicotinamide phosphoribosyl transferase (NAMPT) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide (NAD) biosynthesis. As NAMPT inhibitors (NAMPTi) have been shown to be substrates of NAMPT, binding of NAMPTi to NAMPT results in the NAMPTi-phosphoribose adduct (RP) that binds tightly and strongly inhibits the NAMPT enzyme. Structural analyses performed in this study unveiled the proximity of the NAMPTi-RP complex to the phosphoribosyl diphosphate (PRPP)-binding loop within the NAMPT catalytic site. The PRPP-binding loop of NAMPT is subject to conformational flexibility. The PRPP-binding loop domain is oriented to the outer side of the NAMPT dimer and can potentially serve as an antigen-binding site for antibodies. Interestingly, we show that the NAMPTi-RP adduct bound to NAMPT decreases NAMPT capture by an antibody that is directed against the c-terminal 5-phosphoribosyl-1-pyrophosphate-binding loop in NAMPT. This finding was then used to explore cellular NAMPT occupancy. The NAMPTi-RP complex displays a sustained, cellular NAMPT occupancy that correlates with the inhibition of NAMPT activity. Moreover, a good correlation between NAMPT occupancy, NAD decrease, and NAMPTi efficacy was observed in-vivo in a NCI-H82 small cell lung cancer (SCLC) xenograft model. NAMPT-occupancy assay can be used in clinical settings to better define the optimal dose levels and dose regimen for effective NAMPT inhibition. Citation Format: Maysoun Shomali, Sandrine Hilairet, Marianne Duhamel, Frederico Nardi, Thomas Bertrand, Geraldine Penarier, Laurent Debussche, Monsif Bouaboula. NAMPT inhibitor decreases NAMPT capture by an antibody directed against the 5-phosphoribosyl-1-pyrophosphate-binding loop: Rationale for an NAMPT occupancy assay [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 4024.
Abstract 1960: Targeted androgen receptor (AR) protein degradation for the treatment of metastatic castration-resistant prostate cancer (mCRPC)
Authors: Xin Han, Lijie Zhao, Weiguo Xiang, Chong Qin, Bukeyan Miao, Tianfeng Xu, Jianfeng Lu, Mi Wang, Shaomeng Wang
Journal: Cancer Research (2020)

Abstract Androgen receptor (AR) and its downstream signaling play a critical role in the development and progression of both localized and metastatic prostate cancer. As a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC), previous strategies that successfully target AR signaling have focused on blocking androgen synthesis by drugs such as abiraterone and inhibition of AR function by AR antagonists such as enzalutamide and apalutamide (ARN-509). However, such agents become ineffective in advanced prostate cancer with AR gene amplification, mutation and alternate splicing. It is very clear however that in most patients with CRPC, the AR protein continues to be expressed and tumors are still dependent upon AR signaling. Here we describe our design, synthesis and evaluation of small-molecule AR degraders based on the proteolysis targeting chimera (PROTAC) concept and our investigation of their therapeutic potential and mechanism of action in vitro and in vivo. In vitro, our potent AR degraders effectively induce degradation of AR protein in AR+ LNCaP, VCaP and 22Rv1 prostate cancer cell lines with DC50 values as low as 1 nM. AR degraders are capable of reducing the AR protein level by &amp;gt;95% in these AR+ cancer cell lines and effectively reduces AR-regulated gene expression suppression. In vivo, our AR degrader showed potent AR degradation effects and anti-tumor activities in multiple murine xenograft models of prostate cancer at well-tolerated dosing schedules. Our data provides clear evidence that targeting AR for degradation by the PROTAC methodology is a novel and very exciting therapeutic approach for the treatment of mCRPC. Citation Format: Xin Han, Lijie Zhao, Weiguo Xiang, Chong Qin, Bukeyan Miao, Tianfeng Xu, Jianfeng Lu, Mi Wang, Shaomeng Wang. Targeted androgen receptor (AR) protein degradation for the treatment of metastatic castration-resistant prostate cancer (mCRPC) [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 1960.
Abstract CT219: Efficacy of TTFields in elderly patients with newly diagnosed glioblastoma (GBM): Sub-group analysis of the EF-14 trial
Authors: Zvi Ram, Jay-Jiguang Zhu
Journal: Cancer Research (2020)

Abstract Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. In the EF-14 phase 3 study leading to FDA approval, TTFields significantly extended survival in newly diagnosed GBM when added to maintenance temozolomide (TMZ). Elderly GBM patients usually have worse prognosis and often receive only partial treatment for the disease. The aim of the following post-hoc analysis was to examine the effects of TTFields in the elderly population (≥65 years of age) enrolled in the EF-14 study. Method: All 134 elderly patients (≥65 years of age) from the EF-14's intent-to-treat population were included in the analysis, Overall survival (OS) and progression-free survival (PFS), as well as adverse event frequency and severity were compared between the TMZ + TTFields arm and the TMZ alone arm. Result: The median age was 69 (range: 65-83), 69% were male. Median PFS from randomization was 6.5 months versus 3.9 months in the TTFields + TMZ Vs. TMZ alone arms, respectively (hazard ratio [HR], 0.47 [95%CI 0.30, 0.74] P&amp;lt;0.0236). Median OS was 17.4 months versus 13.7 months in the TTFields + TMZ versus TMZ alone arm, respectively (HR 0.51 [CI 0.33, 0.77] P&amp;lt;0.020). Serious adverse events (SAEs) were reported in 39% of patients treated with TTFields + TMZ and in 33% of patients treated with TMZ alone. None of the SAEs were considered related to TTFields. SAEs were considered related to TMZ or to the underlying disease. Grades 1-2 skin AEs were observed in 51% of patients. Conclusion: Consistent with the overall outcome of the EF-14 study, elderly patients treated with TMZ + TTFields showed significantly better OS compared to patients on TMZ alone, and without increase in grade 3-4 toxicity. Citation Format: Zvi Ram, Jay-Jiguang Zhu. Efficacy of TTFields in elderly patients with newly diagnosed glioblastoma (GBM): Sub-group analysis of the EF-14 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 CT219.
Abstract 5674: Discovery of AZD9833, an oral small molecule selective degrader of the estrogen receptor (SERD)
Authors: James S. Scott, Thomas Moss, Steve Stokes, Willem M. Nissink, Christopher J. Morrow, Mandy Lawson, Natalie Cureton, Eric Gangl, Pablo Morentin Gutierrez, Richard Mather, Justin P. Lindemann, Andrew Sykes, David Fisher, Radoslaw Polanski, Danielle Carroll, Aisling Barton Twomey, Teresa Klinowska
Journal: Cancer Research (2020)

Abstract The estrogen receptor alpha (ERα) is expressed in &amp;gt;70% of breast cancers and is a clinically validated target in oncology. Anti-hormonal therapies that block ER function directly (e.g. tamoxifen) or therapies that block the production of estrogen itself (e.g., aromatase inhibitors) have proven to be effective treatments of the disease. Further advances in disease control have been made with the development of the Selective Estrogen Receptor Degrader (SERD) fulvestrant, which both antagonizes ERα-driven tumor cell growth and causes degradation of the ERα receptor. The first-generation oral SERDs, including AZD9496, showed full ER degradation in MCF-7 cells but incomplete ER degradation in other cell lines, and partial agonism. Building on that learning, extensive structure-enabled chemical optimization has resulted in the identification of a next generation oral SERD AZD9833, a potent degrader and antagonist of the ERα receptor (both EC50 &amp;lt;1 nM in MCF7 cells) with favorable physicochemical properties (logD7.4 &amp;lt;3). AZD9833 delivers maximal ERα degradation equivalent to fulvestrant in all ER+ cell lines tested, including MCF7, CAMA1, T47D and BT474. In addition, and in contrast to AZD9496, AZD9833 does not cause ER agonism in the endometrial carcinoma cell line Ishikawa in vitro and does not cause an increase in the thickness of the endometrium in juvenile rats. In several patient-derived and cell line xenograft models, including models with clinically relevant ESR1 mutations, AZD9833 completely suppresses tumor growth and gives equivalent pharmacodynamic activity to supra-clinical levels of fulvestrant. Furthermore, in an ESR1 wild-type and an ESR1 D538G PDX model, AZD9833 demonstrated combinatorial benefit with palbociclib. Based on this preclinical data AZD9833 has progressed into a multi-stage monotherapy and palbociclib combination First Time in Patient clinical trial, SERENA-1 (NCT03616587). Citation Format: James S. Scott, Thomas Moss, Steve Stokes, Willem M. Nissink, Christopher J. Morrow, Mandy Lawson, Natalie Cureton, Eric Gangl, Pablo Morentin Gutierrez, Richard Mather, Justin P. Lindemann, Andrew Sykes, David Fisher, Radoslaw Polanski, Danielle Carroll, Aisling Barton Twomey, Teresa Klinowska. Discovery of AZD9833, an oral small molecule selective degrader of the estrogen receptor (SERD) [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 5674.
Abstract 4988: Multiplex immunofluorescence detection of resident memory T cells in solid tumors
Authors: Elena Baranova, Amanda Finan-Marchi, Manon Motte, Maroua Tliba, Sabine Iglesias, Carole Belda, Alexandra Mace, Sylvie Hunt, Domenico Lazzaro, Jean-Philippe Coton, Renaud Burrer
Journal: Cancer Research (2020)

Abstract Tissue-resident memory T cells (TRM) represent a lineage of T cells localized in peripheral tissues that do not reenter the circulation. Their establishment in the tissue makes them the initial T cell response in local infections and inflammatory conditions. TRM are characterized by the expression of CD103, CD69, and CD49a. TRM play a role in the efficacy of cancer vaccines and have been correlated with improved prognosis and/or survival in a number of cancers. Comparisons of TRM and cytotoxic CD8 T cells in the tumor microenvironment are limited. Due to this, we have developed a Histoprofile TRM multiplex immunohistochemistry panel, validated by in-depth image analysis, for TRM and CD8 T cell profiling. Here we present our in depth multiplex immunofluorescence validation assay including tests of repeatability and reproducibility. Human tissue microarrays of tumors in a range of tissues were investigated with the TRM multiplex panel. After multi-spectral acquisition, the TRM and CD8 T cells could be differentiated in all of the tissue types examined. After delineation by a pathologist, we demonstrate the capability to quantify TRM and CD8 cells within the tumor and stroma compartments. The presented approach has the power to expand the clinical implications of TRM in cancer vaccine and immunotherapy. Citation Format: Elena Baranova, Amanda Finan-Marchi, Manon Motte, Maroua Tliba, Sabine Iglesias, Carole Belda, Alexandra Mace, Sylvie Hunt, Domenico Lazzaro, Jean-Philippe Coton, Renaud Burrer. Multiplex immunofluorescence detection of resident memory T cells in solid 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 4988.
Abstract 823: Gene expression analysis reveals a pitfall in the molecular research of prostate tumors relevant to Gleason score
Authors: Wensheng Zhang, Yan Dong, Kun Zhang
Journal: Cancer Research (2020)

Abstract Gleason score (GS) is a powerful prognostic factor in prostate cancer (PCa). A GS-7 tumor typically has the primary architectural pattern and secondary prevalent one being graded as 3 and 4 or 4 and 3, respectively. Due to the well-known multifocal occurrence of different patterns, a biological sample from a GS-7 tumor used in a molecular experiment will be uncertain regarding the actually represented pattern if no special attention is given to specimen preparation. In this study, by an integrative analysis of public gene expression datasets for PCa, we demonstrate that such an uncertainty is not uncommon. First, based on a unique dataset (Sowalsky, et.al, Clin. Cancer Res., 2017) of paired Gleason pattern 3 (GP-3) and Gleason pattern 4 (GP- 4) specimens of 13 GS-7 tumors, we identify 303 differentially expressed genes with respect to those two architectural patterns. Then, using the TCGA data, we show that the profile of these genes is a strong signature for distinguishing the GS-6 (3+3) tumors from the GS-8 (4+4) ones (AUC = 0.96, p-value = 9*10E-17), implying that the differences of transcription program between the GS-8 (4+4) and GS-6 (3+3) samples resemble the differences between the GP-3 and GP-4 specimens. We further demonstrate that the co-expression pattern of the signature genes in the subset of the GS-7 samples resembles that present in the aggregate of GS-6 and GS-8 samples. Finally, we verify the findings using the GSE21032 data. Our results suggest that the GS-7 specimens used to generate two frequently-cited genome-wide expression datasets largely are individual GP-3 or GP-4 specimens rather than the “intermediate” specimens of GP-3 and GP-4. This provides molecular evidence for the aforementioned uncertainty of GS-7 tumor samples, indicating a potential pitfall in the existing molecular and translational research of prostate tumors relevant to GS. Citation Format: Wensheng Zhang, Yan Dong, Kun Zhang. Gene expression analysis reveals a pitfall in the molecular research of prostate tumors relevant to Gleason score [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 823.
Catheter-integrated soft multilayer electronic arrays for multiplexed sensing and actuation during cardiac surgery
Authors: Mengdi Han, Lin Chen, Kedar Aras, Cunman Liang, Xuexian Chen, Hangbo Zhao, Kan Li, Ndeye Rokhaya Faye, Bohan Sun, Jae-Hwan Kim, Wubin Bai, Quansan Yang, Yuhang Ma, Wei Lu, Enming Song, Janice Mihyun Baek, Yujin Lee, Clifford Liu, Jeffrey B. Model, Guanjun Yang, Roozbeh Ghaffari, Yonggang Huang, Igor R. Efimov, John A. Rogers
Journal: Nature Biomedical Engineering (2020)