tbuckley/cabot-search huggingface dataset:
Polyclonality, Shared Strains, and Convergent Evolution in Chronic Cystic Fibrosis <i>Staphylococcus aureus</i> Airway Infection
Authors: Dustin R. Long, Daniel J. Wolter, Michael Lee, Mimi Precit, Kathryn McLean, Elizabeth Holmes, Kelsi Penewit, Adam Waalkes, Lucas R. Hoffman, Stephen J. Salipante
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale:Staphylococcus aureus is the most common respiratory pathogen isolated from patients with cystic fibrosis (CF) in the United States. Although modes of acquisition and genetic adaptation have been described for Pseudomonas aeruginosa, resulting in improved diagnosis and treatment, these features remain more poorly defined for S. aureus.Objectives: To characterize the molecular epidemiology and genetic adaptation of S. aureus during chronic CF airway infection and in response to antibiotic therapy.Methods: We performed whole-genome sequencing of 1,382 S. aureus isolates collected longitudinally over a mean 2.2 years from 246 children with CF at five U.S. centers between 2008 and 2017. Results were integrated with clinical and demographic data to characterize bacterial population dynamics and identify common genetic targets of in vivo adaptation.Measurements and Main Results: Results showed that 45.5% of patients carried multiple, coexisting S. aureus lineages, often having different antibiotic susceptibility profiles. Adaptation during the course of infection commonly occurred in a set of genes related to persistence and antimicrobial resistance. Individual sequence types demonstrated wide geographic distribution, and we identified limited strain-sharing among children linked by common household or clinical exposures. Unlike P. aeruginosa, S. aureus genetic diversity was unconstrained, with an ongoing flow of new genetic elements into the population of isolates from children with CF.Conclusions: CF airways are frequently coinfected by multiple, genetically distinct S. aureus lineages, indicating that current clinical procedures for sampling isolates and selecting antibiotics are likely inadequate. Strains can be shared by patients in close domestic or clinical contact and can undergo convergent evolution in key persistence and antimicrobial-resistance genes, suggesting novel diagnostic and therapeutic approaches for future study.
Myeloproliferative Neoplasms: Emerging Treatment Options for Myelofibrosis
Authors: Aaron T. Gerds
Journal: Journal of the National Comprehensive Cancer Network (2020)

Myelofibrosis (MF) is a symptom-forward disease, and its treatment focuses on alleviating those symptoms, as well as improving survival. An initial disease risk assessment is critical for deciding on a course of therapy (and a number of models can be used depending on the available patient information), and anemia can be considered a special case within the treatment algorithms for MF. JAK-STAT inhibition is currently the cornerstone of treatment for MF, but these inhibitors are not perfect. Future research will focus on the microenvironment in reversing fibrosis, immunotherapies, proliferative signaling pathways, epigenetic regulators, and stem cells.
82P Novel analysis of F. nucleatum subspecies in human CRC tissue and engineering of therapeutic F. nucleatum phage
Authors: L. Ninio-Many, N. Buchshtab, I. Vainberg Slutskin, I. Weiner, S. Yahav, D. Berko-Ashur, J. Nicenboim, L. Zelcbuch, E. Safyon Gartman, M. Kahan-Hanum, S. Kredo-Russo, M. Golembo, N. Zak, I. Gahali-Sass, S. Puttagunta, M. Bassan
Journal: Annals of Oncology (2020)
IMMU-11. DUAL TARGETING OF IL-6 AND CD40 OVERCOMES GLIOBLASTOMA RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE
Authors: Fan Yang, Steven Brem, Yi Fan
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is refractory to current T cell-based immunotherapies such as checkpoint blockade. GBM is characterized by extensive infiltration of immunosuppressive macrophages (Mφs) that contribute to the treatment resistance. Here we develop a dual-targeting strategy to synergistically activate tumor-associated Mφs, which overcomes GBM resistance to therapeutic blockade of the PD1 and CTLA4 checkpoints. Consistent with a previously established role of IL-6 in alternative Mφ polarization, we show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T cell infiltration and enhances animal survival in a genetically engineered mouse GBM model. However, IL-6 inhibition does not synergize PD-1 and CTLA-4 blockade in GBM. Interestingly, we reveal that anti-IL-6 therapy reduces CD40 expression in GBM-associated Mφs. Our transcriptome analysis identifies a Stat3/HIF-1a-mediated axis, through which IL-6 regulates CD40 expression in Mφs. Finally, we show that combination of IL-6 blockade with CD40 stimulation robustly reverses Mφ-mediated tumor immunosuppression, enhances T cell infiltration, and sensitizes GBM to PD-1 and CTLA-4 blockade treatment, cumulating in inhibited tumor growth and extended animal survival. These findings illustrate a cellular mechanism that regulates Mφ-mediated tumor immunity, and suggest that dual-targeting IL-6 and CD40 may offer exciting opportunities for improving immunotherapy against GBM.
TMOD-24. GENERATION AND CHARACTERIZATION OF A NOVEL TRANSGENIC IDO REPORTER MOUSE FOR IDO POSTTRANSLATIONAL MODIFICATION ANALYSIS IN SITU
Authors: April Bell, Lijie Zhai, Erik Ladomersky, Kristen Lauing, Lakshmi Bollu, Derek Wainwright
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most common and aggressive primary central nervous system tumor in adults with a median survival of 14.6 months. GBM is a potently immunosuppressive cancer due in-part to the prolific expression of immunosuppressive indoleamine 2,3 dioxygenase 1 (IDO). Tumor cell IDO facilitates the intratumoral accumulation of regulatory T cells (Tregs; CD4+CD25+FoxP3+). Although immunosuppressive IDO activity is canonically characterized by the conversion of tryptophan into kynurenine, we have utilized transgenic and syngeneic mouse models and mutant glioma lines to demonstrate that tumor cell IDO increases Treg accumulation independent of tryptophan metabolism. Here, we address the gap in our understanding of IDO signaling activity in vivo. Subcutaneously-engrafted human GBM expressing human IDO-GFP cDNA was isolated from immunodeficient humanized NSG-SGM3 mice. The tumor was immunoprecipitated for the GFP tag using GFP-TRAP followed by mass spectrometry which revealed a novel methylation site on a lysine residue at amino acid 373 in the IDO C-terminus region. Western blot analysis of IDO protein also revealed the presence of tyrosine phosphorylation. Additionally, we recently created a new transgenic IDO reporter mouse model whereby endogenous IDO is fused to GFP via a T2A linker (IDO→GFP). This model allows for the isolation of IDO+ cells in real-time and without causing cell death, thereby creating the opportunity for downstream molecular analysis of in situ-isolated GFP+ cells. Collectively, our work suggests that IDO non-enzyme activity may involve the post-translational modifications we recently identified. As IDO activity may differ between in vitro and in vivo modeling systems, we will use the new IDO→GFP reporter mouse model for an improved mechanistic understanding of how immunosuppressive IDO facilitates Treg accumulation in vivo.
Effective Management of 177Lu-DOTA0-Tyr3-Octreotate Extravasation
Authors: Bruno Maucherat, Nicolas Varmenot, Vincent Fleury, Helene Senellart, Caroline Rousseau
Journal: Clinical Nuclear Medicine (2020)

Radiopharmaceutical extravasation is a known nuclear medicine adverse effect, mostly with no complication in case of diagnostic radiopharmaceutical. However, a therapeutic radiopharmaceutical extravasation may have clinical consequences and must be treated quickly and effectively. We report here a case of 177Lu-DOTA0-Tyr3-octreotate extravasation.
EPCO-11. IN VIVO FUNCTIONAL GENOMIC SCREEN IDENTIFIES WISP1 AS AN OVEREXPRESSED DRIVER OF GLIOBLASTOMA
Authors: Pushan Dasgupta, Joy Gumin, Piergiorgio Pettazzoni, Floris Barthel, Angela Deem, Prasenjit Dey, Emmet Huang-Hobbs, Erik Sulman, Roel Verhaak, Frederick Lang, Giulio Draetta
Journal: Neuro-Oncology (2020)

Abstract There is a tremendous need to identify new genetic drivers of glioblastoma which can serve as potential therapeutic targets. In order to find new drivers, we leveraged genomic datasets to conduct a context specific in vivo functional genomic screen of overexpressed and/or amplified genes in GBM. We identified WISP1, a secreted extracellular matrix protein, to be an overexpressed driver in GBM. Overexpression of WISP1 was able to drive tumor growth in various in vivo models. Knockdown of WISP1 with shRNAs resulted in reduced colony formation in vitro and reduced tumor growth in vivo. Rescue experiments validated that the shRNAs were on target. Functional characterization of the protein revealed that the TSP module is necessary for the phenotype. Intriguingly, overexpression of WISP1 lacking the signal peptide module for secretion resulted in a strong phenotype. Co-culture and conditioned medium experiments further supported a secretion independent intracellular role of WISP1 in GBM. Though WISP1 is a secreted protein we have found some basal localization in the cytosol. Overall, we have revealed WISP1 to be a driver of GBM with possible therapeutic potential as a target. This study has expanded our understanding of WISP1 by supporting a new role as a driver in GBM which can function in a non-canonical manner in the cytosol. Overall, we have revealed WISP1 to be a driver of GBM with possible therapeutic potential as a target.
FDA Approval Summary: Lurbinectedin for the Treatment of Metastatic Small Cell Lung Cancer
Authors: Sonia Singh, Adnan A. Jaigirdar, Flora Mulkey, Joyce Cheng, Salaheldin S. Hamed, Yangbing Li, Jiang Liu, Hong Zhao, Anwar Goheer, Whitney S. Helms, Xing Wang, Rajiv Agarwal, Rajan Pragani, Kwadwo Korsah, Shenghui Tang, John Leighton, Atiqur Rahman, Julia A. Beaver, Richard Pazdur, Marc R. Theoret, Harpreet Singh
Journal: Clinical Cancer Research (2020)

On June 15, 2020, the FDA granted accelerated approval to lurbinectedin for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was granted on the basis of the clinically meaningful effects on overall response rate (ORR) and duration of response (DOR), and the safety profile observed in a multicenter, open-label, multicohort clinical trial (PM1183-B-005-14, NCT02454972), referred to as Study B-005, in patients with advanced solid tumors. The trial included a cohort of 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. The confirmed ORR determined by investigator assessment using RECIST 1.1 in the approved SCLC patient population was 35% [95% confidence interval (CI): 26-45], with a median DOR of 5.3 (95% CI: 4.1-6.4) months. The drug label includes warnings and precautions for myelosuppression, hepatotoxicity, and embryo-fetal toxicity. This is the first drug approved by the FDA in over 20 years in the second line for patients with metastatic SCLC. Importantly, this approval includes an indication for patients who have platinum-resistant disease, representing an area of particular unmet need.
Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE)
Authors: Milan J. Sonneveld, Jun Yong Park, Apichat Kaewdech, Wai-Kay Seto, Yasuhito Tanaka, Ivana Carey, Margarita Papatheodoridi, Florian van Bömmel, Thomas Berg, Fabien Zoulim, Sang Hoon Ahn, George N. Dalekos, Nicole S. Erler, Christoph Höner zu Siederdissen, Heiner Wedemeyer, Markus Cornberg, Man-Fung Yuen, Kosh Agarwal, Andre Boonstra, Maria Buti, Teerha Piratvisuth, George Papatheodoridis, Benjamin Maasoumy
Journal: Clinical Gastroenterology and Hepatology (2020)

Predictors of successful nucleo(s)tide analogue (NA) therapy withdrawal remain elusive. We studied the relationship between end-of-treatment levels of hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) and outcome after therapy cessation.Patients who discontinued NA therapy in centers in Asia and Europe were enrolled. HBcrAg and HBsAg were measured at treatment cessation, and associations with off-treatment outcomes were explored. The SCALE-B (Surface antigen, Core-related antigen, Age, ALT, and tenofovir for HBV) score was calculated as previously reported. End points included sustained virologic response (VR; hepatitis B virus DNA level <2000 IU/mL), HBsAg loss, and alanine aminotransferase (ALT) flares (>3× upper limit of normal). Re-treated patients were considered nonresponders.We analyzed 572 patients, 457 (80%) were Asian and 95 (17%) were hepatitis B e antigen positive at the start of NA therapy. The median treatment duration was 295 weeks. VR was observed in 267 (47%), HBsAg loss was observed in 24 (4.2%), and ALT flare was observed in 92 (16%). VR (67% vs 42%) and HBsAg loss (15% vs 1.5%) was observed more frequently in non-Asian patients when compared to Asian patients (P < .001). Lower HBcrAg levels were associated with higher rates of VR (odds ratio [OR], 0.701; P < .001) and HBsAg loss (OR, 0.476; P < .001), and lower rates of ALT flares (OR, 1.288; P = .005). Similar results were observed with HBsAg (VR: OR, 0.812; P = .011; HBsAg loss: OR, 0.380; P < .001; and ALT flare: OR, 1.833; P < .001). Lower SCALE-B scores were associated with higher rates of VR, HBsAg loss, and lower rates of ALT flares in both Asian and non-Asian patients (P < .001).In this multicenter study, off-treatment outcomes after NA cessation varied with ethnicity. Lower levels of HBcrAg and HBsAg were associated with favorable outcomes. A risk score comprising both factors can be used for risk stratification.
TAMI-30. LOCAL TARGETING OF NAD+ SALVAGE PATHWAY ALTERS THE IMMUNE TUMOR MICROENVIRONMENT AND ENHANCES CHECKPOINT IMMUNOTHERAPY IN GLIOBLASTOMA
Authors: Ming Li, Ameya Kirtane, Juri Kiyokawa, Hiroaki Nagashima, Giovanni Traverso, Daniel Cahill, Hiroaki Wakimoto
Journal: Neuro-Oncology (2020)

Abstract The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic sub-types of malignant glioma are sensitive to selective inhibition of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT). However, the potential impact of NAD+ depletion on the brain tumor microenvironment has not been elaborated. In addition, systemic toxicity of NAMPT inhibition remains a significant concern. Here, we show that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induces specific immunological changes in the tumor microenvironment of murine GBM, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+ and CD8+ T cells and reduction of M2-polarized immunosuppressive macrophages. NAD+ depletion and autophagy induced by NAMPT inhibitors mediated the upregulation of PD-L1 transcripts and cell surface protein levels in GBM cells. NAMPT inhibitor modulation of the tumor immune microenvironment was therefore combined with PD-1 checkpoint blockade in vivo, significantly increasing the survival of GBM bearing animals. Thus, the therapeutic impacts of NAMPT inhibition extended beyond neoplastic cells, shaping surrounding immune effectors. Microparticle delivery and release of NAMPT inhibitor at the tumor site offers a safe and robust means to alter an immune tumor microenvironment that could potentiate checkpoint immunotherapy for glioblastoma.
EXTH-17. LOCAL DELIVERY OF CYTOKINES AND SYNTHETIC IMMUNOMODULATORS INCREASES T CELL INFILTRATION AND SIGNIFICANTLY IMPROVES SURVIVAL IN A POORLY IMMUNOGENIC MODEL OF GLIOBLASTOMA
Authors: Alexander Haddad, Jordan Spatz, Sara Collins, Matheus Pereira, Sabraj Gill, Megan Montoya, Polly Chuntova, Jacob Young, Nikhil Mummaneni, Noriyuki Kasahara, Manish Aghi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Severe local and systemic immune suppression in glioblastoma (GBM) contributes to the failure of single-agent immunotherapies in clinical trials. In this study, we evaluated the efficacy of locally delivered combination immunotherapy in a poorly immunogenic murine GBM model. METHODS Immunomodulators used in these studies included: IL-15 and IL-7 (T cell activation), LIGHT (T cell tumor infiltration), FLT3L (dendritic cell maturation/proliferation), a surface T cell engager (T cell killing of tumor cells), and a bispecific PD-L1/T cell engager (T cell killing targeted to PD-L1-expressing cells). We first assessed T cell-mediated cytotoxicity in vitro against SB28, a poorly immunogenic murine GBM cell line, after expressing these immunomodulators in combination. Next, tumor growth inhibition in vivo was evaluated in syngeneic C57BL/6 mice, initially by establishment of intracranial tumors with pre-transduced SB28 cells, and subsequently by delivering these immunomodulators to pre-established naïve SB28 tumors using neural stem cells (NSCs) and retroviral replicating vectors (RRV). RESULTS SB28 cells transduced with immunomodulators activated dose-dependent T cell-mediated cytotoxicity in vitro. Mice with pre-transduced intracranial SB28 gliomas showed significantly longer survival (minimum survival: 60 days, long-term survival in 57% of mice) vs. control mice (median survival: 20 days) (p&amp;lt; 0.001), and significantly increased tumor infiltration of CD4+ and CD8+ T cells. NSC- and RRV-mediated immunomodulator delivery to pre-established SB28 gliomas also resulted in significantly increased survival of treated mice vs. controls (median survival: 31 days vs. 22 days, p&amp;lt; 0.001). Immunomodulator-treated tumors again showed significantly increased infiltration of CD4+ and CD8+ T cells, along with decreased CD11b+ cell infiltration. CONCLUSIONS A novel combination therapy for GBM immunotherapy activated T cell killing of SB28 GBM cells in vitro and achieved a significant survival benefit in vivo, associated with anti-tumor alterations to the GBM tumor microenvironment. Further studies to optimize the efficiency of combinatorial immunomodulator delivery are currently underway.
Menopausal status and current usage of oral contraceptives and hormone replacement therapy in relationship to soluble concentrations of adhesion molecules
Authors: Ellen W Demerath, Christine Zeller, Bradford Towne, Shumei S Guo, Wm. Cameron Chumlea, Roger M Siervogel
Journal: Circulation (2001)

P35 Epidemiological studies have shown that hormone replacement therapy (HRT) generally reduces coronary heart disease mortality in post-menopausal women. A smaller number of reports also indicate that oral contraceptive (OC) use provides some cardioprotective effects. However, the mechanisms by which these commonly-used exogenous hormones affect the vascular system are not entirely known and comparisons to males are not always made. We measured the circulating concentrations of four inflammatory markers [intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin (ESEL), and P-selectin (PSEL)] in 281 healthy men and 307 healthy women (204 pre-menopausal, 103 post-menopausal) aged 18-85 years. Individuals were grouped according to sex, and in women, menopausal status (pre/post), OC use (yes/no), and HRT use (yes/no). The effects of these variables on adhesion molecule concentrations were examined using analysis of variance, adjusting for smoking, age, body mass index, and waist-hip ratio. The means shown are ± standard error and the values are in ng/ml. We found significantly higher mean ICAM-1 concentrations in post-menopausal women (358±15) than in pre-menopausal women (317±15) and men (295±10), p&lt;0.01. ESEL was significantly higher in men (61±2) and post-menopausal women (63±3) than in pre-menopausal women (54±2), p&lt;0.05. Similarly, there was a tendency for VCAM-1 and PSEL to be higher in post-menopausal women and men compared to pre-menopausal women, although these contrasts were not statistically significant. Among pre-menopausal women, OC users (N=59) had lower mean VCAM-1 and E-SEL concentrations than those not using OC (N=145)(VCAM-1: 494±47 vs. 644±29, p&lt;0.001 and ESEL 42±4 vs..54±2, p&lt;0.005). Among post-menopausal women, those using HRT (N=52) had lower ICAM-1 and VCAM-1 than those not using HRT (N=51) (ICAM-1: 342±26 vs. 408±24, p&lt;0.05 and VCAM-1: 682±89 vs. 790±82, p=0.15). We conclude that current use of OC and HRT is associated with a beneficial effect on the expression of certain inflammatory markers.
Recent Advances on the Role of EGFR Tyrosine Kinase Inhibitors in the Management of NSCLC With Uncommon, Non Exon 20 Insertions, EGFR Mutations
Authors: Antonio Passaro, Tony Mok, Solange Peters, Sanjay Popat, Myung-Ju Ahn, Filippo de Marinis
Journal: Journal of Thoracic Oncology (2020)

The first-line treatment of choice for patients with EGFR mutation-positive NSCLC is an EGFR tyrosine kinase inhibitor (TKI), of which five as follows are predominantly available in practice: gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib. Most prospective clinical trial data with these agents are limited to patients with the common activating and sensitizing EGFR mutations as follows: exon 19 deletions and exon 21 L858R point mutations. However, 10% to 20% of patients with NSCLC harbor uncommon EGFR mutations that have variable sensitivity to different EGFR TKIs. Owing to their molecular structures, afatinib, dacomitinib, and osimertinib have broader inhibitory profiles than the first-generation agents, gefitinib and erlotinib. Nevertheless, the paucity of prospective clinical data, the wide heterogeneity of uncommon mutations, and the existence of compound mutations in up to 25% of the cases complicate treatment decisions in this patient subgroup. Here, we collate the latest preclinical and clinical data regarding the activity of different TKIs against major uncommon EGFR mutations including compound mutations, but excluding exon 20 insertions which are generally insensitive to TKIs. On the basis of these data, we offer suggestions regarding treatment strategies for uncommon EGFR mutations. Moving forward, it will be important to include uncommon EGFR mutations in the first-line molecular analysis of all patients with adenocarcinoma of the lung, as this will help optimize patient outcomes according to their precise genotype.
C-Reactive protein and cardiac allograft vasculopathy: is inflammation the critical link?**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Hector O Ventura, Mandeep R Mehra
Journal: Journal of the American College of Cardiology (2003)