tbuckley/cabot-search huggingface dataset:
Abstract 3570: Adoptive transfer of tumor antigen-specific CTLs requires anti-CTLA-4 and anti-PD-1 to drive tumor eradication
Authors: Lewis Zhichang Shi, Jianjun Gao, Luis Vence, Jorge Brando, James Allison, Padmanee Sharma
Journal: Cancer Research (2018)

Abstract Adoptive transfer of tumor-reactive T cells (ACT) has led to significant clinical responses in hematologic malignancies. However, its efficacy in solid tumors has been dismal, likely due to the immunosuppression imposed by the tumor microenvironment (TME) of solid tumors. A proven effective strategy to revert the immunosuppressive TME is immune checkpoint blockades (ICBs), including anti-CTLA-4 and anti-PD-1/PD-L1, which have been recently approved by FDA for cancer therapy. Here, using the orthotopic B16-F10 melanoma model, we combine ACT of PMEL-1 Tg+ CTLs that recognize the endogenous melanoma antigen gp100 with dual blockade of CTLA-4 and PD-1, the highly pursued effective combinatorial ICB, to treat established tumors. Although ACT alone transiently suppresses tumor growth, complete tumor regression requires additional dual anti-CTLA-4 and anti-PD-1 blockade. Mechanistically, we demonstrate that the ICOS-Eomes-IFN-γαμμα axis, but not the ICOS-T-bet-IFN-γαμμα axis, in CTLs mediates the therapeutic effects of ACT and ICBs. Our data provide direct evidence that combining ACT of CTLs with ICBs confers long-term protection to tumor challenges, which largely depends on CTL-intrinsic expression of ICOS. Citation Format: Lewis Zhichang Shi, Jianjun Gao, Luis Vence, Jorge Brando, James Allison, Padmanee Sharma. Adoptive transfer of tumor antigen-specific CTLs requires anti-CTLA-4 and anti-PD-1 to drive tumor eradication [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3570.
Abstract 2564: Selection of affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10
Authors: Ellen Border, Joseph P. Sanderson, Thomas Weissensteiner, Natalie Hyland, Tom Holdich, Francine Brophy, Rafael Amado, Andrew Gerry, Nicholas Pumphrey
Journal: Cancer Research (2018)

Abstract Circulating T-cells, bearing T-cell receptors (TCRs) that have passed thymic selection, generally have low affinity for self-protein-derived cancer antigens and therefore have a limited ability to detect and eliminate tumor cells. Engineering TCRs to enhance and optimize their affinity, and therefore potency, for cancer targets is a promising strategy for adoptive immunotherapy in cancer patients. Modification of TCRs can potentially generate cross-reactivity to antigens expressed by normal tissue. Such cross reactivity might not be detected by in vivo animal studies, due to species differences in the antigenic repertoire. To mitigate the risk of such toxicities in clinical trials, we developed a comprehensive in vitro testing strategy. This strategy involves systematic substitution at each position of the antigenic peptide sequence using all natural amino acids to generate a profile of peptide specificity (“X-scan”). The likelihood of off-target reactivity was investigated by searching the human proteome for sequences matching this profile and testing against a panel of cell lines. Starting from a panel of parental TCRs with diverse sequences, we engineered several affinity-enhanced TCRs specific for the cancer-testis antigen MAGE-A10. The properties of two of these TCRs, which had the optimal balance of potency and specificity, could not be distinguished effectively with conventional biochemical and cellular assays. The X-scan method permitted us to select the most specific and potent candidate for further pre-clinical testing. This MAGE-A10c796 TCR is now being studied in clinical trials to treat HLA-A2+ patients with non-small cell lung cancer (NCT02592577), urothelial cancers, melanoma, or head and neck cancers (NCT02989064). Citation Format: Ellen Border, Joseph P. Sanderson, Thomas Weissensteiner, Natalie Hyland, Tom Holdich, Francine Brophy, Rafael Amado, Andrew Gerry, Nicholas Pumphrey. Selection of affinity-enhanced T-cell receptors for adoptive T-cell therapy targeting MAGE-A10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2564.
Dysbiosis-Associated Change in Host Metabolism Generates Lactate to Support Salmonella Growth
Authors: Caroline C. Gillis, Elizabeth R. Hughes, Luisella Spiga, Maria G. Winter, Wenhan Zhu, Tatiane Furtado de Carvalho, Rachael B. Chanin, Cassie L. Behrendt, Lora V. Hooper, Renato L. Santos, Sebastian E. Winter
Journal: Cell Host & Microbe (2018)
Therapy-induced stress response is associated with downregulation of pre-mRNA splicing in cancer cells
Authors: Ksenia S. Anufrieva, Victoria О. Shender, Georgij P. Arapidi, Marat S. Pavlyukov, Michail I. Shakhparonov, Polina V. Shnaider, Ivan O. Butenko, Maria A. Lagarkova, Vadim M. Govorun
Journal: Genome Medicine (2018)

Abnormal pre-mRNA splicing regulation is common in cancer, but the effects of chemotherapy on this process remain unclear. To evaluate the effect of chemotherapy on slicing regulation, we performed meta-analyses of previously published transcriptomic, proteomic, phosphoproteomic, and secretome datasets. Our findings were verified by LC-MS/MS, western blotting, immunofluorescence, and FACS analyses of multiple cancer cell lines treated with cisplatin and pladienolide B. Our results revealed that different types of chemotherapy lead to similar changes in alternative splicing by inducing intron retention in multiple genes. To determine the mechanism underlying this effect, we analyzed gene expression in 101 cell lines affected by ɣ-irradiation, hypoxia, and 10 various chemotherapeutic drugs. Strikingly, оnly genes involved in the cell cycle and pre-mRNA splicing regulation were changed in a similar manner in all 335 tested samples regardless of stress stimuli. We revealed significant downregulation of gene expression levels in these two pathways, which could be explained by the observed decrease in splicing efficiency and global intron retention. We showed that the levels of active spliceosomal proteins might be further post-translationally decreased by phosphorylation and export into the extracellular space. To further explore these bioinformatics findings, we performed proteomic analysis of cisplatin-treated ovarian cancer cells. Finally, we demonstrated that the splicing inhibitor pladienolide B impairs the cellular response to DNA damage and significantly increases the sensitivity of cancer cells to chemotherapy. Decreased splicing efficiency and global intron retention is a novel stress response mechanism that may promote survival of malignant cells following therapy. We found that this mechanism can be inhibited by pladienolide B, which significantly increases the sensitivity of cancer cells to cisplatin which makes it a good candidate drug for improving the efficiency of cancer therapy.
Combined Systemic and Intratumoral Administration of Human Papillomavirus Vaccine to Treat Multiple Cutaneous Basaloid Squamous Cell Carcinomas
Authors: Anna J. Nichols, Adrianna Gonzalez, Emily S. Clark, Wasif N. Khan, Alyx C. Rosen, Wellington Guzman, Harold Rabinovitz, Evangelos V. Badiavas, Robert S. Kirsner, Tim Ioannides
Journal: JAMA Dermatology (2018)

Squamous cell carcinoma (SCC) is the second most common form of skin cancer, and its incidence is increasing. When surgical management is not an option, finding a safe and efficacious treatment is a challenge. Mounting evidence suggests that the human papillomavirus (HPV) is involved in the pathogenesis of some SCCs.To assess whether the 9-valent HPV vaccine could be an effective treatment strategy for cutaneous SCC.A woman in her 90s with multiple, inoperable cutaneous basaloid SCCs was successfully treated at a university-based outpatient dermatology clinic with a combination of systemic and intratumoral delivery of the 9-valent HPV vaccine from March 17, 2016, through February 27, 2017, and then followed up through May 21, 2018.Reduction in tumor size and number after a combination of systemic and intratumoral administration of the HPV vaccine.All tumors resolved 11 months after the first intratumoral injection of the vaccine. The patient remained free of tumors at the end of follow-up.This is the first report, to our knowledge, of complete regression of a cutaneous malignant tumor after combined systemic and direct intratumoral injection of the 9-valent HPV vaccine. This report suggests that the HPV vaccine may have therapeutic utility for SCCs in patients who are poor surgical candidates, have multiple lesions, or defer surgery.
Abstract LB-075: Structural stabilization of protein fragments by membrane anchoring for generation of cell-permeable protein mimetics
Authors: Nadya Tarasova, Karen Stefanisko, Lyuba Khavrutskii, Sergey Tarasov
Journal: Cancer Research (2018)

Abstract Targeting protein-protein interactions can provide plentiful opportunities for the discovery of novel drug candidates and powerful chemical biology tools. However, the majority of these interactions are ‘undruggable”, and we still know very little about the structural mechanisms and functions for the vast majority of them. We have developed a rational approach that allows for the straightforward development of cell-permeable metabolically stable inhibitors of protein-protein interactions. The approach is based on structural stabilization of peptides by membrane anchoring. Biophysical data suggests that proximity to the membrane facilitates interactions of hydrophobic side chains of amphiphilic peptides with the bilayer and stabilizes natural fold of not only helical but also stretched and hairpin-type peptides. Membrane tethering is achieved through straightforward derivatization of peptides with fatty acids of appropriate length that depends on peptide's hydrophobicity. Lipidation facilitates cell entry and allows intracellular delivery of peptides up to 14-16 residues long. Negative charges can interfere with the entry, while positive charges generally have little effect. Wide applicability of this method was confirmed by generation of selective and highly potent dominant negative inhibitors of RAS oncogenes, β-catenin, STAT1, STAT3 and STAT5 N-domains, Il10R1, IFNGR1 and other non-druggable targets. Rational design of inhibitors can be accomplished even in the absence of the target tertiary structure by using conservation of certain sequence parts during the evolution. High throughput generation of selective chemical biology tools allows for effective interrogation of protein-protein interactions leading to discovery of mechanistic details of molecular signaling that could not be obtained with the help of genetic approaches. Citation Format: Nadya Tarasova, Karen Stefanisko, Lyuba Khavrutskii, Sergey Tarasov. Structural stabilization of protein fragments by membrane anchoring for generation of cell-permeable protein mimetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-075.
Abstract 15807: Comparison of Conventional and Compression Only Bystander CPR Following Pediatric Out of Hospital Cardiac Arrest in the United States: A Study From the Cardiac Arrest Registry to Enhance Survival (CARES)
Authors: Maryam Y Naim, Rita V Burke, Bryan F McNally, Lihai Song, Robert A Berg, Vinay M Nadkarni, Kimberly Vellano, David Markenson, Richard N Bradley, Joseph W Rossano
Journal: Circulation (2016)

Introduction:  Bystander compression only CPR (Co-CPR) is as effective as conventional CPR in adults with out of hospital cardiac arrest (OHCA). There are few data on Co-CPR in children.   Hypothesis:  We aimed to characterize bystander Co-CPR in pediatric OHCA and test the hypothesis that conventional CPR would be associated with improved overall survival and neurologically favorable survival at hospital discharge compared to Co-CPR from a large cardiac arrest registry in the United States.   Methods:  We conducted an analysis of the Cardiac Arrest Registry to Enhance Survival database. Inclusion criteria were age ≤ 18 years of age and non-traumatic OHCA from January 1, 2013 through December 31, 2015. Neurologically favorable survival was defined as a Cerebral Performance Category Scale of 1 or 2.   Results:  A total of 3972 cardiac arrests were evaluated of which 1855 received bystander CPR and type of CPR data were available for 1458 arrests (79%). For those events where the type of CPR data was available, 49% (n=708) received conventional CPR, 50% (n=731) received Co-CPR, and 1% (n=19) received ventilation only CPR. Infants were more likely to receive conventional CPR and children > 1 to 18 years were more likely to receive Co-CPR (53% vs. 55%, p=0.0033). Compared to white children (49%), Hispanic children (64%) and black children (56%) were more likely to receive Co-CPR compared to conventional CPR (p   Conclusions:  In this study of pediatric OHCA bystander Co-CPR was provided as often frequently as conventional CPR. A racial disparity exists in the provision of conventional CPR. Conventional CPR was associated with improved overall survival and favorable neurological outcome compared to Co-CPR.
Jejunal endoscopic submucosal dissection is feasible using the pocket-creation method and balloon-assisted endoscopy
Authors: Mizuho Iida, Hirotsugu Sakamoto, Yoshimasa Miura, Tomonori Yano, Yoshikazu Hayashi, Alan Lefor, Hironori Yamamoto
Journal: Endoscopy (2018)

Endoscopic submucosal dissection (ESD) is widely used for the resection of superficial gastrointestinal neoplasms. Previously, we reported that the pocket-creation method (PCM) overcomes difficulties in ESD, such as in duodenal lesions [1] and subpedunculated neoplastic lesions [2]. Here, we describe the use of the PCM to facilitate ESD of a jejunal lesion.
Abstract 3816: Efficacy of CDX-1140, an agonist CD40 antibody, in preclinical tumor models
Authors: Lawrence J. Thomas, Li-Zhen He, James Testa, Anna Wasiuk, Jeffrey Weidlick, Crystal Sisson, Laura A. Vitale, Thomas O'Neill, Eric Forsberg, Catherine D. Pilsmaker, Lauren E. Gergel, Elizabeth Q. Do, James Boyer, April R. Baronas, Mallary Rocheleau, Michelle E. Grealish, Kathleen M. Borrelli, Henry C. Marsh, Tibor Keler
Journal: Cancer Research (2018)

Abstract CD40 on antigen presenting cells plays a critical role in the induction of effective innate and adaptive immune responses. In contrast, CD40 signaling on certain malignant cells, particularly B cell lymphomas, inhibits proliferation or triggers apoptotic cell death. Thus, two independent mechanisms provide opportunities for the use of agonist anti-CD40 monoclonal antibodies in cancer therapy: enhancement of anti-tumor immunity, and direct inhibition of tumor growth. CDX-1140 is a human IgG2 antibody selected from a panel of fully human mAbs specific for CD40 generated by hybridoma technology from human Ig transgenic mice. We previously demonstrated the potent immune enhancing effects of CDX-1140 using in vitro models and in non-human primates. CDX-1140 was shown to activate dendritic cells and B cells in an Fc receptor independent manner. CDX-1140 does not bind to the CD40L binding site, and synergizes with CD40L in stimulation of the CD40 receptor and subsequent functional activities. Here we further characterized the anti-tumor activity of CDX-1140 on CD40 positive tumors using xenograft models in immunodeficient mice. Using the Ramos and Raji human lymphoblastoma cell lines, CDX-1140 was shown to attenuate tumor growth and prolong survival. Addition of CDX-1140 and human PBMC was highly effective at promoting complete rejection of both Ramos and Raji tumors. Importantly, the epithelial EJ138 bladder carcinoma cell line was also highly sensitive to CDX-1140 treatment. For example, in a study where mice received EJ138 cells subcutaneously, all animals that were treated with 300 µg of CDX-1140 on days 1, 8, and 15, showed suppression of tumor growth through day 60, in comparison to saline-treated animals which developed significant tumors in 7 of 8 animals. These data support the potential of CDX-1140 for direct anti-tumor effects on CD40-positive tumors (including epithelial tumors) that may supplement its activity as an immune activating agent. CDX-1140 is currently in a phase 1 dose-escalation study in patients with advanced solid tumors. Citation Format: Lawrence J. Thomas, Li-Zhen He, James Testa, Anna Wasiuk, Jeffrey Weidlick, Crystal Sisson, Laura A. Vitale, Thomas O'Neill, Eric Forsberg, Catherine D. Pilsmaker, Lauren E. Gergel, Elizabeth Q. Do, James Boyer, April R. Baronas, Mallary Rocheleau, Michelle E. Grealish, Kathleen M. Borrelli, Henry C. Marsh, Tibor Keler. Efficacy of CDX-1140, an agonist CD40 antibody, in preclinical tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3816.
Abstract 14985: Enhanced Angiotensin-(1-7) Positive Modulation on Left Ventricular Functional Performance in Conscious Dog With Pacing-Induced Heart Failure: Assessment by Pressure-Volume Analysis
Authors: Xiaowei Zhang, Atsushi Morimoto, Heng-Jie Cheng, Tiankai Li, Nobuyuki Ohte, David M Herrington, Che-Ping Cheng
Journal: Circulation (2016)

Background:  Angiotensin1-7 [A-(1-7)] opposes various actions of angiotensin II (AII) and has emerged as a key protective pathway against heart failure (HF). However, its effect on LV contractility is unclear. We previously demonstrated that in HF, AII decreases LV contractility. Whether A-(1-7) might antagonize AII-induced cardiac depression, thereby contributing to its cardioprotection in HF remains undefined. We assessed the hypothesis that A-(1-7) may enhance LV contraction and relaxation, independent of loading conditions in HF.   Methods:  We studied the responses to A-(1-7) (600 ng/kg plus 150 ng/kg/min, iv) administration in 8 instrumented conscious dogs before and after pacing-induced HF.   Results:  Compared with normal, after HF, not only the basal circulating A-(1-7) were significantly higher, A-(1-7) infusion also resulted greater increase in plasma levels of A-(1-7) (Normal: 175.6 vs 4.4 pg/ml; HF: 267.4 vs 23.4 pg/ml). A-(1-7) caused no changes in heart rate, but significantly decreased LV end-systolic pressure (P ES ) in both normal and HF. Prior to HF, A-(1-7) had no direct effects on LV contractility (E ES , 6.6 vs 6.9 mmHg/ml) and the time constant of LV relaxation (τ, 27.5 vs 26.6 ms). In contrast, after HF, A-(1-7) significantly decreased LV end-diastolic pressure (P) (39.0 vs 42.3 mmHg), end-diastolic volume (V), arterial elastance (E A , 6.2 vs 8.8 mmHg/ml) and τ (34.2 vs 38.9 ms), but increased stroke volume. Importantly, A-(1-7) augmented LV contractility with significantly increased E ES  (5.2 vs 4.3 mmHg/ml) and M SW  (60.9 vs 54.8 mmHg). LV-arterial (A) coupling, E ES /E A  (0.54 vs 0.42) improved. The mechanical efficiency quantitated as the ratio of stroke work and total P-V area also improved (0.50 vs 0.41). These effects were not modified with autonomic blockade, but were prevented by an A-(1-7) selective antagonist, A-779 (6 μg/kg, iv.).   Conclusions:  Before HF, levels of A-(1-7) seen with ACE-inhibition have no direct cardiac effects. After HF, A-(1-7) antagonizes AII-induced cardiac depression. A-(1-7) produces arterial vasodilatation, improves LV relaxation, LV contractility, LV-A coupling, and mechanical efficiency. This study provides new evidence for a critical counter-regulatory role of A-(1-7) on the activated RAS in HF.
Abstract 19550: Incidence, Correlates and Impact of Acute Kidney Injury in Diabetic Patients With Multivessel Disease Undergoing Coronary Revascularization: Results From the FREEDOM Trial
Authors: Yaron Arbel, Michael Farkouh, Usman Buber, Taye Hamza, Flora S Siami, Valentin Fuster
Journal: Circulation (2016)

Introduction:  The incidence and prognostic significance of acute kidney injury (AKI) in diabetic patients with multivessel coronary artery disease undergoing coronary revascularization is not well known. The current analysis included patients randomized to PCI vs. CABG as part of the FREEDOM trial. We sought to examine the impact of AKI and its predictors in diabetic patients with multivessel coronary artery disease undergoing PCI vs. CABG.   Hypothesis:  AKI has clinical impact in both PCI and CABG treated patients.   Methods:  We conducted a pre-specified subgroup analysis of the FREEDOM trial to examine the therapeutic efficacy of CABG versus PCI among patients stratified by the presence (n=210) or absence (n=1645) of AKI. Renal function was calculated using the CKD-EPI formula and AKI was defined using the AKIN network definition (greater than 0.3mg/dl or 50% increase). We grouped together stages 1-3. Baseline characteristics and clinical outcomes were compared between PCI and CABG groups according to the presence or absence of AKI. The primary endpoint was the composite occurrence of all-cause death, stroke or myocardial infarction (major adverse cardiovascular events; [MACCE]) at 5 years of follow-up.   Results:  AKI was more prevalent in patients undergoing CABG compared to PCI (14.3% vs. 8.5%, p   Conclusions:  Although AKI was more prevalent in patients undergoing CABG, the impact of AKI on MACCE risk was substantial irrespective of revascularization strategy. Preventive Strategies to identify patients at risk for AKI are warranted to mitigate the long-term effects of this complication.
Clinical Predictors of Prophylaxis Use Prior to the Onset of Acute Venous Thromboembolism in Hospitalized Patients: Swiss Venous ThromboEmbolism Registry (SWIVTER)
Authors: Nils Kucher, David Spirk, Christoph Kalka, Lucia Mazzolai, Daniel Nobel, Martin Banyai, Beat Frauchiger, Henri Bounameaux
Journal: Blood (2008)
Prevalence of Missed Opportunities for HIV Testing Among Persons Unaware of Their Infection
Authors: Cyprian Wejnert, Joseph Prejean, Brooke Hoots, H. Irene Hall, Eugene McCray, Jonathan Mermin
Journal: JAMA (2018)

This study uses National HIV Behavioral Surveillance survey data to estimate the proportion of men who have sex with men and persons who inject drugs unaware of their HIV infection who missed opportunities for testing and diagnosis in clinical settings.