tbuckley/cabot-search huggingface dataset:
Allogeneic Stem Cell Transplantation Provides Durable Remission in Patients with Primary Mediastinal Large B-Cell Lymphoma
Authors: Alex F. Herrera, Lu Chen, Sirin Khajavian, Matthew Lewis Chase, Justin Darrah, David G. Maloney, Vincent T. Ho, Robert J. Soiffer, Joseph H. Antin, Stephen J Forman, Auayporn P. Nademanee, Yi-Bin Chen, Philippe Armand, Mazyar Shadman
Journal: Blood (2018)
Abstract 11242: Clopidogrel Improves Endothelial Function in Healthy Individuals With Heightened Platelet Aggregation
Authors: Shabnam Salimi, Joshua P Lewis, Laura Yerges-Armstrong, Braxton D Mitchell, Jeffrey R O’Connell, Alan R Shuldiner, Afshin Parsa
Journal: Circulation (2016)

Introduction: Platelet activation can lead to enhanced oxidative stress, inflammatory response and endothelial dysfunction. To quantify the effects of platelet inhibition on endothelial function, we assessed platelet activity of healthy individuals before and after clopidogrel administration and evaluated its effects on endothelial function. Hypothesis: We hypothesized that clopidogrel, by attenuating platelet activity, would result in enhanced endothelial function. Methods: Microcirculatory endothelial function was quantified by thermal hyperemia (TH) and post-occlusive reactive hyperemia (PORH) laser Doppler flowmetry (LDF) in 287 and 241 relatively healthy and homogenous Old Order Amish individuals, respectively. LDF and platelet aggregation measures were obtained at baseline and after 7 days of clopidogrel administration. Our primary outcome was percent change in post- versus pre-clopidogrel LDF measures. Results: Pre-clopidogrel TH-LDF and platelet aggregation were higher in women than men (p&lt;0.001). Clopidogrel administration was associated with an approximately twofold higher percent change in TH-LDF, in subjects with high compared to low baseline platelet aggregation (39.4%±10.1 vs. 17.4%±5.6, p=0.03). Clopidogrel also increased absolute TH-LDF measures in individuals with high platelet aggregation (1757.2 ± 765.6 to 2153.8 ± 1054.5, p=0.03), with a more prominent effect in women (1909.4 ± 845.7 to 2518.1 ± 1047.9, p=0.001). There was no evidence that clopidogrel influenced PORH-LDF measures. Conclusions: The administration of clopidogrel, in healthy individuals with high baseline platelet aggregation, results in improved TH-induced microcirculatory endothelial function. These data suggest that clopidogrel may have a beneficial effect on microcirculatory endothelial function, presumably through anti-platelet activity, and may confer additional vascular benefits.
226. Lentiviral Vector Gene Therapy Protects XCGD Mice from Acute Staphylococcus aureus Pneumonia and Inflammatory Response
Authors: Giada Farinelli, Raisa Jofra Hernandez, Alice Rossi, Serena Ranucci, Francesca Sanvito, Maddalena Migliavacca, Chiara Brombin, Aleksandar Pramov, Clelia Di Serio, Bernhard Gentner, Alessandra Bragonzi, Alessandro Aiuti
Journal: Molecular Therapy (2016)

Chronic Granulomatous Disease (CGD) is a primary immunodeficiency due to the mutation of one of the subunits of the NADPH oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections as well as granuloma formation due to the excessive inflammatory responses. Several gene therapy (GT) approaches with lentiviral vectors have been proposed but in vivo preclinical data on the ability to control infections and inflammation are lacking. We set up a model of acute infection closely mimicking CGD patients airway infection by an intratracheal injection in X-CGD mice of a methicillin-sensitive reference strain (MSSA) of S. aureus. GT with hematopoietic stem cells transduced with regulated lentiviral vectors encoding CYBB gene restored the functional activity of NADPH oxidase complex (30-99% of dihydrorhodamine-DHR positive granulocytes and 16-73% of DHR positive monocytes) and rescued all mice from mortality due to S. aureus as compared to X-CGD or mock-transduced X-CGD mice (40% survival). Neutrophil infiltrate, bacterial burden and residual lung damage were similar to WT mice. When challenged with bacteria, X-CGD untreated mice showed an exaggerated production of pro-inflammatory cytokines and chemokine, while in GT treated mice inflammation was controlled to levels that were comparable to WT mice. In conclusion, we developed a useful and manageable infection model that can be used for the evaluation of the efficacy of GT treatment for CGD. Taken together, our results further support the clinical development of a gene therapy protocol for X-CGD using lentiviral vectors for the protection from infections and inflammation.
Abstract 20791: Incremental Prognostic Value of Sarcopenia in Older Adults Undergoing Transcatheter Aortic Valve Replacement: The FRAILTY-AVR Study
Authors: Samuel Mamane, Louis Mullie, Matthew Ades, Amanda Trnkus, John Webb, Nicolo Piazza, Louis Perrault, Nicolas Noiseux, Sandra Lauck, Rakesh Arora, Mark Peterson, Andre Lamy, Mario Labinaz, Jeffrey Popma, Dae Hyun Kim, Caroline Kim, Igor Palacios, Thierry Lefevre, Philippe Genereux, Brian Lindman, Kevin Lachapelle, Giuseppe Martucci, Jose Morais, Yves Langlois, Lawrence Rudski, Jean-Francois Morin, Jonathan Afilalo
Journal: Circulation (2017)

Introduction: Sarcopenia is a “biologic substrate of frailty”. Low muscle mass has recently emerged as a predictor of outcomes in older adults undergoing transcatheter aortic valve replacement (TAV...
Treatment Patterns and Intensity Differ between Pediatric and Adult Centers in AYA with Hodgkin's Lymphoma but Result in Equivalent Outcomes: A Population-Based Study Using the IMPACT Cohort
Authors: Sumit Gupta, Nancy Baxter, Jason Pole, Chenthila Nagamuthu, Cindy Lau, Rinku Sutradhar, Paul Nathan
Journal: Blood (2018)
Association of Estrogen Receptor Alpha Expression With Survival in Oropharyngeal Cancer Following Chemoradiation Therapy
Authors: Maria B Koenigs, Armida Lefranc-Torres, Juliana Bonilla-Velez, Krupal B Patel, D Neil Hayes, Krzysztof Glomski, Paul M Busse, Annie W Chan, John R Clark, Daniel G Deschler, Kevin S Emerick, Rebecca J Hammon, Lori J Wirth, Derrick T Lin, Edmund A Mroz, William C Faquin, James W Rocco
Journal: JNCI Journal of the National Cancer Institute (2018)

Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor α (ERα), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC.
Abstract 12894: The Relations of Central Hemodynamics and Aortic Stiffness With Cardiac Structure and Function: The Framingham Heart Study
Authors: Bernhard Kaess, Jian Rong, Martin G Larson, Naomi M Hamburg, Joseph A Vita, Susan Cheng, Jayashree Aragam, Daniel Levy, Emelia J Benjamin, Ramachandran S Vasan, Gary F Mitchell
Journal: Circulation (2015)

Introduction: Relations of steady and pulsatile components of central hemodynamics and aortic stiffness with cardiac dimensions and function have not been fully elucidated. Methods: We measured mean arterial pressure (MAP, steady component of blood pressure), central pulse pressure (CPP, pulsatile component of central blood pressure), and carotid-femoral pulse wave velocity (CFPWV, a measure of aortic stiffness) by arterial tonometry in 5799 Framingham Heart Study participants (mean age 51 years, 54% women). We related these to echocardiographic left ventricular (LV) dimensions and systolic and diastolic function using multivariable-adjusted partial Pearson correlations. Results: MAP was associated positively with LV wall thickness (r=0.168; p&lt;0.0001) and LV diastolic dimension (r=0.035, p=0.006). Adjusting for MAP, CPP was positively associated with LV wall thickness and LV diastolic dimension (r=0.044 and r=0.080, both p&lt;0.0001). CFPWV was not associated significantly with LV structure (all p≥0.27) in MAP-adjusted models. MAP and CFPWV were associated negatively with LV diastolic function (E’; r=-0.140 and r=-0.153, respectively; both p&lt;0.0001). The MAP relation persisted after adjustment for LV mass and CPP (r=-0.142) and the CFPWV relation persisted after adjustment for LV mass and MAP (r=-0.108, both p&lt;0.0001). MAP and CFPWV were not associated significantly with LV fractional shortening (p≥0.10), whereas CPP was positively related (r=0.064, p&lt;0.0001). The figure shows adjusted LV diastolic dimension (Panel A) and LV wall thickness (Panel B) partioned by tertiles of MAP and CPP, and E’ partitioned by CFPWV tertiles (Panel C). Conclusions: Steady and pulsatile components of central pressure are jointly yet differentially related to LV structure and function. Higher CFPWV is related to reduced LV diastolic function, but not systolic function.
Activated platelets in the tumor microenvironment for targeting of antibody-drug conjugates to tumors and metastases
Authors: May Lin Yap, James D McFadyen, Xiaowei Wang, Melanie Ziegler, Yung-Chih Chen, Abbey Willcox, Cameron J Nowell, Andrew M Scott, Erica K Sloan, P Mark Hogarth, Geoffrey A Pietersz, Karlheinz Peter
Journal: Theranostics (2019)

Rationale: Platelets are increasingly recognized as mediators of tumor growth and metastasis.Hypothesizing that activated platelets in the tumor microenvironment provide a targeting epitope for tumor-directed chemotherapy, we developed an antibody-drug conjugate (ADC), comprised of a single-chain antibody (scFv) against the platelet integrin GPIIb/IIIa (scFvGPIIb/IIIa) linked to the potent chemotherapeutic microtubule inhibitor, monomethyl auristatin E (MMAE).Methods: We developed an ADC comprised of three components: 1) A scFv which specifically binds to the high affinity, activated integrin GPIIb/IIIa on activated platelets.2) A highly potent microtubule inhibitor, monomethyl auristatin E. 3) A drug activation/release mechanism using a linker cleavable by cathepsin B, which we demonstrate to be abundant in the tumor microenvironment.The scFvGPIIb/IIIa-MMAE was first conjugated with Cyanine7 for in vivo imaging.The therapeutic efficacy of the scFvGPIIb/IIIa-MMAE was then tested in a mouse metastasis model of triple negative breast cancer. Results:In vitro studies confirmed that this ADC specifically binds to activated GPIIb/IIIa, and cathepsin B-mediated drug release/activation resulted in tumor cytotoxicity.In vivo fluorescence imaging demonstrated that the newly generated ADC localized to primary tumors and metastases in a mouse xenograft model of triple negative breast cancer, a difficult to treat tumor for which a selective tumor-targeting therapy remains to be clinically established.Importantly, we demonstrated that the scFvGPIIb/IIIa-MMAE displays marked efficacy as an anti-cancer agent, reducing tumor growth and preventing metastatic disease, without any discernible toxic effects.Conclusion: Here, we demonstrate the utility of a novel ADC that targets a potent cytotoxic drug to activated platelets and specifically releases the cytotoxic agent within the confines of the tumor.This unique targeting mechanism, specific to the tumor microenvironment, holds promise as a novel therapeutic approach for the treatment of a broad range of primary tumors and metastatic disease, particularly for tumors that lack specific molecular epitopes for drug targeting.
NSABP FC-11: A phase II study of neratinib (N) plus trastuzumab (T) or n plus cetuximab (C) in patients (pts) with "quadruple wild-type (WT)" (KRAS/NRAS/BRAF/PIK3CA WT) metastatic colorectal cancer (mCRC) based on HER2 status—Amplified (amp), non-amplified (non-amp), WT, or mutated (mt).
Authors: Samuel A. Jacobs, James J. Lee, Thomas J. George, Greg Yothers, Tatjana Kolevska, Kathleen J Yost, James Lloyd Wade, Gary L Buchschacher, Philip J. Stella, Asheesh Shipstone, Katherine L. Pogue-Geile, Ashok Srinivasan, Peter C. Lucas, Carmen Joseph Allegra
Journal: Journal of Clinical Oncology (2019)

TPS716 Background: HER2 has been shown to be a validated therapeutic target for the treatment of mCRC. Preclinical and clinical evidence supports the use of HER2-targeted agents in each of these mCRC cohorts. In HERACLES, treatment–refractory, KRAS exon 2 (codons 12 and 13) WT, HER2 amp mCRC pts were treated with T and lapatinib (L). Objective response rate (CR or PR) was 8/27 and disease control rate (CR, PR, and SD &gt; 16 wks) was 16/27. Duration of response ranged from 24-94+ wks. Anecdotal reports have shown activity of N in HER2 mts from several cancer types. In mCRC PDX models with qualifying HER2 mts, T plus N is more active than either drug alone. In quad WT, HER2 non-amp PDX models, C plus TKI resulted in major tumor regressions not seen with C monotherapy. In NSABP FC-7, a trial of C + N in cetuximab refractory pts, HER2 amp was observed in 2/23 primary tissue samples; after C exposure, HER2 amp was seen in 5/17 samples, presumably signal upregulation under selective pressure of C. HER2 amp was concordant in tissue (CISH) and blood using cfDNA. Methods: This multi-center 3-cohort phase II trial is currently enrolling pts (total planned N = 35). Pts with quad WT, HER2 amp (n = 15) with prior anti-EGFR therapy and/or HER2 mt mCRC (n = 5) will receive T 4 mg/kg iv loading dose followed by 2 mg/kg/wk and N 240 mg po daily (Arm 1). Pts with quad WT, HER2 non-amp (n = 15) with no prior anti-EGFR therapy will receive C 400 mg/m2 iv loading dose followed by 250 mg/m2/wk, and N 240 mg (Arm 2). Specific pt eligibility for quad WT and HER2 status are defined below: Arm 1: HER2 amp confirmed in blood by Guardant360 assay, and prior treatment with C or panitumumab (P). HER2 mt (with qualifying mt) with or without prior treatment with C or P. Arm 2: HER2 non-amp or HER2 amp and no prior therapy with C or P. The primary aim is 6-mos progression-free survival for each cohort. Secondary aims: response rates and toxicity. Exploratory aims: genetic and molecular analyses. Specific drug combinations will be evaluated in PDX models. NCT03457896. Support: Puma Biotechnology, Inc.; NSABP Foundation, Inc. Clinical trial information: NCT03457896.
High-income is a stronger predictor than race in understanding disparate survival outcomes in PDAC.
Authors: Marcus A Alvarez, Jeremiah Lee Deneve, Stephen W Behrman, Paxton Vandiver Dickson, David Shibata, Evan Scott Glazer
Journal: Journal of Clinical Oncology (2019)

241 Background: Patients with pancreatic ductal adenocarcinoma (PDAC) from low income and minority racial groups have a lower reported long-term survival rates. It is unknown whether this is related to access to care, variations in genetic polymorphisms, or income status. We hypothesized that income status predicts survival better than race in PDAC. Methods: The pancreatic cancer data set of the National Cancer Database (NCDB) was studied for years 2011-15. Income groups were divided into top quartile (high income) or bottom three quartiles (non-high income) while racial groups were classified as Caucasian or non-Caucasian. Kaplan-Meier survival analysis and Cox proportional hazard models (CoxHR) were utilized. Analysis was controlled for established risk factors such as stage, grade, lymphovascular invasion, resection, and margin status. Results: Of the 164,631 patients meeting criteria, the average age was 68 ± 12 years, 51% were male, and 84% were Caucasian (the remaining patients were predominantly African American, 11%). Of patients with stage I or II PDAC who underwent resection, Caucasian patients had worse survival (CoxHR = 1.21, P&lt;0.001) while high-income patients had better survival (CoxHR= 0.86, P&lt;0.001). To investigate only differences due to income or race, a survival model of highly selected, low risk patients (stage I or II lymph node negative well-differentiated tumors without lymphovascular invasion and in patients who underwent margin negative resection who received chemotherapy) found that high-income predicted survival similar to race (CoxHR =0.89, P&lt;0.001 vs. CoxHR = 1.12, P=0.005, respectively). On multivariable analysis, high-income was more impactful on survival (CoxHR = 0.83, P&lt;0.001) than Caucasian race (CoxHR = 1.16, P &lt;0.001). High-income, non-Caucasian patients had a median survival of 64 months while all other groups had a median survival of 40 months (P=0.005). Conclusions: Caucasian PDAC patients have worse survival compared to non-Caucasian patients after selecting for patients with favorable tumor biology who received adequate therapy. The data suggests that high-income is slightly more important than race in understanding disparate outcomes in PDAC.
A phase Ib study of nivolumab plus trastuzumab with S-1/capecitabine plus oxaliplatin for HER2 positive advanced gastric cancer (Ni-HIGH study).
Authors: Daisuke Takahari, Takeru Wakatsuki, Naoki Ishizuka, Naoki Fukuda, Hirokazu Shoji, Hiroki Hara, Keiko Minashi, Narikazu Boku, Kensei Yamaguchi
Journal: Journal of Clinical Oncology (2019)

TPS177 Background: Trastuzumab (Tmab) with cisplatin and fluoropyrimidines improved the overall survival (OS) of patients (pts) with HER2 (+) advanced gastric cancer (AGC). Nivolumab (Nivo) is an anti-programmed cell death-1 (PD-1) antibody that demonstrated a survival benefit as third line or later of AGC. To date, most trials investigating anti-PD-1 antibody for 1 st line treatment focus on HER2 (-) AGC. In HER2(+) breast cancer mouse model, combining Tmab with anti-PD-1 antibody was reported to enhance ADCC activity of Tmab, and show greater tumor regression. In our data, the PD-L1 expression was observed in 44% of tumor cells and 70% of immune cells in human HER2(+) AGC. Based on these data, we have plannedthis phase Ib investigator-initiated trial to investigate the safety and tolerabirity of Nivo plus Tmab and either S-1 or capecitabine (Cape) plus Oxaliplatin (Ox) for pts with HER2(+) AGC. Methods: Histopathologically confirmed HER2(+) AGC with mesurable lesions, aged &gt; 20 years, chemo-naïve pts are enrolled in this study. Pts receive Nivo (360 mg/body; day 1) plus Tmab (course1, 8 mg/kg; course 2 onward, 6 mg/kg; day 1) and either S-1 (40 mg/m 2 bid d1-14; cohort 1) or Cape (1000 mg/m 2 bid d1-14; cohort 2) plus Ox (130 mg/m 2 ; day 1) every three weeks until desease progression or unacceptable toxicity. In the primary part, six pts for each cohort will be assessed for tolerability.To estimate the objective response rate (ORR) in the analysis-set, on our hypothesis that a true response rate is 80%, 20 pts are required for the 90% C.I. to be ± 20%. Therefore the expansion part for each cohort will be 12-15 pts. Primary endpoint is safety. Secondary endpoint is tolerability and exploratory endpoints include ORR, disease control rate, progression free survival and OS. Collaborative biomarker analysis includes whole exome sequences, RNA sequences, gut microbiome, and IHC using biopsy specimens. In addition, T-cell repartry, circulating tumor DNA and exomes will be also analyzed using blood obtained during treatment. This study just has been initiated at four sites in Japan. Clinical trial information: UMIN000034222.
Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma
Authors: Timothy F. Cloughesy, Aaron Y. Mochizuki, Joey R. Orpilla, Willy Hugo, Alexander H. Lee, Tom B. Davidson, Anthony C. Wang, Benjamin M. Ellingson, Julie A. Rytlewski, Catherine M. Sanders, Eric S. Kawaguchi, Lin Du, Gang Li, William H. Yong, Sarah C. Gaffey, Adam L. Cohen, Ingo K. Mellinghoff, Eudocia Q. Lee, David A. Reardon, Barbara J. O’Brien, Nicholas A. Butowski, Phioanh L. Nghiemphu, Jennifer L. Clarke, Isabel C. Arrillaga-Romany, Howard Colman, Thomas J. Kaley, John F. de Groot, Linda M. Liau, Patrick Y. Wen, Robert M. Prins
Journal: Nature Medicine (2019)
A Foreign Body Response‐on‐a‐Chip Platform
Authors: Fatemeh Sharifi, Su Su Htwe, Martina Righi, Hua Liu, Anna Pietralunga, Ozlem Yesil‐Celiktas, Sushila Maharjan, Byung‐Hyun Cha, Su Ryon Shin, Mehmet Remzi Dokmeci, Nihal Engin Vrana, Amir M. Ghaemmaghami, Ali Khademhosseini, Yu Shrike Zhang
Journal: Advanced Healthcare Materials (2019)

Abstract Understanding the foreign body response (FBR) and desiging strategies to modulate such a response represent a grand challenge for implant devices and biomaterials. Here, the development of a microfluidic platform is reported, i.e., the FBR‐on‐a‐chip (FBROC) for modeling the cascade of events during immune cell response to implants. The platform models the native implant microenvironment where the implants are interfaced directly with surrounding tissues, as well as vasculature with circulating immune cells. The study demonstrates that the release of cytokines such as monocyte chemoattractant protein 1 (MCP‐1) from the extracellular matrix (ECM)‐like hydrogels in the bottom tissue chamber induces trans‐endothelial migration of circulating monocytes in the vascular channel toward the hydrogels, thus mimicking implant‐induced inflammation. Data using patient‐derived peripheral blood mononuclear cells further reveal inter‐patient differences in FBR, highlighting the potential of this platform for monitoring FBR in a personalized manner. The prototype FBROC platform provides an enabling strategy to interrogate FBR on various implants, including biomaterials and engineered tissue constructs, in a physiologically relevant and individual‐specific manner.
Development Of A Subcutaneous Immunotherapy (SCIT) With A Modified Peanut Extract Formulation For The Treatment Of Peanut Allergy
Authors: Andrey S. Larionov, Ioanna Stavrakaki, Edwin Kim, Scott H. Sicherer, Robert A. Wood, Peter R. Couroux, Erika G. Gonzalez-Reyes, Iftikhar Hussain, Stephen A. Tilles, Dirk-Jan Opstelten, Annemie Narkus
Journal: Journal of Allergy and Clinical Immunology (2019)