tbuckley/cabot-search huggingface dataset:
Abstract 3623: Mesenchymal stem cells engineered with TAT peptide functionalized nanoparticles improve therapeutic efficacy of paclitaxel in an orthotopic lung tumor model
Authors: Swayam Prabha, Gopikrishna Moku, Buddhadev Layek, Jayanth Panyam
Journal: Cancer Research (2019)

Abstract Tumors are characterized by uneven vascular perfusion with near normal blood flow in the outer most regions, while the inner regions can be avascular. In addition, elevated interstitial fluid pressure and rigid extracellular matrix compromise intra-tumoral solute transport and hence limited drug efficacy. Mesenchymal stem cells (MSCs) have the unique advantage of being able to migrate specifically to both primary tumors and metastases following systemic administration. However, poor payload capacity of MSCs limits their use as drug delivery carriers. To address this issue, we investigated polymeric nanoparticles that were functionalized with transactivator of transcription (TAT) peptide. Paclitaxel loaded PLGA nanoparticles (15-16 % w/w paclitaxel; diameter of 225 ± 7 nm; and zeta potential of −15 ± 4 mV) were prepared by emulsion-solvent evaporation method, followed by TAT-conjugation to the surface of nanoparticles via maleimide-thiol chemistry. Nanoengineered MSCs were generated by incubating MSCs in suspension with 100 µg/mL paclitaxel loaded nanoparticles for 4 hours at 37°C. Our studies demonstrated that TAT functionalization improved the paclitaxel loading in MSCs. In addition, engineering MSCs with TAT functionalized nanoparticles did not affect the differentiation and migration properties of MSCs. Further, MSCs engineered with TAT peptide functionalized nanoparticles resulted in significant inhibition of tumor growth and overall improved survival in a mouse orthotopic model of lung cancer compared to that with free drug treatment. In summary, our results demonstrated that MSCs nanoengineered using TAT functionalized nanoparticles can serve as an efficient carrier for tumor specific delivery of anticancer drugs, resulting in greatly improved therapeutic efficacy. Citation Format: Swayam Prabha, Gopikrishna Moku, Buddhadev Layek, Jayanth Panyam. Mesenchymal stem cells engineered with TAT peptide functionalized nanoparticles improve therapeutic efficacy of paclitaxel in an orthotopic lung tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3623.
Abstract 4949: Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigen
Authors: Gerald P. Linette, Beatriz M. Carreno, Zackary L. Skidmore, Jasreet Hundel, Obi L. Griffith, Malachi Griffith, Vincent Magrini, Elaine R. Mardis
Journal: Cancer Research (2019)

Abstract The impact of intratumor heterogeneity (ITH) and the neoantigen landscape on T cell immunity is poorly understood. ITH is a widely recognized feature of solid tumors and poses distinct challenges related to the development of effective therapeutic strategies, including cancer immunotherapy. Cutaneous melanoma is characterized by C-&amp;gt;T transitions caused by UV exposure which leads to a large mutational burden encoding putative neoantigens. Here, we performed ultra-deep DNA sequencing of multiple metastases from melanoma patients and observed ubiquitious sharing of clonal and subclonal single nucleotide variants (SNV) encoding putative HLA class I restricted neoantigen epitopes among tumors. MEL66, a reference melanoma patient with a large mutational burden (53 SNV/Mb), provided six resected metastases for study. The spontaneous T-cell response features an oligo/monoclonal T cell-receptor (TCR) repertoire which targets a few clonal neoantigens; most neoantigen-specific T cell clones ignore the tumor. CD8+ T cells to additional HLA class I restricted neoantigens can be elicited by DC vaccination (NCT03092453) with tumor-encoded amino acid substituted (mutated) peptides resulting in a diverse, high frequency TCR repertoire. Isolation of T cell clones by limiting dilution from blood and TIL permits functional validation regarding neoantigen-specificity. Gene transfer of paired abTCR heterodimers specific for clonal neoantigens confirmed correct clonotype assignments based on high throughput CDR3 sequencing. Additional melanoma patients with 2-6 resected metastases were investigated and similar observations were found. Our observations implicate ineffective neoantigen cross-presentation as the basis for immunological ignorance. We postulate that therapeutic vaccination is required to increase the breadth and diversity of neoantigen-specific CD8+ T cells as an adjunct to checkpoint inhibitor treatment for cancer. Citation Format: Gerald P. Linette, Beatriz M. Carreno, Zackary L. Skidmore, Jasreet Hundel, Obi L. Griffith, Malachi Griffith, Vincent Magrini, Elaine R. Mardis. Immunological ignorance is an enabling feature of the oligo-clonal T cell response to melanoma neoantigen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4949.
Abstract 3847: Knockout of DNMT1 using CRISPR gene-editing technology confers resistance to DNMT inhibitors in human breast cancer cells
Authors: Angelo B. Laranjeira, Erich Huang, Larry Rubinstein, Dat Nguyen, Sherry X. Yang
Journal: Cancer Research (2019)

Abstract DNA methyltransferase (DNMT) 1 plays an important role for DNA replication and cell proliferation, and it is implicated in the maintenance and propagation of DNA methylation patterns. Targeting DNMT represents a promising approach for epigenetic therapy in cancer. To better elucidate the function of DNMT1 on the treatment effect of DNMT inhibitors in cancer cells derived from human solid tumors, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas9) to edit DNMT1 gene in MCF-7 breast carcinoma cells. The co-transfection of the DNMT1 target sequence that directs to exon 1 of the gene in pCas-guide vector and a donor DNA vector effectively knocked down DNMT1 protein in MCF-7 cells as detected by Western blot. After 96h of drug exposure, IC50s of azacitidine (5-azacytidine) and decitabine (5-aza-2’-deoxycytidine) were all higher than 10 µM in DNMT1 knockout (DNMT1-/-) cells assessed by MTT; in contrast, IC50s were 1.44 µM and 10 µM in parental (DNMT1+/+) cells. As for the cellular survival in the presence of drugs, a remarkable increase in the colony formation was observed in DNMT1-/- cells compared to DNMT1+/+ cells. The annexin-V/propidium iodide test by flow cytometry provided evidence of lower percentages of necroptosis in the DNMT1-/- cells than DNMT1+/+ cells when the cells were exposed to these inhibitors for 48 hours at 5 µM (7.12 ± 5.24 vs. 39.0 ± 2.65 by azacitidine, p = 4.11 × 10-5, and 5.77 ± 4.19 vs. 20.0 ± 6.66 by decitabine, p = 4.11 × 10-5); in addition, there were large fractions of viable cells in the DNMT1-/- cells versus DNMT1+/+ cells (85.86 ± 6.39 vs. 56.86 ± 4.00 for azacitidine treatment, p = 4.11 × 10-5 and 87.4 ± 5.56 vs. 76.2 ± 9.36 for decitabine, p = 5.60 × 10-3). The findings demonstrate that knockout of DNMT1 using CRISPR/Cas9 method leads to an increased resistance to azacitidine and decitabine, in corroboration with our previous data in DNMT1 knockout HCT116 colorectal cancer cells. Therefore, DNMT1 is critical to antitumor activity of DNMT inhibitors in human solid tumor cell lines. Citation Format: Angelo B. Laranjeira, Erich Huang, Larry Rubinstein, Dat Nguyen, Sherry X. Yang. Knockout of DNMT1 using CRISPR gene-editing technology confers resistance to DNMT inhibitors in human breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3847.
Abstract 1399: Ex-vivo targeting of urothelial carcinomas by fluorescent pHLIP imaging agents
Authors: Borivoj Golijanin, Anna Moshnikova, Donald M. Engelman, Oleg A. Andreev, Yana K. Reshetnyak, Ali Amin, Dragan Golijanin
Journal: Cancer Research (2019)

Abstract Introduction: The detection of urothelial carcinomas of the bladder and upper tract is not satisfactory. Incomplete findings by contemporary imaging modalities provide a challenge in patient care, so there is a definitive need to improve diagnosis and treatment methods for urothelial carcinomas. Experimental procedures: ICG (indocyanine green) near infrared fluorescent (NIRF) dyes were conjugated with a pH-Low Insertion Peptide (pHLIP®), which senses and targets the acidity at the surfaces of cancer cells. In a few cases IR800 pHLIP® was used. Urinary neoplasm (kidney, ureter and bladder) specimens obtained through radical surgery were irrigated and incubated ex-vivo with ICG pHLIP® followed by fluorescence imaging. Pathology findings were correlated with the ICG pHLIP® NIRF imaging. Results: In the upper urothelial tract, nine of ten patients with nephroureterectomy had urothelial carcinomas (UTUC). Eighteen (100%) malignant lesions were found in NIRF imaging. Only thirteen (72%) of malignant lesions were found under white light macroscopic examination. ICG pHLIP® NIRF imaging gave a 28% increase in diagnosis of UTUC in ex-vivo specimens. There was no non-specific uptake in the non-tumoral tissue. The ICG pHLIP® imaging agent identified malignant upper tract urothelial lesions with 100% specificity and sensitivity. In the lower urinary tract, thirty-eight radical cystectomy specimens were incubated with pHLIP® conjugated with one of the NIRF dyes (ICG or IR800). In the thirty-eight bladders, eighty-one lesions were identified using fluorescent pHLIP®(specificity (97%) and sensitivity (100%)). White light cystoscopy did not detect 20.5% of lesions identified under NIRF cystoscopy (p&amp;lt;.001). Normal tissue did not show any uptake by the construct; however, entrapment of the dye in the necrotic tumor bed was noted. All regions showing the NIRF signal of pHLIP® were confirmed by standard pathological analysis. Conclusions: The ICG pHLIP® NIRF revealed additional lesions not seen with white light ex-vivo cystoscopy or preoperative ureteroscopy. pHLIP® based agents promise to improve diagnostic accuracy for urothelial carcinomas and may enable targeted treatment. Citation Format: Borivoj Golijanin, Anna Moshnikova, Donald M. Engelman, Oleg A. Andreev, Yana K. Reshetnyak, Ali Amin, Dragan Golijanin. Ex-vivo targeting of urothelial carcinomas by fluorescent pHLIP imaging agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1399.
Stress-Associated Neurobiological Pathway Linking Socioeconomic Disparities to Cardiovascular Disease
Authors: Ahmed Tawakol, Michael T. Osborne, Ying Wang, Basma Hammed, Brian Tung, Tomas Patrich, Blake Oberfeld, Amorina Ishai, Lisa M. Shin, Matthias Nahrendorf, Erica T. Warner, Jason Wasfy, Zahi A. Fayad, Karestan Koenen, Paul M Ridker, Roger K. Pitman, Katrina A. Armstrong
Journal: Journal of the American College of Cardiology (2019)
A phase II study (NCI9775) of sapanisertib (MLN0128/TAK-228) in relapsed and/or refractory acute lymphoblastic leukemia (ALL): Interim analysis.
Authors: Aref Al-Kali, Ibrahim Aldoss, Carrie Strand, Bijal D. Shah, Jonathan Allen Webster, Bhavana Bhatnagar, Mojtaba Akhtari, L. Austin Doyle, Scott H. Kaufmann
Journal: Journal of Clinical Oncology (2019)

e18506 Background: Sapanisertib (SAP) is an oral small molecule dual mTOR complex 1 and 2 (TORC1/2) inhibitor that showed activity in lymphoid neoplasms. It blocks a feedback loop involving mTORC2 activation when TORC1 is selectively inhibited (Yun S et al, Blood 2016). SAP induces apoptosis of malignant lymphoid cells in vitro and in xenografts, with greatest effects in ALL cell lines. We aim to assess potential efficacy of SAP when used as a single agent in relapsed/refractory ALL. Methods: Adults (age ≥18) with ECOG performance status 0-2 and normal organ function (creatinine/total bilirubin &lt;1.5 upper limit of normal) with relapsed and/or refractory ALL (B- or T-cell) were enrolled. Newly diagnosed patients (pts) unfit for aggressive treatments and BCR-ABL + ALL were allowed if there was no suitable standard treatment. SAP was given at 3 mg orally daily for 21 days every 28 days. Dose escalation was allowed after 2 cycles. Hydroxyurea and corticosteroids were not allowed after starting SAP. The primary end point was complete remission (CR) or CR with incomplete count recovery (CRi). This is a one stage Simon design study with interim analysis after 11 pts completed treatment. Enrollment was continued until interim analysis was done. Results: A total of 16 pts were enrolled on the study with a median age of 46 years old, 56% being males. 1/16 (6%) was treatment naïve. Median number of prior therapies is 3 (range, 1-9). The mean duration on SAP was 14.7 days (range 1-22). Three pts were able to start cycle 2. Safety was evaluable in 14 pts. All 14 pts had at least one G3 AE, while 10 pts had at least one G4 AE. G3/4 related non-hematological adverse events (AE) included 3 mucositis, 1 hepatic failure, 1 sepsis, 3 hyperglycemia, 1 anorexia, 1 seizure, 1 confusion, and 1 pneumonitis. One pt had G5 AE with malignancy. G3/4 hematological AEs included 2 with lymphopenia, 1 thrombocytopenia, 3 with leukopenia, and 1 with neutropenia. No pt achieved a CR/CRi. Best response was stable disease in 2 (12.5%) pts. Five pts had progressive disease while 9 were not evaluable because of early removal. Conclusions: SAP exhibited the expected safety profile. Although several pts developed cytopenias on drug, there was no evidence of clinically meaningful single-agent activity against ALL. Analysis of paired bone marrow aspirates from this trial is being performed to assess whether mTOR was substantially inhibited at therapeutically achievable drug concentrations. Clinical trial information: NCT02484430.
Abstract 15992: Risk Stratification Following Complex PCI: Anatomic Vs. Clinical Risk Stratification Compared with the “Post PCI Residual Syntax-score” as Quantification of Incomplete Revascularization
Authors: Thomas Schwietz, Steven Pfeiffer, Stephan Fichtlscherer, Volker Schächinger, Salvatore De Rosa, Rafael Laskowski, Gregor Baier, Andreas M Zeiher, Ioakim Spyridopoulos, Ralf Lehmann
Journal: Circulation (2012)

Background: We have previously shown, that clinical risk stratification using the EuroSCORE and completeness of revascularization predicts long-term survival after multivessel PCI (MV-PCI). The SYN...
Abstract 2393: Bridging MOA-based reporter bioassays with PBMC based ADCC for immunotherapy drug <i>d</i>evelopment
Authors: Mei Cong, Pete Stecha, Aileen paguio, brock binkowski, Zhi-Jie Cheng, Frank Fan
Journal: Cancer Research (2019)

Abstract Having a functional bioassay that is MOA-based, accurate, precise, robust and reproducible is critical for the development of antibody-based biologics. We have developed reporter bioassays that meet these criteria for a broad range of antibody modalities including Fc effector function, immune checkpoint modulation, bispecific antibody engagement, cytokine modulation, and others. Here we will present the latest technology advancements and bridging of the PBMC based ADCC cell killing assay with reporter based ADCC Bioassay. Citation Format: Mei Cong, Pete Stecha, Aileen paguio, brock binkowski, Zhi-Jie Cheng, Frank Fan. Bridging MOA-based reporter bioassays with PBMC based ADCC for immunotherapy drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2393.
Silver nanoparticle-adjuvanted vaccine protects against lethal influenza infection through inducing BALT and IgA-mediated mucosal immunity
Authors: Daniel Sanchez-Guzman, Pierre Le Guen, Berengere Villeret, Nuria Sola, Remi Le Borgne, Alice Guyard, Alix Kemmel, Bruno Crestani, Jean-Michel Sallenave, Ignacio Garcia-Verdugo
Journal: Biomaterials (2019)
Mammalian diaphanous-related formin 1 (mDia1) coordinates mast cell migration and secretion through its actin-nucleating activity
Authors: Ofir Klein, Rebecca A. Krier-Burris, Pia Lazki-Hagenbach, Yaara Gorzalczany, Yang Mei, Peng Ji, Bruce S. Bochner, Ronit Sagi-Eisenberg
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 18232: Usefulness of Intraoperative Three-dimensional Transesophageal Echocardiography to Detect Treatable Residual Mitral Regurgitation Immediately After Mitral Valve Plasty
Authors: Takeshi Okubo, Kanako Kishiki, Haruka Fujimaki, Hironori Yamamoto, Shuichiro Takanashi, Keitaro Mahara
Journal: Circulation (2017)

Introduction: Residual mitral regurgitation (MR) immediately after mitral valve plasty (MVP) in the operating room is a well-known risk factor for late re-intervention. We sought to determine the f...
Lack of Glycemic Legacy Effects in the Veterans Affairs Diabetes Trial
Authors: Kasia J. Lipska, Neda Laiteerapong
Journal: New England Journal of Medicine (2019)

In randomized trials, intensive glycemic control has not resulted in lower risks of major cardiovascular events or death than standard glycemic control among patients with type 1 or type 2 diabetes during intervention periods. However, extended follow-up in some of these trials indicates that cardiovascular benefits may emerge over time. For example, follow-up in the Diabetes Control and Complications Trial (DCCT) involving patients with type 1 diabetes showed that intensive glycemic control was associated with beneficial effects with regard to cardiovascular events.1 Similar postintervention follow-up in the United Kingdom Prospective Diabetes Study (UKPDS) showed reductions in the risks of cardiovascular . . .
The use of photoplethysmography for assessing hypertension
Authors: Mohamed Elgendi, Richard Fletcher, Yongbo Liang, Newton Howard, Nigel H. Lovell, Derek Abbott, Kenneth Lim, Rabab Ward
Journal: npj Digital Medicine (2019)

Abstract The measurement of blood pressure (BP) is critical to the treatment and management of many medical conditions. High blood pressure is associated with many chronic disease conditions, and is a major source of mortality and morbidity around the world. For outpatient care as well as general health monitoring, there is great interest in being able to accurately and frequently measure BP outside of a clinical setting, using mobile or wearable devices. One possible solution is photoplethysmography (PPG), which is most commonly used in pulse oximetry in clinical settings for measuring oxygen saturation. PPG technology is becoming more readily available, inexpensive, convenient, and easily integrated into portable devices. Recent advances include the development of smartphones and wearable devices that collect pulse oximeter signals. In this article, we review (i) the state-of-the-art and the literature related to PPG signals collected by pulse oximeters, (ii) various theoretical approaches that have been adopted in PPG BP measurement studies, and (iii) the potential of PPG measurement devices as a wearable application. Past studies on changes in PPG signals and BP are highlighted, and the correlation between PPG signals and BP are discussed. We also review the combined use of features extracted from PPG and other physiological signals in estimating BP. Although the technology is not yet mature, it is anticipated that in the near future, accurate, continuous BP measurements may be available from mobile and wearable devices given their vast potential.
Abstract 1035: PLEK2 promotes epithelial mesenchymal transition through increasing Snail1 in lung cancer cells
Authors: En-Chu Liu, Tsai-Tu Lee, Shey-Lin Wu, Tai-Lin Lee, Meng-Feng Tsai
Journal: Cancer Research (2019)

Abstract Pleckstrin 2 (PLEK2), one of the pleckstrin homology domain proteins, have been suggested to modulate actin rearrangement and cell spreading in T lymphocytes. Recently studies also implicated that PLEK2 paly an importance role in human myeloproliferative neoplasms, melanoma, and lung cancers. PLEK2 mRNA genes were related to poor overall survival in lung adenocarcinoma patients. However, the biological functions of PLEK2 in lung cancer is not clear. We detected the expression of PLEK2 in various lung adenocarcinoma cell lines using quantitative RT-PCR methods. Molecular manipulations were performed to investigate the roles of PLEK2 in lung cancer cells. Over-expression of PLEK2 in lung cancer cells exhibited markedly promoting in the proliferation and anchorage independent growth, whereas reduced of PLEK2 was found to suppress lung cancer cell progression. This studies also indicated that PLEK2 may play an important role in the epithelial-mesenchymal transition (EMT) features, including a morphological change, increased invasive and migratory ability, reduction the epithelial marker expression and up-regulated EMT regulators. Our results suggested that PLEK2 expression induce lung cancer cell EMT phenomenon through up-regulation Snail1 expression. These results will provide information and help us to understand the roles of PLEK2 in lung cancer cells. Citation Format: En-Chu Liu, Tsai-Tu Lee, Shey-Lin Wu, Tai-Lin Lee, Meng-Feng Tsai. PLEK2 promotes epithelial mesenchymal transition through increasing Snail1 in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1035.
PXR: a center of transcriptional regulation in cancer
Authors: Yaqi Xing, Jiong Yan, Yongdong Niu
Journal: Acta Pharmaceutica Sinica B (2019)

Pregnane X receptor (PXR, NR1I2) is a prototypical member of the nuclear receptor superfamily. PXR can be activated by both endobiotics and xenobiotics. As a key xenobiotic receptor, the cellular function of PXR is mostly exerted by its binding to the regulatory gene sequences in a ligand-dependent manner. Classical downstream target genes of PXR participate in xenobiotic responses, such as detoxification, metabolism and inflammation. Emerging evidence also implicates PXR signaling in the processes of apoptosis, cell cycle arrest, proliferation, angiogenesis and oxidative stress, which are closely related to cancer. Here, we discussed, in addition to the characterization of PXR per se, the biological function and regulatory mechanism of PXR signaling in cancer, and its potential for the targeted prevention and therapeutics.