tbuckley/cabot-search huggingface dataset:
19. A Phase I Clinical Trial of Autologous HER2 CMV Bispecific CAR T Cells for Progressive Glioblastoma
Authors: Nabil Ahmed, Vita Brawley, Oumar Diouf, Amanda Wakefield, Aidin Ashoori, Alexia Ghazi, Claudia Gerken, Joanna Yi, Hao Liu, Cliona M. Rooney, Gianpietro Dotti, Adrian Gee, Robert Grossman, Yvonne Kew, David Baskin, Jonathan Zhang, Pamela New, John Hicks, Suzanne Z. Powell, Winfried Wels, Malcolm K. Brenner, Helen E. Heslop, Stephen Gottschalk
Journal: Molecular Therapy (2015)

INTRODUCTION: Glioblastoma (GBM) remains virtually incurable. T-cell therapy holds the promise to improve outcomes for GBM patients since it does not rely on the cytotoxic mechanisms of conventional therapies. We have shown in preclinical studies that HER2 and CMV are potential T-cell therapy targets for GBM. METHODS: We report the results of the Phase I clinical study, NCT01109095, administering autologous CMV.pp65 cytotoxic T lymphocytes (CTL) expressing a HER2-specific CD28.zeta second generation chimeric antigen receptor (CAR; HER2/CMV biCTLs) to patients with progressive GBM. RESULTS: Sixteen CMV-seropositive patients, aged 11-70 years (median 49 years) with HER2-positive GBM and radiological evidence of active tumor were enrolled. Autologous HER2/CMV biCTLs were successfully generated for all patients from a peripheral blood draw (maximum 90mL). HER2/CMV biCTLs expressed HER2-CAR at a median of 67% (range: 46-82), and exhibited CMV. pp65 T cell receptor-mediated reactivity as judged by IFN-g Elispot assays (median 985.5 (range 390 to 1292) SFC/105 T cells). Infusions of 1×106/m2, 3×106/m2, 1×107/m2, 3×107/m2 or 1×108/m2 HER2/CMV biCTLs were well tolerated without systemic side effects and no dose limiting toxicity was observed. HER2/CMV biCTLs were detected in the peripheral blood for up to 12 weeks post infusion as judged by real-time PCR of a CAR-specific amplicon. Out of fifteen evaluable patients 10 had progressive disease. 5/15 patients had objective responses: 1 patient had a partial response with a ~62% reduction in tumor volume lasting 8 months, 1 patient had stable disease lasting 4 months and 3 patients have stable disease and are currently alive with a follow up of 18 to >26 months, after T cell infusion. CONCLUSION: This initial evaluation of the safety and efficacy of autologous HER2-CAR CMV bispecific T cells in patients with progressive GBM shows that infusions are safe and that cells could persist for up to 12 weeks in the peripheral blood. Clinical benefit was observed in 33% of patients setting the stage for studies that combine HER2-CAR CMV T cells with other immunomodulatory approaches to enhance their expansion and anti-GBM activity.
A Step towards Reconstitution or Maintenance of Remission before or after Stem Cell Transplantation in AML/MDS by Ex Vivo Generation of Leukaemia-Derived DC (DCleu) and DC-Activated T-Cells: Role of the Quality and Quantity of DC/DCleu and Anti-Leukemia-Directed T-Cells To Predict the Course and Success of Immunotherapy.
Authors: Helga M. Schmetzer, Anja Liepert, Christine Grabrucker, Andreas Kremser, Julia Loibl, Christoph Schmid, Raymund Buhmann, Ting Yang, Tanja Kroell, Helmut Salih, Horst Zitzelsberger, Hans-Jochem Kolb
Journal: Blood (2006)
Pleotrophic action of renal cell carcinoma: Dysregulated microRNAs on hypoxia-related signaling pathways.
Authors: Georg A. Bjarnason, Zsuzsanna Lichner, Salvador Mejia-Guerrero, Monika Ignacak, Adriana Krizova, Tian Tian Bao, Andrew Girgis, Youssef M. Youssef, George M. Yousef
Journal: Journal of Clinical Oncology (2012)

428 Background: The von Hippel-Lindau (VHL) gene is lost in 70% of clear cell Renal Cell Carcinomas (ccRCC); however, additional mechanisms are proposed to regulate VHL expression, including suppression by microRNAs (miRNAs). miRNAs are a class of naturally occurring, small non-coding RNA molecules that downregulate gene expression of target mRNAs. We demonstrate that ccRCC-dysregulated miRNAs can target multiple members of the ccRCC-related signaling pathways. Methods: miR-17 and miR-224 mimics and inhibitors were transfected into ccRCC cell lines using siPORT (Ambion). PicTar and TargetScan were used for target prediction. Target expression and miRNA expression was analyzed by qRT-PCR (Ambion). Western blot antibodies were purchased from Millipore or Cell Signaling. Cell lines were purchased from ATCC. All methods followed the manufacturer’s protocol. Results: According to our preliminary results, the miRNAs that are dysregulated in ccRCC specimens are predicted to target multiple members of the hypoxia-related pathways. To confirm the in silico analysis, miR-17 and miR-224 were selected for experimental target validation, as they were among the most up-regulated miRNAs in ccRCC. We experimentally validated VHL and HIF1α as likely direct targets of miR-17 and miR-224. Luciferase reporter assay confirmed that miR-17 directly downregulates VHL. Moreover, VHL protein level decreased upon miR-17 and miR-224 transfection. We also established a negative correlation between the expression of miR-17 and two predicted targets VEGF-A, EGLN3 in RCC specimens, and miR-224 and its predicted targets SMAD4 and SMAD5. This suggests that downstream signaling pathways are also modulated by miR-17 and miR-224. These results confirm the most important findings of the bioinformatics analysis: miR-17 targets different molecules along the same signaling pathway and that multiple ccRCC-dysregulated miRNAs can synergistically suppress a single target, which functions in the pathogenesis. Conclusions: Our results indicate that miRNAs possibly regulate hypoxia-related pathways at multiple points. This is of special interest as miRNAs may serve as potential therapeutic targets.
Cross-talk between iNKT cells and monocytes triggers an atheroprotective immune response in SLE patients with asymptomatic plaque
Authors: Edward Smith, Sara Croca, Kirsty E. Waddington, Reecha Sofat, Maura Griffin, Andrew Nicolaides, David A. Isenberg, Ines Pineda Torra, Anisur Rahman, Elizabeth C. Jury
Journal: Science Immunology (2016)

Altered activation of invariant natural killer T cells protects against atherogenesis in systemic lupus erythematosus patients.
639. Combination Therapy of Bufalin and rAd-p53 for the Treatment of Hepatocellular Carcinoma In Vivo
Authors: Lina Wang, Chen Ling, Meng Wang, Zifei Yin, Changquan Ling, Min Li
Journal: Molecular Therapy (2015)

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, yet effective therapeutic options for advanced HCC are limited. Recombinant adenovirus-p53 (rAd-p53) was the first commercial gene therapy product in the world, which was shown to be effective in treating various cancer types. Bufalin, a bioactive monomeric compound in toad venom that belongs to Traditional Chinese Medicine (TCM), is also a commercial antitumor drug for HCC. Thus, we wished to investigate the possibility of combining the therapeutic effects of rAdv-p53 and of bufalin, both in vitro and in vivo. We previously observed that bufalin, at as low a concentration as 40 nM, significantly enhanced rAd vector-mediated transgene expression, not only a reporter gene, EGFP, but also a therapeutic gene, p53, in various HCC cell lines. The combination of rAd-p53 and bufalin strongly inhibited the proliferation of HCC cell lines in vitro. The combined therapeutic effect was more effective than either treatment alone, both in a time-dependent and a dose-dependent manner. Additional mechanistic studies suggested that bufalin increased the rAd vector-medicated p53 gene expression, which induced apoptosis through the Bcl-2-PARP pathway, and eventually resulted the inhibition of proliferation. In the current studies, we evaluated the therapeutic effects of the combination of rAd-p53 and bufalin in a murine HCC xenograft model in vivo. HCC tumor-bearing nude mice were divided into 5 groups (n=6): i) PBS treatment as a negative control; ii) rAd-p53 treatment; iii) bufalin treatment; iv) rAd-null + bufalin treatment; and v) rAd-p53 + bufalin treatment. Bufalin was administered intra-peritoneally, whilst rAd vectors were injected intra-tumorally. Post-treatment, we observed a statistically significant suppression of tumor growth resulting from administration of a combination of rAd-p53 and bufalin, in comparison with other groups. Survival was also prolonged significantly in the combination group. H&E staining of subcutaneous tumor sections showed that most necrotic regions were visible in the combination group. In addition, most apoptotic cells were localized in tumor tissues from the combination group, as determined by immunohistochemical staining. Furthermore, in tumor tissues from the rAd-p53 vector-treated group, cancer cells around the necrotic areas were positive for p53 protein expression, and co-treatment with bufalin resulted in a significant increase in p53 protein expression. These studies suggest that rAd-p53 + bufalin combination therapy may be a useful strategy for targeting malignant tumors.
Increases in Drug and Opioid-Involved Overdose Deaths — United States, 2010–2015
Authors: Rose A. Rudd, Puja Seth, Felicita David, Lawrence Scholl
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

The U.S. opioid epidemic is continuing, and drug overdose deaths nearly tripled during 1999-2014. Among 47,055 drug overdose deaths that occurred in 2014 in the United States, 28,647 (60.9%) involved an opioid (1). Illicit opioids are contributing to the increase in opioid overdose deaths (2,3). In an effort to target prevention strategies to address the rapidly changing epidemic, CDC examined overall drug overdose death rates during 2010-2015 and opioid overdose death rates during 2014-2015 by subcategories (natural/semisynthetic opioids, methadone, heroin, and synthetic opioids other than methadone).* Rates were stratified by demographics, region, and by 28 states with high quality reporting on death certificates of specific drugs involved in overdose deaths. During 2015, drug overdoses accounted for 52,404 U.S. deaths, including 33,091 (63.1%) that involved an opioid. There has been progress in preventing methadone deaths, and death rates declined by 9.1%. However, rates of deaths involving other opioids, specifically heroin and synthetic opioids other than methadone (likely driven primarily by illicitly manufactured fentanyl) (2,3), increased sharply overall and across many states. A multifaceted, collaborative public health and law enforcement approach is urgently needed. Response efforts include implementing the CDC Guideline for Prescribing Opioids for Chronic Pain (4), improving access to and use of prescription drug monitoring programs, enhancing naloxone distribution and other harm reduction approaches, increasing opioid use disorder treatment capacity, improving linkage into treatment, and supporting law enforcement strategies to reduce the illicit opioid supply.
Everolimus in locally advanced rectal cancer (E-LARC study, Ib): biomarkers evaluation
Authors: A. Fontana, B. Federica, L. Reggiani-Bonetti, E. Pettorelli, S. Noventa, B. Meduri, F. Gelsomino, S. Zironi, A. Spallanzani, E. Mazzeo, A. Maiorana, P. Conte, G. Luppi
Journal: Annals of Oncology (2015)
Sensitive subgroups and normal variation in pulmonary function response to air pollution episodes.
Authors: B Brunekreef, P L Kinney, J H Ware, D Dockery, F E Speizer, J D Spengler, B G Ferris
Journal: Environmental Health Perspectives (1991)

The Clean Air Act requires that sensitive subgroups of exposed populations be protected from adverse health effects of air pollution exposure. Hence, data suggesting the existence of sensitive subgroups can have an important impact on regulatory decisions. Some investigators have interpreted differences among individuals in observed pulmonary function response to air pollution episodes as evidence that individuals differ in their sensitivity. An alternative explanation is that the differences are due entirely to normal variation in repeated pulmonary function measurements. This paper investigates this question by reanalyzing data from three studies of children exposed to air pollution episodes to determine whether the observed variability in pulmonary function response indicates differences in sensitivity or natural interoccasion variability. One study investigated exposures to total suspended particulates (TSP), the other two investigated exposure to ozone. In all studies, each child's response to air pollution exposures was summarized by regressing that child's set of pulmonary function measurements on the air pollution concentrations on the day or days before measurement. The within-child and between-child variances of these slopes were used to test the hypothesis of variable sensitivity. Regression slopes did not vary significantly among children exposed to episodes of high TSP concentration, but there was evidence of heterogeneity in both studies of ozone exposures. The finding of heterogeneous response to ozone exposure is consistent with the epidemiologic and chamber studies of ozone exposures, but the lack of evidence for heterogeneous response to TSP exposures implies that observed variation in response can be explained by sampling variability rather than the presence of sensitive subgroup.
Abstract 5090: Targeting metastatic prostate cancer with polyisoprenylated cysteinyl amides
Authors: Rosemary Aniwaa Poku, Augustine Nkembo, Olufisayo Salako, Felix Amissah, Hernan Flores-Rozas, Tryphon Mazu, Nazarius S. Lamango
Journal: Cancer Research (2015)

Abstract Background: Metastatic castration-resistant prostate cancer (mCRPC) poses a major clinical management challenge due to lack of effective therapies. Monomeric G- proteins of the Ras superfamily such as Rho, Rac and Cdc42 are critical mediators in prostate cancer progression and metastasis, due to their effect on F-actin organization in cell migration. These proteins are polyisoprenylated and subject to regulation by polyisoprenylated methylated protein methyl esterase (PMPMEase). We hypothesized that metabolism of monomeric G-proteins by PMPMEase regulates growth, survival and differentiation as well as cell migration and invasion through its effects on F-actin assembly. Methods: The effects of polyisoprenylated cysteinyl amides (PCAIs), NSL-RD-036, NSL-BA-040, NSL-BA-055 and NSL-BA-056 on the viability and proliferation of prostate cancer cell lines were investigated using the MTS assay. Docetaxel and paclitaxel were used as positive controls. Metastatic PC -3 cell migration and invasion in the presence of NSL-RD-036 were determined using the scratch and matrigel invasion assays. The effect of NSL-RD-040 on F-actin organization in TagRFP F-actin marker-transfected PC 3 cells was also investigated. Results: The PCAIs were cytotoxic to all prostate cancer cell lines (PC-3, DU 145, LNCaP and 22Rv1). In all the cell lines, NSL-BA-040 showed the highest activity (EC50 4.3 - 5.0 μM) followed by NSL-RD-036 (EC50 2.0 - 9.2 μM), NSL-BA-056 (EC50 4.8 - 7.5 μM) and NSL-BA-055 (EC50 2.9 - 11.2 μM) while docetaxel and paclitaxel were not as effective (EC50 &amp;gt;100 μM). Metastatic PC-3 cell proliferation was inhibited in a concentration-dependent manner by NSL-RD-036 and at 2 μM PC-3 cell proliferation was halted. Exposure of PC-3 cells to NSL-BA-040 induced apoptosis and disrupted F-actin cytoskeleton organization in TagRFP F-actin marker transfected metastatic PC-3 cells. NSL-RD-036 also significantly inhibited PC-3 cell migration and invasion through matrigel. Conclusions: Polyisoprenylated small molecules suppress migration and invasion as well as disrupt F-actin organization of metastatic PC-3 cells. Polyisoprenylated small molecules could serve as a new class of therapeutic agents in metastatic castration resistant prostate cancer. Citation Format: Rosemary Aniwaa Poku, Augustine Nkembo, Olufisayo Salako, Felix Amissah, Hernan Flores-Rozas, Tryphon Mazu, Nazarius S. Lamango. Targeting metastatic prostate cancer with polyisoprenylated cysteinyl amides. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5090. doi:10.1158/1538-7445.AM2015-5090
NIH Awards $150 Million for BRAIN Initiative Research in 2016
Authors: Jennifer Abbasi
Journal: JAMA (2016)

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95. Comprehensive wtAAV Integration Site Analysis Reveals Integration Site Formation Throughout the Whole Viral Genome
Authors: Karl Petri, Richard Gabriel, Leticia Agundez Cortes, Raffaele Fronza, Saira Afzal, Christine Kaeppel, Christof von Kalle, Els Henckaerts, Manfred Schmidt
Journal: Molecular Therapy (2015)

To establish latency, wildtype adeno-associated virus (wtAAV) is able to integrate its DNA into a specific region on chromosome 19 of the human genome, named AAVS1. This targeted integration mechanism relies on the function of the two larger versions (Rep78/68) of the Rep protein family, expressed by wtAAV. Rep is able to bind a 12 bp long sequence, called Rep binding site (RBS). The RBS can be found both in the viral ITRs and in AAVS1. By the formation of a trimeric complex between wtAAV, Rep and the genomic locus, targeted integration can be achieved. However, the exact mechanisms of Rep-mediated integration still remain unknown. To analyze wtAAV IS distribution genome-wide, large-scale integration analyses using high-throughput next generation sequencing have been performed. These studies revealed that Rep-mediated wtAAV integration preferentially occurs in AAVS1, but that additional integration hotspots associated with RBS can be found as well throughout the genome. Up to this point most integration sites (IS) reported for wtAAV were derived from vector-genome fusion sequences, where the viral sequence fragment was mapped near the ITRs or near the p5 region of the viral genome. Most currently available methods for the analysis of viral IS rely on amplification of the vector-genome junction with primers that bind in the vicinity of the viral ends. Therefore, knowledge about the nature and structure of the internal wtAAV genome remains limited. To address this question, we investigated ~3e6 wtAAV concatemeric structures generated by IS analyses using linear amplification-mediated (LAM) PCR to identify potential alternative breakpoints throughout the wtAAV genome. We discovered that breakpoints occur at any position of the wtAAV genome. Apart from the ITRs and the p5 promoter, there are a number of other preferred breakpoints throughout the wtAAV genome. Using a novel approach involving targeted enrichment of AAV and AAVS1 sequences, we also were able to consider viral IS at any position of the AAV genome. Targeted HiSeq sequencing of wtAAV and AAVS1 determined several hundreds of exact IS and confirmed that wtAAV genome junctions form at any position of its genome. Those cryptic integration events, not picked up by the majority of methods currently available, shed new light onto wtAAV persistence and may further improve current AAV persistence analyses in gene therapy.
Combination of Low Rate of γδ T Cells and High Rate of Regulatory T Cells after Allogeneic Stem Cell Transplantation Is a Poor Prognostic Factor for Patients with Hematological Neoplasm
Authors: Yasuhiko Shibasaki, Syukuko Miyakoshi, Takayuki Katagiri, Kyoko Fuse, Hironori Kobayashi, Takashi Ushiki, Masato Moriyama, Jun Takizawa, Miwako Narita, Hirohito Sone, Masayoshi Masuko
Journal: Blood (2015)
Abstract 3407: FGFR4 Arg388 polymorphism is a poor prognostic factor for resected stage III colon cancer
Authors: Sang-Hee Cho, Min-Ho Shin, Sun-Seog Kweon, Hee-Nam Kim, Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Ik-Joo Chung
Journal: Cancer Research (2015)

Abstract Purpose To evaluate the prognostic role of fibroblast growth factor receptor 4 (FGFR4) polymorphism in patients with surgically resected stage III colon cancer. Patients and Methods FGFR4 polymorphism was checked in peripheral blood from 273 patients who received curative resection and diagnosed as stage III colon cancer. Genomic DNA was extracted from blood which was drawn before curative resection. FGFR4 Gly388Arg genotyping was carried out using high-resolution melting (HRM) analysis. Results In total 273 patients, 92 patients (34%) were homozygous for Gly388 allele, with 146 heterozygous (54%) and 35 homozygous (13%) for Arg388. No significant association was found between clinical or histopathologic tumor characteristics and FGFR4 genotype. In survival analysis, Gly388 allele showed better 3Y-DFS than Arg388 carriers (heterozygous or Arg388 homozygous) in patients with no adjuvant (p = 0.26) or 5-FU/LV treated (p = 0.038). However, patients receiving adjuvant FOLFOX showed similar 3Y-DFS regardless of genotype. In addition, 5Y-OS was found significant improvement in Gly388 allele compared with Arg388 carriers (92.5% vs. 74.9%, p = 0.04) regardless of adjuvant treatment. In univariate analysis, age, N stage, tumor differentiation, lymphocyte response, adjuvant chemotherapy and FGFR4 genotype were associated with poor OS. In multivariate analysis, FGFR4 Arg388 carriers (HR 5.17; 95% CI, 2.06-12.92, p&amp;lt;0.001) showed significantly poor prognostic factors for OS together with age (≥ 70Y), N stage, poorly differentiation, absence of lymphocyte response, no adjuvant chemotherapy. Conclusion FGFR4Arg388 polymorphism is an independent poor prognostic factor in surgically resected stage III colon cancer. This result could guide the individual selection for adjuvant chemotherapy and potential therapeutic target for surgically resected stage III colon cancer. Citation Format: Sang-Hee Cho, Min-Ho Shin, Sun-Seog Kweon, Hee-Nam Kim, Hyun-Jeong Shim, Jun-Eul Hwang, Woo-Kyun Bae, Ik-Joo Chung. FGFR4 Arg388 polymorphism is a poor prognostic factor for resected stage III colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3407. doi:10.1158/1538-7445.AM2015-3407