tbuckley/cabot-search huggingface dataset:
Quantitation of circulating methylated <i>RASSF1A</i> in prognostication and monitoring of treatment response in unresectable hepatocellular carcinoma (HCC).
Authors: S. L. Chan, A. K. Chan, E. P. Hui, S. Yu, L. Leung, H. H. F. Loong, B. Ma, T. Mok, A. T. C. Chan, W. Yeo
Journal: Journal of Clinical Oncology (2011)

4058 Background: Methylation of RASSF1A is a frequent molecular event along hepatocarcinogenesis. Our group previously developed a sensitive and specific assay in the quantitation of circulating methylated (m) RASSF1A in serum of patients (pts) with HCC. We aimed to evaluate the use of circulating mRASSF1A in prognostication and monitoring of treatment response during trans-arterial therapy of HCC. Methods: 42 pts with histologically confirmed HCC who underwent transarterial therapy were recruited. The mRASSF1A levels in serum at baseline and 8 weeks post 1st cycle of treatment were measured. The assay makes use of methylation-sensitive restriction enzyme to specifically digest unmethylated DNA, followed by real-time PCR assay to quantitate the remaining mRASSF1A(Clin. Chem. 08;54:1528-36). The prognostic significance of baseline level was evaluated by univariate and multivariate analyses. Tumor viability was determined in contrast computed tomography (CT) conducted 8 weeks after first treatment, and its association between the trend of post-treatment mRASSF1A was analyzed. Results: Mean age was 65 yrs (range 30-80). 31 were male. The mean level of mRASSF1A was 1028.1 copies/mL (range: 18.6-12732.0 copies/mL). Total 28 (67.2%) had baseline level higher than 100 copies/mL. A higher baseline level of mRASSF1A was associated with larger tumor diameter (p<0.0001). The median overall survival of pts with mRASSF1A ≥ 1,000 copies/mL (8.9 ms) was worse than pts with level <1,000 copies/mL (19.1 ms; p=0.001). Baseline mRASSF1A level remained to be an independent prognostic factor after adjustment with socio-demographics, AFP, liver function, Child’s stage, and tumor staging. 25 pts had reduction of ≥50% in post-treatment mRASSF1A. Achievement of ≥50% drop of mRASSF1A after treatment is associated with absence of residual viable disease in CT (80% vs. 20%; p=0.01), and a trend of better OS (21.1 vs. 12.0 ms; p=0.054). Conclusions: Our pilot data showed that quantitation of mRASSF1A in circulation of HCC pts is of potential value in prognostication and monitoring of treatment response during transarterial therapy. Further validation works are currently planned.
Abstract SY21-04: Starting an immune response against pancreatic cancer: Getting past the stroma
Authors: Robert H. Vonderheide
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and lethal cancer which is poorly responsive to standard therapies. Although the PDA tumor microenvironment is considered especially immunosuppressive, recent data mostly from genetically engineered and other mouse models of the disease suggest that novel immunotherapeutic approaches hold promise. Here, both laboratory and clinical efforts to target the CD40 pathway for immunotherapy in PDA will be described. Findings suggest that CD40 agonists can mediate both T-cell-dependent and T-cell-independent immune mechanisms of tumor regression in mice and patients. T-cell-independent mechanisms are associated with macrophage activation and the destruction of PDA tumor stroma, but these effects are transient. T cell-dependent mechanisms can be elicited with novel chemotherapy combinations and further extended by checkpoint blockade (with anti-PD-1 and/or anti-CTLA4). In the absence of anti-CD40 agonist antibody, neither chemotherapy nor checkpoint blockade can achieve meaningful tumor regressions nor long-term remissions, but inclusion of anti-CD40 can establish immune memory and cures in murine models. Overall, immune modulation of the PDA tumor microenvironment represents a useful approach in cancer immunotherapy. Citation Format: Robert H. Vonderheide. Starting an immune response against pancreatic cancer: Getting past the stroma. [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 SY21-04. doi:10.1158/1538-7445.AM2015-SY21-04
Genetically engineered and self-assembled oncolytic protein nanoparticles for targeted cancer therapy
Authors: Joong-jae Lee, Jung Ae Kang, Yiseul Ryu, Sang-Soo Han, You Ree Nam, Jong Kook Rho, Dae Seong Choi, Sun-Woong Kang, Dong-Eun Lee, Hak-Sung Kim
Journal: Biomaterials (2016)
Acute Myeloid Leukemia in Elderly Patients: Experience of the Antoine Lacassagne Center and a New Score to Define Fit Patients
Authors: Bailleux Caroline, Fieux Thomas, Doyen Jerome, Gastaud Lauris, Gallamini Andrea, Kaphan Regis, Re Daniel, Gutnecht Jean, Garnier Georges, Rossignol Benoit, Thyss Antoine, Franck E. Nicolini, Frederic Peyrade
Journal: Blood (2015)
755. One-time Gene Therapy for Hereditary Angioedema
Authors: Odelya E. Pagovich, Ting Qiu, Adele S. Whaley, Anthony R. Russo, Jonathan Rosenberg, Bishnu P. De, Carlo Russo, Maria J. Chiuchiolo, Dolan Sondhi, Stephen M. Kaminsky, Ronald G. Crystal
Journal: Molecular Therapy (2016)

Hereditary angioedema (HAE) is a potentially life-threatening autosomal dominant deficiency affecting 1 in 50,000 individuals from all ethnic groups worldwide. More than 99% of HAE cases are caused by a deficiency in functional plasma C1 esterase inhibitor (C1E-INH, a serine protease inhibitor) due to mutations in the SERPING1 gene. Low plasma C1E-INH activity dysregulates the contact, complement, and fibrinolytic systems, resulting in unpredictable, recurrent submucosal edema of cutaneous tissues, gastrointestinal and respiratory tracts. If not treated in a timely manner, laryngeal edema can result in death by asphyxiation. Current HAE treatments consist of management of acute attacks, repeated prophylactic therapy with C1E-INH or long term prophylaxis with attenuated androgens, each complicated by a high economic burden, limited compliance, drug side effects and contraindications. To circumvent this challenge, we hypothesized that a one-time administration of an adeno-associated virus (AAV) gene transfer vector expressing the genetic sequence of C1 esterase-inhibitor (serotype 10 expressing the human CIE-INH coding sequence, AAVrh.10hC1EI) would provide sustained C1E-INH activity levels in plasma, sufficient to prevent angioedema episodes. To study the efficacy of AAVrh.10hC1EI, using CRISPR/Cas9 technology we created a novel C1E-INH deficient mouse model analogous to human HAE disease, and characterized the resulting SERPING1 gene mutations by genome sequencing. The heterozygous mouse model shares characteristics associated with HAE in humans including decreased C1E-INH and C4 levels in plasma and increased vascular permeability. Administration of AAVrh.10hC1EI to the heterozygous mice resulted in sustained human C1E levels above the predicted therapeutic levels. In order to demonstrate that the increased vascular permeability observed in heterozygote C1E-INH+/- mice was a direct result of C1E-INH deficiency, Evans blue dye was injected intravenously and extravasation of dye from the vasculature evaluated. Compared to wild type mice under baseline conditions, the C1EINH+/- mice had increased extravasation of the dye into the hind paws quantitated by optical absorbance at 600 nm. Strikingly, AAVrh10.hC1EI-treated (1011 gc) mice displayed a marked decrease in dye extravasation, whereas non-treated C1E-INH +/- mice had markedly increased dye extravasation. These results demonstrate that a single treatment with AAVrh.10hC1EI has the potential to provide long term protection from angioedema attacks in the affected population, representing a paradigm shift in current therapeutic approaches.
Targeting BTK By a microRNA Mechanism in Chronic Lymphocytic Leukemia
Authors: Arianna Bottoni, Rizzotto Lara, Lai Tzung-Huei, Rose Mantel, Lisa Simith, Dalia El-Gamal, Amy J. Johnson, Rosa Lapalombella, James S. Blachly, John C. Byrd, Jennifer A. Woyach, Deepa Sampath
Journal: Blood (2015)
Abstract 5084: A multifaceted role of the Hedgehog pathway in modulating pancreatic ductal adenocarcinoma biology
Authors: Dafydd Huw Thomas, Albert Lee, Carmine Palermo, Stephen Sastra, Raul Rabadan, Kenneth Olive
Journal: Cancer Research (2015)

Abstract The Hedgehog (Hh) developmental pathway is reactivated in pancreatic ductal adenocarcinoma (PDA) and forms a paracrine axis from the tumor cells to the supporting stromal cells. Previous work from this laboratory found that, in established tumors, inhibition of the Hedgehog (Hh) pathway caused a loss of tumor stroma implicating this axis in the development of the profuse desmoplastic stroma observed in PDA. However, the mechanisms by which Hh signaling modulates the stroma in PDA remain unknown. In this study we have attempted to identify the target genes of the Hh pathway in the stroma of pancreatic tumors. Using a novel tumor biopsy procedure coupled with RNA-SEQ analysis we have identified genes acutely sensitive to Hh pathway inhibition in the KPC mouse model of PDA. The gene signature of down-regulated genes following Hh inhibition implicated the Hh pathway in the proliferation of its target stromal cells as well as a possible indirect effect on the proliferation of tumor cells. Interestingly, a significant number of genes were also up-regulated following inhibition of the Hh pathway. This gene signature was consistent with the migration and infiltration of leukocytes. Taken together these data suggest that the Hh pathway can drive proliferation of both the stromal and epithelial compartments as well as actively suppress leukocyte infiltration into pancreatic tumors. In addition we have utilized a Gli1-GFP reporter mouse to study the Hh target cells in the stroma of KPC mice. Previous work has suggested that Hh target cells in pancreatic tumors are myofibroblasts and thus α-Smooth muscle actin (α-SMA) positive. However, we observed that while some Gli1 positive stromal cells are α-SMA positive a significant proportion are α-SMA negative. In addition, costaining KPC-Gli1-GFP tumors for other stromal markers, including Fibroblast specific protein-1 (FSP-1), Glial Fibrillary Acidic Protein (GFAP), Desmin, Vimentin and Platelet-derived growth factor receptor β (PDGFRβ) reveals subsets of Hh target cells in the tumor stroma. These data suggest the Hh pathway targets a complex set of stromal fibroblasts to mediate its effects. Taken together, these data suggest that the Hh pathway regulates multiple facets of pancreatic tumor biology both in negative and positive manner and does so through targeting a complex array of stromal cells. Citation Format: Dafydd Huw Thomas, Albert Lee, Carmine Palermo, Stephen Sastra, Raul Rabadan, Kenneth Olive. A multifaceted role of the Hedgehog pathway in modulating pancreatic ductal adenocarcinoma biology. [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 5084. doi:10.1158/1538-7445.AM2015-5084
Abstract 655: The next generation of targeted toxins: A novel deimmunized sarcin ribotoxin fused with an EphA2 Abdurin binder
Authors: Kurt R. Gehlsen, Anna Demartis, Tim Jones
Journal: Cancer Research (2015)

Abstract Abdurins are a novel antibody-like scaffold derived from the engineering of a single CH2 domain (CH2D) of IgG. The prolonged serum half-life of Abdurins, the result of retained FcRn binding, is 10-20 times longer than the serum half-life of any other protein scaffold of comparable molecular weight. Here we present data on the isolation and characterization of high affinity ABDURIN binders to the cancer target EphA2. α-Sarcin is a small (17 kDa) fungal ribonuclease produced by Aspergillus giganteus. Sarcin functions by catalytically cleaving a single phosphodiester bond in the sarcin-ricin loop, a well-defined RNA motif within the rRNA scaffold of the large ribosomal subunit. This cleavage makes the ribosome unrecognizable to elongation factors and hence, blocks protein synthesis. We have deimmunized α-sarcin (Sarcin-DI) and made several variants lacking T cell epitopes while retaining cytotoxic activity. This novel Abdurin EphA2 binder fusion with Sarcin-DI creates a new generation of targeted toxins with a longer half-life, low immunogenicity and potent tumor cell killing. Citation Format: Kurt R. Gehlsen, Anna Demartis, Tim Jones. The next generation of targeted toxins: A novel deimmunized sarcin ribotoxin fused with an EphA2 Abdurin binder. [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 655. doi:10.1158/1538-7445.AM2015-655
Epigenetic Manipulation of Cancer Testis Antigen (CTA) Expression: A Strategy for Manipulating the Graft-Versus Leukaemia Response in Patients Allografted for Haematological Malignancies
Authors: Tatjana Stankovic, Andrew McLarnon, Angelo Agathanggelou, Oliver Goodyear, Charles Craddock, Paul Moss
Journal: Blood (2008)
Cord Blood Transplantation from Unrelated Donors for Children with Acute Lymphoblastic Leukemia in Japan: The Impact of Methotrexate on the Clinical Outcome.
Authors: Koji Kato, Ayami Yoshimi, Etsuro Ito, Kentaro Oki, Jun Hara, Yoshihisa Nagatoshi, Akira Kikuchi, Ryoji Kobayashi, Tokiko Nagamura-Inoue, Shunro Kai, Hiroshi Azuma, Minoko Takanashi, Keiichi Isoyama, Shunichi Kato
Journal: Blood (2007)
Incidence, Predictors, and Mid-Term Outcomes of Possible Leaflet Thrombosis After TAVR
Authors: Ryo Yanagisawa, Kentaro Hayashida, Yoshitake Yamada, Makoto Tanaka, Fumiaki Yashima, Taku Inohara, Takahide Arai, Takashi Kawakami, Yuichiro Maekawa, Hikaru Tsuruta, Yuji Itabashi, Mitsushige Murata, Motoaki Sano, Kazuma Okamoto, Akihiro Yoshitake, Hideyuki Shimizu, Masahiro Jinzaki, Keiichi Fukuda
Journal: JACC. Cardiovascular imaging (2016)
Array Comparative Genomic Hybridization of Ribosomal Protein Genes In Diamond-Blackfan Anemia Patients; Evidence for Three New DBA Genes, RPS8, RPS14 and RPL15, with Large Deletion or Duplication
Authors: Hanna Gazda, Michael Landowski, Christopher Buros, Adrianna Vlachos, Colin A. Sieff, Peter E. Newburger, Edyta Niewiadomska, Michal Matysiak, Bertil Glader, Lori Dobson, Eva Atsidaftos, Jeffrey Michael M. Lipton, Alan Beggs
Journal: Blood (2010)
Abstract 4777: Triptolide inhibits Wnt signaling due to DNA methylation alteration that is determined by dynamic histone 3 K79 lysine methylation in NSCLC
Authors: Youqiang Li, Binghui Shen, Jae Kim, Dan Raz
Journal: Cancer Research (2015)

Abstract Epigenetic alterations including DNA methylation and histone modifications have been associated with virtually every step of tumor development and progression. This realization has triggered an impressive quest for the development of “epigenetic drugs” and epigenetic therapies. Here we present data demonstrating that triptolide, with a unique mechanism, has anticancer effect in lung cancer development and progression. With the use of our unique non-small cell lung cancer (NSCLC) mouse model (ED160, Fen1 mutation), data shows triptolide decreases lung cancer incidence from 70% to 10%. In addition, triptolide effectively inhibits lung cancer growth and metastasis in NSG mouse Xenograft. Triptolide inactivates Wnt signaling by restoring WIF1 expression which is due to WIF1 gene demethylation. Furthermore, we revealed histone 3 lysine methylation alteration determines DNA methylation status by the communication between DNMT1 and histone 3. Together, these evidences indicated that sequential histone and DNA methylation active Wnt signaling; further it contributes to NSCLC development and progression. This discovery potentially is yielding epigenetic therapeutic opportunities for NSCLC. Note: This abstract was not presented at the meeting. Citation Format: Youqiang Li, Binghui Shen, Jae Kim, Dan Raz. Triptolide inhibits Wnt signaling due to DNA methylation alteration that is determined by dynamic histone 3 K79 lysine methylation in NSCLC. [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 4777. doi:10.1158/1538-7445.AM2015-4777
Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: an analysis of a national observational cohort
Authors: Sara Croxford, Aileen Kitching, Sarika Desai, Meaghan Kall, Michael Edelstein, Andrew Skingsley, Fiona Burns, Andrew Copas, Alison E Brown, Ann K Sullivan, Valerie Delpech
Journal: The Lancet Public Health (2016)

Deaths in HIV-positive people have decreased since the introduction of highly active antiretroviral therapy (HAART) in 1996. Fewer AIDS-related deaths and an ageing cohort have resulted in an increase in the proportion of HIV patients dying from non-AIDS-related disorders. Here we describe mortality and causes of death in people diagnosed with HIV in the HAART era compared with the general population.In this observational analysis, we linked cohort data collected by Public Health England (PHE) for individuals aged 15 years and older, diagnosed with HIV in England and Wales from 1997 to 2012, to the Office for National Statistics (ONS) national mortality register. Cohort inclusion began at diagnosis with follow-up clinical information collected every year from all 220 National Health Service (NHS) HIV outpatient clinics nationwide. To classify causes of death we used a modified Coding Causes of Death in HIV (CoDe) protocol, which uses death certificate data and clinical markers. We applied Kaplan-Meier analysis for survival curves and mortality rate estimation and Cox regression to establish independent predictors of all-cause mortality, adjusting for sex, infection route, age at diagnosis, region of birth, year of diagnosis, late diagnosis, and history of HAART. We used standardised mortality ratios (SMRs) to make comparisons with the general population.Between 1997 and 2012, 88 994 people were diagnosed with HIV, contributing 448 839 person-years of follow up. By the end of 2012, 5302 (6%) patients had died (all-cause mortality 118 per 10 000 person-years, 95% CI 115-121). In multivariable analysis, late diagnosis was a strong predictor of death (hazard ratio [HR] 3·50, 95% CI 3·13-3·92). People diagnosed more recently had a lower risk of death (2003-07: HR 0·66, 95% CI 0·62-0·70; 2008-12: HR 0·65, 95% CI 0·60-0·71). Cause of death was determinable for 4808 (91%) of 5302 patients; most deaths (2791 [58%] of 4808) were attributable to AIDS-defining illnesses. Cohort mortality was significantly higher than the general population for all causes (SMR 5·7, 95% CI 5·5-5·8), particularly non-AIDS infections (10·8, 9·8-12·0) and liver disease (3·7, 3·3-4·2). All-cause mortality was highest in the year after diagnosis (SMR 24·3, 95% CI 23·4-25·2).Despite the availability of free treatment and care in the UK, AIDS continues to account for the majority of deaths in HIV-positive people, and mortality remains higher in HIV-positive people than in the general population. These findings highlight the importance of prompt diagnosis, care engagement, and optimum management of comorbidities in reducing mortality in people with HIV.Public Health England.
Vancomycin therapy in secondary care; investigating factors that impact therapeutic target attainment
Authors: Timothy M. Rawson, Esmita Charani, Luke S.P. Moore, Pau Herrero, Ji Soo Baik, Akash Philip, Mark Gilchrist, Eimear T. Brannigan, Pantelis Georgiou, William Hope, Alison H. Holmes
Journal: Journal of Infection (2016)
693. Potent and Targeted Activation of Latent HIV-1 Using Multiplexed Guide RNAs and the CRISPR/dCas9 Activator Complex
Authors: Sheena M. Saayman, Daniel C. Lazar, Tristan A. Scott, John Burnett, Mayumi Takahashi, Marc S. Weinberg, Kevin V. Morris
Journal: Molecular Therapy (2015)

Cells latently infected with HIV provide a reservoir that promotes new viral infection indefinitely, thus making it exceedingly difficult for antiretroviral therapy (ART) to completely ablate the infection. A powerful strategy to eradicate latent HIV reservoirs has been to reactivate proviral gene expression using histone deacetylase (HDAC) inhibitors followed by ART: an approach called "shock and kill". However, this approach suffers from lack of efficacy and specificity. Gene specific transcriptional activation can be achieved using the RNA-guided CRISPR-Cas9 system comprising a nuclease deficient mutant of Cas9 (dCas9) fused to a C-terminal VP64 or VP160 acidic transactivation domain. We initially identified 18 sites for targeting of small guide RNAs (sgRNAs) in the U3 region, upstream of the canonical HIV transcriptional start site TSS (-450 to 0 bp). Activating sgRNA candidates were identified and verified by transient transfection in TZM-Bl cells and also in HEK293 cells with Subtype B and C LTR-driven luciferase reporters. Several candidate sgRNA individually induced a 10-fold increase in gene expression, with a "hotspot" region between -200 and -250 bp of the TSS. However, when combined in multiplex fashion, with four conserved gRNAs expressed off four independent Pol III promoters in a single vector, a synergistic enhancement of HIV transcription of ~30 fold was observed. Given the complexity and multifaceted mechanisms of latency, current cell line models are unable to completely recapitulate the conditions of endogenous HIV reservoirs. As an initial proof-of-concept that the CRISPR/Cas9 system can be used to purge the latent HIV proviral genome, we used a CEM T cell-based reporter system, comprising a single copy of HIV, that encodes mCherry-IRES-Tat from the full-length HIV LTR (LChIT). The LChIT system enables a Tat-mediated positive feedback loop that drives expression of Tat and mCherry allowing for exquisite sensitivity to alterations in viral gene expression, either directly or indirectly. CEM-LChIT clone 3.2 expressed mCherry in 50% of the population (a bimodal state). In this model, nucleofected sgRNAs and dCas9-VP64 led to a 200-fold activation of gene expression; a result higher than treatment controls using a combination of HDAC inhibitor trichostatin A (TSA) and TNFa. In conclusion, the potential for RNA-guided gene activation systems to provide maximum efficiency and specificity in a targeted reactivation strategy augurs well for the future of the "shock and kill" approach as an impending cure for HIV.