tbuckley/cabot-search huggingface dataset:
Augmentation of therapy for favorable-histology Wilms Tumor with combined loss of heterozygosity of chromosomes 1p and 16q: A report from the Children’s Oncology Group studies AREN0532 and AREN0533.
Authors: David B. Dix, Conrad Vincent Fernandez, Yueh-Yun Chi, James Robert Anderson, Elizabeth Anne Mullen, James I. Geller, Eric J. Gratias, Geetika Khanna, John A. Kalapurakal, Elizabeth Jones Perlman, Nita Seibel, Peter F. Ehrlich, Marcio H. Malogolowkin, Kenneth William Gow, Thomas Edward Hamilton, Paul Edward Grundy, Jeffrey Dome
Journal: Journal of Clinical Oncology (2015)

10009 Background: In National Wilms Tumor Study-5, tumor-specific combined loss of heterozygosity (LOH) of chromosomes 1p and 16q was associated with adverse outcome in patients with favorable histology Wilms Tumor (FHWT): stage I/II patients treated with Regimen EE4A (vincristine (VCR)/dactinomycin (DACT)) had 4-year EFS of 91.2% without LOH and 74.9% with LOH; stage III/IV patients treated with Regimen DD4A (VCR/ DACT/doxorubicin(DOX)) and radiotherapy (RT) had 4-year EFS of 83% without LOH and 65.9% with LOH. The AREN0533/AREN0532 studies assessed whether augmenting therapy would improve EFS for FHWT with combined 1p/16q LOH. Stage I/II patients were treated with the addition of DOX (Regimen DD4A) but no RT. Stage III/IV patients were treated with Regimen M (VCR/DACT/DOX alternating with cyclophosphamide/etoposide) and RT. Methods: Patients were enrolled through the AREN03B2 Biology and Classification study between10/2006 and 7/2013. All patients underwent central review of pathology, surgical reports and diagnostic imaging. Tumor tissue was evaluated for LOH 1p and 16q by microsatellite testing. Descriptive statistics were used to compare the EFS/OS between NWTS-5 and the current studies. Results: Median follow up for 1,134 patients enrolled on AREN0532/0533 was 3.6 years (0.1 to 8.1 years). Combined LOH 1p and 16q was detected in 35 evaluable stage I/II patients and 52 stage III/IV patients. At analysis in December 2014 the number of events was 6 observed versus 9 expected for stage I/II, and 4 observed versus 18 expected for stage III/IV. The 4 year EFS for the stage I/II LOH patients and stage III/IV LOH patients was 83.9% (95%CI: 64.9%, 93.1%) and 91.5% (95%CI: 78.5%, 96.8%) respectively. Grade 3 or higher hematological toxicity was the most common toxicity observed with Regimen M, affecting 60% of patients. There were no unexpected toxicities. Conclusions: Regimen M therapy improved EFS for patients with stage III/IV FHWT with LOH at 1p/16q as compared to the historical comparison group treated with Regimen DD4A. The benefit of using Regimen DD4A instead of Regimen EE4A for stage I/II FHWT with LOH is less clear. Clinical trial information: NCT00379340; NCT00352534.
Molecular Pathways: Immune Checkpoint Antibodies and their Toxicities
Authors: Sophie Cousin, Antoine Italiano
Journal: Clinical Cancer Research (2016)

The emergence of immune checkpoint inhibitors for solid tumor treatments represents a major oncologic advance. Since the approval of ipilimumab, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody, for the treatment of metastatic melanoma, many drugs, especially those targeting PD-1/PD-L1, have demonstrated promising antitumor effects in many types of cancer. By reactivating the immune system, these immunotherapies have led to the development of new toxicity profiles, also called immune-related adverse events (irAE). IrAEs can involve many organ systems, and their management is radically different from that of cytotoxic drugs; irAEs require immunosuppressive treatments, such as corticoids or TNFα antibody. In addition, the occurrence of irAEs has raised significant questions. Here, we summarize progress that has been made toward answering these questions, focusing on (i) the impact of immunotherapy dose on irAE occurrence, (ii) the correlation between irAE and patient outcome, (iii) the safety of immune checkpoint inhibitors in patients already treated for autoimmune disease, and (iv) the suspected effect on tumor growth of steroids used for the management of irAEs. Clin Cancer Res; 22(18); 4550-5. ©2016 AACR.
People's willingness to accept overdetection in cancer screening: Population survey OPEN ACCESS
Authors: A Van Den Bruel, C Jones, Y Yang, J Oke, P Hewitson
Journal: BMJ (2015)

Objectives To describe the level of overdetection people would find acceptable in screening for breast, prostate, and bowel cancer and whether acceptability is influenced by the magnitude of the benefit from screening and the cancer specific harms from overdetection. Design Online survey. Women were presented with scenarios on breast and bowel cancer, men with scenarios on prostate and bowel cancer. For each particular cancer, we presented epidemiological information and described the treatment and its consequences. Secondly, we presented two different scenarios of benefit: one indicating a 10% reduction in cancer specific mortality and the second indicating a 50% reduction. Setting Online survey of the population in the United Kingdom. Participants Respondents were part of an existing panel of people who volunteer for online research and were invited by email or online marketing. We recruited 1000 respondents, representative for age and sex for the UK population. Main outcome measures Number of cases of overdetection people were willing to accept, ranging from 0-1000 (complete screened population) for each cancer modality and each scenario of benefit. Results There was large variability between respondents in the level of overdetection they would find acceptable, with medians ranging from 113 to 313 cases of overdetection per 1000 people screened. Across all scenarios, 4-7% of respondents indicated they would accept no overdetection at all compared with 7-14% who thought that it would be acceptable for the entire screened population to be overdetected. Acceptability in screening for bowel cancer was significantly lower than for breast and prostate cancer. People aged 50 or over accepted significantly less overdetection, whereas people with higher education levels accepted more; 29% of respondents had heard of overdetection before. Conclusions Acceptability of overdetection in cancer screening is variable. Invitations for screening should include clear information on the likelihood and consequences of overdetection to allow people to make an informed choice.
Polylactides in additive biomanufacturing
Authors: Patrina S.P. Poh, Mohit P. Chhaya, Felix M. Wunner, Elena M. De-Juan-Pardo, Arndt F. Schilling, Jan-Thorsten Schantz, Martijn van Griensven, Dietmar W. Hutmacher
Journal: Advanced Drug Delivery Reviews (2016)
Functional Limitations, Physical Disability and Social Competence among HCT Survivors Transplanted during Childhood or Adolescence: A Report from the Bone Marrow Transplant Survivor Study.
Authors: Kirsten K. Ness, James G. Gurney, K. S. Baker, Liton Francisco, Andrea Carter, Stephen J. Forman, Leslie L. Robison, Joseph Rosenthal, Smita Bhatia
Journal: Blood (2004)
Risk Alleles Associated with Neovascularization in a Pachychoroid Phenotype
Authors: Kunal K. Dansingani, Lorah T. Perlee, Sara Hamon, May Lee, Vinnie P. Shah, Richard F. Spaide, John Sorenson, James M. Klancnik, Lawrence A. Yannuzzi, Irene A. Barbazetto, Michael J. Cooney, Michael Engelbert, Christine Chen, Alex W. Hewitt, K. Bailey Freund
Journal: Ophthalmology (2016)
Réseaux de surveillance internationaux et principes de collaboration
Authors: I. S.T. Fisher, O N Gill
Journal: Eurosurveillance (2001)

Face a la multiplication et au developpement de reseaux internationaux de surveillance des maladies transmissibles, de nombreuses questions sur la transmission de donnees et d’informations personnelles se posent. Ainsi, la nature confidentielle des donnees partagees et leur divulgation a une echelle internationale au sein et en dehors du reseau sont des sources de conflits potentiels. Pour resoudre ces problemes, le reseau Enter-net a edicte des  Principes de collaboration  destines a tous les participants du reseau et a tous les acteurs de sante publique concernes. Ces objectifs proposent des solutions aux questions relatives a l'acces aux bases de donnees creees dans le cadre du reseau, a la qualite et a la confidentialite des donnees diffusees, a la responsabilite de chacun lors de l’identification d’un produit mis en cause dans une epidemie ou encore a la transmission d'information en dehors du reseau. Ces principes, qui doivent etre revises regulierement, ont pour objectif premier d'optimiser la detection precoce et la gestion des epidemies alimentaires, ainsi que la prise de decision pour des reponses de sante publique. Etant donne la nature des problemes abordes, certains de ces principes concernent egalement d'autres reseaux de surveillance.
Abstract 66: High-throughput screening using patient derived tumor cell to conduct personalized medicine
Authors: Seung T. Kim, Charny Park, Sun Kim, Won Lee, Joon Park, Kyoung-Mee Kim, Woongyang Park, Jeeyun Lee, young park, Jiryeon Jang
Journal: Cancer Research (2016)

Abstract Background: Patient-derived cell (PDC) model is one of prospective technologies to investigate drug response for precision medicine. Previously drug sensitivity derived PDC model has been studied in colorectal cancer organoid culture or lung cancer model. They revealed that PDC model recapitulates genomic characteristic and drug high-throughput screening is amenable. We established PDC models from metastatic cancer cohort of multiple cancer types, and revealed genomic characteristics and matched drug response. Method: Target sequencing was performed using OncoPanel. We called SNV, and CNV from target sequencing using GATK, then clinically unassociated SNPs were eliminated. Somatic submodules were identified from integrative variant profiles using HotNet referring HPRD. Drug high-throughput screening was performed SEMCO platform. In order to identify sensitive drug and variant gene pairs, drug sensitivity was tested by ANOVA using IC50 values. Result: Target sequencing of exome were generated from our 165 PDC models, and drug high-throughput screening was performed from 30 PDCs and ant-cancer 15 drugs. We tried integrative analysis approaches from genomic profile including mutation and copy number alteration, and identified genomic modules related with Fanconi, Hedgehog, FGFR receptor, Cytokine-cytokine receptor pathway. Variants of known oncogenes were successfully identified in MET, BRAF, FGFR and PIK4CA. Especially novel and recurrent mutations were identified in FGFR2, and corresponding samples indicated AZD4547 sensitivity as well as known drug response case such as BRAF V600E targeting Vemurafenib. Conclusion: Our study explains that PDC cohort sustains cancer related pathways, and its drug response follows genomic features. It is expected that our research would contribute to facilitate precision medicine from PDC model to utilize genomics and drug response. Citation Format: Seung T. Kim, Charny Park, Sun Kim, Won Lee, Joon Park, Kyoung-Mee Kim, Woongyang Park, Jeeyun Lee, young park, Jiryeon Jang. High-throughput screening using patient derived tumor cell to conduct personalized medicine. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 66.
Selective Allodepletion by TH9402-Mediated Photosensitization Results in Early Full Donor T Cell Reconstitution in the Absence of High-Grade, Acute GvHD and Is Associated with Favorable Outcome after HLA Matched Sibling SCT for Hematologic Malignancies
Authors: Stephan Mielke, Aarthi Shenoy, Vicki S. Fellowes, Katayoun Rezvani, Bipin N. Savani, Laura Musse, Laura Wisch, Roger Kurlander, Hanh Khuu, Carol Boss, A. John Barrett
Journal: Blood (2008)
Abstract 4928: MiR expression profiles can predict response to systemic treatment in patients with advanced colorectal cancer
Authors: Dennis Poel, Maarten Neerincx, Daoud L.S. Sie, Nicole C.T. van Grieken, R Shankaraiah, F. S.W. van der Wolf, J. H.T.M van Waesberghe, J. D. Burggraaf, Paul P. Eijk, Bauke Ylstra, Cees Verhoef, Mark A. van de Wiel, Henk M.W. Verheul, Tineke E. Buffart
Journal: Cancer Research (2016)

Abstract Background and aim: Patients with advanced colorectal cancer (mCRC) are commonly treated with systemic treatment consisting of fluoropyrimidine-based regimens being ineffective in 20-25% of the patients. Currently, selection criteria for patients to predict who will respond to this treatment is lacking. The aim of this study is to identify which patients will respond to first line fluoropyrimidine-based treatment based using microRNA (miR) expression profiles in order to avoid ineffective treatment. Material and methods: Total RNA was isolated from 88 fresh frozen colorectal cancer tissue samples consisting of ≥ 70% tumor cells, collected from patients with mCRC. MiR expression profiles were generated by next generation sequencing using the Illumina High Seq 2000 platform. Of all patients clinical and pathological data, including treatment response based on RECIST criteria, were collected. Class prediction and miR selection were performed using the GRidge package in R. Penalized selection and internal cross validation were used to select miRs predictive for treatment response. RESULTS: Next generation sequencing resulted in a mean of 10.087.107 (range 6.114.932 to 74.313.067) reads per sample corresponding to 2567 unique mature miR sequences, including 457 novel candidate and 2110 known miRs sequences (miRbase version 19). Penalized regression analysis on tumor specific miRs identified an expression profile which was predictive for clinical benefit (defined as response and stable disease) from first line treatment. Conclusion: With miR profiling of CRC tissue samples response prediction to first line fluoropyrimidine-based treatment in patients with mCRC is possible. We foresee that selection of treatment using miR expression profiling will avoid unnecessary treatment related toxicity and improve outcome for patients with mCRC Citation Format: Dennis Poel, Maarten Neerincx, Daoud L.S. Sie, Nicole C.T. van Grieken, R Shankaraiah, F. S.W. van der Wolf, J. H.T.M van Waesberghe, J. D. Burggraaf, Paul P. Eijk, Bauke Ylstra, Cees Verhoef, Mark A. van de Wiel, Henk M.W. Verheul, Tineke E. Buffart. MiR expression profiles can predict response to systemic treatment in patients with advanced colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4928.
Abstract 1361: Progress in light activatable prodrug for the combinational treatment of PDT and site-specific chemotherapy: paclitaxel prodrugs
Authors: Pritam Thapa, Mengjie Li, Moses Bio, Pallavi Rajaputra, Yajing Sun, Sukyung Woo, Youngjae You
Journal: Cancer Research (2016)

Abstract We developed the photoactivatable prodrug of Paclitaxel (PTX) for the combinational treatment of chemo and photodynamic therapy (PDT). PTX causes dose-limiting side effects as other anticancer drugs when administered systemically. On the other hand, PDT suffers from incomplete ablation and subsequent reoccurrence in part due to the short half-life and poor diffusion rate of singlet oxygen. We prepared a conjugate of PTX with phthalocyanine via a singlet oxygen cleavable linker, as a unique prodrug of PTX, to overcome the problems of PDT and systemic chemotherapy. The PTX prodrug was evaluated for tubulin polymerization, the release rate of PTX from prodrug upon illumination at 690 nm, stability in complete media, and the combination effect in killing ovarian cancer cells in vitro (SKOV-3). The PTX prodrug did not enhance the tubulin polymerization unlike PTX. While it was stable in the media under dark, it rapidly released PTX upon illumination with far-red light: &amp;gt; 90% release in 30 min. The prodrug showed much lower dark toxicity compared to PTX. When illuminated with 690 nm at 5.6 mW/cm2, the prodrug showed very potent phototoxicity: IC50 = 3.9 nM, through the combinational effect of PDT and PTX. In conclusion, we found that the PTX prodrug have desired properties as light-activatable prodrug expressing the combinational effect of PDT and local PTX chemotherapy. Animal study is underway to evaluate the antitumor effect of the PTX prodrug. Citation Format: Pritam Thapa, Mengjie Li, Moses Bio, Pallavi Rajaputra, Yajing Sun, Sukyung Woo, Youngjae You. Progress in light activatable prodrug for the combinational treatment of PDT and site-specific chemotherapy: paclitaxel prodrugs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1361.
The altered response of bone marrow derived endothelial progenitor cells from normal and heart failure rats to angiotensin-(1-7)
Authors: Cheng Qian, Anton J. Roks, Wiek H. van Gilst, Regien G. Schoemaker
Journal: Circulation (2006)

Background: Angiotensin-(1–7) [Ang-(1–7)] attenuates in-stent restenosis and improves endothelial function. Endothelial progenitor cells (EPCs) have been implicated in cardiovascular repair. We hyp...
240. A Recombinant Adenovirus Type 35 Fiber Knob Protein Sensitizes Lymphoma Cells to Rituximab Therapy
Journal: Molecular Therapy (2009)

Many tumors, including lymphomas, up-regulate expression of CD46 to escape destruction by complement. Tumor cells are therefore relatively resistant to therapy by monoclonal antibodies, which act through complement-dependent cytotoxicity (CDC). From an Escherichia coli expression library of adenovirus type 35 fiber knob mutants, we selected a variant (Ad35K++) that had a higher affinity to CD46 than did the natural Ad35 fiber knob. We demonstrated that incubation of lymphoma cells with recombinant Ad35K++ protein resulted in transient removal of CD46 from the cell surface. Preincubation of lymphoma cells with Ad35K++ sensitized cells to CDC, triggered by the CD20-specific monoclonal antibody rituximab. In xenograft models with human lymphoma cells, preinjection of Ad35K++ dramatically increased the therapeutic effect of rituximab. Blood cell counts and organ histology were normal after intravenous injection of Ad35K++ into mice that express human CD46. The presence of polyclonal anti-Ad35K++ antibodies did not affect the ability of Ad35K++ to enhance rituximab-mediated CDC in in vitro assays. The Ad35K++-based approach has potential implications in monoclonal antibody therapy of malignancies beyond the combination with rituximab.
Abstract 4465: Targeted disruption of HDAC3 induces terminal myogenic differentiation of embryonal rhabdomyosarcoma
Authors: Michael Phelps, Jenna Bailey, Terra Vleeshouwer-Neumann, Eleanor Chen
Journal: Cancer Research (2016)

Abstract Embryonal rhabdomyosarcoma (ERMS), one of the most common and lethal pediatric sarcomas, is characterized by an arrest in myogenic differentiation. We have previously shown that treatment of ERMS cells with pan histone deacetylase (HDAC) inhibitors promotes myogenic differentiation. However, the underlying mechanism specific to each HDAC in ERMS remains unknown. We have completed a high-efficiency CRISPR/Cas9 gene knockout screen of class I and II HDAC genes, revealing HDAC3 as a major driver of myogenic suppression in ERMS. HDAC3-deficient ERMS cells showed robust terminal myogenic differentiation with the formation of multinucleated myotubes. Expanding on our in vitro studies, we developed a novel tamoxifen-inducible CRISPR gene-targeting system in ERMS xenografts established in immune-compromised mice. Disruption of HDAC3 in vivo significantly suppressed tumor growth by inducing myogenic differentiation of ERMS cells. By combining inducible CRISPR gene targeting with HDAC3 structure-function analysis, we showed that HDAC3 functions in concert with the nuclear receptor co-repressor (NCOR1 and NCOR2) complex to regulate gene transcription. HDAC3/NCOR binding and HDAC3 deacetylase activity are both required for suppressing myogenic differentiation in ERMS. RNA sequencing analysis of differentially expressed genes in HDAC3-deficient ERMS cells highlighted key pathways dysregulated in ERMS. Our results suggest that epigenetic silencing of the myogenic program is a major mechanism required for ERMS tumor growth. Identification of the essential interaction between HDAC3 and the NCOR transcriptional repressor complex as well as downstream genes and pathways provides important insights into the biology of ERMS tumorigenesis. Our findings highlight potential new drug targets specific to the activity of HDAC3 in order to improve treatment of ERMS patients. Citation Format: Michael Phelps, Jenna Bailey, Terra Vleeshouwer-Neumann, Eleanor Chen. Targeted disruption of HDAC3 induces terminal myogenic differentiation of embryonal rhabdomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4465.
Abstract 1128: Role of STAT3 in pediatric sarcoma cell lines
Authors: Seethalakshmi Hariharan, Doris A. Phelps, Peter J. Houghton
Journal: Cancer Research (2016)

Abstract Signal transducer and activator of transcription-3 (STAT3) is a transcription factor that plays a major role in embryonic development, cell growth, differentiation and apoptosis. STAT3 becomes activated in the cytosol via phosphorylation at tyrosine-705 by JAK-1/2 kinases, in response to stimulation of either cytokine receptors or receptor tyrosine kinases. Phospho-STAT3 forms dimers, which then translocate into the nucleus to function as a transcription factor. Various pro-survival and anti-apoptotic genes including VEGF, Bcl-xL, Bcl-2 and survivin have been identified as STAT3 gene targets. Constitutive activation of STAT3 is observed in various cancers including breast, lung, pancreatic cancers and sarcomas. Since our studies indicate that STAT3 is upregulated in a number of pediatric sarcomas as well, we set out to understand the functional significance of STAT3 activation in these tumors in the context of tumor cell proliferation, survival, migration and resistance to apoptosis. High basal expression levels of phospho-STAT3 (Tyr705) were detected in a number of rhabdomyosarcoma, Ewing's sarcoma and osteosarcoma xenografts and cell lines. Interleukin-6 (IL-6) was capable of inducing STAT3 (Tyr705) phosphorylation in these cell lines in a time-dependent manner. On the other hand, stimulation with insulin-like growth factors-1 and 2 or IGF-1/2 resulted only in a weak induction in STAT3 phosphorylation during early timepoints. Treatment with a potent JAK-1/2 inhibitor, ruxolitinib suggested that STAT3 phosphorylation in these cell lines is dependent on JAK-1/2 activities. To understand the role of STAT3 in tumorigenesis, STAT3 was either knocked down using siRNAs or STAT3 phosphorylation was attenuated using ruxolitinib in sarcoma cell lines that express constitutively activated STAT3. Neither complete knockdown of STAT3, nor inhibition of STAT3 phosphorylation by ruxolitinib inhibited proliferation or decreased survival. These results indicate that activation of STAT3 may not have a significant role in tumor cell proliferation and survival under culture conditions. However, STAT3 inhibition resulted in decreased cell migration implicating STAT3 in regulation of tumor cell migration and invasion. Overall, our data demonstrates a role for STAT3 activation in sarcoma cell migration and invasion and we speculate that targeting STAT3 might serve as a useful therapeutic approach to control tumor invasion and metastasis. Supported by USPHS grant CA165995. Citation Format: Seethalakshmi Hariharan, Doris A. Phelps, Peter J. Houghton. Role of STAT3 in pediatric sarcoma cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1128.