tbuckley/cabot-search huggingface dataset:
Abstract 3827: Preclinical characterization of DCR-BCAT as a component of combination therapy
Authors: Shanthi Ganesh, Wendy Cyr, Martin Koser, Girish Chopda, Edmond Chipumuro, Zakir Siddiquee, Kevin Craig, Serena Shui, Dongyu Chen, Cheng Lai, Hank Dudek, Weimin Wang, Bob Brown, Marc Abrams
Journal: Cancer Research (2016)

Abstract Dicer-substrate siRNAs (DsiRNAs) are a potent class of RNA interference (RNAi) triggers capable of silencing any expressed mRNA with high specificity. DCR-MYC, a first-in-class DsiRNA targeting the MYC oncogene is currently in Phase 1b/II clinical trials [ASCO 2015, abstract 11006]. DCR-BCAT is an advanced preclinical development candidate that targets CTNNB1, the gene which encodes β-catenin. The β-catenin/Wnt pathway is consistently activated in human tumors, including &amp;gt;50% of hepatocellular carcinomas (HCC) and &amp;gt;80% of colorectal cancers (CRC). Robust preclinical and genetic evidence strongly suggests that inhibiting β-catenin function would yield broad therapeutic benefit in oncology, but efforts to target it using conventional drug modalities have been unsuccessful to-date. We have previously reported extensive preclinical pharmacology for DCR-BCAT in mouse tumor models of diverse origin. Here, we explore DCR-BCAT as a monotherapy and in combination with both standard-of-care and experimental therapeutics. Interestingly, when mice bearing HCC tumors were treated with a combination of CTNNB1 and MYC DsiRNAs, the antitumor efficacy was additive or synergistic relative to either single agent alone. Additionally, since up to 50% of colorectal tumors have both activated Wnt signaling and mutant KRAS, we also explored combination therapy of DCR-BCAT and FDA-approved MEK inhibitors. A major advantage of DCR-BCAT is that the improved nanoparticle formulation is more selective for siRNA delivery to tumors over liver and other normal tissues. These data support continued development of DCR-BCAT as a first-in-class RNAi therapeutic, and highlight the potential for use in combination with other promising agents. Citation Format: Shanthi Ganesh, Wendy Cyr, Martin Koser, Girish Chopda, Edmond Chipumuro, Zakir Siddiquee, Kevin Craig, Serena Shui, Dongyu Chen, Cheng Lai, Hank Dudek, Weimin Wang, Bob Brown, Marc Abrams. Preclinical characterization of DCR-BCAT as a component of combination therapy. [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 3827.
Coated minispheres of salmon calcitonin target rat intestinal regions to achieve systemic bioavailability: Comparison between intestinal instillation and oral gavage
Authors: Tanira A.S. Aguirre, Vincenzo Aversa, Mónica Rosa, Sílvia S. Guterres, Adriana R. Pohlmann, Ivan Coulter, David J. Brayden
Journal: Journal of Controlled Release (2016)
Dose MTX-based chemotherapy followed by consolidating radiotherapy in Non-Aids related Primary Central Nervous System Lymphoma.
Authors: JC Kluin-Nelemans, P Poortmans, H Haaxma-Reicher, MB van't Veer, M Hansen, MJ Taphoorn, P Soubeyran, M Fickers, OJ Loosveld, HT Roerdink, MJ van den Bent, GW van Imhoff, [No Value] Teodorovic, C Rozewicz, MM Van Glabbeke, JM Raemaekers
Journal: Blood (2002)
Abstract 291: Single cell analyses reveal resistance heterogeneity in EGFR mutant NSCLC
Authors: Matt J. Niederst, Huidan Zhang, Haichuan Hu, Naiwen Cui, Yamei Cai, Hillary Mulvey, Zofia Piotrowska, Lecia Sequist, David A. Weitz, Jeffrey A. Engelman
Journal: Cancer Research (2016)

Abstract In EGFR mutant lung adenocarcinomas, the activating mutation to EGFR is the founder alteration, present in every cancer cell. Most patients with this genetic alteration respond to EGFR tyrosine kinase inhibitors, although the average duration of the response is only one year before the cancer develops acquired resistance. Efforts to identify the mechanisms underlying the resistance in patients have led to the identification of a resistance mechanism in the majority of cases. However, preliminary data is emerging indicating that multiple resistance mechanisms can be present within an individual patient's disease, and thus, classifying resistant disease with a single mechanism is an oversimplification. Here, utilizing single cell approaches on patient samples, we demonstrate heterogeneity within individual biopsies with respect to resistance mechanisms, epigenetic state, and sensitivity to TKI. Additionally, we observe that the fraction of T790M-positive cells is predictive of response to 3rd generation EGFR inhibitor treatment, suggesting that the degree of heterogeneity has important clinical implications. As therapies designed to target singular resistance mechanisms become more widely implemented, assessing heterogeneity will become increasingly critical in order to choose the most effective therapy for the patient. Citation Format: Matt J. Niederst, Huidan Zhang, Haichuan Hu, Naiwen Cui, Yamei Cai, Hillary Mulvey, Zofia Piotrowska, Lecia Sequist, David A. Weitz, Jeffrey A. Engelman. Single cell analyses reveal resistance heterogeneity in EGFR mutant NSCLC. [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 291.
Dynamic<i>O</i>-(2-<sup>18</sup>F-fluoroethyl)-L-tyrosine positron emission tomography differentiates brain metastasis recurrence from radiation injury after radiotherapy
Authors: Garry Ceccon, Philipp Lohmann, Gabriele Stoffels, Natalie Judov, Christian P Filss, Marion Rapp, Elena Bauer, Christina Hamisch, Maximilian I Ruge, Martin Kocher, Klaus Kuchelmeister, Bernd Sellhaus, Michael Sabel, Gereon R Fink, Nadim J Shah, Karl-Josef Langen, Norbert Galldiks
Journal: Neuro-Oncology (2016)

The aim of this study was to investigate the potential of dynamic O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET for differentiating local recurrent brain metastasis from radiation injury after radiotherapy since contrast-enhanced MRI often remains inconclusive.Sixty-two patients (mean age, 55 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 76) on MRI after radiotherapy of brain metastases (predominantly stereotactic radiosurgery) were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) of 18F-FET uptake were determined (20-40 min postinjection) as well as tracer uptake kinetics (ie, time-to-peak and slope of time-activity curves). Diagnoses were confirmed histologically (34%; 26 lesions in 25 patients) or by clinical follow-up (66%; 50 lesions in 37 patients). Diagnostic accuracies of PET parameters for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or the chi-square test.TBRs were significantly higher in recurrent metastases (n = 36) than in radiation injuries (n = 40) (TBRmax 3.3 ± 1.0 vs 2.2 ± 0.4, P < .001; TBRmean 2.2 ± 0.4 vs 1.7 ± 0.3, P < .001). The highest accuracy (88%) for diagnosing local recurrent metastasis could be obtained with TBRs in combination with the slope of time-activity curves (P < .001).The results of this study confirm previous preliminary observations that the combined evaluation of the TBRs of 18F-FET uptake and the slope of time-activity curves can differentiate local brain metastasis recurrence from radiation-induced changes with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases.
Relief of severe cancer pain by subarachnoid analgesia in a young patient with peritonitis carcinomatosa of gastric cancer, allowing him to share the birth of his first daughter
Authors: Hiroyuki Tabuse, Toshiyuki Kuriyama, Naoki Shingaki, Naoki Fukuda, Tomoyuki Maruyama, Takao Maekita, Mikitaka Iguchi, Hideyuki Tamai, Jun Kato, Masao Ichinose
Journal: Annals of Oncology (2015)
Abstract 2528: Mechanism and role ofSOX2repression in human germline specification
Authors: Kushwaha Ritu, Nirmala Jagadish, George Bosl, Raju Chaganti
Journal: Cancer Research (2016)

Abstract The core pluripotency regulatory master transcription factor SOX2 is repressed in human primordial germ cells (PGCs) and in the seminoma (SEM) subset of human germ cell tumors (GCTs), which arises by transformation of PGCs. Neither the mechanism of this repression not its significance to GC and GCT development have so far been clarified. Here we show that SOX2 repression in TCam-2 SEM cells is mediated by the presence of the Polycomb repressive complex (PcG) and by the H3K27me3 chromatin mark at the SOX2 transcription start site. Moreover, repression can be abrogated by recruitment of the H3K27 demethylase UTX to the SOX2 promoter through retinoid signaling. SOX2-activated TCam-2 cells express neuronal and other lineage genes, consistent with the gene's function as a neurectodermal effector. Based on the recent discovery that SOX17 initiates human PGC specification, with its downstream target PRDM1 acting to suppress mesendodermal genes, we propose that SOX2 repression is required for PGC specification to suppress neuroectodermal genes. Overt pluripotency is initiated in latently pluripotent transformed PGCs presenting as the SOX2 upregulated embryonal carcinoma (EC) subset of GCTs; by gene expression profiling analysis we characterize the functional pathways that distinguish PGC-like unipotent SEM from blastocyst-like pluripotent EC. Citation Format: Kushwaha Ritu, Nirmala Jagadish, George Bosl, Raju Chaganti. Mechanism and role of SOX2 repression in human germline specification. [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 2528.
External validation of nomogram to predict progression-free survival at 6 months (PFS6) in patients receiving salvage therapy for advanced urothelial carcinoma (UC).
Authors: Guru Sonpavde, Joaquim Bellmunt, Ronan Fougeray, Yacine Salhi, Gregory Russell Pond
Journal: Journal of Clinical Oncology (2014)

4542 Background: A nomogram incorporating baseline prognostic factors has been reported to facilitate the evaluation of activity of salvage therapy for advanced UC (Pond GR, BJUI 2013). We performed an external validation in a phase III trial dataset. Methods: Data were obtained for patients randomized to vinflunine in the phase III trial comparing best supportive care +/- vinflunine. Progression-free survival at 6 months (PFS6) as well as the 4 prognostic factors: hemoglobin (Hb), performance status (PS), liver metastasis (LM) and time from prior chemotherapy (TFPC) were analyzed. Patients were grouped based on nomogram score and risk groups. Bootstrap analysis was performed and 95% bias-corrected and accelerated [BCa] CI were calculated. Results: Of 253 patients, 5 had missing TFPC and were excluded; thus, 248 were evaluable (Table). The number of nomogram points as a continuous variable was associated with PFS6 (odds ratio [OR]=1.10, 95% confidence interval [CI] = 1.05 to 1.15 / 10 point increase, c-index=0.680, p<0.001). Risk group was also significantly associated with PFS6 (OR=0.51, 95% CI=0.37 to 0.70 / increase in risk group, c-index=0.674, p<0.001). 95% BCa CI were calculated for the c-index (0.602 to 0.747) and for the estimated odds ratio (0.37 to 0.70). Conclusions: This external validation confirms the utility of the previously reported nomogram to predict PFS6 with salvage therapy in advanced UC. The nomogram is a useful tool to estimate the required minimal efficacy of agents in phase II trials to justify further investigation. N (%) N (%) with PFS ≥6 months p-value All patients 248 63 (25.4) PS 0 ≥1 72 176 (71.0%) 26 (36.1) 37 (21.0) 0.016‡ LM No Yes 177 71 (28.6%) 56 (31.6) 7 (9.9) <0.001‡ Hb ≥10 g/dL <10 g/dL 212 36 (14.5%) 58 (27.4) 5 (7.9) 0.10‡ TFPC ≥6 months <6 months 74 174 (70.2%) 26 (35.1) 37 (21.3) 0.026‡ Risk factors 0 1 2 3 4 25 (10.1) 66 (26.6) 86 (34.7) 65 (26.2) 6 (2.4) 12 (48.0) 23 (34.9) 21 (24.4) 7 (10.8) 0 (0.0) <0.001† Nomogram estimated risk >30% 20-29.9% 10-19.9% 5-9.9% <5% 49 (19.8%) 75 (30.2%) 76 (30.7%) 43 (17.3%) 5 (2.0%) 23 (46.9) 21 (28.0) 15 (19.7) 4 (9.3) 0 (0.0) <0.001† † Cochran-Armitage test for trend. ‡ Fisher’s exact test.
Impact of Enzalutamide Compared with Bicalutamide on Quality of Life in Men with Metastatic Castration-resistant Prostate Cancer: Additional Analyses from the TERRAIN Randomised Clinical Trial
Authors: Axel Heidenreich, Simon Chowdhury, Laurence Klotz, David Robert Siemens, Arnauld Villers, Cristina Ivanescu, Stefan Holmstrom, Benoit Baron, Fong Wang, Ping Lin, Neal D. Shore
Journal: European Urology (2016)
Case 5-1971
Authors: Richard C. Cabot, Benjamin Castleman, Betty U. McNeely, Robert P. McCombs, Harold F. Dvorak
Journal: New England Journal of Medicine (1971)

Presentation of CaseA 34-year-old woman was admitted to the hospital because of a rash.Fourteen years previously asthma developed, and she came to the Medical Clinic. On each of several visits the blood pressure was normal except on one occasion, when it was 145 systolic, 105 diastolic. The white-cell count was 19,800, with 63 per cent neutrophils, 3 per cent band forms, 16 per cent lymphocytes, 6 per cent monocytes and 12 per cent eosinophils. Skin tests for multiple common antigens were negative. A mixture of theophylline, ephedrine and phenobarbital was prescribed, together with penicillin and potassium iodide. Erythematous . . .
Abstract 2970: MEDI4276, a HER2-targeting antibody tubulysin conjugate, displays potent in <i>vitro</i> and <i>in vivo</i> activity in preclinical studies
Authors: John Li, Dorin Toader, Samuel R. Perry, Vanessa Muniz-Medina, Leslie Wetzel, Marlon C. Rebelatto, Mary Jane Masson Hinrichs, Ryan Fleming, Binyam Bezabeh, Pamela Thompson, Nazzareno Dimasi, Brandon Lam, Xian-Qing Yu, Changshou Gao, Rakesh Dixit, Steven Coats, Jane Osbourn, Herren Wu
Journal: Cancer Research (2016)

Abstract Antibody drug conjugates (ADCs) combine the specificity of antibodies with the potent cytotoxicity of small molecule drugs and have shown to provide therapeutic options for various cancers. We report herein the discovery of a HER2-targeting ADC MEDI4276 that showed potent cell killing activity in vitro in cancer cell lines that express the HER2 receptor. The observed in vitro activity translated into in vivo tumor growth inhibition in various xenograft mouse models. MEDI4276 is a homogeneous molecule with precise control of drug loading following site specific conjugation of a cytotoxic drug. The drug in MEDI4276 is MMETA, a fully synthetic analog of the tubulysin family that showed pM potency in a panel of cancer cell lines. MMETA was conjugated to the antibody via engineered cysteines with a maleimide-bearing mc-Lys protease cleavable linker. The antibody in MEDI4276 is a bivalent biparatopic antibody targeting two distinct non-overlapping epitopes on HER2 that leads to antibody-receptor clustering following binding and thus promoting internalization, lysosomal trafficking and degradation. The combination of enhanced internalization and potent cytotoxic drug allows for this ADC to kill tumor cell populations with a broader range of HER2 expression. Preclinical studies showed that MEDI4276 induced tumor regression in HER2-positive tumor models that had developed acquired resistance to T-DM1 and in a number of models with lower HER2 expression that are refractory to T-DM1 treatment. Overall, our findings underscore the potential application of MEDI4276 to treat a large patient population that is ineligible for or relapsed/refractory to current HER2-targeted therapies. MEDI4276 is currently being investigated in a Phase I clinical trial. Citation Format: John Li, Dorin Toader, Samuel R. Perry, Vanessa Muniz-Medina, Leslie Wetzel, Marlon C. Rebelatto, Mary Jane Masson Hinrichs, Ryan Fleming, Binyam Bezabeh, Pamela Thompson, Nazzareno Dimasi, Brandon Lam, Xian-Qing Yu, Changshou Gao, Rakesh Dixit, Steven Coats, Jane Osbourn, Herren Wu. MEDI4276, a HER2-targeting antibody tubulysin conjugate, displays potent in vitro and in vivo activity in preclinical studies. [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 2970.
Abstract 1131: Uncovering oncogenic KRAS allele specific phenotypes using an isogenic MEF cell line system
Authors: Nicole Fer, Brian Smith, Leslie Garvey, William Burgan, Katie Powell, Kanika Sharma, Andrew Waters, Xiaolin Wu, Dan Soppet, Robert Stephens, Dwight Nissley, Matthew Holderfield, Rachel K. Bagni
Journal: Cancer Research (2016)

Abstract The RAS Initiative at the Frederick National Laboratory has generated an isogenic mouse embryonic fibroblast (MEFs) cell line panel containing single transgene alleles using the RAS-less MEF system developed by Matthias Drosten and Mariano Barbacid (CNIO). These MEFs are H, N and K-RAS null, growth is dependent on exogenous RAS or MAPK pathway activation. The panel includes: KRAS 4A WT, KRAS 4B WT, KRAS 4B G12C, G12D, G12V, G13D, Q61L, Q61R, HRAS WT, NRAS WT or BRAF V600E. The workflow to generate the lines requires cre-lox removal of endogenous KRAS and the cells arrest in the G1 phase of the cycle. Proliferation is resumed through the delivery of the transgene to the cells using lentiviral transduction. Clonal cell lines are derived from the initial pools and are thoroughly characterized including confirmation of endogenous KRAS gene removal, identification of the transgene insertion site(s), calculation of proliferation rates and doubling times, analysis of signaling pathways, response to tool compounds and exome sequenced to exclude lines with mutations in onco-relevant genes. This panel is a unique resource that can be used to ask allele and isoform specific questions (gene expression profiles, GTP-loading, etc.) and screen for RAS inhibitors as well as determine novel compound specificity. This panel is available to the academic RAS research community. Citation Format: Nicole Fer, Brian Smith, Leslie Garvey, William Burgan, Katie Powell, Kanika Sharma, Andrew Waters, Xiaolin Wu, Dan Soppet, Robert Stephens, Dwight Nissley, Matthew Holderfield, Rachel K. Bagni. Uncovering oncogenic KRAS allele specific phenotypes using an isogenic MEF cell line system. [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 1131.
Abstract 4089: Thyroid tumor microenvironment: mutual interaction between cancer and inflammatory cells
Authors: Neha Yashpal Tuli, Robert B. Bednarczyk, Ghada M. Ben Rahoma, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari
Journal: Cancer Research (2016)

Abstract Thyroid cancer is the most prevalent endocrine malignancy in the United States with an unacceptably high recurrence rate of 20-30%. Tumor associated macrophages (TAMs), one of the most critical component of solid tumor microenvironments, promote cancer initiation, growth, progression, metastasis and angiogenesis. These TAMs release cytokines as well as other secretory components like exosomes in the tumor microenvironment. Previously, we found that M1 polarized TAMs modulate thyroid cancer phenotype by inducing epithelial-mesenchymal transition (EMT), facilitating tissue metastasis and dissemination. In our present study, we used an in vitro model system to assess the crosstalk between the secretory components of macrophages and the epithelial cells in the thyroid tumor microenvironment. We used THP-1 monocyte/macrophage cell line along with thyroid cancer cell lines: consisting of two papillary cancer cell lines (BCPAP and TPC-1), one anaplastic cancer cell line (8505C) and one follicular cancer cell line (CGTHW-1). We observed that activated THP-1 macrophages are polarized towards M1 phenotype, secreting pro-inflammatory cytokines such as TGF-β, IL6, TNF-α, IL-1β, amongst others. These cytokines are responsible for halt in proliferation and change in morphology to mesenchymal phenotype promoting EMT in thyroid cancer cells. Similar pattern in phenotypical changes were noted in thyroid cancer cells treated with activated THP-1 macrophage exosomes. We also observed that EMT markers, such as vimentin and NFκ-B, are modulated in response to activated macrophage secreted exosomes. Moreover, secretory components from anaplastic thyroid cancer cells led to enhanced activation of THP-1 cells. These findings support a mutual cooperation between thyroid cancer cells and inflammatory cells in tumor microenvironment in defining thyroid cancer phenotype. Such correlation can identify early markers and prevent thyroid cancer differentiation, and are putative targets for therapy. Citation Format: Neha Yashpal Tuli, Robert B. Bednarczyk, Ghada M. Ben Rahoma, Augustine Moscatello, Jan Geliebter, Raj K. Tiwari. Thyroid tumor microenvironment: mutual interaction between cancer and inflammatory cells. [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 4089.
ZAP-70 Enhances BCR Signaling and Migration of Malignant B Lymphocytes towards CCL21 Via Induction of CCR7 Expression
Authors: Eva Calpe, Maria Joao Baptista, Carles Codony, Neus Villamor, Pau Abrisqueta, Olga Salamero, Pere Barba, Mercedes Gironella, Noelia Purroy, Marta Crespo, Francesc Bosch
Journal: Blood (2010)
Single Arm, Multi-Center, Phase II Study Of Clofarabine In Chinese Pediatric Patients With Refractory Or Relapsed Acute Lymphoblastic Leukemia
Authors: Leping Zhang, Xin Du, Yan Li, Zhen Cai, Kang Yu, Fenlai Tan, Yi Fang, Xiaojun Huang, Jin Lu
Journal: Blood (2013)
Is rehabilitation post critical illness a new anti-inflammatory agent?
Authors: Doug Elliott, Zudin Puthucheary
Journal: Thorax (2016)

Physical recovery following a critical illness is important for patients, family and clinicians.1–3 However, there is limited beneficial effect demonstrated from the intervention studies that have investigated physical rehabilitation across the continuum of critical illness recovery, starting in the intensive care unit (ICU) and continuing to the community setting with home-based rehabilitation and follow-up clinics4–8 What is the reason for this lack of treatment effect? As with all trials that show a lack of effect, we must consider a number of factors, including the intervention delivered, the target population and the outcome measure used.

In the recent RECOVER trial,8 there was an improvement in the functional status of patients following critical illness, as evidenced by the Rivermead Mobility Index (RMI); however, the delivery of a post-ICU bundled therapies intervention did not enhance the physical outcome over and above the normal trajectory of recovery. As there was clear demonstration that the treatment was delivered, this raises the question of whether the target population was appropriate and, in particular, whether we can identify cohorts of patients that are more or less likely to respond to rehabilitation treatment.

In Thorax , Griffith et al 9 report an a …