tbuckley/cabot-search huggingface dataset:
Abstract 4975: Detection and characterization of circulating and disseminated tumor cells in patients with bladder and prostate cancer
Authors: James E. Verdone, Emma E. van der Toom, Kenneth J. Pienta, Michael A. Gorin
Journal: Cancer Research (2016)

Abstract Introduction: Increasing evidence suggests that cancer cells display dynamic molecular changes in response to systemic therapy. Circulating tumor cells (CTCs) in the peripheral blood and disseminated tumor cells (DTCs) in bone marrow represent a readily available source of cancer cells with which to measure this dynamic process. To date, many strategies to isolate and characterize these cells have been described. These techniques, however, have been limited by the requirement for positive or negative selection thus resulting in cell losses. Herein we report a method to detect and characterize CTCs and DTCs in matched peripheral blood and bone marrow samples without need for a selection step. Methods: Following blood or bone marrow aspirate collection, nucleated cells were extracted using a modified density-media centrifugation technique. Nucleated cells were spread on positively charged slides and stained with epithelial markers (Pan-cytokeratin and EpCAM) and a leukocyte marker CD45. High throughput scanning microscopy was performed followed by image processing and subsequent ranking for probability of being a cancer cell. Candidate cancer cells were defined as events which were positive for PanCK and/or EpCAM but negative for CD45. Candidate cells were independently confirmed with high resolution microscopy. Results: Cytokeratin-positive, EpCAM-positive DTCs and CTCs were readily detectable in patients with clinically-localized bladder and prostate cancer without need for positive or negative selection. Conclusions: Future work aims to incorporate disease specific makers to confirm that the observed cells truly represent cells of either bladder or prostate origin. This method offers the flexibility to preserve samples for downstream molecular assays including single cell isolation and sequencing. All told, this assay provides a novel means to detect and characterize CTCs and DTCs without positive or negative selection methods. Citation Format: James E. Verdone, Emma E. van der Toom, Kenneth J. Pienta, Michael A. Gorin. Detection and characterization of circulating and disseminated tumor cells in patients with bladder and prostate 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 4975.
Abstract 1842: Overexpressing human endogenous retroviral elements (HERVs) in chemorefractory colorectal adenocarcinoma cells are repressed by antiviral drugs
Authors: David Diaz-Carballo
Journal: Cancer Research (2016)

Abstract Background: HERVs account for ca. 8% of all transposable elements found in the genome of humans and other animals. They represent a genetic footprint of ancestral germ-cell infections of exoviruses that is transmittable to the progeny by Mendelian segregation. Traces of human endogenous retroviruses are physiologically expressed in ovarial, testicular and placental tissues as well as in stem cells. In addition, a number of these fossil viral elements have also been related to carcinogenesis. However, a relation between endoretroviruses expression and chemoresistance has not been reported yet. Methods: Twenty colorectal carcinoma patient samples were analyzed for HERV-WE1 and HERV-FRD1 endoretroviruses using immunohistochemical approaches. In addition, to examine for differential expression of HERVs in chemotherapy refractory cells, a resistant HCT8 colon carcinoma subline was developed by serial etoposide exposure. Endoretroviral elements were detected by immunocytochemical staining, qPCR and ELISA. IC50-values of antiviral and cytostatic drugs in HCT8 cells were determined by MTT proliferation assay. The antivirals-cytostatics interaction was evaluated by the isobologram method. Results: In this work, we show for the first time that HERV-WE1, HERV-FRD1, HERV-31, and HERV-V1 are a) simultaneously expressed in treatment-naïve colon carcinoma cells from patients and b) upregulated after cytostatic exposure in colon-cancer cell lines, suggesting that these retroviral elements are intimately related to chemotherapy resistance. A number of antiviral drugs showed not only cytotoxic activity but also downregulation of HERV proteins in vitro. We also demonstrate that the use of different antiviral compounds alone or in combination with anticancer agents present synergistic antiproliferative activity and downregulation of different endoretroviral elements in highly chemotherapy-resistant colorectal tumor cells. Conclusions: Enhanced HERV-expression is associated with chemo-resistance in colon carcinoma cells which can be repressed by antiviral drugs alone or in combination with anticancer drugs. Therefore, the introduction of antiviral compounds to antiproliferative chemotherapy regimens potentially improves patient outcomes. Citation Format: David Diaz-Carballo. Overexpressing human endogenous retroviral elements (HERVs) in chemorefractory colorectal adenocarcinoma cells are repressed by antiviral drugs. [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 1842.
Treatment intensification by induction chemotherapy (ICT) and radiation dose escalation in locally advanced squamous cell anal canal carcinoma (LAAC): Definitive analysis of the intergroup ACCORD 03 trial
Authors: T. Conroy, M. Ducreux, C. Lemanski, E. Francois, M. Giovannini, F. Cvitkovic, X. Mirabel, O. Bouché, C. Montoto-Grillot, D. Peiffert
Journal: Journal of Clinical Oncology (2009)

4033 Background: Concomitant radiochemotherapy (CRT) is the standard treatment of LAAC. The addition of an ICT (2 cycles of 5 FU-Cisplatin) and of a higher dose of irradiation boost (HDRT) to CRT were evaluated in a factorial 2X2 arms trial (A= ICT; B=ICT+HDRT; C= Reference arm = Pelvic RT 45 Gy/25 fractions with 2 cycles of 5FU-Cisplatin and a boost of 15 Gy; D= HDRT). The aim of the study was to detect a increase from 70 to 85% of colostomy-free survival (CFS) at 3 years. Methods: 307 pts with T2 &gt; 4 cm or T3-T4 Nx or any T, N1–3 M0 LAAC were included. Mean age was 59 y and sex-ratio was 1/6. The 4 arms were well balanced concerning the sex-ratio, age, stage, T size and differentiation. Results: 306/307 pts were eligible. Toxicities were similar in the 4 arms (toxic deaths: A=4, B=2, C=2, D=1). The compliance was: 99% for ICT, 100% for pelvic RT-CT, and 96% for the boost. The tumour complete response (+ partial response) at 2 months were: A=78% (+18%), B=86% (+13%), C=74% (+21%), D=74 % (+22%) (NS). The median follow-up was 43 months. Overall failure rates were 28% (A=28%, B=21%, C=30%, D= 30%). The actuarial results at 3 years were: CFS was 83%: A= 83%, B= 85%, C= 86%, D= 80% with no significant difference of ICT nor HDRT (A+B=84% vs C+D=83% for ICT; A+C= 84% vs B+D=83% for HDRT). Local control was 88%: A= 80%, B= 96%, C= 90 %, D= 87%: (NS). Event-free survival was 71% : A= 70%, B= 78%, C= 67%, D= 68%: (NS). Overall survival was 78% at 3 y (73% at 5 y) with no difference between arms. Specific survival was 84 % : A= 79%, B= 88,5%, C= 89%, D= 79%: (NS) Conclusions: Neither ICT nor HDRT improved the CFS at 3 years, nor the secondary end points. No significant financial relationships to disclose.
S0536: Carboplatin, paclitaxel, cetuximab, and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung cancer (NSCLC): A SWOG phase II study
Authors: D. Gandara, E. S. Kim, R. S. Herbst, J. Moon, M. W. Redman, S. R. Dakhil, F. Hirsch, P. C. Mack, W. Franklin, K. Kelly
Journal: Journal of Clinical Oncology (2009)

8015 Background: Cetuximab (CX) plus platinum-based chemotherapy improves overall survival (OS) in advanced NSCLC (FLEX). SWOG previously showed that EGFR FISH is associated with efficacy outcomes in patients (pts) receiving CB/P/CX (S0342). Bevacizumab (B) plus chemotherapy also increases survival (E4599) in eligible pts. Given the biologic rationale for combining EGFR and VEGFR targeted agents, S0536 investigated the safety and efficacy of carboplatin (CB), paclitaxel (P) and CX plus B. Methods: Eligibility: treatment-naïve advanced stage non-squamous cell NSCLC, no requirement for EGFR positivity, PS 0–1, no brain metastases or hemoptysis. Treatment: CB AUC 6, P 200 mg/m 2 , B 15 mg/kg IV day 1 every 3 weeks, CX 400 mg/m 2 day 1 then 250 mg/m 2 weekly for up to 6 cycles; then B 15 mg/kg every 3 weeks and CX 250 mg/m 2 weekly until progression. Primary endpoint: feasibility defined by the frequency and severity of ≥grade 4 hemorrhagic toxicities. Secondary endpoints: response rate, progression-free survival (PFS), OS and toxicity. Results: 110 pts enrolled from August 2006 to September 2007; 104 assessable. Pt characteristics: median age 64 years (42–78), Male/Female 52/52, PS 0/1 43/61, stage IIIB/IV 9/95, adenocarcinoma: 81, current/former smoker: 82. Overall toxicities were acceptable and comparable to S0342 and E4599. Primary endpoint was met: grade ≥4 hemorrhage: 2% (95% CI: 0–7%). There were 4 treatment-related deaths: lung hemorrhage (2), infection (1), unknown (1). Partial response (PR): 51/95 assessable (54%; 43%-64%); Stable disease (SD): 22/95 (23%). Disease control rate (PR+SD): 77%. With median follow up of 15 months (mos), PFS is 7 mos (18 pts remain progression-free) and OS is 14 mos. 1 year survival is 57% (47–67%). EGFR IHC by H score (&gt;0 vs 0) showed a nonsignificant trend toward improved survival: 15 vs 11 mos (p=0.14). Conclusions: CB/P, CX plus B demonstrates safety, tolerability and efficacy in advanced NSCLC and is the most active regimen studied to date in SWOG. Additional S0536 biomarker studies including EGFR FISH will be presented. S0819, a Phase III trial of CB/P ± CX (plus B in eligible pts) is under development and is designed to validate EGFR FISH as a predictive biomarker. [Table: see text]
Light-Chain Nephropathy
Journal: New England Journal of Medicine (1976)

On decrit 2 cas d'atteinte renale provoquee par le depot de determinants monoclonaux de chaines legeres d'immunoglobulines dans le mesangium et les membranes basales glomerulaires ainsi que dans les membranes basales tubulaires des reins (nephropathie des chaines legeres). Les 2 cas etaient associes a un myelome. Le diagnostic differentiel en microscopie electronique comprend la glomerulosclerose diabetique, l'amyloidose et la glomerulonephrite mesangiocapillaire type 1
Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an analysis from the St Jude Lifetime Cohort Study
Authors: Nickhill Bhakta, Qi Liu, Frederick Yeo, Malek Baassiri, Matthew J Ehrhardt, Deo K Srivastava, Monika L Metzger, Matthew J Krasin, Kirsten K Ness, Melissa M Hudson, Yutaka Yasui, Leslie L Robison
Journal: The Lancet Oncology (2016)
A brief history of the discovery of PXR and CAR as xenobiotic receptors
Authors: Jiong Yan, Wen Xie
Journal: Acta Pharmaceutica Sinica B (2016)

The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) were cloned and/or established as xenobiotic receptors in 1998. Due to their activities in the transcriptional regulation of phase I and phase II enzymes as well as drug transporters, PXR and CAR have been defined as the master regulators of xenobiotic responses. The discovery of PXR and CAR provides the essential molecular basis by which drugs and other xenobiotic compounds regulate the expression of xenobiotic enzymes and transporters. This article is intended to provide a historical overview on the discovery of PXR and CAR as xenobiotic receptors.
London 2012 relived
Authors: Gareth Iacobucci
Journal: BMJ (2016)

With the Rio Olympics kicking off on 5 August, NHS staff who volunteered at the London 2012 Olympic games are reminded of their experience of the opening ceremony, with its sequence celebrating the NHS, complete with dancing doctors and nurses. 

Joe Cosgrove, a consultant in anaesthesia and intensive care at Freeman Hospital in Newcastle upon Tyne, volunteered as a crowd doctor that night and throughout the games. His role was to respond to any illness or injury within the crowd during the events, supported by a team of nurses and other staff.

“It’s something I’m very proud of,” he tells The BMJ . “Everyone was blown away by the opening ceremony and I think it lifted everybody.

“It reinforced your …
Abstract 4381: High-throughputin vivosystems biology using implantable microdevices
Authors: Oliver Jonas
Journal: Cancer Research (2016)

Abstract We have developed an implantable device that can perform drug sensitivity testing of a large number of anti-cancer drugs inside the living tumor. This device contains reservoirs which release microdoses of single agents or drug combinations into distinct spatial regions of the tumor in local concentrations that are representative of concentrations achieved during systemic drug treatment. The efficacy of each of up to 30 individual drugs or combinations can be assessed from a single specimen without systemic drug exposure through minimally invasive biopsy. This assay takes into consideration physiologic effects that contribute to drug response by allowing drugs to interact with the living tumor in its native microenvironment. Using this technology, we have been able to assess phenotypic drug response for up to 100 therapies in a single mouse, probing all clinically relevant single and combination treatments related to the estrogen receptor, CDK4/6 and PI3K pathways in ER+ PDX mouse models. We also examined a range of targeted and cytotoxic drug therapies in parallel before, during and after systemic drug treatments to investigate emerging drug resistance at the phenotypic level in BRAF-mutant melanoma models. The results demonstrate new patterns of escape and adaptive signaling mechanisms, and may offer clues for effective combination therapy. Citation Format: Oliver Jonas. High-throughput in vivo systems biology using implantable microdevices. [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 4381.
Abstract 223: Comparison of human-specific versus cross-reactive Complex I inhibitor for in vivo tumor efficacy
Authors: Sven Christian, Carolyn Algire, Wolfgang Schwede, Jeffrey S. Mowat, Alexander Ehrmann, Stephan Menz, Marcus Bauser, Andrea Haegebarth
Journal: Cancer Research (2016)

Abstract Mitochondria are both key regulators of energy supply and apoptotic cell death. The mitochondrial electron transport chain (ETC) consists of four enzyme complexes that transfer electrons from NADH to oxygen. During electron transfer, the ETC (Complex I to IV) pumps protons into the inter-membrane space, generating a gradient across the inner mitochondrial membrane that is used by Complex V to drive ATP synthesis. Recent publications have shown that tumor cells harboring specific mutations (LKB1, mIDH and others) are more sensitive to Complex I inhibition, compared to cells that do not have these mutations. We have identified an optimized human/mouse cross-reactive Complex I inhibitor that allows profiling of Complex I inhibitors in pharmacological models. We have pursued different approaches based on the literature, an unbiased screen and in-house results generated with the human-specific Complex I inhibitor BAY 872243 to identify sensitive in vivo tumor models. However, using the cross-reactive Complex I inhibitor we were unable to identify sensitive models apart from weakly sensitive LKB1-deficient tumors (A549, G361) when animals were treated at maximum tolerated dose (MTD). In addition, all approaches for combination therapy failed to improve efficacy in vivo. Direct comparison of human-specific Complex I inhibitor BAY 87-2243 and cross-reactive inhibitor BAY179 in a sensitive LKB1-deficient melanoma model, G361, demonstrated that inhibition of Complex I specifically in the tumor is a valid approach as it results in tumor growth inhibition of ∼50%. However, cross-reactive compounds do not reach exposures at MTD to generate comparable effects. Citation Format: Sven Christian, Carolyn Algire, Wolfgang Schwede, Jeffrey S. Mowat, Alexander Ehrmann, Stephan Menz, Marcus Bauser, Andrea Haegebarth. Comparison of human-specific versus cross-reactive Complex I inhibitor for in vivo tumor efficacy. [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 223.
Abstract 3590: A Neil1 DNA glycosylase germline variant induces genomic instability and cellular transformation
Authors: Joann B. Sweasy, Heather Galick, Scott Kathe, Susan Wallace
Journal: Cancer Research (2016)

Abstract NEIL1 DNA glycosylase is a bifunctional enzyme that recognizes oxidized pyrimidines and formamidopyrimidines, and appears to remove damage in advance of the replication fork. The rs5745906 SNP of the NEIL1 gene has a minor allele frequency of 1% and is a G to A base substitution that encodes the G83D NEIL1 protein. Interestingly, this mutation is also present in cholangiocarcinomas. Unlike WT NEIL1, the G83D variant is not able to recognize oxidized bases efficiently due to a shift in the void filling residues that stabilize the DNA duplex once a damaged base has been extruded into the glycosylase substrate binding pocket. The goal of our study was to determine if the G83D NEIL1 variant exhibits a cancer-related phenotype in cells. We found that unlike wild-type (WT) NEIL1, expression of G83D in MCF10A immortal human breast epithelial cells induces genomic instability and cellular transformation. Expression of G83D but not WT NEIL1, in MCF10A cells leads to replication fork stalling and slow replication fork velocity. Our results suggest that G83D is unable to remove oxidative DNA damage at the replication fork, resulting in genomic instability and cellular transformation. Our results are consistent with the idea that individuals who harbor the G83D NEIL1 variant are at increased risk for cancer. Citation Format: Joann B. Sweasy, Heather Galick, Scott Kathe, Susan Wallace. A Neil1 DNA glycosylase germline variant induces genomic instability and cellular transformation. [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 3590.
High Insta High Instability Of The CSF3R Gene In Severe Congenital Neutropenia Patients As Judged By Multiple CSF3R Mutations In The Majority Of Patients
Authors: Maksim Klimiankou, Murat Uenalan, Siarhei Kandabarau, Lutz Wiehlmann, Anna-Lena Hagemann, Annette Müller Brechlin, Marlene Reuter, Cornelia Zeidler, Karl Welte, Julia Skokowa
Journal: Blood (2013)
Pharmaceutical salts: Theory, use in solid dosage forms and in situ preparation in an aerosol
Authors: Timothy Scott Wiedmann, Amir Naqwi
Journal: Asian Journal of Pharmaceutical Sciences (2016)

In this article, the theoretical foundation for salts is given with an emphasis on the amount of drug in solution. Consideration is given for the solubility of the non-ionized form, acid dissociation constant and solubility product, which are the limiting constraints. For dissolution of nonionized drugs, the surface pH differs from the bulk pH, giving rise to a lower than expected rate. For salts, theoretical considerations are relatively complex, and an experimental approach to estimating the surface pH is more likely to be of value in predicting the dissolution rate. General guidelines are described for screening, preparing and characterizing drugs as salts, which critically depend on the goal of the product development. Thereafter, our work involving the preparation of salts as a means to generate aerosols from a solution is provided. The solubility of six structurally related compounds was determined in four acids. Thereafter, the amount of the compound in solution was determined as a function of pH, using the acid that provided the highest solubility. Because the pH required to achieve the needed concentration for aerosol generation was low, ammonia vapor was introduced into the air stream to neutralize aerosol droplets. Solvent was then removed from the aerosol by a silica column. The resulting aerosol had a concentration of 96 µg/l and a mass median particle size of 1.8 µm. The reported pharmacokinetic study substantiated the feasibility of evaluating its safety and efficacy of inhalation administration in the rat model.
Abstract 3825: Disrupting p-STAT3-mediated VEGF-A paracrine and autocrine feed-forward loops by targeting SHP-1 suppresses triple negative breast cancer cell metastasis
Authors: Jung-Chen Su, Hao-Chieh Chiu, Chun-Yu Liu, Kuen-Feng Chen, Chung-Wai Shiau
Journal: Cancer Research (2016)

Abstract Patients with metastatic triple-negative breast cancer (TNBC) relapse quickly, representing an unmet need for effective therapy. Regorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor targeting tumor angiogenesis, oncogenesis and the tumor microenvironment and has been approved for metastatic colorectal cancer and advanced gastrointestinal stromal tumor. Recent studies suggest regorafenib also acts as a SHP-1 phosphatase agonist. Here, we investigated the potential of regorafenib to suppress metastasis of TNBC cells by mitigating autocrine and paracrine feed-forward loops of p-STAT3-mediated VEGF-A signaling through targeting the SHP-1/p-STAT3/VEGF axis. We found a significant correlation between cancer cell migration and SHP-1/p-STAT3/VEGF-A expression in a panel of human TNBC cells. Clinically VEGF-A expression is associated with disease-free and distant metastasis-free survival, independent of tumor stage. Regorafenib induced significant anti-migratory effects, in association with downregulation of p-STAT3 and VEGF-A. Overexpression and knockdown experiments validated the indispensable roles of SHP-1, p-STAT3 and VEGF-A in regorafenib-induced anti-migration. To exclude the role of RTK inhibition in regorafenib-induced inhibition of migration, we synthesized a regorafenib derivative, SC-78, that had minimal effect on VEGFR2 and PDGFR kinase inhibition, while having more potent effects on SHP-1/p-STAT3/VEGF-A signaling. SC-78 demonstrated superior in vitro anti-migration to regorafenib. Furthermore, VEGF-A dependent autocrine/paracrine loops were disrupted by regorafenib and SC-78. SC-78 revealed more potent in vivo efficacy than regorafenib in both xenograft and orthotopic models, as well as in a tail vein metastatic model. This study implies that the more potent SC-78 may be a promising lead for suppressing metastasis of TNBC, and the SHP-1/p-STAT3/VEGF axis is a potential therapeutic target for metastatic TNBC. Citation Format: Jung-Chen Su, Hao-Chieh Chiu, Chun-Yu Liu, Kuen-Feng Chen, Chung-Wai Shiau. Disrupting p-STAT3-mediated VEGF-A paracrine and autocrine feed-forward loops by targeting SHP-1 suppresses triple negative breast cancer cell metastasis. [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 3825.
Allogeneic Hematopoietic Cell Transplantation in AML with Normal Karyotype and NPM1 Mutated FLT3-ITD Negative: A Retrospective Analysis from the Acute Leukemia Working Party of EBMT
Authors: Ali Bazarbachi, Myriam Labopin, Mohamed A Kharfan-Dabaja, Rainer Schwerdtfeger, Liisa Volin, Jean-Henri Bourhis, Gerard Socie, Eric Deconinck, Tobias Gedde-Dahl, Alessandro Rambaldi, Pavel Jindra, Günter Schlimok, Didier Blaise, Patrice Chevallier, Arnon Nagler, Christoph Schmid, Jordi Esteve, Mohamad Mohty
Journal: Blood (2014)