tbuckley/cabot-search huggingface dataset:
Abstract 1572: Overexpression of Axl delays metastatic outgrowth of prostate cancer bone marrow disseminated tumor cells
Authors: Haley D. Axelrod, Kenneth C. Valkenburg, Kenneth J. Pienta
Journal: Cancer Research (2016)

Abstract The presence of detectable metastases in the bone marrow of prostate cancer patients represents lethal, incurable disease. These metastases that may emerge years or decades after prostatectomy are derived from small colonies of dormant tumor cells that disseminated from the primary tumor. Our group has previously shown that Gas6/Axl signaling is associated with disseminated tumor cell (DTC) dormancy in mouse models of prostate cancer metastasis. In this study we explored the functional significance of this association and tested the hypothesis that overexpression of Axl in prostate cancer cells would prolong their dormant phase in the bone marrow. Axl overexpression in the AR-positive Axl-negative human prostate cancer cell line C42B slowed proliferation in vitro. Select cells were completely dormant as detected by the lack of EdU incorporation over 40 hours, and this fraction was increased when co-cultured with bone-forming osteoblasts. To assess the functional effects of Axl on prostate cancer progression in vivo, we utilized a mouse model of prostate cancer metastasis in which subcutaneous tumors are established and surgically removed upon reaching 200mm3. At 10 weeks post-tumor removal, mice bearing C42B-Axl tumors did not have overt osteoblastic or osteolytic lesions in their femurs or tibiae, whereas mice bearing C42B-WT tumors had visible lesions by x-ray. Immunohistochemistry staining of mouse femurs and tibiae corroborated these findings. To confirm that the absence of metastases in mice with C42B-Axl tumors was not due to the inability of the cells to disseminate, we used immunofluorescence to detect human cells in the bone marrow of flushed femurs and tibiae. At 12 weeks post-tumor removal, fewer prostate cancer cells were detected in the bone marrow of mice with C42B-Axl tumors compared to those with C42B-WT tumors. Notably however, both groups had detectable prostate cancer cells in the bone marrow, indicating that the absence of C42B-Axl metastasis was not due to failure of primary tumor cells to disseminate. The presence of disseminated C42B-Axl cells in the bone marrow coupled with their failure to develop into clinical metastases at the time of C42B-WT metastatic outgrowth establishes a functional role for the association of Axl expression with DTC dormancy. Axl may be sufficient to induce and maintain dormancy, and ongoing experiments will address the requirement of Axl in this setting. Citation Format: Haley D. Axelrod, Kenneth C. Valkenburg, Kenneth J. Pienta. Overexpression of Axl delays metastatic outgrowth of prostate cancer bone marrow disseminated tumor 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 1572.
Abstract 612: Identification of selective inhibitors of diffuse-type gastric cancer cells by screening of annotated compounds
Authors: Shu Shimada, Yoshimitsu Akiyama, Hiroshi Fukamachi, Yasuhito Yuasa, Shinji Tanaka
Journal: Cancer Research (2016)

Abstract Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and a poor prognosis. We have reported an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. We have also established mouse gastric cancer (GC) cell lines from DGC of the DCKO mice, demonstrating strong resistance to cytotoxic anti-cancer agents and high tumorigenic property when subcutaneously injected to nude mice. Then, we performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates with selective inhibitory activity against the GC cell lines. These candidate drugs were classified into some classes, and members of the most potent class specifically attenuated cell proliferation of the GC cell lines by induction of apoptosis as well as suppressing tumor growth in vivo. Expectedly, E-cadherin-mutant and -low human gastric cancer cell lines were more sensitive to them in contrast to E-cadherin-intact ones. These findings may lead to development of novel drugs and discovery of potential targets in human DGC. Citation Format: Shu Shimada, Yoshimitsu Akiyama, Hiroshi Fukamachi, Yasuhito Yuasa, Shinji Tanaka. Identification of selective inhibitors of diffuse-type gastric cancer cells by screening of annotated compounds. [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 612.
Abstract 3772: SHP-1 determines the radiosensitivity of liver cancer cell and dovitinib acts as a novel radiosensitizer in hepatocellular carcinoma via targeting SHP-1/STAT3 signaling
Authors: Man-Hsin Hung, Chao-Yuan Huang, Wei-Tien Tai, Ming-Hsien Tsai, Chih-Ting Shin, Szu-Yuan Wu, Chung-Wai Shiau, Kuen-Feng Chen
Journal: Cancer Research (2016)

Abstract Background Hepatocellular carcinoma (HCC) is one of the most lethal human malignancies and curative therapy is not an option for most patients. There is growing interest in the potential benefit of radiotherapy (RT)-integrated therapy. This study aimed to investigate the biological impacts of a novel tumor suppressor Src homology 2 (SH2) domain-containing phosphatase 1 (SHP-1) and its downstream effecter, STAT3, in regulating the radiosensitivity of HCC cells. Furthermore, we explored the efficacy and mechanism of an investigational drug, dovitinib, used in combination with RT. Material and methods To understand the impacts of SHP-1/STAT3 signaling affects radiosensitivity, HCC cells with ectopic expression of STAT3, SHP-1 and a catalytic mutant SHP-1 were treated with or without radiotherapy and analyzed by flow cytometry and colony formation assay. Furthermore, five HCC cell lines (PLC5, Hep3B, SK-Hep1, HA59T and Huh-7) were treated with dovitnib, RT or both. The in vitro and in vivo effects of above-mentioned treatments were analyzed. Results By sub-G1 analysis and colony formation, we found that HCC cell with ectopic expression of SHP-1 was much more sensitive to RT-induced apoptotic effects, while overexpression of STAT3 or catalytic-dead mutant SHP-1 restored RT-induced reduction of HCC cell survival. Next, we investigated the effects of dovitinib, which showed that dovitinib treatment resulted in SHP-1-mediated downregulation of p-STAT3 and promoted potent apoptosis of HCC cells. Ectopic expression of STAT3, or inhibition of SHP-1 diminished the effects of dovitinib on HCC cells. Furthermore, by ectopic expression and purified recombinant proteins of various mutant forms of SHP-1, the N-SH2 domain of SHP-1 was found to be required for dovitinib treatment. Importantly, we found that dovitinib potentiated the in vitor and in vivo effects of RT in HCC cells through affecting the SHP-1/STAT3 signaling. Conclusions SHP-1/STAT3 signaling is critically associated with the radiosensitivity of HCC cells. A combination therapy with RT and the SHP-1 agonist, such as dovitinib, resulted in enhanced in vitro and in vivo anti-HCC effects. Citation Format: Man-Hsin Hung, Chao-Yuan Huang, Wei-Tien Tai, Ming-Hsien Tsai, Chih-Ting Shin, Szu-Yuan Wu, Chung-Wai Shiau, Kuen-Feng Chen. SHP-1 determines the radiosensitivity of liver cancer cell and dovitinib acts as a novel radiosensitizer in hepatocellular carcinoma via targeting SHP-1/STAT3 signaling. [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 3772.
A Platform for the Scalable Derivation of Genetically-Enhanced T and NK Lymphocytes from Naive Human Induced Pluripotent Stem Cells for Cancer Immunotherapy
Authors: Raedun Clarke, William Kim, Brian Groff, Ramzey Abujarour, Megan Robinson, Xiaosong Huang, Newsha Sahaf, Sarah Raynel, Betsy Rezner, David Robbins, Lisa Guerrettaz, Daniel Shoemaker, Bahram Valamehr
Journal: Blood (2015)
A Phase 1b Study of Birinapant in Combination with 5-Azacitadine in Patients with Myelodysplastic Syndrome Who Are Naïve, Refractory or Have Relapsed to 5-Azacitadine
Authors: Gautam Borthakur, James M. Foran, Eunice S. Wang, Amol Rakkar, Hans Minderman, Jennifer Burns, Michael Andreeff, Raoul Tibes
Journal: Blood (2015)
Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study
Authors: Dheeraj Kalladka, John Sinden, Kenneth Pollock, Caroline Haig, John McLean, Wilma Smith, Alex McConnachie, Celestine Santosh, Philip M Bath, Laurence Dunn, Keith W Muir
Journal: The Lancet (2016)
Abstract 4222: Usefulness of VE1 immunohistochemical detection of BRAFV600E in aggressive thyroid cancers (PDCs and UCs)
Authors: Noa Feás-Rodríguez, Angela M. Costa, Tomás Alvarez Gago, Juan José Mateos Otero, Jose Manuel Cameselle Teijeiro, Raquel Muñoz, Ginesa Maria Garcia-Rostan
Journal: Cancer Research (2016)

Abstract Activating BRAF mutations are frequent in thyroid follicular cell carcinogenesis. The BRAFV600E point mutation represents the most common oncogenic event in sporadic papillary thyroid cancer (PTC). Although at a much lower frequency the BRAFV600E mutation is also present among less differentiated, more aggressive, I131 resistant forms of thyroid cancer as poorly differentiated carcinomas (PDCs) and undifferentiated carcinomas (UCs). Small molecule inhibitors targeting either the BRAF V600E protein or upstream or downstream kinases involved in MAPK signalling are currently under pre-clinical or clinical investigation in advanced, metastatic, I131 resistant thyroid cancers. Recently, immunohistochemical (IHC) studies on PTCs, using the VE1 mouse anti-human BRAF V600E antibody have shown to be a reliable means for detecting the BRAFV600E mutation in a clinical setting without molecular genotyping units. In this study we sought to determine the usefulness of the VE1 antibody for detecting the BRAF V600E mutant protein in a series of 103 aggressive thyroid cancers (59 PDCs and 44 UCs) previously characterized by PCR-SSCP for the presence of BRAF mutations in exons 11 and 15. The BRAFV600E mutation was present in 10/59 PDCs (17%) and 11/44 UCs (25%). Immunohistochemistry revealed 9 mutated PDCs (sensitivity 90%) and 9 mutated UCs (82% sensitivity). The staining intensity in BRAF V600E mutated samples ranged from weak to strong. Non valuable results were found in 3 PDCs and 4 UCs. Overall the results indicate that immunohistochemistry with VE1 antibody may be an alternative to molecular biology approaches for the routine detection of BRAFV600E point mutations in clinical settings without molecular genotyping facilities. It may help clinicians in targeted therapy decision making. Citation Format: Noa Feás-Rodríguez, Angela M. Costa, Tomás Alvarez Gago, Juan José Mateos Otero, Jose Manuel Cameselle Teijeiro, Raquel Muñoz, Ginesa Maria Garcia-Rostan. Usefulness of VE1 immunohistochemical detection of BRAFV600E in aggressive thyroid cancers (PDCs and UCs). [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 4222.
Concordance of Van-Nuys Prognostic Index, Memorial Sloan Kettering Breast Cancer nomogram and Oncotype Dx DCIS scores in prediction of ductal carcinoma in situ(DCIS) recurrence risk.
Authors: Kinzie Matlock, Jillian M. Lloyd, W. Bradford Carter, Edina Grujic, Thomas G. Frazier
Journal: Journal of Clinical Oncology (2015)

56 Background: Ductal Carcinoma in situ (DCIS) has a wide spectrum of bioagressiveness. Three models used to assess recurrence risk (RR) of DCIS include: the Van-Nuys Prognostic Index (VN), Memorial Sloan Kettering Breast Cancer Nomogram (MN) and Oncotype Dx DCIS Score (OD; Genomic Health, Redwood City, CA). The aim of our study was to evaluate the concordance between these RR models. Methods: An IRB-approved retrospective chart review was performed on 37 consecutive patients at our institution with DCIS from 12/2011-4/2015 who underwent breast conservation surgery and in whom an OD was obtained. The OD and ‘any recurrent event at 10-years’ scores were used to stratify patients into low risk (LR; OD DCIS score &lt;39/&lt;17%), intermediate risk (IR; 39-54/17-24%) and high risk (HR; &gt;54/&gt;24%), as outlined in the original OD study. The ‘10-year RR’ scores from MN were stratified using the same percentile breakdown as OD. The VN were stratified into LR (4-6), IR (7-9) and HR (&gt;9) groups based on the updated VN study’s guideline. Pathologic slides were re-reviewed by one pathologist blinded to OD score to determine size and margin width based on the protocol outlined in the original VN paper. The three scores for each patient were compared. Results: Eleven patients (29.7%) had concordance between all three scores and all were LR. In 10.8% of patients, there was no concordance between the three scores. The concordance between the OD and VN, OD and MN, and VN and MN was 64.9%, 48.6% and 35.1%, respectively. Conclusions: In evaluating RR, determining LR may have the greatest implication since this group may be the least likely to benefit from adjuvant radiotherapy. Concordance between all three models was seen only in LR patients. All patients who were LR by VN were also LR by OD and MN. Determining a VN initially may help guide additional testing. The added value of OD may be primarily in patients who are not LR by VN. The MN seems to be of limited value in this study. Larger studies assessing these relationships and their outcomes in predicting potential RR in DCIS are warranted.
The Rab27A effector MYRIP as a regulator of survival in non-small cell lung cancer cells.
Authors: A. Chacko, P. V. Jithesh, C. Grills, I. Paul, N. Crawford, D. A. Fennell
Journal: Journal of Clinical Oncology (2011)

e13537 Background: Personalising therapy for non-small cell lung cancer has been validated as an effective treatment paradigm. Somatic gene alterations confer sensitivity to inhibition of growth survival pathways irrespective of underlying resistance to chemotherapeutic agents, and enables efficient activation of BCL-2 family-dependent pro-apoptotic signalling. In platinum resistant cancers this signalling is blocked, however the intrinsic pathway remains sensitive to exogenous BH3 death signals. Methods: Microarray profiling coupled to focused RNAi screening was used to reveal those resistance genes involved in derepression of proapoptotic BCL-2 family proteins. Analysis of the effect of MYRIP expression on survival was generated from studying 6 NSCLC datasets from Gene Expression Omnibus which were paired with survival time and status information. The toxic effect of MYRIP depletion on NSCLC and non-cancerous lung cells was determined by cell viability and clonogenic assays. Apoptotic induction was examined by caspase and PARP cleavage experiments, and fractionation of mitochondrial proteins. FACS analysis was used to examine effects on cell cycle. Results: MYRIP/Slac2c, a gene hitherto associated with vesicle trafficking but not apoptosis, was overexpressed in platinum resistant NSCLC cells. In particular, cisplatin resistant cells expressed a heavier protein isoform of MYRIP which appeared to be associated with the mitochondria. Silencing of MYRIP induced BIM and BAX/BAK-dependent mitochondrial apoptosis which was selective for NSCLC, but not non-cancerous lung cells. In addition, loss of MYRIP induced S-phase arrest. Conclusions: Overexpression of MYRIP is an independent, poor prognostic factor suggesting that targeting these genes may be therapeutically relevant. In summary, MYRIP exhibits a previously unknown survival function associated with suppression of pro-apoptotic BCL-2 family proteins and maintenance of cancer cell proliferation and survival.
Phase II/III randomized study of hyperfractionated radiotherapy with concomitant cetuximab versus concomitant chemotherapy in advanced nonmetastatic head and neck cancer: Preliminary report.
Authors: Khalid Al Saleh, Reham Safwat, Ahmed Bedair, Amany AL Basmy, H.S. Hooda, Jitendra Shete
Journal: Journal of Clinical Oncology (2012)

e16002 Background: This is a randomized study to compare the use of cetuximab versus platinum based chemotherapy with concurrent hyperfractionated radiation therapy (HRT). Acute and late morbidity, locoregional control (LC) and disease free survival (DFS) were set as primary end points, while overall survival (OS) was set as secondary end point. Methods: Between December 2009 and May 2011, 24 patients were randomly assigned to HRT consisting of 120 cGy twice daily, for a total of 69.6 Gys in 58 fractions over 6 weeks, plus either cisplatin chemotherapy at weeks 1, 4, 6 (Arm A: 14 patients) or weekly cetuximab (Arm B: 10 patients). The overall radiation dose was the same for the two groups. The median follow up time of the whole group was 14.07 months (IQR: 5.8- 25.0 ms). Results: Overall treatment time was 72 days in arm A and 63 days in arm B (p= 0.64). Grade 3 skin toxicity was experienced in 42.9% of patients in arm A and 9.1% in arm B (p= 0.09). Grade 3 mucositis was 64.3% in arm A and 45.5% in arm B (p= 0.43). Hematologic toxicity of G3-4 occurred in 21.4% and 18% of the cases respectively (p= 0.06). The mean percent of weight loss was (13 % +/- 0.1%) in group A, and (10.75 % +/- 0.1%) in group B respectively (p=0.56). Complete response was observed in 12 (85.7%) and 100% of patients of arm A and B respectively. Partial response was achieved in the remaining 2 (14.2%) patients in arm A. Loco-regional recurrence occurred in 2 (14.2%) of the patients in arm A after partial response, and one of them died eventually due to progressive disease. Two patients developed distant metastasis, one patient in arm A and another one in arm B. As the sample size was small and events were limited, survival analysis could not be computed at this stage of the study Conclusions: Hyperfractionated radiotherapy and concurrent cetuximab seems to have less side effects compared to concurrent platinum. There's a trend of less skin, mucosal and haematological toxicity with cetuximab that might become significant as the number of patients increase. We will be able to evaluate the outcomes of the patients regarding LC, DFS and OS within 2 years.
Rapid molecular determination of methicillin resistance in staphylococcal bacteraemia improves early targeted antibiotic prescribing: a randomized clinical trial
Authors: S. Emonet, P.G. Charles, S. Harbarth, A.J. Stewardson, G. Renzi, I. Uckay, A. Cherkaoui, M. Rougemont, J. Schrenzel
Journal: Clinical Microbiology and Infection (2016)
Abstract 2635: Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer
Authors: Benjamin A. Rybicki, Andrew Rundle, Oleksandr Kryvenko, Dhananjay Chitale, Steven Belinsky, Deliang Tang
Journal: Cancer Research (2016)

Abstract In DNA from prostate cancer tumors, methylation patterns in gene promoter regions can be a biomarker for disease progression. It remains unclear whether methylation patterns in benign prostate tissue—prior to malignant transformation—may provide similar prognostic information. To determine whether early methylation events predict prostate cancer outcomes, we evaluated histologically benign prostate specimens from 353 men who eventually developed prostate cancer and received “definitive” treatment (radical prostatectomy [58%] or radiation therapy [42%]). Cases were drawn from a large hospital-based cohort of men with benign prostate biopsy specimens collected between 1990 and 2002. Risk of disease progression associated with methylation was estimated using time-to-event analyses. Average follow-up was over 5 years; biochemical recurrence (BCR) occurred in 91 cases (26%). In White men, methylation of the APC gene was associated with increased risk of BCR, even after adjusting for standard clinical risk factors for prostate cancer progression (adjusted hazard ratio (aHR) = 2.26; 95%CI 1.23-4.16). APC methylation was most strongly associated with a significant increased risk of BCR in White men with low prostate specific antigen at cohort entry (HR = 3.66; 95%CI 1.51-8.85). In additional stratified analyses, we found that methylation of the RARB gene significantly increased risk of BCR in African American cases who demonstrated methylation of at least one of the other four genes under study (HR = 3.80; 95%CI 1.07-13.53). These findings may have implications in the early identification of aggressive prostate cancer as well as reducing unnecessary medical procedures and emotional distress for men who present with markers of indolent disease. Citation Format: Benjamin A. Rybicki, Andrew Rundle, Oleksandr Kryvenko, Dhananjay Chitale, Steven Belinsky, Deliang Tang. Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with 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 2635.
Abstract 1318: Pancreatic cancer therapy using polyion micelles co-loaded with cyclopamine and paclitaxel
Authors: Jun Zhao, Chunhui Wu, Xiaoxia Wen, Junjie Li, Qian Huang, Ying Ma, Stephen Ullrich, Huamin Wang, Jason Fleming, Chun Li
Journal: Cancer Research (2016)

Abstract Sonic hedgehog (SHH) signaling pathway is an important regulator during the initiation and progression of pancreatic cancer, and sustained activation of this pathway contributes to excessive deposition of tumor stroma and maintenance of tumor-initiating cells. Cyclopamine, a potent inhibitor of the SHH pathway, has shown promising antitumor efficacy. However, cyclopamine is insoluble in water and is highly toxic, and cyclopamine monotherapy did not effectively inhibit tumor growth in a range of preclinical pancreatic cancer models. We hypothesized that polyion complex polymeric micelles that simultaneously deliver cyclopamine and paclitaxel (M-CPA/PTX) would display greater efficacy against pancreatic tumor than micelles loaded with cyclopamine alone (M-CPA) or paclitaxel alone (M-PTX). We tested this hypothesis in cell cultures and in an orthotopic human pancreatic cancer Miapaca-2 xenograft model and a genetically engineered mouse model of pancreatic ductal carcinoma (PDAC), the KPC model. Our results showed that M-CPA interrupted the SHH pathway by antagonizing the smoothened receptor, reduced expression of Gli-1 transcription factor, and inhibited proliferation of Miapaca-2 cells and stroma-producing human pancreatic stellate cells. In Miapaca-2 cells, M-CPA decreased the fraction of CD133+ cells (cancer stem cells) and decreased tumorsphere formation, whereas M-TXL increased the fraction of CD133+ cells and tumorsphere formation. M-CPA negated the stimulation of human pancreatic stellate cells by exogenous SHH ligands. In vivo, M-CPA/PTX reduced tumor cell proliferation, depleted tumor stroma, and increased tumor vasculature density, leading to effective inhibition of tumor growth in Miapaca-2 xenografts. In the KPC model, M-CPA/PTX significantly prolonged media survival of mice with PDAC compared to non-treatment control mice. In conclusion, M-CPA/PTX was an effective strategy to treat pancreatic cancer. (supported in part by the Viragh Family Foundation and the John S. Dunn Foundation) Citation Format: Jun Zhao, Chunhui Wu, Xiaoxia Wen, Junjie Li, Qian Huang, Ying Ma, Stephen Ullrich, Huamin Wang, Jason Fleming, Chun Li. Pancreatic cancer therapy using polyion micelles co-loaded with cyclopamine and paclitaxel. [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 1318.