tbuckley/cabot-search huggingface dataset:
Abstract LB-139: In situ Treg immunomodulation at a single tumor site with CpG and immune checkpoint antibodies cures metastatic disease
Authors: aurelien marabelle, Holbrook Kohrt, Joshua Brody, James Torchia, ranjani rajapaksa, Richard Luong, Gang Zhou, Hyam Levitsky, Victor Tse, Ronald Levy
Journal: Cancer Research (2012)

Abstract Background: CD4+CD25+FOXP3+ regulatory T-cells (Tregs) infiltrate all tumor sites and play a central role in maintaining immune tolerance to cancers. Scientific question: Is the local immunomodulation of Tregs from a single tumor site sufficient to trigger a systemic anti-tumor immune response able to eradicate distant tumor sites ≤ Results: We found that tumor infiltrating Tregs preferentially express CTLA4 (CD152) and OX40 (CD134) compared to their counterparts in the blood and other lymphoid organs, both in mice and in human lymphomas. We show in a murine lymphoma model that OX40 and CTLA4 upregulation occurs specifically on Tregs directed against tumor antigens. Injections of low doses of anti-CTLA4 and anti-OX40 together with CpG, a TLR-9 agonist, directly into a single tumor site depletes the Tregs from the injected tumor but not from distant ones. This immunomodulation subsequently triggers an anti-tumor immune response able to cure mice with established disseminated disease. This triple combination is uniquely required as neither CpG alone nor mAbs without CpG are effective. Significance: immunomodulatory antibodies are currently under clinical development for cancer therapy. Their major toxicity is the triggering of auto-immune diseases. We show here that after injections of very little doses of these antibodies with CpG at one tumor site, their serum levels become undetectable. However, these doses are sufficient to trigger a systemic anti-tumor response able to eradicate distant sites. Impact: we recently have published positive results of intra-tumoral CpG in patients with follicular Lymphoma (Brody, Levy, et al. JCO, 2010). Anti-CTLA4 has just been approved by the FDA/EMEA in patients with metastatic melanoma. Anti-Ox40 antibodies are currently being tested in phase I/II clinical trials. Therefore, the combination described here can be tested in patients with injectable sites of lymphoma. Together, these results are in favor of a paradigm shift in cancer therapy where the immune system is targeted rather than the tumor itself. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-139. doi:1538-7445.AM2012-LB-139
Abstract 271: Validation of Polo-like Kinase 1 as a novel therapeutic target in alveolar rhabdomyosarcoma
Authors: Verena Thalhammer, David Herrero-Martin, Regina Hecker, Felix K. Niggli, Beat W. Schäfer
Journal: Cancer Research (2012)

Abstract Oncogenic transcription factors are the second most frequently mutated class of proteins. They represent ideal therapeutic targets because oncogene addiction is common to a broad spectrum of tumors and their inhibition may help to develop further alternative treatment strategies to improve therapy and to minimize treatment related side effects. However, thus far it has not been possible to target these oncogenic transcription factors as they usually do not respond to small-molecule inhibition. As a model system we use alveolar rhabdomyosarcoma (aRMS), an aggressive childhood tumor, which often displays resistance to conventional chemo-and radiotherapy. aRMS is characterized by the expression of the tumor-specific chimeric transcription factor PAX3/FKHR that is essential for survival of tumor cells. This transcription factor is post-translationally modified by phosphorylation which is required for efficient transcriptional activity. We believe that identification of upstream protein kinases mediating PAX3/FKHR phosphorylation will be an efficient strategy to impair the activity of the oncogenic fusion protein and subsequently induce tumor cell specific apoptosis. Having performed both siRNA and kinase-inhibitor library screens against the human kinome, we claim that Polo-like Kinase 1 (PLK1) might represent a very attractive and specific potential therapeutic target in aRMS. Its inhibition by RNAi and the small-molecule inhibitor BI 2536 reduces PAX3/FKHR activity and consequently aRMS cell viability. Moreover drug treatment causes tumor regression in xenograft mouse models. Therefore we are elucidating mechanisms causing these antitumorigenic effects and especially focus on the interaction of PLK1 and PAX3/FKHR. Our data suggest that PLK1 warrants further investigations as a novel drug target for the treatment of aRMS and may lead to a general strategy for treatment of tumors addicted to post-translationally modified oncogenic transcription factors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 271. doi:1538-7445.AM2012-271
Abstract 4725: Inhibition of the Hedgehog signaling pathway - a new target in treatment for children with neuroblastoma
Authors: Malin Wickstrom, Cecilia Dyberg, Takashi Shimokawa, Ninib Baryawno, Jelena Milosevic, Ole M. Fuskevag, Rolf Larsson, Peter G. Zaphiropoulos, Per Kogner, John I. Johnsen
Journal: Cancer Research (2012)

Abstract Background: Neuroblastoma originates from neural crest cells and is one of the most common and deadly tumors of childhood. The majority of tumors develop therapy resistance with fatal clinical outcome despite intensive multimodal therapy. The Hedgehog (HH) signaling pathway is fundamental in embryonic development, controlling cell fate and proliferation. Activation of HH signaling is involved in several cancers, among them pediatric cancers. Studies have revealed that human neuroblastoma cells express high levels of proteins involved in HH signaling. GANT61 was recently identified as an inhibitor of GLI1 and GLI2, important transcription factors in the HH signaling pathway. The aim of this study was to investigate the impact of antagonists of HH signaling in neuroblastoma through characterization of the effects of small molecule inhibitors of the HH pathway, in vitro and in vivo. Methods: Cytotoxic activity of HH inhibitors was studied in cell viability and clonogenic assays. The molecular mechanisms were characterized using cell- and molecular biology techniques. Xenograft studies in mice were performed to validate the therapeutic effects and toxicity in vivo. Results: The cytotoxicity of different HH inhibitors (cyclopamine, SANT1 and GANT61) was evaluated in a panel of human neuroblastoma cell lines. GANT61 was the most potent drug tested with IC50 values in the range of 5.8 - 13 µM after 72h incubation. Expression of GLI1 significantly correlated to the log IC50 for GANT61 (R2=0.88), the higher the expression of GLI1 the lower the amount of GANT61 was required to inhibit cellular growth. We also saw an inverse correlation with MYCN (R2=−0.88). When measured with a GLI-dependent luciferase reporter plasmid, the GLI activity was decreased with 36% to 80% after GANT61 treatment (10 µM, 48h) depending on cell line. Investigation of cell cycle regulation and cell death demonstrated that GANT61 inhibited proliferation and induced apoptosis. siRNA experiments revealed that knockdown of GLI1 reduced proliferation more potently than GLI2, GLI3 and SMO inhibition. GANT61 significantly inhibited tumor growth in neuroblastoma xenografts in nude NMRI nu/nu mice without causing any sign of toxicity. Conclusions: These results suggest that inhibitors of the HH signaling pathway such as GANT61 may constitute a novel option for treatment to patient with high-risk neuroblastoma without MYCN-amplification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4725. doi:1538-7445.AM2012-4725
Biodegradable stents: another big step in the field of non-surgical therapy for fibrostenotic Crohn's disease
Authors: U. Saritas, Y. Ustundag
Journal: Endoscopy (2012)

We read with interest the article by Rejchrt et al. entitled “Biodegradable stents for the treatment of benign stenoses of the small and large intestines” [1]. The authors successfully inserted biodegradable stents transanally in 10 of 11 patients with fibrostenotic Crohn’s disease. The authors reported that seven of these patients were symptom-free after stent insertion and that all of them remained asymptomatic after full biodegradation of the stents, which took place within a period of 4 months. However, a high rate of early stent migration in 30 % of cases was also reported.
Primary non-Hodgkin''s lymphoma in esophagus-a case report
Authors: Q Zhu, B Xu, J Li, K Xu
Journal: Endoscopy (2006)

A 57-year old man with gradually appeared dysphagia during one year period. Barium meal imaging of upper digestive tract and chest CT indicated esophageal stricture and incrassation of total esophageal wall, but there was no clinical evidence suggesting swelling of lymph nodes appearing in cervix, lung and mediastinum. 1 year later, incrassation of esophageal mocosa still existed in middle and distal part of esophagus by EGD examination. Then esophageal motility investigation and intra-luminal miniature probe sonography (MPS) were performed, it revealed that disorder of esophageal movement and 1.5˜2.0cm thickened mucosal layer of the esophagus with homogeneous hypoechoic structure. Followed by large piecemeal biopsy, the histo-pathological examination suggested: squamous epithelia was partially disappeared and replaced by same size, round or ovoid with clear nuclei proliferated lymphoid cells. Immunohistochemical and special staining indicated: I1415: AE1/AE3-, EMA-, LCA+, L26+, CD3-, CHG-, CD138-, κ+, λ-, Bcl2+, Bcl6-. Final result was primary Non-Hodgkin's lymphoma (NHL) microcyte type-B.
Endoscopic palliative management of esophageal and tracheal rupture
Authors: Girolamo Geraci, Francesco Raffaele, Giuseppe Modica, Carmelo Sciumè
Journal: Endoscopy (2014)

The increasing number of patients requiring intensive care and airway support has led to a growing recognition that significant short- and long-term morbidity may be associated with the use of artificial airways; this is despite significant improvements in the materials used in laryngeal tubes, which aim to decrease the trauma associated with long-term intubation [1]. We present the first case, to our knowledge, of huge, nontraumatic, esophageal perforation, widely communicating with the trachea, and which was treated successfully with double endoscopic stent placement.
Abstract 802: A key role for ARF in drug resistance in invasive bladder cancer
Authors: Takashi Kobayashi, Joan C. Delto, Cory Abate-Shen
Journal: Cancer Research (2012)

Abstract Although most superficial bladder cancers can be removed transurethrally with excellent prognosis, clinical outcome is much more problematic for patients with muscle-invasive disease. Indeed, invasive bladder cancer is a major clinical challenge since it is highly associated with postoperative recurrence and metastasis. Current treatments for those lethal forms of bladder cancer include systemic chemotherapy and molecular targeted therapy; however, survival is poor since most patients develop resistance to the drugs within a short timeframe. Clearly, there is a need to identify novel therapeutic options for invasive bladder cancer as well as a greater understanding of the molecular mechanisms of drug resistance. We have been investigating mechanisms of drug resistance using genetically-engineered mouse models of invasive bladder cancer based on the combinatorial deletion of p53 and Pten in bladder epithelium. p53 and PTEN are frequently inactivated in human bladder cancers, particularly those with poor prognosis. Indeed, allograft tumors established from these mice responded initially to the treatment with cisplatin, docetaxel, or rapamycin but eventually developed resistance. We have observed that these p53; PTEN deficient tumors express robust levels of p19Arf, while targeted deletion of Arf retards the aquisition of resistance following drug treatment. The significance of this expression was further suggested by analysis of a published gene expression profile of human bladder cancers which revealed that high Arf expression is an independent predictor of poor survival of invasive bladder cancer patients. Furthermore, following drug treatment in the mouse model, the Arf-positive, compared to the Arf-negative, tumors were significantly enriched in extracellular matrix/integrin signaling gene signature consistent with activation of downstream PI3K-mTOR pathway, suggesting that a model for drug resistance is via PI3K pathway activation. We have observed similar results in human bladder cancer cell lines either following knock-down of p14Arf in J82 cells that express endogenous p14Arf or following forced expression of p14Arf in ARF-negative UMUC3 human bladder cancer cells, and in both cases it was coincident with deregulated activation of PI3K-mTOR pathway. Thus, we propose that Arf confers drug resistance on bladder cancer by activating PI3K-mTOR pathway, highlighting a potential therapeutic target for advanced invasive bladder cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 802. doi:1538-7445.AM2012-802
Abstract 1896: Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer
Authors: Shigeki Nanjo, Tadaaki Yamada, Shinji Takeuchi, Seiji Yano
Journal: Cancer Research (2012)

Abstract Introduction: Epidermal growth factor receptor (EGFR) is an attractive drug target in lung cancer, with several anti-EGFR antibodies and small-molecule inhibitors showing efficacy in lung cancer patients. Patients, however, may develop resistance to EGFR inhibitors. We demonstrated previously that hepatocyte growth factor (HGF) induced resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) in lung cancers harboring EGFR mutations. We therefore determined whether HGF could induce resistance to the anti-EGFR antibody (EGFR Ab) cetuximab in lung cancer cells, regardless of EGFR gene status. Methods: Cetuximab sensitivity and signal transduction in lung cancer cells were examined in the presence or absence of HGF, HGF-producing fibroblasts, and cells tranfected with the HGF gene in vitro and in vivo. Results: HGF induced resistance to cetuximab in H292 (EGFR wild) and Ma-1(EGFR mutant) cells. Western blotting showed that HGF-induced resistance was mediated by the Met/Gab1/Akt signaling pathway. Resistance of H292 and Ma-1 cells to cetuximab was also induced by co-culture with lung fibroblasts producing high levels of HGF and by cells stably transfected with the HGF gene. This resistance was abrogated by treatment with anti-HGF neutralizing antibody. Conclusions:HGF-mediated resistance is a novel mechanism of resistance to EGFR Ab in lung cancers, with fibroblast-derived HGF inducing cetuximab resistance in H292 tumors in vivo. The involvement of HGF-Met-mediated signaling should be assessed in acquired resistance to EGFR Ab in lung cancer, regardless of EGFR gene status. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1896. doi:1538-7445.AM2012-1896
Thirteen Cases of Leukemia in a Family 2
Authors: F. W. Gunz, J. P. Gunz, P. C. Vincent, M. Bergin, F. L. Johnson, H. Bashir, R. L. Kirk
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Thirteen Cases of Leukemia in a Family Get access F. W. Gunz, F. W. Gunz Search for other works by this author on: Oxford Academic PubMed Google Scholar J. P. Gunz, J. P. Gunz Search for other works by this author on: Oxford Academic PubMed Google Scholar P. C. Vincent, P. C. Vincent Search for other works by this author on: Oxford Academic PubMed Google Scholar M. Bergin, M. Bergin Search for other works by this author on: Oxford Academic PubMed Google Scholar F. L. Johnson, F. L. Johnson Search for other works by this author on: Oxford Academic PubMed Google Scholar H. Bashir, H. Bashir Search for other works by this author on: Oxford Academic PubMed Google Scholar R. L. Kirk R. L. Kirk Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 60, Issue 6, June 1978, Pages 1243–1250, https://doi.org/10.1093/jnci/60.6.1243 Published: 01 June 1978 Article history Received: 25 August 1977 Accepted: 09 January 1978 Published: 01 June 1978
P81 Lung Transplantation in Alpha-1-Antitrypsin Deficiency
Authors: HM Stone, R Edgar, RA Stockley
Journal: Thorax (2012)

<h3>Background</h3> Lung transplantation is an option for a proportion of patients with end-stage lung disease who deteriorate despite optimal medical therapy. In patients with alpha-1-antitrypsin deficiency (A1ATD), survival benefit has been demonstrated following transplantation. Patient selection is often subjective and the effects of transplantation on Health Related Quality of Life (HRQOL) in A1ATD are unknown. The aims of the current study were to determine objective measures influencing patient selection, survival benefit and health status following lung transplantation in A1ATD patients. <h3>Methods</h3> Between 1996 and 2011, patients with A1ATD (PiZ) who had undergone lung transplantation were identified from the UK A1ATD registry. Lung function parameters, including rates of decline pre-transplant, were compared to matched subjects who did not undergo transplantation (matched for sex, age, smoking history and FEV1). HRQOL, assessed using the St George’s Respiratory Questionnaire (SGRQ), was measured pre and post-transplant together with mortality data. <h3>Results</h3> Patients who underwent transplantation (n=32) had significantly worse HRQOL than patients who did not in all domains of the SGRQ (total score 64.2; SE±2.5 vs. 55.3±2.04, p=0.008). Markers of gas transfer (TLCO and KCO) were both significantly lower in the transplantation group (33.5%±3.0 and 41.0%±3.9 predicted respectively, compared to 50.6%±.69 and 57.58%±3.1 predicted in the non-transplant group p&lt;0.001 &amp; p=0.001). There were no differences in the rate of lung function decline compared to non-transplanted patients. Sixteen transplant patients died in the follow up period (6 perioperatively). Figure 1 summarises the Kaplan-Meier survival curve following transplantation. There was no relationship to pre-transplant physiology. Once a survival time of 5 years had been reached, mortality was due to causes unrelated to A1ATD or the transplant. There was a significant improvement in spirometry (23.94±1.0 vs. 92.73±9.2, p=0.002, N=16) and all domains of the SGRQ post lung transplantation, including the total score (64.2±2.5 vs. 15.6 ±4.9, p=0.002). <h3>Conclusion</h3> Patients who underwent lung transplantation had worse gas transfer parameters pre transplant compared to the otherwise matched A1ATD patients who did not. Lung transplantation in patients with end-stage lung disease secondary to A1ATD significantly improved HRQOL.
Abstract P5-06-14: Ezrin Binding Protein Ebp50 Negatively Regulates HER2 and Alters Tamoxifen Sensitivity
Authors: G Gu, KR Covington, NM Fernandez, S Ando, SAW. Fuqua
Journal: Cancer Research (2010)

Abstract Background: Targeted therapy with antiestrogens and aromatase inhibitors are the mainstay of treatment for estrogen receptor (ER) a-positive breast cancer; however, resistance to these therapies ultimately occurs and patients recur with resistant disease. Materials and Methods: Stable overexpression of a shRNA to Ebp50 or full-length Ebp50 was performed in MCF-7 breast cancer cells. Cell responsiveness to tamoxifen (Tam) was evaluated using soft agar and MTT growth assays. The molecular signaling pathways affected by Ebp50 knockdown were explored using immunoblot analysis, and immunoprecipitation assays. Cellular localization was determined using confocal microscopy. Results: Modulation of Ebp50 levels altered cellular response to Tam treatment. Overexpression enhanced Tam sensitivity, whereas knockdown decreased Tam sensitivity. Thus reduction in Ebp50 levels analygous to that discovered in resistant patients, conferred resistance to the growth inhibitory effects of Tam. Since it is known that Ebp50 can bind to a number of cell surface receptors, we performed binding assays, and found that Ebp50 was able to bind to HER-2 in MCF-7 cells. In addition, this interaction was enhanced with Tam treatment. Enhanced activation of phospho-HER2 and total-HER2 levels, as well as pAKT were seen in the Ebp50 knockdown cells. We expressed deletion mutants of Ebp50 we saw increased levels of cytoplasmic ERa when the ERM domain was deleted. The ERM domain, which is know to be important for the binding cytoplasmic proteins, may thus be a determinant of ERa localization. Ebp50 was also shown to affect ERa transcriptional activity. Discussion: Our data suggest that Ebp50 may be a negative regulator of HER2 signaling, and its loss confered homrone resistance. Ebp50 loss might function to stabilize HER2 levels. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-06-14.