tbuckley/cabot-search huggingface dataset:
Sulindac enhances arsenic trioxide mediated apoptosis of HCT116 colon cancer cell line by inhibition of nuclear factor-kappa B
Authors: Hee-Jeong Cheong, Hae-Ran Lee, Sook-Ja Kim, Hyun-Jung Kim, Nam-Su Lee, Sang-Byung Bae, Chan-Kyu Kim, Kyu-Taeg Lee, Sung-Kyu Park, Jong-Ho Won, Dae-Sik Hong, Hee-Sook Park
Journal: Cancer Research (2006)

4938  Transduction of the E2F-1 gene in melanoma cells markedly increases cell sensitivity to doxorubicin, thereby producing a synergistic effect on melanoma cell apoptosis. However, the molecular mechanisms of E2F-1 gene therapy in combination with chemotherapy have not been fully elucidated. We used microarray analysis to screen novel genes or pathways that may play key roles in apoptosis when E2F-1 gene therapy is combined with doxorubicin chemotherapy. SK-MEL-2 melanoma cells were infected with Ad-E2F-1 alone, Ad-E2F-1 plus doxorubicin, or Ad-LacZ plus doxorubicin. After 16 hours of infection or combination treatment, the total RNA was extracted from these cells and subjected to microarray analysis. Two control groups, Ad-E2F-1 infection alone at an MOI of 2 and Ad-LacZ infection at an MOI of 2 combined with doxorubicin at 0.1 μM, were chosen for the microarray experiment. Two completely independent experiments of the three samples were performed. Our results showed that the combination treatment of Ad-E2F-1 and doxorubicin in melanoma cells affected the expression of a diverse range of genes, including cytokines, transcription factors, as well as genes involved in signal transduction, cell cycle regulation, and apoptosis. Among them, NF-κB pathway related genes, such as NFKBIA (I-κBα), TRAF-1, and SQSTM1 were up-regulated 3.2-, 2.7- and 2.4- fold, respectively. Subsequent quantitative real-time polymerase chain reaction (PCR) confirmed the microarray data. This result suggests that the NF-κB pathway and related genes could be an important molecular mechanism by which E2F-1 and doxorubicin in combination inhibits the growth of melanoma cells and induces apoptosis. Further investigation on the role of NF-κB was performed by using NF-κB inhibitor, MG132 and sulfasalazine. MTT assay showed that incubation of SK-MEL-2 melanoma cells with sulfasalazine (0.5mM) or MG132 (1μM) for 3h before combined treatment of E2F-1 and doxorubicin could inhibit more than ∼18% growth inhibition. Electrophoretic mobility shift assay (EMSA) showed that the combination therapy of E2F-1 and doxorubicin significantly inhibited NF-κB DNA binding activity, and the inhibitory effect was more pronounced when sulfasalazine or MG132 was added before the combination treatment. Luciferase reporter gene assay also showed that the combination of E2F-1 and doxorubicin attenuated the NF-κB activity by 3-fold. Furthermore, incubation with sulfasalazine combined with E2F-1 and doxorubicin exhibited decreased NF-κB activity by 5-fold. Our findings have identified, for the first time, a novel pathway–NF-κB pathway, that might be involved in apoptosis in melanoma cells when Ad-E2F-1 is combined with doxorubicin. The molecular information provided here will enhance further mechanistic studies.
Safety of bevacizumab when given perioperatively for colorectal cancer with liver metastases: McGill University pilot study
Authors: P. Kavan, N. Bouganim, M. Eid, P. Metrakos, P. Chaudhury, G. Batist
Journal: Journal of Clinical Oncology (2009)

e15083 Background: Bevacizumab (BV) increases responses and survival rates when used with chemotherapy in metastatic colorectal cancer (CRC). Current practice is to give peri-operative chemotherapy for resectable CRC liver metasases (LM). The safety and efficacy of chemo-BV in this setting is unknown. Post-operative complications have been reported in patients (pts) who underwent surgery while receiving BV. The goals were to determine safety of perioperative BV. Methods: In a prospective pilot study, patients with resectable LM from October 2005 to 2008 that received BV perioperatively along with chemotherapy. Of a total of 60 pts, 34 had oxaliplatin-based CTX, 22 CPT-11 (FOLFIRI) and 4 IROX. All but seven pts received BV pre and postoperatively. The average age was 55 years. All patients underwent liver surgery 6–8weeks post last dose of BV. Univariate Cox regression models were used to evaluate the association of patient and tumour characteristics, therapy and postoperative complications. Results: Postoperative complications developed in a total of 24 pts (40%). 12 pts (35%) who received Oxaliplatin CTX + BV, 9 pts (40%) with CPT 11 CTX + BV and 3 pts (75%) with Oxaliplatin + CPT-11 CTX +BV. The average time from BV discontinuation to surgery was 49 days. No significant associations were identified between BV and CTX regimen or timing and postoperative complications. Wound healing complication were most frequent with 8 pts (13%), DVT diagnosed in 6 pts (10%), protracted pancytopenia 4 pts (7%), sepsis 1pt, infections 2pts, MI 1pt, acute cardiomyopathy 1pt, and billiary leak 1pt. No bowel perforations or sudden deaths were reported. These side effects apart from thromboembolic events are comparable to previously reported post-operative complications. Conclusions: Neither the use of BV with CTX nor timing of BV administration were associated with a non acceptable increase in complication rates as compared to previously published by EORTC intergroup. Our data confirm that the combination of BV with neoadjuvant chemotherapy is feasible and safe in patients CRC LM. A higher incidence of thromboembolic events was seen. To determine the optimal timing and drug combination prospective randomized trials are urgently required. [Table: see text]
Efficacy and safety results of pemetrexed administration in non-small cell lung cancers, a multicenter study of the Association of Anatolian Medical Oncology.
Authors: Nurgul Yasar, Olcun Umit Unal, Caglayan Geredeli, Ali Inal, Veli Berk, Ebru Sari, Ayse Durnali, Ali Suner, Nuriye Ozdemir, Burcin Budakoglu, Umut Demirci, Ozge Gumussoy, Dogan Uncu, Cem Melih Boruban, Ilhan Oztop, Metin Ozkan, Mahmut Gumus, Tamer Elkiran
Journal: Journal of Clinical Oncology (2013)

e19107 Background: In this study, the efficacy and safety of pemetrexed chemotherapy was evaluated retrospectively in patients who were non-responders to or who have demonstrated progression after the first and/or second line treatments in local advanced and metastatic NSCLC. Methods: 175 patients (139 males, 36 females) were assessed in years 2008 – 2012. Patients were given pemetrexed 500 mg/m 2 , and the ones receiving combined treatment were given pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 once in every 21 days. Supplementary steroid and vitamin treatment were administered to all patients. Age, gender, performance status (PS), stage, single agent or combined administration of treatment, progression-free survival (PFS) and overall (OS) were investigated. Patients were assessed in terms of treatment efficacy and toxicity. Results: Median follow-up period was 6 months (1 - 25), and median age was 55 years (28 - 83). In 82% of patients, PS was 0 – 1. 73% of patients were at stage 4. 71% of the patients received single agent pemetrexed, and 14% received platinum - pemetrexed combination treatment. 93% of patients received pemetrexed treatment as second line. Median 3 cycles of treatment (1 – 12) were administered. In side effect assessment, while side effects (grade 1 – 4) were observed in 62% of the patients, the most frequently observed side effects were anemia (18%) and nausea-vomiting (15%). Febrile neutropenia was detected in 6 patients (3.4%).In assessment of the response, the disease control ratio was 50% (21% partial response, 29% stable disease). 1- and OS rates were respectively 14% and 41%. Median OS was 10 months (SE:1, 95% CI: 7-12) and median PFS was 3 months (SE:1, 95% CI: 2-4). In multivariate analysis, PS of 0 – 1 and response to treatment were found as factors with prognostic significance (p=0.047, p=0.014, respectively). Conclusions: It is observed that chemotherapy regimen containing pemetrexed in NSCLC treatment is a treatment approach, which provides an efficient disease control with a manageable side effect profile, in patients especially with good performance status and with no platinum resistance, who can receive treatment in combination form.
Abstract 17750: Prolyl Hydroxylase Inhibition Induces Sdf-1 and Cxcr4 Expression to Increase Cxcr4+ Cell Homing and Myocardial Repair
Authors: Santhosh Kumar Ghadge, Thi Van Pham, Moritz Messner, Maximilian Doppelhammer, Britta Husse, Wolfgang-Michael Franz, Marc-Michael Zaruba
Journal: Circulation (2015)

Objective: Stabilization of the cardiac SDF-1/CXCR4 axis attenuates ischemic cardiomyopathy. However, HIF-1α dependent SDF-1 upregulation lasts only for 48-72 hours after myocardial infarction (MI) limiting the targeting of regenerative cells. Therefore, we hypothesized that activation of the HIF-1α target genes SDF-1 and CXCR4 by stabilization of HIF-1α through inhibition of prolyl hydroxylase stimulates myocardial repair. Methods: Genetically tagged SDF1-EGFP and CXCR4-EGFP mice were subjected to optimal doses (80mg/kg i.p.) of the prolyl hydroxylase Inhibitor dimethyloxalylglycine (DMOG). To examine the time frame of SDF-1 and CXCR4 expression in vitro (HEK cells) and in vivo (BM &amp; heart), DMOG was treated at different dosing regimens (50μM to 1000μM &amp; 80mg/kg i.p.) and time intervals (1 to 6 hrs). FACS and immunhistochemical analyses of CXCR4+ BM, peripheral blood, and heart cells as well as infarct size measurements and hemodynamic analyses were performed with and without DMOG treatment after MI. Results: SDF1-EGFP mice treated with DMOG showed robust induction of SDF-1 in heart vessels. In vitro , SDF-1 was transiently upregulated within 60 mins to 2 hrs after DMOG treatment, followed by significant decrease after 6hrs. CXCR4 was elevated at later time points (6h). In vivo , CXCR4 expression was significantly upregualted in BM (6h). FACS analyses of transgenic CXCR4-EGFP BM and hearts revealed that CXCR4+ was frequently expressed on CD11b+ monocytes, and at lower Levels on angiogenic CD31+ , CD34+, c-kit+, and Flk1+ cells, and stem cell populations like CD133+ and Lin-/c-kit+/Sca-1+. DMOG treatment after MI revealed a robust upregulation of CXCR4+ cell populations, predominantly of angiogenic CXCR4+/CD11b+ monocytes. Subanalysis of the latter showed that DMOG treatment leads to a shift of the CD206+/CD86 ratio in favor of M2 macrophages associated CD206+ subpopulation after MI associated by attenuated infarct remodeling. Myocardial function was significantly improved after DMOG treatment (EF: 33,5 vs. 16%). Conclusion: Our data suggest that inhibition of prolyl hydroxylase may be a promising target for HIF-1a mediated SDF-1 activation to increase CXCR4+ stem cell homing and myocardial repair.
Artery-Associated Sympathetic Innervation Drives Rhythmic Vascular Inflammation of Arteries and Veins
Authors: Alba de Juan, Louise Madeleine Ince, Robert Pick, Chien-Sin Chen, Filippo Molica, Gabriele Zuchtriegel, Chen Wang, Dachuan Zhang, David Druzd, Maximilian E.T. Hessenauer, Graziano Pelli, Isa Kolbe, Henrik Oster, Colette Prophete, Sophia Martina Hergenhan, Urs Albrecht, Jürgen Ripperger, Eloi Montanez, Christoph A. Reichel, Oliver Soehnlein, Brenda R. Kwak, Paul S. Frenette, Christoph Scheiermann
Journal: Circulation (2019)

The incidence of acute cardiovascular complications is highly time-of-day dependent. However, the mechanisms driving rhythmicity of ischemic vascular events are unknown. Although enhanced numbers of leukocytes have been linked to an increased risk of cardiovascular complications, the role that rhythmic leukocyte adhesion plays in different vascular beds has not been studied. We evaluated leukocyte recruitment in vivo by using real-time multichannel fluorescence intravital microscopy of a tumor necrosis factor-α-induced acute inflammation model in both murine arterial and venous macrovasculature and microvasculature. These approaches were complemented with genetic, surgical, and pharmacological ablation of sympathetic nerves or adrenergic receptors to assess their relevance for rhythmic leukocyte adhesion. In addition, we genetically targeted the key circadian clock gene Bmal1 (also known as Arntl) in a lineage-specific manner to dissect the importance of oscillations in leukocytes and components of the vessel wall in this process. In vivo quantitative imaging analyses of acute inflammation revealed a 24-hour rhythm in leukocyte recruitment to arteries and veins of the mouse macrovasculature and microvasculature. Unexpectedly, although in arteries leukocyte adhesion was highest in the morning, it peaked at night in veins. This phase shift was governed by a rhythmic microenvironment and a vessel type-specific oscillatory pattern in the expression of promigratory molecules. Differences in cell adhesion molecules and leukocyte adhesion were ablated when disrupting sympathetic nerves, demonstrating their critical role in this process and the importance of β2-adrenergic receptor signaling. Loss of the core clock gene Bmal1 in leukocytes, endothelial cells, or arterial mural cells affected the oscillations in a vessel type-specific manner. Rhythmicity in the intravascular reactivity of adherent leukocytes resulted in increased interactions with platelets in the morning in arteries and in veins at night with a higher predisposition to acute thrombosis at different times as a consequence. Together, our findings point to an important and previously unrecognized role of artery-associated sympathetic innervation in governing rhythmicity in vascular inflammation in both arteries and veins and its potential implications in the occurrence of time-of-day-dependent vessel type-specific thrombotic events.
Overcoming cisplatin resistance in lung cancer by inhibiting mTOR
Authors: Chunjing Wu, Medhi Wangpaichitr, Tien Kuo, Lynn G. Feun, Carlos Robles, Alex J. Furst, Theodore J. Lampidis, Niramol Savaraj
Journal: Cancer Research (2005)

1498  Cisplatin resistance is usually complex and involves several mechanisms. Employing gene array analysis in a variety of cisplatin resistant cell lines, we found that they share the common characteristics of increase in ribosomal proteins and in elongation factors. We hypothesize that in order to survive cisplatin treatment, tumor cells have to turn on the protein synthesis machinery to make DNA repair proteins, antiapoptotic and growth survival proteins which account for their common feature of increased ribosomal proteins and elongation factors. To overcome this complex resistance, we have used mTOR inhibitor (CCI-779, known to inhibit ribosomal biogenesis, elongation factor and other 5’CAP mRNAs) in 4 cisplatin resistant lung cancer cell lines and in 3 de-novo cisplatin resistant cell lines derived from lung cancer patients who failed cisplatin. Indeed, our results demonstrated that after adding 10 ng/ml of CCI-779 (10% growth inhibitory dose), the ID50 of cisplatin decreased by 5-6 fold in 6 cell lines. Only one cisplatin resistant cell line did not respond to the reversal effect of CCI-779 (ID50 decreased by 1.7 fold). This resistant cell line and its parental line also were also relatively resistant to CCI-779 with the ID50 of 8-9 ug/ml. Furthermore, after adding CCI-779 to cisplatin, these resistant cells also undergo apoptosis. In contrast, this potentiation effect is not seen in their parental lines (the ID50 decreased only by 1-2 fold). Biochemical studies showed that after adding CCI-779, the amount of elongation factor is much less. 4E-BP phosphorylation (at Thr 70) as well as phospho P70S6kinase (at Thr 389) were also much less when compared with cisplatin alone. In contrast, in parental cells, the phosphorylation of 4E-BP was already decreased after cisplatin and only slightly decreased after CCI-779 which may explain why CCI-779 has less potentiation with cisplatin in parental cells. In addition, hTERT which is higher in cisplatin resistant cells, also decreased after adding CCI-779. Interestingly, gene specific array data obtained from this panel of cell lines demonstrated that the cell line which is relatively resistant to the reversal effect of CCI-779 has much less AKT1, AKT2, PDK1and PDK2. These results suggest that AKT signaling may be important in determining mTOR sensitivity and its ability to reverse cisplatin resistance. Overall, we conclude that mTOR inhibitor can restore cisplatin sensitivity in cisplatin resistant lung cancer cell lines. This drug combination should be further explored for future clinical use. Supported by VA research fund
Computational Biology Model of ETP-ALL Used to Accurately Classify ETP-ALL Vs Non ETP-ALL Patients with Genomic Input
Authors: Leylah M. Drusbosky, Ansu Kumar, Shwetha K, Sumanth Vasista, Anuj Tyagi, Swaminathan Rajagopalan, Aftab Alam, Taher Abbasi, Shireen Vali, Girish Chinnaswamy, Manju Sengar, Bijal D. Shah, Christopher R. Cogle
Journal: Blood (2017)
Combining tumor-targeted superantigens with docetaxel results in synergistic anti-tumor effects in B16 tumor bearing mice.
Authors: Anette Sundstedt, Mona Celander, Marie Wallen Ohman, Goran Forsberg, Gunnar Hedlund
Journal: Cancer Research (2008)

2075  In this study we explored the possibility of combining immunotherapy against cancer with the well-established cytostatic drug docetaxel. Tumor-targeted superantigens (TTS) utilizes the powerful T cell activating property of the superantigen staphylococcal enterotoxin A (SEA) in fusion with an anti-tumor Fab-fragment to target this T cell activity against tumor cells. TTS fusion proteins are efficient in a number of experimental tumor models including the B16 mouse melanoma transfected with a human tumor-associated antigen (GA733-2 or EpCam) recognized by the C215 monoclonal antibody. The distinct mechanisms of action of TTS and docetaxel provide the prerequisites for successful combination treatment. However, as a result of the anti-proliferative properties of cytostatic drugs, chemotherapy may potentially interfere with TTS immune activation during combination treatment. Here we evaluated the anti-tumor effects of combining the TTS protein C215Fab-SEA (4 daily injections of 10 μg/mouse i.v.) with docetaxel (1 mg/mouse i.p.) against B16-C215 tumors growing in the lung of C57Bl/6 mice. Both drugs showed a significant reduction in the number of lung tumors when administered alone. Prior treatment with docetaxel at therapeutic doses did not interfere with superantigen induced T cell activation but rather appeared to enhance the response, while simultaneous treatment was suppressive. Thus, docetaxel was given before or before and after the TTS cycle and these combinations significantly improved therapy further reducing the number of lung tumors as compared to mono therapies. In long term tumor survival experiments using the same tumor model, docetaxel treatment before and/or after one or two TTS treatment cycles synergistically prolonged the survival. When docetaxel was given before and after (days 2 and 9) C215Fab-SEA treatment (days 3-6), the prolonged median survival time of the combination treatment was more than 6.3 and 11.4 times the prolonged median survival times of C215Fab-SEA and docetaxel mono therapies, respectively. These results demonstrate that TTS immunotherapy is highly compatible with docetaxel and suggest a significant potential of the combination for human cancer therapy.
Evaluation of treatment benefit to an unselected population of patients with metastatic colorectal cancer, referred to oncological treatment.
Authors: Svend Erik Nielsen
Journal: Journal of Clinical Oncology (2013)

e14677 Background: Patients, with metastatic colorectal cancer (mCRC), participating in clinical trials are a selected group with a better performance status compared to all patients, who are referred to oncological treatment. The aim of the study was to evaluate the benefit of standard treatment modalities, offered to an unselected group of patients, referred to our Dept. of Oncology. Methods: Consecutive patients treated with more than one cycle of chemotherapy, registrated in our database from May 2003 to July 2012, were included. Clinical information was obtained from patient files. The outcome was overall survival for various groups. Following parameters were collected: Gender, age, primary tumor site, resection status of primary tumor, number of metastic sites, liver-only mets, number of chemotherapy regimens, +/- Bevazicumab and rate of palliative radiation. Results: 266 consequtive patients, treated with more than one cycle of chemotherapy, were included. Median age 67 (31-86) years, 150 male (59%). Distribution of the primary tumor was 35/37/28% for rectum/left colon/right colon. 192/59/15 (72/22/6%) had the primary tumor resected/not resected/stent. 54/37/9% had one metastic site/ two sites/three or more sites. 24% had liver only. As first line chemotherapy 29% received Capecitabine (CAP), 55% CAP + Oxaliplatin, and 8% CAP + Irinotecan. 44% received Bevacizumab. 69%/27% received either second and third line chemotherapy. 19% received palliative radiotherapy. Median OS for the whole population was 17 months CI ( 15-19). Patients with one, two or three, or more mets sites had a OS of 21(CI: 16-26)/17 (14-20)/9 (4-149) months, respectively. For patients receiving one, two, or three lines of chemotherapy OS was respectively 8/16/28 months. Addition of Bevacizumab to chemotherapy regimens had an OS of 27 months CI (24-30), compared to 20 months (16-24) for chemotherapy alone. Conclusions: Unselected mCRC patients, treated with standard chemotherapy regimens, seem to obtain the same OS benefit as seen in clinical trials. Survival benefit was dependent on the number of metastatic sites, the number of cht. regimens received and addition of Bevacizumab to the treatment.
Lectures on Nasal Obstruction.
Journal: JAMA (1901)

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