tbuckley/cabot-search huggingface dataset:
HotBalloon Ablation of the Pulmonary Veins for Paroxysmal AF
Authors: Hiroshi Sohara, Tohru Ohe, Ken Okumura, Shigeto Naito, Kenzo Hirao, Morio Shoda, Youichi Kobayashi, Yasuteru Yamauchi, Yoshio Yamaguchi, Taishi Kuwahara, Haruo Hirayama, Chun YeongHwa, Kengo Kusano, Kazuaki Kaitani, Kimikazu Banba, Satoki Fujii, Koichiro Kumagai, Hisashi Yoshida, Masashi Matsushita, Shutaro Satake, Kazutaka Aonuma
Journal: Journal of the American College of Cardiology (2016)

Point-by-point catheter ablation is an established treatment for drug-refractory paroxysmal atrial fibrillation (PAF). However, it is time consuming, requires excellent technique to achieve complete pulmonary vein (PV) isolation, and is associated with severe complications. The purpose of this study was to evaluate the safety and effectiveness of a HotBalloon ablation (HBA) compared with antiarrhythmic drug therapy (ADT) for the treatment of PAF. A prospective multicenter randomized controlled study was conducted in Japan. Patients with symptomatic PAF refractory to antiarrhythmic drugs (Class I to IV) were randomized to HBA or ADT at a 2:1 ratio and assessed for effectiveness in a comparable 9-month follow-up period. A total of 100 patients in the HBA group and 43 patients in the ADT group received treatment at 17 sites. HBA procedure produced acute complete PV isolation in 98.0% (392 of 400) of the PVs and in 93.0% (93 of 100) of patients in the HBA group. The chronic success rates after the 9-month effective evaluation period were 59.0% in the HBA group (n = 100) and 4.7% in the ADT group (n = 43; p < 0.001). The incidence of major complications was 11.2% (15 of 134 patients). The incidences of PV stenosis (>70%) and transient phrenic nerve injury were 5.2% and 3.7%, respectively. The mean fluoroscopy time was 49.4 ± 26.6 min (n = 134), and the mean procedure duration was 113.9 ± 31.9 min (n = 133). This study demonstrates the superiority of HBA compared with ADT for treatment of patients with PAF, and a favorable safety profile.
The Protein Kinase C beta (PKCβ) Inhibitor Enzastaurin HCl (LY317615) Augments Chemosensitivity of Multiple Myeloma (MM) Cells to Dexamethasone and the Proteasome Inhibitor Bortezomib.
Authors: Attaya Suvannasankha, Dawei Xu, Rafat Abonour
Journal: Blood (2004)
Abstract 4210: Patient-derived models of human acute myeloid and lymphoid leukemia in immunocompromised mice for preclinical drug development
Authors: Eva Oswald, Kerstin Klingner, Benedikt Hammerich, Gabriele Greve, Dorothee Lenhard, Milena Pantic, Heinz-Herbert Fiebig, Michael Luebbert, Julia B. Schüler
Journal: Cancer Research (2015)

Abstract The generation of functional and reproducible in vivo models is a prerequisite for a better understanding of hematological malignancies and for the development of improved therapeutic strategies. Here, we report the establishment of transplantable PDX models of acute myeloid and lymphoid leukemia (AML, ALL) growing subcutaneously (s.c.) as well as in a disseminated fashion in immunocompromised mice. Bone marrow (BM) and peripheral blood (PB) cells from 25 AML/ALL patients were injected intratibially into NSG or NOG mice (n = 1-9/patient) and in later passages also s.c. in nude mice (n = 1-3/model). Tumor growth was monitored via determination of overall survival, flow cytometry (verification of patient-derived leukemic clones by hCD34, hCD33, hCD38, hHLA-ABC, hCD3, hCD45, mCD45), and, where applicable, by caliper measurement. Engraftment is defined as ≥5% hCD45+ cells in the BM and/or ≥1% hCD45+ cells in PB. Transplantable models (higher or equal passage 2) were tested with the respective standard of care drugs (SoC) mainly Cytarabine and Dexamethasone. Bone marrow engraftment in passage 1 was observed for 11 out of 25 leukemia models. Four of them could be established as disseminated models in serial passage. No engraftment was detected for nine models during the observation period of at least 95 days while observation for five models is still ongoing. The four established models were further characterized by fluorescence-in-situ-hybridization (FISH) to confirm patient origin. Treatment of mice bearing the models with the SoC drugs cytarabine and dexamethasone significantly prolonged overall survival. Antitumoral activity was consistent with clinical response of the donor patient. One T-ALL and two AMLs were additionally successfully propagated following s.c. injection in nude mice. They showed stable growth behavior and displayed a similar chemo-sensitivity pattern as their disseminated growing counterparts. In conclusion, we have established a panel of transplantable PDX models of ALL and AML displaying stable and reproducible growth patterns suitable for in vivo efficacy studies. Our results confirm that PDX models of hematological malignancies replicate important clinical characteristics of the disease and are valuable tools for preclinical drug testing. Citation Format: Eva Oswald, Kerstin Klingner, Benedikt Hammerich, Gabriele Greve, Dorothee Lenhard, Milena Pantic, Heinz-Herbert Fiebig, Michael Luebbert, Julia B. Schüler. Patient-derived models of human acute myeloid and lymphoid leukemia in immunocompromised mice for preclinical drug development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4210. doi:10.1158/1538-7445.AM2015-4210
Abstract 657: Microtubule stabilizers inhibit the cellular transport and signaling of EGFR in breast cancer cells
Authors: Cristina Coral Rohena, Nicholas F. Dybdal-Hargreaves, Susan L. Mooberry
Journal: Cancer Research (2015)

Abstract Breast cancer is the second most diagnosed cancer in women and it is estimated that approximately 40,000 women die every year from this disease in this country alone. The overexpression of EGFR in breast cancer is associated with drug resistance and an aggressive nature resulting in an overall poor outcome. The EGFR signaling pathway requires internalization of the receptor, endosomal translocation and in some cases nuclear accumulation of the receptor. These processes are dependent on functional microtubules. Microtubule targeting agents (MTAs) have been used with great success in the treatment of breast cancer alone and in combination with other agents. MTAs impair microtubule dynamics, which results in the inhibition of mitosis. Microtubules are additionally important in cellular signaling events including cellular transport of the EGFR. The effects of the microtubule stabilizer taccalonolide AJ on EGFR transport and activation in breast cancer cells were compared to the effects of paclitaxel. Our results show that microtubule stabilization interrupts the cellular trafficking of EGFR, leading to the retention of the receptor in the cell periphery.. Taccalonolide AJ and paclitaxel impaired the association of EGFR with the early endosome and delayed its association with the lysosome. This disruption in cellular transport also led to decreased phosphorylation of EGFR downstream targets AKT, ERK1/2 and STAT3, with taccalonolide AJ being the more effective inhibitor. Our studies show that microtubule stabilizers also prevent the association of EGFR with the Golgi instead leading to the fragmentation of this organelle. Paclitaxel caused a higher degree of Golgi fragmentation and it was observed in nearly all cells. The inhibition of EGFR localization to the Golgi caused by taccalonolide AJ and paclitaxel suggests that microtubule stabilization interferes with the trafficking of EGFR to the nucleus. This was confirmed by our results showing that microtubule stabilization impairs the nuclear transport of EGFR in breast cancer cells. Not surprisingly, in this case, paclitaxel was much more effective at preventing this nuclear accumulation. These studies highlight the utility and versatility of microtubule stabilizers and suggest the potential for combination treatments with microtubule stabilizers and small molecule inhibitors of EGFR and EGFR dependent pathways in breast cancer. Citation Format: Cristina Coral Rohena, Nicholas F. Dybdal-Hargreaves, Susan L. Mooberry. Microtubule stabilizers inhibit the cellular transport and signaling of EGFR in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 657. doi:10.1158/1538-7445.AM2015-657
Detection of Pre-Transplant Clonal Cytogenetic Abnormalities in Stem Cells Used for Autologous Stem Cell Transplant in Relapsed Non-Hodgkin Lymphoma Is a Predictor of Relapse
Authors: Ana Maria Rojas, Lauren Pinter-Brown, Sven De Vos, Ronald Paquette, Gary J Schiller, Mary Carol Territo
Journal: Blood (2008)
A Phase II Study of Denileukin Diftitox (Ontak®) with CHOP Chemotherapy in Patients with Newly-Diagnosed Aggressive T-Cell Lymphomas, the CONCEPT Trial: Interim Analysis.
Authors: Francine M. Foss, Nelida Sjak-Shie, Andre Goy, Ranjana Advani, Eric Jacobsen, Mark Acosta
Journal: Blood (2006)
606. Use of a Bicistronic Vector to Silence SOD1 in Motoneurons and Astrocytes for the Treatment of Familial Amyotrophic Lateral Sclerosis
Authors: Julianne Bobela-Aebischer, Cylia Rochat, Nathalie Bernard-Marissal, Patrick Aebischer, Bernard L. Schneider
Journal: Molecular Therapy (2016)

Mutations in the superoxide dismutase 1 (SOD1) gene account for 20% of the familial cases of Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disorder mainly characterized by motoneuron degeneration. Mutant SOD1 exerts multiple pathogenic effects through the gain of toxic properties in both neurons and glial cells. While the expression of mutant SOD1 in motoneurons mainly determines disease onset, SOD1 pathology in non-neuronal cell types plays a key role in disease progression. In this setting, silencing mutant SOD1 expression by gene therapy in the key cell types appears as a logical approach to counteract its toxicity. To design the most effective approach for SOD1 silencing, we have evaluated the respective therapeutic contribution of AAV-miRNA-based targeting of mutated SOD1 either in motoneurons or in astrocytes. In this set of experiments, we used two separate vectors to target either cell type. Following vector administration to both newborn and adult ALS mice, most complete protection of motor units was obtained when targeting human SOD1 principally in motoneurons. Suppressing SOD1 in astrocytes also showed neuroprotective effects, which were clearly different from those observed with the motoneuron-targeting vector. Although we observed only partial protection of spinal motoneurons when suppressing SOD1 in astrocytes, muscle innervation was nearly completely preserved, indicating a possible effect on the ability of the remaining motoneurons to re-innervate the muscle. Therefore, while SOD1 silencing in motoneurons provides most effective neuroprotection in this ALS mouse model, targeting SOD1 in astrocytes may have complementary effects in restoring neuromuscular function. Based on these complementary effects, we tested if therapeutic efficacy could be improved by targeting SOD1 in both motoneurons and astrocytes using a single vector. We therefore designed a bicistronic AAV9 vector, allowing expression of miRNA against SOD1 in motoneurons and astrocytes using cell-type specific promoters. This vector contains an expression cassette under the control of the neuronal promoter synapsin, and a second cassette based on the astrocytic GFAP promoter. Compared to vectors targeting SOD1 in a single cell type, the bicistronic AAV9-miRNA SOD1 vector showed a superior therapeutic efficacy on the motor performance, following intrathecal injection in adult SOD1G93A mice. These results demonstrate the synergistic effect of targeting SOD1 in motoneurons and astrocytes by gene therapy. A further main advantage of this bicistronic vector is that it promotes the safety of this gene therapy approach. Indeed, the use of cell-type specific promoters can avoid undesired expression of the artificial miRNA in periphery. This new vector system has the potential to drastically improve the therapeutic benefits obtained by gene therapy in ALS patients.
5-Azacytidine for the Treatment of Acute Myeloid Leukemia: A Retrospective, Multicenter Study of 55 Patients.
Authors: Luca Maurillo, Alessandra Spagnoli, Mariella Genuardi, Monia Lunghi, Nicola Di Renzo, Alfonso Maria D’Arco, Giuseppe Mele, Alessandro Levis, Antonella Gozzini, Mario Petrini, Manuela Mianulli, Grazia Sanpaolo, Alberto Santagostino, Giuseppe Pietrantuono, Fiorella D’Auria, Dario Ferrero, Gianluca Gaidano, Felicetto Ferrara, Adriano Venditti, Giuseppe Leone, Valeria Santini, Pellegrino Musto
Journal: Blood (2008)
Functional Characterization of CD4+ T-Cells in Aplastic Anemia (AA)
Authors: Shahram Y Kordasti, Judith C. W. Marsh, Sufyan Al-Khan, Jie Jiang, Alexander E Smith, Azim M Mohamedali, Pilar Perez Abellan, Caroline Veen, Benedetta Costantini, Nana Benson Quarm, Thomas Seidl, Syed A Mian, Farzin Farzaneh, Ghulam J. Mufti
Journal: Blood (2011)
TIP30 acts as a tumor suppressor in hepatocarcinogenesis
Authors: Chao Jiang, Mitsuhiro Ito, Kristy Krumm, Xia Zhang, Jill Pecha, Jian Zhao, Yajun Guo, Robert Roeder, Hua Xiao
Journal: Cancer Research (2004)

5557  TIP30, a Tat-interacting protein, also called CC3 is a metastasis suppressor for small cell lung carcinoma (SCLC). Ectopic expression of TIP30 promotes apoptosis and inhibits angiogenesis. Although TIP30 has several characteristic features of a tumor suppressor in in vitro analyses, tumor development as a result of TIP30 inactivation has not been demonstrated in vivo and abnormal expression of TIP30 in human cancer has not been reported. Using genetically-engineered mice we found that TIP30-deficient mice have a high incidence of hepatocellular carcinoma and other tumors (41%) compared to wild type TIP30 mice (0%). Also, loss of TIP30 in mouse embryonic fibroblasts (MEFs) enhances susceptibility to transformation by the SV40 large T antigen. Moreover, immunohistochemical analysis indicates that reduced TIP30 expression is associated with 33% of human hepatocellular carcinomas. DNA sequencing indicated that some of these carcinomas harbor missense mutations in the TIP30 gene. Additionally by transient transfection of GFP-TIP30 and GFP-TIP30 mutant to hepatocellular carcinoma cell line, HepG2, we found mutantions in TIP30 changed cellular localization of TIP30. Furthermore, western blot analysis and protein stability assay showed mutantions in TIP30 also reduced the half-life of TIP30 in HepG2 cells, thereby causing abnormal expression of TIP30. Taken together, these results suggest that the TIP30 gene is a tumor susceptibility gene which plays an important role in the suppression of hepatocarcinogenesis.
L-Leucine Improves the Anemia of DBA and the 5q- Syndrome Via Activation of the mTOR Pathway in a p53-Independent Manner
Authors: Nirmalee Abayasekara, Anupama Narla, Slater Hurst, Hong Sun, Maria Virgilio, Elspeth Payne, Benjamin L. Ebert, A. Thomas Look, Nancy Berliner, Arati Khanna-Gupta
Journal: Blood (2012)
A Two Step Approach to Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for High Risk Patients with Hematologic Disorders.
Authors: Neal Flomenberg, Dolores Grosso, Janet Brunner, Matthew Carabasi, Scott Dessain, Joanne Filicko-OHara, Bijoyesh Mookerjee, Nyree Tedesco, John L. Wagner, Maria Werner-Wasik
Journal: Blood (2007)
Post-remission therapy with 4 cycles of intermediate (I) or high-dose (HD) cytarabine (AC) or autologous hematopoietic stem cell transplantation (ASCT) for acute myeloid leukemia (AML) patients &lt;60 years with normal cytogenetics: A Cancer and Leukemia Group B (CALGB) Study
Authors: S. S. Farag, A. Ruppert, K. Mrozek, J. E. Kolitz, R. J. Mayer, A. J. Carroll, B. L. Powell, J. O. Moore, R. A. Larson, C. D. Bloomfield
Journal: Journal of Clinical Oncology (2004)

6542 Background: The optimal post-remission treatment (Rx) of AML patients with normal cytogenetics has not been extensively studied. Methods: We compared the outcome of 4 intensive post-remission treatment in 280 AML patients with normal cytogenetics, median age 44 (range, 18–59) years, who achieved complete remission (CR) on 5 successive front-line CALGB protocols. Patients were in CR after induction treatmen with AC + daunorubicin (D), ACD + etoposide (E) or ACDE + PSC-833. Post-remission intensification included 1 cycle HDAC (3 g/m2) followed by 1 cycle E+cyclophosphamide and 1 cycle mitoxantrone +diaziquone (Rx-I); HDAC for 3 cycles (Rx-II); IDAC (400 mg/m2) for 4 cycles or HDAC for 4 cycles (Rx-III), or HDAC+E followed by HD busulfan/E and ASCT (Rx-IV). IDAC and HDAC x 4 gave similar DFS (P=0.99) and OS (0.81) and were combined (I/HDAC) in further analysis. Median follow-up is 7.4 (range, 2.2–16.6) years. Results: The outcome of an intent-to-treat analysis of post-remission treatment is shown in the table. Multivariable analysis (MVA) controlling for number of induction cycles, age, white cell count and other pre-treatment variables showed that I/HDAC x 4 improved DFS over HDAC x 3 (P=0.01) and Rx-I (P=0.0005), but was similar to ASCT (P=0.20). ASCT also improved DFS over Rx-I (P=0.04). On MVA I/HDAC improved OS only over Rx-I (P=0.02), whereas ASCT did not significantly improve OS relative to Rx-I (P=0.28). Conclusions: In AML patients <60 years with normal karyotype, either 4 cycles of I/HDAC or ASCT improved DFS relative to less intensive post-remission therapy. No significant financial relationships to disclose.
Abstract 4104: LIX1L, an EMT-correlated gene that behaves as if it inhibits the EMT
Authors: Mihoko Yamade, Yves Pommier, Kurt W. Kohn
Journal: Cancer Research (2015)

Abstract Background: We previously reported that LIX1L (LIX1-like), a gene whose functions are unknown, has an expression pattern exhibiting strong negative correlation with the expression of genes of epithelial-specific functions in the NCI-60 human cancer cell line panel of the US National Cancer Institute (Kohn et al PLoS ONE 9:6, 2014). This observation suggested a possible role in the epithelial-to-mesenchymal transition (EMT) and led to the current investigation. Method]: We examined the correlation of LIX1L with gene expression in the data of the Broad Institute's CCLE cell lines and the cancer genome atlas (TCGA) tissues. We then investigated the functions of LIX1L in breast and colon cancer cell lines. We knocked down LIX1L expression by means of siRNA and overexpressed LIX1L by means of recombinant LIX1L-GFP plasmid. We also generated LIX1L knockout cell lines (LIX1L-KO) using the CRISPR/Cas system. We compared the expression levels of LIX1L with well-known EMT-related genes by Western blot and quantitative PCR. We examined the migration and invasion properties of these cell lines and constructs by means of wound healing assays, and migration and invasion assays. Results: LIX1L expression is correlated with non-epithelial or mesenchymal genes in analyses of the CCLE and TCGA gene expression data. Experiments suggested the surprising result that LIX1L-KO MDA-MB231 cell lines showed higher expression of ZEB1 and increased invasion ability. Conclusion: LIX1L gene expression is positively correlated with the expression of non-epithelial or mesenchymal genes in the NCI-60, CCLE and TCGA databases. Up- or down-regulation of LIX1L however seemed to produce the opposite of the expected phenotypic changes. Our findings suggest that LIX1L may be expressed coordinately with genes that favor epithelial-to-mesenchymal transitions in cancer cells while having a moderating effect on the transition. Citation Format: Mihoko Yamade, Yves Pommier, Kurt W. Kohn. LIX1L, an EMT-correlated gene that behaves as if it inhibits the EMT. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4104. doi:10.1158/1538-7445.AM2015-4104
Differential Expression of Mirna* Species in Cancer and the Contribution of MiR-223* to the Development of Acute Myeloid Leukemia.
Authors: Florian Kuchenbauer, Sarah M Mah, Andrew McPherson, Michael Heuser, Bob Argiropolous, Ryan Morin, Tobias Berg, David Lai, Andrew L Muranyi, Donna E. Hogge, Jens Ruschmann, Daniel T. Starczynowski, Aly Karsan, Michael O'Connor, Connie J. Eaves, Akira Watahiki, Yuzhuo Wang, Samuel Aparicio, Arnold Ganser, Juergen Krauter, Jonathan Johnnidis, Marco Marra, Fernando Carmago, R. Keith Humphries
Journal: Blood (2009)
Multidimensional Flow Cytometry Significantly Improves Upon the Morphologic Assessment of Post-Induction Marrow Remission Status – Comparison of Morphology and Multidimensional Flow Cytometry; A Report From the Children's Oncology Group AML Protocol AAML0531
Authors: Michael R. Loken, Todd A. Alonzo, Laura Pardo, Robert B. Gerbing, Richard Aplenc, Lillian Sung, Susana C. Raimondi, Betsy A. Hirsch, Samir Kahwash, Amy Heerema-McKenney, Laura Winter, Kathleen Glick, Patti Byron, Laura Fransisco, Tanya Wallas, Stella M. Davies, Franklin O. Smith, Alan S. Gamis, Soheil Meshinchi
Journal: Blood (2011)
Final results of a chemoprevention trial with enzastaurin in former smokers.
Authors: J. E. Gray, S. Altiok, M. Alexandrow, F. Walsh, J. Chen, D. Tai, G. Bepler
Journal: Journal of Clinical Oncology (2011)

1507 Background: Current treatment options for lung cancer have low cure rates. Chemoprevention is crucial for reducing lung cancer incidence and mortality. Enzastaurin is a selective inhibitor of protein kinase C β with potent antiproliferative, proapoptotic, and antiangiogenic activities. The primary objective of this study was to compare average Ki-67 LI (percentage of cells positively labeled with Ki-67, a marker of cellular proliferation) in bronchial biopsy specimens of former smokers, collected before and after treatment between enzastaurin and placebo. Methods: Persons ≥45 yrs of age with bronchial meta/dysplasia and smoking ≥30 PY with ≥1 yr cessation were enrolled in this phase IIB, randomized, placebo-controlled, double-blind study. Eligible subjects had a bronchoscopy with collection of at least three biopsies at prespecified sites. Subjects were then randomized (2:1) to receive 6 months treatment with either enzastaurin (500 mg QD orally) or placebo. Stratification occurred based on presence vs. absence of dysplasia, prior stage I non-small cell lung cancer (NSCLC), and airway obstruction (FEV1/FVC ≤0.7 vs. >0.7). Results: Of 40 subjects randomized, 68% were male and mean age=66.9 yrs. Two had stage I NSCLC, 3 had dysplasia, 24 had airway obstruction, and 9 had an ECOG PS 1. Of all patients with pre-and post-treatment bronchial samples (n=32), 9 had decreased Ki-67 LI from baseline to 6 months of therapy with either enzastaurin or placebo (greatest mean change %:−27.7%). Of patients with meta/dysplastic lesions (n=27), 5 had decreased Ki-67 LI (greatest mean change %:−19.2). Treatment-related adverse events (AEs) are as follows: G1=20; G2=9, and G3=5. Seven subjects discontinued due to AEs (n=3: DVT, hyponatraemia, and rash), subject decision (n=2), or physician decision (n=2). Two subjects had ≥1 serious AEs (bradycardia, DVT, and hypotension). Conclusions: This represents the first completed chemoprevention trial with a non-FDA approved, oral, small molecule targeted agent and provides insight into the implementation and conduct of such trials. Few subjects experienced serious AEs. Final unblinded Ki-67 results and translational work will be available at meeting. Funded by NCI SPORE: P50-CA119997 & U01-CA101222.