tbuckley/cabot-search huggingface dataset:
Abstract 688: Activating JAK1-S703I mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma patient-derived xenograft tumor models
Authors: Shuqun Yang, Chonglin Luo, Qingyang Gu, Qiang Xu, Hongye Sun, Ziliang Qian, Yexiong Tan, Hao Wu, Yuxin Qin, Yuhong Shen, Xiaowei Xu, Shu-Hui Chen, Chi-Chung Chan, Hongyang Wang, Mao Mao, Douglas D. Fang
Journal: Cancer Research (2015)

Abstract Hepatocellular carcinoma (HCC) is the fifth most common type of cancer worldwide. However, current therapeutic approaches for this epidemic disease are limited and its 5-year survival rate has not been improved in the past decades. Patient-derived xenograft (PDX) tumor models have become an excellent in vivo system for understanding of disease biology and drug discovery. In order to identify new therapeutic targets for HCC, whole-exome sequencing (WES) was performed on more than 60 HCC PDX models. Among them, four models exhibited point mutations in JAK1 (Janus Kinase) gene, which were confirmed by Sanger sequencing. To explore the transforming capability, these mutations were then introduced into 293T and Ba/F3 cells by transient transfection and retroviral infection, respectively. The results demonstrated that JAK1S703I mutation was able to activate JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway and drive cell proliferation in the absence of cytokine stimulation in vitro. Furthermore, a modest sensitivity to the treatment of a JAK1/2 inhibitor, Ruxolitinib, was observed in JAK1S703I mutant PDX model, but not in other mutant or wild type models. Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib-treated tumor tissues was significantly inhibited. Collectively, our results suggested that JAK1S703I is an activating mutation for JAK-STAT signaling pathway in vitro and in vivo. JAK-STAT pathway might represent a new therapeutic opportunity for HCC. Monotherapy using a more potent inhibitor and combinatory therapy may be further explored in JAK1S703I mutant PDX model. Citation Format: Shuqun Yang, Chonglin Luo, Qingyang Gu, Qiang Xu, Hongye Sun, Ziliang Qian, Yexiong Tan, Hao Wu, Yuxin Qin, Yuhong Shen, Xiaowei Xu, Shu-Hui Chen, Chi-Chung Chan, Hongyang Wang, Mao Mao, Douglas D. Fang. Activating JAK1-S703I mutation may predict the sensitivity of JAK-STAT inhibition in hepatocellular carcinoma patient-derived xenograft tumor models. [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 688. doi:10.1158/1538-7445.AM2015-688
Loss of Imprinting at the 14q32 Domain Leads to MicroRNA Overexpression in Acute Promyelocytic Leukemia
Authors: Floriana Manodoro, Jacek Marzec, Jun Wang, Tracy Chaplin, Jelena V Jovanovic, Moravcsik Eva, Iqbal Sameena, David Grimwade, John Gribben, Bryan D Young, Silvana Debernardi
Journal: Blood (2013)
Abstract 4365: Targeting the SF3B1 spliceosome protein: Development of a reporter for HTS screen and pharmacodynamic profiling of small molecule drug leads
Authors: Yihui Shi, Chandraiah Lagisetti Lagisetti, Amanda S. Joyner, Lidia C. Sambucetti, Thomas R. Webb
Journal: Cancer Research (2015)

Abstract The spliceosome is an important emerging target for cancer therapy that has only recently been uncovered that represents an exciting new opportunity for therapeutic intervention in cancer. Two naturally occurring bacterial products show striking selective toxicity to tumors and have recently been found to act by targeting the SF3b subunit of the spliceosome, thus modulating pre-mRNA splicing in tumor cells. However, these natural products, and analogs derived from them, are synthetically quite complex. We have designed and optimized a class of novel synthetic small molecules, called sudemycins, which also modulate alternative splicing and have substantial antitumor activity. Previous work in our lab has shown that our lead compound, sudemycin D6 has significant in vivo antitumor activity. We now report the development of a high-throughput cell-based luciferase reporter system that has multiple applications in facilitating splicing modulatory drug discovery and development. Citation Format: Yihui Shi, Chandraiah Lagisetti Lagisetti, Amanda S. Joyner, Lidia C. Sambucetti, Thomas R. Webb. Targeting the SF3B1 spliceosome protein: Development of a reporter for HTS screen and pharmacodynamic profiling of small molecule drug leads. [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 4365. doi:10.1158/1538-7445.AM2015-4365
Effects of a Novel Histone Deacetylase Inhibitor, PXD101, When Used as Monotherapy or in Combination with Bortezomib on Tumor Growth in Mouse Models of Human Multiple Myeloma.
Authors: Richard A. Campbell, Eric Sanchez, Haiming Chen, Lauren Turker, Olivia Trac, Mingjie Li, Dror Shalitin, Melinda S. Gordon, Shen Pang, Benjamin Bonavida, Jonathan Said, Michael Jeffers, Xiaozhong Qian, Henri S. Lichenstein, James R. Berenson
Journal: Blood (2006)
Enhancing Effects of CCL19 on Antigen Uptake and Antigen Presenting Ability of Human Mature Dendritic Cells (DCs).
Authors: Ayumi Yokoyama, Miwako Narita, Naoko Sato, Asuka Sekiguchi, Anri Saito, Norihiro Watanabe, Masuhiro Takahashi
Journal: Blood (2004)
Global gene expression analysis of heterotypic interaction between cancer cells and osteoblasts in vitro to detect signaling pathways relevant for bone metastasis in breast cancer patients.
Authors: M. Buess, M. Rajski, B. Vogel, C. Rochlitz
Journal: Journal of Clinical Oncology (2011)

10515 Background: Bone metastasis is a main cause of morbidity in breast cancer. Since breast cancer is a heterogeneous disease, the interactions of cancer cells with the skeletal host cells might also be diverse. On a genome-wide scale gene expression alterations caused by interactions between tumor cells and osteoblasts are not yet well characterized. We hypothesized that gene expression signatures induced by tumor-osteoblast interaction might be clinically relevant. Methods: We established an ex vivo co-culture model with either benign or a panel of 5 malignant breast epithelial cells and primary human osteoblasts and determined associated gene expression changes with HEEBO microarrays. Pretreatment expression profiles of 295 early stage breast cancers from the Netherlands Cancer Institute with a median follow up of 12.6 years allowed evaluating in vitro effects in the in vivo situation. Results: The effects of the interaction between osteoblasts and breast cancer cell lines of different origin were very heterogeneous. Hs578T cells proliferated better in co-culture with osteoblasts, SKBR-3 induced a TGF-β response and MDA-MB231 cells showed two distinct sets of up-regulated genes: A set of interferon response genes associated with an up-regulation of STAT1 was remarkably coherent in vivo providing a basis for segregation of tumors into two groups. In a uni-variate analysis, early stage tumors with high expression levels (n=136) of this gene set had a significantly lower overall survival rate (p= 0.005) (63% at 10 years) than tumors with low expression levels (n=159) (overall survival: 77% at 10 years). The second gene set was associated with IL-6 and did not significantly change the overall survival rate (p=0.165), but was significantly associated with a shorter time to bone metastasis (p=0.049; 74% vs. 83% at 10 years). Conclusions: An IL-6 gene expression pattern induced by heterotypic interaction of breast cancer cells with osteoblasts in vitro is associated with a higher rate of bone metastasis in vivo. This suggests that blocking the IL-6 pathway might be a therapeutic strategy to reduce bone metastasis in breast cancer.
Cured meat intake is associated with worsening asthma symptoms
Authors: Zhen Li, Marta Rava, Annabelle Bédard, Orianne Dumas, Judith Garcia-Aymerich, Bénédicte Leynaert, Christophe Pison, Nicole Le Moual, Isabelle Romieu, Valérie Siroux, Carlos A Camargo, Rachel Nadif, Raphaëlle Varraso
Journal: Thorax (2016)

<h3>Background</h3> Cured meat intake—a recent carcinogenic factor—may increase the risk of COPD, but its association with asthma remains unknown. Though body mass index (BMI) is a likely risk factor for asthma, its role in the diet–asthma association as a mediator has never been studied. We investigated the association between cured meat intake and worsening asthma symptoms in adults, and the role of BMI as a potential mediator. <h3>Methods</h3> Using data from the French prospective EGEA study (baseline: 2003–2007; follow-up: 2011–2013), we applied a mediation analysis in the counterfactual framework, a marginal structural model (MSM), to estimate the direct effect of baseline cured meat intake (&lt;1, 1–3.9, ≥4 servings/week) on change in asthma symptom score (worsening or not), and the indirect effect mediated by BMI. <h3>Results</h3> Among the 971 participants (mean age 43 years; 49% men; 42% with asthma), 20% reported worsening asthma symptoms during the mean follow-up time of 7 years. Using the MSM, we reported a positive direct effect of cured meat intake on worsening asthma symptoms (multivariable OR=1.76, 95% CI 1.01 to 3.06 for ≥4 vs &lt;1 serving/week). We also reported an indirect effect mediated by BMI (OR=1.07; 95% CI 1.01 to 1.14), accounting for 14% of the total effect. <h3>Conclusions</h3> Higher cured meat intake was associated with worsening asthma symptoms over time, through a direct effect and to a lesser extent an effect mediated by BMI. This research extends the effect of diet on asthma in adults.
Comparable Long-Term Persistence of Anti-FVIII Antibodies in Hemophilic E17 Mice on Different Genetic Backgrounds Despite Significant Differences in the Amplitude of the Immune Responses.
Authors: Natalie Bauer, Christina Hausl, Rafi U. Ahmad, Bernhard Baumgartner, Hans Peter Schwarz, Birgit M. Reipert
Journal: Blood (2006)
Outcome of Alternative Donor Transplantation for Severe Aplastic Anemia Can Be Comparable to Outcome with Matched Related Donors.
Authors: Alana A. Kennedy-Nasser, Kathryn Leung, Steven Gottschalk, Dean A. Lee, George Carrum, Helen E. Heslop, Malcolm K. Brenner, Catherine M. Bollard, Robert A. Krance
Journal: Blood (2005)
Abstract 2831: Development of selective GRP94 inhibitors for the treatment of cancer
Authors: Stefan O. Ochiana, Tony Taldone, Hardik J. Patel, Pallav Patel, Yan Pengrong, Weilin Sun, Anna Rodina, Smit Shah, Daniel T. Gewirth, Gabriela Chiosis
Journal: Cancer Research (2015)

Abstract Glucose Regulated Protein 94 (Grp94) is an Hsp90 paralog localized in the lumen of the endoplasmic reticulum (ER) of higher eukaryotes. While the mechanisms associated with Grp94-pathogenic expression are still actively studied, the focus thus far of most cancer related studies has been primarily on the immunogenic activity of Grp94/peptide complexes and the involvement of this protein in the secretion of IGF-I and IGF-II and the regulation of Toll-like receptors and integrins. This status quo has recently changed when work from our lab has shown that in certain breast cancers the maintenance of a high density HER2 species at the plasma membrane and its associated aberrant signaling also requires Grp94, rendering these tumors highly sensitive to Grp94 inhibition. The discovery of selective and potent Grp94 inhibitors has been hindered due to the high similarity of the ATP-binding regulatory pocket of the Hsp90 paralogs. However, recent work from our lab has shown that this apparent roadblock can be overcome by using library screening and structural and computational analysis to discover purine-based molecules that show 100-fold selectivity for the Grp94 isoform. Herein, we detail for the first time the structure activity relationship of the selective purine derived Grp94 molecules. This work provides insights on how to overcome the high structural similarity of Hsp90s in the ligand binding pocket, and also reports selective and therapeutically relevant Grp94 inhibitors based on a purine scaffold. These initial inhibitors have potent activity against cancer cells providing an important platform for the development of Grp94 inhibitors with drug-like features and potential for clinical translation. Citation Format: Stefan O. Ochiana, Tony Taldone, Hardik J. Patel, Pallav Patel, Yan Pengrong, Weilin Sun, Anna Rodina, Smit Shah, Daniel T. Gewirth, Gabriela Chiosis. Development of selective GRP94 inhibitors for the treatment of cancer. [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 2831. doi:10.1158/1538-7445.AM2015-2831
PTH-007 Percutaneous endoscopic colostomy prevents repeated hospital admission in colonic pseudo-obstruction with or without sigmoid volvulus
Authors: C C L Liao, J N L Simson
Journal: Gut (2010)

<h3>Introduction</h3> Percutaneous endoscopic colostomy (PEC) for venting and fixation is a treatment option in patients with severe physical and/or mental disability and chronic intestinal pseudo-obstruction/megacolon, who need repeated hospital admissions with acute episodes of pseudo-obstruction with or without sigmoid volvulus. These patients are normally treated by repeated endoscopic decompression but are unfit for major surgery. We present our series of 38 such patients who underwent PEC with a mean follow-up of 10.6 (range 1–79) months. <h3>Methods</h3> Thirty-eight patients underwent PEC. Mean age was 72.4 (range 40–93) years. One or two PEC tubes were placed in the dilated sigmoid colon for venting and fixation. The tubes were subsequently changed to low-profile ballooned devices which were left in place indefinitely. Patients or carers vented the tubes as necessary to keep the colon decompressed. Data were collected prospectively. <h3>Results</h3> There were no deaths within 30 days. Two patients underwent Hartmann9s operation after early PEC dislodgement. There were no further hospital admissions for pseudo-obstruction or volvulus in the remaining 36 patients after 10.6 (range 1–79) months including four patients whose PEC device fell out at 8–10 months. Two patients died at 10 and 12 months, respectively, due to peritonitis and 13 patients died of unrelated causes. <h3>Conclusion</h3> PEC is a relatively safe treatment option in high-risk patients with colonic pseudo-obstruction/megacolon with or without volvulus and prevents further hospital admissions in all patients.
Abnormal CD34 Positive Cells Are Present in NPM+ Acute Myeloid Leukemia (AML) Samples at Diagnosis.
Authors: Clara M. Martinez, Elena Bussaglia, Carmen Hernandez, Camino Estivill, Josep Ubeda, Salut Brunet, Anna M. Aventin, Jorge Sierra, Josep F. Nomdedeu
Journal: Blood (2007)
CML with E8A2 BCR-ABL Fusion: The Fourth Breakpoint Cluster Region?.
Authors: Shadmehr Demehri, Thoralf Lange, Peter Paschka, Susan Branford, Tamio Koizumi, Takeshi Sugimoto, Lay-Cheng Lim, Beate Schultheis, Thomas Kegel, Giovanni Martinelli, Andreas Hochhaus, Brian J. Druker, Michael W. Deininger
Journal: Blood (2004)
445. cGMP Compliant Production for Human Embryonic Stem Cell Derived Retinal Pigment Epithelial Cells on a Synthetic Substrate for the Treatment of Non-Neovascular Age-Related Macular Degeneration for Phase I Clinical Study
Authors: P.M. Lopez, T. Aguilar, Rl Wu, A. Krishnan, D. Kong, J. Patel, H. Javier, W. Dang, D. Wong, D. Zhu, J. Dodd, Y. Shad, M. Humayun, D.R. Hinton, D.O. Clegg, L.V. Johnson, C.M. Lin, D. Hsu, L. Couture
Journal: Molecular Therapy (2016)

Non-neovascular age-related macular degeneration (dry AMD) is a leading cause of irreversible vision loss and is associated with retinal pigment epithelium (RPE) dystrophy. The RPE monolayer is integral for maintenance of healthy photoreceptors. Many studies have shown that AMD can be recovered by cellular therapy through transplantation of RPEs into the sub-retinal space to re-establish RPE functionality and halt neurological degeneration. Here we present a cGMP compliant manufacturing process to producing transplantable RPE cells on a synthetic substrate for clinical phase I study. The cGMP compliant process contains two major steps for generating the final product. The first step is to produce an intermediate cell bank (ICB) of RPE derived from human embryonic stem cell (hESC-RPE). The second step is to culture hESC-RPEs on a synthetic substrate as the final product. Analytical assays were also developed for the release testing of the final product and for evaluating transportation protocols of the final product. Three qualification runs were performed to assess the feasibility and the reproducibility of the manufacturing process. The results have shown a high success rate (88-98%) of the productions. 133 out of 144 hESC-RPEs seeded substrates met assay criteria for release including sterility, identity, purity, morphology, and viability. The assay results also showed the comparability of the final products between day 28 and day 43. In addition, 14 transportations of the non-cryopreserved products were successfully conducted by courier to the clinical site in a temperature regulated incubator. In conclusion, we have adapted and optimized laboratory protocols to establish a cGMP-compliant manufacturing process for generating the final product of hESC-RPE on a synthetic substrate for early phase clinical studies. A transportation protocol was also established to deliver the non-cryopreserved final product to clinical site. Moreover, analytical assays were developed and qualified for release testing of the final product.
Patterns of Survival and Causes of Death In 9,384 Patients with Myeloproliferative Neoplasms Diagnosed In Sweden Between 1973 and 2008
Authors: Malin Hultcrantz, Sigurdur Y. Kristinsson, Therese M-L Andersson, Sandra Eloranta, Åsa Rangert Derolf, Ola Landgren, Paul W Dickman, Magnus Bjorkholm
Journal: Blood (2010)
Long-Term Ultra-Low-Dose Acyclovir Against Varicella-Zoster Virus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Yuki Asano-Mori, Yoshinobu Kanda, Kumi Oshima, Shinichi Kako, Akihito Shinohara, Hideki Nakasone, Hiroyuki Sato, Takuro Watanabe, Noriko Hosoya, Koji Izutsu, Takashi Asai, Akira Hangaishi, Toru Motokura, Shigeru Chiba, Mineo Kurokawa
Journal: Blood (2007)
Abstract 2253: Cadherin 17 plays an important role in breast cancer metastasis to bone marrow
Authors: Tomoko Okada, Mutsuo Furihata, Atsushi Kurabayashi, Toru Imamura
Journal: Cancer Research (2015)

Abstract To understand the mechanism underlying bone marrow metastasis in breast cancer, we have established a highly bone marrow metastatic mouse breast cancer cell line, 4T1E/M3. While metastatic potential of 4T1E/M3 to bone was quite high (about 80%) when injected intravenously to mice, it was rather low (about 20%) when injected subcutaneously. Then using 4T1E/M3 cells, we carried out the in vitro and in vivo selection and established higher bone marrow metastatic cells, FP10SC2, which have a very high potential of metastases to lungs (100%) and spines (85%) when subcutaneously injected to mice. DNA microarray analysis revealed that the gene expression of cadherin17 was upregulated in FP10SC2 compared to the parental 4T1E/M3. When the expression of cadherin17 was suppressed by RNAi, the anchorage independent growth and migration activity was dramatically decreased. Moreover, metastatic activity of cadherin17(-)/FP10SC2 to spines was significantly reduced compared to control/FP10SC2. When cadherin 17 was overexpressed in 4T1E/M3 parental cells, the colony formation and migration activity was clearly augmented. Taken together, it was suggested that cadherin 17 plays an important role on breast cancer metastasis to bone marrow. Citation Format: Tomoko Okada, Mutsuo Furihata, Atsushi Kurabayashi, Toru Imamura. Cadherin 17 plays an important role in breast cancer metastasis to bone marrow. [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 2253. doi:10.1158/1538-7445.AM2015-2253
Small RNA Deep Sequencing Highlights the Important Contribution of Mirnas in Regulating IRF4/c-Myc Axis in Myeloma Development
Authors: Hanna Radomska, Alessandro Canella, Consiglio Jessica, Alberto Rocci, Cascione Luciano, Hector Cordero, Liu Joseph, Enrico Caserta, Santhanam Ramasamy, Yvonne A. Efebera, Stefano Volinia, Craig C Hofmeister, Flavia Pichiorri
Journal: Blood (2015)
A new alphabet for COPD care: where “E” stands for España
Authors: Edward Kerwin
Journal: European Respiratory Journal (2017)

In their correspondence, R.P. Young and R.J. Hopkins helpfully identify the Spanish guidelines [1] for chronic obstructive pulmonary disease (COPD) which, along with a later publication [2], have helped specify key subgroups of COPD (marked by high eosinophil count, personal history of asthma or atopy, or positive IgE or skin tests) who potentially have an asthma–COPD overlap syndrome (ACOS) component benefiting from inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) combinations. Not so helpful in profiling ACOS patients are forced expiratory volume in 1 s reversibility criteria, since up to 50% of all COPD patients may reverse over 12% and 200 mL after bronchodilator use [3–5]. A revised GOLD guide should identify patients likely to benefit from inhaled corticosteroids/long-acting β-agonists <http://ow.ly/mXxM306bDeN>