tbuckley/cabot-search huggingface dataset:
Abstract 5379: A potent EZH2 inhibitor exhibits long residence time and anti-tumor activity
Authors: Heidi Ott, Glenn van Aller, Jessica Ward, BaoChau Le, Cynthia Rominger, James Foley, Susan Korenchuk, Charles McHugh, Michael Butticello, Charles Blackledge, James Brackley, Joelle Burgess, Celine Duquenne, Neil Johnson, Jiri Kasparec, Louis LaFrance, Mei Li, Kenneth McNulty, Kenneth Newlander, Stuart Romeril, Stanley Schmidt, Mark Schulz, Dai-Shi Su, Dominic Suarez, Xinrong Tian, Christopher Carpenter, Juan Luengo, Ryan Kruger, Steven Knight, Michael T. McCabe
Journal: Cancer Research (2015)

Abstract The EZH2 histone methyltransferase is frequently mutated in diffuse large B-cell lymphoma leading to increased trimethylation of histone H3 lysine 27 (H3K27me3). Drug discovery efforts have previously identified a pyridone-based chemical series of EZH2 inhibitors that potently and selectively inhibit EZH2 catalytic activity. These compounds are capable of globally decreasing H3K27me3 levels, de-repressing EZH2 target genes, and inducing growth inhibition of many lymphoma cell lines both in cell culture and in vivo. Through medicinal chemistry optimization, we have developed EZH2 inhibitors with significantly improved potency in both biochemical and cellular assays. These compounds exhibit a prolonged enzyme residence time that can be further extended in vitro through the addition of an H3K27me3 peptide. Herein, we report the biochemical and cellular activity of these new EZH2 inhibitors. Citation Format: Heidi Ott, Glenn van Aller, Jessica Ward, BaoChau Le, Cynthia Rominger, James Foley, Susan Korenchuk, Charles McHugh, Michael Butticello, Charles Blackledge, James Brackley, Joelle Burgess, Celine Duquenne, Neil Johnson, Jiri Kasparec, Louis LaFrance, Mei Li, Kenneth McNulty, Kenneth Newlander, Stuart Romeril, Stanley Schmidt, Mark Schulz, Dai-Shi Su, Dominic Suarez, Xinrong Tian, Christopher Carpenter, Juan Luengo, Ryan Kruger, Steven Knight, Michael T. McCabe. A potent EZH2 inhibitor exhibits long residence time and anti-tumor activity. [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 5379. doi:10.1158/1538-7445.AM2015-5379
Comment on Hatzoglou et al: Dynamic contrast-enhanced MRI perfusion versus<sup>18</sup>FDG PET/CT in differentiating brain tumor progression from radiation injury
Authors: Francesco Cicone, Norbert Galldiks, Giuseppe Minniti, Christian P. Filss, Francesco Scopinaro, John O. Prior, Nathalie L. Albert, Karl-Josef Langen
Journal: Neuro-Oncology (2016)
Determining vancomycin Etest MICs in patients with MRSA bloodstream infection does not support switching antimicrobials
Authors: Nina J. Hos, Nathalie Jazmati, Danuta Stefanik, Martin Hellmich, Halil AlSael, Winfried V. Kern, Siegbert Rieg, Hilmar Wisplinghoff, Harald Seifert, Achim J. Kaasch
Journal: Journal of Infection (2016)
The Immunosuppressor Sirolimus Reduces the Number and Maturation of Colony-Forming Units of Erythroid Progenitor Cells.
Authors: Maribel Diaz-Ricart, Edgar Marcelo Arellano, Jordi Rovira, Josep M. Jou, Josep M. Campistol, Joan L. Vives-Corrons, Gines Escolar, Fritz Diekmann
Journal: Blood (2007)
Immunophenotypic and molecular features, clinical outcome, treatment, and prognostic factors in subcutaneous panniculitis-like T-cell lymphoma (SPTCL): Systematic analysis of 156 cases reported in the literature
Authors: R. S. Go, S. M. Wester
Journal: Journal of Clinical Oncology (2004)

6601 Background: The natural history, optimal therapy, and prognostic factors of SPTCL are not well defined. Methods: The English medical literature was reviewed for reported SPTCL cases up to June 2003. In most cases, microscopic descriptions and photographs were available for review to confirm diagnosis. Results: We identified 156 cases of SPTCL. The median age at diagnosis was 39 years (range, 0.5–84). Hemophagocytic syndrome (HPS) was reported to be present in 51 patients. The type of T-cell receptor (TCR) was reported in 61 patients with 62% expressing α/β receptor. After a median follow-up of 24 months, 51% of the patients had died (48% from disease, 2% with disease, 1% without disease). Of the 49% who were alive, 30% and 10% were without and with disease, respectively. The median survival for the whole group was approximately 27 months. Anthracycline-based combination regimens were the most frequently employed and most effective initial therapy (n=45) producing overall and complete response (CR) rates of 53% and 32%, respectively, and median response duration of 11.5+ months (range, 2+-72+). Thirteen patients underwent high dose therapy and stem cell transplantation (HDT-SCT) as salvage therapy and achieved 92% CR, with a median response duration of 14+ months (range, 3–70+). The presence of HPS at diagnosis and expression of γ/δ TCR in the tumor cells predicted for an inferior survival. Age at diagnosis was not prognostic of overall survival. Conclusions: In general, SPTCL has an aggressive natural history. A subgroup can have long-term disease remission with anthracycline-based therapy, while HDT-SCT seems to be an effective strategy for refractory or relapsed patients. HPS and TCR phenotype may be useful prognostic markers. No significant financial relationships to disclose.
A retrospective study comparing pemetrexed with taxanes as front-line cytotoxic chemotherapy for lung adenocarcinoma
Authors: Kakuhiro Yamaguchi, Kei Miwata, Yasushi Horimasu, Takeshi Masuda, Taku Nakashima, Hiroshi Iwamoto, Kazunori Fujitaka, Hironobu Hamada, Noboru Hattori, Nobuoki Kohno
Journal: Annals of Oncology (2015)
The F-Box Protein Skp2 Regulates Expression of p27 in BCR-ABL Transformed Cell Lines and Is Required for Induction of Myeloproliferative Disease in a Murine Model.
Authors: Anupriya Agarwal, Thomas G.P. Bumm, Amie Corbin, Thomas O’Hare, Marc Loriaux, Stephanie G. Willis, Jutta Deininger, Brian J. Druker, Michael W.N. Deininger
Journal: Blood (2006)
Thinking Critically About Classifying Adverse Events: Incidence of Pancreatitis in Patients Treated With Nivolumab + Ipilimumab
Authors: Claire F. Friedman, Varina Clark, Andrew V. Raikhel, Tim Barz, Alexander N. Shoushtari, Parisa Momtaz, Margaret K. Callahan, Jedd D. Wolchok, Paul B. Chapman, Matthew D. Hellmann, Michael A. Postow
Journal: JNCI Journal of the National Cancer Institute (2016)

The Common Terminology Criteria for Adverse Events (CTCAE) were developed to document the adverse effects of chemotherapy but are now also used to document immune-related adverse events (irAE). Characterization of irAE by the CTCAE has implications for determining dose-limiting toxicity (DLT) and, consequently, the recommended phase II dose (RP2D) of investigational agents. In the phase I trial of nivolumab + ipilimumab, an asymptomatic increase in lipase was the primary DLT that informed the RP2D. We performed a retrospective study of 119 patients with melanoma who were treated at Memorial Sloan Kettering Cancer Center with the combination of nivolumab + ipilimumab to investigate the relationship between asymptomatic grade 3 or higher increases in amylase and/or lipase and pancreatitis, a known irAE. Of the 119 patients, there were only two cases of pancreatitis, representing 20% of patients with grade 3 or higher amylase, 6.3% of patients with grade 3 or higher lipase, and 20% of patients with grade 3 or higher elevations of both enzymes. The application of the CTCAE, especially in grading independent lab values, should be considered carefully in clinical trials of novel immunotherapeutic agents.
463. Suspension-Adapted HEK 293 Cells in Orbital Shaken Bioreactors for the Production of Adeno-Associated Virus Vectors
Authors: Daniel R. Blessing, Bernard Schneider, Florian M. Wurm, Nicole Déglon
Journal: Molecular Therapy (2016)

In recent years adeno-associated virus (AAV) has become one of the most popular vectors for gene therapy applications. AAV mediated gene therapy approaches offer the advantages of safety, broad tissue tropism and long-term transgene expression. The screening and engineering of novel recombinant AAV (rAAV) capsids has led to the generation of several promising candidates with highly interesting in-vivo characteristics. The evaluation of these vectors in pre-clinical studies and potential applications in the clinic require the production of considerable amounts of vectors. Even though much progress has been made in the last decade, AAV production remains a challenge for translating basic research into clinic. Here we describe the production of rAAV vectors comparing different protocols for the polyethyleneimine (PEI) based transfection of suspension adapted HEK 293 cells. Suspension cells were cultivated with serum-free medium in disposable, orbital shaken bioreactors (OSR), a technology which allows an easy scale-up of production. Using cultures from a milliliter to a liter scale, AAV6 and AAV9 vectors were produced and purified using gradient centrifugation, filtration and chromatographic methods. Purified virus stocks were then analyzed and titrated to determine viral genomes and transducing units. Preliminary results indicate that our protocol for the production of rAAV particles using suspension cells grown in OSR yields infectious titers that are equal or higher to what has been reported for the production with human cell lines. Further work is ongoing to analyze and implement this OSR platform. The presented process offers a novel method to produce rAAV for pre-clinical and clinical trials, scalable, based on single-use material and compliant to Good Manufacturing Practice (GMP).
Abstract 2308: The role of LKB1 in development of lung squamous cell carcinoma in mice
Authors: Jian Liu, Sung-Nam Cho, Yiqun Zhang, Chad J. Creighton, Francesco J. DeMayo
Journal: Cancer Research (2015)

Abstract LKB1 is frequently dysregulated in human lung cancer and has been shown to be one of the critical genes controlling the development of lung squamous cell carcinoma (SCC) in mice1,2. However, it's unclear that the contribution of LKB1 in the development of lung SCC in mice. Here we took advantage of our new enhanced Cre (CCSPiCre) to efficiently deplete Lkb1 in the mouse airway epithelial cells. Although ablation of Lkb1 failed to show any discernable morphological changes, microarray analysis revealed 503 genes and 202 LincRNAs were significantly altered after single ablation of Lkb1. Ingenuity Pathway Analysis (IPA) showed that LXR/RXR activation and inflammatory pathways were significantly dysregulated by ablation of Lkb1. Using the CCSPiCre mouse, we ablated Pten in addition to Lkb1. As previously reported by Xu and coworkers who used Adenoviral delivery of Cre recombinase to achieve Lkb1 and Pten ablation2, the resulting phenotype was SCC while much rapider tumor initiation age, higher mouse metastasis ratio and a worse mortality were observed in this efficient mouse model. Analysis of the tumor development showed progression from mucous cell hyperplasia of the large airways to a papillary transition stage, then to the SCC phenotype. Mice with airway specific loss of Lkb1 and only one allele of Pten (CCSPiCrePtenf/+Lkb1f/f) showed slower tumor progression with the strong metastasis ability to multiple organs, such as liver, uterus, intestine and spleen. Comparison of the microarrays of CCSPiCrePtenf/f and CCSPiCrePtenf/fLkb1f/f in the pretumor stage showed 1463 genes and 339 LincRNAs were significantly altered. Again the major altered pathways were inflammatory and cholesterol biosynthesis. Using this model the developmental progression of lung SCC and the contribution of LKB1 to lung SCC progression were determined. References 1. Ji, H., et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807-810 (2007). 2. Xu, C., et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer cell 25, 590-604 (2014). Citation Format: Jian Liu, Sung-Nam Cho, Yiqun Zhang, Chad J. Creighton, Francesco J. DeMayo. The role of LKB1 in development of lung squamous cell carcinoma in mice. [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 2308. doi:10.1158/1538-7445.AM2015-2308
Abstract 5352: Mesenchymal stem cell as delivery carrier for prodrug gene therapy against colorectal cancer cell
Authors: Nasrin Salehi, Ching-An Peng
Journal: Cancer Research (2015)

Abstract Gene-directed enzyme prodrug therapy (GDEPT) is an approach that delivers a suicidal gene to cancer cells for the expression of prodrug-activating enzyme which converts prodrug into cytotoxic drug. One of the major impediments of GDEPT is to have the therapeutic gene specifically target on cancer cells prior to the administration of prodrug. Among various gene delivery methods, mesenchymal stem cells (MSCs) have emerged as potential carriers for gene delivery. They exhibit remarkable tumor-tropic and low immunogenic capacities. In this study, MSCs was engineered to express thymidine phosphorylase (TP) which has the capability of converting the prodrug doxifluridine into toxic 5-fluorouracil. TP expression in the MSCs post-transfection of TP cDNA was confirmed by immunoblotting analysis and its activity was determined by spectrophotometric assay. Our results showed the anticancer effectiveness of human HT29 colorectal adenocarcinoma cells co-cultured with TP-expressing MSCs was enhanced with the addition of various dosages of doxifluridine. Citation Format: Nasrin Salehi, Ching-An Peng. Mesenchymal stem cell as delivery carrier for prodrug gene therapy against colorectal cancer cell. [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 5352. doi:10.1158/1538-7445.AM2015-5352
Deferasirox (Exjade®) Given During Conditioning Regimen (FLAMSA/Busulfan/ATG) Reduces the Appearance of Labile Plasma Iron in Patients Undergoing Allogeneic Stem Cell Transplantation
Authors: Annekathrin Fritsch, Claudia Langebrake, Peter Nielsen, Ulrike Bacher, Michael Baehr, Dorothee C. Dartsch, Nicolaus Kroeger
Journal: Blood (2011)
Abstract B46: VLA-4 targeted nanoparticles carrying a novel anti-Myc prodrug prolongs survival in a mouse model of multiple myeloma.
Authors: Deepti Sood Gupta, Dipanjan Pan, Grace Hu, Anagana Senpan, Xiaoxiao Yang, Edward V. Prochownik, Gregory M. Lanza, Michael H. Tomasson
Journal: Clinical Cancer Research (2015)

Abstract The MYC oncoprotein drives multiple myeloma (MM) pathogenesis, but the utility of small molecule inhibitors of MYC-MAX dimerization is limited by poor efficacy. We determined the efficacy of lipase labile MYC-MAX inhibitor prodrug (MI1-PD) loaded nanoparticles targeted via integrin {alpha 4 beta1 α4β1) or Very Late Antigen-1 (VLA-4)} in myeloma mice. We hypothesized that NPs containing specific targeting to myeloma cells, would enhance the therapeutic efficacy of MI1-PD containing NPs. The antiproliferative activity of intergin VLA-4-Targeted MI-1PD NPs (iTM-NPs) was determined in mouse cell line (5TGM1) in vitro and its effect on the survival in C57Bl/KaLwRij-5TGM1 murine model of myeloma in vivo. iTM-NPs (approximately 20 nm in diameter, 5% w/w MI1-PD loading) under in vitro conditions exhibited inhibition of cell growth compared to the controls. Also, C57Bl/KaLwRij-5TGM1 mice that received intravenous injection of iTM-NPs demonstrated greater survival rate over the controls. These results demonstrate the feasibility of using VLA-4 targeted nanotherapy approach to improve the availability of anti-Myc small molecule inhibitors for multiple myeloma and other cancers. Citation Format: Deepti Sood Gupta, Dipanjan Pan, Grace Hu, Anagana Senpan, Xiaoxiao Yang, Edward V. Prochownik, Gregory M. Lanza, Michael H. Tomasson. VLA-4 targeted nanoparticles carrying a novel anti-Myc prodrug prolongs survival in a mouse model of multiple myeloma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B46.
Antithrombin, Protein C, Protein S and Activated Protein C Resistance in the General Healthy Chinese Population: Normal Plasmatic Ranges and Genetic Defects.
Authors: Yongqiang Zhao, Xuefeng Wang, Qiulan Ding, Xuqian Wei, Tienan Zhu, Florentia Kaguelidou, Renchi Yang, Changgeng Ruan, Zhaoyue Wang, Xia Bai, Nicole Schlegel
Journal: Blood (2007)
Leukotrienes provide an NFAT-dependent signal that synergizes with IL-33 to activate ILC2s
Authors: Jakob von Moltke, Claire E. O’Leary, Nora A. Barrett, Yoshihide Kanaoka, K. Frank Austen, Richard M. Locksley
Journal: The Journal of Experimental Medicine (2016)

Group 2 innate lymphoid cells (ILC2s) and type 2 helper T cells (Th2 cells) are the primary source of interleukin 5 (IL-5) and IL-13 during type 2 (allergic) inflammation in the lung. In Th2 cells, T cell receptor (TCR) signaling activates the transcription factors nuclear factor of activated T cells (NFAT), nuclear factor κB (NF-κB), and activator protein 1 (AP-1) to induce type 2 cytokines. ILC2s lack a TCR and respond instead to locally produced cytokines such as IL-33. Although IL-33 induces AP-1 and NF-κB, NFAT signaling has not been described in ILC2s. In this study, we report a nonredundant NFAT-dependent role for lipid-derived leukotrienes (LTs) in the activation of lung ILC2s. Using cytokine reporter and LT-deficient mice, we find that complete disruption of LT signaling markedly diminishes ILC2 activation and downstream responses during type 2 inflammation. Type 2 responses are equivalently attenuated in IL-33– and LT-deficient mice, and optimal ILC2 activation reflects potent synergy between these pathways. These findings expand our understanding of ILC2 regulation and may have important implications for the treatment of airways disease.
How to make an engaging infographic?
Authors: Hilary Scott, Samantha Fawkner, Christopher W Oliver, Andrew Murray
Journal: British Journal of Sports Medicine (2016)

Visual data are all around us. A clear purpose of information graphics (infographics) is to communicate key messages in an engaging fashion.1 They are increasingly being used to complement and add value to scientific papers. Some infographics are completely ignored or not given a second glance, while others draw people in and efficiently convey a message to the engaged reader.2 While people are able to form an opinion of infographic content in a split second, the process of successful infographic design can be much more time-consuming. Knowledge, good ingredients and an oven are helpful in making a delicious cake to suit consumer taste. There is an increasing appetite for infographics. We describe some theory and key ingredients, and discuss infographic computer programs that can help you produce outstanding infographics, and consider how to help effectively share infographics (figure 1).

Sufficient knowledge of the topic area is as important as artistic skill. Thus, as health professionals and scientists we can be encouraged …
Diabetic Neuropathy: A Position Statement by the American Diabetes Association
Authors: Rodica Pop-Busui, Andrew J.M. Boulton, Eva L. Feldman, Vera Bril, Roy Freeman, Rayaz A. Malik, Jay M. Sosenko, Dan Ziegler
Journal: Diabetes Care (2016)

Diabetic neuropathies are the most prevalent chronic complications of diabetes. This heterogeneous group of conditions affects different parts of the nervous system and presents with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important for a number of reasons: 

1.  Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable by specific measures.

2.  A number of treatment options exist for symptomatic diabetic neuropathy.

3.  Up to 50% of diabetic peripheral neuropathies may be asymptomatic. If not recognized and if preventive foot care is not implemented, patients are at risk for injuries to their insensate feet.

4.  Recognition and treatment of autonomic neuropathy may improve symptoms, reduce sequelae, and improve quality of life.

Among the various forms of diabetic neuropathy, distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies, particularly cardiovascular autonomic neuropathy (CAN), are by far the most studied (1–4). There are several atypical forms of diabetic neuropathy as well (1–4). Patients with prediabetes may also develop neuropathies that are similar to diabetic neuropathies (5–10). Table 1 provides a comprehensive classification scheme for the diabetic neuropathies.

View this table:

Table 1 
Classification for diabetic neuropathies



Due to a lack of treatments that target the underlying nerve damage, prevention is the key component of diabetes care. Screening for symptoms and signs of diabetic neuropathy is also critical in clinical practice, as it may detect the earliest stages of neuropathy, enabling early intervention. Although screening for rarer atypical forms of diabetic neuropathy may be warranted, DSPN and autonomic neuropathy are the most common forms encountered in practice. The strongest available evidence regarding treatment pertains to these forms.

This Position Statement is based on several recent technical reviews, to which the reader is referred for detailed discussion …
Abstract 4470: Targeting autophagy and apoptosis to enhance anticancer effect on esophageal carcinoma in vitro
Authors: Yan Cai, Jiajing Cai, Qiang Ma, Yuan Xu, Dongsheng Wang, Xiaolan Guo
Journal: Cancer Research (2015)

Abstract Esophageal cancer is one of the malignancies threatening human health with high incidence and a very low 5-year survival rate with poor outcomes in the developing countries. As one of the main treatment for esophageal cancer, chemotherapy has been played indispensable roles along with more and more chemoresistance and side effects arised though. Recent studies showed that induction of autophagy has emerged as a drug resistance mechanism that promotes cancer cell survival via self-digestion. Therefore targeting autophagy in cancer might be another promising approach of therapeutics. In this study, chloroquine (CQ) was used as the autophagy inhibitor, which has been the anti-malarial drug with 60 years history and safety performance, to study esophageal carcinoma cells EC109 in vivo and explore the potential molecular mechanisms. Chloroquine was employed to treat EC109 cells at different dosages and time points, and MTT results showed that the viability of EC109 was reduced dramatically in a dose dependent manner after 24 hours treatment. Moreover, we found that CQ could inhibit the migration and invasion abilities through scratch test and cell invasion Transwell chamber test, also significantly suppressed the colony formation using soft agar assay. Further investigation showed that mTOR pathway was activated with CQ exposure, and autophagy marker LC3I/II conversion decreased at early-stage, with obvious elevation eventually. More interestingly, we observed that CQ promoted the EC109 cells apoptosis by flow cytometry, also the mRNA expression of apoptosis associated proteins, such as Fas and Bax were increased. According to our findings, chloroquine showed its anticancer effect through modulating autophagy and promoting cell apoptosis, which might have promising therapeutic benefits for esophageal carcinoma. Citation Format: Yan Cai, Jiajing Cai, Qiang Ma, Yuan Xu, Dongsheng Wang, Xiaolan Guo. Targeting autophagy and apoptosis to enhance anticancer effect on esophageal carcinoma in vitro. [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 4470. doi:10.1158/1538-7445.AM2015-4470