tbuckley/cabot-search huggingface dataset:
Evaluation of Renal Function by Glomerular Filtration Rate (GFR) in Infants with Sickle Cell Anemia.
Authors: Winfred C. Wang, Renee R. Rees, Daner Li, Zora Rogers, Rathi Iyer, Sohail Rana, Julio C. Barredo, James F. Casella, Catherine Driscoll, Stuart Toledano, Scott T. Miller, Sherri Zimmerman, Eglal Shalaby-Rana, Bruce Thompson, John H. Miller, Russell E. Ware
Journal: Blood (2004)
Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia
Authors: Stefanie Göllner, Thomas Oellerich, Shuchi Agrawal-Singh, Tino Schenk, Hans-Ulrich Klein, Christian Rohde, Caroline Pabst, Tim Sauer, Mads Lerdrup, Sigal Tavor, Friedrich Stölzel, Sylvia Herold, Gerhard Ehninger, Gabriele Köhler, Kuan-Ting Pan, Henning Urlaub, Hubert Serve, Martin Dugas, Karsten Spiekermann, Binje Vick, Irmela Jeremias, Wolfgang E Berdel, Klaus Hansen, Arthur Zelent, Claudia Wickenhauser, Lutz P Müller, Christian Thiede, Carsten Müller-Tidow
Journal: Nature Medicine (2016)
Defining the temporal course of murine neurofibromatosis-1 optic gliomagenesis reveals a therapeutic window to attenuate retinal dysfunction
Authors: Joseph A. Toonen, Yu Ma, David H. Gutmann
Journal: Neuro-Oncology (2016)

Optic gliomas arising in the neurofibromatosis type 1 (NF1) cancer predisposition syndrome cause reduced visual acuity in 30%–50% of affected children. Since human specimens are rare, genetically engineered mouse (GEM) models have been successfully employed for preclinical therapeutic discovery and validation. However, the sequence of cellular and molecular events that culminate in retinal dysfunction and vision loss has not been fully defined relevant to potential neuroprotective treatment strategies. Nf1flox/mut GFAP-Cre (FMC) mice and age-matched Nf1flox/flox (FF) controls were euthanized at defined intervals from 2 weeks to 24 weeks of age. Optic nerve volumes were measured, and optic nerves/retinae analyzed by immunohistochemistry. Optical coherence tomography (OCT) was performed on anesthetized mice. FMC mice were treated with lovastatin from 12 to 16 weeks of age. The earliest event in tumorigenesis was a persistent elevation in proliferation (4 wk), which preceded sustained microglia numbers and incremental increases in S100+ glial cells. Microglia activation, as evidenced by increased interleukin (IL)-1β expression and morphologic changes, coincided with axonal injury and retinal ganglion cell (RGC) apoptosis (6 wk). RGC loss and retinal nerve fiber layer (RNFL) thinning then ensued (9 wk), as revealed by direct measurements and live-animal OCT. Lovastatin administration at 12 weeks prevented further RGC loss and RNFL thinning both immediately and 8 weeks after treatment completion. By defining the chronology of the cellular and molecular events associated with optic glioma pathogenesis, we demonstrate critical periods for neuroprotective intervention and visual preservation, as well as establish OCT as an accurate biomarker of RGC loss.
Abstract 2650: PI 3-Kinase inhibitors enhance the synthetic lethality of Parp inhibitors
Authors: Ashish P. Juvekar, Sina Yadegarynia, Hai Hu, Costas A. Lyssiotis, Hui Liu, John M. Asara, Ralph Scully, Lewis C. Cantley, Gerburg M. Wulf
Journal: Cancer Research (2015)

Abstract Introduction: Clinical trials have shown promising responses of BRCA-linked breast and ovarian cancers to PARP inhibitor therapy, but remissions are often short-lived and incomplete. Frequent loss of INPP4B and PTEN leads to activation in the PI3K pathway in TNBC, making the PI3K pathway an attractive treatment target. Here we present mechanistic data that explain how PI3K- and PARP-inhibition enhance each other. Methods: We examined the effects of PI3K-inhibitors BKM120 or BYL719 and PARP-inhibitor Olaparib on the metabolism of HCC1937 cells (BRCA1 5382C mutation and homozygous deletion of PTEN and p53) measuring lactic acid production, via seahorse analysis, carbon metabolism using targeted Mass Spectrometry (LC-MS/MS) and DNA synthesis. PI3K- but not Akt- or SGK-inhibition induced a DNA damage response in this BRCA1 mutant cell line as well as in a mouse model of BRCA1-related breast cancer (K14-Cre BRCA1f/f p53f/f) mouse model. Summary: Metabolic profiling showed that PI3K-inhibition decreased flux through glycolysis and specifically through the non-oxidative pentose-phosphate pathway, the main source of ribose-5-phosphate required for the de novo synthesis of nucleotides in BRCA1-mutant breast cancer cells. Nucleotide shortage led to replication stress with the appearance of γH2AX, increased poly-ADP-ribosylation and an acute drop in DNA synthesis in cell cultures as well as in vivo. PI3K inhibition led to a reduced and error-prone S-phase due to a decrease in nucleotide biosynthesis which could be rescued upon exogenous supply of nucleosides. In a mouse model (K14-Cre BRCA1f/fp53f/f induced breast cancers) we could confirm that both BKM120 and BYL719 enhanced the efficacy of Parp-inhibitor Olaparib (median PFS for Olaparib 50 days, for BKM120 4 days, for BYL719 6 days and for both combinations, BKM120+Olaparib and BYL719+Olaparib &amp;gt; 120 days). Conclusion: Preceding cell cycle arrest, PI3K-inhibition leads to a decrease in DNA synthesis due to decreased Ribose-5-phosphate production required for nucleotide synthesis. PI3K-inhibitors lower nucleotide pools, lead to impaired DNA damage repair and S-phase progression and further augment the synthetic lethality of Parp-inhibitors in BRCA1-related breast cancer. Citation Format: Ashish P. Juvekar, Sina Yadegarynia, Hai Hu, Costas A. Lyssiotis, Hui Liu, John M. Asara, Ralph Scully, Lewis C. Cantley, Gerburg M. Wulf. PI 3-Kinase inhibitors enhance the synthetic lethality of Parp inhibitors. [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 2650. doi:10.1158/1538-7445.AM2015-2650
Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia
Authors: Jason A. Powell, Alexander C. Lewis, Wenying Zhu, John Toubia, Melissa R. Pitman, Craig T. Wallington-Beddoe, Paul A. B. Moretti, Diana Iarossi, Saumya E. Samaraweera, Nik Cummings, Hayley S. Ramshaw, Daniel Thomas, Andrew H. Wei, Angel F. Lopez, Richard J. D’Andrea, Ian D. Lewis, Stuart M. Pitson
Journal: Blood (2016)
Mechanism of the Potent Activated Protein C Resistance of Novel Factor V Mutation with W1920R (FV Nara) Relative to R506Q (FV Leiden)
Authors: Kenichi Ogiwara, Keiko Shinozawa, Keiji Nogami, Tomoko Matsumoto, Katsumi Nishiya, Nobuyuki Tsujii, Koji Yada, Katsuyuki Fukutake, Midori Shima
Journal: Blood (2011)
Results of the AFR07 Prospective Study in De Novo Philadelphia Positive ALL Patients Aged over 55 Years: Efficacy and Safety of a Glivec® Based Induction Followed by Maintenance Therapy with Glivec® and Pegasys®.
Authors: Philippe Rousselot, Christian Recher, Agnès Buzyn, Francis Witz, Norbert Vey, Martine Escoffre-Barbe, Olivier Legrand, Pascal Turlure, Françoise Huguet, Thibaut Leguay, Jacques Delaunay, Bruno Audhuy, Cécile Fohrer, Sébastien Maury, Sylvie Castaigne, Eric Vicaux, Hervé Dombret, Jean Michel Cayuela
Journal: Blood (2007)
Role of RPL39 in Metaplastic Breast Cancer
Authors: Bhuvanesh Dave, Daniel D. Gonzalez, Zhi-Bin Liu, Xiaoxian Li, Helen Wong, Sergio Granados, Nadeer E. Ezzedine, Douglas H. Sieglaff, Joe E. Ensor, Kathy D. Miller, Milan Radovich, Agda KarinaEtrovic, Steven S. Gross, Olivier Elemento, Gordon B. Mills, Michael Z. Gilcrease, Jenny C. Chang
Journal: JNCI Journal of the National Cancer Institute (2016)

Background: Metaplastic breast cancer is one of the most therapeutically challenging forms of breast cancer because of its highly heterogeneous and chemoresistant nature. We have previously demonstrated that ribosomal protein L39 (RPL39) and its gain-of-function mutation A14V have oncogenic activity in triple-negative breast cancer and this activity may be mediated through inducible nitric oxide synthase (iNOS). The function of RPL39 and A14V in other breast cancer subtypes is currently unknown. The objective of this study was to determine the role and mechanism of action of RPL39 in metaplastic breast cancer. Methods: Both competitive allele-specific and droplet digital polymerase chain reaction were used to determine the RPL39 A14V mutation rate in metaplastic breast cancer patient samples. The impact of RPL39 and iNOS expression on patient overall survival was estimated using the Kaplan-Meier method. Co-immunoprecipitation and immunoblot analyses were used for mechanistic evaluation of RPL39. Results: The RPL39 A14V mutation rate was 97.5% (39/40 tumor samples). High RPL39 (hazard ratio = 0.71, 95% confidence interval = 0.55 to 0.91, P = .006) and iNOS expression (P = .003) were associated with reduced patient overall survival. iNOS inhibition with the pan-NOS inhibitor NG-methyl-L-arginine acetate decreased in vitro proliferation and migration, in vivo tumor growth in both BCM-4664 and BCM-3807 patient-derived xenograft models (P = .04 and P = .02, respectively), and in vitro and in vivo chemoresistance. Mechanistically, RPL39 mediated its cancer-promoting actions through iNOS signaling, which was driven by the RNA editing enzyme adenosine deaminase acting on RNA 1. Conclusion: NOS inhibitors and RNA editing modulators may offer novel treatment options for metaplastic breast cancer.
Quality Controls of Immune Regulatory Properties of Ex-Vivo, GMP-Grade Expanded Mesenchymal Stromal Cells for Clinical Use (European multicenter study CASCADE),
Authors: Mauro Krampera, Cedric Mènard, Luciano Pacelli, Giulio Bassi, Joelle Dulong, Isabelle Bezier, Francesco Bifari, Jasmina Zanoncello, Hubert Schrezenmeier, Luc Sensebé, Karin Tarte
Journal: Blood (2011)
452. MegaTAL Disruption of CCR5 To Protect Anti-HIV CAR+ Lymphocytes from HIV Infection
Authors: Thor A. Wagner, Malika Hale, Guillermo Romano, Iram Kahn, Jaya Sahni, Andy Scharenberg, David J. Rawlings
Journal: Molecular Therapy (2015)

More than 30 million people are infected with HIV. Antiretroviral therapy (ART) dramatically decreases mortality, but HIV-infected individuals on ART have an increased risk of malignancies, cardiovascular disease, neurologic disease, and shortened life expectancy. Therefore a cure for HIV remains an important treatment goal. A previous Phase II randomized clinical trial of anti-HIV Chimeric antigen receptor (CAR)-expressing T-cells was partially effective. We hypothesize that a limitation of the previous strategy was that the anti-HIV CAR+ lymphocytes were susceptible to HIV infection.
Eltrombopag Delivers Clinical Benefit in Chronic Idiopathic Thrombocytopenic Purpura (ITP) Patients Not Achieving Platelet Counts ≥50,000/μL - Data from the EXTEND Study.
Authors: Gregory Cheng, James B Bussel, Mansoor N Saleh, Balkis Meddeb, Maria E De Obaldia, Manuel Aivado, Nicole L Stone
Journal: Blood (2008)
Ignore reality but not the consequences of its ignorance: Broaden guidelines in surgery of hepatocellular carcinoma
Authors: Demetrios Moris, Evangelos Felekouras
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. TO THE EDITOR: The Hippocratic quote “Life is short, the art long, opportunity fleeting, experience misleading and judgment difficult” summarizes the challenges of hepatobiliary surgeons in treating patients with hepatocellular carcinoma (HCC). The art is long: Hepatobiliary surgeons have been constantly pushing the frontiers of resectability in HCC patients by introducing strategies to resect lesions previously considered unresectable. Yang et al.1 raised this issue by discussing the need to operate on HCC patients beyond guidelines, given that these “suboptimal” candidates may still potentially benefit from resection over other treatment modalities.2 Surgical guidelines gained widespread recognition attributable to their potential to improve surgical outcomes. However, this can only be achieved if they are, indeed, implemented.3 So, what is the price paid by treating HCC patients beyond the guidelines given that “we are unable to cure all patients?” This is where the misleading experience occurs. A recent study demonstrated that surgeon perception of “cure” varied considerably, from “absence of recurrence” to “return to baseline population cancer risk.”4 If surgeons cannot find a commonplace definition of “cure,” it is probably unwise to believe that the law will do so. Life is short: The underlying fear of litigation is enhanced in the current litigious culture. Surgeons can be publically accused of malpractice, which can have financial and professional consequences. Judgment is difficult: Many hepatobiliary surgeons feel that current HCC algorithm guidelines interfere with their surgical freedom, but are also concerned about the legal implications of not following them. When a “personal surgical truth” is questioned, it will likely cause a crisis even in the most seasoned surgeons. The opportunity fleeting: The superiority of liver resection in patients with intermediate/advanced HCCs2 as well as the predicted increase in number of patients diagnosed with HCC in the years ahead make the need to discuss the broadening of the resection criteria necessary. Ayn Rand said that we can ignore reality but we cannot ignore the consequences of ignoring reality. By broadening guidelines and clarifying whether practicing beyond them could expose surgeons to the possibility of being found legally negligent, surgeons will feel confident to incorporate “cure” into discussions with patients about the risks, benefits, and goals of surgery. Given that no classification system than Barcelona Clinic Liver Cancer (BCLC) has been adopted widely for HCC staging and treatment, a revision of the BCLC algorithm should be developed using emerging clinical treatment data, as well as including patient's preferences.
Subnormal Vitamin D Levels Are Associated with Adverse Outcome In Newly-Diagnosed Similarly-Treated Adult Acute Myeloid Leukemia (AML) Patients.
Authors: Hun Ju Lee, Josephia Muindi, Tan Wei, Gregory Wilding, Laurie A Ford, Sheila Sait, Annmarie Block, Maurice Barcos, Carlos E. Vigil, Elizabeth A Griffiths, James E. Thompson, Eunice S. Wang, Candace S. Johnson, Donald Trump, Meir Wetzler
Journal: Blood (2010)
272. Nucleic Acid Scavenging Nanofibers as Anti-Inflammatory Meshes
Authors: Jennifer G. Jackman, Hemraj Juwarker, Latif Bashirov, Kam Leong, Howard Levinson, Bruce Sullenger
Journal: Molecular Therapy (2015)

Dying cells release extracellular nucleic acids (NA) that can activate the inflammatory pathways of immune cells. Over-activation of these pathways contributes to sustained inflammation related to chronic wounds as well as autoimmune diseases like SLE, RA and IBD. The Sullenger lab previously showed that certain soluble, cationic polymers can scavenge extracellular nucleic acids and inhibit RNA-and DNA-mediated activation of Toll-like receptors (TLRs) and inflammation [1]. We hypothesize that incorporation of cationic polymers onto insoluble nanofibers would enable the scavenging of negatively charged pro-inflammatory species in a localized area, reducing cytotoxicity related to unwanted internalization of soluble cationic polymers. Herein, we report in vitro data to support that electrospun nanofibers grafted with cationic polymers (NASFs) can absorb agonists of TLR 3 and 9 directly from serum and prevent the production of NF-κβ, an immune system activating transcription factor while also demonstrating low cytotoxicity. Electropsinning of 60% Poly (styrene-co-maleic anhydride) in 1:1:1 tetrahydrofuran, dimethylformamide, and acetone resulted in randomly aligned fibers with diameters of 297±13 nm. Neutral fibers were made into NASFs by adding highly cationic 1.8 kDa bPEI, which increased the average fiber diameter to 486±9 nm. Cell viability and proliferation studies with STO, Ramos blue, and Normal Human Dermal Fibroblast cells show minimal toxicity of the fibers upon direct contact with the cells. NASFs effectively eliminated the immune stimulating response of NA based agonists CpG (TLR 9) and poly (I:C) (TLR 3) while not affecting the activation caused by non-anionic TLR agonists, R848 and pam3CSK4. The NASFs reduced the Ramos-Blue™ NF-κβ response to the baseline of un-stimulated cells. To test the NASFs in a more biologically relevant context, cell debris from RAW cells that were killed with Doxorubicin (DOX) was incubated with the fibers and this cell debris medium was used to treat Ramos-Blue cells. NASFs were able to block NF-κβ response anywhere from ~27-41% depending on the initial DOX treatment concentration, showing their ability to work in a biologically relevant setting. We suspect that complete blocking cannot be achieved due to the presence of non-cationic agonists in the cell debris medium; currently studies are being conducted to determine the approximate percent activation of various TLRs from cell debris medium. Together, this data demonstrates the effective formation of NASFs and their use as localized anti-inflammatory meshes.
Abstract 2538: The dietary isoflavone biochanin-A in combination with atorvastatin induces cell cycle arrest and apoptosis in human pancreatic cancer cells
Authors: Alok Bhushan, Ponniah Selvakumar, Satya Murthy Tadinada, James C.K. Lai
Journal: Cancer Research (2015)

Abstract Pancreatic cancer is a devastating disease with a poor prognosis. The American Cancer Society's estimates for pancreatic cancer in the United States for 2014 are about 46,420 new cases of pancreatic cancer and about 39,590 deaths from pancreatic cancer. There remains a clear need for effective mechanism-based approaches that can achieve long-term improvements in the management pancreatic cancer. While natural products are well recognized as sources of drugs for various diseases including cancer, very few studies systematically explored the role of natural products for their potential preventive/therapeutic benefit in pancreatic cancer. Although several studies have examined the effect of flavonoids, there are no studies examining how biochanin-A or atorvastatin regulates pancreatic cancer cells. We investigated the cell proliferation studies in pancreatic cancer cell lines, AsPC-1 and MiaPaCa-2. Interestingly, we observed that by combination of treatment of Biochanin-A and atorvastatin significantly decreased the viability of AsPC-1 and MiaPaCa-2 cells. Several studies have been demonstrated the STAT3 play an important roll in the progression cancer pathogenesis in various cancers. We examined the STAT3 expression in pancreatic cell line, PANC-1 in biochanin-A or atorvastatin or in combination treatments and observed 95% decrease in the phosphorylation of STAT3 observed. Similarly the combination drug treatment employing biochanin A and atorvastatin decreased activation of Akt in AsPC-1 cell line. The decreased cell viability in AsPC-1 cell line involved increased induction of apoptosis with combination treatment and this evidence was further strengthened by increased PARP cleavage in combination treated cells. Further studies will delineate the mechanism of signaling arrested by the combination of drugs, Biochanin-A and atorvastatin in pancreatic cells with the possibility for uncovering improved therapeutic strategies to overcome the effectiveness to treat pancreatic cancer patients. Citation Format: Alok Bhushan, Ponniah Selvakumar, Satya Murthy Tadinada, James C.K. Lai. The dietary isoflavone biochanin-A in combination with atorvastatin induces cell cycle arrest and apoptosis in human pancreatic 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 2538. doi:10.1158/1538-7445.AM2015-2538
612. Systemic AAV Injection in Guinea Pigs and Non-Human Primates Targets the Enteric Nervous System
Authors: Sara E. Gombash, Christopher J. Cowley, Julie A. Fitzgerald, Kathryn Hook, Emily Armstrong, Brian K. Kaspar, Andrew J. Fischer, Levi Todd, Eric C. Bielefeld, Kevin D. Foust
Journal: Molecular Therapy (2016)

We previously reported that intravenous delivery of AAV8 or AAV9 produces robust transduction in the enteric nervous system (ENS) of mice that is capsid dependent. The current proof-of-concept studies were to determine if intravenous AAV delivery transduces the ENS of two higher species, specifically guinea pigs, a commonly used species for ENS physiology studies, and cynomolgus macaques. Neonatal guinea piglets (P2) were intravenously injected with either of scAAV8 (2.8-3.1×1010 vg/g) or scAAV9-CB (2.8-3.4×1010 vg/g) expressing green fluorescent protein (GFP) which was 3-10x lower than our previous mouse studies. Twenty-one days post-injection, piglets were euthanized and tissues were harvested for vector biodistribution with special focus on the ENS. Overall, AAV8 more efficiently transduced guinea pig tissues than AAV9. scAAV8 produced robust transgene expression in the ENS, reaching 23-39% submucosal plexus (SMP) neurons and 3-21% of myenteric neurons with higher percentages of transduction in upper gastrointestinal tract regions. Intravenous scAAV9 produced GFP expression in 0.5-4% of SMP neurons and 1-4% of myenteric neurons. AAV9 transduction was spread evenly through the GI tract. Capsid had limited effect on the types of neurons targeted in the myenteric plexus of the guinea pig. Biodistribution in injected animals revealed GFP expression in the liver, spleen, kidneys, cardiac muscle, skeletal muscle, brain and spinal cord of AAV8 and AAV9 injected guinea pigs, with AAV8 always producing higher expression. Cochlea and eyes were negative for GFP expression in all animals. To determine the translational potential of ENS gene delivery, gastrointestinal tissues from cynomolgus macaques previously IV injected with scAAV9-CB-GFP (1-3 × 1014 vg/kg) at P1 or P30 were dissected and examined for GFP expression. GFP was detected in the myenteric plexus of the small intestine and distal colon myenteric plexus, the lone regions examined. Together these data indicate that intravenous delivery of AAVs for ENS transduction is translatable across species.