tbuckley/cabot-search huggingface dataset:
Expectations for Physicians Prescribing Marijuana—Reply
Authors: Humayun J. Chaudhry
Journal: JAMA (2016)

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Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial
Authors: Michael Schwameis, Thomas Kündig, Gustave Huber, Luzi von Bidder, Lorenz Meinel, Roland Weisser, Elisabeth Aberer, Georg Härter, Thomas Weinke, Tomas Jelinek, Gerd Fätkenheuer, Uwe Wollina, Gerd-Dieter Burchard, Roland Aschoff, Ruth Nischik, Gerhard Sattler, Georg Popp, Wolfgang Lotte, Dirk Wiechert, Gerald Eder, Olga Maus, Petra Staubach-Renz, Andrea Gräfe, Veronika Geigenberger, Ingomar Naudts, Michael Sebastian, Norbert Reider, Ridwan Weber, Marc Heckmann, Emil C Reisinger, Georg Klein, Johannes Wantzen, Bernd Jilma
Journal: The Lancet Infectious Diseases (2016)
Influence of Statins and Cholesterol on Mortality Among Patients With Pancreatic Cancer
Authors: Brian Z. Huang, Jonathan I. Chang, Erica Li, Anny H. Xiang, Bechien U. Wu
Journal: JNCI Journal of the National Cancer Institute (2016)

Recent studies have suggested associations between statins and enhanced survival among patients with pancreatic ductal adenocarcinoma (PDAC). However, the relationship between statins, cholesterol, and survival remains unclear.We conducted a retrospective cohort study on 2142 PDAC patients in a regional integrated healthcare system from 2006 to 2014. Electronic pharmacy records were used to abstract information on the type, length, and dosage of statin exposures starting in the year prior to diagnosis. The cumulative and individual effects of simvastatin, lovastatin, atorvastatin, pravastatin, and rosuvastatin on mortality were assessed using Cox proportional hazards regression. Statins were evaluated as any use (pre- and postdiagnosis as a time-dependent variable) and baseline use (prediagnosis only). We also evaluated whether low-density lipoprotein (LDL) cholesterol, measured at various time windows prior to diagnosis, had an independent influence on survival. Additional analyses were performed to examine whether cholesterol mediated the relationship between statins and mortality. All models included age, race, stage, surgery, gemcitabine-based chemotherapy, and the Charlson comorbidity index as covariates.Any (hazard ratio [HR] = 0.87, 95% confidence interval [CI] = 0.79 to 0.97) and baseline (HR = 0.88, 95% CI = 0.79 to 0.98) statin use were both associated with a decreased risk in mortality. When assessing individual statins, we found reduced mortality among simvastatin (HR = 0.87, 95% CI = 0.77 to 0.98) and atorvastatin (HR = 0.58, 95% CI = 0.46 to 0.72) users. Cholesterol was not associated with mortality and did not mediate any relationships between statins and survival.Statin use rather than cholesterol level was associated with lower mortality risk in patients with pancreatic cancer. Statins appear to improve survival through a lipid-independent mechanism.
Could the Increased Prevalence of Thrombotic Complications at High Altitude In Polycythemia Vera (PV) Be Contributed by Hypoxia?
Authors: Jasmine CH Lee#, Maurizio Zangari#, Brady L Stein, Kimberly Hickman, Andrew Wilson, Alison Moliterno, Jerry L Spivak, Victor R. Gordeuk, Josef T. Prchal
Journal: Blood (2010)
Stem Cell Mobilization Following Initial Therapy with Lenalidomide and Dexamethasone in Patients with Newly Diagnosed Multiple Myeloma
Authors: Shaji Kumar, Martha Lacy, Angela Dispenzieri, Suzzanne Hayman, Francis Buadi, David Dingli, Teresa Miceli, Mark Litzow, S. Vincent Rajkumar, Morie Gertz
Journal: Blood (2008)
Abstract 2388: Interaction between connective tissue growth factor and a disintegrin and metalloproteinase with thrombospondin type I repeats 7 during cancer development
Authors: Liya Pi, Bryon E. Petersen
Journal: Cancer Research (2015)

Abstract Introduction: Connective tissue growth factor (CTGF) is a secreted pro-angiogenic protein within the CCN (Cyr61/CTGF/Nov) family and modulates multiple angiogenic pathways through its broad binding ability to cysteine knot motifs presents in key angiogenic factors including vascular endothelial growth factor (VEGF)-A. Overexpression of CTGF has been found in many cancers such as Lewis lung carcinoma (LLC), cholangiocarcinoma (CC), and hepatocellular carcinoma (HCC). In an effort to understand the molecular action of CTGF, we identified a disintegrin and metalloproteinase with thrombospondin type I repeat 7 (ADAMTS7) as a CTGF binding protein in yeast two-hybrid analysis. This enzyme belongs to the ADAMTS family capable of cleaving extracellular matrix (ECM) components and extracellular regulatory molecules. Here, we show that ADAMTS7 binds to and degrades CTGF during cancer development. Methods: Adamts7 knockout mice were used to investigate the importance of ADAMTS7 in CTGF interaction and cleavage during LLC development. Adamts7+/+ and Adamts7−/− mice were subcutaneously implanted with LLC cells. Tumor growth was quantitatively measured within two weeks after implantation. Tumor angiogenesis was assessed utilizing a microvascular density assay. In addition, Adamts7 expression was tracked via X-gal staining of LLC tumors grown in Adamts7−/− mice that contained a LacZ trap-in cassette in the targeted Adamts7 allele. VEGF-A, CTGF, and ADAMTS7 were determined at both the mRNA and protein levels. Results: Adamts7 induction as indicated by the β-galactosidase activity in X-gal staining was found in intra-tumor stromal cells of LLC tumors grown in Adamts7−/− mice. The association of CTGF and ADAMTS7 proteins in protein lysates of LLC tumors grown in Adamts7+/+ mice was confirmed in immunoprecipitation assays. Higher levels of VEGF-A, CTGF and ADAMTS7 mRNAs were found in LLC tumors from Adamts7−/− animals as compared to Adamts7+/+ controls. Slower rate of CTGF turnover, faster growth of LLC tumors, and higher microvascular density were also found in Adamts7−/− animals than controls. Conclusion: These observations confirmed the binding and processing of CTGF by ADAMTS7 during LLC growth. The host-derived ADAMTS7 appears to regulate CTGF turnover and provides a protective effect towards aberrant LLC tumorigenesis and angiogenesis. Citation Format: Liya Pi, Bryon E. Petersen. Interaction between connective tissue growth factor and a disintegrin and metalloproteinase with thrombospondin type I repeats 7 during cancer 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 2388. doi:10.1158/1538-7445.AM2015-2388
Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy
Authors: Maria Josè Polanco, Sara Parodi, Diana Piol, Conor Stack, Mathilde Chivet, Andrea Contestabile, Helen C. Miranda, Patricia M.-J. Lievens, Stefano Espinoza, Tobias Jochum, Anna Rocchi, Christopher Grunseich, Raul R. Gainetdinov, Andrew C. B. Cato, Andrew P. Lieberman, Albert R. La Spada, Fabio Sambataro, Kenneth H. Fischbeck, Illana Gozes, Maria Pennuto
Journal: Science Translational Medicine (2016)

Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMA belongs to the family of polyQ diseases, which are fatal neurodegenerative disorders mainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the form of aggregates. The neurotoxicity of the polyQ proteins can be modified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments. We sought to identify signaling pathways that modulate polyQ-AR phosphorylation for therapy development. We report that cyclin-dependent kinase 2 (CDK2) phosphorylates polyQ-AR specifically at Ser
Targeted therapy selection-based on tumor tissue kinase activity profiles in patients with refractory solid tumors: An exploratory study.
Authors: M. Labots, J. C. Van der Mijn, H. Dekker, K. Gotink, M. Voebel-de Jong, R. Ruijter, M. Neerincx, T. V. Pham, H. J. Van Der Vliet, C. R. Jimenez, J. Van Der Hoeven, G. A. Meijer, H. M. Verheul
Journal: Journal of Clinical Oncology (2011)

e21080 Background: Clinically applicable response prediction tools are urgently needed to optimize treatment selection for individual patients. We designed an exploratory study to determine feasibility and clinical benefit of treatment with clinically available kinase inhibitors (KIs) selected by kinase activity profiling, performed in lysates of fresh-frozen tumor biopsies from patients with solid malignancies refractory to standard treatment. We here report the preplanned feasibility analysis. Methods: From September 2010 thirteen patients were enrolled in this ongoing study for treatment selection between dasatinib, erlotinib, everolimus, lapatinib, sorafenib and sunitinib according to a standardized method. At first, from a mandatory, snap-frozen tumor needle biopsy multiple 10 µm cryosections are prepared, with conventional H&E staining of 2 sections every 0.25 mm to determine tumor cell content. If these reveal more than 50% tumor cells, remaining sections are lysed. In this lysate the inhibitory potency of a KI is determined by using a peptide-based array of PamGene with 144 tyrosine kinase substrates. Based on the number of significantly inhibited substrates and percentage inhibition, the most potent KI is selected for treatment of the individual patient. Treatment response is evaluated according to RECIST criteria. Results: Thus far, per patient a median of 3 biopsies with a median size of 16G were taken from a metastatic site guided by US in 77%. In 92% of patients at least one biopsy contained sufficient tumor cells; 1 patient required re-biopsy. Lysates yielded 636 ±254 µg protein (range 247-1188). Following kinase activity profiling in 12 patients, 11 started treatment with a selected KI. To date 6 patients were evaluable, showing 1 SD and 5 PD at 6 weeks. Two patients were not evaluable due to early clinical deterioration. Conclusions: We here show that needle biopsies from metastases of refractory solid cancer patients provide sufficient protein to reliably determine kinase inhibition profiles of KIs. Patient accrual and updated clinical benefit data will be presented at the meeting.
Spending on Children’s Personal Health Care in the United States, 1996-2013
Authors: Anthony L. Bui, Joseph L. Dieleman, Hannah Hamavid, Maxwell Birger, Abigail Chapin, Herbert C. Duber, Cody Horst, Alex Reynolds, Ellen Squires, Paul J. Chung, Christopher J. L. Murray
Journal: JAMA Pediatrics (2016)

Health care spending on children in the United States continues to rise, yet little is known about how this spending varies by condition, age and sex group, and type of care, nor how these patterns have changed over time.To provide health care spending estimates for children and adolescents 19 years and younger in the United States from 1996 through 2013, disaggregated by condition, age and sex group, and type of care.Health care spending estimates were extracted from the Institute for Health Metrics and Evaluation Disease Expenditure 2013 project database. This project, based on 183 sources of data and 2.9 billion patient records, disaggregated health care spending in the United States by condition, age and sex group, and type of care. Annual estimates were produced for each year from 1996 through 2013. Estimates were adjusted for the presence of comorbidities and are reported using inflation-adjusted 2015 US dollars.From 1996 to 2013, health care spending on children increased from $149.6 (uncertainty interval [UI], 144.1-155.5) billion to $233.5 (UI, 226.9-239.8) billion. In 2013, the largest health condition leading to health care spending for children was well-newborn care in the inpatient setting. Attention-deficit/hyperactivity disorder and well-dental care (including dental check-ups and orthodontia) were the second and third largest conditions, respectively. Spending per child was greatest for infants younger than 1 year, at $11 741 (UI, 10 799-12 765) in 2013. Across time, health care spending per child increased from $1915 (UI, 1845-1991) in 1996 to $2777 (UI, 2698-2851) in 2013. The greatest areas of growth in spending in absolute terms were ambulatory care among all types of care and inpatient well-newborn care, attention-deficit/hyperactivity disorder, and asthma among all conditions.These findings provide health policy makers and health care professionals with evidence to help guide future spending. Some conditions, such as attention-deficit/hyperactivity disorder and inpatient well-newborn care, had larger health care spending growth rates than other conditions.
Overexpression of the Anti-Apoptotic Genes mcl-1, bcl-w, bcl-xL and a1 Is Correlated with Chronic Myelogenous Leukemia Progression and Resistance to Gleevec.
Authors: F. A. Castro, J. F. Jacysyn, A. G. Ulbrich, P. R. Tobo, L. R. Lopes, M. D. Colassantti, D. Camanho, M. A. Zanichelli, N. Hamerschlak, R. C. Cavalheiro, J.S. R. Oliveira, G. P. Amarante-Mendes
Journal: Blood (2005)
Phase I Study Using Alternate Week Administration of the Farnesyl Transferase Inhibitor R115777 (Zarnestra™) in Patients with Myelodysplastic Syndrome.
Authors: Razelle Kurzrock, Srdan Verstovsek, John J. Wright, Susan R. Pilat, Jorge E. Cortes, Elihu H. Estey, Francis J. Giles, Miloslav Beran, Hagop M. Kantarjian
Journal: Blood (2004)
Abstract 3243: Notch inhibitors and chemoradiation in an orthotopic glioblastoma model
Authors: Sanaz Yahyanejad, Patrick Granton, Stefan van Hoof, Lydie Barbeau, Jan Theys, Frank Verhaegen, Marc Vooijs
Journal: Cancer Research (2015)

Abstract Glioblastoma multiforme (GBM) is the most common and malignant brain tumor in adults. Aggressive multimodal treatment using surgery followed by radiotherapy and chemotherapy extends the median survival of GBM patients to approximately one year after diagnosis. Treatment is not curative because of the intrinsic and acquired radiation resistance of a subpopulation of tumor cells. Notch inhibition has been shown to impair the tumorigenic capacity of these cells as well as enhance their sensitivity towards radiation. Therefore, we investigated if a highly potent and clinically approved Notch pathway inhibitor (g-secretase inhibitor) improves tumor control when combined with radiotherapy and chemotherapy in an orthotopic GBM mouse model. To investigate the treatment efficacy of combinations treatments between standard of care treatment (radiotherapy and temozolomide) and Notch inhibitors, we used a three dimensional spheroid growth assay using both established and primary human glioma cell lines in which spheroid volume growth delay was quantitatively monitored. In addition, we assessed the expression of the putative glioma stem cell marker CD133 using flow cytometry. Furthermore, therapeutic efficacy of these combination treatments was als assessed in vivo in an orthotopic glioma tumor model (U87-luc) wherein tumor progression was evaluated using bioluminescence (BLI) and contrast-enhanced micro-computed tomography (CT) imaging. A small animal precision irradiation platform (PXI, XRAD 225Cx, CT, USA) was used for micro-CT imaging and irradiation delivery of conformal doses between 2- 10 Gy to intracranial tumors in mice receiving single or combination treatments with Notch inhibitors and chemotherapy. Results: Notch blockade alone did not affect the sphere volume compared to control, whereas combination treatment with radiation and / or temozolomide resulted in a substantial spheroid growth delay (p = 0.004). Irradiation enhanced the expression of the stem cell marker CD133, while Notch blockade reduced CD133 expression. In intracranial tumours we found a strong correlation between CT and BLI imaging of tumor growth (Pearson coefficient (r) = 0.85, p = 0.001). The potential of Notch inhibition combined with precision radiotherapy and chemotherapy in our orthotopic GBM model is currently being determined and the outcome of this study will be presented. Citation Format: Sanaz Yahyanejad, Patrick Granton, Stefan van Hoof, Lydie Barbeau, Jan Theys, Frank Verhaegen, Marc Vooijs. Notch inhibitors and chemoradiation in an orthotopic glioblastoma model. [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 3243. doi:10.1158/1538-7445.AM2015-3243
Abstract 2927: Targeting p53 with Bak and Bax mitochondrial targeting signals for the treatment of ovarian cancer
Authors: Phong Lu
Journal: Cancer Research (2015)

Abstract Although the main function of p53 is a nuclear transcription factor that has important roles in cell cycle arrest, DNA repair, and apoptosis, p53 can directly trigger the intrinsic apoptotic pathway through the mitochondria. p53 has been known to bind to mitochondrial anti-apoptotic proteins (Bcl-2 and Bcl-XL) and pro-apoptotic proteins (Bak and Bax), which will cause the oligomerization of Bak and Bax. The result is the formation of permeable pores on the mitochondrial outer membrane, which in turn cause the release of cytochrome c and activation of caspase-3. Targeting p53 to the mitochondria is an attractive approach because it can cause a rapid apoptotic response. We have introduced the mitochondrial targeting signal (MTS) from Bak or Bax to the C-terminus of p53 and have shown the superior efficacy of p53-BakMTS and p53-BaxMTS over wtp53 in many human cancer cell lines. We have identified that the DNA binding domain (DBD) of p53 may be the minimal domain of p53 required for apoptosis. Our preliminary data in SKOV-3 ovarian cancer cells also suggests that DBD-BakMTS may work just as well as full length p53-BakMTS. Further in humans, the single nucleotide polymorphism at codon 72 from Pro to Arg is known to enhance the mitochondrial targeting of p53. We have recently made the P72R mutation in our p53 constructs. Our goal is to use a novel version of p53 directed to the mitochondria as a direct apoptogen to treat ovarian cancer, the most lethal gynecological malignancy with 69% of patients succumbing to this disease. Our next step will be to test these constructs in vitro in human ovarian cancer cell lines and in vivo using the syngeneic ID8 mouse model. 7-AAD cell death assay was performed in the mouse ovarian ID8 cells transfected with our constructs. p53-Bax-MTS and p53-BakMTS appear to be the two most effective constructs. Interestingly, full length p53 is required for its apoptotic activity in this ID8 mouse cell line. In terms of the P72R polymorphism, p53(72R)-BakMTS and p53(72R)-BaxMTS do not show enhanced apoptotic potential in the ID8 mouse line, most likely due to the sequence differences between human and mouse p53. However, it is possible that the combination of 72R polymorphism with MTS from Bak and Bax may produce a superior mitochondrial localization of p53 in human cell lines. Our ultimate goal is to develop mitochondrially targeted p53 constructs that directly induce apoptosis for the treatment of ovarian cancer. Acknowledgements: NIH CA151847 Citation Format: Phong Lu. Targeting p53 with Bak and Bax mitochondrial targeting signals for the treatment of ovarian 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 2927. doi:10.1158/1538-7445.AM2015-2927
Sequential Treatment After Allogeneic Stem Cell Transplantation for Chronic Myelogenous Leukemia.
Authors: Sairah Ahmed, Rima M Saliba, Marcos De Lima, Gabriela Rondon, Partow Kebriaei, Tobi DeAnn Fisher, Elias Jabbour, Julianne Chen, Hagop Kantarjian, Paolo Anderlini, Amin M Alousi, Chitra M Hosing, Borje Andersson, Roy B. Jones, Muzaffar H. Qazilbash, Elizabeth J. Shpall, Sergio Giralt, Richard E Champlin
Journal: Blood (2012)
313. Gesicle Mediated Delivery of a Cas9-sgRNA Protein Complex
Authors: Thomas Quinn, Montse Morell, Tatiana Garachtchenko, Lily Lee, Mei Fong, Michael Haugwitz, Andrew Farmer
Journal: Molecular Therapy (2016)

CRISPR/Cas9-based gene editing has revolutionized the field of cell biology and is quickly being incorporated into the toolboxes of many laboratories. While CRISPR/Cas9 is a powerful technique for genome manipulation, two significant challenges remain: obtaining efficient delivery of Cas9 to all cell types and achieving fewer off-target effects. Recently, it has been demonstrated that genome editing via direct delivery of Cas9 is as effective as plasmid-based delivery, but with the added benefit of fewer off-target effects due to the short duration of the Cas9 protein in the cell (1). Here we report on the delivery of Cas9 using cell-derived nanovesicles termed gesicles. Gesicles are produced via co-overexpression of three components in a mammalian packaging cell: a nanovesicle-inducing glycoprotein, Cas9 endonuclease, and the sgRNA specific to the target gene. Additionally, we have developed a method for actively packaging sgRNA-loaded Cas9 into gesicles via ligand-dependent dimerization (iDimerize™ technology). The active packaging mechanism results in an approximate 4-fold increase in the loading of Cas9 into the gesicles. Moreover, the ligand-dependent dimerization approach also allowed us to efficiently package active Cas9 containing a nuclear localization signal (NLS) into these nanovesicles. We also have developed an optimized, lyophilized, one-step transfection formulation to promote high transfection efficiencies during the production of the Cas9-sgRNA gesicles. Gesicle-based protein delivery does not rely on recombinant protein production from a bacterial source or on the use of a transfection reagent for delivery. In this work, we were able to demonstrate that gesicles carrying a Cas9-sgRNA protein complex can mediate specific target-gene knockout in a wide variety of cell types, including human iPS cells. The observed knockout efficiency is often considerably higher than that observed with plasmid-based delivery of sgRNA and Cas9. This nanovesicle-based method allows for tight control of the dose and duration of the Cas9-sgRNA complex in the cell which has been shown to correlate with the amount of off-target cleavage (1). Through mismatch detection and Sanger sequencing of edited target sequences, we were able to demonstrate a lack of off-target cleavage when compared to plasmid-based delivery. Close analysis of the gesicles shows that they are stable over several freeze/thaw cycles and are consistent in size (~150-170 nm) as determined by nanoparticle tracking analysis. Overall, gesicles can be considered a novel and effective tool for simultaneous Cas9 and sgRNA delivery to any target cells. (1) Zuris, J. A. et al. (2014) Nat. Biotechnol. 33(1): 73-80.