tbuckley/cabot-search huggingface dataset:
Abstract 2603: Combination activity of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 in pancreatic and biliary tract tumor xenograft models
Authors: Jianguo Ma, Sakeena Syed, Lindsey Crowley, Jamie Shaw, Janet Ogden, Brian Elenbaas, Samantha Goodstal
Journal: Cancer Research (2015)

Abstract The efficacy and tolerability of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 combination were explored in pancreatic and biliary tract preclinical tumor xenograft models. These studies were based on the hypotheses that combination efficacy may occur by several possible mechanisms including inhibition of DNA repair or increase of hypoxia by Pimasertib, or by differential targeting of the oxic and hypoxic tumor compartments by Pimasertib and TH-302 respectively. Since Pimasertib and TH-302 had each been tested in separate clinical trials in pancreatic cancer with gemcitabine (NCT01016483 and NCT01144455 respectively), these data could provide the rationale for clinical testing of this novel combination in pancreatic cancer. The combination was also tested in biliary tract cancer models (cholangiocarcinoma and gall bladder) based on the reported sensitivity of these tumor types to MEK inhibitors, their hypoxic nature, and the prevalence and high unmet need of these indications, particularly in Asia. The results showed that in the MIA PaCa-2 human pancreatic xenograft model, combination efficacy was observed and found to be schedule dependent. The greatest combination efficacy occurred when Pimasertib was administered first, 2 hours prior to TH-302, suggesting a unique combination mechanism in cells when the MAPK signaling pathway is suppressed first. The combination was subsequently explored in 2 additional pancreatic models and a panel of biliary tract patient-derived xenograft (PDX) models. In 10 cholangiocarcinoma PDX models tested, 3 models were responders to Pimasertib monotherapy and 4 models converted from being a non-responder with either monotherapy to a responder with the Pimasertib TH-302 combination using the%TV (tumor volume) criteria, which is related to a clinical PR RECIST response. Combination effects were not observed in 2 additional pancreatic or 6 gall bladder models tested. Some models were highly sensitive to Pimasertib or TH-302 monotherapy, making combination effects difficult to observe. Biomarker analyses are ongoing to identify markers that could predict which tumors are the most sensitive to this combination therapy. Citation Format: Jianguo Ma, Sakeena Syed, Lindsey Crowley, Jamie Shaw, Janet Ogden, Brian Elenbaas, Samantha Goodstal. Combination activity of the MEK inhibitor Pimasertib and the hypoxia-activated prodrug TH-302 in pancreatic and biliary tract tumor xenograft 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 2603. doi:10.1158/1538-7445.AM2015-2603
Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier
Authors: Steffen E. Storck, Sabrina Meister, Julius Nahrath, Julius N. Meißner, Nils Schubert, Alessandro Di Spiezio, Sandra Baches, Roosmarijn E. Vandenbroucke, Yvonne Bouter, Ingrid Prikulis, Carsten Korth, Sascha Weggen, Axel Heimann, Markus Schwaninger, Thomas A. Bayer, Claus U. Pietrzik
Journal: Journal of Clinical Investigation (2015)

According to the neurovascular hypothesis, impairment of low-density lipoprotein receptor–related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-β (Aβ) brain accumulation and drives Alzheimer's disease (AD) pathology. However, due to conflicting reports on the involvement of LRP1 in Aβ transport and the expression of LRP1 in brain endothelium, the role of LRP1 at the BBB is uncertain. As global Lrp1 deletion in mice is lethal, appropriate models to study the function of LRP1 are lacking. Moreover, the relevance of systemic Aβ clearance to AD pathology remains unclear, as no BBB-specific knockout models have been available. Here, we developed transgenic mouse strains that allow for tamoxifen-inducible deletion of Lrp1 specifically within brain endothelial cells (Slco1c1-CreERT2 Lrp1fl/fl mice) and used these mice to accurately evaluate LRP1-mediated Aβ BBB clearance in vivo. Selective deletion of Lrp1 in the brain endothelium of C57BL/6 mice strongly reduced brain efflux of injected [125I] Aβ1–42. Additionally, in the 5xFAD mouse model of AD, brain endothelial–specific Lrp1 deletion reduced plasma Aβ levels and elevated soluble brain Aβ, leading to aggravated spatial learning and memory deficits, thus emphasizing the importance of systemic Aβ elimination via the BBB. Together, our results suggest that receptor-mediated Aβ BBB clearance may be a potential target for treatment and prevention of Aβ brain accumulation in AD.
Evidence-Based Treatment of Cancer-Related Breakthrough Pain With Opioids
Authors: Giovambattista Zeppetella
Journal: Journal of the National Comprehensive Cancer Network (2013)

Opioids are considered important analgesics in the treatment armamentarium for moderate-to-severe background cancer pain. The past decade has seen clinical trials of transmucosal opioid formulations for breakthrough pain in cancer (BTPc), beginning with oral transmucosal fentanyl citrate (OTFC), followed by fentanyl buccal tablet and intranasal fentanyl spray, and most recently sublingual fentanyl tablet, fentanyl buccal soluble film, and fentanyl pectin nasal spray. During that time, enough rigorous evidence has accumulated to support the development of recommendations on treating BTPc with transmucosal formulations. This article describes the randomized controlled trials that have led to the support of the use of transmucosal fentanyl therapies for BTPc, starting in 1999 with OTFC formulations through to the end of 2011. Although oral opioids have been used for historical reasons, evidence supports the use of intravenous morphine or transmucosal fentanyl for treating BTPc, regardless of the opioid being taken to manage background pain. Furthermore, most studies have found no meaningful relationship between the effective dose of transmucosal opioid and the around-the-clock scheduled medication nor the previous rescue medication. The accumulated evidence shows that transmucosal fentanyl formulations provide a rapid effect on BTPc, with adverse events typical of opioids.
Editorial
Authors: Tobias Opthof
Journal: Cardiovascular Research (1998)

In the April 1998 issue of Cardiovascular Research [1] remained more or less constant over the last six years.we commented on the gradual changes in the geographical Increases, either gradually over these years or more distribution of submissions over the last six years.Derecently, were observed for several countries (Fig. 3).Very creased and increased numbers, both absolute and relative, large increases in absolute terms were observed for Gerwere observed for North-America and Europe respectively.many and the Netherlands, a two-fold increase for France This change for North-America was fully explained by the and Italy and a large increase in relative terms for Spain submissions from the USA and not from Canada.Both and Austria (Fig. 3).Thus the overall European increase changes, North-American and European, started in 1992, (Fig. 1) mainly resulted from 6 EC countries.The large well before the establishment of Cardiovascular Research increase from Germany and the Netherlands (Fig. 3) as the official basic science journal of the European suggests that the physical neighbourhood of the Editorial Society of Cardiology.Office plays a significant role for authors when they
The human invariant chain is the core protein of the human class II-associated proteoglycan.
Authors: K S Giacoletto, A J Sant, C Bono, J Gorka, D M O'Sullivan, V Quaranta, B D Schwartz
Journal: The Journal of Experimental Medicine (1986)

The human class II-associated chondroitin sulfate proteoglycan (CSPG) was analyzed biochemically and immunologically to determine a possible relationship with the human invariant chain (gamma 1) and its related components. The CSPG was purified by a three-step procedure involving associative ion-exchange chromatography, immunoprecipitation, and dissociative ion-exchange chromatography. Treatment of the CSPG with chondroitinase revealed core proteins of Mr approximately 46,000, 38,000, and 28,000, with the 38,000 species most highly represented. Tryptic peptide analysis revealed identity of the peptides of the 38,000 Mr core protein and gamma 1, and of the 28,000 Mr species and p25. The CSPG and its core proteins were shown to react directly with the mouse anti-human invariant chain monoclonal antibody VIC-Y1 and a rabbit antiserum produced against a synthetic peptide corresponding to the C-terminal end of invariant chain. These results demonstrate that the invariant chain is the core protein of the class II-associated CSPG. In addition, virtually all the CSPG was shown to be present on the cell surface.
Trends in colorectal cancer mortality in Europe: retrospective analysis of the WHO mortality database
Authors: Driss Ait Ouakrim, Cécile Pizot, Magali Boniol, Matteo Malvezzi, Mathieu Boniol, Eva Negri, Maria Bota, Mark A Jenkins, Harry Bleiberg, Philippe Autier
Journal: BMJ (2015)

To examine changes in colorectal cancer mortality in 34 European countries between 1970 and 2011.Retrospective trend analysis.World Health Organization mortality database.Deaths from colorectal cancer between 1970 and 2011. Profound changes in screening and treatment efficiency took place after 1988; therefore, particular attention was paid to the evolution of colorectal cancer mortality in the subsequent period.Time trends in rates of colorectal cancer mortality, using joinpoint regression analysis. Rates were age adjusted using the standard European population.From 1989 to 2011, colorectal cancer mortality increased by a median of 6.0% for men and decreased by a median of 14.7% for women in the 34 European countries. Reductions in colorectal cancer mortality of more than 25% in men and 30% in women occurred in Austria, Switzerland, Germany, the United Kingdom, Belgium, the Czech Republic, Luxembourg, and Ireland. By contrast, mortality rates fell by less than 17% in the Netherlands and Sweden for both sexes. Over the same period, smaller or no declines occurred in most central European countries. Substantial mortality increases occurred in Croatia, the former Yugoslav republic of Macedonia, and Romania for both sexes and in most eastern European countries for men. In countries with decreasing mortality, reductions were more important for women of all ages and men younger than 65 years. In the 27 European Union member states, colorectal cancer mortality fell by 13.0% in men and 27.0% in women, compared with corresponding reductions of 39.8% and 38.8% in the United States.Over the past 40 years, there has been considerable disparity in the level of colorectal cancer mortality between European countries, as well as between men and women and age categories. Countries with the largest reductions in colorectal cancer mortality are characterised by better accessibility to screening services, especially endoscopic screening, and specialised care.
E Pluribus Unum: 50 Years of Research, Millions of Viruses, and One Goal—Tailored Acceleration of AAV Evolution
Authors: Dirk Grimm, Sergei Zolotukhin
Journal: Molecular Therapy (2015)

Fifty years ago, a Science paper by Atchison et al. reported a newly discovered virus that would soon become known as adeno-associated virus (AAV) and that would subsequently emerge as one of the most versatile and most auspicious vectors for human gene therapy. A large part of its attraction stems from the ease with which the viral capsid can be engineered for particle retargeting to cell types of choice, evasion from neutralizing antibodies or other desirable properties. Particularly powerful and in the focus of the current review are high-throughput methods aimed at expanding the repertoire of AAV vectors by means of directed molecular evolution, such as random mutagenesis, DNA family shuffling, in silico reconstruction of ancestral capsids, or peptide display. Here, unlike the wealth of prior reviews on this topic, we especially emphasize and critically discuss the practical aspects of the different procedures that affect the ultimate outcome, including diversification protocols, combinatorial library complexity, and selection strategies. Our overall aim is to provide general guidance that should help users at any level, from novice to expert, to safely navigate through the rugged space of directed AAV evolution while avoiding the pitfalls that are associated with these challenging but promising technologies.
Mobile dating apps could be driving HIV epidemic among adolescents in Asia Pacific, report says
Authors: Jocalyn Clark
Journal: BMJ (2015)

A recent upsurge in HIV infections among teenagers in the Asia Pacific region may be due to casual sex after using mobile dating apps, a new report from the United Nations has said.

A UN inter-agency team has released data showing a worrying surge of HIV infections among 10-19 year olds in the Asia Pacific region, where more than half of the world’s 1.2 billion adolescents live.1 An estimated 50 000 new HIV infections occurred among adolescents aged 15-19 in 2014, accounting for 15% of new infections in the …
Sequencing and phylogenetic characterisation of a fatal Crimean – Congo haemorrhagic fever case imported into the United Kingdom, October 2012
Authors: B Atkinson, J Latham, J Chamberlain, C Logue, L O'Donoghue, J Osborne, G Carson, T Brooks, M Carroll, M Jacobs, S Hopkins, R Hewson
Journal: Eurosurveillance (2012)

A patient with fever, and haemorrhagic symptoms was admitted to a hospital in Glasgow on 2 October 2012. Since he had returned from Afghanistan, serum samples were sent for diagnosis at the Rare and Imported Pathogens Laboratory, where a real-time reverse transcriptase-PCR diagnosis of Crimean – Congo haemorrhagic fever was made within 3 hrs after receipt of the sample. Hereafter the patient was transferred to a high-security infectious diseases unit in London but died on 6 October.
Cancer drugs can be four times more costly in some wealthy countries than in others
Authors: Zosia Kmietowicz
Journal: BMJ (2015)

<h3>Objective.</h3> Our study investigated the natural history of magnetic resonance imaging (MRI)–determined bone marrow edema over a 12-week period in individuals with suspected axial spondyloarthritis. <h3>Methods.</h3> There were 109 MRI scans performed on 30 patients who fulfilled the Assessment of Spondyloarthritis international Society inflammatory back pain criteria at baseline and at 4, 8, and 12 weeks. <h3>Results.</h3> There were 29 patients who completed the study. Only 4 (14%) patients changed from MRI-negative to MRI-positive (all HLA-B27–positive, OR 2.74). Three of 7 (43%) male HLA-B27–positive patients, 1 of 8 (12.5%) HLA-B27–positive female patients, and no HLA-B27–negative patients changed from MRI- negative to -positive. <h3>Conclusion.</h3> Repeat MRI scans within a 12-week period should be considered in HLA-B27–positive males.
Secondary transmissions during the outbreak of Shiga toxin-producing Escherichia coli O104 in Hesse, Germany, 2011
Authors: A M Hauri, U Götsch, I Strotmann, J Krahn, G Bettge-Weller, H J Westbrock, O Bellinger, H Uphoff
Journal: Eurosurveillance (2011)

During the recent outbreak of Shiga toxin-producing Escherichia coli (STEC) O104:H4 in Germany most cases notified in the State of Hesse (6 million inhabitants) were linked to satellite clusters or had travelled to the outbreak area in northern Germany. Intensified surveillance was introduced to rapidly identify cases not linked to known clusters or cases and thus to obtain timely information on possible further contaminated vehicles distributed in Hesse, as well to describe the risk of secondary transmission among known cases. As of 2 August 2011* [corrected], 56 cases of haemolytic uraemic syndrome (HUS) including two fatal cases, and 124 cases of STEC gastroenteritis meeting the national case definitions have been reported in Hesse. Among the 55 HUS and 81 STEC gastroenteritis cases thatmet the outbreak case definition, one HUS case and eight STEC gastroenteritis cases may have acquired their infection through secondary transmission. They include six possible transmissions within the family, two possible nosocomial and one possible laboratory transmission. Our results do not suggest an increased transmissibility of the outbreak strain compared to what is already known about E. coli O157 and other STEC serotypes.
Clinical Study Evaluating the Safety, Tolerability and Efficacy of Weekly Nab-Paclitaxel Dosed at 100 Mg/M2 for Metastatic Breast Cancer : Hbcc1101 Trial
Authors: M. Takahashi, K. Watanabe, H. Akabane, K. Ichinokawa, K. Ogasawara, H. Kato, K. Konishi, Y. Suzuki, K. Tanaka, Y. Narita, T. Hata, M. Hosoda, M. Yamamoto
Journal: Annals of Oncology (2014)
Ionizing radiation-engineered nanogels as insulin nanocarriers for the development of a new strategy for the treatment of Alzheimer's disease
Authors: Pasquale Picone, Lorena Anna Ditta, Maria Antonietta Sabatino, Valeria Militello, Pier Luigi San Biagio, Maria Laura Di Giacinto, Laura Cristaldi, Domenico Nuzzo, Clelia Dispenza, Daniela Giacomazza, Marta Di Carlo
Journal: Biomaterials (2015)
Loss of function of myosin chaperones triggers Hsf1-mediated transcriptional response in skeletal muscle cells
Authors: Christelle Etard, Olivier Armant, Urmas Roostalu, Victor Gourain, Marco Ferg, Uwe Strähle
Journal: Genome biology (2015)

Mutations in myosin chaperones Unc45b and Hsp90aa1.1 as well as in the Unc45b-binding protein Smyd1b impair formation of myofibrils in skeletal muscle and lead to the accumulation of misfolded myosin. The concomitant transcriptional response involves up-regulation of the three genes encoding these proteins, as well as genes involved in muscle development. The transcriptional up-regulation of unc45b, hsp90aa1.1 and smyd1b is specific to zebrafish mutants with myosin folding defects, and is not triggered in other zebrafish myopathy models. By dissecting the promoter of unc45b, we identify a Heat shock factor 1 (Hsf1) binding element as a mediator of unc45b up-regulation in myofibers lacking myosin folding proteins. Loss-of-function of Hsf1 abolishes unc45b up-regulation in mutants with defects in myosin folding. Taken together, our data show that skeletal muscle cells respond to defective myosin chaperones with a complex gene program and suggest that this response is mediated by Hsf1 activation.
Superimposed Viral Infection
Authors: B. Juel-Jensen
Journal: Neuro-Oncology (1980)

The problem of infection in patients whom you have done your best to treat for neoplastic disease affecting the nervous system is a very real one as in any form of intensive treatment of cancer in other parts of the body. The title is somewhat misleading. The patient who has been treated with radiotherapy or with cytoxic drugs is not at risk so much from viruses he meets in his environment, as from those that are latent in him. You are all well aware of the hazards the patient runs from bacterial infection that originates in the flora he normally carries on his skin, in his nose, etc., a risk which probably is much greater than that of infection from the environment. I have chosen to say a few words about the behaviour of herpesviruses in the immunosuppressed patient, for this group of viruses may cause you the greatest trouble.
Involvement of R-cadherin in the early stage of glomerulogenesis.
Authors: S Goto, E Yaoita, H Matsunami, D Kondo, T Yamamoto, K Kawasaki, M Arakawa, I Kihara
Journal: Journal of the American Society of Nephrology (1998)

The earliest commitment to the formation of glomeruli is recognizable in S-shaped bodies. Although cell-cell adhesion seems likely to play a crucial role in this process, how glomerular epithelial cells segregate from the other parts of the nephron is unknown. In this study, immunofluorescence microscopy and monoclonal antibodies specific for mouse R-, E-, P- and N-cadherins were used to examine which of these adhesion molecules are involved in glomerulogenesis of the mouse kidney. Weak R-cadherin staining was first found in the vesicle stage, becoming restricted to glomerular visceral epithelial cells (VEC) during the S-shaped body stage. The intensity of this staining became stronger in the capillary loop stage, whereas parietal epithelial cells (PEC) and tubular cells did not stain. In the maturing stage, VEC gradually lost their staining for R-cadherin. E-cadherin was detected in ureteric buds and the upper limb of S-shaped bodies. From the capillary loop to the maturing stage, anti-E-cadherin stained epithelial cells in all tubule segments, but no label was seen in VEC or PEC. P-cadherin was also stained in the ureteric buds and in the upper limb of S-shaped bodies. N-Cadherin was weakly stained in cells at the vesicle stage, but thereafter staining of N-cadherin was not detected at any stage of glomerular formation. Immunoelectron microscopy of differentiating VEC was performed using antibodies specific to alpha-catenin, which is associated with cadherin. Subsequently, immunogold particles identifying alpha-catenin were localized on junctions between primary processes of VEC. These findings indicate that R-cadherin is uniquely expressed in differentiating VEC, suggesting an important role in the early stages of glomerulogenesis.
Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial
Authors: Michael L Wang, Hun Lee, Hubert Chuang, Nicolaus Wagner-Bartak, Frederick Hagemeister, Jason Westin, Luis Fayad, Felipe Samaniego, Francesco Turturro, Yasuhiro Oki, Wendy Chen, Maria Badillo, Krystle Nomie, Maria DeLa Rosa, Donglu Zhao, Laura Lam, Alicia Addison, Hui Zhang, Ken H Young, Shaoying Li, David Santos, L Jeffrey Medeiros, Richard Champlin, Jorge Romaguera, Leo Zhang
Journal: The Lancet Oncology (2015)
Distinct Signaling Profiles of Gemtuzumab Ozogamicin Responsiveness and Refractoriness in Acute Myeloid Leukemia.
Authors: David B. Rosen, James A Cordeiro, David M. Soper, Ying-Wen Huang, Donna E. Hogge, Roland B. Walter, Alessandra Cesano, Wendy J. Fantl
Journal: Blood (2009)
Computed Tomography Angiography and Myocardial Computed Tomography Perfusion in Patients With Coronary Stents
Authors: Matthias Rief, Elke Zimmermann, Fabian Stenzel, Peter Martus, Karl Stangl, Johannes Greupner, Fabian Knebel, Anisha Kranz, Peter Schlattmann, Michael Laule, Marc Dewey
Journal: Journal of the American College of Cardiology (2013)
Cytomegalovirus-specific CD8 T cells kill B16 melanoma cells in vivo when activated by bifunctional major histocompatibility class I - antibody fusion molecules (pMHCI-IgGs).
Authors: Michael Munks, Victor Levitsky, Ann Hill, Hendrik Knoetgen
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Bispecific antibodies (BiAb), some of which simultaneously bind to tumor-associated antigens on tumors and activate the CD3 receptor of T cells, have shown promising results in both pre-clinical models and clinical trials. However, widespread activation of T cells can result in
Abstract 14712: Exosomal Transfer of Hsf1 Prevents Apoptosis in Ischemic Myocytes by Chromatin Remodeling of Mir-34a
Authors: Yuliang Feng, Muhammad Ashraf
Journal: Circulation (2013)

Background: We showed heat shocked Sca-1+ cells (HSSca-1+ cells) transplantation significantly reduced cardiomyocytes (CM) apoptosis and improved cardiac functions post myocardial infarction as com...