tbuckley/cabot-search huggingface dataset:
Abstract CT309: Rapid evaluation of a novel small molecule cMet tyrosine kinase inhibitor in healthy subjects
Authors: A Dawn Millington, Sandra R. Chaplan, Zuleima Aguilar, Dennis M. Fisher, Jo Collier, Marielena Mata, Geert Mannens, Nico Goyvaerts, Vijay Peddareddigari, Chris Takimoto
Journal: Cancer Research (2015)

Abstract Inhibiting cMet has potential therapeutic value in oncology. The Janssen WAVE Early Development unit, a team focused on efficient proof-of-concept evaluations, sought to rapidly assess the safety, pharmacokinetics, and pharmacodynamics of a novel, highly selective small molecule cMet TK inhibitor with a favorable preclinical safety profile. We conducted a placebo-controlled, randomized, double blind single ascending dose and multiple dose trial in 84 healthy males at Quotient Clinical LTD (UK). The trial design was adaptive in several respects: to expedite determination of an optimal formulation and to maintain sufficient systemic exposure to sustain target inhibition. In the single ascending dose phase, doses ranged from 6-350 mg, with early transition from a solution to capsule formulation at 18 mg. Two multiple dose cohorts received 60 mg twice daily for 7 days (inter-dose intervals of 4.5 and 12 hours). Target engagement biomarkers were plasma hepatocyte growth factor and soluble cMet. Evaluation of renal safety was of particular interest. Clinical evaluation, including both single ascending and multiple dose phases, was completed in only 6 months. All doses were safe and well tolerated. Pharmacokinetic analysis revealed dose-proportional increases in exposure. Dose escalation was limited by concentrations of a major metabolite that approached the ceiling established in preclinical toxicology studies. Renal toxicity was not identified. Initial evaluation of this oncology drug in healthy subjects offered the advantages of rapid trial enrollment and completion, robust placebo comparison data, absence of concomitant illness or laboratory abnormalities, rapid dose escalation in a carefully-monitored, controlled setting, a thorough preliminary safety evaluation, and reduced costs. This approach, enabled by the acceptable preclinical safety profile of the compound, efficiently produced high quality clinical safety and pharmacokinetic data to support compound progression decisions. Citation Format: A Dawn Millington, Sandra R. Chaplan, Zuleima Aguilar, Dennis M. Fisher, Jo Collier, Marielena Mata, Geert Mannens, Nico Goyvaerts, Vijay Peddareddigari, Chris Takimoto. Rapid evaluation of a novel small molecule cMet tyrosine kinase inhibitor in healthy subjects. [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 CT309. doi:10.1158/1538-7445.AM2015-CT309
Pre-Transplantation FDG-PET Predicts Early but Not Late Survival Outcomes Following Allogeneic Transplantation in Chemo-Sensitive Hodgkin Lymphoma
Authors: Yasmin Reyal, Irfan Kayani, Ronjon Chakraverty, Adrian Bloor, Christopher P Fox, Kirsty Thomson, Adele K. Fielding, Ben Taylor, Mark Bishton, Emma Morris, Nigel Russell, Stephen Mackinnon, Karl S Peggs
Journal: Blood (2014)
32. Safety Studies Towards a Combined Cell and Gene Therapy To Treat Critical Limb Ischemia
Authors: Julie R. Beegle, Stefanos Kalomoiris, Nataly L. Magner, Jan A. Nolta, Fernando A. Fierro
Journal: Molecular Therapy (2015)

Over 240 clinical trials are in progress worldwide using mesenchymal stem cells (MSCs). Some critical advantages of MSCs include simple isolation and expansion, and ease for allogeneic applications due to their immune evading properties. MSCs produce many paracrine signals that promote tissue regeneration, though at sub-therapeutic levels. We have therefore developed a product that combines cell and gene therapy, by engineering MSCs to overexpress vascular endothelial growth factor (VEGF). Here we show our preclinical data that not only confirms the efficacy of our product (MSC-VEGF), but addresses multiple safety aspects. Here, MSCs are transduced with a GMP-grade lentiviral vector to obtain an average of one copy per cell (ranging from 0.8 to 1.3), minimizing occurrence of insertional mutagenesis. The secretion of VEGF is optimized by using a previously clinically evaluated constitutive promoter (MNDU3) and an enhancer element acting in cis (WPRE). Safety studies at this level of secretion (approx. 80pg/ml VEGF secreted per 1000 cells per 24 hours) did not cause edema or hemangiomas in immune deficient NOD/SCID IL-2R-gnull/null (NSG) mice. The genomic stability of MSC-VEGF was addressed by karyotyping analysis, where no abnormalities were found in MSCs transduced with increasing viral loads, and by PCR to evaluate potential genomic rearrangement of the insert. To rule out tumorigenicity of MSC-VEGF, cells transduced with increased viral load were in injected into NSG mice. In contrast to 3 distinct positive controls used, no tumors were detected in over 50 mice treated with MSC-VEGF up to 6 months after injection. Additional safety studies included confirmation by flow cytometry of homogeneity of the transduction level of MSC-VEGF, absence of replication competent lentivirus, freedom of endotoxin, mycoplasma and absence VSV-G viral envelope coding plasmid. Luciferase-expressing MSC-VEGF consistently decreased to undetectable levels by 28 days after injection and PCR confirmed the absence of human DNA 6 months after injection. Pilot efficacy studies using MSC-VEGF in an immune deficient mouse model of hind limb ischemia (HLI) have been completed. MSC-VEGF were injected IM the day after HLI surgery into the ischemic limbs of NSG mice and blood flow was monitored weekly, demonstrating that MSC-VEGF treatment leads to faster revascularization than control treatment. Furthermore, we show that a small percentage of injected MSC-VEGF take a pericyte position on blood vessels. While future assays are intended as IND-enabling safety studies, these pre-clinical safety and efficacy studies are directed towards our planned Phase I clinical trial.
Hospitals are advised to halt elective surgery to free beds for winter
Authors: Adrian O’Dowd
Journal: BMJ (2016)

An NHS regulator is advising hospitals in England to freeze elective surgery this winter to allow bed space it anticipates will be needed for emergency cases.

NHS Improvement, the regulator that oversees NHS trusts and foundation trusts, has sent a letter to all acute care, mental health, and community trusts saying that they should focus on emergency care patients at a “critical time” for the NHS at least until mid-January.

The letter, sent on behalf of NHS Improvement’s chief executive, Jim Mackey, says, “Given the level of risk facing the system, it is clear that having sufficient bed capacity going into Christmas …
Abstract 3971: Genome-wide tissue-based microRNA signature in healthy women predicting breast cancer risk
Authors: Cenny Taslim, Daniel Y. Weng, Theodore M. Brasky, Ramona G. Dumitrescu, Kun Huang, Bhaskar V. s. Kallakury, Shiva Krishnan, Adana A. Llanos, Catalin Marian, Sallie S. Schneider, Scott L. Spear, Melissa A. Troester, Jo L. Freudenheim, Susan Geyer, Peter G. Shields
Journal: Cancer Research (2015)

Abstract Introduction: Small non-coding microRNAs (miRNAs) play important roles in both normal breast development and breast carcinogenesis. The goal of this study is to identify miRNAs in normal breast tissues which are related to breast cancer risk. Materials and Methods: We used a high-throughput digital counting of miRNAs without amplification (Nanostring®) to examine miRNA expression in 161 reduction mammoplasty (RM) tissues from two independent studies. A multivariate model was used to identify miRNAs associated with breast cancer risk (based upon Gail risk scores) in a training study (n = 90) then the model was validated in a replication study (n = 71). Risk-related microRNAs were then evaluated in serum for associations with real breast cancer cases using publically available prospective cohort (Sister Study, n = 410). Results: We identified a 41-miRNA signature in healthy women distinguishing high risk from low risk women with a prediction accuracy of 82% (95% CI = 80% to 87%) in the training study. Predictive accuracy was 69% (95% CI = 65% to 73%) in the replication study. 34 of 41 serum miRNAs that mapped to public data predicted women who developed breast cancer within 18 months after blood draw from those who remained cancer free with accuracy of 59% (95% CI = 57% to 61%). We have also shown that these accuracies were significantly higher than random chance (P &amp;lt; 0.0001). IPA canonical pathway analysis revealed that the risk-related microRNAs targets were significantly enriched for HER-2 signaling in breast cancer, and estrogen-dependent breast cancer signaling, and other important cancer pathways such as molecular mechanisms of cancer, PI3K/AKT signaling, PTEN signaling, and TGF-beta signaling. Conclusion: Our results indicate that miRNA profiling from breast tissue of healthy patients may identify clinically useful predictors of breast cancer risk and these miRNAs may also work as non-invasive biomarker for early breast cancer prediction. Citation Format: Cenny Taslim, Daniel Y. Weng, Theodore M. Brasky, Ramona G. Dumitrescu, Kun Huang, Bhaskar V. s. Kallakury, Shiva Krishnan, Adana A. Llanos, Catalin Marian, Sallie S. Schneider, Scott L. Spear, Melissa A. Troester, Jo L. Freudenheim, Susan Geyer, Peter G. Shields. Genome-wide tissue-based microRNA signature in healthy women predicting breast cancer risk. [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 3971. doi:10.1158/1538-7445.AM2015-3971
CD73 specific siRNA loaded chitosan lactate nanoparticles potentiate the antitumor effect of a dendritic cell vaccine in 4T1 breast cancer bearing mice
Authors: Farhad Jadidi-Niaragh, Fatemeh Atyabi, Ali Rastegari, Nasim Kheshtchin, Samaneh Arab, Hadi Hassannia, Maryam Ajami, Zahra Mirsanei, Sima Habibi, Farimah Masoumi, Farshid Noorbakhsh, Fazel Shokri, Jamshid Hadjati
Journal: Journal of Controlled Release (2016)
401. In Vivo Expression of Plasmid Encoded IgG for PD-1 or LAG3 by Synthetic DNA as a New Tool for Cancer Immunotherapy
Authors: Kar Muthumani, C. Chung, S. Agarwal, R. Plyler, S. Kudchodkar, S. Flingai, K.E. Ugen, J.J. Kim, N. Sardesai, David B. Weiner
Journal: Molecular Therapy (2016)

Cancers employ various strategies to escape immune surveillance including the exploitation of immune checkpoint inhibitors. Checkpoint inhibitors are receptors found on immune and stromal cells whose function can impact the duration or potency of an immune response. Tumor cells often upregulate ligands for these receptors to protect themselves from the host immune response. Monoclonal antibody (MAb) therapeutics which block checkpoint inhibitor-ligand interactions restore T cell destruction of cancer cells in vivo. MAbs that target the inhibitory T cell signaling mediated by CTLA-4 and/or PD-1 checkpoint inhibitors have recently gained regulatory approval for the treatment of some cancers based on remarkable clinical outcomes. Here we have focused on a new method to improve MAb delivery through direct engineering of MAb in the form of synthetic DNA plasmids. This technology would improve many aspects of such a therapy by lowering cost, increasing in vivo expression times and allowing for simple combination formulations in the absence of a host anti-vector immune response, possibly extending use of these groundbreaking therapies to disadvantaged patient populations. We report that "enhanced and optimized" DNA plasmid technology can be used to direct in vivo production of immunoglobulin heavy and light chains of established monoclonal antibodies which can target the immune checkpoint inhibitors LAG3 and PD-1 as determined in Flow cytometry, ELISA and Western blot assays. Both antibodies are produced at physiologically relevant levels in blood and other tissues of mice using electroporation-enhanced delivery of DNA plasmids encoding genes for each antibody. We report that serum antibodies from inoculated animals retain the ability to bind to their targets and are bioactive in vivo and exhibit immune stimulatory effects for host T cells. These studies have significant implications for prophylactic and therapeutic strategies for cancer and other important diseases and warrants further attention.
All Memory Lymphocytes Share a Common Differentiation Program.
Authors: W. Nicholas Haining, Benjamin Ebert, Aravind Subramanian, E. John Wherry, John Evans, Raymond Mak, Stephen Rivoli, Jill Angelosanto, Jennfer Pretz, Susan Kaech, Rafi Ahmed, Lee M. Nadler, Todd R. Golub
Journal: Blood (2006)
Post-Transplantation Cyclophosphamide (Cy) Reduces Graft Rejection and Graft-Versus-Host Disease (GVHD) after Non-Myeloablative, Partially HLA-Mismatched (Haploidentical) Bone Marrow Transplantation (BMT).
Authors: Ephraim J. Fuchs, Leo Lunzik, Allen R. Chen, Michele Phelps, Angelita Crawford, Robert A. Brodsky, Richard J. Jones
Journal: Blood (2004)
Determination of a Phase II Dose of Panobinostat in Combination with 5-Azacitidine in Patients with Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia
Authors: Oliver G. Ottmann, Daniel J. DeAngelo, Guillermo Garcia-Manero, Michael Lübbert, Anand Jillella, Mikkael A. Sekeres, Anita Zahlten, Margaret Squier, Suddhasatta Acharyya, Ivo J. Winiger, Pierre Fenaux
Journal: Blood (2011)
341. Therapeutic Approach for SOD1-ALS Using AAV9 Delivered Artificial microRNAs
Authors: Lorelei Stoica, Johnny Salameh, Christian Mueller, Robert Brown, Miguel Sena-Esteves
Journal: Molecular Therapy (2015)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons. This results in progressive muscle weakness, atrophy, paralysis and death within five years of diagnosis. About 10% of cases are inherited – typically in a dominant manner – of which twenty percent are due to mutations in the superoxide dismutase gene (SOD1). Experiments in transgenic ALS mouse models that overexpress human SOD1 have shown that decreasing levels of mutant SOD1 protein alters, and in some cases eliminates, disease progression. We postulated that silencing SOD1 expression with a micro RNA (miR) would be therapeutic in ALS. We developed a single stranded AAV9 vector encoding GFP and a miR against human SOD1, driven by a CBA promoter, which we injected into the SOD1G93A ALS mouse at postnatal day one. Each mouse received 2ml into each lateral ventricle, for a total vector dose of 4e10 vector genomes. At four weeks post injection, hSOD1 mRNA was reduced by almost 50% at all three levels of the spinal cord. Transduction was visible in both motor neurons and astrocytes in the spinal cord as well as neurons in layer V of the motor cortex. Transduced cells, assessed by GFP RNA FISH, had a decrease in hSOD1 mRNA. This translated into a 50% extension in median survival of treated mice (206 days) compared to untreated (135 days) mice. To assess neuromuscular health during the duration of the experiment, we performed motor unit number estimates (MUNEs) and needle electromyography (EMG). Treated mice had mild or no muscle denervation as opposed to the severe denervation seen in untreated SOD1. In fact, the treated mice did not develop paralysis but instead had to be euthanized due to weight loss and a hunched posture. We also assessed neuropathology in the spinal cord and nerves in untreated and treated animals, at their respective endpoints. The treated mice showed no spinal cord motor neuron loss, while the untreated mice lost the majority of the motor neurons. The axonal integrity of the lumbar ventral roots was also improved in treated animals. Furthermore, there was no axonal degeneration in the sciatic nerves of the treated animals when analyzed at 120 days, the endpoint of untreated mice. Lastly, treated animals show delayed onset of astrogliosis and microgliosis, as observed by IHC for inflammatory markers GFAP and Iba1, and confirmed by RT-qPRC for genes upregulated in inflammation. In conclusion, we were successful at extending the lifespan of the SOD1G93A mouse by 50% with our high dose neonatal AAV9-miR, and our treated animals remain ambulatory and active until the humane endpoint with minimal or no signs of paralysis.
Adoptive Transfer of CMV-Specific Donor T Cells Following Allogeneic Transplantation Leads to Rapid and Safe Systemic Reconstitution.
Authors: Karl S Peggs, Kirsty Thomson, Edward Samuel, Gemma Dyer, Julie Armoogum, Kwok Pang, Ronjon Chakraverty, Stephen Mackinnon, Mark W Lowdell
Journal: Blood (2009)
OC-045 Antroduodenal manometry: impact on clinical management: Abstract OC-045
Authors: V N Mahesh, B Unsworth, E Wrightham, S Lal, J Mclaughlin, J Shaffer, P Paine
Journal: Gut (2010)

<h3>Introduction</h3> Antroduodenal Manometry (ADM) is a key tool in the characterisation of upper gut motility.1 However the technique is not widely employed in the UK and data demonstrating the impact of short-term stationary manometry on clinical management are sparse. <h3>Aim</h3> To evaluate the clinical outcome and impact of short-term stationary ADM in patients with suspected upper gut dysmotility in a tertiary hospital. <h3>Methods</h3> A retrospective review of all patients undergoing ADM between August 2006 to November 2009 was conducted. After an overnight fast a single water perfused catheter with 8 sensors was passed per nares to 90 to 110 cms, with the flow rate controlled at 0.4 ml/min/sensor. Migrating Motor Complexes (MMC) and phase 1, 2 and 3 contractions were recorded in the fasted state (3 h), then post prandially following a standard feed (Ensure Plus 220 ml; 1–2 h). Parameters included frequency, amplitude and propagation. <h3>Results</h3> 55 patients were included (43 female (78%), 12 male (22%), mean age 43 years, range 18–75). Eleven were external referrals solely for this investigation so complete clinical records were available in 44 patients. Their predominant symptoms were persistent nausea and vomiting in 28 (51%); abdominal pain in 10 (18%), distension 5 (9%) and others 12 (22%) including constipation, diarrhoea, early satiety, intolerance to enteral tube feeds. Clinical indications for the study were primarily diagnostic in 49 (89%), subclassification of known dysmotility in 2 (4%) and assessment for generalised dysmotility in patients with colonic dysmotility 4(7%). ADM was abnormal in 34 (62%) patients. Abnormal findings were most common in patients with persistent nausea and vomiting (19/28, 68%), abdominal pain (6/10, 60%) and colonic dysfunction (3/5, 60%). Key manometric diagnoses are presented in Abstract 045. In patients with complete data (n=44), the manometric findings led directly to a positive change in management in 28 (64%), including commencement of a liquid diet (n=6), initiation (n=3) or withdrawal (n=2) of enteral tube feeding, initiation and/or continuation of total parenteral nutrition (n=6), or avoidance of colonic surgery (n=2). <h3>Conclusion</h3> Short term, stationary manometry influences diagnosis and management of refractory symptoms such as persistent nausea and vomiting and abdominal pain, and is particularly helpful in shaping nutritional management decisions. Whether its utility can be improved in this difficult patient group by using 24 hour ambulatory or high-resolution techniques therefore warrants further exploration.
Humanized Anti CD-40 Antibody SGN-40 Effectively Induces Cytotoxicity Against Chronic Lymphocytic Leukemia (CLL) Cells through Antibody Mediated Cytotoxicity and Demonstrates Modest Biologic Evidence of CD40 Activation.
Authors: Aruna C. Gowda, Xiaobin B. Zhao, Carolyn Cheney, Najma Mehter, Gerard Lozanski, Thomas S. Lin, Sara Guster, J. G. Drachman, Natarajan Muthusamy, John C. Byrd
Journal: Blood (2005)
Abstract 735: Honokiol enhances the anticancer effects of doxorubicin by regulating Mucin 1 and Multidrug resistance-associated protein 1 (MRP1) in mammary carcinoma MDA-MB-231 cells
Authors: Padmamalini Thulasiraman, Saad Alshareedah
Journal: Cancer Research (2015)

Abstract Although great progress has been made in the treatment of breast cancer, resistance to chemotherapeutic drugs is a problem facing current cancer research, promoting the need to understand the molecular mechanisms involved in breast cancer and identify future targeted therapy. One of the mechanisms by which chemoresistance is attained in cancer cells is mediated through the expression of MDR-related proteins (MRPs). These transmembrane proteins efflux drugs across the plasma membrane, conferring resistance of cancer cells to anticancer drugs. Acquiring drug resistance has been correlated to the emergence of metastasis, accounting for two factors that may be related to progression of the disease. One of the diagnostic markers of metastatic progression is Mucin 1 (MUC1), an oncoprotein which has been implicated in reduced survival rate. Interaction of MUC1 with MRP-1 promotes resistance to conventional chemotherapeutic drugs. While several inhibitors have been identified and characterized to overcome drug resistance, thus far none of these have led to effectively managing acquired drug resistance. Along with existing drug treatments for breast cancer, the focus of clinicians and researchers have shifted towards exploring natural products to treat alone or in combination with chemotherapeutic agents to enhance the efficacy of these drugs in cancer. One such compound is honokiol, a natural phenolic compound extracted from Magnolia grandiflora that suppresses breast carcinogenesis in vitro and in vivo. The purpose of the current study is to determine whether honokiol regulates MUC1 and MRP1 in mammary carcinoma cells, MDA-MB-231, and the role of honokiol to enhance the efficacy of chemotherapeutic agent, doxorubicin. We investigated the effects of honokiol on the expression of MUC1 and MRP1 in MDA-MB-231 cells by RT-PCR and Immunoblotting. Cell proliferation assays (MTT-(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) were used to study the effect of honokiol on doxorubicin-mediated growth suppression. Honokiol suppressed mRNA and protein expression levels of MUC1 and MRP1 in MDA-MB-231 cells. In addition, honokiol suppressed the growth of mammary carcinoma MDA-MB-231 cells, and enhanced the efficacy of doxorubicin-mediated mammary carcinoma growth suppression. Taken together, suppressing the expression level of MUC1 and MRP1 by honokiol enhances the effect of conventional chemotherapeutic drugs. Citation Format: Padmamalini Thulasiraman, Saad Alshareedah. Honokiol enhances the anticancer effects of doxorubicin by regulating Mucin 1 and Multidrug resistance-associated protein 1 (MRP1) in mammary carcinoma MDA-MB-231 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 735. doi:10.1158/1538-7445.AM2015-735
Novel Imaging Modalities in Innovative Xenograft Mouse Models of T-Cell Lymphoma Confirm Marked Synergy of Romidepsin and Pralatrexate.
Authors: Salvia Jain, Xavier Jirau-Serrano, Carmine F Palermo, Luigi Scotto, Kenneth P Olive, Govind Bhagat, Serge Cremers, Jennifer E Amengual, Owen A. O'Connor
Journal: Blood (2012)