tbuckley/cabot-search huggingface dataset:
A randomized, phase I/II trial of AMG 102 or AMG 479 in combination with panitumumab (pmab) compared with pmab alone in patients (pts) with wild-type (WT) <i>KRAS</i> metastatic colorectal cancer (mCRC): Safety and efficacy results.
Authors: E. Van Cutsem, C. Eng, J. Tabernero, E. Nowara, A. Swieboda-Sadlej, N. C. Tebbutt, E. P. Mitchell, I. Davidenko, L. Chen, D. Smethurst
Journal: Journal of Clinical Oncology (2011)

366 Background: Pmab is a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb) approved as monotherapy for pts with mCRC. AMG 102 and AMG 479 are investigational, fully human mAbs against hepatocyte growth factor (HGF) and insulin-like growth factor receptor 1 (IGF1R), respectively. This 3-part study evaluated the safety and efficacy of AMG 102 or AMG 479 in combination with pmab. Methods: Part 1 was a phase 1b, open-label, dose-finding study to determine a tolerable dose of AMG 102 in combination with pmab. Part 2 was a phase II, randomized, blinded, placebo-controlled trial that explored pmab + the dose of AMG 102 selected in Part 1 vs pmab + AMG 479 vs pmab + placebo. Part 3 is a 2-arm randomized extension study for pts who developed disease progression (PD) or intolerability to pmab + placebo in part 2. Eligible pts were ≥ 18 years old with WT KRAS mCRC and ECOG PS 0/1. In part 1, all pts received 6 mg/kg pmab + 10 mg/kg AMG 102 Q2W IV until PD or intolerability. The primary endpoint of part 1 was the incidence of dose-limiting toxicities (DLTs). The primary endpoint for part 2 is objective response rate (ORR). Results: In part 1, no DLTs were reported for the first 6 DLT-evaluable pts. A total of 11 pts were enrolled in part 1 prior to the decision to use the 10 mg/kg Q2W AMG 102 dose in part 2; 5 pts were men; mean (range) age was 56 (37-75) yrs; ECOG 0/1 was 55%/45%. Grade 3 treatment-related adverse events (AEs) were acneiform dermatitis or rash (55%), paronychia (18%), infection (9%), capillary leak syndrome (9%), erythema (9%), nail disorder (9%), and pruritus (9%). There were no grade 4 or 5 treatment-related AEs. Serious AEs included acneiform dermatitis (n = 1), intestinal obstruction (n = 1), cerebrovascular accident (n = 1), capillary leak syndrome (n = 1), and anemia/general health deterioration (n = 1). One pt died on study from PD. In part 2, 142 pts received at least one dose of study drug; enrollment is complete, and data analyses are ongoing. Conclusions: In part 1, 6 mg/kg pmab + 10 mg/kg AMG 102 Q2W was well tolerated. Primary efficacy results from part 2, including ORR and progression-free survival, will be presented. [Table: see text]
Screw retained vs. cement retained implant‐supported fixed dental prosthesis
Authors: Julia‐Gabriela Wittneben, Tim Joda, Hans‐Peter Weber, Urs Brägger
Journal: Periodontology 2000 (2016)

Abstract A fixed dental prosthesis can be secured to an endosseous implant via cementation (using a provisional or definitive cement) on an implant abutment that is screw retained to the implant or directly in the implant via screw retention. The clinical decision as to which retention system best suits the individual patient depends on several factors. The aim of this review is to present a detailed overview of the factors potentially influencing whether to choose screw retention or cement retention. These factors include the individual indication, advantages and disadvantages of the different retention mechanisms, the retention provided, retrievability, provisionalization, esthetics and clinical performance, including failures and complications. The results of recently published systematic reviews on this topic are discussed and an overview is provided. A decision tree is presented to facilitate the clinical selection of the retention type. This overview concludes that the choice of retention type (screw retained or cement retained) might not influence the overall survival of the implant‐supported fixed dental prosthesis, but may be responsible for the development of certain complications. The decision may depend on technical feasibility and on weighing the pros and cons.
PTH-039 Assessment of gastrointestinal transit time of a non-digestible solid: can the “old” wireless capsule endoscopy be as useful as the new SmartPill?
Authors: L Marelli, L Jackson, O Epstein
Journal: Gut (2010)

<h3>Introduction</h3> Wireless capsule endoscopy (WCE) has been used since 2001 to detect and diagnose disorders of the small intestine. SmartPill, currently only available in the US, is an innovative method used to evaluate gastrointestinal transit. This is a wireless capsule with similar dimension to WCE that uses the indirect measure of pH change to measure gastric emptying time and small bowel transit time. WCE provides pinpoint accuracy for recognising entry into the stomach, passage into the duodenal bulb and time to reach ileo-caecal valve. It seems likely that like SmartPill, WCE could be used to assess motility as well as mucosal appearance. The aim of our study was to assess gastric emptying time (GET) and small bowel transit time (SBTT) in a series of patients undergoing WCE and to compare these with published studies of SmartPill1. <h3>Methods</h3> Between January 2008 and November 2009, 301 consecutive patients had WCE in our institution; 134 patients had a normal study (59M:75F; mean age 51±17 years). In these individuals, we used WCE to measure GET and SBTT and compared the results with SmartPill data published in healthy individuals. <h3>Results</h3> In the 134 patients with a normal WCE study, indications for WCE were: iron deficiency anaemia in 73 (54%), suspected inflammatory bowel disease in 30 (23%), abdominal pain and/or diarrhoea in 24 (18%) and suspected small bowel tumour in 10 (5%). Mean GET was 36±37 minutes and mean SBTT was 238±84 min. The capsule failed to reach the ileo-caecal valve in eight patients (6%). The mean GET reported using SmartPill in healthy volunteers has been reported as 92±44 min in subjects swallowing the capsule with water, and when given with a test meal mean GET was 190±54 min and mean SBTT 332±39 min. <h3>Conclusion</h3> Highly accurate visual cues observed directly with WCE can be used to accurately measure gastric and small bowel transit times for this non-digestible solid. In our series of patient with normal WCE study, mean GET was 36 min and SBTT was 238 min. This differs substantially from recognised SmartPill values. WCE and SmartPill are insoluble and have similar size and shape; the difference in transit time measurements suggests that measurements based on pH change or direct visualisation of visual landmarks differ. The potential to use either of these capsules to assess motility requires further evaluation.
Rituximab-CHOP21 Plus Lenalidomide (LR-CHOP21) Is Effective and Feasible in Elderly Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results of Phase II REAL07 Study of the Fondazione Italiana Linfomi (FIL)
Authors: Annalisa Chiappella, Silvia Franceschetti, Alessia Castellino, Angelo Michele Carella, Ileana Baldi, Manuela Zanni, Anna Marina Liberati, Michele Spina, Chiara Bottelli, Vincenzo Pavone, Anna Lia Molinari, Pier Luigi Zinzani, Flavia Salvi, Pier Paolo Fattori, Alfonso Zaccaria, Barbara Botto, Angela Congiu, Marco Ladetto, Martin Dreyling, Gianluca Gaidano, Giuseppe Rossi, Umberto Vitolo
Journal: Blood (2012)
Results of T Cell Depleted (TCD) Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) from HLA Matched (HLA-M) or Partially Mismatched (HLA-MM) Unrelated Donors (URD) in Patients with Hematologic Malignancies: Sustained Engraftment and Low Incidence of Graft-vs-Host Disease (GvHD).
Authors: Ann A. Jakubowski, Esperanza B. Papadopoulos, Nancy A. Kernan, Farid Boulad, H.R. Castro-Malaspina, Nancy H. Collins, Katharine Hsu, Miguel-Angel Perales, Trudy N. Small, Marcel van den Brink, James W. Young, Richard J. O’Reilly
Journal: Blood (2006)
Thymoglobuline Is As Effective As Lymphoglobuline in Japanese Patients with Aplastic Anemia Possessing Increased Glycosylphosphatidylinositol-Anchored Protein (GPI-AP) Deficient Cells
Authors: Hirohito Yamazaki, Chizuru Saito, Naomi Sugimori, Kohei Hosokawa, Yu Kiyu, Kanako Mochizuki, Hiroyuki Takamatsu, Shinji Nakao
Journal: Blood (2011)
621. Widespread Gene Delivery to the Nonhuman Primate Brain for the Treatment of Huntington's Disease
Authors: Piotr Hadaczek, Lisa Stanek, Agnieszka Ciesielska, Philip Pivirotto, Catherine O'Riordan, Bryan Mastis, Waldy San Sebastian, John Forsayeth, Seng H. Cheng, Krystof S. Bankiewicz, Lamya S. Shihabuddin
Journal: Molecular Therapy (2016)

Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG-trinucleotide repeat expansion in a coding exon of a single allele in the HTT locus. In HD, the resulting polyglutamine (polyQ) expansion confers a toxic gain-of-function to the mutant huntingtin protein (mHTT). Reduction of expression of mHTT using gene silencing by RNA interference (RNAi) may confer transformative disease modifying therapeutic approach for HD. Adeno associated vectors (AAV) provide an ideal delivery system for nucleic acid therapeutics and have the potential to allow for long lasting and continuous expression of these huntingtin lowering RNAi in the brain. Despite this promise, global delivery of AAV to the adult brain remains an elusive goal. Furthermore, the appropriate brain areas to target for achieving transformative therapeutic benefit in HD patients remain to be defined. Postmortem analyses of HD patient brains reveal extensive medium spiny neuronal loss in the striatum, in addition to loss of pyramidal neurons in the cerebral cortex and hippocampus. Recent studies in rodent models suggest that simultaneous targeting of striatum and cortex is more efficacious than targeting either individually. Thus, available evidence suggests that delivery of Htt-lowering therapeutics to both striatal and cortical regions may provide optimal therapeutic efficacy. The current study demonstrate for the first time the successful use of an AAV targeting strategy that leads to viral transduction in key brain areas considered to be important for HD pathology. The study compared the efficiency of transduction of AAV1 and AAV2 vectors in the rhesus monkey brain following intra-striatal injection. Both vectors encoded green fluorescent protein (GFP) under control of a hybrid CMV enhancer/chicken beta-actin promoter. One month following injection, brains were analyzed for distribution of GFP-positive cells. We found that the AAV1 vector provided extensive delivery to the majority of the primate striatum, and additionally transduced large numbers of cells within the cerebral cortex, thalamus, and hippocampus. In summary, the data suggest that intrastriatal delivery maybe sufficient for the delivery of nucleic acid-based therapeutics to multiple areas of the human brain relevant in HD.
Abstract 5538: A pH-responsive doxorubicin-lipid conjugate loaded nanomedicine for breast cancer treatment
Authors: Feng Li, Marilyn Saulsbury, Simone Heyliger, Mikhail Bondarev, Chengan Du, Corinne C. Ramaley, KiTani P. Lemieux
Journal: Cancer Research (2015)

Abstract Doxorubicin (DOX) is a chemotherapeutic agent widely used in the treatment of various cancers. However, its clinical use is restricted due to serious cardiotoxicity and the development of drug resistance. Many delivery strategies, including the use of liposomes, micelles, and polymer drug conjugates, have been used to improve the therapeutic efficacy and reduce the toxicity of DOX. Recently, lipid-drug conjugates have also been investigated for the delivery of anticancer drugs. The conjugation of lipids with DOX can increase its lipophilicity, thus enhance its loading in lipid-based nanoparticles, facilitate interaction with cells, and improve pharmacokinetic properties. In this study, we developed a micelle formulation with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-amino polyethylene glycol-2000 (DSPE-PEG) to deliver a DOX-lipid conjugate to treat breast cancers. DOX was conjugated with palmitic acid (PA) through a pH sensitive hydrazone bond to yield a lipophilic pro-drug of DOX (PA-DOX). PA-DOX (Log P = 2) showed significantly increased lipophilicity than DOX (Log P = - 0.5). The micelles were prepared using a thin-film dispersion method. Due to the lipophilic nature of PA-DOX, it can be efficiently loaded into the hydrophobic core of DSPE-PEG micelles. In addition, the micelle formulation demonstrated superior stability, showing no leakage or precipitation of PA-DOX for at least two weeks during storage at 4°C. In vitro drug release was tested in sodium phosphate buffer (pH 7.5) and sodium acetate buffer (pH 5.0), respectively. DOX-PA was stable at pH 7.4 and showed minimal DOX release (less than 10% at 24 hours). The release of DOX was significantly increased at pH 5 (approximately 75% at 24 hours). Anticancer activities were evaluated with MCF-7 breast cancer cells and MCF-7/MDR drug-resistant breast cancer cells. Cell viability was determined by a MTT assay. PA-DOX showed similar anticancer activity on MCF-7 cells as DOX itself. Anticancer activity of PA-DOX was significantly reduced in MCF-7/MDR cells but restored when used in combination with lapatinib. Citation Format: Feng Li, Marilyn Saulsbury, Simone Heyliger, Mikhail Bondarev, Chengan Du, Corinne C. Ramaley, KiTani P. Lemieux. A pH-responsive doxorubicin-lipid conjugate loaded nanomedicine for breast cancer treatment. [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 5538. doi:10.1158/1538-7445.AM2015-5538
PP-010 Serum hepcidin: a predictor of early graft dysfunction following orthotopic liver transplantation?
Authors: R Desai, D Ward, M Brookes, C Tselepis, A Holt, T Iqbal
Journal: Gut (2010)

<h3>Introduction</h3> The hepatic peptide hepcidin is a critical regulator of iron metabolism. Serum levels of hepcidin correlate with liver function in humans and rodent studies have shown that liver injury modulate hepcidin expression. This is the first study of hepcidin levels in patients undergoing liver transplantation. We show that post-transplant serum hepcidin levels identify patients with severe preservation/reperfusion injury and hence predict graft dysfunction following liver transplantation. <h3>Methods</h3> Serial serum hepcidin levels were measured by SELDI-TOF mass spectrometry in 11 patients undergoing liver transplantation. Liver biopsies (T0) were taken during transplantation in 9/11 patients. Clinicopathological, biochemical and haematological data were compared. <h3>Results</h3> 5/11 patients had poor graft function after transplantation (determined by graft cholestasis, elevated PT and AST levels). Patients with poor graft function were more likely to have evidence of moderate/severe preservation injury at T0 biopsy than patients with normal graft function and were more likely to have received a liver from a non-heart beating (NHB) than a heart-beating donor (3/5 vs 1/7, respectively). While there was no difference in hepcidin levels between the two groups at the time of transplantation (90 vs 76 ng/ml p=0.68), the five patients with poor graft function had significantly higher hepcidin levels on day 3 post-transplantation compared to the six patients with mild preservation injury (Mean 135 (91–179) vs 39 (17–61) ng/ml, respectively, p&lt; 0.01 ANOVA). Mean serum hepcidin values rose by 393% between day 1 and day 3 post transplant in the group with poor graft function whereas there was a 49% drop in serum hepcidin level in the group with normal function. The rise in hepcidin values at day 3 anticipated the onset of graft cholestasis in all of the patients with severe preservation injury. <h3>Conclusion</h3> This is the first study of serum hepcidin levels in patients undergoing liver transplantation. We show that hepcidin values rapidly fall in patients with normal graft function following transplantation, but remain elevated in patients with early graft dysfunction. Elevated serum hepcidin levels accurately predicted the onset of preservation injury and anticipated graft dysfunction. Moreover we show that hepcidin levels are a better determinant of future graft dysfunction than AST or CRP. Early identification of graft dysfunction is important as it allows for modification of immunosuppression. We show that day 3 hepcidin levels correlate well with the severity of graft injury and can be used as a predictor of early graft dysfunction.
High Cardiac Output By Microfistulas: A New Pulmonary Hypertension Mechanism in Patients with Myelofibrosis and the Impact of the Treatment with Ruxolitinib
Authors: Jose Maria Segovia, Emilio Ojeda, Gomez-Bueno Manuel Francisco, Rafael Fores, Jose A Garcia-Marco, Francisco Javier Haro, Isabel Salcedo, Carlos DeMiguel
Journal: Blood (2015)
671. Potent Anti-Tumor Effects of ApDCs (Aptamer Drug Conjugates) for Targeted Therapeutics in Pancreatic Cancer
Authors: Sorah Yoon, Kai-Wen Huang, Nagy Habib, John Rossi
Journal: Molecular Therapy (2016)

Aptamer Drug Conjugates (ApDCs) are a potential class of targeting therapeutics to improve therapeutic index over traditional chemotherapy. As most existing chemotherapies are absorbed into cells non-specifically through lipophilic interaction, to improve the therapeutic index, the drugs were attached to pancreatic cancer specific RNA aptamer, P19, as targeting moieties that preferentially delivered the payload to tumor cells. Active metabolites of gemcitabine (dFdCMP) and 5FdU (5FdUMP) were incorporated P19 intrinsically to make conjugates. The conjugates of P19-dFdCMP or P19-5FdUMP kept their structural functionality getting internalized in their target cells, PANC-1. P19-dFdCMP and P19-5FdUMP was incorporated into replicating DNA, resulting in chain termination and stalling of replication forks in nuclear. They induced the phosphorylation of histone H2AX on Ser139 (γ-H2AX), markers of double-strand DNA breaks, and increased the forms of nuclear foci at the sites of DNA damage. In consequence, the cell proliferation was significantly inhibited 51-53% in PANC-1 and 54-34% in gemcitabine resistance AsPC-1. Targeted anti-mitotic therapies have emerged as a new concept of cancer drugs. Chemotoxine, monomethyl auristatin E (MMAE) is a very potent antimitotic agent that inhibits cell division by blocking the polymerization of tubulin. However, it can't be used by drug itself because of high toxicity. Herein, toxic molecule, MMAE, was conjugated to P19 for the targeted anti-mitotic therapies. P19-MMAE caused mitotic G2/M phase arrest, consequently inhibited 56% of cell proliferation on dose-dependent manner comparing control. In vivo assay, P19-MMAE induced the tumor regression via tail vein injection. In this study, the drug attached aptamer significantly decreased non-specific uptake of the drug and increase specific uptake of the conjugate in tumor cells. Our approaches suggest guiding cytotoxic drugs into malignant cancer cells specifically without causing significant harm to the normal cells.
70. Safety, Toxicity and Efficacy of Systemic Recombinant VSV Therapy in Pet Dogs With Spontaneous Cancer
Authors: Shruthi Naik, Amy K. Leblanc, Gina Galyon, Sara Frazier, Nathan Jenks, Mike Steele, Amber Miller, Kah Whye Peng, Mark Federspiel, Stephen J. Russell
Journal: Molecular Therapy (2015)

Clinical translation of oncolytic therapy to benefit cancer patients is dependent upon extensive evaluation of viral safety, toxicity and therapeutic efficacy in disease bearing animals. Comparative oncology, the study of naturally occurring cancer in animals, allows evaluation of novel cancer therapies in pet dogs that are similar in size, genetic make-up, physiology and exposure to environmental risk factors to humans. We have previously shown single shot systemic therapy with recombinant Vesicular stomatitis virus (VSV) engineered to express Interferon-beta (IFN) and the sodium-iodide symporter (NIS) in tumor bearing mice results in tumor-specific virus replication that can be monitored noninvasively by SPECT/CT imaging using NIS specific radio-tracer, induces tumor remission and confers significant survival benefit. A comparative oncology approach was utilized to investigate safety, clinical toxicities and therapeutic efficacy of systemic VSV therapy in dogs with spontaneous cancer. A pre-clinical rapid dose-escalation study was performed in healthy lab beagles defined a safe systemic dose range. We initiated evaluation of systemic VSV administration in dogs with spontaneous cancer. 8 dogs with various cancers were treated with VSV expressing either human or canine IFN-beta and NIS. We demonstrate that systemic VSV therapy at a dose of 10(10) TCID is well tolerated in dogs with spontaneous disease. We detected transient hepatotoxicity that resolved spontaneously in 2/8 dogs following systemic VSV-IFN-NIS treatment. No infectious virus was detected in urine or buccal swab samples. Monitoring of disease response indicated that 2/2 dogs with T-cell lymphoma had dramatic disease remission following systemic VSV-hIFN-NIS treatment resulting in partial response, though remission was transient and disease eventually relapsed. Virus pharmacokinetics (PK) studies indicate that dogs with robust responses also had highest viral PK in blood, suggesting therapeutic response is PK dependent. A dose optimization protocol was adopted where gradual dose escalation and multi-dosing protocols are being evaluated. Initial findings indicate two-dose systemic VSV-IFN-NIS therapy in a dog with metastatic Osteosarcoma (OSA) is well tolerated, delays viral decay in blood, and has resulted in improved health of the treated dog with no major disease progression to date. RNAseq analysis of tumor biopsies from treated animals reveals changes in tumor gene expression following systemic VSV therapy. Overall the data demonstrate that recombinant VSV can be safely administered systemically in cancer bearing dogs. Our data suggest that therapeutic response is PK dependent, prompting dose optimization studies that will directly inform and support planned clinical studies to evaluate systemic VSV therapy in patients with relapsed or metastatic cancer.