tbuckley/cabot-search huggingface dataset:
Phase I pharmacokinetics (PK) of humanized anti-MUC-1 antibody R1550
Authors: M. D. Pegram, V. Borges, J. Fuloria, N. Ibrahim, C. L. Shapiro, E. S. Perez, K. Wang, F. Schaedeli Stark, C. Yeon, N. Courtenay-Luck
Journal: Journal of Clinical Oncology (2006)

2533 Background: MUC-1 glycoprotein establishes a molecular barrier at the epithelial surface, and engages in morphogenetic signal transduction. A 20 amino acid MUC-1 core tandem repeat is aberrantly glycosylated in &gt;90% of epithelial tumors, exposing peptide sequence PDTRP. Humanized IgG1 κ monoclonal antibody R1550 binds PDTRP (Kd∼1nM) and induces potent antibody-dependent cellular cytotoxicity. Methods: R1550 clinical tolerability and PK was determined in advanced, PDTRP-expressing (by IHC), breast cancer patients progressing after anthracyclines and taxanes. Key eligibility: informed consent, WHO PS 0–1, life expectancy &gt;4 mos, non-inflammatory histology, and no CNS metastasis. R1550 was infused IV over 1–3 hrs: cohort 1 (N = 3) 1 mg/kg; cohort 2 (N = 9) 3 mg/kg; cohort 3 (N = 6) 9 mg/kg; cohort 4 (N=3) 16 mg/kg, with repeat dosing every 1–2 weeks (patient-individualized PK assessment) until disease progression. Plasma [R1550] was measured by quantitative ELISA. PK parameters were analyzed by a non-compartmental model, and a 2-compartment population PK model. Results: 21 patients (mean age 54, median # of prior chemotherapy agents = 4) have been dosed. Safety data (n=18): R1550 is generally well tolerated with fatigue (28%), gastrointestinal symptoms (22%), skin rash (17%), pyrexia (11%), and elevated liver function tests (11%) as the most frequently reported adverse events (AEs). Two grade 4 AEs were reported: elevated AST, and hyperglycemia, both in cohort 2. Neither have been observed in expanded or subsequent cohorts. Median number of doses received per patient = 3 (range, 3–4), 4 (1–13) and 6 (4–21), in cohorts 1, 2, and 3, respectively. No anti-humanized antibodies were detected. PK parameters of cohorts 1–3 are shown below. Conclusions: R1550 is well tolerated, with MTD exceeding 9 mg/kg. PK parameters using non-compartmental, and 2-compartment population PK models are in agreement. R1550 half-life suggests weekly dosing. Plasma exposure and dose relationships are linear within 1–9 mg/kg dose range. Accrual to cohort 4 is ongoing. [Table: see text] [Table: see text]
Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference
Authors: Iain C. Macdougall, Andreas J. Bircher, Kai-Uwe Eckardt, Gregorio T. Obrador, Carol A. Pollock, Peter Stenvinkel, Dorine W. Swinkels, Christoph Wanner, Günter Weiss, Glenn M. Chertow, John W. Adamson, Tadao Akizawa, Stefan D. Anker, Michael Auerbach, Peter Bárány, Anatole Besarab, Sunil Bhandari, Ioav Cabantchik, Alan J. Collins, Daniel W. Coyne, Ángel L.M. de Francisco, Steven Fishbane, Carlo A.J.M. Gaillard, Tomas Ganz, David J. Goldsmith, Chaim Hershko, Ewa A. Jankowska, Kirsten L. Johansen, Kamyar Kalantar-Zadeh, Philip A. Kalra, Bertram L. Kasiske, Francesco Locatelli, Jolanta Małyszko, Gert Mayer, Lawrence P. McMahon, Ashraf Mikhail, Elizabeta Nemeth, Amy Barton Pai, Patrick S. Parfrey, Roberto Pecoits-Filho, Simon D. Roger, Guy Rostoker, Jacques Rottembourg, Ajay K. Singh, Itzchak Slotki, Bruce S. Spinowitz, Der-Cherng Tarng, Francesca Tentori, Jorge E. Toblli, Yusuke Tsukamoto, Nosratola D. Vaziri, Wolfgang C. Winkelmayer, David C. Wheeler, Elena Zakharova
Journal: Kidney International (2016)

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.
Randomized phase II trial of S-1 plus irinotecan versus S-1 plus paclitaxel as first-line treatment for advanced gastric cancer (OGSG0402): Final report.
Authors: T. Kishimoto, H. Imamura, F. Uedou, K. Fujitani, S. Iijima, H. Takiuchi, M. Imano, T. Shimokawa, Y. Kurokawa, H. Furukawa
Journal: Journal of Clinical Oncology (2010)

4015 Background: S-1-based regimens are commonly used for advanced gastric cancer (AGC) in Japan. Both S-1 plus irinotecan (SI) and S-1 plus paclitaxel (SP) have shown an overall response rate (ORR) of 48% in respective phase II trials. This randomized phase II trial evaluated these two S-1-based regimens in terms of ORR as first-line treatment for AGC in order to choose the optimal regimen for a phase III trial. Methods: Patients with previously untreated, locally advanced and/or metastatic measurable gastric adenocarcinoma, a performance status of < 2, and adequate organ function were randomly assigned to receive S-1 (80 mg/m2/day) for 21 consecutive days plus irinotecan (80 mg/m2) on days 1 and 15, repeated every 5 weeks for the SI arm, or the same dose of S-1 for 14 consecutive days plus paclitaxel (50 mg/m2) on days 1 and 8, repeated every 3 weeks for the SP arm. Both treatments were continued until disease progression or intolerable toxicity occurred. Study endpoints included ORR as primary, progression free survival (PFS), overall survival (OS), and toxicity. Results: Between December 2005 and November 2007, 102 patients were enrolled. The median number of cycles administered was 4 (range, 1-16) for the SI arm, and 5 (range, 1-40) for the SP arm. ORR on RECIST was 33.3% (95% CI, 20.8 to 47.9%) for the SI arm (n = 51) and 31.4% (95% CI, 19.1 to 45.9%) for the SP arm (n = 51), with no significant difference between the two. The best ORR was 37.3% (95% CI, 24.1 to 51.9%) for the SI arm and 35.3% (95% CI, 22.4 to 49.9%) for the SP arm. No treatment-related deaths occurred during the study. Both arms were well tolerated although grade 3/4 neutropenia (19% vs. 2%) and anemia (13% vs. 6%) were more frequent in the SI arm. PFS was 5.7 M (95% CI, 4.4 to 7.5 M) for the SI arm (n = 50) and 4.6 M (95% CI, 4.1 to 5.9 M) for the SP arm (n = 51), and OS was 12.4 M (95% CI, 9.2 to 15.4 M) for the SI arm (n = 50) and 11.9 M (95% CI, 10.2 to 18.0 M) for the SP arm (n = 51), with no significant difference between the two. Conclusions: Although both regimens were well tolerated in patients with AGC, neither of them could demonstrate favorable ORR, PFS or OS. Therefore, we concluded that either regimen couldn't be optimal for a phase III trial. No significant financial relationships to disclose.
A multicenter randomized phase II study of UFT/leucovorin and radiotherapy (RT) with or without cetuximab following induction gemcitabine plus capecitabine (GEM-CAP) in locally advanced pancreatic cancer (LAPC).
Authors: I. Y. Chong, A. F. Okines, D. M. Tait, M. Hawkins, D. Cunningham, C. Saffery, K. Thomas, I. Chau
Journal: Journal of Clinical Oncology (2010)

TPS221 Background: The optimal treatment paradigm for patients (pts) with LAPC has not yet been defined. Pooled analysis of GERCOR phase II-III studies suggests that pts may benefit from chemoradiotherapy (CRT) after achieving disease stabilization from induction chemotherapy (Huguet et al, JCO 2007). GEM-CAP resulted in a significant improvement in response rate and progression-free survival over gemcitabine in pts with LAPC (Cunningham et al, JCO 2009). UFT is well tolerated as a radiosensitizer in LAPC, and results in a R0 resection rate of 17% (J Bjerregaard et al, Radiother Oncol 2009). Cetuximab is an effective radiosensitiser in pts with squamous cell carcinoma of the head and neck (J Bonner et al, NEJM 2006), and its role as a radiosensitizer in other epithelial malignancies warrants further investigation. This randomized study aims to assess the overall survival (OS) for pts with LAPC receiving UFT/LV and radiotherapy with or without cetuximab after receiving induction GEM-CAP. Methods: Pts eligible for this study must have unresectable, histology-proven LAPC. Unresectability is based on extensive peri-pancreatic lymph node involvement; encasement/occlusion of superior mesenteric vein (SMV) or SMV/portal vein confluence ± involvement of superior mesenteric artery, coeliac axis, inferior vena cava, or aorta. Pts receive 3 cycles of neoadjuvant GEM-CAP. Those with disease stabilization or response receive one further cycle of GEM-CAP and proceed to RT (54Gy in 30# over 6 weeks) plus concurrent UFT with randomization to cetuximab. Functional imaging with diffusion weighted MRI and PET will be performed at baseline, weeks 4 and 16 to assess early predictors for efficacy. Pharmacogenetic studies with patients' germline DNA and correlative biomarker studies with pretreatment pancreatic biopsy will be performed. The primary endpoint is 1-yr OS rate. Using Simon one stage design, 1-yr OS rate from the time of registration of ≥55% is considered acceptable (p1) and <35% would be unacceptable (p0). 45 pts per arm will be randomized (2-sided α=0.05, 80% power). The trial opened in December 2009. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, Roche Roche Merck
Identification of pancreatic tumors in vivo with ligand-targeted, pH responsive mesoporous silica nanoparticles by multispectral optoacoustic tomography
Authors: Marie K. Gurka, Dillon Pender, Phillip Chuong, Benjamin L. Fouts, Alexander Sobelov, Molly W. McNally, Megan Mezera, Shiao Y. Woo, Lacey R. McNally
Journal: Journal of Controlled Release (2016)
Abstract 19636: Cardioprotective Role of Ceruloplasmin in Heart Failure via Inhibition of Myeloperoxidase Activity
Authors: David J Kennedy, Malory E Weber, Xi Wang, Kristen M Westfall, Jamie Viterna, Michael Finucan, Jennifer Kirsop, Timothy Engelman, Paul L Fox, Stanley L Hazen, W. H. Wilson Tang
Journal: Circulation (2014)

Elevated levels of the acute phase reactant ceruloplasmin (Cp) and the neutrophil heme protein myeloperoxidase (MPO) predict adverse clinical outcomes in the setting of acute coronary syndromes and heart failure (HF), yet whether the contribution of elevated Cp to HF is beneficial or detrimental is unclear. We tested the hypothesis that elevated Cp is cardioprotective via its ability to inhibit MPO in the following studies. Left anterior descending coronary artery ligation (LADx) was performed on wild type (WT) and Cp+/- mice. Four weeks after LADx, Cp+/- mice demonstrated greater impairment of cardiac structure and function, including increased myocardial fibrosis compared to WT (p<0.05). 24-hour urine MPO activity was increased after LADx, and is further increased in Cp+/- mice compared to WT with corresponding reduction in 24-hour urine Cp activity, thus suggesting the MPO inhibitory effects of Cp. In a series of in vitro assays examining MPO inhibitory capacity (MIC), addition of exogenous Cp (200 ug/...
Lack of evidence for close linkage of the glutamate GluR6 receptor gene with schizophrenia
Authors: A C Chen, G Kalsi, J Brynjolfsson, T Sigmundsson, D Curtis, R Butler, T Read, P Murphy, H Petursson, E A Barnard, H M Gurling
Journal: American Journal of Psychiatry (1996)

Previous research has consistently implicated genetic factors in the pathogenesis of schizophrenia. It has been hypothesized that an abnormality in glutamatergic function is of etiologic importance in schizophrenia, and therefore the glutamate receptor family of genes are potential susceptibility loci for schizophrenia. To test this hypothesis the authors sought to detect linkage between the GluR6 glutamate receptor gene and schizophrenia.Twenty-three English and Icelandic families containing multiple cases of schizophrenia were genotyped with a microsatellite trinucleotide repeat polymorphism localized at the GluR6 glutamate receptor locus. Lod scores, model-free linkage analysis, and extended relative pair analysis were used to test for linkage.No statistically significant evidence of linkage between GluR6 and schizophrenia was found.The results do not support the hypothesis that GluR6 allelic variants provide a major gene contribution to the etiology of schizophrenia in a large proportion of these pedigrees.
Non-coding microRNA hsa-let-7g as a novel chemoresponse biomarker for S-1 in colon cancer
Authors: G. Nakajima, K. Uchida, K. Hayashi, Y. Xi, K. Takasaki, J. Ju
Journal: Journal of Clinical Oncology (2006)

13513 Background: MicroRNAs (miRNAs) are small non-cording RNAs (∼ 22 nucleotide) that regulate gene expression by suppressing their target mRNAs at post-transcriptional level. Previous studies from our group have identified a number of dis-regulated miRNAs due to the loss of p53 tumor suppressor in cancer cell lines. As part of the efforts to further investigate the in vivo biological significance of these miRNAs, the expression of both hsa-let-7g and hsa-miR-200c were investigated using formalin-fixed paraffin embedded (FFPE) colon cancer specimens to evaluate the potential correlation with chemosensitivity and tumorigenesis. Methods: Forty-six patients with recurrent or residual colon cancer lesion assessable were treated with 5-FU based antimetabolite S-1. This includes twenty-one pair of tumor and normal samples. Total RNAs were isolated from these samples FFPE specimens (contains either &gt; 90% normal or &gt; 90% tumor tissue). cDNAs were synthesized using primers specific for hsa-let-7g, hsa-miR-200c and internal control 5S. The expression levels of each particular miRNAs were quantified using real time qRT-PCR analysis. The expression level of each miRNAs was quantified by measuring the difference of threshold cycle (C T ) of candidate miRNAs and internal control 5S (Δ-C T ). Results: The expression level of hsa-let-7g was significantly higher in tumor tissues compare to normal tissues (p=0.0026; Wilcoxon test). In the forty-six tumor tissues, the expression level of hsa-let-7g in disease response group (patients group of complete response, partial response and no change after chemotherapy) was significantly lower than the disease progression group (p=0.03; Mann-Whitney test). The expression of hsa-miR-200c was significantly over-expressed in tumor tissues compare to normal tissues (p=0.0001; Wilcoxon test). Although hsa-let-7g is strongly associated with patient’s response to S-1 treatment, it is not a prognostic factor for predicting survival. Conclusion: hsa-let-7g and hsa-miR-200c may be associated with tumorigenesis in colon cancer. In addition, hsa-let-7g may be a significant indicator for chemoresponse to S-1 based chemotherapy. No significant financial relationships to disclose.
Poor risk assessment in the elderly receiving cloretazine induction for AML or MDS
Authors: R. Geller, D. Rizzieri, N. Vey, S. O’Brien, B. Johnson, J. Karp, G. Mufti, F. Giles
Journal: Journal of Clinical Oncology (2006)

18562 Background: Elderly patients (pts) ≥60 years with acute myelogenous leukemia (AML) have lower response rates, and higher morbidity and mortality than younger pts when treated with cytotoxic induction therapy. Common disease-related factors that predict poor response in the elderly are adverse cytogenetics and secondary leukemia (following antecedent hematologic disorder or exposure to chemotherapy). Pt-related factors such as ECOG performance status (PS) and organ dysfunction affect treatment decisions due to poor tolerability and early death. Cloretazine, a novel alkylating agent has significant activity in AML and MDS with a favorable safety profile. A Phase II study of monotherapy induction was conducted in elderly pts with AML or high risk MDS (N = 105, median age 72, range 60–88), with a 31% complete response rate and minimal non-hematologic toxicity. To describe the pts in this study considered “unfit” for 7+3 induction, disease-related and pt-related information was obtained. The Hematopoietic Cell Transplantation Comorbidity Index (Sorrer et al, 2005) (HCT-CI) is a modification of the Charlson Comorbidity Index (Charlson et al.1987), for pts considered for stem cell transplant. Seventeen medical conditions are included with weighted values predicting non-relapse mortality (NRM). Methods: Baseline demographic and pt-related data was obtained from case report forms. In addition to disease-related prognostic indicators, pt-related data was scored by the HCT-CI. Pts were grouped in risk categories for NRM by HCT-CI scores (low = 0, intermediate = 1 or 2; high ≥3). Results: Either or both disease-related poor risk factors were present in 68 pts (65%): 42 pts (40%) had unfavorable cytogenetics and 45 pts (43%) had secondary AML. No pt had favorable cytogenetics. Ninety-four (89%) pts had at least one HCT-CI comorbidity. The most common were cardiac (46%), psychiatric (28%); hepatic (25%) and controlled infection (24%). By HCT-CI, the risk for NRM was low in 10%, intermediate in 32%, and high in 57% of pts. Conclusions: The majority of these elderly pts were poor-risk by disease-related criteria or comorbidities measured by the HCT-CI. This index warrants further testing for determining NRM risk of induction regimens for elderly pts with AML. [Table: see text]
A nanofluidic immunoassay system to develop proteomic responsive biomarkers in non-small cell lung cancer.
Authors: Jin-Qiu Chen, Jih-hsiang Lee, Michelle Herrmann, Yisong Wang, Kang-seo Park, Madeleine Heldman, Paul Goldsmith, Giuseppe Giaccone
Journal: Journal of Clinical Oncology (2012)

27 Background: Molecular targeted therapy is widely used to treat non-small cell lung cancer (NSCLC). However, errors in predicting response to targeted therapies are 20-30%, based on sequencing or FISH, and patient specimen are at times not sufficient for conventional protein technologies. Developing clinically feasible proteomic biomarkers may be valuable to identify patients who may benefit from targeted therapy. Methods: NanoPro technology (ProteinSimple), is a capillary-based isoelectric-focusing (IEF) immunoassay system, which detects and quantifies multiple protein phosphorylation isoforms that are not readily assessed by traditional immunoassays. The platform only uses nanograms of protein for analysis. Results: We studied dynamic phosphoprotein activities in NSCLC cells (PC9, H827, H4006, H2122 and H322) treated with EGFR or/and MEK inhibitors. In MEK inhibitor (PD325901) treated cells, NanoPro showed that the drug efficiently inhibited Erk phosphorylation, and also revealed a complex MEK response profile which was not detectable by Western blotting, demonstrating its on-target effect. NanoPro also identified a MEK2 signature that associated with erlotinib sensitivity and distinguished erlotinib sensitive from resistant cells. This MEK2 signature was further confirmed in acquired resistant cells to erlotinib (H827R, H4006R). In a H827 xenograft study, NanoPro was able to detect and distinguish human Erk1 isoform from mouse Erk1 based on their pI difference, and clearly demonstrated that erlotinib effectively inhibited Erk phosphorylation in human xenograft cancer cells but not in surrounding mouse stromal cells. We further demonstrated that Nanopro could monitor erlotinib and AZD2644 response in a Kras G12C NSCLC patient (NCT01229150) by profiling 18 signaling molecules with as little as 4ug tumor material. Conclusions: NanoPro provides a valuable platform to monitor signaling response to targeted therapy. Nanopro assesses protein phosphorylation both qualitatively and quantitatively using small sample size, thus creates new opportunities for pharmacodynamic biomarker assessment in clinical studies.
Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations
Authors: Eisaku Mori, Junji Fujikura, Michio Noguchi, Kazuhiro Nakao, Masaki Matsubara, Masakatsu Sone, Daisuke Taura, Toru Kusakabe, Ken Ebihara, Takayuki Tanaka, Kiminori Hosoda, Kazutoshi Takahashi, Isao Asaka, Nobuya Inagaki, Kazuwa Nakao
Journal: Metabolism (2016)
Computer aided mammography yields no clear benefit, research finds
Authors: Jacqui Wise
Journal: BMJ (2015)

Computer aided mammography, widely used in the United States, is not associated with better diagnostic accuracy than normal mammography screening, an observational study published in JAMA Internal Medicine has found.1

Computer aided detection (CAD) acts as an automated second reader by marking potentially suspicious spots for radiologists to review. It was approved by the US Food and Drug Administration in 1988, and the Centers for Medicare and Medicaid Services increased reimbursement for the procedure in 2002. Accordingly, it is now used in …
YKL-40 expression in breast cancer
Authors: A. Roslind, J. S. Johansen, N. Junker, D. L. Nielsen, N. Bentzon, P. A. Price, E. Balslev
Journal: Journal of Clinical Oncology (2005)

9665 Background: YKL-40, a heparinbinding glycoprotein, is a growth factor for connective tissue cells and stimulates migration of endothelial cells. High serum YKL-40 levels are associated with a poor prognosis in patients with metastatic breast cancer, colorectal, ovarian and small cell lung cancer. The function of YKL-40 in cancer is unknown, but in vitro observations suggest an involvement in cell proliferation, angiogenesis and extracellular matrix remodelling. The expression of YKL-40 in breast cancer tissue has never been described. The aim of this study was to determine the expression of YKL-40 in breast cancer by immunohistochemistry and in situ hybridisation. Methods: Tissue sections from 55 patients with primary breast cancer were stained using a monoclonal antibody against YKL-40. The intensity of YKL-40 staining in tumor cells was scored using a semi-quantitative method. Results: YKL-40 protein expression in tumor cells appeared as a dense cytoplasmic granular staining. No nuclear or membrane staining was found. 31 of 42 (74%) invasive ductal carcinomas and 7 of 11 (64%) invasive lobular carcinomas stained positive for YKL-40. Macrophages and leucocytes showed YKL-40 expression whereas lymphocytes were negative. In normal breast glands the epithelial cells appeared with a granular apical staining. The myoepithelial cells appeared negative. In the stroma the fibroblasts were weakly stained. YKL-40 protein expression was confirmed by in situ hybridisation. Conclusions: In the present study an overexpression of YKL-40 was found in the epithelial cells of both invasive ductal and lobular carcinomas of the breast compared to normal breast tissue. These data suggest that the tumor cells in breast cancer are the primary source of elevated serum YKL-40 levels as opposed to small cell lung cancer, where macrophages are the primary source of elevated serum YKL-40 levels. Further studies are needed to determine the significance of these findings in the clinical setting. No significant financial relationships to disclose.
Abstract 13842: Exercise Echocardiographic Adaptations of Right Ventricular Performance and Pulmonary Pressures in Combination with Gas Exchange Analysis in Heart Failure
Authors: Francesco Bandera, Greta Generati, Marta Pellegrino, Eleonora Alfonzetti, Valentina Labate, Marco Guazzi
Journal: Circulation (2014)

Introduction: Echo tricuspid annular systolic plain excursion (TAPSE) is the most used non- invasive indicator of right ventricular (RV) function with strong prognostic value in heart failure (HF) ...