tbuckley/cabot-search huggingface dataset:
A Phase I Pharmacologic Study of Necitumumab (IMC-11F8), a Fully Human IgG1 Monoclonal Antibody Directed Against EGFR in Patients with Advanced Solid Malignancies
Authors: Bart Kuenen, Petronella O. Witteveen, Rita Ruijter, Giuseppe Giaccone, Aruna Dontabhaktuni, Floyd Fox, Terry Katz, Hagop Youssoufian, Junming Zhu, Eric K. Rowinsky, Emile E. Voest
Journal: Clinical Cancer Research (2010)

This study aimed to determine a maximum tolerated dose (MTD) and recommended dose for disease-directed studies of necitumumab (IMC-11F8), a fully human IgG(1) monoclonal antibody directed at the epidermal growth factor receptor, and to characterize the safety profile, pharmacokinetics, preliminary antitumor activity, and immunogenicity of necitumumab.Patients with advanced solid malignancies were treated with 100 to 1,000 mg (flat dosing) necitumumab followed by a 2-week pharmacokinetics sampling period, before beginning 6-week cycles of therapy.Sixty patients received necitumumab weekly (29 patients) or every other week (31 patients). Two patients receiving 1,000 mg every 2 weeks experienced dose-limiting toxicities (DLT; grade 3 headache), accompanied by grade 3 nausea and vomiting in one patient. Occurring hours after the initial dose, these DLTs established 800 mg as the MTD. Mild dose-related skin toxicity was the most common drug-related toxicity (80%). One patient in each arm experienced grade 3 acneform rash, which responded to oral antibiotics and topical therapy. Toxicity was similar on both schedules. Necitumumab exhibited saturable elimination and nonlinear pharmacokinetics. At 800 mg (both arms), its half-life was approximately 7 days. All patients treated with >or=600 mg necitumumab achieved target trough concentrations (>or=40 microg/mL). Antibodies against necitumumab were not detected. Partial response and stable disease were experienced by 2 and 16 patients, respectively.Well tolerated, necitumumab is associated with preliminary evidence of antitumor activity, and achieves biologically relevant concentrations throughout the dosing period. The recommended dose of necitumumab for further clinical development is 800 mg (flat dose) weekly or every 2 weeks based on the clinical setting.
Microsatellite DNA instability and loss of heterozygosity in bronchial asthma
Authors: E. Paraskakis, G. Sourvinos, F. Passam, N. Tzanakis, E.G. Tzortzaki, M. Zervou, D. Spandidos, N.M. Siafakas
Journal: European Respiratory Journal (2003)

Genetic alterations, such as loss of heterozygosity (LOH) or microsatellite instability (MI), have been reported in both malignant and benign disorders. In order to identify loci of deoxyribonucleic acid (DNA) mutation in asthma, MI and LOH were studied in sputum cells. DNA was extracted from cells in the sputum and blood cells of 22 patients with moderate asthma. Cells were analysed for MI and LOH using 18 polymorphic markers on chromosome 5q, 6p, 11q, 14q. Microsatellite analysis was also performed in six healthy subjects. None of the healthy individuals exhibited any genetic alteration. Genetic alterations were found in 16 of 22 asthmatic patients (73%). In total, 12 (54.5%) patients exhibited LOH only, one (4.5%) MI only, while three showed both MI and LOH. The highest incidence of LOH and MI was found on chromosome 14q. Mean immunoglobulin E and blood eosinophil levels were significantly higher in asthmatics with three or more genetic alterations. A high incidence of genetic alterations in the deoxyribonucleic acid of the sputum cells was found in asthmatic patients. Further studies are needed to identify the role of loss of heterozygosity and microsatellite instability in the investigation of genetic susceptibility of asthma and thus, in its pathogenesis.
Global Characterization of the SRC-1 Transcriptome Identifies ADAM22 as an ER-Independent Mediator of Endocrine-Resistant Breast Cancer
Authors: Damian McCartan, Jarlath C. Bolger, Aílis Fagan, Christopher Byrne, Yuan Hao, Li Qin, Marie McIlroy, Jianming Xu, Arnold D. Hill, Peadar Ó Gaora, Leonie S. Young
Journal: Cancer Research (2011)

The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity that permits the emergence of a hormone-independent tumor. The steroid coactivator protein SRC-1, through interactions with developmental proteins and other nonsteroidal transcription factors, drives this tumor adaptability. In this discovery study, we identified ADAM22, a non-protease member of the ADAM family of disintegrins, as a direct estrogen receptor (ER)-independent target of SRC-1. We confirmed SRC-1 as a regulator of ADAM22 by molecular, cellular, and in vivo studies. ADAM22 functioned in cellular migration and differentiation, and its levels were increased in endocrine resistant-tumors compared with endocrine-sensitive tumors in mouse xenograft models of human breast cancer. Clinically, ADAM22 was found to serve as an independent predictor of poor disease-free survival. Taken together, our findings suggest that SRC-1 switches steroid-responsive tumors to a steroid-resistant state in which the SRC-1 target gene ADAM22 has a critical role, suggesting this molecule as a prognostic and therapeutic drug target that could help improve the treatment of endocrine-resistant breast cancer.
Novel Tumor Subgroups of Urothelial Carcinoma of the Bladder Defined by Integrated Genomic Analysis
Authors: Carolyn D. Hurst, Fiona M. Platt, Claire F. Taylor, Margaret A. Knowles
Journal: Clinical Cancer Research (2012)

There is a need for improved subclassification of urothelial carcinoma (UC) at diagnosis. A major aim of this study was to search for novel genomic subgroups.We assessed 160 tumors for genome-wide copy number alterations and mutation in genes implicated in UC. These comprised all tumor grades and stages and included 49 high-grade stage T1 (T1G3) tumors.Our findings point to the existence of genomic subclasses of the "gold-standard" grade/stage groups. The T1G3 tumors separated into 3 major subgroups that differed with respect to the type and number of copy number events and to FGFR3 and TP53 mutation status. We also identified novel regions of copy number alteration, uncovered relationships between molecular events, and elucidated relationships between molecular events and clinico-pathologic features. FGFR3 mutant tumors were more chromosomally stable than their wild-type counterparts and a mutually exclusive relationship between FGFR3 mutation and overrepresentation of 8q was observed in non-muscle-invasive tumors. In muscle-invasive (MI) tumors, metastasis was positively associated with losses of regions on 10q (including PTEN), 16q and 22q, and gains on 10p, 11q, 12p, 19p, and 19q. Concomitant copy number alterations positively associated with TP53 mutation in MI tumors were losses on 16p, 2q, 4q, 11p, 10q, 13q, 14q, 16q, and 19p, and gains on 1p, 8q, 10q, and 12q. Significant complexity was revealed in events affecting chromosome 9.These findings may lead to improved biologic understanding and the development of prognostic biomarkers. Novel regions of copy number alteration may reveal potential therapeutic targets.
Impaired Fasting Glucose Tolerance in First-Episode, Drug-Naive Patients With Schizophrenia
Authors: Martina C M Ryan, Patrick Collins, Jogin H Thakore
Journal: American Journal of Psychiatry (2003)

This study examined the prevalence of impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia.In this cross-sectional study, fasting plasma levels of glucose, insulin, lipids, and cortisol were measured in 15 male and 11 female hospitalized Caucasian patients with DSM-IV schizophrenia (mean age=33.6 years) and age- and sex-matched healthy comparison subjects. The patients and comparison subjects were also matched in terms of various life-style and anthropometric measures.More than 15% of the drug-naive, first-episode patients with schizophrenia had impaired fasting glucose tolerance, compared to none of the healthy volunteers. Compared with the healthy subjects, the patients with schizophrenia had significantly higher fasting plasma levels of glucose (mean=88.2 mg/dl, SD=5.4, for the healthy subjects versus mean=95.8 mg/dl, SD=16.9, for the patients), insulin (mean=7.7 micro u/ml, SD=3.7, versus mean=9.8 micro u/ml, SD=3.9), and cortisol (mean=303.2 nmol/liter, SD=10.5, versus mean=499.4 nmol/liter, SD=161.4) and were more insulin resistant, as measured with homeostasis model assessment (mean=1.7, SD=0.7, for the healthy subjects versus mean=2.3, SD=1.0, for the patients).First-episode, drug-naive patients with schizophrenia have impaired fasting glucose tolerance and are more insulin resistant and have higher levels of plasma glucose, insulin, and cortisol than healthy comparison subjects.
The HIF Pathway and Erythrocytosis
Authors: Frank S. Lee, Melanie J. Percy
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

Because of the central role that red blood cells play in the delivery of oxygen to tissues of the body, red blood cell mass must be controlled at precise levels. The glycoprotein hormone erythropoietin (EPO) regulates red blood cell mass. EPO transcription, in turn, is regulated by a distinctive oxygen-sensing mechanism. In this pathway, prolyl hydroxylase domain protein (PHD) site-specifically hydroxylates the α-subunit of the transcription factor hypoxia-inducible factor α (HIF-α), thereby targeting the latter for degradation by the von Hippel-Lindau tumor-suppressor protein (VHL). Under hypoxic conditions, this posttranslational modification of HIF-α is inhibited, which stabilizes it and promotes the transcriptional activation of genes, including that for EPO. Rare patients with erythrocytosis have mutations in the genes encoding for PHD2, HIF-2α, and VHL, which implicates these proteins as critical to the proper control of red blood cell mass in humans.
Levels of Cyclooxygenase-2 Are Increased in the Oral Mucosa of Smokers: Evidence for the Role of Epidermal Growth Factor Receptor and Its Ligands
Authors: Dimitrios Moraitis, Baoheng Du, Mariana S. De Lorenzo, Jay O. Boyle, Babette B. Weksler, Erik G. Cohen, John F. Carew, Nasser K. Altorki, Levy Kopelovich, Kotha Subbaramaiah, Andrew J. Dannenberg
Journal: Cancer Research (2005)

Cyclooxygenase-2 (COX-2) is a promising pharmacologic target for preventing aerodigestive malignancies. In this study, we investigated the effects of tobacco smoke on the expression of COX-2 in oral mucosa. An approximately 4-fold increase in amount of COX-2 mRNA was observed in the oral mucosa of active smokers versus never smokers. Thus, a series of in vitro studies were carried out to elucidate the mechanism by which tobacco smoke induced COX-2. Treatment of a nontumorigenic oral epithelial cell line (MSK-Leuk1) with a saline extract of tobacco smoke (TS) stimulated COX-2 transcription, resulting in increased amounts of COX-2 mRNA, COX-2 protein, and prostaglandin E(2) (PGE(2)) synthesis. Exposure of cells to TS also caused an increase in epidermal growth factor receptor (EGFR) tyrosine kinase activity. Both an inhibitor of EGFR tyrosine kinase activity and a neutralizing anti-EGFR antibody blocked TS-mediated induction of COX-2. To define the mechanism by which TS activated EGFR, the release of amphiregulin and transforming growth factor alpha, two ligands of the EGFR, was measured. Exposure to TS caused a rapid increase in the release of both ligands. TS also markedly induced the expression of mRNAs for amphiregulin and transforming growth factor alpha. Importantly, increased expression of both ligands was also detected in the oral mucosa of active smokers. Taken together, these results suggest that activation of EGFR signaling contributes to the elevated levels of COX-2 found in the oral mucosa of smokers. Moreover, these findings strengthen the rationale for determining whether inhibitors of COX-2 or EGFR tyrosine kinase activity can reduce the risk of tobacco smoke-related malignancies of the aerodigestive tract.
New Transfusion Strategies: Red Cell Substitutes
Authors: Robert M. Winslow, MD
Journal: Annual Review of Medicine (1999)

Red cell substitutes are solutions that can potentially be used in emergencies or during surgery when rapid expansion of the blood volume with an oxygen carrier is needed. The three main types of products in development are based on cell-free hemoglobin, perfluorocarbon emulsions, or liposome-encapsulated hemoglobin. None is currently approved for clinical use, but several are in advanced clinical trials. Outside the red blood cell, hemoglobin is subject to degradation and heme loss. It readily diffuses in the plasma space and effectively scavenges nitric oxide. These properties must be understood and controlled if hemoglobin-based products are to fulfill their promise. The development of red cell substitutes affords us a deeper insight into how oxygen is delivered to tissues in the microcirculation and how blood-flow distribution is regulated within and between organs. As red cell substitutes become available to clinicians and scientists, clinical applications are expected to expand.
INTRACELLULAR LIPID-BINDING PROTEINS AND THEIR GENES
Authors: David A. Bernlohr, Melanie A. Simpson, Ann Vogel Hertzel, Leonard J. Banaszak
Journal: Annual Review of Nutrition (1997)

▪ Abstract Intracellular lipid-binding proteins are a family of low-molecular-weight single-chain polypeptides that form 1:1 complexes with fatty acids, retinoids, or other hydrophobic ligands. These proteins are products of a large multigene family of unlinked loci distributed throughout the genome. Each lipid-binding protein exhibits a distinctive pattern of tissue distribution. Transcriptional control, regulated by a combination of peroxisome proliferator activated receptors and CCAAT/enhancer-binding proteins, allows for a variety of both cell and tissue-specific expression patterns. In some cells, fatty acids increase the expression of the lipid-binding protein genes. Fatty acids, or their metabolites, are activators of the peroxisome proliferator–activated receptor family of transcription factors. Therefore, as the concentration of lipid in the diet increases, the expression of lipid-binding proteins coordinately increases. As revealed by X-ray crystallography, the lipid-binding proteins fold into β-barrels, forming a large internal water-filled cavity. Fatty acid ligands are bound within the cavity, occupying only about one-third of the accessible volume. The bound fatty acid is stabilized via a combination of enthalpic and entropic forces that govern ligand affinity and selectivity. Cytoplasmic lipid-binding proteins are the intracellular receptors for hydrophobic ligands, delivering them to the appropriate site for use as metabolic fuels and regulatory agents.
Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis
Authors: Cristina Bosetti, Francesca Bravi, Eva Negri, Carlo La Vecchia
Journal: Human Reproduction Update (2009)

Various studies have reported an inverse relation between oral contraceptive (OC) use and the risk of colorectal cancer, but the issue is still open. In order to quantify the association between OC use and colorectal cancer risk, we performed a systematic review and meta-analysis of studies on this issue. We identified all relevant studies published, in English, as original articles up to December 2008 through a search of the literature using PubMed and EMBASE, and by reviewing the references from the retrieved articles. The summary relative risk of colorectal cancer for ever versus never OC use was 0.82 (95% confidence interval, CI, 0.69–0.97) from 11 case–control studies, 0.81 (95% CI, 0.75–0.89) from seven cohort studies, and 0.81 (95% CI, 0.72–0.92) from all studies combined. The results were similar for colon and rectal cancer. No difference was evident according to duration of OC use both for colon and rectal cancer, although there is an indication that the protection is stronger for more recent use (OR = 0.70, 95% CI, 0.53–0.90, on the basis of four studies). Epidemiological data consistently indicate that OC users have a reduced risk of colorectal cancer, and that the protection is greater for recent use in the absence, however, of a duration–risk relation.
Diagnosis and management of vitamin D deficiency
Authors: S. H. Pearce, T. D Cheetham
Journal: BMJ (2010)

#### Summary Points

Rickets in children and osteomalacia in adults are the classic manifestations of profound vitamin D deficiency. In recent years, however, non-musculoskeletal conditions—including cancer, metabolic syndrome, infectious and autoimmune disorders—have also been found to be associated with low vitamin D levels.1 The spectrum of these common disorders is of particular concern because observational studies have demonstrated that vitamin D insufficiency is widespread in many northern regions of the world, including industrialised countries.2 3 The increasing prevalence of disorders linked to vitamin D deficiency is reflected in the several hundred children with rickets treated each year in the UK.4 However, these children represent a small proportion of the individuals with a suboptimal vitamin D status in the UK population.1 3 5

A recent nationwide survey in the United Kingdom showed that more than 50% of the adult population have insufficient levels of vitamin D and that 16% have severe deficiency during winter and spring.5 The survey also demonstrated a gradient of prevalence across the UK, with highest rates in Scotland, northern England, and Northern Ireland.5 People with pigmented skin are at high risk, …
Acetaldehyde binds to liver cell membranes without affecting membrane function.
Authors: R E Barry, J D McGivan, M Hayes
Journal: Gut (1984)

Acetaldehyde is a major metabolic product of ethanol and is found in high concentrations in the serum during alcohol abuse. The effects of acetaldehyde on isolated rat liver cells and on purified hepatocyte plasma membrane vesicles have been studied. In concentrations of 0-10 millimolar acetaldehyde has been shown to have no detectable effect on either hepatocyte metabolism or gross membrane function and is therefore unlikely to act as a direct metabolic poison. Acetaldehyde, however, is shown to bind to hepatocyte membranes via intermediary Schiff's base formation. The adduction of acetaldehyde to liver cell plasma membranes may have an effect on membrane structure. These findings are consistent with the hypothesis that any injurious effect of acetaldehyde on the liver may be mediated via the immune system rather than being a direct effect on cell metabolism.
Suppression of Aurora-A-FLJ10540 signaling axis prohibits the malignant state of head and neck cancer
Authors: Chang-Han Chen, Alice YW Chang, Shau-Hsuan Li, Hsin-Ting Tsai, Li-Yen Shiu, Li-Jen Su, Wen-Lung Wang, Tai-Jen Chiu, Sheng-Dean Luo, Tai-Lin Huang, Chih-Yen Chien
Journal: Molecular Cancer (2015)

Head and neck cancer (HNC) is a highly invasive cancer. Aurora-A has been reported for a number of malignancies. However, the identity of downstream effectors responsible for its aggressive phenotype in HNC remains underinvestigated. The mRNA and protein expression levels of Aurora-A and FLJ10540 were assessed in HNC specimens and cell lines using RT-qPCR, western blot, Oncomine, and microarray database analysis. The downstream molecular mechanisms of Aurora-A were confirmed by RT-qPCR, western blot, luciferase reporter, confocal microscopy analyses, immunoprecipitation, colony formation, cell viability, and xenograft model. Cellular functions in response to Aurora-A-modulated downstream targets such as FLJ10540 and MMPs were examined in vitro and in vivo, including cell growth, motility and chemosensitivity. Aurora-A/FLJ10540/MMPs expression was determined in cancer and adjacent normal tissues from HNC patients by immunohistochemistry approach. In the current study, Aurora-A exhibited similar gene expression profiles with FLJ10540 by using accessibly public microarray and Oncomine database analysis, raising the possibility that these molecules might coordinately participate in cancer progression and metastasis of HNC. These two molecules connection were also examined in cell lines and tissues of HNC. Aurora-A overexpression could not only bind to the promoter of FLJ10540 to induce FLJ10540 expression, but also increase both mRNA and protein levels of MMP-7 and MMP-10 in HNC cells. Conversely, depletion of Aurora-A expression by using siRNA or Aurora-A kinase inhibitor, MLN8237, suppressed FLJ10540, MMP-7 and MMP-10 mRNA and protein expressions in vitro and in vivo. In addition, the FLJ10540-PI3K complex was destroyed by inhibition the Aurora-A kinase activity. Forced overexpression of FLJ10540 in Aurora-A-depleted or in MLN8237-treated HNC cells attenuated the effect on cytotoxicity to cisplatin. Elevated Aurora-A expression in HNC cells led to the characteristics of more aggressive malignancy, including enhanced chemoresistance and increased the abilities of proliferation, migration and invasion, which was required for FLJ10540/MMP-7 or FLJ10540/MMP-10 expressions. Finally, immunohistochemical analysis of human HNC specimens showed a significant positively correlation among Aurora-A, FLJ10540, MMP-7 and MMP-10 expressions. Together, our findings define a novel mechanism by which Aurora-A promotes cell malignancy, with potential implications for understanding the clinical action of Aurora-A.
Tumor <i>O</i>6-methylguanine-DNA Methyltransferase Inactivation by Oral Lomeguatrib
Authors: Amanda J. Watson, Ami Sabharwal, Mary Thorncroft, Gail McGown, Richard Kerr, Stana Bojanic, Zahir Soonawalla, Alexandra King, Andrea Miller, Sue Waller, Hing Leung, Geoffrey P. Margison, Mark R. Middleton
Journal: Clinical Cancer Research (2010)

Abstract Purpose: A major mechanism of resistance to chlorethylnitrosureas and methylating agents involves the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). We sought to determine the dose of oral 6-(4-bromo-2-thienyl) methoxy purin-2-amine (lomeguatrib), a pseudosubstrate inactivator of MGMT, required to render active protein undetectable 12 hours after dosing in prostate, primary central nervous system (CNS), and colorectal cancer patients. Experimental Design: Lomeguatrib was administered orally as a single dose (20-160 mg) ∼12 hours before tumor resection. Dose escalation was projected to continue until grade 2 toxicity or until complete inactivation of tumor MGMT was encountered. Total MGMT protein levels were quantified by ELISA, and active protein levels were quantified by biochemical assay. MGMT promoter methylation was determined in glioblastoma DNA by methylation-specific PCR. Results: Thirty-seven patients were dosed with lomeguatrib, and 32 informative tumor samples were obtained. Mean total MGMT level varied between tumor types: 554 ± 404 fmol/mg protein (±SD) for prostate cancer, 87.4 ± 40.3 fmol/mg protein for CNS tumors, and 244 ± 181 fmol/mg protein for colorectal cancer. MGMT promoter hypermethylation did not correlate with total protein expression. Consistent total MGMT inactivation required 120 mg of lomeguatrib in prostate and colorectal cancers. Complete consistent inactivation in CNS tumors was observed only at the highest dose of lomeguatrib (160 mg). Conclusions: Total MGMT inactivation can be achieved in prostate, primary CNS, and colorectal cancers with a single administration of 120 or 160 mg lomeguatrib. The dose needed did not correlate with mean total MGMT protein concentrations. One hundred twenty to 160 mg/d of lomeguatrib should be administered to achieve total MGMT inactivation in future studies. Clin Cancer Res; 16(2); 743–9
Phenotype and Genotype Characteristics of Age-related Macular Degeneration in a Japanese Population
Authors: Keisuke Mori, Kuniko Horie-Inoue, Peter L. Gehlbach, Hiroyasu Takita, Sho Kabasawa, Izumi Kawasaki, Tomoko Ohkubo, Susumu Kurihara, Hiroyuki Iizuka, Yumi Miyashita, Shigehiro Katayama, Takuya Awata, Shin Yoneya, Satoshi Inoue
Journal: Ophthalmology (2010)