tbuckley/cabot-search huggingface dataset:
Development of a Colon Cancer GEMM-Derived Orthotopic Transplant Model for Drug Discovery and Validation
Authors: Eric S. Martin, Peter J. Belmont, Mark J. Sinnamon, Larissa Georgeon Richard, Jing Yuan, Erin M. Coffee, Jatin Roper, Lydia Lee, Pedram Heidari, Sophia Y. Lunt, Gautam Goel, Xiadong Ji, Zhi Xie, Tao Xie, John Lamb, Scott L. Weinrich, Todd VanArsdale, Roderick T. Bronson, Ramnik J. Xavier, Matthew G. Vander Heiden, Julie L. C. Kan, Umar Mahmood, Kenneth E. Hung
Journal: Clinical Cancer Research (2013)

Effective therapies for KRAS-mutant colorectal cancer (CRC) are a critical unmet clinical need. Previously, we described genetically engineered mouse models (GEMM) for sporadic Kras-mutant and non-mutant CRC suitable for preclinical evaluation of experimental therapeutics. To accelerate drug discovery and validation, we sought to derive low-passage cell lines from GEMM Kras-mutant and wild-type tumors for in vitro screening and transplantation into the native colonic environment of immunocompetent mice for in vivo validation.Cell lines were derived from Kras-mutant and non-mutant GEMM tumors under defined media conditions. Growth kinetics, phosphoproteomes, transcriptomes, drug sensitivity, and metabolism were examined. Cell lines were implanted in mice and monitored for in vivo tumor analysis.Kras-mutant cell lines displayed increased proliferation, mitogen-activated protein kinase signaling, and phosphoinositide-3 kinase signaling. Microarray analysis identified significant overlap with human CRC-related gene signatures, including KRAS-mutant and metastatic CRC. Further analyses revealed enrichment for numerous disease-relevant biologic pathways, including glucose metabolism. Functional assessment in vitro and in vivo validated this finding and highlighted the dependence of Kras-mutant CRC on oncogenic signaling and on aerobic glycolysis.We have successfully characterized a novel GEMM-derived orthotopic transplant model of human KRAS-mutant CRC. This approach combines in vitro screening capability using low-passage cell lines that recapitulate human CRC and potential for rapid in vivo validation using cell line-derived tumors that develop in the colonic microenvironment of immunocompetent animals. Taken together, this platform is a clear advancement in preclinical CRC models for comprehensive drug discovery and validation efforts.
Leucocyte kinesis in blood, bronchoalveoli and nasal cavities during late asthmatic responses in guinea-pigs
Authors: T Nabe, N Shinoda, K Yamashita, H Yamamura, S Kohno
Journal: European Respiratory Journal (1998)

Recently, we reported a reproducible model of asthma in guinea-pigs in vivo, which developed a late asthmatic response (LAR) as well as an early response. In this study, time-related changes in the occurrence of the LAR and leucocyte kinesis were assessed. Furthermore, the state of the activation of eosinophils that migrated into the lower airways was characterized in vitro. Guinea-pigs were alternately sensitized/challenged by inhalation with aerosolized ovalbumin adsorbed on aluminium hydroxide and ovalbumin alone, once every 2 weeks. At defined times before and after the fifth challenge, airway resistance was measured, blood was drawn and bronchoalveolar lavage (BAL) and nasal cavity lavage (NCL) were performed. Superoxide anion (.O2-) production of eosinophils was measured with cytochrome c. Occurrence of LAR and considerable increases in circulating eosinophils coincided with each other 5-7 h after the challenge. After 7 h, eosinophil infiltrations into bronchoalveolar spaces were observed. The capacity of eosinophils from the sensitized animals to produce .O2- was higher than those from the non-sensitized ones, when eosinophils were stimulated by platelet-activating factor. Although an increased number of eosinophils in the NCL fluid was observed, it was much less than that in the BAL fluid. Thus, it has been concluded that eosinophilia in the blood and the lung may participate in the occurrence of the late asthmatic response, which is thought to be preferentially evoked in the lower airways in guinea-pigs in vivo.
Preliminary Results on Safety and Activity of a Randomized, Double-Blind, 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in Premenopausal Women
Authors: Aliana Guerrieri-Gonzaga, Chris Robertson, Bernardo Bonanni, Davide Serrano, Massimiliano Cazzaniga, Serena Mora, Marcella Gulisano, Harriet Johansson, Franca Formelli, Mattia Intra, Antuono Latronico, Dorella Franchi, Giuseppe Pelosi, Karen Johnson, Andrea Decensi
Journal: Journal of Clinical Oncology (2005)

To determine whether low-dose tamoxifen and fenretinide have a synergistic effect on surrogate biomarkers, including circulating insulin-like growth factor I (IGF-I) and mammographic density, in premenopausal women at risk for breast cancer and to study drug safety.Premenopausal women (n = 235) were randomly assigned in a double-blind four-arm trial to receive tamoxifen 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years. The present analysis refers to preliminary data on safety, IGF-I, and breast cancer events.Patients were included if they had an excised ductal carcinoma-in-situ (57%), lobular carcinoma-in-situ (13%), minimal invasive breast cancer (7%), or a 5-year Gail risk > or = 1.3% (23%). After a median follow-up of 40 months, there was a reduction of 13%, 2%, 20%, and 1% in IGF-I levels for patients on tamoxifen, fenretinide, tamoxifen plus fenretinide, and placebo, respectively. Recruitment was stopped based on the lack of an interaction on IGF-I levels, which was a primary end point for the study. Thirty-six patients have dropped out of the study, 17 because of adverse events and 19 for various other reasons. One stage I endometrial cancer occurred in a patient on fenretinide, and one optic nerve ischemia and one deep venous thrombosis occurred on tamoxifen. There was no difference in menopausal symptoms, endometrial thickness, polyps, or ovarian cysts among treatment arms. To date, 24 breast cancers have been observed, without differences among arms.The combination of low-dose tamoxifen and fenretinide is safe but not synergistic in lowering IGF-I levels in premenopausal women. The clinical implications require further follow-up.
The promotion of hepatic maturation of human pluripotent stem cells in 3D co-culture using type I collagen and Swiss 3T3 cell sheets
Authors: Yasuhito Nagamoto, Katsuhisa Tashiro, Kazuo Takayama, Kazuo Ohashi, Kenji Kawabata, Fuminori Sakurai, Masashi Tachibana, Takao Hayakawa, Miho Kusuda Furue, Hiroyuki Mizuguchi
Journal: Biomaterials (2012)
Absorption of 51Cr EDTA across the human nasal airway barriers in the presence of topical histamine.
Authors: L Greiff, P Wollmer, U Pipkorn, C G Persson
Journal: Thorax (1991)

Whether histamine, a mediator that causes exudation, affects the airway absorption of luminal solutes has been examined in a study of eight healthy volunteers. Fluid containing the absorption tracer chromium-51 labelled EDTA was instilled into one nasal cavity for 15 minutes, with a nasal pool-device (total volume 14 ml). The airway absorption of 51Cr EDTA determined by urinary recovery of radioactivity corresponded to 0.095 (SE 0.023) ml of the instillate in the absence of histamine. When histamine was added to the nasal instillate at a concentration of 2.0 mg/ml, which is known to produce substantial exudation of plasma into the airway lumen, the absorption of 51Cr EDTA was unchanged (0.093 (0.025) ml of the instillate). Separate experiments excluded the possibility that any swallowed portion of 51Cr EDTA could have contributed significantly to the amount absorbed. The present data agree with previous observations in guinea pig tracheobronchial airways, where histamine and other exudative agents did not increase the mucosal absorption of solutes from the airway lumen. These data suggest that the potent protein systems of blood plasma can transverse the endothelial-epithelial linings and operate on the surface of the airway mucosa without compromising its integrity as a barrier to luminal material.
Dietary Cod Protein Improves Insulin Sensitivity in Insulin-Resistant Men and Women
Authors: Véronique Ouellet, Julie Marois, S. John Weisnagel, Hélène Jacques
Journal: Diabetes Care (2007)

OBJECTIVE—The purpose of this article was to compare the effects of cod protein to those of other animal proteins on insulin sensitivity in insulin-resistant human subjects. RESEARCH DESIGN AND METHODS—Insulin sensitivity (M/I) was assessed using a hyperinsulinemic-euglycemic clamp in 19 insulin-resistant subjects fed a cod protein diet and a similar diet containing lean beef, pork, veal, eggs, milk, and milk products (BPVEM) for 4 weeks in a crossover design study. Both diets were formulated to differ only in protein source, thus providing equivalent amounts of dietary fibers and monounsaturated, polyunsaturated (including n-3), and saturated fatty acids (1.1:1.8:1.0). β-Cell function, estimated by oral glucose tolerance test–derived parameters, was also assessed. RESULTS—There was a significant improvement in insulin sensitivity (P = 0.027) and a strong tendency for a better disposition index (β-cell function × M/I) (P = 0.055) in subjects consuming the cod protein diet compared with those consuming the BPVEM diet. When median baseline M/I (4.8 × 10−3 mg · kg−1 · min−1 · pmol−1) was taken into account, an interaction on the 30-min C-peptide–to–30-min glucose ratio, used as an index of β-cell function, was observed between diet and M/I status (P = 0.022). Indeed, this ratio strongly tended to increase in subjects with low M/I consuming the cod protein diet compared with those consuming the BPVEM diet (P = 0.065). CONCLUSIONS—Dietary cod protein improves insulin sensitivity in insulin-resistant individuals and thus could contribute to prevention of type 2 diabetes by reducing the metabolic complications related to insulin resistance.
Clinical relevance and therapeutic potential of angiopoietin-like protein 4 in hepatocellular carcinoma
Authors: Kevin Tak-Pan Ng, Aimin Xu, Qiao Cheng, Dong Yong Guo, Zophia Xue-Hui Lim, Chris Kin-Wai Sun, Jeffrey Hon-Sing Fung, Ronnie Tung-Ping Poon, Sheung Tat Fan, Chung Mau Lo, Kwan Man
Journal: Molecular Cancer (2014)

Development of novel adjuvant therapy to eradicate tumor angiogenesis and metastasis is a pressing need for patients with advanced hepatocellular carcinoma (HCC). We aimed to investigate the clinical relevance and therapeutic potential of angiopoietin-like 4 (ANGPTL4) in HCC. ANGPTL4 mRNA levels in tumor and non-tumor liver tissues of HCC patients were analyzed to investigate its clinical relevance. The mechanisms of deregulation of ANGPTL4 in HCC were studied by copy number variation (CNV) and CpG methylation analyses. The orthotopic liver tumor nude mice model was applied using a human metastatic cell line. ANGPTL4-overexpressing adenovirus (Ad-ANGPTL4) was injected via portal vein to investigate its anti-tumorigenic and anti-metastatic potentials. HCC tissues expressed significantly lower levels of ANGPTL4 mRNA than non-tumor tissues. The copy number of ANGPTL4 gene in tumor tissues was significantly lower than in non-tumor tissues of HCC patients. Higher frequency of methylation of CpG sites of ANGPTL4 promoter was detected in tumor tissues compared to non-tumor tissues. Downregulation of ANGPTL4 mRNA in HCC was significantly associated with advanced tumor stage, presence of venous infiltration, poor differentiation, higher AFP level, appearance of tumor recurrence, and poor postoperative overall and disease-free survivals of HCC patients. Treatment with Ad-ANGPTL4 significantly inhibited the in vivo tumor growth, invasiveness and metastasis by promoting tumoral apoptosis, inhibiting tumoral angiogenesis and motility, and suppressing tumor-favorable microenvironment. Moreover, administration of recombinant ANGPTL4 protein suppressed the motility of HCC cells and altered the secretion profile of cytokines from macrophages. ANGPTL4 is a diagnostic and prognostic biomarker for HCC patients and a potential therapeutic agent to suppress HCC growth, angiogenesis and metastasis.
Vascular endothelial growth factor-D expression in human atherosclerotic lesions
Authors: J Rutanen
Journal: Cardiovascular Research (2003)

Vascular endothelial growth factor-D (VEGF-D) is a recently characterized member of the VEGF family, but its expression in atherosclerotic lesions remains unknown. We studied the expression of VEGF-D and its receptors (VEGFR-2 and VEGFR-3) in normal and atherosclerotic human arteries, and compared that to the expression pattern of VEGF-A.Human arterial samples (n=39) obtained from amputation operations and fast autopsies were classified according to the stage of atherosclerosis and studied by immunohistochemistry. The results were confirmed by in situ hybridization and RT-PCR.We found that while VEGF-A expression increased during atherogenesis, VEGF-D expression remained relatively stable only decreasing in complicated lesions. In normal arteries and in early lesions VEGF-D was mainly expressed in smooth muscle cells, whereas in complicated atherosclerotic lesions the expression was most prominent in macrophages and also colocalized with plaque neovascularization. By comparing the staining profiles of different antibodies, we found that proteolytic processing of VEGF-D was efficient in the vessel wall. VEGFR-2, but not VEGFR-3, was expressed in the vessel wall at every stage of atherosclerosis.Our results suggest that in large arteries VEGF-D is mainly expressed in smooth muscle cells and that it may have a role in the maintenance of vascular homeostasis. However, in complicated lesions it was also expressed in macrophages and may contribute to plaque neovascularization. The constitutive expression of VEGFR-2 in arteries suggests that it may be one of the principal mediators of the VEGF-D effects in large arteries.
Oculomotor capture by abrupt onsets reveals concurrent programming of voluntary and involuntary saccades
Authors: Arthur F. Kramer, David E. Irwin, Jan Theeuwes, Sowon Hahn
Journal: Behavioral and Brain Sciences (1999)

In several recent experiments we have found that the eyes are often captured by the appearance of a sudden onset in a display, even though subjects intend to move their eyes elsewhere. Very brief fixations are made on the abrupt onset before the eyes complete their intended movement to the previously defined target. These results indicate concurrent programming of a voluntary saccade to the defined saccade target and an involuntary saccade to the sudden onset. This is inconsistent with the idea that a single salience map determines the location of a saccade in a winner-take-all fashion. Other results indicate that subjects attend to more than one location in a display during saccade preparation, contrary to the claim that covert attentional scanning plays no role in saccade generation.
Optimizing Insulin Absorption and Insulin Injection Technique in Older Adults
Authors: Lee Ann Trimble, Graydon S. Meneilly
Journal: Diabetes Care (2014)

The objective of our study was to determine the impact of anatomic site and injection technique on insulin absorption in the elderly. Twenty elderly insulin-naive subjects (age 80 ± 1 years; sex 7 female, 13 male; BMI 29 ± 1 kg/m2; diabetes duration 11 ± 2 years; A1C 7.1 ± 0.2% [54 ± 2 mmol/mol]) were studied (clinicaltrials.gov NCT01213901). All subjects provided informed written consent (Declaration of Helsinki). Subjects underwent three 360-min euglycemic glucose clamp studies in random order. In each, 0.1 units/kg of insulin lispro (Humalog; Eli Lilly, Indianapolis, IN) was administered subcutaneously using a 5-mm needle. The investigator conducting the clamp and the technician collecting samples were blind to treatment. In two studies, insulin was given 6.0 cm from the umbilicus using either a skin lift or no skin lift …
Daily alcohol consumption and the risk of type 2 diabetes in Japanese men: the Osaka Health Survey.
Authors: K Tsumura, T Hayashi, C Suematsu, G Endo, S Fujii, K Okada
Journal: Diabetes Care (1999)

To investigate the relationship between daily alcohol consumption and the risk of type 2 diabetes in a large Japanese cohort.We enrolled 6,362 Japanese men aged 35-61 years who did not have diabetes, impaired fasting glucose, hypertension, or liver cirrhosis at study entry. Type 2 diabetes was defined as a fasting plasma glucose (FPG) level > or =126 mg/dl or was diagnosed by a physician. Data on alcohol consumption were obtained from questionnaires. We confirmed 456 cases of type 2 diabetes during the 62,016 person-years of follow-up.The relationship between daily alcohol consumption and the risk of type 2 diabetes among lean men and among men with a higher BMI was paradoxical. Among lean men (BMI < or =22.0 kg/m2), heavy drinking was associated with an increased risk of type 2 diabetes. Men who consumed > or =50.1 ml/day of alcohol had a relative risk (RR) of 2.48 (95% CI 1.31-4.71) compared with nondrinkers after adjusting for age, BMI, regular physical exercise, parental history of diabetes, smoking habits, and FPG level. However, among men with a BMI > or =22.1 kg/m2, moderate drinking (29.1-50.0 ml/day) was associated with a decreased risk of type 2 diabetes. Daily moderate drinkers had a multiple adjusted RR of 0.58 (0.39-0.87) compared with nondrinkers.Among men with a BMI > or =22.1 kg/m2, moderate alcohol consumption was associated with a reduced risk of type 2 diabetes, but among lean men (BMI < or =22.0 kg/m2), heavy alcohol consumption was associated with an increased risk of type 2 diabetes.
<i>PIK3CA</i> and <i>PTEN</i> Gene and Exon Mutation-Specific Clinicopathologic and Molecular Associations in Colorectal Cancer
Authors: Fiona L. Day, Robert N. Jorissen, Lara Lipton, Dmitri Mouradov, Anuratha Sakthianandeswaren, Michael Christie, Shan Li, Cary Tsui, Jeannie Tie, Jayesh Desai, Zheng-Zhou Xu, Peter Molloy, Vicki Whitehall, Barbara A. Leggett, Ian T. Jones, Stephen McLaughlin, Robyn L. Ward, Nicholas J. Hawkins, Andrew R. Ruszkiewicz, James Moore, Dana Busam, Qi Zhao, Robert L. Strausberg, Peter Gibbs, Oliver M. Sieber
Journal: Clinical Cancer Research (2013)

PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal-regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial.A total of 1,093 stage I-IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12-13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3-8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports (n = 5,594).PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), and BRAF mutation (P < 0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation (P < 0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS-mutated cancers (P ≤ 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P ≤ 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status.PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAF(mut)), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRAS(mut)) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes.
Possible Effects of the New Medicare Reimbursement Policy on African Americans with ESRD
Authors: Areef Ishani, Haifeng Guo, Thomas J. Arneson, David T. Gilbertson, Lih-Wen Mau, Suying Li, Stephan Dunning, Allan J. Collins
Journal: Journal of the American Society of Nephrology (2009)

<h3>Purpose</h3> To determine the changes in the expression profiles of microRNAs (miRNAs) in retinas during the development of experimental autoimmune uveoretinitis (EAU) in rats. <h3>Methods</h3> The levels of interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) were measured in aqueous humour samples and supernatants of homogenised posterior eye cups obtained from Lewis rats immunised with interphotoreceptor retinoid binding protein peptide (R14) and complete Freund9s adjuvant. Microarray analysis was performed to determine the miRNA profiles in the retina of eyes with EAU on days 0 (baseline), 7, 14 and 21 after immunisation. <h3>Results</h3> The levels of IL-1β and MCP-1 in the aqueous humour and the supernatants of posterior eye cups were significantly elevated in eyes with EAU, and the levels corresponded with the stage of the EAU. On day 14 after immunisation, the expressions of nine miRNAs (miRNA-223, 142-5p, 142-3p, 21, 146a, 146b, 1949, 1188-3p and 193) were significantly elevated, and the expressions of four miRNAs (miRNA-181a, 183*, 124* and 331) were downregulated relative to the baseline. Quantitative PCR analyses confirmed the elevation of miRNA-223 and miRNA-146 and the downregulation of miRNA-181a in retinas with EAU on day 14 after immunisation. In situ hybridisation confirmed increased expression of miR-223 and miR-146 in retinas with EAU. <h3>Conclusions</h3> Several miRNAs were significantly increased or decreased in retinas during the course of EAU. The expression of miR-223 and miR-146a corresponded with the clinical score of the EAU and elevation of IL-1β/MCP-1 in the eye with EAU. Further studies are required to clarify the role of miRNA in eyes with autoimmune uveoretinitis.
Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials
Authors: J.D. Wolchok, J.S. Weber, M. Maio, B. Neyns, K. Harmankaya, K. Chin, L. Cykowski, V. de Pril, R. Humphrey, C. Lebbé
Journal: Annals of Oncology (2013)
Diagnosing lung cancer earlier in the UK
Authors: R. B. Hubbard, D. R. Baldwin
Journal: Thorax (2010)

The 30 326 deaths from lung cancer in England and Wales in 2008 represent 22% of the total mortality burden from cancer in that year.1 The next two most common causes of cancer death were colorectal cancer (10%) and breast cancer (8%). These familiar statistics outline the enormous impact that lung cancer continues to have on public health in the UK.

The dramatic fall in the prevalence of smoking in the UK over the last 60 years means that the lung cancer epidemic in the UK has peaked, particularly in men, and this is good news.2 In order to protect future generations of people in the UK from developing lung cancer, however, steps to drive down the prevalence of smoking as much as possible, and across all sectors of society, remains a pressing public health priority.3 4 This will inevitably need a broad spectrum of approaches.5 6

People who are currently at high risk of developing lung cancer, but do not yet have the disease, may benefit in the future if an effective screening programme can be developed to detect early subclinical disease. At the moment the use of CT imaging seems the approach most likely to succeed, but no trial yet has been able to demonstrate a reduction in mortality. A number of trials are currently ongoing, however, and more definitive evidence is expected between 2012 and 2016.7–13 Recently, a feasibility study for a randomised trial of CT screening in the UK has been completed and currently the arrangements are being finalised to undertake a pilot randomised trial. We hope that this project will stimulate more research in this area in the UK, including a trial powered to detect a mortality benefit of screening as well as research into the natural history of early lung cancer …