tbuckley/cabot-search huggingface dataset:
Loss of HLTF function promotes intestinal carcinogenesis
Authors: Sumit Sandhu, Xiaoli Wu, Zinnatun Nabi, Mojgan Rastegar, Sam Kung, Sabine Mai, Hao Ding
Journal: Molecular Cancer (2012)

Abstract Background HLTF (Helicase-like Transcription Factor) is a DNA helicase protein homologous to the SWI/SNF family involved in the maintenance of genomic stability and the regulation of gene expression. HLTF has also been found to be frequently inactivated by promoter hypermethylation in human colon cancers. Whether this epigenetic event is required for intestinal carcinogenesis is unknown. Results To address the role of loss of HLTF function in the development of intestinal cancer, we generated Hltf deficient mice. These mutant mice showed normal development, and did not develop intestinal tumors, indicating that loss of Hltf function by itself is insufficient to induce the formation of intestinal cancer. On the Apc min/+ mutant background, Hltf - deficiency was found to significantly increase the formation of intestinal adenocarcinoma and colon cancers. Cytogenetic analysis of colon tumor cells from Hltf -/- /Apc min/+ mice revealed a high incidence of gross chromosomal instabilities, including Robertsonian fusions, chromosomal fragments and aneuploidy. None of these genetic alterations were observed in the colon tumor cells derived from Apc min/+ mice. Increased tumor growth and genomic instability was also demonstrated in HCT116 human colon cancer cells in which HLTF expression was significantly decreased. Conclusion Taken together, our results demonstrate that loss of HLTF function promotes the malignant transformation of intestinal or colonic adenomas to carcinomas by inducing genomic instability. Our findings highly suggest that epigenetic inactivation of HLTF, as found in most human colon cancers, could play an important role in the progression of colon tumors to malignant cancer.
Comparison of Continuous versus Categorical Tumor Measurement–Based Metrics to Predict Overall Survival in Cancer Treatment Trials
Authors: Ming-Wen An, Sumithra J. Mandrekar, Megan E. Branda, Shauna L. Hillman, Alex A. Adjei, Henry C. Pitot, Richard M. Goldberg, Daniel J. Sargent
Journal: Clinical Cancer Research (2011)

Abstract Purpose: The categorical definition of response assessed via the Response Evaluation Criteria in Solid Tumors has documented limitations. We sought to identify alternative metrics for tumor response that improve prediction of overall survival. Experimental Design: Individual patient data from three North Central Cancer Treatment Group trials (N0026, n = 117; N9741, n = 1,109; and N9841, n = 332) were used. Continuous metrics of tumor size based on longitudinal tumor measurements were considered in addition to a trichotomized response [TriTR: response (complete or partial) vs. stable disease vs. progression). Cox proportional hazards models, adjusted for treatment arm and baseline tumor burden, were used to assess the impact of the metrics on subsequent overall survival, using a landmark analysis approach at 12, 16, and 24 weeks postbaseline. Model discrimination was evaluated by the concordance (c) index. Results: The overall best response rates for the three trials were 26%, 45%, and 25%, respectively. Although nearly all metrics were statistically significantly associated with overall survival at the different landmark time points, the concordance indices (c-index) for the traditional response metrics ranged from 0.59 to 0.65; for the continuous metrics from 0.60 to 0.66; and for the TriTR metrics from 0.64 to 0.69. The c-indices for TriTR at 12 weeks were comparable with those at 16 and 24 weeks. Conclusions: Continuous tumor measurement–based metrics provided no predictive improvement over traditional response–based metrics or TriTR; TriTR had better predictive ability than best TriTR or confirmed response. If confirmed, TriTR represents a promising endpoint for future phase II trials. Clin Cancer Res; 17(20); 6592–9. ©2011 AACR.
STRUCTURE AND FUNCTION OF PANCREATIC LIPASE AND COLIPASE
Authors: Mark E. Lowe
Journal: Annual Review of Nutrition (1997)

▪ Abstract Dietary fats are essential for life and good health. Efficient absorption of dietary fats is dependent on the action of pancreatic triglyceride lipase. In the last few years, large advances have been made in describing the structure and lipolytic mechanism of human pancreatic triglyceride lipase and of colipase, another pancreatic protein that interacts with pancreatic triglyceride lipase and that is required for lipase activity in the duodenum. This review discusses the advances made in protein structure and in understanding the relationships of structure to function of pancreatic triglyceride lipase and colipase.
Use of adjuvant containing mycobacterial cell-wall skeleton, monophosphoryl lipid A, and squalane in malaria circumsporozoite protein vaccine
Authors: L.S Rickman, L.S Rickman, R Wistar, S.L Hoffman, D.M Gordon, U Krzych, J.E Egan, J.D Chulay, M Gross, M.R Hollingdale
Journal: The Lancet (1991)
Perfusion pressure and volume status determine the microvascular response of the rat kidney to NG-monomethyl-L-arginine.
Authors: J C Lockhart, T S Larson, F G Knox
Journal: Circulation Research (1994)

This study investigated the role of volume status and perfusion pressure on the hemodynamic response of cortical and medullary renal capillaries to systemic inhibition of nitric oxide. NG-Monomethyl-L-arginine (L-NMMA) was infused intravenously (15-mg/kg bolus and 500-micrograms.min-1.kg-1 infusion), and blood flow in cortical capillaries (QCC) and in descending (QDVR) and ascending vasa recta (QAVR) was measured by fluorescence videomicroscopy in euvolemic and volume-expanded anesthetized Munich-Wistar rats. L-NMMA in euvolemic rats decreased vasa recta blood flow (delta QDVR, 3.97 +/- 0.80 nL/min [P &lt; .01]; delta QAVR, 1.90 +/- 0.39 nL/min [P &lt; .01]; n = 6) and QCC (delta QCC, 0.57 +/- 0.15 nL/min [P &lt; .01]; n = 7) despite increases in renal perfusion pressure (RPP). Fractional excretion of sodium (FENa) remained unchanged. In volume-expanded rats, L-NMMA decreased vasa recta blood flow when RPP increased (delta QDVR, 1.42 +/- 0.79 nL/min [P = .05]; delta QAVR, 1.95 +/- 0.34 nL/min [P &lt; .001]; n = 9) or was held constant by partial aortic occlusion (delta QDVR, 1.19 +/- 0.45 nL/min [P &lt; .05]; delta QAVR, 1.44 +/- 0.40 nL/min [P &lt; .01]; n = 8). QCC was unchanged by L-NMMA when RPP increased (delta QCC, 0.27 +/- 0.20 nL/min; n = 8) but decreased significantly by 0.61 +/- 0.11 nL/min (P &lt; .01, n = 8) when increases in RPP were prevented. FENa increased when RPP increased (delta FENa, 2.47 +/- 0.51%; P &lt; .001) and was held constant (delta FENa, 2.64 +/- 0.46%; P &lt; .001).(ABSTRACT TRUNCATED AT 250 WORDS)
The G-quadruplex Ligand Telomestatin Inhibits POT1 Binding to Telomeric Sequences <i>In vitro</i> and Induces GFP-POT1 Dissociation from Telomeres in Human Cells
Authors: Dennis Gomez, Marie-Françoise O'Donohue, Thomas Wenner, Céline Douarre, Jérome Macadré, Pascale Koebel, Marie-Josèphe Giraud-Panis, Hervé Kaplan, Alain Kolkes, Kazuo Shin-ya, Jean-François Riou
Journal: Cancer Research (2006)

Abstract Telomestatin is a potent G-quadruplex ligand that specifically interacts with the 3′ telomeric overhang, leading to its degradation and that induces a delayed senescence and apoptosis of cancer cells. Protection of Telomere 1 (POT1) was recently identified as a specific single-stranded telomere-binding protein involved in telomere capping and T-loop maintenance. We showed here that a telomestatin treatment inhibits POT1 binding to the telomeric overhang in vitro. The treatment of human EcR293 cells by telomestatin induces a dramatic and rapid delocalization of POT1 from its normal telomere sites but does not affect the telomere localization of the double-stranded telomere-binding protein TRF2. Thus, we propose that G-quadruplex stabilization at telomeric G-overhang inactivates POT1 telomeric function, generating a telomere dysfunction in which chromosome ends are no longer properly protected. (Cancer Res 2006; 66(14): 6908-12)
Comments on Plasmalemmal Vesicle Associated Protein-1 as a Novel Marker Implicated in Brain Tumor Angiogenesis
Authors: Laura A. Sanders (Strickland), Hartmut Koeppen
Journal: Clinical Cancer Research (2006)

To the Editor: We have read with great interest the November 1, 2005 article by Carson-Walter et al. ([1][1]) on plasmalemmal vesicle–associated protein 1 (PV-1; also called PLVAP) expression in malignant brain. The authors have shown that PLVAP is expressed in a subset of malignant and diseased
Genetic architecture of retinal and macular degenerative diseases: the promise and challenges of next-generation sequencing
Authors: Rinki Ratnapriya, Anand Swaroop
Journal: Genome Medicine (2013)

Inherited retinal degenerative diseases (RDDs) display wide variation in their mode of inheritance, underlying genetic defects, age of onset, and phenotypic severity. Molecular mechanisms have not been delineated for many retinal diseases, and treatment options are limited. In most instances, genotype-phenotype correlations have not been elucidated because of extensive clinical and genetic heterogeneity. Next-generation sequencing (NGS) methods, including exome, genome, transcriptome and epigenome sequencing, provide novel avenues towards achieving comprehensive understanding of the genetic architecture of RDDs. Whole-exome sequencing (WES) has already revealed several new RDD genes, whereas RNA-Seq and ChIP-Seq analyses are expected to uncover novel aspects of gene regulation and biological networks that are involved in retinal development, aging and disease. In this review, we focus on the genetic characterization of retinal and macular degeneration using NGS technology and discuss the basic framework for further investigations. We also examine the challenges of NGS application in clinical diagnosis and management.
The taccalonolides and paclitaxel cause distinct effects on microtubule dynamics and aster formation
Authors: April L Risinger, Stephen M Riffle, Manu Lopus, Mary A Jordan, Leslie Wilson, Susan L Mooberry
Journal: Molecular Cancer (2014)

Microtubule stabilizers suppress microtubule dynamics and, at the lowest antiproliferative concentrations, disrupt the function of mitotic spindles, leading to mitotic arrest and apoptosis. At slightly higher concentrations, these agents cause the formation of multiple mitotic asters with distinct morphologies elicited by different microtubule stabilizers. We tested the hypothesis that two classes of microtubule stabilizing drugs, the taxanes and the taccalonolides, cause the formation of distinct aster structures due, in part, to differential effects on microtubule dynamics. Paclitaxel and the taccalonolides suppressed the dynamics of microtubules formed from purified tubulin as well as in live cells. Both agents suppressed microtubule dynamic instability, with the taccalonolides having a more pronounced inhibition of microtubule catastrophe, suggesting that they stabilize the plus ends of microtubules more effectively than paclitaxel. Live cell microscopy was also used to evaluate the formation and resolution of asters after drug treatment. While each drug had similar effects on initial formation, substantial differences were observed in aster resolution. Paclitaxel-induced asters often coalesced over time resulting in fewer, larger asters whereas numerous compact asters persisted once they were formed in the presence of the taccalonolides. We conclude that the increased resistance of microtubule plus ends to catastrophe may play a role in the observed inability of taccalonolide-induced asters to coalesce during mitosis, giving rise to the distinct morphologies observed after exposure to these agents.
Acquired von Willebrand's disease: A concise review
Authors: Morton R. Rinder, Robert E. Richard, Henry M. Rinder
Journal: American Journal of Hematology (1997)

Acquired von Willebrand's disease (AvWD), an adult-onset bleeding diathesis, has most commonly been found in patients with an underlying lymphoproliferative disease or monoclonal gammopathy. Other malignancies, autoimmune diseases, hypothyroidism, and drugs have also been associated with AvWD. We have included an illustrative case history of a patient with a bleeding diathesis consistent with AvWD and a monoclonal gammopathy who required emergent cardiac surgery. Our review of the literature determined that most cases of AvWD are due to a circulating antibody that combines with the high molecular weight multimers (HMWM) of von Willebrand factor (vWF). These vWF multimer-antibody complexes are subsequently cleared from the circulation either by the reticuloendothelial system or by adsorption onto tumor cells. Clearance of the HMWM of vWF thus results in extremely low functional levels and variable antigenic levels. Mixing studies which are traditionally used to diagnose factor inhibitors are useful only if removal of vWF-antibody complexes can be accomplished in vitro. Treatment with intravenous immunoglobulin has recently been shown to be the most effective therapy for patients with an underlying lymphoproliferative disorder or monoclonal gammopathy. This therapeutic strategy is based on the observed immune complex clearance phenomenon that appears to be operative in most cases. Other AvWD-associated diseases require treatment specifically directed at the underlying disorder. Am. J. Hematol. 54:139–145, 1997 © 1997 Wiley-Liss, Inc.
Effect of Aging on the Prognostic Significance of Ambulatory Systolic, Diastolic, and Pulse Pressure in Essential Hypertension
Authors: Rajdeep S. Khattar, John D. Swales, Caroline Dore, Roxy Senior, Avijit Lahiri
Journal: Circulation (2001)

Background This study compared the relative prognostic significance of 24 hour intra-arterial ambulatory systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP) parameters in middle-aged versus elderly hypertensives. Methods and Results A total of 546 subjects aged &lt;60 years and 142 subjects aged ≥60 years who had undergone baseline pretreatment 24-hour intra-arterial ambulatory blood pressure monitoring were followed for 9.2±4.1 years. Multivariate analysis showed that in younger subjects, 24-hour, daytime, and nighttime DBP, MAP, and SBP, when considered individually, were positively related to morbid events; DBP parameters provided the best predictive values. In the group ≥60 years (elderly group), 24-hour, daytime, and nighttime PP and SBP were the most predictive parameters, whereas ambulatory DBP and MAP measurements failed to provide any prognostic value. When 24-hour values of SBP and DBP were jointly included in the baseline model, DBP (z=2.02, P =0.04) but not SBP (z=−0.43, P =0.67) was related to outcome in younger subjects, whereas in the elderly group, SBP (z=3.33, P =0.001) was positively and DBP (z=−1.75, P =0.07) was negatively related to outcome. Clinic blood pressure measurements failed to provide any independent prognostic value in either age group. Conclusions The relative prognostic significance of ambulatory blood pressure components depends on age; DBP parameters provided the best prognostic value in middle-aged individuals, whereas PP parameters were the most predictive in the elderly. This may reflect differing underlying hemodynamic mechanisms of hypertension in these age groups.
LSC 2011 Abstract: Differential effects of diesel exhaust particules and endotoxin on phagocytosis and cytokine release by monocyte-derived macrophages
Authors: Gurpreet Sehra, Duncan Rogers, Louise Donnelly
Journal: European Respiratory Journal (2011)

Atmospheric pollution is associated with COPD exacerbations. Diesel exhaust particles (DEP) are major contributors to pollution and when inhaled become targets for lung macrophages. The interaction between DEP and bacteria/endotoxin is unclear. Monocyte-derived macrophages (MDM) from non-smokers (NS), smokers (S) or patients with COPD were exposed to DEP (1-300μg/ml) with or without bacterial endotoxin (LPS; 10ng/ml) for 24h. Release of TNFα, IL-6 and CXCL8 was analysed by ELISA, and phagocytosis of fluorescent beads was assessed by fluorimetry. MDM viability was determined by MTT assay.  Exposure of MDM to DEP did not stimulate release of IL-6 or TNFα but increased CXCL8 release (EC 50 : NS 8±4 μg/ml, n=7; S 4±1 μg/ml, n=4 and COPD 10±4 μg/ml, n=7). MDM from COPD patients were 3.3 times more responsive to DEP (30μg/ml; p 50 : NS: 33±14 μg/ml, n=10; smokers: 25±15 μg/ml, n=4; COPD: 18±14 μg/ml, n=10). Exposure of MDM to DEP in both the absence and presence of LPS inhibited phagocytosis of beads in a concentration-dependent manner with 300μg/ml showing ∼80% inhibition (control: 31±3 X 10 3  vs  300μg/ml DEP: 6±1 X 10 3  RFU, n=29), with MDM being 70% viable at this concentration, with no difference in response between the different subject groups. These data show that DEP impair macrophage phagocytosis and promote chemokine release. These data suggest that DEP may lead to reduced clearance of debris and pathogens from airways and promote COPD exacerbations.
Expression of equivalent clonotypes in BALB/c and A/J mice after immunization with phosphorylcholine.
Authors: S Rudikoff, J L Claflin
Journal: The Journal of Experimental Medicine (1976)

Analysis of A/J antibody to phosphorylcholine (PC) revealed a striking degree of similarity to PC-binding myeloma proteins of BALB/c origin. By quantitative idiotypic analysis A/J anti-PC antibody was composed to antibodies bearing binding site idiotypic determinants indistinguishable from two different BALB/c myeloma proteins, T15 and M511. Idiotypic determinants of three other PC-binding proteins, W3207, M167, and M603 were not detected. Isoelectric focusing of the light chains verified the presence of antibodies similar to T15 and M511 and indicated the presence of a third antibody whose light chains had a pI identical to that of M603. When the sequence of A/J heavy chains were compared to the heavy chains of T15, M511, and M603, both the framework and first complementarity regions were identical in all cases. Sequences analysis of the light chains through part of the first complementarity region revealed three chains, one similar to each of the myeloma proteins T15, M603, and M167-M511. The latter two sequences differ by only a single amino acid (a single base substitution) in the first 23 residues, suggesting that the two light chains may be very similar if not identical. Thus, BALB/c and A/J mice which differ genetically at multiple loci including the heavy chain allotype complex locus show a remarkable preservation of their anti-PC antibodies. These results indicate that the genes encoding these antibodies are contained in the germ line.
Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen
Authors: Eric Van Cutsem, Josep Tabernero, Radek Lakomy, Hans Prenen, Jana Prausová, Teresa Macarulla, Paul Ruff, Guy A. van Hazel, Vladimir Moiseyenko, David Ferry, Joe McKendrick, Jonathan Polikoff, Alexia Tellier, Rémi Castan, Carmen Allegra
Journal: Journal of Clinical Oncology (2012)

Purpose Treatment for metastatic colorectal cancer (mCRC) commonly involves a fluoropyrimidine-based chemotherapy regimen such as infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) or fluorouracil, leucovorin, and oxaliplatin, often combined with bevacizumab or an epidermal growth factor receptor monoclonal antibody. We studied the effect of adding the novel antiangiogenic agent aflibercept (also known as ziv-aflibercept in the United States) to FOLFIRI in patients with mCRC previously treated with oxaliplatin, including patients who received prior bevacizumab. Patients and Methods Patients were randomly assigned to receive aflibercept (4 mg/kg intravenously; 612 patients) or placebo (614 patients) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival. Results Adding aflibercept to FOLFIRI significantly improved overall survival relative to placebo plus FOLFIRI (hazard ratio [HR], 0.817; 95.34% CI, 0.713 to 0.937; P = .0032) with median survival times of 13.50 versus 12.06 months, respectively. Aflibercept also significantly improved progression-free survival (PFS; HR, 0.758; 95% CI, 0.661 to 0.869; P &lt; .0001), with median PFS times of 6.90 versus 4.67 months, respectively. The effects on overall survival and PFS exhibited a consistent trend across prespecified subgroup analyses, including bevacizumab pretreated patients. Response rate was 19.8% (95% CI, 16.4% to 23.2%) with aflibercept plus FOLFIRI compared with 11.1% (95% CI, 8.5% to 13.8%) with placebo plus FOLFIRI (P = .0001). Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti–vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities. Conclusion Aflibercept in combination with FOLFIRI conferred a statistically significant survival benefit over FOLFIRI combined with placebo in patients with mCRC previously treated with oxaliplatin.
Therapeutic Targeting of Neuropilin-2 on Colorectal Carcinoma Cells Implanted in the Murine Liver
Authors: M. J. Gray, G. Van Buren, N. A. Dallas, L. Xia, X. Wang, A. D. Yang, R. J. Somcio, Y. G. Lin, S. Lim, F. Fan, L. S. Mangala, T. Arumugam, C. D. Logsdon, G. Lopez-Berestein, A. K. Sood, L. M. Ellis
Journal: JNCI Journal of the National Cancer Institute (2008)

Neuropilin-2 (NRP2) is a high-affinity kinase-deficient receptor for vascular endothelial growth factor (VEGF) and semaphorin 3F. We investigated its function in human colorectal cancers.Immunohistochemistry and immunoblotting were used to assess NRP2 expression levels in colorectal tumors and colorectal cancer cell lines, respectively. HCT-116 colorectal cancer cells stably transfected with short hairpin RNA (shRNAs) against NRP2 or control shRNAs were assayed for proliferation by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and for activation of the VEGFR1 pathway by immunoblotting. Soft agar assays, Annexin V staining, and Boyden chamber assays were used to examine anchorage-independent growth, apoptosis in response to hypoxia, and cell migration/invasion, respectively, in HCT-116 transfectants. Tumor growth and metastasis were analyzed in mice (groups of 10) injected with shRNA-expressing HCT-116 cells. The effect of in vivo targeting of NRP2 by small interfering RNA (siRNA) on the growth of hepatic colorectal tumors derived from luciferase-expressing HCT-116 cells was assessed by measuring changes in bioluminescence and final tumor volumes. All statistical tests were two-sided.NRP2 expression was substantially higher in tumors than in adjacent mucosa. HCT-116 transfectants with reduced NRP2 levels had reduced VEGFR1 signaling, but proliferation was unchanged. Anchorage-independent growth, survival under hypoxic conditions, and motility/invasiveness were also reduced. In vivo, HCT-116 transfectants with reduced NRP2 demonstrated decreased tumor growth, fewer metastases, and increased apoptosis compared with control cells. Hepatic colorectal tumors in mice treated with NRP2 siRNAs were statistically significantly smaller than those in mice treated with control siRNAs (at 28 days after implantation, mean control siRNAs = 420 mm3, mean NRP2 siRNAs = 36 mm3, NRP2 vs control: difference = 385 mm3, 95% confidence interval = 174 mm3 to 595 mm3, P = .005).NRP2 on colorectal carcinoma cells is important for tumor growth and is a potential therapeutic target in human cancers where it is expressed.