tbuckley/cabot-search huggingface dataset:
Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-κB-dependent upregulation of ICAM-1, VCAM-1 and IL-8 expression
Authors: Chia-Ron Yang, Shie-Liang Hsieh, Feng-Ming Ho, Wan-Wan Lin
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2036 

Decoy receptor 3 (DcR3), a soluble receptor for FasL, LIGHT and TL1A, is highly expressed in cancer cells. We show that pretreatment of human umbilical vein endothelial cells (HUVECs) with DcR3 enhances the adhesion of THP-1, U937 and primary monocytes. A similar stimulatory effect of DcR3 on THP-1 adhesion was also observed in human microvascular endothelial cells (HMVECs). Flow cytometry and ELISA showed that DcR3-treated HUVECs exhibited significant increases in ICAM-1 and VCAM-1 expression. We also demonstrate the ability of DcR3 to stimulate the secretion of IL-8 by HUVECs. RT-PCR and reporter assays revealed that the expression of adhesion molecules and IL-8 are regulated at the level of gene transcription. Experiments with PDTC indicated the involvement of an NF-κB signaling pathway. DcR3 was found to induce IKK activation, IκB degradation, p65 nuclear translocation and NF-κB-DNA-binding activity. The enhancement by DcR3 of cell adhesion to HUVECs was not mimicked by the TL1A antibody, which has been shown in our previous work to be a neutralizing antibody against TL1A, thereby inducing HUVECs angiogenesis. Moreover, DcR3-induced cell adhesion could be detected in human aortic EC where TL1A expression is lacking. Together, our data demonstrate that DcR3 increases monocyte adhesion to EC via NF-κB activation, leading to the transcriptional upregulation of adhesion molecules and IL-8 in EC. This novel action appears not to be due to TL1A neutralization, but occurs through an as yet undefined target(s). This study implicates DcR3 in the relationship between inflammation and cancer development.
Abstract B2-44: Structure-based design of inhibitory peptides for LRP6
Authors: Elham Rismani, Hamzeh Rahimi, Kayhan Azadmanesh, Shahriar Arab, Morteza Karimipoor, Ladan Teimoori-Toolabi
Journal: Cancer Research (2015)

Abstract Wnt signaling pathway plays a major role in regulation of cell proliferation, migration, tissue homeostasis, tumor progression and cancer. This pathway can be antagonized by DKK proteins, which disrupt the intiationary complex (Frizzled-LRP5/6 complex). Nowadays, use of peptides in order to target tumor cells is attracting much attention. In this study, a computational protocol is presented to structural design of inhibitory peptides aginst Low-density lipoprotein receptor-related protein 6 (LRP6) as receptor. Firstly, natural ligand of LRP6 divided to 12 fragments as peptide derivatives. Then, molecular dynamics simulations used for structural energy minimization by means of Gromacs 4.5.4. The binding affinities of designed peptides were investigated via molecular docking using ClusPro webTool. Finally, stability and binding free energy of peptides were calculated by FoldX software. The results showed that four of designed peptides had the highest affinity to interact with the receptor and can be considered as candidates for inhibition of wnt signaling pathway through LRP5/6 receptor. Citation Format: Elham Rismani, Hamzeh Rahimi, Kayhan Azadmanesh, Shahriar Arab, Morteza Karimipoor, Ladan Teimoori-Toolabi. Structure-based design of inhibitory peptides for LRP6. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-44.
Selection Maintains Low Genomic GC Content in Marine SAR11 Lineages
Authors: Haiwei Luo, Luke R. Thompson, Ulrich Stingl, Austin L. Hughes
Journal: Molecular Biology and Evolution (2015)

The genomic G+C content of ocean bacteria varies from below 30% to over 60%. This broad range of base composition is likely shaped by distinct mutational processes, recombination, effective population size, and selection driven by environmental factors. A number of studies have hypothesized that depletion of G/C in genomes of marine bacterioplankton cells is an adaptation to the nitrogen-poor pelagic oceans, but they failed to disentangle environmental factors from mutational biases and population history. Here, we reconstructed the evolutionary changes of bases at synonymous sites in genomes of two marine SAR11 populations and a freshwater counterpart with its evolutionary origin rooted in the marine lineage. Although they all have similar genome sizes, DNA repair gene repertoire, and base compositions, there is a stronger bias toward A/T changes, a reduced frequency of nitrogenous amino acids, and an exclusive occurrence of polyamine, opine, and taurine transport systems in the ocean populations, consistent with a greater nitrogen stress in surface oceans compared with freshwater lakes. Furthermore, the ratio of nonsynoymous to synonymous nucleotide diversity is not statistically distinguishable among these populations, suggesting that population history has a limited effect. Taken together, the ecological transition of SAR11 from ocean to freshwater habitats makes nitrogen more available to these organisms, and thus relaxation of purifying selection drove a genome-wide reduction in the frequency of G/C to A/T changes in the freshwater population.
Etoposide and carboplatin in extraocular retinoblastoma: a study by the Société Française d'Oncologie Pédiatrique.
Authors: F Doz, S Neuenschwander, D Plantaz, B Courbon, J C Gentet, E Bouffet, V Mosseri, J P Vannier, F Mechinaud, L Desjardins
Journal: Journal of Clinical Oncology (1995)

PURPOSE A phase II study of etoposide (VP-16) and carboplatin was performed in patients with extraocular retinoblastoma to evaluate the response rate with this drug combination. PATIENTS AND METHODS Twenty patients with extraocular retinoblastoma, age 9 to 120 months, were included in a cooperative multicenter phase II study of the Société Francçaise d'Oncologie Pédiatrique (SFOP). The schedule consisted of consecutive 5-day treatment with VP-16 100 mg/m2/d and carboplatin 160 mg/m2/d. RESULTS The response rate for the 20 patients was 85%; there were nine complete responses and eight partial responses. Hematologic toxicity was the only serious observed toxicity and was always manageable. CONCLUSION This combination of VP-16 and carboplatin is highly effective in extraocular retinoblastoma. The high response rate is encouraging for further evaluation of this drug combination in adjuvant chemotherapy when necessary after enucleation or in neoadjuvant chemotherapy for intraocular tumors.
Screening with Low-Dose Computed Tomography Does Not Improve Survival of Small Cell Lung Cancer
Authors: Mario Silva, Carlotta Galeone, Nicola Sverzellati, Alfonso Marchianò, Giuseppina Calareso, Stefano Sestini, Carlo La Vecchia, Gabriella Sozzi, Giuseppe Pelosi, Ugo Pastorino
Journal: Journal of Thoracic Oncology (2015)
Number of lymph nodes with metastasis predict survival in patients with esophageal or esophagogastric junction adenocarcinoma treated with preoperative chemoradiation
Authors: Y. Gu, S. G. Swisher, J. A. Ajani, A. M. Correa, W. Hofstetter, Z. Liao, R. R. Komaki, A. Rashid, S. R. Hamilton, T.-T. Wu
Journal: Journal of Clinical Oncology (2005)

4046 Background: The survival of patients with local-regional adenocarcinoma of the esophagus or esophagogastric junction (EGJ) treated with preoperative chemoradiation is better in patients with pathologic complete response than those with residual tumor. Residual tumor, including the presence of lymph node (LN) metastasis, is associated with poor outcome. However, the prognostic significance of number of lymph node metastases remains unclear. Methods: We studied 187 consecutive patients treated with chemoradiation followed by esophagectomy. Post-therapy depth of residual tumor invasion (T stage) and LN status were evaluated. The number of positive LN was recorded and size of metastatic tumor was measured as the greatest dimension in each positive LN, and compared with overall survival (OS) and recurrence-free (RF) probability. Results: Pathologic complete response was present in 54 of 187 (29%) patients. No lymph node metastasis (N0) was present in 65 of 133 (49%) patients with residual carcinoma, and lymph node metastasis (N1) was present in 68 of 133 (51%) patients. Twenty-one (31%) patients with LN metastasis had one positive LN, 19 (28%) had two, 15 (22%) had three or four, and 13 (19%) had five or more LNs. The 5-year OS and 2-year RF rates of patients with residual carcinoma was significantly better in N0 than N1 group (38% vs 15%, p=0.003 and 50% vs 28%, p=0.04, respectively). The 5-year OS and 2-year RF rates in patients with one positive LN were similar to patients in N0 group (34%, p=0.84 and 46%, p=0.77, respectively), but were significantly better than patients with two or more positive LNs (6%, p=0.002 and 18%, p=0.01, respectively). The size of metastatic tumor in LN in patients with one positive LN was a prognostic factor (≥4 mm vs <4 mm, p=0.04). In multivariate analysis, OS was better in patients with one LN metastasis among patients with LN metastasis (p=0.02), independent of the T stage. Conclusions: Our results suggest that number of lymph nodes with metastasis is an independent prognostic factor in patients with residual local-regional adenocarcinoma of the esophagus or EGJ treated with preoperative chemoradiation. No significant financial relationships to disclose.
The correction of monocyte-derived neohepatocytes from alpha1 antitrypsin deficient patients
Authors: Gillian McNab, Robert Stockley
Journal: European Respiratory Journal (2012)

This study explores the culture of monocyte-derived neohepatocytes from PiZ alpha1 antitrypsin deficient (α 1 ATD) patients and homologous replacement using small DNA fragments (SDFs) to correct the Z defect.  Monocytes from 6 patients were de-differentiated with MCSF and IL3 and then differentiated into neohepatocytes with FGF-4. Albumin, urea and α 1 AT were measured. SDF enclosing the normal sequence at the PiZ mutation site was generated from genomic DNA of a healthy volunteer. SDFs were transfected into neohepatocytes and cDNA checked for the M or Z message.  No albumin was detected from monocytes. Neohepatocytes secreted 250±50 mg/dL albumin/72h. Monocytes secreted both urea (5±2 µg/dL) and α 1 AT (272±42 µg/ml) over 72h. Neohepatocytes secreted 103±30 µg/dL urea and 311±34 µg/ml α 1 AT.  Neohepatocytes produced PCR products from Z primers. M SDF treated neohepatocytes generated bands using M primers, indicating the generation of a corrected transcript.  Neohepatocytes transfected with a monocyte transfection kit but no DNA control produced 163 ± 42µg/ml α 1 AT in 24h, whereas 20µg M SDF significantly increased secretion (173 ± 41µg/ml/24h, p=0.046, n=3). Using a hepatocyte transfection kit caused further increases in the amount of α 1 AT released. Control transfected neohepatocytes produced 322µg/ml/24h α 1 AT and 20µg M SDF significantly increased secretion (590 ± 104µg/ml/24h, p=0.026, n=3). Moreover, 50 µgM SDF caused more α 1 AT production (886 ± 298µg/ml/24h).  Neohepatocytes can be generated from α 1 ATD monocytes. The defective gene can be corrected and is associated with an increase in α 1 AT secretion. Development of this technique could be beneficial and protect both the liver and lungs.
Multilingual literature is useful
Authors: M. Buchanan, E B. Butler, O A N Husain
Journal: BMJ (1995)

support junior medical staff in their initial management ofpatients with acute stroke.As Dennis and Langhorne highlight, patients with stroke in acute facilities compete for nursing time with patients who are seen to have more urgent need.They also compete for medical, physiotherapy, and occupational therapy time.Rehabilitation of patients with stroke is time consuming and should include education and emotional and psychological support for the patients and their carers.For these reasons the use of resources by patients with acute stroke in most acute facilities is inadequate, and improvements in stroke care can realistically be achieved only by correcting deficiencies and targeting resources at the patients and their carers.We believe that high quality care of patients with acute stroke and their carers can be achieved only by establishing acute and rehabilitation stroke units.Deficiencies in resources should be addressed to allow these units to function optimally.
Use of Prostate-Specific Antigen Testing Is in the Eye of the Beholder
Authors: David S. Aaronson, Rita F. Redberg
Journal: JAMA Internal Medicine (2016)

Michael E. Zavaski, MD; Christian P. Meyer, MD; Jesse D. Sammon, DO; Julian Hanske, MD; Soham Gupta; Maxine Sun, MPH; Quoc-Dien Trinh, MD
A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of CHR-3996, a class 1 selective histone deacetylase inhibitor (HDACi), in patients with advanced solid tumors.
Authors: U. Banerji, L. van Doorn, D. Papadatos-Pastos, P. Debnam, M. Tall, M. Toal, L. Hooftman, J. Verweij, F. A. L. M. Eskens
Journal: Journal of Clinical Oncology (2010)

2552 Background: CHR-3996, a class 1 selective HDACi inhibiting HDAC 1, 2, and 3 at low nanomolar concentrations, demonstrated antitumor activity in several xenograft tumor models. Objectives of this study were to explore (1) tolerability and safety profile, (2) PK, (3) PD effects in PBMC and hair follicles, and (4) antitumor activity of once-daily continuous oral administration of 28-day cycles. Methods: 3 patients were enrolled at each dose level and the cohort was expanded in the event of a DLT. Results: 21 subjects, 5F:16M, median age 61 yrs (23–77) have been enrolled at 5 (n=3), 10 (n=4), 20 (n=3), 40 (n=7), and 80 mg (n=4). Median number of cycles administered is 2 (1–10). Dose-limiting toxicity (DLT) was observed in one patient at 40 mg (grade 3 atrial fibrillation). This cohort was expanded, but no further DLTs were observed. Most frequent drug-related AEs were fatigue (11), nausea (9), and vomiting (5). PK analysis revealed rapid absorption (Tmax 1-3 h) and mean elimination plasma half-life of 3 hrs. Cmax and AUC (0- t) increased dose proportionally. Mean AUC values at doses ≥ 40 mg exceeded levels effective in xenograft studies. No accumulation of CHR-3996 was seen on Day 28. 5 subjects demonstrated stable disease at or after cycle 2 (SD lasting 2, 10, 2.5, 3, 4 cycles, respectively). Preliminary PD analysis in PBMCs shows increases in histone acetylation with increasing dose. Confocal analysis of protein acetylation in hair follicles will be reported on. Conclusions: CHR-3996 is well tolerated and accrual is ongoing to establish the recommended dose for phase II studies. Plasma levels of CHR-3996 achieved exceed those required for antitumor efficacy in preclinical models, without significant toxicity. Dose escalation is ongoing, and updated results will be presented at the meeting, along with an assessment of histone acetylation as a pharmacodynamic biomarker in PBMCs and hair follicles. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chroma Therapeutics, The Institute of Cancer Research Chroma Therapeutics
Abstract P255: Association of Mild Chronic Kidney Disease with Venous Thromboembolism: Pooled Analysis of Prospective General Population Cohorts
Authors: Bakhtawar K Mahmoodi, Ron T Gansevoort, Inger Anne Naess, Pamela L Lutsey, Sigrid K Braekkan, Nic J Veeger, Ellen E Brodin, Karina Meijer, Yingying Sang, Kunihiro Matsushita, Stein Hallan, Jens Hammerstrøm, Brad C Astor, Josef Coresh, Aaron R Folsom, John-Bjarne Hansen, Mary Cushman
Journal: Circulation (2012)

Background: Recent findings suggest that mild chronic kidney disease (CKD) might be associated with increased risk of venous thromboembolism (VTE). However, results were partially inconsistent, which may be due to lack of power. We therefore performed a meta-analysis to investigate the association between mild CKD and VTE incidence. Methods: A literature search was performed to retrieve community-based cohorts with information on the association of estimated glomerular filtration rate (eGFR) and albuminuria with VTE. Five cohorts were identified that were pooled on individual level. To obtain pooled hazard ratios (HRs) for VTE, linear spline models were fitted using Cox regression with shared-frailty. Models were adjusted for age, sex, hypertension, total cholesterol, smoking, diabetes, history of cardiovascular disease and body-mass index. Random-effect meta-analysis was used to obtain adjusted pooled HRs of VTE with CKD versus no CKD. Results: The analysis included 95,154 participants with 1,178 VTE cases and 599,453 person-years of follow-up. Risk of VTE increased continuously with lower eGFR and higher ACR (Figure). Compared with eGFR 100 mL/min/1.73m², pooled adjusted HRs for VTE were 1.3 (1.0–1.7) for eGFR 60, 1.8 (1.3–2.6) for 45 and 1.9 (1.2–2.9) for 30 mL/min/1.73m². Compared with albumin-creatinine ratio (ACR) 5 mg/g, pooled adjusted HRs for VTE were 1.3 (1.04–1.7) for ACR 30, 1.6 (1.1–2.4) for 300 and 1.9 (1.2–3.1) for 1000 mg/g. There was no evidence for interaction between eGFR and ACR (P=0.22). The pooled adjusted HR for CKD (eGFR &lt;60 ml/min/1.73m² or albuminuria ≥30 mg/g) vs. no CKD was 1.5 (95%CI, 1.2–2.1). Results were similar for idiopathic and provoked VTE. Conclusion: Both reduced eGFR and elevated albuminuria are novel independent predictors of VTE in the general population.
Abstract 4890: Duplex sequencing of AML reveals extensive sub clonal heterogeneity
Authors: Lawrence A. Loeb, Michael W. Schmitt, Mark J. Prindle, Pamela S. Becker
Journal: Cancer Research (2015)

Abstract Subclonal mutations, that are present in a small subset of tumor cells prior to chemotherapy, could serve as a reservoir for the emergence of drug resistance. These could selectively expand during chemotherapy and result in relapse and death. We have used Duplex DNA Sequencing (DS) to detect low frequency subclonal mutations in AML, both prior to treatment and after relapse. DS focuses on a limited number of target genes at the level of single DNA molecules. Mutations are scored only if they are present at the same position in both strands of the same DNA molecule and are complementary, resulting in sequencing accuracy that is more than 10,000-fold greater than that of conventional next-generation DNA sequencing (NGS). To follow the course of mutation accumulation in AML, we used capture hybridization to enrich for 15 genes previously reported to be mutated in AML. We identified multiple subclonal mutations prior to therapy that would not be detected by routine NGS. For example, in one relapse sample, we identified a mutation in NRAS that was present in 32% of the cells. The identical mutation was detected by DS prior to treatment in 1% of cells. To further assess the frequency of subclonal mutations in AML, we targeted a 30 kb panel of genes at 500,000 fold depth, which facilitates detection of mutations present in fewer than 0.01% of cells. 5 subclonal mutations were identified within the 30 kb target, corresponding to a frequency of 170 mutations per megabase, Extrapolation of these results to the whole genome indicates that there are approximately 500,000 subclonal mutations per AML genome, which is 1,000 fold higher than the frequency of clonal mutations. These subclonal mutations would be unevenly distributed throughout the genome and be an important source for the selection of drug resistance during therapy. Citation Format: Lawrence A. Loeb, Michael W. Schmitt, Mark J. Prindle, Pamela S. Becker. Duplex sequencing of AML reveals extensive sub clonal heterogeneity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4890. doi:10.1158/1538-7445.AM2015-4890
Axons of Sympathetic Neurons: Transport of Enzymes in Vivo and Properties of Axonal Sprouts in Vitro
Authors: Irwin J. Kopin, Stephen D. Silberstein
Journal: Pharmacological Reviews (1972)

Enzymes involved in catecholamine synthesis are formed in the cell body and transported to the nerve terminals. DBH, which is present in the vesicles, is rapidly transported by a mechanism involving the neurotubules. The turnover of DBH is more rapid than that of TH.

Axonal damage or interference with integrity of the neurotubules results in diminished synthesis of catecholamine-forming enzymes with a switch to production of structural and membrane components. Levels of DBH and TH in the ganglia decline; however, uptake of NE increases, presumably as a consequence of increased membrane surface.

In vitro, axonal sprouts from cultured ganglia appear to have the properties of nerve endings almost as soon as they form. They avidly take up 3H-NE, and although they contain only large granular vesicles, stimulation induces release of the labeled catecholamine. Thus large granules are sufficient to support adrenergic function.

The granules may be carried directly to the nerve terminal by the neurotubules. When the nerve impulse arrives and the contents of the large granular vesicle are extruded, the residual membranes with adherent proteins may form the smaller granular vesicles concerned with synthesis and storage of the reserve transmitter.
<i>THSD1</i>preserves vascular integrity and protects against intraplaque haemorrhaging in ApoE<sup>−/−</sup>mice
Authors: Remco A. Haasdijk, Wijnand K. Den Dekker, Caroline Cheng, Dennie Tempel, Robert Szulcek, Frank L. Bos, Dorien M.A. Hermkens, Ihsan Chrifi, Maarten M. Brandt, Chris Van Dijk, Yan Juan Xu, Esther H.M. Van De Kamp, Lau A.J. Blonden, Jan Van Bezu, Judith C. Sluimer, Erik A.L. Biessen, Geerten P. Van Nieuw Amerongen, Henricus J. Duckers
Journal: Cardiovascular Research (2016)

Impairment of the endothelial barrier leads to microvascular breakdown in cardiovascular disease and is involved in intraplaque haemorrhaging and the progression of advanced atherosclerotic lesions that are vulnerable to rupture. The exact mechanism that regulates vascular integrity requires further definition. Using a microarray screen for angiogenesis-associated genes during murine embryogenesis, we identified thrombospondin type I domain 1 (THSD1) as a new putative angiopotent factor with unknown biological function. We sought to characterize the role of THSD1 in endothelial cells during vascular development and cardiovascular disease. Functional knockdown of Thsd1 in zebrafish embryos and in a murine retina vascularization model induced severe haemorrhaging without affecting neovascular growth. In human carotid endarterectomy specimens, THSD1 expression by endothelial cells was detected in advanced atherosclerotic lesions with intraplaque haemorrhaging, but was absent in stable lesions, implying involvement of THSD1 in neovascular bleeding. In vitro, stimulation with pro-atherogenic factors (3% O2 and TNFα) decreased THSD1 expression in human endothelial cells, whereas stimulation with an anti-atherogenic factor (IL10) showed opposite effect. Therapeutic evaluation in a murine advanced atherosclerosis model showed that Thsd1 overexpression decreased plaque vulnerability by attenuating intraplaque vascular leakage, subsequently reducing macrophage accumulation and necrotic core size. Mechanistic studies in human endothelial cells demonstrated that THSD1 activates FAK-PI3K, leading to Rac1-mediated actin cytoskeleton regulation of adherens junctions and focal adhesion assembly. THSD1 is a new regulator of endothelial barrier function during vascular development and protects intraplaque microvessels against haemorrhaging in advanced atherosclerotic lesions.
The Effects Of The Histone Methyltransferase Inhibitor UNC0638 Upon Gamma Globin Gene and Protein Expression Are Erythroblast Differentiation Stage Specific
Authors: Ki Soon Kim, Colleen Byrnes, Y. Terry Lee, Jaira F. de Vasconcellos, Megha Kaushal, Antoinette Rabel, Jeffery L. Miller
Journal: Blood (2013)