tbuckley/cabot-search huggingface dataset:
Inhibition of Src Impairs the Growth of Met-Addicted Gastric Tumors
Authors: Andrea Bertotti, Cecilia Bracco, Flavia Girolami, Davide Torti, Stefania Gastaldi, Francesco Galimi, Enzo Medico, Paul Elvin, Paolo M. Comoglio, Livio Trusolino
Journal: Clinical Cancer Research (2010)

We examined whether inhibition of Src tyrosine kinase, a downstream effector of the MET oncogene, can hinder the malignant properties of gastric tumors dependent on Met for growth and survival.Sensitivity to Src inhibition was determined in vitro by measuring clonogenic survival (anchorage-independent growth) and in vivo by establishing xenograft models. Four "Met-addicted" gastric carcinoma cell lines (GTL16, MKN45, HS746T, and SNU5) and three Met-independent gastric carcinoma cell lines (KATO III, AGS, and NCI-N87) were treated with the Src inhibitor saracatinib (AZD0530). In GTL16 and KATO III, Src neutralization was also achieved by dasatinib and RNA interference. The biochemical and transcriptional consequences of Src inhibition were explored using anti-phosphoprotein antibodies and oligonucleotide microarrays.Inhibition of Src in Met-addicted gastric carcinoma cell lines (a) decreased the phosphorylation/activation levels of signaling intermediates involved in cell proliferation and protection from apoptosis and down-modulated the expression of several cell cycle regulators; (b) reduced anchorage-independent growth; (c) enhanced impairment of cell viability produced by Met inhibition; and (d) delayed tumorigenesis in xenotransplantation models. Immunohistochemical analysis of tumor xenograft tissues following systemic treatment with saracatinib showed a reduction of tumor cell proliferation index, increased apoptosis, and diminished phospho-focal adhesion kinase and phospho-paxillin staining. Tumor stroma parameters such as angiogenesis or inflammatory infiltration were unaffected. In clonogenic survival assays, gastric carcinoma cells without addiction to Met were less sensitive than Met-addicted cells to Src inhibition.Src is as a key downstream transducer of Met-driven tumor growth. Targeting Src might provide therapeutic benefit in Met-addicted tumors.
Erratum: Corrigendum: Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking
Authors: Linda V Sinclair, David Finlay, Carmen Feijoo, Georgina H Cornish, Alex Gray, Ann Ager, Klaus Okkenhaug, Thijs J Hagenbeek, Hergen Spits, Doreen A Cantrell
Journal: Nature Immunology (2008)
Productive infection of primary cultures of endothelial cells from the cat liver sinusoid with the feline immunodeficiency virus
Authors: A Steffan, M Lafon, J Gendrault, B Smedsrod, H Nonnenmacher, F Koehren, J Gut, M de Monte, J Martin, C Royer, A Kirn
Journal: Hepatology (1996)

Given the similarities between the two viruses, the feline immunodeficiency virus (FIV) is becoming an interesting animal model for human immunodeficiency virus (HIV) studies. To explore the still controversial role of the liver in the development of HIV infection, sinusoidal endothelial cells (SEC) were isolated, and primary cultures were infected with the FIV Villefranche IFFA strain. The isolated cells were characterized by their typical fenestrations, the presence of von Willebrand factor (vWf), and their ability to take up acetylated low-density lipoproteins and denatured collagen. Two weeks after infection, significant amounts of FIV p24 antigen were detected by immunofluorescence in both multinucleated giant and single cells and by enzyme-linked immunosorbent assay in the culture medium. High amounts of viral particles were observed together with different steps of budding at the plasma membrane or at the membrane of intracytoplasmic vacuoles. The released viral particles were shown to be infectious for a permissive cell line. During the first 3 weeks of infection, the only cytopathic effect of FIV was syncytia formation. No noticeable impairment of the pattern of fenestrations and the modulation of their number by a cytoskeleton-mediated process occurred. The productive infection of SEC may contribute to the progression of the infection.
690 THE HEPATIC ANTIBACTERIAL RESPONSE DURING CHOLESTATIC LIVER INJURY IS REGULATED VIA GP130 AND C-MET DEPENDENT PATHWAYS
Authors: A. Giebeler, L.O. Brandenburg, S. Erschfeld, M. Kaldenbach, C. Birchmeier, C. Trautwein, K. Streetz
Journal: Journal of Hepatology (2011)
Phase I Dose-Finding Study of Weekly Single-Agent Patupilone in Patients With Advanced Solid Tumors
Authors: Eric H. Rubin, John Rothermel, Fisseha Tesfaye, Tianling Chen, Martine Hubert, Yu-Yun Ho, Chyi-Hung Hsu, Amit M. Oza
Journal: Journal of Clinical Oncology (2005)

To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors.Patients were treated with patupilone (0.3 to 3.6 mg/m2) for 6 weeks on/3 weeks off or 3 weeks on/1 week off. Dose-limiting toxicities (DLTs), MTD, and pharmacokinetics were determined for each schedule of administration.Ninety-one patients were enrolled. The most common tumor types included ovarian, breast, and colon cancers. Doses of patupilone less than 2.5 mg/m2 using either the 6 weeks on/3 weeks off or the 3 weeks on/1 week off schedule were tolerated well. At higher doses, DLTs were observed using both dosing schedules, with diarrhea the most common DLT. The MTD for both treatment schedules was 2.5 mg/m2. After a short infusion, patupilone blood concentrations declined in a multiphasic manner with a terminal half-life of 4 days. Drug clearance was nonrenal and was not related to body-surface area. Over the dose range evaluated, systemic drug exposure was approximately dose proportional. Three patients achieved a partial response, and 31 patients had stable disease. Two patients experiencing a partial response had received prior taxane therapy.Patupilone is well tolerated when administered at a dose of 2.5 mg/m2, using either a 6 weeks on/3 weeks off or a 3 weeks on/1 week off schedule. In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results.
Evidence for Airway Acidity and Oxidative Stress in Exhaled Breath Condensates from Grain Workers
Authors: Ron Do, Karen Bartlett, Helen Dimich-Ward, Winnie Chu, Susan Kennedy
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

In their article, Dr. Do and colleagues described exhaled breath condensate (EBC) studies that they interpret to indicate airway acidity and oxidative stress (8-isoprostane) in grain workers (1). Unfortunately, neither of these conclusions can be drawn on the basis of the data they have collected. With regard to pH, the species NH4 1 and HCO3 2 represent approximately 90% of the acids and bases found in most samples of EBC (2). Generation of approximately 90% of the NH4 1 is in the mouth rather than the airways, much of it from bacterial degradation of urea (3). Low concentrations of volatile organic acids (e.g., acetic acid) may be found in EBC, but these may also represent oral contamination. Abnormal EBC pH probably reflects oral rather than airway metabolism (3), and the pH and constituents of saliva should have been measured. Furthermore, the investigators did not measure amylase concentrations in the EBC to detect direct salivary contamination, which is more likely because the condenser they used is close to the mouth during collection. Filtering the EBC is not well justified in the article and had no effect. Furthermore, exposure of the samples to argon leaves behind much of the CO2/HCO3 2 and may cause loss of other volatile acids and bases. Interpretation of EBC pH is problematical because the buffering capacity of the EBC was not measured. Condensates should not be used to collect volatile constituents such as NH3 since recovery of these solutes in the aqueous phase can be influenced by local pH, temperature, airflow, and turbulence in airways and condensers. With regard to isoprostane, EBC concentrations of isoprostane cannot be reliably used to estimate either concentrations or changes in concentrations of isoprostane in the airways unless a dilutional indicator is also measured (e.g., conductivity of lyophilized samples, which is readily measured with simple equipment) (4). Increased 8-isoprostane concentrations may reflect the production of more respiratory droplets in the airways rather than increased concentrations in the airway fluid. EBC concentrations of nonvolatiles are approximately 1% those in bronchoalveolar lavage (BAL) and 0.01% those in respiratory fluids. It is therefore puzzling that EBC 8-isoprostane levels in the normals of Do and coworkers (z10 pg/mL) are nearly the same as those reported in BAL by others (5). The EBC approach holds the promise that airway constituents may be measured noninvasively, but oral contamination with volatile solutes and extreme and variable dilution by water vapor from the airways must be experimentally addressed in all studies of this sort.
Numerous Fragmented Spliceosomal Introns, AT-AC Splicing, and an Unusual Dynein Gene Expression Pathway in Giardia lamblia
Authors: S. W. Roy, A. J. Hudson, J. Joseph, J. Yee, A. G. Russell
Journal: Molecular Biology and Evolution (2011)

Spliceosomal introns are hallmarks of eukaryotic genomes, dividing coding regions into separate exons, which are joined during mRNA intron removal catalyzed by the spliceosome. With few known exceptions, spliceosomal introns are cis-spliced, that is, removed from one contiguous pre-mRNA transcript. The protistan intestinal parasite Giardia lamblia exhibits one of the most reduced eukaryotic genomes known, with short intergenic regions and only four known spliceosomal introns. Our genome-wide search for additional introns revealed four unusual cases of spliceosomal intron fragmentation, with consecutive exons of conserved protein-coding genes being dispersed to distant genomic sites. Independent transcripts are trans-spliced to yield contiguous mature mRNAs. Most strikingly, a dynein heavy chain subunit is both interrupted by two fragmented introns and also predicted to be assembled as two separately translated polypeptides, a remarkably complex expression pathway for a nuclear-encoded sequence. For each case, we observe extensive base-pairing potential between intron halves. This base pairing provides both a rationale for the in vivo association of independently transcribed mRNAs transcripts and the apparent specificity of splicing. Similar base-pairing potential in two cis-spliced G. lamblia introns suggests an evolutionary pathway whereby intron fragmentation of cis-spliced introns is permissible and a preliminary evolutionary step to complete gene fission. These results reveal remarkably complex genome dynamics in a severely genomically reduced parasite.
A–Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance—Part 29
Authors: M K Ranchordas, N Burd, D S Senchina, L M Burke, S J Stear, L M Castell
Journal: British Journal of Sports Medicine (2012)

Part 29 includes two supplements which are traditionally paired (phlogenzym and wobenzym) and which have been popular in the Eastern Bloc countries though hardly, if at all, used by athletes in the UK and USA. Phosphatidylserine (a phospholipid present in cell membranes) and plant sterols (several of which have been dealt with in the previous issues of this series) are also discussed here.

### M K Ranchordas

The active ingredients found in phlogenzym are the hydrolase trypsin, the endopeptidase bromelain and the bioflavonoid rutin. Trypsin is a digestive enzyme produced by the pancreas and secreted into the small intestine, where it hydrolyses proteins. Bromelain is a proteolytic enzyme obtained from pineapples, and rutin is a bioflavonoid found in many plants, fruits and vegetables but the richest source is buckwheat. Similarly, wobenzym also contains trypsin, bromelain and rutin but also includes the proteolytic enzyme papain, the endopeptidase chymotrypsin and pancreatin which is an extract from the pancreas of animals that contains pancreatic enzymes.

Phlogenzym and wobenzym are commonly known as hydrolytic enzymes or systemic enzymes and have been purported to possess anti-inflammatory, fibrinolytic and analgesic properties as well as having positive effects on oedema. Studies investigating the efficacy of phlogenzym and wobenzym in the athletic population are lacking but several studies have investigated their effects on recuperation following injury, disease and health.1,–,7

In a double-blind prospective randomised study, phlogenzym was compared with diclofenac in the treatment of activated osteoarthritis …
Whole proteome identification of plant candidate G-protein coupled receptors in Arabidopsis, rice, and poplar: computational prediction and in-vivo protein coupling
Authors: Timothy E Gookin, Junhyong Kim, Sarah M Assmann
Journal: Genome biology (2008)

The classic paradigm of heterotrimeric G-protein signaling describes a heptahelical, membrane-spanning G-protein coupled receptor that physically interacts with an intracellular Gα subunit of the G-protein heterotrimer to transduce signals. G-protein coupled receptors comprise the largest protein superfamily in metazoa and are physiologically important as they sense highly diverse stimuli and play key roles in human disease. The heterotrimeric G-protein signaling mechanism is conserved across metazoa, and also readily identifiable in plants, but the low sequence conservation of G-protein coupled receptors hampers the identification of novel ones. Using diverse computational methods, we performed whole-proteome analyses of the three dominant model plant species, the herbaceous dicot Arabidopsis thaliana (mouse-eared cress), the monocot Oryza sativa (rice), and the woody dicot Populus trichocarpa (poplar), to identify plant protein sequences most likely to be GPCRs. Our stringent bioinformatic pipeline allowed the high confidence identification of candidate G-protein coupled receptors within the Arabidopsis, Oryza, and Populus proteomes. We extended these computational results through actual wet-bench experiments where we tested over half of our highest ranking Arabidopsis candidate G-protein coupled receptors for the ability to physically couple with GPA1, the sole Gα in Arabidopsis. We found that seven out of eight tested candidate G-protein coupled receptors do in fact interact with GPA1. We show through G-protein coupled receptor classification and molecular evolutionary analyses that both individual G-protein coupled receptor candidates and candidate G-protein coupled receptor families are conserved across plant species and that, in some cases, this conservation extends to metazoans. Our computational and wet-bench results provide the first step toward understanding the diversity, conservation, and functional roles of plant candidate G-protein coupled receptors.
Economic Burden of Cancer Survivorship Among Adults in the United States
Authors: Gery P. Guy, Donatus U. Ekwueme, K. Robin Yabroff, Emily C. Dowling, Chunyu Li, Juan L. Rodriguez, Janet S. de Moor, Katherine S. Virgo
Journal: Journal of Clinical Oncology (2013)

To present nationally representative estimates of the impact of cancer survivorship on medical expenditures and lost productivity among adults in the United States.
Antitumor Granuloma Formation by CD4<sup>+</sup> T Cells in a Patient With Rapidly Progressive Melanoma Experiencing Spiking Fevers, Neuropathy, and Other Immune-Related Toxicity After Treatment With Ipilimumab
Authors: Jason J. Luke, Cecilia Lezcano, F. Stephen Hodi, George F. Murphy
Journal: Journal of Clinical Oncology (2014)

Case ReportA 61-year-old woman was diagnosed in 1990 with malignant melanoma arising on the left shoulder and underwent wide local excision.No other details are available regarding the initial histology or work-up.In late 2011, the patient developed a left axillary mass.An attempted resection took place in early 2012.This procedure was aborted after the mass was deemed unresectable as a result of close proximity to essential neurovascular structures.However, a biopsy revealed metastatic melanoma with immunohistochemistry positive for Melan-A and S100.Histologically, this biopsy revealed sparse, individually disposed CD4 ϩ and CD8 ϩ T cells that were scattered throughout the tumor nodule (Figs 1A through 1C; H&E, CD4 and CD8, respectively).Mutational analysis of the tumor revealed a point mutation in codon 61 of NRAS resulting in replacement of glutamine for arginine in the product protein.Only wild-type sequences were found in BRAF.A positron-emission tomography scan revealed extensive hypermetabolic left axillary, infraclavicular, supraclavicular, and cervical lymphadenopathy as well as a hypermetabolic intraparotid lymph node.The patient was then referred to our institution, where she began receiving treatment with ipilimumab at a dose of 3 mg/kg every 3 weeks.In the 3 weeks between doses one and two, the patient was noted to have a massive increase in axillary lymphadenopathy.Before treatment, she had palpable disease within the axilla, although it did not affect her left arm.By the second dose, the mass had grown such that adduction of the patient's arm was limited in the final 45 degrees of motion.Two days after the second dose of ipilimumab, the patient began experiencing twice-daily relapsing fevers.These were consistently in the range of 38.9°C to 40°C and were associated with drenching sweats.The patient was evaluated on two occasions in emergency departments over the next 7 days, where blood cultures were negative, CBC was unremarkable, chest x-ray was clear, computed tomography (CT) of the abdomen was unremarkable, and no localizing signs of infection were observed.By day 10 of these fevers, the patient was admitted for palliative support.On physical examination, the left axillary lymphadenopathy had decreased to the size noted at her initial consultation.In the context of what seemed clinically to be an ipilimumab-induced cytokine storm, a biopsy of the left axillary tumor was obtained.This biopsy revealed focally brisk infiltration of tumor by T cells, with a marked CD4 predominance over CD8 (Figs 1D through 1F; H&E, CD4 and CD8, respectively) and multinucleated histiocytes (Fig 1D and 1H, arrows) that also stained for CD4 (Fig 1I, arrow) and formed small microgranulomas.The T cells varied from
Early Changes in Protein Expression Detected by Mass Spectrometry Predict Tumor Response to Molecular Therapeutics
Authors: Michelle L. Reyzer, Robert L. Caldwell, Teresa C. Dugger, James T. Forbes, Christoph A. Ritter, Marta Guix, Carlos L. Arteaga, Richard M. Caprioli
Journal: Cancer Research (2004)

Abstract Biomarkers that predict therapeutic response are essential for the development of anticancer therapies. We have used matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to directly analyze protein profiles in mouse mammary tumor virus/HER2 transgenic mouse frozen tumor sections after treatment with the erbB receptor inhibitors OSI-774 and Herceptin. Inhibition of tumor cell proliferation and induction of apoptosis and tumor reduction were predicted by a &amp;gt;80% reduction in thymosin β4 and ubiquitin levels that were detectable after 16 hours of a single drug dose before any evidence of in situ cellular activity. These effects were time- and dose-dependent, and their spatial distribution in the tumor correlated with that of the small-molecule inhibitor OSI-774. In addition, they predicted for therapeutic synergy of OSI-774 and Herceptin as well as for drug resistance. These results suggest that drug-induced early proteomic changes as measured by MALDI-MS can be used to predict the therapeutic response to established and novel therapies.
Modeling the Transcriptional Consequences of Epidermal Growth Factor Receptor Ablation in Ras-Initiated Squamous Cancer
Authors: Lisa Nolan Wright, Andrew Ryscavage, Glenn Merlino, Stuart H. Yuspa
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Epidermal growth factor receptor (EGFR)–targeted therapy is in clinical use to treat squamous cell carcinoma of the head and neck and other cancers of lining epithelium. RAS mutations in these tumors are a negative prognostic factor for response, and skin inflammation is an adverse reaction to therapy. We investigated transcriptional and biochemical changes that could account for the confounding effects of RAS activation and inflammation in a squamous tissue. Experimental Design: We carried out gene expression profiling on oncogenic Ras-transformed and wild-type mouse and human keratinocytes with EGFR ablated chronically by genetic deletion or acutely by drug treatment and followed leads provided by pathway analysis with biochemical studies. Results: We identified a 25-gene signature specific to the Ras–EGFR ablation interaction and a distinct 19-gene EGFR ablation signature on normal keratinocytes. EGFR ablation in the context of wild-type Ras reduces ontologies favoring cell-cycle control and transcription, whereas oncogenic Ras enriches ontologies for ion channels and membrane transporters, particularly focused on calcium homeostasis. Ontologies between chronic EGFR ablation and acute pharmacologic ablation were unique, both with and without Ras activation. p38α is activated in response to abrogation of EGFR signaling under conditions of Ras activation in both mouse and human keratinocytes and in RAS-transformed tumor orthografts of EGFR-ablated mouse keratinocytes. EGFR ablation in the absence of oncogenic Ras revealed Erk and interleukin-1β–related pathways. Conclusion: These findings reveal unrecognized interactions between Ras and EGFR signaling in squamous tumor cells that could influence the therapeutic response to EGFR ablation therapy. Clin Cancer Res; 18(1); 170–83. ©2011 AACR.