tbuckley/cabot-search huggingface dataset:
Role of Omi/HtrA2 in Apoptotic Cell Death After Myocardial Ischemia and Reperfusion
Authors: Hui-Rong Liu, Erhe Gao, Aihua Hu, Ling Tao, Yan Qu, Patrick Most, Walter J. Koch, Theodore A. Christopher, Bernard L. Lopez, Emad S. Alnemri, Antonis S. Zervos, Xin L. Ma
Journal: Circulation (2004)

Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent as well as caspase-independent cell death. However, the role of Omi/HtrA2 in the apoptotic cell death that occurs in vivo under pathological conditions remains unknown. The present study was designed to investigate whether Omi/HtrA2 plays an important role in postischemic myocardial apoptosis.Male adult mice were subjected to 30 minutes of myocardial ischemia followed by reperfusion and treated with vehicle or ucf-101, a novel and specific Omi/HtrA2 inhibitor, 10 minutes before reperfusion. Myocardial ischemia/reperfusion significantly increased cytosolic Omi/HtrA2 content and markedly increased apoptosis. Treatment with ucf-101 exerted significant cardioprotective effects, as evidenced by less terminal dUTP nick end-labeling staining, a lower incidence of DNA ladder fragmentation, and smaller infarct size. Furthermore, treatment with ucf-101 before reperfusion attenuated X-linked inhibitor of apoptosis protein degradation and inhibited caspase-9 and caspase-3 activities.Taken together, these results demonstrate for the first time that ischemia/reperfusion results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it promotes cardiomyocyte apoptosis via a protease activity-dependent, caspase-mediated pathway.
Participation of prostaglandin E2 in the purinergic neurotransmission of gut.
Authors: J T Cheng, K Shinozuka
Journal: Gut (1987)

Output of prostaglandin E2 (PGE2) from guinea pig ileal strips was detected by radioimmunoassay and the effect of adenosine and adenosine nucleotides on PGE2 output investigated in vitro. Adenosine triphosphate (ATP) and alpha, beta-methylene ATP, as well as adenosine, stimulate the output of PGE2 in a concentration dependent-manner. Potency of these compounds is in the order of alpha, beta-methylene ATP greater than ATP greater than adenosine. The effect of ATP was totally blocked by the cyclooxygenase inhibitor, indomethacin. Actions of these adenylyl compounds were attenuated by apamin, an antagonist of postjunctional P2-purinoceptor-mediated activity. Effectiveness of these compounds was not modified by 8-phenyltheophylline, a P1-purinoceptor antagonist, and it was not obtained in the isolated synaptosomal preparations. In addition, effects of adenosine and adenosine nucleotides were augmented only slightly by dipyridamole, a blocker of adenosine uptake. These findings suggest that the formation of PGE2 is stimulated in muscle cells, through the postjunctional P2-purinoceptor, taking an active role in the purinergic neurotransmission of guinea pig gut.
Inactivation of Anthracyclines by Cellular Peroxidase
Authors: Krzysztof J. Reszka, Brett A. Wagner, Lynn M. Teesch, Bradley E. Britigan, Douglas R. Spitz, C. Patrick Burns
Journal: Cancer Research (2005)

Abstract The anticancer anthracyclines, doxorubicin and daunorubicin, are highly cytotoxic to both cancer and normal cells. In this work, we have investigated the capacity of cellular myeloperoxidase to inactivate these agents. We show that incubation of human leukemia HL-60 cells with the anthracyclines in the presence of hydrogen peroxide and nitrite causes irreversible oxidation of the drugs, suggesting an extensive modification of their chromophores. Methimazole, 4-aminobenzoic acid hydrazide, or azide inhibits the reaction, suggesting that it is mediated by the cellular myeloperoxidase, an enzyme naturally present in large amounts in HL-60 cells. In contrast to the intact drugs, the oxidatively transformed anthracyclines were substantially less cytotoxic for HL-60 (assayed by apoptosis) and PC3 prostate cancer cells and H9c2 rat cardiac myoblasts in vitro (assayed by clonogenic survival), indicating that the oxidative metabolism of these agents leads to their inactivation. Using tandem mass spectrometry, we identified two specific metabolic products of the anthracycline degradation, 3-methoxyphthalic acid and 3-methoxysalicylic acid. These two metabolic products were obtained as authentic compounds and were nontoxic to HL-60 leukemic cells and cardiac myocytes. These findings may have important implications for the cellular pharmacology of anthracyclines and for clinical oncology.
THE EFFECT OF BILATERAL STELLECTOMY UPON THE CEREBRAL CIRCULATION OF MAN 1
Authors: Henry A. Shenkin, Fernando Cabieses, Gordon Van Den Noordt
Journal: Journal of Clinical Investigation (1951)

The role of the sympathetic nervous system in the intrinsic control of the cerebral circulation has always been controversial. Experiments heretofore have centered on the effects of stimulation of the cervical sympathetic nerves on changes in cerebral blood flow detected by instruments applied directly to the brain of animals. The results have generally agreed that cervical sympathetic stimulation causes only mild cerebral vasoconstriction. The marked effects of chemical agents (CO2 in particular) in affecting the cerebral circulation have led to the probably correct conclusion that the intrinsic control of the cerebral circulation in health is predominantly mediated via chemical agents in the blood and that neurogenic vasomotor control is at best only
Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma
Authors: Yoshinori Imura, Hirohiko Yasui, Hidetatsu Outani, Toru Wakamatsu, Kenichiro Hamada, Takaaki Nakai, Shutaro Yamada, Akira Myoui, Nobuhito Araki, Takafumi Ueda, Kazuyuki Itoh, Hideki Yoshikawa, Norifumi Naka
Journal: Molecular Cancer (2014)

Epithelioid sarcoma (EpS) is a high-grade malignant soft-tissue sarcoma characterized by local recurrences and distant metastases. Effective treatments for EpS have not been established and thus novel therapeutic approaches against EpS are urgently required. mTOR inhibitors exert antitumor effects on several malignancies but AKT reactivation by mTOR inhibition attenuates the antitumor effects of mTOR inhibitors. This reactivation is receptor tyrosine kinase (RTK)-dependent due to a release of negative feedback inhibition. We found that c-MET was the most highly activated RTK in two human EpS cell lines, Asra-EPS and VAESBJ. Here we investigated the functional and therapeutic relevance of mTOR and/or c-MET signaling pathways in EpS both in vitro and in vivo. We first examined the effects of an mTOR inhibitor, RAD001 (everolimus), on cell proliferation, cell cycle, AKT/mTOR signaling, and xenograft tumor growth in EpS cell lines. Next, we determined whether RAD001-induced AKT reactivation was blocked by silencing of c-MET or treatment with a selective c-MET inhibitor, INC280. Finally, we evaluated the antitumor effects of RAD001 combined with INC280 on EpS cell lines compared with either single agent or control in vitro and in vivo. Constitutive AKT phosphorylation was observed in Asra-EPS and VAESBJ cells. RAD001 suppressed EpS cell growth by inducing cell cycle arrest but enhanced AKT phosphorylation, which resulted in intrinsic resistance to mTOR inhibitors. In both EpS cell lines, RAD001-induced AKT phosphorylation was dependent on c-MET signaling. INC280 inhibited phosphorylation of c-MET and its downstream molecules, and decreased RAD001-induced phosphorylation of both AKT and ERK in EpS. Compared with a single agent or control, the combination of RAD001 and INC280 exerted superior antitumor effects on the growth of EpS cell lines in vitro and in vivo. Targeting of mTOR and c-MET signaling pathways significantly abrogates the growth of EpS in preclinical models and may be a promising therapeutic approach for patients with EpS.
The K121Q Polymorphism of the PC-1 Gene Is Associated With Insulin Resistance but not With Dyslipidemia
Authors: Agata Kubaszek, Jussi Pihlajamäki, Pauli Karhapää, Ilkka Vauhkonen, Markku Laakso
Journal: Diabetes Care (2003)

OBJECTIVE—To investigate the relationship of the K121Q polymorphism of the plasma cell glycoprotein 1 (PC-1) gene with insulin resistance, insulin secretion, and lipids and lipoproteins. RESEARCH DESIGN AND METHODS—Altogether, 110 normoglycemic subjects (group I) underwent a hyperinsulinemic-euglycemic clamp for evaluation of insulin sensitivity. The first-phase insulin secretion was determined by the intravenous glucose tolerance test (IVGTT) in a separate sample of 295 normoglycemic subjects (group II). RESULTS—The 121Q allele (genotypes K121Q and Q121Q) compared with the K121K genotype was related to higher fasting insulin levels (group I: 69.6 ± 45.6 vs. 51.9 ± 28.4 pmol/l [mean ± SD], P = 0.050; group II: 66.6 ± 38.8 vs. 53.8 ± 26.6 pmol/l, P = 0.009). In group I, subjects carrying the 121Q allele compared with subjects with the K121K genotype had lower rates of whole-body glucose uptake (51.17 ± 12.07 vs. 60.12 ± 14.86 μmol · kg−1 · min−1, P = 0.012) and nonoxidative glucose disposal (33.71 ± 10.51 vs. 41.51 ± 13.36 μmol · kg−1 · min−1, P = 0.015) during the clamp. In group II, there was no significant difference between the 121Q allele carriers and subjects with the K121K genotype in total first-phase insulin secretion during the first 10 min of the IVGTT (2,973 ± 2,224 vs. 2,520 ± 1,492 pmol · l−1 · min−1, P = 0.415). No association of the K121Q polymorphism with serum lipids and lipoproteins was found. CONCLUSIONS—In healthy normoglycemic Finnish subjects, the K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with impaired insulin secretion or dyslipidemia.
Cancer stem cell definitions and terminology: the devil is in the details
Authors: Peter Valent, Dominique Bonnet, Ruggero De Maria, Tsvee Lapidot, Mhairi Copland, Junia V. Melo, Christine Chomienne, Fumihiko Ishikawa, Jan Jacob Schuringa, Giorgio Stassi, Brian Huntly, Harald Herrmann, Jean Soulier, Alexander Roesch, Gerrit Jan Schuurhuis, Stefan Wöhrer, Michel Arock, Johannes Zuber, Sabine Cerny-Reiterer, Hans E. Johnsen, Michael Andreeff, Connie Eaves
Journal: Nature reviews. Cancer (2012)
Mimp, a Mitochondrial Carrier Homologue, Inhibits Met-HGF/SF-Induced Scattering and Tumorigenicity by Altering Met-HGF/SF Signaling Pathways
Authors: Raya Leibowitz-Amit, Galia Tsarfaty, Yamit Abargil, Gil M. Yerushalmi, Judith Horev, Ilan Tsarfaty
Journal: Cancer Research (2006)

Abstract We have recently shown that Mimp, a mitochondrial carrier protein homologue, is induced by Met-hepatocyte growth factor/scatter factor (HGF/SF) signaling and decreases the mitochondrial membrane potential in DA3 mammary adenocarcinoma cells. We show here that induction of Mimp leads to growth arrest in response to HGF/SF by arresting cells at the S phase of the cell cycle. Induction of Mimp or its transient expression does not lead to apoptosis. Mimp also attenuates HGF/SF-induced cellular scattering in vitro and tumor growth in vivo. The exogenous induction of Mimp at levels similar to its endogenous induction by HGF/SF increases the level of the Met protein and its phosphorylation by HGF/SF but reduces the levels of Shc and prevents the HGF/SF-induced tyrosine phosphorylation of Grb2 and Shc. In contrast, the level of phosphatidylinositol 3-kinase (PI3K) increases following Mimp induction and the level of phosphorylated PI3K in response to HGF/SF is unaffected by the exogenous induction of Mimp. Moreover, exogenous Mimp prevents the HGF/SF-induced transcription of the serum response element-luciferase reporter gene. Our results show that Mimp expression reduces Met-HGF/SF-induced proliferation and scattering by attenuating and altering the downstream signaling of Met. These data show a new link between a tyrosine kinase growth factor receptor and a mitochondrial carrier homologue that regulates cellular growth, motility, and tumorigenicity. (Cancer Res 2006; 66(17): 8687-97)
Cyclosporin for refractory ulcerative colitis
Authors: C G Loftus
Journal: Gut (2003)

Approximately 15% of patients with ulcerative colitis will have a severe attack requiring hospitalisation for intravenous steroids at some stage in their illness.1 Sixty per cent of patients treated with corticosteroids will be symptom free by the end of five days, 15% will have significant improvement, and 25% will not improve. Those who fail to improve may be treated with intravenous cyclosporin or undergo colectomy.

There have been four controlled studies of intravenous cyclosporin in patients with severe ulcerative colitis. Of 20 patients reported by Lichtiger et al , nine were randomised to receive placebo and 11 to receive cyclosporin 4 mg/kg/day as a continuous infusion for 14 days.2 Nine of 11 cyclosporin treated patients (82%) responded compared with none of the placebo treated patients. Those who responded were continued on oral cyclosporin 8 mg/kg/day. At six months, 5/11 cyclosporin treated patients (45%) maintained a …
Selective High-Affinity Ligand Antibody Mimics for Cancer Diagnosis and Therapy: Initial Application to Lymphoma/Leukemia
Authors: Rod Balhorn, Saphon Hok, Patricia A. Burke, Felice C. Lightstone, Monique Cosman, Adam Zemla, Gary Mirick, Julie Perkins, Arutselvan Natarajan, Michele Corzett, Sally J. DeNardo, Huguette Albrecht, Jeff P. Gregg, Gerry L. DeNardo
Journal: Clinical Cancer Research (2007)

Abstract Purpose: More than two decades of research and clinical trials have shown radioimmunotherapy to be a promising approach for treating various forms of cancer. Lym-1 antibody, which binds selectively to HLA-DR10 on malignant B-cell lymphocytes, has proved to be effective in delivering radionuclides to non–Hodgkin's lymphoma and leukemia. Using a new approach to create small synthetic molecules that mimic the targeting properties of the Lym-1 antibody, a prototype, selective high-affinity ligand (SHAL), has been developed to bind to a unique region located within the Lym-1 epitope on HLA-DR10. Experimental Design: Computer docking methods were used to predict two sets of small molecules that bind to neighboring cavities on the β subunit of HLA-DR10 surrounding a critical amino acid in the epitope, and the ligands were confirmed to bind to the protein by nuclear magnetic resonance spectroscopy. Pairs of these molecules were then chemically linked together to produce a series of bidentate and bisbidentate SHALs. Results: These SHALs bind with nanomolar to picomolar Kd's only to cell lines expressing HLA-DR10. Analyses of biopsy sections obtained from patients also confirmed that SHAL bound to both small and large cell non–Hodgkin's lymphomas mimicking the selectivity of Lym-1. Conclusions: These results show that synthetic molecules less than 1/50th the mass of an antibody can be designed to exhibit strong binding to subtle structural features on cell surface proteins similar to those recognized by antibodies. This approach offers great potential for developing small molecule therapeutics that target other types of cancer and disease.
Roger Fenton Hunt
Authors: R. B. S. Taylor
Journal: BMJ (2014)

Roger Fenton Hunt was in the same group in the dissecting room at St Thomas’ Hospital as Cicely Saunders, later to build St Christopher’s Hospice in London. He was bright and didn’t have to work as hard as the rest of us. But, like us, he had girlfriends among the Nightingales (as the nurses were called).

Before qualifying he was interested in anaesthetics. He was giving anaesthesia under supervision before he qualified. But afterwards he worked on a surgical firm and looked after a general practitioner from Devon. This GP persuaded Roger to do a short locum in his practice, to help out. While there, a partnership became available, and he was invited to take it. By this time he was married. He was thrown into general practice …
Differences in proliferation of the hematopoietic cell line TF-1 and cytokine production by peripheral blood leukocytes induced by 2 naturally occurring forms of human IL-3
Authors: Andrea Schweiger, Debra Stern, I.Carla Lohman, Mauro Baldini, Fernando D. Martinez, Marilyn Halonen
Journal: Journal of Allergy and Clinical Immunology (2001)
Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study
Authors: Julio Delgado, Kirsty Thomson, Nigel Russell, Joanne Ewing, Wendy Stewart, Gordon Cook, Stephen Devereux, Richard Lovell, Rajesh Chopra, David I. Marks, Stephen Mackinnon, Donald W. Milligan
Journal: Blood (2005)
Independent Predictors of Enteric Fistula and Abdominal Sepsis After Damage Control Laparotomy
Authors: Matthew J Bradley, Joseph J Dubose, Thomas M Scalea, John B Holcomb, Binod Shrestha, Obi Okoye, Kenji Inaba, Tiffany K Bee, Timothy C Fabian, James F Whelan, Rao R Ivatury
Journal: JAMA Surgery (2013)

Enterocutaneous fistula (ECF), enteroatmospheric fistula (EAF), and intra-abdominal sepsis/abscess (IAS) are major challenges for surgeons caring for patients undergoing damage control laparotomy after trauma.To determine independent predictors of ECF, EAF, or IAS in patients undergoing damage control laparotomy after trauma, using the AAST Open Abdomen Registry.The AAST Open Abdomen registry of patients with an open abdomen following damage control laparotomy was used to identify patients who developed ECF, EAF, or IAS and to compare these patients with those without these complications. Univariate analyses were performed to compare these groups of patients. Variables from univariate analyses differing at P < .20 were entered into a stepwise logistic regression model to identify independent risk factors for ECF, EAF, or IAS.Fourteen level I trauma centers.A total of 517 patients with an open abdomen following damage control laparotomy.Complication of ECF, EAF, or IAS.More patients in the ECF/EAF/IAS group than in the group without these complications underwent bowel resection (63 of 111 patients [57%] vs 133 of 406 patients [33%]; P < .001). Within the first 48 hours after surgery, the ECF/EAF/IAS group received more colloids (P < .03) and total fluids (P < .03) than did the group without these complications. The ECF/EAF/IAS group underwent almost twice as many abdominal reexplorations as did the group without these complications (mean [SD] number, 4.1 [4.1] vs 2.2 [3.4]; P < .001). After multivariate analysis, the independent predictors of ECF/EAF/IAS were a large bowel resection (adjusted odds ratio [AOR], 3.56 [95% CI, 1.88-6.76]; P < .001), a total fluid intake at 48 hours of between 5 and 10 L (AOR, 2.11 [95% CI, 1.15-3.88]; P = .02) or more than 10 L (AOR, 1.93 [95% CI, 1.04-3.57]; P = .04), and an increasing number of reexplorations (AOR, 1.14 [95% CI, 1.06-1.21]; P < .001).Large bowel resection, large-volume fluid resuscitation, and an increasing number of abdominal reexplorations were statistically significant predictors of ECF, EAF, or IAS in patients with an open abdomen after damage control laparotomy.
Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up
Authors: J H Scholefield, S M Moss, C M Mangham, D K Whynes, J D Hardcastle
Journal: Gut (2011)

<h3>Background</h3> Three large randomised trials have shown that screening for colorectal cancer (CRC) using the faecal occult blood test (FOBt) can reduce the mortality from this disease. The largest of these trials, conducted in Nottingham since 1981, randomised 152 850 individuals between the ages of 45 and 74 years to an intervention arm receiving biennial Haemoccult (FOB) test kit or to a control arm. In 2006, the National Bowel Cancer Screening Programme was launched in England using the FOBt, with the expectation that it will reduce CRC mortality. <h3>Aims</h3> To compare the CRC mortality and incidence in the intervention arm with the control arm after long-term follow-up. <h3>Methods</h3> The 152 850 randomised individuals were followed up through local health records and central flagging (Office for National Statistics). <h3>Results</h3> At a median follow-up of 19.5 years there was a 13% reduction in CRC mortality (95% CI 3% to 22%) in the intervention arm despite an uptake at first invitation of approximately 57%. The CRC mortality reduction in those accepting the first screening test, adjusted for the rate of non-compliers, was 18%. There was no significant difference in mortality from causes other than CRC between the intervention and control arms. Despite removing 615 adenomas &gt;10 mm in size from the intervention arm, there was no significant difference in CRC incidence between the two arms. <h3>Conclusions</h3> Although the reduction in CRC mortality was sustained, further follow-up of the screened population has not shown a significant reduction in the CRC incidence. Moreover, despite the removal of many large adenomas there was no reduction in the incidence of invasive cancer which was independent of sex and site of the tumour.
Additive effects of exposure to silica dust and smoking on pulmonary epithelial permeability: a radioaerosol study with technetium-99m labelled DTPA.
Authors: L E Nery, R T Florencio, P R Sandoval, R T Rodrigues, G Alonso, G R Mason
Journal: Thorax (1993)

BACKGROUND: Increased pulmonary epithelial permeability evaluated by the rate of clearance from lung to blood of the radioaerosol solute technetium-99m labelled diethylenetriamine pentaacetate (99mTc-DTPA) has been reported in smokers and in workers exposed to silica dust. A study was carried out to determine whether there are additive effects of cigarette smoke and exposure to silica dust on clearance rates of 99mTc-DTPA in ceramic workers. METHODS: Thirty one subjects with silicosis were studied, of whom 18 smoked cigarettes and 13 were non-smokers. They had similar histories of exposure to silica dust, and radiological alterations consistent with silicosis. The results from these patients were compared with those from normal subjects and smokers previously studied by the authors. RESULTS: Pulmonary function values were normal in most patients and not significantly different among groups. The median (range) rate of clearance of 99mTc-DTPA in smokers with silicosis was 4.1 (1.9-12.7) %/minute, which was higher than the rates in non-smoking patients with silicosis of 2.2 (1.1-6.6) %/minute and in smokers without exposure to silica dust of 2.9 (1.6-4.5) %/minute. These differences were more evident and significant when the clearance rates of the lower lobes of the three groups were compared. Clearance rates higher than 3%/minute were much more frequent in smokers with silicosis (85%) than in non-smoking patients with silicosis (15%) and in smokers (40%). CONCLUSION: In ceramic workers with radiographic changes resulting from exposure to silica dust, there is an additive effect of inhalation of silica dust and cigarette smoking on clearance rates of 99mTc-DTPA.
Next-Generation Sequencing: Targeting Targeted Therapies
Authors: Justine N. McCutcheon, Giuseppe Giaccone
Journal: Clinical Cancer Research (2015)

Next-generation sequencing (NGS) has given new perspective in oncology. With the ongoing development of targeted therapies, NGS is evolving molecular diagnostics by providing comprehensive interrogation of clinically actionable genomic aberrations in tumors. Having this assay as the primary testing method produces clinically beneficial results. See related article by Drilon et al., p. 3631.