tbuckley/cabot-search huggingface dataset:
Abstract LB-217: A gene signature that predicts deficiency of homologous recombination DNA repair.
Authors: Guang Peng, Gordon Mills, Shiaw-Yih Lin
Journal: Cancer Research (2013)

Abstract DNA repair pathways play a fundamental role to maintain genomic stability. Defects in specific DNA repair pathways predispose to cancer development, but also provide therapeutic opportunities: for example, poly-ADP ribose polymerase (PARP) inhibitors are synthetically lethal with cancer cells, which are defective in homologous recombination (HR)-mediated DNA repair, such as BRCA1/BRCA2-deficient tumors. However, recent clinical trials of PARP inhibitors have shown rather disappointing results, particularly in the treatment of triple-negative breast cancer (TNBC), which has a molecular phenotype similar to that of BRCA-deficient breast cancer. As a targeted therapy, the clinical success of PARP inhibitors is dependent on identifying cancer cells with HR repair deficiency. Thus the observations of PARP inhibitors from clinical trials raise a key question: Can we identify a molecular signature of HR repair deficiency in cancer cells? To answer this question, we utilized the gene expression profiling approach to measure the cellular transcriptional reprograming in HR-deficient cell lines. By analyzing the molecular changes of transcriptional landscape, we identified an HR-defect gene signature that predicted HR repair deficiency in cells, predicted clinical outcomes of multiple human cancers, and predicted sensitivity of human cancer cells to PARP inhibitors. HR repair deficiency leads to genomic instability and often promotes accumulation of additional mutations. Our gene signature analysis further revealed that combinatorial effects of co-existing genetic changes such as loss of both BRCA1 and PTEN may extensively rewire the HR repair network and confer resistance to PARP inhibitor treatment. Moreover, to combat PARP inhibitor resistance, we successfully used our HR-defect gene signature as a drug discovery tool and found that TTK, mTOR and PI3K inhibitors could induce HR repair deficiency and sensitize cancer cells to PARP inhibitor treatment. Collectively, our findings demonstrate that transcriptional signature can be used to define the functional status of the HR repair network in cells. In summary, our study identifies a gene signature of HR repair deficiency, which provides a novel network view of the DNA repair process. In addition to using our gene signature as a prognostic marker for multiple cancers including breast, ovarian and lung cancer, our findings potentially have a significant impact on predicting responsiveness and overcoming resistance to targeted therapeutic regimens with DNA repair inhibitors such as PARP inhibitors. Citation Format: Guang Peng, Gordon Mills, Shiaw-Yih Lin. A gene signature that predicts deficiency of homologous recombination DNA repair. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-217. doi:10.1158/1538-7445.AM2013-LB-217
Human alveolar macrophages have 15-lipoxygenase and generate 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid and lipoxins.
Authors: B D Levy, M Romano, H A Chapman, J J Reilly, J Drazen, C N Serhan
Journal: Journal of Clinical Investigation (1993)

Eicosanoids derived from lipoxygenase (LO)-catalyzed reactions play important roles in pulmonary inflammation. Here, we examined formation of LO-derived products by human alveolar macrophages (HAM). HAM converted [1-14C]-arachidonic acid to a product carrying 14C-radiolabel that was identified as 15(S)-hydroxy-5,8,11-cis-13-trans-eicosatetraenoic acid (15-HETE) by physical methods. 15-LO mRNA was demonstrated in HAM by reverse transcription-polymerase chain reaction. Incubation of HAM for 3 d with interleukin 4(IL-4) before exposure to [1-14C]arachidonic acid led to both increased mRNA for 15-LO and a 4-fold increase in 15-HETE formation. In contrast, 5(S)-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid generation was not significantly altered by prior exposure to IL-4. Additionally, lipoxins (LXA4 and LXB4) were detected from endogenous substrate, albeit in lower levels than leukotriene B4 (LTB4), in electrochemical detection/high performance liquid chromatography profiles from HAM incubated in the presence and absence of the chemotactic peptide (FMLP) or the calcium ionophore (A23187). Exposure of HAM to leukotriene A4 (LTA4) resulted in a 2-fold increase in LXA4 and 10-fold increase in LXB4. These results demonstrate the presence of 15-LO mRNA and enzyme activity in HAM and the production of LXA4 and LXB4 by these cells. Along with 5-LO-derived products, the biosynthesis of 15-LO-derived eicosanoids by HAM may also be relevant in modulating inflammatory responses in the lung.
Comparison of Tc-99m Depreotide and In-111 Octreotide in Recurrent Meningioma
Authors: DIRK HELLWIG, SAMUEL SAMNICK, JOHANNES REIF, BERND F.M. ROMEIKE, WOLFGANG REITH, JEAN R. MORINGLANE, CARL-MARTIN KIRSCH
Journal: Clinical Nuclear Medicine (2002)

Purpose For more than a decade, In-111 octreotide has been known to accumulate in meningiomas as a result of the expression of subtype 2 somatostatin receptors. Improved imaging characteristics can be expected with the recently developed radiotracer Tc-99m depreotide, which also binds to subtype 2 somatostatin receptors. Materials and Methods The authors examined a patient with intraorbital and extracranial recurrent meningioma using SPECT with Tc-99m depreotide and In-111 octreotide. The tumor-to-background ratios in the lesions were compared and the findings were correlated with histopathologic findings. Results Although the tumor-to-background ratios were higher for the In-111–labeled tracer in the largest tumor lesion (5.7 versus 3.3), SPECT with the Tc-99m–labeled compound showed a proved second site of recurrence as a result of the better resolution that can be achieved with that isotope. Conclusions SPECT with Tc-99m depreotide appears to be clinically useful for detecting recurrent meningiomas with higher resolution and may outperform In-111 octreotide imaging in patients with meningiomas.
Points from Letters: Register of Pharmacists
Authors: J. L. Furness
Journal: BMJ (1968)

The mechanisms underlying dopamine neuron loss in Parkinson9s disease (PD) are not clearly defined. Here, we delineate a pathway by which dopaminergic loss induced by 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) is controlled <i>in vivo</i>. We reported previously that calpains play a central required role in dopamine loss after MPTP treatment. Here, we provide evidence that the downstream effector pathway of calpains is through cyclin-dependent kinase 5 (cdk5)-mediated modulation of the transcription factor myocyte enhancer factor 2 (MEF2). We show that MPTP-induced conversion of the cdk5 activator p35 to a pathogenic p25 form is dependent on calpain activity <i>in vivo</i>. In addition, p35 deficiency attenuates MPTP-induced dopamine neuron loss and behavioral outcome. Moreover, MEF2 is phosphorylated on Ser444, an inactivating site, after MPTP treatment. This phosphorylation is dependent on both calpain and p35 activity, consistent with the model that calpain-mediated activation of cdk5 results in phosphorylation of MEF2 <i>in vivo</i>. Finally, we provide evidence that MEF2 is critical for dopaminergic loss because “cdk5 phosphorylation site mutant” of MEF2D provides neuroprotection in an MPTP mouse model of PD. Together, these data indicate that calpain-p35-p25/cdk5-mediated inactivation of MEF2 plays a critical role in dopaminergic loss <i>in vivo</i>.
MEHRAN BLEEDING SCORE PREDICTS BLEEDING BUT NOT MORTALITY IN UNSELECTED REAL-WORLD PATIENTS UNDERGOING PRIMARY PCI FOR ST-ELEVATION ACUTE MYOCARDIAL INFARCTION
Authors: Arturo Ruben Vergara, Guido Parodi, Renato Valenti, Angela Migliorini, Guia Moschi, Nazario Carrabba, David Antoniucci
Journal: Journal of the American College of Cardiology (2011)
Alloplasty in Surgery of the Eye
Authors: William Stone
Journal: New England Journal of Medicine (1958)

Lid SurgeryIf the levator of the upper lid is functioning, a ptosis is usually corrected by one of several lid-shortening procedures. If there is partial or complete paresis of the levator, the frontalis muscle can be made to replace levator action. The tarsus is usually attached to the frontalis muscle by various substances. The most popular is fascia lata.22 However, this requires two operative sites and is a fairly long procedure. Buried, braided, waxed silk can also be used for this purpose. The sutures pass under the skin from the free border of the eyelid upward to above the . . .
Alveolar Macrophage Dysfunction and Chronic Alcohol Use. Time to Think about Zinc
Authors: William J. Janssen
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

As the resident professional phagocyte in the lungs, the alveolar macrophage plays a central role in the maintenance of alveolar homeostasis, lung host defense, and immune regulation. During health, the alveolar macrophage operates both as an antiinflammatory effector cell that silently removes particulate debris and microbial organisms from the air spaces, and as a sentinel that initiates inflammatory responses when host defense systems are overwhelmed. During inflammation the role of the alveolar macrophage further expands to include clearance of apoptotic cells from sites of injury and initiation of antiinflammatory and tissue repair programs. A growing body of evidence suggests that chronic ingestion of alcohol impairs many of these essential functions, including phagocytosis of bacteria and ingestion of apoptotic cells. It is therefore not surprising that chronic alcohol use places individuals at increased risk for pneumonia and development of acute respiratory distress syndrome (ARDS) (1, 2). In this issue of the Journal, Mehta and colleagues (pp. 716–723) add to their previous work on alcohol-related lung disease by systematically characterizing alveolar macrophages isolated from individuals with alcohol use disorder and carefully matched control subjects (3). In doing so, they highlight important mechanisms that underpin alveolar macrophage dysfunction in the alcoholic lung. These include intracellular zinc deficiency, altered redox state, and impaired signaling through the granulocyte–monocyte colony–stimulating factor (GM-CSF) receptor.
Impaired Protein Stability of 11β-Hydroxysteroid Dehydrogenase Type 2
Authors: Atanas G. Atanasov, Irena D. Ignatova, Lyubomir G. Nashev, Bernhard Dick, Paolo Ferrari, Felix J. Frey, Alex Odermatt
Journal: Journal of the American Society of Nephrology (2007)

Apparent mineralocorticoid excess (AME) is a severe form of hypertension that is caused by impaired activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts biologically active cortisol into inactive cortisone. Mutations in HSD11B2 result in cortisol-induced activation of mineralocorticoid receptors and cause hypertension with hypokalemia, metabolic alkalosis, and suppressed circulating renin and aldosterone concentrations. This study uncovered the first patient with AME who was described in the literature, identified the genetic defect in HSD11B2, and provided evidence for a novel mechanism of reduced 11beta-HSD2 activity. This study identified a cluster of amino acids (335 to 339) in the C-terminus of 11beta-HSD2 that are essential for protein stability. The cluster includes Tyr(338), which is mutated in the index patient, and Arg(335) and Arg(337), previously reported to be mutated in hypertensive patients. It was found that wild-type 11beta-HSD2 is a relatively stable enzyme with a half-life of 21 h, whereas that of Tyr(338)His and Arg(337)His was 3 and 4 h, respectively. Enzymatic activity of Tyr(338)His was partially retained at 26 degrees C or in the presence of the chemical chaperones glycerol and dexamethasone, indicating thermodynamic instability and misfolding. The results provide evidence that the degradation of both misfolded mutant Tyr(338)His and wild-type 11beta-HSD2 occurs through the proteasome pathway. Therefore, impaired 11beta-HSD2 protein stability rather than reduced gene expression or loss of catalytic activity seems to be responsible for the development of hypertension in some individuals with AME.
Aseptic Peritonitis Revealed Through Recurrent Catheter Obstructions in Type 1 Diabetic Patients Treated with Continuous Peritoneal Insulin Infusion
Authors: Eric Renard, Isabelle Raingeard, Guy Costalat, Dominique Apostol, Dominique Lauton, Françoise Boulet, Jacques Bringer
Journal: Diabetes Care (2004)

Reiterated catheter obstructions thwart improved diabetes control with continuous peritoneal insulin infusion (CPII) from implantable pumps (1). Occlusions, from either fibrin clots or omental encapsulations, are promoted by CPII and diabetes duration and insulin instability (2,3). Pathological analysis of encapsulation tissues disclosed, among predominant collagen fibrosis, inflammatory reactions, including lymphocytes and amyloid-like deposits reacting to anti-insulin antibodies, surrounded by histiocytes or giant cells (2). However, catheter obstructions were not related to high plasma anti-insulin antibody levels (4,5). Enhanced migration toward insulin and the chemotactic peptide formyl-methionyl-leucyl-phenylalanine of monocyte-issued macrophages from three patients with previous catheter encapsulations suggested that higher macrophage chemotaxis might promote these events (5). We report two unique observations of …
Letter: Fetomaternal haemorrhage and fetofetal transfusion syndrome.
Authors: E Bryan, B Slavin
Journal: BMJ (1976)

Vitamin C and the common cold SIR,-Some of the trial evidence to which you refer' in your leading article (13 March, p 606) was subsequently discussed.2 3Repetition of the trial4 demonstrated that vitamin C administration produces a significant bene- ficial effect on cold symptoms induced by intranasal instillation of the common cold virus.)You discuss our trial in schoolchildren'i and comment on the criticisms of Dykes and Meier.They drew our attention to an error of transcription in table I of our paper.'iThe mean i standard error of the symptom intensity of catarrhal colds in bovs who were receiving placebo tablets was 0 31 + 0 09, not 0 18 + 0 05.This provides a t value of -096 as stated in our table.The description of our trial was also criticised in that we did not comment on the make-up of the placebo or provide any evidence on the maintenance of double-blind conditions.We described these details fully in another paper to which reference was given."White tablets, identical in colour, taste, and consistency, were provided as active and dummy tablets to the students.During the trial it was never suggested by the students to the school matrons that the tablets differed in any way from each other.The school matrons who administered the tablets were unaware that they differed in formulation.The trial was therefore fully double-blind with respect to both tablet constitution and administration.Results obtained from pro- phylactic trials on the effect of vitamin C on common cold symptoms indicate that daily administration of vitamin C within the dose range 200-2000 mg exerts a significant effect against the common cold.The evidence from these and other recent trials which you omit to mention was reviewed last year.5When vitamin C is used for cold prophylaxis the raised ascorbic acid tissue concentrations during periods of normal health may induce greater tissue utilisation of the vitamin, thus
Impact of macrophage infiltration of skin lesions on survival after allogeneic stem cell transplantation: a clue to refractory graft-versus-host disease
Authors: Satoshi Nishiwaki, Seitaro Terakura, Masafumi Ito, Tatsunori Goto, Aika Seto, Keisuke Watanabe, Mayumi Yanagisawa, Nobuhiko Imahashi, Shokichi Tsukamoto, Makoto Shimba, Yukiyasu Ozawa, Koichi Miyamura
Journal: Blood (2009)
Eomesodermin Controls Interleukin-5 Production in Memory T Helper 2 Cells through Inhibition of Activity of the Transcription Factor GATA3
Authors: Yusuke Endo, Chiaki Iwamura, Makoto Kuwahara, Akane Suzuki, Kaoru Sugaya, Damon J. Tumes, Koji Tokoyoda, Hiroyuki Hosokawa, Masakatsu Yamashita, Toshinori Nakayama
Journal: Immunity (2011)
Brown backtracks on promise to allow local authorities to ban 24 hour drinking
Authors: C. Dyer
Journal: BMJ (2009)

The UK government has dropped proposed powers for local councils to ban 24 hour drinking, outlaw “happy hour” promotions, and take other steps to tackle binge drinking.

The provisions have been dropped from the code on alcohol sales in the Policing and Crime Bill, only weeks after the prime minister, Gordon Brown, promised at the Labour Party conference that the government would give local authorities the power to ban 24 hour drinking.

The prime minister told the conference on 29 September, “No one has yet cracked the whole problem of a youth drinking culture. We …
Heparin Therapy for Heatstroke
Authors: SHLOMO SHIBOLET
Journal: Annals of Internal Medicine (1975)

Comments and Corrections1 June 1975Heparin Therapy for HeatstrokeSHLOMO SHIBOLET, M.D., ZVI FARFEL, M.D.SHLOMO SHIBOLET, M.D., ZVI FARFEL, M.D.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-82-6-857_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: In their letter Cornell and colleagues (1) express the view that disseminated intravascular dissemination rather than primary fibrinolysis contributes to the morbidity and mortality of heatstroke, and that consequently the early administration of heparin is advocated.We proposed that excessive body temperature, as implied by its term heatstroke, should be considered as the primary cause of its manifestations. Hence, heat damage to cells and enzymes should be expected to occur in all the body systems. Because of the time-intensity relation of the effects of physical agents, early and effective cooling off while preventing shivering with a "lytic...References1. CORNELL C, FEIN S, and REILLY B: Heparin therapy for heatstroke (letter). Ann Intern Med 81:702-703, 1974 LinkGoogle Scholar2. SHIBOLET S, COLL R, and GILAT T: Heatstroke: its clinical picture and mechanism in 36 cases. Q J Med 36:525-548, 1967 MedlineGoogle Scholar3. STEFANINI M and SPICER D: Hemostatic breakdown, fibrinolysis and acquired hemolytic anemia in a patient with fatal heatstroke: pathogenetic mechanisms. Am J Clin Pathol 55:180-186, 1971 CrossrefMedlineGoogle Scholar4. ROSENTHAL T, SHAPIRO Y, and SELIGSOHN U: Disseminated intravascular coagulation in experimental heatstroke. Thromb Diath Haemorrh 26:417-425, 1971 MedlineGoogle Scholar5. NANNINGA L and GUEST M: Activity pH relationship and Michaelis constants during activation of profibrinolysin and fibrinolysis. Thromb Diath Haemorrh 19:492-498, 1968 MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: SHLOMO SHIBOLET, M.D.; ZVI FARFEL, M.D.Affiliations: Heller Institute of Medical Research Chaim Sheba Medical Center Tel-Hashomer Israel PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited bySerum histones as biomarkers of the severity of heatstroke in dogsBlood coagulation and fibrinolysis in heat strokeHaemostasis in heat strokeHeat illnessHeat illness. II. Pathogenesis 1 June 1975Volume 82, Issue 6Page: 857-858KeywordsCellsEnzymesFibrinolysisHeparinMorbidityMortalityTemperature ePublished: 1 December 2008 Issue Published: 1 June 1975 PDF downloadLoading ...
Odds Ratio and Relative Risk
Authors: B.C. Williams
Journal: Annals of Internal Medicine (1989)

Letters and Corrections1 September 1989Odds Ratio and Relative RiskB.C. Williams, MD, MPHB.C. Williams, MD, MPHSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-111-5-444 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editor:Biomedical research is becoming sophisticated in applying the tools of epidemiology, but slips occasionally still occur. This was the case in the recent American College of Physicians position paper (1) on parenteral nutrition in patients receiving cancer chemotherapy. The effectiveness of parenteral nutrition was reported in terms of "odds ratios," defined as "the probability that patients receiving nutritional support will experience the outcome divided by the probability that control patients will experience the same outcome." This ratio of two probabilities is a relative risk (2), not an odds ratio. An odds ratio is exactly that—a ratio of...References1. . Parenteral nutrition in patients receiving cancer chemotherapy. Ann Intern Med. 1989;110:734-6. LinkGoogle Scholar2. Rothman K. Modern Epidemiology. Boston: Little, Brown, and Company; 1986:37. Google Scholar3. Schlesselman J. Case-control Studies: Design, Conduct, Analysis. New York: Oxford University Press; 1982:33. Google Scholar1. L'AbbeDetskyO'Rourke KA. Meta-analysis in clinical research. Ann Intern Med. 1987;107:224-33. LinkGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByEstimating Confidence intervals of Likelihood Ratios 1 September 1989Volume 111, Issue 5Page: 444-445KeywordsCancer chemotherapyEpidemiologyNutritionOdds ratioRelative risk Issue Published: 1 September 1989 PDF DownloadLoading ...
Malignant Progression and Blockade of Angiogenesis in a Murine Transgenic Model of Neuroblastoma
Authors: Louis Chesler, David D. Goldenberg, Isha T. Seales, Ronit Satchi-Fainaro, Matt Grimmer, Rodney Collins, Chris Struett, Kim N. Nguyen, Grace Kim, Tarik Tihan, Yun Bao, Rolf A. Brekken, Gabriele Bergers, Judah Folkman, William A. Weiss
Journal: Cancer Research (2007)

Abstract Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a well-established model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, α-SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described water-soluble HPMA copolymer–TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumor–microenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma. [Cancer Res 2007;67(19):9435–42]