tbuckley/cabot-search huggingface dataset:
AB0654 Survey of the Tolerance to the First Anti-TNF Therapy: Reasons for Discontinuation Including Loss of Efficacy and Adverse Effect of Different Anti-TNF Therapies (Data From Moscow Register):
Authors: A. Bochkova, O. Rumyantseva, E. Tukchova, E. Gubar, T. Dubinina, S. Krasnenko, S. Erdes
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Anti-TNF therapy has been proven highly effective in patients with spondyloarthritis, but about 30% of the patients developed secondary inefficacy or adverse effects (AE). <h3>Objectives</h3> Establishing the reasons and the frequency of discontinuation of different anti-TNF therapies in patients with axial SpA (axSpA) including ankylosing spondylitis (AS). <h3>Methods</h3> We reviewed 214 patients with axial SpA who were treated with the first anti-TNF therapy. The diagnoses were: ankylosing spondylitis -190 patients, nr-axSpA –25 patients. Clinical activity was measured by BASDAI at baseline before the 1st anti-TNF therapy. The 1st anti-TNF therapy was considered ineffective if BASDAI was &gt;4.0 during 3 months and CRP or RSE were above normal. We considered discontinuation due to AE (psoriasis de novo, drug hepatitis, tuberculosis). <h3>Results</h3> Patients were treated with infliximab (n-156), adalimumab (n-24), etanercept (n-32), golimumab (n– 2). Mean age, male/female, duration disease were comparable. At baseline clinical activity was not different in patients of different groups. AE incident rates were similar (infliximab, adalimumab, etanercept), but pulmonary tuberculosis and conversion of PPD skin test were observed only in the infliximab group. Loss of efficacy was observed reliably more frequently in treatment with monoclonal antibodies. <h3>Conclusions</h3> Failure of anti-TNF treatment was observed more frequently in monoclonal antibodies anti-TNF therapy. Pulmonary tuberculosis and conversion of PPD skin test were developed only in infliximab therapy. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4439
Abstract 2146: Role of apoptosis-inducing factor in the death of MDA-MB-231 breast carcinoma cells after DNA damage
Authors: Xiaoxing Feng, Yiran Zhou, David W. Koh
Journal: Cancer Research (2011)

Abstract Apoptosis-inducing factor (AIF) is a flavoprotein that plays a cytoprotective role within mitochondria and induces cell death when it translocates to the nucleus in response to apoptotic signals. The objective of this study was to pursue the relevance of AIF in cancer. We showed that AIF translocated to the nucleus and mediated caspase-independent cell death in MDA-MB-231 breast cancer cells following treatment with the DNA alkylating agent N-methyl-N’-nitro-N-nitrosoguanidine (MNNG). We utilized small interfering RNA (siRNA) to down-regulate AIF expression in various human cancer cell lines and mouse trophoblast stem (TS) cells. AIF levels were reduced approximately 90% compared to untransfected cells. Analysis of AIF levels after subcellular fractionations demonstrated that nuclear translocation was compromised in these AIF knockdown cells. FACS analysis showed that AIF knockdown protected MDA-MB-231 against apoptosis induced by the chemotherapeutic agent cyclophosphamide. Furthermore, siRNA knockdown of AIF increased MDA-MB-231 cell survival following UV radiation. Taken together, the results demonstrate a role for AIF in cancer cell death following radio- or chemotherapeutic treatments. Thus, the activation of AIF mediated cell death is a promising method to improve the treatment of breast cancer patients. This research was supported by funding from the American Cancer Society and the Pharmaceutical Research Manufacturers of America. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2146. doi:10.1158/1538-7445.AM2011-2146
Abstract 3025: Receptor tyrosine kinase ErbB2/HER2 translocates into mitochondria and regulates cellular metabolism.
Authors: Yan Ding, Zixing Liu, Shruti Desai, Lewis Pannell, Hong Yi, Elizabath Wright, Laurie Owen, Windy Dean-Colomb, Oystein Fodstad, Jianrong Lu, Ming Tan
Journal: Cancer Research (2013)

Abstract It is well accepted that ErbB2, an important oncoprotein, localizes on the plasma membrane as a receptor tyrosine kinase. This study describes a novel observation that ErbB2 localizes in mitochondria of multiple cancer cell lines and patient samples. We identified an endogenous mitochondrial targeting sequence in ErbB2 and found that ErbB2 translocates into mitochondria through the association with mtHSP70, a key player in the canonical mitochondrial protein importation pathway. Additionally, we observed that mitochondrial ErbB2 (mtErbB2) negatively regulates mitochondrial respiratory functions. Oxygen consumption and activities of complex I, II and IV of the mitochondrial electron transport chain were decreased in mtErbB2-overexpressing cells. Mitochondrial membrane potential and the cellular ATP level also were decreased by mtErbB2. In contrast, mtErbB2 enhanced cellular glycolysis. The translocation of ErbB2 and its impact on mitochondrial function are kinase dependent. Mitochondrial ErbB2 regulates the phosphorylation and activity of COX II and consequently the cytochrome c release and apoptosis. Additional studies showed that cancer cells with higher levels of mtErbB2 were more resistant to Trastuzumab and deletion of the mitochondrial targeting sequence of ErbB2 sensitized the cells to Trastuzumab. Our study provides a novel perspective on the metabolic regulatory functions of ErbB2 and reveals that mtErbB2 plays an important role in the regulation of cellular metabolism and cancer cell resistance to therapeutics. Since ErbB2 plays important roles in multiple organs and multiple types of cancers, the study may have broad impact on the fields of cancer biology. The work was supported by The Vincent F. Kilborn Jr. Cancer Research Foundation and National Institutes of Health Grant RO1CA149646. Citation Format: Yan Ding, Zixing Liu, Shruti Desai, Lewis Pannell, Hong Yi, Elizabath Wright, Laurie Owen, Windy Dean-Colomb, Oystein Fodstad, Jianrong Lu, Ming Tan. Receptor tyrosine kinase ErbB2/HER2 translocates into mitochondria and regulates cellular metabolism. [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 3025. doi:10.1158/1538-7445.AM2013-3025
GE-14 * TRANSCRIPTOMICPLASTICITYIS ASSOCIATED WITH THE TUMOR MICROENVIRONMENT IN GLIOBLASTOMA
Authors: X. Hu, H. Kim, S. Zheng, T. Mikkelsen, L. Scarpace, Q. Wang, K. Yoshihara, J. N. Weinstein, R. G. W. Verhaak
Journal: Neuro-Oncology (2014)

Transcriptional profiling has classified glioblastoma (GBM) into four subtypes, termed proneural, neural, classical, and mesenchymal, with different genomic characteristics. However, we observed that the across platform concordance of 130 GBM with expression profiles generated using RNA sequencing as well as Affymetrix U133A microarrays rate, was only 76%, suggesting lack of robustness. Redefined gene signatures to only include upregulated genes improved the concordance of classification from 76% to 86%. Integrating subtypes with genomic alterations verified previously observed associations, such as significant MYC, CDK4, and PDGFRA alterations in proneural and EGFR abnormalities in the classical subtype. Interestingly, we found that GBMs classified as mesenchymal showed significant reduction in tumor purity and a related increase in the proportion of stromal cells. Since GBM have frequently been described as undergoing a proneural-to-mesenchymal transition, we asked the question how these tumor-associated normal cells relate to GBM recurrence, and whether these are increased relative to their primary original tumor. To address this we analyzed RNA profiles from 45 pairs of primary-recurrent GBM, and we found that 20 of the 45 tumors retained their original subtype after treatment, 7 switched from one subtype to another, and the remaining 18 showed features of multiple subtypes including their original class. Three recurrent GBMs exclusively expressed the mesenchymal signature and were found to have increased levels of microglia relative to their primary counterparts. This confirmed that tumor microenvironment, including stromal cells and microglia, may play an integral role in shaping the mesenchymal signature. In conclusion, we have deconvoluted the "mesenchymal" subtype and its transition from other subtypes. Our new gene signatures led to more robust and accurate subtypes which highlighted the contribution of the tumor microenvironment to gliomagenesis.
Abstract 16855: Kruppel-Like Factor 5 is Implicated in the Etiology of Pulmonary Arterial Hypertension.
Authors: Veronique Levesque-Tremblay
Journal: Circulation (2010)

Similarly to cancer, pulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery smooth muscle cells (PASMCs) proliferation and decreased apoptosis. Those phenotypicaly alt...
Tips for a Physician in Getting the Right Job, Part XX
Authors: Jay A. Harolds
Journal: Clinical Nuclear Medicine (2014)

This article discusses a variety of important employment contract issues. This includes remuneration, fringe benefits, and time off. It also includes dispute resolution and the protection of assets and information. Several types of restrictive covenants are also discussed. This information should be useful to job seekers attempting to understand contracts. However, all employment contracts should be discussed with the job seeker’s attorney before signing it.
Abstract 349: PI3K inhibitor GDC-0941 synergizes with mTOR inhibitors by blocking negative feedback and causes distinct effects on signaling and apoptosis compared to a dual PI3K/mTOR inhibitor
Authors: Ulka Vijapurkar, Liliane Robillard, Lori S. Friedman, Marcia P. Belvin
Journal: Cancer Research (2010)

Abstract Background: The PI3K/Akt/mTOR pathway is deregulated in many cancers. and activation of Akt leads to the stimulation of cell survival and proliferation pathways. Akt activation also regulates mTOR to control cell growth in response to growth factors and nutrients. The PI3K pathway is therefore an attractive target for cancer therapy. Multiple targeted inhibitors of PI3K, mTOR and PI3K/mTOR are currently in clinical trials, whileTORC1 inhibitors including rapamycin and analogs are approved. In this study we assessed the consequence of the combination of a PI3K inhibitor, GDC-0941, plus a TORC1 or TORC1/2 inhibitor compared to dual PI3K/mTOR inhibitor, in cancer cell lines with different genetic backgrounds. Method: We analyzed the effects of PI3K, TORC1 or TORC1/2 inhibition alone or in combination on the viability, cell cycle profile and apoptosis of cancer cell lines with varying PI3K, PTEN, K-ras, and LKB status. Effects on signaling were analyzed by measuring the phosphorylation of signaling proteins by reverse phase protein array and other techniques. Effects on viability and apoptosis were assessed, along with a calculation of synergy for combinations. Results: Inhibition of PI3K with GDC-0941 or a dual PI3K/mTOR inhibitor inhibited proliferation of cancer cell lines and in certain tumor lines induced apoptosis. Treatment also resulted in the inactivation of downstream markers including pAKT, pPRAS40 and pS6. TORC1/2 inhibition resulted in a potent inhibition of pS6, however it had differential effects on phospho-AKT and survival proteins pBad and pGSK3b, likely due to the release of the negative feedback regulation. The signaling effects demonstrated by TORC1/2 inhibition also differed from TORC1 inhibition by rapamycin. Inhibition of mTOR resulted in a cytostatic response in all lines tested. Combination of PI3K and mTOR inhibitors (either TORC1 or TORC1/2) caused a significant decrease in cell viability, enhanced apoptosis and caused a greater, sustained knockdown of the signaling pathway. However, treatment with a dual PI3K/mTOR inhibitor led to slight but consistently lower levels of apoptosis than the combination of the separate agents. There were also differences in phosphoprotein status of some of the pathway components. Conclusion: Inhibiting multiple nodes within the same signaling pathway is synergistic and can be an effective strategy to enhance potency in cancer cells. However, combinations of selective targeted agents do not necessarily cause identical effects as a single molecule that inhibit multiple targets simultaneously. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 349.
Herpes-Simplex-Virus Encephalitis
Authors: William Leider, Robert L. Magoffin, Edwin H. Lennette, L. N. R. Leonards
Journal: New England Journal of Medicine (1965)

THE clinical manifestations of herpesvirus infection of the central nervous system are indistinguishable from those induced by many other infectious agents. Further characterization of this disease depends upon confirmation by virologic or histologic findings. In a three-year period (1961 to 1963) laboratory diagnosis of infection due to herpes-simplex virus was made in 52 patients with signs of Central-nervous-system disease, from whom specimens were submitted to the Viral and Rickettsial Disease Laboratory of the California State Department of Public Health. This paper describes the clinical course and follow-up findings in 18 of these cases that occurred in the San Francisco Bay . . .
Radiographs and aluminium: a pitfall for the unwary
Authors: D M Bradburn, H F Carr, I Renwick
Journal: BMJ (1994)

diagnostic of diabetes.Fasting estimations rely on patients' compliance.The formal oral glucose tolerance test has been criticised as "grossly overused in the clinical setting."'"Nevertheless, we recommend that an oral glucose tolerance test be used to confirm or refute a suspected diagnosis of diabetes in patients without symptoms.Diagnostic thresholds depend on whether whole blood or plasma glucose concentrations are being measured.'0In recent years many practices have compiled registers for several chronic diseases.We suggest that other registers may be similarly flawed, as has been shown for registers of hypertensive patients.'2Proto- cols for management of all chronic diseases should include formal criteria for entry to an appropriate register.
Abstract P4-06-05: NF-κB Upregulates β1-integrin via Increased Transcriptional Activity in Three-dimensional Culture: a Mechanism by which Malignant Breast Cells Acquire Radioresistance
Authors: KM Ahmed, H Zhang, CC Park
Journal: Cancer Research (2012)

Abstract The molecular mechanisms giving rise to tumor viability after therapeutic radiation remain elusive. We showed previously that β1-integrin is associated with enhanced cell survival of breast cancer cells after exposure to high dose ionizing radiation (IR). Recently, we discovered that a typical binding site for Nuclear factor-κB (NF-κB), a stress-sensitive heterodimeric transcription factor, was located in human β1-integrin promoter, which indicates that β1-integrin-mediated resistance to radiation may be functionally regulated by NF-κB. The aim of the present study was to investigate the relationship between NF-κB and β1-integrin pathways in radioprotection of malignant T4-2 breast cells in three-dimensional laminin-rich extracellular matrix (3D lrECM). We show that NF-κB is required for radiation-induced β1-integrin transactivation. Inhibition of NF-κB activity significantly reduced clonogenic survival with the inhibition of IR-induced total and phosphorylated (Thr 788/789) β1-integrins, correlated with increased DNA binding activity at the β1- integrin promoter. Treatment of T4-2 colonies with NF-κB activation inhibitor before IR resulted in a reduction of the size of colonies, associated with a decrease in proliferation and increase in apoptosis, indicating an increased susceptibility to IR. Further studies revealed that a direct interaction of β1-integrin with α5-integrin was highly induced, but not with NF-κB p65, in T4-2 cells surviving IR. These interactions were found to be oppositely regulated in radiosensitive S1 cells, suggesting that IR induces the formation of α5β1-integrin complexes leading to increased survival post-IR. Together these results provide the first evidence that NF-κB-induced β1-integrin transactivation is responsible for increased survival post IR in breast cancer. Since β1-integrin is shown to activate NF-κB, our data further suggest a loop-like β1-integrin–NF-κB–β1-integrin pathway in tumor radioresistance. This novel pathway may serve as an efficient drug target to re-sensitize radioresistant tumor cells. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-05.
A Clinical Trial of Amygdalin (Laetrile) in the Treatment of Human Cancer
Authors: Charles G. Moertel, Thomas R. Fleming, Joseph Rubin, Larry K. Kvols, Gregory Sarna, Robert Koch, Violante E. Currie, Charles W. Young, Stephen E. Jones, J. Paul Davignon
Journal: New England Journal of Medicine (1982)

One hundred seventy-eight patients with cancer were treated with amygdalin (Laetrile) plus a "metabolic therapy" program consisting of diet, enzymes, and vitamins. The great majority of these patients were in good general condition before treatment. None was totally disabled or in preterminal condition. One third had not received any previous chemotherapy. The pharmaceutical preparations of amygdalin, the dosage, and the schedule were representative of past and present Laetrile practice. No substantive benefit was observed in terms of cure, improvement or stabilization of cancer, improvement of symptoms related to cancer, or extension of life span. The hazards of amygdalin therapy were evidenced in several patients by symptoms of cyanide toxicity or by blood cyanide levels approaching the lethal range. Patients exposed to this agent should be instructed about the danger of cyanide poisoning, and their blood cyanide levels should be carefully monitored. Amygdalin (Laetrile) is a toxic drug that is not effective as a cancer treatment.
Acetaminophen for Fever in Critically Ill Patients with Suspected Infection
Authors: Paul Young, Manoj Saxena, Rinaldo Bellomo, Ross Freebairn, Naomi Hammond, Frank van Haren, Mark Holliday, Seton Henderson, Diane Mackle, Colin McArthur, Shay McGuinness, John Myburgh, Mark Weatherall, Steve Webb, Richard Beasley
Journal: New England Journal of Medicine (2015)

Acetaminophen is a common therapy for fever in patients in the intensive care unit (ICU) who have probable infection, but its effects are unknown.We randomly assigned 700 ICU patients with fever (body temperature, ≥38°C) and known or suspected infection to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. The primary outcome was ICU-free days (days alive and free from the need for intensive care) from randomization to day 28.The number of ICU-free days to day 28 did not differ significantly between the acetaminophen group and the placebo group: 23 days (interquartile range, 13 to 25) among patients assigned to acetaminophen and 22 days (interquartile range, 12 to 25) among patients assigned to placebo (Hodges-Lehmann estimate of absolute difference, 0 days; 96.2% confidence interval [CI], 0 to 1; P=0.07). A total of 55 of 345 patients in the acetaminophen group (15.9%) and 57 of 344 patients in the placebo group (16.6%) had died by day 90 (relative risk, 0.96; 95% CI, 0.66 to 1.39; P=0.84).Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days. (Funded by the Health Research Council of New Zealand and others; HEAT Australian New Zealand Clinical Trials Registry number, ACTRN12612000513819.).
The Cerebrospinal Fluid in Diabetic Ketoacidosis
Authors: John L. Ohman, Errol B. Marliss, Thomas T. Aoki, Choodapasetty S. Munichoodappa, Verinder V. Khanna, George P. Kozak
Journal: New England Journal of Medicine (1971)

Cerebrospinal fluid and blood were studied in six patients with ketoacidosis before and four to nine hours after treatment, when neurologic improvement began. Alkali was excluded from the treatment regimen. Initial spinal-fluid pH was normal or elevated in all patients and fell with therapy in four patients. Osmolality was significantly higher in cerebrospinal fluid than in blood before treatment; lactate was increased initially and did not change with therapy. The concentrations of keto acids and glucose were initially lower in cerebrospinal fluid than in blood and fell with treatment at a less rapid rate consistent with a slow equilibration with blood. It is speculated that bicarbonate therapy would aggravate the spinal-fluid acidosis and could interfere with clinical improvement. Also, the increased osmolality before therapy is viewed as reason for caution against the excessively rapid correction of blood hyperosmolality.
Epstein-Barr virus-associated early gastric cancer presenting as an elevated lesion
Authors: S. Yamamoto, T. Nishida, M. Tsujii, M. Kato, Y. Hayashi, J. Kondo, T. Inoue, T. Akasaka, T. Yamada, K. Watabe, T. Takehara
Journal: Endoscopy (2012)

We report a rare case of Epstein–Barr virus (EBV)-associated gastric carcinoma that presented as an elevated lesion and was treated by complete en-bloc resection using endoscopic submucosal dissection (ESD).
The polyphenols curcumin and resveratrol effectively block IL-1β and PMA-induced IL-6, IL-8 and VEGF-A expression in human rheumatoid synovial fibroblasts
Authors: B Kloesch, E Dietersdorfer, J Broell, H Kiener, G Steiner
Journal: Annals of the Rheumatic Diseases (2012)

<i>Abstract</i>. Passive Heymann nephritis (PHN) in rats is a model of human membranous nephropathy characterized by formation of subepithelial immune deposits in the glomerular capillary wall and complement activation. Oxygen radicals have been implicated in the subsequent glomerular damage which leads to proteinuria. This study examines the involvement of xanthine oxidase in this process. Xanthine oxidase activity was increased nearly twofold in glomeruli isolated 1 and 12 d after induction of PHN, and this was associated with increased glomerular superoxide anion generation. Analysis of glomerular samples by Northern and Western blotting revealed no quantitative changes in xanthine oxidoreductase expression in PHN, suggesting conversion of xanthine dehydrogenase to the oxidase form as the cause of increased activity. Treatment of rats with tungsten, an inhibitor of xanthine oxidase, before induction of PHN resulted in a marked decrease in glomerular xanthine oxidase activity and superoxide anion generation, and decreased proteinuria by 80% (day 12: 423 ± 245 mg/d in PHN <i>versus</i> 78 ± 53 mg/d in tungsten-treated PHN animals, <i>P</i> &lt; 0.01). These findings point to a pivotal role of xanthine oxidase in the pathophysiology of PHN and could be of importance in the therapy of human membranous nephropathy.
Interim estimates of 2018/19 vaccine effectiveness against influenza A(H1N1)pdm09, Canada, January 2019
Authors: Danuta M Skowronski, Siobhan Leir, Suzana Sabaiduc, Michelle Murti, James A Dickinson, Romy Olsha, Jonathan B Gubbay, Matthew A Croxen, Hugues Charest, Tracy Chan, Nathalie Bastien, Yan Li, Mel Krajden, Gaston De Serres
Journal: Eurosurveillance (2019)

Using a test-negative design, the Canadian Sentinel Practitioner Surveillance Network assessed interim 2018/19 vaccine effectiveness (VE) against predominant influenza A(H1N1)pdm09 viruses. Adjusted VE was 72% (95% confidence interval: 60 to 81) against medically attended, laboratory-confirmed influenza A(H1N1)pdm09 illness. This substantial vaccine protection was observed in all age groups, notably young children who appeared to be disproportionately affected. Sequence analysis identified heterogeneity in emerging clade 6B.1 viruses but no dominant drift variant.