tbuckley/cabot-search huggingface dataset:
Reducing Stroke Rates in Patients With Atrial Fibrillation
Authors: Michael D. Ezekowitz, Meghashyam J. Koti, Brian Fulton
Journal: Circulation (2009)

S trokes related to atrial fibrillation tend to be large, life- threatening, and disabling.Multiple factors have synergistically led, over the past 20 years, to an impressive reduction in atrial fibrillation-related stroke rates.Comparisons of these rates between studies are estimates because definitions of stroke and primary end points among trials differ.However, patients assigned to placebo or usual therapy from clinical trials conducted in the late 1980s and early 1990s found approximate rates for patients with the equivalent of a CHADS2 score (an acronym for congestive heart failure, hypertension, age Ն75, diabetes mellitus, and prior stroke or transient ischemic attack) of 2 of Ϸ6% to 8%. 1,2A CHADS2 score of 2 is the approximate stroke risk of patients entered in current trials, including A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation/Atrial Flutter (ATHENA). 3nticoagulation with vitamin k antagonists has been the major contributor to the declining event rates; compared with placebo, vitamin k antagonists have reduced rates from 67% to 86% in completed trials, which translates into stroke rates of Ϸ1.4%/y. 4,5ovel anticoagulants designed to overcome the limitations of warfarin have been evaluated recently and have attained rates comparable to or slightly lower than coumadin, but at the price of either an increased incidence in major bleeding 6 or liver toxicity. 7,8In a recent trial of elderly subjects with atrial fibrillation, warfarin was superior to aspirin, 9 and in patients at intermediate to high risk for stroke, warfarin was superior to the combination of aspirin and clopidogrel with similar bleed rates. 10Thus, for time being, warfarin remains the only effective orally administered anticoagulant available.
Usefulness of 99mTc-Sestamibi Scintigraphy in Suggesting the Therapeutic Effect of Chemotherapy against Gastric Cancer
Authors: Kenji Kawata, Michiyuki Kanai, Tetsuro Sasada, Shingo Iwata, Naritaka Yamamoto, Arimichi Takabayashi
Journal: Clinical Cancer Research (2004)

Imaging with (99m)Tc-sestamibi ((99m)Tc-MIBI) has been used to assess 170-kDa P-glycoprotein (P-gp) expression and predict chemotherapy responses in several types of malignancy, such as breast and lung cancers. The purpose of this study was to evaluate the relationship between (99m)Tc-MIBI accumulation in tumors and sensitivity to chemotherapy in gastric cancer patients.Thirty-six patients with advanced gastric cancer underwent (99m)Tc-MIBI scintigraphy before chemotherapy. Patients also underwent endoscopic biopsy, and the expression of P-gp or multidrug resistance-associated protein was analyzed by immunohistochemical staining. The relationship between the accumulation of (99m)Tc-MIBI in tumors and responses to chemotherapy with 5-fluorouracil/cis-diamminedichloroplatinum(II) or epirubicin was examined.Higher accumulation of (9m)Tc-MIBI in tumors was observed in 25 and 23 of 36 gastric cancer patients at the early (30 min) and delayed (120 min) images, respectively. Accelerated accumulation of (99m)Tc-MIBI negatively correlates with increased expression of P-gp, but not of multidrug resistance-associated protein, as determined by immunohistochemistry in gastric cancer tissues. The response rate to 5-fluorouracil/cis-diamminedichloroplatinum(II) chemotherapy in patients with high (99m)Tc-MIBI accumulation (15.4%) was much lower than that in patients with low (99m)Tc-MIBI accumulation (54.5%). In contrast, patients with high (99m)Tc-MIBI accumulation show a higher response rate (41.7%) to chemotherapy with epirubicin, which is known to be a substrate of P-gp transporter.(99m)Tc-MIBI scintigraphy is useful to suggest the responses to chemotherapy of patients with advanced gastric cancer.
Focal adhesion kinase mediates MEF2 and c-Jun activation by stretch: Role in the activation of the cardiac hypertrophic genetic program
Authors: W NADRUZJR, M CORAT, T MARIN, G GUIMARAESPEREIRA, K FRANCHINI
Journal: Cardiovascular Research (2005)

We have previously reported that myocyte enhancer factor-2 (MEF2) transcription factors and c-Jun are rapidly activated by pressure overload and that these events are involved in the early activation of the myocardial hypertrophic genetic program. In this study, we investigated whether focal adhesion kinase (FAK) mediates the activation of MEF2 and c-Jun by mechanical stress in isolated neonatal rat ventricular myocytes (NRVMs).NRVMs were subjected to cyclic stretch up to 4 h and studied by immunoblotting, reverse transcriptase-polymerase chain reaction, laser confocal analysis, and reporter gene and electrophoretic mobility shift assays. Analysis was extended to NRVMs transfected with FAK-antisense oligodeoxynucleotide, treated with FAK/Src inhibitor PP2 or JNK/c-Jun inhibitor SP600125.Cyclic stretch increased c-Jun expression, JNK/c-Jun phosphorylation, and MEF2-DNA binding activity in NRVMs. Reporter gene assays indicated that the MEF2 site is critical to c-jun transcription in stretched cells. FAK-antisense transfection abolished MEF2 and c-jun promoter activation, while either FAK-antisense or PP2 treatment inhibited the stretch-induced c-Jun expression and JNK/c-Jun phosphorylation. Finally, treatment of NRVMs with the specific JNK/c-Jun inhibitor SP600125 significantly reduced the stretch-induced increase of atrial natriuretic factor promoter activity.The present data indicate that FAK regulates the activation of MEF2 and JNK/c-Jun pathways, which in turn have a key role in the early activation of the hypertrophic genetic program by mechanical stress in cardiac myocytes.
THE NF-κB AND IκB PROTEINS: New Discoveries and Insights
Authors: Albert S. Baldwin
Journal: Annual Review of Immunology (1996)

▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that explain mechanisms involved in the activation of NF-κB. In the nucleus, NF-κB dimers bind to target DNA elements and activate transcription of genes encoding proteins involved with immune or inflammation responses and with cell growth control. Recent data provide evidence that NF-κB is constitutively active in several cell types, potentially playing unexpected roles in regulation of gene expression. In addition to advances in describing the mechanisms of NF-κB activation, excitement in NF-κB research has been generated by the first report of a crystal structure for one form of NF-κB, the first gene knockout studies for different forms of NF-κB and of IκB, and the implications for therapies of diseases thought to involve the inappropriate activation of NF-κB.
A Systematic Approach to Defining the microRNA Landscape in Metastasis
Authors: Giridhar Mudduluru, Mohammed Abba, Jasmin Batliner, Nitin Patil, Maike Scharp, Taral R. Lunavat, Jörg Hendrik Leupold, Olga Oleksiuk, Dilafruz Juraeva, Wilko Thiele, Melanie Rothley, Axel Benner, Yinon Ben-Neriah, Jonathan Sleeman, Heike Allgayer
Journal: Cancer Research (2015)

The microRNA (miRNA) landscape changes during the progression of cancer. We defined a metastasis-associated miRNA landscape using a systematic approach. We profiled and validated miRNA and mRNA expression in a unique series of human colorectal metastasis tissues together with their matched primary tumors and corresponding normal tissues. We identified an exclusive miRNA signature that is differentially expressed in metastases. Three of these miRNAs were identified as key drivers of an EMT-regulating network acting though a number of novel targets. These targets include SIAH1, SETD2, ZEB2, and especially FOXN3, which we demonstrated for the first time as a direct transcriptional suppressor of N-cadherin. The modulation of N-cadherin expression had significant impact on migration, invasion, and metastasis in two different in vivo models. The significant deregulation of the miRNAs defining the network was confirmed in an independent patient set as well as in a database of diverse malignancies derived from more than 6,000 patients. Our data define a novel metastasis-orchestrating network based on systematic hypothesis generation from metastasis tissues.
Reversal of Drug Resistance in Breast Cancer Cells by Transglutaminase 2 Inhibition and Nuclear Factor-κB Inactivation
Authors: Dae-Seok Kim, Sung-Soo Park, Byung-Ho Nam, In-Hoo Kim, Soo-Youl Kim
Journal: Cancer Research (2006)

Abstract Induction of transglutaminase 2 (TGase 2) by epidermal growth factor (EGF) in human breast cancer cells increases their oncogenic potential and chemoresistance. The role of TGase 2 in the development of these tumor-related phenotypes remains to be elucidated, but it has been shown that expression of a dominant-negative form of TGase 2 reverses EGF-mediated chemoresistance in breast cancer cells. We examined several different breast cancer cell lines, representing both EGF receptor (EGFR)-positive and EGFR-negative breast cancers, and found that doxorubicin-resistant cells had a higher level of TGase 2 compared with doxorubicin-sensitive cells independent of the EGFR expression level. TGase 2 inhibition increased the chemosensitivity of drug-resistant cells, concomitant with a decrease in nuclear factor-κB (NF-κB) activity. Increasing the level of TGase 2 in drug-sensitive cells by transient transfection reduced the level of inhibitory subunit α of NF-κB (IκBα) and increased NF-κB activity in these cells. Inhibition of TGase 2 in drug-resistant cells by RNA interference increased the levels of IκBα, and this correlated with a shift in the accumulation of NF-κB from the nucleus to the cytosol. We recently showed that TGase 2 activated NF-κB through polymerization and depletion of free IκBα during inflammation. Therefore, increased expression of TGase 2 and subsequent activation of NF-κB may contribute to drug resistance in breast cancer cells independently of EGF signaling. (Cancer Res 2006; 66(22): 10936-43)
Monaco 2011: IOC commitment moves injury prevention to centre stage
Authors: Roald Bahr
Journal: British Journal of Sports Medicine (2011)

In June 2008, the International Olympic Committee (IOC) Medical Commission Chairman, Professor Arne Ljungqvist, wrote a BJSM editorial related to the 2nd World Congress on Sports Injury Prevention.1 In this, he announced their intentions to organise a 3rd World Congress on ‘prevention of sports-related injuries and disorders’ under the auspices of the IOC in 2011. This is now reality. The IOC World Conference on Prevention of Injury and Illness in Sport takes place in Monaco, 7–9 April 2011, and in this issue you can enjoy the conference abstracts ( see page 310 ).

The inaugural World Congress on Sports Injury Prevention was organised by the Oslo Sports Trauma Research Centre at the Holmenkollen Park Hotel in Oslo, Norway, in June 2005. During three beautiful midsummer days, more than 500 delegates gathered for the first time to focus on how sports injuries may be prevented. This was a hallmark event, signifying a significant shift in interest from a treatment focus towards prevention.

Three years later the second congress attracted over 700 participants from 55 counties, this time in Tromso, Norway. Although the weather well above the Arctic Circle was somewhat cooler, the second congress followed the successful format of the first, with a multidisciplinary perspective on sports injury prevention. The congress had been firmly established as a venue for scientists and practitioners to share new research and discuss the potential for prevention across injury types …
Murine B cell proliferation and protection from apoptosis with an antibody against a 105-kD molecule: unresponsiveness of X-linked immunodeficient B cells.
Authors: K Miyake, Y Yamashita, Y Hitoshi, K Takatsu, M Kimoto
Journal: The Journal of Experimental Medicine (1994)

We established a novel monoclonal antibody, RP/14, that can protect B cells from apoptosis induced by irradiation or dexamethasone. A molecule recognized by RP/14 (the RP antigen) was expressed on B cells with B220bright, IgMdull, and IgDbright. Immunoprecipitation experiments revealed that RP/14 recognized a monomeric protein with an approximate molecular mass of 105 kD. Stimulation of B cells with RP/14 for 48 h induced B cell proliferation and blastogenesis. In contrast to B cells of wild-type mice, X-linked immunodeficient (XID) B cells did not proliferate upon stimulation with RP/14, although the RP antigen was expressed to the same extent as that of wild-type B cells. These results suggest that the RP antigen-mediated signaling pathway is important for rescuing B cells from apoptosis and is deficient in XID B cells.
Beyond dopamine: The noradrenergic system and mental effort
Authors: Nicholas J. Malecek, Russell A. Poldrack
Journal: Behavioral and Brain Sciences (2013)

Abstract An opportunity cost model of effort requires flexible integration of valuation and self-control systems. Reciprocal connections between these networks and brainstem neuromodulatory systems are likely to provide the signals that affect subsequent persistence or failure when faced with effort challenges. The interaction of these systems should be taken into account to strengthen a normative neural model of effort.
Active and latent forms of transforming growth factor beta activity in synovial effusions.
Authors: R Fava, N Olsen, J Keski-Oja, H Moses, T Pincus
Journal: The Journal of Experimental Medicine (1989)

We have evaluated the possible involvement of TGF-beta in rheumatoid arthritis by assay of 16 cell-free synovial fluids for the presence of its active and "latent" forms. Evidence has been obtained for TGF-beta-like activity in synovial effusions by four criteria: (a) TGF-beta receptor competition, (b) soft-agar colony formation of AKR-2B and NRK-49F indicator cells, (c) immunological neutralization of the biological activity, and (d) biochemical activation of a latent form.
Suppressor of Cytokine Signaling 3 Sensitizes Anaplastic Thyroid Cancer to Standard Chemotherapy
Authors: Maria Giovanna Francipane, Vincenzo Eterno, Valentina Spina, Miriam Bini, Gregorio Scerrino, Giuseppe Buscemi, Gaspare Gulotta, Matilde Todaro, Francesco Dieli, Ruggero De Maria, Giorgio Stassi
Journal: Cancer Research (2009)

Abstract We previously showed that cancer cells from papillary, follicular, and anaplastic thyroid carcinomas produce interleukin-4 and interleukin-10, which counteract the cytotoxic activity of conventional chemotherapy through the up-regulation of antiapoptotic molecules. Here, we identify Janus kinase/signal transducers and activators of transcription (STAT) and phosphatidyl inositol 3-kinase (PI3K)/AKT as the down-stream pathways through which these cytokines confer resistance to cell death in thyroid cancer. We found that the absence of suppressors of cytokine signaling (SOCS) molecules allows the propagation of the survival signaling. Exogenous expression of SOCS1, SOCS3, and SOCS5 in the highly aggressive anaplastic thyroid cancer cells reduces or abolishes STAT3 and 6 phosphorylation and PI3K/Akt pathway activation resulting in alteration in the balance of proapoptotic and antiapoptotic molecules and sensitization to chemotherapeutic drugs in vitro. Likewise, exogenous expression of SOCS3 significantly reduces tumor growth and potently enhances the efficacy of chemotherapy in vivo. Our results indicate that SOCS3 regulation of cytokines-prosurvival programs might represent a new strategy to overcome the resistance to chemotherapy-induced cell death of thyroid cancer. [Cancer Res 2009;69(15):6141–8]
Distinct Effects of Ionizing Radiation on <i>In vivo</i> Murine Kidney and Brain Normal Tissue Gene Expression
Authors: Weiling Zhao, Eric Y. Chuang, Mark Mishra, Rania Awwad, Kheem Bisht, Lunching Sun, Phuongmai Nguyen, J. Daniel Pennington, Tony Jau Cheng Wang, C. Matthew Bradbury, Lei Huang, Zhijun Chen, Gil Bar-Sela, Michael E.C. Robbins, David Gius
Journal: Clinical Cancer Research (2006)

Abstract Purpose: There is a growing awareness that radiation-induced normal tissue injury in late-responding organs, such as the brain, kidney, and lung, involves complex and dynamic responses between multiple cell types that not only lead to targeted cell death but also acute and chronic alterations in cell function. The specific genes involved in the acute and chronic responses of these late-responding normal tissues remain ill defined; understanding these changes is critical to understanding the mechanism of organ damage. As such, the aim of the present study was to identify candidate genes involved in the development of radiation injury in the murine kidney and brain using microarray analysis. Experimental Design: A multimodality experimental approach combined with a comprehensive expression analysis was done to determine changes in normal murine tissue gene expression at 8 and 24 hours after irradiation. Results: A comparison of the gene expression patterns in normal mouse kidney and brain was strikingly different. This observation was surprising because it has been long assumed that the changes in irradiation-induced gene expression in normal tissues are preprogrammed genetic changes that are not affected by tissue-specific origin. Conclusions: This study shows the potential of microarray analysis to identify gene expression changes in irradiated normal tissue cells and suggests how normal cells respond to the damaging effects of ionizing radiation is complex and markedly different in cells of differing origin.
Manual of Clinical Microbiology.
Journal: Annals of Internal Medicine (1980)

The 11th edition of the Manual of Clinical Microbiology continues to set the standard for state-of-the-science laboratory practices as the most authoritative reference in the field of clinical microbiology. This new edition presents the numerous microbial taxonomic changes and newer more powerful diagnostic approaches that have been developed since publication of the 10th edition. A collaborative team of editors and authors from around the world, all experienced practitioners, researchers, or public health experts, revised the Manual to include the latest applications of genomics and proteomics, producing an authoritative work of two volumes filled with current findings regarding infectious agents, leading-edge diagnostic methods, laboratory practices, and safety guidelines.
<i>PARD3</i> Inactivation in Lung Squamous Cell Carcinomas Impairs STAT3 and Promotes Malignant Invasion
Authors: Ester Bonastre, Sara Verdura, Ilse Zondervan, Federica Facchinetti, Sylvie Lantuejoul, Maria Dolores Chiara, Juan Pablo Rodrigo, Julian Carretero, Enric Condom, Agustin Vidal, David Sidransky, Alberto Villanueva, Luca Roz, Elisabeth Brambilla, Suvi Savola, Montse Sanchez-Cespedes
Journal: Cancer Research (2015)

Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis.
Group A streptococcal antigen-specific T lymphocytes in guttate psoriatic lesions
Authors: B.S. BAKER, S. BOKTH, A. POWLES, J.J. GARIOCH, H. LEWIS, H. VALDIMARSSON, L. FRY
Journal: British Journal of Dermatology (1993)

A strong association exists between guttate psoriasis and group A, beta-haemolytic streptococcal infections. To demonstrate the presence of streptococcal-specific T cells in psoriatic skin, T-cell lines (TLs) were established from biopsies of lesions from five patients with guttate psoriasis, and compared with TLs from five patients with eczema, five with lichen planus, two with pityriasis rosea and three with nickel contact dermatitis. TLs from purified protein derivative (PPD)-induced delayed hypersensitivity sites in three normal individuals were also studied. All five of the psoriatic TLs responded in a proliferation assay to heat-killed isolates of group A streptococci, compared with only one eczema, two lichen planus and one pityriasis rosea. The response of one nickel contact dermatitis and two PPD TLs to group A streptococci was markedly less than to nickel and PPD, respectively. One of the psoriatic TLs was cloned in the presence of type 5 streptococcal M protein. The nine clones obtained were all CD3+, CD4+, CD45RO+, TCR alpha, beta+, gamma, delta-. However, they were all unreactive with antibodies to TCR V beta 5, 6, 8 or 12. Eight of the nine clones reacted, to a varying extent, to one or two of three preparations of group A streptococci expressing different M proteins. The streptococcal response of four consistently reactive clones from this patient was HLA-DR-restricted and inhibited by anti-HLA-DR antibody in a dose-dependent manner. On stimulation these four clones secreted high levels of gamma-interferon and detectable levels of IL-2, IL-10 and granulocyte/macrophage colony stimulating factor (GM-CSF) depending upon the nature of the stimulus, but no IL-4 or TNF-alpha production was detected. This study has demonstrated, for the first time, that T lymphocytes specific for group A streptococcal antigens can be consistently isolated from guttate psoriatic lesions. The role of streptococcal-specific T cells in the pathogenesis of psoriasis remains to be determined.
Interpersonal Maneuvers of Manic Patients
Authors: DAVID S. JANOWSKY, M. KHALED EL-YOUSEF, JOHN M. DAVIS
Journal: American Journal of Psychiatry (1974)

Manic patients, excited schizoaffective patients, and agitated schizophrenic patients were rated using a "manic interpersonal interaction scale" that evaluated a number of interpersonal interactions including testing of limits, projection of responsibility, sensitivity to others' soft spots, attempts to divide staff, flattering behavior, and ability to evoke anger. Manic patients showed an elevation in each of these items; overall, elevations were greater than those of schizoaffective and schizophrenic patients. The intensity of the manic state also correlated with the degree of elevation of the manic interpersonal interaction scale scores.