tbuckley/cabot-search huggingface dataset:
Activation of Matrix Metalloproteinase-2 (MMP-2) by Membrane Type 1 Matrix Metalloproteinase through an Artificial Receptor for ProMMP-2 Generates Active MMP-2
Authors: Yuki Nishida, Hisashi Miyamori, Erik W. Thompson, Takahisa Takino, Yoshio Endo, Hiroshi Sato
Journal: Cancer Research (2008)

Abstract The suggested model for pro-matrix metalloproteinase-2 (proMMP-2) activation by membrane type 1 MMP (MT1-MMP) implicates the complex between MT1-MMP and tissue inhibitor of MMP-2 (TIMP-2) as a receptor for proMMP-2. To dissect this model and assess the pathologic significance of MMP-2 activation, an artificial receptor for proMMP-2 was created by replacing the signal sequence of TIMP-2 with cytoplasmic/transmembrane domain of type II transmembrane mosaic serine protease (MSP-T2). Unlike TIMP-2, MSP-T2 served as a receptor for proMMP-2 without inhibiting MT1-MMP, and generated TIMP-2–free active MMP-2 even at a low level of MT1-MMP. Thus, MSP-T2 did not affect direct cleavage of the substrate testican-1 by MT1-MMP, whereas TIMP-2 inhibited it even at the level that stimulates proMMP-2 processing. Expression of MSP-T2 in HT1080 cells enhanced MMP-2 activation by endogenous MT1-MMP and caused intensive hydrolysis of collagen gel. Expression of MSP-T2 in U87 glioma cells, which express a trace level of endogenous MT1-MMP, induced MMP-2 activation and enhanced cell-associated protease activity, activation of extracellular signal–regulated kinase, and metastatic ability into chick embryonic liver and lung. MT1-MMP can exert both maximum MMP-2 activation and direct cleavage of substrates with MSP-T2, which cannot be achieved with TIMP-2. These results suggest that MMP-2 activation by MT1-MMP potentially amplifies protease activity, and combination with direct cleavage of substrate causes effective tissue degradation and enhances tumor invasion and metastasis, which highlights the complex role of TIMP-2. MSP-T2 is a unique tool to analyze physiologic and pathologic roles of MMP-2 and MT1-MMP in comparison with TIMP-2. [Cancer Res 2008;68(21):9096–104]
DETERMINATION OF DIFFERENCES IN VIRULENCE OF STRAINS OF SALMONELLA TYPHOSA
Authors: H. C. Batson, Maurice Landy, Martha Brown
Journal: The Journal of Experimental Medicine (1950)

An investigation is reported of a comparison by three methods of the degree and certainty of differentiation of strains of S. typhosa of different virulence for mice. These methods were (a) intracerebral injection, (b) intraperitoneal injection of saline suspensions, and (c) intraperitoneal injection of mucin suspensions of the test organisms. With the strains of S. typhosa employed, differentiation was questionable by the intracerebral method, somewhat more marked by the intraperitoneal-saline suspension method, and most definite by the intraperitoneal-mucin suspension method. Differentiation of the strains employed was found to be independent of the presence or absence of Vi antigen and apparently was more dependent upon the method of testing than upon any known differences in biological characteristics of the organisms.
An unusual case of mediastinal mass due to Fonsecaea pedrosoi
Authors: N. Singh, R. Agarwal, D. Gupta, M. R. Shivaprakash, A. Chakrabarti
Journal: European Respiratory Journal (2006)

Phaeohyphomycosis is a disease caused by dematiaceous fungi. Here, the first culture-proven case of mediastinal mass due to Fonsecaea pedrosoi is reported. The patient was a 40-yr-old male who had presented with history of dyspnoea and dysphagia. Computed tomography of the chest disclosed a mediastinal mass. Cultures of a specimen from the mediastinum grew Fonsecaea pedrosoi . The patient received amphotericin B and itraconazole and showed a remarkable recovery. Repeat computed tomography revealed a reduction in the mediastinal mass. The case highlights the need for a high degree of clinical suspicion and appropriate histopathological and mycological examination of clinical specimens.
Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4<b>+</b> T cells
Authors: Karin Loré, Anna Smed-Sörensen, Jayanand Vasudevan, John R. Mascola, Richard A. Koup
Journal: The Journal of Experimental Medicine (2005)

Dendritic cells (DCs) are essential antigen-presenting cells for the induction of T cell immunity against pathogens such as human immunodeficiency virus (HIV)-1. At the same time, HIV-1 replication is strongly enhanced in DC–T cell clusters, potentially undermining this process. We found that immature CD123+ plasmacytoid DCs (PDCs) and CD11c+ myeloid DCs (MDCs) were susceptible to both a CCR5- and a CXCR4-using HIV-1 isolate in vitro and were able to efficiently transfer that infection to autologous CD4+ T cells. Soon after HIV-1 exposure, both PDCs and MDCs were able to transfer the virus to T cells in the absence of a productive infection. However, once a productive infection was established in the DCs, newly synthesized virus was predominantly spread to T cells. HIV-1 exposure of the MDCs and PDCs did not inhibit their ability to present cytomegalovirus (CMV) antigens and activate CMV-specific memory T cells. As a result, both PDCs and MDCs preferentially transmitted HIV-1 to the responding CMV antigen–specific CD4+ T cells rather than to nonresponding T cells. This suggests that the induction of antigen-specific T cell responses by DCs, a process crucial to immune defense, can lead to preferential HIV-1 infection and the deletion of responding CD4+ T cells.
8-Isoprostane as a marker of oxidative stress in nonsymptomatic cigarette smokers and COPD
Authors: V. L. Kinnula, H. Ilumets, M. Myllärniemi, A. Sovijärvi, P. Rytilä
Journal: European Respiratory Journal (2006)

8-Isoprostane is a potential in vivo marker for oxidant burden, but its usefulness in induced sputum of smokers and chronic obstructive pulmonary disease (COPD) has not been investigated. The current study investigated 58 subjects comprising 11 never-smokers, 11 ex-smokers, 13 healthy current smokers and 23 COPD with stage 0–III disease (according to the Global Initiative for Chronic Obstructive Lung Disease criteria). 8-Isoprostane was determined from induced sputum by enzyme immunoassay. Sputum 8-isoprostane levels were similar in the never-smokers and ex-smokers, but were elevated in the healthy smokers compared with nonsmokers, and in those with stage I–III COPD. Sputum 8-isoprostane levels could not differentiate nonsymptomatic smokers from those with Stage 0 COPD. There was a correlation between sputum 8-isoprostane level and lung function parameters (forced expiratory volume in one second/forced vital capacity and sputum neutrophils. In conclusion, sputum 8-isoprostane levels correlate with the severity of chronic obstructive pulmonary disease. However, they do not appear to differentiate healthy smokers from those who are at risk of developing chronic obstructive pulmonary disease (Global Initiative for Chronic Obstructive Lung Disease stage 0).
Exploratory Analysis of Early Toxicity of Sunitinib in Advanced Hepatocellular Carcinoma Patients: Kinetics and Potential Biomarker Value
Authors: Andrew X. Zhu, Dan G. Duda, Marek Ancukiewicz, Emmanuelle di Tomaso, Jeffrey W. Clark, Rebecca Miksad, Charles S. Fuchs, David P. Ryan, Rakesh K. Jain
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Sunitinib—a multitargeted tyrosine kinase inhibitor—can modulate circulating inflammatory factors in cancer patients that may be relevant for hepatocellular carcinoma (HCC) progression. However, a recent phase III study of sunitinib in HCC was halted due to its toxicity. Here, we studied the early kinetics of adverse events after sunitinib, and explored their association with circulating proteins and clinical outcome in advanced HCC in a single-arm phase II study. Experimental Design: Toxicity was evaluated every two weeks during the first cycle of therapy. Biomarker changes from baseline were tested after adjusting for multiple comparisons. Correlation between toxicities and overall survival (OS) or time-to-tumor progression (TTP) was evaluated in a Cox model using log-transformed levels or change in biomarkers, after stratifying by stage and adjusting for baseline level. Results: Myeloid and lymphoid blood cell counts decreased by 20% to 50% after sunitinib treatment (P &amp;lt; 0.05 for all). The extent of the early decrease in neutrophils and monocytes, and the development of nonhematologic toxicities (i.e., skin toxicities), were significantly associated with both OS and TTP (P &amp;lt; 0.05). Changes in circulating cells significantly associated with specific changes in plasma biomarkers (i.e., changes in platelets with changes in VEGF-C and soluble-VEGFR3; changes in neutrophils with changes in IL-8, TNF-α, and soluble-VEGFR2). Conclusions: The adverse effects of sunitinib, particularly on the hematopoietic system, may be rapid and appear directly related to its activity in HCC. This exploratory study suggests that early hematopoietic toxicities may potentially predict outcome in advanced HCC after sunitinib treatment. Clin Cancer Res; 17(4); 918–27. ©2010 AACR.
What is the Healthcare Commission trying to achieve?
Authors: D. Haslam
Journal: Journal of the Royal Society of Medicine (2006)

You know that you've heard of the Healthcare Commission, even if you aren't sure who or what it is.Typically described as an independent health watchdog, the Commission always seems to be in the news, usually for publishing headline-grabbing reports about such varied issues as hospital cleanliness, the state of outpatient departments, bullying, or problems with mental health services.If you are a clinician who is also involved in management, you will inevitably know a great deal more about the Healthcare Commission.You will be aware that in the past the Commission has published star ratings and performance ratings about NHS bodies, and is currently responsible for the Annual Health Check.But who, or what, is the Healthcare Commission, and what is it trying to achieve?Why does it matter to the average clinician?After all, we all have an apparent alphabet soup of organizations, all of whom seem to be watching our activities.The best known is obviously the GMC, but clinicians in England also may be aware of the NPSA, the NCAS, Monitor and NICE, for a start.Are they all simply quangos of little relevance to everyday practice, or increasingly important parts of medical practice?
Optimally tolerated dose of lapatinib in combination with docetaxel plus trastuzumab in first-line treatment of HER2-positive metastatic breast cancer
Authors: J. Crown, M.J. Kennedy, P. Tresca, M. Marty, M. Espie, H.A. Burris, M. DeSilvio, M.R. Lau, D. Kothari, K.M. Koch, V. Diéras
Journal: Annals of Oncology (2013)
Transcription signatures encoded by ultraconserved genomic regions in human prostate cancer
Authors: Robert S Hudson, Ming Yi, Natalia Volfovsky, Robyn L Prueitt, Dominic Esposito, Stefano Volinia, Chang-Gong Liu, Aaron J Schetter, Katrien Van Roosbroeck, Robert M Stephens, George A Calin, Carlo M Croce, Stefan Ambs
Journal: Molecular Cancer (2013)

Abstract Background Ultraconserved regions (UCR) are genomic segments of more than 200 base pairs that are evolutionarily conserved among mammalian species. They are thought to have functions as transcriptional enhancers and regulators of alternative splicing. Recently, it was shown that numerous RNAs are transcribed from these regions. These UCR-encoded transcripts (ucRNAs) were found to be expressed in a tissue- and disease-specific manner and may interfere with the function of other RNAs through RNA: RNA interactions. We hypothesized that ucRNAs have unidentified roles in the pathogenesis of human prostate cancer. In a pilot study, we examined ucRNA expression profiles in human prostate tumors. Methods Using a custom microarray with 962 probesets representing sense and antisense sequences for the 481 human UCRs, we examined ucRNA expression in resected, fresh-frozen human prostate tissues (57 tumors, 7 non-cancerous prostate tissues) and in cultured prostate cancer cells treated with either epigenetic drugs (the hypomethylating agent, 5-Aza 2 ′ deoxycytidine, and the histone deacetylase inhibitor, trichostatin A) or a synthetic androgen, R1881. Expression of selected ucRNAs was also assessed by qRT-PCR and NanoString®-based assays. Because ucRNAs may function as RNAs that target protein-coding genes through direct and inhibitory RNA: RNA interactions, computational analyses were applied to identify candidate ucRNA:mRNA binding pairs. Results We observed altered ucRNA expression in prostate cancer (e.g., uc.106+, uc.477+, uc.363 + A, uc.454 + A) and found that these ucRNAs were associated with cancer development, Gleason score, and extraprostatic extension after controlling for false discovery (false discovery rate &lt; 5% for many of the transcripts). We also identified several ucRNAs that were responsive to treatment with either epigenetic drugs or androgen (R1881). For example, experiments with LNCaP human prostate cancer cells showed that uc.287+ is induced by R1881 ( P &lt; 0.05) whereas uc.283 + A was up-regulated following treatment with combined 5-Aza 2 ′ deoxycytidine and trichostatin A ( P &lt; 0.05). Additional computational analyses predicted RNA loop-loop interactions of 302 different sense and antisense ucRNAs with 1058 different mRNAs, inferring possible functions of ucRNAs via direct interactions with mRNAs. Conclusions This first study of ucRNA expression in human prostate cancer indicates an altered transcript expression in the disease.
Diagnostic Implications of Elevated Levels of Smooth-Muscle Myosin Heavy-Chain Protein in Acute Aortic Dissection: The Smooth Muscle Myosin Heavy Chain Study
Authors: Toru Suzuki
Journal: Annals of Internal Medicine (2000)

A rapid 30-minute assay of circulating smooth-muscle myosin heavy-chain protein has been developed as a biochemical diagnostic tool for aortic dissection.To determine the sensitivity and specificity of this assay.Cross-sectional study.8 major cardiovascular centers in Japan.95 patients with acute aortic dissection, 48 patients with acute myocardial infarction, and 131 healthy volunteers.Levels of circulating smooth-muscle myosin heavy-chain protein.Patients with acute aortic dissection who presented within 3 hours after onset had elevated levels of circulating smooth-muscle myosin heavy-chain protein. In these patients, the assay had a sensitivity of 90.9%, a specificity of 98% compared with healthy volunteers, and a specificity of 83% compared with patients who had acute myocardial infarction; the clinical decision limit was 2.5 microgram/L. All patients with proximal lesions had elevated levels of smooth-muscle myosin heavy-chain protein, and only patients with distal lesions had decreased levels (<2.5 microgram/L).Levels of smooth-muscle myosin heavy-chain protein can be used to diagnose aortic dissection soon after symptom onset. The assay had the greatest diagnostic value in patients with proximal lesions.
Continuous Low-Level Vagus Nerve Stimulation Reduces Stellate Ganglion Nerve Activity and Paroxysmal Atrial Tachyarrhythmias in Ambulatory Canines
Authors: Mark J. Shen, Tetsuji Shinohara, Hyung-Wook Park, Kyle Frick, Daniel S. Ice, Eue-Keun Choi, Seongwook Han, Mitsunori Maruyama, Rahul Sharma, Changyu Shen, Michael C. Fishbein, Lan S. Chen, John C. Lopshire, Douglas P. Zipes, Shien-Fong Lin, Peng-Sheng Chen
Journal: Circulation (2011)

Background— We hypothesize that left-sided low-level vagus nerve stimulation (LL-VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. Methods and Results— We implanted a neurostimulator in 12 dogs to stimulate the left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activity, vagal nerve activities, and ECGs. Group 1 dogs (N=6) underwent 1 week of continuous LL-VNS. Group 2 dogs (N=6) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Integrated stellate ganglion nerve activity was significantly reduced during LL-VNS (7.8 mV/s; 95% confidence interval [CI] 6.94 to 8.66 versus 9.4 mV/s [95% CI, 8.5 to 10.3] at baseline; P =0.033) in group 1. The reduction was most apparent at 8 am , along with a significantly reduced heart rate ( P =0.008). Left-sided low-level vagus nerve stimulation did not change vagal nerve activity. The density of tyrosine hydroxylase–positive nerves in the left stellate ganglion 1 week after cessation of LL-VNS were 99 684 μm 2 /mm 2 (95% CI, 28 850 to 170 517) in LL-VNS dogs and 186 561 μm 2 /mm 2 (95% CI, 154 956 to 218 166; P =0.008) in normal dogs. In group 2, the frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were 1.4/d (95% CI, 0.5 to 5.1) and 8.0/d (95% CI, 5.3 to 12.0), respectively, significantly lower than during sham stimulation (9.2/d [95% CI, 5.3 to 13.1]; P =0.001 and 22.0/d [95% CI, 19.1 to 25.5], P &lt;0.001, respectively). Conclusions— Left-sided low-level vagus nerve stimulation suppresses stellate ganglion nerve activities and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident 1 week after cessation of continuous LL-VNS.
AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis
Authors: Motoshi Ichikawa, Takashi Asai, Toshiki Saito, Go Yamamoto, Sachiko Seo, Ieharu Yamazaki, Tetsuya Yamagata, Kinuko Mitani, Shigeru Chiba, Hisamaru Hirai, Seishi Ogawa, Mineo Kurokawa
Journal: Nature Medicine (2004)
THE NEUROTIC COMPONENT OF NARCOLEPSY
Authors: ALAN L. MORGENSTERN
Journal: American Journal of Psychiatry (1965)

The psychogenic fraction of narcolepsy is centered about unacceptable impulses and defenses they provoke. In cataplexy episodes, sexual and aggressive actions and fantasies are blocked on a neuromuscular level. A sleep attack is far more complicated and some aspects may be compared to a classical psychoneurosis because the symptom provides not only defense but simultaneous disguised gratification of a wish. A 30-year-old aviator with narcolepsy was found to have an hysterical character disorder. The case is discussed in detail and psychological test data are presented. An abnormal nocturnal EEG typical of narcolepsy was obtained. The patient had the rare symptom of cataplexy at orgasm and abnormalities in the sexual life of narcoleptics are discussed.
Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors
Authors: J. Balmaña, N.M. Tung, S.J. Isakoff, B. Graña, P.D. Ryan, C. Saura, E.S. Lowe, P. Frewer, E. Winer, J. Baselga, J.E. Garber
Journal: Annals of Oncology (2014)
FURTHER OBSERVATIONS ON THE USE OF PNEUMOCOCCUS EXTRACTS IN EFFECTING TRANSFORMATION OF TYPE IN VITRO
Authors: J. Lionel Alloway
Journal: The Journal of Experimental Medicine (1933)

Pneumococcus extracts highly active in inducing the in vitro transformation of the specific types of Pneumococcus have been prepared by dissolving S cells with sodium desoxycholate, precipitating the dissolved material in alcohol in which the bile salt remains soluble, and extracting the precipitate in salt solution. Further purification of these active extracts has been attained by the removal of considerable inactive material by charcoal adsorption and by reprecipitation of the adsorbed extract in alcohol or acetone. The importance of using young cultures for extraction, and of preventing autolysis during the preparation of the extracts, is emphasized. Extracts prepared by the method described have been filtered through Berkefeld Candles (V, N, and W) without appreciable loss in activity, provided the reaction of the extract was slightly alkaline at the time of filtration. The purified and filtered extracts are water-clear, and sterile by rigid cultural and animal tests. They have been heated to temperatures of 60 degrees C. for 30 minutes without appreciable loss in their capacity to induce specific changes in type. And although they have generally shown definite decrease in potency after heating to temperatures above 80 degrees C., some extracts have been found active even after an exposure of 10 minutes to a temperature of 90 degrees C. They have been completely inactivated by boiling. Relatively small amounts of extract have been effective when added to a broth medium containing normal serum or serous fluid. In this medium, R pneumococci, irrespective of their type derivation, have developed and thereafter retained all the type-specific characteristics of the encapsulated S cells from which the extract was prepared. The specific action of the extracts is discussed with reference to their transforming and antigenic properties.
Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release
Authors: Moon-Taek Park, Min-Jung Kim, Young-Hee Kang, Soon-Young Choi, Jae-Hoon Lee, Jung-A Choi, Chang-Mo Kang, Chul-Koo Cho, Seongman Kang, Sangwoo Bae, Yun-Sil Lee, Hee Yong Chung, Su-Jae Lee
Journal: Blood (2004)
Alternaria as a major allergen for asthma in children raised in a desert environment.
Authors: M Halonen, D A Stern, A L Wright, L M Taussig, F D Martinez
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

The relationships of asthma and allergic rhinitis with individual immediate skin test responses were examined for preferential associations and for changes with age in children raised in a semiarid environment. Prevalence of physician-diagnosed asthma was 9.8% at age 6 (n = 948) and 15.5% at age 11 (n = 895). Immediate skin test responses to Bermuda grass were the most prevalent among children with allergic rhinitis and control subjects, whereas responses to the mold, Altenaria alternata, were the most prevalent among asthmatics. Skin test responses for crude house dust, Dermatophagoides farinae, and cat had low prevalences in all groups. By logistic regression, Alternaria was the only allergen independently associated with increased risk for asthma at both ages 6 and 11. Allergic rhinitis showed independent association with sensitization to Bermuda grass and mulberry tree pollen at age 11 but did not show an independent relation to any single allergen at age 6. Logistic regression further revealed that persistent asthma (diagnosed before age 6) was independently associated with Alternaria skin tests at both ages 6 and 11, whereas new asthma (diagnosed after age 6) was associated with Alternaria skin tests at age 6 but not at age 11. We conclude that Alternaria is the major allergen associated with the development of asthma in children raised in a semiarid environment and that skin test responses at age 6 are more closely linked to asthma than those at age 11.
Use of community treatment orders for mental health patients rises 29% in a year
Authors: A. O'Dowd
Journal: BMJ (2011)

The number of people with mental health problems subject to community treatment orders in England has risen by almost a third in the past year, according to the Care Quality Commission.

The commission’s second annual report on the use of the Mental Health Act in England, Monitoring the Mental Health Act in 2010/11, said the number of people subject to the act was 5% higher than in the previous year—rising from 19 947 on 31 March 2010 to 20 938 on 31 March 2011.

This was mostly because of the use of community treatment orders, which were introduced in November 2008 as a way of …