tbuckley/cabot-search huggingface dataset:
Prognostic Value of CD40 in Adult Soft Tissue Sarcomas
Authors: Alessandro Ottaiano, Anna De Chiara, Francesco Perrone, Gerardo Botti, Flavio Fazioli, Vincenzo De Rosa, Nicola Mozzillo, Vincenzo Ravo, Brunello Morrica, Ciro Gallo, Carmela Pisano, Maria Napolitano, Paolo Antonio Ascierto, Rosario Vincenzo Iaffaioli, Gaetano Apice
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose is to evaluate the expression of CD40, a membrane protein predominantly expressed on B cells, dendritic cells, and macrophages, in a series of adult soft tissue sarcomas and to test its possible prognostic value. Experimental Design: CD40 expression was studied by immunohistochemistry. Correlations with other baseline characteristics of patients and tumors were analyzed with χ2 test. The prognostic value was studied with univariable and multivariable analysis adjusted by age, sex, tumor size, grade, location, and distant metastases. Results: Eighty-two patients, between January 1994 and May 2001, were analyzed. Membrane or cytoplasmic staining for CD40 protein was absent in 30% of the tumors but present in &amp;lt;10% of cells in 22 (27%), in 10% to 50% in 23 (28%), and in &amp;gt;50% of cells in 12 (15%) tumors. There was no correlation between CD40 expression and age, sex, size, grade, and location of the primary tumor and distant metastases. With 61 patients (74.4%) progressed and 31 (37.8%) dead, CD40 expression was a significant prognostic factor for disease-free and overall survival at univariable and multivariable analysis. Patients with tumors expressing CD40 in &amp;gt;50% of cells had a dramatically unfavorable prognosis with median disease-free and overall survival of 7 and 17 months, respectively, and hazard ratios of relapse and death as compared with patients with CD40-negative tumors of 2.89 (95% confidence interval: 1.26–6.60) and 6.92 (95% confidence interval: 2.18–22.0), respectively. Conclusions: These data suggest that expression of CD40 protein in &amp;gt;50% of cells might indicate an unfavorable prognosis in adult soft tissue sarcomas.
Postoperative analgesia--a comparison of two methods of administering morphine.
Authors: M E Dodson, G E Robson
Journal: BMJ (1981)

certain test which measures the risk of thrombosis."If he is referring to arterial (platelet aggre- gate) thrombosis, then surely measurement of platelet malonyldialdehyde (MDA) content is the test that is required,' particularly as MDA formation by platelets is known to be an index of thromboxane A, synthesis.Such a study is quoted in the review (reference 36).A fluori- metric technique is preferred.Of course, one can measure plasma fibri- nogen, fibrin monomer complexes, factor VIII antigen, ristocetin cofactor, sensitivity of the platelets to aggregation by ADP, and levels of 13-thromboglobulin and platelet factor 4, just to make life complicated.In the end it all comes back to free fatty acid levels,' which, as Nordoy has emphasised,3 determine how much arachidonic acid will follow the thromboxane- MDA-prostaglandin synthesis pathway.
Surveillance of whole lung lavage for autoimmune pulmonary alveolar proteinosis in Japan
Authors: Toshio Ichiwata, Shuji Oh-ishi, Kenji Uchida, Yoshikazu Inoue, Toru Arai, Haruyuki Ishii, Kou Nakata
Journal: European Respiratory Journal (2013)

Aims: Whole lung lavage (WLL) has been widely performed for the treatment of autoimmune pulmonary alveolar proteinosis (aPAP). However its procedures have not been exactly standardized. In order to understand the present status of WLL in Japan, we conducted the national surveillance.

Method: Questionnaires were sent to 211 institutions in Japan which had been registered as the database of our Japanese large cohort study of aPAP.

Result; 88 institutions answered the questionnaires, where 310 patients with aPAP have been treated. WLL was performed 220 times for 81 patients with 31 institutions. WLL was performed in less than 2 patients with 24/32 institutions and seven or more patients were only 3 institutions. PaO2 (RA) before the initial WLL was 61.7±12.5 Torr. Double lumen tubes for the left side was used in 18/30 institutions. The patients were placed in a lateral position, in which the washed lung was present on the inferior side with 28/30 institutions and in a dorsal position with 33% of institutions. Degassing was performed with 43.3% institutions. Saline at 37 ° was used for lavage in 63.6% institution. Lavage fluid was instilled by volume-controlled lavage method in 62.5%, and by pressure-controlled lavage method in 28.1% of institutions. Extracorporeal membrane oxygenation (ECMO) was used 21 times with 28.1% institutions. WLL was stopped by hypoxemia (n=6) and lavaged fluid leak in a non-washing lung (n=5).

Conclusion;The criteria for ECMO application, enforcement of degassing, the posture, the lavaged fluid, the infusion method were various.

Funding/Support; This study was supported by grant from Japanese Ministry of Health, Labour, and Welfare (H22-Nanchi-Ippan-146).
How low to aim in rheumatoid arthritis? Learning from other disciplines
Authors: Duncan Porter, James Dale, Naveed Sattar
Journal: Annals of the Rheumatic Diseases (2013)

Treat-to-target strategies have been widely adopted as the standard of care for the management of patients with rheumatoid arthritis. The concept of 'tight control' is prevalent in other disciplines, particularly in diabetes and cardiovascular risk management. In these disciplines, evidence has accumulated that the utility of tight control strategies must be carefully weighed against the disutility that may arise from multiple interventions, particularly in patients at low risk. There is a lively debate in rheumatology circles about whether treatment should be targeted at achieving low disease activity, clinical remission or imaging remission. As rheumatologists we should learn the lessons from other disciplines, and ensure that we expand the evidence base to ensure our recommendations are securely underpinned by robust evidence.
Initiation and adaptation: a paradigm for understanding psychotropic drug action
Authors: S E Hyman, E J Nestler
Journal: American Journal of Psychiatry (1996)

This article describes a paradigm--initiation and adaptation--within which to conceptualize the drug-induced neural plasticity that underlies the long-term actions of psychotropic drugs in the brain.Recent advances in neurobiology are reviewed.Recent developments in cellular and molecular neurobiology provide new conceptual and experimental tools for understanding the mechanisms by which psychotropic drugs produce long-lived alterations in brain function. Because of the availability of more robust animal models, the mechanisms by which drugs of abuse produce dependence are better understood than the mechanisms by which antidepressants, antipsychotics, and lithium produce their therapeutic effects. Nonetheless, the fundamental types of mechanisms appear to be similar: chronic drug administration drives the production of adaptations in postreceptor signaling pathways, including regulation of neural gene expression. Whether the results are deleterious or therapeutic depends on the precise neural systems targeted by a particular drug.Biological investigation in psychiatry has often focused too narrowly on synaptic pharmacology, especially on neurotransmitter turnover and neurotransmitter receptors. This review focuses on molecular and cellular changes in neural function that are produced as adaptations to chronic administration of addictive drugs such as psychostimulants and therapeutic drugs such as antidepressants. To understand normal brain function, psychopathology, and the actions of psychiatric treatments, and to exploit the eventual findings of psychiatric genetics, psychiatric research must now extend its efforts beyond the synapse, to an understanding of cellular and molecular neurobiology (in particular, postreceptor signal transduction) as well as to a better understanding of the architecture and function of neural systems. A paradigm is presented to help understand the long-term effects of psychotropic drugs, including the latency in onset of their therapeutic actions.
AMPK Mediates the Initiation of Kidney Disease Induced by a High-Fat Diet
Authors: Anne-Emilie Declèves, Anna V. Mathew, Robyn Cunard, Kumar Sharma
Journal: Journal of the American Society of Nephrology (2011)

The mechanisms underlying the association between obesity and progressive renal disease are not well understood. Exposure to a high-fat diet decreases levels of the cellular energy sensor AMPK in many organs, including the kidney, but whether AMPK contributes to the pathophysiology of kidney disease induced by a high-fat diet is unknown. In this study, we randomly assigned C57BL/6J mice to a standard or high-fat diet. After 1 week, mice fed a high-fat diet exhibited an increase in body weight, renal hypertrophy, an increase in urine H2O2 and urine MCP-1, and a decrease in circulating adiponectin levels and renal AMPK activity. Urine ACR progressively increased after 4 weeks of a high-fat diet. After 12 weeks, kidneys of mice fed a high-fat diet demonstrated a marked increase in markers of fibrosis and inflammation, and AMPK activity remained significantly suppressed. To determine whether inhibition of AMPK activity explained these renal effects, we administered an AMPK activator along with a high-fat diet for 1 week. Although AMPK activation did not abrogate the weight gain, it reduced the renal hypertrophy, urine H2O2, and urine and renal MCP-1. In vitro, AMPK activation completely inhibited the induction of MCP-1 by palmitic acid in mesangial cells. In conclusion, these data suggest that the energy sensor AMPK mediates the early renal effects of a high-fat diet.
Regulation of Insulin-like Growth Factor–Mammalian Target of Rapamycin Signaling by MicroRNA in Childhood Adrenocortical Tumors
Authors: Mabrouka Doghman, Abeer El Wakil, Bruno Cardinaud, Emilie Thomas, Jinling Wang, Wei Zhao, Maria Helena C. Peralta-Del Valle, Bonald C. Figueiredo, Gerard P. Zambetti, Enzo Lalli
Journal: Cancer Research (2010)

MicroRNAs (miRNAs) act at the posttranscriptional level to control gene expression in virtually every biological process, including oncogenesis. Here, we report the identification of a set of miRNAs that are differentially regulated in childhood adrenocortical tumors (ACT), including miR-99a and miR-100. Functional analysis of these miRNAs in ACT cell lines showed that they coordinately regulate expression of the insulin-like growth factor-mammalian target of rapamycin (mTOR)-raptor signaling pathway through binding sites in their 3'-untranslated regions. In these cells, the active Ser(2448)-phosphorylated form of mTOR is present only in mitotic cells in association with the mitotic spindle and midbody in the G(2)-M phases of the cell cycle. Pharmacologic inhibition of mTOR signaling by everolimus greatly reduces tumor cell growth in vitro and in vivo. Our results reveal a novel mechanism of regulation of mTOR signaling by miRNAs, and they lay the groundwork for clinical evaluation of drugs inhibiting the mTOR pathway for treatment of adrenocortical cancer.
A Simple Maneuver to Prevent Food-Choking
Authors: R. Kennedy Gilchrist
Journal: JAMA (1977)

To the Editor.—  Dr Heimlich's maneuver to dislodge a food particle causing lethal choking is no doubt effective (234:398, 1975). However, Dr Visintine's article documents one of the dangers of the method (234:415, 1975).  Before we could begin our surgical residency, Dr V. C. David required us to have three to six months of training in a contagious disease hospital. During the first three weeks of such training, I did 20 intubations for laryngeal diphtheria. As a result of this experience, it was obvious to me that fairly strong traction on the tongue will displace the larynx upward at least 2.5 cm (1 in). When the tongue is steadily pulled out, a finger of the other hand can easily reach the epiglottis.  Several years ago, my 80-year-old dinner partner had a piece of meat impacted, obstructing his airway. He had not yet lost consciousness. He was instructed to raise his index
A monoclonal T cell-replacing activity can act directly on B cells to enhance clonal expansion.
Authors: G D Wetzel, S L Swain, R W Dutton
Journal: The Journal of Experimental Medicine (1982)

We have used a B cell cloning system in which the response of a single isolated B cell to lipopolysaccharide and dextran sulfide can be followed. We have shown that culture supernatants from the Dennert long-term alloreactive T cell line C.C3.11.75 increase the frequency of B cells stimulated to clonal expansion by mitogens. These culture supernatants are devoid of interleukin 1 and 2 but contain the T cell-replacing factor activity (DL)TRF. These experiments provide unequivocal proof that a T cell-derived factor or factors can act directly on a B lymphocyte in the absence of any other cell.
Undesirable Implications of Disclosing Individual Genetic Results to Research Participants
Authors: Leslie A. Meltzer
Journal: The American Journal of Bioethics (2006)

Ravitsky and Wilfond (2006) correctly highlight the need for uniform guidelines to assist investigators and institutional review boards (IRBs) in determining whether to disclose individual genetic results to research participants. However, their results-evaluation framework, like other proposals that call for the disclosure of individual results to research participants (Partridge and Winer 2002; Rothstein 2006; Shalowitz and Miller 2005), is troublesome for two related reasons. First, their justification for disclosure rests on the mistaken view that principles of beneficence, respect, reciprocity, and/or justice ethically require researchers to offer participants individual genetic results. Whereas these principles and others obligate physicians to share individually relevant results with patients in the clinical care setting, they do not similarly obligate investigators to share such information with participants in the research setting. Second, because Ravitsky and Wilfond’s proposal conflates the aims of clinical research with those of clinical care, participants may suffer from a therapeutic or diagnostic misconception (Clayton and Ross 2006), researchers may be inclined to overstate the benefits of enrollment, and institutional review boards (IRBs) may face unforeseen difficulties in assessing trial risks and benefits. Beneficence, respect for persons, reciprocity, and justice are important components of ethical research, but none of these principles are violated or diminished when investigators do not share individual genetic results from research. Beneficence requires investigators to maximize possible benefits to participants and society at large while minimizing possible harms. Whether a clinical trial meets the requirement of beneficence is determined ab initio by an IRB before any participants are enrolled. At this stage of review, an IRB cannot weigh the possibility that some participants may gain individually useful results from participation. There is no guarantee that any given trial will produce such results. In contrast, if a study does generate individual information, it may apply only to participants with certain genomic characteristics. And even in this case it is not possible to determine whether a given participant will perceive the information as a benefit or harm once confronted with it. Because a clinical trial must meet the requirements of beneficence regardless of whether it returns individual research results, it cannot be the case that beneficence requires investigators to offer results.
Effects of strontium ranelate on spinal osteoarthritis progression
Authors: O Bruyere, D Delferriere, C Roux, J D Wark, T Spector, J-P Devogelaer, K Brixen, S Adami, J Fechtenbaum, S Kolta, J-Y Reginster
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> The aim of this study was to determine whether a 3-year treatment with strontium ranelate could delay the progression of spinal osteoarthritis (OA). <h3>Methods:</h3> This study was a post-hoc analysis of pooled data from the Spinal Osteoporosis Therapeutic Intervention (SOTI) and TReatment Of Peripheral OSteoporosis (TROPOS) trials performed on 1105 women with osteoporosis and concomitant radiological spinal OA at baseline, and for whom lumbar <i>x</i>-rays were available at baseline and over the 3-year treatment period. The presence and severity of osteophytes, disc space narrowing and sclerosis in the lumbar intervertebral spaces was graded according to a validated method, and an overall OA score was calculated for each intervertebral space. Back pain (measured on a five-point Likert scale only in SOTI) and health-related quality of life (SF-36 questionnaire) were assessed at baseline and after 3 years. Patients who suffered an incident or progressive vertebral fracture during the study were excluded from the analysis. <h3>Results:</h3> The proportion of patients with worsening overall spinal OA score was reduced by 42% in the strontium ranelate group, compared with placebo (RR, 0.58; 95% CI, 0.42 to 0.79; p = 0.0005). Significantly more patients in the strontium ranelate group experienced an improvement in back pain after 3 years, compared with placebo (p = 0.03), while no significant difference was observed in terms of health-related quality of life between these patient groups. <h3>Conclusions:</h3> The results of this post-hoc analysis suggest that strontium ranelate could reduce the progression of the radiographic features of spinal OA and back pain in women with osteoporosis and prevalent spinal OA.
p21Waf1/Cip1/Sdi1 mediates shear stress-dependent antiapoptotic function
Authors: Stefania Mattiussi, Paolo Turrini, Lucia Testolin, Fabio Martelli, Germana Zaccagnini, Antonella Mangoni, Laura M Barlucchi, Annalisa Antonini, Barbara Illi, Corrado Cirielli, Julio Padron, Chiara Nicolò, Roberto Testi, Francesco Osculati, Paolo Biglioli, Maurizio C Capogrossi, Carlo Gaetano
Journal: Cardiovascular Research (2004)

The antiapoptotic effect of p21(Waf1/Cip1/Sdi1) (p21) was examined in human umbilical vein endothelial cells (HUVEC) exposed to laminar shear stress (SS) or to the nitric oxide donor sodium nitroprusside (SNP) and in a mouse model of hindlimb ischemia.In vitro: Cells were cultured without serum and in the presence of cobalt chloride to simulate hypoxia for 12 h (T0). Shear stress was applied to endothelial cells for additional 12 h. In vivo: Hindlimb ischemia was realized in mice by femoral artery ligation. SNP was acutely administered by subcutaneous injection or by Alzet osmotic pumps for a longer treatment.At T0, HUVEC were either exposed to SS (15 dyn/cm2/s(-1)), treated with SNP or kept in static condition (ST) for 1-12 h; after additional 12 h in ST, 30-35% of cells still alive at T0 had died. In this condition, both SS and SNP treatments markedly increased p21 levels and reduced apoptosis in HUVEC. Recombinant adenoviruses carrying p21 (AdCMV.p21) or antisense p21 (AdCMV.ASp21) cDNA revealed that AdCMV.p21-infected HUVEC were protected from death while AdCMV.ASp21 reduced SS- and SNP-dependent protection from apoptosis. In mice, apoptosis was detected in endothelial cells of ischemic hindlimbs as early as 8 h after femoral artery ligation. Treatment with SNP enhanced p21 expression and protected ischemic tissue from damage. Remarkably, direct in vivo injection of AdCMV.p21 significantly reduced the number of apoptotic nuclei in the presence of ischemia.The present study establishes that, under our experimental conditions, (a) p21 plays an important role in SS and nitric oxide antiapoptotic effect in vitro, and (b) p21 gene transfer prevents apoptosis in vitro and in vivo, following acute interruption of blood flow.
Frequent Immune Responses to a Cancer/Testis Antigen, CAGE, in Patients with Microsatellite instability–Positive Endometrial Cancer
Authors: Takashi Iwata, Tomonobu Fujita, Nobumaru Hirao, Yuriko Matsuzaki, Tsutomu Okada, Hiroshi Mochimaru, Nobuyuki Susumu, Eri Matsumoto, Kokichi Sugano, Naohide Yamashita, Shiro Nozawa, Yutaka Kawakami
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Identification of cancer/testis antigens useful for diagnosis or immunotherapy of cancers was attempted by cDNA expression cloning with patients' sera (SEREX). Experimental Design: cDNA expression libraries made from testis or endometrial cancer cell lines were screened using sera from patients with endometrial cancer or melanoma patients immunized with dendritic cells pulsed with autologous tum or lysates. Tissue-specific expression by RT-PCR and immunogenicity by Western blotting of the bacterial recombinant antigen with sera from cancer patients were evaluated. Results: A cancer/testis antigen, CAGE, was isolated by two independently performed SEREX. CAGE was expressed in various cancer cell lines including endometrial cancer, colon cancer, and melanoma in 7 of 10 endometrial cancer tissues and in 1 of 3 atypical endometrial hyperplasia, but not in normal tissues including the endometrium and testis. The protein expression on cancer cells was confirmed by Western blot analysis with the recombinant CAGE protein, anti-CAGE IgG antibody was detected in sera from 5 of 45 endometrial cancer, 2 of 24 melanoma, and 2 of 33 colon cancer patients, but not in sera from healthy individuals. By ELISA analysis, anti-CAGE antibody was detected in 12 of 45 endometrial cancer, 2 of 20 melanoma, and 4 of 33 colon cancer patients. Intriguingly, anti-CAGE antibody was highly positive in 7 of the 13 (53.8%) microsatellite instability (MSI)-H patients with endometrial cancer, but negative in 20 non–MSI-H patients (P = 0.001). Conclusion: CAGE may be useful for immunotherapy and diagnosis of various cancers particularly MSI-positive endometrial cancer.
Prone Positioning in Severe Acute Respiratory Distress Syndrome
Authors: Claude Guérin, Jean Reignier, Jean-Christophe Richard, Pascal Beuret, Arnaud Gacouin, Thierry Boulain, Emmanuelle Mercier, Michel Badet, Alain Mercat, Olivier Baudin, Marc Clavel, Delphine Chatellier, Samir Jaber, Sylvène Rosselli, Jordi Mancebo, Michel Sirodot, Gilles Hilbert, Christian Bengler, Jack Richecoeur, Marc Gainnier, Frédérique Bayle, Gael Bourdin, Véronique Leray, Raphaele Girard, Loredana Baboi, Louis Ayzac
Journal: New England Journal of Medicine (2013)

Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS.In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone-positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg, with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion.A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group.In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique National 2006 and 2010 of the French Ministry of Health; PROSEVA ClinicalTrials.gov number, NCT00527813.).