tbuckley/cabot-search huggingface dataset:
A Causal Role for the Human Tumor Antigen Preferentially Expressed Antigen of Melanoma in Cancer
Authors: Mirjam T. Epping, René Bernards
Journal: Cancer Research (2006)

Tumor antigens are of interest as diagnostic and prognostic markers and potential therapeutic targets. The tumor antigen preferentially expressed antigen of melanoma (PRAME) is frequently overexpressed in a wide variety of cancers and is a prognostic marker for clinical outcome. It has been shown recently that PRAME functions as a repressor of retinoic acid signaling. Here, we discuss this novel insight in the context of the increasing interest in tumor antigens as targets for therapy.
Controlled trial of a thymic hormone extract (Thymostimulin) in 'autoimmune' chronic active hepatitis.
Authors: J E Hegarty, K T Nouri Aria, A L Eddleston, R Williams
Journal: Gut (1984)

A randomised controlled trial of thymic hormone extracts (Thymostimulin) (1 mg/kg/day for seven days; 1 mg/kg/weekly thereafter) was undertaken in 30 patients (21 women, nine men) with treated, apparently inactive 9autoimmune9 chronic active hepatitis during withdrawal of maintenance corticosteroid and azathioprine therapy. Reactivation of disease occurred in 26 patients (86%) during or after treatment withdrawal and was as frequent in the Thymostimulin treated (11 of 13; 84%) and untreated (15 of 17; 88%; p greater than 0.05) groups. Reactivation of disease was accompanied by a severe defect in concanavalin A induced suppressor cell activity, the magnitude of which was similar in the Thymostimulin treated and untreated groups (mean % suppression = 16.4 and 3.2 respectively; p greater than 0.05 vs 84.4 in control subjects). Further studies assessing the optimal dose, duration of treatment, and mode of administration are required to establish a therapeutic role for thymic hormone extracts in 9autoimmune9 chronic active hepatitis.
Improvement of Antitumor Activity by Gene Amplification with a Replicating but Nondisseminating Adenovirus
Authors: Denis Bourbeau, Cara Jean Lau, Jairo Jaime, Zafiro Koty, Simone P. Zehntner, Geneviève Lavoie, Anne-Marie Mes-Masson, Josephine Nalbantoglu, Bernard Massie
Journal: Cancer Research (2007)

Abstract Gene therapy is a promising approach for cancer treatment; however, efficacy of current vectors remains insufficient. To improve the success of suicide gene therapy, we constructed a replication-competent adenoviral vector that has its protease gene deleted and expresses bacterial cytosine deaminase fused with bacterial uracil phosphoribosyltransferase (CU). The prodrug, 5-fluorocytosine, is transformed into the highly toxic and tissue-diffusible 5-fluorouracil by CU in infected cells. This vector is incapable of producing infectious particles but is able to undergo a single round of replication, thereby increasing transgene copy number and expression. In the presence of 5-FC, compared with the first-generation vector (AdCU), the replication-competent vector, Ad(dPS)CU-IRES-E1A, was significantly more efficacious for in vitro tumor cell killing and in bystander assays, whereas 25-fold fewer viral particles were required in a three-dimensional spheroid model. For in vivo experiments, in which virus was injected into preestablished intracranial glioma xenografts, followed by 5-FC treatment, mice receiving Ad(dPS)CU-IRES-E1A had significantly smaller tumors at 35 days postinjection as well as significantly longer median survival than mice treated with the replication-deficient, protease-deleted vector [Ad(dPS)CU]. In an immunocompetent syngeneic model, Ad(dPS)CU + 5-FC–treated mice had a median survival of only 23 days, whereas Ad(dPS)CU-IRES-E1A + 5-FC–treated animals had a survival of 57.1% at 365 days. In conclusion, Ad(dPS)CU-IRES-E1A in the presence of 5-FC produces more potent tumoricidal effects than its replication-deficient counterparts. [Cancer Res 2007;67(7):3387–95]
Sphingosine 1-phosphate protects rat liver sinusoidal endothelial cells from ethanol-induced apoptosis: Role of intracellular calcium and nitric oxide
Authors: Dong-Mei Zheng, Tsuneo Kitamura, Kenichi Ikejima, Nobuyuki Enomoto, Shunhei Yamashina, Satoko Suzuki, Yoshiyuki Takei, Nobuhiro Sato
Journal: Hepatology (2006)

In alcoholic liver disease, ethanol-induced damage to sinusoidal endothelial cells (SECs) appears to be important in the progression of liver damage. However, little is known about the mechanisms responsible for protection of SECs against ethanol-induced injury. To elucidate the role of sphingosine 1-phosphate (S1P), which is stored in platelets and may be released from them on their activation, we investigated the effect of S1P on rat liver SECs in primary culture. Pretreatment of cells with 1 mumol/L S1P attenuated ethanol-induced apoptosis. Electron microscopy confirmed this protective effect of S1P on damaged SECs in liver tissues after perfusion of ethanol. In the absence of ethanol, S1P increased DNA synthesis as determined via incorporation of bromodeoxyuridine. S1P also ameliorated the decreased DNA synthesis of cells induced by ethanol. Addition of S1P to cells induced an increase in intracellular calcium concentrations and NO production in cells. Western blotting revealed that S1P significantly induced the activation of endothelial NO synthase (eNOS), but not Akt, and that S1P-induced activation of eNOS was blocked by trifluoperazine, a calmodulin inhibitor. Furthermore, N(G)-nitro-L-arginine methyl ester, a NO synthase inhibitor, cancelled the effect of S1P on DNA synthesis, apoptosis, and NO production in vitro as well as the protective effect of S1P on cell damage in situ. In conclusion, the biological effect of S1P is at least partially mediated by Ca(2+)-sensitive eNOS activation and subsequent NO formation; extracellular S1P could contribute to sinusoidal protection and remodeling in alcoholic liver injury.
Outbreak of Moraxella catarrhalis in a respiratory unit.
Authors: S J Richards, A P Greening, M C Enright, M G Morgan, H McKenzie
Journal: Thorax (1993)

The clinical and epidemiological features of an outbreak of nosocomial Moraxella catarrhalis infection in a respiratory unit are described. Six isolates from five patients were shown to be indistinguishable by immunoblotting and restriction endonuclease analysis and different from 11 other, unrelated clinical strains.
Senescence Marker Protein-30 Protects Mice Lungs from Oxidative Stress, Aging, and Smoking
Authors: Tadashi Sato, Kuniaki Seyama, Yasunori Sato, Hiroaki Mori, Sanae Souma, Taeko Akiyoshi, Yuzo Kodama, Takanori Mori, Sataro Goto, Kazuhisa Takahashi, Yoshinosuke Fukuchi, Naoki Maruyama, Akihito Ishigami
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Senescence marker protein-30 (SMP30) is a multifunctional protein providing protection to cellular functions from age-associated deterioration. We previously reported that SMP30 knockout (SMP30Y/-) mice are capable of being novel models for senile lung with age-related airspace enlargement and enhanced susceptibility to harmful stimuli.Aging and smoking are considered as major contributing factors for the development of pulmonary emphysema. We evaluated whether SMP30Y/- mice are susceptible to oxidative stress associated with aging and smoking.Age-related changes of protein carbonyls in lung tissues from the wild-type (SMP30Y/+) and SMP30Y/- mice were evaluated. Both strains were exposed to cigarette smoke for 8 wk. Histopathologic and morphologic evaluations of the lungs, protein carbonyls and malondialdehyde in the lung tissues, total glutathione content in the bronchoalveolar lavage fluid, and degree of apoptosis of lung cells were determined.In the lungs of SMP30Y/- mice, protein carbonyls tended to increase with aging and were significantly higher than the age-matched SMP30Y/+ mice. Cigarette smoke exposure generated marked airspace enlargement (23.3% increase of the mean linear intercepts) with significant parenchymal destruction in the SMP30Y/- mice but not in the SMP30Y/+ mice (5.4%). The protein carbonyls, malondialdehyde, total glutathione, and apoptosis of lung cells were significantly increased after 8-wk exposure to cigarette smoke in the SMP30Y/- mice.Our results suggest that SMP30 protects mice lungs from oxidative stress associated with aging and smoking. The SMP30Y/- mice could be useful animal models for investigating age-related lung diseases, including cigarette smoke-induced pulmonary emphysema.
Diagnosis and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents
Authors: Larry S. Goldman
Journal: JAMA (1998)

To deal with public and professional concern regarding possible overprescription of attention-deficit/hyperactivity disorder (ADHD) medications, particularly methylphenidate, by reviewing issues related to the diagnosis, optimal treatment, and actual care of ADHD patients and of evidence of patient misuse of ADHD medications.Literature review using a National Library of Medicine database search for 1975 through March 1997 on the terms attention deficit disorder with hyperactivity, methylphenidate, stimulants, and stimulant abuse and dependence. Relevant documents from the Drug Enforcement Administration were also reviewed.All English-language studies dealing with children of elementary school through high school age were included.All searched articles were selected and were made available to coauthors for review. Additional articles known to coauthors were added to the initial list, and a consensus was developed among the coauthors regarding the articles most pertinent to the issues requested in the resolution calling for this report. Relevant information from these articles was included in the report.Diagnostic criteria for ADHD are based on extensive empirical research and, if applied appropriately, lead to the diagnosis of a syndrome with high interrater reliability, good face validity, and high predictability of course and medication responsiveness. The criteria of what constitutes ADHD in children have broadened, and there is a growing appreciation of the persistence of ADHD into adolescence and adulthood. As a result, more children (especially girls), adolescents, and adults are being diagnosed and treated with stimulant medication, and children are being treated for longer periods of time. Epidemiologic studies using standardized diagnostic criteria suggest that 3% to 6% of the school-aged population (elementary through high school) may suffer from ADHD, although the percentage of US youth being treated for ADHD is at most at the lower end of this prevalence range. Pharmacotherapy, particularly use of stimulants, has been extensively studied and generally provides significant short-term symptomatic and academic improvement. There is little evidence that stimulant abuse or diversion is currently a major problem, particularly among those with ADHD, although recent trends suggest that this could increase with the expanding production and use of stimulants.Although some children are being diagnosed as having ADHD with insufficient evaluation and in some cases stimulant medication is prescribed when treatment alternatives exist, there is little evidence of widespread overdiagnosis or misdiagnosis of ADHD or of widespread overprescription of methylphenidate by physicians.
The global burden of hip and knee osteoarthritis: estimates from the Global Burden of Disease 2010 study
Authors: Marita Cross, Emma Smith, Damian Hoy, Sandra Nolte, Ilana Ackerman, Marlene Fransen, Lisa Bridgett, Sean Williams, Francis Guillemin, Catherine L Hill, Laura L. Laslett, Graeme Jones, Flavia Cicuttini, Richard Osborne, Theo Vos, Rachelle Buchbinder, Anthony Woolf, Lyn March
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> To estimate the global burden of hip and knee osteoarthritis (OA) as part of the Global Burden of Disease 2010 study and to explore how the burden of hip and knee OA compares with other conditions. <h3>Methods</h3> Systematic reviews were conducted to source age-specific and sex-specific epidemiological data for hip and knee OA prevalence, incidence and mortality risk. The prevalence and incidence of symptomatic, radiographic and self-reported hip or knee OA were included. Three levels of severity were defined to derive disability weights (DWs) and severity distribution (proportion with mild, moderate and severe OA). The prevalence by country and region was multiplied by the severity distribution and the appropriate disability weight to calculate years of life lived with disability (YLDs). As there are no deaths directly attributed to OA, YLDs equate disability-adjusted life years (DALYs). <h3>Results</h3> Globally, of the 291 conditions, hip and knee OA was ranked as the 11th highest contributor to global disability and 38th highest in DALYs. The global age-standardised prevalence of knee OA was 3.8% (95% uncertainty interval (UI) 3.6% to 4.1%) and hip OA was 0.85% (95% UI 0.74% to 1.02%), with no discernible change from 1990 to 2010. Prevalence was higher in females than males. YLDs for hip and knee OA increased from 10.5 million in 1990 (0.42% of total DALYs) to 17.1 million in 2010 (0.69% of total DALYs). <h3>Conclusions</h3> Hip and knee OA is one of the leading causes of global disability. Methodological issues within this study make it highly likely that the real burden of OA has been underestimated. With the aging and increasing obesity of the world9s population, health professions need to prepare for a large increase in the demand for health services to treat hip and knee OA.
Discrepant elevation of sIL-2R levels in sarcoidosis patients with renal insufficiency
Authors: Anouk Verwoerd, Adriane D.M. Vorselaars, Coline H.M. van Moorsel, Willem Jan W. Bos, Heleen van Velzen-Blad, Jan C. Grutters
Journal: European Respiratory Journal (2015)

Sarcoidosis is a systemic, granulomatous disease that can manifest in multiple organs [1]. Several biomarkers are used to assess disease activity and monitor response to therapy, including soluble interleukin-2 receptor (sIL-2R) and angiotensin-converting enzyme (ACE) [2]. sIL-2R was previously shown to correlate with the amount of CD4+ T-lymphocytes in bronchoalveolar lavage fluid [3]. Furthermore, it was shown that sIL-2R >4000 pg·mL−1 was a significant predictor of relapse after discontinuation of infliximab therapy and that sIL-2R is a suitable prognostic marker for disease progression [4, 5]. We observed, however, that in a small number of patients with co-existing renal insufficiency, sIL-2R can be disproportionately high without marked signs of disease activity based on 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), ACE and the clinical presentation. The aim of this pilot study is therefore to evaluate the influence of renal function on sIL-2R levels to determine if and how the marker can be used in sarcoidosis patients with renal insufficiency. In order to further illustrate the discrepancy, we first describe two cases. Levels of soluble IL-2 receptor can be discrepantly elevated in sarcoidosis patients with renal insufficiency <http://ow.ly/ICVrY> We thank Ellen Tromp, statistician at St Antonius Hospital, Nieuwegein, The Netherlands, for her statistical assistance.
Discovery, In Vivo Activity, and Mechanism of Action of a Small-Molecule p53 Activator
Authors: Sonia Lain, Jonathan J. Hollick, Johanna Campbell, Oliver D. Staples, Maureen Higgins, Mustapha Aoubala, Anna McCarthy, Virginia Appleyard, Karen E. Murray, Lee Baker, Alastair Thompson, Joanne Mathers, Stephen J. Holland, Michael J.R. Stark, Georgia Pass, Julie Woods, David P. Lane, Nicholas J. Westwood
Journal: Cancer Cell (2008)

We have carried out a cell-based screen aimed at discovering small molecules that activate p53 and have the potential to decrease tumor growth. Here, we describe one of our hit compounds, tenovin-1, along with a more water-soluble analog, tenovin-6. Via a yeast genetic screen, biochemical assays, and target validation studies in mammalian cells, we show that tenovins act through inhibition of the protein-deacetylating activities of SirT1 and SirT2, two important members of the sirtuin family. Tenovins are active on mammalian cells at one-digit micromolar concentrations and decrease tumor growth in vivo as single agents. This underscores the utility of these compounds as biological tools for the study of sirtuin function as well as their potential therapeutic interest.
Re: Prognostic Significance of a Short Sequence Insertion in the MCL-1 Promoter in Chronic Lymphocytic Leukemia
Authors: Uta C. F. Nenning, Cornelia Eckert, Sven Wellmann, Andrea Barth, Günter Henze, Karl Seeger
Journal: JNCI Journal of the National Cancer Institute (2005)

Wt = wild-type allele; 6 = 6-nucleotide insertion; 18 = 18-nucleotide insertion.† B-CLL = B-cell chronic lymphocytic leukemia
Suppression of Lung Tumor Growth and Metastasis in Mice by Adeno-Associated Virus-Mediated Expression of Vasostatin
Authors: Ke Xia Cai, Lai Ying Tse, Carly Leung, Paul K.H. Tam, Ruian Xu, Mai Har Sham
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Angiogenesis inhibitors have strong therapeutic potential as antitumor agents in suppressing tumor growth and metastatic progression. Vasostatin, the N-terminal domain of calreticulin, is a potent angiogenesis inhibitor. In this study, we determined the effectiveness of vasostatin delivered by recombinant pseudotype adeno-associated virus 2/5 (rAAV2/5-VAS) as a gene therapy approach for lung cancer treatment. Experimental Design: We used rAAV2/5 to deliver vasostatin intratumorally or systemically in different mouse lung tumor models — subcutaneous, orthotopic xenograft, and spontaneous metastasis lung tumor models. The therapeutic efficacy of rAAV2/5-VAS was determined by monitoring tumor volume, survival rate, and degree of neovascularization after treatment in these models. Results: Mice bearing subcutaneous tumor of rAAV2/5-VAS pretreated Lewis lung carcinoma cells showed &amp;gt;50% reduction in primary tumor volume and reduced spontaneous pulmonary metastases. The tumor-suppressive action of rAAV2/5-VAS in subcutaneous human lung tumor A549 xenograft correlated with a reduced number of capillary vessels in tumors. In the orthotopic xenograft model, rAAV2/5-VAS suppressed metastasis of A549 tumors to mediastinal lymph nodes and contralateral lung. Furthermore, treatment of immunocompetent mice in the spontaneous lung metastases model with rAAV2/5-VAS after primary tumor excision prolonged their median survival from 21 to 51.5 days. Conclusion: Our results show the effectiveness of rAAV2/5-VAS as an angiogenesis inhibitor in suppressing tumor growth during different stages of tumor progression, validating the application of rAAV2/5-VAS gene therapy in treatment against lung cancer.
Presence of Urinary Haufen Accurately Predicts Polyomavirus Nephropathy
Authors: Harsharan K. Singh, Kenneth A. Andreoni, Victoria Madden, Karin True, Randal Detwiler, Karen Weck, Volker Nickeleit
Journal: Journal of the American Society of Nephrology (2009)

There are no accurate, noninvasive tests to diagnose BK polyomavirus nephropathy, a common infectious complication after renal transplantation. This study evaluated whether the qualitative detection of cast-like, three-dimensional polyomavirus aggregates ("Haufen") in the urine accurately predicts BK polyomavirus nephropathy. Using negative-staining electron microscopy, we sought Haufen in 194 urine samples from 139 control patients and in 143 samples from 21 patients with BK polyomavirus nephropathy. Haufen detection was correlated with pathology in concomitant renal biopsies and BK viruria (decoy cell shedding and viral load assessments by PCR) and BK viremia (viral load assessments by PCR). Haufen originated from renal tubules containing virally lysed cells, and the detection of Haufen in the urine correlated tightly with biopsy confirmed BK polyomavirus nephropathy (concordance rate 99%). A total of 77 of 143 urine samples from 21 of 21 patients with BK polyomavirus nephropathy (disease stages A-C) contained Haufen, and during follow-up (3 to 120 wk), their presence or absence closely mirrored the course of renal disease. All controls were Haufen-negative, however, high viremia or viruria were detected in 8% and 41% of control samples, respectively. kappa statistics showed fair to good agreement of viruria and viremia with BK polyomavirus nephropathy or with Haufen shedding and demonstrated an excellent agreement between Haufen and polyomavirus nephropathy (kappa 0.98). Positive and negative predictive values of Haufen for BK polyomavirus nephropathy were 97% and 100%, respectively. This study shows that shedding of urinary Haufen and not BK viremia and viruria accurately mark BK polyomavirus nephropathy. It suggests that the detection of Haufen may serve as a noninvasive means to diagnose BK polyomavirus nephropathy in the urine.
Sensory hyperreactivity – a possible mechanism underlying cough and asthma‐like symptoms
Authors: E. Millqvist, M. Bende, O. Löwhagen
Journal: Allergy (1998)

Background Investigations of patients referred for suspected asthma have revealed a little‐known group with symptoms suggesting hyperreactive airways in whom provocation with methacholine does not lead to bronchial obstruction. The underlying mechanisms are not known, and no objective diagnostic method has been available. Methods Provocations by inhalation of capsaicin solutions in stepwise increasing concentrations were used. Ten patients with asthma‐like symptoms after exposure to nonspecific irritating stimuli, but without IgE‐mediated allergy or demonstrable bronchial obstruction, were compared to 10 patients with verified bronchial asthma and 28 healthy controls. Results The patients with asthma‐like symptoms reacted with cough in a dose‐dependent way. The number of coughs was significantly greater than in asthmatic patients and healthy controls. The latter two groups did not differ significantly. Conclusions The capsaicin provocation test may be a valuable method for showing not only a greater cough sensitivity, but also asthma‐like symptoms. The pathophysiology underlying the symptoms may be related to increased sensitivity of free, overactive nerve endings in the respiratory mucosa. Therefore, we suggest that this overreaction in the lower airways be called “sensory hyperreactivity”.
Medical Education
Authors: Catherine Reinis Lucey
Journal: JAMA Internal Medicine (2013)

Medical education today is pedagogically superb, but the graduates of our educational programs are still unable to successfully translate decades of biomedical advances into health care that reliably meets the Institute of Medicine quality criteria. Realizing the promise of high-quality health care will require that medical educators accept that they must fulfill their contract with society to reduce the burden of suffering and disease through the education of physicians. Educational redesign must begin with the understanding that the professional identity of the physician who was successful in the acute disease era of the 20th century will not be effective in the complex chronic disease era of the 21st century. Medical schools and residency programs must restructure their views of basic and clinical science and workplace learning to give equal emphasis to the science and skills needed to practice in and lead in complex systems. They must also rethink their relationships with clinical environments so that the education of students and residents accelerates the transformation in health care delivery needed to fulfill our contract with society.