tbuckley/cabot-search huggingface dataset:
Translating the transcriptome into tools for the early detection and prevention of lung cancer: Figure 1
Authors: Yaron B Gesthalter, Jessica Vick, Katrina Steiling, Avrum Spira
Journal: Thorax (2015)

Despite advances in the management of lung cancer, this disease remains a significant global health burden with survival rates that have not significantly improved in decades. The mortality reduction achieved by low-dose helical CT (LDCT) screening of select high-risk patients is challenged by the high false positive rate of this screening modality and the potential for morbidity associated with follow-up diagnostic evaluation in patients with high risk for iatrogenic complications. The diagnostic dilemma of the indeterminate nodule incidentally identified on diagnostic or screening CT has created a need for reliable biomarkers capable of distinguishing benign from malignant disease. Furthermore, there is an urgent need to develop molecular biomarkers to supplement clinical risk models in order to identify patients at highest risk for having an early stage lung cancer that may derive the greatest benefit from LDCT screening, as well as identifying patients at high-risk for developing lung cancer that may be candidates for emerging chemopreventive strategies. Evolving bioinformatic techniques and the application of these algorithms to analyse the transcriptomic changes associated with lung cancer promise translational discoveries that can bridge these large clinical gaps. The identification of lung cancer associated transcriptomic alterations in readily accessible tissue sampling sites offers the potential to develop early diagnostic and risk stratification strategies applicable to large populations. This review summarises the challenges associated with the early detection, screening and chemoprevention of lung cancer with an emphasis on how genomic information encapsulated by the transcriptome can facilitate future innovations in these clinical settings.
Monoclonal anti-interleukin‐5 treatment suppresses eosinophil but not T‐cell functions
Authors: C. Büttner, A. Lun, T. Splettstoesser, G. Kunkel, H. Renz
Journal: European Respiratory Journal (2003)

Influx of eosinophils in airway mucosa and airway lumen is a hallmark of bronchial asthma. In-vitro data and animal studies indicate that the T‐helper (Th) type‐2 cell cytokine, interleukin (IL)‐5, plays an important role in eosinophil maturation, differentiation, recruitment, and survival. The objective of this study was to determine whether intravenous treatment with monoclonal anti-IL‐5 would affect the number of peripheral blood eosinophils, their activation status, T‐cell activation or the pattern of Th1 and Th2 cytokine production. Over a period of 6 months, 19 asthmatics were investigated in a double-blind, placebo-controlled, multicentre study with mepolizumab (SB 240563) anti-IL‐5 antibody administered three times. Before each infusion and 12 weeks after the last infusion, peripheral blood leukocytes were examined, qualitative and quantitative distribution of eosinophils and lymphocyte subpopulations, frequencies of IL‐2, ‐3, ‐4, ‐5, -10, -13, interferon‐γ‐producing CD4 T‐cells and serum eosinophil cationic protein (ECP) levels were determined. Treatment with mepolizumab resulted in a marked, rapid and sustained decrease of eosinophil numbers (median values from 300 to 45 per µL) paralleled by decreased levels of serum ECP (median values from 15 to 5 µg·L −1 ). Distribution of T‐cell subsets and T‐cell cytokine production were not altered during antibody treatment. In conclusion, administration of mepolizumab to asthmatic patients markedly reduces peripheral blood eosinophils without altering the distribution and activation status of lymphocytes.
Abstract LB-177: New temozolomide analogs with activity independent of mismatch repair and alkyltransferase
Authors: Richard T. Wheelhouse, Dimitrios Pletsas, Li Li, Elrashied A.E. Garelnabi, Roger M. Phillips
Journal: Cancer Research (2010)

Abstract Discussion Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-177.
Unconscious abstraction in motor learning
Authors: Aysha S. Keisler, Daniel T. Willingham
Journal: Behavioral and Brain Sciences (2002)

Given the complexity and generalizability of motor skills, it is difficult to account for learning in this area without incorporating the concept of unconscious abstraction. A model based solely on association does not seem to account for data in this domain; specifically, instances that require learners to execute a practiced motor skill in a novel situation.
Oxygen free radicals, inflammation, and synovitis: and synovitis: the current status.
Authors: P Merry, P G Winyard, C J Morris, M Grootveld, D R Blake
Journal: Annals of the Rheumatic Diseases (1989)

Revue du role des radicaux libres dans la synovite. Definition. Production de radicaux libres chez le sujet sain; role fondamental dans les reactions d'oxydation. Discussion de leur place exacte dans la genese des lesions tissulaires dans les maladies articulaires inflammatoires (modeles animaux, homme)
The Bisecting GlcNAc on <i>N</i>-Glycans Inhibits Growth Factor Signaling and Retards Mammary Tumor Progression
Authors: Yinghui Song, Jason A. Aglipay, Joshua D. Bernstein, Sumanta Goswami, Pamela Stanley
Journal: Cancer Research (2010)

Abstract The branching of complex N-glycans attached to growth factor receptors promotes tumor progression by prolonging growth factor signaling. The addition of the bisecting GlcNAc to complex N-glycans by Mgat3 has varying effects on cell adhesion, cell migration, and hepatoma formation. Here, we show that Chinese hamster ovary cells expressing Mgat3 and the polyoma middle T (PyMT) antigen have reduced cell proliferation and growth factor signaling dependent on a galectin lattice. The Mgat3 gene is not expressed in virgin mammary gland but is upregulated during lactation and is expressed in mouse mammary tumor virus (MMTV)/PyMT tumors. Mice lacking Mgat3 that cannot transfer the bisecting GlcNAc to N-glycans acquire PyMT-induced mammary tumors more rapidly and have an increased tumor burden, increased migration of tumor cells, and increased early metastasis to lung. Tumors and tumor-derived cells lacking Mgat3 exhibit enhanced signaling through the Ras pathway and reduced amounts of functionally glycosylated α-dystroglycan. Constitutive overexpression of an MMTV/Mgat3 transgene inhibits early mammary tumor development and tumor cell migration. Thus, the addition of the bisecting GlcNAc to complex N-glycans of mammary tumor cell glycoprotein receptors is a cell autonomous mechanism serving to retard tumor progression by reducing growth factor signaling. Cancer Res; 70(8); 3361–71. ©2010 AACR.
<i>Diabetes Care:</i> Making a Good Journal Better
Authors: Vivian A. Fonseca
Journal: Diabetes Care (2009)

As I begin my 4th year as Editor-in-Chief of Diabetes Care , I remain proud of the achievements of our editorial team and the tremendous success of the journal. In addition, as I take on additional roles in the American Diabetes Association (ADA), I am conscious of the importance of the ADA's mission in providing the highest quality scientific information to the world. In that regard, we are pleased that the journal remains very high in the rankings in terms of readership, subscriptions, and citations, despite a large number of new journals in the field. The journal's impact factor remains high, and it continues to be rated as fourth among journals in endocrinology and metabolism. With the large number of international editions in several languages, Diabetes Care is clearly established as the leading clinical and clinical research journal worldwide in the field of diabetes.

Last year we were concerned about a small decline in the number of articles submitted to us. I am pleased that this trend was reversed in 2009. I hope it means more support for clinical research as we continue in our quest to find a cure for diabetes and improve the lives of people who suffer from this condition. Unfortunately, for many the increase in submissions also means a lower acceptance rate, now around 18%. Many good papers will inevitably be rejected because we may be forced to give higher priority to other competing papers. We continue to have a broad range of clinically relevant papers that will rapidly impact practice and clinical research in the field.

Despite our success, …
Spondylolysis: a critical review
Authors: C J Standaert, S A Herring
Journal: British Journal of Sports Medicine (2000)

Aim —To provide an understanding of the current concepts in the natural history, pathophysiology, diagnosis, and treatment of spondylolysis based on the available medical literature. Methods —Articles were selected for review by the following methods: ( a ) MEDLINE searches with review of abstracts to select relevant articles; ( b ) review of multiple textbooks considered likely to contain information on spondylolysis; ( c ) review of references in articles identified by ( a ) and ( b ). Over 125 articles were ultimately reviewed fully. Publications were selected for inclusion in this article on the basis of perceived scientific and historical merit, particularly as thought to be relevant to achieving the stated purpose of this review. As no controlled clinical trials were identified, this could not be used as an inclusion criterion. Conclusions —Isthmic spondylolysis is considered to represent a fatigue fracture of the pars interarticularis of the neural arch. There is a relatively high incidence of radiographically identified spondylolysis in the general population, but the vast majority of these lesions probably occur without associated symptoms. Symptomatic pars lesions appear to be particularly a clinical problem in adolescents, especially adolescent athletes. The optimal diagnostic and treatment algorithms are not well identified in the current literature. Multiple imaging studies may have a role in the diagnosis of a pars lesion, and treatment seems likely to require at least relative rest and physical rehabilitation with consideration of bracing or, rarely, surgical intervention depending on the clinical context.
Smoking and musculoskeletal disorders: findings from a British national survey
Authors: K T Palmer
Journal: Annals of the Rheumatic Diseases (2002)

<b>Objectives:</b> To explore the relation between smoking habits and regional pain in the general population. <b>Methods:</b> A questionnaire was mailed to 21 201 adults, aged 16–64 years, selected at random from the registers of 34 British general practices, and to 993 members of the armed services, randomly selected from pay records. Questions were asked about pain in the low back, neck, and upper and lower limbs during the past 12 months; smoking habits; physical activities at work; headaches; and tiredness or stress. Associations were examined by logistic regression and expressed as prevalence ratios (PRs). <b>Results:</b> Questionnaires were completed by 12 907 (58%) subjects, including 6513 who had smoked at some time, among whom 3184 were current smokers. Smoking habits were related to age, social class, report of headaches, tiredness or stress, and manual activities at work. After adjustment for potential confounders, current and ex-smokers had higher risks than lifetime non-smokers for pain at all of the sites considered. This was especially so for pain reported as preventing normal activities (with PRs up to 1.6 in current <i>v</i> never smokers). Similar associations were found in both sexes, and when analysis was restricted to non-manual workers. <b>Conclusions:</b> There is an association between smoking and report of regional pain, which is apparent even in ex-smokers. This could arise from a pharmacological effect of tobacco smoke (for example, on neurological processing of sensory information or nutrition of peripheral tissues); another possibility is that people with a low threshold for reporting pain and disability are more likely to take up and continue smoking.
Inhibition of the Src and Jak Kinases Protects against Lipopolysaccharide-induced Acute Lung Injury
Authors: Mariano Severgnini, Satoe Takahashi, Powen Tu, George Perides, Robert J. Homer, Jhung W. Jhung, Deepa Bhavsar, Brent H. Cochran, Amy R. Simon
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

The cascade of cellular and molecular pathways mediating acute lung injury is complex and incompletely defined. Although the Src and Jak family of kinases is upregulated in LPS-induced murine lung injury, their role in the development of lung injury is unknown. Here we report that systemic inhibition of these kinases using specific small molecule inhibitors (PP2, SU6656, tyrphostin A1) significantly attenuated LPS-induced lung injury, as determined by histologic and capillary permeability assays. These inhibitors blocked LPS-dependent cytokine and chemokine production in the lung and in the serum. In contrast, lung-targeted inhibition of these kinases in the airway epithelium via adenoviral-mediated gene transfer of dominant negative Src or of suppressor of cytokine signaling (SOCS-1) disrupted lung cytokine production but had no effect on systemic cytokine production or lung vascular permeability. Mice were significantly protected from lethal LPS challenge by the small molecule inhibitors of Jak and Src kinase. Importantly, this protection was still evident even when the inhibitors were administered 6 hours after LPS challenge. Taken together, these observations suggest that Jak and Src kinases participate in acute lung injury and verify the potential of this class of selective tyrosine kinase inhibitors to serve as novel therapeutic agents for this disease.
FOURTH COMPONENT OF HUMAN COMPLEMENT: DESCRIPTION OF A THREE POLYPEPTIDE CHAIN STRUCTURE
Authors: Robert D. Schreiber, Hans J. Müller-Eberhard
Journal: The Journal of Experimental Medicine (1974)

The fourth component of human complement (C4) was shown to be composed of three distinct polypeptide chains linked by disulfide bonds and noncovalent forces. The sum of the molecular weights of the chains equalled that of the intact molecule. The mol wt of the alpha-, beta-, and gamma-chains were respectively, 93,000, 78,000, and 33,000 daltons. Action of C1s on C4 affected only the alpha-chain, reducing its mol wt to 87,000 daltons. The size of the activation peptide. C4a, is therefore estimated to be 6,000 and that of the major fragment C4b, 198,000 daltons. Periodic acid-Schiff-stained SDS polyacrylamide gels of reduced C4 revealed carbohydrate to be associated with all three chains. A modification of the original method of isolation of C4 is presented.
MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjögren's syndrome
Authors: Naomi I Maria, Zana Brkic, Matti Waris, Cornelia G van Helden-Meeuwsen, Kim Heezen, Joop P van de Merwe, Paul L van Daele, Virgil A S H Dalm, Hemmo A Drexhage, Marjan A Versnel
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To establish an easy and practical assay for identifying systemic interferon (IFN) type I bioactivity in patients with primary Sjögren9s syndrome (pSS). The IFN type I signature is present in over half of the pSS patients and identifies a subgroup with a higher disease activity. This signature is currently assessed via laborious expression profiles of multiple IFN type I-inducible genes. <h3>Methods</h3> In a cohort of 35 pSS patients, myxovirus-resistance protein A (MxA) was assessed as a potential biomarker for type I IFN activity, using an enzyme immunoassay (EIA) on whole-blood and flow cytometric analyses (fluorescence-activated cell sorting, FACS) of isolated CD14 monocytes. In addition, potential biomarkers such as CD64, CD169 and B cell-activating factor (BAFF) were simultaneously analysed in CD14 monocytes using FACS. The IFNscore, a measure for total type I IFN bioactivity, was calculated using expression values of the IFN type I signature genes—IFI44, IFI44L, IFIT3, LY6E and MX1—in CD14 monocytes, determined by real-time quantitative PCR. <h3>Results</h3> IFNscores correlated the strongest with monocyte MxA protein (r=0.741, p&lt;0.001) and whole-blood MxA levels (r=0.764, p&lt;0.001), weaker with CD169 (r=0.495, p&lt;0.001) and CD64 (r=0.436, p=0.007), and not at all with BAFF protein. In particular, whole blood MxA levels correlated with EULAR Sjögren9s Syndrome Disease Activity Index scores and numerous clinical pSS parameters. Interestingly, patients on hydroxychloroquine showed reduced MxA levels (EIA, p=0.04; FACS p=0.001). <h3>Conclusions</h3> The MxA assays were excellent tools to assess IFN type I activity in pSS, MxA-EIA being the most practical. MxA levels associate with features of active disease and are reduced in hydroxychloroquine-treated patients, suggesting the clinical applicability of MxA in stratifying patients according to IFN positivity.
Normalization of Information Processing Deficits in Schizophrenia With Clozapine
Authors: V Kumari, W Soni, T Sharma
Journal: American Journal of Psychiatry (1999)

The authors tested the hypothesis that the use of an atypical drug, clozapine, for patients with schizophrenia is related to less impairment in information processing deficits (assessed by prepulse inhibition of the startle response) than is the use of typical antipsychotics.Two groups of schizophrenic patients--receiving either clozapine or a range of typical antipsychotics--were tested for prepulse inhibition (a reduction in response to a starting stimulus, if preceded briefly by a weak, nonstartling stimulus; measured at prepulse-to-pulse intervals of 30 msec, 60 msec, and 120 msec) of the acoustic startle response and compared with a group of healthy volunteers.Patients receiving typical antipsychotics showed less prepulse inhibition with 30-msec and 60-msec prepulse trials than did comparison subjects. Clozapine-treated patients showed normal levels of prepulse inhibition.Clozapine is superior to typical antipsychotics in normalizing prepulse inhibition, presumably because of its pharmacological effects on prefrontal regions of the brain or its effects on a broader range of neuroreceptors.
Direct method for detecting small quantities of hepatitis B virus DNA in serum and plasma using the polymerase chain reaction.
Authors: J B Zeldis, J H Lee, D Mamish, D J Finegold, R Sircar, Q Ling, P J Knudsen, I K Kuramoto, L T Mimms
Journal: Journal of Clinical Investigation (1989)

Serum components inhibit DNA polymerase, thereby obviating direct detection of serum viral DNA sequences by the polymerase chain reaction (PCR). This has necessitated extraction of nucleic acid from sera before performing PCR and has resulted in loss of sensitivity. By adsorbing virus to a solid surface (microcentrifuge tubes or antibody coated microparticles) followed by proteinase K digestion, as little as three viruses per 200 microliters serum may be directly detected by PCR without nucleic acid extraction. The sensitivity is dependent on the surface area of the adsorptive surface and is increased by having antibodies on the adsorptive surface. The nucleic acid sequence of the amplified DNA fragments may be directly determined by the dideoxy method. Of 24 plasma samples from HBsAg+ volunteer blood donors, HBV DNA was detected in 7 by dot blot assay, 7 by liquid hybridization, and 9 by PCR. PCR detected DNA in every sample that was positive by another assay. Analysis of serial samples of two patients with acute self-limited hepatitis B found detectable HBsAg and pre-S2 antigenemia before HBV DNA by the PCR method. These results suggest that surface antigenemia may precede viremia during acute hepatitis.
Pfizer has preliminary agreements with firms to take over and develop parts of its Kent site
Authors: A. O'Dowd
Journal: BMJ (2011)

The drug company Pfizer has made 10 confidential agreements with companies that could take over parts of its large site at Sandwich in Kent after it closes its operations there, MPs have been told.

Senior Pfizer executives giving evidence to MPs on the parliamentary science and technology committee on 28 February said the company was investigating more than 100 proposals and ideas for future use of its site.

Pfizer announced in February that it was to close its research and development site and acknowledged that most of the 2400 people who work there would be made redundant over the next two years ( BMJ 2011;342:doi: 10.1136/bmj.d771).

MPs on the select committee asked the …
Dose-Ranging Effects of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-On to Metformin in Subjects With Type 2 Diabetes
Authors: Julio Rosenstock, Naresh Aggarwal, David Polidori, Yue Zhao, Deborah Arbit, Keith Usiskin, George Capuano, William Canovatchel
Journal: Diabetes Care (2012)

To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy.This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed.Canagliflozin was associated with significant reductions in A1C from baseline (7.6-8.0%) to week 12: -0.79, -0.76, -0.70, -0.92, and -0.95% for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus -0.22% for placebo (all P < 0.001) and -0.74% for sitagliptin. FPG was reduced by -16 to -27 mg/dL, and body weight was reduced by -2.3 to -3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non-dose-dependent increase in symptomatic genital infections with canagliflozin (3-8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3-9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low.Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females.
The Effects of Antidepressant Step Therapy Protocols on Pharmaceutical and Medical Utilization and Expenditures
Authors: Tami L. Mark, Teresa M. Gibson, Kimberly McGuigan, Bong Chul Chu
Journal: American Journal of Psychiatry (2010)

This study examined the effects of step therapy for antidepressants on prescription drug and other medical utilization and spending. Step therapy is a type of pharmaceutical benefit design that requires that patients try certain specified medications (typically generic medications) prior to using alternative, more expensive medications within the same medication class. Step therapy is not the same as generic substitution.Using the 2003-2006 Thomson Reuters MarketScan claims databases, antidepressant users enrolled in employer plans that implemented antidepressant step therapy were compared with antidepressant users enrolled in employer plans that had not implemented step therapy. Multivariate generalized estimating equation models were used to analyze the relationship between step therapy for antidepressants and 1) pharmacy and medical utilization and 2) spending.Antidepressant days supplied and medication costs decreased after step therapy was implemented, relative to the comparison group. However, overall and mental health-specific inpatient and emergency room utilization and costs increased.Step therapy may have the unintended effect of reducing overall antidepressant use and increasing medical use and costs.