tbuckley/cabot-search huggingface dataset:
Identification of human reduced folate carrier (hRFC) substrate binding sites by site-directed mutagenesis and affinity labeling strategies
Authors: Yijun Deng, Hou Zhanjun, Christina Cherian, Jianmei Wu, Lei Wang, Aleem Gangjee, Larry Matherly
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5731 

The human reduced folate carrier (hRFC) is the major membrane transport system for reduced folate cofactors and antifolates such as methotrexate (MTX) and pemetrexed in human normal tissues and tumors. hRFC is a member of the “Major Facilitator Superfamily” of transporters and is characterized by 12 transmembrane domains (TMDs). Recent studies used cysteine scanning mutagenesis and accessibility methods to identify amino acids located in TMDs 4, 5, 7, 8, 10 and 11 as important structural or functional components of the putative hydrophilic cavity for binding of anionic folate substrates (J Biol Chem 281:33588, 2006). Affinity labeling with N-hydroxysuccinimide (NHS)-MTX localized binding of the substrate carboxyl group(s) to residues in TMD11. A number of amino acids were identified from our cysteine scanning mutants as functionally important including Arg133 and Tyr136 (TMD4), Tyr281 (TMD7), and Arg373 (TMD10). A number of nucleophilic amino acids in TMD11 (e.g., Asn403, Thr408, Thr412) were identified as potential targets for NHS-MTX covalent modification. To further investigate the functional roles of these amino acids, each was mutated to conserved and non-conserved amino acids based on bulk volume and charge. Mutant constructs were transfected into hRFC-null HeLa (R5) cells and assayed for uptake with radioactive MTX. With minor exceptions (e.g., Lys411), non-conservative substitutions abolished transport, whereas conservative substitutions (e.g., Lys for Arg133 or 373; Phe for Tyr136 or 281) did not abolish transport. By alanine/valine-scanning mutagenesis of 7 nucleophilic amino acids in TMD11, transport was variously preserved (60 to 100%). For wild type hRFC and 6 mutants (C396V, N403A, T404A, T408V, T412A, T415A) in TMD11, NHS-MTX treatment inhibited transport activity. Conversely, K411A-hRFC was unaffected by NHS-MTX treatment, suggesting position 411 is the probable target for covalent modification by NHS-MTX. To further characterize binding of the substrate carboxyl groups, we used a series of classic diamino furo[2,3-d] pyrimidine analogs with substituted carboxyl groups as inhibitors of uptake of radioactive MTX. Interestingly, analogs with a single gamma carboxyl but no alpha carboxyl groups, or no carboxyl groups at all, did not bind to wild type hRFC in this assay. However, analogs with only a single alpha carboxyl group were potent inhibitors. Collectively, our results identify critical determinants for substrate binding to hRFC. Identification of amino acids that comprise the substrate binding site and translocation pathway is essential to the design of new antifolate inhibitors that rely on hRFC for cellular entry or with substantially enhanced transport over hRFC, and the development of therapeutic strategies for biochemically modulating transporter activity.
Conquering Anorexia: The Route to Recovery
Authors: Rhona MacDonald
Journal: BMJ (2001)

Clare Lindsay 

Summersdale, £9.99, pp 221 ISBN 1 84024 096 2

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If you are in any doubt that eating disorders are serious physical and psychiatric illnesses—as opposed to the “selfish” fads of “silly” teenagers—then read this book. It is written by a former sufferer of anorexia nervosa, and I use the word “sufferer” in its true sense. Anyone who can write the following is definitely undergoing some sort of mental torture: “My life was a nightmare. If I wasn't starving, I was making myself …

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Abstract 1462: Lineage Analysis of <i>Mesp1</i> Expressing Cells in Cardiac Conduction System
Authors: Reza Rafie, Amir R Hajrasouliha, Sina Tavakoli, Kamal Kotak, Mohammad Pashmforoush
Journal: Circulation (2008)

Mesp1 is the earliest transcription factor detected in cardiac precursor cells considered to play a key role in their early specification. The lineage analysis, using Mesp1- Cre transgenic mouse line, has shown that there is a minor contribution of Mesp1 non-expressing cells to the formation of ventricular conduction system. The purpose of the present study is to evaluate the contribution of Mesp1 -expressing and non-expressing cells to the development of sinoatrial node, atrioventricular node and His bundle in embryonic, neonatal and adult heart. In this study, the contribution of Mesp1 -expressing cells was evaluated by a lineage analysis using the cross of Mesp1 -Cre and ROSA26R reporter mice. Different components of the cardiac conduction system were identified by a combination of histological (hematoxylin/eosin), acetylcholinesterase, and immunofluorescent stainings for specific markers (HCN4 and connexin40). Sinoatrial and atrioventricular nodes as well as His bundle are derived almost exclusively from Mesp1- expressing cells as evident by β-gal activity. The contribution of Mesp1 non-expressing cells becomes prominent, though still less than Mesp1 -expressing cells, in the distal components of cardiac conduction system (i.e. bundle branches). This pattern was consistent in embryonic and neonatal stages as well as adult hearts. Unlike the distal components of cardiac conduction system, which is composed of a mixed population of Mesp1 -expressing and non-expressing cells, sinoatrial node, atrioventricular node and His bundle are derived almost exclusively from Mesp1 -expressing cells.
Novel approach to rescue severe pulmonary hypertension (PH) with intratracheal administration of micro gelatin hydrogel microspheres incorporating basic fibroblast growth factor (bFGF)
Authors: K Hirose, T Ikeda, A Marul, Y Arai, T Kushibiki, Y Kimura, H Sakaguchi, H Yuang, SB Chandra, Y Tabata, M Komeda
Journal: Circulation (2006)
Noninvasive quantification of regional myocardial flow reserve in patients with coronary atherosclerosis using nitrogen-13 ammonia positron emission tomography
Authors: Rob S.B. Beanlands, Otto Muzik, Pierre Melon, Ronald Sutor, Steve Sawada, David Muller, Diane Bondie, Gary D. Hutchins, Markus Schwaiger
Journal: Journal of the American College of Cardiology (1995)
Abstract 321: Reperfusion Target Temperature Study for Resuscitation and Long-Term Survival from Prolonged Ventricular Fibrillation Cardiac Arrest in Rats
Authors: Ingrid A Magnet, Florian Ettl, Andreas Schober, Alexandra-Maria Warenits, Christoph Testori, Daniel Grassmann, Michael Wagner, Christoph Schriefl, Christian Clodi, Ursula Teubenbacher, Sandra Högler, Wolfgang Weihs, Fritz Sterz, Andreas Janata
Journal: Circulation (2014)

BACKGROUND: Emergency cardiopulmonary bypass (ECPB) allows for target temperature reperfusion and resuscitation from prolonged cardiac arrest, although the ideal reperfusion temperature is not know...
Foundations of Anatomy and Physiology.
Authors: Janet S. Ross, Kathleen J. W. Wilson
Journal: JAMA (1963)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Indeterminate solitary pulmonary nodule: Surgical diagnosis and models for predicting malignancy
Authors: Maria Jose Galvez, Mercedes Izquierdo, Maria Josefa Andres, Ana Maria Gomez, Javier Solano, Barbara Steen
Journal: European Respiratory Journal (2014)

Objectives:To analyze the histology of patients with indeterminate solitary pulmonary nodule(ISPN) after surgery.To describe clinical(C) and radiological (Rx) characteristics.To estimate a model for predicting cancer in our series and apply the Mayo Clinic model(MCM).

Methods:Retrospective study of patients with ISPN seen on CT referred for surgery with a diagnosis(Jan98-Aug13).C and Rx variables collected from patient files.Independent predictors for malignant NPS were estimated developing a predictive model with a multivariate logistic regression model.Probability of cancer was calculated with the MCM along with the areas under the curve(AUC) of both.

Results:74cases:82.4%malignant (60.8%adenocarcinoma(Ade))17.6% benign (9.5% hamartoma (H)).

![Figure][1] 



Significant differences were found between the two groups for nodule edges and pack-years;both variables were identified as independent risk factors for malignant SPN.Malignant probability formula=1/1+e–f(x) f(x)=-2.318+3.694x jagged edge(JE) +0.04x pack-years(PY) . Sensitivity(S)=96.7%;specificity(Sp)=69.2%;AUC=0.904(95%CI0.823-0.984).When the MCM was applied to our series, both the S and Sp obtained were lower(p=0.31).

Conclusions:82.4% of the ISPN were malignant mostly Ade;half of the benign ISPN were H. JE and accumulated PY are the only 2 characteristics with significant differences between malignant and benign lesions.This estimated model may enable us to diagnose ISPN.

 [1]: pending:yes
World AIDS Day
Authors: Rebecca Voelker
Journal: JAMA (1998)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA
Authors: Kazuto Nakada, Kimiko Inoue, Tomoko Ono, Kotoyo Isobe, Atsuo Ogura, Yu-Ichi Goto, Ikuya Nonaka, Jun-Ichi Hayashi
Journal: Nature Medicine (2001)
Glycolytic and non-glycolytic functions of GAPDH in cellular response to genotoxic drugs
Authors: Manali Phadke, Natalia Krynetskaia, Evgeny Krynetskiy
Journal: Cancer Research (2008)

3341  Cancer cells obtain about 50% of their energy by metabolizing glucose to lactic acid even in aerobic condition (Warburg effect). Unrelated to its glycolytic functions, GAPDH is involved in critical pathways including export of nuclear RNA, DNA replication and repair, regulation of transcription, and apoptosis. Therefore, a pivotal glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is likely to be an essential element of cancer cell survival. We used human lung adenocarcinoma A549 cells and renal carcinoma UO31 cells to elucidate relationship between the level and activity of GAPDH, and cellular response to genotoxic drugs (cytarabine, araC, and mercaptopurine, MP). Treatment with araC induced apoptosis in A549 and UO31, as evidenced by accumulation of γ-H2AX, activation of caspase 3, and accumulation of cleaved PARP. Using RNA interference technology, we knocked down GAPDH in A549 and UO31 cells. After siGAPDH treatment, intracellular GAPDH level was decreased 4-5-fold in A549 and 2-3-fold in UO31. A549 and UO31 cells with decreased GAPDH level were less sensitive to genotoxic effects of araC; phosphorylation of H2AX (the marker of DNA fragmentation) was reduced by 60%. In parallel, both cell lines challenged by araC demonstrated intranuclear accumulation of GAPDH (up to 5-6-fold), as evidenced by Western blot analysis, immunofluorescent microscopy, and confocal microscopy using GFP-GAPDH fusion protein. To assess intranuclear functions of GAPDH, we determined the content and glycolytic activity of GAPDH in nuclei and cytosol of the cells after genotoxic stress. Specific activity of nuclear GAPDH was decreased after araC treatment suggesting post-translational modification of the enzyme. Unexpectedly, we observed reversible intranuclear accumulation of GAPDH in A549 cells treated with MP even though MP was not cytotoxic for this cell line. In contrast to the effect of araC, nuclear GAPDH retained its enzymatic activity after MP treatment. Our results indicate that the intranuclear accumulation of GAPDH and the inhibition of intranuclear GAPDH are two separable events. We conclude that two distinct mechanisms govern intranuclear accumulation of GAPDH: one mechanism is related to induction of apoptosis following genotoxic stress which is accompanied by modification of GAPDH and inhibition of nuclear GAPDH activity; the second mechanism is a reversible translocation of GAPDH after stress.
Prevalence of undetected tinea capitis in a prospective school survey in Madrid: emergence of new causative fungi
Authors: None CUÉtara, None Del Palacio, None Pereiro, None Noriega
Journal: British Journal of Dermatology (1998)

From October 1994 to December 1996, a prospective study was undertaken in 10,000 unselected school children in Madrid, aged between 2 and 16 years (mean +/- SD 8.5 +/- 3.6 years). Fifty-two (0.52%) (including 13 immigrants from Africa) had dermatophytes in the scalp: 33 (0.33%) (including 10 immigrants from Africa) had tinea capitis and 19 were scalp carriers. Almost half of the symptomatic cases were caused by Trichophyton tonsurans (12 of 33 cases) and Microsporum canis (16 of 33 cases). T. tonsurans (13 of 19 cases) was the predominant species in the scalp carriers. Twenty-four per cent of the subjects with tinea capitis and 42% of the asymptomatic scalp carriers also had ringworm in other body sites. There was a significantly higher occurrence of tinea capitis (P < 0.001) (particularly due to T. tonsurans: P < 0.001) and of asymptomatic scalp carriers (P < 0.05) (particularly due to anthropophilic species: P < 0.01) in the immigrant population from Africa.
Randomized controlled trial of supported employment in England: 2 year follow‐up of the Supported Work and Needs (SWAN) study
Authors: MARGARET HESLIN, LOUISE HOWARD, MORVEN LEESE, PAUL McCRONE, CHRISTOPHER RICE, MANUELA JARRETT, TERRY SPOKES, PETER HUXLEY, GRAHAM THORNICROFT
Journal: World Psychiatry (2011)

Studies from North America have concluded that supported employment using the Individual Placement and Support (IPS) model is effective in helping individuals with severe and persistent mental illness gain competitive employment. The aim of this study was to investigate the effectiveness and cost-effectiveness of IPS in England in patients followed up for 2 years. Patients with severe mental illness were randomised to IPS or local vocational services (treatment as usual). Service use and costs were measured. Two hundred-nineteen participants were randomised, and 86% re-assessed 2 years later. In the multivariate analysis, relatively low rates of competitive employment were found in both the intervention group and the treatment as usual group, although significantly more patients obtained competitive employment in the treatment arm (22% vs. 11%, p=0.041). There were no significant differences in costs. The employment rate among participants receiving IPS was lower than in previously published reports, and the number needed to treat to obtain the benefit of IPS was relatively high. This may reflect difficulties in the implementation of IPS where it is not structurally integrated within mental health teams, as well as economic disincentives which lead to lower levels of motivation for patients and mental health professionals.
Abstract 4163: Chemokine and cytokine levels among lung cancer cases responsive to HPV antigen stimulation
Authors: Michael E. Scheurer, E Susan Amirian, Paul Porter, David B. Corry
Journal: Cancer Research (2014)

Abstract Purpose: Human papillomavirus (HPV), the causative agent for anogenital and certain head and neck cancers, has been detected in lung tumors, but its role as an etiologic agent for lung cancer remains controversial. The lung is often subjected to exogenous inflammatory insults, and patients with chronic lung inflammation have an increased risk for cancer. In addition to the genomic instability that can be caused by HPV oncoproteins, the immunomodulatory impacts of HPV infection may foster a pro-inflammatory state that increases lung cancer risk. We sought to identify such immunomodulatory effects by examining the differences in lymphocyte and cytokine/chemokine profiles between lung cancer cases and HPV-vaccinated healthy controls. Methods: Peripheral blood mononuclear cells were isolated from 22 newly diagnosed lung cancer cases and 11 healthy controls who had prior exposure to HPV antigens (immunized with Gardasil). Cells were enumerated via a hemacytometer, and were exposed to media alone or to 3 doses of Gardasil for 20 hours as an HPV challenge. Interleukin (IL-) 4, IFN-γ, and IL-17A secreting cells were then quantified using enzyme linked immunocell spot (ELISpot) analysis. Individuals were categorized as HPV-responsive if the HPV challenge resulted in an increase in at least 2 types of secreting cells, compared to media-exposed cells. The Milliplex human cytokine detection kit was used to assess circulating levels of 38 key cytokines in the plasma of cases and controls. Cytokine levels among HPV-responsive and HPV-non-responsive cases were compared. Survival analysis was also conducted. Results: All 11 HPV-vaccinated controls demonstrated an increase in cells secreting IFN-γ and IL-4. Of the 22 cases, 13 (59%) were classified as HPV-responsive, with 2 cases displaying an increase in IFN-γ and IL-4 secreting cells upon HPV challenge. Levels of TGF-α, IL-10, IL-3, IL-5, and IL-7 were significantly higher among HPV-responsive compared to non-responsive cases. Significant survival differences were also observed by HPV-responsiveness and cytokine levels. Conclusions: HPV clearly has substantial effects on the host's systemic immune response. Our study may explain whether and how the pathogenic process differs between HPV-infected and -uninfected lung tumors. Citation Format: Michael E. Scheurer, E Susan Amirian, Paul Porter, David B. Corry. Chemokine and cytokine levels among lung cancer cases responsive to HPV antigen stimulation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4163. doi:10.1158/1538-7445.AM2014-4163
The clinical and photobiological characteristics of solar urticaria in 40 patients
Authors: N. Uetsu, H. Miyauchi-Hashimoto, H. Okamoto, T. Horio
Journal: British Journal of Dermatology (2000)

Forty patients with solar urticaria, 16 male and 24 female, were examined personally during the past 25 years. The median age at onset of symptoms was 32 years, ranging from 13 to 76 years. Most commonly (45%) solar urticaria first appeared during the third decade. The mean duration of the disease was 3.6 years at presentation. The action spectrum was found in the visible light range in 24 patients (60%), in the ultraviolet (UV) A range in four, in the UVB in four, from the UVA to UVB in three, from the UVA to visible light in one and in a broad range from UVB to visible light in four patients. An inhibition spectrum was detected in 13 of 19 patients (68%), occurring at longer wavelengths than the action spectrum in 12 of these cases. The augmentation spectrum was found in only four of 14 patients (29%) examined. Twenty-four of 31 patients (77%) developed an urticarial reaction to autologous serum, which had been previously irradiated in vitro at the action spectrum for that patient. In a single patient, solar urticaria was caused by a drug, namely chlorpromazine. In two patients, polymorphic light eruption occurred in association with solar urticaria. No single modality of treatment was satisfactory, but combined use of antihistamines, sunbathing, psoralen UVA photochemotherapy and/or sunscreening agents partially suppressed the symptoms.
Increasing incidence but decreasing in-hospital mortality of adult Staphylococcus aureus bacteraemia between 1981 and 2000
Authors: T. Benfield, F. Espersen, N. Frimodt-Møller, A.G. Jensen, A.R. Larsen, L.V. Pallesen, R. Skov, H. Westh, P. Skinhøj
Journal: Clinical Microbiology and Infection (2006)
Abstract 377: SMYD2-dependent PARP1 methylation promotes Poly(ADP-ribosyl)ation activity in cancer cells
Authors: Lianhua Piao, Yusuke Nakamura, Ryuji Hamamoto
Journal: Cancer Research (2014)

Abstract Poly(ADP-ribose) polymerase-1 (PARP1) catalyzes the poly(ADP-ribosyl)ation of protein acceptors using NAD+ as the substrate is now considered as an important target for development of anticancer therapy. PARP1 is known to be posttranslationally modified in various ways including phosphorylation and ubiquitination, but the physiological role of PARP1 methylation is not well understood. Here we demonstrated that the histone methyltransferase SMYD2 (SET and MYND domain containing 2), which plays critical roles in human carcinogenesis, mono-methylated PARP1. We found lysine 528 to be a target of SMYD2-dependent PARP1 methylationa and that an N-Terminal DNA binding domain of PARP1 interact with an N-terminal domain of SMYD2. Importantly, methylated PARP1 revealed enhanced poly(ADP-ribose) formation after oxidative stress, and positively regulated the poly(ADP-ribosyl)ation activity of PARP1. Hence, our study unveils a novel mechanism of PARP1 in human cancer through its methylation by SMYD2. Citation Format: Lianhua Piao, Yusuke Nakamura, Ryuji Hamamoto. SMYD2-dependent PARP1 methylation promotes Poly(ADP-ribosyl)ation activity in cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 377. doi:10.1158/1538-7445.AM2014-377