tbuckley/cabot-search huggingface dataset:
Development and Characterization of a Novel CD19CherryLuciferase (CD19CL) Transgenic Mouse for the Preclinical Study of B-Cell Lymphomas
Authors: Luigi Scotto, Marianna Kruithof-de Julio, Luca Paoluzzi, Matko Kalac, Enrica Marchi, Jairo Baquero Buitrago, Jennifer Amengual, Michael M. Shen, Owen A. O'Connor
Journal: Clinical Cancer Research (2012)

To generate a transgenic mouse that when crossed with spontaneous mouse models of lymphoma will allow for quantitative in vivo measurement of tumor burden over the entire spectrum of the disease and or response to therapy in a "disease" or lymphoma subtype-specific manner.We developed a novel genetically engineered transgenic mouse using a CherryLuciferase fusion gene targeted to the CD19 locus to achieve B-cell-restricted fluorescent bioluminescent emission in transgenic mouse models of living mice. The use of a dual function protein enables one to link the in vivo analysis via bioluminescence imaging to cell discriminating ex vivo analyses via fluorescence emission.The spatiotemporal tracking of B-cell lymphoma growth and the response of an established B-cell lymphoma to a drug known to induce remission was evaluated in a double transgenic animal obtained by crossing the CD19CherryLuciferase transgenic mouse to a mouse model of an aggressive B-cell lymphoma. The observations validated the use of the CD19CherryLuciferase transgenic mouse in the assessment of an active drug routinely used in the treatment of lymphoproliferative malignancies.The transgenic mouse described here is the first of its kind, intended to be used to hasten translational studies of novel agents in lymphoma, with the intent that understanding the relevant pharmacology before clinical study will accelerate successful development in clinical studies.
Many US doctors do not want to share performance data with patients
Authors: Janice Hopkins Tanne
Journal: BMJ (2005)

Most US doctors do not use quality improvement techniques that provide information about their practice, the first national survey of US doctors has found ( Health Affairs 2005;24:843-53). Nor do they use techniques which show how well they perform. And if they are provided with information about their performance by insurance companies or health plans, many do not want to share that information with their patients.

Health care plans, accrediting organisations, and consumer advocates use quality improvement methods to improve patients' care. Doctors have been slow to follow, perhaps because most US doctors practise in small groups.

The Commonwealth Fund, a non-profit making foundation focusing on health, surveyed 3598 US doctors in 2003. A total of …
Immunization with antigen and interleukin 2 in vivo overcomes Ir gene low responsiveness.
Authors: H Kawamura, S A Rosenberg, J A Berzofsky
Journal: The Journal of Experimental Medicine (1985)

We studied the effect of purified interleukin 2 (IL-2), made by recombinant DNA techniques, on the serum antibody response to myoglobin in high- and low-responder mice. Previous studies (6, 7) have shown that this response is controlled by H-2-linked Ir genes. The IL-2 was emulsified with the antigen in complete Freund's adjuvant to provide a sustained high local concentration. In low-responder B10.BR mice, a single dose (optimum 50,000 U) resulted in a consistent 10-50-fold increase in specific serum antibody throughout the time course of the response, from 10 d to 46 d after immunization. In contrast, no effect of IL-2 was seen in congenic high-responder B10.D2 mice. With IL-2, the low-responder mice achieved specific antibody levels comparable to those of high responders. Vehicle alone had no effect, and IL-2 alone, without antigen, did not induce myoglobin-specific antibody. No effect of IL-2 was seen in athymic nude mice of high-responder H-2 haplotype. The effect of IL-2 may be on a small number of responding T cells in the low responder mice, but it is possible that IL-2 also acts directly on B cells in a response that remains T-dependent, and therefore is not observed in athymic mice. We suggest that IL-2 may enhance suboptimal T cell help in the low responder, whereas help is not limiting in the high responder. This approach may enable the study of antibody responses in low responders otherwise too weak to analyze, and may be useful in producing antibodies to poorly immunogenic antigens. Potential clinical uses include immunization with weak antigens in normal patients, or with any antigen in certain immunodeficient patients.
Inflammatory and immune pathways in the pathogenesis of periodontal disease
Authors: Ali Cekici, Alpdogan Kantarci, Hatice Hasturk, Thomas E. Van Dyke
Journal: Periodontology 2000 (2013)

Abstract The pathogenesis of periodontitis involves a complex immune/inflammatory cascade that is initiated by the bacteria of the oral biofilm that forms naturally on the teeth. The susceptibility to periodontitis appears to be determined by the host response; specifically, the magnitude of the inflammatory response and the differential activation of immune pathways. The purpose of this review was to delineate our current knowledge of the host response in periodontitis. The role of innate immunity, the failure of acute inflammation to resolve (thus becoming chronic), the cytokine pathways that regulate the activation of acquired immunity and the cells and products of the immune system are considered. New information relating to regulation of both inflammation and the immune response will be reviewed in the context of susceptibility to, and perhaps control of, periodontitis.
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin
Authors: Y. Li
Journal: Journal of Clinical Investigation (2006)

Glyceryl trinitrate (GTN), also known as nitroglycerin, has been used to treat angina and heart failure for more than 130 years. Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. In the present study, we show that the common G-to-A polymorphism in exon 12 of ALDH2 — resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes — is associated with a lack of efficacy of sublingual GTN in Chinese subjects. We also show that the catalytic efficiency (Vmax/Km) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. We conclude that the presence of the Lys504 allele contributes in large part to the lack of an efficacious clinical response to nitroglycerin; we recommend that this genetic factor be considered when administering nitroglycerin to patients, especially Asians, 30–50% of whom possess the inactive ALDH2*2 mutant allele.
Long-term Evaluation of AAV-Mediated sFlt-1 Gene Therapy for Ocular Neovascularization in Mice and Monkeys
Authors: Chooi-May Lai, Wei-Yong Shen, Meliha Brankov, Yvonne K Y Lai, Nigel L Barnett, Shu-Yen Lee, Ian Y S Yeo, Ranjana Mathur, Joseph E S Ho, Paul Pineda, Amutha Barathi, Chong-Lye Ang, Ian J Constable, Elizabeth P Rakoczy
Journal: Molecular Therapy (2005)

Vascular endothelial growth factor (VEGF) is one of the major mediators of retinal ischemia-associated neovascularization. We have shown here that adeno-associated virus (AAV)-mediated expression of sFlt-1, a soluble form of the Flt-1 VEGF receptor, was maintained for up to 8 and 17 months postinjection in mice and in monkeys, respectively. The expression of sFlt-1 was associated with the long-term (8 months) regression of neovascular vessels in 85% of trVEGF029 eyes. In addition, it resulted in the maintenance of retinal morphology, as the majority of the treated trVEGF029 eyes (75%) retained high numbers of photoreceptors, and in retinal function as measured by electroretinography. AAV-mediated expression of sFlt-1 prevented the development of laser photocoagulation-induced choroidal neovascularization in all treated monkey eyes. There were no clinically or histologically detectable signs of toxicity present in either animal model following AAV.sFlt injection. These results suggest that AAV-mediated secretion gene therapy could be considered for treatment of retinal and choroidal neovascularizations.
FDG-PET in Addition to Conventional Work-Up in Non–Small-Cell Lung Cancer
Authors: Harm van Tinteren, Egbert F. Smit, Otto S. Hoekstra
Journal: Journal of Clinical Oncology (2005)

were reported, a second RCT on the roleof PET in NSCLC. Both studies were presented at the 36thAnnual Meeting of the American Society of Clinical Oncol-ogy in New Orleans, LA, May 20-23, 2000. Since that time,the results of these studies have often been presented asbeing at variance. A closer look at the study of Viney et alreveals that the major difference between their study andthe PLUS study is the deﬁnition of the term “avoided/futilethoracotomy.”WhereasinthePLUSstudyobjectivecriteriawere applied (ie, benign disease, T4 lesion, macroscopicmediastinal–lymph-node involvement, distant metastaticdisease at follow-up, or exploratory thoracotomy for anyother reason), in the study of Viney et al a very pragmaticapproach was followed by taking the surgeon’s initiative asthe correct diagnosis-therapy decision (gold standard).There is no posterior evaluation of the appropriateness ofthe thoracotomy because no systematic follow-up informa-tion is available. In addition, no differentiation in stage IIIApatients is made, whereas, at the time when both studieswere active, stage IIIA/N2 was considered inoperable byinternational consensus.
The Case of Claire Conroy: Will Administrative Review Safeguard Incompetent Patients?
Authors: BERNARD LO
Journal: Annals of Internal Medicine (1986)

The emotional issue of withdrawing feeding tubes from incompetent patients was reviewed recently by the New Jersey Supreme Court in the case of Claire Conroy. The court ruled that artificial feedings do not differ from other life-sustaining treatments and may be withdrawn or withheld if they are against the patient's wishes or best interests. The ruling rejected the tradition of shared decision making by physicians and families of incompetent patients. Instead, the court required the State Ombudsman to investigate cases like that of Claire Conroy as possible cases of elder abuse. Although such review was intended to safeguard vulnerable patients, it may have detrimental effects and impede humane decisions to withhold care. To minimize cumbersome decision-making procedures, physicians should discuss life-sustaining treatment in advance with patients who are still competent. Such discussions should be more specific than is now customary.
Prognostic Effect of Basal-Like Breast Cancers Is Time Dependent: Evidence from Tissue Microarray Studies on a Lymph Node–Negative Cohort
Authors: Anna Marie Mulligan, Dushanthi Pinnaduwage, Shelley B. Bull, Frances P. O'Malley, Irene L. Andrulis
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To determine whether data obtained from tissue microarrays (TMA) of a prospectively accrued node-negative breast cancer cohort are prognostically informative, we compared data derived from TMA with previously determined molecular markers. Subsequent to this validation, we examined outcome in specific subgroups defined using TMA data. Experimental Design: A consecutive series of 1,561 patients were followed for recurrence (median follow-up of 107 months). Estrogen receptor, progesterone receptor, p53, and HER2 expression, examined using TMA constructed from 887 tumors, was compared with status evaluated previously by biochemical and molecular methods. The associations with risk of recurrence were examined for biomarkers as well as for HER2, luminal, and basal subgroups defined by immunohistochemical expression. Results: In line with earlier molecular studies, a significant risk of recurrence was found in patients with HER2 overexpression (relative risk = 2.30; P = 0.002) and p53-positive tumors (relative risk = 1.81; P = 0.005) in univariate Cox model analysis. Although complete concordance between methodologies was not observed for estrogen receptor and progesterone receptor, their associations with disease-free survival were consistent with established prognostic findings. Patients with basal-type tumors fared worse within 36 months of diagnosis but not thereafter. Conclusions: This study shows the clinical validity of TMA in evaluating the importance of prognostic markers in this cohort. Furthermore, it shows a marked time-dependent effect in tumor subgroups, most notable within the basal subgroup. Our data suggest that patients with basal-like tumors may be broadly separable into two clinically distinctive groups: those likely to experience disease recurrence in the short term and those that will experience long-term survival.
SEASONAL VITAMIN D STATUS AND THE EFFECTIVENESS OF WINTER SUPPLEMENTATION IN ELITE ATHLETES BASED AT A NATIONAL TRAINING CENTRE IN THE UK
Authors: N Lewis
Journal: British Journal of Sports Medicine (2013)

We investigated the seasonal variation in serum vitamin D (25(OH)D) in elite athletes and the effectiveness of vitamin D3 supplementation. 20 athletes comprising the British Modern Pentathlon squad were included. Blood samples for investigation of 25(OH)D were collected in beginning of Oct., end of Feb., and June. From October 2009 to February 2010 the athletes did not receive vitamin D supplements (observation period). However, for winter 2010–11 season, athletes were supplemented with 50,000 IU of D3 per month from November 2010 to March 2011 (supplementation period). Vitamin D3 supplements were from Biotech Pharmacal Inc, USA. Venous blood samples were drawn for analysis of 25(OH)D by chemiluminescence assay for total serum 25 (OH)D. Data are represented as mean (SD). Differences between means were compared using two-sample t-test. Level of significance was set at p&lt;0.05. The mean squad 25(OH)D for the observation period was 98±18 nmol.l −1 , 76±21 nmol.l −1 and 118±15 nmol.l −1 for Oct. 2009, Feb. 2010 and June 2010 respectively. For the supplementation period, mean 25(OH)D was 90±20 nmol.l −1 and 104±19 nmol.l- 1 , for Oct. 2010 and Feb. 2011. The vitamin D supplementation period was effective at elevating the squad 25(OH)D, as the Feb. 2011 result of 104±19 nmol.l −1 was greater than the Feb. 2010 result of 76±21 nmol.l −1 with no supplementation (p&lt;0.01). Supplementation was effective at elevating the squad 25(OH)D; as 6% (n=1) of the squad presented with a 25(OH)D concentration of &lt;80 nmol.l −1 in Feb.2011. In contrast, the winter period with no supplementation, 56% of the squad had 25(OH)D concentrations of &lt;80 nmol.l −1 , and 19% had 25(OH)D concentrations of &lt;50 nmol.l −1 in Feb.2010. Supplementation with 50,000 IU of vitamin D3 per month across the winter is effective in caucasian athletes in maintaining 25(OH)D &gt;80 nmol.l −1 ; as long as 25(OH)D concentrations are &gt;80 nmol.l −1 at the time of commencing supplementation.
Overexpression of transcripts originating from the MMSET locus characterizes all t(4;14)(p16;q32)-positive multiple myeloma patients
Authors: Jonathan J. Keats, Christopher A. Maxwell, Brian J. Taylor, Michael J. Hendzel, Marta Chesi, P. Leif Bergsagel, Loree M. Larratt, Michael J. Mant, Tony Reiman, Andrew R. Belch, Linda M. Pilarski
Journal: Blood (2005)
Acquired Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors Associated with a Novel T854A Mutation in a Patient with <i>EGFR</i>-Mutant Lung Adenocarcinoma
Authors: James Bean, Gregory J. Riely, Marissa Balak, Jenifer L. Marks, Marc Ladanyi, Vincent A. Miller, William Pao
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with sensitivity of lung adenocarcinomas to the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. Acquired drug resistance is frequently associated with a secondary somatic mutation that leads to the substitution of methionine for threonine at position 790 (T790M). We aimed to identify additional second-site alterations associated with acquired resistance. Experimental Design: Tumor samples were obtained from 48 patients with acquired resistance. Tumor cell DNA was analyzed for EGFR kinase domain mutations. Molecular analyses were then done to characterize the biological properties of a novel mutant EGFR allele. Results: A previously unreported mutation in exon 21 of EGFR, which leads to substitution of alanine for threonine at position 854 (T854A), was identified in one patient with a drug-sensitive EGFR L858R–mutant lung adenocarcinoma after long-term treatment with tyrosine kinase inhibitors. The T854A mutation was not detected in a pretreatment tumor sample. The crystal structure analyses of EGFR suggest that the T854 side chain is within contact distance of gefitinib and erlotinib. Surrogate kinase assays show that the EGFR T854A mutation abrogates the inhibition of tyrosine phosphorylation by erlotinib. Such resistance seems to be overcome by a new irreversible dual EGFR/HER2 inhibitor, BIBW 2992. Conclusions: The T854A mutation is the second reported second-site acquired resistance mutation that is within contact distance of gefitinib and erlotinib. These data suggest that acquired resistance to ATP-mimetic EGFR kinase inhibitors may often be associated with amino acid substitutions that alter drug contact residues in the EGFR ATP-binding pocket.
Why doctors don't read research papers
Authors: Michael O'donnell
Journal: BMJ (2005)

Editor—I sympathise with Barraclough.1 The reader deterring style in which most scientific papers are written has evolved because they are written not to be read but to be published. Authors are eager to get their names in print not because they are bursting to tell us something but for more solemn reasons. Another paper means another line on a curriculum vitae, another step towards a job or a research grant.

In 1976 in the Lancet we missed one of the great opportunities of 20th century medicine when Dr J B Healy, like another Irishman 250 years before him, submitted a modest proposal:

“It seems to me that we should for an experimental period of a year, declare a moratorium on the appending of authors' names and of the names of hospitals to articles in medical journals. If the dissemination of information is the reason why papers are submitted for publication, there will be no falling off in the numbers offered... But if far less material is offered to the journals, we shall have unmasked ourselves.”2

No editor has yet been brave enough to conduct that experiment. Not even Richard Smith, who when editor of the BMJ said that only 5% of published papers reached minimum standards of scientific soundness and clinical relevance, and in most journals the figure was less than 1%.3

The reluctance to take up Dr Healy's suggestion confirms the observation of the editor of Nature that scientific papers serve the needs of their authors above those of their readers.4 Why else would a journal devote five pages to a paper that reached this conclusion? “In this pilot study, the null hypothesis that both treatments will show equal results cannot be confirmed or rejected because of the small number of participants.”5

We need to exorcise the myth that, to write readably about science, authors have to write superficially or grossly simplify their subject. The real challenge is to present complexity in an understandable way. Anyone who has tried to do it knows that it is hard work. The writers of too many scientific papers are not prepared to make the effort.
Desoxycorticosterone Acetate (DOCA) and Vitamin C in Rheumatoid Arthritis
Authors: José M. Poal
Journal: Annals of the Rheumatic Diseases (1951)

Among various products studied on account of the similarity of their chemical formulae to that of cortisone, we have progesterone, testosterone, compound S, 17-hydroxy-pregnenolone, several other steroids, listed at present by code letters: MK-08, MK-11, MK-14, MK-18, MK-20; and finally, desoxycorticosterone with vitamin C. Lewin and Wassen (1949) first reported the effects of combined injections of desoxycorticosterone acetate (DOCA) and ascorbic acid in rheumatoid arthritis.This treatment has been repeated with contradictory results, extraordinary success having been reported by some workers, while others emphasized the inefficacy of the method.We have used this treatment with 22 patients, and our results form the subject of this communication. MaterialThe 22 patients were affected with rheumatoid arthritis in the active stage, diagnosis being confirmed by clinical and laboratory findings.There were fourteen females and eight males.The duration of the disease on beginning the treatment varied from 3 months to 15 years, and the patients' ages from 24 to 62 years.The severity of the disease varied from slight pain with little functional limitation (-+), to severe pain with complete functional disability (+ + + +).The duration of the treatment ranged from 12 to 86 days.Technique * We are indebted to the Ciba Laboratories for samples of Percorten and placebo phials, and to the Merck Laboratories for samples of Cebion.
Shear Stress Modulates Expression of Cu/Zn Superoxide Dismutase in Human Aortic Endothelial Cells
Authors: Nobutaka Inoue, Santhini Ramasamy, Tohru Fukai, Robert M. Nerem, David G. Harrison
Journal: Circulation Research (1996)

A major determinant of the level of cellular superoxide anion (O2-.) is the dismutation of O2-. to hydrogen peroxide by the enzyme superoxide dismutase (SOD). Three forms of SOD exist, but in endothelial cells, the major form outside of the mitochondria is the cytosolic copper/zinc-containing superoxide dismutase (Cu/Zn SOD). Since fluid shear stress is an important determinant of the function and structure of endothelial cells in vivo, we examined the effect of laminar shear stress on the expression of Cu/Zn SOD in cultured human aortic endothelial cells. Laminar shear stress of 0.6 to 15 dyne/cm2 increased Cu/Zn SOD mRNA in a time- and dose-dependent manner in human aortic endothelial cells. Shear stress also increased both Cu/Zn SOD protein content and the enzyme activity. Nuclear runon assays showed that nuclei from human aortic endothelial cells exposed to laminar shear stress had a 1.6-fold greater transcriptional activity of the Cu/Zn SOD gene compared with cells not exposed to shear, indicating that an increase in Cu/Zn SOD mRNA induced by laminar shear stress is at least in part mediated by increased transcription. In contrast, shear stress had no effect on Cu/Zn SOD mRNA levels in human aortic smooth muscle cells. These findings show that physiological levels of shear stress increase expression of Cu/Zn SOD in the endothelium. This adaptation to shear stress might augment the effect of locally produced NO. and thereby promote the antiatherogenic and anti-inflammatory properties of the endothelial cell.
An algorithm for referral of patients with IPF for lung transplantation.
Authors: Wim Wuyts, Michael Thomeer, Lieven Dupont, Geert Verleden
Journal: Thorax (2008)

We read with interest the paper by Mackay et al on the use of disease progression in patients with pulmonary fibrosis as a trigger for referral for lung transplantation.1 The authors attempt to identify the reasons why patients with idiopathic pulmonary fibrosis (IPF) have a higher mortality on the waiting list for lung transplantation than non-IPF patients. Although mortality on the waiting list is a major concern, physicians dealing with these patients face even more difficulties such as deciding which treatment to administer to a given patient: transplantation, inclusion in a clinical trial or classical treatment (corticosteroids, …