tbuckley/cabot-search huggingface dataset:
Gold and penicillamine: a proposed mode of action in rheumatoid arthritis, based on synovial fluid analysis.
Authors: M H Pritchard, G Nuki
Journal: Annals of the Rheumatic Diseases (1978)

Although in common use, there is still controversy as to the way in which gold and penicillamine act in rheumatoid arthritis (RA). In this study, synovial fluids from 4 groups of patients have been compared: (1) RA patients on gold/penicillamine, (2) RA patients on non-steriodal anti-inflammatory drugs (NSAID) only, (3) osteoarthritis patients, and (4) patients with sero-negative arthropathies. The parameters measured were differential agglutination titre (DAT), total haemolytic complement (CH50), total protein, total white cell count, and immunoglobulins. RA patients on gold/penicillamine have lower synovial DAT levels and higher CH50 levels than RA patients on NSAID only, and total and cryoprecipitable IgM levels very close to those found in the sero-negative joint fluids. The non-specific inflammatory parameters, ie, white cell count and total protein are unchanged after good/penicillamine therapy. In a second study, the serum DATs of patients in total remission after gold/penicillamine were compared with similar patients on NSAID only. The DAT falls significantly in the former group (P less than 0.001), but not in the latter suggesting that fall in DAT is a consequence of therapy rather than remission. The parameters altered by gold/penicillamine in the synovial fluid are those that distinguish RA from non-rheumatoid arthropathies suggesting the drug's primary effect is to render the disease sero-negative. The results support the hypothesis that both drugs have a common mode of action based on their active thiol groups, and that the fall in DAT is due to the reduction of the antigenicity of the IgG complexes.
Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial
Authors: George D Demetri, Allan T van Oosterom, Christopher R Garrett, Martin E Blackstein, Manisha H Shah, Jaap Verweij, Grant McArthur, Ian R Judson, Michael C Heinrich, Jeffrey A Morgan, Jayesh Desai, Christopher D Fletcher, Suzanne George, Carlo L Bello, Xin Huang, Charles M Baum, Paolo G Casali
Journal: The Lancet (2006)
Re: Proton vs Intensity-Modulated Radiotherapy for Prostate Cancer: Patterns of Care and Early Toxicity
Authors: S. E. Schild, S. R. Keole, R. L. Foote
Journal: JNCI Journal of the National Cancer Institute (2013)

Yu and colleagues used the Medicare billing database to compare intensity-modulated radiotherapy (IMRT) to proton beam radiotherapy (PRT) (1). Unfortunately, this comparison is difficult because of the nature of the groups compared, data within the database, retrospective study design, and various biases. Inherent to this analysis was the attempt to make valid conclusions about endpoints this database was not designed to measure. The most valid conclusion was that PRT was more expensive. Regarding the statement, “Patients were assigned to the PRT group if there were any codes for PRT delivery,” the methodology of including PRT patients who had any PRT may have introduced bias. It is likely that some patients received PRT as a boost after photon radiotherapy (RT). These appear to have been included in the proton group. Patients treated in this manner generally received two-thirds of their radiation as photons. Their inclusion would bias the study, making interpretation incomprehensible. Assuming they were assigned to the PRT arm, they would likely have more toxicity because greater volumes of bladder and intestine would have been irradiated than with PRT alone. Because the majority of their dose was photons, the results would be more likely to reflect photon therapy. Toxicities included that appear unrelated to radiotherapy include genitourinary infection, upper tract dysfunction, and systemic derangements. Including toxicity codes that are likely unrelated to radiotherapy serve to make the outcomes appear more similar than different. The most frequent radiotherapy toxicities are irritative bladder and rectal voiding side effects, which were not considered in this analysis. Also left out was bleeding that did not result in transfusion, which is a common toxicity. Leaving out the more common side effects/toxicities would also make the outcomes appear more similar than different. The problem with the statement, “This study represents the most robust comparison of early toxicity for PRT vs IMRT for prostate cancer to date” is that this study is not robust. The authors did not include the majority of RT-related toxicity and included toxicity unrelated to RT. Then, they make the conclusion that this is robust, whereas the prospective clinical data suggest extremely low risk of PRT-related toxicity (2,3). The Medicare databases do
Ximelagatran vs Low-Molecular-Weight Heparin and Warfarin for the Treatment of Deep Vein Thrombosis
Authors: Jean-Noel Fiessinger, Menno V. Huisman, Bruce L. Davidson, Henri Bounameaux, Charles W. Francis, Henry Eriksson, Torbjörn Lundström, Scott D. Berkowitz, Per Nyström, Mona Thorsén, Jeffrey S. Ginsberg, for the THRIVE Treatment Study Investigators
Journal: JAMA (2005)

ContextXimelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard treatment of acute venous thromboembolism.ObjectiveTo compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism.Design, Setting, and PatientsRandomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002.InterventionsPatients were randomized to receive 6 months of treatment with either oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0.Main Outcome MeasuresRecurrent venous thromboembolism, bleeding, and mortality.ResultsVenous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval [CI], –1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, −1.0%; 95% CI, –2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, –1.1%; 95% CI, –2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients).ConclusionsOral ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients require regular monitoring; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.
A Novel Platform for Detection of CK+ and CK− CTCs
Authors: Chad V. Pecot, Farideh Z. Bischoff, Julie Ann Mayer, Karina L. Wong, Tam Pham, Justin Bottsford-Miller, Rebecca L. Stone, Yvonne G. Lin, Padmavathi Jaladurgam, Ju Won Roh, Blake W. Goodman, William M. Merritt, Tony J. Pircher, Stephen D. Mikolajczyk, Alpa M. Nick, Joseph Celestino, Cathy Eng, Lee M. Ellis, Michael T. Deavers, Anil K. Sood
Journal: Cancer Discovery (2011)

Metastasis is a complex, multistep process that begins with the epithelial-mesenchymal transition (EMT). Circulating tumor cells (CTC) are believed to have undergone EMT and thus lack or express low levels of epithelial markers commonly used for enrichment and/or detection of such cells. However, most current CTC detection methods target only EpCAM and/or cytokeratin (CK) to enrich epithelial CTCs, resulting in failure to recognize other, perhaps more important, CTC phenotypes that lack expression of these markers. Here, we describe a population of complex aneuploid CTCs that do not express CK or CD45 antigen in patients with breast, ovarian, or colorectal cancer. These cells were not observed in healthy subjects. We show that the primary epithelial tumors were characterized by similar complex aneuploidy, indicating conversion to an EMT phenotype in the captured cells. Collectively, our study provides a new method for highly efficient capture of previously unrecognized populations of CTCs.Current assays for CTC capture likely miss populations of cells that have undergone EMT. Capture and study of CTCs that have undergone EMT would allow a better understanding of the mechanisms driving metastasis.
"Runners Index", "Physical Education Index" and "Physical Education/Sports Index"
Authors: H. E. Robson
Journal: British Journal of Sports Medicine (1979)

Suddenly and independently, these three indices have sprung up in the USA, two devoted to physical education in all its aspects, and one devoted to running only, but also to all aspects of fitness and injury that might affect the runner.All three cover a very wide field of journals in the English language, all have a wide selection of references to articles on sports medicine, and all three list the British Journal of Sports Medicine among their publications, which are predominently of American origin.It is the only medical journal in Runners Index (R.l.), which includes also "Vereris"; the only medical journal among seven in PE Index; and one among four journals of British origin.All three contain few medical journals of any country, apart from the obvious sports medicine specialist publications such as J. Sports Med.& Phys.Fitness; Physician & Sp.Med.; Am.J. Sp.Med.It is difficult to compare the sports medicine and exercise physiology contents of each index, as they are arranged in different places in all three, but a careful look through enables some comparisons to be made, best shown in tabular form.
Overexpression of Brain Natriuretic Peptide in Mice Ameliorates Immune-Mediated Renal Injury
Authors: Takayoshi Suganami, Masashi Mukoyama, Akira Sugawara, Kiyoshi Mori, Tetsuya Nagae, Masato Kasahara, Kensei Yahata, Hisashi Makino, Yuriko Fujinaga, Yoshihiro Ogawa, Issei Tanaka, Kazuwa Nakao
Journal: Journal of the American Society of Nephrology (2001)

ABSTRACT. One of major causes of end-stage renal disease is glomerulonephritis, the treatment of which remains difficult clinically. It has already been shown that transgenic mice that overexpress brain natriuretic peptide (BNP), with a potent vasorelaxing and natriuretic property, have ameliorated glomerular injury after subtotal nephrectomy. However, the role of natriuretic peptides in immune-mediated renal injury still remains unknown. Therefore, the effects of chronic excess of BNP on anti-glomerular basement membrane nephritis induced in BNP-transgenic mice (BNP-Tg) were investigated and the mechanisms how natriuretic peptides act on mesangial cells in vitro were explored. After induction of nephritis, severe albuminuria (∼21-fold above baseline), tissue damage, including mesangial expansion and cell proliferation, and functional deterioration developed in nontransgenic littermates. In contrast, BNP-Tg exhibited much milder albuminuria (approximately fourfold above baseline), observed only at the initial phase, and with markedly ameliorated histologic and functional changes. Up-regulation of transforming growth factor-β (TGF-β) and monocyte chemoattractant protein-1 (MCP-1), as well as increased phosphorylation of extracellular signal-regulated kinase (ERK), were also significantly inhibited in the kidney of BNP-Tg. In cultured mesangial cells, natriuretic peptides counteracted the effects of angiotensin II with regard to ERK phosphorylation and fibrotic action. Because angiotensin II has been shown to play a pivotal role in the progression of nephritis through induction of TGF-β and MCP-1 that may be ERK-dependent, the protective effects of BNP are likely to be exerted, at least partly, by antagonizing the renin-angiotensin system locally. The present study opens a possibility of a novel therapeutic potential of natriuretic peptides for treating immune-mediated renal injury.
IL-5 links adaptive and natural immunity in reducing atherosclerotic disease
Authors: Alan Daugherty, Debra L. Rateri, Victoria L. King
Journal: Journal of Clinical Investigation (2004)

Oxidized LDL induces changes in several facets of the immune system, although the relationships between these facets and their contributions to atherogenesis have yet to be fully elucidated. A report in this issue of the JCI provides a novel demonstration of the adaptive immune system influencing the production of natural antibodies. The results demonstrate that injection of malondialdehyde-modified LDL promotes a Th2 response that in turn increases the titers of the natural antibody T15/EO6, which recognizes the oxidized phospholipid POVPC. Atherosclerotic lesion size in LDL receptor–deficient mice is reduced as a consequence of the increase in natural antibody titers, and IL-5 is identified as the link between the adaptive and natural immune systems.
Biallelic Deleterious <i>BRCA1</i> Mutations in a Woman with Early-Onset Ovarian Cancer
Authors: Susan M. Domchek, Jiangbo Tang, Jill Stopfer, Dana R. Lilli, Nancy Hamel, Marc Tischkowitz, Alvaro N.A. Monteiro, Troy E. Messick, Jacquelyn Powers, Alexandria Yonker, Fergus J. Couch, David E. Goldgar, H. Rosemarie Davidson, Katherine L. Nathanson, William D. Foulkes, Roger A. Greenberg
Journal: Cancer Discovery (2012)

BRCA1 and BRCA2 are the most important breast and ovarian cancer susceptibility genes. Biallelic mutations in BRCA2 can lead to Fanconi anemia and predisposition to cancers, whereas biallelic BRCA1 mutations have not been confirmed, presumably because one wild-type BRCA1 allele is required during embryogenesis. This study describes an individual who was diagnosed with ovarian carcinoma at age 28 and found to have one allele with a deleterious mutation in BRCA1, c.2457delC (p.Asp821Ilefs*25), and a second allele with a variant of unknown significance in BRCA1, c.5207T>C (p.Val1736Ala). Medical records revealed short stature, microcephaly, developmental delay, and significant toxicity from chemotherapy. BRCA1 p.Val1736Ala cosegregated with cancer in multiple families, associated tumors showed loss of wild-type BRCA1, and BRCA1 p.Val1736Ala showed reduced DNA damage localization. These findings represent the first validated example of biallelic deleterious human BRCA1 mutations and have implications for the interpretation of genetic test results.Accurate assessment of genetic testing data for BRCA1 mutations is essential for clinical monitoring and treatment strategies. Here, we report the fi rst validated example of an individual with biallelic BRCA1 mutations, early-onset ovarian cancer, and clinically significant hypersensitivity to chemotherapy.
In Early-Stage Breast Cancer, the Estrogen Receptor Interacts With Correlation Between Human Epidermal Growth Factor Receptor 2 Status and Age at Diagnosis, Tumor Grade, and Lymph Node Involvement
Authors: Patrick Neven, Olivier Brouckaert, Vanya Van Belle, Isabelle Vanden Bempt, Wouter Hendrickx, Hyonil Cho, Karen Deraedt, Ben Van Calster, Sabine Van Huffel, Philippe Moerman, Frederic Amant, Karin Leunen, Ann Smeets, Hans Wildiers, Robert Paridaens, Ignace Vergote, Marie-Rose Christiaens
Journal: Journal of Clinical Oncology (2008)
The Solitary Pulmonary Nodule
Authors: E. Metz Wright
Journal: JAMA (1980)

<h3>To the Editor.—</h3> Referring to the response in the QUESTIONS AND ANSWERS section (243:1468, 1980), to "The Solitary Pulmonary Nodule," I am concerned that Hermes C. Grillo, MD, for whom I have a great respect, did not mention the possibility of coccidioidomycosis that is a common endemic fungus disease in the Sonoran Desert area; we have found this to be one of the most common causes of solitary pulmonary nodules in asymptomatic persons who live in Arizona, California, and parts of Mexico. In a middle-aged, nonsmoking asymptomatic patient with a finding of a well-circumscribed pulmonary nodule on a routine chest x-ray film, the most likely diagnosis would be coccidioidomycosis. I believe efforts should be made to secure more corroborative evidence such as findings from skin tests and serological, bronchoscopic, and sputum cytological examinations before performing thoracotomy. If the lesion is readily accessible, results of a percutaneous needle biopsy under fluoroscopic
Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells
Authors: Zi Jian Pan, Shannon Maier, Karen Schwarz, Jennifer Azbill, Shizuo Akira, Satoshi Uematsu, A. Darise Farris
Journal: Annals of the Rheumatic Diseases (2009)

Objectives The objectives of this study were to determine whether late apoptotic cell material directly induces autoantibodies characteristic of systemic lupus erythematosus (SLE) and to investigate the innate recognition pathways involved. Methods B6, B6.MyD88 –/– , B6.TLR7 –/– and B6.TLR9 –/– mice were subcutaneously injected with B6 syngeneic late apoptotic thymocytes (SLATs) without adjuvant on days 0, 10, 24 and 37. Sera were tested for IgG antibodies to histones and double-stranded DNA (dsDNA) by ELISA and Crithidia luciliae indirect immunofluorescence. IgG and C3 deposition in kidney glomeruli was assessed by immunostaining and fluorescence microscopy. Results SLAT injections induced anti-dsDNA and anti-histone antibodies of the IgG1 and IgG2b isotypes in B6 but not MyD88 –/– mice. TLR7 –/– and TLR9 –/– mice injected with SLATs produced delayed or slightly more robust responses, respectively. SLAT injections induced IgG deposits in renal glomeruli of B6, TLR7 –/– and TLR9 –/– mice that were absent in MyD88 –/– mice. Unlike B6 and TLR9 –/– animals, TLR7 –/– mice failed to exhibit IgG colocalised glomerular C3 deposits and demonstrated autoantibodies of primarily the IgG2a isotype. Conclusions Late apoptotic cell-induced anti-histone and anti-dsDNA antibodies require MyD88 but not Toll-like receptor (TLR)9. Moreover, TLR7 promotes glomerular C3 deposition, possibly through a mechanism of altered antibody isotype switching.
Genetic Load on Amygdala Hypofunction During Sadness in Nonaffected Brothers of Schizophrenia Patients
Authors: Ute Habel, Martina Klein, N. Jon Shah, Ivan Toni, Karl Zilles, Peter Falkai, Frank Schneider
Journal: American Journal of Psychiatry (2004)

In a previous study, the authors reported that patients with schizophrenia show subcortical-limbic hypoactivity during sadness. In this study, they capitalized on those findings in order to assess the genetic influence of negative mood experience in schizophrenia patients. Brain activity was measured during mood induction in patients with schizophrenia and their first-degree nonaffected relatives.Functional magnetic resonance imaging was used to investigate 13 male patients with schizophrenia, their nonaffected brothers (N=13), and a group of 26 individually matched healthy subjects unrelated to the siblings during induction of sad and happy moods as well as during a cognitive control task. A regional analysis was applied to investigate a possible subcortical-limbic dysfunction in relatives.Mood induction was successful in all groups according to subjective ratings. During sadness induction, the patients and their nonaffected siblings demonstrated less activity in the amygdala compared with the healthy group of nonrelatives. Other regions of interest, such as the left orbitofrontal cortex, the left superior temporal cortex, and the left precuneus/posterior cingulate revealed significant group differences only between patients and nonrelated healthy subjects. During positive mood induction, no group differences could be found in the amygdala.Following induction of sad mood, both patients with schizophrenia and their nonaffected brothers displayed reduced brain activity in the amygdala. Such hypoactivity is likely to represent a genetic influence and indicates that efficient compensatory mechanisms capable of preventing the onset of the illness must exist in nonaffected relatives.
Variation in circulating immune complex levels with diet, exercise, and sleep: a comparison between normal controls and patients with systemic lupus erythematosus.
Authors: D A Isenberg, A J Crisp, W J Morrow, D Newham, M L Snaith
Journal: Annals of the Rheumatic Diseases (1981)

Circulating immune complexes (CIC) were measured in 4 normal controls and 8 patients with systemic lupus erythematosus (SLE) by a polyethylene glycol precipitation (PEG) method during a 24-hour period. In all the normal controls levels fell during sleep and after drinking 1 pint (568 ml) of milk and rose before getting out of bed and after moderate exercise. There were also marked differences in the patterns of rise and fall of the CIC levels between the normal controls and patients with SLE. Insufficient account has been taken of these physiological influences in CIC levels in previous studies attempting to relate disease activity to quantitative levels.
Constant relative rate of protein evolution and detection of functional diversification among bacterial, archaeal and eukaryotic proteins
Authors: I King Jordan, Fyodor A Kondrashov, Igor B Rogozin, Roman L Tatusov, Yuri I Wolf, Eugene V Koonin
Journal: Genome biology (2001)

Detection of changes in a protein's evolutionary rate may reveal cases of change in that protein's function. We developed and implemented a simple relative rates test in an attempt to assess the rate constancy of protein evolution and to detect cases of functional diversification between orthologous proteins. The test was performed on clusters of orthologous protein sequences from complete bacterial genomes (Chlamydia trachomatis, C. muridarum and Chlamydophila pneumoniae), complete archaeal genomes (Pyrococcus horikoshii, P. abyssi and P. furiosus) and partially sequenced mammalian genomes (human, mouse and rat).Amino-acid sequence evolution rates are significantly correlated on different branches of phylogenetic trees representing the great majority of analyzed orthologous protein sets from all three domains of life. However, approximately 1% of the proteins from each group of species deviates from this pattern and instead shows variation that is consistent with an acceleration of the rate of amino-acid substitution, which may be due to functional diversification. Most of the putative functionally diversified proteins from all three species groups are predicted to function at the periphery of the cells and mediate their interaction with the environment.Relative rates of protein evolution are remarkably constant for the three species groups analyzed here. Deviations from this rate constancy are probably due to changes in selective constraints associated with diversification between orthologs. Functional diversification between orthologs is thought to be a relatively rare event. However, the resolution afforded by the test designed specifically for genomic-scale datasets allowed us to identify numerous cases of possible functional diversification between orthologous proteins.