tbuckley/cabot-search huggingface dataset:
Regulatory T cells and toll-like receptors: regulating the regulators
Authors: R. Sutmuller, A. Garritsen, G. J Adema
Journal: Annals of the Rheumatic Diseases (2007)

Regulatory T cells (Treg) play a crucial role in maintaining control of leucocytes. Several studies have shown that in vivo Treg depletion results in autoimmune syndromes like thyroiditis, gastritis, diabetes mellitus and colitis, but at the same time, may also result in improved anti-tumour vaccination. Although Treg are recognised to maintain peripheral tolerance in healthy individuals, recent research has shown that Treg also suppress immune responses during infections to prevent tissue damage. How the Treg themselves are regulated is still under investigation. Their suppressive activity must be regulated in order to allow for the effective elimination of pathogens. Until recently, this control of Treg function was found to be through modulation via cytokines or by stimulation via co-stimulatory molecules on antigen-presenting cells. It is now demonstrated, however, that the presence of pathogens can be communicated to Treg directly through toll-like receptors (TLRs). Up until now, Treg have been reported to respond to ligands for TLR2, 4, 5 and 8, and different TLRs can have alternative effects on Treg resulting in more suppression or, in contrast, abrogation of suppression. As TLRs can also recognise endogenous proteins, such as heat shock proteins, it is tempting to speculate on the role of these proteins in modulating Treg function during chronic inflammation. In this review, we will discuss the implications of TLR engagement on Treg and any consequences this may have for chronic autoinflammatory diseases like rheumatoid arthritis (RA).
Prospective Identification of Tumorigenic Prostate Cancer Stem Cells
Authors: Anne T. Collins, Paul A. Berry, Catherine Hyde, Michael J. Stower, Norman J. Maitland
Journal: Cancer Research (2005)

Existing therapies for prostate cancer eradicates the bulk of cells within a tumor. However, most patients go on to develop androgen-independent disease that remains incurable by current treatment strategies. There is now increasing evidence in some malignancies that the tumor cells are organized as a hierarchy originating from rare stem cells that are responsible for maintaining the tumor. We report here the identification and characterization of a cancer stem cell population from human prostate tumors, which possess a significant capacity for self-renewal. These cells are also able to regenerate the phenotypically mixed populations of nonclonogenic cells, which express differentiated cell products, such as androgen receptor and prostatic acid phosphatase. The cancer stem cells have a CD44+/alpha2beta1hi/CD133+ phenotype, and we have exploited these markers to isolate cells from a series of prostate tumors with differing Gleason grade and metastatic states. Approximately 0.1% of cells in any tumor expressed this phenotype, and there was no correlation between the number of CD44+/alpha2beta1hi/CD133+ cells and tumor grade. The identification of a prostate cancer stem cell provides a powerful tool to investigate the tumorigenic process and to develop therapies targeted to the stem cell.
Disulfiram-like Reaction to a Cephalosporin
Authors: F. Gilbert McMahon
Journal: JAMA (1980)

To the Editor.—  The disulfiram reaction to ethanol usually lasts a couple of hours and is characterized by a flushed face and a feeling of warmth. Often nausea, vomiting, sweating, and headaches occur. Rarely, hypotension, syncope, vertigo, or chest pains develop. Besides disulfiram, these reactions are known to occur after chlorpropamide, where the tendency to flush after alcohol appears to be inherited as an autosomal dominant trait.1The antiprotozoal agent, metronidazole, may cause similar reactions. Cefoperazone is a new semisynthetic parenteral cephalosporin. We recently administered cefoperazone to 24 healthy male volunteers as part of a tolerance-kinetics study. After a week of infusions, several of the subjects noted a peculiar facial flushing and tachycardia (to 180 beats per minute) occurring two to three days after discharge and within a few minutes after drinking one or two glasses of beer.  We then deliberately challenged five other subjects 36 hours after their
Police surgeons are important part of criminal justice system
Authors: M. M Stark
Journal: BMJ (2000)

EDITOR—Clinical forensic medicine is one of the most dynamic and rapidly advancing specialties, but the article in Career Focus missed an opportunity to show just how the work of a police surgeon has changed in recent years.1

In contrast to the views expressed, the assessment of drink-drivers is now a minor component of the work. Much more of the doctor's time is spent assessing substance misusers, mentally ill people, injured prisoners, and people with pre-existing morbidity to determine …
Allelic polymorphisms of human Fc gamma receptor IIA and Fc gamma receptor IIIB. Independent mechanisms for differences in human phagocyte function.
Authors: J E Salmon, J C Edberg, N L Brogle, R P Kimberly
Journal: Journal of Clinical Investigation (1992)

Two different allelic polymorphisms among the isoforms of human Fc gamma receptors have been defined: the low-responder (LR)-high-responder (HR) polymorphism of huFc gamma RIIA expressed on both PMN and monocytes and the NA1-NA2 polymorphism of the neutrophil Fc gamma RIII (huFc gamma RIIIB). To address the issues of whether the LR-HR polymorphism has a significant impact on Fc gamma R-mediated functions in human blood cells and whether any differences in LR-HR might be related to higher Fc gamma R-mediated phagocytosis in NA1 donors, we examined Fc gamma R-specific binding and internalization by donors homozygous for the two huFc gamma RIIA alleles. PMN from LR homozygotes showed consistently higher levels of internalization of erythrocytes opsonized with pooled human IgG (E-hIgG). The absence of an LR-HR phagocytic difference with erythrocytes opsonized with either anti-Fc gamma RIIA MAb IV.3 or rabbit IgG, as opposed to E-hIgG, suggested that the Fc piece of the opsonin might be important for this LR-HR difference. Accordingly, we studied HR and LR homozygotes with human IgG subclass-specific probes. Both PMN (independent of huFc gamma RIIIB phenotype) and monocytes from LR donors bound and internalized erythrocytes coated with human IgG2 (E-hIgG2) efficiently, whereas phagocytes from HR donors did so poorly. E-hIgG2 internalization was completely abrogated by blockade of the ligand binding site of huFc gamma RIIA with IV.3 Fab, indicating that huFc gamma RIIA is essential for the handling of hIgG2 and that the mechanism of the LR-HR phagocytic difference is at the level of ligand binding to huFc gamma RIIA. In contrast, the difference in internalization of E-hIgG between NA1 and NA2 homozygous donors was independent of the huFc gamma RIIA phenotype and did not manifest differences in ligand binding. Thus, the two known allelic polymorphisms of human Fc gamma R have distinct and independent mechanisms for altering receptor function, which may influence host defense and immune complex handling.
Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma?
Authors: J. L. Clarke , M. M. Ennis , W. K. A. Yung, S. M. Chang, P. Y. Wen, T. F. Cloughesy, L. M. DeAngelis, H. I. Robins, F. S. Lieberman, H. A. Fine, L. Abrey, M. R. Gilbert, M. Mehta, J. G. Kuhn, K. D. Aldape, K. R. Lamborn, M. D. Prados
Journal: Neuro-Oncology (2011)

Historically, the North American Brain Tumor Consortium used 6-month progression-free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes. Two data sets were analyzed. The first included 511 patients enrolled during the period 1998-2005, 105 of whom had surgery (excluding biopsies) during the study or ≤ 30 days prior to registration. Analysis was stratified on the basis of whether temozolomide was part of the protocol treatment regimen. The second data set included 247 patients enrolled during 2005-2008, 103 of whom underwent surgery during the clinical trial or immediately prior to study registration. A combined data set consisting of all patients who did not receive temozolomide was also compiled. No statistically significant difference in PFS6 or OS was found between the surgery and nonsurgery groups in either data set alone or in the combined data set (P > .45). We conclude that PFS6 and OS results for patients with and without surgical intervention at the time of progression are similar, allowing data from these patients to be combined in assessing the benefit of new treatments without the need for stratification or other statistical adjustment.
Global variation in the prevalence and severity of asthma symptoms: Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC)
Authors: C K W Lai, R Beasley, J Crane, S Foliaki, J Shah, S Weiland
Journal: Thorax (2009)

<h3>Background:</h3> Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC) measured the global prevalence and severity of asthma symptoms in children. <h3>Methods:</h3> A cross-sectional questionnaire survey of 798 685 children aged 13–14 years from 233 centres in 97 countries, and 388 811 children aged 6–7 years from 144 centres in 61 countries, was conducted between 2000 and 2003 in &gt;90% of the centres. <h3>Results:</h3> The prevalence of wheeze in the past 12 months (current wheeze) ranged from 0.8% in Tibet (China) to 32.6% in Wellington (New Zealand) in the 13–14 year olds, and from 2.4% in Jodhpur (India) to 37.6% in Costa Rica in the 6–7 year olds. The prevalence of symptoms of severe asthma, defined as ⩾4 attacks of wheeze or ⩾1 night per week sleep disturbance from wheeze or wheeze affecting speech in the past 12 months, ranged from 0.1% in Pune (India) to 16% in Costa Rica in the 13–14 year olds and from 0% to 20.3% in the same two centres, respectively, in the 6–7 year olds. Ecological economic analyses revealed a significant trend towards a higher prevalence of current wheeze in centres in higher income countries in both age groups, but this trend was reversed for the prevalence of severe symptoms among current wheezers, especially in the older age group. <h3>Conclusion:</h3> Wide variations exist in the symptom prevalence of childhood asthma worldwide. Although asthma symptoms tend to be more prevalent in more affluent countries, they appear to be more severe in less affluent countries.
Increased circulating platelet microparticles as a potential biomarker in asthma
Authors: D. Duarte, T. Taveira-Gomes, O. Sokhatska, C. Palmares, R. Costa, R. Negrão, J. T. Guimarães, L. Delgado, R. Soares, A. Moreira
Journal: Allergy (2013)

Background Endothelial (EMPs) and platelet microparticles (PMPs) have been studied as biomarkers in several inflammatory diseases and as central players in intercellular communication. Methods In this cross-sectional study, we aimed to assess microparticle levels in asthma. Circulating microparticles and inflammatory and angiogenic markers were assessed by clinical and laboratorial evaluation, flow cytometry, and immunoassays, in a group of 20 asthmatic and 15 nonasthmatic subjects. Results Circulating levels of PMPs (either CD31+/42b+ or CD31+/42b+/AnV+) were significantly increased in asthmatics (P = 0.021) even after adjustment for confounders. Apoptotic EMPs (CD31+/42b−−/AnV+) were significantly increased before (P = 0.005) but not after adjustments (P = 0.117). Conclusions We propose that PMPs may be putative asthma biomarkers, playing a role in asthma pathophysiology.
AT-05 * TARGETING mTOR DOWNSTREAM OF LIN28 IN ATYPICAL TERATOID RHABDOID TUMORS PROMOTES APOPTOSIS AND SUPPRESSES TUMORIGENICITY
Authors: J. Rubens, A. Price, C. Eberhart, E. Raabe
Journal: Neuro-Oncology (2015)

LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers. One of the canonical downstream targets of LIN28 is the mTOR pathway. We have previously shown that overexpression of LIN28 in Atypical Teratoid Rhabdoid Tumors (AT/RT) contributes to the aggressive nature of the tumor. We hypothesized that AT/RT would have increased expression of mTOR signaling due to high-level expression of LIN28. We found that primary human AT/RT samples do have high levels of P-S6 and P-AKT expression by immunohistochemistry staining (mean H-score for P-S6 36.3; p-AKT 150.4). The dual TORC1/2 inhibitor MLN0128 has good brain penetration and is currently being tested in phase I clinical trials in children. Treatment of AT/RT cell lines with MLN0128 inhibits TORC1/2 targets in vitro and suppresses cell proliferation at 10nM concentration (MTS assay for BT12 p = 0.0034 vs DMSO control; BT37 p = 0.0064 vs DMSO control; and CHLA-06 p = 0.002 vs DMSO control by t-test). MLN0128 also slows cell proliferation via BrdU assay (BT-37 p = 0.0241 10nM vs DMSO control; CHLA-06 p = 0.045 10nM vs DMSO control by t-test) and induces apoptosis measured by Western blot for PARP and cleaved caspase 3 assay (BT-37 p = 0.001 100nM vs DMSO; CHLA-06 p = 0.007 10nM vs DMSO by t-test). MLN0128 treatment of AT/RT xenograft mouse models leads to rapid reduction in tumor volume compared to controls treated with vector alone (61.9% average reduction in tumor volume with MLN0128 treatment vs 272.1% average increase in tumor volume in vector control; p = 0.006 by t-test). Targeting the overexpressed mTOR pathway with the TORC1/TORC2 inhibitor MLN0128 leads to potent in vitro and in vivo activity against AT/RT. MLN0128 may be a candidate for future clinical trials to treat this aggressive tumor.
Detection of hepatitis C virus antibodies and hepatitis C virus RNA in patients with alcoholic liver disease
Authors: Shuhei Nishiguchi, Tetsuo Kuroki, Tsuneo Yabusako, Shuichi Seki, Kenzo Kobayashi, Takeyuki Monna, Shuzo Otani, Masami Sakurai, Toshio Shikata, Sukeo Yamamoto
Journal: Hepatology (1991)

The relationship between alcoholic liver disease and hepatitis C virus was studied in 80 patients by searching for hepatitis C virus RNA with the polymerase chain reaction and by measuring hepatitis C virus antibodies. By C-100 enzyme-linked immunosorbent assay, hepatitis C virus antibodies were found in 2 of 10 patients with fibrosteatosis, 8 of 20 patients with alcoholic hepatitis, 14 of 19 patients with chronic hepatitis and 19 of 31 patients with cirrhosis. Percentages of patients with antibodies found by C-100 radioimmunoassay and by enzyme-linked immunosorbent assay based on sequence peptide 42 were lower; of the 16 patients with a low titer by C-100 enzyme-linked immunosorbent assay, 10 were negative by radioimmunoassay and 6 were negative by sequence peptide 42. By a second-generation recombinant immunoblot assay, hepatitis C virus antibodies were found in 1 of 10 patients with fibrosteatosis, 2 of 20 patients with alcoholic hepatitis, 15 of 19 patients with chronic hepatitis and 18 of 31 patients with cirrhosis. Hepatitis C virus RNA was found in 1 of 10 patients with fibrosteatosis, 3 of 20 patients with alcoholic hepatitis, 13 of 19 patients with chronic hepatitis and 20 of 31 patients with cirrhosis. Of the 37 patients with hepatitis C virus RNA, 31 had antibodies by C-100 enzyme-linked immunosorbent assay (25 patients at a high titer [cut-off index greater than 6]), and 31 had antibodies by second-generation recombinant immunoblot assay. Patients with cirrhosis and hepatitis C virus RNA had higher ALT activity than such patients without hepatitis C virus RNA (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
CORRELATES OF MOTIVATION TO PRACTICE PHYSICAL ACTIVITY AMONG STUDENTS FROM PORTUGUESE MILITARY COLLEGE
Authors: M Peralta, J Martins, A Marques, C Correia
Journal: British Journal of Sports Medicine (2013)

The study of physical activity (PA) is important for many reasons, including the need to identify determinants of physically active lifestyles for health, educational and social benefits. This study sought to examine the variables that can explain the motivation of students attending the military superior education to practice PA. 415 young men (age 22±2 y) participated in the study. Data were collected using a questionnaire about leisure time activities, PA participation, goal orientation, perceptions of health and competence, and attitudes towards school, PE and PA. A multiple linear regression was used for data processing. Nearly all participants participate in extracurricular PA (85.5%). On a scale of 1 to 10, the mean level of motivation to practice PA was 7.8±1.3. 93% had a positive attitude toward PA. The mean levels of task orientation were higher (mean=3.3±0.4) than ego orientation (2.3±1). Most students considered themselves competent (3.2±0.6), varying between 1 and 4. Finally, they were asked how important it was to be good at sports, also measured on a scale between 1 and 4.The mean level was 3.2±0.6. The model of multiple linear regression used to explain the variation of motivation to practice PA according to age, attitude toward PA, goal orientation, perception of competence and importance assigned to be good at sports is significant (F(8,406)=13.581, p&lt;0.001) and explained 20% of motivation variations. The students’ motivation to practice PA could be explained by the attitude toward PA (p&lt;0.001), perception of competence (p=0.001) and the importance assigned to be good at sports (p=0.005). This means it is possible to increase the students’ motivation to practice PA if the attitude and perception of competence increase. On the other hand, changing the school climate, valuating the practice of PA, seems to contribute to enhancing the levels of motivation and, consequently, the levels of PA.
Interactions of C-reactive protein with the complement system. III. Complement-dependent passive hemolysis initiated by CRP.
Authors: A.P. Osmand, R.F. Mortensen, Joan Siegel, H. Gewurz
Journal: The Journal of Experimental Medicine (1975)

Interactions of CRP with various substrates in the presence of human serum have been shown to result in efficient activation of C components C1-C5. We now report the ability of CRP to initiate C-dependent hemolysis. For this purpose CRP was isolated by affinity chromatography using pneumococcal CPS and gel filtration; its purity was established by several criteria. Erythrocytes were coated with CPS (E-CPS) and passively sensitized with CRP. C-dependent lysis of these cells was observed upon the addition of suitably absorbed human serum, and the efficiency of hemolysis compared favorably with that initiated by rabbit IgG anti-CPS antibody. CRP also sensitized E-CPS for lysis by guinea pig C; partial lysis was seen when C4-deficient guinea pig serum was used, suggesting that CRP also shares with antibody the ability of CRP to fully activate the C system and provide further evidence for a role for CRP similar to that of antibody in the initiation and modulation of inflammatory reactions via the complete system.
Contractile shortening response of ventricular cells to extracellular acidosis. Evidence for two-site control of H+-Ca2+ interaction.
Authors: G A Langer, T L Rich, S Ji
Journal: Circulation Research (1989)

The effect of extracellular acidosis on contraction of single isolated ventricular cells from rabbit was measured in a system in which pHo could be changed in less than 200 msec. The contractile response to acidotic levels was complete within 25 seconds. The response was measured 30 seconds after pHo was decreased to 7.0, 6.5, 6.0, and 5.5 at each of 8 [Ca]o levels (0.125-4.0 mM). Cell shortening versus [Ca]o was plotted to construct a curve for each pHo level, with each point relative to shortening at pH 7.5, [Ca]o = 1 mM (100% value). Calcium current (1 mM [Ca]o) was also measured 30 seconds after pHo was decreased from 7.5 to 6.5 with single-cell patch clamp technique. The contractile response to extracellular acidosis is accurately predicted by assuming two (probably sarcolemmal) sites at which H+ ions affect calcium binding and/or flux: (equation; see text) The first factor represents a set of sites that are proposed to control access, dependent on the degree of their ionization, to sites represented by the second factor. The latter sites are proposed to accept calcium according to mass-action law. The response of calcium channel current to extracellular acidosis was also complete and reversible within 25 seconds. The current response indicates that the two-site model could be predictive for the effect of extracellular acidosis on calcium current in ventricular cells.
Dystrophin glycoprotein complex dysfunction: A regulatory link between muscular dystrophy and cancer cachexia
Authors: Swarnali Acharyya, Matthew E.R. Butchbach, Zarife Sahenk, Huating Wang, Motoyasu Saji, Micheal Carathers, Matthew D. Ringel, Richard J.E. Skipworth, Kenneth C.H. Fearon, Michael A. Hollingsworth, Peter Muscarella, Arthur H.M. Burghes, Jill A. Rafael-Fortney, Denis C. Guttridge
Journal: Cancer Cell (2005)
Diabetes Mellitus and Risk of Colorectal Cancer: A Meta-Analysis
Authors: Susanna C. Larsson, Nicola Orsini, Alicja Wolk
Journal: JNCI Journal of the National Cancer Institute (2005)

Diabetes has been associated with an increased risk of colorectal cancer in most, but not all, studies. Findings have also been inconclusive with regard to sex and subsite in the colorectum. To resolve these inconsistencies, we conducted a meta-analysis of published data on the association between diabetes and the incidence and mortality of colorectal cancer.We identified studies by a literature search of Medline from January 1, 1966, through July 31, 2005, and by searching the reference lists of pertinent articles. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with a random-effects model. All statistical tests were two-sided.Analysis of 15 studies (six case-control and nine cohort studies), including 2 593 935 participants, found that diabetes was associated with an increased risk of colorectal cancer, compared with no diabetes (summary RR of colorectal cancer incidence = 1.30, 95% CI = 1.20 to 1.40), without heterogeneity between studies (P(heterogeneity) = .21). These results were consistent between case-control and cohort studies and between studies conducted in the United States and in Europe. The association between diabetes and colorectal cancer incidence did not differ statistically significantly by sex (summary RR among women = 1.33, 95% CI = 1.23 to 1.44; summary RR among men = 1.29, 95% CI = 1.15 to 1.44; P(heterogeneity) = .26) or by cancer subsite (summary RR for colon = 1.43, 95% CI = 1.28 to 1.60; summary RR for rectum = 1.33, 95% CI = 1.14 to 1.54; P(heterogeneity) = .42). Diabetes was positively associated with colorectal cancer mortality (summary RR = 1.26, 95% CI = 1.05 to 1.50), but there was evidence for heterogeneity between studies (P(heterogeneity) = .04).Our findings strongly support a relationship between diabetes and increased risk of colon and rectal cancer in both women and men.