tbuckley/cabot-search huggingface dataset:
T Regulatory Type 1 Cells in Squamous Cell Carcinoma of the Head and Neck: Mechanisms of Suppression and Expansion in Advanced Disease
Authors: Christoph Bergmann, Laura Strauss, Yun Wang, Miroslaw J. Szczepanski, Stephan Lang, Jonas T. Johnson, Theresa L. Whiteside
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Regulatory T cells play a major role in tumor escape from immunosurveillance. T regulatory cells type 1 (Tr1), a subset of regulatory T cells present in the tumor and peripheral circulation of patients with head and neck squamous cell carcinoma (HNSCC), mediate immune suppression and might contribute to tumor progression. Experimental Design: CD4+CD25−T cells were isolated from peripheral blood mononuclear cells (PBMC) or tumor-infiltrating lymphocytes (TIL) of 26 HNSCC patients and 10 normal controls. The Tr1 cell phenotype was determined before and after culture in the presence of interleukin (IL)-2, IL-10, and IL-15, each at 10 to 20 IU/mL. Suppression was measured in carboxyfluorescein diacetate succinimidyl ester–based proliferation assays with or without neutralizing anti-IL-10 or anti–transforming growth factor-β1 (TGF-β1) monoclonal antibodies in Transwell systems. ELISA was used to define the Tr1 cytokine profile. Results: Tr1 cells originate from CD4+CD25− precursors present in TIL and PBMC of HNSCC patients. Cytokine-driven ex vivo expansion of Tr1 precursors yielded CD4+CD25−Foxp3lowCD132+IL-10+TGF-β1+ populations that mediated higher suppression than Tr1 cells of normal controls (P &amp;lt; 0.0001). Tr1 cells suppressed proliferation of autologous responders via IL-10 and TGF-β1 secretion. Expression of these cytokines was higher in TIL-derived than PBMC-derived Tr1 cells (P &amp;lt; 0.0001). The Tr1 cell frequency and suppressor function were significantly higher in patients presenting with advanced than early disease stages and in patients “cured” by oncologic therapies than in those with active disease. Conclusions: In HNSCC, Tr1 cell generation is promoted at the tumor site. Tr1 cells use TGF-β and IL-10 to mediate suppression. They expand during disease progression and also following cancer therapy in patients with no evident disease.
The clinical effect and expression of alpha-methylacyl-CoA racemace (AMACR) in the differential diagnosis of malign mesothelioma and adenocarcinoma of lung
Authors: Sezgi Sahin Duyar, Aydin Yilmaz, Funda Demirag, Yurdanur Erdogan, Ulku Yazici, Jale Karakaya
Journal: European Respiratory Journal (2012)

Background:  Alpha-methylacyl-CoA racemace (AMACR) which is an intracellular enzyme involving in the beta-oxidation of branched fatty acids has emerged as an immunohistochemical marker for many types of cancer. This study is conducted to investigate AMACR expression in the differential diagnosis of malign pleural mesothelioma (MPM) and lung adenocarcinoma, and its correlation with clinical characteristics and survival.   Methods:  The clinicopathologic characteristics of 144 patients (73 adenocarcinoma, 71 MPM) were reviewed retrospectively. The resection materials were evaluated by immunohistochemical method. The patients who were given adjuvant chemotherapy and/or radiotherapy, with an evidence of residual tumor and who died due to postoperative mortality and due to reasons not related to lung cancer were excluded for survival analysis. Data from remaining 77 patients (37 adenocarcinoma, 40 MPM) were used for survival analysis.   Results:  AMACR expression was more frequent in adenocarcinoma group than MPM group (p=0,046). The specificity and sensitivity of AMACR immunostaining in detecting adenocarcinoma were %58,9, and %57,7 respectively. AMACR positive and negative groups were similar for age, sex, smoking history, tumor diameter, lymph node involvement, tumoral differentiation, T-N factor, and stage. Overall survival was not significantly different between the groups, either.   Conclusion:  The specificity and sensitivity of AMACR immunostaining was not high enough to use it as a diagnostic tool in differential diagnosis of MPM and lung adenocarcinoma. AMACR expression did not have a prognostic value in MPM or in adenocarcinoma.
Mechanical instability destabilises the ankle joint directly in the ankle-sprain mechanism
Authors: Dominic Gehring, Katrin Faschian, Benedikt Lauber, Heinz Lohrer, Tanja Nauck, Albert Gollhofer
Journal: British Journal of Sports Medicine (2013)

Background Despite massive research efforts, it remains unclear how mechanical ankle instability (MAI) and functional ankle instability (FAI) affect joint control in the situation of ankle sprain. Thus, the purpose of this study was to evaluate whether individuals with MAI have deficits in stabilising their ankle joint in a close-to-injury situation compared with those with FAI and healthy controls. Methods Ankle-joint control was assessed by means of three-dimensional motion analysis and electromyography in participants with FAI and MAI (n=19), in participants with pure FAI (n=9) and in healthy controls (n=18). Close-to-injury situations were simulated during standing, walking and jumping by means of a custom-made tilt platform. Results Individuals with FAI and MAI displayed significantly greater maximum ankle inversion angles (+5°) and inversion velocities (+50°/s) in the walking and jumping conditions compared to those with pure FAI and controls. Furthermore, individuals in the FAI and MAI group showed a significantly decreased pre-activation of the peroneus longus muscle during jumping compared to those with FAI. No differences between groups were found for plantar flexion and internal rotation, or for muscle activities following tilting of the platform. Conclusions The present study demonstrates that MAI is characterised by impairments of ankle-joint control in close-to-injury situations. This could make these individuals more prone to recurrent ankle sprains, and suggests the need for additional mechanical support such as braces or even surgery. In addition, the study highlights the fact that dynamic experimental test conditions in the acting participant are needed to further unravel the mystery of chronic ankle instability.
Critical roles of Bim in T cell activation and T cell–mediated autoimmune inflammation in mice
Authors: Maciej W. Ludwinski, Jing Sun, Brendan Hilliard, Shunyou Gong, Fan Xue, Ruaidhri J. Carmody, Jennifer DeVirgiliis, Youhai H. Chen
Journal: Journal of Clinical Investigation (2009)

Bim, the B cell lymphoma 2-interacting (Bcl2-interacting) mediator, maintains immunological tolerance by deleting autoreactive lymphocytes through apoptosis. We report here that Bim is also, paradoxically, required for the activation of autoreactive T cells. Deletion of Bim in hematopoietic cells rendered mice resistant to autoimmune encephalomyelitis and diabetes, and Bim-deficient T cells had diminished cytokine production. Upon T cell receptor activation, Bim-deficient T cells exhibited severe defects in both calcium release and dephosphorylation of nuclear factor of activated T cells (NFAT) but maintained normal levels of activation of NF-kappaB and MAPKs. The defective calcium signaling in Bim-deficient T cells was associated with a significant increase in the formation of an inhibitory complex containing Bcl2 and the inositol triphosphate receptor (IP3R). Thus, in addition to mediating the death of autoreactive T cells, Bim also controlled T cell activation through the IP3R/calcium/NFAT pathway. These results indicate that a single protein is used to control both the activation and apoptosis of autoreactive T cells and may explain why Bim-deficient mice do not reject their own organs despite lacking thymic negative selection.
Relationship of Anginal Symptoms to Lung Mechanics during Myocardial Ischemia
Authors: CARL J. PEPINE, LESLIE WIENER
Journal: Circulation (1972)

The anginal syndrome (AP) typically includes sensations of chest tightness or difficulty in breathing. Left ventricular (LV) dysfunction during myocardial ischemia incident with AP is now well documented. Since secondary alterations in lung mechanics could relate to these symptoms, we examined airway resistance (Raw), lung volume (TGV), lung compliance (C L ), and LV pressure-volume relations during pacing-induced AP. LV end-diastolic pressure (EDP) increased suddenly with AP, (mean + 41%, p &lt; 0.01), without change in end-diastolic volume (EDV). LV distensibility (EDV/EDP) decreased abruptly, (–37%, P &lt; 0.01), with reduction in airway conductance (1/Raw/TGV), (–40%, P &lt; 0.05), and C L (–27%, P &lt; 0.05). When AP was relieved, these changes returned toward preangina levels. Ischemia-induced LV dysfunction abruptly increases LVEDP. The resulting increased pulmonary capillary pressure effects an alteration of lung mechanics consisting of increasing Raw and reduced C L . The changes in ventilatory effort which ensue may be interpreted as chest tightness, heaviness, or constriction by the AP patient.
Changes in total and specific IgE following treatment with mebendazole in patients with persistent asthma and IgE to Ascaris lumbricoides
Authors: Rosanna Qualizza, Cristoforo Incorvaia, Rita Ballerini, Romualdo Grande
Journal: European Respiratory Journal (2012)

Background Recent studies have reported that patients with ascaridiasis and high IgE levels may suffer from asthma. This study aims at evaluating the changes in total and Ascaris-specific IgE, as well as in symptoms, following anti-helminthic therapy in patients with asthma not controlled with standard drug treatment.

Methods 30 adult patients with persistent asthma and high levels of total and Ascaris-specific IgE were included in the study. Though they had been treated by associations of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA), they shared irregular and unjustified asthma attacks and therefore referred to us in order to have a further check-up. They underwent spirometry, skin prick tests, total and specific IgE (aeroallergens + A. lumbricoides ). To all patients a treatment by mebendazole 100 mg b.i.d for 3 days, based on two courses with a 20-day interval, was proposed. After 6 and 12 months, in case of persistent positivity, 2 other courses of mebendazole were prescribed.

Results 24 patients underwent the treatment. The mean value of total IgE increased after 6 months of treatment from 1556 to 2206 but decreased after 12 months to 1352 kU/L. Similarly, specific IgE increased from 3.1 to 4.5 after 6 months and decreased to 2.4 kU/L after 12 months. Spirometry showed a basal FEV1 mean value of 59% and a rise to 71% after 6 months and to 78% after 12 months.

Conclusion These findings confirm the association between Ascaris infestation and allergy-like symptoms and demonstrate that antiparasitic therapy remarkably reduces asthma attacks in patients who show high levels of total and specific IgE for A. lumbricoides.
Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis
Authors: Carlo Merkel, Renato Marin, David Sacerdoti, Carlo Donada, Giorgio Cavallarin, Pierluigi Torboli, Piero Amodio, Giuliana Sebastianelli, Massimo Bolognesi, Martina Felder, Cesare Mazzaro, Angelo Gatta
Journal: Hepatology (2000)

It is clearly established that β-blockers decrease the risk of a first variceal bleeding in cirrhosis. We have recently shown that the addition of isosorbide mononitrate to nadolol decreases the rate of variceal bleeding in patients with cirrhosis and varices, compared with nadolol alone, after a median follow-up of 30 months. It is not established if the long-term treatment with the combination continues to be beneficial. Therefore, we assessed the long-term effect of this combination on first variceal bleeding, complications, and death. One hundred forty-six cirrhotic patients with esophageal varices included in a previously published multicenter, randomized study comparing nadolol (40-160 mg/d) with the combination nadolol plus isosorbide mononitrate (10-20 mg 3 times per day) were followed up for up to 7 years (median follow-up, 55 months). The primary end-point was variceal bleeding of any severity. Twenty-four patients (16 in the nadolol group, and 8 in the combination group) experienced variceal bleeding (log rank test, P = .02). Cumulative risk of bleeding was 29% and 12%, respectively (95% CI for the difference, 1%-23%). Two and 4 patients, respectively, had bleeding from portal hypertensive gastropathy (log rank test, P = .20). Thirty and 25 patients, respectively, died during follow-up (log rank test, P = .13). Twelve and 10 patients, respectively, had de novo occurrence of ascites during follow-up (log rank test, P = .29). In conclusion, nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the long-term use. Side effects are few, and no deleterious effects on ascites occurrence or on survival occur after long-term use of this combination.
Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine
Authors: Joao Pedro Werneck de Castro, Tatiana L. Fonseca, Cintia B. Ueta, Elizabeth A. McAninch, Sherine Abdalla, Gabor Wittmann, Ronald M. Lechan, Balazs Gereben, Antonio C. Bianco
Journal: Journal of Clinical Investigation (2015)

The current treatment for patients with hypothyroidism is levothyroxine (L-T4) along with normalization of serum thyroid-stimulating hormone (TSH). However, normalization of serum TSH with L-T4 monotherapy results in relatively low serum 3,5,3′-triiodothyronine (T3) and high serum thyroxine/T3 (T4/T3) ratio. In the hypothalamus-pituitary dyad as well as the rest of the brain, the majority of T3 present is generated locally by T4 deiodination via the type 2 deiodinase (D2); this pathway is self-limited by ubiquitination of D2 by the ubiquitin ligase WSB-1. Here, we determined that tissue-specific differences in D2 ubiquitination account for the high T4/T3 serum ratio in adult thyroidectomized (Tx) rats chronically implanted with subcutaneous L-T4 pellets. While L-T4 administration decreased whole-body D2-dependent T4 conversion to T3, D2 activity in the hypothalamus was only minimally affected by L-T4. In vivo studies in mice harboring an astrocyte-specific Wsb1 deletion as well as in vitro analysis of D2 ubiquitination driven by different tissue extracts indicated that D2 ubiquitination in the hypothalamus is relatively less. As a result, in contrast to other D2-expressing tissues, the hypothalamus is wired to have increased sensitivity to T4. These studies reveal that tissue-specific differences in D2 ubiquitination are an inherent property of the TRH/TSH feedback mechanism and indicate that only constant delivery of L-T4 and L-T3 fully normalizes T3-dependent metabolic markers and gene expression profiles in Tx rats.
Risk, Judgment and Fairness in Research Incentives
Authors: Benjamin Hale
Journal: The American Journal of Bioethics (2007)

By many people’s standards, £2,000 is a sizable chunk of change. In some medical trials, it may even be enough to offset the costs and risks of participating. It is also true that by standards of some very rich people, Michael Jordan and Adam Sandler for instance, £2,000 is a niggling sum, hardly worth the paper it is written on. The very rich, we might assume, would have little time or interest in participating in a medical trial that offered such insignificant incentives. By still other people’s standards, however, £2,000 is the difference between providing for oneself and one’s family and depending on others. These people, we might further assume, could be willing to take substantial risks to acquire such money. The familiar observation here relates to the diminishing marginal utility of wealth because the value of a dollar to a poor man is greater than the value of a dollar to a rich man. Given the diminishing marginal utility of wealth, consider also the Rawlsian claim that to be just a practice must be fair. Rawls’ second principle of justice proposes that social and economic inequalities should be arranged so that they are to the greatest benefit of the least well off. The central idea is that the rights of all individuals must be respected, and that the surest way to guarantee that the rights of each are respected is to endorse principles that are sensitive to the proclivities of the least well off. If enticement incentives function in the manner explained previously, such that they entice wayward souls into accepting them even when it is against their self-interest, then such incentives can be said to be not only irrational and unreasonable, but unfair, unjust, and undue. Taken together, these principles suggest that the problem with money in the TeGenero trial might not be that participants did not have all of the facts, nor that all of the human subjects protection procedures were not followed properly, nor even that coercion was somehow involved, but that some participants were probably more willing to engage in a risky trial precisely because a reward was offered, despite the facts and despite the procedures. The participants in the trial were arguably members of an economically vulnerable population; members who, presumably, would have made a different decision had they been
β <sub>3</sub> -Integrins Rather Than β <sub>1</sub> -Integrins Dominate Integrin-Matrix Interactions Involved in Postinjury Smooth Muscle Cell Migration
Authors: Marvin J. Slepian, Stephen P. Massia, Behrooz Dehdashti, Anne Fritz, Luke Whitesell
Journal: Circulation (1998)

Background —Smooth muscle cell (SMC) migration is a vital component in the response of the arterial wall to revascularization injury. Cell surface integrin–extracellular matrix interactions are essential for cell migration. SMCs express both β 1 - and β 3 -integrins. In this study, we examined the relative functional roles of β 1 - and β 3 -integrin–matrix interactions in postinjury SMC migration. Methods and Results —Flow cytometry and fluorescence microscopy of migrating SMCs immunostained with anti-β 1 and anti-α v β 3/5 antibodies (Abs) revealed expression of both β 1 - and β 3 -integrins, with β 1 observed as linear streaks and β 3 found in focal contacts. In a scrape-wound migration assay, anti-β 1 Abs (92.0±10.7% of control, P =.1) and 0.5 mmol/L linear RGD (105±5% of control, P =.2) did not alter SMC migration at 48 hours after injury. β 3 -Blockade, however, via Abs (anti-β 3/5 35.7±4.5% of control, anti-β 3 61±12% of control, both P &lt;.001) and cyclic RGD (0.5 mmol/L) (12±10% of control, P &lt;.001) decreased migration. Neither β 1 - nor β 3 -inhibition altered postinjury [ 3 H]thymidine incorporation. In the rat carotid injury model, local adventitial polymer-based delivery of radiolabeled linear or cyclic RGD led to uptake and retention of label, for both peptides, over a 72-hour period after injury. Local arterial wall β 1 -blockade via polymer-based delivery of linear RGD had no effect on SMC migration at 4.5 days (11.5±3.2 versus 12.8 SMCs per ×600 field [control], P =.6) or on neointimal thickening at 14 days (I/M area ratio, 0.664±0.328 versus 1.179±0.324 [control], P =.6) after injury. In contrast, local β 3 -blockade via cRGD limited migration (0.8±0.8 versus 12.8±4.4 SMCs per ×600 field [control], P &lt;.01) and thickening (I/M area ratio, 0.004±0.008 versus 1.179±0.324 [control], P &lt;.01). Conclusions —In postinjury migrating SMCs, β 3 - rather than β 1 -integrin–matrix interactions are of greater functional significance in adhesive processes essential for SMC migration in vitro and in vivo. Blockade of dominant SMC integrin (β 3 )–matrix interactions may be a valuable approach for limiting injury-induced SMC migration and late arterial renarrowing.
M19 The impact of co-morbidities on physical function and health status in chronic obstruction pulmonary disease (COPD): Abstract M19 Table 1.
Authors: NS Gale, AM Albarrati, IC Munnery, MM Munnery, JC Cockcroft, DJ Shale
Journal: Thorax (2013)

<h3>Background</h3> Co-morbidities are of increasing importance in patients with COPD. However, the implications for function and health status have not been fully established. We hypothesised that the number of co-morbidities would relate to physical capacity, health status and impairments as measured by the comprehensive geriatric assessment (CGA) in COPD but not comparator subjects. <h3>Method</h3> As part of the longitudinal Assessment of Risk in Chronic Airways Disease Evaluation (ARCADE), 500 patients with stable COPD (confirmed with spirometry) were compared to 141 comparator subjects (past or current smokers) free from respiratory disease. In all subjects previously diagnosed co-morbidities including; hypertension, hypercholesterolemia, angina, myocardial infarction, Stroke/TIA, atrial fibrillation, diabetes, and osteoporosis were recorded using a standardised health questionnaire. Spirometry, BMI, six minute walk distance (6MWD), the Timed Up and Go (TUG), and the number of impairments were determined using the CGA. Patients with COPD also completed the St George’s Respiratory Questionnaire (SGRQ). <h3>Results</h3> Patients and comparators were similar in age, gender and BMI, but differed in FEV<sub>1</sub>% predicted 59 (20) and 105 (14) respectively (p &lt; 0.01). Patients had more co-morbidities median (range) 2 (0–6) than comparators 1 (0–3) (p &lt; 0.01). Of the patients, 24% had no co-morbidity, 54% had 1–2 co-morbidities and 22% had over 3 co-morbidities, while 54% of comparators had no co-morbidities and 45% had 1–2 co-morbidities (p &lt; 0.01). Patients also had more impairments (CGA score), reduced 6MWD and increased TUG (all p &lt; 0.001). The number of co-morbidities related to age, BMI, 6MWD, TUG, fibrinogen, the CGA and SGRQ and but not FEV<sub>1 </sub>in patients with COPD, and only to CGA score in comparators (Table 1). <h3>Conclusion</h3> The number of comorbidities in COPD related to physical function, health status and impairments, independent of lung disease. Early management of co-morbidities may improve outcomes in patients with COPD.
Rational use of anti-tuberculosis drugs in the EU: better patient care and less drug resistance
Authors: A. Zumla, F. Blasi, M. Raviglione
Journal: European Respiratory Journal (2012)

Worldwide, resistance to antibiotics routinely used to treat a range of common infectious diseases is increasing [1,2]. Apart from microbial genetic factors, antimicrobial resistance (AMR) is generally attributed to widespread inappropriate antibiotic prescription and usage by physicians, poor drug quality and lack of adherence to proper treatment. The serious and ominous situation of AMR worldwide has led to the formulation and recent launch of the World Health Organization (WHO) policy package to combat AMR [3]. Resistance to tuberculosis (TB) drugs is of particular concern and has been highlighted recently [4–7]. Since the current portfolio of TB drugs is limited and drug-resistant TB is becoming widespread across all continents [8], the spread of drug-resistant TB now threatens the achievements made over a decade of intensive control efforts. TB drug resistance emerges spontaneously through chromosomal mutations in Mycobacterium tuberculosis strains. These can be induced by selection of mutants due to poor prescription, lack of patient adherence and poor drug quality [4–6]. The challenge of TB drug resistance extends beyond low-resource and high-TB-burden countries, now encompassing high-resource settings such as European Union (EU) member states. Worryingly, in the EU, resistance to first- and second-line TB drugs is failing to reduce and hot spots for drug-resistant TB within and beyond the EU borders remain [8–13]. Treatment for multidrug-resistant (MDR)-TB lasts at least 2 yrs, is very expensive to patients and society, is associated with several side-effects [14] and the treatment outcomes are comparatively poor [7,15,16]. Treatment is also challenging in the EU, with failure to reach acceptable levels of success rates particularly among MDR-TB patients [11].

Since the vast majority of the world’s annual …