tbuckley/cabot-search huggingface dataset:
Id2-, RORγt-, and LTβR-independent initiation of lymphoid organogenesis in ocular immunity
Authors: Takahiro Nagatake, Satoshi Fukuyama, Dong-Young Kim, Kaoru Goda, Osamu Igarashi, Shintaro Sato, Tomonori Nochi, Hiroshi Sagara, Yoshifumi Yokota, Anton M. Jetten, Tsuneyasu Kaisho, Shizuo Akira, Hitomi Mimuro, Chihiro Sasakawa, Yoshinori Fukui, Kohtaro Fujihashi, Taishin Akiyama, Jun-ichiro Inoue, Josef M. Penninger, Jun Kunisawa, Hiroshi Kiyono
Journal: The Journal of Experimental Medicine (2009)

The eye is protected by the ocular immunosurveillance system. We show that tear duct-associated lymphoid tissue (TALT) is located in the mouse lacrimal sac and shares immunological characteristics with mucosa-associated lymphoid tissues (MALTs), including the presence of M cells and immunocompetent cells for antigen uptake and subsequent generation of mucosal immune responses against ocularly encountered antigens and bacteria such as Pseudomonas aeruginosa. Initiation of TALT genesis began postnatally; it occurred even in germ-free conditions and was independent of signaling through organogenesis regulators, including inhibitor of DNA binding/differentiation 2, retinoic acid-related orphan receptor gammat, lymphotoxin (LT) alpha1beta2-LTbetaR, and lymphoid chemokines (CCL19, CCL21, and CXCL13). Thus, TALT shares immunological features with MALT but has a distinct tissue genesis mechanism and plays a key role in ocular immunity.
LEUKEMIA EVOKED WITH 7, 8, 12-TRIMETHYLBENZ(A)ANTHRACENE IN RAT
Authors: Colin Bird, Charles Huggins
Journal: The Journal of Experimental Medicine (1971)

An early sign of erythroblastic leukemia in rat was nodule formation in the spleen. Hyperplastic foci of stem cells, indistinguishable histologically from leukemic stem cells, were found in the red pulp whereas the malpighian corpuscles were uninvolved. Anemia is a normal phenomenon in immature rats and the spleen of the prepubertal rat possesses considerable hemopoietic potential. Pulse-doses of 7, 8, 12-trimethylbenz(a)anthracene prevented the physiologic hematological development of maturing rats and was associated with subsequent development of leukemic stem cells in the red pulp of the spleen. Significant enzyme changes were observed in leukemic spleens. Compared with the spleens of normal littermates, the concentration of lactate dehydrogenase rose while that of malate dehydrogenase fell; the content of alkaline phosphatase rose whereas acid phosphatase fell. Increased alkaline phosphatase activity in leukemic spleen was attributed to nonleukemic foci of myelopoiesis.
US billionaires donate $500m to reduce smoking worldwide
Authors: J. Hopkins Tanne
Journal: BMJ (2008)

Bill Gates, the founder of Microsoft, and the mayor of New York, Michael Bloomberg, announced last week that they would donate a total of $500m (£250m; €320m) to efforts to stop smoking around the world.

The funding will focus on poor and middle income countries, which face an increasing number of smoking related deaths. Special attention will go to China and India, which have high smoking rates, and to Africa, where the smoking epidemic is growing.

Mr Bloomberg and Mr Gates said that tobacco kills five million people every year, more than AIDS, tuberculosis, and malaria combined. China …
THE DEVELOPMENT OF THE BACTERIAL FLORA IN THE GASTROINTESTINAL TRACT OF MICE
Authors: Russell W. Schaedler, René Dubos, Richard Costello
Journal: The Journal of Experimental Medicine (1965)

Selective culture media, and equipment for anaerobic incubation of large numbers of specimens, have been developed to facilitate the quantitative enumeration of the various aerobic and anaerobic bacterial species present in the gastrointestinal tract. The evolution of this flora has been followed in young mice from several colonies by cultivating homogenates of the different parts of the gastrointestinal tract at daily intervals from the time of birth to the time of weaning. It has been found that the lactobacilli and anaerobic streptococci become established immediately after birth and persist in large numbers, not only in the large intestine but also in the stomach and in the small intestine. In contrast, the anaerobic bacilli of the bacteroides group become established only after the 16th day; they multiply only in the large intestine but persist in this organ in very large numbers. Other bacterial species become established at different periods of time after birth, exhibit characteristic anatomic localizations, and greatly fluctuate in numbers. In general, the populations of enterobacilli and enterococci decrease precipitously after having reached a maximum level shortly after the beginning of colonization.
Perception and knowledge of clinical trials and factors affecting participation of regional and rural cancer patients of North Queensland
Authors: S. S. Sabesan, B. Burgher, S. Varma, P. Piliouras
Journal: Journal of Clinical Oncology (2009)

e17558 Background: The best treatment option for most cancers is participation in clinical trials. Participation in trials is generally low and among rural patients it is likely to be even lower. The aim of this study was to assess knowledge about and attitudes towards clinical trials among rural and regional cancer patients of North Queensland. Methods: A questionnaire-based survey was conducted in outpatient clinics at the Townsville Cancer Centre on all types of cancer patients. Results: The mean age of the 178 participants was 56 years and 45.4% lived in rural or remote areas. Median distance to the trial centre (Townsville) for rural participants was 180 km (range 80 - 1300 km). Being asked whether they would take part in a RCT, 13.2% of participants said no, 56.3% said yes, and 30.5% were unsure. There were no significant relationships between willingness to participate and rurality (p = 0.896) or education level (p = 0.943). For the majority of patients, the number of clinic visits and blood tests required did not matter. Cost of travel (41.1% rural/remote; 23.5% regional; p &lt; 0.001) and the need for family or friends to accompany (38.9% rural/remote; 24.1% regional; p = 0.021) were more important for rural/remote than regional patients as factors affecting participation. Only 16.4% of participants were aware of early studies. After education, percentage of patients willing to participate in phase I and II studies were 57% and 84%, respectively. Rural patients were less willing to participate in phase I studies than regional patients (33.9% vs 52.6%, p = 0.029). Conclusions: Rural patients are as interested in participating in clinical trials as urban patients except for phase 1 trials and should not be excluded because of rurality. Knowledge of trials is poor and there is a need for education early. Cost of travel seems more important for rural patients and as such budgets should include cost of travel to encourage participation of rural patients. No significant financial relationships to disclose.
Effect of a multistage ultra-endurance triathlon on body composition: World Challenge Deca Iron Triathlon 2006
Authors: B Knechtle, O Salas Fraire, J L Andonie, G Kohler
Journal: British Journal of Sports Medicine (2007)

To investigate the effect of a multistage ultra-endurance triathlon on body composition in ultra-triathletes.Descriptive field study.The "World Challenge Deca Iron Triathlon 2006" in Monterrey, Mexico, in which every day for 10 consecutive days athletes had to perform the distance of one Ironman triathlon.Eight male ultra-endurance athletes (mean (SD) age 40.6 (10.7) years, weight 76.4 (8.4) kg, height 175 (4) cm and body mass index (BMI) 24.7 (2.2) kg/m2).None.Determination of body mass, protein mass, body fat, per cent body fat, mineral mass, total body water, intracellular water, extracellular water and lean body mass with a direct segmental multifrequency bioelectrical impedance method before the race and after each stage in order to show changes in body composition.A statistically significant decrease of body mass (-2.4 kg, p = 0.014), body fat (-5 kg, p = 0.0078) and per cent body fat (-6.4%, p = 0.0078) occurred at the end of the first day compared to values taken in the pre-race period. In contrast, at the same time, a statistically significant increase of protein mass (+0.7 kg, p = 0.035), mineral mass (+0.2 kg, p = 0.04), total body water (+1.8 litres, p = 0.042), intracellular water (+1.6 litres, p = 0.034) and lean body mass (+2.6 kg, p = 0.023) was shown. After the first day until the end of the challenge, body fat (-3 kg, p>0.05) and per cent body fat (-3.9%, p>0.05) showed a statistically significant decrease, whereas the other parameters showed no changes.Athletes taking part in a multistage ultra-endurance triathlon over 10 Ironman triathlon distances in 10 consecutive days lost 3 kg of body fat; skeletal muscle mass, mineral mass and body water were unchanged.
HTLV-1 bZIP Factor RNA and Protein Impart Distinct Functions on T-cell Proliferation and Survival
Authors: Yuichi Mitobe, Jun-ichirou Yasunaga, Rie Furuta, Masao Matsuoka
Journal: Cancer Research (2015)

Infection of T cells with human T-cell leukemia virus type-1 (HTLV-1) induces clonal proliferation and is closely associated with the onset of adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. Although Tax expression is frequently suppressed in HTLV-1-infected cells, the accessory gene, HTLV-1 bZIP factor (HBZ), is continuously expressed and has been implicated in HTLV-1 pathogenesis. Here, we report that transduction of mouse T cells with specific mutants of HBZ that distinguish between its RNA and protein activity results in differential effects on T-cell proliferation and survival. HBZ RNA increased cell number by attenuating apoptosis, whereas HBZ protein induced apoptosis. However, both HBZ RNA and protein promoted S-phase entry of T cells. We further identified that the first 50 bp of the HBZ coding sequence are required for RNA-mediated cell survival. Transcriptional profiling of T cells expressing wild-type HBZ, RNA, or protein revealed that HBZ RNA is associated with genes involved in cell cycle, proliferation, and survival, while HBZ protein is more closely related to immunological properties of T cells. Specifically, HBZ RNA enhances the promoter activity of survivin, an inhibitor of apoptosis, to upregulate its expression. Inhibition of survivin using YM155 resulted in impaired proliferation of several ATL cell lines as well as a T-cell line expressing HBZ RNA. The distinct functions of HBZ RNA and protein may have several implications for the development of strategies to control the proliferation and survival mechanisms associated with HTLV-1 infection and ATL.
Blood flow and pressure measurements of right coronary artery to left ventricle fistula.
Authors: I Kiso, T Itoh, M Morishita, K Kato, Y Ishikura
Journal: Thorax (1978)

Blood flow and pressure measurements of right coronary artery to left ventricle fistula.A case of a dilated and tortuous right coronary artery to left ventricle fistula was surgically repaired.Preoperative intracoronary pressure measurements showed a sudden depression of diastolic pressure in the terminal part of the right coronary artery.Intraoperative mean right coronary flow was recorded as 315 ml/min.After repair of the fistula, blood flow measurements showed only 35 ml/min, which suggested that a large amount of blood was stolen by the fistula.Although systolic and diastolic murmurs only were heard in our patient, continuous murmurs have been noticed by some observers.From a study of the preoperative physical findings, intraoperative coronary flow measurements, and other operative findings, the genesis of heart murmurs relating to this type of anomaly is discussed.To date, more than 250 cases of coronary artery fistula have been reported, but communications with the left ventricle or atrium are rare.
Tolerability to high doses of formoterol and terbutaline via Turbuhaler for 3 days in stable asthmatic patients
Authors: KJ Totterman, L Huhti, E Sutinen, R Backman, A Pietinalho, M Falck, P Larsson, O Selroos
Journal: European Respiratory Journal (1998)

This randomized, double-blind, crossover study in two parts compared tolerability to high doses of formoterol (Oxis Turbuhaler) with that of high doses of terbutaline (Bricanyl Turbuhaler). After Holter monitoring at home, 12 patients were treated with 4+4+4 doses of formoterol Turbuhaler, 6 microg x dose(-1), (total daily metered dose 72 microg) or 4+4+4 doses of terbutaline Turbuhaler, 0.5 mg x dose(-1) (daily dose 6 mg) given in the morning, after lunch and in the evening, for 3 consecutive days. After a one week washout period at home, patients received the alternative treatment. Thereafter, 15 other patients received 8+6+6 doses of formoterol Turbuhaler (total daily metered dose 120 microg) or 8+6+6 doses of terbutaline Turbuhaler (daily dose 10 mg). Pulse, cardiac frequency, blood pressure, serum potassium, electrocardiogram and forced expiratory volume in one second (FEV1) were registered at regular intervals and Holter monitoring was applied during all 4 treatment days. Terbutaline 6 mg showed significantly greater systemic effects than formoterol 72 microg on pulse, blood pressure, cardiac frequency and QTc (QT interval corrected for heart rate). Terbutaline 10 mg had significantly greater effects than formoterol 120 microg on serum potassium levels, pulse, cardiac frequency and QTc. No differences in FEV1 levels were found. Both drugs were safe and generally well tolerated on both dose levels. In conclusion, high doses of formoterol Turbuhaler over 3 days were generally safe and well tolerated. Daily doses of 6 mg and 10 mg terbutaline Turbuhaler were systemically more potent than 72 microg and 120 microg formoterol, respectively. The safety margin thus appears to be wide if patients happen to use extra doses of formoterol in addition to those prescribed for regular use.
p53 Modulates Acquired Resistance to EGFR Inhibitors and Radiation
Authors: Shyhmin Huang, Sergio Benavente, Eric A. Armstrong, Chunrong Li, Deric L. Wheeler, Paul M. Harari
Journal: Cancer Research (2011)

There is presently great interest in mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms, we established EGFR inhibitor-resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor-resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell-cycle arrest, apoptosis, and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation.
Infliximab treatment in combination with cyclosporin A in patients with severe refractory rheumatoid arthritis
Authors: T I Temekonidis
Journal: Annals of the Rheumatic Diseases (2002)

<b>Objective:</b> To investigate whether infliximab can be used in combination with cyclosporin A (CsA) in patients with refractory rheumatoid arthritis (RA) who cannot tolerate methotrexate (MTX). <b>Materials and methods:</b> Eighteen patients with refractory RA receiving low dose CsA (2 mg/kg/day) and prednisone (5 mg/day) were treated with intravenous infliximab. The patients were given infliximab (3 mg/kg weight) at 0, two, six, and every eight weeks thereafter for a total period of 12 months. Clinical improvement was evaluated according to the American College of Rheumatology (ACR) 20% response criteria. <b>Results:</b> Eighty per cent of patients receiving the combination treatment with CsA and infliximab achieved the 20% ACR criteria for response to treatment, whereas 39% satisfied the 50% response criteria. In addition, a 76% reduction in swollen and tender joint count was found. Finally, a reduction in C reactive protein and erythrocyte sedimentation rate was maintained throughout the study. In general, treatment was well tolerated, with minimal adverse drug reactions. Two patients dropped out; one because of an immediate hypersensitivity reaction and the other because of the development of pulmonary tuberculosis. <b>Conclusion:</b> Multiple infusions of infliximab and low doses of CsA improve patients with refractory RA. It seems that CsA may be an alternative disease modifying drug to be used in combination with infliximab in patients with refractory RA who cannot tolerate MTX.
Loss of Tubular Bone Morphogenetic Protein—7 in Diabetic Nephropathy
Authors: SHI-NONG WANG, JANINE LAPAGE, RAIMUND HIRSCHBERG
Journal: Journal of the American Society of Nephrology (2001)

Bone morphogenetic protein—7 (BMP7), a member of the transforming growth factor—β (TGF—β) superfamily of cytokines, is highly expressed in renal tubules and generally promotes maintenance of epithelial phenotype. It was examined whether, during the evolution of experimental diabetic nephropathy, the renal expression of BMP7 and BMP7 receptors declines, and the hypothesis that loss of BMP7 activity is profibrogenic in proximal tubular cells was tested. Moreover, in vitro studies in cultured proximal tubular cells were performed to examine putative mechanisms that cause these changes. At 15 wk of streptozotocin-induced diabetes, renal expression of BMP7 is declined by about half, and it decreased further by 30 wk to <10% of timed controls. Renal expression of the high-affinity BMP type II receptor and the type I receptor Alk2 (activin receptor—like kinase-2) decreased. Alk3 tended to decrease, but Alk6 remained unchanged. During the evolution of diabetic nephropathy, the secreted BMP antagonist gremlin increased substantially. In cultured tubular cells, TGF-β reduced BMP7 and Alk3 expression and increased gremlin but did not interrupt BMP7-induced activation of smad5 or Erk1 and -2. In contrast, BMP7 did not alter TGF-β expression. Neutralization of endogenous BMP7 in cultured proximal tubular cells raised the expression of fibronectin and tended to increase collagen α1 III mRNA levels. In conclusion, in experimental diabetic nephropathy, renal tubular BMP7 and some of its receptors decreased and gremlin, a secreted BMP antagonist, increased. Some, but not all, of these changes are explained by increased TGF-β. The loss of BMP7 activity per se is profibrogenic in tubular cells.
Balancing the risks and benefits of prolonged use of infliximab
Authors: J. Scholmerich
Journal: Gut (2009)

In this issue of Gut , two papers describe the vast experience of the group in Leuven, Belgium, with the use of infliximab in Crohn’s disease. The first report ( see page 492 ) describes 614 patients, mostly with luminal disease and about 25% with fistulising disease treated over a period of 12 years. A sustained benefit was seen in 63%; in a third even after stopping the drug while in remission.1 Twenty percent of patients withdrew from treatment due to loss of response and 11% had no initial response. Of those patients with an initially elevated C-reactive protein (CRP), 77% showed a “biological response”, which had a positive predictive value for a better clinical outcome. Out of 10 deaths, one was directly related to therapy, three were possibly related and six were not related.

The second report ( see page 501 ) assessed medical records of 734 patients with inflammatory bowel disease (IBD), the majority with Crohn’s disease, treated with infliximab during 14 years, and compared them with 666 patients who did not receive infliximab followed during this period.2 Median follow-up was more than twice as long for controls than for infliximab patients (58 months; 33–88 months). A total of 113 severe adverse events occurred in 93 treated patients, and 157 in 126 control patients. Mortality, malignancies and infection rates did not differ between the two populations. However, the control group was older and received steroids much more often during the much longer follow-up.

To me there is an important message from these data to all patients with Crohn’s disease …
Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenecity of human platelets
Authors: Hansjörg Schwertz, Neal D. Tolley, Jason M. Foulks, Melvin M. Denis, Ben W. Risenmay, Michael Buerke, Rachel E. Tilley, Matthew T. Rondina, Estelle M. Harris, Larry W. Kraiss, Nigel Mackman, Guy A. Zimmerman, Andrew S. Weyrich
Journal: The Journal of Experimental Medicine (2006)

Tissue factor (TF) is an essential cofactor for the activation of blood coagulation in vivo. We now report that quiescent human platelets express TF pre-mRNA and, in response to activation, splice this intronic-rich message into mature mRNA. Splicing of TF pre-mRNA is associated with increased TF protein expression, procoagulant activity, and accelerated formation of clots. Pre-mRNA splicing is controlled by Cdc2-like kinase (Clk)1, and interruption of Clk1 signaling prevents TF from accumulating in activated platelets. Elevated intravascular TF has been reported in a variety of prothrombotic diseases, but there is debate as to whether anucleate platelets—the key cellular effector of thrombosis—express TF. Our studies demonstrate that human platelets use Clk1-dependent splicing pathways to generate TF protein in response to cellular activation. We propose that platelet-derived TF contributes to the propagation and stabilization of a thrombus.
Functional characterization of macrophage receptors for in vitro phagocytosis of unopsonized Pseudomonas aeruginosa.
Authors: D P Speert, S D Wright, S C Silverstein, B Mah
Journal: Journal of Clinical Investigation (1988)

The phagocytic receptor for unopsonized Pseudomonas aeruginosa was characterized functionally using human monocyte-derived macrophages. Freshly isolated human peripheral blood monocytes were unable to ingest unopsonized P. aeruginosa; ingestion did not occur until the cells had been in culture for 2 d and it became maximal after 4 d. Macrophages plated on coverslips derivatized with anti-BSA IgG or with human gamma-globulin lost the capacity to phagocytose unopsonized P. aeruginosa, unopsonized zymosan, and EIgG but bound C3bi-coated erythrocytes normally. Each of the four human IgG subclasses and Fc fragments of anti-BSA IgG inhibited phagocytosis of both unopsonized P. aeruginosa and EIgG. Phagocytosis of P. aeruginosa and zymosan was markedly impaired and EIgG minimally inhibited if macrophages were plated on coverslips derivatized with mannan or when mannan was added to the phagocytosis buffer. Phagocytosis of P. aeruginosa and zymosan, and binding of EC3bi was dependent on the presence of divalent cations, but phagocytosis of EIgG was not. The macrophage phagocytic receptor for unopsonized P. aeruginosa was inactivated by proteolytic enzymes. Phagocytosis of P. aeruginosa was inhibited by D-mannose, L-fucose, and alpha methyl mannoside, but not by L-mannose, D-fucose, or D-glucose. The same sugars inhibited phagocytosis of unopsonized zymosan. We conclude that phagocytosis of unopsonized P. aeruginosa by human monocyte-derived macrophages is facilitated by mannose receptors.