tbuckley/cabot-search huggingface dataset:
Inhaled Granulocyte-Macrophage Colony Stimulating Factor for First Pulmonary Recurrence of Osteosarcoma: Effects on Disease-Free Survival and Immunomodulation. A Report From the Children's Oncology Group
Authors: Carola A.S. Arndt, Nadya V. Koshkina, Carrie Y. Inwards, Douglas S. Hawkins, Mark D. Krailo, Doojduen Villaluna, Peter M. Anderson, Allen M. Goorin, Martin L. Blakely, Mark Bernstein, Sharon A. Bell, Kaylee Ray, Darryl C. Grendahl, Neyssa Marina, Eugenie S. Kleinerman
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Osteosarcoma most commonly recurs in the lung. Based on preliminary data on the antitumor effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in animal models, and promising phase I trials, we embarked on a feasibility study of inhaled GM-CSF in patients with first isolated pulmonary recurrence of osteosarcoma. Experimental Design: Forty-three eligible patients received inhaled GM-CSF at doses from 250 to 1,750 μg twice daily on alternate weeks. Following two cycles, patients underwent thoracotomy to resect tumor and analyze pulmonary nodules for expression of Fas/Fas ligand (Fas/FasL), and the presence of dendritic cells by immunostaining for CD1a, clusterin, and S100. Following surgery, patients received 12 additional cycles of therapy on alternating weeks or until progression. Event-free survival and survival, and feasibility of therapy delivery were evaluated. Results: Dose escalation to 1,750 μg twice daily was feasible with no dose-limiting toxicity. Mean scores for Fas/FasL in nodules from patients with bilateral recurrence who underwent unilateral thoracotomy pretreatment (using a scoring system of 0-3) were 1.3 and 0.88, respectively, compared with 0.78 and 0.62 in nodules resected following two cycles of therapy. Only 11 of 30 nodules postinhalation were positive for CD1a, 4 of 30 for S100, and 6 of 30 for clusterin. Event-free and overall survival at 3 years were 7.8% and 35.4%, respectively. Conclusions: Inhalation of GM-CSF at doses from 250 to 1,750 μg twice daily on alternate weeks was feasible with low toxicity. However, no detectable immunostimulatory effect in pulmonary metastases or improved outcome postrelapse was seen. Clin Cancer Res; 16(15); 4024–30. ©2010 AACR.
Effects of Aerobic Training, Resistance Training, or Both on Glycemic Control in Type 2 Diabetes
Authors: Ronald J. Sigal, Glen P. Kenny, Normand G. Boulé, George A. Wells, Denis Prud'homme, Michelle Fortier, Robert D. Reid, Heather Tulloch, Douglas Coyle, Penny Phillips, Alison Jennings, James Jaffey
Journal: Annals of Internal Medicine (2007)

Background: Previous trials have evaluated the effects of aerobic training alone and of resistance training alone on glycemic control in type 2 diabetes, as assessed by hemoglobin A1c values. However, none could assess incremental effects of combined aerobic and resistance training compared with either type of exercise alone. Objective: To determine the effects of aerobic training alone, resistance training alone, and combined exercise training on hemoglobin A1c values in patients with type 2 diabetes. Design: Randomized, controlled trial. Setting: 8 community-based facilities. Patients: 251 adults age 39 to 70 years with type 2 diabetes. A negative result on a stress test or clearance by a cardiologist, and adherence to exercise during a 4-week run-in period, were required before randomization. Interventions: Aerobic training, resistance training, or both types of exercise (combined exercise training). A sedentary control group was included. Exercise training was performed 3 times weekly for 22 weeks (weeks 5 to 26 of the study). Measurements: The primary outcome was the change in hemoglobin A1c value at 6 months. Secondary outcomes were changes in body composition, plasma lipid values, and blood pressure. Results: The absolute change in the hemoglobin A1c value in the combined exercise training group compared with the control group was −0.51 percentage point (95% CI, −0.87 to −0.14) in the aerobic training group and −0.38 percentage point (CI, −0.72 to −0.22) in the resistance training group. Combined exercise training resulted in an additional change in the hemoglobin A1c value of −0.46 percentage point (CI, −0.83 to −0.09) compared with aerobic training alone and −0.59 percentage point (CI, −0.95 to −0.23) compared with resistance training alone. Changes in blood pressure and lipid values did not statistically significantly differ among groups. Adverse events were more common in the exercise groups. Limitations: The generalizability of the results to patients who are less adherent to exercise programs is uncertain. The participants were not blinded, and the total duration of exercise was greater in the combined exercise training group than in the aerobic and resistance training groups. Conclusion: Either aerobic or resistance training alone improves glycemic control in type 2 diabetes, but the improvements are greatest with combined aerobic and resistance training. ClinicalTrials.gov registration number: NCT00195884.
Brain-derived neurotrophic factor contributes to abdominal pain in irritable bowel syndrome
Authors: Yan-Bo Yu, Xiu-Li Zuo, Qiu-Jie Zhao, Fei-Xue Chen, Jing Yang, Yan-Yan Dong, Peng Wang, Yan-Qing Li
Journal: Gut (2011)

<h3>Objective</h3> Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, may play a critical role in many chronic pain conditions. The possible involvement of BDNF in the altered gut sensation in patients with irritable bowel syndrome (IBS) was investigated in the present study. <h3>Methods</h3> Rectosigmoid biopsies were collected from 40 patients with IBS fulfilling the Rome II criteria and 21 healthy controls. Abdominal pain was quantified by a validated questionnaire. The presence of BDNF and nerve fibres in the mucosa was assessed by immunohistochemistry. The structure of mucosal nerve fibres was assessed by transmission electron microscopy. Mucosal BDNF release was measured by ELISA and correlated with abdominal pain scores. Animal studies using BDNF<sup>+/−</sup> mice were carried out to evaluate visceral sensitivity, mucosal nerve fibre density and ultrastructural changes. Alterations of visceral sensitivity and TrkB expression in dorsal root ganglia were examined in BDNF<sup>+/+</sup> mice following different doses of BDNF administration. <h3>Results</h3> Biopsies from patients with IBS revealed a significant upregulation of BDNF (p=0.003), as compared with controls. Total nerve fibres were also substantially increased in patients with IBS. Electron microscopy showed ultrastructural damage on the mucosal nerve fibres (eg, swollen mitochondria and nerve axons). Elevated BDNF release was significantly correlated with the abdominal pain scores. Meanwhile, abdominal withdrawal reflex scores to colorectal distension and mucosal protein gene product 9.5 immunoreactivity were significantly lowered in BDNF<sup>+/−</sup> than in BDNF<sup>+/+</sup> mice. Electron microscopy showed degenerative changes on the mucosal nerve fibres in BDNF<sup>+/−</sup> mice. Exogenous BDNF induced an obvious dose-dependent increase in TrkB expression in dorsal root ganglia and dose-dependent decrease in threshold pressure in BDNF<sup>+/+</sup> mice. <h3>Conclusions</h3> The increased expression of BDNF in colonic mucosa, together with the structural alterations of mucosal innervation, may contribute to the visceral hyperalgesia in IBS.
Relevance of an extensive follow-up after surgery for nonsmall cell lung cancer
Authors: Delphine Gourcerol, Arnaud Scherpereel, Stephane Debeugny, Henri Porte, Alexis B. Cortot, Jean-Jacques Lafitte
Journal: European Respiratory Journal (2013)

There are no international guidelines for an appropriate and cost-effective follow-up for resected nonsmall cell lung cancer (NSCLC). We retrospectively reviewed the outcome of NSCLC patients after curative surgery. Follow-up included physical examination and chest radiography every 3 months, and chest computed tomography (CT) scan, bronchoscopy, abdominal ultrasound, brain CT scan and bone scan every 6 months for 3 years, then every year over the following 2 years. Prognostic factors and costs were analysed. Median overall survival following surgery for NSCLC in 162 patients was 38.5 months. Recurrence occurred in 85 (52.5%) patients including 41 (48%) symptomatic subjects. Disease-free survival was similar between patients with asymptomatic recurrence versus symptomatic patients (11.4 versus 12 months; p=0.41). Recurrence was detected by physical examination or chest radiography in 47 (55.3%) patients. Curative-intent therapy was provided in 18 (41%) out of 44 patients with asymptomatic recurrence and in four (10%) out of 41 symptomatic cases (p=0.001). Median overall survival from time of recurrence was higher in asymptomatic patients than in symptomatic patients (15.5 versus 7.2 months; p=0.001). The cost per year of life gained was USD32 700 (€22 397). An extensive follow-up, with acceptable cost, may improve the outcome of patients with resected NSCLC through detection of asymptomatic recurrences; however, validation by prospective studies is required.
<i>Gata3</i> drives development of RORγt+ group 3 innate lymphoid cells
Authors: Nicolas Serafini, Roel G.J. Klein Wolterink, Naoko Satoh-Takayama, Wei Xu, Christian A.J. Vosshenrich, Rudi W. Hendriks, James P. Di Santo
Journal: The Journal of Experimental Medicine (2014)

Group 3 innate lymphoid cells (ILC3) include IL-22–producing NKp46+ cells and IL-17A/IL-22–producing CD4+ lymphoid tissue inducerlike cells that express RORγt and are implicated in protective immunity at mucosal surfaces. Whereas the transcription factor Gata3 is essential for T cell and ILC2 development from hematopoietic stem cells (HSCs) and for IL-5 and IL-13 production by T cells and ILC2, the role for Gata3 in the generation or function of other ILC subsets is not known. We found that abundant GATA-3 protein is expressed in mucosa-associated ILC3 subsets with levels intermediate between mature B cells and ILC2. Chimeric mice generated with Gata3-deficient fetal liver hematopoietic precursors lack all intestinal RORγt+ ILC3 subsets, and these mice show defective production of IL-22 early after infection with the intestinal pathogen Citrobacter rodentium, leading to impaired survival. Further analyses demonstrated that ILC3 development requires cell-intrinsic Gata3 expression in fetal liver hematopoietic precursors. Our results demonstrate that Gata3 plays a generalized role in ILC lineage determination and is critical for the development of gut RORγt+ ILC3 subsets that maintain mucosal barrier homeostasis. These results further extend the paradigm of Gata3-dependent regulation of diversified innate ILC and adaptive T cell subsets.
Genome Scan for Familial Abdominal Aortic Aneurysm Using Sex and Family History as Covariates Suggests Genetic Heterogeneity and Identifies Linkage to Chromosome 19q13
Authors: Hidenori Shibamura, Jane M. Olson, Clarissa van Vlijmen-van Keulen, Sarah G. Buxbaum, Doreen M. Dudek, Gerard Tromp, Toru Ogata, Magdalena Skunca, Natzi Sakalihasan, Gerard Pals, Raymond Limet, Gerald L. MacKean, Olivier Defawe, Alain Verloes, Claudette Arthur, Alan G. Lossing, Marjorie Burnett, Taijiro Sueda, Helena Kuivaniemi
Journal: Circulation (2004)

Abdominal aortic aneurysm (AAA) is a relatively common disease, with 1% to 2% of the population harboring aneurysms. Genetic risk factors are likely to contribute to the development of AAAs, although no such risk factors have been identified.We performed a whole-genome scan of AAA using affected-relative-pair (ARP) linkage analysis that includes covariates to allow for genetic heterogeneity. We found strong evidence of linkage (logarithm of odds [LOD] score=4.64) to a region near marker D19S433 at 51.88 centimorgans (cM) on chromosome 19 with 36 families (75 ARPs) when including sex and the number of affected first-degree relatives of the proband (N(aff)) as covariates. We then genotyped 83 additional families for the same markers and typed additional markers for all families and obtained a LOD score of 4.75 (P=0.00014) with sex, N(aff), and their interaction as covariates near marker D19S416 (58.69 cM). We also identified a region on chromosome 4 with a LOD score of 3.73 (P=0.0012) near marker D4S1644 using the same covariate model as for chromosome 19.Our results provide evidence for genetic heterogeneity and the presence of susceptibility loci for AAA on chromosomes 19q13 and 4q31.
Ischaemic preconditioning changes the pattern of coronary reactive hyperaemia in the goat: role of adenosine and nitric oxide
Authors: Donatella Gattullo, Ronald J. Linden, Gianni Losano, Pasquale Pagliaro, Nico Westerhof
Journal: Cardiovascular Research (1999)

Objectives: After ischaemic preconditioning (IP), obtained by short episodes of ischaemia, cardiac protection occurs due to a reduction in myocardial metabolism through the activation of A1 adenosine receptors. The antiarrhythmic effect of IP is attributed to an increase in the release of nitric oxide (NO) by the endothelium. On the basis of the above consideration the present investigation studies the changes induced by preconditioning in coronary reactive hyperaemia (RH) and how blockade of A1 receptors and inhibition of NO synthesis can modify these changes. Methods: In anaesthetised goats, an electromagnetic flow-probe was placed around the left circumflex coronary artery. Preconditioning was obtained with two episodes of 2.5 min of coronary occlusion, separated by 5 min of reperfusion. RH was obtained with a 15 s occlusion. In a control group (n=7) RH was studied before and after IP. In a second group (n=7), 0.2 mg kg−1 of 8-cyclopentyl-dipropylxanthine, an A1 receptor blocker, and in a third group (n=7) 10 mg kg−1 of NG-nitro-l-arginine (LNNA), an NO inhibitor, were given before IP. Reactive hyperaemia was again obtained before and after IP. Results: In the control group, after IP, the time to peak hyperaemic flow and total hyperaemic flow decreased by about 50% and 25%, respectively. The A1 receptor blockade alone did not change RH. During A1 blockade, IP reduced the time to peak of RH similar as in control (45%), but did not alter total hyperaemic flow. LNNA alone reduced resting flow and total hyperaemic flow. After NO inhibition, IP only reduced total hyperaemic flow by about 15%, but the time to peak flow was not affected. Conclusions: IP alters RH by decreasing total hyperaemic flow and reducing the time to peak hyperaemic flow. While the former effect is attributed to a reduction in myocardial metabolism through the activation of the A1 receptors, the latter is likely to be due to an increased endothelial release of NO, suggesting that in addition to a protective effect on the myocardium, IP also exerts a direct effect on the responsiveness of the coronary vasculature (vascular preconditioning).
Geographic Distribution of Human Immunodeficiency Virus-associated <i>Pneumocystis carinii</i> Pneumonia in San Francisco
Authors: ALISON M. MORRIS, MELINDA SWANSON, HUAN HA, LAURENCE HUANG
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The epidemiology of Pneumocystis carinii pneumonia (PCP) and its geographic distribution are incompletely understood. We examined the influence of geographic location as a risk factor for PCP through a retrospective case–control study of HIV-infected persons evaluated for PCP at San Francisco General Hospital. Subjects had microscopically confirmed PCP diagnosed between January 1996 and June 1999. Control subjects had a presentation suggestive of PCP, but had bronchoalveolar lavage examination that did not reveal P. carinii. Medical chart review was performed to obtain demographic and clinical characteristics of the subjects as well as their addresses at time of PCP evaluation. Multivariate analyses were performed in order to identify variables associated with PCP. Lack of P. carinii prophylaxis and a CD4 cell count ⩽ 50 cells/ μ l were independent predictors of an increased risk of PCP. Interestingly, subjects living in the 94103 zip code had a significantly lower risk of PCP than subjects in other areas (odds ratio = 0.2, 95% confidence interval 0.1–0.6, p < 0.01). This effect was present despite controlling for risk factors for PCP such as use of prophylaxis or antiretroviral therapy, CD4 cell count, and HIV RNA level. We conclude that residence in the 94103 zip code of San Francisco is associated with a substantially lower risk of PCP than residence in other areas of the city.
Use of Reverse Genetics to Enhance the Oncolytic Properties of Newcastle Disease Virus
Authors: Adam Vigil, Man-Seong Park, Osvaldo Martinez, Mark A. Chua, Sa Xiao, Jerome F. Cros, Luis Martínez-Sobrido, Savio L.C. Woo, Adolfo García-Sastre
Journal: Cancer Research (2007)

Abstract Naturally occurring strains of Newcastle disease virus (NDV) have shown oncolytic therapeutic efficacy in preclinical studies and are currently in clinical trials. Here, we have evaluated the possibility to enhance the cancer therapeutic potential of NDV by means of reverse genetics. Mice bearing s.c. implanted CT26 tumors were treated with intratumoral (i.t.) injections of a recombinant NDV modified to contain a highly fusogenic F protein. These treated mice exhibited significant reduction in tumor development compared with mice treated with the unmodified virus. Furthermore, mice in a CT26 metastatic tumor model treated with an i.v. injection of the genetically engineered NDV exhibited prolonged survival compared with wild-type control virus. In addition, we examined whether the oncolytic properties of NDV could be improved by expression of immunostimulatory molecules. In this regard, we engineered several NDVs to express granulocyte macrophage colony-stimulating factor, IFN-γ, interleukin 2 (IL-2), or tumor necrosis factor α, and evaluated their therapeutic potential in an immunocompetent colon carcinoma tumor model. Mice bearing s.c. CT26 tumors treated with i.t. injections of recombinant NDV expressing IL-2 showed dramatic reductions in tumor growth, with a majority of the mice undergoing complete and long-lasting remission. Our data show the use of reverse genetics to develop enhanced recombinant NDV vectors as effective therapeutic agents for cancer treatment. [Cancer Res 2007;67(17):8285–92]
Patients' understanding of anticoagulant therapy
Authors: H. Lambert, H. Wynne
Journal: Journal of the Royal Society of Medicine (2003)

The paper by Dr Nadar and co-workers (April 2003 JRSM1) pointed out gaps in knowledge about antithrombotic therapy of anticoagulated patients from ethnic minorities in Birmingham. It also indicated that being over 61 years is associated with a low knowledge score. Attempts are made in our monitoring service to inform patients about their warfarin therapy, but only by providing new patients with written information and continuing opportunities to have their questions addressed.
NICE's draft guideline on intrapartum care
Authors: D. Rajasingam, K. Harding
Journal: BMJ (2014)

Where is the evidence?

In March 2014 the National Institute for Health and Care Excellence (NICE) released for consultation a draft of its updated guideline on intrapartum care.1 Publication of the final version is scheduled for October this year.

Although this update has involved a broad group of professionals and lay people (appointed through a transparent process of competitive interview), the “collective clinical experience” of obstetric practice came from just three obstetricians and two midwives. The guideline includes over 300 recommendations, and the evidence published with the full guideline will provide clinicians with a comprehensive, quality assessed resource of clinical trials and expert discussion. NICE has followed the suggested presentation of recommendations by the GRADE Working Group. However, we are concerned that using the terminology “strongly recommend,” “consider,” or “offer” for each point rather than the previous grading system (A to D) could make it more difficult to judge the level of evidence underpinning each recommendation without reading the full guideline. Most clinicians will not have the time to do this given that the complete guideline has increased from 305 to 805 pages, and this …
Hypophosphatemia
Authors: Steven M. Brunelli, Stanley Goldfarb
Journal: Journal of the American Society of Nephrology (2007)

Current evidence regarding the clinical consequences of hypophosphatemia is not straightforward. Given the potentially different implications of hypophosphatemia among various patient groups, this commentary touches on patients with low serum phosphate after acute hospitalization, those with chronic ambulatory hypophosphatemia, and those with hypophosphatemia in the setting of advanced renal disease. Finally, this commentary examines the evidence regarding how best to replete phosphorous in the hypophosphatemic patient.
Targeting Adhesion Molecules as a Potential Mechanism of Action for Intravenous Immunoglobulin
Authors: Varinder Gill, Christopher Doig, Derrice Knight, Emma Love, Paul Kubes
Journal: Circulation (2005)

Intravenous immunoglobulin (IVIg) therapy has been shown to have therapeutic benefit in more than 50 inflammatory and immune-related diseases; however, the potential benefit of IVIg in cardiovascular disease is more limited, in part because our understanding of the mechanisms underlying the effects of IVIg in innate immunity is incomplete.In this study, a systematic assessment of the role of IVIg in leukocyte recruitment was completed with an in vitro flow-chamber system and in vivo intravital microscopy in a feline ischemia-reperfusion model system. IVIg treatment of blood resulted in a profound decrease in recruitment of either immobilized P-selectin or E-selectin due to direct effects of IVIg on the leukocyte (not substratum). Similar results were observed on endothelium treated with histamine, which induces P-selectin-dependent rolling and beta2-integrin-dependent adhesion. IVIg reduced P-selectin glycoprotein ligand-1 (PSGL-1) antibody binding to PSGL-1 on leukocytes. Use of a beta2-integrin-dependent static assay to bypass selectin-dependent recruitment revealed some inhibitory effectiveness (60%), which suggests that the majority of the effects of IVIg were due to selectin inhibition, with some inhibition of integrin function. In vivo intravital microscopy revealed a potent inhibitory effect of IVIg on P-selectin-dependent rolling and beta2-integrin-dependent adhesion that led to reduced leukocyte recruitment and vascular dysfunction in postischemic microvessels.Our data demonstrate that IVIg has direct inhibitory effects on leukocyte recruitment in vitro and in vivo through inhibition of selectin and integrin function.