tbuckley/cabot-search huggingface dataset:
24-h duration of the novel LABA vilanterol trifenatate in asthma patients treated with inhaled corticosteroids
Authors: Jan Lötvall, Eric D. Bateman, Eugene R. Bleecker, William W. Busse, Ashley Woodcock, Richard Follows, Jessica Lim, Sally Stone, Loretta Jacques, Brett Haumann
Journal: European Respiratory Journal (2012)

Current guidelines recommend adding a long-acting inhaled β 2 -agonist (LABA) to inhaled corticosteroids (ICS) in patients with uncontrolled asthma. This study evaluated the novel, once-daily LABA vilanterol trifenatate (VI) in asthma patients who remained symptomatic despite existing ICS therapy. The study involved a randomised, double-blind, placebo-controlled trial of VI (3, 6.25, 12.5, 25 and 50 μg), administered once daily in the evening by dry powder inhaler for 28 days, in asthma patients aged ≥12 yrs symptomatic on current ICS therapy. The primary end-point was trough (24 h post-dose) forced expiratory volume in 1 s (FEV 1 ); secondary end-points were weighted mean FEV 1 , peak expiratory flow (PEF), symptom-/rescue-free 24-h periods, and safety. A significant relationship was observed between VI dose and improvements in trough FEV 1 (p=0.037). Statistically significant increases in mean trough FEV 1 , relative to placebo, were documented for VI 12.5–50 μg (121–162 mL; p≤0.016). Dose-related effects of VI were observed on weighted mean (0–24 h) FEV 1 , morning/evening PEF, and symptom-/rescue-free 24-h periods. All doses of VI were well tolerated with low incidences of recognised LABA-related adverse events (tremor 0–2%; palpitations 0–2%; glucose effects 0–1%; potassium effects 0–&lt;1%). Once-daily VI 12.5–50 μg resulted in prolonged bronchodilation of at least 24 h with good tolerability in asthma patients receiving ICS. Based on the overall efficacy and adverse event profile from this study, the optimum dose of VI appears to be 25 μg.
Phase I Trial Evaluating the Safety of Bevacizumab With Concurrent Radiotherapy and Capecitabine in Locally Advanced Pancreatic Cancer
Authors: Christopher H. Crane, Lee M. Ellis, James L. Abbruzzese, Christina Amos, Henry Q. Xiong, Linus Ho, Douglas B. Evans, Eric P. Tamm, Chaan Ng, Peter W.T. Pisters, Chusilp Charnsangavej, Marc E. Delclos, Michael O'Reilly, Jeffrey E. Lee, Robert A. Wolff
Journal: Journal of Clinical Oncology (2006)

To study the safety of bevacizumab with capecitabine-based chemoradiotherapy.Patients with inoperable pancreatic adenocarcinoma received bevacizumab 2 weeks before radiotherapy (50.4 Gy treating the primary tumor and gross adenopathy), every 2 weeks during radiotherapy (12 patients each at 2.5, 5.0, 7.5, and 10 mg/kg), and after radiotherapy until disease progression. Capecitabine was administered on days 14 through 52 (650 mg/m2 orally twice daily for the first six patients; 825 mg/m2 for the remaining patients).Significant acute gastrointestinal (43% grade 2; 4% grade 3), hand and foot syndrome (21% grade 2), and transient hematologic (8% grade 3 or greater) events were uncommon with protocol mandated dose reductions of capecitabine grade 2 toxicity (43% of patients). Among the first 30 patients treated, three patients had tumor-associated bleeding duodenal ulcers, and one had a contained duodenal perforation. No additional bleeding events occurred among the final 18 patients after patients with duodenal involvement by tumor were excluded. Nine (20%) of 46 assessable patients had confirmed partial responses until distant progression for a median of 6.2 months. Four patients have undergone pancreaticoduodenectomy without perioperative complication. The median survival was 11.6 months (95% CI, 9.6 to 13.6), from the start of protocol therapy.Concurrent bevacizumab did not significantly increase the acute toxicity of a relatively well-tolerated chemoradiotherapy regimen. However, ulceration and bleeding in the radiation field possibly related to bevacizumab occurred when tumor involved the duodenal mucosa. The encouraging efficacy end points suggest that the further study of bevacizumab with chemoradiotherapy is warranted.
Coping with sports injuries: psychological strategies for rehabilitation
Authors: J Louder
Journal: British Journal of Sports Medicine (2005)

Edited by J Crossman. London: Published by Oxford University Press, 2001, pp 202, £27.50, softcover. ISBN 0192632159

This is the first injury specific text that, I have felt, brings together, and acknowledges, all parties involved in rehabilitation (medical staff to athlete to support networks). My medical colleagues (doctors, physiotherapists, masseurs, etc) should read this book and recognise that, if psychological recovery from injury is not included, they run the risk of an incomplete, possibly extended, rehabilitation programme for their athletes.

One of the main attractions of this book is that …
Dermatophagoides pteronyssinus and bioelectric properties of airway epithelium: role of cysteine proteases
Authors: N. Roche, T.C. Chinet, N‐E Belouchi, C Julié, G.J Huchon
Journal: European Respiratory Journal (2000)

Several epidemiological studies suggest that exposure to house dust mite allergens plays a role in the pathogenesis of asthma. Since many of these allergens exhibit enzymatic properties, they may damage the airway epithelium. To characterize the effects of low doses of Dermatophagoides pteronyssinus on the airway epithelium, the effect of D. pteronyssinus on the epithelial bioelectric properties of tracheal fragments of non-sensitized Lewis rats was studied, using Ussing-type chamber technique. The addition of a crude D. pteronyssinus extract containing 20 microg mL(-1) of Der pI allergen in the presence of 1.5 mM dithiothreitol (DTT, an activator of cysteine proteases), induced a progressive increase in bioelectrical conductance (+12.0+/-1.5%, n=12, p&lt;0.005), an index of epithelial permeability, without affecting the short circuit current (which reflects active ion transports). The D. pteronyssinus-induced increase in epithelial conductance was related to the cysteine-protease activity of the allergen since it was not observed in the absence of DTT (n=12), and was completely suppressed in the presence of 10 nM E-64, a specific inhibitor of cysteine proteases (n=12). D. pteronyssinus-induced increase in epithelial conductance could be entirely attributed to an increase in the paracellular conductance (+11.2+/-1.2%, n=8, p&lt;0.01). There was no electrophysiological evidence of rupture in epithelial continuity, and no cell detachment was observed on microscopic examination. In conclusion, the cysteine protease activity of crude Dermatophagoides pteronyssinus extract is able to increase the epithelial paracellular conductance of rat tracheal tissues, even at relatively low doses that do not induce cell detachment or cell death.
Prevention of Hormone-Related Cancers: Breast Cancer
Authors: Barbara K. Dunn, D. Lawrence Wickerham, Leslie G. Ford
Journal: Journal of Clinical Oncology (2005)

Carcinogenesis in the breast is a hormonally dependent process. Evidence implicating estrogen as a key breast carcinogen comes from various lines of investigation. Traditional epidemiologic studies demonstrate associations between estrogen exposure, both exogenous and endogenous, and increased breast cancer risk. Ongoing genetic epidemiologic studies also show associations between specific polymorphisms in estrogen-metabolizing genes and risk, albeit inconsistently. The application of these findings to the treatment and, more recently, the prevention of breast cancer has led to the development of agents that either (1) inhibit estrogen action at the estrogen receptor (selective estrogen receptor modulators (SERMs]); or (2) inhibit estrogen-synthesizing enzymes, thereby abrogating synthesis of this hormone (aromatase inhibitors). Large phase III trials have evaluated the ability of such agents to reduce the incidence of breast cancer in women at increased risk of the disease. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1: Breast Cancer Prevention Trial (BCPT) demonstrated the superiority of the SERM tamoxifen to placebo in reducing breast cancer risk, leading to the Food and Drug Administration approval of tamoxifen for risk reduction. The implementation of tamoxifen for this indication has not become widespread in clinical practice, however, for a variety of reasons that we discuss. Results from the NSABP Study of Tamoxifen and Raloxifene, which compares the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk population, will be available in the near future. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole, and exemestane, are being incorporated into trials evaluating their efficacy as preventive agents in women at increased risk.
Amelioration of experimental arthritis by stroke-induced immunosuppression is independent of T<sub>reg</sub>cell function
Authors: Ingo M Irmler, Mieczyslaw Gajda, Thomas Kamradt
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Clinical evidence suggests that neurological lesions can protect from arthritis. Acute cerebral ischaemia induces severe immunosuppression, resulting in enhanced susceptibility to infections. We aimed to determine if stroke-induced immunosuppression can ameliorate arthritis and to delineate the immunological mechanisms involved. <h3>Methods</h3> Unilateral cerebral ischaemia was induced in mice by occlusion of one middle cerebral artery (MCAO) at different time points after induction of G6PI-induced arthritis in mice. Clinical and histological signs of arthritis were assessed. Regulatory T cells were specifically depleted by injection of diphtheria toxin into transgenic DEREG mice. Immunological correlates of MCAO were determined by flow cytometry and serological methods. <h3>Results</h3> MCAO reduced the clinical and histological signs of arthritis significantly. To be effective, stroke had to be induced during the induction phase or the early clinical stage of arthritis. MCAO induced a global loss of leucocytes. Despite the reduced absolute number of lymphocytes, the functional differentiation of T helper cells into Th1/17 cells and the production of autoantibodies were unimpaired. Depletion experiments showed that regulatory T cells were dispensable for the protective effect of MCAO. <h3>Conclusions</h3> MCAO ameliorates arthritis. The correlate of protection from arthritis is not the reduction of a particular pathogenic leucocyte subset or the preferential expansion or emergence of a protective cell population but the global reduction of leucocytes during arthritis.
Molecular Evolution of Transferrin: Evidence for Positive Selection in Salmonids
Authors: Michael J. Ford
Journal: Molecular Biology and Evolution (2001)

Transferrins are iron-binding proteins that are involved in iron storage and resistance to bacterial disease. Previous work has shown that nonsynonymous-to-synonymous-site substitution ratios (d(n)/d(s) ratios) between transferrin genes from some salmonid species were significantly greater than 1.0, providing evidence for positive selection at the transferrin gene. The purpose of the current study was to put these earlier results in a broader evolutionary context by examining variation among 25 previously published transferrin sequences from fish, amphibians, and mammals. The results of the study show that evidence for positive selection at transferrin is limited to salmonids-d(n)/d(s) ratios estimated for nonsalmonid lineages were generally less than 1.0. Within the salmonids, approximately 13% of the transferrin codon sites are estimated to be subject to positive selection, with an estimated d(n)/d(s) ratio of approximately 7. The three- dimensional locations of some of the selected sites were inferred by comparing these sites to homologous sites in the bovine lactoferrin crystallographic structure. The selected sites generally fall on the outside of the molecule, within and near areas that are bound by transferrin-binding proteins from human pathogenic bacteria. The physical locations of sites estimated to be subject to positive selection support previous speculation that competition for iron from pathogenic bacteria could be the source of positive selection.
Evidence of Oligogenic Inheritance in Nephronophthisis
Authors: Julia Hoefele, Matthias T.F. Wolf, John F. O’Toole, Edgar A. Otto, Ulla Schultheiss, Georges De[Combining Circumflex Accent]schenes, Massimo Attanasio, Boris Utsch, Corinne Antignac, Friedhelm Hildebrandt
Journal: Journal of the American Society of Nephrology (2007)

Nephronophthisis is a recessive cystic renal disease that leads to end-stage renal failure in the first two decades of life. Twenty-five percent of nephronophthisis cases are caused by large homozygous deletions of <i>NPHP1</i>, but six genes responsible for nephronophthisis have been identified. Because oligogenic inheritance has been described for the related Bardet-Biedl syndrome, we evaluated whether mutations in more than one gene may also be detected in cases of nephronophthisis. Because the nephrocystins 1 to 4 are known to interact, we examined patients with nephronophthisis from 94 different families and sequenced all exons of the <i>NPHP1, NPHP2</i>, <i>NPHP3</i>, and <i>NPHP4</i> genes. In our previous studies involving 44 families, we detected two mutations in one of the <i>NPHP1–4</i> genes. Here, we detected in six families two mutations in either <i>NPHP1</i>, <i>NPHP3</i>, or <i>NPHP4</i>, and identified a third mutation in one of the other <i>NPHP</i> genes. Furthermore, we found possible digenic disease by detecting one individual who carried one mutation in <i>NPHP2</i> and a second mutation in <i>NPHP3</i>. Finally, we detected the presence of a single mutation in nine families, suggesting that the second recessive mutation may be in another as yet unidentified <i>NPHP</i> gene. Our findings suggest that oligogenicity may occur in cases of nephronophthisis.
B Virus (Herpesvirus simiae) Infection in Humans: Epidemiologic Investigation of a Cluster
Authors: G P Holmes, J K Hilliard, K C Klontz, A H Rupert, C M Schindler, E Parrish, D G Griffin, G S Ward, N D Bernstein, T W Bean
Journal: Annals of Internal Medicine (1990)

A cluster of four cases of symptomatic B virus infection in humans occurred in Pensacola, Florida, in March 1987. Three cases occurred in persons who worked with monkeys at a research facility, and the fourth resulted from apparent autoinoculation through use of a nonprescription skin cream. Contact tracing identified 159 persons who may have been exposed to B virus (21 had been exposed to monkeys at the facility and 138 had been exposed to one or more of the case-patients), but no further cases were identified. Comparisons of restriction endonuclease patterns from B virus isolates linked two of the three cases in monkey handlers to one clinically ill monkey and the other to a second, healthy monkey. Three risk factors for human infection were identified: nonuse of mechanical or chemical restraints for monkeys before handling, nonuse of available protective gear, and direct viral inoculation through the application of a topical medication.
LIP5 Interacts with Aquaporin 2 and Facilitates Its Lysosomal Degradation
Authors: Bas W.M. van Balkom, Michelle Boone, Giel Hendriks, Erik-Jan Kamsteeg, Joris H. Robben, H. Christiaan Stronks, Anne van der Voorde, Francois van Herp, Peter van der Sluijs, Peter M.T. Deen
Journal: Journal of the American Society of Nephrology (2009)

Vasopressin binding to the V2 receptor in renal principal cells leads to activation of protein kinase A, phosphorylation of aquaporin 2 (AQP2) at Ser256, and the translocation of AQP2 to the apical membrane, resulting in concentration of the urine. In contrast, phorbol ester-induced activation of protein kinase C pathway leads to ubiquitination of AQP2 at Lys270 and its internalization to multivesicular bodies, where it is targeted for lysosomal degradation or stored for recycling. Because little is known about the regulation of AQP2 trafficking, we used the carboxy-terminal tail of constitutively nonphosphorylated AQP2 (S256A) as a bait for interacting proteins in a yeast two-hybrid assay. We isolated lysosomal trafficking regulator-interacting protein 5 (LIP5) and found that LIP5 interacted with the proximal carboxy-terminal tail (L230-D243) of AQP2 in vitro but not with AQP3 or AQP4, which are also expressed in principal cells. Immunohistochemistry revealed that LIP5 co-localized with AQP2 in principal cells. LIP5 binding occurred independent of the state of Ser256 phosphorylation or Lys270 ubiquitination. LIP5 has been shown to facilitate degradation of the EGF receptor; here, LIP5 seemed to bind this receptor. Knockdown of LIP5 in mouse renal cells (mpkCCD) reduced the phorbol ester-induced degradation of AQP2 approximately two-fold. In summary, LIP5 binds cargo proteins and, considering the role of LIP5 in protein sorting to multivesicular bodies, plays a role in the degradation of AQP2, possibly by reducing the formation of late endosomes.
Treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet A
Authors: M.A. De Rie, A. Sommer, R. Hoekzema, H.A.M. Neumann
Journal: British Journal of Dermatology (2002)

Summary Background Necrobiosis lipoidica (NL) is a rare skin disease, mostly seen on the legs and often occurring in patients with diabetes mellitus. The disease belongs to the idiopathic cutaneous palisading granulomatous dermatitides associated with a degeneration of collagen, thus leading to skin atrophy. Application of topical corticosteroids is the most widely used treatment but the results are not always satisfactory and may worsen skin atrophy. Preliminary studies in patients with NL have shown a clinical response with psoralen plus ultraviolet (UV) A (PUVA). Objectives To study the effect of topical PUVA on NL in a multicentre prospective study. Methods Thirty patients (27 women and three men) including 13 with insulin‐dependent diabetes mellitus, with a diagnosis of NL proven by histopathology, were included. All patients had been unsuccessfully treated with topical and/or intralesional corticosteroids. Patients were treated twice weekly with an aqueous gel containing 0·005% psoralen followed by irradiation with UVA. Clinical photographs were taken for evaluation. In addition, 20‐MHz high‐frequency ultrasound analysis was performed in 10 patients to evaluate the thickness and density of the dermis during topical PUVA therapy. Results Five patients (17%) showed complete clearing (healing of ulceration and disappearance of erythema) after a mean of 22 exposures (range 15–30). Eleven patients (37%) showed improvement, defined as healing of ulceration and/or reduction of erythema, after a mean of 23 exposures (range 11–42). Ten patients (33%) showed no effect and four patients (13%) worsened during topical PUVA therapy. The treatment results of the patients who suffered from diabetes mellitus were not different from those who did not have diabetes mellitus. No difference was seen in mean dermal thickness (1666 vs. 1706 µm) and density (17 vs. 16 units) before and after topical PUVA therapy. Side‐effects were seen in 10 patients: hyperpigmentation (n = 4), blistering (n = 4) and bacterial infection (n = 2). Conclusions Topical PUVA may be a useful treatment modality for NL in patients not responding to topical or intralesional corticosteroids.
Palliative use of non-invasive ventilation in end-of-life patients with solid tumours: a randomised feasibility trial
Authors: Stefano Nava, Miguel Ferrer, Antonio Esquinas, Raffaele Scala, Paolo Groff, Roberto Cosentini, Davide Guido, Ching-Hsiung Lin, Anna Maria Cuomo, Mario Grassi
Journal: The Lancet Oncology (2013)
Melanoma-Educated CD14+ Cells Acquire a Myeloid-Derived Suppressor Cell Phenotype through COX-2–Dependent Mechanisms
Authors: Yumeng Mao, Isabel Poschke, Erik Wennerberg, Yago Pico de Coaña, Suzanne Egyhazi Brage, Inkeri Schultz, Johan Hansson, Giuseppe Masucci, Andreas Lundqvist, Rolf Kiessling
Journal: Cancer Research (2013)

Tumors can suppress the host immune system by employing a variety of cellular immune modulators, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). In the peripheral blood of patients with advanced stage melanoma, there is an accumulation of CD14(+)HLA-DR(lo/-) MDSC that suppress autologous T cells ex vivo in a STAT-3-dependent manner. However, a precise mechanistic basis underlying this effect is unclear, particularly with regard to whether the MDSC induction mechanism relies on cell-cell contact of melanoma cells with CD14(+) cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14(+) monocytes, leading them to resemble MDSCs characterized in patients with advanced stage melanoma. These MDSC-like cells potently suppress autologous T-cell proliferation and IFN-γ production. Notably, induction of myeloid-suppressive functions requires contact or close proximity between monocytes and tumor cells. Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14(+) cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE2), STAT-3, and superoxide. Indeed, PGE2 was sufficient to confer to monocytes the ability to suppress proliferation and IFN-γ production by autologous T cells ex vivo. In summary, our results reveal how immune suppression by MDSC can be initiated in the tumor microenvironment of human melanoma.
Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib
Authors: George Mulligan, Constantine Mitsiades, Barb Bryant, Fenghuang Zhan, Wee J. Chng, Steven Roels, Erik Koenig, Andrew Fergus, Yongsheng Huang, Paul Richardson, William L. Trepicchio, Annemiek Broyl, Pieter Sonneveld, John D. Shaughnessy, P. Leif Bergsagel, David Schenkein, Dixie-Lee Esseltine, Anthony Boral, Kenneth C. Anderson
Journal: Blood (2006)