tbuckley/cabot-search huggingface dataset:
Evaluation of Prostate-Specific Antigen Declines for Surrogacy in Patients Treated on SWOG 99-16
Authors: Daniel P. Petrylak, Donna Pauler Ankerst, Caroline S. Jiang, Catherine M. Tangen, Maha H. A. Hussain, Primo N. Lara, Jeffrey A. Jones, Mary Ellen Taplin, Patrick A. Burch, Manish Kohli, Mitchell C. Benson, Eric J. Small, Derek Raghavan, E. David Crawford
Journal: JNCI Journal of the National Cancer Institute (2006)

Background: The identification of surrogate endpoints that can replace true outcome endpoints is crucial to the rapid evaluation of new cancer drugs. Retrospective analyses of phase II and III trials in metastatic androgen-independent prostate cancer have shown associations between declines in serum prostate-specific antigen (PSA) levels and survival. We evaluated PSA changes as potential surrogate markers for survival by using data from a clinical trial. Methods: Men with androgen-independent prostate cancer were randomly assigned to either docetaxel/estramustine (D/E) or mitoxantrone/prednisone (M/P) treatment on Southwest Oncology Group Protocol 99-16. Of 674 eligible patients, 551 had a baseline PSA measurement and at least one PSA measurement during the first 3 months on protocol. PSA level declines of 5%–90% and PSA velocity at 1, 2, and 3 months were tested for surrogacy by using three statistical criteria: Prentice's criteria, the proportion of treatment effect explained, and the proportion of variation explained. All statistical tests were two-sided. Results: Three-month PSA level declines of 20%–40%, a 2-month PSA decline of 30%, and PSA velocity at 2 and 3 months met all three surrogacy criteria. For example, a 3-month PSA decline of at least 30% was associated with a more than 50% decrease in the risk of death compared with the lack of such a decline (hazard ratio [HR]= 0.43, 95% confidence interval [CI] = 0.34 to 0.55; P <.001), and the increased risk of death for men treated with M/P compared with D/E (HR = 1.24, 95% CI = 1.02 to 1.51; P = .032) lost statistical significance after adjustment for this surrogate, whereas the decrease in risk of death associated with a 3-month 30% PSA decline remained statistically significant after adjustment for treatment. PSA level declines of 50%, commonly reported in clinical trials, did not meet the criteria for surrogacy. Conclusions: Several PSA measures satisfied the surrogacy criteria for survival in a retrospective analysis of data from SWOG 99-16. However, these measures await prospective validation in future clinical trials of chemotherapy in men with androgen-independent prostate cancer.
Neuroprotective effects and mechanism of cognitive-enhancing choline analogs JWB 1-84-1 and JAY 2-22-33 in neuronal culture and Caenorhabditis elegans
Authors: Roongpetch Keowkase, Marwa Aboukhatwa, Bao-Ling Adam, J Warren Beach, Alvin V Terry, Jerry J Buccafussco, Yuan Luo
Journal: Molecular Neurodegeneration (2010)

Our previous work indicated that novel analogs of choline have cytoprotective effects in vitro that might be useful in neurodegenerative conditions such as Alzheimer's disease (AD). Furthermore, two lead compounds (JWB1-84-1 and JAY2-22-33) from a library of more than 50 improved cognitive performances in a transgenic mouse model of AD. The purpose of these experiments was to more specifically investigate the neuroprotective capabilities of these lead compounds both in vitro and in vivo.We used N2a cells which express a Swedish mutation in the amyloid precursor protein and presenilin 1 genes to investigate the effect of JWB1-84-1 and JAY2-22-33 on β-amyloid (Aβ) levels and found that both compounds significantly reduced Aβ levels. JWB1-84-1 and JAY2-22-33 also protected rat primary cortical neurons from Aβ toxicity. Subsequently, we utilized the nematode Caenorhabditis elegans (C. elegans) as an in vivo model organism to identify potential molecular targets of these compounds. In the C. elegans model of Aβ toxicity, human Aβ is expressed intracellularly in the body wall muscle. The expression and subsequent aggregation of Aβ in the muscle leads to progressive paralysis.We found that JAY2-22-33 (but not JWB1-84-1) significantly reduced Aβ toxicity by delaying paralysis and this protective effect required both the insulin signaling pathway and nicotinic acetylcholine receptors (nAChRs).
Inhaled iloprost suppresses the cardinal features of asthma via inhibition of airway dendritic cell function
Authors: Marco Idzko, Hamida Hammad, Menno van Nimwegen, Mirjam Kool, Nanda Vos, Henk C. Hoogsteden, Bart N. Lambrecht
Journal: Journal of Clinical Investigation (2007)

Inhalation of iloprost, a stable prostacyclin (PGI(2)) analog, is a well-accepted and safe treatment for pulmonary arterial hypertension. Although iloprost mainly acts as a vasodilator by binding to the I prostanoid (IP) receptor, recent evidence suggests that signaling via this receptor also has antiinflammatory effects through unclear mechanisms. Here we show in a murine model of asthma that iloprost inhalation suppressed the cardinal features of asthma when given during the priming or challenge phase. As a mechanism of action, iloprost interfered with the function of lung myeloid DCs, critical antigen-presenting cells of the airways. Iloprost treatment inhibited the maturation and migration of lung DCs to the mediastinal LNs, thereby abolishing the induction of an allergen-specific Th2 response in these nodes. The effect of iloprost was DC autonomous, as iloprost-treated DCs no longer induced Th2 differentiation from naive T cells or boosted effector cytokine production in primed Th2 cells. These data should pave the way for a clinical effectiveness study using inhaled iloprost for the treatment of asthma.
The Can-SAD Study: A Randomized Controlled Trial of the Effectiveness of Light Therapy and Fluoxetine in Patients With Winter Seasonal Affective Disorder
Authors: Raymond W. Lam, Anthony J. Levitt, Robert D. Levitan, Murray W. Enns, Rachel Morehouse, Erin E. Michalak, Edwin M. Tam
Journal: American Journal of Psychiatry (2006)

Objective: Light therapy and antidepressants have shown comparable efficacy in separate studies of seasonal affective disorder treatment, but few studies have directly compared the two treatments. This study compared the effectiveness of light therapy and an antidepressant within a single trial. Method: This double-blind, randomized, controlled trial was conducted in four Canadian centers over three winter seasons. Patients met DSM–IV criteria for major depressive disorder with a seasonal (winter) pattern and had scores ≥23 on the 24-item Hamilton Depression Rating Scale. After a baseline observation week, eligible patients were randomly assigned to 8 weeks of double-blind treatment with either 1) 10,000-lux light treatment and a placebo capsule, or 2) 100-lux light treatment (placebo light) and fluoxetine, 20 mg/day. Light treatment was applied for 30 minutes/day in the morning with a fluorescent white-light box; placebo light boxes used neutral density filters. Results: A total of 96 patients were randomly assigned to a treatment condition. Intent-to-treat analysis showed overall improvement with time, with no differences between treatments. There were also no differences between the light and fluoxetine treatment groups in clinical response rates (67% for each group) or remission rates (50% and 54%, respectively). Post hoc testing found that light-treated patients had greater improvement at 1 week but not at other time points. Fluoxetine was associated with greater treatment-emergent adverse events (agitation, sleep disturbance, palpitations), but both treatments were generally well-tolerated with no differences in overall number of adverse effects. Conclusions: Light treatment showed earlier response onset and lower rate of some adverse events relative to fluoxetine, but there were no other significant differences in outcome between light therapy and antidepressant medication. Although limited by lack of a double-placebo condition, this study supports the effectiveness and tolerability of both treatments for seasonal affective disorder and suggests that other clinical factors, including patient preference, should guide selection of first-line treatment.
Evolving Principles of Surgical Management and Prognostic Factors for Outcome in Renal Cell Carcinoma
Authors: John S. Lam, Alberto Breda, Arie S. Belldegrun, Robert A. Figlin
Journal: Journal of Clinical Oncology (2006)

The generally accepted principles for the surgical management of renal cell carcinoma (RCC) were first described more than 30 years ago. Since then, much has changed in the understanding of the basic biology and genetics of kidney cancer. Improvements in cross-sectional imaging has allowed for more accurate preoperative clinical staging of renal tumors, and the necessity of completing all the components of the radical nephrectomy have been questioned. Surgical techniques have also evolved, and technology has advanced to make possible new methods of managing renal tumors. The TNM staging system is currently the most extensively used system to provide prognostic information for RCC. However, data published in the last few years has led to significant controversies as to whether further revisions are needed and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors. Furthermore, the recent discovery of molecular tumor markers are expected to revolutionize the staging of RCC and lead to the development of new therapies based on molecular targeting. This review will examine the evolving principles in the surgical management of RCC as well as provide an update on current staging modalities and prognostic factors.
The European pharmaceutical industry: coming to a screen near you?
Authors: Paul Rutter, Simon Gilbody
Journal: Journal of the Royal Society of Medicine (2008)

The European Commission Pharmaceuticals Unit is currently developing a legal proposal to increase the public provision of information about prescription medicines. Their preliminary proposal would achieve this by permitting pharmaceutical companies to provide unsolicited information about their prescription-only products directly to the public via the mass-media.1 The permitted channels of dissemination would include television, radio and print media, as well as standalone products distributed directly or via healthcare professionals. The stated intention of this controversial proposal is to meet a public need for high quality, reliable information about medications.

Legislative debate in this area is not new. In 2002, the European Parliament debated a proposed five-year pilot scheme of mass-media advertising limited to drugs for diabetes, asthma and AIDS. The proposal was rejected by 494 votes to 42.2 Currently, the USA and New Zealand are the only developed countries that permit direct-to-consumer advertising (DTCA) of prescription-only medications; it is a contentious issue in both.3,4

The preliminary proposal insists that our ban on advertising should be maintained, instead forwarding a suggestion that the pharmaceutical industry be able to disseminate ‘non-promotional information’. Herein lies the conundrum, as the distinction between ‘advertising’ and mass-provision of unsolicited information by industry is not immediately obvious. Indeed, despite widespread agreement that such a distinction is absolutely crucial to the current proposal, neither the proposer nor any stakeholder has yet offered a clear means to achieve this.5 Opponents therefore fear that permitting such legislation would be tantamount to allowing advertising in all but name.6

The importance of this debate cannot be underestimated: widespread information dissemination has the potential to significantly impact the public's understanding of health, disease and medications, and to alter the nature of the doctor-patient relationship. Whilst this debate may be relatively new to Europeans, it is both long-standing and familiar in North America and Australasia. We are therefore fortunate to have the benefit of others' experiences. Indeed, we are urged to learn from these experiences by physicians in New Zealand. They fear that Europe's current trajectory represents a ‘slippery slope’ to their own situation in which drug advertising is omnipresent, though unpopular with doctors and with patient groups.7

Within this article we draw on international experience to contextualize and consider the potential European policy. We summarize the discourse that surrounds DTCA in the USA and New Zealand and present a taxonomic framework. Starting from a discussion of Canada's experience, we discuss the distinction between information and advertising. We consider how Europe could draw all of this together to carve its own path towards world-class provision of patient-centred information.
No added benefit from nebulized amiloride in patients with cystic fibrosis
Authors: A Graham, A Hasani, EW Alton, GP Martin, C Marriott, ME Hodson, SW Clarke, DM Geddes
Journal: European Respiratory Journal (1993)

In cystic fibrosis (CF) airway epithelial sodium absorption is increased 2-3 fold. Since sodium absorption is inhibited by the sodium channel blocker amiloride, our aim was to assess its therapeutic benefit in cystic fibrosis. A randomized, double-blind, placebo-controlled, cross-over trial of nebulized amiloride was performed in 23 patients with cystic fibrosis. Amiloride or placebo was administered four times daily for two six month periods. Existing treatment was continued, and any infective exacerbations treated in the usual way. Fourteen patients completed the study. No significant changes occurred in forced expiratory volume in one second, forced vital capacity, oxygen saturation, body weight, sputum volume, culture and rheology, serum urea, and electrolytes, white cell count and erythrocyte sedimentation rate during either treatment period. The frequency of infective exacerbations was also not different in either treatment period. We were thus unable to confirm the benefit shown in the only other clinical trial of nebulized amiloride in cystic fibrosis and conclude that, in the presence of established treatment for cystic fibrosis lung disease, nebulized amiloride offers no additional clinical benefit.
Asymptomatic airway hyperresponsiveness: relationships with airway inflammation and remodelling
Authors: C. Laprise, M. Laviolette, M Boutet, L Boulet
Journal: European Respiratory Journal (1999)

To study the physiopathology and significance of asymptomatic airway hyperresponsiveness (AHR), the clinical and bronchial immunohistological parameters were evaluated in subjects with asymptomatic and symptomatic AHR. Asymptomatic subjects with AHR (eight females/two males, no respiratory symptoms, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20) &lt;8 mg x mL(-1) and no treatment) were compared with asthmatic subjects paired for age, sex and PC20, and with nonatopic, nonasthmatic controls paired for age and sex. All three groups were evaluated once at baseline, whilst the asymptomatic AHR subjects were re-evaluated after 1 and 2 yrs. Measurements included spirometry, methacholine challenge, serum immunoglobulin (Ig)E, blood eosinophils, and bronchoscopy (at baseline and after 2 yrs only). At first evaluation, the mean blood eosinophil count, total serum IgE level, atopic index, baseline forced expiratory volume in one second (FEV1) and the degree of bronchial epithelial desquamation of the asymptomatic AHR subjects were similar to those of asthmatic subjects. However, they presented focal rather than the continuous bronchial subepithelial fibrosis observed in asthmatics. Their mucosal CD3, CD4, CD25, EG1 and EG2-positive cell counts were intermediate between those of the control subjects and asthmatics. At the end of the 2-yr follow-up, four of them had developed asthma symptoms. At this time, bronchial biopsies revealed an increase in the extent of subepithelial fibrosis and in the number of CD25 and CD4-positive cells, and a decrease in the number of CD8+ cells, particularly in subjects who developed asthma symptoms. These data suggest that asymptomatic airway hyperresponsiveness is associated with airway inflammation and remodelling, and that the appearance of asthma symptoms is associated with an increase in these features, particularly the CD4/CD8 ratio and airway fibrosis. Consequently, this study proposes an association between asymptomatic airway hyperresponsiveness and airway inflammation, structural changes and asthma although these relationships remain to be further evaluated.
Outcome of pulmonary multidrug-resistant tuberculosis: a 6-yr follow-up study
Authors: C-Y. Chiang, D. A. Enarson, M-C. Yu, K-J. Bai, R-M. Huang, C-J. Hsu, J. Suo, T-P. Lin
Journal: European Respiratory Journal (2006)

A retrospective study was performed to determine factors associated with the outcome of pulmonary multidrug-resistant tuberculosis (MDR-TB) in Taipei, Taiwan. All patients newly diagnosed with pulmonary MDR-TB in a referral centre from 1992–1996 were enrolled and their outcome over the subsequent 6 yrs was determined. A total of 299 patients were identified, comprising 215 (71.9%) males and 84 (28.1%) females with a mean age of 47.3 yrs. The patients received a mean of 3.7 effective drugs. Out of the 299 patients, 153 (51.2%) were cured, 31 (10.4%) failed, 28 (9.4%) died and 87 (29.1%) defaulted. Of the 125 patients receiving second-line drugs with ofloxacin, 74 (59.2%) were cured. Those who received ofloxacin had a lower risk of relapse than those receiving only first-line drugs (hazard ratio (HR) 0.16, 95% confidence interval (CI) 0.03–0.81) and a lower risk of TB-related death than those receiving second-line drugs but not ofloxacin (adjusted HR 0.50, 95% CI 0.31–0.82). In conclusion, multidrug-resistant tuberculosis patients who received ofloxacin were more likely to be cured, and were less likely to die, fail or relapse. The utility of new-generation fluoroquinolones, such as moxifloxacin, in the treatment of multidrug-resistant tuberculosis needs to be evaluated. Default from treatment is a major challenge in the treatment of multidrug-resistant tuberculosis.
The Evolutionary Implications of knox-I Gene Duplications in Conifers: Correlated Evidence from Phylogeny, Gene Mapping, and Analysis of Functional Divergence
Authors: Carine Guillet-Claude, Nathalie Isabel, Betty Pelgas, Jean Bousquet
Journal: Molecular Biology and Evolution (2004)

Class I knox genes code for transcription factors that play an essential role in plant growth and development as central regulators of meristem cell identity. Based on the analysis of new cDNA sequences from various tissues and genomic DNA sequences, we identified a highly diversified group of class I knox genes in conifers. Phylogenetic analyses of complete amino acid sequences from various seed plants indicated that all conifer sequences formed a monophyletic group. Within conifers, four subgroups here named genes KN1 to KN4 were well delineated, each regrouping pine and spruce sequences. KN4 was sister group to KN3, which was sister group to KN1 and KN2. Genetic mapping on the genomes of two divergent Picea species indicated that KN1 and KN2 are located close to each other on the same linkage group, whereas KN3 and KN4 mapped on different linkage groups, correlating the more ancient divergence of these two genes. The proportion of synonymous and nonsynonymous substitutions suggested intense purifying selection for the four genes. However, rates of substitution per year indicated an evolution in two steps: faster rates were noted after gene duplications, followed subsequently by lower rates. Positive directional selection was detected for most of the internal branches harboring an accelerated rate of evolution. In addition, many sites with highly significant amino acid rate shift were identified between these branches. However, the tightly linked KN1 and KN2 did not diverge as much from each other. The implications of the correlation between phylogenetic, structural, and functional information are discussed in relation to the diversification of the knox-I gene family in conifers.
SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis
Authors: P. K.K. Wong
Journal: Journal of Clinical Investigation (2006)

RA is an autoimmune disease characterized by sustained imbalance between pro- and antiinflammatory immune mechanisms. The SOCS proteins are negative regulators of cytokine signaling, but to date there has been little information on their function in disease. The generation of Socs3–/Δvav mice, which lack SOCS-3 in the hematopoietic and endothelial cell compartment, allowed us to explore the role of endogenous SOCS-3 during acute inflammatory arthritis. Joint inflammation in Socs3–/Δvav mice was particularly severe and was characterized by increased numbers of neutrophils in the inflamed synovium, bone marrow, peripheral blood, and spleen. These features were most likely due to increased production of and enhanced responsiveness to G-CSF and IL-6 during arthritis in these mice. Local osteoclast generation and bone destruction were also dramatically increased in the absence of SOCS-3, as was macrophage activation. Finally, SOCS-3 was found to negatively regulate CD4+ T lymphocyte activation, including production of the pleiotropic cytokine IL-17. The absence of SOCS-3 therefore had dramatic effects in this disease model, with a broader impact on cellular responses than SOCS-1 deficiency. These findings provide direct in vivo evidence that endogenous SOCS-3 is a critical negative regulator of multiple cell types orchestrating inflammatory joint disease.
Next-generation personalized drug discovery: the tripeptide GHK hits center stage in chronic obstructive pulmonary disease
Authors: Silke Meiners, Oliver Eickelberg
Journal: Genome Medicine (2012)

Chronic lung diseases (CLDs), including chronic obstructive pulmonary disease (COPD), are the second leading cause of death worldwide. The first report of database-driven drug discovery in carefully phenotyped COPD specimens has now been published in Genome Medicine, combining gene expression data in defined emphysematous areas with connectivity-map-based compound discovery. This joint effort may lead the way to novel and potentially more efficient concepts of personalized drug discovery for COPD in particular, and CLD in general. See research article http://genomemedicine.com/content/4/8/67/abstract