Through detailed case studies on Costa Rica, El Salvador, and Nicaragua, Spalding examines the debate surrounding the adoption of CAFTA alongside the simultaneous changes to the economic and ...political landscape of Central America at the turn of this century.
Much has changed in the last two years at DGVa (http://www.ebi.ac.uk/dgva) and dbVar (http://www.ncbi.nlm.nih.gov/dbvar). We are now processing direct submissions rather than only curating data from ...the literature and our joint study catalog includes data from over 100 studies in 11 organisms. Studies from human dominate with data from control and case populations, tumor samples as well as three large curated studies derived from multiple sources. During the processing of these data, we have made improvements to our data model, submission process and data representation. Additionally, we have made significant improvements in providing access to these data via web and FTP interfaces.
A systematic way of recording data use conditions that are based on consent permissions as found in the datasets of the main public genome archives (NCBI dbGaP and EMBL-EBI/CRG EGA).
Objective
To assess the efficacy and safety of rilonacept, an interleukin‐1 inhibitor, in a randomized, double‐blind, placebo‐controlled trial.
Methods
An initial 4‐week double‐blind placebo phase ...was incorporated into a 24‐week randomized multicenter design, followed by an open‐label phase. Seventy‐one children who had active arthritis in ≥2 joints were randomized (1:1) to the 2 arms of the study. Patients in the rilonacept arm received rilonacept (loading dose 4.4 mg/kg followed by 2.2 mg/kg weekly, subcutaneously) beginning on day 0. Patients in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary end point was time to response, using the adapted American College of Rheumatology Pediatric 30 criteria coupled with the absence of fever and taper of the dosage of systemic corticosteroids, using prespecified criteria.
Results
The time to response was shorter in the rilonacept arm than in the placebo arm (χ2 = 7.235, P = 0.007). The secondary analysis, which used the same response criteria, showed that 20 (57%) of 35 patients in the rilonacept arm had a response at week 4 compared with 9 (27%) of 33 patients in the placebo arm (P = 0.016). Exacerbation of systemic juvenile idiopathic arthritis (JIA) was the most common severe adverse event. More patients in the rilonacept arm had elevated liver transaminase levels (including levels more than 3 times the upper limit of normal) compared with those in the placebo arm. Adverse events were similar in the 2 arms of the study.
Conclusion
Rilonacept was generally well tolerated and demonstrated efficacy in active systemic JIA.
Background
The prognostic value of tumor‐associated dendritic cells (DC) in colon cancer remains poorly understood. This may be in part due to the interchangeable expression of immunostimulatory and ...immunoinhibitory molecules on DC. Here we investigated the prognostic impact of CD11c+ DC co–expressing the immunoinhibitory molecule PD‐L1 and their spatial relationship with CD8+ T‐cells in patients treated for stage III colon cancer.
Methods
Tissue microarrays containing representative cores of central tumor, leading edge, and adjacent normal tissue from 221 patients with stage III colon cancer were immunostained for CD8, CD11c, PD‐L1, and cytokeratin using immunofluorescent probes. Cells were quantified using StrataQuest digital image analysis software, with intratumoral and stromal regions analyzed separately. Kaplan‐Meier estimates and Cox regression were used to assess survival.
Results
Intratumoral CD8+ cell density (HR = .52, 95% confidence interval CI .33‐.83, P = .007), stromal CD11c+ cell density (HR = .52, 95% CI .33‐.83, P = .006), intratumoral CD11c+PD‐L1+ cell density (HR = .57, 95% CI .35‐.92, P = .021), and stromal CD11c+PD‐L1+ cell density (HR = .48, 95% CI .30‐.77, P = .003) on leading‐edge cores were all significantly associated with good survival. CD8+ cell density was positively correlated with both CD11c+ cell density and CD11c+PD‐L1+ cell density in tumor epithelium and stromal compartments.
Conclusion
Here we showed that PD‐L1‐expressing DC in the tumor microenvironment are associated with improved survival in stage III colon cancer and likely reflect an immunologically “hot” tumor microenvironment. Further investigation into the expression of immunomodulatory molecules by tumor‐associated DC may help to further elucidate their prognostic value.
In this study, using immunofluorescence analysis of fixed surgical samples, we demonstrate that PD‐L1 expressing dendritic cells are associated with good prognosis in stage III colon cancer. However, densities of PD‐L1 expressing dendritic cells were correlated to CD8 T cell density, indicating that they may represent an immunologically “hot” tumor microenvironment. Further investigation into the expression of immunomodulatory molecules by DC is required.
To present longitudinal changes in Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores during 25-week treatment with enzalutamide or placebo in men with progressive metastatic ...castration-resistant prostate cancer (mCRPC) after chemotherapy in the AFFIRM trial.
Patients were randomly assigned to enzalutamide 160mg/day or placebo. FACT-P was completed before randomization, at weeks 13, 17, 21, and 25, and every 12 weeks thereafter while on study treatment. Longitudinal changes in FACT-P scores from baseline to 25 weeks were analyzed using a mixed effects model for repeated measures (MMRM), with a pattern mixture model (PMM) applied as secondary analysis to address non-ignorable missing data. Cumulative distribution function (CDF) plots were generated and different methodological approaches and models for handling missing data were applied. Due to the exploratory nature of the analyses, adjustments for multiple comparisons were not made. AFFIRM is registered with ClinicalTrials.gov, number NCT00974311.
The intention-to-treat FACT-P population included 938 patients (enzalutamide, n = 674; placebo n = 264) with evaluable FACT-P assessments at baseline and ≥1 post-baseline assessment. After 25 weeks, the mean FACT-P total score decreased by 1.52 points with enzalutamide compared with 13.73 points with placebo (P < 0.001). In addition, significant treatment differences at week 25 favoring enzalutamide were evident for all FACT-P subscales and indices, whether analyzed by MMRM or PMM. CDF plots revealed differences favoring enzalutamide compared with placebo across the full range of possible response levels for FACT-P total and all disease- and symptom-specific subscales/indices.
In men with progressive mCRPC after docetaxel-based chemotherapy, enzalutamide is superior to placebo in health-related quality-of-life outcomes, regardless of analysis model or threshold selected for meaningful response.
NCT00974311.
This work examines the inter-relationship between the unbound drug fractions in blood and brain homogenate, passive membrane permeability, P-glycoprotein (Pgp) efflux ratio, and log octanol/water ...partition coefficients (cLogP) in determining the extent of central nervous system (CNS) penetration observed in vivo. The present results demonstrate that compounds often considered to be Pgp substrates in rodents (efflux ratio greater than 5 in multidrug resistant Madin-Darby canine kidney cells) with poor passive permeability may still exhibit reasonable CNS penetration in vivo; i.e., where the unbound fractions and nonspecific tissue binding act as a compensating force. In these instances, the efflux ratio and in vitro blood-brain partition ratio may be used to predict the in vivo blood-brain ratio. This relationship may be extended to account for the differences in CNS penetration observed in vivo between mdr1a/b wild type and knockout mice. In some instances, cross-species differences that might initially seem to be related to differing transporter expression can be rationalized from knowledge of unbound fractions alone. The results presented in this article suggest that the information exists to provide a coherent picture of the nature of CNS penetration in the drug discovery setting, allowing the focus to be shifted away from understanding CNS penetration toward the more important aspect of understanding CNS efficacy.
Background:
The anatomy of the anterior cruciate ligament (ACL) has become the subject of much debate. There has been extensive study into attachment points of the native ligament, especially ...regarding the femoral attachment. Some of these studies have suggested that fibers in the ACL are of differing functional importance. Fibers with higher functional importance would be expected to exert larger mechanical stress on the bone. According to Wolff’s law, cortical thickening would be expected in these areas.
Purpose:
To examine cortical thickening in the region of the ACL footprint (ie, the functional footprint of the ACL).
Study Design:
Descriptive laboratory study.
Methods:
Using micro–computed tomography with resolutions ranging from 71 to 91 μm, the cortical thickness of the lateral wall of the intercondylar notch in 17 cadaveric knees was examined, along with surface topography. After image processing, the relationship between the cortical thickening and surface topology was visually compared.
Results:
A pattern of cortical thickening consistent with the functional footprint of the ACL was found. On average, this area was 3 times thicker than the surrounding bone and significantly thicker than the remaining lateral wall (P < .0001). This thickening was roughly elliptical in shape (with a mean centroid at 23.5 h:31 t on a Bernard and Hertel grid) and had areas higher on the wall where greater thickness was present. The relationship to previously reported osseous landmarks was variable, although the patterns were broadly consistent with those reported in previous studies describing direct and indirect fibers of the ACL.
Conclusion:
The findings of this study are consistent with those of recent studies describing fibers in the ACL of differing functional importance. The area in which the thickening was found has been defined and is likely to represent the functional footprint of the ACL.
Clinical Relevance:
This information is of value to surgeons when determining the optimal place to position the femoral attachment site of the reconstructed ACL.
To develop and evaluate a Localized Scleroderma (LS) Skin Severity Index (LoSSI) and global assessments' clinimetric property and effect on quality of life (QOL).
A 3-phase study was conducted. The ...first phase involved 15 patients with LS and 14 examiners who assessed LoSSI surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension (N/E) twice for inter/intrarater reliability. Patient global assessment of disease severity (PtGA-S) and Children's Dermatology Life Quality Index (CDLQI) were collected for intrarater reliability evaluation. The second phase was aimed to develop clinical determinants for physician global assessment of disease activity (PhysGA-A) and to assess its content validity. The third phase involved 2 examiners assessing LoSSI and PhysGA-A on 27 patients. Effect of training on improving reliability/validity and sensitivity to change of the LoSSI and PhysGA-A was determined.
Interrater reliability was excellent for ER intraclass correlation coefficient (ICC) 0.71, ST (ICC 0.70), LoSSI (ICC 0.80), and PhysGA-A (ICC 0.90) but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. Examiners' experience did not affect the scores, but training/practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman's rho = 0.71-0.89) and moderate for SA. PtGA-S and CDLQI showed good intrarater agreement (ICC 0.63 and 0.80). mLoSSI correlated moderately with PhysGA-A and PtGA-S. Both mLoSSI and PhysGA-A were sensitive to change following therapy.
mLoSSI and PhysGA-A are reliable and valid tools for assessing LS disease severity and show high sensitivity to detect change over time. These tools are feasible for use in routine clinical practice. They should be considered for inclusion in a core set of LS outcome measures for clinical trials.
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