Citations

Abstract Destruction of tumor cells is a key function of lymphocytes, but the molecular processes driving it are unclear. Analysis of signal molecules indicated that mitogen-activated protein kinase (MAPK)/extracellular regulated kinase 2 critically controlled lytic function in human NK cells. We now have evidence to indicate that target ligation triggers a Ras-independent MAPK pathway that is required for lysis of the ligated tumor cell. Target engagement caused NK cells to rapidly activate MAPK within 5 min, and PD098059 effectively blocked both MAPK activation and tumoricidal function in NK cells. Target engagement also rapidly activated Ras, detected as active Ras-GTP bound to GST-Raf-RBD, a GST fusion protein linked to the Raf protein fragment containing the Ras-GTP binding domain. However, Ras inactivation by pharmacological disruption with the farnesyl transferase inhibitor, FTI-277, had no adverse effect on the ability of NK cells to lyse tumor cells or to express MAPK activation upon target conjugation. Notably, MAPK inactivation with PD098059, but not Ras inactivation with FTI-277, could interfere with perforin and granzyme B polarization within NK cells toward the contacted target cell. Using vaccinia delivery of N17 Ras into NK cells, we demonstrated that IL-2 activated a Ras-dependent MAPK pathway, while target ligation used a Ras-independent MAPK pathway to trigger lysis in NK cells.

SummaryObjectiveTo better understand the relationship between efficacy and perampanel dose, integrated actual (last) dose data from three phase III trials and an extension study (blinded Conversion Period; open‐label Maintenance Period) were analyzed.MethodsSeizure frequency data were analyzed in patients who were randomized to and completed the 13‐week Maintenance Period of the phase III studies on perampanel 8 mg, and who received an actual (last) dose of 12 mg during (1) the extension 16‐week blinded Conversion Period or (2) weeks 1–13 of the extension Maintenance Period. Due to a treatment‐by‐region interaction (p = 0.042), analyses excluded patients from the Latin America region (n = 162/1,480; 10.9% of the treated cohort).ResultsOf 372 patients randomized to 8 mg in the phase III studies, 273 completed the Maintenance Period at 8 mg and 267 entered the extension study. In patients who then had an actual (last) dose of 12 mg during the extension blinded Conversion Period (n = 217), median percent change in seizure frequency per 28 days improved from −32.4% (8 mg, phase III Maintenance Period) to −44.2% (12 mg, extension blinded Conversion Period); 50% responder rates increased slightly from 37.3% to 42.9%. In patients who completed the phase III studies on 8 mg and had an actual (last) dose of 12 mg during weeks 1–13 of the extension Maintenance Period (n = 181), median percent change in seizure frequency per 28 days improved from −34.1% (phase III Maintenance Period) to −46.0% (weeks 1–13 extension Maintenance Period); 50% responder rates were 39.2% and 46.4%. Seizure control remained substantially unchanged in patients who completed the phase III studies at 12 mg and continued on that dose during the extension.SignificanceIncreasing perampanel dose from 8 to 12 mg can produce additional benefits in seizure control in at least some patients who tolerate the higher dose.

Background: Hypoglycemia is often cited as a barrier to achieving inpatient glycemic targets. We sought to characterize hypoglycemic events in our institution by work-shift cycle and by specific treatment area. Methods: Capillary (bedside) and blood (laboratory) glucose values of <70 mg/dl for patients with either a known diagnosis of diabetes or with evidence of hyperglycemia were abstracted from our laboratory database for hospitalizations between October 1, 2007, and February 3, 2008. Hypoglycemic events were analyzed by 12 h nursing work-shift cycles (day shift, 07:00 to 18:59; night shift, 19:00 to 06:59) and by the six medical, surgical, and intensive care areas in the hospital (designated areas 1 to 6). Results: We identified 206 individual patients with either diabetes or hyperglycemia (mean age, 67 years; 56% men; 83% white) who had 423 hypoglycemic events. There were 78% more hypoglycemic events during the night shift ( n = 271 events in 128 individual patients) than during the day shift ( n = 152 events in 96 individual patients). Most of the night-shift hypoglycemic measurements were detected between 04:00 and 04:59 or 06:00 and 06:59. The mean hypoglycemic level was comparable between shifts ( p = .79) and across the six inpatient areas. The number of hypoglycemic events per person increased with lengths of hospital stay >5 days. The prevalence of hypoglycemia varied across patient care areas within the hospital, with most (28%) detected in one area of the hospital. Conclusion: There are temporal and geographic patterns in the occurrence of hypoglycemia among patients with diabetes or hyperglycemia in our hospital. Further study should focus on the reasons underlying these variations so that specific interventions can address the risk of hypoglycemia during peak times and places.

Background: This article reviews the performance of our hospital's inpatient insulin pump policy. Methods: Twenty-five hospital admissions of 21 unique patients receiving outpatient insulin pump therapy were reviewed. Results: Between November 1, 2005, and November 30, 2006, there were 25 hospital admissions involving 21 patients receiving outpatient insulin pump therapy. The average age and duration of diabetes among these 21 patients was 50 and 29 years, respectively; 67% were women, 90% had type 1 diabetes, and all were white. The mean length of hospital stay was 4 days, and the average reported length of insulin pump therapy was 4 years. Patients in 16 of the admissions were identified as candidates for continued use of the insulin pump during the hospital stay. Over 90% of patients remaining on the insulin pump had documentation by nursing of the presence of the pump at the time of admission; 100% of the patients had an admission glucose recorded; 88% had a record of signed patient consent; 81% had evidence of completed preprinted insulin pump orders; 75% received a required endocrine consultation; and 75% of cases had documentation of completed bedside flow sheet. A high frequency of both hypoglycemic and hyperglycemic events occurred in the patients; however, no adverse events were related directly to the insulin pump. Conclusions: Insulin pump therapy can be safely continued in the hospital setting. While staff compliance with required procedures was high, there was still room for improvement. More data are needed, however, on whether this method of insulin delivery is effective for controlling hyperglycemia in hospitalized patients.

ABSTRACTGenes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene‐environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P‐values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.

Abstract Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P &lt; 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P &lt; 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P &lt; 10−8. Results from the second analytic approach were consistent with those from the first (P &gt; 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.

Abstract Objective Our objective was to formulate a clinical practice guideline for the management of the pregnant woman with diabetes. Participants The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, 5 additional experts, a methodologist, and a medical writer. Evidence This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. Consensus Process One group meeting, several conference calls, and innumerable e-mail communications enabled consensus for all recommendations save one with a majority decision being employed for this single exception. Conclusions Using an evidence-based approach, this Diabetes and Pregnancy Clinical Practice Guideline addresses important clinical issues in the contemporary management of women with type 1 or type 2 diabetes preconceptionally, during pregnancy, and in the postpartum setting and in the diagnosis and management of women with gestational diabetes during and after pregnancy.

Significance Beta-amyloid plaque accumulation, glucose hypometabolism, and neuronal atrophy are hallmarks of Alzheimer’s disease. However, the regional ordering of these biomarkers prior to dementia remains untested. In a cohort with Alzheimer’s disease mutations, we performed an integrated whole-brain analysis of three major imaging techniques: amyloid PET, [ 18 F]fluro-deoxyglucose PET, and structural MRI. We found that most gray-matter structures with amyloid plaques later have hypometabolism followed by atrophy. Critically, however, not all regions lose metabolic function, and not all regions atrophy, even when there is significant amyloid deposition. These regional disparities have important implications for clinical trials of disease-modifying therapies.