Citations

The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid-β protein (Aβ), which forms amyloid plaques in Alzheimer's disease (AD), secreted APPα (sAPPα) which enhances memory, and the APP intracellular domain (AICD), which has been implicated in the regulation of gene transcription and calcium signaling. The β-site APP cleaving enzyme 1 (BACE1) cleaves APP in an activity-dependent manner to form Aβ, AICD, and secreted APPβ. Because this neural activity was shown to diminish synaptic transmission in vitro [Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) Neuron 37:925–937], the prevailing notion has been that this pathway diminishes synaptic function. Here we investigated the role of this pathway in vivo . We studied transgenic mice overproducing APP that do not develop AD pathology or memory deficits but instead exhibit enhanced spatial memory. We showed enhanced synaptic plasticity in the hippocampus that depends on prior synaptic activity. We found that the enhanced memory and synaptic plasticity are abolished by the ablation of one or both copies of the BACE1 gene, leading to a significant decrease in AICD but not of any other APP cleavage products. In contrast to the previously described negative effect of BACE1-mediated cleavage of APP on synaptic function in vitro , our in vivo work indicates that BACE1-mediated cleavage of APP can facilitate learning, memory, and synaptic plasticity.

Purpose Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer. Patients and Methods Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity. Results The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively (P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting. Conclusion The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal cancer.

Abstract To better understand the molecular changes that occur in Waldenstrom macroglobulinemia (WM), we employed antibody-based protein microarrays to compare patterns of protein expression between untreated WM and normal bone marrow controls. Protein expression was defined as a &gt;2-fold or 1.3-fold change in at least 67% of the tumor samples. Proteins up-regulated by &gt;2-fold included Ras family proteins, such as Rab-4 and p62DOK, and Rho family proteins, such as CDC42GAP and ROKα. Other proteins up-regulated by &gt;1.3-fold included cyclin-dependent kinases, apoptosis regulators, and histone deacetylases (HDAC). We then compared the samples of patients with symptomatic and asymptomatic WM and showed similar protein expression signatures, indicating that the dysregulation of signaling pathways occurs early in the disease course. Three proteins were different by &gt;2-fold in symptomatic versus asymptomatic, including the heat shock protein HSP90. Elevated protein expression was confirmed by immunohistochemistry and immunoblotting. Functional significance was validated by the induction of apoptosis and inhibition of proliferation using specific HDAC and HSP90 inhibitors. This study, therefore, identifies, for the first time, multiple novel proteins that are dysregulated in WM, which both enhance our understanding of disease pathogenesis and represent targets of novel therapeutics. [Cancer Res 2007;67(8):3777–8]

Abstract Two variants (rs1447295/DG8S737) of chromosome 8q24 were recently reported to be associated with increased risk of prostate cancer (PC). To confirm this finding, we genotyped and compared the frequencies of these polymorphisms among 1,121 Caucasian men with PC (435 men with familial PC, 491 men with sporadic PC, and 195 men with aggressive PC) to 545 population-based controls. For the single nucleotide polymorphism marker rs1447295, frequencies of the minor allele (A) were 10.3% in controls, 11.9% in sporadic cases, 16.7% in familial cases, and 17.2% in aggressive cases. Compared with controls, the A allele was significantly more common in both familial PC [odds ratios (OR), 1.93; 95% confidence intervals (95% CI), 1.37–2.72; P = 0.0004] and aggressive PC (OR, 1.87; 95% CI, 1.28–2.74; P = 0.0005) but not for sporadic PC (OR, 1.16; 95% CI, 0.85–1.58; P = 0.25). Although the A allele was more frequent in aggressive PC cases when compared with controls, the allele frequencies were similar among cases with high- and low-grade PC (Gleason grades &lt;7 and ≥7, respectively). For the microsatellite marker DG8S737, the −8 allele was significantly more frequent in familial PC (OR, 1.68; 95% CI, 1.09–2.60; P = 0.031), whereas the −10 allele was more frequent in aggressive PC (OR, 2.85; 95% CI, 1.52–5.36; P = 0.0004). Haplotype analysis showed significant differences in haplotype frequencies between the familial PC (P = 0.006) and aggressive PC (P = 0.005) cases versus controls. The −8/A haplotype showed the strongest association with familial PC (P = 0.008), whereas the −10/A haplotype was most strongly associated with aggressive PC (P = 0.00005). These results further confirm the importance of these two polymorphic variants (rs1447295 and DG8S737) as risk factors for PC. However, the mechanism explaining this increased risk has not yet been established. [Cancer Res 2007;67(7):2944–50]

The congenital myasthenic syndromes include end-plate (EP) acetylcholinesterase deficiency, presynaptic abnormalities affecting the evoked release or size of transmitter quanta, and acetylcholine (ACh) receptor (AChR) channelopathies stemming from a kinetic abnormality and/or deficiency of AChR. A kinetic abnor mality predicts, and AChR deficiency may predict, one or more mutations in an AChR subunit gene. These clues have led to the identification of 53 mutations in different subunits of AChR in 55 kinships of the congenital myasthenic syndromes. The mutations either increase or decrease the response to ACh, produce AChR deficiency, or both. In the slow-channel syndromes, prolonged opening episodes of AChR cause cationic overloading of the EP and an EP myopathy; the mutations occur in different subunits and different domains of the subunits and have dominant positive effects. The M1 and M2 mutations slow channel closure, increase apparent affinity for ACh, and variably enhance desensitization, and the extracellular αG153S enhances affinity for ACh, promoting reopening of the diliganded receptor. In the low-affinity fast-channel syndrome, εP121L reduces affinity for ACh and reopening of the diliganded receptor, resulting in a de creased response to ACh and shorter burst durations. Severe EP AChR deficiency results from heterozy gous or homozygous mutations that terminate translation prematurely; these are concentrated in the ε subunit, probably because substitution of the fetal γ for the adult ε subunit can rescue the phenotype from fatal null mutations in ε. Variable AChR deficiency and variable functional abnormalities stem from hetero allelic nonsense and missense mutations in AChR subunit genes. NEUROSCIENTIST 4:185-194, 1998

Background— Heart failure (HF) is a progressive disorder associated with frequent morbidity and mortality. An American Heart Association/American College of Cardiology staging classification of HF has been developed to emphasize early detection and prevention. The prevalence of HF stages and their association with mortality are unknown. We sought to estimate HF stage prevalence in the community and to measure the association of HF stages with mortality. Methods and Results— A population-based, cross-sectional, random sample of 2029 Olmsted County, Minnesota, residents aged ≥45 years was identified. Participants were classified by medical record review, symptom questionnaire, physical examination, and echocardiogram as follows: stage 0, healthy; stage A, HF risk factors; stage B, asymptomatic cardiac structural or functional abnormalities; stage C, HF symptoms; and stage D, severe HF. In the cohort, 32% were stage 0, 22% stage A, 34% stage B, 12% stage C, and 0.2% stage D. Mean B-type natriuretic peptide concentrations (in pg/mL) increased by stages: stage 0=26, stage A=32, stage B=53, stage C=137, and stage D=353. Survival at 5 years was 99% in stage 0, 97% in stage A, 96% in stage B, 75% in stage C, and 20% in stage D. Conclusions— The present study provides prevalence estimates and prognostic validation for HF staging in a community cohort. Of note, 56% of adults ≥45 years of age were classified as being in stage A (risk factors) or B (asymptomatic ventricular dysfunction). HF staging underscores the magnitude of the population at risk for progression to overt HF.

OBJECTIVE—Multiple daily insulin injection programs are commonly accompanied by considerable glycemic variation and hypoglycemia. We conducted a randomized crossover design clinical trial to compare glargine with ultralente insulin as a basal insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS—To determine whether the use of glargine insulin as a basal insulin would result in a comparable HbA1c and less glycemic variation and hypoglycemia than ultralente insulin, 22 individuals (aged 44 ± 14 years [±SD], 55% men) with type 1 diabetes who were experienced with multiple daily insulin injections and had an HbA1c of &lt;7.8% were randomized in a crossover design to receive either glargine or ultralente as the basal insulin for 4 months. Aspart insulin was used as the prandial insulin. Physicians providing insulin dose adjustment advice were masked to the type of basal insulin. RESULTS—Treatment with glargine resulted in lower mean HbA1c (6.82 ± 0.13 vs. 7.02 ± 0.13, difference: 0.2 ± 0.08, P = 0.026), less nocturnal variability (plasma glucose 49.06 ± 4.74 vs. 62.36 ± 5.21 mg/dl, P = 0.04), and less hypoglycemia (24.5 ± 2.99 vs. 31.3 ± 4.04 events, P = 0.05), primarily due to less daytime hypoglycemia (P = 0.002). On the other hand, serious hypoglycemia and average glucose concentration measured with continuous subcutaneous glucose monitoring did not differ. CONCLUSIONS—We conclude that while use of either ultralente or glargine as a basal insulin can result in excellent glycemic control, treatment with glargine is associated with slightly but significantly lower HbA1c and less nocturnal glycemic variability and hypoglycemia.