Citations

PurposeFatigue is one of the most common symptoms experienced by patients with cancer. This trial was developed to evaluate the efficacy of long-acting methylphenidate for improving cancer-related fatigue and to assess its toxicities.Patients and MethodsAdults with cancer were randomly assigned in a double-blinded manner to receive methylphenidate (target dose, 54 mg/d) or placebo for 4 weeks. The Brief Fatigue Inventory was the primary outcome measure, while secondary outcome measures included a Symptom Experience Diary (SED), the Short Form-36 (SF-36) Vitality Subscale, a linear analog self-assessment, the Pittsburgh Sleep Quality Index, and the Subject Global Impression of Change.ResultsIn total, 148 patients were enrolled. Using an area under the serum concentration-time curve analysis, there was no evidence that methylphenidate, as compared with placebo, improved the primary end point of cancer-related fatigue in this patient population (P = .35). Comparisons of secondary end points, including clinically significant changes in quality-of-life variables and cancer-related fatigue change from baseline, were similarly negative. However, a subset analysis suggested that patients with more severe fatigue and/or with more advanced disease did have some fatigue improvement with methylphenidate (eg, in patients with stage III or IV disease, the mean improvement in usual fatigue was 19.7 with methylphenidate v 2.1 with placebo; P = .02). There was a significant difference in self-reported toxicities (SED), with increased levels of nervousness and appetite loss in the methylphenidate arm.ConclusionThis clinical trial was unable to support the primary prestudy hypothesis that the chosen long-acting methylphenidate product would decrease cancer-related fatigue.

The RNA-dependent RNA-polymerase,3Dpol, is an essential component in the picornavirus genome for the replication of single stranded RNA. However, transgenic expression of3Dpolin mice has antiviral effects. Here, we discuss the structure and function of3Dpolduring picornavirus replication, we review the evidence and consequence of a host immune response to epitopes in3Dpolafter picornavirus infection, highlight data showing the antiviral effects of transgenic3Dpolfrom Theiler's murine encephalomyelitis virus (TMEV), and discuss potential mechanisms by which3Dpolis causing this antiviral effect in mice.

The role of the Alzheimer's Disease Neuroimaging Initiative Genetics Core is to facilitate the investigation of genetic influences on disease onset and trajectory as reflected in structural, functional, and molecular imaging changes; fluid biomarkers; and cognitive status. Major goals include (1) blood sample processing, genotyping, and dissemination, (2) genome‐wide association studies (GWAS) of longitudinal phenotypic data, and (3) providing a central resource, point of contact and planning group for genetics within the Alzheimer's Disease Neuroimaging Initiative. Genome‐wide array data have been publicly released and updated, and several neuroimaging GWAS have recently been reported examining baseline magnetic resonance imaging measures as quantitative phenotypes. Other preliminary investigations include copy number variation in mild cognitive impairment and Alzheimer's disease and GWAS of baseline cerebrospinal fluid biomarkers and longitudinal changes on magnetic resonance imaging. Blood collection for RNA studies is a new direction. Genetic studies of longitudinal phenotypes hold promise for elucidating disease mechanisms and risk, development of therapeutic strategies, and refining selection criteria for clinical trials.

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein–Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the γ-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.

The potential for endogenous remyelination and axonal protection can be an important factor in determining disease outcome in demyelinating diseases like multiple sclerosis. In many multiple sclerosis (MS) patients CNS repair fails or is incomplete whereas in others the disease is accompanied by extensive repair of demyelinated lesions. We have described significant differences in the ability of two strains of mice to repair CNS damage following Theiler’s virus-induced demyelination: FVB/NJ (FVB) mice repair damaged myelin spontaneously and completely, whereas B10.D1-H2 q /SgJ (B10.Q) mice are deficient in the repair process. A QTL analysis was performed to identify genetic loci that differentially regulate CNS repair following chronic demyelination in these strains and two QTL were detected: one on chromosome 3 with a LOD score of 9.3 and a second on chromosome 9 with a LOD score of 14.0. The mouse genes for epidermal growth factor (EGF) and Tyk2 are encoded within the QTL on chromosomes 3 and 9, respectively. Sequence polymorphisms between the FVB and B10.Q strains at both the EGF and Tyk2 loci define functional variations consistent with roles for these genes in regulating myelin repair. EGF is a key regulator of cell growth and development and we show a sevenfold increase in EGF expression in FVB compared to B10.Q mice. Tyk2 is a Janus kinase that plays a central role in controlling the T H 1 immune response and we show that attenuation of Tyk2 function correlates with enhanced CNS repair.

AbstractThe clinical management of amyloidosis is based on the treatment of the underlying etiology, and accurate identification of the protein causing the amyloidosis is of paramount importance. Current methods used for typing of amyloidosis such as immunohistochemistry have low specificity and sensitivity. In this study, we report the development of a highly specific and sensitive novel test for the typing of amyloidosis in routine clinical biopsy specimens. Our approach combines specific sampling by laser microdissection (LMD) and analytical power of tandem mass spectrometry (MS)–based proteomic analysis. We studied 50 cases of amyloidosis that were well-characterized by gold standard clinicopathologic criteria (training set) and an independent validation set comprising 41 cases of cardiac amyloidosis. By use of LMD/MS, we identified the amyloid type with 100% specificity and sensitivity in the training set and with 98% in validation set. Use of the LMD/MS method will enhance our ability to type amyloidosis accurately in clinical biopsy specimens.