Abstract
Background
Copper (Cu) is an essential metal for brain health. Limited studies reported no association of plasma Cu and inverse association of Cu in human hair with cognitive abilities in ...older adults. However, no study investigated the association of Cu levels in the human brain with the long‐term change in cognitive functioning before death. Thus, we aim to examine the association of brain Cu with cognitive decline in a community‐based cohort study.
Method
Using data from 625 deceased participants from the Rush Memory and Aging Project. Brain copper levels were measured using ICP‐MS in gray matter from inferior temporal, mid frontal, anterior cingulate, and cerebellum. Composite global cognition and specific domains were derived from z‐scores of a 19‐panel cognitive tests that were performed annually for up to 14 years proximate to death. We used linear mixed‐effects models to examine associations of Cu (grouped in tertiles) in the brain with cognitive decline. All the models were controlled for age at death, sex, education, late‐life cognitive activity, physical activity, smoking, and APOE‐ɛ4 status.
Result
The mean age at first cognitive assessment was 82.7 (±5.8) years, 71% were women, and 25% carried an APOE‐ɛ4 allele. Participants in the highest and the middle tertile of Brain Cu in the inferior temporal region had a slower annual rate of cognitive decline (T3 vs. T1:β= 0.027; T2 vs. T1: β= 0.032; p for trend= 0.007). Similar associations were found for specific domains, including episodic memory (T3 vs. T1: β= 0.027; T2 vs. T1: β= 0.033; p for trend= 0.03), semantic memory ((T3 vs. T1:β= 0.040; T2 vs. T1: β= 0.050; p for trend= 0.001) and perceptual speed (T3 vs. T1:β= 0.024; T2 vs. T1: β= 0.035; p for trend= 0.03). Concentrations of Cu in the other brain regions were not associated with cognitive decline.
Conclusion
The association of higher brain copper levels in the vulnerable region of Alzheimer’s disease, such as the inferior temporal region with slower cognitive decline, supports the role of copper dyshomeostasis in the disease process.
Fifty-eight patients with histologically verified spinal cord ependymomas were treated at the Royal Marsden Hospital and Atkinson Morley's Hospital between 1950 and 1987. The median age in this ...series was 40 years (range 1 to 79 years) and the male:female ratio was 1.8:1. Ten patients had tumors in the cervical cord and 10 in the thoracic cord; 14 tumors involved the conus medullaris and 24 the cauda equina. Forty ependymomas were grade I and 13 were grades II to IV (in five patients there was insufficient material for grading). Eleven patients underwent biopsy only, 33 had partial or subtotal resection, and 14 had complete resection. Forty-three patients received postoperative radiotherapy. The median follow-up period was 70 months (range 3 to 408 months). Cause-specific survival rates were 74% and 68% at 5 and 10 years, respectively. On univariate analysis, age, histological grade, postoperative neurological function, and era of treatment were significant prognostic factors for survival. The histological grade was the only significant independent prognostic factor. The relative risk of death from ependymoma was 9.0 for patients with tumor grades II to IV compared to grade I (p less than 0.005, 95% confidence interval 2.7 to 30). The survival rates of patients following complete excision were significantly better compared to those after incomplete surgery (p less than 0.025). The majority of completely resected neoplasms were low-grade cauda equina tumors. Despite incomplete surgery, 5- and 10-year progression-free survival rates following radical radiotherapy were both 59%, and cause-specific survival rates were 69% at 5 years and 62% at 10 years. This suggests that radiotherapy may achieve long-term tumor control in over half of those patients with residual spinal ependymoma.
The intensity of angiogenesis, as measured by microvessel density, is a strong independent predictor of survival in breast carcinoma patients. The impact of chemotherapy and/or endocrine therapy on ...this process is unknown.
Histologic samples from patients randomized to a trial of neoadjuvant (NEO) versus adjuvant (ADJ) chemoendocrine therapy for operable breast carcinoma were obtained. Samples from 195 patients (90 NEO samples and 105 ADJ samples) were analyzed. Immunostaining was performed with the CD34 monoclonal antibody and the scoring of microvessels was performed using the Chalkley method.
The median score of the NEO patients was 5.7 (95% confidence interval CI, 5.3-6.0) and the median score of the ADJ patients was 6.3 (95% CI, 6-6.7) (P=0.025). Using previously validated scoring categories, there were fewer samples with a poor prognosis (score > or =7) in the NEO group (26%) compared with the ADJ group (32%) (P=0.04).
The results of the current study suggest that NEO chemoendocrine therapy causes a reduction in microvessel density in primary breast carcinomas, which could be secondary to tumor regression or due to a direct effect on angiogenesis.
Myeloid sarcomas (MS), commonly referred to as chloromas, are extramedullary tumors of acute myeloid leukemia (AML) with varying incidence and influence on outcomes. Pediatric MS has both a higher ...incidence and unique clinical presentation, cytogenetic profile, and set of risk factors compared to adult patients. Optimal treatment remains undefined, yet allogeneic hematopoietic stem cell transplantation (allo-HSCT) and epigenetic reprogramming in children are potential therapies. Importantly, the biology of MS development is poorly understood; however, cell-cell interactions, epigenetic dysregulation, cytokine signaling, and angiogenesis all appear to play key roles. This review describes pediatric-specific MS literature and the current state of knowledge about the biological determinants that drive MS development. While the significance of MS remains controversial, the pediatric experience provides an opportunity to investigate mechanisms of disease development to improve patient outcomes. This brings the hope of better understanding MS as a distinct disease entity deserving directed therapeutic approaches.
Carbon fibers are unique reinforcing agents for lightweight composite materials due to their outstanding mechanical properties and low density. Current technologies are capable of producing carbon ...fibers with 90–95% of the modulus of perfect graphite (∼1025 GPa). However, these same carbon fibers possess less than 10% of the theoretical carbon fiber strength, estimated to be about 100 GPa. Traditionally, attempts to increase carbon fiber rigidity above a certain level results in lower breaking strength. Therefore, to develop advanced carbon fibers with both very high strength and modulus demands a new manufacturing methodology. Here, we report a method of manufacturing moderate strength, very high modulus carbon fibers from a very high molecular weight (VHMW) polyacrylonitrile (PAN) precursor without the use of nanomaterial additives such as nucleating or structure-templating agents, as have been used by others.
The features of 100 mixed-phenotype acute leukemias (MPALs), fulfilling WHO 2008 criteria, are documented. Myeloid and T-lineage features were demonstrated by cytoplasmic myeloperoxidase and CD3; ...B-lineage features were demonstrated by at least 2 B-lymphoid markers. There were 62 men and 38 women; 68% were adults. Morphology was consistent with acute lymphoblastic leukemia (ALL; 43%), acute myeloid leukemia (AML; 42%), or inconclusive (15%). Immunophenotyping disclosed B + myeloid (59%), T + myeloid (35%), B + T (4%), or trilineage (2%) combinations. Cytogenetics evidenced t(9;22)/(Ph+) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes. There was no correlation between age, morphology, immunophenotype, or cytogenetics. Response to treatment and outcome were available for 67 and 70 patients, respectively; 27 received ALL, 34 AML, 5 a combination of ALL + AML therapy, and 1 imatinib. ALL treatment induced a response in 85%, AML therapy in 41%; 3 of 5 patients responded to the combination therapy. Forty (58%) patients died, 33 of resistant disease. Overall median survival was 18 months and 37% of patients are alive at 5 years. Age, Ph+, and AML therapy were predictors for poor outcome (P < .001; P = .002; P = .003). MPAL is confirmed to be a poor-risk disease. Adults and Ph+ patients should be considered for transplantation in first remission.
Timing of surgery in breast cancer Hrushesky, WilliamJ.M.; Powles, TrevorJ; Ashley, SueE ...
The Lancet (British edition),
06/1991, Volume:
337, Issue:
8757
Journal Article
Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate ...involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAG
. To investigate the role of UVRAG
in vivo, we generated mutant mice that inducibly express UVRAG
(iUVRAG
). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAG
mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAG
mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant β-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.
PDF
