Citations

Adenosine monophosphate–activated protein kinase (AMPK) is a major energy sensor that maintains cellular energy homeostasis. Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. In this paper, we report that activation of the α1 isoform of AMPK (AMPK-α1) occurred in striatal neurons of humans and mice with HD. Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD. Such nuclear accumulation of AMPK-α1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-α1 ameliorated cell death and down-regulation of Bcl2 caused by mutant Htt (mHtt). Conversely, enhanced expression of Bcl2 protected striatal cells from the toxicity evoked by mHtt and AMPK overactivation. These data demonstrate that aberrant activation of AMPK-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.

Abstract Background: The Preoperative Endocrine Prognostic Index (PEPI) scores the independent prognostic effects of tumor pathologic staging and expression levels of ER and the “proliferation” marker Ki67 in the surgical sample to predict long term outcomes after completion of neoadjuvant endocrine treatment (Ellis et al JNCI 100:1380, 2008). A limitation of the PEPI is that the prognostic information becomes available only after 4 months of treatment. We therefore evaluated the value of an early assessment of the Ki67 level in a tumor biopsy sample taken two to four weeks after initiating treatment in two neoadjuvant endocrine therapy trials for the purposes of the early identification of non- respondersMethods: A Ki67 cut point of greater than 10% for poor outcome in ER+ breast cancer was derived by comparing the PAM50 intrinsic subtype profile using a qRT-PCR assay with Ki67 data in a 700+ sample data set. A baseline level of 10% or less correlated most closely with a PAM50-based definition of LumA breast cancer and above 10% LumB breast cancer. We subsequently applied the 10% cut point to the baseline and early on-treatment Ki67 data in two trials, POL (Olson et al JACS 208:906, 2009) and IMPACT (Smith et al JCO: 23, 5108, 2005).Results: At baseline the dichotomized Ki67 definition was not significantly predictive for surgical Ki67 level, PEPI score or RFS in this modest size sample set. In contrast, in a result that emphasizes the enhaced prognostic properties of the on-treatment Ki67 approach, the one month POL sample Ki67 values (62 patients) predicted a higher level of Ki67 in the surgical samples at four months after treatment initiation (P=.01), a poorer PEPI score (P=0.01), a smaller number of patients in the PEPI risk point zero group (P=0.08) and worse relapse free survival (P=0.003). The IMPACT data (153 patients) confirmed that a two week Ki67 >10% predicted higher Ki67 in the surgical specimen (P=0.001), a poorer PEPI score (P=0.001), smaller numbers of patients in the PEPI 0 risk point group (P= 0.004) and worse relapse free survival (P=0.008).Ki67 and OutcomePOL 4W Ki67% PEPI 0RFS (events)10%>1/19 (5%)5/21 (23%)10%≤10/36 (28%)1/41 (2.4%)P ValueP=0.08 (Fisher)P=0.003 (log rank)IMPACT 2W Ki67% PEPI 0RFS (events)10%>0/32 (0%)9/35 (26%)10%≤21/101 (21%)13/118 (11%)P ValueP=0.004 (Fisher)P=0.008 (log rank) Conclusions: A tumor Ki67 assessment taken a short time (2 to 4 week window) after the initiation of neoadjuvant AI identifies patients with poor outcome ER+ disease. Amendment 6 of the neoadjuvant endocrine therapy protocol ACOSOG Z1031 will triage patients with an “on treatment” Ki67 value above 10% to chemotherapy in order to assess the pathological response rate to cytotoxic therapy in this important tumor subset.Supported by R01 CA095614, Avon PFP award 3P50 CA68438-07S2, U01 CA114722, ACOSOG U10 CA 76001, Breakthrough Cancer UK and AstraZenica (IMPACT trial). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 78.

AbstractDo some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]–matched, n = 941) or HLA-identical sibling donor (n = 3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P < .001) and relapse (RR, 1.50; P < .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P < .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect.

AbstractImatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM+) and 900 subjects who did not receive IM before HCT (IM−) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM+ and IM− groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.

In this study, we propose a quality control program for MR‐guided focused ultrasound (FUS) ablation treatment to assess FUS beam positioning accuracy, FUS power delivery accuracy, MR imaging quality, and FUS ablation system safety. A total of 353 sonication points in Lucite cards were measured, the average placement errors were in the SI direction and in the LR direction. Temperature elevation was calculated from MR phase difference images and the measured water proton chemical shift (WPCS) temperature coefficient. WPCS temperature calibration for phantoms yielded a temperature coefficient of 0.011 ppm/°C. Sixteen experiments were conducted using six different phantoms to test the reliability of FUS power delivery. SNR and RF power calculated from phantom images were analyzed and stored at the MR console. A computer program was developed to integrate the system power delivery and the MR image quality control into one automated process. In the clinical trial at our institution, we expect this quality control program to be carried out before each patient treatment. If measured quality control values exceeds or below the preset values, a system service and retest should be conducted before the treatment.PACS number(s): 87.61.–c, 87.54.–n

ABSTRACTDuring the first 45 days after intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV), the levels of mRNAs encoding chemokines MCP-1/CCL2, RANTES/CCL5, and IP-10/CXCL10 in the central nervous system (CNS) are closely related to the sites of virus gene expression and tissue inflammation. In the present study, these chemokines were monitored during the latter 135 days of a 6-month course of TMEV-induced disease in susceptible (PLJ) or resistant (C57BL/6) mice that possessed or lacked either CD4+or CD8+T cells. These data were additionally correlated to mouse genotype, virus persistence in the CNS, antiviral antibody titers, mortality, and the severity of neurological disease. Surprisingly, the major determinant of chemokine expression was virus persistence: the factors of susceptible or resistant genotype, severity of neuropathology, and presence or absence of regulatory T cells exerted minimal effects. Our observations indicated that chemokine expression in the CNS in this chronic viral disorder was intrinsic to the CNS innate immune response to infection and was not governed by elements of the adaptive immune system.