BACKGROUND: Results from a phase 2a study indicated that treatment with the novel α7 nicotinic acetylcholine receptor agonist ABT-126 25 mg once daily (QD) was associated with a trend for improvement in cognition in subjects with mild-to-moderate Alzheimer's dementia (AD). A phase 2b program was designed to evaluate a broader dose range of ABT-126 as monotherapy in subjects with mild-to-moderate AD. The program consisted of a double-blind, placebo and active controlled study of ABT-126 (dose range 25-75 mg) and an open-label extension study (75 mg).

METHODS: The randomized double-blind study enrolled 438 subjects (Mini-Mental Status Examination score of 10-24, inclusive) not currently taking acetylcholinesterase inhibitors or memantine. Subjects received 24 weeks of ABT-126 25 mg QD (n = 77), ABT-126 50 mg QD (n = 108), ABT-126 75 mg QD (n = 73), donepezil 10 mg QD (n = 76), or placebo (n = 104). The primary endpoint was the change from baseline to week 24 in the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) total score. Subjects completing the double-blind study could enroll in the 28-week open-label extension study. Adverse events (AEs) and other safety parameters were monitored in both studies.

RESULTS: A total of 367 patients (83.8 %) completed the double-blind study and 349 (79.7 %) entered the open-label study. Compared with placebo, donepezil significantly improved ADAS-Cog 11-item total scores from baseline to week 24 (-2.29 ± 0.95; one-sided P = 0.008). No ABT-126 dose demonstrated a statistically significant improvement vs placebo at week 24 in the ADAS-Cog total score: ABT-126 25 mg, -0.47 ± 0.94 (P = 0.309); ABT-126 50 mg, -0.87 ± 0.85 (P = 0.153); and ABT-126 75 mg, -1.08 ± 0.94 (P = 0.127). Rates of serious AEs and discontinuations due to AEs were similar across treatment groups. The most frequently reported AEs in both studies were constipation, fall, and headache. No clinically meaningful changes were observed in other parameters.

CONCLUSIONS: In the double-blind trial, donepezil significantly improved ADAS-Cog scores but no statistically significant improvement was seen with any ABT-126 dose. ABT-126 had an acceptable safety profile in subjects with mild-to-moderate AD in both studies.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01527916 , Registered 3 February 2012 (randomized trial). ClinicalTrials.gov NCT01676935 . Registered 29 August 2012 (open-label extension study).

This paper presents a new technique for pointer analysis of distributed programs executed on parallel machines with hierarchical memories. One motivation for this research is the languages whose global address space is partitioned. Examples of these languages are Fortress, X10, Titanium, Co-Array Fortran, UPC, and Chapel. These languages allow programmers to adjust threads and data layout and to write to and read from memories of other threads. The techniques presented in this paper have the form of type systems which are simply structured. The proposed technique is shown on a language which is the while langauge enriched with basic commands for pointer manipulations and also enriched with commands vital for distributed execution of programs. An abstraction analysis that for a given statement calculates the set of function abstractions that the statement may evaluate-to is introduced in this paper. The abstraction analysis is needed in the proposed pointer analysis. The mathematical soundness of all techniques presented in this paper are discussed. The soundness is proved against a new operational semantics presented in this paper. Our work has two advantages over related work. In our technique, each analysis result is associated with a correctness proof in the form of type derivation. The hierarchical memory model used in this paper is in line with the hierarchical character of concurrent parallel computers.

BACKGROUND: Cellular and clinical sensitivity to ionizing radiation (IR) is determined by DNA double-strand breaks (DSB) repair. Here, we investigate the molecular mechanism underlying the extreme response of a head and neck tumor case (SKX) to standard radiotherapy.

METHODS: Immunofluorescence (IF) was used for the assessment of DSB repair, Western blot and real-time PCR for protein and mRNA expression, respectively.

RESULTS: SKX cells exhibited a pronounced radiosensitivity associated with numerous residual γ-H2AX foci after IR. This was not associated with lacking canonical repair proteins. SKX cells did not express any ATM protein. Accordingly, immunoblotting revealed no ATM kinase activity toward substrates such as p-SMC1, p-CHK2 and p-KAP1. Sequencing of all 66 exons of ATM showed no mutation. ATM mRNA level was moderately reduced, which could be reverted by 5'-Aza-C treatment but without restoring protein levels. Importantly, we demonstrated a post-transcriptional regulation in SKX cells via 6-fold enhanced levels of miR-421, which targets the 3'-UTR of ATM mRNA. Transfection of SKX cells with either anti-miR-421 inhibitor or a microRNA-insensitive ATM vector recovered ATM expression and abrogated the hyper-radiosensitivity.

CONCLUSION: This is the first report describing microRNA-mediated down-regulation of ATM leading to clinically manifest tumor radiosensitivity.

BACKGROUND: Cellular and clinical sensitivity to ionizing radiation (IR) is determined by DNA double-strand breaks (DSB) repair. Here, we investigate the molecular mechanism underlying the extreme response of a head and neck tumor case (SKX) to standard radiotherapy. METHODS: Immunofluorescence (IF) was used for the assessment of DSB repair, Western blot and real-time PCR for protein and mRNA expression, respectively. RESULTS: SKX cells exhibited a pronounced radiosensitivity associated with numerous residual gamma-H2AX foci after IR. This was not associated with lacking canonical repair proteins. SKX cells did not express any ATM protein. Accordingly, immunoblotting revealed no ATM kinase activity toward substrates such as p-SMC1, p-CHK2 and p-KAP1. Sequencing of all 66 exons of ATM showed no mutation. ATM mRNA level was moderately reduced, which could be reverted by 5'-Aza-C treatment but without restoring protein levels. Importantly, we demonstrated a post-transcriptional regulation in SKX cells via 6-fold enhanced levels of miR-421, which targets the 3'-UTR of ATM mRNA. Transfection of SKX cells with either anti-miR-421 inhibitor or a microRNA-insensitive ATM vector recovered ATM expression and abrogated the hyper-radiosensitivity. CONCLUSION: This is the first report describing microRNA-mediated down-regulation of ATM leading to clinically manifest tumor radiosensitivity.