Newcastle University

About: Newcastle University is a education organization based out in Newcastle upon Tyne, United Kingdom. It is known for research contribution in the topics: Population & Context (language use). The organization has 31772 authors who have published 71187 publications receiving 2539147 citations. The organization is also known as: University of Newcastle upon Tyne.

Phase I Study of the Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, in Combination with Temozolomide in Patients with Advanced Solid Tumors

Abstract: Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA. Poly(ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m 2 /d temozolomide × 5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m 2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m 2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m 2 AG014699 and 200 mg/m 2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.

Subcortical volumetric abnormalities in bipolar disorder

Abstract: Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case–control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen’s d=−0.232; P=3.50 × 10−7) and thalamus (d=−0.148; P=4.27 × 10−3) and enlarged lateral ventricles (d=−0.260; P=3.93 × 10−5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

The prevalence and incidence of dementia with Lewy bodies: a systematic review of population and clinical studies.

Abstract: Background Dementia with Lewy bodies (DLB) is increasingly recognized as a common cause of dementia in older people. However, its true frequency remains unclear, with previous studies reporting a prevalence range from zero to 22.8% of all dementia cases. This review aimed to establish the population prevalence and incidence for DLB and to compare this to its prevalence in secondary care settings. Method A literature review of all relevant population and clinical studies was conducted using PubMed. Additional references from papers found during that process were added to this. Results DLB accounted for 4.2% of all diagnosed dementias in the community. In secondary care this increased to 7.5%. The incidence of DLB was 3.8% of new dementia cases. There was a significant increase in DLB diagnoses when using the revised (2005) International Consensus Criteria (ICC) for DLB compared to the original (1996) criteria. Conclusions DLB currently accounts for around one in 25 dementia cases diagnosed in the community and one in 13 cases in secondary care. The significantly higher rates of DLB in secondary care may reflect enhanced diagnostic accuracy in specialist settings and/or the increased morbidity and carer burden of the DLB syndrome compared to other dementias. However, the true prevalence is likely to be much higher because DLB diagnoses are often missed, although there is evidence that new criteria aid case identification.