No abstract

The apolipoprotein E (APOE) ε2 allele has been associated with both Parkinson's disease (PD) and lower low density lipoprotein cholesterol (LDL-C). The study is to test the hypothesis that lower LDL-C may be associated with PD. This case-control study used fasting lipid profiles obtained from 124 PD cases and 110 controls, the PD cases recruited from consecutive cases presenting at our tertiary Movement Disorder Clinic, and controls recruited from the spouse populations of the same clinic. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were calculated from unconditional logistic regressions, adjusting for age, gender, smoking status, and use of cholesterollowering agents. Lower LDL-C concentrations were associated with a higher prevalence of PD. Compared with participants with the highest LDL-C (≥139 mg/dL), the OR was 2.2 (95% CI 0.9-5.1) for participants with LDL-C of 115-138, 3.5 (95% CI 1.6-8.1) for LDL-C of 93-114, and 2.6 (95% CI 1.1 -5.9) for LDL-C ≤ 92. Interestingly, use of cholesterol lowering drugs or just statins was related to lower PD prevalence. Our data provide preliminary evidence that low LDL-C may be associated with higher occurrence of PD, and/or that statin use may lower PD occurrence; either of which findings warrant further investigations. KeywordsParkinson's disease; LDL cholesterol; apolipoprotein E; statin; case control study Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder affecting 1-2% of the population over the age of 60 years. The lifetime risk for PD is higher in men than in women. 1 Although a few PD cases are due to several known genetic mutations, the disorder is largely idiopathic, and likely involves interactions of the genome and the environment 2 .The role of apolipoprotein (APOE) in Alzheimer's disease (AD), another age-related neurodegenerative disease, has been elucidated in the past decade. It is generally believed that the ε4 allele is a major susceptibility gene, whereas the ε2 allele is protective for AD and possibly other neurological disorders see review 3 . A recent systematic review, however, Previous epidemiological evidence on dietary fats/cholesterol and PD risk has not been consistent. 10;11 Further, these studies are not directly relevant to the potential role of cholesterol in PD etiology, as non-dietary factors may play more important roles in regulating serum lipid levels. For example, the APOE ε4 allele has been associated with higher low density lipid cholesterol (LDL-C), whereas the ε2 allele has been consistently associated with lower plasma LDL-C. 12;13 Interestingly, there has been one published abstract reporting lower plasma cholesterol concentrations in PD patients than in controls. 14 Further, Musanti et al. 15 reported dramatically lower cholesterol biosynthesis in PD patients than in controls, although there has been no subsequent follow up on this association. The above evidence, coupled with the association between ε2 and PD, led us to test hypothesis that lower serum LDL-C may be ass...

Purpose: Radiotherapy is an effective cancer treatment, but a few patients suffer severe radiation toxicities in neighboring normal tissues.There is increasing evidence that the variable susceptibility to radiation toxicities is caused by the individual genetic predisposition, by subtle mutations, or polymorphisms in genes involved in cellular responses to ionizing radiation. Doublestrand breaks (DSB) are the most deleterious form of radiation-induced DNA damage, and DSB repair deficiencies lead to pronounced radiosensitivity. Using a preclinical mouse model, the highly sensitive gH2AX-foci approach was tested to verify even subtle, genetically determined DSB repair deficiencies known to be associated with increased normal tissue radiosensitivity. Experimental Design: By enumerating gH2AX-foci in blood lymphocytes and normal tissues (brain, lung, heart, and intestine), the induction and repair of DSBs after irradiation with therapeutic doses (0.1-2 Gy) was investigated in repair-proficient and repair-deficient mouse strains in vivo and blood samples irradiated ex vivo. Results: gH2AX-foci analysis allowed to verify the different DSB repair deficiencies; even slight impairments caused by single polymorphisms were detected similarly in both blood lymphocytes and solid tissues, indicating that DSB repair measured in lymphocytes is valid for different and complex organs. Moreover, gH2AX-foci analysis of blood samples irradiated ex vivo was found to reflect repair kinetics measured in vivo and, thus, give reliable information about the individual DSB repair capacity. Conclusions: gH2AX analysis of blood and tissue samples allows to detect even minor genetically defined DSB repair deficiencies, affecting normal tissue radiosensitivity. Future studies will have to evaluate the clinical potential to identify patients more susceptible to radiation toxicities before radiotherapy.

PURPOSE Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor approved in China. This double-blind phase III trial evaluated the efficacy and safety of aumolertinib compared with gefitinib as a first-line treatment for locally advanced or metastatic EGFR-mutated non–small-cell lung cancer (NSCLC; ClinicalTrials.gov identifier: NCT03849768 ). METHODS Patients at 53 sites in China were randomly assigned 1:1 to receive either aumolertinib (110 mg) or gefitinib (250 mg) once daily. The primary end point was progression-free survival (PFS) per investigator assessment. RESULTS A total of 429 patients who were naïve to treatment for locally advanced or metastatic NSCLC were enrolled. PFS was significantly longer with aumolertinib compared with gefitinib (hazard ratio, 0.46; 95% CI, 0.36 to 0.60; P < .0001). The median PFS with aumolertinib was 19.3 months (95% CI, 17.8 to 20.8) versus 9.9 months with gefitinib (95% CI, 8.3 to 12.6). Objective response rate and disease control rate were similar in the aumolertinib and gefitinib groups (objective response rate, 73.8% and 72.1%, respectively; disease control rate, 93.0% and 96.7%, respectively). The median duration of response was 18.1 months (95% CI, 15.2 to not applicable) with aumolertinib versus 8.3 months (95% CI, 6.9 to 11.1) with gefitinib. Adverse events of grade ≥ 3 severity (any cause) were observed in 36.4% and 35.8% of patients in the aumolertinib and gefitinib groups, respectively. Rash and diarrhea (any grade) were observed in 23.4% and 16.4% of patients who received aumolertinib compared with 41.4% and 35.8% of those who received gefitinib, respectively. CONCLUSION Aumolertinib is a well-tolerated third-generation epidermal growth factor receptor tyrosine kinase inhibitor that could serve as a treatment option for EGFR-mutant NSCLC in the first-line setting.