SULT1A1 genotype, active and passive smoking, and breast cancer risk by age 50 years in a German case–control study

INTRODUCTION: Sulfotransferase 1A1 (encoded by SULT1A1) is involved in the metabolism of procarcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons, both of which are present in tobacco smoke. We recently reported a differential effect of N-acetyltransferase (NAT) 2 genotype on the association between active and passive smoking and breast cancer. Additional investigation of a common SULT1A1 genetic polymorphism associated with reduced enzyme activity and stability might therefore provide deeper insight into the modification of breast cancer susceptibility. METHODS: We conducted a population-based case–control study in Germany. A total of 419 patients who had developed breast cancer by age 50 years and 884 age-matched control individuals, for whom risk factor information and detailed smoking history were available, were included in the analysis. Genotyping was performed using a fluorescence-based melting curve analysis method. Multivariate logistic regression analysis was used to estimate breast cancer risk associated with the SULT1A1 Arg(213)His polymorphism alone and in combination with NAT2 genotype in relation to smoking. RESULTS: The overall risk for breast cancer in women who were carriers of at least one SULT1A1*2 allele was not significantly different from that for women with the SULT1A1*1/*1 genotype (adjusted odds ratio 0.83, 95% confidence interval 0.66–1.06). Risk for breast cancer with respect to several smoking variables did not differ substantially between carriers of the *2 allele and noncarriers. However, among NAT2 fast acetylators, the odds ratio associated with passive smoking only (3.23, 95% confidence interval 1.05–9.92) was elevated in homozygous carriers of the SULT1A1*1 allele but not in carriers of the SULT1A1*2 allele (odds ratio 1.28, 95% confidence interval 0.50–3.31). CONCLUSION: We found no evidence that the SULT1A1 genotype in itself modifies breast cancer risk associated with smoking in women up to age 50 years. In combination with NAT2 fast acetylator status, however, the SULT1A1*1/*1 genotype might increase breast cancer risk in women exposed to tobacco smoke

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

Paving the Way for Predicting the Progression of Cognitive Decline: The Potential Role of Machine Learning Algorithms in the Clinical Management of Neurodegenerative Disorders

Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder. The prodromal phase of AD is mild cognitive impairment (MCI). The capacity to predict the transitional phase from MCI to AD represents a challenge for the scientific community. The adoption of artificial intelligence (AI) is useful for diagnostic, predictive analysis starting from the clinical epidemiology of neurodegenerative disorders. We propose a Machine Learning Model (MLM) where the algorithms were trained on a set of neuropsychological, neurophysiological, and clinical data to predict the diagnosis of cognitive decline in both MCI and AD patients. Methods: We built a dataset with clinical and neuropsychological data of 4848 patients, of which 2156 had a diagnosis of AD, and 2684 of MCI, for the Machine Learning Model, and 60 patients were enrolled for the test dataset. We trained an ML algorithm using RoboMate software based on the training dataset, and then calculated its accuracy using the test dataset. Results: The Receiver Operating Characteristic (ROC) analysis revealed that diagnostic accuracy was 86%, with an appropriate cutoff value of 1.5; sensitivity was 72%; and specificity reached a value of 91% for clinical data prediction with MMSE. Conclusion: This method may support clinicians to provide a second opinion concerning high prognostic power in the progression of cognitive impairment. The MLM used in this study is based on big data that were confirmed in enrolled patients and given a credibility about the presence of determinant risk factors also supported by a cognitive test score

Nanoplastics causes extensive congenital malformations during embryonic development by passively targeting neural crest cells

Nanomaterials are widespread in the human environment as pollutants, and are being actively developed for use in human medicine. We have investigated how the size and dose of polystyrene nanoparticles affects malformations in chicken embryos, and have characterized the mechanisms by which they interfere with normal development. We find that nanoplastics can cross the embryonic gut wall. When injected into the vitelline vein, nanoplastics become distributed in the circulation to multiple organs. We find that the exposure of embryos to polystyrene nanoparticles produces malformations that are far more serious and extensive than has been previously reported. These malformations include major congenital heart defects that impair cardiac function. We show that the mechanism of toxicity is the selective binding of polystyrene nanoplastics nanoparticles to neural crest cells, leading to the death and impaired migration of those cells. Consistent with our new model, most of the malformations seen in this study are in organs that depend for their normal development on neural crest cells. These results are a matter of concern given the large and growing burden of nanoplastics in the environment. Our findings suggest that nanoplastics may pose a health risk to the developing embryo