Search

Physicochemical studies on the interactions of small molecules with different polymorphs of DNA are relevant for elucidation at the molecular level of the processes occurring in vivo. In our work, various spectroscopic techniques combined with molecular modeling computations have been used to explore the interactions of luteolin (LTN), a pharmacologically important bioactive flavone, with two polymorphic forms of natural DNA. These include the low pH induced left-handed protonated and right-handed B forms of DNA in aqueous buffer medium. The association was characterized by hypochromic and red shifted absorption maxima, enhanced fluorescence intensity and strong perturbation in the circular dichroism (CD) spectra. Binding parameters along with significant thermal stabilization indicate a greater extent of association of LTN with the protonated form in comparison to the native B form structure of DNA. Viscometric and molecular docking studies together infer that the binding mode of LTN to the protonated DNA is external stacking while with B DNA it is intercalation.

Fisetin (FTN) and its metal chelates are critically important since this bioflavonoid possesses wide range of pharmacological properties. Usually, metal binding property enhances the pharmaceutical activity of FTN. Thus in this report, we investigated the complexation of FTN with biologically essential metal ion Cu2+ and further examined the effect of such complexation on calf thymus DNA (CT DNA) binding in comparison with free FTN. We have characterized the complex formation of FTN with Cu2+ using UV-visible, fluorimetric and FTIR studies. Within our experimental concentration range we found that, FTN forms a 2:1 complex with Cu2+ in terms of FTN:Cu2+. Spectroscopic analysis revealed that both FTN and FTN2-Cu2+ complex bind with CT DNA and the binding constant is higher for free FTN. Perturbation of circular dichroism spectrum of CT DNA was observed in presence of free FTN due to structural alteration in DNA double helix. Viscometric, thermal melting and fluorescence quenching study confirm that FTN intercalates in between the base pairs of CT DNA while its Cu (II) complex acts as a groove binder. Molecular docking study further confirms that FTN intercalates into AT rich region of CT DNA while its Cu (II) complex binds at the minor groove.

In pursuit of a systematized interdiffusion study in Ti | TiN multilayers at low temperature (300 - 973 K), x-ray reflectivity measurement aided with soft x-ray absorption and secondary ion mass spectroscopy were employed in the present scope of findings. Despite of TiN interfaced with Ti being a well-known diffusion blocking unit, modulation of individual stacking thickness in nm regime in two set of samples: SET – A : [TiN (10 nm) | Ti (5 nm)] 10 , SET – B : [TiN (5 nm) | Ti (10 nm)] 10 , out turns higher interfacial mixing for SET – B samples at elevated temperatures as expected due to lower N repository and eventually lesser Ti-N covalent bonds and higher Ti-Ti metal bonds, leading to plausible lower potential barrier for migration of the diffusion species. In turn, interdiffusion across interfaces promotes two distinct distribution profiles — (i) For SET – A samples, as opposed to discrete multilayer stacks, interdiffusion led to uniformly distributed single volume matrix transformation at 973 K, and (ii) For SET – B samples, such transformation is pronounced even at 773 K due to faster migration of N and at 973 K, surprisingly N diffuses out, with some kind of residual interstitial TiN compound residing in the system.

Polymorphism of DNA plays a very important part of research relating to the drug-DNA interactions. Here main focus of our investigation is to monitor the interaction of the benzophenanthridine plant alkaloid, nitidine (NIT) with two different forms of DNA i.e. B-DNA and protonated form of DNA maintaining proper temperatures and buffer conditions. Binding interaction of NIT was ascertained from the UV–Visible spectroscopic and spectrofluorimetric titration experiments. Binding constants of the interactions of NIT with different polymorphic forms were calculated from UV-absorption study. The binding constants were 3.8 × 105 M−1 and 1.3 × 105 M−1 for B-DNA and protonated DNA respectively. Red shift in the absorption maxima of NIT on binding with DNA, comparatively greater relative quenching of fluorescence intensity of free NIT than bound NIT, perturbation in the CD spectrum of DNA in presence of NIT confirmed the mode of binding as intercalation. Moreover, spectropolarimetric experiment confirms that left handed protonated form of DNA gets partially converted to the canonical B form of DNA while binds with NIT. Besides the CD experiment, thermal melting experiment also showed that on binding with NIT stabilization of protonated DNA was increased to an appreciable extent.

We performed a systematic review and meta-analysis of the observational or interventional studies assessing the association of vasomotor symptoms (hot flushes and night sweats) with various cardiovascular risk markers (systolic (SBP) and diastolic blood pressure (DBP), hypertension, total cholesterol, body mass index (BMI), and measures of subclinical atherosclerosis), in pen-menopausal, menopausal, or postmenopausal women. Eleven unique studies were identified with data available on 19,667 non-overlapping participants. Pooled analysis showed that women with hot flushes, compared to those without, tended to have significant higher levels of SBP (mean difference (MD): 1.95 mmHg (95%CI, 0.27 to 33.63)), and DBP (MD 1.17 mmHg (95%CI, -0.21 to 2.54)) and higher odds of having hypertension (OR: 1.18, 95%CI: 0.93 to 1.51), albeit non-significant. Similarly, women who reported night sweats compared to those who did not, had significant higher levels of SBP, (MD: 1.33 mmHg (95%Cl, 0.63 to 2.03)), DBP (MD: 0.55 mmHg (95%CI, 0.19 to 0.91)), total cholesterol (MD: 0.17 mmHg (95%CI, 0.03 to 0.31)) and BMI (MD: 0.64 mmHg (95%Cl, 0.47 to 0.80)). Vasomotor symptoms in women were not associated with measures of subclinical atherosclerosis. Women with vasomotor symptoms may have an unfavorable cardiovascular risk profile compared to women without vasomotor complaints. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Using the principles of public health genomics, we examined the opportunities and challenges of implementing personalized prevention programmes for cancer at the population level. Our model-based estimates indicate that polygenic risk stratification can potentially improve the effectiveness and cost-effectiveness of screening programmes. However, compared with 'one-size-fits-all' screening programmes, personalized screening adds further layers of complexity to the organization of screening services and raises ethical, legal and social challenges. Before polygenic inheritance is translated into population screening strategy, evidence from empirical research and engagement with and education of the public and the health professionals are needed.

Individual risk prediction and stratification based on polygenic profiling may be useful in disease prevention. Risk-stratified population screening based on multiple factors including a polygenic risk profile has the potential to be more efficient than age-stratified screening. In this article, we summarize the implications of personalized screening for breast and prostate cancers. We report the opinions of multidisciplinary international experts who have explored the scientific, ethical, and logistical aspects of stratified screening. We have identified (i) the need to recognize the benefits and harms of personalized screening as compared with existing screening methods, (ii) that the use of genetic data highlights complex ethical issues including discrimination against high-risk individuals by insurers and employers and patient autonomy in relation to genetic testing of minors, (iii) the need for transparency and clear communication about risk scores, about harms and benefits, and about reasons for inclusion and exclusion from the risk-based screening process, and (iv) the need to develop new professional competences and to assess cost-effectiveness and acceptability of stratified screening programs before implementation. We conclude that health professionals and stakeholders need to consider the implications of incorporating genetic information in intervention strategies for health-care planning in the future.

Background: Improving understanding of the genetic basis of disease susceptibility enables us to estimate individuals' risk of developing cancer and offer them disease prevention, including screening, stratified to reflect that risk. Little attention has so far been given to the implementation of stratified screening. This article reviews the issues that would arise in delivering such tailored approaches to prevention in practice. Results: Issues analysed include the organisational context within which implementation of stratified prevention would occur, how the offer of screening would be made, making sure consent is adequately informed, how individuals' risk would be assessed, the age at which risk estimation should occur, and the potential use of genetic data for other purposes. The review also considers how management might differ depending on individuals' risk, how their results would be communicated and their follow-up arranged, and the different issues raised by modification of an existing screening programme, such as that for breast cancer, and the establishment of a new one, for example for prostate cancer. Conclusion: Stratified screening based on genetic testing is a radically new approach to prevention. Various organisational issues would need to be considered before it could be introduced, and a number of questions require further research.

Background The identification of common genetic variants associated with common cancers including breast, prostate and ovarian cancers would allow population stratification by genotype to effectively target screening and treatment. As scientific, clinical and economic evidence mounts there will be increasing pressure for risk-stratified screening programmes to be implemented. Methods This paper reviews some of the main ethical, legal and social issues (ELSI) raised by the introduction of genotyping into risk-stratified screening programmes, in terms of Beauchamp and Childress's four principles of biomedical ethics—respect for autonomy, non-maleficence, beneficence and justice. Two alternative approaches to data collection, storage, communication and consent are used to exemplify the ELSI issues that are likely to be raised. Results Ultimately, the provision of risk-stratified screening using genotyping raises fundamental questions about respective roles of individuals, healthcare providers and the state in organizing or mandating such programmes, and the principles, which underpin their provision, particularly the requirement for distributive justice. Conclusions The scope and breadth of these issues suggest that ELSI relating to risk-stratified screening will become increasingly important for policy-makers, healthcare professionals and a wide diversity of stakeholders.

Available literature suggests that both vitamin D and calcium may be associated with a wide range of non-skeletal outcomes. However, epidemiological evidence supporting their individual associations with incident cerebrovascular disease is scarce. We conducted a systematic review and meta-analysis of prospective cohort studies, published before February 2012 and sought from MEDLINE, EMBASE, BIOSIS and the Science Citation Index databases, and reported cerebrovascular disease (defined as any fatal or non-fatal ischemic stroke, hemorrhagic stroke, cerebrovascular accident or transient ischemic attack) by circulating vitamin D (25-hydroxy vitamin D [25(OH)D] as active metabolite) and calcium levels. Two independent investigators abstracted information on 25(OH)D and calcium, cerebrovascular outcomes and other characteristics from selected studies. Relative risks (RRs) were pooled by both random and fixed effects meta-analyses and were further examined under different study-level characteristics. Publication bias was assessed with funnel plots and Egger's asymmetry test. From 5,778 initial references, nine unique prospective cohort studies met our inclusion criteria. Seven studies (involving 47,809 participants and 926 cerebrovascular events) focused on circulating 25(OH)D and 3 reported on circulating calcium (22,577 participants and 727 events). For 25(OH)D, in a comparison of individuals in the top third versus those in the bottom third at baseline, the combined RR for cerebrovascular disease, adjusted for several conventional risk factors, was 0.60 (95 % CI 0.48, 0.72). The corresponding RR in the prospective studies that reported on baseline circulating calcium levels for cerebrovascular disease was 1.40 (95 % CI 1.19, 1.64). There was no apparent evidence of heterogeneity or publication bias among included studies. Available data indicate that higher circulating level of vitamin D is associated with a decreased risk of cerebrovascular disease. Conversely, higher circulating calcium concentration is associated with an increased risk of cerebrovascular disease.