Breast cancer metastasis to the bone: mechanisms of bone loss

Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFκB ligand) and several osteoclastogenic cytokines. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies

Biophysical techniques for distinguishing ligand binding modes in cytochrome P450 monooxygenases

The cytochrome P450 superfamily of heme monooxygenases catalyzes important chemical reactions across nature. The changes in the optical spectra of these enzymes, induced by the addition of substrates or inhibitors, are critical for assessing how these molecules bind to the P450, enhancing or inhibiting the catalytic cycle. Here we use the bacterial CYP199A4 enzyme (Uniprot entry Q2IUO2), from Rhodopseudomonas palustris HaA2, and a range of substituted benzoic acids to investigate different binding modes. 4-Methoxybenzoic acid elicits an archetypal type I spectral response due to a ≥95% switch from the low- to high-spin state with concomitant dissociation of the sixth aqua ligand. 4-(Pyridin-3-yl)- and 4-(pyridin-2-yl)benzoic acid induced different type II ultraviolet–visible (UV–vis) spectral responses in CYP199A4. The former induced a greater red shift in the Soret wavelength (424 nm vs 422 nm) along with a larger overall absorbance change and other differences in the α-, β-, and δ-bands. There were also variations in the ferrous UV–vis spectra of these two substrate-bound forms with a spectrum indicative of Fe–N bond formation with 4-(pyridin-3-yl)benzoic acid. The crystal structures of CYP199A4, with the pyridinyl compounds bound, revealed that while the nitrogen of 4-(pyridin-3-yl)benzoic acid is coordinated to the heme, with 4-(pyridin-2-yl)benzoic acid an aqua ligand remains. Continuous wave and pulse electron paramagnetic resonance data in frozen solution revealed that the substrates are bound in the active site in a form consistent with the crystal structures. The redox potential of each CYP199A4–substrate combination was measured, allowing correlation among binding modes, spectroscopic properties, and the observed biochemical activity

Mitigating the risk of arsenic and fluoride contamination of groundwater through a multi-model framework of statistical assessment and natural remediation techniques

The present book chapter discusses the mechanism of Arsenic and Fluoride release in the groundwater and its related toxicity. The use of spatial modelling techniques involving machine learning classification algorithms can help predict the concentration in binary outputs. The variability in the cause of occurrence of Arsenic forces researchers to try different adsorption materials that could help decrease the concentration levels of contaminants to permissible levels. The co-occurrence of Fluoride and Arsenic at places complicates both prediction as well as remediation. Therefore a multi-model technique involving statistical assessment and natural remediation is required to be used in tandem.by Ashwin Singh, Arbind Kumar Patel and Manish Kuma