Upregulation of Endothelin-1 May Predict Chemotherapy-Induced Cardiotoxicity in Women with Breast Cancer.

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer.

Trpc6 Promotes Doxorubicin-Induced Cardiomyopathy in Male Mice With Pleiotropic Differences Between Males and Females.

Background: Doxorubicin is a widely used and effective chemotherapy, but the major limiting side effect is cardiomyopathy which in some patients leads to congestive heart failure. Genetic variants in TRPC6 have been associated with the development of doxorubicin-induced cardiotoxicity, suggesting that TRPC6 may be a therapeutic target for cardioprotection in cancer patients. Methods: Assessment of Trpc6 deficiency to prevent doxorubicin-induced cardiac damage and function was conducted in male and female B6.129 and Trpc6 knock-out mice. Mice were treated with doxorubicin intraperitoneally every other day for a total of 6 injections (4 mg/kg/dose, cumulative dose 24 mg/kg). Cardiac damage was measured in heart sections by quantification of vacuolation and fibrosis, and in heart tissue by gene expression of Tnni3 and Myh7. Cardiac function was determined by echocardiography. Results: When treated with doxorubicin, male Trpc6-deficient mice showed improvement in markers of cardiac damage with significantly reduced vacuolation, fibrosis and Myh7 expression and increased Tnni3 expression in the heart compared to wild-type controls. Similarly, male Trpc6-deficient mice treated with doxorubicin had improved LVEF, fractional shortening, cardiac output and stroke volume. Female mice were less susceptible to doxorubicin-induced cardiac damage and functional changes than males, but Trpc6-deficient females had improved vacuolation with doxorubicin treatment. Sex differences were observed in wild-type and Trpc6-deficient mice in body-weight and expression of Trpc1, Trpc3 and Rcan1 in response to doxorubicin. Conclusions: Trpc6 promotes cardiac damage following treatment with doxorubicin resulting in cardiomyopathy in male mice. Female mice are less susceptible to cardiotoxicity with more robust ability to modulate other Trpc channels and Rcan1 expression.

ATR-FTIR observations of water structure in colloidal silica: implications for the hydration force mechanism.

Attenuated total internal reflection Fourier-transform infrared spectroscopy (ATR-FTIR) was used to probe the change in water structure in silica colloids as a function of particle density. The absorption index (k) spectra were calculated from the ATR spectra using the subtractive Kramers-Kronig transform in order to avoid the effects of the density-dependent refractive index on the raw spectra and allow direct comparison of the different chemical environments. Normalized difference spectra were obtained by subtracting the k spectrum of bulk water from those of the silica colloids. At low particle densities, these difference spectra reveal the presence of a strongly hydrogen-bonded hydration layer at the surface of the colloidal particles. At higher particle densities, the hydrogen-bonding network is increasingly disrupted. The results provide direct experimental evidence of hydrogen-bond breaking as the mechanism for the hydration force, which provides the extraordinary stability of colloidal silica.

Spectroscopic investigations of Fe2+ complexation on nontronite clay.

Diffuse reflectance (visible) and attenuated total internal reflection Fourier-transform infrared (ATR-FTIR) spectroscopies were used to examine a colloidal nontronite clay in the presence of Fe2+(aq). pH-dependent changes are observed in both types of spectra. In the visible region, a broad feature at approximately 750 nm appears as the pH is raised to circumneutral values. This absorbance band overlaps with a portion of the spectrum of the chemically reduced clay which is dominated by an intervalence charge-transfer transition between Fe2+ and Fe3+ within the mineral structure. The similarities between these spectra suggest that Fe2+(aq) adsorbs to the clay in such a way that it can undergo charge transfer with structural Fe3+ within the clay. ATR-FTIR spectra at pH 5-8 reveal a transformation in the Si-O stretching region between pH 6 and pH 7 with a shift of the component peaks to lower frequency. Taken together, these spectroscopic studies indicate that Fe2+ forms an inner-sphere complex with the clay at higher pH values. The pH threshold for these observed changes in physical and electronic structure is in good agreement with the point of zero charge (pzc) of the hydroxyl groups on the edge surfaces of the clay, suggesting that complexation of Fe2+ to deprotonated edge sites leads to the observed spectroscopic features.

Influence of surface composition on the kinetics of alachlor reduction by iron pyrite.

Even though naturally occurring iron sulfide minerals have previously been shown capable of promoting reductive dehalogenations, the role of surface composition has not been fully investigated. Some researchers have proposed that sulfur species represent redox-active moieties on iron pyrite surfaces. Results from this study indicate that neitherthe stoichiometric (100) pyrite surface, nor monosulfide defects, play direct roles in the observed reduction of the herbicide alachlor [2-chloro-2',6'-diethyl-N-(methoxymethyl)acetanilide]. Pyrite surfaces were initially characterized by X-ray photoelectron spectroscopy (XPS); the samples were then transferred to a liquid cell coupled to the ultrahigh vacuum chamber. Aliquots were periodically removed from the liquid cell to monitor the appearance of the reductive dechlorination product, 2',6'-diethyl-N-(methoxymethyl)acetanilide. In experiments with unaltered pyrite (100) surfaces, rates of reaction decreased over time, even though no change in surface composition could be discerned via XPS. In contrast, ion-bombarded surfaces, which are dominated by monosulfide species, exhibit an initial induction period of low reactivity during which the highly defective surface is oxidized by water. Only after the monosulfide defects undergo oxidation does the rate of alachlor reduction increase, precluding a direct role for these defects as alachlor reductants.