Potential Role of Fourier Transform Infrared Spectroscopy as a Screening Approach for Breast Cancer.

Breast cancer is a heterogeneous disease, and its spread involves a succession of clinical and pathological stages. Screening is predominantly based on mammography, which has critical limitations related to the effectiveness and production of false-positive or false-negative results, generating discomfort and low adherence. In this context, infrared with attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy emerges as a non-destructive sample tool, which is non-invasive, label-free, has a low operating-cost, and requires only a small amount of sample, including liquid plasma samples. We sought to evaluate the clinical applicability of ATR FT-IR in breast cancer screening. ATR FT-IR spectroscopy through its highest potential spectral biomarker could distinguish, by liquid plasma biopsy, breast cancer patients and healthy controls, obtaining a sensitivity of 97%, specificity of 93%, a receiver operating characteristic ROC curve of 97%, and a prediction accuracy of 94%. The main variance between the groups was mainly in the band 1511 cm-1 of the control group, 1502 and 1515 cm-1 of the cancer group, which are the peaks of the bands referring to proteins and amide II. ATR FT-IR spectroscopy has demonstrated to be a promising tool for breast cancer screening, given its time efficiency, cost of approach, and its high ability to distinguish between the liquid plasma samples of breast cancer patients and healthy controls.

Myosins and MyomiR Network in Patients with Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The molecular mechanisms determining HCM phenotypes are incompletely understood. Myocardial biopsies were obtained from a group of patients with obstructive HCM (n = 23) selected for surgical myectomy and from 9 unused donor hearts (controls). A subset of tissue-abundant myectomy samples from HCM (n = 10) and controls (n = 6) was submitted to laser-capture microdissection to isolate cardiomyocytes. We investigated the relationship among clinical phenotype, cardiac myosin proteins (MyHC6, MyHC7, and MyHC7b) measured by optimized label-free mass spectrometry, the relative genes (MYH7, MYH7B and MYLC2), and the MyomiR network (myosin-encoded microRNA (miRs) and long-noncoding RNAs (Mhrt)) measured using RNA sequencing and RT-qPCR. MyHC6 was lower in HCM vs. controls, whilst MyHC7, MyHC7b, and MyLC2 were comparable. MYH7, MYH7B, and MYLC2 were higher in HCM whilst MYH6, miR-208a, miR-208b, miR-499 were comparable in HCM and controls. These results are compatible with defective transcription by active genes in HCM. Mhrt and two miR-499-target genes, SOX6 and PTBP3, were upregulated in HCM. The presence of HCM-associated mutations correlated with PTBP3 in myectomies and with SOX6 in cardiomyocytes. Additionally, iPSC-derived cardiomyocytes, transiently transfected with either miR-208a or miR-499, demonstrated a time-dependent relationship between MyomiRs and myosin genes. The transfection end-stage pattern was at least in part similar to findings in HCM myectomies. These data support uncoupling between myosin protein/genes and a modulatory role for the myosin/MyomiR network in the HCM myocardium, possibly contributing to phenotypic diversity and providing putative therapeutic targets.

BACE1 Translation: At the Crossroads Between Alzheimer's Disease Neurodegeneration and Memory Consolidation.

 Human life unfolds not only in time and space, but also in the recollection and interweaving of memories. Therefore, individual human identity depends fully on a proper access to the autobiographical memory. Such access is hindered under pathological conditions such as Alzheimer's disease, which affects millions of people worldwide. Unfortunately, no effective cure exists to prevent this disorder, the impact of which will rise alarmingly within the next decades. While Alzheimer's disease is largely considered to be the outcome of amyloid-ß (Aß) peptide accumulation in the brain, conceiving this complex disorder strictly as the result of Aß-neurotoxicity is perhaps a too straight-line simplification. Instead, complementary to this view, the tableau of molecular disarrangements in the Alzheimer's disease brain may be reflecting, at least in part, a loss of function phenotype in memory processing. Here we take BACE1 translation and degradation as a gateway to study molecular mechanisms putatively involved in the transition between memory and neurodegeneration. BACE1 participates in the excision of Aß-peptide from its precursor holoprotein, but plays a role in synaptic plasticity too. Its translation is governed by eIF2α phosphorylation: a hub integrating cellular responses to stress, but also a critical switch in memory consolidation. Paralleling these dualities, the eIF2α-kinase HRI has been shown to be a nitric oxide-dependent physiological activator of hippocampal BACE1 translation. Finally, beholding BACE1 as a representative protease active in the CNS, we venture a new perspective on the cellular basis of memory, which may incorporate neurodegeneration in itself as a drift in memory consolidating systems.

Theranostic biomarkers in hypertrophic cardiomyopathy: insights in a long road ahead.

The study of biomarkers and their related signalling pathways has allowed the development of new therapeutic strategies in a range of disorders. However, in hypertrophic cardiomyopathy (HCM), which is the most common hereditary cardiac disease, there are many potential biomarkers described, but their specificity and applicability for HCM remains an open field. The aim of the present review is to provide an overview of molecules that could give some insight into the pathophysiologic mechanisms underlying HCM, especially to those with "theranostic" - a combination of diagnostics and therapy - potential. The clinical and pre-clinical state of the art and theranostic perspectives of this topic will be part of the current discussion. The better understanding of this subject would provide an algorithm, to optimize the integration of diagnosis, prognostics and therapeutics findings in HCM, leading to a tailored approach for this pathology.

Cardiotoxicity in oncology and coronary microcirculation: future challenges in theranostics.

Many of the patients undergoing chemotherapy or radiotherapy for cancer are at increased risk of developing cardiovascular diseases. Recent evidence suggests that cardiac dysfunction and subsequent heart failure are mainly due to vascular toxicity rather than only to due to myocyte toxicity. However, not all of the vascular toxicity of cancer therapies can be explained by epicardial coronary artery disease. In fact, in the last decades, it has been found that myocardial ischemia may occur as a consequence of structural or functional dysfunction of the complex network of vessels, which cannot be seen by a coronary angiography: the coronary microcirculation. Nowadays many diagnostic and therapeutic options are available both in coronary microvascular dysfunction and cardio-oncology. Aim of this review is to suggest future theranostic implications of the relationship between cardiotoxicity in oncology and coronary microvascular dysfunction, showing common pathophysiologic mechanisms, proposing new diagnostic approaches and therapeutic options for cardioprotection.

T3 and T4 decrease ROS levels and increase endothelial nitric oxide synthase expression in the myocardium of infarcted rats.

UNLABELLED: Myocardial infarction leads to a reduction in nitric oxide (NO) bioavailability and an increase in reactive oxygen species (ROS) levels. This scenario has been shown to be detrimental to the heart. Recent studies have shown that thyroid hormone (TH) administration presents positive effects after ischaemic injury. Based on this, the aim of this study was to evaluate the effect of TH on NO bioavailability as well as on endothelial nitric oxide synthase (eNOS) expression after myocardial infarction. Male Wistar rats were divided into three groups: Sham-operated (SHAM), infarcted (AMI) and infarcted + TH (AMIT). During 26 days, the AMIT group received T3 and T4 (2 and 8 µg/100 g/day, respectively) by gavage, while SHAM and AMI rats received saline. After this, the rats underwent echocardiographic analysis were sacrificed, and the left ventricle was collected for biochemical and molecular analysis. STATISTICAL ANALYSIS: one-way ANOVA with Student-Newman-Keuls post test. AMI rats presented a 38% increase in ROS levels. TH administration prevented these alterations in AMIT rats. The AMIT group presented an increase in eNOS expression, in NOS activity and in nitrite levels. TH administration also increased PGC-1α expression in the AMIT group. In conclusion, TH effects seem to involve a modulation of eNOS expression and an improvement in NO bioavailability in the infarcted heart.

Cardioprotective effects of thyroid hormones in a rat model of myocardial infarction are associated with oxidative stress reduction.

Reactive oxygen species (ROS) are involved with progression from infarction to heart failure. Studies show that thyroid hormones (TH) present cardioprotective effects. This study aims to evaluate whether TH effects after infarction are associated to redox balance modulation. Male Wistar rats were divided into four groups: Sham-operated (SHAM), infarcted (AMI), sham-operated+TH (SHAMT), and infarcted+TH (AMIT). During 26 days, animals received T3 (2 µg/100g/day) and T4 (8 µg/100g/day) by gavage. Echocardiographic parameters were assessed and heart tissue was collected to biochemical analysis. AMIT rats presented absence of lung congestion, less cardiac dilatation, and normalization in myocardial performance index, compared with AMI. AMI rats presented an increase in hydrogen peroxide levels and in lipid peroxidation and a decrease in GSH/GSSG. TH prevented these alterations in AMIT. In conclusion, TH seem to reduce the levels of ROS, preventing oxidative stress, and improving cardiac function in infarcted rats.

Low-dose estrogen is as effective as high-dose treatment in rats with postmenopausal hypertension.

: This study was conducted to test the hypothesis that 17ß-estradiol therapy improves redox balance by decreasing reactive oxygen species production and increasing nitric oxide (NO) bioavailability, favoring Akt pathway activation and resulting in a better autonomic vascular control. Ovariectomized female Wistar rats were divided into 4 groups: (1) vehicle (VL) and animals treated with a pellet of 17ß-estradiol for 21 days; (2) low dose (LE; 0.05 mg); (3) medium dose (ME; 0.2 mg); and (4) high dose (HE; 0.5 mg). Arterial pressure and its sympathetic nervous system modulation were evaluated by spectral analysis. Nitric oxide synthase and NADPH oxidase (Nox) activities, H2O2 concentration, redox status (GSH/GSSG), protein expression of Trx-1 and p-Akt/Akt were evaluated in the aorta, whereas NO metabolites were measured in the serum. Estrogen-treated groups showed a significant decrease in arterial pressure and sympathetic vascular drive. Redox status was significantly improved and NADPH oxidase and H2O2 were decreased in all estrogen-treated groups. Estrogen also induced an enhancement in NO metabolites, nitric oxide synthase activity, and Akt phosphorylation. This study demonstrated that estrogen treatment to ovariectomized rats induced cardioprotection, which was evidenced by reduced blood pressure variability and vascular sympathetic drive. These effects were associated with an improved redox balance and Akt activation, resulting in an enhanced NO bioavailability.