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Background: Cancer cells are characterized by metabolic heterogeneity. Al-though many research groups make efforts to analyze this heterogeneity, little attention has been paid to cancer cells utilizing otherwise unusable substrates as fuel for tumor de-velopment. Of the two stereoisomers of glucose, D-glucose but not L-glucose, the mirror image isomer of D-glucose is abundantly found in nature. D-glucose is the human body's key source of energy through aerobic respiration. However, data from in vitro and in vivo studies examining the ability of cancer cells to take up L-glucose are scarce. Objectives: The present mini-review aims to present current literature data on the role of L-glucose in cancer diagnosis based on in vitro and in vivo studies. Methods: The MEDLINE, EMBASE, and the Cochrane Library with restrictions to arti-cles in English language databases were searched to retrieve available data. Results: There are limited data in the literature regarding in vitro and in vivo studies that examined the ability of cancer cells to take up L-glucose. Research work so far has shown that that the binding of a fluorescent detector to an L-glucose molecule produced a fluorescent probe that was specifically taken up by malignant cancer cells, thus provid-ing a unique method for their detection. Conclusion: Given that L-glucose is taken up by cancer cells, L-glucose fluorescent probes can be a useful tool for visualization and characterization of cancer cells. More research on the potential biologic effects of L-glucose in cancer is necessary. © 2021 Bentham Science Publishers.

Sepsis and septic shock result in impaired microcirculation and red blood cell rheology which lead to tissue hypoxia and multi-organ failure. Early administration of triiodothyronine prevents tissue hypoxia in experimental sepsis. In this context, a clinical trial was initiated to test the efficacy of acute triiodothyronine administration to combat tissue hypoxia in critically ill COVID19 patients. Here, we provide preliminary data from interim analysis of this study showing a novel acute effect of triiodothyronine on erythrocyte sedimentation rate which may have an important therapeutic impact on red blood cell rheology and tissue hypoxia in sepsis and particular in COVID19 critical illness.Trial registration: ClinicalTrials.gov, NCT04348513. Registered 16 April 2020, https://clinicaltrials.gov/ct2/show/NCT04348513.

Why can we still not translate preclinical research to clinical treatments for acute strokes? Despite > 1000 successful preclinical studies, drugs, and concepts for acute stroke, only two have reached clinical translation. This is the translational block. Yet, we continue to routinely model strokes using almost the same concepts we have used for over 30 years. Methodological improvements and criteria from the last decade have shed some light but have not solved the problem. In this conceptual analysis, we review the current status and reappraise it by thinking “out-of-the-box” and over the edges. As such, we query why other scientific fields have also faced the same translational failures, to find common denominators. In parallel, we query how migraine, multiple sclerosis, and hypothermia in hypoxic encephalopathy have achieved significant translation successes. Should we view ischemic stroke as a “chronic, relapsing, vascular” disease, then secondary prevention strategies are also a successful translation. Finally, based on the lessons learned, we propose how stroke should be modeled, and how preclinical and clinical scientists, editors, grant reviewers, and industry should reconsider their routine way of conducting research. Translational success for stroke treatments may eventually require a bold change with solutions that are outside of the box. © Copyright © 2021 Lourbopoulos, Mourouzis, Xinaris, Zerva, Filippakis, Pavlopoulos and Pantos.

Ιn this study we aim to examine and integrate current literature and research on attachment theory and its expression on the specific field of obstetrics, the perinatal period. In medical settings in general, and in the field of obstetrics in specific, which is the clinical domain of the perinatal period, obstetricians, psychiatrists and psychologists frequently come across antenatal and postnatal concerns, psychological issues as well as psychiatric symptomatology stemming from closer observation of the women's difficulties or reported by women themselves. To our theoretical understanding, in order to better comprehend these psychosocial concerns and deliver timely and more effective personalized interventions to women in need, it is of paramount importance to thoroughly examine the perspective proposed by attachment theory, as it was first developed by child psychiatrist-psychoanalyst John Bowlby and the newest theoretical developments on the field that followed. Subtypes of attachment style are examined regarding their imprint on the benefits, as well as the difficulties and risks they place on women during each perinatal stage. "Insecurity" in attachment and significant relationships appears to render women more vulnerable in relation to psychopathology, according to the literature reviewed. As far as the psychopathological symptoms and disorders related to the perinatal period and their connection to attachment are concerned, the main disorders and symptomatology discussed in the literature appear to be perinatal depression, postpartum depression, perinatal anxiety and posttraumatic stress symptoms related to pregnancy and labor. At the same time, "security" attachment-wise, tangibly observed in couples with strong intramarital support, appears to offer a protective barrier against adversities by enabling securely attached women to remain calmer and make better use of their emotional and social resources throughout the challenging perinatal phase. Consequently, mothers-to-be become more eligible to overcome perinatal difficulties by the use of patterns of behavior that promote their well-being. Through the in-depth review of the current literature on attachment theory available and the tools of knowledge it equips us with, we attempted to assemble the real challenges and needs deriving from the demands that pregnancy, labor and the postpartum place on new mothers, as well as the way close relationships become affected by or, correspondingly, can be positively used in order to protect and shield women and their families from acknowledged stressful perinatal phases.

Background: The transmembrane-TNF transgenic mouse, TgA86, has been shown to develop spontaneously peripheral arthritis with signs of axial involvement. To assess similarity to human spondyloarthritis, we performed detailed characterization of the axial, peripheral, and comorbid pathologies of this model. Methods: TgA86 bone pathologies were assessed at different ages using CT imaging of the spine, tail vertebrae, and hind limbs and characterized in detail by histopathological and immunohistochemical analysis. Cardiac function was examined by echocardiography and electrocardiography and bone structural parameters by μCT analysis. The response of TgA86 mice to either early or late anti-TNF treatment was evaluated clinically, histopathologically, and by μCT analysis. Results: TgA86 mice developed with 100% penetrance spontaneous axial and peripheral pathology which progressed with time and manifested as reduced body weight and body length, kyphosis, tail bendings, as well as swollen and distorted hind joints. Whole-body CT analysis at advanced ages revealed bone erosions of sacral and caudal vertebrae as well as of sacroiliac joints and hind limbs and, also, new ectopic bone formation and eventually vertebral fusion. The pathology of these mice highly resembled that of SpA patients, as it evolved through an early inflammatory phase, evident as enthesitis and synovitis in the affected joints, characterized by mesenchymal cell accumulation, and neutrophilic infiltration. Subsequently, regression of inflammation was accompanied by ectopic bone formation, leading to ankylosis. In addition, both systemic bone loss and comorbid heart valve pathology were evident. Importantly, early anti-TNF treatment, similar to clinical treatment protocols, significantly reduced the inflammatory phase of both the axial and peripheral pathology of TgA86 mice. Conclusions: The TgA86 mice develop a spontaneous peripheral and axial biphasic pathology accompanied by comorbid heart valvular dysfunction and osteoporosis, overall reproducing the progression of pathognomonic features of human spondyloarthritis. Therefore, the TgA86 mouse represents a valuable model for deciphering the role of transmembrane TNF in the pathogenic mechanisms of spondyloarthritis and for assessing the efficacy of human therapeutics targeting different phases of the disease. © 2020 The Author(s).

Thyroid hormone (TH) signalling is a key modulator of fundamental biological processes that has been evolutionarily conserved in both vertebrate and invertebrate species. TH may have initially emerged as a nutrient signal to convey environmental information to organisms to induce morpho-anatomical changes that could maximise the exploitation of environmental resources, and eventually integrated into the machinery of gene regulation and energy production to become a key regulator of development and metabolism. As such, TH signalling is particularly sensitive to environmental stimuli, and its alterations result in fundamental changes in homeostasis and physiology. Stressful stimuli of various origins lead to changes in the TH–TH receptor (TR) axis in different adult mammalian organs that are associated with phenotypical changes in terminally differentiated cells, the reactivation of foetal development programmes, structural remodelling and pathological growth. Here, we discuss the evolution of TH signalling, review evolutionarily conserved functions of THs in essential biological processes, such as metamorphosis and perinatal development, and analyse the role of TH signalling in the phenotypical and morphological changes that occur after injury, repair and regeneration in adult mammalian organs. Finally, we examine the potential of TH treatment as a therapeutic strategy for improving organ structure and functions following injury. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Aims: To examine for differences in circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) in patients with and without diabetic peripheral neuropathy (DPN). Methods: A total of 105 participants were included: 50 patients with type 2 diabetes (T2DM) and DPN, 30 patients with T2DM without DPN and 25 healthy individuals. CPCs and 6 different EPCs phenotypes were assessed with flow cytometry. We also measured plasma levels of vascular endothelial growth factor (VEGF), stromal cell-derived factor 1 (SDF-1), vascular cell adhesion protein-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM) and tumor necrosis factor a (TNFa). Results: No difference was observed in the number of CPCs among the 3 groups. Patients with DPN had higher numbers of all 6 EPCs phenotypes when compared with patients without DPN and higher number of 5 EPCs phenotypes when compared with healthy individuals. Plasma VEFG, VCAM-1, ICAM-1 and TNFa levels did not differ among the 3 groups. Patients with DPN had lower SDF-1 levels in comparison with healthy individuals. Conclusion: Circulating EPCs are increased while SDF-1 levels are decreased in the presence of DPN. Our findings suggest that DPN may be associated with impaired trafficking of EPCs and impaired EPCs homing to the injured endothelium. © 2020 Elsevier Inc.

Osteopontin (OPN) is involved in the atherosclerotic and inflammatory process. In this article, we examined the relationship between circulating OPN levels with lower extremity arterial disease (LEAD) in individuals with type 2 diabetes mellitus (T2DM). Seventy individuals with T2DM and 66 individuals without T2DM were recruited. Diagnosis of LEAD was based on the absence of triphasic waveform on the pedal arteries. Plasma OPN levels were determined by Luminex Multiplex immunoassay. LEAD was present in 34 (48.6%) patients with T2DM. In the diabetes cohort, individuals with LEAD had higher plasma OPN concentrations than those without LEAD (geometric mean [95% confidence intervals]; 43.4 [37.5-50.4] vs 26.1 [22.9-29.8] ng/mL, respectively, P

Background: Sclerostin inhibits bone formation and its expression is upregulated in the vasculature during the arterial calcification process as a counterregulatory mechanism preventing further calcification. Lower extremity arterial calcification (LEAC) is common in neuropathic patients with type 2 diabetes (T2DM). Herein, we investigated for associations between plasma sclerostin levels and diabetic neuropathy as well as LEAC in subjects with T2DM. Methods: A total of 74 individuals with and 76 without T2DMwere recruited. Plasma sclerostin levels were measured by ELISA. Diagnosis of cardiac autonomic neuropathy (CAN) was based on the battery of the four autonomic tests, while of somatosensory peripheral neuropathy (DPN) on neuropathy symptom score and neuropathy disability score. LEAC was assessed with conventional ankle and foot x-rays. Results: Plasma sclerostin levels were higher in participants with LEAC vs. those without LEAC in both diabetes and non-diabetes cohorts (p = 0.035 and p = 0.003, respectively). In the diabetes cohort, patients with CAN, but not with DPN, had higher sclerostin levels when compared with those without CAN (p < 0.001). Multivariate analysis in the diabetes cohort demonstrated that sclerostin levels were associated positively with CAN and LEAC, while in the non-diabetes cohort there was a trend for a positive association with male gender and presence of LEAC. Conclusion: Plasma sclerostin levels are increased in individuals with LEAC irrespectively of diabetes status. In addition, plasma sclerostin concentrations are associated independently with LEAC and CAN in people with T2DM. © 2020 Elsevier Inc.

Lipofuscin accumulation is a hallmark of senescence. This nondegradable material aggregates in the cytoplasm of stressed or damaged cells due to metabolic imbalance associated with aging and age-related diseases. Indications of a soluble state of lipofuscin have also been provided, rendering the perspective of monitoring such processes via lipofuscin quantification in liquids intriguing. Therefore, the development of an accurate and reliable method is of paramount importance. Currently available assays are characterized by inherent pitfalls which demote their credibility. We herein describe a simple, highly specific and sensitive protocol for measuring lipofuscin levels in any type of liquid. The current method represents an evolution of a previously described assay, developed for in vitro and in vivo senescent cell recognition that exploits a newly synthesized Sudan Black-B analog (GL13). Analysis of human clinical samples with the modified protocol provided strong evidence of its usefulness for the exposure and surveillance of age-related conditions. © Springer Science+Business Media, LLC, part of Springer Nature 2019.

In Chapter 12, figure 1 was published with truncated texts within. This figure has now been replaced with a revised figure with the updated text.

Aims: Endothelin has been implicated in various processes in the brain, including the modulation of sympathetic responses. The present study examined the pathophysiologic role of brain endothelin-receptors in the setting of acute myocardial infarction, characterized by high incidence of ventricular tachyarrhythmias. Main methods: We investigated the effects of intracerebroventricular administration of antagonists of endothelin-receptors ETA, ETB, or both, during a 24 h-observation period post-coronary ligation in (n = 70) rats. Continuous recording was performed via implanted telemetry transmitters, followed by arrhythmia-analysis and calculation of autonomic indices derived from heart rate variability. The regional myocardial electrophysiologic properties were assessed by monophasic action potentials and multi-electrode recordings. Key findings: Sympathetic-activity was decreased and vagal-activity was enhanced after intracerebroventricular ETA-receptor blockade, thus attenuating regional myocardial repolarization inhomogeneity. As a result, the incidence of ventricular tachyarrhythmias was markedly lower in this group. Such effects were also observed after intracerebroventricular blockade of ETB-, or both, ETA- and ETB-receptors, although to a lesser extent. Significance: ETA-receptors in the brain modulate sympathetic and vagal responses and alter arrhythmogenesis during evolving myocardial necrosis in rats. These findings provide insights into arrhythmogenic mechanisms during acute myocardial infarction and call for further investigation on the role of endothelin in the central autonomic network. © 2019

Endothelin alters central sympathetic responses, but the resultant effects on arrhythmogenesis are unknown. We examined ventricular tachyarrhythmias after endothelin receptor-A blockade in the brain of Wistar rats with acute myocardial infarction. For this aim, BQ-123 (n=6) or phosphate-buffered saline (n=6) were injected intracerebroventricularly. After 10 min, the left coronary artery was ligated, followed by implantation of telemetry transmitters. Electrocardiography and voluntary activity (as a surrogate of acute left ventricular failure) were continuously monitored for 24 h. Infarct-size was similar in the two groups. There were fewer episodes of ventricular tachyarrhythmias of shorter average duration in treated rats, leading to markedly shorter total duration (12.3±8.9 s), when compared to controls (546.2±130.3 s). Voluntary activity increased in treated rats during the last hours of recording, but bradyarrhythmic episodes were comparable between the two groups. Endothelin receptor-A blockade in the brain of rats decreases the incidence of ventricular tachyarrhythmias post-ligation, without affecting bradyarrhythmic episodes. These findings call for further research on the pathophysiologic role of endothelin during acute myocardial infarction. © 2019 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.

The cellular stress response (CSR) is a universal inducible reaction modulated, among others, by heat, drugs, and hormones. We aimed to investigate the role of l-thyroxine (T4) on the heat shock (HS) response in Saccharomyces cerevisiae. The CSR was evaluated by determining growth and viability of post-logarithmic phase grown yeast cultures after HS at 53 °C for 30 min. We found that long-term T4 exposure can induce a dose-dependent and Hsp90 and H+ trafficking-related thermotolerance in yeast. © 2019, Cell Stress Society International.

OBJECTIVES:Patients with rheumatoid arthritis and spondyloarthritisshow higher mortality rates, mainly caused by cardiac comorbidities. The TghuTNF (Tg197) arthritis model develops tumour necrosis factor (TNF)-driven and mesenchymalsynovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and explore cellular and molecular mechanisms linking arthritis to cardiac comorbidities. METHODS:Histopathological analysis and echocardiographic evaluation of cardiac function were performed in the Tg197 model. Valve interstitial cells (VICs) were targeted by mice carrying theColVI-Cretransgene. Tg197ColVI-Cre Tnfr1fl/fland Tg197ColVI-Cre Tnfr1cneo/cneomutant mice were used to explore the role of mesenchymal TNF signalling in the development of heart valve disease. Pathogenic VICs and SFs were further analysed by comparative RNA-sequencing analysis. RESULTS:Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consist almost entirely of hyperproliferativeColVI-expressing mesenchymal VICs. Development of pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signalling. Tg197-derived VICs exhibited an activated phenotypeex vivo, reminiscent of the activated pathogenic phenotype of Tg197-derived SFs. Significant functional similarities between SFs and VICs were revealed by RNA-seq analysis, demonstrating common cellular mechanisms underlying TNF-mediated arthritides and cardiac comorbidities. CONCLUSIONS:Comorbidheart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms.

Irisin is a myokine that increases energy expenditure. In this cross-sectional study, we examined for differences in plasma irisin concentrations between subjects with type 1 diabetes mellitus and healthy individuals and searched for associations between plasma irisin levels and clinical and biochemical characteristics as well as self-reported physical activity. A total of 79 subjects with type 1 diabetes [age 38.2±12.5 years, men/women (n): 27/52], were consecutively recruited. Moreover, 53 healthy controls, matched for age and body mass index with those with diabetes were recruited. Plasma irisin was measured with ELISA. Participants were asked about their physical activity during the last week. We also measured trunk and visceral fat. Circulating irisin levels were lower in subjects with diabetes than in controls [median value (interquartile range): 53.0 (35.2, 106.3) vs. 178.1 (42.6, 641.6) ng/ml, respectively, p

Cardiac function is reduced following myocardial infarction (MI) due to myocardial injury and alterations in the viable non-ischemic myocardium, a process known as cardiac remodeling. The current treatments available for patients with acute MI (AMI) reduce infarct size, preserve left ventricular (LV) function and improve survival; however, these treatments do not prevent remodeling, which can lead to heart failure. The aim of the present study was to investigate the effects of thyroid hormone (TH) treatment following MI in an in vivo rat model. A total of 199 rats were separated into 3 groups: Sham operated and 2 different coronary artery ligation (CAL) groups. Rats subjected to CAL were randomly divided into a further 2 groups 24 h following surgery. The first group received standard rat chow (designated the CAL group), while the second group received food containing 0.05% thyroid powder (designated the CALTH group). The mean daily intake of TH per rat was estimated at 3.0 µg T3 and 12 µg T4. Echocardiography was used to monitor the rats. Large-scale analysis confirmed the favorable effects of TH treatment following CAL on various parameters of cardiac function. TH treatment reduced LV dilation, and increased global and regional LV function. The development of cardiac hypertrophy was induced and, thus, wall stress was limited. Furthermore, TH treatment improved cardiac geometry, which manifested as an increased sphericity index. Myocardial function, as well as LV dilatation, following CAL and TH treatment was not closely associated with the extent of injury, indicating a novel therapeutic intervention that may alter the course of LV remodeling that typically leads to post-MI heart failure. Data modelling and regressions may be developed to enable the simulation of the pathophysiological processes that occur following MI, and to predict with accuracy the effects of novel or current treatments that act via the modulation of tissue injury, LV dilation, LV geometry and hypertrophy. Copyright © Spandidos Publications 2017. All rights reserved.

Objectives: Patients with rheumatoid arthritis and spondyloarthritisshow higher mortality rates, mainly caused by cardiac comorbidities. The TghuTNF (Tg197) arthritis model develops tumour necrosis factor (TNF)-driven and mesenchymalsynovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and explore cellular and molecular mechanisms linking arthritis to cardiac comorbidities. Methods: Histopathological analysis and echocardiographic evaluation of cardiac function were performed in the Tg197 model. Valve interstitial cells (VICs) were targeted by mice carrying the ColVI-Cretransgene. Tg197 ColVI-Cre Tnfr1fl/fl and Tg197 ColVI-Cre Tnfr1cneo/cneo mutant mice were used to explore the role of mesenchymal TNF signalling in the development of heart valve disease. Pathogenic VICs and SFs were further analysed by comparative RNA-sequencing analysis. Results: Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consist almost entirely of hyperproliferative ColVI-expressing mesenchymal VICs. Development of pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signalling. Tg197-derived VICs exhibited an activated phenotype ex vivo, reminiscent of the activated pathogenic phenotype of Tg197-derived SFs. Significant functional similarities between SFs and VICs were revealed by RNA-seq analysis, demonstrating common cellular mechanisms underlying TNF-mediated arthritides and cardiac comorbidities. Conclusions: Comorbidheart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms. © 2018 Article author(s).

Aims Fetuin-A is a hepatic glycoprotein that is involved in insulin resistance and atherosclerosis. Herein we examined the association of plasma fetuin-A levels with peripheral arterial disease (PAD) in patients with type 2 diabetes mellitus (T2DM). Material and Methods A total of 71 patients with T2DM and 57 non-diabetic individuals were recruited. Diagnosis of PAD was based on the absence of triphasic waveform at pedal arteries, while ankle–brachial index (ABI) was calculated. Radiographs of both feet and ankles were taken for the assessment of lower extremity arterial calcification (LEAC). Plasma fetuin-A levels were measured using ELISA. Results Patients with T2DM had higher fetuin-A levels than non-diabetic participants. Participants with diabetes and PAD had lower fetuin-A levels than non-PAD diabetic patients. In subjects with T2DM fetuin-A levels were associated with ABI. Multivariate analysis demonstrated that in patients with T2DM the odds of PAD increased with long diabetes duration, smoking, presence of arterial hypertension and dyslipidemia, as well as with lower fetuin-A levels. A trend towards higher fetuin-A levels in subjects with less severe LEAC was found. Conclusion Plasma fetuin-A levels are lower in patients with T2DM and PAD and are associated with PAD, irrespective of traditional cardiovascular risk factors. Moreover, fetuin-A may be involved in arterial calcification. © 2016 Elsevier Inc.

Mitochondria have emerged as key players regarding cellular homeostasis not only due to their contribution regarding energy production through oxidative phosphorylation, but also due to their involvement in signaling, ion regulation, and programmed cell death. Indeed, current knowledge supports the notion that mitochondrial dysfunction is a hallmark in the pathogenesis of various diseases. Mitochondrial biogenesis and function require the coordinated action of two genomes: nuclear and mitochondrial. Unfortunately, both intrinsic and environmental genotoxic insults constantly threaten the integrity of nuclear as well as mitochondrial DNA. Despite the extensive research that has been made regarding nuclear genome instability, the importance of mitochondrial genome integrity has only recently begun to be elucidated. The specific architecture and repair mechanisms of mitochondrial DNA, as well as the dynamic behavior that mitochondria exert regarding fusion, fission, and autophagy participate in mitochondrial genome stability, and therefore, cell homeostasis. © 2017 by the authors. Licensee MDPI, Basel, Switzerland.

Objective. This study investigated whether thyroid hormone (TH) levels are correlated to cell proliferation (Ki67), in euthyroid breast cancer patients. Design and Methods. 86 newly diagnosed breast cancer patients with estrogen receptor (ER) positive tumors, who referred for surgery, were included in the study. Results. FT3, FT4, and TSH were within normal range. No correlation was seen between Ki67 and FT3 (r=-0.17, P=0.15), FT4 (r=-0.13, P=0.25), or TSH (r=-0.10, P=0.39) in all patients studied. However, subgroup analysis showed that, in HER2(+) patients, a negative correlation existed between FT3 levels and Ki67 (r=-0.60 and P=0.004) but not between Ki67 and FT4 (r=0.04 and P=0.85) or TSH (r=-0.23 and P=0.30). In HER2(-) patients, there was no significant correlation between Ki67 and FT3 (r=-0.06, P=0.67), FT4 (r=-0.15, P=0.26), or TSH (r=-0.09, P=0.49). Phospho-p44/total p44 ERK levels were found to be increased by 2-fold in HER2(+) versus HER2(-) tumors. No difference was detected in phospho-p42/total p42 ERK levels. Conclusions. TH profile is not altered in patients with newly diagnosed breast cancer. However, FT3 levels, even within normal range, are negatively correlated with cell proliferation in HER2(+) breast cancer tumors. This response may be due to the interaction between ERK and TH signaling. © 2015 Iordanis Mourouzis et al.

Thyroid hormone (TH) appears to have a critical role in cardiac repair after injury beyond its role in development and metabolism homeostasis. This unique action is due to the fact that TH effect on the heart is shown to be differentiated depending on its administration on injured or healthy myocardium. Thus, TH can limit ischemia–reperfusion injury via a fine balance between pro-apoptotic and pro-survival signaling pathways. This response is thyroid hormone receptor (TRα1) dependent. Furthermore, an interaction between stress-induced growth kinase signaling and TRα1 is shown to occur and determine postischemic remodeling and cardiac recovery depending on the availability of TH. This new evidence is consistent with clinical observations showing the cardioprotective effect of TH treatment in cardiac surgery, transplantation and heart failure. TH and/or thyroid analogs may be novel agents in treating heart diseases. © 2014, Springer Science+Business Media New York.

Background Slow spaced eating is associated with improved satiety and gut hormone responses in normal-weight participants. This crossover study compared the effect of slow and rapid eating patterns on hunger, fullness, glucose, insulin, and the appetite-related gut hormones peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and ghrelin in overweight and obese participants with type 2 diabetes mellitus (T2DM). Methods 20 overweight and obese participants with T2DM on metformin were recruited. A test meal of 300 mL ice-cream was consumed in random order in two different sessions by each participant; meal duration was 5 or 30 min. Fullness and hunger as assessed by visual analog scales (VAS), and glucose, insulin, PYY, GLP-1, and ghrelin were measured at baseline and at 30 min intervals after meal termination for 3 h. Results Fullness VAS ratings were significantly higher at the 90’, 120’, 150’, and 180’ time points and hunger ratings were lower at 90’, 150’, and 180’ for the 30 min meal. The area under the curve (AUC) for fullness was higher after the 30 min meal than after the 5 min meal (11 943.7±541.2 vs 10 901.0±568.8 mm min, p=0.003) whereas the hunger AUC was lower (4442.9±328 vs 4966.7±347.5 mm min, p=0.012). There were no differences in glucose, insulin, PYY, GLP-1, and ghrelin responses. Conclusions Slow spaced eating increased fullness and decreased hunger ratings in overweight and obese participants with T2DM, without the improvement in gut hormone responses found in normal-weight participants. Slow spaced eating may be a useful prevention strategy, but might also help curb food intake in those already suffering from obesity and diabetes.

Ranolazine (RAN) is known to exert both anti-ischemic and antidiabetic actions. Thus, this study has explored the hypothesis that RAN would have greater effect on the recovery of cardiac function in diabetic mellitus (DM) rat hearts following myocardial infarction (MI). Myocardial infarction was induced in nondiabetic (MI, n= 14) and diabetic (streptozotocin induced; DM-MI, n= 13)Wistar rats by permanent ligation of the left coronary artery. Cardiac function was evaluated using echocardiography (left ventricular ejection fraction %) and in isolated heart preparations by measuring left ventricular developed pressure (LVDP), and the positive and negative first derivative of LVDP (+dp/dt). Ranolazine (20 mg/kg, ip once a day) was administered 24 hours after surgical procedure for 4 weeks to nondiabetic (MIRAN, n=17) and diabetic rats (DM-MIRAN, n=15). The RANimproved the recovery of function in both the nondiabetic and the diabetic postinfarcted hearts but this effect was greater and achieved statistical significance only in the diabetic group. The RAN resulted in increased levels of phosphorylated protein kinase B (Akt) and mammalian target of rapamycin (mTOR, a component of Akt signaling) in both nondiabetic and diabetic infarcted heartswithout changes in the activation of mitogen-activated protein kinases (MAPKs; p38MAPK, c-JunN-terminal kinase, and extracellular signal-regulated kinase). In addition, in diabetic hearts, RANresulted in a significant increase in the ratio of sarcoplasmic Ca2-ATPase/phospholamban (a target of Akt signaling, 2.0-fold increase) and increased levels of phosphorylated calcium-regulated adenosine monophosphate-activated protein kinase (AMPK; 2.0-fold increase). In diabetic animals, RANincreased insulin and lowered glucose levels in serum. In conclusion, the beneficial effect of RANon the recovery of cardiac function afterMIwas greater inDMrats. This response was associatedwith activation of Akt/mTOR and AMPK.These findings provide a plausible explanation for the results of the Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina (TERISA) trial,which showed a greater antianginal effect of RAN in patients with coronary artery disease and diabetes.

Thyroid hormone (TH) is critical for adapting living organisms to environmental stress. Plasma circulating tri-iodothyronine (T3) levels drop in most disease states and are associated with increased oxidative stress. In this context, T3 levels in plasma appear to be an independent determinant for the recovery of cardiac function after myocardial infarction in patients. Thyroid hormone receptor 1 (TR1) seems to be crucial in this response; TR1 accumulates to cell nucleus upon activation of stress induced growth kinase signaling. Furthermore, overexpression of nuclear TR1 in cardiomyocytes can result in pathological or physiological growth (dual action) in absence or presence of its ligand, respectively. Accordingly, inactivation of TR1 receptor prevents reactive hypertrophy after myocardial infarction and results in heart failure with increased phospholamban (PLB) expression and marked activation of p38MAPK. In line with this evidence, TH is shown to limit ischemia/reperfusion injury and convert pathologic to physiologic growth after myocardial infarction via TR1 receptor. TR1 receptor may prove to be a novel pharmacological target for cardiac repair/regeneration therapies. © 2014 Constantinos Pantos and Iordanis Mourouzis.

Thyroid hormones (TH) and receptors (TRs) may play an important role in the pathophysiology of acute cerebral ischemia. In the present study, we sought to determine whether serum triodothyronine (T3)/thyroxine (T4) and brain TRs (TRα1, TRβ1) might change after experimental stroke. Male adult Wistar rats were subjected to permanent middle cerebral artery occlusion (group P) and compared to sham-operated controls (group S). Animals were followed clinically for 14 days until brain collection for Western blot (WB) or neuropathological analysis of TRs in three different brain areas (infarcted tissue, E1; noninfarcted ipsilateral hemisphere, E2; and contralateral hemisphere, E3). Analysis of serum TH levels showed a reduction of T4 in group P (p∈=∈0.002) at days 2 to 14, while half of the animals also displayed "low T3" values (p∈=∈0.012) on day 14. This T4 reduction was inversely correlated to the clinical severity of stroke and the concomitant body weight loss (p∈