Publications

Adiponectin, an adipocyte-secreted hormone, is closely and inversely associated with insulin resistance and was recently found to be inversely and independently associated with endometrial cancer. Because insulin resistance in the setting of obesity has also been associated with the development of breast cancer, we have hypothesized that decreased adiponectin levels might underlie the association between breast cancer and obesity/insulin resistance. We evaluated the association of adiponectin with the occurrence of breast cancer in a case-control study comprising 174 women with newly diagnosed, histologically confirmed breast cancer and 167 controls. We found an inverse, fairly strong, and statistically significant association of serum adiponectin with breast cancer (odds ratio, 0.84; 95% confidence interval, 0.71-0.99). Importantly, despite a fairly robust inverse association of adiponectin with breast cancer risk among postmenopausal women (odds ratio, 0.82; 95% confidence interval, 0.67-1.00), no such significant association between adiponectin and breast cancer was found among premenopausal women. The observed associations were independent of possible effects of major components of the IGF system, leptin, body mass index, sociodemographic variables, and known risk factors for breast cancer. Future studies are needed to prove causality and provide further insights into both the mechanisms underlying the actions of this hormone and its potential role in breast cancer.

To determine whether petrosal sinus sampling is useful to distinguish patients with mild or intermittent Cushing's disease from normal subjects and individuals with pseudo-Cushing states, we performed bilateral inferior petrosal sinus sampling for ACTH before and after the administration of CRH in 7 eucortisolemic volunteers, 8 hypercortisolemic patients with pseudo-Cushing states, and 40 patients with ACTH-dependent Cushing's disease whose urinary free cortisol excretion was within the range found in patients with, pseudo-Cushing states (< 1000 nmol/day; < 360 micrograms/day). The ACTH level, the ratio of the inferior petrosal sinus ACTH to the peripheral venous ACTH concentration (the IPS:P ratio), and the greater ratio of right to left or left to right petrosal sinuses (the R:L ratio) were compared in patients with and without Cushing's disease. Maximal petrosal ACTH values were significantly elevated in patients with Cushing's disease compared to patients with pseudo-Cushing states before CRH administration (P < 0.001), but not after CRH. Maximal petrosal plasma ACTH values after the administration of CRH as high as 808 pmol/L (3670 pg/mL) and 469 pmol/L (2130 pg/mL) were found in patients with pseudo-Cushing states and in normal volunteers, respectively, whereas maximal petrosal ACTH levels as low as 10 pmol/L (46 pg/mL) were observed in patients with surgically proven Cushing's disease. Maximal and minimal IPS:P ratios were significantly greater in patients with Cushing's disease than in subjects without Cushing's disease before, but not after, CRH treatment. R:L ratios did not differ among groups either before or after CRH. All of the subjects without Cushing's disease showed large R:L gradients, consistent with the notion of one dominant petrosal sinus containing a greater percentage of pituitary effluent. The ACTH concentrations, IPS:P ratios, and R:L ratios exhibited great overlap between those with and without Cushing's disease, which resulted in a diagnostic accuracy of 81% at best for the diagnosis of Cushing's disease. We conclude that petrosal sinus sampling is of limited usefulness in distinguishing either normal individuals or patients with pseudo-Cushing states from those with mild Cushing's disease. This limited usefulness must be recognized when interpreting the results of petrosal sinus sampling in patients with mild or intermittent hypercortisolism who may have a pseudo-Cushing state. Because of these limitations, petrosal sinus sampling should be reserved for patients with clear clinical and biochemical evidence of Cushing's syndrome.

Abstract Background This large cross‐sectional, multi‐centre study evaluated the association of body composition measurements by a novel dual frequency bioimpedance device (BIA‐ACC) with chronic stress/inflammation biomarkers and the presence of medically unexplained symptoms (MUS). Materials and methods Participants were adult Caucasians of both sexes and included 10 416 lean subjects with no MUS (Group A), 58 710 lean subjects with MUS (Group B) and 30 445 overweight/obese subjects with no MUS and excessive fat mass (FM) (Group C). Results Total body extracellular water (ECW) was higher, while intracellular water (ICW) was lower in Group B than both other groups ( P &lt; 0·01). Group A had significantly lower FM and higher skeletal mass (SK) and phase angle (PA) than Group B and lower circulating high sensitivity (hs) CRP levels than both other groups. hsCRP was higher in Group C than Group A though ( P &lt; 0·01). Salivary cortisol in Group B was lower in the morning and higher in the evening than both other groups ( P &lt; 0·001), indicating circadian rhythm obliteration or reversal in this group. ECW correlated positively with serum hsCRP and 8 p.m. salivary cortisol, but negatively with 8 a.m. salivary cortisol, while PA correlated positively with 8 a.m. and negatively with 8 p.m. salivary cortisol and serum hsCRP. Both 8 a.m. and 8 p.m. salivary cortisol and serum hsCRP were associated with the presence of MUS and BIA‐ACC measurements, including ECW, ICW, FM, SK and PA. Conclusions MUS is an index of chronic stress and inflammation and BIA‐ACC may provide a useful, bloodless and rapid tool in the clinical setting, distinguishing patients with chronic stress/inflammation from healthy subjects and monitoring their response to treatment.

Stress is known to precipitate or worsen a number of disorders, such as migraines, in which mast cells are suspected of being involved by releasing vasoactive, nociceptive, and proinflammatory mediators. However, no functional association has been demonstrated yet between a migraine trigger and brain mast cell activation. Nontraumatic immobilization (restrain) stress has been shown to stimulate the hypothalamic-pituitary-adrenal axis and to cause redistribution of immune cells. Here, restrain stress caused degranulation in 70% of rat dura mast cells within 30 min, as shown both by light and electron microscopy. These morphologic findings were accompanied by cerebrospinal fluid elevation of rat mast cell protease I, but not II, indicating secretion from connective tissue type mast cells. Mast cell activation due to stress was abolished in animals that had been treated neonatally with capsaicin, indicating that neuropeptides in sensory nerve endings are involved in this response. Complete inhibition was also achieved by pretreating the animals ip with polyclonal antiserum to CRH. Mast cells in the dura were localized close to nerve processes containing substance P, but no CRH-positive fibers were identified even though these were found close to mast cells in the median eminence. This is the first time that stress is shown to activate intracranial mast cells; apparently through the sequential action of CRH and sensory neuropeptides. These findings may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders such as migraines, which are induced or exacerbated by stress.

Cancer treatment aims to exploit properties that define malignant cells. In recent years, it has become apparent that malignant cells often survive cancer treatment and ensuing cell stress by switching on auxiliary turnover pathways, changing cellular metabolism and, concomitantly, the gene expression profile. The changed profile impacts the material exchange of cancer cells with affected tissues. Herein, we show that pathways of proteostasis and energy generation regulate common transcription factors. Namely, when one pathway of intracellular turnover is blocked, it triggers alternative turnover mechanisms, which induce transcription factor proteins that control expression of cytokines and regulators of apoptosis, cell division, differentiation, metabolism, and response to hormones. We focus on several alternative turnover mechanisms that can be blocked by drugs already used in clinical practice for the treatment of other non-cancer related diseases. We also discuss paradigms on the challenges posed by cancer cell adaptation mechanisms.

Obesity, a chronic, preventable disease, has significant comorbidities that are associated with a great human and financial cost for society. The aim of the present work is to reconstruct the interactomes of non-hereditary obesity to highlight recent advances of its pathogenesis, and discover potential therapeutic targets. Obesity and biological-clock-related genes and/or gene products were extracted from the biomedical literature databases PubMed, GeneCards and OMIM. Their interactions were investigated using STRING v11.0 (a database of known and predicted physical and indirect associations among genes/proteins), and a high confidence interaction score of &gt;0.7 was set. We also applied virtual screening to discover natural compounds targeting obesity- and circadian-clock-associated proteins. Two updated and comprehensive interactomes, the (a) stress- and (b) inflammation-induced obesidomes involving 85 and 93 gene/gene products of known and/or predicted interactions with an average node degree of 9.41 and 10.8, respectively, were produced. Moreover, 15 of these were common between the two non-hereditary entities, namely, ADIPOQ, ADRB2/3, CCK, CRH, CXCL8, FOS, GCG, GNRH1, IGF1, INS, LEP, MC4R, NPY and POMC, while phelligridin E, a natural product, may function as a potent FOX1-DBD interaction blocker. Molecular networks may contribute to the understanding of the integrated regulation of energy balance/obesity pathogenesis and may associate chronopharmacology schemes with natural products.

Practitioners in cosmetic and aesthetic treatment practices are likely to unknowingly work with patients with Body Dysmorphic Disorder (BDD). Screening questionnaires to identify the disorder in Greece are lacking. The purpose of this study was to validate a Greek version of the Cosmetic Procedure Screening (COPS) questionnaire, a self-report measure of how the respondents feel about their appearance, before an aesthetic intervention. The COPS was translated into Greek and was completed by 216 adult females from several areas of Attica (four private beauty centers, three dermatology clinics, five plastic surgery clinics, and Thriasio General Hospital of Elefsina) who pursued a cosmetic procedure. Participants also completed the Perceived Stress Scale (PSS-14). The Greek version of the COPS questionnaire demonstrated high internal consistency (Cronbach's α of 0.856) with corrected item’s total range 0.468 to 0.687. Two of the factors explained 58.98% of total variance. Twenty (9.26%) women had a possible diagnosis of BDD (80% were unmarried, 95% had no children, 80% had university education). An increase in perceived stress levels was associated with an increase in the likelihood of being diagnosed with BDD (Pearson’s r=0.726). The Greek version of the COPS questionnaire is a valid instrument that can be used by professionals to screen adult women for BDD.