Are synchronous and metachronous bilateral breast cancers different? An immunohistochemical analysis aimed at intrinsic tumor phenotype

The biology and pathomechanism of bilateral breast cancers is not fully understood. We compared the morphological and immunohistochemical characteristics of primary tumors in patients with synchronous bilateral breast cancers and metachronous bilateral breast cancers, with special focus on intrinsic tumor phenotype. Methods: Tumor morphology and expression of 8 immunohistochemical markers were assessed in tissue microarrays containing primary breast tumor cores from 113 metachronous bilateral breast cancers and 61 synchronous bilateral breast cancers. Analyzed markers included hormone receptors (estrogen receptor, progesterone receptor), HER2, Ki67, cytokeratin 5/6, E-cadherin, vimentin and epidermal growth factor receptor. Cutoff levels are provided in the table. Results: Metachronous bilateral breast cancers tumors had lower estrogen receptor expression (p=0.047) and higher expression of cytokeratin 5/6 (p=0.017) and of vimentin (p=0.008); in multivariate analysis only vimentin retained the significance (p=0.01). Ten (13%) and 11 (26%) of metachronous bilateral breast cancers and synchronous bilateral breast cancers had luminal A phenotype, 39 (50%) and 15 (36%) were luminal B HER2-negative, 13 (17%) and 12 (28%) - luminal B HER2-positive, 3 (4%) and 2 (5%) - HER2-positive (not luminal), and 12 (16%) and 2 (5%) had triple negative phenotype (p=0.07). Conclusion: Metachronous bilateral breast cancers, compared to synchronous bilateral breast cancers, are characterized by more aggressive phenotype, expressed by lower expression of estrogen receptor and stronger expression of cytokeratin 5/6 and vimentin; this does not, however, translate into differences in the distribution of intrinsic tumor phenotypes.     

Structure and Properties of Gas-Nitrided,Precipitation-Hardened Martensitic Stainless Steel

Nanoflex stainless steel is a promising material for medical applications. However, improvement of its mechanical properties without compromising its corrosion resistance is still a challenge. In order to investigate the effect of the nitriding process on the corrosion and wear resistance of Sandvik Nanoflex^TM steel, a number of processes were carried out in a gas atmosphere with differing ammonia contents in the temperature range of 425–475 °C for 4 h. The mechanical properties and wear resistance of the layers were tested using the nanoindentation and pin-on-disc methods, respectively. In order to assess corrosion resistance, potentiodynamic tests were carried out in Ringer’s artificial body fluid and in a 3% aqueous solution of sodium chloride. The results are discussed herein with respect to the microstructural characteristics of the layers studied using light and scanning electron microscopy, X-ray diffraction phase analysis and wavelength dispersive X-ray microanalysis. The structure of nitrided layers included three zones: the subsurface zone composed of nitrides and the zones composed of metastable phases, i.e., the S phase (γN) and expanded martensite (αN) with possible precipitates of nitrides. The third zone adjacent to the steel core was enriched with carbon. The nitrided samples showed significant improvement in the wear rate while maintaining good corrosion resistance in comparison to the non-treated steel. We concluded that nitriding should be carried out at a temperature below 450 °C and in an atmosphere containing no more than approximately 50% ammonia in order to avoid nitrides precipitation.     

Assessment of insulin sensitivity during exercise training program in obese women. Comparison of simple indices with hyperinsulinemic euglycemic clamp technique

Insulin resistance is a key element of metabolic syndrome, which includes disturbances of glucose tolerance, obesity, hypertension, coronary heart disease dyslipidemia and many other defects. An important problem in scientific research is precise measurement of insulin sensitivity. The method considered "the gold standard" is glucose clamp, however, it is difficult to apply this method in large studies. Therefore, simple indices of insulin resistance are proposed. It remains unclear whether those indices are able to reflect changes occurring during insulin-sensitizing intervention. The aim of the present study was to assess the use of indirect indices for the changes in insulin sensitivity during exercise training and to compare those indices with results derived from clamp. Fourteen obese normoglycemic women participated in 12-week exercise training program, which included exercise performed on a bicycle ergometer, 5 days a week for 30 minutes. Insulin sensitivity (M/FFM value) before and after training was measured with hyperinsulinemic euglycemic clamp technique. Simple indices of insulin resistance were also assessed: fasting plasma insulin (INS), logarithm INS (log [INS]), homeostasis model assessment (HOMA), logarithm HOMA (log [HOMA]) and quantitative insulin sensitivity check index (QUICKI). Before training, all those indices were markedly related to M/FFM. After training, an increase in M/FFM was observed. None of the examined indices markedly changed after training. There was no correlations between changes of evaluated indices and in M/FFM during training, and no relationships of those parameters after training. Our study indicates that simple indices are not able to reflect changes occurring during insulin-sensitizing intervention.     

Dietary Natural Compounds and Vitamins as Potential Cofactors in Uterine Fibroids Growth and Development

An analysis of the literature generated within the past 20 year-span concerning risks of uterine fibroids (UFs) occurrence and dietary factors was carried out. A link between Vitamin D deficiency and UFs formation is strongly indicated, making it a potent compound in leiomyoma therapy. Analogs of the 25-hydroxyvitamin D3, not susceptible to degradation by tissue 24-hydroxylase, appear to be especially promising and tend to show better therapeutic results. Although research on the role of Vitamin A in the formation of fibroids is contradictory, Vitamin A-enriched diet, as well as synthetic retinoid analogues, may be preventative or limit the growth of fibroids. Unambiguous conclusions cannot be drawn regarding Vitamin E and C supplementation, except for alpha-tocopherol. Alpha-tocopherol as a phytoestrogen taking part in the modulation of estrogen receptors (ERs) involved in UF etiology, should be particularly avoided in therapy. A diet enriched in fruits and vegetables, as sources of carotenoids, polyphenols, quercetin, and indole-3-carbinol, constitutes an easily modifiable lifestyle element with beneficial results in patients with UFs. Other natural substances, such as curcumin, can reduce the oxidative stress and protect against inflammation in leiomyoma. Although the exact effect of probiotics on uterine fibroids has not yet been thoroughly evaluated at this point, the protective role of dairy products, i.e., yogurt consumption, has been indicated. Trace elements such as selenium can also contribute to antioxidative and anti-inflammatory properties of a recommended diet. In contrast, heavy metals, endocrine disrupting chemicals, cigarette smoking, and a diet low in antioxidants and fiber were, alongside genetic predispositions, associated with UFs formation.     

Synthesis and 5-HT1A/5-HT2A receptor activity of N-(4-arylpiperazin-1-yl)alkyl derivatives of 2-azaspiro([4.4]nonane and [4.5]decane-1,3-dione

Two series of N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.4]nonane (5-10) and [4.5]decane-1,3-dione (11-16) derivatives were synthesized and their serotonin 5-HT1A and 5-HT2A receptor affinities were determined. Compounds with the methylene spacer (5-7 and 11-13) exhibited low 5-HT1A/5-HT2A receptor affinity, in contrast to their ethylene analogues regarded as potent 5-HT1A ligands, especially those containing a cyclohexane moiety (14-16; Ki = 5.1, 2.7 and 4.3 nM, respectively) in the 3-position of the pyrrolidine-2,5-dione ring. Moreover, derivatives with 3-chloro substituent (10 and 14) showed distinct affinity for 5-HT2A receptors. The functional activity of compounds 10, 14, 15 and 16 was tested in vivo in the commonly used animal models. In those experiments, the tested compounds showed features of agonists of pre- and postsynaptic (14), agonists of presynaptic and antagonists of postsynaptic (10, 15), or agonists of postsynaptic (16) 5-HT1A receptors. Additionally, 10 and 16 exhibited properties of potential 5-HT2A receptor antagonists. The above results suggested a crucial role of the spacer between the amide fragment and 4-arylpiperazine moiety, as well as of the size of the cycloalkyl ring at the 3-position of pyrrolidine-2,5-dione ring in functional 5-HT1A/5-HT2A properties.     

Brainstem system of hippocampal theta induction: The role of the ventral tegmental area

This article summarizes the results of studies concerning the influence of the ventral tegmental area (VTA) on the hippocampal theta rhythm. Temporary VTA inactivation resulted in transient loss of the hippocampal theta. Permanent destruction of the VTA caused a long‐lasting depression of the power of the theta and it also had some influence on the frequency of the rhythm. Activation of glutamate (GLU) receptors or decrease of GABAergic tonus in the VTA led to enhancement of dopamine release and increased hippocampal theta power. High time and frequency cross‐correlation was detected for the theta band between the VTA and hippocampus during paradoxical sleep and active waking. Thus, the VTA may belong to the broad network involved in theta rhythm regulation. This article also presents a model of brainstem–VTA–hippocampal interactions in the induction of the hippocampal theta rhythm. The projections from the VTA which enhance theta rhythm are incorporated into the main theta generation pathway, in which the septum acts as the central node. The neuronal activity that may be responsible for the ability of the VTA to regulate theta probably derives from the structures associated with rapid eye movement (sleep) (REM) sleep or with sensorimotor activity (i.e., mainly from the pedunculopontine and laterodorsal tegmental nuclei and also from the raphe). Synapse 69:553–575, 2015 . © 2015 Wiley Periodicals, Inc.     

Cysteine protease inhibitors suppress the development of tolerance to morphine antinociception

The effects of various protease inhibitors on the development of antinociceptive tolerance to morphine were examined in mice. Intrathecal (i.t.) administration of morphine (0.01-1 nmol) produced a dose-dependent and significant antinociceptive effect in the 0.5% formalin test. When the doses of morphine (mg/kg, s.c. per injection) were given as pretreatment twice daily for two days [first day (30) and second day (60)], i.t. administration of morphine (0.1 nmol) was inactive due to antinociceptive tolerance on the third day. Tolerance to i.t. morphine was significantly suppressed by the i.t. injection of N-ethylmaleimide or Boc-Tyr-Gly-NHO-Bz, inhibitors of cysteine proteases involved in dynorphin degradation, as well as by dynorphin A, dynorphin B and (-) U-50,488, a selective kappa-opioid receptor agonist. On the other hand, amastatin, an aminopeptidase inhibitor, phosphoramidon, an endopeptidase 24.11 inhibitor, lisinopril, an angiotensin-converting enzyme inhibitor, and phenylmethanesulfonyl fluoride, a serine protease inhibitor, were inactive. These results suggest that cysteine protease inhibitors suppress the development of morphine tolerance presumably through the inhibition of dynorphin degradation.