Introduction: Epigenetic mechanisms of gene regulatory control play fundamental roles in developmental morphogenesis, and, as more recently appreciated, are heavily implicated in the onset and progression of neoplastic disease, including cancer. Many epigenetic mechanisms are therapeutically targetable, providing additional incentive for understanding of their contribution to cancer and other types of neoplasia.
Areas covered: The Jumonji-domain histone demethylase (JHDM) family exemplifies many of the above traits. This review summarizes the current state of knowledge of the functions and pharmacologic targeting of JHDMs in cancer and other neoplastic processes, with an emphasis on diseases affecting the pediatric population.
Expert opinion: To date, the JHDM family has largely been studied in the context of normal development and adult cancers. In contrast, comparatively few studies have addressed JHDM biology in cancer and other neoplastic diseases of childhood, especially solid (non-hematopoietic) neoplasms. Encouragingly, the few available examples support important roles for JHDMs in pediatric neoplasia, as well as potential roles for JHDM pharmacologic inhibition in disease management. Further investigations of JHDMs in cancer and other types of neoplasia of childhood can be expected to both enlighten disease biology and inform new approaches to improve disease outcomes. 相似文献
Aim. This article reports a study to evaluate the efficacy of a self‐help manual in reducing psychological distress in individuals with moderate depression. Background. The prevalence of depression in Thailand is increasing markedly (e.g. from 56–197 per 100,000 population between 1997–2007). Design. We conducted a randomized controlled trial with 54 outpatients with depression in Chiang Mai Province in Thailand. Method. Participants were assigned randomly to an intervention or control group. The intervention group participants were given a self‐help manual in addition to standard care and treatment while the control group received standard care and treatment. Psychological distress was measured with the Kessler Psychological Distress Scale. Data were collected between October 2007–April 2008. Results. The findings showed statistically significant differences between both groups in their levels of psychological distress (e.g. tiredness, hopelessness, restlessness). At post‐test, the distress scores of the intervention group were lower than those in the control group. Between post‐test and 1‐month follow‐up, distress scores continued to decrease steadily in the intervention group but only decreased slightly in the control group. Conclusion. The findings affirm the benefits of bibliotherapy or self‐help therapy in book form in helping to reduce psychological distress in people with moderate depression. The approach is easy to use and can be incorporated as an adjunct to standard care and treatment. Bibliotherapy can be used by community mental health nurses and other clinicians to reduce psychological distress and promote recovery in people with moderate depression. 相似文献
Granulocyte colony-stimulating factor (G-CSF) induces rapid phosphorylation of JAK kinases as well as activation of the p21ras route through interaction with its specific receptor (G-CSF-R). The cytoplasmic membrane-proximal region of G-CSF-R (amino acids 631 to 684) is necessary for proliferation induction and activation of JAK2. In contrast, activation of Shc and Syp, signaling molecules implicated in the p21ras signaling route, depends on the phosphorylation of tyrosine residues located in the membrane-distal region (amino acids 685 to 813) of G-CSF-R. We investigated whether G-CSF-induced activation of signaling complexes of the p21ras route depends on the function of the membrane-proximal cytoplasmic region of G-CSF-R. A G- CSF-R mutant was constructed in which tryptophan 650 was replaced by arginine and expressed in BAF3 cells (BAF/W650R). In contrast to BAF3 cell transfectants expressing wild-type G-CSF-R, BAF/W650-R cells did not proliferate and did not show activation of JAK2, STAT1, or STAT3 in response to G-CSF. Immunoprecipitations with anti-Shc and anti-Grb2 antisera showed that mutant W650R also failed to activate Syp and Shc. These data indicate that the membrane-proximal cytoplasmic domain of G- CSF-R is not only crucial for proliferative signaling and activation of JAK2 and STATs, but is also required for activation of the p21ras route, which occurs via the membrane-distal region of G-CSF-R. 相似文献
The in vivo effects of GnRH-associated peptide (GAP) on PRL, LH, and FSH release have been examined by injecting this peptide iv into the following types of conscious rats: 1) ovariectomized steroid-blocked females, 2) ether-stressed males, and 3) lactating females. GAP (2.4 X 10(-10) and 2.4 X 10(-9) mol) suppressed plasma PRL release but did not affect the levels of plasma LH and FSH in ovariectomized steroid-blocked rats. Furthermore, with 1-min etherization, GAP (1.6 X 10(-10) and 8.0 X 10(-10) mol) reduced the stress-induced rise of plasma PRL, but had no effect on the stress-induced decline of plasma gonadotropin levels in male rats. A single iv injection of GAP (8.0 X 10(-10) mol) into lactating rats before the onset of nursing did not block the elevation of plasma PRL induced by suckling. However, a second injection of GAP (1.6 X 10(-10) mol) at 30 min after the onset of suckling partially lowered plasma PRL levels 15 min later. By contrast, plasma FSH levels were significantly elevated by the second injection of GAP, and plasma LH also rose after iv administration of GAP in the nursing rats. These results indicate that the activity of GAP to stimulate FSH and LH release is limited, since GAP stimulated the release of FSH and LH only when plasma gonadotropin levels were extremely low. However, the in vivo evidence that GAP inhibited PRL release in a variety of conditions reinforces the possibility that GAP could be the peptidic PRL-inhibiting factor. 相似文献
Previous research indicates that norepinephrine and dopamine stimulate release of luteinizing hormone (LH)-releasing hormone (LHRH), which then reaches the adenohypophysis via the hypophyseal portal vessels to release LH. Norepinephrine exerts its effect via alpha 1-adrenergic receptors, which stimulate the release of nitric oxide (NO) from nitricoxidergic (NOergic) neurons in the medial basal hypothalamus (MBH). The NO activates guanylate cyclase and cyclooxygenase, thereby inducing release of LHRH into the hypophyseal portal vessels. We tested the hypothesis that these two catecholamines modulate NO release by local feedback. MBH explants were incubated in the presence of sodium nitroprusside (NP), a releaser of NO, and the effect on release of catecholamines was determined. NP inhibited release of norepinephrine. Basal release was increased by incubation of the tissue with the NO scavenger hemoglobin (20 micrograms/ml). Hemoglobin also blocked the inhibitory effect of NP. In the presence of high-potassium (40 mM) medium to depolarize cell membranes, norepinephrine release was increased by a factor of 3, and this was significantly inhibited by NP. Hemoglobin again produced a further increase in norepinephrine release and also blocked the action of NP. When constitutive NO synthase was inhibited by the competitive inhibitor NG-monomethyl-L-arginine (NMMA) at 300 microM, basal release of norepinephrine was increased, as was potassium-evoked release, and this was associated in the latter instance with a decrease in tissue concentration, presumably because synthesis did not keep up with the increased release in the presence of NMMA. The results were very similar with dopamine, except that reduction of potassium-evoked dopamine release by NP was not significant. However, the increase following incubation with hemoglobin was significant, and hemoglobin, when incubated with NP, caused a significant elevation in dopamine release above that with NP alone. In this case, NP increased tissue concentration of dopamine along with inhibiting release, suggesting that synthesis continued, thereby raising the tissue concentration in the face of diminished release. When the tissue was incubated with NP plus hemoglobin, which caused an increase in release above that obtained with NP alone, the tissue concentration decreased significantly compared with that in the absence of hemoglobin, indicating that, with increased release, release exceeded synthesis, causing a fall in tissue concentration. When NO synthase was blocked by NMMA, the release of dopamine, under either basal or potassium-evoked conditions, was increased. Again, in the latter instance the tissue concentration declined significantly, presumably because synthesis did not match release. Therefore, the results were very similar with both catecholamines and indicate that NO acts to suppress release of both amines. Since both catecholamines activate the release of LHRH, the inhibition of their release by NO serves as an ultra-short-loop negative feedback by which NO inhibits the release of the catecholamines, thereby reducing the activation of the NOergic neurons and decreasing the release of LHRH. This may be an important means for terminating the pulses of release of LHRH, which generate the pulsatile release of LH that stimulates gonadal function in both male and female mammals. 相似文献
BACKGROUND AND AIM: Dietary and lifestyle characteristics may differ for drinkers of specific alcoholic beverages and nondrinkers which would have important implications for studies of alcohol and disease. Our aim in this study was to describe differences in dietary and lifestyle characteristics associated with alcoholic beverage preference in a population-based sample of healthy study participants. METHODS AND RESULTS: Data were collected as part of a series of case-control studies of alcohol use, myocardial infarction, and lung, breast and prostate cancer in western New York from 1846 men and 1910 women aged 35 to 79, randomly selected from the general population of Erie and Niagara Counties. Beverage preference was defined for noncurrent vs current drinkers, and drinkers of beer, wine, liquor, and mixed beverages. Generalized linear models for continuous variables and Cochran-Mantel-Haenszel statistics for categorical variables were computed for the entire sample and stratified by gender. Participant characteristics differed by alcoholic beverage preference and drinking status. In general, wine drinkers had higher education and household incomes, lower prevalence of current smoking, higher intakes of dietary fiber, potassium, vitamin E, and total carotenoids, lower total fat intakes and higher amounts of fruits, vegetables, and grain products than consumers of other beverages. Conversely, beer and liquor drinkers had somewhat lower education and household incomes, higher rates of current smoking, higher energy and total fat intakes and consumed lower amounts of fruits, vegetables, and grain products. Finally, current nondrinkers were more likely to be older, less educated, have lower household incomes, and consume diets less consistent with dietary guidelines than current drinkers. CONCLUSIONS: These results suggest that usual beverage preference may encompass other health-related behaviors and underline the importance of accurate exposure measurement and use of statistical methods to accommodate these interrelationships. 相似文献
Interleukin 1 alpha (IL-1 alpha), a powerful endogenous pyrogen released from monocytes and macrophages by bacterial endotoxin, stimulates corticotropin, prolactin, and somatotropin release and inhibits thyrotropin release by hypothalamic action. We injected recombinant human IL-1 alpha into the third cerebral ventricle, to study its effect on the pulsatile release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in conscious, freely moving, ovariectomized rats. Intraventricular injection of 0.25 pmol of IL-1 alpha caused an almost immediate reduction of plasma LH concentration; this decrease was statistically significant 20 min after injection and occurred through a highly significant reduction in the number of LH pulses, with no effect on pulse amplitude. In contrast, there was no change in pulse frequency but a small significant elevation in amplitude of FSH pulses. Intraventricular injection of the diluent had no effect on gonadotropin release. The results provide further evidence for separate hypothalamic control mechanisms for FSH and LH release. To determine the mechanism of the suppression of LH release, mediobasal hypothalamic fragments were incubated in vitro with IL-1 alpha (10 pM) and the release of LH-releasing hormone (LHRH) and prostaglandin E2 into the medium was measured by RIA in the presence or absence of norepinephrine (50 microM). IL-1 alpha reduced basal LHRH release and blocked LHRH release induced by norepinephrine. It had no effect on the basal release of prostaglandin E2; however, it completely inhibited the release of PGE2 evoked by norepinephrine. To evaluate the possibility that IL-1 alpha might also interfere with the epoxygenase pathway of arachidonic acid metabolism, epoxyeicosatrienoic acids were also measured. IL-1 alpha had no effect on the content of epoxyeicosatrienoic acids in the hypothalamic fragments as measured by gas chromatography and mass spectrometry. In conclusion, IL-1 alpha suppresses LH but not FSH release by an almost complete cessation of pulsatile release of LH in the castrated rat. The mechanism of this effect appears to be by inhibition of prostaglandin E2-mediated release of LHRH. 相似文献