The role of histone demethylases in cancer therapy

Reversible histone methylation has emerged in the last few years as an important mechanism of epigenetic regulation. Histone methyltransferases and demethylases have been identified as contributing factors in the development of several diseases, especially cancer. Therefore, they have been postulated to be new drug targets with high therapeutic potential. Here, we review histone demethylases with a special focus on their potential role in oncology drug discovery. We present an overview over the different classes of enzymes, their biochemistry, selected data on their role in physiology and already available inhibitors.     

Promoting positive well‐being in employed mothers: A pilot study

In this quasi‐experimental pilot study, women who were returning to work within 6 months after the birth of a first baby were assigned to participate in a control group (n = 13) or a six‐session small group intervention (n = 18). The content of the group intervention was developed based on a stress and coping framework (Lazarus & Folkman, 1984).”; The experimental and control groups were surveyed at 2 months after their return to employment and on their baby's first birthday on measures of well‐being in marriage, work, and parenting. Repeated measures analysis of covariance was used to examine differences over time between the experimental and control group with length of maternity leave and number of hours worked as covariates. Participants in the intervention reported increasing levels of marital satisfaction over time, whereas the control group experienced a decline in marital satisfaction over time (p = .04). Implications for practice and research are presented.     

Call for Papers/Directions for A.E.H. Contributors

The effects of industrial noise on resting heart rate and blood pressure were studied in 3 105 blue-collar workers. Heart rate and blood pressure were measured in different workers at various times during the workday. After controlling for several possible confounders, we found that resting heart rate in females was associated positively with noise intensity (p = .036) and with time of day (p = .054). In males, resting heart rate was associated with noise intensity; however, such association was related to time of day (p = .046). No such associations were found for blood pressure in either sex. We plotted the mean resting heart rate by time of day for workers exposed to high [≥ 80 db(A)] and low noise, and no difference was evident with respect to morning heart rate in either sex. After 4 h of noise exposure for males (and less time for females), individuals who were exposed to high noise had higher heart rates; however, in females this was not observed at the end of the workday. Thus, recurrent daily exposure to high noise at work has an acute, though not residual, effect on resting heart rate.     

美学区软组织水平和骨水平植体周围骨丧失和牙龈生物型的分析

目的: 植体周围一定程度的骨丧失可能会给牙种植治疗的美观效果带来不利影响。这种情况可能更容易影响软组织水平（Tissue-Level, TL）设计,因此,当强调形态的美观自然性时,骨组织水平（Bone-Level, BL）设计可能更有优势。除了植体的设计,牙龈生物型也被认为是维持牙槽骨稳定的重要因素。本研究拟针对具有不同牙龈生物型的患者,在其美学区域行软组织水平和骨水平牙种植治疗,探究其骨丧失的程度。材料和方法: 对41位患者行20个TL和22个BL种植治疗,术后即刻、术后随访对这42个位点行口内影像学检查;运用计算机技术行牙槽骨高度测量分析;运用TRAN法鉴定患者的牙龈生物型。结果: TL组平均4.9年的存留期里,厚龈型的12颗植体周围平均骨丧失0.21mm（SD：0.43mm）;薄龈型的8颗植体周围平均骨丧失0.05mm（SD：0.47mm;P=0.31）。BL组平均1.9年的存留期里,厚龈型的14颗植体周围骨丧失为-0.03mm（SD：0.38mm）,薄龈型的8颗植体周围骨丧失为+0.09mm（SD：0.32mm;P=0.84）。结论: 分析得到的数据发现,牙槽骨高度的变化与种植设计或是牙龈生物型并无直接相关性。然而在选择种植设计之前,评价软组织的厚度是有利的,其中BL种植设计更能获得自然的外形。为实现以上评价目的,TRAN法是最快速、简易的方法。     

Calcium lability of cytoplasmic microtubules and its modulation by microtubule-associated proteins

Detergent-extracted BSC-1 monkey cells have been used as a model system to study the Ca²⁺ sensitivity of in vivo polymerized microtubules under in vitro conditions. The effects of various experimental treatments were observed by immunofluorescence microscopy. Whereas microtubules are completely stable at Ca²⁺ concentrations below 1 μM, Ca²⁺ at greater than 1-4 μM induces microtubule disassembly that begins in the cell periphery and proceeds towards the cell center. At concentrations of up to 500 μM, both the pattern and time course of disassembly are not markedly altered, suggesting that, within this concentration range, Ca²⁺ effects are catalytic rather than stoichiometric. Higher (millimolar) Ca²⁺ concentration results in rapid destruction of microtubules. Of other divalent cations, only Sr²⁺ has a slight depolymerizing effect, whereas millimolar Ba²⁺, Mg²⁺, or Mn²⁺ is ineffective. Disassembly induced by micromolar Ca²⁺ is inhibited by pharmacological agents known to bind to calmodulin and inhibit its function, suggesting that calmodulin mediates Ca²⁺ effects. Both the addition of exogenous brain microtubule-associated proteins (MAPs) after lysis and the retention of endogenous cellular MAPs normally extracted during the lysis step stabilize microtubules against the depolymerizing effect of micromolar Ca²⁺. The results indicate that, in this model system, microtubules are sensitive to physiological Ca²⁺ concentrations and that this sensitivity may be conferred by calmodulin associated with the microtubules. MAPs appear to have a modulating effect on microtubular Ca²⁺ sensitivity and thus may function as a discriminating factor in cellular functions performed by calmodulin. It is hypothesized that Ca²⁺-stimulated microtubule disassembly depends on the relative amount of MAPs.     

Effect of Pluronic L-81 on intestinal lipoprotein secretion in the rat

The hydrophobic nonionic detergent Pluronic L-81 has been shown to lower plasma very-low-and low-density lipoprotein cholesterol, thus preventing diet-induced atherogenesis. The major effect of this agent is a pronounced interference with intestinal lipid metabolism. For studying mesenteric lymph lipoproteins during detergent exposure, a combined micromorphological and biochemical assessment of mucosa and lymph during steady-state lipid absorption was performed. Pluronic L-81 was infused intraduodenally at a constant rate in combination with mixed micellar solutions or saline in mesenteric lymph fistula rats. Pluronic L-81 impairs transepithelial lipid flux during fat absorption, trapping export lipids within the enterocytes and leading to a cytosolic and endoplasmic reticulum lipid accumulation sparing the Golgi region. Pluronic L-81 markedly (P<0.001) reduces mesenteric triglyceride, phospholipid, and total cholesterol secretion almost exclusively by a reduction of chylomicron formation. Chylomicron and very-low-density lipoprotein lipid composition was only insignificantly altered, except for somewhat higher phospholipid/triglyceride ratios. The chylomicron apoprotein pattern was almost unaffected. Thus, chylomicron formation decreased dramatically without major compositional alterations. The reduction of lipid and apoprotein secretion without particle augmentation is not in favour of a selective interference of Pluronic L-81 with intestinal apoprotein B-48 secretion.Parts of this work have been presented at the Annual Meeting of the American Gastroenterological Association, Washington, DC, May 1989, and published in abstract form (1).     

Lymphocytes proliferate in blood and lymph nodes following interleukin-2 therapy in addition to highly active antiretroviral therapy.

BACKGROUND: Substantial redistribution of lymphocytes occurs upon the initiation of highly active antiretroviral therapy (HAART) and immune-based HIV therapies. OBJECTIVE: To evaluate the relative contribution of apoptosis and proliferation to changes in lymphocyte populations in peripheral blood and lymph node resulting from interleukin-2 (IL-2) therapy in patients receiving stable HAART. METHODS: Lymphocyte apoptosis was analyzed on various subtypes using fluorescence activated cell sorting with an annexin-V antibody in peripheral blood and by the TUNEL (terminal uridine nucleotide end labelling) method in corresponding lymph node sections. Lymphocyte proliferation was evaluated using an antibody against the cell cycle-associated marker Ki-67 (MIB-1) in peripheral blood and lymph nodes. RESULTS: A transient increase in apoptosis was seen in peripheral blood and lymph nodes during a cycle of subcutaneous IL-2. A pronounced proliferative effect of IL-2 (from 6.4% of total lymphocytes in patients only treated with HAART to 23.4% in those treated with HAART + IL-2) was detected in peripheral blood, affecting the CD4, CD8 and CD16/56 subsets to a similar extent. Remarkably, the proliferative effect also occurred in lymphoid tissues. While the lymph node structure gradually disintegrated over 24 months in some individuals, the amount of proliferating lymphocytes, including CD4 cells, B cells and follicular dendritic cells, greatly increased upon IL-2, while HIV RNA load in lymph nodes remained unaffected. CONCLUSION: These results show that IL-2 leads to lymphocyte proliferation in peripheral blood and lymph nodes without an impact on viral load in lymphoid tissue. These results have important implications for attempts to reconstitute the immune system in HIV disease.