Effects of environmental stressors on histone modifications and their relevance to carcinogenesis: a systematic review

Carcinogenesis is a complex process involving both genetic and epigenetic mechanisms. The cellular molecular epigenetic machinery, including histone modifications, is associated with changes in gene expression induced by exposure to environmental agents. In this paper, we systematically reviewed publications regarding the effects of xenobiotic stressors, mainly heavy metal exposure, on specific histone modifications. We included a total of 18 publications describing the effect of environmental stressors on histone structure modifications. We then constructed an interaction map to visualize the effect of environmental exposure(s) on specific histone modifications. In the studies we considered, a total of 20 modifications were reported, of which H3Me3K4 and H3Me2K9 were the most frequently studied histone modifications. These modifications were affected mostly by heavy metals and ethanol exposure. Based on the interaction map, we explored the molecular mechanisms mediating the histone modifications induced by environmental stressors in the respective selected studies. This resulted in the identification of seven target proteins and two families of proteins mediating the effects of environmental stressors on histone modifications. This review contributes to the understanding of environmental exposure and its possible effects on cancer risk by inducing changes in histone modifications and hence gene expression.     

Postpartum physical activity after preeclampsia

ObjectiveAfter mild and severe preeclampsia, to assess whether women meet the physical activity recommendation at 3 and 6 months postpartum, and whether demographic, obstetric and anthropometric characteristics, mental health, and health-related quality of life are associated with less physical activity than recommended.Study designProspective cohort study.Main outcome measuresSelf-reported physical activity in MET-min/week, percentage of women who fail to meet the physical activity recommendation.MethodsOf the 255 women diagnosed with preeclampsia invited to participate in this prospective cohort study, 174 (68%) provided informed consent. Analyses were restricted to 141 participants who completed the short form of the International Physical Activity Questionnaire at 3 and/or 6 months postpartum. Logistic regression analysis was used to evaluate changes in physical activity level over time, and to establish which variables were associated with failure to meet the postpartum physical activity recommendation.ResultsAt both 3 and 6 months postpartum, 38% of women failed to meet the physical activity recommendation. Failure was associated with severe preeclampsia, cesarean section, admission to the neonatal intensive care unit, low gestational age at delivery, and low birth weight (all p < 0.05).ConclusionsThere seems to be a need to stimulate physical activity in about one third of women after a pregnancy complicated by preeclampsia, particularly in case of severe preeclampsia and other adverse pregnancy outcomes. Tailored lifestyle interventions are needed for women who fail to meet the recommendation.     

Hypocalcaemia after treatment with [177Lu-DOTA0,Tyr3]octreotate

Purpose

The aim of this study was to explore the possible mechanisms involved in an observed decline in serum calcium levels in patients with a neuroendocrine tumour (NET) treated with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate (¹⁷⁷Lu-octreotate).

Methods

In 47 patients with NET who were normocalcaemic at baseline, serum calcium, albumin, creatinine, alkaline phosphatase, gamma glutamyl transpeptidase, magnesium, phosphate and 25-hydroxyvitamin D were prospectively analysed at baseline and up to 6 months after treatment. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D₃, type 1 aminoterminal propeptide of procollagen, bone-specific alkaline phosphatase, carboxyterminal crosslinking telopeptide of bone collagen, collagen type I crosslinked N-telopeptide, and creatinine and calcium in 24-h urine samples, were evaluated at baseline and at 3 and 6 months. Another 153 patients with NET were included in a retrospective study to estimate the occurrence of hypocalcaemia in a larger patient group.

Results

In the prospectively included patients, the mean serum calcium level decreased significantly after treatment (2.31?±?0.01 to 2.26?±?0.02 mmol/l, p?=?0.02). Eight patients (17 %) showed a marked decrease in serum calcium levels with a nadir of ≤2.10 mmol/l. In five patients (11 %), calcium substitution therapy was prescribed. PTH increased significantly (5.9?±?0.6 to 6.7?±?0.8 pmol/l, p?=?0.02), presumably in response to the decreasing serum calcium levels. 25-Hydroxyvitamin D remained stable after treatment. Creatinine levels increased significantly (73?±?3 to 77?±?3 μmol/l, p?=?0.01), but not enough to explain the hypocalcaemia. Phosphate levels remained unaffected. In the retrospectively analysed patients, the mean serum calcium level decreased significantly from 2.33?±?0.01 at baseline to a nadir of 2.24?±?0.01 mmol/l at 18 months after treatment (p?<?0.001). Of the 153 patients, 33 (22 %) showed a serum calcium nadir of ≤2.10 mmol/l, and 11 (7 %) received calcium substitution therapy.

Conclusion

The mean serum calcium level decreased significantly after treatment with ¹⁷⁷Lu-octreotate, resulting in mild hypocalcaemia in about 20 % of patients. We excluded several potential causes of this hypocalcaemia, so the cause remains unknown. Serum calcium levels should be monitored after peptide receptor radionuclide therapy, and calcium substitution therapy should be initiated if appropriate.     

Nephrotoxicity after PRRT with <Superscript>177</Superscript>Lu-DOTA-octreotate

Purpose

After peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with ⁹⁰Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [¹⁷⁷Lu-DOTA⁰,Tyr³]-Octreotate (¹⁷⁷Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with ⁹⁰Y-radiolabelled somatostatin analogues.

Methods

The annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed.

Results

Of the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5?–?3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (±?SD) was 108?±?5 ml/min and the estimated average annual decrease in CLR (±?SD) was 3.4?±?0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1?±?4.9 Gy.

Conclusion

Nephrotoxicity in patients treated with ¹⁷⁷Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with ⁹⁰Y-labelled somatostatin analogues, does not seem valid for PRRT with ¹⁷⁷Lu-octreotate.

     

Spin-echo and diffusion-weighted MRI in differentiation between progressive massive fibrosis and lung cancer

PURPOSEWe aimed to investigate the value of magnetic resonance imaging (MRI)-based parameters in differentiating between progressive massive fibrosis (PMF) and lung cancer.METHODSThis retrospective study included 60 male patients (mean age, 67.0±9.0 years) with a history of more than 10 years working in underground coal mines who underwent 1.5 T MRI of thorax due to a lung nodule/mass suspicious for lung cancer on computed tomography. Thirty patients had PMF, and the remaining ones had lung cancer diagnosed histopathologically. The sequences were as follows: coronal single-shot turbo spin echo (SSH-TSE), axial T1- and T2-weighted spin-echo (SE), balanced turbo field echo, T1-weighted high-resolution isotropic volume excitation, free-breathing and respiratory triggered diffusion-weighted imaging (DWI). The patients’ demographics, lesion sizes, and MRI-derived parameters were compared between the patients with PMF and lung cancer.RESULTSApparent diffusion coefficient (ADC) values of DWI and respiratory triggered DWI, signal intensities on T1-weighted SE, T2-weighted SE, and SSH-TSE imaging were found to be significantly different between the groups (p < 0.001, for all comparisons). Median ADC values of free-breathing DWI in patients with PMF and cancer were 1.25 (0.93–2.60) and 0.76 (0.53–1.00) (× 10⁻³ mm²/s), respectively. Most PMF lesions were predominantly iso- or hypointense on T1-weighted SE, T2-weighted SE, and SSH-TSE, while most malignant ones predominantly showed high signal intensity on these sequences.CONCLUSIONMRI study including SE imaging, specially T1-weighted SE imaging and ADC values of DWI can help to distinguish PMF from lung cancer.

Pneumoconiosis, defined as the accumulation of inhaled particles is relatively common in industrial areas (1). Coal worker’s pneumoconiosis, silicosis, and asbestosis are the most common forms of pneumoconiosis (2). Progressive massive fibrosis (PMF) of the lung is defined as a combination of anthracosilicotic nodules and connective tissue, and it may be seen in the chronic stage of pneumoconiosis (1).The imaging features of PMF on chest radiography and computed tomography (CT) have been well investigated (3, 4). The main characteristic finding of PMF on CT is an irregular nodule or mass with or without calcification, located mostly in the upper and middle lung zones (5). However, it is occasionally difficult to distinguish PMF from lung cancer due to a similar appearance on these imaging modalities as well as similar clinical presentation. The differentiation is especially difficult, when PMF lesion appears as a mass or mass-like lesion and grows in size during the follow-up. Additionally, lung cancer may be seen together with underlying PMF lesion. 18F-fluoro-2-deoxy-D-glucose positron emission tomography/CT (¹⁸F-FDG PET/CT) can be used in differentiation between PMF and lung cancer but it may not be helpful in some cases (6).Magnetic resonance imaging (MRI) with high conrast resolution and additional diignostic facility tools may be helpful in terms of avoiding biopsy and its possible complications in the differentiation between PMF and lung cancer (7, 8). A low signal intensity (SI) on T2-weighted MRI and a gradual increase in SI in a dynamic MRI study are the reported, characteristic MRI findings of PMF (9, 10). However, the use of several MRI sequences has not yet been fully explored for the differentiation between PMF and lung cancer. In addition to the SI changes, assessment of quantitative MRI parameters could also be helpful in the differentiation of these entities. The purpose of this study was to investigate the value of MRI-based parameters in differentiating between PMF and lung cancer.     

Architectural configuration and microstructural properties of the sacral plexus: a diffusion tensor MRI and fiber tractography study

The ability to investigate microstructural properties of the central nervous system with diffusion tensor imaging (DTI) has been shown in many studies. More recently, DTI is being applied outside the brain showing promising results, for instance, for investigating muscle tissue. In this work, we demonstrate the feasibility of diffusion tensor imaging (DTI) and fiber tractography to study the nerves of the sacral plexus in humans in vivo and to assess the architectural configuration and microstructural properties of these peripheral nerves. For this research goal we optimized the acquisition parameters of a DTI sequence and acquired data from 10 healthy adults and one 12-year patient having spina bifida and neurogenic bladder dysfunction. For the healthy volunteers, we estimated the fractional anisotropy (FA) and mean (MD), axial (AD), and radial diffusivities (RD) of the sacral plexus nerves which may serve as a baseline for future studies. We demonstrated that tractography of the sacral plexus on a 3 Tesla MR scanner is feasible, giving 3D insight in the general anatomy and organization of the nerves L4 to S3. In addition, branches to the pudendal nerve were also found in 4 volunteers. There were no significant differences in any of the estimated diffusion measures between the right and left sided nerves or between the nerves L4 to S3 on an intra-subject basis. Furthermore, clinical feasibility of DTI and tractography in a child having spina bifida and neurogenic bladder dysfunction is demonstrated. The architectural configuration of the child's sacral plexus was comparable with the healthy volunteers and no significant disrupted nerve fibers were observed. However, there are strong indications that abnormal diffusion characteristics are present at the level of the neural tube defect due to incomplete segments of the nerves that are close to the vertebrae. These findings are encouraging for using DTI as a means to investigate changes in microstructural properties of the nerves of the sacral plexus. Moreover, this new methodology may provide a new avenue to a better analysis and diagnosis of neurogenic bladder dysfunctions.     

Effect of postpartum lifestyle interventions on weight loss, smoking cessation, and prevention of smoking relapse: a systematic review

Postpartum lifestyle interventions are recommended for women after pregnancies complicated by preeclampsia, intrauterine growth restriction, and/or gestational diabetes, since they are at increased cardiovascular risk. To identify potential intervention strategies to reduce this risk, a systematic review of the literature is presented on the effectiveness of postpartum lifestyle interventions aimed at weight loss, smoking cessation, and smoking relapse prevention. The main characteristics of these postpartum lifestyle interventions are briefly described. The PubMed, Embase, Web of Science, PsychInfo, and Cinahl databases were searched for studies on the effects of postpartum lifestyle interventions on weight loss, and smoking cessation or prevention of smoking relapse, initiated for up to 1 year postpartum. No studies on the effectiveness of postpartum lifestyle interventions after the aforementioned specific pregnancy complications were found. However, 21 studies are included that describe existing postpartum lifestyle interventions, which were applied to unselected (on the basis of pregnancy complications) postpartum women. Six of 8 weight loss interventions, 4 of 5 smoking cessation interventions, and 4 of 8 smoking relapse prevention interventions were effective. Individually tailored counseling, group counseling sessions, and use of diaries or other correspondence materials were shown to be effective. Currently, postpartum lifestyle interventions tailored specifically for women who experienced the pregnancy complications are lacking. While awaiting their development, it seems reasonable to utilize existing lifestyle interventions shown to be effective in unselected postpartum women. LEARNING OBJECTIVES: After completion of this educational activity, the obstetrician/gynecologist should be better able to: counsel patients on how to apply existing postpartum lifestyle intervention strategies aimed at weight loss, smoking cessation, and smoking relapse prevention to lower future cardiovascular risk; and educate postpartum women who have experienced preeclampsia, intra-uterine growth restriction, and/or gestational diabetes about their increased cardiovascular risk later in life. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians.     

Localization and potential role of matrix metalloproteinase-1 and tissue inhibitors of metalloproteinase-1 and -2 in different phases of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) can evolve in prematurely born infants who require mechanical ventilation because of hyaline membrane disease (HMD). The development of BPD can be divided in an acute, a regenerative, a transitional, and a chronic phase. During these different phases, extensive remodeling of the lung parenchyma with re-epithelialization of the alveoli and formation of fibrosis occurs. Matrix metalloproteinase-1 (MMP-1) is an enzyme that is involved in re-epithelialization processes, and dysregulation of MMP-1 activity contributes to fibrosis. Localization of MMP-1 and its inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, were investigated in lung tissue obtained from infants who died during different phases of BPD development. In all studied cases (n = 50) type-II pneumocytes were found to be immunoreactive for MMP-1, TIMP-1, and TIMP-2. During the acute and regenerative phase of BPD, type-II pneumocytes re-epithelialize the injured alveoli. This may suggest that MMP-1 and its inhibitors, expressed by type-II pneumocytes, play a role in the re-epithelialization process after acute lung injury. Although MMP-1 staining intensity remained constant in type-II pneumocytes during BPD development, TIMP-1 increased during the chronic fibrotic phase. This relative elevation of TIMP-1 compared with MMP-1 is indicative for reduced collagenolytic activity by type-II pneumocytes in chronic BPD and may contribute to fibrosis. Fibrotic foci in chronic BPD contained fibroblasts immunoreactive for MMP-1 and TIMP-1 and -2. This may indicate that decreased collagen turnover by fibroblasts contributes to fibrosis in BPD development.