Significance of histone methyltransferase SETDB1 expression in colon adenocarcinoma

This study investigated the clinical implications of SETDB1 (also known as KMT1E) in human colon adenocarcinoma. Expression levels of SETDB1 proteins were analyzed by immunohistochemistry staining, and tissue microarrays were used to examine expression profiles in human patients. Our results revealed that SETDB1 protein expression was significantly higher in tumor tissue than in normal tissue for the breast, colon, liver, and lung (p < 0.05). Moreover, an analysis with SurvExpress software suggested that elevated expression of SETDB1 mRNA was significantly associated with the overall survival of colon adenocarcinoma patients (p < 0.05); and additional analysis involving 90 paired samples of colon adenocarcinoma tissue and normal tissue revealed that SETDB1 protein expression was 82% higher in cancerous cells (p < 0.001). High SETDB1 expression was also found to be significantly correlated with histological grade (p = 0.005), TNM stage (p = 0.003), T‐class/primary tumor (p = 0.001), and N‐class/regional lymph nodes (p = 0.017); and Kaplan–Meier survival curves indicated that SETDB1 protein expression was significantly associated with poor survival. Finally, univariate analysis demonstrated that SETDB1 protein expression was related to TNM stage (p = 0.004) and SETDB1 score (p = 0.001), whereas multivariate analysis showed that the influence of SETDB1 on overall colon adenocarcinoma survival was independent from other risk factors. Taken together, our results suggest that the SETDB1 protein could serve as a clinical prognostic indicator for colon adenocarcinoma.     

Evidence that the retroviral DNA integration process triggers an ATR-dependent DNA damage response

Caffeine is an efficient inhibitor of cellular DNA repair, likely through its effects on ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) kinases. Here, we show that caffeine treatment causes a dose-dependent reduction in the total amount of HIV-1 and avian sarcoma virus retroviral vector DNA that is joined to host DNA in the population of infected cells and also in the number of transduced cells. These changes were observed at caffeine concentrations that had little or no effect on overall cell growth, synthesis, and nuclear import of the viral DNA, or the activities of the viral integrase in vitro. Substantial reductions in the amount of host-viral-joined DNA in the infected population, and in the number of transductants, were also observed in the presence of a dominant-negative form of the ATR protein, ATRkd. After infection, a significant fraction of these cells undergoes cell death. In contrast, retroviral transduction is not impeded in ATM-deficient cells, and addition of caffeine leads to the same reduction that was observed in ATM-proficient cells. These results suggest that activity of the ATR kinase, but not the ATM kinase, is required for successful completion of the viral DNA integration process and/or survival of transduced cells. Components of the cellular DNA damage repair response may represent potential targets for antiretroviral drug development.     

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

Background:

Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT).

Methods:

Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect.

Results:

After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different.

Conclusions:

We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT.     

Disproportionate Reduction of Serotonin Transporter May Predict the Response and Adherence to Antidepressants in Patients with Major Depressive Disorder: A Positron Emission Tomography Study with 4-[18F]-ADAM

Background:

Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants.

Methods:

We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[¹⁸F]fluorophenylthio)benzylamine (4-[¹⁸F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more.

Results:

Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders.

Conclusions:

The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD.     

Impacts of early insulin treatment vs glimepiride in diabetic patients with background metformin therapy: A nationwide retrospective cohort study

Type 2 diabetes mellitus (T2DM) is a progressive disease. After metformin failure, the addition of insulin or sulfonylureas might increase the risk of hypoglycemia and cardiovascular (CV) morbidity. Here, the risk of all-cause mortality was compared between early insulin treatment and glimepiride use in T2DM patients with background metformin therapy.We conducted a 9-year retrospective cohort study from the population-based National Health Insurance Research Database in Taiwan. A total of 2054 patients with T2DM under insulin or glimepiride treatment were enrolled during 2004 to 2012. Overall event rates of all-cause mortality were compared between 1027 insulin users and 1027 matched glimepiride users.After the propensity score matching, the mortality rates were 72.5 and 4.42 per 1000 person-years for insulin users and glimepiride users. The adjusted hazard ratio of mortality was 14.47 (95% CI: 8.64–24.24; P value <.001) as insulin compared with glimepiride users. The insulin users had significantly higher risk of CV death (adjusted hazard ratio 7.95, 95% CI 1.65–38.3, P = .01) and noncardiovascular death (adjusted hazard ratio 14.9, 95% CI 8.4–26.3, P < .001).The nationwide study demonstrated that metformin plus insulin therapy was associated with higher risk of all-cause mortality.     

Shortened Telomere Length in Sputum Cells of Bronchiectasis Patients is Associated with Dysfunctional Inflammatory Pathways

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta?=????1.167, P_Adj?=?2.75?×?10^?4). We further performed global gene expression analysis and identified genes involved in processes such as NLRP3 inflammasome activation and regulation of adaptive immune cells when bronchiectasis sputum telomere length was shortened. Our study provides insights on dysfunctions related to shortened telomere length in sputum immune cells of bronchiectasis patients.

     

Basal sympathetic predominance in periodic limb movements in sleep with obstructive sleep apnea

Because the impact of periodic limb movements in sleep (PLMS) is controversial, no consensus has been reached on the therapeutic strategy for PLMS in obstructive sleep apnea (OSA). To verify the hypothesis that PLMS is related to a negative impact on the cardiovascular system in OSA patients, this study investigated the basal autonomic regulation by heart rate variability (HRV) analysis. Sixty patients with mild‐to‐moderate OSA who underwent polysomnography (PSG) and completed sleep questionnaires were analysed retrospectively and divided into the PLMS group (n = 30) and the non‐PLMS group (n = 30). Epochs without any sleep events or continuous effects were evaluated using HRV analysis. No significant difference was observed in the demographic data, PSG parameters or sleep questionnaires between the PLMS and non‐PLMS groups, except for age. Patients in the PLMS group had significantly lower normalized high frequency (n‐HF), high frequency (HF), square root of the mean of the sum of the squares of difference between adjacent NN intervals (RMSSD) and standard deviation of all normal to normal intervals index (SDNN‐I), but had a higher normalized low frequency (n‐LF) and LF/HF ratio. There was no significant difference in the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the Short‐Form 36 and the Hospital Anxiety and Depression Scale between the two groups. After adjustment for confounding variables, PLMS remained an independent predictor of n‐LF (β = 0.0901, P = 0.0081), LF/HF ratio (β = 0.5351, P = 0.0361), RMSSD (β = ?20.1620, P = 0.0455) and n‐HF (β = ?0.0886, P = 0.0134). In conclusion, PLMS is related independently to basal sympathetic predominance and has a potentially negative impact on the cardiovascular system of OSA patients.     

Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity

Circulating levels of adrenal delta 5-androgens [dehydroepiandrosterone (DHEA), and its sulfate (DS)] selectively decrease with age in both sexes, while cortisol secretion remains unchanged. The mechanism(s) to account for this dissociation is unclear. We tested the hypothesis that a reduced enzymatic activity for delta 5-androgen biosynthesis may be responsible for this phenomenon by examining the ultradian and circadian rhythmicity (15-min sampling frequency for 24 h) of DHEA and cortisol and the responsiveness of DHEA, DS, and cortisol to human CRF stimulation and by the analysis of relative enzymatic activities in the biosynthesis of adrenal steroids in older postmenopausal women (PMW) and younger cycling women (NCW). Our data show that the timing of the circadian rhythm of DHEA secretion was not altered, but the acrophase amplitude was decreased (P less than 0.01) in aged PMW compared to NCW. While the pulse frequency of DHEA remained unchanged, the pulse amplitude was markedly attenuated in PMW compared with NCW (3.5 +/- 0.6 vs. 8.1 +/- 1.1 nmol/L; P less than 0.01). Correspondingly, the 24-h mean of DHEA was markedly reduced (P less than 0.001) in PMW (5.5 +/- 0.8 nmol/L) from that in NCW (12.1 +/- 1.4 nmol/L). For cortisol, all parameters were similar between the two groups. Thus, compared to NCW, the decline of circulating DHEA level in PMW was expressed by attenuations of pulse amplitude and circadian amplitude, without changes in the timing of the circadian rhythm or pulse frequency. Further, DHEA and DS, but not cortisol, responses to 8-h hCRF infusion were significantly (P less than 0.01) diminished in PMW. These findings together with decreased product/precursor ratios for DHEA/17-hydroxypregnenolone (P less than 0.01) and androstenedione/17-hydroxyprogesterone (P less than 0.05) suggest a reduction of 17,20-desmolase enzymatic activity in PMW compared to that in NCW. Steroid ratios for 3 beta-hydroxysteroid dehydrogenase and 17 alpha-hydroxylase were unaltered. We conclude from these preliminary data that the disparity of DHEA and cortisol secretion in aged PMW is probably related to an intraadrenal event, resulting from a decrease in 17,20-desmolase expression, which governs the biosynthesis of delta 5-adrenal androgen.     

Pulmonary complications in bone marrow transplantation: a practical approach to diagnosis and treatment

Pulmonary complications occur in 40% to 60% of recipients of bone marrow trans-plants, account for more than 90% of mortality, and develop during identifiable phases. Phase 1 (Days 1-30) includes pulmonary edema; diffuse alveolar hemorrhage; and various bacterial, fungal, and viral infections; Phase 2 (Days 31-100) usually requires a distinction between cytomegalovirus pneumonitis and idiopathic pneumonia syndrome; and Phase 3 (Day 100+) includes complications that are due to chronic graft-versus-host disease and associated bronchiolitis obliterans. The spectrum of pulmonary complications has been influenced by changes in transplantation technique, prophylactic treatment for infections, and the use of new chemotherapeutic agents that contribute to lung injury. Nonetheless, infections remain a leading cause of morbidity and mortality. The most serious complications result in respiratory failure, for which the prognosis has not improved significantly over the last 2 decades. In this article, we describe our algorithmic approach to the diagnosis and management of these complications.