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Objective To examine the effect of older versus younger age on change in anthropometric and metabolic measures during extended treatment of psychotic depression with sertraline plus olanzapine. Methods Two hundred and sixty-nine men and women aged 18–85 years with an episode of psychotic depression were treated with open-label sertraline plus olanzapine for up to 12 weeks. Participants who remained in remission following an 8-week stabilization phase were eligible to participate in a 36-week randomized controlled trial (RCT) that compared the efficacy and tolerability of sertraline plus olanzapine with sertraline plus placebo. Weight, waist circumference and plasma lipids, glucose, HbA1c, and insulin were measured at regular intervals during the acute, stabilization and randomized phases of the study. Linear mixed models were used to analyze the trajectories of anthropometric and metabolic measures. Results Participants aged 60 years or older experienced less weight gain and less increase in cholesterol during the combined acute and stabilization phases of the study compared with those aged 18–59 years. At the acute-stabilization termination visit, mean weight in older participants was 6.5 lb. less than premorbid weight, whereas it was 17.9 lb. more than premorbid weight in younger participants. In the RCT, there was a significant interaction of treatment and age group for the trajectory of weight, but the post hoc tests that compared age groups within each treatment arm were not statistically significant. There were no clinically significant differences between younger and older participants in glycemic measures. Conclusion Older patients with psychotic depression experienced less increase in weight and total cholesterol than their younger counterparts during acute and stabilization treatment with sertraline plus olanzapine. In the older group, weight gained during the acute and stabilization phases appeared to be partial restoration of weight lost during the index episode of depression, whereas weight gain in younger participants was not.

Magnetic resonance imaging/ultrasound-guided fusion biopsy (FBx) is more accurate at detecting clinically significant prostate cancer than conventional transrectal ultrasound-guided systematic biopsy. However, learning curves for attaining accuracy may limit the generalizability of published outcomes.To delineate and quantify the learning curve for FBx by assessing the targeted biopsy accuracy and pathological quality of systematic biopsy over time.We carried out a retrospective analysis of 173 consecutive men who underwent Artemis FBx with computer-template systematic sampling between July 2015 and May 2017.The accuracy of targeted biopsy was determined by calculating the distance between planned and actual core trajectories stored on Artemis. Systematic sampling proficiency was assessed via pathological analysis of fibromuscular tissue in all cores and then comparing pathology elements from individual cores from men in the first and last tertiles. Polynomial linear regression models, change-point analysis, and piecewise linear regression were used to quantify the learning curve.A significant improvement in targeted biopsy accuracy occurred up to 98 cases (p0.01). There was a significant decrease in fibromuscular tissue in the systematic biopsy cores up to 84 cases (p0.01) and an improvement in pathological quality when comparing systematic cores from the first and third tertiles. Use of a different fusion platform may limit the generalizability of our results.There is a significant learning curve for targeted and systemic biopsy using the Artemis platform. Improvements in accuracy of targeted biopsy and better sampling for systematic biopsy can be achieved with greater experience.We define the learning curve for magnetic resonance imaging/ultrasound-guided fusion biopsy (FBx) using targeted biopsy accuracy and systematic core sampling quality as measures. Our findings underscore the importance of overcoming learning curves inherent to FBx to minimize patient discomfort and biopsy risk and improve the quality of care for accurate risk stratification, active surveillance, and treatment selection.

First-principles calculations have been performed to study the structural properties and defect energetics of orthorhombic Ln2TiO5 (Ln = La, Pr, Nd, Sm, Gd, Dy and Y). The lattice parameters decrease with increasing lanthanide cation radius. The mean 〈Ln1-O〉 and 〈Ln2-O〉 bond lengths increase systematically by respectively 1.16% and 1.19% from Dy2TiO5 to La2TiO5. Meanwhile, mean 〈Ti-O〉 bond length increases slightly with increasing Ln cation radius from Y2TiO5 to La2TiO5. The calculated results of point defect formation energies suggest that Ln2-Ti antisite defect is the most energetically favorable defect type for Ln2TiO5. The trend of Ln2-Ti antisite defect formation energy of Ln2TiO5 is precisely consistent with the radiation resistance, as demonstrates by the critical amorphization temperature, which indicates that the formation of Ln2-Ti antisite defect may has a significant influence on the radiation behavior of Ln2TiO5.

The Wnt signaling pathway is a critical developmental pathway which operates through control of cellular functions such as proliferation and differentiation. Aberrant Wnt signaling has been linked to the formation and metastasis of tumors. Porcupine, a member of the membrane-bound O-acyltransferase family of proteins, is an important component of the Wnt pathway. Porcupine catalyzes the palmitoylation of Wnt proteins, a process needed for their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from a known porcupine inhibitor class. The leading compound 59 demonstrated subnanomolar inhibition of Wnt signaling in a paracrine cellular assay. Compound 59 also showed excellent chemical, plasma and liver microsomal stabilities. Furthermore, compound 59 exhibited good pharmacokinetic profiles with 30% oral bioavailability in rat. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors.

The Wnt signaling pathway is a pivotal developmental pathway. It operates through control of cellular functions such as proliferation, differentiation, migration and polarity. Aberrant Wnt signaling has been implicated in the formation and metastasis of tumors. Porcupine is a component of the Wnt signaling pathway. It is a member of the membrane-bound O-acyltransferase family of proteins. Porcupine catalyzes the palmitoylation of Wnt proteins, a process which is essential to their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from two known porcupine inhibitor classes. The leading compound 62 demonstrated subnanomolar (IC50 0.11 nM) inhibition of Wnt signaling in a paracrine cellular reporter gene assay. Compound 62 also potently inhibited Wnt secretion into culture medium, an indication of direct inhibition of the porcupine protein. Furthermore, compound 62 showed excellent chemical, plasma and liver microsomal stabilities. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors.

The repressor element-1 (RE1) silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) has an irreplaceable role during the differentiation of neurons. REST has multiple splice variants which link to various types of cancer. Previous work had highlighted the role of REST in glioma, where the expression of REST is enhanced. But whether alternative splicing of REST is expressed in glioma has not been described. Here, we show that a specific isoform REST4 is expressed in glioma specimens, and will influence the mRNA level of REST in vivo. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have a role of antineoplastic in various tumor cells, which including glioma cells. Moreover, study indicated that PPARγ agonist pioglitazone can promote alternative splicing of REST pre-mRNA. In this study, we selected pioglitazone as a tool drug to explore whether the role of pioglitazone in anti-glioma is mediated by regulating REST expression or promoting alternative splicing of REST in glioma cells. Results show that pioglitazone can inhibit proliferation and induce apoptosis of glioma cell in vitro, which may be mediated by down-regulating REST mRNA level but not by inducing alternative splicing of REST pre-mRNA. Our study firstly reports the expression of REST4 in glioma tissue samples. And we recommend that pioglitazone, which can reduce the expression level of REST, represents a promising drug for therapy of glioma.

Ethnopharmacological relevance Alantolactone (AL), one of the main active ingredients in Inula helenium L. , has been included in various prescriptions of traditional Chinese medicine. The effects of AL on cytochrome P450 (CYP450) were still unclear. This study evaluated the inhibitory effect of AL on cytochrome P450s in vitro and in vivo . Materials and methods The inhibitory effects of AL on the CYPs activity were evaluated in human liver microsomes (HLMs) and recombinant cDNA-expressed enzymes incubation system, and then determined by LC-MS/MS based CYPs probe substrate assay. C57BL/6 mice were treated AL orally (0, 25, 50, 100 mg/kg) for 15 days. The inhibitory effects of AL on major Cyps in mice were examined at both the mRNA and enzyme activity levels. Results AL showed a potent inhibitory effect on CYP3A4 activity with IC 50 values of 3.599 (HLMs) and 3.90 (recombinant CYP3A4) μM, respectively. AL strongly decreased CYP3A4 activity in a dose-dependent but not time-dependent way in HLMs. Results from typical Lineweaver–Burk plots showed that AL could inhibit CYP3A4 activity noncompetitively, with a Ki value of 1.09 μM in HLMs. Moreover, activity of CYP2C19 could also be inhibited by AL with IC 50 of 36.82 μM. Other CYP450 isoforms were not markedly affected by AL. The inhibition was also validated by in vivo study of mice. AL significantly decreased mRNA expression of Cyp2c and 3a family. Conclusion The study indicates that herb–drug interaction should be paid more attention between AL and drugs metabolized by CYP3A4.

Clinically significant cytomegalovirus (CMV) infection in allogeneic blood or marrow transplant recipients has dramatically declined in recent years by the strategy of early detection of reactivation and pre-emptive therapy with Ganciclovir (GCV). We have previously shown that even in the absence of overt CMV disease, persisting post-transplant antigenemia predicts for increased late relapse and treatment failure. (Nakamura, et al BBMT 2004) In other words, frequent CMV reactivation serves as a surrogate for impaired post-transplant immune reconstitution. To explain the observed association between CMV reactivation and relapse we also raised the possibility that several weeks of GCV therapy could exert a deleterious effect on a fragile immune system. Clinical association between GCV administration and impaired lymphocyte function has not received attention previously; perhaps because of confounding effects from the underlying conditions (HIV or post-transplant) that induce CMV reactivation. We examined the effect of GCV in vitro on normal human PBMCs. Human PBMCs were extracted from normal volunteers and subjected to mitogenic stimulation (PHA) in the absence or presence of varying concentrations of GCV. PHA-induced proliferation, measured by uptake of 3[H]-thymidine after 5 days incubation in RPMI-10% AB serum, was reduced by 35% at peak therapeutic concentrations (10mg/ml) of GCV as opposed to 73% by Tacrolimus (10ng/ml). GCV did not induce lymphocyte apoptosis in the presence or absence of stimulation. Flow cytometry-based BrdU incorporation assays show that GCV exerts a time-dependent impairment of DNA synthesis in lymphocytes. Collectively, these results show that GCV suppresses T-lymphocyte proliferation in vitro at therapeutic concentrations and the likely mechanism of action is inhibition of DNA synthesis. Further work is ongoing to evaluate the effect of GCV on proliferative responses to specific antigens and to confirm these effects in comparison to other drugs used in the transplant setting. Figure Figure