In vivo quantification of β-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions.

Purpose: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-inhuman phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). Patients and Methods: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. Results: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. Conclusions: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.

The rumen microbiome is thought to play an important role in maintaining normal gastrointestinal metabolism and nutrient absorption in ruminants. The present study was designed to investigate the effect of heat stress on the rumen microbiome of goats using 16S rRNA sequencing technology. Six female goats were randomly allocated into two control metabolic chambers: A and B (in which the temperature and humidity could be precisely controlled with a precision deviation of ± 0.5°C and ± 5%, with three goats/chamber). Dynamic changes in the rumen bacterial community were detected under 16 gradually increasing temperature and humidity indexes (THIs). Heat stress had no significant effect on alpha diversity but affected the main phyla and genera of the goat rumen microbiota. With a deeper level of heat stress, the TH groups formed a distinct cluster that differed from that of the control check (CK) group. The dominant phylum transitioned from Firmicutes to Bacteroidetes, and co-exclusion occurred between these two phyla. With the increase in THI, the content of probiotics in the Lachnospiraceae_ND3007_group (P < 0.05) decreased, and the abundance of pathogenic bacteria, such as Erysipelotrichaceae_UCG-004 and Treponema_2, increased; however, the difference between the groups was not significant (P > 0.05). Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was used to predict bacterial function, and we found that the ambient environment significantly affected the balance between carbohydrate and energy metabolism (P < 0.05). In conclusion, heat stress changed the composition of rumen microbes and affected metabolic function. This experiment provides a theoretical basis for exploring the effects of environmental factors on the rumen of goats.

A single normal dose of levamisole can induce leukoencephalopathy in patients with RAU or Ascaris. The diagnosis depends on the clinical features and imaging appearances. Steroid therapy might be a good choice of treatment.

Isoliquiritigenin (ISL), a member of the flavonoids, has been demonstrated to possess antitumor activity in various cancer cell lines in vitro and in vivo. In this study, we investigated the antitumor effects of ISL on U87 glioma cells in vitro. As determined by MTT assay, ISL inhibited the proliferation of U87 cells in a time-dependent and dose-dependent manner. The results of fluorescence-activated cell sorting (FACS) analysis suggested that ISL induced the apoptosis of the U87 cells and blocked cell cycle progression at the S and G2/M phases. Moreover, it was identified that ISL induced the apoptosis of the U87 cells in a caspase-dependent manner. Although treatment with the pan-caspase inhibitor Z-VAD-FMK efficiently blocked the ISL-induced caspase activation, it did not eliminate the ISL-induced cell death. Further examination using western blot analysis revealed that ISL upregulated p21/WAF1 and p27. These results indicate that cell cycle arrest and the caspase-mediated apoptosis pathway may participate in the antiproliferative activity of ISL in U87 cells by regulating the expression of specific molecules.

No abstract

Progression-free survival is the end point most commonly used to assess the effectiveness of experimental regimens, and biomarker-based patient selection is rarely used in ongoing clinical trials for NSCLC.

Abstract.Marital status is an independent prognostic factor for survival in several types of cancer, but has not been fully studied in prostate cancer (PCa). A total of 95,846 men diagnosed with PCa were treated with radical prostatectomy (RP) between 2004 and 2009 within 18 Surveillance, Epidemiology and End Results registries. Survival curves were generated using Kaplan-Meier estimates and differences in survival were assessed using the log-rank test. Cox regression models were used to assess the impact of marital status on survival outcomes. The results demonstrated that the 8-year cancer-cause specific survival (CSS) rate of married men was higher than unmarried individuals. Further analyses revealed that divorced/separated men had a higher proportion of high Gleason scores (GS) PCa at diagnosis [hazard ratio (HR), 1.12; P=0.007] and those patients had the worst survival outcomes independent of age, ethnicity, grade, stage and sequence number [HR, 1.61; 95% confidence interval (CI), 1.34-1.93]. Interestingly, it was observed that CSS among divorced/separated men decreased as the GS increased (GS≤6: HR, 2.5; GS=7: HR, 1.71; GS≥8: HR, 1.50; all P<0.05). Apart from that, no significant differences in CSS were observed in those who had never been married (HR, 1.20) or were widowed (HR, 1.13) relative to the married group. The results of the present study support the hypothesis that marital status is an independent prognostic factor among men with PCa who underwent RP. It was demonstrated that the mortality rates of divorced or separated men with PCa were significantly greater compared with the other groups. A further understanding of the potential associations among marital status, psychosocial factors and survival outcomes may help in developing novel, more effective methods of treating different groups of patients with PCa.