Therapeutic Co-targeting of WEE1 and ATM Downregulates PD-L1 Expression in Pancreatic Cancer

Purpose Pancreatic cancer (PC) is one of the most lethal cancers worldwide, but there are currently no effective treatments. The DNA damage response (DDR) is under investigation for the development of novel anti-cancer drugs. Since DNA repair pathway alterations have been found frequently in PC, the purpose of this study was to test the DDR-targeting strategy in PC using WEE1 and ATM inhibitors. Materials and Methods We performed in vitro experiments using a total of ten human PC cell lines to evaluate antitumor effect of AZD1775 (WEE1 inhibitor) alone or combination with AZD0156 (ATM inhibitor). We established Capan-1-mouse model for in vivo experiments to confirm our findings. Results In our research, we found that WEE1 inhibitor (AZD1775) as single agent showed anti-tumor effects in PC cells, however, targeting WEE1 upregulated p-ATM level. Here, we observed that co-targeting of WEE1 and ATM acted synergistically to reduce cell proliferation and migration, and to induce DNA damage in vitro. Notably, inhibition of WEE1 or WEE1/ATM downregulated programmed cell death ligand 1 expression by blocking glycogen synthase kinase-3 beta serine 9 phosphorylation and decrease of CMTM6 expression. In Capan-1 mouse xenograft model, AZD1775 plus AZD0156 (ATM inhibitor) treatment reduced tumor growth and downregulated tumor expression of programmed cell death ligand 1, CMTM6, CD163, and CXCR2, all of which contribute to tumor immune evasion. Conclusion Dual blockade of WEE1 and ATM might be a potential therapeutic strategy for PC. Taken together, our results support further clinical development of DDR-targeting strategies for PC.

The Differential Effects of Acute Right- vs. Left-Sided Vestibular Deafferentation on Spatial Cognition in Unilateral Labyrinthectomized Mice

This study aimed to investigate the disparity in locomotor and spatial memory deficits caused by left- or right-sided unilateral vestibular deafferentation (UVD) using a mouse model of unilateral labyrinthectomy (UL) and to examine the effects of galvanic vestibular stimulation (GVS) on the deficits over 14 days. Five experimental groups were established: the left-sided and right-sided UL (Lt.-UL and Rt.-UL) groups, left-sided and right-sided UL with bipolar GVS with the cathode on the lesion side (Lt.-GVS and Rt.-GVS) groups, and a control group with sham surgery. We assessed the locomotor and cognitive-behavioral functions using the open field (OF), Y maze, and Morris water maze (MWM) tests before (baseline) and 3, 7, and 14 days after surgical UL in each group. On postoperative day (POD) 3, locomotion and spatial working memory were more impaired in the Lt.-UL group compared with the Rt.-UL group (p < 0.01, Tamhane test). On POD 7, there was a substantial difference between the groups; the locomotion and spatial navigation of the Lt.-UL group recovered significantly more slowly compared with those of the Rt.-UL group. Although the differences in the short-term spatial cognition and motor coordination were resolved by POD 14, the long-term spatial navigation deficits assessed by the MWM were significantly worse in the Lt.-UL group compared with the Rt.-UL group. GVS intervention accelerated the vestibular compensation in both the Lt.-GVS and Rt.-GVS groups in terms of improvement of locomotion and spatial cognition. The current data imply that right- and left-sided UVD impair spatial cognition and locomotion differently and result in different compensatory patterns. Sequential bipolar GVS when the cathode (stimulating) was assigned to the lesion side accelerated recovery for UVD-induced spatial cognition, which may have implications for managing the patients with spatial cognitive impairment, especially that induced by unilateral peripheral vestibular damage on the dominant side

Applying Data Mining Methods to Understand User Interactions within Learning Management Systems: Approaches and Lessons Learned

This article describes our processes for analyzing and mining the vast records of instructor and student usage data collected by a learning management system (LMS) widely used in higher education, called Canvas. Our data were drawn from over 33,000 courses taught over three years at a mid-sized public Western U.S. university. Our processes were guided by an established data mining framework, called Knowledge Discovery and Data Mining (KDD). In particular, we use the KDD framework in guiding our application of several educational data mining (EDM) methods (prediction, clustering, and data visualization) to model student and instructor Canvas usage data, and to examine the relationship between these models and student learning outcomes. We also describe challenges and lessons learned along the way

Revascularization of immature retinas with retinopathy of prematurity using combination therapy of deferred laser treatment after a single intravitreal bevacizumab injection

Background This study aimed to observe the extent of retinal vascularization in patients with retinopathy of prematurity (ROP) who underwent deferred laser treatment (LT) after a single intravitreal bevacizumab injection (IVB). Methods This study retrospectively evaluated 40 consecutive eyes in 21 infants who received a single IVB or LT. Deferred LT was performed in cases of ROP recurrence after a single IVB. To assess the amount of retinal vascularization between the initial IVB and deferred LT, the cases were divided into three groups based on treatment: single IVB, deferred LT after a single IVB, and prompt LT. The growth and associated complications were compared between groups. Results There were 12, 16, and 12 eyes in the single IVB, deferred LT, and prompt LT groups, respectively. Deferred LT was performed at an average of 7.9 weeks after a single IVB. In the single IVB group, retinal vascularization proceeded to zone III, whereas the prompt LT group did not show any growth of vascularization beyond the laser scars. In the deferred LT group, during the window period before LT, retinal vascularization progressed from zone I to zone II posterior and from zone II posterior to zone II anterior, respectively, without further ROP recurrence. Conclusions Retinal vascularization progressed during the deferred window period, thereby reducing the area of the retina ablated by LT. A single IVB followed by deferred LT can be an alternative treatment option to prevent ablation of zone I or multiple IVBs

Titanium dioxide nanoparticles oral exposure to pregnant rats and its distribution

Background: Titanium dioxide (TiO2) nanoparticles are among the most manufactured nanomaterials in the industry, and are used in food products, toothpastes, cosmetics and paints. Pregnant women as well as their conceptuses may be exposed to TiO2 nanoparticles; however, the potential effects of these nanoparticles during pregnancy are controversial, and their internal distribution has not been investigated. Therefore, in this study, we investigated the potential effects of oral exposure to TiO2 nanoparticles and their distribution during pregnancy. TiO2 nanoparticles were orally administered to pregnant Sprague-Dawley rats (12 females per group) from gestation days (GDs) 6 to 19 at dosage levels of 0, 100, 300 and 1000 mg/kg/day, and then cesarean sections were conducted on GD 20. Results: In the maternal and embryo-fetal examinations, there were no marked toxicities in terms of general clinical signs, body weight, food consumption, organ weights, macroscopic findings, cesarean section parameters and fetal morphological examinations. In the distribution analysis, titanium contents were increased in the maternal liver, maternal brain and placenta after exposure to high doses of TiO2 nanoparticles. Conclusion: Oral exposure to TiO2 during pregnancy increased the titanium concentrations in the maternal liver, maternal brain and placenta, but these levels did not induce marked toxicities in maternal animals or affect embryo-fetal development. These results could be used to evaluate the human risk assessment of TiO2 nanoparticle oral exposure during pregnancy, and additional comprehensive toxicity studies are deemed necessary considering the possibility of complex exposure scenarios and the various sizes of TiO2 nanoparticles

Correlation of photoluminescent quantum efficiency and device characteristics for the soluble electrophosphorescent light emitter with interfacial layers

We have investigated the effects of interfacial layers on the properties of soluble phosphorescent organic light emitting devices. Two kinds of polyfluorene-based interfacial layer materials have been studied; both were spin coated on top of PEDOT:PSS to form the insoluble layers by thermal annealing. The molecular-doped, phosphorescent light emitting layer comprising a polymeric host, small molecular host, and guest molecule was fabricated onto the thin interfacial layer. The photoluminescence quantum yield (PLQY) of these layers was measured with an integrating sphere. We have calculated the PLQY values of the single phosphorescent light emitting layer and various organic multilayers incorporating the interfacial layers, showing that a reduction in PLQY due to the interfacial quenching is more significant in the thicker interfacial layer structures. In spite of the decrease in PLQY induced by the triplet energy mismatch, polyfluorene-based interfacial layers improved the charge injection from PEDOT:PSS to the emitting layer, which results in the enhanced brightness and current. The triplet quenching by the interfacial layer could explain the reduction in luminous efficiency of the devices compared to the reference. This was also investigated by studying the charge carrier trapping, change in the spectral characteristics induced by the shift in the emission zone, and the analysis on the carrier balance of devices.This research was supported by the Seoul R&BD support program (CR070048) and SystemIC2010 project, Ministry of Knowledge Economy, Korea

Correction: Cytochrome P450 1B1 inhibition suppresses tumorigenicity of prostate cancer via caspase-1 activation.

[This corrects the article DOI: 10.18632/oncotarget.16598.]

PolyA_DB 2: mRNA polyadenylation sites in vertebrate genes

Polyadenylation of nascent transcripts is one of the key mRNA processing events in eukaryotic cells. A large number of human and mouse genes have alternative polyadenylation sites, or poly(A) sites, leading to mRNA variants with different protein products and/or 3′-untranslated regions (3′-UTRs). PolyA_DB 2 contains poly(A) sites identified for genes in several vertebrate species, including human, mouse, rat, chicken and zebrafish, using alignments between cDNA/ESTs and genome sequences. Several new features have been added to the database since its last release, including syntenic genome regions for human poly(A) sites in seven other vertebrates and cis-element information adjacent to poly(A) sites. Trace sequences are used to provide additional evidence for poly(A/T) tails in cDNA/ESTs. The updated database is intended to broaden poly(A) site coverage in vertebrate genomes, and provide means to assess the authenticity of poly(A) sites identified by bioinformatics. The URL for this database is