Esthetic dental perception comparisons between 2D- and 3D-simulated dental discrepancies.

STATEMENT OF PROBLEM: Intraoral scanners (IOSs), facial scanners (FSs), and computer-aided design (CAD) software programs have become powerful tools for treatment planning. However, discrepancies in perception regarding 2-dimensional (2D) or 3-dimensional (3D) simulations by dentists, dental students, and laypeople have not been analyzed. PURPOSE: The purpose of this observational study was to analyze the perceptions of laypersons, dental students, and dentists regarding disparities of the maxillary dental midline and the occlusal plane when analyzing the dental discrepancies on 2D- and 3D-clinical simulations. MATERIAL AND METHODS: A female model was digitized by using an FS, IOS, and a full-face smile photograph. Dental discrepancies were simulated by using a 2D photograph (2D group) and 3D scan (3D group) of the model. In both simulation groups, 2 subgroups were produced. The occlusal plane of the first subgroup was modified in 1-degree increments without changing the dental midline or the position of the maxillary dental incisors. In the second subgroup, the occlusal plane was modified by using the same increments, but the maxillary central incisors and dental midline were altered to match the inclination of the occlusal plane. A total of 300 participants (N=300) were asked to rate the 2D images (N=12) and 3D videos (N=12) on a 1-to-6 scale and answer a questionnaire. Ordinal logistic regression was used to analyze the ratings. RESULTS: The ratings decreased with the increased tilt of the occlusal plane, and the layperson group gave consistently higher ratings than the other 2 groups. For dentists, the odds of giving a higher versus lower rating decreased by almost a half for each degree of tilt. However, for students, that effect was diminished by a positive interaction term, and for laypersons, the effect was even less. Students gave similar ratings to dentists, but laypersons gave higher ratings. As the age of the participants increased, however, the ratings also increased. The use of 3D versus 2D images had a positive effect on the ratings, but the effect decreased for the student observers and decreased even further for laypersons. Furthermore, midline alteration led to higher ratings but also resulted in worsening of the odds ratio for the tilt. Seventy percent of the dentists, 57% of the dental students, and 52% of the laypersons preferred 2D simulations to 3D simulations. CONCLUSIONS: Dentists, dental students, and laypersons decreased their ratings with increased inclination of the occlusal plane; however, laypersons still graded all the 2D and 3D images as esthetically pleasant, giving consistently higher ratings than the dentists and dental students. Overall, 3D simulations obtained higher ratings than 2D images, but the positive effect decreased for the student observers and decreased even further for laypersons.

Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy.

Sustained therapeutic responses from traditional and next-generation antiandrogen therapies remain elusive in clinical practice due to inherent and/or acquired resistance resulting in persistent androgen receptor (AR) activity. Antisense oligonucleotides (ASO) have the ability to block target gene expression and associated protein products and provide an alternate treatment strategy for castration-resistant prostate cancer (CRPC). We demonstrate the efficacy and therapeutic potential of this approach with a Generation-2.5 ASO targeting the mouse AR in genetically engineered models of prostate cancer. Furthermore, reciprocal feedback between AR and PI3K/AKT signaling was circumvented using a combination approach of AR-ASO therapy with the potent pan-AKT inhibitor, AZD5363. This treatment strategy effectively improved treatment responses and prolonged survival in a clinically relevant mouse model of advanced CRPC. Thus, our data provide preclinical evidence to support a combination strategy of next-generation ASOs targeting AR in combination with AKT inhibition as a potentially beneficial treatment approach for CRPC.

Leptin, BMI, and a Metabolic Gene Expression Signature Associated with Clinical Outcome to VEGF Inhibition in Colorectal Cancer.

VEGF (vascular endothelial growth factor) signaling inhibitors are widely used in different cancer types; however, patient selection remains a challenge. Analyses of samples from a phase III clinical trial in metastatic colorectal cancer testing chemotherapy versus chemotherapy with the small molecule VEGF receptors inhibitor cediranib identified circulating leptin levels, BMI, and a tumor metabolic and angiogenic gene expression signature associated with improved clinical outcome in patients treated with cediranib. Patients with a glycolytic and hypoxic/angiogenic profile were associated with increased benefit from cediranib, whereas patients with a high lipogenic, oxidative phosphorylation and serine biosynthesis signature did not gain benefit. These findings translated to pre-clinical tumor xenograft models where the same metabolic gene expression profiles were associated with in vivo sensitivity to cediranib as monotherapy. These findings suggest a link between patient physiology, tumor biology, and response to antiangiogenics, which may guide patient selection for VEGF therapy in the future.

AKT Antagonist AZD5363 Influences Estrogen Receptor Function in Endocrine-Resistant Breast Cancer and Synergizes with Fulvestrant (ICI182780) In Vivo.

PI3K/AKT/mTOR signaling plays an important role in breast cancer. Its interaction with estrogen receptor (ER) signaling becomes more complex and interdependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility; however, a negative feedback loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve breast cancer treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER(+) breast cancer cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term estrogen deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50 < 500 nmol/L) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50 ∼ 100 nmol/L). AZD5363 resensitized TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context-specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen response elements located on the TFF1, PGR, and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5, and IGFI signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER(+) patient-derived xenograft and delayed tumor progression after cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for breast cancer that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation.

Repression of transcription by WT1-BASP1 requires the myristoylation of BASP1 and the PIP2-dependent recruitment of histone deacetylase.

The Wilms' tumor 1 protein WT1 is a transcriptional regulator that is involved in cell growth and differentiation. The transcriptional corepressor BASP1 interacts with WT1 and converts WT1 from a transcriptional activator to a repressor. Here, we demonstrate that the N-terminal myristoylation of BASP1 is required in order to elicit transcriptional repression at WT1 target genes. We show that myristoylated BASP1 binds to nuclear PIP2, which leads to the recruitment of PIP2 to the promoter regions of WT1-dependent target genes. BASP1's myristoylation and association with PIP2 are required for the interaction of BASP1 with HDAC1, which mediates the recruitment of HDAC1 to the promoter and elicits transcriptional repression. Our findings uncover a role for myristoylation in transcription, as well as a critical function for PIP2 in gene-specific transcriptional repression through the recruitment of histone deacetylase.

Dynamic interaction between WT1 and BASP1 in transcriptional regulation during differentiation.

The Wilms' tumour suppressor protein WT1 plays a central role in the development of the kidney and also other organs. WT1 can act as a transcription factor with highly context-specific activator and repressor functions. We previously identified Brain Acid Soluble Protein 1 (BASP1) as a transcriptional cosuppressor that can block the transcriptional activation function of WT1. WT1 and BASP1 are co-expressed during nephrogenesis and both proteins ultimately become restricted to the podocyte cells of the adult kidney. Here, we have analysed the WT1/BASP1 complex in a podocyte precursor cell line that can be induced to differentiate. Chromatin immunoprecipitation revealed that WT1 and BASP1 occupy the promoters of the Bak, c-myc and podocalyxin genes in podocyte precursor cells. During differentiation-dependent upregulation of podocalyxin expression BASP1 occupancy of the podocalyxin promoter is reduced compared to that of WT1. In contrast, the repressive WT1/BASP1 occupancy of the c-myc and Bak promoters is maintained and these genes are downregulated during the differentiation process. We provide evidence that the regulation of BASP1 promoter occupancy involves the sumoylation of BASP1. Our results reveal a dynamic cooperation between WT1 and BASP1 in the regulation of gene expression during differentiation.