It is shown that in the K-user interference channel, if for each user the desired signal strength is no less than the sum of the strengths of the strongest interference from this user and the strongest interference to this user (all values in dB scale), then the simple scheme of using point to point Gaussian codebooks with appropriate power levels at each transmitter and treating interference as noise at every receiver (in short, TIN scheme) achieves all points in the capacity region to within a constant gap. The generalized degrees of freedom (GDoF) region under this condition is a polyhedron, which is shown to be fully achieved by the same scheme, without the need for time-sharing. The results are proved by first deriving a polyhedral relaxation of the GDoF region achieved by TIN, then providing a dual characterization of this polyhedral region via the use of potential functions, and finally proving the optimality of this region in the desired regime.

The p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2 [nuclear receptor coactivator (NCOA)2], and SRC-3 [amplified in breast cancer 1 (AIB1)/NCOA3] are key pleiotropic "master regulators" of transcription factor activity necessary for cancer cell proliferation, survival, metabolism, and metastasis. SRC overexpression and overactivation occur in numerous human cancers and are associated with poor clinical outcomes and resistance to therapy. In prostate cancer (PC), the p160 SRCs play critical roles in androgen receptor transcriptional activity, cell proliferation, and resistance to androgen deprivation therapy. We recently demonstrated that the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger (POZ) domain protein (SPOP) interacts directly with SRC-3 and promotes its cullin 3-dependent ubiquitination and proteolysis in breast cancer, thus functioning as a potential tumor suppressor. Interestingly, somatic heterozygous missense mutations in the SPOP substrate-binding cleft recently were identified in up to 15% of human PCs (making SPOP the gene most commonly affected by nonsynonymous point mutations in PC), but their contribution to PC pathophysiology remains unknown. We now report that PC-associated SPOP mutants cannot interact with SRC-3 protein or promote its ubiquitination and degradation. Our data suggest that wild-type SPOP plays a critical tumor suppressor role in PC cells, promoting the turnover of SRC-3 protein and suppressing androgen receptor transcriptional activity. This tumor suppressor effect is abrogated by the PC-associated SPOP mutations. These studies provide a possible explanation for the role of SPOP mutations in PC, and highlight the potential of SRC-3 as a therapeutic target in PC.proteasome | MATH domain | BTB domain

The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both fulllength and splice-variant AR. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a firstin-field approach to target AR expression and function and improve outcomes in CRPC.prostate cancer | small molecule inhibitor | AR signaling | GATA2 | steroid receptor coactivator

Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas (PC), but are rare in other malignancies suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator factor SRC-3. However, the relative contributions that SPOP substrates may contribute to the pathophysiology of SPOP-mutant (mt) PC is unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of PC cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger effect on AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR mediated. Indeed, we found that wild-type (wt) but not PC-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of PC cells expressing mt-SPOP expressed higher AR protein levels and grew faster than tumors composed of PC cells expressing wt-SPOP. Further, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human PC datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in PC, and they provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.

We first report AlGaN-based deep ultraviolet light-emitting diodes (UV-LEDs) grown on nano-patterned sapphire substrates (NPSS) prepared through a nanosphere lithography technique. The AlN coalescence thickness on NPSS is only 3 μm due to AlN's nano-scaled lateral growth, which also leads to low dislocation densities in AlN and epi-layers above. On NPSS, the light-output power of a 282-nm UV-LED reaches 3.03 mW at 20 mA with external quantum efficiency of 3.45%, exhibiting 98% better performance than that on flat sapphire. Temperature-dependent photoluminescence reveals this significant enhancement to be a combination of higher internal quantum efficiency and higher light extraction efficiency.