The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSCs) as the major infiltrating immune cell type and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified Cxcl5 as a cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving Cxcl5 upregulation in cancer cells through YAP-TEAD complex and promoting MDSCs recruitment. Clinico-pathological studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC relevant genes. Together, YAP-driven MDSC recruitment via heterotypic Cxcl5-Cxcr2 signaling reveals effective therapeutic strategy for advanced prostate cancer. Significance We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell non-autonomous function of Hippo-YAP pathway in regulation of Cxcl5, a ligand for Cxcr2 expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CxCl5-Cxcr2 signaling circuit elicits robust anti-tumor responses and prolongs survival.

A significant fraction of advanced prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC)1. Immune checkpoint blockade (ICB) using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types2. However, mCRPC showed overwhelming de novo resistance to ICB3–5, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumor immune evasion6. Circulating MDSC abundance correlates with PSA levels and metastasis in PCa patients7–9. Mouse models of PCa show that MDSCs (CD11b+ Gr1+) promote tumor initiation10 and progression11. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of ICB agents together with targeted agents that neutralize MDSCs yet preserve T cell function. Here we developed a novel chimeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumor activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when ICB was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of IL-1ra and suppression of MDSC-promoting cytokines secreted by PCa cells. These observations illuminate a clinical path hypothesis for combining ICB with MDSC-targeted therapies in the treatment of mCRPC.

Highlights d Oncogenic KRAS promotes an immune-suppressive profile in CRC d IRF2 is a key downstream target of oncogenic KRASmediating immune suppression d IRF2 suppresses MDSC migration and infiltration by targeting the CXCL3-CXCR2 axis d Enforced IRF2 expression or CXCR2 inhibition overcomes anti-PD1 resistance in CRC

Perovskite ferroelectrics with prominent nonlinear optical absorption have attracted great attention in the field of photonics. However, they are traditionally dominated by inorganic oxides and exhibit relatively small nonlinear optical absorption coefficients, which hinder their further applications. Herein, we report a new organic-inorganic hybrid bilayered perovskite ferroelectric, (CHNH)(NHCHNH)PbBr (1), showing an above-room-temperature Curie temperature (∼322 K) and notable spontaneous polarization (∼3.8 μC cm). Significantly, the unique quantum-well structure of 1 results in intriguing two-photon absorption properties with a giant nonlinear optical absorption coefficient as high as 5.76 × 10 cm GW, which is almost two-orders of magnitude larger than those of mostly traditional all-inorganic perovskite ferroelectrics. To our best knowledge, 1 is the first example of hybrid ferroelectrics with giant two-photon absorption coefficient. The mechanisms for ferroelectric and two-photon absorption are revealed. This work will shed light on the design of new ferroelectrics with two-photon absorption and promote their potentials in the photonic application.

Summary Synthetic and collateral lethality have provided conceptual frameworks to identify cancer-specific vulnerabilities1–3. Here, we explored an approach to identify potential synthetic lethal interactions through screening mutually exclusive deletion patterns in cancer genomes. We sought to identify ‘synthetic essential’ genes, which might be occasionally deleted in some cancers but almost always retained in the context of a specific tumor suppressor deficiency, and posited that such synthetic essential genes would be therapeutic targets in cancers harboring specific tumor suppressor deficiencies. In addition to known synthetic lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic essential gene in PTEN-deleted cancers. In PTEN-deleted prostate and breast cancers, functional analysis showed that CHD1 depletion profoundly and specifically suppressed cell proliferation, survival and tumorigenic potential. Mechanistically, functional PTEN stimulates GSK3β-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via β-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in CHD1 protein stabilization, which in turn engages the H3K4me3 mark to activate transcription of the pro-tumorigenic TNFα/NF-κB gene network. Together, this study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of trackable targets in cancers harboring specific tumor suppressor deficiencies.

Background The aim of this study was to investigate the effect of virtual reality (VR) technology on balance and gait in patients with Parkinson’s disease (PD). Material/Methods The study design was a single-blinded, randomized, controlled study. Twenty-eight patients with PD were randomly divided into the experimental group (n=14) and the control group (n=14). The experimental group received VR training, and the control group received conventional physical therapy. Patients performed 45 minutes per session, 5 days a week, for 12 weeks. Individuals were assessed pre- and post-rehabilitation with the Berg Balance Scale (BBS), Timed Up and Go Test (TUGT), Third Part of Unified Parkinson’s Disease Rating Scale (UPDRS3), and Functional Gait Assessment (FGA). Results After treatment, BBS, TUGT, and FGA scores had improved significantly in both groups (P<0.05). However, there was no significant difference in the UPDRS3 between the pre- and post-rehabilitation data of the control group (P>0.05). VR training resulted in significantly better performance compared with the conventional physical therapy group (P<0.05). Conclusions The results of this study indicate that 12 weeks of VR rehabilitation resulted in a greater improvement in the balance and gait of individuals with PD when compared to conventional physical therapy.

Nickel nanospheres, nanowires, and nanoflowers are synthesized via a facile non‐aqueous sol–gel route involving the reaction of nickel acetylacetonate with benzyl alcohol at 200 °C in the presence of varying magnetic fields, as illustrated in the figure. Benzyl alcohol acts as both the solvent and reductant in this system. The nanostructures show substantial enhancement in coercivity as compared to bulk nickel.

We report the controlled synthesis of monodisperse NaCeF4:Er/Yb nanoprobes that exhibit intense NIR-II emission for in vitro bioassay and in vivo bioimaging.