Opposing roles of TGFß and BMP signaling in prostate cancer development.

SMAD4 constrains progression of Pten-null prostate cancer and serves as a common downstream node of transforming growth factor ß (TGFß) and bone morphogenetic protein (BMP) pathways. Here, we dissected the roles of TGFß receptor II (TGFBR2) and BMP receptor II (BMPR2) using a Pten-null prostate cancer model. These studies demonstrated that the molecular actions of TGFBR2 result in both SMAD4-dependent constraint of proliferation and SMAD4-independent activation of apoptosis. In contrast, BMPR2 deletion extended survival relative to Pten deletion alone, establishing its promoting role in BMP6-driven prostate cancer progression. These analyses reveal the complexity of TGFß-BMP signaling and illuminate potential therapeutic targets for prostate cancer.

Thermally Stable and Transparent Polyimide Derived from Side-Group-Regulated Spirobifluorene Unit for Substrate Application.

Advancements in flexible electronic technology, especially the progress in foldable displays and under-display cameras (UDC), have created an urgent demand for high-performance colorless polyimide (CPI). However, current CPIs lack sufficient heat resistance for substrate applications. In this work, four kinds of rigid spirobifluorene diamines are designed, and the corresponding polyimides are prepared by their condensation with 5,5'-(perfluoropropane-2,2-diyl) bis(isobenzofuran-1,3-dione) (6FDA) or 9,9-bis(3,4-dicarboxyphenyl) fluorene dianhydride (BPAF). The rigid and conjugated spirobifluorene units endow the polyimides with higher glass transition temperature (Tg) ranging from 356 to 468 °C. Their optical properties are regulated by small side groups and spirobifluorene structure with a periodically twisted molecular conformation. Consequently, a series of CPIs with an average transmittance ranging from 75% to 88% and a yellowness index (YI) as low as 2.48 are obtained. Among these, 27SPFTFA-BPAF presents excellent comprehensive performance, with a Tg of 422 °C, a 5 wt.% loss temperature (Td5) of 562 °C, a YI of 3.53, and a tensile strength (δmax) of 140 MPa, respectively. The mechanism underlying the structure-property relationship is investigated by experimental comparison and theoretical calculation, and the proposed method provides a pathway for designing highly rigid conjugated CPIs with excellent thermal stability and transparency for photoelectric engineering.

Myeloid-derived suppressor cells inhibit T cell activation through nitrating LCK in mouse cancers.

Potent immunosuppressive mechanisms within the tumor microenvironment contribute to the resistance of aggressive human cancers to immune checkpoint blockade (ICB) therapy. One of the main mechanisms for myeloid-derived suppressor cells (MDSCs) to induce T cell tolerance is through secretion of reactive nitrogen species (RNS), which nitrates tyrosine residues in proteins involved in T cell function. However, so far very few nitrated proteins have been identified. Here, using a transgenic mouse model of prostate cancer and a syngeneic cell line model of lung cancer, we applied a nitroproteomic approach based on chemical derivation of 3-nitrotyrosine and identified that lymphocyte-specific protein tyrosine kinase (LCK), an initiating tyrosine kinase in the T cell receptor signaling cascade, is nitrated at Tyr394 by MDSCs. LCK nitration inhibits T cell activation, leading to reduced interleukin 2 (IL2) production and proliferation. In human T cells with defective endogenous LCK, wild type, but not nitrated LCK, rescues IL2 production. In the mouse model of castration-resistant prostate cancer (CRPC) by prostate-specific deletion of Pten, p53, and Smad4, CRPC is resistant to an ICB therapy composed of antiprogrammed cell death 1 (PD1) and anticytotoxic-T lymphocyte-associated protein 4 (CTLA4) antibodies. However, we showed that ICB elicits strong anti-CRPC efficacy when combined with an RNS neutralizing agent. Together, these data identify a previously unknown mechanism of T cell inactivation by MDSC-induced protein nitration and illuminate a clinical path hypothesis for combining ICB with RNS-reducing agents in the treatment of CRPC.

Reversible Micrometer-Scale Spiral Self-Assembly in Liquid Crystalline Block Copolymer Film with Controllable Chiral Response.

The spiral is a fundamental structure in nature and spiral structures with controllable handedness are of increasing interest in the design of new chiroptical materials. In this study, micrometer-scale spiral structures with reversible chirality were fabricated based on the assembly of a liquid crystalline block copolymer film assisted by enantiopure tartaric acid. Mechanistic insight revealed that the formation of the spiral structures was closely related to the liquid crystalline properties of the major phase of block copolymer under the action of chiral tartaric acid. The chiral spiral structures with controllable handedness were easily erased under ultraviolet light irradiation and restored via thermal annealing. This facile thermal treatment method provides guidance for fabrication of chiral micrometer-scale spiral structures with adjustable chiral properties.

High-Level Extraction of Recyclable Nanocatalysts by Using Polyphosphazene Microparticles.

Improper disposal of metal nanoparticles has caused serious environmental and pathological problems because of their active nanotoxicity. Therefore, there is an urgent need to develop a strategy for efficiently removing redundant metal nanoparticles from water, while also permitting restoration of their catalytic activities to those of pristine particles for reapplication. Herein, we present intrinsically nitrogen-rich cross-linked polyphosphazene microparticles to capture silver nanoparticles (AgNPs) from aqueous media by a simple one-step method. The described microparticles exhibit an outstanding adsorption capacity for AgNPs of approximately 59.35 mg/g, exceeding those of other adsorbents. The adsorption kinetics of AgNPs on these microparticles obeyed a pseudo-second-order kinetic model. More importantly, the recovered AgNPs maintained good catalytic activity in the reduction of methylene blue by sodium borohydride. Based on their simple preparation, high adsorption efficiency, and nondestructive effect on the catalytic activity of the recovered AgNPs, the described polyphosphazene microparticles display promising potential for the removal and recovery of AgNPs from water.

Double-Helical Nanostructures with Controllable Handedness in Bulk Diblock Copolymers.

Double-helical nanostructures with controllable handedness in bulk materials is of high interest in science and technology for the design and fabrication of new materials, in particular metamaterials, which mimic their natural homologues or even show superior properties. Herein, we report the fabrication of double-helical structures with controlled handedness through the self-assembly of an achiral diblock copolymer doped with d- and l-tartaric acid (TA). The helices showed clear handedness dependence on the chirality of the TA. The chiral arrangement of different achiral tectonic units, such as nanoparticles and organic molecules, was confirmed using this helical structure as a template. The double-helical structure will provide new knowledge for understanding the function of helices, and will enable the application of these systems as chiroptical materials.

Repositioning of the Annular Ligament in the Management of Missed Monteggia Fracture.

BACKGROUND: Successful treatment of missed Monteggia fractures usually requires ulnar osteotomy and open reduction of the radial head with reconstruction of the annular ligament. We have observed cases in which the annular ligament was displaced into the joint but remained intact. Here we report our experience with repositioning of the annular ligament at the time of the open reduction rather than reconstruction in the management of missed Monteggia fractures. METHODS: We retrospectively reviewed 23 patients with missed Monteggia fractures treated by repositioning of the annular. There were 16 males and 7 females with an average age of 6 years (range, 4 to 9 y). The average time from injury to definitive treatment was 7 months (range, 6 wk to 16 mo). The average follow-up was 18 months (range, 8 to 36 mo). We evaluated the patients by clinical examination, Kim score, and radiographs. RESULTS: All patients had no pain and full elbow function at the latest follow-up. There were no significant differences between the preoperative and postoperative Kim scores. Radiographs at the latest follow-up demonstrated maintenance of radial head reduction in all cases. CONCLUSIONS: Repositioning of an intact annular ligament in cases of missed Monteggia fractures is a viable alternative to reconstruction of the ligament and provides long-term stability. LEVEL OF EVIDENCE: Level IV-therapeutic.

[Mutagenicity study of water samples from a waterworks taking Yangtze River as its water source in Jiangsu Province].

OBJECTIVE: To understand the occurrence and change of mutagencity of water samples in the process of drinking water treatment and distribution in a waterworks taking Yangtze River as its water source in Jiangsu Province. METHODS: Large volume of inlet water, finished water and tap water samples were extracted by XAD-2 resin. Mutagencities were assessed by Ames test and a mutation ratio( MR) of 2 or greater was judged as a positive result. RESULTS: Compared with the samples with S9, samples without S9 presented more positive results( P = 0. 005). That water treatment elevated MR values( P = 0. 007) while the pipe transport made MR values down( P = 0. 038) was observed in samples without S9. The tap water showed weaker mutagenicities than the raw water in samples with S9( P = 0. 008). Compared to the raw water samples, the finished water samples showed more positive results(-S9) and lower MR values( + S9, P =0. 002). CONCLUSION: Significant mutagenicities of water samples from the Yangtze Riverand its processed water were presented, and frame shit and direct mutagens deserved special concern.

Large-Volume Self-Organization of Polymer/Nanoparticle Hybrids with Millimeter-Scale Grain Sizes Using Brush Block Copolymers.

We report that an exceptionally large volume of highly ordered arrays (single grains) on the order of millimeters in scale can be rapidly created through a unique innate guiding mechanism of brush block copolymers (BBCPs). The grain volume is over 10(9) times larger than that of typical self-assembled linear BCPs (LBCPs). The use of strong interactions between nanoparticles (NPs) and BBCPs enables high loadings of functional materials, up to 76 wt % (46 vol %) in the target domain, while maintaining excellent long-range order. Overall, this work provides a simple method to precisely control the spatial orientation of functionalities at nanometer length scales over macroscopic volumes, thereby enabling the production of hybrid materials for many important applications.

Targeted grafting of thermoresponsive polymers from a penetrative honeycomb structure for cell sheet engineering.

Responsive membranes have been used to construct smart biomaterial interfaces. We report a novel approach to fabricate honeycomb films with a pattern of thermoresponsive polymer, namely poly(N-isopropylacrylamide). The approach was based on a combination of the breath figure method and reversible addition-fragmentation chain transfer. The hybrid film had morphological and chemical patterns resulting in varied wettability and morphology at various stages, as well as high thermo-responsiveness. Enhanced cell adhesion was observed at an incubation temperature of 37 °C, which is above its lower critical solution temperature (LCST). Furthermore, cells could be harvested at temperatures below the LCST without trypsin treatment. The non-invasive characteristics give this membrane potential as a substrate for cell sheet engineering.

Electrochemically Tunable Cell Adsorption on a Transparent and Adhesion-Switchable Superhydrophobic Polythiophene Film.

A superhydrophobic polythiophene film (SSPTH) is prepared by double-layer electrodeposition on an indium tin oxide (ITO) glass electrode. This film shows not only electroresponsive superhydrophobic features, but also high transparency compared with the usual polythiophene film. The water-droplet adhesion on the SSPTH film can be switched between sliding and pinned states under the applied potential. More intresetingly, the change in water-droplet adhesion results in a change in cell adsorption on the SSPTH film. The low-adhesion (dedoped) SSPTH films can prevent Hela cell adhesion, whereas high-adhesion (doped) SSPTH films can promote Hela cell adsorption. This controllable cell adhesion on a SSPTH film may be developed as a smart biointerface material.

Electrically conductive PEDOT coating with self-healing superhydrophobicity.

A self-healing electrically conductive superhydrophobic poly(3,4-ethylenedioxythiophene) (PEDOT) coating has been prepared by chemical vapor deposition of a fluoroalkylsilane (POTS) onto a PEDOT film, which was obtained by electrochemical deposition. The coating not only maintained high conductivity with a low resistivity of 3.2 × 10(-4) Ω·m, but also displayed a water contact angle larger than 156° and a sliding angle smaller than 10°. After being etched with O2 plasma, the coating showed an excellent self-healing ability, spontaneously regaining its superhydrophobicity when left under ambient conditions for 20 h. This superhydrophobicity recovery process was found to be humidity-dependent, and could be accelerated and completed within 2 h under a high humidity of 84%. The coating also exhibited good superhydrophobicity recovering ability after being corroded by strong acid solution at pH 1 or strong base solution at pH 14 for 3 h.

Airflow-field-induced sandwich-type membrane of block copolymer for selective ion separation.

A simple and effective airflow method to prepare sandwich-type block copolymer films is reported. The films are composed of three layers: vertically oriented nanocylinders align in both upper and bottom layers and irregular nanocylinders exist in the bulk of the film. The vertically oriented nanocylinders in both sides can provide high accessibility to ions and ensures the exchange of chemical species between the membrane and external environment, while the irregularly oriented nanocylinders in the middle part of the film can prolong the pathway of ions transportation and enhance ions selectivity.

[Clinical application of computer navigation in physeal bridge resection in pediatric partial epiphyseal plate closure].

OBJECTIVE: To report our experience of using image-guided computer navigation for bone bridge resection in children. METHODS: Between August 2008 and March 2011 at our hospital, computed tomography (CT)-based navigation system for bone bridge resection was used in 42 children with lower extremity deformities due to partial physeal growth arrest. There were 26 males and 16 females with an average age of 9.8 (5.0-13.0) years. RESULTS: Six patients were lost to follow-up. In other 36 patients, the average duration of radiographic and clinical follow-up was 25 (15-44) months. Among them, 13 were corrected to neutral while 15 had insufficient correction. The average correction angle of deformities was 14 (8-25) degrees. CONCLUSION: The image-guided computer navigation system enhances the accuracy and safety of bone bridge resection in children.

Controllable Circularly Polarized Luminescence with High Dissymmetry Factor via Co-Assembly of Achiral Dyes in Liquid Crystal Polymer Films.

Circularly polarized luminescence (CPL) materials are highly demanded due to their great potential in optoelectronic and chiroptical elements. However, the preparation of CPL films with high luminescence dissymmetry factors (glum ) remains a formidable task, which impedes their practical application in film-based devices. Herein, a facile strategy to prepare solid CPL film with a high glum through exogenous chiral induction and amplification of liquid crystal polymers is proposed. Amplification and reversion of the CPL appear when the films are annealed at the chiral nematic liquid crystalline temperature and the maximal glum up to 0.30 due to the enhancement of selective reflection. Thermal annealing treatment at different liquid crystalline states facilitates the formation of the chiral liquid phase and adjusts the circularly polarized emission. This work not only provides a straightforward and versatile platform to construct organic films capable of exhibiting strong circularly polarized emission but also is helpful in understanding the exact mechanism for the liquid crystal enhancement of CPL performance.

Protein Signature Differentiating Neutrophils and Myeloid-Derived Suppressor Cells Determined Using a Human Isogenic Cell Line Model and Protein Profiling.

Myeloid-derived suppressor cells (MDSCs) play an essential role in suppressing the antitumor activity of T lymphocytes in solid tumors, thus representing an attractive therapeutic target to enhance the efficacy of immunotherapy. However, the differences in protein expression between MDSCs and their physiological counterparts, particularly polymorphonuclear neutrophils (PMNs), remain inadequately characterized, making the specific identification and targeting of MDSCs difficult. PMNs and PMN-MDSCs share markers such as CD11b+CD14-CD15+/CD66b+, and some MDSC-enriched markers are emerging, such as LOX-1 and CD84. More proteomics studies are needed to identify the signature and markers for MDSCs. Recently, we reported the induced differentiation of isogenic PMNs or MDSCs (referred to as iPMNs and iMDSCs, respectively) from the human promyelocytic cell line HL60. Here, we profiled the global proteomics and membrane proteomics of these cells with quantitative mass spectrometry, which identified a 41-protein signature ("cluster 6") that was upregulated in iMDSCs compared with HL60 and iPMN. We further integrated our cell line-based proteomics data with a published proteomics dataset of normal human primary monocytes and monocyte-derived MDSCs induced by cancer-associated fibroblasts. The analysis identified a 38-protein signature that exhibits an upregulated expression pattern in MDSCs compared with normal monocytes or PMNs. These signatures may provide a hypothesis-generating platform to identify protein biomarkers that phenotypically distinguish MDSCs from their healthy counterparts, as well as potential therapeutic targets that impair MDSCs without harming normal myeloid cells.

Ketogenic Diet Alters the Epigenetic and Immune Landscape of Prostate Cancer to Overcome Resistance to Immune Checkpoint Blockade Therapy.

Resistance to immune checkpoint blockade (ICB) therapy represents a formidable clinical challenge limiting the efficacy of immunotherapy. In particular, prostate cancer poses a challenge for ICB therapy due to its immunosuppressive features. A ketogenic diet (KD) has been reported to enhance response to ICB therapy in some other cancer models. However, adverse effects associated with continuous KD were also observed, demanding better mechanistic understanding and optimized regimens for using KD as an immunotherapy sensitizer. In this study, we established a series of ICB-resistant prostate cancer cell lines and developed a highly effective strategy of combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic KD (CKD), or dietary supplementation of the ketone body ß-hydroxybutyrate (BHB), which is an endogenous HDACi. CKD and BHB supplementation each delayed prostate cancer tumor growth as monotherapy, and both BHB and adaptive immunity were required for the antitumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that HDACi and ketogenesis enhanced ICB efficacy through both cancer cell-intrinsic mechanisms, including upregulation of MHC class I molecules, and -extrinsic mechanisms, such as CD8+ T-cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen-presenting cells, and diminished neutrophil infiltration. Overall, these findings illuminate a potential clinical path of using HDACi and optimized KD regimens to enhance ICB therapy for prostate cancer. SIGNIFICANCE: Optimized cyclic ketogenic diet and 1,3-butanediol supplementation regimens enhance the efficacy of immune checkpoint blockade in prostate cancer through epigenetic and immune modulations, providing dietary interventions to sensitize tumors to immunotherapy.

Formation and properties of self-assembly-driven fluorescent nanoparticle sensors.

Fluorescent nanoparticles (FNPs) are obtained in water by self-assembly from a polymeric ionic liquid, fluorescent carboxylate moiety, and a surfactant through two main supramolecular interactions, that is, ionic bonds and hydrophobic/hydrophilic interactions. The hydrophobicity of the surfactant is tunable and a highly hydrophobic surfactant increases the fluorescence intensity and stability of the FNPs. The fluorescence of the FNPs is sensitive to a quenching effect by various ions with high selectivity, and consequently, they may be used as sensors. The self-assembly approach used to generate the FNPs is considerably simpler than other methods based on more challenging synthetic methods and the flexibility of the approach should allow a wide and diverse range of FNPs to be prepared with specific sensor applications.

Management of missed Monteggia fractures with ulnar osteotomy, open reduction, and dual-socket external fixation.

BACKGROUND: Open reduction of the radial head is usually necessary in the treatment of a missed Monteggia fracture. However, the best way to stabilize the reduction remains controversial. The purpose of this study is to present our experience using the dual-socket external fixator to stabilize the ulna osteotomy and capture the reduction of the radial head. METHODS: We reviewed 33 patients with missed Monteggia fracture who underwent open reduction, ulnar osteotomy, and dual-socket external fixation from 2004 to 2010. The average age of this group was 7 years and the average time to surgical treatment after the fracture was 15 months. We treated all patients with open reduction of the radial head, fully releasing the capsular contracture, removing the fibrous scar tissue within the joint, performing ulnar osteotomy, and fixing the osteotomy with dual-socket external fixation. The clinical and radiographic follow-up averaged 38 months. Descriptive statistics utilized the Student test to compare the preoperative and postoperative functional movement of elbow and forearm. RESULTS: All patients had excellent clinical and radiographic outcomes without losing motion of the elbow and forearm, and all patients maintained reduction of the radial head at the final follow-up. There were no significant differences in the motion of the elbow and forearm between preoperative and postoperative examinations. Delayed union of the ulna occurred in 2 cases, both successfully treated with autologous iliac crest bone graft at 7 months after the operation. Three cases had early redislocation of the radial head, and these were treated successfully by changing the position of the ulnar osteotomy and readjusting the external fixators. CONCLUSIONS: Dual-socket external fixation has the major advantage of permitting and capturing the optimal position of the ulna osteotomy to achieve the best possible reduction of the radial head. A further advantage is the possibility of easily changing the position of the ulnar osteotomy by adjustment of the fixator should the radial head subluxate or redislocate in the early postoperative period as had occurred in 3 of our cases. We conclude that our procedure of fully releasing the capsular contractures, removing scar tissue, ulnar osteotomy, reduction of the radial head, and fixation of the osteotomy with dual-socket external fixation is a safe and effective way to manage children with a missed Monteggia fracture. LEVEL OF EVIDENCE: Therapeutic level IV.

Cancer-cell-intrinsic mechanisms shaping the immunosuppressive landscape of prostate cancer.

Although immunotherapy has revolutionized cancer treatment and achieved remarkable success across many different cancer types, only a subset of patients shows meaningful clinical responses. In particular, advanced prostate cancer exhibits overwhelming de novo resistance to immune checkpoint blockade therapy. This is primarily due to the immunosuppressive tumor microenvironment of prostate cancer. Therefore, it is paramount to understand how prostate cancer cell-intrinsic mechanisms promote immune evasion and foster an immunosuppressive microenvironment. Here, we review recent findings that reveal the roles of the genetic alterations, androgen receptor signaling, cancer cell plasticity, and oncogenic pathways in shaping the immunosuppressive microenvironment and thereby driving immunotherapy resistance. Based on preclinical and clinical observations, a variety of therapeutic strategies are being developed that may illuminate new paths to enhance immunotherapy efficacy in prostate cancer.