Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis.

BACKGROUND: Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR+) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC. METHODS: PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection. The progression of metastases was monitored by bioluminescent imaging. Histological phenotypes of metastases were characterized by immunohistochemistry and immunofluorescence staining. Castration responses were further investigated in two AR-positive models. RESULTS: Our PDX-derived metastasis (PDM) model collection comprises three AR+ adenocarcinomas (ARPC) and one AR- neuroendocrine carcinoma (NEPC). All ARPC models developed bone metastases with either an osteoblastic, osteolytic, or mixed phenotype, while the NEPC model mainly developed brain metastasis. Different mechanisms of castration resistance were observed in two AR+ PDM models with distinct genotypes, such as combined loss of TP53 and RB1 in one model and expression of AR splice variant 7 (AR-V7) expression in another model. Intriguingly, the castration-resistant tumors displayed inter- and intra-tumor as well as organ-specific heterogeneity in lineage specification. CONCLUSION: Genetically diverse PDM models provide a clinically relevant system for biomarker identification and personalized medicine in metastatic castration-resistant prostate cancer.

Tumor-derived biomarkers predict efficacy of B7H3 antibody-drug conjugate treatment in metastatic prostate cancer models.

Antibody-drug conjugates (ADCs) are a promising targeted cancer therapy; however, patient selection based solely on target antigen expression without consideration for cytotoxic payload vulnerabilities has plateaued clinical benefits. Biomarkers to capture patients who might benefit from specific ADCs have not been systematically determined for any cancer. We present a comprehensive therapeutic and biomarker analysis of a B7H3-ADC with pyrrolobenzodiazepine(PBD) payload in 26 treatment-resistant, metastatic prostate cancer (mPC) models. B7H3 is a tumor-specific surface protein widely expressed in mPC, and PBD is a DNA cross-linking agent. B7H3 expression was necessary but not sufficient for B7H3-PBD-ADC responsiveness. RB1 deficiency and/or replication stress, characteristics of poor prognosis, and conferred sensitivity were associated with complete tumor regression in both neuroendocrine (NEPC) and androgen receptor positive (ARPC) prostate cancer models, even with low B7H3 levels. Non-ARPC models, which are currently lacking efficacious treatment, demonstrated the highest replication stress and were most sensitive to treatment. In RB1 WT ARPC tumors, SLFN11 expression or select DNA repair mutations in SLFN11 nonexpressors governed response. Importantly, WT TP53 predicted nonresponsiveness (7 of 8 models). Overall, biomarker-focused selection of models led to high efficacy of in vivo treatment. These data enable a paradigm shift to biomarker-driven trial designs for maximizing clinical benefit of ADC therapies.

Minimal change disease with papillary thyroid carcinoma: a report of two adult cases.

BACKGROUND: Minimal change disease (MCD), a pathological type of nephrotic syndrome (NS), can occur in patients with tumors. We report two adult cases of MCD associated with papillary thyroid carcinoma (PTC), known to be extremely rare in adults. CASE PRESENTATION: A 35-year-old female patient was simultaneously diagnosed with MCD and PTC. The MCD was effectively treated with thyroidectomy and prednisone.In addition, a 50-year-old male patient, who had been diagnosed with PTC three years prior, had MCD confirmed by renal biopsy. The patient achieved complete remission following treatment with tacrolimus and rituximab. CONCLUSIONS: The present case report describes and discusses the diagnostic and treatment processes employed in these two patients. Clinicians need to be aware of the renal effects of treating patients with solid tumors.

Negatively charged polymer-shielded supramolecular nano-micelles with stimuli-responsive property for anticancer drug delivery.

A new kind of negatively charged polymer-shielded supramolecular nano-micelles with dual-responsive property was designed for tumor treatment, which was prepared on the basis of adamantane terminated linear PAsp(DIP) and disulfide-ß-cyclodextrin-terminated PAsp(EDA). The supramolecular nano-micelles comprised a 2,3-dimethylmaleic anhydride (DA) protective layer to stabilize the micelles, a pH-responsive core to package hydrophobic model drugs, and a disulfide-crosslinked interlayer to shackle the core against drug leakage under normal physiological conditions. After arriving at the tumor tissue via EPR, the targeting function could be turned on by dislodging DA groups on the surface of micelles, which allowed the drug-loaded nano-micelles to be easily phagocytized by the tumor cells, and then release the drug inside the cells induced by the increased glutathione level and acidic pH. The results indicated that the charge-conversional dual-responsive supramolecular nano-micelles showed excellent antitumor activity.

Starch and chitosan-based antibacterial dressing for infected wound treatment via self-activated NO release strategy.

In this work, a positively charged chitosan-grafted-polyarginine (CS-N-PArg) as the macro-molecular NO donor, and a negatively charged acetalated starch (AcSt-O-PAsp) as a glucose donor, have been synthesized. To achieve the multi-enzymatic cascade system for local generation of self-supply glucose to increase the H2O2 concentration for the subsequent oxidization of L-Arg into NO, the designed positively charged CS-N-PArg, negatively charged AcSt-O-PAsp, glucoamylase (GA) and glucose oxidase (GOx) are absorbed and assembled in the pore of the gelatin sponge via electrostatic interaction to establish a smart antibacterial dressings (CS/St + GOx/GA). Once stimulated by Escherichia coli (E. coli)-infected wounds (a slightly acidic environment), the cascade reaction system can sequentially induce to generate glucose, H2O2 and NO, which exhibits a meaningful alternative idea for a high-performance antibacterial therapy.

Ionic conductive hydroxypropyl methyl cellulose reinforced hydrogels with extreme stretchability, self-adhesion and anti-freezing ability for highly sensitive skin-like sensors.

Ionically-conductive hydrogels are attracting increasing interest as skin-like sensors, however, the fabrication of ion-conductive hydrogels with excellent mechanical properties, high conductivity, self-adhesion and anti-freezing ability for high-performance sensors remains a challenge. Herein, a highly ion-conductive hydrogel is prepared by introducing LiCl into polyacrylamide/hydroxypropyl methyl cellulose (PAM/HPMC) composite hydrogel. The introduction of LiCl simultaneously endows the PAM/HPMC/LiCl hydrogel with outstanding stretchability (1453 %), high tensile strength (135 kPa), skin-like elasticity (9.18 kPa), high conductivity (7.85 S/m), good adhesiveness and wide operating temperature range. Impressively, this ion-conductive hydrogel can be utilized in skin-like sensor, which achieves high strain sensitivity (GF = 11.19) with wide sensing ranges (up to 600 %), and excellent endurance over 250 consecutive stretching. As a result, the wearable sensor assembled from the hydrogels can be used to detect complex human activities with high stability even at -40 °C. This work promotes the development of ion-conductive hydrogels with broad operating temperature in advanced sensory platform.

TMPRSS2-ERG promotes the initiation of prostate cancer by suppressing oncogene-induced senescence.

ERG translocations are commonly involved in the initiation of prostate neoplasia, yet previous experimental approaches have not addressed mechanisms of oncogenic inception. Here, in a genetically engineered mouse model, combining TMPRSS2-driven ERG with KrasG12D led to invasive prostate adenocarcinomas, while ERG or KrasG12D alone were non-oncogenic. In primary prostate luminal epithelial cells, following inducible oncogenic Kras expression or Pten depletion, TMPRSS2-ERG suppressed oncogene-induced senescence, independent of TP53 induction and RB1 inhibition. Oncogenic KRAS and TMPRSS2-ERG synergized to promote tumorigenesis and metastasis of primary luminal cells. The presence of TMPRSS2-ERG compared to a wild-type background was associated with a stemness phenotype and with relatively increased RAS-induced differential gene expression for MYC and mTOR-regulated pathways, including protein translation and lipogenesis. In addition, mTOR inhibitors abrogated ERG-dependent senescence resistance. These studies reveal a previously unappreciated function whereby ERG expression primes preneoplastic cells for the accumulation of additional gene mutations by suppression of oncogene-induced senescence.

Cross-domain heterogeneous residual network for single image super-resolution.

Single image super-resolution is an ill-posed problem, whose purpose is to acquire a high-resolution image from its degraded observation. Existing deep learning-based methods are compromised on their performance and speed due to the heavy design (i.e., huge model size) of networks. In this paper, we propose a novel high-performance cross-domain heterogeneous residual network for super-resolved image reconstruction. Our network models heterogeneous residuals between different feature layers by hierarchical residual learning. In outer residual learning, dual-domain enhancement modules extract the frequency-domain information to reinforce the space-domain features of network mapping. In middle residual learning, wide-activated residual-in-residual dense blocks are constructed by concatenating the outputs from previous blocks as the inputs into all subsequent blocks for better parameter efficacy. In inner residual learning, wide-activated residual attention blocks are introduced to capture direction- and location-aware feature maps. The proposed method was evaluated on four benchmark datasets, indicating that it can construct the high-quality super-resolved images and achieve the state-of-the-art performance. Code and pre-trained models are available at https://github.com/zhangyongqin/HRN.

The tumor phototherapeutic application of nanoparticles constructed by the relationship between PTT/PDT efficiency and 2,6- and 3,5-substituted BODIPY derivatives.

BODIPY dyes have recently been used for photothermal and photodynamic therapy of tumors. However, complex multi-material systems, multiple excitation wavelengths and the unclear relationship between BODIPY structures and their PTT/PDT efficiency are still major issues. In our study, nine novel BODIPY near-infrared dyes were designed and successfully synthesized and then, the relationships between BODIPY structures and their PTT/PDT efficiency were investigated in detail. The results showed that modifications at position 3,5 of the BODIPY core with conjugated structures have better effects on photothermal and photodynamic efficiency than the modifications at position 2,6 with halogen atoms. Density functional theory (DFT) calculations showed that this is mainly due to the extension of the conjugated chain and the photoinduced electron transfer (PET) effect. By encapsulating BDPX-M with amphiphilic DSPE-PEG2000-RGD and lecithin, the obtained NPs not only show good water solubility and biological stability, but also could act as superior agents for photothermal and photodynamic synergistic therapy of tumors. Finally, we obtained BODIPY NPs that exhibited excellent photothermal and photodynamic effects at the same time under single irradiation with an 808 nm laser (photothermal conversion efficiency: 42.76%, A/A0: ∼0.05). In conclusion, this work provides a direction to design and construct phototherapeutic nanoparticles based on BODIPY dyes for tumor treatment.

Preparation and application of quick hemostatic gauze based on biomimetic mineralized thrombin.

Thrombin is a serine protease known as activated coagulation factor II and is primarily applied as an effective local hemostatic agent. However, its clinical application is hindered by drawbacks, such as high sensitivity to the surrounding environment, instability and poor storage stability, easy inactivation, and low bioavailability. The biological functions of biomacromolecules in harsh environments can be preserved through biomineralization. Despite the success of biomimetic mineralization, limited consideration has been given to the mineral-based methods and the effect of various metal ions on enzyme activity. To explore an efficient technique for biomimetic mineralized thrombin, six kinds of ion/thrombin hybrid microflowers and two kinds of thrombin/MOF were synthesized in this work. The results showed that Zn-HNFs-G exhibits good hemostatic effect and maintains high enzymatic activity when exposed to high-temperature conditions. Meanwhile, Fe-HNFs-G, Thrombin@ZIF-8-G and Thrombin@MAF-7-G possess negligible enzyme protection.

Copper Peroxide-Loaded Gelatin Sponges for Wound Dressings with Antimicrobial and Accelerating Healing Properties.

Catalytic conversion of hydrogen peroxide (H2O2) to more toxic hydroxyl radicals (•OH) is a good choice for sterilization and anti-infection, but endogenous H2O2 is insufficient to achieve satisfactory sterilization efficacy. Despite great efforts, designing and developing antimicrobial materials that specifically and effectively self-supply H2O2 at the wound site remain as tremendous challenges. Here, we report a pH-responsive copper peroxide-loaded wound dressing made from copper hydroxide and gelatin sponge and then reacted with H2O2. In vitro experiments show that the prepared wound dressing has good bactericidal properties against Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Pseudomonas aeruginosa (P. aeruginosa). Moreover, the as-prepared wound dressing can release •OH specifically in the bacterial-infected skin wound, rather than in normal tissues, and in vivo skin wound-healing experiments proved that the synthesized copper peroxide-loaded gelatin sponge could combat E. coli effectively; in addition, Cu2+ released from the gelatin sponge could stimulate angiogenesis and collagen deposition simultaneously. The study provides a strategy to improve antibacterial efficacy and reduce the toxic side effects through the release of •OH by bacterial self-activation.

Hydrogel sunscreen based on yeast /gelatin demonstrates excellent UV-shielding and skin protection performance.

Traditional organic and inorganic sunscreens suffer from the disadvantages of low stability and poor biocompatibility. In the study, we developed a novel hydrogel sunscreen based on the yeast and gelatin, which demonstrated excellent UV protection property and broad absorption of UV across UVA and UVB region. Yeast was used as effective component and gelatin as matrix to fabricate the hydrogel, which is high hydrated and reasonable to simulate natural living tissue. As a common probiotic, yeast shows safety and satisfactory UV protection capability. Furthermore, the hydrogel sunscreen shows excellent biocompatibility and UV protection performance both in vitro and in vivo. Moreover, they can be prepared conveniently and provide an eco-friendly strategy, which provides experience and inspiration of probiotics in the cosmetics application.

Construction of Nanocrystalline Cellulose-Based Composite Fiber Films with Excellent Porosity Performances via an Electrospinning Strategy.

Cellulose nanocrystals (CNCs) not only have environmental protection characteristics of being lightweight, degradable, green, and renewable but also have some nanocharacteristics of high strength, large specific surface area, and obvious small size effect, so they are often used as a reinforcing agent in various polymers. However, the hydrogen bonding between CNC molecules is relatively strong, and they can easily aggregate and get entangled with each other. In this work, several large-porosity composite nanofiber films, KH550-CNC/waterborne polyurethane (WPU)/poly(vinyl alcohol) (PVAL) with KH550-modified CNCs, are prepared using poly(vinyl alcohol) (PVAL) solution and electrospinning technology. A variety of characterization methods are used to discuss and analyze the nanofiber materials, and the effects of the added amount of CNCs modified with KH550, spinning voltage, curing distance, and advancing speed on the morphology and performance of composite fibers are discussed separately. The results show that when the content of KH550-CNC is 1%, the composite fiber film obtained has the most regular morphology and the best spinnability, which is convenient for the specific application of fiber materials in a later period. In addition, the porosity of the obtained composite fiber film is 62.61%. Therefore, this work provides a theoretical basis and research strategy for the preparation of higher-porosity composite films as well as the development of new textile materials.

Self-Assembled Sandwich-like MXene-Derived Composites as Highly Efficient and Sustainable Catalysts for Wastewater Treatment.

Photocatalysts play an increasingly important role in environmental remediation polluted by industrial wastewater. However, the preparation of adsorbents and catalysts with high activity by simple and easy methods is still a great challenge. Here, sandwich-like composite catalyst Cu2O/TiO2/Ti3C2 was prepared by an easily available solvent reduction measure for the highly efficient catalytic nitro compounds. In particular, sandwich-like composite catalyst Cu2O/TiO2/Ti3C2 exhibits excellent catalysis for 2-nitroaniline (2-NA) and 4-nitrophenol (4-NP), and its pseudo-first-order reaction rate constants (k) are 0.163 and 0.114 min-1, respectively. Interestingly, even after eight consecutive cycles of catalytic experiments, the conversion rates of catalytic 2-NA and 4-NP are still greater than 95 and 92%, respectively, demonstrating that the obtained catalyst has excellent catalytic capability and a high reutilization rate. The excellent catalytic performances of Cu2O/TiO2/Ti3C2 can be attributed to the fact that Ti3C2 provides a greater reaction site for the formation of Cu2O and reduces the aggregation during the formation of Cu2O by in situ synthesis. Therefore, ternary composite catalyst Cu2O/TiO2/Ti3C2 prepared by solvent reduction not only supplies a technical method for the catalytic reaction of MXene-based material but also lays the foundation for the development of new photocatalysts.

Multi-functional Nanodrug Based on a Three-dimensional Framework for Targeted Photo-chemo Synergetic Cancer Therapy.

Targeted synergistic therapy has broad prospects in tumor treatments. Here, a multi-functional nanodrug GDYO-CDDP/DOX@DSPE-PEG-MTX (GCDM) based on three traditional anticancer drugs (doxorubicin (DOX), cisplatin (CDDP) and methotrexate (MTX)) modified graphdiyne oxide (GDYO) is described, for diagnosis and targeted cancer photo-chemo synergetic therapy. In this system, for the first time, these three traditional anti-cancer drugs have played new roles and can reduce multidrug resistance through synergistic anti-tumor effects. Cisplatin can be hybridized with GDYO to form a multifunctional and well-dispersed three-dimensional framework, which can not only be used as nano-drug carriers to achieve high drug loading rates (40.3%), but also exhibit excellent photothermal conversion efficiency (47%) and good photodynamic effects under NIR irradiation. Doxorubicin (DOX) is loaded onto GDYO-CDDP through π-π stacking, which is used as an anticancer drug and as a fluorescent probe for nanodrug detection. Methotrexate (MTX) can be applied in tumor targeting and play a role in synergistic chemotherapy with DOX and CDDP. The synthesized multi-functional nanodrug GCDM has good biocompatibility, active targeting, long-term retention, sustained drug release, excellent fluorescence imaging capabilities, and remarkable photo-chemo synergistic therapeutic effects.

Chemical Vapor Deposition-Assisted Fabrication of Self-Assembled Co/MnO@C Composite Nanofibers as Advanced Anode Materials for High-Capacity Li-Ion Batteries.

Constructing the nanostructure of transition metal oxides for high energy density lithium-ion batteries has been widely studied recently. Prompted by the idea that the transition metal can serve as a catalyzer influence on the reversibility of solid-electrolyte interphase films, Co/MnO@C composite nanofibers were designed by electrospinning and chemical vapor deposition methods. The Co/MnO@C electrode showed superior electrochemical performance with a large capacity increase for the first 400 cycles and a high rate performance of 1345 mA h g-1 at 1000 mA g-1. There was no obvious decay of capacity over the whole 1000 cycles, demonstrating the excellent cycling stability of the samples. The new design and synthesis of the anodic materials may offer a prototype for high-performance and strong-stability batteries.

Acidity-Triggered Tumor-Targeted Nanosystem for Synergistic Therapy via a Cascade of ROS Generation and NO Release.

Nitric oxide (NO) gas therapy has aroused intense interest in recent years. l-Arginine (l-Arg) reacts with reactive oxygen species (ROS) in tumor cells to generate NO. This phenomenon represents an effective method for tumor therapy. However, endogenous ROS levels in most types of tumor cells cannot enable an effective reaction. ß-Lapachone is generally used to increase H2O2, which can oxidize guanidine derivatives to form nitric oxide in tumor cells. In addition, based on the ferrocene (Fc)-catalyzed Fenton reaction, ·OH is generated from H2O2, and the ONOO- could be generated from an interaction between ·O2- (generated through the Haber-Weiss reaction) and NO. Arg-rich poly(ε-caprolactone) (PCL)-b-PArg, a macromolecular NO donor, was accurately synthesized to avoid premature l-Arg leakage during in vivo transport. In this design, the self-assembled PCL-b-PArg nanoparticles were dressed with the tumor-shreddable masking (PEG-b-PDMA, a negatively charged pH-sensitive hydrophilic diblock polymer), to prepare P-lapa-Fc nanoparticles and hide penetrative capability in the circulation. The experimental results confirmed that this synergistic therapy based on ROS and NO had a significant inhibitory effect on cancer cells, thereby providing new inspiration for NO gas treatment.

Facile Synthesis of Ag/Pd Nanoparticle-Loaded Poly(ethylene imine) Composite Hydrogels with Highly Efficient Catalytic Reduction of 4-Nitrophenol.

Poly(ethylene imine) (PEI) has abundant amino groups in a macromolecular chain and can be used as a graft source for metal nanocomposites, which shows excellent ability to form stable complexes with heavy metal ions. In this work, a simple and convenient method was used to make PEI into a stable hydrogel with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-N-hydroxysuccinimide and subsequently coprecipitate with silver nitrate solution or palladium chloride solution to form metal-loaded composite hydrogels. In addition, the characterizations of composite hydrogels were investigated by scanning electron microscopy, specific surface area tests (Brunauer-Emmett-Teller), X-ray photoelectron spectroscopy, and ultraviolet spectroscopy. The properties of composite hydrogels on the catalytic reduction of 4-nitrophenol were studied. The results showed that the composite hydrogels could be easily separated from the water environment, which indicated the large-scale potential application in organic catalytic degradation and wastewater treatment.

Fabrication of hierarchical SrTiO3@MoS2 heterostructure nanofibers as efficient and low-cost electrocatalysts for hydrogen-evolution reactions.

The construction of low-cost, high-performance electrocatalysts instead of platinum catalysts is critical to solving the energy crisis. Here, using simple electrospinning and hydrothermal methods, new MoS2 nanosheets on SrTiO3 nanofibers (NFs) and 2D SrTiO3@MoS2 heterostructure NFs are synthesized. In addition, SrTiO3@MoS2 heterostructure NFs are compared with bare SrTiO3 NFs and MoS2 nanosheets. Importantly, the prepared SrTiO3@MoS2 heterostructure shows better hydrogen-evolution reaction performance than other MoS2-based electrocatalysts with an overpotential of 165 mV at 10 mA cm-2, a Tafel slope of 81.41 mV dec-1, and long-term electrochemical durability of 3000 cycles. Therefore, the present work strongly demonstrates the positive synergy between SrTiO3 NFs and layered MoS2, and also provides a strategy for preparing low-cost and high-activity water-decomposition electrocatalysts.

Self-assembled functional components-doped conductive polypyrrole composite hydrogels with enhanced electrochemical performances.

A conductive hydrogel is a composite conductive material formed by combining a conductive polymer with a nanogel structure of a hydrogel. Conductive hydrogels not only have potential applications in supercapacitors, sensors, and modulators, they can also be synthesized by many methods, such as copolymerization, crosslinking, and grafting. In this work, we successfully prepared three conductive composite hydrogels by in situ polymerization, namely polypyrrole sodium alginate conductive hydrogel, ferric chloride-doped polypyrrole sodium alginate hydrogel and doped polypyrrole sodium alginate hydrogel with sodium dodecylbenzene sulfonate. In addition, a series of characterizations were performed for the three conductive hydrogels described above. The results show that the polypyrrole sodium alginate hydrogel doped with ferric chloride forms a nanofiber network with a more stable structure and better electrochemical performance.