CHIP inhibits odontoblast differentiation through promoting DLX3 polyubiquitylation and degradation.

Dentin is the major hard tissue of teeth formed by differentiated odontoblasts. How odontoblast differentiation is regulated remains enigmatic. Here, we report that the E3 ubiquitin ligase CHIP is highly expressed in undifferentiated dental mesenchymal cells and downregulated after differentiation of odontoblasts. Ectopic expression of CHIP inhibits odontoblastic differentiation of mouse dental papilla cells, whereas knockdown of endogenous CHIP has opposite effects. Chip (Stub1) knockout mice display increased formation of dentin and enhanced expression of odontoblast differentiation markers. Mechanistically, CHIP interacts with and induces K63 polyubiquitylation of the transcription factor DLX3, leading to its proteasomal degradation. Knockdown of DLX3 reverses the enhanced odontoblastic differentiation caused by knockdown of CHIP. These results suggest that CHIP inhibits odontoblast differentiation by targeting its tooth-specific substrate DLX3. Furthermore, our results indicate that CHIP competes with another E3 ubiquitin ligase, MDM2, that promotes odontoblast differentiation by monoubiquitylating DLX3. Our findings suggest that the two E3 ubiquitin ligases CHIP and MDM2 reciprocally regulate DLX3 activity by catalyzing distinct types of ubiquitylation, and reveal an important mechanism by which differentiation of odontoblasts is delicately regulated by divergent post-translational modifications.

Simulating domain architecture evolution.

MOTIVATION: Simulation is an essential technique for generating biomolecular data with a 'known' history for use in validating phylogenetic inference and other evolutionary methods. On longer time scales, simulation supports investigations of equilibrium behavior and provides a formal framework for testing competing evolutionary hypotheses. Twenty years of molecular evolution research have produced a rich repertoire of simulation methods. However, current models do not capture the stringent constraints acting on the domain insertions, duplications, and deletions by which multidomain architectures evolve. Although these processes have the potential to generate any combination of domains, only a tiny fraction of possible domain combinations are observed in nature. Modeling these stringent constraints on domain order and co-occurrence is a fundamental challenge in domain architecture simulation that does not arise with sequence and gene family simulation. RESULTS: Here, we introduce a stochastic model of domain architecture evolution to simulate evolutionary trajectories that reflect the constraints on domain order and co-occurrence observed in nature. This framework is implemented in a novel domain architecture simulator, DomArchov, using the Metropolis-Hastings algorithm with data-driven transition probabilities. The use of a data-driven event module enables quick and easy redeployment of the simulator for use in different taxonomic and protein function contexts. Using empirical evaluation with metazoan datasets, we demonstrate that domain architectures simulated by DomArchov recapitulate properties of genuine domain architectures that reflect the constraints on domain order and adjacency seen in nature. This work expands the realm of evolutionary processes that are amenable to simulation. AVAILABILITY AND IMPLEMENTATION: DomArchov is written in Python 3 and is available at http://www.cs.cmu.edu/~durand/DomArchov. The data underlying this article are available via the same link. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Perineural invasion affects prognosis of patients undergoing colorectal cancer surgery: a propensity score matching analysis.

BACKGROUND: Tumour perineural invasion (PNI) is a predictor of poor prognosis, but its effect on the prognosis of patients with colorectal cancer (CRC) has not yet been elucidated. METHODS: This retrospective study used propensity score matching (PSM). The clinical case data of 1470 patients with surgically treated stage I-IV CRC at Wuhan Union Hospital were collected. PSM was used to analyse and compare the clinicopathological characteristics, perioperative outcomes, and long-term prognostic outcomes of the PNI(+) and PNI(-) groups. The factors influencing prognosis were screened using Cox univariate and multivariate analyses. RESULTS: After PSM, 548 patients were included in the study (n = 274 in each group). Multifactorial analysis showed that neurological invasion was an independent prognostic factor affecting patients' OS and DFS (hazard ratio [HR], 1.881; 95% confidence interval [CI], 1.35-2.62; P = 0.0001; HR, 1.809; 95% CI, 1.353-2.419; P < 0.001). Compared to PNI(+) patients without chemotherapy, those who received chemotherapy had a significant improvement in OS (P < 0.01). The AUROC curve of OS in the PNI(+) subgroup (0.802) was higher than that after PSM (0.743), while that of DFS in the PNI(+) subgroup (0.746) was higher than that after PSM (0.706). The independent predictors of PNI(+) could better predict the prognosis and survival of patients with PNI(+). CONCLUSIONS: PNI significantly affects the long-term survival and prognosis of patients with CRC undergoing surgery and is an independent risk factor for OS and DFS in patients with CRC undergoing surgery. Postoperative chemotherapy significantly improved the OS of PNI(+) patients.

Modified Naples prognostic score for evaluating the prognosis of patients with obstructive colorectal cancer.

BACKGROUND: Inflammatory, immune, and nutritional status are key factors in obstructive colorectal cancer (OCRC). This study aims to investigate the value of modified Naples prognostic score (M-NPS) in evaluating OCRC prognosis. METHODS: A total of 196 OCRC patients were retrospectively analyzed to construct M-NPS based on serum albumin (ALB), total cholesterol (CHOL), neutrophil:lymphocyte ratio (NLR), and lymphocyte:monocyte ratio (LMR), and then they were divided into three groups. The Kaplan-Meier (KM) method and Cox proportional hazard regression analysis were performed for overall survival (OS) and disease-free survival (DFS) of OCRC patients. RESULTS: Patients with high M-NPS had worse OS and DFS (P = 0.0001, P = 0.0011). Multivariate COX analysis showed that M-NPS was an independent prognostic factor for OCRC patients. Patients in the M-NPS 2 group had significantly worse OS (hazard ratio [HR] = 4.930 (95% confidence interval [95% CI], 2.217-10.964), P < 0.001) and DFS (HR = 3.508 (95% CI, 1.691-7.277), P < 0.001) than those in the 0 group. CONCLUSION: M-NPS was an independent prognostic factor for OCRC patients; it might provide a potential reference for immunonutritional intervention in patients with obstruction.

Endoscopic fully covered self-expandable metal stent and vacuum-assisted drainage to treat postoperative colorectal cancer anastomotic stenosis with fistula.

BACKGROUND: Digestive tract reconstruction is required after the surgical resection of a colorectal malignant tumor. Some patients may have concomitant anastomotic complications, such as anastomotic stenosis with fistula (ASF), postoperatively. Therefore, we evaluated the efficacy and safety of endoscopic fully covered self-expandable metal stent and homemade vacuum sponge-assisted drainage (FSEM-HVSD) for the treatment of ASF following the radical resection of colorectal cancer. METHODS: Patients treated with FESM-HVSD were prospectively analyzed and followed up for ASF following colorectal cancer treatment in our medical center from 2017 to 2021 for the observation and evaluation of its safety and efficacy. RESULTS: Fifteen patients with a mean age of 55.80 ± 11.08 years were included. Nine patients (60%) underwent protective ileostomy. All 15 patients were treated with endoscopic FSEM-HVSD. The median time from the index operation to the initiation of FSEM-HVSD was 80 ± 20.34 days in patients who underwent protective ileostomy versus 11.4 ± 4.4 days in those who did not. The average number of endoscopic treatments per patient was 5.70 ± 1.25 times. The mean length of hospital stay was 27.60 ± 4.43 days. FSEM-HVSD treatment was successful in 13 patients, and no patients had any complications. The follow-up time was 1 year. Twelve of 15 (80%) patients achieved prolonged clinical success after FSEM-HVSD treatment, 1 experienced anastomotic tumor recurrence and underwent surgery again, and 1 patient required balloon dilation for anastomotic stenosis recurrence. CONCLUSIONS: FSEM-HVSD is an effective, safe, and minimally invasive treatment for ASF following colorectal cancer treatment. This technique could be the preferred treatment strategy for patients with ASF.

A novel DSPP frameshift mutation causing dentin dysplasia type 2 and disease management strategies.

The present study aims to investigate the mutation in a Chinese family with dentin dysplasia type II (DD-II) and to summarize mutation hotspots, clinical manifestations, and disease management strategies. Phenotype analysis, clinical intervention, mutation screening, and cosegregation analysis within the enrolled family were performed. A summary of the reported mutations in the dentin phosphoprotein (DPP) region of dentin sialophosphoprotein (DSPP) was analyzed. Pathogenicity prediction analysis of the physical properties and function of DSPP variants was performed by bioinformatic processing. Clinical management strategies are discussed. A novel pathogenic mutation (c.2035delA) in the DPP region of DSPP was identified, which was cosegregated in the family. The immature permanent teeth of patients with DD-II presented with X-shaped root canal phenotypes. Most of the identified mutations for DD-II were clustered in the DPP region between nucleotides 1686-2134. Points of differential diagnosis, clinical interventions, and management strategies are proposed. This study revealed a novel DSPP frameshift mutation and presented new clinical features of DD-II. The locus involving nucleotides 1686-2134 of DSPP may represent a mutational hotspot for the disease. Appropriate management of DD-II at different stages is important to avoid the development of secondary dental lesions.

Development and validation of a prognostic scoring system for patients with colorectal cancer hepato-pulmonary metastasis: a retrospective study.

BACKGROUND: Hepato-pulmonary metastasis of colorectal cancer (CRC) is a rare disease with poor prognosis. This study aims to establish a highly efficient nomogram model to predict overall survival (OS) and cancer-specific survival (CSS) in patients with colorectal cancer hepato-pulmonary metastasis (CRCHPM). METHODS: We retrospectively analyzed the data of patients with CRCHPM from SEER database and Wuhan Union Hospital Cancer Center (WUHCC). A total of 1250 CRCHPM patients were randomly assigned to the training, internal validation, and external validation cohorts from 2010 to 2016.Univariate and multivariate cox analysis were performed to identify independent clinicopathological predictors of OS and CSS, and a nomogram was constructed to predict OS and CSS in CRCHPM patients. RESULTS: A nomogram of OS was constructed based on seven independent predictors of age, degree of differentiation, T stage, chemotherapy, number of lsampled lymph nodes, number of positive lymph nodes, and tumor size. Nomogram showed favorable sensitivity in predicting OS at 1, 3 and 5 years, with area under the receiver operating characteristic curve (AUROC) values of 0.802, 0.759 and 0.752 in the training cohort;0.814, 0.769 and 0.716 in the internal validation cohort;0.778, 0.756 and 0.753 in the external validation cohort, respectively. A nomogram of CSS was constructed based on three independent predictors of T stage, chemotherapy, and tumor size. The AUROC values of 1, 3 and 5 years were 0.709,0.588,0.686 in the training cohort; 0.751, 0.648,0.666 in the internal validation cohort;0.781,0.588,0.645 in the external validation cohort, respectively. Calibration curves, Concordance index (C-index), and decision curve analysis (DCA) results revealed that using our model to predict OS and CSS is more efficient than other single clinicopathological characteristics. CONCLUSION: A nomogram of OS and CSS based on clinicopathological characteristics can be conveniently used to predict the prognosis of CRCHPM patients.

Application of nanotechnology in the early diagnosis and comprehensive treatment of gastrointestinal cancer.

Gastrointestinal cancer (GIC) is a common malignant tumour of the digestive system that seriously threatens human health. Due to the unique organ structure of the gastrointestinal tract, endoscopic and MRI diagnoses of GIC in the clinic share the problem of low sensitivity. The ineffectiveness of drugs and high recurrence rates in surgical and drug therapies are the main factors that impact the curative effect in GIC patients. Therefore, there is an urgent need to improve diagnostic accuracies and treatment efficiencies. Nanotechnology is widely used in the diagnosis and treatment of GIC by virtue of its unique size advantages and extensive modifiability. In the diagnosis and treatment of clinical GIC, surface-enhanced Raman scattering (SERS) nanoparticles, electrochemical nanobiosensors and magnetic nanoparticles, intraoperative imaging nanoparticles, drug delivery systems and other multifunctional nanoparticles have successfully improved the diagnosis and treatment of GIC. It is important to further improve the coordinated development of nanotechnology and GIC diagnosis and treatment. Herein, starting from the clinical diagnosis and treatment of GIC, this review summarizes which nanotechnologies have been applied in clinical diagnosis and treatment of GIC in recent years, and which cannot be applied in clinical practice. We also point out which challenges must be overcome by nanotechnology in the development of the clinical diagnosis and treatment of GIC and discuss how to quickly and safely combine the latest nanotechnology developed in the laboratory with clinical applications. Finally, we hope that this review can provide valuable reference information for researchers who are conducting cross-research on GIC and nanotechnology.

Systematic discovery of the functional impact of somatic genome alterations in individual tumors through tumor-specific causal inference.

Cancer is mainly caused by somatic genome alterations (SGAs). Precision oncology involves identifying and targeting tumor-specific aberrations resulting from causative SGAs. We developed a novel tumor-specific computational framework that finds the likely causative SGAs in an individual tumor and estimates their impact on oncogenic processes, which suggests the disease mechanisms that are acting in that tumor. This information can be used to guide precision oncology. We report a tumor-specific causal inference (TCI) framework, which estimates causative SGAs by modeling causal relationships between SGAs and molecular phenotypes (e.g., transcriptomic, proteomic, or metabolomic changes) within an individual tumor. We applied the TCI algorithm to tumors from The Cancer Genome Atlas (TCGA) and estimated for each tumor the SGAs that causally regulate the differentially expressed genes (DEGs) in that tumor. Overall, TCI identified 634 SGAs that are predicted to cause cancer-related DEGs in a significant number of tumors, including most of the previously known drivers and many novel candidate cancer drivers. The inferred causal relationships are statistically robust and biologically sensible, and multiple lines of experimental evidence support the predicted functional impact of both the well-known and the novel candidate drivers that are predicted by TCI. TCI provides a unified framework that integrates multiple types of SGAs and molecular phenotypes to estimate which genome perturbations are causally influencing one or more molecular/cellular phenotypes in an individual tumor. By identifying major candidate drivers and revealing their functional impact in an individual tumor, TCI sheds light on the disease mechanisms of that tumor, which can serve to advance our basic knowledge of cancer biology and to support precision oncology that provides tailored treatment of individual tumors.

Gel Formation Induced Slow Dissolution of Amorphous Indomethacin.

PURPOSE: Amorphous indomethacin (IMC) forms gel with a decreased dissolution behavior compared to crystalline IMC during dissolution. The current study aims to explore gelation mechanism and attempt to eliminate gelling effect by formulation development. METHODS: Amorphous IMC was prepared by melt-quenching method. Dissolution tests of amorphous IMC were performed at various temperatures under sink condition. The formed gels were characterized by PLM, SEM, DSC and XRPD. RESULTS: Amorphous IMC exhibited an initial higher dissolution followed by a decreased dissolution lower than its crystalline counterpart at 32 and 37°C, and even a much lower dissolution during the whole dissolution period at 45°C. Meanwhile, a viscous soft mass ("gel") was observed to adhere upon the paddle or wall of the vessel. The formed gel could be characterized as a three-dimensional dense micro-fiber structure under SEM. The gel formation was proposed to be related to the decreased Tg of amorphous IMC when contacting aqueous medium, resulting in entering into supercooled liquid state with high viscosity. The addition of hydrophilic silica accelerated gel formation, while mixing with hydrophobic silica was able to weaken and even eliminate the gelation, and hence significantly enhancing dissolution. CONCLUSIONS: The present study recommends that gel formation should be included in the investigation of amorphous materials in order to find ways for resolving defects of amorphous materials while keeping their advantages in pharmaceutics.

Adult sex ratio, sexual dimorphism and sexual selection in a Mesozoic reptile.

The evolutionary history of sexual selection in the geologic past is poorly documented based on quantification, largely because of difficulty in sexing fossil specimens. Even such essential ecological parameters as adult sex ratio (ASR) and sexual size dimorphism (SSD) are rarely quantified, despite their implications for sexual selection. To enable their estimation, we propose a method for unbiased sex identification based on sexual shape dimorphism, using size-independent principal components of phenotypic data. We applied the method to test sexual selection in Keichousaurus hui, a Middle Triassic (about 237 Ma) sauropterygian with an unusually large sample size for a fossil reptile. Keichousaurus hui exhibited SSD biased towards males, as in the majority of extant reptiles, to a minor degree (sexual dimorphism index -0.087). The ASR is about 60% females, suggesting higher mortality of males over females. Both values support sexual selection of males in this species. The method may be applied to other fossil species. We also used the Gompertz allometric equation to study the sexual shape dimorphism of K. hui and found that two sexes had largely homogeneous phenotypes at birth except in the humeral width, contrary to previous suggestions derived from the standard allometric equation.

Evidence-Based Practice Point-of-Care Resources: A Quantitative Evaluation of Quality, Rigor, and Content.

OBJECTIVE: Clinicians and other healthcare professionals need access to summaries of evidence-based information in order to provide effective care to their patients at the point-of-care. Evidence-based practice (EBP) point-of-care resources have been developed and are available online to meet this need. This study aimed to develop a comprehensive list of available EBP point-of-care resources and evaluate their processes and policies for the development of content, in order to provide a critical analysis based upon rigor, transparency and measures of editorial quality to inform healthcare providers and promote quality improvement amongst publishers of EBP resources. DESIGN: A comprehensive and systematic search (Pubmed, CINAHL, and Cochrane Central) was undertaken to identify available EBP point-of-care resources, defined as "web-based medical compendia specifically designed to deliver predigested, rapidly accessible, comprehensive, periodically updated, and evidence-based information (and possibly also guidance) to clinicians." MAIN OUTCOME MEASURES: A pair of investigators independently extracted information on general characteristics, content presentation, editorial quality, evidence-based methodology, and breadth and volume. RESULTS: Twenty-seven summary resources were identified, of which 22 met the predefined inclusion criteria for EBP point-of-care resources, and 20 could be accessed for description and assessment. Overall, the upper quartile of EBP point-of-care providers was assessed to be UpToDate, Nursing Reference Centre, Mosby's Nursing Consult, BMJ Best Practice, and JBI COnNECT+. LINKING EVIDENCE TO ACTION: The choice of which EBP point-of-care resources are suitable for an organization is a decision that depends heavily on the unique requirements of that organization and the resources it has available. However, the results presented in this study should enable healthcare providers to make that assessment in a clear, evidence-based manner, and provide a comprehensive list of the available options.

Facile Synthesis of a Multifunctional Porous Organic Polymer Nanosonosensitizer (mHM@HMME) for Enhanced Cancer Sonodynamic Therapy.

Sonodynamic therapy (SDT), which involves the activation of sonosensitizers to generate cytotoxic reactive oxygen species under ultrasound irradiation, is a promising noninvasive modality for cancer treatment. However, the clinical translational application of SDT is impeded by the lack of efficient sonosensitizers, the inefficient accumulation of sonosensitizers at tumor sites, and the complicated immunosuppressive tumor microenvironment. Herein, we developed a facilely synthesized multifunctional porous organic polymer nanosonosensitizer (mHM@HMME) for enhanced SDT. Specifically, mHM@HMME nanosonosensitizers were prepared by incorporating chemotherapeutic mitoxantrone into the one-step synthesis process of disulfide bond containing porous organic polymers, followed by loading with organic sonosensitizer (HMME) and camouflaging with a cancer cell membrane. Due to the cancer cell membrane camouflage, this multifunctional mHM@HMME nanosonosensitizer showed prolonged blood circulation and tumor targeting aggregation. Under ultrasound irradiation, the mHM@HMME nanosonosensitizer exhibited a satisfactory SDT performance both in vitro and in vivo. Moreover, the potent SDT combined with glutathione-responsive drug release in tumor cells induced robust immunogenic cell death to enhance the antitumor effect of SDT in turn. Overall, this facilely synthesized multifunctional mHM@HMME nanosonosensitizer shows great potential application in enhanced SDT.

Injectable Hydrogel Delivery System with High Drug Loading for Prolonging Local Anesthesia.

Peripheral nerve block is performed for precise pain control and lesser side effects after surgery by reducing opioid consumption. Injectable hydrogel delivery systems with high biosafety and moisture content have good clinical application prospects for local anesthetic delivery. However, how to achieve high drug loading and long-term controlled release of water-soluble narcotic drugs remains a big challenge. In this study, heterogeneous microspheres and an injectable gel-matrix composite drug delivery system are designed in two steps. First, heterogeneous hydrogel microspheres loaded with ropivacaine (HMS-ROP) are prepared using a microfluidic chip and in situ alkalization. An injectable self-healing hydrogel matrix (Gel) is then prepared from modified carboxymethylcellulose (CMC-ADH) and oxidized hyaluronic acid (OHA). A local anesthetic delivery system, Gel/HMS-ROP/dexmedetomidine (DEX), with long-term retention and drug release in vivo is prepared by combining HMS-ROP and Gel/DEX. The drug loading of HMS-ROP reached 41.1%, with a drug release time of over 160 h in vitro, and sensory and motor blockade times in vivo of 48 and 36 h, respectively. In summary, the sequential release and synergistic analgesic effects of the two anesthetics are realized using core-shell microspheres, DEX, and an injectable gel, providing a promising strategy for long-acting postoperative pain management.

Pharmacological suppression of the OTUD4/CD73 proteolytic axis revives antitumor immunity against immune-suppressive breast cancers.

Despite widespread utilization of immunotherapy, treating immune-cold tumors remains a challenge. Multiomic analyses and experimental validation identified the OTUD4/CD73 proteolytic axis as a promising target in treating immune-suppressive triple negative breast cancer (TNBC). Mechanistically, deubiquitylation of CD73 by OTUD4 counteracted its ubiquitylation by TRIM21, resulting in CD73 stabilization inhibiting tumor immune responses. We further demonstrated the importance of TGF-ß signaling for orchestrating the OTUD4/CD73 proteolytic axis within tumor cells. Spatial transcriptomics profiling discovered spatially resolved features of interacting malignant and immune cells pertaining to expression levels of OTUD4 and CD73. In addition, ST80, a newly developed inhibitor, specifically disrupted proteolytic interaction between CD73 and OTUD4, leading to reinvigoration of cytotoxic CD8+ T cell activities. In preclinical models of TNBC, ST80 treatment sensitized refractory tumors to anti-PD-L1 therapy. Collectively, our findings uncover what we believe to be a novel strategy for targeting the immunosuppressive OTUD4/CD73 proteolytic axis in treating immune-suppressive breast cancers with the inhibitor ST80.

Which visual elements on packaging affect perceived credibility? A case study of in vitro diagnostic kits.

With increasing public health awareness and the unprecedented global health crisis, consumers' demand for in vitro diagnostic (IVD) reagents is gradually increasing. However, consumer mistrust remains a significant barrier to purchasing and using IVD products. Pharmaceutical companies and governments prioritizing direct-to-consumer (DTC) marketing have recognized the impact of visual packaging elements on consumer perception. Thus, we researched whether visual packaging elements systematically influence consumers' perceived credibility of IVD products' credence attributes, namely, their ability to protect personal and public health. Combining previous related studies, this study was conducted experimentally with rapid diagnostic test (RDT) kits, assuming that the visual elements (i.e., typeface, color, pattern, and information) of packaging can influence consumers' perceived credibility of RDT kits and explored which elements are more credible. Questionnaires were randomly selected and assigned to 216 participants. The results indicated that all four elements influenced the participants' perceived credibility. Specifically, a sans serif typeface, realistic pattern, chromatic color, and more information made the participants feel more credible. Our research results fill a gap in the consumer perception of over-the-counter (OTC) pharmaceutical products by providing new insights into dissecting consumer perceptions. This offers a novel design strategy for online and offline marketing and promotional efforts by different companies and governmental organizations.

Engineering Diselenide-IR780 Homodimeric Nanoassemblies with Enhanced Photodynamic and Immunotherapeutic Effects for Triple-Negative Breast Cancer Treatment.

Photodynamic therapy (PDT) has emerged as an efficient approach for non-invasive cancer treatment. However, organic small-molecule photosensitizers are often associated with defects in hydrophobicity, poor photostability, and aggregation-caused quenching, which limit their application. Usually, the carrier-assisted drug delivery system is a common strategy to solve the above obstacles, but additional carrier material could increase the risk of potential biological toxicity. The carrier-free drug delivery system with easy preparation and high drug-loading capability is proposed subsequently as a potential strategy to develop the clinical use of hydrophobic drugs. Herein, we rationally designed three IR780-based carrier-free nanosystems formed by carbon/disulfide/diselenide bond conjugated IR780-based homodimers. The IR780-based homodimers could self-assemble to form nanoparticles (DC-NP, DS-NP, DSe-NP) and exhibited higher reactive oxygen species generation capability and photostability than free IR780, in which DSe-NP with 808 nm laser irradiation performed best and resulted in the strongest cytotoxicity to 4T1 cells. Meanwhile, the glutathione consumption ability of DSe-NP boosted its PDT effect and then induced excessive oxidative stress of 4T1 cells, increasing antitumor efficacy by enhancing immunogenic cell death further. In tumor-bearing mice, DSe-NP displayed obvious tumor site accumulation, which obviously inhibited tumor growth and metastasis, and enhanced the immunological effect by effectively inducing dendritic cells to mature and activating T lymphocytes and natural killer cells. In summary, our study presented an IR780-based carrier-free nanodelivery system for a combination of PDT and immunity therapy and established expanding the application of organic small-molecule photosensitizers by an approach of carrier-free drug delivery system.

Microvascularized tumor assembloids model for drug delivery evaluation in colorectal cancer-derived peritoneal metastasis.

Peritoneal metastasis (PM) is a fatal state of colorectal cancer, and only a few patients may benefit from systemic chemotherapy. Although hyperthermic intraperitoneal chemotherapy (HIPEC) brings hope for affected patients, the drug development and preclinical evaluation of HIPEC are seriously lagging behind, mainly due to the lack of an ideal in vitro PM model that makes drug development over-reliant on expensive and inefficient animal experiments. This study developed an in vitro colorectal cancer PM model [microvascularized tumor assembloids (vTA)] based on an assembly strategy of endothelialized microvessels and tumor spheroids. Our data showed that the in vitro perfusion cultured vTA could maintain a similar gene expression pattern to their parental xenografts. Also, the drug penetration pattern of the in vitro HIPEC in vTA could mimic the drug delivery behavior in tumor nodules during in vivo HIPEC. More importantly, we further confirmed the feasibility of constructing a tumor burden-controlled PM animal model using vTA. In conclusion, we propose a simple and effective strategy to construct physiologically simulated PM models in vitro, thus providing a basis for PM-related drug development and preclinical evaluation of locoregional therapies. STATEMENT OF SIGNIFICANCE: This study developed an in vitro colorectal cancer peritoneal metastasis (PM) model based on microvascularized tumor assembloids (vTA) for drug evaluation. With perfusion culture, vTA could maintain a similar gene expression pattern and tumor heterogeneity to their parental xenografts. And the drug penetration pattern in vTA was similar to the drug delivery behavior in tumor nodules under in vivo treatment. Moreover, vTA was more conducive to construct PM animal models with controllable tumor burden. In conclusion, the construction of vTA could provide a new strategy for the PM-related drug development and preclinical evaluation of locoregional therapies.

Direct Z-scheme GaN/WSe2 heterostructure for enhanced photocatalytic water splitting under visible spectrum.

van der Waals heterostructures are widely used in the field of photocatalysis due to the fact that their properties can be regulated via an external electric field, strain engineering, interface rotation, alloying, doping, etc. to promote the capacity of discrete photogenerated carriers. Herein, we fabricated an innovative heterostructure by piling monolayer GaN on isolated WSe2. Subsequently, a first principles calculation based on density functional theory was performed to verify the two-dimensional GaN/WSe2 heterostructure and explore its interface stability, electronic property, carrier mobility and photocatalytic performance. The results demonstrated that the GaN/WSe2 heterostructure has a direct Z-type band arrangement and possesses a bandgap of 1.66 eV. The built-in electric field is caused by the transfer of positive charge between the WSe2 layers to the GaN layer, directly leading to the segregation of photogenerated electron-hole pairs. The GaN/WSe2 heterostructure has high carrier mobility, which is conducive to the transmission of photogenerated carriers. Furthermore, the Gibbs free energy changes to a negative value and declines continuously during the water splitting reaction into oxygen without supplementary overpotential in a neural environment, satisfying the thermodynamic demands of water splitting. These findings verify the enhanced photocatalytic water splitting under visible light and can be used as the theoretical basis for the practical application of GaN/WSe2 heterostructures.

MYL9 expressed in cancer-associated fibroblasts regulate the immune microenvironment of colorectal cancer and promotes tumor progression in an autocrine manner.

BACKGROUND: The tumor microenvironment (TME) is an important factor that regulates the progression of colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs) are the main mesenchymal cells in the TME and play a vital role in tumor progression; however, the specific underlying mechanisms require further study. METHODS: Multiple single-cell and transcriptome data were analyzed and validated. Primary CAFs isolation, CCK8 assay, co-culture assay, western blotting, multiple immunofluorescence, qRT-PCR, ELISA, immunoprecipitation, ChIP, double luciferase, and animal experiments were used to explore the potential mechanism of MYL9 regulation in CRC. RESULTS: Our findings revealed that MYL9 was predominantly localized and expressed in CAFs rather than in CRC cells, and bioinformatics analysis revealed that high MYL9 expression was strongly associated with poor overall and disease-free survival in various tumors. In addition, high MYL9 expression is closely associated with M2 macrophage infiltration, which can lead to an immunosuppressive microenvironment in CRC, making it insensitive to immunotherapy. Mechanically, MYL9 can regulate the secretion of CAFs on CCL2 and TGF-ß1, thus affecting the immune microenvironment and progression of CRC. In addition, MYL9 bounded with IQGAP1 to regulate CCL2 and TGF-ß1 secretion through the ERK 1/2 pathway, and CCL2 and TGF-ß1 synergistically promoted CRC cells progression through the PI3K-AKT pathway. Furthermore, MYL9 promotes epithelial-mesenchymal transition (EMT) in CRC. During the upstream regulation of MYL9 in CAFs, we found that the EMT transcription factor ZEB1 could bind to the MYL9 promoter in CAFs, enhancing the activity and function of MYL9. Therefore, MYL9 is predominantly expressed in CAFs and can indirectly influence tumor biology and EMT by affecting CAFs protein expression in CRC. CONCLUSIONS: MYL9 regulates the secretion of cytokines and chemokines in CAFs, which can affect the immune microenvironment of CRC and promote CRC progression. The relationship between MYL9 expression and CRC clinical staging and immunotherapy is closer in CAFs than in tumor cells; therefore, studies using CAFs as a model deserve more attention when exploring tumor molecular targets in clinical research.