Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial.

PURPOSE: Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC. PATIENTS AND METHODS: A prospective, single-arm, phase II study was conducted to treat locally advanced GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses. RESULTS: The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC to NAIC. More importantly, an intestinal-subtype specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts. CONCLUSIONS: Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.

V2 Protein Enhances the Replication of Genomic DNA of Mulberry Crinkle Leaf Virus.

Mulberry crinkle leaf virus (MCLV), identified in mulberry plants (Morus alba L.), is a member of the genus Mulcrilevirus in the family Geminiviridae. The functions of the V2 protein encoded by MCLV remain unclear. Here, Agrobacterium-mediated infectious clones of a wild-type MCLV vII (MCLVWT) and two V2 mutant MCLV vIIs, including MCLVmV2 (with a mutation of the start codon of the V2 ORF) and MCLVdV2 (5'-end partial deletion of the V2 ORF sequence), were constructed to investigate the roles of V2 both in planta and at the cellular level. Although all three constructs (pCA-1.1MCLVWT, pCA-MCLVmV2, and pCA-MCLVdV2) were able to infect both natural host mulberry plants and experimental tomato plants systematically, the replication of the MCLVmV2 and MCLVdV2 genomes in these hosts was significantly reduced compared to that of MCLVWT. Similarly, the accumulation of MCLVmV2 and MCLVdV2 in protoplasts of Nicotiana benthamiana plants was significantly lower than that of MCLVWT either 24 h or 48 h post-transfection. A complementation experiment further confirmed that the decreased accumulation of MCLV in the protoplasts was due to the absence of V2 expression. These results revealed that MCLV-encoded V2 greatly enhances the level of MCLV DNA accumulation and is designated the replication enhancer protein of MCLV.

Reduced intestinal-to-diffuse conversion and immunosuppressive responses underlie superiority of neoadjuvant immunochemotherapy in gastric adenocarcinoma.

Neoadjuvant immunochemotherapy (NAIC) achieves superior clinical benefits over neoadjuvant chemotherapy (NAC) in multiple types of human cancers, including gastric adenocarcinoma (GAC). However, it is poorly understood how the malignant epithelial cells and tumor immune microenvironment (TIME) might respond distinctly to NAIC and NAC that underlies therapeutic efficacy. Here treatment-naive and paired tumor tissues from multiple centers were subjected to pathological, immunological, and transcriptomic analysis. NAIC demonstrated significantly increased rate of pathological complete response compared to NAC (pCR: 25% vs. 4%, p < 0.05). Interestingly, pretreatment intestinal subtype of Lauren's classification was predictive of pathologic regression following NAIC, but not NAC. A substantial portion of cancers underwent intestinal-to-diffuse transition, which occurred less following NAIC and correlated with treatment failure. Moreover, NAIC prevented reprogramming to an immunosuppressive TIME with less active fibroblasts and exhausted CD8+ T cells, and increased numbers of mature tertiary lymphoid structures. Mechanistically, activation of the tumor necrosis factor alpha (TNFα)/nuclear factor-kappa B (NF-κB) signaling pathway was associated with response to NAIC. Together, NAIC is superior to NAC for locally advanced GAC, likely due to reduced intestinal-to-diffuse conversion and reprogramming to an immuno-active TIME. Modulation of the histological conversion and immunosuppressive TIME could be translatable approaches to improve neoadjuvant therapeutic efficacy.

A urethral leiomyoma presenting with dysuria: A rare case report.

RATIONALE: Leiomyoma is a benign smooth muscle tumor which is rarely found in urethra. We hereby report a case of a 44-year-old female who presented with complaints of dysuria. PATIENT CONCERNS: A 44-year-old female patient presented to the urology outpatient clinic with symptoms of dysuria. The patient described the presence of a protrusion from the urethra during urination. DIAGNOSIS: Urethral leiomyoma. INTERVENTIONS: Physical examination confirmed a solid urethral mass. CT scan and USG reports indicated that the mass originated from the mid-urethra with vascularity at the base. We performed a complete resection of the urethral mass. The patient was discharged after 3 days of observation. OUTCOME: During a follow-up after 1 month, the patient reported improved urinary flow and no occurrence of hematuria. The patient recovered well after discharge. LESSON: Urethral leiomyoma is a rare benign tumor that is often misdiagnosed in clinical practice. Diagnosis requires careful clinical examination. Surgical removal usually works well. It is important to remember that in some cases of acute urinary retention, it can be caused by a complete obstruction of a mass in the urethra. Urologists should be more cautious and experienced in handling such cases.

A pyocin-like T6SS effector mediates bacterial competition in Yersinia pseudotuberculosis.

Within the realm of Gram-negative bacteria, bacteriocins are secreted almost everywhere, and the most representative are colicin and pyocin, which are secreted by Escherichia coli and Pseudomonas aeruginosa, respectively. Signal peptides at the amino terminus of bacteriocins or ABC transporters can secrete bacteriocins, which then enter bacteria through cell membrane receptors and exert toxicity. In general, the bactericidal spectrum is usually narrow, killing only the kin or closely related species. Our previous research indicates that YPK_0952 is an effector of the third Type VI secretion system (T6SS-3) in Yersinia pseudotuberculosis. Next, we sought to determine its identity and characterize its toxicity. We found that YPK_0952 (a pyocin-like effector) can achieve intra-species and inter-species competitive advantages through both contact-dependent and contact-independent mechanisms mediated by the T6SS-3 while enhancing the intestinal colonization capacity of Y. pseudotuberculosis. We further identified YPK_0952 as a DNase dependent on Mg2+, Ni2+, Mn2+, and Co2+ bivalent metal ions, and the homologous immune protein YPK_0953 can inhibit its activity. In summary, YPK_0952 exerts toxicity by degrading nucleic acids from competing cells, and YPK_0953 prevents self-attack in Y. pseudotuberculosis.IMPORTANCEBacteriocins secreted by Gram-negative bacteria generally enter cells through specific interactions on the cell surface, resulting in a narrow bactericidal spectrum. First, we identified a new pyocin-like effector protein, YPK_0952, in the third Type VI secretion system (T6SS-3) of Yersinia pseudotuberculosis. YPK_0952 is secreted by T6SS-3 and can exert DNase activity through contact-dependent and contact-independent entry into nearby cells of the same and other species (e.g., Escherichia coli) to help Y. pseudotuberculosis to exert a competitive advantage and promote intestinal colonization. This discovery lays the foundation for an in-depth study of the different effector protein types within the T6SS and their complexity in competing interactions. At the same time, this study provides a new development for the toolbox of toxin/immune pairs for studying Gram-negative bacteriocin translocation.

Number of Positive Lymph Nodes and Survival in Endometrial Carcinoma: A Proposal for a Modified Staging.

Purpose: To construct a new clinical staging system including the number of lymph node metastases to supplement the International Federation of Gynecology and Obstetrics (FIGO) staging for the prognosis of endometrial carcinoma patients. Methods: This cohort study retrieved the data of 28,824 patients confirmed as endometrial carcinoma between 2010 and 2015 in the surveillance, epidemiology, and end results (SEER) database. COX risk proportional model was established to evaluate the association between FIGO staging with the all-cause mortality of endometrial carcinoma. The diagnostic value of FIGO staging and the new staging for the mortality of patients were evaluated by receiver operator characteristic curve (ROC). Hazard ratio (HR) and 95% confidence interval (CI) were effect size. Results: The 5-year survival rate of all participants was 77.21%. The median follow-up time was 60.00 (60.00,60.00) months. Patients at FIGO staging IB (HR=1.75, 95% CI: 1.62-1.90), FIGO staging II (HR=2.22, 95% CI: 2.00-2.47), FIGO staging IIIA (HR=2.74, 95% CI: 2.43-3.09), FIGO staging IIIB (HR=4.07, 95% CI: 3.48-4.76), FIGO staging IIIC1 (HR=3.84, 95% CI: 3.52-4.20), FIGO staging IIIC2 (HR=4.52, 95% CI: 4.09-4.99), FIGO staging IVA (HR=5.56, 95% CI: 4.58-6.74), and FIGO staging IVB (HR=7.62, 95% CI: 6.94-8.36) were associated with increased risk of all-cause mortality of endometrial carcinoma patients. After adding positive lymph nodes as another covariate in Model 3, the effect on of FIGO staging survival was reduced when the FIGO staging was higher than stage III/IV. The C-index of the new staging 0.781 (95% CI: 0.774-0.787) was higher than FIGO staging 0.776 (95% CI: 0.770-0.783). Conclusion: Our new staging using the number of positive lymph nodes supplement to the FIGO staging was superior than the FIGO staging for predicting the prognosis of endometrial cancer patients, which might help more accurately identify endometrial carcinoma patients who were at high risk of mortality and offer timely treatments in these patients.

Fabrication and Properties of a Biodegradable Zn-Ca Composite.

In recent years, Zn and its alloys have become some of the most promising degradable metals as in vivo implants due to their acceptable biocompatibility and more suitable degradation rate compared with Mg-based and Fe-based alloys. However, the degradation rate of Zn-based materials after implantation in the body for orthopedic applications is relatively slow, leading to long-term retention of the implants after fulfilling their missions. Moreover, the excessive release of Zn2+ during the degradation process of Zn-based implants usually leads to high cytotoxicity and delayed osseointegration. To provide a feasible solution to the problem faced by Zn-based implants, a Zn-Ca composite was fabricated by an air pressure infiltration method in this work. The XRD pattern of the composite suggests that the composite is fully composed of Zn-Ca intermetallic compounds. The degradation tests in vitro show that the composite has a much higher degradation rate than pure Zn, and the high Ca content regions in the composite can preferentially degrade as sacrificial anodes. In addition, the composite can efficiently induce Ca-P deposition during immersion tests in Hank's solution. Cytotoxicity tests indicate that L-929 cells exhibit around 82% cell viability (Grade 1) even after being cultured in the 100% extract prepared from the Zn-Ca composite for 1 day and show excellent cell viability.

L-Arginine self-delivery supramolecular nanodrug for NO gas therapy.

NO gas therapy is a supplementary approach for tumor treatment due to the advantages of minimal invasion, little drug resistance, low side effect and amplified efficacy. l-Arginine (L-Arg), a natural NO source with good biocompatibility, can release NO under the stimulation of H2O2 in tumor microenvironment. However, the conventional l-Arg delivery systems via noncovalent loading usually lead to inevitable premature leakage of nano-cargos during blood circulation. In this work, an efficient l-Arg self-delivery supramolecular nanodrug (SDSND) for tumor treatment is demonstrated by combining Mannich reaction and π-π stacking. l-Arg links to (-)-epigallocatechin gallate (EGCG) with the assistance of formaldehyde through Mannich reaction, and then assembles into nanometer-sized particles via π-π stacking. The guanidine group of l-Arg and the phenolic hydroxyl groups of EGCG are preserved in the SDSNDs, which allows for accomplishing gas therapy by provoking tumor cell apoptosis and combining with EGCG to amplify apoptosis, respectively. In addition, the SDSNDs exhibit high biocompatibility and avoid the premature leakage of l-Arg in blood circulation, providing an alternative l-Arg delivery system for NO gas therapy. STATEMENT OF SIGNIFICANCE: NO gas therapy has attracted emerging interest in tumor treatment. However, the controlled NO release and the avoidance of premature leakage of NO donors remain challenging. In this work, L-Arginine (L-Arg) self-delivery supramolecular nanodrug for efficient tumor therapy is demonstrated through the Mannich reaction of L-Arg, (-)-epigallocatechin gallate (EGCG) and formaldehyde. Stimulated by tumor microenvironment, the guanidine groups of L-Arg allow for accomplishing NO release and thus provoking tumor cell apoptosis. The nanodrug also avoids the premature leakage of L-Arg in blood circulation. Moreover, the preserved phenolic hydroxyl groups of EGCG combine with L-Arg to amplify apoptosis. The nanodrug exhibits high biocompatibility and good therapeutic effect, providing an alternative L-Arg delivery system for NO gas therapy.

Effects of the Interactive Features of Virtual Partner on Individual Exercise Level and Exercise Perception.

BACKGROUND: We designed an exercise system in which the user is accompanied by a virtual partner (VP) and tested bodyweight squat performance with different interactive VP features to explore the comprehensive impact of these VP features on the individual's exercise level (EL) and exercise perception. METHODS: This experiment used three interactive features of VP, including body movement (BM), eye gaze (EG), and sports performance (SP), as independent variables, and the exercise level (EL), subjective exercise enjoyment, attitude toward the team formed with the VP, and local muscle fatigue degree of the exerciser as observational indicators. We designed a 2 (with or without VP's BM) × 2 (with or without VP's EG) × 2 (with or without VP's SP) within-participants factorial experiment. A total of 40 college students were invited to complete 320 groups of experiments. RESULTS: (1) Regarding EL, the main effects of BM and SP were significant (p < 0.001). The pairwise interaction effects of the three independent variables on EL were all significant (p < 0.05). (2) Regarding exercise perception, the main effects of BM (p < 0.001) and EG (p < 0.001) on subjective exercise enjoyment were significant. The main effect of BM on the attitude toward the sports team formed with the VP was significant (p < 0.001). The interaction effect of BM and SP on the attitude toward the sports team formed with the VP was significant (p < 0.001). (3) Regarding the degree of local muscle fatigue, the main effects of BM, EG, and SP and their interaction effects were not significant (p > 0.05). CONCLUSION: BM and EG from the VP elevate EL and exercise perception during squat exercises, while the VP with SP inhibited the EL and harmed exercise perception. The conclusions of this study can provide references to guide the interactive design of VP-accompanied exercise systems.

Employing single valency polyphenol to prepare metal-phenolic network antitumor reagents through FeOOH assistance.

Metal-phenolic networks (MPNs) have been conventionally formed by the coordination of metal ions and polyphenols, which can responsively release metal ions and polyphenols under the trigger of tumor microenvironment (TME), showing high potential in the field of antitumor. However, MPNs are mainly limited to multi-valency polyphenols, and the unavailability of single valency polyphenols greatly hinders their applications even though they have excellent antitumor activity. Herein, we demonstrate a FeOOH assisted preparation method for MPNs antitumor reagent by introducing the complexes of Fe3+, H2O and polyphenol (Fe(H2O)x-polyphenoly) in the preparation process, which overcomes the shortage of single valency polyphenols. Taking apigenin (Ap) as an example, Fe(H2O)x-Apy complexes are foremost formed, in which the Fe(H2O)x is capable of hydrolyzing to generate FeOOH, thus producing Fe3+-Ap networks-coated FeOOH nanoparticles (FeOOH@Fe-Ap NPs). Under the stimulation of the TME, FeOOH@Fe-Ap NPs could release Fe2+ and Ap, realizing ferroptosis and apoptosis for tumor combination therapy. In addition, FeOOH can shorten transverse relaxation time, acting as a T2-weighted magnetic resonance imaging contrast agent. The current efforts provide an alternative strategy for constructing MPNs by exploiting single valency polyphenols, which strengthens the potential of MPNs in antitumor applications.

Fe3O4 Composite Superparticles with RGD/Magnetic Dual-Targeting Capabilities for the Imaging and Treatment of Non-Small Cell Lung Cancer.

In clinical practice, the incidence and mortality of non-small cell lung cancer are increasing year by year, which is a serious threat to the health of patients. Once the optimal surgical window is missed, the toxic side effects of chemotherapy have to be confronted. With the rapid development of nanotechnology in recent years, medical science and health have been greatly impacted. Therefore, in this manuscript, we design and prepare chemotherapeutic drug vinorelbine (VRL)-loaded polydopamine (PDA) shell-coated Fe3O4 superparticles, and further graft the targeted ligand RGD onto their surface. Because of the introduction of the PDA shell, the toxicity of the prepared Fe3O4@PDA/VRL-RGD SPs is greatly reduced. At the same time, due to the existence of Fe3O4, the Fe3O4@PDA/VRL-RGD SPs also have MRI contrast capability. Under the dual-targeting effect of RGD peptide and external magnetic field, Fe3O4@PDA/VRL-RGD SPs can accumulate into tumors effectively. The accumulated superparticles in the tumor sites can not only effectively identify and mark the location and boundary of the tumor under MRI, guideing the application of near-infrared laser, but also release the loaded VRL under the stimulation of the acidic microenvironment of the tumor to play the role of chemotherapy. On further combination with photothermal therapy under laser irradiation, A549 tumors are completely eliminated without recurrence. Our proposed RGD/magnetic field dual-targeting strategy can effectively improve the bioavailability of nanomaterials and contribute to better imaging and therapeutic effects, which has a promising application prospect in the future.

Iron-Containing Protein-Mimic Supramolecular Iron Delivery Systems for Ferroptosis Tumor Therapy.

Ferroptosis provides an innovative theoretical basis and method for tumor therapy but is limited by the low efficiency of conventional iron delivery systems. Herein, an efficient supramolecular iron delivery system (SIDS) is demonstrated upon the hydrolysis of FeCl3, condensation of amino acids, and self-assembly of iron-containing components. The as-assembled SIDS possesses a shuttle-like core/shell structure with ß-FeOOH as the core and Fe3+/polyamino acid coordinated networks as shells. The iron content of SIDS is up to 42 wt %, which is greatly higher than that of ferritin. The iron-containing protein-mimic structure and shuttle-like morphology of SIDS facilitate tumor accumulation and cell internalization. Once exposed to the tumor microenvironment with overexpressed glutathione (GSH), the SIDS will disassemble, accompanied by the depletion of GSH and the release of Fe2+, leading to dual amplified ferroptosis. Primary studies indicate that SIDS exhibits outstanding antitumor efficacy on bladder cancer.

Exploration of the roles of microbiota on biogenic amines formation during traditional fermentation of Scomber japonicus.

The influence of microbiota composition and metabolisms on the safety and quality of fermented fish products is attracting increasing attention. In this study, the total viable count (TVC), pH, total volatile base nitrogen (TVB-N) as well as biogenic amines (BAs) of traditional fermented Scomber japonicus (zaoyu) were quantitatively determined. To comprehend microbial community variation and predict their functions during fermentation, 16S rRNA-based high-throughput sequencing (HTS) and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) were employed, respectively. The fresh samples stored without fermentation were used as controls. TVC and TVB-N values increased rapidly, and the content of BAs exceeded the permissible limit on day 2 in the controls, indicating serious spoilage of the fish. In contrast, a slower increase in TVC and TVB-N was observed and the content of BAs was within the acceptable limit throughout the fermentation of zaoyu. Significant differences in microbiota composition were observed between zaoyu and the controls. The bacterial community composition of zaoyu was relatively simple and Lactobacillus was identified as the dominant microbial group. The accumulation of histamine was inhibited in zaoyu, which was positively correlated with the relative abundance of Vibrio, Enterobacter, Macrococcus, Weissella, et al. based on Redundancy analysis (RDA), while Lactobacillus showed a positive correlation with tyramine, cadaverine, and putrescine. Functional predictions, based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis, revealed that the relative abundance of metabolic function exhibited a decreasing trend with prolonged fermentation time and the abundance of metabolism-related genes was relatively stable in the later stage of fermentation. Those metabolisms related to the formation of BAs like histidine metabolism and arginine metabolism were inhibited in zaoyu. This study has accompanied microbiota analysis and functional metabolism with the accumulation of BAs to trace their correspondences, clarifying the roles of microorganisms in the inhibition of BAs during fermentation of Scomber japonicus.

Attenuated Porcine Reproductive and Respiratory Syndrome Virus Regains Its Fatal Virulence by Serial Passaging in Pigs or Porcine Alveolar Macrophages To Increase Its Adaptation to Target Cells.

Porcine reproductive and respiratory syndrome (PRRS) is a globally important disease threatening the pork industry, and modified live-virus (MLV) vaccines are widely used for its prevention. However, PRRS MLV shows high potential for reversion to virulence, leading to a major concern about its safety. Yet the revertant mechanism is still poorly understood. Here, attenuated virus JXwn06-P80, derived from the highly pathogenic PRRS virus (PRRSV) strain JXwn06 by serial passaging in MARC-145 cells, was reversely passaged in pigs through intranasal inoculation to mimic natural infection for 13 rounds, and the pathogenicity of viruses at the 3rd, 5th, 9th, 10th, and 11th passages was evaluated in pigs. From the 9th passage, the viruses caused mortality, which was related to their increased adaptability and replication efficiency (100 times higher than those of JXwn06-P80) in porcine alveolar macrophage (PAM) target cells. Similarly, JXwn06-P80 could also regain fatal virulence through reverse passage in PAMs for 25 or more passages, indicating that the increased adaptability in PAMs directly contributes to its regained fatal virulence. Next, the full-genome sequences were analyzed to explore the genetic evolutionary processes during adaptation both in vivo and in vitro. Finally, by a reverse genetic operation, four reverse mutation sites, NSP12-W121R, ORF2b (open reading frame 2b)-H9D, ORF5-H15L, and ORF5-V189L, were finally identified to partially contribute to the ability of the virus to adapt to PAMs, which may be related to virulence reversion during reverse passage. These findings provided direct scientific evidence for the virulence reversion of PRRS MLV and provided valuable clues for exploring its molecular mechanism. IMPORTANCE Reversion to virulence of a live attenuated vaccine is a public concern; however, direct scientific evidence is limited, and the mechanism is still poorly understood. Here, we present direct evidence for the reversion to virulence of PRRS MLV after serial passaging in pigs or target cells and found a correlation between virulence reversion and increased replication fitness in primary PAMs. The genetic evolutionary process during adaptation will provide valuable clues for exploring the molecular mechanism of PRRS MLV virulence reversion and offer important implications for understanding the reversion mechanisms of other vaccines.

The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress glioblastoma progression.

BACKGROUND: Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors, especially glioblastoma (GBM). The ubiquitin-proteasome system (UPS) mediates a reversible, stringent and stepwise post-translational modification which is closely associated with malignant processes of GBM. To this end, developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease. This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM. Based on the molecular identification, functional characterization, and mechanism investigation, we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM. METHODS: We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase. Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT, UBA and WWE domain-containing E3 ubiquitin ligase 1 (HUWE1) in GBM. dCas9 synergistic activation mediator system and recombinant adeno-associated virus (rAAV) were used to endogenously overexpress full-length HUWE1 in vitro and in glioma orthotopic xenografts. RESULTS: Low expression of HUWE1 was closely associated with worse prognosis of GBM patients. The ubiquitination and subsequent degradation of N-Myc mediated by HUWE1, leading to the inactivation of downstream Delta-like 1 (DLL1)-NOTCH1 signaling pathways, inhibited the proliferation, invasion, and migration of GBM cells in vitro and in vivo. A rAAV dual-vector system for packaging and delivery of dCas9-VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts. CONCLUSIONS: The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress GBM progression. Antitumor activity of rAAV dual-vector delivering dCas9-HUWE1 system uncovers a promising therapeutic strategy for GBM.

PLXDC2 enhances invadopodium formation to promote invasion and metastasis of gastric cancer cells via interacting with PTP1B.

Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. In this study, we found that PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients' outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 enhanced the level of phosphorylated Cortactin (p-Cortactin) by physically interacting with protein tyrosine phosphatase 1B (PTP1B), an important dephosphorylase, to prevent its dephosphorylating of p-Cortactin, thereby promoting the formation of invadopodia. Collectively, our results indicate that PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.

Copper Ion and Ruthenium Complex Codoped Polydopamine Nanoparticles for Magnetic Resonance/Photoacoustic Tomography Imaging-Guided Photodynamic/Photothermal Dual-Mode Therapy.

Phototherapy, such as photodynamic therapy (PDT) and photothermal therapy (PTT), refers to the therapeutic strategy using a visible or near-infrared (NIR) laser to generate free radicals or heat for noninvasive and localized tumor treatment. However, limited by the low photoconversion efficiency of therapeutic agents, a single treatment method can hardly lead to complete tumor ablation, even when enhancing the power density of the laser and/or prolonging the irradiation duration. In this work, copper ion and ruthenium complex codoped polydopamine nanoparticles (Cu(II)/LRu/PDA NPs) are designed for PDT/PTT dual-mode therapy. The doped LRu in the NPs can generate reactive oxygen species under visible laser irradiation and enable PDT. Because of the strong absorption in the NIR region, PDA can not only generate heat for PTT under irradiation but also be used for photoacoustic tomography (PAT) imaging. Meanwhile, the doping of Cu(II) in the NPs through the coordination with PDA facilitates T1-weighted magnetic resonance imaging (MRI). Thus, MR/PAT imaging-guided PDT/PTT dual-mode therapy is achieved. The in vivo experiments indicate that the Cu(II)/LRu/PDA NPs can accumulate in HeLa tumors with a retention rate up to 8.34%ID/g. MR/PAT imaging can clearly identify the location and boundary of the tumors, permitting precise guidance for phototherapy. Under the combined effect of PDT and PTT, a complete ablation of HeLa tumors is achieved. The current work provides an alternative nanoplatform for performing PDT/PTT dual-mode therapy, which can be further guided by MR/PAT imaging.

Influence of Barium Intercalated Ions on Magnetic Interaction in the Tellurate Compound BaNi2TeO6.

A novel transition metal tellurate single-crystal BaNi2TeO6 with layered honeycomb lattices has been successfully synthesized. The crystal structure of BaNi2TeO6 reveals that there are the Ni2+ honeycomb lattice layers and Te6+ triangle lattice layers in the ab plane. BaNi2TeO6 shows an antiferromagnetic (AFM) transition at ∼25 K, which is almost the same temperature as the Curie-Weiss temperature θ ∼ -27 K, indicating the presence of the AFM interactions without obvious magnetic frustration in the system. However, the field-induced successive magnetic transitions observed at Hc1 ∼ 16.2 T and Hc2 ∼ 42.2 T show the complicated spin structure in BaNi2TeO6. Compared with the isostructural Na2Ni2TeO6, the various magnetic properties indicate that the intercalated ions (Ba2+) can significantly affect the magnetic properties of the layered honeycomb lattices, which may be useful for exploring the spin-liquid state and valence bond liquid state in the layered honeycomb lattice compounds.

Elevated Kir2.1/nuclear N2ICD defines a highly malignant subtype of non-WNT/SHH medulloblastomas.

Medulloblastoma (MB) is one of the most common childhood malignant brain tumors (WHO grade IV), traditionally divided into WNT, SHH, Group 3, and Group 4 subgroups based on the transcription profiles, somatic DNA alterations, and clinical outcomes. Unlike WNT and SHH subgroup MBs, Group 3 and Group 4 MBs have similar transcriptomes and lack clearly specific drivers and targeted therapeutic options. The recently revised WHO Classification of CNS Tumors has assigned Group 3 and 4 to a provisional non-WNT/SHH entity. In the present study, we demonstrate that Kir2.1, an inwardly-rectifying potassium channel, is highly expressed in non-WNT/SHH MBs, which promotes tumor cell invasion and metastasis by recruiting Adam10 to enhance S2 cleavage of Notch2 thereby activating the Notch2 signaling pathway. Disruption of the Notch2 pathway markedly inhibited the growth and metastasis of Kir2.1-overexpressing MB cell-derived xenograft tumors in mice. Moreover, Kir2.1high/nuclear N2ICDhigh MBs are associated with the significantly shorter lifespan of the patients. Thus, Kir2.1high/nuclear N2ICDhigh can be used as a biomarker to define a novel subtype of non-WNT/SHH MBs. Our findings are important for the modification of treatment regimens and the development of novel-targeted therapies for non-WNT/SHH MBs.

Fe(III)-Doped Polyaminopyrrole Nanoparticle for Imaging-Guided Photothermal Therapy of Bladder Cancer.

Clinically, the surgical treatment of bladder cancer often faces the problem of tumor recurrence, and the surgical treatment combined with postoperative chemotherapy to inhibit tumor recurrence also faces high toxicity and side effects. Therefore, the need for innovative bladder cancer treatments is urgent. For the past few years, with the development of nano science and technology, imaging-guided therapy using nanomaterials with both imaging and therapy functions has shown great advantages and can not only identify the locations of the tumors but also exhibit biodistributions of nanomaterials in the tumors, significantly improving the accuracy and efficacy of treatment. In this work, we synthesized Fe(III)-doped polyaminopyrrole nanoparticles (FePPy-NH2 NPs). With low cytotoxicity and a blood circulation half-life of 7.59 h, high levels of FePPy-NH2 NPs accumulated in bladder tumors, with an accumulation rate of up to 5.07%ID/g. The coordination of Fe(III) and the amino group in the structure can be used for magnetic resonance imaging (MRI), whereas absorption in the near-infrared region can be applied to photoacoustic imaging (PAI) and photothermal therapy (PTT). MRI and PAI accurately identified the location of the tumor, and based on the imaging data, laser irradiation was employed accurately. With a high photothermal conversion efficiency of 44.3%, the bladder tumor was completely resected without recurrence. Hematological analysis and histopathological analysis jointly confirmed the high level of safety of the experiment.