Oral bomb effect nanotherapeutics alleviate ulcerative colitis through coordinated anti-inflammatory and pro-resolving strategies.

Background: Ulcerative colitis (UC) is a debilitating chronic inflammatory bowel disease, and current treatments primarily focus on suppressing inflammation with limited efficacy. However, the resolution of inflammation also plays a crucial role in UC prognosis. Combining anti-inflammatory and pro-inflammatory resolution interventions may be a promising approach for treating UC. Materials and methods: The nano-bomb nanoparticles were validated for their ability to load CD98 siRNA (siCD98) and Annexin A1-mimetic peptides (Ac2-26 peptides), as well as release CO2 upon lysosomal escape. Surface modification with hyaluronic acid (HA) was assessed for its capability to target inflammatory tissues and cells. Biocompatibility and biosafety were evaluated through in vitro and in vivo studies. The anti-inflammatory and pro-resolving effects of siCD98@NPs and Ac2-26@NPs, both individually and in combination, were evaluated by measuring ROS production, pro-inflammatory cytokine expression, CD98 gene expression, and macrophage polarization. Results: These nanoparticles could efficiently load siCD98 and Ac2-26 peptides and release CO2 under acidic pH in the endo/lysosome to deliver drugs to the cytoplasm. HA could effectively target the inflammatory tissue and cells, showing good biocompatibility and biosafety both in vitro and in vivo. siCD98@NPs and Ac2-26@NPs showed anti-inflammatory effects by eliminating the over-production of ROS and down-regulating the expression of pro-inflammatory cytokines (TNF-α and IL-1ß) and the CD98 gene; meanwhile, it showed pro-resolving function by inhibiting M0 to pro-inflammatory M1 macrophage conversion, with a more pronounced effect when combined with siCD98 and Ac2-26. The oral administration of chitosan-alginate hydrogel-encapsulated nanoparticles in UC model mice effectively alleviated inflammatory symptoms, reduced the expression of pro-inflammatory cytokines (TNF-α and IL-1ß) and the CD98 gene, restored intestinal barrier function, and promoted M1 to M2 polarization, with a more pronounced effect when combined. Conclusion: By combining anti-inflammatory and pro-resolution interventions, these nanoparticles offer a novel therapeutic approach. This study offered a new approach for combination therapy of UC.

MARCH1 negatively regulates TBK1-mTOR signaling pathway by ubiquitinating TBK1.

BACKGROUND: TBK1 positively regulates the growth factor-mediated mTOR signaling pathway by phosphorylating mTOR. However, it remains unclear how the TBK1-mTOR signaling pathway is regulated. Considering that STING not only interacts with TBK1 but also with MARCH1, we speculated that MARCH1 might regulate the mTOR signaling pathway by targeting TBK1. The aim of this study was to determine whether MARCH1 regulates the mTOR signaling pathway by targeting TBK1. METHODS: The co-immunoprecipitation (Co-IP) assay was used to verify the interaction between MARCH1 with STING or TBK1. The ubiquitination of STING or TBK1 was analyzed using denatured co-immunoprecipitation. The level of proteins detected in the co-immunoprecipitation or denatured co-immunoprecipitation samples were determined by Western blotting. Stable knocked-down cells were constructed by infecting lentivirus bearing the related shRNA sequences. Scratch wound healing and clonogenic cell survival assays were used to detect the migration and proliferation of breast cancer cells. RESULTS: We showed that MARCH1 played an important role in growth factor-induced the TBK1- mTOR signaling pathway. MARCH1 overexpression attenuated the growth factor-induced activation of mTOR signaling pathway, whereas its deficiency resulted in the opposite effect. Mechanistically, MARCH1 interacted with and promoted the K63-linked ubiquitination of TBK1. This ubiquitination of TBK1 then attenuated its interaction with mTOR, thereby inhibiting the growth factor-induced mTOR signaling pathway. Importantly, faster proliferation induced by MARCH1 deficiency was weakened by mTOR, STING, or TBK1 inhibition. CONCLUSION: MARCH1 suppressed growth factors mediated the mTOR signaling pathway by targeting the STING-TBK1-mTOR axis.

Biomimetic "Gemini nanoimmunoregulators" orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages.

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy. Here, a new type of spatiotemporal biomimetic "Gemini nanoimmunoregulators" was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death (ICD), tumor-associated macrophages (TAMs) phenotype reprogramming and programmed cell death ligand 1 (PD-L1) degradation. The "Gemini nanoimmunoregulators" PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine (mPDA) as nanovectors to deliver metformin (Met) and toll-like receptor 7/8 agonist resiquimod (R848) to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane (RM) inlaid with T7 or M2 peptides. mPDA/Met@RM-T7 (abbreviated as PM@RM-T7) was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity. Meanwhile, PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion. Subsequently, mPDA/R848@RM-M2 (abbreviated as PR@RM-M2) specifically recognized TAMs and reset the phenotype from M2 to M1 state, thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes. This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity, which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis. This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

Worldwide productivity and research trend of publications concerning SIAD: a bibliometric study.

Background: Syndrome of inappropriate antidiuretic(SIAD) occurs secondary to various diseases, which is characterised by hypotonic hyponatremia and impaired urinary diluting capacity. Research on SIAD in both domestic and international contexts has a long history. This study objectively and comprehensively analyses the research trends, hotspots and development of SIAD research of the past 20 years using the method of bibliometric analysis. Methods: The 2003-2022 data in the Web of Science Core Collection database were searched. The Bibliometrix software package, VOSviewer and CiteSpace were used to mine, extract and visualise the retrieved literature, and the generated maps were used in analysing the main topics and trends in the field of SIAD research. Results: A total of 1215 articles published in 623 journals were included in the analysis, with a total of 18,886 citations. Results showed that the research output on SIAD has continuously increased in the past 20 years, and the United States had the highest number of publications and citations. Keywords with the highest burst strength in recent years were the most mentioned keywords, in addition to the search terms 'hyponatremia', 'covid-19', and 'mortality'. Thus, the relationship among SIAD, covid-19 and mortality may become research frontiers and trends. Fifteen milestone articles were identified through co-citation analysis, which mainly focused on the pathophysiology and treatment of SIAD. Conclusion: Based on bibliometric analysis and knowledge mapping, this study summarises development trends in the field of SIAD research, providing references for current and future research into SIAD.

Ototoxicity of polystyrene nanoplastics in mice, HEI-OC1 cells and zebrafish.

Polystyrene nanoplastics are a novel class of pollutants. They are easily absorbed by living organisms, and their potential toxicity has raised concerns. However, the impact of polystyrene nanoplastics on auditory organs remains unknown. Here, our results showed that polystyrene nanoplastics entered the cochlea of mice, HEI-OC1 cells, and lateral line hair cells of zebrafish, causing cellular injury and increasing apoptosis. Additionally, we found that exposure to polystyrene nanoplastics resulted in a significant elevation in the auditory brainstem response thresholds, a loss of auditory sensory hair cells, stereocilia degeneration and a decrease in expression of Claudin-5 and Occludin proteins at the blood-lymphatic barrier in mice. We also observed a significant decrease in the acoustic alarm response of zebrafish after exposure to polystyrene nanoplastics. Mechanistic analysis revealed that polystyrene nanoplastics induced up-regulation of the Nrf2/HO-1 pathway, increased levels of malondialdehyde, and decreased superoxide dismutase and catalase levels in cochlea and HEI-OC1 cells. Furthermore, we observed that the expression of ferroptosis-related indicators GPX4 and SLC7A11 decreased as well as increased expression of ACLS4 in cochlea and HEI-OC1 cells. This study also revealed that polystyrene nanoplastics exposure led to increased expression of the inflammatory factors TNF-α, IL-1ß and COX2 in cochlea and HEI-OC1 cells. Further research found that the cell apoptosis, ferroptosis and inflammatory reactions induced by polystyrene nanoplastics in HEI-OC1 cells was reversed through the pretreatment with N-acetylcysteine, a reactive oxygen species inhibitor. Overall, our study first discovered and systematically revealed the ototoxicity of polystyrene nanoplastics and its underlying mechanism.

Frequency and associated factors of accommodation and non-strabismic binocular vision dysfunction among medical university students.

AIM: To investigate the frequency and associated factors of accommodation and non-strabismic binocular vision dysfunction among medical university students. METHODS: Totally 158 student volunteers underwent routine vision examination in the optometry clinic of Guangxi Medical University. Their data were used to identify the different types of accommodation and non-strabismic binocular vision dysfunction and to determine their frequency. Correlation analysis and logistic regression were used to examine the factors associated with these abnormalities. RESULTS: The results showed that 36.71% of the subjects had accommodation and non-strabismic binocular vision issues, with 8.86% being attributed to accommodation dysfunction and 27.85% to binocular abnormalities. Convergence insufficiency (CI) was the most common abnormality, accounting for 13.29%. Those with these abnormalities experienced higher levels of eyestrain (χ2=69.518, P<0.001). The linear correlations were observed between the difference of binocular spherical equivalent (SE) and the index of horizontal esotropia at a distance (r=0.231, P=0.004) and the asthenopia survey scale (ASS) score (r=0.346, P<0.001). Furthermore, the right eye's SE was inversely correlated with the convergence of positive and negative fusion images at close range (r=-0.321, P<0.001), the convergence of negative fusion images at close range (r=-0.294, P<0.001), the vergence facility (VF; r=-0.234, P=0.003), and the set of negative fusion images at far range (r=-0.237, P=0.003). Logistic regression analysis indicated that gender, age, and the difference in right and binocular SE did not influence the emergence of these abnormalities. CONCLUSION: Binocular vision abnormalities are more prevalent than accommodation dysfunction, with CI being the most frequent type. Greater binocular refractive disparity leads to more severe eyestrain symptoms.

SPOP negatively regulates mTORC1 activity by ubiquitinating Sec13.

The mammalian target of rapamycin complex1 (mTORC1) can response to amino acid to regulate metabolism and cell growth. GATOR2 act as important role in amino acid mediated mTORC1 signaling pathway by repressing GTPase activity (GAP) of GATOR1. However, it is still unclear how GATOR2 regulates mTORC1 signaling pathway. Here, we found that K63-ubiquitination of Sce13, one component of GATOR2, suppresses the mTORC1 activity by lessening the inter-interaction of GATOR2. Mechanistically, the ubiquitination of Sec13 was mediated by SPOP. Subsequently, the ubiquitination of Sec13 attenuated its interaction with the other component of GATOR2, thus suppressing the activity of mTORC1. Importantly, the deficiency of SPOP promoted the faster proliferation and migration of breast cancer cells, which was attenuated by knocking down of Sec13. Therefore, SPOP can act as a tumor suppressor gene by negatively regulating mTORC1 signaling pathway.

Biomimetic Nano-Immunoactivator via Ionic Metabolic Modulation for Strengthened NIR-II Photothermal Immunotherapy.

Reprogramming the immunologically "cold" environment of solid tumors is currently becoming the mainstream strategy to elicit powerful and systemic anticancer immunity. Here, a facile and biomimetic nano-immunnoactivator (CuS/Z@M4T1 ) is detailed by engineering a Zn2+ -bonded zeolitic imidazolate framework-8 (ZIF-8) with CuS nanodots (NDs) and cancer cell membrane for amplified near-infrared-II (NIR-II) photothermal immunotherapy via Zn2+ metabolic modulation. Taking advantage of the NIR-II photothermal effect of CuS NDs and the acidic responsiveness of ZIF-8, CuS/Z@M4T1 rapidly causes intracellular Zn2+ pool overload and disturbs the metabolic flux of 4T1 cells, which effectively hamper the production of heat shock proteins and relieve the resistance of photothermal therapy (PTT). Thus, amplified immunogenic cell death is evoked and initiates the immune cascade both in vivo and in vitro as demonstrated by dendritic cells maturation and T-cell infiltration. Further combination with antiprogrammed death 1 (aPD-1) achieves escalated antitumor efficacy which eliminates the primary, distant tumor and avidly inhibits lung metastasis due to cooperation of enhanced photothermal stimulation and empowerment of cytotoxic T lymphocytes by aPD-1. Collectively, this work provides the first report of using the intrinsic modulation property of meta-organometallic ZIF-8 for enhanced cancer photoimmunotherapy together with aPD-1, thereby inspiring a novel combined paradigm of ion-rich nanomaterials for cancer treatment.

The incentive role of media companies' executive compensation system in transformation and upgrading: Evidence from listed media companies in China.

Media companies in various countries are transforming and upgrading to improve their competitiveness in the digital economy. However, existing research only focuses on the issue of how media companies transform while ignoring whether internal governance mechanisms such as compensation incentives can promote corporate value during the transformation process. According to the principal-agent theory, we examined the incentive effects of the executive compensation system in terms of monetary compensation, equity compensation, and perks in a sample of Chinese media companies in the process of transformation and upgrading. The results have revealed that monetary compensation does not have a significant incentive effect, and equity compensation and perks have an incentive effect when they are in the suitable range. Based on the results, we proposed policy recommendations from three aspects: monetary compensation, equity compensation, and perks. This study complements the research content on the executive compensation system in media enterprises' transformation and upgrading. It can provide a reference for setting the administrative compensation system for media companies in China and other emerging economies.

Stimulus-Detonated Biomimetic "Nanobomb" with Controlled Release of HSP90 Inhibitor to Disrupt Mitochondrial Function for Synergistic Gas and Photothermal Therapy.

Photothermal therapy (PTT) is considered a promising treatment for tumors; however, its efficacy is restricted by heat shock proteins (HSPs). Herein, a stimuli-responsive theranostic nanoplatform (M/D@P/E-P) is designed for synergistic gas therapy and PTT. This nanoplatform is fabricated by a load of manganese carbonyl (MnCO, CO donor) in dendritic mesoporous silicon (DMS), followed by the coating with polydopamine (PDA) and loading of epigallocatechin gallate (EGCG, HSP90 inhibitor). Upon near-infrared (NIR) irradiation, the photothermal effect of PDA can kill tumor cells and allow for the controlled drug release of MnCO and EGCG. Moreover, the acidity and H2 O2 -rich tumor microenvironment enable the decomposition of the released MnCO, accompanied by the production of CO. CO-initiated gas therapy can realize to disrupt the mitochondrial function, which will accelerate cell apoptosis and down-regulate HSP90 expression by decreasing intracellular ATP. The combination of EGCG and MnCO can significantly minimize the thermo-resistance of tumors and improve PTT sensitivity. In addition, the released Mn2+ enables T1 -weighted magnetic imaging of tumors. The therapeutic efficacy of the nanoplatform is methodically appraised and validated both in vitro and in vivo. Taken together, this study affords a prime paradigm for applying this strategy for enhanced PTT via mitochondrial dysfunction.

A tumor-specific ROS self-supply enhanced cascade-responsive prodrug activation nanosystem for amplified chemotherapy against multidrug-resistant tumors.

Chemotherapy remains the mainstay of cancer treatment, and doxorubicin (DOX) is recommended as a first-line chemotherapy drug against cancer. However, systemic adverse drug reactions and multidrug resistance limit its clinical applications. Here, a tumor-specific reactive oxygen species (ROS) self-supply enhanced cascade responsive prodrug activation nanosystem (denoted as PPHI@B/L) was developed to optimize multidrug resistance tumor chemotherapy efficacy while minimizing the side effects. PPHI@B/L was constructed by encapsulating the ROS-generating agent ß-lapachone (Lap) and the ROS-responsive doxorubicin prodrug (BDOX) in acidic pH-sensitive heterogeneous nanomicelles. PPHI@B/L exhibited particle size decrease and charge increase when it reached the tumor microenvironment due to acid-triggered PEG detachment, to favor its endocytosis efficiency and deep tumor penetration. Furthermore, after PPHI@B/L internalization, rapidly released Lap was catalyzed by the overexpressed quinone oxidoreductase-1 (NQO1) enzyme NAD(P)H in tumor cells to selectively raise intracellular ROS levels. Subsequently, ROS generation further promoted the specific cascade activation of the prodrug BDOX to exert the chemotherapy effects. Simultaneously, Lap-induced ATP depletion reduced drug efflux, synergizing with increased intracellular DOX concentrations to assist in overcoming multidrug resistance. This tumor microenvironment-triggered cascade responsive prodrug activation nanosystem potentiates antitumor effects with satisfactory biosafety, breaking the chemotherapy limitation of multidrug resistance and significantly improving therapy efficiency. STATEMENT OF SIGNIFICANCE: Chemotherapy remains the mainstay of cancer treatment, and doxorubicin (DOX) is recommended as a first-line chemotherapy drug against cancer. However, systemic adverse drug reactions and multidrug resistance limit its clinical applications. Here, a tumor-specific reactive oxygen species (ROS) self-supply enhanced cascade responsive prodrug activation nanosystem (denoted as PPHI@B/L) was developed to optimize multidrug resistance tumor chemotherapy efficacy while minimizing the side effects. The work provides a new sight for simultaneously addressing the molecular mechanisms and physio-pathological disorders to overcome MDR in cancer treatment.

Hemichorea Associated With Nonketotic Hyperglycemia.

CONTEXT: Hemichorea associated with nonketotic hyperglycemia (HC-NH) is a rare diabetic complication for which the pathogenesis remains unclear. OBJECTIVE: This study reported 16 cases of HC-NH to improve the understanding of the disease and avoid misdiagnosis and missed diagnosis. METHODS: Data of 16 patients with HC-NH in a single center from 2000 to 2021 were analyzed retrospectively, and the relevant literature was reviewed. RESULTS: The participants (8 men and 8 women) had a mean age of 67.6 ± 16.4 years. Bilateral limbs were involved in 2 cases, and the others had hemichorea (6 in the left side and 8 in the right side). The average random blood glucose level was 17.51 ± 7.67 mmol/L, and the glycated hemoglobin A1c level was 11.9%±3.1% at admission. Eleven patients had a history of diabetes, and the other 5 patients were diagnosed with new-onset diabetes mellitus, but no remarkable differences were observed in the presentation or treatment of chorea. Ketonuria was detected in 7 patients. The basal ganglia (putamen, globus pallidus, and caudate nucleus) of 9 cases had typical hyperdensity on computed tomography and/or hyperintensity signals from magnetic resonance imaging. The chorea symptoms of 15 patients improved within 5.0 ± 1.9 days after treatment. CONCLUSION: This study provides additional valuable information about the clinical and neuroimaging features of HC-NH. We hypothesize that chronic ischemia of the basal ganglia due to cerebral atherosclerosis combined with hyperglycemia is associated with HC-NH.

Corrigendum to "Remodeling tumor immunosuppressive microenvironment via a novel bioactive nanovaccines potentiates the efficacy of cancer immunotherapy" [Bioactive Mater. 16 107-119].

[This corrects the article DOI: 10.1016/j.bioactmat.2022.03.008.].

3D Soma Detection in Large-Scale Whole Brain Images via a Two-Stage Neural Network.

3D soma detection in whole brain images is a critical step for neuron reconstruction. However, existing soma detection methods are not suitable for whole mouse brain images with large amounts of data and complex structure. In this paper, we propose a two-stage deep neural network to achieve fast and accurate soma detection in large-scale and high-resolution whole mouse brain images (more than 1TB). For the first stage, a lightweight Multi-level Cross Classification Network (MCC-Net) is proposed to filter out images without somas and generate coarse candidate images by combining the advantages of the multi convolution layer's feature extraction ability. It can speed up the detection of somas and reduce the computational complexity. For the second stage, to further obtain the accurate locations of somas in the whole mouse brain images, the Scale Fusion Segmentation Network (SFS-Net) is developed to segment soma regions from candidate images. Specifically, the SFS-Net captures multi-scale context information and establishes a complementary relationship between encoder and decoder by combining the encoder-decoder structure and a 3D Scale-Aware Pyramid Fusion (SAPF) module for better segmentation performance. The experimental results on three whole mouse brain images verify that the proposed method can achieve excellent performance and provide the reconstruction of neurons with beneficial information. Additionally, we have established a public dataset named WBMSD, including 798 high-resolution and representative images ( 256 ×256 ×256 voxels) from three whole mouse brain images, dedicated to the research of soma detection, which will be released along with this paper.

Polydopamine-Engineered Theranostic Nanoscouts Enabling Intracellular HSP90 mRNAs Fluorescence Detection for Imaging-Guided Chemo-Photothermal Therapy.

The combination of photothermal therapy (PTT) and chemotherapy is considered a promising tumor treatment modality, nevertheless, cellular resistance induced by heat shock proteins (HSPs) overexpressed in tumor cells will restrict the therapeutic effect. Herein, a multifunctional nanobeacon DOX/HCuS@PDA-MB (D/CP-MB) with a scout function for HSP90 mRNA fluorescence detection and near-infrared (NIR) triggered drug release for sensitizing chemo-photothermal therapy, is proposed. In the theranostic nanobeacons, HSP90MBs not only enable fluorescence detection of intracellular HSP90 mRNAs, but also downregulate the expression of HSP90 to reduce cell resistance. With the assistance of NIR and guidance of fluorescence imaging, spatiotemporal doxorubicin release can be achieved by the trigger of the photothermal effect, allowing for combined chemotherapy and photothermal treatment. Furthermore, the dual photothermal effect of hollow mesoporous CuS (HCuS) and polydopamine will lead to a better photothermal effect. Moreover, compared with other control groups, D/CP-MB nanobeacons exhibit effective boost therapeutic efficacy by inducing significant suppression of tumor proliferation and enhancement of apoptosis both in vitro and in vivo. In summary, this work provides novel theranostic nanobeacons that integrate imaging and therapy in a single nanoparticle, this strategy of imaging-guided therapy can enable precise tumor treatment and effectively improve tumor treatment efficacy.

Tumor homing-penetrating and nanoenzyme-augmented 2D phototheranostics against hypoxic solid tumors.

Tumor microenvironment (TME)-oriented nanomedicine emerges as an efficient routine to greatly improve the efficiency of cancer treatment. The typical feature of hypoxia in TME remains as the main obstacle of many therapeutics like photodynamic therapy. Herein, a specific two-dimensional (2D) phototheranostics (GO-MnO2@tLyP-1/Ce6, denoted as GMtC) with the function of oxygen self-producing and tumor barrier-breaking was detailed by integrating the nanoenzyme MnO2 colloids, tumor homing-penetrating peptide tLyP-1 and photosensitizer chlorin e6 (Ce6) to tackle the hypoxic tumors. GMtC was capable to accumulate into the inner of murine mammary 4T1 tumor spheroids (and the depth could be as far as 90 µm) and to relieve the hypoxia state by catalytic decomposition of endogenous H2O2 to oxygen, which subsequently enhanced the yield of cytotoxic singlet oxygen under laser irradiation. In vivo dual-modal imaging of magnetic resonance and biofluorescence demonstrated the targeted accumulation and distribution of GMtC in tumor regions, thus facilitating the tumor hypoxia alleviation. Notably, GMtC achieved the highest photodynamic anticancer efficiency against 4T1 tumors without obvious systemic toxicity compared with the non-penetrating and no oxygen-generating counterparts. This study suggests the great promise of GMtC as an endogenous TME-responsive and exogenous laser-triggered theranostic platform against the solid hypoxic tumors. STATEMENT OF SIGNIFICANCE: The hostile tumor hypoxia not only induces the tumor angiogenesis, invasiveness and irreversible metastasis, but also inherently impairs the efficiency of many therapeutic modalities like photodynamic therapy (PDT). Though numerous hypoxia-alleviating strategies based on nanomedicine have been proposed, little attention is paid to the hypoxia-specific transportation barriers. This study develops a type of 2D phototheranostics GMtC against hypoxic solid tumors by integrating the function of tumor homing-penetrating and in situ oxygen-generating. GMtC displays outstanding performance in tumor deep penetration to hypoxia center and generating abundant oxygen in responsive to tumor microenvironment, thus exerting the highest efficiency of PDT against 4T1 mammary tumor. GMtC can be a potent theranostics to treat the solid hypoxic tumors.

Cascade-activatable NO release based on GSH-detonated "nanobomb" for multi-pathways cancer therapy.

Therapeutic approaches of combining conventional photodynamic therapy (PDT) with other adjuvant treatments to sensitize PDT represent an appealing strategy. Herein, a novel synergetic "nanobomb" strategy based on glutathione (GSH)-responsive biodegradation was proposed to effectively destroy tumors expeditiously and accurately. This "nanobomb" was rationally constructed via the simultaneous encapsulation of methylene blue (MB) and l-arginine (L-Arg) into polyethylene glycol (PEG) modified mesoporous organosilicon nanoparticles (MON). The resulting L-Arg/MB@MP initially exhibited prolonged blood circulation, improved bioavailability, and enhanced tumor accumulation in mice after tail vein injection according to the pharmacokinetic investigations, before the nanoparticles were entirely excreted. Under laser irradiation, L-Arg/MB@MP produced remarkable reactive oxygen species (ROS) directly for PDT therapy, while a portion of ROS may oxidize L-Arg to generate nitric oxide (NO) not only for gas therapy (GT) but also serve as a biological messenger to regulate vasodilation to alleviate the tumor hypoxia. Subsequently, the rapidly released NO was further oxidized to reactive nitrogen species, which together with ROS promote immunogenic cell death by inducing G2/M cell-cycle arrest and apoptosis in cancer cells, and eventually resulting in enhanced anti-tumor immune responses. Moreover, the GSH depletion in tumor tissues induced by L-Arg/MB@MP biodegradation can cooperate with GT to amplify the therapeutic effect of PDT. These results demonstrate that this "nanobomb" provides new ideas for clinical translation to treat tumor patients in terms of synergistic PDT-GT nanotherapy in hypoxic-solid tumors.

An unusual case of hyperthyroidism with recurrent vomiting and hypercalcemia as the main manifestations.

Complicated vomiting and hypercalcemia are clinically rare in patients with hyperthyroidism. We describe a case of a woman whose main symptoms were palpitations, sweating, and vomiting. She was diagnosed with Graves' disease by an analysis of thyroid function, thyroid-related antibodies, and color Doppler ultrasound. Biochemical tests showed that her serum calcium levels were greatly elevated. Her symptoms were relieved following the administration of antithyroid drugs, propranolol for heart rate control, fluid replacement, diuresis and calcium reduction, antiemesis, and liver protection. This case suggests that the thyroid function should be screened when hypercalcemia is seen in the clinic.

Remodeling tumor immunosuppressive microenvironment via a novel bioactive nanovaccines potentiates the efficacy of cancer immunotherapy.

The clinical outcomes of cancer nanovaccine have been largely impeded owing to the low antigen-specific T cell response rate and acquired resistance caused by the immunosuppressive tumor microenvironment (TME). Here, we reported a tumor acidity-responsive nanovaccine to remodel the immunosuppressive TME and expand the recruitment of tumor infiltrating lymphocytes (TILs) using hybrid micelles (HM), which encapsulated colony stimulating factor 1 receptor (CSF1-R) inhibitor BLZ-945 and indoleamine 2,3-dioxygenase (IDO) inhibitor NLG-919 in its core and displayed a model antigen ovalbumin (OVA) on its surface (denoted as BN@HM-OVA). The bioactive nanovaccine is coated with a polyethylene glycol (PEG) shell for extending nanoparticle circulation. The shell can be shed in response to the weakly acidic tumor microenvironment. The decrease in size and the increase in positive charge may cause the deep tumor penetration of drugs. We demonstrated that the bioactive nanovaccine dramatically enhance antigen presentation by dendritic cells (DCs) and drugs transportation into M1-like tumor-associated macrophages (TAMs) and tumor cells via size reduction and increasing positive charge caused by the weakly acidic TME. Such bioactive nanovaccine could remodel the immunosuppressive TME into an effector T cells favorable environment, leading to tumor growth inhibition in prophylactic and therapeutic E.G7-OVA tumor models. Furthermore, combining the bioactive nanovaccine with simultaneous anti-PD-1 antibody treatment leads to a long-term tumor inhibition, based on the optimal timing and sequence of PD-1 blockade against T cell receptor. This research provides a new strategy for the development of efficient cancer immunotherapy.

Light-responsive hyaluronic acid nanomicelles co-loaded with an IDO inhibitor focus targeted photoimmunotherapy against "immune cold" cancer.

Nanomedicine enabled cancer combination immunotherapy not only sufficiently activates the host immune system, but also reprograms the immunosuppressive microenvironment, representing a new generation approach to treat cancer. Herein, we demonstrated a targeted photo- and immune-active nanoplatform termed NLG919@HA-Ce6 to simultaneously elicit efficient immunogenic cell death (ICD) using the photosensitizer Ce6 and modulate the tryptophan metabolic pathway using an indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919 for the combined photodynamic therapy (PDT) and checkpoint blockade immunotherapy. Against the triple-negative and poorly immunogenic 4T1 breast cancer model, the stable spherical nanomicelle NLG919@HA-Ce6 selectively killed tumour cells via the toxic singlet oxygen upon laser excitation, thus in situ triggering a potent antitumor immune response, as seen via the obvious CRT exposure, ATP release, dendritic cell maturation, etc. Meanwhile, the IDO1-mediated immunosuppression was effectively reprogrammed to an immunostimulatory phenotype, which was accompanied by an enhanced cytotoxic T cell response as well as reduced Treg infiltration in tumour bed. Ultimately, the 4T1 tumour was synergistically suppressed by NLG919@HA-Ce6 due to the outcome of focused PDT, obvious ICD post PDT and IDO1 blockade. This study suggests the promise of NLG919@HA-Ce6 as an alternative simple, stimulative and targeted nanoagent to enable the whole-body photo-immune therapy against "immune cold" cancer.