Environmentally responsive hydrogel promotes vascular normalization to enhance STING anti-tumor immunity.

The immunosuppressive microenvironment of malignant tumors severely hampers the effectiveness of anti-tumor therapy. Moreover, abnormal tumor vasculature interacts with immune cells, forming a vicious cycle that further interferes with anti-tumor immunity and promotes tumor progression. Our pre-basic found excellent anti-tumor effects of c-di-AMP and RRx-001, respectively, and we further explored whether they could be combined synergistically for anti-tumor immunotherapy. We chose to load these two drugs on PVA-TSPBA hydrogel scaffolds that expressly release drugs within the tumor microenvironment by in situ injection. Studies have shown that c-di-AMP activates the STING pathway, enhances immune cell infiltration, and reverses tumor immunosuppression. Meanwhile, RRx-001 releases nitric oxide, which increases oxidative stress injury in tumor cells and promotes apoptosis. Moreover, the combination of the two presented more powerful pro-vascular normalization and reversed tumor immunosuppression than the drug alone. This study demonstrates a new design option for anti-tumor combination therapy and the potential of tumor environmentally responsive hydrogel scaffolds in combination with anti-tumor immunotherapy.

Overcoming challenges in the delivery of STING agonists for cancer immunotherapy: A comprehensive review of strategies and future perspectives.

STING (Stimulator of Interferon Genes) agonists have emerged as promising agents in the field of cancer immunotherapy, owing to their excellent capacity to activate the innate immune response and combat tumor-induced immunosuppression. This review provides a comprehensive exploration of the strategies employed to develop effective formulations for STING agonists, with particular emphasis on versatile nano-delivery systems. The recent advancements in delivery systems based on lipids, natural/synthetic polymers, and proteins for STING agonists are summarized. The preparation methodologies of nanoprecipitation, self-assembly, and hydrogel, along with their advantages and disadvantages, are also discussed. Furthermore, the challenges and opportunities in developing next-generation STING agonist delivery systems are elaborated. This review aims to serve as a reference for researchers in designing novel and effective STING agonist delivery systems for cancer immunotherapy.

Nanomaterial-Based Antivascular Therapy in the Multimodal Treatment of Cancer.

Abnormal tumor vasculature and a hypoxic tumor microenvironment (TME) limit the effectiveness of conventional cancer treatment. Recent studies have shown that antivascular strategies that focus on antagonizing the hypoxic TME and promoting vessel normalization effectively synergize to increase the antitumor efficacy of conventional therapeutic regimens. By integrating multiple therapeutic agents, well-designed nanomaterials exhibit great advantages in achieving higher drug delivery efficiency and can be used as multimodal therapy with reduced systemic toxicity. In this review, strategies for the nanomaterial-based administration of antivascular therapy combined with other common tumor treatments, including immunotherapy, chemotherapy, phototherapy, radiotherapy, and interventional therapy, are summarized. In particular, the administration of intravascular therapy and other therapies with the use of versatile nanodrugs is also described. This review provides a reference for the development of multifunctional nanotheranostic platforms for effective antivascular therapy in combined anticancer treatments.

Admission D-dimer to lymphocyte counts ratio as a novel biomarker for predicting the in-hospital mortality in patients with acute aortic dissection.

BACKGROUND: Inflammatory factors are well-established indicators for vascular disease, but the D-dimer to lymphocyte count ratio (DLR) is not measured in routine clinical care. Screening of DLR in individuals may identify individuals at in-hopital mortality of acute aortic dissection (AD). METHODS: A retrospective analysis of clinical data from 2013 to 2020 was conducted to identify which factors were related to in-hospital mortality risk of AD. Baseline clinical features, cardiovascular risk factors, and laboratory parameters were obtained from the hospital database. The end point was in-hospital mortality. Forward conditional logistic regression was performed to identify independent risk factors for AA in-hospital death. The cutoff value of the DLR should be ideally calculated by receiver operating characteristic (ROC) analysis. RESULTS: The in-hospital mortality rate was 15% (48 of 320 patients). Patients with in-hospital mortality had a higher admission mean DLR level than the alive group (1740 vs. 1010, P < .05). The cutoff point of DLR was 907. The in-hospital mortality rate in the high-level DLR group was significantly higher than that in the low-level DLR group (P < .05). Univariate analysis showed that 8 of 38 factors were associated with in-hospital mortality (P < .05), including admission WBC, neutrophils, lymphocytes, neutrophils/lymphocytes (NLR), prothrombin time (PT), heart rate (HR), D-dimer, and DLR. In multivariate analysis, DLR (odds ratio [OR] 2.127, 95% CI 1.034-4.373, P = 0.040), HR (odds ratio [OR] 1.016, 95% CI 1.002-1.030, P = 0.029) and PT (odds ratio [OR] 1.231, 95% CI 1.018-1.189, P = 0.032) were determined to be independent predictors of in-hospital mortality (P < .05). CONCLUSION: Compared with the common clinical parameters PT and HR, serum DLR level on admission is an uncommon but independent parameter that can be used to assess in-hospital mortality in patients with acute AD.

Metal-Cyclic Dinucleotide Nanomodulator-Stimulated STING Signaling for Strengthened Radioimmunotherapy of Large Tumor.

Combined treatment of immunotherapy and radiotherapy shows promising therapeutic effects for the regression of a variety of cancers. However, even multi-modality therapies often fail to antagonize the regression of large tumors due to the extremely immunosuppressive tumor microenvironment (TME). Here, a radioimmunotherapeutic paradigm based on stimulator of interferon genes (STING)-dependent signaling is applied to preclude large tumor progression by utilizing the metal-cyclic dinucleotide (CDN) nanoplatform, which integrates STING agonist c-di-AMP and immunomodulating microelement manganese (II) within the tannic acid nanostructure (TMA-NPs). As observed by magnetic resonance imaging, the localized administration of TMA-NPs effectively relieves hypoxia within TME and causes radical oxygen species overproduction and apoptosis in cancer cells after exposure to X-ray irradiation. The DNA fragments released from the apoptotic cells after the combined treatment augment the production of endogenous CDNs in cancer cells, hence significantly activating the STING-mediated pathway for stronger anti-tumor immunity. The localized therapy of TMA-NPs + X-ray not only inhibits the primary large tumor progression but also retards distant tumor growth by promoting dendritic cell maturation and activating cytotoxic immune cells whil suppressing immunosuppressive cells. Therefore, this work represents the combinatorial potency of TMA-NPs and X-rays on large tumor regression through strengthened STING-mediated radioimmunotherapeutics.

PEIGel: A biocompatible and injectable scaffold with innate immune adjuvanticity for synergized local immunotherapy.

Intratumoral immunotherapeutic hydrogel administration is emerging as an effective method for inducing a durable and robust antitumor immune response. However, scaffold hydrogels that can synergize with the loaded drugs, thus potentiating therapeutic efficacy, are limited. Here, we report a ternary hydrogel composed of polyvinyl alcohol (PVA), polyethylenimine (PEI)‒a cationic polymer with potential immunoactivation effects, and magnesium ions‒a stimulator of the adaptive immune response, which exhibits an intrinsic immunomodulation function of reversing the immunologically "cold" phenotype of a murine breast tumor to a "hot" phenotype by upregulating PD-L1 expression and promoting M1-like macrophage polarization. PEI hydrogel (PEIGel) encapsulating an immune checkpoint blockade (ICB) inhibitor‒anti-PD-L1 antibody (α-PDL1) exhibits synergistic effects resulting in elimination of primary tumors and remote metastases and prevention of tumor relapse after surgical resection. A preliminary mechanistic study revealed a probably hidden role of PEI in modulating the polyamine metabolism/catabolism of tumors to potentiate the immune adjuvant effect. These results deepen our understanding of the innate immune activation function of PEI and pave the way for harnessing PEI as an immune adjuvant for ICB therapy.

Interference With Redox Homeostasis Through a G6PD-Targeting Self-Assembled Hydrogel for the Enhancement of Sonodynamic Therapy in Breast Cancer.

Sonodynamics has emerged as a new potential therapy for breast cancer in recent years. However, GSH-mediated redox systems in cancer cells make them tolerable to oxidative stress-related therapy. Herein, in this study, with G6PD, the gatekeeper enzyme of the pentose phosphate pathway, as the regulative target, a self-assembled thermosensitive chitosan-pluronic hydrogel coloaded with ICG (sono-sensitive agent) and RRx-001 (IR@CPGel) was successfully prepared to enhance SDT through interference with redox homeostasis. Both in vitro and in vivo antitumor investigations verified that when integrated with sonodynamic therapy applied in breast cancer treatment, local administration of IR@CPgel could enhance ROS generation under LIFU irradiation and trigger the intrinsic apoptotic pathway of cancer cells, thus effectively inhibiting tumor growth in a safe manner. Moreover, RRx-001 may interfere with redox homeostasis in cancer cells by downregulating G6PD expression. Due to this redox imbalance, proapoptotic signals, such as P21 and P53, were enhanced, and metastasis-related signals, including MMP-2, ZEB1 and HIF-1α, were effectively reduced. Taken together, this work aimed to enhance the efficacy of sonodynamic therapy through local administration of self-assembled IR@CPGel to interfere with redox homeostasis and thus amplify the oxidative stress microenvironment in tumor tissues. In a word, this work provides a new strategy for the SDT enhancement in breast cancer therapy.

Cetuximab Combined With Sonodynamic Therapy Achieves Dual-Modal Image Monitoring for the Treatment of EGFR-Sensitive Non-Small-Cell Lung Cancer.

BACKGROUND: Blocking signaling by epidermal growth factor receptor (EGFR), can effectively inhibit the proliferation and differentiation of non-small-cell lung cancer (NSCLC). Additionally, an increasing number of NSCLC patients have treatment limitations caused by EGFR overexpression or mutations. Therefore, we constructed a nanotherapy platform consisting of cetuximab (CTX) to target EGFR-sensitive NSCLC with an iron tetroxide core loading the sound-sensitive agent IR780 for dual-mode imaging diagnosis by combining targeting and sonodynamic therapy (SDT) to reshape the tumor microenvironment (TME), enhance the SDT antitumor effects and improve the therapeutic effects of EGFR sensitivity. METHODS: IR780@INPs were prepared by reverse rotary evaporation, CTX was adsorbed/coupled to obtain IR780@INPs-CTX, and the morphology and structure were characterized. Intracellular ROS levels and cell apoptosis first verified its killing effects against tumor cells. Then, a nude mouse lung cancer subcutaneous xenograft model was established with HCC827 cells. A real-time fluorescence IVIS imaging system determined the targeting and live distribution of IR780@INPs-CTX in the transplanted tumors and the imaging effects of the T2 sequence of the INPs by magnetic resonance imaging (MRI) 0 h, 2 h, 4 h and 6 h after administration to confirm drug efficacy. RESULTS: In vitro, US+IR780@INPs-CTX produced a large amount of ROS after SDT to induce cell apoptosis, and significant cell death after live/dead staining was observed. In vivo fluorescence imaging showed the IR780@INPs-CTX was mainly concentrated in the tumor with a small amount in the liver. MRI displayed rapid enrichment of the IR780@INPs into tumor tissue 0h after injection and the T2 signal intensity gradually decreases with time without obvious drug enrichment in the surrounding tissues. In vivo, at the end of treatment, the US+IR780@INPs-CTX group showed disappearance or a continued decrease in tumor volume, indicating strong SDT killing effects. CONCLUSION: The combination of CTX and SDT is expected to become a novel treatment for EGFR-sensitive NSCLC.

A multifunctional nanotheranostic agent potentiates erlotinib to EGFR wild-type non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as Erlotinib, have demonstrated remarkable efficacy in the treatment of non-small cell lung cancer (NSCLC) patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type (wt) EGFR tumours has been shown to be marginal. Methods that can sensitize Erlotinib to EGFR wild-type NSCLC remain rare. Herein, we developed a multifunctional superparamagnetic nanotheranostic agent as a novel strategy to potentiate Erlotinib to EGFR-wt NSCLCs. Our results demonstrate that the nanoparticles can co-escort Erlotinib and a vascular epithermal growth factor (VEGF) inhibitor, Bevacizumab (Bev), to EGFR-wt tumours. The nanotheranostic agent exhibits remarkable effects as an inhibitor of EGFR-wt tumour growth. Moreover, Bev normalizes the tumour embedded vessels, further promoting the therapeutic efficacy of Erlotinib. In addition, the tumour engagement of the nanoparticles and the vascular normalization could be tracked by magnetic resonance imaging (MRI). Collectively, our study, for the first time, demonstrated that elaborated nanoparticles could be employed as a robust tool to potentiate Erlotinib to EGFR-wt NSCLC, paving the way for imaging-guided nanotheranostics for refractory NSCLCs expressing EGFR wild-type genes.

Structure of Venezuelan equine encephalitis virus with its receptor LDLRAD3.

Venezuelan equine encephalitis virus (VEEV) is an enveloped RNA virus that causes encephalitis and potentially mortality in infected humans and equines1. At present, no vaccines or drugs are available that prevent or cure diseases caused by VEEV. Low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) was recently identified as a receptor for the entry of VEEV into host cells2. Here we present the cryo-electron microscopy structure of the LDLRAD3 extracellular domain 1 (LDLRAD3-D1) in complex with VEEV virus-like particles at a resolution of 3.0 Å. LDLRAD3-D1 has a cork-like structure and is inserted into clefts formed between adjacent VEEV E2-E1 heterodimers in the viral-surface trimer spikes through hydrophobic and polar contacts. Mutagenesis studies of LDLRAD3-D1 identified residues that are involved in the key interactions with VEEV. Of note, some of the LDLRAD3-D1 mutants showed a significantly increased binding affinity for VEEV, suggesting that LDLRAD3-D1 may serve as a potential scaffold for the development of inhibitors of VEEV entry. Our structures provide insights into alphavirus assembly and the binding of receptors to alphaviruses, which may guide the development of therapeutic countermeasures against alphaviruses.

Ultrasonic Features of Uncommon Congenital Heterotopic Colon and Pancreas in the Neck: An Extremely Rare Case Report.

Congenital heterotopic colon and pancreas localized to the neck has not been reported. Herein, we describe an extremely uncommon case of congenital heterotopic colon and pancreas aberrantly presented within a cyst on the neck, and the thickened wall of the cyst on ultrasound may represent an important ultrasonic feature.

Evaluating the Treatment Efficacy of Nano-Drug in a Lung Cancer Model Using Advanced Functional Magnetic Resonance Imaging.

OBJECTIVES: Nano-drug delivery system is an interesting field in precise cancer treatment, but few study has reported the microenvironmental changes after such treatment. This study aimed to detect the hemodynamic and microenvironmental changes in a lung cancer xenograft model after treated with doxorubicin (DOX) encapsulated by a cyclic arginine-glycine-aspartic acid polypeptide modified poly-(lactic-co-glycolic acid) nanosystem (cRGD-PLGA@DOX) using functional magnetic resonance imaging. MATERIALS AND METHODS: Thirty-two tumor-bearing mice were randomly divided into four groups. Group A was treated with 0.9% saline, Group B with 4 mg/kg of doxorubicin, Group C with 2 mg/kg of cRGD-PLGA@DOX, and Group D with 4 mg/kg of cRGD-PLGA@DOX. Intravoxel incoherent motion diffusion-weighed imaging (IVIM-DWI) and R2∗ mapping were performed, and D∗, f, D, and R2∗ values were obtained before and1, 2, and 3 weeks after treatment. They were sacrificed for pathological examination after examinations. RESULTS: The reconstructed cRGD-PLGA@DOX was homogeneous, well-dispersed, and spherical in shape, with an average size of 180 nm. Group D demonstrated the smallest tumor volume and highest tumor inhibition rate in 3 weeks. D value of Group B, C, and D manifested an upward trend in 3 weeks with the highest increase in Group D. D∗ values shared a similar increased trends with f values in Group A, B, and C in 3 weeks, except Group D. R2∗ value of Group A gradually increased in 3 weeks, but the trends were reversed in the treatment groups. D value was significantly negative with Ki-67 expression (r = -0.757, P < 0.001) but positive with TUNEL (r = 0.621, P < 0.001), and phosphate and tension homology deleted on chromosome ten (PTEN) staining (r = 0.57, P = 0.004). R2∗ value was closely correlated with HIF-1a (r = 0.721, P < 0.001). CONCLUSION: The nano-drug demonstrated an enhanced anti-tumor effect without the need of increased chemotherapeutic dosage. The tumor microenvironment such as cellular and perfusion changes during treatment can be non-invasively detected by two functional MRI including IVIM-DWI and R2∗ mapping.

Diagnostic Performance of Perfusion Computed Tomography for Differentiating Lung Cancer from Benign Lesions: A Meta-Analysis.

BACKGROUND Numerous studies have explored diagnosis of pulmonary nodules using perfusion computed tomography (CT); however, findings were not always consistent between studies. Th e present study aimed to summarize evidence on the diagnostic value of perfusion CT for distinguishing between lung cancer and benign lesions. MATERIAL AND METHODS We performed a systematic literature search on lung cancer and benign pulmonary lesions performed with perfusion CT. The searches were undertaken in English or Chinese language in Medline, PubMed, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure database from Jan 2010 to Nov 2018. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) of blood volume (BV), blood flow (BF), mean transit time (MTT), and permeability surface (PS) were calculated using Review Manager 5.3. Publication bias, sensitivity, specificity, and the area under the curve (AUC) were calculated using Stata12.0. RESULTS Fourteen studies comprising 1032 malignant and 447 benign pulmonary lesions were analyzed. Lung cancer had higher BV, BF, MTT, and PS values than benign lesions. SMDs and 95% CIs of BV, BF, MTT, and PS were 2.29 (1.43, 3.16), 0.50 (0.14, 0.86), 0.55 (0.39, 0.72), and 1.21 (0.87, 1.56), respectively. AUC values of BV and PS were 0.92 (0.90, 0.94) and 0.83 (0.80, 0.86), respectively. CONCLUSIONS CT perfusion imaging is a valuable technique for the diagnosis of pulmonary nodules. Lung cancer had higher perfusion and permeability than benign lesions. The evidence suggests blood volume is the best surrogate marker for characterizing the blood supply, while permeability surface has a high specificity in quantifying the vascular permeability.