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Surface micro-morphology of 304 SS before corrosion (a), after corrosion in molten NaNO3–NaCl–NaF salt (b) and molten NaNO3–NaCl–NaF vapor (c). (Local enlarged region of A1 (b-1), A2 (c-1) and A3 (c-2)).

Liposomal drug delivery for cancer therapy can be limited due to drug leakage in circulation. Here, we develop a new method to enhance the stability of actively loaded liposomal doxorubicin (DOX) through embedding a stiff nanobowl in the liposomal water cavity. Nanobowl-supported liposomal DOX (DOX@NbLipo) resists the influence of plasma protein and blood flow shear force to prevent drug leakage. This approach yields improved drug delivery to tumor sites and enhanced antitumor efficacy. Compared to alternative methods of modifying liposome surface and composition for stability, this approach designs a physical support for an all-aqueous nanoliposomal cavity. Nanobowl stabilization of liposomes is a simple and effective method to improve carrier stability and drug delivery.

In view of the multiple pathological hallmarks of tumors, nanosystems for the sequential delivery of various drugs whose targets are separately located inside and outside tumor cells are desired for improved cancer therapy. However, current sequential delivery is mainly achieved through enzyme- or acid-dependent degradation of the nanocarrier, which would be influenced by the heterogeneous tumor microenvironment, and unloading efficiency of the drug acting on the target outside tumor cells is usually unsatisfactory. Here, a light-triggered sequential delivery strategy based on a liposomal formulation of doxorubicin (DOX)-loaded small-sized polymeric nanoparticles (DOX-NP) and free sunitinib in the aqueous cavity, is developed. The liposomal membrane is doped with photosensitizer porphyrin-phospholipid (PoP) and hybridized with red blood cell membrane to confer biomimetic features. Near-infrared light-induced membrane permeabilization triggers the "ultrafast" and "thorough" release of sunitinib (100% release in 5 min) for antiangiogenic therapy and also myeloid-derived suppressor cell (MDSC) inhibition to reverse the immunosuppressive tumor environment. Subsequently, the small-sized DOX-NP liberated from the liposomes is more easily uptaken by tumor cells for improved immunogenic chemotherapy. RNA sequencing and immune-related assay indicates therapeutic immune enhancement. This light-triggered sequential delivery strategy demonstrates the potency in cancer multimodal therapy against multiple targets in different spatial positions in tumor microenvironment.

Domestic wastewater depth processing and reclamation are essential in the alleviation of global water shortage. In this study, an innovative filter media (i.e., Fe3O4@Carbon filter media [FCM]) was...

In liver transplant cases, severe hepatic ischemia/reperfusion injury (HIRI) is a strong predictor of adverse liver graft and overall outcomes. During HIRI, high-mobility group box 1 (HMGB1) promotes hepatocellular death and proinflammatory cytokine secretion by toll-like receptor 4 (TLR4). Because salicylates inhibit HMGB1/TLR4 interaction, we hypothesized that salicylates may ameliorate HIRI-induced liver damage by inhibiting HMGB1/TLR4 axis activation. Using a murine model of HIRI, we found that the salicylate acetyl-3-aminoethyl salicylic acid (ac3AESA) reduced serum alanine aminotransferase and aspartate aminotransferase as well as Suzuki scores and apoptotic cell counts after HIRI. Ac3AESA also down-regulated hepatocellular HMGB1 and TLR4 expression, phosphorylated inhibitor of κBα, extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, cleaved caspase 3, and cleaved caspase 1 levels after HIRI. Ac3AESA reduced liver Kupffer cell transcription of proinflammatory mediators tumor necrosis factor α (TNF-α), interleukin (IL) 6, IL1β, chemokine (C-X-C motif) ligand (CXCL) 1, CXCL2, and CXCL8 after HIRI. Ac3AESA also dose-dependently reduced in vitro release of Kupffer cell TNF-α. Employing a murine orthotopic liver transplantation model, we found daily ac3AESA administration up to day 10 after transplant improved liver graft survival, suppressed allograft damage, and down-regulated HMGB1/TLR4 signaling. These benefits to survival and allograft health were maintained for cold ischemia times of 12 and 18 hours. Notably, TLR4 knockout eliminated all foregoing ac3AESA-induced effects. In conclusion, ac3AESA partially rescues the negative effects of HIRI and prolongs liver graft survival in a TLR4-dependent manner.

BackgroundTuberculosis (TB) is a leading cause of morbidity and mortality in underdeveloped and developing countries. Disseminated TB may induce uncommon and potentially fatal secondary hemophagocytic lymphohistiocytosis (HLH). Timely treatment with anti-tuberculosis therapy (ATT) and downmodulation of the immune response is critical. However, corticosteroid treatment for TB-associated HLH remains controversial. Herein, we report a successful case of disseminated TB-associated HLH in a pregnant woman with Evans syndrome accompanied by a literature review.Case PresentationA 26-year-old pregnant woman with Evans syndrome was transferred to the Third Affiliated Hospital of Sun Yat-Sen University because of severe pneumonia. She presented with cough, fever, and aggravated dyspnea. Nested polymerase chain reaction for Mycobacterium tuberculosis (M. tuberculosis) complex in sputum was positive. Sputum smear sample for acid-fast bacilli was also positive. Metagenome next-generation sequencing (mNGS) of the bronchoalveolar lavage fluid identified 926 DNA sequence reads and 195 RNA sequence reads corresponding to M. tuberculosis complex, respectively. mNGS of blood identified 48 DNA sequence reads corresponding to M. tuberculosis. There was no sequence read corresponding to other potential pathogens. She was initially administered standard ATT together with a low dose of methylprednisolone (40 mg/day). However, her condition deteriorated rapidly with high fever, acute respiratory distress syndrome, pancytopenia, and hyperferritinemia. Bone marrow smears showed hemophagocytosis. And caseating tuberculous granulomas were found in the placenta. A diagnosis of disseminated TB-associated HLH was made. Along with the continuation of four drug ATT regimen, therapy with a higher dose of methylprednisolone (160 mg/day) combined with immunoglobulin and plasma exchange was managed. The patient’s condition improved, and she was discharged on day 19. Her condition was good at follow-up with the continuation of the ATT.ConclusionsClinicians encountering patients with suspected TB accompanied by unexplainable inflammation not responding to ATT should consider complications with HLH. Timely administration of ATT combined with corticosteroids may result in a favorable outcome.

In article number 2003679, Chao Fang, Hong‐Zhuan Chen, and co‐workers develop a biomimetic liposomal nano‐Pt for targeted cancer chemophototherapy. At the tumor site, oxygen produced by nano‐Pt catalyzation improves the verteporfin‐mediated photodynamic therapy, which in turn triggers the release of nano‐Pt via membrane permeabilization. The ultrasmall 3–5 nm nano‐Pt enables better penetration in tumors for enhanced chemotherapy. [Image: see text]

Modeling antigenic variation in influenza (flu) virus A H3N2 using amino acid sequences is a promising approach for improving the prediction accuracy of immune efficacy of vaccines and increasing the efficiency of vaccine screening. Antigenic drift and antigenic jump/shift, which arise from the accumulation of mutations with small or moderate effects and from a major, abrupt change with large effects on the surface antigen hemagglutinin (HA), respectively, are two types of antigenic variation that facilitate immune evasion of flu virus A and make it challenging to predict the antigenic properties of new viral strains. Despite considerable progress in modeling antigenic variation based on the amino acid sequences, few studies focus on the deep learning framework which could be most suitable to be applied to this task. Here, we propose a novel deep learning approach that incorporates a convolutional neural network (CNN) and bidirectional long-short-term memory (BLSTM) neural network to predict antigenic variation. In this approach, CNN extracts the complex local contexts of amino acids while the BLSTM neural network captures the long-distance sequence information. When compared to the existing methods, our deep learning approach achieves the overall highest prediction performance on the validation dataset, and more encouragingly, it achieves prediction agreements of 99.20% and 96.46% for the strains in the forthcoming year and in the next two years included in an existing set of chronological amino acid sequences, respectively. These results indicate that our deep learning approach is promising to be applied to antigenic variation prediction of flu virus A H3N2.

Hepatocellular carcinoma (HCC) is a malignant tumor and is associated with necroinflammation driven by various immune cells, such as dendritic cells, macrophages and natural killer cells. Innate immune cells can directly affect HCC or regulate the T-cell responses that mediate HCC. In addition, innate immune cells and T cells are not isolated, which means the interaction between them is important in the HCC microenvironment. Considering the current unsatisfactory efficacy of immunotherapy in patients with HCC, understanding the relationship between innate immune cells and T cells is necessary. In the present review the roles and clinical value of innate immune cells that have been widely reported to be involved in HCC, including dendritic cells, macrophages (including kupffer cells), neutrophils, eosinophils, basophils and innate lymphoid cells and the crosstalk between the innate and adaptive immune responses in the antitumor process have been discussed. The present review will facilitate researchers in understanding the importance of innate immune cells in HCC and lead to innovative immunotherapy approaches for the treatment of HCC.

Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano‐Pt) as a catalase‐like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the cytotoxic activity of nano‐Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano‐Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed “nano‐Pt/VP@MLipo,” is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano‐Pt catalyzation improves the VP‐mediated PDT, which in turn triggers the release of nano‐Pt via membrane permeabilization. The ultrasmall 3–5 nm nano‐Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano‐Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity., The biomimetic liposomal nano‐Pt (nano‐Pt/VP@MLipo) targets the tumor sites, where oxygen produced by nano‐Pt catalyzation enhances the verteporfin (VP)‐mediated photodynamic therapy (PDT). PDT in turn permeabilizes the liposome membrane for efficient nano‐Pt release. These ultrasmall particles (3–5 nm) achieve penetration in deeper tumor tissue, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy.

OBJECTIVE: To investigate the role of endoplasmic reticulum (ER)-stress of Kupffer cells (KCs) and KCs-derived tumor necrosis factor-α (TNF-α) in medicating apoptosis of hepatic stellate cell (HSC). METHODS: Sixty male SD rats were randomized into control group, model group, ER- stress group, depletion group and KCs block group (n=15). The 4 groups of rats were given intraperitoneal injections (twice a week for 8 weeks) of normal saline (2 mg/kg); 40% CCl4 solution (in peanut oil, 2 mg/kg); 40% CCl4 solution (2 mg/kg) and tunicamycin (1 mg/kg); and 40% CCl4 solution (2 mg/kg) and tunicamycin (1 mg/kg) followed by clodronate liposomes (50 mg/kg), respectively. After the treatments, samples of the liver tissue and serum were collected from the rats from the 4 groups to isolate KC cells, which were co-cultured with LX2 cells. In the depletion group, the rats were injected with anti-rat TNFR mAb (0.35 mg/kg) via the portal vein before isolating the KCs. Liver function examination, Eirius red staining, ELISA, immuno- histochemical staining, and RT-PCR were performed to assess the liver function, liver fibrosis, KC phenotypes, expression of the in fl ammatory factors, and the number of active HSC was detected. The isolated KCs were treated with tunicamycin before co-culture with LX2 cells, and ELISA, RT-PCR and Western blot were performed to examine KC phenotypes, in fl ammatory factors, LX2 cell apoptosis and TNFR/caspase8 pathway activity. RESULTS: Compared with the rats in the control group, the rats in the model group had significantly increased ALT and AST levels, Sirius red staining-positive area, and Desmin-positive cells (activated HSCs) (P < 0.05) with significantly lowered number of CD16-positive KCs (M1), and TNF-α protein and mRNA expression (P < 0.05). Compared with those in the model group, the rats in ER-stress group showed significantly decreased ALT and AST levels, Sirius red staining positivity and Desmin-positive cells (P < 0.05) and increased number of CD16-positive KCs and TNF-α expressions (P < 0.05). In the depletion group, compared with the ER-stress group, the rats had significantly increased ALT and AST levels of, Sirius red staining positivity and Desmin-positive cells (P < 0.05) and reduced CD16- positive KCs and TNF-αexpressions (P < 0.05). In the cell co-culture experiment, the model group showed significantly reduced TUNEL-positive LX2 cells, CD16-positive cells, and expressions of TNFR1, cleaved caspase- 8 and cleaved caspase- 3 in the KCs (P < 0.05) with increased Desmin-positive LX2 cells (P < 0.05). Compared with the model group, the ER- stress group exhibited significantly increased TUNEL-positive LX2 cells, CD16-positive cells and expressions of TNFR, cleaved caspase-8 and cleaved caspase-3 in the KCs (P < 0.05) and decreased Desmin-positive LX2 cells (P < 0.05). In the depletion group, blocking TNFR resulted in significantly decreased expressions of cleaved caspase-8 and cleaved caspase-3 compared with those in ER- stress group (P < 0.05) although there was no significant changed in TNFR expression. CONCLUSION: ER stress of KCs promotes the transformation of KCs towards M1 phenotype and increases the expression of TNF-α, which triggers the apoptosis of HSCs through the TNFR/caspase-8 pathway.

Recent research has revealed the use of graphene oxide (GO) and its derivatives as a potential biomaterial because of their attractive physicochemical characteristics and functional properties. However, if GO and related derivatives are to become useful materials for biomedical applications, it will be necessary to evaluate their biodistribution for health and safety considerations. To obtain a more accurate biodistribution for GO, we (i) developed a postadministration labeling strategy employing DNA-conjugated gold nanoparticles (DNA-AuNPs) to selectively label administered GO in Solvable-treated tissue samples and (ii) constructed an automatic sample pretreatment scheme (using a C18-packed minicolumn) to effectively separate the DNA-AuNP-labeled GO from the unbound DNA-AuNPs and the dissolved tissue matrices, thereby enabling ultrasensitive, interference-free quantification of GO through measurement (inductively coupled plasma mass spectrometry) of the Au signal intensities. The DNA-AuNPs can bind to GO in a concentration- and time-dependent manner. After optimizing the labeling conditions (DNA length, incubation pH, DNA-AuNP concentration, and incubation time) and the separation scheme (sample loading flow rate, rinsing volume, and eluent composition), we found that A20R20-AuNPs (R20: random DNA sequence including A, T, C, and G) had the strongest binding affinity for labeling of the administered GO (dissociation constant: 36.0 fM) and that the method's detection limit reached 9.3 ag L-1 with a calibration curve having a working range from 10-1 to 1010 fg L-1. Moreover, this approach revealed that the intravenously administered GO accumulated predominantly in the liver and spleen at 1 and 12 h post administration, with apparent discrepancies in the concentrations measured using pre- and postadministration labeling strategies.

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor ( S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III-IVB (except T3-4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2 /d civ d1-5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein-Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.