Multi-Strategy Boosted Fick's Law Algorithm for Engineering Optimization Problems and Parameter Estimation.

To address the shortcomings of the recently proposed Fick's Law Algorithm, which is prone to local convergence and poor convergence efficiency, we propose a multi-strategy improved Fick's Law Algorithm (FLAS). The method combines multiple effective strategies, including differential mutation strategy, Gaussian local mutation strategy, interweaving-based comprehensive learning strategy, and seagull update strategy. First, the differential variation strategy is added in the search phase to increase the randomness and expand the search degree of space. Second, by introducing the Gaussian local variation, the search diversity is increased, and the exploration capability and convergence efficiency are further improved. Further, a comprehensive learning strategy that simultaneously updates multiple individual parameters is introduced to improve search diversity and shorten the running time. Finally, the stability of the update is improved by adding a global search mechanism to balance the distribution of molecules on both sides during seagull updates. To test the competitiveness of the algorithms, the exploration and exploitation capability of the proposed FLAS is validated on 23 benchmark functions, and CEC2020 tests. FLAS is compared with other algorithms in seven engineering optimizations such as a reducer, three-bar truss, gear transmission system, piston rod optimization, gas transmission compressor, pressure vessel, and stepped cone pulley. The experimental results verify that FLAS can effectively optimize conventional engineering optimization problems. Finally, the engineering applicability of the FLAS algorithm is further highlighted by analyzing the results of parameter estimation for the solar PV model.

Lipophilic AIEgens as the "Trojan Horse" with Discrepant Efficacy in Tracking and Treatment of Mycobacterial Infection.

The highly contagious tuberculosis is a leading infectious killer, which urgently requires effective diagnosis and treatment methods. To address these issues, three lipophilic aggregation-induced emission (AIE) photosensitizers (TTMN, TTTMN, and MeOTTMN) are selected to evaluate their labeling and antimicrobial properties in vitro and in vivo. These three lipophilic AIEgens preserve low cytotoxicity and achieve real-time and non-invasive visualization of the process of mycobacteria infection in vitro and in vivo. More importantly, these AIEgens can be triggered by white light to produce reactive oxygen species (ROS), which is a highly efficient antibacterial reagent. Among these AIEgens, the TTMN photosensitizer has an outstanding antibacterial efficacy over the clinical first-line drug rifampicin at the same therapeutic concentration. Interestingly, this study also finds that TTMN can increase the expression of pro-inflammatory cytokines in the early stage of infection after light irradiation, indicating an additional pro-inflammatory role of TTMN. This work provides some feasibility basis for developing AIEgens-based agents for effectively destroying mycobacterium.

Celastrol-loaded bovine serum albumin nanoparticles target inflamed neutrophils for improved rheumatoid arthritis therapy.

Inflammatory neutrophils (INEs), motivated by cytokines, continue to migrate into the inflamed joints, driving the development of RA. Hence, inducing apoptosis of INEs to reduce recruitment at inflamed joints is an effective strategy for the treatment of RA. However, simply apoptotic INEs may trigger the release of neutrophil extracellular traps (NETs) and accelerate the inflammatory process. To overcome these drawbacks, an RGD-modified bovine serum albumin (BSA) nanoparticles (CBR NPs) was fabricated to selectively target INEs in situ for intracellular delivery of CLT. Studies have demonstrated that CBR NPs can selectively target circulating INEs and induce INEs apoptosis. Meanwhile, CBR NPs inhibited the activation of NETs via NF-κB pathway and the release of Cit-H3 thereby blocking the release process of NETs. In collagen-induced arthritis (CIA) mouse model, CBR NPs suppressed the inflammatory response, and reduced the toxic effects of CLT. In summary, this study shed light on an innovative approach to treat RA by inducing apoptosis of circulating INEs and inhibiting NETs. STATEMENT OF SIGNIFICANCE: RGD-modified bovine serum albumin (BSA) nanoparticles for delivering celastrol, abbreviated as CBR NPs, were constructed to inhibit the infiltration of circulating inflammatory neutrophils (INEs) into inflamed joints while inhibiting the release of NETs to alleviate tissue damage. CBR NPs were prepared for the first time to induce apoptosis of INEs; CBR NPs could inhibit the release of NETs while inducing apoptosis of INEs in vivo and vitro cellular experiments; CBR NPs had favorable anti-inflammatory effects and low toxicity side-effects in collagen-induced arthritis (CIA) mouse models. The application of nanotechnology to induce apoptosis of INEs while inhibiting the release of NETs was a promising approach for the treatment of RA.

pH-Responsive Injectable Multifunctional Pluronic F127/Gelatin-Based Hydrogels with Hydrogen Production for Treating Diabetic Wounds.

Diabetic chronic wounds remain a major clinical challenge with long-term inflammatory responses and extreme oxidative damage. Hence, a pH-responsive injectable multifunctional hydrogel [Gel/CUR-FCHO/Mg (GCM) micromotors] via a Schiff base reaction between gelatin and benzaldehyde-grafted Pluronic F127 drug-loaded micelles (FCHO) was fabricated for the first time. Dynamic Schiff base linkage endowed the GCM hydrogel with the ability to be self-healing, injectable, and pH-responsive for on-demand drug delivery at the wound site. Curcumin (CUR), a hydrophobic drug with antioxidative, anti-inflammatory, and antibacterial activities, was encapsulated into the hydrogel matrix by micellization (CUR-FCHO micelles). Simultaneously, magnesium-based micromotors (Mg micromotors) were physically entrapped into the system for providing active hydrogen (H2) to scavenge reactive oxygen species and alleviate inflammatory responses. As a result, the GCM micromotor hydrogel displayed an inherent antibacterial property, extraordinary antioxidative performance, and remarkable biocompatibility. In the diabetic mouse with a full-thickness cutaneous defect wound, the GCM hydrogel could remodel the inflammatory microenvironment and stimulate vascularization and collagen deposition, thereby facilitating wound closure and enhancing tissue regeneration, which offered a promising therapeutic option for diabetic chronic wound management.

Stimuli-responsive nanoparticles delivered by a nasal-brain pathway alleviate depression-like behavior through extensively scavenging ROS.

Depression is one of the most common mental diseases, which seriously affects patients' physical and mental health. Emerging evidence has indicated that oxidative stress (OS) is a major cause of neurodegeneration involved in the pathogenesis of depression. Consequently, targeted reactive oxygen species (ROS) elimination is regarded as a promising strategy for efficient depression therapy. In addition, insufficient brain drug delivery is the main obstacle to depression therapy owing to the presence of the blood-brain barrier (BBB). To achieve the goals of bypassing the BBB and promoting antioxidant therapy for depression, a broad-spectrum ROS scavenging NPs was rationally designed through a nasal-brain pathway developed for combined ROS scavenging and brain drug delivery. A hexa-arginine (R6) modified ROS-responsive dextran (DEX) derivate was synthesized for antidepressant olanzapine (Olz) and H2 donor amino borane (AB) loading to prepare Olz/RDPA nanoparticles (NPs). Subsequently, the NPs were dispersed into a thermoresponsive hydrogel system based on poloxamer. In vitro and in vivo results demonstrated that Olz/RDPA in situ thermoresponsive hydrogel system could effectively deliver NPs to the brain via the nasal-brain pathway and alleviate depression-like behaviors through combined ROS depletion and inhibition of 5-HT dysfunction of the oxidative stress-induced. The proposed ROS-scavenging nanotherapeutic would open a new window for depression treatment. STATEMENT OF SIGNIFICANCE: ROS is an innovative therapeutic target involving the pathology of depression whereas targeted delivery of ROS scavenging has not been achieved yet. In the current study, ROS-responsive nanoparticles (Olz/RDPA NPs) were prepared and dispersed in a thermosensitive hydrogel for delivery through the nasal-brain pathway for the treatment of depression. Sufficient ROS depletion and improvement of delivery capacity by the nasal-brain pathway effectively could reverse oxidative stress and alleviate depressive-like behavior. Collectively, these nanoparticles may represent a promising strategy for the treatment of depression.

Efficacy and complications of single-port thoracoscopic minimally invasive esophagectomy in esophageal squamous cell carcinoma: a single-center experience.

The traditional surgical technique for esophageal cancer is mainly open esophagectomy. With the innovation of surgical instruments, it is necessary to re-optimize the minimally invasive surgery. Therefore, single-port thoracoscopic minimally invasive esophagectomy (SPTE) is an important direction of development. This study retrospectively analyzed 202 patients with esophageal squamous cell carcinoma undergoing SPTE. Surgical variables and postoperative complications were further evaluated. All procedures were performed using SPTE. The number of patients who received R0 resection was 201 (99.5%). The total number of resected lymph nodes during the whole operation was on average 32.01 ± 12.15, and the mean number of positive lymph nodes was 1.56 ± 2.51. In 170 cases (84.2%), intraoperative blood loss did not exceed 100 ml (ml), while 1 case had postoperative bleeding. Only 1 patient (0.5%) required reoperation after surgery. Postoperative complications included 42 cases of pneumonia (20.8%), 9 cases of anastomotic leak (4.5%), 7 cases of pleural effusion (3.8%), and 1 case (0.5%) of both pleural hemorrhage and acute gastrointestinal hemorrhagic ulcer. Besides, we also recorded the time to remove the drain tube, which averaged 9.13 ± 5.31 days. In our study, we confirmed that the application of SPTE in clinical practice is feasible, and that the postoperative complications are at a low level.

Seeing is believing: Efficiency evaluation of multifunctional ionic-dependent AIEgens for tuberculosis.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant public health threat with high rates of infection and mortality. Rapid and reliable theranostics of TB are essential to control transmission and shorten treatment duration. In this study, we report two cationic aggregation-inducing emission luminogens (AIEgens) named TTVP and TTPy, which have different functional charged moieties, to investigate their potential for simultaneous tracing and photodynamic therapy in TB infection. TTVP and TTPy exhibit intrinsic positive charges, excellent water solubility, and near-infrared (NIR) emission. Based on ionic-function relationships, TTVP, with more positive charges, demonstrates a stronger binding affinity to Mycobacterium marinum (M.m), (a close genetic relative of Mtb), compared to TTPy. Both TTVP and TTPy exhibit high efficiency in generating reactive oxygen species (ROS) when exposed to white light irradiation, enabling effective photodynamic killing of M.m in vitro. Additionally, we achieved long-term, real-time, noninvasive, continuous tracing, and evaluated therapeutic performance in vivo. Notably, TTVP outperformed TTPy in intracellular killing of M.m, suggesting a possible correlation between the labeling and photodynamic killing abilities of AIEgens. These findings provide valuable insights and a design basis for cationic AIEgens in TB research, offering potential advancements in TB theranostics.

Testing the validity and reliability of the Chinese version of the Staden schizophrenia anxiety rating scale.

Accurate assessment of anxiety disorders and their symptomatology in schizophrenic patients is important for prognosis and treatment. Measuring anxiety on the traditional anxiety assessment scales such as the Hamilton Anxiety Rating (HAMA) Scale or the self-rating depression scale (SAS) is challenging and often considered unsuitable for assessing anxiety symptoms in patients with schizophrenia. The Staden schizophrenia anxiety rating scale (S-SARS) has been shown to reliably measure specified and undifferentiated anxiety in schizophrenia. The present study aims to test the reliability and validity of the S-SARS version, thereby facilitating Chinese psychiatrists in assessing anxiety symptoms in schizophrenic patients. A total of 300 patients meeting ICD-10 diagnostic criteria of schizophrenia were recruited by convenience sampling. We used the exploratory factor analysis (EFA) to evaluate the structural validity of S-SARS and receiver operating characteristic (ROC) curves to acquire the cutoff point of S-SARS to define the severity of anxiety. Internal consistency was assessed using Cronbach's and Krippendorff's α scores. 1-week test-retest reliability was assessed using the intra-class correlation coefficient (ICC). Correlation analysis with HAMA was used to determine the Chinese version of S-SARS criterion validity. We have the following results: Our version of S-SARS showed Cronbach's α score as 0.899, Krippendorff's α as 0.874, and a correlation coefficient of 0.852 between S-SARS and HAMA. The EPA demonstrated that the contribution rate of major factors was 69.45%. All the items of S-SARS were located in one factor and showed a high factor load (0.415-0.837). The correlation coefficient of S-SARS and HAMA was 0.852. Our results indicated that Chinese version of S-SARS showed good constructive validity and reliability. It also showed better criterion validity compared to HAMA. The S-SARS and its Chinese version can thus serve as an effective tool for assessing anxiety symptoms in patients with schizophrenia.

Combining immune checkpoint blockade with ATP-based immunogenic cell death amplifier for cancer chemo-immunotherapy.

Amplifying "eat me signal" during tumor immunogenic cell death (ICD) cascade is crucial for tumor immunotherapy. Inspired by the indispensable role of adenosine triphosphate (ATP, a necessary "eat me signal" for ICD), a versatile ICD amplifier was developed for chemotherapy-sensitized immunotherapy. Doxorubicin (DOX), ATP and ferrous ions (Fe2+) were co-assembled into nanosized amplifier (ADO-Fe) through π‒π stacking and coordination effect. Meanwhile, phenylboric acid-polyethylene glycol-phenylboric acid (PBA-PEG-PBA) was modified on the surface of ADO-Fe (denoted as PADO-Fe) by the virtue of d-ribose unit of ATP. PADO-Fe could display active targetability against tumor cells via sialic acid/PBA interaction. In acidic microenvironment, PBA-PEG-PBA would dissociate from amplifier. Moreover, high H2O2 concentration would induce hydroxyl radical (·OH) and oxygen (O2) generation through Fenton reaction by Fe2+. DOX and ATP would be released from the amplifier, which could induce ICD effect and "ICD adjuvant" to amplify this process. Together with programmed death ligands 1 (PD-L1) checkpoint blockade immunotherapy, PADO-Fe could not only activate immune response against primary tumor, but also strong abscopal effect against distant tumor. Our simple and multifunctional ICD amplifier opens a new window for enhancing ICD effect and immune checkpoint blockade therapy.

Blockage of the IDO1 pathway by charge-switchable nanoparticles amplifies immunogenic cell death for enhanced cancer immunotherapy.

Immunosuppressive tumor microenvironment (ITM), poor immunogenicity, and low tumor penetration markedly reduce the capability of tumor immunotherapy. To address these challenges, we successfully engineered acidity-triggered nanoparticles (NPs) with size reduction and charge switchable features to boost tumor immunotherapy based on indoleamine 2,3-dioxygenase 1 siRNA (IDO1 siRNA) and immunogenic cell death (ICD). The NPs significantly augmented tumor penetrating ability and improved cellular uptake via the detachment of 2,3-dimethylmaleic anhydride-grafted poly(ethylene glycol)-poly(L-lysine) copolymer (mPEG-PLL-DMA, PLM) from large-sized NPs with a negative charge. Subsequently, the NPs with a positive charge and small size rapidly escaped from the lysosomes and released mitoxantrone (MIT) and IDO1 siRNA. The antitumor immune response of IDO1 siRNA and MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in tumor tissues. In summary, the results demonstrated that charge-switchable NPs based on the blockage of the IDO1 pathway and ICD activation induce an efficient antitumor immune response, thus showing high potential for treating primary/distant tumors and reducing metastasis. STATEMENT OF SIGNIFICANCE: Acidity-triggered nanoparticles (NPs) with size reduction and charge reversal to boost tumor immunotherapy based on indoleamine 2,3-dioxygenase 1 siRNA (IDO1 siRNA) and immunogenic cell death (ICD) were engineered. NPs augmented tumor penetrating ability and improved cellular uptake through the detachment of mPEG-PLL-DMA (PLM) from the large-sized MIT/siR-PLM/PPA NPs with negative charge to expose miniature and positively charged MIT/siR-PPA NPs. The NPs rapidly escaped from the lysosome and sequentially released mitoxantrone (MIT) and IDO1 siRNA. The antitumor synergistic effect of inhibiting the IDO1 pathway by IDO1 siRNA and inducing ICD by MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in tumor tissues. Thus, the NPs showed a promising pathway against aggressive and difficult-to-treat cancers.

Nanoscale Hf-hematoporphyrin frameworks for synergetic sonodynamic/radiation therapy of deep-seated tumors.

Most of tumors are located in deep-depth of animals, and the therapy of deep-seated tumors remains a severe challenge due to the performance reduction of promising technologies including phototherapy. To solve the problem, herein we have developed a hafnium-hemoporfin frameworks (HfHFs) as multifunctional theranostic nanoplatforms for synergetic sonodynamic therapy (SDT) and radiation therapy (RT) of deep-seated tumors. HfHFs are constructed by a sonication-assisted assembly route with hematoporphyrin monomethyl ether (HMME) sonosensitizer molecules as bridging linkers and Hf4+ as metal nodes. The resulting HfHFs sample is composed of spherical nanoparticles with size of 90-130 nm, and then surface-modified with DSPE-PEG to improve the water-dispersity. Under ultrasound (US) irradiation, HMME ligands in HfHFs can be motivated to produce singlet oxygen (1O2) due to sonodynamic effect. When the HfHFs sample is exposed by X-ray, the high atomic-number Hf4+ in the HfHFs can effectively absorb X-ray to increase RT effect by producing hydroxyl radicals (•OH). When HfHFs dispersion is intravenously injected in the tumor-bearing mice, the tumor can be monitored by CT imaging. Moreover, the deep-seated tumors coated by tissue barriers can be suppressed effectively by the synergistic SDT and RT, which is better than that of SDT or RT alone. Therefore, HfHFs can be employed as a novel nanoagent for the SDT-RT of deep-seated tumors.

MicroRNA-30c-2-3p represses malignant progression of gastric adenocarcinoma cells via targeting ARHGAP11A.

MicroRNAs are crucial tumor regulators to tumor development and progression. MiR-30c-2-3p can suppress malignant progression of tumor cells, but no study has reported the modulatory process of miR-30c-2-3p in gastric adenocarcinoma (GA). We herein investigated role of miR-30c-2-3p in GA cells. Here, we evaluated gene level in cancer cells by qRT-PCR. CCK-8, colony formation, flow cytometry, and transwell assays revealed biological functions of miR-30c-2-3p and ARHGAP11A. Genes downstream of miR-30c-2-3p were acquired through bioinformatics analysis. Our results suggested a low level of miR-30c-2-3p in GA tissue and cells, while its high expression could repress the malignant progression and promote cell cycle arrest and apoptosis of GA cells. Besides, ARHGAP11A was downstream of miR-30c-2-3p, with up-regulated ARHGAP11A facilitating malignant progression and repressing cell cycle arrest and apoptosis of GA cells. In addition, changes in GA cell functions caused by high ARHGAP11A expression could be partially offset by enhancing miR-30c-2-3p. Thus, our observations indicated that miR-30c-2-3p was a tumor repressor that could inhibit GA progression via modulating ARHGAP11A.

A phenolic based tumor-permeated nano-framework for immunogenic cell death induction combined with PD-L1 immune checkpoint blockade.

A critical obstacle for programmed death ligand 1 (PD-L1) immune checkpoint blockade immunotherapy is the insufficient T cell infiltration and low immunogenicity of tumor cells. Improving tumor immunogenicity through immunogenic cell death (ICD) can make tumor sensitive to PD-L1 checkpoint blockade immunotherapy. Herein, a phenolic based tumor-permeated nano-framework (EGPt-NF) was fabricated by cross-linking phenylboric acid modified platinum nanoparticles (PBA-Pt, ICD inducer) and epigallocatechin-3-O-gallate (EGCG, PD-L1 inhibitor) via pH-reversible borate ester. In particular, PBA-Pt could not only induce ICD cascade but also relieve tumor hypoxia. Consequently, EGPt-NF could effectively promote dendritic cell maturation and downregulate PD-L1 expression in tumor cells. Furthermore, EGPt-NF could also relieve tumor hypoxia to facilitate cytotoxic T lymphocyte infiltration and IFN-γ secretion. The synergistic effect of EGPt-NF could effectively improve tumor immunogenicity and amplify the therapeutic outcomes of cancer immunotherapy, resulting in a strong antitumor immune response in primary tumor and metastasis inhibition. Our simple approach expands the application of platinum-based drug delivery systems for cancer immunotherapy.

A Self-amplifying ROS-sensitive prodrug-based nanodecoy for circumventing immune resistance in chemotherapy-sensitized immunotherapy.

Circumventing immune resistance and boosting immune response is the ultimate goal of cancer immunotherapy. Herein, we reported a tumor-associated macrophage (TAM) membrane-camouflaged nanodecoy containing a self-amplifying reactive oxygen species (ROS)-sensitive prodrug nanoparticle for specifically inducing immunogenic cell death (ICD) in combination with TAM depletion. A versatile ROS-cleavable camptothecin (CPT) prodrug (DCC) was synthesized through a thioacetal linker between CPT and the ROS generator cinnamaldehyde (CA), which could self-assemble into a uniform prodrug nanoparticle to realize a positive feedback loop of "ROS-triggered CA/CPT release and CA/CPT-mediated ROS generation." This DCC was further modified with the TAM membrane (abbreviated as DCC@M2), which could not only target both primary tumors and lung metastasis nodules through VCAM-1/α4ß1 integrin interaction but also absorb CSF-1 secreted by tumor cells to disturb the interaction between TAMs and cancer cells. Our nanodecoy could effectively induce ICD cascade and deplete TAMs for priming tumor-specific effector T cell infiltration for antitumor immune response activation, which represents a versatile approach for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A tumor-associated macrophage (TAM) membrane-camouflaged nanodecoy containing a self-amplifying reactive oxygen species (ROS)-sensitive prodrug nanoparticle was fabricated for the first time. This ROS-cleavable camptothecin (CPT)/cinnamaldehyde (CA) prodrug (DCC) could self-assemble into a uniform nanoparticle to realize the positive feedback loop of "ROS-triggered CA/CPT release and CA/CPT-mediated ROS generation." After TAM membrane coating, this system (DCC@M2) could not only target both primary tumors and lung metastatic nodules but also scavenge CSF-1 secreted by tumor cells for TAM depletion for sufficient chemotherapy-sensitized immunotherapy.

Watson-Crick Base Pairing-Inspired Laser/GSH Activatable miRNA-Coordination Polymer Nanoplexes for Combined Cancer Chemo-Immuno-Photothermal Therapy.

The tumor immunosuppressive microenvironment (TIM) greatly hindered the efficacy of cancer immunotherapy. Overexpressed indoleamine 2,3-dioxygenase-1 (IDO1) in tumor tissues plays a vital role in TIM generation, and downregulation of IDO1 expression may reverse TIM. Inspired by the Watson-Crick base-pairing rule, a versatile noncationic miRNA vector (miDAC@PDA) is developed for cancer immunotherapy. Doxorubicin (DOX), adenosine triphosphate (ATP), and copper ions (Cu2+) are coassembled into coordination polymer nanoparticles (DAC) and bind miRNA via the hydrogen bond interaction (miDAC) between adenine residues (ATP) and uracil residues (miRNA). Polydopamine (PDA) is deposited onto the surface of miDAC for photothermal therapy. miDAC@PDA can efficiently accumulate into tumor tissues for cellular uptake. Under laser irradiation and high intracellular GSH levels, the PDA shell of miDAC@PDA can dissociate from miDAC for miRNA release due to local hyperthermia. Cu2+-mediated GSH consumption and intracellular ATP release can amplify the DOX-based immunogenic cell death (ICD) cascade, together with miR-448-mediated IDO1 inhibition, and these versatile nanoplexes will not only restrain primary tumor growth but also display a remarkable abscopal effect on distant tumors. Collectively, our study provides a unique strategy for intracellular gene delivery and an inspirational approach for multimechanism cancer management.

Tumor-specific nitric oxide generator to amplify peroxynitrite based on highly penetrable nanoparticles for metastasis inhibition and enhanced cancer therapy.

Multiple biological barriers and tumor metastasis severely impede the tumor therapy. To address these adversities, an acid-activated poly (ethylene glycol)-poly-l-lysine-2,3-dimethylmaleic anhydride/poly (ε-caprolactone)-poly(l-arginine)/ß-lapachone nanoparticles (mPEG-PLL-DMA/PCL-P(L-arg)/ß-Lap, PLM/PPA/ß-Lap NPs) were constructed with charge-reversal and size-reduction for ß-Lap delivery with a cascade reaction of reactive oxygen species (ROS) and nitric oxide (NO) production. The nanosystem exhibited highly penetrable, superior cellular uptake and desirable endo-lysosomal escape thanks to size-reduction, charge-reversal and proton sponge, respectively. The vast bulk of ROS, which rapidly generated from ß-Lap under high concentration quinone oxidoreductase 1 (NQO1), catalyzed guanidine groups to produce NO and generated highly toxic peroxynitrite (ONOO-). ONOO- would activate pro-matrix metalloproteinases (pro-MMPs) to generate MMPs, degrade the dense extracellular matrix (ECM) to augment the penetration capability, and aggravate DNA damage. NO and ONOO- influenced mitochondrial function by decreasing mitochondrial membrane potential and prevented the production of adenosine triphosphate (ATP), which inhibited the ATP-dependent tumor-derived microvesicles (TMVs) and restrained tumor metastasis. NO was defined as an epithelial mesenchymal transition (EMT) inhibitor to restrain tumor metastasis. All consequences demonstrated that PLM/PPA/ß-lap NPs exhibited efficient penetration capability, outstanding anti-metastasis activity and favorable antitumor efficacy. Those novel acid-activated NPs are intended to provide further inspiration for multifunctional NO gas therapy.

Binary regulation of the tumor microenvironment by a pH-responsive reversible shielding nanoplatform for improved tumor chemo-immunotherapy.

The limited infiltration of specific T cells in an immunosuppressive microenvironment is a major challenge for cancer immunotherapy. Reversing tumor microenvironment and inducing an antitumor immune response are crucial for cancer therapy. Here, phenylboronic acid (PBA) derivative-stabilized ultrasmall platinum nanoparticles (PBA-Pt) and dextran-coated BLZ-945 nanoparticles (DNPs) were co-assembled through a pH-responsive borate ester bond to construct a versatile reversible shielding multifunctional nanoplatform (Pt@DNPs) for the first time. Pt@DNPs dissociated into two individual components, namely PBA-Pt and DNPs, in the tumor acid microenvironment. Both in vitro and in vivo studies revealed that Pt@DNPs induced immunogenic cell death (ICD) (through multimechanisms involving PtⅡ release and a multienzyme catalytic process by PBA-Pt) and relieved immunosuppressive microenvironment (depletion of tumor-associated macrophages by BLZ-945), which led to tumor-associated antigen release, maturation of dendritic cells, and infiltration of cytotoxic T cells for efficient antitumor immune response against both primary tumor and pulmonary metastatic tumor nodules. Therefore, Pt@DNPs is a promising option for cancer chemo-immunotherapy. STATEMENT OF SIGNIFICANCE: A versatile reversible shielding multifunctional nanoplatform (Pt@DNPs) was engineered for the first time for combinational cancer chemo-immunotherapy. Multimechanisms involving induction of immunogenic cell death by PBA-Pt and sufficient TAM depletion by DNPs could efficiently relieve tumor immunosuppressive microenvironment and activate the antitumor immune response. The synergistic effect not only increased the infiltration of specific T cells in primary tumor, but it also induced a strong immune response against pulmonary metastatic nodules. Collectively, this nanoplatform may represent a promising strategy for combinational chemo-immunotherapy for cancers.

Combination of albumin concentration and neutrophil-to-lymphocyte ratio for predicting overall survival of patients with non-small cell lung cancer.

BACKGROUND: Lung cancer contributes significantly to the total of cancer-linked deaths globally, accounting for 1.3 million deaths each year. Preoperative albumin (Alb) concentration and neutrophil-to-lymphocyte ratio (NLR) may reflect chronic inflammation and be used to predict lung cancer outcomes. METHODS: The clinical records of 293 patients with non-small cell lung cancer (NSCLC) in Fujian Medical University Cancer Hospital & Fujian Cancer Hospital were reviewed retrospectively in this current study. Clinicopathologic pretreatment, including NLR, Glasgow prognostic score (GPS), and post-treatment value, such as tumor-node-metastasis (TNM) were documented. The cut-off finder application was employed to calculate the optimal threshold values. The significance of Alb concentration combined with NLR (COA-NLR) on the prediction of overall survival (OS) was explored using Kaplan-Meier analysis along with Cox proportional hazards. RESULTS: The results revealed that COA-NLR could independently assess the OS of patients with NSCLC [hazard ratio (HR) =1.952, 95% confidence interval (CI): 1.367 to 2.647, P<0.001]. Moreover, the 3-year OS rates were 87.2%, 68.5%, and 52.8% for the COA-NLR =0, COA-NLR =1, and COA-NLR =2, respectively (P<0.001). CONCLUSIONS: Preoperative COA-NLR value can effectively stratifies prognosis in NSCLC patients by classified patients into three independent groups. It can be adopted as an effective biomarker for prognosis in NSCLC patients treated with resection.

Construction of Hierarchical-Targeting pH-Sensitive Liposomes to Reverse Chemotherapeutic Resistance of Cancer Stem-like Cells.

Cancer stem-like cells (CSLCs) have been considered to be one of the main problems in tumor treatment owing to high tumorigenicity and chemotherapy resistance. In this study, we synthesized a novel mitochondria-target derivate, triphentlphosphonium-resveratrol (TPP-Res), and simultaneously encapsulated it with doxorubicin (Dox) in pH-sensitive liposomes (PSL (Dox/TPP-Res)), to reverse chemotherapeutic resistance of CSLCs. PSL (Dox/TPP-Res) was approximately 165 nm in size with high encapsulation efficiency for both Dox and TPP-Res. Cytotoxicity assay showed that the optimal synergistic effect was the drug ratio of 1:1 for TPP-Res and Dox. Cellular uptake and intracellular trafficking assay indicated that PSL (Dox/TPP-Res) could release drugs in acidic endosomes, followed by mitochondrial targeting of TPP-Res and nucleus transports for Dox. The mechanisms for reversing the resistance in CSLCs were mainly attributed to a synergistic effect for reduction of mitochondrial membrane potential, activation of caspase cascade reaction, reduction of ATP level and suppression of the Wnt/ß-catenin pathway. Further, in vivo assay results demonstrated that the constructed liposomes could efficiently accumulate in the tumor region and possess excellent antineoplastic activity in an orthotopic xenograft tumor model with no evident systemic toxicity. The above experimental results determined that PSL (Dox/TPP-Res) provides a new method for the treatment of heterogenecity tumors.

Laser/GSH-Activatable Oxaliplatin/Phthalocyanine-Based Coordination Polymer Nanoparticles Combining Chemophotodynamic Therapy to Improve Cancer Immunotherapy.

There are two severe obstacles in cancer immunotherapy. The first is that the low response rate challenges the immune response owing to the immunosuppressive tumor microenvironment (ITM) and poor immunogenicity of the tumor. The second obstacle is that the dense and intricate pathophysiology barrier seriously restricts deep drug delivery in solid tumors. A laser/glutathione (GSH)-activatable nanosystem with tumor penetration for achieving highly efficient immunotherapy is reported. The core of the nanosystem was synthesized by coordinating zinc ions with GSH-activatable oxaliplatin (OXA) prodrugs and carboxylated phthalocyanine. Such an OXA/phthalocyanine-based coordination polymer nanoparticle (OPCPN) was wrapped by a phospholipid bilayer and NTKPEG. NTKPEG is a PEGylated indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor prodrug containing a thioketal (TK) linker, which was modified on the OPCPN (OPCPN@NTKPEG). Upon the laser irradiation tumor site, ROS production of the OPCPN@NTKPEG triggers cleavage of NTKPEG by degradation of TK for promoted tumor penetration and uptake. OXA, phthalocyanine, and IDO1 inhibitor were released by the intracellular high-level GSH. OXA inhibits cell growth and is combined with photodynamic therapy (PDT) to induce immunogenic cell death (ICD). The IDO1 inhibitor reversed the ITM by suppressing IDO1-mediated Trp degradation and exhaustion of cytotoxic T cells. Laser/GSH-activatable drug delivery was more conducive to enhancing ICD and reversing ITM in deep tumors. Chemo-PDT with OPCPN@NTKPEG significantly regressed tumor growth and reduced metastasis by improved cancer immunotherapy.