3D Printing of Thermo-Mechano-Responsive Photoluminescent Noncovalent Cross-Linked Ionogels with High-Stretchability and Ultralow-Hysteresis for Wearable Ionotronics and Anti-Counterfeiting.

Ionogel has recently emerged as a promising ionotronic material due to its good ionic conductivity and flexibility. However, low stretchability and significant hysteresis under long-term loading limit their mechanical stability and repeatability. Developing ultralow hysteresis ionogels with high stretchability is of great significance. Here, a simple and effective strategy is developed to fabricate highly stretchable and ultralow-hysteresis noncovalent cross-linked ionogels based on phase separation by 3D printing of 2-hydroxypropyl acrylate (HPA) in 1-butyl-3-methylimidazolium tetrafluoroborate (BMIMBF4). Ingeniously, the sea-island structure of the physically cross-linked network constructed by the smaller nanodomains and larger nanodomain clusters significantly minimizes the energy dissipation, endowing these ionogels with remarkable stretchability (>1000%), ultra-low hysteresis (as low as 0.2%), excellent temperature tolerance (-33-317 °C), extraordinary ionic conductivity (up to 1.7 mS cm-1), and outstanding durability (5000 cycles). Moreover, due to the formation of nanophase separation and cross-linking structure, the as-prepared ionogels exhibit unique thermochromic and multiple photoluminescent properties, which can synergistically be applied for anti-counterfeiting and encrypting. Importantly, flexible thermo-mechano-multimodal visual ionotronic sensors for strain and temperature sensing with highly stable and reproducible electrical response over 20 000 cycles are fabricated, showing synergistically optical and electrical output performances.

Assembling Au8 clusters on surfaces of bifunctional nanoimmunomodulators for synergistically enhanced low dose radiotherapy of metastatic tumor.

BACKGROUND: Radiotherapy is one of the mainstays of cancer therapy and has been used for treating 65-75% of patients with solid tumors. However, radiotherapy of tumors has two limitations: high-dose X-rays damage adjacent normal tissue and tumor metastases cannot be prevented. RESULTS: Therefore, to overcome the two limitations of radiotherapy, a multifunctional core-shell R837/BMS@Au8 nanoparticles as a novel radiosensitizer were fabricated by assembling Au8NCs on the surface of a bifunctional nanoimmunomodulator R837/BMS nanocore using nanoprecipitation followed by electrostatic assembly. Formed R837/BMS@Au8 NP composed of R837, BMS-1, and Au8 clusters. Au8NC can enhance X-ray absorption at the tumor site to reduce X-ray dose and releases a large number of tumor-associated antigens under X-ray irradiation. With the help of immune adjuvant R837, dendritic cells can effectively process and present tumor-associated antigens to activate effector T cells, meanwhile, a small-molecule PD-L1 inhibitor BMS-1 can block PD-1/PD-L1 pathway to reactivate cytotoxic T lymphocyte, resulting in a strong systemic antitumor immune response that is beneficial for limiting tumor metastasis. According to in vivo and in vitro experiments, radioimmunotherapy based on R837/BMS@Au8 nanoparticles can increase calreticulin expression on of cancer cells, reactive oxygen species generation, and DNA breakage and decrease colony formation. The results revealed that distant tumors were 78.2% inhibited depending on radioimmunotherapy of primary tumors. Therefore, the use of a novel radiosensitizer R837/BMS@Au8 NPs realizes low-dose radiotherapy combined with immunotherapy against advanced cancer. CONCLUSION: In conclusion, the multifunctional core-shell R837/BMS@Au8 nanoparticles as a novel radiosensitizer effectively limiting tumor metastasis and decrease X-ray dose to 1 Gy, providing an efective strategy for the construction of nanosystems with radiosensitizing function.

The effective separation of photogenerated carriers in MIL101 nanocomposites promoting the efficient photocatalytic desulfurization in air.

The extensive industrial applications of fuel oil, a critical strategic resource, are accompanied by significant environmental and health concerns due to the presence of sulfur-containing compounds in its composition, which result in hazardous combustion waste. Extensive research has been conducted to develop technologies for low-vulcanization fuel production to address this issue. Consequently, the investigation of catalysts for environmentally friendly and safe photocatalytic desulfurization becomes imperative. To that end, we have designed efficient MIL-101(Fe)/CQDs@g-C3N4 (MIL101/CDs-C3N4) Z-scheme heterojunction photocatalysts with high carrier separation and mobility through a thermal polymerization-hydrothermal strategy. The high concentration of photogenerated carriers facilitates the activation of oxygen and H2O2, leading to increased production of ROS (·O2-, ·OH, h+), thereby enhancing the photocatalytic desulfurization (PODS). Additionally, DFT calculations were utilized to determine the electron migration pathways of the catalysts and adsorption energies of DBT (dibenzothiophene). Moreover, Gibbs free energy calculations indicated that MIL101/CDs-C3N4 exhibited the lowest activation energy for oxygen and H2O2. The mechanism of photocatalytic desulfurization was proposed through a combination of theoretical calculations and experimental studies. This study provides guidance for the development of MOF-based Z-scheme systems and their practical application in desulfurization processes.

Characterization and synthesis of new adsorbents with some natural waste materials for the purification of aqueous solutions.

In this study, hexavalent chromium Removal from aqueous environments was investigated by using polyaniline composites with some natural waste materials. Batch experiments were used, and some parameters such as contact time, pH and adsorption isotherms were determined for the best composite with the highest removal efficiency. Scanning Electron Microscope (SEM), Fourier Transform Infrared (FTIR) spectroscopy, and X-ray Diffraction (XRD) were used to characterize the composites. According to the results, the polyaniline/walnut shell charcoal/PEG composite outperformed other composites and showed the highest chromium removal efficiency of 79.22%. Polyaniline/walnut shell charcoal/PEG has a larger specific surface area of 9.291 (m2/gr) which leads to an increase in its removal efficiency. For this composite, the highest removal efficiency was obtained at the pH = 2 and 30 min contact time. The maximum calculated adsorption capacity was 500 mg/g.

Screening a Prognosis-Related Target Gene in Patients with HER-2-Positive Breast Cancer by Bioinformatics Analysis.

OBJECTIVE: The objective of the present study was to determine a target gene and explore the molecular mechanisms involved in the pathogenesis of HER-2-positive breast cancer. METHODS: Three RNA expression profiles obtained from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) were used to identify differentially expressed genes (DEGs) using the R software. A protein-protein interaction network was then constructed, and hub genes were determined. Subsequently, the relationship between clinical parameters and hub genes was examined to screen for target genes. Next, DNA methylation and genomic alterations of the target gene were evaluated. To further explore potential molecular mechanisms, a functional enrichment analysis of genes coexpressed with the target gene was performed. RESULTS: The differential expression analysis revealed 217 DEGs in HER-2-positive breast cancer samples compared to normal breast tissues. RRM2 was the only hub gene closely associated with lymphatic metastasis and the patients' prognosis. Additionally, RRM2 was found to be consistently amplified and negatively associated with the level of methylation. Functional enrichment analysis showed that the coexpressed genes were mainly involved in cell cycle regulation. CONCLUSIONS: RRM2 was identified as a target gene associated with the initiation, progression, and prognosis of HER-2-positive breast cancer, which may be considered as a new biomarker and therapeutic target.

Concordance Study Between IBM Watson for Oncology and Clinical Practice for Patients with Cancer in China.

BACKGROUND: IBM Watson for Oncology (WFO), which can use natural language processing to evaluate data in structured and unstructured formats, has begun to be used in China. It provides physicians with evidence-based treatment options and ranks them in three categories for treatment decision support. This study was designed to examine the concordance between the treatment recommendation proposed by WFO and actual clinical decisions by oncologists in our cancer center, which would reflect the differences of cancer treatment between China and the U.S. PATIENTS AND METHODS: Retrospective data from 362 patients with cancer were ingested into WFO from April 2017 to October 2017. WFO recommendations were provided in three categories: recommended, for consideration, and not recommended. Concordance was analyzed by comparing the treatment decisions proposed by WFO with those of the multidisciplinary tumor board. Concordance was achieved when the oncologists' treatment decisions were in the recommended or for consideration categories in WFO. RESULTS: Ovarian cancer showed the highest concordance, which was 96%. Lung cancer and breast cancer obtained a concordance of slightly above 80%. The concordance of rectal cancer was 74%, whereas colon cancer and cervical cancer showed the same concordance of 64%. In particular, the concordance of gastric cancer was very low, only 12%, and 88% of cases were under physicians choice. CONCLUSION: Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major cause of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. ClinicalTrials.gov Identifier: NCT03400514. IMPLICATIONS FOR PRACTICE: IBM Watson for Oncology (WFO) has begun to be used in China. In this study, concordance was examined between the treatment recommendation proposed by WFO and clinical decisions for 362 patients in our cancer center, which could reflect the differences of cancer treatment between China and the U.S. Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major causes of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. This study may have a significant effect on application of artificial intelligence systems in China.

Immune Checkpoint Blockade Mediated by a Small-Molecule Nanoinhibitor Targeting the PD-1/PD-L1 Pathway Synergizes with Photodynamic Therapy to Elicit Antitumor Immunity and Antimetastatic Effects on Breast Cancer.

Targeting programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immunologic checkpoint blockade with monoclonal antibodies has achieved recent clinical success in antitumor therapy. However, therapeutic antibodies exhibit several issues such as limited tumor penetration, immunogenicity, and costly production. Here, Bristol-Myers Squibb nanoparticles (NPs) are prepared using a reprecipitation method. The NPs have advantages including passive targeting, hydrophilic and nontoxic features, and a 100% drug loading rate. BMS-202 is a small-molecule inhibitor of the PD-1/PD-L1 interaction that is developed by BMS. Transfer of BMS-202 NPs to 4T1 tumor-bearing mice results in markedly slower tumor growth to the same degree as treatment with anti-PD-L1 monoclonal antibody (α-PD-L1). Consistently, the combination of Ce6 NPs with BMS-202 NPs or α-PD-L1 in parallel shows more efficacious antitumor and antimetastatic effects, accompanied by enhanced dendritic cell maturation and infiltration of antigen-specific T cells into the tumors. Thus, inhibition rates of primary and distant tumors reach >90%. In addition, BMS-202 NPs are able to attack spreading metastatic lung tumors and offer immune-memory protection to prevent tumor relapse. These results indicate that BMS-202 NPs possess effects similar to α-PD-L1 in the therapies of 4T1 tumors. Therefore, this work reveals the possibility of replacing the antibody used in immunotherapy for tumors with BMS-202 NPs.

Nonswellable and Tough Supramolecular Hydrogel Based on Strong Micelle Cross-Linkings.

Because of the difference in osmotic pressure, most tough hydrogels swell under physiological conditions, which seriously weakens their mechanical properties, limiting their applications in biomedicine. Herein, a novel strategy based on strong and high-density micelle cross-linkings is proposed to prepare nonswellable and tough hydrogel. To realize a strong micelle cross-linker, the synergetic effect of hydrophobic and quadruple hydrogen-bonding interactions is employed by introducing an alkyl chain-protected ureido pyrimidinone moiety into a segmented copolymer backbone. The length of the alkyl is the key factor in determining the strength of the hydrophobic interaction, which was carefully tailored to gain micelles with high strength and suitable solubility. A supramolecular hydrogel was formed in situ by simply linking micelle cross-linkers with poly(ethylene glycol) chains. The strong and high-density micelle cross-linkings restrain multiple effective chains outside the micelle from stretching during swelling, and the deformability of micelle cross-linkings disperses the local stress to maintain the network with high cross-linking density upon loading. Therefore, the hydrogel exhibited an outstanding nonswelling behavior under physiological conditions and excellent mechanical properties with a compressive strength of 4 MPa. The rapid in situ gelation also facilitated injection and cell encapsulation. Meanwhile, it also showed good tissue adhesion, cytocompatibility, and suitable degradability. This novel and facile strategy can offer new insights into the exploitation of cross-linkings to prepare nonswellable hydrogels for biomedical applications.

Synthesis of porphyrin-conjugated silica-coated Au nanorods for synergistic photothermal therapy and photodynamic therapy of tumor.

Synergistic therapy of tumor has attracted the attention of an increasing number of researchers because of its higher efficiency compared to single therapy. Herein, 4-carboxyphenyl porphyrin-conjugated silica-coated gold nanorods (AuNR@SiO2-TCPP) were synthesized. The synergistic treatment of photothermal therapy and photodynamic therapy on A549 cancer was researched in vivo and in vitro. In the AuNR@SiO2-TCPP, Au NRs and TCPP act as photothermal agent and photosensitizer, respectively. The temperature of the AuNR@SiO2-TCPP (0.11 nmol L-1) rises to 56.8 °C for 10 min under the illumination of 808 nm laser (2 Wcm-2). In MTT assays, the viability of A549 cancer cell treated with AuNR@SiO2-TCPP (100 µg ml-1) is only 21%. In animal experiments, the relative tumor volumes in mice receiving AuNR@SiO2-TCPP (5 mg kg-1) with 660 and 808 nm irradiations were significantly inhibited and the average value is decreased to 0.78 while the average value of the control group is increased to 7.2. These results demonstrate that the AuNR@SiO2-TCPP is a potential nanomedicine against tumor for clinical application in the near future.

A polyurethane-based hydrophilic elastomer with multi-biological functions for small-diameter vascular grafts.

Thrombosis and intimal hyperplasia (IH) are two major problems faced by the small-diameter vascular grafts. Mimicking the native endothelium and physiological elasticity of blood vessels is considered an ideal strategy. Polyurethane (PU) is suitable for vascular grafts in mechanics because of its molecular designability and elasticity; however, it generally lacks the endothelium-like biofunctions and hydrophilicity. To solve this contradiction, a hydrophilic PU elastomer is developed by crosslinking the hydrophobic hard-segment chains containing diselenide with diaminopyrimidine-capped polyethylene glycol (PEG). In this network, the hydrophobic aggregation occurs underwater due to the uninterrupted hard-segment chains, leading to a significant self-enhancement in mechanics, which can be tailored to the elasticity similar to natural vessels by adjusting the crosslinking density. A series of in vitro studies confirm that the hydrophilicity of PEG and biological activities of aminopyrimidine and diselenide give the PU multi-biological functions similar to the native endothelium, including stable catalytic release of nitric oxide (NO) in the physiological level; anti-adhesion and anti-activation of platelets; inhibition of migration, adhesion, and proliferation of smooth muscle cells (SMCs); and antibacterial effect. In vivo studies further prove the good histocompatibility with both significant reduction in immune response and calcium deposition. STATEMENT OF SIGNIFICANCE: Constructing small-diameter vascular grafts similar to the natural vessels is considered an ideal method to solve the restenosis caused by thrombosis and intimal hyperplasia (IH). Because of the long-term stability, bulk modification is more suitable for implanted materials, however, how to achieve the biofunctions, hydrophilicity, and elasticity simultaneously is still a big challenge. In this work, a kind of polyurethane-based elastomer has been designed and prepared by crosslinking the functional long hard-segment chains with PEG soft segments. The underwater elasticity based on hydration-induced stiffening and the multi-biological functions similar to the native endothelium are compatible with natural vessels. Both in vitro and in vivo experiments demonstrate the potential of this PU as small-diameter vascular grafts.

Strain-Induced Phase Separation and Mechanomodulation of Ionic Conduction in Anisotropic Nanocomposite Ionogels.

Ionogels have great potential for the development of tissue-like, soft, and stretchable ionotronics. However, conventional isotropic ionogels suffer from poor mechanical properties, low efficient force transmission, and tardy mechanoelectric response, hindering their practical utility. Here, we propose a simple one-step method to fabricate bioinspired anisotropic nanocomposite ionogels based on a combination of strain-induced phase separation and mechanomodulation of ionic conduction in the presence of attapulgite nanorods. These ionogels show high stretchability (747.1% strain), tensile strength (6.42 MPa), Young's modulus (83.49 MPa), and toughness (18.08 MJ/m3). Importantly, the liquid crystalline domain alignment-induced microphase separation and ionic conductivity enhancement during stretching endow these ionogels with an unusual mechanoelectric response and dual-programmable shape-memory properties. Moreover, the anisotropic structure, good elasticity, and unique resistance-strain responsiveness give the ionogel-based strain sensors high sensitivity, rapid response time, excellent fatigue resistance, and unique waveform-discernible strain sensing, which can be applied to real-time monitoring of human motions. The findings offer a promising way to develop bioinspired anisotropic ionogels to modulate the microstructure and properties for practical applications in advanced ionotronics.

Genetic polymorphism of XRCC1 correlated with response to oxaliplatin-based chemotherapy in advanced colorectal cancer.

In this study, we investigated the association between genetic polymorphisms of XRCC1 Arg399Gln (G→A) and response to oxaliplatin-based chemotherapy in advanced colorectal cancer. XRCC1 genotypes of totally 99 patients (37 stage III and 62 stage IV) with advanced colorectal cancer treated with oxaliplatin-based chemotherapy were detected by the TaqMan-MGB probe allelic discrimination method, and clinical response of 62 patients in stage IV after 2 to 3 cycles of chemotherapy were evaluated. Also, time to progression (TTP) of all patients was evaluated. The results showed that of the genotype frequencies in all patients, up to 52.53% were G/G genotype, 9.09% were A/A genotype, and 38.38% were G/A genotype. The response rate (CR + PR) of 62 patients in stage IV was 61.29% (19/31). Patients with G/G genotype showed enhanced response to chemotherapy compared with those with G/A + A/A (x(2) = 5.6, p = .029; Odds Ratio (OR) = 3.845, 95% Confidence Interval (CI) = 1.231 ∼ 12.01, p = .018). Individuals with the G/G genotype had a TTP of 10.0 (8.88-11.12) months, and those with the G/A + A/A genotype had a TTP of 5.0 (4.26-5.74) months. The Log-Rank test was marginally significant (x(2) = 29.20, p < .01). The Cox proportional hazards model, adjusted for stage, performance status, and chemotherapy regimen showed that only XRCC1 G/G genotype increases the OR significantly (OR = 3.555; 95% CI, 2.119 ∼ 5.963; p < .01). These results indicate that XRCC1 Arg399Gln polymorphism is associated with response to oxaliplantin-based chemotherapy and TTP in advanced colorectal cancer in Chinese population. It is proposed that the XRCC1 Arg399Gln polymorphism should be routinely detected to screen patients who are more likely to benefit from oxaliplantin-based treatment.

Fabrication of mechanical skeleton of small-diameter vascular grafts via rolling on water surface.

Mimicking the multilayered structure of blood vessels and constructing a porous inner surface are two effective approaches to achieve mechanical matching and rapid endothelialization to reduce occlusion in small-diameter vascular grafts. However, the fabrication processes are complex and time consuming, thus complicating the fabrication of personalized vascular grafts. A simple and versatile strategy is proposed to prepare the skeleton of vascular grafts by rolling self-adhesive polymer films. These polymer films are directly fabricated by dropping a polymer solution on a water surface. For the tubes, the length and wall thickness are controlled by the rolling number and position of each film, whereas the structure and properties are tailored by regulating the solution composition. Double-layer vascular grafts (DLVGs) with microporous inner layers and impermeable outer layers are constructed; a microporous layer is formed by introducing a hydrophilic polymer into a polyurethane (PU) solution. DLVGs exhibit a J-shaped stress-strain deformation profile and compliance comparable to that of coronary arteries, sufficient suture retention strength and burst pressure, suitable hemocompatibility, significant adhesion, and proliferation of human umbilical vein endothelial cells. Freshly prepared PU tubes exhibit good cytocompatibility. Thus, this strategy demonstrates potential for rapid construction of small-diameter vascular grafts for individual customization.

Circular RNA hsa_circ_0077837 is upregulated in non-small cell lung cancer to downregulate phosphatase and tensin homolog through methylation.

Circular RNA (circRNA) hsa_circ_0077837 inhibits colorectal cancer. Our research studied the participation of hsa_circ_0077837 in non-small cell lung cancer (NSCLC). Hsa_circ_0077837 and phosphatase and tensin homolog (PTEN) expression in cancer and paired non-cancer tissues from a total of 64 NSCLC patients were studied with RT-qPCR. To evaluate the prognostic value of hsa_circ_0077837 for NSCLC, these 64 patients were monitored for 5 years. Expression of PTEN in NSCLC cells with hsa_circ_0077837 overexpression was determined by RT-qPCR and Western blot. The methylation of PTEN gene in cells transfected with hsa_circ_0077837 expression vector was analyzed by methylation specific PCR (MSP). The roles of hsa_circ_0077837 and PTEN in NSCLC cell proliferation were evaluated using cell apoptosis assay. Our data showed that hsa_circ_0077837 was upregulated in NSCLC and predicted poor survival. Besides, hsa_circ_0077837 expression level was higher in 36 advanced cases (stage III and IV) than in 28 early-stage cases (stage I and II). Hsa_circ_0077837 was inversely correlated with PTEN across cancer tissues. In NSCLC cells, hsa_circ_0077837 overexpression decreased PTEN expression, increased PTEN gene methylation, and reduced HCC827 cell apoptosis via PTEN. Overall, hsa_circ_0077837 is upregulated in NSCLC and downregulates PTEN by increasing its gene methylation to suppress cell apoptosis.List of abbreviations:Non-small cell lung cancer (NSCLC); circRNAs (circular RNAs); methylation-specific PCR (MSP).

Construction of bismuth-based porous carbon models by 3D printing technology for light-enhanced removal of chloride ions in wastewater.

The bismuth oxide (Bi2O3) based chloride (Cl-) removal method is one of the chemical precipitation methods possessing good selectivity and high removal efficiency of Cl- ions, but Bi2O3 often appears in the powder form, which is difficult to be recovered for regeneration. In this work, the combination of 3D printing technology and the Bi2O3 method was explored to construct the resin model including the Bi-precursors. In the optimum carbonization process at 400 °C for 30 min, the Bi3+ ions of the Bi-precursor were reduced into the metallic Bi0 nanoparticles, whose surfaces were covered by the thin Bi2O3 layers to form the heterostructured Bi0/Bi2O3 core/shell nanoparticles with an average size of 43 nm. These Bi0/Bi2O3 nanoparticles were tightly adhered to the internal and external surfaces of the hierarchical porous carbon model (Bi-PCM), which greatly facilitated their regeneration and ensured the stable Cl- removal performance. After five cycles of Cl- removal, the chloride removal efficiency over the multiple Bi-PCMs in the dark and pH 1 conditions maintained at about 26%, which then largely increased to 63.6% with UV light irradiation. The light-enhanced mechanism was related to the improved release rate of Bi3+ ions caused by photocorrosion and the Cl• radicals produced from the holes and the •OH and O2•- radicals, which quickly reacted with Bi2O3 to form BiOCl. The construction of Bi-PCMs by using 3D printing technology provides a very promising strategy for the removal of Cl- ions from wastewater.

Ionic Rigid Organic Dual-State Emission Compound With Rod-Shaped and Conjugated Structure for Sensitive Al3+ Detection.

Dual-state emission (DSE) luminogens, a type of luminescent material which can effectively emit light in both dilute solution and solid states, have attracted tremendous attention, due to their widespread applications in chemical sensing, biological imaging, organic electronic devices, and so on. They overcome the shortcomings of aggregation-induced emission (AIE)-type compounds that do not emit light in dilute solutions and aggregation-caused quenching (ACQ)-type compounds that do not emit light in a concentrated or aggregated state. This work reports a novel ionic DSE material based on rigid rod-shaped organic conjugated structure using 4,4'-bis(2-sulfonatostyryl) biphenyl disodium salt (BSBDS); the ion repulsion effect can reduce the strong π-π interaction in aggregation and achieve high-efficiency luminescence in solution and solid states. In addition to excellent DSE characteristics, BSBDS also exhibits a mechanochromic nature and sensitive detection performance for aluminum ion (Al3+).

Effects of Low-dose Splenic Irradiation on T lymphocyte Immune Function.

ABSTRACT: Relevant studies have confirmed that the stimulation of spleen function caused by low-dose splenic irradiation can have positive effects on tumors and other diseases. This study aimed to determine radiation-induced changes in spleen index, lymphocyte subsets, spleen cell apoptosis, and pathological features of the spleen in mice. The mouse model was established by irradiating the spleen at different doses. The mice were divided into the following groups: blank control, low-dose, low-dose fractionated irradiation, and challenge dose irradiation. The mice were sacrificed under humanitarian conditions, and spleen tissue and peripheral blood were collected. The spleen index was calculated, and flow cytometry was used to analyze spleen T lymphocyte subsets and spleen apoptosis. The pathological changes in the spleen were determined by hematoxylin and eosin (H&E) staining. The spleen index of mice in the low-dose fractionated irradiation group was significantly increased compared with that in the blank control group. The spleen indexes of the low-dose irradiation and low-dose fractionated irradiation groups were much higher than that of the challenge dose irradiation group. Compared with the blank control group, the percentage of CD3+ and CD4+ T lymphocytes in the peripheral blood and spleen tissues in the low-dose irradiation and low-dose fractionated irradiation groups was significantly increased, whereas that from the challenge dose irradiation group was obviously decreased. CD8+ T lymphocytes in the peripheral blood and spleen tissues in the low-dose irradiation, low-dose fractionated irradiation, and challenge dose irradiation groups were significantly lower than those in the blank control group. The apoptosis rate of the spleen in the challenge dose irradiation group was significantly higher than that in the blank control, low-dose irradiation, and low-dose fractionated irradiation groups. H&E staining analysis of the spleen showed pathological changes in the different irradiation groups compared with the blank control group. Low-dose irradiation and low-dose fractionated irradiation can change the T lymphocyte subsets in the peripheral blood and spleen of mice, which can promote immune excitation and improve immune effects.

Genomic Features of Organ-Specific Metastases in Lung Adenocarcinoma.

Background: The genomic features of cancer cells may confer the metastatic ability of lung adenocarcinoma (LUAD) to metastasize to specific organs. We aimed to identify the differences in genomic alterations between patients with primary LUAD with and without metastases and to elucidate the metastatic biology that may help developing biomarker-directed therapies for advanced or metastatic disease. Methods: A retrospective cohort of 497 patients with LUAD including 388 primary tumors (PR), 53 bone metastases (MT-bone), 30 liver metastases (MT-liver), and 26 brain metastases (MT-brain) was tested for genomic alterations by a next-generation sequencing assay. Results: The EGFR, TP53, TERT, LRP1B, CDKN2A, ERBB2, ALK, and KMT2C genes had a high frequency of mutations, and the mutations were shared by PR and metastases groups. TP53 and EGFR were the most common mutated genes. In comparison with PR, KRAS, STK11, ATM, NPM1, and ROS1 were significantly mutated in MT-brain, and TP53, MYC, RSPO2, CDKN2a, and CDKN2B were significantly mutated in MT-liver. The frequencies of TP53, CDKN2A, MTAP, PRKCI, and APC mutations were higher in MT-bone than that in PR. The ERBB, phosphoinositide-3-kinase/protein kinase B (PI3K-AKT), cell cycle, Fibroblast growth factor (FGF), and homologous recombination deficiency signaling pathways were affected in both PR and metastases, and there is higher frequency of mutations in metastases. Moreover, the co-mutations in patients with PR and metastasis were respectively analyzed. In addition, the programmed death ligand 1 (PD-L1) level was obviously related to tumor stage and tumor metastases, and the tumor mutational burden was correlated to clinicopathological features including age, gender, pathological stages, and tumor metastases. FGFR1, KAT6A, MYC, RAD21, TP53, and DAXX were also dramatically correlated to the tumor mutational burden. Conclusion: Metastases are the most devastating stage of tumors and the main cause of cancer-related deaths. Our results provided a clinically relevant view of the tumor-intrinsic mutational landscape of patients with metastatic LUAD.

A four-in-one pure nanomedicine for synergistic multi-target therapy against breast cancer.

Designing a multi-target nanomedicine without a carrier is pivotal for successful cancer nanotherapy. This study details a novel four-in-one RRX/BMS/CA4/PTX nanomedicine by simple nanoprecipitation. In this multi-target pure nanomedicine, paclitaxel (PTX) causes the immunogenic cell death of 4T1 tumour cells and the differentiation of marrow-derived suppressor cells (MDSCs) into dendritic cells (DCs) at low dose; repertaxin (RRX) selectively depletes cancer stem cells (CSCs) that are not killed by paclitaxel to inhibit lung metastasis from the breast; BMS-1 blocks the PD-1/PD-L1 pathway for proliferating effector T cells; and combretastatin A4 (CA4) targets tumour microvessels to cut off the blood supply in the tumour microenvironment. The synergy of multi-target therapies results in excellent antitumour effects. The tumour inhibition rate of 4T1 tumours is 92.5%, and the lung metastasis suppression rate exceeds 90%; no relapse is observed at 46 days after the treatment endpoint, and the survival of 50% of mice is prolonged by 95 days. Due to the low dose of PTX administration, the systemic toxicity of the RRX/BMS/CA4/PTX nanomedicine is not found. Our results suggest a strategy for designing multi-target pure nanomedicines with simple construction and efficacious therapeutic responses that present potential for clinical transformation.

DTX@VTX NPs synergy PD-L1 immune checkpoint nanoinhibitor to reshape immunosuppressive tumor microenvironment for enhancing chemo-immunotherapy.

Immunosuppressed tumor microenvironment (TME) is a major cause of the low response rate in solid tumor patients during PD-1/PD-L1 checkpoint blockade therapy. In this study, a series of small molecule nanomedicines with a 100% drug loading rate were prepared via the nanoprecipitation method. They were used in synergistic chemo-immunotherapy for 4T1 tumors. Among four PD-L1 small-molecule nanoinhibitors, BMS-1 NP with the best anti-tumor performance was selected to replace the therapeutic PD-L1 antibody. The core-shell small-molecule nanomedicine DTX@VTX NP (DTX: Docetaxel and VTX: VTX-2337 or Motolimod) was used to reverse immunosuppressed TME through the depletion of myeloid-derived suppressor cells (MDSCs) and the polarization of macrophages from an M2-like phenotype to M1-like phenotype. Thus, the frequency of cytotoxic CD8+ T cells was significantly increased, resulting in an effective attack on cancer cells. Combining BMS-1 NPs with DTX@VTX NPs, synergistic chemo-immunotherapy of 4T1 tumors was performed, and the results indicate that the inhibition rates of primary and rechallenge tumors achieved 90.5% and 94.3%, respectively. These results indicate that DTX@VTX NPs can synergize PD-L1 nanoinhibitor BMS-1 NPs to reshape the immunosuppressive tumor microenvironment for enhancing the anti-tumor effect of chemo-immunotherapy for breast.