Cabazitaxel-Loaded Thermosensitive Hydrogel System for Suppressed Orthotopic Colorectal Cancer and Liver Metastasis.

The treatment of colorectal cancer is always a major challenge in the field of cancer research. The number of estimated new cases of colorectal cancer worldwide in 2020 is 1 148 515, and the estimated number of deaths is 576 858, revealing that mortality accounted for approximately half of the disease incidence. The development of new drugs and strategies for colorectal cancer treatment is urgently needed. Thermosensitive injectable hydrogel PDLLA-PEG-PDLLA (PLEL) loaded with cabazitaxel (CTX) is used to explore its anti-tumor effect on mice with orthotopic colorectal cancer. CTX/PLEL is characterized by a solution state at room temperature and a hydrogel state at physiologic temperature. The excipients MPEG-PCL and PDLLA-PEG-PDLLA have good biocompatibility and biodegradability. The simple material synthesis and preparation process renders this system cost-effective and more conducive to clinical transformation. An orthotopic colorectal cancer model is established by transplantation subcutaneous tumors onto the cecum of mice. According to the results of experiments in vivo, CTX/PLEL significantly inhibits orthotopic colorectal cancer and liver metastasis in mice. The results indicate that CTX/PLEL nanoparticle preparations have high security and excellent anti-tumor effects, and have great application potential in colorectal cancer therapy.

Pretargeted radiotherapy and synergistic treatment of metastatic, castration-resistant prostate cancer using cross-linked, PSMA-targeted lipoic acid nanoparticles.

Metastatic castration-resistant prostate cancer (CRPC) is a currently incurable disease associated with high mortality. Novel therapeutic approaches for CRPC are urgently needed to improve prognosis. In this study, we developed cross-linked, PSMA-targeted lipoic acid nanoparticles (cPLANPs), which can interact with transmembrane glycoprotein to accumulate inside prostate cancer cells, where they upregulate caspase-3, downregulate anti-apoptotic B-cell lymphoma-2 (BCL-2), and thereby induce apoptosis. The trans-cyclooctene (TCO) decoration on cPLANPs acts as a bioorthogonal handle allowing pretargeted single-photon emission computed tomography and radiotherapy, which revealed significantly enhanced tumor accumulation and minimal off-target toxicity in our experiments. The developed strategy showed a strong synergistic anti-cancer effect in vivo, with a tumor inhibition rate of up to 95.6% after 14 days of treatment. Our results suggest the potential of combining bioorthogonal pretargeted radiotherapy with suitable PSMA-targeted nanoparticles for the treatment of metastatic CRPC.

Intracellular and extracellular synergistic therapy for restoring macrophage functions via anti-CD47 antibody-conjugated bifunctional nanoparticles in atherosclerosis.

Atherosclerosis is a significant contributor to global cardiovascular disease. Reducing the formation of atherosclerotic plaque effectively can lead to a decrease in cardiovascular diseases. Therefore, controlling macrophage function is crucial. This study presents the creation of a bifunctional nanoparticle that is specific to macrophages to achieve intracellular and extracellular synergistic therapy for restoring macrophage functions. The nanoparticle is conjugated with anti-CD47 antibody to modulate extracellular CD47-SIRPα phagocytic signaling axis on the outer surface of macrophages and encapsulates the NLRP3 inhibitor (CY-09) to regulate intracellular inflammation response of macrophages. The results showed that the nanoparticles accumulate in the atherosclerotic plaque, alter macrophage phagocytosis, inhibit NLRP3 inflammasome activation, and decrease the plaque burden in Apoe-/- mice whilst ensuring safety. Examination of single-cell RNA sequencing indicates that this multifunctional nanoparticle decreases the expression of genes linked to inflammation and manages inflammatory pathways in the plaque lesion. This study proposes a synergistic therapeutic approach that utilizes a bifunctional nanoparticle, conjugated with anti-CD47, to regulate the microenvironment of plaques.

A bioorthogonal cell sorting strategy for isolation of desired cell phenotypes.

Here we describe a cost-effective and simplified cell sorting method using tetrazine bioorthogonal chemistry. We successfully isolated SKOV3 cells from complex mixtures, demonstrating efficacy in separating mouse lymphocytes expressing interferon and HeLa cells expressing virally transduced green fluorescent protein post-infection.

A facile boronophenylalanine modified polydopamine dual drug-loaded nanoparticles for enhanced anti-tumor immune response in hepatocellular carcinoma comprehensive treatment.

Hepatocellular carcinoma (HCC) has an insidious onset and high malignancy. Most patients have progressed to intermediate and advanced stages by the time of diagnosis, and the long-term efficacy of traditional treatments is not satisfactory. Immunotherapy has shown great promise in the treatment of HCC in recent years; however, the low immunogenicity and severe immunosuppressive tumor microenvironment result in a low response rate to immunotherapy in HCC patients. Therefore, it is of great significance to improve the immunogenicity of HCC and thus enhance its sensitivity to immunotherapy. Here, we prepared the boronophenylalanine-modified dual drug-loaded polydopamine nanoparticles by a facile method. This system used boronophenylalanine-modified polydopamine nanoparticles as a delivery vehicle and photothermal material for the chemotherapeutic drug doxorubicin and the immune agonist CpG oligodeoxynucleotides (CpG-ODN), with both active targeting and lysosomal escape functions. The cancer cells are rapidly killed by photothermal treatment, and then chemotherapy is used to further kill cancer cells that are inadequately treated by photothermal treatment. The combination of photothermal-chemotherapy synergistically induces the release of relevant antigens from tumor cells, thus initiating anti-tumor immunity; and then cooperates with CpG-ODN to trigger a powerful anti-tumor immune memory effect, potently and durably inhibiting HCC recurrence.

Gold Nanorods and Polymer Micelles Mediated Dual TLR Stimulators Delivery System CPG@Au NRs/M-R848 Regulate Macrophages Reprogramming and DC Maturation for Enhanced Photothermal Immunotherapy of Melanoma.

Synergistic photothermal immunotherapy has emerged as a favorable therapeutic approach to fight cancer. However, design of an effective photothermal immunotherapy system to suppress tumor growth and simultaneously inhibit tumor metastases continues to be a challenge. Here a dual toll-like receptor agonists delivery system CPG@Au NRs/m-R848 for combined photothermal immunotherapy of melanoma is developed. CPG@Au NRs/m-R848 displays strong antitumor effects by promoting maturation of dendritic cells (DCs) and reprogramming of M2 macrophages into M1 phenotype. Moreover, immunogenic cell death (ICD) induced by photothermal ablation of Au NRs could synergistically produce in situ vaccination effect with CPG ODN and R848, generating systemic and lasting antitumor immunity. It is further proved that CPG@Au NRs/m-R848 treatment inhibits tumor growth in bilateral B16F10 tumors model by eliciting CD8+ T cell response. Overall, this work suggests that this strategy hold great potential in tumor immunotherapy by regulating tumor-associated macrophage polarization, triggering DCs maturation and inducing ICD.

Comprehensive Molecular Analyses of a Macrophage-Related Gene Signature With Regard to Prognosis, Immune Features, and Biomarkers for Immunotherapy in Hepatocellular Carcinoma Based on WGCNA and the LASSO Algorithm.

Macrophages have been reported to exert a crucial role in hepatocellular carcinoma (HCC). This study aimed to explore the macrophage-related genes and establish a macrophage-related signature (MRS) model to predict the overall survival (OS) of patients with HCC based on these genes' expression. We screened the macrophage-related gene module by weighted gene coexpression network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was utilized for further selection, and the selected genes were entered into stepwise regression to develop the MRS model, which was further validated in the Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) datasets. We analyzed the biological phenotypes associated with macrophages in terms of functional enrichment, tumor immune signature, and tumor mutational signature. The patient's response to immunotherapy was inferred by the tumor immune dysfunction and exclusion (TIDE) score, the immunophenotype score (IPS), and the IMvigor210 dataset. A novel MRS model was established based on the LASSO regression coefficients of the genes PON1, IL15RA, NEIL3, HILPDA, PFN2, HAVCR1, ANXA10, CDCA8, EPO, S100A9, TTK, KLRB1, SPP1, STC2, CYP26B1, GPC1, G6PD, and CBX2. In either dataset, MRS was identified as an independent risk factor for OS in HCC patients. Additionally, our research indicated that a high-risk score in the MRS model was significantly correlated with tumor staging, pathological grade, tumor-node-metastasis (TNM) stage, and survival. Several genes of the human leukocyte antigen (HLA) family and immune checkpoints were highly expressed in the high-risk group. In addition, the frequency of tumor mutations was also higher in the high-risk group. According to our analyses, a higher risk score in the MRS model may predict a better response to immunotherapy.

The Effect of Preoperative Rehabilitation Training on the Early Recovery of Joint Function after Artificial Total Knee Arthroplasty and Its Effect Evaluation.

OBJECTIVE: To study the effect of preoperative rehabilitation training on the rehabilitation of patients after total knee arthroplasty. METHODS: A total of 120 patients diagnosed with knee osteoarthritis and undergoing total knee arthroplasty were selected and divided into experimental group and control group according to a random number table, with 60 cases in each group. The control group only carried out routine clinical nursing before the operation, and the experimental group used the formulated preoperative rehabilitation training method based on the control group for training. By comparing the visual analogue score (VAS), keen society score (KSS), postoperative time to get out of bed for the first time, patient satisfaction, and other related indicators between the two groups of patients, the recovery of keen joint function of patients after surgery was evaluated. RESULTS: The visual analogue scale (VAS) of the experimental group was significantly lower than that of the experimental group at three days after operation. The keen society score (KSS) of the experimental group was significantly better than that of the control group at three days after surgery and one month after surgery. The time to get out of bed for the first time after operation in the experimental group (44.93 ± 13.63) was significantly less than that in the control group (78.33 ± 13.52). The patient satisfaction of the experimental group was significantly higher than that of the control group (88.30 ± 3.61). The above statistical results were all p < 0.05 of the two groups, and the differences were statistically significant. CONCLUSION: Preoperative rehabilitation training can significantly reduce the pain of patients after knee replacement, improve the functional state of knee joints, shorten the time to get out of bed for the first time after surgery, and win the best recovery opportunity, which can better improve patient satisfaction in hospitalization and improve medical care services level.

[Study on the level of daily living function and its influencing factors in elderly patients after hip fracture surgery].

OBJECTIVE: To analyze the short-term prognosis of elderly patients with hip fracture after operation, and to explore the main factors affecting the recovery of daily life function. METHODS: From November 2015 to November 2016, 130 elderly patients with hip fracture were analyzed, including 43 males and 87 females, aged from 60 to 95 (77.54±8.49) years. The death, fall and complications were recorded 3 months after operation. The daily life function of the patients was followed up 3 months after operation with the functional recovery of daily life scale (FRS). T-test, analysis of variance and single factor linear regression analysis were used to analyze the general clinical data. The factors with P<0.05 were analyzed by multi factor linear regression method, and the influencing factors of postoperative ADL were obtained. RESULTS: Among 130 patients, 7 died (5.4%), 4 fell (3.1%), 103 (79.2%) had postoperative complications, and the FRS score of 123 patients was 65.92±22.79. The results showed that gender, age, fracture site, pre fracture Basel rating, frailty index, postoperative hospital stay and total number of postoperative complications had significant differences in the recovery of daily life function (P<0.05);multiple linear regression analysis showed that pre fracture Basel rating (t=-2.727, P=0.007), frailty index (t=-2.573, P=0.011) and postoperative hospital stay had significant differences. The days of hospital stay (t=-3.391, P=0.001) and the total number of postoperative complications (t=-3.281, P=0.001) were the independent risk factors for postoperative ADL in elderly patients with hip fracture (R2=0.411). CONCLUSION: The short term rehabilitation level of elderly patients with hip fracture after operation is poor. Basel rating before fracture, frailty index, postoperative hospital stay and total number of postoperative complications may be related risk factors affecting the recovery of daily life function of patients after operation.

PSMA-targeted melanin-like nanoparticles as a multifunctional nanoplatform for prostate cancer theranostics.

Prostate-specific membrane antigen (PSMA) is highly expressed on the surface of most prostate tumor cells and is considered a promising target for prostate cancer imaging and treatment. It is possible to establish a PSMA-targeted theranostic probe to achieve early diagnosis and treatment of this cancer type. In this contribution, we prepared a multifunctional melanin-like polydopamine (PDA) nanocarrier decorated with a small-molecule PSMA inhibitor, N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-l-lysine (DCL). PDA-DCL was then functionalized with perfluoropentane (PFP) and loaded with the photosensitizer chlorin e6 (Ce6) to give Ce6@PDA-DCL-PFP, which was successfully used for ultrasound-guided combined photodynamic/photothermal therapy (PDT/PTT) of prostate cancer. Compared with the corresponding non-targeted probe (Ce6@PDA-PEG-PFP), our targeted probe induced higher cellular uptake in vitro (6.5-fold) and more tumor accumulation in vivo (4.6-fold), suggesting strong active targeting capacity. Meanwhile, this new nanoplatform significantly enhanced the ultrasound contrast signal at the tumor site in vivo, thus facilitating precise and real-time detection of the tumor. In addition, this Ce6-loaded PDA nanoplatform produced a synergistic effect of PDT and PTT under 660 nm and 808 nm irradiation, inducing a more efficient killing effect compared with the individual therapy in vitro and in vivo. Furthermore, the tumor in the targeted group was more effectively suppressed than that in the non-targeted group under the same irradiation condition. This multifunctional probe may hold great potential for precise and early theranostics of prostate cancer.

A General Strategy to Design Highly Fluorogenic Far-Red and Near-Infrared Tetrazine Bioorthogonal Probes.

Highly fluorogenic tetrazine bioorthogonal probes emitting at near-infrared wavelengths are in strong demand for biomedical imaging applications. Herein, we have developed a strategy for forming a palette of novel Huaxi-Fluor probes in situ, whose fluorescence increases hundreds of times upon forming the bioorthogonal reaction product, pyridazine. The resulting probes show large Stokes shifts and high quantum yields. Manipulating the conjugate length and pull-push strength in the fluorophore skeleton allows the emission wavelength to be fine-tuned from 556 to 728 nm. The highly photo-stable and biocompatible probes are suitable for visualizing organelles in live cells without a washing step and for imaging of tumors in live small animals to depths of 500 µm by two-photon excitation.

Comparison of two frailty indexes in hip fractures.

AIM: Modified-Krishnan's frailty index (FI) is an FI calculation method developed by Krishnan et al. in 2014. This study aimed to compare the effectiveness and correlation of the FIs from Krishnan and the Canadian study of health and aging (CSHA) in predicting postoperative outcomes of elderly patients with hip fracture. METHODS: Based on clinical follow-up and observation, we utilized these two instruments to predict 3-month mortality, hip function, and recovery of daily activities. The area under the curve (AUC) and the Pearson correlation coefficient were used to compare the two scales' predictive validities for postoperative outcomes. RESULTS: A total of 130 patients were included; 67% female and mean age 77.5 ± 8.5 years. The AUCs of modified-Krishnan's FI (AUC = 0.856; 95% confidence interval (CI) = 0.767-0.945) and the CSHA-FI (AUC = 0.793; 95% CI = 0.652-0.934) were used to compare the effectiveness in predicting patient mortality. The optimal predictive scores were 0.335 and 0.28, respectively. The Pearson correlation analysis showed that the modified-Krishnan's FI correlated with the Japanese Orthopaedic Association hip score (pain, activity, walking ability, and ability for daily living; R = -0.249, p = 0.005), while the CSHA-FI was not correlated (R = -0.125, p = 0.170). The modified-Krishnan's FI (R = -0.415, p < 0.001) and the CSHA-FI (R = -0.332, p < 0.001) were both significantly correlated with the functional recovery scale score. CONCLUSIONS: The modified-Krishnan's FI and the CSHA-FI were effective in the prediction of postoperative mortality. But the modified-Krishnan's FI was more consistently associated with the recovery of hip function and daily activities at 3 months after the operation than that of the CSHA-FI. The modified-Krishnan's FI was more suitable to utilize for risk stratification, identifying deficits, and predicting recovery capacity in hip fracture patients.

Heme oxygenase-1 dependant pathway contributes to protection by tetramethylpyrazine against chronic hypoxic injury on medulla oblongata in rats.

Tetramethylpyrazine (TMP), one of the active ingredients of the Chinese herb Lingusticum Wallichii (Chuan Xiong) has been proved to protect the medulla oblongata from chronic hypoxia injury. However, the underlying mechanism remains unclear. The purpose of this study was to determine whether the protective effects of TMP are associated with the heme oxygenase-1 (HO-1) dependant pathway in adult rats. The morphological changes of neurons in the hypoglossal nucleus (12N), the nucleus ambiguus (Amb), the nucleus tractus solitarius (NTS), and the pre-Bötzinger complex (pre-BötC) were investigated by Nissl staining; the malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured to evaluate the anti-oxidant effect; some apoptosis parameters, Bax mRNA and Bcl-2 mRNA, were tested; and the double immunochemistry staining of active caspase-3/NeuN was performed. Meanwhile, the HO-1 protein expression and heme oxygenase (HO) activity were examined. Tin-protoporphyrin (SnPP), a potent inhibitor of HO, was used to further confirm the effect of HO-1. We found that TMP ameliorated the neuron loss in 12N, Amb and NTS, the decrease in SOD activity and the increase in MDA content, the decrease in Bcl-2 mRNA of medulla oblongata (P<0.05), and the increase in percentage of apoptotic neurons in Amb (P<0.05) induced by chronic hypoxia. Co-administration with SnPP abolished the beneficial effects above of TMP to some extent (P<0.05). Moreover, TMP significantly increased HO activity and HO-1 protein expression, which was most likely enhanced in the neurons (P<0.05), and co-administration of SnPP reduced these up-regulated effects (P<0.05). This study demonstrated that HO-1 dependant pathway may be involved in the protective action of TMP against chronic hypoxic damage on medulla oblongata in the rats.

Postcollisional mafic igneous rocks record crust-mantle interaction during continental deep subduction.

Findings of coesite and microdiamond in metamorphic rocks of supracrustal protolith led to the recognition of continental subduction to mantle depths. The crust-mantle interaction is expected to take place during subduction of the continental crust beneath the subcontinental lithospheric mantle wedge. This is recorded by postcollisional mafic igneous rocks in the Dabie-Sulu orogenic belt and its adjacent continental margin in the North China Block. These rocks exhibit the geochemical inheritance of whole-rock trace elements and Sr-Nd-Pb isotopes as well as zircon U-Pb ages and Hf-O isotopes from felsic melts derived from the subducted continental crust. Reaction of such melts with the overlying wedge peridotite would transfer the crustal signatures to the mantle sources for postcollisional mafic magmatism. Therefore, postcollisonal mafic igneous rocks above continental subduction zones are an analog to arc volcanics above oceanic subduction zones, providing an additional laboratory for the study of crust-mantle interaction at convergent plate margins.