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Abstract Existing tensioning cable prestress ensures bridge safety. This work presents the micro-hole release technique, which accurately measures the effective prestress of strands in existing prestressed concrete bridges. The strand drilling model was produced in Solidworks and Abaqus. The effect of drilling depth, diameter, deflection angle, and hole edge distance on strand stress release was then examined. The findings indicate that strand drilling tension relief is directly related to hole depth and diameter. As aperture size increases, stress alleviation decreases. The stress release error rate increases as the strand drilling deflection angle increases from 0° to 15°. Portable electric drill bits are 1.5 mm. A 5.0 mm hole was bored into the steel wire. The steel strand drilling wire is 3.0 mm from the hole’s edge. The drill bit is designed to maintain a drilling deflection angle of less than 5°, ensuring accuracy and ease of testing. After that, the 1860 grade strand drilling test was used to compare stress release and associated circumstances between P-T and T-P operating conditions. The strain-tension fitting equations for strand release were compared to finite element simulation results under P-T and T-P operating conditions. We found that the formula for fitting the strain-tension force of strand release under T-P condition matches finite element simulation results. It also matches real-world engineering methods.

Interleukin-12 (IL-12) is considered to be a promising cytokine for enhancing an antitumor immune response; however, recombinant IL-12 has shown significant toxicity and limited efficacy in early clinical trials. Recently, many strategies for delivering IL-12 to tumor tissues have been developed, such as modifying IL-12, utilizing viral vectors, non-viral vectors, and cellular vectors. Previous studies have found that the fusion of IL-12 with extracellular matrix proteins, collagen, and immune factors is a way to enhance its therapeutic potential. In addition, studies have demonstrated that viral vectors are a good platform, and a variety of viruses such as oncolytic viruses, adenoviruses, and poxviruses have been used to deliver IL-12—with testing previously conducted in various cancer models. The local expression of IL-12 in tumors based on viral delivery avoids systemic toxicity while inducing effective antitumor immunity and acting synergistically with other therapies without compromising safety. In addition, lipid nanoparticles are currently considered to be the most mature drug delivery system. Moreover, cells are also considered to be drug carriers because they can effectively deliver therapeutic substances to tumors. In this article, we will systematically discuss the anti-tumor effects of IL-12 on its own or in combination with other therapies based on different delivery strategies.

Non-uniform temperature action can cause cracks, damages, and other issues (or diseases) on bridges, which have serious impacts on the durability and even safety of bridges. At present, both domestic and international bridge design codes predominantly focus on addressing non-uniform temperature effects in relation to bridge decks and box girders. There has been comparatively less research and provision for addressing non-uniform temperature effects on bridge piers. In view of this, we conducted continuous temperature testing over a period of 212 days on the cross-section of the thin-walled hollow pier of Changjiahe Bridge. The aim was to systematically analyze the rectangular hollow pier non-uniform temperature field change rule. The results show that the depth of influence of day-to-day cyclic changes in air temperature and solar radiation is approximately 50 cm or less. The most unfavorable condition of positive temperature difference can easily occur when solar radiation is strong during continuous sunny days; the most unfavorable condition of negative temperature difference occurs when radiative cooling and strong cooling weather combine. A power function distribution curve of temperature difference along the direction of wall thickness is established, and the fitting accuracy is found to be higher than the commonly used exponential function curve. Subsequently, we introduced two methods to derive the maximum temperature difference of concrete rectangular hollow piers based on meteorological conditions. Method 1 involves obtaining the maximum daily difference of wall surface temperature difference using a regression formula, and then calculating the maximum positive temperature difference of wall surface according to the proportion of the maximum positive temperature difference of wall surface in the daily difference of wall surface temperature difference. Method 2 involves calculating the maximum positive temperature difference of wall surface over a period of time using a regression formula directly with the data of daily difference of air temperature. Through trial calculations during the observation period, the prediction accuracy of method 1 was found to be slightly better than that of method 2.

Abstract With the development and regulatory approval of immune checkpoint inhibitors and adoptive cell therapies, cancer immunotherapy has undergone a profound transformation over the past decades. Recently, therapeutic cancer vaccines have shown promise by eliciting de novo T cell responses targeting tumor antigens, including tumor-associated antigens and tumor-specific antigens. The objective was to amplify and diversify the intrinsic repertoire of tumor-specific T cells. However, the complete realization of these capabilities remains an ongoing pursuit. Therefore, we provide an overview of the current landscape of cancer vaccines in this review. The range of antigen selection, antigen delivery systems development the strategic nuances underlying effective antigen presentation have pioneered cancer vaccine design. Furthermore, this review addresses the current status of clinical trials and discusses their strategies, focusing on tumor-specific immunogenicity and anti-tumor efficacy assessment. However, current clinical attempts toward developing cancer vaccines have not yielded breakthrough clinical outcomes due to significant challenges, including tumor immune microenvironment suppression, optimal candidate identification, immune response evaluation, and vaccine manufacturing acceleration. Therefore, the field is poised to overcome hurdles and improve patient outcomes in the future by acknowledging these clinical complexities and persistently striving to surmount inherent constraints.

Abstract Despite the remarkable success of immune checkpoint inhibitors (ICIs), primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment (TME). Oncolytic viruses (OVs) can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts. Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy. According to the diverse immune cell landscapes among different types of tumors, we rationally and precisely generated three recombinant oncolytic adenoviruses (OAds): OAd-SIRPα-Fc, OAd-Siglec10-Fc and OAd-TIGIT-Fc. These viruses were designed to locally deliver SIRPα-Fc, Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47, CD24 or CD155, respectively, in the TME to achieve enhanced antitumor effects. Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors, while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+ T-cell-dominated tumors. Importantly, the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory. In addition, the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME. In summary, rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.

Abstract Background & Aims In liver cancer, leucine‐rich repeat‐containing G‐protein coupled receptor 5 (LGR5) compartment represents an important tumor‐initiating cell (TIC) population and served as a potential therapeutic target. Cancer‐associated fibroblasts (CAFs) is a critical part of the tumor microenvironment, heavily influenced TIC function and fate. However, deeply investigations have been hindered by the lack of accurate preclinical models to investigate the interaction between CAFs and TIC. Organoids model have achieved major advancements as a precious research model for recapitulating the morphological aspects of organs, and thus also serving as a candidate model to investigate the mutual interaction between different cell types. Consequently, this study aimed to construct a three‐dimensional (3D) co‐culture organoid model of primary LGR5‐expressing tumor stem cells from primary murine liver tumors with CAFs to investigate the impact of CAFs on LGR5 marked TICs in liver cancer. Materials and Methods First, both of the transgenic LGR5‐diphtheria toxin receptor (DTR)‐GFP knock‐in mice and transgenic Rosa26‐mT mice developed primary liver tumors by diethylnitrosamine (DEN) administration. Tumor organoids and CAFs were generated from those primary liver cancer separately. Second, LGR5‐expressing TICs organoid with CAFs were established ex vivo based on cell–cell contact or trans‐well co‐culture system, and the mutual influence between those two types of cells was further investigated. Subsequently, immunodeficient mouse‐based xenograft model was further adopted to evaluate the influence of CAFs to LGR5 tumor stem cell, tumor formation, and metastasis. Results The co‐culture organoid model composed of murine liver tumor LGR5+ tumor‐initiating cells and CAFs in 3D co‐culture was successfully established, with the intention to investigate their mutual interaction. The existence of CAFs upon engrafting tumor organoids resulted in dramatic higher number of LGR5+ cells in the neoplasia when compared with engrafting tumor organoids alone. Furthermore, ex vivo culture of isolated LGR5+ cells from tumors of co‐engrafted mice formed significantly larger size of organoids than mono‐engrafted. Our results also indicated significantly larger size and number of formed organoids, when LGR5+ cells co‐cultured with CAF in both cell–cell contact and paracrine signaling in vitro, comparing to LGR5+ cells alone. Furthermore, we found that specific knockout of LGR5 expressing cells suppressed CAF‐mediated promotion of tumor formation, growth, and metastasis in the experimental mice model. Conclusions Altogether, in a 3D co‐culture type of murine liver LGR5+ cells and cancer‐associated fibroblasts, we have demonstrated robust effects of CAFs in the promotion of LGR5 marked liver TICs. We also further revealed the influence of tumor microenvironment on stem cell‐related therapy, suggesting the possibility of combing CAF‐targeted and tumor stem cell targeted therapy in treating liver cancer.

Background: Activating Transcription Factor 4 (ATF4) expression exhibits differential patterns across different types of tumors. Besides, the pathogenesis of breast cancer is complex, and the exact relationship between ATF4 and ATF4 remains uncertain. Methods: The analysis of ATF4 expression was conducted by utilizing The Cancer Genome Atlas (TCGA) pan-cancer data, while the gene expression profile of breast cancer was checked by the comprehensive database-Gene Expression Omnibus database. In order to gain a more comprehensive understanding of the specific cell types that exhibit ATF4 expression within the microenvironment of breast cancer, we conducted a single-cell analysis of ATF4 using two distinct datasets of human breast cancer (GSE114717 and GSE11088, respectively). The spatial distribution of ATF4 within a tissue was demonstrated based on datasets obtained from the Human Protein Atlas (HPA) and SpatialDB. The clinical prognostic significance of ATF4 was assessed by analyzing clinical survival data obtained from TCGA, GSE4830, and GSE25055 datasets. We used the R package clusterProfiler to carry out an enrichment analysis of ATF4. We assessed how ATF4 impacts the growth and movement of breast cancer cell lines. We manipulated ATF4 levels using plasmid transfection techniques. Results: The expression of ATF4 was found to be suboptimal and demonstrated a significant correlation with enhanced disease-specific survival (p = 0.012) and overall survival (p = 0.032) in breast cancer as well as other malignancies. We conducted an analysis to investigate the interaction between the infiltration level of immune cells and the expression of ATF4, using samples obtained from TCGA with known immune cell infiltration scores. Furthermore, a notable positive correlation exists between the elevated expression of ATF4 and immune-related genomes, specifically those associated with chemokine as well as immunity. Subsequent examination revealed a notable augmentation in the cytodifferentiation of T cells into regulatory T (Treg) cells within tissues exhibiting elevated levels of ATF4 expression. ATF4 exhibits notable upregulation in the MDA-MB-231 cell, thereby exerting a substantial impact on cell proliferation and migration upon its knockdown. Conversely, the overexpression of ATF4 in the MCF7 Luminal A breast cancer cell line can also modulate cellular function. Conclusions: Our study suggests that ATF4 helps T cells differentiate into Treg cells in breast cancer. ATF4 can represent a clinically useful biomarker to predict the overall survival rate, especially in patients with different subtypes of breast cancer. Provide certain guidance value for the development of targeted drugs or inhibitors targeting ATF4.

Abstract Studies have shown that antidiabetic drugs can alter the gut microbiota. The hypoglycemic effects of the drugs can be attributed in part to certain species in the gut microbiome that help the drugs work more effectively. In addition, increasing energy expenditure via the induction of adipose tissue browning has become an appealing strategy to treat obesity and associated metabolic complications. Currently, glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) treatment for metabolic disorders such as obesity and type 2 diabetes has been widely studied. To determine the mechanism of a long‐acting GLP‐1 RA affects adipose tissue browning and the gut microbiome, we treated high‐fat diet mice with GLP‐1 RA and demonstrated that the drug can regulate adipose tissue browning. 16S rRNA and untargeted metabolomics assays suggested that it increased the abundance of bacterium Lactobacillus reuteri and decreased serum ceramide levels in mice. L. reuteri was negatively correlated with ceramide. We found that the mechanism of ceramide decline was alkaline ceramidase 2 (Acer2) overexpression. Moreover, L. reuteri can play a therapeutic synergistic role with GLP‐1 RA, suggesting that gut microbiota can be used as a part of the treatment of diabetes.

Abstract Snail is a denoted transcriptional repressor that plays key roles in epithelial-mesenchymal transition (EMT) and metastasis. Lately, a plethora of genes can be induced by stable expression of Snail in multiple cell lines. However, the biological roles of these upregulated genes are largely elusive. Here, we report identification of a gene encoding the key GlcNAc sulfation enzyme CHST2 is induced by Snail in multiple breast cancer cells. Biologically, CHST2 depletion results in inhibition of breast cancer cell migration and metastasis, while overexpression of CHST2 promotes cell migration and lung metastasis in nude mice. In addition, the expression level of MECA79 antigen is elevated and blocking the cell surface MECA79 antigen with specific antibodies can override cell migration mediated by CHST2 upregulation. Moreover, the sulfation inhibitor sodium chlorate effectively inhibits the cell migration induced by CHST2. Collectively, these data provide novel insights into the biology of Snail/CHST2/MECA79 axis in breast cancer progression and metastasis as well as potential therapeutic strategy for the diagnosis and treatment of breast cancer metastasis.

Abstract The clinical efficacy of personalized cancer vaccines still needs to be improved due to their insufficient immune effect. The development of innovative adjuvants and lymph node‐targeted delivery systems is the key to improving the clinical efficacy of personalized vaccines. However, there is still a lack of an adjuvant delivery system that is simple in preparation and capable of mass production and integrates adjuvant and lymph node targeted delivery functions. Here, this work reports that a simple dendrimer polypeptide (KK2DP7) nanoparticle enhances the immune efficacy of an OVA/neoantigen‐based vaccine. Due to its multiple functions as a delivery vehicle, immune adjuvant, and facilitator of dendritic cell migration, KK2DP7 efficiently increases the efficiency of antigen uptake and cross‐presentation by antigen‐presenting cells (APCs) and delivers antigens to lymph nodes via APCs. Strikingly, the antitumor effect of KK2DP7/OVA is superior to that of commonly used adjuvants such as poly(I:C), CpG, and aluminum adjuvant combined with OVA. Furthermore, KK2DP7/OVA combined with anti‐PD‐1 antibody is able to prevent tumor recurrence in a postoperative recurrent tumor model. Thus, KK2DP7‐based cancer vaccines alone or in combination with immune checkpoint blockade therapies to treat tumors or postoperative tumor recurrence are a powerful strategy to enhance antitumor immunity.

Abstract Background Non-redundant properties such as hypoxia and acidosis promote tumor metabolic adaptation and limit anti-cancer therapies. The key to the adaptation of tumor cells to hypoxia is the transcriptional and stable expression of hypoxia-inducible factor-1 alpha (HIF-1α). The phosphorylation-activated tumorigenic signal PI3K/AKT/mTOR advances the production of downstream HIF-1α to adapt to tumor hypoxia. Studies have elucidated that acid favors inhibition of mTOR signal. Nonetheless, carbonic anhydrase IX (CAIX), overexpressed on membranes of hypoxia tumor cells with pH-regulatory effects, attenuates intracellular acidity, which is unfavorable for mTOR inhibition. Herein, a drug delivery nanoplatform equipped with dual PI3K/mTOR inhibitor Dactolisib (NVP-BEZ235, BEZ235) and CAIX inhibitor 4‐(2‐aminoethyl) benzene sulfonamide (ABS) was designed to mitigate hypoxic adaptation and improve breast cancer treatment. Results ABS and PEG-NH2 were successfully modified on the surface of hollow polydopamine (HPDA), while BEZ235 and Chlorin e6 (Ce6) were effectively loaded with the interior of HPDA to form HPDA-ABS/PEG-BEZ235/Ce6 (H-APBC) nanoparticles. The release of BEZ235 from H-APBC in acid microenvironment could mitigate PI3K/mTOR signal and resist HIF-1α-dependent tumor hypoxia adaptation. More importantly, ABS modified on the surface of H-APBC could augment intracellular acids and enhances the mTOR inhibition. The nanoplatform combined with phototherapy inhibited orthotopic breast cancer growth while reducing spontaneous lung metastasis, angiogenesis, based on altering the microenvironment adapted to hypoxia and extracellular acidosis. Conclusion Taken together, compared with free BEZ235 and ABS, the nanoplatform exhibited remarkable anti-tumor efficiency, reduced hypoxia adaptation, mitigated off-tumor toxicity of BEZ235 and solved the limited bioavailability of BEZ235 caused by weak solubility. Graphical Abstract

Human bone marrow-derived mesenchymal stem cells (hBMSCs) are promising candidates for stem cell therapy in clinical trials. Applications of hBMSCs in clinical therapy are limited by cellular senescence due to long-term ex vivo expansion. Metformin, an oral hypoglycemic drug for type 2 diabetes, has been shown to have antiaging effects. However, the mechanisms of metformin in antiaging treatment remain controversial. Here, we used D-galactose (D-gal) to establish an appropriate model of senescent hBMSCs to explore the antiaging effects of metformin. Following metformin treatment with a low concentration range, senescence phenotypes induced by D-gal significantly changed, including generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and cell cycle arrest. In contrast, no apparent change was found in unsenescent hBMSCs. Furthermore, the results show that activation of 5′AMP-activated protein kinase (AMPK) by metformin enhances cell autophagy in senescent hBMSCs. These findings suggest that metformin exerts antiaging function within the low concentration range by enhancing autophagy and exhibits potential benefits for clinical stem cell therapy by ameliorating the ex vivo replicative senescence of hBMSCs.

Methotrexate (MTX) is a preferred disease-modifying anti-rheumatic drug in the management of rheumatoid arthritis (RA). However, the toxicity and inefficiency of MTX limit its clinical application. Gut microbiota has been implicated in the side effects and efficacy of MTX. In this study, the analysis of the gut microbiota in RA patients revealed that the abundances of intestinal Bacteroides fragilis was reduced after MTX treatment. We observed that MTX has no obvious therapeutic effect in the absence of B. fragilis, while transplantation of B. fragilis restored the efficacy of MTX in antibiotics-pretreated collagen-induced arthritis (CIA) mice. In addition, B. fragilis gavage was accompanied by an increase in butyrate. Supplementation of butyrate restored the response to MTX in gut microbiota-deficient mice, to a similar level achieved by B. fragilis gavage. These results show that gut microbiota-regulated butyrate plays an essential role in the efficacy of MTX, which will provide new strategies to improve the effectiveness of methotrexate in RA treatment.

Severely hypoxic condition of tumour represents a notable obstacle against the efficiency of photodynamic therapy (PDT). While mitochondria targeted therapy by metformin has been considered as a promising strategy for reducing oxygen consumption in tumours, its low treatment sensitivity, short half-life and narrow absorption window in vivo remain the intractable challenges. In this report, 5′-guanosine monophosphate (5′GMP), indocyanine green (ICG), hemin and metformin, were combined to construct a smart G-quadruplex (G4) hydrogel named HMI@GEL for breast cancer (BC) treatment. Benefiting from the photothermal (PTT) effect of ICG, HMI@GEL exhibited excellent characteristics of NIR-light-triggered and persistent drug delivery to maintain high intratumoral concentration of metformin. Furthermore, drug loading concentration of metformin reached an amazing 300 ​mg ​mL−1 in HMI@GEL. To our knowledge, it might be the highest loading efficiency in the reported literatures. With the combination of catalase-mimicking Hemin@mil88, metformin could inhibit tumour mitochondrial respiratory significantly, which sequentially permitted in situ efficient oxygen generation. Remarkable apoptosis and necrosis were achieved by the combination of PTT and synergistically enhanced PDT as well as the activated tumour immunotherapy. Collectively, the HMI@GEL in situ injectable platform showed a promising strategy for enhanced PDT by metformin, and opened new perspectives for treating BC versatilely.

Abstract Background Chemodynamic therapy (CDT), employing Fenton or Fenton-like catalysts to convert hydrogen peroxide (H2O2) into toxic hydroxyl radicals (·OH) to kill cancer cells, holds great promise in tumor therapy due to its high selectivity. However, the therapeutic effect is significantly limited by insufficient intracellular H2O2 level in tumor cells. Fortunately, β-Lapachone (Lapa) that can exert H2O2-supplementing functionality under the catalysis of nicotinamide adenine dinucleotide (phosphate) NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme offers a new idea to solve this problem. However, extensive DNA damage caused by high levels of reactive oxygen species can trigger the “hyperactivation” of poly(ADP-ribose) polymerase (PARP), which results in the severe interruption of H2O2 supply and further the reduced efficacy of CDT. Herein, we report a self-amplified nanocatalytic system (ZIF67/Ola/Lapa) to co-deliver the PARP inhibitor Olaparib (Ola) and NQO1-bioactivatable drug Lapa for sustainable H2O2 production and augmented CDT (“1 + 1 + 1 > 3”). Results The effective inhibition of PARP by Ola can synergize Lapa to enhance H2O2 formation due to the continuous NQO1 redox cycling. In turn, the high levels of H2O2 further react with Co2+ to produce the highly toxic ·OH by Fenton-like reaction, dramatically improving CDT. Both in vitro and in vivo studies demonstrate the excellent antitumor activity of ZIF67/Ola/Lapa in NQO1 overexpressed MDA-MB-231 tumor cells. Importantly, the nanocomposite presents minimal systemic toxicity in normal tissues due to the low NQO1 expression. Conclusions This design of nanocatalytic system offers a new paradigm for combing PARP inhibitor, NQO1-bioactivatable drug and Fenton-reagents to obtain sustained H2O2 generation for tumor-specific self-amplified CDT. Graphic Abstract

Objective: Cervical cancer poses a remarkable health burden to females globally. Despite major advances in early detection and treatment modalities, some patients still relapse. The present study proposed a novel immune molecular classification that reflected distinct recurrent risk and therapeutic responses in cervical cancer.Methods: We retrospectively collected two cervical cancer cohorts: TCGA and GSE44001. Consensus clustering approach was conducted based on expression profiling of recurrence- and immune-related genes. The abundance of immune cells was inferred via five algorithms. Immune functions and signatures were quantified through ssGSEA. Genetic mutations were analyzed by maftools package. Immunotherapeutic response was inferred via tumor mutation burden (TMB), Tumor Immune Dysfunction and Exclusion (TIDE), and Submap methods. Finally, we developed a LASSO model for recurrence prediction.Results: Cervical cancer samples were categorized into two immune subtypes (IC1, and IC2). IC2 exhibited better disease free survival (DFS), increased immune cell infiltration within the immune microenvironment, higher expression of immune checkpoints, higher activity of immune-relevant pathways (APC co-inhibition and co-stimulation, inflammation-promoting, MHC class I, IFN response, leukocyte and stromal fractions, macrophage regulation, and TCR Shannon), and higher frequencies of genetic mutations. This molecular classification exhibited a remarkable difference with existing immune subtypes, with diverse PANoptosis (pyroptosis, apoptosis and necroptosis) features. Patients in IC2 were more likely to respond to immunotherapy and targeted, and chemotherapeutic agents. The immune subtype-relevant signature was quantified to predict patients’ recurrence risk.Conclusion: Altogether, we developed an immune molecular classification, which can be utilized in clinical practice to aid decision-making on recurrence management.

Rituximab (RTX) is a widely used anticancer drug with gastrointestinal side effects, such as nausea, vomiting, and diarrhea. The reason for these side effects is still poorly understood. Previous studies have reported that the intestinal microbiota is associated with the occurrence of disease and the therapeutic effect of drugs. In this study, we observed mucosal damage, inflammatory cell infiltration and increased intestinal inflammatory factor expression in RTX-treated mice. RTX also changed the diversity of the intestinal microbiota in mice, and decreased abundance of Lactobacillus reuteri was observed in RTX-treated mice. Further experiments revealed that intragastric administration of L. reuteri in RTX-treated mice attenuated the intestinal inflammatory response induced by RTX and regulated the proportion of helper T (Th) cells. In conclusion, our data characterize the effect of the intestinal microbiota on RTX-induced intestinal inflammation, suggesting that modifying the gut microbiota may represent a positive strategy for managing adverse reactions.

Immunotherapy begins to be widely used due to the increasing exploration and gratifying effects in multiple cancers. Chordoma, as a rare bone malignant tumor, often recurs and metastasizes after undergoing surgery and radiotherapy. Therefore, immunotherapy can be explored as an emerging, potentially effective treatment to improve the survival rate and clinical benefit of patients. However, a variety of immune-related adverse events (irAEs) cannot be avoided completely. And the immunotherapy-induced myocarditis, as a rare but fatal irAE, has been increasingly reported. Understanding the mechanism involved in irAEs can inform best practices for side effects management. Here, we firstly reported a case of immune myocarditis and subsequent myasthenia gravis (MG) following anti-PD-1 treatment for chordoma.

IntroductionFor patients with limited-stage small-cell lung cancer (LS-SCLC), effective treatment methods still remain a clinical challenge. The aim of this study is to evaluate the survival outcome of surgery plus chemotherapy vs. surgery alone in patients with LS-SCLC.MethodsLS-SCLC patients selected from the Surveillance, Epidemiology and End Results (SEER) database diagnosed between January 1, 2004, and December 31, 2015. Comparison of overall survival (OS) and cancer-specific survival (CSS) between two groups performed propensity score matching (PSM), inverse probability of treatment weight (IPTW), and overlap weighting analysis.ResultsOf the 477 LS-SCLC patients identified from the SEER database between 2004 and 2015, 262 (54.9%) received surgery-plus-chemotherapy treatment and the others received surgery-alone treatment. Univariate and multivariate analyses showed that treatment option (P< 0.001), tumor location (P= 0.02) and AJCC stage (P< 0.001) were independent prognostic predictors of OS in LS-SCLC patients. Median OS was 35 months in surgery-plus-chemotherapy group vs. 23 months in surgery-alone group. Survival analysis showed that surgery plus chemotherapy offered significantly improved OS as compared with surgery-alone treatment before and after IPTW, PSM and overlap weighting method (all P< 0.05). According to AJCC stage stratification, OS of the unmatched patients with stage I (P= 0.049) and II (P= 0.001) SCLC who received surgery-plus-chemotherapy treatment was significantly better than that of surgery-alone patients.ConclusionsThis cohort study showed that surgery plus chemotherapy was associated with longer survival time than surgery alone in LS-SCLC patients, especially in those with stage I and II SCLC. Further prospective studies are required to confirm our conclusions.

Photodynamic therapy (PDT) has shown great promise in breast cancer treatment. However, simplex target ligand modification or stimuli release cannot meet the requirement of effective drug delivery to solid tumor tissue. To overcome continuous bio-barriers existing in the tumor microenvironment, multi-stage response drug delivery was desirable. Herein, we developed a unique tumor microenvironment tailored nanoplatform for chlorin e6 (Ce6) delivery. We chose bovine serum albumin (BSA) as “mother ships” material for effective tumor periphery resident, cyclopamine (CYC) as extracellular matrix (ECM) inhibitor and synergistic anti-tumor agent, and diselenide containing amphiphilic hyaluronic acid-chlorin e6 polymers (HA-SeSe-Ce6) synthesized as “small bombs” for internal tissue destruction. The above three distinct function compositions were integrated into an independent CYC and HA-SeSe-Ce6 co-delivery albumin nano-system (ABN@HA-SeSe-Ce6/CYC). The obtained nano-system presents good biocompatible, long circulation and effective tumor accumulation. After entering tumor microenvironment, CYC gradually releases to disrupt the ECM barrier to open the way for further penetration of HA-SeSe-Ce6. Subsequently, targeted tumor cell internalization and intracellular redox response release of Ce6 would achieve. Moreover, CYC could also make up the deficiency of Ce6 in hypoxia area, owing to its anti-tumor effect. Improved therapeutic efficacy was verified in a breast cancer cell line and tumor-bearing mice model.

The off-target activation of photosensitizers is one of the most well-known obstacles to effective photodynamic therapy (PDT). The selected activation of photosensitizers in cancer cells is highly desired to overcome this problem. We developed a strategy that enabled diselenide bonds to link hyaluronic acid (HA) and photosensitizer chlorin e6 (Ce6) to assemble the micelles (HA-sese-Ce6 NPs) that can target cancer and achieve a redox responsive release of drugs to enhance the PDT efficiency in breast cancer. The HA was used to form a hydrophilic shell that can target cluster of differentiation 44 (CD44) on the cancer cells. The selenium-containing core is easily dissembled in a redox environment to release Ce6. The triggered release of Ce6 in a redox condition and the positive feedback release by activated Ce6 were observed in vitro. In cytotoxicity assays and in vitro cellular uptake assays, the increased PDT efficiency and targeted internalization of HA-sese-Ce6 NPs in the cells were verified, compared to a free Ce6 treated group. Similar results were showed in the therapeutic study and in vivo fluorescence imaging in an orthotopic mammary fat pad tumor model. In addition, a significant inhibition of metastasis was found after the HA-sese-Ce6 NPs treatment. In general, this study promises an ingenious and easy strategy for improved PDT efficiency.

Recent findings suggest that tumor microenvironment (TME) plays an important regulatory role in the occurrence, proliferation, and metastasis of tumors. Different from normal tissue, the condition around tumor significantly altered, including immune infiltration, compact extracellular matrix, new vasculatures, abundant enzyme, acidic pH value, and hypoxia. Increasingly, researchers focused on targeting TME to prevent tumor development and metastasis. With the development of nanotechnology and the deep research on the tumor environment, stimulation-responsive intelligent nanostructures designed based on TME have attracted much attention in the anti-tumor drug delivery system. TME-targeted nano therapeutics can regulate the distribution of drugs in the body, specifically increase the concentration of drugs in the tumor site, so as to enhance the efficacy and reduce adverse reactions, can utilize particular conditions of TME to improve the effect of tumor therapy. This paper summarizes the major components and characteristics of TME, discusses the principles and strategies of relevant nano-architectures targeting TME for the treatment and diagnosis systematically.