Xuzhou Cancer Hospital

Immunogenic cell death (ICD) provides momentous theoretical principle for modern cancer immunotherapy. However, the currently available ICD inducers are still very limited and photosensitizer-based ones can hardly induce sufficient ICD to achieve satisfactory cancer immunotherapy by themselves. Herein, an organic photosensitizer (named TPE-DPA-TCyP) with a twisted molecular structure, strong aggregation-induced emission activity, and specific ability is reported for effectively inducing focused mitochondrial oxidative stress of cancer cells, which can serve as a much superior ICD inducer to the popularly used ones, including chlorin e6 (Ce6), pheophorbide A, and oxaliplatin. Furthermore, more effective in vivo ICD immunogenicity of TPE-DPA-TCyP than Ce6 is also demonstrated using a prophylactic tumor vaccination model. The underlying mechanism of the effectiveness and robustness of TPE-DPA-TCyP in inducing antitumor immunity and immune-memory effect in vivo is verified by immune cell analyses. This study thus reveals that inducing focused mitochondrial oxidative stress is a highly effective strategy to evoke abundant and large-scale ICD.

BACKGROUND: Sensitive and specific biomarkers for the early detection of esophageal squamous cell carcinoma (ESCC) are urgently needed to reduce the high morbidity and mortality of the disease. The discovery of serum microRNAs (miRNAs) and their unique concentration profiles in patients with various diseases makes them attractive, novel noninvasive biomarkers for tumor diagnosis. In this study, we investigated the serum miRNA profile in ESCC patients to develop a novel diagnostic ESCC biomarker. METHODS: Serum samples were taken from 290 ESCC patients and 140 age- and sex-matched controls. Solexa sequencing technology was used for an initial screen of miRNAs in serum samples from 141 patients and 40 controls. A hydrolysis probe-based stem-loop quantitative reverse-transcription PCR (RT-qPCR) assay was conducted in the training and verification phases to confirm the concentrations of selected miRNAs in serum samples from 149 patients and 100 controls. RESULTS: The Solexa sequencing results demonstrated marked upregulation of 25 serum miRNAs in ESCC patients compared with controls. RT-qPCR analysis identified a profile of 7 serum miRNAs (miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a, and miR-127-3p) as ESCC biomarkers. The area under the ROC curve for the selected miRNAs ranged from 0.817 to 0.949, significantly higher than for carcinoembryonic antigen (0.549; P < 0.0005). More importantly, this panel of 7 miRNAs clearly distinguished stage I/II ESCC patients from controls. CONCLUSIONS: This panel of 7 serum miRNAs holds promise as a novel blood-based biomarker for the diagnosis of ESCC.

Self-assembly is a powerful tool for constructing supramolecular materials for many applications, ranging from energy harvesting to biomedicine. Among the methods to prepare supramolecular materials for biomedical applications, enzyme-instructed self-assembly (EISA) has several advantages. Herein, the unique properties and advantages of EISA in preparing biofunctional supramolecular nanomaterials and hydrogels from peptides are highlighted. EISA can trigger molecular self-assembly in situ. Therefore, using overexpression enzymes in disease sites, supramolecular materials can be formed in situ to improve the selectivity and efficacy of the treatment. The precursor may be involved during the EISA process, and it is actually a two-component self-assembly process. The precursor can help to stabilize the assembled nanostructures of hydrophobic peptides formed by EISA. More importantly, the precursor may determine the outcome of molecular self-assembly. Recently, it was also observed that EISA can kinetically control the peptide folding and morphology and cellular uptake behavior of supramolecular nanomaterials. With the combination of other methods to trigger molecular self-assembly, researchers can form supramolecular nanomaterials in a more precise mode and sometimes under spatiotemporal control. EISA is a powerful and unique methodology to prepare supramolecular biofunctional materials that cannot be generated from other common methods.

Abnormalities in the TP53 gene and overexpression of MDM2, a transcriptional target and negative regulator of p53, are commonly observed in cancers. The MDM2-p53 feedback loop plays an important role in tumor progression and thus, increased understanding of the pathway has the potential to improve clinical outcomes for cancer patients. Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. We review the current studies of the MDM2-p53 pathway in cancer with a focus on HCC and specifically discuss the impact of p53 mutations along with other alterations of the MDM2-p53 feedback loop in HCC. We also discuss the potential diagnostic and prognostic applications of p53 and MDM2 in malignant tumors as well as therapeutic avenues that are being developed to target the MDM2-p53 pathway.

The involvement of circulating microRNAs (miRNAs) in cancer and their potential as biomarkers of diagnosis and prognosis are becoming increasingly appreciated; however, little is known about circulating miRNA profiles in astrocytomas. In our study, we performed genome-wide serum miRNA analysis by the Solexa sequencing followed by validation conducted in the training and verification sets with a stem-loop quantitative reverse-transcription PCR (RT-qPCR) assay from serum samples of 122 untreated astrocytomas patients (WHO grades III-IV) and 123 normal controls. Identified miRNAs were subsequently examined in 55 grade II, 15 grade I astrocytomas, 11 astrogliosis, 42 other primary brain tumors and 8 tumor tissues from grades II-IV astrocytomas. In addition, paired serum samples before and after operation were collected from 14 malignant astrocytomas to determine the effect of surgery on the miRNAs' levels. A marked difference in serum miRNA profile was observed between high-grade astrocytomas and normal controls. Seven miRNAs were validated by RT-qPCR assay to be significantly decreased in grades II-IV patients (p < 0.001), including miR-15b*, miR-23a, miR-133a, miR-150*, miR-197, miR-497 and miR-548b-5p, and the seven-miRNA panel demonstrated a high sensitivity (88.00%) and specificity (97.87%) for malignant astrocytomas prediction. These identified miRNAs also exhibited a global decrease in tumor tissues relative to normal tissues. Furthermore, these miRNAs in serum were markedly elevated after operation (p < 0.001). In addition, some of these serum miRNAs were significantly different between malignant and benign cases, astrogliosis and other primary brain tumors. The seven serum miRNAs identified in our study hold potential as noninvasive biomarker for malignant astrocytomas.

BACKGROUND: Circular RNAs (circRNAs) play important roles in cancer development and progression. The purpose of this study is to identify aberrantly expressed circRNAs in gastric cancer (GC), unravel their roles in GC progression, and provide new targets for GC diagnosis and therapy. METHODS: Bioinformatic analyses were performed to identify the aberrantly expression of hsa_circ_0061137 (termed as circDIDO1) in GC. Gain- and loss-of-function studies were performed to examine the biological roles of circDIDO1 in GC progression. Tagged RNA affinity purification, mass spectrometry, immunofluorescence, co-immunoprecipitation, and Western blot were used to identify circRNA-interacting and circRNA-encoded proteins. RNA sequencing, qRT-PCR, and Western blot were performed to analyze circRNA-regulated downstream target genes and signaling pathways. Mouse tumor models were used to analyze the effects of circDIDO1 on GC growth and metastasis. RESULTS: CircDIDO1 was transcribed from human DIDO1 (death-inducer obliterator 1) gene and formed by back-splicing of exons 2-6 of the linear transcript. circDIDO1 was down-regulated in GC tissues and its low levels were associated with larger tumor size, distal metastasis, and poor prognosis. CircDIDO1 overexpression inhibited while knockdown promoted GC cell proliferation, migration and invasion. CircDIDO1 overexpression suppressed GC growth and metastasis in mouse tumor models. Mechanistically, circDIDO1 encoded a novel 529aa protein that directly interacted with poly ADP-ribose polymerase 1 (PARP1) and inhibited its activity. CircDIDO1 also specifically bound to peroxiredoxin 2 (PRDX2) and promoted RBX1-mediated ubiquitination and degradation of PRDX2, which led to the inactivation of its downstream signaling pathways. CONCLUSIONS: CircDIDO1 is a new circRNA that has tumor suppressor function in GC and it may serve as a potential prognostic biomarker and therapeutic target for GC.

AIMS: Facial features were associated with increased risk of coronary artery disease (CAD). We developed and validated a deep learning algorithm for detecting CAD based on facial photos. METHODS AND RESULTS: We conducted a multicentre cross-sectional study of patients undergoing coronary angiography or computed tomography angiography at nine Chinese sites to train and validate a deep convolutional neural network for the detection of CAD (at least one ≥50% stenosis) from patient facial photos. Between July 2017 and March 2019, 5796 patients from eight sites were consecutively enrolled and randomly divided into training (90%, n = 5216) and validation (10%, n = 580) groups for algorithm development. Between April 2019 and July 2019, 1013 patients from nine sites were enrolled in test group for algorithm test. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated using radiologist diagnosis as the reference standard. Using an operating cut point with high sensitivity, the CAD detection algorithm had sensitivity of 0.80 and specificity of 0.54 in the test group; the AUC was 0.730 (95% confidence interval, 0.699-0.761). The AUC for the algorithm was higher than that for the Diamond-Forrester model (0.730 vs. 0.623, P < 0.001) and the CAD consortium clinical score (0.730 vs. 0.652, P < 0.001). CONCLUSION: Our results suggested that a deep learning algorithm based on facial photos can assist in CAD detection in this Chinese cohort. This technique may hold promise for pre-test CAD probability assessment in outpatient clinics or CAD screening in community. Further studies to develop a clinical available tool are warranted.

OBJECTIVES: To evaluate the prevalence and determinants of anxiety and depression and to assess their impact on glycaemic control in participants with type 2 diabetes mellitus. DESIGN: A cross-sectional study. SETTING: Community-based investigation in Xuzhou, China. PARTICIPANTS: 893 Chinese men and women aged 18-84 years who fulfilled the inclusion criteria. METHODS: People with type 2 diabetes completed the Pittsburgh Sleep Quality Index and the Zung Self-Rating Anxiety and Depression Scales. Demographic and physiological characteristics were recorded. Multiple logistic regression was used to evaluate the combined effect of factors associated with anxiety and depression and to assess the effects of anxiety and depression on glycaemic control. RESULTS: The prevalence of depressive symptoms and anxiety symptoms was 56.1% and 43.6%, respectively. Multivariate logistic regression analysis indicated that anxiety symptoms were associated with being woman, low income, chronic disease, depressive symptoms and poor sleep quality. Depressive symptoms were associated with being woman, older age, low education level, being single, diabetes complications, anxiety symptoms and poor sleep quality. Glycaemic control was not related to anxiety symptoms (OR=1.31, 95% CIs 0.94 to 1.67) or depressive symptoms (OR=1.23, 95% CI 0.85 to 1.63). A combination of depressive symptoms and anxiety symptoms was associated with poor glycaemic control (relative excess risk due to interaction: 4.93, 95% CI 2.09 to 7.87; attributable proportion due to interaction: 0.27, 95% CI 0.12 to 0.45). CONCLUSIONS: There was a high prevalence of depressive and anxiety symptoms in this Chinese sample of participants, although depression and anxiety were not singly associated with glycaemic control. However, a combination of depressive and anxiety symptoms was negatively correlated with glycaemic control in participants with type 2 diabetes.

Abstract Nanoparticle‐based combination therapy strategy of photothermal therapy (PTT) and immunotherapy is an attractive cancer treatment for ablating tumors and eliciting host immune responses. However, this strategy is often hampered by tedious treatment process and limited immune response, and usually needs to be combined with checkpoint blockades to enhance therapeutic effect. Herein, a nanoplatform with mesoporous silica nanoparticles (MSNs) as a vector, which integrated photothermal agent polydopamine (PDA), model antigen ovalbumin (OVA), and antigen release promoter ammonium bicarbonate (ABC) in an easy way for melanoma PTT‐immunotherapy is designed. The formulated MSNs‐ABC@PDA‐OVA nanovaccine exhibits excellent photothermal properties and effectively eliminates primary tumors. Under laser irradiation, the MSNs‐ABC@PDA‐OVA nanovaccine realizes rapid antigen release and endosome escape, enhances dendritic cells activation and maturation, facilitates migration to tumor‐draining lymph nodes, and induces robust antitumor immune responses. Impressively, single injection of MSNs‐ABC@PDA‐OVA combines with single round of PTT successfully eradicates melanoma tumors with a cure rate of 75% and generates strong immunological memory to inhibit tumor recurrence and lung metastasis. Hence, the research offers a simple and promising strategy of synergistic PTT‐immunotherapy to effectively treat cancer.

The imbalance of immune status in cancer microenvironment plays an important role in the development and progression of cancer. Immunotherapy based on this has become an important field of cancer research in recent years. Many studies on long noncoding RNA (lncRNA) in cancer have focus on its regulation in cancer development and metastasis. Recent studies have suggested that lncRNAs play crucial roles in different phases of cancer immunity, including antigen releasing, antigen presentation, immune activation, immune cells migration, infiltrating into cancer tissues, and killing cancer cells. The functional studies of lncRNAs in cancer immuntity revealed the complicated molecular mechanisms in cancer immunity from a new point of view, which may provide novel potential targets for cancer immunotherapies. Based on the classical cancer-immunity cycle theory, we review the recent studies on the functions and mechanisms of immune-related lncRNAs in different stages of cancer immunity, to summarize the relationship between lncRNAs, and cancer immunity and to provide a framework for further research.

Numerous studies have indicated that primary tumors induce the formation of a pre-metastatic niche in distant organs by secreting tumor-derived factors. The present study shows that pre-exposure to chronic stress enhanced lung colonization efficiency by circulating tumor cells, suggesting that chronic stress critically influences pre-metastatic lungs before the arrival of disseminated tumor cells. Ablation of the sympathetic nerve function by 6-OHDA or blockage of the β-adrenergic signaling by propranolol remarkably suppressed stress-induced lung metastasis. Depletion of circulating monocytes or lung macrophages strongly abolished stress-induced lung seeding by tumor cells, whereas treatment of mice with the β-adrenergic agonist isoproterenol (ISO) during the pre-metastatic phase promoted the infiltration of macrophages to the lung. Meanwhile, the numbers of monocytes in peripheral blood, spleen, and bone marrow were remarkably increased in response to ISO stimulation. These data indicate that the β-adrenergic signaling promotes lung metastatic colonization by tumor cells through increased output of monocytes in the pre-metastatic phase and infiltration of macrophages into the pre-metastatic lung. Mechanistic studies revealed that ISO stimulation upregulated the expression of CCL2 in pulmonary stromal cells and CCR2 in monocytes/macrophages, leading to the recruitment and infiltration of macrophages into the pre-metastatic lung. By inducing a response of monocytes/macrophages driven by the CCL2/CCR2 axis, stress-related catecholamine may act as a crucial factor in regulating the pre-metastatic niche for and lung colonization by tumor cells. Our data demonstrate that disturbance of host macro-environmental homeostasis has an influence on future metastatic organs. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Immunotherapy has received tremendous attention for tumor treatment, but the efficacy is greatly hindered by insufficient tumor-infiltration of immune cells and immunosuppressive tumor microenvironment. The strategy that can efficiently activate cytotoxic T lymphocytes and inhibit negative immune regulators will greatly amplify immunotherapy outcome, which is however very rare. Herein, a new kind of semiconducting polymer (SP) nanoparticles is developed, featured with surface-mimicking protein secondary structure (SPSS NPs) for self-synergistic cancer immunotherapy by combining immunogenic cell death (ICD) and immune checkpoint blockade therapy. The SPs with excellent photodynamic property are synthesized by rational fluorination, which can massively induce ICD. Additionally, the peptide antagonists are introduced and self-assembled into β-sheet protein secondary structures on the photodynamic NP surface via preparation process optimization, which function as efficient lysosome-targeting chimaeras (LYTACs) to mediate the degradation of programmed cell death ligand-1 (PD-L1) in lysosome. In vivo experiments demonstrate that SPSS NPs can not only elicit strong antitumor immunity to suppress both primary tumor and distant tumor, but also evoke long-term immunological memory against tumor rechallenge. This work introduces a new kind of robust immunotherapy agents by combining well-designed photosensitizer-based ICD induction and protein secondary structures-mediated LYTAC-like multivalence PD-L1 blockade, rendering great promise for synergistic immunotherapy.

The accumulation of acidic metabolic waste products within the tumor microenvironment inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it remains unclear how an acidic environment affects T cell metabolism and differentiation. Here we show that prolonged exposure to acid reprograms T cell intracellular metabolism and mitochondrial fitness and preserves T cell stemness. Mechanistically, elevated extracellular acidosis impairs methionine uptake and metabolism via downregulation of SLC7A5, therefore altering H3K27me3 deposition at the promoters of key T cell stemness genes. These changes promote the maintenance of a 'stem-like memory' state and improve long-term in vivo persistence and anti-tumor efficacy in mice. Our findings not only reveal an unexpected capacity of extracellular acidosis to maintain the stem-like properties of T cells, but also advance our understanding of how methionine metabolism affects T cell stemness.

BACKGROUND AND AIM: Circulating microRNAs (miRNAs) are potential biomarkers for cancer detection; however, little is known about their prognostic impact on oesophageal squamous cell carcinoma (ESCC). The current study aims to uncover novel miRNAs for prognostic biomarkers in ESCC patients. PATIENTS AND METHODS: We initially screened the expression of 754 serum miRNAs using TaqMan Low Density Array in two pooled samples respectively from 28 ESCC and 28 normal controls. Markedly upregulated miRNAs in ESCC and some miRNAs reported to be differently expressed in ESCC tissue were then validated individually by RT-qPCR in another 83 patients and 83 controls arranged in two phases. The changes of the selected miRNAs during the esophagectomy and their prognostic value were examined. RESULTS: Seven serum miRNAs were found to be significantly higher in ESCC than in controls; namely, miR-25, miR-100, miR-193-3p, miR-194, miR-223, miR-337-5p and miR-483-5p (P<0.0001), and the area under the receiver-operating-characteristic (ROC) curve (AUC) for the seven-miRNA panel was 0.83 (95% CI 0.75-0.90). Most of these miRNAs declined markedly in postoperative samples versus preoperative samples (P<0.05). Moreover, high level of miR-25 was significantly correlated with shorter overall survival in patients (P = 0.027). Cox regression analysis identified lymph node metastasis, miR-25 and miR-100 as the independent risk factors for overall survival (hazard ratio (HR) 2.98 [1.36-6.55], P = 0.006; HR 3.84 [1.02-14.41], P = 0.029; HR 4.18 [1.21-14.50], P = 0.024, respectively). CONCLUSION: The seven serum miRNAs could potentially serve as novel biomarkers for ESCC; moreover, specific miRNAs such as miR-25 and miR-100 can predict poor survival in ESCC.

Supramolecular self-assembling peptide systems are attracting increasing interest in the field of cancer theranostics. Additionally, transformation of the immunologically cold tumor microenvironment into hot is of great importance for obtaining high antitumor responses for most immunotherapies. However, as far as it is known, there are nearly no studies on self-assembling peptides reported to be able to convert cold to hot tumors. Herein, a self-assembling peptide-based cancer theranostic agent (named DBT-2FFGYSA) is designed and synthesized, which can target tumor-specific transmembrane Eph receptor A2 (EphA2) receptors selectively and make the receptors form large aggregates. Such aggregate formation promotes the cross-phosphorylations among EphA2 receptors, leading to signal transduction of antitumor pathway. As a consequence, DBT-2FFGYSA can not only visualize EphA2 receptors in a fluorescence turn-on manner, but also specifically suppress the EphA2 receptor-overexpressed cancer cell proliferation and tumor growth. What is more, DBT-2FFGYSA also serves as an effective agent to convert immunologically cold tumors to hot by inducing the immunogenic cell death of EphA2 receptor-overexpressed cancer cells and recruiting massive tumor-infiltrating T cells. This study, thus, introduces a new category of agents capable of converting cold to hot tumors by pure supramolecular self-assembly without any aid of known anticancer drugs.

Mesoporous silica nanoparticles (MSNs) show great promise to be exploited as versatile multifunctional nanocarriers for effective cancer diagnosis and treatment. In this work, perfluorohexane (PFH)-encapsulated MSNs with indocyanine green (ICG)-polydopamine (PDA) layer and poly(ethylene glycol)-folic acid coating (designated as MSNs-PFH@PDA-ICG-PEG-FA) are successfully fabricated to achieve tumor ultrasonic (US)/near-infrared fluorescence (NIRF) imaging as well as photothermal therapy (PTT)/photodynamic therapy (PDT). MSNs-PFH@PDA-ICG-PEG-FA exhibits good monodispersity with high ICG loading, significantly enhances ICG photostability, and greatly improves cellular uptake. Upon single 808 nm NIR irradiation, the nanocarrier not only efficiently generates hyperthermia to realize PTT, but also produces reactive oxygen species (ROS) for effective PDT. Meanwhile, NIR irradiation can trigger PFH to undergo vaporization and provide a super-resolution US image. Thus, the PTT/PDT combination therapy can be dually guided by PFH-induced US imaging and ICG-induced NIRF imaging. In vivo antitumor studies demonstrate that PTT/PDT from MSNs-PFH@PDA-ICG-PEG-FA significantly inhibits tumor growth and achieves a cure rate of 60% (three out of five mice are completely cured). Hence, the multifunctional MSNs appear to be a promising theragnostic nanoplatform for multimodal cancer imaging and therapy.

Abstract Fluorescent probes capable of precise detection of atherosclerosis (AS) at an early stage and fast assessment of anti‐AS drugs in animal level are particularly valuable. Herein, a highly bright aggregation‐induced emission (AIE) nanoprobe is introduced by regulating the substituent of rhodanine for early detection of atherosclerotic plaque and screening of anti‐AS drugs in a precise, sensitive, and rapid manner. With dicyanomethylene‐substituted rhodanine as the electron‐withdrawing unit, the AIE luminogen named TPE‐T‐RCN shows the highest molar extinction coefficient, the largest photoluminescence quantum yield, and the most redshifted absorption/emission spectra simultaneously as compared to the control compounds. The nanoprobes are obtained with an amphiphilic copolymer as the matrix encapsulating TPE‐T‐RCN molecules, which are further surface functionalized with anti‐CD47 antibody for specifically binding to CD47 overexpressed in AS plaques. Such nanoprobes allow efficient recognition of AS plaques at different stages in apolipoprotein E‐deficient (apoE −/− ) mice, especially for the recognition of early‐stage AS plaques prior to micro‐computed tomography (CT) and magnetic resonance imaging (MRI). These features impel to apply the nanoprobes in monitoring the therapeutic effects of anti‐AS drugs, providing a powerful tool for anti‐AS drug screening. Their potential use in targeted imaging of human carotid plaque is further demonstrated.

The success of bioengineered dental pulp depends on two principles, (1) whether the transplanted tissue can develop its own vascular endothelial tubule network and (2) whether the host vasculature can be induced to penetrate the bioengineered pulp replacement and conjoin. Major inductive molecules that participate in laying down blood vessels include vascular endothelial growth factor (VEGF), ephrinB2, and hypoxia-inducible factor 1α (HIF-1α). Being able to modulate the genes encoding these angiogenic molecules is a therapeutic target in pulp regeneration for endogenous blood vessel formation, prevention of graft rejection, and exclusion of infection. Once implanted inside the root canal, bioengineered pulp is subjected to severe hypoxia that causes tissue degeneration. However, short-term hypoxia is known to stimulate angiogenesis. Thus, it may be feasible to prime dental cells for angiogenic activity before implantation. Stem cells from apical papilla (SCAP) are arguably one of the most potent and versatile dental stem cell populations for bioengineering pulp in vitro. Our study aimed to investigate whether coculture of SCAP and human umbilical vein endothelial cells (HUVECs) under hypoxia promotes the formation of endothelial tubules and a blood vessel network. In addition, we clarified the interplay between the genes that orchestrate these important angiogenic molecules in SCAP under hypoxic conditions. We found that SCAP cocultured with HUVEC at a 1:5 ratio increased the number of endothelial tubules, tubule lengths, and branching points. Fluorescence staining showed that HUVEC formed the trunk of tubular structures, whereas SCAP located adjacent to the endothelial cell line, resembling the pericyte location. When we used CoCl2 (0.5 mM) to induce hypoxic environment, the expression of proteins, HIF-1α and VEGF, and transcript of ephrinB2 in SCAP was upregulated. However, minimal VEGF levels in supernatants of HUVEC and coculture Petri dishes were detected, suggesting that VEGF secreted by SCAP might be used by HUVEC to accelerate the formation of vessel-like structures. Taken together, we revealed that artificial hypoxia stimulates angiogenic responses in SCAP for possible use in engineering dental pulp replacements. Our results may help to delineate the optimal therapeutic target to promote angiogenesis so that future bioengineered pulp replacements integrate faster and permanently within the host.

Necroptosis, a distinctive type of programmed cell death different from apoptosis or necrosis, triggered by a series of death receptors such as tumor necrosis factor receptor 1 (TNFR1), TNFR2, and Fas. In case that apoptosis process is blocked, necroptosis pathway is initiated with the activation of three key downstream mediators which are receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). The whole process eventually leads to destruction of the cell membrane integrity, swelling of organelles, and severe inflammation. Over the past decade, necroptosis has been found widely involved in life process of human beings and animals. In this review, we attempt to explore the therapeutic prospects of necroptosis regulators by describing its molecular mechanism and the role it played in pathological condition and tissue homeostasis, and to summarize the research and clinical applications of corresponding regulators including small molecule inhibitors, chemicals, Chinese herbal extracts, and biological agents in the treatment of various diseases.

Abstract Development of highly efficient radiosensitizers is urgently desirable for addressing the resistance of cancer cells to ionizing radiation, which is the main reason for the failure of radiotherapy. Here, it is reported for the first time that supramolecular nanomaterials can serve as an excellent nanoplatform for developing superior radiosensitizers. A new curcumin‐based supramolecular nanofiber (Cur‐SNF) by virtue of a self‐assembling short peptide is developed, which greatly boosts the radiosensitivity of colorectal cancers to ionizing radiation. The drug–peptide conjugate Curcumin‐FFE‐CS‐EE is synthesized and can self‐assemble into small‐molecule hydrogel containing Cur‐SNFs triggered by reductant. In vitro and in vivo radiosensitization studies reveal that as compared to free curcumin Cur‐SNFs show much better performance as a radiosensitizer to sensitize colorectal cancer cells to ionizing radiation thanks to the supramolecular nanostructure. Due to the exceptionally high radiosensitization efficacy, Cur‐SNFs in combination with radiation realize significant reduction in tumor volume in vivo. Besides, the molecular mechanism studies demonstrate that Cur‐SNFs promote the radiosensitivity of colorectal cancer cells through inhibiting radiation‐induced nuclear factor kappa B activation. Cur‐SNF achieves an ultralarge sensitizer enhancement ratio at 10% cell survival value of 2.01, the highest among currently reported curcumin‐based radiosensitizers.