Adipose Triglyceride Lipase-Mediated Adipocyte Lipolysis Exacerbates Acute Pancreatitis Severity in Mouse Models and Patients.

Dyslipolysis of adipocytes plays a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, the degree of adipocyte lipolysis related to the prognoses in acute pancreatitis (AP) and the role of ATGL-mediated lipolysis in the pathogenesis of AP remain elusive. Herein, the visceral adipose tissue consumption rate in the acute stage was measured in both patients with AP and mouse models. Lipolysis levels and ATGL expression were detected in cerulein-induced AP models. CL316,243, a lipolysis stimulator, and adipose tissue-specific ATGL knockout mice were used to further investigate the role of lipolysis in AP. The ATGL-specific inhibitor, atglistatin, was used in C57Bl/6N and ob/ob AP models. This study indicated that increased visceral adipose tissue consumption rate in the acute phase was independently associated with adverse prognoses in patients with AP, which was validated in mouse AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis aggravated AP. Genetic blockage of ATGL specifically in adipocytes alleviated the damage to AP. The application of atglistatin effectively protected against AP in both lean and obese mice. These findings demonstrated that ATGL-mediated adipocyte lipolysis exacerbates AP and highlighted the therapeutic potential of ATGL as a drug target for AP.

Efficacy of molnupiravir and interferon for the treatment of SARS-CoV-2 in golden Syrian hamster.

The mortality and hospitalization rate by COVID-19 dropped significantly currently, but its seasonal outbreaks make antiviral treatment still vital. The mortality and hospitazation rate by COVID-19 dropped significantly currently, but its seasonal ourbreaks make antiviral treatment still vital. In our study, syrian golden hamsters were treated with molnupiravir and interferons (IFNs) after SARS-CoV-2 infection. Their weight changes, pathological changes, virus replication and inflammation levels were evaluated. In the IFNs single treatment, only IFN-α group reduced viral load (p < 0.05) and virus titer in hamster lungs. The TNF-α expression decreased significantly in both IFNs treatment at 2dpi. Histological and immunofluorescence results showed lung damage in the IFNs groups were milder at 4dpi. In the molnupiravir/IFN-α combination treatment, weight loss and virus replication in lung were significantly decreased in the mono-molnupiravir group and combination group (p < 0.05), the expression of IL-6, TNF-α, IL-1ß and MIP-1α also decreased significantly (p < 0.05), but the combination treatment was not more effective than the mono-molnupiravir treatment. Histological and immunofluorescence results showed the lung damage and inflammation in mono-molnupiravir and combination groups were milder. In summary, IFNs treatment had anti-inflammatory effect against SARS-CoV-2, only IFN-α showed a weak antiviral effect. Molnupiravir/IFN-α combination treatment was effective against SARS-CoV-2 but was not superior to mono-molnupiravir treatment. IFN-α could be considered for immunocompromised patients to stimulate and activate early immune responses.

Leveraging Radiation-triggered Metal Prodrug Activation Through Nanosurface Energy Transfer for Directed Radio-chemo-immunotherapy.

Metal-based drugs currently dominate the field of chemotherapeutic agents; however, achieving the controlled activation of metal prodrugs remains a substantial challenge. Here, we propose a universal strategy for the radiation-triggered activation of metal prodrugs via nanosurface energy transfer (NSET). The core-shell nanoplatform (Ru-GNC) is composed of gold nanoclusters (GNC) and ruthenium (Ru)-containing organic-inorganic hybrid coatings. Upon X-ray irradiation, chemotherapeutic Ru (II) complexes were released in a controlled manner through a unique NSET process involving the transfer of photoelectron energy from the radiation-excited Ru-GNCs to the Ru-containing hybrid layer. In contrast to the traditional radiation-triggered activation of prodrugs, such an NSET-based system ensures that the reactive species in the tumor microenvironment are present in sufficient quantity and are not easily quenched. Additionally, ultrasmall Ru-GNCs preferably target mitochondria and profoundly disrupt the respiratory chain upon irradiation, leading to radiosensitization by generating abundant reactive oxygen species. Consequently, Ru-GNC-directed radiochemotherapy induces immunogenic cell death, resulting in significant therapeutic outcomes when combined with the programmed cell death-ligand 1 (PD-L1) checkpoint blockade. This NSET strategy represents a breakthrough in designing radiation-triggered nanoplatforms for metal-prodrug-mediated cancer treatment in an efficient and controllable manner.

Self-polymerized platinum (II)-Polydopamine nanomedicines for photo-chemotherapy of bladder Cancer favoring antitumor immune responses.

Systemic administration of platinum-based drugs has obvious limitations in the treatment of advanced bladder cancer (BC) owing to lower tumor accumulation and uncontrolled release of chemotherapeutics. There is an urgent need for advanced strategies to overcome the current limitations of platinum-based chemotherapy, to achieve maximal therapeutic outcomes with reduced side effects. In this study, self-polymerized platinum (II)-polydopamine nanocomplexes (PtPDs) were tailored for efficient chemo-photoimmunotherapy of BC. PtPDs with high Pt loading content (11.3%) were degradable under the combination of a reductive tumor microenvironment and near-infrared (NIR) light irradiation, thus controlling the release of Pt ions to achieve efficient chemotherapy. In addition, polydopamine promoted stronger photothermal effects to supplement platinum-based chemotherapy. Consequently, PtPDs provided effective chemo-photothermal therapy of MB49 BC in vitro and in vivo, strengthening the immunogenic cell death (ICD) effect and robust anti-tumoral immunity response. When combined with a PD-1 checkpoint blockade, PtPD-based photochemotherapy evoked systemic immune responses that completely suppressed primary and distant tumor growth without inducing systemic toxicities. Our work provides a highly versatile approach through metal-dopamine self-polymerization for the precise delivery of metal-based chemotherapeutic drugs, and may serve as a promising nanomedicine for efficient and safe platinum-based chemotherapy for BC.

Predictive value of serum cholinesterase in the mortality of acute pancreatitis: A retrospective cohort study.

BACKGROUND: Severe acute pancreatitis has a high mortality of 20%-40%, but there is a lack of optimal prognostic biomarker for the severity of acute pancreatitis (AP) or mortality. This study is designed to investigate the relationship between serum cholinesterase (ChE) level and poor outcomes of AP. METHODS: A total of 1904 AP patients were screened in the study, and we finally got 692 patients eligible for analysis. Patients were divided into 2 groups based on serum ChE. The primary outcome was mortality, and multivariable logistic regression analysis for mortality was completed. Additionally, we used receiver operating characteristic (ROC) curve analysis to clarify the predictive value of serum ChE for mortality and organ failure. RESULTS: Three hundred and seventy eight patients and 314 patients were included in the ChE-low and ChE-normal group, respectively. Patients in the ChE-low group were older (46.68 ± 12.70 vs. 43.56 ± 12.13 years old, p = .001) and had a lower percentage of man (62.4% vs. 71.0%, p = .017) when compared to the ChE-normal group. Mortality was significantly different in two groups (10.3% vs. 0.0%, p < .001). Moreover, organ failure also differed significantly in two groups (46.6% vs. 8.6%, p < .001). Decreased ChE level was independently associated with mortality in acute pancreatitis (odds ratio: 0.440; 95% confidence interval, 0.231, 0.838, p = .013). The area under the curve of serum ChE was 0.875 and 0.803 for mortality and organ failure, respectively. CONCLUSIONS: Lower level of serum ChE was independently associated with the severity and mortality of AP.

Increased circulating total bile acid levels were associated with organ failure in patients with acute pancreatitis.

BACKGROUND: Recent studies have shown that bile acids (BAs) are closely related to metabolic and inflammatory diseases. Our study aimed to investigate whether circulating total bile acid (TBA) levels were associated with the severity of acute pancreatitis (AP). METHODS: We retrospectively collected data on patients diagnosed with AP in a tertiary center from 01 January 2014 to 31 December 2016. The highest TBA value during the first 1,2,3,5,7 days after admission was determined as D1, D2, D3, D5, D7 TBAmax. Patients were divided into the high TBA (HTBA) group and the normal TBA (NTBA) group according to whether the TBAmax was ≥10 µmol/L. The prognosis and complications, including death, organ failure (OF) and pancreatic necrosis, were compared between the two groups. Logistic regression analysis and receiving operating characteristic (ROC) curve were used to evaluate the relationship between circulating TBA and organ failure in AP patients. RESULTS: Through stratified analysis of each time period, we found that the incidence of OF in the HTBA group was significantly higher than that in the NTBA group, and the AP severity classification in the HTBA group was more serious than that in the NTBA group. In addition, according to the D7 TBAmax values, the pancreatic necrosis rate, percutaneous catheter drainage (PCD) rate and mortality in the HTBA group were higher than those in the NTBA group. Multivariate regression analysis showed that HTBA (odds ratio (OR), 4.894; P = 0.002) was an independent risk factor for AP complicated with OF, which was verified in the grouping based on D7 TBAmax. ROC analysis revealed that a circulating D7 TBAmax cutoff point of 6.450 umol/L had optimal predictive value for the development of OF in AP patients with an area under the curve of the ROC curve (AUCROC) of 0.777. CONCLUSIONS: The increase of circulating TBA in early stage of AP is independently related to organ failure, which indicates the adverse prognosis of AP patients.

Parental phubbing accelerates depression in late childhood and adolescence:A two-path model.

INTRODUCTION: Phubbing is a social exclusion behavior related to mobile phone use. It undermines interpersonal relationships and mental health. This study aimed to test the connections between parental phubbing and depression in late childhood and adolescence, as well as the mediating roles of parental warmth, parental rejection, and relatedness need satisfaction. METHODS: We conducted two studies. Study 1 was a cross-sectional study of 530 Chinese students (268 boys and 262 girls, Mage = 13.15 ± 0.64 years) who completed self-report questionnaires. We conducted structural modeling to test the relationship between parental phubbing and depression. Study 2 used a short longitudinal design to validate the results of Study 1 and test the mediating roles of parental warmth, parental rejection, and relatedness need satisfaction. In Study 2, we recruited 293 Chinese students (151 boys, 141 girls, and one participant with no reported gender information, Mage = 12.87 ± 0.74 years) to complete the questionnaires and applied structural equation modeling to analyze the data. RESULTS: Two sequential mediation effects were found. The first was parental phubbing → parental warmth → relatedness need satisfaction → depression (protection-reduced effect). The second was parental phubbing → parental rejection → relatedness need satisfaction → depression (risk-increased effect). Gender differences were non-significant. CONCLUSIONS: The study revealed that parental phubbing was associated with students' depression in late childhood and adolescence through two paths. The present study highlights the need to establish family norms regulating mobile phone use to reduce phubbing.

NQDI-1 protects against acinar cell necrosis in three experimental mouse models of acute pancreatitis.

NQDI-1, an inhibitor of ASK1, has been reported to have protective effects in several experimental human disease models. However, the role of NQDI-1 in acute pancreatitis (AP) has not been reported. In this study, we found that NQDI-1 could attenuate histological damage of pancreatic tissue as well as the levels of serum amylase and lipase in a mouse model of AP induced by caerulein. Moreover, the production of reactive oxygen species (ROS) and the expression of necrosis-related proteins (RIP3 and p-MLKL) were also reduced after NQDI-1 administration. Correspondingly, we elucidated the effect of NQDI-1 in vitro and found that NQDI-1 protected against pancreatic acinar cells necrosis via decreasing the ROS production and RIP3 and p-MLKL expression. In addition, we identified the protective effect of NQDI-1 on AP through two other mouse models induced by l-arginine and pancreatic duct ligation. Taken together, these findings showed that NQDI-1 could reduce the acinar cells necrosis and alleviate the severity of AP, which may afford a new therapeutic target on pancreatic necrosis in AP clinically.

Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis by possible reduction of NLRP3 activation and up-regulation of NET expression.

OBJECTIVE: Previous studies have shown that acute inflammation is associated with increased sympathetic activity, which in turn increases the inflammatory response and leads to organ damage. The present study aimed to investigate whether dexmedetomidine administration during acute pancreatitis (AP) lessens pancreatic pathological and functional injury and the inflammatory response, and to explore the underlying mechanisms. METHODS: Mild pancreatitis was induced in mice with caerulein, and severe pancreatitis was induced with caerulein plus lipopolysaccharide (LPS). After pancreatitis induction, dexmedetomidine at 10 or 20 µg/kg was injected via the tail vein. Pancreatic pathological and functional injury was assessed by histology and serum levels of amylase and lipase, respectively. The inflammatory response was evaluated by determining serum levels of inflammatory factors. The expression of myeloperoxidase (MPO) was examined by immunohistochemistry. The expression of norepinephrine transporter (NET), NLRP3, pro-IL-1ß, and interleukin (IL)-1ß in pancreatic tissue was detected by Western blot and real-time PCR. RESULTS: Dexmedetomidine at 20 µg/kg significantly attenuated pancreatic pathological injury, reduced serum levels of amylase, lipase, IL-1ß, IL-6, and tumor necrosis factor (TNF)-α, and decreased the expression of MPO in pancreatic tissue in both mouse models of pancreatitis. In addition, dexmedetomidine at 20 µg/kg significantly down-regulated the expression of NLRP3, pro-IL-1ß, and IL-1ß in pancreatic tissue, but up-regulated the expression of NET in both mouse models. CONCLUSION: Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis possibly by reducing NLRP3 activation and up-regulating NET expression.

INT-777, a bile acid receptor agonist, extenuates pancreatic acinar cells necrosis in a mouse model of acute pancreatitis.

Bile acids receptor TGR5 and its agonist INT-777, which has been found to be involved in the NLRP3 inflammasome pathway, play an important role in inflammatory diseases. However, the role of INT-777 in acute pancreatitis (AP) has not been reported. In this present study, we found that TGR5 was expressed in pancreatic tissue and increased after AP onset induced by caerulein and further evaluated the impact of INT-777 on the severity of AP. The results showed that INT-777 could reduce the severity of AP in mice, which was manifested as decreased pancreatic tissue damage as well as the decrease of serum enzymes (amylase and lipase), pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and the expression of necrosis related proteins (RIP3 and p-MLKL). Furthermore, we found that INT-777 reduced the reactive oxygen species (ROS) production in pancreatic acinar cells and inhibited the activation of NLRP3 inflammasome pathway. In conclusion, our data showed that INT-777 could protect pancreatic acinar cell against necrosis and reduce the severity of AP, which may be mediated by inhibiting ROS/NLRP3 inflammasome pathway.

Viewing Fantastical Events Versus Touching Fantastical Events: Short-Term Effects on Children's Inhibitory Control.

Three pretest-posttest experiments were conducted to compare the effects of viewing versus interacting with either fantastical or real events on 4- and 6-year-old children's inhibitory control. Experiment 1 (N = 72) suggested that although viewing fantastical events had a negative effect on inhibitory control, interacting with them produced no such disruption. Experiment 2 (N = 17) also found that children's inhibitory control decreased after viewing fantastical events but not after interacting with them. In addition, functional near-infrared spectroscopy (fNIRS) data showed that viewing fantastical events resulted in greater activation in the dorsolateral prefrontal cortex. Experiment 3 (N = 72) showed that children's inhibitory control increased after viewing and interacting with real events. The implications for studying the effects of mobile devices are discussed.

Corrigendum to "Naringenin Protects against Acute Pancreatitis in Two Experimental Models in Mice by NLRP3 and Nrf2/HO-1 Pathways".

[This corrects the article DOI: 10.1155/2018/3232491.].

Naringenin Protects against Acute Pancreatitis in Two Experimental Models in Mice by NLRP3 and Nrf2/HO-1 Pathways.

BACKGROUND: Naringenin (Nar) is a type of flavonoid and has been shown to have anti-inflammatory and antioxidative properties. However, the effects of Nar on acute pancreatitis (AP) have not been well studied. In this study, we aimed to investigate the function of Nar in a mouse model of AP. METHODS: Mild acute pancreatitis (MAP) was induced by caerulein (Cae), and severe acute pancreatitis (SAP) was induced by L-arginine in mice. Nar was administered intraperitoneally at doses of 25, 50, or 100 mg/kg following MAP induction and at a dose of 100 mg/kg following SAP induction. The serum levels of cytokines, lipase, and amylase were determined, and pancreatic and pulmonary tissues were harvested. RESULTS: The serum levels of amylase, lipase, and cytokines were significantly decreased in both MAP and SAP models after Nar treatment. The malondialdehyde (MDA) levels of the pancreatic tissue was significantly reduced in both MAP and SAP after Nar treatment. In contrast, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), total sulfhydryl (T-SH), and non-proteinsulthydryl (NP-SH) were markedly increased in both MAP and SAP after Nar treatment. The injury in pancreatic and pulmonary tissues was markedly improved as evidenced by the inhibited expression of myeloperoxidase, nod-like receptor protein 3, and interleukin 1 beta as well as the enhanced expression of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 in pancreatic tissues. CONCLUSIONS: Nar exerted protective effects on Cae-induced MAP and L-arginine-induced SAP in mice, suggesting that Nar may be a potential therapeutic intervention for AP.

Ribavirin-resistant variants of foot-and-mouth disease virus: the effect of restricted quasispecies diversity on viral virulence.

UNLABELLED: Mutagenic nucleoside analogues can be used to isolate RNA virus high-fidelity RNA-dependent RNA polymerase (RdRp) variants, the majority of which are attenuated in vivo. However, attenuated foot-and-mouth disease virus (FMDV) high-fidelity RdRp variants have not been isolated, and the correlations between RdRp fidelity and virulence remain unclear. Here, the mutagen ribavirin was used to select a ribavirin-resistant population of FMDV, and 4 amino acid substitutions (D5N, A38V, M194I, and M296V) were identified in the RdRp-coding region of the population. Through single or combined mutagenesis using a reverse genetics system, we generated direct experimental evidence that the rescued D5N, A38V, and DAMM mutants but not the M194I and M296V mutants are high-fidelity RdRp variants. Mutagen resistance assays revealed that the higher replication fidelity was associated with higher-level resistance to ribavirin. In addition, significantly attenuated fitness and virulence phenotypes were observed for the D5N, A38V, and DAMM mutants. Based on a systematic quantitative analysis of fidelity and virulence, we concluded that higher replication fidelity is associated with a more attenuated virus. These data suggest that the resulting restricted quasispecies diversity compromises the adaptability and virulence of an RNA virus population. The modulation of replication fidelity to attenuate virulence may represent a general strategy for the rational design of new types of live, attenuated vaccine strains. IMPORTANCE: The ribavirin-isolated poliovirus (PV) RdRp G64S variant, the polymerases of which were of high replication fidelity, was attenuated in vivo. It has been proposed (M. Vignuzzi, E. Wendt, and R. Andino, Nat. Med. 14:154-161, http://dx.doi.org/10.1038/nm1726) that modulation of replication fidelity is a promising approach for engineering attenuated virus vaccines. The subsequently mutagen-isolated RdRp variants also expressed the high-fidelity polymerase, but not all of them were attenuated. Few studies have shown the exact correlation between fidelity and virulence. The present study investigates the effect of restricted quasispecies diversity on viral virulence via several attenuated FMDV high-fidelity RdRp variants. Our findings may aid in the rational design of a new type of vaccine strain.

Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients.

AIM: To evaluate the effects of UDP-glucuronosyltransferases (UGTs) polymorphisms on the pharmacokinetics of the immunosuppressant mycophenolate mofetil (MMF) in Chinese renal transplant recipients. METHODS: A total of 127 renal transplant patients receiving MMF were genotyped for polymorphisms in UGT1A9 -1818T>C, I399C>T, -118T9/10, -440C>T, -331T>C, UGT2B7 IVS1+985A>G, 211G>T, -900A>G, UGT1A8 518C>G and UGT1A7 622T>C. The plasma concentrations of the MMF active moiety mycophenolic acid (MPA) and main metabolite 7-O-MPA-glucuronide (MPAG) were analyzed using HPLC. Univariate and multivariate analyses were used to assess the effects of UGT-related gene polymorphisms on MPA pharmacokinetics. RESULTS: The dose-adjusted MPA AUC0-12 h of the patients with the UGT2B7 IVS1+985AG genotype was 48% higher than that of the patients with the IVS1+985AA genotype, which could explain 11.2% of the inter-individual variation in MPA pharmacokinetics. The dose-adjusted MPAG AUC0-12 h of the patients with the UGT1A7 622CC and UGT1A9 -440CT/-331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and -440C/-331T homozygotes. Furthermore, the genotypes UGT1A9 -1818T>C and UGT1A8 518C>G were associated with a low dose-adjusted MPAG AUC0-12 h. CONCLUSION: The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing.

Foot-and-mouth disease virus low-fidelity polymerase mutants are attenuated.

Previous studies have shown that RNA viruses can be attenuated by either increased or decreased viral polymerase replication fidelity. Although foot-and-mouth disease virus (FMDV) high-fidelity RNA-dependent RNA polymerase (RdRp) variants with an attenuated phenotype have been isolated using mutagens, no FMDV mutant with a low-fidelity polymerase has been documented to date. Here, we describe the generation of several FMDV RdRp mutants using site-directed mutagenesis via a reverse genetic system. Mutation frequency assays confirmed that five rescued FMDV RdRp mutant populations had lower replication fidelity than the wild-type virus population, which allowed us to assess the effects of the change in replication fidelity on the virus phenotype. These low-fidelity FMDV RdRp mutants showed increased sensitivity to ribavirin or 5-fluorouracil (5-FU) treatment without a loss of growth capacity in cell cultures. In addition, decreased fitness and attenuated virulence were observed for the RdRp mutants with lower fidelity. Importantly, based on a quantitative analysis for fidelity and virulence, we concluded that lower replication fidelity is associated with a more attenuated virus phenotype. These results further contribute to our understanding of the replication fidelity of polymerases of RNA viruses and its relationship to virulence attenuation.

How COVID-19 Information Fear of Missing out Increases the Risk of Depression and Anxiety: Roles of Resilience and Personality Types.

During major health emergencies (e.g., the COVID-19 pandemic) people often fear missing relevant information. COVID-19 information fear of missing out (FOMO) is a phenomenon where people feel anxiety about losing control of COVID-19-related information. The present study aimed to examine how COVID-19 information FOMO relates to mental health (e.g., depression and anxiety), the mediating role of resilience, and the moderating role of personality types during the COVID-19 pandemic. We surveyed 1442 Chinese undergraduates (Mage = 21.68 ± 2.35 years) on the relevant variables. The results showed that COVID-19 information FOMO was positively associated with depression and anxiety, and resilience mediated these associations. Latent profile analysis (LPA) identified three personality types (undercontrolled, adaptive, and overcontrolled). Personality types moderated the mediation models, in which the indirect effects were only significant in the participants classified in the undercontrolled group rather than the participants classified in the other two groups. This study told us that undergraduates' mental health, particularly that of the undercontrollers, should be paid attention to when responding to a major public health emergency (e.g., the COVID-19 pandemic).

Predicting non-chemotherapy drug-induced agranulocytosis toxicity through ensemble machine learning approaches.

Agranulocytosis, induced by non-chemotherapy drugs, is a serious medical condition that presents a formidable challenge in predictive toxicology due to its idiosyncratic nature and complex mechanisms. In this study, we assembled a dataset of 759 compounds and applied a rigorous feature selection process prior to employing ensemble machine learning classifiers to forecast non-chemotherapy drug-induced agranulocytosis (NCDIA) toxicity. The balanced bagging classifier combined with a gradient boosting decision tree (BBC + GBDT), utilizing the combined descriptor set of DS and RDKit comprising 237 features, emerged as the top-performing model, with an external validation AUC of 0.9164, ACC of 83.55%, and MCC of 0.6095. The model's predictive reliability was further substantiated by an applicability domain analysis. Feature importance, assessed through permutation importance within the BBC + GBDT model, highlighted key molecular properties that significantly influence NCDIA toxicity. Additionally, 16 structural alerts identified by SARpy software further revealed potential molecular signatures associated with toxicity, enriching our understanding of the underlying mechanisms. We also applied the constructed models to assess the NCDIA toxicity of novel drugs approved by FDA. This study advances predictive toxicology by providing a framework to assess and mitigate agranulocytosis risks, ensuring the safety of pharmaceutical development and facilitating post-market surveillance of new drugs.

Gold Nanocluster: A Photoelectric Converter for X-Ray-Activated Chemotherapy.

Despite the promise of activatable chemotherapy, the development of a spatiotemporally controllable strategy for prodrug activation in deep tissues remains challenging. Herein, a proof-of-concept is proposed for a gold nanocluster-based strategy that utilizes X-ray irradiation to trigger the liberation of platinum (Pt)-based prodrug conjugates, thus enabling radiotherapy-directed chemotherapy. Mechanistically, the irradiated activation of prodrugs is achieved through direct photoelectron transfer from the excited-state gold nanoclusters to the Pt(IV) center, resulting in the release of cytotoxic Pt(II) agents. Compared to the traditional combination of chemotherapy and radiotherapy, this radiotherapy-directed chemotherapy strategy offers superior antitumor efficacy and safety benefits through spatiotemporal synergy at the tumor site. Additionally, this strategy elicits robust immunogenic cell death and yields profound outcomes for combined immunotherapy of breast cancer. This versatile strategy is ushering in a new era of radiation-mediated chemistry for controlled drug delivery and the precise regulation of biological processes.

Leveraging Senescent Cancer Cell Membrane to Potentiate Cancer Immunotherapy Through Biomimetic Nanovaccine.

Senescent cancer cells are endowed with high immunogenic potential that has been leveraged to elicit antitumor immunity and potentially complement anticancer therapies. However, the efficacy of live senescent cancer cell-based vaccination is limited by interference from immunosuppressive senescence-associated secretory phenotype and pro-tumorigenic capacity of senescent cells. Here, a senescent cancer cell-based nanovaccine with strong immunogenicity and favorable potential for immunotherapy is reported. The biomimetic nanovaccine integrating a senescent cancer cell membrane-coated nanoadjuvant outperforms living senescent cancer cells in enhancing dendritic cells (DCs) internalization, improving lymph node targeting, and enhancing immune responses. In contrast to nanovaccines generated from immunogenic cell death-induced tumor cells, senescent nanovaccines facilitate DC maturation, eliciting superior antitumor protection and improving therapeutic outcomes in melanoma-challenged mice with fewer side effects when combined with αPD-1. The study suggests a versatile biomanufacturing approach to maximize immunogenic potential and minimize adverse effects of senescent cancer cell-based vaccination and advances the design of biomimetic nanovaccines for cancer immunotherapy.