Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.

Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.

Activation of α7 nicotinic acetylcholine receptors inhibits hepatic necroptosis and ameliorates acute liver injury in mice.

BACKGROUND: Acute liver injury (ALI) is a disease characterized by severe liver dysfunction, caused by significant infiltration of immune cells and extensive cell death with a high mortality. Previous studies demonstrated that the α7 nicotinic acetylcholine receptor (α7nAChR) played a crucial role in various liver diseases. The hypothesis of this study was that activating α7nAChR could alleviate ALI and investigate its possible mechanisms. METHODS: ALI was induced by intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal) in wild type (WT), α7nAChR knockout (α7nAChR -/-) and Sting mutation (Stinggt/gt) mice in the presence or absence of a pharmacological selective α7nAChR agonist (PNU-282987). The effects of α7nAChR on hepatic injury, inflammatory response, mitochondrial damage, necroptosis and infiltration of immune cells during ALI were assessed. RESULTS: The expression of α7nAChR in liver tissue was increased in LPS/D-Gal induced ALI mice. Compared to the age-matched WT mice, α7nAChR deficiency decreased the survival rate, exacerbated the hepatic injury accompanied with enhanced inflammatory response and oxidative stress, and aggravated hepatic mitochondrial damage and necroptosis. Conversely, pharmacological activation of α7nAChR by PNU-282987 displayed the opposite trends. Furthermore, PNU-282987 significantly reduced the proportion of infiltrating monocyte-derived macrophages (CD45+CD11bhiF4/80int), M1 macrophages (CD45+CD11b+F4/80+CD86 hiCD163low), Ly6Chi monocytes (CD45+CD11b+MHCⅡ lowLy6C hi), but increased the resident Kupffer cells (CD45+CD11bintF4/80 hiTIM4 hi) in the damaged hepatic tissues caused by LPS/D-Gal. Interestingly, α7nAChR deficiency promoted the STING signaling pathway under LPS/D-Gal stimulation, while PNU-282987 treatment significantly prevented its activation. Finally, it was found that Sting mutation abolished the protective effects against hepatic injury by activating α7nAChR. CONCLUSIONS: Our study revealed that activating α7nAChR could protect against LPS/D-Gal induced ALI by inhibiting hepatic inflammation and necroptosis possibly via regulating immune cells infiltration and inhibiting STING signaling pathway.

Rectal adenocarcinoma: Ex vivo 9.4T MRI-correlation with histopathologic treatment response to neoadjuvant chemoradiotherapy.

OBJECTIVES: To determine the imaging details and diagnostic information of the treatment response to neoadjuvant chemoradiotherapy (nCRT) of rectal adenocarcinoma at 9.4T magnetic resonance imaging (MRI) by ex vivo. METHODS: Fifteen cases with locally advanced rectal cancer (LARC) followed by radical surgery after nCRT between September 2022 and February 2023 were recruited. Resected specimens were fixed in a perfluoropolyether-filled test tube and scanned with a 3.0T and 9.4T MRI system ex vivo. The residual tumor depth and MRI-based tumor regression grade (TRG) were subjectively assessed and then compared with the pathological findings. RESULTS: The ex vivo 9.4T T2WI without fat suppression clearly differentiated tumor tissue, fibrosis and normal rectal wall, which clearly corresponded to the pathologic tissues of the rectal specimens. The TRG could be accurately assessed on ex vivo 9.4T images in 13/15 specimens (86.7%), while in 11/15 specimens (73.3%) on ex vivo 3.0T images. CONCLUSION: Ex vivo 9.4T MR imaging clearly displayed the components of rectal wall and proved excellent diagnostic performance for evaluating the treatment response to nCRT, which allow radiologists to understand and then assess more accurately the TRG of LARC after nCRT.

GSDME promotes MASLD by regulating pyroptosis, Drp1 citrullination-dependent mitochondrial dynamic, and energy balance in intestine and liver.

Dysregulated metabolism, cell death, and inflammation contribute to the development of metabolic dysfunction-associated steatohepatitis (MASH). Pyroptosis, a recently identified form of programmed cell death, is closely linked to inflammation. However, the precise role of pyroptosis, particularly gasdermin-E (GSDME), in MASH development remains unknown. In this study, we observed GSDME cleavage and GSDME-associated interleukin-1ß (IL-1ß)/IL-18 induction in liver tissues of MASH patients and MASH mouse models induced by a choline-deficient high-fat diet (CDHFD) or a high-fat/high-cholesterol diet (HFHC). Compared with wild-type mice, global GSDME knockout mice exhibited reduced liver steatosis, steatohepatitis, fibrosis, endoplasmic reticulum stress, lipotoxicity and mitochondrial dysfunction in CDHFD- or HFHC-induced MASH models. Moreover, GSDME knockout resulted in increased energy expenditure, inhibited intestinal nutrient absorption, and reduced body weight. In the mice with GSDME deficiency, reintroduction of GSDME in myeloid cells-rather than hepatocytes-mimicked the MASH pathologies and metabolic dysfunctions, as well as the changes in the formation of neutrophil extracellular traps and hepatic macrophage/monocyte subclusters. These subclusters included shifts in Tim4+ or CD163+ resident Kupffer cells, Ly6Chi pro-inflammatory monocytes, and Ly6CloCCR2loCX3CR1hi patrolling monocytes. Integrated analyses of RNA sequencing and quantitative proteomics revealed a significant GSDME-dependent reduction in citrullination at the arginine-114 (R114) site of dynamin-related protein 1 (Drp1) during MASH. Mutation of Drp1 at R114 reduced its stability, impaired its ability to redistribute to mitochondria and regulate mitophagy, and ultimately promoted its degradation under MASH stress. GSDME deficiency reversed the de-citrullination of Drp1R114, preserved Drp1 stability, and enhanced mitochondrial function. Our study highlights the role of GSDME in promoting MASH through regulating pyroptosis, Drp1 citrullination-dependent mitochondrial function, and energy balance in the intestine and liver, and suggests that GSDME may be a potential therapeutic target for managing MASH.

Correction: Tumor Immunotherapy-Related Information on Internet-Based Videos Commonly Used by the Chinese Population: Content Quality Analysis.

[This corrects the article DOI: 10.2196/50561.].

Targeting EFHD2 inhibits interferon-γ signaling and ameliorates non-alcoholic steatohepatitis.

BACKGROUND & AIMS: The precise pathomechanisms underlying the development of non-alcoholic steatohepatitis (NASH, also known as metabolic dysfunction-associated steatohepatitis [MASH]) remain incompletely understood. In this study, we investigated the potential role of EF-hand domain family member D2 (EFHD2), a novel molecule specific to immune cells, in the pathogenesis of NASH. METHODS: Hepatic EFHD2 expression was characterized in patients with NASH and two diet-induced NASH mouse models. Single-cell RNA sequencing (scRNA-seq) and double-immunohistochemistry were employed to explore EFHD2 expression patterns in NASH livers. The effects of global and myeloid-specific EFHD2 deletion on NASH and NASH-related hepatocellular carcinoma were assessed. Molecular mechanisms underlying EFHD2 function were investigated, while chemical and genetic investigations were performed to assess its potential as a therapeutic target. RESULTS: EFHD2 expression was significantly elevated in hepatic macrophages/monocytes in both patients with NASH and mice. Deletion of EFHD2, either globally or specifically in myeloid cells, improved hepatic steatosis, reduced immune cell infiltration, inhibited lipid peroxidation-induced ferroptosis, and attenuated fibrosis in NASH. Additionally, it hindered the development of NASH-related hepatocellular carcinoma. Specifically, deletion of myeloid EFHD2 prevented the replacement of TIM4+ resident Kupffer cells by infiltrated monocytes and reversed the decreases in patrolling monocytes and CD4+/CD8+ T cell ratio in NASH. Mechanistically, our investigation revealed that EFHD2 in myeloid cells interacts with cytosolic YWHAZ (14-3-3ζ), facilitating the translocation of IFNγR2 (interferon-γ receptor-2) onto the plasma membrane. This interaction mediates interferon-γ signaling, which triggers immune and inflammatory responses in macrophages during NASH. Finally, a novel stapled α-helical peptide targeting EFHD2 was shown to be effective in protecting against NASH pathology in mice. CONCLUSION: Our study reveals a pivotal immunomodulatory and inflammatory role of EFHD2 in NASH, underscoring EFHD2 as a promising druggable target for NASH treatment. IMPACT AND IMPLICATIONS: Non-alcoholic steatohepatitis (NASH) represents an advanced stage of non-alcoholic fatty liver disease (NAFLD); however, not all patients with NAFLD progress to NASH. A key challenge is identifying the factors that trigger inflammation, which propels the transition from simple fatty liver to NASH. Our research pinpointed EFHD2 as a pivotal driver of NASH, orchestrating the over-activation of interferon-γ signaling within the liver during NASH progression. A stapled peptide designed to target EFHD2 exhibited therapeutic promise in NASH mice. These findings support the potential of EFHD2 as a therapeutic target in NASH.

Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.

Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.

Tumor Immunotherapy-Related Information on Internet-Based Videos Commonly Used by the Chinese Population: Content Quality Analysis.

BACKGROUND: Tumor immunotherapy is an innovative treatment today, but there are limited data on the quality of immunotherapy information on social networks. Dissemination of misinformation through the internet is a major social issue. OBJECTIVE: Our objective was to characterize the quality of information and presence of misinformation about tumor immunotherapy on internet-based videos commonly used by the Chinese population. METHODS: Using the keyword "tumor immunotherapy" in Chinese, we searched TikTok, Tencent, iQIYI, and BiliBili on March 5, 2022. We reviewed the 118 screened videos using the Patient Education Materials Assessment Tool-a validated instrument to collect consumer health information. DISCERN quality criteria and the JAMA (Journal of the American Medical Association) Benchmark Criteria were used for assessing the quality and reliability of the health information. The videos' content was also evaluated. RESULTS: The 118 videos about tumor immunotherapy were mostly uploaded by channels dedicated to lectures, health-related animations, and interviews; their median length was 5 minutes, and 79% of them were published in and after 2018. The median understandability and actionability of the videos were 71% and 71%, respectively. However, the quality of information was moderate to poor on the validated DISCERN and JAMA assessments. Only 12 videos contained misinformation (score of >1 out of 5). Videos with a doctor (lectures and interviews) not only were significantly less likely to contain misinformation but also had better quality and a greater forwarding number. Moreover, the results showed that more than half of the videos contain little or no content on the risk factors and management of tumor immunotherapy. Overall, over half of the videos had some or more information on the definition, symptoms, evaluation, and outcomes of tumor immunotherapy. CONCLUSIONS: Although the quality of immunotherapy information on internet-based videos commonly used by Chinese people is moderate, these videos have less misinformation and better content. Caution must be exercised when using these videos as a source of tumor immunotherapy-related information.

Turn-on Near-Infrared Phosphorescent Recognition of Anion Based on Self-Assembly of Cyclometalated Platinum Complexes That Induce Oncosis and Monitor Living Cells.

The design of bio-responsive functional molecular materials that can undergo self-assembly to form nanostructures within cells in response to cellular endogenous stimuli and the clarification of their prospective reaction mechanisms are of paramount significance. This work aims to elucidate the spatiotemporal generation of subcellular nanostructures and their influence on cellular functionality. Three sets of cyclometalated platinum complexes have been designed and synthesized as near-infrared phosphorescent turn-on probes for specific anions based on dynamic self-assembly in aqueous solution. The augmentation of the quantity of aromatic rings in the NN bidentate ligand of the complex modifies both the intensity of the intermolecular Pt-Pt interaction and the capacity to generate self-assembled nanowires with near-infrared emission. Besides, we explored the impact of the CN ligand's substituent effect on anion recognition, which revealed that complexes with electron-absorbing F atom substitution exhibit superior selectivity for Br-. These complexes display vivid green turn-on luminescence upon interaction with cellular biomolecules, enabling dynamic monitoring of their subcellular distribution and their interaction on diverse conditions. Furthermore, our complexes were observed to induce oncosis in cancer cells, underscoring the potential of our work in facilitating in vitro diagnosis and developing effective theranostic agents for cancer therapy.

A Mobile Applet for Assessing Medication Adherence and Managing Adverse Drug Reactions Among Patients With Cancer: Usability and Utility Study.

BACKGROUND: Medication adherence and the management of adverse drug reactions (ADRs) are crucial to the efficacy of antitumor drugs. A WeChat applet, also known as a "Mini Program," is similar to the app but has marked advantages. The development and use of a WeChat applet makes follow-up convenient for patients with cancer. OBJECTIVE: This study aimed to assess the usability and utility of a newly developed WeChat applet, "DolphinCare," among patients with cancer in Shanghai. METHODS: A qualitative methodology was used to obtain an in-depth understanding of the experiences of patients with cancer when using DolphinCare from the usability and utility aspects. The development phase consisted of 2 parts: alpha and beta testing. Alpha testing combined the theory of the Fogg Behavior Model and the usability model. Alpha testing also involved testing the design of DolphinCare using a conceptual framework, which included factors that could affect medication adherence and ADRs. Beta testing was conducted using in-depth interviews. In-depth interviews allowed us to assist the patients in using DolphinCare and understand whether they liked or disliked DolphinCare and found it useful. RESULTS: We included participants who had an eHealth Literacy Scale (eHEALS) score of ≥50%, and a total of 20 participants were interviewed consecutively. The key positive motivators described by interviewers were to be reminded to take their medications and to alleviate their ADRs. The majority of the patients were able to activate and use DolphinCare by themselves. Most patients indicated that their trigger to follow-up DolphinCare was the recommendation of their known and trusted health care professionals. All participants found that labels containing the generic names of their medication and the medication reminders were useful, including timed pop-up push notifications and text alerts. The applet presented the corresponding information collection forms of ADRs to the patient to fill out. The web-based consultation system enables patients to consult pharmacists or physicians in time when they have doubts about medications or have ADRs. The applet had usabilities and utilities that could improve medication adherence and the management of ADRs among patients with cancer. CONCLUSIONS: This study provides preliminary evidence regarding the usability and utility of this type of WeChat applet among patients with cancer, which is expected to be promoted for managing follow-up among other patients with other chronic disease.

Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence.

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD+ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD+ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.

The role of HSP40 in cancer: Recent advances.

Heat shock proteins (HSPs) are a family of proteins involved in protein folding and maturation that are expressed by cells in response to stressors including heat shock. Recent studies have demonstrated that HSPs play major roles in carcinogenesis by regulating angiogenesis, cell proliferation, migration, invasion, metastasis, apoptosis, as well as therapy resistance to certain anticancer drugs. Despite being the largest and most diverse subgroup of the HSP family, HSP40 (DNAJ) is an understudied family of co-chaperones. HSP40 family members are also known to be involved in various types of cancers. In this article, we review the involvement of human HSP40 family members in various aspects of cancer biology. In addition, we highlight the possible potential of HSP40 as a tumor biomarker or drug target for improving the prognosis and treatment of cancer patients in the future.

High-sensitivity flip chip blue Mini-LEDs miniaturized optical instrument for non-invasive glucose detection.

The colorimetric detection of glucose typically involves a peroxidase reaction producing a color, which is then recorded and analyzed. However, enzyme detection has difficulties with purification and storage. In addition, replacing enzyme detection with chemical methods involves time-consuming steps such as centrifugation and purification and the optical instruments used for colorimetric detection are often bulky and not portable. In this study, ammonium metavanadate and sulfuric acid were used to prepare the detection solution instead of peroxidase to produce color. We also analyzed the effect of different concentrations of detection solution on absorbance sensitivity. Finally, a flip chip blue Mini-LEDs miniaturized optical instrument (FC blue Mini-LEDs MOI) was designed for glucose detection using optics fiber, collimating lenses, a miniaturized spectrometer, and an FC Blue Mini-LEDs with a center wavelength of 459 nm. While detecting glucose solutions in the concentration range of 0.1-10 mM by the developed MOI, the regression equation of y = 0.0941x + 0.1341, R2 of 0.9744, the limit of detection was 2.15 mM, and the limit of quantification was 7.163 mM. Furthermore, the preparation of the detection solution only takes 10 min, and the absorbance sensitivity of the optimized detection solution could be increased by 2.3 times. The detection solution remained stable with only a 0.6% decrease in absorbance compared to the original after storing it in a refrigerated environment at 3 °C for 14 days. The method proposed in this study for detecting glucose using FC blue light Mini-LEDs MOI reduces the use of peroxidase. In addition, it has a wide detection range that includes blood as well as non-invasive saliva and tear fluids, providing patients with a miniaturized, highly sensitive, and quantifiable glucose detection system.

Spectral analysis with highly collimated mini-LEDs as light sources for quantitative detection of direct bilirubin.

Because the human eye cannot visually detect the results of direct bilirubin test papers accurately and quantitatively, this study proposes four different highly collimated mini light-emitting diodes (HC mini-LEDs) as light sources for detection. First, different concentrations of bilirubin were oxidized to biliverdin by FeCl3 on the test paper, and pictures were obtained with a smartphone. Next, the red, green, and blue (RGB) channels of the pictures were separated to average grayscale values, and their linear relationship with the direct bilirubin concentration was analyzed to detect bilirubin on the test paper noninvasively and quantitatively. The experimental results showed that when green HC mini-LEDs were used as the light sources and image analysis was performed using the G channel, for a direct bilirubin concentration range of 0.1-2 mg/dL, the G channel determination coefficient (R2) reached 0.9523 and limit of detection was 0.459 mg/dL. The detection method proposed herein has advantages such as rapid analysis, noninvasive detection, and digitization according to RGB grayscale changes in the images of the detection test paper.

Deep learning-based clinical-radiomics nomogram for preoperative prediction of lymph node metastasis in patients with rectal cancer: a two-center study.

Background: Precise preoperative evaluation of lymph node metastasis (LNM) is crucial for ensuring effective treatment for rectal cancer (RC). This research aims to develop a clinical-radiomics nomogram based on deep learning techniques, preoperative magnetic resonance imaging (MRI) and clinical characteristics, enabling the accurate prediction of LNM in RC. Materials and methods: Between January 2017 and May 2023, a total of 519 rectal cancer cases confirmed by pathological examination were retrospectively recruited from two tertiary hospitals. A total of 253 consecutive individuals were selected from Center I to create an automated MRI segmentation technique utilizing deep learning algorithms. The performance of the model was evaluated using the dice similarity coefficient (DSC), the 95th percentile Hausdorff distance (HD95), and the average surface distance (ASD). Subsequently, two external validation cohorts were established: one comprising 178 patients from center I (EVC1) and another consisting of 88 patients from center II (EVC2). The automatic segmentation provided radiomics features, which were then used to create a Radscore. A predictive nomogram integrating the Radscore and clinical parameters was constructed using multivariate logistic regression. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were employed to evaluate the discrimination capabilities of the Radscore, nomogram, and subjective evaluation model, respectively. Results: The mean DSC, HD95 and ASD were 0.857 ± 0.041, 2.186 ± 0.956, and 0.562 ± 0.194 mm, respectively. The nomogram, which incorporates MR T-stage, CEA, CA19-9, and Radscore, exhibited a higher area under the ROC curve (AUC) compared to the Radscore and subjective evaluation in the training set (0.921 vs. 0.903 vs. 0.662). Similarly, in both external validation sets, the nomogram demonstrated a higher AUC than the Radscore and subjective evaluation (0.908 vs. 0.735 vs. 0.640, and 0.884 vs. 0.802 vs. 0.734). Conclusion: The application of the deep learning method enables efficient automatic segmentation. The clinical-radiomics nomogram, utilizing preoperative MRI and automatic segmentation, proves to be an accurate method for assessing LNM in RC. This approach has the potential to enhance clinical decision-making and improve patient care. Research registration unique identifying number UIN: Research registry, identifier 9158, https://www.researchregistry.com/browse-the-registry#home/registrationdetails/648e813efffa4e0028022796/.

Deep learning models for preoperative T-stage assessment in rectal cancer using MRI: exploring the impact of rectal filling.

Background: The objective of this study was twofold: firstly, to develop a convolutional neural network (CNN) for automatic segmentation of rectal cancer (RC) lesions, and secondly, to construct classification models to differentiate between different T-stages of RC. Additionally, it was attempted to investigate the potential benefits of rectal filling in improving the performance of deep learning (DL) models. Methods: A retrospective study was conducted, including 317 consecutive patients with RC who underwent MRI scans. The datasets were randomly divided into a training set (n = 265) and a test set (n = 52). Initially, an automatic segmentation model based on T2-weighted imaging (T2WI) was constructed using nn-UNet. The performance of the model was evaluated using the dice similarity coefficient (DSC), the 95th percentile Hausdorff distance (HD95), and the average surface distance (ASD). Subsequently, three types of DL-models were constructed: Model 1 trained on the total training dataset, Model 2 trained on the rectal-filling dataset, and Model 3 trained on the non-filling dataset. The diagnostic values were evaluated and compared using receiver operating characteristic (ROC) curve analysis, confusion matrix, net reclassification index (NRI), and decision curve analysis (DCA). Results: The automatic segmentation showed excellent performance. The rectal-filling dataset exhibited superior results in terms of DSC and ASD (p = 0.006 and 0.017). The DL-models demonstrated significantly superior classification performance to the subjective evaluation in predicting T-stages for all test datasets (all p < 0.05). Among the models, Model 1 showcased the highest overall performance, with an area under the curve (AUC) of 0.958 and an accuracy of 0.962 in the filling test dataset. Conclusion: This study highlighted the utility of DL-based automatic segmentation and classification models for preoperative T-stage assessment of RC on T2WI, particularly in the rectal-filling dataset. Compared with subjective evaluation, the models exhibited superior performance, suggesting their noticeable potential for enhancing clinical diagnosis and treatment practices.

Sting mutation attenuates acetaminophen-induced acute liver injury by limiting NLRP3 activation.

Acetaminophen (N-acetyl-p-aminophenol; APAP), a widely used effective nonsteroidal anti-inflammatory drug, leads to acute liver injury at overdose worldwide. Evidence showed that the severity of liver injury associated with the subsequent involvement of inflammatory mediators and immune cells. The innate immune stimulator of interferon genes protein (STING) pathway was critical in modulating inflammation. Here, we show that STING was activated and inflammation was enhanced in the liver in APAP-overdosed C57BL/6J mice, and Sting mutation (Stinggt/gt) mice exhibited less liver damage. Multiplexing flow cytometry displayed that Sting mutation changed hepatic recruitment and replacement of macrophages/monocytes in APAP-overdosed mice, which was inclined to anti-inflammation. In addition, Sting mutation limited NLRP3 activation in the liver in APAP-overdosed mice, and inhibited the expression of inflammatory cytokines. Finally, MCC950, a potent and selective NLRP3 inhibitor, significantly ameliorated APAP-induced liver injury and inflammation. Besides, pretreatment of MCC950 in C57 mice resulted in changes of immune cells infiltration in the liver similar to Stinggt/gt mice. Our study revealed that STING played a crucial role in APAP-induced acute liver injury, possibly by maintaining liver immune cells homeostasis and inhibiting NLRP3 inflammasome activation, suggesting that inhibiting STING-NLRP3 pathway might be a potential therapeutic strategy for acute liver injury.

Investigating anorectal function using postoperative MRI-based fibrosis score in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy: a two-center study.

PURPOSE: This study aimed to develop a postoperative MRI-based fibrosis scoring system and to assess its correlation with anorectal function in locally advanced rectal cancer (LARC) cases administered neoadjuvant chemoradiotherapy (nCRT). METHODS: Pathologically confirmed LARC cases administered nCRT and radical resection were assessed retrospectively. Based on postoperative magnetic resonance imaging (MRI) findings, anastomotic fibrosis score (AFS) and perirectal fibrosis score (PFS) were determined to evaluate the extent of fibrosis. The Wexner continence score for anorectal function was obtained 2 years postoperatively and assessed for correlation with MRI fibrosis scores. The cases were divided into 2 groups by the median Wexner score. Univariable and multivariable analyses were adopted for building a nomogram model, whose diagnostic performance was estimated by receiver operating characteristic (ROC) and decision curve analyses (DCA). RESULTS: Finally, 144 patients with LARC were included in cohort 1 (training set). 52 patients were enrolled in cohort 2 (external validation set). Spearman correlation analysis indicated that AFS and PFS were positively correlated with the Wexner score. Univariable and multivariable analyses revealed age, tumor height, AFS, and PFS were independent predictors of anorectal function. The nomogram model achieved a good diagnostic performance, with AUCs of 0.800 and 0.827 in the training and validation sets, respectively; its predicting value was also confirmed by DCA. CONCLUSION: The present study showed AFS and PFS derived from postoperative MRI are positively correlated with Wexner score. In addition, the new scoring system was effective in predicting anorectal function in LARC cases administered nCRT.

Colchicine protects against the development of experimental abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is characterized by at least 1.5-fold enlargement of the infrarenal aorta, a ruptured AAA is life-threatening. Colchicine is a medicine used to treat gout and familial Mediterranean fever, and recently, it was approved to reduce the risk of cardiovascular events in adult patients with established atherosclerotic disease. With an AAA mice model created by treatment with porcine pancreatic elastase (PPE) and ß-aminopropionitrile (BAPN), this work was designed to explore whether colchicine could protect against the development of AAA. Here, we showed that colchicine could limit AAA formation, as evidenced by the decreased total aortic weight per body weight, AAA incidence, maximal abdominal aortic diameter and collagen deposition. We also found that colchicine could prevent the phenotypic switching of vascular smooth muscle cells from a contractile to synthetic state during AAA. In addition, it was demonstrated that colchicine was able to reduce vascular inflammation, oxidative stress, cell pyroptosis and immune cells infiltration to the aortic wall in the AAA mice model. Finally, it was proved that the protective action of colchicine against AAA formation was mainly mediated by preventing immune cells infiltration to the aortic wall. In summary, our findings demonstrated that colchicine could protect against the development of experimental AAA, providing a potential therapeutic strategy for AAA intervention in the clinic.

Advanced Messaging Intervention for Medication Adherence and Clinical Outcomes Among Patients With Cancer: Randomized Controlled Trial.

BACKGROUND: Medication adherence is crucial for improving clinical outcomes in the treatment of patients with cancer. The lack of adherence and adverse drug reactions can reduce the effectiveness of cancer therapy including the quality of life. The commonly used intervention methods for medication adherence continue to evolve, and the age of fifth-generation (5G) messaging has arrived. OBJECTIVE: In this study, we conducted a prospective, pilot randomized controlled trial to evaluate the effect of 5G messaging on medication adherence and clinical outcomes among patients with cancer in China. METHODS: The research population was patients with nonsmall cell lung cancer undergoing pemetrexed chemotherapy who require regular folic acid (FA) and vitamin B12 supplements. The intervention and control groups were assigned to 5G messaging and second-generation (2G) messaging, respectively. The patients' medication adherence and quality of life were assessed at baseline and 1-month and 3-month time points. Moreover, the chemotherapy-related hematologic or nonhematologic toxicities, as well as the serum levels of FA and vitamin B12, were measured. RESULTS: Of the 567 patients assessed for eligibility between January and May 2021, a total of 154 (27.2%) patients were included. Overall, 80 were randomized to the control group and 74 to the intervention group. The odds of adherence in the 5G messaging intervention group were significantly higher than the control group at the 1-month (62/69, 90% vs 56/74, 76%; adjusted odds ratio 2.67, 95% CI 1.02-7.71) and 3-month (50/60, 83% vs 48/64, 75%; adjusted odds ratio 2.36, 95% CI 1.00-5.23) time points. Correspondingly, the FA and vitamin B12 serum levels of patients in the 5G messaging group were higher than those of the control group. Regarding hematologic toxicities, only the incidence of leukopenia in the intervention group was lower than that in the control group (25/80, 31% in the control group vs 12/74, 16% in the intervention group; P=.04). There were no differences in nonhematologic toxicities and quality of life between the 2 groups. CONCLUSIONS: In summary, we conclude that compared with conventional 2G text-based messaging, a 5G messaging intervention can better improve medication adherence and clinical outcome among patients with cancer. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200058188; https://www.chictr.org.cn/showproj.html?proj=164489.