Computed tomography-based radiomics diagnostic approach for differential diagnosis between early- and late-stage pancreatic ductal adenocarcinoma.

BACKGROUND: One of the primary reasons for the dismal survival rates in pancreatic ductal adenocarcinoma (PDAC) is that most patients are usually diagnosed at late stages. There is an urgent unmet clinical need to identify and develop diagnostic methods that could precisely detect PDAC at its earliest stages. AIM: To evaluate the potential value of radiomics analysis in the differentiation of early-stage PDAC from late-stage PDAC. METHODS: A total of 71 patients with pathologically proved PDAC based on surgical resection who underwent contrast-enhanced computed tomography (CT) within 30 d prior to surgery were included in the study. Tumor staging was performed in accordance with the 8th edition of the American Joint Committee on Cancer staging system. Radiomics features were extracted from the region of interest (ROI) for each patient using Analysis Kit software. The most important and predictive radiomics features were selected using Mann-Whitney U test, univariate logistic regression analysis, and minimum redundancy maximum relevance (MRMR) method. Random forest (RF) method was used to construct the radiomics model, and 10-times leave group out cross-validation (LGOCV) method was used to validate the robustness and reproducibility of the model. RESULTS: A total of 792 radiomics features (396 from late arterial phase and 396 from portal venous phase) were extracted from the ROI for each patient using Analysis Kit software. Nine most important and predictive features were selected using Mann-Whitney U test, univariate logistic regression analysis, and MRMR method. RF method was used to construct the radiomics model with the nine most predictive radiomics features, which showed a high discriminative ability with 97.7% accuracy, 97.6% sensitivity, 97.8% specificity, 98.4% positive predictive value, and 96.8% negative predictive value. The radiomics model was proved to be robust and reproducible using 10-times LGOCV method with an average area under the curve of 0.75 by the average performance of the 10 newly built models. CONCLUSION: The radiomics model based on CT could serve as a promising non-invasive method in differential diagnosis between early and late stage PDAC.

Eukaryotic initiation factor 3a promotes the development of diffuse large B-cell lymphoma through regulating cell proliferation.

BACKGROUND: One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. METHODS: RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients. Protein level of eIF3a was estimated by western blot and immunohistochemical. Next, DLBCL cells were transfected with lentiviral vector either eIF3a-knockdown or empty to assess the biological role of eIF3a. Then, samples were divided into 2 clusters based on eIF3a expression and differentially expressed genes (DEGs) were identified. Function enrichment and mutation analysis of DEGs were employed to detect potential biological roles. Moreover, we also applied pan-cancer and chemosensitivity analysis for deep exploration. RESULTS: eIF3a expression was found to be higher in DLBCL than healthy controls, which was associated with worse prognosis. The expression of eIF3a protein was significantly increased in DLBCL cell lines compared with peripheral blood mononuclear cells (PBMCs) from healthy donors. eIF3a knockdown inhibited the proliferation of DLBCL cells and the expression of proliferation-related proteins and increase cell apoptosis rate. Besides, 114 DEGs were identified which had a close linkage to cell cycle and tumor immune. eIF3a and DEGs mutations were found to be correlated to chemosensitivity and vital signal pathways. Pan-cancer analysis demonstrated that high eIF3a expression was associated with worse prognosis in several tumors. Moreover, eIF3a expression was found to be related to chemosensitivity of several anti-tumor drugs in DLBCL, including Vincristine and Wee1 inhibitor. CONCLUSIONS: We firstly revealed the high expression and prognostic role of eIF3a in DLBCL, and eIF3a might promote the development of DLBCL through regulating cell proliferation and apoptosis. eIF3a expression was related to immune profile and chemosensitivity in DLBCL. These results suggest that eIF3a could serve as a potential prognostic biomarker and therapeutic target in DLBCL.

Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3ß1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. METHODS: Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma. FINDINGS: We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3ß1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3ß1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy. CONCLUSIONS: Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy. FUNDING: This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).

Multimodal Imaging-Guided Photoimmunotherapy of Pancreatic Cancer by Organosilica Nanomedicine.

Immune checkpoint blockade (ICB) treatments have contributed to substantial clinical progress. However, challenges persist, including inefficient drug delivery and penetration into deep tumor areas, inadequate response to ICB treatments, and potential risk of inflammation due to over-activation of immune cells and uncontrolled release of cytokines following immunotherapy. In response, this study, for the first time, presents a multimodal imaging-guided organosilica nanomedicine (DCCGP) for photoimmunotherapy of pancreatic cancer. The novel DCCGP nanoplatform integrates fluorescence, magnetic resonance, and real-time infrared photothermal imaging, thereby enhancing diagnostic precision and treatment efficacy for pancreatic cancer. In addition, the incorporated copper sulfide nanoparticles (CuS NPs) lead to improved tumor penetration and provide external regulation of immunotherapy via photothermal stimulation. The synergistic immunotherapy effect is realized through the photothermal behavior of CuS NPs, inducing immunogenic cell death and relieving the immunosuppressive tumor microenvironment. Coupling photothermal stimulation with αPD-L1-induced ICB, the platform amplifies the clearance efficiency of tumor cells, achieving an optimized synergistic photoimmunotherapy effect. This study offers a promising strategy for the clinical application of ICB-based combined immunotherapy and presents valuable insights for applications of organosilica in precise tumor immunotherapy and theranostics.

Differential diagnostic value of tumor markers and contrast-enhanced computed tomography in gastric hepatoid adenocarcinoma and gastric adenocarcinoma.

Objective: This study aimed to investigate the effectiveness of tumor markers and contrast-enhanced computed tomography (CE-CT) in differentiating gastric hepatoid adenocarcinoma (GHA) from gastric adenocarcinoma (GA). Methods: This retrospective study included 160 patients (44 with GHA vs. 116 with GA) who underwent preoperative CE-CT. Preoperative serum concentrations of tumor biomarkers and CT imaging features were analyzed, including alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), tumor location, growth pattern, size, enhancement pattern, cystic changes, and mass contrast enhancement. Multivariate logistic regression analyses were performed to evaluate useful tumor markers and CT imaging features for differentiating GHA from GA. Results: When compared to GA, GHA showed a higher serum AFP [13.27 ng/ml (5.2-340.1) vs. 2.7 ng/ml (2.2-3.98), P <0.001] and CEA levels [4.07 ng/ml (2.73-12.53) vs. 2.42 ng/ml (1.38-4.31), P <0.001]. CT imaging showed GHA with a higher frequency of tumor location in the gastric antrum (P <0.001). GHA had significantly lower attenuation values at the portal venous phase [PCA, (82.34 HU ± 8.46 vs. 91.02 HU ± 10.62, P <0.001)] and delayed phase [DCA, (72.89 HU ± 8.83 vs. 78.27 HU ± 9.51, P <0.001)] when compared with GA. Multivariate logistic regression analyses revealed that tumor location, PCA, and serum AFP level were independent predictors of differentiation between GHA and GA. The combination of these three predictors performed well in discriminating GHA from GA, with an AUC of 0.903, a sensitivity of 86.36%, and a specificity of 81.90%. Conclusions: Integrated evaluation of tumor markers and CT features, including tumor location, PCA, and serum AFP, allowed for more accurate differentiation of GHA from GA.

Exploring the key genetic association between chronic pancreatitis and pancreatic ductal adenocarcinoma through integrated bioinformatics.

Background: Pancreatic ductal adenocarcinoma (PDAC) develops rapidly and has a poor prognosis. It has been demonstrated that pancreatic ductal adenocarcinoma and chronic pancreatitis (CP) have a close connection. However, the underlying mechanisms for chronic pancreatitis transforming into pancreatic ductal adenocarcinoma are still unclear. The purpose of this study was to identify real hub genes in the development of chronic pancreatitis and pancreatic ductal adenocarcinoma. Methods: RNA-seq data of chronic pancreatitis and pancreatic ductal adenocarcinoma were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between chronic pancreatitis and pancreatic ductal adenocarcinoma. GEO2R and a Venn diagram were used to identify differentially expressed genes. Then visualized networks were constructed with ClueGO, and modules of PPI network were calculated by MCODE plugin. Further validation of the results was carried out in two additional cohorts. Analyses of CEL-coexpressed genes and regulators including miRNAs and transcription factors were performed by using the corresponding online web tool. Finally, the influence of CEL in the tumor immune microenvironment (TIME) was assessed by immune contextual analysis. Results: With the help of WGCNA and GEO2R, four co-expression modules and six hub genes were identified, respectively. ClueGO enrichment analysis and MCODE cluster analysis revealed that the dysfunctional transport of nutrients and trace elements might contribute to chronic pancreatitis and pancreatic ductal adenocarcinoma development. The real hub gene CEL was identified with a markedly low expression in pancreatic ductal adenocarcinoma in external validation sets. According to the miRNA-gene network construction, hsa-miR-198 may be the key miRNA. A strong correlation exists between CEL and TIME after an evaluation of the influence of CEL in TIME. Conclusion: Our study revealed the dysfunctional transport of nutrients and trace elements may be common pathogenesis of pancreatic ductal adenocarcinoma and chronic pancreatitis. Examination on these common pathways and real hub genes may shed light on the underlying mechanism.

Cuproptosis-related risk score based on machine learning algorithm predicts prognosis and characterizes tumor microenvironment in head and neck squamous carcinomas.

Cuproptosis is a recently discovered type of programmed cell death that shows significant potential in the diagnosis and treatment of cancer. It has important significance in the prognosis of HSNC. This study aims to construct a cuproptosis-related prognostic model and risk score through new data analysis methods such as machine learning algorithms for the prognosis analysis of HSNC. Protein-protein interaction network and machine learning methods were employed to identify hub genes that were used to construct a TreeGradientBoosting model for predicting overall survival. The relationship between the risk scores obtained from the model and features such as tumor microenvironment (TME) and tumor immunity was explored. The C-indexes of the TreeGradientBoosting model in the training and validation cohorts were 0.776 and 0.848, respectively. The nomogram based on risk scores and clinical features showed good performance, and distinguished the TME and immunity between high-risk and low-risk groups. The cuproptosis-associated risk score can be used to predict prognoses, TME, and tumor immunity of HNSC patients.

Diagnostic accuracy of apparent diffusion coefficient to differentiate intrapancreatic accessory spleen from pancreatic neuroendocrine tumors.

BACKGROUND: Intrapancreatic accessory spleen (IPAS) shares similar imaging findings with hypervascular pancreatic neuroendocrine tumors (PNETs), which may lead to unnecessary surgery. AIM: To investigate and compare the diagnostic performance of absolute apparent diffusion coefficient (ADC) and normalized ADC (lesion-to-spleen ADC ratios) in the differential diagnosis of IPAS from PNETs. METHODS: A retrospective study consisting of 29 patients (16 PNET patients vs 13 IPAS patients) who underwent preoperative contrast-enhanced magnetic resonance imaging together with diffusion-weighted imaging/ADC maps between January 2017 and July 2020 was performed. Two independent reviewers measured ADC on all lesions and spleens, and normalized ADC was calculated for further analysis. The receiver operating characteristics analysis was carried out for evaluating the diagnostic performance of both absolute ADC and normalized ADC values in the differential diagnosis between IPAS and PNETs by clarifying sensitivity, specificity, and accuracy. Inter-reader reliability for the two methods was evaluated. RESULTS: IPAS had a significantly lower absolute ADC (0.931 ± 0.773 × 10-3 mm2/s vs 1.254 ± 0.219 × 10-3 mm2/s) and normalized ADC value (1.154 ± 0.167 vs 1.591 ± 0.364) compared to PNET. A cutoff value of 1.046 × 10-3 mm2/s for absolute ADC was associated with 81.25% sensitivity, 100% specificity, and 89.66% accuracy with an area under the curve of 0.94 (95% confidence interval: 0.8536-1.000) for the differential diagnosis of IPAS from PNET. Similarly, a cutoff value of 1.342 for normalized ADC was associated with 81.25% sensitivity, 92.31% specificity, and 86.21% accuracy with an area under the curve of 0.91 (95% confidence interval: 0.8080-1.000) for the differential diagnosis of IPAS from PNET. Both methods showed excellent inter-reader reliability with intraclass correlation coefficients for absolute ADC and ADC ratio being 0.968 and 0.976, respectively. CONCLUSION: Both absolute ADC and normalized ADC values can facilitate the differentiation between IPAS and PNET.

Based on network pharmacology to explore the effect and mechanism of Yipibushen decoction in improving obese type 2 diabetes mellitus with oligoasthenotspermia.

ETHNOPHARMACOLOGICAL RELEVANCE: A traditional Chinese medicine experience compound known as Yipibushen (YPBS) decoction stimulates qi and nourishes yin, stimulates the kidney and solid essence, dissolves phlegm and eliminates stasis. YPBS decoction has proven to be successful in treating obese type 2 diabetes mellitus with oligoasthenotspermia in clinical settings. Nevertheless, the pharmacological mechanism is not understood. AIM OF THE STUDY: Investigating the mechanism of action of YPBS decoction in enhancing the obese type 2 diabetes mellitus with oligoasthenotspermia involved network pharmacology and animal validation techniques. METHODS AND MATERIALS: The YPBS Decoction' active components were found in the TCMSP database and their targets were identified using UniProtKB. Additionally, targets for the obese type 2 diabetes mellitus with oligoasthenotspermia were found in the GeneCard, DisGeNet, TTD and OMIM databases. The intersection of active ingredients, the obese type 2 diabetes mellitus with oligoasthenotspermia was chosen as the intersection target. The protein-protein interaction (PPI) network of the intersection target was built with the aid of Cytoscape 3.9.1, the core target of PPI was obtained through software analysis in R-project, GO enrichment and KEGG enrichment analysis was carried out on the core target. Finally, animal experiments were used to verify the intersection target. RESULTS: The research revealed 74 intersection targets of YPBS decoction active ingredients in the obese type 2 diabetes mellitus with oligoasthenotspermia. There were also 18 PPI core targets, GO enrichment analysis of PPI core targets involving response to oxidative stress, membrane raft, DNA-binding transcription regulator complex and other biological processes; KEGG involving endocrine resistance, PI3K/AKT signaling pathway, apoptosis and other signal pathways. In the obese type 2 diabetes mellitus with oligoasthenotspermia mice, animal studies have shown that YPBS decoction group could decrease blood glucose levels and improve insulin resistance; improve testicular function, enhance sperm count, sperm motility, sperm viability, and decrease the malformation rate. It could increase the levels of T-SOD and GSH-Px, and decrease the MDA level. In addition to this, it could improve the amount of testosterone hormone, and enhance the expression of PI3K, p-AKT and Bcl-2. CONCLUSION: By controlling the degree of oxidative stress and the PI3K/AKT/Bcl-2 pathway, YPBS decoction may enhance the obese type 2 diabetes mellitus with Oligoasthenotspermia, provide a scientific basis for clinical diagnosis and therapy.

Untargeted metabolomics characterization of the resectable pancreatic ductal adenocarcinoma.

Background: Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is difficult due to the lack of specific symptoms and screening methods. Only less than 10% of PDAC patients are candidates for surgery at the time of diagnosis. Thus, there is a great global unmet need for valuable biomarkers that could improve the opportunity to detect PDAC at the resectable stage. This study aimed to develop a potential biomarker model for the detection of resectable PDAC by tissue and serum metabolomics. Methods: Ultra-high-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS) was performed for metabolome quantification in 98 serum samples (49 PDAC patients and 49 healthy controls (HCs)) and 20 pairs of matched pancreatic cancer tissues (PCTs) and adjacent noncancerous tissues (ANTs) from PDAC patients. Univariate and multivariate analyses were used to profile the differential metabolites between PDAC and HC. Results: A total of 12 differential metabolites were present in both serum and tissue samples of PDAC. Among them, a total of eight differential metabolites showed the same expressional levels, including four upregulated and four downregulated metabolites. Finally, a panel of three metabolites including 16-hydroxypalmitic acid, phenylalanine, and norleucine was constructed by logistic regression analysis. Notably, the panel was capable of distinguishing resectable PDAC from HC with an AUC value of 0.942. Additionally, a multimarker model based on the 3-metabolites-based panel and CA19-9 showed a better performance than the metabolites panel or CA19-9 alone (AUC: 0.968 vs. 0.942, 0.850). Conclusions: Taken together, the resectable early-stage PDAC has unique metabolic features in serum and tissue samples. The defined panel of three metabolites has the potential value for early screening of PDAC at the resectable stage.

A Gold Nanocage Probe Targeting Survivin for the Diagnosis of Pancreatic Cancer.

In this paper, Au nanocages (AuNCs) loaded with the MRI contrast agent gadolinium (Gd) and capped with the tumor-targeting gene survivin (Sur-AuNC•Gd-Cy7 nanoprobes) were designed and applied as a targeted imaging agent for pancreatic cancer. With its capacity to transport fluorescent dyes and MR imaging agents, the gold cage is an outstanding platform. Furthermore, it has the potential to transport different drugs in the future, making it a unique carrier platform. The utilization of Sur-AuNC•Gd-Cy7 nanoprobes has proven to be an effective means of targeting and localizing survivin-positive BxPC-3 cells within their cytoplasm. By targeting survivin, an antiapoptotic gene, the Sur-AuNC•Gd-Cy7 nanoprobe was able to induce pro-apoptotic effects in BxPC-3 pancreatic cancer cells. The biocompatibility of AuNCs•Gd, AuNCs•Gd-Cy7 nanoparticles, and Sur-AuNC•Gd-Cy7 nanoprobes is evaluated through the hemolysis rate assay. The stability of AuNCs•Gd, AuNCs•Gd-Cy7 nanoparticles, and Sur-AuNC•Gd-Cy7 nanoprobes was evaluated by determining their hydrodynamic dimensions following storage in different pH solutions for a corresponding duration. Excellent biocompatibility and stability of the Sur-AuNC•Gd-Cy7 nanoprobes will facilitate their further utilization in vivo and in vitro. The surface-bound survivin plays a role in facilitating the Sur-AuNC•Gd-Cy7 nanoprobes' ability to locate the BxPC-3 tumor. The probe was modified to incorporate Gd and Cy7, thereby enabling the simultaneous utilization of magnetic resonance imaging (MRI) and fluorescence imaging (FI) techniques. In vivo, the Sur-AuNC•Gd-Cy7 nanoprobes were found to effectively target and localize survivin-positive BxPC-3 tumors through the use of MRI and FI. After being injected via the caudal vein, the Sur-AuNC•Gd-Cy7 nanoprobes were found to accumulate effectively in an in situ pancreatic cancer model within 24 h. Furthermore, these nanoprobes were observed to be eliminated from the body through the kidneys within 72 h after a single injection. This characteristic is crucial for a diagnostic agent. Based on the aforementioned outcomes, the Sur-AuNC•Gd-Cy7 nanoprobes have significant potential advantages for the theranostic treatment of pancreatic cancer. This nanoprobe possesses distinctive characteristics, such as advanced imaging abilities and specific drug delivery, which offer the possibility of enhancing the precision of diagnosis and efficacy of treatment for this destructive illness.

Biomimetic Gold Nanorods Modified with Erythrocyte Membranes for Imaging-Guided Photothermal/Gene Synergistic Therapy.

Pancreatic cancer (PC) is one of the most malignant cancers that develops rapidly and carries a poor prognosis. Synergistic cancer therapy strategy could enhance the clinical efficacy compared to either treatment alone. In this study, gold nanorods (AuNRs) were used as siRNA delivery vehicles to interfere with the oncogenes of KRAS. In addition, AuNRs were one of anisotropic nanomaterials that can absorb near-infrared (NIR) laser and achieve rapid photothermal therapy for malignant cancer cells. Modification of the erythrocyte membrane and antibody Plectin-1 occurred on the surface of the AuNRs, making them a promising target nanocarrier for enhancing antitumor effects. As a result, biomimetic nanoprobes presented advantages in biocompatibility, targeting capability, and drug-loading efficiency. Moreover, excellent antitumor effects have been achieved by synergistic photothermal/gene treatment. Therefore, our study would provide a general strategy to construct a multifunctional biomimetic theranostic multifunctional nanoplatform for preclinical studies of PC.

Threshold of Main Pancreatic Duct Diameter in Identifying Malignant Intraductal Papillary Mucinous Neoplasm by Magnetic Resonance Imaging.

Objective: Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic lesion. The identification of malignancy is critical for the establishment of treatment strategies. Main pancreatic duct (MPD) diameter is one critical feature for malignant IPMNs. However, the threshold of 1.0 cm is challenged. In this study, we explored independent risk factors and further calculated the threshold of MPD in identifying malignant IPMNs. Method: A total of 151 IPMN patients were included in this retrospective study. Demographic information, clinicopathological features, laboratory testing, and preoperative radiological characteristics by magnetic resonance imaging were collected. The receiver operating characteristic (ROC) curves were performed to determine the MPD diameter's cutoff levels and evaluate the predicted factors' diagnostic ability. Results: A cutoff value of 0.77 cm MPD (an area under the curve (AUC) = 0.746) in all IPMNs and 0.82 cm (AUC = 0.742) in the main duct involved IPMNs was obtained. MPD diameter (odds ratio (OR), 12.67; 95% confidence interval (CI), 4.80-33.48) and the mural nodule (OR, 12.98; 95% CI, 3.18-52.97) were the independent associated factors with high-risk IPMNs. The combined model with MPD and mural nodule showed a better predictive performance than mural nodule or MPD diameter alone (AUC = 0.803 vs 0.619, 0.746). A nomogram was developed and showed good performance (C index = 0.803). Conclusion: Our data show that mural nodule and MPD diameter are independent risk factors in identifying malignant intraductal papillary mucinous neoplasms. A cutoff value of 0.77 cm of MPD diameter may be a threshold value in identifying malignant intraductal papillary mucinous neoplasms or undergoing surgical resection.

Reversing Immune Suppression and Potentiating Photothermal Immunotherapy via Bispecific Immune Checkpoint Inhibitor Loaded Hollow Polydopamine Nanospheres.

Despite the great achievements of immune checkpoint blockade (ICB) therapy on programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis, ICB monotherapy still faces obstacles in eradicating solid tumors due to the lack of tumor-associated antigens or tumor-specific cytotoxicity. Photothermal therapy (PTT) is a potential therapeutic modality because it can noninvasively kill tumor cells by thermal ablation and generate both tumor-specific cytotoxicity and immunogenicity, which holds great feasibility to improve the efficiency of ICB by providing complementary immunomodulation. Except for the PD-1/PD-L1 axis, the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRPα) pathway has been considered as a novel strategy of tumor cells to evade the surveillance of macrophages and inactivate the immune response of PD-L1 blockade therapy. Therefore, it is necessary to synergize the antitumor effect of dual-targeting PD-L1 and CD47. Although promising, the application of PD-L1/CD47 bispecific antibodies, especially in combination with PTT, remains a formidable problem, due to the low objective response, activity loss at relatively high temperature, or nonvisualization. Herein, instead of using antibodies, we use MK-8628 (MK) to down-regulate both PD-L1 and CD47 simultaneously through halting the active transcription of oncogene c-MYC, leading to elicitation of the immune response. The hollow polydopamine (HPDA) nanospheres are introduced as a biocompatible nanoplatform with high loading capacity and magnetic resonance imaging (MRI) ability to deliver MK and induce PTT (HPDA@MK). Compared to preinjection, HPDA@MK exhibits the strongest MRI signal at 6 h postintravenous injection to guide the precise combined treatment time. However, due to the local delivery and controlled release of inhibitors, HPDA@MK down-regulates c-MYC/PD-L1/CD47, promotes the activation and recruitment of cytotoxic T cells, regulates the M2 macrophages polarization in tumor sites, and especially boosts the combined therapeutic efficacy. Collectively, our work presents a simple but distinctive approach for c-MYC/PD-L1/CD47-targeted immunotherapy combined with PTT that may provide a desirable and feasible strategy for the treatment of other clinical solid tumors.

Metformin improves polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis.

Background and objective: PCOS is a common metabolic disorder in women of reproductive age, which pathogenesis is very complex. The role of ferroptosis in PCOS is a novel finding, and the mechanistic studies are not clear. Metformin is a commonly used drug of PCOS but few studies on whether metformin can improve the follicle development and ovarian function in PCOS. We aims to use PCOS mouse model to study the effect of metformin on PCOS based on the ovarian function and explored the regulation of metformin in PCOS mice by intervening in ferroptosis pathway. Materials and methods: C57 BL/6J female mice aged 4-5 weeks were purchased and gavaged with letrozole (1 mg/kg/day) combined with high-fat diet for 21days to establish PCOS model, and control group was set up. After modeling, the mice were divided into PCOS model group and metformin treatment group (Met) (n=6).The Met group were gavaged metformin (200 mg/kg/day) for 28 days. The body weight, estrous cycle, glucose tolerance test (OGTT)and insulin resistance test (ITT) were monitored. Then, The mice were euthanized to collect serum and ovaries. Elisa was used to detect changes in related serum hormones (E2, LH, FSH, TP). Ovaries used for molecular biology experiments to detect changes in GPX4, SIRT3, AMPK/p-AMPK, and mTOR/p-mTOR by Western blot and qPCR. Results: Compared with the model group mice, body weight was significantly reduced, and their estrous cycle was restored in Met group. The results of OGTT and ITT showed an improvment of glucose tolerance and insulin resistance. Morphological results showed that after metformin treatment, polycystic lesions in ovaries were reduced, the ovarian function was restored, and the expressions of SIRT3 and GPX4 were elevated. WB results demonstrated that the expressions of p-mTOR and p-AMPK in ovaries were significantly reduced in Model group, but reversed in MET group. Conclusion: Our study confirmed metformin could not only improve body weight and metabolism disorders, but also improve ovarian dysfunction in PCOS mice.In addition, we explored metformin could regulate ferroptosis to improve PCOS via the SIRT3/AMPK/mTOR pathway. Our study complements the mechanisms by which metformin improves PCOS.

Biomarkers for pancreatic cancer based on tissue and serum metabolomics analysis in a multicenter study.

BACKGROUND: Early detection of pancreatic ductal adenocarcinoma (PDAC) may improve the prognosis of patients. This study was to identify metabolic features of PDAC and to discover early detection biomarkers for PDAC by tissue and serum metabolomics analysis. METHODS: We conducted nontargeted metabolomics analysis in tissue samples of 51 PDAC tumors, 40 noncancerous pancreatic tissues (NT), and 14 benign pancreatic neoplasms (BP) as well as serum samples from 80 patients with PDAC, 36 with BP, and 48 healthy controls (Ctr). The candidate metabolites identified from the initial analysis were further quantified using targeted analysis in serum samples of an independent cohort of 22 early stage PDAC, 27 BP, and 27 Ctr subjects. Unconditional binary logistic regression analysis was used to construct the optimal model for PDAC diagnosis. RESULTS: Upregulated levels of fatty acids and lipids and downregulated amino acids were observed in tissue and serum samples of PDAC patients. Proline, creatine, and palmitic acid were identified as a panel of potential biomarkers to distinguish PDAC from BP and Ctr (odds ratio = 2.17, [95% confidence interval 1.34-3.53]). The three markers showed area under the receiver-operating characteristic curves (AUCs) of 0.854 and 0.865, respectively, for the comparison of PDAC versus Ctr and PDAC versus BP. The AUCs were 0.830 and 0.852 in the validation set and were improved to 0.949 and 0.909 when serum carbohydrate antigen 19-9 (CA19-9) was added to the model. CONCLUSION: The novel metabolite biomarker panel identified in this study exhibited promising performance in distinguishing PDAC from BP or Ctr, especially in combination with CA19-9.

Periurethral and Intravenous Injections of Adipose-Derived Stem Cells to Promote Local Tissue Recovery in a Rat Model of Stress Urinary Incontinence.

OBJECTIVE: To compare the effects of periurethral and intravenous injection of adipose-derived stem cells (ADSCs) on voiding function and tissue recovery in a stress urinary incontinence (SUI) rat model. METHODS: Sixty-four postpartum rats were randomly allocated to a normal group and the SUI model was established in 48 rats by vagina balloon dilation and bilateral ovariectomy. The SUI rats were randomized into 3 groups and received urethral injection of PBS (SUI group), periurethral injection of ADSCs (PU group), and intravenous injection of ADSCs (IV group) in 10 days after the ovariectomy. After 1, 7, and 14 days, ADSCs were tracked in urethra specimen. The urinary function of the remaining rats was analyzed at day 28, and urethral tissues were harvested for Western blotting and histochemical analyses. RESULTS: Alpha smooth muscle actin, myosin heavy chain, vascular endothelial growth factor, and neurofilament protein expression was increased in the IV and PU groups. Voiding function was also improved, with no significant differences between the IV and PU groups. The cell retention rate in rat urethral tissues was higher in the PU group than that in the IV group. Compared with the IV group, myosin heavy chain, vascular endothelial growth factor, neurofilament and transforming growth factor-ß1 (TGF-ß1)/Smad pathway protein expression levels were significantly higher in the PU group, while alpha smooth muscle actin expression was significantly lower (P < .05). CONCLUSION: Periurethral and intravenous injection of ADSCs induces different degrees of recovery of the urethral sphincter, cytokine secretion levels and cell retention rates in the urethral tissues in SUI rats, however, there was no significant difference in 2 methods.

Partial Restoration of Spinal Cord Neural Continuity via Sural Nerve Transplantation Using a Technique of Spinal Cord Fusion.

BACKGROUND: Spinal cord injury (SCI) can cause paralysis and serious chronic morbidity, and there is no effective treatment. Based on our previous experimental results of spinal cord fusion (SCF) in mice, rats, beagles, and monkeys, we developed a surgical protocol of SCF for paraplegic human patients. We designed a novel surgical procedure of SCF, called sural nerve transplantation (SNT), for human patients with lower thoracic SCI and distal cord dysfunction. METHODS: We conducted a clinical trial (ChiCTR2000030788) and performed SNT in 12 fully paraplegic patients due to SCI between T1 and T12. We assessed pre- and postoperative central nerve pain, motor function, sensory function, and autonomic nerve function. Conduction of action potentials across the sural nerve transplant was evaluated. Neural continuity was also examined by diffusion tensor imaging (DTI). RESULTS: Among the 12 paraplegic patients enrolled in this clinical trial, seven patients demonstrated improved autonomic nerve functions. Seven patients had clinically significant relief of their symptoms of cord central pain. One patient, however, developed postoperative cord central pain (VAS: 4). Five patients had varying degrees of recovered sensory and/or motor functions below the single neurologic level 1 month after surgery. One patient showed recovery of electrophysiologic, motor-evoked potentials 6 months after the operation. At 6 months after surgery, DTI indicated fusion and nerve connections of white cord and sural nerves in seven patients. CONCLUSION: SNT was able to fuse the axonal stumps of white cord and sural nerve and at least partially improve the cord central pain in most patients. Although SNT did not restore the spinal cord continuity in white matter in some patients, SNT could restore spinal cord continuity in the cortico-trunco-reticulo-propriospinal pathway, thereby restoring in part some motor and sensory functions. SNT may therefore be a safe, feasible, and effective method to treat paraplegic patients with SCI. Future clinical trials should be performed to optimize the type/technique of nerve transplantation, reduce surgical damage, and minimize postoperative scar formation and adhesion, to avoid postoperative cord central pain. CLINICAL TRIAL REGISTRATION: [http://www.chictr.org.cn/showproj.aspx?proj=50526], identifier [ChiCTR2000030788].