Squalene-epoxidase-catalyzed 24(S),25-epoxycholesterol synthesis promotes trained-immunity-mediated antitumor activity.

The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for ß-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity.

NRPS-like ATRR in Plant-Parasitic Nematodes Involved in Glycine Betaine Metabolism to Promote Parasitism.

Plant-parasitic nematodes (PPNs) are among the most serious phytopathogens and cause widespread and serious damage in major crops. In this study, using a genome mining method, we identified nonribosomal peptide synthetase (NRPS)-like enzymes in genomes of plant-parasitic nematodes, which are conserved with two consecutive reducing domains at the N-terminus (A-T-R1-R2) and homologous to fungal NRPS-like ATRR. We experimentally investigated the roles of the NRPS-like enzyme (MiATRR) in nematode (Meloidogyne incognita) parasitism. Heterologous expression of Miatrr in Saccharomyces cerevisiae can overcome the growth inhibition caused by high concentrations of glycine betaine. RT-qPCR detection shows that Miatrr is significantly upregulated at the early parasitic life stage (J2s in plants) of M. incognita. Host-derived Miatrr RNA interference (RNAi) in Arabidopsis thaliana can significantly decrease the number of galls and egg masses of M. incognita, as well as retard development and reduce the body size of the nematode. Although exogenous glycine betaine and choline have no obvious impact on the survival of free-living M. incognita J2s (pre-parasitic J2s), they impact the performance of the nematode in planta, especially in Miatrr-RNAi plants. Following application of exogenous glycine betaine and choline in the rhizosphere soil of A. thaliana, the numbers of galls and egg masses were obviously reduced by glycine betaine but increased by choline. Based on the knowledge about the function of fungal NRPS-like ATRR and the roles of glycine betaine in host plants and nematodes, we suggest that MiATRR is involved in nematode-plant interaction by acting as a glycine betaine reductase, converting glycine betaine to choline. This may be a universal strategy in plant-parasitic nematodes utilizing NRPS-like ATRR to promote their parasitism on host plants.

Combination of DCE-MRI and NME-DWI via Deep Neural Network for Predicting Breast Cancer Molecular Subtypes.

BACKGROUND: To explore whether the combination of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and nonmono-exponential (NME) model-based diffusion-weighted imaging (DWI) via deep neural network (DNN) can improve the prediction of breast cancer molecular subtypes compared to either imaging technique used alone. PATIENTS AND METHODS: This prospective study examined 480 breast cancers in 475 patients undergoing DCE-MRI and NME-DWI at 3.0 T. Breast cancers were classified as follows: human epidermal growth factor receptor 2 enriched (HER2-enriched), luminal A, luminal B (HER2-), luminal B (HER2+), and triple-negative subtypes. A total of 20% cases were withheld as an independent test dataset, and the remaining cases were used to train DNN with an 80% to 20% training-validation split and 5-fold cross-validation. The diagnostic accuracies of DNN in 5-way subtype classification between the DCE-MRI, NME-DWI, and their combined multiparametric-MRI datasets were compared using analysis of variance with least significant difference posthoc test. Areas under the receiver-operating characteristic curves were calculated to assess the performances of DNN in binary subtype classification between the 3 datasets. RESULTS: The 5-way classification accuracies of DNN on both DCE-MRI (0.71) and NME-DWI (0.64) were significantly lower (P < .05) than on multiparametric-MRI (0.76), while on DCE-MRI was significantly higher (P < .05) than on NME-DWI. The comparative results of binary classification between the 3 datasets were consistent with the 5-way classification. CONCLUSION: The combination of DCE-MRI and NME-DWI via DNN achieved a significant improvement in breast cancer molecular subtype prediction compared to either imaging technique used alone. Additionally, DCE-MRI outperformed NME-DWI in differentiating subtypes.

Effect of butylphthalide combined with idebenone on vascular dementia: A retrospective observational analysis.

To explore the efficacy and safety of butylphthalide combined with idebenone in the treatment of vascular dementia. The clinical data of 126 patients with vascular dementia who were admitted to our hospital between March 2021 and February 2023 were retrospectively reviewed. Among them, 62 patients received butylphthalide alone (single group) and 64 patients received butylphthalide combined with idebenone (combined group). Cognitive function scores, serum inflammatory factor levels, oxidative stress index levels, and incidence of adverse reactions were compared between the 2 groups before and after treatment. After treatment, the Hasegawa Dementia Scale, Mini Mental State Examination Scale, and activities of daily living scores in both groups were higher than before treatment, and the scores in the combined group were higher than before treatment (P < .05). After treatment, the levels of serum C-reactive protein, tumor necrosis factor-α, and interleukin 6 in both groups were lower than those before treatment, and those in the combined group were lower than those in the simple group (P < .05). After treatment, the levels of serum glutathione peroxidase and superoxide dismutase in the 2 groups were higher than those before treatment, and the level of malondialdehyde was lower than that before treatment. The levels of serum glutathione peroxidase and superoxide dismutase in the combined group were higher than those in the simple group, and the level of malondialdehyde was lower than that in the simple group (P < .05). There was no significant difference in the incidence of adverse reactions between the combined group (6.25%) and the simple group (3.23%) (P > .05). Compared with butylphthalide alone, intervention of butylphthalide combined with idebenone on vascular dementia can effectively reduce the degree of inflammatory and oxidative stress reactions, improve cognitive function, and promote the ability to perform activities of daily living in a safe manner.

Identification of cuproptosis-related lncRNAs signature for predicting the prognosis in patients with kidney renal clear cell carcinoma.

BACKGROUND: Kidney renal clear cell carcinoma (KIRC), with low survival rate, is the most frequent subtype of renal cell carcinoma. Recently, more and more studies indicate that cuproptosis-related genes (CRGs) and long non-coding RNAs (lncRNAs) play a vital role in the occurrence and development of many types of cancers. However, the roles of cuproptosis-related lncRNAs (CRlncRNAs) in the KIRC was uncertain. RESULTS: In our study, CRlncRNAs were obtained by coexpression between differentially expressed and prognostic CRGs and differentially expressed and prognostic lncRNAs, and an 8-CRlncRNAs (AC007743.1, AC022915.1, AP005136.4, APCDD1L-DT, HAGLR, LINC02027, MANCR and SMARCA5-AS1) risk model was established according to least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression. This risk model could differentiate immune cell infiltration, immune function and gene mutation. CONCLUSIONS: This 8-CRlncRNAs risk model may be promising for the clinical prediction of prognoses, tumor immune, immunotherapy response and chemotherapeutic response in KIRC patients.

Clinical prediction of microvascular invasion in hepatocellular carcinoma using an MRI-based graph convolutional network model integrated with nomogram.

OBJECTIVES: Based on enhanced MRI, a prediction model of microvascular invasion (MVI) for hepatocellular carcinoma (HCC) was developed using graph convolutional network (GCN) combined nomogram. METHODS: We retrospectively collected 182 HCC patients confirmed histopathologically, all of them performed enhanced MRI before surgery. The patients were randomly divided into training and validation groups. Radiomics features were extracted from the arterial phase (AP), portal venous phase (PVP), and delayed phase (DP), respectively. After removing redundant features, the graph structure by constructing the distance matrix with the feature matrix was built. Screening the superior phases and acquired GCN Score (GS). Finally, combining clinical, radiological and GS established the predicting nomogram. RESULTS: 27.5% (50/182) patients were with MVI positive. In radiological analysis, intratumoural artery (P = 0.007) was an independent predictor of MVI. GCN model with grey-level cooccurrence matrix-grey-level run length matrix features exhibited area under the curves of the training group was 0.532, 0.690, and 0.885 and the validation group was 0.583, 0.580, and 0.854 for AP, PVP, and DP, respectively. DP was selected to develop final model and got GS. Combining GS with diameter, corona enhancement, mosaic architecture, and intratumoural artery constructed a nomogram which showed a C-index of 0.884 (95% CI: 0.829-0.927). CONCLUSIONS: The GCN model based on DP has a high predictive ability. A nomogram combining GS, clinical and radiological characteristics can be a simple and effective guiding tool for selecting HCC treatment options. ADVANCES IN KNOWLEDGE: GCN based on MRI could predict MVI on HCC.

Mrc1+ macrophage-derived IGF1 mitigates crystal nephropathy by promoting renal tubule cell proliferation via the AKT/Rb signaling pathway.

Rationale: The present understanding of the cellular characteristics and communications in crystal nephropathy is limited. Here, molecular and cellular studies combined with single-cell RNA sequencing (scRNA-seq) were performed to investigate the changes in cell components and their interactions in glyoxylate-induced crystallized kidneys to provide promising treatments for crystal nephropathy. Methods: The transcriptomes of single cells from mouse kidneys treated with glyoxylate for 0, 1, 4, or 7 days were analyzed via 10× Genomics, and the single cells were clustered and characterized by the Seurat pipeline. The potential cellular interactions between specific cell types were explored by CellChat. Molecular and cellular findings related to macrophage-to-epithelium crosstalk were validated in sodium oxalate (NaOx)-induced renal tubular epithelial cell injury in vitro and in glyoxylate-induced crystal nephropathy in vivo. Results: Our established scRNA atlas of glyoxylate-induced crystalline nephropathy contained 15 cell populations with more than 40000 single cells, including relatively stable tubular cells of different segments, proliferating and injured proximal tubular cells, T cells, B cells, and myeloid and mesenchymal cells. In this study, we found that Mrc1+ macrophages, as a subtype of myeloid cells, increased in both the number and percentage within the myeloid population as crystal-induced injury progresses, and distinctly express IGF1, which induces the activation of a signal pathway to dominate a significant information flow towards injured and proliferating tubule cells. IGF1 promoted the repair of damaged tubular epithelial cells induced by NaOx in vitro, as well as the repair of damaged tubular epithelial cells and the recovery of disease outcomes in glyoxylate-induced nephrolithic mice in vivo. Conclusion: After constructing a cellular atlas of glyoxylate-induced crystal nephropathy, we found that IGF1 derived from Mrc1+ macrophages attenuated crystal nephropathy through promoting renal tubule cell proliferation via the AKT/Rb signaling pathway. These findings could lead to the identification of potential therapeutic targets for the treatment of crystal nephropathy.

Analysis of complete hydatidiform mole in one twin using traditional and molecular techniques.

A pregnant woman with hydatidiform mole in one twin was misdiagnosed as one of the twins with embryonic arrest. She chose to terminate the pregnancy and developed distant lung metastasis. After chemotherapy, she eventually recovered. This article systematically analyzes the diagnosis and treatment of hydatidiform mole in one twin to increase the awareness and reduce misdiagnosis of the disease.

A Channel-Dimensional Feature-Reconstructed Deep Learning Model for Predicting Breast Cancer Molecular Subtypes on Overall b-Value Diffusion-Weighted MRI.

BACKGROUND: Dynamic contrast-enhanced (DCE) MRI commonly outperforms diffusion-weighted (DW) MRI in breast cancer discrimination. However, the side effects of contrast agents limit the use of DCE-MRI, particularly in patients with chronic kidney disease. PURPOSE: To develop a novel deep learning model to fully exploit the potential of overall b-value DW-MRI without the need for a contrast agent in predicting breast cancer molecular subtypes and to evaluate its performance in comparison with DCE-MRI. STUDY TYPE: Prospective. SUBJECTS: 486 female breast cancer patients (training/validation/test: 64%/16%/20%). FIELD STRENGTH/SEQUENCE: 3.0 T/DW-MRI (13 b-values) and DCE-MRI (one precontrast and five postcontrast phases). ASSESSMENT: The breast cancers were divided into four subtypes: luminal A, luminal B, HER2+, and triple negative. A channel-dimensional feature-reconstructed (CDFR) deep neural network (DNN) was proposed to predict these subtypes using pathological diagnosis as the reference standard. Additionally, a non-CDFR DNN (NCDFR-DNN) was built for comparative purposes. A mixture ensemble DNN (ME-DNN) integrating two CDFR-DNNs was constructed to identify subtypes on multiparametric MRI (MP-MRI) combing DW-MRI and DCE-MRI. STATISTICAL TESTS: Model performance was evaluated using accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). Model comparisons were performed using the one-way analysis of variance with least significant difference post hoc test and the DeLong test. P < 0.05 was considered significant. RESULTS: The CDFR-DNN (accuracies, 0.79 ~ 0.80; AUCs, 0.93 ~ 0.94) demonstrated significantly improved predictive performance than the NCDFR-DNN (accuracies, 0.76 ~ 0.78; AUCs, 0.92 ~ 0.93) on DW-MRI. Utilizing the CDFR-DNN, DW-MRI attained the predictive performance equal (P = 0.065 ~ 1.000) to DCE-MRI (accuracies, 0.79 ~ 0.80; AUCs, 0.93 ~ 0.95). The predictive performance of the ME-DNN on MP-MRI (accuracies, 0.85 ~ 0.87; AUCs, 0.96 ~ 0.97) was superior to those of both the CDFR-DNN and NCDFR-DNN on either DW-MRI or DCE-MRI. DATA CONCLUSION: The CDFR-DNN enabled overall b-value DW-MRI to achieve the predictive performance comparable to DCE-MRI. MP-MRI outperformed DW-MRI and DCE-MRI in subtype prediction. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Enhancement of the viability of T cells electroporated with DNA via osmotic dampening of the DNA-sensing cGAS-STING pathway.

Viral delivery of DNA for the targeted reprogramming of human T cells can lead to random genomic integration, and electroporation is inefficient and can be toxic. Here we show that electroporation-induced toxicity in primary human T cells is mediated by the cytosolic pathway cGAS-STING (cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase-stimulator of interferon genes). We also show that an isotonic buffer, identified by screening electroporation conditions, that reduces cGAS-STING surveillance allowed for the production of chimaeric antigen receptor (CAR) T cells with up to 20-fold higher CAR T cell numbers than standard electroporation and with higher antitumour activity in vivo than lentivirally generated CAR T cells. The osmotic pressure of the electroporation buffer dampened cGAS-DNA interactions, affecting the production of the STING activator 2'3'-cGAMP. The buffer also led to superior efficiencies in the transfection of therapeutically relevant primary T cells and human haematopoietic stem cells. Our findings may facilitate the optimization of electroporation-mediated DNA delivery for the production of genome-engineered T cells.

Hydrogen sulfide inhibits alveolar type II cell senescence and limits pulmonary fibrosis via promoting MDM2-mediated p53 degradation.

AIM: Senescence of alveolar type II (AT2) cells is an important driver of pulmonary fibrosis. This study aimed to investigate whether and how dysregulation of hydrogen sulfide (H2 S) production affected AT2 cell senescence, and then explored the effect of H2 S on the communication between AT2 and fibroblasts. METHODS: ICR mice were intratracheally administered with bleomycin (3 mg/kg). Sodium hydrosulfide (NaHS, 28 µmol/kg/d) was intraperitoneally injected for 2 weeks. The H2 S-generating enzyme cystathionine-ß-synthase (CBS) knockout heterozygous (CBS+/- ) mice were used as a low H2 S production model. RESULTS: Analysis of microarray datasets revealed downregulation of H2 S-generating enzymes in lung tissues of patients with pulmonary fibrosis. Decreased H2 S production was correlated with higher levels of cell senescence markers p53 and p21 in bleomycin-induced lung fibrosis. CBS+/- mice exhibited increased levels of p53 and p21. The numbers of AT2 cells positive for p53 and p21 were increased in CBS+/- mice as compared to control mice. H2 S donor NaHS attenuated bleomycin-induced AT2 cell senescence both in vivo and in vitro. H2 S donor suppressed bleomycin-induced senescence-associated secretory phenotype (SASP) of AT2 cells via inhibiting p53/p21 pathway, consequently suppressing proliferation and myofibroblast transdifferentiation of fibroblasts. Mechanically, H2 S suppressed p53 expression by enhancing the mouse double-minute 2 homologue (MDM2)-mediated ubiquitination and degradation of p53. CONCLUSION: H2 S inactivated p53-p21 pathway, consequently suppressing AT2 cell senescence as well as cell communication between senescent AT2 cells and fibroblasts. Aberrant H2 S synthesis may contribute to the development of pulmonary fibrosis through promoting the activation loop involving senescent AT2 cells and activated fibroblasts.

Experimental study on monitoring microwave ablation efficacy by real-time shear wave elastography in ex vivo porcine brain.

Objective: Glioma constitutes the most common primary malignant tumor in the central nervous system. In recent years, microwave ablation (MWA) was expected to be applied in the minimally invasive treatment of brain tumors. This study aims to evaluate the feasibility and accuracy of microwave ablation in ex vivo brain tissue by Shear Wave Elastography (SWE) to explore the application value of real-time SWE in monitoring the process of MWA of brain tissue.Methods: Thirty ex vivo brain tissues were treated with different microwave power and ablation duration. The morphologic and microscopic changes of MWA tissues were observed, and the diameter of the ablation areas was measured. In this experiment, SWE is used to quantitatively evaluate brain tissue's degree of thermal injury immediately after ablation.Results: This study It is found that the ablation range measured by SWE after ablation is in good consistency with the pathological range [ICCSWEL1-L1 = 0.975(95% CI:0.959 - 0.985), ICCSWEL2-L2 = 0.887(95% CI:0.779 - 0.938)]. At the same time, the SWE value after ablation is significantly higher than before (mean ± SD,9.88 ± 2.64 kPa vs.23.6 ± 13.75 kPa; p < 0.001). In this study, the SWE value of tissues in different pathological states was further analyzed by the ROC curve (AUC = 0.86), and the threshold for distinguishing normal tissue from tissue after ablation was 13.7 kPa. The accuracy of evaluating ablation tissue using SWE can reach 84.72%, providing data support for real-time quantitative observation of the ablation range.Conclusion: In conclusion the accurate visualization and real-time evaluation of the organizational change range of the MWA process can be realized by real-time SWE.

A model for predicting lymph node metastasis of thyroid carcinoma: a multimodality convolutional neural network study.

Background: Early preoperative evaluation of cervical lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) is critical for further surgical treatment. However, insufficient accuracy in predicting LNM status for PTC based on ultrasound images is a problem that needs to be urgently resolved. This study aimed to clarify the role of convolutional neural networks (CNNs) in predicting LNM for PTC based on multimodality ultrasound. Methods: In this study, the data of 308 patients who were clinically diagnosed with PTC and had confirmed LNM status via postoperative pathology at Beijing Tiantan Hospital, Capital Medical University, from August 2018 to April 2022 were incorporated into CNN algorithm development and evaluation. Of these patients, 80% were randomly included into the training set and 20% into the test set. The ultrasound examination of cervical LNM was performed to assess possible metastasis. Residual network 50 (Resnet50) was employed for feature extraction from the B-mode and contrast-enhanced ultrasound (CEUS) images. For each case, all of features were extracted from B-mode ultrasound images and CEUS images separately, and the ultrasound examination data of cervical LNM information were concatenated together to produce a final multimodality LNM prediction. Sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the predictive model. Heatmaps were further developed for visualizing the attention region of the images of the best-working model. Results: Of the 308 patients with PTC included in the analysis, 158 (51.3%) were diagnosed as LNM and 150 (48.7%) as non-LNM. In the test set, when a triple-modality method (i.e., B-mode image, CEUS image, and ultrasound examination of cervical LNM) was used, accuracy was maximized at 80.65% (AUC =0.831; sensitivity =80.65%; specificity =82.26%), which showed an expected increased performance over B-mode alone (accuracy =69.00%; AUC =0.720; sensitivity =70.00%; specificity =73.00%) and a dual-modality method (B-mode image plus CEUS image: accuracy =75.81%; AUC =0.742; sensitivity =74.19%; specificity =77.42%). The heatmaps of our triple-modality model demonstrated a possible focus area and revealed the model's flaws. Conclusions: The PTC lymph node prediction model based on the triple-modality features significantly outperformed all the other feature configurations. This deep learning model mimics the workflow of a human expert and leverages multimodal data from patients with PTC, thus further supporting clinical decision-making.

Modulation of natural killer cell exhaustion in the lungs: the key components from lung microenvironment and lung tumor microenvironment.

Lung cancer is the leading cause of tumor-induced death worldwide and remains a primary global health concern. In homeostasis, due to its unique structure and physiological function, the lung microenvironment is in a state of immune tolerance and suppression, which is beneficial to tumor development and metastasis. The lung tumor microenvironment is a more complex system that further enhances the immunosuppressive features in the lungs. NK cells are abundantly located in the lungs and play crucial roles in lung tumor surveillance and antitumor immunity. However, the immunosuppressive microenvironment promotes significant challenges to NK cell features, leading to their hypofunction, exhaustion, and compromised antitumor activity. Thus, understanding the complex interactions among the lung microenvironment, lung tumor microenvironment, and NK cell exhaustion is critical for the development of effective cancer immunotherapeutic strategies. The present review will discuss NK cell hypofunction and exhaustion within the lung microenvironment and lung tumor microenvironment, focusing on lung tissue-specific factors, including key cytokines and unique environmental components, that modulate NK cell activation and function. Understanding the functional mechanisms of key factors would help to design strategies to reverse NK cell exhaustion and restore their antitumor function within the lung tumor microenvironment.

SHP2 potentiates anti-PD-1 effectiveness through intervening cell pyroptosis resistance in triple-negative breast cancer.

Triple negative breast cancer (TNBC) presents a formidable challenge due to the lack of effective treatment modalities. Immunotherapy stands as a promising therapeutic approach; however, the emergence of drug resistance mechanisms within tumor cells, particularly those targeting apoptosis and pyroptosis, has hampered its clinical efficacy. SHP2 is intricately involved in diverse physiological processes, including immune cell proliferation, infiltration, and tumor progression. Nevertheless, the precise contribution of SHP2 to tumor cell pyroptosis resistance remains inadequately understood. Herein, we demonstrate that SHP2 inhibition hampers the proliferative, migratory, and invasive capabilities of TNBC, accompanied by noticeable alterations in cellular membrane architecture. Mechanistically, we provide evidence that SHP2 depletion triggers the activation of Caspase-1 and GSDMD, resulting in GSDMD-dependent release of LDH, IL-1ß, and IL-18. Furthermore, computational analyses and co-localization investigations substantiate the hypothesis that SHP2 may hinder pyroptosis through direct binding to JNK, thereby impeding JNK phosphorylation. Our cellular experiments further corroborate these findings by demonstrating that JNK inhibition rescues pyroptosis induced by SHP2 knockdown. Strikingly, in vivo experiments validate the suppressive impact of SHP2 knockdown on tumor progression via enhanced JNK phosphorylation. Additionally, SHP2 knockdown augments tumor sensitivity to anti-PD-1 therapy, thus reinforcing the pro-pyroptotic effects and inhibiting tumor growth. In summary, our findings elucidate the mechanism by which SHP2 governs TNBC pyroptosis, underscoring the potential of SHP2 inhibition to suppress cell pyroptosis resistance and its utility as an adjunctive agent for tumor immunotherapy.

Generation of an induced pluripotent stem cell line (SDASi001-A) from a Schimke immune-osseous dysplasia patient with SMARCAL1 mutations.

A human induced pluripotent stem cell (iPSC) line (SDASi001-A) was generated from patient with Schimke immune-osseous dysplasia (SIOD), carrying heterozygous mutations in SMARCAL1 gene. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using non-integrating delivery of OCT4, SOX2, KFL4, BCL-XL and c-MYC. The iPSC line expresses pluripotency markers, displays a normal karyotype, and has the ability to differentiate into cells of three germ layers in vitro. This iPSC line represents a valuable cell model for SIOD in humans.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulant in the treatment of patients with morbid obesity or high body weight with venous thromboembolism: A meta-analysis.

BACKGROUND: Venous thromboembolism (VTE) poses a significant health risk to patients with morbid obesity or high body weight. Non-vitamin K antagonist oral anticoagulants (NOACs) are emerging treatments, but their effectiveness and safety compared with vitamin K antagonists (VKAs) in this population are yet to be thoroughly studied. METHODS: We conducted a systematic review and meta-analysis, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four electronic databases were searched for relevant studies comparing the efficacy and safety of NOACs and VKAs in treating patients with VTE with a body mass index > 40 kg/m2 or body weight > 120 kg. Eligible studies were scored for quality using the Newcastle-Ottawa Scale. RESULTS: Thirteen studies were included. The meta-analysis results showed that compared to VKAs, NOACs significantly decreased the risk of VTE occurrence (odds ratio = 0.72, 95% CI: 0.57-0.91, I2 = 0%, P < .001) and were associated with a lower risk of bleeding (odds ratio = 0.74, 95% CI: 0.58-0.95, I2 = 0%, P < .05). Subgroup analysis showed that in the cancer patient subgroup, both risks of VTE occurrence and bleeding were lower in the NOAC group than in the VKA group. In patients without cancer, the risk of VTE was significantly lower in the NOAC group. CONCLUSION: NOACs appear to be more effective and safer than VKAs in patients with morbid obesity or a high body weight with VTE. However, further large-scale randomized controlled trials are required to confirm these findings.

A near-infrared fluorescence-enhancing plasmonic biosensing microarray identifies soluble PD-L1 and ICAM-1 as predictive checkpoint biomarkers for cancer immunotherapy.

Sensitive and accurate biomarker-driven assay guidance has been widely adopted to identify responsive patients for immune checkpoint blockade (ICB) therapy to impede disease progression and extend survival. However, most current assays are invasive, requiring surgical pathology specimens and only informing monochronic information. Here, we report a multiplexed enhanced fluorescence microarray immunoassay (eFMIA) based on a nanostructured gold nanoisland substrate (AuNIS), which macroscopically amplifies near-infrared fluorescence (NIRF) of a structurally symmetric IRDye78 fluorophore by over two orders of magnitude of 202.6-fold. Aided by non-contact piezo-driven micro-dispensing (PDMD), eFMIA simultaneously and semi-quantitatively detected intracellular and secreted programmed death-ligand 1 (PD-L1) and intercellular adhesion molecule-1 (ICAM-1) in human nasopharyngeal carcinoma (NPC) cells. The assay performance was superior to fluorescence immunoassays (FIA) and enzyme-linked immunosorbent assays (ELISA), with lower detection limits. Using eFMIA, we found significantly differential levels of soluble PD-L1 (sPD-L1) and sICAM-1 in the sera of 28 cancer patients, with different clinical outcomes following anti-PD-1 ICB therapy. With a well-characterized mechanism, the high-performance plasmonic multiplexed assay with the composite biomarkers may be a valuable tool to assist clinicians with decision-making and patient stratification to afford predictive ICB therapy responses.

Pericyte Dysfunction Contributes to Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats.

Vascular cognitive impairment (VCI) encompasses cognitive disorders associated with cerebrovascular disease, often manifesting as white matter lesions (WMLs), irrespective of precise triggers. The integrity of white matter is essential for neural communication and cognitive function maintenance. Persistent cerebral hypoperfusion-induced WMLs are now acknowledged as a key driver of VCI and dementia, though their exact formation mechanism remains unclear. Recent studies link pericyte dysfunction to diverse brain disorders like Alzheimer disease. However, the exact pathological connection between pericyte dysfunction and cognitive impairment in VCI remains unexplored. In this study, we aimed to examine whether pericyte dysfunction could impact WMLs and cognitive impairment in a rat VCI model. Using a rat model of chronic cerebral hypoperfusion-induced VCI through two-vessel occlusion (2VO), we verified that 2VO induced both WMLs and cognitive impairment. Notably, the number of pericytes in the brain was significantly altered after 2VO. Furthermore, we observed significantly increased capillary constrictions at pericyte bodies in the brains of 2VO-induced rats compared to sham-operated rats, accompanied by reduced cerebral blood flow (CBF). To tackle this issue, we administered CGS21680, a specific adenosine A2A subtype receptor agonist, intranasally twice a day for 7 days. We found that rats treated with CGS21680 exhibited a significant increase in CBF at 7 and 14 days after 2VO, compared to the vehicle group. Moreover, capillary lumens beneath pericytes also increased after the CGS21680 treatment. Importantly, the treatment led to substantial improvements in WMLs and cognitive impairment compared to the vehicle group. Our findings suggest a critical role of pericyte dysfunction in WMLs and cognitive impairment within the rat VCI model. This insight contributes to our understanding of pathogenesis and offers prospects for targeted intervention in VCI.

Longitudinal detection of subcategorized CD44v6+ CTCs and circulating tumor endothelial cells (CTECs) enables novel clinical stratification and improves prognostic prediction of small cell lung cancer: A prospective, multi-center study.

Current management of small cell lung cancer (SCLC) remains challenging. Effective biomarkers are needed to subdivide patients presenting distinct treatment response and clinical outcomes. An understanding of heterogeneous phenotypes of aneuploid CD31- circulating tumor cells (CTCs) and CD31+ circulating tumor endothelial cells (CTECs) may provide novel insights in the clinical management of SCLC. In the present translational and prospective study, increased cancer metastasis-related cell proliferation and motility, accompanied with up-regulated mesenchymal marker vimentin but down-regulated epithelial marker E-cadherin, were observed in both lentivirus infected SCLC and NSCLC cells overexpressing the stemness marker CD44v6. Aneuploid CTCs and CTECs expressing CD44v6 were longitudinally detected by SE-iFISH in 120 SCLC patients. Positive detection of baseline CD44v6+ CTCs and CD44v6+ CTECs was significantly associated with enhanced hepatic metastasis. Karyotype analysis revealed that chromosome 8 (Chr8) in CD44v6+ CTCs shifted from trisomy 8 towards multiploidy in post-therapeutic patients compared to pre-treatment subjects. Furthermore, the burden of baseline CD44v6+ CTCs (t0) or amid the therapy (t1-2), the ratio of baseline CD31+ CTEC/CD31- CTC (t0), and CTC-WBC clusters (t0) were correlated with treatment response and distant metastases, particularly brain metastasis, in subjects with limited disease (LD-SCLC) but not in those with extensive disease (ED-SCLC). Multivariate survival analysis validated that longitudinally detected CD44v6+/CD31- CTCs was an independent prognostic factor for inferior survival in SCLC patients. Our study provides evidence for the first time that comprehensive analyses of CTCs, CTECs, and their respective CD44v6+ subtypes enable clinical stratification and improve prognostic prediction of SCLC, particularly for potentially curable LD-SCLC.