Trafficking circuit of CD8+ T cells between the intestine and bone marrow governs antitumour immunity.

Immunotherapy elicits a systemic antitumour immune response in peripheral circulating T cells. However, the T cell trafficking circuit between organs and their contributions to antitumour immunity remain largely unknown. Here we show in multiple mouse leukaemia models that high infiltration of leukaemic cells in bone marrow (BM) stimulates the transition of CD8+CD44+CD62L+ central memory T cells into CD8+CD44-CD62L- T cells, designated as inter-organ migratory T cells (TIM cells). TIM cells move from the BM to the intestine by upregulating integrin ß7 and downregulating C-X-C motif chemokine receptor 3 during leukaemogenesis. Upon immunogenic chemotherapy, these BM-derived TIM cells return from the intestine to the BM through integrin α4-vascular cell adhesion molecule 1 interaction. Blocking C-X-C motif chemokine receptor 3 function boosts the immune response against leukaemia by enhancing T cell trafficking. This phenomenon can also be observed in patients with leukaemia. In summary, we identify an unrecognized intestine-BM trafficking circuit of T cells that contributes to the antitumour effects of immunogenic chemotherapy.

Comparison of Volatile Compounds among Four Types of Teas Analyzed Using Gas Chromatography-Ion Mobility Spectrometry.

Gas chromatography-ion mobility spectrometry (GC-IMS) is a smart method that has been applied to determine the volatile compounds in Chinese teas, but its use in comparing the volatile compounds of different types of tea has not been mentioned. In this study, the volatile compounds found in four types of samples (green, yellow, white, and black teas) made with fresh leaves of Camellia sinensis (L.) Kuntze 'Zhongcha 111' were analyzed using GC-IMS. The results showed that 93 volatile compounds were identified from our tea samples and that the average volume of aldehydes was higher than that for other compounds, especially in white tea. The different samples were successfully categorized using multivariate statistical analysis. Using partial least squares discriminant analysis (PLS-DA), we found 15 key compounds, including four differential components: (E)-2-hexenal, 2-furanmethanethio, 2-hexanol, and 1-octene. There were 29 common components, and their total content reached 386.0 µg/g. Moreover, the 3-methyl-2-butenal and dimethyl disulfide detected in the four samples were also differential compounds, varying according to the manufacturing technology. Thus, this study demonstrates that different types of teas can be discriminated easily using GC-IMS and that this is helpful to shorten the time for improving tea quality and developing new products.

Destruction mechanism of anterior cervical discectomy and fusion in frontal impact.

The aim of this study was to quantitatively study the effect of anterior cervical discectomy and fusion (ACDF) on the risk of spinal injury under frontal impact. A head-neck finite element model incorporating active neck muscles and soft tissues was developed and validated. Based on the intact head-neck model, three ACDF models (single-level, two-level and three-level) were used to analyze the frontal impact responses of the head-neck. The results revealed that various surgical approaches led to distinct patterns of vertebral damage under frontal impact. For single-level and three-level ACDFs, vertebral destruction was mainly concentrated at the lower end of the fused segment, while the other vertebrae were not significantly damaged. For two-level ACDF, the lowest vertebra was the first to suffer destruction, followed by severe damage to both the upper and lower vertebrae, while the middle vertebra of the cervical spine exhibited only partial damage around the screws. Fusion surgery for cervical spine injuries predominantly influences the vertebral integrity of the directly fused segments when subjected to frontal impact, while exerting a comparatively lesser impact on the cross-sectional properties of adjacent, non-fused segments.

PSTNet: Enhanced Polyp Segmentation With Multi-Scale Alignment and Frequency Domain Integration.

Accurate segmentation of colorectal polyps in colonoscopy images is crucial for effective diagnosis and management of colorectal cancer (CRC). However, current deep learning-based methods primarily rely on fusing RGB information across multiple scales, leading to limitations in accurately identifying polyps due to restricted RGB domain information and challenges in feature misalignment during multi-scale aggregation. To address these limitations, we propose the Polyp Segmentation Network with Shunted Transformer (PSTNet), a novel approach that integrates both RGB and frequency domain cues present in the images. PSTNet comprises three key modules: the Frequency Characterization Attention Module (FCAM) for extracting frequency cues and capturing polyp characteristics, the Feature Supplementary Alignment Module (FSAM) for aligning semantic information and reducing misalignment noise, and the Cross Perception localization Module (CPM) for synergizing frequency cues with high-level semantics to achieve efficient polyp segmentation. Extensive experiments on challenging datasets demonstrate PSTNet's significant improvement in polyp segmentation accuracy across various metrics, consistently outperforming state-of-the-art methods. The integration of frequency domain cues and the novel architectural design of PSTNet contribute to advancing computer-assisted polyp segmentation, facilitating more accurate diagnosis and management of CRC. Our source code is available for reference at https://github.com/clearxu/PSTNet.

Modulatory Effects of XIAOPI Formula on CXCL1 and Selected Outcomes in Triple-Negative Breast Cancer: A Randomized Controlled Clinical Trial.

Background: Triple-negative breast cancer (TNBC) is the most aggressive malignancy. Psychological distress and elevated CXCL1 level have been reported to be closely associated with the poor prognosis and quality of life of patients with TNBC. In preclinical studies using xenograft mouse models, XIAOPI formula, a nationally approved drug prescribed to patients at high risk for breast cancer, inhibited CXCL1 expression and improved survival. Traditional Chinese medicine has unique advantages in improving patients' emotional disorders and quality of life. However, the impact of XIAOPI formula on the serum level of CXCL1, psychological distress, and quality of life among patients with TNBC is currently unknown. Methods: In this study, we designed a randomized, double-blind, placebo-controlled trial. Patients with TNBC were randomly assigned to receive either the XIAOPI formula or a placebo for three months. The primary outcomes include serum CXCL1 expression, Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS). Secondary outcomes included the Pittsburgh Sleep Quality Index (PSQI) and the Functional Assessment of Cancer Therapy-Breast (FACT-B). Results: A total of 60 patients with TNBC were enrolled in the investigation. The results showed that the XIAOPI formula significantly decreased CXCL1 expression compared with the control group. Moreover, in comparison to the placebo, the XIAOPI formula increased FACT-B scores while decreasing SDS, SAS, and PSQI scores. Conclusion: In patients with TNBC, XIAOPI formula may be effective in reducing CXCL1 levels, enhancing psychological well-being, and quality of life. While our research offers a natural alternative therapy that may enhance the prognosis of TNBC, future validation of its therapeutic effects will require large-scale, long-term clinical trials. Clinical Registration Number: Registration website: www.chictr.org.cn, Registration date: 2018-1-19, Registration number: ChiCTR1800014535.

Scriptaid is a prospective agent for improving human asthenozoospermic sample quality and fertilization rate in vitro.

ABSTRACT: Male infertility is a global issue caused by poor sperm quality, particularly motility. Enhancement of the sperm quality may improve the fertilization rate in assisted reproductive technology (ART) treatment. Scriptaid, with a novel human sperm motility-stimulating activity, has been investigated as a prospective agent for improving sperm quality and fertilization rate in ART. We evaluated the effects of Scriptaid on asthenozoospermic (AZS) semen, including its impact on motility stimulation and protective effects on cryopreservation and duration of motility, by computer-aided sperm analysis (CASA). Sperm quality improvement by Scriptaid was characterized by increased hyaluronan-binding activity, tyrosine phosphorylation, adenosine triphosphate (ATP) concentration, mitochondrial membrane potential, and an ameliorated AZS fertilization rate in clinical intracytoplasmic sperm injection (ICSI) experiments. Furthermore, our identification of active Scriptaid analogs and different metabolites induced by Scriptaid in spermatozoa lays a solid foundation for the future biomechanical exploration of sperm function. In summary, Scriptaid is a potential candidate for the treatment of male infertility in vitro as it improves sperm quality, prolongs sperm viability, and increases the fertilization rate.

Differential reinforcement of cGAS-STING pathway-involved immunotherapy by biomineralized bacterial outer membrane-sensitized EBRT and RNT.

Radiotherapy (RT), including external beam radiation therapy (EBRT) and radionuclide therapy (RNT), realizes physical killing of local tumors and activates systemic anti-tumor immunity. However, these effects need to be further strengthened and the difference between EBRT and RNT should be discovered. Herein, bacterial outer membrane (OM) was biomineralized with manganese oxide (MnO2) to obtain OM@MnO2-PEG nanoparticles for enhanced radio-immunotherapy via amplifying EBRT/RNT-induced immunogenic cell death (ICD) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) activation. OM@MnO2-PEG can react with H2O2 and then gradually produce O2, Mn2+ and OM fragments in the tumor microenvironment. The relieved tumor hypoxia improves the radio-sensitivity of tumor cells, resulting in enhanced ICD and DNA damage. Mn2+ together with the DNA fragments in the cytoplasm activate the cGAS-STING pathway, further exhibiting a positive role in various aspects of innate immunity and adaptive immunity. Besides, OM fragments promote tumor antigen presentation and anti-tumor macrophages polarization. More importantly, our study reveals that OM@MnO2-PEG-mediated RNT triggers much stronger cGAS-STING pathway-involved immunotherapy than that of EBRT, owing to the duration difference of RT. Therefore, this study develops a powerful sensitizer of radio-immunotherapy and uncovers some differences between EBRT and RNT in the activation of cGAS-STING pathway-related anti-tumor immunity.

Single­cell RNA­seq necroptosis­related genes predict the prognosis of breast cancer and affect the differentiation of CD4+ T cells in tumor immune microenvironment.

Breast cancer (BC) is one of the most prevalent types of malignancy and a major cause of cancer-related death. The purpose of the present study was to identify prognostic models of necroptosis-related genes (NRGs) in BC at the single-cell RNA-sequencing level and reveal the role of NRGs in tumour immune microenvironment (TIME). A risk model was constructed based on Cox regression and LASSO methods. Next, high-scoring cell populations were searched through AUCell scores, and cell subtypes were then analyzed by pseudotime analysis. Finally, the expression level of the model genes was verified by reverse transcription-quantitative (RT-qPCR). A new prognostic model was constructed and validated based on five NRGs (BCL2, BIRC3, AIFM1, IFNG and VDAC1), which could effectively predict the prognosis of patients with BC. NRGs were found to be highly active in CD4+ T cells and differentially expressed in their developmental trajectories. Finally, the RT-qPCR results showed that most of the model genes were significantly overexpressed in MDA-MB-231 and MCF-7 cells (P<0.05). In conclusion, an NRG signature with excellent predictive properties in prognosis and TIME was successfully established. Moreover, NRGs were involved in the differentiation and development of CD4+ T cells in TIME. These findings provide potential therapeutic strategies for BC.

Aromatization-driven deconstructive functionalization of spiro dihydroquinazolinones via dual photoredox/nickel catalysis.

Aromatization-driven deconstruction and functionalization of spiro dihydroquinazolinones via dual photoredox/nickel catalysis is developed. The aromatization effect was introduced to synergistically drive unstrained cyclic C-C bond cleavage, with the aim of overcoming the ring-size limitation of nitrogen-centered radical induced deconstruction of carbocycles. Herein, we demonstrate the synergistic photoredox/nickel catalyzed deconstructive cross-coupling of spiro dihydroquinazolinones with organic halides. Remarkably, structurally diverse organic halides including aryl, alkenyl, alkynyl, and alkyl bromides were compatible for the coupling. In addition, this protocol is also characterized by its mild and redox-neutral conditions, excellent functional group compatibility, high atom economy, and easy scalability. A telescoped procedure involving condensation and ring-opening/coupling was found to be accessible. This work provides a complementary strategy to the existing radical-mediated C-C bond cleavage of unstrained carbocycles.

Exploring the Role of Clustered Mutations in Carcinogenesis and Their Potential Clinical Implications in Cancer.

Abnormal cell proliferation and growth leading to cancer primarily result from cumulative genome mutations. Single gene mutations alone do not fully explain cancer onset and progression; instead, clustered mutations-simultaneous occurrences of multiple mutations-are considered to be pivotal in cancer development and advancement. These mutations can affect different genes and pathways, resulting in cells undergoing malignant transformation with multiple functional abnormalities. Clustered mutations influence cancer growth rates, metastatic potential, and drug treatment sensitivity. This summary highlights the various types and characteristics of clustered mutations to understand their associations with carcinogenesis and discusses their potential clinical significance in cancer. As a unique mutation type, clustered mutations may involve genomic instability, DNA repair mechanism defects, and environmental exposures, potentially correlating with responsiveness to immunotherapy. Understanding the characteristics and underlying processes of clustered mutations enhances our comprehension of carcinogenesis and cancer progression, providing new diagnostic and therapeutic approaches for cancer.

Imaging-Guided Percutaneous Endovascular Biopsy Applied in Patients with Pulmonary Artery Masses: A Review.

INTRODUCTION: Pulmonary artery (PA) masses are rare. Distinguishing PA tumours from embolism is sometimes difficult, and surgical biopsy is expensive and risky. We aimed to evaluate the efficacy of imaging-guided percutaneous endovascular biopsy (PEB) for obtaining tissues for histological diagnosis. METHODS: We searched Cochrane, Medline, Embase, and Web of Science for PEB trials involving patients with PA masses, published from the inception of the database until August 2023. RESULTS: We retrospectively reviewed 33 studies including 87 patients (median age 55 ± 69.3 years, 44 men) with PA masses who underwent a total of 110 PEBs. Of these patients, 34.5% (n = 38) underwent PEB-catheter aspiration (PEB-CA), 50.9% (n = 56) underwent PEB-forceps biopsy (PEB-FB) and 2.7% (n = 3) underwent PEB-directional atherectomy (PEB-DA). The most common histological aetiology of PA masses was mesenchymal tumours (n = 67, 75.9%). Tumour embolism (n = 6, 6.9%) and pulmonary embolism (n = 3, 3.4%) were the second and third most common types of PA masses, respectively. The technical success rates of PEB-CA, PEB-FB and PEB-DA were 92.1%, 94.6% and 100% (p = 0.796), respectively. Histopathological analysis provided clinical diagnostic success rates of 44.7%, 85.7% and 100% for PEB-CA, PEB-FB and PEB-DA (p < 0.001), respectively. In pairwise comparison, PEB-FB had a higher success rate in pathological diagnosis than PEB-CA (p = 0.000). Apart from one patient suffering from haemorrhagic cardiac tamponade, no other complications occurred. CONCLUSION: Imaging-guided PEB is a safe and effective technique for the early pathological diagnosis of PA masses.

Design and construction of high strength double network hydrogel with flow-induced orientation.

The design and construction of high strength hydrogels is a widely discussed topic in hydrogel research. In this study, we combined three toughening strategies, including dual network, oriented structure construction and nanophase doping, to develop an alginate/polyacrylamide (PAM)/modified titanium dioxide fiber (TiO2 NF@PAM) dual network composite hydrogel prepared via syringe. The effects of different preparation methods, AM/Alginate ratios, inorganic doping phases and TiO2 NF@PAM/AM ratios on the mechanical properties of composite hydrogels were investigated. The study found that the alginate hydrogel prepared by syringe exhibited superior axial orientation and achieved a tensile strength of (1091 ± 46) kPa. And the composite hydrogel doped with 0.2 wt% TiO2 NF@PAM had a tensile strength of (1006 ± 64) kPa, which was higher than that of the composite hydrogel doped with 0.2 wt% TiO2 nanoparticles (976 ± 66) kPa. The highest tensile strength (1120 ± 67) kPa and elongation at break (182 ± 8) % were achieved when the ratio of TiO2 NF@PAM/AM was 0.6 wt%. The force applied to the gel solution in the syringe affects the orientation of the polymer chains and TiO2 NF@PAM within the gel, which subsequently impacts the mechanical properties of the hydrogel. Therefore, we further investigated the mechanical properties of composite hydrogels under varying propulsion speeds, syringe diameters, and syringe lengths. It was observed that the gel solution's shear strength increased as the syringe diameter decreased. The resulting composite hydrogels were better oriented and had improved mechanical properties. The composite hydrogels' tensile strength peaked at (1117 ± 47) kPa when the syringe advance rate was between 1-7 mL/min. The mechanical properties of the hydrogels were optimal when the syringe length was 30 mm, with a maximum tensile strength of (1131 ± 67) kPa and a tensile ratio of (166 ± 5) %. This study demonstrates the viability of integrating three distinct strengthening methodologies to generate hydrogels of considerable strength. Furthermore, the Alginate/PAM/TiO2 NF@PAM composite hydrogels possess remarkable potential as adaptable, wearable sensors due to their exemplary mechanical properties, knittability, and conductivity.

A new perspective: deciphering the aberrance and clinical implication of disulfidptosis signatures in clear cell renal cell carcinoma.

Recent research has discovered disulfidptosis as a form of programmed cell death characterized by disulfide stress. However, its significance in clear cell renal cell carcinoma (ccRCC) remains unclear. To investigate this, data from The Cancer Genome Atlas were collected and used to identify ccRCC subgroups. Unsupervised clustering was employed to determine ccRCC heterogeneity. The mutation landscape and immune microenvironment of the subgroups were analyzed. The Disulfidptosis-Related Score was calculated using the LASSO-penalized Cox regression algorithm. The E-MATB-1980 cohort was used to validate the signature. The role of SLC7A11 in ccRCC metastasis was explored using western blotting and Transwell assays. Disulfidptosis-related genes are commonly downregulated in cancers and are linked to hypermethylation and copy number variation. The study revealed that ccRCC is divided into two sub-clusters: the disulfidptosis-desert sub-cluster, which is associated with a poor prognosis, a higher mutation frequency, and an immunosuppressive microenvironment. A 14-gene prognostic model was developed using differentially expressed genes and was validated in the E-MATB-1980 cohort. The low-risk group demonstrated longer overall and disease-free survival and responded better to targeted immunotherapy. Results from in vitro experiments identified SLC7A11 as a key participant in ccRCC metastasis.

A Single-Cell Atlas of the Murine Pancreatic Ductal Tree Identifies Novel Cell Populations With Potential Implications in Pancreas Regeneration and Exocrine Pathogenesis.

BACKGROUND & AIMS: Pancreatic ducts form an intricate network of tubules that secrete bicarbonate and drive acinar secretions into the duodenum. This network is formed by centroacinar cells; terminal, intercalated, intracalated ducts; and the main pancreatic duct. Ductal heterogeneity at the single-cell level has been poorly characterized; therefore, our understanding of the role of ductal cells in pancreas regeneration and exocrine pathogenesis has been hampered by the limited knowledge and unexplained diversity within the ductal network. METHODS: We used small conditional RNA sequencing to comprehensively characterize mouse ductal heterogeneity at single-cell resolution of the entire ductal epithelium from centroacinar cells to the main duct. Moreover, we used organoid cultures, injury models, and pancreatic tumor samples to interrogate the role of novel ductal populations in pancreas regeneration and exocrine pathogenesis. RESULTS: We have identified the coexistence of 15 ductal populations within the healthy pancreas and characterized their organoid formation capacity and endocrine differentiation potential. Cluster isolation and subsequent culturing let us identify ductal cell populations with high organoid formation capacity and endocrine and exocrine differentiation potential in vitro, including a Wnt-responsive population, a ciliated population, and FLRT3+ cells. Moreover, we have characterized the location of these novel ductal populations in healthy pancreas, chronic pancreatitis, and tumor samples. The expression of WNT-responsive, interferon-responsive, and epithelial-to-mesenchymal transition population markers increases in chronic pancreatitis and tumor samples. CONCLUSIONS: In light of our discovery of previously unidentified ductal populations, we unmask potential roles of specific ductal populations in pancreas regeneration and exocrine pathogenesis. Thus, novel lineage-tracing models are needed to investigate ductal-specific populations in vivo.

Application of convolutional neural network for differentiating ovarian thecoma-fibroma and solid ovarian cancer based on MRI.

BACKGROUND: Ovarian thecoma-fibroma and solid ovarian cancer have similar clinical and imaging features, and it is difficult for radiologists to differentiate them. Since the treatment and prognosis of them are different, accurate characterization is crucial. PURPOSE: To non-invasively differentiate ovarian thecoma-fibroma and solid ovarian cancer by convolutional neural network based on magnetic resonance imaging (MRI), and to provide the interpretability of the model. MATERIAL AND METHODS: A total of 156 tumors, including 86 ovarian thecoma-fibroma and 70 solid ovarian cancer, were split into the training set, the validation set, and the test set according to the ratio of 8:1:1 by stratified random sampling. In this study, we used four different networks, two different weight modes, two different optimizers, and four different sizes of regions of interest (ROI) to test the model performance. This process was repeated 10 times to calculate the average performance of the test set. The gradient weighted class activation mapping (Grad-CAM) was used to explain how the model makes classification decisions by visual location map. RESULTS: ResNet18, which had pre-trained weight, using Adam and one multiple ROI circumscribed rectangle, achieved best performance. The average accuracy, precision, recall, and AUC were 0.852, 0.828, 0.848, and 0.919 (P < 0.01), respectively. Grad-CAM showed areas associated with classification appeared on the edge or interior of ovarian thecoma-fibroma and the interior of solid ovarian cancer. CONCLUSION: This study shows that convolution neural network based on MRI can be helpful for radiologists in differentiating ovarian thecoma-fibroma and solid ovarian cancer.

Advances in therapeutic cancer vaccines: Harnessing immune adjuvants for enhanced efficacy and future perspectives.

Preventive cancer vaccines are highly effective in preventing viral infection-induced cancer, but advances in therapeutic cancer vaccines with a focus on eliminating cancer cells through immunotherapy are limited. To develop therapeutic cancer vaccines, the integration of optimal adjuvants is a potential strategy to enhance or complement existing therapeutic approaches. However, conventional adjuvants do not satisfy the criteria of clinical trials for therapeutic cancer vaccines. To improve the effects of adjuvants in therapeutic cancer vaccines, effective vaccination strategies must be formulated and novel adjuvants must be identified. This review offers an overview of the current advancements in therapeutic cancer vaccines and highlights in situ vaccination approaches that can be synergistically combined with other immunotherapies by harnessing the adjuvant effects. Additionally, the refinement of adjuvant systems using cutting-edge technologies and the elucidation of molecular mechanisms underlying immunogenic cell death to facilitate the development of innovative adjuvants have been discussed.

Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction.

BACKGROUND: Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2. AIM: To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism. METHODS: In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured. RESULTS: LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage. CONCLUSION: Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.