Closed-Loop Control of Macrophage Engineering Enabled by Focused-Ultrasound Responsive Mechanoluminescence Nanoplatform for Precise Cancer Immunotherapy.

Macrophage engineering has emerged as a promising approach for modulating the anti-tumor immune response in cancer therapy. However, the spatiotemporal control and real-time feedback of macrophage regulatory process is still challenging, leading to off-targeting effect and delayed efficacy monitoring therefore raising risk of immune overactivation and serious side effects. Herein, a focused ultrasound responsive immunomodulator-loaded optical nanoplatform (FUSION) is designed to achieve spatiotemporal control and status reporting of macrophage engineering in vivo. Under the stimulation of focused ultrasound (FUS), the immune agonist encapsulated in FUSION can be released to induce selective macrophage M1 phenotype differentiation at tumor site and the near-infrared mechanoluminescence of FUSION is generated simultaneously to indicate the initiation of immune activation. Meanwhile, the persistent luminescence of FUSION is enhanced due to hydroxyl radical generation in the pro-inflammatory M1 macrophages, which can report the effectiveness of macrophage regulation. Then, macrophages labeled with FUSION as a living immunotherapeutic agent (FUSION-M) are utilized for tumor targeting and focused ultrasound activated, immune cell-based cancer therapy. By combining the on-demand activation and feedback to form a closed loop, the nanoplatform in this work holds promise in advancing the controllability of macrophage engineering and cancer immunotherapy for precision medicine.

The Effects of Parental Food Education on Children's Food Literacy: The Mediating Role of Parent-Child Relationship and Learning Motivation.

Parental food education has been recognized among the important factors influencing children's food literacy; however, the intrinsic mechanisms through which this influence occurs are unclear. In this study, a mediation model was constructed to explore this issue, using the parent-child relationship and learning motivation as mediating variables. In total, 204 children, aged 9-14 years old, responded to questionnaires on parental food education, children's food literacy, the parent-child relationship, and learning motivation, which were used to measure the variables of interest. The results showed that parental food education was significantly and positively related to the parent-child relationship, learning motivation, and children's food literacy; the parent-child relationship was significantly and positively related to learning motivation; and learning motivation was significantly and positively related to children's food literacy. Parental food education influenced children's food literacy in the following two main ways: the mediating role of learning motivation and the chain-mediating roles of the parent-child relationship and learning motivation. In addition, we attempt to explore the moderating role of the teaching stage between parental food education and the parent-child relationship, learning motivation, and children's food literacy. In this paper, we discuss possible guidelines for family food education and children's health based on the findings of the current study.

Gut Roseburia is a protective marker for peritoneal metastasis of gastric cancer.

BACKGROUND: Gastric cancer (GC), particularly for advanced stage of GC, commonly undergoes peritoneal metastasis (PM), which is the leading cause of GC-related death. However, there currently has no reliable biomarker to predict the onset of GCPM. It is well known that the imbalance of gut microbiota contributes to the development and metastasis of gastrointestinal tumors. Unfortunately, little is known about how the alternation in gut microbiota is associated with the onset of GCPM. METHODS: Our current study analyzed structural characteristics and functional prediction of gut microbiota in GC patients with PM (PM group) and without PM (non-PM group). Fresh fecal samples were collected from a discovery cohort (PM = 38, non-PM = 54) and a validation cohort (PM = 15, non-PM = 21) of GC patients and their 16S ribosomal RNA (16s rRNA) gene amplicons were sequenced, followed by bioinformatics. RESULTS: The results indicated an increase in the biodiversity of gut microbiota in the non-PM group of the discovery cohort, compared with the PM group. Moreover, LEfSe analysis found 31 significantly different microorganisms, of which the Roseburia ranked the fifth in the random forest (RF) model. The characteristics of intestinal microbiota in GCPM patients were changed, and the abundance of Roseburia in gut microbiota from the GCPM patients was reduced and receiver operating characteristic (ROC) analysis revealed that the reduced abundance of gut Roseburia effectively predicted the onset of GCPM. CONCLUSION: This signature was also observed in the validation cohort. Therefore, Roseburia is a protective microbial marker and the reduced abundance of Roseburia in gut microbiota may help early diagnosis of GCPM.

Recent progress in adverse events of carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) and their association with the metabolism: the consequences on mitochondrial dysfunction and oxidative stress, and prevention with natural plant extracts.

INTRODUCTION: Carboxylic acid non-steroidal anti-inflammatory drugs (CBA-NSAIDs) are extensively used worldwide due to their antipyretic, analgesic, and anti-inflammatory effects. CBA-NSAIDs have reasonable margin of safety at therapeutic doses, and in the current climate, do not possess addiction potential like opioid drugs. Studies have revealed that various adverse events of CBA-NSAIDs are related mitochondrial dysfunction and oxidative stress. AREAS COVERED: This review article summarizes adverse events induced by CBA-NSAIDs, mechanisms of mitochondrial damage, oxidative stress, and metabolic interactions. Meanwhile, this review discusses the treatment and prevention of CBA-NSAIDs damage by natural plant extracts based on antioxidant effects. EXPERT OPINION: CBA-NSAIDs can induce reactive oxygen species (ROS) production, mediate DNA, protein and lipid damage, lead to imbalance of cell antioxidant status, change of mitochondrial membrane potential, activate oxidative stress signal pathway, thus leading to oxidative stress and cell damage. Adverse events caused by CBA-NSAIDs often exhibit dose and time dependence. In order to avoid adverse events caused by CBA-NSAIDs, it is necessary to provide detailed patient consultation and eliminate influencing factors. Moreover, constructive research studies on the organ-specific toxicity and mechanism of natural plant extracts in preventing and treating metabolic abnormalities of CBA-NSAIDs, will provide important value for warning and guidance for use of CBA-NSAIDs.

Identification of toll-like receptor 2 as a key regulator of neuronal apoptosis in vascular dementia by bioinformatics analysis and experimental validation.

BACKGROUND: Vascular dementia (VaD), the second most prevalent type of dementia, lacks a well-defined cause and effective treatment. Our objective was to utilize bioinformatics analysis to discover the fundamental disease-causing genes and pathological mechanisms in individuals diagnosed with VaD. METHODS: To identify potential pathogenic genes associated with VaD, we conducted weighted gene co-expression network analysis (WGCNA), differential expression analysis, and protein-protein interaction (PPI) analysis. The exploration of potential biological mechanisms involved the utilization of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. Moreover, a bilateral common carotid artery stenosis (BCAS) mouse model of VaD was established, and the expression of the hub gene, its relationship with cognitive function and its potential pathogenic mechanism were verified by cognitive behavior tests, cerebral blood flow measurement, Western blotting, and immunofluorescence experiments. RESULTS: This study identified 293 DEGs from the brain cortex of VaD patients and healthy controls, among these genes, the Toll-like receptor 2 (TLR2) gene was identified as hub gene, and it was associated with the apoptosis-related pathway PI3K/AKT.The BCAS model demonstrated that the use of TLR2 inhibitors greatly enhanced the cognitive function of the mice (p < 0.05). Additionally, there was a notable decrease in the number of apoptotic cells in the brain cortex of the mice (p < 0.01). Moreover, significant alterations in the levels of proteins related to the PI3K/AKT pathway and cleaved-caspase3 proteins were detected (p < 0.05). CONCLUSIONS: TLR2 plays a role in the pathophysiology of VaD by enhancing the neuronal apoptotic pathway, suggesting it could be a promising therapeutic target.

Therapeutic efficacy of acupuncture point stimulation for stomach cancer pain: a systematic review and meta-analysis.

Purpose: In recent years, traditional Chinese medicine has received widespread attention in the field of cancer pain treatment. This meta-analysis is the first to evaluate the effectiveness and safety of acupuncture point stimulation in the treatment of stomach cancer pain. Methods: For this systematic review and meta-analysis, we searched PubMed, Web of Science, Cochrane Library, Embase, WANFANG, China National Knowledge Infrastructure (CNKI), and Chinese Journal of Science and Technology (VIP) databases as well as forward and backward citations to studies published between database creation to July 27, 2023. All randomized controlled trials (RCTs) on acupuncture point stimulation for the treatment of patients with stomach cancer pain were included without language restrictions. We assessed all outcome indicators of the included trials. The evidence from the randomized controlled trials was synthesized as the standardized mean difference (SMD) of symptom change. The quality of the evidence was assessed using the Cochrane Risk of Bias tool. This study is registered on PROSPERO under the number CRD42023457341. Results: Eleven RCTs were included. The study included 768 patients, split into 2 groups: acupuncture point stimulation treatment group (n = 406), medication control group (n = 372). The results showed that treatment was more effective in the acupuncture point stimulation treatment group than in the medication control group (efficacy rate, RR = 1.63, 95% CI 1.37 to 1.94, p < 0.00001), decreasing in NRS score was greater in acupuncture point stimulation treatment group than in the medication control group (SMD = -1.30, 95% CI -1.96 to -0.63, p < 0.001). Systematic Review Registration: https://clinicaltrials.gov/, identifier CRD42023457341.

Acupuncture for insomnia symptoms in hypertensive patients: a systematic review and meta-analysis.

Purpose: In the realm of pain management, traditional Chinese medicine, specifically acupuncture, has garnered increasing attention. This meta-analysis pioneers the evaluation of acupuncture's effectiveness in treating insomnia among hypertensive patients. Methods: We conducted a comprehensive search across several databases-PubMed, Web of Science, Cochrane Library, WANFANG, China National Knowledge Infrastructure (CNKI), Sinomed, and the Chinese Journal of Science and Technology (VIP). Additionally, forward and backward articles of studies published from the inception of these databases until 10 September 2023, were reviewed. This systematic review and meta-analysis included all randomized controlled trials (RCTs) focusing on acupuncture for insomnia in hypertensive patients, without imposing language or date restrictions. We rigorously assessed all outcome measures reported in these trials. The evidence was synthesized by calculating the difference between mean differences (MD) in symptom change. The quality of the evidence was determined using the Cochrane Risk of Bias tool. This study is registered with PROSPERO under number CRD42023461760. Results: Our analysis included 16 RCTs, comprising 1,309 patients. The findings revealed that acupuncture was significantly more effective than the control group in reducing insomnia symptoms, as indicated by a greater decrease in the PSQI score (MD = -3.1, 95% CI [-3.77 to -2.62], p < 0.00001). Additionally, improvements in both systolic and diastolic blood pressure were more pronounced in the acupuncture group compared to the control group (SBP: MD = -10.31, 95% CI [-16.98 to -3.64], p = 0.002; DBP: MD = -5.71, 95% CI [-8.19 to -3.23], p < 0.00001). These results suggest that acupuncture not only improves sleep quality but also lowers blood pressure in patients suffering from hypertension and insomnia. Further research is warranted to elucidate optimal acupuncture points and the duration of treatment for maximized therapeutic effect.Systematic review registration:https://www.crd.york.ac.uk/prospero, CRD42023461760.

Customized Enhancement of Thermal Sensitivity of Tumors at Different Subcutaneous Depths by Multichannel Lanthanide Nanocomposites.

The photothermal therapeutic effect on tumors located at different subcutaneous depths varies due to the attenuation of light by tissue. Here, based on the wavelength-dependent optical attenuation properties of tissues, the tumor depth is assessed using a multichannel lanthanide nanocomposite. A zeolitic imidazolate framework (ZIF-8)-coated nanocomposite is able to deliver high amounts of the hydrophilic heat shock protein 90 inhibitor epigallocatechin gallate through a hydrogen-bonding network formed by the encapsulated highly polarized polyoxometalate guest. It is superior to both bare and PEGylated ZIF-8 for drug delivery. With the assessment of tumor depth and accumulated amount of nanocomposite by fluorescence, an irradiation prescription can be customized to release sufficient HSP90 inhibitor and generate heat for sensitized photothermal treatment of tumors, which not only ensured therapeutic efficacy but also minimized damage to the surrounding tissues.

Deciphering a Prognostic Signature Based on Soluble Mediators Defines the Immune Landscape and Predicts Prognosis in HNSCC.

BACKGROUND: The study on Head and Neck Squamous Cell Carcinoma (HNSCC), a prevalent and aggressive form of head and neck cancer, focuses on the often-overlooked role of soluble mediators. The objective is to leverage a transcriptome-based risk analysis utilizing soluble mediator-related genes (SMRGs) to provide novel insights into prognosis and immunotherapy efficacy in HNSCC patients. METHODS: We analyzed the expression and prognostic significance of 10,859 SMRGs using 502 HNSCC and 44 normal samples from the TCGA-HNSC cohort in The Cancer Genome Atlas (TCGA). The samples were divided into training and test sets in a 7:3 ratio, with an additional external validation using 40 tumor samples from the International Cancer Genome Consortium (ICGC). Key differentially expressed genes (DEGs) with prognostic significance were identified through univariate and Lasso-Cox regression analyses. A prognostic model based on 20 SMRGs was developed using Lasso and multivariate Cox regression. We assessed the clinical outcomes and immune status in high-risk (HR) and low-risk (LR) HNSCC patients utilizing the BEST databases and single-sample Gene Set Enrichment Analysis (ssGSEA). RESULTS: The 20 SMRGs were crucial in predicting the prognosis of HNSCC, with the SMRG signature emerging as an independent prognostic indicator. Patients classified in the HR group exhibited poorer outcomes compared to those in the LR group. A nomogram, integrating clinical characteristics and risk scores, demonstrated substantial prognostic value. Immunotherapy appeared to be more effective in the LR group, possibly attributed to enhanced immune infiltration and expression of immune checkpoints. CONCLUSIONS: The model based on soluble mediator-associated genes offers a fresh perspective for assessing the pre-immune efficacy and showcases robust predictive capabilities. This innovative approach holds significant promise in advancing the field of precision immuno-oncology research, providing valuable insights for personalized treatment strategies in HNSCC.

Lanthanide luminescence nanothermometer with working wavelength beyond 1500 nm for cerebrovascular temperature imaging in vivo.

Nanothermometers enable the detection of temperature changes at the microscopic scale, which is crucial for elucidating biological mechanisms and guiding treatment strategies. However, temperature monitoring of micron-scale structures in vivo using luminescent nanothermometers remains challenging, primarily due to the severe scattering effect of biological tissue that compromises the imaging resolution. Herein, a lanthanide luminescence nanothermometer with a working wavelength beyond 1500 nm is developed to achieve high-resolution temperature imaging in vivo. The energy transfer between lanthanide ions (Er3+ and Yb3+) and H2O molecules, called the environment quenching assisted downshifting process, is utilized to establish temperature-sensitive emissions at 1550 and 980 nm. Using an optimized thin active shell doped with Yb3+ ions, the nanothermometer's thermal sensitivity and the 1550 nm emission intensity are enhanced by modulating the environment quenching assisted downshifting process. Consequently, minimally invasive temperature imaging of the cerebrovascular system in mice with an imaging resolution of nearly 200 µm is achieved using the nanothermometer. This work points to a method for high-resolution temperature imaging of micron-level structures in vivo, potentially giving insights into research in temperature sensing, disease diagnosis, and treatment development.

Focused Ultrasound-Responsive Nanocomposite with Near-Infrared II Mechanoluminescence for Spatiotemporally Selective Immune Activation in Lymph Nodes.

The immune regulation of the lymphatic system, especially the lymph node (LN), is of great significance for the treatment of diseases and the inhibition of pathogenic organisms spreading in the body. However, achieving precise spatiotemporal control of immune cell activation in LN in vivo remains a challenge due to tissue depth and off-target effects. Furthermore, minimally invasive and real-time feedback methods to monitor the regulation of the immune system in LN are lacking. Here, focused ultrasound responsive immunomodulator loaded nanoplatform (FURIN) with near-infrared II (NIR-II) luminescence is designed to achieve spatiotemporally controllable immune activation in LN in vivo. The NIR-II persistent luminescence of FURIN can track its delivery in LN through bioimaging. Under focused ultrasound (FUS) stimulation, the immunomodulator encapsulated in FURIN can be released locally in the LN to activate immune cells such as dendritic cells and the NIR-II mechanoluminescence of FURIN provides real-time optical feedback signals for immune activation. This work points to a FUS mediated, spatiotemporal selective immune activation strategy in vivo with the feedback control of luminescence signals via ultrasound responsive nanocomposite, which is of great significance in improving the efficacy and reducing the side effect of immune regulation for the development of potential immunotherapeutic methods in the future.

A bone-targeting near-infrared luminescence nanocarrier facilitates alpha-ketoglutarate efficacy enhancement for osteoporosis therapy.

Osteoporosis (OP), which largely increases the risk of fractures, is the most common chronic degenerative orthopedic disease in the elderly due to the imbalance of bone homeostasis. Alpha-ketoglutaric acid (AKG), an endogenous metabolic intermediate involved in osteogenesis, plays critical roles in osteogenic differentiation and mineralization and the inhibition of osteoclastogenic differentiation. However, the low bioavailability and poor bone-targeting efficiency of AKG seriously limit its efficacy in OP treatment. In this work, a bone-targeting, near-infrared emissive lanthanide luminescence nanocarrier loaded with AKG (ß-NaYF4:7%Yb, 60%Nd@NaLuF4@mSiO2-EDTA-AKG, abbreviated as LMEK) is developed for the enhancement of AKG efficacy in OP therapy. By utilizing the NIR-II luminescence (>1000 nm) of LMEK, whole-body bone imaging with high spatial resolution is achieved to confirm the bone enrichment of AKG noninvasively in vivo. The results reveal that LMEK exhibits a remarkable OP therapeutic effect in improving the osseointegration of the surrounding bone in the ovariectomized OP mice models, which is validated by the enhanced inhibition of osteoclast through hypoxia-inducible factor-1α suppression and promotion of osteogenic differentiation in osteoblast. Notably, the dose of AKG in LMEK can be reduced to only 0.2 % of the dose when pure AKG is used in therapy, which dramatically improves the bioavailability of AKG and mitigates the metabolism burden. This work provides a strategy to conquer the low utilization of AKG in OP therapy, which not only overcomes the challenges in AKG efficacy for OP treatment but also offers insights into the development and application of other potential drugs for skeletal diseases. STATEMENT OF SIGNIFICANCE: Alpha-ketoglutarate (AKG) is an intermediate within the Krebs cycle, participating in diverse metabolic and cellular processes, showing potential for osteoporosis (OP) therapy. However, AKG's limited bioavailability and inefficient bone-targeting hinder its effectiveness in treating OP. Herein, a near-infrared emissive nanocarrier is developed that precisely targets bones and delivers AKG, bolstering its effectiveness in OP therapy. Thanks to this efficient bone-targeting delivery, the AKG dosage is reduced to 0.2 % of the conventional treatment level. This marks the first utilization of a bone-targeting nanocarrier to amplify AKG's bioavailability and OP therapy efficacy. Furthermore, the mechanism of AKG-loaded nanocarrier regulating the biological behavior of osteoclasts and osteoblasts mediated is tentatively explored.

Arbitrary Programming of Racetrack Resonators Using Low-Loss Phase-Change Material Sb2Se3.

The programmable photonic integrated circuit (PIC) is an enabling technology behind optical interconnects and quantum information processing. Conventionally, the programmability of PICs is driven by the thermo-optic effect, free carrier dispersion, or mechanical tuning. These effects afford either high speed or a large extinction ratio, but all require constant power or bias to maintain the states, which is undesirable for programmability with infrequent switching. Recent progress in programmable PICs based on nonvolatile phase-change materials (PCMs) offers an attractive solution to a truly "set-and-forget" switch that requires zero static energy. Here, we report an essential building block of large-scale programmable PICs─a racetrack resonator with independent control of coupling and phase. We changed the resonance extinction ratio (ER) without perturbing the resonance wavelength, leveraging a programmable unit based on a directional coupler and a low-loss PCM Sb2Se3. The unit is only 33-µm-long and has an operating bandwidth over 50 nm, a low insertion loss (∼0.36 dB), high ER (∼15 dB), and excellent fabrication yield of over 1000 cycles endurance across nine switches. The work is a crucial step toward future large-scale energy-efficient programmable PICs.

Genetic difference between two Schistosoma japonicum isolates with contrasting cercarial shedding patterns revealed by whole genome sequencing.

Schistosoma japonicum is one of the major infectious agents of human schistosomiasis, mainly endemic in China and the Philippines. We have previously reported the finding of two schistosome isolates, each with a different cercarial emergence pattern adapted to their different hosts. However, there are currently no whole-genome sequencing studies to investigate the underlining genetics of the adaptive traits. We sampled schistosomes in 2013 and 2020 from a hilly area Shitai (ST) and a marshland area Hexian (HX) of Anhui, China. Ten to 15 male or female adult worms from each site/year were sent for whole genome sequencing. Genetics were analyzed, and selection signals along genomes were detected. Gene enrichment analysis was performed for the genome regions under selection. The results revealed considerable genetic differentiation between the two isolates. The genome "windows" affected by natural selection were fewer in ST (64 windows containing 78 genes) than in HX (318 windows containing 276 genes). Twelve significantly enriched genes were identified in ST, but none in HX. These genes were mainly related to specific DNA binding and intercellular signaling transduction. Some functional region changes identified along the genome of the hilly schistosome may be related to its unique late afternoon cercarial emergence.

Title: Différence génétique entre deux isolats de Schistosoma japonicum présentant des schémas contrastés d'émergence de cercaires, révélés par séquençage du génome entier. Abstract: Schistosoma japonicum est l'un des principaux agents infectieux de la schistosomiase humaine, principalement endémique en Chine et aux Philippines. Nous avons précédemment rapporté la découverte de deux isolats de schistosomes, chacun présentant un schéma différent d'émergence de cercaires, adapté à leurs différents hôtes. Cependant, il n'existe actuellement aucune étude de séquençage du génome entier pour comprendre la génétique sous-jacente aux traits adaptatifs. Nous avons échantillonné des schistosomes en 2013 et 2020 dans une zone de collines de Shitai (ST) et une zone marécageuse de Hexian (HX) de l'Anhui, en Chine. Dix à 15 vers adultes mâles ou femelles de chaque site/année ont été envoyés pour séquençage du génome entier. La génétique a été analysée et des signaux de sélection le long des génomes ont été détectés. Une analyse d'enrichissement génétique a été réalisée pour les régions du génome sélectionnées. Les résultats ont révélé une différenciation génétique considérable entre deux isolats. Les « fenêtres ¼ du génome affectées par la sélection naturelle étaient moins nombreuses dans ST (64 fenêtres contenant 78 gènes) que dans HX (318 fenêtres contenant 276 gènes). Douze gènes significativement enrichis ont été identifiés dans ST mais aucun dans HX. Ces gènes étaient principalement liés à la liaison spécifique à l'ADN et à la transduction de la signalisation intercellulaire. Certains changements de régions fonctionnelles identifiés le long du génome du schistosome des collines peuvent être liés à son émergence cercarienne exceptionnelle en fin d'après-midi.

Uncovering the Impact of Aggrephagy in the Development of Alzheimer's Disease: Insights Into Diagnostic and Therapeutic Approaches from Machine Learning Analysis.

BACKGROUND: Alzheimer's disease (AD) stands as a widespread neurodegenerative disorder marked by the gradual onset of memory impairment, predominantly impacting the elderly. With projections indicating a substantial surge in AD diagnoses, exceeding 13.8 million individuals by 2050, there arises an urgent imperative to discern novel biomarkers for AD. METHODS: To accomplish these objectives, we explored immune cell infiltration and the expression patterns of immune cells and immune function-related genes of AD patients. Furthermore, we utilized the consensus clustering method combined with aggrephagy-related genes (ARGs) for typing AD patients and categorized AD specimens into distinct clusters (C1, C2). A total of 272 candidate genes were meticulously identified through a combination of differential analysis and Weighted Gene Co-Expression Network Analysis (WGCNA). Subsequently, we applied three machine learning algorithms-namely random forest (RF), support vector machine (SVM), and generalized linear model (GLM)-to pinpoint a pathogenic signature comprising five genes associated with AD. To validate the predictive accuracy of these identified genes in discerning AD progression, we constructed nomograms. RESULTS: Our analyses uncovered that cluster C2 exhibits a higher immune expression than C1. Based on the ROC(0.956). We identified five characteristic genes (PFKFB4, PDK3, KIAA0319L, CEBPD, and PHC2T) associated with AD immune cells and function. The nomograms constructed on the basis of these five diagnostic genes demonstrated effectiveness. In the validation group, the ROC values were found to be 0.760 and 0.838, respectively. These results validate the robustness and reliability of the diagnostic model, affirming its potential for accurate identification of AD. CONCLUSION: Our findings not only contribute to a deeper understanding of the molecular mechanisms underlying AD but also offer valuable insights for drug development and clinical analysis. The limitation of our study is the limited sample size, and although AD-related genes were identified and some of the mechanisms elucidated, further experiments are needed to elucidate the more in-depth mechanisms of these characterized genes in the disease.

Unraveling the role of disulfidptosis-related LncRNAs in colon cancer: a prognostic indicator for immunotherapy response, chemotherapy sensitivity, and insights into cell death mechanisms.

Background: Colon cancer, a prevalent and deadly malignancy worldwide, ranks as the third leading cause of cancer-related mortality. Disulfidptosis stress triggers a unique form of programmed cell death known as disulfidoptosis, characterized by excessive intracellular cystine accumulation. This study aimed to establish reliable bioindicators based on long non-coding RNAs (LncRNAs) associated with disulfidptosis-induced cell death, providing novel insights into immunotherapeutic response and prognostic assessment in patients with colon adenocarcinoma (COAD). Methods: Univariate Cox proportional hazard analysis and Lasso regression analysis were performed to identify differentially expressed genes strongly associated with prognosis. Subsequently, a multifactorial model for prognostic risk assessment was developed using multiple Cox proportional hazard regression. Furthermore, we conducted comprehensive evaluations of the characteristics of disulfidptosis response-related LncRNAs, considering clinicopathological features, tumor microenvironment, and chemotherapy sensitivity. The expression levels of prognosis-related genes in COAD patients were validated using quantitative real-time fluorescence PCR (qRT-PCR). Additionally, the role of ZEB1-SA1 in colon cancer was investigated through CCK8 assays, wound healing experiment and transwell experiments. Results: disulfidptosis response-related LncRNAs were identified as robust predictors of COAD prognosis. Multifactorial analysis revealed that the risk score derived from these LncRNAs served as an independent prognostic factor for COAD. Patients in the low-risk group exhibited superior overall survival (OS) compared to those in the high-risk group. Accordingly, our developed Nomogram prediction model, integrating clinical characteristics and risk scores, demonstrated excellent prognostic efficacy. In vitro experiments demonstrated that ZEB1-SA1 promoted the proliferation and migration of COAD cells. Conclusion: Leveraging medical big data and artificial intelligence, we constructed a prediction model for disulfidptosis response-related LncRNAs based on the TCGA-COAD cohort, enabling accurate prognostic prediction in colon cancer patients. The implementation of this model in clinical practice can facilitate precise classification of COAD patients, identification of specific subgroups more likely to respond favorably to immunotherapy and chemotherapy, and inform the development of personalized treatment strategies for COAD patients based on scientific evidence.

Uncovering the immune microenvironment and molecular subtypes of hepatitis B-related liver cirrhosis and developing stable a diagnostic differential model by machine learning and artificial neural networks.

Background: Hepatitis B-related liver cirrhosis (HBV-LC) is a common clinical disease that evolves from chronic hepatitis B (CHB). The development of cirrhosis can be suppressed by pharmacological treatment. When CHB progresses to HBV-LC, the patient's quality of life decreases dramatically and drug therapy is ineffective. Liver transplantation is the most effective treatment, but the lack of donor required for transplantation, the high cost of the procedure and post-transplant rejection make this method unsuitable for most patients. Methods: The aim of this study was to find potential diagnostic biomarkers associated with HBV-LC by bioinformatics analysis and to classify HBV-LC into specific subtypes by consensus clustering. This will provide a new perspective for early diagnosis, clinical treatment and prevention of HCC in HBV-LC patients. Two study-relevant datasets, GSE114783 and GSE84044, were retrieved from the GEO database. We screened HBV-LC for feature genes using differential analysis, weighted gene co-expression network analysis (WGCNA), and three machine learning algorithms including least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) for a total of five methods. After that, we constructed an artificial neural network (ANN) model. A cohort consisting of GSE123932, GSE121248 and GSE119322 was used for external validation. To better predict the risk of HBV-LC development, we also built a nomogram model. And multiple enrichment analyses of genes and samples were performed to understand the biological processes in which they were significantly enriched. And the different subtypes of HBV-LC were analyzed using the Immune infiltration approach. Results: Using the data downloaded from GEO, we developed an ANN model and nomogram based on six feature genes. And consensus clustering of HBV-LC classified them into two subtypes, C1 and C2, and it was hypothesized that patients with subtype C2 might have milder clinical symptoms by immune infiltration analysis. Conclusion: The ANN model and column line graphs constructed with six feature genes showed excellent predictive power, providing a new perspective for early diagnosis and possible treatment of HBV-LC. The delineation of HBV-LC subtypes will facilitate the development of future clinical treatment of HBV-LC.

M2 macrophage inhibits the antitumor effects of Lenvatinib on intrahepatic cholangiocarcinoma.

Background and objectives: The relationship between the tumor microenvironment and the network of key signaling pathways in cancer plays a key role in the occurrence and development of tumors. Tumor-associated macrophages (TAMs) are important inflammatory cells in the tumor microenvironment and play an important role in tumorigenesis and progression. Macrophages in malignant tumors, mainly the M2 subtype, promote tumor progression by producing cytokines and down-regulating anti-inflammatory immune responses. Several articles have investigated the effect of macrophages on the sensitivity of cancer chemotherapeutic agents, but few such articles have been reported in cholangiocarcinoma, so we investigated the effect of M2 macrophage on the sensitivity of cholangiocarcinoma cells to Lenvatinib compared to M1. Methods: THP-1 monocytes were polarized to M0 macrophage by phorbol 12-myristate 13-acetate (PMA) and then induced to differentiate into M1 and M2 macrophages by LPS, IFN-γ and IL-4 and IL-13, respectively. Macrophages and cholangiocarcinoma cells were co-cultured prior to 24 hours of Lenvatinib administration, cancer cell apoptosis was detected by western-blot, FACS analysis of Annexin V and PI staining. Furthermore, we use xCELLigence RTCA SP Instrument (ACEA Bio-sciences) to monitor cell viability of Lenvatinib administration in co-culture of cholangiocarcinoma cells and macrophages. After tumorigenesis in immunodeficient mice, Lenvatinib was administered, and the effects of M2 on biological characteristics of cholangiocarcinoma cells were investigated by immuno-histochemistry. Results: mRNA and protein expression of M1 and M2 markers confirmed the polarization of THP-1 derived macrophages, which provided a successful and efficient model of monocyte polarization to TAMs. Lenvatinib-induced apoptosis of cholangiocarcinoma cells was significantly reduced when co-cultured with M2 macrophage, whereas apoptosis of cholangiocarcinoma cells co-cultured with M1 macrophage was increased. In the CDX model, Lenvatinib-induced cancer cell apoptosis was markedly reduced, and proliferative cells increased in the presence of M2 macrophages. Angiogenesis related factors was significantly increased in cholangiocarcinoma cells co-cultured with M2. Conclusion: Compared with M1, M2 macrophages can inhibit the anti-tumor effect of Lenvatinib on cholangiocarcinoma through immune regulation, which may be related to the tumor angiogenesis factor effect of M2 macrophage.