Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy.

The interplay between extracellular matrix (ECM) stiffness and the tumor microenvironment is increasingly recognized as a critical factor in cancer progression and the efficacy of immunotherapy. This review comprehensively discusses the key factors regulating ECM remodeling, including the activation of cancer-associated fibroblasts and the accumulation and crosslinking of ECM proteins. Furthermore, it provides a detailed exploration of how ECM stiffness influences the behaviors of both tumor and immune cells. Significantly, the impact of ECM stiffness on the response to various immunotherapy strategies, such as immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines, is thoroughly examined. The review also addresses the challenges in translating research findings into clinical practice, highlighting the need for more precise biomaterials that accurately mimic the ECM and the development of novel therapeutic strategies. The insights offered aim to guide future research, with the potential to enhance the effectiveness of cancer immunotherapy modalities.

Longitudinal ultrasound-based AI model predicts axillary lymph node response to neoadjuvant chemotherapy in breast cancer: a multicenter study.

OBJECTIVES: Developing a deep learning radiomics model from longitudinal breast ultrasound and sonographer's axillary ultrasound diagnosis for predicting axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) in breast cancer. METHODS: Breast cancer patients undergoing NAC followed by surgery were recruited from three centers between November 2016 and December 2022. We collected ultrasound images for extracting tumor-derived radiomics and deep learning features, selecting quantitative features through various methods. Two machine learning models based on random forest were developed using pre-NAC and post-NAC features. A support vector machine integrated these data into a fusion model, evaluated via the area under the curve (AUC), decision curve analysis, and calibration curves. We compared the fusion model's performance against sonographer's diagnosis from pre-NAC and post-NAC axillary ultrasonography, referencing histological outcomes from sentinel lymph node biopsy or axillary lymph node dissection. RESULTS: In the validation cohort, the fusion model outperformed both pre-NAC (AUC: 0.899 vs. 0.786, p < 0.001) and post-NAC models (AUC: 0.899 vs. 0.853, p = 0.014), as well as the sonographer's diagnosis of ALN status on pre-NAC and post-NAC axillary ultrasonography (AUC: 0.899 vs. 0.719, p < 0.001). Decision curve analysis revealed patient benefits from the fusion model across threshold probabilities from 0.02 to 0.98. The model also enhanced sonographer's diagnostic ability, increasing accuracy from 71.9% to 79.2%. CONCLUSION: The deep learning radiomics model accurately predicted the ALN response to NAC in breast cancer. Furthermore, the model will assist sonographers to improve their diagnostic ability on ALN status before surgery. CLINICAL RELEVANCE STATEMENT: Our AI model based on pre- and post-neoadjuvant chemotherapy ultrasound can accurately predict axillary lymph node metastasis and assist sonographer's axillary diagnosis. KEY POINTS: Axillary lymph node metastasis status affects the choice of surgical treatment, and currently relies on subjective ultrasound. Our AI model outperformed sonographer's visual diagnosis on axillary ultrasound. Our deep learning radiomics model can improve sonographers' diagnosis and might assist in surgical decision-making.

Manufacturing, quality control, and GLP-grade preclinical study of nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles.

BACKGROUND: Human adipose stromal cells-derived extracellular vesicles (haMSC-EVs) have been shown to alleviate inflammation in acute lung injury (ALI) animal models. However, there are few systemic studies on clinical-grade haMSC-EVs. Our study aimed to investigate the manufacturing, quality control (QC) and preclinical safety of clinical-grade haMSC-EVs. METHODS: haMSC-EVs were isolated from the conditioned medium of human adipose MSCs incubated in 2D containers. Purification was performed by PEG precipitation and differential centrifugation. Characterizations were conducted by nanoparticle tracking analysis, transmission electron microscopy (TEM), Western blotting, nanoflow cytometry analysis, and the TNF-α inhibition ratio of macrophage [after stimulated by lipopolysaccharide (LPS)]. RNA-seq and proteomic analysis with liquid chromatography tandem mass spectrometry (LC-MS/MS) were used to inspect the lot-to-lot consistency of the EV products. Repeated toxicity was evaluated in rats after administration using trace liquid endotracheal nebulizers for 28 days, and respiratory toxicity was evaluated 24 h after the first administration. In vivo therapeutic effects were assessed in an LPS-induced ALI/ acute respiratory distress syndrome (ARDS) rat model. RESULTS: The quality criteria have been standardized. In a stability study, haMSC-EVs were found to remain stable after 6 months of storage at - 80°C, 3 months at - 20 °C, and 6 h at room temperature. The microRNA profile and proteome of haMSC-EVs demonstrated suitable lot-to-lot consistency, further suggesting the stability of the production processes. Intratracheally administered 1.5 × 108 particles/rat/day for four weeks elicited no significant toxicity in rats. In LPS-induced ALI/ARDS model rats, intratracheally administered haMSC-EVs alleviated lung injury, possibly by reducing the serum level of inflammatory factors. CONCLUSION: haMSC-EVs, as an off-shelf drug, have suitable stability and lot-to-lot consistency. Intratracheally administered haMSC-EVs demonstrated excellent safety at the tested dosages in systematic preclinical toxicity studies. Intratracheally administered haMSC-EVs improved the lung function and exerted anti-inflammatory effects on LPS-induced ALI/ARDS model rats.

New frontiers in salivary extracellular vesicles: transforming diagnostics, monitoring, and therapeutics in oral and systemic diseases.

Salivary extracellular vesicles (EVs) have emerged as key tools for non-invasive diagnostics, playing a crucial role in the early detection and monitoring of diseases. These EVs surpass whole saliva in biomarker detection due to their enhanced stability, which minimizes contamination and enzymatic degradation. The review comprehensively discusses methods for isolating, enriching, quantifying, and characterizing salivary EVs. It highlights their importance as biomarkers in oral diseases like periodontitis and oral cancer, and underscores their potential in monitoring systemic conditions. Furthermore, the review explores the therapeutic possibilities of salivary EVs, particularly in personalized medicine through engineered EVs for targeted drug delivery. The discussion also covers the current challenges and future prospects in the field, emphasizing the potential of salivary EVs in advancing clinical practice and disease management.

[Analysis of 141 cases with benign upper airway occupying in infant].

Objective:To analyze and summarize the clinical characteristics, diagnosis, treatment and prognosis of benign upper airway space occupancy in infants. Methods:The clinical data of 141 cases with begin upper airway space from January 2012 to January 2022 were analyzed. Among them, 101 were male and 68 were female, the age is 0-3 years old. In which there were 24 newborns. The clinical characteristics, auxiliary examination and treatment results were summarized and analyzed. Results:The main clinical manifestations of 141 infants were dyspnea and/or laryngeal wheezing, including 116 cases of congenital cyst of tongue, 15 cases of hair polyps, 4 cases of nasopharyngeal second pharyngeal fissure cysts, 2 cases of congenital laryngeal cysts, 2 cases of pharyngeal bronchial cyst, 1 case of nasopharyngeal teratoma and 1 case of myofibroma. All the infants had completed the corresponding examination and treatment. The diagnosis was clear, and there was no missed diagnosis or misdiagnosis. Among them, 19 infants with congenital cyst of tongue were given cyst puncture to relieve dyspnea. 2 cases of congenital cyst of tongue recurred half a year after operaion, and then they underwent reoperation. The prognosis of the remaining infants were good. Conclusion:The most common occupying of benign upper airway space occupancy is cyst, and low-temperature plasma resection under endoscope is the main treatment method. Timely puncture therapy is also a safe and effective treatment for infants who are dyspnea and life threatening.

Ginsenoside Rg1 Induces Autophagy in Colorectal Cancer through Inhibition of the Akt/mTOR/p70S6K Pathway.

This study aimed to elucidate the anti-colon cancer mechanism of ginsenoside Rg1 in vitro and in vivo. Cell viability rate was detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tetrazolium assay. The inhibitory effect of ginsenoside Rg1 against CT26 cell proliferation gradually increased with increasing concentration. The in vivo experiments also demonstrated an antitumor effect. The monodansylcadaverine (MDC), transmission electron microscopy (TEM), and expression of autophagy marker proteins confirmed that ginsenoside Rg1 induced autophagy in vitro. Ginsenoside Rg1 induced autophagy death of CT26 cells, but this effect could be diminished by autophagy inhibitor (3-methyladenine, 3-MA). Additionally, in a xenograft model, immunohistochemical analysis of tumor tissues showed that the LC3 and Beclin-1 proteins were highly expressed in the tumors from the ginsenoside Rg1-treated nude mice, confirming that ginsenoside Rg1 also induced autophagy in vivo. Furthermoer, both in vivo and in vitro, the protein expressions of p-Akt, p-mTOR, and p-p70S6K were inhibited by ginsenoside Rg1, which was verified by Akt inhibitors. These results indicated that the mechanism of ginsenoside Rg1 against colon cancer was associated with autophagy through inhibition of the Akt/mTOR/p70S6K signaling pathway.

Diagnostic and prognostic nomograms for laryngeal carcinoma patients with lung metastasis: a SEER-based study.

PURPOSE: To establish two nomograms to quantify the risk of lung metastasis (LM) in laryngeal carcinoma (LC) and predict the overall survival of LC patients with LM. METHODS: Totally 9515 LC patients diagnosed histologically from 2000 to 2019 were collected from the Surveillance, Epidemiology, and End Results database. The independent diagnostic factors for LM in LC patients and prognostic factors for LC patients with LM were identified by logistic and Cox regression analysis, respectively. Nomograms were established based on regression coefficients and evaluated by receiver operating characteristic curve, calibration curves, and decision curve analysis. RESULTS: Patients with supraglottis, higher pathological grade, higher N stage, and distant metastasis (bone, brain, or liver) were more likely to have LM (P < 0.05). Chemotherapy, surgery and radiotherapy were independent factors of the overall survival of LC patients with LM (P < 0.05). The area under curve of diagnostic nomogram were 0.834 and 0.816 in the training and validation cohort respectively. For the prognostic nomogram, the area under curves of 1-, 2-, and 3-years were 0.735, 0.734, and 0.709 in the training cohort and 0.705, 0.803, and 0.809 in the validation cohort. The calibration curves and decision curve analysis indicated good performance of the nomograms. CONCLUSION: Distant metastasis (bone, brain, or liver) and N stage should be considered for prediction of LM in LC patients. Chemotherapy is the most significant influencing prognostic factor improving the survival of LC patients with LM. Two nomograms may benefit for providing better precautionary measures and treatment decision.

Characterization of the structure, anti-inflammatory activity and molecular docking of a neutral polysaccharide separated from American ginseng berries.

AIM: American ginseng berries, grown in the aerial parts and harvested in August, are a potentially valuable material. The aim of the study was to analyze the specific polysaccharides in American ginseng berries, and to demonstrate the anti-inflammation effect through in vitro and in vivo experiments and molecular docking. METHODS: After deproteinization and dialysis, the extracted crude polysaccharide was separated and purified. The structure of the specific isolated polysaccharide was investigated by Fourier Transform infrared spectroscopy (FT-IR), GC-MS and nuclear magnetic resonance (NMR), and anti-inflammatory activity was evaluated using in vitro and in vivo models (Raw 264.7 cells and zebrafish). Molecular docking was used to analyze the binding capacity and interaction with cyclooxygenase-2 (COX-2). RESULTS: A novel neutral polysaccharide fraction (AGBP-A) was isolated from American ginseng berries. The structural analysis demonstrated that AGBP-A had a weight-average molecular weight (Mw) of 122,988 Da with a dispersity index (Mw/Mn) value of 1.59 and was composed of arabinose and galactose with a core structure containing →6)-Gal-(1→ residues as the backbone and a branching substitution at the C3 position. The side-chains comprised of α-L-Ara-(1→, α-L-Ara-(1→, →5)-α-L-Ara-(1→, ß-D-Gal-(1→. The results showed that it significantly decreased pro-inflammatory cytokines in the cell model. In a zebrafish model, AGBP-A reduced the massive recruitment of neutrophils to the caudal lateral line neuromast, suggesting the relief of inflammation. Molecular docking was used to analyze the combined capacity and interaction with COX-2. CONCLUSION: Our study indicated the potential efficacy of AGBP-A as a safe and valid natural anti-inflammatory component.

Resveratrol mediates mitochondrial function through the sirtuin 3 pathway to improve abnormal metabolic remodeling in atrial fibrillation.

This study investigated the impact of resveratrol on abnormal metabolic remodeling in atrial fibrillation (AF) and explored potential molecular mechanisms. An AF cell model was established by high-frequency electrical stimulation of HL-1 atrial muscle cells. Resveratrol concentrations were optimized using CCK-8 and flow cytometry. AF-induced increases in ROS and mitochondrial calcium, along with decreased adenosine triphosphate (ATP) and mitochondrial membrane potential, were observed. Resveratrol mitigated these changes and maintained normal mitochondrial morphology. Moreover, resveratrol acted through the SIRT3-dependent pathway, as evidenced by its ability to suppress AF-induced acetylation of key metabolic enzymes. SIRT3 overexpression controls acetylation modifications, suggesting its regulatory role. In conclusion, resveratrol's SIRT3-dependent pathway intervenes in AF-induced mitochondrial dysfunction, presenting a potential therapeutic avenue for AF-related metabolic disorders. This study sheds light on the role of resveratrol in mitigating AF-induced mitochondrial remodeling and highlights its potential as a novel treatment for AF.

Development of a Novel Contrast-Enhanced Ultrasound-Based Nomogram for Superficial Lymphadenopathy Differentiation: Postvascular Phase Value.

OBJECTIVE: The aim of this study was to develop and prospectively validate a prediction model for superficial lymphadenopathy differentiation using Sonazoid contrast-enhanced ultrasound (CEUS) combined with ultrasound (US) and clinical data. METHODS: The training cohort comprised 260 retrospectively enrolled patients with 260 pathological lymph nodes imaged between January and December 2020. Two clinical US-CEUS models were created using multivariable logistic regression analysis and compared using receiver operating characteristic curve analysis: Model 1 included clinical and US characteristics; Model 2 included all confirmed predictors, including CEUS characteristics. Feature contributions were evaluated using the SHapley Additive exPlanations (SHAP) algorithm. Data from 172 patients were prospectively collected between January and May 2021 for model validation. RESULTS: Age, tumor history, long-axis diameter of lymph node, blood flow distribution, echogenic hilus, and the mean postvascular phase intensity (MPI) were identified as independent predictors for malignant lymphadenopathy. The area under the curve (AUC), sensitivity, specificity, and accuracy of MPI alone was 0.858 (95% confidence interval [CI], 0.817-0.891), 86.47%, 74.55%, and 81.2%, respectively. Model 2 had an AUC of 0.919 (95% CI, 0.879-0.949) and good calibration in training and validation cohorts. The incorporation of MPI significantly enhanced diagnostic capability (p < 0.0001 and p = 0.002 for training and validation cohorts, respectively). Decision curve analysis indicated Model 2 as the superior diagnostic tool. SHAP analysis highlighted MPI as the most pivotal feature in the diagnostic process. CONCLUSION: The employment of our straightforward prediction model has the potential to enhance clinical decision-making and mitigate the need for unwarranted biopsies.

Association of Rare NOTCH3 Variants With Prevalent and Incident Stroke and Dementia in the General Population.

BACKGROUND: It is uncertain whether rare NOTCH3 variants are associated with stroke and dementia in the general population and whether they lead to alterations in cognitive function. This study aims to determine the associations of rare NOTCH3 variants with prevalent and incident stroke and dementia, as well as cognitive function changes. METHODS AND RESULTS: In the prospective community-based Shunyi Study, a total of 1007 participants were included in the baseline analysis. For the follow-up analysis, 1007 participants were included in the stroke analysis, and 870 participants in the dementia analysis. All participants underwent baseline brain magnetic resonance imaging, carotid ultrasound, and whole exome sequencing. Rare NOTCH3 variants were defined as variants with minor allele frequency <1%. A total of 137 rare NOTCH3 carriers were enrolled in the baseline study. At baseline, rare NOTCH3 variant carriers had higher rates of stroke (8.8% versus 5.6%) and dementia (2.9% versus 0.8%) compared with noncarriers. After adjustment for associated risk factors, the epidermal growth factor-like repeats (EGFr)-involving rare NOTCH3 variants were associated with a higher risk of prevalent stroke (odds ratio [OR], 2.697 [95% CI, 1.266-5.745]; P=0.040) and dementia (OR, 8.498 [95% CI, 1.727-41.812]; P=0.032). After 5 years of follow-up, we did not find that the rare NOTCH3 variants increased the risk of incident stroke and dementia. There was no statistical difference in the change in longitudinal cognitive scale scores. CONCLUSIONS: Rare NOTCH3 EGFr-involving variants are genetic risk factors for stroke and dementia in the general Chinese population.

Bowel preparation protocol for hospitalized patients ages 50 years or older: A randomized controlled trial.

BACKGROUND: The incidence and mortality rate of colorectal cancer progressively increase with age and become particularly prominent after the age of 50 years. Therefore, the population that is ≥ 50 years in age requires long-term and regular colonoscopies. Uncomfortable bowel preparation is the main reason preventing patients from undergoing regular colonoscopies. The standard bowel preparation regimen of 4-L polyethylene glycol (PEG) is effective but poorly tolerated. AIM: To investigate an effective and comfortable bowel preparation regimen for hospitalized patients ≥ 50 years in age. METHODS: Patients were randomly assigned to group 1 (2-L PEG + 30-mL lactulose + a low-residue diet) or group 2 (4-L PEG). Adequate bowel preparation was defined as a Boston bowel preparation scale (BBPS) score of ≥ 6, with a score of ≥ 2 for each segment. Non-inferiority was prespecified with a margin of 10%. Additionally, the degree of comfort was assessed based on the comfort questionnaire. RESULTS: The proportion of patients with a BBPS score of ≥ 6 in group 1 was not significantly different from that in group 2, as demonstrated by intention-to-treat (91.2% vs 91.0%, P = 0.953) and per-protocol (91.8% vs 91.0%, P = 0.802) analyses. Furthermore, in patients ≥ 75 years in age, the proportion of BBPS scores of ≥ 6 in group 1 was not significantly different from that in group 2 (90.9% vs 97.0%, P = 0.716). Group 1 had higher comfort scores (8.85 ± 1.162 vs 7.59 ± 1.735, P < 0.001), longer sleep duration (6.86 ± 1.204 h vs 5.80 ± 1.730 h, P < 0.001), and fewer awakenings (1.42 ± 1.183 vs 2.04 ± 1.835, P = 0.026) than group 2. CONCLUSION: For hospitalized patients ≥ 50 years in age, the bowel preparation regimen comprising 2-L PEG + 30-mL lactulose + a low-residue diet produced a cleanse that was as effective as the 4-L PEG regimen and even provided better comfort.

Differences in the perceptions of patients with primary biliary cholangitis and physicians from various hospital departments: An online survey.

OBJECTIVES: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease that affects the quality of life (QoL) of patients. This study aimed to evaluate the differences in perceptions of PBC among physicians from different hospital departments and patients with PBC. METHODS: An online survey regarding the general knowledge, diagnosis, and management of PBC was completed by physicians and patients. RESULTS: A total of 239 patients with PBC and 239 physicians from eight hospital departments (gastroenterology, infectious diseases, rheumatology, hepatobiliary surgery, pathology, clinical laboratory, ultrasound, and radiology) completed the survey. The results showed that physicians from departments other than gastroenterologists and rheumatologists lacked knowledge of PBC, and that junior gastroenterologists were uncertain about the diagnostic and treatment pathways of PBC. Importantly, the lack of knowledge significantly impacted the QoL of patients, especially the emotional scores of PBC-40 (odds ratio -2.556, 95% confidence interval -3.852 to -1.260, P < 0.001). In addition, there was a perceived knowledge gap between patients and gastroenterologists. CONCLUSIONS: Physicians must improve their awareness of PBC. Patient education and patient-physician communication are important for improving the patient's QoL.

Application Research Progress of Nanomaterial Graphene and its Derivative Complexes in Tumor Diagnosis and Therapy.

Functional nanomaterial graphene and its derivatives have attracted considerable attention in many fields because of their unique physical and chemical properties. Most notably, graphene has become a research hotspot in the biomedical field, especially in relation to malignant tumors. In this study, we briefly review relevant research from recent years on graphene and its derivatives in tumor diagnosis and antitumor therapy. The main contents of the study include the graphene-derivative diagnosis of tumors in the early stage, graphene quantum dots, photodynamics, MRI contrast agent, acoustic dynamics, and the effects of ultrasonic cavitation and graphene on tumor therapy. Moreover, the biocompatibility of graphene is briefly described. This review provides a broad overview of the applications of graphene and its derivatives in tumors. Conclusion, graphene and its derivatives play an important role in tumor diagnosis and treatment.

Application of computer-aided diagnosis to predict malignancy in BI-RADS 3 breast lesions.

Purpose: To evaluate the ability of computer-aided diagnosis (CAD) system (S-Detect) to identify malignancy in ultrasound (US) -detected BI-RADS 3 breast lesions. Materials and methods: 148 patients with 148 breast lesions categorized as BI-RADS 3 were included in the study between January 2021 and September 2022. The malignancy rate, accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) were calculated. Results: In this study, 143 breast lesions were found to be benign, and 5 breast lesions were malignant (malignancy rate, 3.4 %, 95 % confidence interval (CI): 0.5-6.3). The malignancy rate rose significantly to 18.2 % (4/22, 95 % CI: 2.1-34.3) in the high-risk group with a "possibly malignant" CAD result (p = 0.017). With a "possibly benign" CAD result, the malignancy rate decreased to 0.8 % (1/126, 95 % CI: 0-2.2) in the low-risk group (p = 0.297). The AUC, sensitivity, specificity, accuracy, PPV, and NPV of the CAD system in BI-RADS 3 breast lesions were 0.837 (95 % CI: 77.7-89.6), 80.0 % (95 % CI: 73.6-86.4), 87.4 % (95 % CI: 82.0-92.7), 87.2 % (95 % CI: 81.8-92.6), 18.2 % (95 % CI: 2.1-34.3) and 99.2 % (95 % CI: 97.8-100.0), respectively. Conclusions: CAD system (S-Detect) enables radiologists to distinguish a high-risk group and a low-risk group among US-detected BI-RADS 3 breast lesions, so that patients in the low-risk group can receive follow-up without anxiety, while those in the high-risk group with a significantly increased malignancy rate should actively receive biopsy to avoid delayed diagnosis of breast cancer.

Size effects of microplastics on antibiotic resistome and core microbiome in an urban river.

Microplastics (MPs) in aquatic environments provide a new ecological niche that facilitates the attachment of antibiotic-resistance genes (ARGs) and pathogens. However, the effect of particle size on the colonization of antibiotic resistomes and pathogens remains poorly understood. To address this knowledge gap, this study explored the antibiotic resistome and core microbiome on three distinct types of MPs including polyethylene, polypropylene, and polystyrene (PS), with varying sizes of 30, 200, and 3000 µm by metagenomic sequencing. Our finding showed that the ARG abundances of the PS type increased by 4-folds with increasing particle size from 30 to 3000 µm, and significant differences in ARG profiles were found across the three MP types. In addition, the concentrations of ARGs and mobile genetic elements (MGEs) were markedly higher in the MPs than in the surrounding water, indicating their enrichment at these artificial interfaces. Notably, several pathogens such as Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Legionella pneumophila were enriched in MP biofilms, and the co-occurrence of ARGs and virulence factor genes (VFGs)/MGEs suggested the presence of pathogenic antibiotic-resistant microbes with potential mobility. Both redundancy analysis (RDA) and structural equation modeling (SEM) demonstrated that physicochemical properties such as zeta potential, MP size, and contact angle were the most significant contributors to the antibiotic resistome. Strikingly, no significant differences were observed in the health risk scores of the ARG profiles among different sizes and types of MPs. This study expands our knowledge on the impact of MP size on microbial risks, thus enhancing our understanding of the potential health hazards they pose.

Sono-anatomy of the middle cervical sympathetic ganglion verified with pathology.

Objectives: Cervical discomfort and other symptoms may be attributable to the middle cervical sympathetic ganglion. The aim of this study was to explore the sonographic features of this ganglion in anatomical specimens and cadavers and evaluate the feasibility of its visualization using high-resolution ultrasonography. Methods: We examined three cervical sympathetic-ganglion specimens and two fresh cadavers using high-resolution ultrasound to explore the sonographic features of this ganglion. Basic imaging characteristics examined included the shape, echo intensity, and location of the ganglion. Core-needle biopsy was performed to examine the suspected middle cervical sympathetic ganglion in the two fresh cadavers and verify the accuracy of the sonographic identification via pathological examination. Results: The middle cervical sympathetic ganglion appeared on high-resolution ultrasonography as an oval-shaped hypoechoic structure, with at least one continuous hypoechoic line connected to each ending in the anatomical specimens and fresh cadavers, and it was distinctly different from the adjacent lymph nodes. Discussion: Based on an adequate understanding of both its location and sonographic features, the direct visualization of the middle cervical sympathetic ganglion using high-resolution ultrasonography is feasible.

Hypoxia-driven TNS4 fosters HNSCC tumorigenesis by stabilizing integrin α5ß1 complex and triggering FAK-mediated Akt and TGFß signaling pathways.

Head and neck squamous cell carcinoma (HNSCC) remains a formidable clinical challenge due to its high recurrence rate and limited targeted therapeutic options. This study aims to elucidate the role of tensin 4 (TNS4) in the pathogenesis of HNSCC across clinical, cellular, and animal levels. We found a significant upregulation of TNS4 expression in HNSCC tissues compared to normal controls. Elevated levels of TNS4 were associated with adverse clinical outcomes, including diminished overall survival. Functional assays revealed that TNS4 knockdown attenuated, and its overexpression augmented, the oncogenic capabilities of HNSCC cells both in vitro and in vivo. Mechanistic studies revealed that TNS4 overexpression promotes the interaction between integrin α5 and integrin ß1, thereby activating focal adhesion kinase (FAK). This TNS4-mediated FAK activation simultaneously enhanced the PI3K/Akt signaling pathway and facilitated the interaction between TGFßRI and TGFßRII, leading to the activation of the TGFß signaling pathway. Both of these activated pathways contributed to HNSCC tumorigenesis. Additionally, we found that hypoxia-inducible factor 1α (HIF-1α) transcriptionally regulated TNS4 expression. In conclusion, our findings provide the basis for innovative TNS4-targeted therapeutic strategies, which could potentially improve prognosis and survival rates for patients with HNSCC.

PD-1 inhibitors plus chemotherapy as first-line therapy for stage IV ESCC.

To evaluate the anti-tumor efficacy and tolerability of programmed cell death protein 1 (PD-1) inhibitors plus chemotherapy versus chemotherapy alone as first-line therapy for unresectable esophageal squamous cell carcinoma (ESCC) patients at stage IV in a real-world cohort. All unresectable ESCC patients at stage IV who initiated first-line therapy with PD-1 inhibitors plus chemotherapy between August 2018 and March 2021 in a general hospital in China were retrospectively analyzed in this study. Propensity score matching (1:1) with control patients receiving chemotherapy alone was performed. Overall survival (OS) and progression-free survival (PFS) were assessed by the Kaplan-Meier method. In this study, fifty patients (n = 25 each group) were included, all of whom could be evaluated for efficacy. PD-1 inhibitors plus chemotherapy exhibited better OS than chemotherapy alone (median 15.8 vs 12.4 months, hazard ratio [HR] 0.46 [95% CI 0.23-0.95]; P = 0.036). The median PFS for the PD-1 inhibitors plus chemotherapy group was 8.7 months compared with 6.1 months for the chemotherapy group (HR 0.48 [95% CI 0.26-0.90]; P = 0.014). Adverse events (AEs) of grade 3 or above related to treatment were found in 24.0% and 32.0% of the PD-1 inhibitors plus chemotherapy and chemotherapy alone groups, respectively. PD-1 inhibitors plus chemotherapy exhibited durable anti-tumor activity and relatively controllable safety as first-line therapy for unresectable ESCC patients at stage IV, but these results need to be confirmed by further research.

Epitranscriptomic modifications in mesenchymal stem cell differentiation: advances, mechanistic insights, and beyond.

RNA modifications, known as the "epitranscriptome", represent a key layer of regulation that influences a wide array of biological processes in mesenchymal stem cells (MSCs). These modifications, catalyzed by specific enzymes, often termed "writers", "readers", and "erasers", can dynamically alter the MSCs' transcriptomic landscape, thereby modulating cell differentiation, proliferation, and responses to environmental cues. These enzymes include members of the classes METTL, IGF2BP, WTAP, YTHD, FTO, NAT, and others. Many of these RNA-modifying agents are active during MSC lineage differentiation. This review provides a comprehensive overview of the current understanding of different RNA modifications in MSCs, their roles in regulating stem cell behavior, and their implications in MSC-based therapies. It delves into how RNA modifications impact MSC biology, the functional significance of individual modifications, and the complex interplay among these modifications. We further discuss how these intricate regulatory mechanisms contribute to the functional diversity of MSCs, and how they might be harnessed for therapeutic applications. The review also highlights current challenges and potential future directions in the study of RNA modifications in MSCs, emphasizing the need for innovative tools to precisely map these modifications and decipher their context-specific effects. Collectively, this work paves the way for a deeper understanding of the role of the epitranscriptome in MSC biology, potentially advancing therapeutic strategies in regenerative medicine and MSC-based therapies.