Hydrogen Therapy Reverses Cancer-Associated Fibroblasts Phenotypes and Remodels Stromal Microenvironment to Stimulate Systematic Anti-Tumor Immunity.

Tumor microenvironment (TME) plays an important role in the tumor progression. Among TME components, cancer-associated fibroblasts (CAFs) show multiple tumor-promoting effects and can induce tumor immune evasion and drug-resistance. Regulating CAFs can be a potential strategy to augment systemic anti-tumor immunity. Here, the study observes that hydrogen treatment can alleviate intracellular reactive oxygen species of CAFs and reshape CAFs' tumor-promoting and immune-suppressive phenotypes. Accordingly, a controllable and TME-responsive hydrogen therapy based on a CaCO3 nanoparticles-coated magnesium system (Mg-CaCO3) is developed. The hydrogen therapy by Mg-CaCO3 can not only directly kill tumor cells, but also inhibit pro-tumor and immune suppressive factors in CAFs, and thus augment immune activities of CD4+ T cells. As implanted in situ, Mg-CaCO3 can significantly suppress tumor growth, turn the "cold" primary tumor into "hot", and stimulate systematic anti-tumor immunity, which is confirmed by the bilateral tumor transplantation models of "cold tumor" (4T1 cells) and "hot tumor" (MC38 cells). This hydrogen therapy system reverses immune suppressive phenotypes of CAFs, thus providing a systematic anti-tumor immune stimulating strategy by remodeling tumor stromal microenvironment.

Neurotransmitter accumulation and Parkinson's disease-like phenotype caused by anion channelrhodopsin opto-controlled astrocytic mitochondrial depolarization in substantia nigra pars compacta.

Parkinson's disease (PD) is a mitochondria-related neurodegenerative disease characterized by locomotor deficits and loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Majority of PD research primarily focused on neuronal dysfunction, while the roles of astrocytes and their mitochondria remain largely unexplored. To bridge the gap and investigate the roles of astrocytic mitochondria in PD progression, we constructed a specialized optogenetic tool, mitochondrial-targeted anion channelrhodopsin, to manipulate mitochondrial membrane potential in astrocytes. Utilizing this tool, the depolarization of astrocytic mitochondria within the SNc in vivo led to the accumulation of γ-aminobutyric acid (GABA) and glutamate in SNc, subsequently resulting in excitatory/inhibitory imbalance and locomotor deficits. Consequently, in vivo calcium imaging and interventions of neurotransmitter antagonists demonstrated that GABA accumulation mediated movement deficits of mice. Furthermore, 1 h/day intermittent astrocytic mitochondrial depolarization for 2 weeks triggered spontaneous locomotor dysfunction, α-synuclein aggregation, and the loss of DA neurons, suggesting that astrocytic mitochondrial depolarization was sufficient to induce a PD-like phenotype. In summary, our findings suggest the maintenance of proper astrocytic mitochondrial function and the reinstatement of a balanced neurotransmitter profile may provide a new angle for mitigating neuronal dysfunction during the initial phases of PD.

Single-cell analyses reveal the metabolic heterogeneity and plasticity of the tumor microenvironment during head and neck squamous cell carcinoma progression.

Metabolic reprogramming is a hallmark of cancer. In addition to metabolic alterations in the tumor cells, multiple other metabolically active cell types in the tumor microenvironment (TME) contribute to the emergence of a tumor-specific metabolic milieu. Here, we defined the metabolic landscape of the TME during progression of head and neck squamous cell carcinoma (HNSCC) by performing single-cell RNA sequencing (scRNA-seq) on 26 human patient specimens, including normal tissue, pre-cancerous lesions, early-stage cancer, advanced-stage cancer, lymph node metastases, and recurrent tumors. The analysis revealed substantial heterogeneity at the transcriptional, developmental, metabolic, and functional levels in different cell types. SPP1+ macrophages were identified as a pro-tumor and pro-metastatic macrophage subtype with high fructose and mannose metabolism, which was further substantiated by integrative analysis and validation experiments. An inhibitor of fructose metabolism reduced the proportion of SPP1+ macrophages, reshaped the immunosuppressive TME, and suppressed tumor growth. In conclusion, this work delineated the metabolic landscape of HNSCC at a single-cell resolution and identified fructose metabolism as a key metabolic feature of a pro-tumor macrophage subpopulation.

Cross-domain information fusion and personalized recommendation in artificial intelligence recommendation system based on mathematical matrix decomposition.

Given the challenges of inter-domain information fusion and data sparsity in collaborative filtering algorithms, this paper proposes a cross-domain information fusion matrix decomposition algorithm to enhance the accuracy of personalized recommendations in artificial intelligence recommendation systems. The study begins by collecting Douban movie rating data and social network information. To ensure data integrity, Levenshtein distance detection is employed to remove duplicate scores, while natural language processing technology is utilized to extract keywords and topic information from social texts. Additionally, graph convolutional networks are utilized to convert user relationships into feature vectors, and a unique thermal coding method is used to convert discrete user and movie information into binary matrices. To prevent overfitting, the Ridge regularization method is introduced to gradually optimize potential feature vectors. Weighted average and feature connection techniques are then applied to integrate features from different fields. Moreover, the paper combines the item-based collaborative filtering algorithm with merged user characteristics to generate personalized recommendation lists.In the experimental stage, the paper conducts cross-domain information fusion optimization on four mainstream mathematical matrix decomposition algorithms: alternating least squares method, non-negative matrix decomposition, singular value decomposition, and latent factor model (LFM). It compares these algorithms with the non-fused approach. The results indicate a significant improvement in score accuracy, with mean absolute error and root mean squared error reduced by 12.8% and 13.2% respectively across the four algorithms. Additionally, when k = 10, the average F1 score reaches 0.97, and the ranking accuracy coverage of the LFM algorithm increases by 54.2%. Overall, the mathematical matrix decomposition algorithm combined with cross-domain information fusion demonstrates clear advantages in accuracy, prediction performance, recommendation diversity, and ranking quality, and improves the accuracy and diversity of the recommendation system. By effectively addressing collaborative filtering challenges through the integration of diverse techniques, it significantly surpasses traditional models in recommendation accuracy and variety.

FUT8-mediated aberrant N-glycosylation of SEMA7A promotes head and neck squamous cell carcinoma progression.

SEMA7A belongs to the Semaphorin family and is involved in the oncogenesis and tumor progression. Aberrant glycosylation has been intricately linked with immune escape and tumor growth. SEMA7A is a highly glycosylated protein with five glycosylated sites. The underlying mechanisms of SEMA7A glycosylation and its contribution to immunosuppression and tumorigenesis are unclear. Here, we identify overexpression and aberrant N-glycosylation of SEMA7A in head and neck squamous cell carcinoma, and elucidate fucosyltransferase FUT8 catalyzes aberrant core fucosylation in SEMA7A at N-linked oligosaccharides (Asn 105, 157, 258, 330, and 602) via a direct protein‒protein interaction. A glycosylated statue of SEMA7A is necessary for its intra-cellular trafficking from the cytoplasm to the cytomembrane. Cytokine EGF triggers SEMA7A N-glycosylation through increasing the binding affinity of SEMA7A toward FUT8, whereas TGF-ß1 promotes abnormal glycosylation of SEMA7A via induction of epithelial-mesenchymal transition. Aberrant N-glycosylation of SEMA7A leads to the differentiation of CD8+ T cells along a trajectory toward an exhausted state, thus shaping an immunosuppressive microenvironment and being resistant immunogenic cell death. Deglycosylation of SEMA7A significantly improves the clinical outcome of EGFR-targeted and anti-PD-L1-based immunotherapy. Finally, we also define RBM4, a splice regulator, as a downstream effector of glycosylated SEMA7A and a pivotal mediator of PD-L1 alternative splicing. These findings suggest that targeting FUT8-SEMA7A axis might be a promising strategy for improving antitumor responses in head and neck squamous cell carcinoma patients.

Progress of Multiparameter Magnetic Resonance Imaging in Bladder Cancer: A Comprehensive Literature Review.

Magnetic resonance imaging (MRI) has been proven to be an indispensable imaging method in bladder cancer, and it can accurately identify muscular invasion of bladder cancer. Multiparameter MRI is a promising tool widely used for preoperative staging evaluation of bladder cancer. Vesical Imaging-Reporting and Data System (VI-RADS) scoring has proven to be a reliable tool for local staging of bladder cancer with high accuracy in preoperative staging, but VI-RADS still faces challenges and needs further improvement. Artificial intelligence (AI) holds great promise in improving the accuracy of diagnosis and predicting the prognosis of bladder cancer. Automated machine learning techniques based on radiomics features derived from MRI have been utilized in bladder cancer diagnosis and have demonstrated promising potential for practical implementation. Future work should focus on conducting more prospective, multicenter studies to validate the additional value of quantitative studies and optimize prediction models by combining other biomarkers, such as urine and serum biomarkers. This review assesses the value of multiparameter MRI in the accurate evaluation of muscular invasion of bladder cancer, as well as the current status and progress of its application in the evaluation of efficacy and prognosis.

Generation of induced pluripotent stem cells (ZZUCSBi001-A) from skin fibroblasts of a healthy donor.

Fibroblasts were extracted from the scalp of a healthy 55-year-old male and subsequently transformed into pluripotent stem cells by introducing episomal plasmids harboring essential reprogramming factors. These induced pluripotent stem cells exhibited a normal karyotype and demonstrated the capacity to differentiate into all three germ layers, as confirmed through teratoma assays. This specific cell line serves as a valuable reference for comparative investigations alongside other induced pluripotent stem cell lines generated from somatic cells of patients afflicted by genetic neurodegenerative disorders.

Macrophage heterogeneity and its interactions with stromal cells in tumour microenvironment.

Macrophages and tumour stroma cells account for the main cellular components in the tumour microenvironment (TME). Current advancements in single-cell analysis have revolutionized our understanding of macrophage diversity and macrophage-stroma interactions. Accordingly, this review describes new insight into tumour-associated macrophage (TAM) heterogeneity in terms of tumour type, phenotype, metabolism, and spatial distribution and presents the association between these factors and TAM functional states. Meanwhile, we focus on the immunomodulatory feature of TAMs and highlight the tumour-promoting effect of macrophage-tumour stroma interactions in the immunosuppressive TME. Finally, we summarize recent studies investigating macrophage-targeted therapy and discuss their therapeutic potential in improving immunotherapy by alleviating immunosuppression.

Non-contrast-enhanced magnetic resonance urography for measuring split kidney function in pediatric patients with hydronephrosis: comparison with renal scintigraphy.

BACKGROUND: Split kidney function (SKF) is critical for treatment decision in pediatric patients with hydronephrosis and is commonly measured using renal scintigraphy (RS). Non-contrast-enhanced magnetic resonance urography (NCE-MRU) is increasingly used in clinical practice. This study aimed to investigate the feasibility of using NCE-MRU as an alternative to estimate SKF in pediatric patients with hydronephrosis, compared to RS. METHODS: Seventy-five pediatric patients with hydronephrosis were included in this retrospective study. All patients underwent NCE-MRU and RS within 2 weeks. Kidney parenchyma volume (KPV) and texture analysis parameters were obtained from T2-weighted (T2WI) in NCE-MRU. The calculated split KPV (SKPV) percent and texture analysis parameters percent of left kidney were compared with the RS-determined SKF. RESULTS: SKPV showed a significant positive correlation with SKF (r = 0.88, p < 0.001), while inhomogeneity was negatively correlated with SKF (r = - 0.68, p < 0.001). The uncorrected and corrected prediction models of SKF were established using simple and multiple linear regression. Bland-Altman plots demonstrated good agreement of both predictive models. The residual sum of squares of the corrected prediction model was lower than that of the uncorrected model (0.283 vs. 0.314) but not statistically significant (p = 0.662). Subgroup analysis based on different MR machines showed correlation coefficients of 0.85, 0.95, and 0.94 between SKF and SKPV for three different scanners, respectively (p < 0.05 for all). CONCLUSIONS: NCE-MRU can be used as an alternative method for estimating SKF in pediatric patients with hydronephrosis when comparing with RS. Specifically, SKPV proves to be a simple and universally applicable indicator for predicting SKF.

Evaluation of Whole-Tumor Texture Analysis Based on MRI Diffusion Kurtosis and Biparametric VI-RADS Model for Staging and Grading Bladder Cancer.

BACKGROUND: to evaluate the feasibility of texture analysis (TA) based on diffusion kurtosis imaging (DKI) in staging and grading bladder cancer (BC) and to compare it with apparent diffusion coefficient (ADC) and biparametric vesical imaging reporting and data system (VI-RADS). MATERIALS AND METHODS: In this retrospective study, 101 patients with pathologically confirmed BC underwent MRI with multiple-b values ranging from 0 to 2000 s/mm2. ADC- and DKI-derived parameters, including mean kurtosis (MK) and mean diffusivity (MD), were obtained. First-order texture histogram parameters of MK and MD, including the mean; 5th, 25th, 50th, 75th, and 90th percentiles; inhomogeneity; skewness: kurtosis; and entropy; were extracted. The VI-RADS score was evaluated based on the T2WI and DWI. The Mann-Whitney U-test was used to compare the texture parameters and ADC values between non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), as well as between low and high grades. Receiver operating characteristic analysis was used to evaluate the diagnostic performance of each significant parameter and their combinations. RESULTS: The NMIBC and low-grade group had higher MDmean, MD5th, MD25th, MD50th, MD75th, MD90th, and ADC values than those of the MIBC and the high-grade group. The NMIBC and low-grade group yielded lower MKmean, MK25th, MK50th, MK75th, and MK90th than the MIBC and high-grade group. Among all histogram parameters, MD75th and MD90th yielded the highest AUC in differentiating MIBC from NMIBC (both AUCs were 0.87), while the AUC for ADC was 0.86. The MK75th and MK90th had the highest AUC (both 0.79) in differentiating low- from high-grade BC, while ADC had an AUC of 0.68. The AUC (0.92) of the combination of DKI histogram parameters (MD75th, MD90th, and MK90th) with biparametric VI-RADS in staging BC was higher than that of the biparametric VI-RADS (0.89). CONCLUSIONS: Texture-analysis-derived DKI is useful in evaluating both the staging and grading of bladder cancer; in addition, the histogram parameters of the DKI (MD75th, MD90th, and MK90th) can provide additional value to VI-RADS.

Lipid metabolism marker CD36 is associated with 18FDG-PET/CT false negative lymph nodes in head and neck squamous cell carcinoma.

Background: Lymph node metastasis frequently occurs in head and neck squamous cell carcinoma (HNSCC) patients, and [18F] fluorodeoxyglucose positron emission tomography with computed tomography (18FDG-PET/CT) examination for lymph node metastasis could result in false negativity and delay following treatment. However, the mechanism and resolution for 18FDG-PET/CT false negatives remain unclear. Our study was aim to found biomarkers for false negativity and true positivity from a metabolic perspective. Methods: Ninety-two patients diagnosed with HNSCC who underwent preoperative 18FDG-PET/CT and subsequent surgery in our institution were reviewed. Immunohistochemistry (IHC) examinations of glucose metabolism (GLUT1 and GLUT5), amino acid metabolism4 (GLS and SLC1A5), and lipid metabolism (CPT1A and CD36) markers were conducted on their primary lesion and lymph node sections. Results: We identified specific metabolic patterns of the false-negative group. Significantly, CD36 IHC score of primary lesions was higher in false-negative group than true-positive group. Moreover, we validated pro-invasive biological effects of CD36 by bioinformatics analysis as well as experiments. Conclusion: IHC examination of CD36 expression, which is a lipid metabolism marker, in primary lesions could distinguish HNSCC patients' lymph nodes false negatives in 18FDG-PET/CT.

Amide Proton Transfer-Weighted Imaging Combined with ZOOMit Diffusion Kurtosis Imaging in Predicting Lymph Node Metastasis of Cervical Cancer.

BACKGROUND: The aim of this study is to investigate the feasibility of amide proton transfer-weighted (APTw) imaging combined with ZOOMit diffusion kurtosis imaging (DKI) in predicting lymph node metastasis (LNM) in cervical cancer (CC). MATERIALS AND METHODS: Sixty-one participants with pathologically confirmed CC were included in this retrospective study. The APTw MRI and ZOOMit diffusion-weighted imaging (DWI) were acquired. The mean values of APTw and DKI parameters including mean kurtosis (MK) and mean diffusivity (MD) of the primary tumors were calculated. The parameters were compared between the LNM and non-LNM groups using the Student's t-test or Mann-Whitney U test. Binary logistic regression analysis was performed to determine the association between the LNM status and the risk factors. The diagnostic performance of these quantitative parameters and their combinations for predicting the LNM was assessed with receiver operating characteristic (ROC) curve analysis. RESULTS: Patients were divided into the LNM group (n = 17) and the non-LNM group (n = 44). The LNM group presented significantly higher APTw (3.7 ± 1.1% vs. 2.4 ± 1.0%, p < 0.001), MK (1.065 ± 0.185 vs. 0.909 ± 0.189, p = 0.005) and lower MD (0.989 ± 0.195 × 10-3 mm2/s vs. 1.193 ± 0.337 ×10-3 mm2/s, p = 0.035) than the non-LNM group. APTw was an independent predictor (OR = 3.115, p = 0.039) for evaluating the lymph node status through multivariate analysis. The area under the curve (AUC) of APTw (0.807) was higher than those of MK (AUC, 0.715) and MD (AUC, 0.675) for discriminating LNM from non-LNM, but the differences were not significant (all p > 0.05). Moreover, the combination of APTw, MK, and MD yielded the highest AUC (0.864), with the corresponding sensitivity of 76.5% and specificity of 88.6%. CONCLUSION: APTw and ZOOMit DKI parameters may serve as potential noninvasive biomarkers in predicting LNM of CC.

Identification of predictive factors for outcomes after robot-assisted partial nephrectomy based on three-dimensional reconstruction of preoperative enhanced computerized tomography.

Background: Information from the RENAL score is limited. This study aimed to identify new parameters based on three-dimensional (3D) reconstruction of preoperative enhanced computerized tomography (CT) for predicting outcomes after robot-assisted partial nephrectomy (RPN). Materials and methods: The records of kidney cancer patients who underwent RPN at Tongji Hospital from March 2015 to July 2019 were reviewed. Demographic data, laboratory examinations, postoperative hospitalization time, and enhanced CT were retrospectively collected. Some tumor parameters were obtained from 3D reconstruction of CT data. The association between these predictive factors and outcomes after RPN was analyzed. Results: A larger tumor bed area (TBA) was associated with a longer warm ischemia time (WIT) (P-value <0.001) and tumor resection time (P-value <0.001). Moreover, TBA was significantly associated with the elevation of postoperative creatinine (P-value = 0.005). TBA (P = 0.008), distance from the tumor to the first bifurcation of the renal artery (DTA) (P <0.034), and RENAL score (P = 0.005) were significantly associated with WIT in univariate logistic regression. In multivariate logistic regression, TBA (P = 0.026) and DTA (P = 0.048) were independent risk factors for prolonged WIT (over 25 min). The predictive effect of the combination of TBA, DTA, and RENAL score was higher than the predictive effect of RENAL score alone for WIT (area under curve: 0.786 versus 0.72). Conclusion: TBA and DTA are independently associated with the WIT of RPN, which provides additional assessment value for the complexity of kidney cancer in RPN over the RENAL score.

Autologous fat grafting to the paravertebral space seems to prevent the postherpetic neuralgia-A single-arm pilot study.

INTRODUCTION: Postherpetic neuralgia (PHN) is one of the most common complications of Herpes zoster (HZ), yet the mechanism and the treatment for PHN remains elusive. We first performed this feasibility study to verify the safety and efficiency of autologous fat grafting into the paravertebral space in early HZ to prevent PHN. METHODS: Patients suffering from HZ with a rash in chest, back, or abdomen were arranged for autologous fat grafting to the paravertebral space. The primary endpoint was the incidence of PHN, which was defined as persistence pain in the affected dermal area in 12 weeks after fat grafting. Secondary endpoints including patient-reported changes in pain intensity, assessed pain threshold and the quality of life during follow-ups. RESULTS: Eight patients accept the intervention and completed all follow-ups. Most patients report immediate pain relief after injection, one patient has a mild to moderate dizzy symptom after injection. No other short- or long-term adverse events occurred. For primary outcome, all patients have a timely reduced pain intensity, with no PHN events occurred, as all patients report pain intensity ≤3 in the VAS scale in 3 months after treatment. For electrical pain threshold, we identify that fat grafting differentially increases sensation and pain threshold in HZ area and healthy skin of patients. Besides, our results indicate significant improvement in patients' life quality decrease in analgesic consumption. DISCUSSION: Autologous fat transplantation to the paravertebral space is a safe and feasible technique in preventing PHN from HZ in a rash. Further randomized controlled trial to investigate the actual long-term benefice of autologous fat grafting to the paravertebral space in preventing PHN is needed. TRIAL REGISTRATION: ChiCTR, (ChiCTR1900025416); registered August 26, 2019.

Bile duct ligation differently regulates protein expressions of organic cation transporters in intestine, liver and kidney of rats through activation of farnesoid X receptor by cholate and bilirubin.

Body is equipped with organic cation transporters (OCTs). These OCTs mediate drug transport and are also involved in some disease process. We aimed to investigate whether liver failure alters intestinal, hepatic and renal Oct expressions using bile duct ligation (BDL) rats. Pharmacokinetic analysis demonstrates that BDL decreases plasma metformin exposure, associated with decreased intestinal absorption and increased urinary excretion. Western blot shows that BDL significantly downregulates intestinal Oct2 and hepatic Oct1 but upregulates renal and hepatic Oct2. In vitro cell experiments show that chenodeoxycholic acid (CDCA), bilirubin and farnesoid X receptor (FXR) agonist GW4064 increase OCT2/Oct2 but decrease OCT1/Oct1, which are remarkably attenuated by glycine-ß-muricholic acid and silencing FXR. Significantly lowered intestinal CDCA and increased plasma bilirubin levels contribute to different Octs regulation by BDL, which are confirmed using CDCA-treated and bilirubin-treated rats. A disease-based physiologically based pharmacokinetic model characterizing intestinal, hepatic and renal Octs was successfully developed to predict metformin pharmacokinetics in rats. In conclusion, BDL remarkably downregulates expressions of intestinal Oct2 and hepatic Oct1 protein while upregulates expressions of renal and hepatic Oct2 protein in rats, finally, decreasing plasma exposure and impairing hypoglycemic effects of metformin. BDL differently regulates Oct expressions via Fxr activation by CDCA and bilirubin.

Incremental prognostic value of ADC histogram analysis in patients with high-risk prostate cancer receiving adjuvant hormonal therapy after radical prostatectomy.

Purpose: To investigate the incremental prognostic value of preoperative apparent diffusion coefficient (ADC) histogram analysis in patients with high-risk prostate cancer (PCa) who received adjuvant hormonal therapy (AHT) after radical prostatectomy (RP). Methods: Sixty-two PCa patients in line with the criteria were enrolled in this study. The 10th, 50th, and 90th percentiles of ADC (ADC10, ADC50, ADC90), the mean value of ADC (ADCmean), kurtosis, and skewness were obtained from the whole-lesion ADC histogram. The Kaplan-Meier method and Cox regression analysis were used to analyze the relationship between biochemical recurrence-free survival (BCR-fs) and ADC parameters and other clinicopathological factors. Prognostic models were constructed with and without ADC parameters. Results: The median follow-up time was 53.4 months (range, 41.1-79.3 months). BCR was found in 19 (30.6%) patients. Kaplan-Meier curves showed that lower ADCmean, ADC10, ADC50, and ADC90 and higher kurtosis could predict poorer BCR-fs (all p<0.05). After adjusting for clinical parameters, ADC50 and kurtosis remained independent prognostic factors for BCR-fs (HR: 0.172, 95% CI: 0.055-0.541, p=0.003; HR: 7.058, 95% CI: 2.288-21.773, p=0.001, respectively). By adding ADC parameters to the clinical model, the C index and diagnostic accuracy for the 24- and 36-month BCR-fs were improved. Conclusion: ADC histogram analysis has incremental prognostic value in patients with high-risk PCa who received AHT after RP. Combining ADC50, kurtosis and clinical parameters can improve the accuracy of BCR-fs prediction.

Esketamine-based opioid-free anaesthesia alleviates postoperative nausea and vomiting in patients who underwent laparoscopic surgery: study protocol for a randomized, double-blinded, multicentre trial.

BACKGROUND: Although opioids are commonly prescribed in clinical anaesthesia, the significant side effects attributed to their overuse are raising increasing concerns. One way to reduce perioperative opioid consumption is to apply opioid-reduced anaesthesia (ORA) and even opioid-free anaesthesia (OFA), which involves regional techniques, neuraxial anaesthesia, nonopioid analgesics or combined use. The aim of this study was to investigate whether the application of OFA by using esketamine in intraoperative analgesia could minimize the side effects of postoperative nausea and vomiting (PONV), as well as other short-term side effects related to anaesthesia. METHODS/DESIGN: The study was designed as a prospective, randomized, controlled, multicentre trial. A total of 278 patients were enrolled; participants were nonsmoking female patients aged 18-50 years and scheduled for laparoscopic appendectomy or cholecystectomy, ASA at I-III, with no serious physical or mental diseases. Both groups received usual perioperative care except for the analgesic medication of either esketamine or sufentanil. The primary outcome was the incidence of PONV 3 days after surgery. Secondary outcomes included recovery status, pain, sedation level and overall recovery, delirium and cognition, anxiety and depression and total consumption of analgesic agents. DISCUSSION: This trial may show that the synergy of esketamine and propofol anaesthesia reduces PONV as well as other short-term adverse events, thereby providing a better safety and satisfaction profile of ERAS for laparoscopic appendectomy and cholecystectomy. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100047169. Registered on June 9, 2021.

Intratumoral tertiary lymphoid structures promote patient survival and immunotherapy response in head neck squamous cell carcinoma.

Tertiary lymphoid structures (TLSs) hold the potential role in the prediction of immunotherapy response in several clinical trials. TLSs in head neck squamous cell carcinoma (HNSCC) have been investigated through IHC analysis, whereas there is no TLS gene signature to evaluate the level of TLS neogenesis. We here proposed a TLS signature containing 13 chemokines and determined TLS-hi and TLS-low groups in HNSCC samples from The Cancer Genome Atlas. TLS-hi condition signified a better overall survival. A more inflamed immune infiltrative landscape was identified in the TLS-hi tumors characterized by higher proportion of T cells, TCR/BCR activation and antigen processing. High level of TLSs has a determined role in the clinical significance of T cells. Interesting discovery was that innate lymphoid cells and cancer-associated fibroblasts were positively associated with TLS neogenesis in TME of HNSCC. Furthermore, by integrated TLSs with stromal cells and score, immune cells and score, TMB and malignant cells, we proposed a novel HNSCC TME classifications (HNSCC-TCs 1-5), unravelling the counteracted role of stromal cells and score in inflamed immune landscape, which may provide a novel stromal targeted modality in HNSCC therapy. Finally, we verified that TLS statue is an ideal predictor for immune checkpoint blockade immunotherapy. Current study indicated that the TLSs serve as a novel prognostic biomarker and predictor for immunotherapy, which may provide directions to the current investigations on immunotherapeutic strategies for HNSCC.

WHO/ISUP grade and pathological T stage of clear cell renal cell carcinoma: value of ZOOMit diffusion kurtosis imaging and chemical exchange saturation transfer imaging.

OBJECTIVES: To evaluate the value of ZOOMit diffusion kurtosis imaging (DKI) and chemical exchange saturation transfer (CEST) imaging in predicting WHO/ISUP grade and pathological T stage in clear cell renal cell carcinoma (ccRCC). METHODS: Forty-six patients with ccRCC were included in this retrospective study. All participants underwent MRI including ZOOMit DKI and CEST. The non-Gaussian mean kurtosis (MK), mean diffusivity (MD), magnetization transfer ratio asymmetry (MTRasym (3.5 ppm)), and Ssat (3.5 ppm)/S0 were analyzed based on different WHO/ISUP grades and pT stages. Binary logistic regression was used to identify the best combination of the parameters. Pearson's correlation coefficients were calculated between CEST and diffusion-related parameters. RESULTS: The ADC, MD, and Ssat (3.5 ppm)/S0 values were significantly lower for higher WHO/ISUP grade tumors, whereas the MK and MTRasym (3.5 ppm) were higher in higher WHO/ISUP grade and higher pT stage tumors. MTRasym (3.5 ppm) combined with MD (AUC, 0.930; 95% CI, 0.858-1.000) showed the best diagnostic efficacy in evaluating the WHO/ISUP grade. MTRasym (3.5 ppm) and MK were mildly positively correlated (r = 0.324, p = 0.028). Ssat (3.5 ppm)/S0 was moderately positively correlated with ADC (r = 0.580, p < 0.001), mildly positively correlated with MD (r = 0.412, p = 0.005), and moderately negatively correlated with MK (r = -0.575, p < .001). CONCLUSION: The microstructural and biochemical assessment of ZOOMit DKI and CEST allowed for the characterization of different WHO/ISUP grades and pT stages in ccRCC. MTRasym (3.5 ppm) combined with MD showed the best diagnostic performance for WHO/ISUP grading. KEY POINTS: • Both diffusion kurtosis imaging (DKI) and chemical exchange saturation transfer (CEST) can be used to predict the WHO/ISUP grade and pathological T stage. • MTRasym (3.5 ppm) combined with MD showed the highest AUC (0.930; 95% CI, 0.858-1.000) in WHO/ISUP grading. • MTRasym at 3.5 ppm showed a positive correlation with mean kurtosis.

Progress in pH-Sensitive sensors: essential tools for organelle pH detection, spotlighting mitochondrion and diverse applications.

pH-sensitive fluorescent proteins have revolutionized the field of cellular imaging and physiology, offering insight into the dynamic pH changes that underlie fundamental cellular processes. This comprehensive review explores the diverse applications and recent advances in the use of pH-sensitive fluorescent proteins. These remarkable tools enable researchers to visualize and monitor pH variations within subcellular compartments, especially mitochondria, shedding light on organelle-specific pH regulation. They play pivotal roles in visualizing exocytosis and endocytosis events in synaptic transmission, monitoring cell death and apoptosis, and understanding drug effects and disease progression. Recent advancements have led to improved photostability, pH specificity, and subcellular targeting, enhancing their utility. Techniques for multiplexed imaging, three-dimensional visualization, and super-resolution microscopy are expanding the horizon of pH-sensitive protein applications. The future holds promise for their integration into optogenetics and drug discovery. With their ever-evolving capabilities, pH-sensitive fluorescent proteins remain indispensable tools for unravelling cellular dynamics and driving breakthroughs in biological research. This review serves as a comprehensive resource for researchers seeking to harness the potential of pH-sensitive fluorescent proteins.