Application of Recombinant Human Superoxide Dismutase in Radical Concurrent Chemoradiotherapy for Cervical Cancer to Prevent and Treat Radiation-induced Acute Rectal Injury: A Multi-center, Randomized, Open-label, Prospective Trial.

PURPOSE: To evaluate the efficacy of recombinant human superoxide dismutase (rhSOD) enemas in radiation-induced acute rectal injury (RARI) in patients with locally advanced cervical cancer. METHODS: In this phase III, randomized, open-label trial (NCT04819685) conducted across 14 medical centers in China from June 2021 to August 2023, all patients received concurrent chemoradiotherapy (CCRT). The experimental group was treated with a rhSOD enema during chemoradiotherapy, and the control group had no enema. The Common Terminology Criteria for Adverse Events (version 5.0) was used to evaluate radiotherapy-induced side effects. Endoscopic appearance was assessed using the Vienna Rectoscopy Score. The primary endpoint in the acute phase was the occurrence rate and duration of grade ≥1 (≥G1) diarrhea during CCRT. Secondary endpoints included the occurrence rate and duration of ≥G2 and ≥G3 diarrhea; ≥G1 and ≥G2 diarrhea lasting at least 3 days; and damage to the rectal mucosa due to radiotherapy measured by endoscopy. RESULTS: Two-hundred-and-eighty-three patients were randomly divided into the experimental (n = 141) or control group (n = 140). The mean number of ≥G1 and ≥G2 diarrhea days were significantly lower in the experimental group than in the control group (3.5 and 0.8 days vs. 14.8 and 4.5 days, respectively; P<0.001). The incidence of ≥G2 diarrhea decreased from 53.6% to 24.1% when rhSOD enemas were used. Use of antidiarrheals was lower in the experimental group (36.2% vs. 55.7%, P<0.001). Three patients felt intolerable or abdominal pain following rhSOD enema. RARI grades in the experimental group tended to be lower than those in the control group (P=0.061). Logistic regression analysis revealed that rhSOD enema was associated with a lower occurrence rate of ≥G1/2 diarrhea for at least 3 days (P<0.001). CONCLUSION: The results of this study suggest that rhSOD enema is safe and significantly reduces the incidence, severity, and duration of RARI, protecting the rectal mucosa.

Effects of ambient temperature, relative humidity and absolute humidity on risk of nasopharyngeal carcinoma in China.

Nasopharyngeal carcinoma (NPC) has a unique geographic distribution. It is unknown whether meteorological factors are related to the incidence of NPC. To investigate the effect of ambient temperature, relative humidity (RH), and absolute humidity (AH) on the incidence of NPC, we collected the incidence rate of NPC in 2016 and meteorological data from 2006 to 2016 from 484 cities and counties across 31 provinces in China. Generalized additive models with quasi-Poisson regression and generalized linear models with natural cubic splines were employed respectively to elucidate the nonlinear relationships and specify the partial linear relationships. Subgroup and interactive analysis were also conducted. Temperature (R2 = 0.68, p < .001), RH (R2 = 0.47, p < .001), and AH (R2 = 0.70, p < .001) exhibited nonlinear correlations with NPC incidence rate. The risk of NPC incidence increased by 20.3% (95% confidence intervals [CI]: [18.9%, 21.7%]) per 1°C increase in temperature, by 6.3% (95% CI: [5.3%, 7.2%]) per 1% increase in RH, and by 32.2% (95% CI: [30.7%, 33.7%]) per 1 g/m3 increase in AH, between their the 25th and the 99th percentiles. In addition, the combination of low temperature and low RH was also related to increased risk (relative risk: 1.60, 95% CI: [1.18, 2.17]). Males and eastern or rural populations tended to be more vulnerable. In summary, this study suggests that ambient temperature, RH, and particularly AH are associated with the risk of NPC incidence.

Bifidobacterium pseudocatenulatum NCU-08 ameliorated senescence via modulation of the AMPK/Sirt1 signaling pathway and gut microbiota in mice.

Aging is a degenerative disease in which organisms and neurological functions decline. Emerging research has underscored the vital role of the gut microbiota in age-related processes. However, the identification of aging-associated core microbiota remains limited. In this investigation, we isolated a strain of B. pseudocatenulatum NCU-08 from the feces of centenarians and assessed its impact on aging using a mouse model induced by D-gal. Our study revealed the exceptional probiotic attributes of B. pseudocatenulatum NCU-08. Administration of B. pseudocatenulatum NCU-08 significantly ameliorated age-related memory impairment, motor dysfunction, and anxiety-like behaviors in aging mice (p < 0.01). Moreover, tissue staining analysis demonstrated that B. pseudocatenulatum NCU-08 reduced the intensity of SA-ß-gal-positive in the hippocampus of aging mice. It also reversed pathological damage and structural abnormalities in brain and intestinal tissue. B. pseudocatenulatum NCU-08 inhibited neuroinflammation induced by TLR4/NF-κB (p < 0.01) and preserved the blood-brain barrier integrity by activating the AMPK/Sirt1 pathway (p < 0.05). Furthermore, it mitigated neuronal apoptosis and oxidative stress by upregulating the PI3K/AKT signaling pathway (p < 0.01) and enhancing the activities of antioxidant enzymes, including GSH-Px (p < 0.01), SOD (p < 0.01), and CAT (p < 0.01). Besides, analysis of 16S rRNA sequencing data demonstrated that treatment with B. pseudocatenulatum NCU-08 restored intestinal microbiota homeostasis after senescence. It enhanced the abundance of beneficial bacteria while suppressing the growth of pathogenic microorganisms. In summary, our study unveiled that this novel strain of B. pseudocatenulatum NCU-08 exerts anti-aging effects through regulating the AMPK/Sirt1 pathway and intestinal microbiota. It holds promise as a functional food for promoting anti-aging effects and offers a novel approach to address aging and associated metabolic disorders.

GINS2 promotes the progression of human HNSCC by altering RRM2 expression.

INTRODUCTION: GINS2 exerts a carcinogenic effect in multiple human malignancies, while it is still unclear that the potential roles and underlying mechanisms of GINS2 in HNSCC. METHODS: TCGA database was used to screen out genes with significant differences in expression in HNSCC. Immunohistochemistry and qRT-PCR were used to measure the expression of GINS2 in HNSCC tissues and cells. GINS2 was detected by qRT-PCR or western blot after knockdown or overexpression. Celigo cell counting, MTT, colony formation, and flow cytometric assay were used to check the ability of proliferation and apoptosis. Bioinformatics and microarray were used to screen out the downstream genes of GINS2. RESULTS: GINS2 in HNSCC tissues and cells was up-regulated, which was correlated with poor prognosis. GINS2 gene expression was successfully inhibited and overexpressed in HNSCC cells. Knockdown of GINS2 could inhibit proliferation and increase apoptosis of cells. Meanwhile, overexpression of GINS2 could enhance cell proliferation and colony formation. Knockdown of RRM2 may inhibit HNSCC cell proliferation, while overexpression of RRM2 rescued the effect of reducing GINS2 expression. CONCLUSION: Our study reported the role of GINS2 in HNSCC for the first time. The results demonstrated that in HNSCC cells, GINS2 promoted proliferation and inhibited apoptosis via altering RRM2 expression. Therefore, GINS2 might play a carcinogen in HNSCC, and become a specific promising therapeutic target.

Clinical efficacy of montelukast sodium combination therapy for cough variant asthma in children: A meta-analysis.

This meta-analysis aims to assess the clinical effectiveness of combination therapy with montelukast sodium for the treatment of cough variant asthma (CVA) in children, intending to provide clinical evidence and data to guide the selection of clinical therapy. A literature review was conducted using numerous databases, including China National Knowledge Infrastructure (CNKI), Wanfang database, Embase, PubMed, and Web of Science, from inception to December 2023. Trials meeting the criteria for the combined treatment of montelukast sodium for CVA in children were included. Stata 16.0 software was utilized for meta-analysis. The combined treatment group received montelukast sodium in addition to the control group, while the control group received budesonide, fluticasone propionate, salmeterol-fluticasone, or ketotifen alone. This investigation included 18 papers. All subjects were from the Chinese population. Compared to the control group, the combined treatment group demonstrated a higher effective rate (relative ratio [RR] = 1.23, 95% confidence interval [CI]: 1.18-1.29, p < .001), but no difference in the incidence of adverse reactions (RR = 0.65, 95% CI: 0.42-1.02, p = .060) after treatment. Moreover, the peak expiratory flow (PEF) (SMD = 1.69, 95% CI: 1.09-2.30, p < .001), forced vital capacity (FVC) (SMD = 1.67, 95% CI: 0.94-2.39, p < .001), forced expiratory volume in 1 s (FEV1) (SMD = 1.74, 95% CI: 1.09-2.40, p < .001), and FEV1/FVC (SMD = 1.84, 95% CI: 0.41-3.28, p = .012) were significantly higher in the combined treatment group than in the control group after treatment. Compared with the control group, the levels of tumor necrosis factor-α (SMD = -2.38, 95% CI: -3.22 to -1.55, p < .001), IL-4 (SMD = -2.65, 95% CI: -3.26 to -2.04, p < .001), and IgE (SMD = -2.98, 95% CI: -3.24 to -2.72, p < .001) were significantly lower in the combined treatment group after treatment. The combined use of montelukast sodium in the treatment of pediatric CVA in China is associated with a significant clinical effect, making it a reasonable therapeutic approach.

D-dimer-to-platelet count ratio as a novel indicator for predicting prognosis in HBV-related decompensated cirrhosis.

Background: Hepatitis B virus-related decompensated cirrhosis (HBV-DC) is a critical illness with a low survival rate. Timely identification of prognostic indicators is crucial for risk stratification and personalized management of patients. The present study aimed to investigate the potential of the D-dimer-to-platelet count ratio (DPR) as a prognostic indicator for HBV-DC. Methods: A retrospective review of medical records was conducted for 164 patients diagnosed with HBV-DC. Baseline clinical and laboratory characteristics were extracted for analysis. The endpoint was 30-day mortality. Disease severity was assessed by the Model for End-stage Liver Disease (MELD) score. A multivariate logistic regression model and receiver operating characteristic curve analysis (ROC) were used to evaluate the predictive value of DPR for mortality. Results: During the 30-day follow-up period, 30 (18.3%) patients died. Non-survivors exhibited significantly higher DPR values than survivors, and a high DPR had a strong association with increased mortality. Importantly, DPR was identified as an independent risk factor for mortality in HBV-DC patients after adjustments for confounding factors (Odds ratio = 1.017; 95% Confidence interval, 1.006-1.029; p = 0.003). The cut-off value of DPR as a predictor of mortality was>57.6 (sensitivity = 57%, specificity = 86%, p < 0.001). The area under ROC curve for DPR for 30-day mortality was 0.762, comparable to the MELD score (p = 0.100). Furthermore, the combined use of DPR and MELD score further increased the area under the ROC curve to 0.897. Conclusion: Elevated DPR was demonstrated to have a correlation with unfavorable outcomes in HBV-DC patients, suggesting its potential utility as an effective biomarker for assessment of prognosis in these patients.

Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial.

BACKGROUND: The optimal dosages, timing, and treatment sequencing for standard-of-care neoadjuvant chemoradiotherapy necessitate re-evaluation when used in conjunction with immune checkpoint inhibitors for patients with resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC). The SCALE-1 phase Ib study aimed to evaluate the safety and efficacy of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in this patient population. METHODS: RLaESCC patients with clinical stages cT3-4aN0M0/cT1-4aN+M0 received neoadjuvant paclitaxel (135 mg/m2), carboplatin (area under the curve=5), and toripalimab (240 mg) every 3 weeks for two cycles. Short-course neoadjuvant radiotherapy (30 Gy in 12 fractions; 5 days per week) was administered between neoadjuvant immune-chemotherapy (nICT) doses. Esophagectomies were scheduled 4-6 weeks after completing neoadjuvant treatment. The primary endpoint was safety, with secondary endpoints including pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), and overall survival (OS). Exploratory biomarker analysis used gene expression profiles via the nCounter platform. RESULTS: Of the 23 patients enrolled, all completed neoadjuvant radiotherapy, while 21 cases finished full nICT doses and cycles. Common grade 3/4 adverse events included neutropenia (57%), leukopenia (39%), and skin rash (30%). No grade 3 or higher esophagitis or pneumonitis occured. Twenty patients underwent surgery, and 11 achieved pCR (55%). Two patients (10%) experienced grade IIIb surgical complications. At the database lock, a 2-year PFS rate of 63.8% (95% CI 43.4% to 84.2%) and 2-year OS rate was 78% (95% CI 64.9% to 91.1%) were achieved. Tumor immune microenvironment analysis indicated that tumors with pCR exhibited significantly higher pretreatment T-cell-inflamed score and post-treatment reshaping of antitumor immunity. CONCLUSIONS: Combining short-course neoadjuvant radiotherapy with chemotherapy and toripalimab demonstrated favorable safety and promising efficacy in RLaESCC patients. TRIAL REGISTRATION NUMBER: ChiCTR2100045104.

Hypoxia promotes non-small cell lung cancer cell stemness, migration, and invasion via promoting glycolysis by lactylation of SOX9.

BACKGROUND: Lung cancer is the deadliest form of malignancy and the most common subtype is non-small cell lung cancer (NSCLC). Hypoxia is a typical feature of solid tumor microenvironment. In the current study, we clarified the effects of hypoxia on stemness and metastasis and the molecular mechanism. METHODS: The biological functions were assessed using the sphere formation assay, Transwell assay, and XF96 extracellular flux analyzer. The protein levels were detected by western blot. The lactylation modification was assessed by western blot and immunoprecipitation. The role of SOX9 in vivo was explored using a xenografted tumor model. RESULTS: We observed that hypoxia promoted sphere formation, migration, invasion, glucose consumption, lactate production, glycolysis, and global lactylation. Inhibition of glycolysis suppressed cell stemness, migration, invasion, and lactylation. Moreover, hypoxia increased the levels of SOX9 and lactylation of SOX9, whereas inhibition of glycolysis reversed the increase. Additionally, knockdown of SOX9 abrogated the promotion of cell stemness, migration, and invasion. In tumor-bearing mice, overexpression of SOX9 promoted tumor growth, and inhibition of glycolysis suppressed tumor growth. CONCLUSION: Hypoxia induced the lactylation of SOX9 to promote stemness, migration, and invasion via promoting glycolysis. The findings suggested that targeting hypoxia may be an effective way for NSCLC treatment and reveal a new mechanism of hypoxia in NSCLC.

PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the pentose phosphate pathway.

ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy originating from transformed hematopoietic stem or progenitor cells. AML prognosis remains poor owing to resistance and relapse driven by leukemia stem cells (LSCs). Targeting molecules essential for LSC function is a promising therapeutic approach. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is often dysregulated in AML. We found that although PI3Kγ is highly enriched in LSCs and critical for self-renewal, it was dispensable for normal hematopoietic stem cells. Mechanistically, PI3Kγ-AKT signaling promotes nuclear factor erythroid 2-related factor 2 (NRF2) nuclear accumulation, which induces 6-phosphogluconate dehydrogenase (PGD) and the pentose phosphate pathway, thereby maintaining LSC stemness. Importantly, genetic or pharmacological inhibition of PI3Kγ impaired expansion and stemness of murine and human AML cells in vitro and in vivo. Together, our findings reveal a key role for PI3Kγ in selectively maintaining LSC function by regulating AKT-NRF2-PGD metabolic pathway. Targeting the PI3Kγ pathway may, therefore, eliminate LSCs without damaging normal hematopoiesis, providing a promising therapeutic strategy for AML.

A novel model for predicting prognosis and response to immunotherapy in nasopharyngeal carcinoma patients.

Blood-based biomarkers of immune checkpoint inhibitors (ICIs) response in patients with nasopharyngeal carcinoma (NPC) are lacking, so it is necessary to identify biomarkers to select NPC patients who will benefit most or least from ICIs. The absolute values of lymphocyte subpopulations, biochemical indexes, and blood routine tests were determined before ICIs-based treatments in the training cohort (n = 130). Then, the least absolute shrinkage and selection operator (Lasso) Cox regression analysis was developed to construct a prediction model. The performances of the prediction model were compared to TNM stage, treatment, and Epstein-Barr virus (EBV) DNA using the concordance index (C-index). Progression-free survival (PFS) was estimated by Kaplan-Meier (K-M) survival curve. Other 63 patients were used for validation cohort. The novel model composed of histologic subtypes, CD19+ B cells, natural killer (NK) cells, regulatory T cells, red blood cells (RBC), AST/ALT ratio (SLR), apolipoprotein B (Apo B), and lactic dehydrogenase (LDH). The C-index of this model was 0.784 in the training cohort and 0.735 in the validation cohort. K-M survival curve showed patients with high-risk scores had shorter PFS compared to the low-risk groups. For predicting immune therapy responses, the receiver operating characteristic (ROC), decision curve analysis (DCA), net reclassifcation improvement index (NRI) and integrated discrimination improvement index (IDI) of this model showed better predictive ability compared to EBV DNA. In this study, we constructed a novel model for prognostic prediction and immunotherapeutic response prediction in NPC patients, which may provide clinical assistance in selecting those patients who are likely to gain long-lasting clinical benefits to anti-PD-1 therapy.

The Emerging Role of Deubiquitinases in Radiosensitivity.

Radiation therapy is a primary treatment for cancer, but radioresistance remains a significant challenge in improving efficacy and reducing toxicity. Accumulating evidence suggests that deubiquitinases (DUBs) play a crucial role in regulating cell sensitivity to ionizing radiation. Traditional small-molecule DUB inhibitors have demonstrated radiosensitization effects, and novel deubiquitinase-targeting chimeras (DUBTACs) provide a promising strategy for radiosensitizer development by harnessing the ubiquitin-proteasome system. This review highlights the mechanisms by which DUBs regulate radiosensitivity, including DNA damage repair, the cell cycle, cell death, and hypoxia. Progress on DUB inhibitors and DUBTACs is summarized, and their potential radiosensitization effects are discussed. Developing drugs targeting DUBs appears to be a promising alternative approach to overcoming radioresistance, warranting further research into their mechanisms.

Red cell distribution width-to-albumin ratio is a predictor of survival in hepatitis B virus-associated decompensated cirrhosis.

OBJECTIVE: The aim of this study was to ascertain whether red cell distribution width-to-albumin ratio (RAR) is associated with survival in hepatitis B virus (HBV)-associated decompensated cirrhosis (DC) patients. METHODS: A cohort of 167 patients with confirmed HBV-DC was enrolled in our study. Demographic characteristics and laboratory data were obtained. The main endpoint was mortality at 30 days. The receiver operating characteristic curve and multivariable regression analysis were used to assess the power of RAR for predicting prognosis. RESULTS: Mortality at 30 days was 11.4% (19/167). The RAR levels were higher in the nonsurvivors than the survivors, and elevated RAR levels were clearly associated with poor prognosis. Moreover, the predictive powers of RAR and Model for End-Stage Liver Disease score were not obviously different. CONCLUSION: Our data indicate that RAR is a novel potential prognostic biomarker of mortality in HBV-DC.

Association Study of Esomeprazole Pharmacokinetics and CYP2C19 Gene Polymorphisms.

To investigate the association between esomeprazole pharmacokinetics and CYP2C19 gene polymorphisms in a cohort of 95 healthy Chinese participants. A cohort of 95 participants was assembled and stratified into 2 distinct groups, receiving either 20 or 40 mg of esomeprazole through oral administration. The subjects encompassed 17 poor metabolizers, 47 intermediate metabolizers, and 31 rapid metabolizers, and their genotypes were ascertained using the polymerase chain reaction-restriction fragment length polymorphism technique. Esomeprazole plasma concentrations were quantified employing a high-performance liquid chromatography-ultraviolet method. Pharmacokinetic parameters were computed via Phoenix WinNonlin 6.1 software, while SPSS 26.0 facilitated statistical analysis to contrast the pharmacokinetics and the CYP2C19 genotypes. In the aftermath of administering 20 or 40 mg esomeprazole, marked differences were discerned between terminal elimination half-life, maximum concentration/dose, and area under the plasma concentration-time curve from time zero to infinity/dose of esomeprazole (P < .05), with the exception of time to maximum concentration. The findings of this investigation signify a significant association between esomeprazole metabolism and CYP2C19 gene polymorphisms. There were no unprecedented adverse events documented subsequent to the administration of 20 and 40 mg esomeprazole dosages. Esomeprazole has manifested promising safety and tolerability profiles in pertinent clinical trials.

Association of NUDT15 gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis.

6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.

Machine learning-based radiomics nomograms to predict number of fields in postoperative IMRT for breast cancer.

BACKGROUND: Breast cancer is now the most commonly diagnosed cancer in women worldwide. Radiotherapy is an important part of the treatment for breast cancer, while setting proper number of fields dramatically affects the benefits one can receive. Machine learning and radiomics have been widely investigated in the management of breast cancer. This study aims to provide models to predict the best number of fields based on machine learning and improve the prediction performance by adding clinical factors. METHODS: Two-hundred forty-two breast cancer patients were retrospectively enrolled for this study, all of whom received postoperative intensity modulated radiation therapy. The patients were randomized into a training set and a validation set at a ratio of 7:3. Radiomics shape features were extracted for eight machine learning algorithms to predict the number of fields. Univariate and multivariable logistic regression were implemented to screen clinical factors. A combined model of rad-score and clinical factors were finally constructed. The area under receiver operating characteristic curve, precision, recall, F1 measure and accuracy were used to evaluate the model. RESULTS: Random Forest outperformed from eight machine learning algorithms while predicting the number of fields. Prediction performance of the radiomics model was better than the clinical model, while the predictive nomogram combining the rad-score and clinical factors performed the best. CONCLUSIONS: The model combining rad-score and clinical factors performed the best. Nomograms constructed from the combined models can be of reliable references for medical dosimetrists.

Six undescribed guaianolide-type sesquiterpenes from the aerial parts of Daphne penicillata.

Six undescribed guaianolide sesquiterpenes (1-6) were obtained from the aerial parts of Daphne penicillata. Their structures and absolute configuration were elucidated by HRESIMS, NMR analyses, ECD calculations and single-crystal X-ray diffraction analysis. Structurally, all compounds possess the typical 5,7-fused system of 8,12-guaianolides and this guaianolide-type was first reported to be isolated from Daphne penicillata. All compounds (1-6) were evaluated for anti-inflammatory and cytotoxic activity. Among them, compounds 1 and 5 showed moderate inhibitory effects on LPS-induced NO production in BV2 cells and 4 displayed potential inhibition against Hep3B cells with an IC50 value of 7.33 µM.

MTDH enhances radiosensitivity of head and neck squamous cell carcinoma by promoting ferroptosis based on a prognostic signature.

Ionizing radiation (IR) induces ferroptosis in head and neck squamous cell carcinoma (HNSCC). But, it remains unclear whether ferroptosis affects the prognosis of HNSCC patients after receiving radiotherapy. This study aims to develop a ferroptosis signature to predict the radiosensitivity and prognosis of HNSCC. Ferroptosis-related genes, clinical data and RNA expression profiles were obtained from the FerrDb database, The Cancer Genome Atlas and GEO database. Prognostic genes were identified by random survival forest, univariate Cox regression, Kaplan-Meier and ROC analyses. Principal component analysis, multivariate Cox regression, nomogram and DCA analyses were conducted to estimate its predictive ability. Functional enrichment and immune-related analyses were performed to explore potential biological mechanisms and tumor immune microenvironment. The effect of the hub gene on ferroptosis and radiosensitivity was verified using flow cytometry, quantitative real-time PCR and clonogenic survival assay. We constructed a ferroptosis-related signature, including IL6, NCF2, metadherin (MTDH) and CBS. We classified patients into high-risk (HRisk) and low-risk groups according to the risk scores. The risk score was confirmed to be an independent predictor for overall survival (OS). Combining the clinical stage with the risk score, we established a predictive nomogram for OS. Furthermore, pathways related to tumorigenesis and tumor immune suppression were mainly enriched in HRisk. MTDH was verified to have a potent effect on IR-induced ferroptosis and consequently promoted radiosensitivity. We constructed a ferroptosis-related signature to predict radiosensitivity and OS in HNSCC patients. MTDH was identified as a promising therapeutic target in radioresistant HNSCC patients.

Structurally diverse rearranged sesquiterpenoids, including a pair of rare tautomers, from the aerial parts of Daphne penicillata.

Eight structurally diverse rearranged sesquiterpenoids, including seven undescribed sesquiterpenoids (1a/1b and 3-8) were obtained from the aerial parts of Daphne penicillata. 1a/1b, 3, 5 and 6 possess rare rearranged guaiane skeletons and 4 represents the first example of rearranged carotene sesquiterpenoids. Their structures and absolute configurations were determined by extensive spectroscopic analyses, NMR and ECD calculations. Interestingly, 1a and 1b were a pair of magical interconverting epimers that may interconvert by retro-aldol condensation. The mechanism of interconversion has been demonstrated indirectly by 9-OH derivatization of 1a/1b and a hypothetical biogenetic pathway was proposed. All compounds were evaluated for anti-inflammatory and cytotoxic activities. Among them, 1a/1b and 2 exhibited potential inhibitory activities on the production of NO against LPS-induced BV2 microglial cells.

Lactobacillus acidophilus JYLA-126 Ameliorates Obesity-Associated Metabolic Disorders by Positively Regulating the AMPK Signaling Pathway Through the Gut-Liver Axis.

Obesity is a chronic metabolic disease worldwide and is considered a major health problem in contemporary society. Lactobacillus acidophilus have demonstrated beneficial effects on obesity, but the specific mechanism of how it exerts beneficial effects has not been elucidated. Here, we found that L. acidophilus JYLA-126 had good biological properties for intestinal health, such as antioxidation, acid tolerance, bile salt tolerance, antimicrobial activity, and gut colonization. We further identified that supplementation of L. acidophilus JYLA-126 obese mice possessed a dose-dependent amelioration of body weight, intestinal imbalance, and metabolic disorders compared to HFD-induced mice. Mechanistically, the excellent slimming effect of L. acidophilus JYLA-126 was achieved mainly by reversing HFD-induced gut dysbiosis, inhibiting inflammatory factors and balancing the homeostasis of the gut-liver axis. Specifically, L. acidophilus JYLA-126 improved hepatic glycogen synthesis, lowered oxidative stress, and facilitated lipid metabolism by regulating AMPK signaling pathway-related protein expression to restore the overall metabolic level. Accordingly, L. acidophilus JYLA-126 promoted energy uptake efficiency in obese mice, resulting in significant expression of uncoupling protein 1 (UCP1) protein in brown adipose tissue (BAT), and markedly reduced the size of adipocytes. These findings indicate that the anti-obesity activity of L. acidophilus JYLA-126 correlates with activation of the AMPK signaling pathway through improved gut-liver interactions.

Octopus-inspired sensorized soft arm for environmental interaction.

Octopuses can whip their soft arms with a characteristic "bend propagation" motion to capture prey with sensitive suckers. This relatively simple strategy provides models for robotic grasping, controllable with a small number of inputs, and a highly deformable arm with sensing capabilities. Here, we implemented an electronics-integrated soft octopus arm (E-SOAM) capable of reaching, sensing, grasping, and interacting in a large domain. On the basis of the biological bend propagation of octopuses, E-SOAM uses a bending-elongation propagation model to move, reach, and grasp in a simple but efficient way. E-SOAM's distal part plays the role of a gripper and can process bending, suction, and temperature sensory information under highly deformed working states by integrating a stretchable, liquid-metal-based electronic circuit that can withstand uniaxial stretching of 710% and biaxial stretching of 270% to autonomously perform tasks in a confined environment. By combining this sensorized distal part with a soft arm, the E-SOAM can perform a reaching-grasping-withdrawing motion across a range up to 1.5 times its original arm length, similar to the biological counterpart. Through a wearable finger glove that produces suction sensations, a human can use just one finger to remotely and interactively control the robot's in-plane and out-of-plane reaching and grasping both in air and underwater. E-SOAM's results not only contribute to our understanding of the function of the motion of an octopus arm but also provide design insights into creating stretchable electronics-integrated bioinspired autonomous systems that can interact with humans and their environments.