Tumor metastasis remains the leading cause of cancer-related mortality, and effective prevention of clinically occult dissemination remains limited. In the immunotherapy era, the biological role of prophylactic radiotherapy targeting high-risk sites before overt metastasis or regional failure requires critical reassessment. This review summarizes evidence for prophylactic radiotherapy and elective nodal irradiation, distinguishing them from adjuvant radiotherapy and treatment of established but asymptomatic metastases. It further examines the invasion-metastasis cascade, pre-metastatic niche formation, radiation-induced immune microenvironment remodeling, and low-dose hyper-radiosensitivity. Particular attention is given to low-dose radiotherapy’s potential to convert permissive metastatic “soil” into an inhospitable environment, which remains clinically unvalidated. We further discuss major translational barriers, including dose-response windows, toxicity, radiation-induced lymphopenia, biomarker limitations, and integration with immune checkpoint inhibitors. Prophylactic radiotherapy reduces site-specific recurrence but is not universally survival-improving. Future advances require biomarker-enriched trials, lymphocyte-sparing planning, modern imaging surveillance, and mechanistically informed dose and timing selection.

Esophageal cancer (EC) is a leading cause of cancer-related mortality worldwide and early detection strategies and precise postoperative interventions must be developed. However, the identification of noninvasive biomarkers for the diagnosis and prognosis remains limited. We performed 16S rRNA gene sequencing on tongue-coating samples from 440 participants, including 157 EC patients, 167 healthy controls (HCs) and 120 EC patients who received radiotherapy. We characterized the oral microbiome and constructed microbial diagnostic and prognostic classifiers. Furthermore, the oral microbiome of EC who received radiotherapy (n = 120) was characterized. The oral microbial diversity of EC patients was increased, with differences in the microbial community between EC patients and HCs. In EC, the genera Veillonella, Streptococcus and Actinomyces were enriched, whereas Porphyromonas and Rothia were depleted. The classifier based on six optimal microbial markers was constructed using random forest algorithm and achieved area under the curves (AUCs) of 93.69

AIM:Loss-of-function mutations in KCNJ10, encoding Kir4.1, cause EAST/SeSAME syndrome, with renal salt-wasting tubulopathy and hypokalemia. We hypothesized that Kir4.1 deletion specifically in the distal convoluted tubule (DCT) stimulates ENaC activity via the mammalian target of rapamycin (mTOR)-dependent mechanisms, contributing to hypokalemia. METHODS:Metabolic cages, electrophysiology, immunoblotting, immunostaining, and in vivo diuretic response experiments were used to examine biochemical parameters, Kir4.1/Kir5.1 activity, NCC and ENaC function in the DCT-specific Kir4.1 knockout (DCT-Kir4.1 KO) mice under normal or K+ restriction conditions. RESULTS:DCT-Kir4.1 KO mice exhibited impaired basolateral K+ channel and NCC activity, enhanced ENaC activity, and mild hypokalemia. Amiloride treatment induced similar natriuresis and kaliuresis in DCT-Kir4.1 KO and kidney-specific Kir4.1 KO mice, but had minimal effects in collecting system Kir4.1 KO mice, suggesting high ENaC activity following Kir4.1 deletion in the DCT. Notably, severe hypokalemia, along with upregulated ENaC expression and activity, was observed in DCT-Kir4.1 KO mice under dietary K+ restriction. Patch-clamp experiments further revealed elevated ENaC currents in the DCT2 of KO mice on a low-K+ diet, independent of aldosterone levels. Inhibition of mTOR with AZD8055 reduced SGK1/Nedd4-2 phosphorylation, cleaved α-ENaC expression, and DCT2 ENaC currents, suggesting a role for mTOR in ENaC hyperactivity in K+-restricted DCT-Kir4.1 KO mice. This notion was also supported by the upregulated Rictor expression observed in the isolated DCT of these KO mice. CONCLUSION:We conclude that Kir4.1 deletion drives ENaC hyperactivity in the DCT via the mTORC2-dependent SGK1/Nedd4-2 signaling pathway, promoting low potassium diet-induced hypokalemia.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by persistent mucosal inflammation and marked clinical heterogeneity, yet the contribution of metabolic dysregulation to disease pathogenesis remains poorly defined. This study aimed to elucidate the role of glycolytic reprogramming in CRSwNP, with a particular focus on eosinophilic CRSwNP (eCRSwNP). Integrated analyses of publicly available bulk RNA-seq data from GSE136825 (28 controls and 42 CRSwNP samples) and single-cell RNA sequencing data from HRA000772 (5 controls, 5 neCRSwNP, and 6 eCRSwNP samples) were performed to characterize metabolic alterations across distinct cell populations in CRSwNP. Glycolytic activity was quantified using pathway enrichment and module scoring approaches. Seurat was used for single-cell analysis, Monocle3 for macrophage trajectory analysis, and CellChat for cell–cell communication analysis. Key findings were further validated in independently collected human nasal tissue samples using RT-qPCR, immunohistochemistry (IHC), and immunofluorescence (IF). A murine model of eCRSwNP was established, and glycolysis was pharmacologically inhibited using 2-deoxy-D-glucose (2-DG) to assess its effects on inflammation and tissue remodeling. Glycolytic activity was markedly elevated in nasal polyp tissues, especially in eCRSwNP, with myeloid cells exhibiting the most pronounced metabolic reprogramming. A distinct subset of glycolysis-high, M2-like macrophages characterized by high expression of SPP1 (SPP1⁺ macrophages) was selectively enriched in eCRSwNP and positively correlated with disease severity. These macrophages were actively involved in Th2 inflammatory responses and extracellular matrix remodeling. SPP1⁺ macrophages communicated with Th2 cells, ILC2s, and fibroblasts predominantly through SPP1-CD44 signaling. Importantly, glycolysis inhibition with 2-DG significantly attenuated sinonasal inflammation, polyp-like lesion formation, and collagen deposition in vivo, accompanied by a reduced accumulation of pathogenic SPP1⁺ macrophage subsets. This study identifies glycolysis-high SPP1⁺ macrophages as a key pathogenic subset in eCRSwNP and implicates SPP1-CD44-mediated crosstalk as a potential mechanism underlying disease progression. Targeting macrophage glycolysis may represent a potential therapeutic strategy for this disease. 1. Glycolysis is markedly enhanced in CRSwNP, particularly in eCRSwNP. 2. SPP1⁺ macrophages are expanded in eCRSwNP and exhibit M2-like features with elevated glycolytic activity. 3. SPP1⁺ macrophages communicate with Th2 cells, ILC2s, and fibroblasts predominantly through SPP1-CD44 signaling. 4. Glycolysis inhibition by 2-DG alleviates nasal inflammation and suppresses metabolic reprogramming in the nasal mucosa.

Background: Accurate prediction of pathologic response to neoadjuvant chemoradiotherapy (nCRT) in esophageal squamous cell carcinoma (ESCC) patients is essential for optimizing individualized treatment strategies. This study investigates the potential of diffusion-weighted magnetic resonance imaging (DWIMRI) and the neutrophil-to-lymphocyte ratio (NLR) at baseline as predictive biomarkers for the pathologic response to nCRT in patients with ESCC. Methods: A retrospective analysis was conducted at Zhengzhou University Affiliated Cancer Hospital on a cohort of thirty ESCC patients who underwent nCRT followed by surgery between December 2013 and July 2017. Baseline DWI-MRI parameters and hematology data were collected within one week before initiating nCRT. The NLR and average apparent diffusion coefficient (ADC) value of the tumor were calculated. Receiver operating characteristic (ROC) curves were employed to evaluate the accuracy of ADC, NLR, and a combined index in predicting the pathologic response to nCRT. Results: Among the thirty patients, twenty exhibited a favorable pathologic response to nCRT. High ADC values (>1.86 & times;10 mm2/s) and low NLR (<= 2.31) at baseline were significantly associated with a positive pathologic response in ESCC patients. ROC analysis revealed area under the curves (AUCs) of 0.750 and 0.758 for ADC value and NLR, respectively, with optimal cut-off values of 1.86 & times;10-3 mm2/s [sensitivity: 63.6%] and 2.31 (sensitivity: 75.0%, specificity: 80.0%, PPV: 88.2%, NPV: 61.5%). The combined index demonstrated an improved sensitivity (95.0%) and NPV (87.5%) at an optimal threshold of 0.48, yielding an AUC of 0.840. Conclusions: In conclusion, the pre-treatment ADC-NLR index is a promising biomarker that may guide personalized nCRT strategies in ESCC by identifying patients for treatment modification, a potential that now requires validation in prospective trials to impact clinical care.

e16046 Background: Immunotherapy combined with chemotherapy is the standard first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC). However, data regarding the efficacy of sequential immune checkpoint inhibitor (ICI) therapy following disease progression are limited. This study evaluates the real-world clinical efficacy of immune rechallenge in advanced ESCC patients to identify optimal strategies for overcoming resistance. Methods: This single-center, retrospective study analyzed patients with advanced ESCC treated at the First Affiliated Hospital of Zhengzhou University between Jan 1, 2020, and Dec 31, 2024. Eligible patients received ≥2 cycles of ICI-based therapy in both 1L and 2L settings. Primary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Subgroup analyses were performed based on different 2L treatment regimens. Results: A total of 135 patients were enrolled (median age: 64 years; 71% male). The median PFS for second-line treatment (mPFS2) was 7.23 months (95% CI: 5.75–9.30). The ORR and DCR were 14.81% and 69.63%, respectively. Subgroup analysis by 2L regimen revealed that the triple combination (ICI + anti-angiogenic targeted therapy + chemotherapy, n = 39) achieved the longest mPFS2 of 9.03 months (95% CI: 5.95–25.00), followed by ICI + anti-angiogenic therapy (n = 39) with 6.77 months (95% CI: 4.96–11.66), ICI + chemotherapy (n = 48) with 5.75 months (95% CI: 4.07–9.66), and ICI monotherapy (n = 9) with 4.67 months (95% CI: 2.73–NR). Multivariate COX regression identified the triple combination as an independent prognostic factor for improved PFS2. Regarding target consistency, patients maintaining the same immune checkpoint target (n = 123, 91.11%) achieved an mPFS2 of 7.23 months (95% CI: 5.75–9.66), compared to 6.37 months (95% CI: 2.60–NR) in those who switched targets (n = 12). Notably, efficacy was independent of the duration of response to prior 1L treatment (PFS1 < 6 months vs. ≥6 months). Conclusions: Immune rechallenge represents a viable therapeutic strategy for advanced ESCC. The triple combination of immunotherapy, anti-angiogenic targeted therapy, and chemotherapy yielded the optimal progression-free survival benefit. Furthermore, maintaining the original immune checkpoint target demonstrated a trend toward superior efficacy compared to switching targets, and efficacy was observed regardless of the duration of benefit from prior first-line treatment. Clinical trial information: ChiCTR2500113885. Subgroup analysis of efficacy. n mPFS2（m） ORR（%） DCR（%） ITT 135 7.23 14.8 69.6 2L treatment I 9 4.67 0 66.7 I+C 48 5.75 12.5 56.3 I+A 39 6.77 20.5 87.2 I+C+A 39 9.03 15.4 69.2 Target Consistency Same Target (Yes) 123 7.23 15.5 68.3 Switch Target (No) 12 6.37 8.3 83.3

Zinc is an essential trace metal in the human body,playing a crucial role in various biological processes.It exists in 2 forms in cells:"bound"and"labile,"depending on its affinity with ligands.Zinc homeostasis is tightly regulated by zinc transporters,including the ZIP and ZnT pro-tein families.However,zinc dyshomeostasis has been observed in various cancers,including breast cancer,pancreatic cancer,and he-patocellular carcinoma.Recent studies indicate that the zinc content in blood and tumor tissues can either increase or decrease,whereas specific zinc transporters may be upregulated or downregulated.Zinc dysregulation in cancer cells,as well as in immune cells and non-immune stromal cells,potentially affects the cell cycle,apoptosis,metabolism,immunity,and treatment resistance.Although many reviews have discussed zinc homeostasis under physiological conditions,few have explores its role in cancer pathology.We conducted a literature search on PubMed and Google Scholar using the keywords"tumor,""zinc levels,"and"zinc transporter,"excluding outdated articles and those lacking full-text access.Among similar studies,we selected articles with more recent publication dates and larger sample sizes.In this review,we summarize recent advances in the study of zinc in tumors,highlighting studies on abnormal zinc levels and zinc transporters in various cancers.We also explore the effects of zinc dysregulation,its potential mechanisms,and the emerging concept that zinc dyshomeostasis may be a hallmark of cancer.

BackgroundNonalcoholic fatty liver disease (NAFLD) has emerged as a significant global health concern, with advanced fibrosis increasing mortality risks. Despite the abundance of dietary guidelines for managing NAFLD, the precise impact of diet quality on mortality among individuals with advanced fibrosis remains elusive. This study aims to explore the influence of five dietary quality indexes on mortality among NAFLD patients and advanced fibrosis patients.MethodsThis study utilized data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2005 to 2018 to assess dietary quality based on the Alternate Mediterranean Diet (aMED), Healthy Eating Index-2020 (HEI-2020), Dietary Approach to Stop Hypertension (DASH), Alternate Healthy Eating Index (AHEI), and Dietary Inflammatory Index (DII). Weighted Cox proportional hazard regression models along with restricted cubic splines and subgroup analyses were employed in this study.ResultsThe analysis encompassed 3,634 NAFLD patients. After a median follow-up of 89 months, it was found that higher scores on the aMED (HR 0.814, 95% CI 0.681–0.972), HEI-2020 (HR 0.984, 95% CI 0.972–0.997), DASH (HR 0.930, 95% CI 0.883–0.979), and AHEI (HR 0.980, 95% CI 0.966–0.995) were associated with lower mortality risks, while DII scores (HR 1.280, 95% CI 1.098–1.493) indicated an increased risk of mortality. Additionally, a nonlinear relationship was identified solely between AHEI scores and all-cause mortality in NAFLD patients. Notably, among patients with advanced fibrosis, HEI-2020 as a categorical variable (T3: HR 0.519, 95% CI 0.280–0.964), DASH as a continuous variable (continuous: HR 0.921, 95% CI 0.849–0.999), AHEI (continuous: HR 0.971, 95% CI 0.945–0.997; T2: HR 0.545, 95% CI 0.310–0.960; T3: HR 0.444, 95% CI 0.245–0.804), and DII (continuous: HR 1.311, 95% CI 1.121–1.534; T3: HR 2.772, 95% CI 1.477–5.202) exhibited significant associations with all-cause mortality. Subgroup analyses revealed an interaction between AHEI scores and sex among NAFLD patients, where higher AHEI scores correlated with lower all-cause mortality in females, but no such association was observed in males. For other dietary quality, subgroup analyses indicated that their relationships with mortality were robust.ConclusionOur study suggests that a high-quality diet could potentially mitigate mortality risk in both NAFLD and advanced fibrosis patients.

Extrahepatic cholangiocarcinoma (eCCA) is a rare but refractory cancer with dense desmoplasia. Prognosis-associated stromal cells in eCCA remain poorly characterized. Here, we profiled the tumor cellular composition and identified prognosis-related stromal signatures by single-cell RNA sequencing (scRNA-seq) in eCCA. ECCA patients were further stratified into different categories based on identified stromal signatures. Using scRNA-seq, we profiled the transcriptomes of 37,498 individual cells from eight eCCA biopsies, including five tumor tissues and three paired adjacent normal tissues. Bulk RNA sequencing (bRNA-seq) was also performed on 43 eCCA tumor tissues. Stromal cell composition and heterogeneity were examined through differential gene expression and gene set enrichment analyses. By assessing the expression levels of marker genes in bRNA-seq data, the correlation of stromal cell clusters with survival was explored. The GSVA scores of the cell-specific signature genes of the prognosis-related stromal cell subtypes were calculated and used to stratify eCCA patients. The results revealed that tumor stroma in eCCA were composed of hematopoietic progenitor-like cells (HPLCs), fibroblasts (Fb), Schwann cells (Sch), endothelial cells and immune cells. Prognosis-associated stromal cell subpopulations included MKI67 + HPLC, TMEM158 + C3-Fb, FOXP3 + regulatory T cells (Treg), SLIT2 + Sch, TPSD1 + C2-mast cells (MC) and CTSG + C3-MC. Based on these stromal signatures, the eCCA tumors were categorized into three classes: proliferative Group 1 with enrichment of MKI67 + HPLC, inflammatory and fibrotic Group 2 with enrichment of TPSD1 + C2- MC, FOXP3 + Treg and TMEM158 + C3-Fb, and neuronal Group 3 with enrichment of SLIT2 + Sch and CTSG + C3-MC. ECCA patients in Group 3 had a better prognosis when compared to Group 1 and 2, reflecting different impact of stromal subtypes on tumor progression. Single-cell transcriptomic analysis reveals prognosis-related stromal signatures that potentiate the stratification of eCCA into proliferative, inflammatory and fibrotic, and neuronal phenotypes, which has important implications on molecular classification and exploring therapeutic targets in eCCA.

ObjectivesRecently, there has been extensive research on dual immunotherapy for advanced or metastatic non-small cell lung cancer (NSCLC), yet a comprehensive evaluation is lacking. This study aimed to rank the available treatment options and assess the efficacy and safety of dual immunotherapy regimens through the implementation of a Bayesian network meta-analysis (NMA).Materials and methodsA thorough search was conducted to recognize eligible randomized controlled trials (RCTs) on March 20, 2023. Overall survival (OS), progression-free survival (PFS), treatment-related adverse events (TRAEs) and grade ≥3 TRAEs were evaluated to identify the efficacy and safety of dual immunotherapy regimens. The surface under the cumulative ranking curve (SUCRA) and P score were employed to rank the treatments.ResultsEleven clinical trials involving six different regimens were included in this study. The combination of anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) antibodies with anti-T-cell immunoglobulin and ITIM domain (TIGIT) antibodies emerged as the most promising regimen for improving OS and PFS, followed by anti-PD-1/PD-L1 + anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) + chemotherapy treatment and anti-PD-1/PD-L1 + anti-CTLA-4 treatment. The forest plots demonstrated that these three regimens were all superior to chemotherapy. The above results were observed in both unselected treatment line and first-line settings. The least likely to be associated with TRAEs and grade ≥3 TRAEs were respectively anti-CTLA-4 treatment and anti-PD-1/PD-L1 + anti-TIGIT treatment, with anti-PD-1/PD-L1 + anti-CTLA-4 + chemotherapy treatment to be the worst.ConclusionsThis NMA validated the promising efficacy and safety of dual immunotherapy in advanced or metastatic NSCLC. Among them, anti-PD-1/PD-L1 + anti-TIGIT regimen emerges as a highly potential therapeutic approach. Ongoing research efforts should focus on improving treatment regimens, identifying biomarkers, and managing TRAEs to optimize the patient benefits of dual immunotherapy.

Background Definitive concurrent chemoradiotherapy (dCCRT) is the gold standard for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC). However, the potential benefits of consolidation chemotherapy after dCCRT in patients with esophageal cancer remain debatable. Prospective randomized controlled trials comparing the outcomes of dCCRT with or without consolidation chemotherapy in patients with ESCC are lacking. In this study, we aim to generate evidence regarding consolidation chemotherapy efficacy in patients with locally advanced, inoperable ESCC. Methods This is a multicenter, prospective, open-label, phase-III randomized controlled trial comparing non-inferiority of dCCRT alone to consolidation chemotherapy following dCCRT. In total, 600 patients will be enrolled and randomly assigned in a 1:1 ratio to receive either consolidation chemotherapy after dCCRT (Arm A) or dCCRT alone (Arm B). Overall survival will be the primary endpoint, whereas progression-free survival, locoregional progression-free survival, distant metastasis-free survival, and treatment-related toxicity will be the secondary endpoints. Discussion This study aid in further understanding the effects of consolidation chemotherapy after dCCRT in patients with locally advanced, inoperable ESCC. Trial registration ChiCTR1800017646.

Diabetes is closely associated with K+ disturbances during disease progression and treatment. However, it remains unclear whether K+ imbalance occurs in diabetes with normal kidney function. In this study, we examined the effects of dietary K+ intake on systemic K+ balance and renal K+ handling in streptozotocin (STZ)-induced diabetic mice. The control and STZ mice were fed low or high K+ diet for 7 days to investigate the role of dietary K+ intake in renal K+ excretion and K+ homeostasis and to explore the underlying mechanism by evaluating K+ secretion-related transport proteins in distal nephrons. K+-deficient diet caused excessive urinary K+ loss, decreased daily K+ balance, and led to severe hypokalemia in STZ mice compared with control mice. In contrast, STZ mice showed an increased daily K+ balance and elevated plasma K+ level under K+-loading conditions. Dysregulation of the NaCl cotransporter (NCC), epithelial Na+ channel (ENaC), and renal outer medullary K+ channel (ROMK) was observed in diabetic mice fed either low or high K+ diet. Moreover, amiloride treatment reduced urinary K+ excretion and corrected hypokalemia in K+-restricted STZ mice. On the other hand, inhibition of SGLT2 by dapagliflozin promoted urinary K+ excretion and normalized plasma K+ levels in K+-supplemented STZ mice, at least partly by increasing ENaC activity. We conclude that STZ mice exhibited abnormal K+ balance and impaired renal K+ handling under either low or high K+ diet, which could be primarily attributed to the dysfunction of ENaC-dependent renal K+ excretion pathway, despite the possible role of NCC. NEW & NOTEWORTHY Neither low dietary K+ intake nor high dietary K+ intake effectively modulates renal K+ excretion and K+ homeostasis in STZ mice, which is closely related to the abnormality of ENaC expression and activity. SGLT2 inhibitor increases urinary K+ excretion and reduces plasma K+ level in STZ mice under high dietary K+ intake, an effect that may be partly due to the upregulation of ENaC activity.

Introduction:Immune checkpoint inhibitors (ICIs) have transformed advanced gastric cancer treatment, yet patient responses vary, highlighting the need for effective biomarkers. Common markers, such as programmed cell death ligand-1 (PD-L1), microsatellite instability/mismatch repair (MSI/MMR), tumor mutational burden, tumor-infiltrating lymphocytes, and Epstein-Barr virus, face sampling challenges and high costs. This study seeks practical, minimally invasive biomarkers to enhance patient selection and improve outcomes. Methods:This multicenter retrospective study analyzed 617 patients with advanced gastric or gastroesophageal junction cancer treated with programmed cell death protein-1 (PD-1)/PD-L1 inhibitors from January 2019 to March 2023. Clinical data and peripheral blood marker data were collected before and after treatment. The primary endpoints were overall survival (OS) and progression-free survival (PFS); the secondary endpoints included the objective response rate (ORR) and disease control rate (DCR). Least absolute shrinkage and selection operator (LASSO)-Cox and LASSO logistic regression analyses identified independent factors for OS, PFS, and ORR. Predictive nomograms were validated using receiver operating characteristic (ROC) curves, areas under the curve (AUCs), C-indices, and calibration curves, with clinical utility assessed via decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Results:OS-related factors included treatment line, T stage, ascites, pretreatment indirect bilirubin (pre-IBIL), posttreatment CA125, CA199, CA724, and the PLR. PFS-related factors included treatment lines, T stage, metastatic sites, pre-IBIL, posttreatment globulin (GLOB), CA125, and CA199 changes. ORR-related factors included treatment line, T stage, N stage, liver metastasis, pretreatment red cell distribution width-to-platelet ratio (RPR), CA125, and CA724 changes. The nomograms showed strong predictive performance and clinical utility. Conclusions:Early treatment, lower T stage, the absence of ascites, and lower pre-IBIL, post-CA125, CA199, CA724, and PLR correlate with better OS. Factors for improved PFS include early treatment, lower T stage, fewer metastatic sites, and lower pre-IBIL, post-GLOB, and post-CA125 levels. Nomogram models can help identify patients who may benefit from immunotherapy, providing valuable clinical guidance.

OBJECTIVES:Potassium supplementation reduces blood pressure and the occurrence of cardiovascular diseases, with K + -induced natriuresis playing a potential key role in this process. However, whether these beneficial effects occur in diabetes remains unknown. METHODS:In this study, we examined the impact of high-K + intake on renal Na + /K + transport by determining the expression of major apical Na + transporters, diuretics responses (as a proxy for specific Na + transporter function), urinary Na + /K + excretion, and plasma Na + /K + concentrations in db/db mice, a model of type 2 diabetes mellitus. RESULTS:Although db/m mice exhibited increased fractional excretion of sodium (FE Na ) and fractional excretion of potassium (FE K ) under high-K + intake, these responses were largely blunted in db/db mice, suggesting impaired K + -induced natriuresis and kaliuresis in diabetes. Consequently, high-K + intake increased plasma K + levels in db/db mice, which could be attributed to the abnormal activity of sodium-hydrogen exchanger 3 (NHE3), sodium-chloride cotransporter (NCC), and epithelial Na + channel (ENaC), as high-K + intake could not effectively decrease NHE3 and NCC and increase ENaC expression and activity in the diabetic group. Inhibition of NCC by hydrochlorothiazide could correct the hyperkalemia in db/db mice fed a high-K + diet, indicating a key role for NCC in K + -loaded diabetic mice. Treatment with metformin enhanced urinary Na + /K + excretion and normalized plasma K + levels in db/db mice with a high-K + diet, at least partially, by suppressing NCC activity. CONCLUSION:Collectively, the impaired K + -induced natriuresis in diabetic mice under high-K + intake may be primarily attributed to impaired NCC-mediated renal K + excretion, despite the role of NHE3.

Background Accumulating evidence indicates that mitophagy is crucial for the development of diabetic nephropathy (DN). However, little is known about the key genes involved. The present study is to identify the potential mitophagy-related genes (MRGs) in DN. Methods Five datasets were obtained from the Gene Expression Omnibus (GEO) database and were split into the training and validation set. Then the differentially expressed MRGs were screened and further analyzed for GO and KEGG enrichment. Next, three algorithms (SVM-RFE, LASSO and RF) were used to identify hub genes. The ROC curves were plotted based on the hub genes. We then used the CIBERSORT algorithm to assess the infiltration of 22 types of immune cells and explore the correlation between hub genes and immune cells. Finally, the Nephroseq V5 tool was used to analyze the correlation between hub genes and GFR in DN patients. Results Compared with the tubulointerstitium, the expression of MRGs was more noticeably varied in the glomeruli. Twelve DE-MRGs were identified in glomerular samples, of which 11 genes were down-regulated and only MFN1 was up-regulated. GO and KEGG analysis indicated that several enrichment terms were associated with changes in autophagy. Three genes ( MFN1 , ULK1 and PARK2 ) were finally determined as potential hub genes by three algorithms. In the training set, the AUROC of MFN1 , ULK1 and PARK2 were 0.839, 0.906 and 0.842. However, the results of the validation set demonstrated that MFN1 and PARK2 had no significant difference in distinguishing DN samples from healthy controls, while the AUROC of ULK1 was 0.894. Immune infiltration analysis using CIBERSORT showed that ULK1 was positively related to neutrophils, whereas negatively related to M1 and M2 macrophages. Finally, ULK1 was positively correlated with GFR in Nephroseq database. Conclusions ULK1 is a potential biomarker for DN and may influence the development of diabetic nephropathy by regulating mitophagy.

Myocardial infarction is a very dangerous cardiovascular disease with a high mortality rate under the modern developed medical technology. miRNA is a small molecule regulatory RNA discovered in recent years, which can play an important role in many cancers and other diseases. Medical data, machine learning and medical care strategies supporting the Internet of Things (IoMT) have certain applications in the treatment of myocardial infarction. However, the specific pathogenesis of myocardial infarction is still unclear. Therefore, this paper aimed to explore the expression of microRNA-320 and microRNA-204 in myocardial infarction and used the expression of microRNA-320 and microRNA-204 to predict the prognosis of patients with myocardial infarction. In order to discuss the expression of microRNA-320 and microRNA-204 in myocardial infarction in more detail. In this paper, 40 patients in the trial period were selected for clinical research, and 10 patients with normal cardiac function were selected in NHF group as control group. 10 patients with heart failure were selected as AMHF group. 10 patients with acute myocardial infarction were selected as AMNHF group. 10 patients with heart failure after old myocardial infarction were selected as OMHF group. AMHF group, AMNHF group and OMHF group were taken as the case group. This paper analyzed the difference of miR between different groups and determined that there were significant differences in the expression of miR-320 and miR-204 between different groups. Finally, the expression and prognosis of miR-320 and miR-204 in myocardial infarction were analyzed. The analysis results showed that the expression of microRNA-320 and microRNA-204 can inhibit the activity of myocardial cells. On the fifth day, the corresponding expression of microRNA-320 and microRNA-204 reduced the optical density of myocardial cells to 1.75 and 1.76, which was significantly lower than that on the first day. Moreover, excessive miR-320 expression and excessive miR-204 expression can increase the apoptosis rate of myocardial cells. The above results indicated that the high expression of microRNA-320 and microRNA-204 can be a bad prognostic factor in patients with myocardial infarction, showing that medical data, machine learning and medical care strategies supporting IoMT can play a role in the treatment of myocardial infarction. Therefore, it is urgent to understand the pathogenesis of heart failure after myocardial infarction and find new treatment schemes to improve the positive prognosis.

Tumour–stroma cell interactions impact cancer progression and therapy responses. Intercellular communication between fibroblasts and cancer cells using various soluble mediators has often been reported. In this study, we find that a zinc-transporter (ZIP1) positive tumour-associated fibroblast subset is enriched after chemotherapy and directly interconnects lung cancer cells with gap junctions. Using single-cell RNA sequencing, we identify several fibroblast subpopulations, among which Zip1 + fibroblasts are highly enriched in mouse lung tumours after doxorubicin treatment. ZIP1 expression on fibroblasts enhances gap junction formation in cancer cells by upregulating connexin-43. Acting as a Zn 2+ reservoir, ZIP1 + fibroblasts absorb and transfer Zn 2+ to cancer cells, leading to ABCB1-mediated chemoresistance. Clinically, ZIP1 high stromal fibroblasts are also associated with chemoresistance in human lung cancers. Taken together, our results reveal a mechanism by which fibroblasts interact directly with tumour cells via gap junctions and contribute to chemoresistance in lung cancer.

Abstract Purpose: The study aimed to evaluate the causal association between the level of total testosterone and the risk of non-small cell lung cancer (NSCLC) utilizing Mendelian randomization (MR) approach. Methods: Genetic variants extracted from genome-wide association studies (GWAS) datasets of total testosterone level and NSCLC were utilized as instrumental variables (IVs). Five methods were employed to generate overall estimates of the effect, including the inverse variance weighted (IVW), MR Egger, maximum likelihood (ML), weighted median, and IVW (multiplicative random effects). Leave-one-out validation, MR Steiger test, pleiotropy and heterogeneity testing were conducted to ensure the reliability of our results. Results: The MR analysis demonstrated a causal effect between total testosterone level and NSCLC, IVW (OR = 0.74, 95% CI = 0.60-0.92, P= 7.44E-03), MR Egger (OR = 0.53, 95% CI = 0.34-0.84, P = 6.98E-03), ML (OR = 0.74, 95% CI = 0.61-0.91, P = 3.49E-03), weighted median (OR = 0.66, 95% CI = 0.48-0.91, P = 1.25E-03), and IVW (multiplicative random effects) (OR = 0.74, 95% CI = 0.60-0.92, P = 7.44E-03). The leave-one-out test revealed that removing any IV did not significantly alter the results. The MR Steiger test confirmed the direction of causality. The absence of significant pleiotropy and negligible effect of heterogeneity supported our finding. Conclusion: According to our findings, increased levels of testosterone may potentially reduce the likelihood of developing NSCLC. These outcomes could provide valuable insights for the advancement of innovative therapeutic strategies manipulating testosterone levels to lower the risk of NSCLC.