MicroRNAs (miRNAs) are key regulators of skeletal muscle development and homeostasis. As secretory factors, previous studies have identified and validated a space flight-associated circulating microRNA (miRNA) signature in response to space flight. However, the muscle-derived miRNAs are not clear. Here, we comprehensively analyzed the variations of miRNA during mouse myoblast myogenesis in response to space flight, including expression and secretion. We validated some miRNA expression by qRT-PCR analysis in the limb muscle of a disuse-induced atrophy mouse model, mimicking the unloading following microgravity. Functional assays using miRNA mimics further supported the regulatory roles of some miRNAs in target gene expression, as well as in myoblast proliferation and differentiation. These results suggest that deregulation of these miRNAs may play a functional role in muscle atrophy, and they could be candidate biomarkers of muscle atrophy-associated muscular disease. Importantly, our analysis also suggests that spaceflight may regulate miRNA secretion and retention by modulating RNA-binding proteins (RBPs). Secreted miRNAs originating from skeletal muscle cells have been implicated in various diseases affecting the nervous and skeletal systems. Collectively, these findings highlight the potential role of skeletal muscle-derived miRNAs in systemic adaptation to spaceflight.

A better understanding of functional heterogeneity of tumor cells may lead to the improvement of the diagnosis and development of effective therapies for patients with papillary thyroid cancer (PTC). Here, the transcriptional heterogeneity and hierarchical trajectory of malignant thyrocytes were investigated by single-cell RNA sequencing analysis in an adult-onset autochthonous mouse model of PTC driven by a BRAFV600E. Within BRAFV600E thyrocytes, we identified distinct subpopulations exhibiting varying degrees of mesenchymal transformation and stability. Further analysis uncovered an epithelial-mesenchymal transition (EMT) trajectory, where malignant subpopulations progress from an intermediate to a more mesenchymal and malignant state. The EMT-related phenotype of each subpopulation was validated with an organoid culture system. Further analysis demonstrated that major malignant subpopulations maintain distinct EMT states through subpopulation-specific pathway usage, whereas transitioning cells undergo a dynamic shift in molecular strategy by using different pathway combinations or distinct gene sets within the same EMT-related pathways along the EMT trajectory. Moreover, metformin diminished the most malignant subpopulation in the PTC mouse model and inhibited EMT potential in both regular and organoid cultures. Importantly, the functional heterogeneity of tumor cells identified in PTC mouse model have clinical relevance. Furthermore, transcriptome dynamics analysis revealed an EMT trajectory-related gene module with substantial predictive value for human PTCs with BRAFV600E. Lastly, our analysis reveals that p53 deficiency lowers the tumorigenic threshold for BRAFV600E and promotes cell state transition towards a more malignant state, rather than altering cellular heterogeneity or the transition trajectory. Subsequent analysis in vitro demonstrated that p53 loss might confer more malignant potential to BRAFV600E thyrocytes through modulating metabolic plasticity. Collectively, our work not only deciphers the functional intra-tumoral heterogeneity of BRAFV600E-drieven PTC but also thereby provides a theoretical foundation for developing EMT-targeted treatment.

The intracellular abundance of NAD+, a vital metabolic cofactor, critically influences muscle stem cell (MuSC) function. However, the spatial regulation of NAD+ and its impact on MuSC function remain unclear. In this study, we demonstrated that the loss of miR-183 and miR-96 leads to inefficient skeletal muscle regeneration upon injury and triggers premature differentiation of MuSC-derived primary myoblasts. The underlying mechanism involves miRNA-mediated regulation through targeting SLC25A51, a mitochondrial transporter for NAD+ that elevates mitochondrial NAD+ while reducing cytoplasmic NAD+ levels. Our results suggest that the reduction in cytoplasmic NAD+ diminishes SIRT1-mediated deacetylation, increasing H4K16ac at the promoters of myogenic genes to promote differentiation. Concurrently, the mitochondrial NAD+ accumulation stimulates the tricarboxylic acid cycle, leading to elevated levels of ATP and citrate. These metabolites allosterically activate the ACLY pathway, which in turn increases acetyl-CoA production, thereby supplying acetyl groups for H4K16ac. Furthermore, SIRT3 knockdown impaired myogenic differentiation and attenuated the increased levels of both ATP and acetyl-CoA in miR-183/96-deficient cells, suggesting that the elevated mitochondrial NAD+ also enhances differentiation via SIRT3-mediated regulation of mitochondrial metabolism and acetyl-CoA production. Our work establishes miR-183 and miR-96 as critical regulators of epigenetic-metabolic networks that influence MuSC differentiation through subcellular partitioning of NAD+, ensuring proper regeneration timing.

110 Background: Immune checkpoint blockade (ICB) shows limited efficacy in mismatch repair proficient (pMMR) locally advanced rectal cancer (LARC). Recent clinical studies have shown that neoadjuvant chemoradiotherapy (nCRT) plus ICB improve response. However, radiotherapy is associated with toxicities, including radiation proctitis, anastomotic leakage, and anal dysfunction. Moreover, radiotherapy is not feasible for high position LARC. Radiotherapy-free neoadjuvant strategy warrants further exploration. The FIRM trial is the first phase 2, proof-of-concept study evaluating neoadjuvant immuno-chemotherapy (nICT) with mFOLFOX6 plus PD1 blockade for pMMR LARC. Methods: Patients (pts) with T3/4 or N+, pMMR LARC located ≤15 cm from anal verge were eligible. Pts received 6 cycles of mFOLFOX6 and serplulimab followed by surgery. Primary endpoints were pathological complete response (pCR) rate and major pathological response (MPR) rate. Enrollment of 30 pts was planned, with hypothesis of an increased pCR of 24% compared with reported data of 6.6% after mFOLFOX6 (FOWARC trial, JCO 2016). Multi-omics profiling (single cell RNAseq, bulk RNAseq, whole exome sequencing) was performed to elucidate response mechanisms and develop an immuno-response molecular subtype (IRMS) for immunotherapy stratification. Results: 30 pts were enrolled, 28 completed ≥4 cycles of nICT. 2 discontinued due to adverse events (AE). The pCR and MPR rate were 42.9% and 67.9%, respectively. Tumor regression grade (TRG) 0, 1, 2, and 3 were observed in 44.4%, 11.1%, 40.7%, and 3.7% of pts. 6 pts experienced grade 3 AEs, with no grade 4-5 AE or anastomotic leakage observed. Baseline profiling identified two novel subsets predicting nICT response: inflammatory/migratory tumor cells (IMT) and ITGAX⁺ activated B cells (IAB). Post-nICT samples showed increased enrichment of CD8⁺ T, cDC1, pDC, memory B and Tfh cells, together with reduced exhausted CD8⁺ T, Tregs, extracellular matrix deposition and tumor angiogenesis. IRMS stratified pts into immune-sensitive and immune-resistant types and showed strong predictive performance in internal cohort (AUC =0.87, sensitivity =0.74, specificity =1.0, accuracy =0.81), outperforming conventional biomarkers including CPS (AUC = 0.48) and TMB (AUC =0.47). Notably, IRMS was validated across multiple external immunotherapy cohorts (melanoma, colorectal, lung, breast cancers), showing robust predictive value (AUC =0.70-0.86). Conclusions: These findings provide the first evidence supporting immuno-chemotherapy as a promising radiotherapy-free neoadjuvant strategy for pMMR LARC. nICT converts the immune-cold tumors into immune-activated state by orchestrating a dual-pathway immune remodeling involving IMT-cDC1-CD8 and IAB-CD4 axes. The IRMS provides a high-precision, pan-cancer tool to guide patient selection and personalized immunotherapy. Clinical trial information: NCT06688786 .

Skeletal muscle aging is characterized by a functional decline in muscle stem cells (MuSCs), yet the key regulatory mechanisms driving this deterioration remain poorly understood. By integrating transcriptomic profiles from aged MuSCs with data from C2C12 cells exposed to spaceflight conditions (which mimic an aging-like phenotype), we identified MORF4-related gene on chromosome 15 (MRG15) as a putative epigenetic regulator involved in age-related myogenic decline. Using a MuSC-specific inducible knockout (iKO) mouse model, we found that loss of MRG15 severely compromises myogenic differentiation and muscle regeneration. Subsequent RNA sequencing of iKO MuSCs, combined with ChIP-seq analysis of histone modifications, revealed that MRG15 modulates the chromatin landscape of myogenic genes through interaction with MyoD, thereby facilitating transcriptional activation and differentiation. Our findings establish MRG15 as a critical epigenetic regulator that cooperates with MyoD to orchestrate chromatin remodeling, thereby promoting transcriptional activation of the myogenic program. Dysregulation of MRG15 may underlie impaired muscle regeneration during aging.

Diabetes and its complications cause serious global health and economic burdens. Various medicine-food plant polysaccharides (MFPPs) have garnered increasing attention due to their low toxicity, minimal side effects, and efficacy in suppressing hyperglycemia and reversing insulin resistance, positioning them as potential antidiabetic agents. These polysaccharides enhance gut barrier integrity, improve gut microbiota diversity, and ameliorate metabolic disorders linked to intestinal flora dysregulation in Type 2 diabetes mellitus, thereby achieving glycemic control. This review outlines the sources, antidiabetic mechanisms, and gut-modulatory effects of polysaccharides from medicinal plants. Specific polysaccharides, including Astragalus polysaccharides, Ginseng polysaccharides, Pueraria lobata polysaccharides, and Lycium barbarum polysaccharides, demonstrate the ability to repair intestinal barrier damage, prevent gut microbiota dysbiosis, and promote short-chain fatty acid (SCFA) accumulation. Additionally, the advantages of MFPP nanoparticles and their role in diabetes regulation via gut modulation are summarized. This review provides novel insights for designing dietary formulations for diabetic patients and serves as a reference for clinical applications of these polysaccharides as therapeutic or adjunctive interventions.

BACKGROUND:In laparoscopic anterior rectal resection with diverting loop ileostomy, specimen extraction through stoma incision avoids auxiliary incisions and contributes to a more minimally invasive postoperative outcome but enlarges the stoma site. The traditional suture method reduces incision size but creates peristomal incisions that are prone to stomal complications. The authors introduce the "dumpling suture method," a skin-folding technique that reduces incision size without creating peristomal incisions. OBJECTIVE:This study aimed to assess the efficacy of the dumpling suture method in reducing stoma-related complications in patients undergoing specimen extraction through stoma incision surgery. DESIGN:Single-center, randomized, parallel-group controlled study. SETTINGS:This study was conducted at a tertiary referral center. PATIENTS:Seventy-two patients scheduled for laparoscopic anterior rectal resection surgery with specimen extraction through a stoma incision were enrolled and randomly assigned to the dumpling suture method or traditional suture method group. INTERVENTIONS:The experimental group received ileostomy creation using the dumpling suture method, whereas the control group underwent the traditional suture method. MAIN OUTCOME MEASURES:The primary end point was the rate of stoma-related complications. Secondary end points included peristomal skin lesions, pain scores, and quality-of-life scores. RESULTS:Patients in the dumpling suture method group had a significantly lower overall stomal complication rate compared to those in the traditional suture method group (11.1% vs 41.7%). The dumpling suture method reduced skin-related complications, including fecal dermatitis (8.3% vs 33.3%), skin erosion or infection (0% vs 25%), and mucocutaneous detachment (2.8% vs 13.9%). Peristomal skin infection scores for peristomal skin lesions were lower in the dumpling suture method group, and patients reported less stoma pain and improved quality of life. LIMITATIONS:Limitations include its single-center design and inability to blind participants. CONCLUSIONS:The dumpling suture method uses a skin-folding suture to reduce an enlarged stomal incision, effectively decreasing stoma-related complications. This procedure offers a novel suturing approach for loop ileostomy with enlarged incision, effectively eliminating postoperative incisions and minimizing surgical trauma. See Video Abstract. MTODO DE SUTURA CON NUDO VERSUS MTODO DE SUTURA TRADICIONAL PARA LA ILEOSTOMA EN ASA DESVIADA EN LA RESECCIN RECTAL ANTERIOR LAPAROSCPICA CON EXTRACCIN DE LA MUESTRA A TRAVS DE LA INCISIN DEL ESTOMA ENSAYO ALEATORIZADO Y CONTROLADO EN PARALELO:ANTECEDENTES:En la resección rectal anterior laparoscópica con ileostomía en bucle de derivación, la extracción de la muestra a través de la incisión del estoma evita incisiones auxiliares y contribuye a un resultado postoperatorio menos invasivo, pero aumenta el tamaño del estoma. El método de sutura tradicional reduce el tamaño de la incisión, pero crea incisiones periestomales, propensas a complicaciones estomales. Presentamos el «método de sutura Dumpling», que utiliza una técnica de pliegue cutáneo para reducir el tamaño de la incisión sin crear incisiones peristomales.OBJETIVO:El objetivo de este estudio fue evaluar la eficacia del método de sutura Dumpling para reducir las complicaciones relacionadas con el estoma en pacientes sometidos a cirugía de extracción de muestras a través de la incisión del estoma.DISEÑO:Estudio controlado, aleatorizado, de grupos paralelos, realizado en un único centro.ENTORNO:Este estudio se llevó a cabo en un centro de referencia terciario.PACIENTES:Se inscribieron 72 pacientes programados para una cirugía de resección rectal anterior laparoscópica con extracción de muestras a través de una incisión estomal, que fueron asignados aleatoriamente al grupo del método de sutura Dumpling o al grupo del método de sutura tradicional.INTERVENCIONES:El grupo experimental se sometió a una ileostomía mediante el método de sutura Dumpling, mientras que el grupo de control se sometió al método de sutura tradicional.PRINCIPALES MEDIDAS DE RESULTADO:El criterio de valoración principal fue la tasa de complicaciones relacionadas con el estoma. Los criterios de valoración secundarios incluyeron lesiones cutáneas peristomales, puntuaciones de dolor y puntuaciones de calidad de vida.RESULTADOS:El grupo del método de sutura tipo dumpling tuvo una tasa global de complicaciones estomales significativamente menor en comparación con el método de sutura tradicional (11,1 % frente a 41,7 %). El método de sutura tipo dumpling redujo las complicaciones relacionadas con la piel, incluyendo la dermatitis fecal (8,3 % frente a 33,3 %), la erosión o infección de la piel (0 % frente a 25 %) y el desprendimiento mucocutáneo (2,8 % frente a 13,9 %). Las puntuaciones de infección cutánea peristomal para las lesiones cutáneas peristomales fueron más bajas en el grupo del método de sutura tipo dumpling, y los pacientes informaron de menos dolor en el estoma y una mejor calidad de vida.LIMITACIONES:Las limitaciones incluyen su diseño unicéntrico y la imposibilidad de cegar a los participantes.CONCLUSIONES:La técnica del método de sutura tipo dumpling emplea una sutura con pliegues cutáneos para reducir la incisión estomal agrandada, lo que disminuye eficazmente las complicaciones relacionadas con el estoma. Este procedimiento ofrece un nuevo enfoque de sutura para la ileostomía en bucle con incisión agrandada, lo que elimina eficazmente las incisiones postoperatorias y minimiza el trauma quirúrgico. (AI-generated translation ).

Background:Colorectal cancer (CRC) progression and treatment resistance are closely linked to cancer stem cells (CSCs), yet their spatial dynamics and regulatory mechanisms remain poorly characterized. This study integrates single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to define CRC stem cell subtypes (Co-CSS), map their interactions within the tumor microenvironment, and identify novel prognostic markers driving clinical outcomes. Methods:scRNA-seq was used to analyze cellular heterogeneity in CRC, identifying key Co-CSS. CytoTRACE was applied to assess stemness. ST further mapped the distribution and interactions of Co-CSS with the tumor microenvironment. Gene intersection analysis identified NPDC1 and NSMF, whose high expression correlated with poor prognosis. Patient classification based on NPDC1 and NSMF expression highlighted treatment response variability, suggesting targets for precision medicine. Results:The findings indicate that Co-CSS in CRC can modulate the tumor microenvironment and influence the progression of the disease through various ligand-receptor interactions. It is possible that Co-CSS is regulated by fibroblasts through the WNT signaling pathway. The expression levels of NPDC1 and NSMF are significantly correlated with the overall survival of CRC patients, suggesting their potential value as independent prognostic markers. Conclusions:This study offers insights into the role of Co-CSS in CRC through ST and gene expression profiling, uncovering novel markers and pathways. It redefines the interplay between Co-CSS and the tumor microenvironment, offering a foundation for future mechanistic studies and therapeutic interventions aimed at targeting Co-CSS to improve CRC treatment.

Non-coding genes, such as microRNA and lncRNA, which have been widely studied, play an important role in the regulatory network of skeletal muscle development. However, the functions and mechanisms of most non-coding RNAs in skeletal muscle regulatory networks are unclear. This study investigated the function and mechanism of miR-34b in muscle growth and development. MiR-34b overexpression and interference tests were performed in C2C12 myoblasts and animal models. It was demonstrated that miR-34b significantly promoted mouse muscle growth and development in vivo, while miR-34b inhibited myoblast proliferation and promoted myoblast differentiation in vitro. Bioinformatics prediction using TargetScan for miRNA target identification and Bibiserv2 for potential miRNA-gene interaction analysis revealed a miR-34b binding site in the SYlSL sequence. The molecular mechanism of miR-34b regulating muscle growth and development was studied by co-transfection experiment, luciferase reporter gene detection, RNA immunoprecipitation, and RNA pull-down. MiR-34b can directly bind to SYISL and AGO2 proteins and regulate the expression of SYISL target genes p21 and MyoG by targeting SYISL, thereby regulating muscle growth and development. This study highlights that, as a novel regulator of myogenesis, miR-34b regulates muscle growth and development by targeting SYISL.

In the cardiovascular system, different types of cardiovascular cells can secrete specific exosomes and participate in the maintenance of cardiovascular function and the occurrence and development of diseases. Exosomes carry biologically active substances such as proteins and nucleic acids from cells of origin and can be used as biomarkers for disease diagnosis and prognosis assessment. In addition, exosome-mediated intercellular communication plays a key role in the occurrence and development of cardiovascular diseases and has become a potential therapeutic target. This article emphasizes the importance of understanding the mechanism of exosomes in cardiovascular diseases and systematically details the current understanding of exosomes as regulators of intercellular communication in cardiomyocytes, providing a basis for future research and therapeutic intervention.

Emerging evidence suggests that autophagy is activated during exercise, mediating the benefits of exercise. However, the molecular mechanisms underlying the regulation of skeletal muscle autophagy during exercise are incompletely understood. Here, we show lactate severs as a positive regulator of autophagy in myocytes and its levels increase rapidly in response to a single bout of exercise. Mice with low lactate levels due to the lack of myocyte lactate dehydrogenase A exhibit significant abnormalities in skeletal muscle, including impaired autophagy. Our mechanistic study demonstrates that lactate enhances autophagy by inactivating mTOR complex 1 (mTORC1) through promoting mTOR lactylation at lysine 921 (K921) in myocytes. Accordingly, mutation of mTOR at K921 site causes sustained mTORC1 activation, leading to defects in skeletal muscle autophagy. Thus, our work uncovers a previously undescribed physiological action of lactate in the regulation of mTORC1-controlled skeletal muscle autophagy during acute exercise, which involves a lactylation-based post-translational modification mechanism.

Dysregulated autophagy contributes to liver steatosis, yet its regulation under distinct metabolic contexts remains poorly defined. Here, we identify bile acids (BAs) as critical modulators of hepatic autophagy. Circulating BA levels are elevated in human subjects with liver steatosis and independently associated with increased hepatic steatosis risk. High-fat diet (HFD) feeding increases circulating BA levels, while simultaneously reducing hepatic autophagic flux in mice, whereas pharmacological inhibition of farnesoid X receptor (FXR) enhances autophagy and alleviates steatosis in the livers of HFD-fed mice. Mechanistically, circulating BAs promote hepatic acetyl-CoA production through FXR-induced acyl-CoA oxidase 1 (ACOX1), which in turn suppresses autophagy by increasing the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar to HFD feeding, prolonged fasting elevates BA levels and hepatic lipid accumulation, while concurrently upregulating hepatic miR-378, a positive regulator of BA synthesis. Although miR-378 exerts a cell-autonomous pro-autophagic effect during short-term fasting, it paradoxically drives lipid accumulation by suppressing hepatic autophagy via BA/FXR/ACOX1/acetyl-CoA axis in a non-cell-autonomous manner during either HFD feeding or prolonged fasting when BA action becomes considerable. Together, our study uncovers BAs as a previously unrecognized class of inhibitors of hepatic autophagy during prolonged fasting and in metabolic dysfunction-associated steatotic liver disease (MASLD), providing novel insights into context-dependent autophagic regulation of hepatic lipid metabolism and potential therapeutic strategies for MASLD.

BackgroundMicrosatellite instability-high (MSI-H) tumors, with elevated tumor mutational burden and expression of neoantigens, represent a distinct immune-activated subpopulation in colorectal cancer (CRC), characterized by strong lymph node reaction, locally advanced tumor and higher total lymph nodes harvested (TLN), but less metastatic lymph nodes and fewer incidence of III-IV stage. Host immune response to tumor and lymph nodes may be an important prognostic factor. However, N stage and LNR (Lymph-Node Ratio) have limitations in predicting the prognosis of MSI-H patients. Negative lymph node count (NLC) provided a more precise representation of immune activation status and extent of tumor metastasis. The study aims to detect prognostic significance of NLC in MSI-H CRC patients, and compare it with N stage, TLN and LNR.MethodsRetrospective data of 190 consecutive MSI-H CRC patients who received curative resection were collected. Survival analyses were performed using the Kaplan-Meier method. Clinicopathological variables including NLC, N stage, TLN and LNR were studied in univariate and multivariate COX regression analyses. ROC (receiver operating characteristic curve) and concordance index were employed to compare the differences in predictive efficacy between NLC, N stage, TLN and LNR.ResultsPatients with increased NLC experienced a significantly improved 5-years DFS and OS in Kaplan-Meier analysis, univariate analysis, and multivariate analysis, independent of potential confounders examined. Increased NLC corresponded to elevated 5-years DFS rate and 5-years OS rate. AUC (area under curve) and concordance index of NLC in DFS and OS predicting were both significantly higher than N stage, TLN and LNR.ConclusionsNegative lymph node is an important independent prognostic factor for MSI-H patients. Reduced NLC is associated with tumor recurrence and poor survival, which is a stronger prognostic factor than N stage, TLN and LNR.

Aim: The article explores celery-derived extracellular vesicles (CDEVs), characterized by high cellular uptake, low immunogenicity, and high stability, as a therapeutic strategy for antitumor nanomedicines. Methods: The methods employed in this study include in vitro cell experiments such as co-culture, Western Blot, and flow cytometry. In vivo experiments were conducted in C57BL/6 tumor-bearing mice subcutaneously injected with Lewis lung carcinoma (LLC) cells. The experiments encompassed parameters such as survival rate, body weight, tumor size, flow cytometry, immunohistochemistry, and spectral live imaging system. Results: Our study revealed that CDEVs could be used as drugs to effectively downregulate the phosphorylated signal transducer and activator of transcription 3 (p-STAT3)/programmed cell death ligand 1 (PD-L1) axis in lung cancer cells. In co-culture experiments, CDEVs were observed to impede the expression of PD-L1, thereby interfering with the interaction between PD-L1 and programmed death 1 (PD-1) and subsequently preventing the suppression of T cells. In in vivo distribution experiments, CDEVs loaded with paclitaxel (PTX) demonstrated better tumor targeting capabilities. Remarkably, following CDEVs-PTX treatment, CD8+ T cell levels in mice were increased, presumably leading to improved antitumor effects. Conclusion: CDEVs not only serve as drug carriers but also function as drugs themselves; as such, through a single administration of CDEVs, it is possible to combine immunotherapy and chemotherapy to achieve better effects between the two, providing a more comprehensive and effective cancer treatment strategy that promises to improve treatment outcomes and reduce the adverse effects of therapy.

Background: A diverting loop ileostomy (DLI) is performed in laparoscopic anterior rectal resection (LAR) surgery at high risk of anastomotic fistula. Minimally invasive surgery promotes postoperative recovery and cosmetics. To reduce abdominal trauma, specimen extraction through stoma incision (EXSI) is usually performed to avoid auxiliary abdominal incision with enlarged stomal incision. The traditional suture method (TSM) reduces the incision size by suturing the ends of the enlarged incision, leading to peristomal incisions and a higher risk of stomal complications. The study aimed to introduce the dumpling suture method (DSM) of PLI and compare this new method with TSM. Materials and Methods: The authors propose a novel stoma suture technique, which utilized a method of skin folding suture to reduce the enlarged incision size. A retrospective analysis was conducted on 71 consecutive patients with rectal cancer who underwent LAR-DLI with EXSI, and the intraoperative details and postoperative outcomes of the two groups were measured. Results: The DSM group showed a lower stomal complication rate (10.3 vs. 35.7%, P=0.016) than that of the TSM group. The scores of DET (Discoloration, Erosion, Tissue overgrowth), stomal pain, quality of life were all significantly lower in DSM group than in TSM group. In multivariate analysis, DSM was an independent protective factor for stoma-related complications. Operative time, time to first flatus, defecation and eat, nonstomal related postoperative complications were similar in both groups. Conclusion: DSM utilizes a method of skin folding suture to reduce the enlarged incision size, which is safe and effective in reducing the incidence of peristomal skin infections and stomal complications. This procedure offers a novel suturing approach for loop ileostomy with enlarged incision, effectively reducing the postoperative trauma and incidence of stomal complications.

Objective To explore the relationship between pyroptosis and treatment in non-small cell lung cancer patients treated with tyrosine kinase inhibitors targeted therapy. Methods Stable transfection strains with common EGFR mutations found in clinical practice were constructed through lentiviral transfection. LDH and Western blot experiments were conducted to determine the degree and mechanism of pyroptosis after osimertinib treatment. Animal experiments verified the effect of pyroptosis on treatment efficacy. ELISA was used to explore the potential connection between pyroptosis and tumor immunotherapy. Results After osimertinib treatment on stable lines, the EGFR-L858R mutation had obvious pyroptosis at the morphology and protein levels. Western blot experiment confirmed that pyroptosis was mediated by GSDME (P < 0.0001). Experiments through the overexpression of GSDME and corresponding animal studies discovered that the degree of pyroptosis affected the treatment outcome. Blood analysis revealed that the level of IL-1β secreted by EGFR-L858R and EGFR-L858R-GSDME-OE mice after treatment was higher than that of the control group (P < 0.0001), and it may regulate tumor immunity to a certain extent. Conclusion Osimertinib can induce pyroptosis in EGFR-L858R mutant strains mediated by GSDME, and the level of pyroptosis in cell lines is positively correlated with therapeutic effect to a certain extent.

NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors, but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown. Besides, the WW domain containing proteins can be recognized by NDFIP1, resulted in the loading of the target proteins into exosomes. However, whether WW domain-containing transcription regulator 1 (WWTR1, also known as TAZ) can be packaged into exosomes by NDFIP1 and if so, whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any extent. Here, we first found that NDFIP1 was low expressed in NSCLC samples and cell lines, which is associated with shorter OS. Then, we confirmed the interaction between TAZ and NDFIP1, and the existence of TAZ in exosomes, which requires NDFIP1. Critically, knockout of NDFIP1 led to TAZ accumulation with no change in its mRNA level and degradation rate. And the cellular TAZ level could be altered by exosome secretion. Furthermore, NDFIP1 inhibited proliferation in vitro and in vivo, and silencing TAZ eliminated the increase of proliferation caused by NDFIP1 knockout. Moreover, TAZ was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples, and the serum exosomal TAZ level was lower in NSCLC patients. In summary, our data uncover a new tumor suppressor, NDFIP1 in NSCLC, and a new exosome-related regulatory mechanism of TAZ.

Purpose PARP inhibitors have revolutionized the treatment landscape for advanced prostate cancer (PCa) patients who harboring mutations in homologous recombination repair (HRR) genes. However, the molecular mechanisms underlying PARP inhibitors function beyond DNA damage repair pathways remain elusive, and identifying novel predictive targets that favorably respond to PARP inhibitors in PCa is an active area of research. Methods The expression of GSDME in PCa cell lines and human PCa samples was determined by western blotting. Targeted bisulfite sequencing, gene enrichment analysis (GSEA), clone formation, construction of the stably transfected cell lines, lactate dehydrogenase (LDH) assay, western blotting as well as a mouse model of subcutaneous xenografts were used to investigate the role of GSDME in PCa. The combinational therapeutic effect of olaparib and decitabine was determined using both in vitro and in vivo experiments. Results We have found low expression of GSDME in PCa. Interestingly, we demonstrated that GSDME activity is robustly induced in olaparib-treated cells undergoing pyroptosis, and that high methylation of the GSDME promoter dampens its activity in PCa cells. Intriguingly, genetically overexpressing GSDME does not inhibit tumor cell proliferation but instead confers sensitivity to olaparib. Furthermore, pharmacological treatment with the combination of olaparib and decitabine synergistically induces GSDME expression and cleavage through caspase-3 activation, thus promoting pyroptosis and enhancing anti-tumor response, ultimately resulting in tumor remission. Conclusion Our findings highlight a novel therapeutic strategy for enhancing the long-term response to olaparib beyond HRR-deficient tumors in PCa, underscoring the critical role of GSDME in regulating tumorigenesis.

With the emergence of novel variants, there have been widespread COVID-19 infections in the Chinese mainland recently. Compared to ancestral COVID-19 variants, Omicron variants become more infectious, but less virulent. Previous studies have recommended postponing non-emergency surgery for at least 4–8 weeks after COVID-19 infection. However, delayed surgery has been shown to be associated with tumor progression and worse overall survival for cancer patients. Here, we examined surgery risk and optimal timing for colorectal cancer patients with perioperative COVID-19 infection. A total of 211 patients who underwent colorectal cancer surgery from 1 October 2022 to 20 January 2023 at Xinhua Hospital were included. In addition, COVID-19-infected patients were further categorized into three groups based on infected time (early post-COVID-19 group, late post-COVID-19 group and postoperative COVID-19 group). The complication rate in patients with COVID-19 infection was 26.3%, which was significantly higher than in control patients (8.4%). The most common complications in COVID-19-infected patients were pneumonia, ileus and sepsis. Patients who underwent surgery close to the time of infection had increased surgery risks, whereas surgery performed over 1 week after recovery from COVID-19 did not increase the risk of postoperative complications. In conclusion, surgery performed during or near the time of COVID-19 infection is associated with an increased risk of developing postoperative complications. We recommend that the safe period for patients with recent COVID-19 infection in colorectal cancer surgery be at least 1 week after recovery from COVID-19.

Purpose:Metastatic lung squamous cell carcinoma (LUSC) is one of the most common causes of cancer death worldwide. As yet, however, the molecular mechanism underlying LUSC metastasis remains elusive. In this study, we report a novel mechanism involving signaling interactions between FGF19 and GLI2 that could drive the progression of LUSC. Methods:The expression of FGF19 in human LUSC samples was assessed by immunohistochemistry. The concentration of FGF19 in serum samples was assessed by ELISA. RNA sequencing, scratch wound-healing, trans-well, GO analysis, GSEA, luciferase reporter, Western blotting, immunofluorescence and immunohistochemistry assays, as well as an animal model were used to investigate the molecular mechanism underlying FGF19 driven LUSC progression. The therapeutic effect of a GLI2 inhibitor was determined using both in vitro cellular and in vivo animal experiments. Results:We found that FGF19, a member of the fibroblast growth factor family, plays a crucial role in the invasion and metastasis of LUSC, and identified GLI2 as an important downstream effector of FGF19 involved in metastasis. Surprisingly, we found that FGF19 and GLI2 could reciprocally induce the expression of each other, and form a positive feedback loop to promote LUSC cell invasion and metastasis. These findings were corroborated by an association between a poor prognosis of LUSC patients and FGF19/GLI2 co-expression. In addition, we found that the GLI inhibitor GANT61 could effectively reduce FGF19-mediated LUSC invasion and metastasis. Conclusion:Our data suggest that FGF19 may serve as a novel biomarker for predicting metastatic LUSC. Intervening with the FGF19-GLI2 feedback loop may be a strategy for the treatment of FGF19-driven LUSC metastasis.