Intratumoral and fecal microbiota reveals microbial markers associated with gastric carcinogenesis.

Background: The relationship between dysbiosis of the gastrointestinal microbiota and gastric cancer (GC) has been extensively studied. However, microbiota alterations in GC patients vary widely across studies, and reproducible diagnostic biomarkers for early GC are still lacking in multiple populations. Thus, this study aimed to characterize the gastrointestinal microbial communities involved in gastric carcinogenesis through a meta-analysis of multiple published and open datasets. Methods: We analyzed 16S rRNA sequencing data from 1,642 gastric biopsy samples and 394 stool samples across 11 independent studies. VSEARCH, QIIME and R packages such as vegan, phyloseq, cooccur, and random forest were used for data processing and analysis. PICRUSt software was employed to predict functions. Results: The α-diversity results indicated significant differences in the intratumoral microbiota of cancer patients compared to non-cancer patients, while no significant differences were observed in the fecal microbiota. Network analysis showed that the positive correlation with GC-enriched bacteria increased, and the positive correlation with GC-depleted bacteria decreased compared to healthy individuals. Functional analyses indicated that pathways related to carbohydrate metabolism were significantly enriched in GC, while biosynthesis of unsaturated fatty acids was diminished. Additionally, we investigated non-Helicobacter pylori (HP) commensals, which are crucial in both HP-negative and HP-positive GC. Random forest models, constructed using specific taxa associated with GC identified from the LEfSe analysis, revealed that the combination of Lactobacillus and Streptococcus included alone could effectively discriminate between GC patients and healthy individuals in fecal samples (area under the curve (AUC) = 0.7949). This finding was also validated in an independent cohort (AUC = 0.7712). Conclusions: This study examined the intratumoral and fecal microbiota of GC patients from a dual microecological perspective and identified Lactobacillus, Streptococcus, Roseburia, Faecalibacterium and Phascolarctobacterium as intratumoral and intestinal-specific co-differential bacteria. Furthermore, it confirmed the validity of the combination of Lactobacillus and Streptococcus as GC-specific microbial markers across multiple populations, which may aid in the early non-invasive diagnosis of GC.

Low-dose estrogen release from silastic capsule enhanced flap wound healing in an animal model.

BACKGROUND: Deep and extensive wounds usually cannot be closed directly by suturing or skin grafting. Flap transplantation is typically used to reconstruct large wounds clinically. The flap survival is based on a stable blood perfusion. It is established that estrogen promotes wound healing and angiogenesis, and regulates the inflammatory response, leading to enhanced flap survival after transplantation. However, estrogen concentrations administered in previous studies were significantly higher than physiological levels, potentially causing systemic side effects. Estrogen-sustained-release silastic capsules can maintain blood serum estrogen closer to physiological levels. This study aimed to investigate whether administering estrogen at a lower concentration, closer to physiological levels, could still enhance flap survival. MATERIALS AND METHODS: This study was performed in a random skin flap model in ovariectomized (OVX) mice. Sustained-release estrogen silastic capsules were implanted into OVX mice to determine the functional role of estrogen in wound healing after flap transplantation. Flap blood perfusion was analysed using a colour laser Doppler scanner. Immunohistochemical staining of CD31, hypoxia-inducible factor 1 alpha (HIF-1α), alpha-smooth muscle actin (α-SMA), cleaved caspase 3 and apoptotic terminal dUTP nick end-labelling stain was used to investigate flap angiogenesis, tissue hypoxia, wound healing and cell death in the flap tissue, respectively. RESULTS: We observed that administering estrogen at a lower concentration enhanced superficial blood perfusion while reducing the flap's ischemic area and tissue necrosis. HIF-1α expression was significantly decreased in the dermis layer but not in the fascia, whereas cleaved caspase 3 levels decreased in the fascia but remained unchanged in the dermis. Additionally, there was no significant difference in CD31and α-SMA expression between the groups. CONCLUSION: In summary, the study showed that an estrogen silastic capsule maintained physiological estrogen levels and improved superficial perfusion, thereby reducing dermal hypoxia, and cell death in a mouse random pattern skin flap model. Although no significant promotion of angiogenesis was observed, the study suggests that appropriate estrogen supplements could enhance flap wound recovery.

Cytidine Deaminase Enhances Liver Cancer Invasion by Modulating Epithelial-Mesenchymal Transition via NFκB Signaling.

BACKGROUND: Cancer metastasis is the leading cause of cancer-related deaths, underscoring the importance of understanding its underlying mechanisms. Hepatocellular carcinoma (HCC), a highly malignant type of cancer, was selected as our research model. MATERIAL AND METHODS: We aimed to develop high-metastatic cell lines using in vitro and in vivo selection strategies and identify critical metastasis-related genes through microarray analyses by comparing them with parental cells. RESULTS: Our results showed that the high-metastatic cell lines exhibited significantly stronger invasion abilities than parental cells. Microarray analyses identified cytidine deaminase (CDA), a gene associated with systemic chemotherapy resistance, as one of the overexpressed genes in the high-metastatic cells. Data analysis from The Cancer Genome Atlas Program revealed that while CDA is downregulated in HCC, patients with high CDA expression tend to have poorer prognoses. Cell models confirmed that CDA overexpression enhances cell migration and invasion, whereas CDA knockdown inhibits these abilities. Investigating the key molecules involved in the epithelial-mesenchymal transition (EMT), we found that CDA overexpression increases the expression of fascin, N-cadherin, ß-catenin, and snail while decreasing E-cadherin expression. Conversely, CDA knockdown produced opposite results. Additionally, we discovered that CDA regulates NF-κB signaling, which controls the expression of N-cadherin, thereby promoting the invasion capability of HCC cells. CONCLUSIONS: We isolated highly metastatic cells and identified potential HCC metastasis-related genes. CDA promotes cell invasion by regulating EMT through the NF-κB pathway. Future studies are warranted to explore the potential of CDA as a biomarker for prognosis and therapeutic decision-making.

SIRT5 safeguards against T-2 toxin induced liver injury by repressing iron accumulation, oxidative stress, and the activation of NLRP3 inflammasome.

T-2 toxin, a highly toxic trichothecene mycotoxin widely found in food and feed, poses a significant threat to human health as well as livestock and poultry industry. Liver, being a crucial metabolic organ, is particularly susceptible to T-2 toxin induced damage characterized by inflammation and oxidative stress. Despite the role of Sirtuin 5 (SIRT5) in mitigating liver injury has been confirmed, its specific impact on T-2 toxin induced liver injury remains to be elucidated. The objective of this study was to investigate the protective role of SIRT5 against T-2 toxin induced liver injury in mice. Following the oral administration of 1 mg/kg.bw of T-2 toxin for 21 consecutive days to SIRT5 knockout (SIRT5-/-) and wild-type (WT) male mice, liver assessments were conducted. Our findings demonstrated that aggravated hepatic pathological injury was observed in SIRT5-/- mice, accompanied by elevated malondialdehyde (MDA) and Fe levels, as well as enhanced expression of glutathione peroxidase 4 (GPX4), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, Gasdermin-D (GSDMD), tumour necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1ß). These results indicated that SIRT5 alleviated hepatic structural damage and dysfunction, while inhibiting oxidative stress, iron accumulation, and NLRP3 inflammasome activation. Analysis revealed a positive correlation among NLRP3 inflammasome activation, iron accumulation, and oxidative stress. Overall, our study demonstrated that SIRT5 mitigated liver injury induced by T-2 toxin through inhibiting iron accumulation, oxidative stress, and NLRP3 inflammasome activation, providing novel insights into the management and prevention of T-2 toxin poisoning.

The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice.

Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of Toll-Like Receptor (TLR) 4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of Liver X Receptor (LXR) and Sterol Regulatory Element-binding Protein-1 (SREBP). These acute anti-inflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of lipopolysaccharide (LPS)-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), Interferon Regulatory Factor 2 (IRF2), B-cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both subcutaneous and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

Using Dual-Target rTMS, Single-Target rTMS, or Sham rTMS on Post-Stroke Cognitive Impairment.

BACKGROUND: The clinical application of 10 Hz repetitive transcranil magnetic stimulation (rTMS) remains limited despite its demonstrated effectiveness in enhancing cortical excitability and improving cognitive function. The present study used a novel stimulus target [left dorsolateral prefrontal cortex + primary motor cortex] to facilitate the enhancement of cognitive function through the bidirectional promotion of cognitive and motor functions; Methods: Post-stroke cognitive impairment patients (n = 48) were randomly assigned to receive either dual-target, single-target, or sham rTMS for 4 weeks. Before and after 4 weeks of treatment, participants were asked to complete the Montreal Cognitive Assessment (MoCA) test, the Modified Barthel Index (MBI), the Trail-making Test (TMT), and the Digital Span Test (DST). In addition, the levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in serum were also measured. RESULTS: After adjusting for pre-intervention (baseline) MoCA scores, the post-intervention MoCA scores varied significantly. After post-hoc analysis, differences existed between the post-treatment scores of the dual-target rTMS group and the sham rTMS group (the experimental group scores were significantly higher), and between those of the dual-target rTMS group and the single-target rTMS group (the dual-target rTMS scores were significantly higher). The serum VEGF levels of the dual-target rTMS group were significantly higher those that of the sham rTMS group. CONCLUSIONS: The present study presented data showing that a dual-target rTMS therapy is effective for Post-stroke cognitive impairment (PSCI). The stimulation exhibited remarkable efficacy, suggesting that dual-target stimulation (left dorsolateral prefrontal cortex+motor cortex (L-DLPFC+M1)) holds promise as a potential target for TMS therapy in individuals with cognitive impairment after stroke. CLINICAL TRIAL REGISTRATION: No: ChiCTR220066184. Registered 26 November, 2022, https://www.chictr.org.cn.

Linderangolides A-D, four new butanolides from the roots of Lindera angustifolia and their cytotoxic activity.

Four undescribed butanolides, linderangolides A-D (1-4), along with four known congeners, lincomolide A (5), (-)-epilitsenolide C2 (6), (-)-epilitsenolide C1 (7) and litseakolide H (8), were isolated from the roots of Lindera angustifolia. The planar structures of 1-4 were elucidated based on extensive spectroscopic analyses, the relative and absolute configurations of 1-4 were determined by the NOESY spectra and the comparison of calculated and experimental ECD. The cytotoxic activities of all isolated compounds were tested, 4 showed inhibitory activity against SGC-7 cells with IC50 value of 6.62 µM.

Comparison of the TNM9th and 8th editions for localized and locally advanced anal squamous cell carcinoma treated nonsurgically and proposal of a new stage grouping system.

OBJECTIVE: To compare the survival discrimination of the TNM9th and 8th editions for localized and locally advanced anal squamous cell carcinoma (ASCC) treated nonsurgically and suggest a simple revised staging system with data from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Overall survival (OS) was the primary endpoint. Survival comparisons between the T and N stages and the different staging systems were performed using the Kaplan-Meier method and log-rank test, followed by correlation analysis and variable importance analysis (VIA). Additionally, multivariate analysis was employed to identify significant predictors, which were further visualized using a nomogram. Finally, calibration curve, C-index, and decision curve analysis (DCA) were applied to assess the performance of the different staging systems. RESULTS: A total of 5384 patients with ASCC were analyzed, revealing superior discrimination OS by the TNM9th edition compared to that by the TNM8th edition. Multivariate analysis identified the T and N stages as significant OS predictors (all p < 0.001). However, ambiguity persisted in stage III subgroups within the TNM9th edition, showing OS times of 102 months for stage IIIA disease, 88 months for stage IIIB disease, and 128 months for stage IIIC disease (all p > 0.05). Correlation analysis demonstrated an increased correlation for the T stage between the TNM8th and 9th editions (ρ value from 0.7 to 0.89), while the N stage correlation decreased (ρ value from 0.84 to 0.56). VIA and the prognostic nomogram highlighted the greater importance of the T stage over the N stage. Based on these findings, a new staging system was developed, and its clinical utility was confirmed through calibration curves, C-index values (from 0.598 to 0.604), and DCAs. CONCLUSIONS: Our new staging system exhibited slightly better prognostic value compared to the TNM9th staging systems for nonmetastatic ASCC and warrants further validation.

Single-Cell Time-Resolved Metabolomics and Lipidomics Reveal Apoptotic and Ferroptotic Heterogeneity during Foam Cell Formation.

Macrophage-derived foam cells play a crucial role in plaque formation and rupture during the progression of atherosclerosis. Traditional studies have often overlooked the heterogeneity of foam cells, focusing instead on populations of cells. To address this, we have developed time-resolved, single-cell metabolomics and lipidomics approaches to explore the heterogeneity of macrophages during foam cell formation. Our dynamic metabolomic and lipidomic analyses revealed a dual regulatory axis involving inflammation and ferroptosis. Further, single-cell metabolomics and lipidomics have delineated a continuum of macrophage states, with varied susceptibilities to apoptosis and ferroptosis. Single-cell transcriptomic profiling confirmed these divergent fates, both in established cell lines and in macrophages derived from peripheral blood monocytes. This research has uncovered the complex molecular interactions that dictate these divergent cell fates, providing crucial insights into the pathogenesis of atherosclerosis.

Bacteriocins in Cancer Treatment: Mechanisms and Clinical Potentials.

Cancer poses a severe threat to human health. Although conventional chemotherapy remains a cornerstone of cancer treatment, its significant side effects and the growing issue of drug resistance necessitate the urgent search for more efficient and less toxic anticancer drugs. In recent years, bacteriocins, antimicrobial peptides of microbial origin, have garnered significant attention due to their targeted antitumor activity. This unique activity is mainly attributed to their cationic and amphiphilic nature, which enables bacteriocins to specifically kill tumor cells without harming normal cells. When involving non-membrane-disrupting mechanisms, such as apoptosis induction, cell cycle blockade, and metastasis inhibition, the core mechanism of action is achieved by disrupting cell membranes, which endows bacteriocins with low drug resistance and high selectivity. However, the susceptibility of bacteriocins to hydrolysis and hemolysis in vivo limits their clinical application. To overcome these challenges, structural optimization of bacteriocins or their combination with nanotechnology is proposed for future development. This review aims to study the mechanism of action and current research status of bacteriocins as anticancer treatments, thus providing new insights for their clinical development and application.

Advances in CAR-NK cell therapy for hematological malignancies.

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematological malignancies, demonstrably improving patient outcomes and prognosis. However, its application has introduced new challenges, such as safety concerns, off-target toxicities, and significant costs. Natural killer (NK) cells are crucial components of the innate immune system, capable of eliminating tumor cells without prior exposure to specific antigens or pre-activation. This inherent advantage complements the limitations of T cells, making CAR-NK cell therapy a promising avenue for hematological tumor immunotherapy. In recent years, preclinical and clinical studies have yielded preliminary evidence supporting the safety and efficacy of CAR-NK cell therapy in hematological malignancies, paving the way for future advancements in immunotherapy. This review aims to succinctly discuss the characteristics, significant therapeutic progress, and potential challenges associated with CAR-NK cell therapy.

Single-cell profiling reveals altered immune landscape and impaired NK cell function in gastric cancer liver metastasis.

Gastric cancer (GC) is a substantial global health concern, and the development of liver metastasis (LM) in GC represents a critical stage linked to unfavorable patient prognoses. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the immune landscape of GC liver metastasis, revealing several immuno-suppressive components within the tumor immune microenvironment (TIM). Our findings unveiled an increased presence of cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cell (MDSC)-like macrophages, tumor-associated macrophage (TAM)-like macrophages, and naive T cells, while conventional dendritic cells (cDCs) and effector CD8 T cells declined in LM. Additionally, we identified two distinct natural killer (NK) cell clusters exhibiting differential cytotoxicity-related gene expression, with cytotoxic NK cells notably reduced in LM. Strikingly, TGFß was identified as an inducer of NK cell dysfunction, potentially contributing to immune evasion and tumor metastasis. In preclinical LM models, the combined approach of inhibiting TGFß and transferring NK cells exhibited a synergistic impact, resulting in a significant reduction in liver metastasis. This work highlights the importance of understanding the complex immune dynamics within GC liver metastasis and presents a promising strategy combining TGFß inhibition and NK-based immunotherapy to improve patient outcomes.

Identification the role of necroptosis in rheumatoid arthritis by WGCNA network.

Rheumatoid arthritis (RA) is the predominant manifestation of inflammatory arthritis, distinguished by an increasing burden of morbidity and mortality. The intricate interplay of genes and signalling pathways involved in synovial inflammation in patients with RA remains inadequately comprehended. This study aimed to ascertain the role of necroptosis in RA, as along with their associations with immune cell infiltration. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify central genes for RA. In this study, identified total of 28 differentially expressed genes (DEGs) were identified in RA. Utilising WGCNA, two co-expression modules were generated, with one module demonstrating the strongest correlation with RA. Through the integration of differential gene expression analysis, a total of 5 intersecting genes were discovered. These 5 hub genes, namely fused in sarcoma (FUS), transformer 2 beta homolog (TRA2B), eukaryotic translation elongation factor 2 (EEF2), cleavage and polyadenylation specific factor 6 (CPSF6) and signal transducer and activator of transcription 3 (STAT3) were found to possess significant diagnostic value as determined by receiver operating characteristic (ROC) curve analysis. The close association between the concentrations of various immune cells is anticipated to contribute to the diagnosis and treatment of RA. Furthermore, the infiltration of immune cells mentioned earlier is likely to exert a substantial influence on the initiation of this disease.

Ethylene promotes fruit ripening initiation by downregulating photosynthesis, enhancing abscisic acid and suppressing jasmonic acid in blueberry (Vaccinium ashei).

BACKGROUND: Blueberry fruit exhibit atypical climacteric ripening with a non-auto-catalytic increase in ethylene coincident with initiation of ripening. Further, application of ethephon, an ethylene-releasing plant growth regulator, accelerates ripening by increasing the proportion of ripe (blue) fruit as compared to the control treatment. To investigate the mechanistic role of ethylene in regulating blueberry ripening, we performed transcriptome analysis on fruit treated with ethephon, an ethylene-releasing plant growth regulator. RESULTS: RNA-Sequencing was performed on two sets of rabbiteye blueberry ('Powderblue') fruit: (1) fruit from divergent developmental stages; and (2) fruit treated with ethephon, an ethylene-releasing compound. Differentially expressed genes (DEGs) from divergent developmental stages clustered into nine groups, among which cluster 1 displayed reduction in expression during ripening initiation and was enriched with photosynthesis related genes, while cluster 7 displayed increased expression during ripening and was enriched with aromatic-amino acid family catabolism genes, suggesting stimulation of anthocyanin biosynthesis. More DEGs were apparent at 1 day after ethephon treatment suggesting its early influence during ripening initiation. Overall, a higher number of genes were downregulated in response to ethylene. Many of these overlapped with cluster 1 genes, indicating that ethylene-mediated downregulation of photosynthesis is an important developmental event during the ripening transition. Analyses of DEGs in response to ethylene also indicated interplay among phytohormones. Ethylene positively regulated abscisic acid (ABA), negatively regulated jasmonates (JAs), and influenced auxin (IAA) metabolism and signaling genes. Phytohormone quantification supported these effects of ethylene, indicating coordination of blueberry fruit ripening by ethylene. CONCLUSION: This study provides insights into the role of ethylene in blueberry fruit ripening. Ethylene initiates blueberry ripening by downregulating photosynthesis-related genes. Also, ethylene regulates phytohormone-metabolism and signaling related genes, increases ABA, and decreases JA concentrations. Together, these results indicate that interplay among multiple phytohormones regulates the progression of ripening, and that ethylene is an important coordinator of such interactions during blueberry fruit ripening.

Cornus officinalis with high pressure wine steaming enhanced anti-hepatic fibrosis: Possible through SIRT3-AMPK axis.

Cornus officinalis, a medicinal and edible plant known for its liver-nourishing properties, has shown promise in inhibiting the activation of hepatic stellate cells (HSCs), crucial indicators of hepatic fibrosis, especially when processed by high pressure wine steaming (HPWS). Herein, this study aims to investigate the regulatory effects of cornus officinalis, both in its raw and HPWS forms, on inflammation and apoptosis in liver fibrosis and their underlying mechanisms. In vivo liver fibrosis models were established by subcutaneous injection of CCl4, while in vitro HSCs were exposed to transforming growth factor-ß (TGF-ß). These findings demonstrated that cornus officinalis with HPWS conspicuously ameliorated histopathological injury, reduced the release of proinflammatory factors, and decreased collagen deposition in CCl4-induced rats compared to its raw form. Utilizing ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS) combined with network analysis, we identified that the pharmacological effects of the changed components of cornus officinalis before and after HPWS, primarily centered on the adenosine phosphate (AMP)-activated protein kinase (AMPK) pathway. Of note, cornus officinalis activated AMPK and Sirtuin 3 (SIRT3), promoting the apoptosis of activated HSCs through the caspase cascade by regulating caspase3, caspase6 and caspase9. siRNA experiments showed that cornus officinalis could regulate AMPK activity and its mediated-apoptosis through SIRT3. In conclusion, cornus officinalis exhibited the ability to reduce inflammation and apoptosis, with the SIRT3-AMPK signaling pathway identified as a potential mechanism underlying the synergistic effect of cornus officinalis with HPWS on anti-liver fibrosis.

PFDN4 as a Prognostic Marker Was Associated with Chemotherapy Resistance through CREBP1/AURKA Pathway in Triple-Negative Breast Cancer.

Breast cancer is the most common malignancy and its incidence is increasing. It is currently mainly treated by clinical chemotherapy, but chemoresistance remains poorly understood. Prefolded proteins 4 (PFDN4) are molecular chaperone complexes that bind to newly synthesized polypeptides and allow them to fold correctly to stabilize protein formation. This study aimed to investigate the role of PFDN4 in chemotherapy resistance in breast cancer. Our study found that PFDN4 was highly expressed in breast cancer compared to normal tissues and was statistically significantly associated with stage, nodal status, subclasses (luminal, HER2 positive and triple negative), triple-negative subtype and disease-specific survival by TCGA database analysis. CRISPR knockout of PFDN4 inhibited the growth of 89% of breast cancer cell lines, and the triple-negative cell line exhibited a stronger inhibitory effect than the non-triple-negative cell line. High PFDN4 expression was associated with poor overall survival in chemotherapy and resistance to doxorubicin and paclitaxel through the CREBP1/AURKA pathway in the triple-negative MDAMB231 cell line. This study provides insightful evidence for the value of PFDN4 in poor prognosis and chemotherapy resistance in breast cancer patients.

BATF promotes extramedullary infiltration through TGF-ß1/Smad/MMPs axis in acute myeloid leukemia.

Acute myeloid leukemia (AML) is one of the most prevalent types of leukemia and is challenging to cure for most patients. Basic Leucine Zipper ATF-Like Transcription Factor (BATF) has been reported to participate in the development and progression of numerous tumors. However, its role in AML is largely unknown. In this study, the expression and prognostic value of BATF were examined in AML. Our results demonstrated that BATF expression was upregulated in AML patients, which was significantly correlated with poor clinical characteristics and survival. Afterward, functional experiments were performed after knocking down or overexpressing BATF by transfecting small interfering RNAs and overexpression plasmids into AML cells. Our findings revealed that BATF promoted the migratory and invasive abilities of AML cells in vitro and in vivo. Moreover, the target genes of BATF were searched from databases to explore the binding of BATF to the target gene using ChIP and luciferase assays. Notably, our observations validated that BATF is bound to the promoter region of TGF-ß1, which could transcriptionally enhance the expression of TGF-ß1 and activate the TGF-ß1/Smad/MMPs signaling pathway. In summary, our study established the aberrantly high expression of BATF and its pro-migratory function via the TGF-ß1-Smad2/3-MMP2/9 axis in AML, which provides novel insights into extramedullary infiltration of AML.

Development and Validation of a Nomogram Predicting Postoperative Recurrent Lumbar Disc Herniation Based on Activity Factors.

Purpose: To develop an individualized predictive model for postoperative recurrent lumbar disc herniation (PRLDH) in patients undergoing percutaneous endoscopic transforaminal discectomy (PETD) by considering postoperative activity factors. Patients and Methods: Retrospectively collected data from 612 LDH patients who underwent PETD in our institution from January 2017 to June 2023. They were divided into a training group (429 cases) and a validation group (183 cases). Lasso regression (Model 1) and random forest (Model 2) were applied for variable selection in the training group. The two models were compared in terms of discrimination (the area under curve, AUC), calibration (calibration curve), and clinical utility (decision curve analysis, DCA). Akaike information criterion (AIC) was used for model comparison, and internal validation employed 1000 times Bootstrap + 10-fold cross-validation. Finally, a Nomogram was constructed to display the results and uploaded to the web version. Results: Among 612 treated LDH patients, 66 (10.78%) developed PRLDH. Model 1, superior in AUC, calibration, DCA, and AIC over Model 2, was chosen as the predictive model. Logistic regression in the training group identified BMI, smoking, activity level score, time to first ambulation, diabetes, Modic change, and Pfirrmann grade as independent predictors of PRLDH. Model 1 exhibited a training group AUC of 0.813 (95% CI 0.753-0.872) and a validation group AUC of 0.868 (95% CI 0.773-0.962). At a Youden index of 0.50, sensitivity was 0.73, specificity was 0.77. Internal validation (1000 times Bootstrap + 10-fold cross-validation) for the training group showed accuracy of 0.889, kappa consistency of 0.112, and AUC of 0.757. The Hosmer-Lemeshow goodness-of-fit tests indicated good discriminative ability for Model 1 in both the training (χ2=2.895, P=0.941) and validation groups (χ2=8.197, P=0.414). The DCA and Nomogram are accessible at https://sofarnomogram.shinyapps.io/PRLDHNom/. Conclusion: The Nomogram predictive model, developed based on postoperative activity factors in this study, demonstrates excellent predictive capability, facilitating risk assessment for the occurrence of PRLDH after PETD.

Long-read sequencing unveils novel somatic variants and methylation patterns in the genetic information system of early lung cancer.

Lung cancer poses a global health challenge, necessitating advanced diagnostics for improved outcomes. Intensive efforts are ongoing to pinpoint early detection biomarkers, such as genomic variations and DNA methylation, to elevate diagnostic precision. We conducted long-read sequencing on cancerous and adjacent non-cancerous tissues from a patient with lung adenocarcinoma. We identified somatic structural variations (SVs) specific to lung cancer by integrating data from various SV calling methods and differentially methylated regions (DMRs) that were distinct between these two tissue samples, revealing a unique methylation pattern associated with lung cancer. This study discovered over 40,000 somatic SVs and over 180,000 DMRs linked to lung cancer. We identified approximately 700 genes of significant relevance through comprehensive analysis, including genes intricately associated with many lung cancers, such as NOTCH1, SMOC2, CSMD2, and others. Furthermore, we observed that somatic SVs and DMRs were substantially enriched in several pathways, such as axon guidance signaling pathways, which suggests a comprehensive multi-omics impact on lung cancer progression across various biological investigation levels. These datasets can potentially serve as biomarkers for early lung cancer detection and may hold significant value in clinical diagnosis and treatment applications.

Anatomical Anal Stenosis after PPH: Insights from a Retrospective Study and Rat Model.

High-grade hemorrhoids are usually recommended to receive operational treatments. However, these traditional surgeries are associated with severe postoperative pain. A procedure for prolapse and hemorrhoids (PPH), a circular staple device, has been developed to improve short-term outcomes, including reducing the severity of postoperative pain. PPH, compared to conventional surgery, has been associated with the incidence of anatomical anal stenosis. The causes of stenosis after PPH are not yet clear. We first analyzed the complications of our patients with PPH, and then developed a rat model to verify the tension force of PPH using Hematoxylin-eosin, Masson's trichrome, immunohistochemistry, and immunofluorescence staining. Our clinical data showed that PPH significantly improved postoperative pain, but that it resulted in higher incidences of complications, including anal stenosis, than hemorrhoidectomy. We simulated the status of PPH and developed a rat model to verify PPH's tension force, including the scarring area and the deposition of proinflammatory factors, angiogenic factors, and fibrotic factors. The tension wound histological data showed more extensive granulation tissue and inflammatory cell infiltration and a thicker epidermis than the control group on day 12 post-operation and tension treatment. In addition to IL-1ß and IL-10 cytokines on day 3 and IL-1ß, IL-6, and IL-10 cytokines on day 12 post-operation in the tension group, two angiogenic factors, CD31 and VEGF-A, were found to have a more significant expression on day 7 post-operation in the tension group. The mean scar area was larger and the distribution of fibrotic proteins (collagen 1, α-SMA, CTGF, and MMP2) in the tension group was significantly broader than in the control on day 12 post-operation and tension treatment. Based on the findings of our animal model, the development of a lesser tensile force for PPH to decrease the deposition of proinflammatory factors, angiogenic factors, and fibrotic factors is urgently required.