Interactions between fibroblasts and monocyte-derived cells in chronic lung injuries induced by real-ambient particulate matter exposure.

Long-term exposure to fine particulate matter (PM2.5) can lead to chronic lung injury, including inflammation, idiopathic pulmonary fibrosis, and cancer. Mesenchymal cells, such as fibroblasts, myeloid-derived suppressor cells (MDSCs), and interstitial macrophages (IMs), contribute to immune regulation in lung, yet their diversity and functions upon long-term exposure to particulate matter (PM) remain inadequately characterized. In this study, we conducted a 16-week real-ambient PM exposure experiment on C57BL/6 J male mice in Shijiazhuang, China. We used single-cell RNA sequencing to analyze the cellular and molecular changes in lung tissues. Notably, we revealed a significant increase in specific fibroblast (ATX+, Col5a1+Meg3+, universal fibroblasts) and monocyte-derived cell subpopulations (monocytic-MDSCs (M-MDSCs), Lyve1loMHC-Ⅱhi IMs, Lyve1hiMHC-Ⅱlo IMs) that exhibited pro-inflammatory and pro-fibrotic functions. These cell subpopulations engaged in immunosuppressive signaling pathways and interactions with various cytokines, shaping a pulmonary microenvironment similar to those associated with cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). This altered immune environment may promote the development of pulmonary fibrosis caused by PM exposure, underscoring the intricate roles of mesenchymal cells in chronic lung injury and highlighting the cancer-causing potential of PM2.5 exposure.

Exploring the impact of microfluidic chip structure on the efficacy of three-dimensional tumor microspheres cultivation.

Three-dimensional (3D) tumor microspheres can simulate the interaction and growth dynamics of tumor cells, and have been used as a new in vitro model for drug screening and tumor biology related research. The scaffold-free culture of 3D tumor microspheres on microfluidic chips has many advantages, including low cost, high throughput, convenience and flexibility. However, it is still unclear how various factors, such as chip structure, influence the culture effect of tumor microspheres. The lack of standardized evaluation and characterization of the culture effect hinders the further optimization and development of chip function. This study presents numerical simulations of multiple parts or processes of the proposed 3D culture chips with two different structural parameters based on computational fluid dynamics (CFD) methods. An evaluation system for tumor microspheres was established. The prediction of the CFD simulation was consistent with the culture results of the chips, reflecting the important role of the structural parameters of the microtrap in the formation of uniform tumor microspheres. Furthermore, the velocity of cell suspension also had a significant impact on the retention of tumor cells. Additionally, the drug screening results of tumor microspheres indicated that tumor microspheres exhibit greater drug resistance, which may be attributed to their size. These results offer valuable insights into the factors that influence the characteristics of tumor microspheres. This research provides a reference and direction for the optimal design and functional evaluation of scaffold-free 3D culture chips, and holds promise for promoting the development of novel drug research platforms.

The interplay between persistent pathogen infections with tumor microenvironment and immunotherapy in cancer.

BACKGROUND: Chronic infections by pathogenic microorganisms play a significant role in cancer development, disrupting the body's immune system and microenvironment. This interference impairs the body's ability to eliminate these microorganisms promptly, allowing them to persist by evading immune defenses. AIMS: This study aimed to explore how chronic pathogenic infections influence the immune microenvironment, impacting tumorigenesis, cancer progression, and treatment strategies. Additionally, it seeks to investigate the effects of these infections on specific immune checkpoints and identify potential targets for immunotherapy. METHODS: We conducted searches, readings, and detailed analyses of key terms in databases like PubMed and Web of Science to evaluate the impact of chronic infections by pathogenic microorganisms on the immune microenvironment. RESULTS: Our analysis demonstrates a significant association between persistent chronic infections by pathogenic microorganisms and tumorigenesis. Notable impacts on the immune microenvironment include changes in immune cell function and the regulation of immune checkpoints, offering insights into potential targets for cancer immunotherapy. DISCUSSION: This study highlights the complex relationship between chronic infections and cancer development, presenting new opportunities for cancer immunotherapy by understanding their effects on the immune microenvironment. The influence of these infections on immune checkpoints emphasizes the crucial role of the immune system in cancer treatment. CONCLUSION: Chronic infections by pathogenic microorganisms greatly affect the immune microenvironment, tumorigenesis, and cancer treatment. Unraveling the underlying mechanisms can unveil potential targets for immunotherapy, improving our comprehension of the immune response to cancer and potentially leading to more effective cancer treatments in the future.

Cadmium exposure elicited dynamic RNA m6A modification and epi-transcriptomic regulation in the Pacific whiteleg shrimp Litopenaeus vannamei.

N6-methyladenosine (m6A) methylation is the most prevalent post-transcriptional RNA modification in eukaryotic organisms, but its roles in the regulation of physiological resistance of marine crustaceans to heavy metal pollutants are poorly understood. In this study, the transcriptome-wide m6A RNA methylation profiles and dynamic m6A changes induced by acute Cd2+ exposure in the the pacific whiteleg shrimp Litopenaeus vannamei were comprehensively analyzed. Cd2+ toxicity caused a significant reduction in global RNA m6A methylation level, with major m6A regulators including the m6A methyltransferase METTL3 and the m6A binding protein YTHDF2 showing declined expression. Totally, 11,467 m6A methylation peaks from 6415 genes and 17,291 peaks within 7855 genes were identified from the Cd2+ exposure group and the control group, respectively. These m6A peaks were predominantly enriched in the 3' untranslated region (UTR) and around the start codon region of the transcripts. 7132 differentially expressed genes (DEGs) and 7382 differentially m6A-methylated genes (DMGs) were identified. 3186 genes showed significant changes in both gene expression and m6A methylation levels upon cadmium exposure, and they were related to a variety of biological processes and gene pathways. Notably, an array of genes associated with antioxidation homeostasis, transmembrane transporter activity and intracellular detoxification processes were significantly enriched, demonstrating that m6A modification may mediate the physiological responses of shrimp to cadmium toxicity via regulating ROS balance, Cd2+ transport and toxicity mitigation. The study would contribute to a deeper understanding of the evolutionary and functional significance of m6A methylation to the physiological resilience of decapod crustaceans to heavy metal toxicants.

Paradoxical action of PP2A inhibition and its potential for therapeutic sensitization.

The protein phosphatase 2A (PP2A), a serine/threonine phosphatase, is recognized as a tumor suppressor involved in diverse cellular processes and essential for maintaining cell viability in vivo. However, endogenous inhibitors of PP2A such as cancerous inhibitor of PP2A (CIP2A) and endogenous nuclear protein inhibitor 2 of PP2A (SET) counteract the anticancer function of PP2A, promoting tumorigenesis, development, and drug resistance in tumors. Surprisingly though, contrary to conventional understanding, inhibition of the tumor suppressor gene PP2A with exogenous small molecule compounds can enhance the efficacy of cancer treatment and achieve superior tumor inhibition. Moreover, exogenous PP2A inhibitors resensitize cancers to treatment and provide novel therapeutic strategies for drug-resistant tumors, which warrant further investigation.

Nutrition Intervention and Microbiome Modulation in the Management of Breast Cancer.

Breast cancer (BC) is one of the most common cancers worldwide and a leading cause of cancer-related deaths among women. The escalating incidence of BC underscores the necessity of multi-level treatment. BC is a complex and heterogeneous disease involving many genetic, lifestyle, and environmental factors. Growing evidence suggests that nutrition intervention is an evolving effective prevention and treatment strategy for BC. In addition, the human microbiota, particularly the gut microbiota, is now widely recognized as a significant player contributing to health or disease status. It is also associated with the risk and development of BC. This review will focus on nutrition intervention in BC, including dietary patterns, bioactive compounds, and nutrients that affect BC prevention and therapeutic responses in both animal and human studies. Additionally, this paper examines the impacts of these nutrition interventions on modulating the composition and functionality of the gut microbiome, highlighting the microbiome-mediated mechanisms in BC. The combination treatment of nutrition factors and microbes is also discussed. Insights from this review paper emphasize the necessity of comprehensive BC management that focuses on the nutrition-microbiome axis.

Complement factor I knockdown inhibits colon cancer development by affecting Wnt/ß-catenin/c-Myc signaling pathway and glycolysis.

BACKGROUND: Colon cancer (CC) occurrence and progression are considerably influenced by the tumor microenvironment. However, the exact underlying regulatory mechanisms remain unclear. AIM: To investigate immune infiltration-related differentially expressed genes (DEGs) in CC and specifically explored the role and potential molecular mechanisms of complement factor I (CFI). METHODS: Immune infiltration-associated DEGs were screened for CC using bioinformatics. Quantitative reverse transcription polymerase chain reaction was used to examine hub DEGs expression in the CC cell lines. Stable CFI-knockdown HT29 and HCT116 cell lines were constructed, and the diverse roles of CFI in vitro were assessed using CCK-8, 5-ethynyl-2'-deoxyuridine, wound healing, and transwell assays. Hematoxylin and eosin staining and immunohistochemistry staining were employed to evaluate the influence of CFI on the tumorigenesis of CC xenograft models constructed using BALB/c male nude mice. Key proteins associated with glycolysis and the Wnt pathway were measured using western blotting. RESULTS: Six key immune infiltration-related DEGs were screened, among which the expression of CFI, complement factor B, lymphoid enhancer binding factor 1, and SRY-related high-mobility-group box 4 was upregulated, whereas that of fatty acid-binding protein 1, and bone morphogenic protein-2 was downregulated. Furthermore, CFI could be used as a diagnostic biomarker for CC. Functionally, CFI silencing inhibited CC cell proliferation, migration, invasion, and tumor growth. Mechanistically, CFI knockdown downregulated the expression of key glycolysis-related proteins (glucose transporter type 1, hexokinase 2, lactate dehydrogenase A, and pyruvate kinase M2) and the Wnt pathway-related proteins (ß-catenin and c-Myc). Further investigation indicated that CFI knockdown inhibited glycolysis in CC by blocking the Wnt/ß-catenin/c-Myc pathway. CONCLUSION: The findings of the present study demonstrate that CFI plays a crucial role in CC development by influencing glycolysis and the Wnt/ß-catenin/c-Myc pathway, indicating that it could serve as a promising target for therapeutic intervention in CC.

Financial burden in a US cohort of patients with HCC.

BACKGROUND: High financial burden for patients has been reported for multiple types of cancer, but there are limited data in those with HCC. We aimed to describe the financial burden for patients diagnosed with HCC and identify correlates of high financial burden. METHODS: We used the IQVIA PharMetrics Plus for Academics database to identify commercially insured patients diagnosed with HCC between 2006 and 2021. Patient financial liability was defined as the difference between allowed and paid amounts from adjudicated insurance claims. We reported total and HCC-related financial liabilities (i.e., cost for HCC-related claims), with high total financial liability defined as ≥$3000 annually and high HCC-related financial liability as ≥$1000 annually. We used multivariable logistic regression modeling to identify factors associated with high total and HCC-related financial liability. RESULTS: Among 11,609 patients with HCC, the median total financial liability during the year after HCC diagnosis was $2955 (Q1-Q3: $972-$6293). Nearly half (45%) of patients experienced high total financial liability, with the greatest liability incurred in the 3-month period immediately following HCC diagnosis. Older age, increased comorbidity, and cirrhosis-related complications were associated with higher total patient liability. Patient liability also varied by type of HCC treatment, with systemic therapy and liver transplantation having the highest financial liability in multivariable analysis. However, only 66.7% of the patients experienced HCC-related liability. CONCLUSIONS: Patients with HCC experience significant financial liability underscoring a need for price transparency as well as financial counseling in this population.

Quantitative Proteomics Reveal the Role of Matrine in Regulating Lipid Metabolism.

Hyperlipidemia (HLP) is a prevalent systemic metabolic disorder characterized by disrupted lipid metabolism. Statin drugs have long been the primary choice for managing lipid levels, but intolerance issues have prompted the search for alternative treatments. Matrine, a compound derived from the traditional Chinese medicine Kushen, exhibits anti-inflammatory and lipid-lowering properties. Nevertheless, the mechanism by which matrine modulates lipid metabolism remains poorly understood. Here, we investigated the molecular mechanisms underlying matrine's regulation of lipid metabolism. Employing quantitative proteomics, we discovered that matrine increases the expression of LDL receptor (LDLR) in HepG2 and A549 cells, with subsequent experiments validating its role in enhancing LDL uptake. Notably, in hyperlipidemic hamsters, matrine effectively lowered lipid levels without affecting body weight, which highlights LDLR as a critical target for matrine's impact on HLP. Moreover, matrine's potential inhibitory effects on tumor cell LDL uptake hint at broader applications in cancer research. Additionally, thermal proteome profiling analysis identified lipid metabolism-related proteins that may interact with matrine. Together, our study reveals matrine's capacity to upregulate LDLR expression and highlights its potential in treating HLP. These findings offer insights into matrine's mechanism of action and open new avenues for drug research and lipid metabolism regulation.

Exploring the Molecular Therapeutic Mechanisms of Gemcitabine through Quantitative Proteomics.

Gemcitabine (GEM) is widely employed in the treatment of various cancers, including pancreatic cancer. Despite their clinical success, challenges related to GEM resistance and toxicity persist. Therefore, a deeper understanding of its intracellular mechanisms and potential targets is urgently needed. In this study, through mass spectrometry analysis in data-dependent acquisition mode, we carried out quantitative proteomics (three independent replications) and thermal proteome profiling (TPP, two independent replications) on MIA PaCa-2 cells to explore the effects of GEM. Our proteomic analysis revealed that GEM led to the upregulation of the cell cycle and DNA replication proteins. Notably, we observed the upregulation of S-phase kinase-associated protein 2 (SKP2), a cell cycle and chemoresistance regulator. Combining SKP2 inhibition with GEM showed synergistic effects, suggesting SKP2 as a potential target for enhancing the GEM sensitivity. Through TPP, we pinpointed four potential GEM binding targets implicated in tumor development, including in breast and liver cancers, underscoring GEM's broad-spectrum antitumor capabilities. These findings provide valuable insights into GEM's molecular mechanisms and offer potential targets for improving treatment efficacy.

Psychiatric disorders in patients with hepatocellular carcinoma: A large US cohort of commercially insured individuals.

BACKGROUND/AIMS: Patients with hepatocellular cancer (HCC) are vulnerable to psychological distress given a new cancer diagnosis superimposed on pre-existing chronic liver disease. We aimed to characterise the psychiatric burden in HCC, risk factors for incident diagnosis and treatment patterns over time. METHODS: Using IQVIA PharMetrics® Plus for Academics-a nationally representative claims database of the commercially insured US population-we identified psychiatric diagnoses and treatment among patients with newly diagnosed HCC. Multivariable logistic regression modelling identified factors associated with psychiatric diagnosis and treatment. RESULTS: Of 11,609 patients with HCC, 2166 (18.6%) had a psychiatric diagnosis after cancer diagnosis with depression (58.3%) and anxiety (53.0%) being most common. Women (aOR 1.33, 95% CI [1.19-1.49]), pre-existing psychiatric diagnoses (aOR 9.12 [8.08-10.3]) and HCC treatment type (transplant: aOR 2.15 [1.66-2.77]; locoregional therapies: aOR 1.74 [1.52-1.99]; hospice: aOR 2.43 [1.79-3.29]) were significantly associated with psychiatric diagnosis. Female sex, ascites, higher comorbidity and treatment type were associated with incident psychiatric diagnosis. Pharmacotherapy was used in 1392 (64.3%) patients with a psychiatric diagnosis, with antidepressants (46.2%) and anxiolytics (32.8%) being most common. Psychiatric diagnoses increased from 14.8% in 2006-2009 to 21.1% in 2018-2021 (p < 0.001). In almost 20% of patients with pre-existing psychiatric conditions, therapy was discontinued after HCC diagnosis. CONCLUSIONS: Nearly 2 of 10 patients with HCC were diagnosed with a psychiatric condition after cancer diagnosis with unique sociodemographic and clinical risk factors identified. This highlights a risk for increased psychological burden in need of early evaluation and treatment among patients with newly diagnosed HCC.

Mitofusin 2 inhibits high glucose-induced apoptosis of human lens epithelial cells via modulating mitochondrial function and autophagy.

INTRODUCTION: Diabetic cataract (DC) is a common ocular complication of diabetes. Mitofusin 2 (MFN2), a mitochondrial fusion protein, is involved in the pathogenesis of cataract and diabetic complications. However, its role and molecular mechanisms in DC remain unclear. MATERIALS AND METHODS: DC models in rats were induced by intraperitoneal injection of streptozocin (STZ) for 12 weeks. We measured the body weight of rats, blood glucose concentrations, sorbitol dehydrogenase (SDH) activity and advanced glycation end products (AGE) content in the lenses of rats. MFN2 mRNA and protein expression levels in the lenses were detected by RT-qPCR and western blot assays. In vitro, human lens epithelial (HLE) B3 cells were treated for 48 h with 25 mM glucose (high glucose, HG) to induce cell damage. To determine the role of MFN2 in HG-induced cell damage, HLE-B3 cells were transfected with lentivirus loaded with MFN2 overexpression plasmid or short hairpin RNA (shRNA) to overexpress or knock down MFN2 expression, followed by HG exposure. Cell viability was assessed by CCK-8 assay. Flow cytometry was used to detect cell apoptosis and reactive oxygen species (ROS) level. JC-1 staining showed the changes in mitochondrial membrane potential (Δψm). The mediators related to apoptosis, mitochondrial damage, and autophagy were determined. RESULTS: STZ-administrated rats showed reduced body weight, increased blood glucose levels, elevated SDH activity and AGE content, suggesting successful establishment of the DC rat model. Interestingly, MFN2 expression was significantly downregulated in DC rat lens and HG-induced HLE-B3 cells. Further analysis showed that under HG conditions, MFN2 overexpression enhanced cell viability and inhibited apoptosis accompanied by decreased Bax, cleaved caspase-9 and increased Bcl-2 expression in HLE-B3 cells. MFN2 overexpression also suppressed the mitochondrial damage elicited by HG as manifested by reduced ROS production, recovered Δψm and increased mitochondrial cytochrome c (Cyto c) level. Moreover, MFN2 overexpression increased LC3BⅡ/LC3BⅠ ratio and Beclin-1 expression, but decreased p62 level, and blocked the phosphorylation of mTOR in HG-treated HLE-B3 cells. In contrast, MFN2 silencing exerted opposite effects. CONCLUSIONS: Presented findings indicate that MFN2 expression may be essential for preventing lens epithelial cell apoptosis during development of diabetic cataract.

Sodium para-aminosalicylic acid attenuates combined manganese/iron-induced cortical synaptic damage in rats.

We established experimental models of manganese (Mn) and iron (Fe) exposure in vitro and in vivo, and addressed the effects of manganese and iron combined exposure on the synaptic function of pheochromocytoma derived cell line 12 (PC12) cells and rat cortex, respectively. We investigated the protective effect of sodium para-aminosalicylate (PAS-Na) on manganese and iron combined neurotoxicity, providing a scientific basis for the prevention and treatment of ferromanganese combined neurotoxicity. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to detect the expression levels of protein and mRNA related to synaptic damage. Y-maze novelty test and balance beam test were used to evaluate the motor and cognitive function of rats. Haematoxylin and eosin (H&E) and Nissl staining were performed to observe the cortical damage of rats. The results showed that the combined exposure of Mn and Fe in rats led to a synergistic effect, attenuating growth and development, and altering learning and memory as well as motor function. The combination of Mn and Fe also caused damage to the synaptic structure of PC12 cells, which is manifested as swelling of dendrites and axon terminals, and even lead to cell death. PAS-Na displayed some antagonistic effects against the Mn- and Fe-induced synaptic structural damage, growth, learning and memory impairment.

Safety of Immunosuppression in a Prospective Cohort of Inflammatory Bowel Disease Patients With a HIstoRy of CancEr: SAPPHIRE Registry.

BACKGROUND & AIMS: In patients with inflammatory bowel disease (IBD) and a history of cancer, retrospective studies have suggested that exposure to immunosuppressive agents does not increase the risk of incident (recurrent or new) cancer compared with unexposed patients. SAPPHIRE is a prospective registry aimed at addressing this issue. METHODS: Since 2016, patients with IBD and confirmed index cancer before enrollment were followed up annually. Patients receiving chemotherapy or radiation at enrollment, or recurrent cancer within 5 years, were excluded. The primary outcome was development of incident cancer related to exposure to immunosuppressive medications. RESULTS: Among 305 patients (47% male, 88% white), the median age at IBD diagnosis and cancer were 32 and 52 years, respectively. Index cancers were solid organ (46%), dermatologic (32%), gastrointestinal (13%), and hematologic (9%). During a median follow-up period of 4.8 years, 210 patients (69%) were exposed to immunosuppressive therapy and 46 patients (15%) developed incident cancers (25 new, 21 recurrent). In unadjusted analysis, the crude rate of incident cancer in unexposed patients was 2.58 per 100 person-years vs 4.78 per 100 person-years (relative risk, 1.85; 95% CI, 0.92-3.73) for immunosuppression-exposed patients. In a proportional hazards model adjusting for sex, smoking history, age and stage at index malignancy, and nonmelanoma skin cancer, no significant association was found between receipt of immunosuppression and incident cancer (adjusted hazard ratio, 1.41; 95% CI, 0.69-2.90), or with any major drug class. CONCLUSIONS: In this interim analysis of patients with IBD and a history of cancer, despite numerically increased adjusted hazard ratios, we did not find a statistically significant association between subsequent exposure to immunosuppressive therapies and development of incident cancers.

Brachytherapy in craniopharyngiomas: a systematic review and meta-analysis of long-term follow-up.

OBJECTIVE: Brachytherapy has been indicated as an alternative option for treating cystic craniopharyngiomas (CPs). The potential benefits of brachytherapy for CPs have not yet been clarified. The purpose of this work was to conduct a meta-analysis to analyze the long-term efficacy and adverse reactions profile of brachytherapy for CPs. MATERIALS AND METHODS: The relevant databases were searched to collect the clinical trials on brachytherapy in patients with CPs. Included studies were limited to publications in full manuscript form with at least 5-year median follow-up, and adequate reporting of treatment outcomes and adverse reactions data. Stata 12.0 was used for data analysis. RESULTS: According to the inclusion and exclusion criteria, a total of 6 clinical trials involving 266 patients with CPs were included in this meta-analysis. The minimum average follow-up was 5 years. The results of the meta-analysis showed that 1-year, 2-3 years and 5 years progression free survival rates (PFS) are 75% (95%CI: 66-84%), 62% (95%CI: 52-72%) and 57% (95%CI: 22-92%), respectively. At the last follow-up, less than 16% of patients with visual outcomes worser than baseline in all included studies. While, for endocrine outcomes, less than 32% of patients worser than baseline level. CONCLUSION: In general, based on the above results, brachytherapy should be considered as a good choice for the treatment of CP.

Intestinal carcinogenicity screening of environmental pollutants using organoid-based cell transformation assay.

The high incidence of colorectal cancer (CRC) is closely associated with environmental pollutant exposure. To identify potential intestinal carcinogens, we developed a cell transformation assay (CTA) using mouse adult stem cell-derived intestinal organoids (mASC-IOs) and assessed the transformation potential on 14 representative chemicals, including Cd, iPb, Cr-VI, iAs-III, Zn, Cu, PFOS, BPA, MEHP, AOM, DMH, MNNG, aspirin, and metformin. We optimized the experimental protocol based on cytotoxicity, amplification, and colony formation of chemical-treated mASC-IOs. In addition, we assessed the accuracy of in vitro study and the human tumor relevance through characterizing interdependence between cell-cell and cell-matrix adhesions, tumorigenicity, pathological feature of subcutaneous tumors, and CRC-related molecular signatures. Remarkably, the results of cell transformation in 14 chemicals showed a strong concordance with epidemiological findings (8/10) and in vivo mouse studies (12/14). In addition, we found that the increase in anchorage-independent growth was positively correlated with the tumorigenicity of tested chemicals. Through analyzing the dose-response relationship of anchorage-independent growth by benchmark dose (BMD) modeling, the potent intestinal carcinogens were identified, with their carcinogenic potency ranked from high to low as AOM, Cd, MEHP, Cr-VI, iAs-III, and DMH. Importantly, the activity of chemical-transformed mASC-IOs was associated with the degree of cellular differentiation of subcutaneous tumors, altered transcription of oncogenic genes, and activated pathways related to CRC development, including Apc, Trp53, Kras, Pik3ca, Smad4 genes, as well as WNT and BMP signaling pathways. Taken together, we successfully developed a mASC-IO-based CTA, which might serve as a potential alternative for intestinal carcinogenicity screening of chemicals.

Transhiatal bilateral cervical approach for mediastinoscopy-assisted esophagectomy: A retrospective cohort study.

BACKGROUND: The McKeown minimally invasive esophagectomy (McMIE) procedure has various limitations, including surgical contraindications and a high rate of postoperative pulmonary complications. A novel mediastinoscopic esophagectomy procedure was described in this study by using esophageal invagination and a transhiatal and bilateral cervical approach (EITHBC). METHODS: According to the mode of operation, a total of 259 patients were divided into two groups, among which 106 underwent EITHBC and 153 underwent McMIE. The number of lymph nodes dissected, intraoperative outcomes, and postoperative outcomes were compared between the two groups of patients. RESULTS: The results revealed that the average number of resected lymph node in the EITHBC group was significantly higher in the recL106 and TbL106 stations (recL106: 1.75 vs. 1.51, p = 0.016, TbL106: 1.53 vs. 1.19, p = 0.016) and significantly lower in the 107 stations (1. 74 vs. 2. 07, p < 0.001) than in the McMIE group. The intraoperative blood loss in the EITHBC group was significantly lower than that in the McMIE group (63.30 vs. 80.45 mL, p < 0.001). The incidence of postoperative pulmonary complications in the EITHBC group was lower than that in the McMIE group (14.15% vs. 27.45%, p = 0.008). The incidence of recurrent laryngeal nerve paralysis in the EITHBC group was significantly higher than that in the McMIE group (26.41% vs. 10.46%, p = 0.003). CONCLUSION: Compared with the McMIE procedure, the EITHBC procedure has advantages in terms of removing the upper mediastinal lymph nodes and reducing postoperative pulmonary complications.

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia.

OBJECTIVE: In B-cell acute lymphoblastic leukemia (B-ALL), current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50% of cases, underscoring the urgent need for new therapeutic regimens for this patient population. The present study aimed to determine whether HZX-02-059, a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase (PIKfyve) and tubulin, is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients. METHODS: Cell proliferation, vacuolization, apoptosis, cell cycle, and in-vivo tumor growth were evaluated. In addition, Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL. RESULTS: HZX-02-059 was found to inhibit cell proliferation, induce vacuolization, promote apoptosis, block the cell cycle, and reduce in-vivo tumor growth. Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations. CONCLUSION: Overall, these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

Functional roles of circular RNAs in lung injury.

Lung injury leads to respiratory dysfunction, low quality of life, and even life-threatening conditions. Circular RNAs (circRNAs) are endogenous RNAs produced by selective RNA splicing. Studies have reported their involvement in the progression of lung injury. Understanding the roles of circRNAs in lung injury may aid in elucidating the underlying mechanisms and provide new therapeutic targets. Thus, in this review, we aimed to summarize and discuss the characteristics and biological functions of circRNAs, and their roles in lung injury from existing research, to provide a theoretical basis for the use of circRNAs as a diagnostic and therapeutic target for lung injury.

Analysis of brain structural covariance network in Cushing disease.

Background: Cushing disease (CD) is a rare clinical neuroendocrine disease. CD is characterized by abnormal hypercortisolism induced by a pituitary adenoma with the secretion of adrenocorticotropic hormone. Individuals with CD usually exhibit atrophy of gray matter volume. However, little is known about the alterations in topographical organization of individuals with CD. This study aimed to investigate the structural covariance networks of individuals with CD based on the gray matter volume using graph theory analysis. Methods: High-resolution T1-weighted images of 61 individuals with CD and 53 healthy controls were obtained. Gray matter volume was estimated and the structural covariance network was analyzed using graph theory. Network properties such as hubs of all participants were calculated based on degree centrality. Results: No significant differences were observed between individuals with CD and healthy controls in terms of age, gender, and education level. The small-world features were conserved in individuals with CD but were higher than those in healthy controls. The individuals with CD showed higher global efficiency and modularity, suggesting higher integration and segregation as compared to healthy controls. The hub nodes of the individuals with CD were Short insular gyri (G_insular_short_L), Anterior part of the cingulate gyrus and sulcus (G_and_S_cingul-Ant_R), and Superior frontal gyrus (G_front_sup_R). Conclusions: Significant differences in the structural covariance network of patients with CD were found based on graph theory. These findings might help understanding the pathogenesis of individuals with CD and provide insight into the pathogenesis of this CD.