3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension.

BACKGROUND: Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure. METHODS: Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function. RESULTS: Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments. CONCLUSIONS: 3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.

A Case of a Eustachian Tube Hairy Polyp Misdiagnosed as an Adenoid Residual in a Child.

Hairy polyps, considered a highly unusual congenital anomaly of the pharynx, are believed by many scholars to arise from the ectoderm and mesoderm during the embryonic stage. These growths often have a pear or sausage shape, are pedunculated, and their size ranges between 0.5 and 6 cm. They are typically grayish white or pink in color. This article discusses a 12-year-old female who had a growth at the Eustachian tube's entrance on the left side of the nasopharyngeal wall, as identified by a computed tomography scan of the neck soft tissue; it was suspected to be a hairy polyp originating from the left Eustachian tube. The diagnosis of a hairy polyp was confirmed through pathology. The hairy polyp at the Eustachian tube, in this case, showed an irregular form with a wide base, making it look similar to an adenoid; thus, increasing the risk of it being misdiagnosed as residual adenoid tissue.

Epidemiological and clinical characteristics of death from hemorrhagic fever with renal syndrome: a meta-analysis.

Introduction: Hemorrhagic fever with renal syndrome (HFRS) is an acute infectious disease comprising five stages: fever, hypotension, oliguria, diuresis (polyuria), and convalescence. Increased vascular permeability, coagulopathy, and renal injury are typical clinical features of HFRS, which has a case fatality rate of 1-15%. Despite this, a comprehensive meta-analyses of the clinical characteristics of patients who died from HFRS is lacking. Methods: Eleven Chinese- and English-language research databases were searched, including the China National Knowledge Infrastructure Database, Wanfang Database, SinoMed, VIP Database, PubMed, Embase, Scopus, Cochrane Library, Web of Science, Proquest, and Ovid, up to October 5, 2023. The search focused on clinical features of patients who died from HFRS. The extracted data were analyzed using STATA 14.0. Results: A total of 37 articles on 140,295 patients with laboratory-confirmed HFRS were included. Categorizing patients into those who died and those who survived, it was found that patients who died were older and more likely to smoke, have hypertension, and have diabetes. Significant differences were also observed in the clinical manifestations of multiple organ dysfunction syndrome, shock, occurrence of overlapping disease courses, cerebral edema, cerebral hemorrhage, toxic encephalopathy, convulsions, arrhythmias, heart failure, dyspnea, acute respiratory distress syndrome, pulmonary infection, liver damage, gastrointestinal bleeding, acute kidney injury, and urine protein levels. Compared to patients who survived, those who died were more likely to demonstrate elevated leukocyte count; decreased platelet count; increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels; prolonged activated partial thromboplastin time and prothrombin time; and low albumin and chloride levels and were more likely to use continuous renal therapy. Interestingly, patients who died received less dialysis and had shorter average length of hospital stay than those who survived. Conclusion: Older patients and those with histories of smoking, hypertension, diabetes, central nervous system damage, heart damage, liver damage, kidney damage, or multiorgan dysfunction were at a high risk of death. The results can be used to assess patients' clinical presentations and assist with prognostication.Systematic review registration:https://www.crd.york.ac.uk/prospero/, (CRD42023454553).

Application of propofol-remifentanil intravenous general anesthesia combined with regional block in pediatric ophthalmic surgery.

OBJECTIVE: The aim of this study is to observe the anesthetic effect and safety of intravenous anesthesia without muscle relaxant with propofol-remifentanil combined with regional block under laryngeal mask airway in pediatric ophthalmologic surgery. METHODS: A total of 90 undergoing ophthalmic surgery were anesthetized with general anesthesia using the laryngeal mask airway without muscle relaxant. They were randomly divided into two groups: 45 children who received propofol-remifentanil intravenous anesthesia combined with regional block (LG group), and 45 children who received total intravenous anesthesia (G group). The peri-operative circulatory indicators, awakening time after general anesthesia, postoperative analgesic effect and the incidence of anesthesia-related adverse events were respectively compared between the two groups. RESULTS: All the children successfully underwent the surgical procedure. The awakening time after general anesthesia and removal time of laryngeal mask were significantly shorter in the LG group than in the G group (P < 0.05). There was no statistically significant difference in the heart rates in the perioperative period between the two groups (P > 0.05). There was no statistically significant difference in the incidence of intraoperative physical response, respiratory depression, postoperative nausea and vomiting (PONV) and emergence agitation (EA) between the two groups (P > 0.05). The pain score at the postoperative hour 2 was lower in the LG group than in the G group (P < 0.05). CONCLUSION: Propofol-remifentanil intravenous anesthesia combined with long-acting local anesthetic regional block anesthesia, combined with laryngeal mask ventilation technology without muscle relaxants, can be safely used in pediatric eye surgery to achieve rapid and smooth recovery from general anesthesia and better postoperative analgesia. This anesthesia scheme can improve the comfort and safety of children in perioperative period, and has a certain clinical popularization value.

Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders.

Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.

Application of natural products in regulating ferroptosis in human diseases.

BACKGROUND: Ferroptosis is a type of cell death caused by excessive iron-induced peroxidation. It has been found to be involved in a variety of diseases, and natural products can be used to target ferroptosis in treatments. Natural products are biologically active compounds extracted or synthesized from nature. It is an important resource for the discovery of skeletons with a high degree of structural diversity and a wide range of bioactivities, which can be developed directly or used as a starting point for the optimization of new drugs. PURPOSE: In this review, we aim to discuss the interactions between natural products and ferroptosis in the treatment of human diseases. METHODS: Literature was searched in Pubmed, Science Direct, and Web of Science databases for the 11-year period from 2012 to 2023 using the search terms "natural products", "ferroptosis", "human disease", "neurodegenerative disease", "cardiovascular disease", and "cancer". RESULTS: In this research, the roles of natural products and ferroptosis were investigated. We suggest that natural products, such as terpenoids, flavonoids, polyphenols, alkaloids, and saponins, can be used in therapeutic applications for human diseases, as well as in ferroptosis. Additionally, the main mechanisms of ferroptosis were summarized and discussed. Furthermore, we propose that natural products can be utilized to enhance the sensitivity of cancer cells to ferroptosis, thus helping to overcome drug resistance and inhibit metastasis. Moreover, natural products have the potential to modulate the expression levels of ferroptosis-related factors. Finally, the future directions of this field were highlighted. CONCLUSION: The potential of natural products which focus on ferroptosis to treat human illnesses, particularly cancer, is very encouraging for human wellbeing.

Cannabidiol Alleviates Chronic Prostatitis and Chronic Pelvic Pain Syndrome via CB2 Receptor Activation and TRPV1 Desensitization.

PURPOSE: This study elucidates the mechanism of the physiological effect of cannabidiol (CBD) by assessing its impact on lipopolysaccharide (LPS)-induced inflammation in RWPE-1 cells and prostatitis-induced by 17ß-estradiol and dihydrotestosterone in a rat model, focusing on its therapeutic potential for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). MATERIALS AND METHODS: RWPE-1 cells were stratified in vitro into three groups: (1) controls, (2) cells with LPS-induced inflammation, and (3) cells with LPS-induced inflammation and treated with CBD. Enzyme-linked immunosorbent assays and western blots were performed on cellular components and supernatants after administration of CBD. Five groups of six Sprague-Dawley male rats were assigned: (1) control, (2) CP/CPPS, (3) CP/CPPS and treated with 50 mg/kg CBD, (4) CP/CPPS and treated with 100 mg/kg CBD, and (5) CP/CPPS and treated with 150 mg/kg CBD. Prostatitis was induced through administration of 17ß-estradiol and dihydrotestosterone. After four weeks of CBD treatment, a pain index was evaluated, and prostate tissue was collected for subsequent histologic examination and western blot analysis. RESULTS: CBD demonstrated efficacy in vivo for CP/CPPS and in vitro for inflammation. It inhibited the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway by activating the CB2 receptor, reducing expression of interleukin-6, tumor necrosis factor-alpha, and cyclooxygenase-2 (COX2) (p<0.01). CBD exhibited analgesic effects by activating and desensitizing the TRPV1 receptor. CONCLUSIONS: CBD inhibits the TLR4/NF-κB pathway by activating the CB2 receptor, desensitizes the TRPV1 receptor, and decreases the release of COX2. This results in relief of inflammation and pain in patients with CP/CPPS, indicating CBD as a potential treatment for CP/CPPS.

Biotransformation of zearalenone to non-estrogenic compounds with two novel recombinant lactonases from Gliocladium.

BACKGROUND: The mycotoxin zearalenone (ZEA) produced by toxigenic fungi is widely present in cereals and its downstream products. The danger of ZEA linked to various human health issues has attracted increasing attention. Thus, powerful ZEA-degrading or detoxifying strategies are urgently needed. Biology-based detoxification methods are specific, efficient, and environmentally friendly and do not lead to negative effects during cereal decontamination. Among these, ZEA detoxification using degrading enzymes was documented to be a promising strategy in broad research. Here, two efficient ZEA-degrading lactonases from the genus Gliocladium, ZHDR52 and ZHDP83, were identified for the first time. This work studied the degradation capacity and properties of ZEA using purified recombinant ZHDR52 and ZHDP83. RESULTS: According to the ZEA degradation study, transformed Escherichia coli BL21(DE3) PLySs cells harboring the zhdr52 or zhdp83 gene could transform 20 µg/mL ZEA within 2 h and degrade > 90% of ZEA toxic derivatives, α/ß-zearalanol and α/ß-zearalenol, within 6 h. Biochemical analysis demonstrated that the optimal pH was 9.0 for ZHDR52 and ZHDP83, and the optimum temperature was 45 °C. The purified recombinant ZHDR52 and ZHDP83 retained > 90% activity over a wide range of pH values and temperatures (pH 7.0-10.0 and 35-50 °C). In addition, the specific activities of purified ZHDR52 and ZHDP83 against ZEA were 196.11 and 229.64 U/mg, respectively. The results of these two novel lactonases suggested that, compared with ZHD101, these two novel lactonases transformed ZEA into different products. The slight position variations in E126 and H242 in ZDHR52/ZEA and ZHDP83/ZEA obtained via structural modelling may explain the difference in degradation products. Moreover, the MCF-7 cell proliferation assay indicated that the products of ZEA degradation using ZHDR52 and ZHDP83 did not exhibit estrogenic activity. CONCLUSIONS: ZHDR52 and ZHDP83 are alkali ZEA-degrading enzymes that can efficiently and irreversibly degrade ZEA into non-estrogenic products, indicating that they are potential candidates for commercial application. This study identified two excellent lactonases for industrial ZEA detoxification.

KAT8 is upregulated and recruited to the promoter of Atg8 by FOXO to induce H4 acetylation for autophagy under 20-hydroxyecdysone regulation.

Selective gene expression in cells in physiological or pathological conditions is important for the growth and development of organisms. Acetylation of histone H4 at K16 (H4K16ac) catalyzed by histone acetyltransferase 8 (KAT8) is known to promote gene transcription; however, the regulation of KAT8 transcription and the mechanism by which KAT8 acetylates H4K16ac to promote specific gene expression are unclear. Using the lepidopteran insect Helicoverpa armigera as a model, we reveal that the transcription factor FOXO promotes KAT8 expression and recruits KAT8 to the promoter region of autophagy-related gene 8 (Atg8) to increase H4 acetylation at that location, enabling Atg8 transcription under the steroid hormone 20-hydroxyecdysone (20E) regulation. H4K16ac levels are increased in the midgut during metamorphosis, which is consistent with the expression profiles of KAT8 and ATG8. Knockdown of Kat8 using RNA interference results in delayed pupation and repression of midgut autophagy and decreases H4K16ac levels. Overexpression of KAT8-GFP promotes autophagy and increases H4K16ac levels. FOXO, KAT8, and H4K16ac colocalized at the FOXO-binding region to promote Atg8 transcription under 20E regulation. Acetylated FOXO at K180 and K183 catalyzed by KAT8 promotes gene transcription for autophagy. 20E via FOXO promotes Kat8 transcription. Knockdown or overexpression of FOXO appeared to give similar results as knockdown or overexpression of KAT8. Therefore, FOXO upregulates KAT8 expression and recruits KAT8 to the promoter region of Atg8, where the KAT8 induces H4 acetylation to promote Atg8 transcription for autophagy under 20E regulation. This study reveals the mechanism that KAT8 promotes transcription of a specific gene.

Investigating the clinical role and prognostic value of genes related to insulin-like growth factor signaling pathway in thyroid cancer.

BACKGROUND: Thyroid cancer (THCA) is the most common endocrine malignancy having a female predominance. The insulin-like growth factor (IGF) pathway contributed to the unregulated cell proliferation in multiple malignancies. We aimed to explore the IGF-related signature for THCA prognosis. METHOD: The TCGA-THCA dataset was collected from the Cancer Genome Atlas (TCGA) for screening of key prognostic genes. The limma R package was applied for differentially expressed genes (DEGs) and the clusterProfiler R package was used for the Gene Ontology (GO) and KEGG analysis of DEGs. Then, the un/multivariate and least absolute shrinkage and selection operator (Lasso) Cox regression analysis was used for the establishment of RiskScore model. Receiver Operating Characteristic (ROC) analysis was used to verify the model's predictive performance. CIBERSORT and MCP-counter algorithms were applied for immune infiltration analysis. Finally, we analyzed the mutation features and the correlation between the RiskScore and cancer hallmark pathway by using the GSEA. RESULT: We obtained 5 key RiskScore model genes for patient's risk stratification from the 721 DEGs. ROC analysis indicated that our model is an ideal classifier, the high-risk patients are associated with the poor prognosis, immune infiltration, high tumor mutation burden (TMB), stronger cancer stemness and stronger correlation with the typical cancer-activation pathways. A nomogram combined with multiple clinical features was developed and exhibited excellent performance upon long-term survival quantitative prediction. CONCLUSIONS: We constructed an excellent prognostic model RiskScore based on IGF-related signature and concluded that the IGF signal pathway may become a reliable prognostic phenotype in THCA intervention.

Surgical outcomes and perioperative risk factors of patients with interstitial lung disease after pulmonary resection.

BACKGROUND: Patients of interstitial lung disease (ILD) combined with pulmonary lesions are increasingly common in clinical practice. Patients with ILD are at significantly higher risk for complications after pulmonary resection (including lobectomy and sublobar resection), especially acute exacerbations of ILD (AE-ILD). The purpose of this study is to summarize the short-term and long-term outcomes after pulmonary resection in ILD patients and to analyze the clinical factors affecting surgical safety. METHODS: From January 2004 to January 2022, a total of 78 patients who were diagnosed with ILD and underwent pulmonary resection at our center were enrolled in this study. Clinical data, pathological findings, surgical procedures, and intraoperative safety of these patients were collected retrospectively. Postoperative 90-day complications and mortality, long-term surgical outcomes from postoperative 90 days to 24 months, and changes in ILD condition were investigated. Logistic regression analysis was used to identify the risk factors associated with postoperative complications. RESULTS: The median age of patients was 66.5 (range 33-86) years, 82.1% (64/78) of patients were male, and 78.2% (61/78) of patients had comorbidities. Idiopathic ILD and secondary ILD accounted for 86% and 14%, thoracotomy and video-assisted thoracoscopic surgery accounted for 12.8% and 87.2%, and lobectomy and sublobar resection accounted for 37.2% and 62.8%, respectively. Postoperative 90-day complications occurred in 25.6% (20/78) of patients, with pulmonary complications and AE-ILD occurring in 15.4% and 9.0% of patients, respectively. The postoperative 90-day mortality rate was 5.1% (4/78), and the cause of death was AE-ILD. Exacerbation of ILD or other complications occurred in 12.8% (10/78) of patients from postoperative 90 days to 24 months. Univariate logistic regression analysis showed that comorbidity, extent of resection, systemic lymph node dissection, operation time, intraoperative blood loss, and pathology of pulmonary lesion were associated with postoperative 90-day complications. In multivariate logistic regression analysis, age-adjusted Charlson Comorbidity Index and intraoperative blood loss were identified as independent risk factors of postoperative 90-day complications. CONCLUSIONS: Patients with ILD have a significantly higher risk of postoperative 90-day complications and mortality after pulmonary resection, especially pulmonary complications and AE-ILD. After postoperative 90 days, the risk of deterioration of pulmonary status remains high, including exacerbation of ILD and complications associated with long-term use of glucocorticoids and immunosuppressant. Age, comorbidity and intraoperative blood loss are high risk factors for postoperative 90-day complications.

The application of custom 3D-printed prostheses with ultra-short stems in the reconstruction of bone defects: a single center analysis.

Objective: Considering the advantages and widespread presence of 3D-printing technology in surgical treatments, 3D-printed porous structure prostheses have been applied in a wide range of the treatments of bone tumor. In this research, we aimed to assess the application values of the 3D-printed custom prostheses with ultra-short stems for restoring bone defects and maintaining arthrosis in malignant bone tumors of lower extremities in children. Methods: Seven cases of pediatric patients were included in this study. In all cases, the prostheses were porous titanium alloy with ultra-short stems. MSTS 93 (Musculoskeletal Tumor Society) scores were recorded for the functional recovery of the limbs. VAS (Visual analogue scale) scores were utilized to assess the degree of painfulness for the patients. X-ray and MRI (magnetic resonance imaging) were applied to evaluate the bone integration, prostheses aseptic loosening, prostheses fracture, wound healing, and tumor recurrence during follow-up. Results: During follow-up, none of the patients developed any postoperative complications, including prostheses aseptic loosening, prostheses fracture, or tumor recurrence. Radiological examinations during the follow-up showed that prostheses implanted into the residual bone were stably fitted and bone defects were effectively reconstructed. The MSTS 93 scores were 24.9 ± 2.9 (20-28). VAS scores were decreased to 5.8 ± 1.2 (4.0-7.0). No statistically significant differences in leg length discrepancy were observed at the time of the last follow-up. Conclusion: 3D-printing technology can be effectively applied throughout the entire surgical treatment procedures of malignant bone tumors, offering stable foundations for the initial stability of 3D-printed prostheses with ultra-short stems through preoperative design, intraoperative precision operation, and personalized prosthesis matching. With meticulous postoperative follow-up, close monitoring of postoperative complications was ensured. These favorable outcomes indicate that the utilization of 3D-printed custom prostheses with ultra-short stems is a viable alternative for reconstructing bone defects. However, further investigation is warranted to determine the long-term effectiveness of the 3D-printing technique.

Four undescribed coumarin derivatives, with ten amides from the roots of Ficus hirta and their cytotoxic activities.

Four undescribed coumarin derivatives, ficusalt A (1) and ficusalt B (2), a pair of racemic coumarins, (±) ficudimer A (3a/3b), along with ten known amides, were isolated from the roots of Ficus hirta. Their structures were elucidated by several spectroscopic data analyses, including HRESIMS, NMR, and X-ray single-crystal diffraction. The cytotoxic activities of all compounds against HeLa, HepG2, MCF-7, and H460 cell lines were detected using the MTT assay. Among these, 5 showed the highest activity against HeLa cells. Subsequently, the apoptotic, anti-invasive, and anti-migration effects of 5 on HeLa cells were determined by flow cytometer, transwell invasion assay, and wound-healing assay, respectively. The result suggested that 5 distinctly induced the apoptosis in HeLa cells and inhibited their invasion and migration. Further studies on anticancer mechanisms were conducted using Western blotting. As a result, 5 increased the cleavage of PARP and the expression of pro-apoptotic protein Bax. Moreover, 5 notably upregulated the phosphorylation of p38 and JNK, whereas inhibited the expression of p-ERK and p-AKT. Our results demonstrated that 5 could be a potential leading compound for further application in the treatment of cervical cancer.

Drug-repurposing by virtual and experimental screening of PFKFB3 inhibitors for pancreatic cancer therapy.

Pancreatic cancer (PC) is the most frequently occurring cancer, with few effective treatments and a 5-year survival rate of only about 11%. It is characterized by stiff interstitium and pressure on blood vessels, leading to an increased glycolytic metabolism. PFKFB3 plays an important role in glycolysis, and its products (fructose-2,6-bisphosphate), which are allosteric PFK1 activators, limit the glycolytic rate. In this study, 14 PFKFB3 inhibitors were obtained by virtually screening the FDA-approved compound library. Subsequently, the in-vitro investigations confirmed that Lomitapide and Cabozantinib S-malate exhibit the excellent potential to inhibit PFKFB3. The combined administration of Lomitapide and Gemcitabine at a certain molar ratio indicated an enhanced anti-tumor effect in Orthotopic Pancreatic Cancer (OPC) models. This investigation provides a new treatment strategy for PC therapy.

NQO1 Mediates Lenvatinib Resistance by Regulating ROS-induced Apoptosis in Hepatocellular Carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated death worldwide. As a first-line drug for advanced HCC treatment, lenvatinib faces a significant hurdle due to the development of both intrinsic and acquired resistance among patients, and the underlying mechanism remains largely unknown. The present study aims to identify the pivotal gene responsible for lenvatinib resistance in HCC, explore the potential molecular mechanism, and propose combinatorial therapeutic targets for HCC management. METHODS: Cell viability and colony formation assays were conducted to evaluate the sensitivity of cells to lenvatinib and dicoumarol. RNA-Seq was used to determine the differences in transcriptome between parental cells and lenvatinib-resistant (LR) cells. The upregulated genes were analyzed by GO and KEGG analyses. Then, qPCR and Western blotting were employed to determine the relative gene expression levels. Afterwards, the intracellular reactive oxygen species (ROS) and apoptosis were detected by flow cytometry. RESULTS: PLC-LR and Hep3B-LR were established. There was a total of 116 significantly upregulated genes common to both LR cell lines. The GO and KEGG analyses indicated that these genes were involved in oxidoreductase and dehydrogenase activities, and reactive oxygen species pathways. Notably, NAD(P)H:quinone oxidoreductase 1 (NQO1) was highly expressed in LR cells, and was involved in the lenvatinib resistance. The high expression of NQO1 decreased the production of ROS induced by lenvatinib, and subsequently suppressed the apoptosis. The combination of lenvatinib and NQO1 inhibitor, dicoumarol, reversed the resistance of LR cells. CONCLUSION: The high NQO1 expression in HCC cells impedes the lenvatinib-induced apoptosis by regulating the ROS levels, thereby promoting lenvatinib resistance in HCC cells.

RNA Modifications in Hematologic Malignancies.

Chemical modifications on macromolecules such as DNA, RNA and proteins play important roles in almost all biological processes. The revival of RNA modification research began with the discovery of RNA modification machineries, and with the development of better techniques for characterizing and profiling these modifications at the transcriptome-wide level. Hematopoietic system is maintained by hematopoietic stem cells that possess efficient self-renewal capacity and the potential of differentiation into all lineages of blood cells, and the imbalance of this homeostasis frequently causes hematologic malignancies such as leukemia. Recent studies reveal that dysregulated RNA modifications play essential roles in hematologic malignancies. Herein, we summarize recent advances in some major RNA modifications, the detection methods, roles and mechanisms of these RNA modifications in hematologic malignancies.

Clinical exploration of the international society of limb salvage classification of endoprosthetic failure using Henderson in the application of 3D-printed pelvic tumor prostheses.

Background: The use of 3D-printed pelvic prosthesis for postoperative reconstruction after pelvic tumor resection has become one of the primary reconstruction methods the incidence of complications related to postoperative prosthesis reconstruction is high. Drawing on the failure of the type of bone tumor reconstruction in Henderson,the occurrence of postoperative complications was explored to take advantage of the design improvement of the 3D-printed prosthesis of subsequent pelvic tumors. Methods: The data for patients who underwent 3D-printed pelvic tumor prostheses in the Department of Bone and Soft Tissue Surgery at the Affiliated Cancer Hospital of Guangxi Medical University from January 2019 to October 2022 were collected and analyzed. Results: The median follow-up time for all patients was 15.99 months (1.33-31.16 months). At the most recent follow-up,all patients were alive,with an average Musculoskeletal Tumor Society (MSTS) score of 21.46 (17 to 26 points). Local recurrence occurred in two cases (15.3%), metastasis in four cases (30.7%), and complications in 10 cases (76.9%). Early complications after surgery were primarily local wound fissure, deep tissue infection, and postoperative neuralgia. Later complications included loose dissolution of internal fixation, postoperative prosthetic dislocation, and postoperative gluteal middle muscle gait. Conclusion: 3D printing personalized design pelvic tumor prosthesis is an effective way to reconstruct, and designing pelvic 3D printed tumor prosthesis with the help of Henderson's bone tumor reconstruction failure concept may help bone tumor surgeons develop better pelvic tumor prosthesis.

Identification of cancer-associated fibroblasts signature for predicting the prognosis and immunotherapy response in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies globally with poor prognosis. Cancer-associated fibroblasts (CAFs) play multiple functions in the regulation of tumorigenesis, metastasis and therapeutic resistance of cancer. The current study aimed to explore the role of CAFs-related genes in the prognosis and immunotherapy response in HCC. CAFs-related genes were identified by using single-cell RNA-sequencing analysis. Least absolute shrinkage and selection operator (LASSO) analysis was conducted to develop a CAFs-related prognostic signature (FRPS) in TCGA dataset and verified in ICGC, GSE14520 and GSE76427 cohorts. Several tools, including Tumor Immune Dysfunction and Exclusion (TIDE) score, immunophenoscore, and Tumor Mutation Burden (TMB) score were used to evaluate the value of FRPS in predicting immunotherapy benefits. The FRPS constructed based on 10 genes (RGS5, CNN3, PALLD, FLNA, KLHL23, MYC, NDRG2, SERPINE1, CD151 CALU) served as an independent risk factor and showed stable and powerful performance in predicting the overall survival rate of HCC patients with an AUCs of 0. 734, 0.727, and 0.717 in 2-, 3-, and 4-year ROC curve in TCGA cohort. Low risk score indicated a higher abundance of CD8+ T cells and NK, and lower abundance of Treg. Moreover, HCC patients with low risk score had a higher PD1&CTLA4 immunophenoscore, higher TMB score, and lower TIDE score. Moreover, high risk score indicated a lower IC50 value of 5-fluorouracil, camptothecin, cisplatin, docetaxel, gemcitabine, paclitaxel, afatinib, crizotinib, dasatinib, erlotinib, erlotinib, gefitinib, lapatinib, and osimertinib in HCC. Our study develops a novel FRPS HCC. The FRPS acts as a risk factor for the prognosis of HCC patients and it can predict the immunotherapy benefits of HCC patients.

Etoposide soft capsule combined with anlotinib in the third-line treatment of advanced non-small cell lung cancer: a retrospective cohort study.

Background: The physical tolerance in the advanced non-small cell lung cancer (NSCLC) patient often deteriorates, with a limited effective rate of the third-line treatment. This study retrospectively analyzed the efficacy and safety of etoposide soft capsules combined with anlotinib in the third-line treatment of advanced NSCLC. Methods: A retrospective study was conducted on 46 patients with advanced NSCLC who had failed second-line treatment. Progression-free survival (PFS) of advanced NSCLC patients served as an endpoint. Kaplan-Meier survival curves were applied to evaluate the short-term efficacy of anlotinib treatment in advanced NSCLC patients. Results: Among 46 third-line NSCLC patients, none had complete remission (CR), 9 had partial remission (PR), 29 had stable disease (SD), and 8 had progressive disease (PD). The objective response rate (ORR) was 19.57%, the disease control rate (DCR) was 82.61%, the median progression-free survival (mPFS) was 6.3 months, and the median overall survival (mOS) was 10.1 months. Common adverse reactions included fatigue, hypertension, nausea, stomatitis, leukopenia, hand-foot syndrome, abnormal liver function, proteinuria, hemoptysis, and hypothyroidism, among others. The incidence of grade 3 adverse reactions was 8.9%, and there were no grade 4 adverse reactions. Conclusions: Etoposide soft capsule combined with anlotinib demonstrated a marked effect on the third-line treatment of advanced NSCLC patients, and is well tolerated.