Myclobutanil induces cardiotoxicity in developing zebrafish larvae by initiating oxidative stress and apoptosis: The protective role of curcumin.

Myclobutanil (MYC) is a common triazole fungicide widely applied in agriculture. MYC extensively exists in the natural environment and can be detected in organisms. However, little is known about MYC-induced embryonic developmental damage. This study aimed to unravel the cardiotoxicity of MYC and the underlying mechanisms, as well as the cardioprotective effect of curcumin (CUR, an antioxidant polyphenol) using the zebrafish model. Here, zebrafish embryos were exposed to MYC at concentrations of 0, 0.5, 1 and 2 mg/L from 4 to 96 h post fertilization (hpf) and cardiac development was assessed. As results, MYC reduced the survival and hatching rate, body length and heart rate, but increased the malformation rate and spontaneous movement. MYC caused abnormal cardiac morphology and function in myl7:egfp transgenic zebrafish, and downregulated cardiac developmental genes. MYC promoted oxidative stress through excessive reactive oxygen species (ROS) accumulation and suppressed the activities of antioxidant enzymes, triggering cardiomyocytic apoptosis via upregulated expression of apoptosis-related genes. These adverse toxicities could be significantly ameliorated by the antioxidant properties of CUR, indicating that CUR rescued MYC-induced cardiotoxicity by inhibiting oxidative stress and apoptosis. Overall, our study revealed the potential mechanisms of oxidative stress and apoptosis in MYC-induced cardiotoxicity in zebrafish and identified the cardioprotection of CUR in this pathological process.

The selective sponging of miRNAs by OIP5-AS1 regulates metabolic reprogramming of pyruvate in adenoma-carcinoma transition of human colorectal cancer.

RNA interactomes and their diversified functionalities have recently benefited from critical methodological advances leading to a paradigm shift from a conventional conception on the regulatory roles of RNA in pathogenesis. However, the dynamic RNA interactomes in adenoma-carcinoma sequence of human CRC remain unexplored. The coexistence of adenoma, cancer, and normal tissues in colorectal cancer (CRC) patients provides an appropriate model to address this issue. Here, we adopted an RNA in situ conformation sequencing technology for mapping RNA-RNA interactions in CRC patients. We observed large-scale paired RNA counts and identified some unique RNA complexes including multiple partners RNAs, single partner RNAs, non-overlapping single partner RNAs. We focused on the antisense RNA OIP5-AS1 and found that OIP5-AS1 could sponge different miRNA to regulate the production of metabolites including pyruvate, alanine and lactic acid. Our findings provide novel perspectives in CRC pathogenesis and suggest metabolic reprogramming of pyruvate for the early diagnosis and treatment of CRC.

Cuproptosis is involved in decabromodiphenyl ether-induced ovarian dysfunction and the protective effect of melatonin.

Decabromodiphenyl ether (BDE-209) has been universally detected in environmental media and animals, but its damage to ovarian function and mechanism is still unclear, and melatonin has been shown to improve mammalian ovarian function. This study aimed to investigate the toxic effects of BDE-209 on the ovary and tried to improve ovarian function with melatonin. Herein, BDE-209 was administered orally to female SD rats for 60 days. Enzyme-linked immunosorbent assay, HE staining, transcriptome analysis, qPCR and immunohistochemical staining were used to explore and verify the potential mechanism. We found that BDE-209 exposure had effects on the ovary, as shown by abnormal changes in the estrous cycle, hormone levels and ovarian reserve function in rats, while increasing the proportion of collagen fibres in ovarian tissue. In terms of mechanism, cuproptosis, a form of cell death, was identified to play a crucial role in BDE-209-induced ovarian dysfunction, with the phenotype manifested as copper salt accumulation in ovary, downregulation of glutathione pathway metabolism and copper transfer molecule (ATP7A/B), and upregulation of FDX1, lipoic acid pathway (LIAS, LIPT1), pyruvate dehydrogenase complex components (DLAT, PDHB, PDHA1), and copper transfer molecule (SLC31A1). Furthermore, possible interventions were explored. Notably, a supplement with melatonin has a repair effect on the damage to ovarian function by reversing the gene expression of cuproptosis-involved molecules. Overall, this study revealed that cuproptosis is involved in BDE-209-induced ovarian damage and the beneficial effect of melatonin on ovarian copper damage, providing evidence for the prevention and control of female reproductive damage induced by BDE-209.

Case report: Cutaneous anthrax diagnosed using mNGS of a formalin-fixed paraffin-embedded tissue sample.

The metagenomic next-generation sequencing (mNGS) method is preferred for genotyping useful for the identification of organisms, illumination of metabolic pathways, and determination of microbiota. It can accurately obtain all the nucleic acid information in the test sample. Anthrax is one of the most important zoonotic diseases, infecting mainly herbivores and occasionally humans. The disease has four typical clinical forms, cutaneous, gastrointestinal, inhalation, and injection, all of which may result in sepsis or meningitis, with cutaneous being the most common form. Here, we report a case of cutaneous anthrax diagnosed by mNGS in a butcher. Histopathology of a skin biopsy revealed PAS-positive bacilli. Formalin-fixed paraffin-embedded (FFPE) tissue sample was confirmed the diagnosis of anthrax by mNGS. He was cured with intravenous penicillin. To our knowledge, this is the first case of cutaneous anthrax diagnosed by mNGS using FFPE tissue. mNGS is useful for identifying pathogens that are difficult to diagnose with conventional methods, and FFPE samples are simple to manage. Compared with traditional bacterial culture, which is difficult to cultivate and takes a long time, mNGS can quickly and accurately help us diagnose anthrax, so that anthrax can be controlled in a timely manner and prevent the outbreak of epidemic events.

Myclobutanil induces neurotoxicity by activating autophagy and apoptosis in zebrafish larvae (Danio rerio).

Myclobutanil (MYC), a typical broad-spectrum triazole fungicide, is often detected in surface water. This study aimed to explore the neurotoxicity of MYC and the underlying mechanisms in zebrafish and in PC12 cells. In this study, zebrafish embryos were exposed to 0, 0.5 and 1 mg/L of MYC from 4 to 96 h post fertilization (hpf) and neurobehavior was evaluated. Our data showed that MYC decreased the survival rate, hatching rate and heart rate, but increased the malformation rate and spontaneous movement. MYC caused abnormal neurobehaviors characterized by decreased swimming distance and movement time. MYC impaired cerebral histopathological morphology and inhibited neurogenesis in HuC:egfp transgenic zebrafish. MYC also reduced the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and downregulated neurodevelopment related genes (gfap, syn2a, gap43 and mbp) in zebrafish and PC12 cells. Besides, MYC activated autophagy through enhanced expression of the LC3-II protein and suppressed expression of the p62 protein and autophagosome formation, subsequently triggering apoptosis by upregulating apoptotic genes (p53, bax, bcl-2 and caspase 3) and the cleaved caspase-3 protein in zebrafish and PC12 cells. These processes were restored by the autophagy inhibitor 3-methyladenine (3-MA) both in vivo and in vitro, indicating that MYC induces neurotoxicity by activating autophagy and apoptosis. Overall, this study revealed the potential autophagy and apoptosis mechanisms of MYC-induced neurotoxicity and provided novel strategies to counteract its toxicity.

Differential innate immune responses to fowl adenovirus serotype 4 infection in Leghorn male hepatocellular and chicken embryo fibroblast cells.

Fowl adenovirus serotype 4 (FAdV-4) infections result in substantial economic losses in the poultry industry. Recent findings have revealed that FAdV-4 significantly suppresses the host immune response upon infection; however, the specific viral and host factors contributing to this immunomodulatory activity remain poorly characterized. Moreover, diverse cell types exhibit differential immune responses to FAdV-4 infection. To elucidate cell-specific host responses, we performed transcriptomic analysis of FAdV-4 infected leghorn male hepatocellular (LMH) and chicken embryo fibroblast (CEF) cells. Although FAdV-4 replicated more efficiently in LMH cells, it provoked limited interferon-stimulated gene induction. In contrast, FAdV-4 infection triggered robust antiviral responses in CEF cells, including upregulation of cytosolic DNA sensing and interferon-stimulated genes. Knockdown of key cytosolic DNA sensing molecules enhanced FAdV-4 replication in LMH cells while reducing interferon-stimulated gene expression. Our findings reveal cell-specific virus-host interactions that provide insight into FAdV-4 pathogenesis while identifying factors that mediate antiviral immunity against FAdV-4.

Treatment of ureteropelvic junction obstruction in patients with renal calculi via laparoscopic pyeloplasty and flexible vacuum-assisted ureteral access sheath ureteroscopy: a multicenter retrospective observational study.

BACKGROUND: Ureteropelvic junction obstruction (UPJO) is a common obstructive disease of the urinary tract. UPJO patients commonly exhibit coexistent renal calculi. The main aim of therapy is to relieve the obstruction and remove the stones at the same time. METHODS: This retrospective study included 110 patients diagnosed with UPJO coexisting with multiple renal calculi at Shanxi Bethune Hospital and the First Hospital of Shanxi Medical University between March 2016 and January 2022. Patients were divided according to the methods used for dealing with UPJO and renal calculi. In Group A, patients underwent traditional open pyeloplasty and pyelolithotomy. In Group B, patients underwent percutaneous nephrolithotomy first and then laparoscopic pyeloplasty. In Group C, patients underwent flexible cystoscopy to remove stones and then laparoscopic pyeloplasty. In Group D, patients underwent flexible vacuum-assisted ureteral access sheath (FV-UAS)assisted flexible ureteroscopy (f-URS) and underwent laparoscopic pyeloplasty. The stones were broken up using a holmium laser. The pyeloplasty success rate, stone clearance rate, operation time, bleeding amount, complication occurrence rate, postsurgical pain, length of stay, and hospitalization cost were compared between the groups. The follow-up period was at least 2 years. RESULTS: The use of f-URS and the FV-UAS, significantly increased the renal stone clearance rate and significantly reduced the complication incidence and operation time in UPJO patients with multiple coexisting renal calculi. CONCLUSIONS: Laparoscopic pyeloplasty combined with f-URS and FV-UAS is safe and effective for treating UPJO in patients complicated by renal caliceal stones. TRIAL REGISTRATION: Retrospectively registered.

Association of serum 25-hydroxyvitamin D concentration with all-cause and cause-specific mortality in hypertensive patients.

BACKGROUND AND AIMS: To examine the association of serum 25-hydroxyvitamin D [25(OH)D] with all-cause mortality and disease-specific mortality in patients with hypertension. METHODS AND RESULTS: This cohort study included US adults in the National Health and Nutrition Examination Survey from 2007 to 2018. All-cause mortality and cause-specific mortality outcomes were determined by association with National Death Index records. Cox proportional risk models were used to estimate hazard ratios (HRs) for all-cause mortality and cause-specific mortality and 95% confidence intervals (CIs) for serum 25(OH)D concentrations. The cohort included 10,325 adult participants. The mean serum 25(OH)D level was 65.87 nmol/L, and 32.2% of patients were vitamin D deficient (<50 nmol/L). During a mean follow-up of 77 months, 1290 deaths were recorded, including 345 cardiovascular deaths and 237 cancer deaths. Patients with higher serum 25(OH)D were more likely to have lower all-cause mortality and cardiovascular mortality than those with serum 25(OH)D < 25.00 nmol/L. For cancer mortality in hypertensive patients, vitamin D may not have a predictive role in this. CONCLUSIONS: This study shows that higher 25(OH)D levels are significantly associated with lower all-cause mortality and cardiovascular disease (CVD) mortality. These findings suggest that maintaining adequate vitamin D status may reduce the risk of death in patients with hypertension.

Gut microbiota-palmitoleic acid-interleukin-5 axis orchestrates benzene-induced hematopoietic toxicity.

Due to the annual increase in its production and consumption in occupational environments, the adverse blood outcomes caused by benzene are of concern. However, the mechanism of benzene-induced hematopoietic damage remains elusive. Here, we report that benzene exposure causes hematopoietic damage in a dose-dependent manner and is associated with disturbances in gut microbiota-long chain fatty acids (LCFAs)-inflammation axis. C57BL/6J mice exposed to benzene for 45 days were found to have a significant reduction in whole blood cells and the suppression of hematopoiesis, an increase in Bacteroides acidifaciens and a decrease in Lactobacillus murinus. Recipient mice transplanted with fecal microbiota from benzene-exposed mice showed potential for hematopoietic disruption, LCFAs, and interleukin-5 (IL-5) elevation. Abnormally elevated plasma LCFAs, especially palmitoleic acid (POA) exacerbated benzene-induced immune-inflammation and hematopoietic damage via carnitine palmitoyltransferase 2 (CPT2)-mediated disorder of fatty acid oxidation. Notably, oral administration of probiotics protects the mice against benzene-induced hematopoietic toxicity. In summary, our data reveal that the gut microbiota-POA-IL-5 axis is engaged in benzene-induced hematopoietic damage. Probiotics might be a promising candidate to prevent hematopoietic abnormalities from benzene exposure.

Peptide Self-Assembly Facilitating DNA Transfection and the Application in Inhibiting Cancer Cells.

Non-viral vectors have been developing in gene delivery due to their safety and low immunogenicity. But their transfection effect is usually very low, thus limiting the application. Hence, we designed eight peptides (compounds 1-8). We compared their performances; compound 8 had the best transfection efficacy and biocompatibility. The transfection effect was similar with that of PEI, a most-widely-employed commercial transfection reagent. Atomic force microscope (AFM) images showed that the compound could self-assemble and the self-assembled peptide might encapsulate DNA. Based on these results, we further analyzed the inhibitory result in cancer cells and found that compound 8 could partially fight against Hela cells. Therefore, the compound is promising to pave the way for the development of more effective and less toxic transfection vectors.

The m6A reader IGF2BP1 attenuates the stability of RPL36 and cell proliferation to mediate benzene hematotoxicity by recognizing m6A modification.

Benzene exposure leads to hematotoxicity, and epigenetic modification is considered to be a potential mechanism of benzene pathogenesis. As a newly discovered post-transcriptional modification, the roles of N6-methyladenosine (m6A) in benzene hematotoxicity are still unclear. m6A can only exert its gene regulatory function after being recognized by m6A reading proteins. In this study, we found that the expression of m6A reader IGF2BP1 decreased in benzene poisoning workers and in 20 µM benzene metabolite 1,4-BQ-treated AHH-1 cells. Further overexpression of IGF2BP1 in mice alleviated 50 ppm benzene-induced hematopoietic damage, suggesting that IGF2BP1 plays a critical role in benzene hematotoxicity. Next, we examined transcriptome-wide m6A methylation in vitro to search for target genes of IGF2BP1. We found that benzene metabolite 1,4-BQ treatment altered the m6A methylation levels of various genes. The comprehensive analysis of mRNA expression and m6A methylation uncovered that the hypomethylated Ribosomal Protein L36 (RPL36) and its consequent reduced expression impaired cell proliferation. Mechanically, m6A modification reduced RNA stability to down-regulate RPL36 expression. Moreover, overexpression of IGF2BP1 relieved RPL36 reduction and cell proliferation inhibition caused by benzene in vitro and in vivo by directly binding with RPL36 mRNA. In conclusion, the m6A reader IGF2BP1 attenuates the stability of RPL36 and cell proliferation to mediate benzene hematotoxicity by recognizing m6A modification. IGF2BP1 and RPL36 may be key molecules and potential therapeutic targets for benzene hematotoxicity.

Spinal infection after vertebral augmentation: a covert complication with serious havoc.

INTRODUCTION: Vertebral augmentation, including percutaneous vertebroplasty (PVP) or kyphoplasty (PKP), is the current least invasive surgical option and has been widely used to treat the painful osteoporotic vertebral compression fractures (OVCF). However, the postoperative infections could be life-threatening, even though they rarely occur. Our studies aim to clarify the causation and outcomes of spinal infections following augmentation and meanwhile to identify the risk factors. METHODS: A retrospective study was conducted on patients with OVCF who underwent PVP or PKP, and were subsequently admitted to our institution with postoperative spinal infection between January 2010 and December 2022. A total of 33 patients were finally included. RESULTS: The rate of spinal infection after augmentation in our single institute was 0.05% (2/3893). In addition to these 2 patients, the remaining 31 were referred from other hospitals. All 33 patients exhibited elevated inflammatory parameters, 14 patients presented with fever, and 9 patients experienced neurological deficits. Additionally, 29 patients had comorbidity and risk factors. Pathogens were identified in 26 patients, while only 7 patients were examined as culture negative. 27 patients underwent revision surgery and 6 patients only received conservative therapy. Anterior surgery was performed in 2 patients, while posterior surgery was performed in 20 patients. A combined anterior-posterior surgery was performed in 5 patients. At the final follow-up, 18 patients had unrestricted mobility, 10 patients required assistance from crutches or a walker for ambulation, 4 patients needed a wheelchair, and 1 patients died after revision surgery. CONCLUSIONS: Spinal infection after vertebral augmentation is rare, but it cannot be ignored. Surgeons should make every effort to detect the potential preoperative spondylitis or discitis. Once postoperative spinal infection is confirmed, a prompt intravenous antibiotic therapy is warranted. If medication therapy fails, revision surgery involving debridement and spinal reconstruction should be considered.

A Journey of Challenges and Victories: A Bibliometric Worldview of Nanomedicine since the 21st Century.

Nanotechnology profoundly affects the advancement of medicine. Limitations in diagnosing and treating cancer and chronic diseases promote the growth of nanomedicine. However, there are very few analytical and descriptive studies regarding the trajectory of nanomedicine, key research powers, present research landscape, focal investigative points, and future outlooks. Herein, articles and reviews published in the Science Citation Index Expanded of Web of Science Core Collection from first January 2000 to 18th July 2023 are analyzed. Herein, a bibliometric visualization of publication trends, countries/regions, institutions, journals, research categories, themes, references, and keywords is produced and elaborated. Nanomedicine-related academic output is increasing since the COVID-19 pandemic, solidifying the uneven global distribution of research performance. While China leads in terms of publication quantity and has numerous highly productive institutions, the USA has advantages in academic impact, commercialization, and industrial value. Nanomedicine integrates with other disciplines, establishing interdisciplinary platforms, in which drug delivery and nanoparticles remain focal points. Current research focuses on integrating nanomedicine and cell ferroptosis induction in cancer immunotherapy. The keyword "burst testing" identifies promising research directions, including immunogenic cell death, chemodynamic therapy, tumor microenvironment, immunotherapy, and extracellular vesicles. The prospects, major challenges, and barriers to addressing these directions are discussed.

2A2 protein of DHAV-1 induces duck embryo fibroblasts gasdermin E-mediated pyroptosis.

The duck hepatitis A virus type 1 (DHAV-1) causes rapid death in ducklings by triggering a severe cytokine storm. Pyroptosis is an inflammatory form of programmed cell death that is directly related to an increase in pro-inflammatory cytokine levels. Only a few studies have explored the mechanisms underlying pyroptosis in virus-infected avian cells. In this study, we established an avian infection model in vitro by infecting duck embryo fibroblasts (DEFs) with the virulent DHAV-1 LY0801 strain. DHAV-1 infection induced pyroptosis in the DEFs by activating gasdermin E (GSDME) protein via caspase-3-mediated cleavage. The genes encoding the different structural and non-structural DHAV-1 proteins were cloned into eukaryotic expression plasmids, and the 2A2 protein was identified as the key protein involved in pyroptosis. The HPLC-tandem mass spectrometry (HPLC-MS/MS) and co-immunoprecipitation (Co-IP) analysis established that DHAV-1 2A2 directly interacted with the mitochondrial anti-viral signaling protein (MAVS) both intracellularly and in vitro. Furthermore, we got the results that N-terminal 1-130 aa of 2A2 was involved in the interaction with MAVS and the C-terminal TM domain of MAVS is necessary for the interaction with 2A2 by Co-IP analysis. To our knowledge, this is the first study to reveal that DHAV-1 protein interacts with host proteins to induce pyroptosis. Our findings provide new insights into the molecular pathogenesis of DHAV-1 infection, and a scientific basis for the prevention and treatment of duck viral hepatitis.

The lncRNA GAS5 upregulates ANXA2 to mediate the macrophage inflammatory response during atherosclerosis development.

Inflammatory macrophages play a crucial role in atherosclerosis development. The long non-coding RNA growth arrest-specific 5 (GAS5) regulates THP-1 macrophage inflammation by sponging microRNAs. The purpose of this study was to investigate the regulatory mechanism of GAS5 in atherosclerosis development. GSE40231, GSE21545, and GSE28829 datasets from the Gene Expression Omnibus database were integrated after adjusting for batch effect. Differential analysis was performed on the integrated dataset and validated using the Genotype-Tissue Expression and GSE57691 datasets. Potential biological functions of GAS5 and annexin A2 (ANXA2) were identified using gene set enrichment analysis (GSEA). ssGSEA, CIBERSORTx, and ImmuCellAI algorithms were used to identify immune infiltration in plaque samples. GAS5 and ANXA2 expression levels in RAW264.7 cells treated with oxidized low-density lipoprotein (ox-LDL) were measured by qRT-PCR and Western blot. Small interfering and short hairpin RNA were used to silence GAS5 expression. Plasmids of ANXA2 were used to establish ANXA2 overexpression. Apoptosis and inflammatory markers in macrophages were detected by Western blot. Aortic samples from APOE-/- mice were collected to validate the expression of GAS5 and ANXA2. GAS5 expression was significantly increased during atherosclerosis. GAS5 expression was positively correlated with macrophage activation and ANXA2 expression in plaques. Furthermore, ANXA2 upregulation was also related to the activation of macrophage. GSEA indicated similar biological functions for GAS5 and ANXA2 in plaques. Moreover, in vitro experiments showed that both GAS5 and ANXA2 contributed to macrophage apoptosis and inflammation. Rescue assays revealed that the inflammatory effects of GAS5 on macrophages were ANXA2-dependent. In vivo experiments confirmed the highly expression of Gas5 and Anxa2 in the plaque group. We identified the atherogenic roles of GAS5 and ANXA2 in the inflammatory response of macrophages. The inflammatory response in ox-LDL-treated macrophages was found to be mediated by GAS5-ANXA2 regulation, opening new avenues for atherosclerosis therapy.

The single-cell evolution trajectory presented different hypoxia heterogeneity to reveal the carcinogenesis of genes in clear cell renal cell carcinoma: Based on multiple omics and real experimental verification.

INTRODUCTION: Clear cell renal cell carcinoma (ccRCC) is the most prevalent and aggressive subtype of renal cell carcinoma, originating from renal tubular epithelial cells in the kidney. Hypoxia proves to be a feature commonly observed in solid tumors, leading to increased resistance to treatment and tumor progression. METHODS: scRNA-seq data were procured from GSE159115 data set. We utilized UMAP and NMF algorithm for clustering and dimensionality reduction. The FindAllMarkers function was used to compare various groups and identify potential hypoxia marker genes. A series of in vitro experiments, including CFA, flow cytometry targeting cell cycle, CCK-8, and EDU, was applied to investigate how ANGPTL4 regulated the ccRCC progression. Two cell lines of ccRCC cells, 786-O and Caki, were used for si-ANGPTL4 transfection. RESULTS: We annotated a total of a total of 6 cell clusters, namely ccRCC malignant cells, T cells, endothelial cells, myeloid cells, smooth muscle cells, and B cells. We observed higher levels of hypoxia-score in the ccRCC malignant cells, while lowest hypoxia-score in T and B cells. We detected multiple hypoxia-related subclusters of TME cells in ccRCC, among which S100A4 CD8+ T cells and nonhypoxia CD8+ T cells were found with a marked elevation of T cell inhibitory gene score. We identified that ANGPTL4+ endothelial cells might function as an integrative role in tumor angiogenesis. Multiple TME subclusters showed high potency in stratification of the prognosis of ccRCC patients. Moreover, by a series of in vitro experiment, we found ANGPTL4 regulated the ccRCC cell proliferation, probably through ERK/P38 pathway. CONCLUSION: We discerned multiple hypoxia-related subclusters of TME cells in ccRCC, which displayed distinct functional features and great potency in predicting prognosis of ccRCC patients. We identified the role of ANGPTL4 in regulating ccRCC proliferation via ERK/p38 pathway.

Comparative efficacy and safety of different doses of ponatinib versus other tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia: a systematic review and network meta-analysis.

OBJECTIVE: Ponatinib was recommended with caution because of its high risk of causing arterial occlusion events in chronic myeloid leukemia (CML) patients. The purpose of this study was to understand the efficacy and safety of different doses of ponatinib in the treatment of CML, and to compare it with other tyrosine kinase inhibitors (TKIs). METHOD: A network meta-analysis (NMA) was conducted by searching randomized controlled trials (RCTs) of ponatinib in patients with CML to compare the efficacy and safety of ponatinib, and ranked under the cumulative ranking curve (SUCRA) to evaluate the optimal treatment. RESULTS: A total of seven articles with eight RCTs were included in this study, involving 45 mg, 30 mg and 15 mg ponatinib doses. Seven outcome indexes were analyzed. The results showed that 45 mg ponatinib was superior to other doses of ponatinib and other TKIs in CCyR, MCyR and CHR, but the incidence of SAEs and AOEs was significantly higher than other treatment regimens. CONCLUSION: Ponatinib, with an initial dosage of 45 mg and a gradual reduction to 15 mg, may be a more favorable option for patients with CML at all stages of disease progression, rather than just those in the chronic phase of CML.

Profiling cardiomyocytes at single cell resolution reveals COX7B could be a potential target for attenuating heart failure in cardiac hypertrophy.

Cardiac hypertrophy can develop to end-stage heart failure (HF), which inevitably leading to heart transplantation or death. Preserving cardiac function in cardiomyocytes (CMs) is essential for improving prognosis in hypertrophic cardiomyopathy (HCM) patients. Therefore, understanding transcriptomic heterogeneity of CMs in HCM would be indispensable to aid potential therapeutic targets investigation. We isolated primary CM from HCM patients who had extended septal myectomy, and obtained transcriptomes in 338 human primary CM with single-cell tagged reverse transcription (STRT-seq) approach. Our results revealed that CMs could be categorized into three subsets in nonfailing HCM heart: high energy synthesis cluster, high cellular metabolism cluster and intermediate cluster. The expression of electron transport chain (ETC) was up-regulated in larger-sized CMs from high energy synthesis cluster. Of note, we found the expression of Cytochrome c oxidase subunit 7B (COX7B), a subunit of Complex IV in ETC had trends of positively correlation with CMs size. Further, by assessing COX7B expression in HCM patients, we speculated that COX7B was compensatory up-regulated at early-stage but down-regulated in failing HCM heart. To test the hypothesis that COX7B might participate both in hypertrophy and HF progression, we used adeno associated virus 9 (AAV9) to mediate the expression of Cox7b in pressure overload-induced mice. Mice in vivo data supported that knockdown of Cox7b would accelerate HF and Cox7b overexpression could restore partial cardiac function in hypertrophy. Our result highlights targeting COX7B and preserving energy synthesis in hypertrophic CMs could be a promising translational direction for HF therapeutic strategy.

Effect of a 630 nm light on vasculogenic mimicry in A549 lung adenocarcinoma cells in vitro.

OBJECTIVE: The objective of this study was to investigate the effect of photodynamic therapy (PDT) on the formation of vasculogenic mimicry (VM) in the human lung adenocarcinoma A549 cell line in vitro. METHODS: The participants were divided into a blank control group, a photosensitizer group, a light group, and a PDT group. Cells from each group were cultured in three dimensions using Matrigel, and vasculogenic mimicry generation was observed microscopically. Periodic Acid-Schiff (PAS) staining was used to verify the vasculogenic mimicry structure. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was used to detect the expression levels of cellular osteopontin (OPN) and vascular endothelial growth factor (VEGF) mRNA. Western blotting was used to detect the expression levels of cellular OPN and VEGF protein. RESULTS: A549 cells cultured on Matrigel for about six hours revealed VM on PAS staining, and the number of formations was significantly reduced in the PDT group compared with other groups (P < 0.05). The RT-PCR results showed that the PDT group downregulated OPN and VEGF mRNA expression compared with each control group (P < 0.05). Western blot results showed that OPN and VEGF protein expression was downregulated in the PDT group compared with each control group (P < 0.05). The results of RT-PCR showed that the expression of OPN and VEGF mRNA was downregulated in the PDT group compared with each control group (P < 0.05). The results of Western blotting showed that the expression of OPN and VEGF was downregulated in the protein PDT group compared with each control group (P < 0.001). CONCLUSION: Photodynamic therapy significantly inhibited the formation of vasculogenic mimicry in human lung adenocarcinoma A549 cells in vitro and downregulated the expression of OPN, VEGF mRNA, and protein levels.