Prenylated indole diketopiperazine alkaloids as phosphatase inhibitors from the marine-derived fungus Talaromyces purpureogenus.

Six previously undescribed prenylated indole diketopiperazine alkaloids, talaromyines A-F (1-6), were isolated from the marine-derived fungus Talaromyces purpureogenus SCSIO 41517. Their structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic data including NMR, HR-ESI-MS, and electronic circular dichroism calculations, together with chemical analysis of hydrolysates. Compounds 1-5 represent the first example of spirocyclic indole diketopiperazines biosynthesized from the condensation of L-tryptophan and L-alanine. Compounds 2 and 4-5 showed selective inhibitory activities against phosphatases TCPTP and MEG2 with IC50 value of 17.9-29.7 µM, respectively. Compounds 4-5 exhibited mild cytotoxic activities against two human cancer cell lines H1975 and HepG-2.

New Antibacterial Peptaibiotics against Plant and Fish Pathogens from the Deep-Sea-Derived Fungus Simplicillium obclavatum EIODSF 020.

Bacterial diseases could severely harm agricultural production. To develop new antibacterial agents, the secondary metabolites of a deep-sea-derived fungus Simplicillium obclavatum EIODSF 020 with antibacterial activities against plant and fish pathogens were investigated by a bioassay-guided approach, which led to the isolation of 11 new peptaibiotics, simplicpeptaibs A-K (1-11). They contain 16-19 residues, including ß-alanine, tyrosine, or tyrosine O-sulfate, that were rarely present in peptaibiotics. Their structures were elucidated by spectroscopic analyses (NMR, HRMS, HRMS2, and ECD) and Marfey's method. The primary and secondary structures of novel sulfated peptaibiotic 9 were reconfirmed by single-crystal X-ray diffraction analysis. Genome sequencing of S. obclavatum EIODSF 020 allowed the detection of a gene cluster encoding two individual NRPSs (totally containing 19 modules) that was closely related to simplicpeptaib biosynthesis. Antibacterial investigations of 1-11 together with the previously isolated linear and cyclic peptides from this strain suggested the antibacterial property of this fungus was attributed to the peptaibiotics and cyclic lipopeptides. Among them, compounds 4, 6, 7, and 9 showed significant activity against the tobacco pathogen Ralstonia solanacearum or tilapia pathogens Streptococcus iniae and Streptococcus agalactiae. The antibacterial activity of 6 against R. solanacearum could be enhanced by the addition of 1% NaCl. The structure-bioactivity relationship of simplicpeptaibs was discussed.

Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma.

Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24-74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43-79%) and 68% (95%CI, 47-84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45-83%) and 86% (95%CI, 63-95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

[A case of sudden hearing loss combined with familial hyperlipidemia].

Hyperlipidemia is characterized by elevated levels of blood lipids. The clinical manifestations are mainly atherosclerosis caused by the deposition of lipids in the vascular endothelium. The link between abnormal lipid metabolism and sudden hearing loss remains unclear. This article presents a case study of sudden hearing loss accompanied by familial hyperlipidemia. Pure tone audiometry indicated intermediate frequency hearing loss in one ear. Laboratory tests showed abnormal lipid metabolism, and genetic examination identified a heterozygous mutation in theAPOA5 gene. Diagnosis: Sudden hearing loss; hypercholesterolemia. The patient responded well to pharmacological treatment. This paper aims to analyze and discuss thepotential connection between abnormal lipid metabolism and sudden hearing loss.

NOTCH3 inhibits transcription factor ZEB1 expression and metastasis of breast cancer cells via transcriptionally upregulating miR-223.

Background: NOTCH receptor 3 (NOTCH3) and zinc finger E-box binding protein 1 (ZEB1) play important roles in breast cancer respectively. NOTCH3 maintains the luminal phenotype and inhibits epithelial-mesenchymal transition (EMT) in breast cancer, while ZEB1 and NOTCH3 have the opposite effects. Methods: Public databases were used to predict the expression of NOTCH3 and ZEB1 in breast cancer cell lines. The regulatory effect of NOTCH3 on ZEB1 expression was verified by western blot and RT-PCR. MiRNAs regulating ZEB1 expression were identified by using multiple databases and confirmed by reporter gene experiments. Cellular function experiments were conducted to evaluate the role of NOTCH3/miR-223/ZEB1 in the proliferation and invasion of triple-negative breast cancer (TNBC). Results: NOTCH3 and ZEB1 have opposite expression pattern in MCF-7 cells that over-express LncATB or were incubated in TGF-ß to induce EMT. Western blotting and RT-PCR showed that NOTCH3 could regulate expression of ZEB1. MiR-223 inhibited the proliferation and invasion of breast cancer cells via down-regulating the expression of ZEB1. NOTCH3 inhibited the proliferation and invasion of breast cancer cells via up-regulating the expression of miR-223. Clinically, high expression of NOTCH3, miR-223 or low expression of ZEB1 were related to good prognosis of breast cancer patients. Conclusion: The current study reports a novel NOTCH3/miR-223/ZEB1 axis, which can inhibit the proliferation and invasion of breast cancer cells, and may serve as a potential biomarker for the prognosis of breast cancer.

Design, Synthesis, and Antitumor Activity Evaluation of Artemisinin Bivalent Ligands.

Five artemisinin bivalent ligands molecules 4a-4e were designed, synthesized, and confirmed by 1H NMR, 13C NMR, and low-resolution mass spectrometry, and the bioactivities of the target compounds were investigated against four human tumor cell lines in vitro, including BGC-823, HepG-2, MCF-7, and HCT-116. The results showed 4a, 4d, and 4e exhibited significantly tumor cell inhibitory activity compared with the artemisinin and dihydroartemisinin; compound 4e has good biological activity inhibiting BGC-823 with an IC50 value of 8.30 µmol/L. Then, the good correlations with biological results were validated by molecular docking through the established bivalent ligands multi-target model, which showed that 4e could bind well with the antitumor protein MMP-9.

The multiple reference range of mean uterine artery pulsatility index for natural and in vitro fertilization singletons during 11-14 gestational weeks.

Background: Ultrasonography of the uterine artery (UtA) in the first and second trimesters of pregnancy can assess uterine-placental blood perfusion and guide early clinical prevention. Establishing normal ranges of the UtA pulsatility index (UtA-PI) at 11-14 weeks of pregnancy is helpful for the early identification of high-risk pregnant women and improving the prognosis. This study aimed to establish a reference range of UtA-PI based on crown-rump length (CRL) for spontaneous and in vitro fertilization (IVF) singleton pregnancy during 11-14 weeks, respectively. Methods: A prospective study was performed at Peking Union Medical College Hospital. Healthy, low-risk women with a singleton pregnancy at 11-14 gestational weeks were consecutively recruited for this study from December 2017 to December 2020. All participants underwent routine prenatal ultrasound examination. The CRL of the fetus and the UtA-PI were measured in both uterine arteries, and average values were calculated. The LMS method was used to fit the percentile (P)5, P10, P25, P50, P75, P90, and P95 curves of the UtA-PI value of spontaneous and IVF singleton pregnancy with CRL changes, respectively. Results: A total of 1,962 pregnant women with normal fetuses were included in this study, including 1,792 pregnancies conceived naturally and 170 IVF fetuses. The UtA-PI reference range in the spontaneous pregnancy group was consistently higher than that in the IVF group during 11-14 weeks, and showed a statistically significant difference in UtA-PI for spontaneous and IVF pregnancies (P<0.001). According to the LMS method, each percentile curve of UtA-PI decreased with the increase of CRL in both the natural pregnancy group and the IVF group. The P95 range of UtA-PI for pregnant women with naturally conceived and IVF pregnancy was 2.74 to 2.11 and 2.50 to 1.94, respectively. The overall change of UtA-PI differentials of the two groups showed a downward trend and decreased slightly with the increase of CRL. Conclusions: This study provided a single-center, large sample of data and constructed a CRL-based reference value of UtA-PI for spontaneous and IVF singleton pregnancy, which provides a reliable basis for early UtA evaluation and early clinical decision-making during 11-14 gestational weeks.

Development of novel quinoline-NO donor hybrids inducing human breast cancer cells apoptosis via inhibition of topoisomerase I.

A number of NO-releasing quinoline derivatives have been designed and synthesized by introducing NO donor to quinoline carboxylic acid fragment. The anti-proliferation of all target compounds was evaluated against human cancer cell lines (HCT-116, MCF-7, and A549), MCF-7/ADR and normal cell (MCF-10A). Most compounds showed cytotoxic activity on cancer cells and drug-resistant cells with IC50 values in the range of 0.62-5.51 µM. Importantly, these compounds showed low toxicity to normal cells (4.21-34.08 µM). Further mechanism studies showed that the most potent compound 9 could release high concentration of NO and inhibit the activity of topoisomerase I. In addition, 9 regulated apoptosis-related proteins, generated ROS and blocked MCF-7 cells in G2/M phase to induce cell apoptosis. Furthermore, the P-gp-mediated transport was also influenced by 9. And 9 could significantly inhibit the growth of tumor in vivo without observable organ-related toxicities. Overall, as a novel NO-releasing quinoline derivative, 9 was worthy for further in-depth study.

Dexmedetomidine alleviates ferroptosis following hepatic ischemia-reperfusion injury by upregulating Nrf2/GPx4-dependent antioxidant responses.

Hepatic ischemia-reperfusion injury (HIRI) adversely affects liver transplant and resection outcomes. Recently, ferroptosis has been associated with HIRI. Dexmedetomidine (Dex), a potent sedative with anti-inflammatory, antioxidant, and anti-apoptotic properties, protects organs from hypoxic or ischemia-reperfusion (I/R) injuries. However, the mechanisms underlying this protective effect against I/R-induced liver injury remain unclear. This study evaluated the effect of Dex on HIRI in mouse models and the oxygen-glucose deprivation/reperfusion (OGD/R) AML12 cell model. We examined ferroptosis-related markers, including Fe2+ levels, reactive oxygen species (ROS) content, mitochondrial morphology, GPX4 protein expression, 4-hydroxynonenal (4-HNE), and Nrf2. The Nrf2 inhibitor ML385 was used in combination with Dex to treat HIRI mice and OGD/R-induced cellular models to explore the pathways by which Dex counteracts ferroptosis. Our results showed that Dex treatment significantly ameliorated OGD/R-induced ferroptosis in AML12 cells, including reduced Fe2+, ROS, malondialdehyde (MDA), and 4-HNE levels. Dex also ameliorated liver tissue damage and reduced serum AST, ALT, and inflammatory factor levels in HIRI mice. Additionally, Dex increased the levels of GSH, an antioxidative stress marker, and GPX4 expression in HIRI mice. Mechanistically, Nrf2 expression and nuclear translocation were significantly inhibited in both HIRI mice and OGD/R-treated AML12 cells. Dex treatment also restored the I/R-induced inhibition of Nrf2 expression and nuclear translocation. ML385 significantly inhibited Dex-promoted Nrf2 nuclear aggregation with Gpx4 protein expression, hindering the efficacy of Dex. In conclusion, Dex ameliorates ferroptosis in HIRI by positively regulating the Nrf2/GPx4 axis, potentially presenting a therapeutic avenue for addressing HIRI.

[Characteristics of gut microbiome communities in the invasive African giant snail under urbanization gradient]. / åŸŽå¸‚åŒ–æ¢¯åº¦ä¸‹å ¥ä¾µç”Ÿç‰©éžæ´²å¤§èœ—ç‰›è‚ é“å¾®ç”Ÿç‰©ç¾¤è½ç‰¹å¾.

To investigate the diversity and community structure of gut microbiome of the invasive species, Achatina fulica, along an urbanization gradient, we collected 30 A. fulica samples from five parks in the urban, suburban, and rural areas of Xiamen City. Using full-length 16S rRNA gene sequencing performed by the third generation PacBio sequencing platform, we analyzed the community characteristics of gut microbiome and soil microbiome in different habitats. We found a significant disparity between the composition of gut microbiome of A. fulica and that of the soil microbiome in their habitats. Furthermore, the gut microbiome of A. fulica were more sensitive to urbanization. The microbial α-diversity indices (Sobs, Chao, Shannon indices) in the soil of A. fulica habitats were consistently higher than those within their guts. Despite the similar ß-diversity indices of microbial communities in urban, suburban, and rural soils, we found a significant discrepancy in gut microbiome composition. Urbanization significantly influenced A. fulica gut microbiome composition. Gut microbiome of A. fulica in urban and suburban regions primarily consisted of Enterobacteriaceae, Xanthomonadaceae, and Mycoplasmataceae, while that in rural areas chiefly composed of Streptococcaceae and Paenibacillaceae. The diversity and abundance of potential human pathogenic bacteria within the gut microbiome of A. fulica significantly increased in urban environments, suggesting that urbanization escalated the risk of A. fulica transmitting potential pathogens.

Mir-142-5p inhibits the osteogenic differentiation of bone marrow mesenchymal stem cells by targeting Lhx8.

Osteoporosis (OP), a common systemic bone metabolism disease with a high incidence rate, is a serious health risk factor. Osteogenic differentiation balance is regulated by bone marrow mesenchymal stem cells (BMSCs) and plays a key role in OP occurrence and progression. Although, LIM homeobox 8 (Lhx8) has been identified to affect BMSCs osteogenic differentiation, its roles in OP and the associated mechanism remains unclear. Here, we aimed to elucidate the role and mechanism of Lhx8 in the osteogenic differentiation of BMSCs. BMSCs isolated from wild type and OP Sprague-Dawley rats were cultured and confirmed via flow cytometry and microscopy. Based on dual-luciferase reporter assay, BMSCs were transfected with miR-142-5p mimics and miR-NC (negative control). Real-time quantitative reverse transcription polymerase chain reaction and Western blot analyses were performed to determine the role of Lhx8 in BMSCs osteogenic differentiation. Lhx8 expression was significantly reduced in OP, whereas that of miR-142-5p, a possible Lhx8 regulator, was significantly upregulated. Dual-luciferase reporter assay demonstrated that miR-142-5p exerted a direct targeted regulatory effect on Lhx8. Moreover, miR-142-5p mimics significantly inhibited BMSCs osteogenic differentiation as well as Lhx8 expression in vitro, indicating that miR-142-5p may be involved in BMSCs osteogenic differentiation via Lhx8 expression regulation and may serve as a potential diagnostic target for OP. Overall, these findings indicated that miR-142-5p inhibits BMSCs osteogenic differentiation by suppressing Lhx8. These may serve as a foundation for further studies on OP treatment based on miR-142-5p targeting.

Contrast-Enhanced Ultrasound Liver Imaging Reporting and Data System in Hepatocellular Carcinoma ≤5 cm: Biological Characteristics and Patient Outcomes.

Introduction: The present study aimed to evaluate the influence of biological characteristics of hepatocellular carcinoma (HCC) on the Liver Imaging Reporting and Data System (LI-RADS) v2017 category of contrast-enhanced ultrasound (CEUS) in patients with high risk and compare the outcomes among different categories after radical resection. Methods: Between June 2017 and December 2020, standardized CEUS data of liver nodules were prospectively collected from multiple centers across China. We conducted a retrospective analysis of the prospectively collected data on HCCs measuring no more than 5 cm, as diagnosed by pathology. LI-RADS categories were assigned after thorough evaluation of CEUS features. Then, CEUS LI-RADS categories and major features were compared in different differentiation, Ki-67, and microvascular invasion (MVI) statuses. Differences in recurrence-free survival (RFS) among different LI-RADS categories were further analyzed. Results: A total of 293 HCC nodules in 293 patients were included. This study revealed significant differences in the CEUS LI-RADS category of HCCs among differentiation (p < 0.001) and levels of Ki-67 (p = 0.01) and that poor differentiation (32.7% in LR-M, 12% in LR-5, and 6.2% in LR-4) (p < 0.001) and high level of Ki-67 (median value 30%) were more frequently classified into the LR-M category, whereas well differentiation (37.5% in LR-4, 15.1% in LR-5, and 11.5% in LR-M) and low levels of Ki-67 (median value 11%) were more frequently classified into the LR-4 category. No significant differences were found between MVI and CEUS LI-RADS categories (p > 0.05). With a median follow-up of 23 months, HCCs assigned to different CEUS LI-RADS classes showed no significant differences in RFS after resection. Conclusions: Biological characteristics of HCC, including differentiation and level of Ki-67 expression, could influence major features of CEUS and impact the CEUS LI-RADS category. HCCs in different CEUS LI-RADS categories showed no significant differences in RFS after resection.

Study on the postoperative visual function recovery of children with concomitant exotropia based on an augmented reality plasticity model.

Objective: This study aimed to investigate the clinical application effect of an augmented reality (AR) plasticity model on the postoperative visual function recovery of children with concomitant exotropia. Methods: Between September 2019 and October 2021, 28 patients with concomitant exotropia who visited Shenzhen Children's Hospital (9 male and 19 female) were enrolled in this study. The average age of the patients was 6.4 ± 1.8 years. Postoperative rehabilitation training was conducted using a personalized AR binocular visual perception plasticity model developed based on the patient's examination results. After 1 month, 3 months, and 6 months of training, the patients returned to the hospital for examinations of perceptual eye position, static zero-order stereopsis, dynamic first-order fine stereopsis, and dynamic second-order coarse stereopsis to compare the changes in eye position control and stereovision function. Results: After 6 months of eye position training, the horizontal perception eye position of the 28 patients was significantly lower than that before training. The difference in eye position at the first and third months compared with that before training was not statistically significant (1st month: z = -2.255, p = 0.024 > 0.017; 3rd month: z = -2.277, p = 0.023 > 0.017; 6th month: z = -3.051, p = 0.002 < 0.017). The difference in vertical perceptual eye position after training compared with that before training was not statistically significant (1st month: z = -0.252, p = 0.801 > 0.017; 3rd month: z = -1.189, p = 0.234 > 0.017; 6th month: z = -2.225, p = 0.026 > 0.017). The difference in 0.8-m static zero-order stereopsis before and after training was not statistically significant (1st month: z = -2.111, p = 0.035 > 0.017; 3rd month: z = -1.097, p = 0.273 > 0.017; 6th month: z = -1.653, p = 0.098 > 0.017). The 1.5-m static zero-order stereopsis was improved after 1 month, 3 months, and 6 months of training compared with that before training (1st month: z = -3.134, p = 0.002 < 0.017; 3rd month: z = -2.835, p = 0.005 < 0.017; 6th month: z = -3.096, p = 0.002 < 0.017). Dynamic first-order fine stereopsis and dynamic second-order coarse stereopsis were measured in the 28 patients before and after training. Patients 1 and 18 had no dynamic first-order fine stereopsis before training, but both regained dynamic stereopsis after 1 month, 3 months, and 6 months of training. Patient 16 had no dynamic first-order fine stereopsis or dynamic second-order coarse stereopsis before training, but first-order and second-order stereopsis had been reconstructed after 1 month, 3 months, and 6 months of training. Conclusion: Concomitant exotropia surgery improved the basic problem of eye position at the ocular muscle level, but the patient's perceptual eye position and visual function defects at the brain visual level remained. This might partly explain the poor postoperative clinical effect. The AR plasticity model can improve patients' horizontal perceptual eye position and multi-dimensional stereoscopic function, and its clinical effect warrants further study.

BOLA3 and NFU1 link mitoribosome iron-sulfur cluster assembly to multiple mitochondrial dysfunctions syndrome.

The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play a structural role during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We find that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3 node. Additionally, the assembly of the small subunit depends on the mitoribosome biogenesis factor METTL17, recently reported containing a [4Fe-4S] cluster, which we propose is inserted via the ISCA1-NFU1 node. Consistently, fibroblasts from subjects suffering from 'multiple mitochondrial dysfunction' syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, one of the mitoribosomal [2Fe-2S] clusters and the [4Fe-4S] cluster in mitoribosome assembly factor METTL17 sense changes in the redox environment, thus providing a way to regulate organellar protein synthesis accordingly.

GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis.

Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.

Risk factors for mitral valve dysfunction, reoperation and death following repair of the primary mitral valve disease in children.

Background: After primary mitral valve (MV) repair, residual mitral valve regurgitation (MR) and recurred mitral valve stenosis (MS) are the principal occurrences. This study's purpose is to identify the risk factors of MV dysfunction, reoperation and death following repair of primary MV diseases. Methods: We retrospectively reviewed 98 patients (47 males and 51 females) with primary MV diseases between January 2013 and December 2021. The median age was 34 months [interquartile range (IQR), 11.4-59] for male and 24 months (IQR, 7.35-72) for female. The left ventricular ejection fraction (LVEF), the left ventricular end-diastolic volume index (LVEDVI) and left ventricular end-systolic volume index (LVESVI) were assessed to evaluate patient's left ventricular function. Risk factors that increased the likelihood of MV dysfunction, reoperation and death after surgery were investigated. Results: During the 23.5 months (IQR, 9-44.5) of follow-up, 5 (5.1%) patients died, including one early death and two late deaths (n=3; 3.9%) in the MR group and one early death and one late death (n=2; 9.1%) in the MS group. Seven (9.2%) patients in the primary MR disease group and 2 (9.1%) patients in the primary MS disease group required a second MV operation for a total reoperation rate of 9.2% (9/98). As of the most recent follow-up, 34 patients experienced MV dysfunction. No significant difference was recorded between primary MR and MS disease groups in Kaplan-Meier freedom from MV dysfunction and reoperation. Mixed MV pathology (P=0.014) acted as an independent risk factor for MV dysfunction, and ≥ moderate MR at 24 h after first surgery (P=0.014) an independent risk factor for MV reoperation. Double-orifice MV technique (P=0.002), MV reoperation (P=0.023) and severe MR at 24 h after first surgery (P=0.028) were independent risk factors for death. Conclusions: The Kaplan-Meier freedom from MV dysfunction and reoperation were comparable between primary MR and MS disease groups. A high probability of MV dysfunction was predicted due to the mixed MV pathology. Patients with ≥ moderate MR at 24 h after first surgery had a higher risk of MV reoperation. Double-orifice MV technique, MV reoperation and severe MR at 24 h after first surgery had a higher risk for death.

Monopolar spindle 1 contributes to tamoxifen resistance in breast cancer through phosphorylation of estrogen receptor α.

PURPOSE: The overexpression of mitotic kinase monopolar spindle 1 (Mps1) has been identified in many tumor types, and targeting Mps1 for tumor therapy has shown great promise in multiple preclinical cancer models. However, the role played by Mps1 in tamoxifen (TAM) resistance in breast cancer has never been reported. METHODS: The sensitivity of breast cancer cells to tamoxifen was analysed in colony formation assays and wound healing assays. Enhanced transactivational activity of estrogen receptor α (ERα) led by Mps1 overexpression was determined by luciferase assays. The interaction between Mps1 and ERα was verified by co-immunoprecipitation and proximity ligation assay. Phosphorylation of ERα by Mps1 was detected by in vitro kinase assay and such phosphorylation process in vivo was proven by co-immunoprecipitation. The potential phosphorylation site(s) of ERα were analyzed by mass spectrometry. RESULTS: Mps1 determines the sensitivity of breast cancer cells to tamoxifen treatment. Mps1 overexpression rendered breast cancer cells more resistant to tamoxifen, while an Mps1 inhibitor or siMps1 oligos enabled cancer cells to overcome tamoxifen resistance. Mechanistically, Mps1 interacted with estrogen receptor α and stimulated its transactivational activity in a kinase activity-dependent manner. Mps1 was critical for ERα phosphorylation at Thr224 amino acid site. Importantly, Mps1 failed to enhance the transactivational activity of the ERα-T224A mutant. CONCLUSION: Mps1 contributes to tamoxifen resistance in breast cancer and is a potential therapeutic that can overcome tamoxifen resistance in breast cancer.

Elastic stable intramedullary nail fixation versus submuscular plate fixation of pediatric femur shaft fractures in school age patients: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Studies of clinical outcomes that compare the elastic stable intramedullary nail (ESIN) with the submuscular plate (SMP) were controversial. The meta-analysis was performed to summarize existing evidence, aiming to determine whether ESIN was superior to SMP in pediatric femur shaft fractures. METHODS: Search strategies followed the recommendations of the Cochrane collaboration. Electronic searches such as PubMed, Embase, Web of Science, Cochrane were systematically searched for publications concerning ESIN and SMP from the inception date to March 2023. Two investigators independently searched, screened, and reviewed the full text of the article. Disagreements generated throughout the process were resolved by consensus, and if divergences remain, they were arbitrated by a third author. RESULTS: This study included 8 articles, comprising a total of 561 patients with a similar baseline. Compared to the SMP, the ESIN had shorter operation time (mean difference = -16.16; 95% CI = -22.83 to -9.48, P < .00001), and less intraoperative blood loss (mean difference = -53.62; 95% CI = -58.89 to -48.36, P < .00001), but had a higher incidence of implant irritation (odds ratio [OR] = 6.49; 95% CI = 3.01 to 13.98, P < .0001), lower limb malalignment (OR = 2.60; 95% CI = 1.12 to 6.04, P = .96) and overall complications(OR = 4.14; 95% CI = 2.51 to 6.84, P < .0001). And there was no significant difference in radiation time, length of hospital stay, limb length discrepancy, infection rate, delayed union rate and unplanned revised surgery rate (P > .05). CONCLUSIONS: Compared to the SMP, the ESIN offers shorter operative time, and less blood loss. However, the SMP is superior to ESINs in complication rates, especially regarding implant irritation and malalignment. Both methods could achieve excellent satisfactory functional outcomes. Thus, the SMP is an alternative choice in the pediatric femur shaft fracture.

Real-World Clinical Characteristics, Management, and Outcomes of 44 Paediatric Patients with Hypopigmented Mycosis Fungoides.

Hypopigmented mycosis fungoides is a rare form of mycosis fungoides that is characterized by achromic lesions, early onset of disease, a predilection for darker skinned populations, and a predominance of CD8+ T cells. Due to the rarity and heterogeneous presentation of hypopigmented mycosis fungoides, there are no criteria that clearly define the clinical characteristics and treatment regimens for this condition. This retrospective study of 44 paediatric patients with hypopigmented mycosis fungoides aimed to summarize their epidemiological and clinical characteristics and assess the effectiveness and safety of different treatment regimens. Clinical manifestations were further classified into 3 morphological groups: hypopigmented lesions, papules overlying hypopigmented lesions, and erythematous plaques overlying hypopigmented lesions. In addition, the results of this study suggest that interferon alpha might be an effective and well-tolerated therapy that could shorten the treatment time to complete response compared with other treatments. Maintenance therapy and long-term follow-up reduced the recurrence rate.

c-JUN is a barrier in hESC to cardiomyocyte transition.

Loss of c-JUN leads to early mouse embryonic death, possibly because of a failure to develop a normal cardiac system. How c-JUN regulates human cardiomyocyte cell fate remains unknown. Here, we used the in vitro differentiation of human pluripotent stem cells into cardiomyocytes to study the role of c-JUN. Surprisingly, the knockout of c-JUN improved cardiomyocyte generation, as determined by the number of TNNT2+ cells. ATAC-seq data showed that the c-JUN defect led to increased chromatin accessibility on critical regulatory elements related to cardiomyocyte development. ChIP-seq data showed that the knockout c-JUN increased RBBP5 and SETD1B expression, leading to improved H3K4me3 deposition on key genes that regulate cardiogenesis. The c-JUN KO phenotype could be copied using the histone demethylase inhibitor CPI-455, which also up-regulated H3K4me3 levels and increased cardiomyocyte generation. Single-cell RNA-seq data defined three cell branches, and knockout c-JUN activated more regulons that are related to cardiogenesis. In summary, our data demonstrated that c-JUN could regulate cardiomyocyte cell fate by modulating H3K4me3 modification and chromatin accessibility and shed light on how c-JUN regulates heart development in humans.