Preclinical 3D model screening reveals digoxin as an effective therapy for a rare and aggressive type of endometrial cancer.

OBJECTIVE: Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. CONCLUSION: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.

Deep learning for multi-type infectious keratitis diagnosis: A nationwide, cross-sectional, multicenter study.

The main cause of corneal blindness worldwide is keratitis, especially the infectious form caused by bacteria, fungi, viruses, and Acanthamoeba. The key to effective management of infectious keratitis hinges on prompt and precise diagnosis. Nevertheless, the current gold standard, such as cultures of corneal scrapings, remains time-consuming and frequently yields false-negative results. Here, using 23,055 slit-lamp images collected from 12 clinical centers nationwide, this study constructed a clinically feasible deep learning system, DeepIK, that could emulate the diagnostic process of a human expert to identify and differentiate bacterial, fungal, viral, amebic, and noninfectious keratitis. DeepIK exhibited remarkable performance in internal, external, and prospective datasets (all areas under the receiver operating characteristic curves > 0.96) and outperformed three other state-of-the-art algorithms (DenseNet121, InceptionResNetV2, and Swin-Transformer). Our study indicates that DeepIK possesses the capability to assist ophthalmologists in accurately and swiftly identifying various infectious keratitis types from slit-lamp images, thereby facilitating timely and targeted treatment.

What is the impact of microbiota on dry eye: a literature review of the gut-eye axis.

BACKGROUND: Dry eye is a chronic and multifactorial ocular surface disease caused by tear film instability or imbalance in the microenvironment of the ocular surface. It can lead to various discomforts such as inflammation of the ocular surface and visual issues. However, the mechanism of dry eye is not clear, which results in dry eye being only relieved but not cured in clinical practice. Finding multiple environmental pathways for dry eye and exploring the pathogenesis of dry eye have become the focus of research. Studies have found that changes in microbiota may be related to the occurrence and development of dry eye disease. METHODS: Entered the keywords "Dry eye", "Microbiota", "Bacteria" through PUBMED, summarised the articles that meet the inclusion criteria and then filtered them while the publication time range of the literature was defined in the past 5 years, with a deadline of 2023.A total of 13 clinical and 1 animal-related research articles were screened out and included in the summary. RESULTS: Study found that different components of bacteria can induce ocular immune responses through different receptors present on the ocular surface, thereby leading to an imbalance in the ocular surface microenvironment. Changes in the ocular surface microbiota and gut microbiota were also found when dry eye syndrome occurs, including changes in diversity, an increase in pro-inflammatory bacteria, and a decrease in short-chain fatty acid-related bacterial genera that produce anti-inflammatory effects. Fecal microbiota transplantation or probiotic intervention can alleviate signs of inflammation on the ocular surface of dry eye animal models. CONCLUSIONS: By summarizing the changes in the ocular surface and intestinal microbiota when dry eye occurs, it is speculated and concluded that the intestine may affect the occurrence of eye diseases such as dry eye through several pathways and mechanisms, such as the occurrence of abnormal immune responses, microbiota metabolites- intervention of short-chain fatty acids, imbalance of pro-inflammatory and anti-inflammatory factors, and release of neurotransmitters, etc. Analyzing the correlation between the intestinal tract and the eyes from the perspective of microbiota can provide a theoretical basis and a new idea for relieving dry eyes in multiple ways in the future.

Advances in Host-Free White Organic Light-Emitting Diodes Utilizing Thermally Activated Delayed Fluorescence: A Comprehensive Review.

The ever-growing prominence and widespread acceptance of organic light-emitting diodes (OLEDs), particularly those employing thermally activated delayed fluorescence (TADF), have firmly established them as formidable contenders in the field of lighting technology. TADF enables achieving a 100% utilization rate and efficient luminescence through reverse intersystem crossing (RISC). However, the effectiveness of TADF-OLEDs is influenced by their high current density and limited device lifetime, which result in a significant reduction in efficiency. This comprehensive review introduces the TADF mechanism and provides a detailed overview of recent advancements in the development of host-free white OLEDs (WOLEDs) utilizing TADF. This review specifically scrutinizes advancements from three distinct perspectives: TADF fluorescence, TADF phosphorescence and all-TADF materials in host-free WOLEDs. By presenting the latest research findings, this review contributes to the understanding of the current state of host-free WOLEDs, employing TADF and underscoring promising avenues for future investigations. It aims to serve as a valuable resource for newcomers seeking an entry point into the field as well as for established members of the WOLEDs community, offering them insightful perspectives on imminent advancements.

Efficient Quasi-Two-Dimensional Perovskite Light-Emitting Diodes Achieved through the Passivation of Multi-Fluorine Phosphate Molecules.

The surface morphology of perovskite films significantly influences the performance of perovskite light-emitting diodes (PeLEDs). However, the thin perovskite thickness (~10 nm) results in low surface coverage on the substrate, limiting the improvement of photoelectric performance. Here, we propose a molecular additive strategy that employs pentafluorophenyl diphenylphosphinate (FDPP) molecules as additives. P=O and Pentafluorophenyl (5F) on FDPP can coordinate with Pb2+ to slow the crystallization process of perovskite and enhance surface coverage. Moreover, FDPP reduces the defect density of perovskite and enhances the crystalline quality. The maximum brightness, power efficiency (PE), and external quantum efficiency (EQE) of the optimal device reached 24,230 cd m-2, 82.73 lm W-1, and 21.06%, respectively. The device maintains an EQE of 19.79% at 1000 cd m-2 and the stability is further enhanced. This study further extends the applicability of P=O-based additives.

Maternal and Perinatal Factors Associated With Childhood Brain Tumors: A Case-Control Study in Vietnam.

INTRODUCTION: Brain cancer is the leading cause of cancer-related deaths in children and the majority of childhood brain tumors are diagnosed without determination of their underlying etiology. Little is known about risk factors for childhood brain tumors in Vietnam. The objective of this case-control study was to identify maternal and perinatal factors associated with brain tumors occurring in young Vietnamese children and adolescents. METHODS: We conducted a hospital-based case-control study at Viet Duc University Hospital in Hanoi, Vietnam. Cases consisted of children with brain tumors aged 0-14 years old admitted to the hospital from January 2020 to July 2022 while the controls were age and sex-matched hospitalized children diagnosed with head trauma. Perinatal characteristics were abstracted from hospital medical records and maternal medical, behavioral, and sociodemographic factors were collected through in-person interviews. Conditional logistic regression models were used to examine maternal and perinatal factors associated with childhood brain tumors. RESULTS: The study sample included 220 children (110 cases and 110 controls) whose average age was 8.9 years and 41.8% were girls. Children born to mothers aged greater than 30 years at the time of the child's birth had a higher risk of childhood brain tumors compared to those born to mothers aged from 18 to 30 years old (OR = 2.55; 95% CI: 1.13-5.75). Additionally low maternal body mass index prior to the current pregnancy of <18.5 kg/m2 significantly increased the odds of having a child with a brain tumor in relation to normal maternal body mass index from 18.5-22.9 kg/m2 (OR = 3.19; 95% CI: 1.36 - 7.50). CONCLUSION: Advanced maternal age and being markedly underweight were associated with an increased odds of having a child with a brain tumor. A population-based study with larger sample size is needed to confirm and extend the present findings.

In Situ Synthesis and Self-Assembly of Peptide-PEG Conjugates: A Facile Method for the Construction of Fibrous Hydrogels.

Peptide-based hydrogels have gained considerable attention as a compelling platform for various biomedical applications in recent years. Their attractiveness stems from their ability to seamlessly integrate diverse properties, such as biocompatibility, biodegradability, easily adjustable hydrophilicity/hydrophobicity, and other functionalities. However, a significant drawback is that most of the functional self-assembling peptides cannot form robust hydrogels suitable for biological applications. In this study, we present the synthesis of novel peptide-PEG conjugates and explore their comprehensive hydrogel properties. The hydrogel comprises double networks, with the first network formed through the self-assembly of peptides to create a ß-sheet secondary structure. The second network is established through covalent bond formation via N-hydroxysuccinimide chemistry between peptides and a 4-arm PEG to form a covalently linked network. Importantly, our findings reveal that this hydrogel formation method can be applied to other peptides containing lysine-rich sequences. Upon encapsulation of the hydrogel with antimicrobial peptides, the hydrogel retained high bacterial killing efficiency while showing minimum cytotoxicity toward mammalian cells. We hope that this method opens new avenues for the development of a novel class of peptide-polymer hydrogel materials with enhanced performance in biomedical contexts, particularly in reducing the potential for infection in applications of tissue regeneration and drug delivery.

Well-Paired-Seq2: High-Throughput and High-Sensitivity Strategy for Characterizing Low RNA-Content Cell/Nucleus Transcriptomes.

Single-cell RNA sequencing (scRNA-seq) is a transformative technology that unravels the intricate cellular state heterogeneity. However, the Poisson-dependent cell capture and low sensitivity in scRNA-seq methods pose challenges for throughput and samples with a low RNA-content. Herein, to address these challenges, we present Well-Paired-Seq2 (WPS2), harnessing size-exclusion and quasi-static hydrodynamics for efficient cell capture. WPS2 exploits molecular crowding effect, tailing activity enhancement in reverse transcription, and homogeneous enzymatic reaction in the initial bead-based amplification to achieve 3116 genes and 8447 transcripts with an average of ∼20000 reads per cell. WPS2 detected 1420 more genes and 4864 more transcripts than our previous Well-Paired-Seq. It sensitively characterizes transcriptomes of low RNA-content single cells and nuclei, overcoming the Poisson limit for cell and barcoded bead capture. WPS2 also profiles transcriptomes from frozen clinical samples, revealing heterogeneous tumor copy number variations and intercellular crosstalk in clear cell renal cell carcinomas. Additionally, we provide the first single-cell-level characterization of rare metanephric adenoma (MA) and uncover potential specific markers. With the advantages of high sensitivity and high throughput, WPS2 holds promise for diverse basic and clinical research.

A highly sensitive ratiometric fluorescence immunoassay based on bioorthogonal nanozymes.

We designed a novel ratiometric fluorescence immunoassay based on bioorthogonal nanozymes for carcinoembryonic antigen detection. The analytical performance of our designed immunoassay showed a wide linear range, a low detection limit, good reproducibility, selectivity and stability. Thus, bioorthogonal nanozymes hold great potential applications in clinical diagnoses.

Reduced Cx43 Expression Induces Autophagy through Activation of the AMPK-mTOR-ULK1 Signaling Pathway in the Common Bile Duct Ligation Rat Heart.

BACKGROUNDS: This study aimed to investigate the relationship between Cx43 expression and autophagy mediated by the AMPK-mTOR-Ulk1 signaling pathway in jaundice heart. METHODS: In this study, a jaundice model was established in common bile duct ligation (CBDL) rats. Cardiac injury was assessed using various methods including myocardial injury indicators, echocardiography, TEM, HE staining, Masson staining, IHC, and IF. We investigated the regulatory relationship between Cx43, autophagy, and the AMPK-mTOR-ULK pathway in vivo by administering autophagy agonists (Rapa), autophagy inhibitors (3-MA), and Cx43 inhibitors (Gap 26). In vitro, we observed the relationship between autophagy and the AMPK-mTOR-ULK1 pathway in cells by exposing them to the AMPK inhibitor Compound C and the AMPK activator AICAR. RESULTS: We found that CBDL induced autophagy through the AMPK-mTOR-ULK pathway, leading to the inhibition of myocardial dysfunction. Rapamycin pretreatment with CBDL3d exhibited a protective effect against myocardial injury and promoted autophagy. In contrast, 3-MA had no impact. Pretreatment with rapamycin at CBDL2w enhanced autophagy and aggravated cardiac injury; however, inhibition of autophagy using 3-MA attenuated cardiac injury. Cell viability was enhanced by AMPK inhibitors and inhibited by AMPK agonists. In addition, we observed that increased autophagy led to decreased Cx43 expression, which negatively affected cardiac function. CONCLUSIONS: CBDL induces myocardial injury in rats and activates autophagy through the AMPK-mTOR-ULK pathway, resulting in decreased Cx43 protein levels. A moderate increase in early autophagy in CBDL can improve cardiac injury, while late inhibition of autophagy can reduce myocardial injury.

Value of magnetic resonance imaging radiomics features in predicting histologic grade of invasive ductal carcinoma of the breast.

BACKGROUND: Breast cancer has the second highest mortality rate of all cancers and occurs mainly in women. OBJECTIVE: To investigate the relationship between magnetic resonance imaging (MRI) radiomics features and histological grade of invasive ductal carcinoma (IDC) of the breast and to evaluate its diagnostic efficacy. METHODS: The two conventional MRI quantitative indicators, i.e. the apparent diffusion coefficient (ADC) and the initial enhancement rate, were collected from 112 patients with breast cancer. The breast cancer lesions were manually segmented in dynamic contrast-enhanced MRI (DCE-MRI) and ADC images, the differences in radiomics features between Grades I, II and III IDCs were compared and the diagnostic efficacy was evaluated. RESULTS: The ADC values (0.77 ± 0.22 vs 0.91 ± 0.22 vs 0.92 ± 0.20, F= 4.204, p< 0.01), as well as the B_sum_variance (188.51 ± 67.803 vs 265.37 ± 77.86 vs 263.74 ± 82.58, F= 6.040, p< 0.01), L_energy (0.03 ± 0.02 vs 0.13 ± 0.11 vs 0.12 ± 0.14, F= 7.118, p< 0.01) and L_sum_average (0.78 ± 0.32 vs 16.34 ± 4.23 vs 015.45 ± 3.74, F= 21.860, p< 0.001) values of patients with Grade III IDC were significantly lower than those of patients with Grades I and II IDC. The B_uniform (0.15 ± 0.12 vs 0.11 ± 0.04 vs 0.12 ± 0.03, F= 3.797, p< 0.01) and L_SRE (0.85 ± 0.07 vs 0.78 ± 0.03 vs 0.79 ± 0.32, F= 3.024, p< 0.01) values of patients with Grade III IDC were significantly higher than those of patients with Grades I and II IDC. All differences were statistically significant (p< 0.05). The ADC radiomics signature model had a higher area-under-the-curve value in identifying different grades of IDC than the ADC value model and the DCE radiomics signature model (0.869 vs 0.711 vs 0.682). The accuracy (0.812 vs 0.647 vs 0.710), specificity (0.731 vs 0.435 vs 0.342), positive predictive value (0.815 vs 0.663 vs 0.669) and negative predictive value (0.753 vs 0.570 vs 0.718) of the ADC radiomics signature model were all significantly better than the ADC value model and the DCE radiomics signature model. CONCLUSION: ADC values and breast MRI radiomics signatures are significant in identifying the histological grades of IDC, with the ADC radiomics signatures having greater value.

SiONx Coating Regulates Mesenchymal Stem Cell Antioxidant Capacity via Nuclear Erythroid Factor 2 Activity under Toxic Oxidative Stress Conditions.

Healing in compromised and complicated bone defects is often prolonged and delayed due to the lack of bioactivity of the fixation device, secondary infections, and associated oxidative stress. Here, we propose amorphous silicon oxynitride (SiONx) as a coating for the fixation devices to improve both bioactivity and bacteriostatic activity and reduce oxidative stress. We aimed to study the effect of increasing the N/O ratio in the SiONx to fine-tune the cellular activity and the antioxidant effect via the NRF2 pathway under oxidative stress conditions. The in vitro studies involved using human mesenchymal stem cells (MSCs) to examine the effect of SiONx coatings on osteogenesis with and without toxic oxidative stress. Additionally, bacterial growth on SiONx surfaces was studied using methicillin-resistant Staphylococcus aureus (MRSA) colonies. NRF2 siRNA transfection was performed on the hMSCs (NRF2-KD) to study the antioxidant response to silicon ions. The SiONx implant surfaces showed a >4-fold decrease in bacterial growth vs. bare titanium as a control. Increasing the N/O ratio in the SiONx implants increased the alkaline phosphatase activity >1.5 times, and the other osteogenic markers (osteocalcin, RUNX2, and Osterix) were increased >2-fold under normal conditions. Increasing the N/O ratio in SiONx enhanced the protective effects and improved cell viability against toxic oxidative stress conditions. There was a significant increase in osteocalcin activity compared to the uncoated group, along with increased antioxidant activity under oxidative stress conditions. In NRF2-KD cells, there was a stunted effect on the upregulation of antioxidant markers by silicon ions, indicating a role for NRF2. In conclusion, the SiONx coatings studied here displayed bacteriostatic properties. These materials promoted osteogenic markers under toxic oxidative stress conditions while also enhancing antioxidant NRF2 activity. These results indicate the potential of SiONx coatings to induce in vivo bone regeneration in a challenging oxidative stress environment.

Use total portosystemic shunt to rescue an emergency PNF with intractable hypotension: A case report.

RATIONALE: Living donor allogeneic liver transplantation is a surgical treatment for patients with end-stage liver disease, wherein a healthy liver is implanted in the patient, facilitating the recovery of the liver function in patients with end-stage liver disease. However, primary nonfunction (PNF) may occur as a result of this procedure. PATIENT CONCERNS: A case of an 65-year-old Asian male with a medical history of cirrhosis and hepatocellular carcinoma is described. Intractable hypotension occurred after open hepatic portal anastomosis, and large doses of vasoactive substances did not improve the condition. DIAGNOSIS: PNF was diagnosed during surgery and it caused intractable hypotension. INTERVENTIONS: we promptly used the total portosystemic shunt to achieve a successful rescue. OUTCOMES: The strengthening of perioperative management and active treatment allowed second liver transplantation and anhepatic phase of up to 10 hours, following which the patient was rescued. LESSONS: The lesson we have learned is that total portosystemic shunt composited with careful anesthesia management can rescue the event of PNF with intractable hypotension in liver transplantation surgery. At the same time, we give attention to blood pressure, electrocardiogram, albumin, calcium, potassium, acidosis, coagulopathy, anti-infection, and protection of vital organs is essential for successful retransplant outcomes.

Theoretical and experimental investigation of Al3+ ion-suppressed phase-separation structures in rare-earth-doped high-phosphorus silica glasses.

Rare-earth-doped silica-based composite glasses (Re-SCGs) are widely used as high-quality laser gain media in defense, aerospace, energy, power, and medical applications. The variable regional chemical environments of Re-SCGs can induce new photoluminescence properties of rare-earth ions but can cause the selective aggregation of rare-earth ions, limiting the application of Re-SCGs in the field of high-power lasers. Here, topological engineering is proposed to adjust the degree of cross-linking of phase-separation network chains in Re-SCGs. A combination of experimental and theoretical characterization techniques suggested that the selective aggregation of rare-earth ions originates from the formation of phase-separated structures in glasses. The decomposition of nanoscale phase separation structures to the sub-nanometer scale, enabled by incorporating Al3+ ions, not only maintains the high luminescence efficiency of rare earth ions but also increases light transmittance and reduces light scattering. Furthermore, our investigation encompassed the exploration of the inhibitory mechanism of Al3+ ions on phase-separation structures, as well as their influence on the spectral characteristics of Re-SCGs. This work provides a new design concept for composite glass materials doped with rare-earth ions and could broaden their application in the field of high-power lasers.

Occurrence, structure, and function of short cells in maize leaf epidermis.

Short cells are specialised epidermal cells of grasses and they include cork and silica cells. The time of occurrence, distribution, and number of short cells differ among plants or tissues of the same plant. The present study aimed to assess the occurrence, structure, and function of short cells in the epidermis of maize (Zea mays L.) leaves from cultivar "Zhengdan 958″ under field and potted experimental conditions. Results showed that short cells occurred synchronously in multiple maize leaves. Few short cells occurred at the base of the fifth leaf; most were found at the middle and base of the sixth leaf, and throughout the seventh leaf. The accumulation of K+ and H2O2 in cork cells changed periodically with stomatal opening and closure, which was consistent with the accumulation of K+ and H2O2 in subsidiary cells; whereas no accumulation was observed in silica cells. Moreover, photosynthetic parameters and stomatal aperture were significantly higher in leaves containing short cells than in those without them in the same parts of different leaves or in different leaves at the same leaf position. Accumulation of K+ and H2O2 in cork cells increased with increasing water stress. In conclusion, short cells not only improved leaf mechanical support and photosynthetic performance, and maize drought resistance, but they also participated in stomatal regulation.

Riboflavin-loaded carbon cloth aids the anaerobic digestion of cow dung by promoting direct interspecies electron transfer.

Cow dung generates globally due to increased beef and milk consumption, but its treatment efficiency remains low. Previous studies have shown that riboflavin-loaded conductive materials can improve anaerobic digestion through enhance direct interspecies electron transfer (DIET). However, its effect on the practical anaerobic digestion of cow dung remained unclear. In this study, carbon cloth loaded with riboflavin (carbon cloth-riboflavin) was added into an anaerobic digester treating cow dung. The carbon cloth-riboflavin reactor showed a better performance than other two reactors. The metagenomic analysis revealed that Methanothrix on the surface of the carbon cloth predominantly utilized the CO2 reduction for methane production, further enhanced after riboflavin addition, while Methanothrix in bulk sludge were using the acetate decarboxylation pathway. Furthermore, the carbon cloth-riboflavin enriched various major methanogenic pathways and activated a large number of enzymes associated with DIET. Riboflavin's presence altered the microbial communities and the abundance of functional genes relate to DIET, ultimately leading to a better performance of anaerobic digestion for cow dung.

Reaction mechanism of the ethynylation of formaldehyde on copper terminated Cu2O(100) surfaces: a DFT study.

1,4-Butanediol (BDO) is an important chemical raw material for a series of high-value-added products. And the ethynylation of formaldehyde is the key step for the production of BDO by the Reppe process. However, little work has been done to reveal the reaction mechanism. In this work, the reaction mechanism for the ethynylation of formaldehyde process on copper-terminated Cu2O(100) surfaces was investigated with density functional theory (DFT). The reaction network of the ethynylation of formaldehyde was constructed first and the adsorption properties of the related species were calculated. Then the energy barrier and reaction energy of the related reactions and the geometric configuration were calculated. It is a consecutive reaction including two processes. For the propargyl alcohol (PA) formation process, the most favorable pathway is the direct addition of acetylene to formaldehyde followed by a hydrogen transfer reaction. And the rate control step is the hydrogen transfer reaction with an energy barrier of 1.43 eV. For the 1,4-butynediol (BYD) formation process, the most competitive pathway is the addition of PA to CH2OH, including formaldehyde hydrogenation to form CH2OH, coupling addition, and dehydrogenation reaction. The rate control step of this pathway is the dehydrogenation reaction with an energy barrier of 1.51 eV.