In-Situ Construction of Functional Multi-Dimensional MXene-based Composites Directly from MAX Phases through Gas-Solid Reactions.

The weak bonding of A atoms with MX layers in MAX phases not only enables the selective etching of A layers for MXene preparation but brings about the chance to construct A derivatives/MXene composites via in-situ conversion. Here, a facile and general gas-solid reaction systems are elegantly devised to construct multi-dimensional MXene based composites including AlF3 nanorods/MXene, AlF3 nanocrystals/MXene, amorphous AlF3/MXene, A filled carbon nanotubes/MXene, layered metal chalcogenides/MXene, MOF/MXene, and so on. The intrinsic effect mechanism of interlayer confinement towards crystal growth, catalytic behavior, van der Waals-heterostructure construction and coordination reaction are rationally put forward. The tight interface combination and synergistic effect from distinct components make them promising active materials for electrochemical applications. More particularly, the AlF3 nanorods/Nb2C MXene demonstrate bi-directional catalytic activity toward the conversion between Li2S and lithium polysulfides, which alleviates the shuttle effect of lithium-sulfur batteries.

Pharmacokinetics of trastuzumab and its efficacy and safety in HER2-positive cancer patients.

Trastuzumab is a potent targeted therapy drug for HER2-positive cancer patients. A comprehensive understanding of trastuzumab's mechanism of action, pharmacokinetic (PK) parameters, and steady-state exposure in different treatment regimens and administration routes is essential for a thorough evaluation of the drug's safety and effectiveness. Due to the distinctive pharmacokinetics, indications, and administration methods of trastuzumab, this understanding becomes crucial. Drug exposure can be assessed by measuring trastuzumab's peak concentration, trough concentration, or area under the curve through assays like enzyme-linked immunosorbent assay (ELISA) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). The dose-response (D-R) and exposure-response (E-R) relationships establish the correlation between drug dosage/exposure and the therapeutic effect and safety. Additionally, various covariates such as body weight, aspartate transaminase, and albumin levels can influence drug exposure. This review provides a comprehensive overview of trastuzumab's mechanism of action, data on steady-state concentration and PK parameters under multiple administration routes and indications, discussions on factors influencing PK parameters, and evaluations of the effectiveness and safety of E-R and D-R in diverse HER2-positive cancer patients.

Exploring Molecular Heteroencoders with Latent Space Arithmetic: Atomic Descriptors and Molecular Operators.

A variational heteroencoder based on recurrent neural networks, trained with SMILES linear notations of molecular structures, was used to derive the following atomic descriptors: delta latent space vectors (DLSVs) obtained from the original SMILES of the whole molecule and the SMILES of the same molecule with the target atom replaced. Different replacements were explored, namely, changing the atomic element, replacement with a character of the model vocabulary not used in the training set, or the removal of the target atom from the SMILES. Unsupervised mapping of the DLSV descriptors with t-distributed stochastic neighbor embedding (t-SNE) revealed a remarkable clustering according to the atomic element, hybridization, atomic type, and aromaticity. Atomic DLSV descriptors were used to train machine learning (ML) models to predict 19F NMR chemical shifts. An R2 of up to 0.89 and mean absolute errors of up to 5.5 ppm were obtained for an independent test set of 1046 molecules with random forests or a gradient-boosting regressor. Intermediate representations from a Transformer model yielded comparable results. Furthermore, DLSVs were applied as molecular operators in the latent space: the DLSV of a halogenation (H→F substitution) was summed to the LSVs of 4135 new molecules with no fluorine atom and decoded into SMILES, yielding 99% of valid SMILES, with 75% of the SMILES incorporating fluorine and 56% of the structures incorporating fluorine with no other structural change.

Hybrid Mn Atomic Clusters/Single-Dispersed Atoms with Dual Antioxidant Activities for a Chemiluminescent Immunoassay.

Single-dispersed atoms (SDAs) as catalysts have drawn extensive attention due to their ultimate atom utilization efficiency and desirable catalytic capability. Atomic clusters (ACs) with potential multiple enzyme-like activities also display great practicability in catalysis-based biosensing. In this work, hybrid Mn ACs/SDAs were implanted in the frameworks of defect-engineered MIL 101(Cr) modulated by excess acetic acid, with a high loading capability of 13.9 wt %. Distinctively, Mn SDAs display weak superoxide dismutase (SOD)-like activity for specifically eliminating superoxide anion (O2•-), while Mn ACs/SDAs display both catalase-like and SOD-like activities for remarkable elimination of total reactive oxygen species (ROS) due to the cooperative effect of the two atom-scale catalytic sites. Thus, Mn ACs/SDAs can efficiently inhibit the chemiluminescent (CL) emission of multiple ROS-mediated luminol systems with a superior quenching rate of 85.5%. To validate the practicability of Mn ACs/SDAs for a sensitive CL assay, an immunoassay method was established to detect acetamiprid by using Mn ACs/SDAs as signal quenchers, which displayed a quantification range of 10 pg mL-1-25 ng mL-1 and a detection limit of 3.3 pg mL-1. This study paves an avenue for developing ACs/SDAs with multiple antioxidant activities that are suitable for application in biosensing.

Identification and Validation of JAM-A as a Novel Prognostic and Immune Factor in Human Tumors.

Junctional adhesion molecule-A (JAM-A), also known as F11 receptor (F11R), is a transmembrane glycoprotein that is involved in various biological processes, including cancer initiation and progression. However, the functional characteristics and significance of JAM-A in pan-cancer remain unexplored. In this study, we used multiple databases to gain a comprehensive understanding of JAM-A in human cancers. JAM-A was widely expressed in various tissues, mainly located on the microtubules and cell junctions. Aberrant expression of JAM-A was detected in multiple cancers at both mRNA and protein levels, which can be correlated with poorer prognosis and may be attributed to genetic alterations and down-regulated DNA methylation. JAM-A expression was also associated with immune infiltration and may affect immunotherapy responses in several cancers. Functional enrichment analysis indicated that JAM-A participated in tight junction and cancer-related pathways. In vitro experiments verified that JAM-A knockdown suppressed the proliferation and migration abilities of breast cancer cells and liver cancer cells. Overall, our study suggests that JAM-A is a pan-cancer regulator and a potential biomarker for predicting prognosis and immune-therapeutic responses for different tumors.

Point-of-care testing of Pseudomonas aeruginosa using PCN-222(Pt) prepared by nanoconfinement-guided protocol to catalyze gas generation reaction.

BACKGROUND: Pathogenic bacteria are keeping threatening global public health since they can cause many infectious diseases. The traditional microorganism identification and molecular diagnostic techniques are insufficiently sensitive, time-consuming, or expensive. Thus it is of great interest to establish pressure signal-based sensing platforms for point-of-care testing of pathogenic bacteria to achieve timely diagnosis of infectious diseases. Rational design and synthesis of nano-sized probes with high peroxidase-mimicking activity have been a long-term cherished goal for improving the sensitivity of pressure signal-based sensing methods. RESULTS: Guided by nanoconfinement effect, PCN-222(Pt) was prepared by confining Pt clusters within the channels of a zirconium porphyrin MOFs material termed as PCN-222. In comparison to regular platinum nanoparticles, palladium@platinum core-shell nanodendrites, and platinum-coated gold nanoparticles, the prepared PCN-222(Pt) displayed superior peroxidase-mimicking activity with outstanding efficiency for catalyzing the decay of H2O2 to produce O2. Thus it was used as a pressure signal probe to establish a sensitive method on a hydrogel pellets platform for analyzing Pseudomonas aeruginosa (P. aeruginosa), for which polymyxin B and a phage termed as JZ1 were used as recognition agents for the target pathogen. P. aeruginosa was quantified with a handheld pressure meter within a broad range of 2.2 × 102-2.2 × 107 cfu mL-1. This method was used to quantify P. aeruginosa in various biological and food samples with acceptable accuracy and reliability. SIGNIFICANCE: The proposed nanoconfinement-guided protocol provides a novel approach for rational design and preparation of nano-sized probes with high peroxidase-mimicking activity for catalyzing gas-generation reaction. Thus this study opens an avenue for establishment of sensitive pressure signal-based sensing methods for pathogenic bacteria, which shows broad application prospects in medical diagnosis of infectious diseases.

Involvement of autophagy in mesaconitine-induced neurotoxicity in HT22 cells revealed through integrated transcriptomic, proteomic, and m6A epitranscriptomic profiling.

Background: Mesaconitine (MA), a diester-diterpenoid alkaloid extracted from the medicinal herb Aconitum carmichaelii, is commonly used to treat various diseases. Previous studies have indicated the potent toxicity of aconitum despite its pharmacological activities, with limited understanding of its effects on the nervous system and the underlying mechanisms. Methods: HT22 cells and zebrafish were used to investigate the neurotoxic effects of MA both in vitro and in vivo, employing multi-omics techniques to explore the potential mechanisms of toxicity. Results: Our results demonstrated that treatment with MA induces neurotoxicity in zebrafish and HT22 cells. Subsequent analysis revealed that MA induced oxidative stress, as well as structural and functional damage to mitochondria in HT22 cells, accompanied by an upregulation of mRNA and protein expression related to autophagic and lysosomal pathways. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed a correlation between the expression of autophagy-related genes and N6-methyladenosine (m6A) modification following MA treatment. In addition, we identified METTL14 as a potential regulator of m6A methylation in HT22 cells after exposure to MA. Conclusion: Our study has contributed to a thorough mechanistic elucidation of the neurotoxic effects caused by MA, and has provided valuable insights for optimizing the rational utilization of traditional Chinese medicine formulations containing aconitum in clinical practice.

Integrating Epigenetics, Proteomics, and Metabolomics to Reveal the Involvement of Wnt/ß-Catenin Signaling Pathway in Oridonin-Induced Reproductive Toxicity.

Oridonin is the primary active component in the traditional Chinese medicine Rabdosia rubescens, displaying anti-inflammatory, anti-tumor, and antibacterial effects. It is widely employed in clinical therapy for acute and chronic pharyngitis, tonsillitis, as well as bronchitis. Nevertheless, the clinical application of oridonin is significantly restricted due to its reproductive toxicity, with the exact mechanism remaining unclear. The aim of this study was to investigate the mechanism of oridonin-induced damage to HTR-8/SVneo cells. Through the integration of epigenetics, proteomics, and metabolomics methodologies, the mechanisms of oridonin-induced reproductive toxicity were discovered and confirmed through fluorescence imaging, RT-qPCR, and Western blotting. Experimental findings indicated that oridonin altered m6A levels, gene and protein expression levels, along with metabolite levels within the cells. Additionally, oridonin triggered oxidative stress and mitochondrial damage, leading to a notable decrease in WNT6, ß-catenin, CLDN1, CCND1, and ZO-1 protein levels. This implied that the inhibition of the Wnt/ß-catenin signaling pathway and disruption of tight junction might be attributed to the cytotoxicity induced by oridonin and mitochondrial dysfunction, ultimately resulting in damage to HTR-8/SVneo cells.

Gelsenicine disrupted the intestinal barrier of Caenorhabditis elegans.

Gelsemium elegans Benth. (G. elegans) is a traditional medicinal herb that has anti-inflammatory, analgesic, sedative, and detumescence effects. However, it can also cause intestinal side effects such as abdominal pain and diarrhea. The toxicological mechanisms of gelsenicine are still unclear. The objective of this study was to assess enterotoxicity induced by gelsenicine in the nematodes Caenorhabditis elegans (C. elegans). The nematodes were treated with gelsenicine, and subsequently their growth, development, and locomotion behavior were evaluated. The targets of gelsenicine were predicted using PharmMapper. mRNA-seq was performed to verify the predicted targets. Intestinal permeability, ROS generation, and lipofuscin accumulation were measured. Additionally, the fluorescence intensities of GFP-labeled proteins involved in oxidative stress and unfolded protein response in endoplasmic reticulum (UPRER) were quantified. As a result, the treatment of gelsenicine resulted in the inhibition of nematode lifespan, as well as reductions in body length, width, and locomotion behavior. A total of 221 targets were predicted by PharmMapper, and 731 differentially expressed genes were screened out by mRNA-seq. GO and KEGG enrichment analysis revealed involvement in redox process and transmembrane transport. The permeability assay showed leakage of blue dye from the intestinal lumen into the body cavity. Abnormal mRNAs expression of gem-4, hmp-1, fil-2, and pho-1, which regulated intestinal development, absorption and catabolism, transmembrane transport, and apical junctions, was observed. Intestinal lipofuscin and ROS were increased, while sod-2 and isp-1 expressions were decreased. Multiple proteins in SKN-1/DAF-16 pathway were found to bind stably with gelsenicine in a predictive model. There was an up-regulation in the expression of SKN-1:GFP, while the nuclear translocation of DAF-16:GFP exhibited abnormality. The UPRER biomarker HSP-4:GFP was down-regulated. In conclusion, the treatment of gelsenicine resulted in the increase of nematode intestinal permeability. The toxicological mechanisms underlying this effect involved the disruption of intestinal barrier integrity, an imbalance between oxidative and antioxidant processes mediated by the SKN-1/DAF-16 pathway, and abnormal unfolded protein reaction.

Systematic review of the efficacy and safety of lenvatinib in various solid tumors.

OBJECTIVE: The purpose of this study was to investigate the efficacy and safety of lenvatinib in various types of solid tumors. METHOD: By searching PubMed, Web of Science, Cochrane, CNKI, Wanfang and other databases, all the literatures about the comparison of clinical efficacy of lenvatinib in the treatment of various solid tumors. According to the criteria of inclusion and exclusion of literature, two participants screened the literature, collated the data and evaluated the literature. RevMan 5.4 software was used for meta-analysis of the included literatures. RESULTS: A total of 12 studies were included, including 5213 patients. Meta-analysis showed that, in terms of efficacy, the risk (HR) of prolonging PFS in the treatment of various solid tumors in the lenvatinib group was 1.91 times that in the control group (HR = 1.91, 95% CI: 1.58-2.31, p < 0.00001), and the risk (HR) of prolonging OS was 1.27 times that in the single targeted drug group (HR = 1.27, 95% CI: 1.15-1.40, p < 0.00001). In terms of safety, the risk of adverse events in the treatment of various solid tumors in the lenvatinib group was higher than that in the control group, especially in Endocrine Toxicities, Renal/Urinary Toxicities, Vascular Toxicities, Musculoskeletal/a Connective Tissue Toxicities and Metabolism/Nutrition Toxicities. CONCLUSIONS: Lenvatinib in various solid tumors can prolong OS and disease PFS of patients, improve the clinical benefit rate and improve the quality of life of patients. At the same time, there is a certain incidence of adverse events, and symptomatic intervention should be given in clinical medication.

Multifunctional Vanadium Nitride-Modified Separator for High-Performance Lithium-Sulfur Batteries.

Lithium-sulfur batteries (LSBs) are recognized as among the best potential alternative battery systems to lithium-ion batteries and have been widely investigated. However, the shuttle effect has severely restricted the advancement in their practical applications. Here, we prepare vanadium nitride (VN) nanoparticles grown in situ on a nitrogen-doped carbon skeleton (denoted as VN@NC) derived from the MAX phase and use it as separator modification materials for LSBs to suppress the shuttle effect and optimize electrochemical performance. Thanks to the outstanding catalytic performance of VN and the superior electrical conductivity of carbon skeleton derived from MAX, the synergistic effect between the two accelerates the kinetics of both lithium polysulfides (LiPSs) to Li2S and the reverse reaction, effectively suppresses the shuttle effect, and increases cathode sulfur availability, significantly enhancing the electrochemical performance of LSBs. LSBs constructed with VN@NC-modified separators achieve outstanding rate performance and cycle stability. With a capacity of 560 mAh g-1 at 4 C, it exhibits enhanced structural and chemical stability. At 1 C, the device has an incipient capacity of 1052.4 mAh g-1, and the degradation rate averaged only 0.085% over 400cycles. Meanwhile, the LSBs also show larger capacities and good cycling stability at a low electrolyte/sulfur ratio and high surface-loaded sulfur conditions. Thus, a facile and efficient way of preparing modified materials for separators is provided to realize high-performance LSBs.

Unveiling the Impact of ApoF Deficiency on Liver and Lipid Metabolism: Insights from Transcriptome-Wide m6A Methylome Analysis in Mice.

Lipid metabolism participates in various physiological processes and has been shown to be connected to the development and progression of multiple diseases, especially metabolic hepatopathy. Apolipoproteins (Apos) act as vectors that combine with lipids, such as cholesterol and triglycerides (TGs). Despite being involved in lipid transportation and metabolism, the critical role of Apos in the maintenance of lipid metabolism has still not been fully revealed. This study sought to clarify variations related to m6A methylome in ApoF gene knockout mice with disordered lipid metabolism based on the bioinformatics method of transcriptome-wide m6A methylome epitranscriptomics. High-throughput methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted in both wild-type (WT) and ApoF knockout (KO) mice. As a result, the liver histopathology presented vacuolization and steatosis, and the serum biochemical assays reported abnormal lipid content in KO mice. The m6A-modified mRNAs were conformed consensus sequenced in eukaryotes, and the distribution was enriched within the coding sequences and 3' non-coding regions. In KO mice, the functional annotation terms of the differentially expressed genes (DEGs) included cholesterol, steroid and lipid metabolism, and lipid storage. In the differentially m6A-methylated mRNAs, the functional annotation terms included cholesterol, TG, and long-chain fatty acid metabolic processes; lipid transport; and liver development. The overlapping DEGs and differential m6A-modified mRNAs were also enriched in terms of lipid metabolism disorder. In conclusion, transcriptome-wide MeRIP sequencing in ApoF KO mice demonstrated the role of this crucial apolipoprotein in liver health and lipid metabolism.

Experimental Study on the Erosion-Corrosion Characteristics of Desulfurization Slurry on Stainless Steel Pipe Materials.

The recovery of low-grade waste heat from power plants greatly benefits energy conservation and emission reduction during electricity generation, while the waste heat utilization directly from desulfurization slurry is a significantly promising method to deeply recover such low-grade energy and has been developed in practical application. However, the pipe materials are subjected to erosion and corrosion challenges due to the high level of solid compositions and the presence of harmful ions, such as Cl-1, which requires further evaluation under the condition of slurry heat exchange. The present study aimed at an experimental study on the erosion-corrosion characteristics of desulfurization slurry on three types of stainless steel, including type 304, 316L, and 2205. Both mass loss and micromorphology features were analyzed with possible mechanisms elucidated. The erosion-corrosion rate is weak at low temperatures, while the increase in the slurry temperature clearly promotes its rate. The influence of the temperature on the corrosion resistance of 304 is much greater than that of 2205. With an increase in duration time, the weight loss rate of stainless steel in the desulfurization slurry declines, and the changing trend of metal mass slightly slows down. The present study offers a better understanding of the erosion-corrosion behaviors of three types of stainless steel under flow and heat transfer conditions of a desulfurization slurry.

Chest x-ray diagnosis via spatial-channel high-order attention representation learning.

Objective. Chest x-ray image representation and learning is an important problem in computer-aided diagnostic area. Existing methods usually adopt CNN or Transformers for feature representation learning and focus on learning effective representations for chest x-ray images. Although good performance can be obtained, however, these works are still limited mainly due to the ignorance of mining the correlations of channels and pay little attention on the local context-aware feature representation of chest x-ray image.Approach. To address these problems, in this paper, we propose a novel spatial-channel high-order attention model (SCHA) for chest x-ray image representation and diagnosis. The proposed network architecture mainly contains three modules, i.e. CEBN, SHAM and CHAM. To be specific, firstly, we introduce a context-enhanced backbone network by employing multi-head self-attention to extract initial features for the input chest x-ray images. Then, we develop a novel SCHA which contains both spatial and channel high-order attention learning branches. For the spatial branch, we develop a novel local biased self-attention mechanism which can capture both local and long-range global dependences of positions to learn rich context-aware representation. For the channel branch, we employ Brownian Distance Covariance to encode the correlation information of channels and regard it as the image representation. Finally, the two learning branches are integrated together for the final multi-label diagnosis classification and prediction.Main results. Experiments on the commonly used datasets including ChestX-ray14 and CheXpert demonstrate that our proposed SCHA approach can obtain better performance when comparing many related approaches.Significance. This study obtains a more discriminative method for chest x-ray classification and provides a technique for computer-aided diagnosis.

Correlation analysis between camrelizumab trough concentration levels and efficacy or safety in East Asian patients with advanced lung cancer.

BACKGROUND: Camrelizumab combined with chemotherapy is approved across tumor types. However, only a fraction of patients benefits from immunotherapy, and biomarkers such as the expression of PD-L1, tumor mutational burden, and CXCL11 are expensive and suboptimal specificity for cancer patients. An exposure-response (E-R) relationship has been reported in many immune checkpoint inhibitors (ICIs), and the trough concentrations and other drug exposure metrics are broadly used to guide dosing decisions, assess exposure-outcomes relationships, and ultimately predict outcomes based on those relationships. However, the potential use of trough concentration levels for camrelizumab is still not clear. METHODS: Blood samples were obtained at trough levels after doses 3 and 4 from 77 patients with advanced lung cancer who received camrelizumab (200 mg Q3 W) monotherapy or combined with chemotherapy. We optimized a competitive ELISA method to measure the trough concentration. RESULTS: We found that the trough concentration was steady after 3 dose cycles, and the trough concentration level of camrelizumab was higher in patients who developed immune-related adverse effects (irAEs) than in those who did not (P < 0.05) but was not observed in disease progression and PFS (P > 0.05). Age (< 65 years old), no smoking history, and efficacy evaluation after 4-dose treatment were associated with PFS (P < 0.05), but no significance was observed in other clinical characteristics. Total bilirubin and albumin had an influence on trough concentration, and monocytes and albumin were independent risk factors for PFS (P < 0.05). CONCLUSIONS: Our results suggest that the trough concentration level of camrelizumab might be a risk factor for the occurrence of irAEs in advanced lung cancer, and using the immunotherapy as early as possible may bring better clinical outcomes.

EphB3 protein is a potential ancillary diagnostic biomarker for thyroid cancers.

OBJECTIVE: To investigate the expression of ephrin type B receptor 3 (EphB3) in thyroid tumors and its usage as an ancillary diagnostic biomarker for thyroid tumors. METHODS: Formalin-fixed and paraffin-embedded (FFPE) tissue samples (78 cases) and FNAC samples (57 cases) were assessed with the EphB3 antibody using immunohistochemistry. PTC and other thyroid follicular tumors were compared regarding their EphB3 expression. Sanger sequencing was used to assess for the presence of a BRAF V600E mutation. RESULTS: EphB3 was positive in 81.8 % (27/33) of papillary thyroid carcinoma (PTC), 83.3 % (5/6) of medullary thyroid carcinoma (MTC), 25 % (1/4) of hyperplastic/adenomatoid nodule (HN), 14.3 % (1/7) of follicular adenoma (FA), and negative in follicular tumors of uncertain malignant potential (FT-UMP) (0/13), noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) (0/7), thyroid follicular carcinoma (TFC) (0/4), Hashimoto's thyroiditis (0/4), and normal thyroid follicular tissues (0/33). In cellular blocks, EphB3 was positive in 87.1 % (20/23) of PTC, 75 % (3/4) of MTC, 20 % (2/10) of HN, and negative in atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (0/20) and normal thyroid follicular cells (0/10). CONCLUSION: EphB3 is expressed in the majority of PTC, but less so in benign follicular nodules. EphB3 expression in fine needle aspiration cytology (FNAC) specimens can be used as a diagnostic tool to differentiate thyroid cancer from other follicular lesions in its differential diagnosis, especially AUS/FLUS and PTC.

An extra-erythrocyte role of haemoglobin body in chondrocyte hypoxia adaption.

Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are largely elusive1,2. Here we found that chondrocytes produced massive amounts of haemoglobin to form eosin-positive bodies in their cytoplasm. The haemoglobin body (Hedy) is a membraneless condensate characterized by phase separation. Production of haemoglobin in chondrocytes is controlled by hypoxia and is dependent on KLF1 rather than the HIF1/2α pathway. Deletion of haemoglobin in chondrocytes leads to Hedy loss along with severe hypoxia, enhanced glycolysis and extensive cell death in the centre of cartilaginous tissue, which is attributed to the loss of the Hedy-controlled oxygen supply under hypoxic conditions. These results demonstrate an extra-erythrocyte role of haemoglobin in chondrocytes, and uncover a heretofore unrecognized mechanism in which chondrocytes survive a hypoxic environment through Hedy.

Kuwanon H Inhibits Melanoma Growth through Cytotoxic Endoplasmic Reticulum Stress and Impaired Autophagy Flux.

Although great progress has been made recently in targeted and immune-based therapies, additional treatments are needed for most melanoma patients due to acquired chemoresistance, recurrence, or metastasis. Elevated autophagy is required for the pathogenesis of melanoma to attenuate metabolic stress, protecting cancer cells from chemotherapeutics or radiation. Thus, intervention with autophagy is a promising strategy for melanoma treatment. Here, we examined a novel antimelanoma natural compound named kuwanon H (KuH), which significantly inhibited melanoma cell growth in vitro/vivo. Mechanistically, KuH induced cytotoxic endoplasmic reticulum (ER) stress, which inhibited cell viability and induced apoptosis. Meanwhile, KuH-induced ER stress mediated autophagysome formation through the ATF4-DDIT3-TRIB3-AKT-MTOR axis. Importantly, KuH impaired autophagy flux, which contributed to the anticancer effects of KuH. Finally, our results showed that KuH enhanced the sensitivity of melanoma cells to cisplatin, both in vitro and in vivo, by impairing autophagy degradation of reactive oxygen species and damaged mitochondria. Our findings indicate that KuH is a promising candidate anticancer natural product for melanoma therapy.

Derivation and characteristics of induced pluripotent stem cells from a patient with acute myelitis.

The emergence and development of induced pluripotent stem cells (iPSCs) provides an approach to understand the regulatory mechanisms of cell pluripotency and demonstrates the great potential of iPSCs in disease modeling. Acute myelitis defines a group of inflammatory diseases that cause acute nerve damage in the spinal cord; however, its pathophysiology remains to be elusive. In this study, we derived skin fibroblasts from a patient with acute myelitis (P-HAF) and then reprogrammed P-HAF cells to iPSCs using eight exogenous factors (namely, OCT4, SOX2, c-MYC, KLF4, NANOG, LIN28, RARG, and LRH1). We performed transcriptomic analysis of the P-HAF and compared the biological characteristics of the iPSCs derived from the patient (P-iPSCs) with those derived from normal individuals in terms of pluripotency, transcriptomic characteristics, and differentiation ability toward the ectoderm. Compared to the control iPSCs, the P-iPSCs displayed similar features of pluripotency and comparable capability of ectoderm differentiation in the specified culture. However, when tested in the common medium, the P-iPSCs showed attenuated potential for ectoderm differentiation. The transcriptomic analysis revealed that pathways enriched in P-iPSCs included those involved in Wnt signaling. To this end, we treated iPSCs and P-iPSCs with the Wnt signaling pathway inhibitor IWR1 during the differentiation process and found that the expression of the ectoderm marker Sox1 was increased significantly in P-iPSCs. This study provides a novel approach to investigating the pathogenesis of acute myelitis.