A Multifunctional Dye Molecule as the Interfacial Layer for Perovskite Solar Cells.

In perovskite solar cells (PSCs), defects in the interface and mismatched energy levels can damage the device performance. Improving the interface quality is an effective way to achieve efficient and stable PSCs. In this work, a multifunctional dye molecule, named ThPCyAc, was designed and synthesized to be introduced in the perovskite/HTM interface. On one hand, various functional groups on the acceptor unit can act as Lewis base to reduce defect density and suppress nonradiative combinations. On the other hand, the stepwise energy-level alignment caused by ThPCyAc decreases the accumulation of interface carriers for facilitating charge extraction and transmission. Therefore, based on the ThPCyAc molecule, the devices exhibit elevated open-circuit voltage and fill factor, resulting in the best power conversion efficiency (PCE) of 23.16%, outperforming the control sample lacking the interface layer (PCE = 21.49%). Excitingly, when attempting to apply it as a self-assembled layer in inverted devices, ThPCyAc still exhibits attractive behavior. It is worth noting that these results indicate that dye molecules have great potential in developing multifunctional interface materials to obtain higher-performance PSCs.

A lipid/PLGA nanocomplex to reshape tumor immune microenvironment for colon cancer therapy.

Immune checkpoint blockade therapy provides a new strategy for tumor treatment; however, the insufficient infiltration of cytotoxic T cells and immunosuppression in tumor microenvironment lead to unsatisfied effects. Herein, we reported a lipid/PLGA nanocomplex (RDCM) co-loaded with the photosensitizer Ce6 and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1MT to improve immunotherapy of colon cancer. Arginine-glycine-aspartic acid (RGD) as the targeting moiety was conjugated on 1,2-distearoyl-snglycero-3-phosphoethanolamine lipid via polyethylene glycol (PEG), and programmed cell death-ligand 1 (PD-L1) peptide inhibitor DPPA (sequence: CPLGVRGK-GGG-d(NYSKPTDRQYHF)) was immobilized on the terminal group of PEG via matrix metalloproteinase 2 sensitive peptide linker. The Ce6 and 1MT were encapsulated in PLGA nanoparticles. The drug loaded nanoparticles were composited with RGD and DPPA modified lipid and lecithin to form lipid/PLGA nanocomplexes. When the nanocomplexes were delivered to tumor, DPPA was released by the cleavage of a matrix metalloproteinase 2-sensitive peptide linker for PD-L1 binding. RGD facilitated the cellular internalization of nanocomplexes via avß3 integrin. Strong immunogenic cell death was induced by 1O2 generated from Ce6 irradiation under 660 nm laser. 1MT inhibited the activity of IDO and reduced the inhibition of cytotoxic T cells caused by kynurenine accumulation in the tumor microenvironment. The RDCM facilitated the maturation of dendritic cells, inhibited the activity of IDO, and markedly recruited the proportion of tumor-infiltrating cytotoxic T cells in CT26 tumor-bearing mice, triggering a robust immunological memory effect, thus effectively preventing tumor metastasis. The results indicated that the RDCM with dual IDO and PD-L1 inhibition effects is a promising platform for targeted photoimmunotherapy of colon cancer.

Tumor-suppressive miR-4732-3p is sorted into fucosylated exosome by hnRNPK to avoid the inhibition of lung cancer progression.

BACKGROUND: Aberrant fucosylation observed in cancer cells contributes to an augmented release of fucosylated exosomes into the bloodstream, where miRNAs including miR-4732-3p hold promise as potential tumor biomarkers in our pilot study. However, the mechanisms underlying the sorting of miR-4732-3p into fucosylated exosomes during lung cancer progression remain poorly understood. METHODS: A fucose-captured strategy based on lentil lectin-magnetic beads was utilized to isolate fucosylated exosomes and evaluate the efficiency for capturing tumor-derived exosomes using nanoparticle tracking analysis (NTA). Fluorescence in situ hybridization (FISH) and qRT-PCR were performed to determine the levels of miR-4732-3p in non-small cell lung cancer (NSCLC) tissue samples. A co-culture system was established to assess the release of miRNA via exosomes from NSCLC cells. RNA immunoprecipitation (RIP) and miRNA pull-down were applied to validate the interaction between miR-4732-3p and heterogeneous nuclear ribonucleoprotein K (hnRNPK) protein. Cell functional assays, cell derived xenograft, dual-luciferase reporter experiments, and western blot were applied to examine the effects of miR-4732-3p on MFSD12 and its downstream signaling pathways, and the impact of hnRNPK in NSCLC. RESULTS: We enriched exosomes derived from NSCLC cells using the fucose-captured strategy and detected a significant upregulation of miR-4732-3p in fucosylated exosomes present in the serum, while its expression declined in NSCLC tissues. miR-4732-3p functioned as a tumor suppressor in NSCLC by targeting 3'UTR of MFSD12, thereby inhibiting AKT/p21 signaling pathway to induce cell cycle arrest in G2/M phase. NSCLC cells preferentially released miR-4732-3p via exosomes instead of retaining them intracellularly, which was facilitated by the interaction of miR-4732-3p with hnRNPK protein for selective sorting into fucosylated exosomes. Moreover, knockdown of hnRNPK suppressed NSCLC cell proliferation, with the elevated levels of miR-4732-3p in NSCLC tissues but the decreased expression in serum fucosylated exosomes. CONCLUSIONS: NSCLC cells escape suppressive effects of miR-4732-3p through hnRNPK-mediated sorting of them into fucosylated exosomes, thus supporting cell malignant properties and promoting NSCLC progression. Our study provides a promising biomarker for NSCLC and opens a novel avenue for NSCLC therapy by targeting hnRNPK to prevent the "exosome escape" of tumor-suppressive miR-4732-3p from NSCLC cells.

Clinical analysis of 1301 children with hand and foot fractures and growth plate injuries.

BACKGROUND: Fractures of hands and feet are common in children, but relevant epidemiological studies are currently lacking. We aim to study the epidemiological characteristics of hand and foot fractures and growth plate injuries in children and provide a theoretical basis for their prevention, diagnosis, and treatment. METHODS: We retrospectively analyzed the data of children with hand and foot fractures who were hospitalized at Shenzhen Children's Hospital between July 2015 and December 2020. Data on demographic characteristics, fracture site, treatment method, etiology of injury, and accompanying injuries were collected. The children were divided into four age groups: infants, preschool children, school children, and adolescents. The fracture sites were classified as first-level (the first-fifth finger/toe, metacarpal, metatarsal, carpal, and tarsal) and second-level (the first-fifth: proximal phalanx, middle phalanx, distal phalanx, metacarpal, and metatarsal) sites. The changing trends in fracture locations and injury causes among children in each age group were analyzed. RESULTS: Overall, 1301 children (1561 fractures; 835 boys and 466 girls) were included. The largest number of fractures occurred in preschool children (n = 549, 42.20%), with the distal phalanx of the third finger being the most common site (n = 73, 15.57%). The number of fractures in adolescents was the lowest (n = 158, 12.14%), and the most common fracture site was the proximal phalanx of the fifth finger (n = 45, 29.61%). Of the 1561 fractures, 1143 occurred in the hands and 418 in the feet. The most and least common first-level fracture sites among hand fractures were the fifth (n = 300, 26.25%) and first (n = 138, 12.07%) fingers, respectively. The most and least common first-level foot fracture locations were the first (n = 83, 19.86%) and fourth (n = 26, 6.22%) toes, respectively. The most common first-level and second level etiologies were life related injuries (n = 1128, 86.70%) and clipping injuries (n = 428, 32.90%), respectively. The incidence of sports injuries gradually increased with age, accounting for the highest proportion in adolescents (26.58%). Hand and foot fractures had many accompanying injuries, with the top three being nail bed injuries (570 cases, 36.52%), growth plate injuries (296 cases, 18.96%), and distal severed fracture (167 cases, 10.70%). Among the 296 growth plate injuries, 246 occurred on the hands and 50 on the feet. CONCLUSIONS: In contrast to previous epidemiological studies on pediatric hand and foot fractures, we mapped the locations of these fractures, including proximal, shaft, distal, and epiphyseal plate injuries. We analyzed the changing trends in fracture sites and injury etiologies with age. Hand and foot fractures have many accompanying injuries that require attention during diagnosis and treatment. Doctors should formulate accident protection measures for children of different ages, strengthen safety education, and reduce the occurrence of accidental injuries.

Dopant-Free Pyrene-Based Hole Transporting Material Enables Efficient and Stable Perovskite Solar Cells.

Dopant-free hole transporting materials (HTMs) is significant to the stability of perovskite solar cells (PSCs). Here, we developed a novel star-shape arylamine HTM, termed Py-DB, with a pyrene core and carbon-carbon double bonds as the bridge units. Compared to the reference HTM (termed Py-C), the extension of the planar conjugation backbone endows Py-DB with typical intermolecular π-π stacking interactions and excellent solubility, resulting in improved hole mobility and film morphology. In addition, the lower HOMO energy level of the Py-DB HTM provides efficient hole extraction with reduced energy loss at the perovskite/HTM interface. Consequently, an impressive power conversion efficiency (PCE) of 24.33 % was achieved for dopant-free Py-DB-based PSCs, which is the highest PCE for dopant-free small molecular HTMs in n-i-p configured PSCs. The dopant-free Py-DB-based device also exhibits improved long-term stability, retaining over 90 % of its initial efficiency after 1000 h exposure to 25 % humidity at 60 °C. These findings provide valuable insights and approaches for the further development of dopant-free HTMs for efficient and reliable PSCs.

A Biodegradable Janus Sponge for Negative Pressure Wound Therapy.

Negative pressure wound therapy (NPWT) is effective in repairing serious skin injury. The dressing used in the NPWT is important for wound healing. In this paper, we develop biodegradable amphiphilic polyurethanes (PUs) and fabricate the PUs into sponges as wound dressings (Bi@e) with Janus pore architectures for NPWT. The Bi@e is adaptive to all the stages of the wound healing process. The Janus Bi@e sponge consists of two layers: the dense hydrophobic upper layer with small pores provides protection and support during negative pressure drainage, and the loose hydrophilic lower layer with large pores absorbs large amounts of wound exudate and maintains a moist environment. Additionally, antibacterial agent silver sulfadiazine (SSD) is loaded into the sponge against Escherichia coli and Staphylococcus aureus with a concentration of 0.50 wt%. The Janus sponge exhibits a super absorbent capacity of 19.53 times its own water weight and remarkable resistance to compression. In a rat skin defect model, the Janus Bi@e sponge not only prevents the conglutination between regenerative skin and dressing but also accelerates wound healing compared to commercially available NPWT dressing. The Janus Bi@e sponge is a promising dressing for the NPWT.

The Effect of Uncertainty Training on the Improvement of Diagnostic Ability in Chinese Medical Students.

Objective: To evaluate the effect of the uncertainty training on improvement of students' diagnostic ability. Methods: Data were collected on 70 fifth-year medical students enrolled in the Case Discussion courses on Obstetrics and Gynecology in the spring of 2020. Of these students, 36 were in the uncertainty training group and 34 in the control group. The effect of training was evaluated by cognitively diagnostic assessment which mapped exam questions to 4 attributes assessing clinical reasoning and basic science knowledge. Results: Uncertainty training was able to improve students' ability to use basic science concepts for inference and problem solving, and the ability to integrate complex clinical information to arrive at a diagnosis. But it could not improve students' ability on the basic recall of foundational concepts and the ability to use basic science concepts in clinical reasoning. Medical students could do well in integrating complex clinical information although they didn't recall basic science knowledge well. Conclusion: Uncertainty training could be used as an effective teaching method in Case Discussion course on Obstetrics and Gynecology. However, students still need to improve their basic knowledge besides the training.

Identification of Hedyotis diffusa Willd-specific mRNA-miRNA-lncRNA network in rheumatoid arthritis based on network pharmacology, bioinformatics analysis, and experimental verification.

Hedyotis diffusa Willd (HDW) possesses heat-clearing, detoxification, anti-cancer, and anti-inflammatory properties. However, its effects on rheumatoid arthritis (RA) remain under-researched. In this study, we identified potential targets of HDW and collected differentially expressed genes of RA from the GEO dataset GSE77298, leading to the construction of a drug-component-target-disease regulatory network. The intersecting genes underwent GO and KEGG analysis. A PPI protein interaction network was established in the STRING database. Through LASSO, RF, and SVM-RFE algorithms, we identified the core gene MMP9. Subsequent analyses, including ROC, GSEA enrichment, and immune cell infiltration, correlated core genes with RA. mRNA-miRNA-lncRNA regulatory networks were predicted using databases like TargetScan, miRTarBase, miRWalk, starBase, lncBase, and the GEO dataset GSE122616. Experimental verification in RA-FLS cells confirmed HDW's regulatory impact on core genes and their ceRNA expression. We obtained 11 main active ingredients of HDW and 180 corresponding targets, 2150 RA-related genes, and 36 drug-disease intersection targets. The PPI network diagram and three machine learning methods screened to obtain MMP9, and further analysis showed that MMP9 had high diagnostic significance and was significantly correlated with the main infiltrated immune cells, and the molecular docking verification also showed that MMP9 and the main active components of HDW were well combined. Next, we predicted 6 miRNAs and 314 lncRNAs acting on MMP9, and two ceRNA regulatory axes were obtained according to the screening. Cellular assays indicated HDW inhibits RA-FLS cell proliferation and MMP9 protein expression dose-dependently, suggesting HDW might influence RA's progression by regulating the MMP9/miR-204-5p/MIAT axis. This innovative analytical thinking provides guidance and reference for the future research on the ceRNA mechanism of traditional Chinese medicine in the treatment of RA.

Multifunctional Interface Modification Enables Efficient and Stable HTL-Free Carbon-Electroded CsPbI2Br Perovskite Solar Cells.

In recent years, hole transport layer-free all-inorganic CsPbI2Br carbon-electroded perovskite solar cells (C-PSCs) have garnered significant attention due to a trade-off between stability and photovoltaic performance. However, there are inevitably many defects generated at the surfaces or grain boundaries of CsPbI2Br perovskite films, which will serve as carrier non-radiative recombination centers, and CsPbI2Br perovskite films are sensitive to water molecules to degrade, together with energy level mismatch between CsPbI2Br perovskite and carbon electrodes. Herein, 1-benzyl-3-methylimidazolium hexafluorophosphate (1-B-3-MIMPF6), an imidazolium-based ionic liquid simultaneously containing benzene ring and fluorine atoms, was introduced for the modification of the perovskite/carbon interface. The results showed that it could effectively reduce defects, enhance carrier transfer, mitigate carrier non-radiative recombination, facilitate energy alignment, and block moisture intrusion. Therefore, the photovoltaic performance of the modified PSCs with ITO/SnO2/CsPbI2Br/1-B-3-MIMPF6/carbon architecture has been boosted with a champion power conversion efficiency (PCE) of 13.47 %, open circuit voltage of 1.20 V, short circuit current density of 14.69 mA/cm2, and fill factor of 76 %. Moreover, the unencapsulated modified devices exhibited an improved stability and the PCE maintained 78 % of their initial PCE after 24 h storage at room temperature in a 30 %-35 % humidity environment, whereas that of the pristine devices dropped to almost zero.

Identifying the in vivo-induced antigenic genes is a strategy to develop DNA vaccine against Nocardia seriolae in hybrid snakehead (Channa maculata ♀ × Channa argus ♂).

Nocardia seriolae has been identified as the causative agent of fish nocardiosis, resulting in serious economic losses in aquaculture. With an aim to screen potential candidates for vaccine development against N. seriolae, the in vivo-induced genes of N. seriolae in hybrid snakehead (Channa maculate ♀ × Channa argus ♂) model were profiled via in vivo-induced antigen technology (IVIAT) in the present study, and 6 in vivo-induced genes were identified as follows: IS701 family transposase (is701), membrane protein insertase YidC (yidC), ergothioneine biosynthesis glutamate-cysteine ligase (egtA), molybdopterin respectively-dependent oxidoreductase (mol), phosphoketolase family protein (Ppl), hypothetical protein 6747 (hp6747). Additionally, the yidC was inserted into eukaryotic expression vector pcDNA3.1-myc-his-A to construct a DNA vaccine named as pcDNA-YidC to evaluate immunoprotection in hybrid snakehead after artificial challenge with N. serioale. Results showed that the transcription of yidC was detected in spleen, trunk kidney, muscle and liver in vaccinated fish, suggesting that this antigenic gene can be recombinantly expressed in fish. Meanwhile, indexes of humoral immunity were evaluated in the vaccinated fish through assessing specific-antibody IgM and serum enzyme activities, including lysozyme (LZM), superoxide dismutase (SOD), acid phosphatase (ACP) and alkaline phosphatase (AKP). Quantitative real-time PCR analysis indicated that pcDNA-YidC DNA vaccine could notably enhance the expression of immune-related genes (CD4、CD8α、MHCIIα、TNFα、IL-1ß and MHCIα) in 4 tissues (spleen, trunk kidney, muscle and liver) of the vaccinated fish. Finally, an immuno-protection with a relative survival rate of 65.71 % was displayed in vaccinated fish in comparison to the control groups. Taken together, these results indicate that pcDNA-YidC DNA vaccine could boost strong immune responses in hybrid snakehead and show preferably protective efficacy against N. seriolae, indicating that IVIAT is a helpful strategy to screen the highly immunogenic antigens for vaccine development against fish nocardiosis.

Artesunate-loaded solid lipid nanoparticles resist esophageal squamous cell carcinoma by inducing Ferroptosis through inhibiting the AKT/mTOR signaling.

Esophageal squamous cell carcinoma (ESCC) is a severe malignancy with high incidence and mortality rate in China, while the application of standard chemotherapeutic drugs for ESCC meets the barriers of high toxicity and multiple drug resistance (MDR). In recent years, the anticancer effects of artesunate (ART), a Chinese medicine monomer have gained extensive attentions due to its characteristics of low toxicity, high potency, and reversal of MDR. In this study, we develop the artesunate-loaded solid lipid nanoparticles (SLNART) to overcome the poor water solubility and bioavailability of ART, further improving the efficiency of ART on ESCC treatment. Especially mentioned, SLNART is shown to present marked inhibitory effects on ESCC development based on the induction of ferroptosis by two pathways included upregulating TFR to increase Fe2+ ions and inhibiting the AKT/mTOR signaling to downregulate GPX4. Collectively, this study is the first to pave a promising approach for ESCC therapy based on a strategy of developing SLNART to induce ferroptosis by mediating Fe2+ ions and AKT/mTOR signaling.

Inhibition of resurgent Na+ currents by rufinamide.

Na+ channels are essential for the genesis of action potentials in most neurons. After opening by membrane depolarization, Na+ channels enter a series of inactivated states (e.g. the fast, intermediate, and slow inactivated states; or If, Ii, and Is). The inactivated Na+ channel may recover via the open state upon membrane repolarization, giving rise to "resurgent" Na+ currents which could be critical for densely repetitive or burst discharges. We incubated CHO-K1 cells transfected with human NaV1.7 cDNA and measured resurgent currents with whole-cell patch recordings. We found Ii is the major inactivated state responsible for the genesis of resurgent currents. Rufinamide, in therapeutic concentrations, could selectively bind to Ii to slow the recovery process and dose-dependently inhibit resurgent currents. The other Na+ channel-inhibiting antiseizure medications (ASM), such as phenytoin and lacosamide (selectively binds to If and Is, separately), fail to show a similar inhibitory effect in clinically relevant concentrations. Resurgent currents are decreased with lengthening of the prepulse, presumably because of redistribution of the channel from Ii to If. Rufinamide could accentuate the decrease to mimic a use-dependent inhibitory effect. The molecular action of slowing of recovery from inactivation by binding to Ii also explains the highly correlative inhibitory effect of rufinamide on both transient and resurgent Na+ currents. The modest but correlative inhibition of both currents may make a novel synergistic effect and thus strong-enough suppression of pathological repetitive and especially burst discharges. Rufinamide may thus have a unique spectrum of therapeutic applications for disorders with excessive neural excitabilities.

Intercellular Interactions Mediated by HGF And TGF-Β Promote the 3D Spherical and Xenograft Growth of Liver Cancer Cells.

BACKGROUND: Recently, the importance of the interactions between liver cancer cells and fibroblasts has been increasingly recognized; however, many details remain to be explored. METHODS: In this work, we first studied their intercellular interactions using conditioned medium from mouse embryonic fibroblasts (MEFs), then through a previously established coculture model. RESULTS: Culturing in a conditioned medium from MEFs could significantly increase the growth, migration, and invasion of liver cancer cells. The coculture model further demonstrated that a positive feedback loop was formed between transforming growth factor-ß (TGF-ß) from HepG2 cells and mHGF (mouse hepatocyte growth factor) from MEFs during coculture. In this feedback loop, c-Met expression in HepG2 cells was significantly increased, and its downstream signaling pathways, such as Src/FAK, PI3K/AKT, and RAF/MEK/ERK, were activated. Moreover, the proportion of activated MEFs was also increased. More importantly, the growth-promoting effects caused by the interaction of these two cell types were validated in vitro by a 3D spheroid growth assay and in vivo by a xenograft mouse model. CONCLUSION: Collectively, these findings provide valuable insights into the interactions between fibroblasts and liver cancer cells, which may have therapeutic implications for the treatment of liver cancer.

Highly sensitive detection of glucose at a novel non-enzyme electrochemical sensing based on Mo-doped CoO Nanosheets.

In this work, a Mo doped CoO nanosheet grown on nickel foam (labeled as: Mo-CoO) with defect-rich and improved electron transfer capacity was designed to be used as a novel non-enzyme electrode material. Physical characterizations demonstrated the Mo elements were doped inside of the samples and they were mutually stabilized with each other, resulting in a high structural stability electrochemical catalytical activity even if the content of Mo was low. For non-enzymatic glucose electrochemical sensing, the prepared Mo-CoO-1 showed a remarkable sensitivity of 89.3 mA cm-2 mM-1 , and a low detection limit of 0.43 µM. Density functional theory (DFT) studies revealed that the doped Mo atom exhibited a higher d-band center compared to the Co atom. A stronger p-d orbital hybridization between the glucose and the Mo atoms indicated the enhancement of glucose adsorption and activation. Importantly, Mo-CoO-1 provided a good selectivity and long-term stability, which can be expected to be used in future practical applications.

The (dis)engagement of different components of inhibitory control in trilingual language control.

Despite the worldwide prevalence of multilingualism, the knowledge of the relationship between domain-general cognitive control and multilingual language control remains scant. Here we provide new insights into this issue by examining systematically how different components of inhibitory control (i.e., response inhibition and interference suppression) contribute to language control in multilingual populations with high L2 proficiency. To this end, 65 Tibetan-Chinese-English trilinguals highly proficient in L2 were recruited to complete three tasks: a picture-naming task measuring the performance of online trilingual speech production, and two nonlinguistic tasks, a go/no-go task and a Simon task, as proxies for measuring response inhibition and interference suppression abilities, respectively. Using mixed-effects modeling, we analyzed both the trilingual language switching/nonswitching performances and their correlations with these two components of inhibitory control. Our data revealed unexpected patterns of reversed language dominance effect and (a)symmetries in switch costs. Notably, interaction analysis revealed that while response inhibition was robustly engaged in trilingual language control, interference suppression did not appear to play a role. Taken together, our study suggests that, for trilingual speakers highly proficient in L2, the recruitment of different subprocesses of inhibitory control in lexical access was selective and was constrained to reactive and local-level language control. We conclude by discussing theoretical implications. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Combination of serum CST1 and HE4 for early diagnosis of endometrial cancer.

Purpose: Optimal serological biomarkers have been absent for the early diagnosis of endometrial cancer, to date. In this study, we aimed to define the diagnostic performances of individual and combined detection of serum cysteine protease inhibitor 1 (CST1) with traditional tumor markers, including glycated antigen 125 (CA125) and human epididymis protein 4 (HE4), in patients with early-stage endometrial cancer (EC). Methods: The performances of individual and combined detection of serum CST1, HE4, and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) and chemiluminescent immunoassay, respectively. A training data set of 67 patients with early EC, 67 patients with endometrial benign lesion (EBL), and 67 healthy controls (HC) was used to develop a predictive model for early EC diagnosis, which was validated by an independent validation data set. Results: In the training data set, serum CST1 and HE4 levels in the early EC group were significantly higher than in EBL/HC groups (P < 0.05), while there was no significant difference of serum CA125 level between the early EC and EBL/HC groups (P > 0.05). Serum CST1 and HE4 exhibited areas under the curve (AUC) of 0.715 with 31.3% sensitivity at 90.3% specificity, and 0.706 with 23.9% sensitivity at 95.5% specificity, respectively. Combined detection of serum CST1 and HE4 exhibited an AUC of 0.788 with 49.3% sensitivity at 92.5% specificity. The combination of serum CST1 and HE4 showed promise in diagnosis. Conclusion: CST1 is a prospective serological biomarker for early EC diagnosis, and the combination of CST1 and HE4 contributes to the further improvement in the diagnosis of patients with early-stage EC.

Construction and validation of a novel lysosomal signature for hepatocellular carcinoma prognosis, diagnosis, and therapeutic decision-making.

Lysosomes is a well-recognized oncogenic driver and chemoresistance across variable cancer types, and has been associated with tumor invasiveness, metastasis, and poor prognosis. However, the significance of lysosomes in hepatocellular carcinoma (HCC) is not well understood. Lysosomes-related genes (LRGs) were downloaded from Genome Enrichment Analysis (GSEA) databases. Lysosome-related risk score (LRRS), including eight LRGs, was constructed via expression difference analysis (DEGs), univariate and LASSO-penalized Cox regression algorithm based on the TCGA cohort, while the ICGC cohort was obtained for signature validation. Based on GSE149614 Single-cell RNA sequencing data, model gene expression and liver tumor niche were further analyzed. Moreover, the functional enrichments, tumor microenvironment (TME), and genomic variation landscape between LRRSlow/LRRShigh subgroup were systematically investigated. A total of 15 Lysosomes-related differentially expressed genes (DELRGs) in HCC were detected, and then 10 prognosis DELRGs were screened out. Finally, the 8 optimal DELRGs (CLN3, GBA, CTSA, BSG, APLN, SORT1, ANXA2, and LAPTM4B) were selected to construct the LRRS prognosis signature of HCC. LRRS was considered as an independent prognostic factor and was associated with advanced clinicopathological features. LRRS also proved to be a potential marker for HCC diagnosis, especially for early-stage HCC. Then, a nomogram integrating the LRRS and clinical parameters was set up displaying great prognostic predictive performance. Moreover, patients with high LRRS showed higher tumor stemness, higher heterogeneity, and higher genomic alteration status than those in the low LRRS group and enriched in metabolism-related pathways, suggesting its underlying role in the progression and development of liver cancer. Meanwhile, the LRRS can affect the proportion of immunosuppressive cell infiltration, making it a vital immunosuppressive factor in the tumor microenvironment. Additionally, HCC patients with low LRRS were more sensitive to immunotherapy, while patients in the high LRRS group responded better to chemotherapy. Upon single-cell RNA sequencing, CLN3, GBA, and LAPTM4B were found to be specially expressed in hepatocytes, where they promoted cell progression. Finally, RT-qPCR and external datasets confirmed the mRNA expression levels of model genes. This study provided a direct links between LRRS signature and clinical characteristics, tumor microenvironment, and clinical drug-response, highlighting the critical role of lysosome in the development and treatment resistance of liver cancer, providing valuable insights into the prognosis prediction and treatment response of HCC, thereby providing valuable insights into prognostic prediction, early diagnosis, and therapeutic response of HCC.

SGK1 is involved in doxorubicin-induced chronic cardiotoxicity and dysfunction through activation of the NFκB pathway.

Breast cancer is the predominant cancer among women worldwide, and chemotherapeutic agents, such as doxorubicin (DOX), have the potential to significantly prolong survival, albeit at the cost of inducing severe cardiovascular toxicity. Inflammation has emerged as a crucial biological process contributing to the remodeling of cardiovascular toxicity. The role of serum glucocorticoid kinase 1 (SGK1) in various inflammatory diseases has been extensively investigated. Here, we studied the molecular mechanisms underlying the function of SGK1 in DOX-induced cardiotoxicity in HL-1 cardiomyocyte cell lines and in a tumor-bearing mouse model. SGK1 was upregulated in the DOX-induced cardiotoxicity model, accompanied by increased levels of inflammatory factors. Furthermore, inhibition of SGK1 suppresses the phosphorylation of nuclear factor-kappa B (NFκB) in cardiomyocytes, which inhibits the production of inflammatory factors and apoptosis of cardiomyocytes, and has cardioprotective effects. Simultaneously, small interfering RNA targeting SGK1 inhibited the proliferation of breast cancer cells. Conversely, overexpression of SGK1 increases the phosphorylation of NFκB and aggravates myocardial injury. In conclusion, our study demonstrates that SGK1 promotes DOX-induced cardiac inflammation and apoptosis by promoting NFκB activity. Our results indicate that inhibiting SGK1 might be an effective treatment strategy that can provide both tumor-killing and cardioprotective functions. Further in vivo research is needed to fully elucidate the effects and mechanisms of combination therapy with SGK1 inhibitors and DOX in breast cancer treatment.

Tamoxifen induced cardiac damage via the IL-6/p-STAT3/PGC-1α pathway.

Tamoxifen (TAM) is an effective anticancer drug for breast and ovarian cancer. However, increased risk of cardiotoxicity is a long-term clinical problem associated with TAM, while the underlying mechanisms remain unclear. Here, we performed experiments in cardiomyocytes and tumor-bearing or nontumor-bearing mice, and demonstrated that TAM induced cardiac injury via the IL-6/p-STAT3/PGC-1α/IL-6 feedback loop, which is responsible for reactive oxygen species (ROS) accumulation. Compared with non-tumor bearing mice, tumor-bearing mice showed stronger cardiac toxicity after TAM injection, although there was no significant difference. In vitro experiments demonstrated STAT3 phosphorylation inhibitor can increase PGC-1α expression and protect cardiomyocyte via decreasing ROS. Since tumor has higher STAT3 phosphorylation and IL-6 expression level, our research results indicated combining TAM and STAT3 inhibitor might be an effective treatment strategy which can provide both tumor killing and cardioprotective function. Further in vivo research is needed to fully elucidate the effect and mechanisms of the combination therapy of TAM and STAT3 inhibitor.

Decoupling control of radial 4 degree of freedom system of magnetic-liquid double suspension bearing based on generalized extended state observer.

As the novel suspension bearing, Magnetic-Liquid Double Suspension Bearing (MLDSB) is mainly supported by magnetic suspension and supplemented by a liquid hydrostatic bearing. Due to its great bearing capacity and stiffness, rapid response, great active control, and so on, MLDSB is suitable for medium speed heavy loads and has a large carrying capacity and high operating stability. In addition, the radial inertia coupling and gyroscopic coupling between radial 4-DOF control channels can reduce control precision, operation stability, and reliability of MLDSB. Therefore, a mathematical model of radial 4-DOF rotor-dynamics of MLDSB is established in this paper, and the inherent coupling mechanism is explored. Taking inertial coupling, gyroscopic coupling, and external disturbance loads as lumped disturbances, a decoupled controller based on Generalized Extended State Observer (GESO) is established. The influence of the GESO controller on the decoupling and control performance of radial 4-DOF control channels is simulated. The results indicate that the decoupling effect of the GESO controller is great. Under the action of step signal, the steady displacement, maximum displacement, adjustment time, and peak time of the rotor after decoupling are all reduced, among which the steady displacement and maximum displacement are the most obvious. Under the sinusoidal signal, the steady displacement and maximum displacement are reduced by 90%, which can effectively avoid the "gap-impact" fault. Under the pulse signal, the steady displacement, maximum displacement, adjustment time, and peak time are all reduced, among which the maximum displacement is the most obvious. The research in this paper can provide a theoretical reference for the stable support and decoupling control of MLDSB.