Comparative study of job burnout in Shanghai-based nurses against Maslach norm and Hangzhou norm.

AIM: This study aimed to analyze the trend in job burnout among nurses in Shanghai, China. BACKGROUND: The nursing profession globally faces a significant challenge due to aging populations, causing a human resources crisis. Job burnout notably impacts nurses' enthusiasm for work and their overall well-being. Understanding the trends in job burnout among nurses is crucial for addressing this issue. METHODS: A cross-sectional study involving 799 nurses from a tertiary-care hospital and 11 community health service centers in Pudong New Area South, Shanghai, was conducted using convenience sampling. Data were collected through a general information questionnaire and the Maslach Burnout Inventory scale, to assess job burnout levels. These data were compared with the established Maslach and Hangzhou norms in China. RESULTS: 74.6% of the participants experienced job burnout. The emotional exhaustion dimension had an average score of 27.27 ± 13.93, indicating high levels of burnout; the depersonalization dimension had an average score of 7.83 ± 6.68, showing moderate levels of fatigue; and the personal achievement dimension had an average score of 26.75 ± 10.26, also indicating moderate fatigue. Notably, nurses aged 32-33 years with 11-12 years of professional experience were the most affected. The findings suggest that job burnout is a significant issue in Pudong New Area South, Shanghai, with a notable increase in severe burnout cases over the past decade. CONCLUSION: Nurses, particularly during the COVID-19 pandemic, face high rates of burnout, with emotional exhaustion being particularly prevalent. To support and retain the nursing workforce, hospital administrators must implement external reward mechanisms and develop policies that encourage personal growth, career development, and a humanistic approach to care. IMPLICATIONS FOR NURSING AND HEALTH POLICY: From our review of the literature, we identified instances where burnout standards are either not assessed or lack uniformity in their application. Therefore, it is imperative to adopt a standardized occupational burnout scale for a nationwide survey, encompassing nurse populations across various levels, including province, region, city, and institution. This approach will facilitate the establishment of a practical norm for occupational burnout within China. This norm would enable conducting regular assessments and comparisons to understand the evolving trends of job burnout among nurses, which could pave the way for the creation of targeted support interventions for the nursing profession.

Competitive-like binding between carbon black and CTNNB1 to ΔNp63 interpreting the abnormal respiratory epithelial repair after injury.

Airway epithelium is extraordinary vulnerable to damage owning to continuous environment exposure. Subsequent repair is therefore essential to restore the homeostasis of respiratory system. Disruptions in respiratory epithelial repair caused by nanoparticles exposure have been linked to various human diseases, yet implications in repair process remain incompletely elucidated. This study aims to elucidate the key stage in epithelial repair disturbed by carbon black (CB) nanoparticles, highlighting the pivotal role of ΔNp63 in mediating the epithelium repair. A competitive-like binding between CB and beta-catenin 1 (CTNNB1) to ΔNp63 is proposed to elaborate the underlying toxicity mechanism. Specifically, CB exhibits a remarkable inhibitory effect on cell proliferation, leading to aberrant airway epithelial repair, as validated in air-liquid culture. ΔNp63 drives efficient epithelial proliferation during CB exposure, and CTNNB1 was identified as a target of ΔNp63 by bioinformatics analysis. Further molecular dynamics simulation reveals that oxygen-containing functional groups on CB disrupt the native interaction of CTNNB1 with ΔNp63 through competitive-like binding pattern. This process modulates CTNNB1 expression, ultimately restraining proliferation during respiratory epithelial repair. Overall, the current study elucidates that the diminished interaction between CTNNB1 and ΔNp63 impedes respiratory epithelial repair in response to CB exposure, thereby enriching the public health risk assessment on CB-related respiratory diseases.

"Cicada Out of the Shell" Deep Penetration and Blockage of the HSP90 Pathway by ROS-Responsive Supramolecular Gels to Augment Trimodal Synergistic Therapy.

Deep penetration and downregulation of heat shock protein (HSP) expression in multimodal synergistic therapy are promising approaches for curing cancer in clinical trials. However, free small-molecule drugs and most drug vehicles have a low delivery efficiency deep into the tumor owing to poor drug penetration and hypoxic conditions at the tumor site. In this study, the objective is to use reactive oxygen species (ROS)-responsive supramolecular gels co-loaded with the photosensitizer Zn(II) phthalocyanine tetrasulfonic acid (ZnPCS4) and functionalized tetrahedral DNA (TGSAs) (G@P/TGSAs) to enhance deep tissue and cell penetration and block the HSP90 pathway for chemo- photodynamic therapy (PDT) - photothermal therapy (PTT) trimodal synergistic therapy. The (G@P/TGSAs) are injected in situ into the tumor to release ZnPCS4 and TGSAs under high ROS concentrations originating from both the tumor and PDT. TGSAs penetrate deeply into tumor tissues and augment photothermal therapy by inhibiting the HSP90 pathway. Proteomics show that HSP-related proteins and molecular chaperones are inhibited/activated, inhibiting the HSP90 pathway. Simultaneously, the TGSA-regulated apoptotic pathway is activated. In vivo study demonstrates efficient tumor penetration and excellent trimodal synergistic therapy (45% tumor growth inhibition).

Rituximab potentially improves clinical outcomes of CAR-T therapy for r/r B-ALL via sensitizing leukemia cells to CAR-T-mediated cytotoxicity and reducing CAR-T exhaustion.

PURPOSE: Despite chimeric antigen receptor (CAR) T-cell therapy has achieved great advances in recent year, approximately 50% of relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) patients treated with CAR-T experience relapse 6 months post CAR-T treatment. CD20 express on 30 to 50% of B-ALL, which makes CD20 Monoclonal Antibody as one of the potential therapy strategies to decrease the tumor burden and improve the efficacy of CAR-T therapy. Adding Rituximab to chemotherapy protocol had been demonstrated to improve the outcome for CD20-positive ALL. However, rare study explored the influence of Rituximab combined with CAR-T therapy. METHODS: We retrospectively analyzed 20 r/r B-ALL patients who received CAR-T therapy, all of whom had failed multiple lines of therapy. Before CAR-T infusion, we administered Rituximab to 10 patients with high CD20 expression at a dose of 375 mg/m2 for 1 day. Meanwhile, we selected 10 patients with the comparable features who underwent CAR-T treatment without Rituximab in the same period as the control group. In vitro, the surface molecule expression and killing of CAR-T post Rituximab-treated B-ALL cells co-incubated with CAR-T cells were detected by flow cytometry. RESULTS: The median follow-up of Rituximab and Control groups were 29.27 and 9.83 months. We found that adding Rituximab may confer a favorable prognosis compared with Control group. The 2-year overall survival (OS) and leukemia-free survival (LFS) rates both were longer in the Rituximab group (90% vs. 26.7%, p = 0.0342; 41.7% vs. 25%, p = 0.308). In vitro, we observed that Rituximab-treated tumour cells are more sensitive to CAR-T killing and a broad range of cytokines and chemokines were produced when Rituximab-treated Nalm-6 cells co-cultured with 19-22CAR-T cells, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). To investigate whether Rituximab has an effect on CAR-T persistence, we stimulated CAR-T cells repeatedly in vitro with Rituximab-treated Nalm-6 to evaluate the changes in CAR-T surface exhaustion molecules at different times. We found that the expression of exhaustion molecules (LAG-3, PD-1, TIM-3) on CAR-T cells were significantly lower in the Rituximab group than in the Control group. CONCLUSION: Rituximab combined with CAR-T therapy is effective for improving the long-term prognosis of B-ALL patients who have failed multiple lines of therapy. In vitro, we observed that rituximab potentially improves CAR-T efficacy by sensitizing ALL to CART-mediated cytotoxicity and reducing CAR-T exhaustion.

Comparison of valganciclovir versus foscarnet for the treatment of cytomegalovirus viremia in adult acute leukemia patients after allogeneic hematopoietic cell transplantation.

Cytomegalovirus (CMV) reactivation increases treatment-related mortality (TRM) after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed 141 adult acute leukemia (AL) patients suffered allo-HCT between 2017 and 2021, who developed CMV viremia post-HCT and treated with valganciclovir or foscarnet, to evaluate effectiveness and safety of both drugs. Viremia clearance rates (14 and 21 d post treatment) and toxicities were similar in two groups. However, valganciclovir was associated with a lower cumulative incidence of CMV recurrence within 180 days (16.7% vs. 35.7%, p=0.029) post CMV clearance. Finally, 2-year TRM was lower in valganciclovir group (9.7% ± 0.2% vs. 26.2% ± 0.3%, p = 0.026), result a superior 2-year overall survival (OS; 88.1% ± 5.2% vs. 64.4% ± 5.5%, p = 0.005) and leukemia-free survival (LFS; 82.0% ± 5.9% vs. 58.9% ± 5.6%, p = 0.009). Valganciclovir might decrease CMV viremia recurrence and led to better long-term outcome than foscarnet in adult AL patients developed CMV viremia post-HCT. Considering the inherent biases of retrospective study, well-designed trials are warranted to validate our conclusion.

Successful treatment of a B/T MPAL patient by chemo-free treatment with venetoclax, azacitidine, and blinatumomab.

B/T mixed phenotype acute leukemia (MPAL), which represents only 2-3% of all MPAL cases, is classified as a high-risk leukemia subtype. Adults diagnosed with B/T MPAL have a notably low 3-year survival rate, estimated at 20-40%. The rarity and undercharacterization of B/T MPAL present substantial challenges in identifying an optimal treatment protocol. This report aims to shed light on this issue by presenting a case in which a patient with a complex karyotype was treated using a combination of venetoclax, azacitidine, and blinatumomab. This novel, chemo-free regimen resulted in the patient achieving both hematologic and molecular complete remission, with no severe organ or hematological toxicity observed. Notably, the patient continued to maintain molecular remission for 1 year following the transplantation. Based on these findings, the combination of venetoclax, azacitidine, and blinatumomab could be considered a potential therapeutic approach for B/T MPAL patients, meriting further investigation.

The Role of IL-6, IL-10, and TNF-α in Ocular GVHD Following Allogeneic Transplantation.

PURPOSE: To figure out the roles of tear inflammatory cytokines in Ocular graft-versus-host disease (oGVHD) symptoms by analyzing tear cytokine levels and related factors. METHODS: This prospective study involved 27 post-HSCT patients and 19 controls with dry eye disease. Analyses included tear cytokine (IL-6, IL-10, and TNF-α), ocular surface evaluation, and conjunctival impression cell examination. Tear cytokine levels were evaluated in three grades of corneal epithelial lesions. The study also analyzed the correlation between tear cytokine levels and ocular surface parameters. Tear cytokine levels were then used in a Receiver Operating Characteristic (ROC) curve and linear regression model to predict oGVHD related factors. RESULTS: IL-6 has good diagnostic efficacy in oGVHD related dry eye. Elevated levels of tear IL-6 and TNF-α were observed in the group with severe corneal epithelial lesions. IL-6 levels were positively correlated with corneal fluorescein staining (CFS), eyelid margin hyperemia, conjunctival lesions, and meibum secretion. IL-6 showed excellent predictive ability with Area Under the Curve (AUC) values all greater than 0.70 (p < 0.05). IL-10 and TNF-α were negatively correlated with the meibomian gland proportion and conjunctival goblet cell (GC) density, while TNF-α was positively correlated with CFS and eyelid margin hyperemia. CONCLUSION: Dry eye symptoms related to ocular GVHD, can be partly diagnosed and assessed using various tear cytokine level detection methods.

Lusianthridin ameliorates high fat diet-induced metabolic dysfunction-associated fatty liver disease via activation of FXR signaling pathway.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease, but there are few specific medications for it. Lusianthridin, a major phenanthrene component that originates from Dendrobium Sonia, has various in vitro biological functions. In this study, we aimed to evaluate the therapeutic effects of lusianthridin on high-fat diet (HFD)-induced MAFLD as well as to examine the mechanism of its effects. We fed male mice high-fat-diet for 12 weeks to induce MAFLD and then continued to feed them, either with or without lusianthridin, for another six weeks. We found that lusianthridin decreased serum triacylglycerol, hepatic triacylglycerol, and serum low density lipoprotein cholesterol. It also reduced hepatic lipid accumulation based on the results of morphology analysis. Besides, it improved hepatic inflammation as well, including a decrease in serum alanine aminotransferase and a reduction in macrophage and neutrophil infiltration. Mechanistically, surface plasmon resonance, cell thermal shift assay and dual-luciferase report system results suggested that lusianthridin combined with farnesoid X receptor (FXR) ligand binding region and activated its transcriptional activity. Lusianthridin also decreased de no lipogenesis though inhibiting Srebp1c and downstream Scd-1, Lpin1 and Dgat2 expression in a FXR-dependent manner in oleic acid treated L02 cells. Correspondingly, lusianthridin inhibited Srebp1c and downstream lipogenesis in MAFLD liver tissues of mice at both of genetic and protein levels. Finally, the protective effects of lusianthridin on hepatic steaotosis were abolished in Fxr-/- mice. Taken together, our results suggested that lusianthridin attenuated high-fat-diet induced MAFLD via activation the FXR signaling pathway.

Selective inhibition of overactive warmth-sensitive Ca2+-permeable TRPV3 channels by antispasmodic agent flopropione for alleviation of skin inflammation.

The temperature-sensitive Ca2+-permeable TRPV3 ion channel is robustly expressed in the skin keratinocytes, and its gain-of-function mutations are involved in the pathology of skin lesions. Here, we report the identification of an antispasmodic agent flopropione that alleviates skin inflammation by selective inhibition of TRPV3. In whole-cell patch clamp recordings, flopropione selectively inhibits macroscopic TRPV3 currents in a concentration-dependent manner with an IC50 value of 17.8 ± 3.5 µM. At the single-channel level, flopropione inhibits TRPV3 channel open probability without alteration of its unitary conductance. In an in vivo mouse model of skin inflammation induced by the skin sensitizer DNFB, flopropione also alleviates dorsal skin lesions and ear skin swelling. Further molecular docking combined with site-directed mutagenesis reveals that two residues E501 and I505 in the channel S2-helix are critical for flopropione-mediated inhibition of TRPV3. Taken together, our findings demonstrate that the spasmolytic drug flopropione as a selective inhibitor of TRPV3 channel not only provides a valuable tool molecule for understanding of TRPV3 channel pharmacology but also holds repurposing potential for therapy of skin disorders, such as dermatitis and pruritus.

Synergistic cytotoxicity of fludarabine, clofarabine, busulfan, vorinostat and olaparib in AML cells.

Combinations of nucleoside analog(s) and DNA alkylating agent(s) are used for cancer treatment as components of pre-transplant regimens used in hematopoietic stem cell transplantation. Their efficacies are enhanced by combining drugs with different mechanisms of action, which also allows a reduction in the individual drug dosages and thus potentially in toxicity to the patient. We hypothesized that addition of SAHA and olaparib, an HDAC- and a PARP-inhibitor, respectively, to the established combination of fludarabine, clofarabine and busulfan would enhance AML cell cytotoxicity. Exposure of the AML cell lines KBM3/Bu2506, MV4-11, MOLM14 and OCI-AML3 to the 5-drug combination resulted in synergistic cytotoxicity with combination indexes < 1. Increased protein acetylation and decreased poly(ADP-ribosyl)ation were observed, as expected. Activation of apoptosis was suggested by cleavage of Caspase 3 and PARP1, DNA fragmentation, increased reactive oxygen species, and decreased mitochondrial membrane potential. The reduction in poly(ADP-ribosyl)ation was independent of caspase activation. Several proteins involved in DNA damage response and repair were downregulated, which may be contributing factors for the observed synergism. The increased phosphorylation of DNAPKcs suggests inhibition of its kinase activity and diminution of its role in DNA repair. A similar synergism was observed in patient-derived cell samples. These findings will be important in designing clinical trials using these drug combinations as pre-transplant conditioning regimens for AML patients.

EQUIBIND: A geometric deep learning-based protein-ligand binding prediction method.

Structure-based virtual screening plays a critical role in drug discovery. However, numerous docking programs, such as AutoDock Vina and Glide, are time-consuming due to the necessity of generating numerous molecular conformations and executing steps like scoring, ranking, and refinement for the ligand-receptor complexes. Consequently, achieving rapid and reliable virtual screening remains a noteworthy challenge. Recently, a team of researchers from Massachusetts Institute of Technology, led by Stärk et al., developed an SE(3)-equivariant geometric deep learning based protein-ligand binding prediction approach, EQUIBIND. In comparison to conventional docking methods, EQUIBIND has the capacity to predict the binding modes of small molecules with target proteins rapidly and precisely. It presents an innovative resolution for high-throughput screening of drug-like compounds.

Hepatotoxicity assessment investigations on PFASs targeting L-FABP using binding affinity data and machine learning-based QSAR model.

Per- and polyfluoroalkyl substances (PFASs) are persistent organic pollutants that have been detected in various environmental media and human serum, but their safety assessment remains challenging. PFASs may accumulate in liver tissues and cause hepatotoxicity by binding to liver fatty acid binding protein (L-FABP). Therefore, evaluating the binding affinity of PFASs to L-FABP is crucial in assessing the potential hepatotoxic effects. In this study, two binding sites of L-FABP were evaluated, results suggested that the outer site possessed high affinity to polyfluoroalkyl sulfates and the inner site preferred perfluoroalkyl sulfonamides, overall, the inner site of L-FABP was more sensitive to PFASs. The binding affinity data of PFASs to L-FABP were used as training set to develop a machine learning model-based quantitative structure-activity relationship (QSAR) for efficient prediction of potentially hazardous PFASs. Further Bayesian Kernel Machine Regression (BKMR) model disclosed flexibility as the determinant molecular property on PFASs-induced hepatotoxicity. It can influence affinity of PFASs to target protein through affecting binding conformations directly (individual effect) as well as integrating with other molecular properties (joint effect). Our present work provided more understanding on hepatotoxicity of PFASs, which could be significative in hepatotoxicity gradation, administration guidance, and safer alternatives development of PFASs.

A fully validated flow cytometry method to quantitatively analyze active rATG in human serum and its application in pharmacokinetic study for therapeutic drug monitoring.

Rabbit anti-thymocyte globulin (rATG) has been widely used to prevent graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The therapeutic window of rATG is narrow, and it may increase the risk of relapse, viral reactivation, delayed immune reconstitution and GvHD when overexposed or underexposed. Therefore, a reliable method for detecting the rATG concentration in human serum by flow cytometry was established and fully validated for therapeutic drug monitoring. In this method, Jurkat T cells were used to capture active rATG in human serum, and PE-labeled donkey anti-rabbit IgG was used as a secondary antibody. The method showed good specificity, selectivity and excellent linearity at concentration of 0.00300-20.0 AU/mL. The intra- and interday precision values were all within 20% at four concentration levels for the analyte. The stock solutions of rATG showed no significant degradation after storage at ambient temperature for 8 h and at - 80 °C for 481 days. No significant degradation of rATG in serum was observed at ambient temperature for 6 h, during six freezethaw cycles and at - 80 °C for at least 373 days. This method was fully validated and successfully applied to monitor active rATG concentration in serum of patients with haploid-identical hematopoietic stem cell transplantation.

Isomerization of bioactive acylhydrazones triggered by light or thiols.

The acylhydrazone unit is well represented in screening databases used to find ligands for biological targets, and numerous bioactive acylhydrazones have been reported. However, potential E/Z isomerization of the C=N bond in these compounds is rarely examined when bioactivity is assayed. Here we analysed two ortho-hydroxylated acylhydrazones discovered in a virtual drug screen for modulators of N-methyl-D-aspartate receptors and other bioactive hydroxylated acylhydrazones with structurally defined targets reported in the Protein Data Bank. We found that ionized forms of these compounds, which are populated under laboratory conditions, photoisomerize readily and the isomeric forms have markedly different bioactivity. Furthermore, we show that glutathione, a tripeptide involved with cellular redox balance, catalyses dynamic E⇄Z isomerization of acylhydrazones. The ratio of E to Z isomers in cells is determined by the relative stabilities of the isomers regardless of which isomer was applied. We conclude that E/Z isomerization may be a common feature of the bioactivity observed with acylhydrazones and should be routinely analysed.