De novo design of a nanoregulator for the dynamic restoration of ovarian tissue in cryopreservation and transplantation.

The cryopreservation and transplantation of ovarian tissue underscore its paramount importance in safeguarding reproductive capacity and ameliorating reproductive disorders. However, challenges persist in ovarian tissue cryopreservation and transplantation (OTC-T), including the risk of tissue damage and dysfunction. Consequently, there has been a compelling exploration into the realm of nanoregulators to refine and enhance these procedures. This review embarks on a meticulous examination of the intricate anatomical structure of the ovary and its microenvironment, thereby establishing a robust groundwork for the development of nanomodulators. It systematically categorizes nanoregulators and delves deeply into their functions and mechanisms, meticulously tailored for optimizing ovarian tissue cryopreservation and transplantation. Furthermore, the review imparts valuable insights into the practical applications and obstacles encountered in clinical settings associated with OTC-T. Moreover, the review advocates for the utilization of microbially derived nanomodulators as a potent therapeutic intervention in ovarian tissue cryopreservation. The progression of these approaches holds the promise of seamlessly integrating nanoregulators into OTC-T practices, thereby heralding a new era of expansive applications and auspicious prospects in this pivotal domain.

Association between preprocedural serum potassium level and atrial fibrillation recurrence after catheter ablation.

BACKGROUND: The association between serum potassium and atrial fibrillation (AF) recurrence after catheter ablation remains unclear. OBJECTIVE: To investigate whether preprocedural serum potassium influences AF recurrence in patients underwent catheter ablation. METHODS: We used data of AF patients who underwent de novo catheter ablation from the prospective Chinese Atrial Fibrillation Registry Study (CAFR). Patients with prior ablation and without baseline serum potassium were excluded. The primary outcome was 1-year AF recurrence after 3-month blanking period from the ablation. Restricted cubic spline and Cox proportional models were used to compare outcomes across serum potassium categories. RESULTS: A total of 4838 AF patients with de novo catheter ablation was enrolled. At 1 year, AF recurrence occurred in 1347 (27.8%) patients. The relationship between preprocedural serum potassium and 1-year AF recurrence after ablation presented as U-shape (P for nonlinear = 0.048). Compared with the group of serum potassium within 4.41-4.60 mmol/L, the risk of AF recurrence increased significantly in the lowest serum potassium group (≤4.00 mmol/L) after multivariate analysis (HR 1.26, 95% CI 1.06-1.51, P = 0.010). Other categories with lower or higher serum potassium levels including 4.01-4.20 mmol/L (HR=1.18), 4.21-4.40 mmol/L (HR=1.16), 4.61-4.80 mmol/L (HR=1.07) and ≥4.81 mmol/L (HR=1.11) showed nonsignificant higher recurrence risk. CONCLUSIONS: The relationship between preprocedural potassium and AF recurrence was U-shaped, with an optimal potassium range (4.41-4.60 mmol/L). Lower potassium level is associated with increased AF recurrence risk after catheter ablation.

Progress of researches on mechanisms of acupuncture for secondary prevention of ischemic stroke. / é’ˆåˆºå‚ä¸Žç¼ºè¡€æ€§è„‘å’ä¸­äºŒçº§é¢„é˜²çš„ç ”ç©¶è¿›å±•.

Ischemic stroke (IS) is one of the main causes inducing death and disability in adults. Because of the high recurrence rate of IS, prevention of recurrence is of great significance to this population, for which the evidence-based and effective secondary prevention strategy is an important means, and acupuncture intervention has a positive effect on its risk factors. In the present article, we reviewed the progress of researches on the mechanisms of acupuncture underlying prevention of IS relapse from the perspective of its main risk factors, namely 1) hypertension (preventing and controlling the adverse effects caused by the imbalance of blood pressure level, vascular and other tissue structures, endocrine factors and central nervous system activities in patients with hypertension after IS), 2) hypercholesterolemia (lowering serum total cholesterol, triglyceride, low-density lipoprotein-cholesterol (LDL-C) and raising high-density lipoprotein cholesterol), 3) diabetes (regulating the secretion function of adipose tissue, activating the insulin signal transduction pathway, protecting the function of pancreatic ß cells, and regulating the central nervous system functions to participate in the secondary prevention of IS), 4) smoking (relieving the symptoms of smoking cessation and reducing the smoker's dependence on smoking by changing the internal environment, lowering the level of blood endorphin and regulating the excitability of central nervous system), 5) sleep apnea syndrome (regulating local muscle function and the excitability of the nervous system, but also affecting some organic changes as reducing tonsil swelling) and 6) obesity (lowering blood glucose and lipid, increasing the ratio of brown/white fat, reducing leptin resistance, and suppressing appetite to induce body weight loss, or directly regulate the changes of fat tissue, etc). Results shows that the acupuncture's regulatory mechanism for IS risk factors is closely related to the neuroendocrine system, and simultaneously involves multiple targets of multiple risk factors. Due to its good efficacy and safety, acupuncture therapy is of great value for clinical promotion as an important intervention for secondary prevention.

Efficacy and safety of sovleplenib (HMPL-523) in adult patients with chronic primary immune thrombocytopenia in China (ESLIM-01): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Sovleplenib, a novel spleen tyrosine kinase (SYK) inhibitor, showed promising safety and activity in patients with primary immune thrombocytopenia in a phase 1b/2 trial. We aimed to evaluate the efficacy and safety of sovleplenib in patients with chronic primary immune thrombocytopenia. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial (ESLIM-01) was done in 34 clinical centres in China. Eligible patients, aged 18-75 years, had chronic primary immune thrombocytopenia, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and received one or more previous treatments. Patients were randomly assigned (2:1) to receive oral sovleplenib or placebo, 300 mg once daily, for 24 weeks. Randomisation was stratified by baseline platelet counts, previous splenectomy, and concomitant treatment for anti-immune thrombocytopenia at baseline. The primary endpoint was durable response rate (proportion of patients with a platelet count of ≥50 × 109/L on at least four of six scheduled visits between weeks 14 and 24, not affected by rescue treatment) assessed by intention-to-treat. The trial is registered with ClinicalTrials.gov, NCT05029635, and the extension, open-label phase is ongoing. FINDINGS: Between Sept 29, 2021, and Dec 31, 2022, 188 patients were randomly assigned to receive sovleplenib (n=126) or placebo (n=62). 124 (66%) were female, 64 (34%) were male, and all were of Asian ethnicity. Median previous lines of immune thrombocytopenia therapy were 4·0, and 134 (71%) of 188 patients had received previous thrombopoietin or thrombopoietin receptor agonist. The primary endpoint was met; durable response rate was 48% (61/126) with sovleplenib compared with zero with placebo (difference 48% [95% CI 40-57]; p<0·0001). The median time to response was 8 days with sovleplenib compared with 30 days with placebo. 125 (99%) of 126 patients in the sovleplenib group and 53 (85%) of 62 in the placebo group reported treatment-emergent adverse events (TEAEs), and most events were mild or moderate. Frequent TEAEs of grade 3 or higher for sovleplenib versus placebo were platelet count decreased (7% [9/126] vs 10% [6/62]), neutrophil count decreased (3% [4/126] vs 0% [0/62]), and hypertension (3% [4/126] vs 0% [0/62]). Incidences of serious TEAEs were 21% (26/126) in the sovleplenib group and 18% (11/62) in the placebo group. There were no deaths in the study. INTERPRETATION: Sovleplenib showed a clinically meaningful sustained platelet response in patients with chronic primary immune thrombocytopenia, with a tolerable safety profile and improvement in quality of life. Sovleplenib could be a potential treatment option for patients with immune thrombocytopenia who received one or more previous therapy. FUNDING: HUTCHMED and Science and Technology Commission of Shanghai Municipality.

Motico: An attentional mechanism network model for smart aging disease risk prediction based on image data classification.

The current disease risk prediction model with many parameters is complex to run smoothly on mobile terminals such as tablets and mobile phones in imaginative elderly care application scenarios. In order to further reduce the number of parameters in the model and enable the disease risk prediction model to run smoothly on mobile terminals, we designed a model called Motico (An Attention Mechanism Network Model for Image Data Classification). During the implementation of the Motico model, in order to protect image features, we designed an image data preprocessing method and an attention mechanism network model for image data classification. The Motico model parameter size is only 5.26 MB, and the memory only takes up 135.69 MB. In the experiment, the accuracy of disease risk prediction was 96 %, the precision rate was 97 %, the recall rate was 93 %, the specificity was 98 %, the F1 score was 95 %, and the AUC was 95 %. This experimental result shows that our Motico model can implement classification prediction based on the image data classification attention mechanism network on mobile terminals.

Altering electronic structure of nickel foam supported CoNi-based oxide through Al ions modulation for efficient oxygen evolution reaction.

Developing highly active and durable non-precious metal-based electrocatalysts for the oxygen evolution reaction (OER) is crucial in achieving efficient energy conversion. Herein, we reported a CoNiAl0.5O/NF nanofilament that exhibits higher OER activity than previously reported IrO2-based catalysts in alkaline solution. The as-synthesized CoNiAl0.5O/NF catalyst demonstrates a low overpotential of 230 mV at a current density of 100 mA cm-2, indicating its high catalytic efficiency. Furthermore, the catalyst exhibits a Tafel slope of 26 mV dec-1, suggesting favorable reaction kinetics. The CoNiAl0.5O/NF catalyst exhibits impressive stability, ensuring its potential for practical applications. Detailed characterizations reveal that the enhanced activity of CoNiAl0.5O/NF can be attributed to the electronic modulation achieved through Al3+ incorporation, which promotes the emergence of higher-valence Ni metal, facilitating nanofilament formation and improving mass transport and charge transfer processes. The synergistic effect between nanofilaments and porous nickel foam (NF) substrate significantly enhances the electrical conductivity of this catalyst material. This study highlights the significance of electronic structures for improving the activity of cost-effective and non-precious metal-based electrocatalysts for the OER.

Effect of Self-developed Ye'an Analgetic Decoction/Jiawei Shaoyao Gancao Decoction Combined with Tramadol on TCM Symptom Scores and RLS Severity of patients with Restless Legs Syndrome.

Objective: To investigate the effect of self-developed Ye'an Analgetic Decoction/Jiawei Shaoyao Gancao Decoction on Traditional Chinese Medicine (TCM) symptom scores and RLS Severity of patients with restless legs syndrome (RLS). Methods: This was a clinical comparative study. Eighty patients with RLS admitted to Baoding No.1 Central Hospital from January 2022 to December 2022 were randomly divided into observation group and control group(n=40). Patients in the control group were given basic and oral tramadol treatment, while those in the observation group were given self-developed Ye'an Analgetic Decoction/Jiawei Shaoyao Gancao Decoction based on the treatment in the control group. The differences of TCM symptom scores, RLS severity (IRLS), quality of life (QOL-RLS), sleep quality (PSQI) and clinical efficacy between the two groups were compared. Results: Before treatment, no statistically significant differences were observed in the TCM symptom scores, IRLS scores, QOL-RLS scores and PSQI scores between the two groups (p>0.05). After treatment, the above scores decreased significantly in both groups, with a higher degree of decrease in the observation group than in the control group, indicating statistically significant differences (p<0.05). The QOL-RLS scores were significantly higher in the observation group than in the control group, with a statistically significant difference (p<0.05). The overall response rate in the observation group was 95.00%, which was higher than that in the control group (80.00%), with a statistically significant difference (p<0.05). Conclusion: Self-developed Ye'an Analgetic Decoction/Jiawei Shaoyao Gancao Decoction leads to numerous benefits in the treatment of RLS, such as obviously ameliorating patients' clinical symptoms, reducing RLS severity, and improving their quality of life and sleep quality.

Exploring the role of vitamin D in cognitive function: mediation by depression with diabetes modulation in older U.S. adults, a NHANES weighted analysis.

Background: The relationship between vitamin D levels, depressive symptoms, and cognitive function has yet to be definitively understood in the elderly, particularly when considering the impact of chronic diseases. This study focuses on how depression mediates the impact of 25-hydroxyvitamin D3 (25(OH)D3) on cognitive performance in older U.S. adults. Methods: We analyzed data from 2,745 elderly individuals extracted from the NHANES 2011-2014 cycles, applying weighted processing to account for the complex multi-stage sampling design characteristic of NHANES data. Utilizing weighted data for covariate and model selection, we conducted mediation analyses on both the overall population and subgroup data. Significant mediation pathways were validated using a stratified weighted bootstrap approach. For significant subgroup pathways, we explored interactive mechanisms through interactive mediation analysis. Results: Mediation analyses, thoroughly accounting for the impact of chronic conditions, revealed significant pathways in both the weighted overall population and the weighted diabetes subgroup. After 1,000 stratified weighted bootstrap replications, the proportion of mediation effects were 10.6% [0.040, 0.268] and 20.9% [0.075, 0.663], respectively. Interactive mediation analysis for diabetes indicated that the interaction between diabetes and depression was not significant in the direct pathway (estimates = 0.050, p = 0.113) but was significant in the mediation pathway, yielding the largest effect size compared to other covariates (estimates = 0.981, p < 0.001). Conclusion: This study highlights the mediating role of depression in the relationship between vitamin D levels and cognitive function in the elderly, particularly emphasizing diabetes as a key moderator. Our findings suggest targeted interventions addressing both vitamin D sufficiency and depression could significantly benefit cognitive health, especially in diabetic individuals.

Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: A long-term follow-up pilot study.

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre- and early-symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early-onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with post-symptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over nine years. The most common adverse events (AEs) within two months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with post-symptomatic juvenile MLD.

Border cells without theta rhythmicity in the medial prefrontal cortex.

The medial prefrontal cortex (mPFC) is a key brain structure for higher cognitive functions such as decision-making and goal-directed behavior, many of which require awareness of spatial variables including one's current position within the surrounding environment. Although previous studies have reported spatially tuned activities in mPFC during memory-related trajectory, the spatial tuning of mPFC network during freely foraging behavior remains elusive. Here, we reveal geometric border or border-proximal representations from the neural activity of mPFC ensembles during naturally exploring behavior, with both allocentric and egocentric boundary responses. Unlike most of classical border cells in the medial entorhinal cortex (MEC) discharging along a single wall, a large majority of border cells in mPFC fire particularly along four walls. mPFC border cells generate new firing fields to external insert, and remain stable under darkness, across distinct shapes, and in novel environments. In contrast to hippocampal theta entrainment during spatial working memory tasks, mPFC border cells rarely exhibited theta rhythmicity during spontaneous locomotion behavior. These findings reveal spatially modulated activity in mPFC, supporting local computation for cognitive functions involving spatial context and contributing to a broad spatial tuning property of cortical circuits.

Association between anti-SSA autoantibodies and conduction disturbances in heart failure.

BACKGROUND: Conduction disturbances play an important role in the occurrence and development of heart failure (HF). Studies suggest autoantibodies may attack conduction system. However, it is unclear whether autoantibodies are associated with conduction disturbances in patients with HF. OBJECTIVE: Assess whether anti-SSA, anti-Ro/Sjögren's syndrome-related antigen A antibodies known for congenital atrioventricular block, is associated with conduction disturbances in patients with HF METHODS: This retrospective observational study used data from patients with HF who admitted to Beijing Anzhen Hospital between January 2018 and June 2022. We included patients who had anti-SSA tested and had electrocardiogram (ECG) examination during hospitalization. Conduction disturbances, including atrioventricular block (AVB), bundle branch block (BBB), and intraventricular conduction delay were confirmed by a cardiologist blinded to the anti-SSA status. Univariate and multivariable logistic regression analyses were performed to assess the association between anti-SSA and conduction disturbances. RESULTS: 766 patients were included in this study, 70(9.1%) of whom were anti-SSA positive. Subjects who were anti-SSA positive showed a higher prevalence of AVB (20% vs 10.6%) and BBB (27.3 % vs 10.9 %), including both left bundle branch block (LBBB) and right bundle branch block (RBBB) (all P<0.05). After adjusting for known risk factors, anti-SSA were independently associated with AVB (OR 2.42 (1.18-5.43), P = 0.03) and BBB (OR 3.15(1.68-5.89), P<0.001). CONCLUSION: Anti-SSA is independently associated with AVB and BBB in patients with HF. We need to study the role of autoantibodies in the development of conduction abnormalities in patient with HF to generate possible targeted treatments.

Identification of therapy-induced clonal evolution and resistance pathways in minimal residual clones in multiple myeloma through single-cell sequencing.

PURPOSE: In multiple myeloma (MM), therapy-induced clonal evolution is associated with treatment resistance and is one of the most important hindrances toward a cure for MM. To further understand the molecular mechanisms controlling the clonal evolution of MM, we applied single-cell RNA-sequencing (scRNA-seq) to paired diagnostic and post-treatment bone marrow (BM) samples. EXPERIMENTAL DESIGN: scRNA-seq was performed on 38 BM samples from patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 1), MM patients at diagnosis (n = 19), MM post-treatment (n = 17), and one healthy donor. The single-cell transcriptome data of malignant plasma cells and the surrounding immune microenvironment were analyzed. RESULTS: Profiling by scRNA-seq data revealed three primary trajectories of transcriptional evolution after treatment: clonal elimination in patients with undetectable minimal residual disease (MRD-), as well as clonal stabilization and clonal selection in detectable MRD (MRD+) patients. We noted a metabolic shift towards fatty acid oxidation in cycling-resistant plasma cells (PCs), while selective PCs favored the NF-κB pathway. Intriguingly, when comparing the genetic and transcriptional dynamics, we found a significant correlation between genetic and non-genetic factors in driving the clonal evolution. Furthermore, we identified variations in cellular interactions between malignant plasma cells and the tumor microenvironment (TME). Selective PCs showed the most robust cellular interactions with the TME. CONCLUSIONS: These data suggest that MM cells could rapidly adapt to induction treatment through transcriptional adaptation, metabolic adaptation, and specialized immune evasion. Targeting therapy-induced resistance mechanisms may help to avert refractory disease in multiple myeloma.

Investigation on activation characterization, secondary electron yield, and surface resistance of novel quinary alloy Ti-Zr-V-Hf-Cu non-evaporable getters.

The performance of next-generation particle accelerators has been adversely affected by the occurrence of electron multipacting and vacuum instabilities. Particularly, minimization of secondary electron emission (SEE) and reduction of surface resistance are two critical issues to prevent some of the phenomena such as beam instability, reduction of beam lifetime, and residual gas ionization, all of which occur as a result of these adverse effects in next-generation particle accelerators. For the first time, novel quinary alloy Ti-Zr-V-Hf-Cu non-evaporable getter (NEG) films were prepared on stainless steel substrates by using the direct current magnetron sputtering technique to reduce surface resistance and SEE yield with an efficient pumping performance. Based on the experimental findings, the surface resistance of the quinary Ti-Zr-V-Hf-Cu NEG films was established to be 6.6 × 10-7 Ω m for sample no. 1, 6.4 × 10-7 Ω m for sample no. 2, and 6.2 × 10-7 Ω m for sample no. 3. The δmax measurements recorded for Ti-Zr-V-Hf-Cu NEG films are 1.33 for sample no. 1, 1.34 for sample no. 2, and 1.35 for sample no. 3. Upon heating the Ti-Zr-V-Hf-Cu NEG film to 150 °C, the XPS spectra results indicated that there are significant changes in the chemical states of its constituent metals, Ti, Zr, V, Hf, and Cu, and these chemical state changes continued with heating at 180 °C. This implies that upon heating at 150 °C, the Ti-Zr-V-Hf-Cu NEG film becomes activated, showing that novel quinary NEG films can be effectively employed as getter pumps for generating ultra-high vacuum conditions.

Central Roles of ZmNAC128 and ZmNAC130 in Nutrient Uptake and Storage during Maize Grain Filling.

Grain filling is critical for determining yield and quality, raising the question of whether central coordinators exist to facilitate the uptake and storage of various substances from maternal to filial tissues. The duplicate NAC transcription factors ZmNAC128 and ZmNAC130 could potentially serve as central coordinators. By analyzing differentially expressed genes from zmnac128 zmnac130 mutants across different genetic backgrounds and growing years, we identified 243 highly and differentially expressed genes (hdEGs) as the core target genes. These 243 hdEGs were associated with storage metabolism and transporters. ZmNAC128 and ZmNAC130 play vital roles in storage metabolism, and this study revealed two additional starch metabolism-related genes, sugary enhancer1 and hexokinase1, as their direct targets. A key finding of this study was the inclusion of 17 transporter genes within the 243 hdEGs, with significant alterations in the levels of more than 10 elements/substances in mutant kernels. Among them, six out of the nine upregulated transporter genes were linked to the transport of heavy metals and metalloids (HMMs), which was consistent with the enrichment of cadmium, lead, and arsenic observed in mutant kernels. Interestingly, the levels of Mg and Zn, minerals important to biofortification efforts, were reduced in mutant kernels. In addition to their direct involvement in sugar transport, ZmNAC128 and ZmNAC130 also activate the expression of the endosperm-preferential nitrogen and phosphate transporters ZmNPF1.1 and ZmPHO1;2. This coordinated regulation limits the intake of HMMs, enhances biofortification, and facilitates the uptake and storage of essential nutrients.

Which factors are associated with adverse prognosis in multiple myeloma patients after surgery? - preliminary establishment and validation of the nomogram.

BACKGROUND: To investigate the prognosis of patients with Multiple Myeloma (MM) after surgery, analyze the risk factors leading to adverse postoperative outcomes, and establish a nomogram. METHODS: Clinical data from 154 patients with MM who underwent surgery at our institution between 2007 and 2019 were retrospectively analyzed. Assessing and comparing patients' pain levels, quality of life, and functional status before and after surgery (P < 0.05) were considered statistically significant. The Kaplan-Meier survival curve was used to estimate the median survival time. Adverse postoperative outcomes were defined as worsened symptoms, lesion recurrence, complication grade ≥ 2, or a postoperative survival period < 1 year. Logistic regression analysis was used to determine the prognostic factors. Based on the logistic regression results, a nomogram predictive model was developed and calibrated. RESULTS: Postoperative pain was significantly alleviated in patients with MM, and there were significant improvements in the quality of life and functional status (P < 0.05). The median postoperative survival was 41 months. Forty-nine patients (31.8%) experienced adverse postoperative outcomes. Multivariate logistic regression analysis identified patient age, duration of MM, International Staging System, preoperative Karnofsky Performance Status, and Hb < 90 g/L as independent factors influencing patient prognosis. Based on these results, a nomogram was constructed, with a C-index of 0.812. The calibration curve demonstrated similarity between the predicted and actual survival curves. Decision curve analysis favored the predictive value of the model at high-risk thresholds from 10% to-69%. CONCLUSION: This study developed a nomogram risk prediction model to assist in providing quantifiable assessment indicators for preoperative evaluation of surgical risk.

Oncolytic Newcastle disease virus carrying the IL24 gene exerts antitumor effects by inhibiting tumor growth and vascular sprouting.

The second-leading cause of death, cancer, poses a significant threat to human life. Innovations in cancer therapies are crucial due to limitations in traditional approaches. Newcastle disease virus (NDV), a nonpathogenic oncolytic virus, exhibits multifunctional anticancer properties by selectively infecting, replicating, and eliminating tumor cells. To enhance NDV's antitumor activity, four oncolytic NDV viruses were developed, incorporating IL24 and/or GM-CSF genes at different gene loci using reverse genetics. In vitro experiments revealed that oncolytic NDV virus augmented the antitumor efficacy of the parental virus rClone30, inhibiting tumor cell proliferation, inducing tumor cell fusion, and promoting apoptosis. Moreover, NDV carrying the IL24 gene inhibited microvessel formation in CAM experiments. Evaluation in a mouse model of liver cancer confirmed the therapeutic efficacy of oncolytic NDV viral therapy. Tumors in mice treated with oncolytic NDV virus significantly decreased in size, accompanied by tumor cell detachment and apoptosis evident in pathological sections. Furthermore, oncolytic NDV virus enhanced T cell and dendritic cell production and substantially improved the survival rate of mice with hepatocellular carcinoma, with rClone30-IL24(P/M) demonstrating significant therapeutic effects. This study establishes a basis for utilizing oncolytic NDV virus as an antitumor agent in clinical practice.

Low-Dose Colchicine Ameliorates Doxorubicin Cardiotoxicity Via Promoting Autolysosome Degradation.

BACKGROUND: The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well-tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin-induced heart failure. METHODS AND RESULTS: Doxorubicin was administered to establish models of heart failure both in vivo and in vitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, P=0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin-induced cardiotoxicity. CONCLUSIONS: Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.

Oridonin, a small molecule inhibitor of cancer stem cell with potent cytotoxicity and differentiation potential.

Cancer stem cells (CSCs) drive malignant tumor progression, recurrence, and metastasis with unique characteristics, including self-renewal and resistance to conventional treatments. Conventional differentiation inducers, although promising, have limited cytotoxicity and may inadvertently enhance CSC stemness. To address these challenges, ongoing efforts are dedicated to developing strategies that can effectively combine both cytotoxicity and differentiation-inducing effects. In this study, we introduce oridonin (Ori), a small molecule with dual differentiation-inducing and cytotoxicity properties capable of eliminating tumor CSCs. We isolated CSCs in B16F10 cells using the Hoechst side population method and assessed the differentiation effect of Ori. Ori's differentiation-inducing effect was further evaluated using human acute promyelocytic leukemia. The cytotoxic potential of Ori against MCF-7 and B16F10 cell lines was assessed through various methods. In vivo anti-tumor and anti-CSC efficacy of Ori was investigated using mouse melanoma and CSCs melanoma models. Safety evaluation included zebrafish embryotoxicity and mouse acute toxicity experiments. As a result, Ori effectively dismantles tumorspheres, inhibits proliferation, and reduces the expression of CSC-specific markers. It induces significant differentiation, especially in the case of NB4. Additionally, Ori upregulates TP53 expression, mitigates the hypoxic tumor microenvironment, suppresses stemness, and inhibits PD-L1 expression, prompting a robust anti-cancer immune response. Ori demonstrates pronounced cytotoxicity, inducing notable pro-apoptotic effects on B16F10 and MCF-7 cells, with specific triggering of mitochondrial apoptosis. Importantly, Ori maintains a commendable biosafety record. The dual-action prowess of Ori not only induces the differentiation of CSCs but also dispatches differentiated and residual tumor cells, effectively thwarting the relentless march of tumor progression.