Combined Mindfulness-Based Stress Reduction and Exercise Intervention for Improving Psychological Well-Being in Patients With Non-Small Cell Lung Cancer.

OBJECTIVE: This study aims to assess the clinical effectiveness of combining mindfulness-based stress reduction (MBSR) with exercise intervention in improving anxiety, depression, sleep quality and mood regulation in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 60 patients with NSCLC who had not received surgical treatment were selected using convenience sampling and divided into an intervention group and control group, with 30 patients in each group. The control group received conventional psychological nursing care, whereas the intervention group received a combination of MBwSR and exercise therapy. Before the intervention, a questionnaire was completed to collect the basic data of the two groups. Further questionnaires were administered at 6 and 8 weeks after treatment to assess anxiety, depression, sleep quality and other items included in the five-item Brief Symptom Rating Scale (BSRS-5). RESULTS: No significant differences between the intervention and control groups were identified in terms of personal and clinical characteristics (p > 0.05). No significant differences were determined in the BSRS-5, Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS) or Pittsburgh Sleep Quality Index (PSQI) scores between the intervention and control groups before the intervention. However, 6 and 8 weeks after the intervention, scores were significantly lower in both groups (p < 0.001). Significant differences in the BSRS-5, SAS, SDS and PSQI scores were identified between the two groups at different time points (p < 0.001). CONCLUSION: The combination of MBSR and exercise intervention demonstrated improvements in anxiety, depression, sleep quality and BSRS-5 scores in patients with NSCLC.

[The Prognostic Value of Del(1p32) in Patients with Newly Diagnosed Multiple Myeloma].

OBJECTIVE: To analyze the prognostic value of del(1p32) in patients with newly diagnosed multiple myeloma (MM). METHODS: The clinical data of 341 newly diagnosed MM attended in Jiangsu Province Hospital were retrospective analyzed. Clinical characteristic combined with genetic features, especially del(1p32), were analyzed for survival and prognostic of patients. RESULTS: Among the 341 patients with newly diagnosed MM, 24(7.0%) patients were del(1p32) positive. The progression-free survival (PFS) and overall survival (OS) were significantly shorter in MM patients with del(1p32) than those without del(1p32) (PFS: P < 0.001;OS: P < 0.001). The COX proportional-hazards model showed that del (1p32) was an independent risk factor for PFS and OS of patients with MM. The patients with both 1q21 gain/amplification and del(1p32), as "double-hit chromosome 1", have worse prognosis than those with only 1q21 gain/amplification or only del(1p32) (PFS: P < 0.001; OS: P < 0.001). CONCLUSION: Del(1p32) is an independent risk factor for PFS and OS of patients with MM. Del(1p32) detection should be widely used in the prognostic analysis for newly diagnosed MM patients.

The effect of macrophages and their exosomes in ischemic heart disease.

Ischemic heart disease (IHD) is a leading cause of disability and death worldwide, with immune regulation playing a crucial role in its pathogenesis. Various immune cells are involved, and as one of the key immune cells residing in the heart, macrophages play an indispensable role in the inflammatory and reparative processes during cardiac ischemia. Exosomes, extracellular vesicles containing lipids, nucleic acids, proteins, and other bioactive molecules, have emerged as important mediators in the regulatory functions of macrophages and hold promise as a novel therapeutic target for IHD. This review summarizes the regulatory mechanisms of different subsets of macrophages and their secreted exosomes during cardiac ischemia over the past five years. It also discusses the current status of clinical research utilizing macrophages and their exosomes, as well as strategies to enhance their therapeutic efficacy through biotechnology. The aim is to provide valuable insights for the treatment of IHD.

Effect of hydrogel drug delivery system for treating ulcerative colitis: A preclinical meta-analysis.

Hydrogel drug delivery systems (DDSs) for treating ulcerative colitis (UC) have garnered attention. However, there is a lack of meta-analysis summarizing their effectiveness. Therefore, this study aimed to conduct a meta-analysis of pre-clinical evidence comparing hydrogel DDSs with free drug administration. Subgroup analyses were performed based on hydrogel materials (polysaccharide versus non-polysaccharide) and administration routes of the hydrogel DDSs (rectal versus oral). The outcome indicators included colon length, histological scores, tumor necrosis factor-α (TNF-α), zonula occludens protein 1(ZO-1), and area under the curve (AUC). The results confirmed the therapeutic enhancement of the hydrogel DDSs for UC compared with the free drug group. Notably, no significant differences were found between polysaccharide and non-polysaccharide materials, however, oral administration was found superior regarding TNF-α and AUC. In conclusion, oral hydrogel DDSs can serve as potential excellent dosage forms in oral colon -targeting DDSs, and in the design of colon hydrogel delivery systems, polysaccharides do not show advantages compared with other materials.

Reduced plasma cortistatin is related to clinical parameters in patients with essential hypertension.

BACKGROUND: Cortistatin (CST), an endogenous bioactive polypeptide, has been acknowledged for its protective effect against several cardiovascular diseases, but its relationship with hypertension remains unclear. Therefore, we aimed to investigate changes in plasma CST in hypertensive patients and further analyze correlations with blood pressure, metabolic parameters and left ventricular structure and function. METHODS: In this hospital-based study, basic information and plasma samples for evaluating clinically relevant indicators such as total cholesterol (TC), triglycerides (TGs), fasting blood glucose (FGB), serum creatinine (Scr) and CST were collected from 81 essential hypertension patients and 75 normotensive subjects. Plasma CST levels were examined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with normotensive subjects, plasma CST was significantly lower in hypertensive patients. Plasma CST levels in hypertensive patients without blood pressure control was significantly lower than those of hypertensive patients with blood pressure control. Plasma CST levels were significantly negatively correlated with SBP and serum creatinine (Scr) in the overall population. Furthermore, multivariate logistic regression analysis showed that the OR of CST for hypertension was 0.64 using the unadjusted model, and there was still statistical significance using the four-adjusted model. CONCLUSIONS: The circulating concentration of CST was significantly lower in hypertensive patients and was higher after blood pressure control, suggesting that CST may be a new endogenous protective target for hypertension.

Computation-Guided Rational Design of Cysteine-Less Protein Variants in Engineered hCGL.

The engineered human cystathionine-γ-lyase (hCGL) resulting in enhanced activity toward both cysteine and cystine unveils a potential robust antitumor activity. However, the presence of cysteine residues has the potential to induce oligomerization or incorrect disulfide bonding, which may decrease the bioavailability of biopharmaceuticals. Through a meticulous design process targeting the cysteine residues within engineered hCGL, a set of potential beneficial mutants were obtained by virtual screening employing Rosetta and ABACUS. Experimental measurements have revealed that most of the mutants showed increased activity toward both substrates l-Cys and CSSC. Furthermore, mutants C109V and C229D demonstrated Tm value increases of 8.2 and 1.8 °C, respectively. After an 80 min incubation at 60 °C, mutant C229D still maintained high residual activity. Unexpectedly, mutant C109V, displaying activity approximately 2-fold higher than the activity of wild type (WT) for both substrates, showed disappointing instability in plasma, which suggests that computational design still requires further consideration. Analysis of their structure and molecular dynamics (MD) simulation revealed the impact of hydrophobic interaction, hydrogen bonds, and near-attack conformation (NAC) stability on activity and stability. This study acquired information about mutants that exhibit enhanced activity or thermal resistance and serve as valuable guidance for subsequent specific cysteine modifications.

Protective effect of synbiotic combination of Lactobacillus plantarum SC-5 and olive oil extract tyrosol in a murine model of ulcerative colitis.

BACKGROUND: Ulcerative colitisis (UC) classified as a form of inflammatory bowel diseases (IBD) characterized by chronic, nonspecific, and recurrent symptoms with a poor prognosis. Common clinical manifestations of UC include diarrhea, fecal bleeding, and abdominal pain. Even though anti-inflammatory drugs can help alleviate symptoms of IBD, their long-term use is limited due to potential side effects. Therefore, alternative approaches for the treatment and prevention of inflammation in UC are crucial. METHODS: This study investigated the synergistic mechanism of Lactobacillus plantarum SC-5 (SC-5) and tyrosol (TY) combination (TS) in murine colitis, specifically exploring their regulatory activity on the dextran sulfate sodium (DSS)-induced inflammatory pathways (NF-κB and MAPK) and key molecular targets (tight junction protein). The effectiveness of 1 week of treatment with SC-5, TY, or TS was evaluated in a DSS-induced colitis mice model by assessing colitis morbidity and colonic mucosal injury (n = 9). To validate these findings, fecal microbiota transplantation (FMT) was performed by inoculating DSS-treated mice with the microbiota of TS-administered mice (n = 9). RESULTS: The results demonstrated that all three treatments effectively reduced colitis morbidity and protected against DSS-induced UC. The combination treatment, TS, exhibited inhibitory effects on the DSS-induced activation of mitogen-activated protein kinase (MAPK) and negatively regulated NF-κB. Furthermore, TS maintained the integrity of the tight junction (TJ) structure by regulating the expression of zona-occludin-1 (ZO-1), Occludin, and Claudin-3 (p < 0.05). Analysis of the intestinal microbiota revealed significant differences, including a decrease in Proteus and an increase in Lactobacillus, Bifidobacterium, and Akkermansia, which supported the protective effect of TS (p < 0.05). An increase in the number of Aspergillus bacteria can cause inflammation in the intestines and lead to the formation of ulcers. Bifidobacterium and Lactobacillus can regulate the micro-ecological balance of the intestinal tract, replenish normal physiological bacteria and inhibit harmful intestinal bacteria, which can alleviate the symptoms of UC. The relative abundance of Akkermansia has been shown to be negatively associated with IBD. The FMT group exhibited alleviated colitis, excellent anti-inflammatory effects, improved colonic barrier integrity, and enrichment of bacteria such as Akkermansia (p < 0.05). These results further supported the gut microbiota-dependent mechanism of TS in ameliorating colonic inflammation. CONCLUSION: In conclusion, the TS demonstrated a remission of colitis and amelioration of colonic inflammation in a gut microbiota-dependent manner. The findings suggest that TS could be a potential natural medicine for the protection of UC health. The above results suggest that TS can be used as a potential therapeutic agent for the clinical regulation of UC.

Interactions between Epichloë endophyte and the plant microbiome impact nitrogen responses in host Achnatherum inebrians plants.

The clavicipitaceous fungus Epichloë gansuensis forms symbiotic associations with drunken horse grass (Achnatherum inebrians), providing biotic and abiotic stress protection to its host. However, it is unclear how E. gansuensis affects the assembly of host plant-associated bacterial communities after ammonium nitrogen (NH4+-N) treatment. We examined the shoot- and root-associated bacterial microbiota and root metabolites of A. inebrians when infected (I) or uninfected (F) with E. gansuensis endophyte. The results showed more pronounced NH4+-N-induced microbial and metabolic changes in the endophyte-infected plants compared to the endophyte-free plants. E. gansuensis significantly altered bacterial community composition and ß-diversity in shoots and roots and increased bacterial α-diversity under NH4+-N treatment. The relative abundance of 117 and 157 root metabolites significantly changed with E. gansuensis infection under water and NH4+-N treatment compared to endophyte-free plants. Root bacterial community composition was significantly related to the abundance of the top 30 metabolites [variable importance in the projection (VIP) > 2 and VIP > 3] contributing to differences between I and F plants, especially alkaloids. The correlation network between root microbiome and metabolites was complex. Microorganisms in the Proteobacteria and Firmicutes phyla were significantly associated with the R00693 metabolic reaction of cysteine and methionine metabolism. Co-metabolism network analysis revealed common metabolites between host plants and microorganisms.IMPORTANCEOur results suggest that the effect of endophyte infection is sensitive to nitrogen availability. Endophyte symbiosis altered the composition of shoot and root bacterial communities, increasing bacterial diversity. There was also a change in the class and relative abundance of metabolites. We found a complex co-occurrence network between root microorganisms and metabolites, with some metabolites shared between the host plant and its microbiome. The precise ecological function of the metabolites produced in response to endophyte infection remains unknown. However, some of these compounds may facilitate plant-microbe symbiosis by increasing the uptake of beneficial soil bacteria into plant tissues. Overall, these findings advance our understanding of the interactions between the microbiome, metabolome, and endophyte symbiosis in grasses. The results provide critical insight into the mechanisms by which the plant microbiome responds to nutrient stress in the presence of fungal endophytes.

Low serum total cholesterol levels predict inferior prognosis of patients with POEMS syndrome.

Low serum cholesterol levels are associated with increased tumor morbidity and mortality. However, the relationship between serum lipid profile and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is still unclear. The aim of our study was to clarify the importance of the serum lipid profile in predicting the severity and prognosis of patients with POEMS syndrome. Forty-three patients with newly diagnosed POEMS syndrome admitted to the Department of Hematology of Jiangsu Provincial People's Hospital between August 2013 and February 2023 were selected. They had explicit serum lipid profiles. There were 27 males and 16 females with a median age of 54 years (range, 28-77 years). Survival curves were plotted using the Kaplan-Meier method, and comparisons between the two groups were performed using the log-rank test. The Cox proportional-hazards model examined risk factors associated with the prognosis of POEMS syndrome. Receiver-operator characteristic (ROC) curves assessed the predictive accuracy. 23 (53.5%) patients had low total cholesterol (TC) levels. Low levels of TC were concerned with unfavorable progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.004), and at the same time, the low circulating TC concentration was an independent risk factor for PFS (p = 0.020) and OS (p = 0.011). Low TC values could improve the risk stratification, especially in high-risk patients. In conclusion, low serum TC levels may predict inferior prognosis in patients with POEMS syndrome; in future clinical application, low TC may be a reliable indicator of prognosis.

Biodegradable poly(ethylene glycol-glycerol-itaconate-sebacate) copolyester elastomer with significantly reinforced mechanical properties by in-situ construction of bacterial cellulose interpenetrating network.

To address the concern that biodegradable elastomers are environmental-friendly but usually associated with poor properties for practical utilization, we report a star-crosslinked poly(ethylene glycol-glycerol-itaconate-sebacate) (PEGIS) elastomer synthesized by esterification, polycondensation and UV curing, and reinforced by bacterial cellulose (BC). The interpenetrating network of primary BC backbone and vulcanized elastomer is achieved by the "in-situ secondary network construction" strategy. With the well dispersion of BC without agglomeration, the mechanical properties of PEGIS are significantly enhanced in tensile strength, Young's modulus and elongation at break. The reinforcement strategy is demonstrated to be efficient and offers a route to the development of biodegradable elastomers for a variety of applications in the future.

Real-world prognostic significance of attaining minimal residual disease negativity in newly diagnosed multiple myeloma.

The aim of the study was to evaluate the prognostic impact of minimal residual disease (MRD) in the real-world setting and the interaction between MRD and molecular risk, clinical response and autologous stem-cell transplant (ASCT). A retrospective analysis of 275 newly diagnosed multiple myeloma (NDMM) patients who achieved very good partial remission (VGPR) or better before maintenance were involved. We examined MRD status by multiparameter flow cytometry (MFC). At a median follow-up of 37 months (4-88 months), In patients who achieved ≥ VGPR, those with MRD negativity had significantly longer PFS (51 vs. 26 months; P < 0.001) and OS (Not reached: NR vs. 62 months, P < 0.001) than those with MRD positivity. MRD positivity was the independent prognostic factor for PFS with hazard ratios of 2.650 (95% CI 1.755-4.033, P < 0.001) and OS with hazard ratios of 2.122 (95% CI 1.155-3.899, P = 0.015). Achieving MRD negativity was able to ameliorate a poor prognosis associated with genetic high risk. MRD negativity was associated with better PFS regardless of ASCT treatment. MRD status was more predictable for clinical outcome than conventional clinical responses. Moreover, Sustained MRD negativity ≥ 12 or ≥ 24 months improved both PFS and OS. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes regardless of high-risk cytogenetics, ASCT and clinical responses in a real-world setting.

A network pharmacology approach to decipher the mechanism of total flavonoids from Dracocephalum Moldavica L. in the treatment of cardiovascular diseases.

AIM OF THE STUDY: Cardiovascular disease (CVD) seriously endangers human health and is characterized by high mortality and disability. The effectiveness of Dracocephalum moldavica L. in the treatment of CVD has been proven by clinical practice. However, the mechanism by which DML can treat CVD has not been systematically determined. MATERIALS AND METHODS: The active compounds in DML were screened by literature mining and pharmacokinetic analysis. Cytoscape software was used to construct the target-disease interaction network of DML in the treatment of CVD. Gene ontology and signalling pathway enrichment analyses were performed. The key target pathway network of DML compounds was constructed and verified by pharmacological experiments in vitro. A hydrogen glucose deprivation/reoxygenation model was established in H9c2 cells using hypoxia and glucose deprivation for 9 h combined with reoxygenation for 2 h. The model simulated myocardial ischaemic reperfusion injury to investigate the effects of total flavonoids of Cymbidium on cell viability, myocardial injury markers, oxidative stress levels, and reactive oxygen radical levels. Western blot analysis was used to examine NOX-4, Bcl-2/Bax, and PGC-1α protein expression. RESULTS: Twenty-seven active components were screened, and 59 potential drug targets for the treatment of CVD were obtained. Through the compound-target interaction network and the target-disease interaction network, the key targets and key signalling pathways, such as NOX-4, Bcl-2/Bax and PGC-1α, were obtained. TFDM significantly decreased LDH and MDA levels and the production of ROS and increased SOD activity levels in the context of OGD/R injury. Further studies indicated that NOX-4 and Bax protein levels and the p-P38 MAPK/P38 MAPK andp-Erk1/2/Erk1/2 ratios were suppressed by TFDM. The protein expression of Bcl-2 and PGC-1α was increased by TFDM. CONCLUSIONS: Our results showed that DML had multicomponent, multitarget and multichannel characteristics in the treatment of CVD. The mechanism may be associated with the following signalling pathways: 1) the NOX-4/ROS/p38 MAPK signalling pathway, which inhibits inflammation and reactive oxygen species (ROS) production, and 2) the Bcl-2/Bax and AMPK/SIRT1/PGC-1α signalling pathways, which inhibit apoptosis.

Microfluidic Fabrication of MicroRNA-Induced Hepatocyte-Like Cells/Human Umbilical Vein Endothelial Cells-Laden Microgels for Acute Liver Failure Treatment.

Acute liver failure (ALF) is a critical life-threatening disease that occurs due to a rapid loss in hepatocyte functions. Hepatocyte transplantation holds great potential for ALF treatment, as it rapidly supports liver biofunctions and enhances liver regeneration. However, hepatocyte transplantation is still limited by renewable and ongoing cell sources. In addition, intravenously injected hepatocytes are primarily trapped in the lungs and have limited efficacy because of the rapid clearance in vivo. Here, we designed a Y-shaped DNA nanostructure to deliver microRNA-122 (Y-miR122), which could induce the hepatic differentiation and maturation of human mesenchymal stem cells. mRNA sequencing analysis revealed that the Y-miR122 promoted important hepatic biofunctions of the induced hepatocyte-like cells including fat and lipid metabolism, drug metabolism, and liver development. To further improve hepatocyte transplantation efficiency and therapeutic effects in ALF treatment, we fabricated protective microgels for the delivery of Y-miR122-induced hepatocyte-like cells based on droplet microfluidic technology. When cocultured with human umbilical vein endothelial cells in microgels, the hepatocyte-like cells exhibited an increase in hepatocyte-associated functions, including albumin secretion and cytochrome P450 activity. Notably, upon transplantation into the ALF mouse model, the multiple cell-laden microgels effectively induced the restoration of liver function and enhanced liver regeneration. Overall, this study presents an efficient approach from the generation of hepatocyte-like cells to hepatocyte transplantation in ALF therapy.

Survival trends and prognostic factors of patients with newly diagnosed multiple myeloma accompanied with extramedullary disease.

Background: Extramedullary disease (EMD) is an unusual event in patients with MM. This study aimed to assess the prognostic impact of EMD and develop an EMD-based risk model to estimate the survival of patients with newly diagnosed multiple myeloma (NDMM).Methods: A total of 518 patients were enrolled in this study, of which 121 presented with EMD at the initial diagnosis. Patients were divided into non-EMD, extramedullary-bone-related (EM-B) and extramedullary-extraosseous (EM-E) groups. Clinical characteristics were compared using the chi-squared test or Fisher's exact test. Survival curves were plotted using the Kaplan-Meier method, and a nomogram was constructed based on the Cox proportional hazards model.Results: Compared to patients without EMDs, patients with EM-E were younger (p = 0.028), and those with EM-B had less renal damage (p < 0.001). The EM-E group had the worst progression-free survival (PFS) and overall survival (OS). In addition, patients with multiple sites of EMD invasion or high Ki67 expression had poor OS. Lenalidomide-based treatment showed the worst outcome, and autologous stem cell transplantation (ASCT) remarkably improved the survival of patients with EMD. A prognostic model (MM prognostic index, MM-PI) comprising lactate dehydrogenase (LDH), circulating plasma cells (CPC), del(17p), and type of extramedullary involvement was developed, and a 4-factor nomogram.Conclusions: We established a risk model incorporating extramedullary disease that provides accurate and individualized survival estimates for patients with NDMM.

Single-cell transcriptomic atlas throughout anti-BCMA CAR-T therapy in patients with multiple myeloma.

Introduction: The emergence of chimeric antigen receptor (CAR)-T therapy targeting B cell maturation antigen (BCMA) has improved the prognosis of patients with multiple myeloma (MM); however, the majority of patients eventually experience relapse. Methods: In this study, employing the latest single-cell RNA sequencing technology, we examined 24 bone marrow or peripheral blood samples collected throughout the course of anti-BCMA CAR-T therapy, analyzing a total of 59,725 bone marrow cells and 72,479 peripheral blood cells. Results: Our findings reveal that tumor cells in relapsed patient exhibit higher expression levels of HSP90B1 and HSPA5, and demonstrate significantly enriched pathways regarding endoplasmic reticulum stress and unfolded protein response. In the analysis of T cells, we observed that patient with impaired effector function and increased expression of immune checkpoints in endogenous T cell are more susceptible to relapse. Notably, T cells from both the bone marrow microenvironment and peripheral blood share highly similar biological characteristics. Discussion: Overall, this study provides a comprehensive atlas of endogenous immune cells, particularly in the relatively long term, after CAR-T therapy. It offers clinical evidence for a deeper understanding of the internal environment post CAR-T treatment and for identifying mechanisms underlying relapse.

Bioactive Components in Fruit Interact with Gut Microbes.

Fruits contain many bioactive compounds, including polysaccharides, oligosaccharides, polyphenols, anthocyanins, and flavonoids. All of these bioactives in fruit have potentially beneficial effects on gut microbiota and host health. On the one hand, fruit rich in active ingredients can act as substrates to interact with microorganisms and produce metabolites to regulate the gut microbiota. On the other hand, gut microbes could promote health effects in the host by balancing dysbiosis of gut microbiota. We have extensively analyzed significant information on bioactive components in fruits based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Although the deep mechanism of action of bioactive components in fruits on gut microbiota needs further study, these results also provide supportive information on fruits as a source of dietary active ingredients to provide support for the adjunctive role of fruits in disease prevention and treatment.

A LIGHTFUL nanomedicine overcomes EGFR-mediated drug resistance for enhanced tyrosine-kinase-inhibitor-based hepatocellular carcinoma therapy.

Targeting the activated epidermal growth factor receptor (EGFR) via clustered regularly interspaced short palindromic repeat (CRISPR) technology is appealing to overcome the drug resistance of hepatocellular carcinoma (HCC) towards tyrosine kinase inhibitor (TKI) therapy. However, combining these two distinct drugs using traditional liposomes results in a suboptimal synergistic anti-HCC effect due to the limited CRISPR/Cas9 delivery efficiency caused by lysosomal entrapment after endocytosis. Herein, we developed a liver-targeting gene-hybridizing-TKI fusogenic liposome (LIGHTFUL) that can achieve high CRISPR/Cas9 expression to reverse the EGFR-mediated drug resistance for enhanced TKI-based HCC therapy efficiently. Coated with a galactose-modified membrane-fusogenic lipid layer, LIGHTFUL reached the targeting liver site to fuse with HCC tumor cells, directly and efficiently transporting interior CDK5- and PLK1-targeting CRISPR/Cas9 plasmids (pXG333-CPs) into the HCC cell cytoplasm and then the cell nucleus for efficient expression. Such membrane-fusion-mediated pXG333-CP delivery resulted in effective downregulation of both CDK5 and PLK1, sufficiently inactivating EGFR to improve the anti-HCC effects of the co-delivered TKI, lenvatinib. This membrane-fusion-participant codelivery strategy optimized the synergetic effect of CRISPR/Cas9 and TKI combinational therapy as indicated by the 0.35 combination index in vitro and the dramatic reduction of subcutaneous and orthotopic TKI-insensitive HCC tumor growth in mice. Therefore, the established LIGHTFUL provides a unique co-delivery platform to combine gene editing and TKI therapies for enhanced synergetic therapy.

Multimodal Tetrahedral DNA Nanoplatform for Surprisingly Rapid and Significant Treatment of Acute Liver Failure.

Acute liver failure (ALF) is a life-threatening disease associated with the rapid development of inflammatory storms, reactive oxygen species (ROS) level elevation, and hepatocyte necrosis, which results in high short-term mortality. Except for liver transplantation, no effective strategies are available for ALF therapy due to the rapid disease progression and narrow therapeutic time window. Therefore, there is an urgent demand to explore fast and effective modalities for ALF treatment. Herein, a multifunctional tetrahedral DNA nanoplatform (TDN) is constructed by incorporating the tumor necrosis factor-α siRNA (siTNF-α) through DNA hybridization and antioxidant manganese porphyrin (MnP4) via π-π stacking interaction with G-quadruplex (G4) for surprisingly rapid and significant ALF therapy. TDN-siTNF-α/-G4-MnP4 silences TNF-α of macrophages by siTNF-α and polarizes them to the anti-inflammatory M2 phenotype, providing appropriate microenvironments for hepatocyte viability. Additionally, TDN-siTNF-α/-G4-MnP4 scavenges intracellular ROS by MnP4 and TDN, protecting hepatocytes from oxidative stress-associated cell death. Furthermore, TDN itself promotes hepatocyte proliferation via modulating the cell cycle. TDN-siTNF-α/-G4-MnP4 shows almost complete liver accumulation after intravenous injection and exhibits excellent therapeutic efficacy of ALF within 2 h. The multifunctional DNA nanoformulation provides an effective strategy for rapid ALF therapy, expanding its application for innovative treatments for liver diseases. This article is protected by copyright. All rights reserved.

High-risk multiple myeloma predicted by circulating plasma cells and its genetic characteristics.

Introduction: Circulating plasma cells (CPC) have been reported to be one of the indicators of high-risk multiple myeloma (MM), yet the prognostic significance of CPC in Chinese population and the genetic mechanisms underlying CPC formation have not been fully elucidated. Methods: Patients with newly diagnosed MM were included in this study. We used multi-parameter flow cytometry (MFC) for CPC quantification and next-generation sequencing (NGS) technology for mutational landscape mapping to identify the correlation of CPC level with clinical characteristics and the mutations. Results: A total of 301 patients were enrolled in this investigation. We demonstrated that CPC quantification could effectively mirror the tumor load, and CPC ≥ 0.105% at diagnosis or detectable CPC after therapy indicates poor treatment response and adverse outcome, and the introduction of CPC into the R-ISS enables a more accurate risk stratification. Interestingly, we noticed an elevated percentage of light-chain MM in patients with higher CPC. Mutational landscape revealed that patients harboring mutations in TP53, BRAF, DNMT3A, TENT5C, and IL-6/JAK/STAT3 pathway-related genes tended to have higher CPC levels. Gene enrichment analysis demonstrated that pathways involving chromosome regulation and adhesion may be potential mechanisms accounting for CPC formation. Discussion: Accordingly, quantification of CPC may provide a less-invasive and reliable approach for identifying high-risk MM in Chinese population.

Tyrosol inhibits NF-κB pathway in the treatment of enterotoxigenic Escherichia coli-induced diarrhea in mice.

Tyrosol is one of the main polyphenol compounds in white wine and extra virgin olive oil (EVOO), which plays an antioxidant and anti-inflammatory role in vitro. In the present study, we investigated the possible anti-inflammatory mechanism of tyrosol in Escherichia coli (ETEC)-induced diarrhea in mice. ICR mice were randomly divided into control group, ETEC group, and ETEC + Tyrosol group with 10 mice in each group. In addition to the control group, a bacterial diarrhea model was induced in mice by continuous administration of 0.2 ml × 109 CFU/ml ETEC. After 7 days, the ETEC + Tyrosol group was given tyrosol (20 mg/kg) once a day by gavage, during which the body weight of mice and the degree of diarrhea were measured daily. On the 15th day, all animals in this experiment were sacrificed, colon tissue was collected, and colon length was recorded. Our results indicate that tyrosol significantly attenuated the extent of ETEC-induced diarrhea, including inhibition of pro-inflammatory cytokine, repair of the intestinal epithelial mechanical barrier, and significant inhibition of NF-κB activation. This finding is helpful for the development and further application of tyrosol in the treatment of diarrhea.