Softening the tumor matrix through cholesterol depletion breaks the physical barrier for enhanced antitumor therapy.

The tumor develops defense tactics, including conversing the mechanical characteristics of tumor cells and their surrounding environment. A recent study reported that cholesterol depletion stiffens tumor cells, which could enhance adaptive T-cell immunotherapy. However, it remains unclear whether reducing the cholesterol in tumor cells contributes to re-educating the stiff tumor matrix, which serves as a physical barrier against drug penetration. Herein, we found that depleting cholesterol from tumor cells can demolish the intratumor physical barrier by disrupting the mechanical signal transduction between tumor cells and the extracellular matrix through the destruction of lipid rafts. This disruption allows nanoparticles (H/S@hNP) to penetrate deeply, resulting in improved photodynamic treatment. Our research also indicates that cholesterol depletion can inhibit the epithelial-mesenchymal transition and repolarize tumor-associated macrophages from M2 to M1, demonstrating the essential role of cholesterol in tumor progression. Overall, this study reveals that a cholesterol-depleted, softened tumor matrix reduces the difficulty of drug penetration, leading to enhanced antitumor therapeutics.

Safety and efficacy of Yaobitong capsules for lumbar disc herniation: A multicenter, randomized, double-blinded, parallel, positive-controlled clinical trial.

BACKGROUND: Lumbar disc herniation (LDH) is one of the most common diseases and is a global medical and socioeconomic problem characterized by leg or back pain, weakness in the lower extremities and paresthesia. OBJECTIVES: A multicenter, randomized, double-blinded, parallel, positive-controlled clinical trial was conducted to evaluate the efficacy and safety of Yaobitong capsules (YBT) for LDH. MATERIAL AND METHODS: Patients (n = 479) were recruited and randomized into YBT and Jingyaokang capsule (JYK) groups (the positive control), and received YBT or JYK at a dose of 3 capsules 3 times per day after a meal for 30 days. The primary efficacy outcome was the Oswestry Disability Index (ODI), with the visual analogue scale (VAS) used as the secondary efficacy outcome. The adverse events and adverse reactions were also evaluated. RESULTS: There was no significant difference in baseline characteristics between YBT (n = 358) and JYK groups (n = 120), and no difference was observed between groups for mean ODI score at day 0 (p = 0.064) or day 7 (p = 0.196), but there were differences at days 14, 21 and 30 (p < 0.001). The YBT showed more decline from baseline, and the decreased ODI score was substantially different from JYK (p < 0.001). The differences in decreased VAS scores between YBT and JYK were also significant at each time point (days 7, 14, 21, and 30), with better scores in the YBT group than in the JYK group (p < 0.001). In terms of safety, there was no obvious disparity in adverse events or adverse reactions between the 2 groups (p > 0.05). CONCLUSIONS: Yaobitong was better than JYK for LDH treatment, with no significant difference in safety. The study suggests that YBT is a promising and effective treatment for LDH.

Immunophenotype of lymphocytes and real-world outcome of COVID-19 infection in children with hematology and oncology.

BACKGROUND: Patients with immunocompromise were suspected to encounter a high risk for severe coronavirus disease 2019 (COVID-19) infection on early period; however, data is lacking nowadays and immune response remain unclear. METHODS: In this retrospective study, internet questionnaire survey and medical records were acquired in pediatric hematology oncology patients. Clinical severity, immunological characteristics, and outcomes were analyzed from December 1, 2022 to January 31, 2023 at the 3rd year of pandemic in China. RESULTS: A total of 306 patients were included, with 21 patients (6.9%) asymptomatic, 262 (85.6%) mild severity, 17 (5.6%) moderate severity, 5 (1.6%) severe severity, and 1 (0.3%) critical severity. Seventy-eight (25.5%) patients were on intensive chemotherapy, and 32.0% children were on maintenance chemotherapy. Delays in cancer therapy occurred in 86.7% patients. Univariable analysis revealed active chemotherapy (P < 0.0001), long duration of symptom (P < 0.0001), low lymphocytes count (P = 0.095), low CD3 + and CD8 + T cell count (P = 0.013, P = 0.022), high percentage of CD4 + TCM (P = 0.016), and low percentage of transitional B cells (P = 0.045) were high risk factors for severe COVID-19 infection. Cox regression model showed that the absolute lymphocytes count (P = 0.027) and long duration of symptom (P = 0.002) were the independent factors for severity. Patients with CD8 + dominant and B cell depletion subtype wasn't related with severity, but had higher percentage of CD8 + effector memory T cells (TEM) and terminally differentiated effector memory T cells (TEMRA) (P < 0.001, P < 0.001), and a longer COVID-19 duration (P = 0.045). CONCLUSION: The severity was relatively mild in children with immunodeficiencies in the third year of COVID-19 pandemic. Low lymphocyte count and long duration of symptom were the independent risk factors with COVID-19 severity. Delays in cancer care remain a major concern and the long outcome is pending.

Analysis of Ethylene Signal Regulating Sucrose Metabolism in Strawberry Fruits Based on RNA-seq.

Ethylene is a key hormone that regulates the maturation and quality formation of horticultural crops, but its effects on non-respiratory climacteric fruits such as strawberries are not yet clear. In this study, strawberry fruits were treated with exogenous ethephon (ETH) and 1-methylcyclopropene (1-MCP). It was found that ETH treatment increased the soluble solids and anthocyanin content of the fruits, reduced hardness, and decreased organic acid content, while 1-MCP treatment inhibited these processes. Transcriptome analysis revealed that differentially expressed genes (DEGs) were enriched in the starch-sucrose metabolism pathway. qRT-PCR results further showed significant changes in the expression levels of sucrose metabolism genes, confirming the influence of ethylene signals on soluble sugar accumulation during strawberry fruit development. This study elucidates the quality changes and molecular mechanisms of ethylene signal in the development of strawberry fruits, providing some key targets and theoretical support for guiding strawberry cultivation and variety improvement.

Fluorescent metal nanoclusters: From luminescence mechanism to applications in enzyme activity assays.

Metal nanoclusters (MNCs) have outstanding fluorescence property and biocompatibility, which show widespread applications in biological analysis. Particularly, evaluation of enzyme activity with the fluorescent MNCs has been developed rapidly within the past several years. In this review, we first introduced the fluorescent mechanism of mono- and bi-metallic nanoclusters, respectively, whose interesting luminescence properties are mainly resulted from electron transfer between the lowest unoccupied molecular orbital (LUMO) and highest occupied molecular orbital (HOMO) energy levels. Meanwhile, the charge migration within the structure occurs through ligand-metal charge transfer (LMCT) or ligand-metal-metal charge transfer (LMMCT). On such foundation, diverse enzyme activities were rigorously evaluated, including three transferases and nine hydrolases, in turn harvesting rapid research progresses within past 5 years. Finally, we summarized the design strategies for evaluating enzyme activity with the MNCs, presented the major issues and challenges remained in the relevant research, coupled by showing some improvement measures. This review will attract researchers dedicated to the studies of the MNCs and provide some constructive insights for their further applications in enzyme analysis.

Effect of acupotomy combined with electroacupuncture on knee function of patients with knee osteoarthritis. / åˆƒé’ˆç»“åˆç”µé’ˆæ²»ç–—å¯¹è†å ³èŠ‚éª¨å ³èŠ‚ç‚Žæ‚£è€ è†å ³èŠ‚åŠŸèƒ½çš„å½±å“.

OBJECTIVES: To compare the clinical effect of combined therapy of acupotomy and electroacupuncture (EA) with the simple application of EA on knee osteoarthritis (KOA), and their influence on knee function. METHODS: Sixty-eight KOA patients were randomly divided into 2 groups, an acupotomy group and an EA group. In the acupotomy group, the combined therapy of acupotomy and EA was adopted. In the EA group, EA was simply used, delivered once every two days, 3 treatments a week；and the duration of treatment was 4 weeks. In the acupotomy group, besides the treatment as the EA group, acupotomy was combined once weekly, and the duration of treatment was 4 weeks. Separately, before and after treatment, and in 4 and 12 weeks after treatment completion (1-month and 3-month follow-up), the results of the timed up and go test (TUG), the 9-step stair climb test (9-SCT) and the knee function (Western Ontario and McMaster University osteoarthritis index visualization scale ［WOMAC］) were measured in the two groups. RESULTS: By the intention-to-treat analysis, the results of TUG, 9-SCT and WOMAC scores were reduced after treatment and in 1-month and 3-month follow-up when compared with those before treatment in the patients of the two groups (P<0.05). Compared with the EA group at the same time point, TUG results were decreased after treatment and in 1-month follow-up, and WOMAC score was reduced after treatment in the acupotomy group. WOMAC score in 1-month follow-up was reduced when compared with that before treatment within the acupotomy group (P<0.05). CONCLUSIONS: Either the simple application of EA or the combined therapy of acupotomy and EA can improve knee function, but the combined therapy obviously increases the walking speed and relieves the symptoms such as joint pain and morning stiffness. The treatment with acupotomy and EA is safe and effective on KOA and the long-term effect is satisfactory.

Antiviral memory B cells exhibit enhanced innate immune response facilitated by epigenetic memory.

The long-lasting humoral immunity induced by viral infections or vaccinations depends on memory B cells with greatly increased affinity to viral antigens, which are evolved from germinal center (GC) responses. However, it is unclear whether antiviral memory B cells represent a distinct subset among the highly heterogeneous memory B cell population. Here, we examined memory B cells induced by a virus-mimicking antigen at both transcriptome and epigenetic levels and found unexpectedly that antiviral memory B cells exhibit an enhanced innate immune response, which appeared to be facilitated by the epigenetic memory that is established through the memory B cell development. In addition, T-bet is associated with the altered chromatin architecture and is required for the formation of the antiviral memory B cells. Thus, antiviral memory B cells are distinct from other GC-derived memory B cells in both physiological functions and epigenetic landmarks.

Ratiometric electrochemical immunoassay based on 2D Co/Fe MOF decorated with toluidine blue and Fc-labeled Schiff base for accurate assay of alpha-fetoprotein in clinical serum.

The high level of alpha-fetoprotein (AFP) expression is closely related to hepatocellular carcinoma (HCC). Herein, a dual signal ratiometric electrochemical immunosensor based on chitosan-ferrocenecarboxaldehyde-spindle gold (Chit-Fc-SAu) and Co/Fe metal-organic framework-toluidine blue/polydopamine (Co/Fe MOF-TB/PDA) was proposed for quantitative analysis of AFP. Specifically, Chit-Fc-SAu worked as a substrate to trap more primary antibodies (Ab1) generating the first electrochemical signal from Fc. Thanks to the large specific surface area, the synergistic and electronic effects of Co/Fe MOF nanosheets, and the rich functional groups of PDA, Co/Fe MOF-TB/PDA could load more secondary antibodies (Ab2) and signal molecules (TB) providing another amplified electrochemical signal. In the presence of AFP, Ab1-AFP-Ab2 formed a sandwich structure, and as the AFP concentration increased, the peak current ratio of TB to Fc (ITB/IFc) also increased. The dual signal ratiometric strategy can avoid environmental signal interference and achieve signal self-calibration, thereby improving the accuracy and reproducibility of detection. After a series of exploration, this self-calibrated ratiometric immunosensor exhibited a wide linear range (0.001-200 ng mL-1), a low detection limit (0.34 pg mL-1), and good repeatability. When applied to the assay of clinical serum samples, the detection results of ratiometric sensor were consistent with that of commercial electrochemiluminescence (ECL) immunoassay, significantly superior to that of non-ratiometric sensor. The self-calibrated strategy based on ratiometric sensor helps to improve the accuracy of AFP in clinical diagnosis.

NRG1-ErbB4 signaling in the medial amygdala controls mating motivation in adult male mice.

Motivation-driven mating is a basic affair for the maintenance of species. However, the underlying molecular mechanisms that control mating motivation are not fully understood. Here, we report that NRG1-ErbB4 signaling in the medial amygdala (MeA) is pivotal in regulating mating motivation. NRG1 expression in the MeA negatively correlates with the mating motivation levels in adult male mice. Local injection and knockdown of MeA NRG1 reduce and promote mating motivation, respectively. Consistently, knockdown of MeA ErbB4, a major receptor for NRG1, and genetic inactivation of its kinase both promote mating motivation. ErbB4 deletion decreases neuronal excitability, whereas chemogenetic manipulations of ErbB4-positive neuronal activities bidirectionally modulate mating motivation. We also identify that the effects of NRG1-ErbB4 signaling on neuronal excitability and mating motivation rely on hyperpolarization-activated cyclic nucleotide-gated channel 3. This study reveals a critical molecular mechanism for regulating mating motivation in adult male mice.

Citrus pectin protects mice from burn injury by modulating intestinal microbiota, GLP-1 secretion and immune response.

Water-soluble rhamnogalacturonan-I enriched citrus pectin (WRP) has promising effect on antimicrobial defense. We aim to determine whether the modified acidic (A) or neutral (B) WRP solutions can improve intestinal microbial dysbiosis in burn-injured mice. Male Balb/c mice were gavaged with WRPs at 80, 160, 320 mg/kg. Body weight daily for 21 days before exposed to thermal injury of 15 % total body surface area and mortality was monitored. Mice with 80 mg/kg WRPs were also subjected to fecal DNAs and T cell metabonomics analysis, intestinal and plasma glucagon-like peptide 1 (GLP-1) detection, plasma defensin, immunoglobin and intestinal barrier examinations at 1 and 3d postburn (p.b.). Burn-induced mortality was only improved by low dose WRP-A (P = 0.039). Both WRPs could prevent the dysbiosis of gut microbiota in burn injury by reducing the expansion of inflammation-promoting bacteria. Both WRPs suppressed ileum GLP-1 production at 1d p.b. (P = 0.002) and plasma GLP-1 levels at 3d p.b. (P = 0.013). Plasma GLP-1 level correlated closely with ileum GLP-1 production (P = 0.019) but negatively with microbiota diversity at 1d p.b. (P = 0.003). Intestinal T cell number was increased by both WRPs in jejunum at 3d p.b. However, the exaggerated splenic T cell metabolism in burn injury was reversed by both WRPs at 1d p.b. The burn-increased plasma defensin ß1 level was only reduced by WRP-B. Similarly, the intestinal barrier permeability was only rescued by WRP-B at 1d p.b. WRP-A rather than WRP-B could reduce burn-induced mortality in mice by suppressing intestinal GLP-1 secretion, restoring gut microbiota dysbiosis and improving adaptive immune response.

Glutamine induces lateral root initiation, stress responses, and disease resistance in Arabidopsis.

The production of glutamine (Gln) from NO3- and NH4+ requires ATP, reducing power, and carbon skeletons. Plants may redirect these resources to other physiological processes using Gln directly. However, feeding Gln as the sole nitrogen (N) source has complex effects on plants. Under optimal concentrations, Arabidopsis (Arabidopsis thaliana) seedlings grown on Gln have similar primary root lengths, more lateral roots, smaller leaves, and higher amounts of amino acids and proteins compared to those grown on NH4NO3. While high levels of Gln accumulate in Arabidopsis seedlings grown on Gln, the expression of GLUTAMINE SYNTHETASE1; 1 (GLN1; 1), GLN1; 2, and GLN1; 3 encoding cytosolic GS1 increases and expression of GLN2 encoding chloroplastic GS2 decreases. These results suggest that Gln has distinct effects on regulating GLN1 and GLN2 gene expression. Notably, Arabidopsis seedlings grown on Gln have an unexpected gene expression profile. Compared with NH4NO3, which activates growth-promoting genes, Gln preferentially induces stress- and defense-responsive genes. Consistent with the gene expression data, exogenous treatment with Gln enhances disease resistance in Arabidopsis. The induction of Gln-responsive genes, including PATHOGENESIS-RELATED1, SYSTEMIC ACQUIRED RESISTANCE DEFICIENT1, WRKY54, and WALL ASSOCIATED KINASE1, is compromised in salicylic acid (SA) biosynthetic and signaling mutants under Gln treatments. Together, these results suggest that Gln may partly interact with the SA pathway to trigger plant immunity.

Bioengineered Hydrogels Recapitulate Fibroblast Heterogeneity in Cancer.

Recently mapped transcriptomic landscapes reveal the extent of heterogeneity in cancer-associated fibroblasts (CAFs) beyond previously established single-gene markers. Functional analyses of individual CAF subsets within the tumor microenvironment are critical to develop more accurate CAF-targeting therapeutic strategies. However, there is a lack of robust preclinical models that reflect this heterogeneity in vitro. In this study, single-cell RNA sequencing datasets acquired from head and neck squamous cell carcinoma tissues to predict microenvironmental and cellular features governing individual CAF subsets are leveraged. Some of these features are then incorporated into a tunable hyaluronan-based hydrogel system to culture patient-derived CAFs. Control over hydrogel degradability and integrin adhesiveness enabled derivation of the predominant myofibroblastic and inflammatory CAF subsets, as shown through changes in cell morphology and transcriptomic profiles. Last, using these hydrogel-cultured CAFs, microtubule dynamics are identified, but not actomyosin contractility, as a key mediator of CAF plasticity. The recapitulation of CAF heterogeneity in vitro using defined hydrogels presents unique opportunities for advancing the understanding of CAF biology and evaluation of CAF-targeting therapeutics.

Treatment of bilateral developmental dysplasia of the hip joint with an improved technique: A case report.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a common osteoarticular deformity in pediatric orthopedics. A patient with bilateral DDH was diagnosed and treated using our improved technique "(powerful overturning acetabuloplasty)" combined with femoral rotational shortening osteotomy. CASE SUMMARY: A 4-year-old girl who was diagnosed with bilateral DDH could not stand normally, and sought surgical treatment to solve the problem of double hip extension and standing. As this child had high dislocation of the hip joint and the acetabular index was high, we changed the traditional acetabuloplasty to "powerful turnover acetabuloplasty" combined with femoral rotation shortening osteotomy. During the short-term postoperative follow-up (1, 3, 6, 9, 12, and 15 months), the child had no discomfort in her lower limbs. After the braces and internal fixation plates were removed, formal rehabilitation training was actively carried out. CONCLUSION: Our "powerful overturning acetabuloplasty" combined with femoral rotational shortening osteotomy is feasible in the treatment of DDH in children. This technology may be widely used in the clinic.

Exploring flatfeet morphology in children aged 6-12 years: relationships with body mass and body height through footprints and three-dimensional measurements.

The aim of the study was to determine the relationship between flatfoot morphology and body mass and height in children aged 6-12 years. A total of 6471 Chinese children (mean age 9.0 ± 1.9 years, 41% female) were assessed for foot morphometry, body height, and body mass index. Foot morphology, including foot length, width, girth, arch height, hallux valgus angle, and rearfoot valgus angle, was measured using a 3D laser scanner. Flatfoot evaluations were conducted using the Sztriter-Godunov index (KY) from footprints. All measurements were analyzed by age and sex using the mean values of the left and right sides. Comparisons were performed between flatfoot groups, between body mass index (BMI) groups, and between body height groups. The study revealed a significant decrease in the incidence of bipedal flatfoot with age (p < 0.001), whereas the prevalence of obesity remained consistent (p > 0.05). Bipedal flatfoot was associated with distinct morphological changes, including lower arches, reduced instep height, diminished ankle heights and a greater rearfoot valgus angle (p < 0.05). When comparing the BMI groups, overweight children had larger and thicker feet (p < 0.05), but no differences were found in arch height and ankle height (p > 0.05). When comparing the body height groups, short-statured children had a shorter feet girth, shorter arches, and shorter ankle height (p < 0.05), but no differences were found in the rearfoot valgus angle (p > 0.05). CONCLUSION: The main characteristics of flat feet include lower arches and instep heights and ankle heights but higher rearfoot valgus angles. In general, overweight children's feet do not have the common features of flat feet. In contrast, short children had similar features of flatfoot except for rearfoot valgus. Assessment of posture, such as rearfoot valgus, can be critical in identifying children with flat feet. WHAT IS KNOWN: • The morphology of children's feet is associated with body growth, but the relationship between flatfeet and body mass and height remains controversial. WHAT IS NEW: • Three-dimensional foot measurement shows that body mass is generally not associated with flatfeet, while short children have lower arches but no rearfoot valgus.

Chromatograms and Mass Spectra of High-Mannose and Paucimannose N-Glycans for Rapid Isomeric Identifications.

N-Linked glycosylation is one of the most essential post-translational modifications of proteins. However, N-glycan structural determination remains challenging because of the small differences in structures between isomers. In this study, we constructed a database containing collision-induced dissociation MSn mass spectra and chromatograms of high-performance liquid chromatography for the rapid identification of high-mannose and paucimannose N-glycan isomers. These N-glycans include isomers by breaking of arbitrary numbers of glycosidic bonds at arbitrary positions of canonical Man9GlcNAc2 N-glycans. In addition, some GlcMannGlcNAc2 N-glycan isomers were included in the database. This database is particularly useful for the identification of the N-glycans not in conventional N-glycan standards. This study demonstrated the application of the database to structural assignment for high-mannose N-glycans extracted from bovine whey proteins, soybean proteins, human mammary epithelial cells, and human breast carcinoma cells. We found many N-glycans that are not expected to be generated by conventional biosynthetic pathways of multicellular eukaryotes.

Dual p38MAPK and MEK inhibition disrupts adaptive chemoresistance in mesenchymal glioblastoma to temozolomide.

BACKGROUND: Precision treatment of glioblastoma is increasingly focused on molecular subtyping, with the mesenchymal subtype particularly resistant to temozolomide. Here, we aim to develop a targeted therapy for temozolomide resensitization in the mesenchymal subtype. METHODS: We integrated kinomic profiles and kinase inhibitor screens from patient-derived proneural and mesenchymal glioma-propagating cells public clinical datasets to identify key protein kinases implicated in temozolomide resistance. RNAseq, apoptosis assays and comet assays were used to examine the role of p38MAPK signaling and adaptive chemoresistance in mesenchymal cells. The efficacy of dual p38MAPK and MEK/ERK inhibition using ralimetinib (selective orally active p38MAPK inhibitor; phase I/II for glioblastoma) and binimetinib (approved MEK1/2 inhibitor for melanoma; phase II for high-grade glioma) in primary and recurrent mesenchymal tumors was evaluated using an intracranial patient-derived tumor xenograft model, focusing on survival analysis. RESULTS: Our transcriptomic-kinomic integrative analysis revealed p38MAPK as the prime target whose gene signature enables patient stratification based on their molecular subtypes and provides prognostic value. Repurposed p38MAPK inhibitors synergize favourably with temozolomide to promote intracellular retention of temozolomide and exacerbate DNA damage. Mesenchymal cells exhibit adaptive chemoresistance to p38MAPK inhibition through a pH-/calcium-mediated MEK/ERK pathway. Dual p38MAPK and MEK inhibition effectively maintains temozolomide sensitivity in primary and recurrent intracranial mesenchymal glioblastoma xenografts. CONCLUSION: Temozolomide resistance in mesenchymal glioblastoma is associated with p38MAPK activation. Adaptive chemoresistance in p38MAPK-resistant cells is mediated by MEK/ERK signaling. Adjuvant therapy with dual p38MAPK and MEK inhibition prolongs temozolomide sensitivity, which can be developed into a precision therapy for the mesenchymal subtype.

Assessing myocardial indices and inflammatory factors to determine anxiety and depression severity in patients with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) have a progressive disease that is associated with poor quality of life and high mortality. Many patients experience anxiety and depression (A&D) symptoms, which can further accelerate disease progression. We hypothesized that indicators of myocardial function and inflammatory stress may reflect the severity of A&D symptoms in patients with CHF. Changes in these biomarkers could potentially predict whether A&D symptoms will deteriorate further in these individuals. AIM: To measure changes in cardiac and inflammatory markers in patients with CHF to determine A&D severity and predict outcomes. METHODS: We retrospectively analyzed 233 patients with CHF treated at the Jingzhou Hospital, Yangtze University between 2018-2022 and grouped them according to Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) scores. We compared clinical data in the no-A&D, mild-A&D, moderate-A&D, and severe-A&D groups, the SAS and SDS scores with the New York Heart Association (NYHA) functional classification, and cardiac markers and inflammatory factors between the no/mild-A&D and moderate/severe-A&D groups. Regression analysis was performed on the markers with P < 0.05 to determine their ability to predict A&D severity in patients and the area under the receiver operating characteristic curve (AUROC) was used to evaluate their accuracy. RESULTS: In the inter-group comparison, the following variables had an effect on A&D severity in patients with CHF: NYHA class, left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter, N-terminal pro-brain natriuretic peptide (NT-proBNP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (P < 0.05). Other variables did not differ significantly between the A&D groups (P > 0.05). In addition, we found that higher NYHA classes were associated with higher the SAS and SDS scores (P < 0.05). Regression analysis showed that LVEF, NT-proBNP, and IL-6 were independent risk factors for A&D severity (P < 0.05). Among them, NT-proBNP had the best predictive ability as a single indicator (AUROC = 0.781). Furthermore, the combination of these three indicators exhibited a good predictive effect toward discriminating the extent of A&D severity among patients (AUROC = 0.875). CONCLUSION: Cardiac and inflammatory biomarkers, such as LVEF, NT-proBNP, and IL-6, are correlated with A&D severity in patients with CHF and have predictive value.

Synthetic self-adjuvanted multivalent Mucin 1 (MUC1) glycopeptide vaccines with improved in vivo antitumor efficacy.

The tumor-associated glycoprotein Mucin 1 (MUC1) is aberrantly glycosylated on cancer cells and is considered a promising target for antitumor vaccines. The weak immunogenicity and low sequence homology of mouse mucins and human MUC1 are the main obstacles for the development of vaccines. Herein, a self-adjuvanted strategy combining toll-like receptor 2 lipopeptide ligands and T-cell epitopes and the multivalent effect were used to amplify the immune response and evade the unpredictable immunogenicity, generating two self-adjuvanted three-component MUC1 vaccines (mono- and trivalent MUC1 vaccines). To simulate the aberrantly glycosylated MUC1 glycoprotein, the MUC1 tandem repeat peptide was bounded with Tn antigens at T9, S15, and T16, and served as B-cell epitopes. Results showed that both vaccines elicited a robust antibody response in wild-type mice compared with a weaker response in MUC1 transgenic mice. The trivalent vaccine did not elevate the antibody response level compared with the monovalent vaccine; however, a more delayed tumor growth and prolonged survival time was realized in wild-type and transgenic mouse models treated with the trivalent vaccine. These results indicate that the self-adjuvanted three-component MUC1 vaccines, especially the trivalent vaccine, can trigger robust antitumor effects regardless of sequence homology, and, therefore, show promise for clinical translation.

Epigenetic mechanisms in depression: Implications for pathogenesis and treatment.

The risk of depression is influenced by both genetic and environmental factors. It has been suggested that epigenetic mechanisms may mediate the risk of depression following exposure to adverse life events. Epigenetics encompasses stable alterations in gene expression that are controlled through transcriptional, post-transcriptional, translational, or post-translational processes, including DNA modifications, chromatin remodeling, histone modifications, RNA modifications, and non-coding RNA (ncRNA) regulation, without any changes in the DNA sequence. In this review, we explore recent research advancements in the realm of epigenetics concerning depression. Furthermore, we evaluate the potential of epigenetic changes as diagnostic and therapeutic biomarkers for depression.