Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.

BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

Expression and prognostic value of APOBEC2 in gastric adenocarcinoma and its association with tumor-infiltrating immune cells.

BACKGROUND: Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 2 (APOBEC2) is associated with nucleotide alterations in the transcripts of tumor-related genes which are contributed to carcinogenesis. Expression and prognosis value of APOBEC2 in stomach adenocarcinoma (STAD) remains unclear. METHODS: The APOBEC2 gene alteration frequency of STAD and APOBEC2 gene expression in STAD and normal tissues were investigated in cBioportal and GEPIA, respectively. We detected expression of APOBEC2, infiltration of CD66b+ tumor-associated neutrophils and CD163+ tumor-associated macrophages in tissue microarrays by immunohistochemistry. APOBEC2 gene expression was explored by western blot and qRT-PCR. Relationships between APOBEC2 and CD66b, CD163, and other clinicopathological characteristics were investigated. Associations among APOBEC2 expression status and patient survival outcome were further analyzed. RESULTS: APOBEC2 gene alteration frequency was 5%, and APOBEC2 gene was downexpressed in STAD compared to normal tissues (P < 0.05). APOBEC2 expression status were associated with the infiltration of CD66b+ TANs, differentiation grade, TNM stage, histological type and gender (all P < 0.05) in STAD. Little or no APOBEC2 expression was detected in STAD and adjacent normal tissues by western blot. We failed to show that APOBEC2 was an independent risk factor for OS (Hazard Ratio 0.816, 95%CI 0.574-1.161, P = 0.259) or DFS (Hazard Ratio 0.821, 95%CI 0.578-1.166, P = 0.270) in STAD by multivariate Cox regression analysis, but APOBEC2 negative subgroup has a worse OS and DFS among patients with adjuvant chemotherapy. CONCLUSIONS: APOBEC2 correlates with CD66b, differentiation grade, TNM stages, histological classification, and gender in STAD. APOBEC2 is not an independent prognostic factor for STAD, our results suggest that patients with positive APOBEC2 can benefit from postoperative chemotherapy, and combination of APOBEC2 and CD66b is helpful to further stratify patients into different groups with distinct prognoses.

Joint Experimental and Theoretical Study on Deposition Morphologies in Polymer Sessile Droplets.

Although past experimental and theoretical research has made substantial progress in understanding evaporation behaviors in various suspensions, the fundamental mechanism for polymer sessile droplets is still lacking. One critical effect is the molecular weight on the evaporation behaviors. Here, systematic experiments are carried out to investigate the evaporation behavior of polymer droplets under the effects of polymer concentration, evaporation rate, and especially molecular weight. We obtain polymer films with various morphologies with molecular weights ranging from 2 orders of magnitude to 4 orders of magnitude and polymer concentration across 4 orders of magnitude. We further develop a theoretical model based on the Onsager principle to explain the evaporation mechanism from a dynamic perspective. Analysis indicates that increasing molecular weight or polymer concentration enhances the contact angle hysteresis and slows down the evaporation, resulting in the transition from multiring to coffee ring and eventually to uniform films. The findings offer a guideline for achieving the desired deposition patterns via droplet processing techniques.

5-HMF attenuates inflammation and demyelination in experimental autoimmune encephalomyelitis mice by inhibiting the MIF-CD74 interaction.

The neuroprotective role of 5-hydroxymethyl-2-furfural (5-HMF) has been demonstrated in a variety of neurological diseases. The aim of this study is to investigate the effect of 5-HMF on multiple sclerosis (MS). IFN-γ-stimulated murine microglia (BV2 cells) are considered a cell model of MS. With 5-HMF treatment, microglial M1/2 polarization and cytokine levels are detected. The interaction of 5-HMF with migration inhibitory factor (MIF) is predicted using online databases. The experimental autoimmune encephalomyelitis (EAE) mouse model is established, followed by a 5-HMF injection. The results show that 5-HMF facilitates IFN-γ-stimulated microglial M2 polarization and attenuates the inflammatory response. According to the network pharmacology and molecular docking results, 5-HMF has a binding site for MIF. Further results show that blocking MIF activity or silencing CD74 enhances microglial M2 polarization, reduces inflammatory activity, and prevents ERK1/2 phosphorylation. 5-HMF inhibits the MIF-CD74 interaction by binding to MIF, thereby inhibiting microglial M1 polarization and enhancing the anti-inflammatory response. 5-HMF ameliorates EAE, inflammation, and demyelination in vivo. In conclusion, our research indicates that 5-HMF promotes microglial M2 polarization by inhibiting the MIF-CD74 interaction, thereby attenuating inflammation and demyelination in EAE mice.

C-Terminal Truncated HBx Facilitates Oncogenesis by Modulating Cell Cycle and Glucose Metabolism in FXR-Deficient Hepatocellular Carcinoma.

Farnesoid X receptor (FXR) is a nuclear receptor known to play protective roles in anti-hepatocarcinogenesis and regulation of the basal metabolism of glucose, lipids, and bile acids. FXR expression is low or absent in HBV-associated hepatocarcinogenesis. Full-length HBx and HBx C-terminal truncation are frequently found in clinical HCC samples and play distinct roles in hepatocarcinogenesis by interacting with FXR or FXR signaling. However, the impact of C-terminal truncated HBx on the progression of hepatocarcinogenesis in the absence of FXR is unclear. In this study, we found that one known FXR binding protein, a C-terminal truncated X protein (HBx C40) enhanced obviously and promoted tumor cell proliferation and migration by altering cell cycle distribution and inducing apoptosis in the absence of FXR. HBx C40 enhanced the growth of FXR-deficient tumors in vivo. In addition, RNA-sequencing analysis showed that HBx C40 overexpression could affect energy metabolism. Overexpressed HSPB8 aggravated the metabolic reprogramming induced by down-regulating glucose metabolism-associated hexokinase 2 genes in HBx C40-induced hepatocarcinogenesis. Overall, our study suggests that C-terminal truncated HBx C40 synergizes with FXR deficiency by altering cell cycle distribution as well as disturbing glucose metabolism to promote HCC development.

Synthetic Particles for Cancer Vaccines: Connecting the Inherent Supply Chain.

Cancer vaccines have opened a new paradigm for safe and effective antitumor therapy, but they still suffer from shortcomings such as insufficient immunogenicity and immune tolerance, which seldom makes them the first choice in clinic. In fact, similar to providing a high-end product, a robust antitumor effect depends on the inherent supply chain, which attains, processes, and presents tumor-associated antigens via antigen presenting cells to T cells, which then leads to lysis of the cancer cells to release more antigens to complete the supply chain. Under these circumstances, the failure of cancer vaccines can be treated as a blockade or chain rupture. Thus, for effective tumor treatment, the key is to rationally design logistic systems to restore the supply chain.Under these circumstances, this Account summarizes our recent attempts to exploit the immunogenic trait of synthetic particles to enhance the distribution, presentation, and immune activations of the whole priming process in cancer vaccines: (1) Raw material (tumor antigen/signals) procurement: We illustrated the efforts to deliver antigens to antigen presenting cells (APCs) and draining lymph nodes for potent internalizations, and put more emphasis on the structural effect of sizes, charges, shapes, and assembly strategies for the antigen depot, lymph node transfer, and APC endocytosis. (2) Manufacture of cytotoxic T lymphocytes (CTLs) via APC recognition and presentation: We centered on exploiting the softness of two-dimensional graphene and Pickering emulsions to dynamically potentiate the immune recognition, and demonstrating the recent advances in lysosome escape strategies for enhanced antigen cross-presentations. (3) Marketing the accumulations of CTLs and the reversal of an immunosuppressive microenvironment within the tumor: We demonstrated the previous attempts to inherently cultivate the tumor tropism of the T cells via the multiantigenic repertoire and discussed the advances and challenges of combinatory cancer vaccines with an immune checkpoint blockade to reinforce the antitumor efficacy. Collectively, this Account aims to illustrate the potential of the particulate cancer vaccines to recapitalize the inherent host immune responses for the maximum antitumor effect. And by integrating the antitumor supply chain, optimized synthetic particles may shed light on the development of safe and effective particulate cancer vaccines.

Prediction Model Combining Clinical and MR Data for Diagnosis of Lymph Node Metastasis in Patients With Rectal Cancer.

BACKGROUND: Determining the status of lymph node (LN) metastasis in rectal cancer patients preoperatively is crucial for the treatment option. However, the diagnostic accuracy of current imaging methods is low. PURPOSE: To develop and test a model for predicting metastatic LNs of rectal cancer patients based on clinical data and MR images to improve the diagnosis of metastatic LNs. STUDY TYPE: Retrospective. SUBJECTS: In all, 341 patients with histologically confirmed rectal cancer were divided into one training set (120 cases) and three validation sets (69, 103, 49 cases). FIELD STRENGTH/SEQUENCE: 3.0T, axial and sagittal T2 -weighted turbo spin echo and diffusion-weighted imaging (b = 0 s/mm2 , 800 s/mm2 ) ASSESSMENT: In the training dataset, univariate logistic regression was used to identify the clinical factors (age, gender, and tumor markers) and MR data that correlated with LN metastasis. Then we developed a prediction model with these factors by multiple logistic regression analysis. The accuracy of the model was verified using three validation sets and compared with the traditional MRI method. STATISTICAL TESTS: Univariate and multivariate logistic regression. The area under the curve (AUC) value was used to quantify the diagnostic accuracy of the model. RESULTS: Eight factors (CEA, CA199, ADCmean, mriT stage, mriN stage, CRM, EMVI, and differentiation degree) were significantly associated with LN metastasis in rectal cancer patients (P<0.1). In the training set (120) and the three validation sets (69, 103, 49), the AUC values of the model were much higher than the diagnosis by MR alone (training set, 0.902 vs. 0.580; first validation set, 0.789 vs. 0.743; second validation set, 0.774 vs. 0.573; third validation set, 0.761 vs. 0.524). DATA CONCLUSION: For the diagnosis of metastatic LNs in rectal cancer patients, our proposed logistic regression model, combining clinical and MR data, demonstrated higher diagnostic efficiency than MRI alone. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY STAGE: 2.

Meta-analysis of the effect of sodium-glucose cotransporter 2 inhibitors on hepatic fibrosis in patients with type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease.

AIM: This study aimed to analyze the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the indexes of liver fibrosis in patients with type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease, and also to observe the effects on liver enzymes and liver fat. METHODS: This meta-analysis was performed using RevMan 5.3 statistical software. RESULTS: SGLT2 inhibitors could significantly reduce the level of hepatic fibrosis index: fibrosis-4 (mean difference [MD] 0.25, 95% CI -0.39 to -0.11, p = 0.0007); serum type â…£ collagen 7s (MD 0.32, 95% CI -0.59 to -0.04, p = 0.02); and ferritin (MD 26.7, 95% CI 50.64, 2.76, p = 0.03). SGLT2 inhibitors could significantly reduce the level of liver enzymes: alanine aminotransferase (MD 3.49, 95% CI -5.1 to 1.58, p < 0.0001); aspartate aminotransferase (MD 3.64, 95% CI -5.10 to -2.18, p < 0.00001); and glutamate aminotransferase (MD 7.13, 95% CI -12.95 to -1.32, p = 0.02). SGLT2 inhibitors could significantly reduce the level of liver fat: liver-to-spleen attenuation ratio (MD 0.16, 95% CI 0.10-0.22, p < 0.00001); magnetic resonance imaging proton density fat fraction (MD 1.97, 95% CI -3.49 to -0.45, p = 0.01); liver controlled attenuation parameter (MD 0.29, 95% CI -26.95 to -13.64, p < 0.00001); liver fat score (MD 0.55, 95% CI 1.04 to -0.05, p = 0.03); and liver fat index (MD 11.21, 95% CI -16.53 to -5.89, p < 0.0001). CONCLUSION: SGLT2 inhibitors could improve liver fibrosis, liver enzymes, liver fat, and metabolic indexes in patients with type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease.

Monocyte Chemoattractant Protein-1 stimulates the differentiation of rat stem and progenitor Leydig cells during regeneration.

BACKGROUND: Monocyte chemoattractant protein-1(MCP-1) is a chemokine secreted by Leydig cells and peritubular myoid cells in the rat testis. Its role in regulating the development of Leydig cells via autocrine and paracrine is still unclear. The objective of the current study was to investigate the effects of MCP-1 on Leydig cell regeneration from stem cells in vivo and on Leydig cell development in vitro. RESULTS: Intratesticular injection of MCP-1(10 ng/testis) into Leydig cell-depleted rat testis from post-EDS day 14 to 28 significantly increased serum testosterone and luteinizing hormone levels, up-regulated the expression of Leydig cell proteins, LHCGR, SCARB1, CYP11A1, HSD3B1, CYP17A1, and HSD17B3 without affecting progenitor Leydig cell proliferation, as well as increased ERK1/2 phosphorylation. MCP-1 (100 ng/ml) significantly increased medium testosterone levels and up-regulated LHCGR, CYP11A1, and HSD3B1 expression without affecting EdU incorporation into stem cells after in vitro culture for 7 days. RS102895, a CCR2 inhibitor, reversed MCP-1-mediated increase of testosterone level after culture in combination with MCP-1. CONCLUSION: MCP-1 stimulates the differentiation of stem and progenitor Leydig cells without affecting their proliferation.

Advanced myocardial characterization in hypertrophic cardiomyopathy: feasibility of CMR-based feature tracking strain analysis in a case-control study.

OBJECTIVES: This study aimed to evaluate the feasibility and reproducibility of using cardiovascular magnetic resonance feature tracking (CMR-FT) for analysis of bi-ventricular strain and strain rate (SR) in hypertrophic cardiomyopathy (HCM) patients as well as to explore the correlation between right ventricular (RV) and left ventricular (LV) deformation. METHODS: A total of 60 HCM patients and 48 controls were studied. Global and segmental peak values of bi-ventricular longitudinal, circumferential, radial strain, and systolic SR were analyzed. Pearson analysis was performed to investigate the correlation of RV and LV deformation. Intra-observer and inter-observer reproducibility were also assessed. RESULTS: LV mass in the HCM group was significantly higher than that in the control group. LV end-systolic and end-diastolic volume and RV end-systolic and end-diastolic volume in the HCM group were all significantly lower than the correlated parameters in the control group (p < 0.001, respectively), whereas no statistical difference was found in ejection fraction (p > 0.05). Global longitudinal strain (GLS), global longitudinal strain rate (GLSR), global circumferential strain (GCS), global circumferential strain rate (GCSR), global radial strain (GRS), and global radial strain rate (GRSR) of the LV and RV were all significantly lower than the control group, and segmental strain and SR were also true (p < 0.001, respectively). Bi-ventricular strain and SR measurements were highly reproducible at both intra- and inter-observer levels. Additionally, Pearson analysis showed RV GCS, GLS, and GRS positively correlated with LV GCS, GLS, and GRS (r = 0.713, p < 0.001; r = 0.728, p < 0.001; r = 0.730, p < 0.001, respectively). CONCLUSIONS: CMR-FT is a promising approach to analyze impairment of global and segmental myocardium deformation in HCM patients non-invasively and quantitatively. KEY POINTS: • CMR-FT allows for advanced myocardial characterization with high reproducibility. • As compared with controls, HCM patients have significant differences in CMR-FT strain analysis while ejection fraction was similar. • CMR-FT may serve as an early biomarker of HCM in subjects at risk.

Incidence, Risk Factors, and Outcomes of Ventilator-Associated Pneumonia in Traumatic Brain Injury: A Meta-analysis.

Ventilator-associated pneumonia (VAP) is one of the most severe complications in patients with traumatic brain injury (TBI) and is considered a risk factor for poor outcomes. However, the incidence of VAP among patients with TBI reported in studies varies widely. What is more, the risk factors and outcomes of VAP are controversial. This study estimates the incidence, risk factors, and outcomes of VAP in patients with TBI and provides evidence for prevention and treatment. PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched from the earliest records to May 2018. Data involving the incidence, risk factors, and outcomes were extracted for meta-analysis. The results showed that the incidence of VAP was 36% (95% confidence interval (CI) 31-41%); risk factors analyses showed that smoking [odds ratio (OR) 2.13; 95% CI 1.16-3.92], tracheostomy (OR 9.55; 95% CI 3.24-28.17), blood transfusion on admission (OR 2.54; 95% CI 1.24-5.18), barbiturate infusion (OR 3.52; 95% CI 1.68-7.40), injury severity score (OR 4.65; 95% CI 1.96-7.34), and head abbreviated injury scale (OR 2.99; 95% CI 1.66-5.37) were related to the occurrence of VAP. When patients developed VAP, mechanical ventilation time (OR 5.45; 95% CI 3.78-7.12), ICU length of stay (OR 6.85; 95% CI 4.90-8.79), and hospital length of stay (OR 10.92; 95% CI 9.12-12.72) were significantly increased. However, VAP was not associated with an increased risk of mortality (OR 1.28; 95% CI 0.74-2.21). VAP is common in patients with TBI. It is affected by a series of factors and has a poor prognosis.

Current status and future prospects of Chinese mobile apps for hypertension management.

OBJECTIVE: This study aimed to evaluate the current situation of Chinese mobile apps for hypertension management and explore patients' real requirements for app use, providing a theoretical basis for the future improvement of hypertension apps. METHODS: We reviewed hypertension management apps from mobile app platforms, and summarized their functional characteristics. In addition, we conducted an online survey among 1000 hypertensive patients, collected valid responses, and analyzed the feedback data. RESULTS: Forty hypertension management apps were analyzed, with 72.5% offering no more than six functions, indicating limited coverage of advanced and comprehensive functionalities. Among the 934 valid survey responses, patients emphasized four main functions in apps for hypertension management: long-term dynamic blood pressure monitoring, scientific lifestyle management, strict medication management and systematic health knowledge delivering. CONCLUSION: The existing hypertension management apps mainly serve as "Digital Health" tools with unclear clinical efficacy. The future development of these apps lies in how they transition to "Digital Therapeutics" solutions to better meet patients' needs and provide clear clinical advantages.

The Forkhead Box Gene, MaSep1, Negatively Regulates UV- and Thermo-Tolerances and Is Required for Microcycle Conidiation in Metarhizium acridum.

Insect pathogenic fungi have shown great potential in agricultural pest control. Conidiation is crucial for the survival of filamentous fungi, and dispersal occurs through two methods: normal conidiation, where conidia differentiate from mycelium, and microcycle conidiation, which involves conidial budding. The conidiation process is related to cell separation. The forkhead box gene Sep1 in Schizosaccharomyces pombe plays a crucial role in cell separation. Nevertheless, the function of Sep1 has not been clarified in filamentous fungi. Here, MaSep1, the homolog of Sep1 in Metarhizium acridum, was identified and subjected to functional analysis. The findings revealed that conidial germination of the MaSep1-deletion strain (ΔMaSep1) was accelerated and the time for 50% germination rate of conidial was shortened by 1 h, while the conidial production of ΔMaSep1 was considerably reduced. The resistances to heat shock and UV-B irradiation of ΔMaSep1 were enhanced, and the expression of some genes involved in DNA damage repair and heat shock response was significantly increased in ΔMaSep1. The disruption of MaSep1 had no effect on the virulence of M. acridum. Interestingly, ΔMaSep1 conducted the normal conidiation on the microcycle conidiation medium, SYA. Furthermore, 127 DEGs were identified by RNA-Seq between the wild-type and ΔMaSep1 strains during microcycle conidiation, proving that MaSep1 mediated the conidiation pattern shift by governing some genes associated with conidiation, cell division, and cell wall formation.

Analysis of online prescription patterns in Chinese patients with sequelae of cerebral infarction: a real-world study.

Cerebral infarction (CI) is a common cerebrovascular disease worldwide, and the burden caused by the sequelae of CI has increased significantly. However, current treatment guidelines lack standardized recommendations for pharmacotherapy of sequelae of CI. This retrospective study collected and analyzed 1.98 million prescriptions concerning sequelae of CI from patients admitted to Zhiyun Health Internet Hospital in 2022. The mean age of patients was 66.2 ± 11.4 years, and 52.40% were male. 79.73% had one or more comorbidities. For treatment, the prescriptions of 1-, 2- and ≥ 3-drug accounted for 64.55%, 23.77% and 11.68% respectively. Chinese patent medicine (CPM) prescriptions, western medicine (WM) prescriptions, and CPM and WM combined (CPM + WM) prescriptions accounted for 53.81%, 27.33%, and 18.86% respectively. In CPM prescriptions, the most frequently prescribed medications were Salvia miltiorrhiza (34.81%), Ginkgo biloba (24.96%), Panax notoginseng (20.67%), Gastrodia (7.15%) and Ligusticum Wallichii (4.90%). For WM prescriptions, the most commonly prescribed agents were anti-hypertensive (32.82%), anti-thrombotic (16.06%), vasodilator (15.70%), anti-dementia (10.88%), and lipid-lowering (9.58%) drugs. Among CPM + WM prescriptions, 72.61% had CPM/WM = 1, 21.20% had CPM/WM < 1, and 6.19% had CPM/WM > 1. This research utilized real-world data extracted from internet hospitals in China to present valuable evidence of online prescription patterns among patients experiencing sequelae of CI.

Augmenting vaccine efficacy: Tailored immune strategy with alum-stabilized Pickering emulsion.

BACKGROUND: The achievement of optimal vaccine efficacy is contingent upon the collaborative interactions between T and B cells in adaptive immunity. Although multiple immunization strategies have been proposed, there is a notable scarcity of comprehensive investigations pertaining to enhance immune effects through immune strategy adjustments for individual vaccine. METHODS: The hierarchically structured aluminum hydroxide microgel-stabilized Pickering emulsion (ASPE) was prepared by ultrasonic method. This study explored the influence of the immune strategy of ASPE to immune responses, including antigen exposure pattern, adjuvants and antigen dosage, and administration interval. RESULTS: The findings revealed that external antigen adsorption facilitated increased exposure of antigen epitopes, leading to elevated IgG titers and secretion of cytokines such as interferon-gamma (IFN-γ) or interleukin-4 (IL-4). Additionally, even a low dose (1 µg/dose) of antigens of ASPE boosted sufficient neutralizing antibody levels and memory T cells compared to high-dose antigens, which consistent with the adjuvant dosage effect. Furthermore, maintaining a 4-week immunization interval yielded optimal levels of antigen-specific IgG titers in both short-term and long-term scenarios, as compared to intervals of 2, 3, and 5 weeks. A consistent trend was observed in the proliferation of memory B cells, reaching a superior level at the 4-week interval, which could enhance protection against viral re-infection. CONCLUSION: Tailoring immunization strategies for specific vaccines has emerged as powerful driver in maximizing vaccine efficacy and eliciting robust immune responses, thereby presenting cutting-edge approaches to enhanced vaccination.

Role of Triglyceride-Glucose Index in Type 2 Diabetes Mellitus and Its Complications.

Insulin resistance (IR) is the major mechanism in the pathogenesis of type 2 diabetes mellitus (T2DM). Early identification of IR is of great significance for preventing the onset of T2DM and delaying the progression of the disease. Previous studies have shown that triglyceride-glucose (TyG) index can be used as an effective surrogate marker for IR. There is a significant correlation between TyG index and T2DM and its common complications. In addition, the predictive efficacy of TyG index is better than that of other IR surrogate indicators. TyG index may not only become an important marker to identify people at high risk of T2DM and its complications, but is also expected to become a strong predictor of the prognosis of these diseases. However, there are still some challenges in the widespread application of TyG index in clinical practice. In the future, more high-quality studies are needed to clarify the assessment methods of TyG index for the prognosis of T2DM and its complications. Further investigations of the relationship between TyG index and T2DM and its complications will be expected to provide new ideas and methods for the prevention and treatment of T2DM and its complications.

Pharmacodynamic and Toxicity Studies of 6-Isopropyldithio-2'-guanosine Analogs in Acute T-Lymphoblastic Leukemia.

(1) Background: The research group has developed a new small molecule, 6-Isopropyldithio-2'-deoxyguanosine analogs-YLS004, which has been shown to be the most sensitive in acute T-lymphoblastic leukemia cells. Moreover, it was found that the structure of Nelarabine, a drug used to treat acute T-lymphoblastic leukemia, is highly similar to that of YLS004. Consequently, the structure of YLS004 was altered to produce a new small molecule inhibitor for this study, named YLS010. (2) Results: YLS010 has exhibited potent anti-tumor effects by inducing cell apoptosis and ferroptosis. A dose gradient was designed for in vivo experiments based on tentative estimates of the toxicity dose using acute toxicity in mice and long-term toxicity in rats. The study found that YLS010 at a dose of 8 mg/kg prolonged the survival of late-stage acute T-lymphoblastic leukemia mice in the mouse model study. (3) Conclusions: YLS010 has demonstrated specific killing effects against acute T-lymphoblastic leukemia both in vivo and in vitro. Preclinical studies of YLS010 offer a new opportunity for the treatment of patients with acute T-lymphoblastic leukemia in clinical settings.

Engineering CaP-Pickering emulsion for enhanced mRNA cancer vaccines via dual DC and NK activations.

mRNA delivery systems, such as lipid nanoparticle (LNP), have made remarkable strides in improving mRNA expression, whereas immune system activation operates on a threshold. Maintaining a delicate balance between antigen expression and dendritic cell (DC) activation is vital for effective immune recognition. Here, a water-in-oil-in-water (w/o/w) Pickering emulsion stabilized with calcium phosphate nanoparticles (CaP-PME) is developed for mRNA delivery in cancer vaccination. CaP-PME efficiently transports mRNA into the cytoplasm, induces pro-inflammatory responses and activates DCs by disrupting intracellular calcium/potassium ions balance. Unlike LNP, CaP-PME demonstrates a preference for DCs, enhancing their activation and migration to lymph nodes. It elicits interferon-γ-mediated CD8+ T cell responses and promotes NK cell proliferation and activation, leading to evident NK cells infiltration and ameliorated tumor microenvironment. The prepared w/o/w Pickering emulsion demonstrates superior anti-tumor effects in E.G7 and B16-OVA tumor models, offering promising prospects as an enhanced mRNA delivery vehicle for cancer vaccinations.

Pickering emulsion-guided monomeric delivery of monophosphoryl lipid A for enhanced vaccination.

Immunological adjuvants are vaccine components that enhance long-lasting adaptive immune responses to weakly immunogenic antigens. Monophosphoryl lipid A (MPLA) is a potent and safe vaccine adjuvant that initiates an early innate immune response by binding to the Toll-like receptor 4 (TLR4). Importantly, the binding and recognition process is highly dependent on the monomeric state of MPLA. However, current vaccine delivery systems often prioritize improving the loading efficiency of MPLA, while neglecting the need to maintain its monomeric form for optimal immune activation. Here, we introduce a Pickering emulsion-guided MPLA monomeric delivery system (PMMS), which embed MPLA into the oil-water interface to achieve the monomeric loading of MPLA. During interactions with antigen-presenting cells, PMMS functions as a chaperone for MPLA, facilitating efficient recognition by TLR4 regardless of the presence of lipopolysaccharide-binding proteins. At the injection site, PMMS efficiently elicited local immune responses, subsequently promoting the migration of antigen-internalized dendritic cells to the lymph nodes. Within the draining lymph nodes, PMMS enhanced antigen presentation and maturation of dendritic cells. In C57BL/6 mice models, PMMS vaccination provoked potent antigen-specific CD8+ T cell-based immune responses. Additionally, PMMS demonstrated strong anti-tumor effects against E.G7-OVA lymphoma. These data indicate that PMMS provides a straightforward and efficient strategy for delivering monomeric MPLA to achieve robust cellular immune responses and effective cancer immunotherapy.