Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

Reference interval establishment and correlation research of urine thromboxane metabolites: Unveiling new possibilities in platelet activation.

BACKGROUND: Thromboxane metabolites could indirectly reflect platelet activation, among which 11-dehydro-thromboxane B2 (11dhTxB2) and 11-dehydro-2, 3-dinor thromboxane B2 (11dh23dinorTxB2) are two stable metabolites that are abundant in urine, and both are closely related to disease progression and drug use. However, most clinical application studies have focused on the single indicator of 11dhTxB2. We propose an LC-MS/MS method suitable for routine clinical screening with simultaneous determination of both metabolites and conduct preliminary studies in different populations. METHODS AND RESULTS: The thromboxane metabolites were extracted by liquid-liquid extraction and determined by LC-MS/MS. Reference intervals (RI) were established in 333 healthy adults and validated in 25 patients with coronary atherosclerosis (CA). This LC-MS/MS method was over a wide quantitative range (0.1---10 µmol/L), the imprecision and accuracy were 5.2 %-11 % and 89.3 %-106.5 %, and was suitable for clinical routine quantitative screening. The 95th percentile RI of unire 11dhTxB2 was 1220 (95 % CI: 1048, 1376) pg mg Cr -1, for 11dh23dinorTxB2, RI was 908 (95 % CI: 821, 1102) pg mg Cr -1. For the first time, we found a significant correlation between 11dhTxB2 and 11dh23dinorTxB2 in both healthy adults (r = 0.67, P < 0.001) and CA patients (r = 0.77, P < 0.001). CONCLUSION: The establishment of RI provides a reference for diseases related to platelet activation and the use of drugs, and the first discovery of the correlation between 11dhTxB2 and 11dh23dinorTxB2 in urine provides a new possibilitie for the diagnostic and prognostic of cardiovascular diseases.

Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate.

Background/Aims: : The histological characteristics and natural history of precirrhotic primary biliary cholangitis (PBC) with portal hypertension (PH) are unclear. Our aim was to clarify the prevalence, risk factors, and histological characteristics of precirrhotic PBC patients with PH. Methods: : This retrospective study compared the clinical features, histological characteristics, and response to ursodeoxycholic acid (UDCA) between the PH and non-PH groups of precirrhotic PBC patients. Results: : Out of 165 precirrhotic PBC patients, 40 (24.2%) also had PH. According to histological stage 1, 2 and 3 disease, 5.3% (1/19), 17.3% (17/98), and 45.8% (22/48) of patients also had PH, respectively. Precirrhotic PBC with PH was significantly positively correlated with bile duct loss, degree of cytokeratin 7 positivity, and degree of fibrosis in the portal area, but significantly negatively correlated with lymphoid follicular aggregation. Compared to the non-PH group, patients in the PH group showed a higher prevalence of obliterative portal venopathy, incomplete septal fibrosis, portal tract abnormalities and non-zonal sinusoidal dilatation (p<0.05). In addition, patients with PH were more likely to present with symptoms of jaundice, ascites, epigastric discomfort, a poorer response to UDCA, and more decompensation events (p<0.05). High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values were risk factors for precirrhotic PBC with PH. Conclusions: : Approximately 24.2% of precirrhotic PBC patients have PH, which is histologically related to the injury of bile ducts. High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values are associated with increased risk of precirrhotic PBC with PH.

Dexmedetomidine affects the NOX4/Nrf2 pathway to improve renal antioxidant capacity.

OBJECTIVES: The study aimed to investigate the protective effects of dexmedetomidine (DEX) on renal injury caused by acute stress in rats and explore the protective pathways of DEX on rat kidneys in terms of oxidative stress. METHODS: An acute restraint stress model was utilized, where rats were restrained for 3 hours after a 15-minute swim. Biochemical tests and histopathological sections were conducted to evaluate renal function, along with the measurement of oxidative stress and related pathway proteins. KEY FINDINGS: The open-field experiments validated the successful establishment of the acute stress model. Acute stress-induced renal injury led to increased NADPH oxidase 4 (NOX4) protein expression and decreased expression levels of nuclear transcription factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO1). Following DEX treatment, there was a significant reduction in renal NOX4 expression. The DEX-treated group exhibited normalized renal biochemical results and less damage observed in pathological sections compared to the acute stress group. CONCLUSIONS: The findings suggest that DEX treatment during acute stress can impact the NOX4/Nrf2/HO-1/NQO1 signaling pathway and inhibit oxidative stress, thereby preventing acute stress-induced kidney injury. Additionally, DEX shows promise for clinical applications in stress syndromes.

Re-exploration of immunotherapy targeting EMT of hepatocellular carcinoma: Starting from the NF-κB pathway.

Hepatocellular carcinoma (HCC) is the fifth most common malignancies worldwide, and its high morbidity and mortality have brought a heavy burden to the global public health system. Due to the concealment of its onset, the limitation of treatment, the acquisition of multi-drug resistance and radiation resistance, the treatment of HCC cannot achieve satisfactory results. Epithelial mesenchymal transformation (EMT) is a key process that induces progression, distant metastasis, and therapeutic resistance to a variety of malignant tumors, including HCC. Therefore, targeting EMT has become a promising tumor immunotherapy method for HCC. The NF-κB pathway is a key regulatory pathway for EMT. Targeting this pathway has shown potential to inhibit HCC infiltration, invasion, distant metastasis, and therapeutic resistance. At present, there are still some controversies about this pathway and new ideas of combined therapy, which need to be further explored. This article reviews the progress of immunotherapy in improving EMT development in HCC cells by exploring the mechanism of regulating EMT.

Variation in monthly and seasonal elevation use impacts behavioral and dietary flexibility in Rhinopithecus bieti.

Black-and-white snub-nosed monkeys (Rhinopithecus bieti) rely on behavioral and dietary flexibility to survive in temperate latitudes at high-elevation habitats characterized by climate and resource seasonality. However, little is known about how elevation influences their behavioral and dietary flexibility at monthly or seasonal scales. We studied an isolated R. bieti population at Mt. Lasha in the Yunling Provincial Nature Reserve, Yunnan, China, between May 2008 and August 2016 to assess the impacts of elevation on feeding behavior and diet. Across our sample, R. bieti occupied elevations between 3031 and 3637 m above mean sea level (amsl), with a 315.1 m amsl range across months and a 247.3 m amsl range across seasons. Contrary to expectations, individuals spent less time feeding when ranging across higher elevations. Lichen consumption correlated with elevation use across months and seasons, with individuals spending more time feeding on this important resource at higher elevations. Leaf consumption only correlated with elevation use during the spring. Our results suggest that R. bieti do not maximize their food intake at higher elevations and that monthly and seasonal changes in lichen and leaf consumption largely explain variation in elevation use. These findings shed light on the responses of R. bieti to environmental change and offer insight into strategies for conserving their habitats in the face of anthropogenic disturbance.

Soy Product Consumption and the Risk of Cancer: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: The association between soy product consumption and cancer risk varies among studies. Therefore, this comprehensive meta-analysis of observational studies examines the association between soy product consumption and total cancer risk. METHODS: This study was conducted following the PRISMA guidelines. Up to October 2023, all eligible published studies were searched through PubMed and Web of Science databases. RESULTS: A total of 52 studies on soy product consumption were included in this meta-analysis (17 cohort studies and 35 case-control studies). High consumption of total soy products (RR: 0.69; 95% CI: 0.60, 0.80), tofu (RR: 0.78; 95% CI: 0.70, 0.86), and soymilk (RR: 0.75; 95% CI: 0.60, 0.93) were associated with reduced total cancer risk. No association was found between high consumption of fermented soy products (RR: 1.18; 95% CI: 0.95, 1.47), non-fermented soy products (RR: 0.95; 95% CI: 0.77, 1.18), soy paste (RR: 1.00; 95% CI: 0.88, 1.14), miso soup (RR: 0.99; 95% CI: 0.87, 1.12), or natto (RR: 0.96; 95% CI: 0.82, 1.11) and cancer risk. A 54 g per day increment of total soy products reduced cancer risk by 11%, a 61 g per day increment of tofu reduced cancer risk by 12%, and a 23 g per day increment of soymilk reduced cancer risk by 28%, while none of the other soy products were associated with cancer risk. CONCLUSION: Our findings suggest that high total soy product consumption, especially soymilk and tofu, is associated with lower cancer risk. More prospective cohort studies are still needed to confirm the causal relationship between soy product consumption and cancer risk.

Two B-box proteins orchestrate vegetative and reproductive growth in summer chrysanthemum.

Floral transition, the switch from vegetative to reproductive growth, is extremely important for the growth and development of flowering plants. In the summer chrysanthemum, CmBBX8, a member of the subgroup II B-box (BBX) family, positively regulates the transition by physically interacting with CmERF3 to inhibit CmFTL1 expression. In this study, we show that CmBBX5, a B-box subgroup I member comprising two B-boxes and a CCT domain, interacts with CmBBX8. This interaction suppresses the recruitment of CmBBX8 to the CmFTL1 locus without affecting its transcriptional activation activity. CmBBX5 overexpression led to delayed flowering under both LD (long-day) and SD (short-day) conditions, while lines expressing the chimeric repressor gene-silencing (CmBBX5-SRDX) exhibited the opposite phenotype. Subsequent genetic evidence indicated that in regulating flowering, CmBBX5 is partially dependent on CmBBX8. Moreover, during the vegetative growth period, levels of CmBBX5 expression were found to exceed those of CmBBX8. Collectively, our findings indicate that both CmERF3 and CmBBX5 interact with CmBBX8 to dampen the regulation of CmFTL1 via distinct mechanisms, which contribute to preventing the premature flowering of summer chrysanthemum.

Investigation of bioactive compounds and their correlation with the antioxidant capacity in different functional vinegars.

There are complex and diverse substances in traditional vinegars, some of which have been identified as biologically active factors, but the variety of functional compounds is currently restricted. In this study, it was aimed to determine the bioactive compounds in 10 typical functional vinegars. The findings shown that total flavonoids (0.21-7.19 mg rutin equivalent/mL), total phenolics (0.36-3.20 mg gallic acid equivalent/mL), and antioxidant activities (DPPH: 3.17-47.63 mmol trolox equivalent/L, ABTS: 6.85-178.29 mmol trolox equivalent/L) varied among different functional vinegars. In addition, the concentrations of the polysaccharides (1.17-44.87 mg glucose equivalent/mL) and total saponins (0.67-12.46 mg oleanic acid equivalent/mL) were determined, which might play key role for the function of tested vinegars. A total of 8 organic acids, 7 polyphenol compounds and 124 volatile compounds were measured and tentatively identified. The protocatechuic acid (4.81-485.72 mg/L), chlorogenic acid (2.69-7.52 mg/L), and epicatechin (1.18-97.42 mg/L) were important polyphenol compounds in the functional vinegars. Redundancy analysis indicated that tartaric acid, oxalic acid and chlorogenic acid were significantly positively correlated with antioxidant capacity. Various physiologically active ingredients including cyclo (Pro-Leu), cyclo (Phe-Pro), cyclo (Phe-Val), cyclo (Pro-Val), 1-monopalmitin and 1-eicosanol were firstly detected in functional vinegars. Principle component analysis revealed that volatiles profile of bergamot Monascus aromatic vinegar and Hengshun honey vinegar exhibited distinctive differences from other eight vinegar samples. Moreover, the partial least squares regression analysis demonstrated that 11 volatile compounds were positively correlated with the antioxidant activity of vinegars, which suggested these compounds might be important functional substances in tested vinegars. This study explored several new functionally active compounds in different functional vinegars, which could widen the knowledge of bioactive factor in vinegars and provide new ideas for further development of functional vinegar beverages.

Fluorine-Containing Ionogels with Stretchable, Solvent-Resistant, Wide Temperature Tolerance, and Transparent Properties for Ionic Conductors.

Stretchable ionogels, as soft ion-conducting materials, have generated significant interest. However, the integration of multiple functions into a single ionogel, including temperature tolerance, self-adhesiveness, and stability in diverse environments, remains a challenge. In this study, a new class of fluorine-containing ionogels was synthesized through photo-initiated copolymerization of fluorinated hexafluorobutyl methacrylate and butyl acrylate in a fluorinated ionic liquid 1-butyl-3-methyl imidazolium bis (trifluoromethylsulfonyl) imide. The resulting ionogels demonstrate good stretchability with a fracture strain of ~1300%. Owing to the advantages of the fluorinated network and the ionic liquid, the ionogels show excellent stability in air and vacuum, as well as in various solvent media such as water, sodium chloride solution, and hexane. Additionally, the ionogels display impressive wide temperature tolerance, functioning effectively within a wide temperature range from -60 to 350 °C. Moreover, due to their adhesive properties, the ionogels can be easily attached to various substrates, including plastic, rubber, steel, and glass. Sensors made of these ionogels reliably respond to repetitive tensile-release motion and finger bending in both air and underwater. These findings suggest that the developed ionogels hold great promise for application in wearable devices.

Extraction, purification, structural characteristics, biological activities, and applications of polysaccharides from the genus Lilium: A review.

The genus Lilium (Lilium) has been widely used in East Asia for over 2000 years due to its rich nutritional and medicinal value, serving as both food and medicinal ingredient. Polysaccharides, as one of the most important bioactive components in Lilium, offer various health benefits. Recently, polysaccharides from Lilium plants have garnered significant attention from researchers due to their diverse biological properties including immunomodulatory, anti-oxidant, anti-diabetic, anti-tumor, anti-bacterial, anti-aging and anti-radiation effects. However, the limited comprehensive understanding of polysaccharides from Lilium plants has hindered their development and utilization. This review focuses on the extraction, purification, structural characteristics, biological activities, structure-activity relationships, applications, and relevant bibliometrics of polysaccharides from Lilium plants. Additionally, it delves into the potential development and future research directions. The aim of this article is to provide a comprehensive understanding of polysaccharides from Lilium plants and to serve as a basis for further research and development as therapeutic agents and multifunctional biomaterials.

Cannabidiol Inhibits Epithelial Ovarian Cancer: Role of Gut Microbiome.

Epithelial ovarian cancer is among the deadliest gynecological tumors worldwide. Clinical treatment usually consists of surgery and adjuvant chemo- and radiotherapies. Due to the high rate of recurrence and rapid development of drug resistance, the current focus of research is on finding effective natural products with minimal toxic side effects for treating epithelial ovarian tumors. Cannabidiol is among the most abundant cannabinoids and has a non-psychoactive effect compared to tetrahydrocannabinol, which is a key advantage for clinical application. Studies have shown that cannabidiol has antiproliferative, pro-apoptotic, cytotoxic, antiangiogenic, anti-inflammatory, and immunomodulatory properties. However, its therapeutic value for epithelial ovarian tumors remains unclear. This study aims to investigate the effects of cannabidiol on epithelial ovarian tumors and to elucidate the underlying mechanisms. The results showed that cannabidiol has a significant inhibitory effect on epithelial ovarian tumors. In vivo experiments demonstrated that cannabidiol could inhibit tumor growth by modulating the intestinal microbiome and increasing the abundance of beneficial bacteria. Western blot assays showed that cannabidiol bound to EGFR/AKT/MMPs proteins and suppressed EGFR/AKT/MMPs expression in a dose-dependent manner. Network pharmacology and molecular docking results suggested that cannabidiol could affect the EGFR/AKT/MMPs signaling pathway.

MEG-PPIS: a fast protein-protein interaction site prediction method based on multi-scale graph information and equivariant graph neural network.

MOTIVATION: Protein-protein interaction sites (PPIS) are crucial for deciphering protein action mechanisms and related medical research, which is the key issue in protein action research. Recent studies have shown that graph neural networks have achieved outstanding performance in predicting PPIS. However, these studies often neglect the modeling of information at different scales in the graph and the symmetry of protein molecules within three-dimensional space. RESULTS: In response to this gap, this paper proposes the MEG-PPIS approach, a PPIS prediction method based on multi-scale graph information and E(n) equivariant graph neural network (EGNN). There are two channels in MEG-PPIS: the original graph and the subgraph obtained by graph pooling. The model can iteratively update the features of the original graph and subgraph through the weight-sharing EGNN. Subsequently, the max-pooling operation aggregates the updated features of the original graph and subgraph. Ultimately, the model feeds node features into the prediction layer to obtain prediction results. Comparative assessments against other methods on benchmark datasets reveal that MEG-PPIS achieves optimal performance across all evaluation metrics and gets the fastest runtime. Furthermore, specific case studies demonstrate that our method can predict more true positive and true negative sites than the current best method, proving that our model achieves better performance in the PPIS prediction task. AVAILABILITY AND IMPLEMENTATION: The data and code are available at https://github.com/dhz234/MEG-PPIS.git.

25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages.

Macrophages are critical to turn noninflamed "cold tumors" into inflamed "hot tumors". Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25Hhi subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8+ T cell surveillance and anti-tumor response.

The design of an RGD in situ sustained delivery system utilizing scallop byssal protein through genetic engineering.

Although bioactive peptides enhancing bone healing have demonstrated effectiveness in treating bone defects, in vivo instability poses a challenge to their clinical application. Currently reported peptide delivery systems do not meet the demands of bone tissue repair regarding stability and peptide release efficacy. Herein, the self-assembling recombinant chimeric protein (Sbp5-2RGD) is developed by genetic engineering with cell adhesion peptide RGD as the targeted peptide and a newly discovered scallop byssal-derived protein Sbp5-2 that can assemble into wet stable films as the structural domain. In vitro studies show that the Sbp5-2RGD film exhibits excellent extensibility and biocompatibility. In vitro and in vivo degradation experiments demonstrate that the film remains stable due to the layer-by-layer degradation mode, resulting in sustained delivery of RGD in situ for up to 4 weeks. Consequently, the film can effectively promote osteogenesis, which accelerates bone defect healing and the implants osseointegration. Cell-level studies further show that the film up-regulates the expression of genes and proteins (ALP, OCN, OSX, OPN, RUNX2, VEGF) associated with osteogenesis and angiogenesis. Overall, this novel protein film represents an intelligent platform for peptide immobilization, protection, and release through its self-assembly, dense structure, and degradation mode, providing a therapeutic strategy for bone repair.

Integrative metagenomic analysis reveals distinct gut microbial signatures related to obesity.

Obesity is a metabolic disorder closely associated with profound alterations in gut microbial composition. However, the dynamics of species composition and functional changes in the gut microbiome in obesity remain to be comprehensively investigated. In this study, we conducted a meta-analysis of metagenomic sequencing data from both obese and non-obese individuals across multiple cohorts, totaling 1351 fecal metagenomes. Our results demonstrate a significant decrease in both the richness and diversity of the gut bacteriome and virome in obese patients. We identified 38 bacterial species including Eubacterium sp. CAG:274, Ruminococcus gnavus, Eubacterium eligens and Akkermansia muciniphila, and 1 archaeal species, Methanobrevibacter smithii, that were significantly altered in obesity. Additionally, we observed altered abundance of five viral families: Mesyanzhinovviridae, Chaseviridae, Salasmaviridae, Drexlerviridae, and Casjensviridae. Functional analysis of the gut microbiome indicated distinct signatures associated to obesity and identified Ruminococcus gnavus as the primary driver for function enrichment in obesity, and Methanobrevibacter smithii, Akkermansia muciniphila, Ruminococcus bicirculans, and Eubacterium siraeum as functional drivers in the healthy control group. Additionally, our results suggest that antibiotic resistance genes and bacterial virulence factors may influence the development of obesity. Finally, we demonstrated that gut vOTUs achieved a diagnostic accuracy with an optimal area under the curve of 0.766 for distinguishing obesity from healthy controls. Our findings offer comprehensive and generalizable insights into the gut bacteriome and virome features associated with obesity, with the potential to guide the development of microbiome-based diagnostics.

Adults prenatally exposed to the Dutch Famine exhibit a metabolic signature associated with a broad spectrum of common diseases.

Background: Exposure to famine in the prenatal period is associated with an increased risk of metabolic disease, including obesity and type-2 diabetes. We employed nuclear magnetic resonance (NMR) metabolomic profiling to provide a deeper insight into the metabolic changes associated with survival of prenatal famine exposure during the Dutch Famine at the end of World War II and explore their link to disease. Methods: NMR metabolomics data were generated from serum in 480 individuals prenatally exposed to famine (mean 58.8 years, 0.5 SD) and 464 controls (mean 57.9 years, 5.4 SD). We tested associations of prenatal famine exposure with levels of 168 individual metabolic biomarkers and compared the metabolic biomarker signature of famine exposure with those of 154 common diseases. Results: Prenatal famine exposure was associated with higher concentrations of branched-chain amino acids ((iso)-leucine), aromatic amino acid (tyrosine), and glucose in later life (0.2-0.3 SD, p < 3×10 -3 ). The metabolic biomarker signature of prenatal famine exposure was positively correlated to that of incident type-2 diabetes (r = 0.77, p = 3×10 -27 ), also when re-estimating the signature of prenatal famine exposure among individuals without diabetes (r = 0.67, p = 1×10 -18 ). Remarkably, this association extended to 115 common diseases for which signatures were available (0.3 :< r :< 0.9, p < 3.2×10 -4 ). Correlations among metabolic signatures of famine exposure and disease outcomes were attenuated when the famine signature was adjusted for body mass index. Conclusions: Prenatal famine exposure is associated with a metabolic biomarker signature that strongly resembles signatures of a diverse set of diseases, an observation that can in part be attributed to a shared involvement of obesity.

First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-ß receptor I inhibitor, in patients with advanced solid tumors.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-ß pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-ß signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. METHODS: This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. RESULTS: Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25-8.60 h from 5 - 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-ß1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. TRIAL REGISTRATION: ClinicalTrial. gov ( https://www. CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02.

FraHMT: A Fragment-Oriented Heterogeneous Graph Molecular Generation Model for Target Proteins.

The molecular generation task stands as a pivotal step in the domains of computational chemistry and drug discovery, aiming to computationally generate molecular structures for specific properties. In contrast to previous models that focused primarily on SMILES strings or molecular graphs, our model placed a special emphasis on the substructure information on molecules, enabling the model to learn richer chemical rules and structure features from fragments and chemical reaction information on molecules. To accomplish this, we fragmented the molecules to construct heterogeneous graph representations based on atom and fragment information. Then our model mapped the heterogeneous graph data into a latent vector space by using an encoder and employed a self-regressive generative model as a decoder for molecular generation. Additionally, we performed transfer learning on the model using a small set of ligand molecules known to be active against the target protein to generate molecules that bind better to the target protein. Experimental results demonstrate that our model is highly competitive with state-of-the-art models. It can generate valid and diverse molecules with favorable physicochemical properties and drug-likeness. Importantly, they produce novel molecules with high docking scores against the target proteins.

DockingGA: enhancing targeted molecule generation using transformer neural network and genetic algorithm with docking simulation.

Generative molecular models generate novel molecules with desired properties by searching chemical space. Traditional combinatorial optimization methods, such as genetic algorithms, have demonstrated superior performance in various molecular optimization tasks. However, these methods do not utilize docking simulation to inform the design process, and heavy dependence on the quality and quantity of available data, as well as require additional structural optimization to become candidate drugs. To address this limitation, we propose a novel model named DockingGA that combines Transformer neural networks and genetic algorithms to generate molecules with better binding affinity for specific targets. In order to generate high quality molecules, we chose the Self-referencing Chemical Structure Strings to represent the molecule and optimize the binding affinity of the molecules to different targets. Compared to other baseline models, DockingGA proves to be the optimal model in all docking results for the top 1, 10 and 100 molecules, while maintaining 100% novelty. Furthermore, the distribution of physicochemical properties demonstrates the ability of DockingGA to generate molecules with favorable and appropriate properties. This innovation creates new opportunities for the application of generative models in practical drug discovery.