Genetic Dissection of Diverse Seed Coat Patterns in Cowpea through a Comprehensive GWAS Approach.

This study investigates the genetic determinants of seed coat color and pattern variations in cowpea (Vigna unguiculata), employing a genome-wide association approach. Analyzing a mapping panel of 296 cowpea varieties with 110,000 single nucleotide polymorphisms (SNPs), we focused on eight unique coat patterns: (1) Red and (2) Cream seed; (3) White and (4) Brown/Tan seed coat; (5) Pink, (6) Black, (7) Browneye and (8) Red/Brown Holstein. Across six GWAS models (GLM, SRM, MLM, MLMM, FarmCPU from GAPIT3, and TASSEL5), 13 significant SNP markers were identified and led to the discovery of 23 candidate genes. Among these, four specific genes may play a direct role in determining seed coat pigment. These findings lay a foundational basis for future breeding programs aimed at creating cowpea varieties aligned with consumer preferences and market requirements.

piSTING: A Pocket-Independent Agonist Based on Multivalency-Driven STING Oligomerization.

The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket-dependent small-molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket-independent STING-activating agonists (piSTINGs), which act through multivalency-driven oligomerization to activate STING. Additionally, a piSTING-adjuvanted vaccine elicited a significant antibody response and inhibited tumour growth in therapeutic models. Moreover, a piSTING-based vaccine combination with aPD-1 showed remarkable potential to enhance the effectiveness of immune checkpoint blockade (ICB) immunotherapy. In particular, piSTING can strengthen the impact of STING pathway in immunotherapy and accelerate the clinical translation of STING agonists.

Diagnosis of Nonalcoholic Fatty Liver Disease via a H2S-Responsive Bioluminescent Probe Combined with Firefly Luciferase mRNA Delivery.

The early detection of nonalcoholic fatty liver disease (NAFLD) through bioluminescent probes is of great significance. However, there remains a challenge to apply them in nontransgenic natural animals due to the lack of exogenous luciferase. To address this issue, we herein report a new strategy for in situ monitoring of endogenous hydrogen sulfide (H2S) in the liver of NAFLD mice by leveraging a H2S-responsive bioluminescent probe (H-Luc) combined with firefly luciferase (fLuc) mRNA delivery. The probe H-Luc was created by installing a H2S recognition moiety, 2,4-dinitrophenol, onto the luciferase substrate (d-luciferin), which is allowed to release cage-free d-luciferin in the presence of H2S via a nucleophilic aromatic substitution reaction. In the meantime, the intracellular luciferase was introduced by lipid nanoparticle (LNP)-mediated fLuc mRNA delivery, rendering it suitable for bioluminescence (BL) imaging in vitro and in vivo. Based on this luciferase-luciferin system, the endogenous H2S could be sensitively and selectively detected in living cells, showing a low limit of detection (LOD) value of 0.72 µM. More importantly, after systematic administration of fLuc mRNA-loaded LNPs in vivo, H-Luc was able to successfully monitor the endogenous H2S levels in the NAFLD mouse model for the first time, displaying a 28-fold higher bioluminescence intensity than that in the liver of normal mice. We believe that this strategy may shed new light on the diagnosis of inflammatory liver disease, further elucidating the roles of H2S.

Intercalation-Induced Localized Conversion Reaction in h-CuSe for Ultrafast-Rechargeable and Long-Cycling Sodium Metal Battery.

Cathode materials of sodium-based batteries with high specific capacity and fast charge/discharge mode, as well as ultralong reversible cycles at wide applied temperatures, are essential for future development of advanced energy storage system. Developing transition metal selenides with intercalation features provides a new strategy for realizing the above cathode materials. Herein, we report a storage mechanism of sodium ion in hexagonal CuSe (h-CuSe) based on the DFT guidance. We reveal that the two-dimensional ion intercalation triggers localized redox reaction in the h-CuSe bulk phase, termed intercalation-induced localized conversion (ILC) mechanism, to stabilize the sodium storage structure by forming localized Cu7Se4 transition phase and adjusting the near-edge coordination state of the Cu sites to achieve high reversible capacity and ultra-long cycling life, while allowing rapid charge/discharge cycling over a wide temperature range. This article is protected by copyright. All rights reserved.

[Correlation between clinical phenotypes and genotypes among 46 children with SCN1A-related developmental epileptic encephalopathy].

OBJECTIVE: To explore the correlation between clinical phenotypes and genotypes among 46 children with SCN1A-related developmental epileptic encephalopathy (DEE). METHODS: Clinical data of 46 children with DEE and SCN1A variants identified at the Guangzhou Women and Children's Medical Center between January 2018 and June 2022 were collected. The children were grouped based on their age of onset, clinical manifestations, neurodevelopmental status, and results of genetic testing. The correlation between SCN1A genotypes and clinical phenotypes was analyzed. RESULTS: Among the 46 patients, 2 children (4.35%) had developed the symptoms before 3 months of age, 42 (91.30%) were between 3 to 9 months, and 2 cases (4.35%) were after 10 months. Two cases (4.35%) presented with epilepsy of infancy with migrating focal seizures (EIMFS), while 44 (95.7%) had presented with Dravet syndrome (DS), including 28 cases (63.6%) with focal onset (DS-F), 13 cases (29.5%) with myoclonic type (DS-M), 1 case (2.27%) with generalized type (DS-G), and 2 cases (4.55%) with status epilepticus type (DS-SE). Both of the two EIMFS children had severe developmental delay, and among the DS patients, 7 cases had normal development, while the remaining had developmental delay. A total of 44 variants were identified through genetic sequencing, which included 16 missense variants and 28 truncating variants. All EIMFS children had carried the c.677C>T (p.Thr226Met) missense variant. In the DS group, there was a significant difference in the age of onset between the missense variants group and the truncating variants group (P < 0.05). Missense variants were more common in D1 (7/15, 46.7%) and pore regions (8/15, 53.3%), while truncating variants were more common in D1 (12/28, 42.9%). Children with variants outside the pore region were more likely to develop myoclonic seizures. CONCLUSION: The clinical phenotypes of DEE are diverse. There is a difference in the age of onset between individuals with truncating and missense variants in the SCN1A gene. Missense variants outside the pore region are associated with a higher incidence of myoclonic seizures.

Prophylactic efficacy of an intranasal spray with 2 synergetic antibodies neutralizing Omicron.

BACKGROUNDAs Omicron is prompted to replicate in the upper airway, neutralizing antibodies (NAbs) delivered through inhalation might inhibit early-stage infection in the respiratory tract. Thus, elucidating the prophylactic efficacy of NAbs via nasal spray addresses an important clinical need.METHODSThe applicable potential of a nasal spray cocktail containing 2 NAbs was characterized by testing its neutralizing potency, synergetic neutralizing mechanism, emergency protective and therapeutic efficacy in a hamster model, and pharmacokinetics/pharmacodynamic (PK/PD) in human nasal cavity.RESULTSThe 2 NAbs displayed broad neutralizing efficacy against Omicron, and they could structurally compensate each other in blocking the Spike-ACE2 interaction. When administrated through the intranasal mucosal route, this cocktail demonstrated profound efficacy in the emergency prevention in hamsters challenged with authentic Omicron BA.1. The investigator-initiated trial in healthy volunteers confirmed the safety and the PK/PD of the NAb cocktail delivered via nasal spray. Nasal samples from the participants receiving 4 administrations over a course of 16 hours demonstrated potent neutralization against Omicron BA.5 in an ex vivo pseudovirus neutralization assay.CONCLUSIONThese results demonstrate that the NAb cocktail nasal spray provides a good basis for clinical prophylactic efficacy against Omicron infections.TRIAL REGISTRATIONwww.chictr.org.cn, ChiCTR2200066525.FUNDINGThe National Science and Technology Major Project (2017ZX10202203), the National Key Research and Development Program of China (2018YFA0507100), Guangzhou National Laboratory (SRPG22-015), Lingang Laboratory (LG202101-01-07), Science and Technology Commission of Shanghai Municipality (YDZX20213100001556), and the Emergency Project from the Science & Technology Commission of Chongqing (cstc2021jscx-fyzxX0001).

Glycated Walnut Meal Peptide-Calcium Chelates: Preparation, Characterization, and Stability.

Finding stable and bioavailable calcium supplements is crucial for addressing calcium deficiency. In this study, glycated peptide-calcium chelates (WMPHs-COS-Ca) were prepared from walnut meal protein hydrolysates (WMPHs) and chitosan oligosaccharides (COSs) through the Maillard reaction, and the structural properties and stability of the WMPHs-COS-Ca were characterized. The results showed that WMPHs and COSs exhibited high binding affinities, with a glycation degree of 64.82%. After glycation, Asp, Lys, and Arg decreased by 2.07%, 0.46%, and 1.06%, respectively, which indicated that these three amino acids are involved in the Maillard reaction. In addition, compared with the WMPHs, the emulsifying ability and emulsion stability of the WMPHs-COS increased by 10.16 mg2/g and 52.73 min, respectively, suggesting that WMPHs-COS have better processing characteristics. After chelation with calcium ions, the calcium chelation rate of peptides with molecular weights less than 1 kDa was the highest (64.88%), and the optimized preparation conditions were 5:1 w/w for WMPH-COS/CaCl2s, with a temperature of 50 °C, a chelation time of 50 min, and a pH of 7.0. Scanning electron microscopy showed that the "bridging role" of WMPHs-COS changed to a loose structure. UV-vis spectroscopy and Fourier transform infrared spectrometry results indicated that the amino nitrogen atoms, carboxyl oxygen atoms, and carbon oxygen atoms in WMPHs-COS chelated with calcium ions, forming WMPHs-COS-Ca. Moreover, WMPHs-COS-Ca was relatively stable at high temperatures and under acidic and alkaline environmental and digestion conditions in the gastrointestinal tract, indicating that WMPHs-COS-Ca have a greater degree of bioavailability.

Alkyne-tagged SERS nanoprobe for understanding Cu+ and Cu2+ conversion in cuproptosis processes.

Simultaneously quantifying mitochondrial Cu+ and Cu2+ levels is crucial for evaluating the molecular mechanisms of copper accumulation-involved pathological processes. Here, a series of molecules containing various diacetylene derivatives as Raman reporters are designed and synthesized, and the alkyne-tagged SERS probe is created for determination Cu+ and Cu2+ with high selectivity and sensitivity. The developed SERS probe generates well-separated distinguishable Raman fingerprint peaks with built-in corrections in the cellular silent region, resulting in accurate quantification of Cu+ and Cu2+. The present probe demonstrates high tempo-spatial resolution for real-time imaging and simultaneously quantifying mitochondrial Cu+ and Cu2+ with long-term stability benefiting from the probe assembly with designed Au-C≡C groups. Using this powerful tool, it is found that mitochondrial Cu+ and Cu2+ increase during ischemia are associated with breakdown of proteins containing copper as well as conversion of Cu+ and Cu2+. Meanwhile, we observe that parts of Cu+ and Cu2+ are transported out of neurons by ATPase. More importantly, cuproptosis in neurons is found including the oxidative stress process caused by the conversion of Cu+ to Cu2+, which dominates at the early stage (<9 h), and subsequent proteotoxic stress. Both oxidative and proteotoxic stresses contribute to neuronal death.

QSAR Study, Molecular Docking and Molecular Dynamic Simulation of Aurora Kinase Inhibitors Derived from Imidazo[4,5-b]pyridine Derivatives.

Cancer is a serious threat to human life and social development and the use of scientific methods for cancer prevention and control is necessary. In this study, HQSAR, CoMFA, CoMSIA and TopomerCoMFA methods are used to establish models of 65 imidazo[4,5-b]pyridine derivatives to explore the quantitative structure-activity relationship between their anticancer activities and molecular conformations. The results show that the cross-validation coefficients q2 of HQSAR, CoMFA, CoMSIA and TopomerCoMFA are 0.892, 0.866, 0.877 and 0.905, respectively. The non-cross-validation coefficients r2 are 0.948, 0.983, 0.995 and 0.971, respectively. The externally validated complex correlation coefficients r2pred of external validation are 0.814, 0.829, 0.758 and 0.855, respectively. The PLS analysis verifies that the QSAR models have the highest prediction ability and stability. Based on these statistics, virtual screening based on R group is performed using the ZINC database by the Topomer search technology. Finally, 10 new compounds with higher activity are designed with the screened new fragments. In order to explore the binding modes and targets between ligands and protein receptors, these newly designed compounds are conjugated with macromolecular protein (PDB ID: 1MQ4) by molecular docking technology. Furthermore, to study the nature of the newly designed compound in dynamic states and the stability of the protein-ligand complex, molecular dynamics simulation is carried out for N3, N4, N5 and N7 docked with 1MQ4 protease structure for 50 ns. A free energy landscape is computed to search for the most stable conformation. These results prove the efficient and stability of the newly designed compounds. Finally, ADMET is used to predict the pharmacology and toxicity of the 10 designed drug molecules.

On-The-Spot Sampling and Detection of Viral Particles on Solid Surfaces Using a Sponge Virus Sensor Incorporated with Finger-Press Fluid Release.

This paper presents a sponge-based electrochemical sensor for rapid, on-site collection and analysis of infectious viruses on solid surfaces. The device utilizes a conducting porous sponge modified with graphene, graphene oxide, and specific antibodies. The sponge serves as a hydrophilic porous electrode capable of liquid collection and electrochemical measurements. The device operation involves spraying an aqueous solution on a target surface, swiping the misted surface using the sponge, discharging an electrolyte solution with a simple finger press, and performing in situ incubation and electrochemical measurements. By leveraging the water-absorbing ability of the biofunctionalized conducting sponge, the sensor can effectively collect and quantify virus particles from the surface. The portability of the device is enhanced by introducing a push-release feature that dispenses the liquid electrolyte from a miniature reservoir onto the sensor surface. This reservoir has sharp edges to rupture a liquid sealing film with a finger press. The ability of the device to sample and quantify viral particles is demonstrated by using influenza A virus as the model. The sensor provided a calculated limit of detection of 0.4 TCID50/mL for H1N1 virus, along with a practical concentration range from 1-106 TCID50/mL. Additionally, it achieves a 15% collection efficiency from single-run swiping on a tabletop surface. This versatile device allows for convenient on-site virus detection within minutes, eliminating the need for sample pretreatment and simplifying the entire sample collecting and measuring process. This device presents significant potential for rapid virus detection on solid surfaces.

Heavy-Atom Effect Regulating Room-Temperature Phosphorescence of Organic-Inorganic Zn-Based Halides for White-Light Emission.

Organic-inorganic metal halides (OIMHs) with room-temperature phosphorescence (RTP) properties have aroused great research enthusiasm as outstanding broadband white-light emitters. Current studies on OIMHs with white-light emission were achieved via self-trapped excitons (STEs), but the unclear mechanism of STE formation is not favorable for the design of materials. In this work, zero-dimensional OIMHs composed of organic 3,4,5-trimethoxybenzylamine (TBA) and zine halide were synthesized, which enhanced the ratio of the RTP emission to the fluorescence emission from the TBA ligand. The experimental and mechanistic analyses demonstrate that the manageable RTP is mainly caused by the heavy-atom effect. In particular, by adjusting the incorporation ratio of halogen, an obvious white-light emission with a chromaticity coordinate value of (0.31, 0.33) can be achieved. This work developed a method for regulating the RTP of OIMHs with the heavy-atom effect to realize white-light emission, providing a new idea for the design of white-light emission materials.

Temperature-Controlled Selective Formation of Silver Nanoclusters and Their Transformation to the Same Product.

Herein, two atomically precise silver nanoclusters, Ag54 and Ag33, directed by inner anion templates (CrO4 2- and/or Cl-), are initially isolated as a mixed phase from identical reactants across a wide temperature range (20-80 °C). Interestingly, fine-tuning the reaction temperature can realize pure phase synthesis of the two nanoclusters; that is, a metastable Ag54 is kinetically formed at a low temperature (20 °C), whereas such a system is steered towards a thermodynamically stable Ag33 at a relatively high temperature (80 °C). Electrospray ionization mass spectrometry illustrates that the stability of Ag33 is superior to that of Ag54, which is further supported by density functional theory calculations. Importantly, the difference in structural stability can influence the pathway of 1,4-bis(pyrid-4-yl)benzene induced transformation reaction starting from Ag54 and Ag33. The former undergoes a dramatic breakage-reorganization process to form an Ag31 dimer (Ag31), while the same product can be also achieved from the latter following a noninvasive ligand exchange process. Both the Ag54 and Ag33 have the potential for further remote laser ignition applications. This work not only demonstrates how temperature controls the isolation of a specific phase, but also sheds light on the structural transformation pathway of nanoclusters with different stability.

The death burden of colorectal cancer attributable to modifiable risk factors, trend analysis from 1990 to 2019 and future predictions.

BACKGROUND: The death burden attributable to modifiable risk factors is key to colorectal cancer (CRC) prevention. This study aimed to assess the prevalence and regional distribution of attributable CRC death burden worldwide from 1990 to 2019. METHODS: We extracted data from the Global Burden of Disease Study in 2019 and assessed the mortality, age-standardized death rate (ASDR), population attributable fractions, and time trend in CRC attributable to risk factors by geography, socio-demographic index (SDI) quintile, age, and sex. RESULTS: Over the past 30 years, from high to low SDI region, the number of deaths increased by 46.56%, 103.55%, 249.64%, 231.89%, 163.11%, and the average annual percentage change (AAPC) for ASDR were -1.06%, -0.01%, 1.32%, 1.19%, and 0.65%, respectively. ASDR in males was 1.88 times than in females in 2019; ASDR in males showed an increasing trend (AAPC 0.07%), whereas ASDR in females showed a decreasing trend (AAPC -0.69%) compared to figures in 1990. In 2019, from high to low SDI region, the 15-49 age group accounted for 3%, 6%, 10%, 11%, and 15% of the total population; dietary and metabolic factors contributed 43.4% and 20.8% to CRC-attributable death worldwide. From high to low SDI region, ASDRs caused by dietary and metabolic factors increased by -23.4%, -5.5%, 25.8%, 29.1%, 13.5%, and 1.4%, 33.3%, 100.8%, 128.4%, 77.7% respectively, compared to 1990. CONCLUSIONS: The attributable CRC death burden gradually shifted from higher SDI to lower SDI regions. The limitation in males was more significant, and the gap is expected to be further expanded. In lower SDI regions, the death burden tended to affect younger people. The leading cause of CRC-attributable deaths was the inadequate control of dietary and metabolic risk factors.

Effects of UV/H2O2 degradation on Moringa oleifera Lam. leaves polysaccharides: Composition, in vitro fermentation and prebiotic properties on gut microorganisms.

Moringa oleifera Lam. leaves are a new raw food material rich in polysaccharides. These polysaccharides exhibit various biological properties, including antioxidant, hypoglycemic and immunoregulatory effects. However, the use of Moringa oleifera Lam. leaves polysaccharides (MOLP) may be limited by their large molecular weight (MW) and presence of numerous impurities, such as pigments. Research has indicated that degraded polysaccharides usually exhibit high biological activity because of changes in physical structure and chemical properties. In this study, we focused on the extraction of a degraded-modified fraction from MOLP using the Ultraviolet/ Hydrogen peroxide (UV/H2O2) method. Specifically, the physicochemical properties and glycosidic bond composition of a particular fraction (UV/H2O2 degraded Moringa oleifera Lam. leaves polysaccharides in 3 h called DMOLP-3) were investigated. In addition, in vitro simulated digestion experiments showed that DMOLP-3 was only partially degraded during gastrointestinal digestion, indicating that DMOLP-3 can be utilised by gut microorganisms. Furthermore, the prebiotic properties of MOLP and DMOLP-3 was studied using an in vitro faecal fermentation model. The results indicated that compared with MOLP, DMOLP-3 led to a decrease in both the colour and MW of the polysaccharides. In addition, this model exhibited enhanced solubility and antioxidant capabilities while also influencing the surface morphology. Moreover, DMOLP-3 can facilitate the proliferation of advantageous microorganisms and enhance the synthesis of short-chain fatty acids (SCFAs). These results provide valuable insights into the utilization of bioactive components in Moringa oleifera Lam. leaves for the intestinal health.

Wavelength dependency and photosensitizer effects in UV-LED photodegradation of iohexol.

Iodinated X-ray contrast media (ICM) are ubiquitously present in water sources and challenging to eliminate using conventional processes, posing a significant risk to aquatic ecosystems. Ultraviolet light-emitting diodes (UV-LED) emerge as a promising technology for transforming micropollutants in water, boasting advantages such as diverse wavelengths, elimination of chemical additives, and no induction of microorganisms' resistance to disinfectants. The research reveals that iohexol (IOX) degradation escalates as UV wavelength decreases, attributed to enhanced photon utilization efficiency. Pseudo-first-order rate constants (kobs) were determined as 3.70, 2.60, 1.31 and 0.65 cm2 J-1 at UV-LED wavelengths of 255, 265, 275 and 285 nm, respectively. The optical properties of dissolved organic matter (DOM) and anions undeniably influence the UV-LED photolysis process through photon competition and the generation of reactive substances. The influence of Cl- on IOX degradation was insignificant at UV-LED 255, but it promoted IOX degradation at 265, 275 and 285 nm. IOX degradation was accelerated by ClO2-, NO3-and HA due to the formation of various reactive species. In the presence of NO3-, the kobs of IOX followed the order: 265 > 255 > 275 > 285 nm. Photosensitizers altered the spectral dependence of IOX, and the intermediate photoactivity products were detected using electron spin resonance. The transformation pathways of IOX were determined through density functional theory calculations and experiments. Disinfection by-products (DBPs) yields of IOX during UV-LED irradiation decreased as the wavelength increased: 255 > 265 > 275 > 285 nm. The cytotoxicity index value decreased as the UV-LED wavelength increased from 255 to 285 nm. These findings are crucial for selecting the most efficient wavelength for UV-LED degradation of ICM and will benefit future water purification design.

Effect of succinylation-assisted glycosylation on the structural characteristics, emulsifying, and gel properties of walnut glutenin.

In this study, we examined the effects of various sodium alginate (ALG) concentrations (0.2%-0.8%) on the functional and physicochemical characteristics of succinylated walnut glutenin (GLU-SA). The results showed that acylation decreased the particle size and zeta potential of walnut glutenin (GLU) by 122- and 0.27-fold, respectively. In addition, the protein structure unfolded, providing conditions for glycosylation. After GLU-SA was combined with ALG, the surface hydrophobicity decreased and the net negative charge and disulfide bond content increased. The protein structure was analyzed by FTIR, Endogenous fluorescence spectroscopy, and SEM, and ALG prompted GLU-SA cross-linking to form a stable three-dimensional network structure. The results indicated that dual modification improved the functional properties of the complex, especially its potential protein gel and emulsifying properties. This research provide theoretical support and a technical reference for expanding the application of GLU in the processing of protein and oil products.

The health-care utilization and economic burden in patients with genetic skeletal disorders.

BACKGROUND: Most genetic skeletal disorders (GSD) were complex, disabling and life-threatening without effective diagnostic and treatment methods. However, its impacts on health system have not been well studied. The study aimed to systematically evaluate the health-care utilization and economic burden in GSD patients. METHODS: The patients were derived from 2018 Nationwide Inpatient Sample and Nationwide Readmissions Database. GSD patients were extracted based on International Classification of Diseases-10th revision codes. RESULTS: A total of 25,945 (0.12%) records regarding GSD were extracted from all 21,400,282 records in NIS database. GSD patients were likely to have significantly longer length of stay (6.50 ± 0.08 vs. 4.63 ± 0.002, P < 0.001), higher total charges ($85,180.97 ± 1,239.47 vs. $49,884.26 ± 20.99, P < 0.001), suffering more procedure, diagnosis and transferring records in comparison to patients with common conditions. GSD patients had a significantly higher 30-day all-cause readmission rate based on Nationwide Readmissions Database. CONCLUSIONS: The heavy health-care utilization and economic burden emphasized the urgency for policy leaders, scientific and pharmaceutical researchers, health care providers and employers to identify innovative ways and take effective measurements immediately, and eventually to help improve the care, management, and treatment of these devastating diseases.

Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys.

AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study.

Immune landscape and response to oncolytic virus-based immunotherapy.

Oncolytic virus (OV)-based immunotherapy has emerged as a promising strategy for cancer treatment, offering a unique potential to selectively target malignant cells while sparing normal tissues. However, the immunosuppressive nature of tumor microenvironment (TME) poses a substantial hurdle to the development of OVs as effective immunotherapeutic agents, as it restricts the activation and recruitment of immune cells. This review elucidates the potential of OV-based immunotherapy in modulating the immune landscape within the TME to overcome immune resistance and enhance antitumor immune responses. We examine the role of OVs in targeting specific immune cell populations, including dendritic cells, T cells, natural killer cells, and macrophages, and their ability to alter the TME by inhibiting angiogenesis and reducing tumor fibrosis. Additionally, we explore strategies to optimize OV-based drug delivery and improve the efficiency of OV-mediated immunotherapy. In conclusion, this review offers a concise and comprehensive synopsis of the current status and future prospects of OV-based immunotherapy, underscoring its remarkable potential as an effective immunotherapeutic agent for cancer treatment.

m 6 A reader IGF2BP1 reduces the sensitivity of nasopharyngeal carcinoma cells to Taxol by upregulation of AKT2.

Taxol is widely used in the treatment of nasopharyngeal carcinoma (NPC); nevertheless, the acquired resistance of NPC to Taxol remains one of the major obstacles in clinical treatment. In this study, we aimed to investigate the role and mechanism of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in Taxol resistance of NPC. Taxol-resistant NPC cell lines were established by exposing to gradually increased concentration of Taxol. Relative mRNA and protein levels were tested using qRT-PCR and western blot, respectively. NPC cell viability and apoptosis were assessed by cell counting kit-8 and flow cytometry analysis, respectively. Cell migration and invasion capacities were measured using transwell assay. Interaction between IGF2BP1 and AKT2 was examined by RNA immunoprecipitation assay. The N6-methyladenosine level of AKT2 was tested using methylated RNA immunoprecipitation-qPCR. IGF2BP1 expression was enhanced in Taxol-resistant NPC cell lines. Knockdown of IGF2BP1 strikingly enhanced the sensitivity of NPC cells to Taxol and repressed the migration and invasion of NPC cells. Mechanistically, IGF2BP1 elevated the expression of AKT2 by increasing its mRNA stability. Furthermore, overexpression of AKT2 reversed the inhibitory roles of IGF2BP1 silence on Taxol resistance and metastasis. Our results indicated that IGF2BP1 knockdown enhanced the sensitivity of NPC cells to Taxol by decreasing the expression of AKT2, implying that IGF2BP1 might be promising candidate target for NPC treatment.