Paradoxical Role for Wild-Type p53 in Driving Therapy Resistance in Melanoma.

Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.

PRODH safeguards human naive pluripotency by limiting mitochondrial oxidative phosphorylation and reactive oxygen species production.

Naive human embryonic stem cells (hESCs) that resemble the pre-implantation epiblasts are fueled by a combination of aerobic glycolysis and oxidative phosphorylation, but their mitochondrial regulators are poorly understood. Here we report that, proline dehydrogenase (PRODH), a mitochondria-localized proline metabolism enzyme, is dramatically upregulated in naive hESCs compared to their primed counterparts. The upregulation of PRODH is induced by a reduction in c-Myc expression that is dependent on PD0325901, a MEK inhibitor routinely present in naive hESC culture media. PRODH knockdown in naive hESCs significantly promoted mitochondrial oxidative phosphorylation (mtOXPHOS) and reactive oxygen species (ROS) production that triggered autophagy, DNA damage, and apoptosis. Remarkably, MitoQ, a mitochondria-targeted antioxidant, effectively restored the pluripotency and proliferation of PRODH-knockdown naive hESCs, indicating that PRODH maintains naive pluripotency by preventing excessive ROS production. Concomitantly, PRODH knockdown significantly slowed down the proteolytic degradation of multiple key mitochondrial electron transport chain complex proteins. Thus, we revealed a crucial role of PRODH in limiting mtOXPHOS and ROS production, and thereby safeguarding naive pluripotency of hESCs.

Arabidopsis VILLIN5 bundles actin filaments using a novel mechanism.

Being a bona fide actin bundler, Arabidopsis villin5 (VLN5) plays a crucial role in regulating actin stability and organization within pollen tubes. Despite its significance, the precise mechanism through which VLN5 bundles actin filaments has remained elusive. Through meticulous deletion analysis, we have unveiled that the link between gelsolin repeat 6 (G6) and the headpiece domain (VHP), rather than VHP itself, is indispensable for VLN5-mediated actin bundling. Further refinement of this region has pinpointed a critical sequence spanning from Val763 to Ser823, essential for VLN5's actin-bundling activity. Notably, the absence of Val763-Ser823 in VLN5 results in decreased filamentous decoration within pollen tubes and a diminished ability to rescue actin bundling defects in vln2vln5 mutant pollen tubes compared to intact VLN5. Moreover, our findings highlight that the Val763-Ser823 sequence harbors a binding site for F-actin, suggesting that this linker-based F-actin binding site, in conjunction with the F-actin binding site localized in G1-G6, enables a single VLN5 to concurrently bind to two adjacent actin filaments. Therefore, our study unveils a novel mechanism by which VLN5 bundles actin filaments.

GATOR2 complex-mediated amino acid signaling regulates brain myelination.

Amino acids are essential for cell growth and metabolism. Amino acid and growth factor signaling pathways coordinately regulate the mechanistic target of rapamycin complex 1 (mTORC1) kinase in cell growth and organ development. While major components of amino acid signaling mechanisms have been identified, their biological functions in organ development are unclear. We aimed to understand the functions of the critically positioned amino acid signaling complex GAP activity towards Rags 2 (GATOR2) in brain development. GATOR2 mediates amino acid signaling to mTORC1 by directly linking the amino acid sensors for arginine and leucine to downstream signaling complexes. Now, we report a role of GATOR2 in oligodendrocyte myelination in postnatal brain development. We show that the disruption of GATOR2 complex by genetic deletion of meiosis regulator for oocyte development (Mios, encoding a component of GATOR2) selectively impairs the formation of myelinating oligodendrocytes, thus brain myelination, without apparent effects on the formation of neurons and astrocytes. The loss of Mios impairs cell cycle progression of oligodendrocyte precursor cells, leading to their reduced proliferation and differentiation. Mios deletion manifests a cell type-dependent effect on mTORC1 in the brain, with oligodendroglial mTORC1 selectively affected. However, the role of Mios/GATOR2 in oligodendrocyte formation and myelination involves mTORC1-independent function. This study suggests that GATOR2 coordinates amino acid and growth factor signaling to regulate oligodendrocyte myelination.

Direct Synthesis of α- and ß-2'-Deoxynucleosides with Stereodirecting Phosphine Oxide via Remote Participation.

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.

Regulation of Hot Electrons Transport Achieved through Controlled Electron-Phonon Coupling in Metallic Heterostructures.

The electron-phonon (e-ph) interactions are pivotal in shaping the electrical and thermal properties, and in particular, determining the carrier dynamics and transport behaviors in optoelectronic devices. By employing pump-probe spectroscopy and ultrafast microscopy, the consequential role of e-ph coupling strength in the spatiotemporal evolution of hot electrons is elucidated. Thermal transport across the metallic interface is controlled to regulate effective e-ph coupling factor Geff in Au and Au/Cr heterostructure, and their impact on nonequilibrium transport of hot electrons is examined. Via the modulation of buried Cr thickness, a strong correlation between Geff and the diffusive behavior of hot electrons is found. By enhancing Geff through the regulation of thermal transport across interface, there is a significant reduction in e-ph thermalization time, the maximum diffusion length of hot electrons, and lattice heated area which are extracted from the spatiotemporal evolution profiles. Therefore, the increased Geff significantly weakens the diffusion of hot electrons and promotes heat relaxation of electron subsystems in both time and space. These insights propose a robust framework for spatiotemporal investigations of G impact on hot electron diffusion, underscoring its significance in the rational design of advanced optoelectronic devices with high efficiency.

Aquaporin-4 Antibody Dynamics and Relapse Risk in Seropositive Neuromyelitis Optica Spectrum Disorder Treated with Immunosuppressants.

OBJECTIVE: To investigate aquaporin-4 antibody (AQP4-IgG) dynamics and relapse risk in patients with seropositive neuromyelitis optica spectrum disorder treated with immunosuppressants. METHODS: This observational cohort study with prospectively collected data included 400 neuromyelitis optica spectrum disorder patients seropositive for AQP4-IgG and treated with immunosuppressants. Serum AQP4-IgG was detected by fixed cell-based assay every 6 months. RESULTS: After treatment with immunosuppressants, 128 patients became AQP4-IgG seronegative. The median time to become seronegative for 400 patients was 76.4 months (61.4 months, NA). Among those patients with negative change of AQP4-IgG, the mean annualized relapse rate significantly decreased after patients became seronegative (0.20 vs 0.77, p < 0.001), and a positive correlation was observed between time to become seronegative and relapse (OR 1.018, 95% CI 1.001-1.035, p < 0.05). Independent risk factors for AQP4-IgG becoming seronegative were older age at onset, initiation of immunosuppressants at onset, and shorter disease duration before maintenance therapy. Independent risk factors for relapse included younger age (≤46.4 years) at onset, poly-system involvement in the first attack, and unchanged or increased AQP4-IgG titer. The relapse risk was not associated with sex, combination with connective tissue disease, seropositivity for systemic autoimmune antibodies, or incomplete recovery from the first attack. INTERPRETATION: Patients with younger age at onset, poly-system involvement in the first attack, and unchanged or increased titer of AQP4-IgG are most likely to experience relapse under treatment with immunosuppressants. Time to AQP4-IgG becoming seronegative and change of AQP4-IgG titer may become the surrogate efficacy biomarkers in clinical trials. ANN NEUROL 2023;93:1069-1081.

Sustainable inflammatory activation following spinal cord injury is driven by thrombin-mediated dynamic expression of astrocytic chemokines.

Acute spinal cord injury (SCI) always results in sustainable recruitment of inflammatory cells driven by sequentially generated chemokines, thereby eliciting excessive neuroinflammation. However, the underlying mechanism of temporally produced chemokines remains elusive. Reactive astrocytes are known to be the main sources of chemokines at the lesion site, which can be immediately activated by thrombin following SCI. In the present study, SCI was shown to induce a sequential production of chemokines CCL2 and CCL5 from astrocytes, which were associated with a persistent infiltration of macrophages/microglia. The rapidly induced CCL2 and later induced CCL5 from astrocytes were regulated by thrombin at the damaged tissues. Investigation of the regulatory mechanism revealed that thrombin facilitated astrocytic CCL2 production through activation of ERK/JNK/NFκB pathway, whereas promoted CCL5 production through PLCß3/NFκB and ERK/JNK/NFκB signal pathway. Inhibition of thrombin activity significantly decreased production of astrocytic CCL2 and CCL5, and reduced the accumulation of macrophages/microglia at the lesion site. Accordingly, the locomotor function of rats was remarkably improved. The present study has provided a new regulatory mechanism on thrombin-mediated sequential production of astrocytic chemokines, which might be beneficial for clinical therapy of CNS neuroinflammation.

Effect of Specific Surface Area and Hydrophobicity of Electrospun Nanofibers on the Sustained Release Performance of Diclofenac Sodium.

Nanofibers produced by electrospinning are suitable options for slow-release materials. Diclofenac sodium (DS) is a nonsteroidal anti-inflammatory medication with a brief half-life that can serve as an effective sustained-release agent. This paper presents a novel method for producing DS-sustained release nanofibers by electrostatic spinning processes. During the preparation, the slow-release capabilities of biodegradable materials poly(lactic acid) (PLA) and polycaprolactone (PCL) are investigated. A composite drug-carrying scaffold is prepared to enhance the sustained-release performance. The sustained release ability is affected by the specific surface area of the nanofibers and the hydrophobicity of the polymer. The findings indicate that the composite nanofiber with a PLA/PCL ratio of 1:1 demonstrates the most effective sustained-release performance. The release rate is mostly influenced by the hydrophobicity of the polymer at this point. Sustained-release kinetic simulations were performed and revealed that the release of nanofibers follows a first-order release paradigm. This work presents a straightforward approach for creating a sustained-release formulation of DS.

Luteal phase support with oral progesterone improves live birth rate in intrauterine insemination cycles using letrozole.

RESEARCH QUESTION: Does luteal phase support (LPS) with oral progesterone improve the live birth rate (LBR) in patients undergoing intrauterine insemination (IUI) cycles with letrozole? DESIGN: This retrospective cohort study included 1199 IUI cycles with letrozole between January 2017 and December 2021. A nearest neighbour random matching approach was employed to pair the LPS group and the control group in a 1:2 ratio. Eight variables were chosen for matching in the propensity score matching (PSM) model: age; body mass index; duration of infertility; cause(s) of infertility; antral follicle count; basal concentration of FSH; rank of IUI attempts; and leading follicle size. LBR was selected as the primary outcome. RESULTS: In total, 427 LPS cycles were matched with 772 non-LPS (control) cycles after PSM. The LBR was significantly higher in the LPS group compared with the control group (19.7% versus 14.5%; P = 0.0255). The clinical pregnancy rate (23.2% versus 17.6%; P = 0.0245) and ongoing pregnancy rate (20.6% versus 15.8%; P = 0.0437) were also significantly higher in the LPS group. The biochemical pregnancy rate, ectopic pregnancy rate and miscarriage rate were similar in the two groups (P > 0.05). The intergroup comparison revealed no significant variances in terms of gestational age, mode of delivery, ectopic pregnancy rate or abortion rate. Furthermore, there were no significant differences in birth weight or birth length between the two groups. CONCLUSIONS: Luteal support with oral progesterone significantly improved the LBR in IUI cycles with letrozole, but did not affect neonatal outcomes.

Repurposing promethazine hydrochloride to inhibit biofilm formation against Burkholderia thailandensis.

Melioidosis is a severe infectious disease caused by Burkholderia pseudomallei, an intracellular pathogen with a high mortality rate and significant antibiotic resistance. The high mortality rate and resistance to antibiotics have drawn considerable attention from researchers studying melioidosis. This study evaluated the effects of various concentrations (75, 50, and 25 µg/mL) of promethazine hydrochloride (PTZ), a potent antihistamine, on biofilm formation and lipase activity after 24 h of exposure to B. thailandensis E264. A concentration-dependent decrease in both biofilm biomass and lipase activity was observed. RT-PCR analysis revealed that PTZ treatment not only made the biofilm structure loose but also reduced the expression of btaR1, btaR2, btaR3, and scmR. Single gene knockouts of quorum sensing (QS) receptor proteins (∆btaR1, ∆btaR2, and ∆btaR3) were successfully constructed. Deletion of btaR1 affected biofilm formation in B. thailandensis, while deletion of btaR2 and btaR3 led to reduced lipase activity. Molecular docking and biological performance results demonstrated that PTZ inhibits biofilm formation and lipase activity by suppressing the expression of QS-regulated genes. This study found that repositioning PTZ reduced biofilm formation in B. thailandensis E264, suggesting a potential new approach for combating melioidosis.

H6N2 reassortant avian influenza virus isolate in wild birds in Jiangxi Province, China.

H6 avian influenza virus is widely prevalent in wild birds and poultry and has caused human infection in 2013 in Taiwan, China. During our active influenza surveillance program in wild waterfowl at Poyang Lake, Jiangxi Province, an H6N2 AIV was isolated and named A/bean goose/JiangXi/452-4/2013(H6N2). The isolate was characterized as a typical low pathogenic avian influenza virus (LPAIV) due to the presence of the amino acid sequence PQIETR↓GLFGAI at the cleavage site of the hemagglutinin (HA) protein. The genetic evolution analysis revealed that the NA gene of the isolate originated from North America and exhibited the highest nucleotide identity (99.29%) with a virus recovered from wild bird samples in North America, specifically A/bufflehead/California/4935/2012(H11N2). Additionally, while the HA and PB1 genes belonged to the Eurasian lineage, they displayed frequent genetic interactions with the North American lineage. The remaining genes showed close genetic relationships with Eurasian viruses. The H6N2 isolate possessed a complex genome, indicating it is a multi-gene recombinant virus with genetic material from both Eurasian and North American lineages.

Creating Atomically Iridium-Doped PdOx Nanoparticles for Efficient and Durable Methane Abatement.

The urgent environmental concern of methane abatement, attributed to its high global warming potential, necessitates the development of methane oxidation catalysts (MOC) with enhanced low-temperature activity and durability. Herein, an iridium-doped PdOx nanoparticle supported on silicalite-1 zeolite (PdIr/S-1) catalyst was synthesized and applied for methane catalytic combustion. Comprehensive characterizations confirmed the atomically dispersed nature of iridium on the surface of PdOx nanoparticles, creating an Ir4f-O-Pdcus microstructure. The atomically doped Ir transferred more electrons to adjacent oxygen atoms, modifying the electronic structure of PdOx and thus enhancing the redox ability of the PdIr/S-1 catalysts. This electronic modulation facilitated methane adsorption on the Pd site of Ir4f-O-Pdcus, reducing the energy barrier for C-H bond cleavage and thereby increasing the reaction rate for methane oxidation. Consequently, the optimized PdIr0.1/S-1 showed outstanding low-temperature activity for methane combustion (T50 = 276 °C) after aging and maintained long-term stability over 100 h under simulated exhaust conditions. Remarkably, the novel PdIr0.1/S-1 catalyst demonstrated significantly enhanced activity even after undergoing harsh hydrothermal aging at 750 °C for 16 h, significantly outperforming the conventional Pd/Al2O3 catalyst. This work provides valuable insights for designing efficient and durable MOC catalysts, addressing the critical issue of methane abatement.

Exploration of quality variation and stability of hybrid rice under multi-environments.

Improving quality is an essential goal of rice breeding and production. However, rice quality is not solely determined by genotype, but is also influenced by the environment. Phenotype plasticity refers to the ability of a given genotype to produce different phenotypes under different environmental conditions, which can be a representation of the stability of traits. Seven quality traits of 141 hybrid combinations, deriving from the test-crossing of 7 thermosensitive genic male sterile (TGMS) and 25 restorer lines, were evaluated at 5 trial sites with intermittent sowing of three to five in Southern China. In the Yangtze River Basin, it was observed that delaying the sowing time of hybrid rice combinations leads to an improvement in their overall quality. Twelve parents were identified to have lower plasticity general combing ability (GCA) values with increased ability to produce hybrids with a more stable quality. The parents with superior quality tend to exhibit lower GCA values for plasticity. The genome-wide association study (GWAS) identified 13 and 15 quantitative trait loci (QTLs) associated with phenotype plasticity and BLUP measurement, respectively. Notably, seven QTLs simultaneously affected both phenotype plasticity and BLUP measurement. Two cloned rice quality genes, ALK and GL7, may be involved in controlling the plasticity of quality traits in hybrid rice. The direction of the genetic effect of the QTL6 (ALK) on alkali spreading value (ASV) plasticity varies in different cropping environments. This study provides novel insights into the dynamic genetic basis of quality traits in response to different cropping regions, cultivation practices, and changing climates. These findings establish a foundation for precise breeding and production of stable and high-quality rice. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01442-3.

STAT5-mediated transcription of miR-33-5p in Mycoplasma gallisepticum-infected DF-1 cells.

RESEARCH HIGHLIGHTS: MG-HS regulates the expression of transcription factor STAT5.Transcription factor STAT5 can target miR-33-5p promoter element.MG-influenced STAT5 regulates miR-33-5p and its target gene expression.

Characterizing the relationship between MRI radiomics and AHR expression and deriving a predictive model for prognostic assessment in glioblastoma.

PURPOSE: Aryl hydrocarbon receptor (AHR), a crucial molecular marker associated with glioma, is a potential therapeutic target. We aimed to establish a non-invasive predictive model for AHR through radiomics. METHODS: Contrast-enhanced T1-weighted (T1W) MRI and the corresponding and clinical variables of glioblastoma patients from The Cancer Genome Atlas (TCGA) and The Cancer Imaging Archive (TCIA) were obtained for analysis. KM curves and Cox regression analyses were used to assess the prognostic value of AHR expression. The radiomics features were screened by Max-Relevance and Min-Redundancy (mRMR) and recursive feature elimination (RFE), followed by the construction of two predictive models using logistic regression (LR) and a support vector machine (SVM). RESULTS: The expression levels of AHR in tumour patients were significantly higher than those in the control group, and higher AHR expression was associated with worse prognosis (P<0.05). AHR remained a risk factor for poor prognosis in glioblastoma after multivariate adjustment (HR: 1.61, 95% CI: 1.085-2.39, P<0.05). The radiomics models constructed using LR and SVM based on three selected features achieved area under the curve (AUC) values of 0.887 and 0.872, respectively. Radiomics score emerged as a key factor influencing overall survival (OS) after multivariate adjustment in the Cox model (HR: 3.931, 95% CI: 1.272-12.148, P < 0.05). CONCLUSION: The radiomics models could effectively distinguish the expression levels of AHR and predict prognosis in patients with glioblastoma, which may serve as a powerful tool to assist clinical assessment and precision treatment.

Characteristic alkaloids from Stemona sessilifolia with lung protective effects.

In the research on lung protective effects from the roots of Stemona sessilifolia, twenty-five Stemona alkaloids have been isolated, including four undescribed components (1, 3-5), a new natural product (2) and 20 known alkaloids (6-25). Their structures were analyzed by NMR spectra, high-resolution mass spectrum data, and other chemical methods. UPLC-QTOF/MS method was used to identify the Stemona alkaloids and summarize the fragmentation patterns of mass spectrometry. The lung-protective effects of these compounds were evaluated using MLE-12 cells induced by NNK and nm SiO2. The results showed that compounds 3, 5, 8, 10-11, 17-21 and 23 exhibited protective effects on NNK-induced cell injury. Compounds 2, 8-11, 14, 17-19 and 22 showed improvement in nm SiO2-induced lung epithelial cell injury. Compound 10 (tuberostemonine D), a representative alkaloid with a high content in Stemona sessilifolia, significantly protected C57BL/6 lung injury mice induced by nm SiO2, suggesting it a key component of Stemona alkaloids that play a protective role in lung injury. The results of in vivo activity showed that compound 10 could improve the lung injury of mice, reduce ROS content, and recover the levels of SOD and MDA in serum. Its protective effect on lung injury might be related to Nrf2 activation.

Intelligent nanovesicle for remodeling tumor microenvironment and circulating tumor chemoimmunotherapy amplification.

Imperceptible examination and unideal treatment effect are still intractable difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). At present, despite 5-fluorouracil (5-FU), as a clinical first-line FOLFIRINOX chemo-drug, has achieved significant therapeutic effects. Nevertheless, these unavoidable factors such as low solubility, lack of biological specificity and easy to induce immunosuppressive surroundings formation, severely limit their treatment in PDAC. As an important source of energy for many tumor cells, tryptophan (Trp), is easily degraded to kynurenine (Kyn) by indolamine 2,3- dioxygenase 1 (IDO1), which activates the axis of Kyn-AHR to form special suppressive immune microenvironment that promotes tumor growth and metastasis. However, our research findings that 5-FU can induce effectively immunogenic cell death (ICD) to further treat tumor by activating immune systems, while the secretion of interferon-γ (IFN-γ) re-induce the Kyn-AHR axis activation, leading to poor treatment efficiency. Therefore, a metal matrix protease-2 (MMP-2) and endogenous GSH dual-responsive liposomal-based nanovesicle, co-loading with 5-FU (anti-cancer drug) and NLG919 (IDO1 inhibitor), was constructed (named as ENP919@5-FU). The multifunctional ENP919@5-FU can effectively reshape the tumor immunosuppression microenvironment to enhance the effect of chemoimmunotherapy, thereby effectively inhibiting cancer growth. Mechanistically, PDAC with high expression of MMP-2 will propel the as-prepared nanovesicle to dwell in tumor region via shedding PEG on the nanovesicle surface, effectively enhancing tumor uptake. Subsequently, the S-S bond containing nanovesicle was cut via high endogenous GSH, leading to the continued release of 5-FU and NLG919, thereby enabling circulating chemoimmunotherapy to effectively cause tumor ablation. Moreover, the combination of ENP919@5-FU and PD-L1 antibody (αPD-L1) showed a synergistic anti-tumor effect on the PDAC model with abdominal cavity metastasis. Collectively, ENP919@5-FU nanovesicle, as a PDAC treatment strategy, showed excellent antitumor efficacy by remodeling tumor microenvironment to circulate tumor chemoimmunotherapy amplification, which has promising potential in a precision medicine approach.

Searching for novel MDM2/MDMX dual inhibitors through a drug repurposing approach.

Disruption of p53-MDM2/MDMX interaction by smaller inhibitors is a promising therapeutic intervention gaining tremendous interest. However, no MDM2/MDMX inhibitors have been marketed so far. Drug repurposing is a validated, practical approach to drug discovery. In this regard, we employed structure-based virtual screening in a reservoir of marketed drugs and identified nintedanib as a new MDM2/MDMX dual inhibitor. The computational structure analysis and biochemical experiments uncover that nintedanib binds MDM2/MDMX similarly to RO2443, a dual MDM2/MDMX inhibitor. Furthermore, the mechanistic study reveals that nintedanib disrupts the physical interaction of p53-MDM2/MDMX, enabling the transcriptional activation of p53 and the subsequent cell cycle arrest and growth inhibition in p53+/+ cancer cells. Lastly, structural minimisation of nintedanib yields H3 with the equivalent potency. In summary, this work provides a solid foundation for reshaping nintedanib as a valuable lead compound for the further design of MDM2/MDMX dual inhibitors.

Risk stratification and predictive modeling of postoperative delirium in chronic subdural hematoma.

Background- Postoperative delirium is a common complication associated with the elderly, causing increased morbidity and prolonged hospital stay. However, its risk factors in chronic subdural hematoma patients have not been well studied. Methods- A total of 202 consecutive patients with chronic subdural hematoma at Peking University Third Hospital between January 2018 and January 2023 were enrolled. Various clinical indicators were analyzed to identify independent risk factors for postoperative delirium using univariate and multivariate regression analyses. Delirium risk prediction models were developed as a nomogram and a Markov chain. Results- Out of the 202 patients (age, 71 (IQR, 18); female-to-male ratio, 1:2.7) studied, 63 (31.2%) experienced postoperative delirium. Univariate analysis identified age (p < 0.001), gender (p = 0.014), restraint belt use (p < 0.001), electrolyte imbalance (p < 0.001), visual analog scale score (p < 0.001), hematoma thickness (p < 0.001), midline shift (p < 0.001), hematoma side (p = 0.013), hematoma location (p = 0.018), and urinal catheterization (p = 0.028) as significant factors. Multivariate regression analysis confirmed the significance of restraint belt use (B = 7.657, p < 0.001), electrolyte imbalance (B = -3.993, p = 0.001), visual analog scale score (B = 2.331, p = 0.016), and midline shift (B = 0.335, p = 0.007). Hematoma thickness and age had no significant impact. Conclusion- Increased midline shift and visual analog scale scores, alongside restraint belt use and electrolyte imbalance elevate delirium risk in chronic subdural hematoma surgery. Our prediction models may offer reference value in this context.