Unveiling the Mechanism of Phenamacril Resistance in F. graminearum: Computational and Experimental Insights into the C423A Mutation in FgMyoI.

Phenamacril (PHA) is a highly selective fungicide for controlling fusarium head blight (FHB) mainly caused by F. graminearum and F. asiaticum. However, the C423A mutation in myosin I of F. graminearum (FgMyoI) leads to natural resistance to PHA. Here, based on the computational approaches and biochemical validation, we elucidate the atomic-level mechanism behind the natural resistance of F. graminearum to the fungicide PHA due to the C423A mutation in FgMyoI. The mutation leads to a rearrangement of pocket residues, resulting in increased size and flexibility of the binding pocket, which impairs the stable binding of PHA. MST experiments confirm that the mutant protein FgMyoIC423A exhibits significantly reduced affinity for PHA compared to wild-type FgMyoI and the nonresistant C423K mutant. This decreased binding affinity likely underlies the development of PHA resistance in F. graminearum. Conversely, the nonresistant C423K mutant retains sensitivity to PHA due to the introduction of a strong hydrogen bond donor, which facilitates stable binding of PHA in the pocket. These findings shed light on the molecular basis of PHA resistance and provide new directions for the creation of new myosin inhibitors.

Carotid revascularisation versus medical treatment for asymptomatic carotid artery stenosis.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To compare the safety and efficacy of carotid revascularisation plus best medical treatment with best medical treatment alone in people with asymptomatic carotid artery stenosis.

Construction and validation of a prognostic model for gastric cancer patients with tumor deposits.

Background: Tumor deposits (TD) was a significant risk factor impacting the prognosis of patients diagnosed with gastric cancer (GC), yet it was not currently incorporated into TNM staging systems. The objective of this research was to develop a predictive model for assessing the prognosis of patients with TD-positive GC. Methods: Retrospective analysis was performed on the data of 4,972 patients treated for GC with D2 radical gastrectomy at Wannan Medical College's Yijishan Hospital between January 2012 and December 2021. The patients were categorized based on the number of TD (L1: 1, L2: 2-3, L3: ≥4) and the anatomical location of TD (Q1: single area, Q2: multiple areas). In a 3:1 ratio, patients were randomly assigned to one of two groups: training or validation. Results: The study included a total of 575 patients who were divided into the training group (n = 432) and validation group (n = 143). Survival analysis showed that the number and anatomical location of TD had a significant impact on the prognosis of patients with TD-positive GC. Univariate analysis of the training group data revealed that tumor size, T-stage, N-stage, histological grade, number and distribution of TD, neural invasion, and postoperative chemotherapy were associated with prognosis. Multivariate Cox regression analysis identified poor histological grade, T4 stage, N3 stage, number of TD, neural invasion, and postoperative chemotherapy as independent prognostic factors for GC patients with TD. A nomogram was developed using these variables, demonstrating well predictive ability for 1, 3, and 5-year overall survival (OS) in the validation set. The DCA curve shows that the constructed model shows a large positive net gain compared to the eighth edition Tumour, Node, Metastasis (TNM) staging system. Conclusion: The prognostic model developed for patients with TD-positive GC has a higher clinical utility compared to the eighth edition of TNM staging.

TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance.

Autophagy plays a pivotal role in diverse biological processes, including the maintenance and differentiation of neural stem cells (NSCs). Interestingly, while complete deletion of Fip200 severely impairs NSC maintenance and differentiation, inhibiting canonical autophagy via deletion of core genes, such as Atg5, Atg16l1, and Atg7, or blockade of canonical interactions between FIP200 and ATG13 (designated as FIP200-4A mutant or FIP200 KI) does not produce comparable detrimental effects. This highlights the likely critical involvement of the non-canonical functions of FIP200, the mechanisms of which have remained elusive. Here, utilizing genetic mouse models, we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1, primarily via TAX1BP1 in NSCs. Conditional deletion of Tax1bp1 in fip200 hGFAP conditional knock-in (cKI) mice led to NSC deficiency, resembling the fip200 hGFAP conditional knockout (cKO) mouse phenotype. Notably, reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200 hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation. Conversely, a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration. Furthermore, conditional deletion of Tax1bp1 in fip200 hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200 hGFAP cKO mice. Collectively, these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function, presenting novel therapeutic targets for neurodegenerative diseases.

Comprehensive analysis of PPP4C's impact on prognosis, immune microenvironment, and immunotherapy response in lung adenocarcinoma using single-cell sequencing and multi-omics.

Background: Elevated PPP4C expression has been associated with poor prognostic implications for patients suffering from lung adenocarcinoma (LUAD). The extent to which PPP4C affects immune cell infiltration in LUAD, as well as the importance of associated genes in clinical scenarios, still requires thorough investigation. Methods: In our investigation, we leveraged both single-cell and comprehensive RNA sequencing data, sourced from LUAD patients, in our analysis. This study also integrated datasets of immune-related genes from InnateDB into the framework. Our expansive evaluation employed various analytical techniques; these included pinpointing differentially expressed genes, constructing WGCNA, implementing Cox proportional hazards models. We utilized these methods to investigate the gene expression profiles of PPP4C within the context of LUAD and to clarify its potential prognostic value for patients. Subsequent steps involved validating the observed enhancement of PPP4C expression in LUAD samples through a series of experimental approaches. The array comprised immunohistochemistry staining, Western blotting, quantitative PCR, and a collection of cell-based assays aimed at evaluating the influence of PPP4C on the proliferative and migratory activities of LUAD cells. Results: In lung cancer, elevated expression levels of PPP4C were observed, correlating with poorer patient prognoses. Validation of increased PPP4C levels in LUAD specimens was achieved using immunohistochemical techniques. Experimental investigations have substantiated the role of PPP4C in facilitating cellular proliferation and migration in LUAD contexts. Furthermore, an association was identified between the expression of PPP4C and the infiltration of immune cells in these tumors. A prognostic framework, incorporating PPP4C and immune-related genes, was developed and recognized as an autonomous predictor of survival in individuals afflicted with LUAD. This prognostic tool has demonstrated considerable efficacy in forecasting patient survival and their response to immunotherapeutic interventions. Conclusion: The involvement of PPP4C in LUAD is deeply intertwined with the tumor's immune microenvironment. PPP4C's over-expression is associated with negative clinical outcomes, promoting both tumor proliferation and spread. A prognostic framework based on PPP4C levels may effectively predict patient prognoses in LUAD, as well as the efficacy of immunotherapy strategy. This research sheds light on the mechanisms of immune interaction in LUAD and proposes a new strategy for treatment.

Integrative analysis of metabolome and transcriptome reveals regulatory mechanisms of flavonoid biosynthesis in soybean under salt stress.

Introduction: Salt stress is a major environmental factor that constrains soybean growth, development, and productivity. Flavonoids are key secondary metabolites that play a crucial role in enhancing plant resistance to both biotic and abiotic stress. However, a comprehensive understanding of the regulatory mechanisms underlying flavonoid biosynthesis under salt stress in soybean is lacking. Methods: In this study, an integrative analysis of soybean metabolome and transcriptome was conducted using two soybean lines, FQ03 (salt-sensitive, SS) and FQ07 (salt-tolerant, ST). Results: A total of 650 significantly changed metabolites were identified in SS and ST after salt stress treatment. Among them, 151 flavonoids were categorized into nine classes, with flavones and flavonols being the predominant flavonoid types in soybean. Heatmap analysis showed higher contents of most flavonoid metabolites in ST than in SS under salt stress, and the total flavonoid content in ST was significantly higher than that in SS. In addition, transcriptome analysis revealed a higher number of differentially expressed genes (DEGs) in ST than in SS under salt stress. KEGG enrichment analysis revealed that DEGs were mainly enriched in pathways related to phenylpropanoid biosynthesis, isoflavonoid biosynthesis, flavonoid biosynthesis, as well as flavone and flavonol biosynthesis. Notably, 55 DEGs that were mapped to the flavonoid biosynthetic pathway were identified, with most showing higher expression levels in ST than in SS. Weighted gene correlation network analysis identified eight structural genes and six transcription factor genes as key regulators of flavonoid biosynthesis within the blue module. Furthermore, qRT-PCR results confirmed the accuracy of the transcriptomic data and reliability of the identified candidate genes. Discussion: This study provides insights into the regulatory mechanisms underlying salt stress responses in soybean and highlights hub genes as potential targets for developing salt-tolerant soybean varieties.

Exploring the causal association between serum metabolites and erectile dysfunction: a bidirectional Mendelian randomisation study.

Erectile dysfunction is a common sexual disorder in men. Some studies have found a strong association between some serum metabolites and erectile dysfunction. To investigate this association further, we used bidirectional Mendelian randomisation to investigate causality and possible biological mechanisms.Firstly, this study screened the statistics of genome-wide association studies of serum metabolites and erectile dysfunction to obtain instrumental variables. Inverse variance weighting was used as the primary method for causal effect analysis of instrumental variables in forward or reverse Mendelian randomisation, and the results obtained by MR-Egger regression and the weighted median method were used as references. Subsequently, the metabolites causally associated with erectile dysfunction were subjected to replication analyses and meta-analyses, and the results of the meta-analyses were analysed by pathway analyses to find influential pathways. In this process, Mendelian randomisation results need to be assessed for stability and reliability using sensitivity analysis.It was found that a total of six serum metabolites were causally associated with erectile dysfunction in a forward Mendelian randomisation study. 1,3,7-trimethyluraten (0.85 (0.73-0.99), P = 0.0368), ergothioneine (0.65 (0.45-0.94), P = 0.0226) and gamma-glutamylglutamate (0.63 (0.46-0.88), P = 0.0059) were protective against the development of erectile dysfunction, whereas 2-hydroxyhippurate (1.10 (1.02-1.19), P = 0.0152), N2,N2-dimethylguanosine (1.57 (1.02-2.40), P = 0.0395) and octanoylcarnitine (1.38 (1.06-1.82), P = 0.0183) were able to induce the development of erectile dysfunction. In addition, metabolic pathway analysis showed that 1,3,7-trimethylurate was able to influence the development of erectile dysfunction via the caffeine metabolism pathway (P = 0.0454). On the other hand, reverse Mendelian randomisation analysis showed that erectile dysfunction reduced serum homocitrulline levels (0.99 (0.97-1.00), P = 0.0360). Sensitivity analyses, including heterogeneity tests and pleiotropy tests, confirmed the reliability of the results.In conclusion, this study demonstrated a bidirectional causal relationship between serum metabolites and erectile dysfunction using bidirectional Mendelian randomisation analysis and replication meta-analysis. On this basis, this study provides a new direction of thinking and strong evidence for the therapeutic application and adjunctive diagnosis of serum metabolites in erectile dysfunction, and provides a certain reference value for subsequent related studies.

Monolithic integrated chip of AWG and PD for an FBG interrogation system.

To advance the development of a compact and highly integrated fiber Bragg grating (FBG) interrogation system, to the best of our knowledge, this paper is the first to present the design and fabrication of a monolithic integration chip based on silicon-on-insulator (SOI), which is specifically intended for application in fiber grating sensing interrogation systems. By considering the impact of coupling structure dimensions on coupling efficiency as well as the effect of the photodetector (PD) parameters on the optical absorption efficiency of the device, we refine the structure of the monolithic integrated chip for arrayed waveguide grating (AWG) and PD. The test results reveal that the coupling loss between AWG and PD is -2.4 dB. The monolithic integrated interrogation chip achieves an interrogation accuracy of approximately 6.79 pm within a dynamic range of 1.56 nm, accompanied by a wavelength resolution of 1 pm. This exceptional performance highlights the potential of the monolithic integrated chip to enhance the integration of AWG-based fiber grating interrogation systems.

Modulation of histone acetylation enables fully mechanized hybrid rice breeding.

Hybrid rice has achieved high grain yield and greatly contributes to food security, but the manual-labour-intensive hybrid seed production process limits fully mechanized hybrid rice breeding. For next-generation hybrid seed production, the use of small-grain male sterile lines to mechanically separate small hybrid seeds from mixed harvest is promising. However, it is difficult to find ideal grain-size genes for breeding ideal small-grain male sterile lines without penalties in the number of hybrid seeds and hybrid rice yield. Here we report that the use of small-grain alleles of the ideal grain-size gene GSE3 in male sterile lines enables fully mechanized hybrid seed production and dramatically increases hybrid seed number in three-line and two-line hybrid rice systems. The GSE3 gene encodes a histone acetyltransferase that binds histones and influences histone acetylation levels. GSE3 is recruited by the transcription factor GS2 to the promoters of their co-regulated grain-size genes and influences the histone acetylation status of their co-regulated genes. Field trials demonstrate that genome editing of GSE3 can be used to immediately improve current elite male sterile lines of hybrid rice for fully mechanized hybrid rice breeding, providing a new perspective for mechanized hybrid breeding in other crops.

Causal effects of gut microbiota on the risk of osteomyelitis: a Mendelian randomization study.

Background: Osteomyelitis is characterized by an inflammatory process initiated by microorganisms, leading to infection and subsequent degradation of bone tissue. Several studies have indicated a potential link between gut microbiota and the occurrence of osteomyelitis. Utilizing the benefits of Mendelian randomization, which mitigates issues of confounding and reverse causation, we employed this approach to ascertain the presence of a causal connection between gut microbiota and osteomyelitis. Additionally, we aimed to pinpoint gut microbiota that could potentially exert substantial influence. Methods: We performed a rigorous screening of single nucleotide polymorphisms in GWAS summary statistics for gut microbiota and osteomyelitis. The 2,542 instrumental variables obtained after screening were subjected to MR analyses, including inverse variance weighting, weighted median, weighted mode, MR-Egger, and Mendelian randomization pleiotropy residual sum and outlier test. We then validated the reliability of the results by performing sensitivity analyses on the MR of 196 well-defined gut microbiota. Result: We established a causal relationship between gut microbiota and osteomyelitis through MR analysis. Additionally, we identified a taxon of significant importance and six taxons with nominal significance. Specifically, the family Bacteroidales S24.7 group exhibited an association with a diminished risk of osteomyelitis development. Conversely, the class Bacilli, class Bacteroidia, order Bacteroidales, order Lactobacillales, family Streptococcaceae, and genus Coprococcus3 displayed an increased risk of developing osteomyelitis. The MR outcomes for these seven taxa remained stable throughout a series of sensitivity analyses. Conclusion: This study demonstrated a causal relationship between gut microbiota and osteomyelitis by Mendelian randomization. We hope that this study will provide a new direction for the treatment of osteomyelitis, which has a paucity of therapeutic options.

Gastric transcatheter chemoembolization combined with systemic chemotherapy vs. systemic chemotherapy alone for patients with advanced gastric cardiac cancer presenting with dysphagia: A case control study.

The present study aimed to assess the effectiveness of gastric transcatheter chemoembolization (GTC) combined with systemic chemotherapy (SYS) compared with SYS alone in managing dysphagia, and improving the quality of life (QoL) and nutritional status of patients with advanced gastric cardiac cancer (AGCC). A retrospective review was performed using data from consecutive patients with AGCC who experienced dysphagia and underwent either SYS alone or SYS combined with GTC from January 2018 to December 2022. Propensity score matching (PSM) analysis was performed to address potential confounding factors. Ogilvie dysphagia scores were used to assess dysphagia, the Functional Assessment of Cancer Therapy-General 7 (FACT-G7) was used to assess QoL, and the Patient-Generated Subjective Global Assessment (PG-SGA) was used to evaluate nutritional status. After PSM, a total of 228 patients were included in the analysis, with 114 in each group. At 4 and 8 weeks after the initial treatment, the GTC + SYS group demonstrated significantly lower median Ogilvie scores compared with the SYS alone group (P<0.001). Similarly, the median PG-SGA score at 4 weeks after the initial treatment was 2.0 in the GTC + SYS group and 6.0 in the SYS alone group. The median FACT-G7 scores in the GTC + SYS group was 13.0, compared with 10.5 in the SYS alone group. These differences remained significant at 8 weeks (P<0.001). In conclusion, the addition of GTC to SYS may more effectively and promptly relieve dysphagia, improve nutritional status and enhance QoL compared with SYS alone in patients with AGCC presenting with dysphagia.

Evidence-based practice attitudes, knowledge and skills of nursing students and nurses, a systematic review and meta-analysis.

AIM/OBJECTIVE: This study aims to carry out a meta-analysis of attitudes, knowledge, and skills level of nursing students and nurses in EBP, providing a reference for optimizing EBP education strategies. BACKGROUND: At present, no meta-analysis has been performed to quantitatively synthesize the attitudes, knowledge and skill levels of nursing students and nurses toward EBP. This makes it difficult to precisely identify the true level of EBP among nurses, implying that there is no evidence to support the adoption of EBP teaching strategies approaches. DESIGN: A total of 9 Chinese and English databases including CNKI, Wan fang, VIP, CBM, PubMed, Embase, Web of Science, Cochrane Library and CINAHL were used to search cross-sectional quantitative articles on EBP attitudes, knowledge and skills level of nurses and nursing students. The search time limit was from the inception of the database to September 2023. METHODS: Two researchers independently screened the literature and extracted the data. The Agency for Healthcare Research and Quality (AHRQ) was used to assess the quality of the included studies. Stata15.0 software was used for statistical analysis to summarize the scores of EBP attitude, knowledge and skills level of nursing students and nurses included in the study. RESULTS: A total of 25 cross-sectional studies from 13 countries were included, involving 11363 nursing students and nurses. The meta-analysis results revealed that nursing students and nurses lacked evidence-based practical knowledge and skills, with pooled mean scores of 3.06 (95 % CI: 2.72, 3.39), 2.91 (95 % CI: 2.60, 3.22), 4.31 (95 % CI: 4.08, 4.54) and 4.45 (95 % CI: 4.20, 4.70). In contrast, nursing students and nurses revealed a positive attitude towards EBP, with pooled mean scores of 3.57 (95 % CI: 3.28, 3.86) and 5.11 (95 % CI: 4.80, 5.42). Subgroup analysis revealed that senior nursing students and nurses with master's degree or above had higher attitudes, knowledge and skills. CONCLUSIONS: In summary, nursing students and nurses have a positive attitude towards EBP. However, they seem to lack the necessary knowledge and skills. Therefore, nursing educators should consider this as an opportunity to strengthen the teaching of their evidence-based practical knowledge and skills. This will lay a reference for developing nursing discipline.

Precise Molecular Subtyping Reveals Heterogeneity of Lung Adenocarcinoma Based on DNA Methylation.

BACKGROUND: Due to the high heterogeneity of lung adenocarcinoma (LUAD), which restricts the effectiveness of therapy, precise molecular subgrouping of LUAD is of great significance. Clinical research has demonstrated the significant potential of DNA methylation as a classification indicator for human malignancies. METHODS: WGML framework (which was developed based on weighted gene correlation network analysis (WGCNA), Gene Ontology (GO), and machine learning) was developed to precisely subgroup molecular subtypes of LUAD. This framework included two parts: the WG algorithm and the machine learning part. The WG algorithm part was an original algorithm used to obtain a crucial module, which was characterized by weighted correlation network analysis, functional annotation, and mathematical algorithms. The machine learning part utilized the Boruta algorithm, random forest algorithm, and Gradient Boosting Regression Tree algorithm to select feature genes. Then, based on the results of the WGML framework, subtypes were computed by the hierarchical clustering algorithm. A series of analyses, including dimensionality reduction methods, survival analysis, clinical stage analysis, immune infiltration analysis, tumor environment analysis, immune checkpoints analysis, TIDE analysis, CYT analysis, somatic mutation analysis, and drug sensitivity analysis, were utilized to demonstrate the effectiveness of subgrouping. GEO datasets were used to externally validate the results. Meanwhile, another subgrouping method of LUAD from another study was employed to compare with the WGML framework. RESULT: By importing DNA methylation data into the WGML framework, nine genes were obtained to further subgroup LUAD. Three subtypes, the Carcinogenesis subtype, Immune-infiltration subtype, and Chemoresistance subtype, were identified. The dimensionality reduction method exhibited great distinctness between subtypes. A series of analyses were employed to exhibit the difference among the three subtypes and to demonstrate the accuracy of the definition of subtypes. Besides, the WGML framework was compared with a LUAD subgrouping method from another research, which demonstrated that WGML had better efficiency for subgrouping LUAD. CONCLUSION: This study provides a novel LUAD subgrouping framework named WGML for the accurate subgrouping of lung adenocarcinoma.

Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: a phase 1b/2a trial.

PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .

Anatomical predispositions for silent cerebral infarction post carotid artery stenting: A retrospective cohort.

BACKGROUND: Silent cerebral infarction (SCI) that manifests following carotid artery stenting (CAS) has been postulated to correlate with cognitive decline, the onset of dementia, and an increased risk of subsequent cerebrovascular events. This investigation aimed to thoroughly examine the potential anatomical predispositions that are linked to the occurrence of SCI post-CAS, and further develop a predictive nomogram that could accurately forecast the risk of SCI post-CAS. METHODS: The present investigation conducted a retrospective examination of datasets from 250 individuals presenting with carotid artery stenosis who had been subjected to CAS within a tertiary healthcare institution from June 2020 to November 2021. Stratified by the procedural date, participants were allocated into a training cohort and a validation cohort. A nomogram was constructed predicated on salient prognostic determinants discerned via a multivariate logistic regression analysis. RESULTS: An aggregate of 184 patients were incorporated into the study, of which 60 (32.6%) manifested SCI, whereas 124 (67.4%) did not. Within the training cohort (n=123), age (OR 1.08, 95%CI 1.01-1.16; P=0.034), aortic arch type (Type III vs. I: OR 10.79, 95%CI 2.12-54.81; P=0.005), aortic arch variant (OR 47.71, 95%CI 6.05-376.09; P<0.001), common carotid artery (CCA) ostium lesions (OR 6.93, 95%CI 1.49-32.32; P=0.014), and proximal tortuosity index (TI) (OR 1.01, 95%CI 1.00-1.02; P=0.029) were demarcated as standalone risk predispositions for SCI subsequent to CAS. The concordance index (C-index) for the training cohort's nomogram stood at 0.89 (95% CI, 0.84-0.95). Moreover, the said nomogram exhibited commendable efficacy within the validation cohort (C-index=0.94) as well as the entire participant base (C-index=0.90). Furthermore, the decision curve analysis illustrated the exemplary clinical applicability of the nomogram. CONCLUSIONS: The findings of this inquiry underscore that age, aortic arch type, aortic arch variant, CCA ostium lesions, and proximal TI serve as independent determinants linked with SCI post-CAS. The formulated nomogram, predicated on these risk factors, possesses robust prognostic significance and might serve as a valuable adjunct to inform clinical decision-making.

Prognostic value of lymphocytes in patients with breast cancer receiving radiotherapy after breast-conserving surgery: A post hoc analysis of a phase III randomized trial.

PURPOSE: To evaluate the prognostic value of peripheral lymphocyte count (PLC) in the breast cancer patients after breast-conserving surgery (BCS) with radiotherapy (RT). METHODS AND MATERIALS: This post hoc analysis was performed using data of 628 patients from a phase III, randomized controlled trial comparing hypofractionated RT (HFRT) with conventional fractionated RT (CFRT) after BCS. PLCs were obtained before, during, and after RT until the 1-year follow-up. The optimal cut-off PLCs were determined using the maxstat package in R. Survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: A total of 275 (46.1 %) patients developed lymphopenia during RT, among them, 17 (2.8 %) had grade 3 lymphopenia and no one developed grade 4 lymphopenia. With a median follow-up of 110.8 months, patients with pre-RT PLCs of < 1.77 × 109/L had a significantly lower 10-year breast cancer-specific survival (BCSS) rate (P = 0.013) and overall survival (OS) rate (P = 0.026). Patients with a nadir PLC of < 1.35 × 109/L had a significantly poorer 10-year OS rate (P = 0.048). Multivariate analysis showed that a pre-RT PLC of < 1.77 × 109/L was an independent factor influencing BCSS and OS, while the effect of the nadir PLC did not remain significant. Neither PLC nor lymphopenia recovery at post-RT 1, 3, and 6 months and 1 year was associated with survival. CONCLUSIONS: Radiation-induced lymphopenia in patients with breast cancer after BCS tends to be mild. The lower pre-RT PLC predicted poorer survival.

Targetable leukaemia dependency on noncanonical PI3Kγ signalling.

Phosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1-4. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid and dendritic lineages. This dependency is characterized by innate inflammatory signalling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3Kγ5 and stabilizes the active enzymatic complex. We identify p21 (RAC1)-activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency and find that dephosphorylation of PAK1 by PI3Kγ inhibition impairs mitochondrial oxidative phosphorylation. Treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukaemias with activated PIK3R5. In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3Kγ-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia.

Mitochondrial outer membrane protein Samm50 protects against hypoxia-induced cardiac injury by interacting with Shmt2.

Cardiac remodeling is a critical process following myocardial infarction (MI), potentially leading to heart failure if untreated. The significance of mitochondrial homeostasis in MI remains insufficiently understood. Samm50 is an essential component of mitochondria. Our study aimed to investigate its role in hypoxia-induced cardiac injury and the underlying mechanisms. First, we observed that Samm50 was dynamically downregulated in mice with MI compared to the control mice. In vitro, Samm50 was also downregulated in oxygen-glucose-deprived neonatal rat cardiomyocytes and fibroblasts. Overexpression and knockdown of Samm50 mitigated and exacerbated cardiac apoptosis and fibrosis, while also improving and worsening mitochondrial homeostasis, respectively. Protein interactions with Samm50 during the protective process were identified via immune-coprecipitation/mass spectroscopy. Mechanistically, serine hydroxymethyltransferase 2 (Shmt2) interacted with Samm50, acting as a crucial element in the protective process by hindering the transfer of Bax from the cytoplasm to the mitochondria and subsequent activation of caspase-3. Inhibition of Shmt2 diminished the protective effect of Samm50 overexpression against cardiac injury. Finally, Samm50 overexpression in vivo mitigated cardiac remodeling and enhanced cardiac function in both acute and chronic MI. In conclusion, Samm50 overexpression mitigated hypoxia-induced cardiac remodeling by inhibiting apoptosis and fibrosis, with Shmt2 acting as a key regulator in this protective process. The Samm50/Shmt2 axis represents a newly discovered mitochondria-related pathway for mitigating hypoxia-induced cardiac injury.

The role of adiponectin and its receptor signaling in ocular inflammation-associated diseases.

Ocular inflammation-associated diseases are leading causes of global visual impairment, with limited treatment options. Adiponectin, a hormone primarily secreted by adipose tissue, binds to its receptors, which are widely distributed throughout the body, exerting powerful physiological regulatory effects. The protective role of adiponectin in various inflammatory diseases has gained increasing attention in recent years. Previous studies have confirmed the presence of adiponectin and its receptors in the eyes. Furthermore, adiponectin and its analogs have shown potential as novel drugs for the treatment of inflammatory eye diseases. This article summarizes the evidence for the interplay between adiponectin and inflammatory eye diseases and provides new perspectives on the diagnostic and therapeutic possibilities of adiponectin.