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Abstract Background Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting. Methods This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8–12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D). Results As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0–74.0) and disease control rate of 94.4% (95% CI, 72.7–99.9). Conclusions First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID. Trial registration ClinicalTrials.gov, NCT04228601.

Abstract The overactivated immune cells in the infectious lesion may lead to irreversible organ damages under severe infections. However, clinically used immunosuppressive anti‐inflammatory drugs will usually disturb immune homeostasis and conversely increase the risk of infections. Regulating the balance between anti‐inflammation and anti‐infection is thus critical in treating certain infectious diseases. Herein, considering that hydrogen peroxide (H2O2), myeloperoxidase (MPO), and neutrophils are upregulated in the inflammatory microenvironment and closely related to the severity of appendectomy patients, an inflammatory‐microenvironment‐responsive nanomedicine is designed by using poly(lactic‐co‐glycolic) acid (PLGA) nanoparticles to load chlorine E6 (Ce6), a photosensitizer, and luminal (Lum), a chemiluminescent agent. The obtained Lum/Ce6@PLGA nanoparticles, being non‐toxic within normal physiological environment, can generate cytotoxic single oxygen via bioluminescence resonance energy transfer (BRET) in the inflammatory microenvironment with upregulated H2O2 and MPO, simultaneously killing pathogens and excessive inflammatory immune cells in the lesion, without disturbing immune homeostasis. As evidenced in various clinically relevant bacterial infection models and virus‐induced pneumonia, Lum/Ce6@PLGA nanoparticles appeared to be rather effective in controlling both infection and inflammation, resulting in significantly improved animal survival. Therefore, the BRET‐based nanoparticles by simultaneously controlling infections and inflammation may be promising nano‐therapeutics for treatment of severe infectious diseases.

Abstract Neuroblastoma (NB) is a common childhood tumor with a high incidence worldwide. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has attracted significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively studied in various types of cancer. However, the specific influence of METTL14 on NB remains unexplored. Using data from the Target database, our study revealed significant upregulation of METTL14 expression in high-risk NB patients, with strong correlation with poor prognosis. Furthermore, we identified ETS1 and YY1 as upstream regulators that control the expression of METTL14. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated significant inhibition of cell proliferation, migration, and invasion. In addition, suppressing METTL14 inhibited NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream target gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly those in the 5′ UTR, were specifically recognized by the m6A “reader” protein YTHDF1, leading to the degradation of YWHAH mRNA. Moreover, the downregulation of YWHAH expression activated the PI3K/AKT signaling pathway, promoting NB cell activity. Overall, our study provides valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in inhibiting YWHAH expression through an m6A-YTHDF1-dependent mechanism. These findings also suggest the potential utility of a biomarker panel for prognostic prediction in NB patients.

Abstract Background The incidence of exertional heat stroke (EHS) escalates during periods of elevated temperatures, potentially leading to persistent cognitive impairment postrecovery. Currently, effective prophylactic or therapeutic measures against EHS are nonexistent. Methods The selection of days 14 and 23 postinduction for detailed examination was guided by TEM of neuronal cells and HE staining of intestinal villi and the hippocampal regions. Fecal specimens from the ileum and cecum at these designated times were analyzed for changes in gut microbiota and metabolic products. Bioinformatic analyses facilitated the identification of pivotal microbial species and metabolites. The influence of supplementing these identified microorganisms on behavioral outcomes and the expression of functional proteins within the hippocampus was subsequently assessed. Results TEM analyses of neurons, coupled with HE staining of intestinal villi and the hippocampal region, indicated substantial recovery in intestinal morphology and neuronal injury on Day 14, indicating this time point for subsequent microbial and metabolomic analyses. Notably, a reduction in the Lactobacillaceae family, particularly Lactobacillus murinus, was observed. Functional annotation of 16S rDNA sequences suggested diminished lipid metabolism and glycan biosynthesis and metabolism in EHS models. Mice receiving this intervention (EHS + probiotics group) exhibited markedly reduced cognitive impairment and increased expression of BDNF/TrKB pathway molecules in the hippocampus during behavioral assessment on Day 28. Conclusion Probiotic supplementation, specifically with Lactobacillus spp., appears to mitigate EHS-induced cognitive impairment, potentially through the modulation of the BDNF/TrKB signaling pathway within the hippocampus, illustrating the therapeutic potential of targeting the gut-brain axis.

Urban regeneration (UR) can improve the physical, social, economic, and ecological environment of urban areas, which is the key path to achieving Sustainable Development Goals (SDGs). However, quantitative assessments of the SDGs dynamics before and after UR process are rarely studied. Taking Shenzhen, China, as a practical example, this study combined multi-source geographic data to proposed a fine-scale SDGs assessment index framework applicable to UR (URSDGi). A comprehensive index of urban regeneration SDGs (URSDGs) was then constructed to evaluate the SDGs performance for four types of UR (industrial, residential, commercial and other types) at street block scale. Results showed that Shenzhen’s 392 blocks underwent UR practice between 2012–2020. The industrial UR exhibited the highest degree of SDGs realization with an increase of 962.29 points in the URSDGs score between 2012 and 2020, followed by residential UR with an increase of 126.41 points, whereas commercial and other types of UR exhibited lower degrees of SDGs realization with an increase of 42.23 and 58.39 points, respectively. In addition, studies have found that all types of UR can obviously promote mixed land use (URSDG5) and improve land use efficiency (URSDG3), with an increase of at least 111.10 points in the URSDGi score between 2012 and 2020. Nevertheless, UR can impose additional pressures on residential housing (URSDG1) and lead to a reduction in urban green space (URSDG4), with a decrease of at least −0.66 points in the URSDGi score. The findings can enrich the research methods of SDGs performance assessment at finer scale and help to guide future UR practices.

Abstract Background Glioblastoma (GBM) is a relatively prevalent primary tumor of the central nervous system in children, characterized by its high malignancy and mortality rates, along with the intricate challenges of achieving complete surgical resection. Recently, an increasing number of studies have focused on the crucial role of super-enhancers (SEs) in the occurrence and development of GBM. This study embarks on the task of evaluating the effectiveness of MZ1, an inhibitor of BRD4 meticulously designed to specifically target SEs, within the intricate framework of GBM. Methods The clinical data of GBM patients was sourced from the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the gene expression data of tumor cell lines was derived from the Cancer Cell Line Encyclopedia (CCLE). The impact of MZ1 on GBM was assessed through CCK-8, colony formation assays, EdU incorporation analysis, flow cytometry, and xenograft mouse models. The underlying mechanism was investigated through RNA-seq and ChIP-seq analyses. Results In this investigation, we made a noteworthy observation that MZ1 exhibited a substantial reduction in the proliferation of GBM cells by effectively degrading BRD4. Additionally, MZ1 displayed a notable capability in inducing significant cell cycle arrest and apoptosis in GBM cells. These findings were in line with our in vitro outcomes. Notably, MZ1 administration resulted in a remarkable decrease in tumor size within the xenograft model with diminished toxicity. Furthermore, on a mechanistic level, the administration of MZ1 resulted in a significant suppression of pivotal genes closely associated with cell cycle regulation and epithelial-mesenchymal transition (EMT). Interestingly, our analysis of RNA-seq and ChIP-seq data unveiled the discovery of a novel prospective oncogene, SDC1, which assumed a pivotal role in the tumorigenesis and progression of GBM. Conclusion In summary, our findings revealed that MZ1 effectively disrupted the aberrant transcriptional regulation of oncogenes in GBM by degradation of BRD4. This positions MZ1 as a promising candidate in the realm of therapeutic options for GBM treatment.

Abstract Objective We investigated the impact of the long noncoding RNA LINC00958 on cellular activity and oxidative stress in osteoarthritis (OA). Methods We performed bioinformatics analysis via StarBase and luciferase reporter assays to predict and validate the interactions between LINC00958 and miR-214-3p and between miR-214-3p and FOXM1. The expression levels of LINC00958, miR-214-3p, and FOXM1 were measured by qRT-PCR and western blotting. To assess effects on CHON-001 cells, we performed MTT proliferation assays, evaluated cytotoxicity with a lactate dehydrogenase (LDH) assay, and examined apoptosis through flow cytometry. Additionally, we measured the levels of apoptosis-related proteins, including BAX and BCL2, using western blotting. The secretion of inflammatory cytokines (IL-6, IL-8, and TNF-α) was measured using ELISA. Results Our findings confirmed that LINC00958 is a direct target of miR-214-3p. LINC00958 expression was upregulated but miR-214-3p expression was downregulated in both OA cells and IL-1β-stimulated CHON-001 cells compared to the corresponding control cells. Remarkably, miR-214-3p expression was further reduced after miR-214-3p inhibitor treatment but increased following LINC00958-siRNA stimulation. Silencing LINC00958 significantly decreased its expression, and this effect was reversed by miR-214-3p inhibitor treatment. Notably, LINC00958-siRNA transfection alleviated the IL-1β-induced inflammatory response, as evidenced by the increased cell viability, reduced LDH release, suppression of apoptosis, downregulated BAX expression, and elevated BCL2 levels. Moreover, LINC00958 silencing led to reduced secretion of inflammatory factors from IL-1β-stimulated CHON-001 cells. The opposite results were observed in the miR-214-3p inhibitor-transfected groups. Furthermore, in CHON-001 cells, miR-214-3p directly targeted FOXM1 and negatively regulated its expression. Conclusion Our findings suggest that downregulating LINC00958 mitigates IL-1β-induced injury in CHON-001 cells through the miR-214-3p/FOXM1 axis. These results imply that LINC00958 plays a role in OA development and may be a valuable therapeutic target for OA.

The size of peanut pods and seeds, which directly affects yield and quality, also has significant implications for mechanized production and market efficiency. Identifying relevant loci and mining candidate genes is crucial for cultivating high-yield peanut varieties. In this study, we employed advanced generation recombinant inbred lines developed by crossbreeding Huayu 44 and DF12 as the experimental material. Quantitative trait locus (QTL) mapping for traits related to pod and seed size was conducted across six environments. A total of 44 QTLs were detected, distributed on chromosomes A02, A05, B04, B08, and B10. An enrichment region for multiple QTLs was also identified on chromosome A05 (19.28~52.32 cm). In this region, 10 KASP markers were developed, narrowing the enrichment area to two candidate gene hotspot regions of 600.9 kb and 721.2 kb. By combining gene prediction and functional annotation within the intervals, 10 candidate genes, including those encoding cytochrome P450 protein, polyamine synthase, mannose-1-phosphate guanylyltransferase, pentatricopeptide repeat protein, and E2F transcription factor, were identified as regulators of pod and seed size. This study provides technical support for the genetic improvement and key gene identification of peanut pod and seed size.