Efficacy of a real-time intelligent quality-control system for the detection of early upper gastrointestinal neoplasms: a multicentre, single-blinded, randomised controlled trial.

Background: Oesophagogastroduodenoscopy (OGD) quality and identification of the early upper gastrointestinal (UGI) neoplasm play an important role in detecting the UGI neoplasm. However, the optimal method for quality control in daily OGD procedures is currently lacking. We aimed to evaluate the efficacy of a real-time intelligent quality-control system (IQCS), which combines OGD quality control with lesion detection of early UGI neoplasms. Methods: We performed a multicentre, single-blinded, randomised controlled trial at 6 hospitals in China. Patients aged 40-80 years old who underwent painless OGD were screened for enrolment in this study. Patients with a history of advanced UGI cancer, stenosis, or obstruction in UGI tract were excluded. Eligible subjects were randomly assigned (1:1) to either the routine or IQCS group to undergo standard OGD examination and OGD examination aided by IQCS, respectively. Patients were masked to the randomisation status. The primary outcome was the detection of early UGI neoplasms. All analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, NCT04720924. Findings: Between January 16, 2021 and December 23, 2022, 1840 patients were randomised (IQCS group: 919, routine group: 921). The full analysis set consisted of 914 in the IQCS group and 915 in the routine group. The early UGI neoplasms detection rate in the IQCS group (6.1%, 56/914) was significantly higher than in the routine group (2.3%, 21/915; P = 0.0001). The IQCS group had fewer blind spots (2.3 vs. 6.2, P < 0.0001). The IQCS group had higher stomach cleanliness on cardia or fundus (99.5% vs. 87.9%, P < 0.0001), body (98.9% vs. 88.0%, P < 0.0001), angulus (99.8% vs. 88.4%, P < 0.0001) and antrum or pylorus (100.0% vs. 87.4%, P < 0.0001). The inspection time (576.2 vs. 574.5s, P = 0.91) and biopsy rate (57.2% vs. 56.6%, P = 0.83) were not different between the groups. The early UGI neoplasms detection rate in the IQCS group increased in both non-academic centres (RR = 3.319, 95% CI 1.277-9.176; P = 0.0094) and academic centres (RR = 2.416, 95% CI 1.301-4.568; P = 0.0034). The same improvements were observed for both less-experienced endoscopists (RR = 2.650, 95% CI 1.330-5.410; P = 0.0034) and experienced endoscopists (RR = 2.710, 95% CI 1.226-6.205; P = 0.010). No adverse events or serious adverse events were reported in the two groups. Interpretation: The IQCS improved the OGD quality and increased early UGI neoplasm detection in different hospital types and endoscopist experiences. IQCS could play an important role in primary basic hospitals and non-expert endoscopists to improve the diagnostic accuracy of early UGI neoplasms. The effectiveness of IQCS in real-world clinical settings needs a larger population validation. Funding: Key R&D Program of Shandong Province, China (Major Scientific and Technological Innovation Project), National Natural Science Foundation of China, the Taishan Scholars Program of Shandong Province, the National Key Research and Development Program of China, and the Shandong Provincial Natural Science Foundation.

Advances in novel biosensors in biomedical applications.

Biosensors, devices capable of detecting biomolecules or bioactive substances, have recently become one of the important tools in the fields of bioanalysis and medical diagnostics. A biosensor is an analytical system composed of biosensitive elements and signal-processing elements used to detect various biological and chemical substances. Biomimetic elements are key to biosensor technology and are the components in a sensor that are responsible for identifying the target analyte. The construction methods and working principles of biosensors based on synthetic biomimetic elements, such as DNAzyme, molecular imprinted polymers and aptamers, and their updated applications in biomedical analysis are summarised. Finally, the technical bottlenecks and future development prospects for biomedical analysis are summarised and discussed.

Enhancing insight into ferroptosis mechanisms in sepsis: A genomic and pharmacological approach integrating single-cell sequencing and Mendelian randomization.

This research investigated the intricate relationship between ferroptosis and sepsis by utilizing advanced genomic and pharmacological methodologies. Specifically, we obtained expression quantitative trait loci (eQTLs) for 435 genes associated with ferroptosis from the eQTLGen Consortium and detected notable cis-eQTLs for 281 of these genes. Next, we conducted a detailed analysis to assess the impact of these eQTLs on susceptibility to sepsis using Mendelian randomization (MR) with data from a cohort of 10,154 sepsis patients and 452,764 controls sourced from the UK Biobank. MR analysis revealed 16 ferroptosis-related genes that exhibited significant associations with sepsis outcomes. To bolster the robustness of these findings, sensitivity analyses were performed to assess pleiotropy and heterogeneity, thus confirming the reliability of the causal inferences. Furthermore, single-cell RNA sequencing data from sepsis patients offered a detailed examination of gene expression profiles, demonstrating varying levels of ferroptosis marker expression across different cell types. Pathway enrichment analysis utilizing gene set enrichment analysis (GSEA) further revealed the key biological pathways involved in the progression of sepsis. Additionally, the use of computational molecular docking facilitated the prediction of interactions between identified genes and potential therapeutic compounds, highlighting novel drug targets. In conclusion, our integrated approach combining genomics and pharmacology offers valuable insights into the involvement of ferroptosis in sepsis, laying the groundwork for potential therapeutic strategies targeting this cell death pathway to enhance sepsis management.

Fabrication and Temporal Dependency Osteogenic Regulation of Dual-Scale Hierarchical Microstructures on Medical Metal Surface.

The structural characteristics at the interface of bone implants can guide biological regulation. In this study, a dual-scale hierarchical microstructure is proposed and customized using hybrid machining to achieve temporal dependency osteogenic regulation. It is observed that osteoblasts induced by dual-scale hierarchical structure exhibit adequate protrusion development and rapid cell attachment through the modulation of mechanical forces in the cell growth environment, and further promot the upregulation of the cell membrane receptor PDGFR-α, which is related to cell proliferation. Afterward, transcriptomic analysis reveals that during the differentiation stage, the DSH structure regulates cellular signaling cascades primarily through integrin adhesion mechanisms and then accelerates osteogenic differentiation by activating the TGF-ß pathway and cAMP signaling pathway. Furthermore, the calcium nodules are preferentially deposited within the lower honeycomb-like channels, thereby endowing the proposed dual-scale hierarchical structure with the potential to induce oriented deposition and improve the long-term stability of the implant.

Patterned Gold Nanoparticle Superlattice Film for Wearable Sweat Sensors.

Nanoparticle superlattices are beneficial in terms of providing strong and uniform signals in analysis owing to their closely packed uniform structures. However, nanoparticle superlattices are prone to cracking during physical activities because of stress concentrations, which hinders their detection performance and limits their analytical applications. In this work, template printing methods were used in this study to prepare a patterned gold nanoparticle (AuNP) superlattice film. By adjustment of the size of the AuNP superlattice domain below the critical size of fracture, the mechanical stability of the AuNP superlattice domain is improved. Thus, long-term sustainable high-performance signal output is achieved. The patterned AuNP superlattice film was used to construct a wearable sweat sensor based on surface-enhanced Raman scattering (SERS). The designed sensor showed promise for long-term reliable use in actual scenarios in terms of recommending water replenishment, monitoring hydration states, and tracking the intensity of activity.

Calmodulin Triggers Activity-Dependent rRNA Biogenesis via Interaction with DDX21.

Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and memory formation. However, the signaling cascades that couple neuronal activity to the translational events remain elusive. In this study, we identified the role of calmodulin (CaM), a conserved Ca2+-binding protein, in ribosomal RNA (rRNA) biogenesis in neurons. We found the CaM-regulated rRNA synthesis is Ca2+-dependent and necessary for nascent protein synthesis and axon growth in hippocampal neurons. Mechanistically, CaM interacts with nucleolar DEAD (Asp-Glu-Ala-Asp) box RNA helicase (DDX21) in a Ca2+-dependent manner to regulate nascent rRNA transcription within nucleoli. We further found CaM alters the conformation of DDX21 to liberate the DDX21-sequestered RPA194, the catalytic subunit of RNA polymerase I, to facilitate transcription of ribosomal DNA. Using high-throughput screening, we identified the small molecules batefenterol and indacaterol that attenuate the CaM-DDX21 interaction and suppress nascent rRNA synthesis and axon growth in hippocampal neurons. These results unveiled the previously unrecognized role of CaM as a messenger to link the activity-induced Ca2+ influx to the nucleolar events essential for protein synthesis. We thus identified the ability of CaM to transmit information to the nucleoli of neurons in response to stimulation.

Comprehensive multiomics analysis of the signatures of gastric mucosal bacteria and plasma metabolites across different stomach microhabitats in the development of gastric cancer.

PURPOSE: As an important component of the microenvironment, the gastric microbiota and its metabolites are associated with tumour occurrence, progression, and metastasis. However, the relationship between the gastric microbiota and the development of gastric cancer is unclear. The present study investigated the role of the gastric mucosa microbiome and metabolites as aetiological factors in gastric carcinogenesis. METHODS: Gastric biopsies from different stomach microhabitats (n = 70) were subjected to 16S rRNA gene sequencing, and blood samples (n = 95) were subjected to untargeted metabolome (gas chromatography‒mass spectrometry, GC‒MS) analyses. The datasets were analysed using various bioinformatics approaches. RESULTS: The microbiota diversity and community composition markedly changed during gastric carcinogenesis. High Helicobacter. pylori colonization modified the overall diversity and composition of the microbiota associated with gastritis and cancer in the stomach. Most importantly, analysis of the functional features of the microbiota revealed that nitrate reductase genes were significantly enriched in the tumoral microbiota, while urease-producing genes were significantly enriched in the microbiota of H. pylori-positive patients. A panel of 81 metabolites was constructed to discriminate gastric cancer patients from gastritis patients, and a panel of 15 metabolites was constructed to discriminate H. pylori-positive patients from H. pylori-negative patients. receiver operator characteristic (ROC) curve analysis identified a series of gastric microbes and plasma metabolites as potential biomarkers of gastric cancer. CONCLUSION: The present study identified a series of signatures that may play important roles in gastric carcinogenesis and have the potential to be used as biomarkers for diagnosis and for the surveillance of gastric cancer patients with minimal invasiveness.

Lignin-based Carbon Nanomaterials for Biochemical Sensing Applications.

Lignin-based carbon nanomaterials offer several advantages, including biodegradability, biocompatibility, high specific surface area, ease of functionalization, low toxicity, and cost-effectiveness. These materials show promise in biochemical sensing applications, particularly in the detection of metal ions, organic compounds, and human biosignals. Various methods can be employed to synthesize carbon nanomaterials with different dimensions ranging from 0D to 3D, resulting in diverse structures and physicochemical properties. This study provides an overview of the preparation techniques and characteristics of multidimensional (0-3D) lignin-based carbon nanomaterials, such as carbon dots (CDs), carbon nanotubes (CNTs), graphene, and carbon aerogels (CAs). Additionally, the sensing capabilities of these materials are compared and summarized, followed by a discussion on the potential challenges and future prospects in sensor development.

Retrospective analysis of the clinical utility of multi-cytokine profiles in smear-negative pulmonary tuberculosis.

OBJECTIVES: To evaluate cytokine profiles and interferon-gamma release assay (IGRA) for their diagnostic capabilities in the differentiation of tuberculosis (TB) from non-TB conditions, as well as smear-negative pulmonary tuberculosis (SNPT) from smear-positive pulmonary tuberculosis (SPPT). METHODS: A total of 125 participants were included, 77 of whom had TB and 48 who didn't, and demographic, clinical, and laboratory data were collected, including cytokine levels and IGRA results. The TB patients were further divided into 2 subgroups: SNPT (n=42) and SPPT (n=35). RESULTS: Compared to non-TB, the TB group had lower BMI, higher WBC, neutrophils, monocytes, ESR and CRP (p<0.05). TB patients showed higher IL-2, IL-6, IFN-γ, IL-8 (p<0.001) and higher IGRA positivity (88.3% versus [vs.] 29.2%, p<0.001). Between SNPT and SPPT, moderate effect sizes were observed for IFN-α, IL-2, IL-10, IL-8 (Cohen's d 0.59-0.76), with lower IGRA positivity in SNPT (81.0% vs. 97.1%, p=0.015). ROC analysis indicated IFN-α, IL-2, IL-10, IL-8 had moderate accuracy for SNPT diagnosis (AUCs 0.668-0.734), and combining these improved accuracy (AUC 0.759, 80% sensitivity, 64.2% specificity). CONCLUSION: A multi-biomarker approach combining these cytokines demonstrates enhanced diagnostic accuracy for tuberculosis.

Federated Learning-Oriented Edge Computing Framework for the IIoT.

With the maturity of artificial intelligence (AI) technology, applications of AI in edge computing will greatly promote the development of industrial technology. However, the existing studies on the edge computing framework for the Industrial Internet of Things (IIoT) still face several challenges, such as deep hardware and software coupling, diverse protocols, difficult deployment of AI models, insufficient computing capabilities of edge devices, and sensitivity to delay and energy consumption. To solve the above problems, this paper proposes a software-defined AI-oriented three-layer IIoT edge computing framework and presents the design and implementation of an AI-oriented edge computing system, aiming to support device access, enable the acceptance and deployment of AI models from the cloud, and allow the whole process from data acquisition to model training to be completed at the edge. In addition, this paper proposes a time series-based method for device selection and computation offloading in the federated learning process, which selectively offloads the tasks of inefficient nodes to the edge computing center to reduce the training delay and energy consumption. Finally, experiments carried out to verify the feasibility and effectiveness of the proposed method are reported. The model training time with the proposed method is generally 30% to 50% less than that with the random device selection method, and the training energy consumption under the proposed method is generally 35% to 55% less.

Machine-learning and scRNA-Seq-based diagnostic and prognostic models illustrating survival and therapy response of lung adenocarcinoma.

Lung cancer is a major cause accounting for cancer-related mortalities, with lung adenocarcinoma (LUAD) being the most prevalent subtype. Given the high clinical and cellular heterogeneities of LUAD, accurate diagnosis and prognosis are crucial to avoid overdiagnosis and overtreatment. Taking full advantage of scRNA-Seq data to resolve the tumor heterogeneities, we explored the overall landscape of LUAD microenvironment. Utilizing the stage-specific tumor cell markers, we have developed highly accurate diagnostic and prognostic models with elevated sensitivity and specificity. The diagnostic model, developed through random forest algorithms with a thirteen-gene signature, achieved an accuracy of 96.4% and an AUC of 0.993. These metrics were further demonstrated by benchmarking with available models and scoring systems in independent cohorts. Concurrently, the prognostic model, formulated via Cox regression with a six-gene signature, effectively predicted overall survival, with elevated risk scores associated with increased fractions of cancer-associated fibroblasts, and higher likelihood of immune escape and T-cell exclusion. Subsequently, two nomograms were developed to predict survival and drug responses, facilitating their integration into clinical practice. Overall, this study underscores the potential of our models for efficient, rapid, and cost-effective diagnosis and prognosis of LUAD, adaptable to multiple expression profiling platforms and quantification methods.

Contribution of oxygen vacancies to phase transition and ferroelectricity of Al:HfO2films.

We investigate the effects of oxygen vacancies on the ferroelectric behavior of Al:HfO2films annealed in O2and N2atmosphere. X-ray photoelectron spectroscopy results showed that the O/Hf atomic ratio was 1.88 for N2-annealed samples and 1.96 for O2-annealed samples, implying a neutralization of oxygen vacancies during O2atmosphere annealing. The O2-annealed films exhibited an increasing remanent polarization from 23µC cm-2to 28µC cm-2after 104cycles, with a negligible leakage current density of ∼2µA cm-2, while the remanent polarization decreased from 29µC cm-2to 20µC cm-2after cycling in the N2-annealed films, with its severe leakage current density decreasing from ∼1200µA cm-2to ∼300µA cm-2.A phase transition from the metastable tetragonal (t) phase to the low-temperature stable orthorhombic (o) phase and monoclinic (m) phase was observed during annealing. As a result of the fierce· competition between the t-to-o transition and the t-to-m transition, clear grain boundaries of several ruleless atomic layers were formed in the N2-annealed samples. On the other hand, the transition from the t-phase to the low-temperature stable phase was found to be hindered by the neutralization of oxygen vacancies, with almost continuous grain boundaries observed. The results elucidate the phase transformation caused by oxygen vacancies in the Al:HfO2films, which may be helpful for the preparation of HfO2-based films with excellent ferroelectricity.

Monocytes release cystatin F dimer to associate with Aß and aggravate amyloid pathology and cognitive deficits in Alzheimer's disease.

BACKGROUND: Understanding the molecular mechanisms of Alzheimer's disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aß) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aß clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aß by monocytes in AD remains unclear. METHODS: Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aß by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aß. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology. RESULTS: Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aß deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aß by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aß to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aß. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice. CONCLUSIONS: Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aß metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.

Analysis of road traffic accidents and casualties associated with electric bikes and bicycles in Guangzhou, China: A retrospective descriptive analysis.

Introduction: Electric bicycles (e-bikes) and bicycles in large Chinese cities have recently witnessed substantial growth in ridership. According to related accident trends, this study analyzed characteristics and spatial distribution in the period when e-bike-related accidents rapidly increased to propose priority measures to reduce accident casualties. Methods: For e-bike- and bicycle-related accident data from the Guangzhou Public Security Traffic Management Integrated System, linear regression was used to examine the trends in the number of accidents and age-adjusted road traffic casualties from 2011 to 2021. Then, for the period when e-bike-related accidents rapidly increased, descriptive statistics were computed regarding rider characteristics, illegal behaviors, road types, collision objects and their accident liability. One-way analysis of variance (ANOVA) followed by Bonferroni's multiple comparison test. P < 0.05 was considered statistically significant. Finally, the density distribution of accidents was presented, and Moran's I (MI) was used for assessing spatial autocorrelation. Hotspots were identified based on an optimized hotspot analysis tool. Results: Between 2011 and 2021, the number of accidents and casualty rate (per 100,000 population) increased for e-bikes but decreased for bicycles. After 2018, e-bike-related accidents increased rapidly, and bicycle-related accidents plateaued. Accident hotspots were concentrated in central city areas and suburban areas close to the former. Three-quarters of accidents occurred in motorized vehicle lanes. Most occurred on roads without physically segregated nonmotorized vehicle lanes. More than three-fifths of the accidents involved motor vehicles with at least four wheels. The prevalence (per 100 people) of casualties among e-bike rider victims and cyclist victims accounted for 92.0 % and 96.5 %, respectively. A total of 71.6 % of e-bike-related accidents involved migrant workers. Riding in motorized vehicle lanes was the most common illegal behavior. Conclusions: Although e-bike-related and bicycle-related accidents presented similar characteristics, the sharp increase in e-bike-related accidents requires attention. To improve e-bike safety, governments should develop appropriate countermeasures to prevent riders from riding on motorways, such as improving road infrastructure, adjusting the driver's license system and addressing priority control areas.

A novel PLS-DYW type PPR protein OsASL is essential for chloroplast development in rice.

Oryza longistaminata (OL), an AA-genome African wild rice which can propagate clonally via rhizome, is an important germplasm for improvement of Asian cultivated rice, however recessive lethal alleles can hitchhike clonal propagation in heterozygous state. Selfing of OL is difficult due to its self-incompatibility, but simple selfing of hybrid progeny between OL and O. sativa is effective to disclose and eliminate recessive lethal alleles. Here, we identified an exhibited albino-lethal phenotype mutant, from an F2 population between OL and O. sativa, named it albino seedling-lethal (asl). The leaves of asl mutant showed abnormal chloroplast development. The albino characteristics of asl were determined to be governed by a set of recessive nuclear genes through genetic analysis. Map-based cloning experiments found that a single nucleotide variation (G to A) was detected in the exon of OsASL in OL, which causes a premature stop codon. OsASL encodes a PLS-type PPR protein with 12 pentratricopeptide repeat domains, and is translocalized to chloroplasts. Complementation and knockout transgenic experiments further confirmed that OsASL is responsible for the albino-lethal phenotype. Loss-of-function OsASL (i.e. osasl) resulted in devoid of intron splicing of chloroplast RNA atpF, ndhA, rpl2 and rps12, and also RNA editing of ndhB, but facilitates the RNA editing of rpl2 in the plastid. Transcriptome sequencing showed that OsASL was mainly involved in chlorophyll synthesis pathway. The expression of Chlorophyll-associated genes were significantly decreased in asl plants, especially PEP (plastid-encoded RNA polymerase)-mediated genes. Our results suggest that OsASL is crucial for RNA editing, RNA splicing of chloroplast RNA group II genes, and plays an essential role in chloroplast development during early leaf development in rice.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.

Direct investigations of interactions between nucleolins and aptamers on pancreatic cancer and normal cells by atomic force microscopy.

Nucleolin is overexpressed on the surface of pancreatic cancer cells and are regarded as the remarkable therapeutic target. Aptamers are capable of binding the external domain of nucleolin on the cell surface with high affinity and specificity. But nucleolin has not been localized on pancreatic cancer cells at very high spatial resolution, and the interactions between nucleolin and aptamers have not been investigated at very high force resolution level. In this work, nucleolin was localized on pancreatic cancer and normal cells by aptamers (9FU-AS1411-NH2, AS1411-NH2 and CRONH2) in Single Molecule Recognition Imaging mode of Atomic Force Microscopy. There are plenty of nucleolin on the surfaces of pancreatic cancer cells (area percentage about 5 %), while there are little nucleolin on the surfaces of normal cells. The interactions between three types of aptamers and nucleolins on the surfaces of pancreatic cancer cells were investigated by Single Molecule Force Spectroscopy. The unbinding forces of nucleolins-(9FU-AS1411-NH2) are larger than nucleolins-(AS1411-NH2). The dissociation activation energy on nucleolin-(9FU-AS1411-NH2) is higher than nucleolin-(AS1411-NH2), which indicates that the former complex is more stable and harder to dissociate than the later complex. There are no unbinding forces between nucleolin and CRONH2. All these demonstrate that nucleolin was localized on pancreatic cancer and normal cells at single molecule level quantitatively, and the interactions (unbinding forces and kinetics) between nucleolin and aptamers were studied at picoNewton level. The approaches and results of this work will pave new ways in the investigations of nucleolin and aptamers, and will also be useful in the studies on other proteins and their corresponding aptamers.

Endothelial lincRNA-p21 alleviates cerebral ischemia/reperfusion injury by maintaining blood-brain barrier integrity.

Blood-brain barrier (BBB) disruption is increasingly recognized as an early contributor to the pathophysiology of cerebral ischemia/reperfusion (I/R) injury, and is also a key event in triggering secondary damage to the central nervous system. Recently, long non-coding RNA (lncRNA) have been found to be associated with ischemic stroke. However, the roles of lncRNA in BBB homeostasis remain largely unknown. Here, we report that long intergenic non-coding RNA-p21 (lincRNA-p21) was the most significantly down-regulated lncRNA in human brain microvascular endothelial cells (HBMECs) after oxygen and glucose deprivation/reoxygenation (OGD/R) treatment among candidate lncRNA, which were both sensitive to hypoxia and involved in atherosclerosis. Exogenous brain-endothelium-specific overexpression of lincRNA-p21 could alleviate BBB disruption, diminish infarction volume and attenuate motor function deficits in middle cerebral artery occlusion/reperfusion (MCAO/R) mice. Further results showed that lincRNA-p21 was critical to maintain BBB integrity by inhibiting the degradation of junction proteins under MCAO/R and OGD/R conditions. Specifically, lincRNA-p21 could inhibit autophagy-dependent degradation of occludin by activating PI3K/AKT/mTOR signaling pathway. Besides, lincRNA-p21 could inhibit VE-cadherin degradation by binding with miR-101-3p. Together, we identify that lincRNA-p21 is critical for BBB integrity maintenance, and endothelial lincRNA-p21 overexpression could alleviate cerebral I/R injury in mice, pointing to a potential strategy to treat cerebral I/R injury.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.

[Clinical analysis of transcranial facial nerve bridging with interpositional graft for the treatment of facial nerve injury].

Objective:To retrospectively analyze the effectiveness of transcranial facial nerve bridging in the treatment of facial nerve dysfunction. Methods:A retrospective analysis was conducted on 27 patients with facial nerve dysfunction who underwent transcranial facial nerve bridging at the Eye, Ear, Nose, and Throat Hospital affiliated with Fudan University from 2017 to 2022. The main collected data includes the patient's age, gender, primary lesion, damaged location, interval from facial paralysis to surgery, and preoperative and postoperative House-Brackmann（HB） scale for facial nerve function. Statistical comparisons were made between the average HB level of patients before and after surgery. Results:A total of 27 patients included 17 males and 10 females. The average age of patients during surgery is（42.50±3.38） years old. Primary lateral skull base diseases include trauma（n=3）, tumors（n=22）, and infections（n=2）. The duration of facial paralysis varies from 6 months to 5 years. Statistics analysis has found that the average postoperative HB score of patients who underwent transcranial facial nerve bridging was significantly lower at（3.750 ± 0.183） compared to preoperative（4.875±0.168）. The proportion of patients with good facial nerve function increased significantly from 7.4% before surgery to 42.9% after surgery. Conclusion:Transcranial facial nerve bridging surgery with interpositional graft has a significant effect on improving facial nerve function in patients with facial nerve injury. Further research is still needed to evaluate the long-term effectiveness of this surgery, to determine the optimal patient selection criteria and postoperative rehabilitation strategies.