Screening of candidate lncRNAs and biologic characterization of LINC00887

Background The diagnosis of hepatocellular carcinoma (HCC) often experiences latency, ultimately leading to unfavorable patient outcomes due to delayed therapeutic interventions. Our study is designed to develop and validate a model that employs triple-phase computerized tomography (CT)-based deep learning radiomics and clinical variables for early warning of HCC in patients with cirrhosis. Methods We studied 1858 patients with cirrhosis primarily from the PreCar cohort (NCT03588442) between June 2018 and January 2020 at 11 centres, and collected triple-phase CT images and laboratory results 3-12 months prior to HCC diagnosis or non-HCC final follow-up. Using radiomics and deep learning techniques, early warning model was developed in the discovery cohort (n = 924), and then validated in an internal validation cohort (n = 231), and an external validation cohort from 10 external centres (n = 703). Findings We developed a hybrid model, named ALARM model, which integrates deep learning radiomics with clinical variables, enabling early warning of the majority of HCC cases. The ALARM model effectively predicted short-term HCC development in cirrhotic patients with area under the curve (AUC) of 0.929 (95% confidence interval 0.918-0.941) in the discovery cohort, 0.902 (0.818-0.987) in the internal validation cohort, and 0.918 (0.898-0.961) in the external validation cohort. By applying optimal thresholds of 0.21 and 0.65, the high-risk (n = 221, 11.9%) and medium-risk (n = 433, 23.3%) groups, which covered 94.4% (84/89) of the patients who developed HCC, had significantly higher rates of HCC occurrence compared to the low-risk group (n = 1204, 64.8%) (24.3% vs 6.4% vs 0.42%, P < 0.001). Furthermore, ALARM also demonstrated consistent performance in subgroup analysis.Interpretation The novel ALARM model, based on deep learning radiomics with clinical variables, provides reliable estimates of short-term HCC development for cirrhotic patients, and may have the potential to improve the precision in clinical decision-making and early initiation of HCC treatments. Funding This work was supported by National Key Research and Development Program of China (2022YFC2303600, 2022YFC2304800), and the National Natural Science Foundation of China (82170610), Guangdong Basic and Applied Basic Research Foundation (2023A1515011211). Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

5-Hydroxymethylfurfural (HMF) is a pivotal multifunctional platform compound. The transformation of glucose to HMF generally follows tandem catalysis including the isomerization of glucose to fructose and the dehydration of fructose...

Abstract Here we proposed DeepImmu, a complete pipeline for neoantigen identification and validation that was based solely on mass spectrometry (MS) immunopeptidomics. In particular, a new enrichment kit was developed for HLA peptide purification from a small amount of biopsied tissue as low as 18mg. To identify candidate neoantigens from such a small amount of sample, we built DeepNovo Peptidome, a highly sensitive de novo sequencing-based workflow for HLA peptide identification. Furthermore, we developed DeepSelf, a personalized model for immunogenicity prediction based on the central tolerance of T cells, which could be used to prioritize candidate neoantigens from de novo HLA peptides for in vitro validation. Finally, we presented a new MS-based immunopeptidomics study of native tumor tissues from five patients with cervical cancer. We applied DeepImmu pipeline to identify and prioritize candidate neoantigens from low amounts of tumor tissues, and then performed in vitro validation of autologous neoantigen-specific T cell responses to confirm our results. Our MS-based de novo sequencing approach provides an unbiased solution for neoantigen discovery, because it does not depend on prior knowledge of protein databases, RNA sequencing data, or the source of neoantigens. By reducing the amount of sample to biopsy size, our DeepImmu pipeline can be easily performed in routine clinical applications.

The tumor-associated macrophages (TAMs) in intratumoral hypoxic regions are key drivers of immune escape. Reprogramming the hypoxic TAMs to antitumor phenotype holds great therapeutic benefits but remains challenging for current drugs. Here, an in situ activated nanoglycocluster is reported to realize effective tumor penetration and potent repolarization of hypoxic TAMs. Triggered by the hypoxia-upregulated matrix metalloproteinase-2 (MMP-2), the nanoglycocluster is self-assembled from the administered mannose-containing precursor glycopeptides and presents densely-arrayed mannoses to multivalently engage with mannose receptors on M2-like TAMs for efficient phenotype switch. By virtue of the high diffusivity of precursor glycopeptides due to their low molecular mass and weak affinity with TAMs in perivascular regions, the nanoglycoclusters are capable of substantially accumulating in hypoxic areas to strongly interact with local TAMs. This enables the efficient repolarization of overall TAMs with a higher rate than the small-molecule drug R848 and CD40 antibody, and beneficial therapeutic effects in mouse tumor models especially when combining with PD-1 antibody. This on-demand activated immunoagent is endowed with tumor-penetrating properties and inspires the design of diverse intelligent nanomedicines for hypoxia-related cancer immunotherapy.

The discovery of aggregation-induced emission (AIE) effect provides opportunities for the rapid development of fluorescence imaging-guided photodynamic therapy (PDT). In this work, a boron dipyrromethene (BODIPY)-based photosensitizer (ET-BDP-O) with AIE characteristics was developed, in which the two linear arms of BODIPY group were linked with triphenylamine to form an electron Donor–Acceptor–Donor (D–A–D) architecture while side chain was equipped with triethylene glycol group. ET-BDP-O was able to directly self-assemble into nanoparticles (NPs) without supplement of any other matrices or stabilizers due to its amphiphilic property. The as-prepared ET-BDP-O NPs had an excellent colloid stability with the size of 125 nm. Benefiting from the AIE property, ET-BDP-O NPs could generate strong fluorescence and reactive oxygen species under light-emitting diode light irradiation (60[Formula: see text]mW/cm[Formula: see text]. After internalized in cancer cells, ET-BDP-O NPs were able to emit bright red fluorescence signal for bioimaging. In addition, the cell viability assay demonstrated that the ET-BDP-O NPs exhibited excellent photo-cytotoxicity against cancer cells, while negligible cytotoxicity under dark environment. Thus, ET-BDP-O NPs might be regarded as a promising photosensitizer for fluorescence imaging-guided PDT in future.

e15074 Background: CDK4/6 kinases associate with cyclin D proteins during transition from G1 to S phase of the cell cycle. Amplification of CDK4/6 may elicit the activity of cyclin D, which hyperphosphorylates RB, ultimately leading to uncontrolled cell proliferation. Currently, three CDK4/6 inhibitors are used in breast cancer, ovarian cancer and sarcoma. Herein, we investigate the prevalence of CDK4/6 amplification in Chinese and Western cancer patients, hope to find more cancer subtypes with CDK4/6 amplification. Methods: Next-generation sequencing data and clinical data were collected from 10828 TCGA pan-cancer patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 4181 Chinese pan-cancer patients (Chinese cohort). CDK4 and CDK6 amplification were calculated on the two cohorts following the same criteria. Results: In total, 182 (4.4%) of the 4181 Chinese patients and 529 (4.9%) of the 10828 Western patients had CDK4 amplification, 133 (3.2%) of the 4181 Chinese patients and 475 (4.4%) of the 10828 Western patients had CDK6 amplification. In Western cohort, the top 5 CDK4 amplification-associated cancer types were sarcoma, glioblastoma multiforme, lung adenocarcinoma, ovarian carcinoma, and adrenocortical carcinoma, and the top 5 CDK6 amplification-associated cancer types were esophageal carcinoma, ovarian carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, sarcoma. In Chinese cohort, the top 5 CDK4 amplification-associated cancer types were lung adenocarcinoma, melanoma, sarcoma, stomach carcinoma, liver cancer, and the top 5 CDK6 amplification-associated cancer types were lung adenocarcinoma, stomach carcinoma, liver cancer, melanoma, glioma. In addition, CDK4 amplification in Chinese cohort, 22 (11%) of the 203 Chinese bone and soft tissue sarcoma patients had CDK4 amplification, and 4 (2%) of the 203 had CDK6 amplification. Bone and soft tissue sarcoma types with CDK4 / 6 amplification including soft tissue sarcoma, bone cancer, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, liposarcoma, synovial sarcoma. Conclusions: Our study provided a characteristic of CDK4/6 amplification in Chinese and Western pan-cancer patients. Analysis revealed frequent CDK4 / 6 amplification in lung cancer, sarcoma, stomach carcinoma, ovarian carcinoma and liver cancer. It is suggested patient with these cancer types may potentially benefit from CDK4/6 inhibitor.

The matrix plays a prominent role in expanding the ability of matrix assisted laser desorption/ionization mass spectrometry (MALDI MS). However, on account of the unclarity of necessary properties of the matrix in MALDI MS, development of a new matrix is still in the exploratory stage and lacks systematic theoretical guidance. Meanwhile, most of the existing matrices are unable to simultaneously detect various high-molecular-weight (high-MW) lipids including (poly-)phosphoinositides, cardiolipins, and gangliosides. In this study, we have successfully screened and optimized the application of commercially available IR-780 as a novel matrix for simultaneously profiling and imaging high-MW lipids in brain tissues by MALDI MS for the first time. The properties of IR-780 related to the matrix of MALDI MS, mainly including the optical properties (UV absorption, fluorescence emission, and photothermal efficiency), proton affinity, collision cross-sections (CCSs), salt-tolerance ability, and homogeneity, were comprehensively characterized, which demonstrated that high photothermal ability and large CCSs might guarantee the superior performance of IR-780 as matrix for the analysis of high-MW lipids in biological samples. This work provided some references for the development of a novel matrix, and especially, the concept of CCS was first introduced as a parameter for the development of a matrix. In addition, the simultaneous identification and imaging of endogenous high-MW lipids in rat brain tissues subjected to traumatic brain injury were successfully performed.

Chemotherapy has been widely used for treatment to malignant cancer, such as hepatocellular carcinoma (HCC). Chemotherapeutic effect was not often efficient to achieve totally tumor ablation due to the poor cellular uptake and drug resistance. To address these problems, a novel nanoplatform was constructed based on nontoxic mesoporous silica nanoparticles (MSNs) for a combined chemo/photothermal therapy to enhance tumor cell accumulation and promote toxicity of chemotherapeutic drugs. Prepared MSNs were consisted of Au nanoshell for photothermal conversion and a first-line anti-HCC drug-sorafenib (SO) for chemotherapy. The SO-Au-MSNs could help SO accumulate more in hepatic cancer cells. Under near infrared irradiation, SO-Au-MSNs exerted a high cell inhibition rate which could be attributed to the enhanced toxicity of SO under hyperthermia and synergistic chemo/photothermal therapy. SO-Au-MSNs showed a good compatibility as well as efficient cell cytotoxicity. Overall, SO-Au-MSNs would be a promising candidate for further enhancing the antitumor effect on HCC.

Fanconi syndrome is a rare disease characterized by dysfunction of the proximal renal tubules as a result of various pathogenic events. Drug-induced Fanconi syndrome may be neglected or misdiagnosed, which increases the level of suffering. The aim of the present study was to conduct an investigation into the effects of adefovir (ADV)-induced Fanconi syndrome. Four typical cases of Fanconi syndrome caused by long-term ADV therapy (2-9 years) were diagnosed at our hospital. A complete medical and therapy history was collected from all four patients prior to a physical examination. Laboratory and diagnostic examinations were also conducted. Following this, the patients were diagnosed and a treatment regimen was decided upon. Outcomes of the treatment regimen were observed. Common manifestations of all the four patients were: Renal tubular reabsorption dysfunction; imbalanced electrolyte acid-base ratio; elevated cystatin C levels; severe hypophosphatemia and diffused systemic pain; osteoporosis; and difficultly walking. When ADV was replaced with supportive treatment, all the four patients exhibited symptom relief. These findings indicate that long-term ADV therapy may induce Fanconi syndrome. For patients with a history of such therapy, the possibility of Fanconi syndrome should be assessed and monitored closely for indicators, including altered glomerular and renal tubular function. Once diagnosed, the agent should be immediately discontinued and prompt symptomatic treatment should be administered.

Hydroxyapatite nanoparticles (HAPs) are increasingly utilized in biomedical fields including dental composites, bone tissue engineering and orthopedic implants due to its similar properties to bone minerals. With their widespread use, toxicological effects of HAPs have aroused people's close attention. However, the potential toxic effects of HAPs on bone cells are poorly understood. In our present work, the HAPs with aspect ratios of 4 were synthesized by a hydrothermal method and characterized by transmission electron microscopy (TEM), X-ray diffractometry (XRD), dynamic light scattering (DLS) and photoluminescence (PL). The cytotoxicity of HAPs on MC3T3-E1 cells and the relevant mechanisms were further studied. The results proved that HAPs could be uptaken into MC3T3-E1 cells via macropinocytosis-mediated endocytosis pathway, and mainly localized in lysosome. HAPs inhibited the cells proliferation in doseand time-dependent manners. Results from annexin V-FITC/PI apoptosis assay showed that HAPs induced cell apoptosis significantly, and the mechanism of apoptosis was related to oxidative stress. HAPs induced ROS generation and antioxidant enzymes superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) decrease, which not only induced a lysosome-dependent damage pathway via lysosomal membrane permeabilization (LMP) and increased the release of cathepsins B, but also a mitochondria-dependent damage pathway via counter regulating expressions of bax and bcl-2, decrease of mitochondrial membrane potential (MMP), activation of caspase3. In addition, the ROS also caused DNA damage. In summary, HAPs induces apoptosis through oxidative stressinduced lysosomal and mitochondrial pathways. Our study will provide some valuable data for biomedical applications of HAPs in the future.

Hydroxyapatite nanoparticles (HAPs) cause apoptosis of osteoblastic MC3T3-E1 cells through oxidative stress-induced lysosomal and mitochondrial pathway.

Mesoporous silica materials have attracted much attention for their potential biomedical applications due to their tailored mesoporous structure, large surface area, good biocompatibility, and the ease of surface functionalization. In the past few years, the mesoporous silica based drug nanocarriers have become the research focus of many researchers. This article reviews the recent research advances of mesoporous silica based multifunctional drug delivery systems with targeting modification and bioimaging, and details the design, surface modification, and applications in drug delivery field of mesoporous silica based drug delivery systems with diverse morphologies (such as hollow/rattle-type, nanotubes, etc.). Finally, we analyze the existing problems in practical applications and outlook the future development trends of mesoporous silica based drug delivery systems (including the specific morphological, multifunctional hybrid, and biodegradable mesoporous silica drug delivery systems).

Objective To evaluate the effects of stromal interaction molecular 1 (STIM1) on proliferation and apoptosis of prostate cancer PC-3 cells.Methods STIMI siRNA sequence was designed and constructed into plasmid pGCSIL-GFP vector.The sequence inserted was confirmed by sequence test and polymerase chain reaction (PCR).The efficiency of plasmid pGCSIL-GFP-STIM1 was confirmed by ectopic cotransfection test.Chromic virus STIM1-RNAi-LV was packed.After it was transfected into prostate cancer PC-3 cells,the proliferation,apoptosis and cell cycle of PC-3 cells were evaluated.Results The plasmid vector pGCSIL-GFP-STIMI was confirmed to be correct and effective by sequence examination,PCR and ectopic target test.After the Chromic virus STIM1-RNAi-LV was transfected into PC-3 cells,the proliferation ability in experimental group was apparently reduced as compared with that in control group.After transfection for 5 days,the apoptosis rate in experimental group was ( 29.85 ± 0.86 ) ％,and that in control group was (2.92 ± 0.14) ％ ( P ＜ 0.05 ).At the same time,the number of cells in the stage G1 and S was reduced and that in stage G2/M was increased in experimental group as compared with control group ( P ＜0.05).Conclusion When STIM1 gene was inhibited in prostate cancer PC-3 cells,the proliferation was reduced,the number of apoptotic was increased and the cell cycle statues were changed,indicating that STIM1 may have important role in proliferation and apoptosis of PC-3 cells. Key words: Prostate neoplasm; Stromal interaction molecular 1; Apoptosis

生物芯片技术以及其临床应用的快速发展,将驱动其研究平台的微型化,以达到更高的阵列排列密度、灵敏度和减少样品消耗;为了满足以上要求,阵列元素的尺寸必须由目前的微米尺度缩小到纳米尺度。蘸礁笔纳米平板印刷术（DPN,Dip-Pen Nanolithography）,采取类似于“书写”的方式,能够直接在合适的基板表面制作各种的纳米尺度的蛋白阵列。DPN技术具有操作简单、材料选择灵活、分辨率高、能够精确控制被阵列分子的位置等优点,是在纳米尺度上制作生物分子的阵列首选。本文介绍了蘸礁笔纳米平板印刷术在蛋白质芯片中的应用。