Redox metabolism maintains the leukemogenic capacity and drug resistance of AML cells.

Rewiring of redox metabolism has a profound impact on tumor development, but how the cellular heterogeneity of redox balance affects leukemogenesis remains unknown. To precisely characterize the dynamic change in redox metabolism in vivo, we developed a bright genetically encoded biosensor for H2O2 (named HyPerion) and tracked the redox state of leukemic cells in situ in a transgenic sensor mouse. A H2O2-low (HyPerion-low) subset of acute myeloid leukemia (AML) cells was enriched with leukemia-initiating cells, which were endowed with high colony-forming ability, potent drug resistance, endosteal rather than vascular localization, and short survival. Significantly high expression of malic enzymes, including ME1/3, accounted for nicotinamide adenine dinucleotide phosphate (NADPH) production and the subsequent low abundance of H2O2. Deletion of malic enzymes decreased the population size of leukemia-initiating cells and impaired their leukemogenic capacity and drug resistance. In summary, by establishing an in vivo redox monitoring tool at single-cell resolution, this work reveals a critical role of redox metabolism in leukemogenesis and a potential therapeutic target.

PepPre: Promote Peptide Identification Using Accurate and Comprehensive Precursors.

Accurate and comprehensive peptide precursor ions are crucial to tandem mass-spectrometry-based peptide identification. An identification engine can derive great advantages from the search space reduction enabled by credible and detailed precursors. Furthermore, by considering multiple precursors per spectrum, both the number of identifications and the spectrum explainability can be substantially improved. Here, we introduce PepPre, which detects precursors by decomposing peaks into multiple isotope clusters using linear programming methods. The detected precursors are scored and ranked, and the high-scoring ones are used for subsequent peptide identification. PepPre is evaluated both on regular and cross-linked peptide data sets and compared with 11 methods. The experimental results show that PepPre achieves a remarkable increase of 203% in PSM and 68% in peptide identifications compared to instrument software for regular peptides and 99% in PSM and 27% in peptide pair identifications for cross-linked peptides, surpassing the performance of all other evaluated methods. In addition to the increased identification numbers, further credibility evaluations evidence the reliability of the identified results. Moreover, by widening the isolation window of data acquisition from 2 to 8 Th, with PepPre, an engine is able to identify at least 64% more PSMs, thereby demonstrating the potential advantages of wide-window data acquisition. PepPre is open-source and available at http://peppre.ctarn.io.

Single-Atom Iron Doped Carbon Dots with Highly Efficient Electrochemiluminescence for Ultrasensitive Detection of MicroRNAs.

Herein, single-atom iron doped carbon dots (SA Fe-CDs) were successfully prepared as novel electrochemiluminescence (ECL) emitters with high ECL efficiency, and a biosensor was constructed to ultrasensitively detect microRNA-222 (miRNA-222). Importantly, compared with the conventional without single-atom doped CDs with low ECL efficiency, SA Fe-CDs exhibited strong ECL efficiency, in which single-atom iron as an advanced coreactant accelerator could significantly enhance the generation of reactive oxygen species (ROS) from the coreactant S2O82- for improving the ECL efficiency. Moreover, a neoteric amplification strategy combining the improved strand displacement amplification with Nt.BbvCI enzyme-induced target amplification (ISDA-EITA) could produce 4 output DNAs in every cycle, which greatly improved the amplification efficiency. Thus, a useful ECL biosensor was built with a detection limit of 16.60 aM in the range of 100 aM to 1 nM for detecting traces of miRNA-222. In addition, miRNA-222 in cancer cell lysate (MHCC-97L) was successfully detected by using the ECL biosensor. Therefore, this strategy provides highly efficient single-atom doped ECL emitters for the construction of sensitive ECL biosensing platforms in the biological field and clinical diagnosis.

Renewable Electrochemiluminescence Biosensor Based on Eu-MOGs as a Highly Efficient Emitter and a DNAzyme-Mediated Dual-drive DNA Walker as a Signal Amplifier for Ultrasensitive Detection of miRNA-222.

Herein, novel europium metal-organic gels (Eu-MOGs) with excellent cathode electrochemiluminescence (ECL) emission are first used to construct biosensors for the ultrasensitive detection of miRNA-222. Impressively, N and O elements of organic ligand 2,2':6,2″-terpyridine 4,4',4″-tricarboxylic acid (H3-tctpy) can perfectly coordinate with Eu3+ to form Eu-MOGs, which not only reduce nonradiative transition caused by the intramolecular free rotation of phenyl rings in other MOGs to enhance the ECL signal with extraordinary ECL efficiency as high as 37.2% (vs the [Ru(bpy)3]2+/S2O82- ECL system) but also reinforce ligand-to-metal charge transfer (LMCT) by the strong affinity between Eu3+ and N and O elements to greatly improve the stability of ECL signals. Besides, an improved nucleic acid cascade amplification reaction is developed to greatly raise the conversion efficiency from target miRNA-222 to a DNAzyme-mediated dual-drive DNA walker as output DNA, which can simultaneously shear the specific recognition sites from two directions. In that way, the proposed biosensor can further enhance the detection sensitivity of miRNA-222 with a linear range of 10 aM-1 nM and a detection limit (LOD) of 8.5 aM, which can also achieve an accurate response in cancer cell lysates of MHCC-97L and HeLa. Additionally, the biosensor can be self-regenerated by the folding/unfolding of related triplets with pH changes to simplify experimental operations and reduce the cost. Hence, this work proposed novel MOGs with stable and intense ECL signals for the construction of a renewable ECL biosensor, supplying a reliable detection method in biomarker analysis and disease diagnosis.

Endothelial cell-derived angiopoietin-like protein 2 supports hematopoietic stem cell activities in bone marrow niches.

Bone marrow niche cells have been reported to fine-tune hematopoietic stem cell (HSC) stemness via direct interaction or secreted components. Nevertheless, how niche cells control HSC activities remains largely unknown. We previously showed that angiopoietin-like protein 2 (ANGPTL2) can support the ex vivo expansion of HSCs by binding to human leukocyte immunoglobulin-like receptor B2. However, how ANGPTL2 from specific niche cell types regulates HSC activities under physiological conditions is still not clear. Herein, we generated an Angptl2-flox/flox transgenic mouse line and conditionally deleted Angptl2 expression in several niche cells, including Cdh5+ or Tie2+ endothelial cells, Prx1+ mesenchymal stem cells, and Pf4+ megakaryocytes, to evaluate its role in the regulation of HSC fate. Interestingly, we demonstrated that only endothelial cell-derived ANGPTL2 and not ANGPTL2 from other niche cell types plays important roles in supporting repopulation capacity, quiescent status, and niche localization. Mechanistically, ANGPTL2 enhances peroxisome-proliferator-activated receptor D (PPARD) expression to transactivate G0s2 to sustain the perinuclear localization of nucleolin to prevent HSCs from entering the cell cycle. These findings reveal that endothelial cell-derived ANGPTL2 serves as a critical niche component to maintain HSC stemness, which may benefit the understanding of stem cell biology in bone marrow niches and the development of a unique strategy for the ex vivo expansion of HSCs.

An LPS-induced TNF-α factor involved in immune response of oyster Crassostrea gigas by regulating haemocytes apoptosis.

LPS induced TNF-α Factor (LITAF) is a transcription factor widely involving in activation of Tumor Necrosis Factor (TNF) and other cytokines in the inflammatory response. In the present study, a homologue of LITAF with a conserved LITAF domain was identified from the Pacific oyster Crassostrea gigas. The transcripts of CgLITAF were detected in all examined tissues with highest expression in hepatopancrease. The immunofluorescence assay and Western blot showed that LPS stimulation induced an obvious nucleus translocation of CgLITAF protein in haemocytes. While the mRNA level of CgLITAF changed slightly after LPS stimulation. When the siRNA of CgLITAF was injected to inhibit its expression, the apoptotic level of haemocytes decreased observably after LPS stimulation. Consistently, the transcripts of CgTNF3 and CgTNF4 (LOC105343080, LOC105341146), the apoptotic-related molecules including CgBax, CgCytochrome c, CgCaspase9 and CgCaspase3, were significantly suppressed in the CgLITAF-RNAi oysters. While the mRNA expression level of CgBcl was enhanced significantly in the CgLITAF-RNAi oysters. These results indicated that CgLITAF promoted haemocyte apoptosis by regulating the expression of apoptotic-related factors, suggesting its important role in the immune response of oysters.

Chronic nicotine exposure elicits pain hypersensitivity through activation of dopaminergic projections to anterior cingulate cortex.

BACKGROUND: Cigarette smoking is commonly reported among chronic pain patients in the clinic. Although chronic nicotine exposure is directly linked to nociceptive hypersensitivity in rodents, underlying neurobiological mechanisms remain unknown. METHODS: Multi-tetrode recordings in freely moving mice were used to test the activity of dopaminergic projections from the ventral tegmental area (VTA) to pyramidal neurones in the anterior cingulate cortex (ACC) in chronic nicotine-treated mice. The VTA→ACC dopaminergic pathway was inhibited by optogenetic manipulation to detect chronic nicotine-induced allodynia (pain attributable to a stimulus that does not normally provoke pain) assessed by von Frey monofilaments (force units in g). RESULTS: Allodynia developed concurrently with chronic (28-day) nicotine exposure in mice (0.36 g [0.0141] vs 0.05 g [0.0018], P<0.0001). Chronic nicotine activated dopaminergic projections from the VTA to pyramidal neurones in the ACC, and optogenetic inhibition of VTA dopaminergic terminals in the ACC alleviated chronic nicotine-induced allodynia in mice (0.06 g [0.0064] vs 0.28 g [0.0428], P<0.0001). Moreover, optogenetic inhibition of Drd2 dopamine receptor signalling in the ACC attenuated nicotine-induced allodynia (0.07 g [0.0082] vs 0.27 g [0.0211], P<0.0001). CONCLUSIONS: These findings implicate a role of Drd2-mediated dopaminergic VTA→ACC pathway signalling in chronic nicotine-elicited allodynia.

NADPHnet: a novel strategy to predict compounds for regulation of NADPH metabolism via network-based methods.

Identification of compounds to modulate NADPH metabolism is crucial for understanding complex diseases and developing effective therapies. However, the complex nature of NADPH metabolism poses challenges in achieving this goal. In this study, we proposed a novel strategy named NADPHnet to predict key proteins and drug-target interactions related to NADPH metabolism via network-based methods. Different from traditional approaches only focusing on one single protein, NADPHnet could screen compounds to modulate NADPH metabolism from a comprehensive view. Specifically, NADPHnet identified key proteins involved in regulation of NADPH metabolism using network-based methods, and characterized the impact of natural products on NADPH metabolism using a combined score, NADPH-Score. NADPHnet demonstrated a broader applicability domain and improved accuracy in the external validation set. This approach was further employed along with molecular docking to identify 27 compounds from a natural product library, 6 of which exhibited concentration-dependent changes of cellular NADPH level within 100 µM, with Oxyberberine showing promising effects even at 10 µM. Mechanistic and pathological analyses of Oxyberberine suggest potential novel mechanisms to affect diabetes and cancer. Overall, NADPHnet offers a promising method for prediction of NADPH metabolism modulation and advances drug discovery for complex diseases.

Fibrotic immune microenvironment remodeling mediates superior anti-tumor efficacy of a nano-PD-L1 trap in hepatocellular carcinoma.

The local microenvironment where tumors develop can shape cancer progression and therapeutic outcome. Emerging evidence demonstrate that the efficacy of immune-checkpoint blockade (ICB) is undermined by fibrotic tumor microenvironment (TME). The majority of hepatocellular carcinoma (HCC) develops in liver fibrosis, in which the stromal and immune components may form a barricade against immunotherapy. Here, we report that nanodelivery of a programmed death-ligand 1 (PD-L1) trap gene exerts superior efficacy in treating fibrosis-associated HCC when compared with the conventional monoclonal antibody (mAb). In two fibrosis-associated HCC models induced by carbon tetrachloride and a high-fat, high-carbohydrate diet, the PD-L1 trap induced significantly larger tumor regression than mAb with no evidence of toxicity. Mechanistic studies revealed that PD-L1 trap, but not mAb, consistently reduced the M2 macrophage proportion in the fibrotic liver microenvironment and promoted cytotoxic interferon gamma (IFNγ)+tumor necrosis factor α (TNF-α)+CD8+T cell infiltration to the tumor. Moreover, PD-L1 trap treatment was associated with decreased tumor-infiltrating polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) accumulation, resulting in an inflamed TME with a high cytotoxic CD8+T cell/PMN-MDSC ratio conductive to anti-tumor immune response. Single-cell RNA sequencing analysis of two clinical cohorts demonstrated preferential PD-L1 expression in M2 macrophages in the fibrotic liver, thus supporting the translational potential of nano-PD-L1 trap for fibrotic HCC treatment.

A W-Shaped Self-Supervised Computational Ghost Imaging Restoration Method for Occluded Targets.

We developed a novel method based on self-supervised learning to improve the ghost imaging of occluded objects. In particular, we introduced a W-shaped neural network to preprocess the input image and enhance the overall quality and efficiency of the reconstruction method. We verified the superiority of our W-shaped self-supervised computational ghost imaging (WSCGI) method through numerical simulations and experimental validations. Our results underscore the potential of self-supervised learning in advancing ghost imaging.

The iron burden of cerebral microbleeds contributes to brain atrophy through the mediating effect of white matter hyperintensity.

The goal of this work was to explore the total iron burden of cerebral microbleeds (CMBs) using a semi-automatic quantitative susceptibility mapping and to establish its effect on brain atrophy through the mediating effect of white matter hyperintensities (WMH). A total of 95 community-dwelling people were enrolled. Quantitative susceptibility mapping (QSM) combined with a dynamic programming algorithm (DPA) was used to measure the characteristics of 1309 CMBs. WMH were evaluated according to the Fazekas scale, and brain atrophy was assessed using a 2D linear measurement method. Histogram analysis was used to explore the distribution of CMBs susceptibility, volume, and total iron burden, while a correlation analysis was used to explore the relationship between volume and susceptibility. Stepwise regression analysis was used to analyze the risk factors for CMBs and their contribution to brain atrophy. Mediation analysis was used to explore the interrelationship between CMBs and brain atrophy. We found that the frequency distribution of susceptibility of the CMBs was Gaussian in nature with a mean of 201 ppb and a standard deviation of 84 ppb; however, the volume and total iron burden of CMBs were more Rician in nature. A weak but significant correlation between the susceptibility and volume of CMBs was found (r = -0.113, P < 0.001). The periventricular WMH (PVWMH) was a risk factor for the presence of CMBs (number: ß = 0.251, P = 0.014; volume: ß = 0.237, P = 0.042; total iron burden: ß = 0.238, P = 0.020) and was a risk factor for brain atrophy (third ventricle width: ß = 0.325, P = 0.001; Evans's index: ß = 0.323, P = 0.001). PVWMH had a significant mediating effect on the correlation between CMBs and brain atrophy. In conclusion, QSM along with the DPA can measure the total iron burden of CMBs. PVWMH might be a risk factor for CMBs and may mediate the effect of CMBs on brain atrophy.

AgAuS Quantum Dots as a Highly Efficient Near-Infrared Electrochemiluminescence Emitter for the Ultrasensitive Detection of MicroRNA.

Herein, the novel alloyed silver gold sulfur quantum dots (AgAuS QDs) with highly efficient near-infrared (NIR) electrochemiluminescence (ECL) emission at 707 nm were successfully prepared to construct a biosensing platform for ultrasensitive detection of microRNA-222 (miRNA-222). Interestingly, AgAuS QDs revealed excellent ECL efficiency (34.91%) compared to that of Ag2S QDs (10.30%), versus the standard [Ru(bpy)3]2+/S2O82- system, which benefited from the advantages of abundant surface defects and narrow bandgaps by Au incorporation. Additionally, an improved localized catalytic hairpin self-assembly (L-CHA) system was developed to display an increased reaction speed by improving the local concentration of DNA strands, which addressed the obstacles of time-consuming traditional CHA systems. As a proof of concept, based on AgAuS QDs as an ECL emitter and improved localized CHA systems as a signal amplification strategy, a "signal on-off" ECL biosensor was developed to exhibit a superior reaction rate and excellent sensitivity with a detection limit of 10.5 aM for the target miRNA-222, which was further employed for the analysis of miRNA-222 from cancer cell (MHCC-97L) lysate. This work advances the exploration of highly efficient NIR ECL emitters to construct an ultrasensitive biosensor for the detection of biomolecules in disease diagnosis and NIR biological imaging.

Zn2+-Induced Gold Cluster Aggregation Enhanced Electrochemiluminescence for Ultrasensitive Detection of MicroRNA-21.

Herein, Zn2+-induced gold cluster aggregation (Zn2+-GCA) as a high-efficiency electrochemiluminescence (ECL) emitter is first employed to construct an ECL biosensor to ultrasensitively detect microRNA-21 (miRNA-21). Impressively, Zn2+ not only can induce the aggregation of monodispersed gold clusters (Au NCs) to limit the ligand vibration of Au NCs for improving ECL emission but also can be utilized as a coreaction accelerator to catalyze the dissociation of coreactant S2O82- into sulfate radicals (SO4•-) to improve the interaction efficiency between Zn2+-GCA and S2O82-, resulting in further intense ECL emission. Compared to Au NCs stabilized by bovine serum albumin with ECL efficiency of 0.40%, Zn2+-GCA possessed high ECL efficiency of 10.54%, regarding the [Ru(bpy)3]2+/S2O82- system as a standard. Furthermore, output DNA modified with poly adenine (polyA) obtained from enzyme-free target recycling amplification can be efficiently immobilized on the surface of gold nanoparticles (Au NPs) to reduce the defect of special design, cumbersome operation, and low stability. Thus, an ultrasensitive ECL biosensor based on the Zn2+-GCA/S2O82- ECL system and enzyme-free target recycling amplification achieved ultrasensitive detection of miRNA-21 with the detection limit of 44.7 aM. This strategy presents a new idea to design highly efficient ECL emitters, which is expected to be used in the field of bioanalysis for clinical diagnosis.

Nitrogen-, Sulfur-, and Fluorine-Codoped Carbon Dots with Low Excitation Potential and High Electrochemiluminescence Efficiency for Sensitive Detection of Matrix Metalloproteinase-2.

In this study, nitrogen-, sulfur-, and fluorine-codoped carbon dots (NSF-CDs) with high electrochemiluminescence (ECL) efficiency were developed as novel emitters to fabricate an ECL biosensor for sensitive detection of matrix metalloproteinase 2 (MMP-2). Impressively, compared to previously reported CDs, NSF-CDs with narrow band gap not only decreased the excitation voltage to reduce the side reaction and the damage on biomolecules but also had hydrogen bonds to vastly enhance the ECL efficiency. Furthermore, an improved exonuclease III (Exo III)-assisted nucleic acid amplification method was established to convert trace MMP-2 into a mass of output DNA, which greatly improved the target conversion efficiency and ECL signal. Hence, the ECL biosensor has realized the sensitive detection of MMP-2 proteins from 10 fg/mL to 10 ng/mL with a limit of detection of 6.83 fg/mL and has been successfully applied in the detection of MMP-2 from Hela and MCF-7 cancer cells. This strategy offered neoteric CDs as ECL emitters for sensitive testing of biomarkers in medical research.

Microglia sustain anterior cingulate cortex neuronal hyperactivity in nicotine-induced pain.

BACKGROUND: Long-term smoking is a risk factor for chronic pain, and chronic nicotine exposure induces pain-like effects in rodents. The anterior cingulate cortex (ACC) has been demonstrated to be associated with pain and substance abuse. This study aims to investigate whether ACC microglia are altered in response to chronic nicotine exposure and their interaction with ACC neurons and subsequent nicotine-induced allodynia in mice. METHODS: We utilized a mouse model that was fed nicotine water for 28 days. Brain slices of the ACC were collected for morphological analysis to evaluate the impacts of chronic nicotine on microglia. In vivo calcium imaging and whole-cell patch clamp were used to record the excitability of ACC glutamatergic neurons. RESULTS: Compared to the vehicle control, the branch endpoints and the length of ACC microglial processes decreased in nicotine-treated mice, coinciding with the hyperactivity of glutamatergic neurons in the ACC. Inhibition of ACC glutamatergic neurons alleviated nicotine-induced allodynia and reduced microglial activation. On the other hand, reactive microglia sustain ACC neuronal excitability in response to chronic nicotine, and pharmacological inhibition of microglia by minocycline or liposome-clodronate reduces nicotine-induced allodynia. The neuron-microglia interaction in chronic nicotine-induced allodynia is mediated by increased expression of neuronal CX3CL1, which activates microglia by acting on CX3CR1 receptors on microglial cells. CONCLUSION: Together, these findings underlie a critical role of ACC microglia in the maintenance of ACC neuronal hyperactivity and resulting nociceptive hypersensitivity in chronic nicotine-treated mice.

Prognostic and predictive biomarkers for anti-EGFR monoclonal antibody therapy in RAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: RAS mutations affect prognosis in patients with metastatic colorectal cancer (mCRC) and have been identified as strong negative predictive markers for anti-epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb) therapy, but many tumors containing wild-type RAS genes still do not respond to these therapies. Some additional biomarkers may have prognostic or predictive roles, but conclusions remain controversial. METHODS: We performed a meta-analysis and systematic review of randomized controlled trials comparing anti-EGFR mAb therapy with alternative therapy that investigated the prognostic and predictive impact of additional biomarkers in RAS wild-type (wt) mCRC patients. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) for objective response rate (ORR) were calculated. The prognostic value of biomarkers was investigated by separately pooling HR and OR for different treatment groups in an individual study. The predictive value was assessed by pooling study interactions between treatment effects and biomarker subgroups. RESULTS: Thirty publications reporting on eighteen trials were selected, including a total of 13,507 patients. In prognostic analysis, BRAF mutations were associated with poorer PFS [HRs = 3.76 (2.47-5.73) and 2.69 (1.82-3.98)] and OS [HRs = 2.66 (1.95-3.65) and 2.45 (1.55-3.88)] in both the experimental and control arms; low miR-31-3p expression appeared to have longer PFS and OS. In terms of predictive effect, a lack of response to anti-EGFR therapy was observed in patients with BRAF mutant tumors (Pinteraction < 0.01 for PFS). Patients with tumors with any mutation in the KRAS/NRAS/BRAF/PIK3CA gene also showed similar results compared with all wild-type tumors (Pinteraction for PFS, OS, and ORR were < 0.01, < 0.01 and 0.01, respectively). While low miR-31-3p expression could predict PFS (Pinteraction = 0.01) and OS (Pinteraction = 0.04) benefit. The prognostic and predictive value regarding PIK3CA mutations, PTEN mutations or deletions, EGFR, EREG/AREG, HER2, HER3, and HER4 expression remains uncertain. CONCLUSIONS: In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.

Analysis of the expression and prognostic significance of DDK complex in Hepatocarcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most common and lethal malignancies worldwide. Although DBF4-dependent kinase (DDK) complex composed of CDC7 kinase and its regulatory subunit DBF4 has been shown to be overexpressed in primary tumors and promotes tumor development, while its role and prognostic value in HCC remain largely unknown. In the present study, the expression of DBF4 and CDC7 and their relationship with clinical characteristics were comprehensively analyzed. METHODS: The mRNA expression profiles of HCC and the corresponding clinical data of HCC patients were downloaded from TCGA and GEO databases, respectively. The differences in DBF4 and CDC7 expression in tumor tissues and adjacent normal tissues were analyzed. HCC-derived tissue microarray (TMA) was used to evaluate and score the expression of CDC7 by immunohistochemistry (IHC) staining. The Kaplan-Meier method and the Cox regression method were used to analyze the relationship between overall survival and clinical characteristics of the patients. Gene set enrichment analysis (GSEA) was used to analyze the pathway enrichment of DBF4 and CDC7. RESULTS: DBF4 and CDC7 had similar expression patterns in HCC patients. Detailly, compared with adjacent tissues, both mRNA and protein of DBF4 and CDC7 were significantly higher in HCC, and their expression was positively correlated with AJCC_T stage, clinical stage and G stage (grade) of liver cancer patients, and higher DBF4 or CDC7 expression predicted a worse prognosis in HCC patients with shorter overall survival (OS), recurrence-free survival (RFS), disease-specific survival (DSS) and progress-free survival (PFS). Cox regression analysis suggested that both DBF4 and CDC7 were independent risk factors for the prognosis of HCC patients in TCGA dataset. GSEA suggested that both DBF4 and CDC7 were positively correlated with cell cycle and DNA replication. Finally, the prognostic value of CDC7 was furtherly confirmed by TMA-based IHC staining results. CONCLUSIONS: Our study showed that DDK complex was significantly increased in HCC. Both DBF4 and CDC7 may be potential diagnostic and prognostic markers for HCC, and high expression of DDK members predicts a worse prognosis in patients with HCC, which may be associated with high tumor cell proliferation rate.

More accurate prediction of treatment response than mean apparent diffusion coefficient value in multiple myeloma using whole body MRI histogram analysis.

Aim: To assess baseline histogram parameters from apparent diffusion coefficient (ADC) images in predicting early treatment response in newly diagnosed multiple myeloma (NDMM) patients. Methods: The histogram parameters of lesions in 68 NDMM patients were obtained with the Firevoxel software. The presence of deep response after two cycles of induction was recorded. Results: Some parameters were significantly different between the two groups, for example, ADC 75% in lumbar spine (p = 0.026). No significant difference in mean ADC for any anatomic site was found (all p > 0.05). The combination of ADC 75, ADC 90 and ADC 95% in lumbar spine; ADC skewness and ADC kurtosis in rib achieved a sensitivity of 100% in predicting deep response. Conclusion: Histogram analysis of ADC images can describe NDMM heterogeneity and accurately predict treatment response.

20(S)-protopanaxatriol inhibited D-galactose-induced brain aging in mice via promoting mitochondrial autophagy flow.

Previous reports have confirmed that saponins (ginsenosides) derived from Panax ginseng. C. A. Meyer exerted obvious memory-enhancing and antiaging effects, and the simpler the structure of ginsenosides, the better the biological activity. In this work, we aimed to explore the therapeutic effect and underlying molecular mechanism of 20(S)-protopanaxatriol (PPT), the aglycone of panaxatriol-type ginsenosides, by establishing D-galactose (D-gal)-induced subacute brain aging model in mice. The results showed that PPT treatment (10 and 20 mg/kg) for 4 weeks could significantly restore the D-gal (800 mg/kg for 8 weeks)-induced impaired memory function, choline dysfunction, and redox system imbalance in mice. Meanwhile, PPT also significantly reduced the histopathological changes caused by D-gal exposure. Moreover, PPT could increase TFEB/LAMP2 protein expression to promote mitochondrial autophagic flow. Importantly, the results from molecular docking showed that PPT had good binding ability with LAMP2 and TFEB, suggesting that TFEB/LAMP2 might play an important role in PPT to alleviate D-gal-caused brain aging.

Synthesis and anti-HIV activity of non-nucleoside reverse-transcriptase inhibitor DB02 phosphate derivatives based on water-soluble optimization.

To improve the water solubility of anti-human immunodeficiency virus (HIV) agent DB02, an excellent non-nucleoside reverse-transcriptase inhibitor (NNRTI) obtained in our previous efforts, we designed and synthesized four phosphate derivatives of DB02 based on the molecular model of DB02 with RT. Here, the antiviral activity of these four derivatives was detected, leading to the discovery of compound P-2, which possessed a superior potency to the lead compound DB02 against wild-type HIV-1 and a variety of HIV-resistant mutant viruses significantly. Furthermore, the water solubility of P-2 was nearly 17 times higher than that of DB02, and the pharmacokinetic test in rats showed that P-2 demonstrate significantly improved oral bioavailablity of 14.6%. Our study showed that the introduction of a phosphate ester group at the end of the C-2 side chain of DB02 was beneficial to the improvement of its antiviral activity and pharmacokinetic properties, which provided a promising lead for the further development of S-DACOs type of NNRTIs.