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OBJECTIVE: This study evaluates the relationship between the Life's Essential 8 (LE8) scoring system and all-cause and cause-specific mortality among obese individuals using NHANES data. METHODS: Data from 9,143 obese participants (BMI ≥30 kg/m2) collected between 2005 and 2018 were analyzed. Participants were categorized based on their LE8 scores: low cardiovascular health (Low CVH, n=2264), moderate cardiovascular health (Moderate CVH, n=6541), and high cardiovascular health (High CVH, n=338). Associations between LE8 scores and mortality were assessed using Kaplan-Meier survival analysis and Cox proportional hazards models. RESULTS: Over a median follow-up of 7.3 years, there were 867 all-cause deaths (9.5%), including 246 cardiovascular disease (CVD) deaths (2.7%) and 621 non-CVD deaths (6.8%). In multivariable Cox regression analysis, compared to the Low CVH group, the Moderate CVH group had an adjusted hazard ratio (HR) for all-cause mortality of 0.63 (95% CI: 0.55-0.72), and the High CVH group had an HR of 0.25 (95% CI: 0.10-0.60). For CVD mortality, the HRs were 0.61 (95% CI: 0.47-0.78) for Moderate CVH and 0.19 (95% CI: 0.03-1.38) for High CVH. For non-CVD mortality, the HRs were 0.64 (95% CI: 0.54-0.75) for Moderate CVH and 0.27 (95% CI: 0.10-0.72) for High CVH. Each 10-point increase in LE8 score was associated with a 20% reduction in all-cause mortality (P<0.001), 21% reduction in CVD mortality (P<0.001), and 20% reduction in non-CVD mortality (P<0.001). CONCLUSION: Higher LE8 scores are significantly associated with lower rates of all-cause, CVD, and non-CVD mortality among obese individuals. These findings support the LE8 scoring system as an effective predictor of health status and mortality risk.

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OBJECTIVES: To evaluate changes of the upper airway and oral cavity volumes in patients with skeletal Class III malocclusion undergoing bimaxillary orthognathic surgery, and to analyze the correlation between postoperative upper airway decrease and the amount of jaw movement and oral cavity volume reduction. MATERIALS AND METHODS: Thirty patients (16 males and 14 females) undergoing bimaxillary surgery were included. Three-dimensional reconstruction of the upper airway and oral cavity were performed using preoperative (T0) and postoperative (T1) (6 months) cone-beam computed tomography scans. RESULTS: The volume, sagittal area and minimum cross-sectional area of the upper airway were diminished (P < .001). The decrease in volume and minimum cross-sectional area in the oropharyngeal region of the upper airway were weakly correlated with B-point posterior movement (P < .05). Total oral cavity volume was decreased, with maxillary oral volume increasing and mandibular oral volume decreasing (P < .001). Upper airway decrease was highly correlated with total oral volume reduction and mandibular oral volume reduction, with the most significant correlation being with total oral volume reduction (P < .001). CONCLUSIONS: Class III bimaxillary surgery reduced the volume, sagittal area, and minimum cross-sectional area of the upper airway as well as oral cavity volume. Upper airway changes were weakly correlated with anterior-posterior mandibular movement but significantly correlated with oral cavity volume changes. Thus, oral cavity volume reduction is a crucial factor of upper airway decrease in patients with skeletal Class III malocclusion undergoing bimaxillary orthognathic surgery.

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We developed a novel hepatitis B virus (HBV) infection-monitoring system using a luminescent, 11-amino acid reporter (HiBiT). We performed high-throughput antiviral screening using this system to identify anti-HBV compounds. After the infection of primary human hepatocytes with the recombinant virus HiBiT-HBV, which contains HiBiT at its preS1, 1262 compounds were tested in a first screening using extracellular HiBiT activity as an indicator of viral infection. Following a second screening, we focused on the compound skimmianine, which showed a potent antiviral effect. When skimmianine was added at the same time as HiBiT-HBV infection, skimmianine inhibited HiBiT activity with EC50 of 0.36 pM, CC50 of 1.67 µM and a selectivity index (CC50:EC50 ratio) of 5,100,000. When skimmianine was added 72 h after HiBiT-HBV infection, the EC50, CC50 and selectivity index were 0.19 µM, 1.87 µM and 8.79, respectively. Time-lapse fluorescence imaging analysis using another recombinant virus, ReAsH-TC155HBV, with the insertion of tetra-cysteine within viral capsid, revealed that skimmianine inhibited the accumulation of the capsid into hepatocytes. Furthermore, skimmianine did not inhibit either attachment or internalization. These results imply that skimmianine inhibits the retrograde trafficking of the virus after internalization. This study demonstrates the usefulness of the recombinant virus, HiBiT-HBV, for high-throughput screening to identify anti-HBV compounds.

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Bone morphogenetic proteins (BMPs) are a group of growth factors belonging to the transforming growth factor ß(TGF-ß) family. While initially recognized for their role in bone formation, BMPs have emerged as significant players in liver diseases. Among BMPs with various physiological activities, this comprehensive review aims to delve into the involvement of BMP9 specifically in liver diseases and provide insights into the complex BMP signaling pathway. Through an enhanced understanding of BMP9, we anticipate the discovery of new therapeutic options and potential strategies for managing liver diseases.

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The hepatitis B virus (HBV) infects many people worldwide. As HBV infection frequently leads to liver fibrosis and carcinogenesis, developing anti-HBV therapeutic drugs is urgent. Therapeutic drugs for preventing covalently closed circular DNA (cccDNA) production, which can eliminate HBV infection, are unavailable. The host factor dedicator of cytokinesis 11 (DOCK11) is involved in the synthesis and maintenance of HBV cccDNA in vitro. However, the effectiveness of DOCK11 as a target for the in vivo elimination of HBV cccDNA remains unclear. In this study, we assess whether DOCK11 inhibitors suppress HBV cccDNA production in mouse models of HBV infection. The tocopherol-conjugate hetero- gapmer, a DNA/RNA duplex of gapmer/complementary RNA targeting the DOCK11 sequence, partially reduces the expression of DOCK11, but not that of HBV cccDNA, in the livers of HBV-infected human hepatocyte chimeric mice, along with weight loss and decreased serum human albumin levels. Lipid nanoparticle-encapsulated chemically modified siRNAs specific for DOCK11 suppress DOCK11 expression and decrease HBV cccDNA levels without adverse effects in the mice. Therefore, nucleic acid-based drugs targeting DOCK11 in hepatocytes are potentially effective anti-HBV therapeutics that can reduce HBV cccDNA levels in vivo.

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Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous sarcoma characterized by the COL1A1-PDGFB fusion gene. This study utilized single-cell RNA sequencing to dissect the cellular and molecular landscape of primary DFSP. Distinct DFSP cell clusters, exhibiting fibroblast-like traits, revealed variations in pathways associated with proliferation, inflammation and metabolism. Differential gene expression analysis during the differentiation from tumour stem cells to DFSP cells unveiled SMOC2, DCN and TGFBR3 as potential regulators of tumour invasion and immune infiltration through VEGF/TGF-ß signalling modulation. Cellular communication analysis highlighted interactions within DFSP cell clusters and with endothelial cells, implicating molecules such as NAMPT, ANGPT2 and PTN in pathogenesis and treatment resistance. These findings offer insights into DFSP intratumour heterogeneity, elucidate molecular mechanisms underlying tumour behaviour, and suggest potential therapeutic targets.

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Background: The recent randomized controlled trials studying intracranial atherosclerotic stenosis (ICAS) have used digital subtraction angiography (DSA) to quantify stenosis and enroll patients. However, some disadvantages of DSA such as invasive features, contrast agent overuse, and X-ray radiation overexposure, were not considered in these studies. This study aimed to explore whether computed tomography angiography (CTA) with semi-automatic analysis could be an alternative method to DSA in quantifying the absolute stenotic degree in clinical trials. Methods: Patients with 50-99% ICAS were consecutively screened, prospectively enrolled, and underwent CTA and DSA between March 2021 and December 2021 at 6 centers. This study was registered at www.chictr.org.cn (ChiCTR2100052925). The absolute stenotic degree of ICAS on CTA with semi-automatic analysis was calculated by several protocols using minimal/maximum/mean diameters of stenosis and reference site from a semi-automatic analysis software. Intraclass correlation coefficient (ICC) was used to evaluate the reliabilities of quantifying stenotic degree on CTA. The optimal protocol for quantifying ICAS on CTA was explored. The agreements of quantifying ICAS in calcified or non-calcified lesions and 50-69% or 70-99% stenosis on CTA and DSA were assessed. Results: A total of 191 participants (58.8±10.7 years; 148 men) with 202 lesions were enrolled. The optimal protocol for quantifying ICAS on CTA was calculated as (1 - the minimal diameter of stenosis/the mean diameter of reference) × 100% for its highest agreement with DSA [ICC, 0.955, 95% confidence interval (CI): 0.944-0.966, P<0.001]. Among the 202 lesions, 80.2% (162/202) exhibited severe stenosis on DSA. The accuracy of CTA in detecting severe ICAS was excellent (sensitivity =95.1%, positive predictive value =98.1%). The agreements between DSA and CTA in non-calcified lesions (ICC, 0.960 vs. 0.849) and severe stenosis (ICC, 0.918 vs. 0.841) were higher than those in calcified lesions and moderate stenosis. Conclusions: CTA with semi-automatic analysis demonstrated an excellent agreement with DSA in quantifying ICAS, making it promising to replace DSA for the measurement of absolute stenotic degree in clinical trials.

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OBJECTIVE: Narrowband ultraviolet B (NB-UVB) has been recommended as first-line therapy for early-stage mycosis fungoides (MF) in international guidelines. NB-UVB can be used as monotherapy or part of a multimodality treatment regimen. There is limited evidence on the effectiveness and optimal patients of NB-UVB in combination with systemic therapies in MF. We aimed to assess the effectiveness of the combination versus NB-UVB monotherapy in early-stage MF and if plaque lesion status was related to these effects. METHODS: This observational cohort study included 247 early-stage MF patients who had received NB-UVB combined with systemic therapies vs. NB-UVB monotherapy from 2009 to 2021. The primary outcome was partial or complete response. Overall response rate and median time to response were calculated. Hazard ratios (HRs) were estimated using the Cox model. RESULTS: In 139 plaque-stage patients, the response rate for combination therapy group was higher than that of monotherapy group (79.0% vs. 54.3%, p = 0.006). The adjusted HR for combination therapy compared with NB-UVB monotherapy was 3.11 (95% CI 1.72-5.63). The combination therapy group also showed shorter time to response (4 vs. 6 months, p = 0.002). In 108 patch-stage patients, the response rate and time to response in two treatment groups showed no significant difference. There was therefore an observed interaction with patients' plaque lesion status for the effect size of NB-UVB combination therapy. No serious adverse events were observed. CONCLUSIONS: Adding systemic treatments to NB-UVB did not improve the treatment outcome of patch-stage patients, but it surpassed NB-UVB monotherapy for early-stage patients with plaques.

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The lymphatic system plays a vital role in the regulation of tissue fluid balance and the immune response to inflammation or infection. The effects of lymphatic endothelial cells (LECs) on the regulation of neutrophil migration have not been well-studied. In three murine models: imiquimod-induced skin inflammation, Staphylococcus aureus-induced skin infection, and ligature-induced periodontitis, we show that numerous neutrophils migrate from inflamed or infected tissues to the draining lymph nodes via lymphatic vessels. Moreover, inflamed or infected tissues express a high level of interleukin (IL)-17A and tumor necrosis factor (TNF)-α, simultaneously with a significant increase in the release of neutrophil attractors, including CXCL1, CXCL2, CXCL3, and CXCL5. Importantly, in vitro stimulation of LECs with IL-17A plus TNF-α synergistically promoted these chemokine secretions. Mechanistically, tetra-transmembrane protein CMTM4 directly binds to IL-17RC in LECs. IL-17A plus TNF-α stimulates CXC chemokine secretion by promoting nuclear factor-kappa B signaling. In contrast, knockdown of CMTM4 abrogates IL-17A plus TNF-α activated nuclear factor-kappa B signaling pathways. Lastly, the local administration of adeno-associated virus for CMTM4 in Prox1-CreERT2 mice, mediating LEC-specific overexpression of CMTM4, promotes the drainage of neutrophils by LECs and alleviates immune pathological responses. Thus, our findings reveal the vital role of LECs-mediated neutrophil attraction and clearance at sites of inflammation or infection.

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HBV infection is challenging to cure due to the persistence of viral covalently closed circular viral DNA (cccDNA). The dedicator of cytokinesis 11 (DOCK11) is recognized as a guanine nucleotide exchange factor (GEF) for CDC42 that has been reported to be required for HBV persistence. DOCK11 is expressed in both the cytoplasm and nucleus of human hepatocytes and is functionally associated with retrograde trafficking proteins Arf-GAP with GTPase domain, ankyrin repeat, and pleckstrin homology domain-containing protein 2 (AGAP2), and ADP-ribosylation factor 1 (ARF1), together with the HBV capsid, in the trans-Golgi network (TGN). This opens an alternative retrograde trafficking route for HBV from early endosomes (EEs) to the TGN and then to the endoplasmic reticulum (ER), thereby avoiding lysosomal degradation. DOCK11 also facilitates the association of cccDNA with H3K4me3 and RNA Pol II for activating cccDNA transcription. In addition, DOCK11 plays a crucial role in the host DNA repair system, being essential for cccDNA synthesis. This function can be inhibited by 10M-D42AN, a novel DOCK11-binding peptide, leading to the suppression of HBV replication both in vitro and in vivo. Treatment with a combination of 10M-D42AN and entecavir may represent a promising therapeutic strategy for patients with chronic hepatitis B (CHB). Consequently, DOCK11 may be seen as a potential candidate molecule in the development of molecularly targeted drugs against CHB.

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Two-pore physiologically based pharmacokinetic (PBPK) modeling has demonstrated its potential in describing the pharmacokinetics (PK) of different-size proteins. However, all existing two-pore models lack either diverse proteins for validation or interspecies extrapolation. To fill the gap, here we have developed and optimized a translational two-pore PBPK model that can characterize plasma and tissue disposition of different-size proteins in mice, rats, monkeys, and humans. Datasets used for model development include more than 15 types of proteins: IgG (150 kDa), F(ab)2 (100 kDa), minibody (80 kDa), Fc-containing proteins (205, 200, 110, 105, 92, 84, 81, 65, or 60 kDa), albumin conjugate (85.7 kDa), albumin (67 kDa), Fab (50 kDa), diabody (50 kDa), scFv (27 kDa), dAb2 (23.5 kDa), proteins with an albumin-binding domain (26, 23.5, 22, 16, 14, or 13 kDa), nanobody (13 kDa), and other proteins (110, 65, or 60 kDa). The PBPK model incorporates: (i) molecular weight (MW)-dependent extravasation through large and small pores via diffusion and filtration, (ii) MW-dependent renal filtration, (iii) endosomal FcRn-mediated protection from catabolism for IgG and albumin-related modalities, and (iv) competition for FcRn binding from endogenous IgG and albumin. The finalized model can well characterize PK of most of these proteins, with area under the curve predicted within two-fold error. The model also provides insights into contribution of renal filtration and lysosomal degradation towards total elimination of proteins, and contribution of paracellular convection/diffusion and transcytosis towards extravasation. The PBPK model presented here represents a cross-modality, cross-species platform that can be used for development of novel biologics.

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Objective: The study aims to explore the relationship between lipoprotein lipase (LPL) variants and hyperlipidemic acute pancreatitis (HLAP) in the southeastern Chinese population. Subjects and methods: In total, 80 participants were involved in this study (54 patients with HLAP and 26 controls). All coding regions and intron-exon boundaries of the LPL gene were sequenced. The correlations between variants and phenotypes were also analysed. Results: The rate of rare LPL variants in the HLAP group is 14.81% (8 of 54), higher than in controls. Among the detected four variants (rs3735959, rs371282890, rs761886494 and rs761265900), the most common variant was rs371282890. Further analysis demonstrated that subjects with rs371282890 "GC" genotype had a 2.843-fold higher risk for HLAP (odds ratio [OR]: 2.843, 95% confidence interval [CI]: 1.119-7.225, p = 0.028) than subjects with the "CC" genotype. After adjusting for sex, the association remained significant (adjusted OR: 3.083, 95% CI: 1.208-7.869, p = 0.018). Subjects with rs371282890 "GC" genotype also exhibited significantly elevated total cholesterol, triglyceride and non-high-density lipoprotein cholesterol levels in all the participants and the HLAP group (p < 0.05). Conclusion: Detecting rare variants in LPL might be valuable for identifying higher-risk patients with HLAP and guiding future individualised therapeutic strategies.

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Hepatocellular carcinoma (HCC) is a highly lethal malignant neoplasm, and the involvement of bone morphogenetic protein 9 (BMP9) has been implicated in the pathogenesis of liver diseases and HCC. Our goal was to investigate the role of BMP9 signaling in regulating N6-methyladenosine (m6A) methylation and cell cycle progression, and evaluate the therapeutic potential of BMP receptor inhibitors for HCC treatment. We observed that elevated levels of BMP9 expression in tumor tissues or serum samples from HCC patients were associated with a poorer prognosis. Through in vitro experiments utilizing the m6A dot blotting assay, we ascertained that BMP9 reduced the global RNA m6A methylation level in Huh7 and Hep3B cells, thereby facilitating their cell cycle progression. This effect was mediated by an increase in the expression of the inhibitor of DNA-binding protein 1 (ID1). Additionally, using methylated RNA immunoprecipitation qPCR(MeRIP-qPCR), we showed that the BMP9-ID1 pathway promoted CyclinD1 expression by decreasing the m6A methylation level in the 5' UTR of mRNA. This occurred through the upregulation of the fat mass and obesity-associated protein (FTO) in Huh7 and Hep3B cells. In our in vivo mouse xenograft models, we demonstrated that blocking the BMP receptor with LDN-212854 effectively suppressed HCC growth and induced global RNA m6A methylation. Overall, our findings indicate that the BMP9-ID1 pathway promotes HCC cell proliferation by down-regulating the m6A methylation level in the 5' UTR of CyclinD1 mRNA. Targeting the BMP9-ID1 pathway holds promise as a potential therapeutic strategy for treating HCC.

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ABSTRACT Objective: The study aims to explore the relationship between lipoprotein lipase (LPL) variants and hyperlipidemic acute pancreatitis (HLAP) in the southeastern Chinese population. Subjects and methods: In total, 80 participants were involved in this study (54 patients with HLAP and 26 controls). All coding regions and intron-exon boundaries of the LPL gene were sequenced. The correlations between variants and phenotypes were also analysed. Results: The rate of rare LPL variants in the HLAP group is 14.81% (8 of 54), higher than in controls. Among the detected four variants (rs3735959, rs371282890, rs761886494 and rs761265900), the most common variant was rs371282890. Further analysis demonstrated that subjects with rs371282890 "GC" genotype had a 2.843-fold higher risk for HLAP (odds ratio [OR]: 2.843, 95% confidence interval [CI]: 1.119-7.225, p = 0.028) than subjects with the "CC" genotype. After adjusting for sex, the association remained significant (adjusted OR: 3.083, 95% CI: 1.208-7.869, p = 0.018). Subjects with rs371282890 "GC" genotype also exhibited significantly elevated total cholesterol, triglyceride and non-high-density lipoprotein cholesterol levels in all the participants and the HLAP group (p < 0.05). Conclusion: Detecting rare variants in LPL might be valuable for identifying higher-risk patients with HLAP and guiding future individualised therapeutic strategies.

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INTRODUCTION: Walking with anterior loads is common in industrial scenarios, but as exoskeletons are increasingly used in work environments to alleviate musculoskeletal disorders (MSDs), this new "human-robot" system composed of the human body and exoskeleton may be associated with new risks and harm that warrant further investigation. Therefore, this study will discuss the effect of a wearable chair on the gait, balance, and discomfort of new users with different weights of anterior loads during level walking. METHOD: Twenty-two healthy subjects (sex balanced) participated in the experiment. Each exposure comprised one of two exoskeleton states (with/without) and four load conditions: No carried load, carrying an empty box (0.3 kg), 5%Body Weight (BW), and 10%BW. The order of exoskeleton states and load conditions was randomly assigned. Using an eight-camera motion capture system to record the entire movement. And the subjective discomfort and perceived balance after each exposure were recorded on an 11-point numeric rating scale, respectively. Using SPSS 26.0 software (IBM Inc., Chicago) to conduct statistical analyses. RESULTS: Level walking with a wearable chair in different load conditions significantly affected gait parameters (like cadence) and gait balance. The perceived balance decreased with the exoskeleton, consistent with objective results. For subjective discomfort, wearing the exoskeleton significantly impacted global discomfort. Also, it increased the local discomfort of the shoulders, waist, thighs, shanks, and feet/ankles. CONCLUSIONS: For new users, the risk of losing balance or falling may be increased when wearing an exoskeleton for non-target task behaviors (level walking/anterior load), and caution is recommended when the anterior load exceeds 5% BW. PRACTICAL APPLICATION: The proposed strategy for assessing human gait, balance, and discomfort in wearable chairs may be applied during the iterative design of the product. These controls will help develop training programs and implementation guidelines for this exoskeleton type.

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Background: Apolipoprotein A5 (APOA5) is involved in serum triglyceride (TG) regulation. Several studies have reported that the rs651821 locus in the APOA5 gene is associated with serum TG levels in the Chinese population. However, no research has been performed regarding the association between the variants of rs651821 and the risk of hyperlipidemic acute pancreatitis (HLAP). Methods: A case-control study was conducted and is reported following the STROBE guidelines. We enrolled a total of 88 participants in this study (60 HLAP patients and 28 controls). APOA5 was genotyped using PCR and Sanger sequencing. Logistic regression models were conducted to calculate odds ratios and a 95% confidence interval. Results: The genotype distribution of the rs651821 alleles in both groups follow the Hardy-Weinberg distribution. The frequency of the "C" allele in rs651821 was increased in HLAP patients compared to controls. In the recessive model, subjects with the "CC" genotype had an 8.217-fold higher risk for HLAP (OR = 8.217, 95% CI: 1.023-66.01, p = 0.046) than subjects with the "TC+TT" genotypes. After adjusting for sex, the association remained significant (OR = 9.898, 95% CI: 1.176-83.344, p = 0.035). Additionally, the "CC" genotype was related to an increased TG/apolipoprotein B (APOB) ratio and fasting plasma glucose (FPG) levels. Conclusions: Our findings suggest that the C allele of rs651821 in APOA5 increases the risk of HLAP in persons from Southeastern China.

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BACKGROUND: HBV infection causes chronic liver disease and leads to the development of HCC. To identify host factors that support the HBV life cycle, we previously established the HC1 cell line that maintains HBV infection and identified host genes required for HBV persistence. METHODS: The present study focused on endothelial lipase (LIPG), which binds to heparan sulfate proteoglycans (HSPGs) in the cell membrane. RESULTS: We found HBV infection was impaired in humanized liver chimeric mouse-derived hepatocytes that were transduced with lentivirus expressing short hairpin RNA against LIPG. Long-term suppression of LIPG combined with entecavir further suppressed HBV replication. LIPG was shown to be involved in HBV attachment to the cell surface by using 2 sodium taurocholate cotransporting peptide (NTCP)-expressing cell lines, and the direct interaction of LIPG and HBV large surface protein was revealed. Heparin and heparinase almost completely suppressed the LIPG-induced increase of HBV attachment, indicating that LIPG accelerated HBV attachment to HSPGs followed by HBV entry through NTCP. Surprisingly, the attachment of a fluorescently labeled NTCP-binding preS1 probe to NTCP-expressing cells was not impaired by heparin, suggesting the HSPG-independent attachment of the preS1 probe to NTCP. Interestingly, attachment of the preS1 probe was severely impaired in LIPG knockdown or knockout cells. Inhibitors of the lipase activity of LIPG similarly impaired the attachment of the preS1 probe to NTCP-expressing cells. CONCLUSIONS: LIPG participates in HBV infection by upregulating HBV attachment to the cell membrane by means of 2 possible mechanisms: increasing HBV attachment to HSPGs or facilitating HSPG-dependent or HSPG-independent HBV attachment to NTCP by its lipase activity.

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Importance: There are limited prognostic statistics and data available on survival outcomes for patients with mycosis fungoides (MF) in Asia. Objective: To determine the prognostic factors and survival outcomes of patients with MF among a cohort in China. Design, Setting, and Participants: This was a retrospective cohort study of patients with MF who received treatment at a tertiary referral center for skin lymphoma (Peking University First Hospital, Beijing, China) from August 1, 2009, to August 31, 2021. Data were analyzed from September 1, 2021, to December 31, 2022. Main Outcomes and Measures: Overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS); for prognostic factors, hazard ratios (HRs), and adjusted HRs (aHRs; adjusted for sex, age, and overall TNMB [tumor, node, metastasis, blood] stage) determined using the Cox proportional hazards model. Results: The study cohort comprised 461 patients with MF (median [range] age at diagnosis, 46 [5-87] years; 275 [59.7%] men and 186 [40.3%] women; 461 [100%] Chinese). The overall 5-year rate was 82.2% for OS, 83.5% for DSS, and 79.6% for PFS. Stage-specific 5-year OS rates were 95.7% for stage IA, 93.2% for IB, 95.7% for IIA, 70.1% for IIB, 55.3% for III, and 23.6% for IV. Compared with a UK cohort, our Chinese cohort had a younger median age at diagnosis (46 years vs 54 years) and a more favorable 5-year OS (82.2% vs 75.0%); however, after adjusting for age, the discrepancy in the 5-year OS rate was diminished (77.3% vs 76.4%). Cox models revealed that unfavorable predictors of OS, PFS, and DSS, respectively, were: age older than 60 years (aHR [95% CI], 2.25 [1.28-3.96]; 2.09 [1.16-3.76]; 2.27 [1.39-3.72]); advanced TNMB stage; advanced overall stage; large-cell transformation (aHR [95% CI], 2.16 [1.17-3.99]; 2.29 [1.21-4.33]; 2.21 [1.26-3.86]); and elevated lactate dehydrogenase levels (aHR [95% CI], 3.92 [1.64-9.36]; 4.77 [1.86-12.22]; 5.05 [2.23-11.42]). Biological sex and plaque lesion type were not associated with prognosis among this study cohort. Conclusion and Relevance: The findings of this retrospective cohort study of patients with MF in China suggest that Asian patients are diagnosed at a younger age and have a higher 5-year OS compared with patients of other races in studies in other countries (predominantly White). Prognostic factors were similar to those of previous studies, except for patient sex and plaque lesion type.

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Periodontitis is a chronic, inflammatory, and destructive disease caused by the imbalance of host immune response and dental biofilm, and has strong epidemiological and pathogenesis correlations with systemic diseases. The immune response in periodontitis involves both innate and adaptive immunity, with numerous immune cells and inflammatory pathways participating in a complex network of interactions. In the past decade, the concept of "trained immunity" has emerged, which highlights the memory characteristics of innate immunity, thus opening up a new avenue of research. There is growing interest in exploring the role of trained immunity in chronic inflammatory and metabolic diseases such as atherosclerosis and diabetes mellitus. Evidence suggests that trained immunity may also regulate the onset and progression of periodontitis, serving as a bridge between periodontitis-related comorbidities. In this review, we summarize concepts related to trained immunity and its development. Furthermore, we present current evidence that endorses the notion of trained immunity in periodontitis and analyze possible roles it may assume regarding periodontitis-associated inflammatory reactions from a cellular perspective. Finally, we discuss various clinical therapeutic strategies for periodontitis and its associated comorbidities that target trained immunity. We hope that more researchers will pay attention to this emerging concept, thereby providing deeper insights into this novel field.

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Infection with hepatitis B virus (HBV) cannot be cured completely because of the persistence of covalently closed circular DNA (cccDNA). We previously found that the host gene dedicator of cytokinesis 11 (DOCK11) was required for HBV persistence. In this study, we further investigated the mechanism that links DOCK11 to other host genes in the regulation of cccDNA transcription. cccDNA levels were determined by quantitative real-time polymerase chain reaction (qPCR) and fluorescence in situ hybridization (FISH) in stable HBV-producing cell lines and HBV-infected PXB-cells®. Interactions between DOCK11 and other host genes were identified by super-resolution microscopy, immunoblotting, and chromatin immunoprecipitation. FISH facilitated the subcellular localization of key HBV nucleic acids. Interestingly, although DOCK11 partially colocalized with histone proteins, such as H3K4me3 and H3K27me3, and nonhistone proteins, such as RNA Pol II, it played limited roles in histone modification and RNA transcription. DOCK11 was functionally involved in regulating the subnuclear distribution of host factors and/or cccDNA, resulting in an increase in cccDNA closely located to H3K4me3 and RNA Pol II for activating cccDNA transcription. Thus, it was suggested that the association of cccDNA-bound Pol II and H3K4me3 required the assistance of DOCK11. DOCK11 facilitated the association of cccDNA with H3K4me3 and RNA Pol II.

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