Background/Aims: Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). Methods: Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). Results: The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and highrisk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). Conclusions We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.

Background/Aims: Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). Methods: Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). Results: The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and highrisk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). Conclusions We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.

Background/Aims: Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). Methods: Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). Results: The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and highrisk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). Conclusions We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.

One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.
Animals ; Mice ; RNA, Untranslated/metabolism* ; Aging/genetics* ; Mice, Transgenic ; Telomerase/metabolism* ; RNA/genetics* ; Hippocampus/metabolism* ; Humans ; Mice, Inbred C57BL

Given the increasing concern regarding antibacterial resistance, the antimicrobial properties of naphthoquinones have recently attracted significant attention. While 1,4-naphthoquinone and its derivatives have been extensively studied, the antibacterial properties of 5,8-dihydroxy-1,4-naphthoquinone derivatives remain relatively unexplored. This study presents a comprehensive in vitro and in vivo analysis of the antibacterial activity of 35 naturally sourced and chemically synthesized derivatives of 5,8-dihydroxy-1,4-naphthoquinone. Kirby-Bauer antibiotic testing identified three compounds with activity against methicillin-resistant Staphylococcus aureus (MRSA), with one compound (PNP-02) demonstrating activity comparable to vancomycin in minimum inhibitory concentration, minimum bactericidal concentration (MBC), and time-kill assays. Microscopic and biochemical analyses revealed that PNP-02 adversely affects the cell wall and cell membrane of MRSA. Mechanistic investigations, including proteomic sequencing analyses, Western blotting, and RT-qPCR assays, indicated that PNP-02 compromises cell membrane integrity by inhibiting arginine biosynthesis and pyrimidine metabolism pathways, thereby increasing membrane permeability and inducing bacterial death. In an in vivo mouse model of skin wound healing, PNP-02 exhibited antibacterial efficacy similar to vancomycin. The compound demonstrated low toxicity to cultured human cells and in hemolysis assays and remained stable during serum incubation. These findings suggest that PNP-02 possesses promising bioactivity against MRSA and represents a potential novel antibacterial agent.
Methicillin-Resistant Staphylococcus aureus/genetics* ; Anti-Bacterial Agents/chemistry* ; Naphthoquinones/administration & dosage* ; Animals ; Microbial Sensitivity Tests ; Mice ; Humans ; Staphylococcal Infections/microbiology* ; Molecular Structure

Objective:To evaluate modified extended trochanteric osteotomy (ETO) applied in the revision of Vancouver B2/B3 periprosthetic femoral fractures (PFF).Methods:A retrospective study was conducted to analyze the 35 patients with Vancouver B2/B3 PFF who had been treated at Joint Disease Department Ⅱ, Zhengzhou Orthopedic Hospital from January 2012 to November 2020. There were 10 males and 15 females with an age of (74.3±7.8) years. The time from their primary replacement to revision was (120.3±28.6) months. By the Vancouver classification, 26 cases were type B2 and 9 ones type B3. The modified ETO was used in the revision surgery for all patients. The clinical efficacy was evaluated using Harris hip score, imaging evaluation was performed using the Beals and Tower criteria at the last follow-up, and complications were recorded.Results:The operation time for this cohort was (148±32) min and intraoperative bleeding (800±150) mL. All patients were followed up for (45.2±15.3) months. The Harris score increased significantly from preoperative (21.3±11.2) points to (86.2±5.2) points at the last follow-up ( P < 0.001). By the Beals and Tower evaluation, 9 cases were rated as excellent, 24 cases as good, and 2 as poor. All the fractures and sites of trochanteric osteotomy got healed after (4.4±2.8) months except for 1 case of nonunion. Prosthesis subsidence occurred in 3 cases, in 2 of which the subsidence stopped 6 months later and in only 1 of which revision was needed due to the subsidence. Upward block displacement of the greater trochanteric fracture occurred in 2 cases, but did not exceed 1 cm. One case of postoperative dislocation responded to manual reduction. Conclusion:In the revision of Vancouver B2/B3 PFF, the modified ETO can improve fracture healing, and reduce postoperative dislocations and complications, leading to satisfactory clinical efficacy.

Objective:To investigate the effect of tofacitinib combined with methotrexate on disease activity, rheumatoid factor (RF) level and morning stiffness time in patients with refractory rheumatoid arthritis (RA).Methods:A total of 120 patients with refractory RA diagnosed and treated in the First Affiliated Hospital of Hebei North University from June 2019 to June 2020 were selected as the study subjects, and they were randomly divided into three groups by random number table method: etanercept group, etanercept+ methotrexate group, and tofacitinib+ methotrexate group, with 40 patients in each group. The etanercept group was given etanercept treatment, the etanercept+ methotrexate group was given etanercept combined with methotrexate treatment, and the tofacitinib+ methotrexate group was given tofacitinib combined with methotrexate treatment. The clinical efficacy (12 W, 24 W and 48 W of treatment), disease activity, RF level, morning stiffness time and incidence of adverse reactions were compared among the three groups.Results:Comparison of the total clinical effective rate of the three groups: the total clinical effective rate of the etanercept+ methotrexate group and the tofacitinib+ methotrexate group was higher than that of the etanercept group (both P<0.05), and the tofacitinib+ methotrexate group was higher than that of the etanercept+ methotrexate group ( P<0.05). After treatment, the clinical symptoms and disease activity scores (DAS28) in the etanercept+ methotrexate and tofacitinib+ methotrexate groups were significantly improved compared with the etanercept group (all P<0.05), and the improvements in the tofacitinib+ methotrexate group were more significant than those in the etanercept+ methotrexate group ( P<0.05). After treatment, the erythrocyte sedimentation rate (ESR), RF and C-reactive protein (CRP) levels were lower in the etanercept+ methotrexate and tofacitinib+ methotrexate groups than those in the etanercept groups (all P<0.05), and the ESR, RF and CRP levels in the tofacitinib+ methotrexate groups were lower than those in the etanercept+ methotrexate group (all P<0.05). There was no significant difference in the incidence of total adverse reactions among 3 groups (7.50% vs 12.50% vs 12.50%) ( P>0.05). Conclusions:Tofacitinib combined with methotrexate can effectively improve the disease activity, RF level and morning stiffness time in patients with refractory RA, with high safety, which is worthy of clinical application and promotion.

Objective To investigate the clinical effect of remimazolam combined with remifentanil in patients undergoing laryngoscope vocal cord surgery under general anesthesia.Methods A total of 180 patients undergoing laryngoscope vocal cord surgery under general anesthesia from January to August 2022,77 males and 103 females,aged 18-64 years,BMI 18-30 kg/m2,ASA physical status Ⅰ-Ⅲ were select-ed.The patients were divided into four groups using a random number table method:propofol group(group C),remimazolam 1.0 mg·kg-1·h-1 group(group R1),remimazolam 1.5 mg·kg-1·h-1 group(group R2),and remimazolam 2.0 mg·kg-1·h-1 group(group R3),45 patients in each group.Group C main-tained by intravenous infusion of propofol 5 mg·kg-1·h-1,groups R1,R2,and R3 were maintained by intravenous infusion of remimazolam 1.0,1.5,and 2.0 mg·kg-1·h-1,respectively.All patients were combined with remifentanil 0.2 μg·kg-1·min-1.HR,MAP,and BIS were recorded before anesthesia in-duction(T1),immediately after laryngoscope insertion(T2),immediately at the end of anesthesia mainte-nance(T3),and at tracheal extubation(T4).The onset time of sedation,awakening time,sedation-agita-tion score at extubation and Ramsay score 5 minutes after extubation were recorded.The intraoperative use of ephedrine and nitroglycerin were recorded.The number of injection pain and remedy sedations were recor-ded,the occurrence of adverse reactions such as nausea and vomiting,respiratory depression within 1 hour after extubation,and intraoperative awareness were recorded.Results Compared with group C,MAP at T3,BIS at T2 and T3 were significantly increased,MAP at T4 was significantly decreased,the onset time of sedation was significantly prolonged,the use of ephedrine and the incidence of injection pain were signifi-cantly decreased in group R1(P＜0.05),HR and MAP were significantly decreased at T2 and T4,MAP was significantly increased at T3,the onset time of sedation,awakening time,extubation time were signifi-cantly prolonged,the use of ephedrine and the incidence of injection pain were significantly reduced in group R2(P＜0.05),HR and MAP were significantly decreased at T2 and T4,the onset time of sedation,awakening time,extubation time were significantly prolonged,Ramsay score was significantly increased in group R3(P＜0.05).Compared with group R1,HR and MAP were significantly decreased at T2 and T4,BIS was significantly decreased at T2 and T3,the awakening time and extubation time were significantly pro-longed in group R2(P＜0.05),HR at T2 and T4,MAP at T2-T4,BIS at T2 and T3 were significantly de-creased,the awakening time and extubation time were significantly prolonged,Ramsay score was significant-ly increased in group R3(P＜0.05).Compared with group R2,MAP at T3 was significantly decreased and Ramsay score was significantly increased in group R3(P＜0.05).There were no significantly differences between the rates of nitroglycerin usage,rescue sedation,nausea and vomiting,and respiratory depression in the four groups.Conclusion Remimazolam can be safely used for anesthesia induction and maintenance in laryngoscope vocal cord surgery.The maintenance of remimazolam 1.5 mg·kg-1·h-1 combined with remifentanil can better maintain the hemodynamics stability during the surgery than remimazolam 1.0 and 2.0 mg·kg-1·h-1.

Background:Gastroesophageal reflux disease(GERD)is a common digestive disorder,but its underlying causes are still unclear.Patients with GERD often experience anxiety,depression,and ineffective esophageal motility.However,there have been limited studies on the relationship between anxiety/depression and esophageal motility.Aims:To investigate the mental state of patients with different subtypes of GERD and explore its correlation with esophageal motility.Methods:From September 2018 to June 2022,a total of 96 outpatients presenting typical acid reflux and heartburn symptoms with a GerdQ score≥10 were enrolled at Jincheng People's Hospital.They were divided into two groups based on gastroscopy findings:non-erosive reflux disease(NERD)group(77 cases)and reflux esophagitis(RE)group(19 cases).General data,clinical symptoms,anxiety/depression scores,and high-resolution esophageal manometry results were compared between the two groups using t-test,chi-square test,and Spearman correlation analysis.Results:There was a statistically significant difference between the NERD group and RE group(P<0.05),with more females in the NERD group.The self-rating anxiety scale(SAS)scores were significantly higher in the NERD group[44.00(29.00-58.00)]compared to the RE group[23.00(20.00-29.38)],indicating a greater presence of anxiety in the NERD group than in the RE group;this difference was statistically significant(P<0.01).However,there was no significant difference in self-rating depression scale(SDS),Hamilton anxiety scale(HAMA),or Hamilton depression scale(HAMD)scores between the two groups.Furthermore,a negative correlation was observed between distal contractile integral(DCI)values and SAS scores among GERD patients(P<0.05).Additionally,a small negative correlation existed between DCI values and SDS,HAMA,and HAMD(P>0.05).Conclusions:The NERD group exhibits a more pronounced anxiety state compared to the RE group.Furthermore,there exists a negative correlation between the anxiety state of GERD patients and DCI,suggesting that anxiety may influence esophageal motility involvement in the pathogenesis of GERD.

Objective:To investigate the relationship between serum 25(OH)D and SIRT4 levels and glycolipid metabolism in children with different levels of obesity.Methods:A total of 124 children with different levels of obesity who received treatment in Shaoxing Women's and Children's Health Care Hospital from February 2016 to February 2021 were included in this study. These children were divided into mild/moderate obesity group ( n = 76) and severe obesity group ( n = 48) according to body mass index. An additional 62 healthy children who concurrently received a physical examination were selected for controls. The general data of all children were collected. The relationship between the factors that affect obesity in children and serum 25(OH)D and SIRT4 levels and glycolipid metabolism was analyzed. Results:In the control, mild/moderate obesity, and severe obesity groups, body mass was (26.68 ± 4.98) kg, (33.24 ± 5.48) kg, (37.18 ± 5.88) kg, respectively; waist circumference was (56.12 ± 4.62) cm, (68.45 ± 5.20) cm, (79.34 ± 5.65) cm, respectively; hip circumference was (68.42 ± 5.08) cm, (72.45 ± 6.45) cm, (80.56 ± 6.95) cm, respectively; body mass index (BMI) was (15.90 ± 2.04) kg/m 2, (23.58 ± 2.45) kg/m 2, (25.89 ± 2.35) kg/m 2], respectively; fasting insulin (FINS) level was (26.65 ± 3.68) pmol/L, (34.82 ± 4.15) pmol/L, (48.56 ± 5.49) pmol/l, respectively; homeostasis model assessment of insulin resistance (HOMA-IR) was (1.06 ± 0.24), (2.12 ± 0.35), (3.84 ± 0.52), respectively; total cholesterol (TC) level was (2.21 ± 0.45) mmol/L, (4.14 ± 0.58) mmol/L, (5.96 ± 0.64) mmol/L, respectively; triacylglycerol (TG) level was (0.68 ± 0.16) mmol/L, (1.12 ± 0.24) mmol/L, (1.56 ± 0.35) mmol/L, respectively; low density lipoprotein cholesterol (LDL-C) was (2.68 ± 0.42) mmol/L, (2.10 ± 0.32) mmol/L, (1.41 ± 0.25) mmol/L, respectively; high density lipoprotein cholesterol (HDL-C) was (1.98 ± 0.42) mmol/L, (3.12 ± 0.51) mmol/L, (4.10 ± 0.56) mmol/L, respectively. There were significant differences in body mass, waist circumference, hip circumference, BMI, FINS, HOMA-IR, TC, TG, HDL-C, and LDL-C among the three groups ( F = 53.62, 280.42, 53.33, 303.44, 338.48, 755.71, 618.75, 165.81, 186.89, 251.42, all P < 0.001). Body mass, waist circumference, hip circumference, BMI, FINS, HOMA-IR, TC level, TG level, HDL-C level, and LDL-C level were lower in the control group than in the mild/moderate obesity group ( t = -7.28, -14.56, -4.00, -19.72, -6.49, -21.45, -12.36, 9.20, -14.12, all P < 0.05). Body mass, waist circumference, hip circumference, BMI, FINS, HOMA-IR, TC, TG, HDL-C and LDL-C were lower in the mild/moderate obesity group than in the severe obesity group ( t = -3.79, -10.98, -6.61, -5.19, -15.81, -22.02, -16.34, -8.30, 12.68, -10.03, all P < 0.05). Serum 25(OH)D [(60.52 ± 8.95) nmol/L vs. (49.88 ± 8.12) nmol /L, t = 7.31, P < 0.05] and SIRT4 [(1.98 ± 0.38) mmol/L vs. (1.06 ± 0.30) mmol/L, t = 15.89, P < 0.05] levels were significantly greater in the control group than in the mild/moderate obesity group. Serum 25(OH)D [(49.88 ± 8.12) nmol/L vs. (41.62 ± 7.50) nmol /L, t = 5.68, P < 0.05] and SIRT4 [(1.06 ± 0.30) mmol/L vs. (0.52 ± 0.15) mmol/L, t = 11.57, P < 0.05] levels were significantly greater in the mild/moderate obesity group than in the severe obesity group. Multiple linear regression analysis showed that body mass, waist circumference, hip circumference, FINS, HOMA-IR, TC, TG, and LDL were the positive influential factors of childhood obesity ( B = 0.170, 0.310, 0.403, 1.000, 3.464, 2.080, 2.656, 4.324); HDL, serum 25(OH)D and SIRT4 were the negative influential factors of childhood obesity ( B = -2.096, -0.156, -6.615). Pearson correlation analysis showed that serum 25(OH)D was significantly negatively correlated with FINS, HOMA-IR, TC, TG and LDL ( r = -0.20, -0.46, -0.30, -0.36, all P < 0.01), and significantly positively correlated with FPG and HDL ( r = 0.43, 0.77, both P < 0.01). Serum SIRT4 was negatively correlated with FINS, TC, TG, and LDL ( r = -0.48, -0.74, -0.61, -0.64, all P < 0.01), and positively correlated with FPG and HDL ( r = 0.21, 0.84, both P < 0.01). Conclusion:Serum 25(OH)D and SIRT4 levels decrease with the aggravation of obesity in children and are closely related to glycolipid metabolism. Therefore, early detection of obesity can reflect the degree of obesity and glycolipid metabolism in children.