Azvudine and nirmatrelvir/ritonavir (Paxlovid) are recommended for COVID-19 treatment in China, but their safety and efficacy in the elderly population are not fully known. In this multicenter, retrospective, cohort study, we identified 5131 elderly hospitalized COVID-19 patients from 32,864 COVID-19 patients admitted to nine hospitals in Henan Province, China, from December 5, 2022, to January 31, 2023. The primary outcome was all-cause death, and the secondary outcome was composite disease progression. Propensity score matching (PSM) was performed to control for confounding factors, including demographics, vaccination status, comorbidities, and laboratory tests. After 2:1 PSM, 1786 elderly patients receiving azvudine and 893 elderly patients receiving Paxlovid were included. Kaplan-Meier and Cox regression analyses revealed that compared with Paxlovid group, azvudine could significantly reduce the risk of all-cause death (log-rank P = 0.002; HR: 0.71, 95% CI: 0.573-0.883, P = 0.002), but there was no difference in composite disease progression (log-rank P = 0.52; HR: 1.05, 95% CI: 0.877-1.260, P = 0.588). Four sensitivity analyses verified the robustness of above results. Subgroup analysis suggested that a greater benefit of azvudine over Paxlovid was observed in elderly patients with primary malignant tumors (P for interaction = 0.005, HR: 0.32, 95% CI: 0.18-0.57) compared to patients without primary malignant tumors. Safety analysis revealed that azvudine treatment had a lower incidence of adverse events and higher lymphocyte levels than Paxlovid treatment. In conclusion, azvudine treatment is not inferior to Paxlovid treatment in terms of all-cause death, composite disease progression and adverse events in elderly hospitalized COVID-19 patients.

RNA modifications affect many biological processes and physiological diseases. The 5-methylcytosine (m⁵C) modification regulates the progression of multiple tumors. However, its characteristics and functions in hepatocellular carcinoma (HCC) remain largely unknown. Here, we found that HCC tissues had a higher m⁵C methylation level than the adjacent normal tissues. Transcriptome analysis revealed that the hypermethylated genes mainly participated in the phosphokinase signaling pathways, such as the Ras and PI3K-Akt pathways. The m⁵C methyltransferase NSUN2 was highly expressed in HCC tissues. Interestingly, the expression of many genes was positively correlated with the expression of NSUN2, including GRB2, RNF115, AATF, ADAM15, RTN3, and HDGF. Real-time PCR assays further revealed that the expression of the mRNAs of GRB2, RNF115, and AATF decreased significantly with the down-regulation of NSUN2 expression in HCC cells. Furthermore, NSUN2 could regulate the cellular sensitivity of HCC cells to sorafenib via modulating the Ras signaling pathway. Moreover, knocking down NSUN2 caused cell cycle arrest. Taken together, our study demonstrates the vital role of NSUN2 in the progression of HCC.
Humans ; ADAM Proteins ; Apoptosis Regulatory Proteins ; Carcinoma, Hepatocellular/metabolism* ; Liver Neoplasms/metabolism* ; Membrane Proteins ; Methyltransferases/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Repressor Proteins ; RNA, Messenger/metabolism* ; Sorafenib ; RNA Methylation/genetics*

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment. However, the mechanisms that control the resistance of EGFR-TKIs remain largely unknown. RNA structures have widespread and crucial functions in many biological regulations; however, the functions of RNA structures in regulating cancer drug resistance remain unclear. Here, the psoralen analysis of RNA interactions and structures (PARIS) method is used to establish the higher-order RNA structure maps of EGFR-TKIs-resistant and -sensitive cells of NSCLC. Our results show that RNA structural regions are enriched in untranslated regions (UTRs) and correlate with translation efficiency (TE). Moreover, yrdC N⁶-threonylcarbamoyltransferase domain containing (YRDC) promotes resistance to EGFR-TKIs. RNA structure formation in YRDC 3' UTR suppresses embryonic lethal abnormal vision-like 1 (ELAVL1) binding, leading to EGFR-TKI sensitivity by impairing YRDC translation. A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics* ; ErbB Receptors/metabolism* ; GTP-Binding Proteins/therapeutic use* ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; RNA ; RNA-Binding Proteins/genetics* ; Tyrosine Kinase Inhibitors/therapeutic use*

Objective To investigate the clinical features of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) associated hypertrophic pachymeningitis (HP).Methods Clinical data of 4 casesdiagnosed with MPO-ANCA vasculitis complicated with HP in our hospital were analyzed retrospectively and the related literaturewere reviewed.Results Four male patients with an age range from 44 to 66 years were diagnosed with ANCA-associated HP.The main clinical manifestations included headache and withvarious degree ofmultiple cranial paralysis.During active phase of the disease,all patients showed perinuclear(p)-ANCA positive,elevated levels of inflammatory biomarkers and titers of MPO-ANCA,whereas renal function,cytoplasmic (c)-ANCA and protease 3 (PR3)-ANCA were negative.Contrast-enhanced cranial magnetic resonance imaging (MRI) scan showed obviously thickened dura mater and sinusitis or mass in paranasal sinus.Four patients were sensitive to glucocorticoid.Three patients had a relapse during glucocorticoid tapering and were undercontrol when the dosage of glucocorticoid was increased and immunosuppressive agents were added.Levels of inflammatory biomarkers,titers of MPO-ANCA and p-ANCA recovered to normal,and the dural thickness on MRI was reduced in the remission stage.Conclusion MPO-ANCA associated HP is a type of central nervous system involvement in ANCA associated vasculitis (AAV).It involves the upper respiratory tract more frequently,and less frequently progresses to systemic AAV.This should be taken into consideration when middle-aged and elderly patients presented with headache and multiple cranial neuropathies.Enhanced MRI is the preferred examination for diagnosis,and dural biopsy should be done when necessary.

Great changes in drug metabolizing enzyme (DME) expression occur in the fetus and child during development. Individual hepatic DME ontogeny can be categorized into one of three groups based on developmental trajectories.Some enzymes such as CYP3A7,are expressed at highest level in the fetus dur-ing the first trimester and either remain elevated or slightly de-crease during gestation,but are silenced or reduced to relatively low levels within one to two years after birth.SULT1 A1 is an ex-ample of the second group of DME.These enzymes are ex-pressed at relatively constant levels throughout gestation and into adulthood.CYP3A4 belongs to the third DME group .These en-zymes are expressed at negligible or low levels in the fetus.Sig-nificant increases in enzyme levels are exhibited within the first one to two years after birth.The epigenetic regulation refers to genomic modifications that do not involve changes in DNA se-quence and include DNA methylation,histone modifications, and non-coding RNAs.The epigenetic regulation mechanisms are responsible for the developmental expression of DME genes dur-ing liver maturation.This review will provide a summary of DME developmental expression profiles and reveal epigenetic mecha-nisms underlying variable drug metabolism and drug response. Thus,knowledge regarding DME ontogeny has permitted im-proved capability to predict drug disposition in pediatric pa-tients,which is crucial for improving drug dosing leading to opti-mal safety and efficacy in children.

Objective To analyze the clinical characteristics of respiratory involvement in relapsing polychondritis(RPC). Methods The clinical data of 38 patients with respiratory (larynx, trachea and bronchus) involvement in RPC were retrospectively analyzed. Results The incidence of respiratory involvement in patients with RPC was 51.35%(38/74), and the most common symptoms were cough, wheezing, chest tightness and dyspnea. The incidences of erythrocyte sedimentation rate (ESR) increasing, C- reactive protein (CRP) increasing, fibrinogen increasing, D- dimer increased and rheumatoid factor (RF) positive in patients with respiratory involvement were significantly higher than those in patients without respiratory involvement: 47.37% (18/38) vs. 30.56% (11/36), 52.63% (20/38) vs. 33.33% (12/36), 31.58% (12/38) vs. 25.00% (9/36), 21.05% (8/38) vs. 13.89% (5/36) and 36.84%(14/38) vs. 5.56% (2/36), and there were statistical differences (P<0.05). CT was the main method to discover the respiratory involvement, and MRI could detect early cartilage inflammation lesions. Laryngoscope and bronchoscope could early detect mucosa and cartilage damage. Pathology was given priority to lymphocytes and neutrophils infiltration. Some patients had epithelium metaplasia and even canceration. Primary treatment methods were glucocorticoids combined with immunosuppressant. Airway stenosis and infection was the main factors influencing the prognosis of patients. Conclusions The respiratory involvement is not uncommon in RPC, and early CT, MRI, laryngoscope and bronchoscope examination is an important means of early diagnosis.Early glucocorticoid combined immunosuppressive therapy is the key to achieve good prognosis.

Objective To investigate the effect of PXR* 1B polymorphism on postoperative analgesia with fentanyl in the patients undergoing gynecological operation.Methods A total of 102 female patients from Henan province, of Han nationality, aged 20-50 yr, of American Society of Anesthesiologists physical status Ⅰ or Ⅱ , with body mass index of 14.8-30.0 kg/m2, scheduled for elective abdominal total hysterectomy or myomectomy under general anesthesia, were enrolled in this study.PXR genetic polymorphic sites were analyzed by polymerase chain reaction (PCR)-direct DNA sequencing.PXR* 1B haplotype was analyzed by the PHASE V.2.1 software.The patients were assigned into 3 groups according to their genotypes: PXR* 1B haplotype group (group PXR* 1B), non-PXR* 1B haplotype group (group n-PXR* 1B) and PXR* 1B/PXR * 1B group (group PXR* 1B/PXR* 1B).Postoperative pain was assessed with visual analogue scale (VAS) score.When VAS ＞ 3, fentanyl 20 μg was injected intermittently until VAS ≤ 3, and then a pump was connected to perform patient-controlled intravenous analgesia (PCIA) with fentanyl.PCIA solution contained fentanyl 1.0 mg and droperidol 5 mg in 100 ml of normal saline.The PCA pump was set up with a 2 ml bolus dose, a 5 min lockout interval and background infusion at a rate of 0.5 ml/h.The number of successfully delivered doses was set at 7 times, and the maximal amount of fentanyl was 145 μg.If exceeding the maximal dose, the VAS score was still more than 3, nonsteroidal anti-inflammatory drugs were given as rescue medication.VAS score immediately after the end of operation, and the consumption of fentanyl within 24 h after operation were recorded.Midazolam 0.1 mg/kg was injected intravenously during induction of general anesthesia, and 1 h later venous blood samples were collected for determination of plasma 1'-hydroxymidazolam and midazolam concentrations.The ratio of 1'-hydroxymidazolam concentration to midazolam concentration was calculated to reflect the activity of CYP3A4.Results No patients required rescue anesthetics in the three groups.There were 27 cases in group PXR * 1B, 53 cases in group n-PXR* 1B, and 22 cases in group PXR* 1B/PXR* 1B.PXR* 1B allele frequency was 37.2％.There was no significant difference in VAS score immediately after the end of operation, consumption of fentanyl within 24 h after operation, and activity of CYP3A4 between the three groups (P＞0.05).Conclusion PXR* 1B polymorphism has no effect on postoperative analgesia with fentanyl in the patients undergoing gynecological operation, and is not one of the genetic factors producing individual variation in postoperative analgesia.

BACKGROUND:Adipose-derived stem cels are regarded as the potential seed cels for tissue engineering. Colagenase digestion is used to isolate adipose-derived stem cels from fat pads currently. However, there are some problems, such as cumbersome operation and high cost.
OBJECTIVE: To study the basic biological characteristics of adipose-derived stem cels by tissue explants culture and to explore the differentiation potential into osteoblasts, adipocytes and endothelial progenitor cels in vitro.
METHODS:Adipose-derived stem cels were isolated by tissue explants technique from the bilateral groin fat pads of rats under aseptic conditions, and cultured in vitro. Cel counting kit-8 was used to detect the proliferative activity, and flow cytometry was employed to analyze the expression of cel surface markers. Passage 4 adipose-derived stem cels were cultured in osteogenic medium, adipogenic medium and endothelial progenitor cel medium for 2-3 weeks, and then the cels were identified.
RESULTS AND CONCLUSION:Adipose-derived stem cels that were isolated by tissue explants culture were easily cultured, and after subculture, cels were mainly spindle-shaped and grew in clone-like manner with swirling arrangement. Cels that experienced repeated subcultures stil kept stronger proliferative ability and the cel growth curve was shaped as a parabola. Immunochemical staining analysis revealed that adipose-derived stem cels were positive for CD44, CD90 and CD29, but negative for CD31, CD45. After adipogenic/osteogenic induction, the cels were respectively positive for oil red O staining and alizarin red staining. Induced endothelial progenitor cels were identified with CD34 and the ability to uptake Dil-ac-LDL and FITC-UEA. These findings indicate using the using tissue explants culture, high-purity adipose-derived stem cels easy to proliferate can be harvested, highly express stem cels-related antigens, and have the ability to differentiate into osteoblasts, adipocytes and endothelial progenitor cels, which meet the needs of seed cels in tissue engineering research.

ObjectiveTo evaluate the effect of high frequency oscillation ventilation (HFOV) vs. conventional mechanical ventilation (CV) on the treatment and prognosis of adult patients with acute respiratory distress syndrome (ARDS).Methods Published articles concerning randomized controlled trials (RCTs) about the effect of HFOV vs. CV on the prognosis of adult patients with ARDS published before May 2014 were retrieved from PubMed, EMBase, Cochrane central registry of controlled trials, CNKI and Wanfang Data. The mortality and data of physiological parameters were analyzed with STATA 12.0, and the mortality rate was also analyzed by trial sequential analysis with TSA 0.9, and the line chart was drawn with Microsoft Office Excel 2003.Results Seven trials with 1 731 patients met the criteria, all of them recorded the physiological parameters data, and mortality rate was mentioned in 6 trials (1 705 patients). Compared with CV, HFOV did not show any statistically significant beneficial effects on mortality [relative risk (RR) = 0.93, 95% confidence interval (95%CI) = 0.70-1.24,P = 0.63], and other clinical outcomes, including survival without mechanical ventilation (RR = 1.05, 95%CI = 0.72-1.54,P = 0.80), survival on mechanical ventilation (RR = 1.23, 95%CI = 0.65-2.35,P = 0.52), or treatment failure (RR = 0.89, 95%CI = 0.50-1.56,P = 0.67). The risk factors of adverse events including hypotension (RR = 0.89, 95%CI = 0.07-10.99,P =0.93), acidosis (RR = 1.05, 95%CI = 0.43-2.56,P = 0.91), and air leakage from ventilator (RR = 0.74, 95%CI = 0.31-1.80,P =0.51) were similar. But the physiologic parameters of patients and parameters of ventilator in HFOV group, including oxygenation index, positive end-expiratory pressure, tidal volume, mean airway pressure, arterial pH, partial pressure of arterial carbon dioxide, fraction of inspired oxygen, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, were better than those in the CV group. Methods adapted from formal interim monitoring boundaries applied to cumulative Meta-analysis showed that the evidence failed by a considerable degree to meet the standards for forgoing studies, and the necessary sample was 3 874 patients. Trial sequential analysis also showed that the accumulatedZ-score did not cross the traditional boundary (P = 0.05) and interim monitoring boundaries. This result indicated that there was no significant difference between CV and HFOV on mortality before the number of needed sample reached (3 874 cases). We could not get a definitive conclusion with current evidences.ConclusionsCompared with CV, the use of HFOV in ARDS was not associated with a significant reduction in mortality. But the physiologic parameters of patients in HFOV group were better than those in the CV group. More RCTs are needed to draw a definitive conclusion.

OBJECTIVETo study the CPS-II mechanism underlying the pathological process of elevated blood ammonia leading to liver injury.

METHODSAn in vitro hyperammonemia hepatocyte cell model was constructed by exposure to various concentrations of NH4Cl. The subsequent changes to cellular morphology were observed by microscopy. to cell apoptosis were determined by flow cytometry, and to mRNA and protein expression of CPS-II were examined by real-time PCR and western blotting, respectively.

RESULTSExposure to NH₄Cl led to dose-dependent morphological damage, apoptosis and necrosis of the hepatocytes. The apoptosis rate was significantly higher for the high-dose group than for the control (no exposure) group (24.7% ± 2.39% vs. 4.1% ± 0.78%, q =8.06, P less than 0.05). Expression of the CPS-II mRNA was significantly elevated in response to NH₄Cl exposure (vs. the control group; F=191.881, P < 0.05).The CPS-II mRNA expression level increased with increasing NH₄Cl concentration (grey values: 1.040 ± 0.045, 1.641 ± 0.123, 2.285 ± 0.167 and 3.347 ± 0.124, respectively). The CPS-II protein expression level was also significantly enhanced in response to the NH₄Cl exposures (CPS-II protein and internal GAPDH grey value ratios: 0.099 ± 0.0130, 0.143 ± 0.025, 0.161 ± 0.036 and 0.223 ± 0.042, respectively; t=3.825, 3.968 and 6.908, P less than 0.05).

CONCLUSIONCPS-II mRNA and protein expression levels become elevated with increase in the NH₄Cl concentrations, suggesting that in addition to the urea cycle, CPS-II may play an important role in the ammonia metabolism under the condition of hyperammonemia.