Viruses constitute a significant group of pathogens that have caused numerous fatalities and substantial economic losses in recent years, particularly with the emergence of coronaviruses. While the impact of SARS-CoV-2 appears to be diminishing in daily life, only a limited number of drugs have received approval or emergency use authorization for its treatment. Given the high mutation rate of viral genomes, host-directed agents (HDAs) have emerged as a preferred choice due to their broad applicability and lasting effectiveness. In contrast to direct-acting antivirals (DAAs), HDAs offer several advantages, including broad-spectrum antiviral activities, potential efficacy against future emerging viruses, and a lower likelihood of inducing drug resistance. In our review article, we have synthesized known host-directed antiviral targets that span diverse cellular pathways and mechanisms, shedding light on the intricate interplay between host cells and viruses. Additionally, we have provided a brief overview of the development of HDAs based on these targets. We aim for this comprehensive analysis to offer valuable perspectives and insights that can guide future antiviral research and drug development efforts.

The regulatory processes in developmental biology research are significantly influenced by long non-coding RNAs (lncRNAs). However, the dynamics of lncRNA expression during human tooth development remain poorly understood. In this research, we examined the lncRNAs present in the dental epithelium (DE) and dental mesenchyme (DM) at the late bud, cap, and early bell stages of human fetal tooth development through bulk RNA sequencing. Developmental regulators co-expressed with neighboring lncRNAs were significantly enriched in odontogenesis. Specific lncRNAs expressed in the DE and DM, such as PANCR, MIR205HG, DLX6-AS1, and DNM3OS, were identified through a combination of bulk RNA sequencing and single-cell analysis. Further subcluster analysis revealed lncRNAs specifically expressed in important regions of the tooth germ, such as the inner enamel epithelium and coronal dental papilla (CDP). Functionally, we demonstrated that CDP-specific DLX6-AS1 enhanced odontoblastic differentiation in human tooth germ mesenchymal cells and dental pulp stem cells. These findings suggest that lncRNAs could serve as valuable cell markers for tooth development and potential therapeutic targets for tooth regeneration.
Humans ; RNA, Long Noncoding/metabolism* ; Odontogenesis/genetics* ; Tooth Germ/embryology* ; Cell Differentiation ; Gene Expression Regulation, Developmental ; Mesoderm/metabolism* ; Tooth/embryology* ; Gene Expression Profiling ; Sequence Analysis, RNA ; Dental Pulp/cytology*

Objective To explore the pharmacokinetic characteristics of sufentanil in individuals with normal body mass index(BMI),overweight BMI,and different CYP3A4/5 enzyme genotypes.Methods The patients receiving laparoscopic surgery under general anesthesia in the First Affiliated Hospital of Army Medical University from November 2020 to September 2021 were prospectively recruited in this study.Before the operation,the oral swabs were collected from all the patients for genotyping using the human CYP3A4/5 gene kit.Based on the potential impact of combination of their polymorphisms on sufentanil metabolism and the proportion of different genotype combinations of CYP3A4/5 enzymes,the patients were divided into groups I(3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation),II(3A4 heterozygous mutation+3A5 heterozygous mutation),and III(3A4 wild type or 3A4 heterozygous mutation+3A5 wild type).According to their BMI,they were also assigned into a normal body weight group(18.5～24.0 kg/m2)and an overweight group(24～<28 kg/m2),and the differences in drug metabolism parameters were statistically analyze between the 2 groups.After routine general anesthesia induction(sufentanil 0.5 μg/kg),venous blood samples were collected to detect the changes in its concentration using high performance liquid chromatography-mass spectrometry(HPLC-MS).The pharmacokinetic data of sufentanil were calculated between the normal BMI group and overweight group in all participants and between the 2 body weight groups among those with different genotype combinations.Results Among the 90 participants completing the blood drug concentration test,8 patients had their blood samples contaminated(including 1 case with an anesthesia duration of<2 h),and 3 were excluded due to low weight or overweight.Eventually,79 participants were included in the pharmacokinetic analysis on the normal body weight group and the overweight group.Compared with the normal body weight group,the central compartment volume of distribution in the overweight group was significantly reduced(P<0.05),while no obvious differences were observed between the 2 groups in terms of peripheral compartment volume of distribution,total clearance rate,peripheral compartment clearance rate,distribution half-life,clearance half-life,and area under the blood concentration-time curve.In group Ⅰ(n=26),the overweight patients(n=13)had significantly reduced central compartment volume of distribution,peripheral compartment volume of distribution,and peripheral compartment clearance rate when compared with the normal body weight patients(n=13)(P<0.05),while no differences were observed in other pharmacokinetic parameters.In groups Ⅱ(n=25)and Ⅲ(n=28),the overweight patients and normal body weight patients had no statistical differences in all pharmacokinetic parameters.Conclusion Among the patients with the same genotype combination of CYP3A4/5 mutations,there was no difference in the metabolism of sufentanil between the overweight and normal weight patients.Additionally,in the population of 3A4 homozygous mutation or 3A4 heterozygous mutation+3A5 homozygous mutation,the overweight patients have smaller peripheral distribution range of sufentanil,and weakened metabolic process.

Identification of disease-specific cell subtypes (DSCSs) has profound implications for understanding disease mechanisms, preoperative diagnosis, and precision therapy. However, achieving unified annotation of DSCSs in heterogeneous single-cell datasets remains a challenge. In this study, we developed the gPRINT algorithm (generalized approach for cell subtype identification with single cell's voicePRINT). Inspired by the principles of speech recognition in noisy environments, gPRINT transforms gene position and gene expression information into voiceprints based on ordered and clustered gene expression phenomena, obtaining unique "gene print" patterns for each cell. Then, we integrated neural networks to mitigate the impact of background noise on cell identity label mapping. We demonstrated the reproducibility of gPRINT across different donors, single-cell sequencing platforms, and disease subtypes, and its utility for automatic cell subtype annotation across datasets. Moreover, gPRINT achieved higher annotation accuracy of 98.37% when externally validated based on the same tissue, surpassing other algorithms. Furthermore, this approach has been applied to fibrosis-associated diseases in multiple tissues throughout the body, as well as to the annotation of fibroblast subtypes in a single tissue, tendon, where fibrosis is prevalent. We successfully achieved automatic prediction of tendinopathy-specific cell subtypes, key targets, and related drugs. In summary, gPRINT provides an automated and unified approach for identifying DSCSs across datasets, facilitating the elucidation of specific cell subtypes under different disease states and providing a powerful tool for exploring therapeutic targets in diseases.
Humans ; Algorithms ; Single-Cell Analysis ; Databases, Genetic ; Molecular Sequence Annotation

Objective:To explore the efficacy of letrozole combined with palbociclib in the treatment of hormone receptor +/human epidermal growth factor receptor-2 - (HR +/HER2 -) advanced breast cancer and its influence on serum thymidine kinase 1 (TK1) and proliferating cell nuclear antigen (Ki67) levels. Methods:A total of 82 patients with HR +/HER2 - advanced breast cancer, all admitted from Jan. 2022 to Jan. 2024 from Department of Oncology, Affiliated Hospital of Jining Medical University, were assigned to the control group ( n=41, letrozole) and the study group ( n=41, letrozole + palbociclib) according to the random number table. The therapeutic effect, tumor markers, immune function and serum TK1 and Ki67 levels were compared between the two groups. Results:The study group higher objective response rate and disease control rate than the other group [14.63% (6/41) and 85.37% (35/41) vs. 0.00% (0/41) and 58.54% (24/41) ] (Continuity correction χ2/χ2=4.50, 7.31, P<0.05). After treatment, carbohydrate antigen 153 (CA153), CA125 and carcinoembryonic antigen (CEA) in the study group were lower than the control group [ (12.17±3.19) U/mL, (23.57±3.35) U/mL and (19.51±4.13) ng/mL vs (24.37±5.25) U/mL, (35.16±5.08) U/mL, (34.28±5.72) ng/mL] ( t=12.72, 12.20, 13.41, P<0.05), serum TK1 and Ki67 levels were also lower [ (3.61±0.75) pmol/L and (7.89±1.16) ng/mL vs. (4.76±0.88) pmol/L and (10.85±1.94) ng/mL] ( t=6.37, 8.39, P<0.05). After treatment, CD3 +, CD4 +, CD4 +/CD8 + higher than the control group [ (48.64±5.88) %, (31.34±4.06) %, (1.22±0.27) vs. (43.16±6.09) %, (27.04±3.35) %, (0.87±0.35) ] ( t=4.15, 5.23, 5.07, P<0.05), while CD8 + was lower [ (25.73±4.11) % vs. (30.94±4.47) %] ( t = 5.49, P<0.05) . Conclusions:Letrozole combined with palbociclib is effective in the treatment of HR +/HER2 - advanced breast cancer and can reduce tumor markers and serum TK1 and Ki67 levels in patients.

Objective:To investigate the factors for adverse pregnancy outcomes and the value of throm-boelastography(TEG)in patients with prethrombotic state(PTS)during pregnancy.Methods:A total of 183 preg-nant women with PTS treated at the Department of Obstetrics,Xiangya Third Hospital,Central South University,from January 2020 to September 2023 were retrospectively analyzed.These women were divided into two groups based on pregnancy outcomes:the favorable pregnancy outcome group(97 cases)and the adverse pregnancy outcome group(86 cases).The risk factors for adverse pregnancy outcomes were evaluated by univariate and multivariate analyses,and the diagnostic value of TEG was assessed using the receiver operating characteristic(ROC)curve and Kaplan-Meier method.Results:The results of univariate analysis indicated that,compared to-the favorable pregnancy outcome group,the positive rates of antinuclear antibody(ANA),anticardiolipin antibody(ACA),and anti-beta2 glycoprotein antibody 1(β2-GP1)were higher in the adverse pregnancy outcome group(P<0.05),and lower utilization rates of hydroxychloroquine and low-molecular heparin(P<0.05),and shorter clotting reaction time in the thromboelastography(TEG-R)(P<0.05).Multivariate Logistic regression analyses revealed that TEG-R,ANA,β2-GP1 and gestational age at treatment initiation were all independent risk factors for adverse pregnancy outcome in pregnant women with PTS during pregnancy(P<0.05).ROC curve analysis showed the area under the curve for TEG-R was 0.632(95%Cl 0.551-0.741).At a TEG-R value of 4.65 min,the specificity was 0.948 and the sensitivity was 0.302.Kaplan-Meier survival curve analysis revealed that the gesta-tional weeks of pregnant women with an TEG-R>4.65 min were significantly longer than those with an TEG-R≤4.65 min.These results were statistically significant(P<0.01).Conclusions:ANA,ACA,β2-GP1,and TEG are valuable for predicting and evaluating adverse pregnancy outcomes in PTS patients.The TEG-R value≤4.65 min may serve as a critical threshold to guid anticoagulant therapy during pregnancy.

Objective:To explore the efficacy of letrozole combined with palbociclib in the treatment of hormone receptor +/human epidermal growth factor receptor-2 - (HR +/HER2 -) advanced breast cancer and its influence on serum thymidine kinase 1 (TK1) and proliferating cell nuclear antigen (Ki67) levels. Methods:A total of 82 patients with HR +/HER2 - advanced breast cancer, all admitted from Jan. 2022 to Jan. 2024 from Department of Oncology, Affiliated Hospital of Jining Medical University, were assigned to the control group ( n=41, letrozole) and the study group ( n=41, letrozole + palbociclib) according to the random number table. The therapeutic effect, tumor markers, immune function and serum TK1 and Ki67 levels were compared between the two groups. Results:The study group higher objective response rate and disease control rate than the other group [14.63% (6/41) and 85.37% (35/41) vs. 0.00% (0/41) and 58.54% (24/41) ] (Continuity correction χ2/χ2=4.50, 7.31, P<0.05). After treatment, carbohydrate antigen 153 (CA153), CA125 and carcinoembryonic antigen (CEA) in the study group were lower than the control group [ (12.17±3.19) U/mL, (23.57±3.35) U/mL and (19.51±4.13) ng/mL vs (24.37±5.25) U/mL, (35.16±5.08) U/mL, (34.28±5.72) ng/mL] ( t=12.72, 12.20, 13.41, P<0.05), serum TK1 and Ki67 levels were also lower [ (3.61±0.75) pmol/L and (7.89±1.16) ng/mL vs. (4.76±0.88) pmol/L and (10.85±1.94) ng/mL] ( t=6.37, 8.39, P<0.05). After treatment, CD3 +, CD4 +, CD4 +/CD8 + higher than the control group [ (48.64±5.88) %, (31.34±4.06) %, (1.22±0.27) vs. (43.16±6.09) %, (27.04±3.35) %, (0.87±0.35) ] ( t=4.15, 5.23, 5.07, P<0.05), while CD8 + was lower [ (25.73±4.11) % vs. (30.94±4.47) %] ( t = 5.49, P<0.05) . Conclusions:Letrozole combined with palbociclib is effective in the treatment of HR +/HER2 - advanced breast cancer and can reduce tumor markers and serum TK1 and Ki67 levels in patients.

Objective:To investigate the factors for adverse pregnancy outcomes and the value of throm-boelastography(TEG)in patients with prethrombotic state(PTS)during pregnancy.Methods:A total of 183 preg-nant women with PTS treated at the Department of Obstetrics,Xiangya Third Hospital,Central South University,from January 2020 to September 2023 were retrospectively analyzed.These women were divided into two groups based on pregnancy outcomes:the favorable pregnancy outcome group(97 cases)and the adverse pregnancy outcome group(86 cases).The risk factors for adverse pregnancy outcomes were evaluated by univariate and multivariate analyses,and the diagnostic value of TEG was assessed using the receiver operating characteristic(ROC)curve and Kaplan-Meier method.Results:The results of univariate analysis indicated that,compared to-the favorable pregnancy outcome group,the positive rates of antinuclear antibody(ANA),anticardiolipin antibody(ACA),and anti-beta2 glycoprotein antibody 1(β2-GP1)were higher in the adverse pregnancy outcome group(P<0.05),and lower utilization rates of hydroxychloroquine and low-molecular heparin(P<0.05),and shorter clotting reaction time in the thromboelastography(TEG-R)(P<0.05).Multivariate Logistic regression analyses revealed that TEG-R,ANA,β2-GP1 and gestational age at treatment initiation were all independent risk factors for adverse pregnancy outcome in pregnant women with PTS during pregnancy(P<0.05).ROC curve analysis showed the area under the curve for TEG-R was 0.632(95%Cl 0.551-0.741).At a TEG-R value of 4.65 min,the specificity was 0.948 and the sensitivity was 0.302.Kaplan-Meier survival curve analysis revealed that the gesta-tional weeks of pregnant women with an TEG-R>4.65 min were significantly longer than those with an TEG-R≤4.65 min.These results were statistically significant(P<0.01).Conclusions:ANA,ACA,β2-GP1,and TEG are valuable for predicting and evaluating adverse pregnancy outcomes in PTS patients.The TEG-R value≤4.65 min may serve as a critical threshold to guid anticoagulant therapy during pregnancy.

Objective To analyze the factors related to early allograft dysfunction(EAD)after liver transplantation and to construct a predictive model.Methods A total of 375 patients who underwent liver transplantation in our hospital from December 2008 to December 2021 were collected,including 90 patients with EAD and 266 patients without EAD.Thirty items of baseline data for the 2 groups were compared and analyzed.Aftergrouping in a ratio of 7∶3,univariate and multivariate logistic regression analyses were used in the training set to evaluate the factors related to EAD and construct a nomogram.Receiver operating characteristic(ROC)curve,decision curve analysis(DCA),sensitivity,specificity,positive predictive value,negative predictive value,Kappa value and other indicators were used to evaluate the model performance.Results The incidence of EAD after liver transplantation was 24%.Multivariate logistic regression analysis showed that preoperative tumor recurrence history(OR=3.15,95%CI:1.28～7.77,P=0.013)and operation time(OR=1.22,95%CI:1.04～1.42,P=0.015)were related to the occurrence of EAD after surgery.After predicting the outcome according to the cut-off point of 0.519 identified by the Youden index,the model performance in the both training set and validation set was acceptable.DCA suggested the model has good clinical applicability.Conclusion The risk factors for EAD after liver transplantation are preoperative tumor recurrence history and operation time,and the established model has predictive effect on prognosis.

Objective:To investigate the value of serum miR-145 and matrixmetallo proteinase-2 (MMP-2) levels in predicting pathologic complete response (pCR) after neoadjuvant chemotherapy in triple-negative breast cancer.Methods:125 patients with triple-negative breast cancer who received neoadjuvant chemotherapy in the Hospital from Jan. 2022 to Dec. 2023 were prospectively included as the study objects, and 130 healthy people matching the age of the case group who underwent physical examination in our hospital during the same period were included as the healthy control group. Real-time fluorescence quantitative polymerase chain reaction was used to detect the serum miR-145 level of all subjects. Serum MMP-2 levels were determined by enzyme-linked immunosorbent assay (ELISA). After neoadjuvant chemotherapy, patients were evaluated according to Miller-Payne (MP) grading criteria and divided into pCR group and non-PCR group.Results:The serum miR-145 level in patients with tertiary breast cancer was 1.49±0.27, which was significantly lower than that in healthy control group (2.79±0.49), with statistical significance ( t=20.33, P<0.001). The serum MMP-2 level in triple negative breast cancer patients was (153.07±38.36) ng/mL, which was significantly higher than that in healthy control group (84.38±12.63) ng/mL, and the difference was statistically significant ( t=26.13, P<0.001). After neoadjuvant chemotherapy, the serum miR-145 level in non-PCR patients before treatment was 1.36±0.21, which was significantly lower than that in pCR group (1.74±0.20), with statistical significance ( t=9.93, P<0.001). After neoadjuvant chemotherapy, the serum MMP-2 level in non-PCR patients before treatment was (169.57±30.45) ng/mL, which was significantly higher than that in pCR group (121.61±31.79) ng/mL, and the difference was statistically significant ( t=8.24, P<0.001). Pearson correlation analysis showed that there was a significant negative correlation between serum miR-145 and MMP-2 levels in patients with triple-negative breast cancer before treatment ( r=-0.47, P<0.001). ROC curve analysis results showed that serum miR-145 and MMP-2 levels before treatment predicted the sensitivity and specificity of pCR after neoadjuvant chemotherapy for triple-negative breast cancer were 82.9% and 74.4%, 45.1% and 99.8%, respectively. The sensitivity and specificity of pCR after neoadjuvant chemotherapy for triple-negative breast cancer were 84.1% and 88.4%, respectively. Conclusion:Serum miR-145 and MMP-2 levels are related to the efficacy of neoadjuvant chemotherapy in patients with triple-negative breast cancer, and the combined application of the two has certain predictive value.