[Exploration and validation of optimal cut-off values for tPSA and fPSA/tPSA screening of prostate cancer at different ages].

Objective: To determine the total and age-specific cut-off values of total prostate specific antigen (tPSA) and the ratio of free PSA divided total PSA (fPSA/tPSA) for screening prostate cancer in China. Methods: Based on the Chinese Colorectal, Breast, Lung, Liver, and Stomach cancer Screening Trial (C-BLAST) and the Tianjin Common Cancer Case Cohort (TJ4C), males who were not diagnosed with any cancers at baseline since 2017 and received both tPSA and fPSA testes were selected. Based on Cox regression, the overall and age-specific (＜60, 60-＜70, and ≥70 years) accuracy and optimal cut-off values of tPSA and fPSA/tPSA ratio for screening prostate cancer were evaluated with time-dependent receiver operating characteristic curve (tdROC) and area under curve (AUC). Bootstrap resampling was used to internally validate the stability of the optimal cut-off value, and the PLCO study was used to externally validate the accuracy under different cut-off values. Results: A total of 5 180 participants were included in the study, and after a median follow-up of 1.48 years, a total of 332 prostate cancer patients were included. In the total population, the tdAUC of tPSA and fPSA/tPSA screening for prostate cancer were 0.852 and 0.748, respectively, with the optimal cut-off values of 5.08 ng/ml and 0.173, respectively. After age stratification, the age specific cut-off values of tPSA in the <60, 60-<70, and ≥70 age groups were 3.13, 4.82, and 11.54 ng/ml, respectively, while the age-specific cut-off values of fPSA/tPSA were 0.153, 0.135, and 0.130, respectively. Under the age-specific cut-off values, the sensitivities of tPSA screening for prostate cancer in males <60, 60-70, and ≥70 years old were 92.3%, 82.0%, and 77.6%, respectively, while the specificities were 84.7%, 81.3%, and 75.4%, respectively. The age-specific sensitivities of fPSA/tPSA for screening prostate cancer were 74.4%, 53.3%, and 55.9%, respectively, while the specificities were 83.8%, 83.7%, and 83.7%, respectively. Both bootstrap's internal validation and PLCO external validation provided similar results. The combination of tPSA and fPSA/tPSA could further improve the accuracy of screening. Conclusion: To improve the screening effects, it is recommended that age-specific cut-off values of tPSA and fPSA/tPSA should be used to screen for prostate cancer in the general risk population.

Dual Role of IGF2BP2 in Osteoimmunomodulation during Periodontitis.

Periodontitis is a complex disease characterized by distinct inflammatory stages, with a peak of inflammation in the early phase and less prominent inflammation in the advanced phase. The insulin-like growth factor 2-binding proteins 2 (IGF2BP2) has recently been identified as a new m6A reader that protects m6A-modified messenger RNAs (mRNAs) from decay, thus participating in multiple biological processes. However, its role in periodontitis remains unexplored. Here, we investigated the role of IGF2BP2 in inflammation and osteoclast differentiation using a ligature-induced periodontitis model. Our findings revealed that IGF2BP2 responded to bacterial-induced inflammatory stimuli and exhibited differential expression patterns in early and advanced periodontitis stages, suggesting its dual role in regulating this disease. Depletion of Igf2bp2 contributed to increased release of inflammatory cytokines, thereby exacerbating periodontitis after 3 d of ligature while suppressing osteoclast differentiation and ameliorating periodontitis after 14 d of ligature. Mechanistically, we demonstrated that IGF2BP2 directly interacted with Cd5l and Cd36 mRNA via RNA immunoprecipitation assay. Overexpression of CD36 or recombinant CD5L rescued the osteoclast differentiation ability of Igf2bp2-null cells upon lipopolysaccharide stimulus, and thus the downregulation of Cd36 and Cd5l effectively reversed periodontitis in the advanced stage. Altogether, this study deepens our understanding of the potential mechanistic link among the dysregulated m6A reader IGF2BP2, immunomodulation, and osteoclastogenesis during different stages of periodontitis.

Osteoprotective Role of the Mir338 Cluster Ablation during Periodontitis.

Periodontitis is a chronic inflammatory disease that compromises the integrity of the supporting tissues of the teeth and leads to the loss of the alveolar bone. The Mir338 cluster has been proven to be a potential target for the treatment of osteoporosis and is also enriched in gingival tissues with periodontitis; however, its role in periodontitis remains unknown. Here, we aimed to use periodontitis as a model to expand our understanding of the Mir338 cluster in osteoimmunology and propose a new target to protect against bone loss during periodontitis progression. Significant enrichment of the Mir338 cluster was validated in gingival tissues from patients with chronic periodontitis and a ligature-induced periodontitis mouse model. In vivo, attenuation of alveolar bone loss after 7 d of ligature was observed in the Mir338 cluster knockout (KO) mice. Interestingly, immunofluorescence and RNA sequencing showed that ablation of the Mir338 cluster reduced osteoclast formation and elevated the inflammatory response, with enrichment of IFN-γ and JAK-STAT signaling pathways. Ablation of the Mir338 cluster also skewed macrophages toward the M1 phenotype and inhibited osteoclastogenesis via Stat1 in vitro and in vivo. Furthermore, the local administration of miR-338-3p antagomir prevented alveolar bone loss from periodontitis. In conclusion, the Mir338 cluster balanced M1 macrophage polarization and osteoclastogenesis and could serve as a novel therapeutic target against periodontitis-related alveolar bone loss.

Identification of Dental Stem Cells Similar to Skeletal Stem Cells.

Stem and progenitor cells play important roles in the development and maintenance of teeth and bone. Surface markers expressed in bone marrow-derived mesenchymal stem cells are also expressed in dental tissue-derived stem cells. Mouse skeletal stem cells (mSSCs, CD45-Ter119-Tie2-CD51+Thy-6C3-CD105-CD200+) and human skeletal stem cells (hSSCs, CD45-CD235a-TIE2-CD31-CD146-PDPN+CD73+CD164+) have been identified in bone and shown to play important roles in skeletal development and regeneration. However, it is unclear whether dental tissues also harbor mSSC or hSSC populations. Here, we employed rainbow tracers and found that clonal expansion occurred in mouse dental tissues similar to that in bone. We sorted the mSSC population from mouse periodontal ligament (mPDL) tissue and mouse dental pulp (mDP) tissue in the lower incisors by fluorescence-activated cell sorting (FACS). In addition, we demonstrated that mPDL-derived skeletal stem cells (mPDL-SSCs) and mDP-derived skeletal stem cells (mDP-SSCs) have similar clonogenic capacity, as well as cementogenic and odontogenic potential, but not adipogenic potential, similar to the characteristics of mSSCs. Moreover, we found that the dental tissue-derived mSSC population plays an important role in repairing clipped incisors. Importantly, we sorted the hSSC population from human periodontal ligament (hPDL) and human dental pulp (hDP) tissue in molars and identified its stem cell characteristics. Finally, hPDL-like and hDP-like structures were generated after transplanting hPDL-SSCs and hDP-SSCs beneath the renal capsules. In conclusion, we demonstrated that mouse and human PDL and DP tissues harbor dental stem cells similar to mSSCs and hSSCs, respectively, providing a precise stem cell population for the exploration of dental diseases.

[Impact of allergic airway diseases on risk of attention deficit hyperactivity disorder in school-age children].

Objective: To investigate the impact of allergic airway diseases on the risk of attention deficit hyperactivity disorder (ADHD) in school-age children. Method: Used stratified cluster sampling method, school-age children in first to sixth grade in primary schools in 9 randomly selected cities including Shanghai, Guangzhou, Xi'an, and Wuhan were enrolled in the study. Interview of parents with questionnaires, which included school-age individual and family social environment questionnaire (including history of diagnosed ADHD, allergic rhinitis, and bronchial asthma) and Children's Sleep Habits Questionnaire (CSHQ), were finished and collected during November to December in 2005.Diagnosed allergic rhinitis and asthma by specialist were independent variables and divided into following three categories as no allergic diseases (neither allergic rhinitis nor asthma), single allergic disease (allergic rhinitis or asthma), and combined allergic diseases (allergic rhinitis and asthma). Diagnosed ADHD as dependent variable, binary logistic regress model was used to analyze the risks of ADHD in school-age children. Result: Totally 23 791 questionnaires were handed out, while 22 018 were collected. The children had an average age of (8.8±1.8) years, within which 10 869 were male, and 11 021 were female. The risk ratios of ADHD were 2.197 (95%CI: 1.823-2.648) and 3.150 (95%CI: 2.082-4.760) in children with single allergic disease and combined allergic diseases separately. There was no significant difference after adjusting for the factor of sleep habits, as the risk ratios were 2.055 (95%CI: 1.683-2.508) and 3.140 (95%CI: 2.061-4.784) in children with single and combined allergic airway disease separately. Conclusion: Allergic rhinitis and bronchial asthma increased the risk of ADHD, not depending on sleep habits. Hence, allergic airway diseases could be independent risk factors of ADHD.

Significance of sarcomere gene mutation in patients with dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a myocardial disease with a high mortality rate. Approximately 40 genes have been found to be associated with DCM to date. Non-familial DCM can also be caused by gene mutations, suggesting that genetic factors were involved in the pathogenesis of DCM; therefore genetic testing is beneficial for the early diagnosis of DCM, which can facilitate the implementation of preventive measures by and within patient's families. Here, we investigated the underlying genetic mutations involved in the cause of patients with DCM. This prospective study included 240 patients with idiopathic DCM and 240 healthy volunteers. Subject clinical data were collected and polymerase chain reaction amplification was carried out on subject DNA for three candidate genes tropomyosin (TPM1), cardiac troponin T type-2 (TNNT2), and nuclear lamina protein A/C. Single nucleotide polymorphism (SNP) loci were detected in the TPM1 (rs1071646) and TNNT2 (rs3729547) genes, respectively. The genotype distributions and allele frequencies were found to satisfy Hardy-Weinberg equilibrium, which indicated that the group was representative. Statistically significant differences were found between the variant frequencies in the two SNP loci between the Kazakh patients with idiopathic DCM (IDCM) and healthy volunteers. A significant difference in the genotype distributions (P = 0.000) and allele frequencies (P = 0.000) of SNP rs1071646, and another significant difference in the genotype distributions (P = 0.000) and allele frequencies (P = 0.039) of SNP rs3729547 between Kazakhs with IDCM and Kazakh controls. These results suggest that the TPM1 (rs1071646) and TNNT2 (rs3729547) gene variants might represent risk factors for patients with DCM in the Kazakh population.

Effect of fasudil hydrochloride on the post-thaw viability of cryopreserved porcine adipose-derived stem cells.

BACKGROUND: Adipose-derived stem cells (ADSCs) are of interest for regenerative medicine as they are isolated easily and can differentiate into multiple cell lineages. Recently, it was reported that a Rho-associated kinase (ROCK) inhibitor Y-27632 could enhance the post-thaw viability and physiological function of cryopreserved BMSC. OBJECTIVE: The present study is to investigate whether Fasudil hydrochloride (FH, a selective Rho-kinase inhibitor like Y-27632) can exert a similar beneficial effect on the post-thaw viability of cryopreserved ADSCs. METHODS: ADSCs were allotted in three cryopreservation solutions [I:10 % (v/v) (DMSO), 30 % (v/v) FBS (as a negative control); II:10µM FH, 10 % (v/v) DMSO, 30 % (v/v) FBS; III:10 µM Y-27632, 10 % (v/v) DMSO, 30 % (v/v) fetal bovine serum, All groups were frozen using a rapid freezing method and stored at -196 degree C in liquid nitrogen for 30 days.After thawing and being cultured 24h,viability of ADSCs were detected by MTT assay. RESULT: The MTT assay showed significant differences in the proportion of adherent viable cells over the concentration of Y-27632 and FH, Additionally, FH did not induce morphological changes in the frozen-thawed ADSCs like Y-27632 did. CONCLUSIONS: FH might represent a promising cryopreservation solution in enhancing the post-thaw viability and physiological function of cryopreserved ADSCs and did not chang the cell appearance.

Effect of glutathione and Y27632 on the viability of cryopreserved porcine adipose-derived stem cells.

BACKGROUND: Recently it has been reported that reduced glutathione (GSH) and/or Rho-associated kinase (ROCK) inhibitor supplemented in cryopreservation solution could improve the viability of cells. OBJECTIVE: To identify the cryopreservation efficiency of GSH and ROCK inhibitor on porcine ADSCs. MATERIALS AND METHODS: Porcine ADSCs were separated and cultured. Cells at the 4th passage were suspended in cryopreservation solution supplemented with Y-27632 and GSH or both, and then frozen and thawed. The viability of cryopreserved ADSCs was compared using a MTT assay. RESULTS: The addition of GSH and Y-27632 to cryopreservation solution (dimethyl sulfoxide) and post-thaw culture medium significantly improves the post-thaw viability of ADSCs. CONCLUSION: GSH and Y-27632 are able to increase the survival of ADSCs, and they have an additive effect, as compared to GSH or Y27632 alone.

The value of decreased plasma gelsolin levels in patients with systemic lupus erythematosus and rheumatoid arthritis in diagnosis and disease activity evaluation.

Plasma gelsolin, the extracellular gelsolin isoform, circulates in the blood of healthy individuals at a concentration of 200 ± 50 mg/l and plays important roles in the extracellular actin-scavenging system during tissue damage. Decreased plasma gelsolin levels have been observed in many inflammatory diseases. In the present study, the variation and potential clinical application of plasma gelsolin levels in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) were analysed. Plasma samples and clinical data were collected from informed and consenting participants: 47 SLE patients, 60 RA patients and 50 age- and gender-matched healthy individuals. Semiquantitative western blotting was used for measuring plasma gelsolin levels. The plasma gelsolin levels in patients with SLE and RA were significantly decreased compared with healthy controls (145.3 ± 40.4 versus 182.7 ± 38.3 mg/l and 100.8 ± 36 versus 182.7 ± 38.3 mg/l, p < 0.001), and plasma gelsolin levels were especially lower in RA than in SLE patients (100.8 ± 36 versus 145.3 ± 40.4 mg/L, p < 0.001). An analysis of the clinical data showed a significant negative correlation between plasma gelsolin levels and SLE Disease Activity Index (SLEDAI) scores (r = 0.659, p < 0.001) but no correlation between plasma gelsolin levels and RA disease activity score 28 (DAS28) (r = 0.076, p = 0.569). Different clinical characteristics were also observed in SLE and RA patients with normal and decreased plasma gelsolin levels.This study found significantly lower plasma gelsolin levels in patients with SLE and RA compared with healthy controls and documented a significant negative correlation between plasma gelsolin levels and SLEDAI, which suggested the potential clinical application of plasma gelsolin in SLE diagnosis and disease activity evaluation. The different clinical characteristics in SLE and RA patients with normal and decreased plasma gelsolin levels indicate differences in the basis of the diseases.