LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer.

Lysine-specific demethylase 1 (LSD1 or KDM1A ) has emerged as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Among mCRPC subtypes, neuroendocrine prostate cancer (NEPC) is an exceptionally aggressive variant driven by lineage plasticity, an adaptive resistance mechanism to androgen receptor axis-targeted therapies. Our study shows that LSD1 expression is elevated in NEPC and associated with unfavorable clinical outcomes. Using genetic approaches, we validated the on-target effects of LSD1 inhibition across various models. We investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor with low nanomolar potency. Our findings demonstrate potent antitumor activity against CRPC models, including tumor regressions in NEPC patient-derived xenografts. Mechanistically, our study uncovers that LSD1 inhibition suppresses the neuronal transcriptional program by downregulating ASCL1 through disrupting LSD1:INSM1 interactions and de-repressing YAP1 silencing. Our data support the clinical development of LSD1 inhibitors for treating CRPC - especially the aggressive NE phenotype. Statement of Significance: Neuroendocrine prostate cancer presents a clinical challenge due to the lack of effective treatments. Our research demonstrates that bomedemstat, a potent and selective LSD1 inhibitor, effectively combats neuroendocrine prostate cancer by downregulating the ASCL1- dependent NE transcriptional program and re-expressing YAP1.

[Humanized anti-CD25 monoclonal antibody as a salvage therapy for steroid-refractory acute graft-versus-host disease after hematopoietic stem cell transplantation].

Objective: To investigate the efficacy of humanized anti-CD25 monoclonal antibody for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods: A total of 64 patients with SR-aGVHD between June 2019 and October 2020 in Suchow Hopes Hematology Hospital were enrolled in this study. Humanized anti-CD25 monoclonal antibodies 1 mg·kg(-1)·d(-1) were administered on days 1, 3, and 8, and then once per week according to the disease progression. Efficacy was assessed at days 7, 14, and 28 after humanized anti-CD 25 treatment. Results: Of the 64 patients with a median age of 31 (15-63) years, 38 (59.4%) were male and 26 (40.6%) were female. The overall response (OR) rate of the humanized CD25 monoclonal antibody in 64 patients with SR-aGVHD on days 7, 14, and 28 were 48.4% (31/64), 53.1% (34/64), and 79.7% (51/64), respectively. Liver involvement is an independent risk factor for poor efficacy of humanized CD25 monoclonal antibody for SR-aGVHD at day 28 (OR=9.588, 95% CI 0.004-0.291, P=0.002). The median follow-up time for all patients was 17.1 (0.2-50.8) months from the start of humanized CD25 monoclonal antibody therapy. The 1- and 2-year OS rates were 63.2% (95% CI 57.1% -69.3%) and 52.6% (95% CI 46.1% -59.1%), respectively. The 1- and 2-year DFS rates were 58.4% (95% CI 52.1% -64.7%) and 49.8% (95% CI 43.4% -56.2%), respectively. The 1- and 2-year NRM rates were 28.8% (95% CI 23.1% -34.5%) and 32.9% (95% CI 26.8% -39.0%), respectively. The results of the multifactorial analysis showed that liver involvement (OR=0.308, 95% CI 0.108-0.876, P=0.027) and GVHD grade Ⅲ/Ⅳ (OR=9.438, 95% CI 1.211-73.577, P=0.032) were independent risk factors for OS. Conclusion: Humanized CD25 monoclonal antibody has good efficacy and safety for SR-aGVHD. This study shows that SR-aGVHD with pretreatment grade Ⅲ/Ⅳ GVHD and GVHD involving the liver has poor efficacy and prognosis and requires early intervention.

[Analysis of clinical presentation and genetic characteristics of malignant infantile osteopetrosis].

Objective: To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. Methods: This was a retrospective case study. Thirty-seven children with malignant infantile osteopetrosis admitted into Beijing Children's Hospital from January 2013 to September 2022 were enrolled in this study. According to the gene mutations, the patients were divided into the CLCN7 group and the TCIRG1 group. Clinical characteristics, laboratory tests, and prognosis were compared between two groups. Wilcoxon test or Fisher exact test were used in inter-group comparison. The survival rate was estimated with the Kaplan-Meier method and the Log-Rank test was used to compare the difference in survival between groups. Results: Among the 37 cases, there were 22 males and 15 females. The age of diagnosis was 0.5 (0.2, 1.0) year. There were 13 patients (35%) and 24 patients (65%) with mutations in CLCN7 and TCIRGI gene respectively. Patients in the CLCN7 group had an older age of diagnosis than those in the TCIRGI group (1.2 (0.4, 3.6) vs. 0.4 (0.2, 0.6) years, Z=-2.60, P=0.008). The levels of serum phosphorus (1.7 (1.3, 1.8) vs. 1.1 (0.8, 1.6) mmol/L, Z=-2.59, P=0.010), creatine kinase isoenzyme (CK-MB) (457 (143, 610) vs. 56 (37, 82) U/L, Z=-3.38, P=0.001) and the level of neutrophils (14.0 (9.9, 18.1) vs. 9.2 (6.7, 11.1) ×109/L, Z=-2.07, P=0.039) at diagnosis were higher in the CLCN7 group than that in the TCIRG1 group. However, the level of D-dimer in the CLCN7 group was lower than that in the TCIRGI group (2.7 (1.0, 3.1) vs. 6.3 (2.5, 9.7) µg/L, Z=2.83, P=0.005). After hematopoietic stem cell transplantation, there was no significant difference in 5-year overall survival rate between the two groups (92.3%±7.4% vs. 83.3%±7.6%, χ²=0.56, P=0.456). Conclusions: TCIRGI gene mutations are more common in children with osteopetrosis. Children with TCIRGI gene mutations have younger age, lower levels of phosphorus, CK-MB, and neutrophils and higher level of D-dimer at the onset. After hematopoietic stem cell transplantation, patients with CLCN7 or TCIRGI gene mutations have similar prognosis.

[Distribution characteristics of plasma renin concentration in patients with aldosterone-producing adenoma].

Objective: To analyze the distribution characteristics of plasma renin concentration (PRC) in patients with aldosterone-producing adenoma (APA) and its impact on diagnosis. Methods: In this retrospective case series, clinical data from 200 patients with APA (80 men and 120 women; mean age 45.6 years) in the First Affiliated Hospital of Chongqing Medical University from November 2013 to January 2022 were evaluated. PRC was determined by automated chemiluminescence immunoassay. The distribution characteristics of PRC were analyzed, and 8.2 mU/L was used as the low renin cutoff to evaluate whether renin was suppressed. Results: The median PRC was 1.6 mU/L (range, 0.4-41.5 mU/L). There were 116 patients with APA with PRC of ≤2 mU/L, 41 patients with 28.2 mU/L) in 8.0% (16/200) of the patients with APA. And PRC was not suppressed in 2.5% (5/200) of the patients with APA, resulting in a primary aldosteronism negative screening outcome. Conclusions: Although most patients with APA have low PRC, there are a small number (8%) of patients whose PRC has not been fully suppressed, which can lead to missed diagnoses during primary aldosteronism screening. While primary aldosteronism is highly suspected, further investigations are required to determine the diagnosis, even if PRC is not fully suppressed at screening.

[Comparison of efficacy and safety of transurethral thulium laser vapoenucleation of prostate and transurethral thulium laser enucleation of prostate in the treatment of benign prostatic hyperplasia].

Objective: To compare early outcomes between transurethral thulium laser vapoenucleation of prostate and transurethral thulium laser enucleation of prostate for the treatment of benign prostatic hyperplasia (BPH). Methods: Retrospective analysis was conducted on the clinical data of 1 638 BPH patients admitted to the Department of Urology of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine from January 2018 to December 2021. There were 916 patients underwent transurethral thulium laser vapoenucleation of prostate (ThuVEP group) and 722 patients underwent transurethral thulium laser enucleation of prostate (ThuLEP group). The operation time, eliminated tissue weight, surgical complications, duration of post-operative catheter implantation were compared between the two groups. The improvement of International Prostate Symptom Score (IPSS), Quality of Life Index (QoL), maximum uroflow rate (Qmax) and post-void residual urine volume (PVR) at 1 month after operation was compared between the two groups. Results: There were no significant differences in age, preoperative and 1-month postoperative prostate volume, IPSS score, QoL score, Qmax, and PVR between the ThuVEP and ThuLEP group (all P>0.05). There were no significant differences in perioperative indicators such as operation time, cutting or enucleation time, tissue crushing time, tissue weight, hemoglobin change, catheter indwelling time, and postoperative hospital stay between ThuVEP group and ThuLEP group (all P>0.05). The incidence of minor gross hematuria after extubation in the ThuVEP group was 7.8% (56/916), which was lower than 9.4% (65/722) in the ThuLEP group (P=0.026); the incidence of temporary incontinence at 1 month after surgery was 5.2% (38/916) in ThuVEP group, lower than 11.9% (86/722) in ThuLEP group (P<0.001). A total of 3 patients (0.4%) in ThuLEP group required operative intervention for severe post-operation bleeding, but none of ThuVEP group suffered from this kind of surgical complications. Conclusions: ThuVEP has similar efficacy with ThuLEP for the treatment of BPH. ThuVEP can significantly reduce the incidence of post-operation temporary urine incontinence, and has much superiority in stanching bleeding.

Dietary alpha-ketoglutarate enhances intestinal immunity by Th17/Treg immune response in piglets after lipopolysaccharide challenge.

Alpha-ketoglutarate (AKG) is important for improving intestinal and systemic immune function. This study aimed to explore whether AKG enhances gut immunity in lipopolysaccharide (LPS)-challenged piglets by modulating the immune-related helper T cells 17 (Th17)/regulatory T cells (Treg) balance pathway. A 2 × 2 factor design was used on 24 pigs, with the major factors being diet (basal diet or 1% AKG diet) and immunological challenge (saline or LPS). Piglets were fed with a basal or AKG diet for 21 d and then received intraperitoneal injection of LPS or saline. The results demonstrated that AKG supplementation enhanced growth performance compared with the control group (P < 0.05). AKG improved the ileal morphological structure (P < 0.01). Finally, AKG supplementation increased interleukin (IL)-10, transforming growth factor beta-1, forkhead box P3, and signal transducer and activator of transcription 5 genes expression whereas decreasing IL-6, IL-8, IL-1ß, tumor necrosis factor-α, IL-17, IL-21, signal transducer and activator of transcription 3 and rar-related orphan receptor c genes expression (P < 0.05). These findings suggested that dietary AKG can improve the growth performance of piglets. Meanwhile, dietary AKG can alleviate LPS-induced intestinal inflammation through Th17/Treg immune response signaling pathway.

Immature digestive and immune systems cause a variety of problems. The balance of helper Tcells 17 (Th17) and regulatory T cells (Treg) is critical in maintaining normal immune function in animals. Piglets' growth performance and immune function are all influenced by alpha-ketoglutarate (AKG). However, how AKG exerts its effect on intestinal immunity in piglets through modulating the immune signaling of Th17/Treg biology has not been explored. In this study, an inflammation model was established by lipopolysaccharide (LPS) injection. This study was to test the hypothesis that AKG can enhance growth performance and attenuate LPS-challenged intestinal inflammation by modulating Th17/Treg response. We concluded that dietary AKG can improve the growth performance of piglets. Dietary AKG alleviated intestinal inflammation induced by LPS through the Th17/Treg response, thereby improving intestinal immunity. These findings can provide a theoretical foundation for utilizing AKG in weaned piglet diets for the regulation of intestinal immune activity through nutrition.

Decreased serum voriconazole levels caused by hepatic enzyme induction after rifapentine discontinuation: a case report and literature review.

BACKGROUND: Rifapentine is a rifamycin with unique bactericidal activity against Mycobacterium tuberculosis. It is also a potent inducer of CYP3A activity. However, the duration of rifapentine-induced hepatic enzyme activity after withdrawal is unclear. CASE REPORT: We report a case of a patient with Aspergillus meningitis treated with voriconazole after discontinuing rifapentine. Within ten days of rifapentine discontinuation, serum levels of voriconazole failed to reach the effective treatment range. CONCLUSIONS: Rifapentine is a potent inducer of hepatic microsomal enzymes. The induction of hepatic enzymes may exceed ten days after rifapentine discontinuation. Clinicians should be reminded of residual enzyme induction by rifapentine, especially when treating critically ill patients.

Virulence assessment of four Glaesserella parasuis strains isolated in Liaoning province of China.

Glaesserella parasuis (G. parasuis) is a part of the normal upper respiratory microbiota of healthy swine. In many studies, the serovars 1, 4, 5, and 12 of G. parasuis are considered to be highly virulent and its serovars 3, 6, 7, 9, and 11 are considered to be non-virulent. Until now, researchers have found that non-virulent strains of G. parasuis cause an increasing number of diseases. However, little is known concerning why non-virulent strains cause disease with the virulence changes. In present study, four G. parasuis strains were evaluated for their cytotoxicity property, which aims to compare their virulence. The results showed that highly virulent strains XX0306 and CY1201, as well as, non-virulent strains HLD0115 and YK1603 caused a series of pathological changes, increased lactate dehydrogenase (LDH) release, and decreased cell activity. In addition, compared to the control group, both highly and non-virulent strains showed similar trends, demonstrating that the method of classifying the virulence of G. parasuis based on its serovar is worth further deliberation. Hence, we investigated the adhesion capacity and invasion rate of G. parasuis, the results indicated that XX0306 and HLD0115 had the strongest adhesion and invasion ability, which contradicts the classification of the virulence of G. parasuis based on its serovar. The apoptosis degree induced by highly virulent strains was more intensive than non-virulent strains, as measured by annexin V and propidium iodide (PI) double staining. Through testing the expression of apoptosis-related genes Bcl-2 and Bax, we found highly virulent strains induced apoptosis by inhibiting the expression of Bcl-2.

[Reclassification of flat type sudden deafness].

Objective: To reclassify the flat type sudden deafness according to the types of audiogram shape, and to explore the correlation between different pattern of hearing loss and prognosis. Methods: All of 1 024 patients with unilateral sudden deafness (492 males and 532 females, aged from 19 to 65 years, with an average age of 41.2 years old) admitted to 33 hospitals nationwide from August 2007 to October 2011 were divided into four types according to Chinese Guideline of Sudden Deafness(2015): low-frequency, high-frequency, flat and total deafness. Then, 402 patients with flat type sudden deafness were further divided into ascending type, descending type and consistent type according to the audiogram shapes. First, we compared the clinical characteristics and prognosis among these three subtypes of flat deafness, then compared the clinical characteristics and prognosis between ascending flat deafness and low-frequency deafness, descending flat deafness and high-frequency deafness, consistent flat deafness and total deafness, explored the factors related to the prognosis of flat deafness. SPSS 21.0 software, ANOVA, χ2 test, t-test and Logistic regression were used to analyze the data. Results: The cure rates of flat ascending, flat descending and flat consistent sudden deafness groups were 70.7%, 17.1% and 34.0% respectively, with a statistically significant difference (χ2=33.984, P<0.001); However, there was no significant difference in age, sex and affected side (all P>0.05). The independent related factors for the recovery of flat type sudden deafness were as follows: whether there was dizziness [OR=0.459; 95% confidence interval (CI): 0.271-0.777], the type of audiogram shape (OR=0.721; 95%CI: 0.530-0.981), and days from onset to therapy (OR=0.903, 95%CI: 0.835-0.978), all of which had P values<0.05. There was no significant difference in the cure rates between ascending flat sudden deafness and low-frequency descending sudden deafness, descending flat sudden deafness and high-frequency descending sudden deafness (all P>0.05). The pure tone average(PTA) of flat consistent sudden deafness and total deafness were (69.1±18.9) and (101.7±17.7) dB HL, respectively, with a statistically significant difference (t=20.890, P<0.001), and the cure rates were 34.0% and 14.5%, respectively, with a statistically significant difference (χ2=29.012, P<0.001). Conclusion: According to the audiogram shape, the flat type sudden deafness can be further divided into ascending flat sudden deafness, descending flat sudden deafness and consistent flat sudden deafness, which can more effectively evaluate the prognosis. The cure rate of ascending flat sudden deafness is similar to that of low-frequency sudden deafness, and the prognosis is well; The cure rate of descending flat sudden deafness is similar to that of high-frequency descending sudden deafness, and the prognosis is poor. The cure rate of consistent flat sudden deafness is higher than that of total deafness. PTA plays an important role in the prognosis of consistent flat sudden deafness and total deafness. Total deafness can be regarded as a single type of sudden deafness.

Heart rate surge at respiratory event termination in preterm and term born children with sleep disordered breathing.

BACKGROUND: Repetitive surges in heart rate (HR) at respiratory event termination underpin the altered autonomic HR control associated with sleep disordered breathing (SDB). As children born preterm are at greater risk of adverse cardiovascular outcomes, we aimed to determine whether the HR response to obstructive respiratory events was elevated compared to term-born children. METHODS: Fifty children (3-12 years) born preterm, were matched for SDB severity, age and gender with term born children. Multilevel modelling determined the effect of preterm birth and arousal on HR changes between a 10s baseline to the latter half of respiratory events and 15s post event during NREM and REM. RESULTS: 1203 events were analysed (NREM: term 380; preterm 383; REM: term 207; preterm 233). During NREM fewer events terminated in arousal in the preterm compared with term group (preterm 68%; term 84%; χ2 = 27.2, p < 0.001). There were no differences in REM. During NREM, HR was lower in the preterm group at all event phases, with and without associated arousals (P < 0.01 for all). % change in HR from baseline to post event was higher in the preterm compared with term group (preterm: median 23% IQR (12%,34%); term: 18% (10%,29%); p < 0.01) and late event to post event (preterm: 30% (21%, 32%); term 28% (20%,39%); p < 0.01) in events associated with arousals. CONCLUSION: The greater magnitude of surges in HR following respiratory events terminating with arousal in preterm born children, although small, occur repeatedly throughout the night and may contribute to adverse cardiovascular outcomes, although further studies are required.

Efficacy of Qingre Huashi decoction on infection of : inhibiting adhesion, antioxidant, and anti-inflammation.

OBJECTIVE: To investigate the phytochemical profile of Qingre Huashi decoction (, QHD) and evaluate the mechanisms rationalizing the use of QHD against ()-associated gastritis. METHODS: QHD is composed of 11 herbs, which was prepared by a fixed Pharmacy and concentrated into clear paste. High-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF/MS) was used to detect the phytochemical profile of QHD. The toxicity of QHD against and human gastric epithelial cells was evaluated by the toxicology test and cell counting kit-8 assay. The adhesion model was constructed by incubating and gastric mucosal epithelial cells for 2 h. The urease assay was used to examine the anti-adhesion effects of QHD, and gene expression of adhesins was evaluated by quantitative polymerase chain reaction. The antioxidant activity was assessed by DCFH-DA labeling. To evaluate the anti-inflammatory effect, the levels of pro-inflammatory cytokines in the culture supernatant were detected by enzyme-linked immunosorbent assay. RESULTS: HPLC-QTOF/MS profiling indicated the presence of primary compounds 1-20 in QHD. Drug concentration was determined as 1, 2, and 5 mg/mL by the toxic concentration of QHD against and human gastric epithelial cells. QHD prevented adhesion to the human gastric epithelial cells and reduced levels of reactive oxygen species. QHD also reduced the level of interleukin-8 and other pro-inflammatory cytokines that were upregulated by infection. CONCLUSION: QHD could inhibit adhesion, and exert antioxidant and anti-inflammatory effects .

Utilizing Fish Skin of Ikan Belida (Notopterus lopis) as a Source of Collagen: Production and Rheology Properties.

Collagen hydrogels have been extensively applied in biomedical applications. However, their mechanical properties are insufficient for such applications. Our previous study showed improved mechanical properties when collagen was blended with alginate. The current study aims to analyze the physico-chemical properties of collagen-alginate (CA) films such as swelling, porosity, denaturation temperature (Td), and rheology properties. Collagen was prepared from discarded fish skin of Ikan Belida (Notopterus lopis) that was derived from fish ball manufacturing industries and cross-linked with alginate from brown seaweed (Sargasum polycystum) of a local species as a means to benefit the downstream production of marine industries. CA hydrogels were fabricated with ratios (v/v) of 1:1, 1:4, 3:7, 4:1, and 7:3 respectively. FTIR spectrums of CA film showed an Amide I shift of 1636.12 cm-1 to 1634.64 cm-1, indicating collagen-alginate interactions. SEM images of CA films show a porous structure that varied from pure collagen. DSC analysis shows Td was improved from 61.26 °C (collagen) to 83.11 °C (CA 3:7). CA 4:1 swelled nearly 800% after 48 h, correlated with the of hydrogels porosity. Most CA demonstrated visco-elastic solid characteristics with greater storage modulus (G') than lost modulus (G″). Shear thinning and non-Newtonian behavior was observed in CA with 0.4% to 1.0% (w/v) CaCl2. CA hydrogels that were derived from discarded materials shows promising potential to serve as a wound dressing or ink for bio printing in the future.

WT1 Inhibits Human Renal Carcinoma Cell Proliferation and Induces G2/M Arrest by Upregulating IL-24 Expression.

The transcription factor Wilms' tumor 1 (WT1) is involved in development, tissue homeostasis, and disease. However, the exact roles and the mechanisms of WT1 in renal carcinoma are not well understood. Therefore, in this study, we evaluated the ability of WT1 to block proliferation in renal carcinoma cells in vitro. Experimental analysis showed that WT1 overexpression inhibited the proliferation of renal carcinoma A498 cells and promoted arrest at the G2/M checkpoint. RNA-Seq identified differentially expressed genes, including IL-24, related to both the cell proliferation and the cell cycle. WT1 overexpression upregulated IL-24 expression, and IL-24 overexpression induced G2/M arrest. ChIP-Seq identified JUN as a direct target of WT1 in A498 cells, in which positive regulation was shown by RT-qPCR. It has been shown that the transcription factor JUN can regulate IL-24 expression, and therefore, we hypothesize that WT1 might regulate the IL-24 through JUN. Furthermore, analysis based on TCGA datasets showed that the expression of WT1-regulated genes, including TXNIP and GADD45A, was significantly correlated with the stage and histological grade of tumors, with high levels linked to favorable prognoses. Our results demonstrated that the overexpression of WT1 upregulates IL-24, leading to G2/M checkpoint arrest to reduce proliferation. These results indicate that regulation of IL-24 by WT1 inhibits proliferation and may represent a potential target for treating renal carcinoma.

Transcriptomics analysis reveals key lncRNAs and genes related to the infection of porcine lung macrophages by Glaesserella parasuis.

Glaesserella parasuis (G. parasuis) is the pathogen of Glässer's disease in pig herds, which can cause severe inflammatory responses. However, at present, the pathogenic mechanism of G. parasuis is not very clear. LncRNAs can regulate the expression of mRNA in a variety of ways, thereby causing host cells to produce a variety of functional changes in response to bacterial infection. Here, we detected the changes in lncRNAs and mRNAs of 3D4/21 cells after G. parasuis CY1201 strain (serotype 13) infection. A total of 876 lncRNAs and 2166 mRNAs were differentially expression in 3D4/21 cells after G. parasuis infection. GO and KEGG enrichment analysis showed that the differentially up-regulated lncRNA target genes were mainly involved in the response to extracellular stimuli, cell receptor signaling pathways and chemokine signaling pathways. The differentially down-regulated lncRNA target genes were mainly involved in ERK1/ERK2 cascade reaction and adhesion junctions. 44 lncRNAs were screened that might be related in inflammation. CeRNA regulatory network of the top five difference inflammation-related lncRNAs showed that the up-regulated lncRNA group involved 5 lncRNAs, 50 miRNAs and 49 mRNAs. Meanwhile, there were 26 miRNAs and 36 mRNAs in the top five down-regulated lncRNA group. Our results contribute to understand the basic role of lncRNAs in 3D4/21 cells during G. parasuis infection, and lay the foundation for following research.

Axin2+ PDL Cells Directly Contribute to New Alveolar Bone Formation in Response to Orthodontic Tension Force.

Wnt-ß-catenin signaling plays a key role in orthodontic tooth movement (OTM), a common clinical practice for malocclusion correction. However, its targeted periodontal ligament (PDL) progenitor cells remain largely unclear. In this study, we first showed a synchronized increase in Wnt-ß-catenin levels and Axin2+ PDL progenitor cell numbers during OTM using immunostaining of ß-catenin in wild-type mice and X-gal staining in the Axin2-LacZ knock-in line. Next, we demonstrated time-dependent increases in Axin2+ PDL progenitors and their progeny cell numbers within PDL and alveolar bones during OTM using a one-time tamoxifen-induced Axin2 tracing line (Axin2CreERT2/+; R26RtdTomato/+). Coimmunostaining images displayed both early and late bone markers (such as RUNX2 and DMP1) in the Axin2Lin PDL cells. Conversely, ablation of Axin2+ PDL cells via one-time tamoxifen-induced diphtheria toxin subunit A (DTA) led to a drastic decrease in osteogenic activity (as reflected by alkaline phosphatase) in PDL and alveolar bone. There was also a decrease in new bone mass and a significant reduction in the mineral apposition rate on both the control side (to a moderate degree) and the OTM side (to a severe degree). Thus, we conclude that the Axin2+ PDL cells (the Wnt-targeted key cells) are highly sensitive to orthodontic tension force and play a critical role in OTM-induced PDL expansion and alveolar bone formation. Future drug development targeting the Axin2+ PDL progenitor cells may accelerate alveolar bone formation during orthodontic treatment.

[The peripheral blood inflammatory markers in Ménière's disease patients with and without migraine].

Objective: To investigate the peripheral blood inflammatory markers including white blood cell count (WBC), monocytes, neutrophils, lymphocytes, platelets, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), high-density lipoprotein(HDL-C), low-density lipoprotein and fibrinogen (FIB) in Ménière's disease (MD) patients with and without migraine, and to explore the relationship between the inflammatory response with MD and migraine. Methods: The general physical condition, clinical manifestations, pure-tone audiometry, and peripheral blood inflammatory markers of 92 unilateral MD patients who were hospitalized in Peking University People's Hospital for surgical treatment from January 2017 to January 2021 were continuously collected. Meanwhile, 50 healthy controls matched with age and sex were included, and their general physical conditions and peripheral blood inflammatory markers were also collected. This study consisted of two parts. First, the differences in epidemical characteristics and peripheral blood inflammatory markers between MD patients and healthy controls were compared by univariate analysis. Second, all 92 MD patients were divided into two subgroups according to whether they were accompanied by migraine. The clinical characteristics and peripheral blood inflammatory markers of MD patients with and without migraine were compared by univariate analysis. Thereafter, binary Logistic regression was used to analyze the related factors of whether MD patients were accompanied with migraine. Results: Compared with the healthy control group, the peripheral blood WBC, neutrophils and FIB of MD patients were significantly increased (all P<0.05). Compared with MD patients without migraine, MD patients with migraine had higher female prevalence, longer disease history, lower low-frequency hearing threshold, higher frequency of vertigo attacks and higher HDL-C levels (all P<0.05), meanwhile, female, frequency of vestibular attacks and HDL-C were independent related factors of whether MD patients were accompanied with migraine. Conclusion: The occurrence of MD and migraine may be related to the inflammatory response. The level of anti-inflammatory factors in the blood of MD patients with migraine are higher, suggesting that the inflammatory response status of MD patients with and without migraine is different.

[Factors related to myasthenic crisis in myasthenia gravis patients with oropharyngeal involvement during hospitalization].

Objective: To investigate the factors related to myasthenic crisis (MC) in myasthenia gravis patients (MG) with oropharyngeal involvement during hospitalization. Methods: The clinical data of 99 MG patients with oropharyngeal involvement who were admitted to Beijing Tongren Hospital from 2018 to 2020 were retrospectively reviewed. There were 52 males and 47 females, aged 17-89 (55±15) years old, with a disease duration of 1-240 [10 (4, 36)] months. Multivariable logistic regression analysis was used to determine the factors associated with MC. Results: A total of 19 (19.19%) patients developed into MC during hospitalization. Multivariate logistic regression analysis showed that age of hospitalization ≥ 60 years old (OR=31.378, 95%CI: 3.868-254.557, P=0.001), type B and C thymoma (OR=29.175, 95%CI: 2.986-285.016, P=0.004), excess oropharyngeal secretions (OR=12.649, 95%CI: 2.057-77.783, P=0.006) and infections (OR=9.539, 95%CI: 1.345-67.645, P=0.024) were independently related to MC in MG patients with oropharyngeal involvement. Conclusions: Older age, malignant thymoma, excess oropharyngeal secretions and infection are independently related to MC in MG patients with oropharyngeal involvement during hospitalization. Therefore, great attention should be paid to this type of MG patients, and increased oropharyngeal secretions and various infections should be actively treated, so as to reduce the occurrence of MC.

Pediatric allergic rhinitis with functional gastrointestinal disease: Associations with the intestinal microbiota and gastrointestinal peptides and therapeutic effects of interventions.

Children are susceptible to allergic rhinitis (caused by external allergens) accompanied by functional gastrointestinal disease, which seriously affects physical and mental health. Antihistamines and nasal spray hormones are commonly used in clinical treatment, but these drugs often have unsatisfactory efficacy and result in high recurrence rates. Therefore, understanding the pathogenesis of allergic rhinitis with functional gastrointestinal disease and seeking safer treatment and prevention methods is essential. Herein, molecular ecology and immunoassays were used to analyze correlations between pediatric allergic rhinitis with functional gastrointestinal disease and both the intestinal microbiota and gastrointestinal peptide levels. Fifty healthy children (healthy group) and 80 children with allergic rhinitis with functional gastrointestinal disease (case group: evenly divided into a control group (conventional drug therapy) and an intervention group (conventional drug therapy + glutamine+probiotics)), were enrolled. Bifidobacterium and Lactobacillus counts and the gastrin and motilin levels were lower in the case group than in the healthy group, whereas Enterobacter, yeast, and Enterococcus counts and the somatostatin, serotonin, and vasoactive intestinal peptide levels were higher. Post treatment, intestinal microbiota indices, gastrointestinal peptide levels, and intestinal barrier function were better in the intervention group than in the control group (p < 0.05). The intervention group had a significantly higher total therapeutic response rate (95.00%) than the control group (77.50%). The intestinal microbiota was closely associated with gastrointestinal peptide levels. Treatment with glutamine and probiotics regulated these levels, re-established balance in the intestinal microbiota, and restored intestinal barrier function.