Background and aims:Primary sclerosing cholangitis(PSC)is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options.The mechanisms underlying the development and progression of PSCs remain unclear.Liver X receptor beta(LXR-β)is recognized to modulate lipid metabolism and immune response,but its specific involvement in the PSC has not been elucidated.Here,we explored the role and mechanism of LXR-β in PSC induced by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine(DDC).Methods:CRISPR-Cas9 technology was applied to generate Abcb4(coding MDR2,next named as Mdr2),Nr1h2(coding LXR-β,next named as Lxrβ),and Rag2(coding RAG2)knockout mice.DDC was used to induce PSC.Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis.Flow cytometry was used to observe immune cell subsets.Results:We observed a declining trend in hepatic Lxrβ in the PSC model.Unexpectedly,Lxrβ knockout failed to modulate DDC-induced PSC pathogenesis.Concomitantly,assessment of the influence of Rag2 deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the Rag2-/-DDC mice.However,Lxrβ depletion intensified DDC-induced PSC in the Rag2-/-mice,with more abundant infiltrative inflammatory cells and more severe liver fibrosis.Compared with Rag2-/-DDC mice,Lxrβ-/-Rag2-/-DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes.Flow cytometry showed that LXR-β deficiency resulted in a diminished population of hepatic innate immune cells.Conclusion:This study indicated innate immune cell LXR-β deficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-β may regulate the function of innate immunity in the fibrotic advancement of PSC.

ObjectiveTo investigate the expression of serum Aldo-keto reductase family 1 member B10 （AKR1B10） in patients with hepatocellular carcinoma （HCC） in northern China， and to provide a new and valuable biomarker for the clinical diagnosis of HCC. MethodsThis study was conducted among 102 patients with HCC， 119 patients with benign liver disease， and 132 patients with other malignant tumors who attended The Affiliated Hospital of Chengde Medical University and 148 healthy individuals who underwent physical examination from May 2020 to May 2024. ELISA and chemiluminescence were used to measure the serum levels of AKR1B10 and alpha-fetoprotein （AFP）. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups， and the Kruskal-Wallis H test was used for comparison between three groups and further comparison between two groups； the chi-square test was used for comparison of categorical data between groups. The area under the ROC curve （AUC） was used to assess diagnostic efficiency. ResultsThe expression level of AKR1B10 was 3 053.79 （1 475.67‍ ‍—‍ ‍4 605.86） pg/mL in the HCC group， 1 324.42 （659.68‍ ‍—‍ ‍2 023.88） pg/mL in the benign liver disease group， 660.68 （377.56‍ ‍—‍ ‍2 087.77） pg/mL in the other malignant tumor group， and 318.30 （82.73‍ ‍—‍ ‍478.82） pg/mL in the healthy group， with a significant difference between the four groups （H=240.86， P<0.001）， and further comparison between two groups showed that the HCC group had a significantly higher level than the other three groups （all P<0.001）. The ROC curve analysis of the HCC group and the other three groups showed that serum AKR1B10 had an optimal cut-off value of 1 584.97 pg/mL in the diagnosis of HCC， with an AUC of 0.86 （95% confidence interval ［CI］： 0.82‍ ‍—‍ ‍0.90）， a sensitivity of 74.3%， and a specificity of 85.2%. Compared with each indicator alone， a combination of AKR1B10 and AFP could improve the sensitivity （81.8%） and specificity （91.4%） of HCC diagnosis. AKR1B10 had an AUC of 0.84 （95%CI： 0.78‍ ‍—‍ ‍0.90） in the diagnosis of patients with early- or middle-stage HCC， with a sensitivity of 76.2% and a specificity of 81.2%. AKR1B10 had an AUC of 0.85 （95%CI： 0.77‍ ‍—‍ ‍0.92） in the diagnosis of patients with AFP-negative HCC， with a sensitivity of 81.6% and a specificity of 79.9%. ConclusionAKR1B10 is a promising serological marker for the diagnosis of HCC， and a combination of AKR1B10 and AFP can improve the detection rate of HCC patients in northern China， especially those with early- or middle-stage HCC and AFP-negative HCC.

Objective:To investigate the clinical effect of free anterolateral thigh myocutaneous flap combined with oral repair membrane in the reconstruction of nasal mucosa defect after maxillary malignant tumor surgery. Methods:A total of 12 patients with maxillary gingival squamous cell carcinoma and maxillary sinus cancer who had been treated in Department of Oral and Maxillofacial Surgery, Beijing Anzhen Nanchong Hospital, Capital Medical University & Nanchong Central Hospital, were selected from November 2020 to November 2023. Free anterolateral thigh musculocutaneous flap transplantation combined with oral repair membrane were used in all patients. Meanwhile, maxillary soft and hard tissue defects and nasal mucosa defects left after tumor operation were repaired and reconstructed. The clinical effect was evaluated after 6-12 months follow-up. Results:Subtotal maxillary resection was performed in 1 case, total maxillary resection in 9 cases and extended maxillary resection in 2 cases. The musculocutaneous flaps of all patients survived, the facial appearance was basically symmetrical, no obvious depression deformity, the swallowing and speech function recovered well, the mouth and nasal cavity were closed completely, the food could be eaten through the mouth, and the lower nasal passage was not blocked. Conclusion:The free anterolateral thigh musculoflap combined with oral repair membrane can be used to repair and reconstruct maxillary malignant tumor complicated with extensive maxillary tissue and nasal mucosa defect after operation, and the appearance and function can be recovered well after operation, which is a choice for maxillary malignant tumor complicated with nasal mucosa defect.
Humans ; Myocutaneous Flap ; Plastic Surgery Procedures/methods* ; Maxillary Neoplasms/surgery* ; Carcinoma, Squamous Cell/surgery* ; Male ; Middle Aged ; Female ; Nasal Mucosa/surgery* ; Maxilla/surgery* ; Thigh/surgery* ; Maxillary Sinus Neoplasms/surgery*

Objective To elucidate the mechanism through which Gypenoside L inhibits the growth of colon cancer by modulating carnitine palmitoyltransferase 1B (CPT1B),a pivotal enzyme in the fatty acid metabolism pathway. Methods Through in vitro experiments,various concentrations of Gypenoside LI LI were applied to inter-vene in colon cancer RKO and SW620 cells. The effects of Gypenoside LI on these cells were comprehensively evalu-ated using the CCK-8 assay,wound healing assay,colony formation assay,and live-dead cell staining,focusing on its impact on cell proliferation,migration,and apoptosis. Additionally,a human colon cancer tissue microarray (TMA) was utilized in conjunction with multiplex fluorescence immunohistochemistry to analyze the expression of CPT1B in colon cancer and adjacent tissues. SW620 cells were transfected with siRNA,and the mRNA and protein expression levels of CPT1B post-transfection were assessed using quantitative real-time PCR (qPCR) and Western blotting. Furthermore,an in vivo nude mouse colon cancer model was established to investigate the inhibitory effect of Gypenoside LI LI on colon cancer growth. Results In vitro experiments demonstrated that Gypenoside LI LI effectively inhibited the proliferation and migration of RKO and SW620 cells in a concentration-and time-dependent manner. Additionally,multiple fluorescence immunohistochemistry analyses revealed that the expression level of CPT1B in colon cancer tissues was significantly higher than that in adjacent non-tumor tissues. Gypenoside LI LI promoted ROS accumulation by inhibiting CPT1B expression. In vivo experiments further confirmed that Gypenoside LI LI could inhibit tumor formation in nude mice and reduce CPT1B expression. Conclusions This study elucidates the mechanism by which Gypenoside LI inhibits the growth of colon cancer cells. Specifically,it downregulates CPT1B,leading to increased accumulation of reactive oxygen species (ROS),disruption of fatty acid oxidation metabolism,and ultimately inducing apoptosis in colon cancer cells. These findings offer valuable insights into colon cancer treatment,suggesting new therapeutic strategies and potential drug targets.

Objective To explore the model of decreased ovarian reserve(DOR)induced by experimental autoimmune thyroiditis(EAT)in mice and investigate the protective mechanism of Jiexu Zichong Granules(ZCWS).Methods Ninety-six Kunming female mice were randomly divided into the J control group,BIW control group,J model group,and BIW model group.The mice were immunized with antigen(0.1 mg,once or twice per week)combined with high iodine water(0.64 g/L)for 7-19 weeks to validate the model.Subsequently,30 mice were randomly divided into the ZCWS group,model group,and control group.The DOR model was established by immunization with the antigen(0.2 mg per week)combined with high iodine water feeding for 13 weeks.The ZCWS group received oral administration of traditional Chinese medicine suspension(0.64 g/mL),while the remaining groups received an equivalent volume of physiological saline for 7 weeks.Thyroid and ovarian tissue morphology and related indicators were detected using HE staining,ELISA,IHC,and Western blot.Results Antigen immunization for 13 weeks(0.1-0.2 mg per week)combined with high iodine water feeding stably constructed the EAT DOR model.ZCWS reduced thyroid lymphocyte infiltration,follicular structure destruction,and serum TPOAb and TGAb levels(P<0.01).It inhibited MDA activity(P<0.01),increased GSH-Px and SOD activities(P<0.05),increased primordial,primary,and secondary follicles(P<0.05),and reduced atretic follicles(P<0.01).ZCWS upregulated AMH and downregulated FSH(P<0.01),regulated the expression of Bcl-2,Bax,and Caspase-3 proteins in ovarian tissue,downregulated Keap1 protein(P<0.01),and upregulated Nrf2(P<0.01),HO-1,and LONP1 proteins(P<0.05).It upregulated Bcl-2 protein(P<0.05),downregulated Bax(P<0.01),and Caspase-3(P<0.05)proteins,downregulated Keap1 protein(P<0.01),and upregulated Nrf2(P<0.01),HO-1,and LONP1 proteins(P<0.05)in ovarian tissue.Conclusion ZCWS improves ovarian reserve function in EAT mice by activating the Nrf2 pathway,inhibiting oxidative stress,and reducing follicular atresia.

A case of Sifrim-Hitz-Weiss syndrome(Sifrim-Hitz-Weiss syndrome,SIHIWES)is presented.The patient was a 35-year-old male with cryptorchidism,growth retardation,skeletal malformations,muscular atrophy,a wide forehead,special facial features like square face,small low-set and cup-shaped ears since birth.Whole-exon sequencing identified a heterozygous mutation(NM_001273:c.3047A>G(chr12-6701125)(p.K1016R))in CHD4 gene.The clinical significance of this mutation is currently unknown,and has not been previously reported.In light of the patient's symptoms,the case was diagnosed as Sifrim-Hitz-Weiss syndrome.This case represents the first instance of Sifrim-Hitz-Weiss syndrome in an adult patient in China.

Objective To study the impact of tympanic membrane opening on respiratory-driven middle ear pressure in patients with patulous eustachian tube(PET),using a simplified in vitro model.Methods CT imaging data from a PET patient(with full-length eustachian tube opening observed during a Valsalva maneuver followed by breath-holding)were used to design a simplified eustachian tube model.Two simplified in vitro models of the eusta-chian tube were constructed using silicone-based 3D printing technology and connected to a pressure controller and pressure sensors.The pressure controller was activated to introduce negative-pressure airflow into the nasopharyn-geal model to simulate respiratory-induced middle ear pressure fluctuations.A hemostat was used to alternately open and close the external interface of the middle ear chamber,simulating conditions of an open and intact tympanic membrane,while middle ear pressure was continuously monitored using pressure sensors.Results In the first mod-el,with-800 mbar negative pressure applied at the nasopharynx,the middle ear pressure stabilized between-3.9 mbar and-4.3 mbar with tympanic membrane opening,and between-7.9 mbar and-8.2 mbar with intact tym-panic membrane.In the second model,under the same pressure setting,middle ear pressure stabilized between-2.7 mbar and-3.1 mbar with tympanic membrane opening,and between-5.0 mbar and-7.7 mbar with intact tympanic membrane.Conclusion This study,based on a simplified in vitro model,demonstrates that tympanic membrane opening can effectively reduce respiratory-driven pressure in the middle ear.This phenomenon may partly explain the clinical efficacy of tympanostomy tube insertion in certain PET patients.

The occurrence and development of atherosclerotic cardiovascular diseases is closely related to abnormally elevated plasma low density lipoprotein cholesterol(LDLC)level.Low density lipoprotein receptor(LDLR)plays a central role in the maintenance of cholesterol homeostasis by mediating the endocytotic clearance of LDLC,and the abundance of LDLR on the surface of the cell membrane is closely related to the expression level and recirculation of LD-LR.Recent studies have found that RING-E3 ubiquitin ligase can regulate LDLR levels through a dual mechanism:on the one hand,it directly ubiquitinates and modifies LDLR to promote its degradation via the endosome-lysosome pathway;on the other hand,it reduces LDLR synthesis through activation of the liver X receptor(LXR)pathway or inhibition of the nuclear translocation of sterol regulatory element-binding protein(SREBP).Together,these two mechanisms lead to a decrease in cell membrane LDLR abundance,impairing cholesterol metabolic homeostasis and exacerbating LDLC accumu-lation.Therefore,targeted inhibition of RING-E3 ubiquitin ligase activity may be a novel strategy to regulate LDLR ex-pression,reduce plasma LDLC levels,and combat cardiovascular disease.This article reviews the mechanism of action of RING-E3 ubiquitin ligase in regulating LDLR and its related research progress.

Objective This study aimed to investigate the efficacy of modified endoscopic autologous cartilage eustachian tube pharyngeal orifice tuboplasty(MEACETT)in patients with patulous eustachian tube(PET).Meth-ods A retrospective analysis was conducted on the clinical data of 27 patients(30 ears)diagnosed with PET who underwent MEACETT.Autologous cartilage was used through the incision at the posterior end of the inferior turbi-nate and filled into the lateral wall of the pharyngeal orifice of the eustachian tube.Without affecting the movement function of the eustachian tube during swallowing,the collapse of the pharyngeal orifice was fully filled.Before and after the surgery,the visual analogue scale(VAS),the eustachian tube dysfunction questionnaire-7(ETDQ-7)and hospital anxiety and depression scale(HADS)was used for assessment to evaluate the surgical efficacy.Results There was no significant difference in depression scores before and after surgery(P＞0.05).However,postopera-tive anxiety scores,ETDQ-7 scores,and VAS scores were significantly lower than preoperative scores(P＜0.05).Among the 27 patients,9 showed significant symptom relief,13 exhibited partial relief,and 5 had no significant change compared to preoperative symptoms.The overall response rate of the treatment(significant relief and partial relief)was 81.48％(22/27).All surgeries were successfully performed.Except for secretory otitis media occurring in 2 cases,no major complications were observed.Conclusion MEACETT demonstrates significant symptom relief in PET patients,with high surgical safety and low complication rates,making it worthy of clinical promotion.

Objective To evaluate the diagnostic efficacy of the R value in tubomanometry(TMM)for the di-agnosis of patulous eustachian tube(PET).Methods The clinical data of 58 patients with PET and 65 controls were retrospectively analyzed.TMM was performed on both groups under nasopharyngeal pressures of 30,40,and 50 mbar respectively.The diagnostic efficacy of the R value for PET was evaluated through receiver operating char-acteristic(ROC)curves.Results In the control group,the average R values under nasopharyngeal pressures of 30,40,and 50 mbar were 0.86±0.50,0.76±0.41,and 0.68±0.34 respectively.In contrast,the corresponding R values in the PET group were significantly lower,which were 0.56±0.38,0.50±0.36,and 0.46±0.38 respec-tively.According to the ROC curve analysis,the areas under the curve(AUC)at these pressures were 0.62,0.74,and 0.74 respectively.The specificity and sensitivity of the R value under nasopharyngeal pressures of 30,40,and 50 mbar were 76.90％and 54.30％,74.60％and 68.10％,86.90％and 54.30％,respectively.Under pressures of 30,40,and 50 mbar,the incidence rates of R＞1 in the control group and the PET group were 29.23％(38/130)and 12.77％(12/94)(x2=8.69,P=0.003),20.00％(26/130)and 6.38％(6/94)(x2=7.20,P=0.007),10.00％(13/130)and 3.19％(3/94)(x2=2.87,P=0.09)respectively.Conclusion Although the low R value in TMM reflects the presence of PET to some extent,it does not provide adequate sensitivity and specificity to serve as an independent diagnostic criterion for PET.