ObjectiveTo investigate the therapeutic effect of sitravatinib on carbon tetrachloride （CCl₄）-induced liver fibrosis in mice. MethodsA total of 30 male C57BL/6J mice， aged 8 weeks， were randomly divided into control group， CCl₄ model group， and low- （5 mg/kg）， middle- （10 mg/kg）， and high-dose （20 mg/kg） sitravatinib groups. All mice except those in the control group were given intraperitoneal injection of CCl₄ for 4 consecutive weeks to induce liver fibrosis， and since the first day of modeling， the mice in the low-， middle-， and high-dose sitravatinib groups were given sitravatinib at the corresponding dose by gavage every day. The serum levels of total cholesterol （TC）， triglyceride （TG）， and alanine aminotransferase （ALT） were measured for the mice in each group； hepatic hydroxyproline content was measured； HE staining， Masson staining， and Sirius Red staining were used to observe liver histopathological changes； quantitative real-time PCR and Western blot were used to measure the mRNA and protein expression levels of α-smooth muscle actin （α-SMA） and collagen type I alpha 1 （Col1a1） in liver tissue. The therapeutic effect of sitravatinib was assessed based on the above results. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the control group， the model group had significant increases in the levels of TC， TG， and ALT （all P<0.05）， and there were no significant differences in the levels of TC， TG， and ALT between the model group and the low-， middle-， and high-dose sitravatinib groups （all P>0.05）. Hepatic hydroxyproline content decreased after sitravatinib intervention， with a significant difference between the middle-/high-dose sitravatinib groups and the CCl₄ model group （both P<0.05）. Histopathological staining showed that the sitravatinib treatment groups had a reduction in collagen deposition， along with thinning and fragmentation of fibrous septa， and in the high-dose sitravatinib group， 4 mice had a fibrosis stage of S0—S1 and 2 mice had a fibrosis stage of S2—S3， suggesting a certain degree of alleviation of liver fibrosis degree compared with the CCl₄ model group （mainly S3—S4）. The measurement of related molecules showed that sitravatinib downregulated the mRNA and protein expression levels of α-SMA and Col1a1 （all P<0.05）. ConclusionSitravatinib can effectively alleviate CCl₄-induced liver fibrosis in mice， possibly by inhibiting hepatic stellate cell activation and collagen synthesis.

To investigate the association between sleep-related phenotypes and the risk of malignancy in pulmonary nodules, and to provide complementary evidence from a general population cohort and genetic analyses.

ObjectiveTo investigate the potential mechanism of Huatan Sanjie Formula （化痰散结方， HSF） in the treatment of triple negative breast cancer （TNBC） based on the integrinβ1/focal adhesion kinase/yes-associated protein （integrinβ1/FAK/YAP） mechanotransduction signaling pathway. MethodsFifty BALB/c mice were randomly assigned to a model group， doxorubicin group， low-， medium-， and high-dose HSF groups， with 10 mice per group. An orthotopic TNBC transplantation model was established in all mice using syngeneic implantation of 4T1 cells. After successful modeling， mice in the model group received intragastric administration of normal saline 0.2 ml each day. Mice in the low-， medium-， and high-dose HSF groups received HSF by gavage at doses of 5.99， 11.97， and 23.94 g/（kg·d）， respectively. The doxorubicin group received intraperitoneal injections of doxorubicin （1.5 mg/kg） once every two days. All treatments lasted for 30 days. After the final administration， mice were sacrificed， and tumor weight and volume were measured. Hematoxylin-eosin （HE）， Masson's trichrome， and Sirius Red staining were performed to evaluate histopathological changes and collagen fiber deposition in tumor tissues. TUNEL staining was used to assess apoptosis. The Young's modulus of tumor tissues was measured using atomic force microscopy （AFM）. The nuclear-cytoplasmic localization of YAP was determined by immunofluorescence staining. Protein expression levels of integrinβ1， focal adhesion kinase （FAK）， YAP， and phosphorylated focal adhesion kinase （p-FAK） were detected by Western Blotting. The mRNA expression levels of integrinβ1， FAK， and YAP were assessed by quantitative real-time polymerase chain reaction （qRT-PCR）. Pearson correlation analysis was performed to evaluate the relationships among tumor tissue Young's modulus， apoptosis rate， and the expression levels of proteins related to the integrinβ1/FAK/YAP signaling pathway. ResultsCompared to the model group， tumor weight was significantly reduced in the doxorubicin group and the medium- and high-dose HSF groups， while tumor volume significantly decreased in the doxorubicin group and the high-dose HSF group （P＜0.01）. Tumor weight in the high-dose HSF group was significantly lower than that in the low-dose group， and tumor volume was significantly smaller than that in both the low- and medium-dose groups （P＜0.05）. Marked improvements in histopathological morphology were observed in the medium- and high-dose HSF groups and the doxorubicin group， while the proportion of collagen fiber deposition and the nuclear-to-cytoplasmic ratio of YAP were significantly reduced （P＜0.01）. Compared to the model group， all three HSF groups and the doxorubicin group exhibited significantly increased apoptosis rates， decreased Young's modulus， and reduced mRNA expression levels of integrinβ1， and YAP （P＜0.05 or P＜0.01）. Furthermore， protein expression levels of integrinβ1， p-FAK， and YAP in the high-dose HSF group were significantly lower than those in the model group （P＜0.05 or P＜0.01）. Pearson correlation analysis demonstrated a significant negative correlation between tumor tissue Young's modulus and apoptosis rate （r =-0.93， P＜0.01）. In contrast， the protein expression levels of integrinβ1， p-FAK， and YAP were positively correlated with Young's modulus （r=0.88， 0.97， and 0.98， respectively； P＜0.05） and negatively correlated with apoptosis rate （r=-0.93，-0.97， and -0.93， respectively； P＜0.05）. ConclusionHSF can significantly inhibit tumor growth in TNBC model mice. Its antitumor effect may be associated with reducing tumor tissue stiffness through suppression of the integrinβ1/FAK/YAP mechanotransduction signaling pathway.

Macrophages are innate immune cells connected with the development of inflammation. Retinoic acid has previously been proved to have anti-inflammatory and anti-arthritic properties. However, the exact mechanism through which retinoic acid modulates arthritis remains unclear. This study aimed to investigate whether retinoic acid ameliorates rheumatoid arthritis by modulating macrophage polarization. This study used retinoic acid to treat mice with adjuvant arthritis and evaluated anti-inflammatory effects by arthritis score, thermal nociceptive sensitization test, histopathologic examination and immunofluorescence assays. In addition, its specific anti-arthritic mechanism was investigated by flow cytometry, cell transfection and inflammatory signaling pathway assays in RAW264.7 macrophages in vitro. Retinoic acid significantly relieved joint pain and attenuated inflammatory cell infiltration in mice. Furthermore, this treatment modulated peritoneal macrophage polarization, increased levels of arginase 1, as well as decreased inducible nitric oxide synthase expression. In vitro, we verified that retinoic acid promotes macrophage transition from the M1 to M2 type by upregulating mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) expression and inhibiting P38, JNK and ERK phosphorylation in lipopolysaccharide-stimulated RAW264.7 cells. Notably, the therapeutic effects of retinoic acid were inhibited by MKP-1 knockdown. Retinoic acid exerts a significant therapeutic effect on adjuvant arthritis in mice by regulating macrophage polarization through the MKP-1/MAPK pathway, and play an important role in the treatment of rheumatic diseases.

Objective To explore the protective effects of genetically modified porcine erythrocyte suspension as a subnormothermic normoxic mechanical perfusate on hypoxic-ischemic brain injury in cynomolgus monkeys caused by traumatic hemorrhage.Methods Cynomolgus monkeys were randomly divided into positive and negative control groups(a total of 3 monkeys,with 3 left cerebral hemispheres as the positive control group and 3 right cerebral hemispheres as the negative control group)and the subnormothermic perfusion group(n=3).The positive control group was directly sampled 1 hour after circulatory arrest,while the negative control group was placed at subnormothermic conditions for 6 hours after circulatory arrest.The subnormothermic perfusion group underwent 6 hours of subnormothermic normoxic mechanical perfusion of the bilateral common carotid arteries of the cynomolgus monkey hypoxic-ischemic brain injury model using genetically modified porcine erythrocyte suspension 1 hour after circulatory arrest.Before perfusion,cross-matching experiments were conducted between the six genetically modified pig and the cynomolgus monkeys.After the start of perfusion,the levels of routine blood indicators in the perfusate were detected at 0,1,2,3,4,5 and 6 hours.Blood oxygen saturation was recorded,and the levels of Na+,K+,Ca2+,glucose and blood pH in the perfusate were measured,as well as the levels of IgG and IgM in the perfusate.After 6 hours of perfusion,the water content of the brain tissue was measured.Nissl staining was performed on the frontal cortex and hippocampal regions,and immunofluorescence staining was used to detect the expression of glial fibrillary acidic protein(GFAP),ionized calcium-binding adapter molecule 1(Iba1)and neuronal nuclear antigen(NEUN).Results The cross-matching results between the six genetically modified pig and the cynomolgus monkeys were negative.The number of red blood cells in the perfusate decreased significantly at 3 hours of perfusion,and the hemoglobin level showed a downward trend at 1,3,5 and 6 hours.The number of white blood cells and platelets decreased at all time points.The blood oxygen saturation in the subnormothermic perfusion group remained stable at 95%-98%,and the levels of blood oxygen saturation,Na+,Ca2+,glucose and pH were stable,while the K+level first increased and then decreased.There was no significant difference in the levels of IgG and IgM before and after perfusion.The water content of brain tissue at the end of perfusion in the subnormothermic perfusion group was significantly higher than that in the positive control group(P<0.001).Nissl staining results showed that compared with the positive control group,the pyramidal neurons in the prefrontal cortex of the subnormothermic perfusion group maintained better morphological integrity,with no significant increase in enlarged and deformed cells.In the hippocampal CA1 region,there was a slight increase in enlarged and deformed cells,and a few cells with undamaged structures showed reduced cell size.In the hippocampal dentate gyrus,fewer granule neurons had compromised structural integrity,with increased cell edema.NEUN immunofluorescence staining showed that compared with the positive control group,the pyramidal neurons in the prefrontal cortex and hippocampal CA1 region of the subnormothermic perfusion group had better morphological states,with clear axons.The granule cells in the hippocampal dentate gyrus were well preserved,but the nuclei were less well protected.GFAP immunofluorescence staining showed that compared with the positive control group,the subnormothermic perfusion group had sparser protrusions that were more tightly associated with neurons.Iba1 immunofluorescence staining showed that compared with the positive control group,the subnormothermic perfusion group had thicker and fewer protrusions.Conclusions Compared with the positive control group,subnormothermic normoxic mechanical perfusion with genetically modified porcine erythrocyte perfusate increases brain tissue edema in cynomolgus monkeys,but better preserves the morphological integrity of neurons and glial cells.The protective effects may be related to the continuous oxygen and energy supply,maintenance of ion homeostasis and perfusate pH,reduced rejection,and low metabolic state of the whole brain.

Objective:To explore the effects of medication interval on the quality of split-dose bowel preparation and analyze the independent risk factors affecting the quality of bowel preparation.Methods:This pilot study involved two centers. Adult outpatients who underwent screening, surveillance, and diagnostic colonoscopy in the First Affiliated Hospital of Naval Medical University ( n=46) and the Fifth Hospital of Zhangjiakou ( n=20) between April and June 2023 were enrolled. Bowel preparation was conducted based on the guideline. Patients were divided into the short-interval group (4-<10 hours, n=45) and the long-interval group (10-16 hours, n=21) based on the time between the two administrations of polyethylene glycol during bowel preparation. Differences in terms of patient-reported outcome measurements (patient-reported willingness to repeat the bowel preparation regimen, satisfaction with bowel preparation, satisfaction with sleep), defecation frequency, Boston bowel preparation scale scores, bowel preparation bubble scores, bowel preparation qualified rates, polyp detection rates and incidence of adverse events were compared. Relevant factors influencing bowel preparation quality were analyzed by univariate logistic regression. Results:There were no significant differences in patient-reported willingness to repeat the bowel preparation regimen [88.9% (40/45) VS 85.7% (18/21), χ2<0.001, P>0.999], the satisfaction with bowel preparation [65.9% (29/45) VS 57.1% (12/21), χ2=0.469, P=0.493], or the satisfaction with sleep quality [35.6% (16/45) VS 28.6% (6/21), χ2=0.314, P=0.575] between the short-interval and long-interval groups. Similarly, no significant differences were observed between the groups in defecation frequency (11.3±4.8 VS 10.2±4.4, t=0.861, P=0.395), Boston bowel preparation scale scores (8.2±1.4 scores VS 7.9±1.2 scores, t=1.024, P=0.311), bowel preparation bubble scores (8.6±1.0 scores VS 8.4±1.5 scores, t=0.672, P=0.506), bowel preparation qualified rates [88.9% (40/45) VS 90.5% (19/21), χ2<0.001, P>0.999], polyp detection rates [33.3% (15/45) VS 47.6% (10/21), χ2=1.242, P=0.265], or incidence of adverse events [24.4% (11/45) VS 14.3% (3/21), χ2=0.381, P=0.537]. Univariate logistic analysis suggested that a low-fiber diet ( OR=8.100, 95% CI:1.400-46.849, P=0.019) was an influencing factor for qualified bowel preparation. Conclusion:Medication interval of the two doses of polyethylene glycol in a split-dose bowel preparation regimen for colonoscopy has no significant impact on bowel preparation quality. Notably, preoperative low-fiber diet emerges as an independent protective factor for qualified bowel preparation.

High-risk non-muscle invasive bladder cancer (HR-NMIBC) is associated with a higher risk of recurrence and progression. The standard treatment involves intravesical Bacillus Calmette-Guérin (BCG) instillation following transurethral resection of the bladder cancer. However, in cases of BCG unresponsiveness, radical cystectomy is typically recommended. Due to the high complication rates and significant impact on quality of life associated with this procedure, bladder-preserving treatment (BPT) strategies have emerged as an alternative. This review summarizes recent advances in BPT, including combined chemoradiotherapy, immune checkpoint inhibitors, targeted therapies, localized precision treatments, and novel immunomodulators. With ongoing technological and therapeutic innovations, BPT has become an effective alternative for patients who are unable or unwilling to undergo surgery, reshaping the treatment landscape of HR-NMIBC.

Objective To conduct microbiological monitoring before the operation of the purified water treatment system in a newly-built endoscopy center,comprehensively analyze the causes for the standard-exceeding results of microbial detection of final rinse water,propose solutions,and provide reference for handling similar events in the future.Methods Microbial detection data of the final rinse water in the newly-built digestive endoscopy center of a tertiary first-class general hospital in Beijing from April to July 2024 were monitored.The potential causes for standard-exceeding results of microbial detection of final rinse water were analyzed from the perspectives of equip-ment maintenance and management of the purified water treatment system as well as the improvement of cleaning and disinfection methods for the purified water supply pipeline in the endoscopy center,targeted improvement mea-sures were proposed accordingly.Results The microbial monitoring result of final rinse water in the newly-built di-gestive endoscopy center built in April 2024 was 1 400 CFU/100 mL,with the main bacterial type being Cupriavi-duspauculus.After five rounds of improvement measures and rechecks,microbial monitoring result of the final rinse water in the newly-built endoscopy center was 0 CFU/100 mL,with a qualification rate of 100％.Analysis suggested that the main causes for the standard-exceeding results of microbial detection of final rinse water were due to the damage of the reverse osmosis membrane,lack of cleaning for the pure water storage tank before use,and non-standard cleaning and disinfection process for the pure water supply pipeline,after targeted improvement,the problem was solved.Conclusion Medical institutions should continuously conduct periodic monitoring on water used for endoscope,regularly perform cleaning and disinfection of the purified water treatment system,standardize cleaning and disinfection procedures,ensure medical quality and patient safety.

Natural killer(NK)cells are essential components of the innate immune system,characterized by their ability to identify and eliminate abnormal cells through receptors that operate independently of major histo-compatibility complex(MHC)restriction.As a result,NK cells play a critical role in anti-tumor,antiviral,and immune regulatory responses.Chimeric antigen receptor NK cell therapy(CAR-NK)enhances the targeting speci-ficity and functional activity of NK cells,thereby augmenting their cytotoxic potential and opening new avenues for cancer treatment.To date,numerous clinical trials have evaluated NK cell therapy for anti-tumor,antiviral,and autoimmune diseases.This article summarizes the current research status of NK cell therapy in clinical applica-tions,highlighting its promising efficacy and safety as an innovative immunotherapy.Despite challenges such as limited cell persistence and tumor microenvironment suppression,the prospects for further development in this field remain promising.

Purpose To investigate the consistency and reliability of immunohistochemistry(IHC)staining and polymerase chain reaction-capillary electrophoresis(PCR-CE)in the detection of microsatellite instability.Methods The clinical data of 735 patients with solid tumors who underwent biopsy or surgical resection were collected,and the microsatellite status of tissue samples was detected by IHC and PCR-CE.Results Among the 344 cases of colorectal cancer(CRC),IHC results showed that 290 cases(84.3％)had proficient mismatch repair(pMMR),and 54 cases(15.7％)had deficient mismatch repair(dMMR).The results of PCR-CE showed that 53 patients(15.4％)had high microsatellite instability(MSI-H),and 291 patients(84.6％)had microsatellite stable(MSS).The consistency analysis of IHC and PCR-CE results showed that the Kappa value was 0.923(P＜0.001).Among the 168 cases of en-dometrial cancer(EC),IHC results showed that 42 cases(25.0％)had dMMR and 126 cases(75.0％)had pMMR;The results of PCR-CE showed that 39 cases(23.2％)had MSI-H and 129 cases(76.8％)had MSS.The consisten-cy analysis of the two methods showed that the Kappa value was 0.854(P＜0.001).Among the 165 cases of gastric cancer,IHC results showed that 22(13.3％)had dMMR and 143(86.7％)had pMMR;The results of PCR-CE showed that 22 cases(13.3％)had MSI-H and 143 cases(86.7％)had MSS/low microsatellite instability(MSI-L).The consistency analysis of IHC and PCR-CE results showed that the Kappa value was 0.843(P＜0.001).Among the 58 cases of head and neck squamous cell carcinoma(HNSCC),IHC results showed that 3 cases(5.2％)had dMMR and 55 cases(94.8％)had pMMR;The results of PCR-CE showed that 3 cases(5.2％)had MSI-H and 55 cases(94.8％)had MSS.The consistency analysis of the two methods showed that the Kappa value was 1.000(P＜0.001).Conclusion IHC and PCR-CE have high consistency and reliability in detecting MSI status in patients with CRC,EC,gastric cancer and HNSCC,and their combined application is helpful to improve the accuracy of MSI detec-tion in patients with solid tumors.