Objective To explore the influencing factors of immune-associated thyroid dysfunction caused by sintilimab treatment in solid tumors and construct a prediction model.Methods Medical records of patients diagnosed with solid tumors and treated with sintilimab at Peking University People's Hospital(Xizhimen Campus,Tongzhou Campus,Shijiazhuang Campus)from January 2023 to September 2024 were collected to explore the influencing factors that caused immune-related thyroid dysfunction using univariate and multifactorial binary logistic regression analyses and to establish a prediction model.The predictive effect of the model was assessed using the receiver operating characteristic(ROC)curve.Results A total of 120 patients were included,and 33 presented with immune-related thyroid dysfunction.Multifactorial logistic regression analysis revealed that thyroid-stimulating hormone(TSH)[OR=2.470,95%CI=(1.279,4.771)]and treatment cycles[OR=1.298,95%CI=(1.117,1.509)]were independent risk factors for the occurrence of immune-associated thyroid dysfunction,and the difference was statistically significant(P＜0.05).The area under the ROC curve was(0.897±0.043)[95%CI=(0.813,0.981)],the Yoden index was 0.703,and the model prediction accuracy was 86.5%.Conclusion The risk of immune-related thyroid dysfunction caused by sintilimab is high,and TSH and treatment cycle are the influencing factors,and the constructed model has certain predictive value and is of reference significance.

Objective To explore the influencing factors of immune-associated thyroid dysfunction caused by sintilimab treatment in solid tumors and construct a prediction model.Methods Medical records of patients diagnosed with solid tumors and treated with sintilimab at Peking University People's Hospital(Xizhimen Campus,Tongzhou Campus,Shijiazhuang Campus)from January 2023 to September 2024 were collected to explore the influencing factors that caused immune-related thyroid dysfunction using univariate and multifactorial binary logistic regression analyses and to establish a prediction model.The predictive effect of the model was assessed using the receiver operating characteristic(ROC)curve.Results A total of 120 patients were included,and 33 presented with immune-related thyroid dysfunction.Multifactorial logistic regression analysis revealed that thyroid-stimulating hormone(TSH)[OR=2.470,95%CI=(1.279,4.771)]and treatment cycles[OR=1.298,95%CI=(1.117,1.509)]were independent risk factors for the occurrence of immune-associated thyroid dysfunction,and the difference was statistically significant(P＜0.05).The area under the ROC curve was(0.897±0.043)[95%CI=(0.813,0.981)],the Yoden index was 0.703,and the model prediction accuracy was 86.5%.Conclusion The risk of immune-related thyroid dysfunction caused by sintilimab is high,and TSH and treatment cycle are the influencing factors,and the constructed model has certain predictive value and is of reference significance.

OBJECTIVE To study the effect of fluoropezil on embryo-fetal developmental toxicity and toxicokinetics in rabbits,and provide reference for clinical medication.METHODS According to the sequence of pregnancy,pregnant rabbits were divided into five groups:vehicle control group(1%hydroxy-propyl methylcellulose+1.5%polyethylene glycol 400 aqueous solution),positive control group(cyclo-phosphamide 18 mg·kg-1),and fluoropezil(3.6,9.0 and 22.5 mg·kg-1)groups.The vehicle control group and the fluoropezil groups were ig administrated on the 6th to 18th day of gestation(GD6-18)while the positive control group was ig given cyclophosphamide on GD6-20.The pregnant rabbits were sacri-ficed on GD28,and the embryo-fetal development was detected.Sex hormone levels of pregnant rabbits on GD5,GD18 and GD28 were detected by ELISA method.Blood samples with toxokinetics were collected for concomitant toxic generation at the first and last administration,and drug concentrations in fetal,placenta and amniotic fluid were detected with liquid chromatography tandem mass spectrometry(LC-MS/MS).RESULTS Fluoropezil 3.6,9.0 and 22.5 mg·kg-1 had no significant effect on body mass,mass gain,food consumption,pregnancy outcomes,fetal appearance,viscera,skeletal and physical growth and development of pregnant rabbits.Only on GD18 or GD28,the levels of follicle stimulating hormone,estra-diol and progesterone in each dose group fluctuated to some extent.The combined toxokinetics results indicated that fluoropezil could cross the placental barrier of the rabbits,but did not accumulate in preg-nant rabbits or fetuses.Fetal mass,crown-rump length and uterus mass in the cyclophosphamide group were lower than those in the vehicle control group.The appearance and bone of the cyclophos-phamide group were positive.CONCLUSION The no observed adverse effect level(NOAEL)of fluoro-pezil toxicity on rabbit embryo-fetal development is 22.5 mg·kg-1,which is 125 times of the effective dose.At the dosage level of 22.5 mg·kg-1,Cmax is 1093 μg·L-1,and AUC(0-24 h)6650 μg·h·L-1 on GD18.

Limb dismemberment injuries are common in clinical practice,and safe and effective protection of the dismembered limb is the key to successful limb replantation.Normothermic machine perfusion has made significant breakthrough in the field of organ transplantation,which may maintain the active function of organs and tissues for a long period of time and prolong the preservation time.These findings have been validated in large animal models and clinical trials.Meantime,this technology is expected to provide novel reference for the preservation and functional recovery of severed limbs.Therefore,this paper reviews the problems of static cold preservation in the preservation of disarticulated limbs,the development history of mechanical perfusion,the current status of clinical application of ambient mechanical perfusion of disarticulated limbs as well as the problems to be solved,and looks forward to the direction of its development and the prospect of its clinical application,with a view to promoting the wide application of this technology in the clinic.

AIM:To evaluate the efficacy,safety,and economy of camrelizumab(CAM)combined with platinum-containing chemotherapy(CT)for the first-line treatment of locally advanced/meta-static non-small cell lung cancer(NSCLC).METH-ODS:Chinese and English databases such as Pubmed,the Cochrane Library,China Knowledge Network,Wanfang Data,and other related web-sites were systematically searched.After literature screening,quality assessment,and data extraction of the literature according to the inclusion and ex-clusion criteria,two researchers conducted a rapid health technology assessment(HTA).RESULTS:A total of 7 systematic evaluations/Meta-analyses and 17 economics evaluations were included.In terms of effectiveness,compared to docetaxel che-motherapy,CAM+CT significantly prolonged the overall survival(OS),progression-free survival(PFS),and improved the objective remission rate(ORR)of mutation-negative patients with locally ad-vanced/metastatic NSCLC.Compared with CT and pembrolizumab(PEM),CAM+CT significantly pro-longed the PFS,and improved the ORR of mutation-negative patients with locally advanced/metastatic NSCLC.Subgroup analysis showed that CAM+CT significantly prolonged PFS in patients with PD-L1 ≥1％and PD-L1 ≥ 50％compared with CT.Compared with CT,CAM+CT significantly prolonged the OS and PFS of mutation-negative patients with locally advanced/metastatic squamous NSCLC.Compared with sintilimab(SIN),CAM+CT significantly pro-longed the PFS of mutation-negative patients with locally advanced/metastatic squamous NSCLC.Sub-group analysis showed that CAM+CT significantly prolonged OS in patients with PD-L1＜1％com-pared with CT.In terms of safety,CAM+CT was comparable in terms of the occurrence of all grades of adverse events,but the incidence of grade 3 or higher treatment-related adverse events was significantly increased compared with CT and PEM for mutation-negative locally advanced/meta-static NSCLC patients.CAM+CT was significantly in-creased the occurrence of all grades of adverse events compared with CT,but was comparable in terms of the occurrence of grade 3 or higher treat-ment-related adverse events.In terms of economy,CAM+CT has a cost-effectiveness advantage over CT for patients with mutation-negative advanced/metastatic squamous NSCLC.CAM+CT has a cost-effectiveness advantage over CT and PEM+CT;and CAM+CT does not have a cost-effectiveness ad-vantage over SIN+CT for patients with mutation-negative locally advanced/metastatic non-squa-mous NSCLC.CONCLUSION:CAM+CT has good ef-ficacy and cost-effectiveness for the first-line treat-ment of locally advanced/metastatic NSCLC,and the safety aspect is compared with CT,PEM or slightly worse.

Nuclear receptor corepressor (NCoR1) interacts with various nuclear receptors and regulates the anabolism and catabolism of lipids. An imbalance in lipid/energy homeostasis is also an important factor in obesity and metabolic syndrome development. In this study, we found that the deletion of NCoR1 in intestinal epithelial cells (IECs) mainly activated the nuclear receptor PPARα and attenuated metabolic syndrome by stimulating thermogenesis. The increase in brown adipose tissue thermogenesis was mediated by gut-derived tricarboxylic acid cycle intermediate succinate, whose production was significantly enhanced by PPARα activation in the fed state. Additionally, NCoR1 deletion derepressed intestinal LXR, increased cholesterol excretion, and impaired duodenal lipid absorption by decreasing bile acid hydrophobicity, thereby reversing the possible negative effects of intestinal PPARα activation. Therefore, the simultaneous regulatory effect of intestinal NCoR1 on both lipid intake and energy expenditure strongly suggests that it is a promising target for developing metabolic syndrome treatment.

Objective:To investigate the protective effect of hypothermic antegrade machine perfusion against canine ischemic brain injury.Methods:Thirteen beagle dogs were divided into the mild hypothermia with perfusion group ( n=6) and normothermia with perfusion group ( n=7) according to the random number table. The model of ischemic brain injury was established by neck transection. After 1 hour of ischemic circulatory arrest, the perfusion fluid based on autologous blood was continuously perfused through bilateral common carotid artery for 6 hours. The temperature of the perfusion fluid was set at 33 ℃ in the mild hypothermia with perfusion group and 37℃ in the normothermia with perfusion group, respectively. Blood oxygen saturation was recorded at 0, 1, 2, 3, 4, 5 and 6 hours after the beginning of perfusion to evaluate the perfusate oxygen level. The perfusate was collected, and the levels of Na +, K +, Ca 2+ and glucose as well as the pH value of the perfusate were detected in the two groups. At the end of perfusion, the parietal brain tissues of 1 dog from each group were collected to evaluate the water contents of brain tissues. Nissl staining was used to evaluate the morphological integrity of the pyramidal neurons in the frontal cortex and hippocampus. Neuronal nuclei antigen (NeuN) was used to evaluate the structural and morphological integrity of pyramidal neurons. Immunofluorescence glial fibrillary acidic protein (GFAP) and ionic calcium binding adaptor molecule 1 (Iba1) were used to evaluate the integrity and activity of astrocytes and microglia fragments. Results:At 0, 1, 2, 3, 4, 5 and 6 hours of perfusion, there was no significant difference in the blood oxygen saturation or Na + concentrations between the two groups (all P>0.05); the K + concentrations in the mild hypothermia with perfusion group were (4.57±0.12)mmol/L, (4.67±0.14)mmol/L, (4.27±0.12)mmol/L, (4.45±0.10)mmol/L, (6.60±0.15)mmol/L, (7.37±0.18)mmol/L and (9.03±0.16)mmol/L, respectively, which were significantly lower than those in the normothermia with perfusion group [(4.84±0.10)mmol/L, (5.31±0.13)mmol/L, (5.44±0.24)mmol/L, (5.70±0.18)mmol/L, (7.79±0.18)mmol/L, (10.44±0.40)mmol/L, (10.40±0.41)mmol/L] (all P<0.01). At 0, 1, 2 and 3 hours of perfusion, the Ca 2+ concentrations in the mild hypothermia with perfusion group were (0.72±0.15)mmol/L, (1.55±0.16)mmol/L, (1.62±0.15)mmol/L and (1.88±0.15)mmol/L, respectively, being significantly higher than those in the normothermia with perfusion group [(0.41±0.13)mmol/L, (0.99±0.12)mmol/L, (1.29±0.13)mmol/L, (1.57±0.11)mmol/L] (all P<0.01), and no significant differences were found at other time points (all P>0.05). At 0, 1 and 2 hours of perfusion, the glucose concentrations in the mild hypothermia with perfusion group were (5.75±0.19)mmol/L, (5.17±0.15)mmol/L and (4.72±0.15)mmol/L, respectively, being significantly higher than those in the normothermia with perfusion group [(5.30±0.22)mmol/L, (4.89±0.20)mmol/L, (4.30±0.17)mmol/L] (all P<0.01), with no significant differences found at other time points (all P>0.05). At 2, 3, 4, 5 and 6 hours of perfusion, the pH values of the mild hypothermia with perfusion group were 7.32±0.06, 7.25±0.02, 7.23±0.02, 7.24±0.02 and 7.24±0.02, respectively, being significantly higher than those in the normothermia with perfusion group (7.26±0.01, 7.21±0.01, 7.17±0.02, 7.15±0.02, 7.08±0.02) ( P<0.05 or 0.01), with no significant differences at other time points (all P>0.05). The water content of brain tissues in the mild hypothermia with perfusion group was (74.9±0.4)%, which was significantly lower than (79.9±0.9)% in the normothermia with perfusion group ( P<0.01). Nissl staining showed that the pyramidal neurons in prefrontal cortex and dentate gyrus had good integrity in the mild hypothermia with perfusion group. NeuN immunofluorescence staining showed that the morphology and structure of pyramidal neuron cells in the mild hypothermia with perfusion group were better with clearly visible axons than those in the normothermia with perfusion group, whereas the cytosol was full and swollen with scarce axons in the normothermia with perfusion group. GFAP and Iba1 immunofluorescence staining showed that more structurally intact glial cells, more abnormally active cells, thickener axons and better axon integrity in all directions were found in the mild hypothermia with perfusion group than those in the normothermia with perfusion group. Conclusion:Compared with normal temperature antegrade mechanical perfusion, the mild hypothermia antegrade mechanical perfusion can protect canine brain tissue and alleviate ischemic brain injury by maintaining stable energy and oxygen supply, balancing ion homeostasis and perfusion fluid pH value, reducing tissue edema, and maintaining low metabolism of pyramidal neurons, astrocytes and microglia.

Objective:To retrospectively analyze the pregnancy outcomes of patients with adenomyosis requiring fertility in a single center under real world condition.Methods:From June 2015 to May 2020, 231 cases of pregnancy complicated with adenomyosis diagnosed by ultrasound with fertility requirements were treated in the Women′s and Children′s Hospital Affiliated to Qingdao University with complete clinical data. And they were divided into three groups according to the treatment of adenomyosis before pregnancy: expectation group, drug group and operation group. The relevant data before pregnancy of the three groups were analyzed, and the pregnancy outcomes of the patients were summarized. According to whether the early pregnancy was treated with medication, the patients who were naturally conceived without symptoms of threatened abortion were divided into observation group and fetus protection group, and the pregnancy outcomes of the two groups were compared.Results:(1) Compared with the expectation group, the ages of patients in the drug group and the operation group were larger [(31.5±1.8) vs (34.1±3.7) vs (36.9±3.6) years old], and the difference was statistically significant ( P<0.05). Only 9 patients (11.5%, 9/78) had clinical symptoms in the expectation group, while the patients in the drug group and the operation group had a higher proportion of dysmenorrhea and increased menstrual volume. The uterine volume of the drug group and the operation group were larger than that of the expectation group [(151±46) vs (166±27) vs (97±18) cm 3], the difference was statistically significant ( P<0.05). 78.6% (33/42) of the operation group were focal adenomyosis. The proportion of natural pregnancy in the expectation group was 97.4% (76/78), and in vitro fertilization and embryo transfer was mainly used in the drug group and the operation group. (2) The abortion rates of the three groups were 48.7% (26/111), 4/17, 67.5% (27/78) respectively. Compared with the drug group and the operation group, the preterm birth rate was lower [55.9% (33/111) vs 11/17 vs 12.5% (5/78)] and the natural delivery rate was higher [44.1% (26/111) vs 4/17 vs 67.5% (27/78)] in the expectation group. (3) There were 89 cases of spontaneous pregnancy without threatened abortion symptoms, including 31 cases in the observation group and 58 cases in the fetus protection group. Compared with the observation group, the abortion rate of patients in the fetus protection group was lower [41.9% (13/31) vs 34.5% (20/58)], and the difference was statistically significant ( P<0.05). Conclusions:Patients with adenomyosis who have fertility requirements should be comprehensively evaluated and individualized treatment plans should be given. Pregnancy patients with adenomyosis have a high rate of miscarriage, and they should be included in the management of high-risk pregnant women. Active fetal protection treatment during early pregnancy might improve pregnancy outcomes.

Drug-drug interactions (DDI) of tyrosine kinase inhibitors (TKIs) mediated by metabolic enzymes and transporters have become an important issue in clinical practice recently. In addition to CYP450 enzymes, uridine diphosphate glucuronidases (UGTs) are another class of metabolic enzymes involved in the metabolism of TKIs, and most TKIs can inhibit the UGTs in vitro. Potential clinically meaningful DDIs may occur with the co-administration of TKIs and substrates or inhibitors of UGTs. This paper will mainly focus on the UGTs-mediated drug-drug and the effect of UGT1A genotype on the drug interactions of TKIs and explores strategies to address, aiming to provide clinicians and pharmacists with references for the safe and rational application of TKIs.

As an effective anticancer drug, the clinical limitation of doxorubicin (Dox) is the time- and dose-dependent cardiotoxicity. Yes-associated protein 1 (YAP1) interacts with transcription factor TEA domain 1 (TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced