Objective:To explore the differences in tumor-specific growth factors, cellular immune function and efficacy of olaparib and platinum-containing regimen for treatment of platinum-sensitive relapsed ovarian cancer patients with BRCA mutation.Methods:A retrospective cohort study was conducted. A total of 100 platinum-sensitive relapsed BRCA-mutant ovarian cancer patients in Baoding Second Central Hospital from September 2017 to March 2020 were retrospectively selected. The clinical data of the patients were analyzed, and they were divided into the olaparib group (treated with olaparib tablets) and the platinum-containing regimen group (treated with paclitaxel and platinum drugs for 6 cycles, followed by olaparib tablets maintenance therapy), with 50 patients in each group. The clinical efficacy, tumor specific growth factor [carbohydrate antigen (CA) 125, CA199, human epididymal protein 4 (HE4)] levels, cellular immune function-related indicators [T-cell subsets (proportions of CD3 + cells and CD4 + cells), CD4 + cells/CD8 + cells ratio (CD4 +/CD8 +)], and quality of life scores before treatment and after 2, 4 and 6 cycles of treatment of the two groups were compared, as well as the safety of the two groups. The data of three years of follow-up were obtained, Kaplan-Meier method was used to analyze the progression-free survival (PFS) of patients in the two groups, and log-rank test was used for comparison between groups. Results:The age of patients in the olaparib and platinum-containing regimen groups was (53±7) years old and (56±7) years old, respectively. The differences in compositions of patients with different age, body mass index, Eastern Cooperative Oncology Group (ECOG) performance status score, primary tumor location, lesion size, pathological stage, pathological type, germline BRCA mutation, and previous chemotherapy response between the two groups were not statistically significant (all P > 0.05). The objective response rate (ORR) [58.0% (29/50) vs. 38.0% (19/50)] and disease control rate (DCR) [80.0% (40/50) vs. 56.0% (28/50)] of the olaparib group after treatment were higher than those of the platinum-containing regimen group, and the differences were statistically significant (both P < 0.05). Serum CA125, CA199 and HE4 levels were gradually decreased in both groups before treatment and after 2, 4 and 6 cycles of treatment (all P < 0.05); serum CA125, CA199 and HE4 levels in the olaparib group after 2, 4 and 6 cycles of treatment were lower than those in the platinum-containing regimen group, and the differences were statistically significant (all P < 0.05). The CD3 + cells ratio, CD4 + cell ratio and CD4 +/CD8 + in the olaparib group gradually increased before treatment and after 2, 4 and 6 cycles of treatment (all P < 0.05), while those in the platinum-containing regimen group all gradually decreased (all P < 0.05); the CD3 + cells ratio, CD4 + cells ratio and CD4 +/CD8 + in the olaparib group were higher than those in the platinum-containing regimen group after 2, 4 and 6 cycles of treatment, and the differences were statistically significant (all P < 0.05). The quality of life scores of both groups increased before treatment and after 2, 4 and 6 cycles of treatment (all P < 0.05), and the quality of life scores of the olaparib group were higher than those of the platinum-containing regimen group after 2, 4 and 6 cycles of treatment, and the differences were statistically significant (all P < 0.05). The incidence of nausea, fatigue and malaise, vomiting, anemia, and diarrhea at all levels in the olaparib group was lower than those in the platinum-containing regimen group (all P < 0.05). By follow-up for 3 years, there was no statistically significant difference in PFS between the olaparib group and the platinum-containing regimen group ( P > 0.05). Conclusions:The efficacy of olaparib treatment in platinum-sensitive relapsed ovarian cancer patients with BRCA mutation is superior to platinum-containing regimen, and it can increase the level of T cells, inhibit the expression of tumor-specific growth factors, improve the quality of life, and have a positive effect on improving the safety of treatment.

This study was designed to investigate the effect of salidroside on Sjogren's syndrome in mice and its mechanism.Mice in negative control group and model group were given normal saline intragastric administration,mice in 3 salidroside groups were given salidroside intragastric administration(doses of 20,40 and 80 mg/kg),and mice in positive control group were given hydroxychloroquine sulfate(100 mg/kg)intragastric administration once a day.After continuous intragastric administration for 8 weeks,water intake and saliva flow rate were detected,infiltrated submandibular gland lymphocytes were evaluated,the levels of IL-17,IL-10,NF-κB P65 and IκBα and the ratio of Th17/Treg cells were detected.In the model group,the acinus atrophied with unclear margin and decreasing in number,and the lymphocyte infiltration were observed and lymphocyte focus was formed.After the intervention with salidroside and hydroxychloroquine sulfate,the degree of acinus lesions was relieved to a certain extent,and the lymphocyte infiltration was reduced.Compared with negative control group,water intake,salivary flow rate,submandibular gland index,IL-10 and IκBα levels were decreased in other groups,while lymphocyte infiltration,the levels of IL-17,IL-17/IL-10,NF-κB P65 and NF-κB P65/IκBα were increased(P<0.05).Compared with model group,water intake,salivary flow rate,submandibular gland index,IL-10 and IκBα levels were increased in each salidroside dose group,while submandibular gland lymphocyte infiltration,the levels of IL-17,IL-17/IL-10,NF-κB P65 and NF-κB P65/IκBα decreased in a dose-dependent manner(P<0.05).Compared with the negative control group,the proportion of Th17 cells in the serum of model group was increased,and the proportion of Treg cells was decreased,while salidroside in all doses could reverse these changes(P<0.05).Taken together,salidroside alleviates submandibular gland inflammatory responses by mediating Th17/Treg immune balance and inhibiting NF-κB P65/IκBα,thus playing a therapeutic role in SS treatment.

OBJECTIVE To provide a reference for the dose adjustment of tacrolimus in patients who underwent lung transplantation after combined use of voriconazole. METHODS The clinical data of lung transplantation patients who used voriconazole and tacrolimus in our hospital from January 2020 to December 2022 were collected retrospectively. The effects of voriconazole on the valley concentration， daily dose and standardized blood concentration of tacrolimus were analyzed by using SPSS 21.0 software； multiple linear regression analysis was conducted for the factors that may affect the standardized blood concentration of tacrolimus. RESULTS A total of 153 lung transplantation patients were included. After the combination of voriconazole， the average daily dose of tacrolimus decreased from 3.37 mg to 0.76 mg， and valley concentration and standardized blood concentration were increased significantly （P＜0.000 1）. The average daily dose of voriconazole was negatively correlated with the standardized blood drug concentration of tacrolimus （P＝0.000 1，r＝－0.224）. The valley concentration of voriconazole was positively correlated with valley concentration （P＜0.000 1，r＝0.316） and standardized blood concentration （P＜0.000 1，r＝ 0.249） of tacrolimus. After combination with voriconazole， the standardized blood drug concentration of patients who underwent single lung transplantation was significantly higher than those who underwent double lung transplantation， and the standardized blood concentration of tacrolimus after oral administration of voriconazole was significantly higher than after intravenous drip of voriconazole （P＜0.05）. Most liver and kidney function indicators showed no significant changes. The results of multiple factor regression analysis showed that the valley concentration of voriconazole had a significant impact on the standardized blood concentration of tacrolimus （P＜0.001）. CONCLUSIONS The valley concentration of voriconazole has greatest influence on the blood concentration and dose adjustment of tacrolimus， which is an independent influencing factor. In clinical practice， the dose of tacrolimus should be reduced in combination with voriconazole， and therapeutic drug monitoring should be conducted for both drugs.

Metabolic-associated fatty liver disease (MAFLD), which is previously known as non-alcoholic fatty liver disease (NAFLD), represents a major health concern worldwide with limited therapy. Here, we provide evidence that ferroptosis, a novel form of regulated cell death characterized by iron-driven lipid peroxidation, was comprehensively activated in liver tissues from MAFLD patients. The canonical-GPX4 (cGPX4), which is the most important negative controller of ferroptosis, is downregulated at protein but not mRNA level. Interestingly, a non-canonical GPX4 transcript-variant is induced (inducible-GPX4, iGPX4) in MAFLD condition. The high fat-fructose/sucrose diet (HFFD) and methionine/choline-deficient diet (MCD)-induced MAFLD pathologies, including hepatocellular ballooning, steatohepatitis and fibrosis, were attenuated and aggravated, respectively, in cGPX4-and iGPX4-knockin mice. cGPX4 and iGPX4 isoforms also displayed opposing effects on oxidative stress and ferroptosis in hepatocytes. Knockdown of iGPX4 by siRNA alleviated lipid stress, ferroptosis and cell injury. Mechanistically, the triggered iGPX4 interacts with cGPX4 to facilitate the transformation of cGPX4 from enzymatic-active monomer to enzymatic-inactive oligomers upon lipid stress, and thus promotes ferroptosis. Co-immunoprecipitation and nano LC-MS/MS analyses confirmed the interaction between iGPX4 and cGPX4. Our results reveal a detrimental role of non-canonical GPX4 isoform in ferroptosis, and indicate selectively targeting iGPX4 may be a promising therapeutic strategy for MAFLD.

Objective:To investigate the expression and phosphorylation level change of adenosine monophosphate activated protein kinase (AMPK) in skeletal muscle of severely scald rats and its roles in skeletal muscle atrophy in severely scalded rats.Methods:The experimental research method was applied. Totally 100 6-week-old male Wistar rats were divided into sham injury group and scald group according to the random number table, with 50 rats in each group. After weighing the body weight, rats in scald group were inflicted with full-thickness scald of 30% total body surface area on the back, and rats in sham injury group were simulated with scald. At 6 h and on 1, 3, 5, and 7 d post injury, 10 rats in each group were taken to measure their body weights and weights of extensor digitorum longus and soleus muscle. At 6 h and on 1, 3, 5, and 7 d post injury, the tibialis anterior muscles were collected, the mRNA expressions of muscle atrophy F-box protein (MAFbx) and muscle-specific RING finger protein 1 (MuRF1) were detected by real-time fluorescent quantitative reverse transcription polymerase chain reaction; the content of adenosine monophosphate (AMP), adenosine diphosphate, and adenosine triphosphate (ATP) were detected by high performance liquid chromatography, and AMP/ATP ratio and energy charge were calculated; the protein expressions of AMPK-α and phosphorylated AMPK-α (p-AMPK-α) were detected by Western blotting, and the p-AMPK-α/AMPK-α ratio was calculated, with sample number of 4 in each time point of each group. Data were statistically analyzed with analysis of variance for factorial design and least significant difference test.Results:The body weights of rats in 2 groups before injury and at each time point post injury were close ( P>0.05). At 6 h post injury, the weight of extensor digitorum longus of rats in scald group was (0.107±0.007) g, which was significantly heavier than (0.086±0.0607) g of sham injury group ( P<0.01). On 3 d post injury, the weight of extensor digitorum longus of rats in scald group was (0.083±0.016) g, which was significantly lighter than (0.102±0.005) g of sham injury group ( P<0.01). The weight of soleus of rats in 2 groups were close at each time point post injury ( P>0.05). Compared with those of sham injury group, the mRNA expression of MAFbx in tibialis anterior muscle of rats in scald group was significantly up-regulated at 6 h post injury ( P<0.01), and the mRNA expressions of MuRF1 in tibial anterior muscle of rats in scald group were significantly up-regulated at 6 h and on 1 d post injury ( P<0.01). At 6 h and on 7 d post injury, compared with those of false injury group, the AMP/ATP ratios of the tibial anterior muscle of rats in scald group were significantly increased ( P<0.05 or P<0.01), and energy charges of the tibial anterior muscle of rats in scald group were significantly decreased ( P<0.01). At each time point post injury, the protein expressions of AMPK-α of the tibial anterior muscle of rats in 2 groups were close ( P>0.05). The p-AMPK-α/AMPK-α ratios of the tibial anterior muscle of rats in scald group at 6 h and on 7 d post injury were significantly higher than those in sham injury group ( P<0.05 or P<0.01). Conclusions:The decrease in energy charge and increase in AMP/ATP ratio of skeletal muscle of rats after severe scald activate AMPK. The activation of AMPK in the early stage of injury is consistent with the up-regulation of MAFbx and MuRF1 expressions and down-regulation of skeletal muscle weight. The above-mentioned changes may be one of the molecular mechanisms of skeletal muscle atrophy in rats with severe scald

Objective:To explore the current status of quality of life in domestic patients with extremely severe burns during the rehabilitation period and its influencing factors, so as to provide guidance for early clinical psychological intervention and continuous nursing.Methods:From June 2016 to June 2020, convenience sampling was adopted to select 168 patients with extremely severe burns admitted to the Burn Department of 22 ClassⅢ Grade A hospitals in China as the research subject for questionnaire survey. The questionnaire included the Burn Specific Health Scale-Chinese Version and the General Information Questionnaire. Multiple linear regression analysis was used to determine the factors affecting the quality of life of patients with extremely severe burns during the rehabilitation period.Results:The initial quality of life score for patients with extremely severe burns during the rehabilitation period was (157.27±30.61) , and the final quality of life score was (49.14±9.56) . The final scores of the quality of life in each field were ranked from high to low in the order of social relations, general health, physical function, and mental health. Multiple linear regression analysis showed that the factors affecting the quality of life of patients with extremely severe burns during the rehabilitation period included gender, age, education level, marital status and source of expenses ( P<0.05) . Conclusions:The quality of life of patients with extremely severe burns in my country during the rehabilitation period is at a relatively low level. Nurses should strengthen the psychological intervention of patients during hospitalization and carry out continuous nursing according to the relevant factors that affect the quality of life of patients.

Objective: To establish a method for repairing extremities with extensively deep burn using large piece of fresh allogeneic scalp spliced by Meek glue combined with autologous microskin and observe its effect. Methods: Medical records of two male patients with extremely extensive deep burn admitted to our hospital from May to November in 2018 were retrospectively analyzed. Two patients aged 44 and 25 years respectively, with total burn area of 90% and 97% total body surface area (TBSA) and full-thickness burn area of 85% and 70% TBSA, respectively. Preoperatively, the surgical area on the extremities was calculated to estimate the necessary amount of allogeneic scalp and Meek miniature skin. The large piece of fresh allogeneic scalp spliced by Meek glue combined with autologous microskin was prepared according to the methods described as follows. Thin medium-thickness fresh scalps with 3% TBSA and 0.30-0.35 mm in depth were harvested from each donor and spliced into a large piece with epidermis upward by spraying Meek glue. Then the spliced scalp was punched after covered with a single-layer gauze. Autologous microskin was transported onto the dermis of fresh large piece of allogeneic scalp by traditional floating method. Bilateral extremities with full-thickness burn of two patients were selected for self-control. The left upper extremity was denoted as treatment group while the right upper extremity was denoted as control group in Patient 1. The right lower extremity was denoted as treatment group while the left lower extremity was denoted as control group in Patient 2. Wounds in the treatment group were treated with fresh large piece of allogeneic scalp spliced by Meek glue and autologous microskin with expansion ratio of 1∶15 after escharectomy, while wounds in control group received grafting of Meek miniature skin with expansion ratio of 1∶6 and or 1∶9 after escharectomy. The donors of allogeneic scalp were 32 males who were the relatives or friends of the patients, aged 21-50 years, with scalp area of (548±48) cm². The healing conditions of donor sites of scalp were observed on post operation day 10, and were followed up within 3 months after operation to observe whether forming alopecia and hypertrophic scar or not. Wound healing condition was evaluated during follow-up in post operation week (POW) 2-5 and 4 months after operation. Wound coverage rates were calculated in both treatment and control groups in POW 2, 3, 4, and 5. Results: The donor sites of all allogeneic scalp of donors healed completely on post operation day 10. There was no alopecia or hypertrophic scar within 3 months after operation for follow-up. In POW 2, allogeneic scalp grafts basically survived in treatment group without obvious exudation, and most of the Meek miniature skin survived in control group with obvious exudation. Part of allogeneic scalp grafts dissolved and detached in treatment group in POW 3, and the surviving grafts scabbed. The eschar detached and new epithelium was observed in treatment group in POW 4 and 5. In POW 3-5, surviving Meek miniature skin in control group creeped and was incorporated, and the wounds shrank. Hypertrophic scar was observed in both treatment and control groups 4 months after operation, without obvious difference in scar as a whole. The wound coverage rates were respectively 84%-98% and 76%-92% in treatment group of two patients in POW 2-5, close to or higher than those of control group (35%-97% and 28%-81%, respectively). Conclusions The study establishes a novel method for splicing fresh allogeneic scalps into a large piece as the covering of microskin, which has good effect for repairing extensively deep burn wounds. Considering that allogeneic skin is scarce, this method may be a new option in clinical treatment for extensively deep burn patients.

Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2 macrophages infiltration. In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease.

Objective To evaluate the performance of the Sendai Guidelines,Fukuoka Guidelines and Pancreatic Cystic Lesions Management Guidelines (Chinese guidelines) in predicting malignant mucinous pancreatic cystic neoplasms (PCN).Methods A retrospective analysis of 196 patients,who received surgery and were pathologically identified as PCN or intraductal papillary mucinous neoplasms (IPMN),underwent surgical resection in Ruijin Hospital affiliated with Shanghai Jiao Tong University from January 2003 to April 2017 was performed.The differences on clinical and pathological parameters between malignant mucinous and benign mucinous PCN were compared.The accuracy,sensitivity,specificity,positive predictive value (PPV)and negative predictive value (NPV) of the indications for surgery in the Sendai,Fukuoka and Chinese Guidelines in predicting malignant mucinous PCN were calculated.Results Of 196 patients,39 patients (19.9％) were confirmed as malignant tumors and 157 patients (80.1％) were confirmed as benign tumors by pathology.There were significant differences on age,symptoms (abdominal pain,jaundice or pancreatitis),tumor solid composition,pancreatic duct diameter,tumor site,tumor diameter ＞3 cm,and serum CA199 level between malignant and benign patients (all P ＜0.05).But there were no significant differences on gender distribution,tumor diameter,mural nodules and the proportion of mucinous cystic neoplasm (MCN)and intra-ductal papillary mucinous neoplasm (IPMN).165 patients (84.2％) met the Sendai Guidelines,153 patients (78.1％) met the Chinese guideline,and only 61 patients (31.1％) met the Fukuoka Guidelines.All 39 patients with malignant tumors met the indications in Sendai Guidelines and Chinese guidelines,and only 35 patients had the indication for surgery in the Fukuoka Guidelines.The accuracy,sensitivity,specificity,PPV and NPV of the Fukuoka Guidelines for predicting the malignancy were 84.7％,89.7％,83.4％,57.4％ and 97.0％,compared to 35.7％,100％,19.8％,23.6％ and 100％ for the Sendai and 41.8％,100％,27.4％,25.5％ and 100％ for the Chinese guidelines,respectively.Conclusions The performance of the Chinese guideline is slightly better than the Sendai Guidelines,while both of them can lead to a larger number of patients undergoing unnecessary surgical resection.Though the rate of missed diagnosis could reach 10.3％,the Fukuoka Guidelines gets the highest accuracy.