Objective:To report the follow-up status of patients participating phase Ⅲ clinical trial (ZGDD3) of Donafenib tosilate (abbreviated as Donafenib) in the treatment of progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), and to explore its efficacy, safety and prognostic factors.Methods:This study was a randomized controlled trial, and the clinicopathological data and follow-up results of 29 patients (16 males, 13 females, age 40-68 years) who participated in the clinical trial ZGDD3 between August 2018 and March 2021 were analyzed. Patients were divided into Donafenib group and placebo group using the central dynamic randomization method with the ratio of 2∶1. Adverse reactions (AE) during the trial were observed. Independent-sample t test, Mann-Whitney U test and Fisher exact test were used to analyze the differences of baseline characteristics between the two groups. Progression-free survival (PFS) and overall survival (OS) were followed up. Kaplan-Meier method was used to draw the survival curve (log-rank test) and Cox regression analysis was used to analyze the prognostic factors. Results:There were 22 patients in Donafenib group and 7 patients in placebo group. There were no significant differences of baseline characteristics between the two groups ( t values: -0.68, Z values: from -1.47 to -0.56, all P>0.05). The follow-up was 32.07(21.07, 49.85) months. During the trial, drug-related AEs occurred in all patients in Donafenib group, mostly was grade Ⅰ-Ⅱ, no grade Ⅳ or Ⅴ AEs were found. The median PFS was significantly longer in Donafenib group than that in placebo group (13.23 vs 4.03 months; χ2=9.68, P=0.002), and the median OS was 55.00 and 24.30 months respectively ( χ2=2.07, P=0.150). Metastasis to less common sites was the independent risk factor for OS (hazard ratio ( HR)=6.789, 95% CI: 1.272-36.246, P=0.025). Conclusions:Donafenib shows good clinical application in the treatment of RAIR-DTC, demonstrating good safety and efficacy. Metastasis to less common sites is closely related to OS.

BACKGROUND:Exosomes derived from human umbilical cord mesenchymal stem cells are widely used for bone repair and reconstruction,significantly enhancing osteogenesis and promoting angiogenesis.OBJECTIVE:To explore the mechanisms of exosomes derived from human umbilical cord mesenchymal stem cells in the treatment of osteoporotic fractures.METHODS:H uman umbilical cord mesenchymal stem cells were extracted using tissue block culture method.Exosomes derived from human umbilical cord mesenchymal stem cells were extracted using ultracentrifugation method for identification.Thirty 12-week-old female SD rats were randomly divided into sham-operated group(n=6)and ovariectomized group(n=24).Osteoporosis model was established by castration in the ovariectomized group.12 weeks after modeling,6 rats in the ovariectomized group and 6 rats in the sham-operated group were randomly selected for Micro-CT and hematoxylin-eosin staining to verify the models.After verification,the remaining 18 rats in the ovariectomized group were randomly assigned to three groups to establish osteoporotic fracture models.The fracture end was separately injected with PBS(PBS group),exosomes at 1.5×1011 particles/mL(low-concentration exosome group),and 3×1011 particles/mL(high-concentration exosome group).Four weeks after operation,fracture healing and bone angiogenesis were evaluated by imaging and histological observations.RESULTS AND CONCLUSION:(1)In the gross specimens,compared with the PBS group,the exosome group had faster fracture healing and more callus formation.(2)The X-ray score of fracture healing in the exosome group was significantly higher than that in the PBS group,and the difference was significant(P＜0.05).(3)Micro-CT three-dimensional imaging:Compared with the PBS group,the fracture healing in the exosome group was accelerated and the callus formation was significantly increased;the bone volume fraction in the exosome group was significantly higher than that in the PBS group,and the difference was significant(P＜0.01).(4)Hematoxylin-eosin staining and Masson's trichrome staining showed that bone trabeculae and the new bone tissue in the exosome group were more than those in the PBS group.(5)Immunohistochemical staining showed that the expression of CD31 and osteocalcin in the exosome group was significantly higher than that in the PBS group.The high-concentration exosome group had a higher density of new blood vessels,more callus formation,and faster fracture healing than the low-concentration exosome group,showing a concentration-dependent manner.The results show that exosomes derived from human umbilical cord mesenchymal stem cells can promote the repair of osteoporotic fracture by enhancing the angiogenesis and osteogenesis.The mechanism may be related to the increased expression of CD31 and osteocalcin.

BACKGROUND:Exosomes derived from human umbilical cord mesenchymal stem cells are widely used for bone repair and reconstruction,significantly enhancing osteogenesis and promoting angiogenesis.OBJECTIVE:To explore the mechanisms of exosomes derived from human umbilical cord mesenchymal stem cells in the treatment of osteoporotic fractures.METHODS:H uman umbilical cord mesenchymal stem cells were extracted using tissue block culture method.Exosomes derived from human umbilical cord mesenchymal stem cells were extracted using ultracentrifugation method for identification.Thirty 12-week-old female SD rats were randomly divided into sham-operated group(n=6)and ovariectomized group(n=24).Osteoporosis model was established by castration in the ovariectomized group.12 weeks after modeling,6 rats in the ovariectomized group and 6 rats in the sham-operated group were randomly selected for Micro-CT and hematoxylin-eosin staining to verify the models.After verification,the remaining 18 rats in the ovariectomized group were randomly assigned to three groups to establish osteoporotic fracture models.The fracture end was separately injected with PBS(PBS group),exosomes at 1.5×1011 particles/mL(low-concentration exosome group),and 3×1011 particles/mL(high-concentration exosome group).Four weeks after operation,fracture healing and bone angiogenesis were evaluated by imaging and histological observations.RESULTS AND CONCLUSION:(1)In the gross specimens,compared with the PBS group,the exosome group had faster fracture healing and more callus formation.(2)The X-ray score of fracture healing in the exosome group was significantly higher than that in the PBS group,and the difference was significant(P＜0.05).(3)Micro-CT three-dimensional imaging:Compared with the PBS group,the fracture healing in the exosome group was accelerated and the callus formation was significantly increased;the bone volume fraction in the exosome group was significantly higher than that in the PBS group,and the difference was significant(P＜0.01).(4)Hematoxylin-eosin staining and Masson's trichrome staining showed that bone trabeculae and the new bone tissue in the exosome group were more than those in the PBS group.(5)Immunohistochemical staining showed that the expression of CD31 and osteocalcin in the exosome group was significantly higher than that in the PBS group.The high-concentration exosome group had a higher density of new blood vessels,more callus formation,and faster fracture healing than the low-concentration exosome group,showing a concentration-dependent manner.The results show that exosomes derived from human umbilical cord mesenchymal stem cells can promote the repair of osteoporotic fracture by enhancing the angiogenesis and osteogenesis.The mechanism may be related to the increased expression of CD31 and osteocalcin.

Objective:To report the follow-up status of patients participating phase Ⅲ clinical trial (ZGDD3) of Donafenib tosilate (abbreviated as Donafenib) in the treatment of progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), and to explore its efficacy, safety and prognostic factors.Methods:This study was a randomized controlled trial, and the clinicopathological data and follow-up results of 29 patients (16 males, 13 females, age 40-68 years) who participated in the clinical trial ZGDD3 between August 2018 and March 2021 were analyzed. Patients were divided into Donafenib group and placebo group using the central dynamic randomization method with the ratio of 2∶1. Adverse reactions (AE) during the trial were observed. Independent-sample t test, Mann-Whitney U test and Fisher exact test were used to analyze the differences of baseline characteristics between the two groups. Progression-free survival (PFS) and overall survival (OS) were followed up. Kaplan-Meier method was used to draw the survival curve (log-rank test) and Cox regression analysis was used to analyze the prognostic factors. Results:There were 22 patients in Donafenib group and 7 patients in placebo group. There were no significant differences of baseline characteristics between the two groups ( t values: -0.68, Z values: from -1.47 to -0.56, all P>0.05). The follow-up was 32.07(21.07, 49.85) months. During the trial, drug-related AEs occurred in all patients in Donafenib group, mostly was grade Ⅰ-Ⅱ, no grade Ⅳ or Ⅴ AEs were found. The median PFS was significantly longer in Donafenib group than that in placebo group (13.23 vs 4.03 months; χ2=9.68, P=0.002), and the median OS was 55.00 and 24.30 months respectively ( χ2=2.07, P=0.150). Metastasis to less common sites was the independent risk factor for OS (hazard ratio ( HR)=6.789, 95% CI: 1.272-36.246, P=0.025). Conclusions:Donafenib shows good clinical application in the treatment of RAIR-DTC, demonstrating good safety and efficacy. Metastasis to less common sites is closely related to OS.

To report 7 Chinese children with characteristic hyperpigmented macules on the forehead and temples. Among the 7 cases, there were 2 males and 5 females, with the age at onset ranging from 9 to 24 months (12.43 ± 5.32 months), and the disease duration being 1 - 4 months (2.57 ± 1.27 months). Skin examination revealed that the children presented with varying numbers of irregular brown macules and patches scattered on their foreheads and temples, without obvious desquamation. Dermoscopic examination revealed multiple yellowish-brown patches with irregular borders, and linear vessels were observable in some skin lesions. A diagnosis of acquired facial hyperpigmented macules was made in these children. The children received no treatment. After 2 years of follow-up, hyperpigmented macules completely subsided in 2 cases and regressed to varying degrees in 4 cases, while 1 case exhibited no changes in the skin lesions. Considering the literature and the cases discussed in this article, it is hypothesized that acquired facial hyperpigmented macules in young children may represent an independent condition.

BACKGROUND:The effect of electroacupuncture on the proliferation and differentiation of hippocampal oligodendrocytes in model mice with Alzheimer's disease remains poorly understood while demyelinating reaction related to oligodendrocytes is a common pathological reaction of Alzheimer's disease. OBJECTIVE:To investigate the effects and mechanism of electroacupuncture stimulation of"Baihui"(GV 20),"Fengfu"(GV 16)and bilateral"Shenshu"(BL 23)in Alzheimer's disease model mice on the proliferation and differentiation of endogenous neural stem cells to neurons and oligodendrocytes. METHODS:Forty 6-week-old SPF APP/PS1 transgenic male Alzheimer's disease model mice were randomly divided into electroacupuncture group(n=20)and Alzheimer's disease model group(n=20).Healthy male C57BL/6J mice of the same age were used as normal controls(n=20).The mice in the electroacupuncture group received electroacupuncture at"Baihui"(GV 20),"Fengfu"(GV 16)and bilateral"Shenshu"(BL 23)for 16 weeks(20 minutes/day and one day off a week).After electroacupuncture,Morris water maze was used to detect the changes of learning and memory function.Immunohistochemistry was utilized to detect hippocampal dentate gyrus β-amyloid senile plaques.The expression of BrdU/NeuN and BrdU/GALC in the hippocampal dentate gyrus was detected by immunofluorescence double labeling.Western blot assay was used to detect the expression levels of neuron specific protein Nestin and oligodendrocyte specific protein GALC in the hippocampus.mRNA and protein levels of Notch1 and Hes1 in the hippocampus were detected by real-time fluorescence quantitative PCR and western blot assay. RESULTS AND CONCLUSION:(1)Compared with the normal control group,the ability of learning and memory in the Alzheimer's disease model group decreased significantly;hippocampal dentate gyrus β-amyloid senile plaques increased significantly(P<0.01);the expression of GALC and Nestin in the hippocampus decreased significantly(P<0.01,P<0.05).(2)Compared with the Alzheimer's disease model group,the learning and memory ability of the electroacupuncture group was significantly increased;β-amyloid senile plaque in the hippocampal dentate gyrus decreased significantly(P<0.01).BrdU/NeuN double labeled positive cells in the hippocampal dentate gyrus and Nestin protein expression in the hippocampus increased significantly(P<0.01,P<0.05);GALC expression in hippocampus increased significantly(P<0.01).The mRNA and protein levels of Notch1 in the hippocampus were significantly increased(P<0.05,P<0.01).The mRNA and protein levels of Hes1 in the hippocampus decreased significantly(P<0.05).(3)These findings indicate that electroacupuncture at"Baihui"(GV 20),"Fengfu"(GV 16)and bilateral"Shenshu"(BL 23)of the Alzheimer's disease model infant mice can promote the proliferation and differentiation of endogenous neural stem cells to neurons and oligodendrocytes,which may be regulated through the Notch1/Hes1 pathway.

Objective:To explore the protective effect of 18α glycyrrhetinic acid (18α-GA) on acute ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in mice, providing theoretical and experimental basis for the clinical application of 18α-GA.Methods:Forty male C57BL/6J mice were randomly divided into 5 groups: DSS model group, positive drug control group, high, medium, and low dose groups of 18α-GA, with 8 mice in each group. The 5 groups of mice were continuously fed with 3% DSS solution for 7 days to establish an acute UC animal model. At the same time, each group was intraperitoneally injected with 100 mg/kg physiological saline, 100 mg/kg sulfasalazine, 40 mg/kg 18α-GA, 20 mg/kg 18α-GA, and 10 mg/kg 18α-GA daily. The weight of mice was measured and recorded daily, and the Disease Activity Index (DAI) of mice was evaluated. On the 8th day, the mice were euthanized and their colon length was measured; After slicing, the colon mucosa was observed and pathological scoring was performed; Western blot was used to detect the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome pathway related proteins in colon tissue; Enzyme linked immunosorbent assay (ELISA) was used to determine the content of interleukin(IL)-1β in colon tissue.Results:Compared with the DSS model group, the weight loss amplitude of the 18α-GA high and medium dose groups was significantly smaller on the 7th day (all P<0.05); Colon length was longer (all P<0.05), the pathological score of colon mucosa was significantly lower (all P<0.05); The expression of GSDMD, cleaved caspase1, and IL-1β in colon tissue was significantly lower (all P<0.05); The 18α-GA high-dose group had lower DAI scores ( P<0.05); The expression of NLRP3 was lower in colon tissue ( P<0.05). Conclusions:18α-GA can improve DSS induced acute ulcerative colitis in mice by inhibiting the activation of NLRP3 inflammasome pathway.

Objective:This paper is to propose a calibration model based on sine function which enables more choices to determine the functional relationship between the absorbance and the concentration of the tested substance.Methods:This paper uses Taylor series expansion and Levenberg-Marquardt to obtain the optimal parameters for the Sine model and then summarizes the characters of the Sine model. On the basis of these characters, this paper compares and evaluates the experimental data processed by the Sine model from four aspects: correctness, precision, linearity and correlation.Results:The generated sine function calibration model achieved deviations within ±3% of the national standard substance, precision ( CV%) less than 2%, and a linear correlation coefficient greater than 0.990 within the measurement range of 32-710 mg/L. The correlation coefficients between the sine model and other well-performing linear calibration models for 104 clinical samples were all greater than 0.990. Conclusions:The performance evaluation of the prealbumin assay kit using the sine function calibration model meets industry standards and shows good correlation with the results of clinical sample measurements. This indicates that the sine function calibration model can serve as a new calibration model for in vitro diagnostic research and clinical applications.

Objective:To analyze the association between thyroglobulin antibody (TgAb) and differentiated thyroid cancer (DTC) metastases detected by post-radioactive iodine (RAI) therapy scan, when stimulated thyroglobulin (sTg) <1 μg/L.Methods:A total of 314 (68 males, 246 females, age (44.5±12.5) years) post-thyroidectomy DTC patients whose sTg <1 μg/L between March 2013 and May 2017 in Henan Cancer Hospital were enrolled retrospectively. Patients underwent 131I whole-body planar imaging ( 131I-WBS) and SPECT/CT imaging 5 d after 131I administration. Iodine avid metastases were compared between TgAb-positive group and TgAb-negative (TgAb<4 kU/L) group. Logistic regression analysis was conducted to assess odds ratio ( OR) for iodine avid metastases in each subgroup (Q1: 4 kU/L≤TgAb≤9.27 kU/L; Q2: 9.27 kU/L101.43 kU/L) of TgAb-positive patients, with the TgAb-negative patients as the reference. χ2 test was used to analyze the data. Results:Iodine avid metastases were found in 16.9% (53/314) of DTC patients and were more frequently in TgAb-positive group with TgAb>26.75 kU/L than TgAb-negative group (26.0%(19/73) vs 13.7%(23/168); χ2=5.382, P=0.02). Most metastases (92.5%, 49/53) occurred in cervical and mediastinal lymph nodes. The OR for iodine avid metastases was obviously high in TgAb-positive patients with 26.75 kU/L

Objective:To analyze the trend of medication use in patients with ulcerative colitis (UC) in recent ten years in at Xijing Hospital, Air Force Military Medical University.Methods:From 2010 to 2019, the clinical data of 1 425 patients diagnosed with UC in the Department of Gastroenterology at Xijing Hospital, Air Force Medical University, were retrospectively collected. According to the period of medication, the UC patients were divided into year 2010 to 2014 group and year 2015 to 2019 group. The general information and the medication trend of year 2010 to 2014 group and year 2015 to 2019 group were analyzed. And then according to gender and age (<40 years old and ≥40 years old), patients were divided into subgroups and analyzed. Independent sample t test and chi-square test were used for statistical analysis. Results:The number of UC patients of year 2010 to 2014 group and year 2015 to 2019 group was 369 and 1 056, respectively. The percentages of patients in remission of the two groups were 9.5% (35/369) and 12.0% (127/1 056), respectively; the percentages of mild patients were 40.4% (149/369) and 41.6% (439/1 056), respectively; the percentages of moderate patients were 37.4% (138/369) and 28.9% (305/1 056), respectively; the percentages of severe patients were 12.7% (47/369) and 17.5% (185/1 056), respectively. There was no significant difference in the proportion of UC patients with different degrees between year 2010 to 2014 group and year 2015 to 2019 group ( P>0.05). There were no significant differences in the age and proportion of female between the year 2010 to 2014 group and year 2015 to 2019 group ((46.2±15.3) years old vs. (44.6±30.6) years old; 45.8%, 169/369 vs. 44.8%, 473/1 056; both P>0.05). The utilization rates of 5-aminosalicylic acid (5-ASA), glucocorticoid, immunosuppressants, and biological agents of the year 2015 to 2019 group were all higher than those of the year 2010 to 2014 group (96.8%, 1 022/1 056 vs. 90.0%, 332/369; 29.9%, 316/1 056 vs. 14.6%, 54/369; 8.4%, 89/1 056 vs. 2.4%, 9/369; 4.8%, 51/1 056 vs. 0.5%, 2/369, respectively), and the differences were all statistically significant ( χ2=26.766, 33.256, 15.315 and 14.038, all P<0.01). Within each of the year 2010 to 2014 group and the year 2015 to 2019 group, there were no significant differences between the female and male in the age, utilization rates of 5-ASA, glucocorticoid, immunosuppressants and biological agents ((47.2±13.6) years old vs. (45.3±16.5) years old, (43.1±12.9) years old vs. (45.8±39.5) years old, 88.8%, 150/169 vs. 91.0%, 182/200; 96.8%, 458/473 vs. 96.7%, 564/583; 13.6%, 23/169 vs. 15.5%, 31/200; 28.3%, 134/473 vs. 31.2%, 182/583; 2.4%, 4/169 vs. 2.5%, 5/200; 7.0%, 33/473 vs. 9.6%, 56/583; 0 vs. 1.0%, 2/200; 5.3%, 25/473 vs. 4.5%, 26/583; all P>0.05). In the patients aged≥40 years old of the year 2010 to 2014 group, the proportion of females was higher than that of the patients aged <40 years old (50.2%, 121/241 vs. 37.5%, 48/128), and the utilization rate of 5-ASA in patients aged ≥40 years old was lower than that of patients aged <40 years old (85.9%, 207/241 vs. 97.7%, 125/128), and the differences were statistically significant ( χ2=5.438 and 12.824, P=0.020 and P<0.01). In the year 2010 to 2014 group, there were no statistically significant differences in the utilization rates of glucocorticoid, immunosuppressants and biological agents between patients aged ≥40 years old and patients aged <40 years old (13.7%, 33/241 vs. 16.4%, 21/128; 2.1%, 5/241 vs. 3.1%, 4/128; 0 vs. 1.6%, 2/128; all P>0.05). In the year 2015 to 2019 group, the utilization rate of biological agents in patients aged≥40 years old was lower than that in patients aged<40 years old (3.7%, 23/630 vs. 46.5%, 198/426), and the difference was statistically significant ( χ2=4.721, P=0.030). In the year 2015 to 2019 group, there were no statistically significant differences in female proportion, utilization rates of 5-ASA, glucocorticoid, immunosuppressants and biological agents between patients aged≥40 years old and patients aged <40 years old (43.7%, 275/630 vs. 46.5%, 198/426; 96.0%, 605/630 vs. 97.9%, 417/426; 29.7%, 187/630 vs. 30.3%, 129/426; 8.6%, 54/630 vs. 8.2%, 35/426; all P>0.05). Conclusions:Compared with year 2010 to 2014, the number of UC patients remarkably increased in the year 2015 to 2019 in the Department of Gastroenterology, Xijing Hospiatal, Air Force Medical University. The utilization rates of 5-ASA, glucocorticoid, immunosuppressants and biological agents all increased in UC patients. The medication trends of UC patients with different gender were almost the same. The medication trends of UC patients with different age were different.