1.Effect of HIF-1α on osteogenic-angiogenic coupling response in BMSCs sheets
ZHANG Dan ; HUANG Yinli ; TENG Yonghui ; HAN Chang
Journal of Prevention and Treatment for Stomatological Diseases 2025;33(9):744-756
Objective:
To explore the effect of HIF-1α on osteogenic-angiogenic coupling response in bone mesenchymal stem cells (BMSCs) and provide new concepts for engineered bone tissue in vitro.
Methods:
With the approval of the hospital’s experimental animal ethics committee, BMSCs were harvested from Wistar rats. The lentivirus carrying hypoxia-inducible factor-1α (HIF-1α) and empty lentivirus were stably transfected into the third generations of BMSCs to form LV-HIF-1α-BMSCs and LV-BMSCs. Meanwhile, BMSCs without transfection of lentivirus were used as a blank control. Then, the effect of HIF-1α transfection was verified by qPCR and Western Blot. LV-HIF-1α-BMSCs were induced to differentiate into endothelium-like cells (iECs). The morphology was observed by optical microscopy, the differentiation rate was detected by cellular flow CD31, and the Transwell test was used to detect the migration ability. At the same time, LV-HIF-1α-BMSCs and LV-BMSCs were continuously cultured to form osteogenic cell sheets (OCTs), which were stained by alkaline phosphatase on day 14 and alizarin red staining on day 21, and counted for mineralization capacity. Finally, iECs were implanted into OCTs to form prevascularized osteogenic cell sheets (P-OCTs), immunofluorescence CD31 was performed to detect the formation of vascular networks, and the results were recorded on days 1, 3, 7, and 14. Meanwhile, osteopontin (OPN) and osteocalcin (OCN) were detected by western blot to verify their ability for osteogenic differentiation on days 1, 7, and 14.
Results:
The optimal multiplicity of infection (MOI) for lentiviral transfection was 30, and the transfection efficiency was >80%. The results of qPCR and western blot showed that compared with the LV-BMSCs group and BMSCs group, the LV-HIF-1α-BMSCs group had stable and high expressions of HIF-1α (P<0.05). LV-HIF-1α-BMSCs showed an enhanced ability to differentiate into endothelial cells, with a differentiation rate as high as 91.81%. Transwell assay verified that HIF-1α could recruit iECs in vitro. Alkaline phosphatase staining and alizarin red staining confirmed that OCTs formed by LV-HIF-1α-BMSCs had a statistically significant osteogenic differentiation ability compared with LV -BMSCs control group (P<0.05). When iECs were implanted into the LV-HIF-1α-BMSCs group OCTs to form P-OCTs, iECs substantially proliferated and rapidly fused, and formation of the progressive lumen was revealed by immunofluorescent CD31 staining. The expressions of OPN and OCN were significantly enhanced compared with those of the LV-BMSCs control group; OCN was the highest on day 7, and OPN was the highest on day 1 (P<0.05).
Conclusion
BMSCs transfected by HIF-1α have good osteogenic-angiogenic effect after induction and differentiation, which provides experimental foundation for optimizing the construction of three-dimensional prevascularized bone tissue.
2.Association of thyroid autoimmunity with thyroid function and gestational diabetes mellitus among pregnant women at first-trimester
Chengcheng HAN ; Xiaofeng WANG ; Jing GAO ; Jing YANG ; Lijuan ZHAO ; Changfang HUANG ; Juanjuan ZHANG ; Jingning XU ; Yinli CAO
Chinese Journal of Perinatal Medicine 2025;28(8):675-681
Objective:To analyze the relationship among thyroid autoimmunity (TAI), thyroid function, and gestational diabetes mellitus (GDM) in early pregnant women in Xi'an.Methods:A prospective study included pregnant women who underwent prenatal check-ups at the Northwest Women's and Children's Hospital from November 2020 to October 2021, with a gestational age of 6 to 14 weeks. Thyroid function, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), and urinary iodine levels were measured, and the prevalence of thyroid disease and GDM was monitored. The subjects were divided into four groups: TPOAb positive only, TgAb positive only, both TPOAb and TgAb positive, and both TPOAb and TgAb negative, to compare the differences in the prevalence of thyroid disease and GDM among the groups. Statistical analysis was performed using Kruskal-Wallis rank-sum test, Bonferroni correction, Chi-square test, and a multivariate logistic regression model was used to analyze the relationship between TAI, thyroid disease, and GDM. Results:A total of 20 243 early pregnant women were included in this study, among which 1 615 (7.98%) were positive for TPOAb only; 865 (4.27%) were positive for TgAb only; 1 672 (8.26%) were positive for both TPOAb and TgAb (both positive group); and 16 091 (79.49%) were negative for both TPOAb and TgAb (both negative group). The thyroid stimulating hormone levels in the TPOAb positive only group, TgAb positive only group, and both positive group were significantly higher than those in the both negative group, respectively (Bonferroni correction, all P<0.05); the free thyroxine level in the TPOAb positive only group was significantly lower than that in the both negative group ( P<0.05). After adjusting for age, pre-pregnancy body mass index, and urinary iodine levels, multivariate logistic regression analysis showed that compared to the both negative group, the risk of developing hypothyroidism during pregnancy was significantly increased in the both positive group ( OR=11.49, 95% CI: 2.84-46.39); the risk of developing subclinical hypothyroidism during pregnancy was significantly increased in the TgAb positive only group ( OR=1.99, 95% CI: 1.05-3.76) and the both positive group ( OR=3.74, 95% CI: 2.49-5.63); the risk of developing GDM was significantly increased in the TgAb positive only group ( OR=1.43, 95% CI: 1.04-1.96) and the both positive group ( OR=1.94, 95% CI: 1.53-2.46). Among early pregnant women with normal thyroid function, after adjusting for age, pre-pregnancy body mass index, and urinary iodine levels, multivariate logistic regression analysis showed that compared to the both negative group, the risk of developing GDM was significantly increased in the TgAb positive only group ( OR=1.46, 95% CI: 1.06-2.02) and the both positive group ( OR=1.80, 95% CI: 1.40-2.32). Conclusion:TgAb positive only is a risk factor for subclinical hypothyroidism and GDM. Screening for thyroid autoantibodies, especially TgAb, during pregnancy helps in the early identification of high-risk pregnant women for thyroid dysfunction and GDM.
3.Clinical significance of cytokeratin 19 fragment in anti-melanoma differentiation-associated protein-5 antibody positive patients
Wenjuan GUAN ; Lijun LIU ; Panpan ZHANG ; Cong WANG ; Xin ZHANG ; Lijuan ZHANG ; Lishuai HAN ; Yinli ZHANG ; Yujie HE ; Shengyun LIU
Chinese Journal of Rheumatology 2025;29(3):189-196
Objective:To investigate the clinical significance of elevated cytokeratin 19 fragment (CYFRA21-1) in patients with dermatomyositis associated with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody.Methods:142 consecutive cases with newly onset anti-MDA5(+) (MADEDM)-DM admitted to the first affiliated hospital of Zhengzhou University from June 2018 to October 2021 were enrolled. They were divided into two groups, the low serum CYFRA21-1 group (CYFRA21-1≤4 ng/ml) and the high serum CYFRA21-1 group (CYFRA21-1>4 ng/ml). The clinical manifestations, laboratory tests results, imaging examinations treatment and outcome were collected for statistical analysis. Enumeration data were expressed as the number of cases and percentage (%). Normally distributed parameters were tested by t-test. Parameters with skewed distribution were tested by Mann-Whitney Wilcoxon analysis. Categorical variables were compared by the Chi-square test or Fisher′s exact test. Risk factor analysis was performed using Logistic regression. Cumulative survivals were described by Kaplan-Meier curves. Results:The age of onset in the high CYFRA21-1 group [(56±9)years vs. (50±10) years, t=-3.50, P=0.001] was higher than that in the low CYFRA21-1 group. Fever [63.3% (38/60) vs. 40.2% (33/82), χ2=7.39, P=0.007] was more common in the high CYFRA21-1 group, and arthritis [41.7% (25/60) vs. 69.5%(57/82), χ2=11.01, P=0.001] was less common. Myalgia, myasthenia, rashes, Raynaud′s phenomenon and skin ulcers had no significant difference between the two groups. The WBC count [5.2(4.1, 6.9)×10 9/L vs. 4.3(3.2, 6.2)×10 9/L, Z=-2.57, P=0.010], neutrophil count [4.0(2.9, 5.5)×10 9/L vs. 2.9(2.1, 4.5)×10 9/L, Z=-3.25, P=0.001] and neutrophil/lymphocyte ratio [5.75(3.50, 9.20) vs. 3.55(2.64, 5.41), Z=-3.77, P<0.001] in high CYFRA21-1 group were significantly higher than those in low CYFRA21-1 group. At the same time, LDH [384(302, 519)U/L vs. 318(260, 405)U/L, Z=-2.98, P=0.003], ferritin [1 204(677, 2 039)ng/ml vs. 570(229, 846)ng/ml, Z=-4.78, P<0.001], KL-6 [995(658, 1 491)U/ml vs. 750(563, 1 197)U/ml, Z=-2.49, P=0.013], ESR [36(22, 61)mm/1 h vs. 28(15, 46)mm/1 h, Z=-2.18, P=0.029] and CRP [9.2(4.7, 31.5)mg/L vs. 3.1(1.1, 11.6)mg/L, Z=-3.53, P<0.001] were significantly increased in the high level of CYFRA21-1 group, while serum albumin[(32±5)g/L vs. (35±5)g/L, t=3.92, P<0.001] was significantly decreased. There was no significant difference in the titers of serum anti-MDA5 antibodies between the two groups. The positive rate of anti-RO52 antibody [44(74.6%) vs. 44(53.7%), χ2=6.40, P=0.011] in high CYFRA21-1 group was higher than that in low CYFRA21-1 group. The ground glass opacity (GGO) score [1.75(1.33, 2.42) vs. 1.09(0.67, 1.67), Z=-4.60, P<0.001] based on high resolution CT (HRCT) was also significantly increased in the CYFRA21-1 high level group. Compared with the low CYFRA21-1 group, the high CYFRA21-1 group had a higher probability of RP-ILD [48.3%(29/60) vs. 23.2%(19/82), χ2=9.80, P=0.002] and a higher 6-month mortality rate[48.3%(29/60) vs.13.4%(11/82), χ2=19.70, P<0.001]. Logistic regression analysis showed that age ≥53 years old [ OR(95% CI)=5.197(1.781, 15.165), P=0.003], duration < 2 months [ OR(95% CI)=3.314 (1.058, 10.378), P=0.040], NE/LYMP >5 [ OR(95% CI)=3.443(1.120, 10.586), P=0.031], CRP>5 mg/L[ OR(95% CI)=6.271(1.749, 22.480), P=0.005], CA125>14 U/ml[ OR(95% CI)=7.500 (2.409, 23.345), P=0.001] and CYFRA21-1>4 ng/ml[ OR(95% CI)=3.665(1.258, 10.676), P=0.017] were independent risk factors for death within 6 months in MDA5-DM patients. Kaplan-Meier survival curve showed that the survival rate of the high CYFRA21-1 group was significantly lower than that of the low CYFRA21-1 group( P<0.001). Conclusion:Elevated CYFRA21-1 is an independent risk factor for early mortality in MDA5-DM patients and can serve as a novel serological marker for risk stratification in these patients.
4.Clinical significance of cytokeratin 19 fragment in anti-melanoma differentiation-associated protein-5 antibody positive patients
Wenjuan GUAN ; Lijun LIU ; Panpan ZHANG ; Cong WANG ; Xin ZHANG ; Lijuan ZHANG ; Lishuai HAN ; Yinli ZHANG ; Yujie HE ; Shengyun LIU
Chinese Journal of Rheumatology 2025;29(3):189-196
Objective:To investigate the clinical significance of elevated cytokeratin 19 fragment (CYFRA21-1) in patients with dermatomyositis associated with positive anti-melanoma differentiation-associated gene 5 (MDA5) antibody.Methods:142 consecutive cases with newly onset anti-MDA5(+) (MADEDM)-DM admitted to the first affiliated hospital of Zhengzhou University from June 2018 to October 2021 were enrolled. They were divided into two groups, the low serum CYFRA21-1 group (CYFRA21-1≤4 ng/ml) and the high serum CYFRA21-1 group (CYFRA21-1>4 ng/ml). The clinical manifestations, laboratory tests results, imaging examinations treatment and outcome were collected for statistical analysis. Enumeration data were expressed as the number of cases and percentage (%). Normally distributed parameters were tested by t-test. Parameters with skewed distribution were tested by Mann-Whitney Wilcoxon analysis. Categorical variables were compared by the Chi-square test or Fisher′s exact test. Risk factor analysis was performed using Logistic regression. Cumulative survivals were described by Kaplan-Meier curves. Results:The age of onset in the high CYFRA21-1 group [(56±9)years vs. (50±10) years, t=-3.50, P=0.001] was higher than that in the low CYFRA21-1 group. Fever [63.3% (38/60) vs. 40.2% (33/82), χ2=7.39, P=0.007] was more common in the high CYFRA21-1 group, and arthritis [41.7% (25/60) vs. 69.5%(57/82), χ2=11.01, P=0.001] was less common. Myalgia, myasthenia, rashes, Raynaud′s phenomenon and skin ulcers had no significant difference between the two groups. The WBC count [5.2(4.1, 6.9)×10 9/L vs. 4.3(3.2, 6.2)×10 9/L, Z=-2.57, P=0.010], neutrophil count [4.0(2.9, 5.5)×10 9/L vs. 2.9(2.1, 4.5)×10 9/L, Z=-3.25, P=0.001] and neutrophil/lymphocyte ratio [5.75(3.50, 9.20) vs. 3.55(2.64, 5.41), Z=-3.77, P<0.001] in high CYFRA21-1 group were significantly higher than those in low CYFRA21-1 group. At the same time, LDH [384(302, 519)U/L vs. 318(260, 405)U/L, Z=-2.98, P=0.003], ferritin [1 204(677, 2 039)ng/ml vs. 570(229, 846)ng/ml, Z=-4.78, P<0.001], KL-6 [995(658, 1 491)U/ml vs. 750(563, 1 197)U/ml, Z=-2.49, P=0.013], ESR [36(22, 61)mm/1 h vs. 28(15, 46)mm/1 h, Z=-2.18, P=0.029] and CRP [9.2(4.7, 31.5)mg/L vs. 3.1(1.1, 11.6)mg/L, Z=-3.53, P<0.001] were significantly increased in the high level of CYFRA21-1 group, while serum albumin[(32±5)g/L vs. (35±5)g/L, t=3.92, P<0.001] was significantly decreased. There was no significant difference in the titers of serum anti-MDA5 antibodies between the two groups. The positive rate of anti-RO52 antibody [44(74.6%) vs. 44(53.7%), χ2=6.40, P=0.011] in high CYFRA21-1 group was higher than that in low CYFRA21-1 group. The ground glass opacity (GGO) score [1.75(1.33, 2.42) vs. 1.09(0.67, 1.67), Z=-4.60, P<0.001] based on high resolution CT (HRCT) was also significantly increased in the CYFRA21-1 high level group. Compared with the low CYFRA21-1 group, the high CYFRA21-1 group had a higher probability of RP-ILD [48.3%(29/60) vs. 23.2%(19/82), χ2=9.80, P=0.002] and a higher 6-month mortality rate[48.3%(29/60) vs.13.4%(11/82), χ2=19.70, P<0.001]. Logistic regression analysis showed that age ≥53 years old [ OR(95% CI)=5.197(1.781, 15.165), P=0.003], duration < 2 months [ OR(95% CI)=3.314 (1.058, 10.378), P=0.040], NE/LYMP >5 [ OR(95% CI)=3.443(1.120, 10.586), P=0.031], CRP>5 mg/L[ OR(95% CI)=6.271(1.749, 22.480), P=0.005], CA125>14 U/ml[ OR(95% CI)=7.500 (2.409, 23.345), P=0.001] and CYFRA21-1>4 ng/ml[ OR(95% CI)=3.665(1.258, 10.676), P=0.017] were independent risk factors for death within 6 months in MDA5-DM patients. Kaplan-Meier survival curve showed that the survival rate of the high CYFRA21-1 group was significantly lower than that of the low CYFRA21-1 group( P<0.001). Conclusion:Elevated CYFRA21-1 is an independent risk factor for early mortality in MDA5-DM patients and can serve as a novel serological marker for risk stratification in these patients.
5.Association of thyroid autoimmunity with thyroid function and gestational diabetes mellitus among pregnant women at first-trimester
Chengcheng HAN ; Xiaofeng WANG ; Jing GAO ; Jing YANG ; Lijuan ZHAO ; Changfang HUANG ; Juanjuan ZHANG ; Jingning XU ; Yinli CAO
Chinese Journal of Perinatal Medicine 2025;28(8):675-681
Objective:To analyze the relationship among thyroid autoimmunity (TAI), thyroid function, and gestational diabetes mellitus (GDM) in early pregnant women in Xi'an.Methods:A prospective study included pregnant women who underwent prenatal check-ups at the Northwest Women's and Children's Hospital from November 2020 to October 2021, with a gestational age of 6 to 14 weeks. Thyroid function, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), and urinary iodine levels were measured, and the prevalence of thyroid disease and GDM was monitored. The subjects were divided into four groups: TPOAb positive only, TgAb positive only, both TPOAb and TgAb positive, and both TPOAb and TgAb negative, to compare the differences in the prevalence of thyroid disease and GDM among the groups. Statistical analysis was performed using Kruskal-Wallis rank-sum test, Bonferroni correction, Chi-square test, and a multivariate logistic regression model was used to analyze the relationship between TAI, thyroid disease, and GDM. Results:A total of 20 243 early pregnant women were included in this study, among which 1 615 (7.98%) were positive for TPOAb only; 865 (4.27%) were positive for TgAb only; 1 672 (8.26%) were positive for both TPOAb and TgAb (both positive group); and 16 091 (79.49%) were negative for both TPOAb and TgAb (both negative group). The thyroid stimulating hormone levels in the TPOAb positive only group, TgAb positive only group, and both positive group were significantly higher than those in the both negative group, respectively (Bonferroni correction, all P<0.05); the free thyroxine level in the TPOAb positive only group was significantly lower than that in the both negative group ( P<0.05). After adjusting for age, pre-pregnancy body mass index, and urinary iodine levels, multivariate logistic regression analysis showed that compared to the both negative group, the risk of developing hypothyroidism during pregnancy was significantly increased in the both positive group ( OR=11.49, 95% CI: 2.84-46.39); the risk of developing subclinical hypothyroidism during pregnancy was significantly increased in the TgAb positive only group ( OR=1.99, 95% CI: 1.05-3.76) and the both positive group ( OR=3.74, 95% CI: 2.49-5.63); the risk of developing GDM was significantly increased in the TgAb positive only group ( OR=1.43, 95% CI: 1.04-1.96) and the both positive group ( OR=1.94, 95% CI: 1.53-2.46). Among early pregnant women with normal thyroid function, after adjusting for age, pre-pregnancy body mass index, and urinary iodine levels, multivariate logistic regression analysis showed that compared to the both negative group, the risk of developing GDM was significantly increased in the TgAb positive only group ( OR=1.46, 95% CI: 1.06-2.02) and the both positive group ( OR=1.80, 95% CI: 1.40-2.32). Conclusion:TgAb positive only is a risk factor for subclinical hypothyroidism and GDM. Screening for thyroid autoantibodies, especially TgAb, during pregnancy helps in the early identification of high-risk pregnant women for thyroid dysfunction and GDM.
6.Spatiotemporally responsive cascade bilayer microneedles integrating local glucose depletion and sustained nitric oxide release for accelerated diabetic wound healing.
Yongnian ZENG ; Chenyuan WANG ; Jiapeng LEI ; Xue JIANG ; Kai LEI ; Yinli JIN ; Tianshu HAO ; Wen ZHANG ; Jianying HUANG ; Wei LI
Acta Pharmaceutica Sinica B 2024;14(11):5037-5052
High glucose level, bacterial infection, and persistent inflammation within the microenvironment are key factors contributing to the delay of diabetic ulcers healing, while traditional therapeutic methods generally fail to address these issues simultaneously. Here, we present a spatiotemporally responsive cascade bilayer microneedle (MN) patch for accelerating diabetic wound healing via local glucose depletion and sustained nitric oxide (NO) release for long-term antibacterial and anti-inflammatory effects. The MN patch (G/AZ-MNs) possesses a degradable tip layer loading glucose oxidase (GOx), as well as a dissolvable base layer encapsulating l-arginine (Arg)-loaded nanoparticles (NPs). After wound administration, the base part rapidly dissolved, resulting in prompt separation of the MN tip within the wound tissue, which subsequently responded to the overexpressed matrix metalloproteinase-9 (MMP-9) in diabetic lesions, leading to the responsive release of GOx. The released enzyme catalyzed glucose into gluconic acid and hydrogen peroxide (H2O2), which not only reduced glucose level within the diabetic wound, but also initiated the cascade reaction between H2O2 with the Arg that was released from NPs, thereby achieving continuous production of NO for 7 days. Our findings demonstrate that a single administration of the MN patch could effectively heal non-infected or biofilm-infected diabetic wounds with the multifunctional properties.
7.Two case reports of rare antisynthetase syndrome and literature review
Dongbin JIANG ; Yinli ZHANG ; Wenjuan GUAN ; Lei ZHANG ; Hongling ZENG ; Xin ZHANG ; Shengyun LIU ; Guanmin GAO
Chinese Journal of Rheumatology 2024;28(2):123-126
Objective:To study the clinical and immunological features of two case of rare antisynthetase syndrome (ASS), so as to improve the level of diagnosis and treatment.Methods:Two cases with rare antisynthetase syndrome admitted to the First Affiliated Hospital of Zhengzhou University from July 2020 to August 2022 were collected.Results:The two rare ASS were anti-Zo antibody and anti-Ha antibody positive patients, both of which had interstitial lung disease (ILD) as the main clinical manifestation and positive anti-Ro52 antibody. Two rare antisynthetase autoantibodies manifested cytoplasmic ANA indirect immunofluorescence (IIF) staining pattern, but it is different from the cytoplasmic dense speckled pattern of several common ASS antibodies. After treatment with glucocorticoids and immunosuppressants, case 1 died of respiratory failure due to a long course of disease and late diagnosis, the lung lesions of case 2 improved significantly.Conclusion:When encountering the cytoplasmic ANA fluorescent pattern in ILD patients, especially with anti-Ro52 antibody, it is necessary to screen more myositis specific antibodies to rule out the possibility of rare ASS.
8.Risk factors for acute kidney injury after off-pump coronary artery bypass grafting: A systematic review and meta-analysis
Jing PAN ; Yunlan JIANG ; Yue ZHANG ; Yaxin LIU ; Xiaoxing HUANG ; Yinli SHEN
Chinese Journal of Clinical Thoracic and Cardiovascular Surgery 2023;30(07):1048-1054
Objective To analyze the risk factors for acute kidney injury (AKI) after off-pump coronary artery bypass grafting (OPCABG). Methods The PubMed, EMbase, The Cochrane Library, Web of Science, Wanfang data, CBM, VIP, CNKI were searched by computer for researches on risk factors associated with the development of AKI after OPCABG from the inception to March 2022. The meta-analysis was performed using RevMan 5.4 software. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies. Results A total of 18 researches were included, involving 9 risk factors. The NOS score of all included studies was≥6 points. Meta-analysis results showed that age [OR=1.03, 95%CI (1.01, 1.06), P=0.020], body mass index (BMI) [OR=1.10, 95%CI (1.05, 1.15), P<0.001], history of hypertension [OR=1.45, 95%CI (1.27, 1.66), P<0.001], history of diabetes [OR=1.50, 95%CI (1.33, 1.70), P<0.001], preoperative serum creatinine level [OR=2.05, 95%CI (1.27, 3.32), P=0.003], low left ventricular ejection fraction [OR=4.51, 95%CI (1.39, 14.65), P=0.010], preoperative coronary angiography within a short period of time [OR=2.10, 95%CI (1.52, 2.91), P<0.001], perioperative implantation of intra-aortic balloon pump [OR=3.42, 95%CI (2.26, 5.16), P<0.001], perioperative blood transfusion [OR=2.00, 95%CI (1.51, 2.65), P<0.001] were risk factors for AKI after OPCABG. Conclusion Age, BMI, history of hypertension, history of diabetes, preoperative serum creatinine level, low left ventricular ejection fraction, preoperative coronary angiography within a short period of time, perioperative implantation of intra-aortic balloon pump, perioperative blood transfusion are risk factors for AKI after OPCABG. Medical staff should focus on monitoring the above risk factors and early identifying, in order to prevent or delay the onset of postoperative AKI and promote early recovery of patients.
9.Genomic and Transcriptomic Characterization Revealed the High Sensitivity of Targeted Therapy and Immunotherapy in a Subset of Endometrial Stromal Sarcoma
Nan KANG ; Yinli ZHANG ; Shichao GUO ; Ran CHEN ; Fangzhou KONG ; Shuchun WANG ; Mingming YUAN ; Rongrong CHEN ; Danhua SHEN ; Jianliu WANG
Cancer Research and Treatment 2023;55(3):978-991
Purpose:
The unique chromosomal rearrangements of endometrial stromal sarcoma (ESS) make it possible to distinguish high-grade ESS (HGESS) and low-grade ESS (LGESS) from the molecular perspective. Analysis of ESS at the genomic and transcriptomic levels can help us achieve accurate diagnosis of ESS and provide potential therapy options for ESS patients.
Materials and Methods:
A total of 36 ESS patients who conducted DNA- and/or RNA-based next-generation sequencing were retrospectively enrolled in this study. The molecular characteristics of ESS at genomic and transcriptomic levels, including mutational spectrum, fusion profiles, gene expression and pathway enrichment analysis and features about immune microenvironment were comprehensively explored.
Results:
TP53 and DNMT3A mutations were the most frequent mutations. The classical fusions frequently found in HGESS (ZC3H7B-BCOR and NUTM2B-YWHAE) and LGESS (JAZF1-SUZ12) were detected in our cohort. CCND1 was significantly up-regulated in HGESS, while the expression of GPER1 and PGR encoding estrogen receptor (ER) and progesterone receptor (PR) did not differ significantly between HGESS and LGESS. Actionable mutations enriched in homologous recombination repair, cell cycle, and phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathways were detected in 60% of HGESS patients. Genes with up-regulated expression in HGESS were significantly enriched in five immune-related pathways. Most HGESS patients (85.7%) had positive predictors of immunotherapy efficacy. Moreover, immune microenvironment analysis showed that HGESS had relatively high immune infiltration. The degree of immune infiltration in HGESS patients with ZC3H7B-BCOR fusion was relatively higher than that of those with NUTM2B-YWHAE fusion.
Conclusion
This study investigated the molecular characteristics of ESS patients at the genomic and transcriptomic levels and revealed the potentially high sensitivity of targeted therapy and immunotherapy in a subset of HGESS with specific molecular features, providing a basis for guiding decision-making of treatment and the design of future clinical trials on precision therapy.
10.Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties.
Zhongtang LI ; Fan FANG ; Yiyan LI ; Xuehui LV ; Ruqiu ZHENG ; Peili JIAO ; Yuxi WANG ; Guiwang ZHU ; Zefang JIN ; Xiangqing XU ; Yinli QIU ; Guisen ZHANG ; Zhongjun LI ; Zhenming LIU ; Liangren ZHANG
Acta Pharmaceutica Sinica B 2023;13(11):4553-4577
Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.


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