Objective:To evaluate the role of minimal residual disease (MRD) monitoring during early induction therapy for the treatment of childhood acute lymphoblastic leukemia (ALL).Methods:This was a multicenter retrospective cohort study. Clinical data of 1 164 ALL patients first diagnosed between October 2016 and June 2019 was collected from 16 hospitals in South China Children′s Leukemia Group. According to MRD assay on day 15 of early induction therapy, they were divided into MRD<0.10% group, MRD 0.10%-<10.00% group and MRD≥10.00% group. According to MRD assay on day 33, they were divided into MRD<0.01% group, MRD 0.01%-<1.00% group and MRD≥1.00% group. Age, onset white blood cell count, central nervous system leukemia (CNSL), molecular genetic characteristics and other data were compared between groups. Kaplan-Meier method was used for survival analysis. Cox regression model was used to analyze prognostic factors.Results:Of the 1 164 enrolled patients, there were 692 males and 472 females. The age of diagnosis was 4.7 (0.5, 17.4) years. The white blood cell count at initial diagnosis was 10.7 (0.4, 1 409.0) ×10 9/L. Among all patients, 53 cases (4.6%) had CNSL. The follow-up time was 47.6 (0.5, 68.8) months. The 5-year overall survival (OS) and 5-year relapse-free survival (RFS) rates were (93.1±0.8) % and (90.3±1.1) %. On day 15 of early induction therapy, there were 466 cases in the MRD<0.10% group, 523 cases in the MRD 0.10%-<10.00% group and 175 cases in the MRD≥10.00% group. The 5-year OS rates of the MRD<0.10% group, MRD 0.10%-<10.00% group and MRD≥10.00% group were (95.4±1.0) %, (93.3±1.1) %, (85.4±2.9) %, respectively, while the RFS rates were (93.2±1.6) %, (90.8±1.4) %, (78.9±4.3) %, respectively ( χ2=16.47, 21.06, both P<0.05). On day 33 of early induction therapy, there were 925 cases in the MRD <0.01% group, 164 cases in the MRD 0.01%-<1.00% group and 59 cases in the MRD≥1.00% group. The 5-year RFS rates in the MRD 0.01%-<1.00% group was lowest among three groups ((91.4±1.2) % vs. (84.5±3.2) % vs. (87.9±5.1) %). The difference between three groups is statistically significant ( χ2=9.11, P=0.010). Among ALL patients with MRD≥10.00% on day 15 of induction therapy, there were 80 cases in the MRD <0.01% group on day 33, 45 cases in the MRD 0.01%-<1.00% group on day 33 and 45 cases in the MRD≥1.00% group on day 33. The 5-year RFS rates of three groups were (83.9±6.0)%, (67.1±8.2)%, (83.3±6.9)% respectively ( χ2=6.90, P=0.032). Univariate analysis was performed in the MRD≥10.00% group on day 15 and the MRD 0.01%-<1.00% group on day 33.The 5-year RFS rate of children with CNSL was significantly lower than that without CNSL in the MRD≥10.00% group on day 15 ((50.0±20.4)% vs. (80.3±4.4)%, χ2=4.13, P=0.042). Patients with CNSL or MLL gene rearrangement in the MRD 0.01%-<1.00% group on day 33 had significant lower 5-year RFS rate compared to those without CNSL or MLL gene rearrangement ((50.0±25.0)% vs. (85.5±3.1)%, χ2=4.06, P=0.044;(58.3±18.6)% vs. (85.7±3.2)%, χ2=9.44, P=0.002). Multivariate analysis showed that age ( OR=0.58, 95% CI 0.35-0.97) and white blood cell count at first diagnosis ( OR=0.43, 95% CI 0.27-0.70) were independent risk factors for OS. The MRD level on day 15 ( OR=0.55,95% CI 0.31-0.97), ETV6-RUNX1 fusion gene ( OR=0.13,95% CI 0.03-0.54), MLL gene rearrangement ( OR=2.55,95% CI 1.18-5.53) and white blood cell count at initial diagnosis ( OR=0.52,95% CI 0.33-0.81) were independent prognostic factors for RFS. Conclusions:The higher the level of MRD in early induction therapy, the worse the OS. The MRD levels on day 15 is an independent prognostic factor for RFS.The MRD in early induction therapy guided accurate risk stratification and individualized treatment can improve the survival rate of pediatric ALL.

Background/Aims: Although the conversion from tacrolimus (TAC) to cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) is effective in reducing TAC-induced nephrotoxicity, it remains unclear whether CTLA4-Ig has a direct effect on TAC-induced renal injury. In this study, we evaluated the effects of CTLA4-Ig on TAC-induced renal injury in terms of oxidative stress. Methods: In vitro study was performed to assess the effect of CTLA4-Ig on TAC-induced cell death, reactive oxygen species (ROS), apoptosis, and the protein kinase B (AKT)/forkhead transcription factor (FOXO) 3 pathway in human kidney 2 cells. In the in vivo study, the effect of CTLA4-Ig on TAC-induced renal injury was evaluated using renal function, histopathology, markers of oxidative stress (8-hydroxy-2’-deoxyguanosine) and metabolites (4-hydroxy-2-hexenal, catalase, glutathione S-transferase, and glutathione reductase), and activation of the AKT/FOXO3 pathway with insulin-like growth factor 1 (IGF-1). Results: CTLA4-Ig significantly decreased cell death, ROS, and apoptosis caused by TAC. TAC treatment increased apoptotic cell death and apoptosis-related proteins (increased Bcl-2-associated X protein and caspase-3 and decreased Bcl-2), but it was reversed by CTLA4-Ig treatment. The activation of p-AKT and p-FOXO3 by TAC decreased with CTLA4-Ig treatment. TAC-induced renal dysfunction and oxidative marker levels were significantly improved by CTLA4-Ig in vivo. Concomitant IGF-1 treatment abolished the effects of CTLA4-Ig. Conclusions CTLA4-Ig has a direct protective effect on TAC-induced renal injury via the inhibition of AKT/FOXO3 pathway.

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC₅₀ = 5.31 ± 1.2 μmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE^-/- mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.

Ginsenoside Rg5 is a rare ginsenoside showing promising tumor-suppressive effects.This study aimed to explore its radio-sensitizing effects and the underlying mechanisms.Human lung adenocarcinoma cell lines A549 and Calu-3 were used for in vitro and in vivo analysis.Bioinformatic molecular docking prediction and following validation by surface plasmon resonance(SPR)technology,cellular thermal shift assay(CETSA),and isothermal titration calorimetry(ITC)were conducted to explore the binding between ginsenoside Rg5 and 90 kD heat shock protein alpha(HSP90α).The effects of ginsenoside Rg5 on HSP90-cell division cycle 37(CDC37)interaction,the client protein stability,and the downstream regulations were further explored.Results showed that ginsenoside Rg5 could induce cell-cycle arrest at the G1 phase and enhance irradiation-induced cell apoptosis.It could bind to HSP90α with a high affinity,but the affinity was drastically decreased by HSP90α Y61A mutation.Co-immunoprecipitation(Co-IP)and ITC assays confirmed that ginsenoside Rg5 disrupts the HSP90-CDC37 interaction in a dose-dependent manner.It reduced irradiation-induced upre-gulation of the HSP90-CDC37 client proteins,including SRC,CDK4,RAF1,and ULK1 in A549 cell-derived xenograft(CDX)tumors.Ginsenoside Rg5 or MRT67307(an IKKe/TBK1 inhibitor)pretreatment suppressed irradiation-induced elevation of the LC3-Ⅱ/β ratio and restored irradiation-induced downregulation of p62 expression.In A549 CDX tumors,ginsenoside Rg5 treatment suppressed LC3 expression and enhanced irradiation-induced DNA damage.In conclusion,ginsenoside Rg5 may be a potential radiosensitizer for lung adenocarcinoma.It interacts with HSP90α and reduces the binding between HSP90 and CDC37,thereby increasing the ubiquitin-mediated proteasomal degradation of the HSP90-CDC37 client proteins.

Objective:To summarize the clinical feature of functional distant metastasis (DM) of differentiated thyroid cancer (DTC) and observe the efficacy of 131I treatment. Methods:Between August 2008 and January 2021, a total of 13 DTC patients (4 males, 9 females; age 26-75 years) with functional DM from Henan Provincial People′s Hospital were retrospectively analyzed. Clinical data of patients were collected, including pathological type, metastasis size, metastasis location, and thyroid stimulating hormone (TSH) before the first 131I treatment. Efficacy of 131I treatment in patients with functional DM-DTC was evaluated by response evaluation criteria in solid tumors (RECIST) 1.1 and thyroglobulin (Tg). Complete remission (CR) and partial remission (PR) were considered as effective. Wilcoxon signed rank test was used to analyze the maximum diameter change of metastatic lesions before and after 131I treatment. Results:Among 13 DM-DTC patients, 8 were follicular thyroid cancer (FTC), 5 were papillary thyroid cancer (PTC). Metastasis lesions were mainly located in lungs ( n=12) and bones ( n=6). There were 12 patients with maximum metastasis diameter ≥1 cm, and 3 patients with TSH≥30 mU/L before the first 131I treatment. Nine patients were assessed as PR by RECIST 1.1, 3 patients were assessed as CR by RECIST 1.1 and the value of Tg, and 1 patient was assessed as PR by the changing of Tg. The effective rate of 131I treatment for patients with functional DM-DTC was 13/13. The maximum metastasis diameter was significantly decreased after 131I treatment (2.6(1.6, 3.3) vs 1.2(0.1, 2.2) cm; z=-3.06, P=0.002). Conclusion:Patients with functional DM-DTC are characterized by high proportion of FTC and the maximum metastasis diameter ≥1 cm, low proportion of TSH ≥30 mU/L before the first 131I treatment, and high effective rate of 131I treatment.

Objective:To study the composition and distribution of human papillomavirus(HPV)in female genital tract of Zhuang and Han nationality in Guangxi.Methods:The composition and distribution of cervical human papillomavirus(HPV)infection in Han and Zhuang women visiting Department of Gynecology and Obstetrics of the First Affiliated Hospital of Guangxi Medical University from August 2012 to October 2020 were retrospectively analyzed to provide the basic data for prevention and treatment of HPV infection.A total of 20 736 cases were divided into Han nationality group(n=16 390 cases)and Zhuang nationality group(n=4 346 cases). Polymerase chain reaction(PCR)was used to detect HPV type 21 and analyze the epidemiological characteristics of cervical HPV in women of different ethnic groups in this area.Results:In the 20, 736 cases, the proportion of positive HPV was 27.0%(5 591/20, 736). Among them, positive HPV accounted for 27.7%(4 536)in the Han group, and 24.3%(1 055)in Zhuang group, which were statistically significant( χ2=20.17, P<0.01). Peak age of infection in Zhuang women was more than 65 years.The most common HPV genotypes in both ethnics groups in Guangxi were HPV 16, 52, 58, 18, and 53.In women with positive HPV, the constituent ratio of HPV16 and HPV 52 rose with age ageing, while constituent ratio of HPV 6 and 11 presented the opposite trend. Conclusions:The HPV and HR(high-risk)-HPV positive composition ratio is lower in Zhuang women than in Han women in Guangxi.Among Han and Zhuang females, HPV 16, 52, 58, 18 and 53 have the highest positive composition ratio.HPV genotyping shows an age-increasing change.

ObjectiveTo establish a method of two-times second derivative Fourier transform infrared spectroscopy （FTIR） for identifying melamine （MEL） and its conjugates with cyanuric acid （MEL-CYA） or with uric acid （MEL-UA） in human urinary calculi. MethodsMEL， MEL-CYA and MEL-UA were added to calcium oxalate stone samples， and then analyzed by two-times second derivative FTIR for identifying the characteristic response bands of MEL and its conjugates in stones as well as confirming the ratio of detection. ResultsThe second derivative FTIR could improve the detection of MEL in CaO_x stones by two orders of magnitude. When CaO_x being mixed with MEL （MEL∶ CaO_x）， the two-times second derivative FTIR showed the characteristic peak at 1 548 cm^-1 and the minimum mass ratio of detection at 1∶100 （1%）. When CaO_x being mixed with MEL-CYA complex （MEL-CYA∶ CaO_x）， the two-times second derivative FTIR showed the characteristic peak on 1 740 cm^-1 and 1 538 cm^-1 and the minimum mass ratio of detection at 1∶500 （0.2%）. When CaO_x being mixed with MEL-UA complex （MEL-UA∶ CaO_x）， the two-times second derivative FTIR showed the characteristic peak at 1 117， 982 and 710 cm^-1 and the minimum mass ratio of detection at 1∶250 （0.4%）.ConclusionCompare to the original spectra， the two-times second derivative FTIR can improve the detection ratio MEL in the CaO_x stones from 0.2% to 1.0%. The second derivative FTIR has the unique characteristic bands and sensitive detection limit for identifying MEL in kidney stones.

Orthodontic tooth movement elicits alveolar bone remodeling and orofacial pain that is manifested by tooth mechanical hyperalgesia. Nerve growth factor (NGF) is upregulated in periodontium and may modulate tooth mechanical hyperalgesia. The objectives were to examine the role of NGF in tooth mechanical hyperalgesia and to elucidate the underlying mechanisms. Tooth mechanical hyperalgesia was induced by ligating closed coil springs between incisors and molars in Sprague-Dawley rats. Retrograde labeling was performed by periodontal administration of fluor-conjugated NGF and the detection of fluorescence in trigeminal ganglia (TG). Lentivirus vectors carrying NGF shRNA were employed to knockdown the expression of NGF in TG. The administration of agonists, antagonists, and virus vectors into TG and periodontium was conducted. Tooth mechanical hyperalgesia was examined through the threshold of biting withdrawal. Our results revealed that tooth movement elicited tooth mechanical hyperalgesia that could be alleviated by NGF neutralizing antibody and that NGF was upregulated in periodontium (mainly in periodontal fibroblasts) and TG. Retrograde labeling revealed that periodontal NGF was retrogradely transported to TG after day 1. Acid-sensing ion channel 3 (ASIC3) and NGF were co-expressed in trigeminal neurons and the percentage of co-expression was significantly higher following tooth movement. The administration of NGF and NGF neutralizing antibody into TG could upregulate and downregulate the expression of ASIC3 in TG, respectively. NGF aggravated tooth mechanical hyperalgesia that could be alleviated by ASIC3 antagonist (APETx2). Moreover, NGF neutralizing antibody mitigated tooth mechanical hyperalgesia that could be recapitulated by ASIC3 agonist (GMQ). NGF-based gene therapy abolished tooth mechanical hyperalgesia and downregulated ASIC3 expression. Taken together, in response to force stimuli, periodontal fibroblasts upregulated the expressions of NGF that was retrogradely transported to TG, where NGF elicited tooth mechanical hyperalgesia through upregulating ASIC3. NGF-based gene therapy is a viable method in alleviating tooth-movement-induced mechanical hyperalgesia.

Objective:To evaluate facial asymmetry among Chinese young population via three-dimensional photogrammetry.Methods:Young subjects were recruited in Beijing from May to December in 2017. Three-dimensional facial images were obtained by VECTRA H1 camera. The images were exported to Geomagic Wrap 2017. Soft tissue landmarks were identified, and a coordinate system was built on every image. The face was divided into upper, middle, and lower part by the horizontal plane passing the exocanthion and the horizontal plane passing the cheilion. On the coronal plane, the distances between the midsagittal plane and the homogeneous landmarks located on the right and left hemifaces as well as bilateral palpebral fissure height were computed. In terms of facial depth, facial depth parameters located on the right and the left hemifaces were computed. There was a total of 13 parameters. Parameters on one hemiface were compared with those on the other hemiface using paired t-test. Mean absolute difference (MAD) and asymmetric rate (AR) were computed. Finally, we compared the result on men to the result on women via t-test. P<0.05 was considered statistically significant. Results:There was a total of 122 young subjects, 60 men (25.1±3.8 years old) and 62 women (27.3±4.3 years old). (1) On coronal plane, among males, the difference between bilateral tragion and midsagittal plane and the difference between bilateral cheilion and midsagittal plane were statistically significant( P<0.05); among females, the difference between bilateral exocanthion and midsagittal plane, the difference between bilateral palpebrale superius and midsagittal plane, and the difference between bilateral tragion and midsagittal plane were statistically significant ( P<0.05). Among bilateral landmarks (except for palpebral fissure height), the MAD of the distance between bilateral exocanthion and midsagittal plane was the smallest, (1.00±0.88) mm (AR=2.1%) and (1.08±0.79) mm (AR=2.4%) among men and women, respectively ( t=0.541, P=0.589). The MAD of the distance between lateral tragion and midsagittal plane was the largest, (3.45±2.54) mm (AR=4.6%) and (2.89±2.86) mm (AR=4.1%) among men and women, respectively ( t=-1.149, P=0.253). (2) In terms of facial depth, among both males and females, the difference between all bilateral facial depth parameters was statistically significant ( P<0.05). The MAD of the distance between the pogonion and bilateral tragion was the largest, (2.62±1.69) mm (AR=1.8%) and (2.45±1.69) mm (AR=1.8%) among men and women, respectively ( t=-0.491, P=0.625); the MAD of the distance between the glabella and bilateral tragion was the smallest, (1.77±1.25) mm (AR=1.4%) and (1.91±1.54) mm (AR=1.6%) among men and women, respectively ( t=0.587, P=0.558). Conclusions:Facial asymmetry is universal among Chinese young population. The MAD does not exceed 3.5 mm. Upper one-third face has higher symmetry while lower one-third face has lower symmetry.

Objective:To evaluate facial asymmetry among Chinese young population via three-dimensional photogrammetry.Methods:Young subjects were recruited in Beijing from May to December in 2017. Three-dimensional facial images were obtained by VECTRA H1 camera. The images were exported to Geomagic Wrap 2017. Soft tissue landmarks were identified, and a coordinate system was built on every image. The face was divided into upper, middle, and lower part by the horizontal plane passing the exocanthion and the horizontal plane passing the cheilion. On the coronal plane, the distances between the midsagittal plane and the homogeneous landmarks located on the right and left hemifaces as well as bilateral palpebral fissure height were computed. In terms of facial depth, facial depth parameters located on the right and the left hemifaces were computed. There was a total of 13 parameters. Parameters on one hemiface were compared with those on the other hemiface using paired t-test. Mean absolute difference (MAD) and asymmetric rate (AR) were computed. Finally, we compared the result on men to the result on women via t-test. P<0.05 was considered statistically significant. Results:There was a total of 122 young subjects, 60 men (25.1±3.8 years old) and 62 women (27.3±4.3 years old). (1) On coronal plane, among males, the difference between bilateral tragion and midsagittal plane and the difference between bilateral cheilion and midsagittal plane were statistically significant( P<0.05); among females, the difference between bilateral exocanthion and midsagittal plane, the difference between bilateral palpebrale superius and midsagittal plane, and the difference between bilateral tragion and midsagittal plane were statistically significant ( P<0.05). Among bilateral landmarks (except for palpebral fissure height), the MAD of the distance between bilateral exocanthion and midsagittal plane was the smallest, (1.00±0.88) mm (AR=2.1%) and (1.08±0.79) mm (AR=2.4%) among men and women, respectively ( t=0.541, P=0.589). The MAD of the distance between lateral tragion and midsagittal plane was the largest, (3.45±2.54) mm (AR=4.6%) and (2.89±2.86) mm (AR=4.1%) among men and women, respectively ( t=-1.149, P=0.253). (2) In terms of facial depth, among both males and females, the difference between all bilateral facial depth parameters was statistically significant ( P<0.05). The MAD of the distance between the pogonion and bilateral tragion was the largest, (2.62±1.69) mm (AR=1.8%) and (2.45±1.69) mm (AR=1.8%) among men and women, respectively ( t=-0.491, P=0.625); the MAD of the distance between the glabella and bilateral tragion was the smallest, (1.77±1.25) mm (AR=1.4%) and (1.91±1.54) mm (AR=1.6%) among men and women, respectively ( t=0.587, P=0.558). Conclusions:Facial asymmetry is universal among Chinese young population. The MAD does not exceed 3.5 mm. Upper one-third face has higher symmetry while lower one-third face has lower symmetry.