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To investigate the regulatory mechanism of pterygium formation, we detected differentially expressed messenger RNAs (DE-mRNAs) and differentially expressed circular RNAs (DE-circRNAs) in pterygium-associated conjunctival epithelium (PCE) and normal conjunctival epithelium (NCE). Genome-wide mRNA and circRNA expression profiles of PCE and NCE were determined using high-throughput sequencing. Bioinformatics analyses, including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, gene set enrichment analysis (GSEA), and protein–protein interaction (PPI) analysis, were conducted. The microRNAs (miRNAs) interacting with the hub DE-mRNAs and DE-circRNAs were predicted and verified using real-time quantitative PCR (RT-qPCR). The data showed that there were 536 DE-mRNAs (280 upregulated and 256 downregulated mRNAs) and 78 DE-circRNAs (20 upregulated and 58 downregulated circRNAs) in PCE. KEGG enrichment analysis indicated that the DE-mRNAs were mainly involved in the following biological processes: IL-17 signalling pathway, viral protein interaction with cytokine and cytokine receptor, cytokine–cytokine receptor interaction, ECM-receptor interaction, and focal adhesion. The GSEA results revealed that the epithelial mesenchymal transition (EMT) process was significantly enriched in upregulated mRNAs. The pterygium-associated circRNA–miRNA–mRNA network was established based on the top 10 DE-circRNAs, 4 validated miRNAs (upregulated miR-376a-5p and miR-208a-5p,downregulated miR-203a-3p and miR-200b-3p), and 31 DE-mRNAs. We found that miR-200b-3p, as a regulator of FN1, SDC2, and MEX3D, could be regulated by 5 upregulated circRNAs. In addition, we screened out EMT-related DE-mRNAs, including 6 upregulated DE-mRNAs and 6 downregulated DE-mRNAs. The EMT-related circRNA–miRNA–mRNA network was established with the top 10 circRNAs, 8 validated miRNAs (upregulated miR-17-5p, miR-181a-5p, and miR-106a-5p, downregulated miR-124-3p, miR-9-5p, miR-130b-5p, miR-1-3p, and miR-26b-5P), and 12 EMT-related DE-mRNAs. We found that hsa_circ_0002406 might upregulate FN1 and ADAM12 by sponging miR-26b-5p and miR-1-3p, respectively, thus promoting EMT in pterygium. Briefly, the study provides a novel viewpoint on the molecular pathological mechanisms in pterygium formation. CircRNA–miRNA–mRNA regulatory networks participate in the pathogenesis of pterygium and might become promising targets for pterygium prevention and treatment.

Ponatinib is a multi-target tyrosine kinase inhibitor that targets ABL, SRC, FGFR, and so on. It was designed to overcome the resistance of BCR-ABL mutation to imatinib, especially the gatekeeper mutation ABL

ObjectiveThis study is undertaken to explore the relationship between obstructive sleep apnea-hypopnea syndrome (OSAHS) and osteoporosis, including the relationship between OSAHS and osteoporosis incidence, lumbar spine bone mineral density (BMD), and lumbar spine T-score.MethodCochrane Library, PubMed, Embase, Web of Science, and other databases are searched from their establishment to April 2022. Literature published in 4 databases on the correlation between OSAHS and osteoporosis,lumbar spine BMD,lumbar spine T-score is collected. Review Manager 5.4 software is used for meta-analysis.ResultsA total of 15 articles are selected, including 113082 subjects. Compared with the control group, the OSAHS group has a higher incidence of osteoporosis (OR = 2.03, 95% CI: 1.26~3.27, Z = 2.90, P = 0.004), the lumbar spine BMD is significantly lower (MD = -0.05, 95% CI: -0.08~-0.02, Z = 3.07, P = 0.002), and the lumbar spine T-score is significantly decreased (MD = -0.47, 95% CI: -0.79~-0.14, Z = 2.83, P = 0. 005).ConclusionCompared with the control group, the OSAHS group has a higher incidence of osteoporosis and decreased lumbar spine BMD and T-score. In order to reduce the risk of osteoporosis, attention should be paid to the treatment and management of adult OSAHS, and active sleep intervention should be carried out.

The FGF19-FGFR4 signaling pathway has been extensively studied as a promising target for the treatment of hepatocellular carcinoma (HCC). Several FGFR4-selective inhibitors have been developed, but none of them receives approval. Additionally, acquired resistance caused by FGFR4 gatekeeper mutations is emerging as a serious limitation for these targeted therapies. Herein, we report a novel series of 5-formyl-pyrrolo[3,2

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative disease, and newly diagnosed patients frequently cannot tolerate hematopoietic stem cell transplantation (HSCT) at diagnosis due to their poor condition. This retrospective analysis aimed to explore the short-term effect of decitabine-dominant therapy on improving the condition of JMML patients before HSCT. The subjects were 10 JMML patients. All patients were treated with decitabine after low-dose chemotherapy with an interval of 4 weeks before bridging to HSCT. The median treatment course was 3 cycles, and the overall response rate (ORR) was 70.0% after one cycle and 71.4% after three cycles. White blood cell (WBC) and monocyte counts were significantly lower after treatment, and spleen volume was also lower, though not significantly lower. The 12 month progression-free survival rate (PFS) was 80.0 ± 12.6%. Decitabine-dominant therapy was beneficial for reducing tumor burden and improving clinical condition.

Purpose DNA damage contributes to the pathogenesis of age-related cataract (ARC) and is repaired through the nucleotide excision repair (NER) pathway, which includes ERCC6. Evidence has demonstrated that defective autophagy leads to lens organelle degradation and cataract. This study aimed to investigate the effects of ERCC6 on autophagy and determine its mechanisms in ARC. Methods The clinical case-control study comprised 30 patients with ARC and 30 age-matched controls who received transparent lens extraction. Transmission electron microscopy was used to assess the ultrastructure of autophagic vesicles in lens anterior capsule tissues and lens epithelial cell line (SRA01/04). Real-time polymerase chain reaction and western blot analyses were performed to measure relative gene expression levels. Gene expression levels and localization were assessed by immunofluorescence. A coimmunoprecipitation assay was used to investigate the relationship between CSB which encoded by ERCC6 and VCP. ERCC6-siRNA and let-7c-5p mimic were used to alter the expression of ERCC6 and let-7c-5p. Results Autophagy induction occurred in lens anterior capsule tissues of patients with ARC and in UVB-induced SRA01/04 cells, where the number of LC3B puncta was increased. Consistent with this result, the expression of beclin1 (BECN1) and LC3B, in addition to that of p62, was increased. Additionally, ERCC6 expression decreased, and silencing ERCC6 induced increases in the expression of BECN1, LC3B and p62. Moreover, CSB interacted with VCP, and let-7c-5p induced dysregulation of autophagy by targeting ERCC6. Conclusion In ARC, Let-7c-5p-mediated downregulation of ERCC6 might prevent the degradation of autophagic vacuoles. CSB binds to VCP, inducing autophagosomes to combine with lysosomes and be degraded.

Forkhead transcription factors bind a canonical consensus DNA motif, RYAAAYA (R = A/G, Y = C/T), as a monomer. However, the molecular mechanisms by which forkhead transcription factors bind DNA as a dimer are not well understood. In this study, we show that FOXO1 recognizes a palindromic DNA element DIV2, and mediates transcriptional regulation. The crystal structure of FOXO1/DIV2 reveals that the FOXO1 DNA binding domain (DBD) binds the DIV2 site as a homodimer. The wing1 region of FOXO1 mediates the dimerization, which enhances FOXO1 DNA binding affinity and complex stability. Further biochemical assays show that FOXO3, FOXM1 and FOXI1 also bind the DIV2 site as homodimer, while FOXC2 can only bind this site as a monomer. Our structural, biochemical and bioinformatics analyses not only provide a novel mechanism by which FOXO1 binds DNA as a homodimer, but also shed light on the target selection of forkhead transcription factors.

Background The preferred salvage treatment for children with relapsed/refractory acute myeloid leukemia (R/R‐AML) remains unclear. The combination of cladribine/Ara‐C/granulocyte‐colony stimulating factor and mitoxantrone (CLAG‐M) shown promising results in adult R/R‐AML. We aim to investigate the efficacy and safety of CLAG‐M versus mitoxantrone/etoposide/cytarabine (MEC) or idarubicin/etoposide/cytarabine (IEC) in R/R‐AML children. Methods Fifty‐five R/R‐AML children were analyzed. The overall response rate (ORR), overall survival (OS), and progression‐free survival (PFS) at 3‐year were documented. Karyotype or mutations status were summarized as different risk groups. Results The ORR was achieved in 80% (16/20) and 51% (18/35) of patients after one‐cycle of CLAG‐M and MEC/IEC treatment (p, CLAG‐M regimen is a more valid option with similar adverse events as a salvage treatment for R/R‐AML in children when compared with conventional chemotherapy no matter in which risk group.

Farnesoid X receptor (FXR) is considered as a potential target for the treatment of several liver disorders such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Tropifexor is a highly potent and non-steroidal FXR agonist that has progressed into phase II clinical trials in patients with PBC. The clinical trials demonstrate that tropifexor improved serum markers of patients with liver diseases and lower side effect such as pruritus that might be implicated with TGR5 activation. However, the molecular mechanism of the potency and selectivity of tropifexor remains unclear. In this study, the binding affinity of FXR and tropifexor is measured by isothermal titration calorimetry (ITC) assays. The crystal structure of the FXR/tropifexor complex is determined at 2.7 A resolution to explain the molecular mechanism of tropifexor bound to FXR-LBD. Structural comparison with other FXR/agonists structures reveals the conformational change in the FXR/tropifexor structure. Moreover the structural superposition of TGR5/tropifexor indicates that the steric hindrance between tropifexor and TGR5 might be a possible explanation for the impotency arises of tropifexor to TGR5. Overall, our analyses might provide an insight into the molecular mechanism of tropifexor binding to FXR-LBD and account for the high selectivity of tropifexor for FXR versus TGR5.

Chronic myeloid leukemia (CML) is a rare disease among children. A retrospective study was conducted from November 2002 to March 2019 at a single institution in China. A total of 36 pediatric CML patients (25 male and 11 female) were enrolled. Median follow-up time was 51 months (range 8-144), and 5-year overall survival and event-free survival were 95.5 ± 4.4% and 88.9 ± 6.0%, respectively. Among the 25 patients whose response to imatinib mesylate (IM) was regularly monitored, 92.0% achieved complete hematologic response at 3 months, 80.0% achieved complete cytogenetic response at 12 months, and 64.0% achieved major molecular response at 18 months after IM therapy. A higher WBC count at diagnosis was associated with failure to achieve early molecular response (EMR). Height standard deviation score after long-term treatment was significantly and positively correlated with age at diagnosis and at the start of IM therapy. Overall, IM therapy was effective in treating pediatric CML, and WBC count at diagnosis might be an ideal predictor of EMR. Moreover, retardation of height and weight growth due to IM tended to affect patients younger than 9 years old at diagnosis, and longitudinal growth might normalize further into treatment.

To create a personal prognostic model and modify the risk stratification of paediatric acute myeloid leukaemia, we downloaded the clinical data of 597 patients from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database as a training set and included 189 patients from our centre as a validation set. In the training set, age at diagnosis, -7/del(7q) or -5/del(5q), core binding factor fusion genes, FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)/nucleophosmin 1 (NPM1) status, Wilms tumour 1 (WT1) mutation, biallelic CCAAT enhancer binding protein alpha (CEBPA) mutation were strongly correlated with overall survival and included to construct the model. The prognostic model demonstrated excellent discriminative ability with the Harrell's concordance index of 0.68, 3- and 5-year area under the receiver operating characteristic curve of 0.71 and 0.72 respectively. The model was validated in the validation set and outperformed existing prognostic systems. Additionally, patients were stratified into three risk groups (low, intermediate and high risk) with significantly distinct prognosis, and the model successfully identified candidates for haematopoietic stem cell transplantation. The newly developed prognostic model showed robust ability and utility in survival prediction and risk stratification, which could be helpful in modifying treatment selection in clinical routine.

ObjectiveThis paper evaluates the application value of the STOP-Bang questionnaire combined with the Epworth Sleepiness Scale (ESS) in screening for obstructive sleep apnea (OSA) in the population.MethodThousand-six hundred seventy-one patients with suspected OSA who visited the Sleep Medicine Center of the First Affiliated Hospital of Guangzhou Medical University from August 2017 to August 2020 were monitored by overnight polysomnography (PSG) after completing the ESS scale and STOP-Bang questionnaire. The sensitivity, specificity, positive predictive value, negative predictive value and receiver operating characteristic (ROC) curves of the two scales were calculated, and the accuracy in predicting OSA of the STOP-Bang questionnaire combined with ESS was analyzed.ResultsWith Apnea Hypopnea Index (AHI) cutoffs of ≥5, ≥15 and ≥30 events/h, the areas under the ROC curve scored by STOP-Bang were 0.724, 0.703 and 0.712, and those of ESS were 0.632, 0.634 and 0.695; the diagnostic odds ratio (DOR) values of STOP-Bang for OSA, moderate to severe OSA, and severe OSA were 3.349, 2.651 and 3.189, and those of ESS were 2.665, 2.279 and 3.289. The STOP-Bang score of three was used as the cut-off point for OSA diagnosis with higher sensitivity and lower specificity, while ESS had higher specificity. STOP-Bang (≥3) combined with ESS significantly improved its specificity for predicting OSA.ConclusionThe STOP-Bang questionnaire is a simple and effective new tool for screening patients for OSA, while a STOP-Bang score of ≥3 combined with ESS can further improve its specificity. Thus, we suggest further screening with ESS after a STOP-Bang score of ≥3 in suspected patients.

Smear-negative pulmonary TB (PTB) is difficult to diagnose. Current diagnosis and treatment monitoring methods have inherent limitations. Droplet digital PCR (ddPCR) is a new technique with high sensitivity. This study presents a novel ddPCR for rapid and sensitive identification of Mycobacterium tuberculosis (MTB).MTB DNA was detected in respiratory specimens from suspected PTB cases using ddPCR assay, which was directed at two different locations within IS6110. We, for the first time, evaluated the clinical diagnostic ability of this ddPCR for paucibacillary smear-negative PTB.A total of 605 PTB suspects were recruited, including 263 patients with confirmed PTB (84.03% from smear-negative PTB) and 342 without PTB. The sensitivity and specificity of IS6110 ddPCR were 61.22% (95% confidence interval (CI) 55.00-67.10%) and 95.03% (95% CI 92.20-97.10%) for total PTB and 57.92% (95% CI 51.10-64.50%) and 94.57% (95% CI 91.20-96.90%) for smear-negative PTB. ddPCR assay outperformed Xpert MTB/RIF (53.08% vs 28.46%, P = 0.020) in smear-negative PTB detection. Furthermore, effective anti-TB treatment was linked to significantly lower IS6110 copies detected by ddPCR.Herein, we developed and validated a highly sensitive and robust ddPCR assay for MTB quantification in respiratory specimens, which improves diagnosis and therapeutic effect evaluation of smear-negative PTB.

The possible mechanism of preeclampsia is investigated in this study to facilitate the exploration of the future remediation of this disease by analysing the changes of IL-17 and IL-35 in peripheral blood and placental tissue of pregnant women with preeclampsia (PE).The study was conducted using 45 healthy pregnant women as the control group and 90 pregnant women in the preeclampsia group, including 45 cases with severe preeclampsia and 45 cases with mild preeclampsia. All of 135 pregnant women underwent caesarean delivery. IL-17 and IL-35 concentrations in the serum were measured by ELISA, and IL-17 and IL-35 expression in placental specimens was detected by immunohistochemistry.There were no statistically significant differences in age among the three study groups. Serum IL-17 levels were significantly higher in PE patients than in healthy pregnant women (P 0.01). The ratio of positive staining for IL-17 was markedly higher in mild PE tissues (84.44%; 38/45) and severe PE tissues (86.67%; 39/45) than in healthy pregnant tissues (35.56%; 16/45) (P 0.01). The strong positive rates for IL-17 were markedly higher in mild PE tissues (48.89%; 22/45) and severe PE tissues (68.89%; 31/45) than in healthy pregnant tissues (13.33%; 6/45) (P 0.01). No differences between mild PE tissues and severe PE tissues were noted in both positive case rates and strong positive rates. Consistent with this finding, the ratio of strong positive staining for IL-35 was higher in healthy pregnant tissues (66.67%; 30/45) than in mild PE tissues (33.11%; 14/45) and severe PE tissues (26.67%; 12/45) (P 0.01).The abnormal increase in serum and placental of IL-17 has an association with the formation and development of PE. IL-35 expression is significantly lower in severe PE placenta tissue and serum compared with normal pregnant women. These results suggested that IL-17/IL-35 imbalance may play a role in the pathophysiology of PE.

The nuclear receptor NR4A subfamily (NR4A1/NGFI-B, NR4A2/Nurr1 and NR4A3/NOR-1) can recognize different classes of DNA response elements either as a monomer, homodimer, or heterodimer. In this study, we determined the structure of the NR4A1 DNA-binding domain (NR4A1-DBD) bound to natural Nur-responsive elements (NurREs) in the promoter region of the pituitary proopiomelanocortin (POMC) gene (NurREPOMC) at 3.12 A resolution. The NR4A1-DBD molecules bound independently to this element in our structure. The N-terminal helix H1 forms specific contacts with major groove, and C-terminal extension interact extensively with minor groove. Moreover our modelling structure of NR4A1 large fragment complexed with NurREPOMC indicated that ligand binding domain of NR4A might form dimer interactions to help recognize DNA. Overall, our analyses provide a molecular basis for DNA binding of NR4A proteins as a homodimer and novel insight into the molecular functions of NR4A modulation of gene expression.

Aberrant FGF19/FGFR4 signaling has been shown to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However, FGFR4 gatekeeper mutation induced acquired resistance remains an unmet clinical challenge for HCC treatment. Thus, a series of aminoindazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. One representative compound (

Background To assess postoperative changes in angle alpha, and to evaluate the postoperative visual quality of patients with different angle alpha values after implantation of extended depth of focus (EDOF) intraocular lenses (IOLs). Methods Seventy-nine eyes of 79 patients who had phacoemulsification with EDOF IOLs implantation were enrolled. A cut-off value of 0.3 mm, 0.4 mm, and 0.5 mm in preoperative angle alpha was chosen to divide eyes into groups. Distance, intermediate, and near visual acuities, modulation transfer function (MTF), and aberrations were recorded during a 6-month follow-up. A patient questionnaire was completed. Results There were no significant differences in angle alpha postoperatively compared to preoperatively. No significant differences were found in visual acuity and MTF between all groups. With 5 mm pupil diameter, there were significant differences of higher-order aberrations and spherical aberration in ocular aberration and internal aberration between angle alpha Conclusions Angle alpha did not affect visual acuity, but the value of 0.4 mm or higher in angle alpha affected the visual quality under scotopic conditions and occurrence of halos and glare. For patients with 0.4 mm or higher in angle alpha, the choice to implant a EDOF IOL should be carefully considered.

Epilepsy is a neurological disorder, caused by various genetic and acquired factors. Electroencephalogram (EEG) is an important means of diagnosis for epilepsy. Aiming at the low efficiency of clinical artificial diagnosis of epilepsy signals, this paper proposes an automatic detection algorithm for epilepsy based on multifeature fusion and convolutional neural network. Firstly, in order to retain the spatial information between multiple adjacent channels, a two-dimensional Eigen matrix is constructed from one-dimensional eigenvectors according to the electrode distribution diagram. According to the feature matrix, sample entropy SE, permutation entropy PE, and fuzzy entropy FE were used for feature extraction. The combined entropy feature is taken as the input information of three-dimensional convolutional neural network, and the automatic detection of epilepsy is realized by convolutional neural network algorithm. Epilepsy detection experiments were performed in CHB-MIT and TUH datasets, respectively. Experimental results show that the performance of the algorithm based on spatial multifeature fusion and convolutional neural network achieves excellent results.

Farnesoid X receptor (FXR) is a bile acid-related nuclear receptor and is considered a promising target to treat several liver disorders. Cilofexor is a selective FXR agonist and has already entered phase III trials in primary sclerosing cholangitis (PSC) patients. Pruritis caused by cilofexor treatment is dose dependent. The binding characteristics of cilofexor with FXR and its pruritogenic mechanism remain unclear. In our research, the affinity of cilofexor bound to FXR was detected using an isothermal titration calorimetry (ITC) assay. The binding mechanism between cilofexor and FXR-LBD is explained by the cocrystal structure of the FXR/cilofexor complex. Structural models indicate the possibility that cilofexor activates Mas-related G protein-coupled receptor X4 (MRGPRX4) or G protein-coupled bile acid receptor 1 (GPBAR1), leading to pruritus. In summary, our analyses provide a molecular mechanism of cilofexor binding to FXR and provide a possible explanation for the dose-dependent pruritis of cilofexor.

The pathology of age-related cataract (ARC) mainly involves the misfolding and aggregation of proteins, especially oxidative damage repair proteins, in the lens, induced by ultraviolet-B (UVB). MSH3, as a key member of the mismatch repair family, primarily maintains genome stability. However, the function of MSH3 and the mechanism by which cells maintain MSH3 proteostasis during cataractogenesis remains unknown. In the present study, the protein expression levels of MSH3 were found to be attenuated in ARC specimens and SRA01/04 cells under UVB exposure. The ectopic expression of MSH3 notably impeded UVB-induced apoptosis, whereas the knockdown of MSH3 promoted apoptosis. Protein half-life assay revealed that UVB irradiation accelerated the decline of MSH3 by ubiquitination and degradation. Subsequently, we found that E3 ubiquitin ligase synoviolin (SYVN1) interacted with MSH3 and promoted its ubiquitination and degradation. Of note, the expression and function of SYVN1 were contrary to those of MSH3 and SYVN1 regulated MSH3 protein degradation via the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. Based on these findings, we propose a mechanism for ARC pathogenesis that involves SYVN1-mediated degradation of MSH3 via the ubiquitin-proteasome pathway and the autophagy-lysosome pathway, and suggest that interventions targeting SYVN1 might be a potential therapeutic strategy for ARC.

Objective Although the interferon-γ release assay (IGRA) has become a common diagnostic method for tuberculosis, its value in the diagnosis of tuberculosis in human immunodeficiency virus (HIV) seropositive patients remains controversial. Therefore, this systematically reviews the data for exploring the diagnostic value of IGRA in HIV-infected individuals complicated with active tuberculosis, aiming to provide a clinical basis for future clinical diagnosis of the disease. Methods Relevant studies on IGRA for diagnosing tuberculosis in HIV-infected patients were comprehensively collected from Excerpta Medica Database (EMBASE), Medline, Cochrane Library, Chinese Sci-tech Periodical Full-text Database, Chinese Periodical Full-text Database, China National Knowledge Infrastructure (CNKI) and China Wanfang Data up to July 2020. Subsequently, Stata 15.0, an integrated statistical software, was used to analyse the sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR) and negative likelihood ratio (NLR) to create receiver operator characteristic (ROC) curves. Results A total of 18 high-quality articles were selected, including 20 studies, 11 of which were related to QuantiFERON-TB Gold In-Tube (QFT-GIT) and nine to T-SPOT.TB. The meta-analysis indicated that the pooled sensitivity = 0.75 (95% CI 0.63–0.85), the pooled specificity = 0.82 (95% CI 0.66–0.92), PLR = 4.25 (95% CI 1.97–9.18), NLR = 0.30 (95% CI 0.18–0.50), DOR = 14.21 (95% CI 4.38–46.09) and the area under summary ROC curve was 0.85 (95% CI 0.81–0.88). Conclusion IGRA has a good diagnostic value and therefore can aid in the preliminary screening of active tuberculosis in HIV-infected individuals. Its diagnostic effectiveness can be improved by modifying and optimizing the assay design.

To investigate the efficacy and adverse reactions of methylprednisolone plus azithromycin in the treatment of children with refractory mycoplasma pneumoniae pneumonia (RMPP) and its effect on fractional exhaled nitric oxide (FeNO) and peripheral blood eosinophils (EOS).Comparative study.Daqing Oilfield General Hospital, China, from June 2019 to January 2021.A total of 102 children with RMPP were randomly divided into Group A (n = 51) and Group B (n = 51) by the random number table. Group A was treated with azithromycin alone, and Group B was treated with methylprednisolone plus azithromycin. The efficacy, adverse reactions, FeNO and EOS levels were compared.The total effective rate of treatment in Group B was higher than that in Group A (p=0.006). Time of cough disappearance, lung shadow disappearance, defervescence and hospitalisation in Group B was shorter than that in Group A (p=0.033, 0.008, 0.004 and0.001, respectively). After treatment, the FeNO and EOS levels in Group B were lower than those in Group A (both p0.001).The efficacy of methylprednisolone plus azithromycin in treatment of RMPP is better than azithromycin alone. The former can reduce the levels of FeNO and EOS more effectively than the latter. Key Words: Refractory mycoplasma pneumoniae pneumonia (RMPP), Methylprednisolone, Azithromycin, Fractional exhaled nitric oxide (FeNO), Eosinophils (EOS).

Tongue squamous cell carcinoma (TSCC) is a common malignancy with aggressive biological behaviors. Mitochondrial fission regulator 1 (MTFR1), is aberrantly expressed in head and neck squamous cell carcinoma (HNSC), but its role in TSCC remains unclear. We aimed to explore the role of MTFR1 in TSCC. The expression of long non-coding RNA small nucleolar RNA host gene 1 (SNHG1), microRNA-194-5p and MTFR1 in TSCC cells was measured by RT-qPCR. Luciferase reporter assay and RNA pull down assay were applied to confirm the binding capacity between miR-194-5p and SNHG1 (or MTFR1). TSCC cell invasion and migration were accessed by Transwell assays. The protein levels of MTFR1 and epithelial-mesenchymal transition (EMT) markers were examined by western blot. MTFR1 had high expression level in TSCC. MTFR1 knockdown inhibited transforming growth factor β1 (TGFβ1)-induced EMT, migration and invasion of TSCC cells in vitro. MiR-194-5p targeted MTFR1 and negatively regulated its expression. In addition, SNHG1 upregulated the expression of MTFR1 by binding with miR-194-5p. Importantly, SNHG1 promoted EMT, invasion and migration of TSCC cells by upregulating MTFR1. SNHG1/miR-194-5p/MTFR1 axis promotes TGFβ1-induced EMT, migration and invasion of cells in TSCC, which could be potential targets for treating TSCC patients.

Objective Higher mortality in COVID-19 in men compared to women is recognized, but sex differences in cardiovascular events are less well established. We aimed to determine the independent contribution of sex to stroke, myocardial infarction and death in the setting of COVID-19 infection. Methods We performed a retrospective cohort study of hospitalized COVID-19 patients in a racially/ethnically diverse population. Clinical features, laboratory markers and clinical events were initially abstracted from medical records, with subsequent clinician adjudication. Results Of 2060 patients, myocardial injury (32% vs 23%, p = 0.019), acute myocardial infarction (2.7% vs 1.6%, p = 0.114), and ischemic stroke (1.8% vs 0.7%, p = 0.007) were more common in men vs women. In-hospital death occurred in 160 men (15%) vs 117 women (12%, p = 0.091). Men had higher odds of myocardial injury (odds ratio (OR) 2.04 [95%CI 1.43–2.91], p

Background: The understanding of the regulation of glucagon secretion by pancreatic islet α-cells remains elusive. We aimed to develop an in vitro model for investigating the function of human α-cells under direct influence of glucose and other potential regulators. Methods: Highly purified human α-cells from islets of deceased donors were re-aggregated in the presence or absence of β-cells in culture, evaluated for glucagon secretion under various treatment conditions, and compared to that of intact human islets and non-sorted islet cell aggregates. Findings: The pure human α-cell aggregates maintained proper glucagon secretion capability at low concentrations of glucose, but failed to respond to changes in ambient glucose concentration. Addition of purified β-cells, but not the secreted factors from β-cells at low or high concentrations of glucose, partly restored the responsiveness of α-cells to glucose with regulated glucagon secretion. The EphA stimulator ephrinA5-fc failed to mimic the inhibitory effect of β-cells on glucagon secretion. Glibenclamide inhibited glucagon secretion from islets and the α- and β-mixed cell-aggregates, but not from the α-cell-only aggregates, at 2.0 mM glucose. Interpretation: This study validated the use of isolated and then re-aggregated human islet cells for investigating α-cell function and paracrine regulation, and demonstrated the importance of cell-to-cell contact between α- and β-cells on glucagon secretion. Loss of proper β- and α-cell physical interaction in islets likely contributes to the dysregulated glucagon secretion in diabetic patients. Re-aggregated select combinations of human islet cells provide unique platforms for studying islet cell function and regulation. Keywords: Human alpha cells glucagon, Insulin inhibition, Somatostatin, Glibenclamide, Paracrine regulation, Cell-to-cell contact

The FOXC family of transcription factors (FOXC1 and FOXC2) plays essential roles in the regulation of embryonic, ocular, and cardiac development. Mutations and abnormal expression of FOXC proteins are implicated in genetic diseases as well as cancer. In this study, we determined two crystal structures of the DNA-binding domain (DBD) of human FOXC2 protein, in complex with different DNA sites. The FOXC2-DBD adopts the winged-helix fold with helix H3 contributing to all the base specific contacts, while the N-terminus, wing 1, and the C-terminus of FOXC2-DBD all make additional contacts with the phosphate groups of DNA. Our structural, biochemical, and bioinformatics analyses allow us to revise the previously proposed DNA recognition mechanism and provide a model of DNA binding for the FOXC proteins. In addition, our structural analysis and accompanying biochemical assays provide a molecular basis for understanding disease-causing mutations in FOXC1 and FOXC2.

Background N6-methyladenosine (m6A) is the most common internal modification present in mRNAs and long noncoding RNAs (lncRNAs), associated with tumorigenesis and cancer progression. However, little is known about the roles of m6A and its regulatory genes in nonsmall cell lung cancer (NSCLC). Here, we systematically explored the roles and prognostic significance of m6A-associated regulatory genes in NSCLC. Methods The copy number variation (CNV), mutation, mRNA expression data, and corresponding clinical pathology information of 1057 NSCLC patients were downloaded from the cancer genome atlas (TCGA) database. The gain and loss levels of CNVs were determined by utilizing segmentation analysis and GISTIC algorithm. The GSEA was conducted to explore the functions related to different levels of m6A regulatory genes. Logrank test was utilized to assess the prognostic significance of m6A-related gene's CNV. Results The genetic alterations of ten m6A-associated regulators were identified in 102 independent NSCLC samples and significantly related to advanced tumor stage. Deletions or shallow deletions corresponded to lower mRNA expression while copy number gains or amplifications were related to increased mRNA expression of m6A regulatory genes. Survival analysis showed the patients with copy number loss of FTO with worse disease-free survival (DFS) or overall survival (OS). Besides, copy number loss of YTHDC2 was also with poor OS for NSCLC patients. Moreover, high FTO expression was significantly associated with oxidative phosphorylation, translation, and metabolism of mRNA. Conclusion Our findings provide novel insight for better understanding of the roles of m6A regulators and RNA epigenetic modification in the pathogenesis of NSCLC.

Mutations in HNF1A cause Maturity Onset Diabetes of the Young (HNF1A-MODY). To understand mechanisms of β-cell dysfunction, we generated stem cell-derived pancreatic endocrine cells with hypomorphic mutations in HNF1A. HNF1A-deficient β-cells display impaired basal and glucose stimulated-insulin secretion, reduced intracellular calcium levels in association with a reduction in CACNA1A expression, and accumulation of abnormal insulin granules in association with SYT13 down-regulation. Knockout of CACNA1A and SYT13 reproduce the relevant phenotypes. In HNF1A deficient β-cells, glibenclamide, a sulfonylurea drug used in the treatment of HNF1A-MODY patients, increases intracellular calcium, and restores insulin secretion. While insulin secretion defects are constitutive in β-cells null for HNF1A, β-cells heterozygous for hypomorphic HNF1A (R200Q) mutations lose the ability to secrete insulin gradually; this phenotype is prevented by correction of the mutation. Our studies illuminate the molecular basis for the efficacy of treatment of HNF1A-MODY with sulfonylureas, and suggest promise for the use of cell therapies.

MiR-29a belongs to one of the subtypes of miRNAs known as non-coding single-stranded RNAs and is preferentially expressed in normal tissues. B7-H3, a member of the B7/CD28 immunoglobulin superfamily, was shown to be overexpressed in several solid malignant tumors, including colon cancer. In addition, it is associated with tumor progression and poor prognosis. We used immunohistochemical and Western blotting to assess B7-H3 protein expression levels in colon cancer and adjacent normal tissues and then compared their relationships with clinicopathological factors. Quantitative real-time reverse-transcription PCR was used to assess B7-H3 and miRNA-29a mRNA expression levels, and then their relationship and clinical significance were evaluated. In addition, colon cancer Caco-2 cells, which constitutively overexpress B7-H3, were transfected with lentivirus particles for miR-29a upregulation. Invasion and migration assays were carried out in vitro along with the establishment of a subcutaneous xenograft model in vivo to determine the role of miRNA-29a in colon cancer progression. The B7-H3 protein showed elevated expression in colon carcinoma and was relevant to TNM staging, lymph node metastasis, and reduced survival. Meanwhile, miR-29a was preferentially expressed in normal colon tissues, while B7-H3 transcript levels had no marked differences between tumor and normal tissue specimens. In vitro, miR-29a upregulation resulted in reduced B7-H3 expression. Furthermore, miR-29a upregulation reduced the invasive and migratory abilities of colon carcinoma cells. In animal models, upregulation of miR-29a slowed down the growth of subcutaneous xenotransplanted tumors and resulted in prolonged survival time. MiR-29a downregulates B7-H3 expression and accordingly inhibits colon cancer progression, invasion, and migration, indicating miR-29a and B7-H3 might represent novel molecular targets for advanced immunotherapy in colon cancer.

Background: Ginseng is widely used as herb or food. Different parts of ginseng have diverse usages. However, the comprehensive analysis on the ginsenosides in different parts of ginseng root is scarce. Methods: An ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) combined with UNIFI informatics platform and ultra-high-performance liquid chromatography-charged aerosol detection (UHPLC-CAD) were employed to evaluate the different parts of cultivated ginseng root. Results: 105 ginsenosides including 16 new compounds were identified or tentatively characterized. 22 potential chemical markers were identified, 20, 17, and 19 for main root (MR) and fibrous root (FR), main root (MR) and branch root (BR), and main root (MR) and rhizome (RH), respectively. The relative contents of Re, Rb1, 20(R)-Rh1, Rd, and Rf were highest in FR. The relative content of Rg1 was highest in RH. The total relative content of pharmacopoeia indicators Rg1, Re, and Rb1 was highest in FR. Conclusion: The differences among these parts were the compositions and relative contents of ginsenosides. Under our research conditions, the peak area ratio of Rg1 and Re could distinguish the MR and FR samples. Fibrous roots showed rich ingredients and high ginsenosides contents which should be further utilized.

PURPOSE Survivors of childhood cancer often experience treatment-related chronic health conditions. Given its vast population, China shares a large proportion of the global childhood cancer burden. Yet, screening and treatment of late effects in survivors of childhood cancer remain underaddressed in most regions of China. This study aimed to identify high-priority late effects for harmonizing screening guidelines within the Chinese Children's Cancer Group (CCCG), as well as barriers and enablers of the implementation of surveillance recommendations in local practice. METHODS To establish clinical consensus, 12 expert panelists who represent major institutions within the CCCG completed a Delphi survey and participated in a focus group discussion. The survey solicited ratings of the prevalence, severity, and priority for screening of 45 late effects. Major themes identified from the focus group were analyzed using thematic analysis. RESULTS The Delphi survey identified eight high-priority late effects for harmonization within CCCG: osteonecrosis, osteoporosis, left ventricular dysfunction, secondary brain tumors, treatment-related myeloid leukemia, gonadal dysfunction, growth hormone deficiency, and neurocognitive deficits. The common barriers to implementing survivorship programs include lack of support and resources for clinicians to provide follow-up care. Patients were also concerned about privacy issues and lacked awareness of late effects. Many institutions also lacked rehabilitation expertise and referral pathways. CONCLUSION By identifying obstacles related to the professional setting, patient behavior, and organization of care, our study identified resources and a framework for establishing collaborative strategies to facilitate follow-up care of childhood cancer survivors in China.

Fibroblast growth factor receptors (FGFRs) play key roles in promoting the proliferation, differentiation, and migration of cancer cell. Inactivation of FGFRs by tyrosine kinase inhibitors (TKI) has achieved great success in tumor-targeted therapy. However, resistance to FGFR-TKI has become a concern. Here, we review the mechanisms of FGFR-TKI resistance in cancer, including gatekeeper mutations, alternative signaling pathway activation, lysosome-mediated TKI sequestration, and gene fusion. In addition, we summarize strategies to overcome resistance, including developing covalent inhibitors, developing dual-target inhibitors, adopting combination therapy, and targeting lysosomes, which will facilitate the transition to precision medicine and individualized treatment.

Variation in normal blood cells during chemotherapy has not been recognised as a risk factor guiding chemotherapy in childhood acute lymphoblastic leukaemia (ALL). This study aims to explore whether variations in normal haematopoiesis determine prognosis as well as to improve risk-stratified treatment in childhood ALL. A retrospective study of 279 cases of ALL treated with the CCCG-ALL-2015 regimen in the Division of Pediatric Blood Diseases Center, Institute of HematologyBlood Diseases Hospital, Chinese Academy of Medical SciencesPeking Union Medical College, from May 2015 to January 2017 was performed to analyse the prognostic impact of blood cell levels on day 19 of induction therapy by Kaplan-Meier method. Patients with childhood ALL with absolute neutrophil count (ANC) ≤ 90 cells/μl, absolute monocyte count (AMC) ≤ 10 cells/μl or absolute lymphocyte count (ALC) ≤ 1000 cells/μl on day 19 of induction therapy had a lower event-free survival (EFS) rate than those with higher values (all P0.05). Multivariate analysis confirmed that ANC ≤ 90 cells/μl and ALC ≤ 1000 cells/μl were independent adverse prognostic factors (HR = 1.981 and 2.162, respectively, both P0.05). Among patients with minimal residual disease (MRD)1% on day 19 of induction therapy, those with ANC ≤ 90 cells/μl had lower EFS than those with ANC90 cells/μl (70.8 ± 6.1% vs 86.4 ± 3.1%, P = 0.001). In the subgroup with the BCR/ABL1 fusion gene, patients with ANC ≤ 90 cells/μl on day 19 of induction therapy also had lower EFS than those with ANC90 cells/μl (34.4 ± 25.2% vs 25.0 ± 21.7%, P = 0.041). ANC and ALC during induction therapy are independent prognostic factors for childhood ALL. ANC contributes to guiding the prognosis of patients with low-level MRD or the BCR/ABL1 fusion gene.

Minimal residual disease that persists after chemotherapy is the most valuable prognostic marker for haematological malignancies and solid cancers. Unfortunately, our understanding of the resistance elicited in minimal residual disease is limited due to the rarity and heterogeneity of the residual cells. Here we generated 161,986 single-cell transcriptomes to analyse the dynamic changes of B-cell acute lymphoblastic leukaemia (B-ALL) at diagnosis, residual and relapse by combining single-cell RNA sequencing and B-cell-receptor sequencing. In contrast to those at diagnosis, the leukaemic cells at relapse tended to shift to poorly differentiated states, whereas the changes in the residual cells were more complicated. Differential analyses highlighted the activation of the hypoxia pathway in residual cells, resistant clones and B-ALL with MLL rearrangement. Both in vitro and in vivo models demonstrated that inhibition of the hypoxia pathway sensitized leukaemic cells to chemotherapy. This single-cell analysis of minimal residual disease opens up an avenue for the identification of potent treatment opportunities for B-ALL.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is rare in China and case reports are varied. We conducted an in-depth analysis of newly diagnosed children with T-ALL from January 1999 to April 2015 in our center, to show the biological differences between Chinese ETP-ALL children and other immune types of T-ALL. The newly diagnosed children with T-ALL were divided into four groups according to their immunophenotype: ETP-ALL, early non-ETP-ALL, cortical T-ALL and medullary T-ALL. Disease-free survival (DFS), event-free survival (EFS), and overall survival (OS) rates were estimated by the Kaplan–Meier method. The Cox regression model was used for multivariate analysis. A total of 117 newly diagnosed children with T-ALL were enrolled in this study. The 10-year EFS and OS rates for all patients were 59.0 ± 4.7% and 61.0 ± 4.7%, respectively, with a median follow-up of 64 (5–167) months. Univariate analysis showed that ETP-ALL patients had the lowest 10-year DFS rate of 32.1 ± 11.7%, while cortical T-ALL had the highest DFS rate of 81.3 ± 8.5% compared with early non-ETP-ALL (61.6 ± 7.0%) and medullary T-ALL (59.1 ± 10.6%). Multivariate analysis demonstrated that only ETP-ALL and involvement of the central nervous system were independent prognostic factors. Compared with other subtypes, pediatric ETP-ALL had a poor treatment response and high recurrence rate while cortical T-ALL appeared to have much better outcome. Our observations highlight the need for an individualized treatment regime for ETP-ALL.

Abnormal activation of the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathway has been shown to drive the proliferation of a significant portion of hepatocellular carcinoma (HCC). Resistance and toxicity are serious drawbacks that have been observed upon use of the current first- and second-line treatment options for HCC, therefore warranting the investigation of alternative therapeutic approaches. We report the development and biological characterization of a covalent inhibitor that is highly potent and exquisitely specific to FGFR4. The crystal structure of this inhibitor in complex with FGFR4 was solved, confirming its covalent binding and revealing its binding mode. We also describe the first clickable probe for FGFR4 that can be used to directly measure target engagement in cells. Our compound exhibited great antitumor activity in HCC cell lines and tumor xenograft models. These results provide evidence of a promising therapeutic lead for the treatment of a subset of HCC patients.

Previous studies have shown that gut microbiota can affect human immune system in many ways. Our aim was to investigate quantitative differences in fecal bacterial compositions of childhood acute lymphoblastic leukemia (ALL) patients compared to those of healthy children, so as to identify individual bacterial species that are related to the etiology of ALL. We recruited 81 subjects, including 58 patients with ALL and 23 healthy controls. Fecal samples were collected and examined by 16S rRNA quantitative arrays and bioinformatics analysis. Both Principal Coordinates Analysis (PCoA) and Non-metric Multidimensional scaling (NMDS) demonstrated that the microbial composition of ALL patients deviated from the tight cluster of healthy controls. Multiple bacterial species exhibited significant changes (e.g., Roseburia faecis, Edwardsiella tarda, and Fusobacterium naviforme) in the ALL samples. Some of the differentially abundant taxa were correlated with the level of interleukin-10. The ALL cases could be efficiently distinguished from healthy controls by the random forest model based on differential species (area under ROC curve = 0.843). Taken together, the composition of gut microbiota differed from healthy controls to pediatric ALL patients. Our study identified a series of ALL-related species in the gut microbiota, providing a new direction for future studies aiming to understand the host-gut microbiota interplay in ALL pathogenesis.

The tumor suppressor p53 is mutated in approximately half of all human cancers. p53 can induce apoptosis through mitochondrial membrane permeabilization by interacting with and antagonizing the anti-apoptotic proteins BCL-xL and BCL-2. However, the mechanisms by which p53 induces mitochondrial apoptosis remain elusive. Here, we report a 2.5 Å crystal structure of human p53/BCL-xL complex. In this structure, two p53 molecules interact as a homodimer, and bind one BCL-xL molecule to form a ternary complex with a 2:1 stoichiometry. Mutations at the p53 dimer interface or p53/BCL-xL interface disrupt p53/BCL-xL interaction and p53-mediated apoptosis. Overall, our current findings of the bona fide structure of p53/BCL-xL complex reveal the molecular basis of the interaction between p53 and BCL-xL, and provide insight into p53-mediated mitochondrial apoptosis., The structure of human tumor suppressor p53 in complex with the antiapoptotic protein BCL-xL reveals the basis of the p53–BCL-xL interaction and provides insight into the mechanisms of p53-mediated mitochondrial apoptosis.

Background Recent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary. Methods We generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL). Results Data from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49–24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74–18.08 months) and 6.93 months (95% CI, 3.13–10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017–0.601). Conclusions The results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy. Trial registration ClinicalTrials.gov: NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687

Ibrutinib is a BTK-targeted irreversible inhibitor. In this study, we demonstrate that ibrutinib potently inhibits SRC activity in a non-covalent manner via mass spectrometry and crystallography. The S345C mutation renders SRC to bind covalently with ibrutinib, and restores the potency of ibrutinib against the gatekeeper mutant. The co-crystal structure of ibrutinib/SRC shows Ser345 of SRC did not form covalent bond with ibrutinib, leading to a decrease of potency and loss of the ability to overcome the gatekeeper mutation of SRC. The X-ray crystallographic studies also provide structural insight into why ibrutinib behaves differently against gatekeeper mutants of different kinases.

Background Angle kappa plays a vital role in the implantation of multifocal intraocular lens (MIOL). Large angle kappa is related to a higher risk of postoperative photic phenomena. This study aims to compare preoperative angle kappa in the eyes of cataract patients obtained from the Pentacam Scheimpflug system (Pentacam), optical low-coherence reflectometry (Lenstar), and ray-tracing aberrometry (iTrace). Methods One hundred thirteen eyes of 113 patients with cataracts were included. Each eye was examined 3 times using all devices to obtain angle kappa and pupil diameter. When considering dependent eyes for one individual, angle kappa in both right eyes and left eyes should be analysed separately. The repeatability and reproducibility were evaluated using the within-subject standard deviation (Sw), repeatability (2.77 Sw), and intraclass correlation coefficient (ICC). The difference, correlation, and agreement between devices were evaluated by paired t-tests, Pearson tests, and Bland-Altman analysis, respectively. Results Intraoperator repeatability and interoperator and intersession reproducibility of angle kappa showed an Sw of less than 0.05 mm, a 2.77 Sw of 0.14 mm or less, and an ICC of more than 0.96. Angle kappa was not significantly different between Pentacam and Lenstar (P > 0.05), while angle kappa was significantly different between Pentacam and iTrace and between Lenstar and iTrace (P < 0.05). There was a strong correlation between Pentacam and Lenstar for angle kappa (r =0.907 to 0.918) and a weak or moderate correlation between Pentacam and iTrace and between Lenstar and iTrace (r =0.292 to 0.618). There were narrow 95% limits of agreement (LoA) between Pentacam and Lenstar for angle kappa and wide 95% LoA between Pentacam and iTrace and between Lenstar and iTrace. No significant differences in pupil diameter were found between Pentacam and Lenstar in either eye (P > 0.05). Positive angle kappa (nasal light reflex) was found in most cataract patients (79.25% to 84.91%) through 3 different devices in both eyes. Conclusions The 3 devices provided high intraoperator repeatability and interoperator and intersession reproducibility for angle kappa measurements. The measurement of preoperative angle kappa in the eyes of patients with cataracts by Pentacam and Lenstar has good agreement.

To evaluate the optimal time to monitor minimal residual disease (MRD) for pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL). Children newly diagnosed with T-ALL were treated per the CCLG-ALL2008 protocol in our hospital. MRD was monitored at days 15, 33 and 90, and the patients were stratified as low-, intermediate- or high-risk according to MRD at days 33 and 90. The 5-year event-free survival (EFS) and overall survival (OS) rates for all patients were 60.1 ± 5.6% and 63.1 ± 5.6%, respectively. The median follow-up time was 54 (0.3-120) months. Univariate analysis showed that the 5-year EFS rate correlated with MRD at days 33 and 90 (

Forkhead box G1 (FOXG1) is a transcription factor mainly expressed in the brain that plays a critical role in the development and regionalization of the forebrain. Aberrant expression of FOXG1 has implications in FOXG1 syndrome, a serious neurodevelopmental disorder. Here, we report the crystal structure of the FOXG1 DNA-binding domain (DBD) in complex with the forkhead consensus DNA site DBE2 at the resolution of 1.6 A. FOXG1-DBD adopts a typical winged helix fold. Compared to those of other FOX-DBD/DBE2 structures, the N terminus, H3 helix and wing2 region of FOXG1-DBD exhibit differences in DNA recognition. The FOXG1-DBD wing2 region adopts a unique architecture composed of two β-strands that differs from all other known FOX-DBD wing2 folds. Mutation assays revealed that the disease-causing mutations within the FOXG1-DBD affect DNA binding, protein thermal stability, or both. Our report provides initial insight into how FOXG1 binds DNA and sheds light on how disease-causing mutations in FOXG1-DBD affect its DNA-binding ability.

The chemical compound LY2874455 has the potential to overcome drug resistance driven by FGFR gatekeeper mutations. X-ray crystallographic studies provide the structural explanation for why this compound is effective against the FGFR gatekeeper mutations.

An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 inhibitor, suggesting its potential application in designing other kinase inhibitors.