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Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.
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Fenotipo , Proteínas Represoras , Humanos , Proteínas Represoras/genética , Anomalías Múltiples/genética , Discapacidad Intelectual/genética , Anomalías Dentarias/genética , Anomalías Dentarias/patología , Craneosinostosis/genética , Craneosinostosis/patología , Deleción Cromosómica , Enfermedades del Desarrollo Óseo , FaciesRESUMEN
OBJECTIVES: This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. METHODS: We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. RESULTS: Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. CONCLUSION: Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.
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Lupus Eritematoso Sistémico , Transcriptoma , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Humanos , Femenino , Adulto , Masculino , Persona de Mediana Edad , Perfilación de la Expresión Génica/métodos , Leucocitos Mononucleares/metabolismo , Mapas de Interacción de Proteínas/genéticaRESUMEN
OBJECTIVE: Metformin, an anti-diabetic drug, regulates blood glucose by affecting gut microbiotas. However, the potential mechanism underlying this effect remains unclear. This study aimed to evaluate the effect of metformin on glucose regulation, lipid levels, and the gut microbiota in rats with type 2 diabetes mellitus induced by a high-fat diet with streptozotocin. RESEARCH DESIGN METHODS: Thirty Wistar rats was using in this experiment. T2DM rats were administered 300 mg/kg metformin for 8 weeks. The glucose regulation, lipid levels, organ coefficients, and gut microbiotawere measured by 16S rDNA. RESULT: The metformin-gavaged rats exhibited significant improvements in blood glucose and serum lipid levels, accompanied by alterations in short-chain fatty acid levels and the intestinal microbiota (p < 0.05). In the diabetic rats, metformin potentially increased specific probiotics, thus improving the hypoglycaemic effects of the oral anti-diabetic drug. Further, damage to the liver and kidney was effectively alleviated in the metformin-gavaged rats. CONCLUSION: This study's findings demonstrate that metformin exerts a positive anti-diabetic effect in HFD- and STZ-induced T2DM rats. These findings potentially provide a basis for the recommended use of metformin as a reliable oral drug for T2DM owing to its positive effect on the intestinal microbiota.
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KBG syndrome is a rare autosomal dominant condition characterized by multisystem developmental disorder, primarily caused by loss-of-function variants in ankyrin repeat domain-containing protein 11 (ANKRD11). Approximately 80 % of ANKRD11 variants associated with KBG syndrome, are frameshift and nonsense variants. Current insight into the pathogenesis of KBG syndrome resulting from ANKRD11 truncating variants remains limited. Here, we presented two members from a non-consanguineous Chinese pedigree both exhibiting characteristics fitting the KBG syndrome-associated phenotypic spectrum. Whole-exome sequencing identified a novel heterozygous frameshift variant in ANKRD11 (NM_013275.6, c.2280_2281delGT, p.Y761Qfs*20) in the proband. Sanger sequencing confirmed that the variant was inherited from her mother and co-segregated with KBG syndrome phenotype. In vitro functional assays revealed that the frameshift variant escaped nonsense-mediated mRNA decay, and resulting in a truncated protein with significantly increased expression levels compared to full-length ANKRD11. Immunofluorescence results demonstrated that truncated protein was predominantly expressed in the nucleus of HEK293 cells, while wild-type ANKRD11 was equally distributed in both the nucleus and cytoplasm. Moreover, the truncated protein significantly reduced CDKN1A/P21-promoter luciferase activity in comparison to wild-type ANKRD11 protein, as well as a remarkably decrease in the endogenous CDKN1A/P21 mRNA level in HEK293 cells. These findings suggest a loss of transcriptional activation function and potentially a dominant-negative mechanism. Overall, our study expands the mutational spectrum of ANKRD11 gene and provides new insights into the pathogenic mechanism of KBG syndrome caused by ANKRD11 truncating variants.
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BACKGROUND: Isolated growth hormone deficiency (IGHD) is a rare genetically heterogeneous disorder caused primarily by mutations in GH1 and GH releasing hormone receptor (GHRHR). The aim of this study was to identify the molecular etiology of a Chinese boy with IGHD. METHODS: Whole-exome sequencing, sanger sequencing and bioinformatic analysis were performed to screen for candidate mutations. The impacts of candidate mutation on gene expression, intracellular localization and protein function were further evaluated by in vitro assays. RESULTS: A novel heterozygous frameshift mutation in the GHRH gene (c.91dupC, p.R31Pfs*98) was identified in a Chinese boy clinically diagnosed as having IGHD. The mutation was absent in multiple public databases, and considered as deleterious using in silico prediction, conservative analysis and three-dimensional homology modeling. Furthermore, mRNA and protein expression levels of mutant GHRH were significantly increased than wild-type GHRH (p < 0.05). Moreover, mutant GHRH showed an aberrant accumulation within the cytoplasm, and obviously reduced ability to stimulate GH secretion and cAMP accumulation in human GHRHR-expressing pituitary GH3 cells compared to wild-type GHRH (p < 0.05). CONCLUSION: Our study discovered the first loss-of function mutation of GHRH in a Chinese boy with IGHD and provided new insights on IGHD pathogenesis caused by GHRH haploinsufficiency.
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Enanismo Hipofisario , Hormona Liberadora de Hormona del Crecimiento , Hormona de Crecimiento Humana , Humanos , Masculino , China , Enanismo Hipofisario/genética , Mutación del Sistema de Lectura , Hormona del Crecimiento , Hormona de Crecimiento Humana/genética , Mutación , Receptores de Neuropéptido/genética , Receptores de Hormona Reguladora de Hormona Hipofisaria/genética , Hormona Liberadora de Hormona del Crecimiento/genética , Pueblos del Este de Asia/genéticaRESUMEN
BACKGROUND: Significant differences have been observed in the efficacy of recombinant human growth hormone (rhGH) treatment for short children. The present study aimed to identify the genetic etiology of short stature and to assess the role of molecular diagnosis in predicting responses to rhGH treatment. METHODS: A total of 407 short children were included in the present study, 226 of whom received rhGH treatment. Whole-exome sequencing (WES) was conducted on short children to identify the underlying genetic etiology. Correlations between molecular diagnosis and the efficacy of rhGH treatment were examined. RESULTS: Pathogenic or likely pathogenic mutations were identified in 86 of the 407 patients (21.1%), including 36 (41.9%) novel variants. Among the multiple pathways affecting short stature, genes involved in fundamental cellular processes (38.7%) play a larger role, especially the RAS-MAPK pathway. In general, patients without pathogenic mutations responded better to rhGH than those with mutations. Furthermore, patients with hormone signaling pathway mutations had a better response to rhGH, while those with paracrine factor mutations had a worse response to rhGH. CONCLUSIONS: This study highlights the utility of WES in identifying genetic etiology in children with short stature. Identifying likely causal mutations is an important factor in predicting rhGH response.
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Enanismo , Hormona de Crecimiento Humana , Niño , Humanos , Hormona de Crecimiento Humana/genética , Hormona de Crecimiento Humana/uso terapéutico , Hormona del Crecimiento , Trastornos del Crecimiento/diagnóstico , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/genética , Proteínas Recombinantes , Estatura/genéticaRESUMEN
Bone marrow stromal cell antigen 2 (BST2) is a type II transmembrane protein that serves critical roles in antiretroviral defense in the innate immune response. In addition, it has been suggested that BST2 is highly expressed in various types of human cancer and high BST2 expression is related to different clinicopathological parameters in cancer. The molecular mechanism underlying BST2 as a potential tumor biomarker in human solid tumors has been reported on; however, to the best of our knowledge, there has been no review published on the molecular mechanism of BST2 in human solid tumors. The present review focuses on human BST2 expression, structure and functions; the molecular mechanisms of BST2 in breast cancer, hepatocellular carcinoma, gastrointestinal tumor and other solid tumors; the therapeutic potential of BST2; and the possibility of BST2 as a potential marker. BST2 is involved in cell membrane integrity and lipid raft formation, which can activate epidermal growth factor receptor signaling pathways, providing a potential mechanistic link between BST2 and tumorigenesis. Notably, BST2 may be considered a universal tumor biomarker and a potential therapeutical target.
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Neoplasias de la Mama , Neoplasias Hepáticas , Humanos , Femenino , Antígeno 2 del Estroma de la Médula Ósea/metabolismo , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Neoplasias de la Mama/patología , Transducción de Señal , Biomarcadores de Tumor/genética , BiologíaRESUMEN
OBJECTIVES: This study was performed to investigate the effectiveness of the combination of letrozole and recombinant human growth hormone (rhGH) to improve the predicted adult height (PAH) and final adult height (FAH) of Chinese short pubertal boys. METHODS: In total, 171 Chinese short pubertal boys were recruited for this study. 96 of them received letrozole (2.5â¯mg/d) combined with rhGH (33.3-66.6⯵g/kg.d), and the others received rhGH alone. Follow-up visits were conducted at 1, 3, 6, 9, and 12 months or regularly after the first treatment. During each visit, plasma samples were collected for clinical tests and biomedical analyses, all of which were performed according to standard protocols. This study was registered at www.chictr.org.cn under ID number ChiCTR1900026142. RESULTS: After receiving treatment for at least 3 months, 68 boys (91â¯%) in the rhGH therapy group and 90 (94â¯%) in the letrozole combined with rhGH (letrozole+rhGH) therapy group achieved an increase in PAH, with the latter treatment leading to a more effective slowing of bone age (BA) advancement. Moreover, the increased PAH showed a significant positive correlation with treatment time in both groups, and letrozole+rhGH increased the PAH to a greater degree than rhGH alone (p=0.0023). And letrozole+rhGH not only slowed the increase in BA more efficiently than rhGH therapy alone (p=0.0025), but also achieved a higher FAH (p=0.0078). CONCLUSIONS: Letrozole combined with rhGH treatment is a promising therapy to increase the PAH and FAH of Chinese short pubertal boys.
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Hormona de Crecimiento Humana , Masculino , Adulto , Humanos , Letrozol/uso terapéutico , Hormona de Crecimiento Humana/uso terapéutico , Trastornos del Crecimiento/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , EstaturaRESUMEN
OBJECTIVES: Systemic lupus erythematosus (SLE) is a complex autoimmune disease with varying symptoms and multi-organ damage. Relapse-remission cycles often persist for many patients for years with the current treatment. Improved understanding of molecular changes caused by SLE flare and intensive treatment may result in more targeted therapies. METHODS: RNA-sequencing was performed on peripheral blood mononuclear cells (PBMCs) from 65 SLE patients in flare, collected both before (SLE1) and after (SLE2) in-hospital treatment, along with 15 healthy controls (HC). Differentially expressed genes (DEGs) were identified among the three groups. Enriched functions and key molecular signatures of the DEGs were analyzed and scored to elucidate the transcriptomic changes during treatment. RESULTS: Few upregulated genes in SLE1 vs HC were affected by treatment (SLE2 vs SLE1), mostly functional in interferon signalling (IFN), plasmablasts, and neutrophils. IFN and plasmablast signatures were repressed, but the neutrophil signature remained unchanged or enhanced by treatment. The IFN and neutrophil scores together stratified the SLE samples. IFN scores correlated well with leukopenia, while neutrophil scores reflected relative cell compositions but not cell counts. CONCLUSIONS: In-hospital treatment significantly relieved SLE symptoms with expression changes of a small subset of genes. Notably, IFN signature changes matched SLE flare and improvement, while enhanced neutrophil signature upon treatment suggested the involvement of low-density granulocytes (LDG) in disease development.
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Background: Evidence regarding the relationship between sleep duration and blood pressure is controversial. Therefore, the aim of this study was to investigate the relationship between sleep duration and blood pressure in children with short stature. Methods: A total of 1,085 participants with short stature were enrolled from the Affiliated Hospital of Jining Medical University in China. The variables involved in this study included sleep duration, anthropometric indicators and biochemical parameters. Sleep duration was evaluated in a face-to-face interview. Results: The average age of the 1,085 selected participants was 10.2 ± 3.5 years old, and approximately 763 (70.32%) of them were male. The results of adjusted linear regression showed that sleep duration was negatively associated with systolic blood pressure z scores (SBP-Z) and diastolic blood pressure z scores (DBP-Z) after adjusting for confounders (ß -0.07, 95% CI -0.13, -0.01 P = 0.038; ß -0.05, 95% CI -0.10, -0.01 P = 0.035, respectively). A nonlinear relationship was detected between sleep duration and blood pressure, including SBP-Z, DBP-Z and mean arterial pressure z scores (MAP-Z). The inflection point of the nonlinear relationship between sleep duration and SBP-Z is 10â h, and the inflection point of DBP-Z and MAP-Z is 8â h. Conclusion: This study revealed a nonlinear relationship between sleep duration and blood pressure in children with short stature. The findings suggest that the optimal sleep duration in children with short stature was 8-10â h, and sleep durations either too short or too long were associated with increased blood pressure levels.
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Purpose: Genetic factors account for a large proportion of idiopathic hypogonadotropic hypogonadism (IHH) etiologies, although not necessarily a complete genetic basis. This study aimed to characterize the clinical presentations, genetic variants, and therapeutic outcomes of patients with sporadic IHH, which may be helpful for genetic counseling and treatment decisions. Patients and Methods: Eleven Chinese patients with IHH were retrospectively analyzed. Rare genetic variants were evaluated using whole-exome sequencing and bioinformatics analysis and were further classified according to the ACMG-AMP guidelines. The therapeutic responses of patients were further evaluated. Results: Six heterozygous variants of SOX10, WDR11, PROKR2, CHD7 and FGF17 were detected in five Kallmann syndrome (KS) patients, whereas two heterozygous variants of CHD7 and PROKR2 were detected in two normosmic IHH (nIHH) patients. Among these variants, a novel likely pathogenic variant in the SOX10 (c.429-1G>C) was considered to cause the KS phenotype in patient 02, and two potential variants of uncertain significance (VUS) in CHD7 (c.3344G>A and c.7391A>G) possibly contributed to the KS phenotype in patient 05 and the nIHH phenotype in patient 07, which need to be confirmed by further evidence. Additionally, long-term testosterone or estradiol replacement treatment effectively improved the development of sexual characteristics in patients with IHH. Conclusion: Next-generation sequencing is a powerful tool for identifying the molecular etiology and early diagnosis of IHH. Efficient therapeutic outcomes strongly indicate a need for timely treatment.
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The aim of this study was to explore the relationship between serum uric acid (SUA) and the triglyceride-glucose (TyG) index, which is a more effective indicator of insulin resistance. The study participants included 1700 children and adolescents with short stature who were recruited at the Affiliated Hospital of Jining Medical University in China between March 2013 and April 2021. A positive association between SUA levels and the TyG index was detected by univariate analysis (p < 0.001). Furthermore, a nonlinear relationship was detected between SUA and the TyG index, whose point was 6.55 mg/dL. There was a positive association between SUA and the TyG index when the SUA level was greater than 6.55 mg/dL (ß 0.17, 95% CI: 0.07, 0.27; P < 0.001). However, we did not observe a significant relationship between SUA and the TyG index when the SUA level was less than 6.55 mg/dL (ß 0.02, 95% CI: - 0.01, 0.05; P = 0.091). In addition, a stratified analysis was performed to appraise changes in this relationship for different sexes. The relationship between SUA and the TyG index in males and females is consistent with that in the general population, showing a nonlinear relationship. However, the inflection points of SUA level were significantly higher in males than in females, and the inflection points were approximately 6.72 and 5.88 mg/dL, respectively. This study revealed a nonlinear relationship between SUA and the TyG index in children with short stature. The nonlinear relationship remained in gender stratification analysis, but the inflection point of SUA level was higher in men. Further studies are needed to establish a causal relationship between SUA levels and the TyG index in children with short stature.
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Enanismo , Ácido Úrico , Femenino , Masculino , Humanos , Adolescente , Niño , China , Glucosa , TriglicéridosRESUMEN
BACKGROUND: Short stature is a common human trait. More severe and/or associated short stature is usually part of the presentation of a syndrome and may be a monogenic disease. The present study aimed to identify the genetic etiology of children with short stature of unknown origin. METHODS: A total of 232 children with short stature of unknown origin from March 2013 to May 2020 were enrolled in this study. Whole exome sequencing (WES) was performed for the enrolled patients to determine the underlying genetic etiology. RESULTS: We identified pathogenic or likely pathogenic genetic variants in 18 (7.8%) patients. All of these variants were located in genes known to be associated with growth disorders. Five of the genes are associated with paracrine signaling or cartilage extracellular matrix in the growth plate, including NPR2 (N = 1), ACAN (N = 1), CASR (N = 1), COMP (N = 1) and FBN1 (N = 1). Two of the genes are involved in the RAS/MAPK pathway, namely, PTPN11 (N = 6) and NF1 (N = 1). Two genes are associated with the abnormal growth hormone-insulin-like growth factor 1 (GH-IGF1) axis, including GH1 (N = 1) and IGF1R (N = 1). Two mutations are located in PROKR2, which is associated with gonadotropin-releasing hormone deficiency. Mutations were found in the remaining two patients in genes with miscellaneous mechanisms: ANKRD11 (N = 1) and ARID1A (N = 1). CONCLUSIONS: The present study identified pathogenic or likely pathogenic genetic variants in eighteen of the 232 patients (7.8%) with short stature of unknown origin. Our findings suggest that in the absence of prominent malformation, genetic defects in hormones, paracrine factors, and matrix molecules may be the causal factors for this group of patients. Early genetic testing is necessary for accurate diagnosis and precision treatment.
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Enanismo , Humanos , Niño , Enanismo/genética , Trastornos del Crecimiento/genética , Pruebas Genéticas , MutaciónRESUMEN
BACKGROUND: Since the triglyceride glucose (TyG) index can reflect insulin resistance, it has been proven to be an efficient predictor of glycolipid-metabolism-related diseases. Therefore, this study aimed to investigate the predictive value of the TyG index for visceral obesity (VO) and body fat distribution in patients with type 2 diabetes mellitus (T2DM). METHODS: Abdominal adipose tissue characteristics in patients with T2DM, including visceral adipose area (VAA), subcutaneous adipose area (SAA), VAA-to-SAA ratio (VSR), visceral adipose density (VAD), and subcutaneous adipose density (SAD), were obtained through analyses of computed tomography images at the lumbar 2/3 level. VO was diagnosed according to the VAA (> 142 cm2 for males and > 115 cm2 for females). Logistic regression was performed to identify independent factors of VO, and receiver operating characteristic (ROC) curves were used to compare the diagnostic performance according to the area under the ROC curve (AUC). RESULTS: A total of 976 patients were included in this study. VO patients showed significantly higher TyG values than non-VO patients in males (9.74 vs. 8.88) and females (9.59 vs. 9.01). The TyG index showed significant positive correlations with VAA, SAA, and VSR and negative correlations with VAD and SAD. The TyG index was an independent factor for VO in both males (odds ratio [OR] = 2.997) and females (OR = 2.233). The TyG index ranked second to body mass index (BMI) for predicting VO in male (AUC = 0.770) and female patients (AUC = 0.720). Patients with higher BMI and TyG index values showed a significantly higher risk of VO than the other patients. TyG-BMI, the combination index of TyG and BMI, showed significantly higher predictive power than BMI for VO in male patients (AUC = 0.879 and 0.835, respectively) but showed no significance when compared with BMI in female patients (AUC = 0.865 and 0.835, respectively). CONCLUSIONS: . TyG is a comprehensive indicator of adipose volume, density, and distribution in patients with T2DM and is a valuable predictor for VO in combination with anthropometric indices, such as BMI.
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Diabetes Mellitus Tipo 2 , Humanos , Masculino , Femenino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Glucosa , Estudios Transversales , Triglicéridos , Obesidad Abdominal/diagnóstico , Glucemia/análisis , Obesidad/complicaciones , Obesidad/diagnósticoRESUMEN
Objective: Uric acid to high-density lipoprotein cholesterol ratio (UHR), the ratio of uric acid to high-density lipoprotein cholesterol, is a newly proposed marker of metabolic abnormalities. There are few previous studies directly investigating the relationship between UHR and alanine aminotransferase (ALT), especially in short stature populations, however, short stature children and adolescents are more likely to have metabolic disorders. This research aimed to investigate the relationship between the UHR and ALT in children and adolescents with short stature. Methods: In this cross-sectional analysis, the clinical data of 1,510 children with height below -2 SD who were evaluated at the Department of Endocrinology, Affiliated Hospital of Jining Medical University from 1 March 2013 to 31 December 2021, were selected. Anthropometric and biochemical indicators were measured. The relationship between UHR and ALT was analysed. Results: The univariate analysis results showed that UHR was positively associated with ALT (ß = 0.43, P < 0.0001). Furthermore, after adjusting for possible confounding factors, a non-linear relationship was detected between UHR and ALT through smooth curve fitting, and the inflection point of UHR was 10.93% after multivariate piecewise linear regression analysis. ALT increased with UHR elevation when the UHR was greater than 10.93% (ß = 0.69, 95% CI 0.39, 0.98; P < 0.0001). However, we did not observe a significant relationship when the UHR was less than 10.93% (P = 0.9229). Conclusion: Our study demonstrated that in Chinese children and adolescents with short stature, UHR may be associated with the regulation of ALT levels, and this relationship merits further investigation.
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BACKGROUND: Peritoneal metastasis (PM) after primary surgery for colorectal cancer (CRC) has the worst prognosis. Prediction and early detection of metachronous PM (m-PM) have an important role in improving postoperative prognosis of CRC. However, commonly used imaging methods have limited sensitivity to detect PM early. We aimed to establish a nomogram model to evaluate the individual probability of m-PM to facilitate early interventions for high-risk patients. AIM: To establish and validate a nomogram model for predicting the occurrence of m-PM in CRC within 3 years after surgery. METHODS: We used the clinical data of 878 patients at the Second Hospital of Jilin University, between January 1, 2014 and January 31, 2019. The patients were randomly divided into training and validation cohorts at a ratio of 2:1. The least absolute shrinkage and selection operator (LASSO) regression was performed to identify the variables with nonzero coefficients to predict the risk of m-PM. Multivariate logistic regression was used to verify the selected variables and to develop the predictive nomogram model. Harrell's concordance index, receiver operating characteristic curve, Brier score, and decision curve analysis (DCA) were used to evaluate discrimination, distinctiveness, validity, and clinical utility of this nomogram model. The model was verified internally using bootstrapping method and verified externally using validation cohort. RESULTS: LASSO regression analysis identified six potential risk factors with nonzero coefficients. Multivariate logistic regression confirmed the risk factors to be independent. Based on the results of two regression analyses, a nomogram model was established. The nomogram included six predictors: Tumor site, histological type, pathological T stage, carbohydrate antigen 125, v-raf murine sarcoma viral oncogene homolog B mutation and microsatellite instability status. The model achieved good predictive accuracy on both the training and validation datasets. The C-index, area under the curve, and Brier scores were 0.796, 0.796 [95% confidence interval (CI) 0.735-0.856], and 0.081 for the training cohort and 0.782, 0.782 (95%CI 0.690-0.874), and 0.089 for the validation cohort, respectively. DCA showed that when the threshold probability was between 0.01 and 0.90, using this model to predict m-PM achieved a net clinical benefit. CONCLUSION: We have established and validated a nomogram model to predict m-PM in patients undergoing curative surgery, which shows good discrimination and high accuracy.
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The current study evaluated the efficacy and safety of a denosumab biosimilar, QL1206 (60 mg), compared to placebo in postmenopausal Chinese women with osteoporosis and high fracture risk. At 31 study centers in China, a total of 455 postmenopausal women with osteoporosis and high fracture risk were randomly assigned to receive QL1206 (60 mg subcutaneously every 6 months) or placebo. From baseline to the 12-month follow-up, the participants who received QL1206 showed significantly increased bone mineral density (BMD) values (mean difference and 95% CI) in the lumbar spine: 4.780% (3.880%, 5.681%), total hip :3.930% (3.136%, 4.725%), femoral neck 2.733% (1.877%, 3.589%) and trochanter: 4.058% (2.791%, 5.325%) compared with the participants who received the placebo. In addition, QL1206 injection significantly decreased the serum levels of C-terminal crosslinked telopeptides of type 1 collagen (CTX): -77.352% (-87.080%, -66.844%), and N-terminal procollagen of type l collagen (P1NP): -50.867% (-57.184%, -45.217%) compared with the placebo over the period from baseline to 12 months. No new or unexpected adverse events were observed. We concluded that compared with placebo, QL1206 effectively increased the BMD of the lumbar spine, total hip, femoral neck and trochanter in postmenopausal Chinese women with osteoporosis and rapidly decreased bone turnover markers. This study demonstrated that QL1206 has beneficial effects on postmenopausal Chinese women with osteoporosis and high fracture risk.
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Biosimilares Farmacéuticos , Conservadores de la Densidad Ósea , Osteoporosis Posmenopáusica , Osteoporosis , Femenino , Humanos , Biosimilares Farmacéuticos/efectos adversos , Densidad Ósea , Conservadores de la Densidad Ósea/uso terapéutico , Remodelación Ósea , Denosumab/uso terapéutico , Denosumab/farmacología , Método Doble Ciego , Pueblos del Este de Asia , Osteoporosis/tratamiento farmacológico , Osteoporosis Posmenopáusica/complicaciones , Osteoporosis Posmenopáusica/tratamiento farmacológico , PosmenopausiaRESUMEN
Background: The ratio of creatinine to cystatin C (Cre/CysC), a marker of muscle function and muscle mass, can be used to predict sarcopenia in different populations. Since sarcopenia is closely associated with osteoporosis, this study investigated the association between Cre/CysC and bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM). Method: This cross-sectional study included 391 Chinese patients with T2DM. General information, biochemical indicators, and the BMD of lumbar spine (LS), femoral neck (FN), and total hip (TH) were measured. Results: Pearson correlation analysis showed that Cre/CysC was significantly positively correlated with the BMD of LS (r = 0.170, p = 0.001), FN (r = 0.178, p < 0.001), and TH (r = 0.205, p < 0.001). The results of stepwise linear regression suggested that Cre/CysC was the only biochemical predictor of the BMD at three sites (LS: ß = 0.137, p = 0.01; FN: ß = 0.097, p = 0.038; TH: ß = 0.145, p = 0.002). Conclusion: In older patients with T2DM, high Cre/CysC value is independently positively associated with BMD and hence, Cre/CysC may serve as a valuable marker of osteoporosis.
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Objective: This study aims to explore the risk signals of osteonecrosis of the jaw induced by antiresorptive drugs and provide references for the clinical safety application. Method: According to the FDA's Adverse Event Reporting System (FAERS), from January 2004 to September 2021, we chose "Osteonecrosis of the jaw (10064658)" and "Exposed bone in jaw (10071014)" as preferred terms, "antiresorptive drugs" as the target drugs, and primary suspect drug as the drug role code in the dataset. We evaluated the association between drugs and adverse events by using reporting odds ratio (ROR) based on disproportionality analysis. We took the High-Level Terms (HLT) of MedDRA® as the classification level of indications to calculate ROR to compare the signal difference of ONJ in different indications. In addition, patients with antiresorptive-induced osteonecrosis of the jaw and the time of onset of the condition following different antiresorptive medications were collected for the study. Results: The FAERS contained 18,421 reports relating to jaw osteonecrosis from January 2004 to September 2021. A total of eight antiresorptive agents were included in the analysis. From high to low, the ROR of ONJ induced by antiresorptive agents (regardless of indication) is pamidronate (ROR = 494.8), zoledronic acid (ROR = 431.9), denosumab (ROR = 194.8), alendronate (ROR = 151.2), risedronate (ROR = 140.2), etidronic acid (ROR = 64.5), ibandronate (ROR = 40.8), and romosozumab (ROR = 6.4). HLT ROR values for "metabolic bone disorders" were the lowest for each drug, while HLT ROR values were high for "tumor-related indications," including breast and nipple neoplasms malignant, plasma cell myelomas, and prostatic neoplasms malignant. The onset time for osteonecrosis of the jaw as median (Q1, Q3), osteoporosis-related indications, and the onset time for ONJ were 730 (368, 1268), 489.5 (236.3, 909.8), 722.5 (314, 1055), 761 (368, 1720), and 153 (50, 346) for zoledronic acid, denosumab, ibandronate, risedronate, and romosozumab, respectively. Cancer-related indications: the onset time for ONJ were 680.5 (255.3, 1283), 488 (245, 851), and 696.5 (347, 1087) for zoledronic acid, denosumab, and pamidronate, respectively. Conclusion: When antiresorptive drugs are used for metastasis, they have the largest risk signal, followed by malignancy, and the smallest is osteoporosis. The onset time of ONJ may not be related to the indications. The onset time of ONJ for BPs was about 2 years, denosumab about 1.3 years, and romosozumab less than 1 year, which may be related to sequential treatment. When used according to the instructions, the risk of ONJ caused by denosumab was higher than that of zoledronic acid, regardless of the indication. Based on these findings, researchers will continue to monitor and identify risk factors.
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OBJECTIVE: To develop a multiplex PCR method for a rapid detection of Y chromosome-specific sequences in patients with Turner syndrome. METHODS: Nine genes were selected from various regions of the Y chromosome for designing the primers, which included SRY, TBL1Y, TSPY on the short arm of the Y chromosome, DDX3Y, HSFY1, RPS4Y2 and CDY1 on the long arm of Y chromosome and SHOX in the short arm and SPRY3 in the long arm of the pseudoautosomal region (PAR) of X and Y chromosomes. A multiplex PCR method for the nine genes in Y chromosome was established and optimized. The sensitivity was tested by using different amounts of genomic DNA. A total of 36 patients with Turner syndrome and a patient with male dwarfism with karyotype of 46, X, +mar were examined by the multiplex PCR method for the existence of materials from the Y chromosome. RESULTS: The optimization results of the multiplex PCR reaction system (50 µL) showed that when the final concentration of upstream and downstream of each pair of primers was 0.1 µM, the multiplex PCR reaction of the 9 pairs of primers clearly amplified the target with the expected band size, and there was no non-specific amplification. The bands were clearly visible when the amount of genomic DNA in the multiple PCR reaction system was as low as 1 ng. By using the method, we have examined the 36 patients with Turner syndrome. One patient with Turner syndrome with karyotype of 45,X[40]/47XYY[21] amplified specific seven genes on Y chromosome, 35 patients with Turner syndrome amplified only two target genes SHOX and SPRY3, but not the other seven specific genes on the Y chromosome, which was in keeping with the clinical manifestations of such patients. CONCLUSION: This study established a multiplex PCR reaction system with nine genes, which can quickly and accurately screen Y chromosome materials in patients with Turner syndrome. It has the advantages of low cost, simple operation, high specificity and rapid turn-around time, and can be used to detect Turner syndrome patients with Y chromosome material in time. The method has provided a diagnostic basis for preventive gonad resection to prevent malignant gonadal tumors.