DNA methylation of IFI44L as a potential blood biomarker for childhood-onset systemic lupus erythematosus.

BACKGROUND: IFN-induced protein 44-like (IFI44L) promoter methylation has been demonstrated to serve as an effective blood diagnostic biomarker for adult-onset SLE. However, its utility as a diagnostic marker for childhood-onset SLE (cSLE) remains to be verified. METHODS: Initially, we conducted a differential analysis of gene methylation and mRNA expression patterns in cSLE whole blood samples obtained from the public GEO database to determine IFI44L gene expression and assess the methylation status at its CpG sites. Subsequently, we collected clinical whole blood samples from 49 cSLE patients and 12 healthy children, employing an HRM-qPCR-based IFI44L methylation detection technique to evaluate its diagnostic efficacy in pediatric clinical practice. RESULTS: A total of 26 hypomethylated, highly expressed genes in cSLE were identified by intersecting differentially expressed genes (DEGs) and differentially methylation genes (DMGs). GO enrichment analysis for these 26 genes indicated a robust association with type I IFN. Among the overlapping genes, IFI44L exhibited the most pronounced differential expression and methylation. In subsequent clinical validation experiments, IFI44L methylation was confirmed as an effective blood-based diagnostic biomarker for cSLE, achieving an AUC of 0.867, a sensitivity of 0.753, and a specificity of 1.000. CONCLUSIONS: IFI44L methylation is a promising blood biomarker for cSLE. IMPACT: IFI44L promoter methylation was reported to serve as a highly sensitive and specific diagnostic marker for adult-onset SLE. However, the diagnostic efficacy of IFI44L in childhood-onset SLE (cSLE) still remains to be confirmed. In this study, we utilized bioinformatics analysis and conducted clinical experiments to demonstrate that IFI44L methylation can also serve as a promising blood biomarker for cSLE. The findings of this study can facilitate the diagnosis of cSLE and broaden our understanding of its molecular mechanisms, with a particular focus on those related to type I interferons.

Development of a Serum-Based MicroRNA Signature for Early Detection of Pancreatic Cancer: A Multicenter Cohort Study.

BACKGROUND: A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease. AIMS: Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients. METHODS: The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction. RESULTS: We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956-0.987) and 0.924 (95% CI 0.899-0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%. CONCLUSIONS: A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic.

Changes of Plasma Blood Ammonia Levels of Chinese Healthy People and the Establishment of Reference Intervals.

BACKGROUND: Blood ammonia detection is used for the diagnosis or differential diagnosis of various hepatitis virus infections, severe liver cirrhosis, and hepatic encephalopathy. It is also one of the important indexes reflecting liver coma, Reyes syndrome, and other diseases. However, blood ammonia changes rapidly with time. If samples are not sent and detected in time, the results will be wrong, resulting in clinical misdiagnosis and life danger to patients. The purpose of this paper is to explore the change of blood ammonia with time and establish its reference interval. METHODS: For this study, 228 healthy patients (111 males and 117 females) were selected who underwent physical examination at the Health Management Center of the Second Xiangya Hospital of Central South University from April to May 2021. The blood ammonia detection kit (colorimetric method) produced by Roche Diagnostics GmbH of Germany was used for detection on the Roche cobas c702 automatic biochemical analyzer. After eliminating outliers from the obtained test results, they were grouped according to gender and age, and SPSS 26.0 software was employed to statistically analyze the blood ammonia test results. RESULTS: The differences in blood ammonia levels at each detection time were statistically significant (p < 0.05). The differences in blood ammonia levels between male and female subjects at 1 hour, 2 hours, and 3 hours were statistically significant (p < 0.05), but all ages saw no statistically significant difference in blood ammonia levels between segments (p > 0.05). The blood ammonia levels of each detection time and different genders showed a normal distribution. Therefore, it is necessary to take the 95% (X ± 1.96S) results of both sides as the reference interval according to the detection time and gender, and establish the reference intervals. The 1-hour blood ammonia reference interval for healthy men in Changsha is 15.8 - 47.5 µmol/L, for healthy women it is 12.4 - 39.6 µmol/L; the 2-hour blood ammonia reference interval for healthy men is 22.3 - 56.5 µmol/L, and for healthy women it is 19.1 - 48.0 µmol/L; the reference interval of 3-hours blood ammonia for healthy men is 27.9 - 65.7 µmol/L, and for healthy women it is 24.6 - 56.7 µmol/L. CONCLUSIONS: There are differences in blood ammonia levels between men and women at different detection times in Changsha. A reference interval suitable for blood ammonia in healthy individuals in the region should be established according to the detection time and gender, so as to provide better relevant evidence for clinical diagnosis.

Clinical value of lymphocyte count in autoimmune diabetic nephropathy. / æ·‹å·´ç»†èƒžè®¡æ•°åœ¨è‡ªèº«å ç–«æ€§ç³–å°¿ç— è‚¾ç— ä¸­çš„ä¸´åºŠä»·å€¼ï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: In recent years, the prevalence of diabetic nephropathy (DN) has increased significantly. An increasing number of studies have shown that lymphocyte-associated inflammatory responses play a role in DN. This study aims to investigate the relationship between lymphocytes and DN in patients with autoimmune diabetes. METHODS: The clinical data of 226 patients with Type 1 diabetes (T1D) and 79 patients with latent autoimmune diabetes in adults (LADA) were retrospectively studied and stratified according to the urinary albumin to creatinine ratio (ACR). Risk factors associated with DN were analyzed using correlation analysis and logistic regression. RESULTS: In T1D and LADA patients, systolic blood pressure (SBP), uric acid duration, and diabetes duration in patients with normoalbuminuria were lower or shorter than those in patients with macroalbuminuria (P<0.05). The lymphocyte count of T1D patients was significantly higher than that in LADA patients (P<0.05), while the neutrophil to lymphocyte ratio (NLR) of T1D patients was significantly lower than that in LADA patients (P<0.05). The lymphocyte count in the T1D patients with normoalbuminuria was lower than that those with macroalbuminuria (P<0.05). The NLR was lower in the T1D patients with macroalbuminuria than those with microalbuminuria and normoproteinuria (all P<0.01). Based on logistic regression analysis, lymphocytes were independently associated with DN in T1D after adjusting for various known risk factors such as course of disease, age, gender, dyslipidemia, hypertension, and smoking status. Analysis of the receiver operating characteristic curve of subjects predicting lymphocytes in normoalbuminuria showed that the area under the curve was 0.601 (95% CI 0.510 to 0.693, P=0.039), and when the cutoff value of lymphocytes was 2.332, the sensitivity was 37.0%, and the specificity was 82.5%. CONCLUSIONS: Lymphocyte counts in autoimmune diabetic patients are closely associated with DN, suggesting that lymphocyte-mediated inflammation may be involved in the pathogenesis of DN in autoimmune diabetic patients. This study provides a possible perspective for using lymphocytes as a potential biomarker for the early identification of individuals at risk for DN and potential therapeutic targets for DN.

Integration of metabolomics and lipidomics reveals serum biomarkers for systemic lupus erythematosus with different organs involvement.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects various organs or systems. We performed metabolomic and lipidomic profiles analyses of 133 SLE patients and 30 HCs. Differential metabolites and lipids were integrated, and then the biomarker panel was identified using binary logistic regression. We found that a combination of four metabolites or lipids could distinguish SLE from HC with an AUC of 0.998. Three lipids were combined to differentiate inactive SLE and active SLE. The AUC was 0.767. In addition, we also identified the biomarkers for different organ phenotypes of SLE. The AUCs for diagnosing SLE patients with only kidney involvement, skin involvement, blood system involvement, and multisystem involvement were 0.766, 0.718, 0.951, and 0.909, respectively. Our study succeeded in identifying biomarkers associated with different clinical phenotypes in SLE patients, which could facilitate a more precise diagnosis and assessment of disease progression in SLE.

Changes of new coagulation markers in healthy pregnant women and establishment of reference intervals in Changsha. / é•¿æ²™å¥åº·å¦Šå¨ å¦‡å¥³æ–°å‡è¡€æ ‡å¿—ç‰©æ°´å¹³å˜åŒ–åŠå ¶å‚è€ƒåŒºé—´çš„å»ºç«‹.

OBJECTIVES: There is a high coagulation state in pregnant women, which is prone to coagulation and fibrinolysis system dysfunction. This study aims to explore the latest coagulation markers-thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasmin-α2 plasmin inhibitor complex (PIC), and tissue plasminogen activator/plasminogen activator inhibitor compound (tPAI-C) in different stages of pregnancy, establish reference intervals (RIs) for healthy pregnant women of Chinese population, and to provide an effective and reliable reference for clinicians. METHODS: A total of 492 healthy pregnant women, who underwent pregnancy examination and delivery in the Department of Obstetrics, Second Xiangya Hospital of Central South University from October 2019 to October 2020, were enrolled for this study. They were assigned into the first trimester group, the second trimester group, the third trimester group, and the puerperium group according to the pregnancy period, and 123 healthy non-pregnant women were selected as the controls. Plasma levels of TM, TAT, PIC and tPAI-C were analyzed by automatic chemiluminescence immunoassay analyzer. The RIs for TM, TAT, PIC, and tPAI-C were defined using non-parametric 95% intervals, determined following Clinical and Laboratory Standards Institute Document C28-A3c (CLSI C28-A3c), and Formulation of Reference Intervals for the Clinical Laboratory Test Items (WS/T402-2012). RESULTS: TM and TAT levels increased gradually in the first, second, and third trimester women and decreased in the puerperium women (P<0.05 or P<0.01). PIC level of healthy non-pregnant women was lower than that of pregnant women (P<0.05 or P<0.01), but PIC level of pregnant and puerperium women did not differ significantly (P>0.05). tPAI-C level in healthy non-pregnant women was lower than that of pregnant women (P<0.05 or P<0.01), and tPAI-C level was significantly decreases in the puerperium women (P<0.01). The RIs for TM were as follows: Healthy non-pregnant women at 3.20-4.60 TU/mL, the first and second trimester at 3.12-7.90 TU/mL, the third trimester at 3.42-8.29 TU/mL, puerperium at 2.70-6.40 TU/mL. The RIs for TAT were as follows: Healthy non-pregnant women at 0.50-1.64 ng/mL, the first and second trimester at 0.52-6.91 ng/mL, the third trimester at 0.96-12.92 ng/mL, puerperium at 0.82-3.75 ng/mL. The RIs for PIC were as follows: Healthy non-pregnant women at 0.160-0.519 ng/mL, pregnant women at 0.162-0.770 µg/mL. The RIs for tPAI-C were as follows: Healthy non-pregnant women at 1.90-4.80 ng/mL, the first and second trimester at 2.03-9.33 ng/mL, the third trimester at 2.80-14.20 ng/mL, puerperium at 1.10-8.40 ng/mL. CONCLUSIONS: The levels of 4 new coagulation markers TM, TAT, PIC, and tPAI-C in pregnant women are increased significantly during pregnancy and gradually return to normal after delivery. The RIs for TM, TAT, PIC, and tPAI-C in pregnant women by trimester are established according to CLSI C28-A3c, thus providing a clinical reference for clinician in judgement of thrombotic risk.

Changes of serum immunoglobulin level in healthy pregnant women and establishment of its reference interval. / å¥åº·å¦Šå¨ å¦‡å¥³è¡€æ¸ å ç–«çƒè›‹ç™½æ°´å¹³çš„å˜åŒ–åŠå ¶å‚è€ƒåŒºé—´çš„å»ºç«‹.

OBJECTIVES: Pregnant women in a special physiological period, the body's blood indicators will change to a certain extent. This study aims to explore the changes of serum immunoglobulin levels in healthy pregnant women and establish its reference interval (RI). METHODS: A total of 369 healthy pregnant women, who underwent pregnancy examination in the Department of Obstetrics, Second Xiangya Hospital of Central South University from August 2019 to October 2019, were enrolled for this study. They were divided into an early pregnancy group, a middle pregnancy group, and a late pregnancy group according to the pregnancy period, and 123 healthy non-pregnant women were selected as the controls. The levels of immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) were determined by immune transmission turbidities. The level of immunoglobulin E (IgE) was determined by electrochemiluminescence. The differences in immunoglobulin levels between pregnant women and non-pregnant women and among different gestational periods were analyzed, and the RI of serum immunoglobulin level during pregnancy was established. RESULTS: Compared to the non-pregnant women, the levels of serum IgG, IgM, IgA, and IgE in pregnant women were significantly decreased (all P<0.01), with 51.81% for IgG, 43.84% for IgM, 55.80% for IgA, and 49.80% for IgE. Except that the IgG level of late pregnancy group was significantly lower than that of early pregnancy group (P<0.05), there were no significant differences in the IgG, IgM, IgA, and IgE levels among the other groups (all P>0.05). The RIs of serum IgG in early pregnancy, middle pregnancy, and late pregnancy were 6.02-7.70 g/L, 5.18-6.85 g/L, and 4.58-5.72 g/L, respectively, while the RIs of serum IgM, IgA, and IgE were 0.71-0.93 g/L, 0.90-1.09 g/L, and 68.30-107.69 ng/mL, respectively in pregnant women. CONCLUSIONS: The levels of immunoglobulin in pregnant women are decreased significantly. The establishment of RIs of IgG, IgM, IgA and IgE in healthy pregnant women could provide scientific basis for clinical decision-making.

A simple and highly efficient method of IFI44L methylation detection for the diagnosis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex heterogenous autoimmune disease that can be challenging to diagnose. We previously identified the IFN-induced protein 44-like (IFI44L) methylation marker for SLE diagnosis, which can be detected by pyrosequencing. Although the previous technique has high sensitivity and specificity, it requires special equipment and high cost for detection. Here, we established a high-resolution melting-quantitative polymerase chain reaction (HRM-qPCR) assay to detect the methylation of IFI44L promoter for the diagnosis of SLE. The result was determined according to the standard melting curve of the methylation level of the IFI44L promoter region. The sensitivity was 88.571% and the specificity was 97.087%. The HRM-qPCR and pyrosequencing results presented good consistency when both methods were used to detect the methylation of the IFI44L promoter for SLE diagnosis. Furthermore, the HRM-qPCR method can be used to distinguish SLE from other autoimmune diseases, infectious diseases and virus-related cancers.

T cell receptor ß repertoires as novel diagnostic markers for systemic lupus erythematosus and rheumatoid arthritis.

OBJECTIVE: T cell receptor (TCR) diversity determines the autoimmune responses in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and is closely associated with autoimmune diseases prognosis and prevention. However, the characteristics of variations in TCR diversity and their clinical significance is still unknown. Large series of patients must be studied in order to elucidate the effects of these variations. METHODS: Peripheral blood from 877 SLE patients, 206 RA patients and 439 healthy controls (HC) were amplified for the TCR repertoire and sequenced using a high-throughput sequencer. We have developed a statistical model to identify disease-associated TCR clones and diagnose autoimmune diseases. RESULTS: Significant differences were identified in variable (V), joining (J) and V-J pairing between the SLE or RA and HC groups. These differences can be utilised to discriminate the three groups with perfect accuracy (V: area under receiver operating curve > 0.99). One hundred ninety-eight SLE-associated and 53 RA-associated TCRs were identified and used for diseases classification by cross validation with high specificity and sensitivity. Disease-associated clones showed common features and high similarity between both autoimmune diseases. SLE displayed higher TCR heterogeneity than RA with several organ specific properties. Furthermore, the association between clonal expansion and the concentration of disease-associated clones with disease severity were identified, and pathogen-related TCRs were enriched in both diseases. CONCLUSIONS: These characteristics of the TCR repertoire, particularly the disease-associated clones, can potentially serve as biomarkers and provide novel insights for disease status and therapeutical targets in autoimmune diseases.

Reference Intervals for Serum Creatinine with Jaffe's Method in Healthy Chinese Geriatric Population.

BACKGROUND: Reliable reference intervals (RIs) for the serum creatinine (SCr), assayed by Jaffe's method and categorized in small intervals, are still lacking in elderly population. The study aims to establish RIs for SCr with Jaffe's method in healthy geriatric population of China. METHODS: Eight hundred twenty cases from six representative geographical regions in China (including 369 male cases and 374 female cases) of apparently healthy Chinese elderly aged 60 - 90 years were recruited. SCr were analyzed by an ARCHITECT c8000 biochemical analyzer with Jaffe's method, and RIs for Scr with Jaffe's method were determined following CLSI C28-A3 guidelines using a nonparametric method. RESULTS: In apparently healthy Chinese geriatric population of China, the RIs for Scr with Jaffe's method were 69.4 ~ 113.1, 74.1 ~ 122.1, 75.2 ~ 126.9 µmol/L, respectively, for males aged 61 - 70, 71 - 80, 81 - 90 years and 60.7 ~ 91.6, 62.2 ~ 102.5, 86.5 ~ 107.2 µmol/L, respectively, for females aged 61 - 70, 71 - 80, 81 - 90 years. CONCLUSIONS: The RIs for Scr using Jaffe's method were established within apparently healthy geriatric Chinese population according to CLSI C28-A3 document, providing a reference for clinical practice.

Serum prolactin levels across pregnancy and the establishment of reference intervals.

BACKGROUND: Reference intervals (RIs) play key roles in clinical diagnosis, treatment and prognosis. However, RIs for clinical testing tend to be confined to the general population, and RIs for pregnant women are not very comprehensive. In this study, we establish RIs for prolactin (PRL) in healthy pregnant and postpartum women in the Chinese population. METHODS: Healthy pregnant women (n=378) were divided into groups according to whether they were in the first, second or third trimester of pregnancy. Healthy postpartum women (n=493) were separated into four groups according to mode of delivery as follows: postvaginal (24 and 48 h) or postcesarean (24 and 48 h). Healthy, non-pregnant women (n=123) were enrolled as a control group. Serum PRL levels were measured by electrochemiluminescence immunoassay, and RIs were established for each group. RESULTS: The RIs for PRL were as follows: healthy non-pregnant women, 178.89-757.52 µIU/mL; first trimester, 621.20-3584.00 µIU/mL; second trimester, 1432.00-5349.68 µIU/mL; third trimester, 4087.33-9733.65 µIU/mL; 24 and 48 h postvaginal delivery (combined), 7865.36-10998.86 µIU/mL; and 24 and 48 h postcesarean delivery, 4556.41-7675.99 and 6578.45-9980.45 µIU/mL, respectively. CONCLUSIONS: PRL RIs for pregnant women were established according to trimester, days postpartum and mode of delivery, thus providing a clinical reference for medical staff.

Reference intervals for serum bilirubin, urea, and uric acid in healthy Chinese geriatric population.

OBJECTIVES: The study aims to establish the reference intervals (RIs) for total bilirubin (TBIL), direct bilirubin (DBIL), urea (UR), and uric acid (UA) in healthy Chinese geriatric population. METHODS: Eight hundred and twenty cases from six representative geographical regions in China (including male 413 cases and female 407 cases) of apparently healthy individuals aged 60-96 years were recruited. Serum TBIL, DBIL, UR, and UA were analyzed by automatic biochemical analyzer and RIs were determined following CLSI C28-A3 guidelines using a non-parametric method. RESULTS: In apparently healthy Chinese geriatric population of China, the RIs of TBIL, DBIL, UR, and UA were 6.6~21.8 µmol/L, 1.9~8.0 µmol/L, 3.60~9.51 mmol/L, 179.2~460.9 µmol/L in males and 6.1~20.0 µmol/L, 1.8~7.1 µmol/L,3.35~8.89 mmol/L, 130.2~443.4 µmol/L in females, respectively. CONCLUSIONS: The RIs of TBIL, DBIL, UR, and UA were established within apparently healthy geriatric Chinese population according to CLSIC28-A3 document, providing a reference for the clinical.

The epigenetic mechanism for discordance of autoimmunity in monozygotic twins.

Monozygotic twins share an identical DNA sequence but are not truly "identical". In fact, when it comes to health and disease, they may often display some level of phenotypic discordance. The cause of this discordance is often unknown. Epigenetic modifications such as DNA methylation, histone modification, and microRNAs-mediated regulation regulate gene expression and are sensitive to external stimuli. These modifications may be seen to bridge the gap between genetics and the environment. Over the years, the importance of epigenetics as a primary mechanism for the role that the environment plays in defining phenotype has been increasingly appreciated. Mechanisms of epigenetics include DNA methylation, histone modifications and microRNAs. Discordance rates in monozygotic twins vary depending on the specific condition, from 11% in SLE to 64% in psoriasis and 77% in PBC. Other autoimmune diseases in which discordance is found among monozygotic twins has also been studied include type 1 diabetes, multiple sclerosis, rheumatoid arthritis, dermatomyositis and systemic sclerosis. In some cases, the differences in various epigenetic modifications is slight, even though the concordance rate is low, suggesting that epigenetics is not the only factor that needs to be considered. Nonetheless, the study of phenotypic discordance in monozygotic twins may shed light on the pathogenesis of autoimmune diseases and contribute to the development of new methodologies for the diagnosis and treatment of these diseases.

IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease with limited reliable diagnostic biomarkers. We investigated whether gene methylation could meet sensitivity and specificity criteria for a robust biomarker. METHODS: IFI44L promoter methylation was examined using DNA samples from a discovery set including 377 patients with SLE, 358 healthy controls (HCs) and 353 patients with rheumatoid arthritis (RA). Two independent sets including 1144 patients with SLE, 1350 HCs, 429 patients with RA and 199 patients with primary Sjögren's syndrome (pSS) were used for validation. RESULTS: Significant hypomethylation of two CpG sites within IFI44L promoter, Site1 (Chr1: 79 085 222) and Site2 (Chr1: 79 085 250; cg06872964), was identified in patients with SLE compared with HCs, patients with RA and patients with pSS. In a comparison between patients with SLE and HCs included in the first validation cohort, Site1 methylation had a sensitivity of 93.6% and a specificity of 96.8% at a cut-off methylation level of 75.5% and Site2 methylation had a sensitivity of 94.1% and a specificity of 98.2% at a cut-off methylation level of 25.5%. The IFI44L promoter methylation marker was also validated in an European-derived cohort. In addition, the methylation levels of Site1 and Site2 within IFI44L promoter were significantly lower in patients with SLE with renal damage than those without renal damage. Patients with SLE showed significantly increased methylation levels of Site1 and Site2 during remission compared with active stage. CONCLUSIONS: The methylation level of IFI44L promoter can distinguish patients with SLE from healthy persons and other autoimmune diseases, and is a highly sensitive and specific diagnostic marker for SLE.

Alpelisib-related adverse events: The FDA Adverse Event Reporting System Database (FAERS) pharmacovigilance study.

Background: Alpelisib was approved for treatment of breast cancer. We assessed the safety signals associated with alpelisib by data mining the FDA pharmacovigilance database. Methods: Data from the second quarter of 2019 to the fourth quarter of 2022 had been retrieved from the FAERS database. Disproportionality analysis by reporting odds ratio were used to evaluate the potential association between adverse events (AEs) and alpelisib. Results: A total of 5,980,090 reports were extracted, 18,149 of them were chosen with alpelisib as the suspected drug. After combining the same PRIMARYID, 5647 patients remained. We observed 10 system organ classes (SOCs) with a reported number >50 and associated with alpelisib as gastrointestinal disorders, general disorders and administration site conditions, metabolism and nutrition disorders, skin and subcutaneous tissue disorders, investigations and neoplasms benign, malignant and unspecified (incl cysts and polyps), immune system disorders, nervous system disorders, psychiatric disorders, eye disorders. The median time to AEs in these patients was 13 days, with an IQR (Interquartile Range) of 7-70 days. 61.12% AEs happened within the initial month of alpelisib usage. Conclusion: Our study provided a more in-depth and extensive understanding of AEs that may be associated with alpelisib, which will help to reduce the risk of AEs in the clinical treatment of alpelisib. AEs with novel preferred term (PTs) were constipation, dysphagia, diabetic ketoacidosis, feeding disorder, urticaria, eye disorders and vision blurred. 61.12% of cases developed AEs within 30 days after taking alpelisib.

Abnormally high expression of D1-like dopamine receptors on lupus CD4+ T cells promotes Tfh cell differentiation.

OBJECTIVE: SLE is a chronic autoimmune disease that places a great burden on human society. T follicular helper (Tfh) cells play a critical role in the pathological process of SLE. Therefore, elucidating the mechanism of Tfh cell differentiation will contribute to SLE treatment. Dopamine receptors (DRDs) are members of the family of G protein-coupled receptors and are primarily divided into D1-like and D2-like receptors. Previous studies have found that DRDs can regulate differentiation of immune cells. However, there is currently a lack of research on DRDs and Tfh cells. We here explore the relationship between DRDs and Tfh cells, and analyse the relationship between DRD expression on Tfh cells and the course of SLE. METHODS: We first detected plasma catecholamine concentrations in patients with SLE and healthy controls by mass spectrometry, followed by reverse transcription-quantitative PCR (RT-qPCR) to detect DRD messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells, and flow cytometry to detect DRD expression in Tfh cells. Finally, in vitro experiments and RNA sequencing (RNA-seq) were used to explore the possible pathway by which DRDs regulate Tfh cell differentiation. RESULTS: The plasma dopamine concentration in patients with SLE was significantly increased, and abnormal mRNA expression of DRDs was observed in both PBMCs and CD4+ T cells. The results of flow cytometry showed that D1-like receptors were highly expressed in Tfh cells of patients with SLE and associated with disease activity. In vitro induction experiments showed that differentiation of naïve T cells into Tfh cells was accompanied by an increase in D1-like receptor expression. RNA-seq and RT-qPCR results indicate that D1-like receptors might promote Tfh cell differentiation through the Phosphatidylinositol3-kinase (PI3K)/protein kinase B (AKT)/Forkhead box protein O1 (FOXO1)/Kruppel-like factor 2 (Klf2) pathway. CONCLUSION: Tfh cells in patients with SLE highly express D1-like receptors, which correlate with disease activity. D1-like receptors may promote Tfh cell differentiation through the PI3K/AKT/FOXO1/Klf2 pathway.

LncRNA SNHG6 Upregulates KPNA5 to Overcome Gemcitabine Resistance in Pancreatic Cancer via Sponging miR-944.

Gemcitabine (GEM) is the gold-standard therapeutic regimen for patients with pancreatic cancer (PC); however, patients may receive limited benefits due to the drug resistance of GEM. LncRNA SNHG6 is reported to play key roles in drug resistance, but its role and molecular mechanism in PC remain incompletely understood. We found that LncRNA SNHG6 is drastically downregulated in GEM-resistant PC and is positively correlated with the survival of PC patients. With the help of bioinformatic analysis and molecular approaches, we show that LncRNA SNHG6 can sponge miR-944, therefore causing the upregulation of the target gene KPNA5. In vitro experiments showed that LncRNA SNHG6 and KPNA5 suppress PC cell proliferation and colony formation. The Upregulation of LncRNA SNHG6 and KPNA5 increases the response of GEM-resistant PANC-1 cells to GEM. We also show that the expression of KPNA5 is higher in patients without GEM resistance than in those who developed GEM resistance. In summary, our findings indicate that the LncRNA SNHG6/miR944/KPNA5 axis plays a pivotal role in overcoming GEM resistance, and targeting this axis may contribute to an increasing of the benefits of PC patients from GEM treatment.

Circular RNA profiles of osteoarthritic synovium.

PURPOSES: To identify the circular RNA (circRNA) expression profile in the synovium of patients with osteoarthritis (OA) and explore their potential regulatory mechanism. METHODS: Transcriptome high-throughput sequencing was used to detect the expression profiles of circRNA and mRNA. We performed real-time PCR for the validation of circRNAs and used bioinformatics analysis to predict their possible biological functions. The conservation of circRNAs was evaluated, a circRNA-miRNA-mRNA interaction network was constructed and the receiver operating characteristic (ROC) curves of target genes were also drawn. RESULTS: We found 136 differentially expressed circRNAs, 64 upregulated and 72 downregulated. We also found 2035 differentially expressed mRNAs, 1216 upregulated and 819 downregulated. It was verified by qRT-PCR that hsa_circ_0072697 was significantly upregulated. The GO analysis results showed that the parental genes were mainly enriched in organelle organization, cytosol and anion binding. The most enriched pathways for these circRNAs participated in cellular senescence. And hsa_circ_0072697 might act as a sponge of hsa-miR-6736-5p, which could therefore lead to increased LEP and ULK1 mRNA expression. CONCLUSIONS: CircRNAs are significantly expressed in the knee synovium of OA patients and may play an important role in the occurrence and development of OA. The potential mechanism could be sponging miRNAs to increase mRNA expression.

Engineering Vacancies at the 2D Nanocrystals for Robust Bifunctional Electrocatalysts.

Hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) through water decomposition are feasible methods to produce green and clean energy. Herein, we report a facile two-step strategy for the preparation of non-noble metal defect-rich nanosheets by an electrochemical process at room temperature. First-principle calculations are used to study the bifunctional catalytic reaction mechanism of defect engineering in transition-metal dichalcogenides (TMDs); from the first-principle calculations, we predicted that the rich S vacancies on the nanosheet promoted electron transfer and reduced the energy barrier of electrocatalysis. As a substantiation, we conducted HER/OER electrochemical characterizations and found that the defect-rich atomic-thick tantalum sulfide is a kind of dual-function electrocatalyst with enhanced comprehensive properties of Tafel slope (39 mV/dec for HER, 38 mV/dec for OER) and low overpotential (0.099 V for HER, 0.153 V for OER) in acidic and alkaline environments, respectively. Likewise, the defect-rich catalysts exhibit high stability in acidic and alkaline solutions, which have potential applications as electrocatalysts for the large-scale production of hydrogen and oxygen.