A prospective cohort-based artificial intelligence evaluation system for the protective efficacy and immune response of SARS-CoV-2 inactivated vaccines.

BACKGROUND: Novel coronaviruses constitute a significant health threat, prompting the adoption of vaccination as the primary preventive measure. However, current evaluations of immune response and vaccine efficacy are deemed inadequate. OBJECTIVES: The study sought to explore the evolving dynamics of immune response at various vaccination time points and during breakthrough infections. It aimed to elucidate the synergistic effects of epidemiological factors, humoral immunity, and cellular immunity. Additionally, regression curves were used to determine the correlation between the protective efficacy of the vaccine and the stimulated immune response. METHODS: Employing LASSO for high-dimensional data analysis, the study utilised four machine learning algorithms-logistical regression, random forest, LGBM classifier, and AdaBoost classifier-to comprehensively assess the immune response following booster vaccination. RESULTS: Neutralising antibody levels exhibited a rapid surge post-booster, escalating to 102.38 AU/mL at one week and peaking at 298.02 AU/mL at two weeks. Influential factors such as sex, age, disease history, and smoking status significantly impacted post-booster antibody levels. The study further constructed regression curves for neutralising antibodies, non-switched memory B cells, CD4+T cells, and CD8+T cells using LASSO combined with the random forest algorithm. CONCLUSION: The establishment of an artificial intelligence evaluation system emerges as pivotal for predicting breakthrough infection prognosis after the COVID-19 booster vaccination. This research underscores the intricate interplay between various components of immunity and external factors, elucidating key insights to enhance vaccine effectiveness. 3D modelling discerned distinctive interactions between humoral and cellular immunity within prognostic groups (Class 0-2). This underscores the critical role of the synergistic effect of humoral immunity, cellular immunity, and epidemiological factors in determining the protective efficacy of COVID-19 vaccines post-booster administration.

A prognostic model for SARS-CoV-2 breakthrough infection: Analyzing a prospective cellular immunity cohort.

BACKGROUND: Following the COVID-19 pandemic, studies have identified several prevalent characteristics, especially related to lymphocyte subsets. However, limited research is available on the focus of this study, namely, the specific memory cell subsets among individuals who received COVID-19 vaccine boosters and subsequently experienced a SARS-CoV-2 breakthrough infection. METHODS: Flow cytometry (FCM) was employed to investigate the early and longitudinal pattern changes of cellular immunity in patients with SARS-CoV-2 breakthrough infections following COVID-19 vaccine boosters. XGBoost (a machine learning algorithm) was employed to analyze cellular immunity prior to SARS-CoV-2 breakthrough, aiming to establish a prognostic model for SARS-CoV-2 breakthrough infections. RESULTS: Following SARS-CoV-2 breakthrough infection, naïve T cells and TEMRA subsets increased while the percentage of TCM and TEM cells decreased. Naïve and non-switched memory B cells increased while switched and double-negative memory B cells decreased. The XGBoost model achieved an area under the curve (AUC) of 0.78, with an accuracy rate of 81.8 %, a sensitivity of 75 %, and specificity of 85.7 %. TNF-α, CD27-CD19+cells, and TEMRA subsets were identified as high predictors. An increase in TNF-α, cTfh, double-negative memory B cells, IL-6, IL-10, and IFN-γ prior to SARS-CoV-2 infection was associated with enduring clinical symptoms; conversely, an increase in CD3+ T cells, CD4+ T cells, and IL-2 was associated with clinical with non-enduring clinical symptoms. CONCLUSION: SARS-CoV-2 breakthrough infection leads to disturbances in cellular immunity. Assessing cellular immunity prior to breakthrough infection serves as a valuable prognostic tool for SARS-CoV-2 infection, which facilitates clinical decision-making.

Lycorine inhibits migration and proliferation of hepatocellular carcinoma cells by reducing transketonase expression.

Background: Previous studies have showed that lycorine can restrain the development of multiple tumor types, containing hepatocellular carcinoma (HCC), but the underlying mechanisms remain unknown. Methods: We assessed the impact of lycorine on hepatocellular cancer cell proliferation, migration, colony formation, cell cycle, and apoptosis. The possible inhibitory effect of lycorine on the activity of HCC cells was analyzed by RNA-seq, and transketolase (TKT) expression in HCC and nontumorous tissues was detected using RT-PCR. The expression of TKT protein in HCC and tumor adjacent non-cancerous tissues was detected by immunohistochemistry. We evaluated the association of expression of TKT in HCC tissues with prognosis, and investigated the inhibitory effect of lycorine on tumor growth in vivo. Results: Lycorine significantly inhibited the proliferation, invasion, migration, colony formation, cell cycle of HCC cells, but had no obvious impact on apoptosis. Twenty-eight genes were found to be down-regulated in HuH7 and HepG2 cells after lycorine treatment, and the difference of TKT gene expression was significantly. The expression of TKT protein was significantly higher in HCC than in non-tumorous tissues. The expression of TKT was correlated with tumor size, Edmondson grade, AFP, and overall survival. Survival analysis suggested that high expression of TKT was associated with a poor survival. The average tumor volume and weight were significantly reduced in the lycorine injection group, but the body weights of the mice did not change significantly. Conclusion: Lycorine can restrict the migration and proliferation of HCC cells by down-regulating TKT expression, and it may be a potential meaningful drug for the prevention and treatment of HCC.

Tripartite-motif 3 represses ovarian cancer progression by downregulating lactate dehydrogenase A and inhibiting AKT signaling.

The E3 ubiquitin ligase Tripartite-motif 3 (TRIM3) is known to play a crucial role in tumor suppression in various tumors through different mechanisms. However, its function and mechanism in ovarian cancer have yet to be elucidated. Our study aims to investigate the expression of TRIM3 in ovarian cancer and evaluate its role in the development of the disease. Our findings revealed a significant decrease in TRIM3 mRNA and protein levels in ovarian cancer tissues and cells when compared to normal ovarian epithelial tissues and cells. Furthermore, we observed a negative correlation between the protein level of TRIM3 and the FIGO stage, as well as a positive correlation with the survival of ovarian cancer patients. Using gain and loss of function experiments, we demonstrated that TRIM3 can inhibit cell proliferation, migration and invasion of the ovarian cancer cells in vitro, as well as suppress tumor growth in vivo. Mechanistic studies showed that TRIM3 interacts with lactate dehydrogenase A, a key enzyme in the glycolytic pathway, through its B-box and coiled-coil domains and induces its ubiquitination and proteasomal degradation, leading to the inhibition of glycolytic ability in ovarian cancer cells. RNA-sequencing analysis revealed significant alterations in the phosphatidylinositol signaling pathways upon TRIM3 overexpression. Additionally, overexpression of TRIM3 inhibited the phosphorylation of AKT. In conclusion, our study demonstrated that TRIM3 exerts a tumor-suppressive effect in ovarian cancer, at least partially, by downregulating LDHA and inhibiting the AKT signaling pathway, and thus leading to the inhibition of glycolysis and limiting the growth of ovarian cancer cells.

New use of preoperative fibrinogen in ovarian cancer management.

Background: Ovarian cancer (OC) is often diagnosed at an advanced stage due to the absence of specific symptoms in its early stages. And the prognosis greatly depends on when the disease is diagnosed. Thus, we conducted to evaluate the value of preoperative fibrinogen (Fib) levels for the diagnosis of OC in the hope of improving its diagnostic efficiency. Methods: A total of 126 ovarian tumor patients were retrospectively included in this study. Four candidate OC markers, including cancer antigen 125 (CA125), Fib, platelet (PLT) and homocysteine (Hcy) were employed to establish a diagnosis model for OC. The diagnostic performance of the model was evaluated using the area under the receiver operating characteristic curve (AUC) and Youden index. Results: All included markers could be used for the diagnosis of OC. The AUCs of CA125, Fib, PLT and Hcy were 0.881, 0.825, 0.676 and 0.647, respectively. The new diagnosis model combining CA125 and Fib (CA125-Fib) had a higher AUC (0.924), Youden index (0.730), and best sensitivity (SN) (74.6%) and specificity (SP) (98.41%). CA125-Fib also had a high value in the diagnosis of stage I-II OC (AUC, Youden index, SN and SP: 0.853, 0.624, 81.48% and 80.95%). Conclusions: Fib could be used for OC diagnosis. In particular, the combination of Fib and CA125 could further improve the diagnostic efficiency. And the diagnostic value of PLT and Hcy was found to be poor.

IGF2BP2 promotes ovarian cancer growth and metastasis by upregulating CKAP2L protein expression in an m6 A-dependent manner.

Ovarian cancer (OC) is the second leading cause of gynecological cancer-related death in women worldwide. N6-methyladenosine (m6 A) is the most abundant internal modification in eukaryotic RNA. Human insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an m6 A reader, can enhance mRNA stability and promote translation by recognizing m6 A modifications. Its tumor-promoting effects have been demonstrated in several cancers. However, the roles of m6 A modification and IGF2BP2 in OC remain unclear. Here, by using methylated RNA immunoprecipitation sequencing, we demonstrated that there is widespread dysregulation of m6 A modification in OC tissues. The m6 A modification and the mRNA and protein levels of IGF2BP2 were significantly elevated in OC. Overexpression of IGF2BP2 facilitated OC cell proliferation, migration, and invasion in vitro and accelerated tumor growth and metastasis in vivo. While IGF2BP2-knockdown showed the opposite effect. Mechanistically, we identified cytoskeleton-associated protein 2-like (CKAP2L) as a target of IGF2BP2. IGF2BP2 promoted CKAP2L translation dependent on m6 A modification, rather than affecting mRNA and protein stability. Overexpression of CKAP2L rescued the tumor-suppressive effect of IGF2BP2 knockdown in OC cells. In conclusion, this study revealed the potential role of IGF2BP2 in tumor progression, at least partially via promoting the translation of CKAP2L in an m6 A-dependent manner.

[Analysis of clinical phenotypes and MMACHC gene variants in 65 children with Methylmalonic acidemia and homocysteinemia].

OBJECTIVE: To carry out Sanger sequencing for MMACHC gene variants among 65 Chinese pedigrees affected with combined methylmalonic aciduria and homocysteinemia, and summarize their genetic and clinical characteristics and prognosis. METHODS: Clinical characteristics of the 65 children identified with Methylmalonic acidemia and homocysteinemia at the Children's Hospital Affiliated to Zhengzhou University (Zhengzhou Children's Hospital) from April 2017 to April 2022 were selected as the study subjects. Potential variants of the MMACHC gene were detected by direct sequencing of the PCR products. RESULTS: The median age of the 65 children was 3 months (14 days to 17 years old). These included 28 cases (43.08%) from neonatal screening, 11 cases (16.92%) with a history of jaundice, and 9 cases (13.85%) with various degrees of anemia. The main clinical symptoms included development delay, slow growth, epilepsy, hydrocephalus, lethargy, feeding difficulty, regression or decline in motor ability, recurrent respiratory infections, anemia, jaundice, respiratory and heart failures, hydrocephalus, limb weakness, and hypertension. Blood and urine tandem mass spectrometry screening has revealed increase of methylmalonic acid, propionyl carnitine, propionyl carnitine/acetylcarnitine ratio, and propionyl carnitine/free carnitine ratio to various extents, and blood homocysteine was increased in all patients. The detection rate of genetic variants was 98.46% (128/130), and in total 22 types of MMACHC gene variants were detected. The most common ones have included c.609G>A (W203X) (58/128), c.658-660del (K220del) (19/128), and c.80A>G (Q27A) (16/128). Two novel variants have been identified, namely c.565C>T (p.R189C) and c.624_ 625delTG (p.A208Afs), which were respectively predicted as likely pathogenic (PM2_Supporting+PM3+PP2+PP3) and pathogenic (PVS1+PM2_Supporting+PM3+PP2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Exon 4 had the highest frequency for the detection. CONCLUSION: Identification of MMACHC gene variants has confirmed the diagnosis in the children, among which the c.609G>A variant has the highest frequency. Discovery of the new variants has enriched the mutational spectrum of the MMACHC gene.

Altered profile of glycosylated proteins in serum samples obtained from patients with Hashimoto's thyroiditis following depletion of highly abundant proteins.

Objectives: Hashimoto's thyroiditis (HT) is one of the most common autoimmune disorders; however, its underlying pathological mechanisms remain unclear. Although aberrant glycosylation has been implicated in the N-glycome of immunoglobulin G (IgG), changes in serum proteins have not been comprehensively characterized. This study aimed to investigate glycosylation profiles in serum samples depleted of highly abundant proteins from patients with HT and propose the potential functions of glycoproteins for further studies on the pathological mechanisms of HT. Methods: A lectin microarray containing 70 lectins was used to detect and analyze glycosylation of serum proteins using serum samples (N=27 HT; N=26 healthy control [HC]) depleted of abundant proteins. Significant differences in glycosylation status between HT patients and the HC group were verified using lectin blot analysis. A lectin-based pull-down assay combined with mass spectrometry was used to investigate potential glycoproteins combined with differentially present lectins, and an enzyme-linked immunosorbent assay (ELISA) was used to identify the expression of targeted glycoproteins in 131 patients with papillary thyroid carcinoma (PTC), 131 patients with benign thyroid nodules (BTN) patients, 130 patients with HT, and 128 HCs. Results: Compared with the HC group, the majority of the lectin binding signals in HT group were weakened, while the Vicia villosa agglutinin (VVA) binding signal was increased. The difference in VVA binding signals verified by lectin blotting was consistent with the results of the lectin microarray. A total of 113 potential VVA-binding glycoproteins were identified by mass spectrometry and classified by gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analyses. Using ELISA, we confirmed that lactoferrin (LTF) and mannan-binding lectin-associated serine protease 1 (MASP-1) levels were elevated in the serum of patients with HT and PTC. Conclusion: Following depletion of abundant proteins, remaining serum proteins in HT patients exhibited lower glycosylation levels than those observed in HCs. An increased level of potential VVA-binding glycoproteins may play an important role in HT development. LTF and MASP-1 expression was significantly higher in the serum of HT and PTC patients, providing novel insight into HT and PTC.

Long non-coding RNA TCL6 induced by SCRT1 promotes proliferation and metastasis of non-small cell lung cancer through PDK1/AKT signaling.

Non-small cell lung cancer (NSCLC) ranks the most lethal malignancies around the world, nearly 85 % of lung cancers are NSCLC. Its high prevalence and morbidity pose a considerable burden to human health, identifying promising therapeutic targets for NSCLC is urgently needed. The essential function of long non-coding RNAs (lncRNAs) in multiple cellular progressions and pathophysiological processes are widely understood, thus we investigated the role of lncRNA T-cell leukemia/lymphoma 6 (TCL6) in NSCLC progression. LncRNA TCL6 level is increased in NSCLC samples and downregulation of lncRNA TCL6 inhibited NSCLC tumorigenesis. Moreover, Scratch Family Transcriptional Repressor 1 (SCRT1) can modulate lncRNA TCL6 expression in NSCLC cells, with lncRNA TCL6 promoting NSCLC development through Pyruvate Dehydrogenase Kinase 1 (PDK1)/AKT signaling by interacting with PDK1, thereby providing a novel framework for NSCLC research.

Value of Autostrain LV in the study of left ventricular systolic function and synchronization in patients with systemic lupus erythematosus.

BACKGROUND: There are relatively few studies investigating cardiac structural and functional abnormalities associated with systemic lupus erythematous (SLE). The long-term prognosis of SLE patients is closely related to the cardiovascular events caused by SLE. Accordingly, it is necessary to assess early myocardial systolic function and synchrony. METHODS: Overall, 90 patients with SLE were randomly selected from our outpatient and inpatient clinics and divided according to SLE Disease Activity Index (SLE-DAI-2000) scores: group A, stable (scores 0-4); group B, mildly active stage (scores 5-9); and group C, moderately active stage (scores ≥10). Each group included 30 patients. Further, 30 sex- and age-matched healthy individuals who were referred for check-ups at the same period were selected as controls (group D). The minimum age for entry into the group was 17 years old. Autostrain LV and three-dimensional quantitative analysis (3DQA) were applied to obtain left ventricular systolic function parameters, information on strain parameters, and correlations between parameters. Simultaneity parameters measured by Autostrain LV and 3DQA were tested for reproducibility. RESULTS: A two-by-two comparison of groups A-C showed that as the disease activity score increased, AP4LS%, AP2LS%, AP3LS%, and the LV mean overall longitudinal strain all gradually decreased, while LV longitudinal strain peak time standard deviation (Tls-SD) gradually increased, with all differences being statistically significant (p < .05). In groups A-C compared with controls, Tmsv-17-SD, Tmsv-17-Dif, Tmsv-17-SD%, and Tmsv-17-Dif% were all significantly prolonged (p < .05). Further, Tls-SD was positively correlated with Tmsv-17-SD and Tmsv-17-Dif, and there was good agreement between Autostrain and 3DQA for the measurement of left ventricular synchrony indexes, with Tmsv-17-Dif having the best repeatability (intraobserver interclass correlation coefficient (ICC) = .979; interobserver ICC = .848, p < .01). CONCLUSION: Autostrain LV can accurately detect changes in left ventricular myocardial strain in patients with SLE early in the disease, with simple operation. The 3DQA technique can quantitatively evaluate left ventricular systolic synchronization in patients with SLE, and Autostrain LV synchronization index measurements correlate significantly with 3DQA. Both methods are reproducible, but 3DQA is more sensitive to left ventricular synchronous motion changes.

Analysis of the Secreted Peptidome from Omental Adipose Tissue in High-Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) is a preferential omental metastasis malignancy. Since omental adipose tissue is an endocrine organ, we used liquid chromatography tandem mass spectrometry (LC-MS/MS) to compare the peptides secreted from omental adipose tissues of HGSOC and benign serous ovarian cysts (BSOC). Among the differentially secreted peptides, we detected 58 upregulated peptides, 197 downregulated peptides, 24 peptides that were only in the HGSOC group and 20 peptides that were only in the BSOC group (absolute fold change ≥ 2 and P < 0.05). Then, the basic characteristics of the differential peptides were analyzed, such as lengths, molecular weights, isoelectric points, and cleavage sites. Furthermore, we summarized the possible functions according to the precursor protein functions of the differentially expressed peptides by Gene Ontology (GO) analysis with the Annotation, Visualization, and Integrated Discovery (DAVID) database and canonical pathway analysis with IPA. For the GO analysis, the differentially secreted peptides were mainly associated with binding in molecular function and cellular processes in biology process. For the canonical pathways, the differentially secreted peptides were related to calcium signaling, protein kinase A signaling, and integrin-linked kinase (ILK) signaling. We also identified 67 differentially secreted peptides that located in the functional domains of the precursor proteins. These functional domains were mainly related to energy metabolism and immunoregulation. Our study might provide drugs that could potentially treat HGSOC or omental metastases of HGSOC cells.

The novel peptide PFAP1 promotes primordial follicle activation by binding to MCM5.

Premature ovarian failure (POF) is a complication of ovarian dysfunction resulting from the depletion or dysfunction of primordial follicles (PFs) in the ovaries. However, residual follicles that have the potential to be activated are present in POF or aged women. Little is known about the mechanisms by which the remaining dormant PFs in POF patients are activated. Using mass spectrometry, we screened differentially generated peptides extracted from the ovarian cortical tissue biopsies of patients with or without POF, during which we identified PFAP1, a peptide that significantly promoted the activation of PFs in the ovaries of 3 dpp mice in vitro. PFAP1 reversed age-related fertility damage in vivo to a certain extent, promoted estrogen (E2) and anti-mullerian hormone (AMH) production (p < .05), and decreased the levels of follicle-stimulating hormone (FSH) (p < .05). In newborn mouse ovaries, PFAP1 could bind to the protein minichromosome maintenance protein 5 (MCM5) and inhibit its ubiquitination and degradation. In addition, PFAP1 promoted the proliferation of GCs, probably by regulating the function and production of MCM5. In conclusion, PFAP1 could promote the activation of PFs in the ovaries of newborn mice, partially restore the ovarian function of aged mice, and increase the proliferation of primary granulosa cells (GCs) by regulating the function of MCM5. PFAP1 is a promising novel peptide that may be developed into a new therapeutic agent for POF and other ovarian diseases.

Integrated in silico-in vitro rational design of oncogenic EGFR-derived specific monoclonal antibody-binding peptide mimotopes.

Human epidermal growth factor receptor (EGFR) is strongly associated with malignant proliferation and has been established as an attractive therapeutic target of diverse cancers and used as a significant biomarker for tumor diagnosis. Over the past decades, a variety of monoclonal antibodies (mAbs) have been successfully developed to specifically recognize the third subdomain (TSD) of EGFR extracellular domain. Here, the complex crystal structures of EGFR TSD subdomain with its cognate mAbs were examined and compared systematically, revealing a consistent binding mode shared by these mAbs. The recognition site is located on the [Formula: see text]-sheet surface of TSD ladder architecture, from which several hotspot residues that significantly confer both stability and specificity to the recognition were identified, responsible for about half of the total binding potency of mAbs to TSD subdomain. A number of linear peptide mimotopes were rationally designed to mimic these TSD hotspot residues in different orientations and/or in different head-to-tail manners by using an orthogonal threading-through-strand (OTTS) strategy, which, however, are intrinsically disordered in Free State and thus cannot be maintained in a native hotspot-like conformation. A chemical stapling strategy was employed to constrain the free peptides into a double-stranded conformation by introducing a disulfide bond across two strand arms of the peptide mimotopes. Both empirical scoring and [Formula: see text]fluorescence assay reached an agreement that the stapling can effectively improve the interaction potency of OTTS-designed peptide mimotopes to different mAbs, with binding affinity increase by [Formula: see text]-fold. Conformational analysis revealed that the stapled cyclic peptide mimotopes can spontaneously fold into a double-stranded conformation that well threads through all the hotspot residues on TSD [Formula: see text]-sheet surface and exhibits a consistent binding mode with the TSD hotspot site to mAbs.

Effect of short-term prehabilitation of older patients with colorectal cancer: A propensity score-matched analysis.

Objective: The aim of this study was to assess the impact of short-term, hospital-based, supervised multimodal prehabilitation on elderly patients with colorectal cancer. Methods: A single-center, retrospective study was conducted from October 2020 to December 2021, which included a total of 587 CRC patients who were scheduled to undergo radical resection. A propensity score-matching analysis was performed to reduce selection bias. All patients were treated within a standardized enhanced recovery pathway, and patients in the prehabilitation group received an additional supervised, short-term multimodal preoperative prehabilitation intervention. Short-term outcomes were compared between the two groups. Results: Among the participants, 62 patients were excluded; 95 participants were included in the prehabilitation group and 430 in the non-prehabilitation group. After PSM analysis, 95 pairs of well-matched patients were included in the comparative study. Participants in the prehabilitation group had better preoperative functional capacity (402.78 m vs. 390.09 m, P<0.001), preoperative anxiety status (9% vs. 28%, P<0.001), time to first ambulation[25.0(8.0) hours vs. 28.0(12.4) hours, P=0.008], time to first flatus [39.0(22.0) hours vs. 47.7(34.0) hours, P=0.006], duration of the postoperative length of hospital stay [8.0(3.0) days vs. 10.0(5.0) days, P=0.007), and quality of life in terms of psychological dimensions at 1 month postoperatively [53.0(8.0) vs. 49.0(5.0), P<0.001]. Conclusion: The short-term, hospital-based, supervised multimodal prehabilitation is feasible with a high degree of compliance in older CRC patients, which improves their short-term clinical outcomes.

LncRNA SLC25A21-AS1 increases the chemosensitivity and inhibits the progression of ovarian cancer by upregulating the expression of KCNK4.

Owing to high mortality rate, ovarian cancer seriously threatens women's health. Extensive abdominal metastasis and chemoresistance are the leading causes of ovarian cancer deaths. Through lncRNA sequencing, our previous study identified lncRNA SLC25A21-AS1, which was significantly downregulated in chemoresistant ovarian cancer cells. In this study, we aimed to evaluate the role and mechanism of SLC25A21-AS1 in ovarian cancer. The expression of SLC25A21-AS1 was analyzed by qRT-PCR and online database GEPIA. The biological functions of SLC25A21-AS1 and KCNK4 were analyzed by CCK-8, transwell, and flow cytometry. The specific mechanism was analyzed by RNA-sequencing, RNA binding protein immunoprecipitation, rescue experiments, and bioinformatic analysis. SLC25A21-AS1 was decreased in ovarian cancer tissues and cell lines. Overexpression of SLC25A21-AS1 enhanced the sensitivity of ovarian cancer cells to paclitaxel and cisplatin, and inhibited cell proliferation, invasion, and migration, while SLC25A21-AS1-silencing showed the opposite effect. Potassium channel subfamily K member 4 (KCNK4) was significantly up-regulated upon enforced expression of SLC25A21-AS1. Overexpression of KCNK4 inhibited cell proliferation, invasion, migration ability, and enhanced the sensitivity of ovarian cancer cells to paclitaxel and cisplatin. Meanwhile, KNCK4-overexpression rescued the promotive effect of SLC25A21-AS1-silencing on cell proliferation, invasion and migration. In addition, SLC25A21-AS1 could interact with the transcription factor Enhancer of Zeste Homolog 2 (EZH2), while EZH2 knockdown increased the expression of KCNK4 in some of the ovarian cancer cell lines. SLC25A21-AS1 enhanced the chemosensitivity and inhibited the proliferation, migration, and invasion ability of ovarian cancer cells at least partially by blocking EZH2-mediated silencing of KCNK4.

Combined use of CA125, neutrophil/lymphocyte ratio and platelet/lymphocyte ratio for the diagnosis of borderline and malignant epithelial ovarian tumors.

BACKGROUND: The mortality rate of ovarian cancer ranks first among three common gynecological malignant tumors due to insidious onset and lack of effective early diagnosis methods. Borderline epithelial ovarian tumor (BEOT) is a type of low malignant potential tumor that is typically associated with better outcomes than ovarian cancer. However, BEOTs are easily confused with benign and malignant epithelial ovarian tumors (EOTs) due to similar clinical symptoms and lack of specific tumor biomarkers and imaging examinations. Notably, a small subset of BEOTs will transform into low-grade serous ovarian carcinoma with a poor prognosis. Therefore, searching for potential biomarkers that can be easily obtained and accurately identify malignant epithelial ovarian tumors (MEOTs) as well as BEOTs is essential for the clinician. Cancer antigen 125 (CA125) is a commonly used biomarker for the diagnosis of EOTs in the preoperative scenario but has low sensitivity and specificity. Nowadays, inflammatory biomarkers including inflammatory cell counts and derived ratios such as neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) have been proved to be associated with tumor progression and poor prognosis, and were considered to be the most economically potential surrogate biomarkers for various malignancies. The purpose of this study was to find appropriate combinations of inflammatory and tumor biomarkers to improve the diagnostic efficiency of EOTs, especially the BEOTs. RESULTS: CA125, NLR and PLR increased steadily among benign, borderline and malignant EOTs and tended to be higher in advanced (stage III-IV) and lymph node metastasis MEOT groups than in early stage (stage I-II) and non-lymph node metastasis MEOT groups. CA125, NLR and PLR could be used separately in the differentiation of EOTs but could not take into account both sensitivity and specificity. The combined use of CA125, NLR and PLR was evaluated to be more efficient, especially in the identification of BEOTs, with both high sensitivity and high specificity. CONCLUSIONS: The levels of CA125, NLR and PLR were closely related to the nature of EOTs and malignant progression of MEOTs. The combination of CA125, NLR and PLR was more accurate in identifying the nature of EOTs than either alone or double combination, especially for BEOTs.

Progress in understanding primary glomerular disease: insights from urinary proteomics and in-depth analyses of potential biomarkers based on bioinformatics.

Chronic kidney disease (CKD) has become a global public health challenge. While primary glomerular disease (PGD) is one of the leading causes of CKD, the specific pathogenesis of PGD is still unclear. Accurate diagnosis relies largely on invasive renal biopsy, which carries risks of bleeding, pain, infection and kidney vein thrombosis. Problems with the biopsy procedure include lack of glomeruli in the tissue obtained, and the sampling site not being reflective of the overall lesion in the kidney. Repeated renal biopsies to monitor disease progression cannot be performed because of the significant risks of bleeding and kidney vein thrombosis. On the other hand, urine collection, a noninvasive method, can be performed repeatedly, and urinary proteins can reflect pathological changes in the urinary system. Advancements in proteomics technologies, especially mass spectrometry, have facilitated the identification of candidate biomarkers in different pathological types of PGD. Such biomarkers not only provide insights into the pathogenesis of PGD but also are important for diagnosis, monitoring treatment, and prognosis. In this review, we summarize the findings from studies that have used urinary proteomics, among other omics screens, to identify potential biomarkers for different types of PGD. Moreover, we performed an in-depth bioinformatic analysis to gain a deeper understanding of the biological processes and protein-protein interaction networks in which these candidate biomarkers may participate. This review, including a description of an integrated analysis method, is intended to provide insights into the pathogenesis, noninvasive diagnosis, and personalized treatment efforts of PGD and other associated diseases.

Differential effects of the LncRNA RNF157-AS1 on epithelial ovarian cancer cells through suppression of DIRAS3- and ULK1-mediated autophagy.

Analyses of several databases showed that the lncRNA RNF157 Antisense RNA 1 (RNF157-AS1) is overexpressed in epithelial ovarian cancer (EOC) tissues. In our study, suppressing RNF157-AS1 strikingly reduced the proliferation, invasion, and migration of EOC cells compared with control cells, while overexpressing RNF157-AS1 greatly increased these effects. By RNA pulldown assays, RNA binding protein immunoprecipitation (RIP) assays, and mass spectrometry, RNF157-AS1 was further found to be able to bind to the HMGA1 and EZH2 proteins. Chromatin immunoprecipitation (ChIP) assays showed that RNF157-AS1 and HMGA1 bound to the ULK1 promoter and prevented the expression of ULK1. Additionally, RNF157-AS1 interacted with EZH2 to bind to the DIRAS3 promoter and diminish DIRAS3 expression. ULK1 and DIRAS3 were found to be essential for autophagy. Combination autophagy inhibitor and RNF157-AS1 overexpression or knockdown, a change in the LC3 II/I ratio was found using immunofluorescence (IF) staining and western blot (WB) analysis. The autophagy level also was confirmed by autophagy/cytotoxicity dual staining. However, the majority of advanced EOC patients require platinum-based chemotherapy, since autophagy is a cellular catabolic response to cell stress. As a result, RNF157-AS1 increased EOC cell sensitivity to chemotherapy and death under cis-platinum (DDP) treatment by suppressing autophagy, as confirmed by cell count Kit-8 (CCK8) assays, flow cytometry, and autophagy/cytotoxicity dual staining. Therefore, the OS and PPS times were longer in EOC patients with elevated RNF157-AS1 expression. RNF157-AS1-mediated autophagy has potential clinical significance in DDP chemotherapy for EOC patients.

Long noncoding RNA RFPL1S-202 inhibits ovarian cancer progression by downregulating the IFN-ß/STAT1 signaling.

BACKGROUND: RFPL1S was first identified as one of the pseudogenes located in the intrachromosomal duplications within 22q12-13. Our previous study found that one of the predicted transcripts of lncRNA RFPL1S, ENST00000419368.1 (GRCh37/hg19), also named as RFPL1S-202 in Ensembl website, is significantly downregulated in the chemoresistant ovarian cancer cells. However, its function and underlying mechanism have not been studied. METHODS: Quantitative Real-time PCR was used to analyze the expression. Cell Counting Kit-8, transwell, flow cytometry analysis and tail vein injected mouse model were used to test the function. RNA-sequencing, RNA pull down, western blot, ELISA and RNA-Binding Protein Immunoprecipitation were performed for studying the mechanism. 5' and 3' rapid amplification of complementary DNA ends were performed to analyze the full length of RFPL1S-202. RESULTS: RFPL1S-202 is significantly downregulated in epithelial ovarian cancer tissues and cell lines. Gain- and loss-of-function study indicated that RFPL1S-202 could enhance cisplatin or paclitaxel in cytotoxicity, inhibit cell proliferation, invasion and migration of ovarian cancer cells in vitro, and inhibit the liver metastasis of ovarian cancer cells in vivo. Mechanistically, RFPL1S-202 could physically interact with DEAD-Box Helicase 3 X-linked (DDX3X) protein, and decrease the expression of p-STAT1 and the IFN inducible genes by increasing the m6A modification of IFNB1. RFPL1S-202 is a spliced and polyadenylated non-coding RNA with a full length of 1071 bp. CONCLUSIONS: Our study suggested that the predicted lncRNA RFPL1S-202 exerts a tumor- suppressive function in oarian cancer chemoresistance and progression by interacting with DDX3X and down-regulating the IFN-ß-STAT1 signaling pathway.

Antibiotic use at planned central line removal in reducing neonatal post-catheter removal sepsis: a systematic review and meta-analysis.

Background: Post-catheter removal sepsis (PCRS) is a notable complication of indwelling central venous catheters (CVCs) in neonates, which is postulated to be secondary to the disruption of biofilms formed along catheter tips up on CVCs removal. It remains controversial whether this could be prevented by antibiotic use upon CVCs removal. We aimed to evaluate the protective effect of antibiotic administration at the time of CVCs removal. Methods: We searched through PubMed, EMBASE, Cochrane databases and reference lists of review articles for studies comparing the use of antibiotics versus no use within 12 h of CVCs removal. Risk of bias was assessed using the modified Newcastle-Ottawa Scale and Cochrane risk-of-bias tool accordingly. Results of quantitative analyses were presented as mean differences (MD) or odds ratio (OR). Subgroup and univariate meta-regression analyses were performed to identify heterogeneity. Results: The review included 470 CVCs in the antibiotic group and 658 in the control group. Antibiotic use within 12 h of CVCs removal did not significantly reduce the incidence of PCRS (OR = 0.35, 95% CI: 0.08-1.53), but was associated with a lower incidence of post-catheter removal blood stream infection (OR = 0.31, 95% CI: 0.11-0.86). Dosage of vancomycin and world region were major sources of heterogeneity. Conclusion: Antibiotic administration upon CVCs removal does not significantly reduce the incidence of PCRS but offers less post-catheter removal blood stream infection. Whether this will be converted to better clinical outcomes lacks evidential support. Further randomized controlled studies with longer follow-up are needed. Summary: Results of our meta-analysis suggest that antibiotic use at planned central line removal removal does not significantly reduce the incidence of PCRS but offers less blood stream infection, which might contribute to future management of central lines in neonates. Systematic Review Registration: https://www.crd.york.ac.uk/, PROSPERO (CRD42022359677).