Home Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
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Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units

  • Stevan Eric , Radica Zivkovic Zaric EMAIL logo , Jasna Jevdjic , Svetlana Miletic Drakulic , Ivan Stanojevic , Danilo Vojvodic , Petar Arsenijevic , Bojan Stojanovic , Stefan Jakovljevic , Nenad Markovic , Milan Zaric , Petar Canovic , Jelena Nesic and Nenad Zornic
Published/Copyright: December 21, 2023

Abstract

Intensive care units (ICUs) are expert hospital areas that provide treatment and 24 h care for people who are very sick. Sepsis represents a serious, severe condition and it can lead to septic shock and multiple organ dysfunction syndromes and is one of the most common reasons for patients’ hospitalization in ICUs. We wanted to explore the prognostic values of interleukin (IL) 33, soluble suppression of tumorigenicity 2 (sST2), IL 27, and galectin 3 in critically-ill patients. We assumed that these parameters in combination or alone could predict mortality in ICU patients. This research represents a clinical non-randomized prospective study, performed at the Medical Military Academy, a tertiary care hospital in Belgrade, Serbia. The patients were divided in four groups: patients with sepsis (peritonitis, pancreatitis, trauma) and patients without sepsis (trauma). Total number of patients enrolled in the study was 151 and average years of patients were 56.48. The values greater than the cut-off were the predictors of mortality. The IL-33, IL-27 as well as galectin-3 can successfully predict the outcome of critically-ill patients in ICUs. The sST2, cannot predict death in critically-ill patients as a single prognostic factor. However, the combination of at least two biomarkers: IL-33, sST2, IL-27, and galectin-3, gives very significant results in predicting the outcome in patients admitted to ICUs.

1 Introduction

Intensive care units (ICUs) are expert hospital areas that provide treatment and 24 h care for people who are very sick. Sepsis represents a serious, severe condition and it can lead to septic shock and multiple organ dysfunction syndromes and is one of the most common reasons for patients’ hospitalization in ICUs [1,2].

Sepsis is a significant public health problem with high morbidity and mortality. In patients with sepsis, the morbidity rate amounts to 29.5% in the hospital and 47% in the ICUs. Furthermore, the death rate in patients with sepsis is about 25.8% in the ICUs and 35.3% in the hospital [1]. Microbiological culture represents a gold standard for diagnosing sepsis, but considering that it takes time for the findings to arrive, which could be fatal for the patient, the need for other biomarkers for the diagnosis and prognosis of sepsis arose [3].

For now, procalcitonin is the most common diagnostic biomarker for sepsis, as well as presepsin [4,5]. Other biomarkers are also mentioned like interleukin (IL) 33. IL-33 is a pro-inflammatory cytokine of the IL-1 family.

Extracellular IL-33 is a ligand for the suppression of tumorigenicity 2 (ST2) receptor and has a vital role at the beginning of severe local inflammation as well as in the guideline of adaptive immune responses. The IL-33/ST2 system has also a significant role in the pathogenesis of acute and chronic inflammatory, autoimmune, and allergic illnesses, i.e., sepsis, asthma, anaphylaxis, rheumatoid arthritis, chronic obstructive pulmonary disease, etc. [6]. ST2 is an associate of the IL-1 receptor family. Soluble ST2 (sST2) is a developing, new biomarker associated with cardiac fibrosis, and its utility as a predictive indicator for heart failure has established rising attention [7]. Binding of IL-33 to sST2 inhibits the useful and defensive properties of IL-33 on the heart. The beginning of the IL-33/transmembrane isoform of the ST2 signaling pathway is also known in other conditions such as inflammation. Exogenous hazard signals such as bacteria and endotoxins motivate inflammatory cytokine excretion, improve sST2 creation and therefore weaken immune responses in the organism [7].

IL 27 is formed by antigen-presenting cells open to inflammatory inducements and other settings. IL-27 encourages the production of naive CD4+ T cells and causes both pro-inflammatory and anti-inflammatory responses and according to some authors, it could be the representative biomarker for sepsis [1,8].

A family of β-galactoside-binding lectins with ≥1 evolutionary preserved carbohydrate-recognition domain is known as galectins. Galectin-3 is extensively expressed in human tissues, as well as in all immune cells (macrophages, monocytes, dendritic cells, eosinophils, mast cells, natural killer cells, and activated T and B cells), epithelial and endothelial cells as well as in sensory neurons [9,10]. Jevdjic et al. suggested galectin-3 as a novel biomarker for sepsis [11].

According to serious cellular and metabolic abnormalities in sepsis, numerous biomarkers if acted together may represent an objective guide for the prognosis of patients with severe sepsis as well as in patients with trauma. According to the literature, there is no information about the prognostic values of IL-33, sST2, IL-27, and galectin 3 in critically-ill patients. Therefore, we wanted to explore the prognostic values of IL-33, sST2, IL-27, and galectin-3 in these patients. We assumed that these parameters in combination or alone could predict mortality in ICU patients.

2 Methods

This research represents a clinical non-randomized prospective study, performed at the Medical Military Academy, tertiary care hospital in Belgrade, Serbia in the period from January 2021 until March 2022. The study was approved by the Ethical Committee of Medical Military Academy. Informed consent was obtained from the patient or first-degree relative. Patients hospitalized in ICUs were included in the study.

Inclusion criteria were (1) adults patients, both male and female, (2) patients with a diagnosis of acute pancreatitis, peritonitis, or trauma, (3) patients with sepsis (two criteria of the systemic inflammatory response plus the above-mentioned diagnosis), (4) patients with injury severity score (ISS) above 10, and (5) critical patients with Acute Physiology and Chronic Health Evaluation score (APACHE II) above 15. Exclusion criteria were (1) secondary sepsis and/or septic shock with an underlying illness other than severe peritonitis, pancreatitis, or trauma, (2) pre-existing immunodeficiency, (3) long-term SICU stay before norms fulfilment, and (4) malignant disease of any source. Patients were divided in four groups according to the reason for admission: patients with sepsis (peritonitis, pancreatitis, trauma) and patients without sepsis (trauma).

The Sequential Organ Failure Assessment (SOFA) score, the Simplified Acute Physiology Score (SAPS) II, and the APACHE II score were considered and verified within the first 24 h after admittance to the ICU as well as blood sample of each patient for further examination. We examined the levels of IL-33, sST2, IL-27, and galectin-3. We also examined each blood sample for hemoculture.

A blood sample was obtained from each patient within 24 h after admission from the arterial or central venous line. Approximately 8 mL of blood was drained into a serum centrifuge tube and centrifuged at 4°C at 2,500 rpm for 15 min in order to separate blood elements and serum. Then, a sample of blood serum was collected for each patient and stored at −70°C for future examination.

Levels of IL-33 were measured using the Human IL-33 DuoSet® ELISA (R & D Systems, Minneapolis, MN, USA) according to the producer’s instructions (sensitivity 1.65 pg/mL) [6]. Levels of sST2 were measured by the Presage ST2 Assay (Critical Diagnostic, San Diego, CA, USA). The mouse monoclonal anti-human sST2 antibodies in combination with enzyme-linked immunosorbent assay was used to evaluate sST2 levels [12]. IL-27 was measured by an enzyme immune assay (Human IL-27 ELISA, Kit: Duo Set [R&D]) according to the manufacturer’s instructions [13]. The concentration of galectin-3 was determined using the Quantikine Human Galectin-3 Immunoassay ELISA test (R&D Systems Europe Ltd, UK) [11].

The basic subdivision of patients was done according to the outcome (survival and non-survival). One of the important hypotheses was based on the correlation between outcome and serum galectin-3 (soluble β-galactosidase-binding lectin) level. A preliminary analysis was done and the expected minimal difference in galectin-3 mean values between survivors and non-survivors was estimated to be 80%. [11]. The calculated number of patients was at least 128 (total sample size) according to the test power of 0.8 (80%) and the alpha probability of 0.05. Due to high values of standard deviations (SDs) and two-independent groups, the Wilcoxon test model was used (statistical software package GPower 3.1).

Complete statistical analysis of data was done with the statistical software package, SPSS Statistics 18. Most of the variables were presented as the frequency of certain categories, while the statistical significance of differences was tested with the Chi-square test.

In the case of continuous data, variables were presented as mean value ± SD or median if the distribution of the data was not normal. The Kolmogorov–Smirnov test was used for the evaluation of the distribution of data. Statistical significance between the groups was tested by Kruskal–Wallis or Mann–Whitney test. Spearman correlation analyses were used to establish the relation between parameters.

Receiver operating characteristic (ROC) curves were constructed to determine the sensitivity and specificity of mediators for the prediction of outcome, diagnosis, and infection. The Youden’s index, is the difference between the true positive rate and the false positive rate, was used.

Maximizing this Youden’s index allowed us to determine an optimal cut-off point from the ROC curve independently. All the analyses were estimated at p < 0.05 level of statistical significance.

3 Results

Total number of patients enrolled in the study was 151 and average years of patients were 56.48. All demographic characteristics of the patients as well as median serum concentration of IL-33, sST2, IL-27, and galectin-3 are shown in Table 1. According to the reason for the hospitalization there were 131 patients with sepsis (76 patients with peritonitis, 22 patients with pancreatitis, and 23 trauma patients) and 30 patients without sepsis. Hospital mortality was 49.7% and it was higher in female patients (66.7%).

Table 1

Characteristics of the patients included in the study

Variable All patients (N = 151)
Age (average, range) 56.48 (17–91)
Sex, n (%)
Male 97 (64.2%)
Female 54 (35.8%)
SAPS II score, mean ± SD 52.45 ± 7.24
APACHE II score, mean ± SD 22.69 ± 3.98
SOFA score, mean ± SD 7.45 ± 2.54
Length of ICU stay, mean ± SD, range (days) 14 ± 10 (2–168)
Length of hospital stay, mean ± SD, range (days) 62 ± 28 (2–338)
Reason for ICU admission, n (%)
Sepsis due to
 Peritonitis 76 (50.3%)
 Pancreatitis 22 (14.6%)
 Severe trauma 23 (15.2%)
Severe trauma (ISS 26.43 ± 8.56) 30 (19.9%)

The results of our research showed that the values of IL-33 were significantly higher in the group of patients with sepsis caused by peritonitis, pancreatitis, and trauma compared to the control population of patients who had only trauma (p < 0.05, Figure 1). The values of sST2 were significantly higher in the group of patients with sepsis caused by peritonitis and pancreatitis compared to the control population of patients who had only trauma, while the values of IL-27 were significantly increased in the group of patients with sepsis caused by peritonitis compared to the control population of patients who had only trauma (p < 0.05, Figure 1). The values of galectin-3 were significantly increased in the group of patients with sepsis caused by peritonitis and pancreatitis compared to the control population of patients who had only trauma (p < 0.05, Figure 1).

Figure 1 
               Average values of IL-33, sST2, IL-27, and galectin-3 in the serum of the patients admitted to ICU with sepsis caused by peritonitis (per), pancreatitis (panc), trauma (T + S), or with trauma without sepsis (T). The results are presented as medians, *p < 0.05 in comparison to the group of patients with trauma.
Figure 1

Average values of IL-33, sST2, IL-27, and galectin-3 in the serum of the patients admitted to ICU with sepsis caused by peritonitis (per), pancreatitis (panc), trauma (T + S), or with trauma without sepsis (T). The results are presented as medians, *p < 0.05 in comparison to the group of patients with trauma.

Patients who had sepsis caused by peritonitis, pancreatitis, or trauma had a significantly decreased survival rate compared to the control group of patients who had only trauma (p < 0.05, Figure 2). Patients who had peritonitis diagnosed, had a 3.4-fold increased occurrence of death, compared to trauma patients. Similarly, patients who had pancreatitis diagnosed had a 2.2-fold increased occurrence of death, compared to trauma patients.

Figure 2 
               Survival rate of the patients admitted to ICU with sepsis caused by peritonitis (per), pancreatitis (panc), trauma (T + S), or with trauma without sepsis (T). The results are presented as relative values.
Figure 2

Survival rate of the patients admitted to ICU with sepsis caused by peritonitis (per), pancreatitis (panc), trauma (T + S), or with trauma without sepsis (T). The results are presented as relative values.

After that, we determined the average values of the examined parameters (IL-33, sST2, IL-27, and galectin-3) in the group of patients who had a satisfactory outcome, i.e., who survived, and we compared the values of these parameters to the values of the same parameters in the group of deceased patients. The results showed that the values of IL-33, IL-27, and galectin-3 were significantly increased in the group of deceased patients compared to the values of IL-33, IL-27, and galectin-3 of surviving patients (p < 0.05, Figure 3). There was no statistically significant difference between the values of sST2 in surviving patients compared to the values of sST2 in deceased patients (p > 0.05, Figure 3). All biomarkers but sST2 were good predictors of outcome.

Figure 3 
               Average values of IL-33, sST2, IL-27, and galectin-3 in the serum of the survived and deceased patients. The results are presented as medians (for IL-33, IL-27, and galectin-3) or mean ± SD (sST2). *p < 0.05 between groups.
Figure 3

Average values of IL-33, sST2, IL-27, and galectin-3 in the serum of the survived and deceased patients. The results are presented as medians (for IL-33, IL-27, and galectin-3) or mean ± SD (sST2). *p < 0.05 between groups.

Afterward, we calculated cut-off values for each examined biomarker (IL-33, sST2, IL-27, and galectin-3). Values greater than the cut-off were the predictors of mortality. The cut-off values for IL-33, sST2, IL-27, and galectin-3 were 30.5, 599.0, 42.47, and 258.93, respectively. The cut-off values for each biomarker, Youden index, sensitivity, and specificity are presented in Table 2.

Table 2

Cut-off values for IL-33, sST2, IL-27, and galectin-3 as predictors of mortality

Cut-off (ng/mL) Youden index Sensitivity (%) Specificity (%)
IL-33 30.5 0.26 63.8 62.2
sST2 599.0 0.158 29.3 86.5
IL-27 42.47 0.168 77.6 39.2
Galectin-3 258.93 0.203 50 70.3

The biomarker with the best sensitivity and specificity as predictor of mortality was IL-33. The next step of our research was to estimate if values above the cut-off for two or more parameters could improve the prediction for outcomes in patients admitted to ICUs. So, in order to increase the overall sensitivity and specificity of these biomarkers combined, we determined their composite score. For a composite score of 1.5, the calculated sensitivity was 76%, specificity was 54%, and Youden index was 0.3. The results showed that two of the tested cytokines (IL-33, sST2, IL-27, and galectin-3) must have values above the cut-off to achieve a statistically highly significant predictive estimate of the outcome for the patients admited in the ICUs (Figure 4).

Figure 4 
               ROC curve of the prediction of mortality for composite scores of IL-33, sST2, IL-27, and galectine-3.
Figure 4

ROC curve of the prediction of mortality for composite scores of IL-33, sST2, IL-27, and galectine-3.

4 Discussion

Our study included 151 ICU patients with male predomination (97 vs 54). The average length of treatment in the ICU was 14 ± 10 days with an average length of hospital stay of 62 ± 28 days. Most of the patients had sepsis due to peritonitis (n = 76). Number of Patients hospitalized because of trauma were 30. Of From the tested biomarkers, IL-33, IL-27, and galectin-3 were a good predictors of outcome. A combination of at least two biomarkers gave the best results in predicting the outcome with the calculated sensitivity 76%, specificity 54%, and Youden index 0.3.

The domination of male patients is following the results of other studies [14,15]. It was concluded that there was a higher morbidity and mortality rate from sepsis in men, and this seems to be associated with differences in respiratory tract infection frequency and IL-6 plasma levels, among the genders [16]. SAPS II score in our study was at an average of 52.45. The SAPS II helps to calculate in-hospital mortality, thanks to the gathering of 17 variables at ICU admission, without considering the aim for admission [17]. APACHE II score has a mean value of 22.69 which is following other research, for the patients admitted in the ICU [18]. SOFA score in our study had a mean value of 7.45. The SOFA value over 72 h has an important confident connection to in-hospital mortality [19].

According to our results IL-33 represented significant predictors for the outcome in critically-ill patients. sST2 had limited prognostic value for the overall outcome as a single prognostic factor. Moreover, IL-27 as well as galectin-3 were also significant predictors for the outcome in critically-ill patients.

IL 33 showed solid sensitivity (63.8) and specificity (62.2). Our results were opposite to the results of other studies because they suggested that IL-33 values were decreased in patients who died from sepsis in comparison to patients who survived [20,21]. Also, according to our results, sST2 was not a significant predictor of outcome in ICU patients. sST2 behaves as a trap for IL-33, so since in our study, it did not prove to be significant, we can explain why increased IL-33 can be a predictor of mortality according to our results. In our population, 30 patients with trauma were included, and IL-33 levels tend to increase following trauma. Therefore, this may be another reason for such difference in the results of our study in comparison to previously published results [22].

For IL-27 values greater than 42.47 ng/mL on the first day of hospitalization, can predict mortality in ICUs patients. The sensitivity of this claim was 77.6 and the specificity was 39.2.

Wang et al. showed that in the meta-analysis, the sensitivity was about 0.84 and the specificity was about 0.71, demonstrating a satisfactory overall diagnostic accuracy of IL 27 [1].

Galectin-3 value greater than 258.93 ng/mL on the first day of hospitalization, was a good predictor of mortality which is in accordance with the results of other studies [5,11,23]. The sensitivity of this analysis was 50 and the specificity was 70.3. It was determined that galectin-3 acts as alarmin and exhibits immune-triggering properties such as motivation of oxidative burst in neutrophils and inflammatory cytokine construction in macrophages. According to Mishra et al., galectin-3 plays a pathogenic character as an alarmin to worsen the inflammatory reaction through pulmonary infection with some bacteria and contributes to the progress of sepsis [24].

Combination of at least two biomarkers gave the best results in predicting the outcome of ICU patients. Values higher than the cut-off, including sST2, can predict death in critically-ill patients.

The limitation of our study was the relatively small number of patients; therefore, it remains a task for future studies to further examine our claims on a larger number of patients.

The conclusion of our study was that IL-33, IL-27, as well as galectin-3 can successfully predict the outcome of critically-ill patients in ICUs. sST2, cannot predict death in critically-ill patients as a single prognostic factor. However, the combination of at least two biomarkers: IL-33, sST2, IL-27, and galectin-3, gives very significant results in predicting the outcome in patients admitted to ICUs.

  1. Funding information: Authors state no funding involved.

  2. Conflict of interest: Authors state no conflict of interest.

  3. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2023-07-01
Revised: 2023-10-15
Accepted: 2023-10-30
Published Online: 2023-12-21

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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