Home Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
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Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid

  • Chuntian Hong , Yonghao Yan , Liyang Su , Debo Chen and Changqing Zhang EMAIL logo
Published/Copyright: March 31, 2022

Abstract

Many breast cancer patients have both non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty pancreas disease (NAFPD). Consequently, we hypothesized that NAFPD and NAFLD were associated with breast cancer, and aimed to build a novel risk-stratification scoring system based on it. In this study, a total of 961 patients with breast cancer and 1,006 non-cancer patients were recruited. The clinical characteristics were collected and analyzed using logistic analysis. Risk factors were assessed by a risk rating system. Univariate analysis showed that body mass index, triglyceride, total cholesterol, NAFLD, NAFPD, low-density lipoprotein, and uric acid (UA) were significantly related to breast cancer. Among them, NAFLD, NAFPD, and UA were independent risk factors related to breast cancer identified by multivariate analysis. The risk assessment model was established based on these factors and demonstrated that the odds ratio sharply increased with the rising scores. Compared with the low-risk group, the odds ratio in the intermediate- and high-risk groups were 1.662 (1.380–2.001) and 3.185 (2.145–4.728), respectively. In conclusion, the risk-stratification scoring system combining NAFLD, NAFPD, and UA can accurately predict the occurrence of breast cancer.

1 Introduction

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women, with approximately 2.1 million new cases and an estimated 0.6 million deaths reported in 2018 [1]. Breast cancer patients in early stages can be cured by local and systemic treatment using surgery and chemotherapy, while the prognosis of breast cancer patients in advanced stage was poor because of recurrence or distant metastasis [2]. Many risk factors for breast cancer have been reported, including genetics, diet, lifestyle, hormonal replacement therapy, alcohol consumption, obesity, and breastfeeding [3,4,5,6,7]. Currently, the growing proportion of obesity worldwide has led to a dramatic rise in patients with metabolic syndrome and even increased risk of certain malignancies, such as breast cancer. Therefore, many studies researched the relationship between breast cancer and metabolic abnormalities [3], and reported that metabolic syndrome was associated with breast cancer [8,9,10].

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, which is closely related to insulin resistance, metabolic syndrome, and abdominal obesity. In addition, more and more studies have shown that NAFLD is a multi-system disease with extrahepatic complications, such as cardiovascular disease, chronic kidney disease, pulmonary insufficiency, and extrahepatic malignancies [11,12]. Bilici et al. [13] found that hepatic steatosis was readily detected in patients of breast cancer, which might be associated with obesity. In addition, Akhondei and Gudbrandsen [14,15] reported that breast cancer patients treated with tamoxifen might produce fatty change in the liver. On the one hand, NAFLD may be an important risk factor for the incidence or treatment effect of breast cancer, while on the other hand, long-term tamoxifen therapy may increase the risk of NAFLD that may result in the patient experiencing uncertainty regarding long-term treatment [16], suggesting that there may be a pathogenesis link between NAFLD and breast cancer.

Non-alcoholic fatty pancreas disease (NAFPD) is also an important manifestation of metabolic syndrome [17]. Pancreatic steatosis was first put forward in 1933 by Oligvie, who reported the incidence of pancreatic fat storage was higher in obese individuals than in the lean ones (17% vs 9%) [18]. After this study, Van Geenen et al. [19] suggested that pancreatic steatosis preceded NAFLD and proposed that the term NAFPD should be used. Milovanovic et al. [17] reported strong correlation between NAFLD and NAFPD, and it is likely that fatty pancreas might be one of the first manifestation of metabolic syndrome. In clinical practice, we found many preoperative patients of breast cancer had both NAFLD and NAFPD. Consequently, we hypothesized that NAFPD was associated with breast cancer, which was similar to NAFLD.

Therefore, in this study, we explored the risk factors for breast cancer and the relationship between breast cancer and NAFLD/NAFPD, and developed a novel risk-stratification scoring system based on the independent risk factors to predict the incidence of breast cancer.

2 Material and methods

2.1 Study population

This retrospective study was approved by the Ethics Committee of Quanzhou First Hospital Affiliated to Fujian Medical University. Written informed consent was not applicable due to retrospective nature of the study.

A total of 961 patients with breast cancer in Quanzhou First Hospital Affiliated to Fujian Medical University from May 2017 to August 2019 were recruited. Exclusion criteria included: (1) drinking > 20 g/day; (2) patients had serious illness at the time of examination, such as cardiovascular disease, malignancies other than breast cancer, etc.; (3) patients with hepatitis A, hepatitis B, and autoimmune hepatitis; (4) history of surgery or chemotherapy. Besides, 1,006 non-breast cancer subjects were included in this study. Exclusion criteria included: (1) drinking > 20 g/day; (2) patients with hepatitis A, hepatitis B, and autoimmune hepatitis; (3) patients with pancreatitis and chronic kidney disease; (4) patients with metabolic disorders caused by drug treatment in the past year. All patients with breast cancer in the study were preoperatively diagnosed by upper endoscopy and preoperatively staged with barium radiography, computed tomography (CT), or endoscopic ultrasonography. All non-breast cancer subjects were confirmed non-breast cancer by the breast ultrasound examination, and some also underwent mammography. Hepatitis A was diagnosed by detection of immunoglobulin M (IgM) antibodies against HAV using colloidal gold strip [20]. Hepatitis B was diagnosed by detection of anti-HBc, anti-HBs, and anti-HBe antibodies using Enzyme-linked immunosorbent assay (ELISA) [21]. Autoimmune hepatitis was diagnosed by detection of serum aspartate transaminase, alanine transaminase, γ- glutamyl transferase, and γ-globulins (mainly IgG) [22]. Demographics of all participants were recorded, including age, height, weight, systolic blood pressure, and diastolic blood pressure.

2.2 Laboratory inspection

After fasting overnight (fasting for more than 8 h), all subjects underwent laboratory tests measured by automatic biochemical analyzer (DXC800, Beckman Coulter, USA), consisting of triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), uric acid (UA), alanine aminotransferase (ALT), and glutamic oxaloacetic transaminase (GOT).

2.3 Diagnosis of NAFLD and NAFPD

All subjects were at least 12 h on an empty stomach and in supine position during examination. The ultrasound examinations were performed by a qualified and experienced radiologist using a high-resolution ultrasound machine equipped with a 5 MHz convex-array probe (Philips iU Elite; Bothell, Washington). The data were evaluated by another experienced radiologist to ensure unbiased evaluation.

NAFLD was diagnosed as the presence of at least two of the following findings (excluding excessive alcohol consumption and viral or autoimmune liver disease): diffusely increased echogenitic (“bright”) liver with liver echogenicity greater than kidney or spleen, vascular blurring, and deep attenuation of ultrasound signal [23].

The diagnosis of NAFPD was based on the previous literature criteria [24]: Pancreatic echogenicity was compared to the liver echogenicity at the same depth on a longitudinal scan taken near the abdominal midline, or compared to the echogenicity of renal cortex if the liver also showed increased echogenicity. NAFPD was diagnosed if an increased echogenicity of pancreatic body over the kidney or liver echogenicity was observed during ultrasonography.

2.4 Statistical analysis

Data were analyzed by SPSS version 18.0 (SPSS Inc, Chicago, IL, USA). Continuous data were expressed as mean values ± SD and analyzed by unpaired two-tailed Student’s t-test. Categorical variables were presented as counts (percentages) and analyzed with χ 2 test. Univariate and multivariate logistic regression analysis were performed to assess the risk factors of breast cancer, and the odds ratio (OR) and 95% confidence interval (95% CI) were calculated. Variables with a value of P < 0.05 in the univariate analysis were subsequently included in a multivariate logistic regression analysis. The risk scoring system was used to evaluate the associations between risk predictors and breast cancer incidence. P values <0.05 were considered statistically significant.

  1. Ethics approval: This retrospective study was approved by the Ethics Committee of Quanzhou First Hospital Affiliated to Fujian Medical University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

3 Results

3.1 Demographic and clinical characteristics

The demographic and clinical characteristics of subjects are summarized in Table 1. There were significant differences in body mass index (BMI), systolic blood pressure, ALT, TC, UA, NAFLD history, and NAFPD history between breast cancer and non-breast cancer groups (P < 0.05), while no significant differences were observed between the two groups in terms of age, diastolic blood pressure, GOT, TG, HDL, and LDL.

Table 1

General characteristics of patients with or without breast cancer

Characteristics Breast cancer (N = 961) No breast cancer (N = 1,006) P
Age (years) 50.0 ± 10.9 50.6 ± 10.9 0.220
BMI (kg/m2) 23.7 ± 2.9 22.7 ± 2.3 <0.001
Systolic blood pressure (mmHg) 130.7 ± 18.5 127.2 ± 15.3 <0.001
Diastolic blood pressure (mmHg) 81.4 ± 10.6 79.4 ± 9.5 0.146
ALT (U/L) 21.0 ± 14.8 22.4 ± 6.7 0.004
GOT(U/L) 23.3 ± 11.6 22.8 ± 5.1 0.315
TG (mmol/L) 1.33 ± 0.86 1.26 ± 0.70 0.074
TC (mmol/L) 5.45 ± 1.06 5.32 ± 0.98 0.007
HDL (mmol/L) 1.40 ± 0.31 1.41 ± 0.32 0.609
LDL (mmol/L) 3.48 ± 0.90 3.33 ± 0.82 0.248
UA (mmol/L) 306.5 ± 78.3 295.8 ± 61.2 0.001
History of NAFLD, n (%) 255 (26.5) 172 (17.1) <0.001
History of NAFPD, n (%) 572 (59.5) 467 (46.4) <0.001

Abbreviations: BMI, body mass index; ALT, alanine aminotransferase; GOT, glutamic oxaloacetic transaminase; TG, triglyceride; TC, total cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; UA, uric acid; NAFLD, non-alcoholic fatty liver disease; NAFPD, non-alcoholic fatty pancreas disease.

3.2 Risk factors associated with breast cancer

Since NAFLD could lead to abnormalities in liver function indicators, such as ALT and GOT, these two indicators were excluded from the logistic analysis to prevent repeated effects of NAFLD. Then, univariate analysis showed that BMI, TG, TC, LDL, UA, NAFLD, and NAFPD were significantly related to breast cancer (P < 0.05), while there were no significant association between breast cancer and the clinical characteristics including age, systolic blood pressure, diastolic blood pressure, and HDL (P > 0.05; Table 2). After removing mixed factors, multivariate analysis further revealed that NAFLD, NAFPD, and UA were independent risk factors related to breast cancer (P < 0.05; Table 3).

Table 2

Univariate analysis of factors associated with breast cancer

Characteristics Odds ratio (95% CI) P
Age 0.720
 <65 Reference
 ≥65 0.947 (0.701–1.278)
BMI 0.002
 <28 Reference
 ≥28 1.710 (1.208–2.420)
Systolic blood pressure 0.066
 <140 Reference
 ≥140 1.207 (0.987–1.475)
Diastolic blood pressure 0.862
 <90 Reference
 ≥90 0.979 (0.769–1.246)
TG
 Normal (<1.17 mmol/L) Reference
 Low abnormal (1.17–2.25 mmol/L) 1.389 (1.018–1.896) 0.038
 High abnormal (>2.25 mmol/L) 1.582 (1.069–2.341) 0.022
TC
 Normal (<5.18 mmol/L) Reference
 Low abnormal (5.18–6.19 mmol/L) 1.428 (1.126–1.811) 0.003
 High abnormal (>6.19 mmol/L) 1.340 (1.046–1.717) 0.021
HDL 0.867
 Normal (≥1.04 mmol/L) Reference
 Abnormal (<1.04 mmol/L) 0.985 (0.825–1.176)
LDL
 Normal (<3.37 mmol/L) Reference
 Low abnormal (3.37–4.12 mmol/L) 1.463 (1.163–1.839) 0.001
 High abnormal (>4.12 mmol/L) 1.082 (0.834–1.402) 0.554
UA <0.001
 Normal (≤420 µmol/L) Reference
 Abnormal (>420 µmol/L) 2.778 (1.815–4.254)
NAFLD <0.001
 No Reference
 Yes 1.751 (1.409–2.178)
NAFPD <0.001
 No Reference
 Yes 1.697 (1.419–2.029)

Abbreviations: BMI, body mass index; TG, triglyceride; TC, total cholesterol; HDL, high-density lipoprotein; LDL, low-density lipoprotein; UA, uric acid; NAFLD, non-alcoholic fatty liver disease; NAFPD, non-alcoholic fatty pancreas disease.

Table 3

Multivariate analysis of factors associated with breast cancer

Characteristics Odds ratio (95% CI) P Score
BMI 0.212
 Normal Reference
 Abnormal 1.264 (0.875–1.826)
TG
 Normal Reference
 Low abnormal 0.915 (0.648–1.291) 0.616
 High abnormal 1.438 (0.959–2.157) 0.079
TC
 Normal Reference
 Low abnormal 0.882 (0.555–1.400) 0.593
 High abnormal 1.128 (0.772–1.649) 0.533
LDL
 Normal Reference
 Low abnormal 1.267 (0.815–1.972) 0.293
 High abnormal 0.935 (0.641–1.363) 0.727
UA <0.001
 Normal Reference 0
 Abnormal 2.228 (1.435–3.459) 1
NAFLD 0.022
 No Reference 0
 Yes 1.369 (1.047–1.791) 1
NAFPD 0.001
 No Reference 0
 Yes 1.445 (1.163–1.795) 1

3.3 Risk-stratification scoring system in assessment on incidence of breast cancer

To estimate the risk of breast cancer occurrence, a scoring system was constructed based on the above independent predictors comprising NAFLD (no, 0 point; yes, 1 point), NAFPD (no, 0 point; yes, 1 point), and UA (normal, 0 point; abnormal, 1 point) (Table 3). In accordance with this scoring system, the patients were divided into low-risk (without a single independent predictor), intermediate-risk (1–2 independent predictors), and high-risk (3 independent predictors) groups. Compared with the low-risk group, the OR values in intermediate- and high-risk groups were sharply increased, indicating the extremely higher risk of breast cancer incidence (Table 4).

Table 4

Risk-stratification scoring system of breast cancer

Characteristics Score N (%) Odds ratio (95% CI) P
Low risk 0 824 (41.9) Reference
Intermediate risk 1–2 1,013 (51.4) 1.662 (1.380–2.001) <0.001
High risk 3 130 (6.7) 3.185 (2.145–4.728) <0.001

4 Discussion

Early diagnosis and accurate treatment are essential for breast cancer. Currently, several predictive risk models of breast cancer were established, but none of the research included NAFPD and NAFLD [25,26]. To the best of our knowledge, this was the first study to develop a risk-stratification scoring system based on NAFPD and NAFLD to predict the occurrence of breast cancer.

NAFPD is a phenotype of pancreatic steatosis, defined as the pancreatic fatty accumulation associated with obesity and metabolic syndrome [27,28], and is closely related to insulin resistance, obesity, NAFLD, type 2 diabetes, and metabolic syndrome [29]. Obesity and metabolic syndrome have been recognized as risk factors for NAFPD. Studies have demonstrated that chronic exposure of β-cells to hyperglycemia and high free fatty acids can promote increased intracellular triglyceride accumulation, resulting in decreased insulin secretion, insulin resistance, and subsequent fat replacement, thereby contributing to the development of metabolic syndrome and pancreatic fat accumulation [27,29]. Furthermore, the pancreatic fat accumulation may trigger β-cell degeneration and further accumulation of pancreatic fat, creating a vicious cycle [27]. Similar to NAFPD, increased breast cancer risk has also been reported to be associated with metabolic syndrome and its components, including obesity, diabetes, hypertension, and dyslipidemia [30]. Metabolic syndrome-induced metabolic abnormalities in breast cancer patients not only increase disease risk and tumor progression but also lead to adverse treatment responses and more treatment side effects [30]. In addition, obesity induced elevation of estrogen levels in the body is thought to be one of the mechanisms associated with breast cancer [30]. Adipose tissue is the main source of estrogen, and NAFPD is a marker of localized fat accumulation [27]. Therefore, we suspected that NAFPD might be related to breast cancer. The result in this study showed that the proportion of NAFPD in the breast cancer group was 59.5%, which was significantly higher than 46.4% in the group of no breast cancer (P < 0.001). Besides, the univariate and multivariate analysis further revealed that NAFPD was an independent risk factor related to breast cancer.

In recent years, the relationship between NAFLD and breast cancer has become a research hotspot. some studies reported that breast cancer was a common extrahepatic complication of NAFLD [31]. At the same time, studies also showed that endocrine therapy for breast cancer could increase the risk of NAFLD [32], suggesting that breast cancer may be related to the occurrence and development of NAFLD. The results of a case-control study by Nseir et al. [3] showed that NAFLD was associated with breast cancer, while the sample size (73 cases) included in this study was small. Another cohort study also showed an association between NAFLD and the incidence of breast cancer [33]. However, the focus of this study is on the incidence of general cancer (including breast cancer). Therefore, conventional risk factors of breast cancer such as menstrual status and age at menarche was not adjusted in the model, which might affect the accuracy of the conclusion. In this study, we analyzed the clinical data of 961 breast cancer patients and 1,006 non-breast cancer patients. The results were consistent with the abovementioned studies, confirming that NAFLD could be regarded as an independent risk factor for breast cancer.

In addition to NAFLD and NAFPD, we also found that UA was an independent risk factor for breast cancer, which was consistent with other study [34]. Yue et al. [34] suggested that high UA concentration could predict poor survival in breast cancer patients, and might serve as a potential marker for appropriate management of breast cancer patients. Therefore, in this study, we constructed a risk-stratification scoring system incorporating three predictors including NAFLD, NAFPD, and UA, by the method described by Sullivan et al. [35]. According to the scoring system, risk for breast cancer was categorized as low (0 point), moderate (1–2 points), or high (3 points). Compared with the low-risk group, the OR in intermediate- and high-risk groups were 1.662 (1.380–2.001) and 3.185 (2.145–4.728), respectively, which were significant, indicating that the scoring system could predict breast cancer risk well. Besides, the diagnosis of NAFLD or NAFPD, and the UA examination were noninvasive and convenient, which provides an easy tool for clinicians to evaluate the risk of breast cancer.

This study had some limitations which should be considered. First, this study was a retrospective analysis, which still need more data for validation. Second, this was a single-center study, and whether the models are applicable to other patient sets need further external validation. Besides, we did not evaluate known risk factors in this study such as family history of breast cancer, diabetes, breast feeding, smoking, hormone replacement therapy, and history of benign breast disease (such as atypical hyperplasia). Then, since biopsy is not clinical recommended for routine examination (except for pathological diagnosis), imaging techniques were used to diagnose NAFLD in this study, although liver biopsy is usually the reference standard for NAFLD diagnosis and staging. Finally, we analyzed only the preoperative clinicopathological data of the patients. In the future research, we should include postoperative data for analysis to better reflect the practical value of this model.

5 Conclusion

NAFLD, NAFPD, and UA were independent risk factors related to breast cancer. The risk-stratification scoring system combining NAFLD, NAFPD, and UA could accurately predict the incidence of breast cancer, which may help clinicians make clinical decisions.

Acknowledgements

We wish to express our appreciation to Quanzhou Science and Technology Bureau for funding this work. We also express our appreciation to the patients who participated in this study.

  1. Funding information: This study was supported by science and technology plan project of Quanzhou (2018Z062).

  2. Author contributions: Chuntian HONG, Debo CHEN and Changqing ZHANG designed the study. Chuntian HONG, Yonghao YAN and Liyang SU performed the experiments. Chuntian HONG performed the analysis and wrote the manuscript. Chuntian HONG and Debo CHEN critically reviewed the manuscript.

  3. Conflict of interest: The authors declare no competing financial interests.

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

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Received: 2021-07-22
Revised: 2022-02-15
Accepted: 2022-02-22
Published Online: 2022-03-31

© 2022 Chuntian Hong et al., published by De Gruyter

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

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  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
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