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The risk of cancer among insulin glargine users in Lithuania: A retrospective population-based study

  • Justinas Jonusas EMAIL logo , Mingailė Drevinskaitė , Donata Linkeviciute-Ulinskiene , Adomas Ladukas , Aušvydas Patašius , Lina Zabulienė and Giedrė Smailytė
Published/Copyright: October 15, 2024

Abstract

Objectives

The aim of this study was to determine the association between insulin glargine usage and the potential increase in cancer risk among the Lithuanian population diagnosed with type 2 diabetes mellitus (T2DM).

Methods

A retrospective cohort study was conducted. The cohort of insulin users was established by identifying all male and female patients diagnosed with T2DM, as recorded in the National Health Insurance Fund database between 1 January 2000 and 31 December 2012. The risk of cancer among insulin glargine users was compared with the risk in non-glargine insulin users. Cox proportional hazard models were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI).

Results

The overall cancer risk for all sites combined showed no significant difference (HR 0.84, 95% CI 0.67–1.05). Although a general decrease in the risk of cancers was observed at most sites for glargine users, the use of insulin glargine was associated with a non-significant increase in the risk of mouth and pharynx, stomach, non-melanoma skin, breast, cervical, ovarian, and central nervous system cancers. There was a tendency for a lower risk of colon, rectum, rectosigmoid, and anus cancer among glargine users (HR 0.45, 95% CI 0.18–1.12, p = 0.09).

Conclusions

Our research contributes to the growing body of evidence showing that insulin glargine is not associated with an increased risk of all cancers or specific types of cancer.

1 Introduction

Over the past 30 years, the prevalence of diabetes mellitus (DM) increased from 4.3 (95% CI 2.4–7.0) to 9.0% (95% CI 7.2–11.1), making it one of the most common diseases worldwide [1]. A recent study reported that more than 90% of patients with DM are diagnosed with type 2 diabetes mellitus (T2DM) [2]. It is estimated that more than 6% of the global population is affected by T2DM, and the number is expected to increase in the coming decade [3]. Therefore, the potential association between DM and cancer could significantly impact the general population in the near future [4].

The umbrella review of existing meta-analyses by Tsilidis et al. showed that there is strong evidence for the significant increase in breast cancer, intrahepatic cholangiocarcinoma, colorectal, and endometrial cancer incidence rates among T2DM patients as well as an increased risk of cancer-related mortality [5]. An increased risk of site-specific cancers was found in a cohort of T2DM patients in Lithuania [6]. A study from China showed that individuals diagnosed with DM at age 51–60 years have a higher incidence and mortality from various site-specific cancers. This indicates that the age at diagnosis of T2DM, together with tobacco control, plays an important role in cancer treatment and could present an opportunity for cancer prevention [7]. Hyperinsulinemia, insulin resistance, obesity, and dyslipidemia play a causal role in linking DM to cancer and can significantly promote mutagenesis and carcinogenesis [8]. Elevated insulin secretion from the pancreas into the portal circulation can increase hepatic growth hormone-mediated synthesis of insulin-like receptors growth factor (IGF-1). Epidemiological studies found an association between high-normal levels of insulin, C-peptide, and IGF-1 with an increased risk of various cancers (such as breast, colon, and prostate) [911]. Hyperinsulinemia may promote cancer progression either by directly binding to the insulin receptor or indirectly by increasing blood insulin and IGF-1 levels and triggering insulin and IGF-1 signaling that activates the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin and mitogen-activated protein kinase pathways, which are crucial for cancer cell proliferation, survival, mobility, and drug resistance [12]. Additionally, in T2DM, metabolic dysfunction triggers a persistent low-grade chronic inflammation marked by an increased release of pro-inflammatory interleukins (ILs), particularly IL-6 and TNF-α, other cytokines (resistin), free fatty acids, C-reactive protein, and other markers of chronic inflammation. Hyperglycaemia and dyslipidemia can promote reactive oxygen species (ROS) production, damaging proteins and DNA with high levels of TNF-α and NF-kB, leading to the proliferation of malignant cells [10,13]. Panigrahi et al.’s investigation showed that diabetes increases DNA damage in breast cancer cells and reduces their ability to repair DNA damage and strand break recovery due to elevated ROS levels [14]. All these factors may increase cancer risk and create an environment conducive to cancer progression.

A discussion on the insulin–cancer relationship includes four consecutive studies arguing that insulin, in particular insulin glargine, used for DM treatment, is associated with an increased risk of cancer [1518]. A study by Colhoun et al. showed that the incidence of breast cancer was significantly higher in glargine-only users compared to non-glargine users (hazard ratio [HR] 3.65, 95% confidence intervals [CI] 1.05–12.68) [15]. Additionally, a cohort study of more than 127,000 patients with DM from Germany showed a dose–response relationship between glargine use and cancer risk compared to human insulin users [17]. Moreover, a study by Jonasson et al. showed that glargine use was only associated with a higher incidence rate of breast cancer compared to other types of insulin (HR 1.97, 95% CI 1.30–3.00) [18]. Currie et al. showed that all insulin-based therapies were associated with a higher risk of cancer compared to metformin monotherapy (HR 1.42, 95% CI 1.27–1.60). However, there was no significant association between cancer risk and glargine-only use [16].

On the other hand, these studies on insulin use and cancer risk have been criticized due to design flaws [19,20]. Therefore, the uncertainty persists, prompting the scientific community to investigate further. Accordingly, this study aimed to determine whether insulin glargine use is associated with the increase in cancer incidence rate among the Lithuanian population diagnosed with T2DM.

2 Materials and methods

2.1 Dataset

We used the National Health Insurance Fund (NHIF) database to identify DM patients. This database contains demographic data and entries on primary and secondary healthcare services, emergency and hospital admissions, and reimbursed medication prescriptions.

Cancer cases were identified by record linkage with the Lithuanian Cancer Registry, a nationwide population-based cancer registry that contains personal and demographic information, as well as information on the diagnosis of all people diagnosed with cancer in Lithuania since 1978.

2.2 Study design and population

A retrospective cohort study was conducted to examine the relationship between insulin and site-specific cancer risk. The cohort of insulin users was established by identifying all male and female patients who had a first recorded diagnosis of T2DM (International Classification of Diseases Australian modification, ICD-10-AM code E11) in the NHIF database from 1 January 2000 until 31 December 2012. To reduce the possibility of incorrect T2DM classification, patients aged 40 years or older were only included. Furthermore, to ensure that the study cohort included only non-incident insulin users, individuals had to have at least five insulin prescriptions to be included in the study.

To calculate the cancer incidence rate within the cohorts, T2DM records were connected to the Lithuanian National Cancer Registry using a personal identification number assigned to every Lithuanian citizen, using data until 31 December 2015. Participants with a primary cancer diagnosis before receiving insulin (1,573 individuals) or within 1 year after their initial insulin prescription (300 individuals) were excluded (Figure 1).

Figure 1 
                  Study flowchart.
Figure 1

Study flowchart.

The remaining cohort included insulin users who were followed for only 1 year after their initial insulin prescription. The cohort’s conclusion date was defined as either the date of death, emigration, or 31 December 2015, whichever occurred first.

2.3 Exposure

The different types of insulin prescribed for T2DM were classified into three categories according to the ATC code: insulin glargine (category 1), other insulin analogs (category 2), and human insulin (category 3). Therefore, we have classified patients into two groups: group 1 – insulin glargine-only users (insulin category 1) and group 2 – non-glargine insulin users (insulin categories 2 and 3).

2.4 Statistical analysis

Cox proportional hazard models were used to estimate HRs and their 95% CIs to compare the cancer risk of diabetic patients by insulin exposure (glargine vs non-glargine insulin users). In addition, multivariate-adjusted Cox proportional hazards model, including age and gender, were conducted to estimate the effect of insulin type on cancer risk.

All statistical analyses were performed using STATA 15 statistical software (StataCorp. 2020. Stata Statistical Software: Release 15.1. College Station, TX, USA).

  1. Ethical approval: All procedures 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. The study protocol was approved by the Vilnius Regional Biomedical Research Ethics Committee (No. 158200-17-913-423).

  2. Patient and public involvement statement: Patients or the public were not involved in our research’s design, conduct, reporting, or dissemination plans.

3 Results

Overall, 10,646 individuals (6,573 women and 4,073 men) were included in the study, with 67665.54 person-years of observation. Eight hundred ninety-four patients were treated with non-glargine insulin, while 9,752 individuals used insulin glargine. Insulin glargine users were younger than patients on other insulin types (58.65 vs 65.11 years, p < 0.05). Table 1 presents the detailed characteristics of the study population.

Table 1

Characteristics of the study population

All participants Glargine users Non-glargine users
T2DM patients, N (%) 10,646 (100) 894 (8.40) 9,752 (91.60)
Gender
  Male, N (%) 6,573 (61.74) 527 (58.95) 6,046 (62.00)
  Female, N (%) 4,073 (38.26) 367 (41.05) 3,706 (38.00)
Mean follow-up time, years (SD) 6.36 (2.85) 7.51 (2.48) 6.25 (2.86)
Mean age at the start of follow-up, years (SD) 64.57 (10.52) 58.65 (9.88) 65.11 (10.41)

N, number of patients; SD, standard deviation; T2DM, type 2 diabetes mellitus.

The risk of malignancies was assessed by comparing insulin glargine users with T2DM patients treated with other types of insulin (Table 2). There was no significant difference in risk for all cancer sites combined (HR 0.84, 95% CI 0.67–1.05). While there was a general decrease in cancer risk at most sites for glargine users, the use of insulin glargine was associated with a non-significantly increase in the risk of cancers of mouth and pharynx, stomach, non-melanoma skin, breast, cervical, ovarian, and central nervous system. Notably, there was a tendency for a reduced risk of colon, rectum, rectosigmoid, and anal cancer among the glargine users (HR 0.45, 95% CI 0.18–1.12, p = 0.09).

Table 2

Risk of malignancies in patients using insulin glargine compared to non-glargine users

Primary site ICD 10-AM Cancer cases HR (95% CI) p-value
All sites C00–C96 82 0.84 (0.67–1.05)* 0.13
Mouth and pharynx C00–C14 3 2.23 (0.60–8.26)* 0.23
Stomach C16 5 1.07 (0.43–2.71)* 0.88
Colon, rectum, rectosigmoid, anus C18–C21 5 0.45 (0.18–1.12)* 0.09
Liver C22 3 0.79 (0.24–2.58)* 0.69
Pancreas C25 3 0.68 (0.21–2.21)* 0.52
Trachea C34 3 0.45 (0.14–1.44)* 0.18
Melanoma C43 1 1.00 (0.12–8.05)* 0.99
Skin, non-melanoma C44 12 1.22 (0.66–2.23)* 0.53
Breast C50 9 1.09 (0.54–2.20)** 0.82
Cervix uteri C53 2 1.07 (0.24–4.77)** 0.93
Corpus uteri C54 7 0.87 (0.39–1.94)** 0.74
Ovary C56 4 1.60 (0.55–4.69)** 0.39
Prostate C61 14 0.97 (0.55–1.69)** 0.91
Kidney C64 2 0.37 (0.09–1.52)* 0.17
Urine bladder C67 1 0.46 (0.062–3.42)* 0.45
Central nervous system C70-C72 3 1.84 (0.52–6.48)* 0.34
Thyroid C73 2 0.92 (0.20–4.32)* 0.92
Hodgkin lymphoma, leukaemia, myeloma C82–C85, C90, C91–C95 2 0.75 (0.23–2.46) 0.64

ICD10-AM – International Classification of Diseases 10, Australian Modification; HR – hazard ratio; CI – confidence interval. *Adjusted for age and gender; **adjusted for age.

4 Discussion

The current study shows no significant difference in cancer risk between insulin glargine users and non-glargine users. While some cancer sites showed a higher risk for glargine users and others lower risk compared to non-glargine insulin users, these risk estimates were not statistically significant.

The debate on whether the insulin analog glargine increases the risk of cancer in T2DM patients stems from four epidemiological articles published in Diabetologia in 2009 [1518]. These articles were criticized for fundamental design flaws, including selection bias, questionable allocation to groups, and unconventional analytical methods [19]. Despite the critiques, these studies were the first efforts in their analysis of the potential effects of insulin glargine on cancer development and have set the way for subsequent research.

According to these publications, a cohort study by Wu et al., including more than 22,000 insulin-treated women with DM, reported 321 cases of breast cancer over a 12-year follow-up [21]. The study was performed using the United Kingdom’s Clinical Practice Research Datalink and showed an increased risk of breast cancer (HR 1.44, 95% CI 1.11–1.85) among insulin glargine users compared to the non-users of insulin glargine. Kostev et al. performed a similar study based on longitudinal data from a large UK database (IMS Disease Analyzer), including demographic information, diagnoses, therapies, and laboratory values, and argued against the likelihood of an actual increase in breast cancer risk with glargine use [22]. In this study, adjusted HRs for breast cancer were 0.92 (95% CI 0.56, 1.50) for LAIA users and 0.98 (95% CI 0.58, 0.65) for insulin glargine users compared to NPH users. A multicentric case–control study performed across 92 institutions in the UK, US, and Canada, including 775 women with DM diagnosed with breast cancer, found no significant risk difference between human insulin users and insulin glargine users (HR 1.29, 95% CI 0.78–2.13) [23]. Similarly, several recent retrospective cohort studies in the US and Europe [24,25], as well as experimental murine model data [26] and a large Taiwanese cohort study of almost 1 million T2DM patients, did not show an increased risk of breast cancer associated with insulin glargine. Our study did not observe an increase in the risk of breast cancer.

In addition, insulin glargine was not associated with a significant increase in the risk of thyroid cancer (HR 1.10, 95% CI 0.89–1.35), which is supported by results of in vitro studies showing a non-significant effect of insulin glargine on thyroid cell proliferation and tumor cell migration at low doses [27]. Subsequent cohort studies also showed no significant increase in cancer risk at other sites in T2DM patients taking insulin glargine [28,29]. Our findings are consistent with the existing evidence that insulin glargine does not increase cancer risk in T2DM patients.

Insulin and insulin-like growth factors are known to activate the mitogenic properties of cells by acting on insulin receptors [30]. In addition, insulin phosphorylates the substrates of these insulin receptors, which subsequently promote growth, proliferation, mobility, and migration [31]. Studies have shown that insulin glargine binds to insulin receptors with an affinity similar to human insulin but with a much higher affinity to insulin-like growth factor receptors [32]. This finding is supported by another study, showing that insulin glargine is more effective in activating insulin-like growth factor receptors [33]. Additionally, insulin-like growth factors have been shown to be strong mitogens in the pancreas, kidneys, prostate, breast, and other solid tumors [34,35]. It is, therefore, not surprising that the mitogenic potential of insulin glargine is almost eight times higher than that of human insulin [32]. However, insulin and IGF-1 receptor signaling is influenced by various factors, such as the duration of contact between ligand and receptor and the dissociation rate [36]. Moreover, insulin glargine is reported to be transformed by cleaving at the carboxy terminus of its B-chain, resulting in the formation of two metabolites, the potency of which in activating IGF-1 receptors is significantly reduced after the injection into the circulation or subcutaneously [37]. This could explain our data, which suggests that insulin glargine is not associated with an increased cancer risk.

Since 2011, the American Diabetes Association (ADA), in their Standards of Medical Care [38], included the review by Giovannucci et al. [39] on diabetes and cancer, pointing attention to the problem of diabetes and cancer risk. Therefore, since 2012, the ADA has recommended that patients with diabetes be encouraged to undergo age- and sex-specific appropriate cancer screenings, as recommended by their primary healthcare professional [40]. Later on, recommendations to reduce their modifiable risk factors for cancer (such as obesity, physical inactivity, and smoking) were added in 2024 [41]. ADA and the European Association for the Study of Diabetes (EASD) do not currently recommend against using insulin glargine. Although some observational studies raise concerns over the increased risk of cancer, the overall evidence does not justify a change in clinical practice for the use of insulin glargine. Both organizations stress that the benefits of good glycaemic control with insulin treatment, including insulin glargine, outweigh the potential risks [41,42]. The ADA, EASD, and the American Association of Clinical Endocrinology recommend continued monitoring and research in this area to ensure patient safety. This is due to endogenous hyperinsulinemia being a suggested factor for the link between cancer, obesity, and DM. Consequently, it is crucial to improve our understanding of how insulin therapy affects cancer risk and progression [43].

Although our study is a retrospective cohort study, it was carefully designed to include only patients who received both glargine and non-glargine insulin, with follow-up started 1 year after the first medication prescription. The strengths of our study include the long follow-up period and the comprehensive inclusion of the entire regional population with verified exposure. However, our study has several limitations. First of all, our study investigated the association between insulin glargine use and cancer risk. However, as an observational study, its findings should be interpreted with caution, as observational studies can identify correlations but are not designed to establish causality. Furthermore, the sample size of T2DM patients who were treated with insulin glargine alone was relatively small, and the study duration from 2000 to 2012 may not be sufficient to observe the potential long-term effects of insulin glargine on cancer risk. This limitation may affect our ability to detect cancers that develop later or comprehensively evaluate the long-term risks associated with insulin glargine use. Third, our focus was solely on the insulin analog glargine as the insulin analog detemir was not yet available in the market. In addition, the study also did not account for potential confounding factors such as lifestyle, dietary habits, body mass index, smoking, and comorbidities due to the retrospective study design. Lastly, our dataset lacks information on the doses of insulin glargine used by patients, which could be a significant factor in cancer risk as suggested by Hemkens et al. [17]. Due to this limitation, we could not analyze or discuss association of insulin dosage on cancer risk in our study. Future research should include larger populations, longer follow-up duration, insulin doses used by patients with DM, and analyze confounding factors to improve understanding of potential long-term cancer risks.

5 Conclusions

Our research contributes to the growing body of evidence showing that the use of insulin glargine is not associated with an increased risk of either all cancers or specific types of cancer.

Acknowledgements

None.

  1. Funding information: This research received no external funding.

  2. Author contribution: Conceptualization: G.S., L.Z., and J.J.; methodology: G.S. and A.P.; software: A.P.; validation: G.S.; formal analysis: A.P.; investigation: J.J.; resources: G.S.; data curation: A.P.; writing – original draft preparation: J.J.; writing – review and editing: J.J., M.D., A.L., D.L-U., L.Z.; visualization: J.J.; supervision: G.S.; project administration: G.S.; funding acquisition: G.S. All authors have read and agreed to the published version of the manuscript.

  3. Conflict of interest: The authors have no competing interests to declare that are relevant to this article’s content.

  4. Data availability statement: The data supporting this study’s findings are available from the corresponding author, J.J., upon reasonable request.

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Received: 2024-02-05
Revised: 2024-06-25
Accepted: 2024-07-18
Published Online: 2024-10-15

© 2024 the author(s), published by De Gruyter

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

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  5. The pyroptosis-related signature predicts prognosis and influences the tumor immune microenvironment in dedifferentiated liposarcoma
  6. METTL3 attenuates ferroptosis sensitivity in lung cancer via modulating TFRC
  7. Identification and validation of molecular subtypes and prognostic signature for stage I and stage II gastric cancer based on neutrophil extracellular traps
  8. Novel lumbar plexus block versus femoral nerve block for analgesia and motor recovery after total knee arthroplasty
  9. Correlation between ABCB1 and OLIG2 polymorphisms and the severity and prognosis of patients with cerebral infarction
  10. Study on the radiotherapy effect and serum neutral granulocyte lymphocyte ratio and inflammatory factor expression of nasopharyngeal carcinoma
  11. Transcriptome analysis of effects of Tecrl deficiency on cardiometabolic and calcium regulation in cardiac tissue
  12. Aflatoxin B1 induces infertility, fetal deformities, and potential therapies
  13. Serum levels of HMW adiponectin and its receptors are associated with cytokine levels and clinical characteristics in chronic obstructive pulmonary disease
  14. METTL3-mediated methylation of CYP2C19 mRNA may aggravate clopidogrel resistance in ischemic stroke patients
  15. Understand how machine learning impact lung cancer research from 2010 to 2021: A bibliometric analysis
  16. Pressure ulcers in German hospitals: Analysis of reimbursement and length of stay
  17. Metformin plus L-carnitine enhances brown/beige adipose tissue activity via Nrf2/HO-1 signaling to reduce lipid accumulation and inflammation in murine obesity
  18. Downregulation of carbonic anhydrase IX expression in mouse xenograft nasopharyngeal carcinoma model via doxorubicin nanobubble combined with ultrasound
  19. Feasibility of 3-dimensional printed models in simulated training and teaching of transcatheter aortic valve replacement
  20. miR-335-3p improves type II diabetes mellitus by IGF-1 regulating macrophage polarization
  21. The analyses of human MCPH1 DNA repair machinery and genetic variations
  22. Activation of Piezo1 increases the sensitivity of breast cancer to hyperthermia therapy
  23. Comprehensive analysis based on the disulfidptosis-related genes identifies hub genes and immune infiltration for pancreatic adenocarcinoma
  24. Changes of serum CA125 and PGE2 before and after high-intensity focused ultrasound combined with GnRH-a in treatment of patients with adenomyosis
  25. The clinical value of the hepatic venous pressure gradient in patients undergoing hepatic resection for hepatocellular carcinoma with or without liver cirrhosis
  26. Development and validation of a novel model to predict pulmonary embolism in cardiology suspected patients: A 10-year retrospective analysis
  27. Downregulation of lncRNA XLOC_032768 in diabetic patients predicts the occurrence of diabetic nephropathy
  28. Circ_0051428 targeting miR-885-3p/MMP2 axis enhances the malignancy of cervical cancer
  29. Effectiveness of ginkgo diterpene lactone meglumine on cognitive function in patients with acute ischemic stroke
  30. The construction of a novel prognostic prediction model for glioma based on GWAS-identified prognostic-related risk loci
  31. Evaluating the impact of childhood BMI on the risk of coronavirus disease 2019: A Mendelian randomization study
  32. Lactate dehydrogenase to albumin ratio is associated with in-hospital mortality in patients with acute heart failure: Data from the MIMIC-III database
  33. CD36-mediated podocyte lipotoxicity promotes foot process effacement
  34. Efficacy of etonogestrel subcutaneous implants versus the levonorgestrel-releasing intrauterine system in the conservative treatment of adenomyosis
  35. FLRT2 mediates chondrogenesis of nasal septal cartilage and mandibular condyle cartilage
  36. Challenges in treating primary immune thrombocytopenia patients undergoing COVID-19 vaccination: A retrospective study
  37. Let-7 family regulates HaCaT cell proliferation and apoptosis via the ΔNp63/PI3K/AKT pathway
  38. Phospholipid transfer protein ameliorates sepsis-induced cardiac dysfunction through NLRP3 inflammasome inhibition
  39. Postoperative cognitive dysfunction in elderly patients with colorectal cancer: A randomized controlled study comparing goal-directed and conventional fluid therapy
  40. Long-pulsed ultrasound-mediated microbubble thrombolysis in a rat model of microvascular obstruction
  41. High SEC61A1 expression predicts poor outcome of acute myeloid leukemia
  42. Comparison of polymerase chain reaction and next-generation sequencing with conventional urine culture for the diagnosis of urinary tract infections: A meta-analysis
  43. Secreted frizzled-related protein 5 protects against renal fibrosis by inhibiting Wnt/β-catenin pathway
  44. Pan-cancer and single-cell analysis of actin cytoskeleton genes related to disulfidptosis
  45. Overexpression of miR-532-5p restrains oxidative stress response of chondrocytes in nontraumatic osteonecrosis of the femoral head by inhibiting ABL1
  46. Autologous liver transplantation for unresectable hepatobiliary malignancies in enhanced recovery after surgery model
  47. Clinical analysis of incomplete rupture of the uterus secondary to previous cesarean section
  48. Abnormal sleep duration is associated with sarcopenia in older Chinese people: A large retrospective cross-sectional study
  49. No genetic causality between obesity and benign paroxysmal vertigo: A two-sample Mendelian randomization study
  50. Identification and validation of autophagy-related genes in SSc
  51. Long non-coding RNA SRA1 suppresses radiotherapy resistance in esophageal squamous cell carcinoma by modulating glycolytic reprogramming
  52. Evaluation of quality of life in patients with schizophrenia: An inpatient social welfare institution-based cross-sectional study
  53. The possible role of oxidative stress marker glutathione in the assessment of cognitive impairment in multiple sclerosis
  54. Compilation of a self-management assessment scale for postoperative patients with aortic dissection
  55. Left atrial appendage closure in conjunction with radiofrequency ablation: Effects on left atrial functioning in patients with paroxysmal atrial fibrillation
  56. Effect of anterior femoral cortical notch grade on postoperative function and complications during TKA surgery: A multicenter, retrospective study
  57. Clinical characteristics and assessment of risk factors in patients with influenza A-induced severe pneumonia after the prevalence of SARS-CoV-2
  58. Analgesia nociception index is an indicator of laparoscopic trocar insertion-induced transient nociceptive stimuli
  59. High STAT4 expression correlates with poor prognosis in acute myeloid leukemia and facilitates disease progression by upregulating VEGFA expression
  60. Factors influencing cardiovascular system-related post-COVID-19 sequelae: A single-center cohort study
  61. HOXD10 regulates intestinal permeability and inhibits inflammation of dextran sulfate sodium-induced ulcerative colitis through the inactivation of the Rho/ROCK/MMPs axis
  62. Mesenchymal stem cell-derived exosomal miR-26a induces ferroptosis, suppresses hepatic stellate cell activation, and ameliorates liver fibrosis by modulating SLC7A11
  63. Endovascular thrombectomy versus intravenous thrombolysis for primary distal, medium vessel occlusion in acute ischemic stroke
  64. ANO6 (TMEM16F) inhibits gastrointestinal stromal tumor growth and induces ferroptosis
  65. Prognostic value of EIF5A2 in solid tumors: A meta-analysis and bioinformatics analysis
  66. The role of enhanced expression of Cx43 in patients with ulcerative colitis
  67. Choosing a COVID-19 vaccination site might be driven by anxiety and body vigilance
  68. Role of ICAM-1 in triple-negative breast cancer
  69. Cost-effectiveness of ambroxol in the treatment of Gaucher disease type 2
  70. HLA-DRB5 promotes immune thrombocytopenia via activating CD8+ T cells
  71. Efficacy and factors of myofascial release therapy combined with electrical and magnetic stimulation in the treatment of chronic pelvic pain syndrome
  72. Efficacy of tacrolimus monotherapy in primary membranous nephropathy
  73. Mechanisms of Tripterygium wilfordii Hook F on treating rheumatoid arthritis explored by network pharmacology analysis and molecular docking
  74. FBXO45 levels regulated ferroptosis renal tubular epithelial cells in a model of diabetic nephropathy by PLK1
  75. Optimizing anesthesia strategies to NSCLC patients in VATS procedures: Insights from drug requirements and patient recovery patterns
  76. Alpha-lipoic acid upregulates the PPARγ/NRF2/GPX4 signal pathway to inhibit ferroptosis in the pathogenesis of unexplained recurrent pregnancy loss
  77. Correlation between fat-soluble vitamin levels and inflammatory factors in paediatric community-acquired pneumonia: A prospective study
  78. CD1d affects the proliferation, migration, and apoptosis of human papillary thyroid carcinoma TPC-1 cells via regulating MAPK/NF-κB signaling pathway
  79. miR-let-7a inhibits sympathetic nerve remodeling after myocardial infarction by downregulating the expression of nerve growth factor
  80. Immune response analysis of solid organ transplantation recipients inoculated with inactivated COVID-19 vaccine: A retrospective analysis
  81. The H2Valdien derivatives regulate the epithelial–mesenchymal transition of hepatoma carcinoma cells through the Hedgehog signaling pathway
  82. Clinical efficacy of dexamethasone combined with isoniazid in the treatment of tuberculous meningitis and its effect on peripheral blood T cell subsets
  83. Comparison of short-segment and long-segment fixation in treatment of degenerative scoliosis and analysis of factors associated with adjacent spondylolisthesis
  84. Lycopene inhibits pyroptosis of endothelial progenitor cells induced by ox-LDL through the AMPK/mTOR/NLRP3 pathway
  85. Methylation regulation for FUNDC1 stability in childhood leukemia was up-regulated and facilitates metastasis and reduces ferroptosis of leukemia through mitochondrial damage by FBXL2
  86. Correlation of single-fiber electromyography studies and functional status in patients with amyotrophic lateral sclerosis
  87. Risk factors of postoperative airway obstruction complications in children with oral floor mass
  88. Expression levels and clinical significance of serum miR-19a/CCL20 in patients with acute cerebral infarction
  89. Physical activity and mental health trends in Korean adolescents: Analyzing the impact of the COVID-19 pandemic from 2018 to 2022
  90. Evaluating anemia in HIV-infected patients using chest CT
  91. Ponticulus posticus and skeletal malocclusion: A pilot study in a Southern Italian pre-orthodontic court
  92. Causal association of circulating immune cells and lymphoma: A Mendelian randomization study
  93. Assessment of the renal function and fibrosis indexes of conventional western medicine with Chinese medicine for dredging collaterals on treating renal fibrosis: A systematic review and meta-analysis
  94. Comprehensive landscape of integrator complex subunits and their association with prognosis and tumor microenvironment in gastric cancer
  95. New target-HMGCR inhibitors for the treatment of primary sclerosing cholangitis: A drug Mendelian randomization study
  96. Population pharmacokinetics of meropenem in critically ill patients
  97. Comparison of the ability of newly inflammatory markers to predict complicated appendicitis
  98. Comparative morphology of the cruciate ligaments: A radiological study
  99. Immune landscape of hepatocellular carcinoma: The central role of TP53-inducible glycolysis and apoptosis regulator
  100. Serum SIRT3 levels in epilepsy patients and its association with clinical outcomes and severity: A prospective observational study
  101. SHP-1 mediates cigarette smoke extract-induced epithelial–mesenchymal transformation and inflammation in 16HBE cells
  102. Acute hyper-hypoxia accelerates the development of depression in mice via the IL-6/PGC1α/MFN2 signaling pathway
  103. The GJB3 correlates with the prognosis, immune cell infiltration, and therapeutic responses in lung adenocarcinoma
  104. Physical fitness and blood parameters outcomes of breast cancer survivor in a low-intensity circuit resistance exercise program
  105. Exploring anesthetic-induced gene expression changes and immune cell dynamics in atrial tissue post-coronary artery bypass graft surgery
  106. Empagliflozin improves aortic injury in obese mice by regulating fatty acid metabolism
  107. Analysis of the risk factors of the radiation-induced encephalopathy in nasopharyngeal carcinoma: A retrospective cohort study
  108. Reproductive outcomes in women with BRCA 1/2 germline mutations: A retrospective observational study and literature review
  109. Evaluation of upper airway ultrasonographic measurements in predicting difficult intubation: A cross-section of the Turkish population
  110. Prognostic and diagnostic value of circulating IGFBP2 in pancreatic cancer
  111. Postural stability after operative reconstruction of the AFTL in chronic ankle instability comparing three different surgical techniques
  112. Research trends related to emergence agitation in the post-anaesthesia care unit from 2001 to 2023: A bibliometric analysis
  113. Frequency and clinicopathological correlation of gastrointestinal polyps: A six-year single center experience
  114. ACSL4 mediates inflammatory bowel disease and contributes to LPS-induced intestinal epithelial cell dysfunction by activating ferroptosis and inflammation
  115. Affibody-based molecular probe 99mTc-(HE)3ZHER2:V2 for non-invasive HER2 detection in ovarian and breast cancer xenografts
  116. Effectiveness of nutritional support for clinical outcomes in gastric cancer patients: A meta-analysis of randomized controlled trials
  117. The relationship between IFN-γ, IL-10, IL-6 cytokines, and severity of the condition with serum zinc and Fe in children infected with Mycoplasma pneumoniae
  118. Paraquat disrupts the blood–brain barrier by increasing IL-6 expression and oxidative stress through the activation of PI3K/AKT signaling pathway
  119. Sleep quality associate with the increased prevalence of cognitive impairment in coronary artery disease patients: A retrospective case–control study
  120. Dioscin protects against chronic prostatitis through the TLR4/NF-κB pathway
  121. Association of polymorphisms in FBN1, MYH11, and TGF-β signaling-related genes with susceptibility of sporadic thoracic aortic aneurysm and dissection in the Zhejiang Han population
  122. Application value of multi-parameter magnetic resonance image-transrectal ultrasound cognitive fusion in prostate biopsy
  123. Laboratory variables‐based artificial neural network models for predicting fatty liver disease: A retrospective study
  124. Decreased BIRC5-206 promotes epithelial–mesenchymal transition in nasopharyngeal carcinoma through sponging miR-145-5p
  125. Sepsis induces the cardiomyocyte apoptosis and cardiac dysfunction through activation of YAP1/Serpine1/caspase-3 pathway
  126. Assessment of iron metabolism and iron deficiency in incident patients on incident continuous ambulatory peritoneal dialysis
  127. Tibial periosteum flap combined with autologous bone grafting in the treatment of Gustilo-IIIB/IIIC open tibial fractures
  128. The application of intravenous general anesthesia under nasopharyngeal airway assisted ventilation undergoing ureteroscopic holmium laser lithotripsy: A prospective, single-center, controlled trial
  129. Long intergenic noncoding RNA for IGF2BP2 stability suppresses gastric cancer cell apoptosis by inhibiting the maturation of microRNA-34a
  130. Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis
  131. Parental control attitudes over their pre-school children’s diet
  132. The role of auto-HSCT in extranodal natural killer/T cell lymphoma
  133. Significance of negative cervical cytology and positive HPV in the diagnosis of cervical lesions by colposcopy
  134. Echinacoside inhibits PASMCs calcium overload to prevent hypoxic pulmonary artery remodeling by regulating TRPC1/4/6 and calmodulin
  135. ADAR1 plays a protective role in proximal tubular cells under high glucose conditions by attenuating the PI3K/AKT/mTOR signaling pathway
  136. The risk of cancer among insulin glargine users in Lithuania: A retrospective population-based study
  137. The unusual location of primary hydatid cyst: A case series study
  138. Intraoperative changes in electrophysiological monitoring can be used to predict clinical outcomes in patients with spinal cavernous malformation
  139. Obesity and risk of placenta accreta spectrum: A meta-analysis
  140. Shikonin alleviates asthma phenotypes in mice via an airway epithelial STAT3-dependent mechanism
  141. NSUN6 and HTR7 disturbed the stability of carotid atherosclerotic plaques by regulating the immune responses of macrophages
  142. The effect of COVID-19 lockdown on admission rates in Maternity Hospital
  143. Temporal muscle thickness is not a prognostic predictor in patients with high-grade glioma, an experience at two centers in China
  144. Luteolin alleviates cerebral ischemia/reperfusion injury by regulating cell pyroptosis
  145. Therapeutic role of respiratory exercise in patients with tuberculous pleurisy
  146. Effects of CFTR-ENaC on spinal cord edema after spinal cord injury
  147. Irisin-regulated lncRNAs and their potential regulatory functions in chondrogenic differentiation of human mesenchymal stem cells
  148. DMD mutations in pediatric patients with phenotypes of Duchenne/Becker muscular dystrophy
  149. Combination of C-reactive protein and fibrinogen-to-albumin ratio as a novel predictor of all-cause mortality in heart failure patients
  150. Significant role and the underly mechanism of cullin-1 in chronic obstructive pulmonary disease
  151. Ferroptosis-related prognostic model of mantle cell lymphoma
  152. Observation of choking reaction and other related indexes in elderly painless fiberoptic bronchoscopy with transnasal high-flow humidification oxygen therapy
  153. A bibliometric analysis of Prader-Willi syndrome from 2002 to 2022
  154. The causal effects of childhood sunburn occasions on melanoma: A univariable and multivariable Mendelian randomization study
  155. Oxidative stress regulates glycogen synthase kinase-3 in lymphocytes of diabetes mellitus patients complicated with cerebral infarction
  156. Role of COX6C and NDUFB3 in septic shock and stroke
  157. Trends in disease burden of type 2 diabetes, stroke, and hypertensive heart disease attributable to high BMI in China: 1990–2019
  158. Purinergic P2X7 receptor mediates hyperoxia-induced injury in pulmonary microvascular endothelial cells via NLRP3-mediated pyroptotic pathway
  159. Investigating the role of oviductal mucosa–endometrial co-culture in modulating factors relevant to embryo implantation
  160. Analgesic effect of external oblique intercostal block in laparoscopic cholecystectomy: A retrospective study
  161. Elevated serum miR-142-5p correlates with ischemic lesions and both NSE and S100β in ischemic stroke patients
  162. Correlation between the mechanism of arteriopathy in IgA nephropathy and blood stasis syndrome: A cohort study
  163. Risk factors for progressive kyphosis after percutaneous kyphoplasty in osteoporotic vertebral compression fracture
  164. Predictive role of neuron-specific enolase and S100-β in early neurological deterioration and unfavorable prognosis in patients with ischemic stroke
  165. The potential risk factors of postoperative cognitive dysfunction for endovascular therapy in acute ischemic stroke with general anesthesia
  166. Fluoxetine inhibited RANKL-induced osteoclastic differentiation in vitro
  167. Detection of serum FOXM1 and IGF2 in patients with ARDS and their correlation with disease and prognosis
  168. Rhein promotes skin wound healing by activating the PI3K/AKT signaling pathway
  169. Differences in mortality risk by levels of physical activity among persons with disabilities in South Korea
  170. Review Articles
  171. Cutaneous signs of selected cardiovascular disorders: A narrative review
  172. XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis
  173. A narrative review on adverse drug reactions of COVID-19 treatments on the kidney
  174. Emerging role and function of SPDL1 in human health and diseases
  175. Adverse reactions of piperacillin: A literature review of case reports
  176. Molecular mechanism and intervention measures of microvascular complications in diabetes
  177. Regulation of mesenchymal stem cell differentiation by autophagy
  178. Molecular landscape of borderline ovarian tumours: A systematic review
  179. Advances in synthetic lethality modalities for glioblastoma multiforme
  180. Investigating hormesis, aging, and neurodegeneration: From bench to clinics
  181. Frankincense: A neuronutrient to approach Parkinson’s disease treatment
  182. Sox9: A potential regulator of cancer stem cells in osteosarcoma
  183. Early detection of cardiovascular risk markers through non-invasive ultrasound methodologies in periodontitis patients
  184. Advanced neuroimaging and criminal interrogation in lie detection
  185. Maternal factors for neural tube defects in offspring: An umbrella review
  186. The chemoprotective hormetic effects of rosmarinic acid
  187. CBD’s potential impact on Parkinson’s disease: An updated overview
  188. Progress in cytokine research for ARDS: A comprehensive review
  189. Utilizing reactive oxygen species-scavenging nanoparticles for targeting oxidative stress in the treatment of ischemic stroke: A review
  190. NRXN1-related disorders, attempt to better define clinical assessment
  191. Lidocaine infusion for the treatment of complex regional pain syndrome: Case series and literature review
  192. Trends and future directions of autophagy in osteosarcoma: A bibliometric analysis
  193. Iron in ventricular remodeling and aneurysms post-myocardial infarction
  194. Case Reports
  195. Sirolimus potentiated angioedema: A case report and review of the literature
  196. Identification of mixed anaerobic infections after inguinal hernia repair based on metagenomic next-generation sequencing: A case report
  197. Successful treatment with bortezomib in combination with dexamethasone in a middle-aged male with idiopathic multicentric Castleman’s disease: A case report
  198. Complete heart block associated with hepatitis A infection in a female child with fatal outcome
  199. Elevation of D-dimer in eosinophilic gastrointestinal diseases in the absence of venous thrombosis: A case series and literature review
  200. Four years of natural progressive course: A rare case report of juvenile Xp11.2 translocations renal cell carcinoma with TFE3 gene fusion
  201. Advancing prenatal diagnosis: Echocardiographic detection of Scimitar syndrome in China – A case series
  202. Outcomes and complications of hemodialysis in patients with renal cancer following bilateral nephrectomy
  203. Anti-HMGCR myopathy mimicking facioscapulohumeral muscular dystrophy
  204. Recurrent opportunistic infections in a HIV-negative patient with combined C6 and NFKB1 mutations: A case report, pedigree analysis, and literature review
  205. Letter to the Editor
  206. Letter to the Editor: Total parenteral nutrition-induced Wernicke’s encephalopathy after oncologic gastrointestinal surgery
  207. Erratum
  208. Erratum to “Bladder-embedded ectopic intrauterine device with calculus”
  209. Retraction
  210. Retraction of “XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis”
  211. Corrigendum
  212. Corrigendum to “Investigating hormesis, aging, and neurodegeneration: From bench to clinics”
  213. Corrigendum to “Frankincense: A neuronutrient to approach Parkinson’s disease treatment”
  214. Special Issue The evolving saga of RNAs from bench to bedside - Part II
  215. Machine-learning-based prediction of a diagnostic model using autophagy-related genes based on RNA sequencing for patients with papillary thyroid carcinoma
  216. Unlocking the future of hepatocellular carcinoma treatment: A comprehensive analysis of disulfidptosis-related lncRNAs for prognosis and drug screening
  217. Elevated mRNA level indicates FSIP1 promotes EMT and gastric cancer progression by regulating fibroblasts in tumor microenvironment
  218. Special Issue Advancements in oncology: bridging clinical and experimental research - Part I
  219. Ultrasound-guided transperineal vs transrectal prostate biopsy: A meta-analysis of diagnostic accuracy and complication rates
  220. Assessment of diagnostic value of unilateral systematic biopsy combined with targeted biopsy in detecting clinically significant prostate cancer
  221. SENP7 inhibits glioblastoma metastasis and invasion by dissociating SUMO2/3 binding to specific target proteins
  222. MARK1 suppress malignant progression of hepatocellular carcinoma and improves sorafenib resistance through negatively regulating POTEE
  223. Analysis of postoperative complications in bladder cancer patients
  224. Carboplatin combined with arsenic trioxide versus carboplatin combined with docetaxel treatment for LACC: A randomized, open-label, phase II clinical study
  225. Special Issue Exploring the biological mechanism of human diseases based on MultiOmics Technology - Part I
  226. Comprehensive pan-cancer investigation of carnosine dipeptidase 1 and its prospective prognostic significance in hepatocellular carcinoma
  227. Identification of signatures associated with microsatellite instability and immune characteristics to predict the prognostic risk of colon cancer
  228. Single-cell analysis identified key macrophage subpopulations associated with atherosclerosis
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