Introduction

Neutrophils could be recruited into liver in autoimmune hepatitis (AIH) and experimental AIH (Concanavalin A induced hepatitis), but the role of neutrophils in these kinds of immune related hepatitis has rare research to clarify. As previous reports, CD177 expressed exclusively on neutrophils, CD177⁺ neutrophils could alleviate inflammation in inflammatory bowel disease, and it could produce neutrophil extracellular traps that promote biliary atresia. However, there is no report about CD177⁺ neutrophils involved in AIH or experimental AIH.

Aims & Methods

In this study, we wanted to explore to role of neutrophils in AIH and wondered whether CD177⁺ neutrophils exert protective effect in it. We collected clinical samples of AIH patients and healthy control (HC), and established experimental AIH animal model by using Concanavalin A (ConA). Anti-Ly6G antibody was used as pretreatment to depleting neutrophils before ConA injection. Wild type (WT) and CD177 knock out (KO) C57BL/6J female mouse were used to construct different experimental AIH model. Flow cytometry analysis was used to detect the percentage of neutrophils in blood and liver. Detected serum biochemical indicators (ALT: alanine aminotransferase, AST: aspartate aminotransferase) and performed staining in liver tissues to evaluate liver injury.

Results

For AIH patients, CD177⁺ neutrophils in peripheral blood were significantly increased (P<0.05). And for immunohistochemistry (IHC), the positive areas of CD66b (a surface marker of neutrophils) and CD177 were more obvious in liver tissues of AIH patients (P<0.05). For animal experiment, we successfully established model of experimental AIH. In this model, liver injury was significant in ConA group than in normal control (NC) group, which showed prominent liver necrosis in hematoxylin-eosin (HE) staining and higher serum ALT and AST (P<0.05). Positive IHC areas of Ly6G and CD177 were more obvious in liver tissues of ConA group, which meant the increased infiltration of neutrophils. We found that distributions of neutrophils were different in different organ. Compared to NC group, the amount of neutrophils in ConA group was decreased in bone marrow and increased in peripheral blood and liver, and its increase in liver trended to be more obvious (P=0.096). So, we speculated that neutrophils mainly migrated to liver from marrow in ConA model. After depleting neutrophils, we through flow cytometry analysis to verify the depletion of neutrophils (CD11b⁺ Ly6G⁺ cells) in anti Ly6G-ConA group was thorough. HE staining showed liver injury appearances in ConA group and Ly6G isotype-ConA group were more severe than that in normal saline (NS) group and in anti Ly6G-ConA group. Similarly, ConA group and Ly6G isotype-ConA group had higher levels of serum ALT and AST than the other two groups. Finally, we used CD177 KO mouse to determine the role of CD177⁺ neutrophils in ConA model. HE staining showed the area of liver necrosis in CD177 KO-ConA group was largest. As for liver function, CD177 KO-ConA group also had the highest levels of serum ALT and AST (P<0.05), which improve that the liver injury in this group was the most severe.

Conclusion

Neutrophils involved in AIH and experimental AIH. In experimental AIH, depletion of neutrophils could alleviate liver injury, and CD177⁺ neutrophils could exert protective effect in it.

Introduction

Cendakimab is a recombinant, humanized, high-affinity, neutralizing monoclonal antibody that binds to interleukin 13 (IL-13) and blocks interaction with both its receptors, IL-13Rα1 and IL-13Rα2. IL-13 is a cytokine implicated in the pathogenesis of atopic dermatitis (AD) and is thought to be a key driver of the complex pathophysiology of eosinophilic esophagitis (EoE). IL-13 signals through both IL-13Rα1 and IL-13Rα2 to regulate cellular and molecular pathways across a variety of cell types. The binding of IL-13 to IL-13Rα1 promotes a Type 2 immune response and eosinophil recruitment, whereas the binding of IL-13 to IL-13Rα2 is believed to play a role in fibrosis and epithelial tissue remodeling. Several biomarkers associated with Type 2 inflammatory diseases are known to be regulated by IL-13. Eotaxin-3, a key biomarker, plays a central role in attracting eosinophils to the site of inflammation. Periostin, an extracellular matrix protein linked to activated fibroblasts, is implicated in tissue remodeling and fibrosis. Another enzyme governed by IL-13 is matrix metalloproteinase-12 (MMP-12)—this enzyme contributes to tissue remodeling and breakdown of extracellular matrix components. Here, we evaluate the pharmacodynamic effects of IL-13 inhibition with cendakimab on the key serum biomarkers eotaxin-3, periostin, and MMP-12 in patients with AD, with a focus on exploring potential implications for EoE.

Aims & Methods

In this phase 2, multicenter, global, randomized, double-blinded, placebo-controlled, parallel-group study (NCT04800315), 220 adults with moderate-to-severe AD received cendakimab 360 mg Q2W, 720 mg QW, 720 mg Q2W, or placebo for 16 weeks. Blood samples were collected, and a panel of biomarkers were assessed. The current analysis focuses on the assessment of serum levels of eotaxin-3, periostin, and MMP-12 using Proximity Extension Assay pre- and post-treatment on day 1 (baseline), at week 1 and week 2, and then biweekly until week 16. The least square mean percent change from baseline at week 16 for each treatment group was evaluated.

Results

For all 3 doses of cendakimab, there was a significant decrease from baseline in the levels of eotaxin-3, periostin, and MMP-12 as early as week 1 post-treatment and continued through week 16 of cendakimab treatment (Table). Compared with placebo, cendakimab resulted in significantly greater reductions in these biomarker levels through week 16.

Conclusion

Cendakimab decreased levels of key inflammatory and remodeling biomarkers over 16 weeks of treatment in patients with AD. These findings suggest that cendakimab modulates pathways of inflammation, fibrosis, and tissue remodeling in AD and add to the existing clinical evidence of its modulation in other Type 2 inflammatory diseases such as EoE.
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Table. Least square mean percent change from baseline in key serum biomarker levels at week 16 in patients with AD

Disclosure

ESD served as a consultant for Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/ Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GlaxoSmithKline, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio, received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/ Bristol Myers Squibb, Regeneron, Revolo, Shire/Takeda, and received educational grant from Allakos, Aqilion, Holoclara, and Invea. JL, SH, LG, CDO, and CC are employees and stockholders of Bristol Myers Squibb. JS served as consultant for Abbvie, Alamar, Aldena, Amgen, AObiome, Apollo, Arcutis, Arena, Asana, Aslan, Attovia, BioMX, Biosion, Bodewell, Boehringer-Ingelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Celgene, Connect Biopharma, Corevitas, Dermavant, Eli Lilly, FIDE, Galderma, GlaxoSmithKline, Incyte, Invea, Kiniksa, Leo Pharma, Merck, My-Or Diagnostics, Nektar, Novartis, Optum, Pfizer, RAPT, Recludix, Regeneron, Sandoz, Sanofi-Genzyme, Shaperon, TARGET-RWE, Teva, Union, UpToDate, participated on a data safety monitoring board or advisory board for Biosion and Sanofi, received grants or contracts from Galderma, Incyte, Pfizer, received honoraria from Abbvie, Eli Lilly, Leo Pharma, Pfizer, Regeneron, Sanofi-Genzyme.

Introduction

Canopy FGF signaling regulator 3 (CNPY3) is a protein predominantly localized in the endoplasmic reticulum. Its expression is increased in several cancers, including colorectal cancer (CRC). However, how CNPY3 affects CRC progression and the function of CNPY3 translocation to the nucleus in CRC is not clear.

Aims & Methods

This study aimed to investigate the role of CNPY3 in the development of CRC. In vitro, the impacts of CNPY3 on CRC growth were evaluated by 5-Ethynyl-2′-deoxyuridine staining, colony formation, wound healing, transwell migration, and apoptosis assay. Tumor xenograft mouse models and orthotopic mouse models of colorectal cancer metastasis were used to assess in vivo. Furthermore, the underlying mechanism of CNPY3 in CRC was revealed by RT-qPCR, western blot, LC-MS/MS analysis, immunofluorescence staining, coimmunoprecipitation, GST-pulldown, confocal microscopy, ubiquitination assays, and rescue experiments.

Results

CNPY3 was significantly upregulated in CRC tissue and cell lines, correlating with their poor prognosis. Functional experiments demonstrated that CNPY3 enhances CRC proliferation, migration, invasion, and tumor growth. Notably, our investigation reveals a nucleus translocation of cnpy3 by activation of nuclear localization sequences through protein conformational changes. Meanwhile, nuclear localization of CNPY3 promotes the binding of TRIM21 and p53 and forms a CNPY3-TRIM21-p53 complex, thereby promoting the ubiquitination-proteasomal degradation of wild-type p53 protein, inhibiting the related genes of the TP53 signaling pathway, and promoting apoptosis of tumor cells. In vivo and in vitro, inhibiting the degradation of p53 was able to suppress CNPY3 in cancer-promoting tumors, whereas the knockdown of CNPY3 in p53^-/- HCT116 cells did not significantly inhibit CRC.

Conclusion

CNPY3, after nuclear translocated, binds to TRIM21 and p53 and stabilizes the TRIM21–p53 interaction. This CNPY3–TRIM21–p53 complex facilitates TRIM21‐mediated p53 ubiquitinoylation and causes p53 proteasome degradation. Collectively, these findings support that CNPY3, an oncogene with CRC progression and poor prognosis, serves as a biomarker and therapeutic target correlated to suppress p53 function.

References

1. Wakabayashi Y, Kobayashi M, Akashi-Takamura S, et al. A protein associated with toll-like receptor 4 (PRAT4A) regulates cell surface expression of TLR4. J Immunol. 2006;177(3):1772-9.
2.
3. Xiao L, Li XX, Chung HK, Kalakonda S, et al. RNA-Binding Protein HuR Regulates Paneth Cell Function by Altering Membrane Localization of TLR2 via Post-transcriptional Control of CNPY3. Gastroenterology. 2019;157(3):731-743.
4. Ghait M, Husain RA, Duduskar SN, et al. The TLR-chaperone CNPY3 is a critical regulator of NLRP3-inflammasome activation. Eur J Immunol. 2022;52(6):907-923.
5. Zhou YQ, Bao TS, Xie JX, et al. The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells. Cell Oncol (Dordr). 2023;46(4):1049-1067.
6. Reddy BA, van der Knaap JA, Bot AG, et al. Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Mol Cell. 2014;53(3):458-70.
7. Liu J, Zhang C, Xu D, et al. The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer. J Clin Invest. 2023;133(6):e164354.

Introduction

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Oxysterol binding protein 3 (OSBPL3) is a protein involved in lipid binding and transport and is known to play an essential role in tumorigenesis. However, its expression and function in colorectal cancer (CRC) is unclear.

Aims & Methods

This study included patients who underwent CRC surgery at Gachon University Gil Medical Center between April 2010 and January 2013. We analyzed 448 patients with primary colorectal cancer (CRC) who underwent surgery and had preserved paraffin blocks. Using immunohistochemical staining, a clinically applicable, rapid, and highly accurate assay method, we aimed to detect OSBPL3 expression in CRC and correlate it with clinicopathologic characteristics, prognosis, and survival to identify novel patient-specific biomarkers.

Results

The 5-year event-free survival (EFS) and disease-specific survival (DSS) hazard ratios (HRs) of the OSBPL3^High subgroup were 1.65 (95% confidence interval (CI): 0.99-2.76, p = 0.05) and 1.49 (95% CI: 0.89-2.61, p = 0.20), respectively. When tumor node metastasis (TNM) staging and OSBPL3 expression were combined, the 5-year EFS and DSS HRs of patients with CRC with OSBPL3^High expression cancer at the same TNM stage (stage III/IV) were 4.06 (95% CI: 2.72-6.07, p = 0.001) and 4.41 (95% CI: 2.91-6.68, p = 0.001), respectively, compared to those with OSBPL3^Low expression cancer, indicating a poor prognosis. Therefore, OSBPL3^High expression is associated with poor prognosis and survival rate in CRC patients. Combining OSBPL3 expression with TNM staging can predict CRC prognosis and survival rate more accurately.

Conclusion

Our data show that increased expression of OSBPL3 is associated with poor prognosis and survival rate in CRC patients. By combining OSBPL3 expression with TNM staging, we can more accurately predict the prognosis of CRC.

Introduction

Lifestyle factors are significant contributors to fatigue, which affects approximately 45% of patients with Inflammatory Bowel Disease (IBD) in remission.

Aims & Methods

In this study, we evaluated the effect of a digital multimodal lifestyle intervention on fatigue in patients with IBD. Patients with IBD in biochemical remission (fecal calprotectin <150 mg/kg) were enrolled in a multicenter, non-randomized, controlled interventional study. The intervention group participated in a 12-month lifestyle program—provided by the non-profit organization Voeding Leeft—that included digital group meetings with a nutritionist and a lifestyle coach focusing on gradual and sustainable behavior change regarding nutrition, physical activity, sleep, and stress management. In addition, the program encouraged patients to exercise more self-control over their personal health. Following the initial six months, attendance at online sessions was not mandatory; however, patients could attend online sessions every six to 12 weeks to stay motivated and foster the lifestyle habits they acquired throughout the course. Patients in the control group received standard care that included an informational leaflet about the potential causes of fatigue in IBD, the leaflet also included basic lifestyle information and advice to exercise more, eat a healthier diet, stop smoking, reduce alcohol intake, improve sleeping habits, and manage stress. The allocation to a study group was determined by the availability within the group and participant’s ability to attend the scheduled intervention. Clinical data and patient-reported outcomes were collected. Fatigue was measured with the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); any increase in FACIT-F after six months was considered a positive response to the intervention. The Minimal Clinically Important Difference (MCID) for fatigue was at least a four-point increase in the FACIT-F score¹. Inverse probability treatment weighting was used to correct confounding by indication.

Results

Thirty-six patients in the intervention group and 32 in the control group were compared. After six months, more patients in the intervention group (82.1% of patients) than in the control group (54.2% of patients) experienced improvement in fatigue, P = 0.029. Likewise, significantly more patients in the intervention group (71.4% of patients) than the control group (33.3% of patients) achieved a MCID regarding fatigue; P = 0.006. The improvements in fatigue were sustained throughout the study period in the intervention group. Acceptance of the health status was a significant factor for improvement in fatigue (β 7.813, SE 1.908, P < 0.001). Compared to the control group, quality of life improved in the intervention group; these patients gained 0.05 more quality-adjusted life years throughout the study. Last but not least, significant improvements in dietary quality were observed as early as three months after the baseline in the intervention but not the control group; these improvements in the intervention group were sustained throughout the study period.

Conclusion

Multimodal lifestyle intervention improves fatigue, quality of life, and dietary quality in patients with IBD who are in remission. Acceptance of the health status appears essential for fatigue improvement; instruments evaluating acceptance could help to personalize treatment and maximize its effectiveness.

References

1. Cella D, Yount S, Sorensen M, et al. Validation of the Functional Assessment of Chronic Illness Therapy Fatigue Scale relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol 2005;32:811-9.

Disclosure

AEvdMdJ received unrestricted research grants from Galapagos, Norgine, Vedanta, Nestle, including speaker’s fees from Galapagos, Tramedico, Takeda, Ferring, and Janssen Pharmaceuticals. PWV has received speaker fee from Galapagos and Takeda and served on the advisory board of Lilly, Galapagos, Janssen, BMS, Takeda, and Abbvie. RL has received travel expenses from Galapagos and Cablon Medical and served on the advisory board at Cablon Medical. NW and MJHB are employed by the non-profit organization Voeding Leeft and were a part of the team that guided participants in the intervention group. All other authors have no conflicts of interest to declare.

Introduction

With the recent rise in the occurrence of esophageal adenocarcinoma (EAC) in Western nations, there is an escalating worry regarding Barrett’s esophagus (BE). In contrast, Asian countries exhibit a lower prevalence of BE compared to their Western counterparts. Given the annual increase in chronic gastroesophageal reflux disease (GERD) cases, there is an expectation of a concurrent rise in the prevalence of BE. Consequently, we are embarking on a multicenter prospective study to assess the current prevalence of BE and pinpoint its risk factors in Taiwan.

Aims & Methods

Aim: to evaluate current prevalence and risk factors of Barrett's esophagus in Taiwan.
Methods: We carried out a prospective multicenter study involving consecutive outpatients who underwent upper gastrointestinal endoscopy for various upper gastrointestinal symptoms. Biopsies were taken from endoscopically suspected esophageal metaplasia (ESEM), clearly visible at least 1 cm above the gastroesophageal junction during endoscopy. The biopsy procedure involved obtaining standardized random samples, with four pieces taken every 2 cm from the four quarters of the esophagus exhibiting the ESEM lesion. BE was defined based on the histological confirmation of specialized intestinal metaplasia in the metaplastic esophageal epithelium.

Results

A total of 8925 subjects were enrolled in this study. The prevalence of BE was 2.6%. A total of 228 subjects with BE were detected among 751 ESEM subjects. Short segment BE (78.1 % , n = 178) was more prevalent than long segment BE (22.9 % , n = 50). The prevalence of GERD symptoms, erosive esophagitis (EE), and hiatal hernia (HH) was 52.5%, 27.3% and 7.85%, respectively. Multivariate analysis disclosed that old age [odds ratio (OR) = 1.59; 95% CI, 1.20-2.11; P <0.01], male gender (OR = 2.27; 95%CI, 1.65-3.11; P < 0.01),alcohol consumption (OR = 1.70, 95%CI, 1.19-2.44; P< 0.01), GERD symptoms (OR = 1.45, 95%CI, 1.10-1.92; P< 0.01), EE (OR = 1.94, 95%CI, 1.47-2.56; P< 0.01) and presence of hiatal hernia (OR = 2.49; 95%CI, 1.78-3.47; P < 0.001) were significant risk factors predicting BE.
Risk factors for Barrett esophagus: multivariable analysis.

Conclusion

The prevalence of BE was identified as 2.6%. Notably, advanced age (>50), male gender, alcohol consumption, symptoms of gastroesophageal reflux disease (GERD), erosive esophagitis, and the presence of hiatal hernia emerged as independently significant risk factors for Barrett's esophagus.

References

1. Sharma P. Barrett Esophagus: A Review. Jama. 2022;328(7):663-71.
2. Marques de Sá I, et al. The global prevalence of Barrett's esophagus: A systematic review of the published literature. United European Gastroenterol J. 2020;8(9):1086-105.
3. Chang CY, et al. Current status of Barrett's esophagus research in Asia. J Gastroenterol Hepatol. 2011;26(2):240-6.
4. Shiota S, et al. Prevalence of Barrett's Esophagus in Asian Countries: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2015;13(11):1907-18.
5. Chang CY, et al. The application of Prague C and M criteria in the diagnosis of Barrett's esophagus in an ethnic Chinese population. Am J Gastroenterol. 2009;104(1):13-20.
6. Fock KM, et al. Asia-Pacific consensus on the management of gastro-oesophageal reflux disease: an update focusing on refractory reflux disease and Barrett's oesophagus. Gut. 2016;65(9):1402-15.
7. Eusebi LH, et al. Global prevalence of Barrett's oesophagus and oesophageal cancer in individuals with gastro-oesophageal reflux: a systematic review and meta-analysis. Gut. 2021;70(3):456-63.
8. Akiyama T, et al. Alcohol consumption is associated with an increased risk of erosive esophagitis and Barrett's epithelium in Japanese men. BMC Gastroenterol. 2008;8:58.
9. Andrici J,et al. Hiatal hernia and the risk of Barrett's esophagus. J Gastroenterol Hepatol. 2013;28(3):415-31.

Introduction

Acute pancreatitis (AP) often has unpredictable and complicated clinical course. Numerous biochemical predictors may aid in the risk stratification of AP (including interleukin 6 (IL-6)), but none of them are accurate. YKL-40 is glycoprotein playing mayor role in inflammation and angiogenesis, with reported average serum concentrations of ≥ 190 ng/mL in inflammatory diseases. It has been shown that IL-6 stimulates the production of YKL-40 and, in reverse, YKL-40 (at least in some tissues) induces the production of IL-6.

Aims & Methods

The aim of our study is to assess whether combined concentrations of both YKL-40 and IL-6 could be more informative in risk stratification of developing more severe form of AP than concentrations of either biomarker alone.
We included 150 consecutive consenting adults with AP admitted to Sestre milosrdnice UHC, Zagreb (June 2020-June 2023). Patients with any acute/chronic diseases known to be associated with dysregulated expression of YKL-40 were excluded. Alongside routine laboratory studies (including C-reactive protein (CRP)), 7 mLs of blood were withdrawn for determining YKL-40 and IL-6 concentrations on admission and 48h after. Severity of disease was defined using revised Atlanta classification. Blood samples for YKL-40 and IL-6 quantification in 30 consenting non-AP adults consistent with previously mentioned exclusion criteria were withdrawn. They were matched 1:1 by age and sex to randomly selected 10 patients from each of AP severity categories. Analysis were performed using enzyme-linked immunosorbent assays. AP patients were classified into 2 categories for each biomarker (based on YKL-40 and IL-6 concentrations on admission and 48h after): 1. for YKL-40: low (<190 ng/mL) and high (≥190 ng/mL); 2. for IL-6: low (<42 pg/mL) and high (≥42 pg/mL). Cumulative multimodal logit models were fitted to ordinal outcome “AP severity” – using raw data, and data after entropy balancing undertaken to balance the two categories of YKL-40 and IL-6 concentrations on age, sex, time between symptom onset and admission, and CRP concentrations.

Results

The results showed lower YKL-40 (<50 ng/mL) and IL-6 (<20 pg/mL) concentrations in 30 non-AP adults compared to AP patients. At both time points (on admission and 48h after), odds of more severe AP were clearly higher with YKL-40 and IL-6 concentrations above vs. below the cut-off values (190 ng/mL and 42 pg/mL, respectively), and were particulary higher in patients with both cytokines above the cut-off vs. patients with both cytokines below the cut-off. The same relationship was maintained with adjustments for age, body mass index, days elapsed since symptom onset and admission, and for CRP concentrations – however, the strength of association was lower. This is in line with the fact that high CRP concentration predicts more strongly severe AP forms when taken 48h after compared to admission. This phenomenon was apparent also when the interaction term was included in the model: at CRP concentrations 45 mg/L, neither YKL-40, or IL-6 or their combination above the cut-off values were associated with the outcome; at CRP concentrations 90 mg/L, odds were higher, and were particularly high for a combination of high YKL-40 and high IL-6. The same was observed at CRP concentrations 180 mg/L.

Conclusion

Overall, data suggest that combined YKL-40 and IL-6 concentrations in acute AP, taken either on admission or 48h after, predict more strongly moderate and/or severe (vs. mild) AP than either cytokine alone, and do so 'on-top' of the CRP concentrations.

References

1. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG et al. Classification of acute pancreatitis - 2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102–111.
2. van den Berg FF, de Bruijn AC, van Santvoort HC, Issa Y, Boermeester MA. Early laboratory biomarkers for severity in acute pancreatitis; A systematic review and meta-analysis. Pancreatology. 2020;20(7):1302-1311.
3. Tizaoui K, Yang JW, Lee KH, Kim JH, Kim M, Yoon S et al. The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review. Int J Biol Sci. 2022;18(9):3731-3746. doi: 10.7150/ijbs.67587.
4. Blazevic N, Rogic D, Pelajic S, Miler M, Glavcic G, Ratkajec V et al. YKL-40 as a biomarker in various inflammatory diseases: A review. Biochem Med. 2023;34(1):010502.