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

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

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

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.

Introduction

Potential celiac disease (PCD) is a clinical condition characterized by the presence of a positive CD-specific serology and a normal intestinal architecture. Asymptomatic PCD patients are generally addressed to continue on a gluten containing diet (GCD), but long-term risks of this approach have never been explored.

Aims & Methods

In the present study we aim at investigating nutritional and autoimmune complications possibly developing overtime in a cohort of asymptomatic PCD children left on a GCD. We compared parameters of growth, nutritional status, and autoimmunity between time of diagnosis and in occasion of last medical check, after a long-term gluten containing diet.

Results

Altogether we collected data from 171 PCD children with a mean follow-up time of 3 years (range 0.35-15.3 years). During follow-up, despite patients did not reduce the amount of daily gluten intake , anti-tissue transglutaminase (anti-TG2) antibodies spontaneously and significantly decreased. Most of parameters analysed did not change over follow-up (height centile, ferritin, albumin., cholesterol, calcium, alkaline phosphatase , parathormone, vitamin D, p>0.05) or even improved (weight and BMI centile, haemoglobin, blood iron, HDL, glycaemia and HbA1C, p<0.05), always remaining in the limit of normality. Equally autoantibodies for other concomitant autoimmune disorders did not increase overtime. Similar results were obtained excluding from the analysis patients that stopped producing anti-TG2 and those with a follow up < 3 years.

Conclusion

Our pilot study provides reassuring results on the maintenance of a gluten containing diet in asymptomatic PCD children, even when a long term follow-up is considered.

Disclosure

no conflict of interest to declare

Introduction

Acute pancreatitis is one of the most frequent and critical gastrointestinal diseases, therefore adequate management is essential to impact the prognosis of patients. Despite advances in the understanding of the pathophysiology of the disease and its complications, management remains a challenge and is mainly based on fluid resuscitation, pain management and early enteral nutrition.
Fluid resuscitation is the cornerstone of initial management, and acute pancreatitis treatment guidelines recommend early and aggressive hydration, however, evidence regarding what type of solution as well as what velocity of infusion should be used, is limited. There is not an established dose of intravenous fluids to prevent or reverse progression to multiple organ failure and reduce overload complications.

Aims & Methods

The main objective is to compare the clinical and biochemical outcomes of patients with acute pancreatitis who receive aggressive fluid resuscitation versus those who receive conservative fluid resuscitation after the first 48 hours of treatment.
195 patients were included, which were divided into two groups: 30 patients who received aggressive fluid resuscitation (more than 2.5 ml/kg/h) and 165 patients who received conservative fluid resuscitation (less than 2.5 ml/kg/h) during the first 48 hours of hospitalization. A second division of groups was performed based on 48-hour fluid balance: 129 patients who had a global fluid balance more than (>) positive 4000 ml and 66 patients who had a global fluid balance less than (<) positive 4000 ml.

Results

Patients with aggressive fluid resuscitation had a statistically significant smaller increase in C-reactive protein delta compared to conservative fluid resuscitation (+ 5.2 vs + 6.8, p 0.035) at 48 hours of treatment. Patients who had a 48-hour fluid balance > 4000 ml had a significantly greater increase in C-reactive protein delta (+ 11.46 vs + 3.94, p 0.012) compared to < 4000 ml 48-hour fluid balance, as well as longer time to start oral intake (79.36 vs 55 hrs, p 0.024) and greater requirement for loop diuretics (33.3% vs 14.8%, p 0.006).

Conclusion

Aggressive fluid resuscitation is associated with lower changes in levels of C-reactive protein delta compared to conservative fluid resuscitation, as long as patients do not have a 48-hour fluid balance greater than 4000 ml at 48 hours, because at this point the levels of delta C-reactive protein and delay in starting oral intake are greater compared to patients with a global balance less than 4000 ml, in addition to requiring loop diuretics in a higher percentage.

References

1.- Xiu‑Wei Li. et al. Comparison of clinical outcomes between aggressive and non-aggressive intravenous hydration for acute pancreatitis: a systematic review and meta-analysis. Critical Care (2023) 27:122.
2.- Crosignani et al. Intravenous fluid therapy in patients with severe acute pancreatitis admitted to the intensive care unit: a narrative review Annals of Intensive Care (2022) 12:98.
3.- Marcello Di Martino, et al. Systematic review and meta-analysis of fluid therapy protocols in acute pancreatitis: type, rate and route, HPB 2021, 23, 1629–1638.
4.- James L. Buxbaum, et al. Early Aggressive Hydration Hastens Clinical Improvement in Mild Acute Pancreatitis. Am J Gastroenterol 2017; 112:797–803.
5.- E de-Madaria et al., Fluid resuscitation with lactated Ringer’s solution vs normal saline in acute pancreatitis: A triple-blind, randomized, controlled trial, United European Gastroenterology Journal 2018, Vol. 6(1) 63–72.
6.- A. Aggarwal, M. Manrai, R. Kochhar. Fluid resuscitation in acute pancreatitis World J Gastroenterol 2014 December 28; 20(48): 18092-18103.
7.- S. Zhou, C. Buitrago, A. Foong et al. Comprehensive meta-analysis of randomized controlled trials of Lactated Ringer’s versus Normal Saline for acute pancreatitis Pancreatology 21 (2021) 1405-1410.

Introduction

Ulcerative colitis (UC) disease course is unpredictable at the diagnosis and its management is still based on a "one-size-fits-all" approach.

Aims & Methods

We aimed to investigate the predictive factors of a rapidly progressive disease course in pediatric UC.
This was a retrospective case-control study conducted at the Pediatric Gastroenterology Unit of Umberto I Hospital in Rome. We included newly diagnosed UC patients aged < 18 years, with a minimum follow-up of 24 months. Demographic data, clinical features, laboratory, endoscopic and histologic findings at the diagnosis were collected and compared between patients with indolent UC and those with a rapidly progressive (RP) course. Children were classified as having a RP course if they experienced at least one of the following within the first 24 months after diagnosis: acute severe colitis, need for colectomy, necessity to transition to anti-TNFα therapy, or initiation of second-line biologic therapy.

Results

One hundred-sixteen patients were included, 67 (58 %) with a RP course and 49 (42 %) with an indolent disease. RP Children had higher age (11.5 vs 9, p=0.0008), PUCAI (50 vs 40, p=0.0005) and UCEIS (4 vs 3, p=0.002) at the diagnosis than those with indolent course. Hemoglobin was lower in the RP group (11.5 vs 12.3 g/dL, p=0.05). RP children had higher rate of cecal patch at endoscopy (18 % vs 2 % p=0.007) and a lower rate of sclerosing cholangitis (0 vs 8.2%, p=0.02). No differences were observed for all other clinical, laboratory, and histologic findings. Multivariate analysis confirmed that age and the presence of a cecal patch were associated with the risk of RP course (p=0.02, and p=0.04, respectively).

Conclusion

Among the clinical and easily obtainable information at the diagnosis in children with UC, an older age at the diagnosis, along with an endoscopic finding of a cecal patch seem associated with the risk of a more aggressive disease. Such results warrant confirmation in larger prospective cohorts for a future personalized approach to UC.