bluuebunny/crossref_metadata_2025 huggingface dataset:
Diffusion with preferential relocation in a confining potential
Authors: Boyer Denis , Evans Martin R , Majumdar Satya N
Published: January 2025

We study the relaxation of a diffusive particle confined in an arbitrary external potential and subject to a non-Markovian resetting protocol. With a constant rate r, a previous time τ between the initial time and the present time t is chosen from a given probability distribution

K
(
τ
,
t
)

, and the particle is reset to the position that it occupied at time τ. Depending on the shape of

K
(
τ
,
t
)

, the particle either relaxes toward the Gibbs–Boltzmann distribution or toward a non-trivial stationary distribution that breaks ergodicity and depends on the initial position and the resetting protocol. From a general asymptotic theory, we find that if the kernel

K
(
τ
,
t
)

is sufficiently localized near τ = 0, i.e. mostly the initial part of the trajectory is remembered and revisited, the steady state is non-Gibbs–Boltzmann. Conversely, if

K
(
τ
,
t
)

decays slowly enough or increases with τ, i.e. recent positions are more likely to be revisited, the probability distribution of the particle tends toward the Gibbs–Boltzmann state at large times. In the latter case, however, the temporal approach to the stationary state is generally anomalously slow, following for instance an inverse power law or a stretched exponential, if

K
(
τ
,
t
)

is not too strongly peaked at the current time t. These findings are verified by the analysis of several exactly solvable cases and by numerical simulations.
Monolithic U-shaped crystal design for TOF-DOI detectors: a flat top versus a tapered top
Authors: Kiyokawa Miho , Kang Han Gyu , Yamaya Taiga
Published: January 2025

For brain-dedicated positron emission tomography (PET) scanners, depth-of-interaction (DOI) information is essential to achieve uniform spatial resolution across the field-of-view (FOV) by minimizing parallax error. Time-of-flight (TOF) information can enhance the image quality. In this study, we proposed a novel monolithic U-shaped crystal design that had a tapered geometry to achieve good coincidence timing resolution (CTR) and DOI resolution simultaneously. We compared a novel tapered U-shaped crystal design with a conventional flat-top geometry for PET detectors. Each crystal had outer dimensions of 5.85 × 2.75 × 15 mm3, with a 0.2 mm central gap forming physically isolated bottom surfaces (2.85 × 2.75 mm2). The novel U-shape crystal design with a tapered top roof resulted in the best CTR of 201 ± 3 ps, and DOI resolution of 3.1 ± 0.6 mm, which were better than flat top geometry. In the next study, we plan to optimize the crystal surface treatment and reflector to further improve the CTR and DOI resolution.
Artificial synapse using flexible and air-stable Cs3Bi2I9 perovskite memristors
Authors: Yumlembam Radharani , Gogoi Himangshu Jyoti , Palathinkal Roy Paily , Mallajosyula Arun Tej
Published: January 2025

Von Neumann bottleneck necessitates the creation of dedicated processors for neuromorphic artificial intelligence tasks such as in-memory computing, where memristors are formulated as synapses. Perovskites are great candidates for memristors owing to their mixed ionic–electronic conduction and their compatibility with cost-effective processing techniques. In this work, we have fabricated a highly stable, lead-free, and flexible perovskite memristors by e-beam evaporation of hot-pressed zero-dimensional (0D) Cs3Bi2I9 pellets. These memristors exhibit reproducible bipolar resistive switching with low operating voltages of −0.18 V and 0.26 V, an excellent ON/OFF ratio (>105), and high endurance (>104 cycles). They were air-stable for more than 30d and were repeatedly tested under high humidity (>80%) atmospheric conditions without encapsulation. The resistive switching in these devices persists even under applied mechanical stress up to a bending radius of 5 mm. A 4 × 4 crossbar array of these Cs3Bi2I9 memristors has been fabricated, which gave a device yield of 81%. Furthermore, their potential for use as artificial synapses has been demonstrated by obtaining critical neuromorphic characteristics such as spike duration dependent plasticity, paired pulse facilitation, and long-term plasticity. This work also shows that 0D Cs3Bi2I9 memristors have the potential to mimic biological synaptic functions of learning and forgetting, which may be useful in realizing flexible and low-power neuromorphic circuits in the near future.
Entropy and curvature: Beyond the Peres-Tetali conjecture
Authors: Caputo Pietro , Münch Florentin , Salez Justin
Published: January 2025

We study Markov chains with non-negative sectional curvature on finite metric spaces. Neither reversibility, nor the restriction to a particular combinatorial distance is imposed. In this level of generality, we prove that a 1-step contraction in the Wasserstein distance implies a 1-step contraction in relative entropy, by the same amount. Our result substantially strengthens a recent breakthrough of the second author, and has the advantage of being applicable to arbitrary scales. This leads to a time-varying refinement of the standard Modified Log-Sobolev Inequality (MLSI), which allows us to leverage the well-acknowledged fact that curvature improves at large scales. We illustrate this principle with several applications, including birth and death chains, colored exclusion processes, permutation walks, Gibbs samplers for high-temperature spin systems, and attractive zero-range dynamics. In particular, we prove an MLSI with constant equal to the minimal rate increment for the mean-field zero-range process, thereby answering a long-standing question.
Women’s and Men’s Work in the Transition from Early Modern to Modern Society
Authors: Ågren Maria
Published: January 2025

This chapter situates the question—how did the division of work between men and women change in the transition from early modern to modern society?—within a larger research field. It argues that methodological consistency is essential for a study that bridges the traditional but somewhat arbitrary divide between these two periods. It makes the case that the transition to modernity—understood as the late nineteenth century—should be studied both ‘backwards’, from the point of view of modern society, and ‘forwards’, from the point of view of early modern society. It demonstrates the fruitfulness of studying work as practice, of including both paid and unpaid work, and of using court records as source. It discusses the role of marriage and the marital partnership in the past and contrasts the two-supporter model against the male-breadwinner model.
The Study Area
Authors: Ulväng Marie , Israelsson Jezzica , Kardell Örjan , Lindström Jonas
Published: January 2025

This chapter introduces the mid-Swedish local society in focus: the city of Västerås, west of Stockholm on Lake Mälaren, and the neighbouring rural districts of Snevringe and Tuhundra, all in the county of Västmanland. It identifies some of the major processes characterizing the 160 years covered in the book: population growth and proletarianization, enclosures, liberalization of the economy, improved infrastructure, and transition from an estate-based to a diversified class society. It identifies Västerås as a hub for trade and distribution of raw materials, especially iron and grain between Bergslagen and Stockholm. It describes the organization of hamlets, villages, and towns, and provides population data. In Västmanland, as in the country as a whole, the population comprised more women than men throughout the study period. In 1760, there were 82 men to 100 women; in 1880, the gap was reduced to 91 men to 100 women.
Method, Sources, and the GaW2 Data Set
Authors: Lindström Jonas , Kardell Örjan , Ulväng Marie
Published: January 2025

This chapter presents the methodology behind the study and describes the source base in detail. It justifies the verb-oriented method with reference to its capacity to capture all forms of work and to do so across large swathes of time. The method also accords with how the United Nations and ILO define and measure work. The chapter acknowledges some drawbacks of the method but concludes that its benefits dominate. The sources for the extraction of verb phrases describing work activities—nearly 19,000 observations—consist of court records (62%), accounts, ego-documents, registers, and petitions. Additional sources are church records and probate inventories. The chapter points to some biases: married men are overrepresented in the data, women’s share of the observed activities decline over time, and some forms of work are underrepresented (agriculture, textile work, and domestic work). It concludes that by mapping people’s activity patterns, it is possible to identify both repertoires of practices, that is, what men and women typically did in this society, and the gender division of work within a given field.
Bridging the gap: Evaluating ChatGPT-generated, personalized, patient-centered prostate biopsy reports
Authors: Proctor Erin S , Nusbaum David J , Lee John M , Benirschke Robert C , Freedman Alexa , Raster Gregory , Glaser Alexander P , Labbate Craig V , Higgins Andrew M , Helfand Brian T , Glassy Eric F , Joseph Lija , Edelstein Robert A , Krupinski Elizabeth A , Alnajar Hussein , Kearns James T , Groth John V
Published: January 2025

Objective

The highly specialized language used in prostate biopsy pathology reports coupled with low rates of health literacy leave some patients unable to comprehend their medical information. Patients’ use of online search engines can lead to misinterpretation of results and emotional distress. Artificial intelligence (AI) tools such as ChatGPT (OpenAI) could simplify complex texts and help patients. This study evaluates patient-centered prostate biopsy reports generated by ChatGPT.

Methods

Thirty-five self-generated prostate biopsy reports were synthesized using National Comprehensive Cancer Network guidelines. Each report was entered into ChatGPT, version 4, with the same instructions, and the explanations were evaluated by 5 urologists and 5 pathologists.

Results

Respondents rated the AI-generated reports as mostly accurate and complete. All but 1 report was rated complete and grammatically correct by the majority of physicians. Pathologists did not rate any reports as having severe potential for harm, but 1 or more urologists rated severe concern in 20% of the reports. For 80% of the reports, all 5 pathologists felt comfortable sharing them with a patient or another clinician, but all 5 urologists reached the same consensus for only 40% of reports. Although every report required edits, all physicians agreed that they could modify the ChatGPT report faster than they could write an original report.

Conclusions

ChatGPT can save physicians substantial time by generating patient-centered reports appropriate for patient and physician audiences with low potential to cause harm. Surveyed physicians have confidence in the overall utility of ChatGPT, supporting further investigation of how AI could be integrated into physicians’ workflows.
Implantable device for intrathecal pseudodelivery of drugs: surgical protocol and proof-of-concept in a porcine model
Authors: Pérez-Martín E , Rodríguez-Cañón M , Roces-Llorián C , Álvarez G , Prado C , Tomás-Zapico C , Menéndez-González M
Published: January 2025

Introduction

Immunotherapy for neurodegenerative diseases often induces severe side effects due to the interaction of monoclonal antibodies (mAb) with the immune and nervous systems. We present a novel platform based on an intrathecal device that clears target molecules from cerebrospinal fluid (CSF) without releasing mAb into the organism (pseudodelivery). This non-GLP pilot study evaluates the device’s functionality and the feasibility and safety of implanting the human prototype in a porcine model.

Methods

Seven female pigs were randomly assigned to three groups: device with mAb solution (n=3), device with artificial CSF (n=3), and a naïve control (n=1). Surgery involved inserting a catheter via lumbar puncture at L4-L5 and advancing it to T7-T8. The catheter was connected to a reservoir implanted in a subcutaneous pocket. Solutions were exchanged percutaneously every 4 weeks. Device functionality was tested using ELISA and SIMOA® every 4 weeks. Daily behavioural monitoring, along with biweekly body weight, temperature, and haematology analyses, were conducted until termination at week 13.

Results

Preliminary analyses demonstrated the device’s functionality by verifying CSF influx into the device and preventing drug outflow to the CNS. All animals exhibited a healthy status, with slight deviations that normalised after one month. Body weight remained stable over time, with minimal reduction in two animals. The main complications included pain, slight gait loss, and subcutaneous pocket infections.

Conclusion

Implantation of a human medical device for intrathecal pseudodelivery of immunotherapy is feasible and safe in pigs, and its functionality has been demonstrated. Further research is needed to refine surgical procedures and long-term implantations.
Utility of 3D Reconstruction for Surgical Planning in the Treatment of Retroperitoneal Sarcomas
Authors: Jiménez Fuertes M , Vizarreta Figueroa A , Carrillo J , Martín M , Romero Triana D , Domínguez Prieto V , Qian S , Villarejo Campos P
Published: January 2025

Introduction

Retroperitoneal sarcomas (RPS) are rare tumors that present significant challenges due to their location and proximity to vital structures. Accurate surgical planning is essential to optimize outcomes, and 3D reconstruction has emerged as a valuable tool for preoperative planning and intraoperative guidance.

Methods

We present our experience of 20 cases of RPS where 3D reconstruction was integrated into the surgical planning process. We retrospectively reviewed 20 patients who underwent surgery at our institution from 2021 to 2024. Preoperative CT or MRI scans were performed on all patients and used to generate 3D models of the tumors with specialized software. These 3D models facilitated the planning of surgical approaches, assessing resectability, and provided immersive visualization through virtual reality (VR) tools for enhanced surgical preparation.

Results

All 20 patients underwent curative-intent surgery using tailored surgical approaches based on 3D modeling insights. The models offered detailed visualization of the tumors and their relationships with adjacent structures, improving the precision of resection and margin assessment.

Conclusion

3D reconstruction proved to be a useful tool in the surgical treatment of RPS, improving preoperative planning and intraoperative guidance. It also provided benefits in medical education and enhanced patient understanding of their disease and treatment plan.
OP41 Duvakitug (TEV-48574), an anti-TL1a monoclonal antibody, demonstrates efficacy and favourable safety as an induction treatment in adults with moderately to severely active ulcerative colitis: Results from a phase 2b, randomised, double-blind, placebo-controlled, dose-ranging, basket trial (RELIEVE UCCD)
Authors: Reinisch W , Stepek D , Kempinski R , Danese S , Sands B E , Ratiu-Duma B , Singh R , Barkay H , Raphael G , Jairath V
Published: January 2025

Background

Duvakitug is a human IgG1 monoclonal antibody that inhibits TL1A binding to DR3, a key driver of inflammation and fibrosis. In comparison, it has less binding selectivity for DcR3, which regulates excess TL1A, maintaining homeostasis. Duvakitug has demonstrated reduced inflammation and fibrosis in colitis animal models.1 The efficacy and safety of duvakitug in adults with moderately to severely active ulcerative colitis (UC) and Crohn’s disease was assessed in a phase 2b basket trial (NCT05499130).2

Methods

RELIEVE UCCD was a randomised, placebo (PBO)-controlled, double-blind induction study. The UC cohort comprised of adults with moderately to severely active disease with inadequate response, loss of response or intolerance to previous conventional and/or advanced therapies (ATs). Eligible patients were randomised to receive subcutaneously a 2250 mg loading dose of duvakitug or PBO, followed by either duvakitug 450 mg, 900 mg or PBO (1:1:1; stratified by prior AT) every 2 weeks.2 The primary endpoint was clinical remission (per modified Mayo score) at week 14. Safety was assessed by adverse event (AE) reporting and laboratory monitoring.

Results

In total, 137 patients were randomised, treated and included in the UC cohort analysis (450 mg: n=47; 900 mg: n=46; PBO: n=44). Demographics and baseline characteristics were generally similar across arms (Table 1). Both duvakitug doses successfully achieved the week 14 primary endpoint of clinical remission (36% [450 mg], 48% [900 mg] versus 20% [PBO]; PBO-adjusted rates: 16% [450 mg], 27% [900 mg]). The results were statistically significant based on the prespecified Bayesian analysis, with a >0.90 posterior probability that each duvakitug dose is superior to PBO. Duvakitug treatment effect was observed in both AT-experienced and -naïve patients (Table 2). AE incidence was lower for duvakitug (49% [450 mg], 43% [900 mg]) versus PBO (52%), as was incidence of AEs leading to discontinuation (0% [450 mg], 2% [900 mg] versus 5% [PBO]).

Conclusion

Duvakitug demonstrated statistically significant and clinically meaningful treatment responses compared to PBO in patients with UC; it was well tolerated with no emergent safety signals observed. These induction study results support further development of duvakitug as a potential treatment option for patients with moderately to severely active UC.

Funding

Duvakitug is being developed in partnership by Teva and Sanofi.

References

1. Clarke AW, et al. MAbs. 2018;10:664–77.

2. Reinisch W, et al. 19th Congress of European Crohn’s and Colitis Organization (ECCO) 2024; 21–24 February 2024; Stockholm, Sweden. Abstract P998.
DOP053 Efficacy of appendectomy in inducing remission in moderate-to-severe ulcerative colitis: preliminary one year results of a multicentre prospective cohort study (COSTA)
Authors: Visser E ,   COSTA study group
Published: January 2025

Background

This study aimed to evaluate the efficacy of appendectomy in inducing remission in patients with moderately to severely active ulcerative colitis (UC), despite biological or small molecule therapy.

Methods

This multicentre, prospective cohort study included patients aged ≥16 years with moderately to severely active UC (total Mayo score [TMS] ≥5; endoscopic subscore of ≥2) despite optimised prior treatment with advanced medical therapy (i.e. biological/small molecule exposed). Eligible patients where those for whom the next treatment step was considered to be switching to a Janus kinase (JAK) inhibitor or undergoing (procto)colectomy. Enrolled patients were counselled (patient-preference model) to either undergo laparoscopic appendectomy (study intervention) or continue standard step-up therapy, which included: 1) switching to a JAK inhibitor or 2) undergoing staged restorative proctocolectomy with ileoanal pouch. The primary outcome was the proportion of patients achieving clinical remission (TMS≤2 with no subscore >1) at 12 months without therapy failure. Therapy failure was defined as (re)start of oral corticosteroids, switch of advanced therapy, start trial medication or proctocolectomy. Patients without therapy failure and pMS≤2 at 12 months without endoscopic follow-up were considered failures for the primary outcome. Primary analyses will be conducted based on a modified intention-to-treat (mITT) principle. Patients who received the assigned intervention (appendectomy in the intervention group, proctocolectomy in the control group) or at least one dose of the assigned medication (JAK-inhibitor in the control group) will be analysed. The last patient 12-month follow-up visit was completed in September 2024.

Results

A total of 120 patients were included in the mITT analysis (appendectomy group: n=65, JAK-inhibitor group: n=50, proctocolectomy group: n=5). Numerical baseline differences across groups (appendectomy vs JAK-i vs proctocolectomy) were: male gender (35.4% vs 54.0% vs 20.0%, p=0.08), family history of IBD (33.8% vs 12.0% vs 0%, p=0.02), current smoking (13.8% vs 2.0% vs 0%, p=0.22), disease extent (E3: 41.5% vs 60.0% vs 80.0%, p=0.18), TMS (median 9 [IQR, 7-10] vs 9 [IQR, 8-10] vs 10 [0-.], p=0.16) and concomitant oral corticosteroids (26.2% vs 46.0% vs 80.0%, p=0.01). The appendectomy group had a significantly higher proportion of patients in clinical remission at 12 months without therapy failure after appendectomy, compared to the JAK inhibitor group (33.8% vs 12.0%, p=0.007, Figure 1.). Final analysis are scheduled for Q4 2024 and Q1 2025.

Conclusion

Appendectomy may be an effective treatment option for inducing clinical remission in moderately to severely active UC. Final analyses are expected in Q1 2025.
DOP082 Disease clearance prevents negative outcomes in ulcerative colitis patients and enhances the impact of independently achieving clinical, endoscopic, or histological remission.
Authors: Ramos Lopez L , De la Barreda R , Nicólas-Pérez D , Quintero E , Hernández-Guerra M
Published: January 2025

Background

Intestinal inflammation even without endoscopic evidence is associated with worse clinical outcomes in ulcerative colitis (UC) . However, recent advances in UC treatments have the potential to modify the disease’s natural history and improve clinical outcomes if inflammation is controlled. The emerging concept of "disease clearance" (DC) in UC aims to achieve combined clinical, endoscopic, and histological remission. Whether DC is associated with better outcomes remains unclear.

Objective

To evaluate the impact of DC during follow-up in UC patients.

Methods

A prospective longitudinal cohort study was conducted between 2012 and 2017. Consecutive UC patients undergoing colonoscopy were included, and those with clinical follow-up longer than 18 months were analyzed. At the time of colonoscopy, clinical condition (PRO: number of stools per day and presence of blood in the stool) and endoscopic index (Mayo endoscopic score, MES) were evaluated. Histological analysis (Geboes score, GS) of biopsies from the area with the greatest macroscopic inflammation was performed. Disease clearance was defined as simultaneous clinical (PRO2 = 0; normalized stool frequency without blood), endoscopic (MES = 0), and histological (GS ≤ 2) remission. Patients were monitored every 6 months to assess negative outcomes, defined as clinical relapse requiring therapy, treatment escalation, hospitalization, or colectomy.

Results

A total of 101 UC patients were included (50 females; 44.5 ± 15 years; UC extent: E3: 32.3%, E2: 52.5%, E1: 15.2%; median time since diagnosis: 103 ± 102 months; 13.3% on anti-TNF agents). DC was present in 52 patients (51.5%) at baseline colonoscopy. During follow-up, 40 patients (39.6%) experienced a negative outcome, most commonly requiring corticosteroids (57.6%). Patients who achieved DC had a significantly lower rate of negative outcomes compared to those without DC (21.2% vs. 59.2%, p < 0.0001). Kaplan-Meier curves confirmed a lower risk of clinical relapse in patients with DC (log-rank, p = 0.001) (Fig. 1). Among patients with endoscopic remission (MES = 0; n = 60), only those with DC (n = 52) had a lower risk of negative outcomes (21.2% vs. 75%, p = 0.005, log-rank, p = 0.0015) (Fig. 1A). Additionally, achieving DC reduced the risk of flare-ups even in patients with clinical remission (PRO2 = 0) (p = 0.044) (Fig.1B) or histological remission (GS ≤ 2) (p = 0.039) (Fig. 1C).

Conclusion

DC in UC patients reduces the risk of negative outcomes during follow-up, supporting its inclusion as a key composite treatment goal in UC management.
DOP129 Integrating genetic risk and omics insights to characterize the molecular alterations in inflammatory bowel disease
Authors: Mateos B , Miguel González J A , Gaite-Reguero A , Rodríguez-Lago I , M Marigorta U
Published: January 2025

Background

High-throughput omic technologies have enabled detailed molecular profiling of IBD patients. Traditionally, studies focus on a single molecular layer (e.g., genomics, transcriptomics, proteomics) to understand the complex interactions driving IBD. We can distinguish two strategies: 1)Genetic studies, such as genome-wide association studies (GWAS), which have identified >300 SNPs linked to increased IBD risk. 2)Omic profiling of patient tissues, which identifies hundreds of genes and molecular pathways altered in disease. We performed integrative analysis to explore consistency across omic findings and to obtain a synthetic picture of the sequence of molecular events that lead to IBD.

Methods

We used three approaches to clarify the interplay between genes identified through GWAS and those identified through other omics. First, we used Mendelian Randomization to infer causality and determine the directionality of interactions between the genes identified through all strategies. We incorporated 220 additional traits using summary statistics from the GWAS Atlas to validate our findings. Second, we assessed the impact of environmental exposures, such as smoking and diet. Finally, we used polygenic risk scores (PRS) to explore if variability in genetic risk shapes the differences in omic findings observed across patients.

Results

We made four relevant findings regarding the molecular changes in IBD. First, we noted low overlap between genes involved in genetic risk and those altered in patient samples. For instance, only 7% of genes identified by GWAS are differentially expressed at the transcriptomic/proteomic levels in IBD, and only 8% of genes identified by omics are significant in GWAS results. This trend was consistent across omic technologies and disease stages. Second, we infer that genes involved in genetic risk often modulate the expression levels of genes altered in patients. This trend is not bidirectional, implying that GWAS genes are drivers of the downstream transcriptional changes that characterize patients. Third, alterations in patients do not strategy according to individual PRS, suggesting that genetic effects lead to alterations pervasively shared across patients. Finally, environmental risk exposures, such as smoking or diet, do not impact GWAS genes (p=0.91) but have ample effects on omics-identified genes (p=1.8 x10-8).

Conclusion

Genetic risk variants identified by GWAS act as upstream regulators of the main patient alterations, while environmental risk factors exert independent effects on these alterations. The model suggests that omic research does not uncover causal alterations, but reveals a convergent endpoint that characterizes IBD patients, regardless of their genetic predisposition and external exposures.
P0026 Multi-omics phenotyping characterizes perturbed molecular divergence underlying different clinical scenarios of under-treatment inflammatory bowel disease
Authors: Lee H S
Published: January 2025

Background

Clinically heterogeneous spectrum and molecular phenotypes of inflammatory bowel disease (IBD) remain to be comprehensively elucidated.

Methods

This study set out to explore the serum molecular profiles (I) underlying the disease subtypes, in association with (II) elevated fecal calprotectin and (III) disease activity states, (IV) upon treatment escalation, and (V) in patients who needed treatment escalation. The serum proteome, metabolome, and lipidome of 75 IBD patients were profiled. Single- and multi-omic data analysis was performed to determine differential analytes and integrative biosignatures.

Results

In (I), chronic inflammation along with tight junction disturbances promoting impaired barrier function might underly the differences between IBD subtypes. Compared to Crohn’s disease, ulcerative colitis showed a lower abundance of hypoxanthine correlating negatively with cell adhesion-related proteins of ITGB2, CD200, PRELP, and positively with lysophosphatidylcholines [LPC(16:0-SN1), LPC(O-18:1)]; and up-regulation of bile acids and FGF19. For (II), while proteins related to inflammatory-promoting signaling pathways, sphingomyelins (SMs), and LPC were increased; bile acids, amino acids, and triacylglycerols (TGs) were decreased. Not only in (II), TGs were a major class change in (III), whose abundance was consistently higher in the active state. This, along with decreased SMs levels, correlated strongly with the up-regulation of inflammatory-inducing proteins (CXCL9, CXCL1, ITGB2, IL17A). In (IV), treatment escalation promoted augmentations of signaling pathways-related proteins and triggered significant metabolome responses, especially decreased amino acids. Noticeably, the levels of TGs were consistently increased in the post-treatment escalation group, thereby suggesting treatment response with relation to (III). For (V), down-regulation of signaling pathways-related proteins and higher levels of SMs and PCs was observed. A consistent decrease of TGs in patients who needed treatment escalation along with lower level of TGs in elevated calprotectin group could imply for the inflammatory level.

Conclusion

This study provided the multi-ome profiles of IBD patients in five clinical scenarios and laid a foundation for opening new doors for disease management and treatment.

References

M. Agrawal, K.H. Allin, F. Petralia, J.-F. Colombel, T. Jess, Multiomics to elucidate inflammatory bowel disease risk factors and pathways, Nature Reviews Gastroenterology & Hepatology 19(6) (2022) 399-409.
P0037 ATF7 Deficiency Exacerbates Mitochondrial Dysfunction and Intestinal Inflammation in Ulcerative Colitis
Authors: Chen Y , Liangru Z
Published: January 2025

Background

Ulcerative colitis (UC), a chronic inflammatory bowel disease, is marked by sustained inflammation and excessive apoptosis of intestinal epithelial cells (IECs). Despite progress in understanding UC pathogenesis, the role of activating transcription factors (ATFs) in disease progression remains elusive. Here, we profile the expression of ATF family members (ATF1–ATF8) in the colonic mucosa of UC patients and identify ATF7 as a critical regulator of mitophagy through its control of PTEN-induced kinase 1 (PINK1).

Methods

Expression levels of ATF1–ATF8 were quantified in colonic mucosal samples from UC patients (n = 200) and healthy controls (n = 100) via quantitative PCR and immunohistochemistry. Using IEC-specific ATF7 and PINK1 knockout mouse models and human CCD 841 CoN colonic epithelial cells, we employed ChIP-seq, dual-luciferase assays, transmission electron microscopy, and immunofluorescence to elucidate their roles in mitophagy and disease progression. Clinical correlation between ATF7 expression and disease severity was assessed using the Mayo score.

Results

ATF7 expression was significantly reduced in UC patients and inversely correlated with disease severity. Mechanistically, ATF7 was identified as a direct transcriptional activator of PINK1, a key mitophagy regulator. Loss of ATF7 or PINK1 disrupted mitophagy, exacerbating mitochondrial dysfunction, IEC apoptosis, and colonic inflammation in vivo and in vitro.

Conclusion

Our findings uncover a pivotal ATF7-PINK1 axis that governs mitophagy and limits UC progression. The inverse correlation between ATF7 expression and UC severity highlights its potential as a therapeutic target, offering new avenues for intervention in this debilitating disease.
P0080 Thalidomide-Carbomer Gel for Rectal Administration Alleviates DSS-Induced Colitis and fibrosis in Mouse by Targeting S1pr5 and Il1f9 (Il36γ)
Authors: He X , Jiang L , Hu J , Yang H
Published: January 2025

Background

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the digestive tract, including ulcerative colitis (UC) and Crohn's disease (CD). Thalidomide, an inhibitor of Tnf-α, is used in IBD treatment but is limited by systemic side effects when taken orally. This study aimed to develop a thalidomide-carbomer gel for rectal administration to reduce systemic side effects and explore new therapeutic targets.

Methods

An acute colitis model was established using DSS-induced wild-type C57 mice. Mice were treated with thalidomide-carbomer gel via rectal administration. Body weight, disease activity index (DAI), colon length, liver and spleen indices, and histological changes were evaluated. RNA-seq, qPCR, WB, and immunohistochemistry were performed to assess inflammation and fibrosis markers. In vitro, an LPS-induced inflammation model was constructed using NCM460 cells, and cell migration and inflammatory cytokine expression were analyzed following drug treatment.

Results

Thalidomide-carbomer gel significantly alleviated symptoms of DSS-induced colitis in mice, including reducing body weight loss, DAI score, colon shortening, and liver/spleen indices. Histological analysis showed decreased infiltration of inflammatory cells and reduced expression of Tnf-α, α-SMA, and Tgf-β. The gel also enhanced intestinal barrier function by increasing the expression of E-cadherin and Occludin. RNA-seq and qPCR analyses suggested that the therapeutic effect may involve the regulation of S1pr5 and Il1f9（Il36γ）pathways. Toxicity tests indicated no significant adverse effects on hematological or liver and kidney functions. In NCM460 cells, thalidomide inhibited LPS-induced cell migration and IL-6 release.

Conclusion

Thalidomide-carbomer gel, through the inhibition of Tnf-α, S1pr5, and Il1f9 (Il36γ), significantly improved DSS-induced colitis and fibrosis in mouse, showing promising therapeutic potential for IBD.
P0199 Development of a high-throughput multiplex immunofluorescence and an AI-assisted image analysis tool to study T cells dynamics in pre-clinical rodent models of IBD
Authors: Preti M , Hofving T , Bretin A , Benonisson H , Gonzalez-King Garibotti H , Burgueno J , Borde A , Birrel M , Preite S , Piras A
Published: January 2025

Background

T cell therapies are emerging as a new approach to treat and cure patients suffering from immune diseases where T cell homeostasis is no longer maintained. For the evaluation of treatments in pre-clinical rodent models, tools are required that enable fast, observer-independent and high-resolution analysis of different T cells in tissue sections. Multiplex staining of tissue samples provides a valuable opportunity for comprehensive analysis of cellular dynamics with enhanced spatial resolution and tissue context compared to traditional staining and flow cytometry methods. We have developed a high-throughput multiplex immunofluorescence panel for detecting different T cell types and activation status in mouse models of inflammatory bowel disease (IBD). Moreover, we used an AI-assisted method to enhance image analysis, enabling automated, accurate, and quantification of complex cellular interactions.

Methods

For the development and optimization of the various stainings we used formalin-fixed paraffin embedded (FFPE) mouse colon sections from an efficacy study with murine polyclonal regulatory T cells (Tregs) in the T cell transfer mouse model of IBD, enabling access to sections with healthy versus diseased pathology, as well as samples where Tregs were transferred to reduce colon pathology. Multiplex staining was performed with antibodies (such as CD3, FOXP3, CD25, CD69, CTLA-4 and KI67) using a Leica BOND RX autostainer, by applying sequential primary antibody staining, followed by secondary HRP-conjugated antibodies and Opal-TSA chemistry. Whole slide images (WSI) were generated by a Phenoimager HT (Akoya) and analyzed using Visiopharm software, with DAPI+ nuclei detection via AI-based application.

Results

We successfully developed a multiplex panel that enables high throughput staining and spatial resolution analysis of over six markers. We were able to determine the activation status of different subtypes of T cells and their specific localization in the colon. We could quantify infiltration of activated effector T cells (Teffs) in both the mucosa and submucosa in colon samples with high pathological scores, as well as FOXP3+ cells in samples from mice treated with Tregs.

Conclusion

We developed an Opal-based multiplex immunofluorescence method to detect T cells in mouse colon samples, focusing on activation and proliferation markers. Additionally, an AI-assisted image analysis tool that provided fast, reproducible, and quantitative results with spatial resolution. This innovative multiplex method holds promise for adaptation to different mouse models of colitis and other rodent models related to immune diseases, furthering its potential impact in the area of T cell therapy research.
P0202 Modeling Inflammatory Bowel Disease in mice with “Humanized” immune system
Authors: Coupe B , Charton A , Placide F , Machet F
Published: January 2025

Background

Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease with unknown etiology. Dextran sulfate sodium (DSS) induced colitis is a common preclinical mouse model in IBD research. DSS colitis involves activation of the submucosal immune system and can be used to study Ulcerative Colitis characteristics in different phases (acute, chronic and remission) and predict compound efficacy. However, optimizing translation to human is still needed and the use of mice with Human Immune System (HIS) provide a better model to study human immune system responses in vivo. HIS mice are created by transplanting human immune cells or their progenitor cells into highly immunodeficient recipient mouse hosts, thereby "humanizing" their immune systems. In this study we discussed colitis feature and the use of humanized mice model for testing therapeutics in preclinical studies

Methods

15-weeks-old female HIS mice were treated with 2.5% dextran sulfate sodium (DSS) in drinking water (ad.lib.) for 5 days to induce acute colitis. Colonic and systemic human cytokines were assessed by MSD plex assay. Human immune cell infiltration into the colon was measured by flow cytometry. Colonic histological damage was assessed on colon Swiss roll after H&E staining

Results

HIS mice challenged with DSS exhibited body weight loss and increase disease activity index (loose stool or diarrhea, rectal bleeding) compared to naive HIS mice. HIS-DSS mice show a strong human pro-inflammatory response, including elevated hIL-1B, hTNF, hIL-6 in plasma and colon as well as specific human cytokines (MCP-4, IL-8, IL-26, IL-37…). Colon microscopic analysis show loss of goblet cells, loss of crypt structure and increase of inflammatory cell infiltration at the level of mucosa and submucosa

Conclusion

These data show a significant increase of human pro-inflammatory cytokines after DSS intake as well as histologic score characteristic of Ulcerative Colitis. They also confirm that HIS mice represent a relevant model for the preclinical assessment of therapeutics in IBD.
P0221 The role of caffeine and its metabolites in the modulation of intestinal inflammation and epithelial barrier integrity
Authors: Kulokiene U , Inciuraite R , Butaite G , Salteniene V , Kiudelis V , Jonaitis L V , Kiudelis G , Kupcinskas J , Skieceviciene J
Published: January 2025

Background

Methylxanthine caffeine and its metabolites are widely consumed bioactive compounds that are known to influence various physiological processes 1. However, their impact on gut health, particularly in modulating inflammation and epithelial permeability, remains underexplored. In this study we aimed to investigate the effects of caffeine and its primary metabolites paraxanthine, theobromine and theophylline on inflammatory responses and barrier integrity in gut epithelial models, providing insights into their potential role in gastrointestinal health in the context of Inflammatory bowel disease (IBD).

Methods

Primary screening of different concentrations of caffeine and its metabolites paraxanthine, theobromine and theophylline was performed in Caco-2 cells. Selected metabolites were further tested on inflamed 3D intestinal epithelial organoids derived from ulcerative colitis patient (n = 1) and non-IBD individual (n = 1). Inflammation was induced for 24 h using TNF-α and IFN-γ cytokine mix. The effects on inflammation status and epithelial barrier integrity were tested through targeted gene expression analysis using RT-PCR, while the effects on generation of reactive oxygen species were investigated by Flow cytometry and DHE assay.

Results

Primary screening revealed that both caffeine and its metabolite paraxanthine affected the expression of genes encoding inflammatory cytokines (TNF-α, CXCL9; p < 0.05) and tight junction proteins (OCLN, ZO-1, CLDN1; p < 0.05) and were selected for further analysis in 3D intestinal organoids. Neither caffeine nor paraxanthine reduced the expression of inflammatory cytokine-encoding genes in inflamed intestinal organoids. However, both metabolites significantly restored the expression of tight junction protein-coding genes OCLN, ZO-1 and CLDN1 (p < 0.05). A tendency of reduction in reactive oxygen species production (by 11 %) was also observed after exposure with paraxanthine.

Conclusion

Methylxanthine caffeine and its primary metabolite paraxanthine might have a positive effect on gut epithelial barrier function through restoration of the expression of tight junction protein-coding genes.

Study was funded by the European Union and the State Secretariat for Education, Research and Innovation (SERI) (project: miGut-Health, grant no. 101095470).

References

Reddy V. S. et al. (2024) Pharmacology of caffeine and its effects on the human body. European Journal of Medicinal Chemistry Reports, 10 (100138). https://doi.org/10.1016/j.ejmcr.2024.100138.
P0282 Fibroblast activation protein (FAP)-cleaved type III Collagen [C3F] is a potential marker for intestinal fibrosis in patients with Crohn’s Disease
Authors: Tsapanou Katranara T , Poulsen A , Sorokina Alexdóttir M , Buhl Riis L , Pehrsson M , Rasmussen J , Gögenur I , Burisch J , Karsdal M A , Bay-Jensen A C , Seidelin J B , Mortensen J H
Published: January 2025

Background

Crohn ‘s disease (CD) is characterized by chronic inflammation in the gut, where severe complications such as fibrotic strictures require surgical resection. Stricture development involves excessive extracellular matrix (ECM) deposition due to continuous activation of intestinal myofibroblasts, that further contribute to intestinal fibrogenesis. Emerging data suggests that stricture-related intestinal myofibroblasts overexpress a serine protease called fibroblast activation protein (FAP). Furthermore, type III collagen deposition is increased during fibrosis in all layers of the intestinal tract, and studies have shown elevated collagen degradation in serum from patients with CD. The present study aimed at evaluating the potential of FAP-cleaved type III collagen [C3F] as a serum marker for intestinal fibrosis in CD.

Methods

The cohort consisted of 49 patients with luminal CD and 62 patients with stenotic CD. Clinical assessment was conducted for all patients at baseline and 12 months post study initiation. For the luminal phenotype, endoscopy was performed at both time points. For the stenotic group, radiographical assessment was done prior to surgery and endoscopy was performed at 12 months. C3F was measured in serum at all timepoints for baseline, post-operative day (POD), 1, 3, 6 and 12 months. To compare C3F levels at baseline for luminal vs stenotic phenotype, Mann-Whitney U-test was conducted. For the stenotic group, mixed-effect analysis, with a Dunnett’s multiple comparison, was conducted to compare C3F levels for baseline vs POD and Spearman’s rank correlation was applied.

Results

C3F baseline levels were significantly higher in patients with stenotic CD compared to luminal CD (Figure 1). In the stenotic group, C3F was significantly increased in patients at POD compared to baseline (Figure 1). Furthermore, C3F showed a positive correlation with C-reactive protein (CRP) (ρ=0.28, p=0.006) and a significant negative correlation with disease duration (ρ= -0.257, p=0.048) for patients with the stenotic CD phenotype (Table 1).

Conclusion

C3F was elevated in patients with stenotic CD, with even higher levels after the surgical resection. The data suggests that C3F reflects fibroblast activity during fibrostenosis and tissue remodeling following surgery. The positive correlation with CRP supports the association with inflammation leading to collagen deposition and fibrosis. Interestingly, C3F shows negative correlation with disease duration suggesting that C3F could reflect fibrosis at early stages of stenotic CD. These findings highlight the potential use of C3F as a novel biomarker for intestinal fibrosis in CD.
P0291 Tailoring Crohn’s disease surveillance after ileocolic resection: the importance of inflammatory biomarkers
Authors: Ferreira A I , Lima Capela T , Xavier S , Arieira C , Cotter J
Published: January 2025

Background

Recurrence of Crohn’s disease (CD) after ileocolic resection is common. However, reliable non-invasive monitoring methods are lacking, for instance, the use of faecal calprotectin (FC) has showed inconsistent results in this subgroup of patients. The aim of this study was to evaluate clinical and biochemical factors associated with post-operative endoscopic recurrence in CD patients.

Methods

Retrospective single-center study including patients with CD who underwent ileocolonoscopy for CD surveillance, after ileocolic resection. The patients’ clinical status was evaluated through Harvey-Bradshaw index (HBI), with clinical remission considered as ≤ 4 points. Biochemical parameters included erythrocyte sedimentation rate (ESR), c-reactive protein (CRP) and FC. Clinical and biochemical parameters were evaluated in the 6 months prior to ileocolonoscopy. Post-operative endoscopic recurrence was defined as a Rutgeerts score ≥ i2b.

Results

A total of 81 patients and 121 ileocolonoscopies were included. Most patients were female (55.6%), with a mean age of 48±13 years. Regarding the Montreal classification, 37 patients had ileal disease (45.7%) and 44 ileocolonic disease (54.3%); 9 patients had nonstricturing, nonpenetrating disease (11.1%), 35 stricturing (43.2%) and 37 penetrating disease (45.7%). Nineteen patients had perianal disease (23.5%). The mean time between the surgery and the endoscopic evaluation was 135±79 months. Post-operative endoscopic recurrence was observed in 52 ileocolonoscopies (43.0%).

Symptomatic patients (HBI > 4 points) were 11 times more likely to have post-operative endoscopic recurrence (OR 10.686, 95%CI 2.930-38.974, p<0.001). Those with post-operative endoscopic recurrence had a significantly higher FC values (median 189 vs 69 µg/g, p<0.001) and higher ESR values (median 14 vs 9 mm, p=0.002). In fact, patients with FC values ≥ 150 µg/g and those with ESR values > 12 mm were 4 and 3 times more likely to have post-operative endoscopic recurrence (OR 3.654, 95%CI 1.605-8.316, p=0.002 and OR 3.059, 95%CI 1.397-6.696, p=0.005, respectively). The presence of post-operative endoscopic recurrence was not associated with CRP values (median 2.9 vs 2.9 mg/L, p=0.466), and neither with mean time between the surgery and the endoscopic evaluation (mean 126±83 vs 142±75 months, p=0.263).

Conclusion

The presence of symptoms (HBI > 4 points), FC values ≥ 150 µg/g and ESR values > 12 mm was associated with post-operative endoscopic recurrence in CD. Therefore, the HBI, FC and ESR values can be used to monitor CD patients after ileocolic resection, and prompt endoscopic evaluation should be performed in those with HBI > 4 points, FC values ≥ 150 µg/g and/or ESR values > 12 mm.