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Background: Bladder cancer is the ninth most prevalent cancer globally. Most cases are urothelial carcinoma, classified as non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC); approximately 70% are diagnosed as NMIBC. Current standard of care for high-risk NMIBC includes transurethral tumour resection, followed by intravesical therapy with Bacillus Calmette-Guérin (BCG). However, significant unmet needs persist due to disease recurrence, BCG unresponsiveness, or progression to MIBC. Radical cystectomy is recommended after BCG unresponsiveness but may not be viable due to its invasiveness and morbidity. The paucity of treatment options for BCG-unresponsive NMIBC has driven research into alternatives such as gene therapy. The bladder’s anatomy allows direct vector–tumour contact, while urine and tissue samples allow for easy monitoring of therapeutic effects. Methods: This narrative review integrates findings from recent clinical and preclinical studies identified through comprehensive searches of peer-reviewed literature to provide an overview of the current landscape of gene therapy for BCG-unresponsive NMIBC. Results: Nadofaragene firadenovec, a recombinant adenovirus delivering interferon alpha-2b (IFNα2b), is the first FDA-approved gene therapy for BCG-unresponsive NMIBC with carcinoma in situ (CIS). A phase III nadofaragene firadenovec study (NCT02773849) demonstrated a 53% complete response (CR) rate at 3 months; and 43% of patients with CIS had bladder preservation at 60 months. Cretostimogene grenadenorepvec (CG0070), an oncolytic vector, demonstrated a 47% 6-month CR rate in a phase II study (NCT02365818). Detalimogene voraplasmid (EG-70), a nonviral gene therapy, demonstrated a 47% 6-month CR in a phase I/II study (NCT04752722). Future advances are likely to focus on patient selection, novel vectors, and combination strategies to improve treatment outcomes. Conclusions: Gene therapy represents a significant addition to the bladder cancer treatment landscape by offering bladder-sparing alternatives where conventional therapies are limited.

Inflammatory bowel disease (IBD) is a chronic and relapsing disease with multiple underlying influences and notable heterogeneity among its clinical and response‐to‐treatment phenotypes. There is no cure for IBD, and none of the currently available therapies have demonstrated clinical efficacies beyond 40%–60%. Data collected about its omics, pathogenesis, and treatment strategies have grown exponentially with time making IBD a prime candidate for artificial intelligence (AI) mediated discovery support. AI can be leveraged to further understand or identify IBD features to improve clinical outcomes. Various treatment candidates are currently under evaluation in clinical trials, offering further approaches and opportunities for increasing the efficacies of treatments. However, currently, therapeutic plans are largely determined using clinical features due to the lack of specific biomarkers, and it has become necessary to step into precision medicine to predict therapeutic responses to guarantee optimal treatment efficacy. This is accompanied by the application of AI and the development of multiscale hybrid models combining mechanistic approaches and machine learning. These models ultimately lead to the creation of digital twins of given patients delivering on the promise of precision dosing and tailored treatment. Interleukin‐6 (IL‐6) is a prominent cytokine in cell‐to‐cell communication in the inflammatory responses’ regulation. Dysregulated IL‐6‐induced signaling leads to severe immunological or proliferative pathologies, such as IBD and colon cancer. This mini‐review explores multiscale models with the aim of predicting the response to therapy in IBD. Modeling IL‐6 biology and generating digital twins enhance the credibility of their prediction.

Machine learning (ML) has been applied to predict the efficacy of biologic agents in ulcerative colitis (UC). ML can offer precision, personalization, efficiency, and automation. Moreover, it can improve decision support in predicting clinical outcomes. However, it faces challenges related to data quality and quantity, overfitting, generalization, and interpretability. This paper comments on two recent ML models that predict the efficacy of vedolizumab and ustekinumab in UC. Models that consider multiple pathways, multiple ethnicities, and combinations of real-world and clinical trial data are required for optimal shared decision-making and precision medicine. This paper also highlights the potential of combining ML with computational models to enhance clinical outcomes and personalized healthcare. Key Insights: (1) ML offers precision, personalization, efficiency, and decision support for predicting the efficacy of biologic agents in UC. (2) Challenging aspects in ML prediction include data quality, overfitting, and interpretability. (3) Multiple pathways, multiple ethnicities, and combinations of real-world and clinical trial data should be considered in predictive models for optimal decision-making. (4) Combining ML with computational models may improve clinical outcomes and personalized healthcare.

(1) Background: Humans and animals are exposed daily to numerous food-associated noxious molecules, including fungal toxins or mycotoxins. Effects of mycotoxins on the intestinal epithelial cells (IECs) are well characterized. However, their impact on the enteric nervous system (ENS), particularly on enteric glial cells (EGCs), has not been evaluated. (2) Methods: In the present work, the impact of major mycotoxins (eighteen mycotoxins in total, both regulated and non-regulated (including emerging ones) mycotoxins) on EGCs was evaluated in vitro in terms of antiproliferative and cytotoxic effects using rat EGCs as a model. Inhibitory concentrations on cell division and cell viability were determined using the resazurin assay, and biochemical analysis was performed to identify the mechanism(s) of action involved. (3) Results: Of the eighteen mycotoxins tested, twelve were found to be toxic; apicidin, deoxynivalenol, and cyclohexadepsipeptide mycotoxins (enniatins and beauvericin) were the most toxic, with active concentrations as low as 0.19 ± 0.07 µM for deoxynivalenol. Mechanistic studies revealed that toxicity occurs through the induction of oxidative stress, alteration of the membrane integrity, and/or induction of apoptosis. (4) Conclusions: As far as we know, the data presented here show for the first time that EGCs are targets of foodborne mycotoxins, even at low concentrations potentially achieved in cases of ingesting contaminated food.

Recurrent Clostridioides difficile infection (rCDI) is a major cause of increased morbidity, mortality, and healthcare costs. Fecal-microbiota-based therapies are recommended for rCDI on completion of standard-of-care (SoC) antibiotics to prevent further recurrence: these therapies include conventional fecal-microbiota transplantation and the US Food and Drug Administration-approved therapies REBYOTA® (RBL) and VOWST Oral Spores™ (VOS). As an alternative to microbiota-based therapies, bezlotoxumab, a monoclonal antibody, is used as adjuvant to SoC antibiotics to prevent rCDI. There are no head-to-head clinical trials comparing different microbiota-based therapies or bezlotoxumab for rCDI. To address this gap, we conducted a systematic literature review to identify clinical trials on rCDI treatments and assess the feasibility of using them to conduct an indirect treatment comparison (ITC). The feasibility analysis determined that trial heterogeneity, particularly relating to inclusion criteria, may significantly compromise ITC and prevent cross-trial comparisons. Our analysis underlines the need to adopt standardized protocols to ensure comparability across trials.

An increasing number of human beings from developed countries are colonized by Escherichia coli strains producing colibactin, a genotoxin suspected to be associated with the development of colorectal cancers. Deoxynivalenol (DON) is the most prevalent mycotoxin that contaminates staple food—especially cereal products—in Europe and North America. This study investigates the effect of the food contaminant DON on the genotoxicity of the E. coli strains producing colibactin. In vitro , intestinal epithelial cells were coexposed to DON and E. coli producing colibactin. In vivo , newborn rats colonized at birth with E. coli producing colibactin were fed a DON-contaminated diet. Intestinal DNA damage was estimated by the phosphorylation of histone H2AX. DON exacerbates the genotoxicity of the E. coli producing colibactin in a time- and dose-dependent manner in vitro . Although DON had no effect on the composition of the gut microbiota, and especially on the number of E. coli , a significant increase in DNA damage was observed in intestinal epithelial cells of animals colonized by E. coli strains producing colibactin and coexposed to DON compared to animals colonized with E. coli strains unable to produce colibactin or animals exposed only to DON. In conclusion, our data demonstrate that the genotoxicity of E. coli strains producing colibactin, increasingly present in the microbiota of asymptomatic human beings, is modulated by the presence of DON in the diet. This raises questions about the synergism between food contaminants and gut microbiota with regard to intestinal carcinogenesis. IMPORTANCE An increasing number of human beings from developed countries are colonized by Escherichia coli strains producing colibactin, a genotoxin suspected to be associated with the development of colorectal cancers. Deoxynivalenol (DON) is the most prevalent mycotoxin that contaminates staple food—especially cereal products—in Europe and North America. Our in vitro and in vivo results demonstrate that the intestinal DNA damage induced by colibactin-producing E. coli strains was exacerbated by the presence of DON in the diet. This raises questions about the synergism between food contaminants and gut microbiota with regard to intestinal carcinogenesis. An increasing number of human beings from developed countries are colonized by Escherichia coli strains producing colibactin, a genotoxin suspected to be associated with the development of colorectal cancers. Deoxynivalenol (DON) is the most prevalent mycotoxin that contaminates staple food—especially cereal products—in Europe and North America. Our in vitro and in vivo results demonstrate that the intestinal DNA damage induced by colibactin-producing E. coli strains was exacerbated by the presence of DON in the diet. This raises questions about the synergism between food contaminants and gut microbiota with regard to intestinal carcinogenesis.

Olamkicept selectively inhibits the cytokine interleukin‐6 (IL‐6) trans‐signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first‐in‐human, randomized, placebo‐controlled, single‐ (SAD) and multiple‐ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment‐emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion‐related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose‐independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription‐3) was achieved in blood around or above olamkicept serum concentrations of 1–5 μg/mL. Overall, these results suggest that olamkicept is safe and well‐tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations.

Interleukin 6 (IL‐6) has previously been identified as playing a role in ulcerative colitis (UC) by activating the signal‐transducing element gp130 through ligation of either the membrane‐bound or soluble IL‐6 receptor (termed classic and trans‐signaling respectively). It has been proposed that selective inhibition of trans‐IL‐6 signaling could ameliorate the deleterious, pro‐inflammatory effects of IL‐6, while preserving the homeostatic activity of classic IL‐6 signaling. We developed an in silico, mechanistic model of UC in two stages to compare the biological effects that result from inhibition of classic and trans‐IL‐6 signaling. In the first stage, we developed a limited‐scope model of IL‐6 signaling to establish the quantitative properties of classic and trans‐signaling pathways on a short timescale following stimulation with IL‐6. The model included both a pan‐inhibitor of IL‐6 classic and trans‐signaling and a soluble gp130‐Fc that selectively inhibited trans‐signaling. In the second stage, we developed a multi‐scale model of UC to study the pharmacodynamic effects of cytokine signaling inhibition and optimize treatment regimens. Across three virtual experiments, both selective and global suppression of IL‐6 signaling were associated with a transition away from an inflammatory state in patients with moderate to severe inflammatory activity. In our multi‐scale model, we identified a dose–response relationship between selective inhibition of trans‐IL‐6 signaling and tissue regeneration. Moreover, selective inhibition of trans‐IL‐6 signaling effectively suppressed inflammation and induced faster gut tissue healing than global IL‐6 suppression. These findings suggest that global suppression of IL‐6 signaling could negatively affect IL‐6‐induced regeneration activity, whereas this effect is less likely for selective inhibition.

Behçet’s disease is an autoinflammatory disorder characterized by relapsing and remitting vasculitis that can manifest in various forms, including gastrointestinal Behçet’s disease (GIBD). Its complications (e.g., intestinal perforation) are among the primary causes of morbidity and mortality. GIBD pathogenesis involves the enhanced production of certain cytokines, e.g., tumor necrosis factor α and interleukin-6 (IL-6), which could serve as a target for potential therapies. This review provides an overview of GIBD, including the diagnosis and immunopathogenesis as it is currently understood, and evaluates the emerging role of the inhibition of IL-6 (classic and trans-signaling) as an alternative treatment option for patients with GIBD. Given the current paucity of data, we reflected on the potential of IL-6 inhibitors such as tocilizumab and olamkicept based on immunopathogenic considerations and available clinical data in patients with inflammatory bowel disease (IBD), in whom clinical response or remission was induced. The selective inhibition of IL-6 trans-signaling may bring new impetus to the development of this drug class, particularly regarding safety. Still, the benefits of IL-6 inhibitors for patients with GIBD need to be evaluated in appropriate proof-of-concept studies. The clinical outcomes of IL-6 inhibitors in IBD are promising and may suggest their potential relevance in GIBD.