cell therapies

2026-07-07 | Localized pH regulation via a dynamic proton-converting raft for gastroesophageal reflux disease.

Current gastroesophageal reflux disease (GERD) therapies either systemically suppress gastric acid, risking physiological disruption, or rely on antacid rafts that offer transient, non-responsive neutralization. We address this with a chemistry-centered strategy that spatially localizes proton conversion around the self-positioning raft at the gastric interface. The dynamic H+ conversion equilibrium system (DH+-CES) integrates a CO2-generating calcium alginate raft which physically impedes reflux via its bubble-stabilized architecture for rapid interfacial self-positioning, with an engineered Lactococcus lactis expressing acid urease. Under acidic challenge, urease catalysis consumes protons locally. As pH normalizes, feedback-regulated enzymatic attenuation constrains the reaction zone, preventing bulk alkalization. DH+-CES elevates interfacial pH from 2.0 to ∼5.0 within 5 min, sustains this zone for hours while modulating only 5.38% of total fluid volume, and reduces reflux-like surge height by 38%. In an acute rat GERD model, it inhibits esophageal injury by 93.95%, downregulates key inflammatory mediators, and shows favorable biocompatibility. These findings establish DH+-CES as a proof-of-concept interface-resident chemical gatekeeper for localized, self-limiting, and physiologically respectful pH control.

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2026-05-24 | Autologous T Cell Antigen Coupler Targeting HER2 (TAC01-HER2) in Advanced or Metastatic Solid Tumors.

The T cell antigen coupler (TAC) is a novel genetically engineered receptor that recruits the native T cell receptor upon recognition of an antigen. The downstream activation of TAC T cells has been effective against tumors in preclinical models and safer than chimeric antigen receptor T cells. Human epidermal growth factor receptor 2 (HER2) is a validated biomarker for cancer-targeted therapy, but cell therapy approaches have been met with unmanageable toxicity. We designed a phase 1 clinical trial of TAC01-HER2, an autologous T cell product that targets HER2, in patients with HER2-positive advanced solid tumors. The trial had a dose-escalation phase and a dose-expansion at the recommended phase 2 dose (RP2D). A total of 23 patients with HER2-positive solid tumors were enrolled in this study. The most common treatment-related adverse events were cytokine release syndrome (n=14, 60.9%), anemia (n=5, 21.7%), and increased alanine aminotransferase (n=5, 21.7%). The RP2D was 6-8 × 106 per kg. No treatment-related deaths or adverse events leading to study discontinuation were reported. Two of 9 patients with gastric and gastroesophageal junction (GEJ) cancers had partial responses, and the disease control rate (stable disease or partial response) was 61.1% in the 18 patients with evaluable assessments. The median progression-free survival was 2.6 months (range 0.8-12.4 months), and the overall survival rate at 6 months was 57.9% (95% CI, 36.3%-76.9%). Persistence of TAC T cells in peripheral blood was observed in all patients until at least day 29 after the first infusion. In summary, we demonstrated that treatment with TAC T cells was safe, feasible, and well-tolerated. TAC01-HER2 showed manageable toxicity and early efficacy for patients with HER2-positive gastric, GEJ or esophageal adenocarcinoma who have undergone extensive previous treatments. These results suggest that TAC may offer a promising approach to control T cell activity through cellular therapy.

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2025-02-08 | CAR-macrophage therapy for HER2-overexpressing advanced solid tumors: a phase 1 trial.

Chimeric antigen receptor (CAR) macrophages (CAR-Ms) mediate antitumor immunity via phagocytosis, cytokine release, activation of the tumor microenvironment and antigen presentation. We report results from a non-prespecified interim analysis of a first-in-human, phase 1 clinical trial of CT-0508, an anti-human epidermal growth factor receptor 2 (HER2) CAR-M in patients with advanced HER2-overexpressing tumors. Fourteen patients were treated across two different regimens. Patients with breast cancer and gastroesophageal cancer were primarily enrolled and had to have demonstrated overexpression of HER2 according to the American Society of Clinical Oncology/College of American Pathologists guidelines (HER2 immunohistochemistry 3+ or immunohistochemistry 2+/in situ hybridization-amplified). No lymphodepletion chemotherapy was used before infusion. The primary endpoints were safety and CAR-M manufacturability. Secondary endpoints included cellular kinetics and efficacy using objective response rate, overall survival, progression-free survival and duration of response. No dose-limiting toxicities, severe cytokine release syndrome (≥grade 3) or immune effector cell-associated neurotoxicity syndrome were observed; 44% (n = 4 of 9, 95% confidence interval = 14-79%) of HER2 3+ tumors achieved stable disease as best overall response 8 weeks after treatment. No meaningful activity was observed in the HER2 2+ population (n = 5). Correlative analyses of serial biopsies confirmed that CT-0508 traffics to and remodels the tumor microenvironment, resulting in expansion of CD8+ T cells. These findings demonstrate the preliminary safety, tolerability and manufacturing feasibility of CT-0508 for HER2+ tumors. ClinicalTrials.gov registration: NCT04660929 .

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2024-07-25 | Sarcopenia-related traits and 10 digestive system disorders: insight from genetic correlation and Mendelian randomization.

Despite observational studies suggest hypotheses indicating a potential link, the precise causal connection between sarcopenia and digestive system illnesses has not been clearly defined. We first use Linkage Disequilibrium Score Regression (LDSC) testing to determine the genetic correlation of traits associated with sarcopenia and 10 specific gastrointestinal diseases. Subsequently, we performed a set of bidirectional Mendelian Randomization (MR) analyses to gauge the genetic inclination towards sarcopenia-related traits in relation to each gastrointestinal condition, individually, across the FinnGen, UK Biobank, and other extensive collaborative consortia. The analytical outcomes were synthesized using a fixed-effects meta-analytic model. For outcomes indicating substantial causal impacts, mediation MR analyses were executed. Additionally, a battery of sensitivity analyses was conducted to evaluate the study's strength and dependability. Our findings established a strong causal link between appendicular lean mass and gastroesophageal reflux disease (OR  =  0.8607; 95% CI: 0.8345-0.8877; p <  0.0001) and a noteworthy correlation with nonalcoholic fatty liver disease (OR  =  0.7981; 95% CI: 0.7281-0.8749; p < 0.0001), as per the meta-analysis data. We also evaluated the intermediary role of metabolic disorders in the association between appendicular lean mass and the aforementioned diseases. The intermediary effect towards gastroesophageal reflux disease is quantified as 0.0087 (95% CI, 8e-04, 0.0183), accounting for 5.9398% (95% CI, 0.5462, 12.4940%) of the overall effect. For non-alcoholic fatty liver, the intermediary impact is 0.0150 (95% CI, 0.0050, 0.0270), representing 19.7808% (95% CI, 6.5936, 35.6055%) of the total effect. The findings posit that augmenting muscle mass may serve as a preventative strategy against gastroesophageal reflux disease and non-alcoholic fatty liver, highlighting the critical role of metabolic disorder management in reducing the risks of these sarcopenia-related conditions.

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2023-03-16 | Stem cell therapy combined with controlled release of growth factors for the treatment of sphincter dysfunction

Abstract Sphincter dysfunction often occurs at the end of tubule organs such as the urethra, anus, or gastroesophageal sphincters. It is the primary consequence of neuromuscular impairment caused by trauma, inflammation, and aging. Despite intensive efforts to recover sphincter function, pharmacological treatments have not achieved significant improvement. Cell- or growth factor-based therapy is a promising approach for neuromuscular regeneration and the recovery of sphincter function. However, a decrease in cell retention and viability, or the short half-life and rapid degradation of growth factors after implantation, remain obstacles to the translation of these therapies to the clinic. Natural biomaterials provide unique tools for controlled growth factor delivery, which leads to better outcomes for sphincter function recovery in vivo when stem cells and growth factors are co-administrated, in comparison to the delivery of single therapies. In this review, we discuss the role of stem cells combined with the controlled release of growth factors, the methods used for delivery, their potential therapeutic role in neuromuscular repair, and the outcomes of preclinical studies using combination therapy, with the hope of providing new therapeutic strategies to treat incontinence or sphincter dysfunction of the urethra, anus, or gastroesophageal tissues, respectively.

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small molecules

2026-06-24 | Efficacy and safety of infigratinib in patients with refractory advanced gastric or gastroesophageal junction adenocarcinoma harboring FGFR2 gene amplification: a single-arm, multicenter phase 2 trial.

FGFR2 has garnered attention as a promising therapeutic target for gastric cancer (GC) because of its role in GC progression. Infigratinib, an FGFR1-3 selective tyrosine kinase inhibitor, has shown potential in preclinical GC models. Infigratinib was evaluated in a phase 2 trial for patients with FGFR2-amplified GC or gastroesophageal junction (GEJ) adenocarcinoma who had failed two or more lines of systemic treatment for locally advanced or metastatic disease. A total of 21 patients received 125 mg of infigratinib orally once daily on a "3 weeks on, 1 week off" schedule. Infigratinib showed preliminary antitumor activity in this molecularly selected population, as reflected by a confirmed objective response rate of 23.8% (95% CI, 8.2-47.2) with median progression-free survival of 3.4 months and median overall survival of 6.7 months. The most common grade 3-4 adverse events were elevated aspartate aminotransferase, decreased white blood cell count, and neutropenia. No treatment-related deaths occurred. Exploratory genomic analyses identified alterations in individual patients with disease progression that may be associated with resistance; however, these findings were based on a limited number of cases and should be interpreted as hypothesis-generating. The findings support continued investigation of FGFR-targeted strategies in FGFR2-amplified GC/GEJ adenocarcinoma, while underscoring the need for larger studies, refined biomarker selection, and deeper characterization of resistance mechanisms. NCT05019794, Registered 28 July 2021, https://clinicaltrials.gov/study/NCT05019794 .

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2026-06-15 | Acidic bile salts induce APE1-dependent PRDX2 activation to drive oxaliplatin resistance via ferroptosis inhibition.

The incidence of esophageal adenocarcinoma (EAC) is rapidly increasing in Western countries. Gastroesophageal reflux, containing acidic bile salts (ABS), is the main risk factor for EAC. Cancer cells develop adaptive abilities to recalibrate redox balance via hijacking the antioxidant systems to maintain reactive oxygen species (ROS) below lethal levels. We investigated the role of PRDX2 and its regulation in EAC chemoresistance under reflux conditions. We analyzed public databases to identify PRDX2's aberrant overexpression and potential role in chemoresistance in EAC. To model acute and chronic GERD in vitro, we applied transient and repeated ABS exposures. Using 2D and 3D organotypic culture models of EAC cells, we investigated PRDX2's anti-ferroptosis, pro-chemoresistance functions, and regulatory mechanisms. In addition, we also utilized patient derived organoids and xenografts, cell line-derived xenografts, and human EAC tissue microarrays. Aberrant expression of PRDX2 was detected in both human EAC tissues and cell lines under ABS exposure. PRDX2 was regulated via an APE1-redox-dependent transcription activation of NF-kB. The knockdown of PRDX2 impaired the recovery of EAC cells from ABS-induced ROS and ROS-dependent lipid peroxidation. Silencing PRDX2 sensitized the chemo-resistant EAC cells to oxaliplatin by enhancing ferroptosis. Mechanistically, we found that PRDX2 inhibits ferroptosis by stabilizing GPX4, a crucial ferroptosis suppressor. PRDX2 enhances GPX4 stability through OTUB1-dependent deubiquitination, preventing its degradation. The APE1-redox inhibitor APX2009 significantly sensitized EAC cells to oxaliplatin by downregulating PRDX2 and inducing ferroptosis. Importantly, the combination of oxaliplatin and APX2009 showed synergistic tumor-suppressive effects in xenograft models. Our findings revealed a novel link between reflux-induced redox rebalance and ferroptosis-related chemoresistance in EAC via APE1-redox/NF-kB/PRDX2/OUTB1/GPX4 signaling cascade. Targeting redox with APE1-redox-specific inhibitors is a potential novel strategy for drug combination in refractory EAC, via inhibition of PRDX2.

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2026-06-09 | Prevalence of CYP2C19 polymorphisms in medically and surgically managed patients with GERD.

The medical therapy of gastroesophageal reflux disease relies predominantly on proton pump inhibitors, with surgery recommended for patients refractory to medical therapy and/or those with symptomatic hiatal hernias. Proton pump inhibitor plasma concentration, and thus the effectiveness and safety of proton pump inhibitors, are dependent on metabolism by cytochrome P450 2C19 (CYP2C19) in the liver. CYP2C19 polymorphisms and resultant enzyme activity influence plasma concentrations of proton pump inhibitors. For patients who are rapid metabolizers (2%-27% of patients) or ultrarapid metabolizers (<1%-5%) of proton pump inhibitors, dose escalation is recommended to obtain therapeutic benefit. Poor (1%-8%) or intermediate (20%-46%) metabolizers of proton pump inhibitors have increased drug effectiveness at lower doses but are at a higher risk of experiencing side effects. This study aimed to determine the prevalence of CYP2C19 phenotypes in medically and surgically managed patients. We hypothesized that surgical patients would have a higher prevalence of rapid and ultrarapid metabolizer phenotype, making them resistant to proton pump inhibitors compared with the medical patients. This was a multisite retrospective cohort study of adult patients with CYP2C19 test results identified in their electronic health record from 2012 to 2023. The medically managed group included gastroesophageal reflux disease patients with positive pH testing, whereas the surgically managed group included patients who underwent antireflux surgery. CYP2C19 phenotypes were categorized as poor/intermediate, normal, or rapid/ultrarapid metabolizer. A positive pH test was defined as acid exposure time >6% or DeMeester score >14.7. Hiatal hernia size was classified as small, medium, or large based on imaging, endoscopy, and intraoperative findings. Descriptive statistics were used to characterize the metabolization status. A total of 138 patients were included in this study: 58 medical patients (female: 59%, median age 62 years [interquartile range 46-68], 84% White) and 80 surgical patients (female: 66%, median age 61 years [interquartile range 53-67], 90% White). In the medical cohort, the mean acid exposure time was 15.3% and the median DeMeester score was 33 (21-69). The majority of medical patients were normal metabolizers (54%, n = 31). In the surgical cohort, 27% (n = 22) were poor or intermediate metabolizers, 30% (n = 24) were normal metabolizers, and 43% (n = 34) were rapid/ultrarapid metabolizers. Surgical patients had a higher prevalence of CYP2C19 rapid/ultrarapid metabolizer phenotypes compared with medical patients, 43% (n = 34) vs 24% (n = 14) (P = .02). Among patients with small- (n = 41) and medium-sized (n = 21) hiatal hernias, the majority were classified as rapid or ultrarapid metabolizer (39% and 57% with small and medium hernias, respectively), suggesting resistance to proton pump inhibitors. Additionally, surgical patients were significantly more likely to have medium- and large-sized hiatal hernias compared with medical patients (P < .01). Surgical patients who underwent antireflux surgery had a higher prevalence of rapid/ultrarapid metabolizer CYP2C19 phenotypes compared with medical patients. These data suggest that proton pump inhibitor dose should be escalated in medical patients with these phenotypes, and if ineffective, a timely referral should be made for surgical management. This is one of the first studies assessing the pharmacogenomic CYP2C19 test in adult patients with gastroesophageal reflux disease. CYP2C19 testing has immense potential to optimize medical and surgical management of patients with gastroesophageal reflux disease, and prospective multisite studies are needed to confirm utility of the test.

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2026-06-05 | Genetic variations in medical versus surgical patients with GERD: beyond PPIs and fundoplications.

Gastroesophageal Reflux Disease (GERD) is treated primarily with proton pump inhibitors (PPIs), with surgery reserved for patients refractory to PPIs or with symptomatic hiatal hernias. PPI efficacy depends on metabolism by cytochrome P450 2C19 (CYP2C19) in the liver, which varies with genetic polymorphisms. Rapid (RM) and ultra-rapid (UM) metabolizers may require higher PPI doses for efficacy, while poor (PM) and intermediate (IM) metabolizers respond to lower doses but have higher risk of side effects. This study assesses CYP2C19 phenotype prevalence in medically versus surgically managed GERD. We hypothesized a higher RM/UM rate among surgical patients, suggesting PPI resistance. This was a multi-site retrospective cohort study of adult patients with GERD and CYP2C19 genotyping from 2012 to 2023. Medical patients included those with Barrett's esophagus, LA grade C/D esophagitis, or abnormal pH testing. Surgical patients included those who underwent anti-reflux surgery. CYP2C19 phenotypes were grouped as PM/IM, normal metabolizer (NM), and RM/UM based on the anticipated need for PPI dose adjustment. Descriptive statistics were used for analysis. A total of 261 patients were included in this study: 187 medical (female: 59%, mean age: 57 (SD 15), 77% White) and 74 surgical (female: 69%, mean age: 58 (SD 13), 89% White). Medical patients included the following esophageal pathologies: 52% Barrett's esophagus, 31% abnormal pH testing, and 17% LA grade C/D esophagitis. Surgical patients had a significantly higher proportion of RM/UM phenotypes compared to medical patients (p = 0.018). There was also a significant difference in hiatal hernia size between medical and surgical patients (p < 0.001). Surgical patients have a higher prevalence of hypermetabolizing (RM/UM) CYP2C19 phenotypes compared to medical patients. Dose escalation of PPI should be considered in medical patients with these phenotypes, and if ineffective, a timely referral for anti-reflux surgery should be made.

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2026-06-04 | Pathology-Driven Epithelial Sulfide Loss Reprograms the Redox Proteome and Triggers Barrett's Esophagus.

Barrett's esophagus (BE), a metaplastic transformation driven by gastroesophageal reflux disease (GERD), induces oxidative stress but the underlying redox mechanisms remain poorly understood. Protein persulfidation (PSSH), a redox-sensitive, reversible, and antioxidative post-translational modification regulated by hydrogen sulfide (H2S) metabolism, has not been explored in this context. Here, we identify epithelial PSSH as a key regulator of this premalignant process. We applied proteomics and chemoproteomics in 2 patient cohorts to map and validate PSSH and total proteome profiles across healthy (squamous), GERD-exposed, and metaplastic epithelium. Using in vitro and in vivo models of chronic GERD and BE, we modulated H2S levels genetically and pharmacologically. Mechanistic and functional effects were assessed using tissue biopsies or recombinant human proteins. GERD-induced oxidative loss of H2S and its enhanced catabolism initiated early PSSH proteome remodeling in squamous epithelium, which expanded in BE and affected >1300 proteins in clinical samples, indicating potential biomarkers. This also included altered persulfidation of enzymes regulating accumulation of prostaglandin E2 (PGE2), a well-established driver of BE development and progression. H2S depletion accelerated metaplastic transformation, whereas H2S donors reversed these effects in experimental models. PSSH of 15-hydroxyprostaglandin dehydrogenase reversibly suppressed its activity, protecting the enzyme and, unlike irreversible oxidation, allowing recovery of PGE2 degradation. These findings redefine the origin of PGE2 accumulation in metaplasia and establish sulfide loss and persulfidomic remodeling as central, druggable drivers of epithelial reprogramming and redox imbalance in BE pathogenesis.

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antibodies

2026-09-19 | Neuroticism increased risk of gastroesophageal reflux disease: Evidence from bidirectional Mendelian randomization.

Gastroesophageal reflux disease (GERD) is a common gastrointestinal disorder that severely reduces quality of life. Emerging data suggest that neuroticism, a personality trait associated with increased stress reactivity and sensitivity to physiological sensations, may contribute to GERD susceptibility. However, the causality remains unknown. A bidirectional Mendelian Randomization (MR) study was conducted to evaluate the causal link between neuroticism and GERD. Genetic data for neuroticism were sourced from the UK Biobank's genome-wide association study (GWAS) (n = 3,80,506), while GERD-associated genetic data were obtained from the FinnGen project (n = 4,17,314) for primary analysis and from the IEU Open GWAS database (n = 6,02,604) for replication and meta-analysis. Sensitivity analyses, including tests for heterogeneity and pleiotropy, were conducted to assess the robustness of causal inferences. Inverse-variance weighted (IVW) analyses revealed significant associations between certain neuroticism traits and an increased risk of GERD. The traits with the strongest associations were mood (odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.60, 2.53, P = 1.5 × 10-9), worry (OR = 1.59, 95% CI = 1.21, 2.07, P = .00078), and tense (OR = 1.70, 95% CI = 1.18, 2.44, P = .004). Weighted median and MR-Egger regression sensitivity analyses supported these findings. The results were validated in replication and meta-analysis. Reverse MR suggested GERD might influence traits like "WORRY" and "FED-UP"; however, these associations were non-significant after Bonferroni correction. Neuroticism traits, including mood, worry, and tense, may be associated with an increased risk of GERD. These findings highlight the potential role of psychological characteristics in GERD development and may provide insights into future risk assessment and management strategies for GERD.

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2026-09-17 | Clinicopathologic Features, Treatment Patterns, and Outcomes of Microsatellite Instability-High Gastric and Gastroesophageal Junction Adenocarcinoma: A Single-Institution Retrospective Analysis.

Microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) gastric or gastroesophageal junction (GEJ) adenocarcinomas are biologically distinct tumors with established sensitivity to immune checkpoint inhibitors (ICIs). However, real-world treatment patterns, response heterogeneity, and predictors of durable benefit remain poorly defined. We retrospectively analyzed patients with biopsy-confirmed MSI-H/dMMR gastric/GEJ adenocarcinoma treated at a single center. Clinicopathologic, genomic, treatment, and outcome data were collected. Molecular profiling included ARID1A, RNF43, TP53, PIK3CA, KRAS, TGFBR2, and human epidermal growth factor 2 (HER2). ICIs-treated patients were classified as achieving clinical benefit (complete response, partial response, or durable stable disease ≥16 weeks) or no clinical benefit using iRECIST v1.1 and clinical assessment. Overall survival (OS) was estimated by using the Kaplan-Meier method. Thirty-four patients were identified (median age, 66 years; 53% male), including 21 with stage IV disease. Tumors were predominantly poorly differentiated (65%) and HER2-negative (94%), and 18% of patients had Lynch syndrome. Among 22 ICI-treated patients, 55% achieved clinical benefit, which was strongly associated with prolonged OS (P < .01). Most responses occurred at the first radiographic assessment (approximately 12 weeks). Elevated tumor mutational burden (TMB; ≥20 mutations/Mb) was present in 56% of patients but was not associated with clinical benefit (P = .40), and no individual genomic alteration significantly correlated with treatment outcome. Exploratory analyses suggested longer OS among patients with liver versus peritoneal metastases. Treatment was well tolerated, with predominantly low-grade immune-related adverse events. Baseline Eastern Cooperative Oncology Group performance status (0-1 v ≥ 2) was associated with clinical benefit (P = .049). Approximately half of the patients with MSI-H/dMMR gastric/GEJ adenocarcinoma cancers derived durable clinical benefit from ICIs, and treatment response was strongly associated with survival. Conventional genomic features, including TMB, did not predict clinical benefit, highlighting the need for additional biomarkers.

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2026-09-10 | Trastuzumab Deruxtecan (T-DXd) in HER2-Positive Advanced Gastric and Gastroesophageal Junction Cancer: Evidence, Sequencing, Patient Selection, and Clinical Decision-Making.

To provide a clinically oriented review of trastuzumab deruxtecan (T-DXd) in HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma, focusing on evidence, post-progression HER2 reassessment, second-line sequencing, patient selection, regional implementation, and toxicity management. This narrative review integrates pivotal DESTINY-Gastric trials, HER2 reassessment studies, realworld cohorts, safety analyses, pathology guidance, and regulatory documents available through August 2026. DESTINY-Gastric04 established T-DXd as a preferred second-line treatment after progression on trastuzumab-containing therapy, improving median overall survival versus ramucirumab plus paclitaxel (14.7 vs 11.4 months; hazard ratio 0.70). HER2 expression is heterogeneous and dynamic; postprogression reassessment is therefore recommended whenever feasible using biopsy-specific scoring criteria. The 494 of 1,088 patients randomized in DESTINY-Gastric04 should not be interpreted as a 55% HER2-loss rate because screening attrition was multifactorial. T-DXd is preferred when HER2 positivity is retained, whereas ramucirumab plus paclitaxel remains appropriate when HER2 loss is documented. When HER2 status is unconfirmed, treatment should be individualized, recognizing regional regulatory differences. Older patients require careful toxicity assessment, particularly for interstitial lung disease (ILD)/pneumonitis. Grade 2 or higher ILD requires permanent discontinuation; grade 1 reinitiation must follow the applicable regional label. T-DXd is a preferred second-line option for post-progression HER2-positive advanced gastric or gastroesophageal junction cancer, but optimal use requires careful HER2 reassessment and regionappropriate safety management. Evidence after T-DXd failure, ctDNA-guided selection, and sequential CLDN18.2-directed therapy remains limited and requires prospective validation.

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2026-09-06 | Causal associations of gastroesophageal reflux disease with sepsis and sepsis mortality within 28 days: A bidirectional 2-sample Mendelian randomization study.

Previous studies have demonstrated a potential correlation between gastroesophageal reflux disease (GERD) and sepsis. However, the causal association between GERD and sepsis remains unclear. We performed a bidirectional 2-sample Mendelian randomization (MR) analysis to investigate the causal associations of GERD with sepsis and sepsis mortality within 28 days. The inverse variance weighted method was used as a major method for the MR study, supplemented with multiple approaches, including MR-Egger, weighted median, and weighted mode. Then, the MR-Egger intercept test, Mendelian randomized polymorphism residual and outlier (MR-PRESSO) test, Cochran's Q test, and leave-one-out test were conducted to assess the reliability of the MR results. Forward MR analysis indicated that GERD significantly increased the risk of sepsis (odd ratio [OR] = 1.36; 95% confidence interval [CI]: 1.21-1.52, P = 1.44E-07) and 28-day sepsis mortality (OR = 1.44; 95% CI: 1.08-1.92, P = .014). Reverse MR analysis indicated that sepsis didn't causally affect GERD, while 28-day sepsis mortality showed a suggestive positive association with GERD (OR = 1.03; 95% CI: 1.01-1.06, P = .015), with a modest but statistically significant effect size. In addition, the MR analyses were found to be robust based on sensitivity tests, indicating no presence of heterogeneity or horizontal pleiotropy. Our study indicated that genetically predicted GERD increases the risk of sepsis and 28-day sepsis mortality, while genetically predicted 28-day sepsis mortality may also increase the risk of GERD, presenting a novel approach to the preventive strategy for sepsis and therapeutic perspectives in patients with GERD. However, given the lenient SNP threshold and small effect size in reverse MR analysis, as well as the exclusive European study cohort, additional studies are required to validate our findings.

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2026-07-23 | Therapeutic management of resectable mismatch-repair deficient/microsatellite instability-high gastroesophageal adenocarcinoma: a real-world analysis from Austria.

Mismatch-repair deficient (dMMR)/microsatellite instability-high (MSI-H) gastroesophageal adenocarcinoma (GEA) is associated with favorable prognosis but limited benefit from perioperative chemotherapy. Although immune checkpoint inhibition (ICI)-based approaches have shown promising activity in early-phase studies, the optimal therapeutic combinations and the feasibility of non-operative management (NOM) in resectable disease remain unclear. This exploratory, retrospective, multicenter, real-world study included 55 patients with resectable dMMR/MSI-H GEA, who were divided into subgroups, characterized and compared according to treatment strategy (chemotherapy, chemoimmunotherapy, immunotherapy and initial resection). Pathological and clinical complete response (pCR, cCR), progression-free (PFS) and overall survival (OS) were evaluated. Patients received chemotherapy (n=10), chemoimmunotherapy (n=16), immunotherapy (n=13), or initial resection without subsequent systemic treatment (n=16). Forty five (82%) patients had surgical resection. The pCR rate was 22% (n=2/9) in the chemotherapy, 27% (n=4/15) in the chemoimmunotherapy, and 100% (n=5/5) in the immunotherapy (i.e., doublet ICI) subgroup, respectively. The overall cCR rate in NOM patients was 33% (n=3/9), with rates of 37.5% (n=3/8) in the immunotherapy subgroup and 0% (n=0/1) in the chemoimmunotherapy subgroup. Complete response rates (pCR/cCR) were significantly associated with PD-L1 CPS ≥10 (p=0.027). This real-world study is, to our knowledge, the first to evaluate a broad spectrum of therapeutic combinations in patients with resectable MSI-H/dMMR GEA, showing meaningful antitumor activity, particularly with doublet ICI. Given the challenges of conducting randomized prospective trials in this setting, such real world data may support clinicians in guiding therapeutic decision-making.

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proteins

2026-07-14 | Causal immune-inflammation mapping of the GERD-Barrett-adenocarcinoma cascade identifies FGF19-HLA-DR⁺ T-cell axis driving esophagogastric junction metaplasia.

Gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC) form a recognized pathological continuum, but the causal immune and inflammatory processes driving progression remain incompletely defined. Summary-level genome-wide association study (GWAS) data were analyzed for 91 circulating inflammatory proteins (n = 14,824), 731 immune cell phenotypes (n = 3,757), and three esophageal diseases (GERD, BE, and EAC). Bidirectional and two-step Mendelian randomization (MR) were used to infer causal effects and mediation, with Cochran's Q, MR-Egger, and MR-PRESSO applied to assess heterogeneity and pleiotropy. Causal interaction networks were reconstructed to map immune- and inflammation-dominant regulatory patterns across disease stages, and MR-prioritized signals were experimentally validated in esophagogastric junction (EGJ) organoids and mouse models. MR supported a causal GERD-BE-EAC sequence, with BE mediating 31.95% of the total GERD-to-EAC effect. In total, 139 immune cell traits and 29 inflammatory proteins showed causal links to disease risk. Mediation analyses highlighted M-CSF1 and HLA-DR+CD4 + T cells as central hubs. Guided by the MR-prioritized FGF19-HLA-DR + T-cell axis, experimental studies demonstrated that FGF19 promotes EGJ glandular conversion and increases infiltration of HLA-DR+ CD4+/CD8 + T cells, validated in EGJ organoids and mouse models. This integrated genetic and experimental framework delineates a bidirectional immune-inflammation regulatory network underlying progression from GERD to BE and EAC. FGF19 emerges as a candidate cytokine driving EGJ glandular remodeling through HLA-DR+ CD4+/CD8 + T-cell associated immune activation, providing candidate molecular targets for early prevention and intervention.

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2025-12-13 | Ocular Safety Evaluation of Bemarituzumab in FGFR2b-Overexpressing Gastroesophageal Adenocarcinoma: A 42-Week Follow-Up Study.

To assess the duration, reversibility, alterations and prognosis of ocular adverse events (AEs) in participants treated with bemarituzumab, a first-in-class FGFR2b-targeted inhibitor in FGFR2b-overexpressing gastric/gastroesophageal junction cancer (G/GEJC), and to propose early intervention management strategy. This was a prospective, observational study of 11 participants with FGFR2b-overexpressing G/GEJC treated with bemarituzumab. All participants received ocular evaluations at baseline, and subsequent 6-week intervals. Evaluations included best-corrected visual acuity (BCVA), dry eye examinations, corneal morphology analysis, and fundus photography. 11 participants occurred ocular AEs, 8 participants finished the study. BCVA loss was first detected on day 131.5 ± 40.2 post-baseline (6.6 ± 2.5 doses following the initial bemarituzumab administration), with a loss of 2.1 ± 0.7 lines. Ocular Surface Disease Index (OSDI) scores increased (55.1 ± 18.1) at week 18. Corneal alterations manifested as punctate epitheliopathy, arc-shaped corneal defects, and ulcerative keratitis. In vivo confocal microscopy (IVCM) demonstrated features of corneal dysmaturation, including intraepithelial microcysts and abnormally thickened, cord-like structures within the basement membrane layer. After 134.1 ± 55.0 days of administering topical eye drops, the BCVA, dry eye and corneal epithelial alterations returned to baseline levels. Prophylactic administration of FGF-based eye drops helped prevent bemarituzumab treatment discontinuation, alleviated drug-related ocular symptoms, and improved prognosis. The ocular AEs occurred frequently in patients receiving bemarituzumab, requiring close ophthalmic monitoring and prophylactic administration of FGF-based eye drops. Collaboration between oncologists and ophthalmologists is critical for the timely management of treatment-related AEs, which could ultimately improve overall clinical outcomes.

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2023-10-01 | Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review

The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life.We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials.We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints.We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.

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2021-04-26 | Salivary Hemoglobin Protects against Erosive Tooth Wear in Gastric Reflux Patients.

Saliva is the most important biological factor to protect against erosive tooth wear (ETW). Gastroesophageal reflux disease (GERD) patients have an increased risk of ETW due to the frequent presence of intrinsic acids in the oral cavity. Remarkably, not all GERD patients suffer from ETW, which might be due to differences in the composition of the saliva. This study compared the proteomic profile of saliva in patients (1) with GERD and ETW (basic erosive wear examination, BEWE, score ≥9; GE group) and (2) with GERD without ETW (BEWE = 0; GNE group) using shotgun label-free quantitative proteomic analysis nLC-ESI-MS/MS. The ability of hemoglobin (Hb) to protect against initial enamel erosion caused by a daily 10-s immersion of enamel specimens in 0.01 M HCl (pH 2.3) for 3 days was evaluated in vitro for proof of concept. Surface hardness change was used as response variable. The differential expression of Hb subunits was significantly increased in the GNE group versus the GE group, in particular the Hb α-subunit that showed a >22-fold increase. Expressions of serum albumin (4.5-fold) and isoforms of cytoskeletal keratin type II (>3-fold) were also increased in the GNE group. Proteinase inhibitors, such as α1-antitrypsin and α2-macroglobulin, were only identified in the GNE group. In vitro, Hb (1.0 and 4.0 mg/mL) significantly reduced initial enamel erosion compared to a negative control after 3 days. Our results indicate that many proteins, with special emphasis on Hb, may be involved in the resistance of GERD patients to the occurrence of ETW. These proteins may be candidates for inclusion in dental products to protect against ETW.

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2016-07-01 | Impaired VEGF Signaling in Lungs with Hypoplastic Esophageal Atresia and Effects on Branching Morphogenesis

Background/Aims: Patients with esophageal atresia (EA) and tracheoesophageal fistula (TEF) often suffer chronic respiratory tract disease. We previously reported that primary lung maldevelopment caused by deficient branching of embryonal airways in experimental EA-TEF was induced by Adriamycin. In this study, we investigated the Vascular endothelial growth factor (VEGF) pathway in the developing lung in an EA-TEF rat model. We further analyzed the effect of recombinant VEGF treatment in vitro on branching morphogenesis of embryo lungs in experimental EA-TEF. Methods: Pregnant rats received either Adriamycin or vehicle on E7, E8 and E9. Lungs were recovered at E15, E18 and E21. Expression of VEGF and receptors (Flk-1 and Flt-1) were assessed by quantitative PCR, immunohistochemistry and immunoblotting. E13 lungs were cultured for 72 hours with 50 ng/mL of recombinant rat VEGF in serum-free medium. The rates of increase in bud count and airway contour were evaluated. Results: Our results showed a significant downregulation of VEGF during pseudoglandular and canalicular stages. In contrast, there were significantly higher levels of the Flt-1 receptor in the canalicular stage, which may represent a compensatory response to decreased VEGF. However, both variables returned to normal levels at the saccular stage. Exogenous VEGF treatment enhanced hypoplastic lung growth, evidenced by the increase in bud count and airway contour. Conclusions: A VEGF signaling defect possibly plays an important role in defective embryonic airway branching. Additionally, VEGF treatment may accelerate lung growth in EA-TEF lungs.

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2026-08-07 | A gene therapy approach to prevent dilated intercellular space, a hallmark of gastroesophageal reflux disease.

The incidence of esophageal disease ranging from gastroesophageal reflux disease (GERD) to cancer has dramatically risen over the last 10 years. However, there have been limited descriptions of effective gene delivery methods for the esophagus. We developed a simple and effective electroporation-based gene delivery procedure to target the distal esophagus in living animals. We have used this approach to prevent formation of dilated intercellular space (DIS), a pathological feature of GERD, which is characterized by disruption of tight junctions and loss of epithelial barrier function. We found that tight junction proteins and the Na+,K+-ATPase β1 subunit were decreased in biopsies from patients with GERD. Transfection of esophageal epithelial cells with plasmids expressing the Na+,K+-ATPase β1 subunit increased levels of tight junction proteins and transepithelial electrical resistance. Electroporation-mediated gene delivery to the distal esophagus resulted in no injury in either rat or rabbit models. Gene expression was detected within 2 days in the esophageal mucosa and persisted for at least 12 weeks. DIS developed by 12 weeks in a rabbit GERD model and was reduced by 70% when the Na+,K+-ATPase β1 subunit was delivered. These results are encouraging for future development of gene-based treatments for GERD and its downstream consequences.

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2026-01-19 | Gene, genetics and genetic medicines in gastroenterology: Current status and its future.

The etiopathogenesis of gastrointestinal diseases is varied in nature. Various etiogenic factors described are infective, inflammatory, viral, bacterial, parasitic, dietary and lifestyle change. Rare causative agents are immunological, and others associated as idiopathic, are undiagnosed by all possible means. Some of the rare diseases are congenital in nature, passing from the parent to the child. Many of the undiagnosed diseases are now being diagnosed as genetic and the genes have been implicated as a causative agent. There is a search for newer treatments for such diseases, which is called genomic medicine. Genomic medicine is an emerging medical discipline that involves the use of genomic information about an individual. This is used both for diagnostic as well as therapeutic decisions to improve the current health domain and pave the way for policymakers for its clinical use. In the developing era of precision medicine, genomics, epigenomics, environmental exposure, and other data would be used to more accurately guide individual diagnosis and treatment. Genomic medicine is already making an impact in the fields of oncology, pharmacology, rare, infectious and many undiagnosed diseases. It is beginning to fuel new approaches in certain medical specialties. Oncology is at the leading edge of incorporating genomics, as diagnostics for genetic and genomic markers are increasingly included in cancer screening, and to guide tailored treatment strategies. Genetics and genetic medicine have been reported to play a role in gastroenterology in several ways, including genetic testing (hereditary pancreatitis and hereditary gastrointestinal cancer syndromes). Genetic testing can also help subtype diseases, such as classifying pancreatitis as idiopathic or hereditary. Gene therapy is a promising approach for treating gastrointestinal diseases that are not effectively treated by conventional pharmaceuticals and surgeries. Gene therapy strategies include gene addition, gene editing, messenger RNA therapy, and gene silencing. Understanding genetic determinants, advances in genetics, have led to a better understanding of the genetic factors that contribute to human disease. Family-member risk stratification and genetic diagnosis can help identify family members who are at risk, which can lead to preventive treatments, lifestyle recommendations, and routine follow ups. Selecting target genes helps identify the gene targets associated with each gastrointestinal disease. Common gastrointestinal diseases associated with genetic abnormalities include-inflammatory bowel disease, gastroesophageal reflux disease, non-alcoholic fatty liver disease, and irritable bowel syndrome. With advancing tools and technology, research in the search of newer and individualized treatment, genes and genetic medicines are expected to play a significant role in human health and gastroenterology.

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2024-07-15 | HiChIP-Based Epigenomic Footprinting Identifies a Promoter Variant of UXS1 That Confers Genetic Susceptibility to Gastroesophageal Cancer.

Genome-wide association studies (GWAS) have identified more than a hundred single nucleotide variants (SNV) associated with the risk of gastroesophageal cancer (GEC). The majority of the identified SNVs map to noncoding regions of the genome. Uncovering the causal SNVs and genes they modulate could help improve GEC prevention and treatment. Herein, we used HiChIP against histone 3 lysine 27 acetylation (H3K27ac) to simultaneously annotate active promoters and enhancers, identify the interactions between them, and detect nucleosome-free regions (NFR) harboring potential causal SNVs in a single assay. The application of H3K27ac HiChIP in GEC relevant models identified 61 potential functional SNVs that reside in NFRs and interact with 49 genes at 17 loci. The approach led to a 67% reduction in the number of SNVs in linkage disequilibrium at these 17 loci, and at 7 loci, a single putative causal SNV was identified. One SNV, rs147518036, located within the promoter of the UDP-glucuronate decarboxylase 1 (UXS1) gene, seemed to underlie the GEC risk association captured by the rs75460256 index SNV. The rs147518036 SNV creates a GABPA DNA recognition motif, resulting in increased promoter activity, and CRISPR-mediated inhibition of the UXS1 promoter reduced the viability of the GEC cells. These findings provide a framework that simplifies the identification of potentially functional regulatory SNVs and target genes underlying risk-associated loci. In addition, the study implicates increased expression of the enzyme UXS1 and activation of its metabolic pathway as a predisposition to gastric cancer, which highlights potential therapeutic avenues to treat this disease. Significance: Epigenomic footprinting using a histone posttranslational modification targeted 3D genomics methodology elucidates functional noncoding sequence variants and their target genes at cancer risk loci.

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2024-05-14 | BCAT1, IKZF1 and SEPT9: methylated DNA biomarkers for detection of pan-gastrointestinal adenocarcinomas.

Methylated circulating tumour DNA (ctDNA) blood tests for BCAT1/IKZF1 (COLVERA) and SEPT9 (Epi proColon) are used to detect colorectal cancer (CRC). However, there are no ctDNA assays approved for other gastrointestinal adenocarcinomas. We aimed to characterize BCAT1, IKZF1 and SEPT9 methylation in different gastrointestinal adenocarcinoma and non-gastrointestinal tumours to determine if these validated CRC biomarkers might be useful for pan-gastrointestinal adenocarcinoma detection. Tissue DNA methylation data from colorectal (COAD, READ), gastroesophageal (ESCA, STAD), pancreatic (PAAD) and cholangiocarcinoma (CHOL) adenocarcinoma cohorts within The Cancer Genome Atlas were used for differential methylation analyses. Clinicodemographic predictors of BCAT1, IKZF1 and SEPT9 methylation, and the selectivity of hypermethylated BCAT1, IKZF1 and SEPT9 for colorectal adenocarcinomas in comparison to other cancers were each explored with beta regression. Hypermethylated BCAT1, IKZF1 and SEPT9 were each differentially methylated in colorectal and gastroesophageal adenocarcinomas. IKZF1 was differentially methylated in pancreatic adenocarcinoma. Hypermethylated DNA biomarkers BCAT1, IKZF1 and SEPT9 were largely stable across different stages of disease and were highly selective for gastrointestinal adenocarcinomas relative to other cancer types. Existing CRC methylated ctDNA blood tests for BCAT1/IKZF1 and SEPT9 might be usefully repurposed for use in other gastrointestinal adenocarcinomas and warrant further prospective ctDNA studies.

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2022-01-27 | The many facets of miR-223 in cancer: Oncosuppressor, oncogenic driver, therapeutic target, and biomarker of response.

Given their intrinsic pleiotropism, microRNAs (miR) play complex biological roles, in both normal and pathological conditions. Often the same miR can act as oncogene or oncosuppressor, depending on the biological process dysregulated in each specific tissue. miR-223 does not represent an exception to this rule and its functions greatly differ in different contexts. miR-223 has been widely studied in the hematopoietic compartment, where it plays a central role in innate immune response, regulating myeloid differentiation and granulocytes function. Accordingly, dysregulated expression of miR-223 has been associated to different inflammatory disorders and tumors arising from the immune compartment. Most carcinomas, breast cancer being the most studied, display loss of miR-223. However, in gastro-esophageal cancers miR-223 is frequently overexpressed and correlates with worse prognosis. A link between miR-223 and response to CDK4/6-inhibitors has been recently proposed, suggesting a role as biomarker of therapeutic response. The notion that one of the most commonly mutated protein in cancer, mutant p53, binds the promoter of miR-223 and suppresses its transcription, adds a further level of complexity to the full understanding of miR-223 in cancer. In this review, we will summarize the current knowledge on the molecular networks that alter or are altered by miR-223, in different cancer types. We will discuss if the times are ready for the exploitation of miR-223 as predictive biomarker of treatment response or, even, as therapeutic target, in specific settings. Finally, we will suggest which could be the next steps to be taken for a realistic clinical application of miR-223. This article is categorized under: RNA in Disease and Development > RNA in Disease.

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