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Caspase-8 is the initiator caspase of extrinsic apoptosis 1 , 2 and inhibits necroptosis mediated by RIPK3 and MLKL. Accordingly, caspase-8 deficiency in mice causes embryonic lethality 3 , which can be rescued by deletion of either Ripk3 or Mlkl 4 – 6 . Here we show that the expression of enzymatically inactive CASP8(C362S) causes embryonic lethality in mice by inducing necroptosis and pyroptosis. Similar to Casp8 −/− mice 3 , 7 , Casp8 C362S/C362S mouse embryos died after endothelial cell necroptosis leading to cardiovascular defects. MLKL deficiency rescued the cardiovascular phenotype but unexpectedly caused perinatal lethality in Casp8 C362S/C362S mice, indicating that CASP8(C362S) causes necroptosis-independent death at later stages of embryonic development. Specific loss of the catalytic activity of caspase-8 in intestinal epithelial cells induced intestinal inflammation similar to intestinal epithelial cell-specific Casp8 knockout mice 8 . Inhibition of necroptosis by additional deletion of Mlkl severely aggravated intestinal inflammation and caused premature lethality in Mlkl knockout mice with specific loss of caspase-8 catalytic activity in intestinal epithelial cells. Expression of CASP8(C362S) triggered the formation of ASC specks, activation of caspase-1 and secretion of IL-1β. Both embryonic lethality and premature death were completely rescued in Casp8 C362S/C362S Mlkl −/− Asc −/− or Casp8 C362S/C362S Mlkl −/− Casp1 −/− mice, indicating that the activation of the inflammasome promotes CASP8(C362S)-mediated tissue pathology when necroptosis is blocked. Therefore, caspase-8 represents the molecular switch that controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood. The enzymatic activity of caspase-8 controls apoptosis, necroptosis and pyroptosis, and prevents tissue damage during embryonic development and adulthood in mice.

Postoperative atrial fibrillation (POAF) is a common complication following transthoracic esophagectomy, with an incidence rate between 12% and 37%. POAF has been associated with adverse outcomes, including pulmonary complications, anastomotic leakage, prolonged ICU stays and increased in-hospital mortality. This study investigates the impact of POAF on postoperative outcomes in a high-volume center and evaluates its role as a predictor of postoperative complications following Ivor-Lewis esophagectomy.This retrospective, single-center cohort study was conducted at the University Hospital of Cologne, Germany. Patients, who underwent elective Ivor-Lewis esophagectomy for cancer, were included ( n  = 617). Perioperative data were extracted retrospectively from a prospectively maintained database, capturing demographic, surgical, and postoperative variables. POAF was defined as a hemodynamically significant tachyarrhythmia absoluta that occurs within the first 7 days postoperatively and has been confirmed via ECG. Statistical analyses included univariate and multivariate logistic regression to identify associations between POAF and postoperative outcomes.POAF occurred in a significant proportion of patients ( n  = 79, 12,8%) and was strongly associated with adverse outcomes. Patients with POAF demonstrated higher rates of pulmonary complications (24.0% vs. 11.2%, * p  < .01), anastomotic leakage (32.9% vs. 10.5%, * p  < .01), and prolonged ICU stays (median 7 days vs. 2 days, * p  < .01). The in-hospital mortality rate in the POAF group was 7.6%, compared to 1% in patients without POAF (* p  < .01). Independent predictors of POAF included older age, pre-existing atrial fibrillation and beta-blocker therapy. Postoperative atrial fibrillation (POAF) was a significant predictor of adverse postoperative outcomes. Logistic regression analysis revealed that POAF was associated with higher odds of anastomotic leakage (OR = 3.11, * p  < .01), ICU readmission (OR = 6.80, * p  < .01), in-hospital mortality (OR = 6.76, * p  < .01) and 90-Day mortality ( OR = 5.44, * p  < .01). In our cohort, POAF was not significantly associated with oncological recurrence (OR = 0.71; p  = .219). These findings highlight the critical role of POAF in predicting postoperative complications.POAF is both - a complication and a potential marker - for systemic stress, predicting further adverse events such as anastomotic leakage and respiratory insufficiency. Although some studies suggest that POAF does not affect long-term survival, its pronounced impact on short-term morbidity underscores the necessity of early identification and focused management. Preoperative risk stratification and intraoperative strategies, such as goal-directed fluid therapy, could mitigate the impact of POAF. Postoperative atrial fibrillation (POAF) significantly influences recovery after esophagectomy, serving as a marker for increased morbidity and mortality. Advanced age, hypertension, and respiratory complications emerged as key independent risk factors. Additionally, POAF was linked to longer hospital stays, in-hospital and 90-day mortality and a heightened incidence of postoperative complications, including pneumonia and anastomotic leakage. These results highlight the critical importance of implementing targeted perioperative strategies to reduce risks and enhance outcomes in this high-risk patient population.

Background Esophageal adenocarcinomas (EACs) represent an evolving tumor entity with high mortality rates. MET amplification is a recurrent driver in EACs and is associated with decreased patient survival. However, the response to MET inhibitors is limited. Recent studies have identified several mechanisms that lead to resistance against MET inhibitors in different tumor entities. Nonetheless, a characterization of additional vulnerable targets beyond MET has not been conducted in MET-amplified EACs. Methods In this study, we determined the MET amplification status in a cohort of more than 900 EACs using fluorescence in situ hybridization (FISH) and compared the proteomes of MET-amplified ( n  = 20) versus non-amplified tumors ( n  = 39) by mass spectrometry. Results We identified a phenotype, present in almost all MET-amplified tumors, which shows an enrichment of alternative RNA splicing, and androgen receptor signaling proteins, as well as decreased patient survival. Additionally, our analyses revealed a negative correlation between MET expression and patient survival in MET-amplified EACs, indicating biological heterogeneity with clinical relevance despite the presence of MET amplification as the predominant oncogenic driver. Furthermore, quantitative immunohistochemical analysis of the inflammatory tumor microenvironment showed that an increased percentage of M2 macrophages is associated with lower overall survival in MET-amplified EACs. Conclusions Our results provide valuable insights into possible new therapeutic approaches for MET-amplified EACs for further research.

Malignant cells have in contrast to non-transformed cells de-regulated transcriptional networks. The activator protein-1 (AP-1) transcription factor complex is expressed in many cancer entities including adenocarcinomas and has been correlated to de-regulated transcription and tumor-promoting mechanisms. Despite complex treatment approaches, esophageal cancer is still associated with poor overall survival. There is an urgent need for better patient stratification to increase the outcome of the multimodal treatment. This study investigated the expression of two AP-1 factors, cJUN and JUNB, and their role in 735 patients with esophageal cancer undergoing surgery. We performed immunohistochemical stainings for cJUN and JUNB and correlated the expression to the clinical outcome. Patients with a high JUNB expression level correlate to a reduced overall survival (OS) compared to patients with a low expression. Furthermore, in the multivariate analysis high JUNB expression was shown to be an independent risk factor for reduced patient survival. In addition, subgroup analysis demonstrated a significantly reduced OS for high JUNB expression in the subgroup of patients with neoadjuvant treatment. Strikingly, tumors co-expressing cJUN and JUNB were associated with poorer overall survival compared to those expressing only one or neither of the transcriptions factors. Our study suggests JUN expression as a novel biomarker to stratify patients, especially in the subgroup of neoadjuvant treated patients. Our findings have translational implications as targeting JUN might complement current available multimodal treatment approaches.

Background Robotic-assisted minimally invasive esophagectomy (RAMIE) has become an increasingly adopted approach for the treatment of esophageal cancer. However, the impact of intraoperative fluid therapy on postoperative outcomes remains poorly defined. Whereas fluid overload has been linked to pulmonary and anastomotic complications, restrictive strategies may impair tissue perfusion and organ function. This study investigates the association between intraoperative fluid balance and postoperative morbidity in patients undergoing RAMIE. Methods We conducted a retrospective single-center cohort study including 254 consecutive patients who underwent elective RAMIE between 2019 and 2024. Intraoperative fluid balance was calculated in mL/kg/h and analyzed as a continuous variable. Primary endpoints included pulmonary complications, anastomotic leakage, postoperative atrial fibrillation (POAF), and acute kidney injury (AKI). Secondary endpoints comprised ICU length of stay (LOS), postoperative delirium, delayed gastric emptying (DGE), and complication severity according to the Clavien-Dindo classification. Multivariable regression models were adjusted for age, sex, BMI, and ASA status. Results Pulmonary complications (23.2%) were significantly associated with higher intraoperative fluid volumes (mean: 5.2 vs. 4.4 ml/kg/h; p  = 0.027; OR: 1.24, 95% CI: 1.05–1.46). Anastomotic leakage (18.5%) exhibited an inverted U-shaped relationship, with the highest risk at fluid levels of 4.7–8.1 ml/kg/h). POAF (16.1%) and AKI (5.5%) were not significantly associated with fluid volume in multivariable analysis. POAF showed no significant association with intraoperative fluid volume in adjusted models. Predicted probabilities illustrated a fivefold increase in pulmonary risk across the 0 to 10 ml/kg/h range, whereas POAF declined steadily over this interval. Postoperative delirium showed a trend toward association with fluid volume (OR: 1.34; p  = 0.056), while DGE, ICU-LOS, and major complications demonstrated no significant associations. Subgroup analyses suggested stronger associations between fluid volume and pulmonary complications in elderly patients, and a more pronounced POAF risk in males, indicating potential effect modification by age and sex. Conclusion Intraoperative fluid volume during RAMIE is variably associatiated with postoperative outcomes. While higher volumes are linked to increased pulmonary morbidity, lower volumes may predispose patients to arrhythmias. Anastomotic complications appear to peak at moderate fluid levels. These findings challenge binary fluid strategies and support a more individualized, risk-adapted approach to intraoperative fluid management in esophageal surgery.

Background For many solid types of cancer including colorectal cancer treatment with the VEGF antibody bevacizumab as anti-angiogenic treatment has become standard of care. Nevertheless, long-term treatment with anti-angiogenic drugs in combination with other treatment modalities or alone can induce resistance through alternative pro-angiogenic pathways. In this study, we investigated the effects of nintedanib, an anti- VEGFR/PDGFR/FGFR kinase inhibitor, on tumor vasculature to determine the potential benefits of combined inhibition of multiple pro-angiogenic factors. Methods In a colorectal xenograft model, subcutaneous tumors were treated with Nintedanib. Tumor growth patterns were measured and tumors were analysed histologically regarding effects on tumor angiogenesis and parameters of vascular normalization. Results Inhibition of VEGFR/PDGFR/FGFR by Nintedanib was able to reduce tumor growth by significantly inhibiting angiogenesis and inducing tumor cell death. The remaining vessels showed decreased vascular leakage and improved oxygen delivery, indicating a functionally and structurally improved vascular bed resulting from vascular normalization. Conclusion In xenograft mouse model of colorectal cancer Nintedanib revealed anti-tumoral effects and induced vascular normalization. Our findings indicate that the treatment with Nintedanib could be able to improve intratumoral oxygen and thereby drug delivery to potentially enhance the efficacy of preexisting oncological therapies such as chemotherapy and radiation.

In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show that proliferating ECs increasingly depend on mitochondrial oxidative phosphorylation (OxPhos) for their increased energy demand. Under growth conditions, ECs consume three times more oxygen than quiescent ECs and work close to their respiratory limit. The increased utilization of the proton motif force leads to a reduced mitochondrial membrane potential in proliferating ECs and sensitizes to mitochondrial uncoupling. The benzoquinone embelin is a weak mitochondrial uncoupler that prevents neoangiogenesis during tumor growth and wound healing by exhausting the low respiratory reserve of proliferating ECs without adversely affecting quiescent ECs. We demonstrate that this can be exploited therapeutically by attenuating tumor growth in syngenic and xenograft mouse models. This novel metabolic targeting approach might be clinically valuable in controlling pathological neoangiogenesis while sparing normal vasculature and complementing cytostatic drugs in cancer treatment. Synopsis Weak mitochondrial uncouplers prevent neoangiogenesis in vitro and in vivo by depleting cellular energy reserves in proliferating but not normal quiescent endothelial cells (ECs). New vessel formation during tumor growth requires EC proliferation and increased oxidative phosphorylation to meet the greater energy demand during angiogenesis. Weak mitochondrial uncouplers prevent neoangiogenesis by depleting cellular energy reserves in proliferating but not normal quiescent ECs. Proliferating ECs are sensitized to mitochondrial uncouplers by a reduction in membrane potential and lower respiratory reserve capacity. Genetic accumulation of mitochondrial DNA mutations in mitochondrial mutator mice highlights the link between reduced OxPhos activity and impaired angiogenic response. Weak mitochondrial uncouplers could be clinically valuable in controlling pathological neoangiogenesis while sparing normal vasculature and complementing cytostatic drugs in cancer treatment. Graphical Abstract Weak mitochondrial uncouplers prevent neoangiogenesis in vitro and in vivo by depleting cellular energy reserves in proliferating but not normal quiescent endothelial cells.

Background Molecular markers predicting survival in esophageal adenocarcinoma (EAC) are rare. Specifically, in favorable oncologic situations, e.g. nodal negativity or major neoadjuvant therapy response, there is a lack of additional risk factors that serve to predict patients’ outcome more precisely. This study evaluated X-linked inhibitor of apoptosis protein (XIAP) as a potential marker improving outcome prediction. Methods Tissue microarrays from 362 patients that were diagnosed with resectable EAC were included in the study. XIAP was stained by immunohistochemistry and correlated to clinical outcome, molecular markers and markers of the cellular tumor microenvironment. Results XIAP did not impact on overall survival (OS) in the whole study collective. Subgroup analyses stratifying for common genetic markers (TP53, ERBB2, ARID1A/SWI/SNF) did not disclose any impact of XIAP expression on survival. Detailed subgroup analyses of [1] nodal negative patients, [2] highly T-cell infiltrated tumors and [3] therapy responders to neoadjuvant treatment revealed a significant inverse role of high XIAP expression in these specific oncologic situations; elevated XIAP expression detrimentally affected patients’ outcome in these subgroups. [1]: OS XIAP low: 202 months (m) vs. XIAP high: 38 m; [2]: OS 116 m vs. 28.2 m; [3]: OS 31 m vs. 4 m). Conclusions Our data suggest XIAP expression in EAC as a worthy tool to improve outcome prediction in specific oncologic settings that might directly impact on clinical diagnosis and treatment of EAC in the future.

The cytosolic appearance and propagation of bacteria cause overwhelming cellular stress responses that induce apoptosis under normal conditions. Therefore, successful bacterial colonization depends on the ability of intracellular pathogens to block apoptosis and to safeguard bacterial replicative niches. Here, we show that the cytosolic Gram-negative bacterium Shigella flexneri stalls apoptosis by inhibiting effector caspase activity. Our data identified lipopolysaccharide (LPS) as a bona fide effector caspase inhibitor that directly binds caspases by involving its O-antigen (O Ag) moiety. Bacterial strains that lacked the O Ag or failed to replicate within the cytosol were incapable of blocking apoptosis and exhibited reduced virulence in a murine model of bacterial infection. Our findings demonstrate how Shigella inhibits pro-apoptotic caspase activity, effectively delays coordinated host-cell demise and supports its intracellular propagation. Next to the recently discovered pro-inflammatory role of cytosolic LPS, our data reveal a distinct mode of LPS action that, through the disruption of the early coordinated non-lytic cell death response, ultimately supports the inflammatory breakdown of infected cells at later time points. The lipopolysaccharide of the intracellular pathogen Shigella , in particular its O antigen, interacts with caspases and blocks their activation to prevent apoptosis.

Esophageal cancer is among the top ten most deadly cancers worldwide with adenocarcinomas of the esophagus showing increasing incidences over the last years. The prognosis is determined by tumor stage at diagnosis and in locally advanced stages by response to (radio-)chemotherapy followed by radical surgery. Less than a third of patients with esophageal adenocarcinomas completely respond to neoadjuvant therapies which urgently asks for further strategies to improve these rates. Aiming at the tumor microenvironment with novel targeted therapies can be one strategy to achieve this goal. This review connects experimental, translational, and clinical findings on each component of the esophageal cancer tumor microenvironment involving tumor angiogenesis, tumor-infiltrating immune cells, such as macrophages, T-cells, myeloid-derived suppressor cells, and cancer-associated fibroblasts. The review evaluates the current state of already approved concepts and depicts novel potentially targetable pathways related to esophageal cancer tumor microenvironment.