Integration of Patient-Derived Organoids and Organ-on-Chip Systems: Investigating Colorectal Cancer Invasion within the Mechanical and GABAergic Tumor Microenvironment.

Three-dimensional (3D) in vitro models are essential in cancer research, but they often neglect physical forces. In our study, we combined patient-derived tumor organoids with a microfluidic organ-on-chip system to investigate colorectal cancer (CRC) invasion in the tumor microenvironment (TME). This allowed us to create patient-specific tumor models and assess the impact of physical forces on cancer biology. Our findings showed that the organoid-on-chip models more closely resembled patient tumors at the transcriptional level, surpassing organoids alone. Using 'omics' methods and live-cell imaging, we observed heightened responsiveness of KRAS mutant tumors to TME mechanical forces. These tumors also utilized the γ-aminobutyric acid (GABA) neurotransmitter as an energy source, increasing their invasiveness. This bioengineered model holds promise for advancing our understanding of cancer progression and improving CRC treatments.

Interleukin-1 Blockade Inhibits the Acute Inflammatory Response in Patients With ST-Segment-Elevation Myocardial Infarction.

Background ST-segment-elevation myocardial infarction is associated with an intense acute inflammatory response and risk of heart failure. We tested whether interleukin-1 blockade with anakinra significantly reduced the area under the curve for hsCRP (high sensitivity C-reactive protein) levels during the first 14 days in patients with ST-segment-elevation myocardial infarction (VCUART3 [Virginia Commonwealth University Anakinra Remodeling Trial 3]). Methods and Results We conducted a randomized, placebo-controlled, double-blind, clinical trial in 99 patients with ST-segment-elevation myocardial infarction in which patients were assigned to 2 weeks treatment with anakinra once daily (N=33), anakinra twice daily (N=31), or placebo (N=35). hsCRP area under the curve was significantly lower in patients receiving anakinra versus placebo (median, 67 [interquartile range, 39-120] versus 214 [interquartile range, 131-394] mg·day/L; P<0.001), without significant differences between the anakinra arms. No significant differences were found between anakinra and placebo groups in the interval changes in left ventricular end-systolic volume (median, 1.4 [interquartile range, -9.8 to 9.8] versus -3.9 [interquartile range, -15.4 to 1.4] mL; P=0.21) or left ventricular ejection fraction (median, 3.9% [interquartile range, -1.6% to 10.2%] versus 2.7% [interquartile range, -1.8% to 9.3%]; P=0.61) at 12 months. The incidence of death or new-onset heart failure or of death and hospitalization for heart failure was significantly lower with anakinra versus placebo (9.4% versus 25.7% [P=0.046] and 0% versus 11.4% [P=0.011], respectively), without difference between the anakinra arms. The incidence of serious infection was not different between anakinra and placebo groups (14% versus 14%; P=0.98). Injection site reactions occurred more frequently in patients receiving anakinra (22%) versus placebo (3%; P=0.016). Conclusions In patients presenting with ST-segment-elevation myocardial infarction, interleukin-1 blockade with anakinra significantly reduces the systemic inflammatory response compared with placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01950299.

Eosinophilic Granulomatosis With Polyangiitis Presenting as an Acute Coronary Syndrome.

Eosinophilic granulomatosis with polyangiitis, formerly Churg-Strauss Syndrome, is an uncommon disorder that carries a high mortality when coronary artery disease develops. Early recognition and treatment is crucial. We highlight an unusual presentation of acute coronary syndrome not associated with atherosclerotic coronary disease. (Level of Difficulty: Intermediate.).

Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial).

BACKGROUND: An enhanced inflammatory response predicts worse outcomes in heart failure (HF). We hypothesized that administration of IL-1 (interleukin-1) receptor antagonist (anakinra) could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF. METHODS AND RESULTS: We randomly assigned 60 patients with reduced left ventricular ejection fraction (<50%) and elevated C-reactive protein levels (>2 mg/L), within 14 days of hospital discharge, to daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo. Patients underwent measurement of peak oxygen consumption (Vo2 [mL/kg per minute]) and ventilatory efficiency (the VE/Vco2 slope). Treatment with anakinra did not affect peak Vo2 or VE/Vco2 slope at 2 weeks. At 12 weeks, patients continued on anakinra showed an improvement in peak Vo2 from 14.5 (10.5-16.6) mL/kg per minute to 16.1 (13.2-18.6) mL/kg per minute (P=0.009 for within-group changes), whereas no significant changes occurred within the anakinra 2-week or placebo groups. The between-groups differences, however, were not statistically significant. The incidence of death or rehospitalization for HF at 24 weeks was 6%, 31%, and 30%, in the anakinra 12-week, anakinra 2-week, and placebo groups, respectively (log-rank test P=0.10). CONCLUSIONS: No change in peak Vo2 occurred at 2 weeks in patients with recently decompensated systolic HF treated with anakinra, whereas an improvement was seen in those patients in whom anakinra was continued for 12 weeks. Additional larger studies are needed to validate the effects of prolonged anakinra on peak Vo2 and rehospitalization for HF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936909.

Severely Impaired Cardiorespiratory Fitness in Patients With Recently Decompensated Systolic Heart Failure.

Hospital admission for decompensated heart failure marks a critical inflection point in a patient's health. Despite the improvement in signs or symptoms during hospitalization, patients have a high likelihood of readmission, reflecting a lack of resolution of the underlying condition. Surprisingly, no studies have characterized the cardiorespiratory fitness of such patients. Fifty-two patients (38 [73%] male, age 57 [52 to 65] years, left ventricular ejection fraction 31% [24 to 38]) underwent cardiopulmonary exercise testing 4 (1 to 10) days after hospital discharge, when stable and without overt signs of volume overload. Transthoracic Doppler echocardiography, measurement of N-terminal pro-B-natriuretic peptide, and quality of life were also assessed. Aerobic exercise capacity was severely reduced: peak oxygen consumption (pVO2) was 14.1 (11.2 to 16.3) ml/kg/min. Ventilatory inefficiency as indicated by the minute ventilation carbon dioxide production relation (VE/VCO2 slope) >30 and oxygen uptake efficiency slope <2.0 was noted in 41 (77%) and 39 (75%) patients, respectively. Forty-five (87%) patients had 1 of 2 high-risk features (pVO2 < 14 ml/kg/min or VE/VCO2 >30). Perceived functional capacity, measured by the Duke Activity Status Index, was also severely reduced and correlated with pVO2. N-terminal pro-B-natriuretic peptide levels and early transmitral velocity/early mitral annulus velocity (E/e') ratio at echocardiography showed a modest correlation with lower pVO2. In conclusion, patients with recently decompensated systolic heart failure demonstrate severe impairment in cardiorespiratory fitness, severely limiting quality of life.

Recombinant human interleukin-1 receptor antagonist provides cardioprotection during myocardial ischemia reperfusion in the mouse.

PURPOSE: Acute myocardial infarction (AMI) drives an intense inflammatory response that contributes to infarct healing and cardiac remodeling. Recently, different studies have identified a role of interleukin-1 (IL-1) in the development of adverse cardiac remodeling. However, in animal models of AMI IL-1 has been shown to be cardioprotective in preconditioning, raising the question of clinical safety of therapeutic IL-1 blockade for autoinflammatory diseases or for the prevention or the treatment of AMI. In this study we proposed to evaluate the effects of pretreatment with recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on ischemia reperfusion (I/R) injury to the heart. METHODS: RhIL-1Ra was given 4 h or 30 min before the surgical induction of I/R. Left ventricular ejection fraction(LVEF) and infarct size were assessed to determine the effects of the drug pretreatment compared to vehicle treated mice. RESULTS: RhIL-1Ra, given 4 h or 30 min before the onset of the ischemia, showed marked cardioprotection though preservation of the LVEF (no change vs sham operated mice) and the reduction of the infarct size (-40 % vs vehicle-treated mice). No differences were observed between the two groups of rhIL-1Ra treatment. CONCLUSIONS: IL-1 blockade therapies using rhIL-1Ra prior the onset of AMI protects the myocardium and preserves cardiac function.