Platelet-Associated CD40/CD154 Mediates Remote Tissue Damage after Mesenteric Ischemia/Reperfusion Injury

Several innate and adaptive immune cell types participate in ischemia/reperfusion induced tissue injury. Amongst them, platelets have received little attention as contributors in the process of tissue damage after ischemia reperfusion (I/R) injury. It is currently unknown whether platelets participate through the immunologically important molecules including, CD40 and when activated, CD154 (CD40L), in the pathogenesis of I/R injury. We hypothesized that constitutive expression of CD40 and activation-induced expression of CD154 on platelets mediate local mesenteric and remote lung tissue damage after I/R injury. Wild type (WT; C57BL/6J), CD40 and CD154 deficient mice underwent mesenteric ischemia for 30 minutes followed by reperfusion for 3 hours. WT mice subjected to mesenteric I/R injury displayed both local intestinal and remote lung damage. In contrast, there was significantly less intestinal damage and no remote lung injury in CD40 and CD154 deficient mice when compared to WT mice. Platelet-depleted WT mice transfused with platelets from CD40 or CD154 deficient mice failed to reconstitute remote lung damage. In contrast, when CD40 or CD154 deficient mice were transfused with WT platelets lung tissue damage was re-established. Together, these findings suggest that multiple mechanisms are involved in local and remote tissue injury and also identify platelet-expressed CD40 and/or CD154 as mediators of remote tissue damage

Intestinal barrier function in patients undergoing colectomy

The aim of this pilot study was to determine whether the type of approach (open or laparoscopic) and the order of devascularization during laparoscopic colectomy affect intestinal barrier function, local inflammatory response and clinical outcome. Twenty-two patients undergoing elective colectomy from April 2006 to July 2008 were randomized to two sequences of vascular ligation, starting with either the inferior mesenteric artery or the ileocolic artery. Eighteen patients scheduled for open surgery served as a prospective control group. To assess the intestinal barrier function, release of intestinal fatty-acid binding protein (I-FABP; a marker of mucosal injury and ischaemia) was measured pre- and postoperatively. Mesenteric lymph nodes were harvested to assess the expression of inflammatory mediator-related genes using multiplex ligation probe amplification. The study was registered under NTR1025. Laparoscopic devascularization starting at the ileocolic artery resulted in a significantly increased excretion of I-FABP over time (P = 0.002). In this group, the I-FABP levels were significantly increased on postoperative days 1 and 3 compared with preoperative values (P = 0.011 and P = 0.001, respectively). There were no differences in expression of inflammatory mediator-related genes or postoperative morbidity among the groups. In this pilot study, devascularization commencing at the ileocolic artery during laparoscopic colectomy was associated with prolonged intestinal mucosal ischaemi

Exploring the human plasma proteome for humoral mediators of remote ischemic preconditioning - A word of caution

Despite major advances in early revascularization techniques, cardiovascular diseases are still the leading cause of death worldwide, and myocardial infarctions contribute heavily to this. Over the past decades, it has become apparent that reperfusion of blood to a previously ischemic area of the heart causes damage in and of itself, and that this ischemia reperfusion induced injury can be reduced by up to 50% by mechanical manipulation of the blood flow to the heart. The recent discovery of remote ischemic preconditioning (RIPC) provides a non-invasive approach of inducing this cardioprotection at a distance. Finding its endogenous mediators and their operative mode is an important step toward increasing the ischemic tolerance. The release of humoral factor(s) upon RIPC was recently demonstrated and several candidate proteins were published as possible mediators of the cardioprotection. Before clinical applicability, these potential biomarkers and their efficiency must be validated, a task made challenging by the large heterogeneity in reported data and results. Here, in an attempt to reproduce and provide more experimental data on these mediators, we conducted an unbiased in-depth analysis of the human plasma proteome before and after RIPC. From the 68 protein markers reported in the literature, only 28 could be mapped to manually reviewed (Swiss-Prot) protein sequences. 23 of them were monitored in our untargeted experiment. However, their significant regulation could not be reproducibly estimated. In fact, among the 394 plasma proteins we accurately quantified, no significant regulation could be confidently and reproducibly assessed. This indicates that it is difficult to both monitor and reproduce published data from experiments exploring for RIPC induced plasma proteomic regulations, and suggests that further work should be directed towards small humoral factors. To simplify this task, we made our proteomic dataset available via ProteomeXchange, where scientists can mine for novel potential targets

Prediction of pathologic complete response after single-dose MR-guided partial breast irradiation in low-risk breast cancer patients: the ABLATIVE-2 trial—a study protocol

Background: Partial breast irradiation (PBI) is standard of care in low-risk breast cancer patients after breast-conserving surgery (BCS). Pre-operative PBI can result in tumor downstaging and more precise target definition possibly resulting in less treatment-related toxicity. This study aims to assess the pathologic complete response (pCR) rate one year after MR-guided single-dose pre-operative PBI in low-risk breast cancer patients. Methods: The ABLATIVE-2 trial is a multicenter prospective single-arm trial using single-dose ablative PBI in low-risk breast cancer patients. Patients ≥ 50 years with non-lobular invasive breast cancer ≤ 2 cm, grade 1 or 2, estrogen receptor-positive, HER2-negative, and tumor-negative sentinel node procedure are eligible. A total of 100 patients will be enrolled. PBI treatment planning will be performed using a radiotherapy planning CT and -MRI in treatment position. The treatment delivery will take place on a conventional or MR-guided linear accelerator. The prescribed radiotherapy dose is a single dose of 20 Gy to the tumor, and 15 Gy to the 2 cm of breast tissue surrounding the tumor. Follow-up MRIs, scheduled at baseline, 2 weeks, 3, 6, 9, and 12 months after PBI, are combined with liquid biopsies to identify biomarkers for pCR prediction. BCS will be performed 12 months after radiotherapy or after 6 months, if MRI does not show a radiologic complete response. The primary endpoint is the pCR rate after PBI. Secondary endpoints are radiologic response, toxicity, quality of life, cosmetic outcome, patient distress, oncological outcomes, and the evaluation of biomarkers in liquid biopsies and tumor tissue. Patients will be followed up to 10 years after radiation therapy. Discussion: This trial will investigate the pathological tumor response after pre-operative single-dose PBI after 12 months in patients with low-risk breast cancer. In comparison with previous trial outcomes, a longer interval between PBI and BCS of 12 months is expected to increase the pCR rate of 42% after 6–8 months. In addition, response monitoring using MRI and biomarkers will help to predict pCR. Accurate pCR prediction will allow omission of surgery in future patients. Trial registration: The trial was registered prospectively on April 28th 2022 at clinicaltrials.gov (NCT05350722)

Randomized clinical trial of observational versus antibiotic treatment for a first episode of CT-proven uncomplicated acute diverticulitis

Item does not contain fulltextBACKGROUND: Antibiotics are advised in most guidelines on acute diverticulitis, despite a lack of evidence to support their routine use. This trial compared the effectiveness of a strategy with or without antibiotics for a first episode of uncomplicated acute diverticulitis. METHODS: Patients with CT-proven, primary, left-sided, uncomplicated, acute diverticulitis were included at 22 clinical sites in the Netherlands, and assigned randomly to an observational or antibiotic treatment strategy. The primary endpoint was time to recovery during 6 months of follow-up. Main secondary endpoints were readmission rate, complicated, ongoing and recurrent diverticulitis, sigmoid resection and mortality. Intention-to-treat and per-protocol analyses were done. RESULTS: A total of 528 patients were included. Median time to recovery was 14 (i.q.r. 6-35) days for the observational and 12 (7-30) days for the antibiotic treatment strategy, with a hazard ratio for recovery of 0.91 (lower limit of 1-sided 95 per cent c.i. 0.78; P = 0.151). No significant differences between the observation and antibiotic treatment groups were found for secondary endpoints: complicated diverticulitis (3.8 versus 2.6 per cent respectively; P = 0.377), ongoing diverticulitis (7.3 versus 4.1 per cent; P = 0.183), recurrent diverticulitis (3.4 versus 3.0 per cent; P = 0.494), sigmoid resection (3.8 versus 2.3 per cent; P = 0.323), readmission (17.6 versus 12.0 per cent; P = 0.148), adverse events (48.5 versus 54.5 per cent; P = 0.221) and mortality (1.1 versus 0.4 per cent; P = 0.432). Hospital stay was significantly shorter in the observation group (2 versus 3 days; P = 0.006). Per-protocol analyses were concordant with the intention-to-treat analyses. CONCLUSION: Observational treatment without antibiotics did not prolong recovery and can be considered appropriate in patients with uncomplicated diverticulitis. Registration number: NCT01111253 (http://www.clinicaltrials.gov)