Intestinal epithelial cell-intrinsic deletion of Setd7 identifies role for developmental pathways in immunity to helminth infection

The intestine is a common site for a variety of pathogenic infections. Helminth infections continue to be major causes of disease worldwide, and are a significant burden on health care systems. Lysine methyltransferases are part of a family of novel attractive targets for drug discovery. SETD7 is a member of the Suppressor of variegation 3-9-Enhancer of zeste-Trithorax (SET) domain-containing family of lysine methyltransferases, and has been shown to methylate and alter the function of a wide variety of proteins in vitro. A few of these putative methylation targets have been shown to be important in resistance against pathogens. We therefore sought to study the role of SETD7 during parasitic infections. We find that Setd7-/- mice display increased resistance to infection with the helminth Trichuris muris but not Heligmosomoides polygyrus bakeri. Resistance to T. muris relies on an appropriate type 2 immune response that in turn prompts intestinal epithelial cells (IECs) to alter differentiation and proliferation kinetics. Here we show that SETD7 does not affect immune cell responses during infection. Instead, we found that IEC-specific deletion of Setd7 renders mice resistant to T. muris by controlling IEC turnover, an important aspect of anti-helminth immune responses. We further show that SETD7 controls IEC turnover by modulating developmental signaling pathways such as Hippo/YAP and Wnt/β-Catenin. We show that the Hippo pathway specifically is relevant during T. muris infection as verteporfin (a YAP inhibitor) treated mice became susceptible to T. muris. We conclude that SETD7 plays an important role in IEC biology during infection

Cardiovascular events and treatment of children with high risk medulloblastoma

Background: Children with high-risk medulloblastoma are treated with chemotherapeutic protocols which may affect heart function. We aimed to assesscardiovascular events (CVE) in children with medulloblastoma/primitive neuroectodermal tumors (PNET). Methods: We retrospectively collected data from a case series of 22 children with high-risk medulloblastoma/PNET admitted to the Santobono-Pausilipon Hospital, Naples, Italy from 2008 to 2016. All patients received the Milan HART protocol for high-risk brain malignancies as first line treatment (induction phase), followed by a consolidation phase with Thiotepa and hematopoietic stem cells transplantation, except for 1 patient who received the Milan HART as second line therapy. Four patients also received second line treatment, while 4 patients also received maintenance therapy. Patients underwent cardiac examination, including ECG, echocardiography and serum biomarkers, before antineoplastic treatment initiation and then when clinically needed. Six patients developed CVE (CVE group); 16 patients had no CVE (NO-CVE group). Findings: In the CVE group, 3 patients presented acute CVE during chemotherapy (2 patients with left ventricular (LV) dysfunction, 1 patient with arterial hypertension), while 3 patients presented chronic CVE after chemotherapy completion (2 patients with LV dysfunction, 1 patient with ectopic atrial tachycardia). After a 51 months median follow-up, 9 patients died: 4 from the CVE group (in 2 cases heart failure-related deaths) and 5 from the NO-CVE group (progression of disease). Interpretation: A relevant percentage of children treated for medulloblastoma/PNET develops CVE. Heart failure potentially due to chemotherapy may represent a cause of death. Hence, in these patients, strict cardiac surveillance is essential. Funding: No funding was associated with this study

Safety of aortic aneurysm repair 8 weeks after percutaneous coronary intervention for coronary artery disease: a cohort study

Guidelines advice against dual antiplatelet therapy (DAPT) discontinuation less than 12 months after percutaneous coronary intervention with drug-eluting stents (DES-PCI). However, any delay of necessary surgery in patients with descending thoracic (DTA) or abdominal aortic aneurysm (AAA), treated by DES-PCI, increases the risk of aneurysm rupture/dissection. We evaluated the safety of 8-week waiting time between DES-PCI and endovascular aortic repair (EVAR). 1152 consecutive patients with coronary artery disease (CAD) needing elective DTA or AAA repair were enrolled and divided into two groups. Group A included 830 patients treated by DES-PCI for significant CAD who underwent surgery 8 weeks after implantation. Group B included 322 patients treated by DES-PCI at least 6 months before with no residual significant CAD and treated by elective EVAR. Groups were compared according to a composite of death, myocardial infarction, stent thrombosis, cerebrovascular events and bleeding. No aneurysm rupture/dissection occurred while waiting for surgery. Hospital averse events occurred in 6.2% (52/830) group A patients versus 6.5% (21/322) group B patients (p = 0.8). Mortality was 0.7% (6/830) in group A and 0.9% (3/322) in group B (p = 0.7). Multivariate predictors of events were triple vessel DES-PCI (p 3 stents implanted (p 30 mm (p = 0.02). Eight weeks of waiting after DES-PCI in addition to an adequate management of DAPT were safe in terms of cardiac morbidity and bleeding complications. No aneurysm rupture occurred in the interval before surgery

New Oral Anticoagulants Versus Warfarin in Atrial Fibrillation After Early Postoperative Period in Patients With Bioprosthetic Aortic Valve

Background: The efficacy of novel nonvitamin K antagonist oral anticoagulants (NOACs) in nonvalvular atrial fibrillation (AF) to prevent stroke is well assessed, but NOACs use in AF that occurs after bioprosthetic aortic valve replacement (AVR) is not endorsed. This retrospective real-world study evaluated the efficacy and safety of NOACs prescribed no earlier than 4 months after AVR as an alternative to warfarin in patients with AF. Methods: We pooled 1032 patients from the databases of 5 centers. Ischemic/embolic events and major bleeding rates were compared between 340 patients assuming NOACs and 692 prescribed warfarin. Propensity score matching was performed to avoid the bias between groups. Results: The NOACs vs warfarin embolic/ischemic rate was 13.5% (46 of 340) vs 22.7% (157 of 692), respectively, (hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.37-0.75; P < .001), and the incidence rate was 3.7% vs 6.9% patients/year, respectively (log-rank test P = .009). The major bleeding rate was 7.3% (25 of 340) vs 13% (90 of 692) (HR, 0.5; 95% CI, 0.33-0.84; P = .007), and the incidence rate was 2% vs 4% patients/year (log-rank test P = .002.) After propensity score matching, the NOACs vs warfarin embolic/ischemic rate was 13.1% (42 of 321) vs 21.8% (70 of 321) (HR, 0.6; 95% CI, 0.4-0.9; P = .02), and the incidence rate was 4.1% vs 6.7% patients/year (log rank test P = .01). The major bleeding rate was 7.8% (25 of /321) vs 13.7% (44 of 321) (HR, 0.5; 95% CI, 0.31-0.86; P = .01), and the incidence rate was 2.4% vs 4.2% patients/year (log-rank P = .01). Conclusions: In a real-word study, NOACs use overcomes the indications provided by guidelines. This study evidenced that NOACs use in patients who developed AF after bioprosthetic AVR was more effective in prevention of thromboembolism and safe in reduction of major bleeding events compared with warfarin

B-type natriuretic peptide as a biochemical marker of left ventricular diastolic function: Assessment in asymptomatic patients 1 year after valve replacement for aortic stenosis.

Objectives: Left ventricular (LV) diastolic dysfunction after aortic valve replacement (AVR) carries a substantial risk of development of heart failure and reduced survival. In addition to echocardiography, B-type natriuretic peptide (BNP) provides a powerful incremental assessment of diastolic function. This study evaluates BNP as a marker of LV diastolic dysfunction in a cohort of patients with preserved LV ejection fraction who underwent AVR for pure aortic stenosis and the relationship between BNP values and the grade of LV diastolic dysfunction. Methods A total of 113 patients were included in the study. Echocardiographic evaluation was performed preoperatively, 5 days postoperatively and at 12-month follow-up, to assess LV dimensional and functional parameters. Diastolic function was labelled as normal, mild, moderate or severe dysfunction. Concomitantly, BNP levels were evaluated. Results Mild to severe diastolic dysfunction occurred preoperatively in all patients. At 12-month follow-up, 65 (62.5%) patients had mild and 25 (24.1%) moderate to severe diastolic dysfunction. BNP values, categorized for quartile distribution, correlated with diastolic dysfunction grade (P < 0.001 for each comparison). At receiver operating characteristic analysis, the BNP level of 120 pg/ml was 91% sensitive and 85% specific for diastolic disease, while 300 pg/ml was 80% sensitive and 91% specific for moderate or severe diastolic dysfunction. Twelve months after AVR, BNP values were strongly correlated with the significant echocardiographic parameters suggestive of diastolic dysfunction (P ≤ 0.006 in all cases). Conclusions The BNP level following AVR is related to diastolic disease severity and may complement echocardiographic evaluation when symptoms are unclear and LV function is difficult to interpret

Status of coronary disease and results from early endovascular aneurysm repair after preventive percutaneous coronary revascularization

Background: The incidence of coronary artery disease (CAD) is high in patients with an aortic aneurysm but preoperative routine coronary angiography and preventive coronary revascularization are not recommended to reduce cardiac events in patients with severe CAD. Aim: This study evaluated the safeness and efficacy of preventive percutaneous coronary intervention (PCI) in patients with severe CAD scheduled for endovascular aneurysm repair (EVAR). Methods: All patients with descending thoracic aneurysm (DTA) or abdominal aortic aneurysm (AAA) scheduled for EVAR underwent preliminary coronary angiography. Based on coronary angiography results, 917 patients (40.7%) had significant CAD and were treated by percutaneous coronary intervention (PCI; CAD group) and 1337 patients (59.3%) were without or with mild/moderate CAD and were considered as controls (no‐CAD group). To evaluate the safeness and efficacy of preventive PCI in patients with severe CAD undergoing EVAR, groups were compared for hospital and 12‐month cardiac adverse events. Results: CAD was present in 1210 patients (53.6%): significant in 917 patients (38%) and mild to moderate in 293 patients (5.3%). Hospital and 12‐month cardiac events occurred in 15 (1.6%) and 13 (1.4%) CAD group patients and in 9 (0.7%) and 8 (0.4%) no‐CAD group patients (p = .05 and p = .08), respectively. Hospital and 12‐month cardiac deaths occurred in 3 (0.3%) and 2 (0.2%) CAD group patients and in 3 (0.2%) and 2 (0.2%) no‐CAD group patients (p = .9 and p = .9), respectively. Conclusion: The strategy to treat severe CAD preoperatively by PCI and early subsequent EVAR brings a similar outcome to that in patients without or with mild/ moderate CAD

SHIP-Deficient Dendritic Cells, Unlike Wild Type Dendritic Cells, Suppress T Cell Proliferation via a Nitric Oxide-Independent Mechanism

Dendritic cells (DCs) not only play a crucial role in activating immune cells but also suppressing them. We recently investigated SHIP's role in murine DCs in terms of immune cell activation and found that TLR agonist-stimulated SHIP-/- GM-CSF-derived DCs (GM-DCs) were far less capable than wild type (WT, SHIP+/+) GM-DCs at activating T cell proliferation. This was most likely because SHIP-/- GM-DCs could not up-regulate MHCII and/or co-stimulatory receptors following TLR stimulation. However, the role of SHIP in DC-induced T cell suppression was not investigated.In this study we examined SHIP's role in DC-induced T cell suppression by co-culturing WT and SHIP-/- murine DCs, derived under different conditions or isolated from spleens, with αCD3+ αCD28 activated WT T cells and determined the relative suppressive abilities of the different DC subsets. We found that, in contrast to SHIP+/+ and -/- splenic or Flt3L-derived DCs, which do not suppress T cell proliferation in vitro, both SHIP+/+ and -/- GM-DCs were capable of potently suppressing T cell proliferation. However, WT GM-DC suppression appeared to be mediated, at least in part, by nitric oxide (NO) production while SHIP-/- GM-DCs expressed high levels of arginase 1 and did not produce NO. Following exhaustive studies to ascertain the mechanism of SHIP-/- DC-mediated suppression, we could conclude that cell-cell contact was required and the mechanism may be related to their relative immaturity, compared to SHIP+/+ GM-DCs.These findings suggest that although both SHIP+/+ and -/- GM-DCs suppress T cell proliferation, the mechanism(s) employed are different. WT GM-DCs suppress, at least in part, via IFNγ-induced NO production while SHIP-/- GM-DCs do not produce NO and suppression can only be alleviated when contact is prevented

Assessing the Role of CD103 in Immunity to an Intestinal Helminth Parasite

In the intestine, the integrin CD103 is expressed on a subset of T regulatory (T(reg)) cells and a population of dendritic cells (DCs) that produce retinoic acid and promote immune homeostasis. However, the role of CD103 during intestinal helminth infection has not been tested.We demonstrate that CD103 is dispensable for the development of protective immunity to the helminth parasite Trichuris muris. While we observed an increase in the frequency of CD103(+) DCs in the lamina propria (LP) following acute high-dose infection with Trichuris, lack of CD103 had no effect on the frequency of CD11c(+) DCs in the LP or mesenteric lymph nodes (mLN). CD103-deficient (CD103(-/-)) mice develop a slightly increased and earlier T cell response but resolve infection with similar kinetics to control mice. Similarly, low-dose chronic infection of CD103(-/-) mice with Trichuris resulted in no significant difference in immunity or parasite burden. Absence of CD103 also had no effect on the frequency of CD4(+)CD25(+)Foxp3(+) T(reg) cells in the mLN or LP.These results suggest that CD103 is dispensable for intestinal immunity during helminth infection. Furthermore, lack of CD103 had no effect on DC or T(reg) recruitment or retention within the large intestine