Milk exosomes: beyond dietary microRNAs

Extracellular vesicles deliver a variety of cargos to recipient cells, including the delivery of cargos in dietary vesicles from bovine milk to non-bovine species. The rate of discovery in this important line of research is slowed by a controversy whether the delivery and bioactivity of a single class of vesicle cargos, microRNAs, are real or not. This opinion paper argues that the evidence in support of the bioavailability of microRNAs encapsulated in dietary exosomes outweighs the evidence produced by scholars doubting that phenomenon is real. Importantly, this paper posits that the time is ripe to look beyond microRNA cargos and pursue innovative pathways through which dietary exosomes alter metabolism. Here, we highlight potentially fruitful lines of exploration

Inhibition of p38 MAPK Suppresses Inflammatory Cytokine Induction by Etoposide, 5-Fluorouracil, and Doxorubicin without Affecting Tumoricidal Activity

Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often experience debilitating fatigue similar to sickness behavior, a normal response to infection or tissue damage caused by the production of the inflammatory cytokines IL-1β, TNF-α, and IL-6. The p38 mitogen activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the development of sickness behavior. Targeted inhibitors of p38 MAPK can reduce systemic inflammatory cytokine production and the development of sickness behavior. Several systemic cancer chemotherapy drugs have been shown to stimulate inflammatory cytokine production, yet whether this response is related to a common ability to activate p38 MAPK is not known and is the focus of this study. This understanding may present the possibility of using p38 MAPK inhibitors to reduce chemotherapy-induced inflammatory cytokine production and consequently treatment-related fatigue. One caveat of this approach is a potential reduction in chemotherapeutic efficacy as some believe that p38 MAPK activity is required for chemotherapy-induced cytotoxicity of tumor cells. The purpose of this study was to demonstrate proof of principal that p38 MAPK inhibition can block chemotherapy- induced inflammatory cytokine production without inhibiting drug-induced cytotoxicity using murine peritoneal macrophages and Lewis Lung Carcinoma (LLC1) cells as model cell systems. Using these cells we assessed the requirement of etoposide, doxorubicin, 5-flourouracil, and docetaxel for p38 MAPK in inflammatory cytokine production and cytotoxicity. Study findings demonstrate that clinically relevant doses of etoposide, doxorubicin, and 5-FU activated p38 MAPK in both macrophages and LLC1 cells. In contrast, docetaxel failed to activate p38 MAPK in either cell type. Activation of p38 MAPK mediated the drug's effects on inflammatory cytokine production in macrophages but not LLC1 cytotoxicity and this was confirmed with inhibitor studies

1-methylnicotinamide and its structural analog 1,4-dimethylpyridine for the prevention of cancer metastasis

Background: 1-methylnicotinamide (1-MNA), an endogenous metabolite of nicotinamide, has recently gained interest due to its anti-inflammatory and anti-thrombotic activities linked to the COX-2/PGI2 pathway. Given the previously reported anti-metastatic activity of prostacyclin (PGI2), we aimed to assess the effects of 1-MNA and its structurally related analog, 1,4-dimethylpyridine (1,4-DMP), in the prevention of cancer metastasis. Methods: All the studies on the anti-tumor and anti-metastatic activity of 1-MNA and 1,4-DMP were conducted using the model of murine mammary gland cancer (4T1) transplanted either orthotopically or intravenously into female BALB/c mouse. Additionally, the effect of the investigated molecules on cancer cell-induced angiogenesis was estimated using the matrigel plug assay utilizing 4T1 cells as a source of pro-angiogenic factors. Results: Neither 1-MNA nor 1,4-DMP, when given in a monotherapy of metastatic cancer, influenced the growth of 4T1 primary tumors transplanted orthotopically; however, both compounds tended to inhibit 4T1 metastases formation in lungs of mice that were orthotopically or intravenously inoculated with 4T1 or 4T1-luc2-tdTomato cells, respectively. Additionally, while 1-MNA enhanced tumor vasculature formation and markedly increased PGI2 generation, 1,4-DMP did not have such an effect. The anti-metastatic activity of 1-MNA and 1,4-DMP was further confirmed when both agents were applied with a cytostatic drug in a combined treatment of 4T1 murine mammary gland cancer what resulted in up to 80 % diminution of lung metastases formation. Conclusions: The results of the studies presented below indicate that 1-MNA and its structural analog 1,4-DMP prevent metastasis and might be beneficially implemented into the treatment of metastatic breast cancer to ensure a comprehensive strategy of metastasis control

Global Chronic Total Occlusion Crossing Algorithm: JACC State-of-the-Art Review

The authors developed a global chronic total occlusion crossing algorithm following 10 steps: 1) dual angiography; 2) careful angiographic review focusing on proximal cap morphology, occlusion segment, distal vessel quality, and collateral circulation; 3) approaching proximal cap ambiguity using intravascular ultrasound, retrograde, and move-the-cap techniques; 4) approaching poor distal vessel quality using the retrograde approach and bifurcation at the distal cap by use of a dual-lumen catheter and intravascular ultrasound; 5) feasibility of retrograde crossing through grafts and septal and epicardial collateral vessels; 6) antegrade wiring strategies; 7) retrograde approach; 8) changing strategy when failing to achieve progress; 9) considering performing an investment procedure if crossing attempts fail; and 10) stopping when reaching high radiation or contrast dose or in case of long procedural time, occurrence of a serious complication, operator and patient fatigue, or lack of expertise or equipment. This algorithm can improve outcomes and expand discussion, research, and collaboration

Global Chronic Total Occlusion Crossing Algorithm

The authors developed a global chronic total occlusion crossing algorithm following 10 steps: 1) dual angiography; 2) careful angiographic review focusing on proximal cap morphology, occlusion segment, distal vessel quality, and collateral circulation; 3) approaching proximal cap ambiguity using intravascular ultrasound, retrograde, and move-the-cap techniques; 4) approaching poor distal vessel quality using the retrograde approach and bifurcation at the distal cap by use of a dual-lumen catheter and intravascular ultrasound; 5) feasibility of retrograde crossing through grafts and septal and epicardial collateral vessels; 6) antegrade wiring strategies; 7) retrograde approach; 8) changing strategy when failing to achieve progress; 9) considering performing an investment procedure if crossing attempts fail; and 10) stopping when reaching high radiation or contrast dose or in case of long procedural time, occurrence of a serious complication, operator and patient fatigue, or lack of expertise or equipment. This algorithm can improve outcomes and expand discussion, research, and collaboration.info:eu-repo/semantics/publishedVersio

Rationale and design of a prospective substudy of clinical endpoint adjudication processes within an investigator-reported randomised controlled trial in patients with coronary artery disease: the GLOBAL LEADERS Adjudication Sub-StudY (GLASSY)

pragmatic and superiority randomised controlled trial designed to challenge the current treatment paradigm of dual antiplatelet therapy (DAPT) for 12 months followed by aspirin monotherapy among patients undergoing percutaneous coronary intervention. By design, all study endpoints are investigator reported (IR) and not subject to formal adjudication by an independent Clinical Event Committee (CEC), which may introduce detection, reporting or ascertainment bias. Methods and analysis We designed the GLOBAL LEADERS Adjudication Sub-StudY (GLASSY) to prospectively implement, in a large sample of patients enrolled within the GLOBAL LEADERS trial (7585 of 15 991, 47.5%), an independent adjudication process of reported and unreported potential endpoints, using standardised CEC procedures, in order to assess whether 23-month ticagrelor monotherapy (90mg twice daily) after 1-month DAPT is non-inferior to a standard regimen of DAPT for 12 months followed by aspirin monotherapy for the primary efficacy endpoint of death, nonfatal myocardial infarction, non-fatal stroke or urgent target vessel revascularisation and superior for the primary safety endpoint of type 3 or 5 bleeding according to the Bleeding Academic Research Consortium criteria. This study will comprehensively assess the comparative safety and efficacy of the two tested antithrombotic strategies on CEC-adjudicated ischaemic and bleeding endpoints and will provide insights into the role of a standardised CEC adjudication process on the interpretation of study findings by quantifying the level of concordance between IR-reported and CEC-adjudicated events. Ethics and dissemination GLASSY has been approved by local ethics committee of all study sites and/or by the central ethics committee for the country depending on country-specific regulations. In all cases, they deemed that it was not neces