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Background: The optimal timing to administer a P2Y12 inhibitor in patients presenting with a non-ST elevation acute coronary syndrome remains a topic of debate. Pretreatment with ticagrelor before coronary anatomy is known as a widely adopted strategy. However, there is poor evidence on how this compares with administration of a P2Y12 inhibitor after defining coronary anatomy (i.e., downstream administration). Moreover, there are limited head-to-head comparisons of the two P2Y12 inhibitors-ticagrelor and prasugrel-currently recommended by the guidelines., Study Design: DUBIUS is a phase 4, multicenter, parallel-group, double randomized study conducted in NSTE-ACS patients designed to compare a pretreatment strategy (including only ticagrelor) versus a downstream strategy (including prasugrel or ticagrelor) and to compare downstream prasugrel with downstream ticagrelor. A total of 2520 patients will be randomly assigned to pretreatment with ticagrelor or to no pretreatment. The PCI group of the downstream arm will be further randomized to receive prasugrel or ticagrelor. The two primary hypotheses are that the downstream strategy is superior to the upstream strategy and that downstream ticagrelor is non-inferior to downstream prasugrel, both measured by the incidence of a composite efficacy and safety endpoint of death from vascular causes, non-fatal MI, or non-fatal stroke, and Bleeding Academic Research Consortium (BARC) type 3, 4, and 5 bleedings., Conclusions: The DUBIUS study will provide important evidence related to the benefits and risks of pretreatment with ticagrelor compared with a strategy of no pretreatment. Moreover, the clinical impact of using downstream ticagrelor compared with downstream prasugrel will be assessed., Trial Registration: ClinicalTrials.gov NCT02618837 . Registered on 1 December 2015.

Background: Although oral P2Y 12 inhibitors are key in the management of patients with non-ST-segment elevation acute coronary syndrome, the optimal timing of their administration is not well defined., Objectives: The purpose of this study was to compare downstream and upstream oral P2Y 12 inhibitors administration strategies in patients with non-ST-segment elevation acute coronary syndrome undergoing invasive treatment., Methods: We performed a randomized, adaptive, open-label, multicenter clinical trial. Patients were randomly assigned to receive pre-treatment with ticagrelor before angiography (upstream group) or no pre-treatment (downstream group). Patients in the downstream group undergoing percutaneous coronary intervention were further randomized to receive ticagrelor or prasugrel. The primary hypothesis was the superiority of the downstream versus the upstream strategy on the combination of efficacy and safety events (net clinical benefit)., Results: We randomized 1,449 patients to downstream or upstream oral P2Y 12 inhibitor administration. A pre-specified stopping rule for futility at interim analysis led the trial to be stopped. The rate of the primary endpoint, a composite of death due to vascular causes; nonfatal myocardial infarction or nonfatal stroke; and Bleeding Academic Research Consortium type 3, 4, and 5 bleeding through day 30, did not differ significantly between the downstream and upstream groups (percent absolute risk reduction: -0.46; 95% repeated confidence interval: -2.90 to 1.90). These results were confirmed among patients undergoing percutaneous coronary intervention (72% of population) and regardless of the timing of coronary angiography (within or after 24 h from enrollment)., Conclusions: Downstream and upstream oral P2Y 12 inhibitor administration strategies were associated with low incidence of ischemic and bleeding events and minimal numeric difference of event rates between treatment groups. These findings led to premature interruption of the trial and suggest the unlikelihood of enhanced efficacy of 1 strategy over the other. (Downstream Versus Upstream Strategy for the Administration of P2Y 12 Receptor Blockers In Non-ST Elevated Acute Coronary Syndromes With Initial Invasive Indication [DUBIUS]; NCT02618837)., Competing Interests: Author Relationship With Industry This work was funded by the Italian Society of Interventional Cardiology (SICI-GISE). Dr. Tarantini has received Speakers Bureau fees from AstraZeneca, Daiichi-Sankyo, and Eli Lilly. Dr. Mojoli has received individual payments for participating on the Advisory Boards of The Medicines Company and Abbott Vascular; and has been a speaker at scientific congresses from AstraZeneca, Daiichi-Sankyo, Chiesi Farmaceutici, and Servier; and his institution has received an unconditioned research grant from Chiesi Farmaceutici. Dr. Varbella has received consulting fees/honoraria from AstraZeneca, Daiichi-Sankyo, Bayer, Pfizer, Boehringer Ingelheim, Servier, Amgen, Sanofi, Piam, Alvi Medica, Teleflex, and Stenty. Dr. Caporale has received an Advisory Board fee from AstraZeneca. Dr. Rigattieri has received a consulting fee from AstraZeneca; and has received a Speakers Bureau fee from Eli Lilly. Dr. Andò has received individual payments as a consultant, for serving on the Advisory Board, or as a speaker at scientific congresses from AstraZeneca, Daiichi-Sankyo, Chiesi Farmaceutici, Pfizer–Bristol Myers Squibb, Boehringer Ingelheim, and Biosensors. Dr. Saia has received Speakers Bureau fees from AstraZeneca and Daiichi-Sankyo. Dr. Ferlini has received individual payment as a consultant, for serving on the Advisory Board, or as a speaker at scientific congresses from AstraZeneca, Chiesi Farmaceutici, Bayer, Biosensors, Sanofi, and Boehringer Ingelheim. Dr. Angiolillo has received consulting fees or honoraria as an individual from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; has received payment as an individual for participation in review activities from CeloNova and St. Jude Medical; and has received institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. All rights reserved.)

Granulosa cell tumors (GCT) are rare ovarian malignancies. Due to the lack of effective treatment in late relapse, there is a clear unmet need for novel therapies. Forkhead Box L2 (FOXL2) is a protein mainly expressed in granulosa cells (GC) and therefore is a rational therapeutic target. Since we identified tumor infiltrating lymphocytes (TILs) as the main immune population within GCT, TILs from 11 GCT patients were expanded, and their phenotypes were interrogated to determine that T cells acquired late antigen-experienced phenotypes and lower levels of PD1 expression. Importantly, TILs maintained their functionality after ex vivo expansion as they vigorously reacted against autologous tumors (100% of patients) and against FOXL2 peptides (57.1% of patients). To validate the relevance of FOXL2 as a target for immune therapy, we developed a plasmid DNA vaccine (FoxL2-tetanus toxin; FoxL2-TT) by fusing Foxl2 cDNA with the immune-enhancing domain of TT. Mice immunization with FoxL2-TT controlled growth of FOXL2-expressing ovarian (BR5) and breast (4T1) cancers in a T cell-mediated manner. Combination of anti-PD-L1 with FoxL2-TT vaccination further reduced tumor progression and improved mouse survival without affecting the female reproductive system and pregnancy. Together, our results suggest that FOXL2 immune targeting can produce substantial long-term clinical benefits. Our study can serve as a foundation for trials testing immunotherapeutic approaches in patients with ovarian GCT.

On March 11, 2020, just after 2 months from the first cases of coronavirus disease 2019 (COVID-19) in China, the Director-General of the World Health Organization stated that COVID-19 has to be considered as a pandemic. Italian doctors were the first protagonists, after the Chinese ones, in the management of this disease. Clinical observations showed that, in addition to the respiratory infection, a systemic inflammatory response occurs, which leads to coagulation disorders and consequent venous thromboembolism as well as other thrombotic complications. We here review the available literature on this issue to better understand the pathophysiological mechanisms of coagulopathy useful to draw future clinical and therapeutic conclusions.

Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.

The introduction of combination of antiretroviral therapy and advancement in care of HIV have dramatically changed the natural history of patients living with HIV. Today, HIV+ patients have a life expectancy not significantly different from HIV uninfected people. However, concerns remain about all the comorbidities associated with aging and the effects of chronic therapies in such high-risk patients. HIV+ subjects exhibited accelerated atherosclerosis and have a 1.5- to 2-fold increased risk of having coronary artery disease (CAD), usually presenting early and aggressively with acute coronary events. Furthermore, HIV+ patients with CAD often complain recurrent acute coronary events, and they are plagued by major adverse cardiac outcomes. This review will focus on the current understanding of the CAD phenotype in HIV+ patients highlighting the topic of acute coronary event recurrence and underscoring the role of percutaneous management strategies in the light of information derived from invasive coronary imaging., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Adoptive T cell therapy (ACT) is a promising new modality for malignancies. Here, we report that adoptive T cell efficacy in tumor-bearing mice is significantly affected by differences in the native composition of the gut microbiome or treatment with antibiotics, or by heterologous fecal transfer. Depletion of bacteria with vancomycin decreased the rate of tumor growth in mice from The Jackson Laboratory receiving ACT, whereas treatment with neomycin and metronidazole had no effect, indicating the role of specific bacteria in host response. Vancomycin treatment induced an increase in systemic CD8α+ DCs, which sustained systemic adoptively transferred antitumor T cells in an IL-12-dependent manner. In subjects undergoing allogeneic hematopoietic cell transplantation, we found that oral vancomycin also increased IL-12 levels. Collectively, our findings demonstrate an important role played by the gut microbiota in the antitumor effectiveness of ACT and suggest potentially new avenues to improve response to ACT by altering the gut microbiota.

DNA-based vaccination is a promising approach to cancer immunotherapy. DNA-based vaccines specific for tumor-associated antigens (TAAs) are indeed relatively simple to produce, cost-efficient and well tolerated. However, the clinical efficacy of DNA-based vaccines for cancer therapy is considerably limited by central and peripheral tolerance. During the past decade, considerable efforts have been devoted to the development and characterization of novel DNA-based vaccines that would circumvent this obstacle. In this setting, particular attention has been dedicated to the route of administration, expression of modified TAAs, co-expression of immunostimulatory molecules, and co-delivery of immune checkpoint blockers. Here, we review preclinical and clinical progress on DNA-based vaccines for cancer therapy.

Cancer immunotherapy relies upon the ability of T cells to infiltrate tumors. The endothelium constitutes a barrier between the tumor and effector T cells, and the ability to manipulate local vascular permeability could be translated into effective immunotherapy. Here, we show that in the context of adoptive T cell therapy, antitumor T cells, delivered at high enough doses, can overcome the endothelial barrier and infiltrate tumors, a process that requires local production of C3, complement activation on tumor endothelium and release of C5a. C5a, in turn, acts on endothelial cells promoting the upregulation of adhesion molecules and T-cell homing. Genetic deletion of C3 or the C5a receptor 1 (C5aR1), and pharmacological blockade of C5aR1, impaired the ability of T cells to overcome the endothelial barrier, infiltrate tumors, and control tumor progression in vivo , while genetic chimera mice demonstrated that C3 and C5aR1 expression by tumor stroma, and not leukocytes, governs T cell homing, acting on the local endothelium. In vitro , endothelial C3 and C5a expressions were required for endothelial activation by type 1 cytokines. Our data indicate that effective immunotherapy is a consequence of successful homing of T cells in response to local complement activation, which disrupts the tumor endothelial barrier.

The increasing rate of cardiovascular diseases, the improved survival after the acute phase, the aging of the population and the implementation of primary prevention caused an exponential increase in outpatient cardiac performance, thereby making it difficult to maintain a balance between the citizen-patient request and the economic sustainability of the healthcare system. On the other side, the prescription of many diagnostic tests with a view to defensive medicine and the related growth of patients' expectations, has led several scientific societies to educational campaigns highlighting the concept that "less is more".The present document is aimed at providing the general practitioner with practical information about a prompt diagnosis of signs/symptoms (angina, dyspnea, palpitations, syncope) of the major cardiovascular diseases. It will also provide an overview about appropriate use of diagnostic exams (echocardiogram, stress test), about the appropriate timing of their execution, in order to ensure effectiveness, efficiency, and equity of the health system.

Mitochondria provide energy for cells via oxidative phosphorylation. Reactive oxygen species, a byproduct of this mitochondrial respiration, can damage mitochondrial DNA (mtDNA), and somatic mtDNA mutations have been found in all colorectal, ovarian, breast, urinary bladder, kidney, lung, and pancreatic tumors studied. The resulting altered mitochondrial proteins or tumor-associated mitochondrial Ags (TAMAs) are potentially immunogenic, suggesting that they may be targetable Ags for cancer immunotherapy. In this article, we show that the RENCA tumor cell line harbors TAMAs that can drive an antitumor immune response. We generated a cellular tumor vaccine by pulsing dendritic cells with enriched mitochondrial proteins from RENCA cells. Our dendritic cell-based RENCA mitochondrial lysate vaccine elicited a cytotoxic T cell response in vivo and conferred durable protection against challenge with RENCA cells when used in a prophylactic or therapeutic setting. By sequencing mtDNA from RENCA cells, we identified two mutated molecules: COX1 and ND5. Peptide vaccines generated from mitochondrial-encoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Background: Laryngeal squamous cell carcinoma (laryngeal SCC) is a frequently occurring cancer of the head and neck area. Epigenetic changes of tumor-related genes contribute to its genesis and progression., Methods: We assessed promoter methylation status of the selected genes (CDKN2A, MGMT, MLH1, and DAPK) using methylation-sensitive high resolution melting (MS-HRM) in 100 patients with laryngeal SCC and studied the correlations with clinical characteristics., Results: The prevalence of promoter methylation in MGMT, CDKN2A, MLH1, and DAPK was 59 of 97 (60.8%), 46 of 97 (47.4%), 45 of 97 (46.4%), and 41 of 97 patients (42.3%), respectively. Significantly increased methylation of CDKN2A was observed in heavy smokers. Epigenetic inactivation of CDKN2A and MLH1 were found to be associated with lymph node involvement. An inverse correlation was present between MLH1 methylation and alcohol consumption., Conclusion: Our results strongly suggest that deregulation of p16-associated, and MLH1-associated pathways, because of promoter hypermethylation, is associated with increased cancer cell migration, tumor invasiveness, and, thus, aggressive phenotype., (Copyright © 2013 Wiley Periodicals, Inc.)

A crucial question recently raised in climate dynamics concerns abrupt climate transitions: Are they due to a tipping point (TP) being exceeded, or is fast noisy dynamics the cause of their excitation? In this respect, a case study based on a low-order ocean model is developed to show that in an excitable dynamical system perturbed by noise (a possible climate condition) the TPs may have limited physical meaning, with the coherence resonance mechanism being predominant. The analysis is based on an operational definition of stochastic TP, which accounts for the effect of noise and reconciles formally the TP and coherence resonance views.

Background: Intravenous periodic Iloprost is proven effective in the treatment of Raynaud phenomenon (RP) related to connective tissue disorder (CTD). It's well known that synthetic prostaglandins are effective drugs for the treatment of pulmonary arterial hypertension (PAH), and that PAH is frequently associated with CTD., Objective: The aim of the study is to evaluate in the chronic effect of cyclic intravenous Iloprost on pulmonary arterial pressure., Methods: We studied 17 consecutive patients with CTD (14 systemic sclerosis, 3 mixed CTD) and RP, at the entry and after at least 6months of treatment of RP with cyclic Iloprost. On both occasions, in all patients we performed transthoracic Doppler echocardiography and we determined NT-proBNP plasma levels, NYHA functional class, 6 Minute-Walk Distance (6MWD)., Results: At follow-up (8.2±1.9months; range 6-12) mean values of pulmonary arterial systolic pressure (PASP) significantly decreased (from 32.2±9.2 to 29.2±7.6mmHg, p<0.04) and mean values of 6MWD significantly increased (from 407.5±101.5 to 448.3±89.9m, p<0.01). Moreover, we observed a significant direct correlation between PASP and NT-proBNP values and a significant inverse correlation both between NT-proBNP and 6MWD values and between PASP and 6MWD values., Conclusion: Our results suggest that cyclic intravenous Iloprost may protect against the development or worsening of PAH in patients with CTD and RP., (Copyright © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Interferon (IFN) therapy is nowadays widely used in clinical practice. In the literature, there are very few reports of the association between IFN therapy and pulmonary arterial hypertension (PAH), and current guidelines do not mention IFNs as a risk factor for PAH. We describe a patient with multiple sclerosis who developed severe PAH after treatment with IFN-β-1a and the clinical response to sildenafil. Furthermore, we stress the need to further investigate the link between IFNs and PAH., (Copyright © 2012 S. Karger AG, Basel.)

Pulmonary arterial hypertension (PAH) is a devastating disease with significant disability and mortality, and it has much higher prevalence than previously thought. During the past 15 years, we have witnessed remarkable advances in our understanding of pathogenesis, in diagnostic process and in the development of disease-specific treatments for PAH. Nowadays, the diagnosis is more clearly defined, non-invasive markers of disease severity can be widely applied, and finally we can adopt evidence-based treatment. Newer drugs availability has resulted in radical change in the management of this disease. The article reviews established approaches to evaluation and treatment of this disorder.

Among forest-dwelling Amazonian Indians and rubber tappers (seringueiros) of the Juruá valley in Acre State, north-western Brazil, snakebite is an important cause of morbidity and death. Overall, 13% of a surveyed population had been bitten during their lifetime. Seventeen per cent of Katukina Indians, but only 8% of Ashaninkas, had been bitten by snakes reflecting, perhaps, different levels of traditional knowledge of the forest and its dangers. Most bites occurred in the jungle or on jungle trails (56%), while people were working (41%) or walking (26%), and were inflicted on the feet (54%). Ninety per cent of bite victims received treatment, usually traditional (93%); the majority (80%) recovered fully. Mortality was estimated at about 400 deaths per 100,000 population per lifetime. Bites and stings from other venomous forest and river animals, especially the freshwater sting ray (Potamotrygon sp.), were also extremely common. One death from an ant bite was recorded.

We studied heart rate variability in 49 uncomplicated diabetics (27 with insulin therapy; 22 with oral hypoglycemic agents) and in 40 age-matched controls. An automatic autoregressive algorithm was used to compute the power spectral density (PSD) of beat by beat RR variability derived from the surface ECG. The PSD contains two major components (a low frequency approximately 0.1 Hz (LF) and a high frequency, respiratory linked, approximately 0.25 Hz (HF] that provide, respectively, quantitative markers of sympathetic and vagal modulatory activities and of their balance. As compared to controls, in diabetics, besides a reduced RR variance at rest (2722 +/- 300 and 1436 +/- 241 ms2, respectively), we observed during passive tilt an altered response of spectral indices of sympathetic activation and vagal withdrawal, suggestive of a complex modification in the neural control activities. In addition, we compared this approach to the commonly used clinical tests score, and observed that the latter provides overall results similar to those obtained with spectral changes induced by tilt (r = 0.42; P less than 0.01). Of potential clinical importance is that the data obtained with spectral analysis appear more thoroughly quantifiable and do not require the active collaboration of the patients.