Dangerous Liaisons Research Articles

Ticagrelor and Statins: Dangerous Liaisons?

Polypharmacy is often necessary in complex, chronic, comorbid and cardiovascular patients and is a known risk factor for potential drug-drug interaction (DDI) that can cause adverse reactions (toxicity or therapeutic failure). Anti-thrombotic drugs (largely low-dose aspirin and a platelet P2Y12 receptor inhibitor) and statins are among the most co-administered drugs in cardiovascular patients. Ticagrelor is a selective antagonist of the platelet P2Y12-receptor, highly effective in inhibiting platelet aggregation and bio-transformed by the CYP3A4 and substrate of transporters, such as the breast cancer resistance protein (BCRP). Statins have different pharmacokinetic profiles; some undergo CYP3A4-mediated metabolism; rosuvastatin is primarily metabolized by the CYP2C9; and they have different affinities for drug transporters. Rhabdomyolysis is a very rare but severe adverse event, which is specific for statins which can be triggered by DDIs that increase statin's concentrations through blockade of their biotransformation and/or elimination. Large pharmacovigilance and small observational studies reported increased rhabdomyolysis in patients treated with some statins and ticagrelor but not aspirin, clopidogrel or prasugrel. Recent studies in vitro, pharmacokinetic trials and in silico drug modelling identified and validated the BCRP inhibition by ticagrelor, as a mechanism contributing to the DDI with statins, as 'victim' drugs, leading to increased rhabdomyolysis. While the clinical impact of this DDI deserves further investigation, a careful evaluation should be advised when ticagrelor is co-prescribed with some statins.

Cancer and Heart Failure: Dangerous Liaisons.

Cancer and heart failure (HF) are increasingly relevant worldwide, both from an epidemiologic and clinical point of view. This review aims to explore the relationship between cancer and HF by underscoring risk factors and disclosing the cardiotoxic effects of the current chemotherapy agents. We also deal with the current evidence on the diagnosis and management of HF related to cancer therapy. Finally, we will address the main gaps in knowledge and future perspectives in this field.

Dangerous liaisons across levels of government in an emergency

Dangerous liaisons across levels of government in an emergency

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches.

Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic strategies have been developed to block this system in tumor cells, but the results of clinical trials have been disappointing. After decades of research in the field, it is safe to say that one of the major reasons underlying the poor efficacy of anti-IGF-targeting agents is derived from an underestimation of the molecular complexity of this axis. Genetic, transcriptional, post-transcriptional and functional interactors interfere with the activity of canonical components of this axis, supporting the need for combinatorial approaches to effectively block this system. In addition, cancer cells interface with a multiplicity of factors from the extracellular compartment, which strongly affect cell destiny. In this review, we will cover novel extracellular mechanisms contributing to IGF system dysregulation and the implications of such dangerous liaisons for cancer hallmarks and responses to known and new anti-IGF drugs. A deeper understanding of both the intracellular and extracellular microenvironments might provide new impetus to better decipher the complexity of the IGF axis in cancer and provide new clues for designing novel therapeutic approaches.

Cardiogenic shock and chronic kidney disease: Dangerous liaisons

BackgroundChronic kidney disease (CKD) is one of the leading causes of death worldwide, closely interrelated with cardiovascular diseases, ultimately leading to the failure of both organs – the so-called “cardiorenal syndrome”. Despite this burden, data related to cardiogenic shock outcomes in CKD patients are scarce. MethodsFRENSHOCK (NCT02703038) was a prospective registry involving 772 patients with cardiogenic shock from 49 centres. One-year outcomes (rehospitalization, death, heart transplantation, ventricular assist device) were analysed according to history of CKD at admission and were adjusted on independent predictive factors. ResultsCKD was present in 164 of 771 patients (21.3%) with cardiogenic shock; these patients were older (72.7 vs. 63.9years) and had more comorbidities than those without CKD. CKD was associated with a higher rate of all-cause mortality at 1month (36.6% vs. 23.2%; hazard ratio 1.39, 95% confidence interval 1.01–1.9; P=0.04) and 1year (62.8% vs. 40.5%, hazard ratio 1.39, 95% confidence interval 1.09–1.77; P<0.01). Patients with CKD were less likely to be treated with norepinephrine/epinephrine or undergo invasive ventilation or receive mechanical circulatory support, but were more likely to receive renal replacement therapy (RRT). RRT was associated with a higher risk of all-cause death at 1month and 1year regardless of baseline CKD status. ConclusionsCardiogenic shock and CKD are frequent “cross-talking” conditions with limited therapeutic options, resulting in higher rates of death at 1month and 1year. RRT is a strong predictor of death, regardless of preexisting CKD. Multidisciplinary teams involving cardiac and kidney physicians are required to provide integrated care for patients with failure of both organs.

Cardiogenic shock and chronic kidney disease: Dangerous liaisons

Cardiogenic shock and chronic kidney disease: Dangerous liaisons

Routing Innate and Adaptive Immune response against M. tuberculosis and boosting Mycobacterium bovis Bacillus Calmette Güerin (BCG) vaccine immunity through prime boost protocols

Tuberculosis (Tb) is still a global health problem, especially in developing countries. Several factors contribute to this, among them the increasing multidrug resistance strains, the dangerous liaisons with other intracellular pathogens, such as HIV, and more recently, SARS-CoV2 pandemics. There are many aspects that remain to understand the bacterial molecular mechanism of pathogenicity and the immune response induced by the interaction of M. tuberculosis (MTb) with the host. The official and current vaccine based on the attenuated Mycobacterium bovis Bacillus Calmette Guerin (BCG) is protective against several forms of Tb meningitis and Miliary TB or disseminated disease in young children. However, it fails to protect young and adult individuals. There are several new promising candidates for vaccines to replace or boost BCG-induced immunity. Several evidences exist from humans and mice on the role of the trained innate memory of monocytes and NK cells, on the second encounter with the same mycobacterial pathogen or other respiratory pathogens. This type of immune response is nonspecific and independent of the T and B cells. Thus, BCG vaccination is a double immunogen that activate specific immune responses and is also able to stimulate nonspecific immune responses. Here, it is outlined the host immunity against MTb, the potential of BCG vaccination and prime boost protocols for routing innate and adaptive immune responses in TB.

Commentary: Risk of Osteoporotic Fracture and Re-Fracture: Dangerous Liaisons

Commentary: Risk of Osteoporotic Fracture and Re-Fracture: Dangerous Liaisons

Dangerous liaisons, or strategies for family management in eighteenth-century Venice

ABSTRACTIn 1745, a lengthy and unusual case was brought before the Venetian Executors against Blasphemy, a secular court with jurisdiction over a wide range of crimes that violated standards of morality. The parents of two young women from the Venetian mainland state were accused of pimping their two eldest daughters to Jewish men from the Venetian Ghetto in return for financial support, helping them to support their ten children. But the story became much more complicated as the court investigated the young women’s relationships; one of the daughters did seem to have a relationship with a married Jew who had promised to convert and marry her, while the other was actually a nobleman’s courtesan, supported by the same patrician who served as a guardian to a young Giacomo Casanova. Although to the patricians who served as judges, any exploitation of a young woman’s sexuality was deemed criminal, ordinary eighteenth-century Venetians saw things differently. Large families were difficult to support, and all members contributed as they were able. Typically we think of apprenticeships, domestic service, and piecework as the key strategies for supporting a family and training children for their future lives. For women, historians have long acknowledged that service carried risks of sexual exploitation, as well. But what has not been recognised as a strategy is the encouragement of premarital relations or of sex work as alternatives to domestic service and piecework. Through a microhistorical approach, this article argues that the case of the Zambelli family shows us a wider range of morally ambiguous options for supporting a large family and setting up daughters to leave the family home, many of which included threats of sexual exploitation, damaged honour, and unwanted pregnancies.

Stroke vs. Preeclampsia: Dangerous Liaisons of Hypertension and Pregnancy.

Stroke during pregnancy and preeclampsia are two distinct but interrelated medical conditions, sharing a common denominator-blood control failure. Along with cardiovascular diseases, diabetes, dyslipidemia, and hypercoagulability, hypertension is undoubtedly a major risk factor associated with stroke. Even though men have higher age-specific stroke rates, women are facing higher life-long stroke risk, primarily due to longer life expectancy. Sex hormones, especially estrogen and testosterone, seem to play a key link in the chain of blood pressure control differences between the genders. Women affected with stroke are more susceptible to experience some atypical stroke manifestations, which might eventually lead to delayed diagnosis establishment, and result in higher morbidity and mortality rates in the population of women. Preeclampsia is a part of hypertensive disorder of pregnancy spectrum, and it is common knowledge that women with a positive history of preeclampsia are at increased stroke risk during their lifetime. Preeclampsia and stroke display similar pathophysiological patterns, including hypertension, endothelial dysfunction, dyslipidemia, hypercoagulability, and cerebral vasomotor reactivity abnormalities. High-risk pregnancies carrying the burden of hypertensive disorder of pregnancy have up to a six-fold higher chance of suffering from stroke. Resemblance shared between placental and cerebral vascular changes, adaptations, and sophisticated auto-regulatory mechanisms are not merely coincidental, but they reflect distinctive and complex cardiovascular performances occurring in the maternal circulatory system during pregnancy. Placental and cerebral malperfusion appears to be in the midline of both of these conditions; placental malperfusion eventually leads to preeclampsia, and cerebral to stoke. Suboptimal performances of the cardiovascular system are proposed as a primary cause of uteroplacental malperfusion. Placental dysfunction is therefore designated as a secondary condition, initiated by the primary disturbances of the cardiovascular system, rather than an immunological disorder associated with abnormal trophoblast invasion. In most cases, with properly and timely applied measures of prevention, stroke is predictable, and preeclampsia is a controllable condition. Understanding the differences between preeclampsia and stroke in pregnancy is vital for healthcare providers to enhance their clinical decision-making strategies, improve patient care, and promote positive maternal and pregnancy outcomes. Management approaches for preeclampsia and stroke require a multidisciplinary approach involving obstetricians, neurologists, and other healthcare professionals.

Long Noncoding RNAs and Cancer Stem Cells: Dangerous Liaisons Managing Cancer.

Decades of research have investigated the mechanisms that lead to the origin of cancer, striving to identify tumor-initiating cells. These cells, also known as cancer stem cells, are characterized by the ability to self-renew, to give rise to differentiated tumor populations, and on a larger scale, are deemed responsible not only for tumor initiation but also for recurrent tumors, often resistant to chemotherapy and radiotherapy. Long noncoding RNAs are RNA molecules longer than 200 nt, lacking the ability to code for proteins, with recognized roles as fine regulators of gene expression. They can exert these functions through a variety of mechanisms, acting at almost all steps of gene expression, from modulation of the epigenetic state of chromatin to modulation of protein stability. In all cases, lncRNAs do not work alone, but they always interact with other RNA molecules, either coding or non-coding, or with protein factors. In this review, we summarize the latest results obtained about the involvement of lncRNAs in the initiating cells of several types of tumors, and highlight the different mechanisms through which they work, while discussing how the modulation of a lncRNA can affect several aspects of tumor onset and progression.

Dangerous Liaisons: Illegal Doping and Corruption

Dangerous Liaisons: Illegal Doping and Corruption

Dangerous Liaisons: Cryptocurrency and Financial Intermediation

Dangerous Liaisons: Cryptocurrency and Financial Intermediation

“Dangerous Liaisons”: Whiteness and Private Relations between German Colonial Officials and Indigenous Women in German Togo and Their Political Consequences

The article addresses the topic of intimate relationships between colonial officials and indigenous women in German Togo (1884–1914), which occurred in the ideological context stimulated by Cultural Darwinism, and the issue of socio-political consequences of such relations, both in the colony and in the homeland. In its analytical part, I draw on the conceptual distinction between “whiteness” and “blackness” – understood as biological phenotypes – as well as between “whiteness” and “Whiteness” – the latter term denoting a sociocultural system in which people of white complexion are more likely to experience privilege and preferential treatment in comparison with their darkskinned counterparts. The fact that “Whiteness” has been historically “porous” and Western imageries about Africans “flexible” – ranging from brutal racism to romanticization – presented numerous possibilities for certain individuals to “become white” by “acting White”, including the sphere of intimate relationships. In the context of the dominant Darwinian discourse – namely, the perceived threat of racial “degeneration” – the mixed marriages and their offspring became politicized in Germany, and a series of – largely ineffective – legal measures were taken to impose a stricter metropolitan control over the conduct of German colonial officials.

Dangerous liaisons of three key secondary stored-product pests in cracked maize

The current study examines the relationships of Oryzaephilus surinamensis (L.) (Coleoptera: Silvanidae) with Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae) and Tenebrio molitor L. (Coleoptera: Tenebrionidae) through Gaussian and Poisson regression models on cracked maize. For this purpose, variable temperatures (25 °C, 30 °C, and 35 °C), relative humidities (RH) (55% and 75%), exposure intervals (65 days, 130 days, and 195 days), and insect combinations (the insect species alone and the combinations per 2 or 3 species that included O. surinamensis) were utilized. Poisson model was the most suitable for the response insects alive while Gaussian model for the weight loss. The increase of temperature from 25 °C to 30 °C and from 30 °C to 35 °C led to a gradual decrease of insects alive and a gradual increase of weight loss, while the enhancement of RH caused increase of both responses. At the 195 days of storage period, insects alive reduced whereas weight loss amplified. The combinations of insects that led to the highest and the lowest numbers of insects alive were O. surinamensis alone and T. molitor alone respectively. The most damaging combination was O. surinamensis-T. molitor while the least damaging was T. molitor alone. Findings of the current study enrich the existing knowledge of the relationships of three secondary stored-product insects in processed maize. The complexity of their coexistence is linked with the forecast of the contingent damage of the insect activity during the storage period.

Psychological inflexibility and valuing happiness: Dangerous liaisons.

Previous evidence has shown that excessive valuing happiness may relate to lower psychological wellbeing across cultures. Considering the lack of data with Spanish population, we examined the relation between tightly holding happiness emotion goals and subjective wellbeing in a sample of Spanish women, and explored the mediation role exerted by psychological inflexibility components (namely, cognitive fusion and experiential avoidance) in the relation between valuing happiness and subjective wellbeing. A female adult sample (n = 168) filled out measures of excessive valuing happiness, psychological inflexibility, positive affect, negative affect, and life satisfaction. Valuing happiness only showed positive total effects on negative affect and strong direct effects on both cognitive fusion and experiential avoidance. Analyses revealed the mediating roles exerted by psychological inflexibility components, with experiential avoidance leading to lower pleasure; and cognitive fusion leading to greater displeasure and lower life satisfaction. Psychological inflexibility components explained between 40 and 80% of the total effect of valuing happiness on our outcome variables. Our findings highlight the need for further research on the benefits of hedonic vs. values-based approaches to happiness.

The Dangerous Liaisons in the Oxidative Stress Response to Leishmania Infection.

Leishmania parasites preferentially invade macrophages, the professional phagocytic cells, at the site of infection. Macrophages play conflicting roles in Leishmania infection either by the destruction of internalized parasites or by providing a safe shelter for parasite replication. In response to invading pathogens, however, macrophages induce an oxidative burst as a mechanism of defense to promote pathogen removal and contribute to signaling pathways involving inflammation and the immune response. Thus, oxidative stress plays a dual role in infection whereby free radicals protect against invading pathogens but can also cause inflammation resulting in tissue damage. The induced oxidative stress in parasitic infections triggers the activation in the host of the antioxidant response to counteract the damaging oxidative burst. Consequently, macrophages are crucial for disease progression or control. The ultimate outcome depends on dangerous liaisons between the infecting Leishmania spp. and the type and strength of the host immune response.

"Dangerous liaisons: NAFLD and liver fibrosis increase cardiovascular risk in HIV".

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with cardiovascular disease in the general population. We aimed to assess the impact of NAFLD and liver fibrosis on intermediate-high cardiovascular risk in people living with HIV. We included people living with HIV from three cohorts. NAFLD and significant liver fibrosis were defined using transient elastography: controlled attenuation parameter ≥288 dB/m and liver stiffness measurement ≥7.1 kPa, respectively. Cardiovascular risk was assessed with the atherosclerotic cardiovascular disease (ASCVD) risk estimator in patients aged between 40 and 75years and categorised as low if <5%, borderline if 5%-7.4%, intermediate if 7.5%-19.9% and high if ≥20% or with the presence of a previous cardiovascular event. Patients with hepatitis B and/or hepatitis C virus co-infection, alcohol abuse and unreliable transient elastography measurements were excluded. Predictors of intermediate-high cardiovascular risk were investigated in multivariable analysis by logistic regression and also by stratifying according to body mass index (BMI; cut-offs of 25 and 30kg/m2 ) and age (cut-off of 60years). Of 941 patients with HIV alone included, 423 (45%), 128 (13.6%), 260 (27.6%) and 130 (13.8%) were categorised as at low, borderline, intermediate and high ASCVD risk, respectively. Predictors of intermediate-high ASCVD risk were NAFLD (adjusted odds ratio [aOR] 2.11; 95% confidence interval [CI] 1.40-3.18; p<0.001), liver fibrosis (aOR 1.64; 95% CI 1.03-2.59; p=0.034), duration of HIV (aOR 1.04; 95% CI 1.02-1.06; p<0.001), and previous exposure to thymidine analogues and/or didanosine (aOR 1.54; 95% CI 1.09-2.18; p=0.014). NAFLD was also associated with higher cardiovascular risk in normoweight patients (aOR 2.97; 95% CI 1.43-6.16; p=0.003), in those with BMI <30kg/m2 (aOR 2.30; 95% CI 1.46-3.61; p<0.001) and in those aged <60 years (aOR 2.19; 95% CI 1.36-3.54; p=0.001). Assessment of cardiovascular disease should be targeted in people living with HIV with NAFLD and/or significant liver fibrosis, even if they are normoweight and young.

Pavojingi ryšiai? Nesusituokusių vyrų ir moterų santykiai Lietuvos katalikiškuose bažnytiniuose teismuose XVIII a.

DANGEROUS LIAISONS? INFORMAL RELATIONS BETWEEN UNMARRIED PERSONS AND THEIR TREATMENT IN THE EIGHTEENTH CENTURY LITHUANIAN CATHOLIC ECCLESIASTICAL COURTS Recent decades saw historical scholarship to pay more attention to the phenomena which were earlier considered unimportant or, in some cases, non-existent. Intimate relations between men and women who were not yet married, extramarital affairs, cohabitation, etc. were rediscovered and reassessed as indispensable to the more accurate understanding of the formation of marriages, families and communities. Theoretically, physical and emotional intimacy could only take place in marriage, and as such all relationships that were extraneous to marital status were prosecuted by legal authorities – civil and ecclesiastical alike. This paper seeks to present how one group of these institutions – Lithuanian ecclesiastical courts – treated informal relations between unmarried laymen and women and what kind of penalties they imposed for such delinquencies. At the first glance it seems that neither canon law, nor the law of the Lithuanian Statutes or the Magdeburg law paid much attention to this kind of illicit sexual practices. The legal norms describe them rather vaguely and, as a result, the prescribed punishments seem to be unclear (except for the Third Lithuanian Statute, which, depending on the interpretation of the text, prescribed capital punishment for unmarried women). Analysis of the court material from three consistories (Vilnius, Samogitia and Trakai) has shown that Lithuanian Catholic consistories might not have been very concerned with such cases as there is only a handful of them mentioned and even less addressed. They seem to have been more common among the Catholic population of Samogitia, and men were likely to be condemned more often than women. The penalties for such crimes were mild – the delinquents mainly had to do public penance, pay fines, and observe fasting. The reasons behind such a low number of cases and even lower number of decisions are not clear, yet. It is possible, that while being mainly concerned with the marital litigation ecclesiastical courts left more initiative to the secular authorities, which could also act in the name of good Christian order and provide harsher punishments if necessary. Since most of the plaintiffs were parish clergymen, who generally initiated judicial processes against fornicators, it is plausible that they could take care of such delinquents themselves, without the help of the court. One must not forget that the Church had even more measures at its discretion – for example, missionary activities of the religious orders, during which the missionaries also attended to the illegal sexual practices of the population, and intervened with them. Keywords: the eighteenth century, the Grand Duchy of Lithuania, informal relations, fornication, ecclesiastical courts, consistories, canon law, the Lithuanian Statutes, the Saxon-Magdeburg law, gender relations.

Autophagy and ncRNAs: Dangerous Liaisons in the Crosstalk between the Tumor and Its Microenvironment.

Simple SummaryTumor cells communicate with the stromal cells within the tumor microenvironment (TME) to create a conducive environment for tumor growth. One major avenue for mediating crosstalk between various cell types in the TME involves exchanges of molecular payloads in the form of extracellular vesicles/exosomes. Autophagy is a fundamental mechanism to maintain intracellular homeostasis but recent reports suggest that secretory autophagy plays an important role in promoting secretion of exosomes that are packaged with non-coding RNAs (ncRNAs) and other biomolecules from the donor cell. Uptake of exosomal autophagy-modulating ncRNAs by recipient cells may further perpetuate tumor progression.Autophagy is a fundamental cellular homeostasis mechanism known to play multifaceted roles in the natural history of cancers over time. It has recently been shown that autophagy also mediates the crosstalk between the tumor and its microenvironment by promoting the export of molecular payloads such as non-coding RNA (ncRNAs) via LC3-dependent Extracellular Vesicle loading and secretion (LDELS). In turn, the dynamic exchange of exosomal ncRNAs regulate autophagic responses in the recipient cells within the tumor microenvironment (TME), for both tumor and stromal cells. Autophagy-dependent phenotypic changes in the recipient cells further enhance tumor growth and metastasis, through diverse biological processes, including nutrient supplementation, immune evasion, angiogenesis, and therapeutic resistance. In this review, we discuss how the feedforward autophagy-ncRNA axis orchestrates vital communications between various cell types within the TME ecosystem to promote cancer progression.