Role of immune and angiogenic markers in the pathology of endometriosis

Background: Endometriosis is an estrogen-dependent, pro-inflammatory, pro-angiogenic condition that affects 5 to 10% of women of reproductive age. Its defining feature is the presence of endometrium-like tissue in sites outside the uterine cavity, primarily on the pelvic peritoneum and ovaries. The main clinical features are chronic pain, pain during intercourse and infertility. In patients with endometriosis, inflammatory and immune responses, angiogenesis and apoptosis are altered in favour of the survival and replenishment of endometriotic tissue. These basic pathological processes depend on the excessive formation of estrogen and prostaglandins. Recently, new cellular and molecular mechanisms for the resolution of inflammation have been discovered, revealing key roles for lipid mediators such as lipoxins, resolvins and protectins. It is possible that disequilibrium in the expression of these molecules exists in endometriosis. Objective: To compare the expression of two proteins involved in the synthe sis and in the function of lipid mediators; the Arachidonate 15-lipoxygenase (ALOXI5), implicated in the synthesis of lipoxins A4 and B4 and the Formyl peptide receptor 1 (FPRLI), the specific receptor for Lipoxin A4 and B4, between women who suffer from endometriosis and a control group. We wish to demonstrate the cellular localisation of these two molecules and to investigate if their expression is alteted in this pathology. Methods and Materials Using immunohistochemistry we will compare ALOXI5 and FPRLI staining, in endometrium, normal peritoneum and endometriotic lesions. The samples are being collected in the department of Gynaecology and Obstetrics at the Centre Hospitalier Universitaire Lausanne (CHUV). Women attending the department for laparoscopic investigation of pain/infertility, suspected endometriosis or for a hysterectomy, are invited to participate. Approval of the ethics committee (Commission d'Ethique de la recherché clinique) was obtained in March 2009. Clinical samples will only be obtained from subjects having consented. Expected results and interpretation: No published studies investigating the expression of these two molecules in endometriotic lesions exist. A better understanding of the mechanisms underlying this disease will result in the development of new medical therapies and new diagnostic tests, with the aim of ameliorating the quality of life of endometriosis patients

Metastatic Breast Cancer as a Chronic Disease: Evidence-Based Data on a Theoretical Concept

Background: We challenge the concept of metastatic breast cancer (MBC) as a chronic disease. Methods: We analyzed an unselected cohort of 367 patients who were diagnosed with MBC over a 22-year period (1990–2011). Results: In order to create a “chronic disease subgroup”, we separated those patients from the entire cohort in whom systemic therapy was not applied after the diagnosis of MBC (n = 53; 14.4%). Three hundred fourteen patients (85.6%) comprised the “chronic disease subgroup”. The vast majority of those patients (89.8%) died of progressive disease after a median metastatic disease survival (MDS) of 25 months. Twenty patients (6.4%) died of non-MBC-related causes (MDS 38.5 months). Approximately 1 in 4 patients (26.8%) died within the first year after the MBC diagnosis. The 3- and 5-year MDS rates were 35.4 and 16.2%, respectively. Only 12 patients (3.8%) were exceptional survivors (MDS >10 years). Conclusion: The term “chronic disease” might be appropriate in selected MBC cases, bringing MBC into alignment with “classical” chronic diseases such as diabetes and hypertension. However, most cases display fundamental differences with regard to temporal progression and above all the case fatality rate. More than 90% of patients in the “chronic disease subgroup” died of the disease with a MDS of 2–3 years (even those who underwent systemic palliative therapies). Doctors and patients might understand the term “chronic disease” differently. The term must be used sparingly and explained carefully in order to create a common level of communication based on a shared understanding which avoids awakening false hopes and fostering misleading expectations

S-nitrosation and ubiquitin-proteasome system interplay in neuromuscular disorders.

Protein S-nitrosation is deemed as a prototype of posttranslational modifications governing cell signaling. It takes place on specific cysteine residues that covalently incorporate a nitric oxide (NO) moiety to form S-nitrosothiol derivatives and depends on the ratio between NO produced by NO synthases and nitrosothiol removal catalyzed by denitrosating enzymes. A large number of cysteine-containing proteins are found to undergo S-nitrosation and, among them, the enzymes catalyzing ubiquitination, mainly the class of ubiquitin E3 ligases and the 20S component of the proteasome, have been reported to be redox modulated in their activity. In this review we will outline the processes regulating S-nitrosation and try to debate whether and how it affects protein ubiquitination and degradation via the proteasome. In particular, since muscle and neuronal health largely depends on the balance between protein synthesis and breakdown, here we will discuss the impact of S-nitrosation in the efficiency of protein quality control system, providing lines of evidence and speculating about its involvement in the onset and maintenance of neuromuscular dysfunctions

A Non-Gaussian Approach to Risk Measures

Reliable calculations of financial risk require that the fat-tailed nature of prices changes is included in risk measures. To this end, a non-Gaussian approach to financial risk management is presented, modeling the power-law tails of the returns distribution in terms of a Student-t distribution. Non-Gaussian closed-form solutions for Value-at-Risk and Expected Shortfall are obtained and standard formulae known in the literature under the normality assumption are recovered as a special case. The implications of the approach for risk management are demonstrated through an empirical analysis of financial time series from the Italian stock market and in comparison with the results of the most widely used procedures of quantitative finance. Particular attention is paid to quantify the size of the errors affecting the market risk measures obtained according to different methodologies, by employing a bootstrap technique.Comment: Latex 15 pages, 3 figures and 5 tables 68% c. levels for tail exponents corrected, conclusions unchange

The impact of the COVID-19 pandemic on surgical management of breast cancer:global trends and future perspectives

Introduction: The rapid spread of COVID-19 across the globe is forcing surgical oncologists to change their daily practice. We sought to evaluate how breast surgeons are adapting their surgical activity to limit viral spread and spare hospital resources. Methods: A panel of 12 breast surgeons from the most affected regions of the world convened a virtual meeting on April 7, 2020, to discuss the changes in their local surgical practice during the COVID-19 pandemic. Similarly, a Web-based poll based was created to evaluate changes in surgical practice among breast surgeons from several countries. Results: The virtual meeting showed that distinct countries and regions were experiencing different phases of the pandemic. Surgical priority was given to patients with aggressive disease not candidate for primary systemic therapy, those with progressive disease under neoadjuvant systemic therapy, and patients who have finished neoadjuvant therapy. One hundred breast surgeons filled out the poll. The trend showed reductions in operating room schedules, indications for surgery, and consultations, with an increasingly restrictive approach to elective surgery with worsening of the pandemic. Conclusion: The COVID-19 emergency should not compromise treatment of a potentially lethal disease such as breast cancer. Our results reveal that physicians are instinctively reluctant to abandon conventional standards of care when possible. However, as the situation deteriorates, alternative strategies of de-escalation are being adopted. Implications for Practice: This study aimed to characterize how the COVID-19 pandemic is affecting breast cancer surgery and which strategies are being adopted to cope with the situation. © 2020 AlphaMed Pres

Opioids and immune checkpoint inhibitors differentially regulate a common immune network in triple-negative breast cancer

BackgroundOpioids are the primary analgesics for cancer pain. Recent clinical evidence suggests opioids may counteract the effect of immune checkpoint inhibition (ICI) immunotherapy, but the mechanism for this interaction is unknown. The following experiments study how opioids and immunotherapy modulate a common RNA expression pathway in triple negative breast cancer (TNBC), a cancer subtype in which immunotherapy is increasingly used. This study identifies a mechanism by which opioids may decrease ICI efficacy, and compares ketamine, a non-opioid analgesic with emerging use in cancer pain, for potential ICI interaction.MethodsTumor RNA expression and clinicopathologic data from a large cohort with TNBC (N=286) was used to identify RNA expression signatures of disease. Various drug-induced RNA expression profiles were extracted from multimodal RNA expression datasets and analyzed to estimate the RNA expression effects of ICI, opioids, and ketamine on TNBC.ResultsWe identified a RNA expression network in CD8+ T-cells that was relevant to TNBC pathogenesis and prognosis. Both opioids and anti-PD-L1 ICI regulated RNA expression in this network, suggesting a nexus for opioid-ICI interaction. Morphine and anti-PD-L1 therapy regulated RNA expression in opposing directions. By contrast, there was little overlap between the effect of ketamine and anti-PD-L1 therapy on RNA expression.ConclusionsOpioids and ICI may target a common immune network in TNBC and regulate gene expression in opposing fashion. No available evidence supports a similar interaction between ketamine and ICI

Pro-Environmental Behaviors: Determinants and Obstacles among Italian University Students

The awareness of citizens concerning the health risks caused by environmental pollution is growing, but studies on determinants of pro-environmental behaviors have rarely examined health-related aspects. In this study, we investigated these determinants using data from a large survey among Italian university students (15 Universities: 4778 filled questionnaires). Besides the health-related aspects, represented by environmental health risk perception and functional health literacy, we considered social and demographic characteristics (gender, area of residence, sources of information, trust in institutional and non-institutional subjects, and students' capacity of positive actions, indicated as internal locus of control). The attitudes towards pro-environmental behaviors were positive for more than 70% of students and positively related with health risk perception, internal locus of control, and health literacy. The correspondence between the positive attitudes towards pro-environmental behaviors and the real adoption of such behaviors was approximately 20% for most behaviors, except for the separate collection of waste (60%). Such a discrepancy can be attributable to external obstacles (i.e., lack of time, costs, lack of support). The health-related aspects were linked to the pro-environmental attitudes, but to a lesser extent to pro-environmental behaviors, owing to the complexity of their determinants. However, they should be taken in account in planning education interventions

Consumption of energy drinks among Italian University students : a cross-sectional multicenter study

Purpose The aim of the study was to evaluate the caffeinated Energy Drinks (EDs) consumption among a large sample of Italian undergraduates and its association with some of the major lifestyle risk factors. Methods Students attending twelve public Italian universities were involved between October 2021 and May 2022. Information on socio-demographic characteristics, ED consumption, and on health-related behaviors of participants was collected by the use of a web-based questionnaire. Results A total of 2165 students participated in the study and 15.2% of them reported having used caffeinated EDs in the last six months, mainly once a month (41.5%). In comparison with non-users, ED users showed a higher proportion of males (p < 0.001) and a higher father’s educational level (p = 0.003), came mainly from Northern universities (p = 0.004) and life sciences degree courses (p < 0.001). Besides, ED users reported higher BMI values (p = 0.003), more particular dietary regimens (p < 0.001), higher levels of weekly moderate–vigorous physical activity (p < 0.001) and participation in sports (p < 0.001) and in team sports (p = 0.003), and higher proportion of smokers (p < 0.001) and alcohol drinkers (p = 0.005). ED use was negatively related with female gender (OR 0.546; 95% CI 0.374–0.798), the Mediterranean diet (OR 0.587; 95% CI 0.362–0.951) and coming from the center of Italy (OR 0.500; 95% CI 0.275–0.909) and positively associated with tobacco smoke (OR 1.712; 95% CI 1.176–2.492) and participation in a team sport (OR 1.686; 95% CI 1.051–2.707). Conclusion These findings could encourage figures engaged in education to increase the students’ awareness on this issue in order to prevent the excessive use of EDs and associated unhealthy behaviors, especially in the most interested subgroups

AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity

Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel-the MYC pathway and the cyclin D-cyclin-dependent kinase (CDK)-retinoblastoma protein (RB) pathway(1,2). Both MYC and the cyclin D-CDK-RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1-cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis