Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi-drug resistance.

BACKGROUND: Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes. METHODS: We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis. RESULTS: We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring. CONCLUSIONS: We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment.

Training in Vascular Microsurgery: The Ex Vivo Biological Model on Domestic Turkey Leg (Meleagris gallopavo).

There are various models for practicing microsurgical anastomoses, from synthetic to ex vivo and in vivo biological ones. In this study, we present the domestic turkey (Meleagris gallopavo) as an ex vivo biological model in the practice of surgical anastomoses. In our opinion, it represents a model that is very similar to a human one, low cost, and easy to find. In fact, our study shows that the diameters of the arteries and veins used for anastomoses (tibial artery diameter: 2.5 ±â€…0.6 mm; tibial vein diameter: 3.5 ±â€…1.2 mm) are similar to those of human arteries and veins most frequently used in microsurgical free flaps. So, we believe that this animal model is a great model for microsurgical training for doctors who approach this difficult and long to learn discipline.

Real-World Safety Data of the Orphan Drug Onasemnogene Abeparvovec (Zolgensma®) for the SMA Rare Disease: A Pharmacovigilance Study Based on the EMA Adverse Event Reporting System.

The recent introduction of the innovative therapy, onasemnogene abeparvovec (Zolgensma®), has revolutionized the spinal muscular atrophy (SMA) therapeutic landscape. Although Zolgensma® therapy has proven to lead to functional improvements in SMA children, some gaps in its safety profile still need to be investigated. To better characterize the Zolgensma® safety profile, we conducted a retrospective observational study, analyzing all the Individual Case Safety Reports (ICSRs) referred to it and collected in the European pharmacovigilance database between 1 January 2019 and 22 September 2023. We found 661 ICSRs related to Zolgensma®, with a growing trend in the annual reporting. The majority of the reports were sent by healthcare professionals and referred to infant females. In more than 90% of the cases, Zolgensma® was the only reported suspected drug. Out of a total of 2744 reported ADRs, increased hepatic enzymes, pyrexia, vomiting, and thrombocytopenia were the most commonly reported adverse reactions. Of these adverse reactions (ADRs), 56.9% were serious, causing or prolonging the patient's hospitalization. A total of 39 ICSRs related to cases with a fatal outcome. Alterations in the heart rhythm, acute hepatic failure, and hepatic cytolysis emerged among the cardiac and hepatic disorders, respectively.

Immune Checkpoint Inhibitors and Scleroderma: Data from the European Pharmacovigilance Database.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can be commonly associated with the occurrence of immune-related adverse drug reactions (irADRs), which can involve any tissue and organ. ICI-induced skin toxicities are common irADRs and they can be a consequence of a rheumatologic ADR, such as in the case of scleroderma. A recent literature review reported that scleroderma and scleroderma mimics represent a group of disorders with significant morbidity that have been described during ICIs' use. OBJECTIVE AND METHODS: Considering the clinical significance of scleroderma cases, the present study aimed to analyze the occurrence of these events in patients receiving ICIs by describing data from individual case safety reports (ICSRs) retrieved from the European spontaneous reporting system, EudraVigilance (EV). RESULTS: Until February 2023, 70 ICSRs with at least one ICI as the suspected drug and at least one preferred term (PT) related to scleroderma cases were retrieved from the EV. Pembrolizumab was reported as suspected in 41 ICSRs, nivolumab in 25 ICSRs, ipilimumab in 8 ICSRs and atezolizumab in 3 ICSRs. Patients who experienced scleroderma cases were adults, and no differences were found in terms of sex distribution. Scleroderma cases were mainly classified as serious, while the outcome was mainly reported as favorable. The most reported PTs were scleroderma and morphea. CONCLUSIONS: Considering the seriousness of ICI-induced scleroderma cases and the recent marketing authorization of some ICIs, we believe that further high-quality clinical studies should be conducted on this topic to better estimate the impact of these events in patients with cancer.

Multiple Foci of Basal Cell Carcinoma Arising in Rhinophyma: A Case Report and Literature Review.

Background: Rhinophyma is a benign condition caused by the excessive growth of sebaceous glands in the nasal tissue, presenting with symptoms such as nasal hypertrophy, erythema, and papules. Cases of basal cell carcinoma in rhinophyma have been reported in literature, but its etiological role remains unclear. It is uncertain whether rhinophyma is predisposed to neoplasm development or if their coexistence is coincidental. Material and Method: We conducted a literature survey to identify such cases reported over the years. Results: We identified 22 studies reporting a total of 47 cases in the literature, all involving male patients. The most common pattern of occurrence was the rapid growth of a nodular formation within the context of rhinophyma. Discussions and Conclusion: The elucidation of the association between basal cell carcinoma and rhinophyma remains challenging. The presence of multiple foci supports the theory that rhinophyma may play a role in their development, but larger studies are needed to establish a causal relationship.

Skin Toxicities Associated with Botulin Toxin Injection for Aesthetic Procedures: Data from the European Spontaneous Reporting System.

Botulinum toxin is a protein deriving from the bacteria Clostridium botulinum and it is widely used for the treatment of a variety of muscle hyperactivity syndromes and for cosmetic indications. Having a long-lasting effect, Botulinum toxin type A (BTA) is one of the most botulin toxin products used. Even if BTA has shown benefits in reducing the vertical lines between the eyebrows, Adverse Drug Reactions (ADRs) have been experienced as well, of which the most common ones are headache and drooping eyelids. In addition, since other local and systemic risks have been identified, a non-interventional post-authorization safety study (PASS) has been started. The aim of the present study was to report cases of skin toxicity associated with this drug, considering Individual Case Safety Reports (ICSRs) existing on the Eudravigilance website. Among 1464 ICSRs sent to the EV database, 718 ICSRs, including 5154 PTs, reported BTA as a suspected drug associated with cutaneous toxicity. The majority of patients experiencing BTA-induced skin toxicity were female (92.1%) belonging mostly to the age group of 18-64 years. The most serious criteria, when reported, were "Other Medically Important Condition" and "Caused/prolonged hospitalization", although the outcome was mainly reported as "Unknown". The most reported PTs, related to skin disorders, were: "Erythema", "Rash", "Pruritus", "Urticaria", "Swelling face", "Brow ptosis", "Eyelid ptosis", "Injection site pain", and "Angioedema". Considering that in most ICSRs, ADRs related to skin disorders were symptoms of hypersensitivity reactions which in some conditions could be life-threatening, further studies are required to better define the safety profile of BTA used for aesthetic procedures.

Prostaglandin E2/EP4 axis is upregulated in Spondyloarthritis and contributes to radiographic progression.

Ankylosing spondylitis (AS) is an inflammatory disease leading to spine ankylosis; however, the mechanisms behind new bone formation are still not fully understood. Single Nucleotide Polymorphisms (SNPs) in PTGER4, encoding for the receptor EP4 of prostaglandin E2 (PGE2), are associated with AS. Since the PGE2-EP4 axis participates in inflammation and bone metabolism, this work aims at investigating the influence of the prostaglandin-E2 axis on radiographic progression in AS. In 185 AS (97 progressors), baseline serum PGE2 predicted progression, and PTGER4 SNP rs6896969 was more frequent in progressors. Increased EP4/PTGER4 expression was observed in AS circulating immune cells, synovial tissue, and bone marrow. CD14highEP4 + cells frequency correlated with disease activity, and when monocytes were cocultured with mesenchymal stem cells, the PGE2/EP4 axis induced bone formation. In conclusion, the Prostaglandin E2 axis is involved in bone remodelling and may contribute to the radiographic progression in AS due to genetic and environmental upregulation.

Post-Partum Depression Lactating Rat Model for Evaluating Ketamine's Safety as a Pharmacotherapeutic Treatment: Roles in Cardiac and Urinary Function.

Depression is one of the world's most common and mentally disabling illnesses. Post-partum depression is a subtype of depression that affects one in seven women worldwide. Successful pharmacological treatment must consider the consequences for both, since the mother-child bond is fundamental for the well-being of both mother and infant as well as the general development of the newborn. Changes in maternal physiology and/or behavior can significantly influence the development of breastfed infants. Ketamine has been extensively studied for use as an antidepressant due to its mixed mechanisms of action. Safety and efficacy studies in the cardiovascular and urinary systems of a lactating postpartum depression animal model are essential for contributing toward ketamine's clinical use in the respective patient population. Thus, this project aimed to study the implications of postpartum maternal exposure to ketamine during lactation on the cardiovascular system of female rats submitted to the depression induction model by maternal separation. This model promotes depressive effects through stress caused by the interruption of mother-infant bond early in the offspring's life. To achieve depression, each dam was separated from her offspring for 3 h per day, from post-natal day 2 (PND2) to PND12. Experimental groups received daily treatment with either 5, 10, or 20 mg/kg of ketamine intraperitoneally during the lactation period, from PND2 to PND21. Behavioral tests consisted of the maternal and aggressive maternal behavior tests, the olfactory preference test, and the forced swim test. A technique for the detection of catecholamines and indoleamines in the heart muscle was developed for the experimental model groups. The histopathological evaluation was performed on these animals' cardiac muscles and urinary bladders. Our findings suggest that ketamine is safe for use in postpartum depression and does not induce cardiovascular and/or urinary systems toxicity.

Histone lysine demethylase inhibition reprograms prostate cancer metabolism and mechanics.

OBJECTIVE: Aberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program. METHODS: We investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy. RESULTS: MC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen-responsive and -unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells. CONCLUSIONS: Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and underscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC.

Development, Optimization, and Validation of Forensic Analytical Method for Quantification of Anticholinesterase Pesticides in Biological Matrices from Suspected Cases of Animal Poisoning.

Anticholinesterase pesticides are a main cause of the intentional or accidental poisoning of animals. Anticholinesterases include several substances that cause the overstimulation of both central and peripheral acetylcholine-dependent neurotransmission. Forensic analyses of poisoning cases require high levels of expertise, are costly, and often do not provide reliable quantitative information for unambiguous conclusions. The purpose of the present study was to develop and validate a method of high-performance liquid chromatography with diode array detector (HPLC−DAD) for the identification and quantitation of n-methyl carbamates, organophosphates and respective metabolites from biological samples of animals that were suspected of poisoning. HPLC−DAD is reliable, fast, simplistic and cost-effective. The method was validated for biological samples obtained from stomach contents, liver, vitreous humor and blood from four different animal species. The validation of the method was achieved using the following analytical parameters: linearity, precision, accuracy, selectivity, recovery, and matrix effect. The method showed linearity at the range of 25−500 µg/mL, and the correlation coefficient (r2) values were >0.99 for all matrices. Precision and accuracy were determined by the (a) coefficient of variation (CV), (b) relative standard deviation low-quality control (LQC), (c) medium-quality control (QCM), and (d) high-quality control (QCA). The indicated parameters were all less than 15%. The recovery of analytes ranged from 31 to 71%. The analysis of results showed no significant interfering peaks due to common xenobiotics or matrix effects. The abovementioned method was used to positively identify pesticide analytes in 44 of the 51 animal samples that were suspected of poisoning, demonstrating its usefulness as a forensic tool.

Fasciola hepatica prevalence in cattle from the Abancay, Curahuasi and Tamburco districts, Abancay province-Apurímac, Peru during the 2018 rainy season

This study aims to determine the prevalence of Fasciola hepatica in cattle from the Abancay, Curahuasi, and Tamburco districts in the Abancay province, Apurímac, Peru, during the 2018 rainy season, and the association between prevalence and age, breed, and district of origin. In total, 295 stool samples were collected, namely 34 from Tamburco, 193 from Curahuasi and 68 from Abancay. For coproparasitological evaluation, the four-sieve sedimentation technique described by Girão and Ueno was used. The total prevalence of F. hepatica in the cattle sampled in this study was 50.8% (150/295), and the prevalence by district was 42.6% (29/68) in Abancay, 53.8% (104/193) in Curahuasi, and 50% (17/34) in Tamburco. No significant association was found with the variable district of origin (p<0.05). However, using a bivariate logistic regression analysis, a significant association was found between F. hepatica prevalence and the breed variable (p=0.008). A similar significant association with the breed variable (p=0.007) was also found using a multiple logistic regression analysis. The high prevalence of F. hepatica identified in this study is consistent with previous reports made in the Apurímac Region, an area considered hyperendemic for the parasite, thus highlighting the need for effective health programs to control disease distribution, which may have an economic and, because of its zoonotic character, public health impact.

The effects of pharmacist interventions on health outcomes in patients with advanced prostate cancer in Brazil

Abstract This study examined the effects of pharmacist interventions for patients with advanced prostate cancer. A pre-post study was conducted between October 2014 and August 2017 in a community pharmacy in Brazil for outpatients with advanced prostate cancer, aged ≥ 18 years, using cyproterone acetate and/or goserelin. The patients had face-to-face meetings with a pharmacist who dispensed antiandrogenic drugs and performed interventions aimed at solving and/or preventing drug-therapy problems. Primary outcomes regarding prostate-specific antigen (PSA) and testosterone levels were compared at 0, 6, and 12 months, whereas secondary outcomes-medication adherence and quality of life-were compared at baseline and at the 12-month follow-up. Medication adherence was assessed using the Morisky-Green test, and quality of life was measured by the Medical Outcomes Study 36-item Short Form (SF-36) and the Functional Assessment of Cancer Therapy-Prostate (FACT-P). The analysis included 20 patients; 311 drug-therapy problems were identified and most of them were related to adverse reactions (78.5%). The most common adverse reactions were reduced libido, erectile dysfunction, hyperglycemia, fatigue, and gynecomastia. Testosterone levels significantly decreased at 6 months, and PSA levels at 6 and 12 months. No significant changes in adherence were noted at the end of the study. A significant increase in the "pain" domain and an improvement trend in the "physical aspects" and "vitality" domains were observed based on the SF-36 instrument. The findings show that pharmacist interventions were able to improve PSA and testosterone levels, and some domains of quality of life of patients.

Adverse events related to oral hormonal contraceptive use in undergraduate pharmacy students: a cross-sectional study

Abstract We aimed to measure the prevalence of adverse events related to oral hormonal contraceptive (OHC) use and their associated factors in undergraduate pharmacy students. A cross-sectional study was conducted by using an online questionnaire for female students of the Faculty of Pharmaceutical Sciences of the University of São Paulo from July to August 2020. A descriptive analysis of the data was carried out, which was followed by determining the prevalence ratios to identify possible factors associated with adverse events resulting from OHC. A total of 269 valid responses were obtained, among which 50.2% (n = 135) of the students reported using OHC as a contraceptive method and 21.2% (n = 57) affirmed that they had at least one adverse event related to OHC use, which corresponds to 42.2% of those who had used OHC. The most common adverse event was headache (70.2%), and a period of less than one month was the most cited (49.1%). Only migraine comorbidity was associated with the occurrence of adverse events related to OHC. These findings reinforce the high incidence of adverse events among OHC users and the low rate of discontinuation due to these events. There is a need to provide more information on contraceptive methods to users, including its risks and contraindications.

HDAC6 Inhibition Extinguishes Autophagy in Cancer: Recent Insights.

Autophagy is an essential intracellular catabolic mechanism involved in the degradation and recycling of damaged organelles regulating cellular homeostasis and energy metabolism. Its activation enhances cellular tolerance to various stresses and is known to be involved in drug resistance. In cancer, autophagy has a dual role in either promoting or blocking tumorigenesis, and recent studies indicate that epigenetic regulation is involved in its mechanism of action in this context. Specifically, the ubiquitin-binding histone deacetylase (HDAC) enzyme HDAC6 is known to be an important player in modulating autophagy. Epigenetic modulators, such as HDAC inhibitors, mediate this process in different ways and are already undergoing clinical trials. In this review, we describe current knowledge on the role of epigenetic modifications, particularly HDAC-mediated modifications, in controlling autophagy in cancer. We focus on the controversy surrounding their ability to promote or block tumor progression and explore the impact of HDAC6 inhibitors on autophagy modulation in cancer. In light of the fact that targeted drug therapy for cancer patients is attracting ever increasing interest within the research community and in society at large, we discuss the possibility of using HDAC6 inhibitors as adjuvants and/or in combination with conventional treatments to overcome autophagy-related mechanisms of resistance.

The Janus-faced effects of COVID-19 perceptions on family healthy eating behavior: Parent's negative experience as a mediator and gender as a moderator.

This research examines the effects of COVID-19 perceptions and negative experiences during the pandemic time on parental healthy eating behavior and whether these relationships interact with a parent's gender. We ran a survey of parents who had at least one child aged 3 to 17 years old living in the United Kingdom. We received 384 valid responses, which were analysed via a variance-based structural equation modeling approach to test our hypotheses. The results revealed that COVID-19 perceptions effects were Janus-faced. While they indirectly and negatively impact healthy eating behavior mediated by triggering negative experiences during the pandemic, COVID-19 perceptions, however, directly get parents, especially fathers, more engaged into healthy eating behavior - making COVID-19 perceptions total effects positive on healthy eating behavior. This explorative model is novel in the sense that it is the first of its kind to cast light on how parental healthy eating behavior can be shaped in pandemic time. The research is particularly timely due to the uncertain times in which the research is situated, that is, the worldwide pandemic (also termed COVID-19); the paper highlights how family eating practices can undergo dramatic shifts during acute crises.

Proteomic fingerprinting of protein corona formed on PEGylated multi-walled carbon nanotubes.

In Nanomedicine, carbon-based nanomaterials, like Carbon Nanotubes (CNT), are considered potential candidates as drug delivery systems. In vivo adsorption of physiological proteins onto carbon nanotubes, through noncovalent interactions, forms a protein corona or bio corona, able to influence biological properties and biocompatibility of CNT. This study aimed to explore the composition of protein corona formed onto PEGylated Multi-Walled Carbon Nanotubes (MWCNT-PEG5k), after their incubation in human plasma. Plasma proteins were sequentially eluted in different conditions by using both native and denaturant buffers, useful to characterize soft and hard corona. Proteomic methods and mass spectrometry analysis have identified proteins in soft corona, involved in the regulation of immune response and in the CNT transport, and biomolecules in hard corona with a role in the maintenance of host homeostasis. These promising results have demonstrated the potential of PEGylated Multi-Walled Carbon Nanotubes as future candidates for drug delivery.

Proteomic exploration of soft and hard biocorona onto PEGylated multiwalled carbon nanotubes.

In nanomedicine, carbon nanotubes (CNTs) are considered potential candidates as drug delivery systems. The absorption of proteins onto CNTs, after their administration in physiological environment, forms the protein corona or biocorona, which is able to influence their biological properties and biocompatibility. For this reason, characterization of protein corona is a crucial aspect in the research to control CNTs toxicity and capability to target cells. Multiwalled carbon nanotubes (MWCNTs) were functionalized with polyethylene glycol (PEG), chosen considering its well-known biocompatibility, and then incubated in human plasma to create the biocorona. Plasma proteins, which bound around PEGylated CNTs, were detached using five different solutions, grouped into native and denaturant buffers, and used to characterize the two components of biocorona. The proteomic fingerprinting of biocorona was performed by SDS-PAGE and 2D-PAGE separation and mass spectrometry analysis. Native eluents were able to capture proteins of soft corona, characterized by complex secondary structures, and formed by both ß-sheet and α-helices domains. Denaturant buffers have eluted many proteins with a high percentage of the α-helix structure that could be involved in specific interactions responsible for the formation of hard corona.

Judicialização da saúde: uma análise do fenômeno e suas consequências para a sociedade brasileira / Judicialization of health: An analysis of the phenomenon and its consequences to Brazilian society

Embora o Sistema Único de Saúde tenha avançado desde sua criação, ainda há falhas no fornecimento de medicamentos e serviços. Com isso, cidadãos têm utilizado o sistema judiciário para aquisição de bens de saúde, prática conhecida como judicialização da saúde, que teve um crescimento abrupto nos últimos anos. Diante disso, o trabalho tem como objetivo analisar as ações judiciais que requerem bens de saúde ao SUS para proporcionar melhor compreensão dos efeitos da naturalização da judicialização da saúde. Foram realizadas uma revisão bibliográfica e análise de 100 processos judiciais do portal eletrônico do Tribunal de Justiça do Estado de São Paulo. Os resultados indicaram que, em 2010, o gasto do governo federal com a judicialização da saúde foi de R$ 120 milhões. Já em 2016, esse gasto foi de cerca de R$ 1,6 bilhão, com 1.346.931 processos movidos no Brasil. A análise descritiva realizada demonstrou que, no mesmo ano, 22,1% das ações judiciais selecionadas solicitaram medicamentos padronizados pelo SUS e, em relação às demais solicitações, 82,8% possuíam alternativa terapêutica disponível na rede pública. Os valores apresentados demonstram a desestabilização do planejamento orçamentário para a área da saúde gerada pela judicialização. É necessário buscar estratégias de garantia do direito à saúde e ampliar o conhecimento das listas disponibilizadas pela rede pública para médicos e juízes. Dessa forma, a judicialização da saúde permanecerá viável para a garantia dos direitos em casos não contemplados pelo sistema de saúde, sem prejuízo ao planejamento orçamentário e acesso universal ao Sistema Único de Saúde.

Although the Brazilian National Health System advanced since its creation, there are still failures in supplying medicines and services. For this reason, citizens have been using the judicial system to acquire health assets, what is known as judicialization of health. In the last years, this practice had an abrupt increase. This work has the purpose of analyzing the lawsuits that request provision of health assets through SUS to provide greater understanding of the effects of the naturalization of judicialization of health. To do this, a bibliographic review was conducted, besides the analysis of 100 lawsuits on the Tribunal de Justiça do Estado de São Paulo's website. The results indicated that in 2010, the government spending on judicialization of health was R$ 120 million, whereas in 2016 it was around R$ 1.6 billion, reaching 1,346,931.00 actions moved in Brazil. The descriptive analysis demonstrated that, in the same year, nearly 22.1% of the selected lawsuits requested medicines, which are standardized by SUS. In relation to the other requests, 82.8% disposed of therapeutic alternative available in public system. The numbers demonstrate the destabilization of budget planning to the health sector caused by judicialization. It is necessary to seek strategies to ensure the right to health and to enlarge the knowledge of standardized lists provided in public system to doctors and judges. The judicialization will therefore remain available to guarantee rights in cases not covered by the health system, without the excesso of lawsuits damaging the budget planning and universal access to the system.

Preclinical and Clinical Epigenetic-Based Reconsideration of Beckwith-Wiedemann Syndrome.

Epigenetics has achieved a profound impact in the biomedical field, providing new experimental opportunities and innovative therapeutic strategies to face a plethora of diseases. In the rare diseases scenario, Beckwith-Wiedemann syndrome (BWS) is a pediatric pathological condition characterized by a complex molecular basis, showing alterations in the expression of different growth-regulating genes. The molecular origin of BWS is associated with impairments in the genomic imprinting of two domains at the 11p15.5 chromosomal region. The first domain contains three different regions: insulin growth like factor gene (IGF2), H19, and abnormally methylated DMR1 region. The second domain consists of cell proliferation and regulating-genes such as CDKN1C gene encoding for cyclin kinase inhibitor its role is to block cell proliferation. Although most cases are sporadic, about 5-10% of BWS patients have inheritance characteristics. In the 11p15.5 region, some of the patients have maternal chromosomal rearrangements while others have Uniparental Paternal Disomy UPD(11)pat. Defects in DNA methylation cause alteration of genes and the genomic structure equilibrium leading uncontrolled cell proliferation, which is a typical tumorigenesis event. Indeed, in BWS patients an increased childhood tumor predisposition is observed. Here, we summarize the latest knowledge on BWS and focus on the impact of epigenetic alterations to an increased cancer risk development and to metabolic disorders. Moreover, we highlight the correlation between assisted reproductive technologies and this rare disease. We also discuss intriguing aspects of BWS in twinning. Epigenetic therapies in clinical trials have already demonstrated effectiveness in oncological and non-oncological diseases. In this review, we propose a potential "epigenetic-based" approaches may unveil new therapeutic options for BWS patients. Although the complexity of the syndrome is high, patients can be able to lead a normal life but tumor predispositions might impair life expectancy. In this sense epigenetic therapies should have a supporting role in order to guarantee a good prognosis.