Serum Extracellular Vesicles Cargo Approach in Bitches with Mammary Tumors.

This study investigated serum extracellular vesicles (EVs) in bitches with mammary neoplasms, in order to understand their size, shape, and concentration, as well as their association with tumor malignancy. Thirty bitches were categorized into control (n = 10), mammary tumor grades I and II (GI, n = 13), and grade III (GII, n = 7). Serum was separated from blood collected during mastectomy, and EVs were isolated using size exclusion chromatography. The analysis revealed no significant differences in EV concentrations among groups, with similar concentrations for control, GI, and GII. Ninety-one proteins were identified in EV-enriched samples, with six showing varied abundance across groups. Notably, keratin 18 was highly abundant in GI, while sushi domain-containing protein, EvC ciliary subunit 2, and the joining chain of multimeric IgM and IgA were increased in GII. Additionally, protocadherin 17 and albumin were upregulated in both GI and GII. ROC curves identified potential biomarkers for differentiating tumor grades. Enrichment pathway analysis revealed AFP gene upregulation in the GI. Mass spectrometry proteomics data were deposited in Mendeley Data. The study provides valuable insights into serum EV characterization in bitches, suggesting keratin 18 and protocadherin 17 as potential biomarkers for canine mammary neoplasia, with implications for future diagnostic and therapeutic strategies.

Riparin II-type benzamides as novel antibiofilm agents against dermatophytes: chemical synthesis, in vitro, ex vivo and in silico evaluation.

BACKGROUND: The ability of dermatophytes to develop biofilms in host tissues confers physical and biochemical resistance to antifungal drugs. Therefore, research to find new compounds against dermatophyte biofilm is crucial. OBJECTIVES: To evaluate the antifungal activity of riparin II (RIP2), nor-riparin II (NOR2) and dinor-riparin II (DINOR2) against Trichophyton rubrum, Microsporum canis and Nannizzia gypsea strains. METHODS: Initially, we determined the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of benzamides. We evaluated the inhibitory effects on the development of dermatophyte biofilms using in vitro and ex vivo models. Finally, we built three-dimensional models of the sulphite pump Ssu1 to investigate the interactions with the benzamides by molecular docking. RESULTS: RIP2 showed a broad spectrum of activity against T. rubrum, M. canis and N. gypsea, whereas NOR2 and DINOR2 were more selective. Furthermore, the shortening of the carbon chain from RIP2 benzamide to NOR2 and DINOR2 homologs caused a decrease in the MIC values. The benzamides reduced biofilm production and viability in vitro (P < 0.05) at MIC. This result was similar ex vivo in human nail fragments tests, but NOR2 and DINOR2 showed significant results at 2xMIC (P < 0.05). We constructed a model of the Ssu1 protein for each dermatophyte with high similarity. Molecular docking showed that the benzamides obtained higher binding energy values than ciclopirox. CONCLUSIONS: Our study shows the antibiofilm potential for riparin II-type benzamides as new drugs targeting dermatophytes by inhibiting the Ssu1 protein.

Evaluation of the antibacterial and inhibitory activity of the MepA efflux pump of Staphylococcus aureus by riparins I, II, III, and IV.

The efflux pump mechanism contributes to the antibiotic resistance of widely distributed strains of Staphylococcus aureus. Therefore, in the present work, the ability of the riparins N-(4-methoxyphenethyl)benzamide (I), 2-hydroxy-N-[2-(4-methoxyphenyl)ethyl]benzamide (II), 2, 6-dihydroxy-N-[ 2-(4-methoxyphenyl)ethyl]benzamide (III), and 3,4,5-trimethoxy-N-[2-(4-methoxyphenethyl)benzamide (IV) as potential inhibitors of the MepA efflux pump in S. aureus K2068 (fluoroquinolone-resistant). In addition, we performed checkerboard assays to obtain more information about the activity of riparins as potential inhibitors of MepA efflux and also analyzed the ability of riparins to act on the permeability of the bacterial membrane of S. aureus by the fluorescence method with SYTOX Green. A molecular coupling assay was performed to characterize the interaction between riparins and MepA, and ADMET (absorption, distribution, metabolism, and excretion) properties were analyzed. We observed that I-IV riparins did not show direct antibacterial activity against S. aureus. However, combination assays with substrates of MepA, ciprofloxacin, and ethidium bromide (EtBr) revealed a potentiation of the efficacy of these substrates by reducing the minimum inhibitory concentration (MIC). Furthermore, increased EtBr fluorescence emission was observed for all riparins. The checkerboard assay showed synergism between riparins I, II, and III, ciprofloxacin, and EtBr. Furthermore, riparins III and IV exhibited permeability in the S. aureus membrane at a concentration of 200 µg/mL. Molecular docking showed that riparins I, II, and III bound in a different region from the binding site of chlorpromazine (standard pump inhibitor), indicating a possible synergistic effect with the reference inhibitor. In contrast, riparin IV binds in the same region as the chlorpromazine binding site. From the in silico ADMET prediction based on MPO, it could be concluded that the molecules of riparin I-IV present their physicochemical properties within the ideal pharmacological spectrum allowing their preparation as an oral drug. Furthermore, the prediction of cytotoxicity in liver cell lines showed a low cytotoxic effect for riparins I-IV.

Hypoglycaemia management with a hypercaloric supplementation in neonatal puppies delivered by caesarean section.

There is a high perinatal mortality rate in dogs, estimated at 20%, and one of the leading causes of this rate is hypoglycaemia. Therefore, we aimed to evaluate the efficacy of a hypercaloric supplement containing vitamins and amino acids in newborn puppies presenting hypoglycaemia at birth. Ninety-nine pups were divided into four groups: normoglycaemic caesarean section (NORMOCS), hypoglycaemic caesarean section supplemented with the hypercaloric (SUPLCS), hypoglycaemic caesarean section supplemented with glucose (GLICCS) and eutocic delivery (EUT). We evaluated the following parameters glycaemia, Apgar score, neurological reflexes and rectal temperature of neonates at the following moments 5 min (M5), 30 min (M30) and 60 min (M60) after birth. Brachycephalic dogs were 73.3% (22/30) of caesarean sections (c-sections). The puppy's average glycaemia represented about 90% of the maternal glycaemia, while 15.1% (14/99) of the neonates had hypoglycaemia (<90 mg/dL) at M0 and 46.5% (44/99) at M60. Only four neonates had glycaemia below 40 mg/dL at M30 but without showing any clinical signs. The puppy's fasting while waiting for the intraoperative period and the dam's anaesthetic recovery was considered risk factors for hypoglycaemia. There was no difference in mean blood glucose levels or vitality parameters among puppies from the SUPLCS and GLICCS. In conclusion, the hypercaloric supplement can be used as a replacement for glucose in hypoglycaemic puppies and it can also bring nutritional benefits for the puppy. The prepartum glycaemia of the dam is an important parameter to be measured, and the appropriate management of it reduces the chances of the puppies being born with hypoglycaemia.

Acceptance of SARS-CoV-2 vaccination among cancer patients in Portugal: attitudes and associated factors.

OBJECTIVE: COVID-19 vaccines have shown efficacy and safety in healthy people. However, cancer patients under active immunosuppressive treatment were not included in the clinical trials conducted to test vaccines' efficacy and safety. This study aimed to evaluate the COVID-19 vaccine acceptance in cancer patients undergoing immunosuppressive therapy. METHODS: A total of 200 adult cancer patients received a questionnaire between March 8 and April 2, 2021, before the beginning of cancer patients' vaccination in Portugal. The questionnaire adapted from previously conducted studies included 11 close-ended items, evaluating variables such as patient sociodemographic and clinical characteristics, and the acceptance and underlying reasons to be or not to be vaccinated. The primary outcome was the intended acceptance of the COVID-19 vaccine in cancer patients. Multiple logistic regression was performed to identify factors associated with intended acceptance. RESULTS: Among the 200 delivered questionnaires, only 169 were included in this study. From those, 142 (84%) patients intended to be vaccinated against COVID-19. Only 27 participants (16%) had not yet decided or were reluctant to COVID-19 vaccination. High school degree (odds ratio (OR) 0.133, 95% confidence interval (C.I.) 0.031-0.579, p = 0.007], rural residence (OR 0.282, 95% C.I. 0.081-0.984, p = 0.047), and reluctance in believing in the vaccine efficacy (OR 0.058, 95% C.I. 0.016-0.204, p < 0.001] were identified predictors factor for COVID-19 vaccine hesitancy. CONCLUSION: Most patients intended to be vaccinated against COVID-19, and specific factors such as education level, rural residence and the belief in vaccine efficacy were related to vaccine acceptance.

Acute toxicity and tolerability of anthracycline-based chemotherapy regimens in older versus younger patients with breast cancer: real-world data.

OBJECTIVES: To compare the non-cardiac acute toxicity and tolerability profile of anthracycline-based regimens between older versus younger women diagnosed with breast cancer in a real-world setting. METHODS: Retrospective cohort of female patients diagnosed with breast cancer and treated with neoadjuvant or adjuvant anthracycline-based regimens between 2017 and 2019. Patients were grouped in young versus older, using an age of 65 as cut-off. Differences in non-cardiac acute toxicity and change in treatment plan were examined. RESULTS: Among the 559 patients, 19.5% were aged ≥ 65 years. Regimens used were fluorouracil, epirubicin, and cyclophosphamide in 56.2% of patients, doxorubicin and cyclophosphamide in 33.3%, and epirubicin and cyclophosphamide in 10.5%; there were no differences in incidence of grade 3 or 4 toxicities between regimens (p = 0.184). Acute grade 3 or 4 toxicities occurred more frequently in the older group (33.9% versus 10.7%, p < 0.0001, OR 4.304, 95%-CI [2.619-7.073]). Delay of at least one chemotherapy cycle due to toxicity occurred more frequently in the older group (24.8% versus 9.3%, p < 0.0001, OR 3.199, 95%-CI [1.867-5.481]). Early termination of treatment also occurred more frequently in the older group (11.9% versus 1.6%, p < 0.0001, OR 8.571, 95%-CI [3.331-22.048]). CONCLUSION: Although acute grade 3 or 4 toxicities were more frequent in older patients, which resulted in increased cycle delay and/or premature termination of treatment, overall treatment was still reasonably well-tolerated, with 88.1% of older patients completing the planed anthracycline regimen.

How protected are marine protected areas: A case study of tributyltin in Latin America.

Protected areas (PAs) are dedicated and managed to achieve long-term conservation of nature with associated ecosystem services and cultural values. However, few studies have assessed contamination/pollution, one of the top five biodiversity threats, within these areas. In fact, more than 100,000 molecules used in consumer goods are potentially affecting over 250,000 protected areas distributed worldwide. As a result, chemical appraisal within PAs require specific approaches to be feasible. Herein, an approach for assessment of contamination in marine protected areas (MPAs) spread over large continental and/or global areas was proposed and tested using, as a case study, the impact of tributyltin (TBT) within Latin America. This approach included area delimitation, bibliographic survey, construction of attribute tables, data insertion in a Geographic Information System, overlapping with worldwide shapefiles of PAs, identification of affected PAs and evaluation of impacts using the outcomes against specific environmental quality guidelines/directives. A total of 259 records of TBT occurrence and/or its biological effect within 53 marine protected areas (including biosphere reserves, Ramsar sites and National parks) were gathered. Among affected species, were recorded 18 gastropods exhibiting imposex. In addition, 6 bivalves, 1 crustacean, and 3 fish species presenting TBT residues in tissues were seen in MPAs from Brazil, Argentina, Ecuador, Peru, Chile and Venezuela. Since levels of TBT recorded in several studied MPAs were enough do induce deleterious biological responses over marine biota, it was clear that conservancy goals of some "protected" areas are under threat. Considering that only TBT exposure was appraised, and these areas are likely to be concomitantly exposed to other classes of contaminants, the actual scenario can be even more frightening. Although initially applied as a TBT case study, the present approach enables an overview for other chemicals within protected areas worldwide.

Prognostic factors for early relapse in non-metastatic triple negative breast cancer - real world data.

BACKGROUND: Triple negative breast cancer (TNBC) has the worst prognosis amongst all subtypes. Studies have shown that the achievement of pathologic complete response in the breast and axilla correlates with improved survival. The aim of this study was to identify clinical or pathological features of real-life TNBC patients with a higher risk of early relapse. MATERIALS AND METHODS: Single-centre retrospective analysis of 127 women with TNBC, stage II-III, submitted to neoadjuvant treatment and surgery between January 2016 and 2020. Multivariate Cox regression analysis for disease free survival (DFS) at 2 years was performed and statistically significant variables were computed into a prognostic model for early relapse. RESULTS: After 29 months of median follow-up, 105 patients (82.7%) were alive and, in total, 38 patients (29.9%) experienced recurrence. The 2-year DFS was 73% (95% CI: 21.3-22.7). In multivariate analysis, being submitted to neoadjuvant radiotherapy [HR 2.8 (95% CI: 1.2-6.4), p = 0.017] and not achieving pathologic complete response [HR 0.3 (95% CI: 0.1-1.7), p = 0.011] were associated with higher risk of recurrence. In our prognostic model, the presence of at least one of these variables defined a subgroup of patients with a worse 2-year DFS than those without these features (59% vs. 90%, p < 0.001, respectively). CONCLUSIONS: In this real-life non-metastatic TNBC cohort, neoadjuvant radiotherapy (performed due to insufficient clinical response to neoadjuvant chemotherapy or significant toxicity) impacted as an independent prognostic factor for relapse along with the absence of pathologic complete response identifying a subgroup of higher risk patients for early relapse that might merit a closer follow-up.

Intensive safety monitoring program of antineoplastic medicines: A pilot study in a Portuguese oncology hospital.

PURPOSE: The aim of this study was to test the feasibility and the usefulness of an intensive safety monitoring program to identify adverse drug reactions for medicines under additional monitoring that are used to treat cancer patients within a Portuguese oncology hospital. METHODS: This pilot intensive safety monitoring program was a three-month prospective, observational study. Patients undergoing treatment with one of the following medicines were included: nivolumab, olaparib, palbociclib, pembrolizumab, pertuzumab, ramucirumab, ribociclib, trastuzumab emtansine, or trifluridine/tipiracil. Potential eligible patients were identified by pharmacists based on prescription data. Clinicians used proper paper-based reporting forms to record adverse drug reactions. Clinical secretariats sent those reports through an electronic platform to the pharmacovigilance department for analysis. RESULTS: Seventy-five patients were on treatment with selected medicines. Of those, 33 (44%) experienced adverse drug reactions: 23 (69.7%) cases were serious and 5 (15.2%) unexpected. Considering the number of patients exposed to each medicine and the number of patients experiencing adverse drug reactions, trifluridine/tipiracil (72.7%; 8/11) was associated with the highest rate of toxicity, followed by olaparib (66.7%; 2/3), trastuzumab emtansine (50.0%; 3/6), pertuzumab (47.8%; 11/23), pembrolizumab (45.5%; 5/11), palbociclib (25.0%; 1/4), and nivolumab (18.8%; 3/16). A total of 59 adverse drug reactions were identified (i.e. 1.8 adverse drug reactions/patient), mainly gastrointestinal disorders (n = 15; 25.4%), and blood and lymphatic system disorders (n = 14; 23.7%). CONCLUSION: This intensive safety monitoring program was feasible and allowed identifying serious and unexpected adverse drug reactions, adding value to pharmacovigilance and therefore contributing to improve patient safety. Further research is needed to confirm the findings of this pilot study.

Experimental mixed infection of Leishmania (Leishmania) amazonensis and Leishmania (L.) infantum in hamsters (Mesocricetus auratus).

In South America, visceral leishmaniasis is frequently caused by Leishmania infantum and, at an unknown frequency, by Leishmania amazonensis. Therefore, mixed infections with these organisms are possible. Mixed infections might affect the clinical course, immune response, diagnosis, treatment and epidemiology of the disease. Here we describe the clinical course of mixed infections with L. amazonensis and L. infantum in a hamster model. We show that mixed infections are associated with more severe clinical disease than infection with L. amazonensis or L. infantum alone. In spleens with mixed infections, L. infantum outcompeted L. amazonensis in the tissue, but not in culture from tissue. We found increased levels of IgG in animals infected with L. infantum. Although more than 30 bands were revealed in a Western blot, the highest immunogenicity was observed with proteins having molecular masses of 95 and 90 kDa, whereas proteins with molecular masses of lower than 50 kDa were reactive frequently with serum from hamsters infected with L. amazonensis, and proteins with molecular masses of 80 and 70 kDa were reactive only with serum from hamsters infected with L. infantum. This finding has important implications regarding the biology of Leishmania and humoral immune responses to infections with these organisms.

Major Cardiac Events After Non-cardiac Surgery.

INTRODUCTION: Postoperative cardiovascular complications might be difficult to assess and are known to be associated with longer hospital stay and increased costs as well as higher morbidity and mortality rates. The aim of this study was to evaluate the predictors for major cardiac events (MCE) after non-cardiac surgery. METHODS: The study included 4398 patients who were admitted to the Surgical Intensive Care Unit between January 1, 2006 and July 19, 2013. Acute physiology and chronic health evaluation II score and simplified acute physiology score (SAPS II) were calculated, and all variables entered as parameters were evaluated independently. Multivariate logistic regression analysis was performed to assess the independent factors for MCE. RESULTS: A total of 107 people experienced MCE. The independent predictors for postoperative MCE were higher fraction of inspired oxygen (FiO2) (odds ratio [OR] 38.97; 95 % confidence interval [CI] 10.81-140.36), history of ischemic heart disease (OR 3.38; 95 % CI 2.12-5.39), history of congestive heart disease (OR 2.39; 95 % CI 1.49-3.85), history of insulin therapy for diabetes (OR 2.93; 95 % CI 1.66-5.19), and increased SAPS II (OR 1.03; 95 % CI 1.01-1.05). Having a MCE was associated with a longer length of stay in the surgical intensive care unit (OR 1.01, 95 % CI 1.00-1.01). CONCLUSIONS: FiO2, ischemic heart disease, congestive heart disease, insulin therapy for diabetes, SAPS II, and length of stay in the surgical intensive care unit were independent predictors for MCE.

Evaluation of Ki-67 antigen expression in the vaginal epithelium of castrated female rats treated with raloxifene and tamoxifen: a comparative study.

OBJECTIVE: The aim of this study was to evaluate the effects of raloxifene and tamoxifen on Ki-67 antigen expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Thirty-nine virgin, adult, castrated female Wistar-Hannover rats were randomly divided into three groups: Group I (control, n = 13), Group II (raloxifene, n = 13) and Group III (tamoxifen, n = 13). After confirmation of their hypoestrogenic state, the rats were given 0.5 ml of propylene glycol (vehicle), 750 µg of raloxifene or 250 µg of tamoxifen, respectively, by gavage, for 30 days. On the 31st day, the rats were euthanized and their vaginas removed and fixed in 10% buffered formalin for of Ki-67 immunohistochemical evaluation. Data were analyzed using Levene's test and Tukey's method (p < 0.05). RESULTS: Mean Ki-67 expression in groups I, II and III was 27 ± 2.6, 32.3 ± 1.9 and 43.7 ± 3.5, respectively. In Group III (tamoxifen), there was a greater proportion of stained cells compared to Groups I and II (p < 0.0003), with no statistically significant difference between Groups I and II (p = 0.3626). CONCLUSIONS: The present results show that tamoxifen significantly increased cell proliferation in the vaginal epithelium of the castrated rats and no difference between the raloxifene and control groups.

Expression of LIN28 and its regulatory microRNAs in adult adrenocortical cancer.

OBJECTIVE: LIN28 control cells reprogramming and pluripotency mainly through miRNA regulation and has been overexpressed in many advanced cancers. In this study, we evaluated the prognostic role of LIN28 and its regulatory miRNAs in a large cohort of adrenocortical tumours (ACTs). PATIENTS AND METHODS: LIN28 protein expression was assessed in 266 adults ACTs (78 adenomas and 188 carcinomas) from Brazil and Germany. LIN28A and LIN28B gene expression was analysed in 59 ACTs (31 adenomas and 28 carcinomas) and copy number variation in 39 ACTs. In addition, we determined the expression of let-7 family, mir-9, mir-30 and mir-125 in 28 carcinomas. RESULTS: LIN28A gene was overexpressed in aggressive ACCs when compared with adenomas and nonaggressive ACCs, but no LIN28A copy number variation was found in ACTs. Unexpectedly, weak LIN28 protein expression was significantly associated with reduced disease-free survival in ACC patients (P = 0·01), but for overall survival only a trend was detectable (P = 0·117). In the multivariate analysis, only Ki67 index ≥10% (HR 4·6, P = 0·000) and weak LIN28 protein expression (HR 2·0, P = 0·03) were independent predictors of recurrence in ACC patients. Interestingly, mir-9 expression, a negative LIN28A/B regulator, was significantly higher in aggressive than in nonaggressive ACCs [2076 (from 36 to 9307) vs 133·4 (from 2·4 to 5193); P = 0·011] and was highly associated with reduced overall (P = 0·01) and disease-free survival (P = 0·01). However, mir-9 prognostic role should be further evaluated in a larger cohort. CONCLUSION: Weak LIN28 protein expression was associated with recurrence in ACCs. Additionally, overexpression of mir-9, a negative LIN28A regulator, was associated with poor outcome.

Rare Presentation and Diagnostic Challenge of a Germ Cell Tumor of the Yolk Sac Type.

Opsoclonus-ataxia paraneoplastic syndrome (OAPS) is a rare neurological disorder often associated with malignancies. This case report highlights an unusual instance of OAPS linked to a yolk sac (germ cell) tumor, a correlation underrepresented in the medical literature. The patient presented with distinct neurological symptoms alongside mediastinal lymphadenopathies. The subsequent diagnostic journey revealed a yolk sac germ cell tumor. Following incisional biopsies and treatment, the patient experienced fluctuations in mental status, leading to challenges in initiating chemotherapy. Despite these complications, a multidisciplinary approach involving neurologists, oncologists, and hematologists was pivotal. The case emphasizes the complexities of managing OAPS in tandem with a germ cell tumor, underscoring the need for further research and highlighting the significance of specialized neurological evaluation in similar cases.

Myocardial Injury Progression after Radiofrequency Ablation in School-Age Children. / Progressão da Lesão Miocárdica após Ablação por Radiofrequência em Crianças em Idade Escolar.

BACKGROUND: The past decades have seen the rapid development of the invasive treatment of arrhythmias by catheter ablation procedures. Despite its safety and efficacy being well-established in adults, to date there has been little data in pediatric scenarios. One of the main concerns is the possible expansion of the ablation procedure scar in this population and its consequences over the years. OBJECTIVES: This study aimed to analyze the risk of myocardial injury progression after radiofrequency catheter ablation in pediatric patients. METHODS: This is a retrospective study of 20 pediatric patients with previous ablation for treatment of supraventricular arrhythmia that underwent cardiac magnetic resonance and coronary angiography for evaluation of myocardial fibrosis and the integrity of the coronary arteries during follow-up. RESULTS: The median age at ablation procedure was 15.1 years (Q1 12.9, Q3 16.6) and 21 years (Q1 20, Q3 23) when the cardiac magnetic resonance was performed. Fourteen of them were women. Nodal reentry tachycardia and Wolf-Parkinson-White Syndrome were the main diagnosis (19 patients), with one patient with atrial tachycardia. Three patients had ventricular myocardial fibrosis, but with a volume < 0.6 cm 3 . None of them developed ventricular dysfunction and no patient had coronary lesions on angiography. CONCLUSION: Radiofrequency catheter ablation did not show to increase the risk of myocardial injury progression or coronary artery lesions.

FUNDAMENTO: As últimas décadas têm assistido ao rápido desenvolvimento do tratamento invasivo de arritmias por procedimentos de ablação por cateter. Apesar da sua segurança e eficácia bem estabelecida em adultos, até o momento, há poucos dados nos cenários pediátricos. Uma das principais preocupações é a possível expansão da cicatriz do procedimento de ablação nessa população e suas consequências ao longo dos anos. OBJETIVOS: Este estudo teve como objetivo analisar o risco da progressão da lesão miocárdica após ablação por cateter de radiofrequência em pacientes pediátricos. MÉTODOS: Este é um estudo retrospectivo de 20 pacientes pediátricos com tratamento prévio de arritmia supraventricular com ablação, submetidos à ressonância magnética cardíaca e angiografia coronária para avaliação de fibrose miocárdica e da integridade das artérias coronárias durante o acompanhamento. RESULTADOS: A idade mediana no procedimento de ablação foi 15,1 anos (Q1 12,9, Q3 16,6) e 21 anos (Q1 20, Q3 23) quando a ressonância magnética cardíaca foi realizada. Quatorze dos pacientes eram mulheres. Taquicardia por reentrada nodal e síndrome de Wolf-Parkinson-White foram os principais diagnósticos (19 pacientes), com um paciente com taquicardia atrial. Três pacientes apresentaram fibrose miocárdica ventricular, mas com um volume inferior a 0,6 cm 3 . Nenhum deles desenvolveu disfunção ventricular e nenhum paciente apresentou lesões coronarianos na angiografia. CONCLUSÃO: A ablação por cateter de radiofrequência não mostrou aumentar o risco de progressão de lesão miocárdica ou de lesões na artéria coronária.

Multitarget Compounds for Neglected Diseases: A Review.

Neglected diseases are a group of infectious diseases, many of them parasitic, that mainly affect the poorest populations with limited access to health services, especially those living in remote rural areas and slums. According to the World Health Organization (WHO), neglected diseases put the lives of more than 200 million people at risk, and treatment is made difficult by the occurrence of resistance to existing medications, as well as the high level of toxicity. In this way, the potential of multitarget compounds is highlighted, defined as compounds designed to modulate multiple targets of relevance to disease, with the overall goal of enhancing efficacy and/or improving safety. Thus, the objective of our study is to evaluate existing multi-target compound approaches for neglected diseases, with an emphasis on Leishmaniasis, Chagas Disease, and Arboviruses. A literature review was performed by searching the database "Web of Sciences". In relation to the diseases covered in this work, Leishmaniasis, individually, was the one that presented the largest number of articles (11) that dealt with the topic, which can be justi-fied by the high prevalence of this disease in the world, the second most common disease was Dengue, followed by Chagas disease, Chikungunya virus, and Zika virus. Furthermore, the multi-target potential of phenolic compounds was observed in all diseases under study, with the mecha-nisms related to the nucleus and transcription being the most reported mechanisms. From this per-spective, it is worth highlighting the effectiveness of approaches related to multitarget drugs in discovering new therapeutic agents for neglected diseases.

Inhibition of the morphological transition of Candida spp. by riparins I-IV.

Candida spp. is an opportunistic pathogen capable of causing superficial to invasive infections. Morphological transition is one of the main virulence factors of this genus and, therefore, is an important variable to be considered in pharmacological interventions. Riparins I, II, III, and IV are alkamide-type alkaloids extracted from the unripe fruit of Aniba riparia, whose remarkable pharmacological properties were previously demonstrated. This work aimed to evaluate in silico and in vitro the inhibitory effects of Riparins on the morphological transition of Candida albicans, Candida tropicalis, and Candida krusei. Molecular docking was applied to analyze the inhibitory effects of riparins against proteins such as N-acetylglucosamine, CYP-51, and protein kinase A (PKA) using the Ramachandran plot. The ligands were prepared by MarvinSketch and Spartan software version 14.0, and MolDock Score and Rerank Score were used to analyze the affinity of the compounds. In vitro analyses were performed by culturing the strains in humid chambers in the presence of riparins or fluconazole (FCZ). The morphology was observed through optical microscopy, and the size of the hyphae was determined using the ToupView software. In silico analysis demonstrated that all riparins are likely to interact with the molecular targets: GlcNAc (>50%), PKA (>60%), and CYP-51 (>70%). Accordingly, in vitro analysis showed that these compounds significantly inhibited the morphological transition of all Candida strains. In conclusion, this study demonstrated that riparins inhibit Candida morphological transition and, therefore, can be used to overcome the pathogenicity of this genus.

Three-year remission of metastatic breast cancer with treatment with ado-trastuzumab emtansine.

Globally, breast cancer is the most frequently diagnosed malignancy and the leading cause of oncological death in women. Metastatic disease at diagnosis (de novo stage IV breast cancer) will be identified in about 5% of patients. Treatment options vary based on several factors, namely whether the tumour is hormone receptor positive and whether human epidermal growth factor receptor 2 (HER2) is overexpressed. Here, we report a case of HER2 positive metastatic breast cancer on a woman in her late 30s, with remission for over 3 years under second-line treatment with ado-trastuzumab emtansine, with no significant toxicity and good tolerability. The timing to stop treatment under these circumstances presents a challenge and more data are needed to substantiate the decision to stop or maintain treatment in this small population.

HER2 Status in RAS and BRAF Wild-Type Metastatic Colorectal Cancer: A Portuguese Study.

INTRODUCTION: Colorectal cancer (CRC) is the second-most deadly cancer worldwide. However, there remains a scarcity of precision treatments available for this type of cancer. Amplification or overexpression of human epidermal growth factor receptor 2 (HER2+) is a well-established therapeutic target in gastric and breast cancer. HER2 is positive in approximately 5% of CRC cases and has been implicated in resistance to therapy with anti-epidermal growth factor receptor antibodies. The aim of this study was to evaluate HER2 status in RAS and BRAF wild-type metastatic CRC (mCRC) and its correlation with survival outcomes. MATERIALS AND METHODS: A single-center retrospective analysis of RAS and BRAF wild-type mCRC patients undergoing systemic treatment was conducted from July 2014 to September 2020. Tissue HER2 status was determined by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) and/or chromogenic in situ hybridization (CISH). HER2+ was defined as IHC3 (+) or IHC2 (+) through FISH or CISH (+). RESULTS: Fifty-nine patients were included. The median age of all the included patients was 64 years (33-82). Four patients had HER2+ tumors (7%). Four patients had HER2+ tumors (7%). The majority of HER2+ mCRC cases were males (n=3) and left-sided CRC (n=3). All patients received FOLFIRI plus cetuximab as first-line treatment. At the median follow-up of 24.0 months, patients with HER2-negative mCRC presented with a median overall survival (mOS) of 39.4 months (95% confidence interval (CI) 32.7-46.0) and the four patients with HER2+ mCRC had a mOS of 20.4 months (95% CI; 9.5-31.3; p=0.07). In HER2-negative patients, the median PFS (mPFS) was 11.3 months (95% CI; 9.2-13.4) vsHER2-positive patients with a mPFS of 10.9 months (95% CI; 1.3-20.4; p=0.47). CONCLUSIONS: To our knowledge, this is the first study reporting HER2+ in mCRC patients in a Portuguese population and the HER2+ rate was consistent with previous studies. Our study suggests that HER2+ may potentially be a marker that is able to predict poor prognosis in RAS and BRAF wild-type mCRC.

Adjuvant Hyperthermic Intravesical Chemotherapy in Intermediate- and High-Risk Non-muscle Invasive Bladder Cancer.

INTRODUCTION: Non-muscle invasive bladder cancer (NMIBC) is a frequently diagnosed neoplasm, which is typically managed with transurethral resection of bladder tumor (TURBT) eventually followed by intravesical therapies. Bacillus Calmette-Guérin (BCG) is used as first-line adjuvant treatment in high- (HR) and intermediate-risk (IR) NMIBC, although, in the latter, mitomycin C (MMC) may also be used. Multiple limitations to the use of BCG encouraged the search for therapeutic alternatives. In this context, hyperthermic intravesical chemotherapy with MMC (HIVEC-MMC) emerged as a promising therapy in the adjuvant setting for NMIBC. The aim of our study was to evaluate the tolerability, compliance, and survival outcomes of HIVEC-MMC in patients with IR- and HR-NMIBC. MATERIAL AND METHODS: This was a single-center retrospective analysis of IR- and HR- NMIBC patients who received HIVEC-MMC after TURBT between August 2018 and August 2022. Levels of risk stratification were defined using the European Association of Urology (EAU) criteria. The protocol consisted of four weekly HIVEC-MMC instillations (induction) followed by six monthly instillations (maintenance). The primary outcomes were to evaluate the tolerability and compliance with the HIVEC-MMC protocol and secondary outcomes were disease-free survival (DFS) and overall survival (OS). For the purpose of statistical analysis, methods of descriptive statistics, survival analysis (Kaplan-Meier estimation), and multivariate analysis (Cox regression, and binary logistic regression) were used. RESULTS: Fifty-seven patients were enrolled with a median age of 67.9 (34.4-83.5) years old. In this cohort, 40 patients (70.2%) had primary tumors. At the time of referral for HIVEC-MMC, the majority of the patients had IR-NMIBC (n= 33, 57.9%). A total of 41 patients (71.9%) completed the HIVEC-MMC protocol. Disease recurrence and adverse events (AEs) were the most common reasons to stop the protocol. After a median follow-up of 31 months (95% CI, 5.0-54.0), 32 patients (61.4%) were disease-free, 22 (38.6%) experienced recurrent disease and six patients (10.5%) died, although only one death was directly attributable to bladder cancer. The median DFS was 42 months (95% CI, 28.0-56.0). Completion of the HIVEC-MMC maintenance phase protocol stood as a predictive factor for DFS (44 months, 95% CI 29.1-58.9 vs. 14 months, 95% CI 0.0-29.6, p < 0.001; HR 4.48, 95% CI 1.65-12.15). The median OS was not reached; the 24- and 48-month OS were 92.6% and 82.7%, respectively. EAU risk group, ECOG-PS, and completion of HIVEC protocol were found to be significant predictive factors of OS but lost their significance on multivariate analysis. However, if we exclude those who experienced recurrence during the maintenance phase protocol, treatment completion had a significant positive impact on OS (HR: 42.8, 95% CI 1.75-1045.072, p= 0.021). CONCLUSIONS: Our study suggests that HIVEC is a secure and well-tolerated treatment with promising efficacy data, making this therapeutic approach a feasible option in IR- and HR-NMIBC patients, mainly in those who cannot tolerate or have contraindications to BCG therapy, but also as an alternative during BCG shortages.