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Aim: Aloysia citrodora has a long history of traditional use in treating various ailments. This study evaluated the in vivo chemopreventive efficacy and systemic toxicity of an extract of A. citrodora in a transgenic mouse model of HPV16 (human papillomavirus type 16)-induced cancer. Methods: The experiment involved six groups (n = 5): group 1 (G1, wild-type (WT), water), group 2 (G2, HPV, water), group 3 (G3, WT, 0.013 g/mL), group 4 (G4, HPV, 0.006 g/mL), group 5 (G5, HPV, 0.008 g/mL), and group 6 (G6, HPV, 0.013 g/mL). Throughout the assay, humane endpoints, body weight, food, and water consumption were recorded weekly. The internal organs and skin of the mice were collected for analysis after they were sacrificed. Toxicological parameters that were studied included hematological and biochemical blood markers, splenic and hepatic histology, and hepatic oxidative stress. Results: A. citrodora extract seems to reduce the incidence of dysplastic and in situ carcinoma skin lesions induced by HPV16 in this model, suggesting that dietary supplementation with concentrations of 0.008 g/mL and 0.013 g/mL may have beneficial chemopreventive effects. Conclusions: The extract did not induce any concentration-dependent toxicological effects on any of the parameters included in the study, indicating a favorable toxicological profile under these experimental conditions.

Venous thromboembolism (VTE) is a challenging clinical obstacle in oncological settings, marked by elevated incidence rates and resulting morbidity and mortality. In the context of cancer-associated thrombosis (CAT), endothelial dysfunction (ED) plays a crucial role in promoting a pro-thrombotic environment as endothelial cells lose their ability to regulate blood flow and coagulation. Moreover, emerging research suggests that this disorder may not only contribute to CAT but also impact tumorigenesis itself. Indeed, a dysfunctional endothelium may promote resistance to therapy and favour tumour progression and dissemination. While extensive research has elucidated the multifaceted mechanisms of ED pathogenesis, the genetic component remains a focal point of investigation. This comprehensive narrative review thus delves into the genetic landscape of ED and its potential ramifications on cancer progression. A thorough examination of genetic variants, specifically polymorphisms, within key genes involved in ED pathogenesis, namely eNOS, EDN1, ACE, AGT, F2, SELP, SELE, VWF, ICAM1, and VCAM1, was conducted. Overall, these polymorphisms seem to play a context-dependent role, exerting both oncogenic and tumour suppressor effects depending on the tumour and other environmental factors. In-depth studies are needed to uncover the mechanisms connecting these DNA variations to the pathogenesis of malignant diseases.

Chronic inflammation plays a crucial role in carcinogenesis. High levels of serum prostaglandin E2 and tissue overexpression of cyclooxygenase-2 (COX-2) have been described in breast, urinary, colorectal, prostate, and lung cancers as being involved in tumor initiation, promotion, progression, angiogenesis, and immunosuppression. Non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed for several medical conditions to not only decrease pain and fever but also reduce inflammation by inhibiting COX and its product synthesis. To date, significant efforts have been made to better understand and clarify the interplay between cancer development, inflammation, and NSAIDs with a view toward addressing their potential for cancer management. This review provides readers with an overview of the potential use of NSAIDs and selective COX-2 inhibitors for breast cancer treatment, highlighting pre-clinical in vitro and in vivo studies employed to evaluate the efficacy of NSAIDs and their use in combination with other antineoplastic drugs.

Distributed throughout the environment are various microorganisms such as bacteria, fungi, parasites, and viruses. Although many are part of the human microbiome, many are pathogenic and cause infections ranging from mild to severe. In recent years, the identification of multidrug-resistant microorganisms has become a serious public health problem. The resulting infections call into question the therapeutic capacity of health systems and lead to approximately 70,000 deaths annually worldwide. The progressive resistance to antibiotics and antifungals has been a major challenge for the medical and pharmaceutical community, requiring the search for new compounds with antimicrobial properties. Several studies have demonstrated the potential of natural and synthesized flavonoids, especially the dimers of these molecules. In this review are presented many examples of dimeric flavonoids that have demonstrated antimicrobial activity against viruses, like influenza and Human Immunodeficiency Virus (HIV), protozoal infections, such as Leishmaniasis and Malaria, fungal infections by Candida albicans and Cryptococcus neoformans, and bacterial infections caused, for example, by Staphylococcus aureus and Escherichia coli. In the pursuit to find potential safe agents for therapy in microbial infections, natural dimeric flavonoids are an option not only for the antimicrobial activity, but also for the low toxicity usually associated with these compounds when compared to classic antimicrobials.

Ovarian cancer (OC) is a leading cause of death among gynaecological malignancies. The haemostatic system, which controls blood flow and prevents clotting disorders, paradoxically drives OC progression while increasing the risk of venous thromboembolism (VTE). MicroRNAs (miRNAs) have emerged as crucial in understanding VTE pathogenesis. Exploring the connection between cancer and thrombosis through these RNAs could lead to novel biomarkers of cancer-associated thrombosis (CAT) and OC, as well as potential therapeutic targets for tumour management. Thus, this study examined the impact of eight plasma miRNAs targeting the tissue factor (TF) coagulation pathway—miR-18a-5p, -19a-3p, -20a-5p, -23a-3p, -27a-3p, -103a-3p, -126-5p and -616-3p—in 55 OC patients. Briefly, VTE occurrence post-OC diagnosis was linked to shorter disease progression time (log-rank test, p = 0.024) and poorer overall survival (OS) (log-rank test, p < 0.001). High pre-chemotherapy levels of miR-20a-5p (targeting coagulation factor 3 (F3) and tissue factor pathway inhibitor 2 (TFPI2)) and miR-616-3p (targeting TFPI2) predicted VTE after OC diagnosis (χ2, p < 0.05). Regarding patients’ prognosis regardless of VTE, miR-20a-5p independently predicted OC progression (adjusted hazard ratio (aHR) = 6.13, p = 0.005), while miR-616-3p significantly impacted patients’ survival (aHR = 3.72, p = 0.020). Further investigation is warranted for their translation into clinical practice.

Cancer patients, prone to severe COVID-19, face immune challenges due to their disease and treatments. Identifying biomarkers, particularly extracellular vesicle (EV)-derived microRNAs (miRNAs), is vital for comprehending their response to COVID-19 vaccination. Therefore, this study aimed to investigate specific EV-miRNAs in the plasma of cancer patients under active treatment who received the COVID-19 booster vaccine. The selected miRNAs (EV-hsa-miR-7-5p, EV-hsa-miR-15b-5p, EV-hsa-miR-24-3p, EV-hsa-miR-145- 5p, and EV-hsa-miR-223-3p) are involved in regulating SARS-CoV-2 spike protein and cytokine release, making them potential biomarkers for vaccination response. The study involved 54 cancer patients. Plasma and serum samples were collected at pre-boost vaccination, and at 3 and 6 months post-boost vaccination. Anti-spike antibody levels were measured. Additionally, RNA was extracted from EVs isolated from plasma and the expression levels of miRNAs were assessed. The results showed a significantly positive antibody response after COVID-19 boost vaccination. The expression levels of EV-hsa-miR-7-5p, EV-hsa-miR-15b-5p, EV-hsa-miR-24-3p, and EV-hsa-miR-223-3p increased significantly after 6 months of COVID-19 booster vaccination. Interestingly, an increased expression of certain EV-hsa-miRNAs was positively correlated. Bioinformatic analysis revealed that these correlated miRNAs play a critical role in regulating the targets present in antiviral responses and cytokine production. These findings suggest that EV-hsa-miR-15b-5p, EV-hsa-miR-24-3p, and EV-hsa-miR-223-3p may be crucial in immune response induced by mRNA vaccines.

Vitis vinifera is the grape variety used in the production of wine and other products. In the wine production process, many of the vine’s by-products are wasted, namely seeds and stems. Given the proportion of wine production worldwide, the quantity of by-products is beginning to be an environmental problem, making it urgent to take measures for their use to obtain bioactive compounds with health benefits. The aim of this work was to study the antioxidant and antimicrobial activities of extracts from the seeds and stems of four Portuguese grape varieties: Touriga Franca, Touriga Nacional, Viosinho, and Tinta Roriz. Total phenolic (TPC) and total flavonoids (TFC) contents present in the different extracts were evaluated, as well as the antioxidant activity, by DPPH and FRAP methods. TPC and TFC values of the stem’s extracts are much higher than those of the seeds of the same grape variety in the same solvent. The antioxidant activity of aqueous and ethanolic stem extracts is higher than that obtained for the seeds, showing that antioxidant activity is related to the content of polyphenols. The antimicrobial activity of different stem and seed extracts was determined against yeasts and Gram-positive and Gram-negative bacteria, and the effect was determined based on the minimal inhibitory concentrations calculated (MIC). In general, the ethanol:water (1:1) extract of the seeds from the different varieties tested inhibited C. albicans ATCC10231 and C. krusei ATCC6258 growth even at 200 μg/mL, and the effect was fungicidal at 200 μg/mL. The same type of extract showed selective antimicrobial activity, inhibiting S. aureus ATCC29213 growth but having no effect against E. coli ATCC25922 even at 200 μg/mL. The effect against S. aureus was bactericidal (at 200 μg/mL) for Touriga Franca, Touriga Nacional, and Viosinho. Taking all these results into account, it can be concluded that the by-products of the grape varieties tested are important sources of bioactive products, particularly as antioxidants and antimicrobials.

Human papillomavirus (HPV)-associated cervical cancer is the most common cancer among women worldwide. The treatment options are strongly related to increased infertility in women. Imiquimod (IQ) is an imidazoquinoline, which has proven antiviral effects against persistent HPV infection by activating immune cells via Toll-like receptors 7/8 when formulated in carriers, like nanogels, for topical use. An effective alternative to conventional therapies is the nanoparticle drug delivery system. We studied lipidic nanoparticles with IQ (Lipo IQ) and functionalized them with a DNA aptamer, AT11 (Lipo IQ AT11), to improve the selectivity for cervical cancer cells combined with the efficacy of essential oils. The formulations showed that the physicochemical properties are adequate for vaginal drug delivery and have antimicrobial activity at higher concentrations (with MIC50 starting from 0.625%). The final formulations exhibited cytotoxicity in cancer cells, enhanced by essential oils without affecting healthy cells, resulting in less than 10% cell viability in HeLa cells and over 60% in NHDF cells. Essential oils potentiate Lipo IQ’s effectiveness, while AT11 increases the selectivity for cervical cancer cells. As suggested by the results of the permeation assay, the formulations were internalized by the cancer cells. Overall, the obtained results suggested that the synergistic effect of the essential oils and the nanosystem potentiate the cytotoxic effect of Lipo IQ and that Lipo IQ AT11 promotes selectivity towards cancer cells.

Cancer-associated cachexia is a multifactorial syndrome characterised by systemic inflammation and hypermetabolism that affects different tissues and organs. Is characterised by progressive and irreversible weight loss, mainly due to skeletal muscle wasting and often accompanied by loss of fat mass. Due to its complexity, and lack of effective treatment, this syndrome is a sign of poor prognosis in cancer patients. Cellular models constitute a valuable and powerful tool offering insights into the molecular pathways and cellular responses associated with cancer cachexia. Currently, there are robust and widely used cell lines used to establish models to study the pathophysiology of muscle wasting and adipose tissue loss. Various methods can be used to induce the cachectic phenotype in the cells, utilising genetic engineering or different inducing agents such as hormones, inflammatory factors and chemotherapeutic drugs. The available experimental data on their metabolic properties and transcriptional and proteomic profiles allows the selection of the most suitable research model to replicate the relevant aspects of cachexia. In this review, we make an overview of the in vitro models used to study biological aspects of cancer-associated cachexia and analyse their strengths and limitations in replicating the complex physiological environment and pathological processes of the syndrome. Herein, we also briefly approach the difficulty of modelling the contribution of different organs and crosstalk between different tissues.

Ovarian cancer (OC) is the deadliest gynaecological malignancy. Identifying new prognostic biomarkers is an important research field. Haemostatic components together with leukocytes can drive cancer progression while increasing the susceptibility to venous thromboembolism (VTE) through immunothrombosis. Unravelling the underlying complex interactions offers the prospect of uncovering relevant OC prognostic biomarkers, predictors of cancer-associated thrombosis (CAT), and even potential targets for cancer therapy. Thus, this study evaluated the expression of F3, F5, F8, F13A1, TFPI1, and THBD in peripheral blood cells (PBCs) of 52 OC patients. Those with VTE after tumour diagnosis had a worse overall survival (OS) compared to their counterparts (mean OS of 13.8 ± 4.1 months and 47.9 ± 5.7 months, respectively; log-rank test, p = 0.001). Low pre-chemotherapy F3 and F8 expression levels were associated with a higher susceptibility for OC-related VTE after tumour diagnosis (χ2, p < 0.05). Regardless of thrombogenesis, patients with low baseline F8 expression had a shorter progression-free survival (PFS) than their counterparts (adjusted hazard ratio (aHR) = 2.54; p = 0.021). Among those who were not under platelet anti-aggregation therapy, low F8 levels were also associated with a shorter OS (aHR = 6.16; p = 0.006). Moving forward, efforts should focus on external validation in larger cohorts.

P-glycoprotein (P-GP) is a transporter molecule expressed on the apical surface of capillary endothelial cells of the Blood–Brain Barrier (BBB), whose activity heavily influences drug distribution, including antidepressants. This transporter is encoded by ABCB1 gene, and genetic variations within ABCB1 gene have been proposed to affect drug efflux and have been previously associated with depression. In this context, we aimed to evaluate the role of C1236T, G2677TA and C3435T ABCB1 genetic polymorphisms in antidepressant treatment phenotypes from a cohort of patients harboring Major Depressive Disorder. Patients enrolled in the study consisted of 80 individuals with Major Depressive Disorder, who took part in a 27-month follow-up study at HML, Portugal. To investigate the correlation between ABCB1 polymorphisms and antidepressant response phenotypes, DNA was extracted from peripheral blood, and C1236T, C3435T and G2677TA polymorphisms were genotyped with TaqMan® SNP Genotyping Assays. Despite the fact that the evaluated polymorphisms (C1236T, C3435T and G2677TA) were not associated with treatment resistant depression, or relapse, we observed that patients carrying TT genotype of the C3435T polymorphism remit earlier than the ones carrying CC or CT genotypes (10.2 weeks vs. 14.9 and 21.3, respectively, p = 0.028, Log-rank test). Since we found an association with C3435T and time to remission, and not to the absence of remission, we suggest that this polymorphism could have an impact on antidepressant drug distribution, and thus influence on the time to remission will occur, without influencing the risk of remission itself.

Mycoses are one of the major causes of morbidity/mortality among immunocompromised individuals. Considering the importance of these infections, the World Health Organization (WHO) defined a priority list of fungi for health in 2022 that include Candida albicans as belonging to the critical priority group and Pichia kudriavzevii (Candida krusei) to the medium priority group. The existence of few available antifungal drugs, their high toxicity, the acquired fungal resistance, and the appearance of new species with a broader spectrum of resistance, points out the need for searching for new antifungals, preferably with new and multiple mechanisms of action. The cyclam salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 was previously tested against several fungi and revealed an interesting activity, with minimal inhibitory concentration (MIC) values of 8 µg/mL for C. krusei and of 128 µg/mL for C. albicans. The main objective of the present work was to deeply understand the mechanisms involved in its antifungal activity. The effects of the cyclam salt on yeast metabolic viability (resazurin reduction assay), yeast mitochondrial function (JC-1 probe), production of reactive oxygen species (DCFH-DA probe) and on intracellular ATP levels (luciferin/luciferase assay) were evaluated. H4[H2(4-CF3PhCH2)2Cyclam]Cl4 induced a significant decrease in the metabolic activity of both C. albicans and C. krusei, an increase in Reactive Oxygen Species (ROS) production, and an impaired mitochondrial function. The latter was observed by the depolarization of the mitochondrial membrane and decrease in ATP intracellular levels, mechanisms that seems to be involved in the antifungal activity of H4[H2(4-CF3PhCH2)2Cyclam]Cl4. The interference of the cyclam salt with human cells revealed a CC50 value against HEK-293 embryonic kidney cells of 1.1 μg/mL and a HC10 value against human red blood cells of 0.8 μg/mL.

Abstract Venous thromboembolism (VTE) is a leading cause of death among cancer patients. Khorana score (KS) is the most studied tool to predict cancer-related VTE, however, it exerts poor sensitivity. Several single-nucleotide polymorphisms (SNPs) have been associated with VTE risk in the general population, but whether they are predictors of cancer-related VTE is a matter of discussion. Compared to other solid tumours, little is known about VTE in the setting of cervical cancer (CC) and whether thrombogenesis-related polymorphisms could be valuable biomarkers in patients with this neoplasia. This study aims to analyse the effect of VTE occurrence on the prognosis of CC patients, explore the predictive capability of KS and the impact of thrombogenesis-related polymorphisms on CC-related VTE incidence and patients’ prognosis regardless of VTE. A profile of eight SNPs was evaluated. A retrospective hospital-based cohort study was conducted with 400 CC patients under chemoradiotherapy. SNP genotyping was carried on by using TaqMan® Allelic Discrimination methodology. Time to VTE occurrence and overall survival were the two measures of clinical outcome evaluated. The results indicated that VTE occurrence (8.5%) had a significant impact on the patient’s survival (log-rank test, P

Abstract Viruses are pathogenic agents responsible for approximately 10% of all human cancers and significantly contribute to the global cancer burden. Until now, eight viruses have been associated with the development of a broad range of malignancies, including solid and haematological tumours. Besides triggering and promoting oncogenesis, viral infections often go hand-in-hand with haemostatic changes, representing a potential risk factor for venous thromboembolism (VTE). Conversely, VTE is a cardiovascular condition that is particularly common among oncological patients, with a detrimental impact on patient prognosis. Despite an association between viral infections and coagulopathies, it is unclear whether viral-driven tumours have a different incidence and prognosis pattern of thromboembolism compared to non-viral-induced tumours. Thus, this review aims to analyse the existing evidence concerning the association of viruses and viral tumours with the occurrence of VTE. Except for hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection, which are associated with a high risk of VTE, little evidence exists concerning the thrombogenic potential associated with oncoviruses. As for tumours that can be induced by oncoviruses, four levels of VTE risk are observed, with hepatocellular carcinoma (HCC) and gastric carcinoma (GC) associated with the highest risk and nasopharyngeal carcinoma (NPC) associated with the lowest risk. Unfortunately, the incidence of cancer-related VTE according to tumour aetiology is unknown. Given the negative impact of VTE in oncological patients, research is required to better understand the mechanisms underlying blood hypercoagulability in viral-driven tumours to improve VTE management and prognosis assessment in patients diagnosed with these tumours.

Traumatic muscle injuries (TMIs) and muscle pain (MP) negatively impact athletes’ performance and quality of life. Both conditions have a complex pathophysiology involving the interplay between genetic and environmental factors. Yet, the existing data are scarce and controversial. To provide more insights, this study aimed to investigate the association of single-nucleotide polymorphisms (SNPs) previously linked to athletic status with TMI and MP after exercise among Brazilian high-performance athletes from different sports modalities (N = 345). The impact of important environmental determinants was also assessed. From the six evaluated SNPs (ACTN3 rs1815739, FAAH rs324420, PPARGC1A rs8192678, ADRB2 rs1042713, NOS3 rs1799983, and VDR rs731236), none was significantly associated with TMI. Regarding MP after exercise, ACTN3 rs1815739 (CC/CT vs. TT; adjusted odds ratio (aOR) = 1.90; 95% confidence interval (95%Cl), 1.01–3.57) and FAAH rs324420 (AA vs. AC/CC; aOR = 2.30; 95%Cl, 1.08–4.91) were independent predictors according to multivariate binomial analyses adjusted for age (≥23 vs. ACTN3 rs1815739 and FAAH rs324420. This could have implications for prophylactic interventions to improve athletes’ quality of life.

The importance of fungal infections, particularly those caused by yeasts, is increasing among the medical community. Candida albicans and Cryptococcus neoformans are amongst the high-priority fungal species identified by the World Health Organization (WHO) and are considered in the critical group, while Candida krusei is included in the medium-priority group. The cyclam salt H4[H2(4-CF3PhCH2)2Cyclam]Cl4 proved to be active against the growth of these three yeasts, and the aim of this work was to verify its interference with their virulence mechanisms, whether shared or unique. H4[H2(4-CF3PhCH2)2Cyclam]Cl4 significantly inhibited biofilm production and catalase activity, being able to interfere with C. albicans dimorphic transition and C. neoformans melanin production. At the minimal inhibitory concentration (MIC) values, H4[H2(4-CF3PhCH2)2Cyclam]Cl4 had no antioxidant effect, as determined by the DPPH method. When using the RAW264.7 macrophage cell line, H4[H2(4-CF3PhCH2)2Cyclam]Cl4 reduced nitric oxide (NO) detection (the Griess reaction), but this effect was associated with a significant toxic effect on the cells.

Ovarian cancer (OC) is the female genital malignancy with the highest lethality. Patients present a poor prognosis mainly due to the late clinical presentation allied with the common acquisition of chemoresistance and a high rate of tumour recurrence. Effective screening, accurate diagnosis, and personalised multidisciplinary treatments are crucial for improving patients’ survival and quality of life. This comprehensive narrative review aims to describe the current knowledge on the aetiology, prevention, diagnosis, and treatment of OC, highlighting the latest significant advancements and future directions. Traditionally, OC treatment involves the combination of cytoreductive surgery and platinum-based chemotherapy. Although more therapeutical approaches have been developed, the lack of established predictive biomarkers to guide disease management has led to only marginal improvements in progression-free survival (PFS) while patients face an increasing level of toxicity. Fortunately, because of a better overall understanding of ovarian tumourigenesis and advancements in the disease’s (epi)genetic and molecular profiling, a paradigm shift has emerged with the identification of new disease biomarkers and the proposal of targeted therapeutic approaches to postpone disease recurrence and decrease side effects, while increasing patients’ survival. Despite this progress, several challenges in disease management, including disease heterogeneity and drug resistance, still need to be overcome.

Ischaemic stroke (IS) and venous thromboembolism (VTE) are two forms of thromboembolism that, although distinct, seem to share numerous risk factors. Concerning genetic risk factors, while many VTE genetic markers have been reported, inclusively by genome-wide association studies (GWAS), the identification and validation of genetic determinants underlying IS pathogenesis have been challenging. Considering that IS and VTE shared biological pathways and aetiological factors, the severity of IS might be also influenced by VTE-related genetic variants. Thus, the present study was designed to analyse the impact of six VTE GWAS-identified genetic variants on the clinical outcome of 363 acute IS patients. Results revealed that the single-nucleotide polymorphism (SNP) F11 rs4253417 was an independent predictor of the 5-year risk of death among patients with total anterior circulation infarct (TACI). Namely, the ones carrying the SNP C allele presented a fourfold increase in the 5-year risk of death compared to TT genotype carriers (CC/CT vs. TT; adjusted HR, 4.240; 95% CI, 1.260–14.270; P = 0.020). This SNP is known to be associated with coagulation factor XI (FXI) levels, thus with implications in haemostasis and inflammation. As such, F11 rs4253417 might be a promising prognostic biomarker among TACI patients to aid in clinical decision-making. However, additional investigation is required to confirm the study's results and dissect the underlying mechanisms.

Abstract Increasing evidence supports a role for local fat depots in cancer outcomes. Despite the robust positive association of obesity with renal cell carcinoma (RCCa) diagnosis, increased adiposity is inversely related to RCCa oncological outcomes. Here, we sought to ascertain whether imagiologically assessed local fat depots associate with RCCa progression and survival and account for this apparent paradox. A retrospective cohort of renal carcinoma patients elective for nephrectomy (n = 137) were included. Beyond baseline clinicopathological characteristics, computed tomography (CT)-scans at the level of renal hilum evaluated areas and densities of different adipose tissue depots (perirenal, subcutaneous, visceral) and skeletal muscle (erector spinae, psoas and quadratus lumborum muscles) were analyzed. Univariate and multivariable Cox proportional hazards models were estimated following empirical analysis using stepwise Cox regression. Age, visceral adipose tissue (VAT) area and body mass index (BMI) predicted tumour-sided perirenal fat area (R 2 = 0.584), which presented upregulated UCP1 expression by 27-fold (P = 0.026) and smaller adipocyte areas, compared with subcutaneous depot. Multivariate analyses revealed that increased area of perirenal adipose tissue (PRAT) on the contralateral and tumour side associate with improved progression-free survival (HR = 0.3, 95CI = 0.1–0.8, P = 0.019) and overall survival (HR = 0.3, 95CI = 0.1–0.7, P = 0.009). PRAT measurements using CT, might become a possible tool, well correlated with other measures of obesity such as VAT and BMI, that will improve determination of obesity and contribute to assess the risk for disease progression and mortality in renal cancer patients. Present data supports the obesity paradox in RCCa, assumed that larger PRAT areas seem to protect from disease progression and death.

Inflammation is a key factor in cancer promotion. Tumor-associated macrophages (TAMs), as part of the tumor microenvironment, are often associated with the progression of tumors and a worse prognosis in many cancers, namely on cervical cancer. This work exhaustively summarizes the conclusions of the different studies published concerning TAMs function in cervical cancer, from in vitro studies using cancer cell lines to the clinical perspective (histological samples-based studies). Most studies have led to the conclusion that TAMs increased density is directly related to increased severity of a malignant cervical lesion. Additionally, TAMs are normally polarized into an M2 phenotype, benefiting and promoting tumor progression, resulting in a worse disease outcome. The tumor microenvironment is also a highly critical contributor that not only influences tumor natural history but also modulates the specific immune response.

Summary: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett’s oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Funding: German Research Foundation (DFG).

Papillomaviruses are small viruses able to cause disease not only in mammalians, but also in birds and reptiles. In recent years, a rising number of papillomaviruses have been identified in dogs and cats, totaling 24 canine papillomavirus (CPV) and six feline papillomavirus (FcaPV). The canine and feline papillomaviruses (CPVs and FcaPVs, respectively) are responsible for multiple lesions in these domestic species but the potential pathological relevance of some recently identified types remains to be determined. CPVs are associated with oral papillomatosis, cutaneous papillomas and viral pigmented plaques, and have been rarely associated with the development of oral and cutaneous squamous cell carcinomas in their canine hosts. FcaPVs are associated with oral papillomas, viral plaques, and Bowenoid in situ carcinomas. The present review provides readers with the more recent advances on dog and cat papillomavirus research, bringing an update on this field to both veterinary practitioners and the virology community at large.

Ovarian cancer (OC) and venous thromboembolism (VTE) have a close relationship, in which tumour cells surpass the haemostatic system to drive cancer progression. Long non-coding RNAs (lncRNAs) have been implicated in VTE pathogenesis, yet their roles in cancer-associated thrombosis (CAT) and their prognostic value are unexplored. Understanding how these lncRNAs influence venous thrombogenesis and ovarian tumorigenesis may lead to the identification of valuable biomarkers for VTE and OC management. Thus, this study evaluated the impact of five lncRNAs, namely MALAT1, TUG1, NEAT1, XIST and MEG8, on a cohort of 40 OC patients. Patients who developed VTE after OC diagnosis had worse overall survival compared to their counterparts (log-rank test, p = 0.028). Elevated pre-chemotherapy MEG8 levels in peripheral blood cells (PBCs) predicted VTE after OC diagnosis (Mann–Whitney U test, p = 0.037; Χ2 test, p = 0.033). In opposition, its low levels were linked to a higher risk of OC progression (adjusted hazard ratio (aHR) = 3.00; p = 0.039). Furthermore, low pre-chemotherapy NEAT1 levels in PBCs were associated with a higher risk of death (aHR = 6.25; p = 0.008). As for the remaining lncRNAs, no significant association with VTE incidence, OC progression or related mortality was observed. Future investigation with external validation in larger cohorts is needed to dissect the implications of the evaluated lncRNAs in OC patients.

Nanomedicine’s advent has promised to revolutionize different biomedical fields, including oncology. Silver Nanoparticles (AgNPs) showed promising results in different tumor models. Clear cell Renal Cell Carcinoma (ccRCC) is especially challenging due to its late diagnosis, poor prognosis and treatment resistance. Therefore, defining new therapeutic targets and regimens could improve patient management. This study intends to evaluate AgNPs’ effect in ccRCC cells and explore their potential combinatory effect with Everolimus and Radiotherapy. AgNPs were synthesized, and their effect was evaluated regarding their entering pathway, cellular proliferation capacity, ROS production, mitochondrial membrane depolarization, cell cycle analysis and apoptosis assessment. AgNPs were combined with Everolimus or used to sensitize cells to radiotherapy. AgNPs are cytotoxic to 786-O cells, a ccRCC cell line, entering through endocytosis, increasing ROS, depolarizing mitochondrial membrane, and blocking the cell cycle, leading to a reduction of proliferation capacity and apoptosis. Combined with Everolimus, AgNPs reduce cell viability and inhibit proliferation capacity. Moreover, 786-O is intrinsically resistant to radiation, but after AgNPs’ administration, radiation induces cytotoxicity through mitochondrial membrane depolarization and S phase blockage. These results demonstrate AgNPs’ cytotoxic potential against ccRCC and seem promising regarding the combination with Everolimus and sensitization to radiotherapy, which can, in the future, benefit ccRCC patients’ management.

Gene variation linked to physiological functions is recognised to affect elite athletic performance by modulating training and competition-enabling behaviour. The fatty acid amide hydrolase (FAAH) has been investigated as a good candidate for drug targeting, and recently, its single-nucleotide polymorphism (SNP) rs324420 was reported to be associated with athletic performance. Given the implications, the biological pathways of this genetic polymorphism linked to elite athletic performance, considering sport type, psychological traits and sports injuries, need to be dissected. Thus, a narrative review of the literature concerning the biological mechanisms of this SNP was undertaken. In addition to its role in athletic performance, FAAH rs324420 is also involved in important mechanisms underlying human psychopathologies, including substance abuse and neural dysfunctions. However, cumulative evidence concerning the C385A variant is inconsistent. Therefore, validation studies considering homogeneous sports modalities are required to better define the role of this SNP in elite athletic performance and its impact on stress coping, pain regulation and inflammation control.

BackgroundPsychosocial stress and depressive disorder have been associated with cancer as putative contributors to worse prognosis. On the other hand, cancer diagnosis is a recognised life event that can contribute to distress and depressive states. Humoral and cellular inflammation can promote depressive disorder by means of decreased monoamine synthesis, glutamate neurotoxicity, neurogenesis and neuroplasticity, dysregulated hypothalamic-pituitary-adrenal axis, and glucocorticoid resistance. This protocol objectives are to observe the interactions between psychosocial variables and biochemical and immunological biomarkers in a longitudinal, prospective design; to identify inflammation-related depression endophenotypes in breast cancer patients and to understand if early diagnosed and treated depression in this population will translate in better inflammation status and better global prognosis.MethodsProspective observational cohort, composed by 100 consecutive premenopausal patients, diagnosed with non-distant metastatic breast carcinoma and with no history of major psychopathology or other organic illness. The participants will have an in-person assessment in three different moments, along illness treatment and follow-up, with respect to cytometric, immunologic, and psychosocial parameters and will be tested for depression vulnerability and resilience inflammation-related functional genetic polymorphisms. Additionally, at years 5 and 10 post enrollment, patients`medical records will be assessed. As a control cohort, all patients excluded due to psychiatric history or past psychiatric treatments will have their clinical records assessed at years 5 and 10 after admission. All the data will be managed with the SPSS® software.Discussion and conclusionThis study is an original longitudinal cohort of breast cancer premenopausal patients, with a comprehensive approach to psychosocial, clinical, inflammatory, and genetic variables. It expects to provide evidence regarding the links between genetic, cytometric, immunologic, and psychosocial factors, their potential contribution to the pathophysiology of depressive disorder, breast cancer course, progression, and prognosis. It may further contribute with data to better efficacy of the psycho-oncological interventions.Trial registrationNational Commission of Data Protection (CNPD) 13413/2017; Ethics Committee of IPOP project code CI-IPOP81/2017.

Abstract Objectives The aim of this systematic review and meta-analysis is to the summarize the evidence on programmed cell death protein ligand 1 (PD-L1) in Epstein-Barr virus associated gastric cancer (EBVaGC) and to estimate the expression rate of PD-L1 among this subtype of Gastric Cancer (GC). Materials and methods For this study, PubMed®, EMBASE® and Web of Science® databases were searched for articles published until 1st November 2021. A total of 43 eligible publications with a total of 11,327 patients were included analysis based on inclusion and exclusion criteria. A total of 41 publications present data for proportion estimation and 33 for comparison of PD-L1 between EBV positive and negative GC. DerSimonian-Laird random-effects model was used for meta-analysis. Results The analysis showed that in EBVaGC the pooled positivity rate for PD-L1 was 54.6% (p

The BDNF gene is associated with high degrees of variability in antidepressant treatments. The Val66Met polymorphism is widely known as a source of this variability, warranting growing interest in genotyping patients that undergo antidepressant treatment to better suit their needs. This paper reports on an electrochemical genosensing platform, based on gold electrodes, capable of detecting this polymorphism, through the use of synthetic enzymatically labeled DNA probes for two different BDNF alleles. The sensor showed promising results, and its applicability to real samples is currently being tested.

Human papillomavirus (HPV) infection is a necessary but not sufficient factor for the development of invasive cervical cancer (ICC) and high-grade intraepithelial lesion (HSIL). Oxidative stress is known to play a crucial role in HPV infection and carcinogenesis. In this study, we comprehensively investigate the modulation of HPV infection, HSIL and ICC, and ICC through an exploration of oxidative stress-related genes: CβS, MTHFR, NOS3, ACE1, CYBA, HAP, ACP1, GSTT1, GSTM1, and CYP1A1. Notably, the ACE1 gene emerges as a prominent factor with the presence of the I allele offering protection against HPV infection. The association of NOS3 with HPV infection is perceived with the 4a allele showing a protective effect. The presence of the GSTT1 null mutant correlates with increased susceptibility to HPV infection, HSIL and ICC, and ICC. This study also uncovers intriguing epistatic interactions among some of the genes that further accentuate their roles in disease modulation. Indeed, the epistatic interactions between the BB genotype (ACP1) and DD genotype (ECA1) were shown to increase the risk of HPV infection, and the interaction between BB (ACP1) and 0.0 (GSTT1) was associated with HPV infection and cervical lesions. These findings underscore the pivotal role of four oxidative stress-related genes in HPV-associated cervical lesions and cancer development, enriching our clinical understanding of the genetic influences on disease manifestation. The awareness of these genetic variations holds potential clinical implications.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provoked a global pandemic identified as coronavirus disease (COVID-19), with millions of deaths worldwide. However, several important questions regarding its impact on public health remain unanswered, such as the impact of vaccination on vulnerable subpopulations such as cancer patients. Cytokine storm and a sustained inflammatory state are commonly associated with immune cell depletion, being manifested in most immunocompromised individuals. This strong immunosuppression can lead to a dysfunctional antiviral response to natural viral infection and compromised vaccination response. Extracellular vesicles (EVs) are membrane-bound vesicles released from cells that are involved in intercellular communication. EVs carry various molecules including microRNAs that play a crucial role in COVID-19 pathophysiology, influencing cellular responses. This review summarizes the state of the art concerning the role of EV-derived miRNAs in COVID-19 infection and their potential use as prognosis biomarkers for vaccination response in cancer patients.

High-risk human papillomavirus (HPV) is etiologically related to cervical cancer, other anogenital cancers and oropharyngeal carcinomas. Low-risk HPV, especially HPV6 and HPV11, cause genital warts and laryngeal papillomas. However, the accumulating data suggests that HPV6 and HPV11 may cause malignant lesions at non-cervical anatomic sites. This review aims to estimate the proportions of single and dual HPV6/11 infections in multiple cancers reported in the last 10 years in the Cochrane, Embasa and PubMed databases. Secondly, the genomes of HPV6/11 were compared with the most common high-risk genotype, HPV16, to determine the similarities and differences. A total of 11 articles were selected, including between one and 334 HPV+ cancer patients. The frequencies of single or dual HPV6/11 infections ranged between 0–5.5% for penile and 0–87.5% for laryngeal cancers and were null for vulvar, vaginal and oral cancers. The genomic similarities between HPV6/11 and HPV16 mainly involved the E7 gene, indicating a limited ability to block cell differentiation. The presence of single or dual HPV6/11 infections in variable proportions of penile and laryngeal cancers support the vaccination strategies that cover these genotypes, not only for preventing genital warts but also for cancer prevention. Other risk factors and co-carcinogens are likely to participate in epithelial carcinogenesis associated with low-risk HPV.

Venous thromboembolism (VTE), a common condition in Western countries, is a cardiovascular disorder that arises due to haemostatic irregularities, which lead to thrombus generation inside veins. Even with successful treatment, the resulting disease spectrum of complications considerably affects the patient’s quality of life, potentially leading to death. Cumulative data indicate that long non-coding RNAs (lncRNAs) may have a role in VTE pathogenesis. However, the clinical usefulness of these RNAs as biomarkers and potential therapeutic targets for VTE management is yet unclear. Thus, this article reviewed the emerging evidence on lncRNAs associated with VTE and with the activity of the coagulation system, which has a central role in disease pathogenesis. Until now, ten lncRNAs have been implicated in VTE pathogenesis, among which MALAT1 is the one with more evidence. Meanwhile, five lncRNAs have been reported to affect the expression of TFPI2, an important anticoagulant protein, but none with a described role in VTE development. More investigation in this field is needed as lncRNAs may help dissect VTE pathways, aiding in disease prediction, prevention and treatment.

Genetic variants are recognized to affect athletic performance, partially by modulating competition-facilitating behavior. In this study, the role of three genetic variants previously linked to athlete status was investigated among elite volleyball players. A total of 228 players (26.7 ± 8.1 years old) participating in the Portuguese championship and with multiple medalists in national and international competitions were evaluated in terms of anthropometrics, training regime, sports experience, and a history of sports lesions. SNP genotyping was conducted by means of TaqMan® Allelic Discrimination Methodology. Volleyball players showed significantly different anthropometric indicators and training habits according to sex (p < 0.05). The A allele of the genetic variant Fatty Acid Amide Hydrolase (FAAH) rs324420 (C385A) was shown to be significantly associated with superior athletic achievements under a dominant genetic model (AA/AC vs. CC, odds ratio (OR) = 1.70; 95% Cl, 0.93–3.13; p = 0.026; p < 0.001 after Bootstrap), which was corroborated by a multivariable analysis (AA/AC vs. CC adjusted OR = 2.00; 95% Cl, 1.04–3.82; p = 0.037). Age and hand length were also found to be independently associated with high-level performance (p < 0.05). Our results confirm the role of FAAH in athletic performance. More investigation into this polymorphism’s potential impact on stress coping, pain, and inflammation regulation in sport, particularly in the scope of lesions prevention and treatment, is required.

Breast cancer is one of the most common and well-known types of cancer among women worldwide and is the most frequent neoplasm in intact female dogs. Female dogs are considered attractive models or studying spontaneous breast cancer, whereas female rats are currently the most widely used animal models for breast cancer research in the laboratory context. Both female dogs and female rats have contributed to the advancement of scientific knowledge in this field, and, in a “One Health” approach, they have allowed broad understanding of specific biopathological pathways, influence of environmental factors and screening/discovery of candidate therapies. This review aims to clearly showcase the similarities and differences among woman, female dog and female rat concerning to anatomical, physiological and histological features of the mammary gland and breast/mammary cancer epidemiology, in order to better portray breast tumorigenesis, and to ensure appropriate conclusions and extrapolation of results among species. We also discuss the major aspects that stand out in these species. The mammary glands of female dogs and women share structural similarities, especially with respect to the lactiferous ducts and lymphatic drainage. In contrast, female rats have only one lactiferous duct per nipple. A comprehensive comparison between humans and dogs is given a special focus, as these species share several aspects in terms of breast/mammary cancer epidemiology, such as age of onset, hormonal etiology, risk factors, and the clinical course of the disease. Holistically, it is clear that each species has advantages and limitations that researchers must consider during the development of experimental designs and data analysis.

Prostate cancer (PCa) is one of the most common malignancies among men worldwide. Inevitably, all advanced PCa patients develop metastatic castration-resistant prostate cancer (mCRPC), an aggressive phase of the disease. Treating mCRPC is challenging, and prognostic tools are needed for disease management. MicroRNA (miRNA) deregulation has been reported in PCa, constituting potential non-invasive prognostic biomarkers. As such, this study aimed to evaluate the prognostic potential of nine miRNAs in the liquid biopsies (plasma) of mCRPC patients treated with second-generation androgen receptor axis-targeted (ARAT) agents, abiraterone acetate (AbA) and enzalutamide (ENZ). Low expression levels of miR-16-5p and miR-145-5p in mCRPC patients treated with AbA were significantly associated with lower progression-free survival (PFS). The two miRNAs were the only predictors of the risk of disease progression in AbA-stratified analyses. Low miR-20a-5p levels in mCRPC patients with Gleason scores of

A deeper understanding of the communication mechanisms of tumor cells in a tumor microenvironment can improve the development of new therapeutic solutions, leading to a more personalized approach. Recently, the field of extracellular vesicles (EVs) has drawn attention due to their key role in intercellular communication. EVs are nano-sized lipid bilayer vesicles that are secreted by all types of cells and can function as intermediators of intercellular communication with the ability to transfer different cargo (proteins, nucleic acids, sugar…) types among cells. This role of EVs is essential in a cancer context as it can affect tumor promotion and progression and contribute to the pre-metastatic niche establishment. Therefore, scientists from basic, translational, and clinical research areas are currently researching EVs with great expectations due to their potential to be used as clinical biomarkers, which are useful for disease diagnosis, prognosis, patient follow-up, or even as vehicles for drug delivery due to their natural carrier nature. The application of EVs presents numerous advantages as drug delivery vehicles, namely their capacity to overcome natural barriers, their inherent cell-targeting properties, and their stability in the circulation. In this review, we highlight the distinctive features of EVs, their application as efficient drug delivery systems, and their clinical applications.

This study aimed to investigate the influence of genetic variants in neuroplasticity-related genes on antidepressant treatment phenotypes. The BDNF-TrkB signaling pathway, as well as the downstream kinases Akt and ERK and the mTOR pathway, have been implicated in depression and neuroplasticity. However, clinicians still struggle with the unpredictability of antidepressant responses in depressed patients. We genotyped 26 polymorphisms in BDNF, NTRK2, NGFR, CREB1, GSK3B, AKT, MAPK1, MTOR, PTEN, ARC, and SYN1 in 80 patients with major depressive disorder treated according to the Texas Medical Algorithm for 27 months at Hospital Magalhães Lemos, Porto, Portugal. Our results showed that BDNF rs6265, PTEN rs12569998, and SYN1 rs1142636 SNP were associated with treatment-resistant depression (TRD). Additionally, MAPK1 rs6928 and GSK3B rs6438552 gene polymorphisms were associated with relapse. Moreover, we found a link between the rs6928 MAPK1 polymorphism and time to relapse. These findings suggest that the BDNF, PTEN, and SYN1 genes may play a role in the development of TRD, while MAPK1 and GSK3B may be associated with relapse. GO analysis revealed enrichment in synaptic and trans-synaptic transmission pathways and glutamate receptor activity with TRD-associated genes. Genetic variants in these genes could potentially be incorporated into predictive models of antidepressant response.

Introduction: AGXT gene codes for the enzyme alanine glyoxylate aminotransferase, which is involved in hepatic peroxisomal metabolism of platinum-based chemotherapeutic agents. The association of genetic variant AGXT rs34116584 on the clinical outcome and response to chemotherapy of patients with non-small cell lung cancer (NSCLC) remains to be established. Our aim was to evaluate the association of functional AGXT gene polymorphism in NSCLC progression, considering as primary and secondary endpoint, progression free survival (PFS) and overall survival (OS), respectively. Methods: Genotyping of theAGXT rs34116584 genetic polymorphism was performed by mass spectrometry on 168 DNA samples from patients with NSCLC (stages IIIA-IVB). Univariate survival analysis included the study of Kaplan-Meier curves with the Log-Rank test, while Cox regression was used as a multivariate analysis. Results: Multivariate analysis showed shorter PFS for T carriers [HR = 2.0, 95% CI, 1.4−3.0, p

Chalcones are synthetic and naturally occurring compounds that have been widely investigated as anticancer agents. In this work, the effect of chalcones 1–18 against the metabolic viability of cervical (HeLa) and prostate (PC-3 and LNCaP) tumor cell lines was tested, to compare the activity against solid and liquid tumor cells. Their effect was also evaluated on the Jurkat cell line. Chalcone 16 showed the highest inhibitory effect on the metabolic viability of the tested tumor cells and was selected for further studies. Recent antitumor therapies include compounds with the ability to influence immune cells on the tumor microenvironment, with immunotherapy being one actual goal in cancer treatment. Therefore, the effect of chalcone 16 on the expression of mTOR, HIF-1α, IL-1β, TNF-α, IL-10, and TGF-β, after THP-1 macrophage stimulation (none, LPS or IL-4), was evaluated. Chalcone 16 significantly increased the expression of mTORC1, IL-1β, TNF-α, and IL-10 of IL-4 stimulated macrophages (that induces an M2 phenotype). HIF-1α and TGF-β were not significantly affected. Chalcone 16 also decreased nitric oxide production by the RAW 264.7 murine macrophage cell line, this effect probably being due to an inhibition of iNOS expression. These results suggest that chalcone 16 may influence macrophage polarization, inducing the pro-tumoral M2 macrophages (IL-4 stimulated) to adopt a profile closer to the antitumor M1 profile.

Abstract Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of skeletal muscle mass, along with adipose tissue wasting, systemic inflammation and other metabolic abnormalities leading to functional impairment. Cancer cachexia has long been recognized as a direct cause of complications in cancer patients, reducing quality of life and worsening disease outcomes. Some related conditions, like sarcopenia (age‐related muscle wasting), anorexia (appetite loss) and asthenia (reduced muscular strength and fatigue), share some key features with cancer cachexia, such as weakness and systemic inflammation. Understanding the interplay and the differences between these conditions is critical to advance basic and translational research in this field, improving the accuracy of diagnosis and contributing to finally achieve effective therapies for affected patients.

Bovine papillomavirus (BPV) are a cause for global concern due to their wide distribution and the wide range of benign and malignant diseases they are able to induce. Those lesions include cutaneous and upper digestive papillomas, multiple histological types of urinary bladder cancers—most often associated with BPV1 and BPV2—and squamous cell carcinomas of the upper digestive system, associated with BPV4. Clinical, epidemiological and experimental evidence shows that exposure to bracken fern (Pteridium spp.) and other related ferns plays an important role in allowing viral persistence and promoting the malignant transformation of early viral lesions. This carcinogenic potential has been attributed to bracken illudane glycoside compounds with immune suppressive and mutagenic properties, such as ptaquiloside. This review addresses the role of BPV in tumorigenesis and its interactions with bracken illudane glycosides. Current data indicates that inactivation of cytotoxic T lymphocytes and natural killer cells by bracken fern illudanes plays a significant role in allowing viral persistence and lesion progression, while BPV drives unchecked cell proliferation and allows the accumulation of genetic damage caused by chemical mutagens. Despite limited progress in controlling bracken infestation in pasturelands, bracken toxins remain a threat to animal health. The number of recognized BPV types has steadily increased over the years and now reaches 24 genotypes with different pathogenic properties. It remains essential to widen the available knowledge concerning BPV and its synergistic interactions with bracken chemical carcinogens, in order to achieve satisfactory control of the livestock losses they induce worldwide.

Sambucus nigra L., popularly known as elderberry, is renowned for its amazing therapeutic properties, as well as its uses as a food source, in nutraceuticals, and in traditional medicine. This study’s aim was to investigate the effects of an elderberry extract (EE) on mice for 29 days, as well as the safety of the extract when used as a natural colorant. Twenty-four FVB/n female mice (n = 6) were randomly assigned to one of four groups: control, 12 mg/mL EE (EE12), 24 mg/mL EE (EE24), or 48 mg/mL EE (EE48). The predominant anthocyanins detected were cyanidin-3-O-sambubioside and cyanidin-3-O-glucoside. Food and drink intake were similar between groups, with the exception of EE48, who drank significantly less compared with the Control. Biochemical analysis of the liver showed that the changes observed in histological analysis had no pathological significance. The EE, at doses of 24 and 48 mg/mL, significantly reduced the oxidative DNA damage compared with the non-supplemented group. The S. nigra extract showed a favorable toxicological profile, affording it potential to be used in the food industry.

Essential oils are natural compounds used by humans for scientific purposes due to their wide range of properties. Eugenol is mostly present in clove oil, while pulegone is the main constituent of pennyroyal oil. To guarantee the safe use of eugenol and pulegone for both humans and animals, this study addressed, for the first time, the effects of these compounds, at low doses (chronic toxicity) and high doses (acute toxicity), in laboratory animals. Thirty-five FVB/n female mice were randomly assigned to seven groups (n = 5): group I (control, non-additive diet); group II (2.6 mg of eugenol + 2.6 mg of pulegone); group III (5.2 mg of eugenol + 5.2 mg of pulegone); group IV (7.8 mg of eugenol + 7.8 mg of pulegone); group V (7.8 mg of eugenol); group VI (7.8 mg of pulegone); and group VII (1000 mg of eugenol + 1000 mg of pulegone). The compounds were administered in the food. Groups I to VI were integrated into the chronic toxicity study, lasting 28 days, and group VII was used in the acute toxicity study, lasting 7 days. Animals were monitored to assess their general welfare. Water and food intake, as well as body weight, were recorded. On the 29th day, all animals were euthanized by an overdose of ketamine and xylazine, and a complete necropsy was performed. Blood samples were collected directly from the heart for microhematocrit and serum analysis, as well as for comet assay. Organs were collected, weighed, and fixed in formaldehyde for further histological analysis and enzymatic assay. Eugenol and pulegone induced behavioral changes in the animals, namely in the posture, hair appearance and grooming, and in mental status. These compounds also caused a decrease in the animals’ body weight, as well as in the food and water consumption. A mortality rate of 20% was registered in the acute toxicity group. Both compounds modulated the serum levels of triglycerides and alanine aminotransferase. Eugenol and pulegone induced genetic damage in all animals. Eugenol increased the activity of the CAT enzyme. Both compounds increased the GR enzyme at the highest dose. Moreover, pulegone administered as a single compound increased the activity of the GST enzyme. Histopathological analysis revealed inflammatory infiltrates in the lungs of groups II, III, and IV. The results suggest that eugenol and pulegone may exert beneficial or harmful effects, depending on the dose, and if applied alone or in combination.

The study of human papillomavirus (HPV)-induced carcinogenesis uses multiple in vivo mouse models, one of which relies on the cytokeratin 14 gene promoter to drive the expression of all HPV early oncogenes. This study aimed to determine the HPV16 variant and sublineage present in the K14HPV16 mouse model. This information can be considered of great importance to further enhance this K14HPV16 model as an essential research tool and optimize its use for basic and translational studies. Our study evaluated HPV DNA from 17 samples isolated from 4 animals, both wild-type (n = 2) and HPV16-transgenic mice (n = 2). Total DNA was extracted from tissues and the detection of HPV16 was performed using a qPCR multiplex. HPV16-positive samples were subsequently whole-genome sequenced by next-generation sequencing techniques. The phylogenetic positioning clearly shows K14HPV16 samples clustering together in the sub-lineage A1 (NC001526.4). A comparative genome analysis of K14HPV16 samples revealed three mutations to the human papillomaviruses type 16 sublineage A1 representative strain. Knowledge of the HPV 16 variant is fundamental, and these findings will allow the rational use of this animal model to explore the role of the A1 sublineage in HPV-driven cancer.

Cancer cells normally develop the ability to rewire or reprogram themselves to become resistant to treatments that were previously effective. Despite progress in understanding drug resistance, knowledge gaps remain regarding the underlying biological causes of drug resistance and the design of cancer treatments to overcome it. So, resistance acquisition remains a major problem in cancer treatment. Targeted therapeutics are considered the next generation of cancer therapy because they overcome many limitations of traditional treatments. Numerous tumor cells overexpress several receptors that have a high binding affinity for hyaluronic acid (HA), while they are poorly expressed in normal body cells. HA and its derivatives have the advantage of being biocompatible and biodegradable and may be conjugated with a variety of drugs and drug carriers for developing various formulations as anticancer therapies such as micelles, nanogels, and inorganic nanoparticles. Due to their stability in blood circulation and predictable delivery patterns, enhanced tumor-selective drug accumulation, and decreased toxicity to normal tissues, tumor-targeting nanomaterial-based drug delivery systems have been shown to represent an efficacious approach for the treatment of cancer. In this review, we aim to provide an overview of some in vitro and in vivo studies related to the potential of HA as a ligand to develop targeted nanovehicles for future biomedical applications in cancer treatment.

Genetic factors are among the major contributors to athletic performance. Although more than 150 genetic variants have been correlated with elite athlete status, genetic foundations of competition-facilitating behavior influencing elite performances are still scarce. This is the first study designed to examine the distribution of genetic determinants in the athletic performance of elite rink-hockey players. A total of 116 of the world’s top best rink-hockey players (28.2 ± 8.7 years old; more than 50% are cumulatively from the best four world teams and the best five Portuguese teams), who participated at the elite level in the National Rink-Hockey Championship in Portugal, were evaluated in anthropometric indicators/measurements, training conditions, sport experience and sport injuries history. Seven genetic polymorphisms were analyzed. Polymorphism genotyping was performed using the TaqMan® Allelic Discrimination Methodology. Rink-hockey players demonstrated significantly different characteristics according to sex, namely anthropometrics, training habits, sports injuries and genetic variants, such as Vitamin D Receptor (VDR) rs731236 (p < 0.05). The Fatty Acid Amide Hydrolase (FAAH) rs324420 A allele was significantly associated with improved athletic performance (AA/AC vs. CC, OR = 2.80; 95% Cl, 1.23–6.35; p = 0.014; p = 0.008 after Bootstrap) and confirmed as an independent predictor among elite rink-hockey players (adjusted OR = 2.88; 95% Cl, 1.06–7.80; p = 0.038). Our results open an interesting link from FAAH-related biology to athletic performance.

Coronavirus disease (COVID-19) is an infectious disease that is caused by a highly contagious and severe acute respiratory syndrome—coronavirus 2 (SARS-CoV-2). This infection started to spread across the world in 2019 and rapidly turned into a global pandemic, causing an urgent necessity for treatment strategies development. The mRNA vaccines against SARS-CoV-2 can trigger an immune response, providing genetic information that allows the production of spike glycoproteins. MiRNAs play a crucial role in diverse key cellular processes, including antiviral defense. Several miRNAs are described as key factors in SARS-CoV-2 human infection through the regulation of ACE2 levels and by the inhibition of SARS-CoV-2 replication and spike expression. Consequently, these molecules have been considered as highly promising biomarkers. In numerous human malignancies, it has been recognized that miRNAs expression is dysregulated. Since miRNAs can target SARS-CoV-2-associated mRNAs, in cancer patients, the deregulation of these molecules can impair the immune response to the vaccines. Therefore, in this review, we propose a miRNA profile of seven SARS-CoV-2-related miRNAs, namely miR-214, miR-98-5p, miR-7-5p, miR-24-3p, miR-145-5p, miR-223-3p and miR-15b-5p, that are deregulated in a high number of cancers and have the potential to be used as prognostic biomarkers to stratify cancer patients.