Antitumor Effect of Chalcone Derivatives against Human Prostate (LNCaP and PC-3), Cervix HPV-Positive (HeLa) and Lymphocyte (Jurkat) Cell Lines and Their Effect on Macrophage Functions.

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-1ß, TNF-α, IL-10, and TGF-ß, after THP-1 macrophage stimulation (none, LPS or IL-4), was evaluated. Chalcone 16 significantly increased the expression of mTORC1, IL-1ß, TNF-α, and IL-10 of IL-4 stimulated macrophages (that induces an M2 phenotype). HIF-1α and TGF-ß 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.

Original Article: MicroRNA Dysregulation in the Gastric Carcinogenesis Cascade: Can We Anticipate Its Role in Individualized Care?

BACKGROUND: Gastric carcinogenesis progresses from normal mucosa, atrophic/metaplastic gastritis, and dysplasia to adenocarcinoma. MicroRNAs (miRNAs) regulate DNA expression and have been implicated; however, their role is not fully established. AIMS: The aim of this study was to characterize plasma and tissue expression of several miRNAs in gastric carcinogenesis stages. METHODS: Single-center cross-sectional study in 64 patients: 19 controls (normal mucosa); 15 with extensive atrophic/metaplastic gastritis; and 30 with early gastric neoplasia (EGN). Seven miRNAs (miR-21, miR-146a, miR-181b, miR-370, miR-375, miR 181b, and miR-490) were quantified by real time-qPCR in peripheral blood and endoscopic biopsy samples. RESULTS: We found a significant upregulation of miR-181b, miR-490, and miR-21 in the EGN mucosa (overexpression 2-14-times higher than controls). We observed a significant underexpression of miR-146a and miR-370 in atrophic/metaplastic gastritis (86 and 66% decrease, p = 0.008 and p = 0.001) and in EGN (89 and 62% reduction, p = 0.034 and p = 0.032) compared with controls. There were no differences between lesions and nonneoplastic mucosa and no dysregulation of plasma miRNAs. CONCLUSION: We found significant dysregulation of 5 miRNAs in gastric carcinogenesis, suggesting a tumor suppressor role for miR-146a and miR-370 and oncogenic potential for miR-21, miR-181, and miR-490. These changes happen diffusely in the gastric mucosa, suggesting a high-risk field defect, which may influence these patients' surveillance.

ceRNA Network of lncRNA/miRNA as Circulating Prognostic Biomarkers in Non-Hodgkin Lymphomas: Bioinformatic Analysis and Assessment of Their Prognostic Value in an NHL Cohort.

Research has been focusing on identifying novel biomarkers to better stratify non-Hodgkin lymphoma patients based on prognosis. Studies have demonstrated that lncRNAs act as miRNA sponges, creating ceRNA networks to regulate mRNA expression, and its deregulation is associated with lymphoma development. This study aimed to identify novel circulating prognostic biomarkers based on miRNA/lncRNA-associated ceRNA network for NHL. Herein, bioinformatic analysis was performed to construct ceRNA networks for hsa-miR-150-5p and hsa-miR335-5p. Then, the prognostic value of the miRNA-lncRNA pairs' plasma levels was assessed in a cohort of 113 NHL patients. Bioinformatic analysis identified MALAT1 and NEAT1 as hsa-miR-150-5p and has-miR-335-5p sponges, respectively. Plasma hsa-miR-150-5p/MALAT1 and hsa-miR335-5p/NEAT1 levels were significantly associated with more aggressive and advanced disease. The overall survival and progression-free survival analysis indicated that hsa-miR-150-5p/MALAT1 and hsa-miR335-5p/NEAT1 pairs' plasma levels were remarkably associated with NHL patients' prognosis, being independent prognostic factors in a multivariate Cox analysis. Low levels of hsa-miR-150-5p and hsa-miR-335-5p combined with high levels of the respective lncRNA pair were associated with poor prognosis of NHL patients. Overall, the analysis of ceRNA network expression levels may be a useful prognostic biomarker for NHL patients and could identify patients who could benefit from more intensive treatments.

Prevalence of Neisseria gonorrhoeae and Trichomonas vaginalis in Portuguese women of childbearing age.

The purpose of this study was to evaluate the prevalence of Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) in Portuguese women of childbearing age. Cervicovaginal self-collected samples of 680 childbearing-age women (15-44 years) were tested for NG and TV by polymerase chain reaction. Sociodemographic, clinical and behavioural data were assessed through an anonymous self-administered questionnaire. NG and TV prevalence was 1.3% (95% confidence interval (CI) 0.7-2.5%) and 1.0% (95% CI 0.5-2.1%), respectively. The prevalence of TV was significantly higher in women aged >22 years (p = .003), with >6 years after sexual intercourse (p = .003), and who reported previous pregnancy (p = .004). Our study suggests that NG and TV are rare in Portuguese women of childbearing age. However, larger epidemiological studies with a nationally representative sample of female subjects are warranted, to clarify the need for screening of these microorganisms in Portuguese women, since its prevalence is probably underestimated.IMPACT STATEMENTWhat is already known on this subject? Studies on the prevalence of NG and TV have been performed in several developed and developing countries. However, limited data is available in Portuguese women. The detection of NG and TV is necessary because, beside the risk of transmission to sex partners, these STIs may be associated with an increased risk of HIV acquisition and transmission, and ultimately with reproductive, pregnancy and perinatal complications.What do the results of this study add? Our study adds new findings to the body of knowledge on NG and TV prevalence in Portuguese women of reproductive age. As so, we found a low prevalence of both NG (1.3%) and TV (1.0%) in the studied population.What are the implications of these findings for clinical practice and/or further research? Our results may be a step ahead to encourage future nationally representative studies evaluating the prevalence of NG and TV genital infection and, consequently, to clarify the need for screening of these microorganisms. In clinical practice, it should be highlighted the appropriate management of NG and TV infection in specific situations, such as pregnancy. Also, sexual partners must be treated to prevent the recurrences in the index cases and reduce transmission to other partners.

Loss of Chromosome Y and Its Potential Applications as Biomarker in Health and Forensic Sciences.

Loss of chromosome Y (LOY) is a mosaic aneuploidy that can be detected mainly in blood samples of male individuals. Usually, LOY occurrence increases with chronological age in healthy men. Moreover, recently LOY has been reported in association with several diseases, such as cancer, where its frequency is even higher. The Y chromosome is one of the shortest chromosomes of the human karyotype, and it is crucial for correct male development. This chromosome has functions beyond the male reproductive system, and loss of its genes or even LOY can have consequences for the male body that are yet to be elucidated. Analyses of the Y chromosome are largely applied in forensic contexts such as paternity testing, ancestry studies, and sexual assault cases, among others. Thus, LOY can be a disadvantage, limiting laboratory methods and result interpretation. However, as an advantage, LOY detection could be used as a biological age biomarker due to its association with the aging process. The potential application of LOY as biomarker highlights the necessity to clarify the molecular mechanism behind its occurrence and its possible applications in both health and forensic studies.

Plasma Extracellular Vesicle-Derived TIMP-1 mRNA as a Prognostic Biomarker in Clear Cell Renal Cell Carcinoma: A Pilot Study.

The tumor microenvironment has gained a lot of attention from the scientific community since it has a proven impact in the development of tumor progression and metastasis. Extracellular vesicles (EVs) are now considered one of the key players of tumor microenvironment modulation. Clear cell renal cell carcinoma (ccRCC) is the most lethal urological neoplasia and presents a high metastatic potential, which reinforces the need for the development of more effective predictive biomarkers. Our goal was to evaluate the applicability of EV-derived matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) as prognostic biomarkers for ccRCC. To do so, we studied the plasma EV content of 32 patients with localized ccRCC and 29 patients with metastatic ccRCC. We observed that patients with localized disease and tumors larger than 7 cm presented higher levels of plasma EV-derived TIMP-1 mRNA when compared with patients presenting smaller tumors (p = 0.020). Moreover, patients with metastatic disease presented higher levels of EV-derived TIMP-1 mRNA when compared with patients with localized disease (p = 0.002) and when we stratified those patients in high and low levels of TIMP-1 EV-derived mRNA, the ones presenting higher levels had a lower overall survival (p = 0.030). EV-derived TIMP-1 mRNA may be a good prognostic biomarker candidate for ccRCC.

Everolimus resistance in clear cell renal cell carcinoma: miRNA-101 and HIF-2α as molecular triggers?

Aim: The majority of clear cell renal cell carcinoma patients develop resistance to mTOR inhibitors. Materials & methods: As an in vitro model four cell lines were used: HKC-8, 786- O, RCC-FG-2 and an everolimus-resistant cell line (786-OR) established during this study. The quantification of miRNA-101 and HIF-2α mRNA levels was assessed by real-time PCR. Results: We observed a significant decrease of miRNA-101 intracellular levels in 786-OR. However, this miRNA presented higher extracellular levels. Additionally, we found a significant increase of HIF-2α in 786-OR. Conclusion: The circulating levels of miRNA-101 may be a potential biomarker of anti-mTOR therapy response and resistance prediction. Moreover, the resistance to mTOR inhibitors seems to be related with the overexpression of HIF-2α.

IL-6 polymorphism in non-small cell lung cancer: a prognostic value?

Lung cancer was found to be the most commonly diagnosed cancer, as well as the primary cause of cancer-related mortality for males worldwide and the second leading cause of cancer-related deaths for women. Cytokines are fundamental for several biological processes-associated malignant tumors. The IL-6 is a cytokine involved in the regulation of cellular functions including processes associated with cancer, such as proliferation, apoptosis, angiogenesis, and differentiation. Furthermore, IL-6 is a potent pleiotropic inflammatory cytokine that is considered a key growth-promoting and antiapoptotic factor. The polymorphism-174G/C SNP is a G to C transition in the -174 position of the promoter region of the IL-6 gene. The aim of our study was to evaluate the influence of -174G/C polymorphism in clinical outcome of non-small cell cancer (NSCLC) patients. DNA was extracted from peripheral blood of 424 patients diagnosed with cytologically or histologically NSCLC. The characterization of IL-6 -174G/C genotypes was performed by PCR-RFLP (NlaIII). IL-6 polymorphism's genotypes were divided according to functional activity, so the G carriers (CG/GG) is the high-producer IL-6, and CC genotype is the low-producer IL-6. Regarding survival, we verify that patients with genotypes carrying the G allele (CG/GG) had a statistically significant diminished survival when compared with patients with CC genotype (62.79 and 42.31 months, respectively; P = 0.032). In the promoter region of the IL-6 gene, polymorphic variants were located and may be responsible for alterations in transcription that consequently affect serum levels of the cytokine. With our study, we demonstrated that genetic variant (-174G/G and G/C) can be responsible for changes in prognosis of NSCLC patients.

Restoring TGFß1 pathway-related microRNAs: possible impact in metastatic prostate cancer development.

In developed countries, prostate cancer (PC) is the neoplasia more frequently diagnosed in men. The signaling pathway induced by the transforming growth factor ß1 (TGFß1) has an important role in cell growth, differentiation, and development, the downregulation of this pathway being associated with cancer development. In PC, the activation of this signaling pathway is lost, resulting in favoring of tumor growth, proliferation, and evasion of apoptosis. Several studies have shown that microRNAs (miRNAs), small non-coding RNA, are closely associated with the development, invasion, and metastasis, suggesting that they have a critical role in cancer development. Recently, Smad proteins, the signal transducers of the TGFß1 signaling pathway, were found to regulate miRNA expression, through both transcriptional and posttranscriptional mechanisms. In this review, we summarize the mechanisms underlying Smad-mediated regulation of miRNA biogenesis and the effects on cancer development, particularly in PC. We identify that TGFß1-related miR-143, miR-145, miR-146a, and miR-199a may have a key role in the development of prostate cancer metastasis and the restoration of their expression may be a promising therapeutic strategy for PC treatment.

The role of inflammation in lung cancer.

Lung cancer remains a serious public health problem and is the first cause of cancer death worldwide, and the overall 5-year survival rate for all stages is 14-17 % for Non-small-cell lung cancer and 6 % for small-cell lung cancer. Clinical and epidemiologic studies have suggested a strong association among chronic infection, inflammation, and cancer. Immune system plays a critical role in maintaining tissue homeostasis, cell turnover, tissue remodeling, and preventing infection and cell transformation. The inflammatory component in the development of the neoplasm includes a diverse leukocyte population; these components are considered inflammatory tumor key factors promoting tumor progression due to its ability to release a variety of cytokines, chemokines, and cytotoxic mediators such as reactive oxygen species (ROS), metalloproteinases, interleukins, and interferons. Cancer-related inflammation affects many aspects of malignancy, including the proliferation and survival of malignant cells, angiogenesis, tumor metastasis, and tumor response to chemotherapeutic drugs and hormones. Moreover, epidemiologic studies and meta-analysis have shown that prolonged use of non-steroid anti-inflammatory (NSAID) drugs reduces the risk of several solid tumor including lung cancer. Strong lines of evidence suggest that the chemopreventive properties of chronic NSAID administration are based on their COX-inhibitory activity. However, the prevention is a much better and more economical way to fight against cancer than treating an already advanced and often incurable disease.

Decoding PTEN regulation in clear cell renal cell carcinoma: Pathway for biomarker discovery and therapeutic insights.

Renal cell carcinoma is the most common adult renal solid tumor and the deadliest urological cancer, with clear cell renal cell carcinoma (ccRCC) being the predominant subtype. The PI3K/AKT signaling pathway assumes a central role in ccRCC tumorigenesis, wherein its abnormal activation confers a highly aggressive phenotype, leading to swift resistance against current therapies and distant metastasis. Thus, treatment resistance and disease progression remain a persistent clinical challenge in managing ccRCC effectively. PTEN, an antagonist of the PI3K/AKT signaling axis, emerges as a crucial factor in tumor progression, often experiencing loss or inactivation in ccRCC, thereby contributing to elevated mortality rates in patients. Therefore, understanding the molecular mechanisms underlying PTEN suppression in ccRCC tumors holds promise for the discovery of biomarkers and therapeutic targets, ultimately enhancing patient monitoring and treatment outcomes. The present review aims to summarize these mechanisms, emphasizing their potential prognostic, predictive, and therapeutic value in managing ccRCC.

Deregulated miRNAs in enzalutamide resistant prostate cancer: A comprehensive review of key molecular alterations and clinical outcomes.

Prostate cancer (PC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related deaths in male population worldwide. Since the growth and progression of PC highly depend on the androgen pathway, androgen deprivation therapy (ADT) is the mainstay of systemic treatment. Enzalutamide is a second-generation antiandrogen, which is widely used for the treatment of advanced and metastatic PC. However, treatment failure and disease progression, caused by the emergence of enzalutamide resistant phenotypes, remains an important clinical challenge. MicroRNAs (miRNAs) are key regulators of gene expression and have recently emerged as potential biomarkers for being stable and easily analysed in several biological fluids. Several miRNAs that exhibit dysregulated expression patterns in enzalutamide-resistant PC have recently been identified, including miRNAs that modulate critical signalling pathways and genes involved in PC growth, survival and in the acquisition of enzalutamide phenotype. The understanding of molecular mechanisms by which miRNAs promote the development of enzalutamide resistance can provide valuable insights into the complex interplay between miRNAs, gene regulation, and treatment response in PC. Moreover, these miRNAs could serve as valuable tools for monitoring treatment response and disease progression during enzalutamide administration. This review summarises the miRNAs associated with enzalutamide resistance in PC already described in the literature, focusing on their biological roles and on their potential as biomarkers.

MicroRNAs Derived from Extracellular Vesicles: Keys to Understanding SARS-CoV-2 Vaccination Response in Cancer Patients?

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.

Extracellular Vesicles as Potential Therapeutic Messengers in Cancer Management.

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.

Silver Nanoparticles (AgNPs) as Enhancers of Everolimus and Radiotherapy Sensitivity on Clear Cell Renal Cell Carcinoma.

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.

Circulating lncRNA- and miRNA-Associated ceRNA Network as a Potential Prognostic Biomarker for Non-Hodgkin Lymphoma: A Bioinformatics Analysis and a Pilot Study.

Non-Hodgkin lymphoma (NHL) is characterized by a great variability in patient outcomes, resulting in the critical need for identifying new molecular prognostic biomarkers. This study aimed to identify novel circulating prognostic biomarkers based on an miRNA/lncRNA-associated ceRNA network for NHL. Using bioinformatic analysis, we identified the miRNA-lncRNA pairs, and using RT-qPCR, we analyzed their plasma levels in a cohort of 113 NHL patients to assess their prognostic value. Bioinformatic analysis identified SNHG16 and SNHG6 as hsa-miR-20a-5p and hsa-miR-181a-5p sponges, respectively. Plasma levels of hsa-miR-20a-5p/SNHG16 and hsa-miR-181a-5p/SNG6 were significantly associated with more aggressive disease and IPI/FLIPI scores. Moreover, we found that patients with risk expression profiles of hsa-miR-20a-5p/SNHG16 and hsa-miR-181a-5p/SNHG6 presented a higher risk of positive bone marrow involvement. Moreover, hsa-miR-20a-5p/SNHG16 and hsa-miR-181a-5p/SNHG6 pairs' plasma levels were associated with overall survival and progression-free survival of NHL patients, being independent prognostic factors in a multivariate Cox analysis. The prediction models incorporating the ceRNA network expression analysis improved the predictive capacity compared to the model, which only considered the clinicopathological variables. There are still few studies on using the ceRNA network as a potential prognostic biomarker, particularly in NHL, which may permit the implementation of a more personalized management of these patients.

MicroRNAs as Potential Tools for Predicting Cancer Patients' Susceptibility to SARS-CoV-2 Infection and Vaccination Response.

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.

Extracellular Vesicles Derived-LAT1 mRNA as a Powerful Inducer of Colorectal Cancer Aggressive Phenotype.

Colorectal cancer (CRC) is the third most common cancer in the world and represents the third most deadly tumor worldwide. About 15-25% of patients present metastasis in the moment of diagnosis, the liver being the most common site of metastization. Therefore, the development of new therapeutic agents is needed, to improve the patients' prognosis. Amino acids transporters, LAT1 and ASCT2, are described as upregulated in CRC, being associated with a poor prognosis. Extracellular vesicles have emerged as key players in cell-to-cell communication due to their ability to transfer biomolecules between cells, with a phenotypic impact on the recipient cells. Thus, this study analyzes the presence of LAT1 and ASCT2 mRNAs in CRC-EVs and evaluates their role in phenotype modulation in a panel of four recipient cell lines (HCA-7, HEPG-2, SK-HEP-1, HKC-8). We found that HCT 116-EVs carry LAT1, ASCT2 and other oncogenic mRNAs being taken up by recipient cells. Moreover, the HCT 116-EVs' internalization was associated with the increase of LAT1 mRNA in SK-HEP-1 cells. We also observed that HCT 116-EVs induce a higher cell migration capacity and proliferation of SK-HEP-1 and HKC-8 cells. The present study supports the LAT1-EVs' mRNA involvement in cell phenotype modulation, conferring advantages in cell migration and proliferation.

Glucose-Functionalized Silver Nanoparticles as a Potential New Therapy Agent Targeting Hormone-Resistant Prostate Cancer cells.

Purpose: Silver nanoparticles (AgNPs) have shown great potential as anticancer agents, namely in therapies' resistant forms of cancer. The progression of prostate cancer (PCa) to resistant forms of the disease (castration-resistant PCa, CRPC) is associated with poor prognosis and life quality, with current limited therapeutic options. CRPC is characterized by a high glucose consumption, which poses as an opportunity to direct AgNPs to these cancer cells. Thus, this study explores the effect of glucose functionalization of AgNPs in PCa and CRPC cell lines (LNCaP, Du-145 and PC-3). Methods: AgNPs were synthesized, further functionalized, and their physical and chemical composition was characterized both in water and in culture medium, through UV-visible spectrum, dynamic light scattering (DLS), transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR). Their effect was assessed in the cell lines regarding AgNPs' entering pathway, cellular proliferation capacity, ROS production, mitochondrial membrane depolarization, cell cycle analysis and apoptosis evaluation. Results: AgNPs displayed an average size of 61nm and moderate monodispersity with a slight increase after functionalization, and a round shape. These characteristics remained stable when redispersed in culture medium. Both AgNPs and G-AgNPs were cytotoxic only to CRPC cells and not to hormone-sensitive ones and their effect was higher after functionalization showing the potential of glucose to favor AgNPs' uptake by cancer cells. Entering through endocytosis and being encapsulated in lysosomes, the NPs increased the ROS, inducing mitochondrial damage, and arresting cell cycle in S Phase, therefore blocking proliferation, and inducing apoptosis. Conclusion: The nanoparticles synthesized in the present study revealed good characteristics and stability for administration to cancer cells. Their uptake through endocytosis leads to promising cytotoxic effects towards CRPC cells, revealing the potential of G-AgNPs as a future therapeutic approach to improve the management of patients with PCa resistant to hormone therapy or metastatic disease.

Medical sharps in Portugal: a cross-sectional survey of disposal practices among the diabetic population.

OBJECTIVE: We aim to determine the disposal site for biohazardous materials resulting from diabetes surveillance and therapy. DESIGN: Cross-sectional study. SETTING: Five Portuguese primary care facilities. PARTICIPANTS: We randomly sampled diabetic patients representative of five primary care facilities. Inclusion criteria consisted in patients≥18 years old with an active diagnosis of diabetes mellitus (DM). Patients unable to provide written informed consent were excluded. OUTCOME MEASURE: Sociodemographic variables, diabetes duration, type of treatment, medical sharps disposal practices and whether adequate disposal information were provided. RESULTS: A total of 1436 diabetics were included. Overall, 53.8% of diabetics conducted regular capillary glicemia measurements, although 45.3% of them had no medical indication. Statistically significant predictors of adequate disposal were not having an active professional status (p=0.011) and having a DM duration between 5 and 10 years (p=0.014). Only being professionally inactive remained an independent predictor after multivariate logistic regression. Less than a fifth of patients on injectable therapy report having been advised by healthcare staff regarding sharps disposal. Over a fifth of the latter report having received wrong advice. The majority of diabetics dispose of biohazardous materials in unsorted household waste (68.1% of needles/devices with needles and 71.6% of lancets). Other incorrect disposal sites identified were recycling bins, toilet and home accumulation. Only 19.1% of the needles/devices with needles and 13.1% of the lancets were disposed of at healthcare facilities. CONCLUSIONS: Most diabetics have unsafe disposal practices for their biohazardous materials, mostly in unsorted household waste. We identified that being unemployed independently predicts adequate disposal of medical sharps and found evidence of low patient literacy on the topic, as well as poor patient education. Therefore, educating and raising awareness among healthcare professionals is crucial to address this public health issue.